WO2005040152A1 - Heteroyclylphenyl-and heterocyclylpyridyl-substituted azolecarboxamides as herbicides - Google Patents

Heteroyclylphenyl-and heterocyclylpyridyl-substituted azolecarboxamides as herbicides Download PDF

Info

Publication number
WO2005040152A1
WO2005040152A1 PCT/US2004/035045 US2004035045W WO2005040152A1 WO 2005040152 A1 WO2005040152 A1 WO 2005040152A1 US 2004035045 W US2004035045 W US 2004035045W WO 2005040152 A1 WO2005040152 A1 WO 2005040152A1
Authority
WO
WIPO (PCT)
Prior art keywords
formula
compound
och
alkyl
sch
Prior art date
Application number
PCT/US2004/035045
Other languages
French (fr)
Inventor
Dominic Ming-Tak Chan
Balreddy Kamireddy
Jeffrey Keith Long
Kanu Maganbhai Patel
Paula Louise Sharpe
Original Assignee
E.I. Dupont De Nemours And Company
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by E.I. Dupont De Nemours And Company filed Critical E.I. Dupont De Nemours And Company
Publication of WO2005040152A1 publication Critical patent/WO2005040152A1/en

Links

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
    • A01N43/56—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
    • A01N43/60—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
    • A01N43/64—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with three nitrogen atoms as the only ring hetero atoms
    • A01N43/647—Triazoles; Hydrogenated triazoles
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/72—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms
    • A01N43/74—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms five-membered rings with one nitrogen atom and either one oxygen atom or one sulfur atom in positions 1,3
    • A01N43/78—1,3-Thiazoles; Hydrogenated 1,3-thiazoles
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/72—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms
    • A01N43/80—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms five-membered rings with one nitrogen atom and either one oxygen atom or one sulfur atom in positions 1,2
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/72—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms
    • A01N43/82—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms five-membered rings with three ring hetero atoms
    • C—CHEMISTRY; METALLURGY
    • C04—CEMENTS; CONCRETE; ARTIFICIAL STONE; CERAMICS; REFRACTORIES
    • C04B—LIME, MAGNESIA; SLAG; CEMENTS; COMPOSITIONS THEREOF, e.g. MORTARS, CONCRETE OR LIKE BUILDING MATERIALS; ARTIFICIAL STONE; CERAMICS; REFRACTORIES; TREATMENT OF NATURAL STONE
    • C04B35/00—Shaped ceramic products characterised by their composition; Ceramics compositions; Processing powders of inorganic compounds preparatory to the manufacturing of ceramic products
    • C04B35/622—Forming processes; Processing powders of inorganic compounds preparatory to the manufacturing of ceramic products
    • C04B35/626—Preparing or treating the powders individually or as batches ; preparing or treating macroscopic reinforcing agents for ceramic products, e.g. fibres; mechanical aspects section B
    • C04B35/63—Preparing or treating the powders individually or as batches ; preparing or treating macroscopic reinforcing agents for ceramic products, e.g. fibres; mechanical aspects section B using additives specially adapted for forming the products, e.g.. binder binders
    • C04B35/632—Organic additives
    • 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
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D403/12—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 linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C07D417/02—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 two hetero rings
    • C07D417/12—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 two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • This invention relates to certain azolecarboxamides, their N-oxides, agriculturally suitable salts and compositions, and methods of their use for controlling undesirable vegetation. BACKGROUND OF THE INVENTION
  • the control of undesired vegetation is extremely important in achieving high crop efficiency. Achievement of selective control of the growth of weeds especially in such useful crops as rice, soybean, sugar beet, corn (maize), potato, wheat, barley, tomato and plantation crops, among others, is very desirable.
  • T is CR 6 or N
  • U is CR ⁇ or N
  • Y is CR 8 or N
  • Z is CR 9 or N
  • R la is H, C!-C 4 alkyl, C!-C 4 fluoroalkyl, C 2 -C 4 alkenyl, C 2 -C 4 fluoroalkenyl, C2-C4 alkynyl or C2-C4 fluoroalkynyl;
  • R lb is halogen, -CN, C!-C 4 alkyl, Cj-C 4 fluoroalkyl, C 2 -C 4 alkenyl, C 2 -C 4 fluoroalkenyl, C 2 -C4 alkynyl or C2-C4 fluoroalkynyl;
  • R2a is Ci-Cg alkyl, C ⁇ -C 6 haloalkyl, C 2 -C 6 alkoxyalkyl, C 2 -C 6 alkylthioalkyl, C2-Cg alkenyl, C2 ⁇ Cg haloalkenyl, C2 ⁇ Cg alkynyl, C2 ⁇ Cg haloalkynyl, C3-C6 cycloalkyl, C4-C6 alkylcycloalkyl, C3-Cg halocycloalkyl, C4-C cycloalkylalkyl, C 5 -C 6 alkylcycloalkylalkyl or SiRiOR 1 ⁇ 12 ;
  • R2b is Ci-C alkyl, haloalkyl, C 2 -C 6 alkoxyalkyl, C 2 -C 6 alkylthioalkyl, C2 ⁇ Cg alkenyl, C2-Cg haloalkenyl, C 2 -Cg alkynyl, C2 ⁇ Cg haloalkynyl, C3 ⁇ Cg cycloalkyl, C 4 -Cg alkylcycloalkyl, C 3 -Cg halocycloalkyl, C4 ⁇ Cg cycloalkylalkyl or C 5 -C 6 alkylcycloalkylalkyl;
  • R 5 is a phenyl ring or a 5- or 6-membered heteroaromatic ring which includes at least one heteroatom selected from N, O and S, each ring optionally substituted with one or more substituents selected from R 15 ; or R 5 is a 5- or 6-membered partially unsaturated heterocyclic ring which includes at least one heteroatom selected from N, O and S, the ring connected through a nitrogen atom or an sp 2 carbon atom to the remainder of Formula I and optionally substituted by one or more substituents selected from R 16 ;
  • R 6 is H, F, Cj-0 2 alkyl, -C2 fluoroalkyl, C!-C 2 fluoroalkoxy, alkylthio or C ⁇ -C 2 fluoroalkylthio;
  • R 7 is H, F, C!-C 2 alkyl, 0 ⁇ 2 fluoroalkyl, CJ- J fluoroalkoxy, Cr-C ⁇ alkylthio or C1-
  • R 12 is C!-C 2 alkyl or Ci-Gj haloalkyl
  • R 13 and R 14 are independently H or ⁇ 2 alkyl
  • each R 15 is independently halogen, -CN, C ⁇ -C 2 alkyl, C ⁇ -C 2 haloalkyl, C ⁇ -C 2 alkoxy, C -C 2 haloalkoxy, C ⁇ C 2 alkylthio, C ] -C alkylsulfinyl, C ⁇ -C 2 alkylsulfonyl, -SCHF 2 or -SCF 3
  • each R 16 is independently C ] -C 2 alkyl
  • W is O or S
  • Y 1 and Y 2 are independently CH 2 , 0, S, NH or NCH 3 ; s is 0 or 1; t is 1 or 2; and u is 0 or 1; provided that the sum of s, t and u is 2 or 3; and v is 0 or 1 ; w is 0 or 1 ; provided that the sum of v and w is 0 or 1 ; provided that
  • R 5 when R 5 comprises a tetrazole ring, said ring is connected through the carbon atom to the remainder of Formula I and substituted on a nitrogen atom with C ⁇ C 2 alkyl;
  • R 7 when R 7 is F and R 5 comprises a 1-pyrazolyl ring, no more than one substituent R 15 attached to said ring is haloalkyl;
  • R 7 and R 9 when J is J-2 or J-6, then R 7 and R 9 are H;
  • R lb when J is J-2 or J-6, and R 2b is 0 ⁇ 2 alkyl, then R lb is halogen, C 2 -C 4 alkyl, C ⁇ -Q 4 fluoroalkyl, C 2 -C 4 alkenyl, C 2 -C 4 fluoroalkenyl, C 2 -C 4 alkynyl or C2-C4 fluoroalkynyl;
  • T when N, then Z is CR 9 ; and
  • J when J is J-8,
  • this invention pertains to a compound of Formula I, including all geometric and stereoisomers, N-oxides or agriculturally suitable salts thereof.
  • This invention also relates to a herbicidal composition comprising a herbicidally effective amount of a compound of Formula I and at least one of a surfactant, a solid diluent or a liquid diluent.
  • This invention further relates to a method for controlling the growth of undesired vegetation comprising contacting the vegetation or its environment with a herbicidally effective amount of a compound of Formula I (e.g., as a composition described herein).
  • This invention also relates to a method for selectively controlling the growth of undesired vegetation in a crop comprising contacting the locus of the crop with a herbicidally effective amount of a compound of Formula I and an antidotally effective amount of a safener.
  • the present invention also relates to a method for controlling the growth of undesired vegetation comprising contacting the vegetation or its environment with a herbicidally effective amount of a compound of Formula I and effective amount of at least one additional active ingredient selected from the group consisting of an other herbicide and a herbicide safener (e.g., in the form of the aforedescribed herbicidal mixture or herbicidal composition).
  • a particular aspect of the present invention relates to a method for selectively controlling the growth of undesired vegetation in a crop comprising contacting the locus of a crop with an effective amount of a compound of Formula I and an antidotally effective amount of a herbicide safener (e.g., safener applied as a seed treatment).
  • a herbicide safener e.g., safener applied as a seed treatment.
  • composition, 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, process, method, article, or apparatus.
  • "or” refers to an inclusive or and not to an exclusive or.
  • 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).
  • 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.
  • alkyl used either alone or in compound words such as “alkylthio” or “haloalkyl” includes straight-chain or branched alkyl, such as, methyl, ethyl, 7i-propyl, /-propyl, or the different butyl, pentyl or hexyl isomers.
  • 1-2 alkyl indicates that one or two of the available positions for that substituent may be alkyl which are independently selected.
  • Alkenyl includes straight-chain or branched alkenes such as ethenyl, 1-propenyl, 2-propenyl, and the different butenyl, pentenyl and hexenyl isomers. "Alkenyl” also includes polyenes such as 1,2-propadienyl and 2,4-hexadienyl. "Alkynyl” includes straight-chain or branched alkynes such as ethynyl, 1-propynyl, 2-propynyl and the different butynyl, pentynyl and hexynyl isomers.
  • Alkynyl can also include moieties comprised of multiple triple bonds such as 2,5-hexadiynyl.
  • Alkoxy includes, for example, methoxy, ethoxy, n-propyloxy, isopropyloxy and the different butoxy and pentoxy 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 OCH2 and CH3CH 2 OCH2CH2.
  • Alkylthio includes branched or straight-chain alkylthio moieties such as methylthio, ethylthio, and the different propylthio, butylthio and pentylthio isomers.
  • Alkylthioalkyl denotes alkylthio substitution on alkyl. Examples of “alkylthioalkyl” include CH 3 SCH 2 , CH 3 SCH 2 CH 2 , CH 3 CH 2 SCH 2 , CH3CH2CH2CH2SCH2 and CH3CH2SCH2CH2.
  • Alkylsulfinyl includes both enantiomers of an alkylsulfinyl group.
  • alkylsulfinyl examples include CH 3 S(O), CH 3 CH 2 S(O), CH 3 CH 2 CH 2 S(O), (CH3)2CHS(O) and the different butylsulfinyl isomers.
  • alkylsulfonyl examples include CH 3 S(O) 2 , CH 3 CH 2 S(O) 2 , CH3CH 2 CH 2 S(O)2, (CH 3 ) 2 CHS(O) 2 and the different butylsulfonyl isomers.
  • Cycloalkyl includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • cycloalkylalkyl examples include cyclopropylmethyl, cyclopentylethyl, and other cycloalkyl moieties bonded to straight-chain or branched alkyl groups.
  • Alkylcycloalkyl denotes alkyl substitution on a cycloalkyl moiety. Examples include 4-methylcyclohexyl and 3-ethylcyclopentyl.
  • heteroaryomatic ring includes fully aromatic heterocycles.
  • Aromatic indicates that each of the ring atoms is essentially in the same plane and has a -orbital perpendicular to the ring plane, and in which (4n + 2) ⁇ electrons, where n is 0 or a positive integer, are associated with the ring to comply with H ⁇ ckel's rule.
  • sp 2 carbon atom refers to a carbon atom that is connected to another atom through a double bond.
  • partially unsaturated heterocyclic ring system denotes heterocycles containing at least one double bond in the ring but lacking sufficient unsaturation to result in aromaticity according to H ⁇ ckel's rule.
  • heterocyclic ring systems can be attached through any available carbon or nitrogen by replacement of a hydrogen on said carbon or nitrogen.
  • 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.
  • N-oxides of heterocycles 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 peracetic and m-chloroperbenzoic acid
  • hydrogen peroxide alkyl hydroperoxides such as t-butyl hydroperoxide, sodium perborate
  • dioxiranes such as dimethyldioxirane
  • halogen either alone or in compound words such as “haloalkyl”, includes fluorine, chlorine, bromine or iodine.
  • 1-2 halogen indicates that one or two of the available positions for that substituent may be halogen which are independently selected. Further, when used in compound words such as “haloalkyl", said alkyl may be partially or fully substituted with halogen atoms which may be the same or different. Examples of “haloalkyl” include F 3 C, C1CH 2 , CF 3 CH 2 and CF 3 CC1 2 .
  • CF 3 CH 2 CH CHCH 2 .
  • haloalkynyl examples include HC ⁇ CCHCl, CF 3 C ⁇ C, CC1 3 C ⁇ C and FCH 2 C ⁇ CCH 2 .
  • haloalkoxy examples include CF 3 O, CCl 3 CH 2 O, HCF 2 CH 2 CH 2 O and CF 3 CH 2 O.
  • fluoroalkyl may be partially or fully substituted with fluorine atoms. 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 6.
  • C j -C 3 alkyl designates methyl through propyl
  • 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 .
  • alkylcarbonyl include C(O)CH 3 , C(O)CH 2 CH 2 CH 3 and C(O)CH(CH 3 ) 2 .
  • substituents when they exceed 1, are independently selected from the group of defined substituents.
  • a group contains a substituent which can be hydrogen, for example R 6 , then, when this substituent is taken as hydrogen, it is recognized that this is equivalent to said group being unsubstituted.
  • stereoisomers 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).
  • the skilled artisan knows how to separate, enrich, and/or to selectively prepare said stereoisomers. Accordingly, the present invention comprises compounds selected from Formula I, N-oxides and agriculturally suitable salts thereof.
  • the compounds of the invention may be present as a mixture of stereoisomers, individual stereoisomers, or as an optically active form.
  • the agriculturally suitable salts of the compounds of the invention include acid-addition salts with inorganic or organic acids such as hydrobromic, hydrochloric, nitric, phosphoric, sulfuric, acetic, butyric, fumaric, lactic, maleic, malonic, oxalic, propionic, salicylic, tartaric, 4-toluenesulfonic or valeric acids.
  • the agriculturally suitable salts of the compounds of the invention also include those formed with strong bases (e.g., hydrides or hydroxides of sodium, potassium or lithium).
  • Embodiments of the present invention include: Embodiment 1. A compound of Formula I wherein at most one of T, U, Y and Z is ⁇ . Embodiment 2. A compound of Formula I wherein W is O. Embodiment 3. A compound of Formula I wherein J is J-1, J-2, J-3, J-5, J-8 or J-9. Embodiment 4. A compound of Embodiment 3 wherein J is J-1, J-3, J-8 or J-9. Embodiment 5.
  • Embodiment 6. A compound of Formula I wherein J is J-1 , J-2, J-3, J-5 or J-8.
  • Embodiment 7. A compound of Embodiment 6 wherein J is J-1, J-3 or J-8.
  • Embodiment 8. A compound of Embodiment 7 wherein J is J-1 or J-3.
  • Embodiment 9. A compound of Formula I wherein J is J-1.
  • Embodiment 10 A compound of Formula I wherein J is J-2.
  • Embodiment 11. A compound of Formula I wherein J is J-3.
  • Embodiment 12. A compound of Formula I wherein J is J-4.
  • Embodiment 13 A compound of Formula I wherein J is J-5.
  • Embodiment 14. A compound of Formula I wherein J is J-6.
  • Embodiment 15 A compound of Formula I wherein J is J-7.
  • Embodiment 16. A compound of Formula I wherein J is J-8.
  • Embodiment 17. A compound of Formula I wherein J in J-9.
  • Embodiment 18. A compound of Formula I wherein Rla is C1-C alkyl, C1-C4 fluoroalkyl, C 2 -C4 alkenyl, C2-C4 fluoroalkenyl, C2-C4 alkynyl or C2-C4 fluoroalkynyl.
  • Embodiment 19 A compound of Formula I wherein Rla is C1-C alkyl, C1-C4 fluoroalkyl, C 2 -C4 alkenyl, C2-C4 fluoroalkenyl, C2-C4 alkynyl or C2-C4 fluoroalkynyl.
  • a compound of Formula I wherein R la or R lb is selected from a radical in the group consisting of C ⁇ C 3 alkyl, C ⁇ C 3 fluoroalkyl, C 2 -C 3 alkenyl, C 2 -C 3 fluoroalkenyl, C 2 -C 3 alkynyl and C2-C3 fluoroalkynyl, each radical unbranched and connected through a terminal end carbon atom to the azole ring.
  • a compound of Embodiment 19 wherein R la or R lb is CH 3 , CH2CH3, CH 2 CH 2 F, CH 2 CHF 2 , CH 2 CF 3 or CH CH 2 .
  • Embodiment 21. A compound of Embodiment 20 wherein R la or R lb is CH3, CH 2 CH 3 or CH 2 CF 3 .
  • Embodiment 22 A compound of Embodiment 21 wherein R la or R lb is CH3 or CH 2 CH .
  • Embodiment 23 A compound of Embodiment 22 wherein R la or R lb is CH 2 CH 3 .
  • Embodiment 24 A compound of Formula I wherein R 2a or R 2b is tert-butyl, isopropyl, cyclopropyl or 1-methylcyclopropyl.
  • Embodiment 25 A compound of Embodiment 24 wherein R 2a or R 2b is tert-butyl, isopropyl or cyclopropyl.
  • Embodiment 26 A compound of Embodiment 25 wherein R 2a or R 2b is tert-butyl or isopropyl.
  • Embodiment 27 A compound of Formula I wherein Y 1 and Y 2 are independently CH 2 or O;
  • Embodiment 28. A compound of Embodiment 27 wherein the sum of s, t and u is 2 and the sum of v and w is 0.
  • Embodiment 29 A compound of Embodiment 28 wherein R 13 is C ⁇ -C 2 alkyl.
  • Embodiment 30 A compound of Embodiment 29 wherein R 13 and R 14 are CH3.
  • Embodiment 31 A compound of Formula I wherein R 3 is H. Embodiment 32. A compound of Formula I wherein R 4 is H. Embodiment 33. A compound of Formula I wherein R 6 is H or F. Embodiment 34. A compound of Formula I wherein R 7 is H or F. Embodiment 35. A compound of Formula I wherein R 8 and R 9 are H or F. Embodiment 36. A compound of Formula I wherein R 5 is a phenyl ring optionally substituted with 1-4 substituents selected from R 15 . Embodiment 37. A compound of Embodiment 36 wherein the phenyl ring is optionally substituted with 1-2 substituents selected from R 15 . Embodiment 38.
  • Embodiment 37 wherein the phenyl ring is optionally substituted with a substituent selected from R 15 .
  • Embodiment 39 A compound of Formula I wherein R 5 is a 5- or 6-membered heteroaromatic ring containing at least one heteroatom selected from N, O and S, the ring optionally substituted with one or more substituents selected from R 15 .
  • Embodiment 40 A compound of Embodiment 39 wherein the 5- or 6-membered heteroaromatic ring is optionally substituted with 1-2 substituents independently selected from R 15 .
  • Embodiment 41 A compound of Embodiment 40 wherein the 5- to 6-membered heteroaromatic ring is optionally substituted with a substituent selected from R15.
  • Embodiment 42 A compound of Formula I wherein R 5 is a 5- or 6-membered partially unsaturated heterocyclic ring containing at least one heteroatom selected from N, O and S, the ring connected through a nitrogen atom or an sp 2 carbon atom to the remainder of Formula I and optionally substituted by one or more substituents selected from R 16 .
  • Embodiment 43 A compound of Embodiment 42 wherein the 5- or 6-membered partially unsaturated heterocyclic ring is optionally substituted by 1-2 substituents selected from R 16 .
  • Embodiment 44 A compound of Embodiment 43 wherein the 5- or 6-membered partially unsaturated heterocyclic ring is optionally substituted by a substituent selected from R 16 .
  • Embodiment 45 A compound of Formula I wherein the 5- or 6-membered heteroaromatic ring or the partially unsaturated heterocyclic ring comprised by R 5 comprises a heteroatom at a ring position adjacent to the ring position connecting the remainder of Formula I.
  • Embodiment 46 A compound of Embodiment 45 wherein the heteroatom is a nitrogen atom.
  • Embodiment 47 A compound of Embodiment 46 wherein the 5- or 6-membered heteroaromatic ring comprised by R 5 is 2-pyridinyl (also termed 2-pyridyl).
  • Embodiment 48 A compound of Formula I wherein R 15 is halogen, -CN, Ci-C 2 alkyl, Cj fluoroalkyl or Ci alkoxy.
  • Embodiment 49 A compound of Embodiment 48 wherein R 15 is methyl.
  • Embodiment 50 A compound of Formula I wherein R 16 is methyl.
  • Embodiment 51 A compound of Formula I wherein R 5 is one of U-1 through U-71 selected from Exhibit 1 Exhibit 1
  • each R 21 is independently halogen, -CN, ⁇ -02 alkyl, C 1 -C 2 haloalkyl, ⁇ - ⁇ alkoxy, C 1 -C2 haloalkoxy, C1-C2 alkylthio, C1-C2 alkylsulfinyl, C ⁇ -C 2 alkylsulfonyl, -SCHF 2 or -SCF 3 ;
  • R2l is H, halogen, -CN, C!-C 2 alkyl, - ⁇ haloalkyl, C ⁇ alkoxy, C l -C 2 haloalkoxy, C!-C 2 alkylthio, Cx- ⁇ alkylsulfinyl, C!-C 2 alkylsulfonyl, -SCHF 2 or -SCF 3 ;
  • R22 is H or C 1 -C 2 alkyl;
  • R 2 3 is C!-C 2 alkyl;
  • Embodiment 52 A compound of Embodiment 51 wherein R 5 is selected from the group consisting of U-2, U-3, U-4, U-5, U-6, U-7, U-8, U-9, U-10, U-ll, U-12, U-13, U-14, U-15, U-16, U-17, U-18, U-19, U-20, U-21, U-25, U-27, U-28, U-31, U-32, U-33, U-34, U-35, U-36, U-38, U-39, U-41, U-42, U-43, U-44, U-46, U-47, U-49, U-50, U-51, U-54, U-55, U-56, U-57, U-58, U-59, U-60, U-62, U-63, U-64, U-66, U-67, U-68, U-69, U-70 and U-71.
  • Embodiment 53 A compound of Embodiment 52 wherein R 5 is selected from the group consisting of U-4, U-6, U-7, U-ll, U-12, U-13, U-14, U-15, U-16, U-17, U-18, U-19, U-20, U-21, U-25, U-27, U-28, U-31, U-32, U-33, U-34, U-35, U-36, U-38, U-39, U-41, U-42, U-43, U-44, U-46, U-47, U-49, U-50, U-51, U-54, U-55, U-56, U-57, U-58, U-59, U-60, U-62, U-63, U-64, U-66, U-67, U-68, U-69, U-70 and U-71.
  • Embodiment 54 A compound of Embodiment 51 wherein R 5 is selected from the group consisting of U-4, U-7, U-23, U-32, U-38, U-41, U-44, U-47, U-49 and U-58.
  • Embodiment 55 A compound of Embodiment 54 wherein R 5 is selected from the group consisting of U-7, U-32, U-38, U-41, U-44, U-49 and U-58.
  • Embodiment 56 A compound of Embodiment 55 wherein R 5 is selected from the group consisting of U-7, U-32, U-38, U-41 and U-44.
  • Embodiment 57 A compound of Embodiment 56 wherein R 5 is U-44.
  • Embodiment 58 A compound of Embodiment 51 wherein g, j, k, m and n are integers from 0 to 2.
  • Embodiment 59 A compound of Embodiment 58 wherein g, j, k, m, n and p are integers from 0 to 1.
  • Embodiment 60 A compound of Embodiment 51 wherein each R 21 is independently halogen, -CN, Cr-C 2 alkyl, Cj fluoroalkyl or Cj alkoxy; and R 21a is H, halogen, -CN, C 1 -C 2 alkyl, Ci fluoroalkyl or C ⁇ alkoxy.
  • Embodiment 61 A compound of Embodiment 60 wherein each R 21 , R 23 and R 24 is methyl.
  • Embodiment 62 A compound of Embodiment 51 wherein R 22 and R 25 are methyl.
  • Embodiment 63 A compound of Formula I wherein when J is J-1, then R 5 is other than phenyl.
  • Embodiment 64. A compound of Formula I wherein when J is J-1, then R 5 is other than optionally substituted phenyl.
  • a compound of Formula I wherein when J is J-1 and R 5 is optionally substituted phenyl, then R la is CH 2 CH 3 , CH 2 CH 2 F, CH 2 CHF 2 , CH 2 CF 3 or CH CH 2 .
  • Embodiment 67. A compound of Formula I wherein when J is J-1 and R 5 is optionally substituted phenyl, then the optionally substituted phenyl is substituted with F at an ortho position.
  • Embodiment 69. A compound of Formula I wherein when J is J-1, then R 5 is other than U-1.
  • Embodiment 71 A compound of Formula I wherein R 5 is other than U-1.
  • Embodiment 72 A compound of Formula I wherein when J is J-1, then R 5 is other than 5-oxazolyl.
  • Embodiment 73 A compound of Formula I wherein when J is J-1, then R 5 is other than optionally substituted 5-oxazolyl.
  • Embodiment A A compound of Formula I wherein when J is J-1, then R 5 is other than U-8 where p is 0.
  • Embodiment 77 A compound of Formula I wherein when J is J-1, then R 5 is other than U-8.
  • Embodiment 78. A compound of Formula I wherein R 5 is other than U-8 where p is 0.
  • Embodiment 79 A compound of Formula I wherein R 5 is other than U-8.
  • J J-1 and R la is H, which is particularly useful as a synthetic intermediate. Combinations of Embodiments 1-79 are illustrated by: Embodiment A.
  • R la or R lb is selected from a radical in the group consisting of C ⁇ C 3 alkyl, C ] -C 3 fluoroalkyl, C -C 3 alkenyl, C 2 -C 3 fluoroalkenyl, C 2 -C 3 alkynyl or C 2 -C 3 fluoroalkynyl, each radical unbranched and connected through a terminal end carbon atom to the azole ring;
  • R 6 is H or F;
  • R 7 is H or F;
  • R 8 is H or F;
  • R 9 is H or F;
  • R 4 is H;
  • R 13 is C ⁇ alkyl;
  • W is O;
  • Y 1 and Y 2 are independently CH 2 or O; the sum of s, t and u is 2; and the sum of v and w is 0.
  • Embodiment B A compound of Embodiment A wherein J is J-1, J-2, J-3, J-5 or J-8.
  • Embodiment D A compound of Embodiment C wherein each R 15 is independently halogen, -CN, C ⁇ C 2 alkyl, Cj fluoroalkyl or C ⁇ alkoxy.
  • Embodiment E A compound of Embodiment C wherein each R 15 is independently halogen, -CN, C ⁇ C 2 alkyl, Cj fluoroalkyl or C ⁇ alkoxy.
  • Embodiment D wherein R 5 is a phenyl ring optionally substituted with 1-2 substituents selected from R 15 .
  • Embodiment G A compound of Embodiment D wherein R 5 is a 5- or 6-membered partially unsaturated heterocyclic ring which includes at least one heteroatom selected from N, O and S and optionally substituted with 1-2 substituents selected from R 16 .
  • Embodiment H A compound of Embodiment D wherein R 5 is a 5- or 6-membered heteroaromatic ring which includes at least one heteroatom selected from N, O and S and optionally substituted with 1-2 substituents selected from R 15 .
  • Embodiment I A compound of Embodiment D wherein R 5 is a phenyl ring optionally substituted with 1-2 substituents selected from R 15 .
  • Specific embodiments include the following compound of Embodiment D: 3-(l,l-dimethylethyl)-l-ethyl-N-[3-(2-pyridinyl)phenyl]-lH-pyrazole- 5-carboxamide.
  • J is J-1, J-2, J-3, J-4, J-5, J-6, J-7 or J-8.
  • herbicidal compositions of the present invention comprising the compounds of embodiments described above.
  • This invention also relates to a method for controlling undesired vegetation comprising applying to the locus of the vegetation herbicidally effective amounts of the compounds of the invention (e.g., as a composition described herein).
  • a method for selectively controlling the growth of undesired vegetation in a crop comprising contacting the locus of the crop with a herbicidally effective amount of the compounds of the invention and an antidotally effective amount of a safener.
  • embodiments relating to methods of use are those involving the compounds of embodiments described above.
  • the compounds of Formula I can be prepared by one or more of the following methods and variations as described in Schemes 1 through 61 and accompanying text.
  • reaction of Scheme 1 is carried out in an anhydrous aprotic solvent such as dichloromethane or tetrahydrofuran, preferably in the presence of a base such as triethylamine, pyridine, 4-(dimethylamino)pyridine or N,N-diisopropylethylamine, at a temperature typically between room temperature and 70 °C to provide the amide of Formula la.
  • a base such as triethylamine, pyridine, 4-(dimethylamino)pyridine or N,N-diisopropylethylamine
  • R 4 is alkylcarbonyl or alkoxycarbonyl
  • a strong base such as sodium hydroxide and phase transfer conditions such as those described by M. J. Haddadin et al., Heterocycles 1984, 22, 773 may be advantageous.
  • the reaction of Scheme 1 is illustrated by Step G of Example 1, which follows.
  • compounds of Formula la can be prepared by coupling the appropriately substituted azole
  • This reaction is carried out in the presence of a dehydrating coupling reagent such as dicyclohexyl carbodiimide, l-(3-dimethylaminopropyl)-3-ethylcarbodiimide, 1-propane- phosphonic acid cyclic anhydride or carbonyl diimidazole in the presence of a base such as triethylamine, pyridine, 4-(dimethylamino)pyridine or N,N-diisopropylethylamine in an anhydrous aprotic solvent such as dichloromethane or tetrahydrofuran at a temperature typically between room temperature and 70 °C.
  • a dehydrating coupling reagent such as dicyclohexyl carbodiimide, l-(3-dimethylaminopropyl)-3-ethylcarbodiimide, 1-propane- phosphonic acid cyclic anhydride or carbonyl diimidazole in the
  • an ester of a carboxylic acid of Formula 3 can be condensed with a substituted amino compound of Formula 2 to provide the compound of Formula la by heating in a high-boiling inert solvent such as ⁇ , ⁇ , ⁇ -trifluorotoluene.
  • a high-boiling inert solvent such as ⁇ , ⁇ , ⁇ -trifluorotoluene.
  • compounds of Formula lb (Formula I wherein W is S) can be prepared from corresponding compounds of Formula la by treatment with a thionating reagent such as P 2 S5 (see for example, E. Klingsberg et al., J. Am. Chem. Soc. 1951, 72, 4988; E. C. Taylor Jr.
  • compounds of Formula lb can be directly prepared from the corresponding carboxylic acid of Formula 3 and amino compound of Formula 2 by treatment with (EtO) 2 P(S)SH according to the general procedure of N. Borthakur et al., Tetrahedron Lett. 1995, 36(37), 6745.
  • compounds of Formula la or lb wherein R 4 is alkyl, alkylcarbonyl, alkoxycarbonyl, alkoxyalkyl or alkylthioalkyl can be prepared from the corresponding compounds of Formula la or lb wherein R 4 is H by treatment with the appropriate alkylating or acylating reagents in the presence of base using methods well known in the art.
  • Acyl chlorides of Formula 1 can be prepared from the carboxylic acids of Formula 3 by using methods well known in the art such as treatment with oxalyl chloride and catalytic N,N-dimethylformamide in dichloromethane or treatment with thionyl chloride. This preparation is illustrated by Step E of Example 1, Step A of Example 5, Step A of Example 6 and Step C of Example 7.
  • Carboxylic acids of Formula 3 can be prepared from corresponding esters of Formula 11 wherein R 31 is a carbon-based radical such as alkyl (e.g., methyl, ethyl), benzyl, etc. as shown in Scheme 4.
  • Scheme 4 Ester cleavage conditions J-C(0)OR31 *- 3 11
  • ester cleavage conditions known in the art can be used for this method. Particularly suitable are conditions involving treatment with hydroxide, such as aqueous sodium hydroxide or aqueous lithium hydroxide in tetrahydrofuran, followed by acidification, typically with a strong mineral acid such as hydrochloric or sulfuric acid.
  • hydroxide such as aqueous sodium hydroxide or aqueous lithium hydroxide in tetrahydrofuran
  • acidification typically with a strong mineral acid such as hydrochloric or sulfuric acid.
  • a strong mineral acid such as hydrochloric or sulfuric acid.
  • Carboxylic esters of Formula 11a (Formula 11 wherein J is J-1 andR 31 is ethyl) can be prepared according to the general method described by J. J. Parlow et al., J. Org. Chem. 1997, 62, 5908-5919 and modifications thereof as discussed for Scheme 5.
  • Scheme 5
  • This method involves base-induced condensation of a ketone of Formula 12 with diethyl oxalate (13) to give a tricarbonyl compound of Formula 14, which is condensed with a hydrazine of Formula 15 to prepare the pyrazolecarboxylate of Formula 11a.
  • the condensation of the tricarbonyl compound of Formula 14 with the hydrazine of Formula 15 is typically conducted in an alcohol, ester or carbonate diester solvent.
  • the hydrazine of Formula 15 can be in the form of a salt.
  • the diketoester of Formula 14 can be alkylated or fluorinated to provide the corresponding diketoester of Formula 14 wherein R 3 is alkyl or fluorine.
  • Compounds of Formula 12 are commercially available or can be prepared by methods well known in the art. The method of Scheme 5 is illustrated in Steps A and B of Example 1.
  • the pyrazolecarboxylate of Formula 11a can be alkylated with the appropriate alkylating agent in the presence of a base and solvent to give a pyrazolecarboxylate of Formula 11a wherein R la is alkyl, fluoroalkyl, alkenyl, fluoroalkenyl, alkynyl or fluoroalkynyl.
  • Appropriate alkylating agents are typically of the formula R la X (16) wherein X is a nucleophilic reaction leaving group (e.g., bromide, iodide, mesylate (OS(O) 2 CH 3 ), triflate (OS(O) 2 CF 3 ), tosylate (OS(O) 2 Ph-4-CH 3 ), etc.).
  • Typical bases include potassium tert-butoxide, potassium carbonate, sodium hydride and potassium hydroxide.
  • Typical solvents include N,N-dimethylfo ⁇ marnide, acetonitrile and tetrahydrofuran. A particularly useful combination of base and solvent is potassium carbonate in acetonitrile.
  • Alkylation isomers can be separated by common methods such as chromatography and crystallization. This modification is illustrated in Step C of Example 1.
  • some of the R la groups can be converted to others on compounds of Formula 11a.
  • DAST diethylaminosulfur trifluoride
  • R la is 2-hydroxyethyl
  • treatment with DAST diethylaminosulfur trifluoride
  • the product compounds of Formula 11a wherein R la is 2-fluoroethyl and vinyl can then be separated by methods known in the art such as chromatography on silica gel and crystallization. Alternate approaches to construct R 2a using variations of the process of Scheme 5 are feasible.
  • a compound of Formula 11a wherein R 2a is a 1,1-dimethyl- 2-haloethyl group can be prepared by first including R 2a in Formula 12 as a 1,1-dimethyl- 2-hydroxyethyl group protected as a tetrahydropyranyl ether (e.g., prepared from dihydropyran and pyridinyl p-tosylate (PPTS) using the general procedure of M. Miyashita et al., J. Org. Chem.
  • PPTS pyridinyl p-tosylate
  • Carboxylic esters of Formula 12b (Formula 12 wherein J is J-2 and R 31 is ethyl) and Formula 12c (Formula 12 wherein J is J-3 and R 31 is ethyl) wherein R lb is alkyl, fluoroalkyl, alkenyl, fluoroalkenyl, alkynyl or fluoroalkynyl can be prepared from sydnones of Formula 17 and alkynes of Formula 18 according to the general method of J. Heterocycl. Chem. 1993, 30, 365-371 and J. Heterocycl. Chem. 1996, 33, 719-726 as depicted in Scheme 6. (One skilled in the art recognizes that to prepare lib without a substituent at the pyrazole 5-position as specified for Formula lib (J-2), the R 3 radical in the sydnone of Formula 17 must be hydrogen.) Scheme 6
  • sydnones of Formula 17 are heated with alkynes of Formula 18 in higher boiling solvents (e.g., xylenes, toluene, dioxane, ethylene glycol) for typically 12-72 hours.
  • solvents e.g., xylenes, toluene, dioxane, ethylene glycol
  • the isomers lib and lie then can be separated by the usual methods such as column chromatography and distillation.
  • the sydnones of Formula 17 can be prepared using the general methods described in /. Heterocycl. Chem. 1993, 30, 365-371, J. Heterocycl. Chem. 1996, 33, 719-726 and the references cited therein.
  • the method of Scheme 6 is illustrated in Step A of Example 7.
  • Carboxylic esters of Formula lid (Formula 11 wherein J is J-3 but R 2c can be H as well as R 2b ; R 3 is H and R 31 is ethyl) wherein R lb is alkyl, fluoroalkyl, alkenyl, fluoroalkenyl, alkynyl or fluoroalkynyl can also be prepared according to the method depicted in Scheme 7 wherein R 32 is NMe 2 or OEt when (MeO) 2 CHNMe 2 or HC(OEt) 3 , respectively, is used to prepare the intermediate of Formula 20.
  • the intermediate of Formula 20 is prepared from the ketoester of Formula 19 according to the general procedures published in J. Heterocycl. Chem., 1987, 24, 693-695.
  • the starting ketoesters of Formula 19 can, in turn, be prepared according to the general procedures of J. Org. Chem. 1997, 62, 5908-5919.
  • the condensation of the ketoester of Formula 20 with the hydrazine of Formula 21 is typically conducted in an alcohol, ester or carbonate diester solvent.
  • the hydrazine of Formula 21 can be in the form of a salt.
  • the pyrazolecarboxylate of Formula lid can be alkylated with the appropriate alkylating agent in the presence of a base and solvent to give a pyrazolecarboxylate of Formula lid wherein R 2 is R 2b .
  • Appropriate alkylating agents are typically of the formula R 2b X (22) wherein X is a nucleophilic reaction leaving group (e.g., bromide, iodide, mesylate (OS(O) 2 CH 3 ), triflate (OS(0) 2 CF 3 ), tosylate (OS(O) 2 Ph-4-CH 3 ), etc.).
  • Typical bases include potassium tert-butoxide, potassium carbonate, sodium hydride and potassium hydroxide.
  • Typical solvents include N,N-dimethylformamide, acetonitrile and tetrahydrofuran.
  • Alkylation isomers can be separated by common methods such as chromatography and crystallization.
  • Compounds of Formula lib i.e. pyrazole isomer J-2
  • pyrazole isomer J-2 can also be prepared using methods or slight modification thereof taught in: J. Heterocycl. Chem. 1999, 36(1), 217- 220, Agric. Biol. Chem. 1984, 48(1), 45-50, Bull. Soc. Chim. Fr. 1978, (7-8, Pt. 2), 401-14, Khim. Geterotsikl. Soedin.
  • pyrazoles of Formulae lib and lie (wherein R lb is halogen) can be prepared from corresponding pyrazoles of Formula lie (Formula 11 wherein J is J-2 but R lb is H; and R 31 is ethyl) and Formula llf (Formula 11 wherein J is J-3 but R lb is H; and R 31 is ethyl), respectively.
  • Scheme 8
  • One variation of the method of Scheme 8 involves heating a compound of Formula lie or llf with N-chloro- or N-bromosuccinimide in an organic solvent such as N,N-dimethyl- formamide, at temperatures between 30 and 110 °C, preferably at about 60 °C.
  • an organic solvent such as N,N-dimethyl- formamide
  • bromine or chlorine can be added at or below room temperature to a compound of Formula lie or llf in a halocarbon solvent such as dichloromethane, trichloromethane or tetrachloromethane to give the corresponding compound of Formula lib or lie, respectively.
  • Pyrazoles of Formula lib and lie wherein Rlb is halogen can also be prepared using the general methods taught in: Bulletin of the Korean Chemical Society 1998, 19(7), 725- 726, Izv. Akad. Nauk SSSR, Ser. Khun. 1981, (6), 1342-8, Izv. AJcad. Nauk SSSR, Ser. Khim. 1980, (5), 1071-7, J. Heterocycl. Chem. 1997, 34(2), 537-540, J. Heterocycl. Chem. 1991, 25(8), 1849-52, J. Fluorine Chem. 1988, 39(3), 435-40, U.S. Patent No.
  • acyl chloride of Formula 23 which can be prepared by a variety of general methods known in the art; many acyl chlorides of Formula 23 are commercially available.
  • the acyl chloride of Formula 23 is treated with an ammonia solution to prepare the carboxamide of Formula 24, which is in turn treated with a thionating reagent such as Lawesson's Reagent (2,4-bis(methoxyphenyl)-l,3-dithia-2,4-diphosphetane-2,4-disulfide) to prepare the thioamide of Formula 25.
  • the thioamide of Formula 25 is then reacted with the chloro compound of Formula 26 to provide the thiazolecarboxylate of Formula llg.
  • Carboxylic esters of Formula llh (Formula 11 wherein J is J-5) can be prepared by the general method shown in Scheme 10.
  • an alpha-bromo ketone of Formula 27 is converted to a Wittig reagent of Formula 28 and then condensed with a 2-oxocarboxylic acid ester of Formula 29 to provide a 4-oxo-2-pentenoic ester of Formula 30 according to the general procedure of P. F. Schuda et al., Synthesis 1987 (12), 1055-7.
  • the 4-oxo-2-pentenoic ester of Formula 30 is then condensed with a hydrazine of Formula 31 to form the carboxylic ester of Formula llh according to the general procedures of G. Westphal & H. H. Stroh, Liebigs Ann. Chem. 1968, 716, 160-163 and R. C.
  • Carboxylic esters of Formula Hi (Formula 11 wherein J is J-6 and R 3i is ethyl) wherein Rl d is H, alkyl, fluoroalkyl, alkenyl, fluoroalkenyl, alkynyl or fluoroalkynyl can be prepared from sydnones of Formula 17 and alkenes of Formula 32 according to the general methods described in Z. Obshch. Khim. 1962, 32(5), 1446-1451 as depicted in Scheme 11.
  • sydnones of Formula 17 are heated with alkenes of Formula 32 in higher boiling solvents (e.g., xylenes, toluene, dioxane, ethylene glycol) for typically 12-72 hours.
  • the isomer Hi can then be isolated by the usual methods such as column chromatography and distillation.
  • the ester of Formula Hi can then be converted to the corresponding carboxylic acid as described for Scheme 4 and coupled to form the compound of Formula la as described for Schemes 1 and 2.
  • Most R l substituents can be introduced as R ld in the method of Scheme 11, but halogen cannot. Halogen as well as other R lb substituents can be introduced in the method shown in Scheme 12.
  • the compound of Formula Ic wherein R i is R ib is prepared from the compound of Formula Ic wherein R id is H.
  • the compound of Formula Ic wherein Rid is H is then deprotonated using a strong base such as lithium diisopropylamide (LDA) and then reacted with an electrophile introducing Rlb.
  • LDA lithium diisopropylamide
  • the electrophile can be elemental halogen (e.g., Cl 2 , Br 2 ) or a halogen derivative such as N-bromosuccinimide or N-chlorosuccinimide.
  • Rl b is alkyl, fluoroalkyl, alkenyl, fluoroalkenyl, alkynyl or fluoroalkynyl
  • the electrophile is typically of the formula Rl b ⁇ (33) wherein X is a nucleophilic reaction leaving group as already described for the compound of Formula 16 in connection with the modified method of Scheme 5.
  • Carboxylic esters of Formula llj (Formula 11 wherein J is J-7) can be prepared by the general method shown in Scheme 13.
  • a 3-oxo-carboxylic acid ester of Formula 34 is condensed with an aldehyde of Formula 35 to provide an unsaturated ester of Formula 36, which is condensed with a hydrazine of Formula 37 to provide the carboxylic ester of Formula llj according to the general procedure of P. S. Engel et al., J. Am. Chem. Soc. 1997, 119 (26), 6059-6065.
  • the ester of Formula llj can then be converted to the corresponding carboxylic acid as described for Scheme 4 and coupled to form the compound of Formula la as described for Schemes 1 and 2.
  • the coupling can be conducted first to prepare the amide of Formula 38, which is then condensed with the aldehyde of Formula 35 to prepare the unsaturated amide of Formula 39, which is condensed with the hydrazine of Formula 37 to prepare the compound of Formula Id.
  • Carboxylic esters of Formula Ilk (Formula 11 wherein J is J-8) can be prepared by the general method shown in Scheme 15. Scheme 15
  • an alkynecarboxylic acid ester of Formula 18 is heated with an excess of azidotrimethylsilane at a temperature of about 100-110 °C under an inert atmosphere.
  • the reaction is worked up by treating the cooled reaction mixture with excess methanol to consume remaining trimethylsilyl azide and desilylate the azide adduct. Evaporation leaves the 1,2,3-triazole of Formula 40.
  • the triazole of Formula 40 is then converted to the triazole of Formula Ilk by alkylation with 2b ⁇ 3 (4i) wherein X 3 is a nucleophilic reaction leaving group such as CI, Br, I, sulfonates such as p-toluenesulfonate, methanesulfonate or trifluoromethanesulfonate, or sulfates such as -OSO 2 OR 2b .
  • X 3 is a strong leaving groups such as I.
  • the reaction is conducted in the presence of a base such as potassium carbonate in a polar aprotic solvent such as acetonitrile at a temperature commonly between 40 and 80 °C, typically about 50- 60 °C.
  • the triazole of Formula Ilk can be isolated and purified by the usual methods known to those skilled in the art such as chromatography and crystallization.
  • R 2b is a tertiary alkyl group such as tert-butyl
  • alkylation with R 2b ⁇ 3 m ay give low yields.
  • bromine is added to an aqueous solution of 1,2,3-triazole (43), and 4,5-dibrorno-l,2,3-triazole (44) is collected by filtration.
  • This is then alkylated with R 2b using either an alkylating agent of Formula 41 or an alcohol of Formula 42 to provide the compound of Formula 45 using methods analogous to those already described for conversion of Formula 40 to Formula Ilk in Scheme 15.
  • the compound of Formula 45 is lithiated using n-butyllithium in an ether solvent such as ethyl ether or tetrahydrofuran at -70 to -100 °C, optionally magnesium bromide is added, followed by ethyl chloroformate to give the compound of Formula Ilk where R is Br.
  • ether solvent such as ethyl ether or tetrahydrofuran at -70 to -100 °C
  • magnesium bromide is added
  • ethyl chloroformate to give the compound of Formula Ilk where R is Br.
  • Lithiation using n-butyllithium in tetrahydrofuran at -78 °C, followed by addition of ethyl chloroformate works well.
  • the compound of Formula Ilk where Rl b is Br is useful for preparing compounds of Formula I where J is J-8 and R ib is Br.
  • Br can be replaced by other Rlb groups such as vinyl by a variety of coupling methods known in the art.
  • the bromine can be replaced by a 1 -alkenyl group through mediation of a palladium catalyst in the Heck Reaction (for reviews, see R. A. Abramovitch et al., Tetrahedron 1988, 44(11), 3039-3071; W. Cabri and I. Candiani, Synthesis 1995, 2S(1), 2- 7; and R. F. Heck, "Palladium-catalyzed Vinylation of Organic Halides", Chapter 2 in Organic Reactions, Vol. 27, Wiley: New York, 1982, pp. 345-390).
  • ethyl esters are shown for the compounds of Formulae 18, 40 and Ilk, one skilled in the art recognizes that corresponding esters wherein ethyl is replaced by other carbon-based radicals, e.g., R 31 , can be used as well for this method. Also known in the art are other methods to prepare 1,2,3-triazole rings, such as those described in PCT Patent Publication WO 02/096258.
  • Carboxylic esters of Formula 111 (Formula 17 wherein J is J-9) can be prepared by the general method shown in Scheme 17.
  • a iminoacetate of Formula 46 is reacted with a carboxylic acid hydrazide of Formula 47 in a suitable solvent such as dichloromethane to give the adduct of Formula 48.
  • a suitable solvent such as dichloromethane
  • the compound of Formula 48 is then cyclized to give the triazole of Formula 49 by heating to a sufficiently high temperature, typically around 200 °C.
  • the reaction can be conducted using a high boiling solvent, most conveniently it is done in the absence of solvent.
  • the triazole of Formula 49 is then alkylated using R la X (16) in the presence of a base and solvent, analogous to the alkylation of pyrazoles already described as a modification of the method of Scheme 5.
  • Amino compounds of Formula 2 can be prepared by a wide variety of methods available to the synthetic organic chemist. Many of these methods involve converting one substituent to another on the aromatic ring. For example, the amino function of Formula 2a can be obtained by reduction of the nitro compound of Formula 51 as shown in Scheme 18.
  • Scheme 18
  • the nitro compound of Formula 51 can be reduced to the aniline of Formula 2a by a variety of reducing agents known in the art, such as iron in acetic acid, tin(II) chloride or hydrogenation over a palladium or platinum sulfide catalyst.
  • the nitro function of Formula 60 can be added by well known nitration reactions.
  • the method of Scheme 18 is illustrated by Step B of Example 2 and Step B of Example 13.
  • Many compounds of Formula 51 are commercially available and others can be readily prepared by methods well known in the art.
  • T, U and/or Z are N
  • the aryl ring of Formula 2 is activated to nucleophilic substitution facilitating introduction of amino by displacement of leaving groups such as halogen.
  • compounds of Formula 51b can be prepared from compounds of Formula 51 by the method of M. F. McKay et al., Aust. J. Chem. 1993, 46, 417 shown in Scheme 19.
  • Scheme 19
  • U 1 , U 2 and U 3 are independently N or CH optionally substituted by R 2 1.
  • a compound of Formula 52 and a compound of Formula 53 are heated with a base (e.g., K2CO3, KOt-Bu, NaH) in an inert solvent (e.g., toluene, xylene, tetrahydrofuran) for typically 6-24 hours.
  • the compound of Formula 2b can be isolated by conventional methods such as recrystallization or chromatography. This method is particularly useful for preparing compounds of Formula I wherein R 5 is U-37, U-38, U-39 or U-40. Analogous to the method of Scheme 19, the R 5 group can also be introduced by displacement using the compound of Formula 53 after formation of the carboxamide linkage in Formula I.
  • Example 10 illustrates this method. Palladium-catalyzed displacement of a boronic acid functionality can also be used to prepare amino compounds of Formula 2.
  • compounds of Formula 2c can be prepared from boronic acid derivatives of Formula 54 and heterocyclic halides of Formula
  • a boronic acid of Formula 54 is reacted with a heterocyclic halide of Formula 55 in a solvent (e.g., water, tetrahydrofuran, dimethoxyethane) in the presence of a base (e.g., triethylamine, K 2 CO 3 ) and a palladium catalyst (e.g., tetrakis(triphenylphosphine)- ⁇ alladium(O), palladium(II) acetate) at a temperature of 25-100 °C from about 2 to 48 hours.
  • a solvent e.g., water, tetrahydrofuran, dimethoxyethane
  • a base e.g., triethylamine, K 2 CO 3
  • a palladium catalyst e.g., tetrakis(triphenylphosphine)- ⁇ alladium(O), palladium(II) acetate
  • the amino function of a compound of Formula 56 is protected as the acetamide by treatment with acetic anhydride.
  • Treatment with potassium permanganate then oxidizes the aromatic methyl radical to a carboxylic acid function to provide the compound of Formula 57.
  • the compound of Formula 57 is then treated with strong acid, such as hydrochloric acid and alcohol of Formula 58 to form the ester group and deprotect the amino radical.
  • This method works particularly well for short aliphatic alcohols (e.g., R 1 is Me or Et).
  • the carboxylic ester functionality of the intermediate of Formula 59 can then be elaborated to provide amino compounds of Formula 2 wherein R 5 is a heterocyclic moiety.
  • Scheme 22 illustrates the preparation of a compound of Formula le starting from a carboxylic acid of Formula 61.
  • Base le 61 rei n n is 1 or 2.
  • the carboxylic acid of Formula 61 is converted to the corresponding intermediate carbonyl chloride by treatment with oxalyl chloride preferably in the presence of a catalytic amount of N,N-dimethylformamide in an inert solvent such as dichloromethane.
  • the intermediate carbonyl chloride is then reacted with the appropriate amine of Formula 62 in the presence of a base (e.g., triethylamine, K2CO 3 , pyridine).
  • a base e.g., triethylamine, K2CO 3 , pyridine
  • the 2-3 equivalents of the base are used in respect to the carbonyl chloride compound.
  • the compound of Formula le can then be isolated and purified by conventional methods such as column chromatography and crystallization.
  • R 42 is a carbon moiety such as C 1-C4 alkyl.
  • the ester compound of Formula 62 is converted to the corresponding carboxylic acid of Formula 61 by general procedures well known in the art such as by treatment with aqueous lithium hydroxide in tetrahydrofuran, followed by acidification.
  • the compound of Formula 62 can in turn be prepared from coupling the corresponding amino compound with the appropriate azole carbonyl chloride of Formula 1 or azole carboxylic acid of Formula 2 using methods analogous to those described for Schemes 1 and 2.
  • Compounds of Formula If can be prepared as shown in Scheme 24 by general methods described in Eur. J. Med. Chem. Chim. Ther. 1985, 20(1), 16; Synthesis 2000, 12, 1814; J. Org. Chem. 1977, 42, 1872; and J. Org. Chem. 1987, 52, 1017.
