WO2002091830A1 - Pyridinyl fused bicyclic amide as fungicides - Google Patents

Pyridinyl fused bicyclic amide as fungicides Download PDF

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WO2002091830A1
WO2002091830A1 PCT/US2002/018394 US0218394W WO02091830A1 WO 2002091830 A1 WO2002091830 A1 WO 2002091830A1 US 0218394 W US0218394 W US 0218394W WO 02091830 A1 WO02091830 A1 WO 02091830A1
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ome
och
alkyl
compound
ocf
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PCT/US2002/018394
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French (fr)
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Ying Song
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E.I. Du Pont De Nemours And Company
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Priority to IL15800902A priority Critical patent/IL158009A0/en
Priority to US10/473,700 priority patent/US20040127361A1/en
Priority to EP02744275A priority patent/EP1387612A1/en
Priority to JP2002588757A priority patent/JP2004529943A/en
Priority to BR0209687-0A priority patent/BR0209687A/en
Priority to MXPA03010436A priority patent/MXPA03010436A/en
Publication of WO2002091830A1 publication Critical patent/WO2002091830A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
    • C07D221/04—Ortho- or peri-condensed ring systems
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/34—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom
    • A01N43/40—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom six-membered rings
    • A01N43/42—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom six-membered rings condensed with carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/38—Nitrogen atoms
    • C07D215/40—Nitrogen atoms attached in position 8
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems

Definitions

  • This invention relates to certain bicyclic amides having a pyridinyl ring fused through two adjacent carbon atoms to a second ring, their N-oxides, agriculturally suitable salts and compositions, and methods of their use as fungicides.
  • WO 99/42447 discloses certain benzamides of formula i as fungicides
  • R 1 is H, alkyl, or acyl
  • R 2 is H or alkyl
  • GB 2219797 discloses certain fused pyridinyl compounds of Formula ii
  • X is NHCO or NHSO 2 ;
  • Ar is an optionally substituted phenyl;
  • R 4 is alkyl, alkoxy, aryl or aralkyl;
  • m is 1, 2 or 3 and n is 1, 2 or 3.
  • Phytophthora spp. and Plasmopara spp. are in constant demand by growers. Combinations of fungicides are often used to facilitate disease control and to retard resistance development. It is desirable to enhance the activity spectrum and the efficacy of disease control by using mixtures of active ingredients that provide a combination of curative, systemic and preventative control of plant pathogens. Also desirable are combinations that provide greater residual control to allow for extended spray intervals. It is also very desirable to combine fungicidal agents that inhibit different biochemical pathways in the fungal pathogens to retard development of resistance to any one particular plant disease control agent.
  • This invention involves compounds of Formula I (including all geometric and stereoisomers), N-oxides, agriculturally suitable salts and compositions thereof:
  • B is a substituted phenyl or pyridinyl ring;
  • L is O or S;
  • R 1 is H; or C C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl or C3-C6 cycloalkyl, each optionally substituted;
  • R is H; or C r C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl or C 3 -C 6 cycloalkyl, C 2 -C 6 alkylcarbonyl, C 2 -Cg alkoxycarbonyl, C 2 -Cg ajkylaminocarbonyl or C 3 -Cg dialkylaminocarbonyl; and n is 1 or 2.
  • this invention includes 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 compound of Formula I (including all geometric and stereoisomers, N-oxides and agriculturally suitable salts thereof) or a composition comprising said compound.
  • This invention also includes fungicidal compositions comprising (1) a fungicidally effective amount of a compound of Formula I (including all geometric and stereoisomers, N-oxides and agriculturally suitable salts thereof); and (2) (i) at least one other insecticide, fungicide, nematocide, bactericide, acaricide, growth regulator, chemosterilant, semiochemical, repellent, attractant, pheromone, feeding stimulant or other biologically active compound; and/or (ii) at least one additional component selected from the group consisting of surfactants, solid diluents and liquid diluents.
  • fungicidal compositions comprising (1) a fungicidally effective amount of a compound of Formula I (including all geometric and stereoisomers, N-oxides and agriculturally suitable salts thereof); and (2) (i) at least one other insecticide, fungicide, nematocide, bactericide, acaricide, growth regulator, chemosterilant, semi
  • compositions comprising (a) at least one compound of Formula I; and (b) at least one compound selected from the group consisting of
  • A is a substituted fused pyridinyl ring and B is a substituted phenyl or pyridinyl ring.
  • substituted in connection with these A or B rings refers to groups that have at least one non-hydrogen substituent that does not extinguish the fungicidal activity.
  • Examples of Formula I incorporating said A and B rings in which A is substituted with one or two substituents selected from R 5 and B is substituted with from one to three substituents selected from R 6 include the rings illustrated in Exhibit 1 wherein m is an integer from 1 to 2 and p is an integer from 1 to 3.
  • attachment point between (R 5 ) m and A and (R 6 ) p and B is illustrated as floating, and (R 5 ) m and (R 6 ) p can be attached to any available carbon atom of the phenyl or pyridinyl rings.
  • R 5 when attached to A and R 6 when attached to B include each R 5 and each R 6 is independently C r C 6 alkyl, C 2 -Cg alkenyl, C 2 -C6 alkynyl, C 3 -C 6 cycloalkyl, C r C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl,
  • R 1 can be (among others) C ⁇ -Cg alkyl, C 2 -Cg alkenyl, C -Cg alkynyl or C 3 -Cg cycloalkyl, each optionally substituted.
  • R 1 groups that are unsubstituted or have at least one non-hydrogen substituent that does not extinguish the fungicidal activity possessed by the unsubstituted analog.
  • R 1 groups are those that are optionally substituted by replacement of a hydrogen on a carbon atom of the R 1 group with one or more (up to the total number of hydrogens available for replacement in any specific R 1 group) substituents independently selected from the group consisting of halogen, CN, NO 2 , hydroxy, -C4 alkoxy, C 1 -C 4 alkylthio, C 1 -C4 alkylsulfinyl, -C4 alkylsulfonyl, C 2 -C 4 alkoxycarbonyl, C1-C4 alkylamino, C 2 -C 8 dialkylamino and C 3 -Cg cycloalkylamino.
  • substituents are Usted in the examples above, it is noted that they do not need to be present since they are optional substituents.
  • R 1 groups optionally substituted with from one to five substituents.
  • N-oxides of Formula I are illustrated as 1-5 through 1-10 in Exhibit 2, wherein R 1 , R 3 , R 5 , R 6 , W, m and p are as defined above.
  • each R 5 and each R 6 can be (among others) a phenyl ring, a 5- or 6-membered heteroaromatic ring, a benzyl ring or a phenoxy ring, each ring optionally substituted with from one to three groups independently selected from R 7 .
  • the term "optionally substituted" in connection with these groups refers to groups which are unsubstituted or have at least one non-hydrogen substituent that does not extinguish the biological activity possessed by the unsubstituted analog.
  • An example of a phenyl ring optionally substituted with one to three groups independently selected from R 7 is the ring illustrated as R x -56 in Exhibit 3, wherein x is either 5 or 6 and r is an integer from one to three.
  • Examples of 5- or 6-membered heteroaromatic rings optionally substituted with one to three groups independently selected from R 7 include the rings R -1 through R x -55 illustrated in Exhibit 3, wherein x is either 5 or 6 and r is an integer from one to three.
  • An example of a benzyl ring optionally substituted with one to three groups independently selected from R 7 is the ring illustrated as R x -57 in Exhibit 3, wherein x is either 5 or 6 and r is an integer from one to three.
  • An example of a phenoxy ring optionally substituted with one to three groups independently selected from R 7 is the ring illustrated as R x -58 in Exhibit 3, wherein x is either 5 or 6 and r is an integer from one
  • R 7 groups represented as (R 7 ) r
  • R x - 1 through R x -58 they do not need to be present since they are optional substituents.
  • the nitrogen atoms that require substitution to fill their valence are substituted with H or R 7 .
  • some R x groups can only be substituted with less than three R 7 groups (e.g. R x -15, R x -16, R x -17 through R -20 and R x -31 through R x -33 can only be substituted with one R 7 ).
  • R 7 r when the attachment point between (R 7 ) r and the R x group is illustrated as floating, (R 7 ) r can be attached to any available carbon atom of the R x group.
  • optionally substituted in connection with the linking chain J refers to J-groups which are unsubstituted or have at least one non-hydrogen substituent that does not extinguish the biological activity possessed by the unsubstituted analog.
  • optionally substituted J-groups include the J-groups illustrated in Exhibit 4.
  • the J-groups in Exhibit 4 are illustrated such that the left end of the J-group is attached to the A-ring at the 3-position and the right end of the J-group is attached to the carbon atom bearing the N(R 3 )WB moiety.
  • the J-groups in Exhibit 4 can be optionally substituted by replacement of a hydrogen on a carbon atom or nitrogen atom of the J-group with one or more (up to the total number of hydrogens available for replacement in any specific J-group) substituents independently selected from the group consisting of C ⁇ -C 2 alkyl, halogen, CN, NO 2 and C ⁇ -C alkoxy. Although these substituents are listed, it is noted that they do not need to be present since they are optional substituents. Of note are J-groups optionally substituted with from one to four substituents selected from the group above.
  • alkyl used either alone or in compound words such as "alkylthio" or "haloalkyl” includes straight-chain or branched alkyl, such as methyl, ethyl, ⁇ -propyl, z ' -propyl, or the different butyl, pentyl or hexyl isomers.
  • Alkenyl includes straight chain or branched alkenes such as ethenyl, 1-propenyl, 2-propenyl, and the different butenyl, pentenyl and hexenyl isomers. "Alkenyl” also includes polyenes such as
  • Alkynyl includes straight chain or branched alkynes such as ethynyl, 1-propynyl, 2-propynyl and the different butynyl, pentynyl andhexynyl isomers. "Alkynyl” can also include moieties comprised of multiple triple bonds such as 2,5-hexadiynyl. "Alkoxy” includes, for example, methoxy, ethoxy, /z-propyloxy, isopropyloxy and the different butoxy, pentoxy and hexyloxy isomers.
  • Alkylthio includes branched or straight chain alkylthio moieties such as methylthio, ethylthio, and the different propylthio, butylthio, pentylthio and hexylfhio isomers.
  • Alkylsulfinyl includes both enantiomers of an alkylsulfinyl group.
  • alkylsulfinyl examples include CH 3 S(O), CH 3 CH 2 S(O), CH 3 CH 2 CH 2 S(O), (CH 3 ) 2 CHS(O) and the different butylsulfinyl, pentylsulfinyl and hexylsulfinyl isomers.
  • alkylsulfonyl examples include CH 3 S(O) 2 , CH 3 CH 2 S(O) 2 , CH 3 CH 2 CH 2 S(O) 2 , (CH 3 ) 2 CHS(O) 2 and the different butylsulfonyl, pentylsulfonyl and hexylsulfonyl isomers.
  • alkylamino "dialkylamino” and the like, are defined analogously to the above examples.
  • Cycloalkyl includes, for example, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • halogen either alone or in compound words such as “haloalkyl”, includes fluorine, chlorine, bromine or iodine. Further, when used in compound words such as “haloalkyl", said alkyl may be partially or fully substituted with halogen atoms which may be the same or different. Examples of “haloalkyl” include F 3 C, C1CH 2 , CF 3 CH and CF 3 CC1 2 .
  • ialoalkynyl examples include HC ⁇ CCHCl, CF 3 C ⁇ C, CC1 3 C ⁇ C and FCH 2 C ⁇ CCH 2 .
  • haloalkoxy include CF 3 O, CCl 3 CH 2 O, HCF 2 CH 2 CH 2 O and CF 3 CH 2 O.
  • haloalkylthio examples include CC1 3 S, CF 3 S, CC1 3 CH 2 S and C1CH 2 CH 2 CH 2 S.
  • haloalkylsulfinyl 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 .
  • Aromaatic indicates that each of the ring atoms is essentially in the same plane and has a >-orbital perpendicular to the ring plane, and in which (4n + 2) ⁇ electrons, when n is 0 or a positive integer, are associated with the ring to comply with H ⁇ ckel's rule.
  • hetero in connection with rings refers to a ring in which at least one ring atom is not carbon and which can contain 1 to 4 heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur, provided that each ring contains, no more than 4 nitrogens, no more than 2 oxygens and no more than 2 sulfurs.
  • the t rms "heteroaromatic ring” includes fully aromatic heterocycles.
  • the heterocyclic ring can be attached through any available carbon or nitrogen by replacement of a hydrogen on said carbon or nitrogen.
  • aryl refers to aromatic hydrocarbon moieties including phenyl, tolyl and naphthalenyl which may be optionally substituted.
  • aralkyl is an alkyl moiety substituted with an aryl moiety including phenylalkyls such as benzyl (which may be optionally substituted).
  • nitrogen containing heterocycles can form N-oxides since the nitrogen requires an available lone pair for oxidation to the oxide; one skilled in the art will recognize those nitrogen containing heterocycles which can form N-oxides.
  • nitrogen containing heterocycles which can form N-oxides.
  • tertiary amines can form N-oxides.
  • N-oxides of heterocycles and tertiary amines are very well known by one skilled in the art including the oxidation of heterocycles and tertiary amines with peroxy acids such as peracetic and -chloroperbenzoic acid (MCPB A), hydrogen peroxide, alkyl hydroperoxides such as t-butyl hydroperoxide, sodium perborate, and dioxiranes such as dimethydioxirane.
  • peroxy acids such as peracetic and -chloroperbenzoic acid (MCPB A)
  • hydrogen peroxide such as peracetic and -chloroperbenzoic acid (MCPB A)
  • alkyl hydroperoxides such as t-butyl hydroperoxide
  • sodium perborate sodium perborate
  • dioxiranes such as dimethydioxirane
  • C r C alkylsulfonyl designates methylsulfonyl through propylsulfonyl
  • C 2 -C 8 dialkylamino designates, for example, (CH 3 ) 2 ⁇ , (CH 3 CH 2 ) 2 N, CH 3 CH 2 (CH 3 )N, CH 3 CH 2 CH 2 (CH 3 )N or (CH 3 ) 2 CHN(CH 3 ) containing a total of from 2 to 8 carbon atoms.
  • substituents When a compound is substituted with a substituent bearing a subscript that indicates the number of said substituents can exceed 1, said substituents (when they exceed 1) are independently selected from the group of defined substituents. Further, when the subscript indicates a range, e.g. (R)j_ j , then the number of substituents may be selected from the integers between i and j inclusive.
  • Compounds involved in this invention can exist as one or more stereoisomers.
  • the various stereoisomers include enantiomers, diastereomers, atropisomers and geometric isomers.
  • 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 present invention comprises compounds selected from Formula I, N-oxides and agriculturally suitable salts thereof.
  • the compounds may be present as a mixture of stereoisomers, individual stereoisomers, or as an optically active form.
  • R 1 and J of Formula I are different, then said formula possesses a chiral center at the carbon to which they are commonly bonded.
  • This invention comprises racemic mixtures of equal parts of Formula F and Formula I".
  • this invention includes compounds and compositions that are enriched in an enantiomer of the Formula I' or Formula I" compared to the racemic mixture. Included are compounds and compositions involving the essentially pure enantiomers of Formula I' or Formula I". For example, this invention includes compounds of Formula I that are enriched in an enantiomer of the Formula F compared to the racemic mixture. Included are the essentially pure enantiomers of Formula F . This invention also includes compositions wherein component (a) is enriched in a component (a) enantiomer of Formula I" compared to the racemic rnixture.
  • This invention also includes compounds of Formula I that are enriched in an enantiomer of the Formula I" compared to the racemic mixture. Included are the essentially pure enantiomers of Formula I". This invention also includes compositions wherein component (a) is enriched in a component (a) enantiomer of Formula I" compared to the racemic mixture.
  • one enantiomer is present in greater amounts than the other and the extent of enrichment can be defined by an expression of enantiomer excess ("ee"), which is defined as 100(2x-l) where x is the mole fraction of the dominant enantiomer in the mixture, (e.g., an ee of 20% corresponds to a 60:40 ratio of enantiomers).
  • ee enantiomer excess
  • enantiomerically pure embodiments of the more active isomer are enantiomerically pure embodiments of the more active isomer.
  • the salts of the compounds of the invention include acid-addition salts with inorganic or organic acids such as hydrobromic, hydrochloric, nitric, phosphoric, sulfuric, acetic, butyric, fumaric, lactic, maleic, malonic, oxalic, propionic, salicylic, tartaric, 4-toluenesulfonic or valeric acids.
  • inorganic or organic acids such as hydrobromic, hydrochloric, nitric, phosphoric, sulfuric, acetic, butyric, fumaric, lactic, maleic, malonic, oxalic, propionic, salicylic, tartaric, 4-toluenesulfonic or valeric acids.
  • the salts of the compounds of the invention also include those formed with organic bases (e.g., pyridine, ammonia, or triethylamine) or inorganic bases (e.g., hydrides, hydroxides, or carbonates of sodium, potassium, hthium, calcium, magnesium or barium) when the compound contains an acidic group such as a carboxylic acid or phenol.
  • organic bases e.g., pyridine, ammonia, or triethylamine
  • inorganic bases e.g., hydrides, hydroxides, or carbonates of sodium, potassium, hthium, calcium, magnesium or barium
  • This invention provides 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 compound of Formula I including all geometric and stereoisomers, N-oxides and agriculturally suitable salts thereof (e.g. as a component of a composition described herein).
  • Preferred 1 Preferred are methods comprising compounds of Formula I wherein
  • B is substituted with from one to three substituents independently selected fromR6;
  • R 1 is H; or Cj-Cg alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl or C 3 -C 6 cycloalkyl, each optionally substituted with one or more substituents selected from the group consisting of halogen, CN, NO 2 , hydroxy, C1-C4 alkoxy, C 1 -C4 alkylthio, C -C4 alkylsulfinyl, -C 4 alkylsulfonyl, C 2 -C 4 alkoxycarbonyl, C1-C4 alkylamino, C 2 -Cg dialkylamino and C 3 -Cg cycloalkylamino; each R 5 and each R 6 is independently C ⁇ -C 6 alkyl, C 2 -C6 alkenyl, C 2 -C6 alkynyl, C 3 -C 6 cycloalkyl, C
  • each R 5 and each R 6 is independently C r C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, Cj-Cg haloalkyl, C 2 ⁇ C 6 haloalkenyl, C 2 -C 6 haloalkynyl, C 3 -C 6 halocycloalkyl, halogen, CN, CO 2 H, CONH 2 , NO 2 , hydroxy, C r C 4 alkoxy, C r C 4 haloalkoxy, C1-C4 alkylthio, C ⁇ -C ⁇ alkylsulfinyl, C ⁇ alkylsulfonyl, C1-C4 haloalkylthio, C !
  • each R 5 and each R 6 is independently phenyl, benzyl or phenoxy, each optionally substituted with C r C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 3 -C 6 cycloalkyl, C r C 4 haloalkyl, C 2 -C 4 haloalkenyl, C
  • J is selected from -CH 2 CH 2 - -CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 -, -OCH 2 - -OCH 2 CH 2 -, -OCH 2 CH 2 CH 2 -, -CH 2 NHCH 2 - -CH 2 N(C r C 2 alkyl)CH 2 -,-CONHCO- and -CON(C r C 2 alkyl)CO-; and each R 5 and each R 6 is independently Ci-Cg alkyl, C 2 -C 6 alkenyl, C 2 -Cg alkynyl, C 3 -Cg cycloalkyl, C Cg haloalkyl, C 2 -Cg haloalkenyl, C 2 -Cg haloalkynyl, C 3 -Cg halocycloalkyl, halogen, CN, NO 2 , C1-C 4 alkoxy, C1-C4 haloal
  • each R 5 is independently halogen, CN, NO 2 , C r C 2 alkyl, C r C 2 haloalkyl, C r C 2 alkoxy, C r C 2 haloalkoxy, C r C 2 alkylthio, C]-C alkylsulfinyl and C ⁇ -C 2 alkylsulfonyl, C ⁇ -C 2 haloalkylthio, C ⁇ -C 2 haloalkylsulfinyl C ⁇ C 2 haloalkylsulfonyl, C 2 -C4 alkoxycarbonyl or C 2 -C4 alkylaminocarbonyl.
  • R 5 is CH 3 , CI, Br, I, CN, NO 2 , CF 3 , CO 2 CH 3 , CONHCH 3 CH 3 , OCF 3 , OCHF 2 , OCH 2 CF 3 , OCF 2 CF 3 , OCF 2 CF 2 H, OCHFCF 3 , SCF 3 , SCHF 2 , SCH 2 CF 3 , SCF 2 CF 3 , SCF 2 CF 2 H, SCHFCF 3 , SOCF 3 , SOCHF 2 , SOCH 2 CF 3 , SOCF 2 CF 3 , SOCF 2 CF 2 H, SOCHFCF 3 , SO 2 CF 3 , SO 2 CHF 2 , SO 2 CH 2 CF 3 , SO 2 CF 2 CF 3 , SO 2 CF 2 CF 2 H or SO 2 CHFCF 3 .
  • each R 6 is independently C ⁇ -C 2 alkyl, C ⁇ _-C 2 haloalkyl, halogen, CN, C ⁇ C alkoxy, C 1 -C haloalkoxy, C ⁇ C 2 alkylthio, C ⁇ -C 2 alkylsulfinyl or C 1 -C 2 alkylsulfonyl and at least one R 6 is located in a position ortho to the link with W.
  • Methods of Preferred 6 wherein J is -CH 2 CH 2 - or -CH 2 CH 2 CH 2 -.
  • Preferred 8 Methods of Preferred 7 wherein each R 5 is independently CH 3 , CI, Br, I, CN, NO 2 , CF 3 , OCF 3 , OCHF 2 , SCF 3 , SCHF 2 , CO 2 CH 3 or CONHCH 3 .
  • R 5 is CH 3 , CI, Br, CN, NO 2 , CF 3 , CO 2 CH 3 or CONHCH 3 .
  • Preferred 14 Methods of any of Preferred 2 through Preferred 13 wherein R 1 is H and R 3 is H. Specifically preferred are the methods comprising a compound selected from the group consisting of 2-chloro-6-methoxy-N-(5,6,7,8-tetiahydro-3-methyl-8-quinolinyl)-4- pyridinecarboxamide,
  • This invention also relates to fungicidal compositions comprising fungicidally effective amounts of the compounds of Formula I.
  • the preferred compositions of the present invention are those which comprise the compounds recited in Preferred 1 through Preferred 14 above.
  • Preferred compounds are those recited in Preferred 1 through Preferred 14 above, subject to the proviso above.
  • a specifically preferred compound is 2-chloro-6-methoxy-N-(5,6,7,8-tetrahydro-3- methyl- 8 -quinolinyl)-4-pyridinecarboxamide.
  • the compounds of Formula I can be prepared by one or more of the following methods and variations as described in Schemes 1-19.
  • Compounds of Formulae la, lb and Ic are subsets of the compounds of Formula I, and all substituents for Formulae la, lb and Ic are as defined above for Formula I.
  • the definitions of A, B, J, L, W, R 1 through R 6 andm in the compounds of Formulae 1-19 below are as defined above.
  • the compounds of Formula la are prepared by treating amine or amine salts of Formula 1 with an appropriate acid chloride in an inert solvent with two molar equivalents of a base (e.g. triethylamine (Et ⁇ ), polymer supported diisopropylethylamine or potassium carbonate) present.
  • a base e.g. triethylamine (Et ⁇ ), polymer supported diisopropylethylamine or potassium carbonate
  • Formula lb are prepared by treating amine or amine salts of Formula 1 with an appropriate sulfonyl chloride in an inert solvent with two molar equivalents of a base (e.g. triethylamine, polymer supported diisopropylethylamine or potassium carbonate) present.
  • a base e.g. triethylamine, polymer supported diisopropylethylamine or potassium carbonate
  • Suitable solvents are selected from the group consisting of ethers such as tettahydrofuran, dimethoxyethane, or diethyl ether; hydrocarbons such as toluene or benzene; and halocarbons such as dichloromethane or chloroform.
  • compounds of Formula la can be synthesized by reacting the amine or amine salts of Formula 1 with an appropriate carboxylic acid in the presence of an organic dehydrating reagent such as 1,3-dicyclohexylcarbodiimide (DCC) or l-[3- (Dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDC) as depicted in Scheme 2.
  • organic dehydrating reagent such as 1,3-dicyclohexylcarbodiimide (DCC) or l-[3- (Dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDC) as depicted in Scheme 2.
  • Suitable solvents are selected from the group consisting of ethers such as tetrahydrofuran, dimethoxyethane, or diethyl ether; hydrocarbons such as toluene or benzene; and halocarbons such as dichlorome
  • Intermediate amine la a compound of Formula 1 wherein A is a 2-pyridyl ring bearing the indicated substituents, J 1 is -(CH 2 ) q -, q is 1, 2, 3 or 4 and R 1 and R 3 are both hydrogen, can be prepared from the commercially available pyridines of Formula 2 (Scheme 3).
  • the CH 2 attached ortho to the pyridine nitrogen atom of Formula 2 can be substituted with NH 2 by a sequence of steps comprising hydrogen peroxide oxidation, acylation, hydrolysis, chlorination, azide displacement and reduction (e.g. catalytic hydrogenation using H 2 and palladium on carbon as catalyst) in procedures analogous to those found in WO00/56729 to provide the amine la.
  • J is (CH 2 ) q and q is 1, 2, 3 or 4
  • J 2 may also be optionally substituted with one or more (up to the total number of hydrogens available for replacement in any specific J- group) substituents independently selected from the group alkyl (e.g. CH(CH 3 )O, C(CH 3 ) 2 O, or CH(CH 2 CH 3 )O), halogen, C ⁇ , ⁇ O 2 and C r C 2 alkoxy.
  • substituents independently selected from the group alkyl (e.g. CH(CH 3 )O, C(CH 3 ) 2 O, or CH(CH 2 CH 3 )O), halogen, C ⁇ , ⁇ O 2 and C r C 2 alkoxy.
  • J may be optionally subsUtuted
  • compounds of Formula 1 c (wherein A and J are as previously defined and R 1 is hydrogen) can be prepared by treating compounds of Formula 7 with isoamyl nitrite and a base such as potassium t-butoxide (t-BuOK) followed by reduction of the resulting oximes of Formula 8 (Scheme 5).
  • the reduction can be accomplished, for example, with hthium aluminum hydride, zinc and acetic acid, or catalytic hydrogenation.
  • compounds of Formula lc (wherein A and J are defined and R 1 is hydrogen) can be prepared by reductive amination of compounds of Formula 9 as shown in Scheme 6.
  • Many methods for reductive amination have been reported. For some leading references, see Jerry March, Advanced Organic Chemistry: Reactions, Mechanism and Structure, Third Edition, John Wiley & Sons, New York, 1985, pp. 798-800.
  • Compounds of Formula 6a wherein J 2 is optionally substituted -CH 2 O- or -CH CH O- can be prepared by transesterification of N-(diphenylmethylene)glycine esters of Formula 9 with the corresponding alcohols of Formula 10 under basic conditions (Scheme 7).
  • Compounds of Formula 6b wherein J 2 is optionally substituted -CH 2 ⁇ H-, -CH 2 CH 2 NH-, -CH N(C ⁇ -C alkyl)- or -CH CH N(C ⁇ -C 2 alkyl)- can be prepared by amidation of N-(diphenylmethylene)glycine esters of Formula 9 with the corresponding amines of Formula 11.
  • Compounds of Formula 6 wherein J 2 is optionally substituted -CO ⁇ H- or -CO ⁇ (Cj-C 2 alkyl) can be prepared by amidation of N-(diphenylmethylene)glycine esters of Formula 9 with the corresponding amides of Formula 15.
  • J and J may be optionally substituted
  • R 8 is HorC ⁇ -C 2 alkyl
  • compounds of Formula 10a wherein J 3 is optionally substituted -CH 2 OH can be prepared by ortho-lithiation of a compound of Formula 12 followed by reaction with an aldehyde or aldehyde synthon (e.g. paraformaldehyde) or ketone.
