Classifications

• • A—HUMAN NECESSITIES
  • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
  • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
  • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
  • A01N43/48—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with two nitrogen atoms as the only ring hetero atoms
  • A01N43/60—1,4-Diazines; Hydrogenated 1,4-diazines
• • A—HUMAN NECESSITIES
  • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
  • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
  • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
  • A01N43/48—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with two nitrogen atoms as the only ring hetero atoms
  • A01N43/56—1,2-Diazoles; Hydrogenated 1,2-diazoles
• • A—HUMAN NECESSITIES
  • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
  • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
  • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
  • A01N43/48—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with two nitrogen atoms as the only ring hetero atoms
  • A01N43/58—1,2-Diazines; Hydrogenated 1,2-diazines
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
  • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
  • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D215/20—Oxygen 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
• • 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
• • 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
  • C07D401/14—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 three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
  • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
  • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
  • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
  • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D419/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms
  • C07D419/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms containing two hetero rings
  • C07D419/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings

Definitions

• This invention relates to certain amides, 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:
• A is a radical selected from the roup consisting of
• Z is O or S
• R 1 is H, cyclopropyl or C 1 -C 2 alkoxy
• L is -C(R 12a )R 12b -C(R 13a )R 13b -, wherein the carbon atom bonded to R 12a and R 12b is also bonded to the carboxamide nitrogen atom in Formula 1; or 1 ,2-phenylene optionally substituted with up to 4 substituents independently selected from halogen and C ⁇ -C 2 alkyl;
• G is a radical selected from the rou consistin of
• each R 2 is independently halogen, nitro, cyano, C1-C5 alkyl, C1-C5 haloalkyl, C1-C5 alkoxy, C1-C5 haloalkoxy or C3-C5 cycloalkyl;
• B 1 is CH or N
• B 2 is CH or N
• B 3 is CH or N
• B 1 and B 2 are both N, then B 3 is CH;
• R 3 is halogen, C1-C3 alkyl or C1-C3 haloalkyl
• R 4 is halogen, C1-C3 alkyl or C1-C3 haloalkyl
• R 5 is H, halogen, C!-C 3 alkyl or -C3 haloalkyl
• R 6 is C!-C 2 alkyl
• R 7 is halogen, C1-C3 alkyl or C1-C3 haloalkyl
• R 8 is H, C!-C 2 alkyl or C[-C 2 haloalkyl
• R 9a is H, halogen, C ⁇ -C 2 alkyl, -C3 haloalkyl or C r C 3 alkylthio;
• R 9b is H, halogen, -C3 alkyl or -C3 haloalkyl
• R 10 is halogen, C ⁇ alkyl or -C3 haloalkyl
• R 1 1 is halogen, -C3 alkyl or -C3 haloalkyl
• R 20 is halogen, C ⁇ alkyl or -C3 haloalkyl
• R 21 is H, C!-C 2 alkyl or - ⁇ haloalkyl
• R 22 is H, halogen, -C3 alkyl, C ⁇ haloalkyl or C r C 3 alkylthio;
• R 23 is H, halogen, -C3 alkyl or -C3 haloalkyl
• R 24 is H, halogen, -C3 alkyl or -C3 haloalkyl
• R 25 is H, C!-C 3 alkyl or Q-C3 haloalkyl; m is 0, 1 or 2;
• n 0, 1 , 2 or 3;
• R 12a and R 12 ⁇ are each independently H, C1-C2 alkyl or C1-C2 haloalkyl; or
• R 12a and R 12 ⁇ are taken together as C2-C5 alkanediyl
• R 13a is H, halogen, C1-C2 alkyl, C1-C2 haloalkyl, C1-C2 alkoxy, C1-C2 haloalkoxy,
• R 13 ⁇ is H, halogen, C1-C2 alkyl or C1-C2 haloalkyl; or
• R 13a and R 13 ⁇ are taken together as C2-C5 alkanediyl
• each R 14c is independently halogen, cyano, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C2-C3 alkoxycarbonyl or C2-C3 alkylcarbonyl; or a phenyl ring optionally substituted with up to 5 substituents independently selected from R 16 ; or a heteroaromatic ring optionally substituted with up to 4 substituents independently selected from R 17c on carbon atom ring members and from R 17n on nitrogen atom ring members; or
• R 1 c bonded to adjacent carbon atoms are taken together with carbon atom ring members to form a 5- or 6-membered carbocyclic or partially aromatic ring, the ring optionally substituted with halogen or Ci -C4 alkyl;
• each R 1 n is independently C1-C3 alkyl, C1-C3 haloalkyl or C1-C3 alkoxy; or a
• phenyl ring optionally substituted with up to 5 substituents independently selected from R 18 ; or a heteroaromatic ring optionally substituted with up to 4 substituents independently selected from R 19c on carbon atom ring members and from R 19n on nitrogen atom ring members;
• each R 15c is independently halogen, C1-C3 alkyl, C1-C3 haloalkyl or C1-C3 alkoxy; each R 15n is independently C1-C3 alkyl, C1-C3 haloalkyl or C1-C3 alkoxy;
• each R 16 , R 17c , R 18 and R 19c is independently halogen, cyano, C!-C 2 alk Y l > c l ⁇ c 2 haloalkyl, C1-C2 alkoxy or C1-C2 haloalkoxy;
• each R 17n and R 19n is independently C!-C 2 C i-C 2 haloalkyl or i ⁇ C 2 alkoxy. More particularly, this invention pertains to a compound of Formula 1 (including all stereoisomers), an N-oxide or a salt thereof.
• This invention also relates to a fungicidal composition
• a fungicidal composition comprising (a) a compound of the invention (i.e. in a fungicidally effective amount); and (b) 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
• a fungicidal composition comprising (a) a compound of the invention; 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).
• compositions, mixture, process, method, article, or apparatus 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, method, article, or apparatus.
• plant includes members of
• 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.
• planting used either alone or in a combination of words means a young plant developing from the embryo of a seed.
• the terms “fungal pathogen” and “fungal plant pathogen” include pathogens in the Ascomycota, Basidiomycota and Zygomycota phyla, and the fungal-like Oomycota class that are the causal agents of a broad spectrum of plant diseases of economic importance, affecting ornamental, turf, vegetable, field, cereal and fruit crops.
• “protecting a plant from disease” or “control of a plant disease” includes preventative action (interruption of the fungal cycle of infection, colonization, symptom development and spore production) and/or curative action (inhibition of colonization of plant host tissues).
• MOA mode of action
• FRAC Fungicide Resistance Action Committee
• A nucleic acid synthesis
• B mitosis and cell division
• C respiration
• D amino acid and protein synthesis
• E signal transduction
• F lipid synthesis and membrane integrity
• G sterol biosynthesis in membranes
• H cell wall biosynthesis in membranes
• I melanin synthesis in cell wall
• P host plant defense induction, multi-site contact activity and unknown mode of action.
• Each MOA class consists of one or more groups based either on individual validated target sites of action, or in cases where the precise target site is unknown, based on cross resistance profiles within a group or in relation to other groups.
• Each of these groupings within a FRAC-defmed MOA, whether the target site is known or unknown, is designated by a FRAC code. Additional information on target sites and FRAC codes can be obtained from publicly available databases maintained, for example, by FRAC.
• cross resistance refers to a phenomenon wherein a pathogen evolves resistance to one fungicide and in addition acquires resistance to others.
• additional fungicides are typically, but not always, in the same chemical class or have the same target site of action, or can be detoxified by the same mechanism.
• 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, pentenyl and hexenyl isomers.
• Alkenyl also includes polyenes such as 1 ,2-propadienyl and 2,4-hexadienyl.
• Alkynyl includes straight-chain or branched alkynes such as ethynyl, 1-propynyl, 2-propynyl and the different butynyl, pentynyl and hexynyl isomers.
• Alkynyl also includes moieties comprised of multiple triple bonds such as 2,5-hexadiynyl.
• Alkanediyl also known as "alkylene”, denotes a straight-chain or branched alkane divalent radicals.
• alkanediyl examples include CH2, CH 2 CH 2 , CH(CH 3 ), CH 2 CH 2 CH 2 , CH 2 CH(CH 3 ), and the different butylene isomers.
• R 13a and R 13 ⁇ taken together the alkanediyl is bonded through the same carbon atom to the remainder of the molecule.
• Alkenylene denotes a straight-chain or branched alkenediyl containing one olefmic bond.
• Alkynylene denotes a straight-chain or branched alkynediyl containing one triple bond. Examples of “alkynylene” include -C ⁇ C-, -CH 2 C ⁇ C-, -C ⁇ CCH 2 -, and the different butynylene 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 .
• Alkoxyalkoxy denotes alkoxy substitution on alkoxy.
• Alkenyloxy includes straight-chain or branched alkenyloxy moieties.
• alkynyloxy includes straight-chain or branched alkynyloxy moieties. Examples of “alkynyloxy” include HC ⁇ CCH 2 0, CH 3 C ⁇ CCH 2 0 and CH 3 C ⁇ CCH 2 CH 2 0.
• Alkylthio includes branched or straight-chain alkylthio moieties such as methylthio, ethylthio, and the different propylthio, butylthio, pentylthio and hexylthio isomers.
• Alkylsulfinyl includes both enantiomers of an alkylsulfinyl group. Examples of “alkylsulfinyl” include 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 butylsulfmyl, pentylsulfmyl and hexylsulfmyl 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, pentylsulfonyl and hexylsulfonyl isomers.