  • Y 2 is O, S or NH, and n is 1 or 2.
  • a nitrile of Formula 63 is heated with an amine of Formula 64 in a solvent such as ethanol, methanol or ethylene glycol for typically 12-72 hours.
  • the compound of Formula If can then be isolated by conventional techniques such as column chromatography or crystallization.
  • R 24 substituents on the alkylene chain of the compound of Formula 64 corresponding compounds of Formula If having the heterocyclic group substituted with R 24 can be prepared.
  • This method is particularly useful for preparing compounds of Formula I wherein R 5 is U-57, U-58, U-60, U-64, U-66 or U-67.
  • Compounds of Formula If can be prepared as shown in Scheme 25 by the general method described in Heterocycles 1997, 45, 29. Scheme 25
  • n 1 or 2.
  • n 1 or 2.
  • a mixture of a hydrazine of Formula 68 and a dibromide of Formula 69 is heated in a solvent (e.g., toluene, xylene) in the presence of a base (e.g., aqueous KOH, NaOH or K 2 CO 3 ) for typically 12-100 hours.
  • a base e.g., aqueous KOH, NaOH or K 2 CO 3
  • the product of Formula Ih can then be isolated using conventional techniques such as crystallization and column chromatography.
  • R 24 substituents on the alkylene chain of the compound of Formula 69 corresponding compounds of Formula Ih having the heterocyclic group substituted with R 24 can be prepared. These methods are particularly useful for preparing compounds of Formula I wherein R 5 is U-63 or U-70.
  • Compounds of Formula Ii can be prepared as shown in Scheme 28.
  • R 2 is H or alkyl
  • a nitrile of Formula 63 is converted to the compound of Formula 70 by treatment with hydroxylamine hydrochloride arid base (e.g., NaOH, KOH, Na 2 CO 3 ) in a solvent (e.g., ethanol, methanol, water) and heating at reflux for 4-12 hours.
  • hydroxylamine hydrochloride arid base e.g., NaOH, KOH, Na 2 CO 3
  • a solvent e.g., ethanol, methanol, water
  • the compound of Formula 70 can typically be isolated by crystallization. General procedures for this method are described in Synthesis 2000, 8, 1148 and Tetrahedron Lett. 2001, 42, 1495.
  • the compound of Formula 70 is then treated with N,N-dimethylformamide dimethyl acetal to prepare a compound of Formula Ii wherein R 2i is H according to the general procedure described in Syn. Comm. 1982, 12, 457.
  • R 2ia is H or alkyl
  • a nitrile of Formula 63 is converted to the compound of Formula 72 by treatment with hydrazine and base (e.g., NaOH, KOH, Na CO 3 ) in a solvent (e.g., ethanol, methanol, water) and heating at reflux for 4—12 hours.
  • a solvent e.g., ethanol, methanol, water
  • a general procedure for this method is described in Angew. Chem. 1963, 75, 344.
  • the compound of Formula 72 is then reacted with a compound of Formula 73 in the presence of a base (e.g., aqueous NaOH, KOH) at -20 to 0 °C for 2-12 hours to provide the compound of Formula Ij, which can be isolated using conventional techniques such as crystallization and column chromatography.
  • a base e.g., aqueous NaOH, KOH
  • a nitrile of Formula 63 is converted to an ethyl imidate of Formula 74 by treatment with a solution of hydrogen chloride in ethanol.
  • This type of reaction is very well known in the art; see, for example, H. Emtenas et al., J. Org. Chem. 2001, 66, 6756-6761.
  • a mixture of the ethyl imidate of Formula 74 and the compound of Formula 75 in acetic acid is then heated at reflux for 4—12 hours according to the general procedure of A. Lawson, J. Chem. Soc. 1957, 4225-4228.
  • the compound of Formula Ika can be isolated by conventional techniques such as column chromatography and crystallization.
  • a compound of Formula 76 is reacted with a compound of Formula 77 in the presence of copper(I) iodide and a base (e.g., Cs 2 CO 3 , K 2 CO 3 , Na 2 CO 3 ) in a solvent (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone) heated at reflux for 2-24 hours.
  • a solvent e.g., N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone
  • the compound of Formula Ikb can be isolated by conventional techniques such as extraction, column chromatography and crystallization.
  • Compounds of Formula II can be prepared according to the general method of B. Sezen and D. Sames, J. Am. Chem. Soc. 2003, 125, 5274-5275 as shown in Scheme 32.
  • a mixture of a compound of Formula 76 and a compound of Formula 78 is heated in the presence of palladium(II) acetate and a base (e.g., MgO, Cs 2 CO 3 , Na 2 CO 3 , NaOH) in a solvent (e.g., tetrahydrofuran, dioxane, dimethoxyethane, water) for typically 12-24 hours.
  • a base e.g., MgO, Cs 2 CO 3 , Na 2 CO 3 , NaOH
  • a solvent e.g., tetrahydrofuran, dioxane, dimethoxyethane, water
  • R 2 l is H, alkyl or haloalkyl.
  • a ketone of Formula 79 is treated with a brominating agent (e.g., bromine, N-bromosuccinimide) in a solvent (e.g., trichloromethane, dichloromethane, tetrabromomethane, acetic acid).
  • a brominating agent e.g., bromine, N-bromosuccinimide
  • a solvent e.g., trichloromethane, dichloromethane, tetrabromomethane, acetic acid.
  • the bromoketone of Formula 80 can be isolated by conventional techniques such as column chromatography. This type of reaction is very well known in the art; see, for example, Chem. Soc Perk. Trans. 2 2001, 9, 1506.
  • the bromoketone of Formula 80 is then reacted with an aldehyde of Formula 81 (e.g., formaldehyde, acetaldehyde, proprionaldehyde) and phosphorus sulfide in the presence of a base (e.g., piperidine, pyridine, morpholine) at room temperature according to the general procedures of Helv. Chim. Acta 1947, 30, 2058.
  • a base e.g., piperidine, pyridine, morpholine
  • R 2ib is H, alkyl or haloalkyl.
  • an aldehyde of Formula 83 is reacted with hydroxylamine hydrochloride in a solvent (e.g., ethanol, methanol, trichloromethane, dichloromethane) at 25-100 °C for 4-24 hours.
  • a solvent e.g., ethanol, methanol, trichloromethane, dichloromethane
  • the solvent is then removed, and the isolated intermediate is redissolved in dichloromethane and treated with a chlorinating agent such as sodium hypochlorite, chlorine or N-chlorosuccinimide to provide the compound of Formula 84.
  • the compound of Formula 84 is then reacted with an equimolar amount of the vinyl acetate of Formula 85 in the presence of triethylamine in a solvent (e.g., diethyl ether, tetrahydrofuran) at about 30 °C for 2-4 hours to form the intermediate of Formula 86.
  • the intermediate of Formula 86 is then heated at 150-180 °C for a short period of time to provide the compound of Formula lo, which can be isolated by conventional techniques such as crystallization and column chromatography. This method is particularly useful for preparing compounds of Formula I wherein R 5 is U-41.
  • Compounds of Formula Ip can be prepared as shown in Scheme 36 by the general method described in Synthesis 2001, 1, 55. Scheme 36
  • a compound of Formula 87 is reacted with a hydrazine of Formula 88 in a solvent (e.g., acetic acid, proprionic acid) at 25-100 °C for 2-18 hours.
  • a solvent e.g., acetic acid, proprionic acid
  • the compound of Formula Ip can be isolated by conventional techniques such as column chromatography and crystallization. This method is particularly useful for preparing compounds of Formula I wherein R 5 is U-25. This method is illustrated by Examples 8 and 9.
  • Compounds of Formula Iq can be prepared as shown in Scheme 37 by the general method described in Helv. Chim. Acta 1947, 30, 2058. Scheme 37
  • a mixture of a bromoketone of Formula 80, formamide, phosphorus pentasulfide and a base e.g., piperidine, morpholine
  • a solvent e.g., toluene, xylene
  • the compound of Formula Iq can be isolated by conventional techniques such as crystallization or column chromatography. This method is particularly useful for preparing compounds of Formula I wherein R 5 is U-28.
  • Compounds of Formula Ir can be prepared as shown in Scheme 38 by the general method described in J. Org. Chem. 1990, 55, 929. Scheme 38
  • a bromoketone of Formula 80 is heated with formamide in a solvent (e.g., acetic acid, formic acid) for 2-12 hours.
  • a solvent e.g., acetic acid, formic acid
  • the compound of Formula Is can be isolated by conventional techniques such as crystallization or column chromatography. This method is particularly useful for preparing compounds of Formula I wherein R 5 is U-31.
  • Compounds of Formula I wherein R 5 is U-31 and R 22 is alkyl can be prepared by well known alkylation methods (using, for example, methyl iodide or ethyl bromide) from corresponding compounds wherein R 22 is H.
  • Compounds of Formula It can be prepared as shown in Scheme 40 by the general method described in Gen. Org. Chem. USSR 1959, 29, 2105. Scheme 40
  • a mixture of a compound of Formula 87, formamide and ammonium formate in a high boiling solvent e.g., xylene, toluene, dioxane, ethylene glycol
  • a high boiling solvent e.g., xylene, toluene, dioxane, ethylene glycol
  • the compound of Formula Iv can be isolated by conventional techniques such as crystallization or column chromatography. This method is particularly useful for preparing compounds of Formula I wherein R 5 is U-54.
  • Compounds of Formula Iw can be prepared as shown in Scheme 43 by the general method described in Helv. Chim. Acta 1966, 49, 2466. Scheme 43
  • a compound of Formula 90 is added to a solution of ammonia in a solvent (e.g., hexane, diethyl ether) at about -20 °C. After 2-12 hours the solvent is evaporated to leave the compound of Formula Iw, which can be purified by conventional techniques such as column chromatography and crystallization.
  • a solvent e.g., hexane, diethyl ether
  • This method is particularly useful for preparing compounds of Formula I wherein R 5 is U-34.
  • Compounds of Formula 90 can be prepared as shown in Scheme 44.
  • a compound of Formula 79 is reacted with sodium or sodium hydride in a solvent (e.g., diethyl ether, tetrahydrofuran) at 0 to 45 °C for 2-6 hours.
  • a solvent e.g., diethyl ether, tetrahydrofuran
  • the stirred mixture is then cooled to 0 °C, ethyl chloroformate is added, and the mixture is allowed to warm to room temperature.
  • Thionyl chloride is added, and the reaction mixture is stirred for an additional 6-24 hours.
  • the compound of Formula 91 is then isolated by conventional techniques such as extraction, column chromatography and crystallization. This procedure is a modification of one described in J. Chem. Soc. Perk. Trans. 1 2002, 3, 402. According to a general procedure described in Chem. Ber.
  • a zinc reagent of Formula 93 is reacted with an iodide of Formula 76 in the presence of a catalyst (e.g., ⁇ i(dppe)Cl 2 , tetrakis(triphenylphosphine)palladium(0)) in a solvent (e.g., tetrahydrofuran, N,N-dimethylformamide) at 25-100 °C for 2-25 hours.
  • a catalyst e.g., ⁇ i(dppe)Cl 2 , tetrakis(triphenylphosphine)palladium(0)
  • a solvent e.g., tetrahydrofuran, N,N-dimethylformamide
  • a boronic acid of Formula 94 is reacted with an iodide of Formula 76 in the presence of a catalyst (e.g., Ni(dppe)Cl 2 , tetrakis(triphenylphosphine)palladium(0)) in a solvent (e.g., tetrahydrofuran, N,N-dimethylformamide) at 25-110 °C for 2-25 hours.
  • a catalyst e.g., Ni(dppe)Cl 2 , tetrakis(triphenylphosphine)palladium(0)
  • a solvent e.g., tetrahydrofuran, N,N-dimethylformamide
  • trialkyltin derivatives can be used instead of boronic acid derivatives.
  • This method variation is illustrated by Example 11.
  • the reaction with the boronic acid derivative of Formula 94 can be conducted with precursor to the compound of Formula 76 before forming the carboxamide linkage.
  • This method variation is illustrated by Example 3.
  • Compounds of Formula Iaa can be prepared as shown in Scheme 48 by the general methods described by Lin and Lang, J. Org. Chem. 1980, 45, 4857. Scheme 48
  • R 2 lb is H, alkyl or haloalkyl.
  • a compound of Formula 79 is reacted with a compound of Formula 95 in a solvent (e.g., toluene, N,N-dimethylformamide, or an excess of the compound of Formula 95) at 25-140 °C for 4 to 24 hours.
  • the compound of Formula 96 can then be isolated by evaporating the solvent.
  • Reaction of the compound of Formula 96 with hydroxylamine hydrochloride in an inert solvent (e.g., ethanol, dioxane) at 25-100 °C for 2 to 24 hours then provides a compound of Formula Iaa, which can be isolated using conventional techniques. This method is particularly useful for preparing compounds of Formula I wherein R 5 is U-10.
  • R2 a is H, alkyl or haloalkyl.
  • a compound of Formula 61 is reacted with oxalyl chloride in the presence of a catalytic amount of N,N-dimethylformamide typically in solvent such as dichloromethane at room temperature for 2-24 hours. Evaporating the solvent leaves the acid chloride derived from the compound of Formula 61.
  • the acid chloride is then added to a solution of a compound of Formula 97 and a base (e.g., triethylamine, pyridine, N-methylmorpholine) in a solvent (e.g., dichloromethane, trichloromethane) at room temperature, and the reaction mixture is stirred for about 2-24 hours.
  • the compound of Formula lab can then be isolated by evaporating the solvent and triturating with water. This method is particularly useful for preparing compounds of Formula I wherein R 5 is U-18.
  • Compounds of Formula lac can be prepared as shown in Scheme 50 by the general methods described in J. Heterocyclic Chem. 1991, 28, 17. Scheme 50
  • R 21a is H, alkyl or haloalkyl.
  • a compound of Formula 61 is reacted with oxalyl chloride in the presence of a catalytic amount of N,N-dimethylformamide typically in solvent such as dichloromethane at room temperature for 2-24 hours. Evaporating the solvent leaves the acid chloride derived from the compound of Formula 61.
  • the acid chloride is then added to a solution of hydrazine in a solvent (e.g., dichloromethane, trichloromethane), and the reaction solution is stirred at room temperature for 2-4 hours.
  • the compound of Formula 98 is isolated by evaporating the solvent.
  • the compound of Formula 98 is then added to a stirred solution of a compound of Formula 99 and a base (e.g., triethylamine, pyridine, N-methylmorpholine) in a solvent (e.g., dichloromethane, trichloromethane, N,N-dimethylformamide) at room temperature, and the reaction mixture is stirred for about 2-24 hours.
  • a base e.g., triethylamine, pyridine, N-methylmorpholine
  • a solvent e.g., dichloromethane, trichloromethane, N,N-dimethylformamide
  • a compound of Formula 61 is reacted with oxalyl chloride in the presence of a catalytic amount of N,N-dimethylformamide typically in solvent such as dichloromethane at room temperature for 2-24 hours. Evaporating the solvent leaves the acid chloride derived from the compound of Formula 61.
  • the acid chloride is then reacted with thiosemicarbazide in the presence of a base (e.g., triethylamine, K 2 CO 3 , pyridine) according to general procedures of Indian J. Chemistry 1985, 24b, 1154 to provide the compound of Formula 100.
  • the compound of Formula 100 is then cyclized in polyphosphoric acid at 80—120 °C for 1-2 hours according to general procedures of /. Chem.
  • U 5 , U 6 , U 7 and U 8 are independently N or CH optionally substituted by R 2 ;
  • X 2 is Br or I; and
  • x is an integer ranging from 0 to the available carbon valency on the heterocycle.
  • a compound of Formula 54 and a compound of Formula 111 are dissolved in a solvent (e.g., water, dioxane, tetrahydrofuran, N,N-dimethylformamide), and a base (e.g., ⁇ a 2 CO 3 , K2CO 3 , triethylamine) is added, followed by a catalytic amount of a palladium derivative (e.g., tetrakis(triphenylphosphine)palladium(0), palladium(H) acetate).
  • a solvent e.g., water, dioxane, tetrahydrofuran, N,N-dimethylformamide
  • a base e.g., ⁇
  • the reaction mixture is heated at 100-150 °C for about 2-24 hours.
  • the compound of Formula 2d can be isolated by conventional techniques such as column chromatography. This method is particularly useful for preparing compounds of Formula I wherein R 5 is a heterocycle selected from U-44 to U-56. This method is illustrated by Step F of Example 1.
  • Compounds of Formula 54 are commercially available or can be prepared by known methods (see, for example, J. Fielding et al., /. Org. Chem. 1999, 64, 4196 and Matondo et al., Synthetic Comm. 2003, 33, 795).
  • Compounds of Formula 111 are also commercially available or can be prepared by known methods.
  • U 5 , U 6 , U 7 and U ⁇ are independently N or CH optionally substituted by R 21 ;
  • X 2 is Br or I;
  • X 3 is CI, Br or I; and
  • x is an integer ranging from 0 to the available carbon valency on the heterocycle.
  • a compound of Formula 112 is reacted with an organozinc compound of Formula 113 in the presence of a soluble palladium catalyst to provide a compound of Formula 114.
  • the nitro group of the compound of Formula 114 can then be reduced to provide the compound of Formula 2d by a variety of reducing agents known in the art, such as iron in acetic acid, tin(II) chloride or hydrogenation over palladium catalyst.
  • Organozinc compounds of Formula 113 can be prepared by reacting the corresponding organic halide compounds with n-butyllithium or an isopropylmagnesium halide to produce an organometallic intermediate, which is then treated with a zinc halide.
  • Compounds of Formula 2e can be prepared as shown in Scheme 54.
  • a compound of Formula 125 is prepared by treating a compound of Formula 124 with hydrogen chloride in ethanol. This general transformation is well known in the art; see, for example, Heterocycles 1979, 12, 745. The compound of Formula 125 is then treated with hydrazine to provide the compound of Formula 126 according to methods described in J. Heterocyclic Chem. 1982, 19, 1205. The compound of Formula 126 is then reacted with a compound of Formula 117 to provide a compound of Formula 128 according to a general method described in J. Medicinal Chem. 1977, 20, 723.
  • nitro group of the compound of Formula 128 can be then reduced to give the amino compound of Formula 2e using methods already described for reduction of the compound of Formula 114 to the compound of Formula 2d in Scheme 53. This method is particularly useful to prepare compounds of Formula I wherein R 5 is U-50.
  • Compounds of Formula 2f can be prepared as shown in Scheme 55.
  • a compound of Formula 129 is reacted with hydroxylamine hydrochoride in ethanol at 25-80 °C for 4-12 hours.
  • the compound of Formula 130 is isolated by pouring the reaction mixture into water, extracting with dichloromethane, and evaporating the solvent.
  • the nitro group of the compound of Formula 130 can be then reduced to give the amino compound of Formula 2f using methods already described for reduction of the compound of Formula 114 to the compound of Formula 2d in Scheme 53.
  • This method is particularly useful for preparing compounds of Formula I wherein R 5 is U-30.
  • Compounds of Formula 129 can be prepared by methods known in the art; see, for example, J. Org. Chem. 1979, 44, 3748 and /. Heterocyclic Chem. 1974, 11, 52.
  • Compounds of Formula 2g can be prepared as shown in Scheme 56.
  • a compound of Formula 131 is prepared from a compound of Formula 129 by treatment with thionyl chloride according to a general method of J. Heterocyclic Chem. 1974, 11, 52.
  • the compound of Formula 131 is then heated with ammonium thiocyanate in a solvent (e.g., acetone, methyl ethyl ketone) at a temperature of 50-100 °C for about 4—6 hours.
  • the compound of Formula 132 can be isolated by conventional methods such as washing with base, column chromatography and crystallization.
  • the nitro group of the compound of Formula 132 can be then reduced to give the amino compound of Formula 2g using methods already described for reduction of the compound of Formula 114 to the compound of Formula 2d in Scheme 53. This method is particularly useful for preparing compounds of Formula I wherein R 5 is U-29.
  • Compounds of Formula 2h can be prepared as shown in Scheme 57.
  • a compound of Formula 131 is reacted with a hydrazine of Formula 134 in ethanol at 25-80 °C for about 1-6 hours according to the general method of Heterocycles 1982, 19, 1223.
  • the compound of Formula 135 can be isolated by conventional techniques such as column chromatography and crystallization.
  • the nitro group of the compound of Formula 135 can be then reduced to give the amino compound of Formula 2h using methods already described for reduction of the compound of Formula 114 to the compound of Formula 2d in Scheme 53.
  • This method is particularly useful for preparing compounds of Formula I wherein R 5 is U-26.
  • Compounds of Formula Iae can be prepared as shown in Scheme 58 by the general procedures described in Synthesis 1983, 483. Scheme 58
  • R 21a is H, alkyl or haloalkyl.
  • a compound of Formula 74 is dissolved in a solvent such as toluene, and triethylamine is added.
  • the stirred reaction mixture is cooled to 0 °C, the acid chloride of Formula 141 is added, and the reaction mixture is allowed to warm and is held at room temperature for 24 hours.
  • the product of Formula 142 is isolated by conventional techniques and then is dissolved in a solvent (e.g., dichloromethane, trichloromethane, tetrachloromethane).
  • a hydrazine of Formula 134 is added, and the reaction mixture is stirred 1-2 hours at room temperature.
  • the compound of Formula Iae can be isolated by conventional techniques such as column chromatography and crystallization.
  • a compound of Formula 68 is reacted with an acetal of Formula 143 in the presence of sodium borohydride and 6 M sulfuric acid in a suitable solvent such as tetrahydrofuran at a temperature of about 5 °C.
  • a suitable solvent such as tetrahydrofuran at a temperature of about 5 °C.
  • sodium hydroxide is added to make the reaction mixture strongly basic, and then the reaction mixture is extracted with diethyl ether solvent. Evaporation of the solvent leaves the compound of Formula laf, which can be purified by techniques such as washing with dilute acid or aqueous copper(JJ) acetate, and column chromatography and crystallization.
  • This method is particularly useful for preparing compounds of Formula I wherein R 5 is U-70.
  • Compounds of Formula lag can be prepared as shown in Scheme 60 by the general procedures described by D. E. Davies et al., J. Chem. Soc. Perkin Trans. 1 1983, 1275-1281. Scheme 60
  • a compound of Formula 80 is treated with hydroxylamine or a hydroxylamine salt such as hydroxylamine hydrochloride or hydroxylamine sulfate in a suitable solvent such as methanol-water or ethanol-water mixtures.
  • the compound of Formula 144 is isolated by conventional techniques and then is reacted with an olefin of Formula 145 in the presence of a base such as sodium carbonate in a solvent such as dichloromethane.
  • the compound of Formula lag is isolated by conventional techniques such as column chromatography and crystallization. This method is particularly useful for preparing compounds of Formula I wherein R 5 is U-69.
  • Compounds of Formula lah can be prepared as shown in Scheme 61.
  • an amino compound of Formula 146 is diazotized using sodium nitrite and a mineral acid such as hydrochloric acid in a solvent such as water, and the reaction product is reduced using tin(II) chloride to provide the hydrazine of Formula 147.
  • the compound of Formula 147 is heated with 1,1,3,3-tetraethoxypropane in a suitable solvent such as ethanol to provide the compound of Formula lah, which can be isolated by evaporation of the solvent and purified by conventional techniques such as column chromatography and crystallization.
  • This method is particularly useful to prepare compounds of Formula I wherein R 5 is U-38. This method is illustrated by Example 14.
  • Step B Preparation of ethyl 5-(l,l-dimethylethyl)-lH-pyrazole-3-carboxylate To a solution of ethyl 2-hydroxy-5,5-dimethyl-4-oxo-2-hexenoate (i.e. the product of
  • Step A) (45.3 g, 226 mmol) in ethanol (200 mL) and acetic acid (2 mL) was added hydrazine monohydrate (12.1 mL, 249 mmol) dropwise under nitrogen atmosphere at room temperature. The reaction mixture was stirred at room temperature overnight and concentrated to give 40.8 g of the title compound.
  • l ⁇ ⁇ MR (CDC1 3 ) ⁇ 6.7 (s, 1 ⁇ ), 6.60 (br s, 1 ⁇ ), 4.40 (q, 2 ⁇ ), 1.40 (t, 3H), 1.32 (s, 9H).
  • Step C Preparation of ethyl 3-(l,l-dimethylethyl)-l-ethyl-lH-pyrazole-5-carboxylate
  • ethyl 5-(l,l-dimethylethyl)-lH- ⁇ yrazole-3-carboxylate i.e. the product of Step B
  • DMF N,N-dimethylformamide
  • Step D Preparation of 3-(l,l-dimethylethyl)-l-ethyl-lH-pyrazole-5-carboxylic acid
  • ⁇ ⁇ MR (CDC1 3 ) ⁇ 10.00 (s, 1 ⁇ ), 6.80 (s, 1 ⁇ ), 4.60 (q, 2 ⁇ ), 1.40 (t, 3H), 1.32 (s, 9H).
  • Step E Preparation of 3-(l,l-dimethylethyl)-l-ethyl-lH-pyrazole-5-carbonyl chloride
  • a solution of 3-(l,l-dimethylethyl)-l-ethyl-lH-pyrazole-5-carboxylic acid (i.e. the product of Step D) (1.2 g, 6.11 mmol) and oxalyl chloride (2 mL) in dichloromethane (30 mL) in the presence of anhydrous DMF (0.1 mL) was stirred under nitrogen atmosphere at room temperature for 4 h. The reaction mixture was then concentrated to yield the title acid chloride as a liquid.
  • Step F Preparation of 3-(2-pyridinyl)benzenamine
  • 2-bromopyridine 1.6 g, 10 mmol
  • dimethoxyethane 50 mL
  • water 17 mL
  • 3-amino ⁇ henylboronic acid hemisulfate 1.86 g, 10 mmol
  • sodium carbonate 5.6 g, 52.8 mmol
  • tetrakis(triphenylphosphine)palladium(0) 0.3 g.
  • Brine 50 mL
  • was added and the mixture was extracted with ethyl acetate (3 x 25 mL).
  • Step A Preparation of 2-(4-fluoro-3-nitrophenyl)pyridine
  • Bromo-2-pyridinylzinc (alternatively named 2-pyridylzi c bromide, Aldrich Chemical Co., 0.5 M in tetrahydrofuran, 20 mL, 10 mmol) was added to a suspension of 4-bromo- l-fluoro-2-nitrobenzene (2.2 g, 10 mmol), and tetrakis(triphe ylphosphine)palladium(0) in N,N-dimethylformamide (20 mL). The mixture was heated at 90 °C for 15 h and then cooled to room temperature.
  • Step B Preparation of 2-fluoro-5-(2-pyridinyl)benzenarrjLine To a mixture of iron powder (0.325 g, 6 mmol) and ammonium chloride (0.325 g, 6 mmol) in water (1.5 mL) was added a solution of 2-(4-fluoro-3-nitrophenyl)pyridine (i.e. the product of Step A) (0.6 g, 2.75 mmol) in dichloromethane (2.2 mL) and isopropanol (2.2 mL). The mixture was heated at reflux over 2 h to remove the dichloromethane and then allowed to cool to room temperature.
  • 2-(4-fluoro-3-nitrophenyl)pyridine i.e. the product of Step A
  • Step C Preparation of 3-(l,l-dimethylethyl)-l-ethyl-N-[2-fluoro-5-(2- ⁇ yridinyl)- henyl]-lH-pyrazole-5-carboxamide
  • 3-(l,l-dimethylethyl)-l-ethyl-lH-pyrazole-5-carboxylic acid i.e.
  • Step D the product of Example 1, Step D) (0.2 g, 1 mmol) in dichloromethane (2 mL) at room temperature was added sequentially 1-propane ⁇ hosphonic acid cyclic anhydride (50% in0 ethyl acetate, 0.5 g, 1.57 mmol) and 2-fluoro-5-(2-pyridinyl)benzenamine (i.e. the product of Step B) (0.2 g, 0.106 mmol).
  • Step D the >5 product of Example 1, Step D) (0.2 g, 1 mmol) in dichloromethane (2 mL) at room temperature was added sequentially 1-propanephosphonic acid cyclic anhydride (50% in ethyl acetate, 0.5 g, 1.57 mmol) and 2',6'-difluoro[l,l'-biphenyl]-3-amine (i.e. the product of Step A) (0.21 g, 0.102 mmol).
  • Step A Preparation of ethyl 5-ethyl-l,2,3-triazole-4-carboxylate
  • Ethyl 2-pentynoate (16.6 g, 0.132 mol) and trimethylsilylazide (38.0 g, 0.333 mol) were stirred at 100-110 °C under nitrogen for 70 h. After cooling and dilution with methanol (60 mL) a white solid precipitated. After evaporation of the mixture under reduced pressure, the residue was crystallized from ethyl ether to afford the title product as a white solid (15.7 g, 0.093 mol, 70% yield).
  • l ⁇ ⁇ MR (CDCI3) ⁇ 4.42 (q, 2 ⁇ ), 3.07 (q, 2H), 1.37 (t, 3H), 1.32 (t, 3H).
  • Step B Preparation of ethyl 2-(l,l-dimethylethyl)-5-ethyl-2H-l,2,3-triazole- 4-carboxylate and ethyl l-(l,l-dimethylethyl)-4-ethyl-lH-l,2,3-triazole- 5 -carboxylate
  • 5-ethyl-l,2,3-triazole-4-carboxylic acid ethyl ester i.e.
  • Step C Preparation of 2-(l,l-dimethylethyl)-5-ethyl-N-[3-(2-pyridinyl)phenyl]- 2H-l,2,3-triazole-4-carboxamide
  • ethyl 2-(l,l-dimethylethyl)-5-ethyl-2/ ⁇ -l,2,3-triazole- 4-carboxylate i.e.
  • Step A Preparation of 3-(l,l-dimethylethyl)-l-ethyl-lH-pyrazole-5-carbonyl chloride
  • a solution of 3-(l,l-dimethylethyl)-l-ethyl-lH-pyrazole-5-carboxylic acid (i.e., product of Example 1, Step D) (1.96 g, 10.0 mmol) in thionyl chloride C99%, ⁇ 5mL) was heated at reflux for about 6 h, and then allowed to cool to room temperature while being stirred overnight. The reaction mixture was then concentrated in vacuo.
  • Step B Preparation of N-(3-cyanophenyl)-3-(l,l-dimethylethyl)-l-ethyl- lH- ⁇ yrazole-5-carboxamide A solution of 3-(l,l-dimethylethyl)-l-ethyl-lH-pyrazole-5-carbonyl chloride (i.e.
  • Step A) the product of Step A) (0.49 g, 2.26 mmol) in tetrahydrofuran ( ⁇ 1 mL) was added dropwise to a stirred solution of 3-aminobenzonitrile (99%, 0.3 g, 2.51 mmol), triethylamine, (1.39 mL, 10.04 mmol) and 4-(dimethylamino)pyridine (catalytic amount) in tetrahydrofuran ( ⁇ 5 mL) at room temperature to afford a yellow solution containing white, suspended solid.
  • 3-aminobenzonitrile 99%, 0.3 g, 2.51 mmol
  • triethylamine (1.39 mL, 10.04 mmol
  • 4-(dimethylamino)pyridine catalytic amount
  • the reaction mixture was allowed to stir at room temperature overnight and then was poured into a Chem-Elute drying tube (Analytichem International, Harbor City, CA, U.S.A.) and eluted with ethyl acetate.
  • the eluted solution was concentrated in vacuo, and the residue was purified with flash chromatography using 25% ethyl acetate/hexane as eluant to provide the title compound as a white solid (0.41g, 55% yield).
  • Step C Preparation of 3-(l,l-dimethylethyl)-l-ethyl-N-[3-[(hydroxyamino)- iminomethyl]phenyl]-lH-pyrazole-5-carboxamide A mixture of N-(3-cyanophenyl)-3-(l,l-dimethylethyl)-l-ethyl-lH-pyrazole-
  • Step D Preparation of 3-(l,l-dimethylethyl)-l-ethyl-N-[3-(5-methyl-l,2,4-oxadiazol- 3-yl)phenyl]-lH-pyrazole-5-carboxamide
  • Step A Preparation of N-(3-acetylphenyl)-3-(l,l-dimethylethyl)-l-ethyl- lH-pyrazole-5-carboxamide
  • a solution of 3-(l,l-dimethylethyl)-l-ethyl-lH-pyrazole-5-carboxylic acid (i.e. the product of Example 1, Step D) (0.5 g, 2.54 mmol) in thionyl chloride (6 mL) was heated at reflux under ⁇ 2 atmosphere for 5 h. The reaction mixture was concentrated under vacuum and then taken up in dichloromethane and concentrated again to provide the corresponding acid chloride as an oil.
  • Triethylamine (533 ⁇ L, 3.82 mmol) was added to a solution of l-(3-aminophenyl)ethanone (alternatively named 3'-aminoacetophenone, 361 mg, 2.67 mmol) in dichloromethane (6 mL) cooled to 0 °C under a N 2 atmosphere.
  • dichloromethane 6 mL
  • a solution of the acid chloride in dichloromethane (2 mL) was added dropwise using an addition funnel. The reaction mixture was then allowed to stir at room temperature overnight, after which time it was diluted with dichloromethane and water.
  • Step B Preparation of N-[3-[[(2E)-3-(dimethylamino)-l-oxo-2-propenyl]phenyl]- 3-(l,l-dimethylethyl)-l-ethyl-lH-pyrazole-5-carboxamide A solution of N-(3-acetylphenyl)-3-(l,l-dimethylethyl)-l-ethyl-lH-pyrazole-
  • Step C Preparation of 3-(l,l-dimethylethyl)-l-ethyl-N-[3-(5-isoxazolyl)phenyl]- 1 H-pyrazole-5-c arboxamide
  • N-[3-[[(2E)-3-(dimethylamino)-l-oxo-2-propenyl]phenyl]-3-(l,l- dimethylethyl)-l-ethyl-lH-pyrazole-5-carboxamide i.e.
  • the product was purified by flash column chromatography using a Supelco (division of Sigma-Aldrich Co., 595 North Harrison Road, Bellefonte, PA 16823, U.S.A.) DSC-Si SPE Tube prepacked with 5 g of silica gel (50 ⁇ m particle diameter, 70 A pore size) and as eluant 10% ethyl acetate / hexanes, then 20% ethyl acetate / hexanes and finally 40% ethyl acetate / hexanes to obtain fractions containing the desired product. The fractions were concentrated to leave an oil (3O0 mg), which was triturated with hexanes to form a solid. The solid was collected using filtration, providing the title product, a compound of the present invention, as a solid (228 mg) melting at 115-116 °C.
  • Step A Preparation of ethyl l-(l,l-dimethylethyl)-3-ethyl-lH-pyrazole-4-carboxylate and ethyl l-(l,l-dimethylethyl)-4-ethyl-lH-pyrazole-3-carboxylate
  • Ethyl 2-pentynoate (5.32 g, 42.2 mmol) was added to a solution of 3-(l,l- dimethylethyl)sydnone (6 g, 42.2 mmol) in xylenes (75 mL) under a nitrogen atmosphere.
  • the reaction mixture was heated to reflux for three days and cooled to room temperature.
  • Step B Preparation of l-(l,l-dimethylethyl)-3-ethyl-lH-pyrazole-4-carboxylic acid
  • Step D was used to convert ethyl l-(l,l-dimethylethyl)-3-ethyl-lH-pyrazole-4-carboxylate (i.e. the major isomer product of Step A) (1.76 g, 7.76 mmol) to the title acid (1.08 g).
  • l ⁇ ⁇ MR (CDCI3) ⁇ 8.0 (s, 1 ⁇ ), 2.9 (q, 2 ⁇ ), 1.58 (s, 9H), 1.26 (t, 3H).
  • Step C Preparation of N-(3-acetylphenyl)-l-(l,l-dimethylethyl)-3-ethyl- lH-pyrazole-4-carboxamide
  • a procedure analogous to that of Step A of Example 6 was used to prepare the acid chloride from l-(l,l-dimethylethyl)-3-ethyl-lH-pyrazole-4-carboxylic acid (i.e.
  • Step B the product of Step B) (0.5 g, 2.54 mmol) using thionyl chloride (6 mL) and then react the acid chloride with l-(3-aminophenyl)ethanone (361 mg, 2.67 mmol) in the presence of triethylamine (533 ⁇ L, 3.82 mmol) to provide the title compound as a solid (0.72 g). l ⁇ .
  • Step E Preparation of l-(l,l-dimethylethyl)-3-ethyl-N-[3-(5-isoxazolyl)phenyl]- lH- ⁇ yrazole-4-carboxamide
  • N-[3-[(2E)-3-(dimethylamino)-l-oxo-2-propenyl]phenyl]-l-(l,l- dimethylethyl)-3-ethyl-lH-pyrazole-4-carboxamide i.e.
  • the product was purified by flash column chromatography using a Supelco DSC-Si SPE Tube prepacked with 5 g of silica gel and as eluant 10% ethyl acetate / hexanes, then 20% ethyl acetate / hexanes and finally 40% ethyl acetate / hexanes to obtain fractions containing the desired product.
  • the fractions were concentrated to leave an oil, which was triturated with hexanes to form a solid.
  • the solid was collected using filtration, providing the title product, a compound of the present invention, as a solid (234 mg) melting at 154-155 °C.
  • Example 6 Step B) in acetic acid (3 mL) under ⁇ 2 atmosphere was cooled to 0 °C, and hydrazine hydrate (0.04 g, 1.25 mmol) was added. The reaction mixture was allowed to slowly warm to room temperature and was then concentrated to provide an oil. The oil was triturated with water to precipitate a solid, which was collected with filtration and rinsed with hexanes to provide the crude product (374 mg).
  • the product was purified by flash column chromatography using a 5-gram pre-packed SPE column and as eluant 10% ethyl acetate / hexanes, then 20% ethyl acetate / hexanes and finally 40% ethyl acetate / hexanes to obtain fractions containing the desired product.
  • the fractions were concentrated to leave a solid, which was rinsed with hexanes and collected to provide the title product, a compound of the present invention, as a solid (174 mg) melting at 185-187 °C.
  • Step A Preparation of N-(6-bromo-2-pyridinyl)-3-(l,l-dimethylethyl)-l-ethyl- lH-pyrazole-5-carboxamide To a solution of 3-(l,l-dimethylethyl)-l-ethyl-lH-pyrazole-5-carboxylic acid (i.e.
  • Step B Preparation of 3-(l,l-dimethylethyl)-l-ethyl-N-[6-(lH-pyrazol-l-yl)- 2-pyridinyl]-lH-pyrazole-5-carboxamide
  • N-(6-bromo-2-pyridinyl)-3-(l,l-dimethylethyl)-l-ethyl-lH-pyrazole- 5-carboxamide i.e. the product of Step B
  • N,N-dimethylformamide 5 mL
  • reaction mixture was then heated at 110 °C with stirring for 12 h. After cooling to room temperature the reaction mixture was diluted with dichloromethane (20 mL) and washed with hydrochloric acid (1 ⁇ ). The organic phase was separated, dried and concentrated. The residue was purified by chromatography on silica gel to give the title product, a compound of the present invention, as a colorless solid (0.11 g).
  • Step A Preparation of N-(3-iodophenyl)-3-oxopentanamide Three solutions of 3-iodobenzenamine (1.03 g, 2.06 g, and 1.70 g respectively) in methyl 3-oxopentanoate (alternatively named methyl propionylacetate; 1.82 g, 3.66 g, and
  • Step B Preparation of l-(l,l-dimethylethyl)-3-ethyl-4,5-dihydro-N-(3-iodophenyl)- lH-pyrazole-4-carboxamide
  • N-(3-iodophenyl)-3-oxopentanamide i.e. the product of Step A
  • aqueous formaldehyde 37%, 1.47 g
  • sodium acetate (1.70 g
  • the reaction mixture was diluted with ethyl acetate (100 mL), washed with saturated brine (2x), and dried (MgSO ⁇ . The solvent was removed in vacuo to leave a crude solid product.
  • the crude product was purified by column chromatography using ethyl acetate-hexane as eluant to provide the title compound as a glassy solid (1.46 g).
  • Step C Preparation of l-(l,l-dimethylethyl)-3-ethyl-4,5-dihydro-N-[3-(2-pyridinyl)- phenyl]-lH-pyrazole-4-carboxamide
  • a solution of l-(l,l-dimethylethyl)-3-ethyl-4,5-dihydro-N-(3-iodophenyl)-lH- pyrazole-4-carboxamide i.e.
  • Step B) the product of Step B) (0.92 g, 2.30 mmol), 2-(tributylstannyl)- pyridine (0.96 g) and dichlorobis(triphenylphosphine)palladium (85 mg) in tetrahydrofuran (T ⁇ F, dry, 20 mL) was heated at reflux for 24 h. Tetrakis(triphenylphosphine)palladium (132 mg) was added, and the reaction mixture was heated at reflux for 24 h more. Then the reaction mixture was cooled to room temperature, and a solution of 2-pyridylzinc bromide (0.5 M in T ⁇ F, 3.8 mL) was added.
  • Step B Preparation of l-(l,l-dimethylethyl)-3-ethyl-N-[3-(2-pyridinyl)phenyl]- lH-pyrazole-4-carboxamideO
  • a solution of l-(l,l-dimethylethyl)-3-ethyl-N-(3-iodophenyl)-lH-pyrazole- 4-carboxamide i.e.
  • Step A) the product of Step A) (0.25 g, 0.63 mmol), tetrakis(triphenyl- phosphine)palladium (72 mg) and 2-pyridylzinc bromide (0.5 M in T ⁇ F, 1.32 mL) in dry tetrahydrofuran (dry, 5 mL) was stirred at room temperature for 24 h. Then additional 2-pyridylzinc bromide solution (1.32 mL) and tetrakis(triphenylphosphine)palladium5 (72 mg) were added.
  • the aqueous solution was extracted with ethyl acetate (3 x 100 mL), and the combined ethyl acetate extracts were dried and concentrated to leave a crude oil, which was purified by column chromatography using ethyl acetate-hexane as eluant to provide the title product, a compound of the present invention, as a white powder5 (50 mg).
  • Step A Preparation of ethyl 4-fluoro-3-nitrobenzoate
  • 4-fluoro-3-nitrobenzoic acid 10 g, 54 mmol
  • diethyl sulfate 8 mL
  • potassium carbonate 10 g
  • anhydrous acetone 120 mL
  • the reaction mixture was then filtered, and the filtrate was concentrated.
  • the residue was purified by chromatography on silica gel to give the title compound (11.2 g) as a yellow oil.
  • l ⁇ ⁇ MR (CDC1 3 ) ⁇ 8.64 (dd, 1 ⁇ ), 8.32 (m, 1 ⁇ ), 7.38 (t, 1 ⁇ ), 4.44 (q, 2 ⁇ ), 1.40 (t, 3H).
  • Step B Preparation of ethyl 3-amino-4-fluorobenzoate
  • acetic acid 50 mL
  • ethyl acetate 60 mL
  • iron powder 6.0 g
  • acetic acid 5% wt, 30 mL
  • the reaction mixture was stirred at 80 °C for an additional 20 minutes.
  • the mixture was then cooled to room temperature. Solids were removed by filtration through Celite® diatomaceous filter aid, and the filtrate was concentrated.
  • Step C Preparation of ethyl 3-[[[3-(l,l-dimethylethyl)-l-ethyl-lH- ⁇ yrazol-5-yl]- carbonyl] amino-4-fluorobenzoate
  • 3-(l,l-dimethylethyl)-l-ethyl-lH-pyrazole-5-carbonyl chloride i.e. the product of Example 1, Step E
  • dichloromethane 40 mL
  • Step D Preparation of 3-[[[3-(l,l-dimethylethyl)-l-ethyl-lH-pyrazol-5-yl]carbonyl]- amino ⁇ -4-fluorobenzoic acid
  • Step E Preparation of N-[5-(4,5-dihydro-2-oxazolyl)-2-fluorophenyl]-3-(l,l- dimethylethyl)-l-ethyl-lH-pyrazole-5-carboxamide
  • Step A Preparation of N-(5-amino-2-fluorophenyl)-3-(l,l-dimethylethyl)-l-ethyl- lH-pyrazole-5-carboxamide
  • 2-fluoro-3-nitrobenzenamine alternatively named 2-fluoro- 3-nitroaniline; 1.0 g, 6.4 mmol
  • pyridine 1.5 mL
  • dichloromethane 200 mL
  • Step B Preparation of 3-(l,l-dimethylethyl)-l-ethyl-N-(2-fluoro-5-hydrazinophenyl)- lH-pyrazole-5-carboxamide monohydrochloride To an ice-cold solution of N-(5-amino-2-fluorophenyl)-3-(l,l-dimethylethyl)-l-ethyl- lH-pyrazole-5-carboxamide (i.e.
  • Step A) the product of Step A) (1.96 g, 6.44 mmol) in concentrated hydrochloric acid (5 mL) combined with ice (5 g) was added over 10 minutes a solution of sodium nitrite (469 mg) in water (1.75 mL). After stirring for 15 minutes, the reaction solution was added over 2-3 minutes to a solution of tin(fl) chloride (3.3 g) in concentrated hydrochloric acid (3.5 mL) chilled using an ice bath. After stirring for 15 minutes the reaction solution was added to a solution prepared from 1 ⁇ aqueous sodium hydroxide
  • Step C Preparation of 3-(l,l-dimethylethyl)-l-ethyl-N-[2-fluoro-5-(lH-pyrazol- l-yl)phenyl]-lH-pyrazole-5-carboxamide
  • Two solutions of 3-(l,l-dimethylethyl)-l-ethyl-N-(2-fluoro-5-hydrazinophenyl)- lH-pyrazole-5-carboxamide monohydrochloride i.e.
  • Step B the product of Step B (0.10 g and 0.50 g, respectively) and 1,1,3,3-tetraethoxypropane (69 mg and 339 mg, respectively) in ethanol (0.5 mL and 2.0 mL, respectively) were prepared. Each solution was heated at 120 °C for 10 minutes using a microwave reactor. The two solutions were then combined and concentrated in vacuo to leave a crude product. The crude product was purified by column chromatography using ethyl acetate-hexane as eluant to provide the title product, a compound of the present invention, as a solid (270 mg).
  • R la is Et; R 2a is tert-Bu; T, U, Y and Z are CH; R 5 is U-6; R 21 are substituents on U-6.
  • R la is Et; R 2a is tert-Bu; T, U, Y and Z are CH; R 5 is U-7; R 2 1 are substituents on U-7.
  • R la is Et; R 2a is tert-Bu; T, U, Y and Z are CH; R 5 is U-10; R 21 are substituents on U-10.
  • R la is Et; R 2a is tert-Bu; T, U, Y and Z are CH; R 5 is U-11 ; R 2i and R 22 are substituents on U-11; R 22 is H.
  • Rla is Et; R 2a is tert-Bu; T, U, Y and Z are CH; R 5 is U-14; R 2 l a is a substituent on U-14.
  • R ia is Et; R 2a is tert-Bu; T, U, Y and Z are CH; R 5 is U-15; R 21a is a substituent on U-15.
  • R ia is Et; R 2a is tert-Bu; T, U, Y and Z are CH; R 5 is U-18; R 21a is a substituent on U-18.
  • R 2 la R21a R 21a g21a R 21a H 0CH 2 CH 3 CHF 2 SCH 3 S(0) 2 CH 3 CI CH 2 C1 OCH 2 F SCH 2 CH 3 SCHF 2 F CH 2 F OCHF 2 S(0)CH 3 SCF 3
  • R ia is Et; R 2a is tert-Bu; T, U, Y and Z are CH; R 5 is U-19; R 21a is a substituent on U-19.
  • Rla is Et; R 2a is tert-Bu; T, U, Y and Z are CH; R 5 is U-23; R 2 1 are substituents on U-23 R 21 R 21 R 21 R 21 R 21 R 21 R21 5-CF3 5-CH 2 CH 3 5-OCH 2 CH 3 5-CHF 2 5-SCH 3 4-S(0) 2 CH 3
  • Rla is Et; R 2a is tert-Bu; T, U, Y and Z are CH; R 5 is U-25; R 21 and R 22 are substituents on U-25; R 22 is H.
  • R la is Et; R 2a is tert-Bu; T, U, Y and Z are CH; R 5 is U-27; R 2 1 are substituents on U-27.
  • R la is Et; R 2a is tert-Bu; T, U, Y and Z are CH; R 5 is U-31; R 21 and R 22 are substituents on U-31; R 22 is H.
  • R la is Et; R 2a is tert-Bu; T, U, Y and Z are CH; R 5 is U-32; R 2ia is a substituent on U-32.
  • R la is Et; R 2a is tert-Bu; T, U, Y and Z are CH; R 5 is U-33; R 21a is a substituent on U-33.
  • R la is Et; R 2a is tert-Bu; T, U, Y and Z are CH; R 5 is U-34; R 21 are substituents on U-34.
  • R la is Et; R 2a is tert-Bu; T, U, Y and Z are CH; R 5 is U-35; R 21a is a substituent on U-35.
  • R ia is Et; R 2a is tert-Bu; T, U, Y and Z are CH; R 5 is U-36; R 22 is H; R 2 l a and R 22 are substituents on U-36.
  • R la is Et; R 2a is tert-Bu; T, U, Y and Z are CH; R 5 is U-36; R 22 is CH3; R 2ia and R 22 are substituents on U-36.
  • R ia is Et; R 2a is tert-Bu; T, U, Y and Z are CH; R 5 is U-36; R 22 is CH 2 CH 3 ; R 2ia and R 22 are substituents on U-36.
  • R ia is Et; R 2a is tert-Bu; T, U, Y and Z are CH; R 5 is U-37; R 2i are substituents on U-37.
  • R ia is Et: ; R 2a is tert-Bu; T, U, Y and Z are CH; R 5 is U-38; R 21 are substituents on U-38 R 21 R 21 R 21 R 21 R 21 R21 5-CF3 5-CH 2 CH 3 5-OCH 2 CH 3 5-CHF 2 5-SCH3 4-S(0) 2 CH 3
  • R la is Et; R 2a is tert-Bu; T, U, Y and Z are CH; R 5 is U-40; R 21 are substituents on U-40.
  • Rla is Et; R 2a is tert-Bu; T, U, Y and Z are CH; R 5 is U-41; R 2i are substituents on U-41 R 21 R 21 R 21 R 21 R 21 E 2 ! 5-CF3 5-CH 2 CH 3 5-OCH 2 CH 3 5-CHF 2 5-SCH3 5-S(0) 2 CH 3
  • Rl a is Et: R 2a is tert-Bu; T, U, Y and Z are CH; R 5 is U-44; R 2i are substituents on U-44, R 21 R 21 R21 R 21 R 21 R21 6-CF3 6-CH 2 CH 3 6-OCH 2 CH 3 6-CHF 2 5-SCH 3 4-S(0) 2 CH 3
  • R la is Et; R 2a is tert-Bu; T, U, Y and Z are CH; R 5 is U-46; R 21 are substituents on U-46. 21 R21 R21 R21 R21 R 1 R21 6-CF 3 6-CH3 4-OCH3 4-CHF 2 4-SCH3 6-S(0) 2 CH 3
  • R is Et; R 2a is tert-Bu; T, U, Y and Z are CH; R 5 is U-48; R 21 are substituents on U-48.
  • R21 R21 R 1 R21 R21 R21 R21 2-CF 3 2-CH 2 CH 3 4-OCH3 2-CHF 2 4-SCH3 2-S(0) 2 CH 3
  • R la is Et; R 2a is tert-Bu T, U, Y and Z are CH; R 5 is U-50 R 21 are substituents on U-50.
  • R a is Et
  • 2a is tert-Bu T
  • U Y and Z are CH
  • R 5 is U-51
  • R 21 are substituents on U-51.
  • Rl a is Et; R 2a is tert-Bu; T, U, Y and Z are CH; R 5 is U-52; R 21 are substituents on U-52 R 21 R 21 R 21 R 21 R 21 5-CF 3 6-CH 3 5-OCH 3 6-CHF 2 5-SCH 3 6-S(0) 2 CH 3
  • R la is Et; R 2a is tert-Bu; T, U Y and Z are CH; R 5 is U-53 R 21 are substituents on U-53.
  • R ia is Et
  • R 2a is tert-Bu
  • T, U, Y and Z are CH
  • R 5 is U-54
  • R 21 are substituents on U-54.
  • R la is Et; R 2a is tert-Bu; T, U, Y and Z are CH; R 5 is U-55; R 21 are substituents on U-55.
  • R la is Et; R 2a is tert-Bu T U Y and Z are CH; R 5 is U-56; R 21 are substituents on U-56.
  • R la is Et; R 2a is tert-Bu; T, U, Y and Z are CH; R 5 is U-57; R 24 are substituents on U-57.
  • R ia is Et; R 2a is tert-Bu; T, U, Y and Z are CH; R 5 is U-58; R 24 are substituents on U-58.
  • R2 R2 R24 4-CH 2 CH 3 4-CH 2 CH 3 , 5-CH 2 CH 3 4-CH3 5-CH 2 CH 3 4-CH3, 5-CH 2 CH 3 5-CH 3 4-CH3, 5-CH3 4-CH 2 CH 3 , 5-CH3
  • R la is Et; R 2a is tert-Bu; T, U, Y and Z are CH; R 5 is U-59; R 24 are substituents on U-59.
  • R 24 R24 4-CH 2 CH 3 4-CH 2 CH 3 , 5-CH 2 CH 3 4-CH3 5-CH 2 CH 3 4-CH3, 5-CH 2 CH 3 5-CH3 4-CH3, 5-CH3 4-CH 2 CH 3 , 5-CH3
  • Rla is Et; R 2a is tert-Bu; T, U, Y and Z are CH; R 5 is U-61; R 24 are substituents on U-61.
  • R24 R24 R24 R24 5-CH 3 5-CH 2 CH 3 2-CH3, 4-CH 2 CH 3 2-CH 3 2-CH 2 CH 3 2-CH3, 4-CH3 4-CH 3 , 5-CH 2 CH 3 4-CH 3 4-CH 2 CH 3 4-CH3, 5-CH3 4-CH 2 CH 3 , 5-CH 3 R ia is Et; R 2a is tert-Bu; T, U, Y and Z are CH; R 5 is U-63; R 24 are substituents on U-63.