  • compounds of Formula 10b wherein J 3 is optionally substituted -CH CH OH can be prepared by ortho-lithiation followed by reaction with an epoxide.
  • Ortho-litiations can be accomphshed by treatment of the substrate with a strong hthium base such as hthium diisopropylamide (LDA) and are typically carried out at reduced temperatures.
  • a strong hthium base such as hthium diisopropylamide (LDA)
  • Suitable solvents are selected from the group consisting of ethers such as tetrahydrofuran, dimethoxyethane, or diethyl ether and hydrocarbons such as hexane, heptane or ethylbenzene.
  • compounds of Formula 10c wherein J 3 is -CH OH also can be prepared by ortho-lithiation of a compound of Formula 12 and reactipn with carbon dioxide to provide a compound of Formula 13, followed by reduction using hthium aluminum hydride (LAH) in a suitable solvent such as toluene.
  • LAH hthium aluminum hydride
  • Some isonicotinic acids of Formula 13 may be available commercially.
  • Q 1 and Q 2 are independently H or C ! -C 2 alkyl 10b
  • compounds of Formula 10c wherein J 3 is -CH OH also can be prepared by ortho-lithiation of a compound of Formula 12 and reaction with carbon dioxide to provide a compound of Formula 13, followed by reduction using hthium aluminum hydride (LAH) in a suitable solvent such as toluene.
  • LAH hthium aluminum hydride
  • Some isonicotinic acids of Formula 13 may be available commercially.
  • Compounds of Formula 11a can be synthesized from nitriles of Formula 14 by reduction of the nitrile using hthium aluminum hydride (LAH) in a suitable solvent such as toluene to give the corresponding aminomethyl intermediates (Scheme 10).
  • Compounds of Formula 11a can also be synthesized from primary amides of Formula 15 wherein R 8 is H by reduction using hthium aluminum hydride (LAH) in a suitable solvent such as toluene.
  • Compounds of Formula 1 lb can be synthesized from secondary amides of Formula 15 wherein R 8 is C ⁇ C alkyl by reduction using hthium aluminum hydride (LAH) in a suitable solvent such as toluene.
  • Compounds of Formula 1 lb can also be synthesized by reductive -unination of formaldehyde or acetaldehyde with compounds of Formula 11a.
  • Reductive amination with formaldehyde can be accomplished in the presence of formic acid under Eschweiler-Clarke procedures (see Jerry March, Advanced Organic Chemistry: Reactions, Mechanism and Structure, Third Edition, John Wiley & Sons, New York, 1985, pp. 798-800 and references therein).
  • Compounds of Formula 15 may be prepared from compounds of Formula 13 by conversion to the corresponding acid chloride and subsequent reaction with ammonia or a primary amine (Scheme 11).
  • Methods of converting carboxylic acids to the corresponding acid chloride are well-known in the art and include, for example, treatment with thionyl chloride or oxalyl chloride.
  • the acid chloride is treated with the amine or amine salt in an inert solvent with two molar equivalents of a base (e.g. triethylamine, polymer supported dhsopropylethylamine or potassium carbonate) present.
  • a base e.g. triethylamine, polymer supported dhsopropylethylamine or potassium carbonate
  • Suitable solvents are selected from the group consisting of ethers such as tetrahydrofuran, dimethoxyethane, or diethyl ether; hydrocarbons such as toluene or benzene; and halocarbons such as dichloromethane or chloroform.
  • compounds of Formula 15 can be synthesized by reacting the appropriate amine or amine salt with a carboxylic acid of Formula 13 in the presence of an organic dehydrating reagent such as 1,3-dicyclohexylcarbodiimide (DCC) or l-[3- (Dimethylammo)propyl]-3-e1hylcarbooUimide hydrochloride (EDC).
  • DCC 1,3-dicyclohexylcarbodiimide
  • EDC 1,3-dicyclohexylcarbodiimide
  • Suitable solvents are selected from the group consisting of ethers such as tetrahydrofuran, dimethoxyethane, or diethyl ether; hydrocarbons such as toluene or benzene; and halocarbons such as dichloromethane or chloroform.
  • compounds of Formula 1 la can be synthesized by reacting compounds of Formula 16, wherein LG is a leaving group such as Br, CI, methanesulfonyl (-OSO Me) or para-toluenesulfonyl (-OSO -p-Tol), with ammonia in a protic solvent such as methanol (Scheme 12).
  • LG is a leaving group such as Br, CI, methanesulfonyl (-OSO Me) or para-toluenesulfonyl (-OSO -p-Tol)
  • a protic solvent such as methanol
  • Compounds of Formula 11a can also be prepared by reacting compounds of Formula 16 with a potassium salt of phthalimide followed by reaction with either aminoethanol or hydrazine in an alcohol solvent to provide the desired aminomethyl intermediates Formula 11a.
  • LG is CI, Br, -OS0 2 Me, -OSO2-P-T0I
  • compounds of Formula 16 wherein LG is -OSO 2 Me or -OSO -p-Tol (16a) can be prepared by reacting a compound of Formula 10c with the corresponding sulfonyl chloride in the presence of a base such as triethylamine, polymer supported diisopropylethylamine or potassium carbonate.
  • Suitable solvents are selected from the group consisting of ethers such as tetrahydrofuran, dimethoxyethane, or diethyl ether; hydrocarbons such as toluene or benzene; and halocarbons such as dichloromethane or chloroform.
  • Compounds of Formula 16 wherein LG is Br or CI (16b) can be prepared by treatment of compounds of Formula 17 with halogenating agents such as bromine, chlorine, or N-halosuccinimides under free radical conditions. These transformations are typically carried out with activation by visible or ultraviolet light (hv) and peroxides and are well known in the art.
  • halogenating agents such as bromine, chlorine, or N-halosuccinimides under free radical conditions.
  • LG is -OS02Me or -OSO2-P-T0I
  • Compounds of Formula l ie can be prepared from compounds of Formula 16 by displacement with cyanide followed by reduction with, for example, hthium aluminum hydride (Scheme 14).
  • Compounds of Formula 8 can be prepared by intramolecular free-radical acylation of compounds of Formula 18 (Scheme 15). These acylations can be carried out in the presence of t-butyl hydroperoxide, sulfuric acid and ferrous sulfate (see Chem. Communications, 1969, 201 and Gazz. Chun. ltd. 1977, 107, 491 for leading references). Scheme 15
  • Compounds of Formula 18 wherein J is OCH 2 orNHCH 2 (18a or 18b respectively) can be prepared by alkylation of compounds of Formula 19 with bromoacetaldehyde diethyl acetal followed by acidic hydrolysis of the acetal protecting group (Scheme 16).
  • Compounds of Formula 18 wherein J is OCH 2 CH 2 orNHCH 2 CH 2 (18c or 18d respectively) can be prepared by Michael addition of acrolein by compounds of Formula 19.
  • 8a J J is OCH 2 8e J D is N(C ⁇ -C 2 alkyl)CH2 8b J 5 is NHCH 2 8f J 5 is N(C ⁇ -C 2 alkyl)CH 2 CH 2 8c J 5 is OCH 2 CH 2 8d J 5 is NHCH 2 CH 2 LG 1 is CI, Br, I, -OS0 2 Me, -OS0 2 -p-Tol
  • J 6 is CH 2 NH or CH 2 CH 2 NH
  • Methanesulfonyl chloride (25.6 g) was added slowly to a solution of the oil (24 g) and triethylamine in dichloromethane (150 mL) at 0 °C. The reaction mixture was slowly warmed up to room temperature and then heated to reflux overnight. The mixture was cooled to room temperature and partitioned between water and dichloromethane. The combined organic extract was dried (Na 2 SO4) and concentrated. The residue was purified by flash chromatography on silica gel (using a gradient of 10% to 60% ethyl acetate in hexanes as eluent) to give the title compound as a light yellowish oil (21.8 g).
  • T and V are both Cl andU is H
  • T Cl and V and U are both Me
  • T Cl and V and U are both Me
  • This invention also includes fungicidal compositions comprising (1)' a fungicidally effective amount of a compound of Formula I (including all geometric md stereoisomers, N-oxides and agriculturally suitable salts thereof); and (2) (i) at least one other insecticide, fungicide, nematocide, bactericide, acaricide, growth regulator, chemosterilant, semiochemical, repellent, attractant, pheromone, feeding stimulant or other biologically active compound; and/or (ii) at least one additional component selected from the group consisting of surfactants, solid diluents and Hquid diluents.
  • fungicidal compositions comprising (1)' a fungicidally effective amount of a compound of Formula I (including all geometric md stereoisomers, N-oxides and agriculturally suitable salts thereof); and (2) (i) at least one other insecticide, fungicide, nematocide, bactericide, acaricide, growth regulator,
  • compositions comprising (a) at least one compound of Formula I; and (b) at least one compound selected from the group consisting of
  • the weight ratios of component (b) to component (a) typically is from 100:1 to 1:100, preferably is from 30:1 to 1:30, and more preferably is from 10:1 to 1:10. Of note are compositions wherein the weight ratio of component (b) to component (a) is from 10:1 to 1:1.
  • Strobilurin fungicides such as azoxystrobin, kresoxim-methyl, metommostrobin/fenominostrobin (SSF-126), picoxystrobin, pyraclostrobin and trifloxystrobin are known to have a fungicidal mode of action which inhibits the bc ⁇ complex in the mitochondrial respiration chain (Angew. Chem. Int. Ed., 1999, 38, 1328-1349).
  • the bci complex is sometimes referred to by other names in the biophemical literature, including complex III of the electron transfer chain, and ub ydroquino exytochrome c oxidoreductase. It is uniquely identified by the Enzyme Commission number ECl .10.2.2.
  • the bc ⁇ complex is described in, for example, J. Biol. Chem. 1989, 264, 14543-38; Methods Enzymol. 1986, 126, 253-71 ; and references cited therein.
  • the Sterol Biosynthesis Inhibitor Fungicides component (b4) or (b5)
  • the class of sterol biosynthesis inhibitors includes DMI and non-DMI compounds, thai control fungi by inhibiting enzymes in the sterol biosynthesis pathway.
  • DMI fungicides have a common site of action within the fungal sterol biosynthesis pathway; that is, an inhibition of demethylation at position 14 of lanosterol or 24-methylene dihydrolanosterol, which are precursors to sterols in fungi.
  • Compounds acting at this site are often referred to as demethylase inhibitors, DMT fungicides, or DMTs.
  • the demethylase enzyme is sometimes referred to by other names in the biochemical literature, including cytochrome P-450
  • DMI fungicides fall into several classes: azoles (including triazoles and imidazoles), pyrimidines, piperazines and pyridines.
  • the triazoles includes bromuconazole, cyproconazole, difenoconazole, diniconazole, epoxiconazole, fenbuconazole, fluquinconazole, flusilazole, flutriafol, hexaconazole, ipconazole, metconazole, penconazole, propiconazole, tebuconazole, tetraconazole, triadimefon, triadimenol, triticonazole and uniconazole.
  • the imidazoles include clotrimazole, econazole, imazalil, isoconazole, miconazole and prochloraz.
  • the pyrimidines include fenarimol, nuarimol and triarimol.
  • the piperazines include triforine.
  • the pyridines include buthiobate and pyrifenox. Biochemical investigations have shown that all of the above mentioned fungicides are DMI fungicides as described by K. H. Kuck, et al. in Modem Selective Fungicides - Properties, Applications and Mechanisms of Action, Lyr, H., Ed.; Gustav Fischer Verlag: New York, 1995, 205-258.
  • the DMI fungicides have been grouped together to distinguish them from other sterol biosynthesis inhibitors, such as, the morpholine and piperidine fungicides.
  • the morpholines and piperidines are also sterol biosynthesis inhibitors but have been shown to inhibit later steps in the sterol biosynthesis pathway.
  • the morpholines include aldimorph, dodemorph, fenpropimorph, tridemorph and trimorphamide.
  • the piperidines include fenpropidin.
  • Biochemical investigations have shown that all of the above mentioned morpholine and piperidine fungicides are sterol biosynthesis inhibitor fungicides as described by K. H. Kuck, et al. in Modern Selective Fungicides - Properties, Applications and Mechanisms of Action, Lyr, H., Ed.; Gustav Fischer Verlag: New York, 1995, 185-204.
  • Pyrimidinone fungicides include compounds of Formula II
  • G is a fused phenyl, thiophene or pyridine ring;
  • R l is C r C 6 alkyl;
  • R 2 is C1-C 6 alkyl or C ⁇ Cg alkoxy; R 3 is halogen; and R 4 is hydrogen or halogen.
  • pyrimidinone fungicides selected from the group: 6-bromo-3-propyl-2-propyloxy-4(3H)-qumazolinone, 6,8-diiodo-3-propyl-2-propyloxy-4(3i ⁇ -qumazolinone, 6-iodo-3-propyl-2-propyloxy-4(3H)-quinazolinone,
  • Phenylamides such as metalaxyl, benalaxyl and oxadixyl
  • fungicides that can be included in compositions of this invention in combination with a Formula I compound or as an additional component in combination with component (a) and component (b) are acibenzolar, benalaxyl, benomyl, blasticidin-S, Bordeaux mixture (tribasic copper sulfate), carpropamid, captafol, captan, carbendazim, chloroneb, 5 chlorothalonil, copper oxychloride, copper salts such as copper sulfate and copper hydroxide, cyazofamid, cymoxanil, cyprodinil, (S)-3,5-dichloro-N-(3-chloro-l -ethyl- 1- methyl- 2-oxopropyl)-4-methylbenzamide (RH 7281), diclocymet (S-2900), diclomezine, dicloran, dimethomorph, diniconazole-M, dode o h, dod
  • Formula I with fungicides of a different biochemical mode of action (e.g. mitochondrial respiration inhibition, inhibition of protein synthesis by interference of the synthesis of ribosomal R ⁇ A or inhibition of beta-tubulin synthesis) that can be particularly advantageous for resistance management.
  • fungicides of a different biochemical mode of action e.g. mitochondrial respiration inhibition, inhibition of protein synthesis by interference of the synthesis of ribosomal R ⁇ A or inhibition of beta-tubulin synthesis
  • Examples include combinations of compounds of Formula I (e.g. Compound 1) with strobilurins such as
  • azoxystrobin kresoxim-methyl, pyraclostrobin and triflo ystrobin
  • carbendazim mitochondrial respiration inhibitors such as famoxadone and fenamidone
  • benomyl cymoxanil
  • dimethomorph folpet
  • fosetyl-aluminum metalaxyl
  • mancozeb maneb.
  • alkylenebis(dithiocarbamate)s such as mancozeb, maneb, propineb and zineb
  • ph alimids such as folpet
  • copper salts such as copper sulfate and copper hydroxide
  • strobilurins such as azoxystrobin, pyraclostrobin and trifloxystrobin
  • mitochondrial respiration inhibitors such as
  • phenylamides such as metalaxyl
  • phosphonates such as fosetyl-AL dimethomorph
  • pyrimidinone fungicides such as 6-iodo-3-propyl-2-propyloxy-4(3H)-quinazolinone and 6-chloro-2-propoxy-3- propylmieno[2,3- ⁇ pyrimidin-4(3H)-one
  • other fungicides such as cymoxanil.
  • fungicides for controlling potato diseases including alkylenebis(dithiocarbamate)s such as mancozeb, maneb, propineb and zineb; copper salts such as copper sulfate and copper hydroxide; strobilurins such as pyraclostrobin and trifloxystrobin; mitochondrial respiration inhibitors such as famoxadone and fenamidone; phenylamides such as metalaxyl; carbamates such as propamocarb; phenylpyridylamines such as fluazinam and other fungicides such as chlorothalonil, cyazofa id, cymoxanil, dimethomorph, zoxamid and ipro valicarb.
  • alkylenebis(dithiocarbamate)s such as mancozeb, maneb, propineb and zineb
  • copper salts such as copper sulfate and copper hydrox
  • component (b) comprises at least one compound from each of two different groups selected from (bl), (b2), (b3), (b4), (b5), (b6), (b7), (b8) and (b9).
  • the weight ratio of the compound(s) of the first of these two component (b) groups to the compound(s) of the second of these component (b) groups typically is from 100:1 to 1:100, more typically from 30:1 to 1:30 and most typically from 10:1 to 1:10.
  • component (b) comprises at least one compound selected from (bl), for example mancozeb
  • a second component (b) group for example, from (b2), (b3), (b6), (b7), (b8) or (b9).
  • the overall weight ratio of component (b) to component (a) is from 30:1 to 1:30 and the weight ratio of component (bl) to component (a) is from 10:1 to 1:1.
  • 6-chloro-2- propoxy-3-propyltMeno[2,3- ⁇ pyrimidin-4(3H)-one, folpet, captan and fosetyl-aluminum a compound selected from the group consisting of famoxadone, fenamidone, azoxystrobin, kresox n-methyl, pyraclostrobin, trifl
  • component (b) comprises at least one compound selected from (b2), for example famoxadone, and at least one compound selected from a second component (b) group, for example, from (bl), (b3), (b6), (b7), (b8) or (b9).
  • the overall weight ratio of component (b) to component (a) is from 30: 1 to 1:30 and the weight ratio of component (b2) to component (a) is from 10:1 to 1:1.
  • compositions comprising mixtures of component (a) (preferably a compound from Index Table A, B or C) with famoxadone and a compound selected from the group consisting of mancozeb, maneb, propineb, zineb, cymoxanil, metalaxyl, benalaxyl, oxadixyl, 6-iodo-3-propyl-2-propyloxy- 4(3H)-quinazolmone, 6-chloro-2-propoxy-3-propyltMeno[2,3- ⁇ pyrimid -4(3H)-one, folpet, captan and fosetyl-aluminum.
  • component (a) preferably a compound from Index Table A, B or C
  • famoxadone a compound selected from the group consisting of mancozeb, maneb, propineb, zineb, cymoxanil, metalaxyl, benalax
  • compositions wherein component (b) comprises the compound of (b3), in other words cymoxanil, and at least one compound selected from a second component (b) group, for example, from (bl), (b2), (b6), (b7), (b8) or (b9).
  • component (b) comprises the compound of (b3), in other words cymoxanil, and at least one compound selected from a second component (b) group, for example, from (bl), (b2), (b6), (b7), (b8) or (b9).
  • the overall weight ratio of component (b) to component (a) is from 30: 1 to 1 :30 and the weight ratio of component (b3) to component (a) is from 10:1 to 1:1.
  • compositions comprising mixtures of component (a) (preferably a compound from Index Table A, B or C) with cymoxanil and a compound selected from the group consisting of famoxadone, fenamidone, azoxystrobin, kresoxim-methyl, pyraclostrobin, trifloxystrobin, mancozeb, maneb, pi pineb, zineb, metalaxyl, benalaxyl, oxadixyl, 6-iodo-3-propyl-2-propyloxy-4(3H)-quinazolinone,
  • component (b) comprises at least one compound selected from (b6), for example metalaxyl, and at least one compound selected from a second component (b) group, for example, from (bl), (b2), (b3), (b7), (b8) or (b9).
  • the overall weight ratio of component (b) to component (a) is from 30: 1 to 1 :30 and the weight ratio of component (b6) to component (a) is from 10:1 to 1:3.
  • compositions comprising mixtures of component (a) (preferably a compound from Index Table A, B or C) with metalaxyl or oxadixyl and a compound selected from the group consisting of famoxadone, fenamidone, azoxystrobin, kresoxim-methyl, pyraclostrobin, trifloxystrobin, cymoxanil, mancozeb, maneb, propineb, zineb, 6-iodo-3-propyl-2-propyloxy-4(3H)-quinazolinone, 6- chloro-2-propoxy-3-propylmieno[2,3-( ⁇ pyrimidin-4(3H)-one, folpet, captan and fosetyl- aluminum.
  • component (a) preferably a compound from Index Table A, B or C
  • metalaxyl or oxadixyl preferably a compound from Index Table A, B or C
  • component (b) comprises at least one compound selected from (b7), for example 6-iodo-3-propyl-2-propyloxy-4(3H)- quinazolinone or 6-chloro-2-propoxy-3-propyltMeno[2,3- ⁇ i]pyrimidin-4(3H)-one
  • a second component (b) group for example, from (bl), (b2), (b3), (b6), (b8) or (b9).
  • compositions wherein the weight ratio of component (b6) to component (a) is from 1:4.5 to 1:9.
  • these compositions include compositions comprising mixtures of component (a) (preferably a compound from Index Table A, B or C) with 6-iodo-3-propyl-2-propyloxy-4(3H)- quinazolinone or 6-chloro-2-propoxy-3-propylt eno[2,3- ⁇ pyrimidin-4(3H)-one and a compound selected from the group consisting of famoxadone, fenamidone, azoxystrobin, kresoxim-methyl, pyraclostrobin, trifloxystrobin, cymoxanil, mancozeb, maneb, propineb, zineb, metalaxyl, benalaxyl, oxadixyl, folpet, captan and fosetyl-aluminum.
  • compositions wherein component (b) comprises the compound of (b9), in other words fosetyl-aginanum, and at least one compound selected from a second component (b) group, for example, from (bl), (b2), (b3), (b6) or (b7).
  • component (b) comprises the compound of (b9), in other words fosetyl-avarnum, and at least one compound selected from a second component (b) group, for example, from (bl), (b2), (b3), (b6) or (b7).
  • the overall weight ratio of component (b) to component (a) is from 30: 1 to 1 :30 and the weight ratio of component (b9) to component (a) is from 10: 1 to 1:1.
  • compositions comprising mixtures of component (a) (preferably a compound from Index Table A, B or C) with fosetyl-aluminum and a compound selected from the group consisting of famoxadone, fenamidone, azoxystrobin, kresoxim-methyl, pyraclostrobin, trifloxystrobin, manco-jeb, maneb, propineb, zineb, metalaxyl, benalaxyl, oxadixyl, 6-iodo-3-propyl-2-propyloxy-4(3H)-qumazolinone, 6- chloro-2-propoxy-3-propylthieno[2,3-rf]pyrimidin-4(3H)-one, folpet, captan and cymoxanil.
  • component (a) preferably a compound from Index Table A, B or C
  • strobilurins such as azoxystrobin, kresoxim-methyl, pyraclostrobin and trifloxystrobin
  • morpholines such as fenpropidine and fenpropimorph
  • triazoles such as bromuconazole, cyproconazole, difenoconazole, epoxyconazole, flusilazole, ipconazole, metconazole, propiconazole, tebuconazole and triticonazole
  • pyrimidinone fungicides benomyl; carbendazim; chlorothalonil; dimethomorph; folpet; mancozeb; maneb; quinoxyfen; validamycin and vinclozolin.
  • fungicides giving an even broader spectrum of agricultural protection including azoxystrobin, kresoxim-methyl, pyrclostrobin, trifloxystrobin, benomyl, carbendazim, chlorothalonil, dimethomorph, folpet, mancozeb, maneb, quinoxyfen, validamycin, vinclozolin, fenpropidine, fenpropimorph, bromuconazole, cyproconazole, difenoconazole, epoxyconazole, flusilazole, ipconazole, metconazole, propiconazole, tebuconazole and triticonazole.
  • fungicides of a different mode of action e.g. mitochondrial respiration inhibition, inhibition of protein synthesis by interference of the synthesis of ribosomal RNA or inhibition of beta-tubulin synthesis
  • examples include combinations of compounds of Formula I (e.g. Compound Al) with azoxystrobin, kresoxim-methyl, pyrclostrobin, trifloxystrobin, carbendazim, famoxadone, fenamidone, benomyl, cymoxanil, dimethomorph, folpet, fosetyl-aluminum, metalaxyl, mancozeb, maneb.
  • These combinations can be particularly advantageous for resistance management, especially where the fungicides of the combination control the same or similar diseases.
  • fungicides for controlling grape diseases including dithiocarbamates such as mancozeb, maneb, propineb and zineb, phthalimids such as folpet, copper salts such as copper sulfate and copper hydroxide, strobilurins such as azoxystrobin, pyrclostrobin and trifloxystrobin, , phenylamides such as metalaxyl, phosphonates such as fosetyl-aluminum, morpholines such as dimethomorph, and other fungicides such as cymoxanil, famoxadone and fenamidone.
  • dithiocarbamates such as mancozeb, maneb, propineb and zineb
  • phthalimids such as folpet
  • copper salts such as copper sulfate and copper hydroxide
  • strobilurins such as azoxystrobin, pyrclostrobin and trifloxystrobin
  • fungicides for controlling potato diseases including dithiocarbamates such as mancozeb, maneb, propineb and zineb, copper salts such as copper sulfate and copper hydroxide, strobilurins such as pyrclostrobin and trifloxystrobin, phenylamides such as metalaxyl, carbamates such as propamocarb, phenylpyriylamines such as fluazinam, morpholines such as dimethomorph, and other fungicides such as chlorothalonil, cyazofamid, cymoxanil, famoxadone, fenamidone, zoxamid and iprovalicarb.
  • dithiocarbamates such as mancozeb, maneb, propineb and zineb
  • copper salts such as copper sulfate and copper hydroxide
  • strobilurins such as pyrclostrobin and trifloxy
  • Preferred compositions comprise a compound of component (a) mixed with cymoxanil.
  • Preferred compositions comprise a compound of component (a) mixed with a compound selected from (bl). More preferred is a composition wherein the compound of (bl) is mancozeb.
  • Preferred compositions comprise a compound of component (a) mixed with a compound selected from (b2).
  • compositions wherein the compound of (b2) is famoxadone.
  • Preferred compositions comprise a compound of component (a) mixed with two compounds selected from two different groups selected from (bl), (b2), (b3), (b4), (b5), (b6), (b7), (b8) and (b9).
  • Preferred compositions are those wherein component (a) is selected from the compounds of Formula I indicated in Preferred 1 through 14 above.
  • Compounds of this invention can also be mixed with one or more insecticides, 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.
  • compositions of this invention can be formulated are: insecticides such as abamectin, acephate, azinphos-methyl, bifenthrin, buprofezin, carbofuran, chlorfenapyr, chlo ⁇ yrifos, chlorpyrifos-methyl, cyfluthrin, beta-cyfluthrin, cyhalothrin, lambda-cyhalothrin, deltamethrin, diafenthiuron, diazinon, diflubenzuron, dimethoate, esfenvalerate, fenoxycarb, fenpropathrin, fenvalerate, fipronil, flucythrinate, tau-fluvalinate, fonophos, imidacloprid, isofenphos, malathion, metaldehyde, methamidophos, methidathion, methomy
  • Formulation Compounds of this invention will generally be used as a formulation or composition with an agriculturally suitable carrier comprising at least one of a liquid diluent, a solid diluent or a surfactant.
  • the formulation or composition ingredients are selected to be consistent with the physical properties of the active ingredient, mode of apphcation 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 (e.g. from 0.01-99.99 weight percent) of active ingredient together with diluent and/or surfactant within the following approximate ranges which add up to 100 percent by weight.
  • 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, N,N-dialkyltaurates, Hgnin 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, N,N-dimethylformamide, dimethyl sulfoxide, N-alkylpyrrolidone, ethylene glycol, polypropylene glycol, paraffins, alkylbenzenes, alkylnaphthalenes, oils of olive, castor, linseed, tung, sesame, corn, peanut, cotton-seed, soybean, rape-seed and coconut, fatty acid esters, ketones such as cyclohexanone, 2-heptanone, isophorone and 4-hydroxy-4-methyl-2-pentanone, and alcohols such as methanol, cyclohexanol, decanol and tetrahydrofurfuryl alcohol.
  • Solutions 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.
  • Preferred suspension concentrates include those containing, in addition to the active ingredient, from 5 to 20% nonionic surfactant (for example, polyethoxylated fatty alcohols) optionally combined with 50-65% liquid diluents and up to 5% anionic surfactants.
  • Granules and pellets can be prepared by spraying the active material upon preformed granular carriers or by agglomeration techniques. See Browning,
  • 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.
  • the compounds and compositions of Formula I are useful as plant disease control agents.