• Alky lthio alkyl 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 .
• Alkylthioalkoxy denotes alkylthio substitution on alkoxy.
• Alkyldithio denotes branched or straight-chain alkyldithio moieties. Examples of “alkyldithio” include CH 3 SS-, CH 3 CH 2 SS-, CH 3 CH 2 CH 2 SS-, (CH 3 ) 2 CHSS- and the different butyldithio and pentyldithio isomers.
• Alkylamino "dialkylamino”, “alkenylthio”, “alkenylsulfmyl”, “alkenylsulfonyl”, “alkynylthio”, “alkynylsulfmyl”, “alkynylsulfonyl”, and the like, are defined analogously to the above examples.
• 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.
• Cycloalkylalkoxy denotes cycloalkylalkyl linked through an oxygen atom attached to the alkyl chain.
• Examples of “cycloalkylalkoxy” include cyclopropylmethoxy, cyclopentylethoxy, and other cycloalkyl moieties bonded to straight-chain or branched alkoxy groups.
• 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 CF 3 CC1 2 -.
• halocycloalkyl haloalkoxy
• haloalkyl haloalkoxy
• haloalkylthio 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 -.
• haloalkynyl examples include HC ⁇ CCHC1-, CF 3 C ⁇ C-, CC1 3 C ⁇ C- and FCH 2 C ⁇ CCH 2 -.
• haloalkoxyalkoxy examples include CF 3 OCH 2 0-, C1CH 2 CH 2 0CH 2 CH 2 0-, Cl 3 CCH 2 OCH 2 0- as well as branched alkyl derivatives.
• C -Cj The total number of carbon atoms in a substituent group is indicated by the "C -Cj" prefix where i and j are numbers from 1 to 5.
• C ⁇ -C 3 alkoxy designates CH 3 0-, CH 3 CH 2 0-, CH 3 CH 2 CH 2 0- and (CH 3 ) 2 CHO-;
• -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 -;
• C4 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
• said substituents are independently selected from the group of defined substituents, e.g., (R 2 ) n , n is 0, 1, 2 or 3.
• substituents which can be hydrogen, for example R 5
• this substituent is taken as hydrogen, it is recognized that this is equivalent to said group being unsubstituted.
• a variable group is shown to be optionally attached to a position, for example (R 2 ) n , wherein n may be 0, then hydrogen may be at the position even if not recited in the variable group definition.
• one or more positions on a group are said to be "not substituted” or "unsubstituted"
• hydrogen atoms are attached to take up any free valency.
• a “ring” or “ring system” as a component of Formula 1 is carbocyclic or heterocyclic.
• the terms “carbocyclic ring”, “carbocycle” or “carbocyclic ring system” denote a ring or ring system wherein the atoms forming the ring backbone are selected only from carbon.
• the terms “heterocyclic ring”, “heterocycle” or “heterocyclic ring system” 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.
• a heterocyclic ring contains no more than 4 nitrogens, no more than 2 oxygens and no more than 2 sulfurs.
• a carbocyclic ring or heterocyclic ring can be a saturated or unsaturated ring.
• “Saturated” refers to a ring having a backbone consisting of atoms linked to one another by single bonds; unless otherwise specified, the remaining carbon valences are occupied by hydrogen atoms. Unless otherwise stated, an "unsaturated ring" may be partially unsaturated or fully unsaturated.
• the term "partially unsaturated ring” denotes a 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 rings and ring systems can be attached through any available carbon or nitrogen by replacement of a hydrogen atom 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 ring system denotes a carbocyclic or heterocyclic ring system in which at least one ring of the ring system is aromatic. When a fully unsaturated carbocyclic ring satisfies Huckel's rule, then said ring is also called an "aromatic ring" or "aromatic carbocyclic ring".
• aromatic carbocyclic ring system denotes a carbocyclic ring system in which at least one ring of the ring system is aromatic.
• 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.
• nonaromatic carbocyclic ring system denotes a carbocyclic ring in which no ring in the ring system is aromatic.
• nonaromatic heterocyclic ring system denotes a heterocyclic ring system in which no ring in the ring system is aromatic.
• optionally substituted in connection with the heterocyclic rings refers to groups which are unsubstituted or have at least one non-hydrogen substituent that does not extinguish the biological activity possessed by the unsubstituted analog. As used herein, the following definitions shall apply unless otherwise indicated.
• 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.
• substituents When a compound is substituted with a substituent bearing a subscript that indicates the number of said substituents can exceed 1 , said substituents (when they exceed 1) are independently selected from the group of defined substituents, e.g., (R 2 ) n n is 0, 1 , 2 or 3.
• R 1 When a group contains a substituent which can be hydrogen, for example, R 1 , then when this substituent is taken as hydrogen, it is recognized that this is equivalent to said group being unsubstituted.
• a variable group is shown to be optionally attached to a position, for example (R 2 ) n , wherein n may be 0, then hydrogen may be at the position even if not recited in the variable group definition.
• one or more positions on a group are said to be "not substituted” or "unsubstituted"
• hydrogen atoms are attached to take up any free valency.
• an "unsaturated or partially unsaturated heterocyclic ring” is a heterocyclic ring wherein at least two ring member atoms are linked together by a double bond.
• an "unsaturated or partially heterocyclic ring” (e.g., substituent Q) may be partially unsaturated or fully unsaturated.
• the expression “fully unsaturated heterocyclic ring” means a heterocyclic ring of atoms in which the bonds between carbon and/or nitrogen atoms in the ring are single or double bonds according to valence bond theory and furthermore the bonds between carbon and/or nitrogen atoms in the ring include as many double bonds as possible without double bonds being cumulative (i.e.
• 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).
• a fully unsaturated heterocyclic ring satisfies Huckel's rule, then said ring is also called a "heteroaromatic ring” or "aromatic heterocyclic ring”.
• G is a radical selected from the group consisting of G-l, G-2, G-3, G-4 and G-5.
• the bond of the G ring projecting to the left is attached to the remainder of Formala 1 through L.
• the bond projecting to the lower right side of the G ring represents the attachment point of the Q ring.
• the Q ring resides in a fixed position on the G ring and does not "float" in relation to the attachment point of the G ring to L.
• the (R 2 ) n variable as depicted on the G ring in the Summary of the Invention may "float" around the G ring and may therefore be bonded to any available carbon atoms on the each respective G ring.
• the heterocyclic ring is optionally substituted with one substituent selected from R 14c or R 14n on one ring member distal relative to the ring member connecting the heteroaromatic ring to the remainder of Formula 1.
• Certain heterocycles forming Q may have two distal ring members available for substitution. In this situation, only one of the distal ring members may be substituted with R 1 c or R 1 n ; the other distal ring member may be substituted with R 15c or R 15n . If neither of the distal ring members of a heterocycle forming Q are available for substitution, then any additional substituents on the heterocycle are selected from R 15c or R 15n . If a distal ring member can have two substituents, one substituent may be selected from R 1 c or R 1 n and the other substituent may be selected from R 15c or R 15n .
• the Q ring is limited to one R 1 c or R 1 n substituent and this substituent must be bonded to a distal ring member; the Q ring can otherwise be further substituted with R 15c or R 15n on any available ring member.
• an attachment point on a group (e.g., ring) is depicted as floating (e.g., as illustrated by the 5-membered unsaturated or partially unsaturated heterocyclic rings Q-l through Q-21 in Exhibit 4) the group can be attached to the remainder of Formula 1 through any available carbon or nitrogen of the group by replacement of a hydrogen atom.
• the attachment point of a substituent on a group (e.g., ring) is depicted as floating (e.g., as illustrated for R 14 and R 15 on the 5-membered unsaturated heterocyclic rings Q-l through Q-21 in Exhibit 4)
• the substituent can be attached to any available carbon or nitrogen atom by replacing a hydrogen atom.
• linking group L in Formula 1 can be -C(R 12a )R 12 ⁇ -C(R 13a )R 13 ⁇ -, wherein the carbon atom bonded to R 12a and R 12 ⁇ is also bonded to the carboxamide nitrogen atom in Formula 1.
• the carboxamide is an ordinary carboxamide when Z is O or a thiocarboxamide when Z is S.
• linking group L in Formula 1 can be 1 ,2-phenylene optionally substituted with up to 4 substituents independently selected from halogen and C1-C2 alkyl.
• 1,2-phenylene is understood to refer to a benzene ring that is connected to the remainder of the molecule (e.g., Formula 1) at ortho positions (hence “1,2-”) and optionally substituted with halogen and C1-C2 alkyl at the four remaining positions on the ring.
• each R 51 is independently halogen or C1-C2 alkyl, and p is 0, 1, 2, 3 or 4.
• Linking group L being optionally substituted 1,2-phenylene is further illustrated by the molecular structure depictions associated with Tables 1-1221 and Index Table A.
• 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.
• Formula 1 possesses chiral centers at the carbon atoms to which R 12 ⁇ and R 13 b are bonded, allowing for two racemic diastereomers, designated as anti and syn.
• Each racemic diastereomer is comprised of a pair of enantiomers, i.e. the anti diastereomer is comprised of enantiomers 1' and 1", and the syn diastereomer is comprised of enantiomers V and 2" as shown below in Exhibit 2, with the chiral centers identified with an asterisk (*).
