WO2013126283A1 - Fungicidal pyrazoles - Google Patents

Fungicidal pyrazoles Download PDF

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Publication number
WO2013126283A1
WO2013126283A1 PCT/US2013/026350 US2013026350W WO2013126283A1 WO 2013126283 A1 WO2013126283 A1 WO 2013126283A1 US 2013026350 W US2013026350 W US 2013026350W WO 2013126283 A1 WO2013126283 A1 WO 2013126283A1
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Prior art keywords
alkyl
ring
independently selected
compound
haloalkyl
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PCT/US2013/026350
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French (fr)
Inventor
Jeffrey Keith Long
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E. I. Du Pont De Nemours And Company
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Publication of WO2013126283A1 publication Critical patent/WO2013126283A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members 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
    • C07D231/38—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members 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
    • C07D231/18—One oxygen or sulfur atom
    • C07D231/20—One oxygen atom attached in position 3 or 5
    • 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
    • C07D401/04—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 directly linked by a ring-member-to-ring-member bond

Definitions

  • This invention relates to certain pyrazoles, their N-oxides, salts and compositions, and methods of their use as fungicides.
  • This invention is directed to compounds of Formula 1 (including all stereoisomers), N-oxides, and salts thereof, agricultural compositions containing them and their use as fungicides:
  • X is O, NR 4 or CR 15 R 16 ;
  • R 1 is H, halogen, -Cg alkyl, C ⁇ -Cg haloalkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 3 - C 7 cycloalkyl, C0 2 R 5 , C(0)NR 6 R 7 , cyano, -Cg alkoxy, -Cg haloalkoxy or
  • R 1 is phenyl optionally substituted with up to 3 R 8 ; or a five- or six-membered
  • nitrogen-containing aromatic heterocycle optionally substituted with up to 3 substituents independently selected from R 9a on carbon atom ring members and R 9 ⁇ on nitrogen atom ring members;
  • R la is H
  • R la and R 1 are taken together with the carbon atom to which they are attached to form a cyclopropyl ring optionally substituted with up to 2 substituents independently selected from halogen and methyl;
  • R 2 is H, C 2 -C 3 alkenyl or C 2 -C 3 alkynyl
  • each R 3 is independently selected from halogen, cyano, nitro, amino, methylamino, dimethy lamino, formylamino, C 2 -C 3 alky lcarbony lamino, C1-C4 alkyl, C1-C4 haloalkyl, C ⁇ -C 3 alkoxy, C ⁇ -C 3 haloalkoxy, C ⁇ -C 3 alkylthio, C ⁇ -C 3 haloalkylthio, C ⁇ -C 3 alkylsulfmyl, C ⁇ -C 3 haloalkylsulfinyl, C ⁇ -C 3
  • alkylsulfonyl C1-C3 haloalkylsulfonyl, C 1 -C 2 alkylsulfonyloxy, C 1 -C 2 haloalkylsulfonyloxy, C 3 -C 4 cycloalkyl, C 3 -C 7 cycloalkoxy, C 4 -C 6
  • R 4 is H, formyl, C 2 -C 5 alkenyl, C 3 -C 5 alkynyl, C 3 -C 7 cycloalkyl, -S0 3 -M+,
  • R 5 is H, C!-C 6 alkyl or Ci ⁇ C 6 haloalkyl
  • R 6 and R 7 are independently selected from H, C j -Cg alkyl, C j -Cg haloalkyl, C 3 -C 7 cycloalkyl, C 4 -C 8 cycloalkylalkyl and C 4 -C 8 alkylcycloalkyl; or
  • R 6 and R 7 are taken together with the nitrogen atom to which they are connected to form a four- to seven-membered nonaromatic heterocyclic ring containing ring members, in addition to the connecting ring nitrogen atom, selected from carbon atoms and optionally up to one ring member selected from O, S(0) n and NR 13 ; each R 8 , R 9a and R 9b is independently selected from halogen, C 1 -C 2 alkyl, C 1 -C 2 haloalkyl, C 1 -C 2 alkoxy, C 1 -C 2 haloalkoxy, cyano, nitro, SCH 3 , S(0)CH 3 and S(0) 2 CH 3 ;
  • R 10 is C!-C 6 alkyl or ⁇ -0 6 haloalkyl
  • each R 11 is independently C j -Cg alkyl, -Cg haloalkyl, C 3 -C 6 cycloalkyl, C j -Cg alkoxy, C 2 -C 7 alkoxyalkyl, C 2 -C 7 alkylaminoalkyl, C 2 -Cg dialkylaminoalkyl, C 1 -C 6 alkylthio or C 2 -C 7 alkylthioalkyl;
  • each R 12 is independently C 3 -C 7 cycloalkyl, Ci ⁇ C 4 alkoxy, Ci ⁇ C 4 haloalkoxy, Ci ⁇ C 4 alkylthio, Ci ⁇ C 4 alkylsulfinyl, Ci ⁇ C 4 alkylsulfonyl or cyano;
  • R 13 is H, C!-C 3 alkyl or C 2 -C 3 haloalkyl
  • each R 14 is independently H, cyano, C ⁇ -C 3 alkyl or C ⁇ -C 3 haloalkyl;
  • R 15 is H or C!-C 4 alkyl
  • R 16 is F, CI or OR 18 ;
  • each R 22 is independently H, -Cg alkyl, C j -Cg haloalkyl, C 2 -C 6 alkylcarbonyl, C 2 - C 6 alkoxycarbonyl, C 2 -C 6 (alkylthio)carbonyl, C 2 -C 6 alkoxy(thiocarbonyl), C 4 -C 8 cycloalkylcarbonyl, C 4 -C 8 cycloalkoxycarbonyl, C 4 -C 8
  • each R 23a and R 23b is independently H, -Cg alkyl, -Cg haloalkyl, C 2 -C 6 alkenyl,
  • each R 24 and R 25 is independently H, C j -Cg alkyl, C ⁇ -Cg haloalkyl, C 2 -C 6 alkenyl, C 3 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 3 -C 6 halocycloalkyl, C 2 -C 6 alkylcarbonyl, C 2 -C 6 alkoxycarbonyl, C 2 -C 6 (alkylthio)carbonyl, C 2 -C 6 alkoxy(thiocarbonyl),
  • each R 28 is H or C1-C4 alkyl
  • each W is independently O or S;
  • each M + is independently a cation
  • n 0, 1 or 2;
  • t 0, 1 or 2;
  • each w is independently 0, 1 or 2;
  • each y is independently 0, 1 or 2;
  • this invention pertains to a compound of Formula 1 (including all geometric and stereoisomers), an N-oxide or a salt thereof.
  • This invention also relates to a fungicidal composition
  • a fungicidal composition comprising a compound of Formula 1, an N-oxide, or a salt thereof, and at least one additional component selected from the group consisting of surfactants, solid diluents and liquid diluents.
  • This invention also relates to a fungicidal composition comprising: (a) a compound of Formula 1, an N-oxide, or a salt thereof, and (b) at least one other fungicide (e.g., at least one other fungicide having a different site of action).
  • This invention further relates to a method for controlling plant diseases caused by fungal plant pathogens comprising applying to the plant or portion thereof, or to the plant seed, a fungicidally effective amount of a compound of the invention (e.g., as a composition described herein).
  • the aforedescribed method can also be described as a method for protecting a plant or plant seed from diseases caused by fungal pathogens comprising applying a fungicidally effective amount of a compound of Formula 1, an N-oxide, or a salt thereof (e.g., as a composition described herein), to the plant (or portion thereof) or plant seed (directly or through the environment (e.g., growing medium) of the plant or plant seed).
  • a fungicidally effective amount of a compound of Formula 1, an N-oxide, or a salt thereof e.g., as a composition described herein
  • compositions comprising, “comprising,” “includes,” “including,” “has,” “having,” “contains”, “containing,” “characterized by” or any other variation thereof, are intended to cover a non-exclusive inclusion, subject to any limitation explicitly indicated.
  • a composition, mixture, process or method that comprises a list of elements is not necessarily limited to only those elements but may include other elements not expressly listed or inherent to such composition, mixture, process or method.
  • transitional phrase consisting essentially of is used to define a composition or method that includes materials, steps, features, components, or elements, in addition to those literally disclosed, provided that these additional materials, steps, features, components, or elements do not materially affect the basic and novel characteristic(s) of the claimed invention.
  • plant includes members of Kingdom Plantae, particularly seed plants (Spermatopsida), at all life stages, including young plants (e.g., germinating seeds developing into seedlings) and mature, reproductive stages (e.g., plants producing flowers and seeds).
  • Portions of plants include geotropic members typically growing beneath the surface of the growing medium (e.g., soil), such as roots, tubers, bulbs and corms, and also members growing above the growing medium, such as foliage (including stems and leaves), flowers, fruits and seeds.
  • seedling used either alone or in a combination of words means a young plant developing from the embryo of a seed.
  • alkylating agent refers to a chemical compound in which a carbon-containing radical is bound through a carbon atom to leaving group such as halide or sulfonate, which is displaceable by bonding of a nucleophile to said carbon atom. Unless otherwise indicated, the term “alkylating” does not limit the carbon-containing radical to alkyl; the carbon-containing radicals in alkylating agents include the variety of carbon-bound substituent radicals specified for R 1 .
  • a molecular fragment i.e. radical
  • a series of atom symbols e.g., C, H, N, O, S
  • the point or points of attachment may be explicitly indicated by a hyphen ("-").
  • -SCN indicates that the point of attachment is the sulfur atom (i.e. thiocyanato, not isothiocyanato).
  • alkyl used either alone or in compound words such as “alkylthio” or “haloalkyl” includes straight-chain or branched alkyl, such as, methyl, ethyl, n-propyl, /-propyl, or the different butyl, pentyl or hexyl isomers.
  • alkenyl includes straight-chain or branched alkenes such as ethenyl, 1-propenyl, 2-propenyl, and the different butenyl isomers.
  • Alkenyl also includes polyenes such as 1,2-propadienyl.
  • Alkynyl includes straight-chain or branched alkynes such as ethynyl, 1-propynyl, 2-propynyl and the different butynyl isomers.
  • Alkylene denotes a straight-chain or branched alkanediyl. Examples of “alkylene” include CH 2 , CH 2 CH 2 , CH(CH 3 ), CH 2 CH 2 CH 2 , CH 2 CH(CH 3 ) and the different butylene isomers.
  • Alkynylene denotes a straight-chain or branched alkynediyl containing one triple bond.
  • alkynylene include CH 2 C ⁇ C, C ⁇ CCH 2 and the different butynylene, pentynylene and hexynylene isomers.
  • Alkoxy includes, for example, methoxy, ethoxy, n-propyloxy, isopropyloxy and the different butoxy, pentoxy and hexyloxy isomers.
  • Alkoxyalkyl denotes alkoxy substitution on alkyl. Examples of “alkoxyalkyl” include CH 3 OCH 2 , CH 3 OCH 2 CH 2 , CH 3 CH 2 OCH 2 , CH 3 CH 2 CH 2 CH 2 OCH 2 and CH 3 CH 2 OCH 2 CH 2 .
  • Alkylthio includes branched or straight-chain alkylthio moieties such as methylthio, ethylthio, and the different propylthio, butylthio, pentylthio and hexylthio isomers.
  • Alkylsulfmyl includes both enantiomers of an alkylsulfmyl group.
  • alkylsulfmyl examples include CH 3 S(0)-, CH 3 CH 2 S(0)-, CH 3 CH 2 CH 2 S(0)-, (CH 3 ) 2 CHS(0)- and the different butylsulfinyl isomers.
  • alkylsulfonyl examples include CH 3 S(0) 2 -, CH 3 CH 2 S(0) 2 -, CH 3 CH 2 CH 2 S(0) 2 -, (CH 3 ) 2 CHS(0) 2 -, and the different butylsulfonyl isomers.
  • Alkylthioalkyl denotes alkylthio substitution on alkyl.
  • alkylthioalkyl examples include CH 3 SCH 2 , CH 3 SCH 2 CH 2 , CH 3 CH 2 SCH 2 , CH 3 CH 2 CH 2 CH 2 SCH 2 and CH 3 CH 2 SCH 2 CH 2 .
  • Alkylaminoalkyl denotes a straight-chain or branched alkyl moieties bonded to a nitrogen atom of an amino(straight-chain or branched)alkyl moiety.
  • alkylaminoalkyl examples include CH 3 NHCH 2 -, (CH 3 ) 2 CHNHCH 2 - and CH 3 NHCH(CH 3 )-.
  • “Dialkylaminoalkyl” denotes two independent straight-chain or branched alkyl moieties bonded to a nitrogen atom of an amino (straight-chain or branched)alkyl moiety.
  • Examples of “dialkylaminoalkyl” include (CH 3 ) 2 NCH 2 -, (CH 3 ) 2 CH(CH 3 )NCH 2 - and (CH 3 ) 2 NCH(CH 3 )-.
  • Cycloalkyl includes, for example, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • alkylcycloalkyl denotes alkyl substitution on a cycloalkyl moiety and includes, for example, ethylcyclopropyl, z ' -propylcyclobutyl, 3-methylcyclopentyl and 4-methylcyclohexyl.
  • cycloalkylalkyl denotes cycloalkyl substitution on an alkyl moiety.
  • cycloalkylalkyl examples include cyclopropylmethyl, cyclopentylethyl, and other cycloalkyl moieties bonded to straight-chain or branched alkyl groups.
  • cycloalkoxy denotes cycloalkyl linked through an oxygen atom such as cyclopentyloxy and cyclohexyloxy.
  • Cycloalkenyl includes carbocyclic rings that contain only one double bond such as cyclopentenyl and cyclohexenyl, as well as carbocyclic rings with more than one double bond such as 1,3- and 1 ,4-cyclohexadienyl, but are not aromatic.
  • cycloalkylene denotes a cycloalkanediyl ring. Examples of “cycloalkylene” include cyclopropylene, cyclobutylene, cyclopentylene and cyclohexylene.
  • cycloalkenylene denotes a cycloalkenediyl ring containing one olefmic bond.
  • Examples of “cycloalkenylene” include cyclopropenediyl and cyclopentenediyl.
  • halogen either alone or in compound words such as “haloalkyl”, or when used in descriptions such as “alkyl substituted with halogen” includes fluorine, chlorine, bromine or iodine. Further, when used in compound words such as “haloalkyl”, or when used in descriptions such as “alkyl substituted with halogen” said alkyl may be partially or fully substituted with halogen atoms which may be the same or different. Examples of “haloalkyl” or “alkyl substituted with halogen” include F 3 C-, C1CH 2 -, CF 3 CH 2 - and CF3CCI2-.
  • halocycloalkyl examples include CH 2 FO-, CHF 2 0-, CF3O-, CC1 3 CH 2 0-, HCF 2 CH 2 CH 2 0- and CF 3 CH 2 0-.
  • fluoroalkoxy examples include CH 2 FO-, CHF 2 0-, CF 3 0- HCF 2 CH 2 CH 2 0- and CF 3 CH 2 0-.
  • fluoromethoxy examples include CH 2 FO-, CHF 2 0- and CF 3 0-.
  • haloalkylthio examples include CC1 3 S-, CF 3 S-, CC1 3 CH 2 S- and C1CH 2 CH 2 CH 2 S-.
  • haloalkylsulfmyl examples include CF 3 S(0)-, CC1 3 S(0)-, CF 3 CH 2 S(0)- and CF 3 CF 2 S(0)-.
  • haloalkylsulfonyl examples include CF 3 S(0) 2 -, CC1 3 S(0) 2 -, CF 3 CH 2 S(0) 2 - and CF 3 CF 2 S(0) 2 -.
  • C1-C4 alkylsulfonyl designates methylsulfonyl through butylsulfonyl
  • C 2 alkoxyalkyl designates CH 3 OCH 2 -
  • C 3 alkoxyalkyl designates, for example, CH 3 CH(OCH 3 )-, CH 3 OCH 2 CH 2 - or CH 3 CH 2 OCH 2 -
  • C 4 alkoxyalkyl designates the various isomers of an alkyl group substituted with an alkoxy group containing a total of four carbon atoms, examples including CH 3 CH 2 CH 2 OCH 2 - and CH 3 CH 2 OCH 2 CH 2 -.
  • an optionally substituted group may have a substituent at each substitutable position of the group, and each substitution is independent of the other.
  • unsubstituted in connection with a group such as a ring or ring system means the group does not have any substituents other than its one or more attachments to the remainder of Formula 1.
  • optionally substituted means that the number of substituents can be zero. Unless otherwise indicated, optionally substituted groups may be substituted with as many optional substituents as can be accommodated by replacing a hydrogen atom with a non-hydrogen substituent on any available carbon or nitrogen atom. The number of optional substituents may be restricted by an expressed limitation. For example, the phrase “optionally substituted with up to 3 substituents selected from R 9a on carbon atom ring members" means that 0, 1, 2 or 3 substituents can be present (if the number of potential connection points allows).
  • the phrase "optionally substituted with up to 5 substituents selected from R 3 on carbon atom ring members” means that 0, 1, 2, 3, 4 or 5 substituents can be present if the number of available connection points allows.
  • a range specified for the number of substituents e.g., r being an integer from 0 to 4 or from 0 to 3 for 5- and 6-membered nitrogen-containing heterocycles in Exhibit A
  • the number of positions available for substituents on a ring e.g., 2 positions available for (R a ) r on U-27 in Exhibit A
  • the actual higher end of the range is recognized to be the number of available positions.
  • said substituents are independently selected from the group of defined substituents, e.g., (R ) p attached to the phenyl ring in the molecular structure at the top of Table 1 where p is 0, 1, 2, 3, 4 or 5.
  • substituents which can be hydrogen, for example R 1 , R 4 , R 5 , R 6 , R 7 or R 13 , then when this substituent is taken as hydrogen, it is recognized that this is equivalent to said group being unsubstituted.
  • variable group When a variable group is shown to be optionally attached to a position, for example (R a ) r in H-23 of Exhibit 1, wherein r may be 0, then hydrogen may be at the position even if not recited in the variable group definition.
  • hydrogen atoms When one or more positions on a group are said to be "not substituted” or “unsubstituted”, then hydrogen atoms are attached to take up any free valency.
  • n being 0, 1 or 2 means that "S(0) n “ can be “S", “S(O)” or “S(0) 2 ".
  • a "ring” as a component of Formula 1 is carbocyclic or heterocyclic.
  • the term “ring system” as a component of Formula 1 denotes two fused rings (e.g., a phenyl ring fused to a pyridinyl ring to form quinolinyl).
  • carbocyclic ring denotes a ring wherein the atoms forming the ring backbone are selected only from carbon. Unless otherwise indicated, a carbocyclic ring can be a saturated, partially unsaturated, or fully unsaturated ring. "Saturated carbocyclic” refers to a ring having a backbone consisting of carbon atoms linked to one another by single bonds; unless otherwise specified, the remaining carbon valences are occupied by hydrogen atoms.
  • heterocyclic ring or “heterocycle” denote a ring or ring system in which at least one atom forming the ring backbone is not carbon, e.g., nitrogen, oxygen or sulfur. Typically a heterocyclic ring contains no more than 4 nitrogens, no more than 2 oxygens and no more than 2 sulfurs. Unless otherwise indicated, a heterocyclic ring can be a saturated, partially unsaturated, or fully unsaturated ring.
  • saturated heterocyclic ring refers to a heterocyclic ring containing only single bonds between ring members.
  • a partially unsaturated heterocyclic ring is intermediate between a saturated heterocyclic ring and a fully unsaturated heterocyclic ring (which may be aromatic). Therefore, as referred to in the present disclosure and claims, the term “partially unsaturated heterocyclic ring” denotes a heterocyclic ring comprising at least one ring member bonded to an adjacent ring member through a double bond and which conceptually potentially accommodates a number of non-cumulated double bonds between adjacent ring members (i.e. in its fully unsaturated counterpart form) greater than the number of double bonds present (i.e. in its partially unsaturated form).
  • heterocyclic ring When a fully unsaturated heterocyclic ring satisfies Huckel's rule, then said ring is also called a “heteroaromatic ring” or “aromatic heterocyclic ring".
  • the terms “heteroaromatic ring system” and “heteroaromatic bicyclic ring system” denote a ring system in which at least one atom forming the ring backbone is not carbon, e.g., nitrogen, oxygen or sulfur, and at least one ring is aromatic. Unless otherwise indicated, heterocyclic rings and ring systems can be attached through any available carbon or nitrogen by replacement of a hydrogen on said carbon or nitrogen.
  • Aromatic indicates that each of the ring atoms is essentially in the same plane and has a / ⁇ -orbital perpendicular to the ring plane, and that (4n + 2) ⁇ electrons, where n is a positive integer, are associated with the ring to comply with Huckel's rule.
  • aromatic heterocyclic ring system denotes a heterocyclic ring system in which at least one ring of the ring system is aromatic.
  • nonaromatic ring system denotes a carbocyclic or heterocyclic ring system that may be fully saturated, as well as partially or fully unsaturated, provided that none of the rings in the ring system are aromatic.
  • four- to seven-membered nonaromatic heterocyclic ring refers to rings containing four to seven ring members and which do not satisfy Huckel's rule. This term (as used where R 6 and R 7 are taken together) is not limited by carbon atoms only and can include ring members selected from O, S(0) n and NR 13 .
  • Q 1 , Q 2 or R 1 comprises a phenyl or a 6-membered fully unsaturated heterocyclic ring
  • the ortho, meta and para positions of each ring is relative to the connection of the ring to the remainder of Formula 1.
  • substituents on the ring or ring system of Q 1 or Q 2 are optional, 0 to 5 substituents may be present, limited only by the number of available points of attachment.
  • the ring members selected from up to 2 O, up to 2 S and up to 4 N atoms are optional, provided at least one ring member is not carbon (e.g., N, O or S).
  • the nitrogen atom ring members may be oxidized as N-oxides, because compounds relating to Formula 1 also include N-oxide derivatives.
  • R 1 can be (among others) 5- or 6-membered nitrogen-containing aromatic heterocycle, which may be optionally substituted with one or more substituents selected from a group of substituents as defined in the Summary of Invention.
  • R 1 is phenyl or a 5- or 6- membered nitrogen-containing aromatic heterocycle, it may be attached to the remainder of Formula 1 through any available carbon or nitrogen ring atom, unless otherwise described.
  • the ring or ring system of Q 1 or Q 2 may be attached to the remainder of Formula 1 through any available carbon or nitrogen ring atom, unless otherwise described.
  • Examples of a 5- to 6-membered fully unsaturated heterocyclic ring include the rings H-1 through H-39 illustrated in Exhibit 1, and examples of an 8- to 10-membered heteroaromatic bicyclic ring system include the ring systems B-l through B-39 illustrated in Exhibit 2.
  • R a is any substituent as defined in the Summary of the Invention for Q 1 , Q 2 or R 1 (e.g., a Q 1 ring or ring system is optionally substituted with R 3 on carbon atom ring members and cyano, C ⁇ -Cg alkyl, C 2 -Cg alkenyl, C 2 -Cg alkynyl, C 3 -C 6 cycloalkyl, C j -Cg alkoxy, C 2 -C 6 alkoxyalkyl, C 2 -C 6 alkylcarbonyl, C 2 -C 6 alkoxycarbonyl, C 2 -Cg alkylaminoalkyl and C3-C6 dialkylaminoalkyl on nitrogen atom ring members) and r is an integer from 0 to 5 for Q 1 and Q 2 or from 0 to 3 for R 1 , limited by the number of available positions on each depicted ring or ring system.
  • R a is any substituent as defined in the Summary of the Invention for Q 2 (e.g., a Q 2 ring is optionally substituted with R 3 on carbon ring members and cyano, Ci -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, Ci -C 6 alkoxy, C 2 -C 6 alkoxyalkyl, C 2 -C 6 alkylcarbonyl, C 2 -C 6 alkoxycarbonyl, C 2 -Cg alkylaminoalkyl and C 3 -C 6 dialkylaminoalkyl on nitrogen atom ring members) and r is an integer from 0 to 5, limited by the number of available positions on each depicted ring or ring system.
  • P-41 P-42 P-43 Examples of a 5- or 6-membered nitrogen-containing heterocycle optionally substituted with from one or more substituents of particular note for Q 1 , Q 2 and R 1 include the rings U-1 through U-56 illustrated in Exhibit A wherein R a is any substituent as defined in the Summary of the Invention for Q 1 Q 2 and R 1 , respectively (i.e.
  • R 3 on carbon atom ring members, and the recited list of possible substituents on nitrogen atom ring members; and for R 1 , R 9a on carbon ring members and R 9 ⁇ on nitrogen ring members) and r is an integer ranging from 0 to 4 for Q 1 and Q 2 and from 0 to 3 for R 1 , limited by the number of available positions on each U group. Note that some U groups can only be substituted with less than 4 R a groups (e.g., U-4 through U-43 and U-47 through U-56).
  • r is limited to the integers 0 or 1 , and r being 0 means that the U group is unsubstituted and a hydrogen is present at the position indicated by (R a ) r .
  • Q 1 , Q 2 and R 1 can be (among others) phenyl optionally substituted with one or more substituents selected from a group of substituents as defined in the Summary of the Invention.
  • An example of phenyl optionally substituted with one to five substituents is the ring illustrated as U-57 in Exhibit A, wherein R a is as defined in the Summary of the Invention for R 3 or R 8 and q is an integer from 0 to 5.
  • R a groups are shown in the structures H-l through H-39, B-l through B-39, P-l through P-43, and U-l through U-57 in Exhibits 1 through 3 and Exhibit A, 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 R a . Note that when the attachment point between (R a ) r and the H, B, P or U group in Exhibits 1 through 3 and Exhibit A is illustrated as floating, (R a ) r can be attached to any available carbon atom or nitrogen atom of the H, B, P or U group.
  • H, B or P group in Exhibits 1 through 3 can be attached to the remainder of Formula 1 through any available carbon or nitrogen of the H, B or P group by replacement of a hydrogen atom.
  • R 6 and R 7 are taken together to form a four- to seven-membered nonaromatic heterocyclic ring
  • examples of where R 6 and R 7 are taken together to form a four- to seven-membered nonaromatic heterocyclic ring include the rings G-l through G-28 as illustrated in Exhibit 4. Note that when R 6 and R 7 are taken together to form a ring comprising a ring selected from G-25 through G-28, G 2 is selected from O, S(0) n or NR 13 . Note that when G 2 is N, the nitrogen atom can complete its valence by substitution with either H or the substituents corresponding to R 13 as defined in the Summary of Invention.
  • Compounds of 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). Additionally, the skilled artisan knows how to separate, enrich, and/or to selectively prepare said stereoisomers.
  • the compounds of the invention may be present as a mixture of stereoisomers, individual stereoisomers or as an optically active form.
  • nitrogen-containing heterocycles can form N-oxides since the nitrogen requires an available lone pair for oxidation to the oxide; one skilled in the art will recognize those nitrogen-containing heterocycles which can form N-oxides.
  • nitrogen-containing heterocycles which can form N-oxides.
  • tertiary amines can form N-oxides.
  • N-oxides of heterocycles and tertiary amines are very well known by one skilled in the art including the oxidation of heterocycles and tertiary amines with peroxy acids such as peracetic and m-chloroperbenzoic acid (MCPBA), hydrogen peroxide, alkyl hydroperoxides such as t-butyl hydroperoxide, sodium perborate, and dioxiranes such as dimethyldioxirane.
  • MCPBA peroxy acids
  • alkyl hydroperoxides such as t-butyl hydroperoxide
  • sodium perborate sodium perborate
  • dioxiranes such as dimethyldioxirane
  • salts of chemical compounds are in equilibrium with their corresponding nonsalt forms, salts share the biological utility of the nonsalt forms.
  • the salts of the compounds of Formula 1 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.
  • Non-crystalline forms include embodiments which are solids such as waxes and gums as well as embodiments which are liquids such as solutions and melts.
  • Crystalline forms include embodiments which represent essentially a single crystal type and embodiments which represent a mixture of polymorphs (i.e. different crystalline types).
  • polymorph refers to a particular crystalline form of a chemical compound that can crystallize in different crystalline forms, these forms having different arrangements and/or conformations of the molecules in the crystal lattice.
  • polymorphs can have the same chemical composition, they can also differ in composition due the presence or absence of co-crystallized water or other molecules, which can be weakly or strongly bound in the lattice. Polymorphs can differ in such chemical, physical and biological properties as crystal shape, density, hardness, color, chemical stability, melting point, hygroscopicity, suspensibility, dissolution rate and biological availability.
  • beneficial effects e.g., suitability for preparation of useful formulations, improved biological performance
  • Embodiment 1 A compound of Formula 1 wherein X is O or NR 4 .
  • Embodiment 2 A compound of Formula 1 wherein X is NR 4 or CR 15 R 16 .
  • Embodiment 3 A compound of Formula 1 wherein X is O or CR 15 R 16 .
  • Embodiment 4 A compound of Embodiment 1 or 3 wherein X is O.
  • Embodiment 5 A compound of Embodiment 1 or 2 wherein X is NR 4 .
  • Embodiment 6 A compound of Embodiment 2 or 3 wherein X is CR 15 R 16 .
  • Embodiment 7 A compound of Formula 1 or any one of Embodiments 1 through 6 wherein when Q 1 is a six-membered ring (e.g., phenyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl) and an R 3 substituent is located at a meta position (relative to the connection of the Q 1 ring to the remainder of Formula 1), then said R 3 substituent is selected from F, CI, Br and cyano (-CN).
  • Q 1 is a six-membered ring
  • R 3 substituent is located at a meta position (relative to the connection of the Q 1 ring to the remainder of Formula 1)
  • said R 3 substituent is selected from F, CI, Br and cyano (-CN).
  • Embodiment 8 A compound of Formula 1 or any one of Embodiments 1 through 7 wherein when Q 1 is a six-membered ring and an R 3 substituent is located at a meta position (relative to the connection of the Q 1 ring to the remainder of Formula 1), then said R 3 substituent is F.
  • Embodiment 9 A compound of Formula 1 or any one of Embodiments 1 through 8 wherein when Q 1 is a six-membered ring (e.g., phenyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl) substituted with only one R 3 substituent, then said R 3 substituent is attached at an ortho position (relative to the connection of the Q 1 ring to the remainder of Formula 1).
  • Q 1 is a six-membered ring (e.g., phenyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl) substituted with only one R 3 substituent, then said R 3 substituent is attached at an ortho position (relative to the connection of the Q 1 ring to the remainder of Formula 1).
  • Embodiment 10 A compound of Formula 1 or any one of Embodiments 1 through 9 wherein Q 1 is phenyl, thienyl, pyridinyl, pyridazinyl, pyrazinyl, pyrimidinyl, naphthalenyl, quinolinyl, isoquinolinyl or quinoxalinyl, each optionally substituted with up to 5 substituents independently selected from R 3 .
  • Embodiment 11 A compound of Embodiment 10 wherein Q 1 is phenyl, thienyl,
  • pyridinyl pyridazinyl, pyrazinyl or pyrimidinyl, each optionally substituted with up to 5 substituents independently selected from R 3 .
  • Embodiment 12 A compound of Embodiment 11 wherein Q 1 is phenyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl, each substituted with from 1 to 4 substituents independently selected from R 3 .
  • Embodiment 13 A compound of Embodiment 12 wherein Q 1 is phenyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl, each substituted with 1, 2 or 3 substituents independently selected from R 3 .
  • Embodiment 14 A compound of Embodiment 13 wherein the substituents are located at the ortho and/or para positions (relative to the connection of the Q 1 ring to the remainder of Formula 1) of the phenyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl of Q 1 .
  • Embodiment 15 A compound of Embodiment 13 or 14 wherein Q 1 is phenyl or
  • Embodiment 16 A compound of Embodiment 15 wherein Q 1 is phenyl or pyridinyl, each substituted with 2 or 3 substituents independently selected from R 3 .
  • Embodiment 17 A compound of Embodiment 16 wherein Q 1 is phenyl substituted at the 2-, 4- and 6-positions with substituents independently selected from R 3 ; or phenyl substituted at the 2- and 4-positions with substituents independently selected from R 3 ; or phenyl substituted at the 2- and 6-positions with substituents independently selected from R 3 .
  • Embodiment 18 A compound of Embodiment 17 wherein Q 1 is phenyl substituted at the 2-, 4- and 6-positions with substituents independently selected from R 3 ; or phenyl substituted at the 2- and 4-positions with substituents independently selected from R 3 .
  • Embodiment 19 A compound of Embodiment 17 wherein Q 1 is phenyl substituted at the 2-, 4- and 6-positions with substituents independently selected from R 3 .
  • Embodiment 20 A compound of Embodiment 17 wherein Q 1 is phenyl substituted at the 2- and 4-positions with substituents independently selected from R 3 .
  • Embodiment 21 A compound of Embodiment 17 wherein Q 1 is phenyl substituted at the 2- and 6-positions with substituents independently selected from R 3 .
  • Embodiment 22 A compound of Embodiment 15 wherein Q 1 is pyridinyl substituted with 1, 2 or 3 substituents independently selected from R 3 .
  • Embodiment 23 A compound of Embodiment 22 wherein Q 1 is pyridinyl substituted with 1 or 2 substituents independently selected from R 3 .
  • Embodiment 24 A compound of Embodiment 23 wherein Q 1 is pyridinyl substituted with 1 substituent independently selected from R 3 .
  • Embodiment 25 A compound of Formula 1 or any one of Embodiments 1 through 24 wherein Q 2 is a phenyl ring or a naphthalenyl ring system, each ring or ring system optionally substituted with up to 5 substituents independently selected from R 3 ; or a 5- to 6-membered saturated, partially unsaturated or fully unsaturated heterocyclic ring or an 8- to 10-membered heteroaromatic bicyclic ring system, each ring or ring system containing ring members selected from carbon atoms and up to 4 heteroatoms independently selected from up to 2 O, up to 2 S and up to 4 N atoms, wherein up to 3 carbon ring members are
  • each ring or ring system optionally substituted with up to 5 substituents independently selected from R 3 on carbon atom ring members and selected from cyano, C ⁇ -C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 3 -C6 cycloalkyl, C ⁇ -C6 alkoxy, C2-C6 alkoxyalkyl, C2-C6 alkylcarbonyl, C2-C6 alkoxycarbonyl, C2-C6 alkoxycarbonyl, C2-C6 alkoxycarbonyl, C2-C6
  • Embodiment 25a A compound of Formula 1 or any one of Embodiments 1 through 25 wherein when Q 2 is a six-membered ring (e.g., phenyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl) and an R 3 substituent is located at a meta position (relative to the connection of the Q 2 ring to the remainder of Formula 1), then said R 3 substituent is selected from F, CI, Br and cyano (-CN).
  • Q 2 is a six-membered ring
  • R 3 substituent is selected from F, CI, Br and cyano (-CN).
  • Embodiment 26 A compound of Formula 1 or any one of Embodiments 1 through 25 a wherein when Q 2 is a six-membered ring and an R 3 substituent is located at a meta position (relative to the connection of the Q 2 ring to the remainder of Formula 1), then said R 3 substituent is F.
  • Embodiment 27 A compound of Formula 1 or any one of Embodiments 1 through 26 wherein when Q 2 is a six-membered ring (e.g., phenyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl) substituted with only one R 3 substituent, then said R 3 substituent is attached at an ortho position (relative to the connection of the Q 2 ring to the remainder of Formula 1).
  • Q 2 is a six-membered ring (e.g., phenyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl) substituted with only one R 3 substituent, then said R 3 substituent is attached at an ortho position (relative to the connection of the Q 2 ring to the remainder of Formula 1).
  • Embodiment 28 A compound of Formula 1 or any one of Embodiments 1 through 27 wherein Q 2 is phenyl, thienyl, pyridinyl, pyridazinyl, pyrazinyl, pyrimidinyl, naphthalenyl, quinolinyl, isoquinolinyl or quinoxalinyl, each optionally substituted with up to 5 substituents independently selected from R 3 .
  • Embodiment 29 A compound of Embodiment 28 wherein Q 2 is phenyl, thienyl,
  • pyridinyl pyridazinyl, pyrazinyl or pyrimidinyl, each optionally substituted with up to 5 substituents independently selected from R 3 .
  • Embodiment 30 A compound of Embodiment 29 wherein Q 2 is phenyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl, each substituted with from 1 to 4 substituents independently selected from R 3 .
  • Embodiment 31 A compound of Embodiment 30 wherein Q 2 is phenyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl, each substituted with 1 , 2 or 3 substituents independently selected from R 3 .
  • Embodiment 32 A compound of Embodiment 31 wherein the substituents are located at the ortho and/or para positions (relative to the connection of the Q 2 ring to the remainder of Formula 1) of the phenyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl of Q 2 .
  • Embodiment 33 A compound of any one of Embodiments 31 or 32 wherein Q 2 is
  • Embodiment 34 A compound of Embodiment 33 wherein Q 2 is phenyl substituted with
  • Embodiment 35 A compound of Embodiment 34 wherein Q 2 is phenyl substituted at the 2-, 4- and 6-positions with substituents independently selected from R 3 ; or phenyl substituted at the 2- and 4-positions with substituents independently selected from R 3 ; or phenyl substituted at the 2- and 6-positions with substituents independently selected from R 3 .
  • Embodiment 36 A compound of Embodiment 35 wherein Q 2 is phenyl substituted at the 2-, 4- and 6-positions with substituents independently selected from R 3 .
  • Embodiment 37 A compound of Embodiment 35 wherein Q 2 is phenyl substituted at the 2- and 4-positions with substituents independently selected from R 3 .
  • Embodiment 38 A compound of Embodiment 35 wherein Q 2 is phenyl substituted at the 2- and 6-positions with substituents independently selected from R 3 .
  • Embodiment 39 A compound of Embodiment 33 wherein Q 2 is pyridinyl substituted with 1, 2 or 3 substituents independently selected from R 3 .
  • Embodiment 40 A compound of Embodiment 39 wherein Q 2 is pyridinyl substituted with 1 or 2 subsituents independently selected from R 3 .
  • Embodiment 41 A compound of Embodiment 40 wherein Q 2 is pyridinyl substituted with 1 substituent selected from R 3 .
  • Embodiment 42 A compound of Formula 1 or any one of Embodiments 1 through 41 wherein at least one of Q 1 and Q 2 is phenyl optionally substituted with R 3 (e.g., optionally substituted with up to 5 substituents independently selected from R 3 ).
  • Embodiment 43 A compound of Embodiment 42 wherein at least one of Q 1 and Q 2 is phenyl substituted with 2, 3 or 4 substituents independently selected from R 3 .
  • Embodiment 44 A compound of Embodiment 43 wherein at least one Q 1 and Q 2 is phenyl substituted with 2 or 3 substituents independently selected from R 3 .
  • Embodiment 45 A compound of Embodiment 44 wherein each of Q 1 and Q 2 is phenyl substituted with 2 or 3 substituents independently selected from R 3 .
  • Embodiment 45 a A compound of Embodiment 44 wherein Q 1 is phenyl substituted with 2 or 3 substituents independently selected from R 3 , and Q 2 is phenyl substituted with 1 or 2 substituents independently selected from R 3 .
  • Embodiment 46 A compound of Formula 1 or any one of Embodiments 1 through 45 a wherein R 1 is H, halogen, Ci ⁇ C 6 alkyl, Ci ⁇ C 6 haloalkyl, C0 2 R 5 , C(0)NR 6 R 7 , cyano, C ⁇ -Cg alkoxy, C ⁇ -Cg haloalkoxy or C2-C5 alkoxyalkyl, or a five- or six- membered nitrogen-containing aromatic heterocycle optionally substituted with up to 3 substituents independently selected from R 9a on carbon atom ring members and R 9 ⁇ on nitrogen atom ring members; or R 1 and R la are taken together with the carbon atom to which they are attached to form a cyclopropyl ring optionally substituted with up to 2 substituents independently selected from halogen and methyl.
  • R 1 is H, halogen, Ci ⁇ C 6 alkyl, Ci ⁇ C 6 haloalkyl, C0 2 R 5 , C(0)NR 6 R 7
  • Embodiment 47 A compound of Embodiment 46 wherein when R 1 is taken alone (i.e.
  • R 1 is not taken together with R la to form an optionally substituted cyclopropyl ring), then R 1 is H, halogen, -Cg alkyl, -Cg haloalkyl, cyano, -Cg alkoxy or C ⁇ -Cg haloalkoxy; or R 1 is pyridinyl, pyrimidinyl, pyrazolyl or oxazolyl, each optionally substituted with up to 3 substituents independently selected from R 9a on carbon atom ring members and R 9 ⁇ on nitrogen atom ring members.
  • Embodiment 48 A compound of Formula 1 or any one of Embodiments 1 through 47 wherein R 1 is other than an optionally substituted phenyl or an optionally substituted five- or six-membered nitrogen-containing aromatic heterocycle.
  • Embodiment 49 A compound of Embodiment 47 wherein when R 1 is taken alone, then R 1 is H, halogen, -Cg alkyl, -Cg haloalkyl, C0 2 R 5 , C(0)NR 6 R 7 , cyano, C ⁇ -Cg alkoxy, C ⁇ -Cg haloalkoxy or C2-C5 alkoxyalkyl.
  • Embodiment 50 A compound of Embodiment 49 wherein when R 1 is taken alone, then R 1 is H, halogen, -Cg alkyl, -Cg haloalkyl, C(0)NR 6 R 7 , cyano, -Cg alkoxy, C ⁇ -Cg haloalkoxy or C2-C5 alkoxyalkyl.
  • Embodiment 51 A compound of Embodiment 50 wherein when R 1 is taken alone, then R 1 is H, halogen, C ⁇ -Cg alkyl, C ⁇ -Cg haloalkyl, cyano, C ⁇ -Cg alkoxy, C ⁇ -Cg haloalkoxy or C2-C5 alkoxyalkyl.
  • Embodiment 52 A compound of Embodiment 51 wherein when R 1 is taken alone, then
  • R 1 is H, halogen, C1-C3 alkyl or C1-C2 haloalkyl.
  • Embodiment 53 A compound of Embodiment 52 wherein when R 1 is taken alone, then R 1 is H, halogen or -C3 alkyl.
  • Embodiment 54 A compound of Formula 1 or any one of Embodiments 1 through 53 wherein when R 1 and R 2 are taken together with the carbon to which they are attached to form a cyclopropyl ring, said cyclopropyl ring is unsubstituted (except for the bond to the pyrazole nitrogen atom).
  • Embodiment 55 A compound of Formula 1 or any one of Embodiments 1 through 53 wherein R la is H (i.e. R 1 and R la are not taken together to form substituted or unsubstituted cyclopropyl ring).
  • Embodiment 56 A compound of Embodiment 55 wherein R 1 is H or CH 3 .
  • Embodiment 57 A compound of Embodiment 56 wherein R 1 is H.
  • Embodiment 58 A compound of Formula 1 or any one of Embodiments 1 through 57 wherein R 2 is H, alkenyl or alkynyl.
  • Embodiment 59 A compound of Embodiment 58 wherein R 2 is H.
  • Embodiment 60 A compound of Formula 1 or any one of Embodiments 1 through 57 wherein R 2 is C2-C3 alkenyl or C2-C3 alkynyl.
  • Embodiment 61 A compound of Embodiment 58 or 60 wherein R 2 is alkenyl or alkynyl.
  • Embodiment 62 A compound of Embodiment 60 wherein R 2 is C2-C3 alkenyl.
  • Embodiment 63 A compound of Embodiment 60 wherein R 2 is C2-C3 alkynyl.
  • Embodiment 64 A compound of Formula 1 or any one of Embodiments 1 through 63 wherein R 5 is H or C ⁇ -C6 alkyl.
  • Embodiment 65 A compound of Embodiment 64 wherein R 5 is H or C ⁇ -C6 alkyl.
  • Embodiment 66 A compound of Embodiment 65 wherein R 5 is C ⁇ -C6 alkyl.
  • Embodiment 67 A compound of Embodiment 66 wherein R 5 is CH 3 or CH2CH3.
  • Embodiment 68 A compound of Formula 1 or any one of Embodiments 1 through 67 wherein when R 6 is separate (i.e. not taken together with R 7 to form a ring), then R 6 is H or C!-C 6 alkyl.
  • Embodiment 69 A compound of Embodiment 68 wherein R 6 is H.
  • Embodiment 70 A compound of Formula 1 or any one of Embodiments 1 through 69 wherein when R 7 is separate (i.e. not taken together with R 6 to form a ring), then R 7 is H, Ci ⁇ C 6 alkyl, Ci ⁇ C 6 haloalkyl or C 4 -C 8 alkylcycloalkyl.
  • Embodiment 71 A compound of Embodiment 70 wherein R 7 is H or C ⁇ -C6 alkyl.
  • Embodiment 72. A compound of Embodiment 71 wherein R 7 is H.
  • Embodiment 73 A compound of Formula 1 or any one of Embodiments 1 through 72 wherein when R 6 and R 7 are taken together with the nitrogen atom to which they are connected to form a nonaromatic heterocyclic ring, the ring contains ring members, in addition to the connecting nitrogen atom, selected from carbon atoms and up to one ring member selected from O and NR 13 .
  • Embodiment 74 A compound of Embodiment 73 wherein when R 6 and R 7 are taken together with the nitrogen atom to which they are connected to form a nonaromatic heterocyclic ring, the ring is six-membered and contains one ring member selected from O and NR 13 in addition to the connecting nitrogen atom and ring members selected from carbon atoms.
  • Embodiment 75 A compound of Embodiment 73 wherein R 6 and R 7 are taken together with the nitrogen atom to which they are connected to form a piperidine ring.
  • Embodiment 76 A compound of Embodiment 74 wherein R 6 and R 7 are taken together with the nitrogen atom to which they are connected to form a piperazine or morpholine ring.
  • Embodiment 77 A compound of Formula 1 or any one of Embodiments 1 through 76 wherein each R 8 is independently selected from halogen, C1-C2 alkyl, C1-C2 haloalkyl, C1-C2 alkoxy, C1-C2 haloalkoxy, cyano and nitro.
  • Embodiment 78 A compound of Embodiment 77 wherein each R 8 is independently selected from halogen, C1-C2 alkyl, Ci ⁇ C 2 alkoxy, cyano and nitro.
  • Embodiment 79 A compound of Embodiment 78 wherein each R 8 is independently CI or F.
  • Embodiment 80 A compound of Formula 1 or any one of Embodiments 1 through 79 wherein each R 9a is independently selected from halogen, C1-C2 alkyl, C1-C2 haloalkyl, C1-C2 alkoxy, C1-C2 haloalkoxy, cyano and nitro.
  • Embodiment 81 A compound of Embodiment 80 wherein each R 9a is independently selected from halogen, C1-C2 alkyl, C1-C2 alkoxy, cyano and nitro.
  • Embodiment 82 A compound of Embodiment 81 wherein each R 9a is independently selected from CI, F, CH 3 , -OCH3 and cyano.
  • Embodiment 83 A compound of Embodiment 82 wherein each R 9a is independently CI or F.
  • Embodiment 84 A compound of Formula 1 or any one of Embodiments 1 through 83 wherein each R 9 ⁇ is independently C1-C2 alkyl.
  • Embodiment 85 A compound of Formula 1 or any one of Embodiments 1 through 84 wherein each R 3 is independently selected from halogen, cyano, nitro, amino, methylamino, dimethylamino, formylamino, C2-C3 alkylcarbonylamino, C1-C4 alkyl, C1-C4 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 alkylthio, C ⁇ -
  • alkylcycloalkyl C 4 -C 6 cycloalkylalkyl, C3-C7 halocycloalkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, hydroxy, formyl, C 2 -C 3 alkylcarbonyl, C 2 -C 3 alkylcarbonyloxy,
  • Embodiment 85a A compound of Formula 1 or any one of Embodiments 1 through 85 wherein each R 3 is independently selected from halogen, cyano, nitro, amino, methylamino, dimethylamino, C1-C4 alkyl, C1-C4 haloalkyl, C1-C3 alkoxy, 1-C3 haloalkoxy, C1-C3 alkylthio, C1-C3 haloalkylthio, C1-C3 alkylsulfinyl,
  • Embodiment 86 A compound of Embodiment 85a wherein each R 3 is independently selected from halogen, cyano, nitro, C1-C4 alkyl, C1-C4 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy and -U-V-T.
  • Embodiment 87 A compound of Embodiment 86 wherein each R 3 is independently selected from F, CI, Br, cyano, nitro, CH 3 , CF 3 , -OCH 3 , -OCHF 2 and -U-V-T.
  • Embodiment 88 A compound of Formula 1 or any one of Embodiments 1 through 87 wherein at least one R 3 substituent on the ring or ring system of Q 1 or Q 2 is
  • Embodiment 89 A compound of Formula 1 or any one of Embodiments 1 through 87 wherein each R 3 is other than -U-V-T.
  • Embodiment 90 A compound of Embodiment 89 wherein each R 3 is independently selected from halogen, cyano, nitro, C1-C4 alkyl, C1-C4 haloalkyl, C1-C3 alkoxy and C1-C3 haloalkoxy.
  • Embodiment 91 A compound of Embodiment 90 wherein each R 3 is independently selected from halogen, cyano, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy and
  • Embodiment 92 A compound of Embodiment 91 wherein each R 3 is independently selected from F, CI, Br, cyano, C1-C2 alkyl, C1-C2 haloalkyl, Ci ⁇ C 2 alkoxy and C1-C2 haloalkoxy.
  • Embodiment 93 A compound of Embodiment 92 wherein each R 3 is independently selected from F, CI, Br, cyano, methyl, C1-C2 alkoxy and difluoromethoxy.
  • Embodiment 94 A compound of Embodiment 93 wherein each R 3 is independently selected from F, CI, Br, cyano, methyl and methoxy.
  • Embodiment 95 A compound of Embodiment 94 wherein each R 3 is independently selected from F, CI, Br and cyano.
  • Embodiment 96 A compound of Embodiment 95 wherein each R 3 is independently selected from F, CI and Br.
  • Embodiment 97 A compound of Formula 1 or any one of Embodiments 1 through 88 wherein each U is independently O or NR 22 .
  • Embodiment 98 A compound of Embodiment 97 wherein each U is independently O or
  • Embodiment 99 A compound of Formula 1 or any one of Embodiments 1 through 88 and 97 through 98 wherein each V is C 2 -C 4 alkylene.
  • Embodiment 100 A compound of Formula 1 or any one of Embodiments 1 through 88 and 97 through 99 wherein each T is independently NR 23a R 23 ⁇ or OR 24 .
  • Embodiment 101 A compound of Formula 1 or any one of Embodiments 1 through 88 and 97 through 100 wherein each R 23a and R 23 ⁇ is independently H, C ⁇ -C6 alkyl or Ci-C haloalkyl.
  • Embodiment 102 A compound of Formula 1 or any one of Embodiments 1 through 88 and 97 through 101 wherein each R 24 is independently H, Ci ⁇ C 6 alkyl or Ci ⁇ C 6 haloalkyl.
  • Embodiment 103 A compound of Formula 1 or any one of Embodiments 1 through 102 wherein when an R 3 substituent attached to phenyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl of Q ⁇ or Q 2 is other than F, CI, Br, cyano, methyl, C ⁇ -
  • Embodiment 104 A compound of Formula 1 or any one of Embodiments 1 through 103 wherein R 4 is H, formyl, C 3 -C 7 cycloalkyl or -SR 10 ; or Ci ⁇ C 6 alkyl or -Cg haloalkyl, each optionally substituted with up to 2 R 12 .
  • Embodiment 105 A compound of Embodiment 104 wherein R 4 is H, formyl, C 3 -C 7 cycloalkyl or -SR 10 ; or -Cg alkyl substituted with one R 12 .
  • Embodiment 106 A compound of Embodiment 105 wherein R 4 is H, formyl,
  • Embodiment 107 A compound of Embodiment 106 wherein R 4 is H, formyl,
  • Embodiment 108 A compound of Embodiment 107 wherein R 4 is H.
  • Embodiment 109 A compound of Formula 1 or any one of Embodiments 1 through 108 wherein R 13 is H or CH 3 .
  • Embodiment 110 A compound of Embodiment 109 wherein R 13 is CH 3 .
  • Embodiment 111 A compound of Formula 1 or any one of Embodiments 1 through 110 wherein each R 12 is independently C 3 -C 7 cycloalkyl, C1-C4 alkoxy or cyano.
  • Embodiment 112. A compound of Embodiment 111 wherein each R 12 is independently cyclopropyl, -OCH 3 or cyano.
  • Embodiment 113 A compound of Formula 1 or any one of Embodiments 1 through 112 wherein R 10 is CH 3 , CH 2 CH 3 , CF 3 or CF 2 CF 3 .
  • Embodiment 114 A compound of Embodiment 113 wherein R 10 is CH 3 .
  • Embodiment 115 A compound of Formula 1 or any one of Embodiments 1 through 114 wherein each R 1 1 is independently C j -Cg alkyl, C j -Cg alkoxy, C 2 -C 7 alkoxyalkyl, C 2 -C 7 alkylaminoalkyl, C 2 -Cg dialkylaminoalkyl, C ⁇ -Cg alkylthio or C 2 -C 7 alkylthioalkyl.
  • Embodiment 115a A compound of Formula 1 or any one of Embodiments 1 through
  • R 1 1 is C ⁇ -Cg alkyl, C ⁇ -Cg alkoxy or C ⁇ -Cg alkylthio.
  • Embodiment 116 A compound of Embodiment 115a wherein R 1 1 is CH 3 , CH 2 CH 3 ,
  • Embodiment 117 A compound of Embodiment 116 wherein R 1 1 is CH 3 , -OCH 3 or
  • Embodiment 118 A compound of Formula 1 or any one of Embodiments 1 through 117 wherein R 15 is H or CH 3 .
  • Embodiment 119 A compound of Embodiment 118 wherein R 15 is H.
  • Embodiment 120 A compound of Formula 1 or any one of Embodiments 1 through 119 wherein R 16 is F or OR 18 .
  • Embodiment 121 A compound of Embodiment 120 wherein R 16 is OR 18 .
  • Embodiment 122 A compound of Formula 1 or any one of Embodiments 1 through 121 wherein R 18 is H.
  • Embodiment 123 A compound of Formula 1 or any one of Embodiments 1 through 122 wherein W is O.
  • Embodiment 124 A compound of Formula 1 or any one of Embodiments 1 through 123 wherein M + is a cation selected from sodium, potassium and lithium ions.
  • Embodiment 125 A compound of Embodiment 124 wherein M + is a cation selected from sodium and potassium ions.
  • Embodiment 126 A compound of Embodiment 125 wherein M + is a sodium ion.
  • Embodiment 127 A compound of Formula 1 or any one of Embodiments 1 through 126 wherein n is 0.
  • Embodiment 128 A compound of Formula 1 or any one of Embodiments 1 through 127 wherein when Q 2 comprises a phenyl ring substituted with nitro on at least one ortho position, then X is O or CR 15 R 16 .
  • Embodiment 129 A compound of Embodiment 128 wherein all instances of R 3 are other than nitro.
  • Embodiment 130 A compound of Embodiment 128 wherein when Q 2 comprises a
  • Embodiment 133 A compound of Formula 1 or any one of Embodiments 1 through 132 wherein when Q 2 comprises a 6-membered heterocyclic ring substituted on at least one meta position with C2-C4 alkynyl, then X is NR 4 or CR 15 R 16 .
  • Embodiment 134 A compound of Formula 1 or any one of Embodiments 1 through 133 wherein when Q 2 comprises an imidazopyrazine ring system, then X is O or CR 15 R 16 .
  • Embodiment 135. A compound of Formula 1 or any one of Embodiments 1 through 134 wherein when Q 2 comprises a tetrahydropyrimidine ring, then X is O or
  • Embodiment 136 A compound of Formula 1 or any one of Embodiments 1 through 135 wherein when Q 1 comprises a phenyl ring, then said ring is not substituted by cyano.
  • Embodiment 137 A compound of Formula 1 or any one of Embodiments 1 through 136 wherein when Q 1 comprises a 6-membered heterocyclic ring, then X is O or CR 15 R 16 .