  • the present invention therefore 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 preferred methods of use are those involving the compounds or compositions preferred above.
  • the compounds and compositions of Formula I 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.
  • pathogens include Plasmopara viticola, Phytophthora infestans, Peronospora tabacina, Pseudoperonospora cubensis, Pythium aphanidermatum, Alternaria brassicae, Septoria nodorum, Septoria tritici, Cercosporidiumpersonatum, 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, Sphaerothecafulig
  • Plant disease control is ordinarily accomplished by applying an effective amount of a compound of Formula I 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.
  • Rates of apphcation for these compounds can be influenced by many factors of the environment and should be determined under actual us e 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.
  • the following TESTS demonstrate the control efficacy of compounds suitable for use in accordance with this invention on specific pathogens.
  • the pathogen control protection afforded by the compounds is not limited, however, to these species.
  • These TESTS can also be used to demonstrate the control efficacy of compositions of this invention on specific pathogens.
  • Test suspensions comprising a single active ingredient are sprayed to demonstrate the control efficacy of the active ingredient individually.
  • the active ingredients can be combined in the appropriate amounts in a single test suspension,
  • stock solutions of individual active ingredients can be prepared and then combined in the appropriate ratioj and diluted to the final desired concentration to form a test suspension or
  • test suspensions comprising single active ingredients can be sprayed sequentially in the desired ratio.
  • Synergism has been described as "the cooperative action of two components [e.g. component (a) and component (b)] of a mixture, such that the total effect is greater or more prolonged than the sum of the effects of the two (or more) taken independently” (see Tames, P. M. L., Neth. J. Plant Pathology, 1964, 70, 73-80).
  • the presence of a synergistic effect between two active ingredients is established with the aid of the Colby equation (see Colby, S. R.
  • test compounds are first dissolved in acetone in an amount equal to 3% of the final volume and then suspended at the desired concentration (in ppm) in acetone and purified water (50/50 mix) containing 250 ppm of the surfactant Trem® 014 (polyhydric alcohol esters). The resulting test suspensions are then used in the following tests. Spraying a 200 ppm test suspension to the point of run-off on the test plants is the equivalent of a rate of 500 g/ha. TEST A
  • 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 suspension was sprayed to the point of run-off on wheat seedlings.
  • 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 hours, 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 tomato seedlings.

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Abstract

This invention involves 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 compound of Formula I (including all geometric and stereoisomers), N-oxides, agriculturally suitable salts and compositions thereof, wherein A is taken together with N-C=C to form a substituted fused pyridinyl ring; B is a substituted phenyl or pyridinyl ring; J is an optionally substituted linking chain of 2 to 5 members including at least one carbon member, optionally including one or two carbon members as C(=O), and optionally including one member selected from nitrogen and oxygen;W is C=L or SOn; L is O or S;R1 is H; or C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C3-C6 cycloalkyl, each optionally substituted;R3 is H; or C1-C6 alkyl, C2-C6 alkenyl, C2191-C6 alkynyl or C3-C6 cycloalkyl, C2-C6 alkylcarbonyl, C2-C6 alkoxycarbonyl, C2-C6 alkylaminocarbonyl or C3-C8 dialkylaminocarbonyl; and n is 1 or 2.This invention also includes fungicidal compositions comprising a compound of Formula I, N-oxides, and agriculturally suitable salts thereof. This invention also includes compounds of Formula I, N-oxides and agriculturally suitable salts thereof, provided that when B is a substituted phenyl ring, W is C=O or SO2, R3 is H and J is a saturated chain of from 2 to 4 carbons that is either unsubstituted or substituted with one to three substituents selected from the group consisting of alkyl, alkoxy, aryl or aralkyl, then the compounds are N-oxides.

Description

TITLE
PYRIDINYL FUSED BICYCLIC AMIDE AS FUNGICIDES
BACKGROUND OF THE INVENTION
This invention relates to certain bicyclic amides having a pyridinyl ring fused through two adjacent carbon atoms to a second ring, their N-oxides, agriculturally suitable salts and compositions, and methods of their use as fungicides.
The control of plant diseases caused by fungal plant pathogens is extremely important in achieving high crop efficiency. Plant disease damage to ornamental,, egetable, field, cereal, and fruit crops can cause significant reduction in productivity and thereby result in increased costs to the consumer. 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.
WO 99/42447 discloses certain benzamides of formula i as fungicides
Figure imgf000003_0001
wherein (among others) R1 is H, alkyl, or acyl; R2 is H or alkyl; and L is -(0=0)-, -SO2- or -(C=S)-.
GB 2219797 discloses certain fused pyridinyl compounds of Formula ii
Figure imgf000003_0002
u wherein (among others) X is NHCO or NHSO2; Ar is an optionally substituted phenyl; R4 is alkyl, alkoxy, aryl or aralkyl; m is 1, 2 or 3 and n is 1, 2 or 3.
Agents that effectively control plant fungi, particularly of the class Oomycetes, such as
Phytophthora spp. and Plasmopara spp., are in constant demand by growers. Combinations of fungicides are often used to facilitate disease control and to retard resistance development. It is desirable to enhance the activity spectrum and the efficacy of disease control by using mixtures of active ingredients that provide a combination of curative, systemic and preventative control of plant pathogens. Also desirable are combinations that provide greater residual control to allow for extended spray intervals. It is also very desirable to combine fungicidal agents that inhibit different biochemical pathways in the fungal pathogens to retard development of resistance to any one particular plant disease control agent.
It is in all cases particularly advantageous to be able to decrease the quantity of chemical agents released in the environment while ensuring effective protection of crops from diseases caused by plant pathogens. Mixtures of fungicides may proyide significantly better disease control than could be predicted based on the activity of the individual components. This synergism has been described as "the cooperative action of two components of a mixture, such that the total effect is greater or more prolonged than the sum of the effects of the two (or more) taken independently" (see Tames, P. M. L., Neth. J. Plant Pathology, (1964), 70, 73-80).
There is a desire to find fungicidal agents that are particularly advantageous in achieving one or more of the preceding objectives.
SUMMARY OF THE INVENTION
This invention involves compounds of Formula I (including all geometric and stereoisomers), N-oxides, agriculturally suitable salts and compositions thereof:
Figure imgf000004_0001
wherein
A is taken together with Ν-C=C to form a substituted fused pyridinyl ring; B is a substituted phenyl or pyridinyl ring;
J is an optionally substituted linking chain of 2 to 5 members including at least one carbon member, optionally including one or two carbon members as C(=O), and optionally including one member selected from nitrogen and oxygen;
W is C=L or SOn; L is O or S;
R1 is H; or C C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C3-C6 cycloalkyl, each optionally substituted; R is H; or CrC6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C3-C6 cycloalkyl, C2-C6 alkylcarbonyl, C2-Cg alkoxycarbonyl, C2-Cg ajkylaminocarbonyl or C3-Cg dialkylaminocarbonyl; and n is 1 or 2. In particular, this invention includes 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 compound of Formula I (including all geometric and stereoisomers, N-oxides and agriculturally suitable salts thereof) or a composition comprising said compound.
This invention also includes compounds of Formula I (including all geometric and stereoisomers), N-oxides and agriculturally suitable salts thereof, provided that when B is a substituted phenyl ring, W is C=O or SO2, R3 is H and J is a saturated chajn of from 2 to 4 carbons that is either unsubstituted or substituted with from one to thre^ substituents selected from the group consisting of alkyl, alkoxy, aryl or aralkyl, then the compounds are N-oxides.
This invention also includes fungicidal compositions comprising (1) a fungicidally effective amount of a compound of Formula I (including all geometric and stereoisomers, N-oxides and agriculturally suitable salts thereof); and (2) (i) at least one other insecticide, fungicide, nematocide, bactericide, acaricide, growth regulator, chemosterilant, semiochemical, repellent, attractant, pheromone, feeding stimulant or other biologically active compound; and/or (ii) at least one additional component selected from the group consisting of surfactants, solid diluents and liquid diluents.
This invention provides, for example, compositions comprising (a) at least one compound of Formula I; and (b) at least one compound selected from the group consisting of
(bl) alkylenebis(dithiocarbamate) fungicides;
(b2) compounds acting at the bc\ complex of the fungal mitochondrial respiratory electron transfer site;
(b3) cymoxanil; (b4) compounds acting at the demethylase enzyme of the sterol biosynthesis pathway;
(b5) morpholine and piperidine compounds that act on the sterol biosynthesis pathway;
(b6) phenylamide fungicides;
(b7) pyrimidinone fungicides;
(b8) phthalimides; and (b9) fosetyl-aluminum.
DETAILS OF THE INVENTION As noted above, A is a substituted fused pyridinyl ring and B is a substituted phenyl or pyridinyl ring. The term "substituted" in connection with these A or B rings refers to groups that have at least one non-hydrogen substituent that does not extinguish the fungicidal activity. Examples of Formula I incorporating said A and B rings in which A is substituted with one or two substituents selected from R5 and B is substituted with from one to three substituents selected from R6 include the rings illustrated in Exhibit 1 wherein m is an integer from 1 to 2 and p is an integer from 1 to 3. Note that the attachment point between (R5)m and A and (R6)p and B is illustrated as floating, and (R5)m and (R6)p can be attached to any available carbon atom of the phenyl or pyridinyl rings.
Exhibit 1
Figure imgf000006_0001
Examples of R5 when attached to A and R6 when attached to B include each R5 and each R6 is independently CrC6 alkyl, C2-Cg alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, CrC6 haloalkyl, C2-C6 haloalkenyl, C2-C6 haloalkynyl,
C3-C6 halocycloalkyl, halogen, CN, CO2H, CONH2, NO2, hydroxy, CrC4 alkoxy, C1-C4 haloalkoxy, -C4 alkylthio, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl, C1-C4 haloalkylthio, Ci^ haloalkyteulfϊnyl, C1-C4 haloalkylsulfonyl, C1-C4 alkoxycarbonyl, C1-C4 alkylamino, C -Cg dialkylamino, C3-Cg cycloalkylamino, C2-Cg alkylcarbonyl, C -C6 alkoxycarbonyl, C -Cg alkylamino carbonyl, C3-C§ dialkylaminocarbonyl, C3-C6 trialkylsilyl; or each R5 and each R6 is independently a phenyl ring, a 5- or 6-membered heteroaromatic ring, a benzyl ring or a phenoxy ring, each ring optionally substituted with from one to three groups independently selected from R7; each R7 is independently C1-C4 alkyl, C2-C4 alkenyl, C2-C alkynyl, C3-C6 cycloalkyl, 0^4 haloalkyl, C2-C4 haloalkenyl, C2-C4 haloalkynyl, C3-Cg halocycloalkyl, halogen, CN, NO2, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylthio, C1-C4 alkylsulfinyl, 0^4 alkylsulfonyl C1-C4 alkoxycarbonyl, C1-C4 alkylamino, C2-Cg dialkylamino, C3-Cg cycloalkylamino, C3-C6
(alkyl)cycloalkylamino, C2-C4 alkylcarbonyl, C2-C6 alkoxycarbonyl, C2-Cg alkylaminocarbonyl, C3-C§ dialkylaminocarbonyl or C3-Cg trialkylsilyl. As noted above, R1 can be (among others) C^-Cg alkyl, C2-Cg alkenyl, C -Cg alkynyl or C3-Cg cycloalkyl, each optionally substituted. The term "optionally substituted" in connection with these R1 groups refers to R1 groups that are unsubstituted or have at least one non-hydrogen substituent that does not extinguish the fungicidal activity possessed by the unsubstituted analog. Examples of optionally substituted R1 groups are those that are optionally substituted by replacement of a hydrogen on a carbon atom of the R1 group with one or more (up to the total number of hydrogens available for replacement in any specific R1 group) substituents independently selected from the group consisting of halogen, CN, NO2, hydroxy, -C4 alkoxy, C1-C4 alkylthio, C1-C4 alkylsulfinyl, -C4 alkylsulfonyl, C2-C4 alkoxycarbonyl, C1-C4 alkylamino, C2-C8 dialkylamino and C3-Cg cycloalkylamino. Although these substituents are Usted in the examples above, it is noted that they do not need to be present since they are optional substituents. Of note are R1 groups optionally substituted with from one to five substituents.
Examples of N-oxides of Formula I are illustrated as 1-5 through 1-10 in Exhibit 2, wherein R1, R3, R5, R6, W, m and p are as defined above.
Exhibit 2
Figure imgf000007_0001
As noted above, each R5 and each R6 can be (among others) a phenyl ring, a 5- or 6-membered heteroaromatic ring, a benzyl ring or a phenoxy ring, each ring optionally substituted with from one to three groups independently selected from R7. The term "optionally substituted" in connection with these groups refers to groups which are unsubstituted or have at least one non-hydrogen substituent that does not extinguish the biological activity possessed by the unsubstituted analog. An example of a phenyl ring optionally substituted with one to three groups independently selected from R7 is the ring illustrated as Rx-56 in Exhibit 3, wherein x is either 5 or 6 and r is an integer from one to three. Examples of 5- or 6-membered heteroaromatic rings optionally substituted with one to three groups independently selected from R7 include the rings R -1 through Rx-55 illustrated in Exhibit 3, wherein x is either 5 or 6 and r is an integer from one to three. An example of a benzyl ring optionally substituted with one to three groups independently selected from R7 is the ring illustrated as Rx-57 in Exhibit 3, wherein x is either 5 or 6 and r is an integer from one to three. An example of a phenoxy ring optionally substituted with one to three groups independently selected from R7 is the ring illustrated as Rx-58 in Exhibit 3, wherein x is either 5 or 6 and r is an integer from one to three. ,
Although one to three R7 groups (represented as (R7)r) are shown, in the structures of Rx- 1 through Rx-58 , it is noted that they do not need to be present since they are optional substituents. The nitrogen atoms that require substitution to fill their valence are substituted with H or R7. Note that some Rx groups can only be substituted with less than three R7 groups (e.g. Rx-15, Rx-16, Rx-17 through R -20 and Rx-31 through Rx-33 can only be substituted with one R7). Note that when the attachment point between (R7)r and the Rx group is illustrated as floating, (R7)r can be attached to any available carbon atom of the Rx group.
Exhibit 3
Figure imgf000008_0001
Rx-1 Rx-2 Rx-3 Rx-4 Rx-5
Figure imgf000008_0002
Rx-6 Rx-7 Rx-8 Rx-9 Rx-10
Figure imgf000008_0003
Rx-ll Rx-12 R -13 Rx-14 R -15
Figure imgf000008_0004
-16 Rx-17 Rx-18 Rx-19 Rx-20
Figure imgf000009_0001
Rx-21 Rx-22 Rx-23 Rx-24 Rx-25
Figure imgf000009_0002
Rx-26 Rx-27 Rx-28 Rx-29 Rx-30
Figure imgf000009_0003
Rx-31 Rx-32 Rx-33 Rx-34 Rx-35
Figure imgf000009_0004
Rx- 6 R -37 Rx-38 R -39 Rx-40
Figure imgf000009_0005
Rx-41 Rx-42 Rx-43 R -44 Rx-45
Figure imgf000009_0006
Rx-46 Rx-47 Rx-48 Rx-49 Rx-50
Figure imgf000010_0001
Rx-51 Rx-52 Rx-53 Rx-54 Rx-55
Figure imgf000010_0002
Rx-56 R -57 Rx-58
As noted above, J is an optionally substituted linking chain of 2 to 5 members including at least one carbon member, optionally including one or two carbon members as C(=O), and optionally including one member selected from nitrogen and oxygen. The term "optionally substituted" in connection with the linking chain J refers to J-groups which are unsubstituted or have at least one non-hydrogen substituent that does not extinguish the biological activity possessed by the unsubstituted analog. Examples of optionally substituted J-groups include the J-groups illustrated in Exhibit 4. The J-groups in Exhibit 4 are illustrated such that the left end of the J-group is attached to the A-ring at the 3-position and the right end of the J-group is attached to the carbon atom bearing the N(R3)WB moiety.
The J-groups in Exhibit 4 can be optionally substituted by replacement of a hydrogen on a carbon atom or nitrogen atom of the J-group with one or more (up to the total number of hydrogens available for replacement in any specific J-group) substituents independently selected from the group consisting of Cχ-C2 alkyl, halogen, CN, NO2 and Cχ-C alkoxy. Although these substituents are listed, it is noted that they do not need to be present since they are optional substituents. Of note are J-groups optionally substituted with from one to four substituents selected from the group above.
Exhibit 4
— CH2CH2— -OCH2- -NHCH2-
— CH2CH CH — -OCH2CH2- -N(C!-C2alkyl)CH2-
-CH2CH2CH2CH2- - OCH CH2CH2— -NHCH2CH2-
~CH2CH2CH2CH2CH2— -CH2OCH2- -N(CrC2alkyl)CH2CH2-
-C(=O)NHC(=O)- -CH2OC(=O)- -CH2NHCH2-
-C(=O)N(Cι-C2alkyl)C(=O)- -CH2CH2OC(=O)- -CH2N(CrC2alkyl)CH2-
-CH2N(CrC2alkyl)C(=O)- -CH2NHC(=O)-
-CH2CH2N(CrC2alkyl)C(-O)- -CH2CH2NHC(=O)- 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, π-propyl, z'-propyl, or the different butyl, pentyl or hexyl isomers. "Alkenyl" includes straight chain or branched alkenes such as ethenyl, 1-propenyl, 2-propenyl, and the different butenyl, pentenyl and hexenyl isomers. "Alkenyl" also includes polyenes such as
1,2-propadienyl and 2,4-hexadienyl. "Alkynyl" includes straight chain or branched alkynes such as ethynyl, 1-propynyl, 2-propynyl and the different butynyl, pentynyl andhexynyl isomers. "Alkynyl" can also include moieties comprised of multiple triple bonds such as 2,5-hexadiynyl. "Alkoxy" includes, for example, methoxy, ethoxy, /z-propyloxy, isopropyloxy and the different butoxy, pentoxy and hexyloxy isomers. "Alkylthio" includes branched or straight chain alkylthio moieties such as methylthio, ethylthio, and the different propylthio, butylthio, pentylthio and hexylfhio isomers. "Alkylsulfinyl" includes both enantiomers of an alkylsulfinyl group. Examples of "alkylsulfinyl" include CH3S(O), CH3CH2S(O), CH3CH2CH2S(O), (CH3)2CHS(O) and the different butylsulfinyl, pentylsulfinyl and hexylsulfinyl isomers. Examples of "alkylsulfonyl" include CH3S(O)2, CH3CH2S(O)2, CH3CH2CH2S(O)2, (CH3)2CHS(O)2 and the different butylsulfonyl, pentylsulfonyl and hexylsulfonyl isomers. "Alkylamino", "dialkylamino" and the like, are defined analogously to the above examples. "Cycloalkyl" includes, for example, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The term "halogen", either alone or in compound words such as "haloalkyl", includes fluorine, chlorine, bromine or iodine. Further, when used in compound words such as "haloalkyl", said alkyl may be partially or fully substituted with halogen atoms which may be the same or different. Examples of "haloalkyl" include F3C, C1CH2, CF3CH and CF3CC12. The terms "haloalkenyl", "haloalkynyl", "haloalkoxy", "halo alkylthio", and the like, are defined analogously to the term "haloalkyl". Examples of "haloalkenyl" include (C1)2C=CHCH2 and CF3CH2CH=CHCH2. Examples of ' ialoalkynyl" include HC≡CCHCl, CF3C≡C, CC13C≡C and FCH2C≡CCH2. Examples of "haloalkoxy" include CF3O, CCl3CH2O, HCF2CH2CH2O and CF3CH2O. Examples of "haloalkylthio" include CC13S, CF3S, CC13CH2S and C1CH2CH2CH2S. Examples of "haloalkylsulfinyl" include CF3S(O), CCl3S(O), CF3CH2S(O) and CF3CF2S(O). Examples of "haloalkylsulfonyl" include CF3S(O)2, CCl3S(O)2, CF3CH2S(O)2 and CF3CF2S(O)2.
Examples of "alkylcarbonyl" include CH3C(=O), CH3CH2C(=O), CH3CH2CH2C(=O) and (CH3)2CHC(=O). Examples of "alkoxycarbonyl" include CH3OC(=O), CH3CH2OC(=O), CH3CH2CH2OC(=O), (CH3)2CHOC(=O) and the different butoxy- or pentoxycarbonyl isomers. Examples of "alkylaminocarbonyl" include CH3NHC(=O), CH3CH2NHC(=O), CH3CH2CH2NHC(=O), (CH3)2CHNHC(=O) and the different butylamino- or pentylamincarbonyl isomers. Examples of "dialkylaminocarbonyl" include (CH3)2NC(=O), (CH3CH2)2NC(=O), CH3CH2(CH3)NC(=O), CH3CH2CH2(CH3)NC(=O), (CH3)2CHN(CH3)C(=O) and the different butylamino- or pentylamincarbonyl isomers.
"Aromatic" indicates that each of the ring atoms is essentially in the same plane and has a >-orbital perpendicular to the ring plane, and in which (4n + 2) π electrons, when n is 0 or a positive integer, are associated with the ring to comply with Hϋckel's rule. The term "hetero" in connection with rings refers to a ring in which at least one ring atom is not carbon and which can contain 1 to 4 heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur, provided that each ring contains, no more than 4 nitrogens, no more than 2 oxygens and no more than 2 sulfurs. The t rms "heteroaromatic ring" includes fully aromatic heterocycles. The heterocyclic ring can be attached through any available carbon or nitrogen by replacement of a hydrogen on said carbon or nitrogen. The term "aryl" refers to aromatic hydrocarbon moieties including phenyl, tolyl and naphthalenyl which may be optionally substituted. The term "aralkyl" is an alkyl moiety substituted with an aryl moiety including phenylalkyls such as benzyl (which may be optionally substituted).
One skilled in the art will appreciate that not all nitrogen containing heterocycles can form N-oxides since the nitrogen requires an available lone pair for oxidation to the oxide; one skilled in the art will recognize those nitrogen containing heterocycles which can form N-oxides. One skilled in the art will also recognize that tertiary amines can form N-oxides. Synthetic methods for the preparation of N-oxides of heterocycles and tertiary amines are very well known by one skilled in the art including the oxidation of heterocycles and tertiary amines with peroxy acids such as peracetic and -chloroperbenzoic acid (MCPB A), hydrogen peroxide, alkyl hydroperoxides such as t-butyl hydroperoxide, sodium perborate, and dioxiranes such as dimethydioxirane. These methods for the preparation of N-oxides have been extensively described and reviewed in the literature, see for example:
T. L. Gilchrist in Comprehensive Organic Synthesis, vol. 7, pp 748-750, S. V. Ley, Ed., Pergamon Press; M. Tisler and B. Stanovnik in Comprehensive Heterocyclic Chemistry, vol. 3, pp 18-20, A. J. Boulton and A. McKillop, Eds., Pergamon Press; M. R. Grimmett and B. R. T. Keene in Advances in Heterocyclic Chemistry, vol. 43, pp 149-161, A. R. Katritzky, Ed., Academic Press; M. Tisler and B. Stanovnik in Advances in Heterocyclic Chemistry, vol. 9, pp 285-291, A. R. Katritzky and A. J. Boulton, Eds., Academic Press; and G. W. H. Cheeseman and E. S. G. Werstiuk in Advances in Heterocyclic Chemistry, vol.22, pp 390-392, A. R. Katritzky and A. J. Boulton, Eds., Academic Press.
The total number of carbon atoms in a substituent group is indicated by the " -Cj" prefix where i and j are numbers from 1 to 8. For example, CrC alkylsulfonyl designates methylsulfonyl through propylsulfonyl; C2-C8 dialkylamino designates, for example, (CH3)2Ν, (CH3CH2)2N, CH3CH2(CH3)N, CH3CH2CH2(CH3)N or (CH3)2CHN(CH3) containing a total of from 2 to 8 carbon atoms. When a compound is substituted with a substituent bearing a subscript that indicates the number of said substituents can exceed 1, said substituents (when they exceed 1) are independently selected from the group of defined substituents. Further, when the subscript indicates a range, e.g. (R)j_j, then the number of substituents may be selected from the integers between i and j inclusive.
The term "optionally substituted with from one to three substituents" and the like indicates that from one to three of the available positions on the group may be substituted. When a group contains a substituent which can be hydrogen, for example R1 or R2 then, when this substituent is taken as hydrogen, it is recognized that this is equivalent to said group being unsubstituted.
Compounds involved in this invention can exist as one or more stereoisomers. The various stereoisomers include enantiomers, diastereomers, atropisomers and geometric isomers. One skilled in the art will appreciate that one stereoisomer may be more active and/or may exhibit beneficial effects when enriched relative to the other stereoisomer(s) or when separated from the other stereoisomer(s). Additionally, the skilled artisan knows how to separate, enrich, and/or to selectively prepare said stereoisomers. Accordingly, the present invention comprises compounds selected from Formula I, N-oxides and agriculturally suitable salts thereof. The compounds may be present as a mixture of stereoisomers, individual stereoisomers, or as an optically active form. In particular, since R1 and J of Formula I are different, then said formula possesses a chiral center at the carbon to which they are commonly bonded. This invention comprises racemic mixtures of equal parts of Formula F and Formula I".
Figure imgf000013_0001
wherein A, B, J, W, R1 R2, and R3 are as defined above. In addition, this invention includes compounds and compositions that are enriched in an enantiomer of the Formula I' or Formula I" compared to the racemic mixture. Included are compounds and compositions involving the essentially pure enantiomers of Formula I' or Formula I". For example, this invention includes compounds of Formula I that are enriched in an enantiomer of the Formula F compared to the racemic mixture. Included are the essentially pure enantiomers of Formula F . This invention also includes compositions wherein component (a) is enriched in a component (a) enantiomer of Formula I" compared to the racemic rnixture. This invention also includes compounds of Formula I that are enriched in an enantiomer of the Formula I" compared to the racemic mixture. Included are the essentially pure enantiomers of Formula I". This invention also includes compositions wherein component (a) is enriched in a component (a) enantiomer of Formula I" compared to the racemic mixture.
When enantiomerically enriched, one enantiomer is present in greater amounts than the other and the extent of enrichment can be defined by an expression of enantiomer excess ("ee"), which is defined as 100(2x-l) where x is the mole fraction of the dominant enantiomer in the mixture, (e.g., an ee of 20% corresponds to a 60:40 ratio of enantiomers). Preferably there is 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 isomer. Of particular note are enantiomerically pure embodiments of the more active isomer.