• This invention comprises racemic mixtures, for example, equal amounts of the enantiomers of Formulae 1' and 1" .
• this invention includes compounds that are enriched compared to the racemic mixture in an enantiomer of Formula 1. Also included are the essentially pure enantiomers of compounds of Formula 1, for example, Formula 1' or Formula 1".
• enantiomeric excess which is defined as (2 ⁇ -1) ⁇ 100 %, where x is the mole fraction of the dominant enantiomer in the mixture (e.g., an ee of 20 % corresponds to a 60:40 ratio of enantiomers).
• compositions of this invention have at least a 50 % enantiomeric excess; more preferably at least a 75 % enantiomeric excess; still more preferably at least a 90 % enantiomeric excess; and the most preferably at least a 94 % enantiomeric excess of the more active isomer.
• Compounds of Formula 1 can comprise additional chiral centers.
• substituents and other molecular constituents such as R 2 may themselves contain chiral centers. This invention comprises racemic mixtures as well as enriched and essentially pure stereoconfigurations at these additional chiral centers.
• Compounds of this invention can exist as one or more conformational isomers due to restricted rotation about the amide bond (e.g., C(O)-N) in Formula 1.
• This invention comprises mixtures of conformational isomers.
• this invention includes compounds that are enriched in one conformer relative to others.
• This invention comprises all stereoisomers, conformational isomers and mixtures thereof in all proportions as well as isotopic forms such as deuterated compounds.
• 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.
• salts also include those formed with organic or inorganic bases such as pyridine, triethylamine or ammonia, or amides, hydrides, hydroxides or carbonates of sodium, potassium, lithium, calcium, magnesium or barium. Accordingly, the present invention comprises compounds selected from Formula 1, N-oxides and agriculturally suitable salts thereof.
• 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 to 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
• 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 A is selected from the group
• Embodiment 2 A compound of Formula 1 or Embodiment 1 wherein A is selected from the group consisting of A-l, A-2 and A-8.
• Embodiment 2a A compound of Formula 1 or Embodiment 1 wherein A is selected from the group consisting of A-l, A-2 and A-4.
• Embodiment 3 A compound of Formula 1 or any one of Embodiments 1 through 2a wherein A is selected from the group consisting of A-l and A-2.
• Embodiment 3 a A compound of Formula 1 or any one of Embodiments 1 through 3 wherein A is A-l .
• Embodiment 4 A compound of Formula 1 or any one of Embodiments 1 through 3 wherein A is A-2.
• Embodiment 5 A compound of Formula 1 wherein A is A-3.
• Embodiment 6 A compound of Formula 1 or Embodiment 1 or 2a wherein A is A-4.
• Embodiment 7 A compound of Formula 1 wherein A is A-5.
• Embodiment 8 A compound of Formula 1 wherein A is A-6.
• Embodiment 8a A compound of Formula 1 or any one of Embodiments 1 through 2 wherein A is A- 8.
• Embodiment 8b A compound of Formula 1 wherein A is A-7.
• Embodiment 8c A compound of Formula 1 wherein A is A-9.
• Embodiment 8d A compound of Formula 1 wherein A is A- 10.
• Embodiment 8e A compound of Formula 1 wherein A is A-l 1.
• Embodiment 9 A compound of Formula 1 or any one of Embodiments 1 through 8e wherein Z is O.
• Embodiment 10 A compound of Formula 1 or any one of Embodiments 1 through 9 wherein G is selected from the group consisting of G-l, G-2, G-3 and G-4.
• Embodiment 11 A compound of Formula 1 or any one of Embodiments 1 through 9 wherein G is selected from the group consisting of G-2, G-4 and G-5.
• Embodiment 12 A compound of Formula 1 or any one of Embodiments 1 through 10 wherein G is selected from the group consisting of G-l and G-4.
• Embodiment 13 A compound of Formula 1 or any one of Embodiments 1 through 10 wherein G is selected from the group consisting of G-l, G-2 and G-3.
• Embodiment 14 A compound of any one of Embodiments 1 through 10 or 12 through
• Embodiment 15 A compound of Formula 1 or any one of Embodiments 1 through 3 a or
• Embodiment 16 A compound of Formula 1 or any one of Embodiments 1 through 3a or 9 through 14 wherein B 1 is N.
• Embodiment 17 A compound of Formula 1 or any one of Embodiments 1 through 3a or
• Embodiment 18 A compound of Formula 1 or any one of Embodiments 1 through 3a or
• Embodiment 18a A compound of Formula 1 or any one of Embodiments 1 through 3a or 9 through 18 wherein B 3 is N, provided at least one of B 1 and B 2 is CH; Embodiment 18b. A compound of Formula 1 or any one of Embodiments 1 through 3a or 9 through 18 wherein B 3 is CH; Embodiment 19. A compound of Formula 1 or any one of Embodiments 1 through 3a or 9 through 18b wherein R 3 is halogen, C1-C2 alkyl or C1-C2 haloalkyl.
• Embodiment 20 A compound of Embodiment 19 wherein R 3 is halogen, CH3 or C ⁇ haloalkyl.
• Embodiment 20a A compound of Embodiment 20 wherein R 3 is halogen.
• Embodiment 21 A compound of Embodiment 20 wherein R 3 is F, CI, Br, CH3, CHF2 or CF 3 .
• Embodiment 21a A compound of Embodiment 20 wherein R 3 is F, CI, or Br.
• Embodiment 22 A compound of Embodiment 21 wherein R 3 is CF3.
• Embodiment 23 A compound of Formula 1 or any one of Embodiments 1 through 3, 4 or 9 through 14 wherein R 4 is halogen, C1-C2 alkyl or C1-C2 haloalkyl.
• Embodiment 24 A compound of Embodiment 23 wherein R 4 is halogen, CH3 or C ⁇ haloalkyl.
• Embodiment 25 A compound of Embodiment 24 wherein R 4 is F, CI, Br, CH3, CHF2 or CF 3 .
• Embodiment 26 A compound of Embodiment 25 wherein R 4 is CHF2.
• Embodiment 27 A compound of Formula 1 or any one of Embodiments 1 through 3, 4,
• R 5 is H, halogen, -C2 alkyl or C1-C2 haloalkyl.
• Embodiment 28 A compound of Embodiment 27 wherein R 5 is H, halogen, CH3 or C ⁇ haloalkyl.
• Embodiment 29 A compound of Embodiment 28 wherein R 5 is H, F, CI, Br, CH3, CHF 2 or CF 3 .
• Embodiment 30 A compound of Embodiment 29 wherein R 5 is H.
• Embodiment 31 A compound of Formula 1 or any one of Embodiments 1 through 3, 4,
• Embodiment 32 A compound of Formula 1 or any one of Embodiments 5 or 9 through
• R 7 is halogen, C1-C2 alkyl or C1-C2 haloalkyl.
• Embodiment 33 A compound of Embodiment 32 wherein R 7 is halogen, CH3 or C ⁇ haloalkyl.
• Embodiment 34 A compound of Embodiment 33 wherein R 7 is F, CI, Br, CH3, CHF2 or CF 3 .
• Embodiment 35 A compound of Formula 1 or any one of Embodiments 5, 9 through 14 or 32 through 34 wherein R 8 is H or CH3.
• Embodiment 36 A compound of Formula 1 or any one of Embodiments 1 , 6 or 9
• Embodiment 36a A compound of Embodiment 36 wherein R 9a is halogen, C1-C2 alkyl or C1-C2 haloalkyl.
• Embodiment 37 A compound of Embodiment 36a wherein R 9a is halogen, CH3 or C ⁇ haloalkyl.
• Embodiment 38 A compound of Embodiment 37 wherein R 9a is F, CI, Br, CHF2 or
• Embodiment 38a A compound of Formula 1 or any one of Embodiments 1 , 2a, 6, 9 through 14 or 36 through 38 wherein R 9b is H, halogen, Ci -C2 alkyl or Ci -C2 haloalkyl.
• Embodiment 38b A compound of Embodiment 38a wherein R 9 ⁇ is H, halogen, Ci -C2 alkyl.
• Embodiment 38c A compound of Embodiment 38b wherein R 9 ⁇ is H or methyl.
• Embodiment 38d A compound of Embodiment 38b wherein R 9 ⁇ is H.
• Embodiment 39 A compound of Formula 1 or any one of Embodiments 7 or 9 through 14 wherein R 10 is halogen, C1-C2 alkyl or C1-C2 haloalkyl.
• Embodiment 40 A compound of Embodiment 39 wherein R 10 is halogen, CH3 or C ⁇ haloalkyl.
• Embodiment 41 A compound of Embodiment 40 wherein R 10 is F, CI, Br, CH3, CHF2 or CF 3 .
• Embodiment 42 A compound of Formula 1 or any one of Embodiments 8 or 9 through
• R 1 1 is halogen, C1-C2 alkyl or C1-C2 haloalkyl.
• Embodiment 43 A compound of Embodiment 42 wherein R 1 1 is halogen, CH3 or C ⁇ haloalkyl.
• Embodiment 44 A compound of Embodiment 43 wherein R 1 1 is F, CI, Br, CH3, CHF2 or CF 3 .
• Embodiment 44a A compound of Formula 1 or any one of Embodiments 1 , 2, 8a or 9 through 14 wherein R 20 is CI, CH 3 or CF 3 .
• Embodiment 44b A compound of Embodiment 44a wherein R 20 is CH3 or CF3.