  • Embodiment 138 A compound of Formula 1 or any one of Embodiments 1 through 137 wherein when Q 1 comprises a phenyl ring substituted at the para position with alkylthio, haloalkylthio, alkylsulfmyl, haloalkylsulfmyl, alkylsulfonyl or haloalkylsulfonyl, then X is NR 4 or CR 15 R 16 .
  • Embodiment 139 A compound of Formula 1 or any one of Embodiments 1 through 138 wherein when Q 1 comprises a 4-pyridinyl or 4-pyrimidinyl ring substituted at the 2-position (according to standard pyridine and pyrimidine ring numbering) with methylamino, then X is O or CR 15 R l 6 .
  • Embodiment 140 A compound of Embodiment 139 wherein when Q 1 comprises a 4- pyridinyl or 4-pyrimidinyl ring substituted at the 2-position with amino, methylamino or dimethylamino, then X is O or CR 15 R 16 .
  • Embodiment 141 A compound of Formula 1 or any one of Embodiments 1 through 140 wherein each R 27 is independently H or C1-C2 alkyl.
  • Embodiment 142 A compound of Formula 1 or any one of Embodiments 1 through 141 wherein each R 28 is H or C1-C2 alkyl.
  • Embodiments of this invention can be combined in any manner, and the descriptions of variables in the embodiments pertain not only to the compounds of Formula 1 but also to the starting compounds and intermediate compounds useful for preparing the compounds of Formula 1.
  • embodiments of this invention including Embodiments 1-142 above as well as any other embodiments described herein, and any combination thereof, pertain to the compositions and methods of the present invention.
  • Embodiment A A compound of Formula 1 wherein
  • Q 1 is phenyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl, each substituted with from 1 to 4 substituents independently selected from R 3 ; provided that when an R 3 substituent is located at a meta position, then said R 3 substituent is selected from F, CI, Br and cyano;
  • Q 2 is phenyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl, each substituted with
  • R 3 1, 2 or 3 substituents independently selected from R 3 , provided that when an R 3 substituent is located at a meta position, then said R 3 substituent is selected from F, CI, Br and cyano;
  • R 1 is H, halogen, -Cg alkyl, -Cg haloalkyl, C0 2 R 5 , C(0)NR 6 R 7 , cyano, C r
  • R la is H
  • R 1 and R la are taken together with the carbon atom to which they are attached to form a cyclopropyl ring optionally substituted with up to 2 substituents independently selected from halogen and methyl;
  • each R 3 is independently selected from halogen, cyano, nitro, amino, methylamino, dimethylamino, C1-C4 alkyl, C1-C4 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy C1-C3 alkylthio, C1-C3 haloalkylthio, C1-C3 alkylsulfinyl, C ⁇ -
  • R 4 is H, formyl, C 3 -C 7 cycloalkyl or -SR 10 ; or -C alkyl or -Cg haloalkyl, each optionally substituted with up to 2 R 12 ;
  • R 5 is Ci-Cg alkyl
  • R 6 is H or -Cg alkyl
  • R 7 is H, C j -Cg alkyl, -Cg haloalkyl or C 4 -C 8 alkylcycloalkyl; or
  • R 6 and R 7 are taken together with the nitrogen atom to which they are connected to form a four- to seven-membered nonaromatic heterocyclic ring containing ring members, in addition to the connecting nitrogen atom, selected from carbon atoms and up to one ring member selected from O and NR 13 ; each R 12 is independently C 3 -C 7 cycloalkyl, C1-C4 alkoxy or cyano;
  • R 13 is H or CH 3 ;
  • R 15 is H or CH 3 ;
  • R 16 is OR 18 .
  • Embodiment B A compound of Embodiment A wherein
  • Q 1 is phenyl or pyridinyl, each substituted with 1, 2 or 3 substituents independently selected from R 3 ;
  • Q 2 is phenyl or pyridinyl, each substituted with 1 , 2 or 3 substituents independently selected from R 3 ;
  • R 1 is H, halogen, C1-C3 alkyl or C1-C2 haloalkyl
  • R la is H; or R 1 and R la are taken together with the carbon atom to which they are attached to form a cyclopropyl ring;
  • R 2 is H
  • each R 3 is independently selected from halogen, cyano, nitro, C1-C4 alkyl, C1-C4 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy and -U-V-T;
  • R 4 is H, formyl, C3-C7 cycloalkyl or -SR 10 ; or Ci ⁇ C 6 alkyl substituted with one R12;
  • each R 12 is independently cyclopropyl, -OCH3 or cyano
  • R 15 is H
  • each U is independently O or NH
  • each V is C 2 -C 4 alkylene
  • each T is independently NR 23a R 23b or OR 24 ;
  • each R 23a and R 23b is independently H, C ⁇ -C6 alkyl or C ⁇ -C6 haloalkyl; and each R 24 is independently H, C ⁇ -C6 alkyl or C ⁇ -C6 haloalkyl.
  • Embodiment C A compound of Embodiment B wherein
  • Q 1 and Q 2 are phenyl substituted with 2 or 3 substituents
  • R 1 is H or CH 3 ;
  • R la is H
  • R 4 is H
  • each R 3 is independently selected from halogen, cyano, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy and C1-C3 haloalkoxy;
  • R 18 is H.
  • Embodiment D A compound of Embodiment C wherein
  • Q 1 is phenyl substituted at the 2-, 4- and 6-positions with substituents
  • Q 2 is phenyl substituted at the 2-, 4- and 6-positions with substituents
  • X is O or NR 4 ;
  • R 1 is H
  • each R 3 is independently selected from F, CI, Br, cyano, C1-C2 alkyl, C1-C2 haloalkyl, C1-C2 alkoxy and C1-C2 haloalkoxy.
  • Embodiment E A compound of Embodiment D wherein
  • each R 3 is independently selected from F, CI, Br, cyano, methyl and methoxy.
  • Specific embodiments include compounds of Formula 1 selected from the group consisting of:
  • This invention provides a fungicidal composition
  • a fungicidal composition comprising a compound of Formula 1 (including all geometric and stereoisomers, N-oxides, and salts thereof), and at least one other fungicide.
  • a compound of Formula 1 including all geometric and stereoisomers, N-oxides, and salts thereof
  • at least one other fungicide are compositions comprising a compound corresponding to any of the compound embodiments described above.
  • This invention provides a fungicidal composition
  • a compound of Formula 1 comprising a compound of Formula 1
  • compositions comprising a compound corresponding to any of the compound embodiments described above.
  • 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, a fungicidally effective amount of a compound of Formula 1 (including all geometric and stereoisomers, N-oxides, and salts thereof).
  • a compound of Formula 1 including all geometric and stereoisomers, N-oxides, and salts thereof.
  • methods comprising applying a fungicidally effective amount of a compound corresponding to any of the compound embodiments described above.
  • the compounds are applied as compositions of this invention.
  • compounds of Formula 1 wherein R 2 is C 2 -C 3 alkenyl or C 2 - C3 alkynyl can be prepared by reacting compounds of Formula 2 with organometallics of Formula 3, in which M is, for example, B(OH) 2 or esters thereof, ZnCl, ZnBr, MgCl, MgBr, SnMe3 or SnBu3.
  • M is, for example, B(OH) 2 or esters thereof, ZnCl, ZnBr, MgCl, MgBr, SnMe3 or SnBu3.
  • compounds of Formula 1 wherein R 2 is C2-C3 alkenyl or C2-C3 alkynyl can be prepared by reacting compounds of Formula 2 with C2-C3 alkenes or C2-C3 alkynes of Formula 4 in the presence of a palladium catalyst such as tetrakis(triphenylphosphine)Pd(0), dichloro[ 1 , 1 '-bis(diphenylphosphino)ferrocene]palladium or Pd(OAc) 2 , optionally with the addition of copper(I) salts such as cuprous iodide, and advantageously in the presence of a base such as triethylamine, sodium acetate, potassium carbonate or sodium tert-butoxide. Procedures of this type may be found in PCT Patent Publications WO 2010/093885 and WO 2011/076725.
  • compounds of Formula 2 can be prepared by reacting compounds of Formula 5 with compounds of Formula 6 using transition-metal-catalyzed cross-coupling reaction conditions. Reaction of a 4-iodopyrazole of Formula 5 with a boronic acid, trialkyltin, zinc or organomagnesium reagent of Formula 6 in the presence of a palladium or nickel catalyst having appropriate ligands (e.g., triphenylphosphine (PPh 3 ), dibenzylideneacetone (dba), dicyclohexyl(2',6'-dimethoxy [ 1 , 1 '-biphenyl]-2-yl)phosphine (SPhos)) and a base, if needed, affords the corresponding compound of Formula 2.
  • a palladium or nickel catalyst having appropriate ligands (e.g., triphenylphosphine (PPh 3 ), dibenzylideneacetone (dba), dicyclohexyl(2'
  • a substituted aryl boronic acid or derivative e.g., Formula 6 wherein Q 1 is optionally substituted phenyl or heterocyclyl and M is B(OH) 2 , B(OC(CH 3 ) 2 C(CH 3 ) 2 0)) or [B(0-z-Pr) 3 ]Li reacts with a 4-iodopyrazole of Formula 5 in the presence of dichlorobis(triphenylphosphine) palladium(II) and aqueous base such as sodium carbonate or potassium hydroxide, in solvents such as 1,4-dioxane, 1,2-dimethoxyethane, toluene or ethyl alcohol, or under anhydrous conditions with a ligand such as phosphine oxide or phosphite ligand (e.g., diphenylphosphine oxide) and potassium fluoride in a solvent such as 1,4-dioxane (see Angewand
  • compounds of Formula 8a i.e. Formula 8 wherein X is NH
  • compounds of Formula 8b i.e., Formula 8 wherein X is O
  • compounds of Formula 9 can be prepared by reacting compounds of Formula 9 with compounds of Formula 11, generally in the presence of a base such as sodium hydroxide, potassium carbonate, or sodium hydride.
  • a base such as sodium hydroxide, potassium carbonate, or sodium hydride.
  • compounds of Formula 5 wherein X is CR 15 R 16 can be prepared by reacting compounds of Formula 12 with an iodinating reagent, such as with iodine under such conditions as described in Journal of Heterocyclic Chemistry 1995, 32(4), 1351-4, or with N-iodosuccinimide (NIS), under conditions such as those disclosed in Journal of Medicinal Chemistry 1990, 33( ⁇ ), 31-8.
  • an iodinating reagent such as with iodine under such conditions as described in Journal of Heterocyclic Chemistry 1995, 32(4), 1351-4, or with N-iodosuccinimide (NIS), under conditions such as those disclosed in Journal of Medicinal Chemistry 1990, 33( ⁇ ), 31-8.
  • compounds of Formula 12a can be prepared by treatment of compounds of Formula 13 with magnesium metal, isopropylmagnesium chloride (optionally as the 1 : 1 lithium chloride complex) or n-butyllithium, in anhydrous solvents such as ether, methyl tert-butyl ether, or tetrahydrofuran, at temperatures ranging from -78 °C to room temperature, followed by the addition of the appropriate aldehyde or ketone of Formula 14 having R 15 as defined in the scope of the invention.
  • the compounds of Formula 14 are commercially available or prepared by general methods well-known in the art.
  • Compounds of Formula 13 are known or are prepared by general methods well-known in the art.
  • compounds of Formula 12b i.e. Formula 12 wherein X is CR 15 R 16 and R 16 is F
  • DAST diethylaminosulfur trifluoride
  • BAST bis(2- methoxyethyl)aminosulfur trifluoride
  • compounds of Formula 12a can be treated with thionyl chloride or phosphorus pentachloride, optionally in the presence of a base such as triethylamine or pyridine, in a solvent such as dichloromethane at temperatures below ambient to about 40 °C or in N,N-dimethylformamide at 90-140 °C for time periods of 1-24 h, using procedures such as described in Bull. Chem. Soc. Japan 2002, 75, 1371-1379, to provide compounds of Formula 12c (i.e. Formula 12 wherein X is CR 15 R 16 and R 16 is CI).
  • R 4 is an acyl- or sulfonyl-based substituent
  • R 4 is alkyl
  • a wide variety of general methods known in the art for forming alcohol derivatives are can be used to prepare compounds of Formula Id (i.e. Formula 1 in which X is CR 15 R 16 and R 16 is OR 18 ) wherein R 18 is other than H from corresponding compounds of Formula lc (i.e. Formula 1 in which X is CR 15 R 16 and R 16 is OH).
  • R 18 is other than H from corresponding compounds of Formula lc (i.e. Formula 1 in which X is CR 15 R 16 and R 16 is OH).
  • compounds of Formula Id wherein R 18 is alkyl can be prepared by reacting compounds of Formula lc with an alkylating agent 16 in the presence of a base.
  • compounds of Formula Id wherein R 18 is an acyl-based substituent can be prepared by reacting compounds of Formula lc with corresponding acylating reagents, respectively, by methods well known in the literature.
  • R 1S is alkyl
  • compounds of Formula le i.e. Formula 1 wherein X is CR 15 R 16 and R 16 is F
  • Formula If i.e. Formula 1 wherein X is CR 15 R 16 and R 16 is CI
  • compounds of Formula lc i.e. Formula 1 wherein X is CR 15 R 16 , R 16 is OR 18 and R 18 is H
  • compounds of Formula lg can be prepared by the reaction of substituted hydrazines of Formula 18 with dialkylaminothioacrylamides of Formula 17.
  • the reaction in Scheme 13 can optionally be carried out in a variety of solvents, such as methanol, ethanol, isopropanol, tetrahydrofuran or 1,4-dioxane, or mixtures of these solvents with each other or with water, at temperatures from below ambient to the boiling point of the solvent or solvent mixture.
  • R, R" are alkyl
  • compounds of Formula 17 can be prepared by reaction of thioamides of Formula 19 with such reagents as dimethylformamide dimethyl acetal, tert- butoxy-bis(dimethylamino)methane (Brederick's reagent), or by a two-stage reaction with a trialkyl orthoformate, such as triethyl orthoformate, followed by the addition of a dialkylamine such as dimethylamine or cyclic secondary amine such as piperidine or morpholine. Examples of analogous reactions are known in the literature (see for example Journal f r Praktician Chemie (Leipzig) 1986, 328(1), 120-6).
  • Compounds of Formula 19 are known or prepared by methods known in the art, such as those found in PCT Patent Publication WO 2010/018874. The method of Scheme 14 is illustrated by Step C of Synthesis Example 2.
  • compounds of Formula lh can be prepared by reacting lH-pyrazoles of Formula 20 with various alkylating agents of Formula 21, preferably in the presence of an organic or inorganic base such as l,8-diazabicyclo[5.4.0]undec-7-ene, potassium carbonate or potassium hydroxide, and in a solvent such as N,N-dimethylformamide, tetrahydrofuran, toluene or water.
  • an organic or inorganic base such as l,8-diazabicyclo[5.4.0]undec-7-ene, potassium carbonate or potassium hydroxide
  • Suitable alkylating agents include but are not limited to iodoalkanes, alkylsulfonates such as mesylates (OMs) or tosylates (OTs) or trialkyl phosphates.
  • OMs mesylates
  • OTs tosylates
  • Compounds of Formula 20 are prepared by reacting compounds of Formula 17 with hydrazine under the conditions described in Scheme 13.
  • compounds of Formula lg also can be prepared by the reaction of 5-aminopyrazoles of Formula 22 with compounds of Formula 23 containing a leaving group G (i.e. halogen or (halo)alkylsulfonate), optionally in the presence of a metal catalyst, and generally in the presence of a base and a polar aprotic solvent such as N,N-dimethylformamide or dimethyl sulfoxide.
  • a leaving group G i.e. halogen or (halo)alkylsulfonate
  • a metal catalyst e.g., metal or metal salt
  • G is Br or I or a sulfonate such as OS(0)2CF 3 or OS(0)2(CF 2 )3CF 3 .
  • copper salt complexes e.g., Cul with A .N'-dimethylethylenediamine, proline or bipyridyl
  • palladium complexes e.g., tris(dibenzylideneacetone)dipalladium(0)
  • palladium salts e.g., palladium acetate
  • ligands such as 4,5-bis(diphenylphosphino)- 9,9-dimethylxanthene (i.e. "Xantphos"), 2-dicyclohexylphosphino-2',4',6'-triisopropyl- biphenyl (i.e.
  • Xphos 2,2'-bis(diphenylphosphino)-l, -binaphthalene
  • BINAP 2,2'-bis(diphenylphosphino)-l, -binaphthalene
  • a base such as potassium carbonate, cesium carbonate, sodium phenoxide or sodium tert-butoxide
  • solvent such as N,N-dimethylformamide, 1 ,2-dimethoxyethane, dimethyl sulfoxide, 1,4-dioxane or toluene
  • the method of Scheme 16 is illustrated by Step C of Synthesis Example 1.
  • 5-aminopyrazoles of Formula 22 can be prepared by reaction of compounds of Formula 24 with substituted hydrazines of Formula 18 under conditions similar to those described for Scheme 13.
  • Compounds of Formula 24 can be prepared from nitriles of Formula 25 by methods knows in the art such as treatment with ethyl formate in the presence of a base.
  • Nitriles of Formula 25 are commercially available or their preparation is known in the art. The method of Scheme 17 is illustrated by Steps A and B of Synthesis Example 1.
  • compounds of Formula 9 wherein R la is H can be prepared by alkylating the IH-pyrazole of Formula 26 with various alkylating agents of Formula 21, similar to the method described in Scheme 15.
  • the IH-pyrazole of Formula 26 is commercially available.
  • compounds of Formula 9 wherein R la is taken together with R 1 and the carbon atom to which they are attached to form an optionally substituted cyclopropyl ring can be prepared by reacting the IH-pyrazole of Formula 26 with a compound of Formula 27 in the presence of a copper catalyst and ligand.
  • a copper catalyst and ligand for example, boronic acids, boronate esters or trifluoroborate salts of Formula 23 are used in the presence of copper(II) acetate and a ligand such as 2,2'-bipyridyl, optionally in the presence of an added base such as sodium carbonate in a solvent such as dichloromethane or 1 ,2-dichloroethane, at temperatures ranging from room temperature to 90 °C.
  • compounds of Formula 2a i.e. Formula 2 wherein X is NR 4 and R 4 is H
  • compounds of Formula 2b i.e. Formula 2 wherein X is CR 15 R 16 , R 16 is OR 18 and R 18 is H
  • compounds of Formula 29 can be prepared from compounds of Formula 29 by the methods analogous to those described in Schemes 6 and 8.
  • compounds of Formula 30 can be prepared by bromination of lH-pyrazoles of Formula 31 by procedures known in the art. For representative procedures see Synthetic Communications 2008, 38(5), 674-683 and Journal of Organic Chemistry, 1968, 57(24), 4656-4660. lH-Pyrazoles of Formula 31 are prepared by methods known in the literature (see e.g., PCT Patent Publication 2008/080969, Tetrahedron Letters 1988, 29(46), 6001-6004, and Helvetica Chimica Acta 1927, 10, 846-848).
  • compounds of Formula 1 or intermediates for their preparation may contain aromatic nitro groups, which can be reduced to amino groups, and then be converted via reactions well known in the art such as the Sandmeyer reaction, to various halides, providing other compounds of Formula 1.
  • aromatic amines anilines
  • diazonium salts can be converted via diazonium salts to phenols, which can then be alkylated to prepare compounds of Formula 1 with alkoxy substituents.
  • aromatic halides such as bromides or iodides prepared via the Sandmeyer reaction can react with alcohols under copper-catalyzed conditions, such as the Ullmann reaction or known modifications thereof, to provide compounds of Formula 1 that contain alkoxy substituents.
  • some halogen groups such as fluorine or chlorine, can be displaced with alcohols under basic conditions to provide compounds of Formula 1 containing the corresponding alkoxy substituents.
  • the resultant alkoxy compounds can themselves be used in further reactions to prepare compounds of Formula 1 wherein R 3 is -U-V-T (see, for example, PCT Publication WO 2007/149448 A2).
  • sulfide groups can be oxidized to the corresponding sulfoxides or sulfones by conditions well-known in the art.
  • Mass spectra are reported as the molecular weight of the highest isotopic abundance parent ion (M+1) formed by addition of H + (molecular weight of 1) to the molecule, observed by mass spectrometry using atmospheric pressure chemical ionization (AP + ) where "amu” stands for atomic mass units.
  • LCMS refers to liquid chromatographic separation with mass spectra detection.
  • Step A Preparation of (aZ)-2-chloro-4-fluoro-a-(hydroxymethylene)- benzeneacetonitrile and (aE)-2-chloro-4-fluoro-a-(hydroxymethylene)- benzeneacetonitrile
  • aqueous layer was acidified with 1 N aqueous hydrochloric acid and extracted with ethyl acetate (50 mL). This second extract was washed with brine, dried (MgS0 4 ), filtered and concentrated under reduced pressure to give a mixture of isomeric title compounds as a white solid (1.53 g, 68% yield).
  • Step B Preparation of 4-(2-chloro-4-fluorophenyl)-l -methyl- lH-pyrazole-5-amine and 4-(2-chloro-4-fluorophenyl)-l -methyl- lH-pyrazole-3-amine
  • Step C Preparation of N,4-bis(2-chloro-4-fluorophenyl)- 1 -methyl- lH-pyrazol-
  • the cooled reaction mixture was filtered through a pad of Celite® diatomaceous filter aid, and the pad was washed with ethyl acetate (25 mL). The filtrate was washed with water and brine, dried (MgS0 4 ), filtered and concentrated under reduced pressure.
  • Step A Preparation of 2-Bromo-N-(2-bromo-4,6-difluorophenyl)-4-fluoro- benzeneacetamide
  • Step B Preparation of 2-Bromo-N-(2-bromo-4,6-difluorophenyl)-4-fluoro- benzeneethanethioamide
  • Step C Preparation of 2-Bromo-N-(2-bromo-4,6-difluorophenyl)-a-[(dimethyl- amino)methylene]-4-fluorobenzeneethanethioamide
  • Step D Preparation of N-(2-Bromo-4,6-difluorophenyl)-4-(2-bromo-4-fluorophenyl)- 1 -methyl- lH-pyrazol-5-amine
  • Step A Preparation of a-(2-Chloro-4-fluorophenyl)-l -methyl- lH-pyrazole- 5 -methanol
  • Step B Preparation of 4-Bromo-a-(2-chloro-4-fluorophenyl)- 1 -methyl- lH-pyrazole-
  • Step C Preparation of a,4-Bis(2-chloro-4-fluorophenyl)-l -methyl- lH-pyrazole- 5 -methanol
  • n- means normal, i- means iso, s- means secondary, t- means tertiary, Me means methyl, Et means ethyl, Pr means propyl, Ph means phenyl, MeO means methoxy, EtO means ethoxy and -CN means cyano.
  • Q 1 is 2,6-di-F-Ph
  • X is NH
  • R 1 and R l a are both H
  • R 2 is H.
  • the present disclosure also includes Tables 2 through 529, each of which is constructed the same as Table 1 above, except that the row heading in Table 1 (i.e. "Q 1 is 2,6-di-F-Ph, X is NH, R 1 and R la are both H, and R 2 is H.") is replaced with the respective row heading shown below.
  • Table 2 the row heading is "Q 1 is 2,6-di-F-Ph, X is NH, R 1 and R la are both H, and R 2 is ethenyl.”
  • (R ) p is as defined in Table 1 above.
  • Table 2 specifically discloses 4-(2,6-difluorophenyl)- 3-ethenyl-N-(2-fluorophenyl)-l -methyl- lH-pyrazole-5-amine.
  • Tables 3 through 529 are constructed similarly.
  • Q 1 is 2,6- -di-F- Ph
  • X is NH
  • R 1 and R l a are both H
  • R 2 is ethenyl.
  • Q 1 is 2,6- -di-F- Ph
  • X is NH
  • R 1 and R l a are both H
  • R 2 is ethynyl.
  • Q 1 is 2,6- -di-F- Ph
  • X is NH
  • R 1 is Me
  • R l a is H
  • R 2 is H.
  • Q 1 is 2,6- -di-F- Ph
  • X is NH
  • R 1 is Me
  • R l a is H
  • R 2 is ethenyl
  • Q 1 is 2,6- -di-F- Ph
  • X is NH
  • R 1 is Me
  • R l a is H
  • R 2 is ethynyl
  • Q 1 is 2,6- -di-F- Ph
  • X is O
  • R 1 and R i a are both H
  • R 2 is H.
  • Q 1 is 2,6- -di-F- Ph
  • X is O
  • R 1 and R i a are both H
  • R 2 is ethenyl.
  • Q 1 is 2,6- -di-F- Ph
  • X is O
  • R 1 and R i a are both H
  • R 2 is ethynyl.
  • Q 1 is 2,6- -di-F- Ph
  • X is O
  • R 1 is Me
  • R l a is H
  • R 2 is H.
  • Q 1 is 2,6- -di-F- Ph
  • X is O
  • R 1 is Me
  • R ⁇ a is H
  • R 2 is ethenyl
  • Q 1 is 2,6- -di-F- Ph
  • X is O
  • R 1 is Me
  • R ⁇ a is H
  • R 2 is ethynyl
  • Q 1 is 2,6- -di-F- Ph
  • X is CHOH
  • R 1 and R i a are both H
  • R 2 is H.
  • Q 1 is 2,6- -di-F- Ph
  • X is CHOH
  • R 1 and R i a are both H
  • R 2 is ethenyl.
  • Q 1 is 2,6- -di-F- Ph
  • X is CHOH
  • R 1 and R i a are both H
  • R 2 is ethynyl.
  • Q 1 is 2,6- -di-F- Ph
  • X is CHOH
  • R 1 is Me
  • R l a is H
  • R 2 is H.
  • Q 1 is 2,6- -di-F- Ph
  • X is CHOH
  • R 1 is Me
  • R ⁇ a is H
  • R 2 is ethenyl
  • Q 1 is 2,4- -di-F- Ph
  • X is NH
  • R 1 and R l a are both H
  • R 2 is H.
  • Q 1 is 2,4- -di-F- Ph
  • X is NH
  • R 1 and R l a are both H
  • R 2 is ethenyl.
  • Q 1 is 2,4-di-F-Ph
  • X is NH
  • R 1 is Me
  • R l a is H
  • R 2 is H.
  • Q 1 is 2,4-di-F-Ph
  • X is NH
  • R 1 is Me
  • R l a is H
  • R 2 is ethenyl
  • Q 1 is 2,4-di-F-Ph
  • X is NH
  • R 1 is Me
  • R l a is H
  • R 2 is ethynyl
  • Q 1 is 2,4-di-F-Ph
  • X is O
  • R 1 and R l a are both H
  • R 2 is H.
  • Q 1 is 2,4-di-F-Ph
  • X is O
  • R 1 and R l a are both H
  • R 2 is ethenyl.
  • Q 1 is 2,4-di-F-Ph
  • X is O
  • R 1 and R l a are both H
  • R 2 is ethynyl.
  • Q 1 is 2,4-di-F-Ph
  • X is O
  • R 1 is Me
  • R l a is H
  • R 2 is H.
  • Q 1 is 2,4-di-F-Ph
  • X is O
  • R 1 is Me
  • R l a is H
  • R 2 is ethenyl
  • Q 1 is 2,4-di-F-Ph
  • X is O
  • R 1 is Me
  • R l a is H
  • R 2 is ethynyl
  • Q 1 is 2,4-di-F-Ph
  • X is CHOH
  • R 1 and R l a are both H
  • R 2 is H.
  • Q 1 is 2,4-di-F-Ph
  • X is CHOH
  • R 1 and R l a are both H
  • R 2 is ethenyl.
  • Q 1 is 2,4-di-F-Ph
  • X is CHOH
  • R 1 and R l a are both H
  • R 2 is ethynyl
  • Q 1 is 2,4-di-F-Ph
  • X is CHOH
  • R 1 is Me
  • R l a is H
  • R 2 is H.
  • Q 1 is 2,4-di-F-Ph
  • X is CHOH
  • R 1 is Me
  • R l a is H
  • R 2 is ethenyl
  • Q 1 is 2,4-di-F-Ph
  • X is CHOH
  • R 1 is Me
  • R l a is H
  • R 2 is ethynyl
  • Q 1 is 2-Cl-4-F-Ph
  • X is NH
  • R 1 and R l a are both H
  • R 2 is H.
  • Q 1 is 2-Cl-4-F-Ph
  • X is NH
  • R 1 and R l a are both H
  • R 2 is ethenyl
  • Q 1 is 2-Cl-4-F-Ph
  • X is NH
  • R 1 and R l a are both H
  • R 2 is ethynyl
  • Q 1 is 2-Cl-4-F-Ph
  • X is NH
  • R 1 is Me
  • R l a is H
  • R 2 is H.
  • Q 1 is 2-Cl-4-F-Ph
  • X is NH
  • R 1 is Me
  • R l a is H
  • R 2 is ethenyl
  • Q 1 is 2-Cl-4-F-Ph
  • X is NH
  • R 1 is Me
  • R l a is H
  • R 2 is ethynyl
  • Q 1 is 2-Cl-4-F-Ph
  • X is O
  • R 1 and R l a are both H
  • R 2 is H.
  • Q 1 is 2-Cl-4-F-Ph
  • X is O
  • R 1 and R l a are both H
  • R 2 is ethenyl.
  • Q 1 is 2-Cl-4-F-Ph
  • X is O
  • R 1 and R l a are both H
  • R 2 is ethynyl.
  • Q 1 is 2-Cl-4-F-Ph
  • X is O
  • R 1 is Me
  • R l a is H
  • R 2 is H.
  • Q 1 is 2-Cl-4-F-Ph
  • X is O
  • R 1 is Me
  • R l a is H
  • R 2 is ethenyl
  • Q 1 is 2-Cl-4-F-Ph
  • X is O
  • R 1 is Me
  • R l a is H
  • R 2 is ethynyl
  • Q 1 is 2-Cl-4-F-Ph
  • X is CHOH
  • R 1 and R l a are both H
  • R 2 is H.
  • Q 1 is 2-Cl-4-F-Ph
  • X is CHOH
  • R 1 and R l a are both H
  • R 2 is ethenyl.
  • Q 1 is 2-Cl-4-F-Ph
  • X is CHOH
  • R 1 and R l a are both H
  • R 2 is ethynyl
  • Q 1 is 2-Cl-4-F-Ph
  • X is CHOH
  • R 1 is Me
  • R l a is H
  • R 2 is H.
  • Q 1 is 2-Cl-4-F-Ph
  • X is CHOH
  • R 1 is Me
  • R l a is H
  • R 2 is ethenyl
  • Q 1 is 2-Cl-4-F-Ph
  • X is CHOH
  • R 1 is Me
  • R l a is H
  • R 2 is ethynyl
  • Q 1 is 2,6-di-Cl-Ph
  • X is NH
  • R 1 and R l a are both H
  • R 2 is H.
  • Q 1 is 2,6-di-Cl-Ph
  • X is NH
  • R 1 and R l a are both H
  • R 2 is ethenyl
  • Q 1 is 2,6-di-Cl-Ph
  • X is NH
  • R 1 and R l a are both H
  • R 2 is ethynyl
  • Q 1 is 2,6-di-Cl-Ph
  • X is NH
  • R 1 is Me
  • R l a is H
  • R 2 is H.
  • Q 1 is 2,6-di-Cl-Ph
  • X is NH
  • R 1 is Me
  • R l a is H
  • R 2 is ethenyl
  • Q 1 is 2,6-di-Cl-Ph
  • X is NH
  • R 1 is Me
  • R l a is H
  • R 2 is ethynyl
  • Q 1 is 2,6-di-Cl-Ph
  • X is O
  • R 1 and R l a are both H
  • R 2 is H.
  • Q 1 is 2,6-di-Cl-Ph
  • X is O
  • R 1 and R l a are both H
  • R 2 is ethenyl.
  • Q 1 is 2,6-di-Cl-Ph
  • X is O
  • R 1 and R l a are both H
  • R 2 is ethynyl.
  • Q 1 is 2,6-di-Cl-Ph
  • X is O
  • R 1 is Me
  • R l a is H
  • R 2 is H.
  • Q 1 is 2,6-di-Cl-Ph
  • X is O
  • R 1 is Me
  • R l a is H
  • R 2 is ethenyl
  • Q 1 is 2,6-di-Cl-Ph
  • X is O
  • R 1 is Me
  • R l a is H
  • R 2 is ethynyl
  • Q 1 is 2,6-di-Cl-Ph
  • X is CHOH
  • R 1 and R l a are both H
  • R 2 is H.
  • Q 1 is 2,6-di-Cl-Ph
  • X is CHOH
  • R 1 and R l a are both H
  • R 2 is ethenyl.
  • Q 1 is 2,6-di-Cl-Ph
  • X is CHOH
  • R 1 and R l a are both H
  • R 2 is ethynyl
  • Q 1 is 2,6-di-Cl-Ph
  • X is CHOH
  • R 1 is Me
  • R l a is H
  • R 2 is H.
  • Q 1 is 2,6-di-Cl-Ph
  • X is CHOH
  • R 1 is Me
  • R l a is H
  • R 2 is ethenyl
  • Q 1 is 2,6-di-Cl-Ph
  • X is CHOH
  • R 1 is Me
  • R l a is H
  • R 2 is ethynyl
  • Q 1 is 2-Br-4-Cl-Ph
  • X is NH
  • R 1 and R l a are both H
  • R 2 is H.
  • Q 1 is 2-Br-4-Cl-Ph
  • X is NH
  • R 1 and R l a are both H
  • R 2 is ethenyl.
  • Q 1 is 2-Br-4-Cl-Ph
  • X is NH
  • R 1 and R l a are both H
  • R 2 is ethynyl.
  • Q 1 is 2-Br-4-Cl-Ph
  • X is NH
  • R 1 is Me
  • R l a is H
  • R 2 is H.
  • Q 1 is 2-Br-4-Cl-Ph
  • X is NH
  • R 1 is Me
  • R l a is H
  • R 2 is ethenyl
  • Q 1 is 2-Br-4-Cl-Ph
  • X is NH
  • R 1 is Me
  • R l a is H
  • R 2 is ethynyl
  • Q 1 is 2-Br-4-Cl-Ph
  • X is O
  • R 1 and R l a are both H
  • R 2 is H.
  • Q 1 is 2-Br-4-Cl-Ph
  • X is O
  • R 1 and R l a are both H
  • R 2 is ethenyl.
  • Q 1 is 2-Br-4-Cl-Ph
  • X is O
  • R 1 and R l a are both H
  • R 2 is ethynyl.
  • Q 1 is 2-Br-4-Cl-Ph
  • X is O
  • R 1 is Me
  • R l a is H
  • R 2 is H.
  • Q 1 is 2-Br-4-Cl-Ph
  • X is O
  • R 1 is Me
  • R l a is H
  • R 2 is ethenyl
  • Q 1 is 2-Br-4-Cl-Ph
  • X is O
  • R 1 is Me
  • R l a is H
  • R 2 is ethynyl
  • Q 1 is 2-Br-4-Cl-Ph
  • X is CHOH
  • R 1 and R l a are both H
  • R 2 is H.
  • Q 1 is 2-Br-4-Cl-Ph
  • X is CHOH
  • R 1 and R l a are both H
  • R 2 is ethenyl.
  • Q 1 is 2-Br-4-Cl-Ph
  • X is CHOH
  • R 1 and R l a are both H
  • R 2 is ethynyl
  • Q 1 is 2-Br-4-Cl-Ph
  • X is CHOH
  • R 1 is Me
  • R l a is H
  • R 2 is H.
  • Q 1 is 2-Br-4-Cl-Ph
  • X is CHOH
  • R 1 is Me
  • R l a is H
  • R 2 is ethenyl
  • Q 1 is 2-Br-4-Cl-Ph
  • X is CHOH
  • R 1 is Me
  • R l a is H
  • R 2 is ethynyl
  • Q 1 is 2-Br-6-Cl-Ph
  • X is NH
  • R 1 and R l a are both H
  • R 2 is H.
  • Q 1 is 2-Br-6-Cl-Ph
  • X is NH
  • R 1 and R l a are both H
  • R 2 is ethenyl.
  • Q 1 is 2-Br-6-Cl-Ph
  • X is NH
  • R 1 and R l a are both H
  • R 2 is ethynyl.
  • Q 1 is 2-Br-6-Cl-Ph
  • X is NH
  • R 1 is Me
  • R l a is H
  • R 2 is H.
  • Q 1 is 2-Br-6-Cl-Ph
  • X is NH
  • R 1 is Me
  • R l a is H
  • R 2 is ethenyl
  • Q is Br-6-Cl-Ph
  • X is NH
  • R 1 is Me
  • R L A is H
  • R 2 is ethynyl
  • Q is Br-6-Cl-Ph
  • X is O
  • R and R I A are both H
  • R2 is H.
  • Q is Br-6-Cl-Ph, X is O, R and R ⁇ A are both H, and R 2 is ethenyl.
  • Q is Br-6-Cl-Ph, X is O, R and R1 a are both H, and R 2 is ethynyl.
  • Q is Br-6-Cl-Ph, X is O, R is Me, R L A is H, and R 2 is H.
  • Q is Br-6-Cl-Ph
  • X is O
  • R is Me
  • R ⁇ A is H
  • R 2 is ethenyl
  • Q is Br-6-Cl-Ph
  • X is O
  • R is Me
  • R ⁇ A is H
  • R 2 is ethynyl
  • Q is Br-6-Cl-Ph, X is CHOH, R and R L A are both H, and R 2 is H.
  • Q is Br-6-Cl-Ph, X is CHOH, R and ⁇ A are both H, and R 2 is ethenyl.
  • Q is Br-6-Cl-Ph, X is CHOH, R and 1 a are both H, and R 2 is ethynyl.
  • Q is Br-6-Cl-Ph, X is CHOH, R is Me, R L A is H, and R 2 is H.
  • Q is Br-6-Cl-Ph, X is CHOH, R is Me, R ⁇ A is H, and R 2 is ethenyl.
  • Q is Br-6-Cl-Ph, X is CHOH, R is Me, R L A is H, and R 2 is ethynyl.
  • Q is Me-4-F-Ph, X is NH, R 1 and R L A are both H, and R 2 is H.
  • Q is Me-4-F-Ph
  • X is NH
  • R 1 and R L A are both H
  • R 2 is ethenyl
  • Q is Me-4-F-Ph
  • X is NH
  • R 1 and R L A are both H
  • R 2 is ethynyl
  • Q is Me-4-F-Ph
  • X is NH
  • R 1 is Me
  • R L A is H
  • R 2 is H.
  • Q is Me-4-F-Ph
  • X is NH
  • R 1 is Me
  • R L A is H
  • R 2 is ethenyl
  • Q is Me-4-F-Ph
  • X is NH
  • R 1 is Me
  • R L A is H
  • R 2 is ethynyl
  • Q is Me-4-F-Ph
  • X is O
  • R 1 and R L A are both H
  • R 2 is H.
  • Q is Me-4-F-Ph, X is O, R 1 and R ⁇ A are both H, and R 2 is ethenyl.
  • Q is Me-4-F-Ph, X is O, R 1 and R la are both H, and R 2 is ethynyl.
  • Q is Me-4-F-Ph, X is O, R 1 is Me, R L A is H, and R 2 is H.
  • Q is Me-4-F-Ph
  • X is O
  • R 1 is Me
  • R ⁇ A is H
  • R 2 is ethenyl
  • Q is Me-4-F-Ph
  • X is O
  • R 1 is Me
  • R ⁇ A is H
  • R 2 is ethynyl
  • Q is Me-4-F-Ph, X is CHOH, R 1 and R L A are both H, and R 2 is H.
  • Q is Me-4-F-Ph, X is CHOH, R 1 and R L A are both H, and R 2 is ethenyl.
  • Q is Me-4-F-Ph, X is CHOH, R 1 and R L A are both H, and R 2 is ethynyl.
  • Q is Me-4-F-Ph, X is CHOH, R 1 is Me, R L A is H, and R 2 is H.
  • Q is Me-4-F-Ph, X is CHOH, R 1 is Me, R L A is H, and R 2 is ethenyl.
  • Q is Me-4-F-Ph, X is CHOH, R 1 is Me, R L A is H, and R 2 is ethynyl.
  • Q is Me-4-Cl-Ph, X is NH, R and R L A are both H, and R 2 is H.
  • Q is Me-4-Cl-Ph, X is NH, R and R ⁇ A are both H, and R 2 is ethenyl.
  • Q is Me-4-Cl-Ph, X is NH, R and R1 a are both H, and R 2 is ethynyl.
  • Q is Me-4-Cl-Ph, X is NH, R is Me, R L A is H, and R 2 is H.
  • Q is Me-4-Cl-Ph
  • X is NH
  • R is Me
  • R ⁇ A is H
  • R 2 is ethenyl
  • Q is Me-4-Cl-Ph
  • X is NH
  • R is Me
  • R ⁇ A is H
  • R 2 is ethynyl
  • Q is 2-Me-4-Cl-Ph
  • X is O
  • R 1 and R 1 a are both H
  • R2 is H.
  • Q is 2-Me-4-Cl-Ph, X is O, R 1 and R ⁇ a are both H, and R 2 is ethenyl.
  • Q is 2-Me-4-Cl-Ph, X is O, R 1 and R ⁇ a are both H, and R 2 is ethynyl.
  • Q is 2-Me-4-Cl-Ph, X is O, R 1 is Me, R l a is H, and R 2 is H.
  • Q is 2-Me-4-Cl-Ph
  • X is O
  • R 1 is Me
  • R ⁇ a is H
  • R 2 is ethenyl
  • Q is 2-Me-4-Cl-Ph
  • X is O
  • R 1 is Me
  • R ⁇ a is H
  • R 2 is ethynyl
  • Q is 2-Me-4-Cl-Ph, X is CHOH, R * and R i a are both H, and R 2 is H.
  • Q is 2-Me-4-Cl-Ph, X is CHOH, R 1 and ⁇ a are both H, and R 2 is ethenyl.
  • Q is 2-Me-4-Cl-Ph, X is CHOH, R 1 and R la are both H, and R 2 is ethynyl.
  • Q is 2-Me-4-Cl-Ph, X is CHOH, R 1 is Me, R l a is H, and R 2 is H.
  • Q is 2-Me-4-Cl-Ph, X is CHOH, R 1 is Me, R ⁇ a is H, and R 2 is ethenyl.
  • Q is 2-Me-4-Cl-Ph, X is CHOH, R 1 is Me, R ⁇ a is H, and R 2 is ethynyl.
  • Q is 2-F-4-MeO-Ph, X is NH, R * and R 1 a are both H, and R 2 is H.
  • Q is 2-F-4-MeO-Ph
  • X is NH
  • R * and R i a are both H
  • R 2 is ethenyl
  • Q is 2-F-4-MeO-Ph
  • X is NH
  • R 1 and R ⁇ a are both H
  • R 2 is ethynyl
  • Q is 2-F-4-MeO-Ph
  • X is NH
  • R 1 is Me
  • R l a is H
  • R 2 is H.
  • Q is 2-F-4-MeO-Ph
  • X is NH
  • R 1 is Me
  • R ⁇ a is H
  • R 2 is ethenyl
  • Q is 2-F-4-MeO-Ph
  • X is NH
  • R 1 is Me
  • R ⁇ a is H
  • R 2 is ethynyl
  • Q is 2-F-4-MeO-Ph
  • X is O
  • R 1 and R l a are both H
  • R 2 is H.
  • Q is 2-F-4-MeO-Ph, X is O, R 1 and R 1 a are both H, and R 2 is ethenyl.
  • Q is 2-F-4-MeO-Ph, X is O, R 1 and R i a are both H, and R 2 is ethynyl.
  • Q is 2-F-4-MeO-Ph, X is O, R 1 is Me, R l a is H, and R 2 is H.
  • Q is 2-F-4-MeO-Ph
  • X is O
  • R 1 is Me
  • R ⁇ a is H
  • R 2 is ethenyl
  • Q is 2-F-4-MeO-Ph
  • X is O
  • R 1 is Me
  • R ⁇ a is H
  • R 2 is ethynyl
  • Q is 2-F-4-MeO-Ph, X s CHOH, R 1 and R la are both H, and R 2 is H.
  • Q is 2-F-4-MeO-Ph, X s CHOH, R 1 and R ⁇ a are both H, and R 2 is ethenyl.
  • Q is 2-F-4-MeO-Ph, X s CHOH, R 1 and R i a are both H, and R 2 is ethynyl.
  • Q is 2-F-4-MeO-Ph, X s CHOH, R 1 is Me, R ⁇ a is H, and R 2 is H.
  • Q is 2-F-4-MeO-Ph, X s CHOH, R 1 is Me, R ⁇ a is H, and R 2 is ethenyl.
  • Q is 2-F-4-MeO-Ph, X s CHOH, R 1 is Me, R ⁇ a is H, and R 2 is ethynyl.
  • Q is 2-Br-4-MeO-Ph, X is NH, R and R are both H, and R 2 is H.
  • Q is 2-Br-4-MeO-Ph
  • X is NH, R * and R i a are both H, and R 2 is ethenyl.
  • Q is 2-Br-4-MeO-Ph, X is NH, R * and R i a are both H, and R 2 is ethynyl.
  • Q is 2-Br-4-MeO-Ph, X is NH, R 1 is Me, R l a is H, and R 2 is H.
  • Q is 2-Br-4-MeO-Ph
  • X is NH, R 1 is Me, R ⁇ a is H, and R 2 is ethenyl.
  • Q is 2-Br-4-MeO-Ph, X is NH, R 1 is Me, R ⁇ a is H, and R 2 is ethynyl.
  • Q is 2-Br-4-MeO-Ph, X is O, R 1 and R l a are both H, and R 2 is H.
  • Q is 2-Br-4-MeO-Ph, X is O, R and R ⁇ a are both H, and R2 is ethenyl.
  • Q is 2-Br-4-MeO-Ph, X is O, R and R i a are both H, and R2 is ethynyl.
  • Q is 2-Br-4-MeO-Ph, X is O, R is Me, R l a is H, and R 2 is H.
  • Q is 2-Br-4-MeO-Ph
  • X is O
  • R is Me
  • R ⁇ a is H
  • R 2 is ethenyl
  • Q is 2-Br-4-MeO-Ph
  • X is O
  • R is Me
  • R ⁇ a is H
  • R 2 is ethynyl
  • Q is 2-Br-4-MeO-Ph, X is CHOH, R 1 and R l a are both H, and R 2 is H.
  • Q is 2-Br-4-MeO-Ph, X is CHOH, R 1 and R l a are both H, and R 2 is ethenyl.
  • Q is 2-Br-4-MeO-Ph, X is CHOH, R 1 and R l a are both H, and R 2 is ethynyl.
  • Q is 2-Br-4-MeO-Ph, X is CHOH, R 1 is Me, R l a is H, and R 2 is H.
  • Q is 2-Br-4-MeO-Ph, X is CHOH, R 1 is Me, R l a is H, and R 2 is ethenyl.
  • Q is 2-Br-4-MeO-Ph, X is CHOH, R 1 is Me, R l a is H, and R 2 is ethynyl.
  • Q is 2-Br-4-Me-Ph, X is NH, R * and R ⁇ a are both H, and R 2 is H.
  • Q is 2-Br-4-Me-Ph, X is NH, R * and R i a are both H, and R 2 is ethenyl.
  • Q is 2-Br-4-Me-Ph, X is NH, R * and R i a are both H, and R 2 is ethynyl.
  • Q is 2-Br-4-Me-Ph, X is NH, R 1 is Me, R l a is H, and R 2 is H.
  • Q is 2-Br-4-Me-Ph
  • X is NH
  • R 1 is Me
  • R ⁇ a is H
  • R 2 is ethenyl
  • Q is 2-Br-4-Me-Ph
  • X is NH
  • R 1 is Me
  • R i a is H
  • R 2 is ethynyl
  • Q is 2-Br-4-Me-Ph
  • X is O
  • R and R 1 are both H
  • R 2 is H.
  • Q is 2-Br-4-Me-Ph, X is O, R and R i a are both H, and R 2 is ethenyl.
  • Q is 2-Br-4-Me-Ph, X is O, R and R ⁇ a are both H, and R 2 is ethynyl.
  • Q is 2-Br-4-Me-Ph, X is O, R is Me, R l a is H, and R 2 is H.
  • Q is 2-Br-4-Me-Ph
  • X is O
  • R is Me
  • R ⁇ a is H
  • R 2 is ethenyl
  • Q is 2-Br-4-Me-Ph
  • X is O
  • R is Me
  • R ⁇ a is H
  • R 2 is ethynyl
  • Q is 2-Br-4-Me-Ph, X is CHOH, R and R i a are both H, and R 2 is H.
  • Q is 2-Br-4-Me-Ph, X is CHOH, R and R ⁇ a are both H, and R 2 is ethenyl.
  • Q is 2-Br-4-Me-Ph, X is CHOH, R and R ⁇ a are both H, and R 2 is ethynyl.
  • Q is 2-Br-4-Me-Ph, X is CHOH, R is Me, R l a is H, and R 2 is H.
  • Q is 2-Br-4-Me-Ph, X is CHOH, R is Me, R ⁇ a is H, and R 2 is ethenyl.
  • Q is 2-Br-4-Me-Ph, X is CHOH, R is Me, R ⁇ a is H, and R 2 is ethynyl.
  • Q is 2-Me-4-EtO-Ph, X is NH, R 1 and R l a are both H, and R 2 is H.
  • Q is 2-Me-4-EtO-Ph
  • X is NH
  • R 1 and R l a are both H
  • R 2 is ethenyl
  • Q is 2-Me-4-EtO-Ph
  • X is NH
  • R 1 and R l a are both H
  • R 2 is ethynyl
  • Q is 2-Me-4-EtO-Ph
  • X is NH, R 1 is Me, R l a is H, and R 2 is H.
  • Q is 2-Me-4-EtO-Ph
  • X is NH
  • R 1 is Me
  • R l a is H
  • R 2 is ethenyl
  • Q is 2-Me-4-EtO-Ph
  • X is NH
  • R 1 is Me
  • R l a is H
  • R 2 is ethynyl
  • Q is 2-Me-4-EtO-Ph
  • X is O
  • R 1 and R l a are both H
  • R 2 is H.
  • Q is 2-Me-4-EtO-Ph
  • X is O
  • R 1 and R l a are both H
  • R 2 is ethenyl.
  • Q is 2-Me-4-EtO-Ph
  • X is CHOH
  • R and R ⁇ a are both H
  • R 2 is H.
  • Q is 2-Me-4-EtO-Ph, X is CHOH, R and R i a are both H, and R 2 is ethenyl.
  • Q is 2-Me-4-EtO-Ph, X is CHOH, R and R i a are both H, and R 2 is ethynyl.
  • Q is 2-Me-4-EtO-Ph, X is CHOH, R is Me, R l a is H, and R 2 is H.
  • Q is 2-Me-4-EtO-Ph, X is CHOH, R is Me, R ⁇ a is H, and R 2 is ethenyl.
  • Q is 2-Me-4-EtO-Ph, X is CHOH, R is Me, R ⁇ a is H, and R 2 is ethynyl.
  • Q is 2-Cl-4-EtO-Ph, X is NH, R and R i a are both H, and R 2 is H.
  • Q is 2-Cl-4-EtO-Ph
  • X is NH
  • R and R ⁇ a are both H
  • R 2 is ethenyl
  • Q is 2-Cl-4-EtO-Ph
  • X is NH
  • R and R ⁇ a are both H
  • R 2 is ethynyl.
  • Q is 2-Cl-4-EtO-Ph
  • X is NH
  • R is Me
  • R l a is H
  • R 2 is H.
  • Q is 2-Cl-4-EtO-Ph
  • X is NH
  • R is Me
  • R ⁇ a is H
  • R 2 is ethenyl
  • Q is 2-Cl-4-EtO-Ph
  • X is NH
  • R is Me
  • R l a is H
  • R 2 is ethynyl
  • Q is 2-Cl-4-EtO-Ph
  • X is O
  • R and R l a are both H
  • R 2 is H.
  • Q is 2-Cl-4-EtO-Ph
  • X is O
  • R and R ⁇ a are both H
  • R 2 is ethenyl.
  • Q is 2-Cl-4-EtO-Ph
  • X is O
  • R and R la are both H
  • R 2 is ethynyl
  • Q is 2-Cl-4-EtO-Ph
  • X is O
  • R is Me
  • R l a is H
  • R 2 is H.
  • Q is 2-Cl-4-EtO-Ph
  • X is O
  • R is Me
  • R l a is H
  • R 2 is ethenyl
  • Q is 2-Cl-4-EtO-Ph
  • X is O
  • R is Me
  • R l a is H
  • R 2 is ethynyl
  • Q is 2-Cl-4-EtO-Ph
  • X is CHOH
  • R and R ⁇ a are both H
  • R 2 is H.
  • Q is 2-Cl-4-EtO-Ph, X is CHOH, R and R la are both H, and R 2 is ethenyl.
  • Q is 2-Cl-4-EtO-Ph, X is CHOH, R and Rla are both H, and R 2 is ethynyl.
  • Q is 2-Cl-4-EtO-Ph, X is CHOH, R is Me, R l a is H, and R 2 is H.
  • Q is 2-Cl-4-EtO-Ph
  • X is CHOH
  • R is Me
  • R l a is H
  • R 2 is ethenyl
  • Q is 2-Cl-4-EtO-Ph
  • X is CHOH
  • R is Me
  • R ⁇ a is H
  • R 2 is ethynyl
  • Q is 3,5-di-Cl-pyridin-2-yl, X is NH, R 1 and R l a are both H, and R 2 is H.
  • Q is 3,5-di-Cl-pyridin-2-yl, X is NH, R 1 and R l a are both H, and R 2 is ethenyl.
  • Q is 3,5-di-Cl-pyridin-2-yl, X is NH, R 1 and R l a are both H, and R 2 is ethynyl.
  • Q 3,5-di-Cl-pyridin-2-yl, X is NH, R 1 is Me, R l a is H, and R 2 is H.
  • Q 3,5-di-Cl-pyridin-2-yl, X is NH, R 1 is Me, R l a is H, and R 2 is ethenyl.
  • Q 3,5-di-Cl-pyridin-2-yl, X is NH, R 1 is Me, R l a is H, and R 2 is ethynyl.
  • Q is 3,5-di-Cl-pyridin-2-yl
  • X is O
  • R 1 is Me
  • R l a is H
  • R 2 is H.
  • Q is 3,5-di-Cl-pyridin-2-yl
  • X is O
  • R 1 is Me
  • R l a is H
  • R 2 is ethenyl
  • Q is 3,5-di-Cl-pyridin-2-yl
  • X is O
  • R 1 is Me
  • R l a is H
  • R 2 is ethynyl
  • Q is 3,5-di-Cl-pyridin-2-yl, X is CHOH, R and R i a are both H, and R 2 is H.
  • Q is 3,5-di-Cl-pyridin-2-yl, X is CHOH, R and R ⁇ a are both H, and R 2 is ethenyl.
  • Q is 3,5-di-Cl-pyridin-2-yl, X is CHOH, R and R ⁇ a are both H, and R 2 is ethynyl.
  • Q is 3,5-di-Cl-pyridin-2-yl, X is CHOH, R is Me, R ⁇ a is H, and R 2 is H.
  • Q is 3,5-di-Cl-pyridin-2-yl, X is CHOH, R is Me, Rl a is H, and R 2 is ethenyl.
  • Q is 3,5-di-Cl-pyridin-2-yl, X is CHOH, R is Me, Rl a is H, and R 2 is ethynyl.
  • Q is 2,4,6-tri-Cl-Ph, X is NH, R 1 and R l a are both H, and R 2 is H.
  • Q is 2,4,6-tri-F-Ph
  • X is NH
  • R 1 and R l a are both H
  • R 2 is ethenyl
  • Q is 2,4,6-tri- F-Ph
  • X is NH
  • R 1 and R l a are both H
  • R 2 is ethynyl
  • Q is 2,4,6-tri-F-Ph
  • X is NH
  • R 1 is Me
  • R l a is H
  • R 2 is H.