  • Rla is Et; R 2a is tert-Bu; T, U, Y and Z are CH; R 5 is U-66; R 24 are substituents on U-66.
  • Rl a is Et; R 2a is tert-B ⁇ 1; T, U, Y and Z are CH; R 5 is U-67; R 24 are substituents on U-67.
  • R is Et R 2a is z-Pr T U Y and Z are CH; R 5 is U-44 R 21 are substituents on U-44.
  • Rla is Et R 2a is tert-Bu; U is CF; T, Y and Z are CH; R 5 i ⁇ U-7; ] R 2 l are substituents on U-7.
  • Rla is Et R 2a is tert-Bu; U is CF; T, Y and Z are CH; R 5 is U-32; R 2ia is a substituent on U-32.
  • R l is Et ;
  • R 2a is tert-Bu;
  • U is CF;
  • T, Y and Z are CH;
  • R 5 is U-38;
  • R 21 are substituents on U-38.
  • R ia is Et ;
  • R 2a is tert-Bu;
  • U is CF;
  • T, Y and Z are CH;
  • R 5 is U-41;
  • R 2i ai e substituents on U-41.
  • R la is E t; R 2a is tert-Bi ⁇ ; U is CF; T, Y a nd Z are CH; R 5 i s U-58; R 24 ai re substituents on U-58.
  • Rla is Et ; R 2a is tert-Bu ; T is N; U, Y and Z are CH; R 5 is J-7; R 2 1 are substituents on U-7.
  • R la is Et; R 2a is tert-Bu; T is N; U, Y and Z are CH; R 5 is U-38; R 2i are substituents on U-38 R 21 R 21 R 21 R 21 R21 R21 5-CF3 5-CH 2 CH 3 5-OCH 2 CH 3 5-CHF 2 5-SCH 3 4-S(0) 2 CHl3
  • R la is Et; R 2 a is tert-Bu; T is N; U, Y and Z are CH; R 5 is U-41; R 2 1 are substituents on U-41.
  • R21 R21 R21 R21 Ell E i R21 5-CF3 5-CH 2 CH 3 5-OCH 2 CH 3 5-CHF 2 5-SCH3 5-S(0) 2 CH 3
  • Rla is Et; R 2a is tert-Bu; T is N; U, Y and Z are CH; R 5 is U-44; R 21 are substituents on U-44.
  • R 1 R 2- 1 R21 R 1 IR21 R21 R 21 6-CF3 6-CH 2 CH 3 6-OCH 2 CH 3 6-CHF 2 5-SCH3 4-S(0) 2 CH 3
  • R la is Et; R 2a is tert-Bu; Y is N; T, U and Z are CH; R 5 is U-44; R 2 are substituents on U-44.
  • R la is Et; R 2a is tert-Bu; T, U, Y and Z are CH; R21 a is H; R 22 i s H; R 23 is CH 3 ; R 25 is H; g, j, k, m, n and p are 0.
  • R ° is Et; R 2b is t-Bu; T, U, Y and Z are CH; R 5 is U-44; R 2 1 are substituents on U-44.
  • R21 R21 R21 g21 Eli g21 g21 6-CH 2 CF 3 6-CH3 6-CH 2 CH 3 6-OCF3 6-OCHF 2 6-S(0) 2 CH 3
  • R lb is Et; R 2b is tert-Bu; T, U, Y and Z are CH; R 21a is H; R 22 is H; R 23 is CH 3 ; R 25 is EC; g, j, k, m, n and are 0.
  • Rl b is Et; R 2 is tert-Bu; T, U, Y and Z are CH; R 5 is U-7; R 21 are substituents on U-7.
  • R21 5-S(0) 2 CH 3 4-SCHF 2 5-SCHF 4-SCF3 5-SCF3
  • R lb is Et; R 2b is tert-Bu; T, U, Y and Z are CH; R 5 is U-23; R 2 1 are substituents on U-23.
  • Rlb is Et; R 2b is tert-Bu; T, U, Y and Z are CH; R 5 is U-32; R 21a is a substituent on U-32.
  • R lb is Et; R 2b is tert-Bu; T, U, Y and Z are CH; R 5 is U-41; R 2i are substituents on U-41.
  • Rlb is Et; R 2b is tert-Bu; T, U, Y and Z are CH; R 5 is U-44; R 2 1 are substituents on U-44.
  • R 1 R21 R21 R21 R21 R21 R21 R21 6-CF3 6-CH 2 CH 3 6-OCH 2 CH 3 6-CHF 2 5-SCH 3 4-S(0) 2 CH 3
  • R lb is Et; R 2b is tert-Bu; T, U, Y and Z are CH; R 5 is U-44; R 2i are substituents on U-44.
  • R lb is Et; R 2 bis tert-Bu; T, U, Y and Z are CH; R 5 is U-47; R 21 are substituents on U-47.
  • Rlb is Et; R 2b is tert-Bu; T, U, Y and Z are CH; R 5 is U-58; R 24 are substituents on U-58.
  • R 24 R24 R24 4-CH 2 CH 3 4-CH 2 CH 3 , 5-CH 2 CH 3
  • Rlb is Et; R 2b is tert-Bu; T, U, Y and Z are CH; R 2ia is H; R 22 is H; R 23 is CH 3 ; R 25 is H; g, j, k, m, n and are 0.
  • R lb is Et; R 2a is t-Bu; T, U, Y and Z are CH; R 5 is U-44; R 2 1 are substituents on U-44.
  • Rlb is Et; R 2a is tert-Bu; T, U, Y and Z are CH; R 2ia is H; R 22 is H; R 23 is CH3; R 25 is H; g, j, k, m, n and are 0.
  • R 2 1 are substituents on U-7.
  • R la is Et; R 2a is tert-Bu T U Y and Z are CH R 5 is U-32; R 2ia is a substituent on U-32.
  • Rla is Et; R 2a is tert-Bu; T, U, Y and Z are CH; R 5 is U-38; R 21 are substituents on U-38.
  • R lb is Et; R 2b is tert-Bu; T, U, Y and Z are CH; R 21a is H; R 22 is H; R 23 is CH3; R 25 is H; g, j, k, m, n and are 0.
  • Rlb is Et; R 2 b is tert-Bu; T, U, Y and Z are CH; R21 is H; R 22 is H; R 23 is CH3 ; R 25 is H; g, j, k, m, n and are 0.
  • Rlb is Et ; R 2b is t-Bu; T, U, Y and Z are CH; R 5 is U-44; R 2i are substituents on U-44.
  • Rlb is Et; R 2 J s tert-Bu; T, U, Y and Z are CH; R 21a is H; R 22 is H; R 23 is CH 3 ; R 25 is H; g, j, k, m, n and are 0.
  • Rlb is Me; R 2b is tert-Bu; T, U, Y and Z are CH; R ⁇ is U-1; R 2 1 are substituents on U-1.
  • Rlb is Me R 2 b i s tert-Bu T U Y and Z are CH R 5 is U-6 R 21 are substituents on U-6.
  • R lb is Me; R 2b is tert-Bu; T, U, Y and Z are CH; R 5 is U-7; R 21 are substituents on U-7.
  • R21 R21 R21 R21 R 21 R21 R21 5-CF3 5-CH 2 CH 3 5-OCH 2 CH 3 5-CHF 2 5-SCH3 5-S(0) 2 CH 3 4-C1 4-CH 2 CF 3 4-CN 4-OCF3 4-OCH 2 F 4-SCH 2 CH 3 4-SCHF 2 5-Cl 5-CH 2 CF 3 5-CN 5-OCF3 5-OCH 2 F 5-SCH 2 CH 3 5-SCHF 2 4-F 4-CH3 4-OCH3 4-CH 2 F 4-OCHF 2 4-S(0)CH 3 4-SCF3 5-F 5-CH3 5-OCH3 5-CH 2 F 5-OCHF 2 5-S(0)CH 3 5-SCF3 4-CF3 4-CH 2 CH 3 4-OCH 2 CH 3 4-CHF 2 4-SCH3 4-S(0) 2 CH 3
  • Rlb is Me; R 2b is tert-Bu; T, U, Y and Z are CH; R 5 is U-10; R 21 are substituents on U-10.
  • R 21 R21 R21 R21 R21 g21 4-CH 2 CF 3 4-CH 2 CH 3 4-CH 2 Cl 4-SCH 3 4-SCHF 2 3-Cl 3-CH 3 3-CN 3-CH 2 F 3-SCH 2 CH 3 3-SCF 3 4-F 4-CH 3 4-OCH 3 4-CHF 2 4-S(0)CH 3 3-CF 3 3-CH 2 CH 3 3-OCH 2 CH 3 3-OCHF 2 3-S(0) 2 CH 3
  • Rl is Me; R 2b is tert-Bu; T, U, Y and Z are CH; R 5 is U-l l; R 2 1 and R 22 are substituents on U-11 ; R 22 is H R 21 R21 R 21 R 21 R21 R21 - 4-CH 2 CF 3 4-CH 2 CH 3 4-CH 2 Cl 4-SCH3 4-SC 3-Cl 3-CH3 3-CN 3-CH 2 F 3-SCH 2 CH 3 3-SC 4-F 4-CH3 4-OCH3 4-CHF 2 4-S(0)CH 3 3-CF3 3-CH 2 CH 3 3-OCH 2 CH 3 3-OCHF 2 3-S(0) 2 CH 3 94
  • Rlb is Me; R 2b is tert-Bu; T, U, Y and Z are CH; R 5 is U-14; R 2 ia is a substituent on U-14.
  • Rlb is Me; R 2b i s tert-Bu; T, U, Y and Z are CH; R 5 is U-15; R 21a is a substituent on U-15.
  • Rlb is Me; R 2 b i s tert-Bu; T, U, Y and Z are CH; R 5 is U-18; R 2 l a is a substituent on U-18.
  • R lb is Me; R 2b is tert-Bu; T, U, Y and Z are CH; R 5 is U-19; R 2i a is a substituent on U-19.
  • Rlb is Me; R 2b is tert-Bu; T, U, Y and Z are CH; R 5 is U- 23; R are substituents on U-23
  • R lb is Me; R 2b is tert-Bu; T, U, Y and Z are CH; R 5 is U-25; R 2i and R 22 are substituents on U-25; R 22 is H.
  • R21 R 1 R21 R21 R21 R21 R21 R21 R 21 5-CF 3 4-CH 2 CH 3 5-OCH 3 4-CHF 2 5-SCH 3 4-S(0) 2 CH 3
  • Rlb is Me; R 2b is tert-Bu; T, U, Y and Z are CH; R 5 is U-27; R 21 are substituents on U-27.
  • R l is Me; R 2b is tert-Bu; T, U, Y and Z are CH; R 5 is U-28; R 21 are substituents on U-28.
  • Rlb is Me; R 2b is tert-Bu; T, U, Y and Z are CH; R 5 is U-31; R 21 and R 22 are substituents on U-31; R 22 is H.
  • Rlb is Me; R 2b is tert-Bu; T U Y and Z are CH; R 5 is U-32; R 2ia is a substituent on U-32.
  • Rlb is Me; R 2 is tert-Bu; T, U, Y and Z are CH; R 5 is U-33; R 21a is a substituent on U-33.
  • Rlb is Me; R 2b is tert-Bu; T, U, Y and Z are CH; R 5 is U-35; R. 21a is a substituent on U-35.
  • Rlb is Me; R 2b is tert-Bu; T, U, Y and Z are CH; R 5 is U-36; R 22 is H; R 21a and R 22 are substituents on U-36.
  • R lb is Me; R 2b is tert-Bu; T, U, Y and Z are CH; R 5 is U-36; R 22 is CH 3 ; R 2ia and R 2 2 are substituents on U-36.
  • Rlb is Me; R 2b is tert-Bu; T, U, Y and Z are CH; R 5 is U-36; R 22 is CH 2 CH 3 ; R 2ia and R 22 are substituents on U-36.
  • Rlb is Me; R 2b is tert-Bu; T, U, Y and Z are CH; R 5 is U-37; R 21 are substituents on U-37.
  • Rlb is Me; R 2b is tert-Bu; T, U, Y and Z are CH; R 5 is U-44; R 2i are substituents on U-44.
  • Rlb is Me; R 2 is tert-Bu; T, U, Y and Z are CH; R 5 is U-45; R 21 are substituents on U-45.
  • R 21 R21 R21 R21 R21_ R21 R21 5-CF3 5-CH 2 CH 3 5-OCH 3 6-CJHF 2 5-SCH 3 6-S(0) 2 CH 3
  • R lb is Me; R 2b is tert-Bu; T, U, Y and Z are CH; R 5 is U-46; R 21 are substituents on U-46.
  • Rlb is Me; R 2 b i s tert-Bu; T, U, Y and Z are CH; R 5 is U-47; R i are substituents on U-47.
  • R lb is Me; R 2b is tert-Bu; T, U, Y and Z are CH; R 5 is U-48; R 2i are substituents on U-48.
  • Rlb is Me; R 2b is tert-Bu; T, U, Y and Z are CH; R 5 is U-49; R 2i are substituents on U-49.
  • Rl is Me; R 2b is tert-Bu; T, U, Y and Z are CH; R 5 is U-51; R 2i are substituents on U-51.
  • Rlb is Me; R 2b is tert-Bu; T, U, Y and Z are CH; R 5 is U-52; R 21 are substituents on U-52.
  • Rlb is Me; R 2b is tert-Bu; T, U, Y and Z are CH; R 5 is U-53; R 2i are substituents on U-53.
  • R lb is Me R 2b i s tert-Bu T U Y and Z are CH R 5 is U-54; R 2 1 are substituents on U-54.
  • R lb is Me; R 2 is tert-Bu; T, U, Y and Z are CH; R 5 is U-55; R 2 are substituents on U-55.
  • R lb is Me; R 2b is tert-Bu; T, U, Y and Z are CH; R 5 is U-56; R 2i are substituents on U-56.
  • R b is Me; R 2b is tert-Bu; T, U, Y and Z are CH; R 5 is U-57; R 24 are substituents on U-57.
  • Rl is Me; R 2b is tert-Bu; T, U, Y and Z are CH; R 5 is U-58; R 24 are substituents on U-58.
  • R 24 R24 R 4-CH 2 CH 3 4-CH 2 CH 3 , 5-CH 2 CH 3 4-CH3 5-CH 2 CH 3 4-CH3, 5-CH 2 CH 3 5-CH3 4-CH3, 5-CH3 4-CH 2 CH 3 , 5-CH3
  • Rlb is Me; R 2b is tert-Bu; T, U, Y and Z are CH; R 5 is U-59; R 24 are substituents on U-59.
  • Rlb is Me; R 2b is tert-Bu; T, U, Y and Z are CH; R 5 is U-63; R 24 are substituents on U-63.
  • R b is Me; R 2b is tert-Bu; T, U, Y and Z are CH; R 5 is U-66; R 24 are substituents on U-66.
  • Rlb is Me; R 2b is tert-Bu; T, U, Y and Z are CH; R 5 is U-67; R 24 are substituents on U-67.
  • Rl is Me; R 2b is tert-Bu; T, U, Y and Z are CH; R 5 is U-69; R 24 are substituents on U-69.
  • Rlb is Et R 2b is tert-Bu; T, U, Y and Z are CH; R 5 is U-32; R 2 l a is a substituent on U-32.
  • Rlb is Et; R 2b is tert-Bu; T, U, Y and Z are CH; R 5 is U-38; R 2i are substituents on U-38.
  • Rl is Et ;
  • R 2b is tert-Bu; T, U, Y and Z are CH;
  • R 5 is U-41;
  • R 2 1 are substituents on U-41.
  • Rlb is Et ;
  • R 2 is tert-Bu; T, U, Y and Z are CH;
  • R 5 is U-44;
  • R 21 are substituents on U-44.
  • R lb is Me
  • R 2b is i-Pr
  • T U Y and Z are CH
  • R 5 is U-44
  • R 2 are substituents on U-44.
  • R lb is Me; R 2 i s tert-Bu; U is CF; T, Y and Z are CH; R 5 is U-7; R 2i are substituents on U-7.
  • Rl is Me; R 2b i s tert-Bu U is CF T Y and Z are CH; R 5 is U-32; R 21a is a substituent on U-32. g21a R21a
  • R l is Me; R 2 i s tert-Bu; U is CF; T, Y and Z are CH; R 5 is U-38; R 21 are substituents on U-38.
  • Rlb is Me; R 2b is tert-Bu; U is CF; T, Y and Z are CH; R 5 is U-41; R 2 l ire substituents on U-41.
  • Rlb is M e; R 2b is tert- ⁇ .u; U is CF; T, Y and Z are CH; R 5 is U-44; R 2 1 ire substituents on U-44.
  • 5-CH3 4-CH3, 5-CH3 4-CH 2 CH 3 , 5-CH3
  • Rlb is Me
  • R 2b is tert-Bu T is N U Y and Z are CH
  • R 5 is U-7
  • R 21 are substituents on U-7.
  • R 21 5-so 2 CH 3 4-SCHF2 5-SCHF2 4-SCF3 5-SCF3
  • Rlb is Me; R 2b is tert-Bu; T is N; U, Y and Z are CH R 5 is U-32; R 2ia is a substituent on U-32.
  • Rlb is Me; R 2b is tert-Bu; T is N; U, Y and Z are CH; R 5 is U-38; R 21 are substituents on U-38.
  • R 21 R21 R 1 R 21 R 21 I R21 R21 5-CF3 5-CH 2 CH 3 5-OCH 2 CH 3 5-CHF 2 5-SCH3 4-S(0) 2 CH 3
  • Rlb is Me; R 2b is tert-Bu; T is N; U, Y and Z are CH; R 5 is U-41; R 2i are substituents on U-41.
  • R lb is Me
  • R 2b is tert-Bu
  • U is N T ⁇ and Z are CH
  • R 5 is U-44
  • R 21 are substituents on U-44.
  • Rl is Me
  • R b is tert-Bu Y is N T U and Z are CH
  • R 5 is U-44;
  • R 21 are substituents on U-44.
  • Rlb is Me; R 2b is tert-Bu; T, U, Y and Z are CH; R 2ia is H; R 22 is H; R 23 is CH 3 ; R 25 is H; g, j, k, m n and are 0.
  • R la is Et R 2a is tert-Bu ; T, U, Y and 2 : are CH; R 5 is U-7; R 2 1 are substituents on U-7.
  • R la is Et R 2a is tert-Bu T, U, Y and Z are CH; R 5 is U-32; R 1 a is a substituent on U-32.
  • R la is Et ;
  • R 2a is tert-Bu ;
  • T, U, Y and 2 _ are CH;
  • R 5 is U-38;
  • R 2i are substituents on U-38.
  • R la is Et; R 2a is tert-Bu; T, U, Y and Z are CH; R 5 is U-41; R 21 are substituents on U-41.
  • R ia is Et: ; R 2a is tert-Bu; T, U, Y and Z are CH; R 5 is U-44; R 21 are substituents on U-44 R21 R 21 R 21 R21 R 21 R21 6-CF3 6-CH 2 CH 3 6-OCH 2 CH 3 6-CHF 2 5-SCH3 4-S(0) 2 CH 3 3-Cl 3-CH 2 CF 3 3-CN 3-OCF3 3-OCH 2 F 6-SCH3 5-S(0) 2 CH 3 4-C1 4-CH 2 CF 3 4-CN 4-OCF3 4-OCH 2 F 3-SCH 2 CH 3 6-S(0) 2 CH 3 5-Cl 5-CH 2 CF 3 5-CN 5-OCF3 5-OCH 2 F 4-SCH 2 CH 3 3-SCHF 2 6-C1 6-CH 2 CF 3 6-CN 6-OCF3 6-OCH 2 F 5-SCH 2 CH 3 4-SCHF 2 3-F 3-CH 3 3-OCH 3 3-CH 2 F 3-OCHF 2 6-SCH 2 CH 3 5-SCHF 2 4-F 4-CH 3 4-OCH3 4-CH 2 F 4-OCHF 2 3-S(0)CH 3 6-
  • Rlb is Et; R2b i s tert-Bu; T, U, Y and Z are CH; R 2ia is H; R 22 is H; R 23 is CH 3 ; R 25 is H; g, j, k, m, n and are 0.
  • Formulation/Utility Compounds of this invention will generally be used as a formulation or composition with an agriculturally suitable carrier comprising at least one of a liquid diluent, a solid diluent or a surfactant.
  • the formulation or composition ingredients are selected to be consistent with the physical properties of the active ingredient, mode of application and environmental factors such as soil type, moisture and temperature.
  • Useful formulations include liquids such as solutions (including emulsifiable concentrates), suspensions, emulsions (including microemulsions and/or suspoemulsions) and the like which optionally can be thickened into gels.
  • Useful formulations further include solids such as dusts, powders, granules, pellets, tablets, films (including seed coatings), and the like which can be water-dispersible (“wettable”) or water-soluble.
  • Active ingredient can be

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Health & Medical Sciences (AREA)
  • Pest Control & Pesticides (AREA)
  • Dentistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Wood Science & Technology (AREA)
  • Zoology (AREA)
  • Environmental Sciences (AREA)
  • Plant Pathology (AREA)
  • Agronomy & Crop Science (AREA)
  • Manufacturing & Machinery (AREA)
  • Ceramic Engineering (AREA)
  • Inorganic Chemistry (AREA)
  • Materials Engineering (AREA)
  • Structural Engineering (AREA)
  • Agricultural Chemicals And Associated Chemicals (AREA)

Abstract

Compounds of Formula (I), and their N-oxides and agriculturally suitable salts, are disclosed which are useful for controlling undesired vegetation : wherein (J) is (J-1), (J-2), (J-3), (J-4), (J-5), (J-6), (J-7), (J-8), or (J-9) ; R5 is a phenyl ring or a 5- or 6-membered heteroaromatic ring which includes at least one heteroatom selected from N, O and S, each ring optionally substituted with one or more substituents selected from R15; or R5 is a 5- or 6-membered partially unsaturated heterocyclic ring which includes at least one heteroatom selected form N, O and S, the ring connected through a nitrogen atom or an sp2 carbon atom to the remainder of Formula (I) and optionally substituted by one or more substituents selected from R16; and R1a, R1b, R2a, R2b, R3, R4, R15, R16, T, U, W, Y and Z are as defined in the disclosure.

Description

TITLE
HETEROYCLYLPHENYL-AND HETEROCYC YLPYRIDYL-SUBSTITUTED AZOLECARBOXAMIDES AS HERBI CIDES FIELD OF THE INVENTION This invention relates to certain azolecarboxamides, their N-oxides, agriculturally suitable salts and compositions, and methods of their use for controlling undesirable vegetation. BACKGROUND OF THE INVENTION The control of undesired vegetation is extremely important in achieving high crop efficiency. Achievement of selective control of the growth of weeds especially in such useful crops as rice, soybean, sugar beet, corn (maize), potato, wheat, barley, tomato and plantation crops, among others, is very desirable. Unchecked weed growth in such useful crops can cause significant reduction in productivity and thereby result in increased costs to the consumer. The control of undesired vegetation in noncrop areas is also important. Many products are commercially available for these purposes, but the need continues for new compounds which are more effective, less costly, less toxic, environmentally safer or have different modes of action. J. J. Parlow, D. A. Mischke and S. S. Woodard, J. Org. Chem. 1997, 62, 5908-5919 and J. J. Parlow, /. Heterocyclic Chem. 1998, 35, 1493-1499 disclose, certain pyrazole- carbonylaminobenzene- and pyridinecarboxamides as herbicides. The present Applicants have discovered herbicidally efficacious azolecarboxamides not disclosed or suggested by these two publications. SUMMARY OF THE INVENTION This invention is directed to a compound of Formula I, including all geometric and stereoisomers, N-oxides or agriculturally suitable salts thereof, agricultural compositions containing them and their use as herbicides:
Figure imgf000003_0001
wherein
Figure imgf000004_0001
Figure imgf000004_0002
J-9
T is CR6 or N;
U is CR^ or N;
Y is CR8 or N;
Z is CR9 or N;
Rla is H, C!-C4 alkyl, C!-C4 fluoroalkyl, C2-C4 alkenyl, C2-C4 fluoroalkenyl, C2-C4 alkynyl or C2-C4 fluoroalkynyl;
Rlb is halogen, -CN, C!-C4 alkyl, Cj-C4 fluoroalkyl, C2-C4 alkenyl, C2-C4 fluoroalkenyl, C2-C4 alkynyl or C2-C4 fluoroalkynyl;
R2a is Ci-Cg alkyl, Cγ-C6 haloalkyl, C2-C6 alkoxyalkyl, C2-C6 alkylthioalkyl, C2-Cg alkenyl, C2~Cg haloalkenyl, C2~Cg alkynyl, C2~Cg haloalkynyl, C3-C6 cycloalkyl, C4-C6 alkylcycloalkyl, C3-Cg halocycloalkyl, C4-C cycloalkylalkyl, C5-C6 alkylcycloalkylalkyl or SiRiOR1^12;
R2b is Ci-C alkyl,
Figure imgf000004_0003
haloalkyl, C2-C6 alkoxyalkyl, C2-C6 alkylthioalkyl, C2~Cg alkenyl, C2-Cg haloalkenyl, C2-Cg alkynyl, C2~Cg haloalkynyl, C3~Cg cycloalkyl, C4-Cg alkylcycloalkyl, C3-Cg halocycloalkyl, C4~Cg cycloalkylalkyl or C5-C6 alkylcycloalkylalkyl;
R3 is H, F or ^-C^ alkyl; or R2 or R2b is taken together with R3 as -C(R13)(R14)-(Y1)s-(CH2)t-(Y2)u- or -C(R13)(R14)-(Y1)V-CH=CH-(Y2)W- wherein the left end of the radical is connected as R2a or R2b, and the right end of the radical is connected as R3; R4 is H, CJ-C2 alkyl, C2-C6 alkylcarbonyl, C2-Cg alkoxycarbonyl, C2-C6 alkoxyalkyl or C2~C alkylthioalkyl;
R5 is a phenyl ring or a 5- or 6-membered heteroaromatic ring which includes at least one heteroatom selected from N, O and S, each ring optionally substituted with one or more substituents selected from R15; or R5 is a 5- or 6-membered partially unsaturated heterocyclic ring which includes at least one heteroatom selected from N, O and S, the ring connected through a nitrogen atom or an sp2 carbon atom to the remainder of Formula I and optionally substituted by one or more substituents selected from R16; R6 is H, F, Cj-02 alkyl, -C2 fluoroalkyl, C!-C2 fluoroalkoxy,
Figure imgf000005_0001
alkylthio or Cι-C2 fluoroalkylthio; R7 is H, F, C!-C2 alkyl, 0^2 fluoroalkyl, CJ- J fluoroalkoxy, Cr-C^ alkylthio or C1-C2 fluoroalkylthio; R8 and R9 are independently selected from H, F, Cι-C2 alkyl, Cι-C2 fluoroalkyl, C1-C2 fluoroalkoxy, C1-C2 alkylthio and C ι-C2 fluoroalkylthio; R10 is C!-C2 alkyl or Ci-C2 haloalkyl; R11 is C!-C2 alkyl or C!-C2 haloalkyl;
R12 is C!-C2 alkyl or Ci-Gj haloalkyl; R13 and R14 are independently H or ι~ 2 alkyl; each R15 is independently halogen, -CN, Cι-C2 alkyl, Cχ-C2 haloalkyl, C ι-C2 alkoxy, C -C2 haloalkoxy, Cι~C2 alkylthio, C]-C alkylsulfinyl, Cι-C2 alkylsulfonyl, -SCHF2 or -SCF3; each R16 is independently C]-C2 alkyl; W is O or S;
Y1 and Y2 are independently CH2, 0, S, NH or NCH3; s is 0 or 1; t is 1 or 2; and u is 0 or 1; provided that the sum of s, t and u is 2 or 3; and v is 0 or 1 ; w is 0 or 1 ; provided that the sum of v and w is 0 or 1 ; provided that
(a) when J is J-1, Rla is CH3, R2a is C(CH3)3, R3 is H, T is CH, U is CH, Y is CH and Z is CH, then R5 is other than phenyl and 5-oxazolyl;
(b) when a R15 or R16 substituent is attached to a nitrogen atom, said substituent is Cr-Cz alkyl;
(c) when R5 comprises a tetrazole ring, said ring is connected through the carbon atom to the remainder of Formula I and substituted on a nitrogen atom with Cι~C2 alkyl; (d) when R7 is F and R5 comprises a 1-pyrazolyl ring, no more than one substituent R15 attached to said ring is haloalkyl; (e) when J is J-2 or J-6, then R7 and R9 are H; (f) when J is J-2 or J-6, and R2b is 0^2 alkyl, then Rlb is halogen, C2-C4 alkyl, Cι-Q4 fluoroalkyl, C2-C4 alkenyl, C2-C4 fluoroalkenyl, C2-C4 alkynyl or C2-C4 fluoroalkynyl; (g) when T is N, then Z is CR9; and (h) when J is J-8, then R2b is other than C5~Cg cycloalkyl. More particularly, this invention pertains to a compound of Formula I, including all geometric and stereoisomers, N-oxides or agriculturally suitable salts thereof. This invention also relates to a herbicidal composition comprising a herbicidally effective amount of a compound of Formula I and at least one of a surfactant, a solid diluent or a liquid diluent. This invention further relates to a method for controlling the growth of undesired vegetation comprising contacting the vegetation or its environment with a herbicidally effective amount of a compound of Formula I (e.g., as a composition described herein). This invention also relates to a method for selectively controlling the growth of undesired vegetation in a crop comprising contacting the locus of the crop with a herbicidally effective amount of a compound of Formula I and an antidotally effective amount of a safener. The present invention also relates to a method for controlling the growth of undesired vegetation comprising contacting the vegetation or its environment with a herbicidally effective amount of a compound of Formula I and effective amount of at least one additional active ingredient selected from the group consisting of an other herbicide and a herbicide safener (e.g., in the form of the aforedescribed herbicidal mixture or herbicidal composition). A particular aspect of the present invention relates to a method for selectively controlling the growth of undesired vegetation in a crop comprising contacting the locus of a crop with an effective amount of a compound of Formula I and an antidotally effective amount of a herbicide safener (e.g., safener applied as a seed treatment). DETAILS OF THE INVENTION As used herein, the terms "comprises," "comprising," "includes," "including," "has," "having" or any other variation thereof, are intended to cover a non-exclusive inclusion. For example, a composition, 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, process, method, article, or apparatus. 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. 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, 7i-propyl, /-propyl, or the different butyl, pentyl or hexyl isomers. The term "1-2 alkyl" indicates that one or two of the available positions for that substituent may be alkyl which are independently selected. "Alkenyl" includes straight-chain or branched alkenes such as ethenyl, 1-propenyl, 2-propenyl, and the different butenyl, pentenyl and hexenyl isomers. "Alkenyl" also includes polyenes such as 1,2-propadienyl and 2,4-hexadienyl. "Alkynyl" includes straight-chain or branched alkynes such as ethynyl, 1-propynyl, 2-propynyl and the different butynyl, pentynyl and hexynyl isomers. "Alkynyl" can also include moieties comprised of multiple triple bonds such as 2,5-hexadiynyl. "Alkoxy" includes, for example, methoxy, ethoxy, n-propyloxy, isopropyloxy and the different butoxy and pentoxy isomers. "Alkoxyalkyl" denotes alkoxy substitution on alkyl. Examples of "alkoxyalkyl" include CH3OCH2, CH3OCH2CH2, CH3CH2OCH2, CH3CH2CH2CH2OCH2 and CH3CH2OCH2CH2. "Alkylthio" includes branched or straight-chain alkylthio moieties such as methylthio, ethylthio, and the different propylthio, butylthio and pentylthio isomers. "Alkylthioalkyl" denotes alkylthio substitution on alkyl. Examples of "alkylthioalkyl" include CH3SCH2, CH3SCH2CH2, CH3CH2SCH2, CH3CH2CH2CH2SCH2 and CH3CH2SCH2CH2. "Alkylsulfinyl" includes both enantiomers of an alkylsulfinyl group. Examples of "alkylsulfinyl" include CH3S(O), CH3CH2S(O), CH3CH2CH2S(O), (CH3)2CHS(O) and the different butylsulfinyl isomers. Examples of "alkylsulfonyl" include CH3S(O)2, CH3CH2S(O)2, CH3CH2CH2S(O)2, (CH3)2CHS(O)2 and the different butylsulfonyl isomers. "Cycloalkyl" includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Examples of "cycloalkylalkyl" include cyclopropylmethyl, cyclopentylethyl, and other cycloalkyl moieties bonded to straight-chain or branched alkyl groups. "Alkylcycloalkyl" denotes alkyl substitution on a cycloalkyl moiety. Examples include 4-methylcyclohexyl and 3-ethylcyclopentyl. The term "heteroaromatic ring" includes fully aromatic heterocycles. Aromatic indicates that each of the ring atoms is essentially in the same plane and has a -orbital perpendicular to the ring plane, and in which (4n + 2) π electrons, where n is 0 or a positive integer, are associated with the ring to comply with Hϋckel's rule. The term "sp2 carbon atom" refers to a carbon atom that is connected to another atom through a double bond. The term "partially unsaturated heterocyclic ring system" denotes heterocycles containing at least one double bond in the ring but lacking sufficient unsaturation to result in aromaticity according to Hϋckel's rule. Unless otherwise indicated, the heterocyclic ring systems can be attached through any available carbon or nitrogen by replacement of a hydrogen on said carbon or nitrogen. 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. Synthetic methods for the preparation of N-oxides of heterocycles 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. N. Ley, Ed., Pergamon Press; M. Tisler and B. Stanovnik in Comprehensive Heterocyclic Chemistry, vol. 3, pp 18-20, A. J. Boulton and A. McKillop, Eds., Pergamon Press; M. R. Grimmett and B. R. T. Keene in Advances in Heterocyclic Chemistry, vol. 43, pp 149-161, A. R. Katritzky, Ed., Academic Press; M. Tisler and B. Stanovnik in Advances in Heterocyclic Chemistry, vol. 9, pp 285-291, A. R. Katritzky and A. J. Boulton, Eds., Academic Press; and G. W. H. Cheeseman and E. S. G. Werstiuk in Advances in Heterocyclic Chemistry, vol. 22, pp 390-392, A. R. Katritzky and A. J. Boulton, Eds., Academic Press. The term "halogen", either alone or in compound words such as "haloalkyl", includes fluorine, chlorine, bromine or iodine. The term "1-2 halogen" indicates that one or two of the available positions for that substituent may be halogen which are independently selected. Further, when used in compound words such as "haloalkyl", said alkyl may be partially or fully substituted with halogen atoms which may be the same or different. Examples of "haloalkyl" include F3C, C1CH2, CF3CH2 and CF3CC12. The terms "haloalkenyl", "haloalkynyl", "haloalkoxy", "haloalkylthio", and the like, are defined analogously to the term "haloalkyl". Examples of "haloalkenyl" include (C1)2C=CHCH2 and
CF3CH2CH=CHCH2. Examples of "haloalkynyl" include HC≡CCHCl, CF3C≡C, CC13C≡C and FCH2C≡CCH2. Examples of "haloalkoxy" include CF3O, CCl3CH2O, HCF2CH2CH2O and CF3CH2O. Similarly, "fluoroalkyl", "fluoroalkenyl" and "fluoroalkynyl" may be partially or fully substituted with fluorine atoms. 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 6. For example, Cj-C3 alkyl designates methyl through propyl; 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. Examples of "alkylcarbonyl" include C(O)CH3, C(O)CH2CH2CH3 and C(O)CH(CH3)2. Examples of "alkoxycarbonyl" include CH3OC(=O), CH3CH2OC(=O), CH3CH2CH2OC(=O), (CH3)2CHOC(=O) and the different butoxy- or pentoxycarbonyl isomers. When a compound is substituted with a substituent bearing a subscript that indicates the number of said substituents can exceed 1, said substituents (when they exceed 1) are independently selected from the group of defined substituents. When a group contains a substituent which can be hydrogen, for example R6, then, when this substituent is taken as hydrogen, it is recognized that this is equivalent to said group being unsubstituted. When a position on a group is said to be "not substituted" or "unsubstituted", then hydrogen atoms are attached to take up any free valency. 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. Accordingly, the present invention comprises compounds selected from Formula I, N-oxides and agriculturally suitable salts thereof. The compounds of the invention may be present as a mixture of stereoisomers, individual stereoisomers, or as an optically active form. The agriculturally suitable salts of the compounds of the invention include acid-addition salts with inorganic or organic acids such as hydrobromic, hydrochloric, nitric, phosphoric, sulfuric, acetic, butyric, fumaric, lactic, maleic, malonic, oxalic, propionic, salicylic, tartaric, 4-toluenesulfonic or valeric acids. The agriculturally suitable salts of the compounds of the invention also include those formed with strong bases (e.g., hydrides or hydroxides of sodium, potassium or lithium). One skilled in the art recognizes that because in the environment and under physiological conditions salts of the compounds of the invention are in equibrium with their corresponding nonsalt forms, agriculturally suitable salts share the biological utility of the nonsalt forms. Embodiments of the present invention include: Embodiment 1. A compound of Formula I wherein at most one of T, U, Y and Z is Ν. Embodiment 2. A compound of Formula I wherein W is O. Embodiment 3. A compound of Formula I wherein J is J-1, J-2, J-3, J-5, J-8 or J-9. Embodiment 4. A compound of Embodiment 3 wherein J is J-1, J-3, J-8 or J-9. Embodiment 5. A compound of Embodiment 4 wherein J is J-1, J-3 or J-9. Embodiment 6. A compound of Formula I wherein J is J-1 , J-2, J-3, J-5 or J-8. Embodiment 7. A compound of Embodiment 6 wherein J is J-1, J-3 or J-8. Embodiment 8. A compound of Embodiment 7 wherein J is J-1 or J-3. Embodiment 9. A compound of Formula I wherein J is J-1. Embodiment 10. A compound of Formula I wherein J is J-2. Embodiment 11. A compound of Formula I wherein J is J-3. Embodiment 12. A compound of Formula I wherein J is J-4. Embodiment 13. A compound of Formula I wherein J is J-5. Embodiment 14. A compound of Formula I wherein J is J-6.
Embodiment 15. A compound of Formula I wherein J is J-7. Embodiment 16. A compound of Formula I wherein J is J-8. Embodiment 17. A compound of Formula I wherein J in J-9. Embodiment 18. A compound of Formula I wherein Rla is C1-C alkyl, C1-C4 fluoroalkyl, C2-C4 alkenyl, C2-C4 fluoroalkenyl, C2-C4 alkynyl or C2-C4 fluoroalkynyl. Embodiment 19. A compound of Formula I wherein Rla or Rlb is selected from a radical in the group consisting of Cι~C3 alkyl, Cι~C3 fluoroalkyl, C2-C3 alkenyl, C2-C3 fluoroalkenyl, C2-C3 alkynyl and C2-C3 fluoroalkynyl, each radical unbranched and connected through a terminal end carbon atom to the azole ring. Embodiment 20. A compound of Embodiment 19 wherein Rla or Rlb is CH3, CH2CH3, CH2CH2F, CH2CHF2, CH2CF3 or CH=CH2. Embodiment 21. A compound of Embodiment 20 wherein Rla or Rlb is CH3, CH2CH3 or CH2CF3.
Embodiment 22. A compound of Embodiment 21 wherein Rla or Rlb is CH3 or CH2CH . Embodiment 23. A compound of Embodiment 22 wherein Rla or Rlb is CH2CH3. Embodiment 24. A compound of Formula I wherein R2a or R2b is tert-butyl, isopropyl, cyclopropyl or 1-methylcyclopropyl.
Embodiment 25. A compound of Embodiment 24 wherein R2a or R2b is tert-butyl, isopropyl or cyclopropyl. Embodiment 26. A compound of Embodiment 25 wherein R2a or R2b is tert-butyl or isopropyl. Embodiment 27. A compound of Formula I wherein Y1 and Y2 are independently CH2 or O; Embodiment 28. A compound of Embodiment 27 wherein the sum of s, t and u is 2 and the sum of v and w is 0. Embodiment 29. A compound of Embodiment 28 wherein R13 is Cι-C2 alkyl. Embodiment 30. A compound of Embodiment 29 wherein R13 and R14 are CH3.
Embodiment 31. A compound of Formula I wherein R3 is H. Embodiment 32. A compound of Formula I wherein R4 is H. Embodiment 33. A compound of Formula I wherein R6 is H or F. Embodiment 34. A compound of Formula I wherein R7 is H or F. Embodiment 35. A compound of Formula I wherein R8 and R9 are H or F. Embodiment 36. A compound of Formula I wherein R5 is a phenyl ring optionally substituted with 1-4 substituents selected from R15. Embodiment 37. A compound of Embodiment 36 wherein the phenyl ring is optionally substituted with 1-2 substituents selected from R15. Embodiment 38. A compound of Embodiment 37 wherein the phenyl ring is optionally substituted with a substituent selected from R15. Embodiment 39. A compound of Formula I wherein R5 is a 5- or 6-membered heteroaromatic ring containing at least one heteroatom selected from N, O and S, the ring optionally substituted with one or more substituents selected from R15. Embodiment 40. A compound of Embodiment 39 wherein the 5- or 6-membered heteroaromatic ring is optionally substituted with 1-2 substituents independently selected from R15. Embodiment 41. A compound of Embodiment 40 wherein the 5- to 6-membered heteroaromatic ring is optionally substituted with a substituent selected from R15. Embodiment 42. A compound of Formula I wherein R5 is a 5- or 6-membered partially unsaturated heterocyclic ring containing at least one heteroatom selected from N, O and S, the ring connected through a nitrogen atom or an sp2 carbon atom to the remainder of Formula I and optionally substituted by one or more substituents selected from R16. Embodiment 43. A compound of Embodiment 42 wherein the 5- or 6-membered partially unsaturated heterocyclic ring is optionally substituted by 1-2 substituents selected from R16.
Embodiment 44. A compound of Embodiment 43 wherein the 5- or 6-membered partially unsaturated heterocyclic ring is optionally substituted by a substituent selected from R16. Embodiment 45. A compound of Formula I wherein the 5- or 6-membered heteroaromatic ring or the partially unsaturated heterocyclic ring comprised by R5 comprises a heteroatom at a ring position adjacent to the ring position connecting the remainder of Formula I. Embodiment 46. A compound of Embodiment 45 wherein the heteroatom is a nitrogen atom. Embodiment 47. A compound of Embodiment 46 wherein the 5- or 6-membered heteroaromatic ring comprised by R5 is 2-pyridinyl (also termed 2-pyridyl). Embodiment 48. A compound of Formula I wherein R15 is halogen, -CN, Ci-C2 alkyl, Cj fluoroalkyl or Ci alkoxy. Embodiment 49. A compound of Embodiment 48 wherein R15 is methyl. Embodiment 50. A compound of Formula I wherein R16 is methyl. Embodiment 51. A compound of Formula I wherein R5 is one of U-1 through U-71 selected from Exhibit 1 Exhibit 1
Figure imgf000012_0001
U-1 U-2 U-3 U-4
Figure imgf000012_0002
U-5 U-6 U-7 U-8
Figure imgf000012_0003
U-9 U-10 U-l l U-12
Figure imgf000012_0004
U-13 U-14 U-15 U-16
Figure imgf000012_0005
U-17 U-18 U-19 U-20
Figure imgf000013_0001
U-21 U-22 U-23 U-24
Figure imgf000013_0002
-25 -26 U-27 U-28
Figure imgf000013_0003
U-29 U-30 U-31 U-32
Figure imgf000013_0004
U-33 U-34 U-35 U-36
Figure imgf000013_0005
U-37 U-38 U-39 U-40
Figure imgf000013_0006
U-41 U-42 U-43 U-44
Figure imgf000014_0001
U-45 U-46 U-47 U-48
Figure imgf000014_0002
U-49 U-50 U-51 U-52
Figure imgf000014_0003
U-53 U-54 U-55 U-56
Figure imgf000014_0004
U-57 U-58 U-59 U-60
Figure imgf000014_0005
U-61 U-62 U-63 U-64
Figure imgf000014_0006
U-65 U-66 U-67 U-68
Figure imgf000015_0001
U-69 U-70 U-71 wherein each R21 is independently halogen, -CN, ^-02 alkyl, C1-C2 haloalkyl, ^-^ alkoxy, C1-C2 haloalkoxy, C1-C2 alkylthio, C1-C2 alkylsulfinyl, Cι-C2 alkylsulfonyl, -SCHF2 or -SCF3; R2l is H, halogen, -CN, C!-C2 alkyl, -^ haloalkyl, C^ alkoxy, Cl-C2 haloalkoxy, C!-C2 alkylthio, Cx- ^ alkylsulfinyl, C!-C2 alkylsulfonyl, -SCHF2 or -SCF3; R22 is H or C1-C2 alkyl; R23 is C!-C2 alkyl; each R24 is independently Cj-^ alkyl; R25 is H or C1-C2 alkyl; g is an integer from 0 to 7; j is an integer from 0 to 6; k is an integer from 0 to 5; m is an integer from 0 to 4; n is an integer from 0 to 3; and p is an integer from 0 to 2. Embodiment 52. A compound of Embodiment 51 wherein R5 is selected from the group consisting of U-2, U-3, U-4, U-5, U-6, U-7, U-8, U-9, U-10, U-ll, U-12, U-13, U-14, U-15, U-16, U-17, U-18, U-19, U-20, U-21, U-25, U-27, U-28, U-31, U-32, U-33, U-34, U-35, U-36, U-38, U-39, U-41, U-42, U-43, U-44, U-46, U-47, U-49, U-50, U-51, U-54, U-55, U-56, U-57, U-58, U-59, U-60, U-62, U-63, U-64, U-66, U-67, U-68, U-69, U-70 and U-71. Embodiment 53. A compound of Embodiment 52 wherein R5 is selected from the group consisting of U-4, U-6, U-7, U-ll, U-12, U-13, U-14, U-15, U-16, U-17, U-18, U-19, U-20, U-21, U-25, U-27, U-28, U-31, U-32, U-33, U-34, U-35, U-36, U-38, U-39, U-41, U-42, U-43, U-44, U-46, U-47, U-49, U-50, U-51, U-54, U-55, U-56, U-57, U-58, U-59, U-60, U-62, U-63, U-64, U-66, U-67, U-68, U-69, U-70 and U-71. Embodiment 54. A compound of Embodiment 51 wherein R5 is selected from the group consisting of U-4, U-7, U-23, U-32, U-38, U-41, U-44, U-47, U-49 and U-58. Embodiment 55. A compound of Embodiment 54 wherein R5 is selected from the group consisting of U-7, U-32, U-38, U-41, U-44, U-49 and U-58. Embodiment 56. A compound of Embodiment 55 wherein R5 is selected from the group consisting of U-7, U-32, U-38, U-41 and U-44. Embodiment 57. A compound of Embodiment 56 wherein R5 is U-44.
Embodiment 58. A compound of Embodiment 51 wherein g, j, k, m and n are integers from 0 to 2. Embodiment 59. A compound of Embodiment 58 wherein g, j, k, m, n and p are integers from 0 to 1. Embodiment 60. A compound of Embodiment 51 wherein each R21 is independently halogen, -CN, Cr-C2 alkyl, Cj fluoroalkyl or Cj alkoxy; and R21a is H, halogen, -CN, C1-C2 alkyl, Ci fluoroalkyl or Cγ alkoxy. Embodiment 61. A compound of Embodiment 60 wherein each R21, R23 and R24 is methyl. Embodiment 62. A compound of Embodiment 51 wherein R22 and R25 are methyl.
Embodiment 63. A compound of Formula I wherein when J is J-1, then R5 is other than phenyl. Embodiment 64. A compound of Formula I wherein when J is J-1, then R5 is other than optionally substituted phenyl. Embodiment 65. A compound of Formula I wherein when J is J-1 and R5 is phenyl, then Rla is CH2CH3, CH2CH2F, CH2CHF2, CH2CF3 or CH=CH2. Embodiment 66. A compound of Formula I wherein when J is J-1 and R5 is optionally substituted phenyl, then Rla is CH2CH3, CH2CH2F, CH2CHF2, CH2CF3 or CH=CH2. Embodiment 67. A compound of Formula I wherein when J is J-1 and R5 is optionally substituted phenyl, then the optionally substituted phenyl is substituted with F at an ortho position. Embodiment 68. A compound of Formula I wherein when J is J-1, then R5 is other than U-1 where k is 0. Embodiment 69. A compound of Formula I wherein when J is J-1, then R5 is other than U-1. Embodiment 70. A compound of Formula I wherein R5 is other than U-1 where k is 0. Embodiment 71. A compound of Formula I wherein R5 is other than U-1. Embodiment 72. A compound of Formula I wherein when J is J-1, then R5 is other than 5-oxazolyl.