• Embodiment 44c A compound of Formula 1 or any one of Embodiments 1 , 2, 8a, 9 through 14, 44a or 44b wherein R 21 is H or CH 3 .
• Embodiment 44d A compound of Embodiment 44c wherein R 21 is H.
• Embodiment 44e A compound of Formula 1 or any one of Embodiments 8b or 9
• R 22 is F, CI, CH 3 or CF 3 .
• Embodiment 44f A compound of Embodiment 44e wherein R 22 is F, CI or CF 3 .
• Embodiment 44g A compound of Formula 1 or any one of Embodiments 8c or 9
• R 23 is H, halogen, C1-C2 alkyl or C1-C2 haloalkyl.
• Embodiment 44h A compound of Embodiment 44g wherein R 23 is halogen.
• Embodiment 44i A compound of Embodiment 44h wherein R 23 is Br.
• Embodiment 44j A compound of Embodiment 44g wherein R 23 is C1-C2 alkyl.
• Embodiment 44k A compound of Embodiment 44g wherein R 23 is methyl.
• Embodiment 44 A compound of Formula 1 or any one of Embodiments 8d or 9
• R 24 is H or C1-C2 alkyl
• Embodiment 44m A compound of Embodiment 441 wherein R 24 is H.
• Embodiment 44n A compound of Embodiment 441 wherein R 24 is methyl.
• Embodiment 44o A compound of Formula 1 or any one of Embodiments 8e or 9
• R 25 is C1-C2 alkyl or cyclopropyl
• Embodiment 44p A compound of Embodiment 44o wherein R 25 is methyl.
• Embodiment 45 A compound of Formula 1 or any one of Embodiments 1 through 44p wherein R 1 is H or cyclopropyl.
• Embodiment 46 A compound of Embodiment 45 wherein R 1 is H.
• Embodiment 47 A compound of Formula 1 or any one of Embodiments 1 through 46 wherein L is -C(R 12a )R 12b -C(R 13a )R 13b -; or 1 ,2-phenylene optionally substituted with up to 2 substituents independently selected from F, CI, Br and
• Embodiment 48 A compound of any one of Embodiments 1 through 47 wherein L is -C(R 1 a )R 1 b -C(R 1 a )R 1 b -.
• Embodiment 49 A compound of Formula 1 or any one of Embodiments 1 through 48 wherein R 12a is H or CH 3 .
• Embodiment 50 A compound of Embodiment 49 wherein R 12a is H.
• Embodiment 51 A compound of Formula 1 or any one of Embodiments 1 through 50 wherein R 12b is H or CH 3 .
• Embodiment 52 A compound of Embodiment 51 wherein R 12b is H.
• Embodiment 53 A compound of Formula 1 or any one of Embodiments 1 through 48 wherein when R 12a and R 12b are taken together, they are taken together as C2 or
• Embodiment 54 A compound of Embodiment 53 wherein R 12a and R 12b are taken together as C2 alkanediyl (i.e. R 12a and R 12b are taken together along with the carbon to which they are attached to form a cyclopropyl ring).
• Embodiment 55 A compound of Formula 1 or any one of Embodiments 1 through 54 wherein R 13a is H, CH 3 or OCH 3 .
• Embodiment 56 A compound of Embodiment 55 wherein R 13a is H or CH 3 .
• Embodiment 57 A compound of Embodiment 56 wherein R 13a is H.
• Embodiment 58 A compound of Formula 1 or any one of Embodiments 1 through 57 wherein R 13b is H or CH 3 .
• Embodiment 59 A compound of Embodiment 58 wherein R 13b is H.
• Embodiment 60 A compound of Formula 1 or any one of Embodiments 1 through 54 wherein when R 13a and R 13b are taken together, they are taken together as C2 or C3 alkanediyl.
• Embodiment 61 A compound of Embodiment 60 wherein R 13a and R 13b are taken
• R 13a and R 13b are taken together as C2 alkanediyl (i.e. R 13a and R 13b are taken together along with the carbon to which they are attached to form a cyclopropyl ring).
• Embodiment 62 A compound of Formula 1 or any one of Embodiments 1 through 47 wherein when L comprises 1,2-phenylene, said 1 ,2-phenylene is optionally substituted with up to 2 substituents independently selected from F, CI, Br and CH 3 .
• Embodiment 63 A compound of Embodiment 62 wherein when L comprises
• 1 ,2-phenylene said 1 ,2-phenylene is optionally substituted with up to 2 substituents independently selected from F and CH 3 .
• Embodiment 64 A compound of Embodiment 63 wherein when L comprises
• Embodiment 65 A compound of Formula 1 or any one of Embodiments 1 through 47 or
• L comprises 1,2-phenylene
• Embodiment 66 A compound of Formula 1 or any one of Embodiments 1 through 65 wherein each R 2 is independently halogen or C1-C5 alkyl.
• Embodiment 67 A compound of Embodiment 66 wherein each R 2 is independently F, CI, Br or CH 3 .
• Embodiment 68 A compound of Embodiment 67 wherein each R 2 is independently F or CI.
• Embodiment 69 A compound of Embodiment 68 wherein each R 2 is independently F.
• Embodiment 70 A compound of Embodiment 68 wherein each R 2 is independently CI.
• Embodiment 71 A compound of Formula 1 or any one of Embodiments 1 through 70 wherein n is 0, 1 or 2.
• Embodiment 72 A compound of Embodiment 71 wherein n is 0 or 1.
• Embodiment 73 A compound of Formula 1 or any one of Embodiments 1 through 61 wherein when L is -C(R 12a )R 12b -C(R 13a )R 13b - and G is selected from G-l and G-4, then n is 1 and the G ring is substituted with R 2 ortho to the bond to L.
• Embodiment 74 A compound of Embodiment 73 wherein R 2 is CI.
• Embodiment 75 A compound of Formula 1 or any one of Embodiments 1 through 47 or 62 through 71 wherein when L is 1,2-phenylene, G is selected from G-l and G-4 then n is 1 and the G ring is substituted with one R 2 is ortho to the bond to Q.
• Embodiment 76 A compound of Embodiment 75 wherein when L is 1,2-phenylene, G is substituted with F ortho to the bond to Q.
• Embodiment 77 A compound of Formula 1 or any one of Embodiments 1 through 76 wherein the heterocyclic ring Q contains at least one nitrogen atom ring member.
• Embodiment 78 A compound of Embodiment 77 wherein the heterocyclic ring Q
• Embodiment 79 A compound of Formula 1 or any one of Embodiments 1 through 78 wherein the heterocyclic ring Q is fully unsaturated (i.e. is heteroaromatic).
• Embodiment 80 A compound of Formula 1 or any one of Embodiments 1 through 79 wherein the heterocyclic ring Q is selected from furan, thiophene, pyrrole, oxazole, thiazole, imidazole, isoxazole, isothiazole, pyrazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, 1,2,4-thiadiazole, 1,2,5-thiadiazole, 1,3,4- thiadiazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole, 4,5-dihydroisoxazole and 4,5- dihydropyrazole.
• the heterocyclic ring Q is selected from furan, thiophene, pyrrole, oxazole, thiazole, imidazole, isoxazole, isothiazole, pyrazole, 1,2,4-oxadiazole,
• Embodiment 81 A compound of Embodiment 80 wherein the heterocyclic ring Q is selected from pyrazole.
• Embodiment 82 A compound of Embodiment 80 wherein Q is selected from Q-l
• R 1 is bonded to a ring member distal relative to the ring member connecting the Q ring to the remainder of Formula 1, and independently selected from R 1 c on carbon atom ring members and R 1 n on nitrogen atom ring members; each R 15 is independently selected from R 15c on carbon atom ring members and R 1 on nitrogen atom ring members;
• each x is independently 0 or 1 ;
• each y is independently 0, 1 or 2;
• each z is independently 0, 1, 2 or 3.
• Embodiment 83 A compound of Embodiment 82 wherein Q is selected from Q-l
• Embodiment 84 A com ound of Embodiment 82 wherein Q is selected from
• Embodiment 85 A compound of Embodiment 84 wherein Q is selected from Q-9A and Q-9B.
• Embodiment 86 A compound of Embodiment 85 wherein Q is Q-9A.
• Embodiment 87 A compound of any one of Embodiments 82 through 86 wherein y is 0 or 1.
• Embodiment 88 A compound of Formula 1 or any one of Embodiments 1 through 87 wherein each R 14c is independently halogen, cyano, C1-C2 alkyl, C1-C2 haloalkyl, C1-C2 alkoxy or C1-C2 haloalkoxy.
• Embodiment 89 A compound of Embodiment 88 wherein each R 14c is independently halogen, CH 3 or C ⁇ haloalkyl.
• Embodiment 90 A compound of Embodiment 89 wherein each R 1 c is independently F, CI, Br, CH 3 , CHF 2 or CF 3 .
• Embodiment 91 A compound of Embodiment 90 wherein each R 1 c is independently
• Embodiment 92 A compound of Formula 1 or any one of Embodiments 1 through 91 wherein each R 14n is independently C1-C2 alkyl or C1-C2 haloalkyl.
• Embodiment 93 A compound of Embodiment 92 wherein each R 14n is C1-C2 alkyl.
• Embodiment 94 A compound of Embodiment 93 wherein each R 14n is CH 3 .