  • Q is 2,4,6-tri-F-Ph
  • X is NH
  • R 1 is Me
  • R l a is H
  • R 2 is ethenyl
  • Q is 2,4,6-tri-F-Ph
  • X is NH
  • R 1 is Me
  • R l a is H
  • R 2 is ethynyl
  • Q is 2,4,6-tri-F-Ph
  • X is O
  • R and R 1 a are both H
  • R 2 is H.
  • Q is 2,4,6-tri-F-Ph
  • X is O
  • R and R ⁇ a are both H
  • R 2 is ethenyl
  • Q is 2,4,6-tri-F-Ph
  • X is O
  • R and R ⁇ a are both H
  • R 2 is ethynyl.
  • Q is 2,4,6-tri-F-Ph
  • X is O
  • R is Me
  • R l a is H
  • R 2 is H.
  • Q is 2,4,6-tri-F-Ph
  • X is O
  • R is Me
  • R l a is H
  • R 2 is ethenyl
  • Q is 2,4,6-tri-F-Ph
  • X is O
  • R is Me
  • R ⁇ a is H
  • R 2 is ethynyl
  • Q is 2,4,6-tri-F-Ph
  • X is CHOH
  • R 1 and R i a are both H
  • R 2 is H.
  • Q is 2,4,6-tri-F-Ph
  • X is CHOH
  • R * and R i a are both H
  • R 2 is ethenyl
  • Q is 2,4,6-tri-F-Ph
  • X is CHOH
  • R 1 and R l a are both H
  • R 2 is ethynyl
  • Q is 2,4,6-tri-F-Ph
  • X is CHOH
  • R 1 is Me
  • R l a is H
  • R 2 is H.
  • Q is 2,4,6-tri-F-Ph
  • X is CHOH
  • R 1 is Me
  • R ⁇ a is H
  • R 2 is ethenyl
  • Q is 2,4,6-tri-F-Ph
  • X is CHOH
  • R 1 is Me
  • R ⁇ a is H
  • R 2 is ethynyl
  • Q is 2,4-di-Cl-Ph
  • X is NH
  • R and R l a are both H
  • R 2 is H.
  • Q is 2,4-di-Cl-Ph
  • X is NH
  • R and R ⁇ are both H
  • R 2 is ethenyl
  • Q is 2,4-di-Cl-Ph
  • X is NH
  • R and R1 are both H
  • R 2 is ethynyl.
  • Q is 2,4-di-Cl-Ph
  • X is NH
  • R is Me
  • R l a is H
  • R 2 is H.
  • Q is 2,4-di-Cl-Ph
  • X is NH
  • R is Me
  • R ⁇ a is H
  • R 2 is ethenyl
  • Q is 2,4-di-Cl-Ph
  • X is NH
  • R is Me
  • R l is H
  • R 2 is ethynyl
  • Q is 2,4-di-Cl-Ph
  • X is O
  • R 1 and R l a are both H
  • R 2 is H.
  • Q is 2,4-di-Cl-Ph
  • X is O
  • R 1 and R l a are both H
  • R 2 is ethenyl.
  • Q is 2,4-di-Cl-Ph
  • X is O
  • R 1 and R l a are both H
  • R 2 is ethynyl.
  • Q is 2,4-di-Cl-Ph
  • X is O
  • R 1 is Me
  • R l is H
  • R 2 is H.
  • Q is 2,4-di-Cl-Ph
  • X is O
  • R 1 is Me
  • R l a is H
  • R 2 is ethenyl
  • Q is 2,4-di-Cl-Ph
  • X is O
  • R 1 is Me
  • R l a is H
  • R 2 is ethynyl
  • Q is 2,4-di-Cl-Ph, X is CHOH, R 1 and R i a are both H, and R 2 is H.
  • Q is 2,4-di-Cl-Ph, X is CHOH, R 1 and R ⁇ a are both H, and R 2 is ethenyl.
  • Q is 2,4-di-Cl-Ph, X is CHOH, R 1 and R ⁇ a are both H, and R 2 is ethynyl.
  • Q is 2,4-di-Cl-Ph, X is CHOH, R 1 is Me, R l a is H, and R 2 is H.
  • Q is 2,4-di-Cl-Ph, X is CHOH, R 1 is Me, R ⁇ a is H, and R 2 is ethenyl.
  • Q is 2,4-di-Cl-Ph, X is CHOH, R 1 is Me, R ⁇ a is H, and R 2 is ethynyl.
  • Q is 2-Br-4-F-Ph, X is NH, R 1 and R l a are both H, and R 2 is H.
  • Q is 2-Br-4-F-Ph
  • X is NH, R 1 and R ⁇ a are both H, and R 2 is ethenyl.
  • Q is 2-Br-4-F-Ph, X is NH, R 1 and R ⁇ a are both H, and R 2 is ethynyl.
  • Q is 2-Br-4-F-Ph, X is NH, R 1 is Me, R l a is H, and R 2 is H.
  • Q is 2-Br-4-F-Ph
  • X is NH
  • R 1 is Me
  • R ⁇ a is H
  • R 2 is ethenyl
  • Q is 2-Br-4-F-Ph
  • X is NH
  • R 1 is Me
  • R ⁇ a is H
  • R 2 is ethynyl
  • Q is 2-Br-4-F-Ph
  • X is O
  • R and R l a are both H
  • R 2 is H.
  • Q is 2-Br-4-F-Ph, X is O, R and R ⁇ a are both H, and R 2 is ethenyl.
  • Q is 2-Br-4-F-Ph, X is O, R and R i a are both H, and R 2 is ethynyl.
  • Q is 2-Br-4-F-Ph, X is O, R is Me, R l a is H, and R 2 is H.
  • Q is 2-Br-4-F-Ph
  • X is O
  • R is Me
  • R ⁇ a is H
  • R 2 is ethenyl
  • Q is 2-Br-4-F-Ph
  • X is O
  • R is Me
  • R ⁇ a is H
  • R 2 is ethynyl
  • Q is 2-Br-4-F-Ph, X is CHOH, R and R i a are both H, and R 2 is H.
  • Q is 2-Br-4-F-Ph, X is CHOH, R and R ⁇ a are both H, and R 2 is ethenyl.
  • Q is 2-Br-4-F-Ph, X is CHOH, R and R ⁇ a are both H, and R 2 is ethynyl.
  • Q is 2-Br-4-F-Ph, X is CHOH, R is Me, R l a is H, and R is H.
  • Q is 2-Br-4-F-Ph, X is CHOH, R is Me, R ⁇ a is H, and R 2 is ethenyl.
  • Q is 2-Br-4-F-Ph, X is CHOH, R is Me, R ⁇ a is H, and R 2 is ethynyl.
  • Q is 2-Br-6-F-Ph, X is NH, R 1 and R l a are both H, and R 2 is H.
  • Q is 2-Br-6-F-Ph
  • X is NH
  • R 1 and R l a are both H
  • R 2 is ethenyl
  • Q is 2-Br-6-F-Ph
  • X is NH
  • R 1 and R l a are both H
  • R 2 is ethynyl
  • Q is 2-Br-6-F-Ph
  • X is NH
  • R 1 is Me
  • R l a is H
  • R 2 is H.
  • Q is 2-Br-6-Fl-Ph, X is NH, R 1 is Me, R l a is H, and R 2 is ethenyl.
  • Q is 2-Br-6-Fl-Ph, X is NH, R 1 is Me, R l a is H, and R 2 is ethynyl.
  • Q is 2-Br-6-F-Ph, X is O, R and R i a are both H, and R 2 is H.
  • Q is 2-Br-6-F-Ph, X is O, R and R ⁇ a are both H, and R 2 is ethenyl.
  • Q is 2-Br-6-F-Ph, X is O, R and R ⁇ a are both H, and R 2 is ethynyl.
  • Q is 2-Br-6-F-Ph, X is O, R is Me, R l a is H, and R 2 is H.
  • Q is 2-Br-6-F-Ph
  • X is O
  • R is Me
  • R l a is H
  • R 2 is ethenyl.
  • Q is 2-Br-6-F-Ph
  • X is O
  • R 1 is Me
  • R l a is H
  • R 2 is ethynyl
  • Q is 2-Br-6-F-Ph
  • X is CHOH
  • R 1 and R l a are both H
  • R 2 is H.
  • Q is 2-Br-6-F-Ph, X is CHOH, R 1 and R l a are both H, and R 2 is ethenyl.
  • Q is 2-Br-6-F-Ph, X is CHOH, R 1 and R l a are both H, and R 2 is ethynyl.
  • Q is 2-Br-6-F-Ph, X is CHOH, R 1 is Me, R l a is H, and R 2 is H.
  • Q is 2-Br-6-F-Ph
  • X is CHOH
  • R 1 is Me
  • R l a is H
  • R 2 is ethenyl
  • Q is 2-Br-6-F -Ph
  • X is CHOH
  • R 1 is Me
  • R l a is H
  • R 2 is ethynyl
  • Q is 2,6-di-F-3-CN-Ph
  • X is NH
  • R 1 and R I A are both H
  • R 2 is H.
  • Q is 2,6-di-F-3-CN-Ph
  • X is NH
  • R 1 and R1 a are both H
  • R 2 is ethenyl
  • Q is 2,6-di-F-3-CN-Ph
  • X is NH
  • R 1 and R ⁇ A are both H
  • R 2 is ethynyl
  • Q is 2,6-di-F-3-CN-Ph
  • X is NH, R 1 is Me, R ⁇ A is H, and R 2 is H.
  • Q is 2,6-di-F-3-CN-Ph
  • X is NH
  • R 1 is Me
  • R ⁇ A is H
  • R 2 is ethenyl
  • Q is 2,6-di-F-3-CN-Ph
  • X is NH
  • R 1 is Me
  • R ⁇ A is H
  • R 2 is ethynyl
  • Q is 2,6-di-F-3-CN-Ph
  • X is O
  • R 1 and R L A are both H
  • R 2 is H.
  • Q is 2,6-di-F-3-CN-Ph, X is O, R 1 and R L A are both H, and R 2 is ethenyl.
  • Q is 2,6-di-F-3-CN-Ph, X is O, R 1 and R L A are both H, and R 2 is ethynyl.
  • Q is 2,6-di-F-3-CN-Ph, X is O, R 1 is Me, R L A is H, and R 2 is H.
  • Q is 2,6-di-F-3-CN-Ph
  • X is O
  • R 1 is Me
  • R L A is H
  • R 2 is ethenyl
  • Q is 2,6-di-F-3-CN-Ph
  • X is O
  • R 1 is Me
  • R L A is H
  • R 2 is ethynyl
  • Q is 2,6-di-F-3-CN-Ph, X is CHOH, R and R I A are both H, and R 2 is H.
  • Q is 2,6-di-F-3-CN-Ph, X is CHOH, R and R1 a are both H, and R 2 is ethenyl.
  • Q is 2,6-di-F-3-CN-Ph, X is CHOH, R and R ⁇ A are both H, and R 2 is ethynyl.
  • Q is 2,6-di-F-3-CN-Ph, X is CHOH, R is Me, R L A is H, and R 2 is H.
  • Q is 2,6-di-F-3-CN-Ph, X is CHOH, R is Me, R ⁇ A is H, and R 2 is ethenyl.
  • Q is 2,6-di-F-3-CN-Ph, X is CHOH, R is Me, R ⁇ A is H, and R 2 is ethynyl.
  • Q is 2-Me-4-MeO-Ph, X is NH, R 1 and R l a are both H, and R 2 is H.
  • Q is 2-Me-4-MeO-Ph
  • X is NH
  • R 1 and R l a are both H
  • R 2 is ethenyl
  • Q is 2-Me-4-MeO-Ph
  • X is NH
  • R 1 and R l a are both H
  • R 2 is ethynyl
  • Q is 2-Me-4-MeO-Ph
  • X is NH, R 1 is Me, R l a is H, and R 2 is H.
  • Q is 2-Me-4-MeO-Ph
  • X is NH
  • R 1 is Me
  • R l a is H
  • R 2 is ethenyl
  • Q is 2-Me-4-MeO-Ph
  • X is NH
  • R 1 is Me
  • R l a is H
  • R 2 is ethynyl
  • Q is 2-Me-4-MeO-Ph
  • X is O
  • R 1 and R l a are both H
  • R 2 is H.
  • Q is 2-Me-4-MeO-Ph, X is O, R 1 and R l a are both H, and R 2 is ethenyl.
  • Q is 2-Me-4-MeO-Ph, X is O, R 1 and R l a are both H, and R 2 is ethynyl.
  • Q is 2-Me-4-MeO-Ph, X is O, R 1 is Me, R l a is H, and R 2 is H.
  • Q is 2-Me-4-MeO-Ph
  • X is O
  • R 1 is Me
  • R l a is H
  • R 2 is ethenyl
  • Q is 2-Me-4-MeO-Ph
  • X is O
  • R 1 is Me
  • R l a is H
  • R 2 is ethynyl.
  • Q is 2-Me-4-MeO-Ph, X is CHOH, R and R ⁇ a are both H, and R2 is H.
  • Q is 2-Me-4-MeO-Ph, X is CHOH, R 1 and R ⁇ a are both H, and R 2 is ethenyl.
  • Q is 2-Me-4-MeO-Ph, X is CHOH, R 1 and R ⁇ a are both H, and R 2 is ethynyl.
  • Q is 2-Me-4-MeO-Ph, X is CHOH, R 1 is Me, R l a is H, and R 2 is H.
  • Q is 2-Me-4-MeO-Ph, X is CHOH, R 1 is Me, R ⁇ a is H, and R2 is ethenyl.
  • Q is 2-Me-4-MeO-Ph, X is CHOH, R 1 is Me, R ⁇ a is H, and R2 is ethynyl.
  • Q is 2-Me-4-Br-Ph, X is NH, R * and R i a are both H, and R2 is H.
  • Q is 2-Me-4-Br-Ph, X is NH, R and R are both H, and R is ethenyl.
  • Q is 2-Me-4-Br-Ph, X is NH, R * and R i a are both H, and R2 is ethynyl.
  • Q is 2-Me-4-Br-Ph, X is NH, R 1 is Me, R l a is H, and R 2 is H.
  • Q is 2-Me-4-Br-Ph
  • X is NH
  • R 1 is Me
  • R ⁇ a is H
  • R 2 is ethenyl
  • Q is 2-Me-4-Br-Ph
  • X is NH
  • R 1 is Me
  • R ⁇ a is H
  • R 2 is ethynyl
  • Q is 2-Me-4-Br-Ph
  • X is O
  • R and R i a are both H
  • R2 is H.
  • Q is 2-Me-4-Br-Ph
  • X is O
  • R and R ⁇ a are both H
  • R2 is ethenyl
  • Q is 2-Me-4-Br-Ph
  • X is O
  • R and R ⁇ a are both H
  • R 2 is ethynyl.
  • Q is 2-Me-4-Br-Ph
  • X is O
  • R is Me
  • R l a is H
  • R 2 is H.
  • Q is 2-Me-4-Br-Ph
  • X is O
  • R is Me
  • R ⁇ a is H
  • R 2 is ethenyl
  • Q is 2-Me-4-Br-Ph
  • X is O
  • R is Me
  • R ⁇ a is H
  • R 2 is ethynyl
  • Q is 2-Me-4-Br-Ph
  • X is CHOH
  • R 1 and R i a are both H
  • R 2 is H.
  • Q is 2-Me-4-Br-Ph, X is CHOH, R 1 and R ⁇ a are both H, and R 2 is ethenyl.
  • Q is 2-Me-4-Br-Ph, X is CHOH, R 1 and R ⁇ a are both H, and R 2 is ethynyl.
  • Q is 2-Me-4-Br-Ph, X is CHOH, R 1 is Me, R l a is H, and R 2 is H.
  • Q is 2-Me-4-Br-Ph, X is CHOH, R 1 is Me, ⁇ a is H, and R 2 is ethenyl.
  • Q is 2-Me-4-Br-Ph, X is CHOH, R 1 is Me, R ⁇ a is H, and R 2 is ethynyl.
  • Q is 2-Cl-4-MeO-Ph, X is NH, R * and R i a are both H, and R 2 is H.
  • Q is 2-Cl-4-MeO-Ph
  • X is NH
  • R * and R i a are both H
  • R 2 is ethenyl
  • Q is 2-Cl-4-MeO-Ph
  • X is NH
  • R 1 and R are both H
  • R 2 is ethynyl
  • Q is 2-Cl-4-MeO-Ph
  • X is NH
  • R 1 is Me
  • R l a is H
  • R 2 is H.
  • Q is 2-Cl-4-MeO-Ph
  • X is NH
  • R 1 is Me
  • R ⁇ a is H
  • R 2 is ethenyl
  • Q is 2-Cl-4-MeO-Ph
  • X is NH
  • R 1 is Me
  • R ⁇ a is H
  • R 2 is ethynyl
  • Q is 2-Cl-4-MeO-Ph
  • X is O
  • R and R 1 a are both H
  • R 2 is H.
  • Q is 2-Cl-4-MeO-Ph, X is O, R and R a are both H, and R 2 is ethenyl.
  • Q is 2-Cl-4-MeO-Ph, X is O, R and R i a are both H, and R 2 is ethynyl.
  • Q is 2-Cl-4-MeO-Ph, X is O, R is Me, R l a is H, and R 2 is H.
  • Q is 2-Cl-4-MeO-Ph
  • X is O
  • R is Me
  • R ⁇ a is H
  • R 2 is ethenyl
  • Q is 2-Cl-4-MeO-Ph
  • X is O
  • R is Me
  • R ⁇ a is H
  • R 2 is ethynyl
  • Q is 2-Cl-4-MeO-Ph
  • X is CHOH
  • R 1 and R l a are both H
  • R 2 is H.
  • Q 2-Cl-4-MeO-Ph, X is CHOH, R 1 and R L A are both H, and R 2 is ethenyl.
  • Q 2-Cl-4-MeO-Ph, X is CHOH, R 1 and R L A are both H, and R 2 is ethynyl.
  • Q 2-Cl-4-MeO-Ph, X is CHOH, R 1 is Me, R L A is H, and R 2 is H.
  • Q 2-Cl-4-MeO-Ph, X is CHOH, R 1 is Me, R L A is H, and R 2 is ethenyl.
  • Q s 2-Cl-4-MeO-Ph, X is CHOH, R 1 is Me, R L A is H, and R 2 is ethynyl.
  • Q is 2-Cl-4-Me-Ph, X is NH, R and R i a are both H, and R 2 is H.
  • Q is 2-Cl-4-Me-Ph
  • X is NH
  • R and R1 a are both H
  • R 2 is ethenyl
  • Q is 2-Cl-4-Me-Ph
  • X is NH
  • R and R ⁇ A are both H
  • R 2 is ethynyl.
  • Q is 2-Cl-4-Me-Ph
  • X is NH
  • R is Me
  • R L A is H
  • R 2 is H.
  • Q is 2-Cl-4-Me-Ph
  • X is NH
  • R is Me
  • R L A is H
  • R 2 is ethenyl
  • Q is 2-Cl-4-Me-Ph
  • X is NH
  • R is Me
  • ⁇ A is H
  • R 2 is ethynyl.
  • Q is 2-Cl-4-Me-Ph
  • X is O
  • R 1 and R L A are both H
  • R 2 is H.
  • Q is 2-Cl-4-Me-Ph
  • X is O
  • R 1 and R L A are both H
  • R 2 is ethenyl
  • Q is 2-Cl-4-Me-Ph
  • X is O
  • R 1 is Me
  • R L A is H
  • R 2 is H.
  • Q is 2 : -Cl-4-Me-Ph, X is O, R 1 is Me, R L A is H, and R 2 is ethenyl.
  • Q is 2-Cl-4-Me-Ph
  • X is O
  • R 1 is Me
  • R L A is H
  • R 2 is ethynyl
  • Q is 2-Cl-4-Me-Ph, X is CHOH, R 1 and R L A are both H, and R 2 is ethenyl.
  • Q is 2-Cl-4-Me-Ph, X is CHOH, R 1 and R L A are both H, and R 2 is ethynyl.
  • Q is 2-Cl-4-Me-Ph, X is CHOH, R 1 is Me, R L A is H, and R 2 is H.
  • Q is 2-Cl-4-Me-Ph
  • X is CHOH
  • R 1 is Me
  • R L A is H
  • R 2 is ethenyl
  • Q is 2-Cl-4-Me-Ph
  • X is CHOH
  • R 1 is Me
  • R L A is H
  • R 2 is ethynyl
  • Q is 2.6-di-Cl-4-Me-Ph
  • X is NH
  • R 1 and R L A are both H
  • R 2 is ethenyl
  • Q is 2.6-di-Cl-4-Me-Ph
  • X is NH
  • R 1 and R L A are both H
  • R 2 is ethynyl
  • Q is 2.6-di-Cl-4-Me-Ph
  • X is NH, R 1 is Me, R L A is H, and R 2 is H.
  • Q is 2.6-di-Cl-4-Me-Ph
  • X is NH
  • R 1 is Me
  • R L A is H
  • R 2 is ethenyl
  • Q is 2.6-di-Cl-4-Me-Ph
  • X is NH
  • R 1 is Me
  • R L A is H
  • R 2 is ethynyl
  • Q is 2.6-di-Cl-4-Me-Ph
  • X is O
  • R 1 and R L A are both H
  • R 2 is H.
  • Q i iss 2.6-di-Cl-4-Me-Ph, X is O, R 1 and R L A are both H, and R 2 is ethenyl.
  • Q is 2.6-di-Cl-4-Me-Ph, X is O, R 1 and R L A are both H, and R 2 is ethynyl.
  • Q is 2.6-di-Cl-4-Me-Ph, X is O, R 1 is Me, R L A is H, and R 2 is H.
  • Q is 2.6-di-Cl-4-Me-Ph
  • X is O
  • R 1 is Me
  • R L A is H
  • R 2 is ethenyl
  • Q is 2.6-di-Cl-4-Me-Ph
  • X is O
  • R 1 is Me
  • R L A is H
  • R 2 is ethynyl.
  • Q 1 is 2.6-di-Cl-4-Me-Ph
  • X is CHOH
  • R 1 and R L A are both H
  • R 2 is H
  • Q 1 is 2.6-di-Cl-4-Me-Ph
  • X is CHOH
  • R 1 and R L A are both H
  • R 2 is ethenyl.
  • Q is 2.6-di-Cl-4-Me-Ph
  • X is CHOH
  • R 1 and R l a are both H
  • R 2 is ethynyl
  • Q is 2.6-di-Cl-4-Me-Ph
  • X is CHOH
  • R 1 is Me
  • R l a is H
  • R 2 is H.
  • Q is 2.6-di-Cl-4-Me-Ph
  • X is CHOH
  • R 1 is Me
  • R l a is H
  • R 2 is ethenyl
  • Q is 2.6-di-Cl-4-Me-Ph
  • X is CHOH
  • R 1 is Me
  • R l a is H
  • R 2 is ethynyl
  • Q is 2-F-4-EtO-Ph
  • X is NH
  • R 1 and R la are both H
  • R 2 is H.
  • Q is 2-F-4-EtO-Ph
  • X is NH
  • R 1 and R l a are both H
  • R 2 is ethenyl
  • Q is 2-F-4-EtO-Ph
  • X is NH
  • R 1 and R l a are both H
  • R 2 is ethynyl
  • Q is 2-F-4-EtO-Ph
  • X is NH
  • R 1 is Me
  • R la is H
  • R 2 is H.
  • Q is 2-F-4-EtO-Ph
  • X is NH
  • R 1 is Me
  • R l a is H
  • R 2 is ethenyl
  • Q is 2-F-4-EtO-Ph
  • X is NH
  • R 1 is Me
  • R l a is H
  • R 2 is ethynyl
  • Q is 2-F-4-EtO-Ph
  • X is O
  • R 1 and R i a are both H
  • R 2 is H.
  • Q is 2-F-4-EtO-Ph
  • X is O
  • R 1 and R ⁇ a are both H
  • R 2 is ethenyl
  • Q is 2-F-4-EtO-Ph
  • X is O
  • R 1 and R ⁇ a are both H
  • R 2 is ethynyl.
  • Q is 2-F-4-EtO-Ph
  • X is O
  • R 1 is Me
  • Rl a is H
  • R 2 is H.
  • Q is 2-F-4-EtO-Ph
  • X is O
  • R 1 is Me
  • R ⁇ a is H
  • R 2 is ethenyl
  • Q is 2-F-4-EtO-Ph
  • X is O
  • R 1 is Me
  • R ⁇ a is H
  • R 2 is ethynyl
  • Q is 2-F-4-EtO-Ph
  • X is CHOH
  • R 1 and R l a are both H
  • R 2 is H.
  • Q is 2-F-4-EtO-Ph, X is CHOH, R 1 and R l a are both H, and R 2 is ethenyl.
  • Q is 2-F-4-EtO-Ph, X is CHOH, R 1 and R l a are both H, and R 2 is ethynyl.
  • Q is 2-F-4-EtO-Ph, X is CHOH, R 1 is Me, R l a is H, and R 2 is H.
  • Q is 2-F-4-EtO-Ph
  • X is CHOH
  • R 1 is Me
  • R l a is H
  • R 2 is ethenyl
  • Q is 2-F-4-EtO-Ph
  • X is CHOH
  • R 1 is Me
  • R l a is H
  • R 2 is ethynyl
  • Q is 2-Br-4-EtO-Ph
  • X is NH
  • R 1 and R l a are both H
  • R 2 is H.
  • Q is 2-Br-4-EtO-Ph
  • X is NH
  • R 1 and R l a are both H
  • R 2 is ethenyl
  • Q is 2-Br-4-EtO-Ph
  • X is NH
  • R 1 and R l a are both H
  • R 2 is ethynyl
  • Q is 2-Br-4-EtO-Ph
  • X is NH, R 1 is Me, R l a is H, and R 2 is H.
  • Q is 2-Br-4-EtO-Ph
  • X is NH
  • R 1 is Me
  • R l a is H
  • R 2 is ethenyl
  • Q is 2-Br-4-EtO-Ph
  • X is NH
  • R 1 is Me
  • R l a is H
  • R 2 is ethynyl
  • Q is 2-Br-4-EtO-Ph
  • X is O
  • R 1 and R l a are both H
  • R 2 is H.
  • Q is 2-Br-4-EtO-Ph
  • X is O
  • R 1 and R l a are both H
  • R 2 is ethenyl.
  • Q is 2-Br-4-EtO-Ph
  • X is O
  • R 1 and R l a are both H
  • R 2 is ethynyl.
  • Q is 2-Br-4-EtO-Ph
  • X is O
  • R 1 is Me
  • R l a is H
  • R 2 is H.
  • Q is 2-Br-4-EtO-Ph
  • X is O
  • R 1 is Me
  • R l a is H
  • R 2 is ethenyl
  • Q is 2-Br-4-EtO-Ph
  • X is O
  • R 1 is Me
  • R l a is H
  • R 2 is ethynyl
  • Q is 2-Br-4-EtO-Ph
  • X is CHOH
  • R 1 and R l a are both H
  • R 2 is H.
  • Q is 2-Br-4-EtO-Ph
  • X is CHOH
  • R 1 and R l a are both H
  • R 2 is ethenyl
  • Q is 2-Br-4-EtO-Ph
  • X is CHOH
  • R 1 and R l a are both H
  • R 2 is ethynyl.
  • Q is 2-Br-4-EtO-Ph
  • X is CHOH
  • R 1 is Me
  • R l a is H
  • R 2 is H.
  • Q is 2-Br-4-EtO-Ph, X is CHOH, R 1 is Me, R l a is H, and R 2 is ethenyl.
  • Q is 2-Br-4-EtO-Ph, X is CHOH, R 1 is Me, R l a is H, and R 2 is ethynyl.
  • Q is 2-Cl-4-CN-Ph, X is NH, R 1 and Rla are both H, and R 2 is H.
  • Q is 2-Cl-4-CN-Ph, X is NH, R * and R i a are both H, and R 2 is ethenyl.
  • Q is 2-Cl-4-CN-Ph, X is NH, R 1 and R ⁇ a are both H, and R 2 is ethynyl.
  • Q is 2-Cl-4-CN-Ph, X is NH, R 1 is Me, R la is H, and R 2 is H.
  • Q is 2-Cl-4-CN-Ph
  • X is NH
  • R 1 is Me
  • R ⁇ a is H
  • R 2 is ethenyl
  • Q is 2-Cl-4-CN-Ph
  • X is NH
  • R 1 is Me
  • R ⁇ a is H
  • R 2 is ethynyl
  • Q is 2-Cl-4-CN-Ph
  • X is O
  • R and R l a are both H
  • R 2 is H.
  • Q is 2-Cl-4-CN-Ph, X is O, R and R 1 a are both H, and R 2 is ethenyl.
  • Q is 2-Cl-4-CN-Ph, X is O, R and R i a are both H, and R 2 is ethynyl.
  • Q is 2-Cl-4-CN-Ph, X is O, R is Me, R l a is H, and R 2 is H.
  • Q is 2-Cl-4-CN-Ph
  • X is O
  • R is Me
  • R ⁇ a is H
  • R 2 is ethenyl
  • Q is 2-Cl-4-CN-Ph
  • X is O
  • R is Me
  • R ⁇ a is H
  • R 2 is ethynyl
  • Q is 2-Cl-4-CN-Ph, X is CHOH, R * and R i a are both H, and R 2 is H.
  • Q is 2-Cl-4-CN-Ph, X is CHOH, R 1 and R ⁇ a are both H, and R 2 is ethenyl.
  • Q is 2-Cl-4-CN-Ph, X is CHOH, R 1 and R ⁇ a are both H, and R 2 is ethynyl.
  • Q is 2-Cl-4-CN-Ph, X is CHOH, R 1 is Me, R l a is H, and R 2 is H.
  • Q is 2-Cl-4-CN-Ph, X is CHOH, R 1 is Me, R ⁇ a is H, and R 2 is ethenyl.
  • Q is 2-Cl-4-CN-Ph, X is CHOH, R 1 is Me, ⁇ a is H, and R 2 is ethynyl.
  • Q is 2-Br-4-CN-Ph, X is NH, R * and R a are both H, and R 2 is H.
  • Q is 2-Br-4-CN-Ph, X is NH, R * and R i a are both H, and R 2 is ethenyl.
  • Q is 2-Br-4-CN-Ph, X is NH, R * and R i a are both H, and R 2 is ethynyl.
  • Q is 2-Br-4-CN-Ph, X is NH, R 1 is Me, R l a is H, and R 2 is H.
  • Q is 2-Br-4-CN-Ph
  • X is NH
  • R 1 is Me
  • R ⁇ a is H
  • R 2 is ethenyl
  • Q is 2-Br-4-CN-Ph
  • X is NH
  • R 1 is Me
  • R ⁇ a is H
  • R 2 is ethynyl
  • Q is 2-Br-4-CN-Ph
  • X is O
  • R and R l a are both H
  • R 2 is H.
  • Q is 2-Br-4-CN-Ph, X is O, R and R i a are both H, and R 2 is ethenyl.
  • Q is 2-Br-4-CN-Ph, X is O, R and R la are both H, and R 2 is ethynyl.
  • Q is 2-Br-4-CN-Ph, X is O, R is Me, R l a is H, and R 2 is H.
  • Q is 2-Br-4-CN-Ph
  • X is O
  • R is Me
  • R ⁇ a is H
  • R 2 is ethenyl
  • Q is 2-Br-4-CN-Ph
  • X is O
  • R is Me
  • R1 a is H
  • R 2 is ethynyl
  • Q is 2-Br-4-CN-Ph, X is CHOH, R 1 and R L A are both H, and R 2 is H.
  • Q is 2-Br-4-CN-Ph, X is CHOH, R 1 and R L A are both H, and R 2 is ethenyl.
  • Q is 2-Br-4-CN-Ph, X is CHOH, R 1 and R L A are both H, and R 2 is ethynyl.
  • Q is 2-Br-4-CN-Ph, X is CHOH, R 1 is Me, R L A is H, and R 2 is H.
  • Q 1 is 2-Br-4-CN-Ph
  • X is CHOH
  • R 1 is Me
  • R l a is H
  • R 2 is ethenyl
  • Q 1 is 2-Br-4-CN-Ph
  • X is CHOH
  • R 1 is Me
  • R l a is H
  • R 2 is ethynyl
  • Q 1 is 2-Cl-thien-3-yl
  • X is NH
  • R 1 and R l a are both H
  • R 2 is H.
  • Q 1 is 2-Cl-thien-3-yl
  • X is NH
  • R 1 and R l a are both H
  • R 2 is ethenyl
  • Q 1 is 2-Cl-thien-3-yl
  • X is NH
  • R 1 and R l a are both H
  • R 2 is ethynyl
  • Q 1 is 2-Cl-thien-3-yl
  • X is NH
  • R 1 is Me
  • R l a is H
  • R 2 is H.
  • Q 1 is 2-Cl-thien-3-yl
  • X is NH
  • R 1 is Me
  • R l a is H
  • R 2 is ethenyl
  • Q 1 is 2-Cl-thien-3-yl
  • X is NH
  • R 1 is Me
  • R l a is H
  • R 2 is ethynyl
  • Q 1 is 2-Cl-thien-3-yl
  • X is O
  • R 1 and R l a are both H
  • R 2 is H.
  • Q 1 is 2-Cl-thien-3-yl
  • X is O
  • R 1 and R l a are both H
  • R 2 is ethenyl.
  • Q 1 is 2-Cl-thien-3-yl
  • X is O
  • R 1 and R l a are both H
  • R 2 is ethynyl.
  • Q 1 is 2-Cl-thien-3-yl
  • X is O
  • R 1 is Me
  • R l a is H
  • R 2 is H.
  • Q 1 is 2-Cl-thien-3-yl
  • X is O
  • R 1 is Me
  • R l a is H
  • R 2 is ethenyl
  • Q 1 is 2-Cl-thien-3-yl
  • X is O
  • R 1 is Me
  • R l a is H
  • R 2 is ethynyl
  • Q 1 is 2-Cl-thien-3-yl
  • X is CHOH
  • R 1 and R l a are both H
  • R 2 is H.
  • Q 1 is 2-Cl-thien-3-yl
  • X is CHOH
  • R 1 and R l a are both H
  • R 2 is ethenyl.
  • Q 1 is 2-Cl-thien-3-yl
  • X is CHOH
  • R 1 and R l a are both H
  • R 2 is ethynyl
  • 520 Q 1 is 2-Cl-thien-3-yl, X is CHOH, R 1 is Me, R l a is H, and R 2 is H.
  • Q 1 is 2-Cl-thien-3-yl
  • X is CHOH
  • R 1 is Me
  • R l a is H
  • R 2 is ethenyl
  • Q 1 is 2-Cl-thien-3-yl
  • X is CHOH
  • R 1 is Me
  • R l a is H
  • R 2 is ethynyl
  • Q 1 is 2,6-di-F-Ph
  • X is NH
  • R 1 and R l a are -CH 2 CH 2 -
  • R 2 is H.
  • Q 1 is 2,4-di-F-Ph
  • X is NH
  • R 1 and R l a are -CH 2 CH 2 -
  • R 2 is ethenyl.
  • Q 1 is 2-Cl-4-F-Ph
  • X is NH
  • R 1 and R l a are -CH 2 CH 2 -
  • R 2 is ethynyl.
  • Q 1 is 2,6-di-Cl-Ph
  • X is NH
  • R 1 and R l a are both H
  • R 2 is 1-propenyl.
  • Q 1 is 2-Br-4-Cl-Ph
  • X is NH
  • R 1 and R l a are both H
  • R 2 is 2-propenyl
  • Q 1 is 2-Br-6-Cl-Ph
  • X is NH
  • R 1 and R l a are both H
  • R 2 is 1-propynyl.
  • Q 1 is 2-Me-4-F-Ph
  • X is NH
  • R 1 and R l a are both H
  • R 2 is 2-propynyl.
  • the present disclosure also includes Tables 531 through 799, each of which is constructed the same as Table 530 above, except that the row heading in Table 530 (i.e. "Q 1 is 2,6-di-F-Ph, X is NH, R 1 and R la are both H, and R 2 is H.") is replaced with the respective row heading shown below.
  • Table 531 the row heading is "Q 1 is 2,4-di-F-Ph, X is NH, R 1 and R la are both H, and R 2 is H", and Q 2 is as defined in Table 530 above.
  • Tables 532 through 799 are constructed similarly.
  • Q 1 is 2,4-di-F-Ph
  • X is NH
  • R 1 and R l a are both H
  • R 2 is H.
  • Q 1 is 2,4,6-tri-F-Ph
  • X is NH
  • R 1 and R l a are both H
  • R 2 is H.
  • Q 1 is 2,6-di-F-4-MeO-Ph
  • X is NH
  • R 1 and R l a are both H
  • R 2 is H.
  • Q 1 is 2,6-di-F-4-EtO-Ph
  • X is NH
  • R 1 and R l a are both H
  • R 2 is H.
  • Q 1 is 2,6-di-F-4-CN-Ph
  • X is NH
  • R 1 and R l a are both H
  • R 2 is H.
  • Q 1 is 2,6-di-F-3-MeO-Ph
  • X is NH
  • R 1 and R l a are both H
  • R 2 is H.
  • Q 1 is 2,6-di-F-3-CN-Ph
  • X is NH
  • R 1 and R l a are both H
  • R 2 is H.
  • Q 1 is 2,4,5-tri-F-Ph
  • X is NH
  • R 1 and R l a are both H
  • R 2 is H.
  • Q 1 is 2,4-di-Cl-Ph
  • X is NH
  • R 1 and R l a are both H
  • R 2 is H.
  • Q 1 is 2,6-di-Cl-Ph
  • X is NH
  • R 1 and R l a are both H
  • R 2 is H.
  • Q 1 is 2-Cl-4-F-Ph
  • X is NH
  • R 1 and R l a are both H
  • R 2 is H.
  • Q 1 is 2-Cl-6-F-Ph
  • X is NH
  • R 1 and R l a are both H
  • R 2 is H.
  • Q 1 is 2-Br-4-F-Ph
  • X is NH
  • R 1 and R l a are both H
  • R 2 is H.
  • Q 1 is 2-Br-6-F-Ph
  • X is NH
  • R 1 and R l a are both H
  • R 2 is H.
  • Q 1 is 2-F-4-MeO-Ph
  • X is NH
  • R 1 and R l a are both H
  • R 2 is H.
  • Q 1 is 2-Cl-4-MeO-Ph
  • X is NH
  • R 1 and R l a are both H
  • R 2 is H.
  • Q 1 is 2-Br-4-MeO-Ph
  • X is NH
  • R 1 and R l a are both H
  • R 2 is H.
  • Q 1 is 2-F-4-EtO-Ph
  • X is NH
  • R 1 and R l a are both H
  • R 2 is H.
  • Q 1 is 2-Cl-4-EtO-Ph
  • X is NH
  • R 1 and R l a are both H
  • R 2 is H.
  • Q 1 is 2-Br-4-EtO-Ph
  • X is NH
  • R 1 and R l a are both H
  • R 2 is H.
  • Q 1 is 2-F-4-Me-Ph
  • X is NH
  • R 1 and R l a are both H
  • R 2 is H.
  • Q 1 is 2-Cl-4-Me-Ph
  • X is NH
  • R 1 and R l a are both H
  • R 2 is H.
  • Q 1 is 2-Br-4-Me-Ph
  • X is NH
  • R 1 and R l a are both H
  • R 2 is H.
  • Q 1 is 2-Me-4-Me-Ph
  • X is NH
  • R 1 and R l a are both H
  • R 2 is H.
  • Q 1 is 2-Me-4-F-Ph
  • X is NH
  • R 1 and R l a are both H
  • R 2 is H.
  • Q 1 is 2-Me-4-MeO-Ph
  • X is NH
  • R 1 and R l a are both H
  • R 2 is H.
  • Q 1 is 2-Me-4-EtO-Ph
  • X is NH
  • R 1 and R l a are both H
  • R 2 is H.
  • Q 1 is 3,5-di-Cl-pyridin-2-yl
  • X is NH
  • R 1 and R l a are both H
  • R 2 is H.
  • Q 1 is 2-Cl-thien-3-yl
  • X is NH
  • R 1 and R l a are both H
  • R 2 is H.
  • Q 1 is 2,6-di-F-Ph
  • X is NH
  • R 1 and R l a are both H
  • R 2 is ethenyl
  • Q 1 is 2,4-di-F-Ph
  • X is NH
  • R 1 and R l a are both H
  • R 2 is ethenyl
  • Q 1 is 2,4,6-tri-F-Ph
  • X is NH
  • R 1 and R l a are both H
  • R 2 is ethenyl
  • Q 1 is 2,6-di-F-4-MeO-Ph
  • X is NH
  • R 1 and R l a are both H
  • R 2 is ethenyl
  • Q 1 is 2,6-di-F-4-EtO-Ph
  • X is NH
  • R 1 and R l a are both H
  • R 2 is ethenyl
  • Q 1 is 2,6-di-F-4-CN-Ph
  • X is NH
  • R 1 and R l a are both H
  • R 2 is ethenyl
  • Q 1 is 2,6-di-F-3-MeO-Ph
  • X is NH
  • R 1 and R l a are both H
  • R 2 is ethenyl
  • Q 1 is 2,6-di-F-3-CN-Ph
  • X is NH
  • R 1 and R l a are both H
  • R 2 is ethenyl
  • Q 1 is 2,4,5-tri-F-Ph
  • X is NH
  • R 1 and R l a are both H
  • R 2 is ethenyl
  • Q 1 is 2,4-di-Cl-Ph
  • X is NH
  • R 1 and R l a are both H
  • R 2 is ethenyl
  • Q 1 is 2,6-di-Cl-Ph
  • X is NH
  • R 1 and R l a are both H
  • R 2 is ethenyl
  • Q 1 is 2-Cl-4-F-Ph
  • X is NH
  • R 1 and R l a are both H
  • R 2 is ethenyl
  • Q 1 is 2-Cl-6-F-Ph
  • X is NH
  • R 1 and R l a are both H
  • R 2 is ethenyl
  • Q 1 is 2-Br-4-F-Ph
  • X is NH
  • R 1 and R l a are both H
  • R 2 is ethenyl
  • Q 1 is 2-Br-6-F-Ph
  • X is NH
  • R 1 and R l a are both H
  • R 2 is ethenyl
  • Q 1 is 2-F-4-MeO-Ph
  • X is NH
  • R 1 and R l a are both H
  • R 2 is ethenyl.
  • Q 1 is 2-Cl-4-MeO-Ph
  • X is NH
  • R 1 and R l a are both H
  • R 2 is ethenyl.
  • Q 1 is 2-Br-4-MeO-Ph
  • X is NH
  • R 1 and R l a are both H
  • R 2 is ethenyl.
  • Q 1 is 2-F-4-EtO-Ph
  • X is NH
  • R 1 and R l a are both H
  • R 2 is ethenyl.
  • Q 1 is 2-Cl-4-EtO-Ph
  • X is NH
  • R 1 and R l a are both H
  • R 2 is ethenyl.
  • Q 2-Br-4-EtO-Ph, X is NH, R 1 and R l a are both H, and R 2 is ethenyl.
  • Q 2-F-4-Me-Ph, X is NH, R 1 and R l a are both H, and R 2 is ethenyl.
  • Q 2-Me-4-Me-Ph, X is NH, R 1 and R l a are both H, and R 2 is ethenyl.
  • Q 2-Me-4-F-Ph, X is NH, R 1 and R l a are both H, and R 2 is ethenyl.
  • Q 2-Me-4-MeO-Ph, X is NH, R 1 and R l a are both H, and R 2 is ethenyl.
  • Q 2-Me-4-EtO-Ph, X is NH, R 1 and R l a are both H, and R 2 is ethenyl.
  • Q 3.5- di-Cl-pyridin-2-yl, X is NH, R 1 and R l a are both H, and R 2 is ethenyl.
  • Q 2-Cl-thien-3-yl, X is NH, R 1 and R l a are both H, and R 2 is ethenyl.
  • Q 2.6- di-F-Ph, X is NH, R 1 and R l a are both H, and R 2 is ethynyl.
  • Q 2,4-di-F-Ph, X is NH, R 1 and R l a are both H, and R 2 is ethynyl.
  • Q 2,6-di-F-4-MeO-Ph, X is NH, R 1 and R l a are both H, and R 2 is ethynyl.
  • Q 2,6-di-F-4-EtO-Ph, X is NH, R 1 and R l a are both H, and R 2 is ethynyl.
  • Q 2,6-di-F-4-CN-Ph, X is NH, R 1 and R l a are both H, and R 2 is ethynyl.
  • Q 2,6-di-F-3-MeO-Ph, X is NH, R 1 and R l a are both H, and R 2 is ethynyl.
  • Q 2,6-di-F-3-CN-Ph, X is NH, R 1 and R l a are both H, and R 2 is ethynyl.
  • Q 2,4,5-tri-F-Ph, X is NH, R 1 and R l a are both H, and R 2 is ethynyl.
  • Q 2,4-di-Cl-Ph X is NH, R 1 and R l a are both H, and R 2 is ethynyl.
  • Q 2,6-di-Cl-Ph, X is NH, R 1 and R l a are both H, and R 2 is ethynyl.
  • Q 2-F-4-MeO-Ph, X is NH, R 1 and R l a are both H, and R 2 is ethynyl.
  • Q 2-Cl-4-MeO-Ph, X is NH, R 1 and R l a are both H, and R 2 is ethynyl.
  • Q 2-Br-4-MeO-Ph, X is NH, R 1 and R l a are both H, and R 2 is ethynyl.
  • Q 2-F-4-EtO-Ph, X is NH, R 1 and R l a are both H, and R 2 is ethynyl.
  • Q 1 is 2-Me-4-F-Ph
  • X is NH
  • R 1 and R l a are both H
  • R 2 is ethynyl
  • Q 1 is 2-Me-4-MeO-Ph
  • X is NH
  • R 1 and R l a are both H
  • R 2 is ethynyl.
  • Q 1 is 2-Me-4-EtO-Ph
  • X is NH
  • R 1 and R l a are both H
  • R 2 is ethynyl.
  • Q 1 is 3,5-di-Cl-pyridin-2-yl
  • X is NH
  • R 1 and R l a are both H
  • R 2 is ethynyl
  • Q 1 is 2-Cl-thien-3-yl
  • X is NH
  • R 1 and R l a are both H
  • R 2 is ethynyl
  • Q 1 is 2,6-di-F-Ph
  • X is O
  • R 1 and R l a are both H
  • R 2 is H.
  • Q 1 is 2,4-di-F-Ph
  • X is O
  • R 1 and R l a are both H
  • R 2 is H.
  • Q 1 is 2,4,6-tri-F-Ph
  • X is O
  • R 1 and R l a are both H
  • R 2 is H.
  • Q 1 is 2,6-di-F-4-MeO-Ph
  • X is O
  • R 1 and R l a are both H
  • R 2 is H.
  • Q 1 is 2,6-di-F-4-EtO-Ph
  • X is O
  • R 1 and R l a are both H
  • R 2 is H.
  • Q 1 is 2,6-di-F-4-CN-Ph
  • X is O
  • R 1 and R l a are both H
  • R 2 is H.
  • Q 1 is 2,6-di-F-3-MeO-Ph
  • X is O
  • R 1 and R l a are both H
  • R 2 is H.
  • Q 1 is 2,6-di-F-3-CN-Ph
  • X is O
  • R 1 and R l a are both H
  • R 2 is H.
  • Q 1 is 2,4,5-tri-F-Ph
  • X is O
  • R 1 and R l a are both H
  • R 2 is H.
  • Q 1 is 2,4-di-Cl-Ph
  • X is O
  • R 1 and R l a are both H
  • R 2 is H.
  • Q 1 is 2,6-di-Cl-Ph
  • X is O
  • R 1 and R l a are both H
  • R 2 is H.
  • Q 1 is 2-Cl-4-F-Ph
  • X is O
  • R 1 and R l a are both H
  • R 2 is H.
  • Q 1 is 2-Cl-6-F-Ph
  • X is O
  • R 1 and R l a are both H
  • R 2 is H.
  • Q 1 is 2-Br-4-F-Ph
  • X is O
  • R 1 and R l a are both H
  • R 2 is H.
  • Q 1 is 2-Br-6-F-Ph
  • X is O
  • R 1 and R l a are both H
  • R 2 is H.
  • Q 1 is 2-F-4-MeO-Ph
  • X is O
  • R 1 and R l a are both H
  • R 2 is H.
  • Q 1 is 2-Cl-4-MeO-Ph
  • X is O
  • R 1 and R l a are both H
  • R 2 is H.
  • Q 1 is 2-Br-4-MeO-Ph
  • X is O
  • R 1 and R l a are both H
  • R 2 is H.
  • Q 1 is 2-F-4-EtO-Ph
  • X is O
  • R 1 and R l a are both H
  • R 2 is H.
  • Q 1 is 2-Cl-4-EtO-Ph
  • X is O
  • R 1 and R l a are both H
  • R 2 is H.
  • Q 1 is 2-Br-4-EtO-Ph
  • X is O
  • R 1 and R l a are both H
  • R 2 is H.
  • Q 1 is 2-F-4-Me-Ph
  • X is O
  • R 1 and R l a are both H
  • R 2 is H.
  • Q 1 is 2-Cl-4-Me-Ph
  • X is O
  • R 1 and R l a are both H
  • R 2 is H.
  • Q 1 is 2-Br-4-Me-Ph
  • X is O
  • R 1 and R l a are both H
  • R 2 is H.
  • Q 1 is 2-Me-4-Me-Ph
  • X is O
  • R 1 and R l a are both H
  • R 2 is H.
  • Q 1 is 2-Me-4-F-Ph
  • X is O
  • R 1 and R l a are both H
  • R 2 is H.
  • Q 1 is 2-Me-4-MeO-Ph
  • X is O
  • R 1 and R l a are both H
  • R 2 is H.
  • Q 1 is 2-Me-4-EtO-Ph
  • X is O
  • R 1 and R l a are both H
  • R 2 is H.

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Abstract

Disclosed are compounds of Formula 1, including all geometric and stereoisomers, N-oxides, and salts thereof, wherein Q1is a phenyl ring, naphthalenyl ring system, a 5- to 6-membered fully unsaturated heterocyclic ring or an 8- to 10-membered heteroaromatic bicyclic ring system, each as described with optional substituents as defined in the disclosure; Q2 is a phenyl ring, a naphthalenyl ring system, a 4-, 5- or 6-membered saturated, partially unsaturated or fully unsaturated heterocyclic ring, or an 8- to 10-membered heteroaromatic bicyclic ring system, each as described with optional substituents as defined in the disclosure; X is O, NR4 or CR15R16; R2 is H, C2-C3 alkenyl or C2-C3 alkynyl; and R1, R1a, R4, R15 and R16 are as defined in the disclosure. Also disclosed are compositions containing the compounds of Formula 1 and methods for controlling plant disease caused by a fungal pathogen comprising applying an effective amount of a compound or a composition of the invention.

Description

TITLE
FUNGICIDAL PYRAZOLES
FIELD OF THE INVENTION
This invention relates to certain pyrazoles, their N-oxides, salts and compositions, and methods of their use as fungicides.
BACKGROUND OF THE INVENTION
The control of plant diseases caused by fungal plant pathogens is extremely important in achieving high crop efficiency. Plant disease damage to ornamental, vegetable, field, cereal, and fruit crops can cause significant reduction in productivity and thereby result in increased costs to the 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 sites of action.