The salts of the compounds of the invention include acid-addition salts with inorganic or organic acids such as hydrobromic, hydrochloric, nitric, phosphoric, sulfuric, acetic, butyric, fumaric, lactic, maleic, malonic, oxalic, propionic, salicylic, tartaric, 4-toluenesulfonic or valeric acids. The salts of the compounds of the invention also include those formed with organic bases (e.g., pyridine, ammonia, or triethylamine) or inorganic bases (e.g., hydrides, hydroxides, or carbonates of sodium, potassium, hthium, calcium, magnesium or barium) when the compound contains an acidic group such as a carboxylic acid or phenol. This invention provides 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 compound of Formula I including all geometric and stereoisomers, N-oxides and agriculturally suitable salts thereof (e.g. as a component of a composition described herein). Preferred methods for reasons of better activity and/or ease of synthesis are:
Preferred 1. Preferred are methods comprising compounds of Formula I wherein
A is taken together with Ν-C=C to form a fused pyridinyl ring substituted with one or two substituents independently selected from R5; B is substituted with from one to three substituents independently selected fromR6;
J is a linking chain of 2 to 5 members including at least one carbon member, optionally including one or two carbon members as C(=O), and optionally including one member selected from nitrogen or oxygen, optionally substituted with one or more substituents selected from the group consisting of Cι-C alkyl, halogen, CN, NO2 and
Figure imgf000014_0001
alkoxy;
R1 is H; or Cj-Cg alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C3-C6 cycloalkyl, each optionally substituted with one or more substituents selected from the group consisting of halogen, CN, NO2, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, C -C4 alkylsulfinyl, -C4 alkylsulfonyl, C2-C4 alkoxycarbonyl, C1-C4 alkylamino, C2-Cg dialkylamino and C3-Cg cycloalkylamino; each R5 and each R6 is independently Cι-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C|-Cg haloalkyl, χ-C6 haloalkenyl, C -C^ haloalkynyl, C3-C6 halocycloalkyl, halogen, CN, CO2H, CONH2, NO2, hydroxy, C1-C4 alkoxy, Cχ-C4 haloalkoxy, C1-C4 alkylthio, Ci -C4 alkylsulfinyl, C1-C4 alkylsulfonyl, C1-C4 haloalkylthio, C1-C4 haloalkylsulfinyl, C1-C4 halo alkylsulfonyl, C1-C4 ^lkoxycarbonyl, C-1-C4 alkylamino, C2-Cg dialkylamino, C3-Cg cycloalkylamino, C2-Cg alkylcarbonyl, C2-Cg alkoxycarbonyl, C2-C6 alkylaminocarbonyl, C3-Cg dialkylaminocarbonyl, C3-Cg trialkylsilyl; or each R5 and each R6 is independently a phenyl ring, a 5- or 6-membered heteroaromatic ring, a benzyl ring or a phenoxy ring, each ring optionally substituted with from one to three groups independently selected from R7; and each R7 is independently C2-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-Cg cycloalkyl, C\ -C4 haloalkyl, C2-C4 haloalkenyl, C2-C4 haloalkynyl, C3-Cg halocycloalkyl, halogen, CN, NO2, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylthio, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl
C1-C4 alkoxycarbonyl, C1-C4 alkylamino, C2-Cg dialkylamino, C3-Cg cycloalkylamino, C3-C6 (alkyl)cycloalkylamino, C2-C4 alkylcarbonyl, C2-Cg alkoxycarbonyl, C2-Cg alkylaminocarbonyl, C3-Cg dialkylaminocarbonyl or C3-Cg trialkylsilyl. Of note are methods of Preferred 1 wherein each R5 and each R6 is independently CrC6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, Cj-Cg haloalkyl, C2~C6 haloalkenyl, C2-C6 haloalkynyl, C3-C6 halocycloalkyl, halogen, CN, CO2H, CONH2, NO2, hydroxy, CrC4 alkoxy, CrC4 haloalkoxy, C1-C4 alkylthio, C^-C^ alkylsulfinyl, C^ alkylsulfonyl, C1-C4 haloalkylthio, C!-C4 haloalkylsulfinyl, CrC4 haloalkylsulfonyl, -C4 alkoxycarbonyl, CrC4 alkylamino, C2-C8 dialkylamino, C3-C6 cycloalkylamino, C2-C6 alkylcarbonyl, C2-C6 alkoxycarbonyl, C2-C6 alkylaminocarbonyl, C3-Cg dialkylaminocarbonyl, C3-C6 trialkylsilyl; or each R5 and each R6 is independently phenyl, benzyl or phenoxy, each optionally substituted with CrC4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl, CrC4 haloalkyl, C2-C4 haloalkenyl, C2-C haloalkynyl, C^-Cβ halocycloalkyl, halogen, CN, NO2, CrC4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylthio, CrC4 alkylsulfinyl, C1-C4 alkylsulfonyl C1-C4 alkoxycarbonyl, C1.-C4 alkylamino, C2-C8 dialkylamino, C3-C6 cycloalkylamino, C3-C6 (alkyl)cycloalkylamino, C2-C alkylcarbonyl, C2-C6 alkoxycarbonyl, C2-C6 alkylaminocarbonyl, C3-C8 dialkylaminocarbonyl or C -C trialkylsilyl. Preferred 2. Methods of Preferred 1 wherein W is C=O.
Preferred 3. Methods of Preferred 2 wherein
J is selected from -CH2CH2- -CH2CH2CH2-, -CH2CH2CH2CH2-, -OCH2- -OCH2CH2-, -OCH2CH2CH2-, -CH2NHCH2- -CH2N(CrC2 alkyl)CH2-,-CONHCO- and -CON(CrC2 alkyl)CO-; and each R5 and each R6 is independently Ci-Cg alkyl, C2-C6 alkenyl, C2-Cg alkynyl, C3-Cg cycloalkyl, C Cg haloalkyl, C2-Cg haloalkenyl, C2-Cg haloalkynyl, C3-Cg halocycloalkyl, halogen, CN, NO2, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylthio, -C4 alkylsulfinyl, C1-C4 alkylsulfonyl, C1-C4 haloalkylthio, C1-C4 haloalkylsulfinyl, C1-C4 haloalkylsulfonyl, C1-C4 alkoxycarbonyl, C2-Cg alkylcarbonyl, C2-Cg alkoxycarbonyl, C -Cg alkylaminocarbonyl or C -Cg dialkylaminocarbonyl. Preferred 4. Methods of Preferred 3 wherein each R5 is independently halogen, CN, NO2, CrC2 alkyl, CrC2 haloalkyl, CrC2 alkoxy, CrC2 haloalkoxy, CrC2 alkylthio, C]-C alkylsulfinyl and Cι-C2 alkylsulfonyl, Cι-C2 haloalkylthio, Cι-C2 haloalkylsulfinyl Cι~C2 haloalkylsulfonyl, C2-C4 alkoxycarbonyl or C2-C4 alkylaminocarbonyl. Of note are methods of Preferred 4 wherein R5 is CH3, CI, Br, I, CN, NO2, CF3, CO2CH3, CONHCH3CH3, OCF3, OCHF2, OCH2CF3, OCF2CF3, OCF2CF2H, OCHFCF3, SCF3, SCHF2, SCH2CF3, SCF2CF3, SCF2CF2H, SCHFCF3, SOCF3, SOCHF2, SOCH2CF3, SOCF2CF3, SOCF2CF2H, SOCHFCF3, SO2CF3, SO2CHF2, SO2CH2CF3, SO2CF2CF3, SO2CF2CF2H or SO2CHFCF3.
Preferred 5. Methods of Preferred 4 wherein B is a phenyl ring optionally substituted with from one to three substituents independently selected from R6.
Preferred 6. Methods of Preferred 5 wherein each R6 is independently Cι-C2 alkyl, Cι_-C2 haloalkyl, halogen, CN, Cι~C alkoxy, C1 -C haloalkoxy, Cι~C2 alkylthio, Cι-C2 alkylsulfinyl or C1-C2 alkylsulfonyl and at least one R6 is located in a position ortho to the link with W. Of note are methods of Preferred 6 wherein there is an R6 at each position ortho to the link with W, and optionally 1 to 2 additional R6 and R6 is either halogen or methyl. Preferred 7. Methods of Preferred 6 wherein J is -CH2CH2- or -CH2CH2CH2-. Preferred 8. Methods of Preferred 7 wherein each R5 is independently CH3, CI, Br, I, CN, NO2, CF3, OCF3, OCHF2, SCF3, SCHF2, CO2CH3 or CONHCH3. Of note are methods of Preferred 8 wherein R5 is CH3, CI, Br, CN, NO2, CF3, CO2CH3 or CONHCH3. Preferred 9. Methods of Preferred 4 wherein B is a 3-pyridinyl or a 4-pyridinyl ring optionally substituted with from one to three substituents independently selected fromR6. Preferred 10. Methods of Preferred 9 wherein eachR6 is independently Cj-C2 alkyl, C]_-C haloalkyl, halogen, CN, Cι-C alkoxy, C1-C2 haloal oxy, Cι-C2 alkylthio, C1-C2 alkylsulfinyl or CrC2 alkylsulfonyl and at least one R6 is located in a position ortho to the link with W. Preferred 11. Methods of Preferred 10 wherein J is -CH2CH2- or -CH2CH2CH2-. Preferred 12. Methods of Preferred 11 wherein each R5 is independently CH3, CI, Br, I, CN, NO2, CF3, OCF3, OCHF2, SCF3, SCHF2, CO2CH3 or CONHCH3. Of note are methods of Preferred 12 wherein R5 is CH , CI, Br, CN, NO2, CF3 ,
CO2CH3 or CONHCH3.
Preferred 13. Methods of Preferred 12 wherein B is a 3-pyridinyl ring wherein one R6 is CI located at the 2-position ortho to the link with G=O, another R6 is selected from CI or methyl and is located at the 4-position ortho to the link with C=O and a third optional R6 is methyl at the 6-position.
Preferred 14. Methods of any of Preferred 2 through Preferred 13 wherein R1 is H and R3 is H. Specifically preferred are the methods comprising a compound selected from the group consisting of 2-chloro-6-methoxy-N-(5,6,7,8-tetiahydro-3-methyl-8-quinolinyl)-4- pyridinecarboxamide,
2,6-dicMoro-N-(5,6,7,8-te1xahydro-3-methyl-8-qumolmyl)benzamide and 2,3,6-1rifluoro-N-(5,6,7,8-tefrahydro-3-methyl-8-qumolmyl)benzamide. This invention also relates to fungicidal compositions comprising fungicidally effective amounts of the compounds of Formula I. The preferred compositions of the present invention are those which comprise the compounds recited in Preferred 1 through Preferred 14 above.
This invention also includes compounds of Formula I including all geometric and stereoisomers, N-oxides and agriculturally suitable salts thereof, provided that when B is a substituted phenyl ring, W is C=O or SO2, R3 is H and J is a saturated chain of from 2 to 4 carbons that is either unsubstituted or substituted with from one to three substituents selected from the group consisting of alkyl, alkoxy, aryl or aralkyl, then the compounds are N-oxides. Preferred compounds are those recited in Preferred 1 through Preferred 14 above, subject to the proviso above.
A specifically preferred compound is 2-chloro-6-methoxy-N-(5,6,7,8-tetrahydro-3- methyl- 8 -quinolinyl)-4-pyridinecarboxamide. The compounds of Formula I can be prepared by one or more of the following methods and variations as described in Schemes 1-19. Compounds of Formulae la, lb and Ic are subsets of the compounds of Formula I, and all substituents for Formulae la, lb and Ic are as defined above for Formula I. The definitions of A, B, J, L, W, R1 through R6 andm in the compounds of Formulae 1-19 below are as defined above. Compounds,of Formula la-e, 6a-c, 8a-f, lOa-c, l la-c, 16a-b, 18a-d and 19a-b are subsets of Formula 1, 6, 8, 10, 11, 16, 18 and 19 respectively. J1 through J6 in the formulae below are subsets of J.
As illustrated in Scheme 1 , the compounds of Formula la are prepared by treating amine or amine salts of Formula 1 with an appropriate acid chloride in an inert solvent with two molar equivalents of a base (e.g. triethylamine (Et Ν), polymer supported diisopropylethylamine or potassium carbonate) present. Similarly, compounds of
Formula lb are prepared by treating amine or amine salts of Formula 1 with an appropriate sulfonyl chloride in an inert solvent with two molar equivalents of a base (e.g. triethylamine, polymer supported diisopropylethylamine or potassium carbonate) present. Suitable solvents are selected from the group consisting of ethers such as tettahydrofuran, dimethoxyethane, or diethyl ether; hydrocarbons such as toluene or benzene; and halocarbons such as dichloromethane or chloroform.
Scheme 1
Figure imgf000018_0001
lb
Alternatively, compounds of Formula la can be synthesized by reacting the amine or amine salts of Formula 1 with an appropriate carboxylic acid in the presence of an organic dehydrating reagent such as 1,3-dicyclohexylcarbodiimide (DCC) or l-[3- (Dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDC) as depicted in Scheme 2. Suitable solvents are selected from the group consisting of ethers such as tetrahydrofuran, dimethoxyethane, or diethyl ether; hydrocarbons such as toluene or benzene; and halocarbons such as dichloromethane or chloroform.
Scheme 2
Figure imgf000019_0001
la
Intermediate amine la, a compound of Formula 1 wherein A is a 2-pyridyl ring bearing the indicated substituents, J1 is -(CH2)q-, q is 1, 2, 3 or 4 and R1 and R3 are both hydrogen, can be prepared from the commercially available pyridines of Formula 2 (Scheme 3). As shown in Scheme 3, the CH2 attached ortho to the pyridine nitrogen atom of Formula 2 can be substituted with NH2 by a sequence of steps comprising hydrogen peroxide oxidation, acylation, hydrolysis, chlorination, azide displacement and reduction (e.g. catalytic hydrogenation using H2 and palladium on carbon as catalyst) in procedures analogous to those found in WO00/56729 to provide the amine la.
Scheme 3
1) K2CQ , methanol
2) CH3S02C1, triethylamine
Figure imgf000019_0002
Figure imgf000019_0003
J is (CH2)q and q is 1, 2, 3 or 4
Compounds of Formula lb wherein J2 is -CH2O-, -CH2CH2O-, -CH2NH-, -CH2CH2NH-, -CH2N(CrC2 alkyl)-, -CH2CH2N(CrC2 alkyl)-, -CONH- or -CH2N(Cι~C2alkyl)- can be synthesized by intramolecular displacement using compounds of Formula 6 in the presence of a strong base such as sodium hydride in a polar, aprotic solvent such as NJV-dimethylformamide followed by heating in acidic medium as shown in Scheme 4. Similar intermolecular displacements with 2,3-dichloro-substituted pyridines are reported in WO99/42447. The groups enumerated for J2 may also be optionally substituted with one or more (up to the total number of hydrogens available for replacement in any specific J- group) substituents independently selected from the group
Figure imgf000020_0001
alkyl (e.g. CH(CH3)O, C(CH3)2O, or CH(CH2CH3)O), halogen, CΝ, ΝO2 and CrC2 alkoxy.
Scheme 4
Figure imgf000020_0002
6 CH2CH2N(CrC2 alkyl) or CON(CrC2 alkyl)
7
J may be optionally subsUtuted
Alternatively, compounds of Formula 1 c (wherein A and J are as previously defined and R1 is hydrogen) can be prepared by treating compounds of Formula 7 with isoamyl nitrite and a base such as potassium t-butoxide (t-BuOK) followed by reduction of the resulting oximes of Formula 8 (Scheme 5). The reduction can be accomplished, for example, with hthium aluminum hydride, zinc and acetic acid, or catalytic hydrogenation. (See Jerry March, Advanced Organic Chemistry: Reactions, Mechanism and Structure, Third Edition, John Wiley & Sons, New York, 1985, p 1105 for leading references for reduction of oximes).
Scheme 5
Figure imgf000020_0003
lc
Alternatively, compounds of Formula lc (wherein A and J are defined and R1 is hydrogen) can be prepared by reductive amination of compounds of Formula 9 as shown in Scheme 6. Many methods for reductive amination have been reported. For some leading references, see Jerry March, Advanced Organic Chemistry: Reactions, Mechanism and Structure, Third Edition, John Wiley & Sons, New York, 1985, pp. 798-800.
Scheme 6
Figure imgf000021_0001
lc
Compounds of Formula 6a wherein J2 is optionally substituted -CH2O- or -CH CH O- can be prepared by transesterification of N-(diphenylmethylene)glycine esters of Formula 9 with the corresponding alcohols of Formula 10 under basic conditions (Scheme 7). Compounds of Formula 6b wherein J2 is optionally substituted -CH2ΝH-, -CH2CH2NH-, -CH N(Cι -C alkyl)- or -CH CH N(Cι-C2 alkyl)- can be prepared by amidation of N-(diphenylmethylene)glycine esters of Formula 9 with the corresponding amines of Formula 11. Compounds of Formula 6 wherein J2 is optionally substituted -COΝH- or -COΝ(Cj-C2alkyl) can be prepared by amidation of N-(diphenylmethylene)glycine esters of Formula 9 with the corresponding amides of Formula 15.
Scheme 7
Figure imgf000021_0002
CH2N(CrC2 alkyl) or CH2CH2N(CrC2 alkyl
2 3 6c J2 is CONHR8
J and J may be optionally substituted
R8 is HorCι-C2 alkyl
As illustrated in Scheme 8, compounds of Formula 10a wherein J3 is optionally substituted -CH2OH can be prepared by ortho-lithiation of a compound of Formula 12 followed by reaction with an aldehyde or aldehyde synthon (e.g. paraformaldehyde) or ketone. Similarly, compounds of Formula 10b wherein J3 is optionally substituted -CH CH OH can be prepared by ortho-lithiation followed by reaction with an epoxide. Ortho-litiations can be accomphshed by treatment of the substrate with a strong hthium base such as hthium diisopropylamide (LDA) and are typically carried out at reduced temperatures. Suitable solvents are selected from the group consisting of ethers such as tetrahydrofuran, dimethoxyethane, or diethyl ether and hydrocarbons such as hexane, heptane or ethylbenzene.
As illustrated in Scheme 9, compounds of Formula 10c wherein J3 is -CH OH also can be prepared by ortho-lithiation of a compound of Formula 12 and reactipn with carbon dioxide to provide a compound of Formula 13, followed by reduction using hthium aluminum hydride (LAH) in a suitable solvent such as toluene. Some isonicotinic acids of Formula 13 may be available commercially.
Scheme 8
Figure imgf000022_0001
Q 1 and Q 2 are independently H or C!-C2 alkyl 10b
As illustrated in Scheme 9, compounds of Formula 10c wherein J3 is -CH OH also can be prepared by ortho-lithiation of a compound of Formula 12 and reaction with carbon dioxide to provide a compound of Formula 13, followed by reduction using hthium aluminum hydride (LAH) in a suitable solvent such as toluene. Some isonicotinic acids of Formula 13 may be available commercially.
Scheme 9
Figure imgf000022_0002
Compounds of Formula 11a can be synthesized from nitriles of Formula 14 by reduction of the nitrile using hthium aluminum hydride (LAH) in a suitable solvent such as toluene to give the corresponding aminomethyl intermediates (Scheme 10). Compounds of Formula 11a can also be synthesized from primary amides of Formula 15 wherein R8 is H by reduction using hthium aluminum hydride (LAH) in a suitable solvent such as toluene. Compounds of Formula 1 lb can be synthesized from secondary amides of Formula 15 wherein R8 is Cι~C alkyl by reduction using hthium aluminum hydride (LAH) in a suitable solvent such as toluene. Compounds of Formula 1 lb can also be synthesized by reductive -unination of formaldehyde or acetaldehyde with compounds of Formula 11a. Reductive amination with formaldehyde can be accomplished in the presence of formic acid under Eschweiler-Clarke procedures (see Jerry March, Advanced Organic Chemistry: Reactions, Mechanism and Structure, Third Edition, John Wiley & Sons, New York, 1985, pp. 798-800 and references therein).
Scheme 10
Figure imgf000023_0001
Compounds of Formula 15 may be prepared from compounds of Formula 13 by conversion to the corresponding acid chloride and subsequent reaction with ammonia or a primary amine (Scheme 11). Methods of converting carboxylic acids to the corresponding acid chloride are well-known in the art and include, for example, treatment with thionyl chloride or oxalyl chloride. The acid chloride is treated with the amine or amine salt in an inert solvent with two molar equivalents of a base (e.g. triethylamine, polymer supported dhsopropylethylamine or potassium carbonate) present. Suitable solvents are selected from the group consisting of ethers such as tetrahydrofuran, dimethoxyethane, or diethyl ether; hydrocarbons such as toluene or benzene; and halocarbons such as dichloromethane or chloroform. Alternatively, compounds of Formula 15 can be synthesized by reacting the appropriate amine or amine salt with a carboxylic acid of Formula 13 in the presence of an organic dehydrating reagent such as 1,3-dicyclohexylcarbodiimide (DCC) or l-[3- (Dimethylammo)propyl]-3-e1hylcarbooUimide hydrochloride (EDC). Suitable solvents are selected from the group consisting of ethers such as tetrahydrofuran, dimethoxyethane, or diethyl ether; hydrocarbons such as toluene or benzene; and halocarbons such as dichloromethane or chloroform.
Scheme 11
Figure imgf000024_0001
Alternatively, compounds of Formula 1 la can be synthesized by reacting compounds of Formula 16, wherein LG is a leaving group such as Br, CI, methanesulfonyl (-OSO Me) or para-toluenesulfonyl (-OSO -p-Tol), with ammonia in a protic solvent such as methanol (Scheme 12). Compounds of Formula 11a can also be prepared by reacting compounds of Formula 16 with a potassium salt of phthalimide followed by reaction with either aminoethanol or hydrazine in an alcohol solvent to provide the desired aminomethyl intermediates Formula 11a.
Scheme 12
a
Figure imgf000024_0002
LG is CI, Br, -OS02Me, -OSO2-P-T0I
As illustrated in Scheme 13, compounds of Formula 16 wherein LG is -OSO2Me or -OSO -p-Tol (16a) can be prepared by reacting a compound of Formula 10c with the corresponding sulfonyl chloride in the presence of a base such as triethylamine, polymer supported diisopropylethylamine or potassium carbonate. Suitable solvents are selected from the group consisting of ethers such as tetrahydrofuran, dimethoxyethane, or diethyl ether; hydrocarbons such as toluene or benzene; and halocarbons such as dichloromethane or chloroform. Compounds of Formula 16 wherein LG is Br or CI (16b) can be prepared by treatment of compounds of Formula 17 with halogenating agents such as bromine, chlorine, or N-halosuccinimides under free radical conditions. These transformations are typically carried out with activation by visible or ultraviolet light (hv) and peroxides and are well known in the art.
Scheme 13
Figure imgf000025_0001
LG is -OS02Me or -OSO2-P-T0I
Figure imgf000025_0002
Compounds of Formula l ie can be prepared from compounds of Formula 16 by displacement with cyanide followed by reduction with, for example, hthium aluminum hydride (Scheme 14).
Scheme 14
Figure imgf000025_0003
Compounds of Formula 8 can be prepared by intramolecular free-radical acylation of compounds of Formula 18 (Scheme 15). These acylations can be carried out in the presence of t-butyl hydroperoxide, sulfuric acid and ferrous sulfate (see Chem. Communications, 1969, 201 and Gazz. Chun. ltd. 1977, 107, 491 for leading references). Scheme 15
Figure imgf000026_0001
18 8
Compounds of Formula 18 wherein J is OCH2 orNHCH2 (18a or 18b respectively) can be prepared by alkylation of compounds of Formula 19 with bromoacetaldehyde diethyl acetal followed by acidic hydrolysis of the acetal protecting group (Scheme 16). Compounds of Formula 18 wherein J is OCH2CH2 orNHCH2CH2 (18c or 18d respectively) can be prepared by Michael addition of acrolein by compounds of Formula 19.
Scheme 16
Figure imgf000026_0002
Compounds of Formula 8 wherein J is N(CrC2 alkyl)CH2 or N(CrC2 alkyl)CH2CH2
(8e and 8 f respectively) can be prepared by alkylation of compounds of Formula 8b or 8d (Scheme 17) with alkylating agents such alkyl halides such as methyl or ethyl iodide or dialkylsulfonates such as dimethylsulfate, typically in the presence of additional base such as sodium or potassium carbonate. Scheme 17
Figure imgf000027_0001
8a JJ is OCH2 8e JD is N(Cι-C2 alkyl)CH2 8b J5 is NHCH2 8f J5 is N(Cι-C2 alkyl)CH2CH2 8c J5 is OCH2CH2 8d J5 is NHCH2CH2 LG1 is CI, Br, I, -OS02Me, -OS02-p-Tol
Compounds of Formula le wherein J6 is CH2NHCH2 or CH2N(C C2 alkyl)CH2 can be prepared by reduction of compounds of Formula Id by hthium aluminum hydride (Scheme 18).
Scheme 18
Figure imgf000027_0002
Id le
J6 is CH2NH or CH2CH2NH
Compounds of Formula Ic (compounds in which W is C=L and L is S) can be synthesized as outlined in Scheme 19. Amides of Formula la shown below can be converted to thioamides of Formula Ic by contacting the amide with Lawesson's reagent or phosphorus pentasulfide in an appropriate solvent (for references, see Jerry March, Advanced Organic Chemistry: Reactions, Mechanism and Structure, Fourth Edition, John Wiley & Sons, New York, pp. 893-4).
Scheme 19
Figure imgf000027_0003
la
Ic
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 t e 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, organometaUic, 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 Example is, therefore, to be construed as merely illustrative, and not limiting of the disclosure in any way whatsoever. The starting material for each of the reaction steps of this Example may not have necessarily been prepared by a particular preparative run whose procedure is described in other steps. 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 is singlet, d is doublet, t is triplet, q is quartet, m is multiplet, dd is doublet of doublets, dt is doublet of triplets, br s is broad singlet. Example 1
Preparation of 2.6-dicMoro-N-f5.6.7.8-tettahydro-3-methyl-8-quinoliny^benzamide Step A: Preparation of 5.6.7.8-teteahydro-3-methylqukoline
At 0 °C, 3-methyl quinoline (20 g, 140mmol) was dissolved in trifluoroacetic acid (80 mL) and 10 weight % palladium on carbon (10 g) was added. The mixture was treated with hydrogen at room temperature at 345 kPa (50 psi) of H2 in a Parr shaker apparatus for 5 hours. The resulting mixture was filtered through a Celite® (SiO2 filter agent) bed to remove the catalyst. The Celite®/charcoal bed was washed with methanol (2 x 20 mL). The filtrates were then concentrated in vacuo. The residue was partitioned between 2 Ν aqueous ΝaOH and diethyl ether. The combined organic extracts were dried (Νa SU4) and concentrated to give the title compound (19 g). *H NMR (CDC13) δ: 8.17 (s,lH), 7.15 (s,lH), 2.87 (t, J = 6.2 Hz,2H), 2.72 (t, J = 6.4 Hz,2H), 2.25 (s,3H), 1.86 (m,2H), 1.80 (m,2H). Step B: Preparation of 5.6.7.8-tettahydro-3-melhyl-8-qu olinyl acetate
A solution of 5,6,7,8-tetrahydro-3-methylquinoline (39.1 g, 266 mmol) in acetic acid (130 L) was treated with 30% aqueous H2O (26 mL) at room temperature, and the resulting reaction mixture was heated to 70 °C for 6 hours. An additional portion of 30% H2O (26 mL) was added, and the mixture was heated to 70 °C overnight. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was dissolved in dichloromethane and treated with Na CO (87 g). After 1 hour, the mixture was filtered and washed with dichloromethane. The filtrate was concentrated in vacuo to give a semi-sohd oil. . A solution of the semi-sohd oil in acetic anhydride (200 mL) was heated to 90 °C overnight. The reaction mixture was cooled to room temperature and the acetic anhydride was removed in vacuo. Distillation of the residue under reduced pressure provided the title compound (49 g). NMR
Figure imgf000029_0001
4.4 Hz,lH), 2.8 (m,2H), 2.31 (s,3H), 2.10 (s,3H), 2.18 - 1.77 (m,4H). Step C: Preparation of 8-chloro-5.6.7.8-tetrahydro-3-methylquinoline
A suspension of 5,6,7,8-tetrahydro-3-methyl-8-quinolinyl acetate (49 g, 195 mmol) and K2CO (100 g) in methanol (250 mL) was stirred at room temperature overnight. The mixture was partitioned between water and dichloromethane. The combined organic extract was dried (Na2SO4) and concentrated. The residue was purified by flash chromatography on silica gel (using a gradient of 10% to 60% ethyl acetate in hexanes as eluent) to give a hght brownish oil (24 g).
Methanesulfonyl chloride (25.6 g) was added slowly to a solution of the oil (24 g) and triethylamine in dichloromethane (150 mL) at 0 °C. The reaction mixture was slowly warmed up to room temperature and then heated to reflux overnight. The mixture was cooled to room temperature and partitioned between water and dichloromethane. The combined organic extract was dried (Na2SO4) and concentrated. The residue was purified by flash chromatography on silica gel (using a gradient of 10% to 60% ethyl acetate in hexanes as eluent) to give the title compound as a light yellowish oil (21.8 g). iHNMR (CDC13) δ: 8.31 (s,lH), 7.24 (s,lH), 5.29 (t, J = 3.0 Hz,lH), 2.81 (m,lH), 2.37 (m,lH), 2.30 (s,3H), 2.19 (m,2H), 1.88 (m,lH).