Embodiment 73. A compound of Formula I wherein when J is J-1, then R5 is other than optionally substituted 5-oxazolyl. Embodiment 74. A compound of Formula I wherein when J is J-1 and R5 is 5-oxazolyl, then Rla is CH2CH3, CH2CH2F, CH2CHF2, CH2CF3 or CH=CH2. Embodiment 75. A compound of Formula I wherein when J is J-1 and R5 is optionally substituted 5-oxazolyl, then Rla is CH2CH3, CH2CH2F, CH2CHF2, CH2CF3 or CH=CH2. Embodiment 76. A compound of Formula I wherein when J is J-1, then R5 is other than U-8 where p is 0. Embodiment 77. A compound of Formula I wherein when J is J-1, then R5 is other than U-8. Embodiment 78. A compound of Formula I wherein R5 is other than U-8 where p is 0. Embodiment 79. A compound of Formula I wherein R5 is other than U-8. Of note is a compound of Formula I wherein J is J-1 and Rla is H, which is particularly useful as a synthetic intermediate. Combinations of Embodiments 1-79 are illustrated by: Embodiment A. A compound of Formula I wherein at most one of T, U, Y and Z is N; Rla or Rlb is selected from a radical in the group consisting of Cι~C3 alkyl, C]-C3 fluoroalkyl, C -C3 alkenyl, C2-C3 fluoroalkenyl, C2-C3 alkynyl or C2-C3 fluoroalkynyl, each radical unbranched and connected through a terminal end carbon atom to the azole ring; R6 is H or F; R7 is H or F; R8 is H or F; R9 is H or F; R4 is H; R13 is C^ alkyl; W is O; Y1 and Y2 are independently CH2 or O; the sum of s, t and u is 2; and the sum of v and w is 0. Embodiment B. A compound of Embodiment A wherein J is J-1, J-2, J-3, J-5 or J-8. Embodiment C. A compound of Embodiment B wherein Rla or Rlb is CH2CH3, CH2CH2F, CH2CHF2, CH2CF3 or CH=CH2, R2 or R2 is tert-butyl, isopropyl or cyclopropyl, and R3 is H. Embodiment D. A compound of Embodiment C wherein each R15 is independently halogen, -CN, Cι~C2 alkyl, Cj fluoroalkyl or C^ alkoxy. Embodiment E. A compound of Embodiment D wherein R5 is a phenyl ring optionally substituted with 1-2 substituents selected from R15. Embodiment G. A compound of Embodiment D wherein R5 is a 5- or 6-membered partially unsaturated heterocyclic ring which includes at least one heteroatom selected from N, O and S and optionally substituted with 1-2 substituents selected from R16. Embodiment H. A compound of Embodiment D wherein R5 is a 5- or 6-membered heteroaromatic ring which includes at least one heteroatom selected from N, O and S and optionally substituted with 1-2 substituents selected from R15. Embodiment I. A compound of Embodiment H wherein the 5- or 6-membered heteroaromatic ring is 2-pyridinyl. Specific embodiments include the following compound of Embodiment D: 3-(l,l-dimethylethyl)-l-ethyl-N-[3-(2-pyridinyl)phenyl]-lH-pyrazole- 5-carboxamide. Of note are compounds of Formula I wherein J is J-1, J-2, J-3, J-4, J-5, J-6, J-7 or J-8. Also noteworthy as embodiments are herbicidal compositions of the present invention comprising the compounds of embodiments described above. This invention also relates to a method for controlling undesired vegetation comprising applying to the locus of the vegetation herbicidally effective amounts of the compounds of the invention (e.g., as a composition described herein). Of note as embodiments relating to methods of use are those involving the compounds of embodiments described above. This invention also relates to a method for selectively controlling the growth of undesired vegetation in a crop comprising contacting the locus of the crop with a herbicidally effective amount of the compounds of the invention and an antidotally effective amount of a safener. Of note as embodiments relating to methods of use are those involving the compounds of embodiments described above. The compounds of Formula I can be prepared by one or more of the following methods and variations as described in Schemes 1 through 61 and accompanying text. The definitions of J, W, Rla, Rlb, R2a, 2b? R3s R4? R5, R6s R7, R8? R9; R105 RU R125 RB RU Ri5, R!6, R21, R21a? R22, R23, R24, R25? j Tj TJ, Y, γl; γ2, Z, g, j, k, m, n, p, S, t, U, V and w, in the compounds of Formulae I through lah, and 1 through 147 below are as defined above in the Summary of the Invention and description of preferred embodiments unless otherwise indicated. Compounds of Formulae la through lah are various subsets of the compounds of Formula I, compounds of Formulae 2a through 2h are subsets of the compounds of Formula 2, and compounds of Formulae 11a through 111 are subsets of the compounds of Formula 11. References to R5 groups U-1 through U-71 refer to Exhibit 1. A wide variety of synthetic strategies and methodologies known in the art can be used to prepare compounds of Formula I. One basic strategy illustrated in the first Schemes shown below involves preparing a completed compound of Formula I by coupling together an acyl-containing left-hand portion (comprising J) with an amine-containing right-hand portion (comprising the six-membered aryl ring and R5) to form a carboxamide linkage. With this basic strategy, the J moiety in the left-hand portion and the six-membered aryl ring with its substituent R5 and any other substituents are fully constructed before the final carboxamide coupling step. In another basic strategy illustrated in the later Schemes shown below, the carboxamide amide linkage is constructed before the substituents on J in the left- hand portion and/or the six-membered aryl ring in the right-hand portion are completed in their final form. With this strategy then, the latter steps of the synthesis involve elaborating substituents, particularly R5, into molecular arrangements needed for Formula I. One skilled in the art recognizes that the general methods suitable for constructing R5 after forming the the carboxamide linkage can usually alternatively be performed before the carboxamide linkage is formed and vice versa. Therefore the methods described below showing attachment or construction of the R5 group should be considered broadly useful in either context irrespective of whether the carboxamide linkage is depicted to be already formed. According to the first basic strategy, compounds of Formula la (Formula I wherein W is O) are prepared by coupling the appropriately substituted azole acyl chloride of Formula 1 with the appropriately substituted amino compound of Formula 2 as shown in Scheme 1. Scheme 1
Figure imgf000019_0001
1 2 la
The reaction is carried out in an anhydrous aprotic solvent such as dichloromethane or tetrahydrofuran, preferably in the presence of a base such as triethylamine, pyridine, 4-(dimethylamino)pyridine or N,N-diisopropylethylamine, at a temperature typically between room temperature and 70 °C to provide the amide of Formula la. When R4 is alkylcarbonyl or alkoxycarbonyl, a strong base such as sodium hydroxide and phase transfer conditions such as those described by M. J. Haddadin et al., Heterocycles 1984, 22, 773 may be advantageous. The reaction of Scheme 1 is illustrated by Step G of Example 1, which follows. Alternatively, compounds of Formula la can be prepared by coupling the appropriately substituted azole carboxylic acid of Formula 3 with appropriately substituted amino compound of Formula 2 as shown in Scheme 2. Scheme 2 J~~^C— OH + 2 >■ ϊa O
This reaction is carried out in the presence of a dehydrating coupling reagent such as dicyclohexyl carbodiimide, l-(3-dimethylaminopropyl)-3-ethylcarbodiimide, 1-propane- phosphonic acid cyclic anhydride or carbonyl diimidazole in the presence of a base such as triethylamine, pyridine, 4-(dimethylamino)pyridine or N,N-diisopropylethylamine in an anhydrous aprotic solvent such as dichloromethane or tetrahydrofuran at a temperature typically between room temperature and 70 °C. The method of Scheme 2 is illustrated by Step C of Example 2, Step B of Example 3, and Step C of Example 4. As a further method, an ester of a carboxylic acid of Formula 3 can be condensed with a substituted amino compound of Formula 2 to provide the compound of Formula la by heating in a high-boiling inert solvent such as α,α,α-trifluorotoluene. As shown in Scheme 3, compounds of Formula lb (Formula I wherein W is S) can be prepared from corresponding compounds of Formula la by treatment with a thionating reagent such as P2S5 (see for example, E. Klingsberg et al., J. Am. Chem. Soc. 1951, 72, 4988; E. C. Taylor Jr. et al., J. Am. Chem. Soc. 1953, 75, 1904; R. Crossley et al., /. Chem. Soc. Perkin Trans. 1 1976, 977; J. Voss et al., Justus Liebigs Ann. Chem. 1968, 716, 209) or Lawesson's Reagent (2,5-bis(4-methoxyphenyl)-l,3-dithia-2,4-diphosphetane-2,4-disulfide; see, for example, S. Prabhakar et al. Synthesis 1984 (10), 829). Scheme 3
Figure imgf000020_0001
lb Alternatively, compounds of Formula lb can be directly prepared from the corresponding carboxylic acid of Formula 3 and amino compound of Formula 2 by treatment with (EtO)2P(S)SH according to the general procedure of N. Borthakur et al., Tetrahedron Lett. 1995, 36(37), 6745. Also, compounds of Formula la or lb wherein R4 is alkyl, alkylcarbonyl, alkoxycarbonyl, alkoxyalkyl or alkylthioalkyl can be prepared from the corresponding compounds of Formula la or lb wherein R4 is H by treatment with the appropriate alkylating or acylating reagents in the presence of base using methods well known in the art. Acyl chlorides of Formula 1 can be prepared from the carboxylic acids of Formula 3 by using methods well known in the art such as treatment with oxalyl chloride and catalytic N,N-dimethylformamide in dichloromethane or treatment with thionyl chloride. This preparation is illustrated by Step E of Example 1, Step A of Example 5, Step A of Example 6 and Step C of Example 7. Carboxylic acids of Formula 3 can be prepared from corresponding esters of Formula 11 wherein R31 is a carbon-based radical such as alkyl (e.g., methyl, ethyl), benzyl, etc. as shown in Scheme 4. Scheme 4 Ester cleavage conditions J-C(0)OR31 *- 3 11
A wide range of ester cleavage conditions known in the art can be used for this method. Particularly suitable are conditions involving treatment with hydroxide, such as aqueous sodium hydroxide or aqueous lithium hydroxide in tetrahydrofuran, followed by acidification, typically with a strong mineral acid such as hydrochloric or sulfuric acid. For cleaving esters of Formula 11 wherein R31 is benzyl, hydrogenation over palladium catalyst according to general procedures known in the art can be particularly advantageous. The method of Scheme 4 is illustrated in Step D of Example 1, Step C of Example 4, and Step B of Example 7. Carboxylic esters of Formula 11a (Formula 11 wherein J is J-1 andR31 is ethyl) can be prepared according to the general method described by J. J. Parlow et al., J. Org. Chem. 1997, 62, 5908-5919 and modifications thereof as discussed for Scheme 5. Scheme 5
Figure imgf000021_0001
This method involves base-induced condensation of a ketone of Formula 12 with diethyl oxalate (13) to give a tricarbonyl compound of Formula 14, which is condensed with a hydrazine of Formula 15 to prepare the pyrazolecarboxylate of Formula 11a. The condensation of the tricarbonyl compound of Formula 14 with the hydrazine of Formula 15 is typically conducted in an alcohol, ester or carbonate diester solvent. The hydrazine of Formula 15 can be in the form of a salt. As a modification of the general method of Scheme 5, when R3 is H, the diketoester of Formula 14 can be alkylated or fluorinated to provide the corresponding diketoester of Formula 14 wherein R3 is alkyl or fluorine. Compounds of Formula 12 are commercially available or can be prepared by methods well known in the art. The method of Scheme 5 is illustrated in Steps A and B of Example 1. As another modification of general method of Scheme 5, when Rla is H, the pyrazolecarboxylate of Formula 11a can be alkylated with the appropriate alkylating agent in the presence of a base and solvent to give a pyrazolecarboxylate of Formula 11a wherein Rla is alkyl, fluoroalkyl, alkenyl, fluoroalkenyl, alkynyl or fluoroalkynyl. Appropriate alkylating agents are typically of the formula RlaX (16) wherein X is a nucleophilic reaction leaving group (e.g., bromide, iodide, mesylate (OS(O)2CH3), triflate (OS(O)2CF3), tosylate (OS(O)2Ph-4-CH3), etc.). Typical bases include potassium tert-butoxide, potassium carbonate, sodium hydride and potassium hydroxide. Typical solvents include N,N-dimethylfoιmarnide, acetonitrile and tetrahydrofuran. A particularly useful combination of base and solvent is potassium carbonate in acetonitrile. Alkylation isomers can be separated by common methods such as chromatography and crystallization. This modification is illustrated in Step C of Example 1. Also, some of the Rla groups can be converted to others on compounds of Formula 11a. For example, when Rla is 2-hydroxyethyl, treatment with DAST (diethylaminosulfur trifluoride) typically gives a mixture of 2-fluoroethyl and vinyl for Rla. The product compounds of Formula 11a wherein Rla is 2-fluoroethyl and vinyl can then be separated by methods known in the art such as chromatography on silica gel and crystallization. Alternate approaches to construct R2a using variations of the process of Scheme 5 are feasible. For example, a compound of Formula 11a wherein R2a is a 1,1-dimethyl- 2-haloethyl group can be prepared by first including R2a in Formula 12 as a 1,1-dimethyl- 2-hydroxyethyl group protected as a tetrahydropyranyl ether (e.g., prepared from dihydropyran and pyridinyl p-tosylate (PPTS) using the general procedure of M. Miyashita et al., J. Org. Chem. 1977, 142(23), 3772-3774), and then after preparation of the pyrazole ring according to the process of Scheme 5, deprotecting using PPTS to give the corresponding alcohol, which can then be converted to the mesylate using methanesulfonyl chloride and base, which is then displaced using an appropriate inorganic halide salt in N,N-dimethylformamide according to the general methods disclosed by P. Sulmon et al., Organic Preparations and Procedures Int. 1989, 21(1), 91-104 and European Patent EP-25,948-Bl. Similarly, substituents can be completed after conducting the processes of other Schemes described herein as an alternative to including the substituents in final form in the starting materials for the processes. Carboxylic esters of Formula 12b (Formula 12 wherein J is J-2 and R31 is ethyl) and Formula 12c (Formula 12 wherein J is J-3 and R31 is ethyl) wherein Rlb is alkyl, fluoroalkyl, alkenyl, fluoroalkenyl, alkynyl or fluoroalkynyl can be prepared from sydnones of Formula 17 and alkynes of Formula 18 according to the general method of J. Heterocycl. Chem. 1993, 30, 365-371 and J. Heterocycl. Chem. 1996, 33, 719-726 as depicted in Scheme 6. (One skilled in the art recognizes that to prepare lib without a substituent at the pyrazole 5-position as specified for Formula lib (J-2), the R3 radical in the sydnone of Formula 17 must be hydrogen.) Scheme 6
Figure imgf000023_0001
In this method, sydnones of Formula 17 are heated with alkynes of Formula 18 in higher boiling solvents (e.g., xylenes, toluene, dioxane, ethylene glycol) for typically 12-72 hours. The isomers lib and lie then can be separated by the usual methods such as column chromatography and distillation. The sydnones of Formula 17 can be prepared using the general methods described in /. Heterocycl. Chem. 1993, 30, 365-371, J. Heterocycl. Chem. 1996, 33, 719-726 and the references cited therein. The method of Scheme 6 is illustrated in Step A of Example 7. Carboxylic esters of Formula lid (Formula 11 wherein J is J-3 but R2c can be H as well as R2b; R3 is H and R31 is ethyl) wherein Rlb is alkyl, fluoroalkyl, alkenyl, fluoroalkenyl, alkynyl or fluoroalkynyl can also be prepared according to the method depicted in Scheme 7 wherein R32 is NMe2 or OEt when (MeO)2CHNMe2 or HC(OEt)3, respectively, is used to prepare the intermediate of Formula 20. Scheme 7
Figure imgf000023_0002
In this method the intermediate of Formula 20 is prepared from the ketoester of Formula 19 according to the general procedures published in J. Heterocycl. Chem., 1987, 24, 693-695. The starting ketoesters of Formula 19 can, in turn, be prepared according to the general procedures of J. Org. Chem. 1997, 62, 5908-5919. The condensation of the ketoester of Formula 20 with the hydrazine of Formula 21 is typically conducted in an alcohol, ester or carbonate diester solvent. The hydrazine of Formula 21 can be in the form of a salt. When R2c is H, the pyrazolecarboxylate of Formula lid can be alkylated with the appropriate alkylating agent in the presence of a base and solvent to give a pyrazolecarboxylate of Formula lid wherein R2 is R2b. Appropriate alkylating agents are typically of the formula R2bX (22) wherein X is a nucleophilic reaction leaving group (e.g., bromide, iodide, mesylate (OS(O)2CH3), triflate (OS(0)2CF3), tosylate (OS(O)2Ph-4-CH3), etc.). Typical bases include potassium tert-butoxide, potassium carbonate, sodium hydride and potassium hydroxide. Typical solvents include N,N-dimethylformamide, acetonitrile and tetrahydrofuran. Alkylation isomers can be separated by common methods such as chromatography and crystallization. Compounds of Formula lib (i.e. pyrazole isomer J-2) can also be prepared using methods or slight modification thereof taught in: J. Heterocycl. Chem. 1999, 36(1), 217- 220, Agric. Biol. Chem. 1984, 48(1), 45-50, Bull. Soc. Chim. Fr. 1978, (7-8, Pt. 2), 401-14, Khim. Geterotsikl. Soedin. 1968, 4(4), 685-94, European Patent Application Publication EP 419917 and Spanish Patent ES 493459 (1981). Compounds of Formula lie (i.e. pyrazole isomer J-3) can also be prepared using methods or slight modification thereof taught in: J. Heterocycl. Chem. 1991, 2S(6), 1545-7, J. Heterocycl. Chem. 1987, 24(6), 1669-75, J. Chem. Res., Synop. 1986, (5), 166-7, Aust. J. Chem. 1983, 36(1), 135-47, Japanese Patent Application Publications JP 01061463, JP 01106866, JP 01061463 and JP 04021671, and Japanese Patents JP 2000212166 and JP 2000044541. As shown in Scheme 8, pyrazoles of Formulae lib and lie (wherein Rlb is halogen) can be prepared from corresponding pyrazoles of Formula lie (Formula 11 wherein J is J-2 but Rlb is H; and R31 is ethyl) and Formula llf (Formula 11 wherein J is J-3 but Rlb is H; and R31 is ethyl), respectively. Scheme 8
Figure imgf000024_0001
Figure imgf000025_0001
llf lie
One variation of the method of Scheme 8 involves heating a compound of Formula lie or llf with N-chloro- or N-bromosuccinimide in an organic solvent such as N,N-dimethyl- formamide, at temperatures between 30 and 110 °C, preferably at about 60 °C. Alternatively, bromine or chlorine can be added at or below room temperature to a compound of Formula lie or llf in a halocarbon solvent such as dichloromethane, trichloromethane or tetrachloromethane to give the corresponding compound of Formula lib or lie, respectively. Pyrazoles of Formula lib and lie wherein Rlb is halogen can also be prepared using the general methods taught in: Bulletin of the Korean Chemical Society 1998, 19(7), 725- 726, Izv. Akad. Nauk SSSR, Ser. Khun. 1981, (6), 1342-8, Izv. AJcad. Nauk SSSR, Ser. Khim. 1980, (5), 1071-7, J. Heterocycl. Chem. 1997, 34(2), 537-540, J. Heterocycl. Chem. 1991, 25(8), 1849-52, J. Fluorine Chem. 1988, 39(3), 435-40, U.S. Patent No. 5201938, German Patent Application Publication DE 19632945-A1, and Japanese Patent Application Publications JP 10114750, JP 06056793, JP 05339242, JP 05043553, JP 03133961 and JP 01029364. Thiazolecarboxylates of Formula llg (Formula 11 wherein J is J-4) can be prepared as illustrated in Scheme 9. Scheme 9
Figure imgf000025_0002
This method starts with an acyl chloride of Formula 23, which can be prepared by a variety of general methods known in the art; many acyl chlorides of Formula 23 are commercially available. The acyl chloride of Formula 23 is treated with an ammonia solution to prepare the carboxamide of Formula 24, which is in turn treated with a thionating reagent such as Lawesson's Reagent (2,4-bis(methoxyphenyl)-l,3-dithia-2,4-diphosphetane-2,4-disulfide) to prepare the thioamide of Formula 25. The thioamide of Formula 25 is then reacted with the chloro compound of Formula 26 to provide the thiazolecarboxylate of Formula llg. Carboxylic esters of Formula llh (Formula 11 wherein J is J-5) can be prepared by the general method shown in Scheme 10. Scheme 10
Figure imgf000026_0001
In this method, an alpha-bromo ketone of Formula 27 is converted to a Wittig reagent of Formula 28 and then condensed with a 2-oxocarboxylic acid ester of Formula 29 to provide a 4-oxo-2-pentenoic ester of Formula 30 according to the general procedure of P. F. Schuda et al., Synthesis 1987 (12), 1055-7. The 4-oxo-2-pentenoic ester of Formula 30 is then condensed with a hydrazine of Formula 31 to form the carboxylic ester of Formula llh according to the general procedures of G. Westphal & H. H. Stroh, Liebigs Ann. Chem. 1968, 716, 160-163 and R. C. Moreau & P. Loiseau, Annales Pharmaceutiques Francoises 1978, 36 (1-2), 67-75. Carboxylic esters of Formula Hi (Formula 11 wherein J is J-6 and R3i is ethyl) wherein Rld is H, alkyl, fluoroalkyl, alkenyl, fluoroalkenyl, alkynyl or fluoroalkynyl can be prepared from sydnones of Formula 17 and alkenes of Formula 32 according to the general methods described in Z. Obshch. Khim. 1962, 32(5), 1446-1451 as depicted in Scheme 11. Scheme 11
Figure imgf000026_0002
In this method, sydnones of Formula 17 are heated with alkenes of Formula 32 in higher boiling solvents (e.g., xylenes, toluene, dioxane, ethylene glycol) for typically 12-72 hours. The isomer Hi can then be isolated by the usual methods such as column chromatography and distillation. The ester of Formula Hi can then be converted to the corresponding carboxylic acid as described for Scheme 4 and coupled to form the compound of Formula la as described for Schemes 1 and 2. Most Rl substituents can be introduced as Rld in the method of Scheme 11, but halogen cannot. Halogen as well as other Rlb substituents can be introduced in the method shown in Scheme 12. Scheme 12
Figure imgf000027_0001
Figure imgf000027_0002
electrophile Ic (Rid is H) Ic (Rid is Rlb)
In this method, the compound of Formula Ic wherein Ri is Rib is prepared from the compound of Formula Ic wherein Rid is H. The compound of Formula Ic wherein Rid is H is then deprotonated using a strong base such as lithium diisopropylamide (LDA) and then reacted with an electrophile introducing Rlb. This general method is discussed by T. M. Stevenson et al., "l-Arylpyrazoline-3-carboxanilides" in Synthesis and Chemistry of Agrochemicals TV (D. R. Baker et al., Eds., American Chemical Society, Washington, D.C., 1995) Chapter 26, pp. 291-299. For halogenation, the electrophile can be elemental halogen (e.g., Cl2, Br2) or a halogen derivative such as N-bromosuccinimide or N-chlorosuccinimide. When Rlb is alkyl, fluoroalkyl, alkenyl, fluoroalkenyl, alkynyl or fluoroalkynyl the electrophile is typically of the formula Rlbχ (33) wherein X is a nucleophilic reaction leaving group as already described for the compound of Formula 16 in connection with the modified method of Scheme 5. Carboxylic esters of Formula llj (Formula 11 wherein J is J-7) can be prepared by the general method shown in Scheme 13. Scheme 13
Figure imgf000027_0003
In this method, a 3-oxo-carboxylic acid ester of Formula 34 is condensed with an aldehyde of Formula 35 to provide an unsaturated ester of Formula 36, which is condensed with a hydrazine of Formula 37 to provide the carboxylic ester of Formula llj according to the general procedure of P. S. Engel et al., J. Am. Chem. Soc. 1997, 119 (26), 6059-6065. The ester of Formula llj can then be converted to the corresponding carboxylic acid as described for Scheme 4 and coupled to form the compound of Formula la as described for Schemes 1 and 2. Alternatively as shown in Scheme 14, the coupling can be conducted first to prepare the amide of Formula 38, which is then condensed with the aldehyde of Formula 35 to prepare the unsaturated amide of Formula 39, which is condensed with the hydrazine of Formula 37 to prepare the compound of Formula Id. Scheme 14
Figure imgf000028_0001
Carboxylic esters of Formula Ilk (Formula 11 wherein J is J-8) can be prepared by the general method shown in Scheme 15. Scheme 15
Figure imgf000028_0002
In this method, an alkynecarboxylic acid ester of Formula 18 is heated with an excess of azidotrimethylsilane at a temperature of about 100-110 °C under an inert atmosphere. The reaction is worked up by treating the cooled reaction mixture with excess methanol to consume remaining trimethylsilyl azide and desilylate the azide adduct. Evaporation leaves the 1,2,3-triazole of Formula 40. These conditions are described by R. S. Klein et al., J. Heterocycl. Chem. 1976, 13, 589-592 and illustrated by Step A of Example 4. The triazole of Formula 40 is then converted to the triazole of Formula Ilk by alkylation with 2bχ3 (4i) wherein X3 is a nucleophilic reaction leaving group such as CI, Br, I, sulfonates such as p-toluenesulfonate, methanesulfonate or trifluoromethanesulfonate, or sulfates such as -OSO2OR2b. Preferably, X3 is a strong leaving groups such as I. The reaction is conducted in the presence of a base such as potassium carbonate in a polar aprotic solvent such as acetonitrile at a temperature commonly between 40 and 80 °C, typically about 50- 60 °C. Filtration to remove solid byproducts and evaporation of the solvent leaves a crude product containing the triazole of Formula Ilk typically together with other alkylation regioisomers. The triazole of Formula Ilk can be isolated and purified by the usual methods known to those skilled in the art such as chromatography and crystallization. When R2b is a tertiary alkyl group such as tert-butyl, alkylation with R2bχ3 may give low yields. Compounds of Formula Ilk wherein R2b is a tertiary alkyl group can be satisfactorily prepared from compounds of Formula 40 by reaction with the appropriate alcohol R2bOH (42) in trifluoroacetic acid solution in the presence of concentrated sulfuric acid according to the general procedure of J. W. Tilley et al., J. Med Chem. 1991, 34(3), 1125-1134. This method is illustrated by Step B of Example 4. Scheme 16 describes another method for preparing carboxylic ester intermediates of Formula Ilk (Formula 11 wherein J is J-8). Scheme 16
Figure imgf000029_0001
According to the method of B. Iddon and M. Nicholas, J. Chem. Soc, Perkin Trans. 1 1996, 1341-1347, bromine is added to an aqueous solution of 1,2,3-triazole (43), and 4,5-dibrorno-l,2,3-triazole (44) is collected by filtration. This is then alkylated with R2b using either an alkylating agent of Formula 41 or an alcohol of Formula 42 to provide the compound of Formula 45 using methods analogous to those already described for conversion of Formula 40 to Formula Ilk in Scheme 15. Following the general method of B. Iddon and M. Nicholas, J. Chem. Soc, Perkin Trans. 1 1996, 1341-1347, the compound of Formula 45 is lithiated using n-butyllithium in an ether solvent such as ethyl ether or tetrahydrofuran at -70 to -100 °C, optionally magnesium bromide is added, followed by ethyl chloroformate to give the compound of Formula Ilk where R is Br. Lithiation using n-butyllithium in tetrahydrofuran at -78 °C, followed by addition of ethyl chloroformate works well. The compound of Formula Ilk where Rlb is Br is useful for preparing compounds of Formula I where J is J-8 and Rib is Br. Furthermore, Br can be replaced by other Rlb groups such as vinyl by a variety of coupling methods known in the art. For example, the bromine can be replaced by a 1 -alkenyl group through mediation of a palladium catalyst in the Heck Reaction (for reviews, see R. A. Abramovitch et al., Tetrahedron 1988, 44(11), 3039-3071; W. Cabri and I. Candiani, Synthesis 1995, 2S(1), 2- 7; and R. F. Heck, "Palladium-catalyzed Vinylation of Organic Halides", Chapter 2 in Organic Reactions, Vol. 27, Wiley: New York, 1982, pp. 345-390). The Heck Reaction is compatible with some fluoroalkenes, such as 3,3,3-trifluoropropene; see G. Meazza et al., Pestic. Sci. 1992, 35, 137-144. Furthermore, compounds of Formula 17k where Rlb is Br can be reacted with alkenyl- and alkynyl- stannanes to afford alkenyl and alkynyl groups, respectively, as Rlb by use of the Stille Reaction, as reviewed by V. Farina et al., "The Stille Reaction", Chapter 1 in Organic Reactions, Vol. 50, Wiley: New York, 1997, pp. 1-652. Although ethyl esters are shown for the compounds of Formulae 18, 40 and Ilk, one skilled in the art recognizes that corresponding esters wherein ethyl is replaced by other carbon-based radicals, e.g., R31, can be used as well for this method. Also known in the art are other methods to prepare 1,2,3-triazole rings, such as those described in PCT Patent Publication WO 02/096258. Carboxylic esters of Formula 111 (Formula 17 wherein J is J-9) can be prepared by the general method shown in Scheme 17. Scheme 17
Figure imgf000030_0001
In this method, a iminoacetate of Formula 46 is reacted with a carboxylic acid hydrazide of Formula 47 in a suitable solvent such as dichloromethane to give the adduct of Formula 48. Although the reaction can be conducted at higher temperatures, it typically proceeds at a useful rate even at room temperature. The compound of Formula 48 is then cyclized to give the triazole of Formula 49 by heating to a sufficiently high temperature, typically around 200 °C. Although the reaction can be conducted using a high boiling solvent, most conveniently it is done in the absence of solvent. The triazole of Formula 49 is then alkylated using RlaX (16) in the presence of a base and solvent, analogous to the alkylation of pyrazoles already described as a modification of the method of Scheme 5. Amino compounds of Formula 2 can be prepared by a wide variety of methods available to the synthetic organic chemist. Many of these methods involve converting one substituent to another on the aromatic ring. For example, the amino function of Formula 2a can be obtained by reduction of the nitro compound of Formula 51 as shown in Scheme 18. Scheme 18
Figure imgf000031_0001
51 2a
The nitro compound of Formula 51 can be reduced to the aniline of Formula 2a by a variety of reducing agents known in the art, such as iron in acetic acid, tin(II) chloride or hydrogenation over a palladium or platinum sulfide catalyst. The nitro function of Formula 60 can be added by well known nitration reactions. The method of Scheme 18 is illustrated by Step B of Example 2 and Step B of Example 13. Many compounds of Formula 51 are commercially available and others can be readily prepared by methods well known in the art. When T, U and/or Z are N, the aryl ring of Formula 2 is activated to nucleophilic substitution facilitating introduction of amino by displacement of leaving groups such as halogen. For example, compounds of Formula 51b can be prepared from compounds of Formula 51 by the method of M. F. McKay et al., Aust. J. Chem. 1993, 46, 417 shown in Scheme 19. Scheme 19
Figure imgf000031_0002
52 2b wherein U1, U2 and U3 are independently N or CH optionally substituted by R21.
In this method a compound of Formula 52 and a compound of Formula 53 are heated with a base (e.g., K2CO3, KOt-Bu, NaH) in an inert solvent (e.g., toluene, xylene, tetrahydrofuran) for typically 6-24 hours. The compound of Formula 2b can be isolated by conventional methods such as recrystallization or chromatography. This method is particularly useful for preparing compounds of Formula I wherein R5 is U-37, U-38, U-39 or U-40. Analogous to the method of Scheme 19, the R5 group can also be introduced by displacement using the compound of Formula 53 after formation of the carboxamide linkage in Formula I. Example 10 illustrates this method. Palladium-catalyzed displacement of a boronic acid functionality can also be used to prepare amino compounds of Formula 2. For example, compounds of Formula 2c can be prepared from boronic acid derivatives of Formula 54 and heterocyclic halides of Formula
55 using methods described in Palladium in Heterocyclic Chemistry (Tetrahedron Organic Chemistry Series Vol. 20), 2000, Li and Gribble, eds., as depicted in Scheme 20. Scheme 20
Figure imgf000032_0001
54 Base 2c wherein U is N or CH optionally substituted by R2*, Y1 is O, S or NH, and Xx is CI, Br or I, and x is an integer ranging from 0 to the available carbon valency on the heterocycle. In this method a boronic acid of Formula 54 is reacted with a heterocyclic halide of Formula 55 in a solvent (e.g., water, tetrahydrofuran, dimethoxyethane) in the presence of a base (e.g., triethylamine, K2CO3) and a palladium catalyst (e.g., tetrakis(triphenylphosphine)- ρalladium(O), palladium(II) acetate) at a temperature of 25-100 °C from about 2 to 48 hours. The compound of Formula 2c can be isolated by conventional techniques such as column chromatography. Compounds of Formula 54 are commercially available or can be prepared by known methods such as those described by J. Fielding et al., J. Org. Chem. 1999, 64, 4196 and Matondo et al., Synthetic Communications 2003, 33, 795. This method is particularly useful for preparing compounds of Formula I wherein R5 is U-2, U-3, U-4, U-6 or U-7. One skilled in the art recognizes that many heterocycles can be prepared starting with a carboxylic acid ester group or a derived functionality such as carboxaldehyde, ketone or nitrile group. Scheme 21 illustrates a method for preparing intermediates of Formula 55 wherein R4i is a carbon moiety such as C1-C5 alkyl or benzyl. Scheme 21
Figure imgf000033_0001
56 57 59
In the method of Scheme 21, the amino function of a compound of Formula 56 is protected as the acetamide by treatment with acetic anhydride. Treatment with potassium permanganate then oxidizes the aromatic methyl radical to a carboxylic acid function to provide the compound of Formula 57. The compound of Formula 57 is then treated with strong acid, such as hydrochloric acid and alcohol of Formula 58 to form the ester group and deprotect the amino radical. This method works particularly well for short aliphatic alcohols (e.g., R 1 is Me or Et). The carboxylic ester functionality of the intermediate of Formula 59 can then be elaborated to provide amino compounds of Formula 2 wherein R5 is a heterocyclic moiety. As already mentioned, many compounds of Formula I can be prepared by completing the R5 functionality after preparing the remainder of the molecule including the carboxamide linkage. As one of many examples, Scheme 22 illustrates the preparation of a compound of Formula le starting from a carboxylic acid of Formula 61. Scheme 22
Figure imgf000033_0002
Base le 61 rei n n is 1 or 2.
In this method the carboxylic acid of Formula 61 is converted to the corresponding intermediate carbonyl chloride by treatment with oxalyl chloride preferably in the presence of a catalytic amount of N,N-dimethylformamide in an inert solvent such as dichloromethane. The intermediate carbonyl chloride is then reacted with the appropriate amine of Formula 62 in the presence of a base (e.g., triethylamine, K2CO3, pyridine). Preferably the 2-3 equivalents of the base are used in respect to the carbonyl chloride compound. The compound of Formula le can then be isolated and purified by conventional methods such as column chromatography and crystallization. One skilled in the art recognizes that by including R24 substituents on the alkylene chain of the compound of Formula 62, corresponding compounds of Formula le having the heterocyclic group substituted with R24 can be prepared. This method is particularly useful for preparing compounds of Formula I wherein R5 is U-58 or U-67. This method is illustrated by Step E of Example 13. Compounds of Formula 61 can be prepared from compounds of Formula 62 as shown in Scheme 23. Scheme 23
Figure imgf000034_0001
62 61 wherein R42 is a carbon moiety such as C 1-C4 alkyl.
In this method, the ester compound of Formula 62 is converted to the corresponding carboxylic acid of Formula 61 by general procedures well known in the art such as by treatment with aqueous lithium hydroxide in tetrahydrofuran, followed by acidification. The compound of Formula 62 can in turn be prepared from coupling the corresponding amino compound with the appropriate azole carbonyl chloride of Formula 1 or azole carboxylic acid of Formula 2 using methods analogous to those described for Schemes 1 and 2. Compounds of Formula If can be prepared as shown in Scheme 24 by general methods described in Eur. J. Med. Chem. Chim. Ther. 1985, 20(1), 16; Synthesis 2000, 12, 1814; J. Org. Chem. 1977, 42, 1872; and J. Org. Chem. 1987, 52, 1017. Scheme 24
Figure imgf000034_0002
63 H wherein Y2 is O, S or NH, and n is 1 or 2.
In this method a nitrile of Formula 63 is heated with an amine of Formula 64 in a solvent such as ethanol, methanol or ethylene glycol for typically 12-72 hours. The compound of Formula If can then be isolated by conventional techniques such as column chromatography or crystallization. One skilled in the art recognizes that by including R24 substituents on the alkylene chain of the compound of Formula 64, corresponding compounds of Formula If having the heterocyclic group substituted with R24 can be prepared. This method is particularly useful for preparing compounds of Formula I wherein R5 is U-57, U-58, U-60, U-64, U-66 or U-67. Compounds of Formula If can be prepared as shown in Scheme 25 by the general method described in Heterocycles 1997, 45, 29. Scheme 25
Figure imgf000035_0001
65 ig wherein n is 1 or 2.
In this method a mixture of a diamine of Formula 65 with N,N-dimethylformamide dimethyl acetal is heated in a solvent (e.g., toluene, xylene, methanol, ethanol) for typically 12-72 hours. The product of Formula Ig can then be isolated using conventional techniques such as crystallization and column chromatography. Compounds of Formula 65 can be prepared as shown in Scheme 26 by the general method described in J. Med. Chem. 1997, 40, 3369. Scheme 26
Figure imgf000035_0002
66 65 wherein n is 1 or 2.
In this method a mixture of an amine of Formula 66 and an amine hydrobromide salt of Formula 67 is heated in a solvent (e.g., toluene, xylene) typically at reflux for 12-100 hours. The product of Formula 65 can then be isolated using conventional techniques such as crystallization and column chromatography. One skilled in the art recognizes that by including R24 substituents on the alkylene chain of the compounds of Formulae 65 and 67 or the acetal carbon of N,N-dimethylformamide dimethyl acetal corresponding compounds of Formula Ig having the heterocyclic group substituted with R24 can be prepared according to the methods of Schemes 25 and 26. These methods are particularly useful for preparing compounds of Formula I wherein R5 is U-61 or U-65. Compounds of Formula Ih can be prepared as shown in Scheme 27 by the general method described in Justus Liebigs Ann. Chem. 1893, 274, 326. Scheme 27
Figure imgf000036_0001
Heat in solvent 68 Ih wherein n is 1 or 2.
In this method a mixture of a hydrazine of Formula 68 and a dibromide of Formula 69 is heated in a solvent (e.g., toluene, xylene) in the presence of a base (e.g., aqueous KOH, NaOH or K2CO3) for typically 12-100 hours. The product of Formula Ih can then be isolated using conventional techniques such as crystallization and column chromatography. One skilled in the art recognizes that by including R24 substituents on the alkylene chain of the compound of Formula 69 corresponding compounds of Formula Ih having the heterocyclic group substituted with R24 can be prepared. These methods are particularly useful for preparing compounds of Formula I wherein R5 is U-63 or U-70. Compounds of Formula Ii can be prepared as shown in Scheme 28. Scheme 28
Figure imgf000036_0002
wherein R2 is H or alkyl.
In this method a nitrile of Formula 63 is converted to the compound of Formula 70 by treatment with hydroxylamine hydrochloride arid base (e.g., NaOH, KOH, Na2CO3) in a solvent (e.g., ethanol, methanol, water) and heating at reflux for 4-12 hours. The compound of Formula 70 can typically be isolated by crystallization. General procedures for this method are described in Synthesis 2000, 8, 1148 and Tetrahedron Lett. 2001, 42, 1495. The compound of Formula 70 is then treated with N,N-dimethylformamide dimethyl acetal to prepare a compound of Formula Ii wherein R2i is H according to the general procedure described in Syn. Comm. 1982, 12, 457. Alternatively, treatment of the compound of Formula 70 with a carboxylic acid anhydride of Formula 71 (e.g., acetic anhydride) at a temperature of 25-100 °C for 2-24 hours provides a compound of Formula Ii wherein R2i is the alkyl group derived from the acid anhydride. This method- ^particularly useful for preparing compounds of Formula I wherein R5 is U-32. This m t _ js illustrated by Steps C and D of Example 5. Compounds of Formula Ij can be prepared as shown in Scheme 29. Scheme 29
Figure imgf000037_0001
72 Ij wherein R2ia is H or alkyl.
In this method a nitrile of Formula 63 is converted to the compound of Formula 72 by treatment with hydrazine and base (e.g., NaOH, KOH, Na CO3) in a solvent (e.g., ethanol, methanol, water) and heating at reflux for 4—12 hours. A general procedure for this method is described in Angew. Chem. 1963, 75, 344. The compound of Formula 72 is then reacted with a compound of Formula 73 in the presence of a base (e.g., aqueous NaOH, KOH) at -20 to 0 °C for 2-12 hours to provide the compound of Formula Ij, which can be isolated using conventional techniques such as crystallization and column chromatography. A general procedure for this method is described in Chem. Ber. 1961, 94, 1682. This method is particularly useful for preparing compounds of Formula I wherein R5 is U-33. Compounds of Formula Ika can be prepared as shown in Scheme 30. Scheme 30
Figure imgf000038_0001
74 Ika
In this method a nitrile of Formula 63 is converted to an ethyl imidate of Formula 74 by treatment with a solution of hydrogen chloride in ethanol. This type of reaction is very well known in the art; see, for example, H. Emtenas et al., J. Org. Chem. 2001, 66, 6756-6761. A mixture of the ethyl imidate of Formula 74 and the compound of Formula 75 in acetic acid is then heated at reflux for 4—12 hours according to the general procedure of A. Lawson, J. Chem. Soc. 1957, 4225-4228. The compound of Formula Ika can be isolated by conventional techniques such as column chromatography and crystallization. One skilled in the art recognizes that by including R2 substituents on the alkylene chain of the compound of Formula 75 corresponding compounds of Formula Ika having the heterocyclic group substituted with R21 can be prepared. This method is particularly useful for preparing compounds of Formula I wherein R5 is U-13. Compounds of Formula I wherein R5 is U-13 and R22 is alkyl can be prepared by well known alkylation methods (using, for example, methyl iodide or ethyl bromide) from corresponding compounds wherein R22 is H. As an alternative method for preparing compounds of Formula I wherein R5 is U-13, compounds of Formula Ikb can be prepared according to the general method of Bull. Chem. Soc. Japan 1998, 71, 467 as shown in Scheme 31. Scheme 31
Figure imgf000038_0002
In this method, a compound of Formula 76 is reacted with a compound of Formula 77 in the presence of copper(I) iodide and a base (e.g., Cs2CO3, K2CO3, Na2CO3) in a solvent (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone) heated at reflux for 2-24 hours. The compound of Formula Ikb can be isolated by conventional techniques such as extraction, column chromatography and crystallization. Compounds of Formula II can be prepared according to the general method of B. Sezen and D. Sames, J. Am. Chem. Soc. 2003, 125, 5274-5275 as shown in Scheme 32. Scheme 32
Figure imgf000039_0001
78 II In this method, a mixture of a compound of Formula 76 and a compound of Formula 78 is heated in the presence of palladium(II) acetate and a base (e.g., MgO, Cs2CO3, Na2CO3, NaOH) in a solvent (e.g., tetrahydrofuran, dioxane, dimethoxyethane, water) for typically 12-24 hours. The compound of Formula II is isolated by conventional techniques such as column chromatography and crystallization. This method is particularly useful for preparing compounds of Formula I wherein R5 is U-12. Compounds of Formula I wherein R5 is U-12 and R22 is alkyl can be prepared by well known alkylation methods (using, for example, methyl iodide or ethyl bromide) from corresponding compounds wherein R22 is H. Compounds of Formula Im can be prepared as shown in Scheme 33. Scheme 33
Figure imgf000039_0002
SO wherein R2l is H, alkyl or haloalkyl.
In this method a ketone of Formula 79 is treated with a brominating agent (e.g., bromine, N-bromosuccinimide) in a solvent (e.g., trichloromethane, dichloromethane, tetrabromomethane, acetic acid). The bromoketone of Formula 80 can be isolated by conventional techniques such as column chromatography. This type of reaction is very well known in the art; see, for example, Chem. Soc Perk. Trans. 2 2001, 9, 1506. The bromoketone of Formula 80 is then reacted with an aldehyde of Formula 81 (e.g., formaldehyde, acetaldehyde, proprionaldehyde) and phosphorus sulfide in the presence of a base (e.g., piperidine, pyridine, morpholine) at room temperature according to the general procedures of Helv. Chim. Acta 1947, 30, 2058. This method is particularly useful for preparing compounds of Formula I wherein R5 is U-5. Compounds of Formula In can be prepared as shown in Scheme 34. Scheme 34
Figure imgf000040_0001
Jn
In this method phosphorous oxychloride is added to a solution of the ketone of Formula 79 in N,N-dimethylformamide at 0-5 °C, and the reaction mixture is then heated at 85 °C for 5- 10 hours according to the general procedure of Syn. Comm. 1995, 25, 1869. The compound of Formula 82 can be isolated by conventional techniques such as extraction, column chromatography and crystallization. Then the compound of Formula 82 is reacted with ammonium thiocyanate in a solvent (e.g., acetonitrile, tetrahydrofuran) at room temperature for 4-24 hours according to the general procedure of J. Prakt. Chem. 1976, 318, 507. The compound of Formula In can be isolated by conventional techniques such as column chromatography and crystallization. This method is particularly useful for preparing compounds of Formula I wherein R5 is U-9. Compounds of Formula lo can be prepared as shown in Scheme 35. Scheme 35
Figure imgf000040_0002
Figure imgf000041_0001
86 lo wherein R2ib is H, alkyl or haloalkyl.
In this method, following the general procedures of Can. J. Chem. 1970, 48, 467 and Synthesis 1989, 1, 12, an aldehyde of Formula 83 is reacted with hydroxylamine hydrochloride in a solvent (e.g., ethanol, methanol, trichloromethane, dichloromethane) at 25-100 °C for 4-24 hours. The solvent is then removed, and the isolated intermediate is redissolved in dichloromethane and treated with a chlorinating agent such as sodium hypochlorite, chlorine or N-chlorosuccinimide to provide the compound of Formula 84. The compound of Formula 84 is then reacted with an equimolar amount of the vinyl acetate of Formula 85 in the presence of triethylamine in a solvent (e.g., diethyl ether, tetrahydrofuran) at about 30 °C for 2-4 hours to form the intermediate of Formula 86. The intermediate of Formula 86 is then heated at 150-180 °C for a short period of time to provide the compound of Formula lo, which can be isolated by conventional techniques such as crystallization and column chromatography. This method is particularly useful for preparing compounds of Formula I wherein R5 is U-41. Compounds of Formula Ip can be prepared as shown in Scheme 36 by the general method described in Synthesis 2001, 1, 55. Scheme 36
Figure imgf000041_0002
87 Ip In this method a compound of Formula 87 is reacted with a hydrazine of Formula 88 in a solvent (e.g., acetic acid, proprionic acid) at 25-100 °C for 2-18 hours. The compound of Formula Ip can be isolated by conventional techniques such as column chromatography and crystallization. This method is particularly useful for preparing compounds of Formula I wherein R5 is U-25. This method is illustrated by Examples 8 and 9. Compounds of Formula Iq can be prepared as shown in Scheme 37 by the general method described in Helv. Chim. Acta 1947, 30, 2058. Scheme 37
Figure imgf000042_0001
iq
In this method a mixture of a bromoketone of Formula 80, formamide, phosphorus pentasulfide and a base (e.g., piperidine, morpholine) in a solvent (e.g., toluene, xylene) is held at 25-100 °C for typically 2-18 hours. The compound of Formula Iq can be isolated by conventional techniques such as crystallization or column chromatography. This method is particularly useful for preparing compounds of Formula I wherein R5 is U-28. Compounds of Formula Ir can be prepared as shown in Scheme 38 by the general method described in J. Org. Chem. 1990, 55, 929. Scheme 38
Figure imgf000042_0002
Ir
In this method a bromoketone of Formula 80 is heated with ammonium formate in formic acid solvent for 2-12 hours. The compound of Formula Ir can be isolated by conventional techniques such as crystallization or column chromatography. This method is particularly useful for preparing compounds of Formula I wherein R5 is U-27. Compounds of Formula Is can be prepared as shown in Scheme 39 by the general method described in Angew. Chem. 1959, 71, 754. Scheme 39
Figure imgf000043_0001
Is
In this method a bromoketone of Formula 80 is heated with formamide in a solvent (e.g., acetic acid, formic acid) for 2-12 hours. The compound of Formula Is can be isolated by conventional techniques such as crystallization or column chromatography. This method is particularly useful for preparing compounds of Formula I wherein R5 is U-31. Compounds of Formula I wherein R5 is U-31 and R22 is alkyl can be prepared by well known alkylation methods (using, for example, methyl iodide or ethyl bromide) from corresponding compounds wherein R22 is H. Compounds of Formula It can be prepared as shown in Scheme 40 by the general method described in Gen. Org. Chem. USSR 1959, 29, 2105. Scheme 40
Figure imgf000043_0002
It
In this method a mixture of a compound of Formula 74 and formic acid hydrazide in a solvent (e.g., toluene, xylene) is heated for 2-24 hours. The compound of Formula It can be isolated by conventional techniques such as crystallization or column chromatography. This method is particularly useful for preparing compounds of Formula I wherein R5 is U-36. Compounds of Formula I wherein R5 is U-36 and R22 is alkyl can be prepared by well known alkylation methods (using, for example, methyl iodide or ethyl bromide) from corresponding compounds wherein R22 is H. Compounds of Formula Iu can be prepared as shown in Scheme 41. Scheme 41
Figure imgf000044_0001
89 Iu
In this method a mixture of a compound of Formula 79, ethyl carbazate and /?-toluenesulfonic acid in a solvent (e.g., toluene, xylene) are heated at reflux with removal of water by a Dean-Stark apparatus f 15 hours according to the general procedure of
J. Org. Chem. 1996, 61, 8929. The resulting product of Formula 89 is then heated with thionyl chloride for 2-10 hours according to the general procedure of J. Am. Chem. Soc. 1955, 77, 5359. The product of Formula Iu is isolated by evaporation of the excess thionyl chloride and can be purified by conventional techniques such as column chromatography and crystallization. This method is particularly useful for preparing compounds of Formula I wherein R5 is U-35. Compounds of Formula Iv can be prepared as shown in Scheme 42 by the general method described in Chem. Ber. 1957, 90, 942. Scheme 42
Figure imgf000044_0002
Iv
In this method a mixture of a compound of Formula 87, formamide and ammonium formate in a high boiling solvent (e.g., xylene, toluene, dioxane, ethylene glycol) is heated for typically 12-72 hours. The compound of Formula Iv can be isolated by conventional techniques such as crystallization or column chromatography. This method is particularly useful for preparing compounds of Formula I wherein R5 is U-54. Compounds of Formula Iw can be prepared as shown in Scheme 43 by the general method described in Helv. Chim. Acta 1966, 49, 2466. Scheme 43
Figure imgf000045_0001
90 Iw
In this method a compound of Formula 90 is added to a solution of ammonia in a solvent (e.g., hexane, diethyl ether) at about -20 °C. After 2-12 hours the solvent is evaporated to leave the compound of Formula Iw, which can be purified by conventional techniques such as column chromatography and crystallization. This method is particularly useful for preparing compounds of Formula I wherein R5 is U-34. Compounds of Formula 90 can be prepared as shown in Scheme 44. Scheme 44
Figure imgf000045_0002
3. SCO, 91
In this method a compound of Formula 79 is reacted with sodium or sodium hydride in a solvent (e.g., diethyl ether, tetrahydrofuran) at 0 to 45 °C for 2-6 hours. The stirred mixture is then cooled to 0 °C, ethyl chloroformate is added, and the mixture is allowed to warm to room temperature. Thionyl chloride is added, and the reaction mixture is stirred for an additional 6-24 hours. The compound of Formula 91 is then isolated by conventional techniques such as extraction, column chromatography and crystallization. This procedure is a modification of one described in J. Chem. Soc. Perk. Trans. 1 2002, 3, 402. According to a general procedure described in Chem. Ber. 1976, 106, 435, a mixture of the compound of Formula 91 and sodium or potassium thiocyanate in a solvent (e.g., acetone, methyl ethyl ketone, cyclohexanone) is heated for 2-24 hours. The compound of Formula 90 is then isolated by conventional techniques. Compounds of Formulae Ixa and Ixb can be prepared as shown in Scheme 45. Scheme 45
Figure imgf000046_0001
Ixa I b
According to a general method of J. Heterocycl. Chem. 1998, 35, 405 and J. Med. Chem. 1984, 27, 1565, a mixture of a compound of Formula 63, sodium azide and ammonium chloride in a solvent (e.g., N,N-dimethylformamide, N-methylpyrrolidinone) is heated for 24-120 hours. The reaction product (Formulae Ixa and Ixb wherein R22 is H) can be isolated by conventional techniques such as crystallization. This product is then treated with a sulfate of Formula 92 (i.e. dimethyl sulfate for R22 being methyl or diethyl sulfate for R22 being ethyl) in the presence of a base (e.g., aqueous ΝaOH, KOH) and a phase transfer catalyst (e.g., tetrabutylammonium bromide) in a solvent (e.g., dichloromethane, toluene) according to a general method of J. Org. Chem. USSR 1984, 20, 357 to provide the isomers of Formulae Ixa and Ixb, which can be separated by column chromatography. This method is particularly useful for preparing compounds of Formula I wherein R5 is U-42 or U-43. Compounds of Formula Iy can be prepared as shown in Scheme 46 by the general methods described in Heterocycles 1982, 18, 117 and J. Org. Chem. 1995, 60, 6658. Scheme 46
catalyst solvent
Figure imgf000046_0003
Figure imgf000046_0002
93 iy wherein Y2 is O, S or ΝH.
In this method a zinc reagent of Formula 93 is reacted with an iodide of Formula 76 in the presence of a catalyst (e.g., Νi(dppe)Cl2, tetrakis(triphenylphosphine)palladium(0)) in a solvent (e.g., tetrahydrofuran, N,N-dimethylformamide) at 25-100 °C for 2-25 hours. The compound of Formula Iy can be isolated by conventional techniques such as column chromatography and crystallization. This method is particularly useful for preparing compounds of Formula I wherein R5 is U-22, U-23 or U-24. Compounds of Formula I wherein R5 is U-24 and R22 is alkyl can be prepared by well known alkylation methods (using, for example, methyl iodide or ethyl bromide) from corresponding compounds wherein R22 is H. The general method of Scheme 46 can also be used to prepare analogs of the compound of Formula Iy to include a six-membered heterocycle such as pyridinyl (also termed "pyridyl") instead of the 5-membered ring. This method is illustrated by Step B of Example 12. Compounds of Formula Iz can be prepared as shown in Scheme 47 by the general method described in Syn Comm. 2000, 30, 3501. Scheme 47
catalyst
Figure imgf000047_0002
solvent
Figure imgf000047_0001
94 Iz
In this method a boronic acid of Formula 94 is reacted with an iodide of Formula 76 in the presence of a catalyst (e.g., Ni(dppe)Cl2, tetrakis(triphenylphosphine)palladium(0)) in a solvent (e.g., tetrahydrofuran, N,N-dimethylformamide) at 25-110 °C for 2-25 hours. The compound of Formula Iy can be isolated by conventional techniques such as column chromatography and crystallization. This method is particularly useful for preparing compounds of Formula I wherein R5 is U-1. The method of Scheme 47 can also be used to introduce heterocycles as R5 by starting with a heterocyclic analogue of Compound 94. Furthermore, trialkyltin derivatives can be used instead of boronic acid derivatives. This method variation is illustrated by Example 11. As another variation on the method of Scheme 47, the reaction with the boronic acid derivative of Formula 94 can be conducted with precursor to the compound of Formula 76 before forming the carboxamide linkage. This method variation is illustrated by Example 3. Compounds of Formula Iaa can be prepared as shown in Scheme 48 by the general methods described by Lin and Lang, J. Org. Chem. 1980, 45, 4857. Scheme 48
Figure imgf000048_0001
96 Iaa
wherein R2lb is H, alkyl or haloalkyl.
In this method a compound of Formula 79 is reacted with a compound of Formula 95 in a solvent (e.g., toluene, N,N-dimethylformamide, or an excess of the compound of Formula 95) at 25-140 °C for 4 to 24 hours. The compound of Formula 96 can then be isolated by evaporating the solvent. Reaction of the compound of Formula 96 with hydroxylamine hydrochloride in an inert solvent (e.g., ethanol, dioxane) at 25-100 °C for 2 to 24 hours then provides a compound of Formula Iaa, which can be isolated using conventional techniques. This method is particularly useful for preparing compounds of Formula I wherein R5 is U-10. This method is illustrated by Steps B and C of Example 6, and Steps D and E of Example 7. Compounds of Formula 95 can be prepared by the general methods reviewed by Abudalla and Brinkkmeyer, Tetrahedron 1979, 35, 1675. Compounds of Formula lab can be prepared as shown in Scheme 49 by the general methods described in J. Heterocyclic Chem. 1991, 28, 17. Scheme 49
Figure imgf000048_0002
wherein R2 a is H, alkyl or haloalkyl.
In this method a compound of Formula 61 is reacted with oxalyl chloride in the presence of a catalytic amount of N,N-dimethylformamide typically in solvent such as dichloromethane at room temperature for 2-24 hours. Evaporating the solvent leaves the acid chloride derived from the compound of Formula 61. The acid chloride is then added to a solution of a compound of Formula 97 and a base (e.g., triethylamine, pyridine, N-methylmorpholine) in a solvent (e.g., dichloromethane, trichloromethane) at room temperature, and the reaction mixture is stirred for about 2-24 hours. The compound of Formula lab can then be isolated by evaporating the solvent and triturating with water. This method is particularly useful for preparing compounds of Formula I wherein R5 is U-18. Compounds of Formula lac can be prepared as shown in Scheme 50 by the general methods described in J. Heterocyclic Chem. 1991, 28, 17. Scheme 50
Figure imgf000049_0001
98 lac
wherein R21a is H, alkyl or haloalkyl.