• Embodiment 95 A compound of Formula 1 or any one of Embodiments 1 through 94 wherein each R 15c is independently halogen, C1-C2 alkyl, C1-C2 haloalkyl or C1-C2 alkoxy.
• Embodiment 96 A compound of Embodiment 95 wherein each R 15c is independently halogen, CH 3 or C ⁇ haloalkyl.
• Embodiment 97 A compound of Embodiment 96 wherein each R 15c is independently F,
• Embodiment 98 A compound of Formula 1 or any one of Embodiments 1 through 97 wherein each R 15n is independently C1-C2 alkyl or C1-C2 haloalkyl.
• Embodiment 99 A compound of Embodiment 98 wherein each R 15n is C1-C2 alkyl.
• Embodiment 100 A compound of Embodiment 99 wherein each R 15n is CH3.
• Embodiment 101 A compound of Formula 1 or any one of Embodiments 1 through 100 wherein each R 16 , R 17c , R 18 and R 19c is independently halogen, C1-C2 alkyl,
• Embodiment 102 A compound of Embodiment 101 wherein each R 16 , R 17c , R 18 and R 19c is independently halogen, CH 3 or C ⁇ haloalkyl.
• Embodiment 103 A compound of Embodiment 102 wherein each R 16 , R 17c , R 18 and
• R 19c is independently F, CI, Br, CH 3 , CHF 2 or CF 3 .
• Embodiment 104 A compound of Formula 1 or any one of Embodiments 1 through 103, wherein each R 17n and R 19n is independently C1-C2 alkyl or C1-C2 haloalkyl.
• Embodiment 105 A compound of Embodiment 104 wherein each R 17n and R 19n is independently C1-C2 alkyl.
• Embodiment 106 A compound of Embodiment 105 wherein each R 17n and R 19n is
• 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 1-106 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 Z is O;
• L is -C(R 12a )R 12b -C(R 13a )R 13b -; or 1 ,2-phenylene optionally substituted with up to 2 substituents independently selected from F, CI, Br and CH 3 ;
• G is selected from the group consisting of G-1, G-2, G-3 and G-4;
• each R 2 is independently halogen or C1-C5 alkyl
• n 0, 1 or 2;
• R 3 is halogen, C1-C2 alkyl or C1-C2 haloalkyl
• R 4 is halogen, C1-C2 alkyl or C1-C2 haloalkyl
• R 5 is H, halogen, C1-C2 alkyl or -C2 haloalkyl
• R 6 is CH 3 ;
• R 7 is halogen, C1-C2 alkyl or C1-C2 haloalkyl
• R 8 is H or CH 3 ;
• R 9a is halogen, C1-C2 alkyl, C1-C2 haloalkyl or C1-C2 alkylthio;
• R 9b is H, halogen or C r C 2 alkyl
• R 10 is halogen, C1-C2 alkyl or C1-C2 haloalkyl
• R 1 1 is halogen, C1-C2 alkyl or C1-C2 haloalkyl
• R 22 is F, CI, CH 3 or CF 3 ;
• R 12a is H or CH 3 ;
• R 12b is H or CH 3 ;
• R 12a and R 12b are taken as C2 or C 3 alkanediyl
• R 13a is H, CH 3 , or OCH 3 ;
• R 13b is H or CH 3 ;
• R 13a and R 13b are taken together as C2 or C 3 alkanediyl
• Q is Q-l through Q-21 (as depicted in Embodiment 82);
• each R 16 , R 17c , R 18 and R 19c is independently F, CI, Br, CH 3 , CHF 2 or CF 3 ; and each R 17n and R 19n is CH 3 .
• Embodiment B A compound of Embodiment A wherein
• A is selected from the group consisting of A-1, A-2, A-4 and A-8;
• L is -C(R 1 a )R 1 b -C(R 1 a )R 1 b -;
• G is selected from the group consisting of G-1 and G-4;
• B 1 is CH
• each R 2 is independently H, F, CI, Br or CH 3 ;
• n 0 or 1 ;
• R 3 is F, CI, Br, CH 3 , CHF 2 or CF 3 ;
• R 4 is F, CI, Br, CH 3 , CHF 2 or CF 3 ;
• R 5 is H, halogen, CH 3 or C ⁇ haloalkyl
• R 6 is CH 3 ;
• R 9a is halogen, F, CI, Br, CHF 2 or CF 3 ;
• R 9b is H, halogen or C r C 2 alkyl;
• R 20 is CI, CH 3 or CF 3 ;
• R 21 is H or CH 3 ;
• R 14c is independently F, CI, Br, CH 3 , CHF 2 or CF 3 ;
• Q is selected from Q-9A, Q-9B and Q-9C (as depicted in Embodiment 84); each R 14n is CH 3 ;
• each R 15c is independently F, CI, Br, CH 3 , CHF 2 or CF 3 ;
• each R 15n is CH 3 .
• Embodiment C A compound of Embodiment B wherein
• A is selected from the group consisting of A-1, A-2 and A-8;
• B 3 is CH
• R 1 is H
• G is G-1 substituted with at least one R 2 ortho to the bond to Q;
• each R 2 is independently F or CI
• Q is selected from Q-9A and Q-9B;
• R 3 is CF 3 ;
• R 4 is CHF 2 ;
• R 5 is H, F, CI, Br, CH 3 , CHF 2 or CF 3 ;
• R 20 is CH 3 or CF 3 ;
• R 21 is H
• R 12a is H
• R 12b is H
• R 13a is H or CH 3 ;
• R 13b is H.
• Embodiment D A compound of Embodiment A wherein
• A is selected from the group consisting of A-1, A-2 and A-4;
• L is 1 ,2-phenylene optionally substituted with up to 2 substituents independently selected from F, CI, Br and CH 3 ;
• G is selected from G-1, G-2 and G-3;
• each R 2 is independently F, CI, Br or CH 3 ;
• n 0 or 1 ;
• R 3 is F, CI, Br, CH 3 , CHF 2 or CF;
• R 4 is F, CI, Br, CH 3 , CHF 2 or CF 3 ;
• R 5 is H, halogen, CH 3 or C j haloalkyl
• R 6 is CH 3 ;
• R 9a is halogen, F, CI, Br, CHF 2 or CF 3 ;
• R 9b is H or methyl; Q is selected from Q-9A, Q-9B and Q-9C (as depicted in Embodiment 84);
• R 14c is independently F, CI, Br, CH 3 , CHF 2 or CF 3 ;
• each R 14n is CH 3 ;
• each R 15c is independently F, CI, Br, CH 3 , CHF 2 or CF 3 ;
• each R 15n is CH 3 .
• Embodiment E A compound of Embodiment D wherein
• A is selected from the group consisting of A-l and A-2;
• L is 1 ,2-phenylene optionally substituted with up to 2 substituents independently selected from F and CH 3 ;
• B 1 is CH
• B 3 is CH
• G is G-l
• each R 2 is independently F or CI
• R 3 is CF 3 ;
• R 4 is CHF 2 ;
• R 5 is H, F, CI, Br, CH 3 , CHF 2 or CF 3 ;
• Q is selected from Q-9A and Q-9B.
• Embodiment F A compound of Embodiment E wherein
• A is A-l
• L is 1,2-phenylene
• G is substituted with at least one R 2 ortho to the bond in Formula 1 bonded to the bond with Q;
• each R 2 is independently F or CI
• Q is Q-9A.
• Specific embodiments include compounds of Formula 1 selected from the group consisting of:
• Specific embodiments also include compounds of Formula 1 selected from the group consisting of:
• This invention also provides a fungicidal composition
• a fungicidal composition comprising a compound of
• Formula 1 (including all stereoisomers, N-oxides, and salts thereof), and at least one other fungicide.
• compositions comprising a compound corresponding to any of the compound embodiments described above.
• This invention also provides a fungicidal composition comprising a compound of Formula 1 (including all stereoisomers, N-oxides, and salts thereof) (i.e. in a fungicidally effective amount), and at least one additional component selected from the group consisting of surfactants, solid diluents and liquid diluents.
• fungicidal composition comprising a compound of Formula 1 (including all stereoisomers, N-oxides, and salts thereof) (i.e. in a fungicidally effective amount), and at least one additional component selected from the group consisting of surfactants, solid diluents and liquid diluents.
• compositions comprising a compound corresponding to any of the compound embodiments described above.
• This invention also 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 stereoisomers, N-oxides, and salts thereof).
• a fungicidally effective amount of a compound of Formula 1 including all stereoisomers, N-oxides, and salts thereof.
• embodiments of such methods are methods comprising applying a fungicidally effective amount of a compound corresponding to any of the compound embodiments describe above.
• the compounds are applied as compositions of this invention.
• Compounds of Formulae 1A, IB, 1C, ID, IE, IF, 7A, 7B, 9A, 9B, 9C, 9D, 9E, 9F, 13A, 14A, 15A, 16A, 16B, 17A, 24A and 24B are various subsets of the compounds of Formula 1, 7, 9, 13, 14, 15, 16, 17 and 24 respectively and all substituents for Formulae 1A, IB, 1C, ID, IE, IF, 7A, 7B, 9A, 9B, 9C, 9D, 9E, 9F, 13A, 14A, 15A, 16A, 16B, 17A, 24A and 24B are as defined above for Formula 1.
• a compound of Formula IB (i.e. a subset of a compound of Formula 1 wherein Z is S) can be prepared as illustrated in Scheme 1.