SUMMARY OF THE INVENTION
This invention is directed to compounds of Formula 1 (including all stereoisomers), N-oxides, and salts thereof, agricultural compositions containing them and their use as fungicides:
Figure imgf000002_0001
1
wherein
Q1 is a phenyl ring or a naphthalenyl ring system, each ring or ring system optionally substituted with up to 5 substituents independently selected from R3; or a 5- to 6-membered fully unsaturated heterocyclic ring or an 8- to 10-membered heteroaromatic bicyclic ring system, each ring or ring system containing ring members selected from carbon atoms and up to 4 heteroatoms independently selected from up to 2 O, up to 2 S and up to 4 N atoms, wherein up to 3 carbon ring members are independently selected from C(=0) and C(=S), and the sulfur atom ring members are independently selected from S(=0)u(=NR14)v, each ring or ring system optionally substituted with up to 5 substituents independently selected from R3 on carbon atom ring members and selected from cyano, C^-Cg alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, Cj-Cg alkoxy, C2-C6 alkoxyalkyl, C2-C6 alkylcarbonyl, C2-C6 alkoxycarbonyl, C2-C6
alkylaminoalkyl and C3-C6 dialkylaminoalkyl on nitrogen atom ring members; Q2 is a phenyl ring or a naphthalenyl ring system, each ring or ring system optionally substituted with up to 5 substituents independently selected from R3; or a 4-, 5- or 6-membered saturated, partially unsaturated or fully unsaturated heterocyclic ring or an 8- to 10-membered heteroaromatic bicyclic ring system, each ring or ring system containing ring members selected from carbon atoms and up to 4 heteroatoms independently selected from up to 2 O, up to 2 S and up to 4 N atoms, wherein up to 3 carbon ring members are independently selected from C(=0) and C(=S), and the sulfur atom ring members are independently selected from S(=0)u(=NR14)v, each ring or ring system optionally substituted with up to 5 substituents independently selected from R3 on carbon atom ring members and selected from cyano, -Cg alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -Cg alkoxy, C2-C6 alkoxyalkyl, C2-C6 alkylcarbonyl, C2- Cg alkoxycarbonyl, C2-Cg alky lamino alkyl and C3-Cg dialkylaminoalkyl on nitrogen atom ring members; or
Cj-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C3-C12 cycloalkyl or C3-C12 cycloalkenyl, each optionally substituted with up to 5 substituents independently selected from R3;
X is O, NR4 or CR15R16;
R1 is H, halogen, -Cg alkyl, C^-Cg haloalkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3- C7 cycloalkyl, C02R5, C(0)NR6R7, cyano, -Cg alkoxy, -Cg haloalkoxy or
C2-C5 alkoxyalkyl; or
R1 is phenyl optionally substituted with up to 3 R8; or a five- or six-membered
nitrogen-containing aromatic heterocycle optionally substituted with up to 3 substituents independently selected from R9a on carbon atom ring members and R9^ on nitrogen atom ring members;
Rla is H; or
Rla and R1 are taken together with the carbon atom to which they are attached to form a cyclopropyl ring optionally substituted with up to 2 substituents independently selected from halogen and methyl;
R2 is H, C2-C3 alkenyl or C2-C3 alkynyl;
each R3 is independently selected from halogen, cyano, nitro, amino, methylamino, dimethy lamino, formylamino, C2-C3 alky lcarbony lamino, C1-C4 alkyl, C1-C4 haloalkyl, C^-C3 alkoxy, C^-C3 haloalkoxy, C^-C3 alkylthio, C^-C3 haloalkylthio, C^-C3 alkylsulfmyl, C^-C3 haloalkylsulfinyl, C^-C3
alkylsulfonyl, C1-C3 haloalkylsulfonyl, C1-C2 alkylsulfonyloxy, C1-C2 haloalkylsulfonyloxy, C3-C4 cycloalkyl, C3-C7 cycloalkoxy, C4-C6
alkylcycloalkyl, C4-C6 cycloalkylalkyl, C3-C7 halocycloalkyl, C2-C4 alkenyl, C2-C4 alkynyl, hydroxy, formyl, C2-C3 alkylcarbonyl, C2-C3 alkylcarbonyloxy, -SF5, -SCN, C(=S)NR19R20, C(=NOR27)R28 or -U-V-T;
R4 is H, formyl, C2-C5 alkenyl, C3-C5 alkynyl, C3-C7 cycloalkyl, -S03-M+,
-S(=0)tR10, -(C=W)Rn, NH2 or OR21; or Ογ-06 alkyl or Ογ-06 haloalkyl, each optionally substituted with up to 2 R12;
R5 is H, C!-C6 alkyl or Ci~C6 haloalkyl;
R6 and R7 are independently selected from H, Cj-Cg alkyl, Cj-Cg haloalkyl, C3-C7 cycloalkyl, C4-C8 cycloalkylalkyl and C4-C8 alkylcycloalkyl; or
R6 and R7 are taken together with the nitrogen atom to which they are connected to form a four- to seven-membered nonaromatic heterocyclic ring containing ring members, in addition to the connecting ring nitrogen atom, selected from carbon atoms and optionally up to one ring member selected from O, S(0)n and NR13; each R8, R9a and R9b is independently selected from halogen, C1-C2 alkyl, C1-C2 haloalkyl, C1-C2 alkoxy, C1-C2 haloalkoxy, cyano, nitro, SCH3, S(0)CH3 and S(0)2CH3;
R10 is C!-C6 alkyl or Ογ-06 haloalkyl;
each R11 is independently Cj-Cg alkyl, -Cg haloalkyl, C3-C6 cycloalkyl, Cj-Cg alkoxy, C2-C7 alkoxyalkyl, C2-C7 alkylaminoalkyl, C2-Cg dialkylaminoalkyl, C1-C6 alkylthio or C2-C7 alkylthioalkyl;
each R12 is independently C3-C7 cycloalkyl, Ci~C4 alkoxy, Ci~C4 haloalkoxy, Ci~C4 alkylthio, Ci~C4 alkylsulfinyl, Ci~C4 alkylsulfonyl or cyano;
R13 is H, C!-C3 alkyl or C2-C3 haloalkyl;
each R14 is independently H, cyano, C^-C3 alkyl or C^-C3 haloalkyl;
R15 is H or C!-C4 alkyl;
R16 is F, CI or OR18;
each R18 is independently H, formyl, C3-C7 cycloalkyl, -S03 M+ or -(C=W)Rn; or Cj-Cg alkyl or Cj-Cg haloalkyl, each optionally substituted with up to 2 R12; each R19 and R20 is independently H or CH3;
R21 is H, formyl, C3-C7 cycloalkyl, -S03-M+ or -(C=W)Rn; or C!-C6 alkyl or Cr C6 haloalkyl, each optionally substituted with up to 2 R12;
each U is independently O, S(=0)w, NR22 or a direct bond;
each V is independently Cj-Cg alkylene, C2-C6 alkenylene, C3-C6 alkynylene, C3-C6 cycloalkylene or C3-Cg cycloalkenylene, wherein up to 3 carbon atoms are independently selected from C(=0), each optionally substituted with up to 5 substituents independently selected from halogen, cyano, nitro, hydroxy, Cj-Cg alkyl, C^-Cg haloalkyl, C^-Cg alkoxy and C^-Cg haloalkoxy;
each T is independently cyano, NR23aR23b, OR24 or S(=0)yR25 each R22 is independently H, -Cg alkyl, Cj-Cg haloalkyl, C2-C6 alkylcarbonyl, C2- C6 alkoxycarbonyl, C2-C6 (alkylthio)carbonyl, C2-C6 alkoxy(thiocarbonyl), C4-C8 cycloalkylcarbonyl, C4-C8 cycloalkoxycarbonyl, C4-C8
(cycloalkylthio)carbonyl or C4-C8 cycloalkoxy(thiocarbonyl);
each R23a and R23b is independently H, -Cg alkyl, -Cg haloalkyl, C2-C6 alkenyl,
C3-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, C2-C6 alkylcarbonyl, C2-C6 alkoxycarbonyl, C2-C6 (alkylthio)carbonyl, C2-C6 alkoxy(thiocarbonyl), C4-C8 cycloalkylcarbonyl, C4-C8 cycloalkoxycarbonyl, C4-C8
(cycloalkylthio)carbonyl or C4-C8 cycloalkoxy(thiocarbonyl); or
a pair of R23a and R23^ attached to the same nitrogen atom are taken together with the nitrogen atom to form a 3- to 6-membered heterocyclic ring, the ring optionally substituted with up to 5 substituents independently selected from R26; each R24 and R25 is independently H, Cj-Cg alkyl, C^-Cg haloalkyl, C2-C6 alkenyl, C3-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, C2-C6 alkylcarbonyl, C2-C6 alkoxycarbonyl, C2-C6 (alkylthio)carbonyl, C2-C6 alkoxy(thiocarbonyl),
C4-C8 cycloalkylcarbonyl, C4-C8 cycloalkoxycarbonyl, C4-C8
(cycloalkylthio)carbonyl or C4-C8 cycloalkoxy(thiocarbonyl);
each R26 is independently halogen, C^-Cg alkyl, C^-Cg haloalkyl or C^-Cg alkoxy; each R27 is independently H, C^-Cg alkyl, C^-Cg haloalkyl, C2-C6 alkenyl, C3-C6 haloalkenyl, C3-Cg alkynyl, C3-Cg haloalkynyl or C4-C7 cycloalkylalkyl;
each R28 is H or C1-C4 alkyl;
each W is independently O or S;
each M+ is independently a cation;
n is 0, 1 or 2;
t is 0, 1 or 2;
each u and v are independently 0, 1 or 2 in each instance of S(=0)u(=NR14)v, provided that the sum of u and v is 0, 1 or 2;
each w is independently 0, 1 or 2; and
each y is independently 0, 1 or 2;
provided that the compound of Formula 1 is other than 4,6-dimethoxy-N-[l-methyl-
4-(2-methyl-2H-tetrazol-5-yl)-lH-pyrazol-5-yl]-2-pyrimidinamine.
More particularly, this invention pertains to a compound of Formula 1 (including all geometric and stereoisomers), an N-oxide or a salt thereof.
This invention also relates to a fungicidal composition comprising a compound of Formula 1, an N-oxide, or a salt thereof, and at least one additional component selected from the group consisting of surfactants, solid diluents and liquid diluents. This invention also relates to a fungicidal composition comprising: (a) a compound of Formula 1, an N-oxide, or a salt thereof, and (b) at least one other fungicide (e.g., at least one other fungicide having a different site of action).
This invention further relates to a method for controlling plant diseases caused by fungal plant pathogens comprising applying to the plant or portion thereof, or to the plant seed, a fungicidally effective amount of a compound of the invention (e.g., as a composition described herein).
The aforedescribed method can also be described as a method for protecting a plant or plant seed from diseases caused by fungal pathogens comprising applying a fungicidally effective amount of a compound of Formula 1, an N-oxide, or a salt thereof (e.g., as a composition described herein), to the plant (or portion thereof) or plant seed (directly or through the environment (e.g., growing medium) of the plant or plant seed).
DETAILS OF THE INVENTION
As used herein, the terms "comprises," "comprising," "includes," "including," "has," "having," "contains", "containing," "characterized by" or any other variation thereof, are intended to cover a non-exclusive inclusion, subject to any limitation explicitly indicated. For example, a composition, mixture, process or method that comprises a list of elements is not necessarily limited to only those elements but may include other elements not expressly listed or inherent to such composition, mixture, process or method.
The transitional phrase "consisting of excludes any element, step, or ingredient not specified. If in the claim, such would close the claim to the inclusion of materials other than those recited except for impurities ordinarily associated therewith. When the phrase "consisting of appears in a clause of the body of a claim, rather than immediately following the preamble, it limits only the element set forth in that clause; other elements are not excluded from the claim as a whole.
The transitional phrase "consisting essentially of is used to define a composition or method that includes materials, steps, features, components, or elements, in addition to those literally disclosed, provided that these additional materials, steps, features, components, or elements do not materially affect the basic and novel characteristic(s) of the claimed invention. The term "consisting essentially of occupies a middle ground between "comprising" and "consisting of.
Where applicants have defined an invention or a portion thereof with an open-ended term such as "comprising," it should be readily understood that (unless otherwise stated) the description should be interpreted to also describe such an invention using the terms "consisting essentially of or "consisting of."
Further, unless expressly stated to the contrary, "or" refers to an inclusive or and not to an exclusive or. For example, a condition A or B is satisfied by any one of the following: A is true (or present) and B is false (or not present), A is false (or not present) and B is true (or present), and both A and B are true (or present).
Also, the indefinite articles "a" and "an" preceding an element or component of the invention are intended to be nonrestrictive regarding the number of instances (i.e. occurrences) of the element or component. Therefore "a" or "an" should be read to include one or at least one, and the singular word form of the element or component also includes the plural unless the number is obviously meant to be singular.
As referred to in the present disclosure and claims, "plant" includes members of Kingdom Plantae, particularly seed plants (Spermatopsida), at all life stages, including young plants (e.g., germinating seeds developing into seedlings) and mature, reproductive stages (e.g., plants producing flowers and seeds). Portions of plants include geotropic members typically growing beneath the surface of the growing medium (e.g., soil), such as roots, tubers, bulbs and corms, and also members growing above the growing medium, such as foliage (including stems and leaves), flowers, fruits and seeds.
As referred to herein, the term "seedling", used either alone or in a combination of words means a young plant developing from the embryo of a seed.
As used herein, the term "alkylating agent" refers to a chemical compound in which a carbon-containing radical is bound through a carbon atom to leaving group such as halide or sulfonate, which is displaceable by bonding of a nucleophile to said carbon atom. Unless otherwise indicated, the term "alkylating" does not limit the carbon-containing radical to alkyl; the carbon-containing radicals in alkylating agents include the variety of carbon-bound substituent radicals specified for R1.
Generally when a molecular fragment (i.e. radical) is denoted by a series of atom symbols (e.g., C, H, N, O, S) the implicit point or points of attachment will be easily recognized by those skilled in the art. In some instances herein, particularly when alternative points of attachment are possible, the point or points of attachment may be explicitly indicated by a hyphen ("-"). For example, "-SCN" indicates that the point of attachment is the sulfur atom (i.e. thiocyanato, not isothiocyanato).
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, n-propyl, /-propyl, or the different butyl, pentyl or hexyl isomers. "Alkenyl" includes straight-chain or branched alkenes such as ethenyl, 1-propenyl, 2-propenyl, and the different butenyl isomers. "Alkenyl" also includes polyenes such as 1,2-propadienyl. "Alkynyl" includes straight-chain or branched alkynes such as ethynyl, 1-propynyl, 2-propynyl and the different butynyl isomers. "Alkylene" denotes a straight-chain or branched alkanediyl. Examples of "alkylene" include CH2, CH2CH2, CH(CH3), CH2CH2CH2, CH2CH(CH3) and the different butylene isomers. "Alkenylene" denotes a straight-chain or branched alkenediyl containing one olefmic bond. Examples of "alkenylene" include CH=CH, CH2CH=CH, CH=C(CH3). "Alkynylene" denotes a straight-chain or branched alkynediyl containing one triple bond. Examples of "alkynylene" include CH2C≡C, C≡CCH2 and the different butynylene, pentynylene and hexynylene isomers. "Alkylcarbonyl" denotes a straight-chain or branched alkyl moieties bonded to a C(=0) moiety. Examples of "alkylcarbonyl" include CH3C(=0)-, CH3CH2CH2C(=0)- and (CH3)2CHC(=0)-.
"Alkoxy" includes, for example, methoxy, ethoxy, n-propyloxy, isopropyloxy and the different butoxy, pentoxy and hexyloxy isomers. "Alkoxyalkyl" denotes alkoxy substitution on alkyl. Examples of "alkoxyalkyl" include CH3OCH2, CH3OCH2CH2, CH3CH2OCH2, CH3CH2CH2CH2OCH2 and CH3CH2OCH2CH2. Examples of "alkoxycarbonyl" include CH3OC(=0)-, CH3CH2OC(=0)-, CH3CH2CH2OC(=0)-, (CH3)2CHOC(=0)- and the different butoxy- or pentoxycarbonyl isomers. "Alkylthio" includes branched or straight-chain alkylthio moieties such as methylthio, ethylthio, and the different propylthio, butylthio, pentylthio and hexylthio isomers. "Alkylsulfmyl" includes both enantiomers of an alkylsulfmyl group. Examples of "alkylsulfmyl" include CH3S(0)-, CH3CH2S(0)-, CH3CH2CH2S(0)-, (CH3)2CHS(0)- and the different butylsulfinyl isomers. Examples of "alkylsulfonyl" include CH3S(0)2-, CH3CH2S(0)2-, CH3CH2CH2S(0)2-, (CH3)2CHS(0)2-, and the different butylsulfonyl isomers. "Alkylthioalkyl" denotes alkylthio substitution on alkyl. Examples of "alkylthioalkyl" include CH3SCH2, CH3SCH2CH2, CH3CH2SCH2, CH3CH2CH2CH2SCH2 and CH3CH2SCH2CH2. "(Alkylthio)carbonyl" denotes a straight-chain or branched alkylthio group bonded to a C(=0) moiety. Examples of "(alkylthio)carbonyl" include CH3SC(=0), CH3CH2CH2SC(=0) and (CH3)2CHSC(=0). "Alkoxy(thiocarbonyl)" denotes a straight-chain or branched alkoxy group bonded to a C(=S) moiety. Examples of "alkoxy(thiocarbonyl)" include CH3OC(=S), CH3CH2CH2OC(=S) and (CH3)2CHOC(=S). "Alkylaminoalkyl" denotes a straight-chain or branched alkyl moieties bonded to a nitrogen atom of an amino(straight-chain or branched)alkyl moiety. Examples of "alkylaminoalkyl" include CH3NHCH2-, (CH3)2CHNHCH2- and CH3NHCH(CH3)-. "Dialkylaminoalkyl" denotes two independent straight-chain or branched alkyl moieties bonded to a nitrogen atom of an amino (straight-chain or branched)alkyl moiety. Examples of "dialkylaminoalkyl" include (CH3)2NCH2-, (CH3)2CH(CH3)NCH2- and (CH3)2NCH(CH3)-. The term
"alkylcarbonylamino" denotes alkyl bonded to a C(=0)NH moiety. Examples of "alkylcarbonylamino" include CH3CH2C(=0)NH and CH3CH2CH2C(=0)NH.
"Cycloalkyl" includes, for example, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The term "alkylcycloalkyl" denotes alkyl substitution on a cycloalkyl moiety and includes, for example, ethylcyclopropyl, z'-propylcyclobutyl, 3-methylcyclopentyl and 4-methylcyclohexyl. The term "cycloalkylalkyl" denotes cycloalkyl substitution on an alkyl moiety. Examples of "cycloalkylalkyl" include cyclopropylmethyl, cyclopentylethyl, and other cycloalkyl moieties bonded to straight-chain or branched alkyl groups. The term "cycloalkoxy" denotes cycloalkyl linked through an oxygen atom such as cyclopentyloxy and cyclohexyloxy. "Cycloalkenyl" includes carbocyclic rings that contain only one double bond such as cyclopentenyl and cyclohexenyl, as well as carbocyclic rings with more than one double bond such as 1,3- and 1 ,4-cyclohexadienyl, but are not aromatic. "Cycloalkylcarbonyl" denotes cycloalkyl bonded to a C(=0) group including, for example, cyclopropylcarbonyl and cyclopentylcarbonyl. The term "cycloalkoxycarbonyl" means cycloalkoxy bonded to a C(=0) group, for example, cyclopropyloxycarbonyl and cyclopentyloxycarbonyl. The term "cycloalkylene" denotes a cycloalkanediyl ring. Examples of "cycloalkylene" include cyclopropylene, cyclobutylene, cyclopentylene and cyclohexylene. The term "cycloalkenylene" denotes a cycloalkenediyl ring containing one olefmic bond. Examples of "cycloalkenylene" include cyclopropenediyl and cyclopentenediyl.
The term "halogen", either alone or in compound words such as "haloalkyl", or when used in descriptions such as "alkyl substituted with halogen" includes fluorine, chlorine, bromine or iodine. Further, when used in compound words such as "haloalkyl", or when used in descriptions such as "alkyl substituted with halogen" said alkyl may be partially or fully substituted with halogen atoms which may be the same or different. Examples of "haloalkyl" or "alkyl substituted with halogen" include F3C-, C1CH2-, CF3CH2- and CF3CCI2-. The terms "halocycloalkyl", "haloalkoxy", "haloalkylthio", and the like, are defined analogously to the term "haloalkyl". Examples of "haloalkoxy" include CH2FO-, CHF20-, CF3O-, CC13CH20-, HCF2CH2CH20- and CF3CH20-. Examples of "fluoroalkoxy" include CH2FO-, CHF20-, CF30- HCF2CH2CH20- and CF3CH20-. Examples of "fluoromethoxy" include CH2FO-, CHF20- and CF30-. Examples of "haloalkylthio" include CC13S-, CF3S-, CC13CH2S- and C1CH2CH2CH2S-. Examples of "haloalkylsulfmyl" include CF3S(0)-, CC13S(0)-, CF3CH2S(0)- and CF3CF2S(0)-. Examples of "haloalkylsulfonyl" include CF3S(0)2-, CC13S(0)2-, CF3CH2S(0)2- and CF3CF2S(0)2-.
The total number of carbon atoms in a substituent group is indicated by the "Cj-Cj" prefix where i and j are numbers from 1 to 12. For example, C1-C4 alkylsulfonyl designates methylsulfonyl through butylsulfonyl; C2 alkoxyalkyl designates CH3OCH2-; C3 alkoxyalkyl designates, for example, CH3CH(OCH3)-, CH3OCH2CH2- or CH3CH2OCH2-; and C4 alkoxyalkyl designates the various isomers of an alkyl group substituted with an alkoxy group containing a total of four carbon atoms, examples including CH3CH2CH2OCH2- and CH3CH2OCH2CH2-.
As used herein, the following definitions shall apply unless otherwise indicated. The term "optionally substituted" is used interchangeably with the phrase "substituted or unsubstituted" or with the term "(un)substituted." Unless otherwise indicated, an optionally substituted group may have a substituent at each substitutable position of the group, and each substitution is independent of the other.
The term "unsubstituted" in connection with a group such as a ring or ring system means the group does not have any substituents other than its one or more attachments to the remainder of Formula 1. The term "optionally substituted" means that the number of substituents can be zero. Unless otherwise indicated, optionally substituted groups may be substituted with as many optional substituents as can be accommodated by replacing a hydrogen atom with a non-hydrogen substituent on any available carbon or nitrogen atom. The number of optional substituents may be restricted by an expressed limitation. For example, the phrase "optionally substituted with up to 3 substituents selected from R9a on carbon atom ring members" means that 0, 1, 2 or 3 substituents can be present (if the number of potential connection points allows). Similarly, the phrase "optionally substituted with up to 5 substituents selected from R3 on carbon atom ring members" means that 0, 1, 2, 3, 4 or 5 substituents can be present if the number of available connection points allows. When a range specified for the number of substituents (e.g., r being an integer from 0 to 4 or from 0 to 3 for 5- and 6-membered nitrogen-containing heterocycles in Exhibit A) exceeds the number of positions available for substituents on a ring (e.g., 2 positions available for (Ra)r on U-27 in Exhibit A), the actual higher end of the range is recognized to be the number of available positions.
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, e.g., (R )p attached to the phenyl ring in the molecular structure at the top of Table 1 where p is 0, 1, 2, 3, 4 or 5. When a group contains a substituent which can be hydrogen, for example R1, R4, R5, R6, R7 or R13, then when this substituent is taken as hydrogen, it is recognized that this is equivalent to said group being unsubstituted. When a variable group is shown to be optionally attached to a position, for example (Ra)r in H-23 of Exhibit 1, wherein r may be 0, then hydrogen may be at the position even if not recited in the variable group definition. When one or more positions on a group are said to be "not substituted" or "unsubstituted", then hydrogen atoms are attached to take up any free valency.
The variables "n", "t", "u", "v", "w" and "y" in the Summary of the Invention and corresponding parts of the patent specification relate to subscripts appearing to the right of atoms or other molecular fragments within parentheses and denote the integral number of instances present of the atoms or other molecular fragments within the parentheses, "n" relates to "S(0)n", "t" relates to "-S(=0)tR10", "u" and "v" relate to "S(=0)u(=NR14)v", "w" relates to "S(=0)w", and "y" relates to "S(=0)yR25. For example, "n" being 0, 1 or 2 means that "S(0)n" can be "S", "S(O)" or "S(0)2". Unless otherwise indicated, a "ring" as a component of Formula 1 is carbocyclic or heterocyclic. The term "ring system" as a component of Formula 1 denotes two fused rings (e.g., a phenyl ring fused to a pyridinyl ring to form quinolinyl). The term "ring member" refers to an atom or other moiety (e.g., O, S(O), S(0)2 or S(=0)u(=NR14)v) forming the backbone of a ring or ring system.
The term "carbocyclic ring" denotes a ring wherein the atoms forming the ring backbone are selected only from carbon. Unless otherwise indicated, a carbocyclic ring can be a saturated, partially unsaturated, or fully unsaturated ring. "Saturated carbocyclic" refers to a ring having a backbone consisting of carbon atoms linked to one another by single bonds; unless otherwise specified, the remaining carbon valences are occupied by hydrogen atoms.
The terms "heterocyclic ring" or "heterocycle" denote a ring or ring system in which at least one atom forming the ring backbone is not carbon, e.g., nitrogen, oxygen or sulfur. Typically a heterocyclic ring contains no more than 4 nitrogens, no more than 2 oxygens and no more than 2 sulfurs. Unless otherwise indicated, a heterocyclic ring can be a saturated, partially unsaturated, or fully unsaturated ring. The term "saturated heterocyclic ring" refers to a heterocyclic ring containing only single bonds between ring members. In regards to degree of saturation, "a partially unsaturated heterocyclic ring" is intermediate between a saturated heterocyclic ring and a fully unsaturated heterocyclic ring (which may be aromatic). Therefore, as referred to in the present disclosure and claims, the term "partially unsaturated heterocyclic ring" denotes a heterocyclic ring comprising at least one ring member bonded to an adjacent ring member through a double bond and which conceptually potentially accommodates a number of non-cumulated double bonds between adjacent ring members (i.e. in its fully unsaturated counterpart form) greater than the number of double bonds present (i.e. in its partially unsaturated form). When a fully unsaturated heterocyclic ring satisfies Huckel's rule, then said ring is also called a "heteroaromatic ring" or "aromatic heterocyclic ring". The terms "heteroaromatic ring system" and "heteroaromatic bicyclic ring system" denote a ring system in which at least one atom forming the ring backbone is not carbon, e.g., nitrogen, oxygen or sulfur, and at least one ring is aromatic. Unless otherwise indicated, heterocyclic rings and ring systems can be attached through any available carbon or nitrogen by replacement of a hydrogen on said carbon or nitrogen.
"Aromatic" indicates that each of the ring atoms is essentially in the same plane and has a /^-orbital perpendicular to the ring plane, and that (4n + 2) π electrons, where n is a positive integer, are associated with the ring to comply with Huckel's rule. The term "aromatic heterocyclic ring system" denotes a heterocyclic ring system in which at least one ring of the ring system is aromatic. The term "nonaromatic ring system" denotes a carbocyclic or heterocyclic ring system that may be fully saturated, as well as partially or fully unsaturated, provided that none of the rings in the ring system are aromatic. The term "four- to seven-membered nonaromatic heterocyclic ring" refers to rings containing four to seven ring members and which do not satisfy Huckel's rule. This term (as used where R6 and R7 are taken together) is not limited by carbon atoms only and can include ring members selected from O, S(0)n and NR13.
In the context of the present invention when an instance of Q1, Q2 or R1 comprises a phenyl or a 6-membered fully unsaturated heterocyclic ring, the ortho, meta and para positions of each ring is relative to the connection of the ring to the remainder of Formula 1.
As noted above, Q1 is, inter alia, a 5- to 6-membered fully unsaturated heterocyclic ring or an 8- to 10-membered heteroaromatic bicyclic ring system, each ring or ring system containing ring members selected from carbon atoms and up to 4 heteroatoms independently selected from up to 2 O, up to 2 S and up to 4 N atoms, wherein up to 3 carbon atom ring members are independently selected from C(=0) and C(=S), the sulfur atom ring members are independently selected from S(=0)u(=NR14)v, each ring or ring system optionally substituted with up to 5 substituents independently selected from any substituent defined in the Summary of the Invention for Q1 (e.g., a Q1 ring or ring system is optionally substituted with R3 on carbon atom ring members and cyano, C^-Cg alkyl, C2-Cg alkenyl, C2-Cg alkynyl, C3-C6 cycloalkyl, Cj-Cg alkoxy, C2-C6 alkoxyalkyl, C2-C6 alkylcarbonyl, C2-C6 alkoxycarbonyl, C2-Cg alkylaminoalkyl and C3-C6 dialkylaminoalkyl on nitrogen atom ring members). Similarly, Q2 is, inter alia, a 4-, 5- or 6-membered saturated, partially unsaturated or fully unsaturated heterocyclic ring or an 8- to 10-membered heteroaromatic bicyclic ring system, each ring or ring system containing ring members selected from carbon atoms and up to 4 heteroatoms independently selected from up to 2 O, up to 2 S and up to 4 N atoms, wherein up to 3 carbon atom ring members are independently selected from C(=0) and C(=S), the sulfur atom ring members are independently selected from S(=0)u(=NR14)v, each ring or ring system optionally substituted with up to 5 substituents independently selected from any substituent defined in the Summary of the Invention for Q2. As the substituents on the ring or ring system of Q1 or Q2 are optional, 0 to 5 substituents may be present, limited only by the number of available points of attachment. In these definitions of heterocyclic ring and heteroaromatic ring system, the ring members selected from up to 2 O, up to 2 S and up to 4 N atoms are optional, provided at least one ring member is not carbon (e.g., N, O or S). The definition of S(=0)u(=NR14)v allows the up to 2 sulfur ring members, to be oxidized sulfur moieties (e.g., S(=0) or S(=0)2) or unoxidized sulfur atoms (i.e. when u and v are both zero). The nitrogen atom ring members may be oxidized as N-oxides, because compounds relating to Formula 1 also include N-oxide derivatives. The up to 3 carbon atom ring members selected from C(=0) and C(=S) are in addition to the up to 4 heteroatoms selected from up to 2 O, up to 2 S and up to 4 N atoms. Also as noted above, R1 can be (among others) 5- or 6-membered nitrogen-containing aromatic heterocycle, which may be optionally substituted with one or more substituents selected from a group of substituents as defined in the Summary of Invention.
When R1 is phenyl or a 5- or 6- membered nitrogen-containing aromatic heterocycle, it may be attached to the remainder of Formula 1 through any available carbon or nitrogen ring atom, unless otherwise described. Likewise, the ring or ring system of Q1 or Q2 may be attached to the remainder of Formula 1 through any available carbon or nitrogen ring atom, unless otherwise described.
Examples of a 5- to 6-membered fully unsaturated heterocyclic ring include the rings H-1 through H-39 illustrated in Exhibit 1, and examples of an 8- to 10-membered heteroaromatic bicyclic ring system include the ring systems B-l through B-39 illustrated in Exhibit 2. In Exhibits 1 and 2 the variable Ra is any substituent as defined in the Summary of the Invention for Q1, Q2 or R1 (e.g., a Q1 ring or ring system is optionally substituted with R3 on carbon atom ring members and cyano, C^-Cg alkyl, C2-Cg alkenyl, C2-Cg alkynyl, C3-C6 cycloalkyl, Cj-Cg alkoxy, C2-C6 alkoxyalkyl, C2-C6 alkylcarbonyl, C2-C6 alkoxycarbonyl, C2-Cg alkylaminoalkyl and C3-C6 dialkylaminoalkyl on nitrogen atom ring members) and r is an integer from 0 to 5 for Q1 and Q2 or from 0 to 3 for R1, limited by the number of available positions on each depicted ring or ring system.
Exhibit 1
Figure imgf000013_0001
H-1 H-2 H-3 H-4
Figure imgf000013_0002
H-10 H-l l H-12 H-13 H-14
Figure imgf000013_0003
H-15
H-16 H-17 H-18 H-19
Figure imgf000014_0001
Figure imgf000015_0001
Figure imgf000016_0001
B-31 B-32 B-33
Figure imgf000016_0002
B-34 B-35 B-36
Figure imgf000016_0003
or
B-37 B-38 B-39
Examples of a saturated or partially unsaturated 5- to 6-membered heterocyclic ring include the rings P-1 through P-43 illustrated in Exhibit 3. In Exhibit 3 the variable Ra is any substituent as defined in the Summary of the Invention for Q2 (e.g., a Q2 ring is optionally substituted with R3 on carbon ring members and cyano, Ci -C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, Ci -C6 alkoxy, C2-C6 alkoxyalkyl, C2-C6 alkylcarbonyl, C2-C6 alkoxycarbonyl, C2-Cg alkylaminoalkyl and C3-C6 dialkylaminoalkyl on nitrogen atom ring members) and r is an integer from 0 to 5, limited by the number of available positions on each depicted ring or ring system.
Exhibit 3
Figure imgf000016_0004
P-l P-2 P-3 P-4 P-5
Figure imgf000016_0005
P-6 P-7 P-8 P-9 P-10
Figure imgf000017_0001
P-l l P-12 P-13 P-14 P-15
Figure imgf000017_0002
P-16 P-17 P-18 P-19 P-20
Figure imgf000017_0003
P-21 P-22 P-23 P-24 P-25
Figure imgf000017_0004
P-26 P-27 P-28 P-29 P-30
Figure imgf000017_0005
P-31 P-32 P-33 P-34 P-35
Figure imgf000017_0006
P-41 P-42 P-43 Examples of a 5- or 6-membered nitrogen-containing heterocycle optionally substituted with from one or more substituents of particular note for Q1, Q2 and R1 include the rings U-1 through U-56 illustrated in Exhibit A wherein Ra is any substituent as defined in the Summary of the Invention for Q1 Q2 and R1, respectively (i.e. for Q1 and Q2: R3 on carbon atom ring members, and the recited list of possible substituents on nitrogen atom ring members; and for R1, R9a on carbon ring members and R9^ on nitrogen ring members) and r is an integer ranging from 0 to 4 for Q1 and Q2 and from 0 to 3 for R1, limited by the number of available positions on each U group. Note that some U groups can only be substituted with less than 4 Ra groups (e.g., U-4 through U-43 and U-47 through U-56). As U-24, U-25, U-31, U-32, U-33, U-34, U-35, U-36, U-37 and U-38 have only one available position, for these U groups, r is limited to the integers 0 or 1 , and r being 0 means that the U group is unsubstituted and a hydrogen is present at the position indicated by (Ra)r.
As noted above, Q1, Q2 and R1 can be (among others) phenyl optionally substituted with one or more substituents selected from a group of substituents as defined in the Summary of the Invention. An example of phenyl optionally substituted with one to five substituents is the ring illustrated as U-57 in Exhibit A, wherein Ra is as defined in the Summary of the Invention for R3 or R8 and q is an integer from 0 to 5.
Exhibit A
Figure imgf000018_0001
U-1 U-2 U-3 U-4 U-5
Figure imgf000018_0002
U-l l U-12 U-13 U-14 U-15
Figure imgf000018_0003
U-16 U-17 U-18 U-19 U-20
Figure imgf000019_0001
U-21 U-22 U-23 U-24 U-25
Figure imgf000019_0002
U-36 U-37 U-38 U-39 U-40
Figure imgf000019_0003
U-56 U-57 Although Ra groups are shown in the structures H-l through H-39, B-l through B-39, P-l through P-43, and U-l through U-57 in Exhibits 1 through 3 and Exhibit A, 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 Ra. Note that when the attachment point between (Ra)r and the H, B, P or U group in Exhibits 1 through 3 and Exhibit A is illustrated as floating, (Ra)r can be attached to any available carbon atom or nitrogen atom of the H, B, P or U group. Note that when the attachment point on the H, B or P group in Exhibits 1 through 3 is illustrated as floating, the H, B or P group can be attached to the remainder of Formula 1 through any available carbon or nitrogen of the H, B or P group by replacement of a hydrogen atom.
Examples of where R6 and R7 are taken together to form a four- to seven-membered nonaromatic heterocyclic ring include the rings G-l through G-28 as illustrated in Exhibit 4. Note that when R6 and R7 are taken together to form a ring comprising a ring selected from G-25 through G-28, G2 is selected from O, S(0)n or NR13. Note that when G2 is N, the nitrogen atom can complete its valence by substitution with either H or the substituents corresponding to R13 as defined in the Summary of Invention.
Exhibit 4
Figure imgf000020_0001
G-l l G-12 G-13 G-14
Figure imgf000020_0002
-16 ■ G-17 G-18 G-19 G-20
Figure imgf000021_0001
G-26 G-27 G-28
A wide variety of synthetic methods are known in the art to enable preparation of aromatic and nonaromatic heterocyclic rings and ring systems; for extensive reviews see the eight volume set of Comprehensive Heterocyclic Chemistry, A. R. Katritzky and C. W. Rees editors-in-chief, Pergamon Press, Oxford, 1984 and the twelve volume set of Comprehensive Heterocyclic Chemistry II, A. R. Katritzky, C. W. Rees and E. F. V. Scriven editors-in-chief, Pergamon Press, Oxford, 1996.
Compounds of 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. The compounds of the invention may be present as a mixture of stereoisomers, individual stereoisomers or as an optically active form.
One skilled in the art will appreciate that not all nitrogen-containing heterocycles can form N-oxides since the nitrogen requires an available lone pair for oxidation to the oxide; one skilled in the art will recognize those nitrogen-containing heterocycles which can form N-oxides. One skilled in the art will also recognize that tertiary amines can form N-oxides. Synthetic methods for the preparation of N-oxides of heterocycles and tertiary amines are very well known by one skilled in the art including the oxidation of heterocycles and tertiary amines with peroxy acids such as peracetic and m-chloroperbenzoic acid (MCPBA), hydrogen peroxide, alkyl hydroperoxides such as t-butyl hydroperoxide, sodium perborate, and dioxiranes such as dimethyldioxirane. 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.
One skilled in the art recognizes that some of the compounds disclosed herein can exist in equilibrium with one or more of their respective tautomeric counterparts. Unless otherwise indicated, reference to a compound by one tautomer description is to be considered to include all tautomers.
One skilled in the art recognizes that because in the environment and under physiological conditions salts of chemical compounds are in equilibrium with their corresponding nonsalt forms, salts share the biological utility of the nonsalt forms. Thus a wide variety of salts of the compounds of Formula 1 are useful for control of plant diseases caused by fungal plant pathogens (i.e. are agriculturally suitable). The salts of the compounds of Formula 1 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.
Compounds selected from Formula 1, geometric and stereoisomers, tautomers, N-oxides, and salts thereof, typically exist in more than one form, and Formula 1 thus includes all crystalline and non-crystalline forms of the compounds that Formula 1 represents. Non-crystalline forms include embodiments which are solids such as waxes and gums as well as embodiments which are liquids such as solutions and melts. Crystalline forms include embodiments which represent essentially a single crystal type and embodiments which represent a mixture of polymorphs (i.e. different crystalline types). The term "polymorph" refers to a particular crystalline form of a chemical compound that can crystallize in different crystalline forms, these forms having different arrangements and/or conformations of the molecules in the crystal lattice. Although polymorphs can have the same chemical composition, they can also differ in composition due the presence or absence of co-crystallized water or other molecules, which can be weakly or strongly bound in the lattice. Polymorphs can differ in such chemical, physical and biological properties as crystal shape, density, hardness, color, chemical stability, melting point, hygroscopicity, suspensibility, dissolution rate and biological availability. One skilled in the art will appreciate that a polymorph of a compound represented by Formula 1 can exhibit beneficial effects (e.g., suitability for preparation of useful formulations, improved biological performance) relative to another polymorph or a mixture of polymorphs of the same compound represented by Formula 1. Preparation and isolation of a particular polymorph of a compound represented by Formula 1 can be achieved by methods known to those skilled in the art including, for example, crystallization using selected solvents and temperatures. Embodiments of the present invention as described in the Summary of the Invention include (where Formula 1 as used in the following Embodiments includes N-oxides and salts thereof):
Embodiment 1. A compound of Formula 1 wherein X is O or NR4.
Embodiment 2. A compound of Formula 1 wherein X is NR4 or CR15R16.
Embodiment 3. A compound of Formula 1 wherein X is O or CR15R16.
Embodiment 4. A compound of Embodiment 1 or 3 wherein X is O.
Embodiment 5. A compound of Embodiment 1 or 2 wherein X is NR4.
Embodiment 6. A compound of Embodiment 2 or 3 wherein X is CR15R16.
Embodiment 7. A compound of Formula 1 or any one of Embodiments 1 through 6 wherein when Q1 is a six-membered ring (e.g., phenyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl) and an R3 substituent is located at a meta position (relative to the connection of the Q1 ring to the remainder of Formula 1), then said R3 substituent is selected from F, CI, Br and cyano (-CN).
Embodiment 8. A compound of Formula 1 or any one of Embodiments 1 through 7 wherein when Q1 is a six-membered ring and an R3 substituent is located at a meta position (relative to the connection of the Q1 ring to the remainder of Formula 1), then said R3 substituent is F.
Embodiment 9. A compound of Formula 1 or any one of Embodiments 1 through 8 wherein when Q1 is a six-membered ring (e.g., phenyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl) substituted with only one R3 substituent, then said R3 substituent is attached at an ortho position (relative to the connection of the Q1 ring to the remainder of Formula 1).
Embodiment 10. A compound of Formula 1 or any one of Embodiments 1 through 9 wherein Q1 is phenyl, thienyl, pyridinyl, pyridazinyl, pyrazinyl, pyrimidinyl, naphthalenyl, quinolinyl, isoquinolinyl or quinoxalinyl, each optionally substituted with up to 5 substituents independently selected from R3.
Embodiment 11. A compound of Embodiment 10 wherein Q1 is phenyl, thienyl,
pyridinyl, pyridazinyl, pyrazinyl or pyrimidinyl, each optionally substituted with up to 5 substituents independently selected from R3.
Embodiment 12. A compound of Embodiment 11 wherein Q1 is phenyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl, each substituted with from 1 to 4 substituents independently selected from R3.
Embodiment 13. A compound of Embodiment 12 wherein Q1 is phenyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl, each substituted with 1, 2 or 3 substituents independently selected from R3.
Embodiment 14. A compound of Embodiment 13 wherein the substituents are located at the ortho and/or para positions (relative to the connection of the Q1 ring to the remainder of Formula 1) of the phenyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl of Q1.
Embodiment 15. A compound of Embodiment 13 or 14 wherein Q1 is phenyl or
pyridinyl, each substituted with 1 , 2 or 3 substituents independently selected from R3.
Embodiment 16. A compound of Embodiment 15 wherein Q1 is phenyl or pyridinyl, each substituted with 2 or 3 substituents independently selected from R3.
Embodiment 17. A compound of Embodiment 16 wherein Q1 is phenyl substituted at the 2-, 4- and 6-positions with substituents independently selected from R3; or phenyl substituted at the 2- and 4-positions with substituents independently selected from R3; or phenyl substituted at the 2- and 6-positions with substituents independently selected from R3.
Embodiment 18. A compound of Embodiment 17 wherein Q1 is phenyl substituted at the 2-, 4- and 6-positions with substituents independently selected from R3; or phenyl substituted at the 2- and 4-positions with substituents independently selected from R3.
Embodiment 19. A compound of Embodiment 17 wherein Q1 is phenyl substituted at the 2-, 4- and 6-positions with substituents independently selected from R3.
Embodiment 20. A compound of Embodiment 17 wherein Q1 is phenyl substituted at the 2- and 4-positions with substituents independently selected from R3.
Embodiment 21. A compound of Embodiment 17 wherein Q1 is phenyl substituted at the 2- and 6-positions with substituents independently selected from R3.
Embodiment 22. A compound of Embodiment 15 wherein Q1 is pyridinyl substituted with 1, 2 or 3 substituents independently selected from R3.
Embodiment 23. A compound of Embodiment 22 wherein Q1 is pyridinyl substituted with 1 or 2 substituents independently selected from R3.
Embodiment 24. A compound of Embodiment 23 wherein Q1 is pyridinyl substituted with 1 substituent independently selected from R3.
Embodiment 25. A compound of Formula 1 or any one of Embodiments 1 through 24 wherein Q2 is a phenyl ring or a naphthalenyl ring system, each ring or ring system optionally substituted with up to 5 substituents independently selected from R3; or a 5- to 6-membered saturated, partially unsaturated or fully unsaturated heterocyclic ring or an 8- to 10-membered heteroaromatic bicyclic ring system, each ring or ring system containing ring members selected from carbon atoms and up to 4 heteroatoms independently selected from up to 2 O, up to 2 S and up to 4 N atoms, wherein up to 3 carbon ring members are
independently selected from C(=0) and C(=S), and the sulfur atom ring members are independently selected from S(=0)u(=NR14)v, each ring or ring system optionally substituted with up to 5 substituents independently selected from R3 on carbon atom ring members and selected from cyano, C^-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C^-C6 alkoxy, C2-C6 alkoxyalkyl, C2-C6 alkylcarbonyl, C2-C6 alkoxycarbonyl, C2-C6
alkylaminoalkyl and C3-C6 dialkylaminoalkyl on nitrogen atom ring members; or C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C3-C12 cycloalkyl or C3-C12 cycloalkenyl, each optionally substituted with up to 5 substituents independently selected from R3.
Embodiment 25a. A compound of Formula 1 or any one of Embodiments 1 through 25 wherein when Q2 is a six-membered ring (e.g., phenyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl) and an R3 substituent is located at a meta position (relative to the connection of the Q2 ring to the remainder of Formula 1), then said R3 substituent is selected from F, CI, Br and cyano (-CN).
Embodiment 26. A compound of Formula 1 or any one of Embodiments 1 through 25 a wherein when Q2 is a six-membered ring and an R3 substituent is located at a meta position (relative to the connection of the Q2 ring to the remainder of Formula 1), then said R3 substituent is F.
Embodiment 27. A compound of Formula 1 or any one of Embodiments 1 through 26 wherein when Q2 is a six-membered ring (e.g., phenyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl) substituted with only one R3 substituent, then said R3 substituent is attached at an ortho position (relative to the connection of the Q2 ring to the remainder of Formula 1).
Embodiment 28. A compound of Formula 1 or any one of Embodiments 1 through 27 wherein Q2 is phenyl, thienyl, pyridinyl, pyridazinyl, pyrazinyl, pyrimidinyl, naphthalenyl, quinolinyl, isoquinolinyl or quinoxalinyl, each optionally substituted with up to 5 substituents independently selected from R3.
Embodiment 29. A compound of Embodiment 28 wherein Q2 is phenyl, thienyl,
pyridinyl, pyridazinyl, pyrazinyl or pyrimidinyl, each optionally substituted with up to 5 substituents independently selected from R3.
Embodiment 30. A compound of Embodiment 29 wherein Q2 is phenyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl, each substituted with from 1 to 4 substituents independently selected from R3.
Embodiment 31. A compound of Embodiment 30 wherein Q2 is phenyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl, each substituted with 1 , 2 or 3 substituents independently selected from R3.
Embodiment 32. A compound of Embodiment 31 wherein the substituents are located at the ortho and/or para positions (relative to the connection of the Q2 ring to the remainder of Formula 1) of the phenyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl of Q2.
Embodiment 33. A compound of any one of Embodiments 31 or 32 wherein Q2 is
phenyl or pyridinyl, each substituted with 1, 2 or 3 substituents independently selected from R3.
Embodiment 34. A compound of Embodiment 33 wherein Q2 is phenyl substituted with
1, 2 or 3 substituents independently selected from R3.
Embodiment 35. A compound of Embodiment 34 wherein Q2 is phenyl substituted at the 2-, 4- and 6-positions with substituents independently selected from R3; or phenyl substituted at the 2- and 4-positions with substituents independently selected from R3; or phenyl substituted at the 2- and 6-positions with substituents independently selected from R3.
Embodiment 36. A compound of Embodiment 35 wherein Q2 is phenyl substituted at the 2-, 4- and 6-positions with substituents independently selected from R3. Embodiment 37. A compound of Embodiment 35 wherein Q2 is phenyl substituted at the 2- and 4-positions with substituents independently selected from R3.
Embodiment 38. A compound of Embodiment 35 wherein Q2 is phenyl substituted at the 2- and 6-positions with substituents independently selected from R3.
Embodiment 39. A compound of Embodiment 33 wherein Q2 is pyridinyl substituted with 1, 2 or 3 substituents independently selected from R3.
Embodiment 40. A compound of Embodiment 39 wherein Q2 is pyridinyl substituted with 1 or 2 subsituents independently selected from R3.
Embodiment 41. A compound of Embodiment 40 wherein Q2 is pyridinyl substituted with 1 substituent selected from R3.
Embodiment 42. A compound of Formula 1 or any one of Embodiments 1 through 41 wherein at least one of Q1 and Q2 is phenyl optionally substituted with R3 (e.g., optionally substituted with up to 5 substituents independently selected from R3). Embodiment 43. A compound of Embodiment 42 wherein at least one of Q1 and Q2 is phenyl substituted with 2, 3 or 4 substituents independently selected from R3. Embodiment 44. A compound of Embodiment 43 wherein at least one Q1 and Q2 is phenyl substituted with 2 or 3 substituents independently selected from R3. Embodiment 45. A compound of Embodiment 44 wherein each of Q1 and Q2 is phenyl substituted with 2 or 3 substituents independently selected from R3.
Embodiment 45 a. A compound of Embodiment 44 wherein Q1 is phenyl substituted with 2 or 3 substituents independently selected from R3, and Q2 is phenyl substituted with 1 or 2 substituents independently selected from R3.
Embodiment 46. A compound of Formula 1 or any one of Embodiments 1 through 45 a wherein R1 is H, halogen, Ci~C6 alkyl, Ci~C6 haloalkyl, C02R5, C(0)NR6R7, cyano, C^-Cg alkoxy, C^-Cg haloalkoxy or C2-C5 alkoxyalkyl, or a five- or six- membered nitrogen-containing aromatic heterocycle optionally substituted with up to 3 substituents independently selected from R9a on carbon atom ring members and R9^ on nitrogen atom ring members; or R1 and Rla are taken together with the carbon atom to which they are attached to form a cyclopropyl ring optionally substituted with up to 2 substituents independently selected from halogen and methyl.
Embodiment 47. A compound of Embodiment 46 wherein when R1 is taken alone (i.e.
R1 is not taken together with Rla to form an optionally substituted cyclopropyl ring), then R1 is H, halogen, -Cg alkyl, -Cg haloalkyl, cyano, -Cg alkoxy or C^-Cg haloalkoxy; or R1 is pyridinyl, pyrimidinyl, pyrazolyl or oxazolyl, each optionally substituted with up to 3 substituents independently selected from R9a on carbon atom ring members and R9^ on nitrogen atom ring members.
Embodiment 48. A compound of Formula 1 or any one of Embodiments 1 through 47 wherein R1 is other than an optionally substituted phenyl or an optionally substituted five- or six-membered nitrogen-containing aromatic heterocycle. Embodiment 49. A compound of Embodiment 47 wherein when R1 is taken alone, then R1 is H, halogen, -Cg alkyl, -Cg haloalkyl, C02R5, C(0)NR6R7, cyano, C^-Cg alkoxy, C^-Cg haloalkoxy or C2-C5 alkoxyalkyl.
Embodiment 50. A compound of Embodiment 49 wherein when R1 is taken alone, then R1 is H, halogen, -Cg alkyl, -Cg haloalkyl, C(0)NR6R7, cyano, -Cg alkoxy, C^-Cg haloalkoxy or C2-C5 alkoxyalkyl.
Embodiment 51. A compound of Embodiment 50 wherein when R1 is taken alone, then R1 is H, halogen, C^-Cg alkyl, C^-Cg haloalkyl, cyano, C^-Cg alkoxy, C^-Cg haloalkoxy or C2-C5 alkoxyalkyl.
Embodiment 52. A compound of Embodiment 51 wherein when R1 is taken alone, then
R1 is H, halogen, C1-C3 alkyl or C1-C2 haloalkyl.
Embodiment 53. A compound of Embodiment 52 wherein when R1 is taken alone, then R1 is H, halogen or -C3 alkyl.
Embodiment 54. A compound of Formula 1 or any one of Embodiments 1 through 53 wherein when R1 and R2 are taken together with the carbon to which they are attached to form a cyclopropyl ring, said cyclopropyl ring is unsubstituted (except for the bond to the pyrazole nitrogen atom).
Embodiment 55. A compound of Formula 1 or any one of Embodiments 1 through 53 wherein Rla is H (i.e. R1 and Rla are not taken together to form substituted or unsubstituted cyclopropyl ring).
Embodiment 56. A compound of Embodiment 55 wherein R1 is H or CH3. Embodiment 57. A compound of Embodiment 56 wherein R1 is H.
Embodiment 58. A compound of Formula 1 or any one of Embodiments 1 through 57 wherein R2 is H, alkenyl or alkynyl.
Embodiment 59. A compound of Embodiment 58 wherein R2 is H.
Embodiment 60. A compound of Formula 1 or any one of Embodiments 1 through 57 wherein R2 is C2-C3 alkenyl or C2-C3 alkynyl.
Embodiment 61. A compound of Embodiment 58 or 60 wherein R2 is alkenyl or alkynyl.
Embodiment 62. A compound of Embodiment 60 wherein R2 is C2-C3 alkenyl.
Embodiment 63. A compound of Embodiment 60 wherein R2 is C2-C3 alkynyl.
Embodiment 64. A compound of Formula 1 or any one of Embodiments 1 through 63 wherein R5 is H or C^-C6 alkyl.
Embodiment 65. A compound of Embodiment 64 wherein R5 is H or C^-C6 alkyl. Embodiment 66. A compound of Embodiment 65 wherein R5 is C^-C6 alkyl.
Embodiment 67. A compound of Embodiment 66 wherein R5 is CH3 or CH2CH3.
Embodiment 68. A compound of Formula 1 or any one of Embodiments 1 through 67 wherein when R6 is separate (i.e. not taken together with R7 to form a ring), then R6 is H or C!-C6 alkyl.
Embodiment 69. A compound of Embodiment 68 wherein R6 is H.
Embodiment 70. A compound of Formula 1 or any one of Embodiments 1 through 69 wherein when R7 is separate (i.e. not taken together with R6 to form a ring), then R7 is H, Ci~C6 alkyl, Ci~C6 haloalkyl or C4-C8 alkylcycloalkyl.
Embodiment 71. A compound of Embodiment 70 wherein R7 is H or C^-C6 alkyl. Embodiment 72. A compound of Embodiment 71 wherein R7 is H.
Embodiment 73. A compound of Formula 1 or any one of Embodiments 1 through 72 wherein when R6 and R7 are taken together with the nitrogen atom to which they are connected to form a nonaromatic heterocyclic ring, the ring contains ring members, in addition to the connecting nitrogen atom, selected from carbon atoms and up to one ring member selected from O and NR13.
Embodiment 74. A compound of Embodiment 73 wherein when R6 and R7 are taken together with the nitrogen atom to which they are connected to form a nonaromatic heterocyclic ring, the ring is six-membered and contains one ring member selected from O and NR13 in addition to the connecting nitrogen atom and ring members selected from carbon atoms.
Embodiment 75. A compound of Embodiment 73 wherein R6 and R7 are taken together with the nitrogen atom to which they are connected to form a piperidine ring. Embodiment 76. A compound of Embodiment 74 wherein R6 and R7 are taken together with the nitrogen atom to which they are connected to form a piperazine or morpholine ring.
Embodiment 77. A compound of Formula 1 or any one of Embodiments 1 through 76 wherein each R8 is independently selected from halogen, C1-C2 alkyl, C1-C2 haloalkyl, C1-C2 alkoxy, C1-C2 haloalkoxy, cyano and nitro.
Embodiment 78. A compound of Embodiment 77 wherein each R8 is independently selected from halogen, C1-C2 alkyl, Ci~C2 alkoxy, cyano and nitro.
Embodiment 79. A compound of Embodiment 78 wherein each R8 is independently CI or F.
Embodiment 80. A compound of Formula 1 or any one of Embodiments 1 through 79 wherein each R9a is independently selected from halogen, C1-C2 alkyl, C1-C2 haloalkyl, C1-C2 alkoxy, C1-C2 haloalkoxy, cyano and nitro.
Embodiment 81. A compound of Embodiment 80 wherein each R9a is independently selected from halogen, C1-C2 alkyl, C1-C2 alkoxy, cyano and nitro.
Embodiment 82. A compound of Embodiment 81 wherein each R9a is independently selected from CI, F, CH3, -OCH3 and cyano.
Embodiment 83. A compound of Embodiment 82 wherein each R9a is independently CI or F.
Embodiment 84. A compound of Formula 1 or any one of Embodiments 1 through 83 wherein each R9^ is independently C1-C2 alkyl.
Embodiment 85. A compound of Formula 1 or any one of Embodiments 1 through 84 wherein each R3 is independently selected from halogen, cyano, nitro, amino, methylamino, dimethylamino, formylamino, C2-C3 alkylcarbonylamino, C1-C4 alkyl, C1-C4 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 alkylthio, C^-
C3 haloalkylthio, C1-C3 alkylsulfinyl, C1-C3 haloalkylsulfmyl, C1-C3 alkylsulfonyl, C1-C3 haloalkylsulfonyl, C1-C2 alkylsulfonyloxy, Ci~C2
haloalkylsulfonyloxy, C3-C4 cycloalkyl, C3-C7 cycloalkoxy, C4-C6
alkylcycloalkyl, C4-C6 cycloalkylalkyl, C3-C7 halocycloalkyl, C2-C4 alkenyl, C2-C4 alkynyl, hydroxy, formyl, C2-C3 alkylcarbonyl, C2-C3 alkylcarbonyloxy,
-SF5, -SCN, C(=S)NR19R20 or -U-V-T.
Embodiment 85a. A compound of Formula 1 or any one of Embodiments 1 through 85 wherein each R3 is independently selected from halogen, cyano, nitro, amino, methylamino, dimethylamino, C1-C4 alkyl, C1-C4 haloalkyl, C1-C3 alkoxy, 1-C3 haloalkoxy, C1-C3 alkylthio, C1-C3 haloalkylthio, C1-C3 alkylsulfinyl,
C1-C3 haloalkylsulfinyl, C1-C3 alkylsulfonyl, C1-C3 haloalkylsulfonyl, C3-C4 cycloalkyl, C(=S)NH2 and -U-V-T. Embodiment 86. A compound of Embodiment 85a wherein each R3 is independently selected from halogen, cyano, nitro, C1-C4 alkyl, C1-C4 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy and -U-V-T.
Embodiment 87. A compound of Embodiment 86 wherein each R3 is independently selected from F, CI, Br, cyano, nitro, CH3, CF3, -OCH3, -OCHF2 and -U-V-T.
Embodiment 88. A compound of Formula 1 or any one of Embodiments 1 through 87 wherein at least one R3 substituent on the ring or ring system of Q1 or Q2 is
-U-V-T.
Embodiment 89. A compound of Formula 1 or any one of Embodiments 1 through 87 wherein each R3 is other than -U-V-T.
Embodiment 90. A compound of Embodiment 89 wherein each R3 is independently selected from halogen, cyano, nitro, C1-C4 alkyl, C1-C4 haloalkyl, C1-C3 alkoxy and C1-C3 haloalkoxy.
Embodiment 91. A compound of Embodiment 90 wherein each R3 is independently selected from halogen, cyano, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy and
C1-C3 haloalkoxy.
Embodiment 92. A compound of Embodiment 91 wherein each R3 is independently selected from F, CI, Br, cyano, C1-C2 alkyl, C1-C2 haloalkyl, Ci~C2 alkoxy and C1-C2 haloalkoxy.
Embodiment 93. A compound of Embodiment 92 wherein each R3 is independently selected from F, CI, Br, cyano, methyl, C1-C2 alkoxy and difluoromethoxy. Embodiment 94. A compound of Embodiment 93 wherein each R3 is independently selected from F, CI, Br, cyano, methyl and methoxy.
Embodiment 95. A compound of Embodiment 94 wherein each R3 is independently selected from F, CI, Br and cyano.