Step D: Preparation of 5.6.7.8-tetrahydro-3-methyl-8-quinolinaminR
A suspension of 8-chloro-5,6,7,8-tetrahydro-3-methylquinoline (21.8 g) and sodium azide (15.6 g) was heated to 70 °C. for 4 hours. The reaction mixture was cooled to room temperature and partitioned between water and diethyl ether. The combined organic extract was dried (Na2SO4) and concentrated. The residue (17.2 g) was dissolved in methanol (170 L) and 10 weight % palladium on carbon (1.73 g) was added. The mixture was treated with hydrogen at room temperature at 276 kPa (40 psi) H2 in a Parr shaker apparatus for 4 hours. The resulting mixture was filtered through a Cehte® bed. The Celite®/charcoal bed was washed with methanol (2 x 10 mL). The filtrates were then concentrated in vacuo to give (13 g) of the title compound. *HNMR (CDC13) δ: 8.32 (s,lH), 7.27 (s,lH), 4.69 (t, J = 4.1 Hz,lH), 2.75 (m,2H), 2.31 (s,3H), 2.01-1.78 (m,4H). Step E: Preparation of 2.6-dichloro-N-(5.6.7.8-tetrahydro-3-methyl-8- qumolinyl)benzamide
A suspension of 5,6,7,8-tefrahyά :o-3-methyl-8-quinolinamine (162 mg, 1 mmol), 2,6-dichlorobenzoyl chloride (209.5 mg, 1 mmol) and polymer-supported diisopropylethylamine (1.0 g, 3 mmol/g) in acetonitrile (5 mL) was shaken at room temperature overnight. The reaction mixture was filtered and the solids, washed with acetonitrile (2 x 2 mL). The filtrate was concentrated and the resulting residue was purified by flash chromatography on silica gel (using a gradient of 10% to 60% ethyl acetate in hexanes as eluent) to give the title compound, a compound of the invention (190 mg). *H ΝMR (CDC13) δ: 8.22 (s,lH), 7.30 (s,lH), 7.36-7.23 (m,3H), 6.99 (bs,lH), 5.03 (m,lH), 2.82 (m,3H), 2.29 (s,3H), 1.94 (m,3H). By the procedures described herein together with methods known in the art, the following compounds of Tables 1-8 can be prepared. The following abbreviations are used in the Tables that follow: "Me" means methyl, "OMe" means methoxy, "SMe" means methylthio, "CΝ" means cyano, "ΝO2" means nitro, "S(O)Me" means methylsulfinyl, and "S(O) Me" means methylsulfonyl. The substituents M and R are equivalent to independent R5 substituents that have been located in the positions indicated. The substituents T, U and V are equivalent to independent R6 substituents that have been located in the positions indicated.
Table 1
Figure imgf000030_0001
T U V T U V T U V T U V
Me Me Me F Me Me F F Me CF3 Me Me
Me Me F F Me F F F F CF3 Me F
Me Me CI F Me CI F F CI CF3 Me CI
Me Me Br F Me Br F F Br CF3 Me Br
Me Me CF3 F Me CF3 F F CF3 CF3 Me CF3
Me Me N02 F Me N02 F F N02 CF3 Me N02
Me Me OMe F Me OMe F F OMe CF3 Me OMe g to g to g to g J- g H
Figure imgf000031_0001
to δ 2 2 H
Figure imgf000032_0001
T U V T U V T U V T U V
OMe OMe CF3 Br OMe CF3 Br H CF3 N02 N02 CF3
OMe OMe N02 Br OMe N02 Br H N02 N02 N02 N02
OMe OMe OMe Br OMe OMe Br H OMe N02 N02 OMe
OMe Br Me OMe CF3 Me CF3 H Me CF3 OMe Me
OMe Br F OMe CF3 F CF3 H F CF3 OMe F
OMe Br Cl OMe CF3 Cl CF3 H Cl CF3 OMe Cl
OMe Br Br OMe CF3 Br CF3 H Br CF3 ■ OMe Br
OMe Br CF3 OMe CF3 CF3 CF3 H CF3 CF3t OMe CF3
OMe Br N02 OMe CF3 N02 CF H N02 CF3 OMe N02
OMe Br OMe OMe CF3 OMe CF3 H OMe CF3 OMe OMe
OMe H Br OMe N02 Me N02 H Me N02 OMe Me
OMe H CF3 OMe N02 F N02 H F N02 OMe F
OMe H N02 OMe N02 Cl N02 H Cl N02 OMe Cl
OMe OMe Me OMe N02 Br N02 H Br N02 OMe Br
OMe OMe F OMe N02 CF3 N02 H CF3 N02 OMe CF3
OMe OMe Cl OMe N02 N02 N02 H N02 N02 OMe N02
OMe OMe Br OMe N02 OMe N02 H OMe N02 OMe OMe
Table 2
Figure imgf000033_0001
T U V T u V T u V T U V
Me Me Me F Me Me F F Me CF3 Me Me
Me Me F F Me F F F F CF3 Me F
Me Me Cl F Me Cl F F Cl CF3 Me Cl
Me Me Br F Me Br F F Br CF3 Me Br
Me Me CF3 F Me CF3 F F CF3 CF3 Me CF3
Me Me N02 F Me N02 F F N02 CF3 Me N02
Me Me OMe F Me OMe F F OMe CF3 Me OMe
Me F Me Cl Me Me Cl F Me N02 Me Me
Me F F Cl Me F Cl F F N02 Me F
Me F Cl Cl Me Cl Cl F Cl N02 Me Cl O
Figure imgf000034_0001
Figure imgf000035_0001
T U V T U V T U V T U V
OMe OMe N02 Br OMe N02 Br H N02 N02 N02 N02
OMe OMe OMe Br OMe OMe Br H OMe N02 N02 OMe
OMe Br Me OMe CF3 Me CF H Me CF3 OMe Me
OMe Br F OMe CF3 F CF3 H F CF3 OMe F
OMe Br Cl OMe CF Cl CF3 H Cl CF3 OMe Cl
OMe Br Br OMe CF3 Br CF3 H Br CF3 OMe Br
OMe Br CF OMe CF3 CF3 CF H CF3 CF3 • OMe CF3
OMe Br N02 OMe CF3 N02 CF3 H N02 CF31 OMe N02
OMe Br OMe OMe CF3 OMe CF3 H OMe CF3 OMe OMe
OMe H Br OMe N02 Me N02 H Me N02 OMe Me
OMe H CF3 OMe N02 F N02 H F N02 OMe F
OMe H N02 OMe N02 Cl N02 H Cl N02 OMe Cl
OMe OMe Me OMe N02 Br N02 H Br N02 OMe Br
OMe OMe F OMe N02 CF3 N02 H CF3 N02 OMe CF3
OMe OMe Cl OMe N02 N02 N02 H N02 N02 OMe N02
OMe OMe Br OMe N02 OMe N02 H OMe N02 OMe OMe
Table 3
Figure imgf000036_0001
T U V T u V T u V T U V
Me Me Me F Me Me F F Me CF3 Me Me
Me Me F F Me F F F F CF3 Me F
Me Me Cl F Me Cl F F Cl CF3 Me Cl
Me Me Br F Me Br F F Br CF3 Me Br
Me Me CF3 F Me CF3 F F CF3 CF3 Me CF3
Me Me N02 F Me N02 F F N02 CF3 Me N02
Me Me OMe F Me OMe F F OMe CF3 Me OMe
Me F Me Cl Me Me Cl F Me N02 Me Me
Me F F Cl Me F Cl F F N02 Me F
Me F Cl Cl Me Cl Cl F Cl N02 Me Cl
Me F Br Cl Me Br Cl F Br N02 Me Br
Me F CF3 Cl Me CF3 Cl F CF3 N02 Me CF3 T U V T U V T U V T U V
Me F N02 Cl Me N02 Cl F N02 N02 Me N02
Me F OMe Cl Me OMe Cl F OMe N02 Me OMe
Me Cl Me F Cl Me F Br Me CF3 F Me
Me Cl F F Cl F F Br F CF3 F F
Me Cl Cl F Cl Cl F Br Cl CF3 F Cl
Me Cl Br F Cl Br F Br Br CF3 F Br
Me Cl CF3 F Cl CF3 F Br CF3 CF3 • F CF3
Me Cl N02 F Cl N02 F Br N02 CFj F N02
Me Cl OMe F Cl OMe F Br OMe CF3 F OMe
Me Br Me Cl Cl Me Cl Br Me N02 F Me
Me Br F Cl Cl F Cl Br F N02 F F
Me Br Cl Cl Cl Cl Cl Br Cl N02 F Cl
Me Br Br Cl Cl Br Cl Br Br N02 F Br
Me Br CF3 Cl Cl CF Cl Br CF3 N02 F CF3
Me Br N02 Cl Cl N02 Cl Br N02 N02 F N02
Me Br OMe Cl Cl OMe Cl Br OMe N02 F OMe
Me CF3 Me F CF3 Me F N02 Me CF3 Cl Me
Me CF3 F F CF3 F F N02 F CF3 Cl F
Me CF3 Cl F CF3 Cl F N02 Cl CF3 Cl Cl
Me CF Br F CF3 Br F N02 Br CF3 Cl Br
Me CF3 CF3 F CF3 CF3 F N02 CF3 CF3 Cl CF3
Me CF3 N02 F . CF3 N02 F N02 N02 CF3 Cl N02
Me CF OMe F CF3 OMe F N02 OMe CF3 Cl OMe
Me N02 Me Cl CF3 Me Cl N02 Me N02 Cl Me
Me N02 F Cl CF F Cl N02 F N02 Cl F
Me N02 Cl Cl CF3 Cl Cl N02 Cl N02 Cl Cl
Me N02 Br Cl CF3 Br Cl N02 Br N02 Cl Br
Me N02 CF3 Cl CF3 CF3 Cl N02 CF3 N02 Cl CF3
Me N02 N02 Cl CF3 N02 Cl N02 N02 N02 Cl N02
Me N02 OMe Cl CF3 OMe Cl N02 OMe N02 Cl OMe
Me OMe Me F OMe Me F H Me CF3 Br Me
Me OMe F F OMe F F H F CF3 Br F
Me OMe Cl F OMe Cl F H Cl CF3 Br Cl
Me OMe Br F OMe Br F H Br CF3 Br Br
Me OMe CF3 F OMe CF3 F H CF3 CF3 Br CF3
Me OMe N02 F OMe N02 F H N02 CF3 Br N02
Me OMe OMe F OMe OMe F H OMe CF3 Br OMe T U V T U V T U V T U V
Me H Me Cl OMe Me Cl H Me N02 Br Me
Me H F Cl OMe F Cl H F N02 Br F
Me H Cl Cl OMe Cl Cl H Cl N02 Br Cl
Me H Br Cl OMe Br Cl H Br N02 Br Br
Me H CF3 Cl OMe CF3 Cl H CF3 N02 Br CF3
Me H N02 Cl OMe N02 Cl H N02 N02 Br N02
Me H OMe Cl OMe OMe cr H OMe N02 ■ Br OMe
OMe Me Me Br Me Me Br F Me CF^ CF3 Me
OMe Me F Br Me F Br F F CF3 CF3 F
OMe Me Cl Br Me Cl Br F Cl CF3 CF3 Cl
OMe Me Br Br Me Br Br F Br CF3 CF3 Br
OMe Me CF3 Br Me CF3 Br F CF3 CF3 CF3 CF3
OMe Me N02 Br Me N02 Br F N02 CF3 CF3 N02
OMe Me OMe Br Me OMe Br F OMe CF3 CF3 OMe
OMe F Me Br Cl Me Br Br Me N02 CF3 Me
OMe F F Br Cl F Br Br F N02 CF3 F
OMe F Cl Br Cl Cl Br Br Cl N02 CF3 Cl
OMe F Br Br Cl Br Br Br Br N02 CF3 Br
OMe F CF3 Br Cl CF3 Br Br CF N02 CF3 CF3
OMe F N02 Br Cl N02 Br Br N02 N02 CF3 N02
OMe F OMe Br Cl OMe Br Br OMe N02 CF3 OMe
OMe Cl Me Br CF3 Me Br N02 Me CF3 N02 Me
OMe Cl F Br CF3 F Br N02 F CF3 N02 F
OMe Cl Cl Br CF3 Cl Br N02 Cl CF3 N02 Cl
OMe Cl Br Br CF3 Br Br N02 Br CF3 N02 Br
OMe Cl CF3 Br CF3 CF3 Br N02 CF3 CF3 N02 CF3
OMe Cl N02 Br CF3 N02 Br N02 N02 CF N02 N02
OMe Cl OMe Br CF3 OMe Br N02 OMe CF3 N02 OMe
OMe H Me Br OMe Me Br H Me N02 N02 Me
OMe H F Br OMe F Br H F N02 N02 F
OMe H Cl Br OMe Cl Br H Cl N02 N02 Cl
OMe H OMe Br OMe Br Br H Br N02 N02 Br
OMe OMe CF3 Br OMe CF3 Br H CF3 N02 N02 CF3
OMe OMe N02 Br OMe N02 Br H N02 N02 N02 N02
OMe OMe OMe Br OMe OMe Br H OMe N02 N02 OMe
OMe Br Me OMe CF3 Me CF3 H Me CF3 OMe Me
OMe Br F OMe CF3 F CF3 H F CF3 OMe F £
Figure imgf000039_0002
Figure imgf000039_0001
T U V T u V T U V T U V
Me Cl Cl F Cl Cl F Br Cl CF3 F Cl
Me Cl Br F Cl Br F Br Br CF3 F Br
Me Cl CF3 F Cl CF3 F Br CF3 CF3 F CF3
Me Cl N02 F Cl N02 F Br N02 CF3 F N02
Me Cl OMe F Cl OMe F Br OMe CF3 F OMe
Me Br Me Cl Cl Me Cl Br Me N02 F Me
Me Br F Cl Cl F Cl Br F N02 • F F
Me Br Cl Cl Cl Cl Cl Br Cl N0| F Cl
Me Br Br Cl Cl Br Cl Br Br N02 F Br
Me Br CF3 Cl Cl CF3 Cl Br CF3 N02 F CF3
Me Br N02 Cl Cl N02 Cl Br N02 N02 F N02
Me Br OMe Cl Cl OMe Cl Br OMe N02 F OMe
Me CF Me F CF3 Me F N02 Me CF3 Cl Me
Me CF3 F F CF3 F F N02 F CF3 Cl F
Me CF Cl F CF3 Cl F N02 Cl CF3 Cl Cl
Me CF3 Br F CF3 Br F N02 Br CF3 Cl Br
Me CF3 CF F CF3 CF3 F N02 CF3 CF3 Cl CF3
Me CF N02 F CF3 N02 F N02 N02 CF3 Cl N02
Me CF3 OMe F CF3 OMe F N02 OMe CF3 Cl OMe
Me N02 Me Cl CF3 Me Cl N02 Me N02 ' Cl Me
Me N02 F Cl CF3 F Cl N02 F N02 Cl F
Me N02 Cl Cl CF3 Cl Cl N02 Cl N02 Cl Cl
Me N02 Br Cl CF3 Br Cl N02 Br N02 Cl Br
Me N02 CF3 Cl CF3 CF3 Cl N02 CF3 N02 Cl CF3
Me N02 N02 Cl CF3 N02 Cl N02 N02 N02 Cl N02
Me N02 OMe Cl CF3 OMe Cl N02 OMe N02 Cl OMe
Me OMe Me F OMe Me F H Me CF Br Me
Me OMe F F OMe F F H F CF3 Br F
Me OMe Cl F OMe Cl F H Cl CF3 Br Cl
Me OMe Br F OMe Br F H Br CF3 Br Br
Me OMe CF3 F OMe CF3 F H CF3 CF3 Br CF3
Me OMe N02 F OMe N02 F H N02 CF3 Br N02
Me OMe OMe F OMe OMe F H OMe CF3 Br OMe
Me H Me Cl OMe Me Cl H Me N02 Br Me
Me H F Cl OMe F Cl H F N02 Br F
Me H Cl Cl OMe Cl Cl H Cl N02 Br Cl
Me H Br Cl OMe Br Cl H Br N02 Br Br
Figure imgf000041_0001
Figure imgf000042_0001
T and V are both Cl andU is H
R M R M
CH2CH2CH2 SOCHFCF H CH2CH2CH2 SOCHFCF3 Me
CH2CH2CH2 S02CF3 H CH2CH2CH2 S02CF3 Me
CH2CH2CH2 S02CHF2 H CH2CH2CH2 S02CHF2 Me
CH2CH2CH2 S02CH2CF3 H CHCH2CH2 S02CH2CF3 Me
CH2CH2CH2 S02CF2CF3 H CH2CH2CH2 S02CF2CF3 Me
CH2CH2CH2 S02CF2CF2H H CH2CH2CH2 S02CF2CF2H Me
CH2CH2CH2 S02CHFCF3 H CH2CH2CH2 S02CHFCF3 Me
CH2CH2CH2 CN H CH2CH2CH2 CN Me
CH2CH2CH2 SMe H CH2CH2CH2 SMe Me
CH2CH2CH2 S(0)Me H CH2CH2CH2 S(0)Me Me
CH2CH2CH2 S(0)2Me H CH2CH2CH2 S(0)2Me Me
CH2CH2CH2 N02 H CH2CH2CH2 N02 Me
CH2CH2 Cl H CH2CH2 Cl Me
CH2CH2 Br H CH2CH2 Br Me
CH2CH2 OCF3 H CH2CH2 OCF3 Me
CH2CH2 OCHF2 H CH2CH2 OCHF2 Me
CH2CH2 OCH2CF H CH2CH2 OCH2CF3 Me
CH2CH2 OCF2CF3 H CH2CH2 OCF2CF3 Me
CH2CH2 OCF2CF2H H CH2CH2 OCF2CF2H Me
CH2CH2 OCHFCF H CH2CH2 OCHFCF3 Me
CH2CH2 SCF3 H CH2CH2 SCF3 Me
CH2CH2 SCHF2 H CH2CH2 SCHF2 Me
CH2CH2 SCH2CF3 H CH2CH2 SCH2CF3 Me
CH2CH2 SCFCF3 H CH2CH2 SCF2CF3 Me
CH2CH2 SCF2CF2H H CH2CH2 SCF2CF2H Me
CH2CH2 SCHFCF3 H CH2CH2 SCHFCF3 Me
CH2CH2 SOCF3 H CH2CH2 SOCF Me
CH2CH2 SOCHF2 H CH2CH2 SOCHF2 Me
CH2CH2 SOCH2CF3 H CH2CH2 SOCH2CF3 Me
CH2CH2 SOCF2CF H CH2CH2 SOCF2CF3 Me
CH2CH2 SOCF2CF2H H CH2CH2 SOCF2CF2H Me
CH2CH2 SOCHFCF3 H CH2CH2 SOCHFCF3 Me
CH2CH2 S02CF3 H CH2CH2 S02CF3 Me
CH2CH2 S02CHF2 H CH2CH2 S02CHF2 Me
CH2CH2 S02CH2CF3 H CH2CH2 S02CH2CF3 Me
CH2CH2 S02CF2CF3 H CH2CH2 S02CF2CF3 Me T and V are both Cl and U is H
J R M J R M
CH2CH2 S02CF2CF2H H CH2CH2 S02CF2CF2H Me
CH2CH2 S02CHFCF3 H CH2CH2 S02CHFCF3 Me
CH2CH2 CN H CH2CH2 CN Me
CH2CH2 SMe H CH2CH2 SMe Me
CH2CH2 S(0)Me H CH2CH2 S(0)Me Me
CH2CH2 S(0)2Me H CH2CH2 S(0)2Me • Me
CH2CH2 N02 H CH2CH2 N021 Me
T andV are both Cl and U is Mc
J R M J R M
CH2CH2CH2 Cl H CH2CH2CH2 Cl Me
CH2CH2CH2 Br H CH2CH2CH2 Br Me
CH2CH2CH2 OCF H CH2CH2CH2 OCF3 Me
CH2CH2CH2 OCHF2 H CH2CH2CH2 OCHF2 Me
CH2CH2CH2 OCH2CF3 H CH2CH2CH2 OCH2CF3 Me
CH2CH2CH2 OCF2CF3 H CH2CH2CH2 OCF2CF3 Me
CH2CH2CH2 OCF2CF2H H CH2CH2CH2 OCF2CF2H Me
CH2CH2CH2 OCHFCF3 H CH2CH2CH2 OCHFCF3 Me
CH2CH2CH2 SCF3 H CH2CH2CH2 SCF3 Me
CH2CH2CH2 SCHF2 H CH2CH2CH2 SCHF2 Me
CHCH2CH2 SCH2CF3 H CH2CH2CH2 SCH2CF3 Me
CH2CH2CH2 SCF2CF3 H CH2CH2CH2 SCF2CF3 Me
CH2CH2CH2 SCF2CF2H H CH2CH2CH2 SCF2CF2H Me
CH2CH2CH2 SCHFCF3 H CH2CH2CH2 SCHFCF3 Me
CH2CH2CH2 SOCF3 H CH2CH2CH2 SOCF3 Me
CH2CH2CH2 SOCHF2 H CH2CH2CH2 SOCHF2 Me
CH2CH2CH2 SOCH2CF3 H CH2CH2CH2 SOCH2CF3 Me
CH2CH2CH2 SOCF2CF3 H CH2CH2CH2 SOCF2CF3 Me
CH2CH2CH2 SOCF2CF2H H CH2CH2CH2 SOCF2CF2H Me
CH2CH2CH2 SOCHFCF3 H CH2CH2CH2 SOCHFCF3 Me
CH2CH2CH2 S02CF3 H CH2CH2CH2 S02CF3 Me
CH2CH2CH2 S02CHF2 H CH2CH2CH2 S02CHF2 Me
CH2CH2CH2 S02CH2CF3 H CH2CH2CH2 S02CH2CF3 Me
CH2CH2CH2 S02CF2CF3 H CH2CH2CH2 S02CF2CF3 Me
CH2CH2CH2 S02CF2CF2H H CH2CH2CH2 S02CF2CF2H Me
CH2CH2CH2 S02CHFCF3 H CH2CH2CH2 S02CHFCF3 Me
Figure imgf000045_0001
T is Cl and V and U are both Me
R M R M
CH2CH2CH2 Cl H CH2CH2CH2 Cl Me
CH2CH2CH2 Br H CH2CH2CH2 Br Me
CH2CH2CH2 OCF3 H CH2CH2CH2 OCF3 Me
CH2CH2CH2 OCHF2 H CH2CH2CH2 OCHF2 Me
CH2CH2CH2 OCH2CF3 H CH2CH2CH2 OCH2CF3 Me
CH2CH2CH2 OCF2CF H CH2CH2CH2 OCF2CF3' Me
CH2CH2CH2 OCF2CF2H H CH2CH2CH2 OCF2Cff2H Me
CH2CH2CH2 OCHFCF3 H CH2CH2CH2 OCHFCF3 Me
CH2CH2CH2 SCF3 H CH2CH2CH2 SCF3 Me
CH2CH2CH2 SCHF2 H CH2CH2CH2 SCHF2 Me
CH2CH2CH2 SCH2CF3 H CH2CH2CH2 SCH2CF3 Me
CH2CH2CH2 SCF2CF3 H CH2CH2CH2 SCF2CF3 Me
CH2CH2CH2 SCF2CF2H H CH2CH2CH2 SCF2CF2H Me
CH2CH2CH2 SCHFCF3 H CH2CH2CH2 SCHFCF3 Me
CH2CH2CH2 SOCF3 H CH2CH2CH2 SOCF Me
CH2CH2CH2 SOCF£F2 H CH2CH2CH2 SOCHF2 Me
CH2CH2CH2 SOCH2CF3 H CH2CH2CH2 SOCH2CF3 Me
CH2CH2CH2 SOCF2CF3 H CH2CH2CH2 SOCF2CF3 Me
CH2CH2CH2 SOCF2CF2H H CH2CH2CH2 SOCF2CF2H Me
CH2CH2CH2 SOCHFCF3 H CH2CH2CH2 SOCHFCF3 Me
CH2CH2CH2 S02CF H CH2CH2CH2 S02CF3 Me
CH2CH2CH2 S02CHF2 H CH2CH2CH2 S02CHF2 Me
CH2CH2CH2 S02CH2CF H CH2CH2CH2 S02CH2CF3 Me
CH2CH2CH2 S02CF2CF3 H CH2CH2CH2 S02CF2CF3 Me
CH2CH2CH2 S02CF2CF2H H CH2CH2CH2 S02CF2CF2H Me
CH2CH2CH2 S02CHFCF3 H CH2CH2CH2 S02CHFCF3 Me
CH2CH2CH2 CN H CH2CH2CH2 CN Me
CH2CH2CH2 SMe H CH2CH2CH2 SMe Me
CH2CH2CH2 S(0)Me H CH2CH2CH2 S(0)Me Me
CH2CH2CH2 S(0)2Me H CH2CH2CH2 S(0)2Me Me
CH2CH2CH2 N02 H CH2CH2CH2 N02 Me
CH2CH2 Cl H CH2CH2 Cl Me
CH2CH2 Br H CH2CH2 Br Me
CH2CH2 OCF H CH2CH2 OCF3 Me
CH2CH2 OCHF2 H CH2CH2 OCHF2 Me
CH2CH2 OCH2CF H CH2CH2 OCH2CF3 Me
Figure imgf000047_0001
to P 0 «° P P ^ M o P S o o co g co o O ? Ω Ω to to tO & ι- y S »i G % to* ? 93 , Ω Ω. 9 Ω TJ Ω >τl o 5 Ω TJ t9 Q ΩJ to ? 9 -Q
Ω T t TJ t
TJ t ^ TJ ITΓJ to J t
°° a co o w a ω a
M feM
Figure imgf000047_0006
feM feM
Figure imgf000047_0004
ϊfe"Tl Ifeι*i MfeM MfeM feM MfeM Mfe
Figure imgf000047_0005
MfeM Mfe MfeM feM feM
Figure imgf000047_0002
MfeM feM fe*T» fe
Figure imgf000047_0003
c