• a prescursor of Formula 1A i.e. a compound of Formula 1 wherein Z is O
• Lawesson's reagent [2,4-Bis-(4-methoxyphenyl)-l,3-dithia-2,4-diphosphetane 2,4-disulfide] in an inert solvent such as dioxane or toluene at temperatures ranging from 0 °C to the reflux temperature of the solvent for 0.1 to 72 h affords a thione of Formula IB.
• This type of transformation is well-known in the literature, and is typified by examples in U.S. Pat. No.
• a compound of Formula 1C (i.e. a subset of a compound of Formula 1 wherein Z is O; and Q is an N-linked heterocycle, Q N ) and a compound of Formula ID (i.e. a subset of a compound of Formula 1 wherein Z is O; and Q is a C-linked heterocycle, Q c ) can be prepared from the intermediates of a compound of Formula 2 as outlined in Scheme 2 below.
• Preparation of a compound of Formula 1C can be achieved via Buchwald-Hartwig coupling of an intermediate of Formula 2 with 1 to 3 eq. of a heterocycle of Formula 3 (wherein H is bonded to a nitrogen atom of the heterocycle) in an inert solvent in the presence of 0.1 to 1.0 eq. of a suitable ligand, 0.1 to 1.0 eq. of a copper(I) salt, and 5 to 10 eq. of a carbonate base.
• Such transformations are well-documented in the literature (see, for example, Tetrahedron Letters 2010, 52(38), 5052 and J. Med. Chem. 2010, 55(10), 4248).
• Typical ligands for the reaction are phenanthroline 1 ,2-diaminocyclohexane or 1 ,2-dialkylaminocyclohexane, while Cul and CuBr may be employed as the copper(I) salts.
• Carbonate bases such as sodium or potassium carbonate can also be used as the base.
• Suitable solvents for the reaction are dioxane, 1 ,2-dimethoxyethane or toluene and the reaction is carried out at temperatures ranging from ambient to the reflux temperature of the solvent for times ranging from 1 to 48 h.
• An amine of Formula 3 is commercially available, or can be readily prepared by the skilled practitioner using well-established protocols.
• a Comound of Formula ID in Scheme 2 can be prepared via Suzuki-Miyura coupling of an intermediate of Formula 2 with one or more equivalents of a boron intermediate such as a compound of Formula 4 in the presence of a catalytic amount of palladium(O) with a ligand, or a palladium(II) salt with a ligand as described analogously to commonly-practiced methods disclosed in Angew. Chem. Int. Ed. 2006, 45, 3484 and Tetrahedron Letters 2002, 55(14), 2885.
• the reaction can be conducted in solvents selected from diethyl ether, dioxane, tetrahydrofuran and acetonitrile.
• a base is also present in amounts ranging from 5 to 20 eq. Suitable bases for this transformation include sodium, potassium or cesium carbonate, while palladium(II) salts such as Pd(OAc)2 or PdCl2 are commonly employed in conjunction with ligands such as triphenylphosphine or ⁇ , ⁇ - bis(diphenylphosphino)ferrocene.
• the reaction is conducted at temperatures ranging from ambient to the reflux temperature of the solvent.
• a boron intermediate of Formula 4 is either commercially available, or can be prepared easily from the corresponding halides or triflates via known methods disclosed in, for example, WO2007/034278, U.S. Pat. No. 8,080,566, Org. Lett. 2011, 75(6), 1366, and Org. Lett. 2012, 14(2), 600.
• Compounds of Formulae 1C and ID can alternatively be prepared from boron intermediates of a compound of Formula 5 as shown in Scheme 3 below. Chan-Lam conversion of an intermediate of a compound of Formula 5 to a compound of Formula 1C can be accomplished as described in Tetrahedron Letters 1998, 38, 2941, or Chemistry Letters 2010, 39(1), 764.
• An intermediate of Formula 5 is reacted in an inert solvent with 1 to 2 eq. of a heterocyclic amine of Formula 3 (i.e. Q N is an heterocycle with a free NH available for bonding) and a base in the presence of 1 to 5 eq. of a Cu(II) salt at temperatures ranging from ambient to the reflux temperature of the solvent for 24 to 72 h.
• Suitable solvents include dichloromethane, chloroform, diethyl ether and tetrahydrofuran.
• Suitable bases include pyridine, quinoline and triethylamine which can be used in the amount of from 1 to 5 eq.
• Examples of Cu(II) salts that may be used include Cu(OAc)2, CuBr 2 and Cul2 which can be used in amounts ranging from 1 to 5 eq.
• An amine of Formula 3 is either commercially available, or is readily prepared as mentioned above.
• a compound of Formula ID can be obtained by reacting a boron intermediate of Formula 5 with a heterocyclic intermediate of Formula 6, where X is bonded to a carbon atom of the heterocycle.
• a boron intermediate of Formula 5 can be prepared from an intermediate of Formula 2 in Scheme 2 using the same methods cited above for the preparation of a boron intermediate of Formula 4 in Scheme 2 from the corresponding halides or triflates as described in WO2007/034278, U.S. Pat. No. 8,080,566, Org. Lett. 2011, 75(6), 1366, and Org. Lett. 2012, 14(2), 600.
• a compound of Formula 2 in Scheme 2 above can be prepared by coupling an amine of Formula 7 with an acid intermediate of Formula 8 as shown in Scheme 4. Such couplings are common in organic synthesis and can be conducted under a wide variety of conditions (see March, Advanced Organic Chemistry, 3 rd ed., John Wiley & Sons, New York, 1985, p. 1152).
• An intermediate of Formula 7A (i.e. a subset of a compound of Formula 7 wherein R 1 is cyclopropyl) can be synthesized from a primary amine of Formula 9 by the analogous methods discussed in J. Med. Chem. 2008, 57(11), 3238 and US2009/0176844 as shown in Scheme 5 below.
• a compound of Formula 9 is treated with from 1 to 4 eq. of 1-ethoxy-l- (trimethylsilyloxy)propane (10) in acetic acid/methanol solution for 1 to 24 h at temperatures ranging from ambient to the reflux temperature of the solvent.
• Molecular sieves can be present as well.
• a reducing agent such as sodium cyanoborohydride can then be added to the reaction mixture followed by further reaction for 1 to 24 h at temperatures ranging from 0 °C to the reflux temperature of the solvent.
• a compound of Formula 9 in Scheme 5 is known in the art and can be synthesized using established methods found in, for example, WO2011/047156, WO2006/117358, Angewandte Chemie, Int. Ed. 2012, 57(24), 5920, and Tetrahedron Letters 1993, 34(13), 2127.
• An intermediate of Formula 7B (i.e. another subset of a compound of Formula 7 wherein R 1 is C r C 2 alkoxy and L is -C(H)R 12b -C(R 13a )R 13b -) as shown in Scheme 6, is accessible from a carbonyl intermediate of Formula 11 via oximation and subsequent reduction with sodium cyanoborohydride as described in US2011/0230537, WO2011/147690 and WO2010/063700.
• An intermediate of Formula 11 is either commercially available or can be prepared by analogous methods described in WO2009/076747, WO2010/135650, WO2011/032277, WO2012/043791 and WO2011/152485.
• a compound of Formula IE (i.e. a subset of a compound of Formula 1 wherein Z is O; and R 1 is H) can be prepared by reacting an amine of Formula 9A with a compound of Formula 8 as shown in Scheme 7 below. This reaction can be accomplished using the methods described in the preparation of a compound of Formula 2 in Scheme 4 above.
• An amine precursor of Formula 13A can be synthesized from the previously described amine of Formula 9 via the reaction sequence illustrated in Scheme 8 below.
• An amine of a compound of Formula 9 can be protected with an appropriate protecting group "PG" (i.e. where PG is BOC-, PhCH 2 OC(0)- or the like) to afford the N-protected intermediates such as a compound of Formula 13A.
• Transformation of an intermediate of Formula 13A to an intermediate of Formula 13 can be accomplished using methods analogous to those shown for the conversion of a compound of Formula 2 to compounds of Formulae 1C and ID as shown in Scheme 2.
• An intermediate of Formula 13 can then be deprotected to provide the intermediate of Formula 9A.
• Many types of protecting groups are available for this sequence as outlined in Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis, 2nd ed.; Wiley: New York, 1991 and the practicing chemist will recognize which protecting groups are appropriate for the sequence.
• An amine intermediate of Formula 9B (i.e. a subset of a compound of Formula 9 wherein L is -C(R 12a )H-C(H)R 13b - and R 13b is H, C r C 2 alkyl, or C r C 2 haloalkyl) are accessible through reduction of a nitro intermediate of Formula 14 as shown in Scheme 9 below.
• the reaction can be carried out using Fe(0), Zn(0) or SnCl 2 in aqueous acidic media at temperatures ranging from ambient to the reflux temperature of the solvent.
• Alcoholic co-solvents such as methanol, ethanol, propanol and z-propanol may also be employed in the reaction.
• Proton sources such as aqueous hydrochloric, hydrobromic, acetic acids or aqueous NH 4 C1 may be used in the reaction.
• the reaction is conducted for a time ranging from 0.25 h to 24 h to obtain a compound of Formula 9B which can be used as a crude intermediate without additional purification as the acid salt.
• the salt may be neutralized to the corresponding amine using procedures familiar to the practicing chemist. Typical examples for the subject reductions are given in J. Labelled Compounds & Radiopharmaceuticals 2011, 54(5), 239 and WO2011/138657.