Embodiment 96. A compound of Embodiment 95 wherein each R3 is independently selected from F, CI and Br.
Embodiment 97. A compound of Formula 1 or any one of Embodiments 1 through 88 wherein each U is independently O or NR22.
Embodiment 98. A compound of Embodiment 97 wherein each U is independently O or
NH.
Embodiment 99. A compound of Formula 1 or any one of Embodiments 1 through 88 and 97 through 98 wherein each V is C2-C4 alkylene.
Embodiment 100. A compound of Formula 1 or any one of Embodiments 1 through 88 and 97 through 99 wherein each T is independently NR23aR23^ or OR24.
Embodiment 101. A compound of Formula 1 or any one of Embodiments 1 through 88 and 97 through 100 wherein each R23a and R23^ is independently H, C^-C6 alkyl or Ci-C haloalkyl. Embodiment 102. A compound of Formula 1 or any one of Embodiments 1 through 88 and 97 through 101 wherein each R24 is independently H, Ci~C6 alkyl or Ci~C6 haloalkyl.
Embodiment 103. A compound of Formula 1 or any one of Embodiments 1 through 102 wherein when an R3 substituent attached to phenyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl of Q^or Q2 is other than F, CI, Br, cyano, methyl, C^-
C2 alkoxy and fluoromethoxy, then said R3 substituent is attached at the para position (of the phenyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl ring). Embodiment 104. A compound of Formula 1 or any one of Embodiments 1 through 103 wherein R4 is H, formyl, C3-C7 cycloalkyl or -SR10; or Ci~C6 alkyl or -Cg haloalkyl, each optionally substituted with up to 2 R12.
Embodiment 105. A compound of Embodiment 104 wherein R4 is H, formyl, C3-C7 cycloalkyl or -SR10; or -Cg alkyl substituted with one R12.
Embodiment 106. A compound of Embodiment 105 wherein R4 is H, formyl,
-CH2OCH3, cyclopropyl, -SCH3, -SCF3 or -CH2CN.
Embodiment 107. A compound of Embodiment 106 wherein R4 is H, formyl,
cyclopropyl or -CH2CN.
Embodiment 108. A compound of Embodiment 107 wherein R4 is H.
Embodiment 109. A compound of Formula 1 or any one of Embodiments 1 through 108 wherein R13 is H or CH3.
Embodiment 110. A compound of Embodiment 109 wherein R13 is CH3.
Embodiment 111. A compound of Formula 1 or any one of Embodiments 1 through 110 wherein each R12 is independently C3-C7 cycloalkyl, C1-C4 alkoxy or cyano. Embodiment 112. A compound of Embodiment 111 wherein each R12 is independently cyclopropyl, -OCH3 or cyano.
Embodiment 113. A compound of Formula 1 or any one of Embodiments 1 through 112 wherein R10 is CH3, CH2CH3, CF3 or CF2CF3.
Embodiment 114. A compound of Embodiment 113 wherein R10 is CH3.
Embodiment 115. A compound of Formula 1 or any one of Embodiments 1 through 114 wherein each R1 1 is independently Cj-Cg alkyl, Cj-Cg alkoxy, C2-C7 alkoxyalkyl, C2-C7 alkylaminoalkyl, C2-Cg dialkylaminoalkyl, C^-Cg alkylthio or C2-C7 alkylthioalkyl.
Embodiment 115a. A compound of Formula 1 or any one of Embodiments 1 through
115 wherein R1 1 is C^-Cg alkyl, C^-Cg alkoxy or C^-Cg alkylthio.
Embodiment 116. A compound of Embodiment 115a wherein R1 1 is CH3, CH2CH3,
-OCH3, -OCH2CH3, -SCH3 or -SCH2CH3.
Embodiment 117. A compound of Embodiment 116 wherein R1 1 is CH3, -OCH3 or
-SCH3. Embodiment 118. A compound of Formula 1 or any one of Embodiments 1 through 117 wherein R15 is H or CH3.
Embodiment 119. A compound of Embodiment 118 wherein R15 is H.
Embodiment 120. A compound of Formula 1 or any one of Embodiments 1 through 119 wherein R16 is F or OR18.
Embodiment 121. A compound of Embodiment 120 wherein R16 is OR18.
Embodiment 122. A compound of Formula 1 or any one of Embodiments 1 through 121 wherein R18 is H.
Embodiment 123. A compound of Formula 1 or any one of Embodiments 1 through 122 wherein W is O.
Embodiment 124. A compound of Formula 1 or any one of Embodiments 1 through 123 wherein M+ is a cation selected from sodium, potassium and lithium ions.
Embodiment 125. A compound of Embodiment 124 wherein M+ is a cation selected from sodium and potassium ions.
Embodiment 126. A compound of Embodiment 125 wherein M+ is a sodium ion.
Embodiment 127. A compound of Formula 1 or any one of Embodiments 1 through 126 wherein n is 0.
Embodiment 128. A compound of Formula 1 or any one of Embodiments 1 through 127 wherein when Q2 comprises a phenyl ring substituted with nitro on at least one ortho position, then X is O or CR15R16.
Embodiment 129. A compound of Embodiment 128 wherein all instances of R3 are other than nitro.
Embodiment 130. A compound of Embodiment 128 wherein when Q2 comprises a
2-pyridinyl ring or when Q2 comprises a phenyl ring substituted on at least one ortho position with nitro, halogen or haloalkyl, then X is O or CR15R16.
Embodiment 131. A compound of Formula 1 or any one of Embodiments 1 through 130 wherein when Q2 comprises a 6-membered ring substituted on at least one ortho position with a substituent selected from -U-V-T wherein U is a direct bond, V is C(=0) and T is NR23aR23b or OR24, then X is O or CR15R16.
Embodiment 132. A compound of Formula 1 or any one of Embodiments 1 through 131 wherein when Q2 comprises a 6-membered heterocyclic ring substituted on at least one meta position with a substituent selected from -U-V-T wherein U is a direct bond, V is C(=0) and T is NR23aR23b, then X is NR4 or CR15R16.
Embodiment 133. A compound of Formula 1 or any one of Embodiments 1 through 132 wherein when Q2 comprises a 6-membered heterocyclic ring substituted on at least one meta position with C2-C4 alkynyl, then X is NR4 or CR15R16. Embodiment 134. A compound of Formula 1 or any one of Embodiments 1 through 133 wherein when Q2 comprises an imidazopyrazine ring system, then X is O or CR15R16.
Embodiment 135. A compound of Formula 1 or any one of Embodiments 1 through 134 wherein when Q2 comprises a tetrahydropyrimidine ring, then X is O or
CR15R16.
Embodiment 136. A compound of Formula 1 or any one of Embodiments 1 through 135 wherein when Q1 comprises a phenyl ring, then said ring is not substituted by cyano.
Embodiment 137. A compound of Formula 1 or any one of Embodiments 1 through 136 wherein when Q1 comprises a 6-membered heterocyclic ring, then X is O or CR15R16.
Embodiment 138. A compound of Formula 1 or any one of Embodiments 1 through 137 wherein when Q1 comprises a phenyl ring substituted at the para position with alkylthio, haloalkylthio, alkylsulfmyl, haloalkylsulfmyl, alkylsulfonyl or haloalkylsulfonyl, then X is NR4 or CR15R16.
Embodiment 139. A compound of Formula 1 or any one of Embodiments 1 through 138 wherein when Q1 comprises a 4-pyridinyl or 4-pyrimidinyl ring substituted at the 2-position (according to standard pyridine and pyrimidine ring numbering) with methylamino, then X is O or CR15Rl 6.
Embodiment 140. A compound of Embodiment 139 wherein when Q1 comprises a 4- pyridinyl or 4-pyrimidinyl ring substituted at the 2-position with amino, methylamino or dimethylamino, then X is O or CR15R16.
Embodiment 141. A compound of Formula 1 or any one of Embodiments 1 through 140 wherein each R27 is independently H or C1-C2 alkyl.
Embodiment 142. A compound of Formula 1 or any one of Embodiments 1 through 141 wherein each R28 is H or C1-C2 alkyl.
Embodiments of this invention, including Embodiments 1-142 above as well as any other embodiments described herein, can be combined in any manner, and the descriptions of variables in the embodiments pertain not only to the compounds of Formula 1 but also to the starting compounds and intermediate compounds useful for preparing the compounds of Formula 1. In addition, embodiments of this invention, including Embodiments 1-142 above as well as any other embodiments described herein, and any combination thereof, pertain to the compositions and methods of the present invention.
Combinations of Embodiments 1-142 are illustrated by:
Embodiment A. A compound of Formula 1 wherein
Q1 is phenyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl, each substituted with from 1 to 4 substituents independently selected from R3; provided that when an R3 substituent is located at a meta position, then said R3 substituent is selected from F, CI, Br and cyano;
Q2 is phenyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl, each substituted with
1, 2 or 3 substituents independently selected from R3, provided that when an R3 substituent is located at a meta position, then said R3 substituent is selected from F, CI, Br and cyano;
R1 is H, halogen, -Cg alkyl, -Cg haloalkyl, C02R5, C(0)NR6R7, cyano, Cr
Cg alkoxy, C^-Cg haloalkoxy or C2-C5 alkoxyalkyl;
Rla is H; or
R1 and Rla are taken together with the carbon atom to which they are attached to form a cyclopropyl ring optionally substituted with up to 2 substituents independently selected from halogen and methyl;
each R3 is independently selected from halogen, cyano, nitro, amino, methylamino, dimethylamino, C1-C4 alkyl, C1-C4 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy C1-C3 alkylthio, C1-C3 haloalkylthio, C1-C3 alkylsulfinyl, C^-
C3 haloalkylsulfinyl, C1-C3 alkylsulfonyl, C1-C3 haloalkylsulfonyl, C3-C4 cycloalkyl, C(=S)NH2 and -U-V-T;
R4 is H, formyl, C3-C7 cycloalkyl or -SR10; or -C alkyl or -Cg haloalkyl, each optionally substituted with up to 2 R12;
R5 is Ci-Cg alkyl;
R6 is H or -Cg alkyl;
R7 is H, Cj-Cg alkyl, -Cg haloalkyl or C4-C8 alkylcycloalkyl; or
R6 and R7 are taken together with the nitrogen atom to which they are connected to form a four- to seven-membered nonaromatic heterocyclic ring containing ring members, in addition to the connecting nitrogen atom, selected from carbon atoms and up to one ring member selected from O and NR13; each R12 is independently C3-C7 cycloalkyl, C1-C4 alkoxy or cyano;
R13 is H or CH3;
R15 is H or CH3; and
R16 is OR18.
Embodiment B. A compound of Embodiment A wherein
Q1 is phenyl or pyridinyl, each substituted with 1, 2 or 3 substituents independently selected from R3;
Q2 is phenyl or pyridinyl, each substituted with 1 , 2 or 3 substituents independently selected from R3;
R1 is H, halogen, C1-C3 alkyl or C1-C2 haloalkyl;
Rla is H; or R1 and Rla are taken together with the carbon atom to which they are attached to form a cyclopropyl ring;
R2 is H;
each R3 is independently selected from halogen, cyano, nitro, C1-C4 alkyl, C1-C4 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy and -U-V-T;
R4 is H, formyl, C3-C7 cycloalkyl or -SR10; or Ci~C6 alkyl substituted with one R12;
each R12 is independently cyclopropyl, -OCH3 or cyano;
R15 is H;
each U is independently O or NH;
each V is C2-C4 alkylene;
each T is independently NR23aR23b or OR24;
each R23a and R23b is independently H, C^-C6 alkyl or C^-C6 haloalkyl; and each R24 is independently H, C^-C6 alkyl or C^-C6 haloalkyl.
Embodiment C. A compound of Embodiment B wherein
at least one of Q1 and Q2 is phenyl substituted with 2 or 3 substituents
independently selected from R3;
R1 is H or CH3;
Rla is H;
R4 is H;
each R3 is independently selected from halogen, cyano, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy and C1-C3 haloalkoxy; and
R18 is H.
Embodiment D. A compound of Embodiment C wherein
Q1 is phenyl substituted at the 2-, 4- and 6-positions with substituents
independently selected from R3; or phenyl substituted at the 2- and 4- positions with substituents independently selected from R3; or phenyl substituted at the 2- and 6-positions with substituents independently selected from R3;
Q2 is phenyl substituted at the 2-, 4- and 6-positions with substituents
independently selected from R3; or phenyl substituted at the 2- and 4- positions with substituents independently selected from R3; or phenyl substituted at the 2- and 6-positions with substituents independently selected from R3;
X is O or NR4;
R1 is H; and
each R3 is independently selected from F, CI, Br, cyano, C1-C2 alkyl, C1-C2 haloalkyl, C1-C2 alkoxy and C1-C2 haloalkoxy. Embodiment E. A compound of Embodiment D wherein
each R3 is independently selected from F, CI, Br, cyano, methyl and methoxy. Specific embodiments include compounds of Formula 1 selected from the group consisting of:
N,4-bis(2-chloro-4-fluorophenyl)-l -methyl- lH-pyrazol-5-amine (Compound 1).
This invention provides a fungicidal composition comprising a compound of Formula 1 (including all geometric and stereoisomers, N-oxides, and salts thereof), and at least one other fungicide. Of note as embodiments of such compositions are compositions comprising a compound corresponding to any of the compound embodiments described above.
This invention provides a fungicidal composition comprising a compound of Formula
1 (including all geometric and stereoisomers, N-oxides, and salts thereof) (in a fungicidally effective amount), and at least one additional component selected from the group consisting of surfactants, solid diluents and liquid diluents. Of note as embodiments of such compositions are compositions comprising a compound corresponding to any of the compound embodiments described above.
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, a fungicidally effective amount of a compound of Formula 1 (including all geometric and stereoisomers, N-oxides, and salts thereof). Of note as embodiment of such methods are methods comprising applying a fungicidally effective amount of a compound corresponding to any of the compound embodiments described above. Of particular note are embodiments where the compounds are applied as compositions of this invention.
Of special note are the compounds of Formula 1 as described in the Summary of the Invention or any one of Embodiments 1-142 or A-E or any other embodiments described herein, fungicidal compositions comprising one or more of said compounds, and methods for controlling plant diseases by applying one or more of said compounds, wherein Q2 is other than an optionally substituted 4-membered heterocyclic ring, each R3 is other than C(=NOR27)R28; and each R1 1 is other than -Cg haloalkyl and C3-C6 cycloalkyl.
One or more of the following methods and variations as described in Schemes 1-23 can be used to prepare the compounds of Formula 1. The definitions of Q1, Q2, R1 and R2 in the compounds of Formulae 1-31 below are as defined above in the Summary of the Invention unless otherwise noted. Formulae la, lb, lc, Id, le, If, lg and lh are various subsets of Formula 1; Formulae 2a and 2b are various subsets of Formula 2; Formulae 8a and 8b are various subsets of Formula 8; Formulae 12a, 12b and 12c are various subsets of Formula 12. Substituents for each subset formula are as defined for its parent formula unless otherwise noted.
As shown in Scheme 1, compounds of Formula 1 wherein R2 is Η can be prepared by hydrogeno lysis of compounds of Formula 2 with hydrogen in the presence of a catalyst such as palladium. This type of transformation is well known in the literature and typical conditions for carrying out this hydrogenolysis can be found in German Patent Publication DE 19619112 Al .
Scheme 1
Figure imgf000037_0001
As shown in Scheme 2, compounds of Formula 1 wherein R2 is C2-C3 alkenyl or C2- C3 alkynyl can be prepared by reacting compounds of Formula 2 with organometallics of Formula 3, in which M is, for example, B(OH)2 or esters thereof, ZnCl, ZnBr, MgCl, MgBr, SnMe3 or SnBu3. Alternatively, compounds of Formula 1 wherein R2 is C2-C3 alkenyl or C2-C3 alkynyl can be prepared by reacting compounds of Formula 2 with C2-C3 alkenes or C2-C3 alkynes of Formula 4 in the presence of a palladium catalyst such as tetrakis(triphenylphosphine)Pd(0), dichloro[ 1 , 1 '-bis(diphenylphosphino)ferrocene]palladium or Pd(OAc)2, optionally with the addition of copper(I) salts such as cuprous iodide, and advantageously in the presence of a base such as triethylamine, sodium acetate, potassium carbonate or sodium tert-butoxide. Procedures of this type may be found in PCT Patent Publications WO 2010/093885 and WO 2011/076725.
Scheme 2
R2-M or
1
R2-H
is C2-C3 alkenyl
4 C2-C3 alkynyl
Pd catalyst
Optional Cu(I)
Base
As shown in Scheme 3, compounds of Formula 2 can be prepared by reacting compounds of Formula 5 with compounds of Formula 6 using transition-metal-catalyzed cross-coupling reaction conditions. Reaction of a 4-iodopyrazole of Formula 5 with a boronic acid, trialkyltin, zinc or organomagnesium reagent of Formula 6 in the presence of a palladium or nickel catalyst having appropriate ligands (e.g., triphenylphosphine (PPh3), dibenzylideneacetone (dba), dicyclohexyl(2',6'-dimethoxy [ 1 , 1 '-biphenyl]-2-yl)phosphine (SPhos)) and a base, if needed, affords the corresponding compound of Formula 2. For example, a substituted aryl boronic acid or derivative (e.g., Formula 6 wherein Q1 is optionally substituted phenyl or heterocyclyl and M is B(OH)2, B(OC(CH3)2C(CH3)20)) or [B(0-z-Pr)3]Li reacts with a 4-iodopyrazole of Formula 5 in the presence of dichlorobis(triphenylphosphine) palladium(II) and aqueous base such as sodium carbonate or potassium hydroxide, in solvents such as 1,4-dioxane, 1,2-dimethoxyethane, toluene or ethyl alcohol, or under anhydrous conditions with a ligand such as phosphine oxide or phosphite ligand (e.g., diphenylphosphine oxide) and potassium fluoride in a solvent such as 1,4-dioxane (see Angewandte Chemie, International Edition 2008, 47(25), 4695-4698) to provide the corresponding compound of Formula 2. Alternatively, compounds of Formula 2 wherein X is NR4 and R4 is H are accessible via routes disclosed in PCT Patent Publication WO 2010/101973.
Scheme 3
Figure imgf000038_0001
(CH3)20),
Sn(Me)3, Sn(Bu)3, ZnCl, MgBr,
MgCl or MgCl-LiCl
As shown in Scheme 4, compounds of Formula 5 wherein X is NH or O can be prepared by the Sandmeyer reaction of compounds of Formula 7 by conditions well-known to one skilled in the art. Conditions for such conversions can be found in PCT Patent Publication WO 2005/012256 and US Patent Publication 2011/0002879.
Scheme 4
Figure imgf000038_0002
As illustrated in Scheme 5, compounds of Formula 7 in which X is NH or O can be prepared by reduction of compounds of Formula 8 with hydrogen in the presence of a catalyst such as nickel under such conditions as described in Chemische Berichte 1955, 88, 866-74, or by use of a metal such as iron or zinc in the presence of an acidic medium such as acetic acid under such conditions as described in Berichte der Deutschen Chemischen Gesellschaft 1904, 37, 3520-3525, or by treatment with SnCl2 as described in Chemische Berichte 1955, 88, 1577-85). Scheme 5
Figure imgf000039_0001
8
As shown in Scheme 6, compounds of Formula 8a (i.e. Formula 8 wherein X is NH) can be prepared by reacting compounds of Formula 9 with compounds of Formula 10 under the metal-catalyzed conditions described for Scheme 3. Also shown in Scheme 6, compounds of Formula 8b (i.e., Formula 8 wherein X is O) can be prepared by reacting compounds of Formula 9 with compounds of Formula 11, generally in the presence of a base such as sodium hydroxide, potassium carbonate, or sodium hydride. For general conditions, procedures and reagents, see PCT Patent Publication WO 93/15060.
Scheme 6
Figure imgf000039_0002
8b
As shown in Scheme 7, compounds of Formula 5 wherein X is CR15R16 can be prepared by reacting compounds of Formula 12 with an iodinating reagent, such as with iodine under such conditions as described in Journal of Heterocyclic Chemistry 1995, 32(4), 1351-4, or with N-iodosuccinimide (NIS), under conditions such as those disclosed in Journal of Medicinal Chemistry 1990, 33(\), 31-8. Scheme 7
Figure imgf000040_0001
12
As shown in Scheme 8, compounds of Formula 12a (i.e. Formula 12 wherein X is CR15R16, R16 is OR18 and R18 is H) can be prepared by treatment of compounds of Formula 13 with magnesium metal, isopropylmagnesium chloride (optionally as the 1 : 1 lithium chloride complex) or n-butyllithium, in anhydrous solvents such as ether, methyl tert-butyl ether, or tetrahydrofuran, at temperatures ranging from -78 °C to room temperature, followed by the addition of the appropriate aldehyde or ketone of Formula 14 having R15 as defined in the scope of the invention. The compounds of Formula 14 are commercially available or prepared by general methods well-known in the art. Compounds of Formula 13 are known or are prepared by general methods well-known in the art.
Scheme 8
Mg or
Figure imgf000040_0002
As shown in Scheme 9, compounds of Formula 12b (i.e. Formula 12 wherein X is CR15R16 and R16 is F) can be prepared by reaction of compounds of Formula 12a with halogenating reagents such as diethylaminosulfur trifluoride (DAST) or bis(2- methoxyethyl)aminosulfur trifluoride (BAST) in a solvent such as dichloromethane at 25- 90 °C for time periods of 1-24 h, using procedures such as described in Heterocycles 2006, 67, 247-254. As also shown in Scheme 9, compounds of Formula 12a can be treated with thionyl chloride or phosphorus pentachloride, optionally in the presence of a base such as triethylamine or pyridine, in a solvent such as dichloromethane at temperatures below ambient to about 40 °C or in N,N-dimethylformamide at 90-140 °C for time periods of 1-24 h, using procedures such as described in Bull. Chem. Soc. Japan 2002, 75, 1371-1379, to provide compounds of Formula 12c (i.e. Formula 12 wherein X is CR15R16 and R16 is CI). Scheme 9
Figure imgf000041_0001
12c
A wide variety of general methods known in the art for forming amine derivatives are can be used to prepare compounds of Formula lb (i.e. Formula 1 in which X is NR4) wherein R4 is other than H from corresponding compounds of Formula la (i.e. Formula 1 in which X is NR4 and R4 is H). For example, as shown in Scheme 10, compounds of Formula lb wherein R4 is alkyl can be prepared by reacting compounds of Formula la with an alkylating agent of Formula 15 in the presence of a base. For reagents, conditions and procedures see PCT Patent Publication WO 2010/101973. As further examples, compounds of Formula lb wherein R4 is an acyl- or sulfonyl-based substituent (e.g., -(C=0)R or -S(=0)2R10) can be prepared by reacting compounds of Formula la with corresponding acylating or sulfonating reagents, respectively, by methods well known in the literature.
Scheme 10
Figure imgf000041_0002
R4 is alkyl
la lb
A wide variety of general methods known in the art for forming alcohol derivatives are can be used to prepare compounds of Formula Id (i.e. Formula 1 in which X is CR15R16 and R16 is OR18) wherein R18 is other than H from corresponding compounds of Formula lc (i.e. Formula 1 in which X is CR15R16 and R16 is OH). For example, as shown in Scheme 11, compounds of Formula Id wherein R18 is alkyl can be prepared by reacting compounds of Formula lc with an alkylating agent 16 in the presence of a base. As further examples, compounds of Formula Id wherein R18 is an acyl-based substituent (e.g., -(C=0)R1 1) can be prepared by reacting compounds of Formula lc with corresponding acylating reagents, respectively, by methods well known in the literature.
Scheme 11
Figure imgf000042_0001
R1S is alkyl
lc Id
As shown in Scheme 12, compounds of Formula le (i.e. Formula 1 wherein X is CR15R16 and R16 is F) and Formula If (i.e. Formula 1 wherein X is CR15R16 and R16 is CI) can be prepared by treating compounds of Formula lc (i.e. Formula 1 wherein X is CR15R16, R16 is OR18 and R18 is H) under the same conditions as described in Scheme 9.
Scheme 12
Figure imgf000042_0002
If
As shown in Scheme 13, compounds of Formula lg (i.e. Formula 1 wherein X is NH and R2 is H) can be prepared by the reaction of substituted hydrazines of Formula 18 with dialkylaminothioacrylamides of Formula 17. The reaction in Scheme 13 can optionally be carried out in a variety of solvents, such as methanol, ethanol, isopropanol, tetrahydrofuran or 1,4-dioxane, or mixtures of these solvents with each other or with water, at temperatures from below ambient to the boiling point of the solvent or solvent mixture. The addition of an acid such as acetic acid, sulfuric acid or methanesulfonic acid, or a base such as sodium hydroxide, sodium hydrogen carbonate, potassium carbonate, sodium ethoxide, potassium tert-butoxide or triethylamine may be used to improve the rate of the reaction. The method of Scheme 13 is illustrated by Step D of Synthesis Example 2.
Figure imgf000043_0001
R, R" are alkyl
As shown in Scheme 14, compounds of Formula 17 can be prepared by reaction of thioamides of Formula 19 with such reagents as dimethylformamide dimethyl acetal, tert- butoxy-bis(dimethylamino)methane (Brederick's reagent), or by a two-stage reaction with a trialkyl orthoformate, such as triethyl orthoformate, followed by the addition of a dialkylamine such as dimethylamine or cyclic secondary amine such as piperidine or morpholine. Examples of analogous reactions are known in the literature (see for example Journal f r Praktische Chemie (Leipzig) 1986, 328(1), 120-6). Compounds of Formula 19 are known or prepared by methods known in the art, such as those found in PCT Patent Publication WO 2010/018874. The method of Scheme 14 is illustrated by Step C of Synthesis Example 2.
Scheme 14
Figure imgf000043_0002
19 7 dialkylamine
As shown in Scheme 15, compounds of Formula lh (i.e. Formula 1 wherein X is NH, R2 is H and Rla is H) can be prepared by reacting lH-pyrazoles of Formula 20 with various alkylating agents of Formula 21, preferably in the presence of an organic or inorganic base such as l,8-diazabicyclo[5.4.0]undec-7-ene, potassium carbonate or potassium hydroxide, and in a solvent such as N,N-dimethylformamide, tetrahydrofuran, toluene or water. Suitable alkylating agents include but are not limited to iodoalkanes, alkylsulfonates such as mesylates (OMs) or tosylates (OTs) or trialkyl phosphates. Compounds of Formula 20 are prepared by reacting compounds of Formula 17 with hydrazine under the conditions described in Scheme 13. Scheme 15
Figure imgf000044_0001
20 OTs or phosphate
As is shown in Scheme 16, compounds of Formula lg also can be prepared by the reaction of 5-aminopyrazoles of Formula 22 with compounds of Formula 23 containing a leaving group G (i.e. halogen or (halo)alkylsulfonate), optionally in the presence of a metal catalyst, and generally in the presence of a base and a polar aprotic solvent such as N,N-dimethylformamide or dimethyl sulfoxide. For example, compounds of Formula 23 in which Q2 is an alkyl, alkenyl or alkynyl group, an electron-deficient heteroaromatic ring, or a benzene ring with electron-withdrawing substituents, react by direct displacement of the leaving group G to provide compounds of Formula lg. Compounds of Formula 23 are commercially available or their preparation is known in the art.
Scheme 16
Figure imgf000044_0002
For reactions according to the method of Scheme 16 of a compound of Formula 22 with a compound of Formula 23 (Q2-G) wherein Q is an aromatic or heteroaromatic ring Q lacking sufficiently electron-withdrawing substituents, or to improve reaction rate, yield or product purity, the use of a metal catalyst (e.g., metal or metal salt) in amounts ranging from catalytic up to superstoichiometric can facilitate the desired reaction. Typically for these conditions, G is Br or I or a sulfonate such as OS(0)2CF3 or OS(0)2(CF2)3CF3. For example, copper salt complexes (e.g., Cul with A .N'-dimethylethylenediamine, proline or bipyridyl), palladium complexes (e.g., tris(dibenzylideneacetone)dipalladium(0)) or palladium salts (e.g., palladium acetate) with ligands such as 4,5-bis(diphenylphosphino)- 9,9-dimethylxanthene (i.e. "Xantphos"), 2-dicyclohexylphosphino-2',4',6'-triisopropyl- biphenyl (i.e. "Xphos") or 2,2'-bis(diphenylphosphino)-l, -binaphthalene (i.e. "BINAP"), in the presence of a base such as potassium carbonate, cesium carbonate, sodium phenoxide or sodium tert-butoxide, in a solvent such as N,N-dimethylformamide, 1 ,2-dimethoxyethane, dimethyl sulfoxide, 1,4-dioxane or toluene can be used. The method of Scheme 16 is illustrated by Step C of Synthesis Example 1.
As shown in Scheme 17, 5-aminopyrazoles of Formula 22 can be prepared by reaction of compounds of Formula 24 with substituted hydrazines of Formula 18 under conditions similar to those described for Scheme 13. Compounds of Formula 24 can be prepared from nitriles of Formula 25 by methods knows in the art such as treatment with ethyl formate in the presence of a base. Nitriles of Formula 25 are commercially available or their preparation is known in the art. The method of Scheme 17 is illustrated by Steps A and B of Synthesis Example 1.
Scheme 17
Figure imgf000045_0001
As shown in Scheme 18, compounds of Formula 9 wherein Rla is H can be prepared by alkylating the IH-pyrazole of Formula 26 with various alkylating agents of Formula 21, similar to the method described in Scheme 15. The IH-pyrazole of Formula 26 is commercially available.
Scheme 18
Figure imgf000045_0002
As shown in Scheme 19, compounds of Formula 9 wherein Rla is taken together with R1 and the carbon atom to which they are attached to form an optionally substituted cyclopropyl ring can be prepared by reacting the IH-pyrazole of Formula 26 with a compound of Formula 27 in the presence of a copper catalyst and ligand. For example, boronic acids, boronate esters or trifluoroborate salts of Formula 23 are used in the presence of copper(II) acetate and a ligand such as 2,2'-bipyridyl, optionally in the presence of an added base such as sodium carbonate in a solvent such as dichloromethane or 1 ,2-dichloroethane, at temperatures ranging from room temperature to 90 °C. For reagents, conditions and procedures see Tetrahedron Letters, 2010, 5(52), 6799-6801 and PCT Patent Publication 2009/134392. Alternatively compounds of Formula 9 wherein Rla is other than H can be prepared by reacting the IH-pyrazole of Formula 22 with trialkylbismuth reagents of Formula 28 under conditions similar to those utilized with compounds of Formula 27, as described in Journal of the American Chemical Society, 2007, 129(1), 44-45.
Scheme 19
Figure imgf000046_0001
28 cyclopropyl ring
Cu(OAc)2/pyridine
As shown in Scheme 20, compounds of Formula 2a (i.e. Formula 2 wherein X is NR4 and R4 is H) and compounds of Formula 2b (i.e. Formula 2 wherein X is CR15R16, R16 is OR18 and R18 is H) can be prepared from compounds of Formula 29 by the methods analogous to those described in Schemes 6 and 8.
Scheme 20
Figure imgf000046_0002
2b
As shown in Scheme 21, compounds of Formula 29 wherein Rla is H can be prepared by alkylation of lH-pyrazoles of Formula 30 by a method analogous to that described in Scheme 15. Scheme 21
Figure imgf000047_0001
30 or phosphate
As shown in Scheme 22, compounds of Formula 29 wherein Rla is taken together with R1 and the carbon atom to which they are attached to form an optionally substituted cyclopropyl ring can be prepared reacting a compound of Formula 30 with compounds of Formula 27 or 28 by a method analogous to that described in Scheme 19.
Scheme 22
R^R^CH-M .
Figure imgf000047_0002
28
Cu(OAc)2/pyridine
As shown in Scheme 23, compounds of Formula 30 can be prepared by bromination of lH-pyrazoles of Formula 31 by procedures known in the art. For representative procedures see Synthetic Communications 2008, 38(5), 674-683 and Journal of Organic Chemistry, 1968, 57(24), 4656-4660. lH-Pyrazoles of Formula 31 are prepared by methods known in the literature (see e.g., PCT Patent Publication 2008/080969, Tetrahedron Letters 1988, 29(46), 6001-6004, and Helvetica Chimica Acta 1927, 10, 846-848).
Scheme 23
Figure imgf000047_0003
31 30
It is recognized by one skilled in the art that various functional groups can be converted into others to provide different compounds of Formula 1. For example, compounds of Formula 1 or intermediates for their preparation may contain aromatic nitro groups, which can be reduced to amino groups, and then be converted via reactions well known in the art such as the Sandmeyer reaction, to various halides, providing other compounds of Formula 1. By similar known reactions, aromatic amines (anilines) can be converted via diazonium salts to phenols, which can then be alkylated to prepare compounds of Formula 1 with alkoxy substituents. Likewise, aromatic halides such as bromides or iodides prepared via the Sandmeyer reaction can react with alcohols under copper-catalyzed conditions, such as the Ullmann reaction or known modifications thereof, to provide compounds of Formula 1 that contain alkoxy substituents. Additionally, some halogen groups, such as fluorine or chlorine, can be displaced with alcohols under basic conditions to provide compounds of Formula 1 containing the corresponding alkoxy substituents. The resultant alkoxy compounds can themselves be used in further reactions to prepare compounds of Formula 1 wherein R3 is -U-V-T (see, for example, PCT Publication WO 2007/149448 A2). Compounds of Formula 1 or precursors thereof in which R2 or R3 is halide, preferably bromide or iodide, are particularly useful intermediates for transition metal-catalyzed cross-coupling reactions to prepare compounds of Formula 1. These types of reactions are well documented in the literature; see, for example, Tsuji in Transition Metal Reagents and Catalysts: Innovations in Organic Synthesis, John Wiley and Sons, Chichester, 2002; Tsuji in Palladium in Organic Synthesis, Springer, 2005; and Miyaura and Buchwald in Cross Coupling Reactions: A Practical Guide, 2002; and references cited therein.
One skilled in the art will recognize that sulfide groups can be oxidized to the corresponding sulfoxides or sulfones by conditions well-known in the art. Likewise, compounds of Formula 1 wherein X is CR15R16, R15 is H, R16 is OR18 and R18 is H can be readily interconverted with corresponding compounds of Formula 1 wherein X is C(=0) by alcohol oxidation and ketone reduction reactions well known in the art. Furthermore, compounds of Formula 1 wherein X is CR15R16, R15 is C!-C4 alkyl, R16 is OR18, and R18 is H can be prepared by adding an alkyl Grignard reagent to the corresponding compounds of Formula 1 wherein X is C(=0).
The above reactions can also in many cases be performed in alternate sequence, such as the preparation of \H pyrazoles for use in the reactions in Schemes 1 and 2 by reactions illustrated later for the general preparation of substituted pyrazoles.
It is recognized that some reagents and reaction conditions described above for preparing compounds of Formula 1 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 1. One skilled in the art will also recognize that it may be necessary to perform a combination of the steps illustrated in the above schemes in an order other than that implied by the particular sequence presented to prepare the compounds of Formula 1. One skilled in the art will also recognize that compounds of Formula 1 and the intermediates described herein can be subjected to various electrophilic, nucleophilic, radical, organometallic, oxidation, and reduction reactions to add substituents or modify existing substituents.
Without further elaboration, it is believed that one skilled in the art using the preceding description can utilize the present invention to its fullest extent. The following Synthesis Examples are, therefore, to be construed as merely illustrative, and not limiting of the disclosure in any way whatsoever. Steps in the following Synthesis Examples illustrate a procedure for each step in an overall synthetic transformation, and the starting material for each step 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. ¾ NMR spectra are reported in ppm downfield from tetramethylsilane in CDC13 unless otherwise noted; "s" means singlet, "m" means multiplet, "br s" means broad singlet. Mass spectra (MS) are reported as the molecular weight of the highest isotopic abundance parent ion (M+1) formed by addition of H+ (molecular weight of 1) to the molecule, observed by mass spectrometry using atmospheric pressure chemical ionization (AP+) where "amu" stands for atomic mass units. LCMS refers to liquid chromatographic separation with mass spectra detection.
SYNTHESIS EXAMPLE 1
Preparation of N,4-bis(2-chloro-4-fluorophenyl)-l-methyl-lH-pyrazole-5-amine
(Compound 1)
Step A: Preparation of (aZ)-2-chloro-4-fluoro-a-(hydroxymethylene)- benzeneacetonitrile and (aE)-2-chloro-4-fluoro-a-(hydroxymethylene)- benzeneacetonitrile
A methanol solution of sodium methoxide (4.5 M, 2.8 mL, 12.5 mmol) was added to anhydrous ethanol (5 mL), and 2-chloro-4-fluorophenylacetonitrile (2.00 g, 11.8 mmol) was added. The solution was stirred under a nitrogen atmosphere for 5 minutes, ethyl formate (2.3 mL, 28 mmol) was added in one portion, and the resultant mixture was refluxed for 2 h. The reaction mixture was concentrated under reduced pressure, and the resulting residue was dissolved in water (50 mL) and extracted once with ethyl acetate (25 mL). The aqueous layer was acidified with 1 N aqueous hydrochloric acid and extracted with ethyl acetate (50 mL). This second extract was washed with brine, dried (MgS04), filtered and concentrated under reduced pressure to give a mixture of isomeric title compounds as a white solid (1.53 g, 68% yield).
!H NMR (acetone-^) δ 7.63 and 7.70 (two s, 1H total), 7.4-7.55 (m, 1H total), 7.34-7.41 (m, 1H total), 7.15-7.25 (m, 1H total), 4.03 (s, 0.5 H).
Step B: Preparation of 4-(2-chloro-4-fluorophenyl)-l -methyl- lH-pyrazole-5-amine and 4-(2-chloro-4-fluorophenyl)-l -methyl- lH-pyrazole-3-amine A stirred solution of (aZ)-2-chloro-4-fluoro-a-(hydroxymethylene)benzeneacetonitrile and (aE)-2-chloro-4-fluoro-a-(hydroxymethylene)benzeneacetonitrile (i.e. the product of Step A, 1.29 g, 6.53 mmol) was cooled in an ice/water bath. Glacial acetic acid (0.486 mL, 8.48 mmol) and methylhydrazine (0.438 mL, 8.16 mmol) were added, and the stirred reaction mixture was allowed to warm to ambient temperature overnight. The reaction mixture was stirred and heated at 40 °C for 6 h, under reflux for an additional 6 h, then stirred at ambient temperature overnight. The reaction mass was concentrated under reduced pressure, diluted with water (50 mL) and extracted with dichloromethane (3 x 25 mL). The combined organic phases were washed with water and brine, dried (MgS04), filtered and concentrated under reduced pressure to give a brown solid (0.45 g, 31% yield). Analysis of the solid by LC/MS showed a single component of mass 226 (AP+). ¾ NMR analysis was consistent with a mixture of the two regioisomeric title compounds, in an apparent ratio of approximately 1 : 1. This material was used directly in the next step without further purification.
!H NMR (acetone-^) δ 7.53 (m, 0.4 H), 7.5 (s, 1H), 7.27-7.34 (m, 1.6 H), 7.08-7.16 (m, 1H total), 5.15, 4.7, and 4.1(br m, ~2H total), 3.71 and 3.73 (two s, 3H total).
Step C : Preparation of N,4-bis(2-chloro-4-fluorophenyl)- 1 -methyl- lH-pyrazol-
5-amine and N,4-bis(2-chloro-4-fluorophenyl)- 1 -methyl- lH-pyrazol-3-amine To a solution of 4-(2-chloro-4-fluorophenyl)-l -methyl- lH-pyrazole-5-amine and
4-(2-chloro-4-fluorophenyl)-l -methyl- lH-pyrazole-3-amine (i.e. the product of Step B) (0.45 g, 1.99 mmol) in tert-butyl alcohol (4 mL previously sparged with dry nitrogen gas for 20 min) at room temperature were added 2-chloro-4-fluoro-l-iodobenzene (0.51 g, 1.99 mmol), sodium tert-butoxide (0.21 g, 2.1 mmol), tris(dibenzylideneacetone)- dipalladium(O) complex (3.5 mg, 0.004 mmol) and tri-tert-butylphosphonium tetrafluoro- borate (24 mg, 0.079 mmol). The mixture was sparged with nitrogen gas for an additional 5 min and then heated at 80 °C overnight. Additional tris(dibenzylideneacetone)- dipalladium(O) complex (37 mg) and tri-tert-butylphosphonium tetrafluoroborate (230 mg) were added, and the mixture was heated at 75-80 °C for 72 h. Additional tris(dibenzylidene- acetone)dipalladium(O) complex (37 mg) and tri-tert-butylphosphonium tetrafluoroborate (230 mg) were added, and the mixture was heated at 80 °C for 24 h. The cooled reaction mixture was filtered through a pad of Celite® diatomaceous filter aid, and the pad was washed with ethyl acetate (25 mL). The filtrate was washed with water and brine, dried (MgS04), filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (12 g) using an elution gradient of 5% ethyl acetate in hexanes to 100% ethyl acetate to give the desired N,4-bis(2-chloro-4-fluorophenyl)-l-methyl- lH-pyrazol-5-amine (18 mg), a compound of the present invention, along with its regioisomer N,4-bis(2-chloro-4-fluorophenyl)-l -methyl- lH-pyrazol-3 -amine (15 mg) as a less-polar component.
!H NMR δ 7.67 (s, 1H), 7.14-7.20 (m, 2H), 7.07 (m, 1H), 6.91 (m, 1H), 6.76 (m, 1H), 6.26 (m, 1H), 5.71 (br s, 1H), 3.74 (s, 3H).
SYNTHESIS EXAMPLE 2
Preparation of N-(2-Bromo-4,6-difluorophenyl)-4-(2-bromo-4-fluorophenyl)-l -methyl- 1H- pyrazol-5 -amine (Compound 3)
Step A: Preparation of 2-Bromo-N-(2-bromo-4,6-difluorophenyl)-4-fluoro- benzeneacetamide
To a solution of 2-bromo-4-fluorobenzeneacetic acid (1.00 g, 4.29 mmol) in dichloromethane (10 mL) was added N-hydroxybenzotriazole (0.65 g, 4.3 mmol), and the reaction mixture was stirred for 10 min at ambient temperature. O-(7-Azabenzotriazol-l-yl)-
Figure imgf000051_0001
hexafluorophosphate (1.63 g, 4.3 mmol) and N,N-diisopropyl- ethylamine (1.66 g, 12.8 mmol) were added sequentially, and then the reaction mixture was stirred for 10 min. 2-Bromo-4,6-difluorobenzenamine (0.89 g, 4.3 mmol) was then added, and the reaction mixture was stirred for 16 h at ambient temperature. Analysis by thin-layer chromatography on silica gel (30% ethyl acetate in petroleum ether) showed completion of the reaction. Water (about an equal volume) was added to the reaction mixture, which was then extracted with dichloromethane (3χ). The combined organic layers were washed with brine and dried (Na2S04). The solvent was evaporated under reduced pressure, and the crude residue was washed with diethyl ether to give the title compound as a solid (1.66 g, 89% yield). This material was used directly in the next reaction step without further characterization.
Step B: Preparation of 2-Bromo-N-(2-bromo-4,6-difluorophenyl)-4-fluoro- benzeneethanethioamide
To a solution of 2-bromo-N-(2-bromo-4,6-difluorophenyl)-4-fluorobenzeneacetamide (i.e. the product of Step 1) (1.66 g, approximately 3.9 mmol) in toluene (15 mL) was added 2,4-bis(4-methoxyphenyl)-l,3,2,4-dithiadiphosphetane-2,4-disulfide (Lawesson's reagent, 1.73 g, 4.32 mmol), and the mixture was stirred and heated at 100 °C for 3 h. Analysis by thin-layer chromatography on silica gel (20% ethyl acetate in petroleum ether) showed completion of the reaction. The solvent was evaporated under reduced pressure, and water was added to the residue. The aqueous layer was extracted with ethyl acetate (3x). The combined organic layers were washed with brine and dried (Na2S04). The solvent was concentrated under reduced pressure, and the crude product was applied to a silica gel column. Elution of the column with 20% ethyl acetate in petroleum ether gave the title compound as white solid (0.97 g, 56% yield).
!H NMR δ 7.96 (br s, 1H), 7.54 (m, 1H), 7.45 (m, 1H), 7.25 (m, 1H), 7.15 (m,lH), 6.9 (m, 1H), 4.4 (s 2H).
MS(AP+) 438 (M+l).
Step C: Preparation of 2-Bromo-N-(2-bromo-4,6-difluorophenyl)-a-[(dimethyl- amino)methylene]-4-fluorobenzeneethanethioamide
To a solution of 2-bromo-N-(2-bromo-4,6-difluorophenyl)-4-fluorobenzeneethane- thioamide (i.e. the compound of Step B) (0.50 g, 1.14 mmol) in toluene (10 mL) was added l,l-dimethoxy-N,N-dimethylmethanamine (dimethylformamide dimethyl acetal, 1 mL), and the reaction mixture was heated at 110 °C for 12 h. Analysis by thin-layer chromatography on silica gel (10% ethyl acetate in petroleum ether) showed consumption of the 2-bromo- N-(2-bromo-4,6-difluorophenyl)-4-fluorobenzeneethanethioamide starting material. Volatiles were removed under reduced pressure, twice a volume of toluene was added, and the volatiles were again removed under reduced pressure to leave the title compound in crude form as a liquid (0.6 g).
Step D: Preparation of N-(2-Bromo-4,6-difluorophenyl)-4-(2-bromo-4-fluorophenyl)- 1 -methyl- lH-pyrazol-5-amine
To a solution of 2-bromo-N-(2-bromo-4,6-difluorophenyl)-a-[(dimethylamino)- methylene]-4-fluorobenzeneethanethioamide (i.e. the compound of Step C) (0.6 g, 1.2 mmol) in ethanol (10 mL) was added triethylamine (0.367 g, 3.64 mmol) and methylhydrazine hemisulfate (0.344 g, 2.42 mmol), and this mixture was stirred at 80 °C for 16 h, at which time analysis by thin-layer chromatography on silica gel (30% ethyl acetate in petroleum ether) showed consumption of the 2-bromo-N-(2-bromo-4,6-difluorophenyl)- a-[(dimethylamino)methylene]-4-fluorobenzeneethanethioamide starting material. Then ethanol was evaporated, and water was added. The aqueous layer was extracted with ethyl acetate (3x). The organic layers were combined, washed with brine and dried (Na2S04). The solvent was evaporated under reduced pressure, and the residue was charged onto a silica gel column and eluted with 30% ethyl acetate/ petroleum ether to afford the title product, a compound of the present invention, as a solid (0.210 g, 40 %> yield), melting at 133-135 °C.
Ή ΝΜΡ δ 7.48 (s, 1Η), 7.25 (m, 1Η), 7.15 (m,lH), 6.95 (m,lH), 6.85 (m,lH), 6.64 (m,lH), 5.4 (s,lH), 3.9 (s,3H).
LCMS(AP+) 460 (M+l). SYNTHESIS EXAMPLE 3
Preparation of a,4-Bis(2-chloro-4-fluorophenyl)- 1 -methyl- lH-pyrazole-5-methanol
(Compound 22)
Step A: Preparation of a-(2-Chloro-4-fluorophenyl)-l -methyl- lH-pyrazole- 5 -methanol
To a stirred solution of 1-methylpyrazole (0.33 mL, 0.33 g, 4.0 mmol) in anhydrous tetrahydrofuran (12 mL) was added n-butyllithium (2.5 M solution in hexanes, 1.8 mL, 4.4 mmol) under an atmosphere of nitrogen at -55 to -60 °C. The reaction mixture was allowed to warm to -30 °C over 30 to 45 minutes, and then recooled to -60 °C. A solution of 2-chloro-4-fluorobenzaldehyde (0.64 g, 4.0 mmol) in tetrahydrofuran (3 mL) was added drop wise over several minutes, and this reaction mixture was allowed to warm to ambient temperature over about 2 h. Water (5 mL) was added, and this mixture was extracted with ethyl acetate (2 x 10 mL). The combined organic layers were washed with brine, dried (Mg2S04), and concentrated under reduced pressure. The residue was applied to a prepacked column of 20 g of silica gel and eluted with 2% to 5% methanol in dichloromethane to afford the title compound as a pale yellow oil (297 mg, 31% yield).
Ή ΝΜΡ δ 7.57 (m, 1Η), 7.33 (s, 1Η), 7.13 (m, 1Η), 7.06 (m, 1Η), 6.20 (s, 1Η), 5.89 (s, 1Η),
3.88 (s, 3Η), 2.86 (br s, 1Η).
MS(AP+) 241.
Step B : Preparation of 4-Bromo-a-(2-chloro-4-fluorophenyl)- 1 -methyl- lH-pyrazole-
5 -methanol
To a solution of a-(2-chloro-4-fluorophenyl)-l-methyl-lH-pyrazole-5-methanol (i.e. the product of Step A) (297 mg, 1.23 mmol) in dichloromethane (12 mL) was added N-bromosuccinimide (231 mg, 1.3 mmol) in one portion. This mixture was stirred at ambient temperature about 40 h, and then a saturated aqueous solution of sodium hydrogen sulfite (2 mL) was added. After about 5 min the layers were separated, and the aqueous layer was diluted with additional water (~5 mL) and extracted with dichloromethane (10 mL). The combined organic layers were washed with water, dried (Mg2S04), and concentrated under reduced pressure to afford the title compound as a white solid (314 mg, 80% yield).
!H NMR δ 7.62 (m, 1H), 7.40 (s, 1H), 7.15 (m, 1H), 7.06 (m, 1H), 6.22 (s, 1H), 3.77 (s, 3H),
2.65 (br s, 1H).
MS(AP+) 321.
Step C: Preparation of a,4-Bis(2-chloro-4-fluorophenyl)-l -methyl- lH-pyrazole- 5 -methanol
To a mixture of 4-bromo-a-(2-chloro-4-fluorophenyl)-l -methyl- lH-pyrazole- 5-methanol (i.e. the product of Step B) (64 mg, 0.20 mmol) and water (1 mL) in 1,4-dioxane (4 mL) was added potassium carbonate (65 mg, 0.47 mmol) and dichloropalladium- l, -bis(diphenylphosphino)ferrocene complex (PdCl2-dppf, 15 mg, 0.02 mmol). This mixture was sparged subsurface for about 10 min with a stream of nitrogen gas, and then i?-(2-chloro-4-fluorophenyl)boronic acid (52 mg, 0.30 mmol) was added, and the stirred mixture was heated under a nitrogen atmosphere at reflux temperature for 5 h. After cooling to ambient temperature, the reaction mixture was poured into a 10-g-size solid-phase extraction tube. After 5 min, ethyl acetate (30 mL) was poured through the tube, and the eluent was concentrated under reduced pressure. The residue was applied to a pre-packed column of 10 g of silica gel and eluted with 2% to 5% methanol in dichloromethane to afford the title product, a compound of the present invention, as a pale yellow solid (24 mg, 32% yield), melting at 174-175 °C.
!H NMR δ 7.65 (m, 1H), 7.43 (m, 1H), 7.34 (s, 1H), 7.05 (m, 1H), 6.96 (m, 1H), 7.75-7.85
(m, 2H), 6.02 (s, 1H), 3.96 (s, 3H), 2.71 (br s, 1H).
MS(AP+) 369.
By the procedures described herein together with methods known in the art, the compounds disclosed in the Tables that follow can be prepared. The following abbreviations are used in the Table which follows: n- means normal, i- means iso, s- means secondary, t- means tertiary, Me means methyl, Et means ethyl, Pr means propyl, Ph means phenyl, MeO means methoxy, EtO means ethoxy and -CN means cyano.
TABLE 1
Figure imgf000054_0001
Q1 is 2,6-di-F-Ph, X is NH, R1 and Rl a are both H, and R2 is H.
Figure imgf000054_0002
2-F-4-Br 2-Cl-4-Br 2-Br-4-Cl 2-Br-4-F-6-Cl 2-Cl-4-Br-6-F
2,6-di-F-4-EtO 2,6-di-Cl-4-CN 2,6-di-Cl-4-EtO 2-C1-6-F 2-Br-6-F
2-I-4,6-di-F 2-Cl-4,6-di-Br 2,6-di-Br-4-Cl 2-C1-4-I 2-F-4-EtO
2,6-di-Br-4-F 2-Br-4-Cl-6-F 2-Br-4,6-di-Cl 2,6-di-Br-4-CN 2,6-di-Br-4-MeO
2,6-di-Br-4-EtO 2-Cl-4-EtO 2-Br-4-I 2-I-4-C1-6-F 2-Cl-6-Br
2,6-di-Cl-4-Br 2-Br-4-EtO 2,4-di-Br 2,4-di-Br-6-F 2-I-4,6-di-Cl
2,6-di-F-4-Me 2-Cl-4-Me-6-F 2-Br-4-Me-6-F 2,6-di-Cl-4-Me 2-Cl-4-MeO-6-F
2-Br-4-MeO-6-F 2-I-4-MeO-6-F 2-C1-4-CN-6-F 2-Br-4-CN-6-F 2-Br-4-CN-6-Cl
The present disclosure also includes Tables 2 through 529, each of which is constructed the same as Table 1 above, except that the row heading in Table 1 (i.e. "Q1 is 2,6-di-F-Ph, X is NH, R1 and Rla are both H, and R2 is H.") is replaced with the respective row heading shown below. For Example, in Table 2 the row heading is "Q1 is 2,6-di-F-Ph, X is NH, R1 and Rla are both H, and R2 is ethenyl." and (R )p is as defined in Table 1 above. Thus, the first entry in Table 2 specifically discloses 4-(2,6-difluorophenyl)- 3-ethenyl-N-(2-fluorophenyl)-l -methyl- lH-pyrazole-5-amine. Tables 3 through 529 are constructed similarly.
Table Row Heading
2 Q1 is 2,6- -di-F- Ph, X is NH, R1 and Rl a are both H, and R2 is ethenyl.
3 Q1 is 2,6- -di-F- Ph, X is NH, R1 and Rl a are both H, and R2 is ethynyl.
4 Q1 is 2,6- -di-F- Ph, X is NH, R1 is Me, Rl a is H, and R2 is H.
5 Q1 is 2,6- -di-F- Ph, X is NH, R1 is Me, Rl a is H, and R2 is ethenyl.
6 Q1 is 2,6- -di-F- Ph, X is NH, R1 is Me, Rl a is H, and R2 is ethynyl.
7 Q1 is 2,6- -di-F- Ph, X is O, R 1 and Ri a are both H, and R2 is H.
8 Q1 is 2,6- -di-F- Ph, X is O, R 1 and Ri a are both H, and R2 is ethenyl.
9 Q1 is 2,6- -di-F- Ph, X is O, R 1 and Ri a are both H, and R2 is ethynyl.
10 Q1 is 2,6- -di-F- Ph, X is O, R 1 is Me, Rl a is H, and R2 is H.
11 Q1 is 2,6- -di-F- Ph, X is O, R 1 is Me, R^a is H, and R2 is ethenyl.
12 Q1 is 2,6- -di-F- Ph, X is O, R 1 is Me, R^a is H, and R2 is ethynyl.
13 Q1 is 2,6- -di-F- Ph, X is CHOH, R 1 and Ri a are both H, and R2 is H.
14 Q1 is 2,6- -di-F- Ph, X is CHOH, R 1 and Ri a are both H, and R2 is ethenyl.
15 Q1 is 2,6- -di-F- Ph, X is CHOH, R 1 and Ri a are both H, and R2 is ethynyl.
16 Q1 is 2,6- -di-F- Ph, X is CHOH, R 1 is Me, Rl a is H, and R2 is H.
17 Q1 is 2,6- -di-F- Ph, X is CHOH, R 1 is Me, R^a is H, and R2 is ethenyl.
18 Q1 is 2,6- -di-F- Ph, X is CHOH, R 1 is Me, R^a is H, and R2 is ethynyl.
19 Q1 is 2,4- -di-F- Ph, X is NH, R1 and Rl a are both H, and R2 is H.
20 Q1 is 2,4- -di-F- Ph, X is NH, R1 and Rl a are both H, and R2 is ethenyl.
21 Q1 is 2,4- -di-F- Ph, X is NH, R1 and Rl a are both H, and R2 is ethynyl. Row Heading
Q1 is 2,4-di-F-Ph, X is NH, R1 is Me, Rl a is H, and R2 is H.