. toa .toa .toa Ω Ω Ω Ω Ω Ω Q Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω to to to to to to to to to to to to to to to to to to a t a to a Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω ._ Ω Ω to a .toa .toa . .toa .toa .ta .toa
Figure imgf000047_0007
. . t.oa .toa t ι.a
Figure imgf000047_0008
.to .toa .toa .t.oa »t.oP *t.oa ιt.oa ιt.oa »t.oH .t.oP KtoF
to δ *°. §
Figure imgf000047_0009
£ £ £ £ £ £ £ £ £ £ £ £ £ £ £ £ £ £ £
Table 6
Figure imgf000048_0001
T andV arebotlClandUisH <
J R M J R t M
CH2CH2CH2 Cl H CH2CH2CH2 Cl Me
CH2CH2CH2 Br H CH2CH2CH2 Br Me
CH2CH2CH2 OCF3 H CH2CH2CH2 OCF3 Me
CH2CH2CH2 OCHF2 H CH2CH2CH2 OCHF2 Me
CH2CH2CH2 OCH2CF3 H CH2CH2CH2 OCH2CF3 Me
CH2CH2CH2 OCF2CF3 H CH2CH2CH2 OCF2CF3 Me
CH2CH2CH2 OCF2CF2H H CH2CH2CH2 OCF2CF2H Me
CH2CH2CH2 OCHFCF H CH2CH2CH2 OCHFCF3 Me
CH2CH2CH2 SCF3 H CH2CH2CH2 SCF3 Me
CH2CH2CH2 SCHF2 H CH2CH2CH2 SCHF2 Me
CH2CH2CH2 SCH2CF3 H CH2CH2CH2 SCH2CF3 Me
CH2CH2CH2 SCF2CF H CH2CH2CH2 SCF2CF3 Me
CH2CH2CH2 SCF2CF2H H CH2CH2CH2 SCF2CF2H Me
CH2CH2CH2 SCHFCF H CH2CH2CH2 SCHFCF3 Me
CH2CH2CH2 SOCF3 H CH2CH2CH2 SOCF3 Me
CH2CH2CH2 SOCHF2 H CH2CH2CH2 SOCHF2 Me
CH2CH2CH2 SOCH2CF3 H CH2CH2CH2 SOCH2CF3 Me
CH2CH2CH2 SOCF2CF3 H CH2CH2CH2 SOCF2CF3 Me
CH2CH2CH2 SOCF2CF2H H CH2CH2CH2 SOCF2CF2H Me
CH2CH2CH2 SOCF£FCF H CH2CH2CH2 SOCHFCF3 Me
CH2CH2CH2 S02CF3 H CH2CH2CH2 S02CF3 Me
CH2CH2CH2 S02CHF2 H CH2CH2CH2 S02CHF2 Me
CH2CH2CH2 S02CH2CF3 H CH2CH2CH2 S02CH2CF3 Me
CH2CH2CH2 S02CF2CF3 H CH2CH2CH2 S02CF2CF3 Me
CH2CH2CH2 S02CF2CF2H H CH2CH2CH2 S02CF2CF2H Me
CH2CH2CH2 S02CHFCF H CH2CH2CH2 S02CHFCF3 Me
CH2CH2CH2 CN H CH2CH2CH2 CN Me
CH2CH2CH2 SMe H CH2CH2CH2 SMe Me
CH2CH2CH2 S(0)Me H CH2CH2CH2 S(0)Me Me
Figure imgf000049_0001
T andV are both Cl andU is Me
J R M J R M
CH2CH2CH2 Cl H CH2CH2CH2 Cl Me
CH2CH2CH2 Br H CH2CH2CH2 Br Me
CH2CH2CH2 OCF3 H CH2CH2CH2 OCF3 Me
CH2CH2CH2 OCHF2 H CH2CH2CH2 OCHF2 Me
CH2CH2CH2 OCH2CF3 H CH2CH2CH2 OCH2CF3 Me
CH2CH2CH2 OCF2CF3 H CH2CH2CH2 OCF2CF3 • Me
CH2CH2CH2 OCF2CF2H H CH2CH2CH2 OCF2Clf2H Me
CH2CH2CH2 OCHFCF3 H CH2CH2CH2 OCHFCF3 Me
CH2CH2CH2 SCF3 H CH2CH2CH2 SCF3 Me
CH2CH2CH2 SCHF2 H CH2CH2CH2 SCHF2 Me
CH2CH2CH2 SCH2CF3 H CH2CH2CH2 SCH2CF3 Me
CH2CH2CH2 SCF2CF H CH2CH2CH2 SCF2CF3 Me
CH2CH2CH2 SCF2CF2H H CH2CH2CH2 SCF2CF2H Me
CH2CH2CH2 SCHFCF3 H CH2CH2CH2 SCHFCF3 Me
CH2CH2CH2 SOCF3 H CH2CH2CH2 SOCF Me
CH2CH2CH2 SOCHF2 H CH2CH2CH2 SOCHF2 Me
CH2CH2CH2 SOCH2CF3 H CH2CH2CH2 SOCH2CF3 Me
CH2CH2CH2 SOCF2CF3 H CH2CH2CH2 SOCF2CF3 Me
CH2CH2CH2 SOCF2CF2H H CH2CH2CH2 SOCF2CF2H Me
CH2CH2CH SOCHFCF3 H CH2CH2CH2 SOCHFCF3 Me
CH2CH2CH2 S02CF3 H CH2CH2CH2 S02CF3 Me
CH2CH2CH2 S0CHF2 H CH2CH2CH2 S02CHF2 Me
CH2CH2CH2 S02CH2CF3 H CH2CH2CH2 S02CH2CF3 Me
CH2CH2CH2 S02CF2CF3 H CH2CH2CH2 S02CF2CF3 Me
CH2CH2CH2 S02CF2CF2H H CH2CH2CH2 S02CF2CF2H Me
CH2CH2CH2 S02CHFCF H CH2CH2CH2 S02CHFCF3 Me
CH2CH2CH2 CN H CH2CH2CH2 CN Me
CH2CH2CH2 SMe H CH2CH2CH2 SMe Me
CH2CH2CH S(0)Me H CH2CH2CH2 S(0)Me Me
CH2CH2CH2 S(0)2Me H CH2CH2CH2 S(0)2Me Me
CH2CH2CH2 N02 H CH2CH2CH2 N02 Me
CH2CH2 Cl H CH2CH2 Cl Me
CH2CH2 Br H CH2CH2 Br Me
CH2CH2 OCF3 H CH2CH2 OCF3 Me
CH2CH2 OCHF2 H CH2CH2 OCHF2 Me
CH2CH2 OCH2CF3 H CH2CH2 OCH2CF Me . toa
Ω Ω Ω Ω Ω Ω t.oH » t.o> i . to^r* . t.o'r*
Figure imgf000051_0001
T is Cl and V and U are both Me
R M R M
CH2CH2CH2 OCHFCF3 H CH2CH2CH2 OCHFCF3 Me
CH2CH2CH2 SCF3 H CH2CH2CH2 SCF3 Me
CH2CH2CH2 SCHF2 H CH2CH2CH2 SCHF2 Me
CH2CH2CH2 SCH2CF3 H CH2CH2CH2 SCH2CF3 Me
CH2CH2CH2 SCF2CF3 H CH2CH2CH2 SCF2CF3 Me
CH2CH2CH2 SCF2CF2H H CH2CH2CH2 SCF2CF2H Me
CH2CH2CH2 SCHFCF3 H CH2CH2CH2 SCHFOF3 Me
CH2CH2CH2 SOCF3 H CH2CH2CH2 SOCF3 Me
CH2CH2CH2 SOCHF2 H CH2CH2CH2 SOCHF2 Me
CH2CH2CH2 SOCH2CF3 H CH2CH2CH2 SOCH2CF3 Me
CH2CH2CH2 SOCF2CF3 H CH2CH2CH2 SOCF2CF3 Me
CH2CH2CH2 SOCF2CF2H H CH2CH2CH2 SOCF2CF2H Me
CH2CH2CH2 SOCHFCF3 H CH2CH2CH2 SOCHFCF Me
CH2CH2CH2 S02CF3 H CH2CH2CH2 S02CF3 Me
CH2CH2CH2 S02CHF2 H CH2CH2CH2 S02CHF2 Me
CH2CH2CH2 S02CH2CF3 H CH2CH2CH2 S02CH2CF3 Me
CH2CH2CH2 S02CF2CF3 H CH2CH2CH2 S02CF2CF3 Me
CH2CH2CH2 S02CF2CF2H H CH2CH2CH2 S02CF2CF2H Me
CH2CHCH2 S02CHFCF3 H CH2CH2CH2 S02CHFCF3 Me
CH2CH2CH2 CN H CH2CH2CH2 CN Me
CH2CH2CH2 SMe H CH2CH2CH2 SMe Me
CH2CH2CH2 S(0)Me H CH2CH2CH2 S(0)Me Me
CH2CH2CH2 S(0)2Me H CH2CH2CH2 S(0)2Me Me
CH2CH2CH2 N02 H CH2CH2CH2 N02 Me
CH2CH2 Cl H CH2CH2 Cl Me
CH2CH2 Br H CH2CH2 Br Me
CH2CH2 OCF3 H CH2CH2 OCF3 Me
CH2CH2 OCHF2 H CH2CH2 OCHF2 Me
CH2CH2 OCH2CF3 H CH2CH2 OCH2CF3 Me
CH2CH2 OCF2CF H CH2CH2 OCF2CF Me
CH2CH2 OCF2CF2H H CH2CH2 OCF2CF2H Me
CH2CH2 OCHFCF3 H CH2CH2 OCHFCF Me
CH2CH2 SCF3 H CH2CH2 SCF3 Me
CH2CH2 SCHF2 H CH2CH2 SCHF2 Me
CH2CH2 SCH2CF H CH2CH2 SCH2CF3 Me
CH2CH2 SCF2CF3 H CH2CH2 SCF2CF3 Me
Figure imgf000053_0001
and V are both Cl and U is H
R J R R
CH2CH2CH2CH2 OCF3 OCH2 OCF3 OCH2CH2 OCF3
CH2CH2CH2CH2 OCHF2 OCH2 OCHF2 OCH2CH2 OCHF2
CH2CH2CH2CH2 OCF3 OCH2 OCF3 OCH2CH2 OCF3
CH2CH2CH2CH2 SCHF2 OCH2 SCHF2 OCH2CH2 SCHF2
0CH2CH2CH2 Cl CH2NHCH2 Cl CH2NMeCH2 Cl
OCH2CH2CH2 Br CH2NHCH2 Br CH2NMeCH2 Br
OCH2CH2CH2 CF3 CH2NHCH2 CF3 CH2NM CH2 CF3
OCH2CH2CH2 C02CH CH2NHCH2 C02CH3 CH2NMeCH2 C02CH3
OCH2CH2CH2 CONHCH3 CH2NHCH2 CONHCH3 CH2NMeCH2 CONHCH3
OCH2CH2CH2 I CH2NHCH2 I CH2NMeCH2 I
OCH2CH2CH2 CH CH2NHCH2 CH3 CH2NMeCH2 CH3
OCH2CH2CH2 OCF3 CH2NHCH2 OCF3 CH2NMeCH2 OCF3
OCH2CH2CH2 OCHF2 CH2NHCH2 OCHF2 CH2NMeCH2 OCHF2
OCH2CH2CH2 OCF3 CH2NHCH2 OCF3 CH2NMeCH2 OCF3
OCH2CH2CH2 SCHF2 CH2NHCH2 SCHF2 CH2NMeCH2 SCHF2
CH2NEtCH2 Cl CONHCO Cl CONMeCO Cl
CH2NEtCH2 Br CONHCO Br CONMeCO Br
CH2NEtCH2 CF3 CONHCO CF3 CONMeCO CF3
CH2NEtCH2 C02CH3 CONHCO C02CH3 CONMeCO C02CH3
CH2NEtCH2 CONHCH3 CONHCO CONHCH3 CONMeCO CONHCH
CH2NEtCH2 I CONHCO I CONMeCO I
CH2NEtCH2 CH3 CONHCO CH3 CONMeCO CH3
CH2NEtCH2 OCF3 CONHCO OCF3 CONMeCO OCF3
CH2NEtCH2 OCHF2 CONHCO OCHF2 CONMeCO OCHF2
CH2NEtCH2 OCF3 CONHCO OCF3 CONMeCO OCF3
CH2NEtCH2 SCHF2 CONHCO SCHF2 CONMeCO SCHF2
T and V are both Cl andU is Me
J R J R J R
CH2CH2CH2CH2 Cl OCH2 Cl OCH2CH2 Cl
CH2CH2CH2CH2 Br OCH2 Br OCH2CH2 Br
CH2CH2CH2CH2 CF3 OCH2 CF3 OCH2CH2 CF3
CH2CH2CH2CH2 C02CH3 OCH2 C02CH3 OCH2CH2 C02CH3
CH2CH2CH2CH2 CONHCH3 OCH2 CONHCH3 OCH2CH2 CONHCH3
CH2CH2CH2CH2 I OCH2 I OCH2CH2 I
CH2CH2CH2CH2 CH3 OCH2 CH3 OCH2CH2 CH3 T and V are both Cl andU is Me
J R J R J R
CH2CH2CH2CH2 OCF3 OCH2 OCF3 OCH2CH2 OCF3
CH2CH2CH2CH2 OCHF2 OCH2 OCHF2 OCH2CH2 OCHF2
CH2CH2CH2CH2 OCF3 OCH2 OCF3 OCH2CH2 OCF3
CH2CH2CH2CH2 SCHF2 OCH2 SCHF2 OCH2CH2 SCHF2
OCH2CH2CH2 Cl CH2NHCH2 Cl CH2NMeCH Cl
OCH2CH2CH2 Br CH2NHCH2 Br CH2NMeCH2 Br
OCH2CH2CH2 CF3 CH2NHCH2 CF CH2NM4CH2 CF3
OCH2CH2CH2 C02CH3 CH2NHCH2 C02CH3 CH2NMeCH2 C02CH3
OCH2CH2CH2 CONHCH CH2NHCH2 CONHCH CH2NMeCH2 CONHCH3
OCH2CH2CH2 I CH2NHCH2 I CH2NMeCH2 I
OCH2CH2CH2 CH3 CH2NHCH2 CH3 CH2NMeCH2 CH3
OCH2CH2CH2 OCF CH2NHCH2 OCF3 CH2NMeCH2 OCF3
OCH2CH2CH2 OCHF2 CH2NHCH2 OCHF2 CH2NMeCH2 OCHF2
OCH2CH2CH2 OCF3 CH2NHCH2 OCF3 CH2NMeCH2 OCF
OCH2CH2CH2 SCHF2 CH2NHCH2 SCHF2 CH2NMeCH2 SCHF2
CH2NEtCH2 Cl CONHCO Cl CONMeCO Cl
CH2NEtCH2 Br CONHCO Br CONMeCO Br
CH2NEtCH2 CF3 CONHCO CF3 CONMeCO CF3
CH2NEtCH2 C02CH CONHCO C02CH3 CONMeCO C02CH3
CH2NEtCH2 CONHCH3 CONHCO CONHCH CONMeCO CONHCH3
CH2NEtCH2 I CONHCO I CONMeCO I
CH2NEtCH2 CH3 CONHCO CH3 CONMeCO CH3
CH2NEtCH2 OCF CONHCO OCF3 CONMeCO OCF3
CH2NEtCH2 OCHF2 CONHCO OCHF2 CONMeCO OCHF2
CH2NEtCH2 OCF3 CONHCO OCF3 CONMeCO OCF3
CH2NEtCH2 SCHF2 CONHCO SCHF2 CONMeCO SCHF2
is Cl and V and U are both Me
R J R R
CH2CH2CH2CH2 Cl OCH2 Cl OCH2CH2 Cl
CH2CH2CH2CH2 Br OCH2 Br OCH2CH2 Br
CH2CH2CH2CH2 CF3 OCH2 CF3 OCH2CH2 CF3
CH2CH2CH2CH2 C02CH3 OCH2 C02CH3 OCH2CH2 C02CH3
CH2CH2CH2CH2 CONHCH OCH2 CONHCH3 OCH2CH2 CONHCH3
CH2CH2CH2CH2 I OCH2 I OCH2CH2 I
CH2CH2CH2CH2 CH3 OCH2 CH3 OCH2CH2 CH3 T is Cl and V and U are both Me
J R J R J R
CH2CH2CH2CH2 OCF3 OCH2 OCF3 OCH2CH2 OCF3
CH2CH2CH2CH2 OCHF2 OCH2 OCHF2 OCH2CH2 OCHF2
CH2CH2CH2CH2 OCF3 OCH2 OCF3 OCH2CH2 OCF3
CH2CH2CH2CH2 SCHF2 OCH2 SCHF2 OCH2CH2 SCHF2
OCH2CH2CH2 Cl CH2NHCH2 Cl CH2NMeCH2 Cl
OCH2CH2CH2 Br CH2NHCH2 Br CH2NMeCH2 Br
OCH2CH2CH2 CF3 CH2NHCH2 CF3 CH2NMdCH2 CF3
OCH2CH2CH2 C02CH3 CH NHCH2 C02CH3 CH2NMeCH2 C02CH3
OCH2CH2CH2 CONHCH3 CH2NHCH2 CONHCH3 CH2NMeCH2 CONHCH3
OCH2CH2CH2 I CH2NHCH2 I CH2NMeCH2 I
OCH2CH2CH2 CH3 CH2NHCH2 CH CH2NMeCH2 CH3
OCH2CH2CH2 OCF3 CH2NHCH2 OCF3 CH2NMeCH2 OCF3
OCH2CH2CH2 OCHF2 CH2NHCH2 OCHF2 CH2NMeCH2 OCHF2
OCH2CH2CH2 OCF3 CH2NHCH2 OCF3 CH2NMeCH2 OCF3
OCH2CH2CH2 SCHF2 CH2NHCH2 SCHF2 CH2NMeCH2 SCHF2
CH2NEtCH2 Cl CONHCO Cl CONMeCO Cl
CH2NEtCH2 Br CONHCO Br CONMeCO Br
CH2NEtCH2 CF3 CONHCO CF3 CONMeCO CF3
CH2NEtCH2 C02CH3 CONHCO C02CH3 CONMeCO C02CH3
CH2NEtCH2 CONHCH3 CONHCO CONHCH3 CONMeCO CONHCH3
CH2NEtCH2 I CONHCO I CONMeCO I
CH2NEtCH2 CH3 CONHCO CH3 CONMeCO CH
CH2NEtCH2 OCF3 CONHCO OCF3 CONMeCO OCF3
CH2NEtCH2 OCHF2 CONHCO OCHF2 CONMeCO OCHF2
CH2NEtCH2 OCF3 CONHCO OCF3 CONMeCO OCF3
CH2NEtCH2 SCHF2 CONHCO SCHF2 CONMeCO SCHF2
Figure imgf000057_0001
1 and V are both Cl and U is H
J R J R J « R
CH2CH2CH2CH2 Cl OCH2 Cl OCH2CH2 Cl
CH2CH2CH2CH2 Br OCH2 Br OCH2CH2 Br
CH2CH2CH2CH2 CF3 OCH2 CF3 OCH2CH2 CF3
CH2CH2CH2CH2 C02CH3 OCH2 C02CH3 OCH2CH2 C02CH3
CH2CH2CH2CH2 CONHCH3 OCH2 CONHCH3 OCH2CH2 CONHCH3
CH2CH2CH2CH2 I OCH2 I OCH2CH2 I
CH2CH2CH2CH2 CH3 OCH2 CH3 OCH2CH2 CH3
CH2CH2CH2CH2 OCF OCH2 OCF3 OCH2CH2 OCF3
CH2CH2CH2CH2 OCHF2 OCH2 OCHF2 OCH2CH2 OCHF2
CH2CH2CH2CH2 OCF3 OCH2 OCF3 OCH2CH2 OCF3
CH2CH2CH2CH2 SCHF2 OCH2 SCHF2 OCH2CH2 SCHF2
OCH2CH2CH2 Cl CH2NHCH2 Cl CH2NMeCH2 Cl
OCH2CH2CH2 Br CH2NHCH2 Br CH2NMeCH2 Br
OCH2CH2CH2 CF3 CH2NHCH2 CF CH2NMeCH2 CF3
OCH2CH2CH2 C02CH3 CH2NHCH2 C02CH3 CH2NMeCH2 C02CH3
OCH2CH2CH2 C0NHCH3 CH2NHCH2 CONHCH3 CH2NMeCH2 CONHCH
OCH2CH2CH2 I CH2NHCH2 I CH2NMeCH2 I
OCH2CH2CH2 CH3 CH2NHCH2 CH3 CH2NMeCH2 CH3
OCH2CH2CH2 OCF3 CH2NHCH2 OCF3 CH2NMeCH2 OCF3
OCH2CH2CH2 OCHF2 CH2NHCH2 OCHF2 CH2NMeCH2 OCHF2
OCH2CH2CH2 OCF3 CH2NHCH2 OCF3 CH2NMeCH2 OCF3
OCH2CH2CH2 SCHF2 CH2NHCH2 SCHF2 CH2NMeCH2 SCHF2
CH2NEtCH2 Cl CONHCO Cl CONMeCO Cl
CH2NEtCH2 Br CONHCO Br CONMeCO Br
CH2NEtCH2 CF3 CONHCO CF3 CONMeCO CF3
CH2NEtCH2 C02CH3 CONHCO C02CH3 CONMeCO C02CH
CH2NEtCH2 CONHCH3 CONHCO CONHCH3 CONMeCO CONHCH3
CH2NEtCH2 I CONHCO I CONMeCO I
CH2NEtCH2 CH3 CONHCO CH3 CONMeCO CH3 T and V are both Cl and U is H
J R J R J R
CH2NEtCH2 OCF3 CONHCO OCF3 CONMeCO OCF3
CH2NEtCH2 OCHF2 CONHCO OCHF2 CONMeCO OCHF2
CH2NEtCH2 OCF3 CONHCO OCF3 CONMeCO OCF3
CH2NEtCH2 SCHF2 CONHCO SCHF2 CONMeCO SCHF2
T and V are both Cl andU is Me
J R J R J l R
CH2CH2CH2CH2 Cl OCH2 Cl OCH2CH2 Cl
CH2CH2CH2CH2 Br OCH2 Br OCH2CH2 Br
CH2CH2CH2CH2 CF3 OCH2 CF3 OCH2CH2 CF3
CH2CH2CH2CH2 C02CH3 OCH2 C02CH3 OCH2CH2 C02CH3
CH2CH2CH2CH2 CONHCH3 OCH2 CONHCH3 OCH2CH2 CONHCH
CH2CH2CH2CH2 I OCH2 I OCH2CH2 I
CH2CH2CH2CH2 CH3 OCH2 CH3 OCH2CH2 CH3
CH2CH2CH2CH2 OCF3 OCH2 OCF3 OCH2CH2 OCF3
CH2CH2CH2CH2 OCHF2 OCH2 OCHF2 OCH2CH2 OCHF2
CH2CH2CH2CH2 OCF3 OCH2 OCF3 OCH2CH2 OCF3
CH2CH2CH2CH2 SCHF2 OCH2 SCHF2 OCH2CH2 SCHF2
OCH2CH2CH2 Cl CH2NHCH2 Cl CH2NMeCH2 Cl
OCH2CH2CH2 Br CH2NHCH2 Br CH2NMeCH2 Br
OCH2CH2CH2 CF3 CH2NHCH2 CF3 CH2NMeCH2 CF3
OCH2CH2CH2 C02CH3 CH2NHCH2 C02CH3 CH2NMeCH2 C02CH3
OCH2CH2CH2 CONHCH3 CH2NHCH2 CONHCH3 CH2NMeCH2 CONHCH3
OCH2CH2CH2 I CH2NHCH2 I CH2NMeCH2 I
OCH2CH2CH2 CH3 CH2NHCH2 CH3 CH2NMeCH2 CH3
OCH2CH2CH2 OCF3 CH2NHCH2 OCF3 CH2NMeCH2 OCF3
OCH2CH2CH2 OCHF2 CH2NHCH2 OCHF2 CH2NMeCH2 OCHF2
OCH2CH2CH2 OCF3 CH2NHCH2 OCF3 CH2NMeCH2 OCF3
OCH2CH2CH2 SCHF2 CH2NHCH2 SCHF2 CH2NMeCH2 SCHF2
CH2NEtCH2 Cl CONHCO Cl CONMeCO Cl
CH2NEtCH2 Br CONHCO Br CONMeCO Br
CH2NEtCH2 CF3 CONHCO CF3 CONMeCO CF3
CH2NEtCH2 C02CH CONHCO C0 CH3 CONMeCO C02CH3
CH2NEtCH2 CONHCH3 CONHCO CONHCH3 CONMeCO CONHCH3
CH2NEtCH2 I CONHCO I CONMeCO I
CH2NEtCH2 CH3 CONHCO CH3 CONMeCO CH3 T and V are both Cl and U is Me
J R J R J R
CH2NEtCH2 OCF3 CONHCO OCF3 CONMeCO OCF3
CH2NEtCH2 0CHF2 CONHCO OCHF2 CONMeCO OCHF2
CH2NEtCH2 OCF3 CONHCO OCF3 CONMeCO OCF3
CH2NEtCH2 SCHF2 CONHCO SCHF2 CONMeCO SCHF
T is Cl and V and U are both Me
J R J R J t R
CH2CH2CH2CH2 Cl OCH2 Cl OCH2CH2 Cl
CH2CH2CH2CH2 Br OCH2 Br OCH2CH2 Br
CH2CH2CH2CH2 CF3 OCH2 CF3 OCH2CH2 CF3
CH2CH2CH2CH2 C02CH3 OCH2 C02CH3 OCH2CH2 C02CH3
CH2CH2CH2CH CONHCH3 OCH2 CONHCH OCH2CH2 CONHCH3
CH2CH2CH2CH2 I OCH2 I OCH2CH2 I
CH2CH2CH2CH2 CH3 OCH2 CH3 OCH2CH2 CH3
CH2CH2CH2CH2 OCF3 OCH2 OCF3 OCH2CH2 OCF3
CH2CH2CH2CH2 OCHF2 OCH2 OCHF2 OCH2CH2 OCHF2
CH2CH2CH2CH2 OCF3 OCH2 OCF3 OCH2CH2 OCF3
CH2CH2CH2CH2 SCHF2 OCH2 SCHF2 OCH2CH2 SCHF2
OCH2CH2CH2 Cl CH2NHCH2 Cl CH2NMeCH2 Cl
OCH2CH2CH2 Br CH2NHCH2 Br CH2NMeCH2 Br
OCH2CH2CH2 CF3 CH2NHCH2 CF3 CH2NMeCH2 CF3
OCH2CH2CH2 C02CH3 CH2NHCH2 C02CH3 CH2NMeCH2 C02CH3
OCH2CH2CH2 CONHCH3 CH2NHCH2 CONHCH3 CH2NMeCH2 CONHCH3
OCH2CH2CH2 I CH2NHCH2 I CH2NMeCH2 I
OCH2CH2CH2 CH3 CH2NHCH2 CH CH2NMeCH2 CH
OCH2CH2CH2 OCF3 CH2NHCH2 OCF3 CH2NMeCH2 OCF
OCH2CH2CH2 OCHF2 CH2NHCH2 OCHF2 CH2NMeCH2 OCHF2
OCH2CH2CH2 OCF3 CH2NHCH2 OCF3 CH2NMeCH2 OCF3
OCH2CH2CH2 SCHF2 CH2NHCH2 SCHF2 CH2NMeCH2 SCHF2
CH2NEtCH2 Cl CONHCO Cl CONMeCO Cl
CH2NEtCH2 Br CONHCO Br CONMeCO Br
CH2NEtCH2 CF3 CONHCO CF3 CONMeCO CF3
CH2NEtCH2 C02CH CONHCO C02CH3 CONMeCO C02CH
CH2NEtCH2 CONHCH3 CONHCO CONHCH3 CONMeCO CONHCH3
CH2NEtCH2 I CONHCO I CONMeCO I
CH2NEtCH2 CH3 CONHCO CH3 CONMeCO CH3 T is Cl and V and U are both Me
J R J R J R
CH2NEtCH2 OCF3 CONHCO OCF3 CONMeCO OCF3
CH2NEtCH2 OCHF2 CONHCO OCHF2 CONMeCO OCHF2
CH2NEtCH2 OCF3 CONHCO OCF3 CONMeCO OCF3
CH2NEtCH2 SCHF2 CONHCO SCHF2 CONMeCO SCHF
Compositions
This invention also includes fungicidal compositions comprising (1)' a fungicidally effective amount of a compound of Formula I (including all geometric md stereoisomers, N-oxides and agriculturally suitable salts thereof); and (2) (i) at least one other insecticide, fungicide, nematocide, bactericide, acaricide, growth regulator, chemosterilant, semiochemical, repellent, attractant, pheromone, feeding stimulant or other biologically active compound; and/or (ii) at least one additional component selected from the group consisting of surfactants, solid diluents and Hquid diluents.
Of note are compositions comprising (a) at least one compound of Formula I; and (b) at least one compound selected from the group consisting of
(bl) alkylenebis(dithiocarbamate) fungicides;
(hi) compounds acting at the b γ complex of the fungal mitochondrial respiratory electron transfer site;
(b3) cymoxanil; (b4) compounds acting at the demethylase enzyme of the sterol biosynthesis pathway;
(b5) morpholine and piperidine compounds that act on the sterol biosynthesis pathway;
(b6) phenylamide fungicides;
(b7) pyrimidinone fungicides;
(b8) ph alirnides; and (b9) fosetyl-aluminum.