In this method a compound of Formula 61 is reacted with oxalyl chloride in the presence of a catalytic amount of N,N-dimethylformamide typically in solvent such as dichloromethane at room temperature for 2-24 hours. Evaporating the solvent leaves the acid chloride derived from the compound of Formula 61. The acid chloride is then added to a solution of hydrazine in a solvent (e.g., dichloromethane, trichloromethane), and the reaction solution is stirred at room temperature for 2-4 hours. The compound of Formula 98 is isolated by evaporating the solvent. The compound of Formula 98 is then added to a stirred solution of a compound of Formula 99 and a base (e.g., triethylamine, pyridine, N-methylmorpholine) in a solvent (e.g., dichloromethane, trichloromethane, N,N-dimethylformamide) at room temperature, and the reaction mixture is stirred for about 2-24 hours. The compound of Formula lac then can be isolated using conventional techniques (e.g., washing with aqueous acid, column chromatography, crystallization). This method is particularly useful for preparing compounds of Formula I wherein R5 is U-14. Compounds of Formula lad can be prepared as shown in Scheme 51. Scheme 51
Figure imgf000050_0001
In this method a compound of Formula 61 is reacted with oxalyl chloride in the presence of a catalytic amount of N,N-dimethylformamide typically in solvent such as dichloromethane at room temperature for 2-24 hours. Evaporating the solvent leaves the acid chloride derived from the compound of Formula 61. The acid chloride is then reacted with thiosemicarbazide in the presence of a base (e.g., triethylamine, K2CO3, pyridine) according to general procedures of Indian J. Chemistry 1985, 24b, 1154 to provide the compound of Formula 100. The compound of Formula 100 is then cyclized in polyphosphoric acid at 80—120 °C for 1-2 hours according to general procedures of /. Chem. Soc. 1949, 1163 to provide the compound of Formula 101. The compound of Formula lad can then be obtained from the compound of Formula 101 by use of Sandmeyer reactions according to the general procedures of Chem. Ber. 1956, 89, 1534 and Tetrahedron 1968, 24, 3209. This method is particularly useful for preparing compounds of Formula I wherein R5 is U-15. Compounds of Formula 2d can be prepared as shown in Scheme 52 by the general methods described in Palladium in Heterocyclic Chemistry, (Tetrahedron Organic Series Volume 20), 2000, Li and Gribble eds., Chapters 4, 10 and 11. Scheme 52
Figure imgf000051_0001
wherein U5, U6, U7 and U8 are independently N or CH optionally substituted by R2 ; X2 is Br or I; and x is an integer ranging from 0 to the available carbon valency on the heterocycle. In this method a compound of Formula 54 and a compound of Formula 111 are dissolved in a solvent (e.g., water, dioxane, tetrahydrofuran, N,N-dimethylformamide), and a base (e.g., Νa2CO3, K2CO3, triethylamine) is added, followed by a catalytic amount of a palladium derivative (e.g., tetrakis(triphenylphosphine)palladium(0), palladium(H) acetate). The reaction mixture is heated at 100-150 °C for about 2-24 hours. The compound of Formula 2d can be isolated by conventional techniques such as column chromatography. This method is particularly useful for preparing compounds of Formula I wherein R5 is a heterocycle selected from U-44 to U-56. This method is illustrated by Step F of Example 1. Compounds of Formula 54 are commercially available or can be prepared by known methods (see, for example, J. Fielding et al., /. Org. Chem. 1999, 64, 4196 and Matondo et al., Synthetic Comm. 2003, 33, 795). Compounds of Formula 111 are also commercially available or can be prepared by known methods. Compounds of Formula 2d wherein R4 is H can also be prepared as shown in Scheme 53 by the general methods described in Palladium in Heterocyclic Chemistry, (Tetrahedron Organic Series Volume 20), 2000, Li and Gribble eds., Chapters 4, 10 and 11. Scheme 53
Figure imgf000051_0002
wherein U5, U6, U7 and Uδ are independently N or CH optionally substituted by R21; X2 is Br or I; X3 is CI, Br or I; and x is an integer ranging from 0 to the available carbon valency on the heterocycle. In this method a compound of Formula 112 is reacted with an organozinc compound of Formula 113 in the presence of a soluble palladium catalyst to provide a compound of Formula 114. The nitro group of the compound of Formula 114 can then be reduced to provide the compound of Formula 2d by a variety of reducing agents known in the art, such as iron in acetic acid, tin(II) chloride or hydrogenation over palladium catalyst. This method is particularly useful for preparing compounds of Formula I wherein R5 is a heterocycle selected from U-44 to U-56. This method is illustrated by Steps 1 and 2 of Example 2. Organozinc compounds of Formula 113 can be prepared by reacting the corresponding organic halide compounds with n-butyllithium or an isopropylmagnesium halide to produce an organometallic intermediate, which is then treated with a zinc halide. Compounds of Formula 2e can be prepared as shown in Scheme 54. Scheme 54
Figure imgf000052_0001
124 125 126
Figure imgf000052_0002
128 2e In this method a compound of Formula 125 is prepared by treating a compound of Formula 124 with hydrogen chloride in ethanol. This general transformation is well known in the art; see, for example, Heterocycles 1979, 12, 745. The compound of Formula 125 is then treated with hydrazine to provide the compound of Formula 126 according to methods described in J. Heterocyclic Chem. 1982, 19, 1205. The compound of Formula 126 is then reacted with a compound of Formula 117 to provide a compound of Formula 128 according to a general method described in J. Medicinal Chem. 1977, 20, 723. The nitro group of the compound of Formula 128 can be then reduced to give the amino compound of Formula 2e using methods already described for reduction of the compound of Formula 114 to the compound of Formula 2d in Scheme 53. This method is particularly useful to prepare compounds of Formula I wherein R5 is U-50. Compounds of Formula 2f can be prepared as shown in Scheme 55. Scheme 55
Figure imgf000053_0001
129 130 2f
In this method a compound of Formula 129 is reacted with hydroxylamine hydrochoride in ethanol at 25-80 °C for 4-12 hours. The compound of Formula 130 is isolated by pouring the reaction mixture into water, extracting with dichloromethane, and evaporating the solvent. The nitro group of the compound of Formula 130 can be then reduced to give the amino compound of Formula 2f using methods already described for reduction of the compound of Formula 114 to the compound of Formula 2d in Scheme 53. This method is particularly useful for preparing compounds of Formula I wherein R5 is U-30. Compounds of Formula 129 can be prepared by methods known in the art; see, for example, J. Org. Chem. 1979, 44, 3748 and /. Heterocyclic Chem. 1974, 11, 52. Compounds of Formula 2g can be prepared as shown in Scheme 56. Scheme 56
Figure imgf000053_0002
In this method a compound of Formula 131 is prepared from a compound of Formula 129 by treatment with thionyl chloride according to a general method of J. Heterocyclic Chem. 1974, 11, 52. The compound of Formula 131 is then heated with ammonium thiocyanate in a solvent (e.g., acetone, methyl ethyl ketone) at a temperature of 50-100 °C for about 4—6 hours. The compound of Formula 132 can be isolated by conventional methods such as washing with base, column chromatography and crystallization. The nitro group of the compound of Formula 132 can be then reduced to give the amino compound of Formula 2g using methods already described for reduction of the compound of Formula 114 to the compound of Formula 2d in Scheme 53. This method is particularly useful for preparing compounds of Formula I wherein R5 is U-29. Compounds of Formula 2h can be prepared as shown in Scheme 57. Scheme 57
Figure imgf000054_0001
135 2h
In this method a compound of Formula 131 is reacted with a hydrazine of Formula 134 in ethanol at 25-80 °C for about 1-6 hours according to the general method of Heterocycles 1982, 19, 1223. The compound of Formula 135 can be isolated by conventional techniques such as column chromatography and crystallization. The nitro group of the compound of Formula 135 can be then reduced to give the amino compound of Formula 2h using methods already described for reduction of the compound of Formula 114 to the compound of Formula 2d in Scheme 53. This method is particularly useful for preparing compounds of Formula I wherein R5 is U-26. Compounds of Formula Iae can be prepared as shown in Scheme 58 by the general procedures described in Synthesis 1983, 483. Scheme 58
Figure imgf000054_0002
142 Iae
wherein R21a is H, alkyl or haloalkyl.
In this method a compound of Formula 74 is dissolved in a solvent such as toluene, and triethylamine is added. The stirred reaction mixture is cooled to 0 °C, the acid chloride of Formula 141 is added, and the reaction mixture is allowed to warm and is held at room temperature for 24 hours. The product of Formula 142 is isolated by conventional techniques and then is dissolved in a solvent (e.g., dichloromethane, trichloromethane, tetrachloromethane). A hydrazine of Formula 134 is added, and the reaction mixture is stirred 1-2 hours at room temperature. The compound of Formula Iae can be isolated by conventional techniques such as column chromatography and crystallization. This method is particularly useful for preparing compounds of Formula I wherein R5 is U-16. Compounds of Formula laf can be prepared as shown in Scheme 59 by the general procedures described by G. Nerardo et al., Tetrahedron 1997, 53, 3707-3722. Scheme 59
Figure imgf000055_0001
laf
In this method a compound of Formula 68 is reacted with an acetal of Formula 143 in the presence of sodium borohydride and 6 M sulfuric acid in a suitable solvent such as tetrahydrofuran at a temperature of about 5 °C. To isolate the compound of Formula laf, sodium hydroxide is added to make the reaction mixture strongly basic, and then the reaction mixture is extracted with diethyl ether solvent. Evaporation of the solvent leaves the compound of Formula laf, which can be purified by techniques such as washing with dilute acid or aqueous copper(JJ) acetate, and column chromatography and crystallization. This method is particularly useful for preparing compounds of Formula I wherein R5 is U-70. Compounds of Formula lag can be prepared as shown in Scheme 60 by the general procedures described by D. E. Davies et al., J. Chem. Soc. Perkin Trans. 1 1983, 1275-1281. Scheme 60
Figure imgf000055_0002
144 lag
In this method a compound of Formula 80 is treated with hydroxylamine or a hydroxylamine salt such as hydroxylamine hydrochloride or hydroxylamine sulfate in a suitable solvent such as methanol-water or ethanol-water mixtures. The compound of Formula 144 is isolated by conventional techniques and then is reacted with an olefin of Formula 145 in the presence of a base such as sodium carbonate in a solvent such as dichloromethane. The compound of Formula lag is isolated by conventional techniques such as column chromatography and crystallization. This method is particularly useful for preparing compounds of Formula I wherein R5 is U-69. Compounds of Formula lah can be prepared as shown in Scheme 61. Scheme 61
Figure imgf000056_0001
146 147 lah
In this method an amino compound of Formula 146 is diazotized using sodium nitrite and a mineral acid such as hydrochloric acid in a solvent such as water, and the reaction product is reduced using tin(II) chloride to provide the hydrazine of Formula 147. The compound of Formula 147 is heated with 1,1,3,3-tetraethoxypropane in a suitable solvent such as ethanol to provide the compound of Formula lah, which can be isolated by evaporation of the solvent and purified by conventional techniques such as column chromatography and crystallization. This method is particularly useful to prepare compounds of Formula I wherein R5 is U-38. This method is illustrated by Example 14. It is recognized that some reagents and reaction conditions described above for preparing compounds of Formula I may not be compatible with certain functionalities present in the intermediates. In these instances, the incorporation of protection/deprotection sequences or functional group interconversions into the synthesis will aid in obtaining the desired products. The use and choice of the protecting groups will be apparent to one skilled in chemical synthesis (see, for example, T. W. Greene, P. G. M. Wuts, Protective Groups in Organic Synthesis, 2nd ed.; Wiley: New York, 1991). One skilled in the art will recognize that, in some cases, after the introduction of a given reagent as it is depicted in any individual scheme, it may be necessary to perform additional routine synthetic steps not described in detail to complete the synthesis of compounds of Formula I. One skilled in the art will also recognize that it may be necessary to perform a combination of the steps illustrated in the above schemes in an order other than that implied by the particular sequence presented to prepare the compounds of Formula I. One skilled in the art will also recognize that compounds of Formula I and the intermediates described herein can be subjected to various electrophilic, nucleophilic, radical, organometallic, oxidation, and reduction reactions to add substituents or modify existing substituents. Without further elaboration, it is believed that one skilled in the art using the preceding description can utilize the present invention to its fullest extent. The following Examples are, therefore, to be construed as merely illustrative, and not limiting of the disclosure in any way whatsoever. Steps in the following 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 Examples or Steps. Percentages are by weight except for chromatographic solvent mixtures or where otherwise indicated. Parts and percentages for chromatographic solvent mixtures are by volume unless otherwise indicated. H NMR spectra are reported in ppm downfield from tetramethylsilane; 19F NMR spectra are reported in ppm relative to CF3CC1 ; "s" means singlet, "d" means doublet, "t" means triplet, "q" means quartet, "m" means multiplet, "dd" means doublet of doublets, "ddd" means doublet of doublets of doublets, "dt" means doublet of triplets, "dq" means doublet of quartets, "br s" means broad singlet, "br d" means broad doublet. EXAMPLE 1 Preparation of 3-(l , 1 -dimethylethyl)- 1 -ethyl-N-[3-(2-pyridinyl)phenyl]-lH-pyrazole- 5-carboxamide (Compound 14) Step A: Preparation of ethyl 2-hydroxy-5,5-dimethyl-4-oxo-2-hexenoate To a solution of sodium ethoxide in ethanol (250 mL, 21% by weight in ethanol, 670 mmol) was added dropwise a solution of diethyl oxalate (45.2 mL, 332.5 mmol) and pinacolone (alternatively named 3,3-dimethyl-2-butanone) (41.7 mL) in ethanol (300 mL) at room temperature under nitrogen atmosphere. The reaction mixture was stirred at room temperature overnight, concentrated to its half volume and poured into ice. Concentrated hydrochloric acid was added to lower the pH to approximately 4, and then the mixture was extracted with ethyl acetate. The extracts were dried over magnesium sulfate and concentrated to give the title compound as an oil (60 g, yield 90%).
Step B: Preparation of ethyl 5-(l,l-dimethylethyl)-lH-pyrazole-3-carboxylate To a solution of ethyl 2-hydroxy-5,5-dimethyl-4-oxo-2-hexenoate (i.e. the product of
Step A) (45.3 g, 226 mmol) in ethanol (200 mL) and acetic acid (2 mL) was added hydrazine monohydrate (12.1 mL, 249 mmol) dropwise under nitrogen atmosphere at room temperature. The reaction mixture was stirred at room temperature overnight and concentrated to give 40.8 g of the title compound. lΗ ΝMR (CDC13) δ 6.7 (s, 1Η), 6.60 (br s, 1Η), 4.40 (q, 2Η), 1.40 (t, 3H), 1.32 (s, 9H). Step C: Preparation of ethyl 3-(l,l-dimethylethyl)-l-ethyl-lH-pyrazole-5-carboxylate To a solution of ethyl 5-(l,l-dimethylethyl)-lH-ρyrazole-3-carboxylate (i.e. the product of Step B) (20.0 g, 102 mmol) in anhydrous N,N-dimethylformamide (DMF) (100 mL) at room temperature was added sequentially potassium carbonate (28.2 g, 204 mmol) and iodoethane (11.4 mL, 143 mmol). After stirring at room temperature in an inert atmosphere for 6 h, the reaction mixture was diluted with ethyl acetate (400 mL) and washed with water (2 x 50 mL). The organic phase was separated, dried and concentrated. The residue was purified by chromatography on silica gel to give the desired isomer (i.e. the title compound) as a white solid (13.8 g, 64% yield) and a minor isomer (2.1 g, 10% yield). !Η ΝMR (CDC13) δ 6.7 (s, 1Η), 4.55 (q, 2Η), 4.32 (q, 2H), 1.40 (m, 6H), 1.32 (s, 9H). H ΝMR (CDC13) (minor isomer) δ 6.7 (s, IH), 4.20 (q, 2H), 4.30 (q, 2H), 1.36 (m, 6H), 1.32 (s, 9H).
Step D: Preparation of 3-(l,l-dimethylethyl)-l-ethyl-lH-pyrazole-5-carboxylic acid A solution of ethyl 3-(l,l-dimethylethyl)-l -ethyl- lH-pyrazole-5-carboxylate (i.e. the product of Step C) (6.9 g, 30.8 mmol) in ethanol (200 mL) was stirred with an aqueous solution of sodium hydroxide (10%, 19 mL) at room temperature for 6 h. The mixture was then concentrated and acidified with 1 Ν hydrochloric acid. The precipitated solids were filtered and dried to give 6 g of the title acid as a white solid. Η ΝMR (CDC13) δ 10.00 (s, 1Η), 6.80 (s, 1Η), 4.60 (q, 2Η), 1.40 (t, 3H), 1.32 (s, 9H).
Step E: Preparation of 3-(l,l-dimethylethyl)-l-ethyl-lH-pyrazole-5-carbonyl chloride A solution of 3-(l,l-dimethylethyl)-l-ethyl-lH-pyrazole-5-carboxylic acid (i.e. the product of Step D) (1.2 g, 6.11 mmol) and oxalyl chloride (2 mL) in dichloromethane (30 mL) in the presence of anhydrous DMF (0.1 mL) was stirred under nitrogen atmosphere at room temperature for 4 h. The reaction mixture was then concentrated to yield the title acid chloride as a liquid.
Step F: Preparation of 3-(2-pyridinyl)benzenamine To a solution of 2-bromopyridine (1.6 g, 10 mmol) in dimethoxyethane (50 mL) and water (17 mL) was added 3-aminoρhenylboronic acid hemisulfate (1.86 g, 10 mmol), sodium carbonate (5.6 g, 52.8 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.3 g). The mixture was heated to reflux for 5 hours and then allowed to cooled to room temperature. Brine (50 mL) was added, and the mixture was extracted with ethyl acetate (3 x 25 mL). The organic extracts were dried (MgSO^ and concentrated to leave the crude product. The crude product was purified by flash column chromatography to provide the title compound as a thick yellow oil (1.1 g). *Η ΝMR (CDC13) δ 8.6 (m, IH), 7.69(m, 2H), 7.3(m, 4H), 6.8(m, IH), 3.8 (br s 2H). Step G: Preparation of 3-(l,l-dimethylethyl)-l-ethyl-N-E3-(2-pyridinyl)ρhenyl]-lH- pyrazole-5-carboxamide To a solution of 3-(2-pyridinyl)benzenamine (i.e. the product of Step F) (0.34 g, 2 mmol) in dichloromethane (5 mL), triethylamine (0.3 mL, Z..2 mmol) was added, and the solution was cooled to 0 °C. To this a solution of 3-(l,l-dimethylethyl)-l-ethyl- lH-pyrazole-5-carbonyl chloride (i.e. the product of Step E) (0.43 g, 2 mmol) in dichloromethane (2 mL) was added over one minute, and then the mixture was allowed to come to room temperature while being stirred for one hour. The mixture was concentrated, and the residue was purified using a silica gel flash chromatography column eluted with hexane-ethyl acetate (8:2 and then 1:1) to provide the title? compound, a compound of present invention, as a white solid (0.25 g).
1Η ΝMR (CDC13) δ 8.7(m, 1Η), 8.2 (s, 1Η), 7.8 (m, 1Η), 7.77 (m, 4Η), 7.5 (m, IH), 7.23 (m, IH), 6.47 (s, IH), 4.59 (q, 2H), 1.49 (t, 3H), 1.36 (s, 9H). EXAMPLE 2 Preparation of 3-(l,l-dimethylethyl)-l-ethyl-N-[2-fluoro-5-(2-pyridinyl)phenyl]-lH- pyrazole-5-carboxamide (Compound 27)
Step A: Preparation of 2-(4-fluoro-3-nitrophenyl)pyridine Bromo-2-pyridinylzinc (alternatively named 2-pyridylzi c bromide, Aldrich Chemical Co., 0.5 M in tetrahydrofuran, 20 mL, 10 mmol) was added to a suspension of 4-bromo- l-fluoro-2-nitrobenzene (2.2 g, 10 mmol), and tetrakis(triphe ylphosphine)palladium(0) in N,N-dimethylformamide (20 mL). The mixture was heated at 90 °C for 15 h and then cooled to room temperature. The mixture was diluted with water (200 mL) and extracted with ethyl acetate (3 x 50 mL). The organic layer was washed successively with water (50 mL) and brine (50 mL). The organic layer was dried (MgSO^.) and concentrated to leave the crude product. The crude product was purified by column chromatography on silica gel to provide the title compound as a yellow solid (1.6 g). !Η ΝMR (CDC13) δ 8.72 (m, 2Η), 8.3 (m, IH), 7.77 (m, 2H), 7.43 (m, IH), 7.39 (m, IH).
Step B : Preparation of 2-fluoro-5-(2-pyridinyl)benzenarrjLine To a mixture of iron powder (0.325 g, 6 mmol) and ammonium chloride (0.325 g, 6 mmol) in water (1.5 mL) was added a solution of 2-(4-fluoro-3-nitrophenyl)pyridine (i.e. the product of Step A) (0.6 g, 2.75 mmol) in dichloromethane (2.2 mL) and isopropanol (2.2 mL). The mixture was heated at reflux over 2 h to remove the dichloromethane and then allowed to cool to room temperature. Ethyl acetate (25 xxύX) was added to the above mixture, which was stirred for 30 minutes and then filtered through Celite® diatomaceous filter aid. The filtrate was washed with water (10 mL) followed by brine (10 mL). The organic layer was dried (MgSO^ and concentrated to provide the title compound as a brown oil (0.4 g). H NMR (CDCI3) δ 8.66 (m, IH), 7.65 (m, IH), 7.64 (m, IH), 7.5 (m, IH), 7.25 (m, 2H), 7.00 (m, IH), 3.82 (br s, 2H)).
5 Step C: Preparation of 3-(l,l-dimethylethyl)-l-ethyl-N-[2-fluoro-5-(2-ρyridinyl)- henyl]-lH-pyrazole-5-carboxamide To a solution of 3-(l,l-dimethylethyl)-l-ethyl-lH-pyrazole-5-carboxylic acid (i.e. the product of Example 1, Step D) (0.2 g, 1 mmol) in dichloromethane (2 mL) at room temperature was added sequentially 1-propaneρhosphonic acid cyclic anhydride (50% in0 ethyl acetate, 0.5 g, 1.57 mmol) and 2-fluoro-5-(2-pyridinyl)benzenamine (i.e. the product of Step B) (0.2 g, 0.106 mmol). After stirring at room temperature 2 h the mixture was concentrated, and the residue was purified using silica gel column chromatography eluted with hexane-ethyl acetate (9:1 then 8:2) to provide the title product, a compound of the present invention, as a white solid (0.25 g). 5 Η ΝMR (CDC13) δ 9.0 (m, 1Η), 8.7 (m, 1Η), 7.9 (br s, 1Η), 7.8 (m, 1Η), 7.75 (d, 1Η), 7.24 (m, 2Η), 6.5 (s, IH), 4.6 (q, 2H), 1.44 (t, 3H), 1.34 (s, 9H). EXAMPLE 3 Preparation of N-(2',6'-difluoro[l,l'-biphenyl]-3-yl)-3-(l,l-dimethylethyl)-l-ethyl- lH-pyrazole-5-carboxamide (Compound 51)0 Step A: Preparation of 2',6'-difluoro[l,r-biphenyl]-3-amine To a solution of 2,6-difluorophenylboronic acid (0.8 g, 5 mmol) in a mixture of 1,2-dimethoxyethane (25 ml) and water (8 mL) was added 3-iodobenzenamine (alternatively named 3-iodoaniline; 1.1 g, 5 mmol), sodium carbonate (2.5 g, 23.6 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.15 g)rThe mixture was heated at reflux for 4 h
15 and then allowed to cool to room temperature. The reaction mixture was diluted with brine (50 mL) and extracted with ethyl acetate (3 x 50 mL). The organic layer was successively washed with water (25 mL) and brine (25 mL), dried (MgSO^.) and concentrated to leave the crude product. The crude product was purified by column chromatography on silica gel eluted with hexane-ethyl acetate (9:1) to provide the title compound as a thick yellow oil
50 (0.6 g). lΗ ΝMR (CDCI3) δ 7.4 ( , 1Η), 7.22 (m, 1Η), 6.89 (m, 4Η), 6.7 (m, IH), 3.8 (br s, IH). Step B Preparation of N-(2',6'-difluoro[ 1 , 1 '-biphenyl]-3-yl)-3-(l , 1 -dimethylethyl)- 1 -ethyl- lH-pyrazole-5-carboxamide To a solution of 3-(l,l-dimethylethyl)-l-ethyl-lH-pyrazole-5-carboxylic acid (i.e. the >5 product of Example 1, Step D) (0.2 g, 1 mmol) in dichloromethane (2 mL) at room temperature was added sequentially 1-propanephosphonic acid cyclic anhydride (50% in ethyl acetate, 0.5 g, 1.57 mmol) and 2',6'-difluoro[l,l'-biphenyl]-3-amine (i.e. the product of Step A) (0.21 g, 0.102 mmol). After stirring at room temperature 2 h the mixture was concentrated, and the residue was purified using silica gel column chromatography eluted with hexane-ethyl acetate (9:1) to provide the title product, a compound of the present invention, as a white solid (0.20 g). H NMR (CDCI3) δ 7.73 (m, 2H), 7.6 (m, IH), 7.43 (m, IH), 7.4 (m, IH), 6.95 (m, IH), 6.48 (s, IH), 4.58 (q, 2H), 1.42 (t, 3H), 1.33 (s, 9H). EXAMPLE 4 Preparation of 2-(l,l-dimethylethyl)-5-ethyl-N-[3-(2-pyridinyl)phenyl]-2H-l,2,3-triazole- 4-carboxamide (Compound 53)
Step A: Preparation of ethyl 5-ethyl-l,2,3-triazole-4-carboxylate Ethyl 2-pentynoate (16.6 g, 0.132 mol) and trimethylsilylazide (38.0 g, 0.333 mol) were stirred at 100-110 °C under nitrogen for 70 h. After cooling and dilution with methanol (60 mL) a white solid precipitated. After evaporation of the mixture under reduced pressure, the residue was crystallized from ethyl ether to afford the title product as a white solid (15.7 g, 0.093 mol, 70% yield). lΗ ΝMR (CDCI3) δ 4.42 (q, 2Η), 3.07 (q, 2H), 1.37 (t, 3H), 1.32 (t, 3H).
Step B: Preparation of ethyl 2-(l,l-dimethylethyl)-5-ethyl-2H-l,2,3-triazole- 4-carboxylate and ethyl l-(l,l-dimethylethyl)-4-ethyl-lH-l,2,3-triazole- 5 -carboxylate To a stirred solution of 5-ethyl-l,2,3-triazole-4-carboxylic acid ethyl ester (i.e. product of Step A) (1.05 g, 6.25 mmol) and tert-butyl alcohol (0.93 g, 12.5 mmol) in trifluoroacetic acid (6 mL) was added concentrated sulfuric acid (0.61 g, 6.25 mmol). After stirring at room temperature for 14 h, the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with water, saturated aqueous sodium carbonate and brine, and then dried (Νa2Sθ4). After concentration, the residue was purified by column chromatography to afford ethyl 2-(l,l-dimethylethyl)-5-ethyl-2H-l,2,3-triazole- 4-carboxylate (0.74 g, 3.76 mmol, 64% yield), followed by its isomer ethyl l-(l,l-dimethyl- ethyl)-4-ethyl-lH-l,2,3-triazole-5-carboxylate (0.24 g, 1.22 mmol, 21% yield) as colorless oils.
Ethyl 2-( 1 , 1 -dimethylethyl)-5-ethyl-2H- 1 ,2,3-triazole-4-carboxylate: lΗ NMR (CDCI3): 4.41 (q, 2Η), 2.93 (q, 2H), 1.68 (d, 9H), 1.40 (t, 3H), 1.27 (t, 3H).
Ethyl l-(l,l-dimethylethyl)-4-ethyl-lH-l,2,3-triazole-5-carboxylate:
1H NMR (CDCI3): 4.40 (q, 2H), 2.87 (q, 2H), 1.77 (d, 6H), 1.42 (t, 3H), 1.29 (t, 3H). Step C: Preparation of 2-(l,l-dimethylethyl)-5-ethyl-N-[3-(2-pyridinyl)phenyl]- 2H-l,2,3-triazole-4-carboxamide To a stirred solution of ethyl 2-(l,l-dimethylethyl)-5-ethyl-2/ϊ-l,2,3-triazole- 4-carboxylate (i.e. the first eluted product of Step B) (1.119 g, 5.64 mmol) in tetrahydrofuran (15 mL) was added a solution of lithium hydroxide (0.54 g, 22.56 mmol) in water (15 mL). The mixture was stirred at room temperature overnight, and then partitioned between ether and water. The aqueous layer was acidified with hydrochloric acid (6 Ν) to pΗ 1-2 and extracted with ethyl acetate, dried (Νa2Sθ4) and concentrated to provide the carboxylic acid intermediate as a white solid (0.94 g, 5.08 mmol, 90% yield). To a solution of the carboxylic acid intermediate (0.1 g, 0.5 mmol) in dichloromethane (2 mL) at room temperature was added sequentially 1-propanephosphonic acid cyclic anhydride (50% in ethyl acetate, 0.25 g, 0.785 mmol), 3-(2-ρyridinyl)benzenamine (i.e. the product of Example 1, Step F) (0.1 g, 0.58 mmol) and triethylamine (0.1 mL, 0.75 mmol). After stirring at room temperature 2 h the mixture was concentrated, and the residue was purified using silica gel column chromatography eluted with hexane-ethyl acetate (9:1) to provide the title product, a compound of the present invention, as an off-white solid (0.07 g). Η NMR (CDC13) δ 7.75 (m, 2Η), 8.2 (m, IH), 8.0 (d, IH), 7.8 (m, IH), 7.75 (m, 2H), 7.4 (t, IH), 7.25 (m, IH), 3.06 (m, 2H), 1.58 (s, 9H), 1.29 (t, 3H). EXAMPLE 5 Preparation of 3-(l,l-dimethylethyl)-l-ethyl-N-[3-(5-methyl-l,2,4-oxadiazol-3-yl)ρhenyl]- lH-ρyrazole-5-carboxamide (Compound 7)
Step A: Preparation of 3-(l,l-dimethylethyl)-l-ethyl-lH-pyrazole-5-carbonyl chloride A solution of 3-(l,l-dimethylethyl)-l-ethyl-lH-pyrazole-5-carboxylic acid (i.e., product of Example 1, Step D) (1.96 g, 10.0 mmol) in thionyl chloride C99%, ~5mL) was heated at reflux for about 6 h, and then allowed to cool to room temperature while being stirred overnight. The reaction mixture was then concentrated in vacuo. Dichloromethane (~10mL) was added to the residue, and the mixture was concentrated again; this was repeated twice to provide the title compound as a yellow liquid (1.80 g, 84% yield). 1Η NMR (CDC13) δ 6.935 (s, 1Η), 4.40-4.47 (m, 2Η), 1.36-1.57 (m, 3H), 1.31-1.32 (s, 9H). Step B: Preparation of N-(3-cyanophenyl)-3-(l,l-dimethylethyl)-l-ethyl- lH-ρyrazole-5-carboxamide A solution of 3-(l,l-dimethylethyl)-l-ethyl-lH-pyrazole-5-carbonyl chloride (i.e. the product of Step A) (0.49 g, 2.26 mmol) in tetrahydrofuran (~1 mL) was added dropwise to a stirred solution of 3-aminobenzonitrile (99%, 0.3 g, 2.51 mmol), triethylamine, (1.39 mL, 10.04 mmol) and 4-(dimethylamino)pyridine (catalytic amount) in tetrahydrofuran (~5 mL) at room temperature to afford a yellow solution containing white, suspended solid. The reaction mixture was allowed to stir at room temperature overnight and then was poured into a Chem-Elute drying tube (Analytichem International, Harbor City, CA, U.S.A.) and eluted with ethyl acetate. The eluted solution was concentrated in vacuo, and the residue was purified with flash chromatography using 25% ethyl acetate/hexane as eluant to provide the title compound as a white solid (0.41g, 55% yield). H NMR (CDCI3) δ 7.73-7.83 (m, 2H), 7.44-7.47 (m, 2H), 6.509 (s, IH), 4.55^1.57 (m, 2H), 1.42-1.47 (m, 3H), 1.335 (s, 9H).
Step C: Preparation of 3-(l,l-dimethylethyl)-l-ethyl-N-[3-[(hydroxyamino)- iminomethyl]phenyl]-lH-pyrazole-5-carboxamide A mixture of N-(3-cyanophenyl)-3-(l,l-dimethylethyl)-l-ethyl-lH-pyrazole-
5-carboxamide (i.e. the product of Step B) (0.15 g, 0.51 mmol), hydroxylamine hydrochloride (99%, 0.053 g, 0.76 mmol) and sodium carbonate, (0.107 g, 1.01 mmol) in tetrahydrofuran (~5 mL) was stirred at room temperature overnight. The reaction mixture was then heated at reflux for 36 hours. After cooling to room temperature, the reaction mixture was poured into water and extracted with ethyl acetate (3x). The combined extracts were dried (MgSO^, filtered and concentrated in vacuo. The residue was purified with flash chromatography using 75% ethyl acetate/hexane as eluant to provide the title compound as a white solid (-0.1 g). lΗ ΝMR (OMSO-d6) δ 10.15 (s, 1Η), 9.64 (s, 1Η) 8.07 (s, 1Η), 7.73-7.76 (d, 1Η), 7.32- 7.42 (m, 2Η), 6.970-6.974 (s, IH), 4.42-4.49 (m, 2H), 1.285-1.318 (m, 12H).
Step D: Preparation of 3-(l,l-dimethylethyl)-l-ethyl-N-[3-(5-methyl-l,2,4-oxadiazol- 3-yl)phenyl]-lH-pyrazole-5-carboxamide A mixture of 3-(l,l-dimethylethyl)-l-ethyl-N-[3-[(hydroxyamino)iminomethyl]- phenyl]-lH-pyrazole-5-carboxamide (i.e. the product of Step C) (100 mg, 0.30 mmol) with acetic anhydride (~6 mL) was stirred at room temperature for 60+ hours. The reaction mixture was then poured into aqueous sodium hydroxide solution (1.0 Ν) and extracted with ethyl acetate. The extract was dried (MgSO^), filtered and concentrated in vacuo to afford the title product, a compound of the present invention, as a white solid (53.1 mg, -50% yield), melting at 140-147 °C. lΗ ΝMR (CDCI3) δ 8.10 (s, 1Η), 7.94-7.98 (d, 1Η), 7.83-7.87 (d, 1Η), 7.73 (s, 1Η), 7.47- 7.52 (m, 1Η), 6.475 (s, 1Η), 4.56-4.59 (m, 2Η), 2.668 (s, 3H), 1.43-1.47, (m, 3H), 1.33- 1.34 (m, 9H). EXAMPLE 6 Preparation of 3-(l,l-dimethylethyl)-l-ethyl-N-[3-(5-isoxazolyl)phenyl]-lH-pyrazole- 5-carboxamide (Compound 46)
Step A: Preparation of N-(3-acetylphenyl)-3-(l,l-dimethylethyl)-l-ethyl- lH-pyrazole-5-carboxamide A solution of 3-(l,l-dimethylethyl)-l-ethyl-lH-pyrazole-5-carboxylic acid (i.e. the product of Example 1, Step D) (0.5 g, 2.54 mmol) in thionyl chloride (6 mL) was heated at reflux under Ν2 atmosphere for 5 h. The reaction mixture was concentrated under vacuum and then taken up in dichloromethane and concentrated again to provide the corresponding acid chloride as an oil. Triethylamine (533 μL, 3.82 mmol) was added to a solution of l-(3-aminophenyl)ethanone (alternatively named 3'-aminoacetophenone, 361 mg, 2.67 mmol) in dichloromethane (6 mL) cooled to 0 °C under a N2 atmosphere. To this mixture a solution of the acid chloride in dichloromethane (2 mL) was added dropwise using an addition funnel. The reaction mixture was then allowed to stir at room temperature overnight, after which time it was diluted with dichloromethane and water. The layers were separated, and the organic layer was washed with water (lx), dried using an Extube™ (tube containing diatomaceous earth marketed by Narian, Inc., 24201 Frampton Avenue, Harbor City, CA 90710 USA) and then concentrated to leave the title compound as an oil (0.84 g). IH ΝMR (CDC13) δ 8.06 (s, IH), 8.0 (d, IH), 7.9 (br s, IH, ΝH), 7.7 (d, IH), 7.4 (t, IH), 6.5 (s, IH), 4.5 (q, 2H), 2.6 (s, 3H), 1.45 (t, 3H), 1.34 (s, 9H).
Step B: Preparation of N-[3-[[(2E)-3-(dimethylamino)-l-oxo-2-propenyl]phenyl]- 3-(l,l-dimethylethyl)-l-ethyl-lH-pyrazole-5-carboxamide A solution of N-(3-acetylphenyl)-3-(l,l-dimethylethyl)-l-ethyl-lH-pyrazole-
5-carboxamide (i.e. the product of Step A) (0.79 g, 2.52 mmol) in N,N-dimethylformamide dimethylacetal (4.2 g, 35.29 mmol) was heated at reflux under Ν2 atmosphere for 7 h. The reaction mixture was then allowed to stand at room temperature overnight. Then the reaction mixture was concentrated under vacuum, and the residue was taken up in hexanes.
Concentration again under vacuum afforded the title compound as an oil (0.77 g).
*Η NMR (CDCI3) δ 8.9 (1Η), 8.1 (1Η), 8.0 (1Η), 7.64 (1Η), 7.6 (d, 1Η), 7.4 (t, 1Η), 6.67 (s, 1Η), 5.7 (d, 1Η), 4.59(q, 2Η), 2.8 and 2.9 (s, 3H each, NMe2), 1.45 (t, 3H), 1.30 (s, 9H).
Step C: Preparation of 3-(l,l-dimethylethyl)-l-ethyl-N-[3-(5-isoxazolyl)phenyl]- 1 H-pyrazole-5-c arboxamide To a solution of N-[3-[[(2E)-3-(dimethylamino)-l-oxo-2-propenyl]phenyl]-3-(l,l- dimethylethyl)-l-ethyl-lH-pyrazole-5-carboxamide (i.e. the product of Step B) (385 mg, 1.04 mmol) in acetic acid (5 mL) in a scintillation vial was added hydroxylamine hydrochloride (101 mg, 1.45 mmol) and then sodium acetate (anhydrous, 120 mg, 1.46 mmol). The reaction mixture in the scintillation vial was then heated at 100 °C for 6 h using a scintillation vial heating block. The reaction mixture was then concentrated to leave an oil, which was triturated with water to precipitate a solid. The solid was collected by filtration and rinsed with hexanes to provide crude product (335 mg). The product was purified by flash column chromatography using a Supelco (division of Sigma-Aldrich Co., 595 North Harrison Road, Bellefonte, PA 16823, U.S.A.) DSC-Si SPE Tube prepacked with 5 g of silica gel (50 μm particle diameter, 70 A pore size) and as eluant 10% ethyl acetate / hexanes, then 20% ethyl acetate / hexanes and finally 40% ethyl acetate / hexanes to obtain fractions containing the desired product. The fractions were concentrated to leave an oil (3O0 mg), which was triturated with hexanes to form a solid. The solid was collected using filtration, providing the title product, a compound of the present invention, as a solid (228 mg) melting at 115-116 °C.
IH NMR (CDC13) δ 8.3 (IH), 8.0 (IH), 7.7 (br s, IH, NH), 7.6 (d, IH), 7.5 (d, IH), 7.4 (t, IH), 6.58 (IH), 6.5 (IH), 4.5 (q, 2H), 1.46 (t, 3H), 1.34 (s, 9H). EXAMPLE 7 Preparation of 1 -( 1 , 1 -dimethylethyl)-3-ethyl-N- [3-(5-isoxazolyl)phenyl]- lH-pyrazole- 4-carboxamide (Compound 47)
Step A: Preparation of ethyl l-(l,l-dimethylethyl)-3-ethyl-lH-pyrazole-4-carboxylate and ethyl l-(l,l-dimethylethyl)-4-ethyl-lH-pyrazole-3-carboxylate Ethyl 2-pentynoate (5.32 g, 42.2 mmol) was added to a solution of 3-(l,l- dimethylethyl)sydnone (6 g, 42.2 mmol) in xylenes (75 mL) under a nitrogen atmosphere.
The reaction mixture was heated to reflux for three days and cooled to room temperature.
The resulting white solids were removed by filtration using xylenes for rinsing. The filtrate was concentrated to leave a liquid, which was applied to a silica gel flash column (eluted with hexanes followed by 5:95 ethyl acetate-hexanes) to give the two title isomeric products as oils. Ethyl l-(l,l-dimethylethyl)-3-ethyl-lH-pyrazole-4-carboxylate (3.62 g) was the major isomer. Ethyl l-(l,l-dimethylethyl)-4-ethyl-lH-pyrazole-3-carboxylate (0.78 g) was the minor isomer. lΗ ΝMR (CDCI3) δ major isomer: 7.92 (s, 1Η), 4.2 (q, 2Η), 2.88 (q, 2H), 1.57 (s, 9H), 1.3 (t, 3H), 1.2 (t, 3H); minor isomer: 7.34 (s, IH), 4.4 (q, 2H), 2.7 (q, 2H), 1.6 (s, 9H), 1.39 (t, 3H), 1.20 (t, 3H).
Step B: Preparation of l-(l,l-dimethylethyl)-3-ethyl-lH-pyrazole-4-carboxylic acid A procedure analogous to that of Example 1, Step D was used to convert ethyl l-(l,l-dimethylethyl)-3-ethyl-lH-pyrazole-4-carboxylate (i.e. the major isomer product of Step A) (1.76 g, 7.76 mmol) to the title acid (1.08 g). lΗ ΝMR (CDCI3) δ 8.0 (s, 1Η), 2.9 (q, 2Η), 1.58 (s, 9H), 1.26 (t, 3H). Step C: Preparation of N-(3-acetylphenyl)-l-(l,l-dimethylethyl)-3-ethyl- lH-pyrazole-4-carboxamide A procedure analogous to that of Step A of Example 6 was used to prepare the acid chloride from l-(l,l-dimethylethyl)-3-ethyl-lH-pyrazole-4-carboxylic acid (i.e. the product of Step B) (0.5 g, 2.54 mmol) using thionyl chloride (6 mL) and then react the acid chloride with l-(3-aminophenyl)ethanone (361 mg, 2.67 mmol) in the presence of triethylamine (533 μL, 3.82 mmol) to provide the title compound as a solid (0.72 g). lΗ. ΝMR (CDC13) δ 7.97-8.0 (m, 2Η), 7.9 (s, IH ), 7.7 (d, IH,), 7.5 (br s, ΝH), 7.4 (t, IH), 2.9 (q, 2H), 2.6 (s, 3H), 1.6 (s, 9H), 1.34 (t, 3H). Ste D: Preparation of N-[3-[(2E)-3-(dimethylamino)-l-oxo-2-propenyl]phenyl]- 1 -( 1 , 1 -dimethylethyl)-3-ethyl- lH-pyrazole-4-carboxamide A solution of N-(3-acetylphenyl)-l-(l,l-dimethylethyl)-3-ethyl-lH-pyrazole- 4-carboxamide (i.e. the product of Step C) (0.72 g, 2.3 mmol) in N,N-dimethylformamide dimethylacetal (3.8 g, 32.16 mmol) was heated at reflux under Ν2 atmosphere for 7 h. The reaction mixture was then allowed to stand at room temperature overnight. The reaction mixture was then concentrated and the residue was taken up in hexanes and concentrated again to provide the title compound as an oil (0.92 g).
*Η NMR (CDC13) δ 8.5 (br s, NΗ), 8.19 (d, 1Η), 8.10 (s, 1Η), 7.9 (s, 1Η), 7.6 (d, CΗ, J = 12.4), 7.5 (d, 1Η), 7.3 (t, 1Η), 5.7 (d, CΗ, J = 12.4), 2.98 (q, 2Η), 2.88 and 2.95 (s, 3H each, NMe2), 1.56 (s, 9H), 1.3 (t, 3H).
Step E: Preparation of l-(l,l-dimethylethyl)-3-ethyl-N-[3-(5-isoxazolyl)phenyl]- lH-ρyrazole-4-carboxamide To a solution of N-[3-[(2E)-3-(dimethylamino)-l-oxo-2-propenyl]phenyl]-l-(l,l- dimethylethyl)-3-ethyl-lH-pyrazole-4-carboxamide (i.e. the product of Step D) (420 mg, 1.14 mmol) in acetic acid (6 mL) in a scintillation vial was added hydroxylamine hydrochloride (110 mg, 1.58 mmol) and then sodium acetate (anhydrous, 130 mg, 1.58 mmol). The reaction mixture in the scintillation vial was then heated at 100 °C for 6 h using a scintillation vial heating block. The reaction mixture was then concentrated to leave an oil, which was triturated with water to precipitate a solid. The solid was collected by filtration and rinsed with hexanes to provide crude product (383 mg). The product was purified by flash column chromatography using a Supelco DSC-Si SPE Tube prepacked with 5 g of silica gel and as eluant 10% ethyl acetate / hexanes, then 20% ethyl acetate / hexanes and finally 40% ethyl acetate / hexanes to obtain fractions containing the desired product. The fractions were concentrated to leave an oil, which was triturated with hexanes to form a solid. The solid was collected using filtration, providing the title product, a compound of the present invention, as a solid (234 mg) melting at 154-155 °C. H NMR (CDCI3) δ 8-2 (d> 1H)> 8-° (s> 1H)> 7-9 (s. IH ), 7.7 (d, IH), 7.5-7.6 (m, 2H), 7.4 (t, IH), 6.5 (d, IH), 2.9 (q, 2H), 1.6 (s, 9H), 1.34 (t, 3H). EXAMPLE 8
Preparation of 3-(l,l-dimethylethyl)-l-ethyl-N-[3-(lH-pyrazol-3-yl)phenyl]-lH-pyrazole- 5-carboxamide (Compound 48) A solution of N-[3-[[(2E)-3-(dimethylamino)-l-oxo-2-propenyl]phenyl]-3-(l,l- dimethylethyl)-l-ethyl-lH-pyrazole-5-carboxamide (i.e. the product of Example 6, Step B) in acetic acid (3 mL) under Ν2 atmosphere was cooled to 0 °C, and hydrazine hydrate (0.04 g, 1.25 mmol) was added. The reaction mixture was allowed to slowly warm to room temperature and was then concentrated to provide an oil. The oil was triturated with water to precipitate a solid, which was collected with filtration and rinsed with hexanes to provide the crude product (374 mg). The product was purified by flash column chromatography using a 5-gram pre-packed SPE column and as eluant 10% ethyl acetate / hexanes, then 20% ethyl acetate / hexanes and finally 40% ethyl acetate / hexanes to obtain fractions containing the desired product. The fractions were concentrated to leave a solid, which was rinsed with hexanes and collected to provide the title product, a compound of the present invention, as a solid (174 mg) melting at 185-187 °C. lΗ NMR (CDC13) δ 12.9 (br s, 1Η, NΗ), 10.1 (br s, 1Η, NΗ), 8.2 (d, 1Η), 7.7 (s, 1Η), 7.6 (d, 1Η), 7.5 (d, 1Η), 7.3 (t, 1Η), 6.98 (s, 1Η), 6.6 (d, 1Η), 4.4 (q, 2Η), 1.3 (t, 3H), 1.2 (s, 9H). EXAMPLE 9
Preparation of l-(l,l-dimethylethyl)-3-ethyl-N-[3-(lH-pyrazol-3-yl)phenyl]-lH-pyrazole-4- carboxamide (Compound 49) A solution of N-[3-[(2E)-3-(dimethylamino)-l-oxo-2-propenyl]phenyl]-l-(l,l- dimethylethyl)-3-ethyl-lH-pyrazole-4-carboxamide (i.e. the product of Example 7, Step D) (420 mg, 1.14 mmol) in acetic acid (3 mL) under Ν2 atmosphere was cooled to 0 °C, and hydrazine hydrate (0.04 g, 1.25 mmol) was added. The reaction mixture was allowed to slowly warm to room temperature and then was heated at reflux for 1 h. The reaction mixture was concentrated to give an oil, which was triturated with water to precipitate a solid. The solid was collected using filtration and rinsed with hexanes to provide a solid (367 mg). The solid was further washed with ethyl acetate and dichloromethane to leave the title product, a compound of the present invention, as a solid (0.97 mg) melting at 209- 211 °C. lΗ NMR (CDCI3) δ 12.9 (br s, 1Η, NΗ ), 9.6 (br s, 1Η, NΗ ), 8.5 (s, 1Η), 8.1 (d, 1Η), 7.7 (s, 1Η), 7.6 (d, 1Η), 7.4 (d, 1Η), 7.3 (t, 1Η), 6.6 (d, 1Η), 2.8 (q, 2Η), 1.5 (s, 9H), 1.17 (t, 3H). EXAMPLE 10 Preparation of 3-(l ,l-dimethylethyl)-l-ethyl-N-[6-(lH-pyrazol-l-yl)-2-ρyridinyl]- lH-pyrazole-5-carboxamide (Compound 11)
Step A: Preparation of N-(6-bromo-2-pyridinyl)-3-(l,l-dimethylethyl)-l-ethyl- lH-pyrazole-5-carboxamide To a solution of 3-(l,l-dimethylethyl)-l-ethyl-lH-pyrazole-5-carboxylic acid (i.e. the product of Example 1, Step D) (1 g) in dichloromethane (10 mL) was added sequentially a solution of 6-bromo-2-pyridinamine (0.80 g) in dichloromethane (5 mL) followed by 1-propanephosphonic acid cyclic anhydride (50% solution in ethyl acetate, 3 mL) and then 4-(dimethylamino)pyridine (0.3 g). After stirring at room temperature for 6 h, the reaction mixture was diluted with dichloromethane (20 mL) and washed with hydrochloric acid (1 Ν). The organic phase was separated, dried and concentrated. The residue was purified by chromatography on silica gel to give the title compound (1.24 g). lΗ ΝMR (CDC13) δ 8.42 (s, 1Η, ΝΗ), 8.32 (d, 1Η), 7.62 (t, 1Η), 7.28 (d, 1Η), 6.64 (s, 1Η), 4.48 (q, 2Η), 1.45 (t, 3H), 1.31 (s, 9H).
Step B: Preparation of 3-(l,l-dimethylethyl)-l-ethyl-N-[6-(lH-pyrazol-l-yl)- 2-pyridinyl]-lH-pyrazole-5-carboxamide To a solution of N-(6-bromo-2-pyridinyl)-3-(l,l-dimethylethyl)-l-ethyl-lH-pyrazole- 5-carboxamide (i.e. the product of Step B) (0.35 g) in N,N-dimethylformamide (5 mL) was added sequentially pyrazole (0.30 g) and then potassium carbonate (0.5 g). The reaction mixture was then heated at 110 °C with stirring for 12 h. After cooling to room temperature the reaction mixture was diluted with dichloromethane (20 mL) and washed with hydrochloric acid (1 Ν). The organic phase was separated, dried and concentrated. The residue was purified by chromatography on silica gel to give the title product, a compound of the present invention, as a colorless solid (0.11 g). lΗ ΝMR (CDCI3) δ 8.62 (s, 1Η, ΝΗ), 8.28 (d, 1Η), 8.16 (d, 1Η), 7.82 (t, 1Η), 7.60 (t, 1Η), 7.28 (d, 1Η), 6.64 (s, 1Η), 6.58 (d, 1Η), 4.48 (q, 2Η), 1.45 (t, 3H), 1.31 (s, 9H). EXAMPLE 11 Preparation of 1 -( 1 , 1 -dimethylethyl)-3 -ethyl-4,5 -dihydro-N- [3 -(2-pyridinyl)phenyl] - lH-pyrazole-4-carboxamide (Compound 33)
Step A: Preparation of N-(3-iodophenyl)-3-oxopentanamide Three solutions of 3-iodobenzenamine (1.03 g, 2.06 g, and 1.70 g respectively) in methyl 3-oxopentanoate (alternatively named methyl propionylacetate; 1.82 g, 3.66 g, and
2.52 g respectively) were prepared. To each solution was added 4-(dimethylamino)pyridine (30-60 mg). Each solution was heated at 180 °C for 5 minutes using a microwave reactor.
The solutions were combined and most of the unreacted methyl 3-oxopentanoate was removed by heating at 90 °C under high vacuum. The residue was purified by column chromatography using ethyl acetate-hexane as eluant to provide the title compound (4.12 g). *H NMR (CDC13) δ 9.23 (br s, IH), 7.97 (s, IH), 7.50 (d, IH), 7.43 (d, IH), 7.04 (t, IH), 3.56 (s, 2H), 2.61 (q, 2H), 1.12 (t, 3H). Step B: Preparation of l-(l,l-dimethylethyl)-3-ethyl-4,5-dihydro-N-(3-iodophenyl)- lH-pyrazole-4-carboxamide A slurry of N-(3-iodophenyl)-3-oxopentanamide (i.e. the product of Step A) (4.11 g, 12.9 mmol), aqueous formaldehyde (37%, 1.47 g) and sodium acetate (1.70 g) in methanol (20 mL) was stirred at room temperature for 2 h. Additional aqueous formaldehyde (0.41 mL) was added, and the reaction mixture was stirred for 2 h more. Then the reaction mixture was diluted with ethyl acetate (300 mL) and washed with saturated brine (2x). The organic layer was dried (MgSO^.), and the solvent was removed in vacuo to give a gummy solid. The solid was added to a mixture of tert-butylhydrazine hydrochloride (1.70 g) and anhydrous sodium carbonate (1.36 g) in methanol (20 mL), and the mixture was stirred at room temperature for 20 h. The reaction mixture was diluted with ethyl acetate (100 mL), washed with saturated brine (2x), and dried (MgSO^. The solvent was removed in vacuo to leave a crude solid product. The crude product was purified by column chromatography using ethyl acetate-hexane as eluant to provide the title compound as a glassy solid (1.46 g). !Η ΝMR (CDCI3) δ 8.73 (br s, 1Η), 7.87 (s, 1Η), 7.41(d, 1Η), 7.39 (d, 1Η), 7.02 (t, 1Η), 3.60 (dd, 1Η), 3.50 (dd, 1Η), 3.22 (t, 1Η), 2.41 (m, 2Η), 1.23 (s, 9H), 1.16 (t, 3H).