• An intermediate of Formula 14 can be prepared by sodium borohydride reduction of a nitroolefm intermediate of Formula 15 as shown in Scheme 10. Typical procedures for this type of reduction can be found, for example, in Med. Chem. Lett. 2012, 5(1), 5 and WO2011/124704 Scheme 10
• R iJD H, C r C 2 alkyl or C r C 2 haloalkyl
• a nitroolefm intermediate of Formula 15 can be synthesized by reacting an intermediate of Formula 16 with a nitro compound of Formula 17 as depicted in Scheme 11. The reaction is conveniently conducted in acetic acid in the presence of ammonium acetate as disclosed analogously in WO2007/141009.
• R 13b H, C r
• An intermediate of Formula 16 can readily be prepared from a precursor of Formula 16A in Scheme 12 according to the methods previously outlined in Scheme 2 for the preparation of compounds of Formulae 1C and ID from intermediates of a compound of Formula 2.
• Precursors of a compound of Formula 16A are readily available from commercial sources or can be prepared by known methods such as those disclosed in WO2012/044567, WO2012/110860, WO2012/103297 and WO2011/156698.
• R 13b H, C j
• An amine of Formula 9C (i.e. a subset of Formula 9 wherein Q is an N-linked heterocycle, Q N ; and R 13a is H) can be alternatively synthesized from a carbonyl intermediate Formula 16B as shown in Scheme 13 below.
• An intermediate of Formula 16A is reacted with a compound of Formula 3 in the presence of suitable bases such as NaH, K2CO3, Na 2 C03 and t-BuO " K + in aprotic solvents such as acetonitrile, tetrahydrofuran, dimethylsulfoxide or N,N-dimethylformamide at temperatures ranging from ambient to the reflux temperature of the solvent to afford a compound of 16B.
• suitable bases such as NaH, K2CO3, Na 2 C03 and t-BuO " K +
• aprotic solvents such as acetonitrile, tetrahydrofuran, dimethylsulfoxide or N,N-dimethylformamide at temperatures ranging from ambient to the reflux temperature of
• Appropriate bases can be employed in amounts ranging from 1.0 to 3 eq., and the reaction times range from 0.5 to 24 h.
• An intermediate of Formula 16B may then be converted to an amine of Formula 9C using the same sequence described in previous Schemes 11, 10 and 9 for the analogous preparation of a compound of Formula 9B from a compound of Formula 16.
• X F, I, Br, CI or -OS0 2 CF 3
• Step 1 See prep of 15 from 16 in Scheme 1 1
• An amine intermediate of Formula 9D (i.e. a subset of Formula 9 wherein L is -C(R 12a )H-C(R 13a )R 13b -; R 13a is C r C 2 alkoxy, C r C 2 alkylthio or C r C 2 alkoxyamino; and R 13b is H, Ci -C 2 alkyl or Ci -C 2 haloalkyl), can be prepared from an intermediate of Formula 14A as shown in Scheme 14 below using the same procedures described above in Scheme 9 for the reduction of a nitro precursor of Formula 14 to the amines of Formula 9B.
• R 13b H, C r C 2 alkyl, C r C 2 haloalkyl
• R , 3a C] -C 2 alkoxy, C r C 2 alkylthio,
• an intermediate of Formula 14A can be accessed from the previously-described nitroolefms of Formula 15A (i.e. a compound of Formula 15 wherein R 13a is C 1 -C2 alkoxy, C 1 -C2 alkylthio or C 1 -C2 alkoxyamino) using methods known in the art such as those disclosed in WO2008/148570.
• R 52 is C!-C 2 alk y L
• R H, C j -C 2 alkyl, C j -C 2 haloalkyl
• R 1Ja C!-C 2 alkoxy, C r C 2 alkylthio,
• R H, C r C 2 alkyl, C r C 2 haloalkyl
• An amine of Formula 9A (i.e. a compound of Formula 9 wherein L is -C(H)H- C(R 13a )R 13b -; and R 13a and R 13b are H, C r C 2 alkyl, or R 13a and R 13b are taken together as C2-C5 alkanediyl) below can be accessed from an intermediate of Formula 17 as shown in Scheme 16 by analogy to the sequence cited in EP1500651.
• An intermediate of Formula 17A can be prepared from a precursor of Formula 17 according to the procedures outlined in Scheme 2 for the preparation of compounds of Formulae 1C and ID from a compound of Formula 2.
• a precursor of Formula 17 is commercial, or can be synthesized in analogy to various known methods (see, for example WO2008/144222, WO2011/159760 and EP1500651).
• An amine of Formula 9E (i.e. a compound of Formula 9 wherein L is -CH 2 CHF-) is preparable as shown in Scheme 17 below from a ketone intermediate of Formula 18.
• reduction of a ketone of Formula 18 to an alcohol of Formula 19 can be achieved using reducing agents such as NaBH 4 as outlined in J. Agricultural and Food Chemistry, 2006, 54(1), 125.
• a fluorinating agent such as diethylamino sulfur trifluride (i.e. DAST) can provide an intermediate of Formula 20 by analogy to the methods cited in WO2006/015159.
• Conversion to an amine Formula 9E can then be accomplished according to the previously-described sequence Scheme 8 for the conversion of an amine of Formula 9 to an amine of Formula 9A.
• An amine of Formula 9F (i.e. a compound of Formula 9 wherein L is -CH 2 CF2-) is preparable as shown in Scheme 18 below from a ketone intermediate of Formula 18.
• a ketone of Formula 18 is first protected with an appropriate protecting group as to afford the protected aminoketone of Formula 21 as described previously in Scheme 8 for the protection of amines of Formula 9 to afford a protected amine of Formula 9A.
• Treatment of the protected amino ketone of Formula 21 with a fluorinating agent such as DAST can deliver a difluorinated intermediate of Formula 22, as described in WO2011/079102.
• the desired amine intermediate of Formula 9F may then be accessed by subjection of a compound of Formula 22 to the previously-described sequence in Scheme 8 for the conversion of an amine of Formula 13 to an amine of Formula 9A.
• An aminoketone of Formula 18 in Schemes 17 and 18 can be synthesized by analogous methods described in U.S. Pat. No. 5,106,986 and Journal of Agricultural and Food Chemistry 2006, 54( ⁇ ).
• a compound of Formula IF (i.e. a compound of Formula 1 wherein Z is O; and L is 1 ,2-phenylene optionally substituted with up to 4-substitutents independently selected from halogen and -C2 alkyl) can be prepared by coupling of a boronate of Formula 23 with an intermediate of Formula 24 under the Suzuki conditions described in Scheme 2.
• a trialkyl tin compound of Formula 25 can be coupled with an intermediate of Formula 24 under Stille conditions to give a compound of Formula IF.
• Stille couplings typically are conducted in the presence of Pd(0) or a Pd(II) salt, a ligand and a Cu(I) salt such as copper(I) iodide.
• reaction is run in a solvent such as dioxane, 1 ,2-dimethoxyethane or toluene at a temperature ranging from ambient to the reflux temperature of the solvent.
• a solvent such as dioxane, 1 ,2-dimethoxyethane or toluene
• An intermediate of Formulae 23 and 25 can be prepared using commercially available starting materials or the methods outlined in Schemes 4 and 7.
• An intermediate of Formula 24 is either commercially available or can be prepared as shown in Scheme 20 from an intermediate of Formula 26 by a variety of methods known to one skilled in the art.
• Q N a nitrogen-linked heterocycle
• J in a compound of Formula 26 is halogen or trifluoromethanesulfonate
• a compound of Formula 24 can either be prepared using the Buchwald-Hartwig conditions described for Scheme 2, or by reaction with heterocyclic amines Q N -H (i.e. a compound of Formula 3) in the presence of a suitable base and solvent as illustrated in U.S. 20120202834, J. Med. Chem.
• an intermediate of Formula 26 wherein J is a boronic acid or boronate ester can be coupled with a heterocycle of Formula 3 using the Chan-Lam conditions as described for Scheme 3 to provide a compound of Formula 24 wherein Q is Q N .
• a compound of Formula 24 wherein Q is a carbon-linked heterocycle denoted by Q c can be accessed by coupling a precursor of Formula 26 wherein J is Br, CI, I or trifluoromethanesulfonate with boronate-substituted heterocycles Q c -B(OR)2 (i.e.
• a compound of Formula 4 in Scheme 2 using the Suzuki conditions of Scheme 2 or with trialkyltin-substituted heterocycles Q c -Sn(R) 3 using the Stille conditions of Scheme 19.
• a compound of Formula 26 wherein J is a boronate or trialkyltin group may also be coupled with halogen-substituted heterocycles Q c -X using the methods shown in Schemes 2 or 19, respectively, to afford a compound of Formula 24 wherein Q is Q c .
• the skilled chemist will realize that prudent choice of groups X 6 and J in reactions involving a compound of Formula 26 is needed, and that isomeric products can occur in cases where groups X 6 and J are similar in reactivity. In cases where regioisomeric mixtures are produced, the desired product can be isolated using routine separation techniques known in the art.
• J in a compound of Formula 26 is a functional group such as an alkene, alkyne, oxime, nitrile or ketone
• the functional group an be converted to various heterocycles using methods described in Katritsky, Advances in Heterocyclic Chemistry, Elsevier, Vol. 1-104.