Q1 is 2,4-di-F-Ph, X is NH, R1 is Me, Rl a is H, and R2 is ethenyl.
Q1 is 2,4-di-F-Ph, X is NH, R1 is Me, Rl a is H, and R2 is ethynyl.
Q1 is 2,4-di-F-Ph, X is O, R1 and Rl a are both H, and R2 is H.
Q1 is 2,4-di-F-Ph, X is O, R1 and Rl a are both H, and R2 is ethenyl.
Q1 is 2,4-di-F-Ph, X is O, R1 and Rl a are both H, and R2 is ethynyl.
Q1 is 2,4-di-F-Ph, X is O, R1 is Me, Rl a is H, and R2 is H.
Q1 is 2,4-di-F-Ph, X is O, R1 is Me, Rl a is H, and R2 is ethenyl.
Q1 is 2,4-di-F-Ph, X is O, R1 is Me, Rl a is H, and R2 is ethynyl.
Q1 is 2,4-di-F-Ph, X is CHOH, R1 and Rl a are both H, and R2 is H.
Q1 is 2,4-di-F-Ph, X is CHOH, R1 and Rl a are both H, and R2 is ethenyl.
Q1 is 2,4-di-F-Ph, X is CHOH, R1 and Rl a are both H, and R2 is ethynyl.
Q1 is 2,4-di-F-Ph, X is CHOH, R1 is Me, Rl a is H, and R2 is H.
Q1 is 2,4-di-F-Ph, X is CHOH, R1 is Me, Rl a is H, and R2 is ethenyl.
Q1 is 2,4-di-F-Ph, X is CHOH, R1 is Me, Rl a is H, and R2 is ethynyl.
Q1 is 2-Cl-4-F-Ph, X is NH, R1 and Rl a are both H, and R2 is H.
Q1 is 2-Cl-4-F-Ph, X is NH, R1 and Rl a are both H, and R2 is ethenyl.
Q1 is 2-Cl-4-F-Ph, X is NH, R1 and Rl a are both H, and R2 is ethynyl.
Q1 is 2-Cl-4-F-Ph, X is NH, R1 is Me, Rl a is H, and R2 is H.
Q1 is 2-Cl-4-F-Ph, X is NH, R1 is Me, Rl a is H, and R2 is ethenyl.
Q1 is 2-Cl-4-F-Ph, X is NH, R1 is Me, Rl a is H, and R2 is ethynyl.
Q1 is 2-Cl-4-F-Ph, X is O, R1 and Rl a are both H, and R2 is H.
Q1 is 2-Cl-4-F-Ph, X is O, R1 and Rl a are both H, and R2 is ethenyl.
Q1 is 2-Cl-4-F-Ph, X is O, R1 and Rl a are both H, and R2 is ethynyl.
Q1 is 2-Cl-4-F-Ph, X is O, R1 is Me, Rl a is H, and R2 is H.
Q1 is 2-Cl-4-F-Ph, X is O, R1 is Me, Rl a is H, and R2 is ethenyl.
Q1 is 2-Cl-4-F-Ph, X is O, R1 is Me, Rl a is H, and R2 is ethynyl.
Q1 is 2-Cl-4-F-Ph, X is CHOH, R1 and Rl a are both H, and R2 is H.
Q1 is 2-Cl-4-F-Ph, X is CHOH, R1 and Rl a are both H, and R2 is ethenyl.
Q1 is 2-Cl-4-F-Ph, X is CHOH, R1 and Rl a are both H, and R2 is ethynyl.
Q1 is 2-Cl-4-F-Ph, X is CHOH, R1 is Me, Rl a is H, and R2 is H.
Q1 is 2-Cl-4-F-Ph, X is CHOH, R1 is Me, Rl a is H, and R2 is ethenyl.
Q1 is 2-Cl-4-F-Ph, X is CHOH, R1 is Me, Rl a is H, and R2 is ethynyl.
Q1 is 2,6-di-Cl-Ph, X is NH, R1 and Rl a are both H, and R2 is H.
Q1 is 2,6-di-Cl-Ph, X is NH, R1 and Rl a are both H, and R2 is ethenyl.
Q1 is 2,6-di-Cl-Ph, X is NH, R1 and Rl a are both H, and R2 is ethynyl.
Q1 is 2,6-di-Cl-Ph, X is NH, R1 is Me, Rl a is H, and R2 is H. Row Heading
Q1 is 2,6-di-Cl-Ph, X is NH, R1 is Me, Rl a is H, and R2 is ethenyl.
Q1 is 2,6-di-Cl-Ph, X is NH, R1 is Me, Rl a is H, and R2 is ethynyl.
Q1 is 2,6-di-Cl-Ph, X is O, R1 and Rl a are both H, and R2 is H.
Q1 is 2,6-di-Cl-Ph, X is O, R1 and Rl a are both H, and R2 is ethenyl.
Q1 is 2,6-di-Cl-Ph, X is O, R1 and Rl a are both H, and R2 is ethynyl.
Q1 is 2,6-di-Cl-Ph, X is O, R1 is Me, Rl a is H, and R2 is H.
Q1 is 2,6-di-Cl-Ph, X is O, R1 is Me, Rl a is H, and R2 is ethenyl.
Q1 is 2,6-di-Cl-Ph, X is O, R1 is Me, Rl a is H, and R2 is ethynyl.
Q1 is 2,6-di-Cl-Ph, X is CHOH, R1 and Rl a are both H, and R2 is H.
Q1 is 2,6-di-Cl-Ph, X is CHOH, R1 and Rl a are both H, and R2 is ethenyl.
Q1 is 2,6-di-Cl-Ph, X is CHOH, R1 and Rl a are both H, and R2 is ethynyl.
Q1 is 2,6-di-Cl-Ph, X is CHOH, R1 is Me, Rl a is H, and R2 is H.
Q1 is 2,6-di-Cl-Ph, X is CHOH, R1 is Me, Rl a is H, and R2 is ethenyl.
Q1 is 2,6-di-Cl-Ph, X is CHOH, R1 is Me, Rl a is H, and R2 is ethynyl.
Q1 is 2-Br-4-Cl-Ph, X is NH, R1 and Rl a are both H, and R2 is H.
Q1 is 2-Br-4-Cl-Ph, X is NH, R1 and Rl a are both H, and R2 is ethenyl.
Q1 is 2-Br-4-Cl-Ph, X is NH, R1 and Rl a are both H, and R2 is ethynyl.
Q1 is 2-Br-4-Cl-Ph, X is NH, R1 is Me, Rl a is H, and R2 is H.
Q1 is 2-Br-4-Cl-Ph, X is NH, R1 is Me, Rl a is H, and R2 is ethenyl.
Q1 is 2-Br-4-Cl-Ph, X is NH, R1 is Me, Rl a is H, and R2 is ethynyl.
Q1 is 2-Br-4-Cl-Ph, X is O, R1 and Rl a are both H, and R2 is H.
Q1 is 2-Br-4-Cl-Ph, X is O, R1 and Rl a are both H, and R2 is ethenyl.
Q1 is 2-Br-4-Cl-Ph, X is O, R1 and Rl a are both H, and R2 is ethynyl.
Q1 is 2-Br-4-Cl-Ph, X is O, R1 is Me, Rl a is H, and R2 is H.
Q1 is 2-Br-4-Cl-Ph, X is O, R1 is Me, Rl a is H, and R2 is ethenyl.
Q1 is 2-Br-4-Cl-Ph, X is O, R1 is Me, Rl a is H, and R2 is ethynyl.
Q1 is 2-Br-4-Cl-Ph, X is CHOH, R1 and Rl a are both H, and R2 is H.
Q1 is 2-Br-4-Cl-Ph, X is CHOH, R1 and Rl a are both H, and R2 is ethenyl.
Q1 is 2-Br-4-Cl-Ph, X is CHOH, R1 and Rl a are both H, and R2 is ethynyl.
Q1 is 2-Br-4-Cl-Ph, X is CHOH, R1 is Me, Rl a is H, and R2 is H.
Q1 is 2-Br-4-Cl-Ph, X is CHOH, R1 is Me, Rl a is H, and R2 is ethenyl.
Q1 is 2-Br-4-Cl-Ph, X is CHOH, R1 is Me, Rl a is H, and R2 is ethynyl.
Q1 is 2-Br-6-Cl-Ph, X is NH, R1 and Rl a are both H, and R2 is H.
Q1 is 2-Br-6-Cl-Ph, X is NH, R1 and Rl a are both H, and R2 is ethenyl.
Q1 is 2-Br-6-Cl-Ph, X is NH, R1 and Rl a are both H, and R2 is ethynyl.
Q1 is 2-Br-6-Cl-Ph, X is NH, R1 is Me, Rl a is H, and R2 is H.
Q1 is 2-Br-6-Cl-Ph, X is NH, R1 is Me, Rl a is H, and R2 is ethenyl. Row Heading
Q is Br-6-Cl-Ph, X is NH, R1 is Me, RL A is H, and R2 is ethynyl.
Q is Br-6-Cl-Ph, X is O, R and RI A are both H, and R2 is H.
Q is Br-6-Cl-Ph, X is O, R and R^ A are both H, and R2 is ethenyl. Q is Br-6-Cl-Ph, X is O, R and R1 a are both H, and R2 is ethynyl. Q is Br-6-Cl-Ph, X is O, R is Me, RL A is H, and R2 is H.
Q is Br-6-Cl-Ph, X is O, R is Me, R^A is H, and R2 is ethenyl.
Q is Br-6-Cl-Ph, X is O, R is Me, R^A is H, and R2 is ethynyl.
Q is Br-6-Cl-Ph, X is CHOH, R and RL A are both H, and R2 is H. Q is Br-6-Cl-Ph, X is CHOH, R and ^ A are both H, and R2 is ethenyl. Q is Br-6-Cl-Ph, X is CHOH, R and 1 a are both H, and R2 is ethynyl. Q is Br-6-Cl-Ph, X is CHOH, R is Me, RL A is H, and R2 is H.
Q is Br-6-Cl-Ph, X is CHOH, R is Me, R^A is H, and R2 is ethenyl. Q is Br-6-Cl-Ph, X is CHOH, R is Me, RL A is H, and R2 is ethynyl. Q is Me-4-F-Ph, X is NH, R1 and RL A are both H, and R2 is H.
Q is Me-4-F-Ph, X is NH, R1 and RL A are both H, and R2 is ethenyl. Q is Me-4-F-Ph, X is NH, R1 and RL A are both H, and R2 is ethynyl. Q is Me-4-F-Ph, X is NH, R1 is Me, RL A is H, and R2 is H.
Q is Me-4-F-Ph, X is NH, R1 is Me, RL A is H, and R2 is ethenyl.
Q is Me-4-F-Ph, X is NH, R1 is Me, RL A is H, and R2 is ethynyl.
Q is Me-4-F-Ph, X is O, R 1 and RL A are both H, and R2 is H.
Q is Me-4-F-Ph, X is O, R 1 and R^ A are both H, and R2 is ethenyl. Q is Me-4-F-Ph, X is O, R 1 and Rla are both H, and R2 is ethynyl. Q is Me-4-F-Ph, X is O, R 1 is Me, RL A is H, and R2 is H.
Q is Me-4-F-Ph, X is O, R 1 is Me, R^A is H, and R2 is ethenyl.
Q is Me-4-F-Ph, X is O, R 1 is Me, R^A is H, and R2 is ethynyl.
Q is Me-4-F-Ph, X is CHOH, R1 and RL A are both H, and R2 is H. Q is Me-4-F-Ph, X is CHOH, R1 and RL A are both H, and R2 is ethenyl. Q is Me-4-F-Ph, X is CHOH, R1 and RL A are both H, and R2 is ethynyl. Q is Me-4-F-Ph, X is CHOH, R1 is Me, RL A is H, and R2 is H.
Q is Me-4-F-Ph, X is CHOH, R1 is Me, RL A is H, and R2 is ethenyl. Q is Me-4-F-Ph, X is CHOH, R1 is Me, RL A is H, and R2 is ethynyl. Q is Me-4-Cl-Ph, X is NH, R and RL A are both H, and R2 is H.
Q is Me-4-Cl-Ph, X is NH, R and R^ A are both H, and R2 is ethenyl. Q is Me-4-Cl-Ph, X is NH, R and R1 a are both H, and R2 is ethynyl. Q is Me-4-Cl-Ph, X is NH, R is Me, RL A is H, and R2 is H.
Q is Me-4-Cl-Ph, X is NH, R is Me, R^A is H, and R2 is ethenyl. Q is Me-4-Cl-Ph, X is NH, R is Me, R^A is H, and R2 is ethynyl. Row Heading
Q is 2-Me-4-Cl-Ph, X is O, R 1 and R1 a are both H, and R2 is H.
Q is 2-Me-4-Cl-Ph, X is O, R 1 and R^a are both H, and R2 is ethenyl. Q is 2-Me-4-Cl-Ph, X is O, R 1 and R^a are both H, and R2 is ethynyl. Q is 2-Me-4-Cl-Ph, X is O, R 1 is Me, Rl a is H, and R2 is H.
Q is 2-Me-4-Cl-Ph, X is O, R 1 is Me, R^ a is H, and R2 is ethenyl.
Q is 2-Me-4-Cl-Ph, X is O, R 1 is Me, R^a is H, and R2 is ethynyl.
Q is 2-Me-4-Cl-Ph, X is CHOH, R * and Ri a are both H, and R2 is H. Q is 2-Me-4-Cl-Ph, X is CHOH, R 1 and ^a are both H, and R2 is ethenyl. Q is 2-Me-4-Cl-Ph, X is CHOH, R 1 and Rla are both H, and R2 is ethynyl. Q is 2-Me-4-Cl-Ph, X is CHOH, R 1 is Me, Rl a is H, and R2 is H.
Q is 2-Me-4-Cl-Ph, X is CHOH, R 1 is Me, R^a is H, and R2 is ethenyl. Q is 2-Me-4-Cl-Ph, X is CHOH, R 1 is Me, R^a is H, and R2 is ethynyl. Q is 2-F-4-MeO-Ph, X is NH, R * and R1 a are both H, and R2 is H.
Q is 2-F-4-MeO-Ph, X is NH, R * and Ri a are both H, and R2 is ethenyl. Q is 2-F-4-MeO-Ph, X is NH, R 1 and R^a are both H, and R2 is ethynyl. Q is 2-F-4-MeO-Ph, X is NH, R 1 is Me, Rl a is H, and R2 is H.
Q is 2-F-4-MeO-Ph, X is NH, R 1 is Me, R^a is H, and R2 is ethenyl.
Q is 2-F-4-MeO-Ph, X is NH, R 1 is Me, R^a is H, and R2 is ethynyl.
Q is 2-F-4-MeO-Ph, X is O, R 1 and Rl a are both H, and R2 is H.
Q is 2-F-4-MeO-Ph, X is O, R 1 and R1 a are both H, and R2 is ethenyl. Q is 2-F-4-MeO-Ph, X is O, R 1 and Ri a are both H, and R2 is ethynyl. Q is 2-F-4-MeO-Ph, X is O, R 1 is Me, Rl a is H, and R2 is H.
Q is 2-F-4-MeO-Ph, X is O, R 1 is Me, R^a is H, and R2 is ethenyl.
Q is 2-F-4-MeO-Ph, X is O, R 1 is Me, R^ a is H, and R2 is ethynyl.
Q is 2-F-4-MeO-Ph, X s CHOH, R 1 and Rla are both H, and R2 is H. Q is 2-F-4-MeO-Ph, X s CHOH, R 1 and R^a are both H, and R2 is ethenyl. Q is 2-F-4-MeO-Ph, X s CHOH, R 1 and Ri a are both H, and R2 is ethynyl. Q is 2-F-4-MeO-Ph, X s CHOH, R 1 is Me, R^a is H, and R2 is H.
Q is 2-F-4-MeO-Ph, X s CHOH, R 1 is Me, R^a is H, and R2 is ethenyl. Q is 2-F-4-MeO-Ph, X s CHOH, R 1 is Me, R^a is H, and R2 is ethynyl. Q is 2-Br-4-MeO-Ph, X is NH, R and R are both H, and R2 is H.
Q is 2-Br-4-MeO-Ph, X is NH, R * and Ri a are both H, and R2 is ethenyl. Q is 2-Br-4-MeO-Ph, X is NH, R * and Ri a are both H, and R2 is ethynyl. Q is 2-Br-4-MeO-Ph, X is NH, R 1 is Me, Rl a is H, and R2 is H.
Q is 2-Br-4-MeO-Ph, X is NH, R 1 is Me, R^a is H, and R2 is ethenyl. Q is 2-Br-4-MeO-Ph, X is NH, R 1 is Me, R^a is H, and R2 is ethynyl. Q is 2-Br-4-MeO-Ph, X is O, R1 and Rl a are both H, and R2 is H. Row Heading
Q is 2-Br-4-MeO-Ph, X is O, R and R^a are both H, and R2 is ethenyl. Q is 2-Br-4-MeO-Ph, X is O, R and Ri a are both H, and R2 is ethynyl. Q is 2-Br-4-MeO-Ph, X is O, R is Me, Rl a is H, and R2 is H.
Q is 2-Br-4-MeO-Ph, X is O, R is Me, R^a is H, and R2 is ethenyl.
Q is 2-Br-4-MeO-Ph, X is O, R is Me, R^a is H, and R2 is ethynyl.
Q is 2-Br-4-MeO-Ph, X is CHOH, R1 and Rl a are both H, and R2 is H. Q is 2-Br-4-MeO-Ph, X is CHOH, R1 and Rl a are both H, and R2 is ethenyl. Q is 2-Br-4-MeO-Ph, X is CHOH, R1 and Rl a are both H, and R2 is ethynyl. Q is 2-Br-4-MeO-Ph, X is CHOH, R1 is Me, Rl a is H, and R2 is H.
Q is 2-Br-4-MeO-Ph, X is CHOH, R1 is Me, Rl a is H, and R2 is ethenyl. Q is 2-Br-4-MeO-Ph, X is CHOH, R1 is Me, Rl a is H, and R2 is ethynyl. Q is 2-Br-4-Me-Ph, X is NH, R * and R^a are both H, and R2 is H.
Q is 2-Br-4-Me-Ph, X is NH, R * and Ri a are both H, and R2 is ethenyl. Q is 2-Br-4-Me-Ph, X is NH, R * and Ri a are both H, and R2 is ethynyl. Q is 2-Br-4-Me-Ph, X is NH, R 1 is Me, Rl a is H, and R2 is H.
Q is 2-Br-4-Me-Ph, X is NH, R 1 is Me, R^a is H, and R2 is ethenyl.
Q is 2-Br-4-Me-Ph, X is NH, R 1 is Me, Ri a is H, and R2 is ethynyl.
Q is 2-Br-4-Me-Ph, X is O, R and R1 are both H, and R2 is H.
Q is 2-Br-4-Me-Ph, X is O, R and Ri a are both H, and R2 is ethenyl. Q is 2-Br-4-Me-Ph, X is O, R and R^a are both H, and R2 is ethynyl. Q is 2-Br-4-Me-Ph, X is O, R is Me, Rl a is H, and R2 is H.
Q is 2-Br-4-Me-Ph, X is O, R is Me, R^ a is H, and R2 is ethenyl.
Q is 2-Br-4-Me-Ph, X is O, R is Me, R^a is H, and R2 is ethynyl.
Q is 2-Br-4-Me-Ph, X is CHOH, R and Ri a are both H, and R2 is H. Q is 2-Br-4-Me-Ph, X is CHOH, R and R^ a are both H, and R2 is ethenyl. Q is 2-Br-4-Me-Ph, X is CHOH, R and R^a are both H, and R2 is ethynyl. Q is 2-Br-4-Me-Ph, X is CHOH, R is Me, Rl a is H, and R2 is H.
Q is 2-Br-4-Me-Ph, X is CHOH, R is Me, R^a is H, and R2 is ethenyl. Q is 2-Br-4-Me-Ph, X is CHOH, R is Me, R^a is H, and R2 is ethynyl. Q is 2-Me-4-EtO-Ph, X is NH, R1 and Rl a are both H, and R2 is H.
Q is 2-Me-4-EtO-Ph, X is NH, R1 and Rl a are both H, and R2 is ethenyl. Q is 2-Me-4-EtO-Ph, X is NH, R1 and Rl a are both H, and R2 is ethynyl. Q is 2-Me-4-EtO-Ph, X is NH, R1 is Me, Rl a is H, and R2 is H.
Q is 2-Me-4-EtO-Ph, X is NH, R1 is Me, Rl a is H, and R2 is ethenyl.
Q is 2-Me-4-EtO-Ph, X is NH, R1 is Me, Rl a is H, and R2 is ethynyl. Q is 2-Me-4-EtO-Ph, X is O, R1 and Rl a are both H, and R2 is H.
Q is 2-Me-4-EtO-Ph, X is O, R1 and Rl a are both H, and R2 is ethenyl. Row Heading
Q 2-Me-4-EtO-Ph, X is O, R1 and Rl a are both H, and R2 is ethynyl.
Q 2-Me-4-EtO-Ph, X is O, R1 is Me, Rl a is H, and R2 is H.
Q 2-Me-4-EtO-Ph, X is O, R1 is Me, Rl a is H, and R2 is ethenyl.
Q IS 2-Me-4-EtO-Ph, X is O, R1 is Me, Rl a is H, and R2 is ethynyl.
Q is 2-Me-4-EtO-Ph, X is CHOH, R and R^a are both H, and R2 is H.
Q is 2-Me-4-EtO-Ph, X is CHOH, R and Ri a are both H, and R2 is ethenyl. Q is 2-Me-4-EtO-Ph, X is CHOH, R and Ri a are both H, and R2 is ethynyl. Q is 2-Me-4-EtO-Ph, X is CHOH, R is Me, Rl a is H, and R2 is H.
Q is 2-Me-4-EtO-Ph, X is CHOH, R is Me, R^a is H, and R2 is ethenyl. Q is 2-Me-4-EtO-Ph, X is CHOH, R is Me, R^a is H, and R2 is ethynyl. Q is 2-Cl-4-EtO-Ph, X is NH, R and Ri a are both H, and R2 is H.
Q is 2-Cl-4-EtO-Ph, X is NH, R and R^a are both H, and R2 is ethenyl.
Q is 2-Cl-4-EtO-Ph, X is NH, R and R^a are both H, and R2 is ethynyl.
Q is 2-Cl-4-EtO-Ph, X is NH, R is Me, Rl a is H, and R2 is H.
Q is 2-Cl-4-EtO-Ph, X is NH, R is Me, R^a is H, and R2 is ethenyl.
Q is 2-Cl-4-EtO-Ph, X is NH, R is Me, Rl a is H, and R2 is ethynyl.
Q is 2-Cl-4-EtO-Ph, X is O, R and Rl a are both H, and R2 is H.
Q is 2-Cl-4-EtO-Ph, X is O, R and R^a are both H, and R2 is ethenyl.
Q is 2-Cl-4-EtO-Ph, X is O, R and Rla are both H, and R2 is ethynyl.
Q is 2-Cl-4-EtO-Ph, X is O, R is Me, Rl a is H, and R2 is H.
Q is 2-Cl-4-EtO-Ph, X is O, R is Me, Rl a is H, and R2 is ethenyl.
Q is 2-Cl-4-EtO-Ph, X is O, R is Me, Rl a is H, and R2 is ethynyl.
Q is 2-Cl-4-EtO-Ph, X is CHOH, R and R^a are both H, and R2 is H.
Q is 2-Cl-4-EtO-Ph, X is CHOH, R and Rla are both H, and R2 is ethenyl. Q is 2-Cl-4-EtO-Ph, X is CHOH, R and Rla are both H, and R2 is ethynyl. Q is 2-Cl-4-EtO-Ph, X is CHOH, R is Me, Rl a is H, and R2 is H.
Q is 2-Cl-4-EtO-Ph, X is CHOH, R is Me, Rl a is H, and R2 is ethenyl.
Q is 2-Cl-4-EtO-Ph, X is CHOH, R is Me, R^a is H, and R2 is ethynyl.
Q is 3,5-di-Cl-pyridin-2-yl, X is NH, R1 and Rl a are both H, and R2 is H. Q is 3,5-di-Cl-pyridin-2-yl, X is NH, R1 and Rl a are both H, and R2 is ethenyl. Q is 3,5-di-Cl-pyridin-2-yl, X is NH, R1 and Rl a are both H, and R2 is ethynyl. Q 3,5-di-Cl-pyridin-2-yl, X is NH, R1 is Me, Rl a is H, and R2 is H.
Q 3,5-di-Cl-pyridin-2-yl, X is NH, R1 is Me, Rl a is H, and R2 is ethenyl. Q 3,5-di-Cl-pyridin-2-yl, X is NH, R1 is Me, Rl a is H, and R2 is ethynyl.
3,5-di-Cl-pyridin-2-yl, X is O, R1 and Rl a are both H, and R2 is H.
3,5-di-Cl-pyridin-2-yl, X is O, R1 and Rl a are both H, and R2 is ethenyl. 3,5-di-Cl-pyridin-2-yl, X is O, R^ and Rla are both H, and R2 is ethynyl. Row Heading
Q is 3,5-di-Cl-pyridin-2-yl, X is O, R1 is Me, Rl a is H, and R2 is H.
Q is 3,5-di-Cl-pyridin-2-yl, X is O, R1 is Me, Rl a is H, and R2 is ethenyl.
Q is 3,5-di-Cl-pyridin-2-yl, X is O, R1 is Me, Rl a is H, and R2 is ethynyl.
Q is 3,5-di-Cl-pyridin-2-yl, X is CHOH, R and Ri a are both H, and R2 is H. Q is 3,5-di-Cl-pyridin-2-yl, X is CHOH, R and R^a are both H, and R2 is ethenyl. Q is 3,5-di-Cl-pyridin-2-yl, X is CHOH, R and R^a are both H, and R2 is ethynyl. Q is 3,5-di-Cl-pyridin-2-yl, X is CHOH, R is Me, R^a is H, and R2 is H.
Q is 3,5-di-Cl-pyridin-2-yl, X is CHOH, R is Me, Rla is H, and R2 is ethenyl. Q is 3,5-di-Cl-pyridin-2-yl, X is CHOH, R is Me, Rla is H, and R2 is ethynyl. Q is 2,4,6-tri-Cl-Ph, X is NH, R1 and Rl a are both H, and R2 is H.
Q is 2,4,6-tri-F-Ph, X is NH, R1 and Rl a are both H, and R2 is ethenyl.
Q is 2,4,6-tri- F-Ph, X is NH, R1 and Rl a are both H, and R2 is ethynyl.
Q is 2,4,6-tri-F-Ph, X is NH, R1 is Me, Rl a is H, and R2 is H.
Q is 2,4,6-tri-F-Ph, X is NH, R1 is Me, Rl a is H, and R2 is ethenyl.
Q is 2,4,6-tri-F-Ph, X is NH, R1 is Me, Rl a is H, and R2 is ethynyl.
Q is 2,4,6-tri-F-Ph, X is O, R and R1 a are both H, and R2 is H.
Q is 2,4,6-tri-F-Ph, X is O, R and R^a are both H, and R2 is ethenyl.
Q is 2,4,6-tri-F-Ph, X is O, R and R^a are both H, and R2 is ethynyl.
Q is 2,4,6-tri-F-Ph, X is O, R is Me, Rl a is H, and R2 is H.
Q is 2,4,6-tri-F-Ph, X is O, R is Me, Rl a is H, and R2 is ethenyl.
Q is 2,4,6-tri-F-Ph, X is O, R is Me, R^a is H, and R2 is ethynyl.
Q is 2,4,6-tri-F-Ph, X is CHOH, R 1 and Ri a are both H, and R2 is H.
Q is 2,4,6-tri-F-Ph, X is CHOH, R * and Ri a are both H, and R2 is ethenyl.
Q is 2,4,6-tri-F-Ph, X is CHOH, R 1 and Rl a are both H, and R2 is ethynyl.
Q is 2,4,6-tri-F-Ph, X is CHOH, R 1 is Me, Rl a is H, and R2 is H.
Q is 2,4,6-tri-F-Ph, X is CHOH, R 1 is Me, R^a is H, and R2 is ethenyl.
Q is 2,4,6-tri-F-Ph, X is CHOH, R 1 is Me, R^a is H, and R2 is ethynyl.
Q is 2,4-di-Cl-Ph, X is NH, R and Rl a are both H, and R2 is H.
Q is 2,4-di-Cl-Ph, X is NH, R and R^ are both H, and R2 is ethenyl.
Q is 2,4-di-Cl-Ph, X is NH, R and R1 are both H, and R2 is ethynyl.
Q is 2,4-di-Cl-Ph, X is NH, R is Me, Rl a is H, and R2 is H.
Q is 2,4-di-Cl-Ph, X is NH, R is Me, R^a is H, and R2 is ethenyl.
Q is 2,4-di-Cl-Ph, X is NH, R is Me, Rl is H, and R2 is ethynyl.
Q is 2,4-di-Cl-Ph, X is O, R1 and Rl a are both H, and R2 is H.
Q is 2,4-di-Cl-Ph, X is O, R1 and Rl a are both H, and R2 is ethenyl.
Q is 2,4-di-Cl-Ph, X is O, R1 and Rl a are both H, and R2 is ethynyl.
Q is 2,4-di-Cl-Ph, X is O, R1 is Me, Rl is H, and R2 is H. Row Heading
Q is 2,4-di-Cl-Ph, X is O, R1 is Me, Rl a is H, and R2 is ethenyl.
Q is 2,4-di-Cl-Ph, X is O, R1 is Me, Rl a is H, and R2 is ethynyl.
Q is 2,4-di-Cl-Ph, X is CHOH, R 1 and Ri a are both H, and R2 is H. Q is 2,4-di-Cl-Ph, X is CHOH, R 1 and R^a are both H, and R2 is ethenyl. Q is 2,4-di-Cl-Ph, X is CHOH, R 1 and R^ a are both H, and R2 is ethynyl. Q is 2,4-di-Cl-Ph, X is CHOH, R 1 is Me, Rl a is H, and R2 is H.
Q is 2,4-di-Cl-Ph, X is CHOH, R 1 is Me, R^a is H, and R2 is ethenyl. Q is 2,4-di-Cl-Ph, X is CHOH, R 1 is Me, R^a is H, and R2 is ethynyl. Q is 2-Br-4-F-Ph, X is NH, R 1 and Rl a are both H, and R2 is H.
Q is 2-Br-4-F-Ph, X is NH, R 1 and R^a are both H, and R2 is ethenyl. Q is 2-Br-4-F-Ph, X is NH, R 1 and R^a are both H, and R2 is ethynyl. Q is 2-Br-4-F-Ph, X is NH, R 1 is Me, Rl a is H, and R2 is H.
Q is 2-Br-4-F-Ph, X is NH, R 1 is Me, R^ a is H, and R2 is ethenyl.
Q is 2-Br-4-F-Ph, X is NH, R 1 is Me, R^a is H, and R2 is ethynyl.
Q is 2-Br-4-F-Ph, X is O, R and Rl a are both H, and R2 is H.
Q is 2-Br-4-F-Ph, X is O, R and R^a are both H, and R2 is ethenyl. Q is 2-Br-4-F-Ph, X is O, R and Ri a are both H, and R2 is ethynyl. Q is 2-Br-4-F-Ph, X is O, R is Me, Rl a is H, and R2 is H.
Q is 2-Br-4-F-Ph, X is O, R is Me, R^ a is H, and R2 is ethenyl.
Q is 2-Br-4-F-Ph, X is O, R is Me, R^ a is H, and R2 is ethynyl.
Q is 2-Br-4-F-Ph, X is CHOH, R and Ri a are both H, and R2 is H. Q is 2-Br-4-F-Ph, X is CHOH, R and R^a are both H, and R2 is ethenyl. Q is 2-Br-4-F-Ph, X is CHOH, R and R^a are both H, and R2 is ethynyl. Q is 2-Br-4-F-Ph, X is CHOH, R is Me, Rl a is H, and R is H.
Q is 2-Br-4-F-Ph, X is CHOH, R is Me, R^ a is H, and R2 is ethenyl. Q is 2-Br-4-F-Ph, X is CHOH, R is Me, R^a is H, and R2 is ethynyl. Q is 2-Br-6-F-Ph, X is NH, R1 and Rl a are both H, and R2 is H.
Q is 2-Br-6-F-Ph, X is NH, R1 and Rl a are both H, and R2 is ethenyl. Q is 2-Br-6-F-Ph, X is NH, R1 and Rl a are both H, and R2 is ethynyl. Q is 2-Br-6-F-Ph, X is NH, R1 is Me, Rl a is H, and R2 is H.
Q is 2-Br-6-Fl-Ph, X is NH, R1 is Me, Rl a is H, and R2 is ethenyl. Q is 2-Br-6-Fl-Ph, X is NH, R1 is Me, Rl a is H, and R2 is ethynyl. Q is 2-Br-6-F-Ph, X is O, R and Ri a are both H, and R2 is H.
Q is 2-Br-6-F-Ph, X is O, R and R^a are both H, and R2 is ethenyl. Q is 2-Br-6-F-Ph, X is O, R and R^a are both H, and R2 is ethynyl. Q is 2-Br-6-F-Ph, X is O, R is Me, Rl a is H, and R2 is H.
Q is 2-Br-6-F-Ph, X is O, R is Me, Rl a is H, and R2 is ethenyl. Row Heading
Q is 2-Br-6-F-Ph, X is O, R1 is Me, Rl a is H, and R2 is ethynyl.
Q is 2-Br-6-F-Ph, X is CHOH, R1 and Rl a are both H, and R2 is H.
Q is 2-Br-6-F-Ph, X is CHOH, R1 and Rl a are both H, and R2 is ethenyl. Q is 2-Br-6-F-Ph, X is CHOH, R1 and Rl a are both H, and R2 is ethynyl. Q is 2-Br-6-F-Ph, X is CHOH, R1 is Me, Rl a is H, and R2 is H.
Q is 2-Br-6-F-Ph, X is CHOH, R1 is Me, Rl a is H, and R2 is ethenyl.
Q is 2-Br-6-F -Ph, X is CHOH, R1 is Me, Rl a is H, and R2 is ethynyl.
Q is 2,6-di-F-3-CN-Ph, X is NH, R 1 and RI A are both H, and R2 is H.
Q is 2,6-di-F-3-CN-Ph, X is NH, R 1 and R1 a are both H, and R2 is ethenyl. Q is 2,6-di-F-3-CN-Ph, X is NH, R 1 and R^A are both H, and R2 is ethynyl. Q is 2,6-di-F-3-CN-Ph, X is NH, R 1 is Me, R^A is H, and R2 is H.
Q is 2,6-di-F-3-CN-Ph, X is NH, R 1 is Me, R^A is H, and R2 is ethenyl.
Q is 2,6-di-F-3-CN-Ph, X is NH, R 1 is Me, R^A is H, and R2 is ethynyl.
Q is 2,6-di-F-3-CN-Ph, X is O, R1 and RL A are both H, and R2 is H.
Q is 2,6-di-F-3-CN-Ph, X is O, R1 and RL A are both H, and R2 is ethenyl. Q is 2,6-di-F-3-CN-Ph, X is O, R1 and RL A are both H, and R2 is ethynyl. Q is 2,6-di-F-3-CN-Ph, X is O, R1 is Me, RL A is H, and R2 is H.
Q is 2,6-di-F-3-CN-Ph, X is O, R1 is Me, RL A is H, and R2 is ethenyl.
Q is 2,6-di-F-3-CN-Ph, X is O, R1 is Me, RL A is H, and R2 is ethynyl.
Q is 2,6-di-F-3-CN-Ph, X is CHOH, R and RI A are both H, and R2 is H. Q is 2,6-di-F-3-CN-Ph, X is CHOH, R and R1 a are both H, and R2 is ethenyl. Q is 2,6-di-F-3-CN-Ph, X is CHOH, R and R^A are both H, and R2 is ethynyl. Q is 2,6-di-F-3-CN-Ph, X is CHOH, R is Me, RL A is H, and R2 is H.
Q is 2,6-di-F-3-CN-Ph, X is CHOH, R is Me, R^A is H, and R2 is ethenyl. Q is 2,6-di-F-3-CN-Ph, X is CHOH, R is Me, R^A is H, and R2 is ethynyl. Q is 2-Me-4-MeO-Ph, X is NH, R1 and Rl a are both H, and R2 is H.
Q is 2-Me-4-MeO-Ph, X is NH, R1 and Rl a are both H, and R2 is ethenyl. Q is 2-Me-4-MeO-Ph, X is NH, R1 and Rl a are both H, and R2 is ethynyl. Q is 2-Me-4-MeO-Ph, X is NH, R1 is Me, Rl a is H, and R2 is H.
Q is 2-Me-4-MeO-Ph, X is NH, R1 is Me, Rl a is H, and R2 is ethenyl.
Q is 2-Me-4-MeO-Ph, X is NH, R1 is Me, Rl a is H, and R2 is ethynyl.
Q is 2-Me-4-MeO-Ph, X is O, R1 and Rl a are both H, and R2 is H.
Q is 2-Me-4-MeO-Ph, X is O, R1 and Rl a are both H, and R2 is ethenyl. Q is 2-Me-4-MeO-Ph, X is O, R1 and Rl a are both H, and R2 is ethynyl. Q is 2-Me-4-MeO-Ph, X is O, R1 is Me, Rl a is H, and R2 is H.
Q is 2-Me-4-MeO-Ph, X is O, R1 is Me, Rl a is H, and R2 is ethenyl.
Q is 2-Me-4-MeO-Ph, X is O, R1 is Me, Rl a is H, and R2 is ethynyl. Row Heading
Q is 2-Me-4-MeO-Ph, X is CHOH, R and R^a are both H, and R2 is H. Q is 2-Me-4-MeO-Ph, X is CHOH, R 1 and R^a are both H, and R2 is ethenyl. Q is 2-Me-4-MeO-Ph, X is CHOH, R 1 and R^a are both H, and R2 is ethynyl. Q is 2-Me-4-MeO-Ph, X is CHOH, R 1 is Me, Rl a is H, and R2 is H.
Q is 2-Me-4-MeO-Ph, X is CHOH, R 1 is Me, R^a is H, and R2 is ethenyl. Q is 2-Me-4-MeO-Ph, X is CHOH, R 1 is Me, R^a is H, and R2 is ethynyl. Q is 2-Me-4-Br-Ph, X is NH, R * and Ri a are both H, and R2 is H.
Q is 2-Me-4-Br-Ph, X is NH, R and R are both H, and R is ethenyl. Q is 2-Me-4-Br-Ph, X is NH, R * and Ri a are both H, and R2 is ethynyl. Q is 2-Me-4-Br-Ph, X is NH, R 1 is Me, Rl a is H, and R2 is H.
Q is 2-Me-4-Br-Ph, X is NH, R 1 is Me, R^a is H, and R2 is ethenyl.
Q is 2-Me-4-Br-Ph, X is NH, R 1 is Me, R^ a is H, and R2 is ethynyl.
Q is 2-Me-4-Br-Ph, X is O, R and Ri a are both H, and R2 is H.
Q is 2-Me-4-Br-Ph, X is O, R and R^a are both H, and R2 is ethenyl.
Q is 2-Me-4-Br-Ph, X is O, R and R^a are both H, and R2 is ethynyl.
Q is 2-Me-4-Br-Ph, X is O, R is Me, Rl a is H, and R2 is H.
Q is 2-Me-4-Br-Ph, X is O, R is Me, R^a is H, and R2 is ethenyl.
Q is 2-Me-4-Br-Ph, X is O, R is Me, R^a is H, and R2 is ethynyl.
Q is 2-Me-4-Br-Ph, X is CHOH, R 1 and Ri a are both H, and R2 is H.
Q is 2-Me-4-Br-Ph, X is CHOH, R 1 and R^a are both H, and R2 is ethenyl. Q is 2-Me-4-Br-Ph, X is CHOH, R 1 and R^a are both H, and R2 is ethynyl. Q is 2-Me-4-Br-Ph, X is CHOH, R 1 is Me, Rl a is H, and R2 is H.
Q is 2-Me-4-Br-Ph, X is CHOH, R 1 is Me, ^a is H, and R2 is ethenyl. Q is 2-Me-4-Br-Ph, X is CHOH, R 1 is Me, R^a is H, and R2 is ethynyl. Q is 2-Cl-4-MeO-Ph, X is NH, R * and Ri a are both H, and R2 is H.
Q is 2-Cl-4-MeO-Ph, X is NH, R * and Ri a are both H, and R2 is ethenyl. Q is 2-Cl-4-MeO-Ph, X is NH, R 1 and R are both H, and R2 is ethynyl. Q is 2-Cl-4-MeO-Ph, X is NH, R 1 is Me, Rl a is H, and R2 is H.
Q is 2-Cl-4-MeO-Ph, X is NH, R 1 is Me, R^a is H, and R2 is ethenyl.
Q is 2-Cl-4-MeO-Ph, X is NH, R 1 is Me, R^a is H, and R2 is ethynyl.
Q is 2-Cl-4-MeO-Ph, X is O, R and R1 a are both H, and R2 is H.
Q is 2-Cl-4-MeO-Ph, X is O, R and R a are both H, and R2 is ethenyl. Q is 2-Cl-4-MeO-Ph, X is O, R and Ri a are both H, and R2 is ethynyl. Q is 2-Cl-4-MeO-Ph, X is O, R is Me, Rl a is H, and R2 is H.
Q is 2-Cl-4-MeO-Ph, X is O, R is Me, R^ a is H, and R2 is ethenyl.
Q is 2-Cl-4-MeO-Ph, X is O, R is Me, R^a is H, and R2 is ethynyl.
Q is 2-Cl-4-MeO-Ph, X is CHOH, R1 and Rl a are both H, and R2 is H. Row Heading
Q 2-Cl-4-MeO-Ph, X is CHOH, R1 and RL A are both H, and R2 is ethenyl. Q 2-Cl-4-MeO-Ph, X is CHOH, R1 and RL A are both H, and R2 is ethynyl. Q 2-Cl-4-MeO-Ph, X is CHOH, R1 is Me, RL A is H, and R2 is H.
Q 2-Cl-4-MeO-Ph, X is CHOH, R1 is Me, RL A is H, and R2 is ethenyl. Q s 2-Cl-4-MeO-Ph, X is CHOH, R1 is Me, RL A is H, and R2 is ethynyl. Q is 2-Cl-4-Me-Ph, X is NH, R and Ri a are both H, and R2 is H.
Q is 2-Cl-4-Me-Ph, X is NH, R and R1 a are both H, and R2 is ethenyl.
Q is 2-Cl-4-Me-Ph, X is NH, R and R^A are both H, and R2 is ethynyl.
Q is 2-Cl-4-Me-Ph, X is NH, R is Me, RL A is H, and R2 is H.
Q is 2-Cl-4-Me-Ph, X is NH, R is Me, RL A is H, and R2 is ethenyl.
Q is 2-Cl-4-Me-Ph, X is NH, R is Me, ^A is H and R2 is ethynyl.
Q is 2-Cl-4-Me-Ph, X is O, R1 and RL A are both H, and R2 is H.
Q is 2-Cl-4-Me-Ph, X is O, R1 and RL A are both H, and R2 is ethenyl.
Q IS 2-Cl-4-Me-Ph, X is O, R1 and RL A are both H, and R2 is ethynyl.
Q is 2-Cl-4-Me-Ph, X is O, R1 is Me, RL A is H, and R2 is H.
Q is 2 : -Cl-4-Me-Ph, X is O, R1 is Me, RL A is H, and R2 is ethenyl.
Q is 2-Cl-4-Me-Ph, X is O, R1 is Me, RL A is H, and R2 is ethynyl.
Q i ss 2-Cl-4-Me-Ph, X is CHOH, R1 and RL A are both H, and R2 is H.
Q is 2-Cl-4-Me-Ph, X is CHOH, R1 and RL A are both H, and R2 is ethenyl. Q is 2-Cl-4-Me-Ph, X is CHOH, R1 and RL A are both H, and R2 is ethynyl. Q is 2-Cl-4-Me-Ph, X is CHOH, R1 is Me, RL A is H, and R2 is H.
Q is 2-Cl-4-Me-Ph, X is CHOH, R1 is Me, RL A is H, and R2 is ethenyl.
Q is 2-Cl-4-Me-Ph, X is CHOH, R1 is Me, RL A is H, and R2 is ethynyl.
Q i ss 2.6-di-Cl-4-Me-Ph, X is NH, R1 and RL A are both H, and R2 is H.
Q is 2.6-di-Cl-4-Me-Ph, X is NH, R1 and RL A are both H, and R2 is ethenyl. Q is 2.6-di-Cl-4-Me-Ph, X is NH, R1 and RL A are both H, and R2 is ethynyl. Q is 2.6-di-Cl-4-Me-Ph, X is NH, R1 is Me, RL A is H, and R2 is H.
Q is 2.6-di-Cl-4-Me-Ph, X is NH, R1 is Me, RL A is H, and R2 is ethenyl.
Q is 2.6-di-Cl-4-Me-Ph, X is NH, R1 is Me, RL A is H, and R2 is ethynyl. Q is 2.6-di-Cl-4-Me-Ph, X is O, R1 and RL A are both H, and R2 is H.
Q iiss 2.6-di-Cl-4-Me-Ph, X is O, R1 and RL A are both H, and R2 is ethenyl. Q is 2.6-di-Cl-4-Me-Ph, X is O, R1 and RL A are both H, and R2 is ethynyl. Q is 2.6-di-Cl-4-Me-Ph, X is O, R1 is Me, RL A is H, and R2 is H.
Q is 2.6-di-Cl-4-Me-Ph, X is O, R1 is Me, RL A is H, and R2 is ethenyl.
Q is 2.6-di-Cl-4-Me-Ph, X is O, R1 is Me, RL A is H, and R2 is ethynyl.
Q1 is 2.6-di-Cl-4-Me-Ph, X is CHOH, R1 and RL A are both H, and R2 is H. Q1 is 2.6-di-Cl-4-Me-Ph, X is CHOH, R1 and RL A are both H, and R2 is ethenyl. Row Heading
Q is 2.6-di-Cl-4-Me-Ph, X is CHOH, R1 and Rl a are both H, and R2 is ethynyl. Q is 2.6-di-Cl-4-Me-Ph, X is CHOH, R1 is Me, Rl a is H, and R2 is H.
Q is 2.6-di-Cl-4-Me-Ph, X is CHOH, R1 is Me, Rl a is H, and R2 is ethenyl. Q is 2.6-di-Cl-4-Me-Ph, X is CHOH, R1 is Me, Rl a is H, and R2 is ethynyl. Q is 2-F-4-EtO-Ph, X is NH, R1 and Rla are both H, and R2 is H.
Q is 2-F-4-EtO-Ph, X is NH, R1 and Rl a are both H, and R2 is ethenyl.
Q is 2-F-4-EtO-Ph, X is NH, R1 and Rl a are both H, and R2 is ethynyl.
Q is 2-F-4-EtO-Ph, X is NH, R1 is Me, Rla is H, and R2 is H.
Q is 2-F-4-EtO-Ph, X is NH, R1 is Me, Rl a is H, and R2 is ethenyl.
Q is 2-F-4-EtO-Ph, X is NH, R1 is Me, Rl a is H, and R2 is ethynyl.
Q is 2-F-4-EtO-Ph, X is O, R 1 and Ri a are both H, and R2 is H.
Q is 2-F-4-EtO-Ph, X is O, R 1 and R^a are both H, and R2 is ethenyl.
Q is 2-F-4-EtO-Ph, X is O, R 1 and R^a are both H, and R2 is ethynyl.
Q is 2-F-4-EtO-Ph, X is O, R 1 is Me, Rla is H, and R2 is H.
Q is 2-F-4-EtO-Ph, X is O, R 1 is Me, R^a is H, and R2 is ethenyl.
Q is 2-F-4-EtO-Ph, X is O, R 1 is Me, R^a is H, and R2 is ethynyl.
Q is 2-F-4-EtO-Ph, X is CHOH, R1 and Rl a are both H, and R2 is H.
Q is 2-F-4-EtO-Ph, X is CHOH, R1 and Rl a are both H, and R2 is ethenyl. Q is 2-F-4-EtO-Ph, X is CHOH, R1 and Rl a are both H, and R2 is ethynyl. Q is 2-F-4-EtO-Ph, X is CHOH, R1 is Me, Rl a is H, and R2 is H.
Q is 2-F-4-EtO-Ph, X is CHOH, R1 is Me, Rl a is H, and R2 is ethenyl.
Q is 2-F-4-EtO-Ph, X is CHOH, R1 is Me, Rl a is H, and R2 is ethynyl.
Q is 2-Br-4-EtO-Ph, X is NH, R1 and Rl a are both H, and R2 is H.
Q is 2-Br-4-EtO-Ph, X is NH, R1 and Rl a are both H, and R2 is ethenyl. Q is 2-Br-4-EtO-Ph, X is NH, R1 and Rl a are both H, and R2 is ethynyl. Q is 2-Br-4-EtO-Ph, X is NH, R1 is Me, Rl a is H, and R2 is H.
Q is 2-Br-4-EtO-Ph, X is NH, R1 is Me, Rl a is H, and R2 is ethenyl.
Q is 2-Br-4-EtO-Ph, X is NH, R1 is Me, Rl a is H, and R2 is ethynyl.
Q is 2-Br-4-EtO-Ph, X is O, R1 and Rl a are both H, and R2 is H.
Q is 2-Br-4-EtO-Ph, X is O, R1 and Rl a are both H, and R2 is ethenyl.
Q is 2-Br-4-EtO-Ph, X is O, R1 and Rl a are both H, and R2 is ethynyl.
Q is 2-Br-4-EtO-Ph, X is O, R1 is Me, Rl a is H, and R2 is H.
Q is 2-Br-4-EtO-Ph, X is O, R1 is Me, Rl a is H, and R2 is ethenyl.
Q is 2-Br-4-EtO-Ph, X is O, R1 is Me, Rl a is H, and R2 is ethynyl.
Q is 2-Br-4-EtO-Ph, X is CHOH, R1 and Rl a are both H, and R2 is H.
Q is 2-Br-4-EtO-Ph, X is CHOH, R1 and Rl a are both H, and R2 is ethenyl. Q is 2-Br-4-EtO-Ph, X is CHOH, R1 and Rl a are both H, and R2 is ethynyl. Row Heading
Q is 2-Br-4-EtO-Ph, X is CHOH, R1 is Me, Rl a is H, and R2 is H.
Q is 2-Br-4-EtO-Ph, X is CHOH, R1 is Me, Rl a is H, and R2 is ethenyl. Q is 2-Br-4-EtO-Ph, X is CHOH, R1 is Me, Rl a is H, and R2 is ethynyl. Q is 2-Cl-4-CN-Ph, X is NH, R 1 and Rla are both H, and R2 is H.
Q is 2-Cl-4-CN-Ph, X is NH, R * and Ri a are both H, and R2 is ethenyl. Q is 2-Cl-4-CN-Ph, X is NH, R 1 and R^a are both H, and R2 is ethynyl. Q is 2-Cl-4-CN-Ph, X is NH, R 1 is Me, Rla is H, and R2 is H.
Q is 2-Cl-4-CN-Ph, X is NH, R 1 is Me, R^a is H, and R2 is ethenyl.
Q is 2-Cl-4-CN-Ph, X is NH, R 1 is Me, R^a is H, and R2 is ethynyl.
Q is 2-Cl-4-CN-Ph, X is O, R and Rl a are both H, and R2 is H.
Q is 2-Cl-4-CN-Ph, X is O, R and R1 a are both H, and R2 is ethenyl. Q is 2-Cl-4-CN-Ph, X is O, R and Ri a are both H, and R2 is ethynyl. Q is 2-Cl-4-CN-Ph, X is O, R is Me, Rl a is H, and R2 is H.
Q is 2-Cl-4-CN-Ph, X is O, R is Me, R^a is H, and R2 is ethenyl.
Q is 2-Cl-4-CN-Ph, X is O, R is Me, R^a is H, and R2 is ethynyl.
Q is 2-Cl-4-CN-Ph, X is CHOH, R * and Ri a are both H, and R2 is H. Q is 2-Cl-4-CN-Ph, X is CHOH, R 1 and R^a are both H, and R2 is ethenyl. Q is 2-Cl-4-CN-Ph, X is CHOH, R 1 and R^a are both H, and R2 is ethynyl. Q is 2-Cl-4-CN-Ph, X is CHOH, R 1 is Me, Rl a is H, and R2 is H.
Q is 2-Cl-4-CN-Ph, X is CHOH, R 1 is Me, R^a is H, and R2 is ethenyl. Q is 2-Cl-4-CN-Ph, X is CHOH, R 1 is Me, ^a is H, and R2 is ethynyl. Q is 2-Br-4-CN-Ph, X is NH, R * and R a are both H, and R2 is H.
Q is 2-Br-4-CN-Ph, X is NH, R * and Ri a are both H, and R2 is ethenyl. Q is 2-Br-4-CN-Ph, X is NH, R * and Ri a are both H, and R2 is ethynyl. Q is 2-Br-4-CN-Ph, X is NH, R 1 is Me, Rl a is H, and R2 is H.
Q is 2-Br-4-CN-Ph, X is NH, R 1 is Me, R^a is H, and R2 is ethenyl.
Q is 2-Br-4-CN-Ph, X is NH, R 1 is Me, R^a is H, and R2 is ethynyl.
Q is 2-Br-4-CN-Ph, X is O, R and Rl a are both H, and R2 is H.
Q is 2-Br-4-CN-Ph, X is O, R and Ri a are both H, and R2 is ethenyl. Q is 2-Br-4-CN-Ph, X is O, R and Rla are both H, and R2 is ethynyl. Q is 2-Br-4-CN-Ph, X is O, R is Me, Rl a is H, and R2 is H.
Q is 2-Br-4-CN-Ph, X is O, R is Me, R^a is H, and R2 is ethenyl.
Q is 2-Br-4-CN-Ph, X is O, R is Me, R1 a is H, and R2 is ethynyl.