Step C: Preparation of l-(l,l-dimethylethyl)-3-ethyl-4,5-dihydro-N-[3-(2-pyridinyl)- phenyl]-lH-pyrazole-4-carboxamide A solution of l-(l,l-dimethylethyl)-3-ethyl-4,5-dihydro-N-(3-iodophenyl)-lH- pyrazole-4-carboxamide (i.e. the product of Step B) (0.92 g, 2.30 mmol), 2-(tributylstannyl)- pyridine (0.96 g) and dichlorobis(triphenylphosphine)palladium (85 mg) in tetrahydrofuran (TΗF, dry, 20 mL) was heated at reflux for 24 h. Tetrakis(triphenylphosphine)palladium (132 mg) was added, and the reaction mixture was heated at reflux for 24 h more. Then the reaction mixture was cooled to room temperature, and a solution of 2-pyridylzinc bromide (0.5 M in TΗF, 3.8 mL) was added. After stirring the reaction mixture at room temperature for 3 days, most of the tetrahydrofuran was removed in vacuo. The residue was first washed with water and then extracted with hydrochloric acid (1 Ν, 20 mL). The residue was taken up in ethyl acetate (30 mL) and extracted with hydrochloric acid (1 Ν, 2 x 20 mL). The combined aqueous extracts were washed with ethyl acetate (10 mL), and the pΗ was adjusted to 8-9 with 50% aqueous sodium hydroxide. The aqueous solution was extracted with ethyl acetate (3 x 30 mL). The combined ethyl acetate extracts were dried (MgSO^, and the solvent was removed in vacuo to give a crude solid, which was purified by column chromatography using ethyl acetate-hexane as eluant to provide the title product, a compound of the present invention, as a thick oil. (183 mg). H NMR (CDC13) δ 8.71 (s, IH), 8.69 (d, IH), 8.05 (s, IH), 7.73 (m, 3H), 7.60 (d, IH), 7.41 (t, IH), 7.22 (m, IH), 3.58 (m, 2H), 3.28 (t, IH), 2.41 (m, 2H), 1.23 (s, 9H), 1.16 (t, 3H).
5 EXAMPLE 12 Preparation of 1 -( 1 , 1 -dimethylethyl)-3 -ethyl-N- [3-(2-pyridinyl)ρhenyl] - lH-pyrazole- 4-carboxamide (Compound 32) Step A: Preparation of 1 -( 1 , 1 -dimethylethyl)-3-ethyl-N-(3-iodophenyl)- lH-pyrazole- 4-carboxamideO A slurry of l-(l,l-dimethylethyl)-3-ethyl-4,5-dihydro-N-(3-iodophenyl)-lH-pyrazole- 4-carboxamide (i.e. the product of Example 11, Step B) (0.30 g) and manganese(IN) oxide (0.65 g) in toluene (3 mL) was heated at 80 °C for 2 h. Then the reaction mixture was filtered through a pad of Celite® diatomaceous filter aid. The Celite® pad was washed with ethyl acetate (50 mL), and the combined filtrates were concentrated in vacuo to leave the5 title compound as a brown solid (0.25 g). !Η ΝMR (CDCI3) δ 7.97 (s, 1Η), 7.88 (s, 1Η), 7.56 (d, 1Η), 7.43 (d, 1Η), 7.30 (br s, 1Η), 7.07 (t, 1Η), 2.94 (q, 2Η), 1.58 (s, 9H), 1.33 (t, 3H). Step B: Preparation of l-(l,l-dimethylethyl)-3-ethyl-N-[3-(2-pyridinyl)phenyl]- lH-pyrazole-4-carboxamideO A solution of l-(l,l-dimethylethyl)-3-ethyl-N-(3-iodophenyl)-lH-pyrazole- 4-carboxamide (i.e. the product of Step A) (0.25 g, 0.63 mmol), tetrakis(triphenyl- phosphine)palladium (72 mg) and 2-pyridylzinc bromide (0.5 M in TΗF, 1.32 mL) in dry tetrahydrofuran (dry, 5 mL) was stirred at room temperature for 24 h. Then additional 2-pyridylzinc bromide solution (1.32 mL) and tetrakis(triphenylphosphine)palladium5 (72 mg) were added. After the reaction mixture was stirred for a further 120 h additional 2-pyridylzinc bromide solution (1.80 mL) and tetrakis(triphenylphosphine)palladium (130 mg) were added. Then after stirring for 24 hr more the solvent was removed in vacuo, and the residue was taken up in ethyl acetate (30 mL) and extracted with aqueous hydrochloric acid (1 Ν, 3 x 20 mL). The combined aqueous acid solutions were washed with0 ethyl acetate (30 mL), and then the pΗ of the aqueous solution was increased to 8-9 by addition of 50% aqueous sodium hydroxide. The aqueous solution was extracted with ethyl acetate (3 x 100 mL), and the combined ethyl acetate extracts were dried and concentrated to leave a crude oil, which was purified by column chromatography using ethyl acetate-hexane as eluant to provide the title product, a compound of the present invention, as a white powder5 (50 mg). lΗ ΝMR (CDC13) δ 8.70 (d, 1Η), 8.09 (s, 1Η), 7.90 (s, 1Η), 7.85 (d, 1Η), 7.85 (m, 2Η), 7.70 (d, IH), 7.52 (br s, IH), 7.46 (t, IH), 7.26 (m, IH), 2.97 (q, 2H), 1.60 (s, 9H), 1.34 (t, 3H). EXAMPLE 13
Preparation of N- [5 -(4,5-dihydro-2-oxazolyl)-2-fluorophenyl] -3 -( 1 , 1 -dimethylethyl)- 1 -ethyl- lH-pyrazole-5-carboxamide (Compound 31)
Step A: Preparation of ethyl 4-fluoro-3-nitrobenzoate A mixture of 4-fluoro-3-nitrobenzoic acid (10 g, 54 mmol), diethyl sulfate (8.5 mL) and potassium carbonate (10 g) in anhydrous acetone (120 mL) was heated to reflux for 6 h. The reaction mixture was then filtered, and the filtrate was concentrated. The residue was purified by chromatography on silica gel to give the title compound (11.2 g) as a yellow oil. lΗ ΝMR (CDC13) δ 8.64 (dd, 1Η), 8.32 (m, 1Η), 7.38 (t, 1Η), 4.44 (q, 2Η), 1.40 (t, 3H). Step B: Preparation of ethyl 3-amino-4-fluorobenzoate A solution of ethyl 4-fluoro-3-nitrobenzoate (the product of Step A) (5.7 g, 26.7 mmol) in acetic acid (50 mL) and ethyl acetate (60 mL) was added dropwise over 20 minutes to a suspension of iron powder (6.0 g) in acetic acid (5% wt, 30 mL) at 80 °C. After the addition, the reaction mixture was stirred at 80 °C for an additional 20 minutes. The mixture was then cooled to room temperature. Solids were removed by filtration through Celite® diatomaceous filter aid, and the filtrate was concentrated. The residue was diluted with ethyl acetate (100 mL) and washed sequentially with water (25 mL) and aqueous sodium bicarbonate solution (5%, 25 mL). The organic layer was dried and concentrated to give the title compound (4.5 g). H ΝMR (CDCI3) δ 7.60 (dd, IH), 7.42 (m, IH), 7.08 (t, IH), 4.34 (q, 2H), 3.90 (br s, 2H), 1.34 (t, 3H).
Step C: Preparation of ethyl 3-[[[3-(l,l-dimethylethyl)-l-ethyl-lH-ρyrazol-5-yl]- carbonyl] amino-4-fluorobenzoate A solution of 3-(l,l-dimethylethyl)-l-ethyl-lH-pyrazole-5-carbonyl chloride (i.e. the product of Example 1, Step E) (4.7 g) in dichloromethane (40 mL) was added to a solution of ethyl 3-amino-4-fluorobenzoate (i.e. the product of Step B) (4.46 g, 24.3 mmol) and NN-diisopropylethylamine (8.5 mL) in dichloromethane (10 mL). After stirring at room temperature overnight, the reaction mixture was diluted with dichloromethane (100 mL) and washed with 1 Ν hydrochloric acid. The organic phase was separated, dried and concentrated. The residue was purified by chromatography on silica gel to give the title compound (6.6 g), a compound of the present invention. lΗ ΝMR (CDCI3) δ 8.14 (m, 1Η), 8.00 (dd, 1Η), 7.26 (s, 1Η), 6.26 (s, 1Η), 4.34 (m, 4Η), 1.41 (m, 6H), 1.20 (s, 9H). Step D: Preparation of 3-[[[3-(l,l-dimethylethyl)-l-ethyl-lH-pyrazol-5-yl]carbonyl]- amino}-4-fluorobenzoic acid A solution of ethyl 3-[[[3-(l,l-dimethylethyl)-l-ethyl-lH-pyrazol-5-yl]carbonyl]- amino-4-fluorobenzoate (i.e. the product of Step C) (6.6 g, 18.3 mmol) in methanol (40 mL) and aqueous sodium hydroxide (10%, 17 mL) was stirred at room temperature for 6 h. The reaction mixture was then concentrated and acidified with 1 N hydrochloric acid. The precipitated solids were filtered and dried to give 5.3 g of the title acid as a white solid. iΗ NMR (DMSO-d6) δ 10.54 (s, 1Η), 8.22 (dd, 1Η), 7.86 (m, 1Η), 7.40 (t, 1Η), 6.89 (s, 1Η), 4.44 (q, 2Η), 1.32 (t, 3H), 1.30 (s, 9H). Step E: Preparation of N-[5-(4,5-dihydro-2-oxazolyl)-2-fluorophenyl]-3-(l,l- dimethylethyl)-l-ethyl-lH-pyrazole-5-carboxamide To a solution of 3-[[[3-(l,l-dimethylethyl)-l-ethyl-lH-pyrazol-5-yl]carbonyl]amino]- 4-fluorobenzoic acid (i.e. the product of Step D) (3.25 g, 9.8 mmol) in dichloromethane (100 mL) was added oxalyl chloride (1.61 g) and N,N-dimethylformamide (1 drop). The solution was stirred under nitrogen for 24 h. Then the solvent was removed in vacuum, methylene chloride (10-20 mL) was added, and the solvent was again removed in vacuo. This was repeated once more, and the residue was dried under high vacuum to provide the crude acid chloride as tan solid (3.44 g). A mixture of 2-bromoethylamine hydrobromide (Aldrich Chem. Co., 300 mg) and triethylamine (1 mL) in (trifluoromethyl)benzene (3 mL) was stirred for 15 minutes at room temperature. The solid acid chloride (0.493 g, 1.40 mmol) was then added, and the resulting slurry was heated at 160 °C for 20 minutes using a microwave reactor. After cooling to room temperature the reaction mixture was diluted with ethyl acetate (60 mL) and washed with water (20 mL). The organic layer was dried and concentrated to leave a crude oil, which was purified by column chromatography using ethyl acetate-hexane as eluant to provide the title product, a compound of the present invention, as a solid (75 mg). lΗ ΝMR (CDC13) δ 8.90 (d, 1Η), 7.90 (br s, 1Η), 7.72 (m, 1Η), 7.16 (dd, 1Η), 6.50 (s, 1Η), 4.58 (q, 2Η), 4.45 (t, 2H), 4.06 (t, 2H), 1.44 (t, 3H), 1.34 (s, 9H). EXAMPLE 14 Preparation of 3-(l,l-dimethylethyl)-l-ethyl-N-[2-fluoro-5-(lH-pyrazol-l-yl)phenyl]-lH- pyrazole-5-carboxamide (Compound 10)
Step A: Preparation of N-(5-amino-2-fluorophenyl)-3-(l,l-dimethylethyl)-l-ethyl- lH-pyrazole-5-carboxamide To a solution of 2-fluoro-3-nitrobenzenamine (alternatively named 2-fluoro- 3-nitroaniline; 1.0 g, 6.4 mmol) and pyridine (1.5 mL) in dichloromethane (200 mL) was added dropwise a solution of 3-(l,l-dimethylethyl)-l-ethyl-lH-pyrazole-5-carbonyl chloride (i.e. the product of Example 1, Step E) (2.0 g) in dichloromethane (100 mL). The reaction mixture was stirred overnight and then added to water (200 mL). The mixture was extracted with ethyl acetate (3 x 200 mL). The combined organic layers were dried (MgSO^, and the solvent was removed in vacuo to leave a crude oil, which was purified by column chromatography using ethyl acetate-hexane as eluant to provide the intermediate amide as a thick oil. This was mixed with platinum(IN) oxide catalyst (-0.1 g) and tetrahydrofuran
(30 mL) and hydrogenated at a pressure of 20 psi (140 kPa). The reaction mixture was filtered to remove the platinum catalyst, and the solvent was removed in vacuo to provide the title compound as a grey solid. !H ΝMR (CDC13) δ 7.80 (dd, IH), 6.92 (dd, IH), 6.45 (s, IH), 6.36 (ddd, IH), 4.56 (q, 2H), 1.45 (t, 3H), 1.33 (s, 9H). 19F ΝMR (CDC13) δ -145.
Step B: Preparation of 3-(l,l-dimethylethyl)-l-ethyl-N-(2-fluoro-5-hydrazinophenyl)- lH-pyrazole-5-carboxamide monohydrochloride To an ice-cold solution of N-(5-amino-2-fluorophenyl)-3-(l,l-dimethylethyl)-l-ethyl- lH-pyrazole-5-carboxamide (i.e. the product of Step A) (1.96 g, 6.44 mmol) in concentrated hydrochloric acid (5 mL) combined with ice (5 g) was added over 10 minutes a solution of sodium nitrite (469 mg) in water (1.75 mL). After stirring for 15 minutes, the reaction solution was added over 2-3 minutes to a solution of tin(fl) chloride (3.3 g) in concentrated hydrochloric acid (3.5 mL) chilled using an ice bath. After stirring for 15 minutes the reaction solution was added to a solution prepared from 1 Ν aqueous sodium hydroxide
(150 mL) and 50% aqueous sodium hydroxide (23 mL). The aqueous reaction solution was then extracted with ethyl acetate (1 x 120 mL, 2 x 90 mL). The combined ethyl acetate extracts were dried (MgSO4), and then an ether solution of hydrogen chloride (2 M, 10 mL) was added. The solution was concentrated in vacuo, and the residual orange oil was triturated with ether. The ether was decanted and the product dried under vacuum, causing it to solidify to provide the title compound as a pinkish solid (2.3 g). lΗ ΝMR (DMSO- 6) δ 10.30 (br s, 2Η), 10.07 (s, IH), 7.23 (m, 2H), 7.00 (s, IH), 6.92 (m, IH), 4.42 (q, 2H), 1.31 (t, 3H), 1.29 (s, 9H).
Step C: Preparation of 3-(l,l-dimethylethyl)-l-ethyl-N-[2-fluoro-5-(lH-pyrazol- l-yl)phenyl]-lH-pyrazole-5-carboxamide Two solutions of 3-(l,l-dimethylethyl)-l-ethyl-N-(2-fluoro-5-hydrazinophenyl)- lH-pyrazole-5-carboxamide monohydrochloride (i.e. the product of Step B) (0.10 g and 0.50 g, respectively) and 1,1,3,3-tetraethoxypropane (69 mg and 339 mg, respectively) in ethanol (0.5 mL and 2.0 mL, respectively) were prepared. Each solution was heated at 120 °C for 10 minutes using a microwave reactor. The two solutions were then combined and concentrated in vacuo to leave a crude product. The crude product was purified by column chromatography using ethyl acetate-hexane as eluant to provide the title product, a compound of the present invention, as a solid (270 mg). !H NMR (CDC13) δ 8.78 (dd, IH), 7.95 (d, IH), 7.92 (br s, IH), 7.72 (d, IH), 7.50 (ddd, IH), 7.22 (dd, IH), 6.50 (s, IH), 6.47 (dd, IH), 4.58 (q, 2H), 1.45 (t, 3H), 1.34 (s, 9H). By the procedures described herein together with methods known in the art, the following compounds of Tables 1 to 9 can be prepared. The following abbreviations are used in the Tables which follow: t means tertiary, i means iso, Me means methyl, Et means ethyl, Pr means propyl, i-Pr means isopropyl, Bu means butyl, t-Bu means tert-butyl, CN means cyano, S(O)Me means methylsulfinyl, and S(O)2Me means methylsulfonyl. References to R5 groups U-1 through U-71 refer to Exhibit 1.
Figure imgf000074_0001
Rla is Et; R2a is tert-Bu; T, U, Y and Z are CH; R5 is U-6; R21 are substituents on U-6.
Figure imgf000074_0002
Rla is Et; R2a is tert-Bu; T, U, Y and Z are CH; R5 is U-7; R21 are substituents on U-7.
R21 R21 R21 R21 R21 R21 R21
- 5-CF3 5-CH2CH3 5-OCH2CH3 5-CHF2 5-SCH3 5-S(0)2CH3
4-C1 4-CH2CF3 4-CN 4-OCF3 4-0CH2F 4-SCH2CH3 4-SCHF2
5-C1 5-CH2CF3 5-CN 5-OCF3 5-0CH2F 5-SCH2CH3 5-SCHF2
4-F 4-CH3 4-OCH3 4-CH2F 4-0CHF2 4-S(0)CH3 4-SCF3
5-F 5-CH3 5-OCH3 5-CH2F 5-0CHF2 5-S(0)CH3 5-SCF3
4-CF3 4-CH2CH3 4-OCH2CH3 4-CHF2 4-SCH3 4-S(0)2CH3
Rla is Et; R2a is tert-Bu; T, U, Y and Z are CH; R5 is U-10; R21 are substituents on U-10.
R21 R21 R21 R21 R21 R21
- 4-CH2CF3 4-CH2CH3 4-CH2Cl 4-SCH3 4-SCHF2
3-C1 3-CH3 3-CN 3-CH2F 3-SCH2CH3 3-SCF3
4-F 4-CH3 4-OCH3 4-CHF2 4-S(0)CH3
3-CF3 3-CH2CH3 3-OCH2CH3 3-OCHF2 3- S(0)2CH3
Rla is Et; R2a is tert-Bu; T, U, Y and Z are CH; R5 is U-11 ; R2i and R22 are substituents on U-11; R22 is H.
Figure imgf000075_0001
Rla is Et; R2a is tert-Bu; T, U, Y and Z are CH; R5 is U-14; R2la is a substituent on U-14. R21a R21a R21a R21a R21a R21a R21a
H CF3 CH2CH3 OCH2CH3 CHF2 SCH3 S(0>2CH3
CI CH2CF3 CN CH2C1 OCH2F SCH2CH3 SCHF2
F CH3 OCH3 CH2F OCHF2 S(0)CH3 SCF3
Ria is Et; R2a is tert-Bu; T, U, Y and Z are CH; R5 is U-15; R21a is a substituent on U-15.
R21a R21a
H S(0)2CH3 CI SCHF2 F
Figure imgf000075_0002
SCF3 Ria is Et; R2a is tert-Bu; T, U, Y and Z are CH; R5 is U-18; R21a is a substituent on U-18.
R2la R21a R21a g21a R21a H 0CH2CH3 CHF2 SCH3 S(0)2CH3 CI CH2C1 OCH2F SCH2CH3 SCHF2 F
Figure imgf000076_0001
CH2F OCHF2 S(0)CH3 SCF3
Ria is Et; R2a is tert-Bu; T, U, Y and Z are CH; R5 is U-19; R21a is a substituent on U-19.
R21a R21a g^la R21a R21a R21a R21a
H CF3 CH2CH3 OCH2CH3 CHF2 SCH3 S(0)2CH3 CI CH2CF3 CN CH2C1 OCH2F SCH2CH3 SCHF2
F CH3 OCH3 CH2F OCHF2 S(0)CH3 SCF3
Rla is Et; R2a is tert-Bu; T, U, Y and Z are CH; R5 is U-23; R21 are substituents on U-23 R21 R21 R21 R21 R21 R21 R21 5-CF3 5-CH2CH3 5-OCH2CH3 5-CHF2 5-SCH3 4-S(0)2CH3
2-C1 2-CH2CF3 2-CN 2-OCF3 2-OCH2F 2-SCH2CH3 5-S(0)2CH3
4-C1 4-CH2CF3 4-CN 4-OCF3 4-OCH2F 4-SCH2CH3 2-SCHF2
5-C1 5-CH2CF3 5-CN 5-OCF3 5-OCH2F 5-SCH2CH3 4-SCHF2
2-F 2-CH3 2-OCH3 2-CH2F 2-OCHF2 2-S(0)CH3 5-SCHF2
4-F 4-CH3 4-OCH3 4-CH2F 4-OCHF2 4-S(0)CH3 2-SCF3
5-F 5-CH3 5-OCH3 5-CH2F 5-OCHF2 5-S(0)CH3 4-SCF3
2-CF3 2-CH2CH3 2-OCH2CH3 2-CHF2 2-SCH3 2-S(0)2CH3 5-SCF3
4-CF3 4-CH2CH3 4-OCH2CH3 4-CHF2 4-SCH3
Rla is Et; R2a is tert-Bu; T, U, Y and Z are CH; R5 is U-25; R21 and R22 are substituents on U-25; R22 is H.
R21 R21 R21 R21 R21 R21 R21 5-CF3 4-CH2CH3 5-OCH3 4-CHF2 5-SCH3 4-S(0)2CH3
5-C1 4-CH3 5-CH2CH3 4-0CH2CH3 5-OCH2F 4-SCH2CH3 5-SCHF2
4-F 5-CH3 4-CN 5-CH2F 4-OCHF2 5-S(0)CH3 4-SCF3
Rla is Et; R2a is tert-Bu; T, U, Y and Z are CH; R5 is U-27; R21 are substituents on U-27.
R21 R21 R21 R21 R21 R21 R21 2-CF3 2-CH2CH3 5-OCH3 2-CHF2 5-SCH3 2-S(0)2CH3
2-C1 2-CH3 5-CH2CH3 2-0CH2CH3 5-OCH2F 2-SCH2CH3 5-SCHF2 5-F 5-CH3 2-CN 5-CH2F 2-OCHF2 5-S(0)CH3 2-SCF3 Rla is Et; R2a is tert-Bu; T, U, Y and Z are CH; R5 is U-28; R2i are substituents on U-28.
R21 R21 R21 R21 R21 R21 R21 2-CF3 2-CH2CH3 5-OCH3 2-CHF2 5-SCH3 2-S(0)2CH3
2-C1 2-CH3 5-CH2CH3 2-OCH2CH3 5-OCH2F 2-SCH2CH3 5-SCHF2 5-F 5-CH3 2-CN 5-CH2F 2-OCHF2 5-S(0)CH3 2-SCF3
Rla is Et; R2a is tert-Bu; T, U, Y and Z are CH; R5 is U-31; R21 and R22 are substituents on U-31; R22 is H.
R21 R21 R21 R 1 R21 R21 R21 2-CF3 2-CH2CH3 5-OCH3 2-CHF2 5-SCH3 2-S(0)2CH3
2-C1 2-CH3 5-CH2CH3 2-OCH CH3 5-OCH2F 2-SCH2CH3 5-SCHF2 5-F 5-CH3 2-CN 5-CH2F 2-OCHF2 5-S(0)CH3 2-SCF3
Rla is Et; R2a is tert-Bu; T, U, Y and Z are CH; R5 is U-32; R2ia is a substituent on U-32. R21a R21a R21a R21a R21a R21a R21a
H CF3 CH2CH3 OCH CH3 CHF2 SCH3 S(0)2CH3
CI CH2CF3 CN CH2C1 OCH2F SCH CH3 SCHF2
F CH3 OCH3 CH2F OCHF2 S(0)CH3 SCF3
Rla is Et; R2a is tert-Bu; T, U, Y and Z are CH; R5 is U-33; R21a is a substituent on U-33. R21a R21a R21a R21a R21a R21a R21a
H CF3 CH2CH3 OCH2CH3 CHF2 SCH3 S(0)2CH3
CI CH2CF3 CN CH C1 OCH2F SCH2CH3 SCHF2
F CH3 OCH3 CH2F OCHF2 S(Q)CH3 SCF3
Rla is Et; R2a is tert-Bu; T, U, Y and Z are CH; R5 is U-34; R21 are substituents on U-34.
R 21 R21 R21 R21 R21 R21 R21 5-CF3 4-CH2CH3 5-OCH3 4-CHF2 5-SCH3 4-S(0)2CH3
5-C1 4-CH3 5-CH2CH3 4-OCH2CH3 5-OCH2F 4-SCH2CH3 5-SCHF2 4-F 5-CH3 4-CN 5-CH2F 4-OCHF2 5-S(0)CH3 4-SCF3
Rla is Et; R2a is tert-Bu; T, U, Y and Z are CH; R5 is U-35; R21a is a substituent on U-35. g21a R21a R21a R21a R21a R21a R21a
H CF3 CH2CH3 0CH3 CHF2 SCH3 S(0)2CH3 CI CH2CF3 CN 0CH2CH3 OCH2F SCH2CH3 SCHF2
F CH3 CH2F OCF3 OCHF2 S(0)CH3 SCF3 Ria is Et; R2a is tert-Bu; T, U, Y and Z are CH; R5 is U-36; R22 is H; R2la and R22 are substituents on U-36.
R21a R21a R21a R21a R21a R2ia R2la
H CF3 CH2CH3 OCH3 CHF2 SCH3 S(0)2CH3 CI CH2CF3 CN OCH2CH3 OCH2F SCH2CH3 SCHF2 F CH3 CH2F OCF3 OCHF2 S(0)CH3 SCF3
Rla is Et; R2a is tert-Bu; T, U, Y and Z are CH; R5 is U-36; R22 is CH3; R2ia and R22 are substituents on U-36.
R21a R21a R21a R21a R21a R21a R21a
H CF3 CH2CH3 OCH3 CHF2 SCH3 S(0)2CH3 CI CH2CF3 CN OCH2CH3 OCH2F SCH2CH3 SCHF2
F CH3 CH2F OCF3 OCHF2 S(0)CH3 SCF3
Ria is Et; R2a is tert-Bu; T, U, Y and Z are CH; R5 is U-36; R22 is CH2CH3; R2ia and R22 are substituents on U-36.
R21a R21a R21a R 21a g21a R21a 221a
H CF3 CH2CH3 OCH3 CHF2 SCH3 S(0)2CH3
CI CH2CF3 CN OCH2CH3 OCH2F SCH2CH3 SCHF2
F CH3 CH2F OCF3 OCHF2 S(0)CH3 SCF3
Ria is Et; R2a is tert-Bu; T, U, Y and Z are CH; R5 is U-37; R2i are substituents on U-37.
R21 R 21 R21 R21 R21 R21 R21 2-CF3 2-CH2CH3 3-OCH3 3-CHF2 2-SCH3 3-S(0)2CH3
2-C1 2-CH3 3-CH2CH3 2-OCH2CH3 3-OCHF2 3-SCH2CH3 2-SCHF2 3-F 3-CH3 2-CN 2-CH2F 2-OCH2F 2-S(0)CH3 3-SCF3
Ria is Et: ; R2a is tert-Bu; T, U, Y and Z are CH; R5 is U-38; R21 are substituents on U-38 R21 R 21 R21 R21 R21 R21 R21 5-CF3 5-CH2CH3 5-OCH2CH3 5-CHF2 5-SCH3 4-S(0)2CH3
3-C1 3-CH2CF3 3-CN 3-OCF3 3-OCH2F 3-SCH2CH3 5-S(0)2CH3
4-C1 4-CH2CF3 4-CN 4-OCF3 4-OCH2F 4-SCH2CH3 3-SCHF2
5-C1 5-CH2CF3 5-CN 5-OCF3 5-OCH2F 5-SCH2CH3 4-SCHF2
3-F 3-CH3 3-0CH3 3-CH2F 3-OCHF2 3-S(0)CH3 5-SCHF2
4-F 4-CH3 4-OCH3 4-CH2F 4-OCHF2 4-S(0)CH3 3-SCF3
5-F 5-CH3 5-OCH3 5-CH2F 5-OCHF2 5-S(0)CH3 4-SCF3
3-CF3 3-CH2CH3 3-OCH2CH3 3-CHF2 3-SCH3 3-S(0)2CH3 5-SCF3
4-CF3 4-CH2CH3 4-OCH2CH3 4-CHF2 4-SCH3
Figure imgf000079_0001
Rla is Et; R2a is tert-Bu; T, U, Y and Z are CH; R5 is U-40; R21 are substituents on U-40.
R21 R21 R21 R21 R21 R21 R21 3-CH2CF3 3-CH3 3-OCH3 3-CHF2 3-SCH3 3-S(0)2CH3
3-C1 3-CF3 3-CH2CH3 3-OCH2CH3 3-OCH2F 3-SCH2CH3 3-SCHF2 3-F 3-CH3, 5-CH3 3-CN 3-CH2F 3-OCHF2 3-S(0)CH3 3-SCF3
Rla is Et; R2a is tert-Bu; T, U, Y and Z are CH; R5 is U-41; R2i are substituents on U-41 R21 R21 R21 R21 R21 R21 E2! 5-CF3 5-CH2CH3 5-OCH2CH3 5-CHF2 5-SCH3 5-S(0)2CH3
4-C1 4-CH2CF3 4-CN 4-OCF3 4-OCH2F 4-SCH2CH3 4-SCHF2
5-C1 5-CH2CF3 5-CN 5-OCF3 5-OCH2F 5-SCH2CH3 5-SCHF2
4-F 4-CH3 4-OCH3 4-CH2F 4-OCHF2 4-S(0)CH3 4-SCF3
5-F 5-CH3 5-OCH3 5-CH2F 5-OCHF2 5-S(0)CH3 5-SCF3
4-CF3 4-CH2CH3 4-OCH2CH3 4-CHF2 4-SCH3 4-S(0)2CH3
Rla is Et: R2a is tert-Bu; T, U, Y and Z are CH; R5 is U-44; R2i are substituents on U-44, R21 R21 R21 R21 R21 R21 R21 6-CF3 6-CH2CH3 6-OCH2CH3 6-CHF2 5-SCH3 4-S(0)2CH3
3-C1 3-CH2CF3 3-CN 3-OCF3 3-OCH2F 6-SCH3 5-S(0)2CH3
4-C1 4-CH2CF3 4-CN 4-OCF3 4-OCH2F 3-SCH2CH3 6-S(0)2CH3
5-C1 5-CH2CF3 5-CN 5-OCF3 5-OCH2F 4-SCH2CH3 3-SCHF2
6-C1 6-CH2CF3 6-CN 6-OCF3 6-OCH2F 5-SCH2CH3 4-SCHF2
3-F 3-CH3 3-OCH3 3-CH2F 3-OCHF2 6-SCH2CH3 5-SCHF2
4-F 4-CH3 4-OCH3 4-CH2F 4-OCHF2 3-S(0)CH3 6-SCHF2
5-F 5-CH3 5-OCH3 5-CH2F 5-OCHF2 4-S(0)CH3 3-SCF3
6-F 6-CH3 6-OCH3 6-CH2F 6-OCHF2 5-S(0)CH3 4-SCF3
3-CF3 3-CH2CH3 3-OCH2CH3 3-CHF2 3-SCH3 6-S(0)CH3 5-SCF3
4-CF3 4-CH2CH3 4-OCH2CH3 4-CHF2 4-SCH3 3-S(0)2CH3 6-SCF3
5-CF3 5-CH2CH3 5-OCH2CH3 5-CHF2
Figure imgf000080_0002
Rla is Et; R2a is tert-Bu; T, U, Y and Z are CH; R5 is U-46; R21 are substituents on U-46. 21 R21 R21 R21 R21 R 1 R21 6-CF3 6-CH3 4-OCH3 4-CHF2 4-SCH3 6-S(0)2CH3
4-C1 4-CH3 5-CH2CH3 5-OCH2CH3 5-OCH2F 5-SCH2CH3 4-SCHF2 5-F 5-CH3 6-CN 6-CH2F 6-OCHF2 6-S(0)CH3 5-SCF3
Figure imgf000080_0003
R is Et; R2a is tert-Bu; T, U, Y and Z are CH; R5 is U-48; R21 are substituents on U-48.
R21 R21 R 1 R21 R21 R21 R21 2-CF3 2-CH2CH3 4-OCH3 2-CHF2 4-SCH3 2-S(0)2CH3
2-C1 2-CH3 4-CH2CH3 2-0CH2CH3 4-OCH2F 2-SCH2CH3 4-SCHF2 4-F 4-CH3 2-CN 4-CH2F 2-OCHF2 4-S(0)CH3 2-SCF3
Figure imgf000080_0001
Rla is Et; R2a is tert-Bu T, U, Y and Z are CH; R5 is U-50 R21 are substituents on U-50.
Figure imgf000081_0001
R a is Et R2a is tert-Bu T U Y and Z are CH R5 is U-51 R21 are substituents on U-51.
Figure imgf000081_0002
Rla is Et; R2a is tert-Bu; T, U, Y and Z are CH; R5 is U-52; R21 are substituents on U-52 R21 R21 R21 R21 R21 R21 R21 5-CF3 6-CH3 5-OCH3 6-CHF2 5-SCH3 6-S(0)2CH3
2-C1 3-CH2CF3 2-CH2CH3 3-OCH2CH3 3-OCH2F 3-SCH2CH3 3-SCHF2
5-Cl 6-CH2CF3 5-CH2CH3 6-OCH2CH3 6-OCH2F 6-SCH2CH3 6-SCHF2
3-F 2-CH3 3-CN 2-CH2F 3-OCHF2 2-S(0)CH3 3-SCF3
6-F 3-CH3 6-CN 5-CH F 6-OCHF2 5-S(0)CH3 6-SCF3
2-CF3 5-CH3 2-OCH3 3-CHF2 2-SCH3 3-S(0)2CH3
Rla is Et; R2a is tert-Bu; T, U Y and Z are CH; R5 is U-53 R21 are substituents on U-53.
Figure imgf000081_0003
Ria is Et R2a is tert-Bu; T, U, Y and Z are CH; R5 is U-54 R21 are substituents on U-54.
Figure imgf000081_0004
Rla is Et; R2a is tert-Bu; T, U, Y and Z are CH; R5 is U-55; R21 are substituents on U-55.
R21 R21 R21 R21 R21 R21 R21 4-CF3 4-CN 4-CH2Cl 4-OCH2F 4-SCH2CH3 4-SCHF2
4-C1 4-CH3 4-OCH3 4-CH2F 4-OCHF2 4-S(0)CH3 4-SCF3 4-F 4-CH2CH3 4-OCH2CH3 4-CHF2 4-SCH3 4-S(0)2CH3 4-CH3, 6-CH3
Rla is Et; R2a is tert-Bu T U Y and Z are CH; R5 is U-56; R21 are substituents on U-56.
Figure imgf000082_0001
Rla is Et; R2a is tert-Bu; T, U, Y and Z are CH; R5 is U-57; R24 are substituents on U-57. R24 R24 R 4-CH2CH3 4-CH2CH3, 5-CH2CH3 4-CH3 5-CH2CH3 4-CH3, 5-CH2CH3 5-CH3 4-CH3, 5-CH3 4-CH2CH3, 5-CH3
Ria is Et; R2a is tert-Bu; T, U, Y and Z are CH; R5 is U-58; R24 are substituents on U-58. R2 R2 R24 4-CH2CH3 4-CH2CH3, 5-CH2CH3 4-CH3 5-CH2CH3 4-CH3, 5-CH2CH3 5-CH3 4-CH3, 5-CH3 4-CH2CH3, 5-CH3
Rla is Et; R2a is tert-Bu; T, U, Y and Z are CH; R5 is U-59; R24 are substituents on U-59. R 24 R24 4-CH2CH3 4-CH2CH3, 5-CH2CH3 4-CH3 5-CH2CH3 4-CH3, 5-CH2CH3 5-CH3 4-CH3, 5-CH3 4-CH2CH3, 5-CH3
Rla is Et; R2a is tert-Bu; T, U, Y and Z are CH; R5 is U-61; R24 are substituents on U-61. R24 R24 R24 R24 5-CH3 5-CH2CH3 2-CH3, 4-CH2CH3 2-CH3 2-CH2CH3 2-CH3, 4-CH3 4-CH3, 5-CH2CH3 4-CH3 4-CH2CH3 4-CH3, 5-CH3 4-CH2CH3, 5-CH3 Ria is Et; R2a is tert-Bu; T, U, Y and Z are CH; R5 is U-63; R24 are substituents on U-63.
R24 R24 R24 R24
- 5-CH3 5-CH2CH3 2-CH3, 4-CH2CH3
2-CH3 2-CH2CH3 2-CH3, 4-CH3 4-CH3, 5-CH2CH3
4-CH3 4-CH2CH3 4-CH3, 5-CH3 4-CH2CH3, 5-CH3
Rla is Et; R2a is tert-Bu; T, U, Y and Z are CH; R5 is U-66; R24 are substituents on U-66.
R24 g24 R24 R24
- 5-CH3 5-CH2CH3 2-CH3, 4-CH2CH3 2-CH3 2-CH2CH3 2-CH3, 4-CH3 4-CH3, 5-CH2CH3
4-CH3 4-CH2CH3 4-CH3, 5-CH3 4-CH2CH3, 5-CH3
Rla is Et; R2a is tert-Bι 1; T, U, Y and Z are CH; R5 is U-67; R24 are substituents on U-67.
R24 R24 R24 R24
- 5-CH3 5-CH2CH3 2-CH3, 4-CH2CH3 2-CH3 2-CH2CH3 2-CH3, 4-CH3 4-CH3, 5-CH2CH3
4-CH3 4-CH2CH3 4-CH3> 5-CH3 4-CH2CH3, 5-CH3
Figure imgf000083_0001
l is Me R2a is tert-Bu T, U Y and Z are CH R5 is U-44 R21 are substituents on U-44.
Figure imgf000083_0002
R is Et R2a is z-Pr T U Y and Z are CH; R5 is U-44 R21 are substituents on U-44.
Figure imgf000083_0003
Rla is Et R2a is tert-Bu; U is CF; T, Y and Z are CH; R5 iε U-7; ] R2l are substituents on U-7.
R21 R21 R21 R21 R21 R21 R21
- 5-CF3 5-CH2CH3 5-OCH2CH3 5-CHF2 5-SCH3 5-S02CH3
4-C1 4-CH2CF3 4-CN 4-CH2Cl 4-OCH2F 4-SCH2CH3 4-SCHF2
5-C1 5-CH2CF3 5-CN 5-CH2Cl 5-OCH2F 5-SCH2CH3 5-SCHF2
4-F 4-CH3 4-OCH3 4-CH2F 4-OCHF2 4-SOCH3 4-SCF3
5-F 5-CH3 5-OCH3 5-CH2F 5-OCHF2 5-SOCH3 5-SCF3
4-CF3 4-CH2CH3 4-OCH2CH3 4-CHF2 4-SCH3 4-S02CH3
Rla is Et R2a is tert-Bu; U is CF; T, Y and Z are CH; R5 is U-32; R2ia is a substituent on U-32.
R21a R21a R21a R21a R21a R21a R21a
H CF3 CH2CH3 OCH2CH3 CHF2 SCH3 S(0)2CH3
CI CH2CF3 CN CH2C1 OCH2F SCH2CH3 SCHF2
F CH3 OCH3 CH2F OCHF2 S(0)CH3 SCF3
Rl is Et ; R2a is tert-Bu; U is CF; T, Y and Z are CH; R5 is U-38; R21 are substituents on U-38.
R21 R21 R21 R21 R21 R21 R21
- 5-CF3 5-CH2CH3 5-OCH2CH3 5-CHF2 5-SCH3 4-S(0)2CH3
3-C1 3-CH2CF3 3-CN 3-OCF3 3-OCH2F 3-SCH2CH3 5-S(0)2CH3
4-C1 4-CH2CF3 4-CN 4-OCF3 4-OCH2F 4-SCH2CH3 3-SCHF2
5-C1 5-CH2CF3 5-CN 5-OCF3 5-OCH2F 5-SCH2CH3 4-SCHF2
3-F 3-CH3 3-OCH3 3-CH2F 3-OCHF2 3-S(0)CH3 5-SCHF2
4-F 4-CH3 4-OCH3 4-CH2F 4-OCHF2 4-S(0)CH3 3-SCF3
5-F 5-CH3 5-OCH3 5-CH2F 5-OCHF2 5-S(0)CH3 4-SCF3
3-CF3 3-CH2CH3 3-OCH2CH3 3-CHF2 3-SCH3 3-S(0)2CH3 5-SCF3
4-CF3 4-CH CH3 4-OCH2CH3 4-CHF2 4-SCH3
Ria is Et ; R2a is tert-Bu; U is CF; T, Y and Z are CH; R5 is U-41; R2i ai e substituents on U-41.
R21 R21 R21 R21 R21 R21 R21
- 5-CF3 5-CH2CH3 5-OCH2CH3 5-CHF2 5-SCH3 5-S(0)2CH3
4-C1 4-CH2CF3 4-CN 4-OCF3 4-OCH2F 4-SCH2CH3 4-SCHF2
5-C1 5-CH2CF3 5-CN 5-OCF3 5-OCH2F 5-SCH2CH3 5-SCHF2
4-F 4-CH3 4-OCH3 4-CH2F 4-OCHF2 4-S(0)CH3 4-SCF3
5-F 5-CH3 5-OCH3 5-CH2F 5-OCHF2 5-S(0)CH3 5-SCF3
4-CF3 4- CH2CH3 4-OCH2CH3 4-CHF2 4-SCH3 4-S(0)2CH3 Rla is Et ; R2a is tert-Bu ; U is CF; T, Y and Z are CH; R5 i 5 U-44; R21 are substituents on U-44.
R21 R21 R21 R21 R 1 R 1 R21
- 6-CF3 6-CH2CH3 6-OCH2CH3 6-CHF2 5-SCH3 4-S(0)2CH3
3-C1 3-CH2CF3 3-CN 3-OCF3 3-OCH2F 6-SCH3 5-S(0)2CH3
4-C1 4-CH2CF3 4-CN 4-OCF3 4-OCH2F 3-SCH2CH3 6-S(0)2CH3
5-C1 5-CH2CF3 5-CN 5-OCF3 5-OCH2F 4-SCH2CH3 3-SCHF2
6-C1 6-CH2CF3 6-CN 6-OCF3 6-OCH2F 5-SCH2CH3 4-SCHF2
3-F 3-CH3 3-OCH3 3-CH2F 3-OCHF2 6-SCH2CH3 5-SCHF2
4-F 4-CH3 4-OCH3 4-CH2F 4-OCHF2 3-S(0)CH3 6-SCHF2
5-F 5-CH3 5-OCH3 5-CH2F 5-OCHF2 4-S(0)CH3 3-SCF3
6-F 6-CH3 6-OCH3 6-CH F 6-OCHF2 5-S(0)CH3 4-SCF3
3-CF3 3-CH2CH3 3-OCH2CH3 3-CHF2 3-SCH3 6-S(0)CH3 5-SCF3
4-CF3 4-CH2CH3 4-OCH2CH3 4-CHF2 4-SCH3 3-S(0)2CH3 6-SCF3
5-CF3 5-CH2CH3 5-OCH2CH3 5-CHF2
U-49.
Figure imgf000085_0001
Rla is E t; R2a is tert-Bi ι; U is CF; T, Y a nd Z are CH; R5 i s U-58; R24 ai re substituents on U-58.
R24 R24 R 4
- 4-CH2CH3 4-CH2Cl ϊ3, 5-CH2CH (
4-CH3 5-CH2CH3 4-CH3, 5 -CH2CH3
5-CH3 4-CH3, 5-CH3 4-CH2CI I3, 5-CH3
Rla is Et ; R2a is tert-Bu ; T is N; U, Y and Z are CH; R5 is J-7; R21 are substituents on U-7.
R21 R21 R21 R21 R21 R21 R21
- 5-CF3 5-CH2CH3 5-OCH2CH3 5-CHF2 5-SCH3 5-S02CH3
4-C1 4-CH2CF3 4-CN 4-CH2Cl 4-OCH2F 4-SCH2CH3 4-SCHF2
5-C1 5-CH2CF3 5-CN 5-CH2Cl 5-OCH2F 5-SCH2CH3 5-SCHF2
4-F 4-CH3 4-OCH3 4-CH2F 4-OCHF2 4-SOCH3 4-SCF3
5-F 5-CH3 5-OCH3 5-CH2F 5-OCHF2 5-SOCH3 5-SCF3
4-CF3 4-CH2CH3 4-OCH2CH3 4-CHF 2 4-SCH3 4-S02CH3 Rla is Et; R2a is tert-Bu T is N U, Y and Z are CH; R5 is U-32; R2ia is a substituent on U-32.
R21a R21a
H S(0)2CH3 CI SCHF2 F SCF3
Figure imgf000086_0001
Rla is Et; R2a is tert-Bu; T is N; U, Y and Z are CH; R5 is U-38; R2i are substituents on U-38 R21 R21 R21 R21 R21 R21 R21 5-CF3 5-CH2CH3 5-OCH2CH3 5-CHF2 5-SCH3 4-S(0)2CHl3
3-C1 3-CH2CF3 3-CN 3-OCF3 3-OCH2F 3-SCH2CH3 5-S(0)2Cff3
4-C1 4-CH2CF3 4-CN 4-OCF3 4-OCH2F 4-SCH2CH3 3-SCHF2
5-C1 5-CH2CF3 5-CN 5-OCF3 5-OCH2F 5-SCH2CH3 4-SCHF2
3-F 3-CH3 3-0CH3 3-CH2F 3-OCHF2 3-S(0)CH3 5-SCHF2
4-F 4-CH3 4-OCH3 4-CH2F 4-OCHF2 4-S(0)CH3 3-SCF3
5-F 5-CH3 5-OCH3 5-CH2F 5-OCHF2 5-S(0)CH3 4-SCF3
3-CF3 3-CH2CH3 3-OCH2CH3 3-CHF2 3-SCH3 3-S(0)2CH3 5-SCF3
4-CF3 4-CH2CH3 4-OCH2CH3 4-CHF2 4-SCH3
Rla is Et; R2a is tert-Bu; T is N; U, Y and Z are CH; R5 is U-41; R21 are substituents on U-41. R21 R21 R21 R21 Ell E i R21 5-CF3 5-CH2CH3 5-OCH2CH3 5-CHF2 5-SCH3 5-S(0)2CH3
4-C1 4-CH2CF3 4-CN 4-OCF3 4-OCH2F 4-SCH2CH3 4-SCHF2
5-C1 5-CH2CF3 5-CN 5-OCF3 5-OCH2F 5-SCH2CH3 5-SCHF2
4-F 4-CH3 4-OCH3 4-CH2F 4-OCHF2 4-S(0)CH3 4-SCF3
5-F 5-CH3 5-OCH3 5-CH2F 5-OCHF2 5-S(0)CH3 5-SCF3
4-CF3 4-CH2CH3 4-OCH2CH3 4-CHF2 4-SCH3 4-S(0)2CH3
Rla is Et; R2a is tert-Bu; T is N; U, Y and Z are CH; R5 is U-44; R21 are substituents on U-44.
R 1 R 2- 1 R21 R 1 IR21 R21 R21 6-CF3 6-CH2CH3 6-OCH2CH3 6-CHF2 5-SCH3 4-S(0)2CH3
3-C1 3-CH CF3 3-CN 3-OCF3 3-OCH2F 6-SCH3 5-S(0)2CH3
4-C1 4-CH2CF3 4-CN 4-OCF3 4-OCH2F 3-SCH2CH3 6-S(0)2CH3
5-C1 5-CH2CF3 5-CN 5-OCF3 5-OCH2F 4-SCH2CH3 3-SCHF2
6-C1 6-CH2CF3 6-CN 6-OCF3 6-OCH2F 5-SCH2CH3 4-SCHF2
3-F 3-CH3 3-OCH3 3-CH2F 3-OCHF2 6-SCH2CH3 5-SCHF2
4-F 4-CH3 4-OCH3 4-CH2F 4-OCHF2 3-S(0)CH3 6-SCHF2
5-F 5-CH3 5-OCH3 5-CH2F 5-OCHF2 4-S(0)CH3 3-SCF3
6-F 6-CH3 6-OCH3 6-CH2F 6-OCHF2 5-S(0)CH3 4-SCF3 3-CF3 3-CH2CH3 3-OCH2CH3 3-CHF2 3-SCH3 6-S(0)CH3 5-SCF3 4-CF3 4-CH2CH3 4-OCH2CH3 4-CHF2 4-SCH3 3-S(0)2CH3 6-SCF3 5-CF3 5-CH2CH3 5-OCH2CH3 5-CHF2
Figure imgf000087_0001
Rla is Et; R2a is tert-Bu; Y is N; T, U and Z are CH; R5 is U-44; R2 are substituents on U-44.
R21 R21 R21 R 21 R21 R21 R21 6-CH2CF3 6-CH3 6-CH2CH3 6-OCF3 6-OCHF2 6-S(0)2CH3
3-C1 3-CH3 3-CH2CH3 3-CN 3-CH2F 3-SCH3 3-SCHF2
4-F 4-CH3 4-CH2CH3 4-OCH3 4-CHF2 4-SCH2CH3 4-SCF3
5-CF3 5-CH3 5-CH2CH3 5-OCH2CH3 5-OCH2F 5-S(0)CH3
Rla is Et; R2a is tert-Bu; T, U, Y and Z are CH; R21a is H; R22 is H; R23 is CH3; R25 is H; g, j, k, m, n and p are 0.
R5 R5 R5 R5 R5 R5 R5 R3 R5 R5 R3 R5 R5
U-2 U-4 U-8 U-12 U-16 U-20 U-22 U-26 U-30 U-43 U-62 U-65 U-70 U-3 U-5 U-9 U-13 U-17 U-21 U-24 U-29 U-42 U-60 U-64 U-68 U-71 TABLE 2
Figure imgf000087_0002
R ° is Et; R2b is t-Bu; T, U, Y and Z are CH; R5 is U-44; R21 are substituents on U-44.
R21 R21 R21 g21 Eli g21 g21 6-CH2CF3 6-CH3 6-CH2CH3 6-OCF3 6-OCHF2 6-S(0)2CH3
3-C1 3-CH3 3-CH2CH3 3-CN 3-CH2F 3-SCH3 3-SCHF2
4-F 4-CH3 4-CH2CH3 4-OCH3 4-CHF2 4-SCH2CH3 4-SCF3
5-CF3 5-CH3 5-CH2CH3 5-OCH2CH3 5-OCH2F 5-S(0)CH3 Rlb is Et; R2b is tert-Bu; T, U, Y and Z are CH; R21a is H; R22 is H; R23 is CH3; R25 is EC; g, j, k, m, n and are 0.
Figure imgf000088_0002
TABLE 3
Figure imgf000088_0001
Rlb is Et; R2 is tert-Bu; T, U, Y and Z are CH; R5 is U-7; R21 are substituents on U-7. R21 5-S(0)2CH3 4-SCHF2 5-SCHF 4-SCF3 5-SCF3
Figure imgf000088_0003
Rlb is Et; R2b is tert-Bu; T, U, Y and Z are CH; R5 is U-23; R21 are substituents on U-23.
R21 R21 R21 R21 R21 R21 R21
- 5-CF3 5-CH2CH 5-OCH2CH3 5-CHF2 5-SCH3 4-S(0)2CH3
2-C1 2-CH2CF3 2-CN 2-OCF3 2-OCH2F 2-SCH2CH3 5-S(0)2CH3
4-α 4-CH2CF3 4-CN 4-OCF3 4-OCH2F 4-SCH2CH3 2-SCHF2
5-Cl 5-CH2CF3 5-CN 5-OCF3 5-OCH2F 5-SCH2CH3 4-SCHF2
2-F 2-CH3 2-OCH3 2-CH2F 2-OCHF2 2-S(0)CH3 5-SCHF2
4-F 4-CH3 4-OCH3 4-CH2F 4-OCHF2 4-S(0)CH3 2-SCF3
5-F 5-CH3 5-OCH3 5-CH2F 5-OCHF2 5-S(0)CH3 4-SCF3
2-CF3 2-CH2CH3 2-OCH2CH3 2-CHF2 2-SCH3 2-S(0)2CH3 5-SCF3
4-CF3 4-CH2CH3 4-OCH2CH3 4-CHF2 4-SCH3 Rlb is Et; R2b is tert-Bu; T, U, Y and Z are CH; R5 is U-32; R21a is a substituent on U-32. R21a R21a 21a R21a R21a R21a R21a
H CF3 CH2CH3 OCH2CH3 CHF2 SCH3 S(0)2CH3
CI CH2CF3 CN CH2C1 OCH2F SCH2CH3 SCHF2
F CH3 OCH3 CH2F OCHF2 S(0)CH3 SCF3
Figure imgf000089_0001
Rlb is Et; R2b is tert-Bu; T, U, Y and Z are CH; R5 is U-41; R2i are substituents on U-41.
R21 R21 R21 R21 R 21 R21 R21 5-CF3 5-CH2CH3 5-OCH2CH3 5-CHF2 5-SCH3 5-S(0)2CH3
4-C1 4-CH2CF3 4-CN 4-OCF3 4-OCH2F 4-SCH2CH3 4-SCHF2
5-C1 5-CH2CF3 5-CN 5-OCF3 5-OCH2F 5-SCH2CH3 5-SCHF2
4-F 4-CH3 4-OCH3 4-CH2F 4-OCHF2 4-S(0)CH3 4-SCF3
5-F 5-CH3 5-OCH3 5-CH2F 5-OCHF2 5-S(0)CH3 5-SCF3
4-CF3 4-CH2CH3 4-OCH2CH3 4-CHF2 4-SCH3 4-S(0)2CH3
Rlb is Et; R2b is tert-Bu; T, U, Y and Z are CH; R5 is U-44; R21 are substituents on U-44.
R 1 R21 R21 R21 R21 R21 R21 6-CF3 6-CH2CH3 6-OCH2CH3 6-CHF2 5-SCH3 4-S(0)2CH3
3-C1 3-CH2CF3 3-CN 3-OCF3 3-OCH2F 6-SCH3 5-S(0)2CH3
4-C1 4-CH2CF3 4-CN 4-OCF3 4-OCH2F 3-SCH2CH3 6-S(0)2CH3
5-C1 5-CH2CF3 5-CN 5-OCF3 5-OCH2F 4-SCH2CH3 3-SCHF2
6-C1 6-CH2CF3 6-CN 6-OCF3 6-OCH2F 5-SCH2CH3 4-SCHF2
3-F 3-CH3 3-OCH3 3-CH2F 3-OCHF2 6-SCH2CH3 5-SCHF2
4-F 4-CH3 4-OCH3 4-CH2F 4-OCHF2 3-S(0)CH3 6-SCHF2
5-F 5-CH3 5-0CH3 5-CH2F 5-OCHF2 4-S(0)CH3 3-SCF3
6-F 6-CH3 6-OCH3 6-CH2F 6-OCHF2 5-S(0)CH3 4-SCF3 Rlb is Et; R2b is tert-Bu; T, U, Y and Z are CH; R5 is U-44; R2i are substituents on U-44.