The weight ratios of component (b) to component (a) typically is from 100:1 to 1:100, preferably is from 30:1 to 1:30, and more preferably is from 10:1 to 1:10. Of note are compositions wherein the weight ratio of component (b) to component (a) is from 10:1 to 1:1. The be} Complex Fungicides (component (b2))
Strobilurin fungicides such as azoxystrobin, kresoxim-methyl, metommostrobin/fenominostrobin (SSF-126), picoxystrobin, pyraclostrobin and trifloxystrobin are known to have a fungicidal mode of action which inhibits the bc\ complex in the mitochondrial respiration chain (Angew. Chem. Int. Ed., 1999, 38, 1328-1349). Me l (E)-2-[[6-(2-cyanoρhenoxy)-4-ρyrimidinyl]oxy]-α-
(methoxyimino)benzeneacetate (also known as azoxystrobin) is described as a bcγ complex inhibitor in Biochemical Society Transactions 1993, 22, 68S. Methyl (E)- - (methoxyimino)-2-[(2-methylphenoxy)methyl]benzeneacetate (also known as kresoxim- methyl) is described as a bcγ complex inhibitor in Biochemical Society Transactions 1993, 22, 64S. (E)-2-[(2,5-Dimemylphenoxy)memyl]-α-(memoxyimino)-N- methylbenzeneacetamide is described as a bc complex inhibitor in Biochemistiγ and Cell Biology 1995, 55(3), 306-311. Other compounds that inhibit the bc\ complex in the mitochondrial respiration chain include famoxadone and fenamidone.
The bci complex is sometimes referred to by other names in the biophemical literature, including complex III of the electron transfer chain, and ub ydroquino exytochrome c oxidoreductase. It is uniquely identified by the Enzyme Commission number ECl .10.2.2. The bc\ complex is described in, for example, J. Biol. Chem. 1989, 264, 14543-38; Methods Enzymol. 1986, 126, 253-71 ; and references cited therein. The Sterol Biosynthesis Inhibitor Fungicides (component (b4) or (b5)
The class of sterol biosynthesis inhibitors includes DMI and non-DMI compounds, thai control fungi by inhibiting enzymes in the sterol biosynthesis pathway. DMI fungicides have a common site of action within the fungal sterol biosynthesis pathway; that is, an inhibition of demethylation at position 14 of lanosterol or 24-methylene dihydrolanosterol, which are precursors to sterols in fungi. Compounds acting at this site are often referred to as demethylase inhibitors, DMT fungicides, or DMTs. The demethylase enzyme is sometimes referred to by other names in the biochemical literature, including cytochrome P-450
(14DM). The demethylase enzyme is described in, for example, J. Biol. Chem. 1992, 267, 13175-79 and references cited therein. DMI fungicides fall into several classes: azoles (including triazoles and imidazoles), pyrimidines, piperazines and pyridines. The triazoles includes bromuconazole, cyproconazole, difenoconazole, diniconazole, epoxiconazole, fenbuconazole, fluquinconazole, flusilazole, flutriafol, hexaconazole, ipconazole, metconazole, penconazole, propiconazole, tebuconazole, tetraconazole, triadimefon, triadimenol, triticonazole and uniconazole. The imidazoles include clotrimazole, econazole, imazalil, isoconazole, miconazole and prochloraz. The pyrimidines include fenarimol, nuarimol and triarimol. The piperazines include triforine. The pyridines include buthiobate and pyrifenox. Biochemical investigations have shown that all of the above mentioned fungicides are DMI fungicides as described by K. H. Kuck, et al. in Modem Selective Fungicides - Properties, Applications and Mechanisms of Action, Lyr, H., Ed.; Gustav Fischer Verlag: New York, 1995, 205-258.
The DMI fungicides have been grouped together to distinguish them from other sterol biosynthesis inhibitors, such as, the morpholine and piperidine fungicides. The morpholines and piperidines are also sterol biosynthesis inhibitors but have been shown to inhibit later steps in the sterol biosynthesis pathway. The morpholines include aldimorph, dodemorph, fenpropimorph, tridemorph and trimorphamide. The piperidines include fenpropidin. Biochemical investigations have shown that all of the above mentioned morpholine and piperidine fungicides are sterol biosynthesis inhibitor fungicides as described by K. H. Kuck, et al. in Modern Selective Fungicides - Properties, Applications and Mechanisms of Action, Lyr, H., Ed.; Gustav Fischer Verlag: New York, 1995, 185-204.
Pyrimidinone Fungicides (component (b7 )
Pyrimidinone fungicides include compounds of Formula II
Figure imgf000062_0001
π wherein
G is a fused phenyl, thiophene or pyridine ring; Rl is CrC6 alkyl;
R2 is C1-C6 alkyl or C^Cg alkoxy; R3 is halogen; and R4 is hydrogen or halogen.
Pyrimidinone fungicides are described in International Patent Application WO94/26722, U.S. Patent No. 6,066,638, U.S. Patent No. 6,245,770, U.S. Patent No. 6,262,058 and U.S. Patent No. 6,277,858.
Of note are pyrimidinone fungicides selected from the group: 6-bromo-3-propyl-2-propyloxy-4(3H)-qumazolinone, 6,8-diiodo-3-propyl-2-propyloxy-4(3i^-qumazolinone, 6-iodo-3-propyl-2-propyloxy-4(3H)-quinazolinone,
6-chloro-2-propoxy-3-propyll eno[2,3-^pyrimidin-4(3H)-one, 6-bromo-2-propoxy-3-propyltmeno[2,3-(^pyrimidin-4(3H)-one, 7-bromo-2-propoxy-3-propyltmeno[3,2-^pyrimidin-4(3H)-one, 6-bromo-2-propoxy-3-propylpyrido[2,3-fi ]pyrimidin-4(3H)-one, 6,7-dibromo-2-propoxy-3-propylt eno[3,2-^pyrimidin-4(3H)-one, and
3-(cyclopropylmemyl)-6-iodo-2-(propylt o)pyrido[2,3-^pyrmιidin-4(3H)-one.
Table 9 Examples of component (b)
(bl) Alkylenebis(dithiocarbamate)s such as mancozeb, maneb, propineb and zineb
(b3) Cymoxanil
(b6) Phenylamides such as metalaxyl, benalaxyl and oxadixyl
(b8) Phthalimids such as folpet or captan Examples of component (b)
(b9) Fosetyl-aluminum
Other fungicides that can be included in compositions of this invention in combination with a Formula I compound or as an additional component in combination with component (a) and component (b) are acibenzolar, benalaxyl, benomyl, blasticidin-S, Bordeaux mixture (tribasic copper sulfate), carpropamid, captafol, captan, carbendazim, chloroneb, 5 chlorothalonil, copper oxychloride, copper salts such as copper sulfate and copper hydroxide, cyazofamid, cymoxanil, cyprodinil, (S)-3,5-dichloro-N-(3-chloro-l -ethyl- 1- methyl- 2-oxopropyl)-4-methylbenzamide (RH 7281), diclocymet (S-2900), diclomezine, dicloran, dimethomorph, diniconazole-M, dode o h, dodine, edifenphos, fencaramid (SZX0722), fenpiclonil, fentin acetate, fentin hydroxide, fluazinam, fludioxonil, flumetover
10 (RPA 403397), flutolanil, folpet, foselyl-aluminum, furalaxyl, furametapyr (S-82658), iprobenfos, iprodione, isoprothiolane, iprovalicarb, kasugamycin, mancozeb, maneb, mefenoxam, mepronil, metalaxyl, metiram-zinc, myclobutanil, neo-asozin (ferric \ methanearsonate), oxadixyl, pencycuron, prochloraz, procymidone, propamocarb, propineb, pyrifenox, pyrimethanil, pyroquilon, quinoxyfen, spiroxamine, sulfur, thifluzamide,
15 thiophanate-methyl, thiram, triadimefon, tricyclazole, validamycin, vinclozolin, zineb and zoxamid.
Descriptions of the commercially available compounds listed above may be found in The Pesticide Manual, Twelfth Edition, C.D.S. Tomlin, ed., British Crop Protection Council, 2000.
20 Of note are combinations of Formula I with fungicides of a different biochemical mode of action (e.g. mitochondrial respiration inhibition, inhibition of protein synthesis by interference of the synthesis of ribosomal RΝA or inhibition of beta-tubulin synthesis) that can be particularly advantageous for resistance management. Examples include combinations of compounds of Formula I (e.g. Compound 1) with strobilurins such as
25 azoxystrobin, kresoxim-methyl, pyraclostrobin and triflo ystrobin; carbendazim, mitochondrial respiration inhibitors such as famoxadone and fenamidone; benomyl, cymoxanil; dimethomorph; folpet; fosetyl-aluminum; metalaxyl; mancozeb and maneb. These combinations can be particularly advantageous for resistance management, especially where the fungicides of the combination control the same or similar diseases.
30 Of note are combinations of Formula I with fungicides for controlling grape diseases
(e.g. Plasmopara viticola,.Botrytis cinerea and Uncinula necatur) including . alkylenebis(dithiocarbamate)s such as mancozeb, maneb, propineb and zineb, ph alimids such as folpet, copper salts such as copper sulfate and copper hydroxide, strobilurins such as azoxystrobin, pyraclostrobin and trifloxystrobin, mitochondrial respiration inhibitors such as
35 famoxadone and fenamidone, phenylamides such as metalaxyl, phosphonates such as fosetyl-AL dimethomorph, pyrimidinone fungicides such as 6-iodo-3-propyl-2-propyloxy-4(3H)-quinazolinone and 6-chloro-2-propoxy-3- propylmieno[2,3-<^pyrimidin-4(3H)-one, and other fungicides such as cymoxanil.
Of note are combinations of Formula I with fungicides for controlling potato diseases (e.g. Phytophthora infestans, Alternaria solani and Rhizoctonia solanϊ) including alkylenebis(dithiocarbamate)s such as mancozeb, maneb, propineb and zineb; copper salts such as copper sulfate and copper hydroxide; strobilurins such as pyraclostrobin and trifloxystrobin; mitochondrial respiration inhibitors such as famoxadone and fenamidone; phenylamides such as metalaxyl; carbamates such as propamocarb; phenylpyridylamines such as fluazinam and other fungicides such as chlorothalonil, cyazofa id, cymoxanil, dimethomorph, zoxamid and ipro valicarb.
Of note are compositions wherein component (b) comprises at least one compound from each of two different groups selected from (bl), (b2), (b3), (b4), (b5), (b6), (b7), (b8) and (b9). The weight ratio of the compound(s) of the first of these two component (b) groups to the compound(s) of the second of these component (b) groups typically is from 100:1 to 1:100, more typically from 30:1 to 1:30 and most typically from 10:1 to 1:10.
Of note are compositions wherein component (b) comprises at least one compound selected from (bl), for example mancozeb, and at least one compound selected from a second component (b) group, for example, from (b2), (b3), (b6), (b7), (b8) or (b9). Of particular note are such compositions wherein the overall weight ratio of component (b) to component (a) is from 30:1 to 1:30 and the weight ratio of component (bl) to component (a) is from 10:1 to 1:1. Examples of these compositions include compositions comprising mixtures of component (a) (preferably a compound from Index Table A, B or C) with mancozeb and a compound selected from the group consisting of famoxadone, fenamidone, azoxystrobin, kresox n-methyl, pyraclostrobin, trifloxystrobin, cymoxanil, metalaxyl, benalaxyl, oxadixyl, 6-iodo-3-propyl-2-propyloxy-4(3H)-q nazolinone, 6-chloro-2- propoxy-3-propyltMeno[2,3-^pyrimidin-4(3H)-one, folpet, captan and fosetyl-aluminum.
Also of note are compositions wherein component (b) comprises at least one compound selected from (b2), for example famoxadone, and at least one compound selected from a second component (b) group, for example, from (bl), (b3), (b6), (b7), (b8) or (b9). Of particular note are such compositions wherein the overall weight ratio of component (b) to component (a) is from 30: 1 to 1:30 and the weight ratio of component (b2) to component (a) is from 10:1 to 1:1. Examples of these compositions include compositions comprising mixtures of component (a) (preferably a compound from Index Table A, B or C) with famoxadone and a compound selected from the group consisting of mancozeb, maneb, propineb, zineb, cymoxanil, metalaxyl, benalaxyl, oxadixyl, 6-iodo-3-propyl-2-propyloxy- 4(3H)-quinazolmone, 6-chloro-2-propoxy-3-propyltMeno[2,3-^pyrimid -4(3H)-one, folpet, captan and fosetyl-aluminum. Also of note are compositions wherein component (b) comprises the compound of (b3), in other words cymoxanil, and at least one compound selected from a second component (b) group, for example, from (bl), (b2), (b6), (b7), (b8) or (b9). Of particular note are such compositions wherein the overall weight ratio of component (b) to component (a) is from 30: 1 to 1 :30 and the weight ratio of component (b3) to component (a) is from 10:1 to 1:1. Examples of these compositions include compositions comprising mixtures of component (a) (preferably a compound from Index Table A, B or C) with cymoxanil and a compound selected from the group consisting of famoxadone, fenamidone, azoxystrobin, kresoxim-methyl, pyraclostrobin, trifloxystrobin, mancozeb, maneb, pi pineb, zineb, metalaxyl, benalaxyl, oxadixyl, 6-iodo-3-propyl-2-propyloxy-4(3H)-quinazolinone,
6-chloro-2-ρropoxy-3-propylmieno[2,3-(^pyrimidin-4(3H)-one, folpet, captan and fosetyl- aluminum.
Also of note are compositions wherein component (b) comprises at least one compound selected from (b6), for example metalaxyl, and at least one compound selected from a second component (b) group, for example, from (bl), (b2), (b3), (b7), (b8) or (b9). Of particular note are such compositions wherein the overall weight ratio of component (b) to component (a) is from 30: 1 to 1 :30 and the weight ratio of component (b6) to component (a) is from 10:1 to 1:3. Examples of these compositions include compositions comprising mixtures of component (a) (preferably a compound from Index Table A, B or C) with metalaxyl or oxadixyl and a compound selected from the group consisting of famoxadone, fenamidone, azoxystrobin, kresoxim-methyl, pyraclostrobin, trifloxystrobin, cymoxanil, mancozeb, maneb, propineb, zineb, 6-iodo-3-propyl-2-propyloxy-4(3H)-quinazolinone, 6- chloro-2-propoxy-3-propylmieno[2,3-(^pyrimidin-4(3H)-one, folpet, captan and fosetyl- aluminum. Also of note are compositions wherein component (b) comprises at least one compound selected from (b7), for example 6-iodo-3-propyl-2-propyloxy-4(3H)- quinazolinone or 6-chloro-2-propoxy-3-propyltMeno[2,3-<i]pyrimidin-4(3H)-one, and at least one compound selected from a second component (b) group, for example, from (bl), (b2), (b3), (b6), (b8) or (b9). Of particular note are such compositions wherein the overall weight ratio of component (b) to component (a) is from 30: 1 to 1:30 and the weight ratio of component (b7) to component (a) is from 1:1 to 1:20. Included are compositions wherein the weight ratio of component (b6) to component (a) is from 1:4.5 to 1:9. Examples of these compositions include compositions comprising mixtures of component (a) (preferably a compound from Index Table A, B or C) with 6-iodo-3-propyl-2-propyloxy-4(3H)- quinazolinone or 6-chloro-2-propoxy-3-propylt eno[2,3-^pyrimidin-4(3H)-one and a compound selected from the group consisting of famoxadone, fenamidone, azoxystrobin, kresoxim-methyl, pyraclostrobin, trifloxystrobin, cymoxanil, mancozeb, maneb, propineb, zineb, metalaxyl, benalaxyl, oxadixyl, folpet, captan and fosetyl-aluminum. Also of note are compositions wherein component (b) comprises the compound of (b9), in other words fosetyl-aluniinum, and at least one compound selected from a second component (b) group, for example, from (bl), (b2), (b3), (b6) or (b7). Of particular note are such compositions wherein the overall weight ratio of component (b) to component (a) is from 30: 1 to 1 :30 and the weight ratio of component (b9) to component (a) is from 10: 1 to 1:1. Examples of these compositions include compositions comprising mixtures of component (a) (preferably a compound from Index Table A, B or C) with fosetyl-aluminum and a compound selected from the group consisting of famoxadone, fenamidone, azoxystrobin, kresoxim-methyl, pyraclostrobin, trifloxystrobin, manco-jeb, maneb, propineb, zineb, metalaxyl, benalaxyl, oxadixyl, 6-iodo-3-propyl-2-propyloxy-4(3H)-qumazolinone, 6- chloro-2-propoxy-3-propylthieno[2,3-rf]pyrimidin-4(3H)-one, folpet, captan and cymoxanil. Of note are combinations of compounds of Formula I with fungicides giving an even broader spectrum of agricultural protection including strobilurins such as azoxystrobin, kresoxim-methyl, pyraclostrobin and trifloxystrobin; morpholines such as fenpropidine and fenpropimorph; triazoles such as bromuconazole, cyproconazole, difenoconazole, epoxyconazole, flusilazole, ipconazole, metconazole, propiconazole, tebuconazole and triticonazole; pyrimidinone fungicides, benomyl; carbendazim; chlorothalonil; dimethomorph; folpet; mancozeb; maneb; quinoxyfen; validamycin and vinclozolin.
Of note are combinations with other fungicides giving an even broader spectrum of agricultural protection including azoxystrobin, kresoxim-methyl, pyrclostrobin, trifloxystrobin, benomyl, carbendazim, chlorothalonil, dimethomorph, folpet, mancozeb, maneb, quinoxyfen, validamycin, vinclozolin, fenpropidine, fenpropimorph, bromuconazole, cyproconazole, difenoconazole, epoxyconazole, flusilazole, ipconazole, metconazole, propiconazole, tebuconazole and triticonazole. Of note are combinations with other fungicides of a different mode of action (e.g. mitochondrial respiration inhibition, inhibition of protein synthesis by interference of the synthesis of ribosomal RNA or inhibition of beta-tubulin synthesis) that can be particularly advantageous for resistance management. Examples include combinations of compounds of Formula I (e.g. Compound Al) with azoxystrobin, kresoxim-methyl, pyrclostrobin, trifloxystrobin, carbendazim, famoxadone, fenamidone, benomyl, cymoxanil, dimethomorph, folpet, fosetyl-aluminum, metalaxyl, mancozeb, maneb. These combinations can be particularly advantageous for resistance management, especially where the fungicides of the combination control the same or similar diseases.
Of note are combinations with other fungicides for controlling grape diseases including dithiocarbamates such as mancozeb, maneb, propineb and zineb, phthalimids such as folpet, copper salts such as copper sulfate and copper hydroxide, strobilurins such as azoxystrobin, pyrclostrobin and trifloxystrobin, , phenylamides such as metalaxyl, phosphonates such as fosetyl-aluminum, morpholines such as dimethomorph, and other fungicides such as cymoxanil, famoxadone and fenamidone.
Of note are combinations with other fungicides for controlling potato diseases including dithiocarbamates such as mancozeb, maneb, propineb and zineb, copper salts such as copper sulfate and copper hydroxide, strobilurins such as pyrclostrobin and trifloxystrobin, phenylamides such as metalaxyl, carbamates such as propamocarb, phenylpyriylamines such as fluazinam, morpholines such as dimethomorph, and other fungicides such as chlorothalonil, cyazofamid, cymoxanil, famoxadone, fenamidone, zoxamid and iprovalicarb. j Of particular note are combinations of Compound Al with azoxystrobin, combinations of Compound Al with kresoxim-methyl, combinations of Compound Al with pyrclostrobin, combinations of Compound lwith trifloxystrobin, combinations of Compound lwith carbendazim, combinations of Compound Al with chlorothalonil, combinations of Compound Al with dimethomorph, combinations of Compound Al with folpet, combinations of Compound Al with mancozeb, combinations of Compound Al with maneb, combinations of Compound Al with quinoxyfen, combinations of Compound Al with validamycin, combinations of Compound Al with vinclozolin, Compound Al with fenpropidine, Compound Al with fenpropimorph, Compound Al with bromuconazole, Compound Al with cyproconazole, Compound Al with difenoconazole, Compound Al with epoxyconazole, Compound Al with flusilazole, Compound Al with ipconazole, Compound Al with metconazole, Compound Al with propiconazole, Compound Al with tebuconazole, Compound Al with triticonazole, Compound Al with famoxadone, Compound Al with fenamidone, Compound Al with benomyl, Compound A 1 with cymoxanil, Compound A 1 with dimethomorph, Compound Al with folpet, Compound Al with fosetyl-aluminum, Compound Al with metalaxyl, Compound Al with Compound Al with propineb,
Compound Al with zineb, Compound Al with copper sulfate, Compound Al with copper hydroxide, Compound Al with propamocarb, Compound Al with cyazofamid, Compound Al with zoxamid and Compound Al with iprovalicarb. Compound numbers refer to compounds in Index Tables A-D. Preferred 15. Preferred compositions comprise a compound of component (a) mixed with cymoxanil. Preferred 16. Preferred compositions comprise a compound of component (a) mixed with a compound selected from (bl). More preferred is a composition wherein the compound of (bl) is mancozeb. Preferred 17. Preferred compositions comprise a compound of component (a) mixed with a compound selected from (b2). More preferred is a composition wherein the compound of (b2) is famoxadone. Preferred compositions comprise a compound of component (a) mixed with two compounds selected from two different groups selected from (bl), (b2), (b3), (b4), (b5), (b6), (b7), (b8) and (b9). Preferred compositions are those wherein component (a) is selected from the compounds of Formula I indicated in Preferred 1 through 14 above.
Compounds of this invention can also be mixed with one or more insecticides, 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 compositions of this invention can be formulated are: insecticides such as abamectin, acephate, azinphos-methyl, bifenthrin, buprofezin, carbofuran, chlorfenapyr, chloφyrifos, chlorpyrifos-methyl, cyfluthrin, beta-cyfluthrin, cyhalothrin, lambda-cyhalothrin, deltamethrin, diafenthiuron, diazinon, diflubenzuron, 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- (hifluoromemoxy)phenyl]ammo]carbonyl]mdeno[l,2-e][l,3,4]oxadiazme-4a(3H)- carboxylate (indoxacarb), monocrotophos, oxamyl, parathion, parathion-methyl, permethrin, phorate, phosalone, phosmet, phosphamidon, pirimicarb, profenofos, rotenone, sulprofos, tebufenozide, tefluthrin, terbufos, tetrachlorvinphos, thiodicarb, tralomethrin, trichlorfon and triflumuron; bactericides such as streptomycin; acaricides such as amitraz, chinomethionat, chlorobenzilate, cyhexatin, dicofol, dienochlor, etoxazole, fenazaquin, fenbutatin oxide, fenpropathrin, fenpyroximate, hexythiazox, propargite, pyridaben and tebufenpyrad; nematocides such as aldoxycarb and fenamiphos; and biological agents such as Bacillus thuringiensis, Bacillus thuringiensis delta endotoxin, baculovirus, and entomopathogenic bacteria, virus and fungi. The weight ratios of these various mixing partners to compounds of Formula I of this invention typically are between 100: 1 and 1 : 100, preferably between 30:1 and 1:30, more preferably between 10:1 and 1:10 and most preferably between 4:1 and 1:4.
Descriptions of the commercially available compounds listed above may be found in The Pesticide Manual, Twelfth Edition, C.D.S. Tomlin, ed., British Crop Protection Council, 2000.
Formulation Compounds of this invention will generally be used as a formulation or composition with an agriculturally suitable carrier comprising at least one of a liquid diluent, a solid diluent or a surfactant. The formulation or composition ingredients are selected to be consistent with the physical properties of the active ingredient, mode of apphcation 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 (e.g. from 0.01-99.99 weight percent) of active ingredient together with diluent and/or 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 0-25
(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, N,N-dialkyltaurates, Hgnin 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, N,N-dimethylformamide, dimethyl sulfoxide, N-alkylpyrrolidone, ethylene glycol, polypropylene glycol, paraffins, alkylbenzenes, alkylnaphthalenes, oils of olive, castor, linseed, tung, sesame, corn, peanut, cotton-seed, soybean, rape-seed and coconut, fatty acid esters, ketones such as cyclohexanone, 2-heptanone, isophorone and 4-hydroxy-4-methyl-2-pentanone, and alcohols such as methanol, cyclohexanol, decanol and tetrahydrofurfuryl alcohol.
Solutions, including emulsifiable concentrates, can be prepared by simply mixing the ingredients. Dusts and powders can be prepared by blending and, usually, grinding as in a hammer mill or fluid-energy mill. Suspensions are usually prepared by wet-milling; see, for example, U.S. 3,060,084. Preferred suspension concentrates include those containing, in addition to the active ingredient, from 5 to 20% nonionic surfactant (for example, polyethoxylated fatty alcohols) optionally combined with 50-65% liquid diluents and up to 5% anionic surfactants. 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 T. S. Woods, "The Formulator's Toolbox - Product Forms for Modern Agriculture" in Pesticide Chemistry and Bioscience, The Food-Environment Challenge, T. Brooks and T. R. Roberts, Eds.,
Proceedings of the 9th International Congress on Pesticide Chemistry, The Royal Society of Chemistry, Cambridge, 1999, pp. 120-133. See also 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 \- \ 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 Al 65.0% dodecylphenol polyethylene glycol ether 2.0% sodium hgninsulfonate 4.0% sodium silicoaluminate 6.0% montmorillonite (calcined) 23.0%,
Example B •
Granule \
!0 Compound Al 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
15 Compound Al 25.0% anhydrous sodium sulfate 10.0% crude calcium Hgninsulfonate 5.0% sodium alkylnaphthalenesulfonate 1.0% calcium/magnesium bentonite 59.0%.
20 Example D
Emulsifiable Concentrate
Compound Al 20.0% blend of oil soluble sulfonates and polyoxyethylene ethers 10.0%
25 isophorone 70.0%.
Example E
Compound Al 20.0% polyethoxylated fatty alcohol no ionic surfactant 15.0% ester derivative of montan wax 3.0%
30 calcium lignosulfonate anionic surfactant 2.0% polyethoxylated/polypropoxylated polyglycol block copolymer surfactant 1.0% propylene glycol diluent 6.4% poly(dimethylsiloxane) antifoam agent 0.6%
35 antimicrobial agent 0.1% water diluent 51.9% The formulation ingredients are mixed together as a syrup, Compound Al is added and the mixture is homogenized in a blender. The resulting slurry is then wet-milled to form a suspension concentrate. Utility The compounds and compositions of Formula I are useful as plant disease control agents. The present invention therefore 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 preferred methods of use are those involving the compounds or compositions preferred above.
The compounds and compositions of Formula I 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, Cercosporidiumpersonatum, 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, Sphaerothecafuliginea, Fusarium oxysporum, Verticillium dahliae, Pythium aphanidermatum, Phytophthora megasperma, Sclerotinia sclerotiorum, Sclerotium rolfsii, Erysiphe polygoni, Pyrenophora teres, Gaeumannomyces graminis, Rynchosporium secalis, Fusarium roseum, Bremia lactucae and other generea and species closely related to these pathogens. The compositions of the invention are especially effective in controlling Plasmopara viticola on grapes and Phytophthora infestans on potatoes and tomatoes.
Plant disease control is ordinarily accomplished by applying an effective amount of a compound of Formula I 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.
Rates of apphcation for these compounds can be influenced by many factors of the environment and should be determined under actual us e 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. The following TESTS demonstrate the control efficacy of compounds suitable for use in accordance with this invention on specific pathogens. The pathogen control protection afforded by the compounds is not limited, however, to these species. These TESTS can also be used to demonstrate the control efficacy of compositions of this invention on specific pathogens. Test suspensions comprising a single active ingredient are sprayed to demonstrate the control efficacy of the active ingredient individually. To demonstrate the control efficacy of a combination, (a) the active ingredients can be combined in the appropriate amounts in a single test suspension, (b) stock solutions of individual active ingredients can be prepared and then combined in the appropriate ratioj and diluted to the final desired concentration to form a test suspension or (c) test suspensions comprising single active ingredients can be sprayed sequentially in the desired ratio.