Q is 2-Br-4-CN-Ph, X is CHOH, R1 and RL A are both H, and R2 is H. Q is 2-Br-4-CN-Ph, X is CHOH, R1 and RL A are both H, and R2 is ethenyl. Q is 2-Br-4-CN-Ph, X is CHOH, R1 and RL A are both H, and R2 is ethynyl. Q is 2-Br-4-CN-Ph, X is CHOH, R1 is Me, RL A is H, and R2 is H. Table Row Heading
503 Q1 is 2-Br-4-CN-Ph, X is CHOH, R1 is Me, Rl a is H, and R2 is ethenyl.
504 Q1 is 2-Br-4-CN-Ph, X is CHOH, R1 is Me, Rl a is H, and R2 is ethynyl.
505 Q1 is 2-Cl-thien-3-yl, X is NH, R1 and Rl a are both H, and R2 is H.
506 Q1 is 2-Cl-thien-3-yl, X is NH, R1 and Rl a are both H, and R2 is ethenyl.
507 Q1 is 2-Cl-thien-3-yl, X is NH, R1 and Rl a are both H, and R2 is ethynyl.
508 Q1 is 2-Cl-thien-3-yl, X is NH, R1 is Me, Rl a is H, and R2 is H.
509 Q1 is 2-Cl-thien-3-yl, X is NH, R1 is Me, Rl a is H, and R2 is ethenyl.
510 Q1 is 2-Cl-thien-3-yl, X is NH, R1 is Me, Rl a is H, and R2 is ethynyl.
511 Q1 is 2-Cl-thien-3-yl, X is O, R1 and Rl a are both H, and R2 is H.
515 Q1 is 2-Cl-thien-3-yl, X is O, R1 and Rl a are both H, and R2 is ethenyl.
513 Q1 is 2-Cl-thien-3-yl, X is O, R1 and Rl a are both H, and R2 is ethynyl.
514 Q1 is 2-Cl-thien-3-yl, X is O, R1 is Me, Rl a is H, and R2 is H.
515 Q1 is 2-Cl-thien-3-yl, X is O, R1 is Me, Rl a is H, and R2 is ethenyl.
516 Q1 is 2-Cl-thien-3-yl, X is O, R1 is Me, Rl a is H, and R2 is ethynyl.
517 Q1 is 2-Cl-thien-3-yl, X is CHOH, R1 and Rl a are both H, and R2 is H.
518 Q1 is 2-Cl-thien-3-yl, X is CHOH, R1 and Rl a are both H, and R2 is ethenyl.
519 Q1 is 2-Cl-thien-3-yl, X is CHOH, R1 and Rl a are both H, and R2 is ethynyl.
520 Q1 is 2-Cl-thien-3-yl, X is CHOH, R1 is Me, Rl a is H, and R2 is H.
521 Q1 is 2-Cl-thien-3-yl, X is CHOH, R1 is Me, Rl a is H, and R2 is ethenyl.
522 Q1 is 2-Cl-thien-3-yl, X is CHOH, R1 is Me, Rl a is H, and R2 is ethynyl.
523 Q1 is 2,6-di-F-Ph, X is NH, R1 and Rl a are -CH2CH2-, and R2 is H.
524 Q1 is 2,4-di-F-Ph, X is NH, R1 and Rl a are -CH2CH2-, and R2 is ethenyl.
525 Q1 is 2-Cl-4-F-Ph, X is NH, R1 and Rl a are -CH2CH2-, and R2 is ethynyl.
526 Q1 is 2,6-di-Cl-Ph, X is NH, R1 and Rl a are both H, and R2 is 1-propenyl.
527 Q1 is 2-Br-4-Cl-Ph, X is NH, R1 and Rl a are both H, and R2 is 2-propenyl.
528 Q1 is 2-Br-6-Cl-Ph, X is NH, R1 and Rl a are both H, and R2 is 1-propynyl.
529 Q1 is 2-Me-4-F-Ph, X is NH, R1 and Rl a are both H, and R2 is 2-propynyl.
TABLE 530
3-Cl-2-pyridinyl
Figure imgf000069_0001
Figure imgf000070_0001
The present disclosure also includes Tables 531 through 799, each of which is constructed the same as Table 530 above, except that the row heading in Table 530 (i.e. "Q1 is 2,6-di-F-Ph, X is NH, R1 and Rla are both H, and R2 is H.") is replaced with the respective row heading shown below. For Example, in Table 531 the row heading is "Q1 is 2,4-di-F-Ph, X is NH, R1 and Rla are both H, and R2 is H", and Q2 is as defined in Table 530 above. Tables 532 through 799 are constructed similarly.
Table Row Heading
531 Q1 is 2,4-di-F-Ph, X is NH, R1 and Rl a are both H, and R2 is H.
532 Q1 is 2,4,6-tri-F-Ph, X is NH, R1 and Rl a are both H, and R2 is H.
533 Q1 is 2,6-di-F-4-MeO-Ph, X is NH, R1 and Rl a are both H, and R2 is H.
534 Q1 is 2,6-di-F-4-EtO-Ph, X is NH, R1 and Rl a are both H, and R2 is H.
535 Q1 is 2,6-di-F-4-CN-Ph, X is NH, R1 and Rl a are both H, and R2 is H.
536 Q1 is 2,6-di-F-3-MeO-Ph, X is NH, R1 and Rl a are both H, and R2 is H.
537 Q1 is 2,6-di-F-3-CN-Ph, X is NH, R1 and Rl a are both H, and R2 is H.
538 Q1 is 2,4,5-tri-F-Ph, X is NH, R1 and Rl a are both H, and R2 is H.
539 Q1 is 2,4-di-Cl-Ph, X is NH, R1 and Rl a are both H, and R2 is H.
540 Q1 is 2,6-di-Cl-Ph, X is NH, R1 and Rl a are both H, and R2 is H.
541 Q1 is 2-Cl-4-F-Ph, X is NH, R1 and Rl a are both H, and R2 is H.
542 Q1 is 2-Cl-6-F-Ph, X is NH, R1 and Rl a are both H, and R2 is H. Row Heading
Q1 is 2-Br-4-F-Ph, X is NH, R1 and Rl a are both H, and R2 is H.
Q1 is 2-Br-6-F-Ph, X is NH, R1 and Rl a are both H, and R2 is H.
Q1 is 2-F-4-MeO-Ph, X is NH, R1 and Rl a are both H, and R2 is H.
Q1 is 2-Cl-4-MeO-Ph, X is NH, R1 and Rl a are both H, and R2 is H.
Q1 is 2-Br-4-MeO-Ph, X is NH, R1 and Rl a are both H, and R2 is H.
Q1 is 2-F-4-EtO-Ph, X is NH, R1 and Rl a are both H, and R2 is H.
Q1 is 2-Cl-4-EtO-Ph, X is NH, R1 and Rl a are both H, and R2 is H.
Q1 is 2-Br-4-EtO-Ph, X is NH, R1 and Rl a are both H, and R2 is H.
Q1 is 2-F-4-Me-Ph, X is NH, R1 and Rl a are both H, and R2 is H.
Q1 is 2-Cl-4-Me-Ph, X is NH, R1 and Rl a are both H, and R2 is H.
Q1 is 2-Br-4-Me-Ph, X is NH, R1 and Rl a are both H, and R2 is H.
Q1 is 2-Me-4-Me-Ph, X is NH, R1 and Rl a are both H, and R2 is H.
Q1 is 2-Me-4-F-Ph, X is NH, R1 and Rl a are both H, and R2 is H.
Q1 is 2-Me-4-MeO-Ph, X is NH, R1 and Rl a are both H, and R2 is H.
Q1 is 2-Me-4-EtO-Ph, X is NH, R1 and Rl a are both H, and R2 is H.
Q1 is 3,5-di-Cl-pyridin-2-yl, X is NH, R1 and Rl a are both H, and R2 is H.
Q1 is 2-Cl-thien-3-yl, X is NH, R1 and Rl a are both H, and R2 is H.
Q1 is 2,6-di-F-Ph, X is NH, R1 and Rl a are both H, and R2 is ethenyl.
Q1 is 2,4-di-F-Ph, X is NH, R1 and Rl a are both H, and R2 is ethenyl.
Q1 is 2,4,6-tri-F-Ph, X is NH, R1 and Rl a are both H, and R2 is ethenyl.
Q1 is 2,6-di-F-4-MeO-Ph, X is NH, R1 and Rl a are both H, and R2 is ethenyl.
Q1 is 2,6-di-F-4-EtO-Ph, X is NH, R1 and Rl a are both H, and R2 is ethenyl.
Q1 is 2,6-di-F-4-CN-Ph, X is NH, R1 and Rl a are both H, and R2 is ethenyl.
Q1 is 2,6-di-F-3-MeO-Ph, X is NH, R1 and Rl a are both H, and R2 is ethenyl.
Q1 is 2,6-di-F-3-CN-Ph, X is NH, R1 and Rl a are both H, and R2 is ethenyl.
Q1 is 2,4,5-tri-F-Ph, X is NH, R1 and Rl a are both H, and R2 is ethenyl.
Q1 is 2,4-di-Cl-Ph, X is NH, R1 and Rl a are both H, and R2 is ethenyl.
Q1 is 2,6-di-Cl-Ph, X is NH, R1 and Rl a are both H, and R2 is ethenyl.
Q1 is 2-Cl-4-F-Ph, X is NH, R1 and Rl a are both H, and R2 is ethenyl.
Q1 is 2-Cl-6-F-Ph, X is NH, R1 and Rl a are both H, and R2 is ethenyl.
Q1 is 2-Br-4-F-Ph, X is NH, R1 and Rl a are both H, and R2 is ethenyl.
Q1 is 2-Br-6-F-Ph, X is NH, R1 and Rl a are both H, and R2 is ethenyl.
Q1 is 2-F-4-MeO-Ph, X is NH, R1 and Rl a are both H, and R2 is ethenyl.
Q1 is 2-Cl-4-MeO-Ph, X is NH, R1 and Rl a are both H, and R2 is ethenyl.
Q1 is 2-Br-4-MeO-Ph, X is NH, R1 and Rl a are both H, and R2 is ethenyl.
Q1 is 2-F-4-EtO-Ph, X is NH, R1 and Rl a are both H, and R2 is ethenyl.
Q1 is 2-Cl-4-EtO-Ph, X is NH, R1 and Rl a are both H, and R2 is ethenyl. Row Heading
Q 2-Br-4-EtO-Ph, X is NH, R1 and Rl a are both H, and R2 is ethenyl. Q 2-F-4-Me-Ph, X is NH, R1 and Rl a are both H, and R2 is ethenyl.
Q 2-Cl-4-Me-Ph, X is NH, R1 and Rl a are both H, and R2 is ethenyl.
Q 2-Br-4-Me-Ph, X is NH, R1 and Rl a are both H, and R2 is ethenyl.
Q 2-Me-4-Me-Ph, X is NH, R1 and Rl a are both H, and R2 is ethenyl. Q 2-Me-4-F-Ph, X is NH, R1 and Rl a are both H, and R2 is ethenyl.
Q 2-Me-4-MeO-Ph, X is NH, R1 and Rl a are both H, and R2 is ethenyl. Q 2-Me-4-EtO-Ph, X is NH, R1 and Rl a are both H, and R2 is ethenyl. Q 3.5- di-Cl-pyridin-2-yl, X is NH, R1 and Rl a are both H, and R2 is ethenyl. Q 2-Cl-thien-3-yl, X is NH, R1 and Rl a are both H, and R2 is ethenyl. Q 2.6- di-F-Ph, X is NH, R1 and Rl a are both H, and R2 is ethynyl.
Q 2,4-di-F-Ph, X is NH, R1 and Rl a are both H, and R2 is ethynyl.
Q 2,4,6-tri-F-Ph, X is NH, R1 and Rl a are both H, and R2 is ethynyl.
Q 2,6-di-F-4-MeO-Ph, X is NH, R1 and Rl a are both H, and R2 is ethynyl. Q 2,6-di-F-4-EtO-Ph, X is NH, R1 and Rl a are both H, and R2 is ethynyl. Q 2,6-di-F-4-CN-Ph, X is NH, R1 and Rl a are both H, and R2 is ethynyl. Q 2,6-di-F-3-MeO-Ph, X is NH, R1 and Rl a are both H, and R2 is ethynyl. Q 2,6-di-F-3-CN-Ph, X is NH, R1 and Rl a are both H, and R2 is ethynyl. Q 2,4,5-tri-F-Ph, X is NH, R1 and Rl a are both H, and R2 is ethynyl.
Q 2,4-di-Cl-Ph, X is NH, R1 and Rl a are both H, and R2 is ethynyl.
Q 2,6-di-Cl-Ph, X is NH, R1 and Rl a are both H, and R2 is ethynyl.
Q 2-Cl-4-F-Ph, X is NH, R1 and Rl a are both H, and R2 is ethynyl.
Q 2-Cl-6-F-Ph, X is NH, R1 and Rl a are both H, and R2 is ethynyl.
Q 2-Br-4-F-Ph, X is NH, R1 and Rl a are both H, and R2 is ethynyl.
Q 2-Br-6-F-Ph, X is NH, R1 and Rl a are both H, and R2 is ethynyl.
Q 2-F-4-MeO-Ph, X is NH, R1 and Rl a are both H, and R2 is ethynyl. Q 2-Cl-4-MeO-Ph, X is NH, R1 and Rl a are both H, and R2 is ethynyl. Q 2-Br-4-MeO-Ph, X is NH, R1 and Rl a are both H, and R2 is ethynyl. Q 2-F-4-EtO-Ph, X is NH, R1 and Rl a are both H, and R2 is ethynyl.
Q 2-Cl-4-EtO-Ph, X is NH, R1 and Rl a are both H, and R2 is ethynyl. Q Q Q Q Q
Q1 is 2-Me-4-F-Ph, X is NH, R1 and Rl a are both H, and R2 is ethynyl.
Q1 is 2-Me-4-MeO-Ph, X is NH, R1 and Rl a are both H, and R2 is ethynyl. Row Heading
Q1 is 2-Me-4-EtO-Ph, X is NH, R1 and Rl a are both H, and R2 is ethynyl.
Q1 is 3,5-di-Cl-pyridin-2-yl, X is NH, R1 and Rl a are both H, and R2 is ethynyl.
Q1 is 2-Cl-thien-3-yl, X is NH, R1 and Rl a are both H, and R2 is ethynyl.
Q1 is 2,6-di-F-Ph, X is O, R1 and Rl a are both H, and R2 is H.
Q1 is 2,4-di-F-Ph, X is O, R1 and Rl a are both H, and R2 is H.
Q1 is 2,4,6-tri-F-Ph, X is O, R1 and Rl a are both H, and R2 is H.
Q1 is 2,6-di-F-4-MeO-Ph, X is O, R1 and Rl a are both H, and R2 is H.
Q1 is 2,6-di-F-4-EtO-Ph, X is O, R1 and Rl a are both H, and R2 is H.
Q1 is 2,6-di-F-4-CN-Ph, X is O, R1 and Rl a are both H, and R2 is H.
Q1 is 2,6-di-F-3-MeO-Ph, X is O, R1 and Rl a are both H, and R2 is H.
Q1 is 2,6-di-F-3-CN-Ph, X is O, R1 and Rl a are both H, and R2 is H.
Q1 is 2,4,5-tri-F-Ph, X is O, R1 and Rl a are both H, and R2 is H.
Q1 is 2,4-di-Cl-Ph, X is O, R1 and Rl a are both H, and R2 is H.
Q1 is 2,6-di-Cl-Ph, X is O, R1 and Rl a are both H, and R2 is H.
Q1 is 2-Cl-4-F-Ph, X is O, R1 and Rl a are both H, and R2 is H.
Q1 is 2-Cl-6-F-Ph, X is O, R1 and Rl a are both H, and R2 is H.
Q1 is 2-Br-4-F-Ph, X is O, R1 and Rl a are both H, and R2 is H.
Q1 is 2-Br-6-F-Ph, X is O, R1 and Rl a are both H, and R2 is H.
Q1 is 2-F-4-MeO-Ph, X is O, R1 and Rl a are both H, and R2 is H.
Q1 is 2-Cl-4-MeO-Ph, X is O, R1 and Rl a are both H, and R2 is H.
Q1 is 2-Br-4-MeO-Ph, X is O, R1 and Rl a are both H, and R2 is H.
Q1 is 2-F-4-EtO-Ph, X is O, R1 and Rl a are both H, and R2 is H.
Q1 is 2-Cl-4-EtO-Ph, X is O, R1 and Rl a are both H, and R2 is H.
Q1 is 2-Br-4-EtO-Ph, X is O, R1 and Rl a are both H, and R2 is H.
Q1 is 2-F-4-Me-Ph, X is O, R1 and Rl a are both H, and R2 is H.
Q1 is 2-Cl-4-Me-Ph, X is O, R1 and Rl a are both H, and R2 is H.
Q1 is 2-Br-4-Me-Ph, X is O, R1 and Rl a are both H, and R2 is H.
Q1 is 2-Me-4-Me-Ph, X is O, R1 and Rl a are both H, and R2 is H.
Q1 is 2-Me-4-F-Ph, X is O, R1 and Rl a are both H, and R2 is H.
Q1 is 2-Me-4-MeO-Ph, X is O, R1 and Rl a are both H, and R2 is H.
Q1 is 2-Me-4-EtO-Ph, X is O, R1 and Rl a are both H, and R2 is H.
Q1 is 3,5-di-Cl-pyridin-2-yl, X is O, R1 and Rl a are both H, and R2 is H.
Q1 is 2-Cl-thien-3-yl, X is O, R1 and Rl a are both H, and R2 is H.
Q1 is 2,6-di-F-Ph, X is O, R1 and Rl a are both H, and R2 is ethenyl.
Q1 is 2,4-di-F-Ph, X is O, R1 and Rl a are both H, and R2 is ethenyl.
Q1 is 2,4,6-tri-F-Ph, X is O, R1 and Rl a are both H, and R2 is ethenyl.
Q1 is 2,6-di-F-4-MeO-Ph, X is O, R1 and Rl a are both H, and R2 is ethenyl. Row Heading
Q is 2,6-di-F-4-EtO-Ph, X is O, R1 and Rl a are both H, and R2 is ethenyl. Q is 2,6-di-F-4-CN-Ph, X is O, R1 and Rl a are both H, and R2 is ethenyl. Q is 2,6-di-F-3-MeO-Ph, X is O, R1 and Rl a are both H, and R2 is ethenyl. Q is 2,6-di-F-3-CN-Ph, X is O, R1 and Rl a are both H, and R2 is ethenyl. Q is 2,4,5-tri-F-Ph, X is O, R1 and Rl a are both H, and R2 is ethenyl.
Q is 2,4-di-Cl-Ph, X is O, R1 and Rl a are both H, and R2 is ethenyl.
Q is 2,6-di-Cl-Ph, X is O, R1 and Rl a are both H, and R2 is ethenyl.
Q is 2-Cl-4-F-Ph, X is O, R1 and Rl a are both H, and R2 is ethenyl.
Q is 2-Cl-6-F-Ph, X is O, R1 and Rl a are both H, and R2 is ethenyl.
Q is 2-Br-4-F-Ph, X is O, R1 and Rl a are both H, and R2 is ethenyl.
Q is 2-Br-6-F-Ph, X is O, R1 and Rl a are both H, and R2 is ethenyl.
Q is 2-F-4-MeO-Ph, X is O, R1 and Rl a are both H, and R2 is ethenyl. Q is 2-Cl-4-MeO-Ph, X is O, R1 and Rl a are both H, and R2 is ethenyl. Q is 2-Br-4-MeO-Ph, X is O, R1 and Rl a are both H, and R2 is ethenyl. Q is 2-F-4-EtO-Ph, X is O, R1 and Rl a are both H, and R2 is ethenyl.
Q is 2-Cl-4-EtO-Ph, X is O, R1 and Rl a are both H, and R2 is ethenyl. Q is 2-Br-4-EtO-Ph, X is O, R1 and Rl a are both H, and R2 is ethenyl. Q is 2-F-4-Me-Ph, X is O, R1 and Rl a are both H, and R2 is ethenyl.
Q is 2-Cl-4-Me-Ph, X is O, R1 and Rl a are both H, and R2 is ethenyl.
Q is 2-Br-4-Me-Ph, X is O, R1 and Rl a are both H, and R2 is ethenyl.
Q is 2-Me-4-Me-Ph, X is O, R1 and Rl a are both H, and R2 is ethenyl. Q is 2-Me-4-F-Ph, X is O, R1 and Rl a are both H, and R2 is ethenyl.
Q is 2-Me-4-MeO-Ph, X is O, R1 and Rl a are both H, and R2 is ethenyl. Q is 2-Me-4-EtO-Ph, X is O, R1 and Rl a are both H, and R2 is ethenyl. Q is 3,5-di-Cl-pyridin-2-yl, X is O, R1 and Rl a are both H, and R2 is ethenyl. Q is 2-Cl-thien-3-yl, X is O, R1 and Rl a are both H, and R2 is ethenyl. Q is 2,6-di-F-Ph, X is O, R1 and Rl a are both H, and R2 is ethynyl.
Q is 2,4-di-F-Ph, X is O, R1 and Rl a are both H, and R2 is ethynyl.
Q is 2,4,6-tri-F-Ph, X is O, R1 and Rl a are both H, and R2 is ethynyl.
Q is 2,6-di-F-4-MeO-Ph, X is O, R1 and Rl a are both H, and R2 is ethynyl. Q is 2,6-di-F-4-EtO-Ph, X is O, R1 and Rl a are both H, and R2 is ethynyl. Q is 2,6-di-F-4-CN-Ph, X is O, R1 and Rl a are both H, and R2 is ethynyl. Q is 2,6-di-F-3-MeO-Ph, X is O, R1 and Rl a are both H, and R2 is ethynyl. Q is 2,6-di-F-3-CN-Ph, X is O, R1 and Rl a are both H, and R2 is ethynyl. Q is 2,4,5-tri-F-Ph, X is O, R1 and Rl a are both H, and R2 is ethynyl.
Q1 is 2,4-di-Cl-Ph, X is O, R1 and Rl a are both H, and R2 is ethynyl.
Q1 is 2,6-di-Cl-Ph, X is O, R1 and Rl a are both H, and R2 is ethynyl. Row Heading
Q is 2-Cl-4-F-Ph, X is O, R1 and Rl a are both H, and R2 is ethynyl.
Q is 2-Cl-6-F-Ph, X is O, R1 and Rl a are both H, and R2 is ethynyl.
Q is 2-Br-4-F-Ph, X is O, R1 and Rl a are both H, and R2 is ethynyl.
Q is 2-Br-6-F-Ph, X is O, R1 and Rl a are both H, and R2 is ethynyl.
Q is 2-F-4-MeO-Ph, X is O, R1 and Rl a are both H, and R2 is ethynyl. Q is 2-Cl-4-MeO-Ph, X is O, R1 and Rl a are both H, and R2 is ethynyl. Q is 2-Br-4-MeO-Ph, X is O, R1 and Rl a are both H, and R2 is ethynyl. Q is 2-F-4-EtO-Ph, X is O, R1 and Rl a are both H, and R2 is ethynyl.
Q is 2-Cl-4-EtO-Ph, X is O, R1 and Rl a are both H, and R2 is ethynyl.
Q is 2-Br-4-EtO-Ph, X is O, R1 and Rl are both H, and R2 is ethynyl. Q is 2-F-4-Me-Ph, X is O, R1 and Rl a are both H, and R2 is ethynyl.
Q is 2-Cl-4-Me-Ph, X is O, R1 and Rl a are both H, and R2 is ethynyl.
Q is 2-Br-4-Me-Ph, X is O, R1 and Rl a are both H, and R2 is ethynyl.
Q is 2-Me-4-Me-Ph, X is O, R1 and Rl a are both H, and R2 is ethynyl. Q is 2-Me-4-F-Ph, X is O, R1 and Rl a are both H, and R2 is ethynyl.
Q is 2-Me-4-MeO-Ph, X is O, R1 and Rl a are both H, and R2 is ethynyl. Q is 2-Me-4-EtO-Ph, X is O, R1 and Rl a are both H, and R2 is ethynyl. Q is 3,5-di-Cl-pyridin-2-yl, X is O, R1 and Rl a are both H, and R2 is ethynyl. Q is 2-Cl-thien-3-yl, X is O, R1 and Rl a are both H, and R2 is ethynyl. Q is 2,6-di-F-Ph, X is CHOH, R1 and Rl a are both H, and R2 is H.
Q is 2,4-di-F-Ph, X is CHOH, R1 and Rl a are both H, and R2 is H.
Q is 2,4,6-tri-F-Ph, X is CHOH, R1 and Rl a are both H, and R2 is H.
Q is 2,6-di-F-4-MeO-Ph, X is CHOH, R1 and Rl a are both H, and R2 is H. Q is 2,6-di-F-4-EtO-Ph, X is CHOH, R1 and Rl a are both H, and R2 is H. Q is 2,6-di-F-4-CN-Ph, X is CHOH, R1 and Rl a are both H, and R2 is H. Q is 2,6-di-F-3-MeO-Ph, X is CHOH, R1 and Rl a are both H, and R2 is H. Q is 2,6-di-F-3-CN-Ph, X is CHOH, R1 and Rl a are both H, and R2 is H. Q is 2,4,5-tri-F-Ph, X is CHOH, R1 and Rl a are both H, and R2 is H.
Q is 2,4-di-Cl-Ph, X is CHOH, R1 and Rl a are both H, and R2 is H.
Q is 2,6-di-Cl-Ph, X is CHOH, R1 and Rl a are both H, and R2 is H.
Q is 2-Cl-4-F-Ph, X is CHOH, R1 and Rl a are both H, and R2 is H.
Q is 2-Cl-6-F-Ph, X is CHOH, R1 and Rl a are both H, and R2 is H.
Q is 2-Br-4-F-Ph, X is CHOH, R1 and Rl a are both H, and R2 is H.
Q is 2-Br-6-F-Ph, X is CHOH, R1 and Rl a are both H, and R2 is H.
Q is 2-F-4-MeO-Ph, X is CHOH, R1 and Rl a are both H, and R2 is H. Q is 2-Cl-4-MeO-Ph, X is CHOH, R1 and Rl a are both H, and R2 is H. Q is 2-Br-4-MeO-Ph, X is CHOH, R1 and Rl a are both H, and R2 is H. Row Heading
Q 2-F-4-EtO-Ph, X is CHOH, R1 and Rl a are both H, and R2 is H.
Q 2-Cl-4-EtO-Ph, X is CHOH, R1 and Rl a are both H, and R2 is H.
Q 2-Br-4-EtO-Ph, X is CHOH, R1 and Rl a are both H, and R2 is H.
Q 2-F-4-Me-Ph, X is CHOH, R1 and Rl a are both H, and R2 is H.
Q 2-Cl-4-Me-Ph, X is CHOH, R1 and Rl a are both H, and R2 is H.
Q 2-Br-4-Me-Ph, X is CHOH, R1 and Rl a are both H, and R2 is H.
Q 2-Me-4-Me-Ph, X is CHOH, R1 and Rl a are both H, and R2 is H.
Q 2-Me-4-F-Ph, X is CHOH, R1 and Rl a are both H, and R2 is H.
Q 2-Me-4-MeO-Ph, X is CHOH, R1 and Rl a are both H, and R2 is H.
Q 2-Me-4-EtO-Ph, X is CHOH, R1 and Rl a are both H, and R2 is H.
Q 3.5- di-Cl-pyridin-2-yl, X is CHOH, R1 and Rl a are both H, and R2 is H. Q 2-Cl-thien-3-yl, X is CHOH, R1 and Rl a are both H, and R2 is H.
Q 2.6- di-F-Ph, X is CHOH, R1 and Rl a are both H, and R2 is ethenyl.
Q 2,4-di-F-Ph, X is CHOH, R1 and Rl a are both H, and R2 is ethenyl.
Q 2,4,6-tri-F-Ph, X is CHOH, R1 and Rl a are both H, and R2 is ethenyl. Q 2,6-di-F-4-MeO-Ph, X is CHOH, R1 and Rl a are both H, and R2 is ethenyl. Q 2,6-di-F-4-EtO-Ph, X is CHOH, R1 and Rl a are both H, and R2 is ethenyl. Q 2,6-di-F-4-CN-Ph, X is CHOH, R1 and Rl a are both H, and R2 is ethenyl. Q 2,6-di-F-3-MeO-Ph, X is CHOH, R1 and Rl a are both H, and R2 is ethenyl. Q 2,6-di-F-3-CN-Ph, X is CHOH, R1 and Rl a are both H, and R2 is ethenyl. Q 2,4,5-tri-F-Ph, X is CHOH, R1 and Rl a are both H, and R2 is ethenyl. Q 2,4-di-Cl-Ph, X is CHOH, R1 and Rl a are both H, and R2 is ethenyl. Q 2,6-di-Cl-Ph, X is CHOH, R1 and Rl a are both H, and R2 is ethenyl.
Q 2-Cl-4-F-Ph, X is CHOH, R1 and Rl a are both H, and R2 is ethenyl.
Q 2-Cl-6-F-Ph, X is CHOH, R1 and Rl a are both H, and R2 is ethenyl.
Q 2-Br-4-F-Ph, X is CHOH, R1 and Rl a are both H, and R2 is ethenyl.
Q 2-Br-6-F-Ph, X is CHOH, R1 and Rl a are both H, and R2 is ethenyl.
Q 2-F-4-MeO-Ph, X is CHOH, R1 and Rl a are both H, and R2 is ethenyl. Q 2-Cl-4-MeO-Ph, X is CHOH, R1 and Rl a are both H, and R2 is ethenyl. Q 2-Br-4-MeO-Ph, X is CHOH, R1 and Rl a are both H, and R2 is ethenyl. Q Q Q Q Q
Q1 is 2-Br-4-Me-Ph, X is CHOH, R1 and Rl a are both H, and R2 is ethenyl. Q1 is 2-Me-4-Me-Ph, X is CHOH, R1 and Rl a are both H, and R2 is ethenyl. Row Heading
Q1 is 2-Me-4-F-Ph, X is CHOH, R1 and Rl a are both H, and R2 is ethenyl.
Q1 is 2-Me-4-MeO-Ph, X is CHOH, R1 and Rl a are both H, and R2 is ethenyl.
Q1 is 2-Me-4-EtO-Ph, X is CHOH, R1 and Rl a are both H, and R2 is ethenyl.
Q1 is 3,5-di-Cl-pyridin-2-yl, X is CHOH, R1 and Rl a are both H, and R2 is ethenyl.
Q1 is 2-Cl-thien-3-yl, X is CHOH, R1 and Rl a are both H, and R2 is ethenyl.
Q1 is 2,6-di-F-Ph, X is CHOH, R1 and Rl a are both H, and R2 is ethynyl.
Q1 is 2,4-di-F-Ph, X is CHOH, R1 and Rl a are both H, and R2 is ethynyl.
Q1 is 2,4,6-tri-F-Ph, X is CHOH, R1 and Rl a are both H, and R2 is ethynyl.
Q1 is 2,6-di-F-4-MeO-Ph, X is CHOH, R1 and Rl a are both H, and R2 is ethynyl.
Q1 is 2,6-di-F-4-EtO-Ph, X is CHOH, R1 and Rl a are both H, and R2 is ethynyl.
Q1 is 2,6-di-F-4-CN-Ph, X is CHOH, R1 and Rl a are both H, and R2 is ethynyl.
Q1 is 2,6-di-F-3-MeO-Ph, X is CHOH, R1 and Rl a are both H, and R2 is ethynyl.
Q1 is 2,6-di-F-3-CN-Ph, X is CHOH, R1 and Rl a are both H, and R2 is ethynyl.
Q1 is 2,4,5-tri-F-Ph, X is CHOH, R1 and Rl a are both H, and R2 is ethynyl.
Q1 is 2,4-di-Cl-Ph, X is CHOH, R1 and Rl a are both H, and R2 is ethynyl.
Q1 is 2,6-di-Cl-Ph, X is CHOH, R1 and Rl a are both H, and R2 is ethynyl.
Q1 is 2-Cl-4-F-Ph, X is CHOH, R1 and Rl a are both H, and R2 is ethynyl.
Q1 is 2-Cl-6-F-Ph, X is CHOH, R1 and Rl a are both H, and R2 is ethynyl.
Q1 is 2-Br-4-F-Ph, X is CHOH, R1 and Rl a are both H, and R2 is ethynyl.
Q1 is 2-Br-6-F-Ph, X is CHOH, R1 and Rl a are both H, and R2 is ethynyl.
Q1 is 2-F-4-MeO-Ph, X is CHOH, R1 and Rl a are both H, and R2 is ethynyl.
Q1 is 2-Cl-4-MeO-Ph, X is CHOH, R1 and Rl a are both H, and R2 is ethynyl.
Q1 is 2-Br-4-MeO-Ph, X is CHOH, R1 and Rl a are both H, and R2 is ethynyl.
Q1 is 2-F-4-EtO-Ph, X is CHOH, R1 and Rl a are both H, and R2 is ethynyl.
Q1 is 2-Cl-4-EtO-Ph, X is CHOH, R1 and Rl a are both H, and R2 is ethynyl.
Q1 is 2-Br-4-EtO-Ph, X is CHOH, R1 and Rl a are both H, and R2 is ethynyl.
Q1 is 2-F-4-Me-Ph, X is CHOH, R1 and Rl a are both H, and R2 is ethynyl.
Q1 is 2-Cl-4-Me-Ph, X is CHOH, R1 and Rl a are both H, and R2 is ethynyl.
Q1 is 2-Br-4-Me-Ph, X is CHOH, R1 and Rl a are both H, and R2 is ethynyl.
Q1 is 2-Me-4-Me-Ph, X is CHOH, R1 and Rl a are both H, and R2 is ethynyl.
Q1 is 2-Me-4-F-Ph, X is CHOH, R1 and Rl a are both H, and R2 is ethynyl.
Q1 is 2-Me-4-MeO-Ph, X is CHOH, R1 and Rl a are both H, and R2 is ethynyl.
Q1 is 2-Me-4-EtO-Ph, X is CHOH, R1 and Rl a are both H, and R2 is ethynyl.
Q1 is 3,5-di-Cl-pyridin-2-yl, X is CHOH, R1 and Rl a are both H, and R2 is ethynyl.
Q1 is 2-Cl-thien-3-yl, X is CHOH, R1 and Rl a are both H, and R2 is ethynyl. Formulation/Utility
A compound of this invention will generally be used as a fungicidal active ingredient in a composition, i.e. formulation, with at least one additional component selected from the group consisting of surfactants, solid diluents and liquid diluents, which serves as a carrier. The formulation or composition ingredients are selected to be consistent with the physical properties of the active ingredient, mode of application and environmental factors such as soil type, moisture and temperature.
Useful formulations include both liquid and solid compositions. Liquid compositions include solutions (including emulsifiable concentrates), suspensions, emulsions (including microemulsions and/or suspoemulsions) and the like, which optionally can be thickened into gels. The general types of aqueous liquid compositions are soluble concentrate, suspension concentrate, capsule suspension, concentrated emulsion, microemulsion and suspo-emulsion. The general types of nonaqueous liquid compositions are emulsifiable concentrate, microemulsifiable concentrate, dispersible concentrate and oil dispersion.
The general types of solid compositions are dusts, powders, granules, pellets, prills, pastilles, tablets, filled films (including seed coatings) and the like, which can be water-dispersible ("wettable") or water-soluble. Films and coatings formed from film- forming solutions or flowable suspensions are particularly useful for seed treatment. 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. An emulsifiable granule combines the advantages of both an emulsifiable concentrate formulation and a dry granular formulation. High-strength compositions are primarily used as intermediates for further formulation.
Sprayable formulations are typically extended in a suitable medium before spraying.
Such liquid and solid formulations are formulated to be readily diluted in the spray medium, usually water. Spray volumes can range from about from about one to several thousand liters per hectare, but more typically are in the range from about ten to several hundred liters per hectare. Sprayable formulations can be tank mixed with water or another suitable medium for foliar treatment by aerial or ground application, or for application to the growing medium of the plant. Liquid and dry formulations can be metered directly into drip irrigation systems or metered into the furrow during planting. Liquid and solid formulations can be applied onto seeds of crops and other desirable vegetation as seed treatments before planting to protect developing roots and other subterranean plant parts and/or foliage through systemic uptake.
The formulations will typically contain effective amounts of active ingredient, diluent and surfactant within the following approximate ranges which add up to 100 percent by weight. Weight Percent
Active
Ingredient Diluent Surfactant
Water-Dispersible and Water- 0.001-90 0-99.999 0-15
soluble Granules, Tablets and
Powders
Oil Dispersions, Suspensions, 1-50 40-99 0-50
Emulsions, Solutions
(including Emulsifiable
Concentrates)
Dusts 1-25 70-99 0-5
Granules and Pellets 0.001-95 5-99.999 0-15
High Strength Compositions 90-99 0-10 0-2
Solid diluents include, for example, clays such as bentonite, montmorillonite, attapulgite and kaolin, gypsum, cellulose, titanium dioxide, zinc oxide, starch, dextrin, sugars (e.g., lactose, sucrose), silica, talc, mica, diatomaceous earth, urea, calcium carbonate, sodium carbonate and bicarbonate, and sodium sulfate. Typical solid diluents are described in Watkins et al., Handbook of Insecticide Dust Diluents and Carriers, 2nd Ed., Dorland Books, Caldwell, New Jersey.
Liquid diluents include, for example, water, N,N-dimethylalkanamides (e.g., N,N-dimethylformamide), limonene, dimethyl sulfoxide, N-alkylpyrrolidones (e.g., N-methylpyrrolidinone), ethylene glycol, triethylene glycol, propylene glycol, dipropylene glycol, polypropylene glycol, propylene carbonate, butylene carbonate, paraffins (e.g., white mineral oils, normal paraffins, isoparaffins), alkylbenzenes, alkylnaphthalenes, glycerine, glycerol triacetate, sorbitol, triacetin, aromatic hydrocarbons, dearomatized aliphatics, alkylbenzenes, alkylnaphthalenes, ketones such as cyclohexanone, 2-heptanone, isophorone and 4-hydroxy-4-methyl-2-pentanone, acetates such as isoamyl acetate, hexyl acetate, heptyl acetate, octyl acetate, nonyl acetate, tridecyl acetate and isobornyl acetate, other esters such as alkylated lactate esters, dibasic esters and γ-butyrolactone, and alcohols, which can be linear, branched, saturated or unsaturated, such as methanol, ethanol, n-propanol, isopropyl alcohol, n-butanol, isobutyl alcohol, n-hexanol, 2-ethylhexanol, n-octanol, decanol, isodecyl alcohol, isooctadecanol, cetyl alcohol, lauryl alcohol, tridecyl alcohol, oleyl alcohol, cyclohexanol, tetrahydrofurfuryl alcohol, diacetone alcohol and benzyl alcohol. Liquid diluents also include glycerol esters of saturated and unsaturated fatty acids (typically C6-C22), such as plant seed and fruit oils (e.g, oils of olive, castor, linseed, sesame, corn (maize), peanut, sunflower, grapeseed, safflower, cottonseed, soybean, rapeseed, coconut and palm kernel), animal-sourced fats (e.g., beef tallow, pork tallow, lard, cod liver oil, fish oil), and mixtures thereof. Liquid diluents also include alkylated fatty acids (e.g., methylated, ethylated, butylated) wherein the fatty acids may be obtained by hydrolysis of glycerol esters from plant and animal sources, and can be purified by distillation. Typical liquid diluents are described in Marsden, Solvents Guide, 2nd Ed., Interscience, New York, 1950.
The solid and liquid compositions of the present invention often include one or more surfactants. When added to a liquid, surfactants (also known as "surface-active agents") generally modify, most often reduce, the surface tension of the liquid. Depending on the nature of the hydrophilic and lipophilic groups in a surfactant molecule, surfactants can be useful as wetting agents, dispersants, emulsifiers or defoaming agents.
Surfactants can be classified as nonionic, anionic or cationic. Nonionic surfactants useful for the present compositions include, but are not limited to: alcohol alkoxylates such as alcohol alkoxylates based on natural and synthetic alcohols (which may be branched or linear) and prepared from the alcohols and ethylene oxide, propylene oxide, butylene oxide or mixtures thereof; amine ethoxylates, alkanolamides and ethoxylated alkanolamides; alkoxylated triglycerides such as ethoxylated soybean, castor and rapeseed oils; alkylphenol alkoxylates such as octylphenol ethoxylates, nonylphenol ethoxylates, dinonyl phenol ethoxylates and dodecyl phenol ethoxylates (prepared from the phenols and ethylene oxide, propylene oxide, butylene oxide or mixtures thereof); block polymers prepared from ethylene oxide or propylene oxide and reverse block polymers where the terminal blocks are prepared from propylene oxide; ethoxylated fatty acids; ethoxylated fatty esters and oils; ethoxylated methyl esters; ethoxylated tristyrylphenol (including those prepared from ethylene oxide, propylene oxide, butylene oxide or mixtures thereof); fatty acid esters, glycerol esters, lanolin-based derivatives, polyethoxylate esters such as polyethoxylated sorbitan fatty acid esters, polyethoxylated sorbitol fatty acid esters and polyethoxylated glycerol fatty acid esters; other sorbitan derivatives such as sorbitan esters; polymeric surfactants such as random copolymers, block copolymers, alkyd peg (polyethylene glycol) resins, graft or comb polymers and star polymers; polyethylene glycols (pegs); polyethylene glycol fatty acid esters; silicone-based surfactants; and sugar-derivatives such as sucrose esters, alkyl polyglycosides and alkyl polysaccharides.
Useful anionic surfactants include, but are not limited to: alkylaryl sulfonic acids and their salts; carboxylated alcohol or alkylphenol ethoxylates; diphenyl sulfonate derivatives; lignin and lignin derivatives such as lignosulfonates; maleic or succinic acids or their anhydrides; olefin sulfonates; phosphate esters such as phosphate esters of alcohol alkoxylates, phosphate esters of alkylphenol alkoxylates and phosphate esters of styryl phenol ethoxylates; protein-based surfactants; sarcosine derivatives; styryl phenol ether sulfate; sulfates and sulfonates of oils and fatty acids; sulfates and sulfonates of ethoxylated alkylphenols; sulfates of alcohols; sulfates of ethoxylated alcohols; sulfonates of amines and amides such as N,N-alkyltaurates; sulfonates of benzene, cumene, toluene, xylene, and dodecyl and tridecylbenzenes; sulfonates of condensed naphthalenes; sulfonates of naphthalene and alkyl naphthalene; sulfonates of fractionated petroleum; sulfosuccinamates; and sulfosuccinates and their derivatives such as dialkyl sulfosuccinate salts.
Useful cationic surfactants include, but are not limited to: amides and ethoxylated amides; amines such as N-alkyl propanediamines, tripropylenetriamines and dipropylenetetramines, and ethoxylated amines, ethoxylated diamines and propoxylated amines (prepared from the amines and ethylene oxide, propylene oxide, butylene oxide or mixtures thereof); amine salts such as amine acetates and diamine salts; quaternary ammonium salts such as quaternary salts, ethoxylated quaternary salts and diquaternary salts; and amine oxides such as alkyldimethylamine oxides and bis-(2-hydroxyethyl)-alkylamine oxides.
Also useful for the present compositions are mixtures of nonionic and anionic surfactants or mixtures of nonionic and cationic surfactants. Nonionic, anionic and cationic surfactants and their recommended uses are disclosed in a variety of published references including McCutcheon 's Emulsifiers and Detergents, annual American and International Editions published by McCutcheon's Division, The Manufacturing Confectioner Publishing Co.; Sisely and Wood, Encyclopedia of Surface Active Agents, Chemical Publ. Co., Inc., New York, 1964; and A. S. Davidson and B. Milwidsky, Synthetic Detergents, Seventh Edition, John Wiley and Sons, New York, 1987.
Compositions of this invention may also contain formulation auxiliaries and additives, known to those skilled in the art as formulation aids (some of which may be considered to also function as solid diluents, liquid diluents or surfactants). Such formulation auxiliaries and additives may control: pH (buffers), foaming during processing (antifoams such polyorganosiloxanes), sedimentation of active ingredients (suspending agents), viscosity (thixotropic thickeners), in-container microbial growth (antimicrobials), product freezing (antifreezes), color (dyes/pigment dispersions), wash-off (film formers or stickers), evaporation (evaporation retardants), and other formulation attributes. Film formers include, for example, polyvinyl acetates, polyvinyl acetate copolymers, polyvinylpyrrolidone-vinyl acetate copolymer, polyvinyl alcohols, polyvinyl alcohol copolymers and waxes. Examples of formulation auxiliaries and additives include those listed in McCutcheon 's Volume 2: Functional Materials, annual International and North American editions published by McCutcheon's Division, The Manufacturing Confectioner Publishing Co.; and PCT Publication WO 03/024222.
The compound of Formula 1 and any other active ingredients are typically incorporated into the present compositions by dissolving the active ingredient in a solvent or by grinding in a liquid or dry diluent. Solutions, including emulsifiable concentrates, can be prepared by simply mixing the ingredients. If the solvent of a liquid composition intended for use as an emulsifiable concentrate is water-immiscible, an emulsifier is typically added to emulsify the active-containing solvent upon dilution with water. Active ingredient slurries, with particle diameters of up to 2,000 μιη can be wet milled using media mills to obtain particles with average diameters below 3 μιη. Aqueous slurries can be made into finished suspension concentrates (see, for example, U.S. 3,060,084) or further processed by spray drying to form water-dispersible granules. Dry formulations usually require dry milling processes, which produce average particle diameters in the 2 to 10 um range. Dusts and powders can be prepared by blending and usually grinding (such as with a hammer mill or fluid-energy mill). 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 1-4; Klingman, Weed Control as a Science, John Wiley and Sons, Inc., New York, 1961, pp 81-96; Hance et al, Weed Control Handbook, 8th Ed., Blackwell Scientific Publications, Oxford, 1989; and Developments in formulation technology, PJB Publications, Richmond, UK, 2000.
In the following Examples, all percentages are by weight and all formulations are prepared in conventional ways. Compound numbers refer to compounds in Index Table A. Without further elaboration, it is believed that one skilled in the art using the preceding description can utilize the present invention to its fullest extent. The following Examples are, therefore, to be construed as merely illustrative, and not limiting of the disclosure in any way whatsoever. Percentages are by weight except where otherwise indicated. Example A
High Strength Concentrate
Compound 1 98.5% silica aerogel 0.5% synthetic amorphous fine silica 1.0%
Example B
Wettable Powder
Compound 1 65.0% dodecylphenol polyethylene glycol ether 2.0%> sodium ligninsulfonate 4.0% sodium silicoaluminate 6.0% montmorillonite (calcined) 23.0%
Example C
Granule
Compound 1 10.0% attapulgite granules (low volatile matter, 0.71/0.30 mm; 90.0% U.S.S. No. 25-50 sieves)
Example D
Extruded Pellet
Compound 1 25.0% anhydrous sodium sulfate 10.0% crude calcium ligninsulfonate 5.0%> sodium alkylnaphthalenesulfonate 1.0% calcium/magnesium bentonite 59.0%
Example E
Emulsifiable Concentrate
Compound 1 10.0% polyoxyethylene sorbitol hexoleate 20.0%
C6-C10 fatty acid methyl ester 70.0%>
Example F
Microemulsion
Compound 1 5.0%> polyvinylpyrrolidone -vinyl acetate copolymer 30.0% alkylpolyglycoside 30.0%> glyceryl monooleate 15.0% water 20.0% Example G
Seed Treatment
Compound 1 20.00% polyvinylpyrrolidone -vinyl acetate copolymer 5.00% montan acid wax 5.00% calcium ligninsulfonate 1.00% polyoxyethylene/polyoxypropylene block copolymers 1.00% stearyl alcohol (POE 20) 2.00% polyorganosilane 0.20% colorant red dye 0.05% water 65.75%
Formulations such as those in the Formulation Table are typically diluted with water to form aqueous compositions before application. Aqueous compositions for direct applications to the plant or portion thereof (e.g., spray tank compositions) typically at least about 1 ppm or more (e.g., from 1 ppm to 100 ppm) of the compound(s) of this invention.
The compounds of this invention are useful as plant disease control agents. The present invention therefore further comprises a method for controlling plant diseases caused by fungal plant pathogens comprising applying to the plant or portion thereof to be protected, or to the plant seed to be protected, an effective amount of a compound of the invention or a fungicidal composition containing said compound. The compounds and/or compositions of this invention provide control of diseases caused by a broad spectrum of fungal plant pathogens in the Basidiomycete, Ascomycete, Oomycete and Deuteromycete classes. They are effective in controlling a broad spectrum of plant diseases, particularly foliar pathogens of ornamental, turf, vegetable, field, cereal, and fruit crops. These pathogens include: Oomycetes, including Phytophthora diseases such as Phytophthora infestans, Phytophthora megasperma, Phytophthora parasitica, Phytophthora cinnamomi and Phytophthora capsici, Pythium diseases such as Pythium aphanidermatum, and diseases in the Peronosporaceae family such as Plasmopara viticola, Peronospora spp. (including Peronospora tabacina and Peronospora parasitica), Pseudoperonospora spp. (including Pseudoperonospora cubensis) and Bremia lactucae; Ascomycetes, including Alternaria diseases such as Alternaria solani and Alternaria brassicae, Guignardia diseases such as Guignardia bidwell, Venturia diseases such as Venturia inaequalis, Septoria diseases such as Septoria nodorum and Septoria tritici, powdery mildew diseases such as Erysiphe spp. (including Erysiphe graminis and Erysiphe polygoni), Uncinula necatur, Sphaerotheca fuligena and Podosphaera leucotricha, Pseudocercosporella herpotrichoides, Botrytis diseases such as Botrytis cinerea, Monilinia fructicola, Sclerotinia diseases such as Sclerotinia sclerotiorum, Magnaporthe grisea, Phomopsis viticola, Helminthosporium diseases such as Helminthosporium tritici repentis, Pyrenophora teres, anthracnose diseases such as Glomerella or Colletotrichum spp. (such as Colletotrichum graminicola and Colletotrichum orbiculare), and Gaeumannomyces graminis; Basidiomycetes, including rust diseases caused by Puccinia spp. (such as Puccinia recondita, Puccinia striiformis, Puccinia hordei, Puccinia graminis and Puccinia arachidis), Hemileia vastatrix and Phakopsora pachyrhizi; other pathogens including Rutstroemia floccosum (also known as Sclerontina homoeocarpa); Rhizoctonia spp. (such as Rhizoctonia solani); Fusarium diseases such as Fusarium roseum, Fusarium graminearum and Fusarium oxysporum; Verticillium dahliae; Sclerotium rolfsii; Rynchosporium secalis; Cercosporidium personatum, Cercospora arachidicola and Cercospora beticola; and other genera and species closely related to these pathogens. In addition to their fungicidal activity, the compositions or combinations also have activity against bacteria such as Erwinia amylovora, Xanthomonas campestris, Pseudomonas syringae, and other related species.
Plant disease control is ordinarily accomplished by applying an effective amount of a compound of this invention either pre- or post-infection, to the portion of the plant to be protected such as the roots, stems, foliage, fruit, seeds, tubers or bulbs, or to the media (soil or sand) in which the plants to be protected are growing. The compounds can also be applied to seeds to protect the seeds and seedlings developing from the seeds. The compounds can also be applied through irrigation water to treat plants.
Accordingly, this aspect of the present invention can also be described as a method for protecting a plant or plant seed from diseases caused by fungal pathogens comprising applying a fungicidally effective amount of a compound of Formula 1, an N-oxide, or salt thereof to the plant (or portion thereof) or plant seed (directly or through the environment (e.g., growing medium) of the plant or plant seed).
Rates of application for these compounds can be influenced by many factors of the environment and should be determined under actual use conditions. Foliage can normally be protected when treated at a rate of from less than about 1 g/ha to about 5,000 g/ha of active ingredient. Seed and seedlings can normally be protected when seed is treated at a rate of from about 0.1 to about 10 g per kilogram of seed.
Compounds of this invention can also be mixed with one or more other biologically active compounds or agents including fungicides, insecticides, nematocides, bactericides, acaricides, herbicides, herbicide safeners, growth regulators such as insect molting inhibitors and rooting stimulants, chemosterilants, semiochemicals, repellents, attractants, pheromones, feeding stimulants, plant nutrients, other biologically active compounds or entomopathogenic bacteria, virus or fungi to form a multi-component pesticide giving an even broader spectrum of agricultural protection. Thus the present invention also pertains to a composition comprising a compound of Formula 1 (in a fungicidally effective amount) and at least one additional biologically active compound or agent (in a biologically effective amount) and can further comprise at least one of a surfactant, a solid diluent or a liquid diluent. The other biologically active compounds or agents can be formulated in compositions comprising at least one of a surfactant, solid or liquid diluent. For mixtures of the present invention, one or more other biologically active compounds or agents can be formulated together with a compound of Formula 1, to form a premix, or one or more other biologically active compounds or agents can be formulated separately from the compound of Formula 1, and the formulations combined together before application (e.g., in a spray tank) or, alternatively, applied in succession.
As mentioned in the Summary of the Invention, one aspect of the present invention is a fungicidal composition comprising (i.e. a mixture or combination of) a compound of Formula 1, an N-oxide, or a salt thereof (i.e. component a), and at least one other fungicide (i.e. component b). Of note is such a combination where the other fungicidal active ingredient has different site of action from the compound of Formula 1. In certain instances, a combination with at least one other fungicidal active ingredient having a similar spectrum of control but a different site of action will be particularly advantageous for resistance management. Thus, a composition of the present invention can further comprise a fungicidally effective amount of at least one additional fungicidal active ingredient having a similar spectrum of control but a different site of action.
Of particular note is a composition which, in addition to the Formula 1 compound of component (a), includes as component (b) at least one fungicidal compound selected from the group consisting of the classes (bl) methyl benzimidazole carbamate (MBC) fungicides; (b2) dicarboximide fungicides; (b3) demethylation inhibitor (DMI) fungicides; (b4) phenylamide fungicides; (b5) amine/morpholine fungicides; (b6) phospholipid biosynthesis inhibitor fungicides; (b7) carboxamide fungicides; (b8) hydroxy(2-amino-)pyrimidine fungicides; (b9) anilinopyrimidine fungicides; (blO) N-phenyl carbamate fungicides; (M l) quinone outside inhibitor (Qol) fungicides; (bl2) phenylpyrrole fungicides; (bl3) quinoline fungicides; (bl4) lipid peroxidation inhibitor fungicides; (bl5) melanin biosynthesis inhibitors-reductase (MBI-R) fungicides; (bl6) melanin biosynthesis inhibitors-dehydratase (MBI-D) fungicides; (bl7) hydroxyanilide fungicides; (bl8) squalene-epoxidase inhibitor fungicides; (bl9) polyoxin fungicides; (b20) phenylurea fungicides; (b21) quinone inside inhibitor (Qil) fungicides; (b22) benzamide fungicides; (b23) enopyranuronic acid antibiotic fungicides; (b24) hexopyranosyl antibiotic fungicides; (b25) glucopyranosyl antibiotic: protein synthesis fungicides; (b26) glucopyranosyl antibiotic: trehalase and inositol biosynthesis fungicides; (b27) cyanoacetamideoxime fungicides; (b28) carbamate fungicides; (b29) oxidative phosphorylation uncoupling fungicides; (b30) organo tin fungicides; (b31) carboxylic acid fungicides; (b32) heteroaromatic fungicides; (b33) phosphonate fungicides; (b34) phthalamic acid fungicides; (b35) benzotriazine fungicides; (b36) benzene-sulfonamide fungicides; (b37) pyridazinone fungicides; (b38) thiophene- carboxamide fungicides; (b39) pyrimidinamide fungicides; (b40) carboxylic acid amide (CAA) fungicides; (b41) tetracycline antibiotic fungicides; (b42) thiocarbamate fungicides; (b43) benzamide fungicides; (b44) host plant defense induction fungicides; (b45) multi-site contact activity fungicides; (b46) fungicides other than classes (bl) through (b45); and salts of compounds of classes (bl) through (b46).
Further descriptions of these classes of fungicidal compounds are provided below.
(bl) "Methyl benzimidazole carbamate (MBC) fungicides" (FRAC (Fungicide Resistance Action Committee) code 1) inhibit mitosis by binding to β-tubulin during microtubule assembly. Inhibition of microtubule assembly can disrupt cell division, transport within the cell and cell structure. Methyl benzimidazole carbamate fungicides include benzimidazole and thiophanate fungicides. The benzimidazoles include benomyl, carbendazim, fuberidazole and thiabendazole. The thiophanates include thiophanate and thiophanate-methy 1.
(b2) "Dicarboximide fungicides" (FRAC code 2) are proposed to inhibit a lipid peroxidation in fungi through interference with NADH cytochrome c reductase. Examples include chlozolinate, iprodione, procymidone and vinclozolin.
(b3) "Demethylation inhibitor (DMI) fungicides" (FRAC code 3) inhibit C14-demethylase which plays a role in sterol production. Sterols, such as ergosterol, are needed for membrane structure and function, making them essential for the development of functional cell walls. Therefore, exposure to these fungicides result in abnormal growth and eventually death of sensitive fungi. DMI fungicides are divided between several chemical classes: azoles (including triazoles and imidazoles), pyrimidines, piperazines and pyridines. The triazoles include azaconazole, bitertanol, bromuconazole, cyproconazole, difenoconazole, diniconazole (including diniconazole-M), epoxiconazole, etaconazole, fenbuconazole, fluquinconazole, flusilazole, flutriafol, hexaconazole, imibenconazole, ipconazole, metconazole, myclobutanil, penconazole, propiconazole, prothioconazole, quinconazole, simeconazole, tebuconazole, tetraconazole, triadimefon, triadimenol, triticonazole and uniconazole. The imidazoles include clotrimazole, econazole, imazalil, isoconazole, miconazole, oxpoconazole, prochloraz, pefurazoate and triflumizole. 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 Modern Selective Fungicides - Properties, Applications and Mechanisms of Action, H. Lyr (Ed.), Gustav Fischer Verlag: New York, 1995, 205-258.