R21 R21 R21 R21 R21 21 R21
3-CF3 3-CH2CH3 3-OCH2CH3 3-CHF2 3-SCH3 6-S(0)CH3 5-SCF3 4-CF3 4-CH2CH3 4-OCH2CH3 4-CHF2 4-SCH3 3-S(0)2CH3 6-SCF3 5-CF3 5-CH2CH3 5-OCH2CH3 5-CHF2
Rlb is Et; R2bis tert-Bu; T, U, Y and Z are CH; R5 is U-47; R21 are substituents on U-47.
R21 R21 R21 R 21 g21 R21 R- 21 5-CF3 5-CH CH3 5-OCH2CH3 5-OCH2F 5-SCH2CH3 5-SCHF2
4-C1 4-CH2CF3 4-CN 4-CH2F 4-OCHF2 4-S(0)CH3 4-SCF3
5-C1 5-CH2CF3 5-CN 5-CH2F 5-OCHF2 5-S(0)CH3 5-SCF3
4-F 4-CH3 4-OCH3 4-CHF2 4-SCH3 4-S(0)2CH3
5-F 5-CH3 5-OCH3 5-CHF2 5-SCH3 5-S02CH3
4-CF3 4-CH2CH3 4-OCH2CH3 4-OCH2F 4-SCH2CH3 4-SCHF2
Figure imgf000090_0001
Rlb is Et; R2b is tert-Bu; T, U, Y and Z are CH; R5 is U-58; R24 are substituents on U-58.
R 24 R24 R24 4-CH2CH3 4-CH2CH3, 5-CH2CH3
4-CH3 5-CH2CH3 4-CH3, 5-CH2CH3 5-CH3 4-CH3, 5-CH3 4-CH2CH3, 5-CH3
Rlb is Et; R2b is tert-Bu; T, U, Y and Z are CH; R2ia is H; R22 is H; R23 is CH3; R25 is H; g, j, k, m, n and are 0.
Figure imgf000090_0002
TABLE 4
Figure imgf000091_0001
Rlb is Et; R2a is t-Bu; T, U, Y and Z are CH; R5 is U-44; R21 are substituents on U-44.
R21 R21 R21 R21 R21 R21 R 1 6-CH2CF3 6-CH3 6-CH2CH3 6-OCF3 6-OCHF2 6-S(0)2CH3
3-C1 3-CH3 3-CH2CH3 3-CN 3-CH2F 3-SCH3 3-SCHF2
4-F 4-CH3 4-CH2CH3 4-OCH3 4-CHF2 4-SCH2CH3 4-SCF3
5-CF3 5-CH3 5-CH2CH3 5-OCH2CH3 5-OCH2F 5-S(0)CH3
Rlb is Et; R2a is tert-Bu; T, U, Y and Z are CH; R2ia is H; R22 is H; R23 is CH3; R25 is H; g, j, k, m, n and are 0.
Figure imgf000091_0005
TABLE 5
Figure imgf000091_0002
R21 are substituents on U-7.
Figure imgf000091_0003
Figure imgf000091_0004
Figure imgf000091_0006
Rla is Et; R2a is tert-Bu T U Y and Z are CH R5 is U-32; R2ia is a substituent on U-32.
R21a g21a
H S(0)2CH3 CI SCHF2 F
Figure imgf000092_0002
SCF3
Rla is Et; R2a is tert-Bu; T, U, Y and Z are CH; R5 is U-38; R21 are substituents on U-38. R21 R21 R21 R21 R21 R 21 R21 5-CF3 5-CH2CH3 5-OCH2CH3 5-CHF2 5-SCH3 4-S(0)2CH3
3-Cl 3-CH2CF3 3-CN 3-OCF3 3-OCH2F 3-SCH2CH3 5-S(0)2CH3
4-C1 4-CH2CF3 4-CN 4-OCF3 4-OCH2F 4-SCH2CH3 3-SCHF2
5-Cl 5-CH2CF3 5-CN 5-OCF3 5-OCH2F 5-SCH2CH3 4-SCHF2
3-F 3-CH3 3-OCH3 3-CH2F 3-OCHF2 3-S(0)CH3 5-SCHF2
4-F 4-CH3 4-OCH3 4-CH2F 4-OCHF2 4-S(0)CH3 3-SCF3
5-F 5-CH3 5-OCH3 5-CH2F 5-OCHF2 5-S(0)CH3 4-SCF3
3-CF3 3-CH2CH3 3-OCH2CH3 3-CHF2 3-SCH3 3-S(0)2CH3 5-SCF3
4-CF3 4-CH2CH3 4-OCH2CH3 4-CHF9 4-SCH3
Figure imgf000092_0001
3-CF3 3-CH2CH3 3-OCH2CH3 3-CHF2 3-SCH3 6-S(0)CH3 5-SCF3 4-CF3 4-CH2CH3 4-OCH2CH3 4-CHF2 4-SCH3 3-S(0)2CH3 6-SCF3 5-CF3 5-CH2CH3 5-OCH2CH3 5-CHF2
Rlb is Et; R2b is tert-Bu; T, U, Y and Z are CH; R21a is H; R22 is H; R23 is CH3; R25 is H; g, j, k, m, n and are 0.
Figure imgf000093_0003
Figure imgf000093_0001
TABLE 6
Figure imgf000093_0002
Figure imgf000093_0004
Rlb is Et; R2b is tert-Bu; T, U, Y and Z are CH; R21 is H; R22 is H; R23 is CH3 ; R25 is H; g, j, k, m, n and are 0.
Figure imgf000093_0005
TABLE 7
Figure imgf000094_0001
Rlb is Et ; R2b is t-Bu; T, U, Y and Z are CH; R5 is U-44; R2i are substituents on U-44. R21 R21 R21 R21 R21 R21 R21 - 6-CH2CF3 6-CH3 6-CH2CH3 6-OCF3 6-OCHF2 6-S(0)2CH3 3-Cl 3-CH3 3-CH2CH3 3-CN 3-CH2F 3-SCH3 3-SCHF2 4-F 4-CH3 4-CH2CH3 4-OCH3 4-CHF2 4-SCH2CH3 4-SCF3 5-CF3 5-CH3 5-CH2CH3 5-OCH2CH3 5-OCH2F 5-S(0)CH3
Rlb is Et; R2 Js tert-Bu; T, U, Y and Z are CH; R21a is H; R22 is H; R23 is CH3; R25 is H; g, j, k, m, n and are 0.
Figure imgf000094_0003
TABLE 8
Figure imgf000094_0002
Rlb is Me; R2b is tert-Bu; T, U, Y and Z are CH; R^ is U-1; R21 are substituents on U-1.
R21 R21 I R21 R21 | R21 R21 R21 2-F, 4-F 2-CH2CH3 4-OCH3 2-CHF2 3-SCH3 4-S(0)2CH3
2-C1 2-CF3 3-CH2CH3 2-OCH2CH3 3-CHF2 4-SCH3 2-SCHF2 3-Cl 3-CF3 4-CH2CH3 3-OCH2CH3 4-CHF2 2-SCH2CH3 3-SCHF2 4-C1 4-CF3 2-CN 4-OCH2CH3 2-OCH2F 3-SCH2CH3 4-SCHF2
2-C1, 6-C1 2-CH2CF3 3-CN 2-OCF3 3-OCH2F 4-SCH2CH3 2-SCF3 2-C1, 4-C1 3-CH2CF3 4-CN 3-OCF3 4-OCH2F 2-S(0)CH3 3-SCF3 2-F 4-CH2CF3 2-F, 6-CN 4-OCF3 2-OCHF2 3-S(0)CH3 4-SCF3
Figure imgf000095_0001
Rlb is Me R2b is tert-Bu T U Y and Z are CH R5 is U-6 R21 are substituents on U-6.
Figure imgf000095_0002
Rlb is Me; R2b is tert-Bu; T, U, Y and Z are CH; R5 is U-7; R21 are substituents on U-7. R21 R21 R21 R21 R21 R21 R21 5-CF3 5-CH2CH3 5-OCH2CH3 5-CHF2 5-SCH3 5-S(0)2CH3 4-C1 4-CH2CF3 4-CN 4-OCF3 4-OCH2F 4-SCH2CH3 4-SCHF2 5-Cl 5-CH2CF3 5-CN 5-OCF3 5-OCH2F 5-SCH2CH3 5-SCHF2 4-F 4-CH3 4-OCH3 4-CH2F 4-OCHF2 4-S(0)CH3 4-SCF3 5-F 5-CH3 5-OCH3 5-CH2F 5-OCHF2 5-S(0)CH3 5-SCF3 4-CF3 4-CH2CH3 4-OCH2CH3 4-CHF2 4-SCH3 4-S(0)2CH3
Rlb is Me; R2b is tert-Bu; T, U, Y and Z are CH; R5 is U-10; R21 are substituents on U-10. R21 R21 R21 R21 R21 g21 4-CH2CF3 4-CH2CH3 4-CH2Cl 4-SCH3 4-SCHF2 3-Cl 3-CH3 3-CN 3-CH2F 3-SCH2CH3 3-SCF3 4-F 4-CH3 4-OCH3 4-CHF2 4-S(0)CH3 3-CF3 3-CH2CH3 3-OCH2CH3 3-OCHF2 3-S(0)2CH3
Rl is Me; R2b is tert-Bu; T, U, Y and Z are CH; R5 is U-l l; R21 and R22 are substituents on U-11 ; R22 is H R21 R21 R21 R21 R21 R21 - 4-CH2CF3 4-CH2CH3 4-CH2Cl 4-SCH3 4-SC 3-Cl 3-CH3 3-CN 3-CH2F 3-SCH2CH3 3-SC 4-F 4-CH3 4-OCH3 4-CHF2 4-S(0)CH3 3-CF3 3-CH2CH3 3-OCH2CH3 3-OCHF2 3-S(0)2CH3 94
Rlb is Me; R2b is tert-Bu; T, U, Y and Z are CH; R5 is U-14; R2 ia is a substituent on U-14. g21a R21a R21a R21a R21a g21a R2
H CF3 CH2CH3 OCH2CH3 CHF2 SCH3 S(0)2CH3 CI CH2CF3 CN CH2C1 OCH2F SCH2CH3 SCHF2 F CH3 OCH3 CH2F OCHF2 S(Q)CH3 SCF3
Rlb is Me; R2b is tert-Bu; T, U, Y and Z are CH; R5 is U-15; R21a is a substituent on U-15. R21a R21a R21a R21a R21a R21a R21a
H CF3 CH2CH3 OCH2CH3 CHF2 SCH3 S(0)2CH3
CI CH2CF3 CN CH2C1 OCH2F SCH2CH3 SCHF2
F CH3 OCH3 CH2F OCHF2 S(0)CH3 SCF3
Rlb is Me; R2b is tert-Bu; T, U, Y and Z are CH; R5 is U-18; R2la is a substituent on U-18.
R21a R21a R21a R21a R21a R21a
H CH2CH3 OCH2CH3 CHF2 SCH3 S(0)2CH3 CI CN CH2C1 OCH2F SCH2CH3 SCHF2 F
Figure imgf000096_0001
OCH3 CH2F OCHF2 SCO)CH3 SCF3
Rlb is Me; R2b is tert-Bu; T, U, Y and Z are CH; R5 is U-19; R2i a is a substituent on U-19.
R21a R21a R21a
H SCH3 S(0)2CH3 CI SCH2CH3 SCHF2
F S(0)CH3 SCF3
Figure imgf000096_0002
Rlb is Me; R2b is tert-Bu; T, U, Y and Z are CH; R5 is U- 23; R are substituents on U-23
R21 R21 IR21 R 1 R21 R21 R21 5-CF3 5-CH2CH3 5-OCH2CH3 5-CHF2 5-SCH3 4-S(0)2CH3
2-C1 2-CH2CF3 2-CN 2-OCF3 2-OCH2F 2-SCH2CH3 5-S(0>2CH3
4-C1 4-CH2CF3 4-CN 4-OCF3 4-OCH2F 4-SCH2CH3 2-SCHF2
5-Cl 5-CH2CF3 5-CN 5-OCF3 5-OCH2F 5-SCH2CH3 4-SCHF2
2-F 2-CH3 2-OCH3 2-CH2F 2-0CHF2 2-S(0)CH3 5-SCHF2
4-F 4-CH3 4-OCH3 4-CH2F 4-0CHF2 4-S(0)CH3 2-SCF3 5-F 5-CH3 5-OCH3 5-CH2F 5-0CHF2 5-S(0)CH3 4-SCF3 2-CF3 2-CH2CH3 2-OCH2CH3 2-CHF2 2-SCH3 2-S(0)2CH3 5-SCF3
4-CF3 4-CH2CH3 4-OCH2CH3 4-CHF2 4-SCH3 3-S(0)2CH3 Rlb is Me; R2b is tert-Bu; T, U, Y and Z are CH; R5 is U-25; R2i and R22 are substituents on U-25; R22 is H.
R21 R 1 R21 R21 R21 R21 R21 5-CF3 4-CH2CH3 5-OCH3 4-CHF2 5-SCH3 4-S(0)2CH3
5-Cl 4-CH3 5-CH2CH3 4-OCH2CH3 5-OCH2F 4-SCH2CH3 5-SCHF2 4-F 5-CH3 4-CN 5-CH2F 4-OCHF2 5-S(0)CH3 4-SCF3
Rlb is Me; R2b is tert-Bu; T, U, Y and Z are CH; R5 is U-27; R21 are substituents on U-27.
R21 R21 R 1 R21 R21 R21 R21 2-CF3 2-CH2CH3 5-0CH3 2-CHF2 5-SCH3 2-S(0)2CH3
2-C1 2-CH3 5-CH2CH3 2-OCH2CH3 5-OCH2F 2-SCH2CH3 5-SCHF2 5-F 5-CH3 2-CN 5-CH2F 2-OCHF2 5-S(0)CH3 2-SCF3
Rl is Me; R2b is tert-Bu; T, U, Y and Z are CH; R5 is U-28; R21 are substituents on U-28.
R21 R21 R21 R21 R21 R21 R21 2-CF3 2-CH2CH3 5-OCH3 2-CHF2 5-SCH3 2-S(0)2CH3
2-C1 2-CH3 5-CH2CH3 2-0CH2CH3 5-OCH2F 2-SCH2CH3 5-SCHF2 5-F 5-CH3 2-CN 5-CH2F 2-OCHF2 5-S(0)CH3 2-SCF3
Rlb is Me; R2b is tert-Bu; T, U, Y and Z are CH; R5 is U-31; R21 and R22 are substituents on U-31; R22 is H.
R21 R21 R21 R21 R21 R21 R21
- 2-CF3 2-CH2CH3 5-OCH3 2-CHF2 5-SCH3 2-S(0)2CH3
2-C1 2-CH3 5-CH2CH3 2-OCH2CH3 5-OCH2F 2-SCH2CH3 5-SCHF2
5-F 5-CH3 2-CN 5-CH2F 2-OCHF2 5-S(0)CH3 2-SCF3
Rlb is Me; R2b is tert-Bu; T U Y and Z are CH; R5 is U-32; R2ia is a substituent on U-32.
R 21a R21a R21a R21a
H CHF2 SCH3 S(0)2CH3 CI OCH2F SCH2CH3 SCHF2 F
Figure imgf000097_0001
OCHF2 S(0)CH3 SCF3
Rlb is Me; R2 is tert-Bu; T, U, Y and Z are CH; R5 is U-33; R21a is a substituent on U-33.
R21a R21a R21a R21a R21a R21a R21a
H CF3 CH2CH3 OCH2CH3 CHF2 SCH3 S(0)2CH3 CI CH2CF3 CN CH2C1 OCH2F SCH2CH3 SCHF2 F CH3 OCH3 CH2F OCHF2 S(0)CH3 SCF3 Rlb is Me; R2b is tert-Bu; T, U, Y and Z are CH; R5 is U-34; R.21 are substituents on U-34.
R21 R21 R21 R21 R21 R21 R21 5-CF3 4-CH2CH3 5-OCH3 4-CHF2 5-SCH3 4-S(0)2CH3
5-Cl 4-CH3 5-CH2CH3 4-0CH2CH3 5-OCH2F 4-SCH2CH3 5-SCHF2 4-F 5-CH3 4-CN 5-CH2F 4-OCHF2 5-S(0)CH3 4-SCF3
Rlb is Me; R2b is tert-Bu; T, U, Y and Z are CH; R5 is U-35; R.21a is a substituent on U-35. g21a R21a R21a R21a R21a R21a R21a
H CF3 CH2CH3 OCH3 CF£F2 SCH3 S(0)2CH3 CI CH2CF3 CN 0CH2CH3 OCH2F SCH2CH3 SCHF2
F CH3 CH2F OCF3 OCHF2 S(0)CH3 SCF3
Rlb is Me; R2b is tert-Bu; T, U, Y and Z are CH; R5 is U-36; R22 is H; R21a and R22 are substituents on U-36.
R21a R21a R21a R21a R2 a R21a R2 a
H CF3 CH2CH3 OCH3 CHF2 SCH3 S(0)2CH3 CI CH2CF3 CN 0CH2CH3 OCH2F SCH2CH3 SCHF2 F CH3 CH2F OCF3 OCHF2 S(0)CH3 SCF3
Rlb is Me; R2b is tert-Bu; T, U, Y and Z are CH; R5 is U-36; R22 is CH3; R2ia and R22 are substituents on U-36.
R21a R21a R21a R21a R21a R21a R21a H CF3 CH2CH3 OCH3 CHF2 SCH3 S(0)2CH3 CI CH2CF3 CN 0CH2CH3 OCH2F SCH2CH3 SCHF2 F CH3 CH2F OCF3 OCHF2 S(Q)CH3 SCF3
Rlb is Me; R2b is tert-Bu; T, U, Y and Z are CH; R5 is U-36; R22 is CH2CH3; R2ia and R22 are substituents on U-36.
R21a R21a R21a R 21a R- 21 a R21a R21a
H CF3 CH2CH3 OCH3 CHF2 SCH3 S(0)2CH3 CI CH2CF3 CN 0CH2CH3 0CH2F SCH2CH3 SCHF2
F CH3 CH2F OCF3 OCHF2 S(0)CH3 SCF3
Rlb is Me; R2b is tert-Bu; T, U, Y and Z are CH; R5 is U-37; R21 are substituents on U-37.
R 21 R21 R21 R21 R 21 R 1 R 2- 1 2-CF3 2-CH2CH3 3-0CH3 3-CEDF2 2-SCH3 3-S(0)2CH3
2-C1 2-CH3 3-CH2CH3 2-0CH2CH3 3-OCHF2 3-SCH2CH3 2-SCHF2 3-F 3-CH3 2-CN 2-CH2F 2-0CH2F 2-S(0)CH3 3-SCF3
Figure imgf000099_0001
Rlb is Me; R2b is tert-Bu; T, U, Y and Z are CH; R5 is U-44; R2i are substituents on U-44.
R21 21 R21 R21 R 21 R21 R21 6-CF3 6-CH2CH3 6-0CH2CH3 6-CHF2 5-SCH3 4-S(0)2CH3
3-Cl 3-CH2CF3 3-CN 3-OCF3 3-OCH2F 6-SCH3 5-S(0)2CH3 4-C1 4-CH2CF3 4-CN 4-OCF3 4-OCH2F 3-SCH2CH3 6-S(0)2CH3
5-Cl 5-CH2CF3 5-CN 5-OCF3 5-OCH2F 4-SCH2CH3 3-SCHF2
6-C1 6-CH2CF3 6-CN 6-OCF3 6-OCH2F 5-SCH2CH3 4-SCHF2
3-F 3-CH3 3-OCH3 3-CH2F 3-OCHF2 6-SCH2CH3 5-SCHF2
4-F 4-CH3 4-OCH3 4-CH2F 4-OCHF2 3-S(0)CH3 6-SCHF2
5-F 5-CH3 5-OCH3 5-CH2F 5-OCHF2 4-S(0)CH3 3-SCF3
6-F 6-CH3 6-OCH3 6-CH2F 6-OCHF2 5-S(0)CH3 4-SCF3
3-CF3 3-CH2CH3 3-OCH2CH3 3-CHF2 3-SCH3 6-S(0)CH3 5-SCF3
4-CF3 4-CH2CH3 4-OCH2CH3 4-CHF2 4-SCH3 3-S(0)2CH3 6-SCF3
5-CF3 5-CH2CH3 5-OCH2CH3 5-CHF2
Rlb is Me; R2 is tert-Bu; T, U, Y and Z are CH; R5 is U-45; R21 are substituents on U-45.
R21 R21 R21 R21 R21_ R21 R21 5-CF3 5-CH2CH3 5-OCH3 6-CJHF2 5-SCH3 6-S(0)2CH3
2-C1 4-CH2CF3 6-CH3 4-OCH2CH3 2-OCH2F 4-SCH2CH3 2-SCHF2
5-Cl 6-CH2CF3 2-CH2CH3 6-OCH2CH3 5-OCH2F 6-SCH2CH3 5-SCHF2
4-F 2-CH3 4-CN 2-CH2F 4-OCHF2 2-S(0)CH3 4-SCF3
6-F 4-CH3 6-CN 5-CH2F 6-OCHF2 5-S(0)CH3 6-SCF3
2-CF3 5-CH3 2-0CH3 4-CHF2 2-SCH3 4-S(0)2CH3
Rlb is Me; R2b is tert-Bu; T, U, Y and Z are CH; R5 is U-46; R21 are substituents on U-46.
R21 R21 R21 R21 R21 R21 R21 6-CF3 6-CH3 4-OCH3 4-CHF2 4-SCH3 6-S(0)2CH3
4-C1 4-CH3 5-CH2CH3 5-OCH2CH3 5-OCH2F 5-SCH2CH3 4-SCHF2 5-F 5-CH3 6-CN 6-CH2F 6-OCHF2 6-S(0)CH3 5-SCF3
Rlb is Me; R2b is tert-Bu; T, U, Y and Z are CH; R5 is U-47; R i are substituents on U-47.
R 1 R21 g21 R21 R21 R21 R21 5-CF3 5-CH2CH3 5-OCH2CH3 5-OCH2F 5-SCH2CH3 5-SCHF2
4-C1 4-CH2CF3 4-CN 4-CH2F 4-OCFIF2 4-S(0)CH3 4-SCF3
5-Cl 5-CH2CF3 5-CN 5-CH2F 5-OCHF2 5-S(0)CH3 5-SCF3
4-F 4-CH3 4-OCH3 4-CHF2 4-SCH3 4-S(0)2CH3
5-F 5-CH3 5-OCH3 5-CHF2 5-SCH3 5-S02CH3
4-CF3 4-CH2CH3 4-OCH2CH3 4-OCH2F 4-SCH2CH3 4-SCHF2
Rlb is Me; R2b is tert-Bu; T, U, Y and Z are CH; R5 is U-48; R2i are substituents on U-48.
R21 R21 R21 R21 R21 R21 R21 2-CF3 2-CH2CH3 4-OCH3 2-CHF2 4-SCH3 2-S(0)2CH3 2-C1 2-CH3 4-CH2CH3 2-OCH2CFΪ3 4-OCH2F 2-SCH CH3 4-SCHF2 4-F 4-CH3 2-CN 4-CH2F 2-OCHF2 4-S(0)CH3 2-SCF3
Rlb is Me; R2b is tert-Bu; T, U, Y and Z are CH; R5 is U-49; R2i are substituents on U-49.
R21 R21 R21 R21 R21 R21 2-CH2CF3 2-CH2CH3 6-OCH3 2-OCH2F 5-S(0)CH3
2-C1 2-CH3 5-CH2CH3 2-OCH2CH3 5-OCHF2 6-S(0)2CH3
5-F 5-CH3 6-CH2CH3 5-CH2F 6-SCH3 2-SCHF2
6-CF3 6-CH3 5-CN 6-CHF2 2-SCH2CH3 5-SCF3 U-50.
Figure imgf000101_0001
Rl is Me; R2b is tert-Bu; T, U, Y and Z are CH; R5 is U-51; R2i are substituents on U-51.
R21 R21 R21 R21 R21 R21 5-CH2CF3 5-CH2CH3 5-CH2F 5-SCH3 5-SCHF2
3-Cl 3-CH3 3-CN 3-CHF2 3-SCH2CH3 3-SCF3
5-F 5-CH3 5-OCH3 5-OCH2F 5-S(0)CH3
3-CF3 3-CH2CH3 3-0CH2CH3 3-OCHF2 3-S(0)2CH3
Rlb is Me; R2b is tert-Bu; T, U, Y and Z are CH; R5 is U-52; R21 are substituents on U-52.
R21 R21 R21 R21 R21 R21 R21 5-CF3 6-CH3 5-OCH3 6-CHF2 5-SCH3 6-S(0)2CH3
2-C1 3-CH2CF3 2-CH2CH3 3-OCH2CH3 3-OCH2F 3-SCH2CH3 3-SCHF2
5-Cl 6-CH2CF3 5-CH2CH3 6-OCH2CH3 6-OCH2F 6-SCH2CH3 6-SCHF2
3-F 2-CH3 3-CN 2-CH2F 3-OCHF2 2-S(0)CH3 3-SCF3
6-F 3-CH3 6-CN 5-CH2F 6-OCHF2 5-S(0)CH3 6-SCF3
2-CF3 5-CH3 2-OCH3 3-CHF2 2-SCH3 3-S(0)2CH3
Rlb is Me; R2b is tert-Bu; T, U, Y and Z are CH; R5 is U-53; R2i are substituents on U-53.
R21 R21 R21 R21 R21 6-CF3 3-CH2CH3 6-OCH3 3-OCH2F 5-S(0)2CH3
3-Cl 3-CH2CF3 5-CH2CH3 3-OCH2CH3 5-OCHF2 6-SCHF2 5-F 5-CH3 6-CH2CH3 5-CH2F 6-SCH3 3-SCF3 3-CH3 6-CH 5-CN 6-CHF2 3-S(0)CH3
Rlb is Me R2b is tert-Bu T U Y and Z are CH R5 is U-54; R21 are substituents on U-54.
Figure imgf000102_0001
Rlb is Me; R2 is tert-Bu; T, U, Y and Z are CH; R5 is U-55; R2 are substituents on U-55.
R 1 R21 R21 R21 R21 R21 R21 4-CF3 4-CN 4-CH2Cl 4-OCH2F 4-SCH2CH3 4-SCHF2
4-C1 4-CH3 4-OCH3 4-CH2F 4-OCHF2 4-S(0)CH3 4-SCF3 4-F 4-CH2CH3 4-OCH2CH3 4-CHF2 4-SCH3 4-S(0)2CH3 4-CH3, 6-CH3
Rlb is Me; R2b is tert-Bu; T, U, Y and Z are CH; R5 is U-56; R2i are substituents on U-56. R21 R21 6-SCH3 6-SCHF2 3-SCH2CH3 3-SCF3 6-S(0)CH3
Figure imgf000102_0002
3-S(0)2CH3
R b is Me; R2b is tert-Bu; T, U, Y and Z are CH; R5 is U-57; R24 are substituents on U-57. R24 R24 R24 4-CH2CH3 4-CH2CH3, 5-CH2CH3 4-CH3 5-CH2CH3 4-CH3, 5-CH2CH3 5-CH3 4-CH3, 5-CH3 4-CH2CH3, 5-CH3
Rl is Me; R2b is tert-Bu; T, U, Y and Z are CH; R5 is U-58; R24 are substituents on U-58. R 24 R24 R 4-CH2CH3 4-CH2CH3, 5-CH2CH3 4-CH3 5-CH2CH3 4-CH3, 5-CH2CH3 5-CH3 4-CH3, 5-CH3 4-CH2CH3, 5-CH3
Rlb is Me; R2b is tert-Bu; T, U, Y and Z are CH; R5 is U-59; R24 are substituents on U-59. R R24 R24 4-CH2CH3 4-CH2CH3, 5-CH2CH3 4-CH3 5-CH2CH3 4-CH3, 5-CH2CH3 5-CH3 4-CH3, 5-CH3 4-CH2CH3, 5-CH3
Figure imgf000103_0001
Rlb is Me; R2b is tert-Bu; T, U, Y and Z are CH; R5 is U-63; R24 are substituents on U-63.
R2 R24 R24 R24
- 5-CH3 5-CH2CH3 2-CH3, 4-CH2CH3
2-CH3 2-CH2CH3 2-CH3, 4-CH3 4-CH3, 5-CH2CH3
4-CH3 4-CH2CH3 4-CH3, 5-CH3 4-CH2CH3, 5-CH3
R b is Me; R2b is tert-Bu; T, U, Y and Z are CH; R5 is U-66; R24 are substituents on U-66.
R24 R24 R24 R24
- 5-CH3 5-CH2CH3 2-CH3, 4-CH2CH3
2-CH3 2-CH2CH3 2-CH3, 4-CH3 4-CH3, 5-CH2CH3
4-CH3 4-CH2CH3 4-CH3, 5-CH3 4-CH2CH3, 5-CH3
Rlb is Me; R2b is tert-Bu; T, U, Y and Z are CH; R5 is U-67; R24 are substituents on U-67.
R24 R24 R24 R24
- 5-CH3 5-CH2CH3 2-CH3, 4-CH2CH3
2-CH3 2-CH2CH3 2-CH3, 4-CH3 4-CH3, 5-CH2CH3
4-CH3 4-CH2CH3 4-CH3, 5-CH3 4-CH CH3, 5-CH3
Rl is Me; R2b is tert-Bu; T, U, Y and Z are CH; R5 is U-69; R24 are substituents on U-69.
R24 R24 R24 R24
- 5-CH3 5-CH2CH3 2-CH3, 4-CH2CH3
2-CH3 2-CH2CH3 2-CH3, 4-CH3 4-CH3, 5-CH2CH3
4-CH3 4-CH2CH3 4-CH3, 5-CH3 4-CH2CH3, 5-CH3
Figure imgf000103_0002
5-F 5-CH3 5-0CH3 5-CH2F 5-OCHF2 5-S(0)CH3 5-SCF3
4-CF3 4-CH2CH3 4-OCH2CH3 4-CHF2 4-SCH3 4-S(0)2CH3
Rlb is Et R2b is tert-Bu; T, U, Y and Z are CH; R5 is U-32; R2la is a substituent on U-32.
R21a R21a R21a R21a R21a R21a R21a
H CF3 CH2CH3 OCH2CH3 CHF2 SCH3 S(0)2CH3
CI CH2CF3 CN CH2C1 OCH2F SCH2CH3 SCHF2
F CH3 OCH3 CH2F OCHF2 S(0)CH3 SCF3
Rlb is Et; R2b is tert-Bu; T, U, Y and Z are CH; R5 is U-38; R2i are substituents on U-38.
R2! R21 R21 R21 R21 R21 R 1
- 5-CF3 5-CH2CH3 5-OCH2CH3 5-CHF2 5-SCH3 4-S(0)2CH3
3-Cl 3-CH2CF3 3-CN 3-OCF3 3-OCH2F 3-SCH2CH3 5-S(0)2CH3
4-C1 4-CH2CF3 4-CN 4-OCF3 4-OCH2F 4-SCH2CH3 3-SCHF2
5-Cl 5-CH2CF3 5-CN 5-OCF3 5-OCH2F 5-SCH2CH3 4-SCHF2
3-F 3-CH3 3-OCH3 3-CH2F 3-OCHF2 3-S(0)CH3 5-SCHF2
4-F 4-CH3 4-OCH3 4-CH2F 4-OCHF2 4-S(0)CH3 3-SCF3
5-F 5-CH3 5-OCH3 5-CH2F 5-OCHF2 5-S(0)CH3 4-SCF3
3-CF3 3-CH2CH3 3-OCH2CH3 3-CHF2 3-SCH3 3-S(0)2CH3 5-SCF3
4-CF3 4-CH2CH3 4-OCH2CH3 4-CHF2 4-SCH3
Rl is Et ; R2b is tert-Bu; T, U, Y and Z are CH; R5 is U-41; R21 are substituents on U-41.
R21 R 1 R21 R21 R21 R21 R 1
- 5-CF3 5-CH2CH3 5-OCH2CH3 5-CHF2 5-SCH3 5-S(0)2CH3
4-C1 4-CH2CF3 4-CN 4-OCF3 4-OCH2F 4-SCH2CH3 4-SCHF2
5-Cl 5-CH2CF3 5-CN 5-OCF3 5-OCH2F 5-SCH2CH3 5-SCHF2
4-F 4-CH3 4-OCH3 4-CH2F 4-OCHF2 4-S(0)CH3 4-SCF3
5-F 5-CH3 5-OCH3 5-CH2F 5-OCHF2 5-S(0)CH3 5-SCF3
4-CF3 4-CH2CH3 4-OCH2CH3 4-CHF2 4-SCH3 4-S(0)2CH3
Rlb is Et ; R2 is tert-Bu; T, U, Y and Z are CH; R5 is U-44; R21 are substituents on U-44.
R 1 R21 R21 R21 R21 R 1 R21
- 6-CF3 6-CH2CH3 6-OCH2CH3 6-CHF2 5-SCH3 4-S(0)2CH3
3-Cl 3-CH2CF3 3-CN 3-OCF3 3-OCH2F 6-SCH3 5-S(0)2CH3
4-C1 4-CH2CF3 4-CN 4-OCF3 4-OCH2F 3-SCH2CH3 6-S(0)2CH3
5-Cl 5-CH2CF3 5-CN 5-OCF3 5-OCH2F 4-SCH2CH3 3-SCHF2
6-C1 6-CH2CF3 6-CN 6-OCF3 6-OCH2F 5-SCH2CH3 4-SCHF2
3-F 3-( H3 3-OCH3 3-CH2F 3-OCHF2 6-SCH2CH3 5-SCHF2 103
4-F 4-CH3 4-OCH3 4-CH2F 4-OCHF2 3-S(0)CH3 6-SCHF2
5-F 5-CH3 5-OCH3 5-CH2F 5-OCHF2 4-S(0)CH3 3-SCF3
6-F 6-CH3 6-OCH3 6-CH2F 6-OCHF2 5-S(0)CH3 4-SCF3
3-CF3 3-CH2CH3 3-OCH2CH3 3-CHF2 3-SCH3 6-S(0)CH3 5-SCF3
4-CF3 4-CH2CH3 4-OCH2CH3 4-CHF2 4-SCH3 3-S(0)2CH3 6-SCF3
5-CF3 5-CH2CH3 5-OCH2CH3 5-CHF2
Rlb is Me R2b is i-Pr; T U Y and Z are CH R5 is U-44 R2 are substituents on U-44.
Figure imgf000105_0001
Rlb is Me; R2 is tert-Bu; U is CF; T, Y and Z are CH; R5 is U-7; R2i are substituents on U-7.
R21 21 R21 R21 R21 R 1 5-CF3 5-CH2CH3 5-OCH2CH3 5-CHF2 5-SCH3 5-S02CH3
4-C1 4-CH2CF3 4-CN 4-CH2Cl 4-OCH2F 4-SCH2CH3 4-SCHF2
5-Cl 5-CH2CF3 5-CN 5-CH2Cl 5-OCH2F 5-SCH2CH3 5-SCHF2
4-F 4-CH3 4-OCH3 4-CH2F 4-OCHF2 4-SOCH3 4-SCF3
5-F 5-CH3 5-OCH3 5-CH2F 5-OCHF2 5-SOCH3 5-SCF3
4-CF3 4-CH2CH3 4-OCH2CH3 4-CHF2 4-SCH3 4-S02CH3
Rl is Me; R2b is tert-Bu U is CF T Y and Z are CH; R5 is U-32; R21a is a substituent on U-32. g21a R21a
H S(0)2CH3 CI SCHF2 F SCF3
Figure imgf000105_0002
Rl is Me; R2 is tert-Bu; U is CF; T, Y and Z are CH; R5 is U-38; R21 are substituents on U-38.
R21 R- 21 R21 ! R21 R21 R21 R21
- 5-CF3 5-CH2CH3 5-OCH2CH3 5-CHF2 5-SCH3 4-S(0)2CH3
3-Cl 3-CH2CF3 3-CN 3-OCF3 3-OCH2F 3-SCH2CH3 5-S(0)2CH3
4-C1 4-CH2CF3 4-CN 4-OCF3 4-OCH2F 4-SCH2CH3 3-SCHF2
5-Cl 5-CH2CF3 5-CN 5-OCF3 5-OCH2F 5-SCH2CH3 4-SCHF2
3-F 3-CH3 3-OCH3 3-CH2F 3-OCHF2 3-S(0)CH3 5-SCHF2
4-F 4-CH3 4-OCH3 4-CH2F 4-OCHF2 4-S(0)CH3 3-SCF3
5-F 5-CH3 5-OCH3 5-CH2F 5-OCHF2 5-S(0)CH3 4-SCF3 3-CF3 3-CH2CH3 3-OCH2CH3 3-CHF2 3-SCH3 3-S(0)2CH3 5-SCF3
4-CF3 4-CH2CH3 4-OCH2CH3 4-CHF2 4-SCH3
Rlb is Me; R2b is tert-Bu; U is CF; T, Y and Z are CH; R5 is U-41; R2l ire substituents on U-41.
R21 R21 R21 R21 R21 R21 R21
- 5-CF3 5-CH2CH3 5-OCH2CH3 5-CHF2 5-SCH3 5-S(0)2CH3
4-C1 4-CH2CF3 4-CN 4-OCF3 4-OCH2F 4-SCH2CH3 4-SCHF2
5-Cl 5-CH2CF3 5-CN 5-OCF3 5-OCH2F 5-SCH2CH3 5-SCHF2
4-F 4-CH3 4-OCH3 4-CH2F 4-OCHF2 4-S(0)CH3 4-SCF3
5-F 5-CH3 5-OCH3 5-CH2F 5-OCHF2 5-S(0)CH3 5-SCF3
4-CF3 4-CH2CH3 4-OCH2CH3 4-CHF2 4-SCH3 4-S(0)2CH3
Rlb is M e; R2b is tert-Ε .u; U is CF; T, Y and Z are CH; R5 is U-44; R21 ire substituents on U-44.
R21 R21 R21 R 1 R21 R 1 R21
- 6-CF3 6-CH2CH3 6-OCH2CH3 6-CHF2 5-SCH3 4-S(0)2CH3
3-Cl 3-CH2CF3 3-CN 3-OCF3 3-OCH2F 6-SCH3 5-S(0)2CH3
4-C1 4-CH2CF3 4-CN 4-OCF3 4-OCH2F 3-SCH CH3 6-S(0)2CH3
5-Cl 5-CH2CF3 5-CN 5-OCF3 5-OCH2F 4-SCH2CH3 3-SCHF2
6-C1 6-CH2CF3 6-CN 6-OCF3 6-OCH2F 5-SCH2CH3 4-SCHF2
3-F 3-CH3 3-OCH3 3-CH2F 3-OCHF2 6-SCH2CH3 5-SCHF2
4-F 4-CH3 4-OCH3 4-CH2F 4-OCHF2 3-S(0)CH3 6-SCHF2
5-F 5-CH3 5-OCH3 5-CH2F 5-OCHF2 4-S(0)CH3 3-SCF3
6-F 6-CH3 6-OCH3 6-CH2F 6-OCHF2 5-S(0)CH3 4-SCF3
3-CF3 3-CH2CH3 3-OCH2CH3 3-CHF2 3-SCH3 6-S(0)CH3 '5-SCF3
4-CF3 4-CH2CH3 4-OCH2CH3 4-CHF2 4-SCH3 3-S(0)2CH3 6-SCF3
5-CF3 5-CH2CH3 5-OCH2CH3 5-CHF2 < ire substituents 0 n U-49.
Figure imgf000106_0001
Figure imgf000106_0002
substituents 0 n U-58.
Figure imgf000106_0003
5-CH3 4-CH3, 5-CH3 4-CH2CH3, 5-CH3
Rlb is Me R2b is tert-Bu T is N U Y and Z are CH R5 is U-7 R21 are substituents on U-7. R21 5-so2CH3 4-SCHF2 5-SCHF2 4-SCF3 5-SCF3
Figure imgf000107_0001
Rlb is Me; R2b is tert-Bu; T is N; U, Y and Z are CH R5 is U-32; R2ia is a substituent on U-32.
R21a R21a R21a R21a
H CF3 CH2CH3 S(0)2CH3 CI CH2CF3 CN SCHF2 F CH3 OCH3
Figure imgf000107_0002
SCF3
Rlb is Me; R2b is tert-Bu; T is N; U, Y and Z are CH; R5 is U-38; R21 are substituents on U-38.
R21 R21 R 1 R21 R 21 I R21 R21 5-CF3 5-CH2CH3 5-OCH2CH3 5-CHF2 5-SCH3 4-S(0)2CH3
3-Cl 3-CH2CF3 3-CN 3-OCF3 3-OCH2F 3-SCH2CH3 5-S(0)2CH3 4-C1 4-CH2CF3 4-CN 4-OCF3 4-OCH2F 4-SCH2CH3 3-SCHF2 5-Cl 5-CH2CF3 5-CN 5-OCF3 5-OCH2F 5-SCH2CH3 4-SCHF2
3-F 3-CH3 3-OCH3 3-CH2F 3-OCHF2 3-S(0)CH3 5-SCHF2
4-F 4-CH3 4-OCH3 4-CH2F 4-OCHF2 4-S(0)CH3 3-SCF3
5-F 5-CH3 5-OCH3 5-CH2F 5-OCHF2 5-S(0)CH3 4-SCF3
3-CF3 3-CH2CH3 3-OCH2CH3 3-CHF2 3-SCH3 3-S(0)2CH3 5-SCF3
4-CF3 4-CH2CH3 4-OCH2CH3 4-CHF2 4-SCH3
Rlb is Me; R2b is tert-Bu; T is N; U, Y and Z are CH; R5 is U-41; R2i are substituents on U-41.
R21 R21 R21 R21 R21 R21 R21 5-CF3 5-CH2CH3 5-OCH2CH3 5-CHF2 5-SCH3 5-S(0)2CH3
4-C1 4-CH2CF3 4-CN 4-OCF3 4-OCH2F 4-SCH2CH3 4-SCHF2
5-Cl 5-CH2CF3 5-CN 5-OCF3 5-OCH2F 5-SCH2CH3 5-SCHF2
4-F 4-CH3 4-OCH3 4-CH2F 4-OCHF2 4-S(0)CH3 4-SCF3
5-F 5-CH3 5-OCH3 5-CH2F 5-OCHF2 5-S(0)CH3 5-SCF3
4-CF3 4-CH2CH3 4-OCH2CH3 4-CHF2 4-SCH3 4-S(0)2CH3
Figure imgf000108_0001
Rlb is Me R2b is tert-Bu U is N T Υ and Z are CH R5 is U-44 R21 are substituents on U-44.
Figure imgf000108_0002
Rl is Me R b is tert-Bu Y is N T U and Z are CH R5 is U-44; R21 are substituents on U-44.
Figure imgf000108_0003
Rlb is Me; R2b is tert-Bu; T, U, Y and Z are CH; R2ia is H; R22 is H; R23 is CH3; R25 is H; g, j, k, m n and are 0.
Figure imgf000108_0004
TABLE 9
Figure imgf000109_0001
Rla is Et R2a is tert-Bu ; T, U, Y and 2 : are CH; R5 is U-7; R21 are substituents on U-7.
R21 R21 R21 R21 R21 R21 R21
- 5-CF3 5-CH2CH3 5-OCH2CH3 5-CHF2 5-SCH3 5-S(0)2CH3
4-C1 4-CH2CF3 4-CN 4-OCF3 4-OCH2F 4-SCH2CH3 4-SCHF2
5-Cl 5-CH2CF3 5-CN 5-OCF3 5-OCH2F 5-SCH2CH3 5-SCHF2
4-F 4-CH3 4-OCH3 4-CH2F 4-OCHF2 4-S(0)CH3 4-SCF3
5-F 5-CH3 5-OCH3 5-CH2F 5-OCHF2 5-S(0)CH3 5-SCF3
4-CF3 4-CH2CH3 4-OCH2CH3 4-CHF2 4-SCH3 4-S(0)2CH3
Rla is Et R2a is tert-Bu T, U, Y and Z are CH; R5 is U-32; R 1a is a substituent on U-32.
R21a R21a R21a R21a R21a R21a R21a
H CF3 CH2CH3 OCH2CH3 CHF2 SCH3 S(0)2CH3
CI CH2CF3 CN CH2C1 OCH2F SCH2CH3 SCHF
F CH3 OCH3 CH2F OCHF2 S(Q)CH3 SCF3
Rla is Et ; R2a is tert-Bu ; T, U, Y and 2 _ are CH; R5 is U-38; R2i are substituents on U-38.
R21 R21 R21 R21 R21 R21 R21
- 5-CF3 5-CH2CH3 5-OCH2CH3 5-CHF 5-SCH3 4-S(0)2CH3
3-Cl 3-CH2CF3 3-CN 3-OCF3 3-OCH2F 3-SCH2CH3 5-S(0)2CH3
4-C1 4-CH2CF3 4-CN 4-OCF3 4-OCH2F 4-SCH2CH3 3-SCHF2
5-Cl 5-CH2CF3 5-CN 5-OCF3 5-OCH2F 5-SCH2CH3 4-SCHF2
3-F 3-CH3 3-OCH3 3-CH2F 3-OCHF2 3-S(0)CH3 5-SCHF2
4-F 4-CH3 4-OCH3 4-CH2F 4-OCHF2 4-S(0)CH3 3-SCF3
5-F 5-CH3 5-OCH3 5-CH2F 5-OCHF2 5-S(0)CH3 4-SCF3
3-CF3 3-CH CH3 3-OCH2CH3 3-CHF2 3-SCH3 3-S(0)2CH3 5-SCF3
4-CF3 4-( 3H2CH3 4-OCH2CH3 4-CHF2 4-SCI *3
Rla is Et; R2a is tert-Bu; T, U, Y and Z are CH; R5 is U-41; R21 are substituents on U-41.
R21 R21 R21 R21 R 1 R21 R21 5-CF3 5-CH2CH3 5-0CH2CH3 5-CHF2 5-SCH3 5-S(0)2CH3
4-C1 4-CH2CF3 4-CN 4-0CF3 4-0CH2F 4-SCH2CH3 4-SCHF2 5-Cl 5-CH2CF3 5-CN 5-0CF3 5-OCH2F 5-SCH2CH3 5-SCHF2 4-F 4-CH3 4-OCH3 4-CH2F 4-OCHF2 4-S(0)CH3 4-SCF3 5-F 5-CH3 5-OCH3 5-CH2F 5-OCHF2 5-S(0)CH3 5-SCF3 4-CF3 4-CH2CH3 4-OCH2CH3 4-CHF2 4-SCH3 4-S(0)2CH3
Ria is Et: ; R2a is tert-Bu; T, U, Y and Z are CH; R5 is U-44; R21 are substituents on U-44 R21 R21 R21 R21 R 21 R21 R21 6-CF3 6-CH2CH3 6-OCH2CH3 6-CHF2 5-SCH3 4-S(0)2CH3 3-Cl 3-CH2CF3 3-CN 3-OCF3 3-OCH2F 6-SCH3 5-S(0)2CH3 4-C1 4-CH2CF3 4-CN 4-OCF3 4-OCH2F 3-SCH2CH3 6-S(0)2CH3 5-Cl 5-CH2CF3 5-CN 5-OCF3 5-OCH2F 4-SCH2CH3 3-SCHF2 6-C1 6-CH2CF3 6-CN 6-OCF3 6-OCH2F 5-SCH2CH3 4-SCHF2 3-F 3-CH3 3-OCH3 3-CH2F 3-OCHF2 6-SCH2CH3 5-SCHF2 4-F 4-CH3 4-OCH3 4-CH2F 4-OCHF2 3-S(0)CH3 6-SCHF2 5-F 5-CH3 5-OCH3 5-CH2F 5-OCHF2 4-S(0)CH3 3-SCF3 6-F 6-CH3 6-OCH3 6-CH2F 6-OCHF2 5-S(0)CH3 4-SCF3 3-CF3 3-CH2CH3 3-OCH2CH3 3-CHF2 3-SCH3 6-S(0)CH3 5-SCF3 4-CF3 4-CH2CH3 4-OCH2CH3 4-CHF2 4-SCH3 3-S(0)2CH3 6-SCF3 5-CF3 5-CH2CH3 5-OCH2CH3 5-CHF2
Rlb is Et; R2b is tert-Bu; T, U, Y and Z are CH; R2ia is H; R22 is H; R23 is CH3; R25 is H; g, j, k, m, n and are 0.