Synergism has been described as "the cooperative action of two components [e.g. component (a) and component (b)] of a mixture, such that the total effect is greater or more prolonged than the sum of the effects of the two (or more) taken independently" (see Tames, P. M. L., Neth. J. Plant Pathology, 1964, 70, 73-80). The presence of a synergistic effect between two active ingredients is established with the aid of the Colby equation (see Colby, S. R. In Calculating Synergistic and Antagonistic Responses of Herbicide Combinations, Weeds, 1967, 15, 20-22): p = A+B- A x B 100 Using the methods of Colby, the presence of a synergistic interaction between two active ingredients is established by first calculating the predicted activity, p, of the mixture based on activities of the two components applied alone. If p is lower than the experimentally established effect, synergism has occurred. In the equation above, A is the fungicidal activity in percentage control of one component applied alone at rate x. The B term is the fungicidal activity in percentage control of the second component applied at rate y. The equation estimates p, the fungicidal activity of the mixture of A at rate x with B at rate y if their effects are strictly additive and no interaction has occurred.
See Index Tables A-D for descriptions of compound suitable for use in this invention. The following abbreviations are used in the Index Tables that follow: Me is methyl, Et is ethyl, Ph is phenyl, OMe is methoxy, OEt is ethoxy. The abbreviation "Ex." stands for "Example" and is followed by a number indicating in which example the compound is prepared. INDEX TABLE A
Figure imgf000074_0001
* See Index Table D for lR NMR spectral data
INDEX TABLE B
Figure imgf000074_0002
Compound Number (R°)D
Bl 2-NH(3-CF3-Ph) *
B2 2-SPh *
B3 2-SMe *
B4 6-C1 *
B5 2-OPh *
B6 2-OEt *
B7 2,4-Cl2 *
B8 2-OH *
* See Index Table D for *H NMR spectral data INDEX TABLE C
Figure imgf000075_0001
Compound Number (R6)r 4-
Cl 2-C1 *
C2 2-Cl-6-OMe *
* See Index Table D for lR NMR spectral data
INDEX TABLE D
Cnφd No. *H NMR Data (300mHz; CDC13 solution unless indicated otherwise)a
Al δ 8.22 (s, IH), 7.30 (s, IH), 7.36-7.23 (m, 3H), 6.99 (bs, IH), 5.03 (m, IH), 2.82 (m, 3H), 2.29 (s,
3H), 1.94 (m, 3H) A2 δ 8.24 (S, IH), 7.71 (d, J=8.7 Hz, 2H), 7.58 (d, J = 8.6 Hz, 2H), 7.33 (bs, IH), 7.27 (s, IH), 4.97
(m, IH), 2.82 (m, 3H), 2.31 (s, 3H), 1.95 (in, 2H), 1.69 (m, IH) A3 δ 8.20 (s, IH), 7.68 (m, 2H), 7.55 (in, 2H), 7.25 (s, IH), 6.87 (bs, IH), 5.02 (m, IH), 2.81 (t,
J=6.4 Hz, 2H), 2.70 (in, IH), 2.29 (s, 3H), 1.94 (in, 2H), 1.79 (m, IH) A4 δ 8.23 (s, IH), 7.35 (m, IH), 7.26 (s, IH), 7.08 (bs, IH), 6.69 (d, J=8.1 Hz, IH), 6.91 (d, J=8.3
Hz, IH), 5.02 ( , IH), 2.81 (in, 2H), 2.74 (m, IH), 2.29 (s, 3H), 1.95 (in, 2H), 1.82 (m, IH) A5 δ 8.24 (s, IH), 7.74 (m, IH), 7.34 (in, 3H), 7.26 (s, IH), 7.15 (bs, IH), 5.10 (m, IH), 2.82 (in,
2H), 2.70 (m, IH), 2.29 (s, 3H), 195 (in, 3H) A6 δ 8.21 (s, IH), 7.35 (s, 2H), 7.24 (s, IH), 6.98 (bs, IH), 4.98 (m, IH), 2.80 (in, 3H), 2.29 (s, 3H),
1.95 (in, 2H), 1.83 (m, IH) A7 δ 8.22 (s, IH), 7.48 (d, J=7.7 Hz, IH), 7.22 (in, 4H), 6.82 (bs, IH), 5.03 (m, IH), 2.81 (t, J=6.41
Hz, 2H), 2.71 (in, IH), 2.52 (s, 3H), 2.29 (s, 3H), 1.94 (m, 2H), 1.78 (in, IH) A8 δ 8.22 (s, IH), 7.26 (s, IH), 7.19 (in, IH), 7.13 (bs, IH), 6.87 (m, IH), 5.02 (m, IH), 2.82 (t,
J=6.4 Hz, 2H), 2.76 (m, IH), 2.30 (s, 3H), 1.95 (m, 2H), 1.78 (m, IH) A9 δ 8.22 (s, IH), 7.25 (m, 3H), 7.04 (t, J=8.4 Hz, IH), 7.00 (bs, IH), 5.02 (m, IH), 2.82 (m, 3H),
2.27 (s, 3H), 1.95 (m, 2H), 1.82 (m, IH) A10 δ 8.23 (s, IH), 7.24 (m, 2H), 6.79 (bs, IH), 6.55 (m, 2H), 5.03 (m, IH), 3.82 (s, 6H), 2.79 (m,
2H), 2.71 (m, IH), 2.28 (s, 3H), 1.92 (in, 3H) Bl δ 10.8 (s, IH), 8.35 (m, IH), 8.25 (s, IH), 8.07 (s, IH), 7.86 (m, 2H), 7.41 (m, 2H), 7.29 (m, IH),
6.77 (in, IH), 4.98 (in, IH), 2.85 (in, 2H), 2.72 (in, IH), 2.32 (s, 3H), 1.98 (in, 2H), 1.72 (m, IH) B2 δ 8.37 (m, IH), 8.24 (s, IH), 7.91 (in, IH), 7.52 (in, 2H), 7.37 (in, 4H), 7.27 (s, IH), 7.07 (m,
IH), 5.07 (m, IH), 2.82 (m, 3H), 2.31 (s, 3H), 198 ( , 2H), 1.80 (in, IH) B3 δ 9.07 (bs, IH), 8.51 (m, IH), 8.24 (s, IH), 7.90 (m, IH), 7.28 (s, IH), 7.05 (m, IH), 5.03 (m,
IH), 2.83 (m, 2H), 2.72 (m, IH), 2.55 (s, 3H), 2.30 (s, 3H), 1.97 (in, 2H), 1.86 (in, IH) B4 δ 8.81 (d, J=2.6 Hz, IH), 8.24 (s, IH), 8.12 (dd, J=2.6, 8.3 Hz, IH), 7.56 (bs, IH), 7.37 (d, J=8.3
Hz, IH), 7.32 (s, IH), 5.02 (m, IH), 2.85 ( , 2H), 2.72 (m, IH), 2.33 (s, 3H), 1.97 (in, 2H), 1.78
( , IH) B5 δ 9.36 (bs, IH), 8.67 (dd, J=1.9, 7.5 Hz, IH), 8.21 (in, IH), 8.15 (s, IH), 7.44 ( , IH), 7.23 ( ,
6H), 5.12 (m,lH), 2.80 (in, 3H), 2.25 (s, 3H), 1.95 (in, 2H), 1.74 (in, IH) B6 δ 9.03 (bs, IH), 8.58 (dd, J= 2.1, 7.5 Hz, IH), 8.29 (s, IH), 8.23 (dd, J=2.1,> 4.9 Hz, IH), 7.28 (s,
IH), 7.03 (dd, J=4.9, 7.5 Hz, IH), 5.10 (in, IH), 4.51 (m, 2H), 2.83 (m,t2H), 2.70 (m, IH), 2.32
(s, 3H), 1.95 (m, 2H), 1.78 (m, IH), 1.39 (t, J=7.1 Hz, 3H) B7 δ 8.29 (d, J=5.4 Hz, IH), 8.21 (s, IH), 7.31 (d, J=5.4 Hz, IH), 7.26 (s, IH), 7.12 (bs, IH), 5.02
(in, IH), 2.82 (m, 3H), 2.29 (s, 3H), 1.97 (m, 2H), 1.84 (m, IH) Cl δ 8.50 (d, J=5.0 Hz, IH), 8.24 (s, IH), 7.73 (s, IH), 7.61 (dd, J= 1.5, 5.0 Hz, IH), 7.50 (bs, IH),
7.29 (s, IH), 4.95 (m, IH), 2.83 (t, J=6.5 Hz, 2H), 2.75 (m, IH), 2.32 (s, 3H), 1.97 (in, 2H), 1.69
(m, IH) C2 δ 8.24 (s, IH), 7.37 (bs, IH), 7.29 (m, 2H), 7.05 (s, IH), 4.91 (m, IH), 3.96 (s, 3H), 2.82 (t, J=6.4
Hz, 2H), 2.73 (m, IH), 2.32 (s, 3H), 1.95 (in, 2H), 1.65 (in, IH) (d)-doublet, (t)-triplet, (q)-quartet, (m)-multiplet, (dd)-doublet of doublets, (dt)-doublet of triplets, (br s)-broad singlet.
BIOLOGICAL EXAMPLES OF THE INVENTION General protocol for preparing test suspensions: Test compounds are first dissolved in acetone in an amount equal to 3% of the final volume and then suspended at the desired concentration (in ppm) in acetone and purified water (50/50 mix) containing 250 ppm of the surfactant Trem® 014 (polyhydric alcohol esters). The resulting test suspensions are then used in the following tests. Spraying a 200 ppm test suspension 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 hours, 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 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 hours, and then moved to a growth chamber at 20 °C for 5 days, after which disease ratings were made.
TEST D 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 oϊyPlasmopara viticola (the causal agent of grape downy mildew) and incubated in a saturated atmosphere at 20 °C for 24 hours, moved to a growth chamber at 20 °C for 6 days, and then incubated in a saturated atmosphere at 20 °C for 24 hours, after which disease ratings were made.
Results for Tests A-D 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.
Table A
Compound Test A TestB Test C TestD
Al ' 0 84 100 -
A2 0 18 5 -
A3 0 41 47 -
A4 0 0 90 -
A5 0 55 46 -
A6 0 9 82 -
A7 0 45 75 -
A8 0 55 100 -
A9 0 38 97 -
A10 - - - -
Bl 0 19 16 -
B2 - - - -
B3 0 23 56 -
B4 0 9 . 32 -
B5 - - - -
B6 - - - -
B7 - - - -
B8 0 19 47 -
Cl 0 55 84 -
C2 95 28 18 -

Claims

CLAIMSWhat is claimed is:
1. 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 compound of Formula I, N-oxides, agriculturally suitable salts and compositions thereof:
Figure imgf000078_0001
wherein
A is taken together with Ν-C=C to form a substituted fused pyridinyl ring; B is a substituted phenyl or pyridinyl ring;
J is an optionally substituted linking chain of 2 to 5 members including at least one carbon member, optionally including one or two carbon members as C(=O), and optionally including one member selected from nitrogen and oxygen; W is C=L or SOn; L is O or S;
R1 is H; or Cγ- ^ alkyl, C2-Cg alkenyl, C2-C6 alkynyl or C3-C6 cycloalkyl, each optionally substituted; R3 is H; or C^Cg alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C3-C6 cycloalkyl, C2-Cg alkylcarbonyl, C2-Cg alkoxycarbonyl, C2-Cg alkylaminocarbonyl or C3-Cg dialkylaminocarbonyl; and n is 1 or 2.
2. The method of Claim 1 wherein
A is taken together with N-C=C to form a fused pyridinyl ring substituted with one or two substituents independently selected from R5; B is substituted with from one to three substituents independently selected from R6;
J is a linking chain of 2 to 5 members mcluding at least one carbon member, optionally including one or two carbon members as C(=O), and optionally including one member selected from nitrogen or oxygen, optionally substituted with one or more substituents selected from the group consisting of Cι_-C alkyl, halogen, CN, NO2 and CrC2 alkoxy;
R1 is H; or C^Cg alkyl, C -C6 alkenyl, C -C6 alkynyl or C3-CG cycloalkyl, each optionally substituted with one or more substituents selected from the group consisting of halogen, CN, NO2, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, 0^4 alkylsulfinyl, C1-C4 alkylsulfonyl, C2-C4 alkoxycarbonyl, C1-C4 alkylamino, C2-Cg dialkylamino and C3-C6 cycloalkylamino; eachR5 and eachR6 is independently -Cg alkyl, C -Cg alkenyl, C2-Cg alkynyl, C -C6 cycloalkyl, Cj-Cg haloalkyl, C2-Cg haloalkenyl, C2-Cg haloalkynyl,
C -C6 halocycloalkyl, halogen, CN, CO2H, CONH2, NO2, hydroxy, CrC4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylthio, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl, Cj-C4 haloalkylthio, C1-C4 haloalkylsulfinyl, C -C4 haloalkylsulfonyl, C1-C4 alkoxycarbonyl, C1-C4 alkylaminp, C2~Cg dialkylamino, C3-Cg cycloalkylamino, C2-Cg alkylcarbonyl, C2-Cg alkoxycarbonyl, C2-C6 alkylaminocarbonyl, C3-Cg dialkylaminocarbonyl, C -Cg trialkylsilyl; or each R5 and each R6 is independently a phenyl ring, a 5- or 6-membered heteroaromatic ring, a benzyl ring or a phenoxy ring, each ring optionally substituted with from one to three groups independently selected from R7; and each R7 is independently C1-C4 alkyl, C2-C4 alkenyl, C2-C alkynyl, C3-C6 cycloalkyl, C1-C4 haloalkyl, C2-C4 haloalkenyl, C2-C4 haloalkynyl, C3-C6 halocycloalkyl, halogen, CN, NO2, C1 -C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylthio, C1 -C4 alkylsulfinyl, C1-C4 alkylsulfonyl C1-C4 alkoxycarbonyl, Cτ-C4 alkylamino, C2-Cg <fra&ylamino, C3-Cg cycloalkylamino, C3-Cg
(a&yl)cycloalkylamino, C2-C4 alkylcarbonyl, C2-Cg alkoxycarbonyl, C2-Cg alkylaminocarbonyl, C3-Cg dialkylaminocarbonyl or C3-Cg trialkylsilyl.
3. The method of Claim 2 wherein W is C=O; J is selected from -CH2CH2- -CH2CH2CH2- -CH2CH2CH2CH2-, -OCH2-
-OCH2CH2-, -OCH2CH2CH2- -CH2NHCH2-, -CH2N(C1-C2a] I)CH2- -CONHCO- and -CON(CrC2 alkyl)CO-; and each R5 and each R6 is independently Cj-Cg alkyl, C2-Cg alkenyl, C2-Cg alkynyl, C3-C6 cycloalkyl, Cj-Cg haloalkyl, C2-Cg haloalkenyl, C2-Cg haloalkynyl, C3-Cg halocycloalkyl, halogen, CN, NO2, C1-C4 alkoxy, C1-C4 haloalkoxy,
CrC4 alkylthio, CrC4 alkylsulfinyl, CrC alkylsulfonyl, C1-C4 haloalkylthio, C1-C haloalkylsulfinyl, C1-C4 haloalkylsulfonyl, C1-C4 alkoxycarbonyl, C2-Cg alkylcarbonyl, C2-Cg alkoxycarbonyl, C2-Cg alkylaminocarbonyl or C3-Cg dialkylaminocarbonyl.
4. The method of Claim 3 wherein
B is a phenyl ring optionally substituted with from one to three substituents independently selected from R6; J is -CH2CH2- or -CH2CH2CH2-; eachR5 is independently CH3, Cl, Br, I, CN, NO2, CF3, OCF3, OCHF2, SCF3,
SCHF2, CO2CH3 or CONHCH3; and eac R6 is independently Cι-C2 alkyl, Cι-C2 haloalkyl, halogen, CN, CrC2 alkoxy, C2~C2 haloalkoxy, CrC2 alkylthio, Ci-C2 alkylsulfinyl or Cι~C2 alkylsulfonyl and at least one R6 is located in a position ortho to the link with W.
5. The method of Claim 3 wherein B is a 3-pyridinyl or a 4-pyridinyl ring optionally substituted with from one to three substituents independently selected from R6; J is -CH2CH2- or -CH2CH2CH2-; , each R5 is independently CH3, Cl, Br, I, CN, NO2, CF3, OCF3, OCHF2, SCF3,
SCHF2, CO2CH3 or CONHCH3; and eachR6 is independently Cι-C alkyl, Cι-C2 haloalkyl, halogen, CN, Cj-C2 alkoxy, Cι~C2 haloalkoxy, C1-C2 alkylthio, Cι-C2 alkylsulfinyl or Cι-C2 alkylsulfonyl and at least one R6 is located in a position ortho to the link with W.
6. The method of Claim 5 wherein B is a 3 -pyridinyl ring wherein one R6 is Cl located at the 2-position ortho to the link with C=O, another R6 is selected from Cl or methyl and is located at the 4-position ortho to the link with C=O and a third optional R6 is methyl at the 6-position.
7. The method of any of Claims 1 through 6 wherein R1 is H and R3 is H. 8. The method of Claim 1 comprising a compound selected from the group consisting of
2-chloro-6-memoxy-N-(5,6,7,8-tetrahydro-3-memyl-8-qumolinyl)-4- pyridinecarboxamide, 2,6-diclnoro-N-(5,6,7}8-tetrahydro-3-memyl-8-qumolinyl)benzamide and 2,3,6-Mfluoro-N-(5,6,7,
8-te1rahydro-3-methyl-8-qumol yl)benzamide.
9. A compound of Formula I of Claim 1 , N-oxides, agriculturally suitable salts thereof, provided that when B is a substituted phenyl ring, W is C=O or SO2, R3 is H and J is a saturated chain of from 2 to 4 carbons that is either unsubstituted or substituted with from one to three substituents selected from the group consisting of alkyl, alkoxy, aryl or aralkyl, then the compound is an N-oxide.
10. The compound of Claim 9 wherein A is taken together with Ν-C=C to form a fused pyridinyl ring substituted with one or two substituents independently selected from R5; B is substituted with from one to three substituents independently selected from R6; J is a linking chain of 2 to 5 members including at least one carbon member, optionally including one or two carbon members as C(=O), and optionally including one member selected from nitrogen or oxygen, optionally substituted with one or more substituents selected from the group consisting of Cj-C2 alkyl, halogen, CN, NO2 and CrC2 alkoxy; R1 is H; or C^-Cg alkyl, C2-Cg alkenyl, C -C6 alkynyl or C3-Cg cycloalkyl, each optionally substituted with one or more substituents selected from the group consisting of halogen, CN, NO2, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl, C2-C4 alkoxycarbonyl, C1-C4 alkylamino, C2-Cg dialkylamino and C3-Cg cycloalkylamino; each R5 and each R6 is independently C^-Cg alkyl, C2-Cg alkenyl, C2-C6 alkynyl, C3-Cg cycloalkyl, C^-Cg haloalkyl, C2-C6 haloalkenyl, C2-Cg haloalkynyl, C3-C6 halocycloalkyl, halogen, CN, CO2H, CONH2, NO2, hydroxy, CrC4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylthio, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl, C1-C4 haloalkylthio, C1-C4 haloalkylsulfinyl, C1-C4 haloalkylsulfonyl, C1-C4 alkoxycarbonyl, C1-C4 alkylamino, C2-Cg dialkylamino, C3-Cg cycloalkylamino, C2-Cg alkylcarbonyl, C2-C6 alkoxycarbonyl, C2-Cg alkylaminocarbonyl, C3-Cg dialkylaminocarbonyl, C3-Cg trialkylsilyl; or each R5 and each R6 is independently a phenyl ring, a 5- or 6-membered heteroaromatic ring, a benzyl ring or a phenoxy ring, each ring optionally substituted with from one to three groups independently selected from R7; and each R7 is independently Cj -C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-Cg cycloalkyl, C2-C4 haloalkyl, C2-C4 haloalkenyl, C2-C4 haloalkynyl, C3-Cg halocycloalkyl, halogen, CN, NO2, C1-C4 alkoxy, Cj-04 haloalkoxy, C1-C4 alkylthio, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl C1-C4 alkoxycarbonyl, C1-C4 alkylamino, C2-Cg diaj^ylamino, C3-Cg cycloalkylamino, C3-Cg (alkyl)cycloalkylamino, C2-C4 alkylcarbonyl, C2-Cg alkoxycarbonyl, C2-C alkylaminocarbonyl, C3-Cg dialkylaminocarbonyl or C3-Cg trialkylsilyl.
11. The compound of Claim 10 wherein W is CO;
J is selected from -CH2CH2- -CH2CH2CH2- -CH2CH2CH2CH2- -OCH2-, -OCH2CH2~, -OCH2CH2CH2-, -CH2NHCH2-,
-CH2N(Cι-C2alky])CH2- -CONHCO- and -CON(Cι-C2 alkyl)CO-; and each R5 and each R6 is independently Cj-Cfi alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, CrC6 haloalkyl, C2-C6 haloalkenyl, C2-C6 haloalkynyl, C3-C6 halocycloalkyl, halogen, CN, NO2, C1-C4 alkoxy, CrC4 haloalkoxy, CrC4 alkylthio, CrC4 alkylsulfinyl, CrC4 alkylsulfonyl, CrC4 haloalkylthio,
C1-C4 haloalkylsulfinyl, C!-C4 haloalkylsulfonyl, CrC4 alkoxycarbonyl, C2-C6 alkylcarbonyl, C2-Cg alkoxycarbonyl, C2-C6 alkylaminocarbonyl or C3-C8 dialkylaminocarbonyl.
12. The compound of Claim 11 wherein B is a phenyl ring optionally substituted with from one to three substituents independently selected from R6; J is -CH2CH2- or -CH2CH2CH2-; each R5 is independently CH3, Cl, Br, I, CN, NO2, CF3, OCF3, OCHF2, SCF3,
SCHF2, CO2CH3 or CONHCH3; and each R6 is independently Cι~C2 alkyl, Cι-C2 haloalkyl, halogen, CN, Cχ-C2 alkoxy, Ci-C2 haloalkoxy, Cj-C2 alkylthio, C1-C2 alkylsulfinyl or Cj-C2 alkylsulfonyl and at least one R6 is located in a position ortho to the link ith W.
13. The compound of Claim 11 wherein
B is a 3-pyridinyl or a 4-pyridinyl ring optionally substituted with from one to three substituents independently selected from R6; J is -CH2CH2- or -CH2CH2CH2-; each R5 is independently CH3, Cl, Br, I, CN, NO2, CF3, OCF3, OCHF2, SCF3, SCHF2, CO2CH3 or CONHCH3; and eachR6 is independently C1-C2 alkyl, Cι-C2 haloalkyl, halogen, CN, Cι-C2 alkoxy, Cι-C2 haloalkoxy, Cι-C2 alkylthio, Cι-C2 alkylsulfinyl or Cι-C2 alkylsulfonyl and at least one R6 is located in a position ortho to the link with W.
14. The compound of Claim 13 wherein B is a 3-pyridinyl ring wherein one R6 is Cl located at the 2-position ortho to the link with C=O, another R6 is selected from Cl or methyl and is located at the 4-position ortho to the link with C=O and a third optional R6 is methyl at the 6-position.
15. The compound of any of Claims 9 through 14 wherein R1 is H and R3 is H.
16. The compound of Claim 9 that is 2-chloro-6-me oxy-N-(5,6,7,8-telrahydro-3-me yl-8-qumolmyl)-4-pyridinecarboxamide.
17. A composition comprising (a) at least one compound of Formula I of Claim 1 ; and
(b) at least one compound selected from the group consisting of (bl) alkylenebis(dithiocarbamate) fungicides; (b2) compounds acting at the bcγ complex of the fungal mitochondrial respiratory electron transfer site; (b3) cymoxanil; (b4) compounds acting at the demethylase enzyme of the sterol biosynthesis pathway; (b5) morpholine and piperidine compounds that act on the sterol biosynthesis pathway; (b6) phenylamide fungicides; (b7) pyrimidinone fungicides; (b8) phthalimides; and (b9) fosetyl-aluminum.
18. The composition of Claim 19 wherein component (b) comprises at least one compound from each of two different groups selected from (bl), (b2), (b3), (b4), (b5), (b6), (b7), (b8) and (b9).
PCT/US2002/018394 2001-05-15 2002-05-14 Pyridinyl fused bicyclic amide as fungicides WO2002091830A1 (en)

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IL15800902A IL158009A0 (en) 2001-05-15 2002-05-14 Pyridinyl fused bicyclic amides as fungicides
US10/473,700 US20040127361A1 (en) 2002-05-14 2002-05-14 Pyridinyl fused bicyclic amides as fungicides
EP02744275A EP1387612A1 (en) 2001-05-15 2002-05-14 Pyridinyl fused bicyclic amide as fungicides
JP2002588757A JP2004529943A (en) 2001-05-15 2002-05-14 Pyridinyl-fused bicyclic amides as fungicides
BR0209687-0A BR0209687A (en) 2001-05-15 2002-05-14 Plant disease control method, compost and composition
MXPA03010436A MXPA03010436A (en) 2001-05-15 2002-05-14 Pyridinyl fused bicyclic amide as fungicides.

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WO2010137351A1 (en) 2009-05-29 2010-12-02 Raqualia Pharma Inc. Aryl substituted carboxamide derivatives as calcium or sodium channel blockers
JP2011516556A (en) * 2008-04-11 2011-05-26 ブリストル−マイヤーズ スクイブ カンパニー CGRP receptor antagonist
US10752640B2 (en) 2014-08-01 2020-08-25 Nuevolution A/S Compounds active towards bromodomains
US11661422B2 (en) 2020-08-27 2023-05-30 Incyte Corporation Tricyclic urea compounds as JAK2 V617F inhibitors
US11691971B2 (en) 2020-06-19 2023-07-04 Incyte Corporation Naphthyridinone compounds as JAK2 V617F inhibitors
US11753413B2 (en) 2020-06-19 2023-09-12 Incyte Corporation Substituted pyrrolo[2,1-f][1,2,4]triazine compounds as JAK2 V617F inhibitors
US11767323B2 (en) 2020-07-02 2023-09-26 Incyte Corporation Tricyclic pyridone compounds as JAK2 V617F inhibitors
US11780840B2 (en) 2020-07-02 2023-10-10 Incyte Corporation Tricyclic urea compounds as JAK2 V617F inhibitors
US11919908B2 (en) 2020-12-21 2024-03-05 Incyte Corporation Substituted pyrrolo[2,3-d]pyrimidine compounds as JAK2 V617F inhibitors
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Cited By (12)

* Cited by examiner, † Cited by third party
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JP2007509944A (en) * 2003-10-27 2007-04-19 メルク　エンド　カムパニー　インコーポレーテッド Method for producing CCR-2 antagonist
JP2011516556A (en) * 2008-04-11 2011-05-26 ブリストル−マイヤーズ スクイブ カンパニー CGRP receptor antagonist
WO2010137351A1 (en) 2009-05-29 2010-12-02 Raqualia Pharma Inc. Aryl substituted carboxamide derivatives as calcium or sodium channel blockers
EP3632899A1 (en) 2009-05-29 2020-04-08 RaQualia Pharma Inc. Aryl substituted carboxamide derivatives as calcium or sodium channel blockers
US10752640B2 (en) 2014-08-01 2020-08-25 Nuevolution A/S Compounds active towards bromodomains
US11691971B2 (en) 2020-06-19 2023-07-04 Incyte Corporation Naphthyridinone compounds as JAK2 V617F inhibitors
US11753413B2 (en) 2020-06-19 2023-09-12 Incyte Corporation Substituted pyrrolo[2,1-f][1,2,4]triazine compounds as JAK2 V617F inhibitors
US11767323B2 (en) 2020-07-02 2023-09-26 Incyte Corporation Tricyclic pyridone compounds as JAK2 V617F inhibitors
US11780840B2 (en) 2020-07-02 2023-10-10 Incyte Corporation Tricyclic urea compounds as JAK2 V617F inhibitors
US11661422B2 (en) 2020-08-27 2023-05-30 Incyte Corporation Tricyclic urea compounds as JAK2 V617F inhibitors
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