(b4) "Phenylamide fungicides" (FRAC code 4) are specific inhibitors of RNA polymerase in Oomycete fungi. Sensitive fungi exposed to these fungicides show a reduced capacity to incorporate uridine into rRNA. Growth and development in sensitive fungi is prevented by exposure to this class of fungicide. Phenylamide fungicides include acylalanine, oxazolidinone and butyrolactone fungicides. The acylalanines include benalaxyl, benalaxyl-M, furalaxyl, metalaxyl, metalaxyl-M (also known as mefenoxam). The oxazolidinones include oxadixyl. The butyrolactones include ofurace.
(b5) "Amine/morpholine fungicides" (FRAC code 5) inhibit two target sites within the sterol biosynthetic pathway, Δ8→ Δ7 isomerase and Δ14 reductase. Sterols, such as ergosterol, are needed for membrane structure and function, making them essential for the development of functional cell walls. Therefore, exposure to these fungicides results in abnormal growth and eventually death of sensitive fungi. Amine/morpholine fungicides (also known as non-DMI sterol biosynthesis inhibitors) include morpholine, piperidine and spiroketal-amine fungicides. The morpho lines include aldimorph, dodemorph, fenpropimorph, tridemorph and trimorphamide. The piperidines include fenpropidin and piperalin. The spiroketal-amines include spiroxamine.
(b6) "Phospholipid biosynthesis inhibitor fungicides" (FRAC code 6) inhibit growth of fungi by affecting phospholipid biosynthesis. Phospholipid biosynthesis fungicides include phosphorothiolate and dithiolane fungicides. The phosphorothiolates include edifenphos, iprobenfos and pyrazophos. The dithiolanes include isoprothiolane.
(b7) "Carboxamide fungicides" (FRAC code 7) inhibit Complex II (succinate dehydrogenase) fungal respiration by disrupting a key enzyme in the Krebs Cycle (TCA cycle) named succinate dehydrogenase. Inhibiting respiration prevents the fungus from making ATP, and thus inhibits growth and reproduction. Carboxamide fungicides include benzamide, furan carboxamide, oxathiin carboxamide, thiazole carboxamide, pyrazole carboxamide, pyridine carboxamide and thiophene carboxamide fungicides. The benzamides include benodanil, flutolanil and mepronil. The furan carboxamides include fenfuram. The oxathiin carboxamides include carboxin and oxycarboxin. The thiazole carboxamides include thifluzamide. The pyrazole carboxamides include benzovindiflupyr, bixafen, furametpyr, isopyrazam, fluxapyroxad, penthiopyrad, sedaxane (N-[2-(lS,2R)-[l,l'- bicyclopropyl] -2-ylphenyl] -3 -(difluoromethyl)- 1 -methyl- 1 H-pyrazole-4-carboxamide) and penflufen (N-[2-(l ,3-dimethylbutyl)phenyl]-5-fluoro- 1 ,3-dimethyl- lH-pyrazole-4- carboxamide). The pyridine carboxamides include boscalid. The thiophene carboxamides include isofetamid.
(b8) "Hydroxy(2-amino-)pyrimidine fungicides" (FRAC code 8) inhibit nucleic acid synthesis by interfering with adenosine deaminase. Examples include bupirimate, dimethirimol and ethirimol.
(b9) "Anilinopyrimidine fungicides" (FRAC code 9) are proposed to inhibit biosynthesis of the amino acid methionine and to disrupt the secretion of hydro lytic enzymes that lyse plant cells during infection. Examples include cyprodinil, mepanipyrim and pyrimethanil.
(blO) "N-Phenyl carbamate fungicides" (FRAC code 10) inhibit mitosis by binding to β-tubulin and disrupting microtubule assembly. Inhibition of microtubule assembly can disrupt cell division, transport within the cell and cell structure. Examples include diethofencarb.
(bl l) "Quinone outside inhibitor (Qol) fungicides" (FRAC code 11) inhibit Complex III mitochondrial respiration in fungi by affecting ubiquinol oxidase. Oxidation of ubiquinol is blocked at the "quinone outside" (Q0) site of the cytochrome bc\ complex, which is located in the inner mitochondrial membrane of fungi. Inhibiting mitochondrial respiration prevents normal fungal growth and development. Quinone outside inhibitor fungicides include methoxyacrylate, methoxycarbamate, oximinoacetate, oximinoacetamide and dihydrodioxazine fungicides (collectively also known as strobilurin fungicides), and oxazolidinedione, imidazolinone and benzylcarbamate fungicides. The methoxyacrylates include azoxystrobin, enestroburin (SYP-Z071) and picoxystrobin. The methoxycarbamates include pyraclostrobin and pyrametostrobin. The oximinoacetates include kresoxim-methyl, pyraoxystrobin and trifloxystrobin. The oximinoacetamides include dimoxystrobin, metominostrobin, orysastrobin and a-(methoxyimino)-N-methyl-2-[[[l-[3-(trifluoro- methyl)phenyl]ethoxy]imino]methyl]benzeneacetamide. The dihydrodioxazines include fluoxastrobin. The oxazolidinediones include famoxadone. The imidazolinones include fenamidone. The benzylcarbamates include pyribencarb.
(bl2) "Phenylpyrrole fungicides" (FRAC code 12) inhibit a MAP protein kinase associated with osmotic signal transduction in fungi. Fenpiclonil and fludioxonil are examples of this fungicide class.
(bl3) "Quinoline fungicides" (FRAC code 13) are proposed to inhibit signal transduction by affecting G-proteins in early cell signaling. They have been shown to interfere with germination and/or appressorium formation in fungi that cause powdery mildew diseases. Quinoxyfen is an example of this class of fungicide.
(bl4) "Lipid peroxidation inhibitor fungicides" (FRAC code 14) are proposed to inhibit lipid peroxidation which affects membrane synthesis in fungi. Members of this class, such as etridiazole, may also affect other biological processes such as respiration and melanin biosynthesis. Lipid peroxidation fungicides include aromatic carbon and 1,2,4- thiadiazole fungicides. The aromatic carbons include biphenyl, chloroneb, dicloran, quintozene, tecnazene and tolclofos-methyl. The 1,2,4-thiadiazoles include etridiazole.
(bl5) "Melanin biosynthesis inhibitors-reductase (MBI-R) fungicides" (FRAC code
16.1) inhibit the naphthal reduction step in melanin biosynthesis. Melanin is required for host plant infection by some fungi. Melanin biosynthesis inhibitors-reductase fungicides include isobenzofuranone, pyrroloquinolinone and triazolobenzothiazole fungicides. The isobenzofuranones include fthalide. The pyrroloquinolinones include pyroquilon. The triazolobenzothiazoles include tricyclazole.
(bl6) "Melanin biosynthesis inhibitors-dehydratase (MBI-D) fungicides" (FRAC code
16.2) inhibit scytalone dehydratase in melanin biosynthesis. Melanin in required for host plant infection by some fungi. Melanin biosynthesis inhibitors-dehydratase fungicides include cyclopropanecarboxamide, carboxamide and propionamide fungicides. The cyclopropanecarboxamides include carpropamid. The carboxamides include diclocymet. The propionamides include fenoxanil.
(bl7) "Hydroxyanilide fungicides" (FRAC code 17) inhibit C4-demethylase which plays a role in sterol production. Examples include fenhexamid.
(bl8) "Squalene-epoxidase inhibitor fungicides" (FRAC code 18) inhibit squalene- epoxidase in ergosterol biosynthesis pathway. Sterols such as ergosterol are needed for membrane structure and function, making them essential for the development of functional cell walls. Therefore exposure to these fungicides result in abnormal growth and eventually death of sensitive fungi. Squalene-epoxidase inhibitor fungicides include thiocarbamate and allylamine fungicides. The thiocarbamates include pyributicarb. The allylamines include naftifme and terbinafme.
(bl9) "Polyoxin fungicides" (FRAC code 19) inhibit chitin synthase. Examples include polyoxin.
(b20) "Phenylurea fungicides" (FRAC code 20) are proposed to affect cell division. Examples include pencycuron.
(b21) "Quinone inside inhibitor (Qil) fungicides" (FRAC code 21) inhibit Complex III mitochondrial respiration in fungi by affecting ubiquinol reductase. Reduction of ubiquinol is blocked at the "quinone inside" (Qj) site of the cytochrome bc\ complex, which is located in the inner mitochondrial membrane of fungi. Inhibiting mitochondrial respiration prevents normal fungal growth and development. Quinone inside inhibitor fungicides include cyanoimidazole and sulfamoyltriazole fungicides. The cyanoimidazoles include cyazofamid. The sulfamoyltriazoles include amisulbrom.
(b22) "Benzamide fungicides" (FRAC code 22) inhibit mitosis by binding to β-tubulin and disrupting microtubule assembly. Inhibition of microtubule assembly can disrupt cell division, transport within the cell and cell structure. Examples include zoxamide.
(b23) "Enopyranuronic acid antibiotic fungicides" (FRAC code 23) inhibit growth of fungi by affecting protein biosynthesis. Examples include blasticidin-S.
(b24) "Hexopyranosyl antibiotic fungicides" (FRAC code 24) inhibit growth of fungi by affecting protein biosynthesis. Examples include kasugamycin.
(b25) "Glucopyranosyl antibiotic: protein synthesis fungicides" (FRAC code 25) inhibit growth of fungi by affecting protein biosynthesis. Examples include streptomycin.
(b26) "Glucopyranosyl antibiotic: trehalase and inositol biosynthesis fungicides" (FRAC code 26) inhibit trehalase in inositol biosynthesis pathway. Examples include validamycin.
(b27) "Cyanoacetamideoxime fungicides" (FRAC code 27) include cymoxanil. (b28) "Carbamate fungicides" (FRAC code 28) are considered multi-site inhibitors of fungal growth. They are proposed to interfere with the synthesis of fatty acids in cell membranes, which then disrupts cell membrane permeability. Propamacarb, iodocarb, and prothiocarb are examples of this fungicide class.
(b29) "Oxidative phosphorylation uncoupling fungicides" (FRAC code 29) inhibit fungal respiration by uncoupling oxidative phosphorylation. Inhibiting respiration prevents normal fungal growth and development. This class includes 2,6-dinitroanilines such as fluazinam, pyrimidonehydrazones such as ferimzone and dinitrophenyl crotonates such as dinocap, meptyldinocap and binapacryl.
(b30) "Organo tin fungicides" (FRAC code 30) inhibit adenosine triphosphate (ATP) synthase in oxidative phosphorylation pathway. Examples include fentin acetate, fentin chloride and fentin hydroxide.
(b31) "Carboxylic acid fungicides" (FRAC code 31) inhibit growth of fungi by affecting deoxyribonucleic acid (DNA) topoisomerase type II (gyrase). Examples include oxolinic acid.
(b32) "Heteroaromatic fungicides" (FRAC code 32) are proposed to affect DNA/ribonucleic acid (RNA) synthesis. Heteroaromatic fungicides include isoxazole and isothiazolone fungicides. The isoxazoles include hymexazole and the isothiazolones include octhilinone.
(b33) "Phosphonate fungicides" (FRAC code 33) include phosphorous acid and its various salts, including fosetyl-aluminum.
(b34) "Phthalamic acid fungicides" (FRAC code 34) include teclofthalam.
(b35) "Benzotriazine fungicides" (FRAC code 35) include triazoxide.
(b36) "Benzene-sulfonamide fungicides" (FRAC code 36) include flusulfamide.
(b37) "Pyridazinone fungicides" (FRAC code 37) include diclomezine.
(b38) "Thiophene-carboxamide fungicides" (FRAC code 38) are proposed to affect ATP production. Examples include silthiofam.
(b39) "Pyrimidinamide fungicides" (FRAC code 39) inhibit growth of fungi by affecting phospholipid biosynthesis and include diflumetorim.
(b40) "Carboxylic acid amide (CAA) fungicides" (FRAC code 40) are proposed to inhibit phospholipid biosynthesis and cell wall deposition. Inhibition of these processes prevents growth and leads to death of the target fungus. Carboxylic acid amide fungicides include cinnamic acid amide, valinamide and other carbamate, and mandelic acid amide fungicides. The cinnamic acid amides include dimethomorph and flumorph. The valinamide and other carbamates include benthiavalicarb, benthiavalicarb-isopropyl, iprovalicarb, tolprocarb and valifenalate (valiphenal). The mandelic acid amides include mandipropamid, N-[2-[4-[[3-(4-chlorophenyl)-2-propyn- 1 -yl]oxy]-3-methoxyphenyl]ethyl]- 3 -methyl-2- [(methylsulfonyl)amino]butanamide and N-[2- [4- [ [3 -(4-chlorophenyl)-2-propyn- 1 -yl]oxy] -3 -methoxyphenyl] ethyl] -3 -methyl-2- [(ethylsulfonyl)amino]butanamide .
(b41) "Tetracycline antibiotic fungicides" (FRAC code 41) inhibit growth of fungi by affecting complex 1 nicotinamide adenine dinucleotide (NADH) oxidoreductase. Examples include oxytetracycline.
(b42) "Thiocarbamate fungicides" (FRAC code 42) include methasulfocarb.
(b43) "Benzamide fungicides" (FRAC code 43) inhibit growth of fungi by derealization of spectrin-like proteins. Examples include acylpicolide fungicides such as fluopicolide and fluopyram.
(b44) "Host plant defense induction fungicides" (FRAC code P) induce host plant defense mechanisms. Host plant defense induction fungicides include benzo-thiadiazole, benzisothiazole and thiadiazole-carboxamide fungicides. The benzo-thiadiazoles include acibenzolar-S-methyl. The benzisothiazoles include probenazole. The thiadiazole- carboxamides include tiadinil and isotianil.
(b45) "Multi-site contact fungicides" inhibit fungal growth through multiple sites of action and have contact/preventive activity. This class of fungicides includes: (b45.1) "copper fungicides (FRAC code Ml)", (b45.2) "sulfur fungicides (FRAC code M2)", (b45.3) "dithiocarbamate fungicides (FRAC code M3)", (b45.4) "phthalimide fungicides (FRAC code M4)", (b45.5) "chloronitrile fungicides (FRAC code M5)", (b45.6) "sulfamide fungicides (FRAC code M6)", (b45.7) "guanidine fungicides (FRAC code M7)", (b45.8) "triazine fungicides (FRAC code M8)" and (b45.9) "quinone fungicides (FRAC code M9)". "Copper fungicides" are inorganic compounds containing copper, typically in the copper(II) oxidation state; examples include copper oxychloride, copper sulfate and copper hydroxide, including compositions such as Bordeaux mixture (tribasic copper sulfate). "Sulfur fungicides" are inorganic chemicals containing rings or chains of sulfur atoms; examples include elemental sulfur. "Dithiocarbamate fungicides" contain a dithiocarbamate molecular moiety; examples include mancozeb, metiram, propineb, ferbam, maneb, thiram, zineb and ziram. "Phthalimide fungicides" contain a phthalimide molecular moiety; examples include folpet, captan and captafol. "Chloronitrile fungicides" contain an aromatic ring substituted with chloro and cyano; examples include chlorothalonil. "Sulfamide fungicides" include dichlofluanid and tolylfluanid. "Guanidine fungicides" include dodine, guazatine and iminoctadine. "Triazine fungicides" include anilazine. "Quinone fungicides" include dithianon.
(b46) "Fungicides other than fungicides of classes (bl) through (b45)" include certain fungicides whose mode of action may be unknown. These include: (b46.1) "thiazole carboxamide fungicides" (FRAC code U5), (b46.2) "phenyl-acetamide fungicides" (FRAC code U6), (b46.3) "quinazolinone fungicides" (FRAC code U7), (b46.4) "benzophenone fungicides" (FRAC code U8) and (b46.5) "triazolopyrimidylamine fungicides" (FRAC code 45). The thiazole carboxamides include ethaboxam. The phenyl-acetamides include cyflufenamid and N-[[(cyclopropylmethoxy)amino][6-(difluoromethoxy)-2,3- difluorophenyl]-methylene]benzeneacetamide. The quinazolinones include proquinazid and 2-butoxy-6-iodo-3-propyl-4H-l-benzopyran-4-one. The benzophenones include metrafenone and pyriofenone. The triazolopyrimidylamines include ametoctradin and are believed to inhibit Complex III mitochondrial respiration by binding to an unelucidated site on ubiquinone-cytochrome bcl reductase. The (b46) class also includes bethoxazin, neo- asozin (ferric methanearsonate), fenpyrazamine, pyrrolnitrin, quinomethionate, tebufloquin, 2-[[2-fluoro-5-(trifluoromethyl)phenyl]thio]-2-[3-(2-methoxyphenyl)-2-thiazolidinyl- idene]acetonitrile, 3-[5-(4-chlorophenyl)-2,3-dimethyl-3-isoxazolidinyl]pyridine, 4-fluoro- phenyl N-[ 1 -[[[1 -(4-cyanophenyl)ethyl]sulfonyl]methyl]propyl] carbamate, 5-chloro-6- (2,4,6-trifluorophenyl)-7-(4-methylpiperidin- 1 -yl)[ 1 ,2,4]triazolo[ 1 ,5-a]pyrimidine, N-(4- chloro-2-nitrophenyl)-N-ethyl-4-methylbenzenesulfonamide, N'-[4-[4-chloro-3-(trifluoro- methyl)phenoxy]-2,5-dimethylphenyl]-N-ethyl-N-methylmethanimidamide and 1 -[(2- propenylthio)carbonyl]-2-(l-methylethyl)-4-(2-methylphenyl)-5-amino-lH-pyrazol-3-one.
The (b46) class also includes (b46.5) 6-quinolinyloxyacetamide compounds of Formula Bl and salts thereof
Figure imgf000093_0001
wherein
Rbl is halogen, C1-C4 alkoxy or C1-C4 alkynyl;
Rb2 is Η, halogen or -C4 alkyl;
Rb3 is C1-C12 alkyl,
Figure imgf000093_0002
haloalkyl, alkoxy, C -C1 alkoxyalkyl, C -C1 alkenyl, C2-Cj2 alkynyl, C4-Cj2 alkoxyalkenyl, C4-Cj2 alkoxyalkynyl, C^-C^ alkylthio or C2-C^2 alkylthioalkyl;
Rb4 is methyl or - Yal -Ra5 ;
Rb5 is C!-C2 alky!; and
Ybl is CH2, O or S.
Compounds of Formula Bl, their use as fungicides and methods of preparation are generally known; see, for example, PCT Patent Publications WO 2004/047538, WO 2004/108663, WO 2006/058699, WO 2006/058700, WO 2008/110355, WO 2009/030469, WO 2009/049716 and WO 2009/087098. Examples of compounds of Formula Bl include: 2-[(3-bromo-6-quinolinyl)oxy]-N-( 1 , 1 -dimethyl-2-butyn- 1 -yl)-2-(methylthio)acetamide, 2-[(3 -ethynyl-6-quinolinyl)oxy] -N-[ 1 -(hydroxymethyl)- 1 -methyl-2-propyn- 1 -yl] -2-(methyl- thio)acetamide, N-( 1 , 1 -dimethyl-2-butyn- 1 -yl)-2- [(3 -ethynyl-6-quinolinyl)oxy] -2-(methyl- thio)acetamide, 2-[(3-bromo-8-methyl-6-quinolinyl)oxy]-N-(l , 1 -dimethyl-2-propyn- 1 -yl)- 2-(methylthio)acetamide and 2- [(3 -bromo-6-quinolinyl)oxy] -N-( 1 , 1 -dimethylethyl)- butanamide.
"Fungicides other than fungicides of classes (bl) through (b45); (b46)" also include
(b46.6) N'-[4-[[3-[(4-chlorophenyl)methyl]-l,2,4-thiadiazol-5-yl]oxy]-2,5-dimethylphenyl]- N-ethyl-N-methylmethanimidamide, which is believed to inhibit C24-methyl transferase involved in biosynthesis of sterols.
Therefore of note is a mixture (i.e. composition) comprising as component (a) a compound of Formula 1 (or an N-oxide or salt thereof) and as component (b) at least one fungicidal compound selected from the group consisting of the aforedescribed classes (bl) through (b46). Also of note are embodiments wherein component (b) comprises at least one fungicide from each of two different groups selected from (bl) through (b46). Also of note is a composition comprising said mixture (in fungicidally effective amount) and further comprising at least one additional component selected from the group consisting of surfactants, solid diluents and liquid diluents. Of particular note is a mixture (i.e. composition) comprising a compound of Formula 1 and at least one fungicidal compound selected from the group of specific compounds listed above in connection with classes (bl) through (b46). Also of particular note is a composition comprising said mixture (in fungicidally effective amount) and further comprising at least one additional surfactant selected from the group consisting of surfactants, solid diluents and liquid diluents.
Examples of component (b) fungicides include acibenzolar-S-methyl, aldimorph, ametoctradin, amisulbrom, anilazine, azaconazole, azoxystrobin, benalaxyl, benalaxyl-M, benodanil, benomyl, benthiavalicarb, benthiavalicarb-isopropyl, benzovindiflupyr, bethoxazin, binapacryl, biphenyl, bitertanol, bixafen, blasticidin-S, boscalid, bromuconazole, bupirimate, buthiobate, carboxin, carpropamid, captafol, captan, carbendazim, chloroneb, chlorothalonil, chlozolinate, clotrimazole, copper salts (such as Bordeaux mixture (tribasic copper sulfate), copper hydroxide and copper oxychloride), cyazofamid, cyflufenamid, cymoxanil, cyproconazole, cyprodinil, dichlofluanid, diclocymet, diclomezine, dicloran, diethofencarb, difenoconazole, diflumetorim, dimethirimol, dimethomorph, dimoxystrobin, diniconazole, diniconazole-M, dinocap, dithianon, dodemorph, dodine, edifenphos, enestroburin, epoxiconazole, etaconazole, ethaboxam, ethirimol, etridiazole, famoxadone, fenamidone, fenarimol, fenbuconazole, fenfuram, fenhexamid, fenoxanil, fenpiclonil, fenpropidin, fenpropimorph, fenpyrazamine, fentin acetate, fentin chloride, fentin hydroxide, ferbam, ferimzone, fluazinam, fludioxonil, flumetover, flumorph, fluopicolide (also known as picobenzamid), fluopyram, fluoroimide, fluoxastrobin, fluquinconazole, flusilazole, flusulfamide, flutianil (2-[[2-fluoro-5-(trifluoromethyl)phenyl]thio]-2-[3-(2-methoxy- phenyl)-2-thiazolidinylidene]acetonitrile), flutolanil, flutriafol, fluxapyroxad, folpet, fosetyl- aluminum, fuberidazole, furalaxyl, furametpyr, hexaconazole, hymexazol, guazatine, imazalil, imibenconazole, iminoctadine, iodocarb, ipconazole, iprobenfos, iprodione, iprovalicarb, isofetamid, isoprothiolane, isopyrazam, isotianil, kasugamycin, kresoxim- methyl, mancozeb, mandipropamid, maneb, mepronil, meptyldinocap, metalaxyl, metalaxyl- M, metconazole, methasulfocarb, metiram, metominostrobin, mepanipyrim, metrafenone, myclobutanil, naftifme, neo-asozin (ferric methanearsonate), nuarimol, octhilinone, ofurace, orysastrobin, oxadixyl, oxolinic acid, oxpoconazole, oxycarboxin, oxytetracycline, penconazole, pencycuron, penflufen, penthiopyrad, pefurazoate, phosphorous acid and salts thereof, phthalide, picoxystrobin, piperalin, polyoxin, probenazole, prochloraz, procymidone, propamocarb, propamocarb-hydrochloride, propiconazole, propineb, proquinazid, prothiocarb, prothioconazole, pyraclostrobin, pyrametostrobin, pyraoxystrobin, pyrazophos, pyribencarb, pyributicarb, pyrifenox, pyrimethanil, pyriofenone, pyroquilon, pyrrolnitrin, quinconazole, quinomethionate, quinoxyfen, quintozene, sedaxane, silthiofam, simeconazole, spiroxamine, streptomycin, sulfur, tebuconazole, tebufloquin, tecloftalam, tecnazene, terbinafme, tetraconazole, thiabendazole, thifluzamide, thiophanate, thiophanate- methyl, thiram, tiadinil, tolclofos-methyl, tolprocarb, tolylfluanid, triadimefon, triadimenol, triarimol, triazoxide, tricyclazole, tridemorph, triflumizole, tricyclazole, trifloxystrobin, triforine, trimorphamide, triticonazole, uniconazole, validamycin, valifenalate (valiphenal), vinclozolin, zineb, ziram, zoxamide, l-[4-[4-[5-(2,6-difluorophenyl)-4,5-dihydro- 3-isoxazolyl]-2-thiazolyl]- 1 -piperidinyl]-2-[5-methyl-3-(trifluoromethyl)- lH-pyrazol-1 -yl]- ethanone, 5 , 8-difluoro-N-[2- [3 -methoxy-4- [ [4-(trifluoromethyl)-2-pyridinyl]oxy]phenyl]- ethyl]-4-quinazolinamine, N'-[4-[4-chloro-3-(trifluoromethyl)phenoxy]-2,5-dimethylphenyl]- N-ethyl-N-methylmethanimidamide, N-(3',4'-difluoro[l, -biphenyl]-2-yl)-3-(trifluoro- methyl)-2-pyrazinecarboxamide, N-[2-(2,4-dichlorophenyl)-2-methoxy- 1 -methylethyl]-3- (difluoromethyl)- 1 -methyl- lH-pyrazole-4-carboxamide, (a ?)-2-[(2,5-dimethylphenoxy)- methyl]-a-methoxy-N-methylbenzeneacetamide, 2,6-dimethyl-lH,5H-[l,4]dithiino[2,3- c:5,6-c']dipyrrole-l,3,5,7(2H,6H)-tetrone, 5-chloro-6-(2,4,6-trifluorophenyl)-7-(4-methyl- piperidin-l-yl)[l,2,4]triazolo[l,5-a]pyrimidine (BAS600), N-[2-[4-[[3-(4-chlorophenyl)-2- propyn- 1 -yl]oxy] -3 -methoxyphenyl] ethyl] -3 -methyl-2-[(methylsulfonyl)amino]butanamide, N-[2-[4-[[3-(4-chlorophenyl)-2-propyn- 1 -yl]oxy]-3-methoxyphenyl]ethyl]-3-methyl-2-
[(ethylsulfonyl)amino]butanamide, 2-butoxy-6-iodo-3-propyl-4H-l-benzopyran-4-one, 3-[5- (4-chlorophenyl)-2,3-dimethyl-3-isoxazolidinyl]pyridine, 4-fluorophenyl N-[ 1 -[[[1 -(4- cyanophenyl)ethyl]sulfonyl]methyl]propyl]carbamate, N-[[(cyclopropylmethoxy)amino][6- (difluoromethoxy)-2,3-difluorophenyl]methylene]benzeneacetamide, a-(methoxyimino)-N- methyl-2-[[[ 1 -[3-(trifluoromethyl)phenyl]ethoxy]imino]methyl]benzeneacetamide, N"-[4-[4- chloro-3-(trifluoromethyl)phenoxy]-2,5-dimethylphenyl]-N-ethyl-N-methylmethan- imidamide, N-(4-chloro-2-nitrophenyl)-N-ethyl-4-methylbenzenesulfonamide, 2-[[[[3-(2,6- dichlorophenyl)- 1 -methyl-2-propen- 1 -ylidene]amino]oxy]methyl]-a-(methoxyimino)- N-methylbenzeneacetamide, 1 - [(2-propenylthio)carbonyl] -2-( 1 -methylethyl)-4-(2-methyl- phenyl)-5-amino-lH-pyrazol-3-one, ethyl-6-octyl-[l ,2,4]triazolo[l ,5-a]pyrimidin-7-ylamine, pentyl N- [4-[ [ [[( 1 -methyl- lH-tetrazol-5 -yl)phenylmethylene] amino]oxy]methyl] -2- thiazolyl]carbamate, pentyl N-[6-[[[[(l -methyl- lH-tetrazol-5-yl)phenylmethylene]amino]- oxy]methyl]-2-pyridinyl]carbamate, 2-[(3-bromo-6-quinolinyl)oxy]-N-(l,l-dimethyl- 2-butyn- 1 -yl)-2-(methylthio)acetamide, 2-[(3-ethynyl-6-quinolinyl)oxy]-N-[ 1 -(hydroxy- methyl)- 1 -methyl-2-propyn- 1 -yl]-2-(methylthio)acetamide, N-( 1 , 1 -dimethyl-2-butyn- 1 -yl)- 2-[(3-ethynyl-6-quinolinyl)oxy]-2-(methylthio)acetamide and N-[4-[[3-[(4-chlorophenyl)- methy 1] - 1 ,2 ,4-thiadiazol-5 -y 1] oxy ] -2 , 5 -dimethy lpheny 1] -N-ethy 1-N-methy lmethanimidamide .
Of note are combinations of compounds of Formula 1 (or an N-oxide or salt thereof)
(i.e. Component (a) in compositions) with azoxystrobin, kresoxim-methyl, trifloxystrobin, pyraclostrobin, picoxystrobin, pyrametostrobin, pyraoxystrobin, dimoxystrobin, metominostrobin/fenominostrobin, carbendazim, chlorothalonil, quinoxyfen, metrafenone, cyflufenamid, fenpropidine, fenpropimorph, bromuconazole, cyproconazole, difenoconazole, epoxiconazole, fenbuconazole, flusilazole, fluxapyroxad, hexaconazole, ipconazole, metconazole, penconazole, propiconazole, proquinazid, prothioconazole, pyriofenone, tebuconazole, triticonazole, famoxadone, prochloraz, penthiopyrad and boscalid (nicobifen) (i.e. as Component (b) in compositions).
Preferred for better control of plant diseases caused by fungal plant pathogens (e.g., lower use rate or broader spectrum of plant pathogens controlled) or resistance management are mixtures of a compound of this invention with a fungicide selected from the group: azoxystrobin, kresoxim-methyl, trifloxystrobin, pyraclostrobin, picoxystrobin, pyrametostrobin, pyraoxystrobin, dimoxystrobin, metominostrobin/fenominostrobin, quinoxyfen, metrafenone, cyflufenamid, fenpropidine, fenpropimorph, cyproconazole, epoxiconazole, flusilazole, metconazole, propiconazole, proquinazid, prothioconazole, pyriofenone, tebuconazole, triticonazole, famoxadone and penthiopyrad.
Examples of other biologically active compounds or agents with which compounds of this invention can be formulated are: insecticides such as abamectin, acephate, acetamiprid, acetoprole, acrinathrin, aldicarb, amidoflumet, amitraz, avermectin, azadirachtin, azinphos-methyl, bifenthrin, bifenazate, bistrif uron, buprofezin, carbofuran, cartap, chinomethionat, chlorfenapyr, chlorf uazuron, chlorantraniliprole, chlorpyrifos, chlorpyrifos- methyl, chlorobenzilate, chromafenozide, clothianidin, cyantraniliprole, cyf umetofen, cyf uthrin, beta-cyfluthrin, cyhalothrin, gamma-cyhalothrin, lambda-cyhalothrin, cyhexatin, cypermethrin, cyromazine, deltamethrin, diafenthiuron, diazinon, dicofol, dieldrin, dienochlor, dif ubenzuron, dimef uthrin, dimethoate, dinotefuran, diofenolan, emamectin, endosulfan, esfenvalerate, ethiprole, etoxazole, fenamiphos, fenazaquin, fenbutatin oxide, fenothiocarb, fenoxycarb, fenpropathrin, fenpyroximate, fenvalerate, fipronil, flonicamid, flubendiamide, flucythrinate, tau-f uvalinate, flufenerim, flufenoxuron, fonophos, halofenozide, hexaflumuron, hexythiazox, hydramethylnon, imicyafos, imidacloprid, indoxacarb, isofenphos, lufenuron, malathion, meperfluthrin, metaflumizone, metaldehyde, methamidophos, methidathion, methomyl, methoprene, methoxychlor, methoxyfenozide, metofluthrin, milbemycin oxime, monocrotophos, nicotine, nitenpyram, nithiazine, novaluron, noviflumuron, oxamyl, parathion, parathion-methyl, permethrin, phorate, phosalone, phosmet, phosphamidon, pirimicarb, profenofos, profluthrin, propargite, prothiocarb, protrifenbute, pymetrozine, pyrafluprole, pyrethrin, pyridaben, pyridalyl, pyrifluquinazon, pyriprole, pyriproxyfen, rotenone, ryanodine, spinetoram, spinosad, spiridiclofen, spiromesifen, spirotetramat, sulfoxaflor, sulprofos, tebufenozide, tebufenpyrad, teflubenzuron, tefluthrin, terbufos, tetrachlorvinphos, tetramethylfluthrin, thiacloprid, thiamethoxam, thiodicarb, thiosultap-sodium, tolfenpyrad, tralomethrin, triazamate, trichlorfon, triflumuron; nematocides such as aldicarb, imicyafos, oxamyl and fenamiphos; bactericides such as streptomycin; acaricides such as amitraz, chinomethionat, chlorobenzilate, cyenopyrafen, cyhexatin, dicofol, dienochlor, etoxazole, fenazaquin, fenbutatin oxide, fenpropathrin, fenpyroximate, hexythiazox, propargite, pyridaben and tebufenpyrad; and biological agents including entomopathogenic bacteria, such as Bacillus thuringiensis subsp. aizawai, Bacillus thuringiensis subsp. kurstaki, and the encapsulated delta-endotoxins of Bacillus thuringiensis (e.g., Cellcap, MPV, MPVII); entomopathogenic fungi, such as green muscardine fungus; and entomopathogenic virus including baculovirus, nucleopolyhedro virus (NPV) such as HzNPV, AfNPV; and granulosis virus (GV) such as CpGV.
General references for agricultural protectants (i.e. insecticides, fungicides, nematocides, acaricides, herbicides and biological agents) include The Pesticide Manual, 13th Edition, C. D. S. Tomlin, Ed., British Crop Protection Council, Farnham, Surrey, U.K., 2003 and The BioPesticide Manual, 2nd Edition, L. G. Copping, Ed., British Crop Protection Council, Farnham, Surrey, U.K., 2001.
For embodiments where one or more of these various mixing partners are used, the weight ratio of these various mixing partners (in total) to the compound of Formula 1 (or an N-oxide or salt thereof) is typically between about 1 :3000 and about 3000: 1. Of note are weight ratios between about 1 :300 and about 300: 1 (for example ratios between about 1 :30 and about 30: 1). One skilled in the art can easily determine through simple experimentation the biologically effective amounts of active ingredients necessary for the desired spectrum of biological activity. It will be evident that including these additional components may expand the spectrum of diseases controlled beyond the spectrum controlled by the compound of Formula 1 alone.
In certain instances, combinations of a compound of this invention with other biologically active (particularly fungicidal) compounds or agents (i.e. active ingredients) can result in a greater-than-additive (i.e. synergistic) effect. Reducing the quantity of active ingredients released in the environment while ensuring effective pest control is always desirable. When synergism of fungicidal active ingredients occurs at application rates giving agronomically satisfactory levels of fungal control, such combinations can be advantageous for reducing crop production cost and decreasing environmental load.
Compounds of this invention and compositions thereof can be applied to plants genetically transformed to express proteins toxic to invertebrate pests (such as Bacillus thuringiensis delta-endotoxins). The effect of the exogenously applied fungicidal compounds of this invention may be synergistic with the expressed toxin proteins.
The following Tests demonstrate the control efficacy of compounds of this invention on specific pathogens. The pathogen control protection afforded by the compounds is not limited, however, to these species. See Index Table A for compound descriptions. The following abbreviations are used in the Index Tables which follow: Me is methyl, Ph is phenyl. "Cmpd No." means compound number. The abbreviation "Ex." stands for "Example" and is followed by a number indicating in which Synthesis Example the compound is prepared. Mass spectra (MS) are reported as the molecular weight of the highest isotopic abundance of the parent ion (M+1) formed by addition of H+ (molecular weight of 1) to the molecule, observed by mass spectrometry using atmospheric pressure chemical ionization (AP+). The presence of molecular ions containing one or more higher atomic weight isotopes of lower abundance (e.g., 37C1, 81Br) is not reported. "M.P." means melting point.
INDEX TABLE A
Figure imgf000098_0001
Cmpd
No. Rl R2 Q1 Q2 X M.P. (°C)
1 (Ex. 1) H H 2-Cl-4-F-Ph 2-Cl-4-F-Ph NH *
2 H H 2-Br-4-F-Ph 2-Br-4-F-Ph NH 93-95
3 (Ex. 2) H H 2-Br-4,6-di-F-Ph 2-Br-4-F-Ph NH *
4 H H 2-Br-6-F-Ph 2-Br-4-F-Ph NH 131-132
5 H H 2-Cl-6-F-Ph 2-Br-4-F-Ph NH 134-136
6 H H 2,4-di-Cl-Ph 2-Br-4-F-Ph NH 80-82
7 H H 2-Cl-4-MeO-Ph 2-Br-4-F-Ph NH 87-89
8 H H 2,4-di-F-Ph 2-Br-4-F-Ph NH 143-145 Cmpd
No. Rl R2 Q1 Q2 X M.P. (°C)
9 Me H 2-Br-4,6-di-F-Ph 2-Br-4-F-Ph NH 128-130
10 Me H 2-Br-6-F-Ph 2-Br-4-F-Ph NH 118-120
11 Me H 2-Br-4-F-Ph 2-Br-4-F-Ph NH **
12 Me H 2,4-di-Cl-Ph 2-Br-4-F-Ph NH **
13 Me H 2-F-6-Cl-Ph 2-Br-4-F-Ph NH 138-140
14 Me H 2,4-di-F-Ph 2-Br-4-F-Ph NH 90-92
15 Me H 2-Cl-4-MeO-Ph 2-Br-4-F-Ph NH 92-94
16 H H 2-Br-4,6-di-F-Ph 2-Cl-4-F-Ph NH 127-129
17 H H 4-Cl-2,6-di-F-Ph 2-Cl-4-F-Ph NH 120-122
18 H H 2-Cl-4,6-di-F-Ph 2-Cl-4-F-Ph NH 153-155
19 H H 2-Br-6-F-4-Me-Ph 2-Cl-4-F-Ph NH 123-126
20 H H 2,4,6-tri-F-Ph 2-Cl-4-F-Ph NH 153-155
21 H H 4-Cl-2,6-di-F-Ph 2-Br-4-F-Ph NH 155-160
22 (Ex. 3) H H 2-Cl-4-F-Ph 2-Cl-4-F-Ph CHOH *
* See Synthesis Example for physical properly data.
** Cmpd. No. 11 MS(AP+) 458 (M+l); Cmpd No. 12 MS(AP+) 430 (M+l).
BIOLOGICAL EXAMPLES OF THE INVENTION
General protocol for preparing test suspensions for Tests A-D: the test compounds were 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 by volume) containing 250 ppm of the surfactant Trem® 014 (polyhydric alcohol esters). The resulting test suspensions were then used in Tests A-D. Each test was conducted in triplicate, and the results were averaged. Spraying a 200 ppm test suspension to the point of run-off on the test plants was the equivalent of a rate of about 800 g/ha. Unless otherwise indicated, the rating values indicate a 200 ppm test suspension was used. (An asterisk "*" next to the rating value in Table A indicates a 40 ppm test suspension was used.)
TEST A
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 Botrytis cinerea (the causal agent of tomato Botrytis) and incubated in saturated atmosphere at 20 °C for 48 h, and then moved to a growth chamber at 24 °C for 3 additional days, after which time visual 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 Septoria tritici (the causal agent of wheat leaf blotch) and incubated in saturated atmosphere at 24 °C for 48 h. and then the seedlings were moved to a growth chamber at 20 °C for 19 additional days, after which time visual disease ratings were made.
TEST C
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 f. sp. tritici (the causal agent of wheat leaf rust) and incubated in a saturated atmosphere at 20 °C for 24 h, and then moved to a growth chamber at 20 °C for 6 days, after which time visual disease ratings were made.
TEST D
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 Blumeria graminis f. sp. tritici (also known as Erysiphe graminis f. sp. tritici, the causal agent of wheat powdery mildew) and incubated in a growth chamber at 20 °C for 8 days, after which time visual 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).
TABLE A
Cmpd No. Test A Test B Test C Test D
1 99* 99* 28* 97*
2 100 100 79 99
3 100 100 94 98
4 100 100 92 98
5 100 100 94 99
6 100 100 85 96
7 100 97 74 92
8 100 100 79 100
9 100 100 9 96
10 12 100 0 0
11 99 100 41 98
12 80 100 27 90
13 0 34 0 0
14 100 96 68 98
15 99 99 86 86 Cmpd No. Test A Test B Test C Test D
16 100 100 98 100
17 100 100 91 99
18 100 - 99 97
19 100 - 99 99
20 100 - 99 96
21 100 - 99 99
22 14 63 0 0
"Cmpd No." means compound number.

Claims

CLAIMS What is claimed is:
1. A compound selected from Formula 1, N-oxides and salts thereof,
Figure imgf000102_0001
1*
1
wherein
Q1 is a phenyl ring or a naphthalenyl ring system, each ring or ring system optionally substituted with up to 5 substituents independently selected from R3; or a 5- to 6-membered fully unsaturated heterocyclic ring or an 8- to 10-membered heteroaromatic bicyclic ring system, each ring or ring system containing ring members selected from carbon atoms and up to 4 heteroatoms independently selected from up to 2 O, up to 2 S and up to 4 N atoms, wherein up to 3 carbon ring members are independently selected from C(=0) and C(=S), and the sulfur atom ring members are independently selected from S(=0)u(=NR14)v, each ring or ring system optionally substituted with up to 5 substituents independently selected from R3 on carbon atom ring members and selected from cyano, Ci-C^ alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, i~C^ alkoxy, C2-C6 alkoxyalkyl, C2-C6 alkylcarbonyl, C2-C6 alkoxycarbonyl, C2-C6
alkylaminoalkyl and C3-C6 dialkylaminoalkyl on nitrogen atom ring members; Q2 is a phenyl ring or a naphthalenyl ring system, each ring or ring system optionally substituted with up to 5 substituents independently selected from R3; or a 4-, 5- or 6-membered saturated, partially unsaturated or fully unsaturated heterocyclic ring or an 8- to 10-membered heteroaromatic bicyclic ring system, each ring or ring system containing ring members selected from carbon atoms and up to 4 heteroatoms independently selected from up to 2 O, up to 2 S and up to 4 N atoms, wherein up to 3 carbon ring members are independently selected from C(=0) and C(=S), and the sulfur atom ring members are independently selected from S(=0)u(=NR14)v, each ring or ring system optionally substituted with up to 5 substituents independently selected from R3 on carbon atom ring members and selected from cyano, Ci~C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, Ci~C6 alkoxy, C2-C6 alkoxyalkyl, C2-C6 alkylcarbonyl, C2- alkoxycarbonyl, C2-C6 alkylaminoalkyl and C3-C6 dialkylaminoalkyl on nitrogen atom ring members; or Ci_C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C3-C12 cycloalkyl or C3-C12 cycloalkenyl, each optionally substituted with up to 5 substituents independently selected from R3;
X is O, NR4 or CR15R16;
R1 is H, halogen, Ci~C6 alkyl, Ci~C6 haloalkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-
C7 cycloalkyl, C02R5, C(0)NR6R7, cyano, -Cg alkoxy, -Cg haloalkoxy or
C2-C5 alkoxyalkyl; or
R1 is phenyl optionally substituted with up to 3 R8; or a five- or six-membered
nitrogen-containing aromatic heterocycle optionally substituted with up to 3 substituents independently selected from R9a on carbon atom ring members and
R9^ on nitrogen atom ring members;
Rl a is H; or
Rl a and R1 are taken together with the carbon atom to which they are attached to form a cyclopropyl ring optionally substituted with up to 2 substituents independently selected from halogen and methyl;
R2 is H, C2-C3 alkenyl or C2-C3 alkynyl;
each R3 is independently selected from halogen, cyano, nitro, amino, methylamino, dimethylamino, formylamino, C2-C3 alkylcarbonylamino, C}-C4 alkyl, C}-C4 haloalkyl, C^-C3 alkoxy, C^-C3 haloalkoxy, C^-C3 alkylthio, C^-C3
haloalkylthio, C^-C3 alkylsulfmyl, C^-C3 haloalkylsulfinyl, C^-C3
alkylsulfonyl, C1-C3 haloalkylsulfonyl, C1-C2 alkylsulfonyloxy, C1-C2 haloalkylsulfonyloxy, C3-C4 cycloalkyl, C3-C7 cycloalkoxy, C4-C6
alkylcycloalkyl, C4-C6 cycloalkylalkyl, C3-C7 halocycloalkyl, C2-C4 alkenyl, C2-C4 alkynyl, hydroxy, formyl, C2-C3 alkylcarbonyl, C2-C3 alkylcarbonyloxy, -SF5, -SCN, C(=S)NR19R20, C(=NOR27)R28 or -U-V-T;
R4 is H, formyl, C2-C5 alkenyl, C3-C5 alkynyl, C3-C7 cycloalkyl, -S03-M+, -
S(=0)tR10, -(C=W)Rn, NH2 or OR21; or -Cg alkyl or -Cg haloalkyl, each optionally substituted with up to 2 R12;
R5 is H, C!-C6 alkyl or -Cg haloalkyl;
R6 and R7 are independently selected from H, Cj-Cg alkyl, -Cg haloalkyl, C3-C7 cycloalkyl, C4-C8 cycloalkylalkyl and C4-C8 alkylcycloalkyl; or
R6 and R7 are taken together with the nitrogen atom to which they are connected to form a four- to seven-membered nonaromatic heterocyclic ring containing ring members, in addition to the connecting ring nitrogen atom, selected from carbon atoms and optionally up to one ring member selected from O, S(0)n and NR13; each R8, R9a and R9b is independently selected from halogen, C1-C2 alkyl, C1-C2 haloalkyl, C1-C2 alkoxy, C1-C2 haloalkoxy, cyano, nitro, SCH3, S(0)CH3 and S(0)2CH3; R10 is Ci-Cg alkyl or -Cg haloalkyl;
each R1 1 is independently -Cg alkyl, -Cg alkoxy, C2-C7 alkoxyalkyl, C2-C7 alkylaminoalkyl, C2-Cg dialkylaminoalkyl, C^-Cg alkylthio or C2-C7 alkylthioalkyl;
each R12 is independently C3-C7 cycloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, Ci~C4 alkylthio, Ci~C4 alkylsulfinyl, Ci~C4 alkylsulfonyl or cyano;
R13 is H, -C3 alkyl or C2-C3 haloalkyl;
each R14 is independently H, cyano, C}-C3 alkyl or C}-C3 haloalkyl;
R15 is H or C!-C4 alkyl;
R16 is F, CI or OR18;
each R18 is independently H, formyl, C3-C7 cycloalkyl, -S03 M+ or -(C=W)Rn; or Cj-Cg alkyl or Cj-Cg haloalkyl, each optionally substituted with up to 2 R12; each R19 and R20 is independently H or CH3;
R21 is H, formyl, C3-C7 cycloalkyl, -S03-M+ or -(C=W)Rn; or -Cg alkyl or Cr
C6 haloalkyl, each optionally substituted with up to 2 R12;
each U is independently O, S(=0)w, NR22 or a direct bond;
each V is independently Cj-Cg alkylene, C2-C6 alkenylene, C3-C6 alkynylene, C3-C6 cycloalkylene or C3-Cg cycloalkenylene, wherein up to 3 carbon atoms are independently selected from C(=0), each optionally substituted with up to 5 substituents independently selected from halogen, cyano, nitro, hydroxy, Cj-Cg alkyl, C^-Cg haloalkyl, C^-Cg alkoxy and C^-Cg haloalkoxy;
each T is independently cyano, NR23aR23b, OR24 or S(=0)yR25
each R22 is independently H, Cj-Cg alkyl, Cj-Cg haloalkyl, C2-C6 alkylcarbonyl, C2- Cg alkoxycarbonyl, C2-Cg (alkylthio)carbonyl, C2-Cg alkoxy(thiocarbonyl), C4-C8 cycloalkylcarbonyl, C4-C8 cycloalkoxycarbonyl, C4-C8
(cycloalkylthio)carbonyl or C4-Cg cycloalkoxy(thiocarbonyl);
each R a and R b is independently H, Cj-Cg alkyl, Cj-Cg haloalkyl, C2-C6 alkenyl, C3-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, C2-C6 alkylcarbonyl, C2-C6 alkoxycarbonyl, C2-C6 (alkylthio)carbonyl, C2-C6 alkoxy(thiocarbonyl), C4-C8 cycloalkylcarbonyl, C4-C8 cycloalkoxycarbonyl, C4-C8
(cycloalkylthio)carbonyl or C4-Cg cycloalkoxy(thiocarbonyl); or
a pair of R23a and R23b attached to the same nitrogen atom are taken together with the nitrogen atom to form a 3- to 6-membered heterocyclic ring, the ring optionally substituted with up to 5 substituents independently selected from R26;
each R24 and R25 is independently H, Cj-Cg alkyl, Cj-Cg haloalkyl, C2-C6 alkenyl, C3-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, C2-C6 alkylcarbonyl, C2-C6 alkoxycarbonyl, C2-C6 (alkylthio)carbonyl, C2-C6 alkoxy(thiocarbonyl), C4-C8 cycloalkylcarbonyl, C4-C8 cycloalkoxycarbonyl, C4-C8
(cycloalkylthio)carbonyl or C4-Cg cycloalkoxy(thiocarbonyl);
each R26 is independently halogen, Cj-Cg alkyl, -Cg haloalkyl or -Cg alkoxy; each R27 is independently H, -Cg alkyl, Cj-Cg haloalkyl, C2-C6 alkenyl, C3-C6 haloalkenyl, C3-C6 alkynyl, C3-C6 haloalkynyl or C4-C7 cycloalkylalkyl;
each R28 is H or C1-C4 alkyl;
each W is independently O or S;
each M+ is independently a cation;
n is 0, 1 or 2;
t is 0, 1 or 2;
each u and v are independently 0, 1 or 2 in each instance of S(=0)u(=NR14)v, provided that the sum of u and v is 0, 1 or 2;
each w is independently 0, 1 or 2; and
each y is independently 0, 1 or 2;
provided that the compound of Formula 1 is other than 4,6-dimethoxy-N-[l-methyl-
4-(2-methyl-2H-tetrazol-5-yl)-lH-pyrazol-5-yl]-2-pyrimidinamine.
2. A compound of Claim 1 wherein:
Q1 is phenyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl, each substituted with from 1 to 4 substituents independently selected from R3; provided that when an R3 substituent is located at a meta position, then said R3 substituent is selected from F, CI, Br and cyano;
Q2 is phenyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl, each substituted with 1, 2 or 3 substituents independently selected from R3, provided that when an R3 substituent is located at a meta position, then said R3 substituent is selected from F, CI, Br and cyano;
R1 is H, halogen, -Cg alkyl, -Cg haloalkyl, C02R5, C(0)NR6R7, cyano, Cr
Cg alkoxy, C^-Cg haloalkoxy or C2-C5 alkoxyalkyl;
Rla is H; or
R1 and Rla are taken together with the carbon atom to which they are attached to form a cyclopropyl ring optionally substituted with up to 2 substituents independently selected from halogen and methyl;
each R3 is independently selected from halogen, cyano, nitro, amino, methylamino, dimethylamino, Cj-C4 alkyl, Cj-C4 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy C1-C3 alkylthio, C1-C3 haloalkylthio, C1-C3 alkylsulfmyl, C^- C3 haloalkylsulfmyl, C1-C3 alkylsulfonyl, C1-C3 haloalkylsulfonyl, C3-C4 cycloalkyl, C(=S)NH2 and -U-V-T;
R4 is H, formyl, C3-C7 cycloalkyl or -SR10; or -Cg alkyl or -Cg haloalkyl, each optionally substituted with up to 2 R12; R5 is Ci-C6 alkyl;
R6 is H or Ci-Cg alkyl;
R7 is H, -Cg alkyl, -Cg haloalkyl or C4-C8 alkylcycloalkyl; or
R6 and R7 are taken together with the nitrogen atom to which they are connected to form a four- to seven-membered nonaromatic heterocyclic ring containing ring members, in addition to the connecting nitrogen atom, selected from carbon atoms and up to one ring member selected from O and NR13;
each R12 is independently C3-C7 cycloalkyl, C1-C4 alkoxy or cyano;
R13 is H or CH3;
R15 is H or CH3; and
R16 is OR18.
3. A compound of Claim 2 wherein
Q1 is phenyl or pyridinyl, each substituted with 1 , 2 or 3 substituents independently selected from R3;
Q2 is phenyl or pyridinyl, each substituted with 1 , 2 or 3 substituents independently selected from R3;
R1 is H, halogen, C1-C3 alkyl or C1-C2 haloalkyl;
Rl a is H; or
R1 and Rl a are taken together with the carbon atom to which they are attached to form a cyclopropyl ring;
R2 is H;
each R3 is independently selected from halogen, cyano, nitro, C1-C4 alkyl, C1-C4 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy and -U-V-T;
R4 is H, formyl, C3-C7 cycloalkyl or -SR10; or -Cg alkyl substituted with one R12;
each R12 is independently cyclopropyl, -OCH3 or cyano;
R15 is H;
each U is independently O or NH;
each V is C2-C4 alkylene;
each T is independently NR23aR23b or OR24;
each R23a and R23b is independently H, C^-Cg alkyl or C^-Cg haloalkyl; and each R24 is independently H, C^-Cg alkyl or C^-Cg haloalkyl.
4. A compound of Claim 3 wherein
at least one of Q1 and Q2 is phenyl substituted with 2 or 3 substituents
independently selected from R3;
R1 is H or CH3;
Rl a is H; R4 is H;
each R3 is independently selected from halogen, cyano, C1-C3 alkyl, C1-C3
haloalkyl, C1-C3 alkoxy and C1-C3 haloalkoxy; and
R18 is H.
5. A compound of Claim 4 wherein
Q1 is phenyl substituted at the 2-, 4- and 6-positions with substituents
independently selected from R3; or phenyl substituted at the 2- and 4- positions with substituents independently selected from R3; or phenyl substituted at the 2- and 6-positions with substituents independently selected from R3;
Q2 is phenyl substituted at the 2-, 4- and 6-positions with substituents
independently selected from R3; or phenyl substituted at the 2- and 4- positions with substituents independently selected from R3; or phenyl substituted at the 2- and 6-positions with substituents independently selected from R3;
X is O or NR4;
R1 is H; and
each R3 is independently selected from F, CI, Br, cyano, C1-C2 alkyl, C1-C2
haloalkyl, C1-C2 alkoxy and C1-C2 haloalkoxy.
6. A compound of Claim 5 wherein
each R3 is independently selected from F, CI, Br, cyano, methyl and methoxy.
7. A compound of Claim 1 which is selected from the group:
N,4-bis(2-chloro-4-fluorophenyl)- 1 -methyl- lH-pyrazol-5-amine.
8. A fungicidal composition comprising (a) a compound of any one of Claims 1 through 7; and (b) at least one other fungicide.
9. A fungicidal composition comprising: (a) a compound of any one of Claims 1 through 7; and (b) at least one additional component selected from the group consisting of surfactants, solid diluents and liquid diluents.
10. A method for protecting a plant or plant seed from diseases caused by fungal pathogens comprising applying a fungicidally effective amount of a compound of any one of Claims 1 through 7 to the plant or plant seed.
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