• a compound of Formula IF can also be prepared by coupling an intermediate analogous to those depicted in Scheme 19 wherein functional groups in the starting reagents have been interchanged.
• coupling of an intermediate of Formula 27 with a boronate ester of Formula 24A and a trialkyltin intermediate of Formula 24B using methods described in Scheme 19 affords a compound of Formula IF.
• R-" is C!-C 4 alkyl It is recognized that some reagents and reaction conditions described above for preparing a compound 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).
• Step B Preparation of 5-(2-nitro-l-propen-l-yl)-2-[3-(trifluoromethyl)-lH-pyrazol-l- yl]pyridine
• Step C Preparation of a-methyl-6-[3-(trifluoromethyl)-lH-pyrazol-l-yl]-3- pyridineethanamine
• Step D Preparation of N-[l-methyl-2-[6-[3-(trifluoromethyl)-lH-pyrazol-l-yl]-3- pyridinyl]ethyl]-3-(trifluoromethyl)-2-pyridinecarboxamide
• reaction was allowed to warm to ambient temperature and stir for approximately 16 h.
• the reaction mixture was diluted with dichloromethane, washed with IN aqueous hydrochloric acid, dried over MgSC ⁇ , concentrated under reduced pressure and then purified by medium pressure liquid chromatography (0 - 100% ethyl acetate in hexanes as eluent) to yield 0.04 g of the title compound, a compound of the present invention.
• Step B Preparation of 3 -(difluoromethyl)-N- [2- [5 -fluoro-6- [3 -(trifluoromethyl)- 1H- pyrazol- 1 -yl] -3 -pyridinyljphenyl] - 1 -methyl- lH-pyrazole-4-carboxamide 3-(Difluoromethyl)-l-methyl-lH-pyrazole-4-carbonyl chloride (prepared from commercial 3-(difluoromethyl)-l -methyl- lH-pyrazole-4-carboxylic acid according to the procedure described in PCT Patent Application WO 2008/053043; 0.30 g, 1.5 mmol), 2-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)-benzenamine (0.31 g, 1.4 mmol) and cesium carbonate (1.0 g, 3.1 mmol) were combined in 5 mL of 1 ,2-dime
• the mixture was heated to 100 °C for 3 h, cooled to ambient temperature, diluted with ethyl acetate, washed 3 times with brine, dried over MgS0 4 , filtered and concentrated under reduced pressure.
• the resulting residue was purified by medium pressure liquid chromatography (0 - 100% ethyl acetate in hexanes as eluent) to yield a crude residue which was subsequently purified by reverse phase medium pressure liquid chromatography (0 - 100% 1 : 1 acetonitrile to methanol in water as eluent) to yield 0.10 g of the title compound, a compound of the present invention.
• Step C Preparation of 2-[5-[3-(trifluoromethyl)-lH-pyrazol-l-yl]-2- pyrazinyljbenzenamine
• Step D Preparation of 3-(trifluoromethyl)-N-[2-[5-[3-(trifluoromethyl)-lH-pyrazol-l- yl]-2-pyrazinyl]phenyl]-2-pyridinecarboxamide)
• Step B Preparation of 3-(2-nitrophenyl)-6-[3-(trifluoromethyl)-lH-pyrazol-l- yl]pyridazine
• Step C Preparation of 2-[6-[3-(trifluoromethyl)-lH-pyrazol-l-yl]-3- pyridazinyljbenzenamine
• Step D Preparation of 3-(trifluoromethyl)-N-[2-[6-[3-(trifluoromethyl)-lH-pyrazol-l- yl]-3-pyridazinyl]phenyl]-2-pyridinecarboxamide
• A-li A-lj A- lk A-ll The below structure (i.e. a compound of Formula 1 wherein Z is O; R 1 is H; L is 1 ,2-phenylene; and G is G-1) is used to construct the following Tables. The value of n is understood to be assigned the appropriate number of R 2 values listed for each Table entry.
• Table 2 is constructed in the same fashion as Table 1 , except in the Row Heading the phrase "A is A-la; n is 0" is replaced with the phrase "A is A-la; (R ⁇ ) n is 5-F” as shown below in the column labeled Row Heading for Table 2.
• R 2 is 5-F it is understood to mean that n is 1 and R 2 is F located at the 5-position of the G ring. Therefore, the first entry in Table 2 is a compound of Formula 1 wherein Z is O; R 1 is H; L is 1 ,2-phenylene; G is G-1; A is A-la; R 2 is 5-F; n is 1; and Q is 3-CF3-pyrazol-l-yl.
• the second entry in Table 2 is a compound of Formula 1 wherein Z is O; R 1 is H; L is 1 ,2-phenylene; G is G-1; A is A-la; R 2 is 5-F; n is 1; and Q is 4-CF3-lH-pyrazol-l-yl.
• the remaining entries in Table 2 are constructed in the same manner.
• Tables 3 through 272 are constructed similarly.
• 60 A is A-lh
• (R 2 ) n is 4-F 96 A is A- 11
• (R 2 ) n is 4,5-di-Cl
• 65 A is A- lk, (R 2 ) n isH(nis 0) 101 A is A-2a, (R 2 ) n is 5-1
• Table 273 is constructed in the same manner as Table 1 except that the chemical structure in Table 1 is replaced with the following structure:
• the first entry in Table 273 is a compound of Formula 1 wherein Z is O; R 1 is H; L is 1 ,2-phenylene; G is G-3; n is 0; and Q is 3-CF3-pyrazol-l-yl.
• the second entry in Table 273 is a compound of Formula 1 wherein Z is O; R 1 is H; L is 1 ,2-phenylene; G is G-3; A is A-la; n is 0; and Q is 4-CF3-lH-pyrazol-l-yl.
• the remaining entries in Table 273 are constructed in the same manner.
• Table 274 is constructed in the same fashion as Table 2.
• Tables 275 through 544 are constructed similarly to the corresponding Table isted in the following chart.
• Table 545 is constructed in the same fashion as Table 1 except the chemical structure is replaced with the following structure:
• the first entry in Table 545 is a compound of Formula 1 wherein Z is O; R 1 is H; L is 1,2-phenylene; G is G-2; A is A- la; n is 0; and Q is 3-CF3-pyrazol-l-yl.
• the second entry in Table 545 is a compound of Formula 1 wherein Z is O; R 1 is H; L is 1,2-phenylene; G is G-2; A is A-la; n is 0; and Q is 4-CF3-lH-pyrazol-l-yl.
• the remaining entries in Table 545 are constructed in the same manner.
• Table 546 is constructed in the same fashion as Table 545 except that the Header Row phrase "A is A-la; n is 0" is replaced with phrase "A is A-la; (R ⁇ ) n is 6-F” (i.e. n is 1).
• Tables 547 through 710 are constructed similarly.
• 560 A is A- Id
• (R 2 ) n is 6-1
• 581 A is A-lh
• (R 2 ) n is 6-Br
• 600 A is A-2b, (R 2 ) n is H (n is 0) 637 A is A-3b, (R 2 ) n is 6-1
• 601 A is A-2b
• (R 2 ) n is 6-Me
• 602 A is A-2b
• (R 2 ) n is 6-Cl 639 A is A-3b
• (R 2 ) n is 6-Et
• 603 A is A-2b, (R 2 ) n is 6-Br 640 A is A-3b, (R 2 ) n is 6-CF3
• 604 A is A-2b, (R 2 ) n is 6-1 641 A is A-3b, (R 2 ) n is 6-CN
• 605 A is A-2b
• (R 2 ) n is 6-Me 642 A is A-3b
• (R 2 ) n is 6-OMe
• 606 A is A-2b
• (R 2 ) n is 6-Et 643 A is A-3b
• (R 2 ) n is 6-N0 2
• 607 A is A-2b
• (R 2 ) n is 6-CF3 644 A is A-3c
• (R 2 ) n is H (n is 0)
• 608 A is A-2b
• (R 2 ) n is 6-F
• 611 A is A-2c
• (R 2 ) n is H
• (n is 0) 648 A is A-3c
• (R 2 ) n is 6-1
• 670 A is A-6c
• (R 2 ) n is 6-1
• 694 A is A-8a
• (R 2 ) n is 6-Et
• 678 A is A-7a
• (R 2 ) n is 6-F 702 A is A-8b
• (R 2 ) n is 6-Br
• 681 A is A-7a
• (R 2 ) n is 6-1 705 A is A-8b
• (R 2 ) n is 6-Et
• Table 710 is constructed in the same fashion as Table 1 except the chemical structure is replaced with the following structur
• Table 710 is a compound of Formula 1 wherein Z is O; R 1 is H; L is 1 ,2-phenylene; G is G-5; A is A-la; n is 0; and Q is 3-CF3-pyrazol-l-yl.
• the second entry in Table 710 is a compound of Formula 1 wherein Z is O; R 1 is H; L is 1 ,2-phenylene; G is G-5; A is A-la; n is 0; and Q is 4-CF3-lH-pyrazol-l-yl.
• Tables 711 through 965 are constructed similarly.
• 726 A is A- Id
• (R 2 ) n is H (n is 0)
• 758 A is A-lh
• (R 2 ) n is H (n is 0)
• 742 A is A- If, (R 2 ) n is H (n is 0) 774 A is A- lk, (R 2 ) n is H (n is 0) Table Row Heading Table Row Heading

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