Figure imgf000110_0001
Formulation/Utility Compounds of this invention will generally be used as a formulation or composition with an agriculturally suitable carrier comprising at least one of a liquid diluent, a solid diluent or a surfactant. The formulation or composition ingredients are selected to be consistent with the physical properties of the active ingredient, mode of application and environmental factors such as soil type, moisture and temperature. Useful formulations include liquids such as solutions (including emulsifiable concentrates), suspensions, emulsions (including microemulsions and/or suspoemulsions) and the like which optionally can be thickened into gels. Useful formulations further include solids such as dusts, powders, granules, pellets, tablets, films (including seed coatings), and the like which can be water-dispersible ("wettable") or water-soluble. Active ingredient can be
(micro)encapsulated and further formed into a suspension or solid formulation; alternatively the entire formulation of active ingredient can be encapsulated (or "overcoated"). Encapsulation can control or delay release of the active ingredient. Sprayable formulations can be extended in suitable media and used at spray volumes from about one to several hundred liters per hectare. High-strength compositions are primarily used as intermediates for further formulation. The formulations will typically contain effective amounts of active ingredient, diluent and surfactant within the following approximate ranges which add up to 100 percent by weight. Weight Percent Active Ingredient Diluent Surfactant Water-Dispersible and Water- 0.001-90 0-99.999 0-15 soluble Granules, Tablets and Powders. Suspensions, Emulsions, 1-50 40-99 0-50 Solutions (including Emulsifiable Concentrates) Dusts 1-25 70-99 0-5 Granules and Pellets 0.001-99 5-99.999 0-15 High Strength Compositions 90-99 0-10 0-2 Typical solid diluents are described in Watkins, et al., Handbook of Insecticide Dust Diluents and Carriers, 2nd Ed., Dorland Books, Caldwell, New Jersey. Typical liquid diluents are described in Marsden, Solvents Guide, 2nd Ed., Interscience, New York, 1950. McCutcheon' s Detergents and Emulsifiers Annual, Allured Publ. Corp., Ridgewood, New Jersey, as well as Sisely and Wood, Encyclopedia of Surface Active Agents, Chemical Publ. Co., Inc., New York, 1964, list surfactants and recommended uses. All formulations can contain minor amounts of additives to reduce foam, caking, corrosion, microbiological growth and the like, or thickeners to increase viscosity. Surfactants include, for example, polyethoxylated alcohols, polyethoxylated alkylphenols, polyethoxylated sorbitan fatty acid esters, dialkyl sulfosuccinates, alkyl sulfates, alkylbenzene sulfonates, organosilicones, N,N-dialkyltaurates, lignin sulfonates, naphthalene sulfonate formaldehyde condensates, polycarboxylates, glycerol esters, poly- ox yethylene/polyoxypropylene block copolymers, and alkylpolyglycosides where the number of glucose units, referred to as degree of polymerization (D.P.), can range from 1 to 3 and the alkyl units can range from C6 to C^ (see Pure and Applied Chemistry 72, 1255- 1264). Solid diluents include, for example, clays such as bentonite, montmorillonite, attapulgite and kaolin, starch, sugar, silica, talc, diatomaceous earth, urea, calcium carbonate, sodium carbonate and bicarbonate, and sodium sulfate. Liquid diluents include, for example, water, N,N-dimethylformamide, dimethyl sulfoxide, N-alkylpyrrolidone, ethylene glycol, polypropylene glycol, propylene carbonate, dibasic esters, paraffins, alkylbenzenes, alkylnaphthalenes, glycerine, triacetine, oils of olive, castor, linseed, tung, sesame, corn, peanut, cotton-seed, soybean, rape-seed and coconut, fatty acid esters, ketones such as cyclohexanone, 2-heptanone, isophorone and 4-hydroxy-4-rnethyl-2-pentanone, acetates such as hexyl acetate, heptyl acetate and octyl acetate, and alcohols such as methanol, cyclohexanol, decanol, benzyl and tetrahydrofurfuryl alcohol. Useful formulations of this invention may also contain materials well known to those skilled in the art as formulation aids such as antifoams, film formers and dyes. Antifoams can include water dispersible liquids comprising polyorganosiloxanes like Rhodorsil® 416. The film formers can include polyvinyl acetates, polyvinyl acetate copolymers, polyvinylpyrrolidone-vinyl acetate copolymer, polyvinyl alcohols, polyvinyl alcohol copolymers and waxes. Dyes can include water dispersible liquid colorant compositions like Pro-lzed® Colorant Red. One skilled in the art will appreciate that this is a non-exhaustive list of formulation aids. Suitable examples of formulation aids include those listed herein and those listed in McCutcheon 's 2001, Volume 2: Functional Materials published by MC Publishing Company and PCT Publication WO 03/024222. Solutions, including emulsifiable concentrates, can be prepared by simply mixing the ingredients. Dusts and powders can be prepared by blending and, usually, grinding as in a hammer mill or fluid-energy mill. Suspensions are usually prepared by wet-milling; see, for example, U.S. 3,060,084. Granules and pellets can be prepared by spraying the active material upon preformed granular carriers or by agglomeration techniques. See Browning, "Agglomeration", Chemical Engineering, December 4, 1967, pp 147-48, Perry's Chemical Engineer's Handbook, 4th Ed., McGraw-Hill, New York, 1963, pages 8-57 and following, and WO 91/13546. Pellets can be prepared as described in U.S. 4,172,714. Water-dispersible and water-soluble granules can be prepared as taught in U.S. 4,144,050, U.S. 3,920,442 and DE 3,246,493. Tablets can be prepared as taught in U.S. 5,180,587, U.S. 5,232,701 and U.S. 5,208,030. Films can be prepared as taught in GB 2,095,558 and U.S. 3,299,566. For further information regarding the art of formulation, see 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 Tables A- F. Example A High Strength Concentrate Compound 14 98.5% silica aerogel 0.5% synthetic amorphous fine silica 1.0%. Example B Wettable Powder Compound 14 65.0% dodecylphenol polyethylene glycol ether 2.0% sodium ligninsulfonate 4.0% sodium silicoaluminate 6.0% montmorillonite (calcined) 23.0%. Example C
Granule Compound 14 10.0% attapulgite granules (low volatile matter, 0.71/0.30 mm; U.S.S. No. 25-50 sieves) 90.0%. Example D Aqueous Suspension Compound 14 25.0% hydrated attapulgite 3.0% crude calcium ligninsulfonate 10.0% sodium dihydrogen phosphate 0.5% water 61.5%. Example E Extruded Pellet Compound 14 25.0% anhydrous sodium sulfate 10.0% crude calcium ligninsulfonate 5.0% sodium alkylnaphthalenesulfonate 1.0% calcium/magnesium bentonite 59.0%. Example F Microemulsion Compound 14 1.0% triacetine 30.0% C8-C10 alkylpolyglycoside 30.0% glyceryl monooleate 19.0% water 20.0%. Test results indicate that the compounds of the present invention are highly active preemergent and/or postemergent herbicides and/or plant growth regulants. Many of them have utility for broad-spectrum pre- and/or postemergence weed control in areas where complete control of all vegetation is desired such as around fuel storage tanks, industrial storage areas, parking lots, drive-in theaters, air fields, river banks, irrigation and other waterways, around billboards and highway and railroad structures. Many of the compounds of this invention, by virtue of selective metabolism in crops versus weeds, or by selective activity at the locus of physiological inhibition in crops and weeds, or by selective placement on or within the environment of a mixture of crops and weeds, are useful for the selective control of grass and broadleaf weeds within a crop/weed mixture. One skilled in the art will recognize that the preferred combination of these selectivity factors within a compound or group of compounds can readily be determined by performing routine biological and/or biochemical assays. Compounds of this invention may show tolerance to important agronomic crops including, but is not limited to, alfalfa, barley, cotton, wheat, rape, sugar beets, corn (maize), sorghum, soybeans, rice, oats, peanuts, vegetables, tomato, potato, perennial plantation crops including coffee, cocoa, oil palm, rubber, sugarcane, citrus, grapes, fruit trees, nut trees, banana, plantain, pineapple, hops, tea and forests such as eucalyptus and conifers (e.g., loblolly pine), and turf species (e.g., Kentucky bluegrass, St. Augustine grass, Kentucky fescue and Bermuda grass). Those skilled in the art will appreciate that not all compounds are equally effective against all weeds. Alternatively, the subject compounds are useful to modify plant growth. As the compounds of the invention have both preemergent and postemergent herbicidal activity, to control undesired vegetation by killing or injuring the vegetation or reducing its growth, the compounds can be usefully applied by a variety of methods involving contacting a herbicidally effective amount of a compound of the invention, or a composition comprising said compound and at least one of a surfactant, a solid diluent or a liquid diluent, to the foliage or other part of the undesired vegetation or to the environment of the undesired vegetation such as the soil or water in which the undesired vegetation is growing or which surrounds the seed or other propagule of the undesired vegetation. A herbicidally effective amount of the compounds of this invention is determined by a number of factors. These factors include: formulation selected, method of application, amount and type of vegetation present, growing conditions, etc. In general, a herbicidally effective amount of compounds of this invention is about 0.0001 to 20 kg/ha with a preferred range of about 0.001 to 5 kg/ha and a more preferred range of about 0.004 to 3 kg/ha. One skilled in the art can easily determine the herbicidally effective amount necessary for the desired level of weed control. Compounds of this invention can be used alone or in combination with other commercial herbicides, insecticides and fungicides, and other agricultural chemicals such as fertilizers. Mixtures of the compounds of the invention with other herbicides can broaden the spectrum of activity against additional weed species, and suppress the proliferation of any resistant biotypes. A mixture of one or more of the following herbicides with a compound of this invention may be particularly useful for weed control: acetochlor, acifluorfen and its sodium salt, aclonifen, acrolein (2-proρenal), alachlor, alloxydim, ametryn, amicarbazone, amidosulfuron, aminopyralid, amitrole, ammonium sulfamate, anilofos, asulam, atrazine, azimsulfuron, beflubutamid, benazolin, benazolin-ethyl, benfluralin, benfuresate, bensulfuron-methyl, bensulide, bentazone, benzobicyclon, benzofenap, bifenox, bilanafos, bispyribac and its sodium salt, bromacil, bromobutide, bromofenoxim, bromoxynil, bromoxynil octanoate, butachlor, butafenacil, butamifos, butralin, butroxydim, butylate, cafenstrole, carbetamide, carfentrazone-ethyl, catechin, chlomethoxyfen, chloramben, chlorbromuron, chlorflurenol-methyl, chloridazon, chlorimuron-ethyl, chlorotoluron, chlorpropham, chlorsulfuron, chlorthal-dimethyl, chlorthiamid, cinidon-ethyl, cinmethylin, cinosulfuron, clethodim, clodinafop-propargyl, clomazone, clomeprop, clopyralid, clopyralid-olamine, cloransulam-methyl, cumyluron, cyanazine, cycloate, cyclosulfamuron, cycloxydim, cyhalofop-butyl, 2,4-D and its butotyl, butyl, isoctyl and isopropyl esters and its dimethylammonium, diola ine and trolamine salts, daimuron, dalapon, dalapon-sodium, dazomet, 2,4-DB and its dimethylammonium, potassium and sodium salts, desmedipham, desmetryn, dicamba and its diglycolammonium, dimethylammonium, potassium and sodium salts, dichlobenil, dichlorprop, diclof op-methyl, diclosulam, difenzoquat metilsulfate, diflufenican, diflufenzopyr, dimefuron, dimepiperate, dimethachlor, dimethametryn, dimethenamid, dimethenamid-P, dimethipin, dimethylarsinic acid and its sodium salt, dinitramine, dinoterb, diphenamid, diquat dibromide, dithiopyr, diuron, DNOC, endothal, EPTC, esprocarb, ethalfluralin, ethametsulfuron-methyl, ethofumesate, ethoxyfen, ethoxysulfuron, etobenzanid, fenoxaprop-ethyl, fenoxaprop-P- ethyl, fentrazamide, fenuron, fenuron-TCA, flamprop-methyl, flamprop-M-isopropyl, flamprop-M-methyl, flazasulfuron, florasulam, fluazifop-butyl, fluazifop-P-butyl, flucarbazone, fluchloralin, flufenacet, flufenpyr, flufenpyr-ethyl, flumetsulam, flumiclorac-pentyl, flumioxazin, fluometuron, fluoroglycofen-ethyl, flupyrsulfuron-methyl and its sodium salt, flurenol, flurenol-butyl, fluridone, flurochloridone, fluroxypyr, flurtamone, fluthiacet-methyl, fomesafen, foramsulfuron, fosamine-arnmonium, glufosinate, glufosinate-ammonium, glyphosate and its salts such as ammonium, isopropylammonium, potassium, sodium (including sesquisodium) and trimesium (alternatively named sulfosate), halosulfuron-methyl, haloxyfop-etotyl, haloxyfop-methyl, hexazinone, imazamethabenz-methyl, imazamox, imazapic, imazapyr, imazaquin, imazaquin-ammonium, imazethapyr, imazethapyr-ammonium, imazosulfuron, indanofan, iodosulfuron-methyl, ioxynil, ioxynil octanoate, ioxynil-sodium, isoproturon, isouron, isoxaben, isoxaflutole, isoxachlortole, isoxadifen, lactofen, lenacil, linuron, maleic hydrazide, MCPA and its dimethylammonium, potassium and sodium salts, MCPA-isoctyl, MCPA-thioethyl, MCPB and its sodium salt, MCPB-ethyl, mecoprop, mecoprop-P, mefenacet, mefluidide, mesosulfuron-methyl, mesotrione, metam-sodium, metamifop, metamitron, metazachlor, methabenzthiazuron, methylarsonic acid and its calcium, monoammonium, monosodium and disodium salts, methyldymron, metobenzuron, metobromuron, metolachlor, S-metholachlor, metosulam, metoxuron, metribuzin, metsulfuron-methyl, molinate, monolinuron, naproanilide, napropamide, naptalam, neburon, nicosulfuron, norflurazon, orbencarb, oryzalin, oxadiargyl, oxadiazon, oxasulfuron, oxaziclomefone, oxyfluorfen, paraquat dichloride, pebulate, pelargonic acid, pendimethalin, penoxsulam, pentanochlor, pentoxazone, perfluidone, pethoxyamid, phenmedipham, picloram, picloram-potassium, picolinafen, piperofos, pretilachlor, primisulfuron-methyl, prodiamine, profoxydim, prometon, prometryn, propachlor, propanil, propaquizafop, propazine, propham, propisochlor, propoxycarbazone, propyzamide, prosulfocarb, prosulfuron, pyraclonil, pyrafluf en-ethyl, pyrazogyl, pyrazolynate, pyrazoxyfen, pyrazosulfuron-ethyl, pyribenzoxim, pyributicarb, pyridate, pyriftalid, pyriminobac-methyl, pyrithiobac, pyrithiobac-sodium, quinclorac, quinmerac, quinoclamine, quizalofop-ethyl, quizalofop-P-ethyl, quizalofop-P-tefuryl, rimsulfuron, sethoxydim, siduron, simazine, simetryn, sulcotrione, sulfentrazone, sulfometuron-methyl, sulfosulfuron, 2,3,6-TBA, TCA, TCA-sodium, tebutam, tebuthiuron, tepraloxydim, terbacil, terbumeton, terbuthylazine, terbutryn, thenylchlor, thiazopyr, thifensulfuron-methyl, thiobencarb, tiocarbazil, tralkoxydim, tri-allate, triasulfuron, triaziflam, tribenuron-methyl, triclopyr, triclopyr-butotyl, triclopyr-triethylammonium, tridiphane, trietazine, trifloxysulfuron, trifluralin, triflusulfuron-methyl, tritosulfuron and vernolate. Other herbicides also include bioherbicides such as Alternaria destruens Simmons, Colletotrichum gloeosporiodes (Penz.) Penz. & Sacc, Drechsiera monoceras (MTB-951), Myrothecium verrucaria (Albertini & Schweinitz) Ditmar: Fries, Phytophthora palmivora (Butl.) Butl. and Puccinia thlaspeos Schub. Combinations of compounds of the invention with other herbicides can result in a greater-than-additive (i.e. synergistic) effect on weeds and or a less-than-additive effect (i.e. safening) on crops or other desirable plants. In certain instances, combinations with other herbicides having a similar spectrum of control but a different mode of action will be particularly advantageous for preventing the development of resistant weeds. Herbicidally effective amounts of compounds of the invention as well as herbicidally effective amounts of other herbicides can be easily determined by one skilled in the art through simple experimentation. Preferred for better control of undesired vegetation (e.g., lower use rate such as from synergism, broader spectrum of weeds controlled, or enhanced crop safety) or for preventing the development of resistant weeds are mixtures of a compound of this invention with a herbicide selected from the group consisting of isoproturon, flupyrsulfuron-methyl and metsulfuron-methyl, including agriculturally suitable salts thereof (e.g., flupyrsulfuron- methyl-sodium). Specifically preferred mixtures (compound numbers refer to compounds in Index Tables A-F) are selected from the group: compound 10 and flupyrsulfuron-methyl; compound 14 and flupyrsulfuron-methyl; compound 10 and isoproturon; compound 14 and isoproturon; compound 10 and metsulfuron-methyl; compound 14 and metsulfuron-methyl. Compounds of this invention can also be used in combination with herbicide safeners such as benoxacor, BCS (l-bromo-4-[(chloromethyl)sulfonyl]benzene), cloquintocet-mexyl, cyometrinil, dichlormid, 2-(dichloromethyl)-2-methyl-l,3-dioxolane (MG 191), fenchlorazole-ethyl, fenclorim, flurazole, fluxofenim, furilazole, isoxadifen-ethyl, mefenpyr- ethyl, methoxyphenone ((4-methoxy-3-methylphenyl)(3-methylphenyl)methanone), naphthalic anhydride (1,8-naphthalic anhydride) and oxabetrinil to increase safety to certain crops. Antidotally effective amounts of the herbicide safeners can be applied at the same time as the compounds of this invention, or applied as seed treatments. Therefore an aspect of the present invention relates to a herbicidal mixture comprising a compound of this invention and an antidotally effective amount of a herbicide safener. Seed treatment is particularly useful for selective weed control, because it physically restricts antidoting to the crop plants. Therefore a particularly useful embodiment of the present invention is a method for selectively controlling the growth of undesired vegetation in a crop comprising contacting the locus of the crop with a herbicidally effective amount of a compound of this invention wherein seed from which the crop is grown is treated with an antidotally effective amount of safener. Antidotally effective amounts of safeners can be easily determined by one skilled in the art through simple experimentation. Compounds of this invention can also be used in combination with plant growth regulators such as aviglycine, N-(phenylmethyl)-lH-purin-6-amine, epocholeone, gibberellic acid, gibberellin A4 and A7, harpin protein, mepiquat chloride, prohexadione calcium, prohydrojasmon, sodium nitrophenolate and trinexapac-methyl, and plant growth modifying organisms such as Bacillus cereus strain BP01. The following Tests demonstrate the control efficacy of the compounds of this invention against specific weeds. The weed control afforded by the compounds is not limited, however, to these species. See Index Tables A-F for compound descriptions. The following abbreviations are used in the Index Tables which follow: t means tertiary, 5 means secondary, n means normal, i means iso, c means cyclo, Me means methyl, Et means ethyl, Pr means propyl, -Pr means isopropyl, Bu means butyl, Ph means phenyl, MeO means methoxy, EtO means ethoxy, and CΝ means cyano. The abbreviation "dec" indicates that the compound appeared to decompose on melting. The abbreviation "Ex." stands for "Example" and is followed by a number indicating in which example the compound is prepared. INDEX TABLE A
Figure imgf000118_0001
R can be one or more substituents; a dash ("-") indicates no substituents.
Compound Ria R2a E Ei 1 R R m.p. TO 1 Me t-Bu Η Η CΗ - 5-isoxazolyl * 2 Me t-Bu Η Η CΗ - 3-(l-Me-pyrazolyl\ 169-171 3 Et t-Bu Η Η CΗ - 2-thiazolyl 195-208 4 Et t-Bu Η Η CΗ - 3-(2- CN-thiophenyl) 153-160 5 Et t-Bu Η Η CΗ - 5-(l- Me-imidazolyl) 233-243 6 Et t-Bu Η Η CΗ - 4-(l,3,5-tri-Me-pyrazolyl) * 7 (Ex.5) Et t-Bu Η Η CΗ - 3-(5-Me-l,2,4-oxadiazolyl) 140-147 8 Et t-Bu Η Η CΗ - 3-(5-Et-l,2,4-oxadiazolyl)
10 (Ex.14) Et t-Bu Η Η CΗ 6-F 1-pyrazolyl
11 (Ex.10) Et t-Bu Η Η N - 1-pyrazolyl 12 Et t-Bu Η Η CΗ - 3-pyridinyl * 13 Et t-Bu Η Η CΗ - 4-pyridinyl Compound Rla R2a Ri s I S s m.p. CQ
14 (Ex. 1) Et t-Bu H H CH - 2-pyridinyl 139-140 15 Et t-Bu H H CH - 2-pyrimidinyl * 16 Et t-Bu H H CH - 2-(3-Me-pyridinyl) * 17 Et t-Bu H H CH - 2-(6-Me-ρyridinyl) * 18 Et t-Bu H H CH - 2-(4-Me-ρyridinyl) * 19 Et t-Bu H H CH - 2-(3-Cl-pyridinyl) * 20 Et t-Bu H H CH - 2-(3-Cl-5-CF3-pyridinyl) * 21 Et t-Bu H H CH - 2-(3,5-di-Cl-pyridinyl) * 22 Et t-Bu H H CH - 2-(6-CF3-pyridinyl) * 23 Et t-Bu H H CH - 2-(4-CF3-pyridinyl) * 24 Et t-Bu H H CH - 2-(5-CF3-pyridinyl) * 25 Et t-Bu H H CH - 2-(3-CF3-pyridinyl) * 26 Et t-Bu H H CH - 2-pyrazinyl *
27 (Ex. 2) Et t-Bu H H CH 6-F 2-pyridinyl ** 28 Et t-Bu H H CH - 2-(6-Cl-pyrazinyl) * 29 Et t-Bu H H CH - 2-F-Ph * 30 Et t-Bu H H CH 6-F 5 ,6-dihydro-4H- 1 ,3-oxazin-2-yl *
31 (Ex. 13) Et t-Bu H H CH 6-F 4,5-dihydro-2-oxazolinyl ** 34 Et t-Bu H H CH - 2-(6-CN-pyridinyl) * 35 Et t-Bu H H CH - 2-(3-CN-pyridinyl) * 36 Et t-Bu H H CH - 2-(3-MeO-pyridinyl) * 37 Et t-Bu H H CH - 2-(4,6-di-MeO-pyrimidinyl) * 43 Et t-Bu H H CH - 2-(3-CN-4-EtO-pyridinyl) * 44 Et 2,2-di-Cl-l-Me-c-propyl H H CH - 2-pyridinyl * 45 Et 1,1-di-Me-n-Pr H H CH - 2-pyridinyl *
46 (Ex. 6) Et t-Bu H H CH - 5-isoxazolyl 115-116
48 (Ex. 8) Et t-Bu H H CH - 3-pyrazolyl 185-187 50 Et t-Bu H H CH - 2-(3-F-pyridinyl) *
51 (Ex. 3) Et t-Bu H H CH - 2,6-di-F-Ph ** 52 Et /-Pr H H CH - 2-pyridinyl * * See Index Table F for *H NMR data. ** See synthesis example for IH NMR data. INDEX TABLE B
Figure imgf000120_0001
Compound Rlb R2b T B m.p. TO 9 CF3 t-Bu CH 5-isoxazolyl * 38 Et t-Bu CH 2-F-Ph * 39 Et t-Bu N 2-F-Ph * 42 Et t-Bu CH 2-pyridinyl 67-69 * See Index Table F for NMR data. INDEX TABLE C
Figure imgf000120_0002
Compound Rlb R2b Bl i s m.n. TO
32 (Ex. 12) Et t-Bu H CH 2-pyridinyl ** 41 Et t-Bu H N 2-F-Ph 164-165
47 (Ex. 7) Et t-Bu H CH 5-isoxazolyl 154-155
49 (Ex. 9) Et t-Bu H CH 3-pyrazolyl 209-211 40 Et t-Bu H CH 2-F-Ph 134-135 * See Index Table F for XH NMR data. ** See synthesis example for H NMR data. INDEX TABLE D
Figure imgf000120_0003
Compound Rlb R2b E El m.p. TO 33 (Ex. 11) Et t-Bu H 2 -pyridinj tl ** * See Index Table F for lR NMR data. ** See synthesis example for IH NMR data. INDEX TABLE E
Figure imgf000121_0001
Compound Rlb g2b g3 Bl .p. TO
53 (Ex. 4) Et t-Bu H 2-pyridinyl ** * See Index Table F for lR NMR data. ** See synthesis example for IH NMR data. INDEX TABLE F Cmpd No. IH NMR Data (CDCI3 solution unless indicated otherwise)a 1 δ 8.6 (s, IH, J = 0.006), 8.3 (s, IH), 7.6 (d, IH), 7.5 (t, IH), 7.03 (s, IH), 7.00 (d, IH, 7 = 0.006), 4.0 (s, 3H), 1.29 (s, 9H). δ 7.65 (br s, IH), 7.5 (m, IH), 7.38-7.42 (m, 2H), 7.05 (m, IH), 6.47 (s, IH), 4.56 (q, 2H), 3.8 (s, 3H), 2.22 (s, 3H), 2.18 (s, 3H), 1.45 (t, 3H), 1.34 (s, 9H). δ 7.8-7.9 (m, 2H), 7.4 (m, 2H), 6.53 (s, IH), 5.1 (br s, NH), 4.48 (q, 2H), 2.53 (q, 2H), 1.44 (t, 3H), 1.34 (s, 9H), 1.27 (t, 3H). δ 8.8 (IH), 8.3 (IH), 8.1 (IH), 7.88 (IH), 7.81 (d, IH), 7.5 (d,lH), 7.4 (t, IH), 6.6 (l, H), 1.6 (s, 9H). 12 δ 8.9 (m, IH), 8.6 (m, IH), 7.95 (m, 2H), 7.6 (m, IH), 7.5 (t, IH), 7.4 (m, 2H), 6.52 (s, IH), 4.6 (q, 2H), 1.43 (t, 2H), 1.33 (s, 9H). 13 δ 8.7 (m, 2H), 8.0 (s, IH), 7.8 (s, IH), 7.6-7.4(m, 4H), 6.5(s, IH), 4.59(q, 2H), 1.48(t, 3H), 1.34(s, 9H). 15 δ 8.80 (d, IH), 8.42 (d, IH), 8.26 (dd, IH), 8.00 (dd, IH), 7.80 (s, IH), 7.46 (t, IH), 7.20 (t, IH), 6.49 (s, IH), 4.60 (q, 2H), 1.34 (s, 9H), 1.20 (t, IH). 16 δ 8.5 (d, IH), 8.2 (s, IH), 7.7 (m, 2H), 7.6(m, IH), 7.4 (t, IH), 7.25 (m, 2H), 6.43 (s, IH), 4.53 (q, 2H), 2.37 (s, 3H), 1.43 (t, 3H), 1.29 (s, 9H). 17 δ 8.2 (br s, IH), 7.85 (m, 2H), 7.7 (m, 2H), 7.5 (m, IH), 7.4 (m, IH), 7.2 (d, IH), 6.47 (s, IH), 4.6 (m, 2H), 2.62 (s, 3H), 1.4 (t, 3H), 1.31 (s, 9H). 18 δ 8.5 (d, IH), 8.2 (s, IH), 7.8 (d, 2H), 7.7 (m, IH), 7.6 (m, IH), 7.4 (t, IH), 7.1 (d, IH), 6.47 (s, IH), 4.6 (q, 2H), 2.42 (s, 3H), 1.45 (t, 3H), 1.33 (s, 9H). 19 δ 8.6 (m, IH), 7.86 (m, 2H), 7.8 (m, 2H), 7.5 (m, 2H), 7.25 (m, IH), 6.45 (s, IH), 4.57 (q, 2H), 1.43 (t, 3H), 1.32 (s, 9H). 20 δ 8.8 (s, IH), 8.1 (s, IH), 7.95 (s, IH), 7.8 (m, 2H), 7.5 (m, IH), 7.45 (m, IH), 6.47 (s, IH), 4.57 (q, 2H), 1.44 (t, 3H), 1.33 (s, 9H). Cmpd No. IH NMR Data (CDCI3 solution unless indicated otherwise)a 21 δ 8.55 (s, IH), 7.83 (s, IH), 7.82 (s, IH), 7.8 (s, IH), 7.7 (m, IH), 7.5 (m, 2H), 6.46 (s, IH), 4.57 (q, 2H), 1.43 (t, 3H), 1.32 (s, 9H). 22 δ 8.2 (m, IH), 7.96 (m, 2H), 7.9 (m, IH), 7.8 (m, 2H), 7.6 (m, IH), 7.5 (t, IH), 6.53 (s, IH), 4.59 (q, 2H), 1.45 (t.3H), 1.35 (s, 9H). 23 δ 8.88 (d, IH), 8.2 (s, IH), 7.95 (s, IH), 7.8 (m, 2H), 7.75 (m, IH), 7.48 (m, 2H), 6.5 (s, IH), 4.59 (q, 2H), 1.46 (t, 3H), 1.34 (s, 9H). 24 δ 8.88 (m, IH), 8.21 (s, IH), 8.0(d, IH), 7.9 (d, IH), 7.8 (m, 3H), 7.5 (t, IH), 6.49 (s, IH), 4.57 (q, 2H), 1.46 (t, 3H), 1.34 (s, 9H). 25 δ 8.8 (d, IH), 8.1 (d, IH), 7.7 (m, 3H), 7.5 (m, 2H), 7.2 (m, IH), 6.44 (s, IH), 4.57 (q, 2H), 1.44 (t, 3H), 1.32 (s, 9H). 26 δ 9.00 (d, IH), 8.82 (d, IH), 8.70 (d, IH), 8.40 (s, IH), 8.22 (s, IH), 7.80 (dd, IH), 7.42 (t, IH), 6.60 (s, IH), 4.60 (q, 2H), 1.34 (s, 9H), 1.20 (t, IH). 28 8.80 (s, IH), 8.80 (d, IH), 8.42 (s, IH), 8.20 (s, IH), 7.82 (dd, IH), 7.66 (dd, IH), 7.40 (t, IH), 6.66 (s, IH), 4.60 (q, 2H), 1.34 (s, 9H), 1.20 (t, IH). 29 δ 7.77 (s, IH), 7.65 (m, 2H), 7.44 (m, 2H), 7.5 (m, 2H), 7.2 (m, 2H), 6.47 (s, IH), 4.6 (q, 2H), 1.42 (t, 3H), 1.33 (s, 9H). 30 δ 8.78 (dd, IH); 7.85 (br s, IH); 7.68 (dd); 7.11 (dd, IH); 6.49 (s, IH); 4.58 (q, 2H); 4.36 (t, 2H); 3.59 (t, 2H); 1.97 (quintet, 2H); 1.45 (t, 3H); 1.34 (s, 9H). 34 δ 8.2 (s, IH), 8.0 (d, IH), 7.9 (m, IH), 7.8 (m, 2H), 7.7 (m, IH), 7.6 (d, IH), 7.5 (t, IH), 6.53 (s, IH), 4.6 (q, 2H), 1.49 (t, 3H), 1.35 (s, 9H). 35 δ 8.9 (m, IH), 8.08 (m, 2H), 7.8 (d, IH), 7.7 (d, 2H), 7.5 (t, IH), 7.4 (m, IH), 6.48 (s, IH), 4.58 (q, 2H), 1.47 (t, 3H), 1.34 (s, 9H). 36 δ 8.3 (d, IH), 7.9 (s, IH), 7.8 (m, IH), 7.73 (m, 2H), 7.44 (t, IH), 7.3 (m, IH), 7.2 (m, IH), 6.45 (s, IH), 4.58 (q, 2H), 3.89 (s, 3H), 1.47 (t, 3H), 1.33 (s, 9H). 37 δ 8.40 (s, IH), 8.22 (d, IH), 8.02 (s, IH), 8.00 (d, IH), 7.44 (t, IH), 7.20, 6.49 (s, IH), 4.60 (q, 2H), 4.00 (s, 6H), 1.34 (s, 9H), 1.20 (t, IH). 38 δ 8.8 (br s, IH), 7.8 (IH), 7.7 (IH), 7.1-7.4 (m, 7H), 2.8(q, 2H), 1.6 (s, 9H), 1.2 (t, 3H). 39 δ 9.4 (br s, IH), 8.3 (d, IH), 8.0 (t, IH), 7.8 (t, IH), 7.5 (m, 1H),7.3 (m, 2H), 7.2 (m, IH), 7.1 (m, IH), 2.8(q, 2H), 1.6 (s, 9H), 1.2 (t, 3H). 43 δ 8.6 (d, IH), 8.0 (m, IH), 7.81 (d, IH), 7.8 (s, IH), 7.7 (d, IH), 7.5 (t, IH), 6.8 (d, IH), 6.47 (s, IH), 4.6 (q, 2H), 4.3 (q, 2H), 1.6 (t, 3H), 1.44 (t, 3H), 1.33 (s, 9H). 44 δ 8.7 (s, IH), 8.2 (s, IH), 7.98 (s, IH), 7.8 (m, 3H), 7.5 (m, IH), 7.2 (m, IH), 6.6 (s, IH), 4.59 (q, 2H), 2.3 (d, IH), 1.72 (s, 3H), 1.6 (d, IH), 1.44 (t, 3H). 45 δ 8.7 (d, IH), 8.1 (s, IH), 7.8 (d, 2H), 7.75 (m, 3H), 7.5 (t, IH), 7.2 (m, IH), 6.45 (s, IH), 4.6 (q, 2H), 1.62 (m, 2H), 1.44 (m, 3H), 1.25 (s, 6H), 0.78 (t, 3H). 50 δ 8.5 (m, IH), 8.05 (m, IH), 7.9 (d, IH), 7.76 (m, 2H), 7.52 (m, 2H), 7.25 (m, IH), 6.47 (s, IH), 4.59 (q, 2H), 1.47 (t, 3H), 1.34 (s, 9H). Cmpd No. IH NMR Data (CDCI3 solution unless indicated otherwise)3 52 δ 8.7 (m, IH), 7.78 (m, 5H), 7.9 (d, IH), 7.5 (t, IH), 7.25 (m, IH), 6.45 (s, IH), 4.59 (q, 2H) 3.0 (m, IH), 1.46 (t, 3H), 1.3 (s, 6H). a IH NMR data are in ppm downfield from tetramethylsilane. Couplings are designated by (s)-singlet, (d)-doublet, (t)-triplet, (q)-quartet, (m)-multiplet, (dd)-doublet of doublets, (dt)-doublet of triplets, (dq)-doublet of quartets, (br s)-broad singlet, (br d)-broad d, (br m)-broad multiplet. BIOLOGICAL EXAMPLES OF THE INVENTION TEST A Seeds of barnyardgrass (Echinochloa crus-galli), crabgrass (Digitaria sanguinalis), giant foxtail (Setaria faberϊ), morningglory (Ipomoea spp.), redroot pigweed (Amaranthus retroflexus) and velvetleaf (Abutilon theophrasti) were planted into a blend of loam soil and sand and treated preemergence with a directed soil spray using test chemicals formulated in a non-phytotoxic solvent mixture which included a surfactant. At the same time these species were also treated with postemergence applications of test chemicals formulated in the same manner. Plants ranged in height from two to ten cm and were in the one- to two-leaf stage for the postemergence treatment. Treated plants and untreated controls were maintained in a greenhouse for approximately ten days, after which time all treated plants were compared to untreated controls and visually evaluated for injury. Plant response ratings, summarized in Table A, are based on a 0 to 100 scale where 0 is no effect and 100 is complete control. A dash (-) response means no test results.
Table A Compounds Table A Compound
2000 g ai/ha 1 10 1000 g ai/ha 15
Postemergence Postemergence
Barnyardgrass 45 85 Barnyardgrass 30
Crabgrass, Large 30 80 Crabgrass, Large 20
Foxtail, Giant 20 90 Foxtail, Giant 30
Morningglory 30 90 Morningglory 20
Pigweed 90 100 Pigweed 60
Velvetleaf 25 100 Velvetleaf 20
Table A Compounds Table A Compound
500 g ai/ha 1 10 250 g ai/ha 15
Postemergence Postemergence
Barnyardgrass 30 50 Barnyardgrass 20
Crabgrass, Large 30 45 Crabgrass, Large 20
Foxtail, Giant 15 45 Foxtail, Giant 20
Morningglory 25 70 Morningglory 10 Pigweed 85 90 Pigweed 20
Velvetleaf 20 80 Velvetleaf 20
Table A Compounds Table A Compound
2000 g ai/ha 1 10 1000 g ai/ha 15
Preemergence Preemergence
Barnyardgrass 25 100 Barnyardgrass 35
Crabgrass, Large 20 100 Crabgrass, Large 20
Foxtail , Giant 0 100 Foxtail, Giant 65
Morningglory 20 50 Morningglory 10
Pigweed 25 100 Pigweed 75
Velvetleaf 5 85 Velvetleaf 20
Table A Compounds Table A Compound
500 g ai/ha 1 10 250 g ai/ha 15
Preemergence Preemergence
Barnyardgrass 15 70 Barnyardgrass 0
Crabgrass, Large 10 95 Crabgrass, Large 0
Foxtail, Giant 0 85 Foxtail, Giant 0
Morningglory 10 20 Morningglory 0
Pigweed 10 100 Pigweed 55
Velvetleaf 0 15 Velvetleaf 5
TESTB Seeds selected from barnyardgrass (Echinochloa crus-galli), Surinam grass (Brachiaria decumbens), cocklebur (Xanthium strumarium), corn (Zea mays), crabgrass (Digitaria sanguinalis), giant foxtail (Setaria faberii), lambsquarters (Chenopodium album), morningglory (Ipomoea hederacea), pigweed (Amaranthus retroflexus), rice (Oryza sativa), velvetleaf (Abutilon theophrasti), and wheat (Triticum aestivum) were planted and treated preemergence with test chemicals formulated in a non-phytotoxic solvent mixture which included a surfactant. At the same time, plants selected from these crop and weed species and also blackgrass (Alopecurus myosuroides) and wild oat (Avena fatua) were treated with postemergence applications of test chemicals formulated in the same manner. Plants ranged in height from 2 to 18 cm (1- to 4-leaf stage) for postemergence treatments. Plant species in the flooded paddy test consisted of rice (Oryza sativa), umbrella sedge (Cyperus difformis), duck salad (Heteranthera limosa) and barnyardgrass (Echinochloa crus-galli) grown to the 2-leaf stage for testing. Treated plants and controls were maintained in a greenhouse for 13 to 15 days, after which time all species were compared to controls and visually evaluated. Plant response ratings, summarized in Table B, are based on a scale of 0 to 100 where 0 is no effect and 100 is complete control. A dash (-) response means no test result.
Table B Compounds
1000 g ai/ha 1 2 3 4 6 7 8 10 11 12 13 14 15
Flood
Barnyardgrass 0 0 40 0 0 0 80 60 70 30 10 0 90 0
Duc salad 0 30 30 0 0 0 80 90 90 30 70 20 90 0
Rice 0 30 30 10 0 0 50 40 70 20 0 0 60 0
Sedge, Umbrella 0 20 90 10 0 0 80 90 80 80 80 40 90 90
Table B Compounds
1000 g ai/ha 16 17 18 19 20 21 22 23 24 25 26 27 28 29
Flood
Barnyardgrass 60 50 30 50 0 0 0 30 0 20 10 10 20
Ducksalad 90 90 90 80 0 0 0 90 0 0 80 90 80
Rice 40 50 50 20 0 0 0 20 0 0 40 20 10
Sedge, Umbrella 90 90 90 90 30 0 0 90 0 20 70 90 80
Table B Compounds
1000 g ai/ha 30 31 32 33 34 35 36 37 38 39 40 41 42 43
Flood
Barnyardgrass 0 40 60 70 0 60 50 10 0 0 0 0 0
Ducksalad 80 80 90 80 0 80 90 0 0 0 0 20 0
Rice 0 50 30 30 0 50 50 0 0 0 0 0 0
Sedge, Umbrella 60 70 90 80 20 80 90 80 0 0 0 0 0
Table B Compounds
1000 g ai/ha 44 45
Flood
Barnyardgras s 10 30
Ducksalad 0 90
Rice 0 50
Sedge, Umbrella 90 90
Table B Compounds
500 g ai/ha 7 8 9 10 11 12 13 14 15
Postemergence
Barnyardgrass 20 30 40 30 0 40 10 0 80 20 10 0 50 10
Blackgrass 10 0 20 0 60 10 0 40 20 10 10 70 30
Cocklebur 90 90 80 100 10 100 40 0 80 10 0 10 90 10 Corn 20 10 20 20 10 20 30 0 30 10 20 10 50 30
Crabgrass, Large 20 30 20 20 10 30 10 0 40 10 10 20 70 20
Foxtail, Giant 0 10 20 10 10 40 10 0 50 10 20 20 80 40
Lambsquarters 100 70 100 90 50 100 40 0 90 30 60 30 100
Morningglory 70 100 80 60 0 90 10 0 60 0 20 50 100 20
Oat, Wild 20 20 20 20 10 20 0 0 70 30 20 20 50 40
Pigweed 90 60 100 90 10 100 20 0 100 80 70 50 100 80
Surinam Grass 20 50 20 20 0 70 10 0 40 20 20 20 60 20
Velvetleaf 30 20 70 70 10 100 10 0 70 50 30 20 90 30
Wheat 20 0 20 10 0 20 10 0 50 10 10 10 20 20
Table B Compounds
500 g ai/ha 16 17 18 19 20 21 22 23 24 25 26 27 28 29
Postemergence
Barnyardgrass 30 30 10 10 0 0 0 20 10 0 0 0 0 10
Blackgrass 50 70 50 50 30 10 30 50 30 50 30 60 40
Cocklebur 70 50 40 50 0 0 0 70 0 40 30 70 70 20
Corn 20 30 20 20 0 10 10 20 10 20 10 10 20 20
Crabgrass, Large 20 20 20 20 0 0 10 20 10 20 10 10 10 30
Foxtail, Giant 50 60 40 30 10 30 30 30 10 20 10 30 20 30
Lambsquarters 100 100 100 90 10 50 50 100 30 100 100 80 100 30
Morningglory 70 50 20 60 0 0 0 30 0 30 50 100 70 20
Oat, Wild 50 50 60 50 20 10 30 60 40 40 40 50 40
Pigweed 70 100 90 90 20 40 60 90 30 90 70 80 90 80
Surinam Grass 60 30 30 30 0 20 10 20 20 10 10 10 20
Velvetleaf 90 70 50 40 0 20 20 50 30 30 30 30 30 20
Wheat 30 40 40 30 0 0 10 30 10 20 20 30 10
Table B Compounds
500 g ai/ha 30 31 32 33 34 35 36 37 38 39 40 41 42 43
Postemergence
Barnyardgrass 10 20 30 20 10 10 40 10 0 0 0 0
Blackgrass 10 40 40 50 30 50 40 40 0 0 0 30
Cocklebur 10 30 60 10 30 40 60 70 0 0 0 60
Corn 30 40 30 20 20 20 20 20 0 0 0 20
Crabgrass, Large 20 30 30 40 20 30 70 20 0 0 0 20
Foxtail, Giant 30 60 50 70 30 50 40 30 0 30 0 30
Lambsquarters 50 80 90 100 100 100 100 90 0 0 0 40 60
Morningglory 20 50 70 50 60 60 50 10 0 0 0 0 60 Oat, Wild 10 40 40 40 40 40 40 40 0 0 0 20 Pigweed 50 80 90 90 100 100 100 90 0 0 30 80 Surinam Grass 20 30 60 70 30 30 60 30 0 0 0 30 Velvetleaf 10 30 20 50 40 50 70 80 0 0 0 30 20 Wheat 0 20 30 20 20 30 20 30 0 0 0 10
Table B Compounds Table B Compound
500 g ai/ha 44 45 250 g ai/ha 5
Postemergence Postemergence
Barnyardgrass 0 20 Barnyardgrass 0
Blackgrass 30 50 Blackgrass 0
Cocklebur 30 30 Cocklebur 0
Corn 10 0 Corn 20
Crabgrass, Large 10 20 Crabgrass, Large 0
Foxtail, Giant 20 20 Foxtail, Giant 0
Lambsquarters 70 90 Lambsquarters 30
Morningglory 20 0 Morningglory 0
Oat, Wild 40 50 Oat, Wild 20
Pigweed 80 100 Pigweed 20
Surinam Grass 30 10 Surinam Grass 0
Velvetleaf 30 60 Velvetleaf 10
Wheat 10 20 Wheat 0
Table B Compounds
125 g ai/ha 7 8 9 10 11 12 13 14 15
Postemergence
Barnyardgrass 10 10 20 10 0 10 0 0 50 0 10 0 20 0
Blackgrass 0 0 10 0 0 20 0 0 40 10 10 10 30 10
Cocklebur 20 20 60 60 0 80 10 0 20 0 0 0 50 0
Corn 10 10 20 20 10 20 10 0 20 0 10 10 0 0
Crabgrass, Large 10 10 20 10 0 30 10 0 30 0 10 10 10 10
Foxtail, Giant 0 10 20 0 0 20 10 0 30 0 20 20 50 20
Lambsquarters 90 60 80 70 0 90 40 0 90 10 30 10 90 70
Morningglory 20 20 30 20 0 60 0 0 40 0 10 30 60 0
Oat, Wild 0 20 10 10 10 20 0 0 50 10 10 0 20 30
Pigweed 70 30 90 70 0 100 0 0 90 30 50 10 100 60
Surinam Grass 20 20 20 10 0 20 10 0 20 10 20 0 10 0
Velvetleaf 20 10 40 20 0 80 0 0 50 10 20 20 80 20
Wheat 0 0 0 10 0 0 10 0 40 0 0 0 0 10 Table B Compounds
125 g ai/ha 16 17 18 19 20 21 22 23 24 25 26 27 28 29
Postemergence
Barnyardgrass 20 20 0 10 0 0 0 10 10 0 0 0 0 0
Blackgrass 30 40 40 40 0 10 10 30 30 20 30 20 40 10
Cocklebur 60 50 30 20 0 0 0 30 0 20 0 10 10 10
Corn 10 10 10 20 0 10 0 10 10 10 10 10 10 10
Crabgrass, Large 10 20 20 20 0 0 10 10 10 10 10 10 10 10
Foxtail, Giant 30 30 30 20 10 10 10 20 10 10 10 20 10 20
Lambsquarters 90 100 80 90 10 30 0 80 - - 80 60 50 20
Morningglory - 50 20 30 0 0 0 0 0 20 0 40 0 10
Oat, Wild 40 40 50 30 0 0 0 40 30 30 30 30 30 20
Pigweed 70 90 70 80 10 30 - 80 - 60 20 70 60 50
Surinam Grass 20 20 20 20 0 0 0 - 10 - 10 10 10 10
Velvetleaf 20 60 50 30 0 10 0 30 10 10 10 10 10 0
Wheat 20 30 30 20 0 0 0 20 10 10 20 20 10 0
Table B Compounds
125 g ai/ha 30 31 32 33 34 35 36 37 38 39 40 41 42 43
Postemergence
Barnyardgrass 0 0 10 10 0 0 10 0 0 0 0 0 0 0
Blackgrass 0 20 20 20 10 30 30 40 0 0 0 0 0 0
Cocklebur 0 0 40 0 30 10 20 10 0 0 0 0 0 0
Corn 0 10 20 10 10 10 10 10 0 0 0 0 10 0
Crabgrass, Large 10 20 10 10 10 10 20 10 0 0 0 0 10 0
Foxtail, Giant 10 10 30 20 20 20 20 20 0 0 0 0 20 0
Lambsquarters 0 50 60 70 - 90 90 90 0 0 0 0 20 0
Morningglory 0 0 - 20 0 0 0 0 0 0 0 0 10 0
Oat, Wild 0 10 30 30 30 40 30 30 0 0 0 0 10 0
Pigweed 20 50 70 70 80 90 90 90 0 0 0 0 70 0
Surinam Grass 10 20 20 20 10 20 30 20 0 0 0 0 10 0
Velvetleaf 0 10 20 20 20 40 60 30 0 0 0 0 10 20
Wheat 0 10 20 10 10 10 10 20 0 0 0 0 0 0 Table B Compounds Tabl<3 B Compound
125 g ai/ha 44 45 62 g ai/ha 5
Postemergence Postemergence
Barnyardgrass 0 0 Barnyardgrass 0
Blackgrass 20 30 Blac]kgrass 0
Cocklebur 10 10 Cocklebur 0
Corn 0 0 Corn 0
Crabgrass , Large 0 10 Crabgrass, Large 0
Foxtail, Giant 0 10 Foxtail, Giant 0
Lambsquarters 50 80 Lambsquarterε 0
Morningglory 10 0 Morningglory 0
Oat, Wild 30 40 Oat, Wild 0
Pigweed 30 90 Pigweed 0
Surinam Grass 10 10 Surinam Grass 0
Velvetleaf 10 50 Velvetleaf 0
Wheat 0 10 Wheat 0
Table B Compounds
500 g ai/ha 1 2 3 4 6 7 8 9 10 11 12 13 14 15
Preemergence
Barnyardgrass 60 0 50 0 0 90 80 0 70 10 0 0 70 40
Cocklebur 0 30 0 0 0 20 0 0 0 0 0 - 10 0
Corn 0 0 10 0 0 30 0 - 20 0 0 0 60 20
Crabgrass, Large 80 10 100 60 0 100 50 0 100 - 10 0 100 70
Foxtail, Giant 20 - 60 20 0 100 20 0 100 10 10 0 100 20
Lambsquarters 80 40 100 100 0 100 100 0 100 100 10 0 100 90
Morningglory 10 - 10 0 0 30 10 0 10 0 0 0 10 0
Pigweed 80 0 100 100 0 100 100 0 100 70 10 0 100 90
Rice - - 0 0 0 30 20 0 30 0 - - - -
Surinam Grass 10 0 30 20 0 90 20 0 60 - 0 0 90 20
Velvetleaf 0 0 60 30 0 100 30 0 40 - 10 0 90 0
Wheat 0 0 30 0
Table B Compounds
500 g ai/ha 16 17 18 19 20 21 22 : 23 24 25 26 27 28 29
Preemergence
Barnyardgrass 50 50 50 40 0 0 o : L0 0 0 20 30 30 20
Cocklebur 20 30 0 0 0 0 0 0 0 0 0 0 0 60
Corn 40 40 40 10 0 0 0 0 0 0 0 10 0 0 Crabgrass, Large 100 100 100 30 0 0 90 0 10 70 100 70 50
Foxtail, Giant 90 90 80 40 0 0 40 0 0 30 90 20 0
Lambsquarters 100 100 100 100 0 0 100 0 - 100 50 100 10
Morningglory 20 30 60 10 0 0 0 0 0 0 0 0 0
Pigweed 90 100 100 100 0 0 100 0 60 70 100 100 70
Rice
Surinam Grass 80 30 30 10 0 0 0 20 0 10 0 40 10 0
Velvetleaf 60 70 30 10 0 0 0 30 0 0 0 0 0 50
Wheat 30 30 30 30 0 0 0 10 0 0 10 0 10 0
Table B Compounds
500 g ai/ha 30 31 32 33 34 35 36 37 38 39 40 41 42 43
Preemergence
Barnyardgrass 0 60 90 80 10 70 80 20 0 0 0 0 0 -
Cocklebur 0 50 20 20 0 50 50 0 0 0 0 0 0 0
Corn 0 20 40 40 - - 100 0 0 0 0 0 30 0
Crabgrass, Large 20 90 100 100 30 100 100 30 0 0 0 0 30 20
Foxtail, Giant 0 90 100 100 20 90 90 60 0 0 0 0 0 0
Lambsquarters 50 100 100 100 100 100 100 90 0 0 0 0 30 0
Morningglory 0 20 20 20 0 10 20 0 0 0 0 0 0 0
Pigweed 40 100 100 100 100 100 100 100 0 0 20 0 70 0
Rice
Surinam Grass 0 50 70 70 10 70 80 20 0 10 20
Velvetleaf 0 50 70 70 20 70 60 30 0 0 0
Wheat 0 0 30 40 0 30 30 30 0 0
Table B Compounds Table B Compound
500 g ai/ha 44 45 250 g ai/ha 5
Preemergence Preemergence
Barnyardgrass 0 70 Barnyardgrass 0
Cocklebur 0 0 Cocklebur 0
Corn 0 0 Corn 0
Crabgrass, Large 20 90 Crabgrass, Large 0
Foxtail, Giant 10 80 Foxtail, Giant 0
Lambsquarters 30 100 Lambsquarters 0
Morningglory 0 0 Morningglory 0
Pigweed 50 100 Pigweed 0
Rice Rice 0
Surinam Grass 0 20 Surinam Grass 0 Velvetleaf 0 30 Velvetleaf 0 Wheat 0 10
Table B Compounds
125 g ai/ha I 7 8 9 10 11 12 13 14 15
Preemergence
Barnyardgrass 0 20 0 40 0 50 0
Cocklebur 0 0 0 0 0 0 0
Corn 0 0 0 0 0 - 0
Crabgrass, Large 0 70 20 0 100 0 80 0 100 0
Foxtail, Giant 0 30 0 0 50 0 50 0 30 0
Lambsquarters 0 90 0 0 100 0 0 100 0
Morningglory 0 10 0 0 20 0 0 0 0 0 0
Pigweed 0 90 0 0 100 40 0 0 100 0
Rice 0 0 0 10 0 0 10
Surinam Grass 0 10 0 0 30 0 0 30 0 10
Velvetleaf 0 30 10 0 70 0 0 10 0 0
Wheat u u A υ
Table B Compounds
125 g ai/ha 16 17 18 19 20 21 22 23 24 25 26 27 28 29
Preemergence
Barnyardgrass 40 40 30 20 0 0 0 0 0 0 0 0 0 0
Cocklebur 0 0 0 0 0 0 0 0 0 0 0 0 0 20
Corn 0 10 20 0 0 0 0 0 0 0 0 0 0 0
Crabgrass, Large 30 70 20 10 0 0 0 10 0 0 0 60 20 0
Foxtail, Giant 30 30 30 10 0 0 0 0 0 0 0 10 10 0
Lambsquarters 100 100 100 80 0 0 0 - 0 - 90 20 60 0
Morningglory 10 10 20 10 0 0 0 0 0 0 0 0 0 0
Pigweed 30 100 70 80 0 0 0 50 0 30 0 80 80 0
Rice
Surinam Grass 10 20 10 10 0 0 0 0 0 0 0 0 10 0
Velvetleaf 10 40 10 0 0 0 0 0 0 0 0 0 0 0
Wheat 0 10 10 10 0 0 0 0 0 0 0 0 0 0
Table B Compounds 125 g ai/ha 30 31 32 33 34 35 36 37 38 39 10 41 42 43 Preemergence Barnyardgrass 0 10 70 50 0 30 50 0 0 0 0 0 0 0 Cocklebur 0 0 0 0 0 0 0 0 0 0 0 0 0 0 Corn 0 0 20 20 0 40 0 0 0 0 0 0 0
Crabgrass, Large 0 40 100 100 10 80 90 30 0 0 0 0 0 0
Foxtail, Giant 0 0 50 60 0 30 40 10 0 0 0 0 0 0
Lambsquarters 20 90 100 100 - 90 100 70 0 0 0 0 0 0
Morningglory 0 0 10 20 0 0 10 0 0 0 0 0 0 0
Pigweed 20 70 100 100 30 90 90 60 0 0 0 0 0 0
Rice
Surinam Grass 0 10 30 30 0 20 30 - 0 0 0 0 0 0
Velvetleaf 0 20 0 60 0 50 40 30 0 0 0 0 0 0
Wheat 0 0 20 0 0 20 10 0 0 0 0 0 0 0
Table B Compounds Table B Compound
125 g ai/ha 44 45 62 g ai/ha 5
Preemergence Preemergence
Barnyardgrass 0 20 Barnyardgrass 0
Cocklebur 0 0 Cocklebur 0
Corn 0 0 Corn 0
Crabgrass, Large 0 60 Crabgrassi , Large 0
Foxtail, Giant 0 50 Foxtail, Giant 0
Lambsquarters 0 0 Lambsquarters 0
Morningglory 0 0 Morningglory 0
Pigweed 0 60 Pigweed 0
Rice - - Rice 0
Surinam Grass 0 10 Surinam Grass 0
Velvetleaf 0 0 Velvetlea .f 0
Wheat 0 0
TESTC Seeds of plant species selected from bermudagrass (Cynodon dactyloή), Surinam grass (Brachiaria decumbens), cocklebur (Xanthium strumarium), corn (Zea mays), crabgrass (Digitaria sanguinalis), woolly cupgrass (Eriochloa villosa), giant foxtail (Setaria faberii), goosegrass (Eleusine indica), johnsongrass (Sorghum halepense), kochia (Kochia scoparia), lambsquarters (Chenopodium album), morningglory (Ipomoea hederacea), yellow nutsedge (Cyperus esculentus), pigweed (Amaranthus retroflexus), common ragweed (Ambrosia elatior), soybean (Glycine max) and velvetleaf (Abutilon theophrasti) were planted and treated preemergence with test chemicals formulated in a non-phytotoxic solvent mixture which included a surfactant. At the same time, plants selected from these crop and weed species and also winter barley (Hordeum vulgare), blackgrass (Alopecurus myosuroides), canarygrass (Phalaris minor), chickweed (Stellaria media), downy brome (Bromus tectorum), green foxtail (Setaria viridis), Italian ryegrass (Lolium multiflorum), wheat (Triticum aestivum), wild oat (Avena fatua) and windgrass (Apera spica-venti) were treated with postemergence applications of some of the test chemicals formulated in the same manner. Plants ranged in height from 2 to 18 cm (1- to 4-leaf stage) for postemergence treatments. Plant species in the flooded paddy test consisted of rice (Oryza sativa), umbrella sedge (Cyperus difformis), duck salad (Heteranthera limosa) and barnyardgrass (Echinochloa crus-galli) grown to the 2-leaf stage for testing. Treated plants and controls were maintained in a greenhouse for 12 to 14 days, after which time all species were compared to controls and visually evaluated. Plant response ratings, summarized in Table C, are based on a scale of 0 to 100 where 0 is no effect and 100 is complete control. A dash (-) response means no test result.
Table C Compounds
500 g ai/ha 7 10 12 14 16 17 18 19 23 26 27 28 31 32
Flood
Barnyardgrass 60 55 20 30 75 60 45 20 25 10 0 0 20 45
Ducksalad 95 70 0 80 90 95 30 90 10 0 25 0 80 90
Rice 60 30 15 20 70 55 25 40 10 30 0 25 15 60
Sedge, Umbrella 95 85 85 90 95 95 80 95 50 0 80 85 75 80
Table C Compounds
500 g ai/ha 33 35 36
Flood
Barnyardgrass 50 50 55
Ducksalad 90 85 95
Rice 70 65 60
Sedge, Umbrella 90 90 95
Table C Compounds
250 g ai/ha 7 10 12 14 16 17 18 19 23 26 27 28 31 32
Flood
Barnyardgrass 60 30 0 25 55 45 10 15 10 0 0 0 0 15
Ducksalad 70 10 0 65 90 95 25 75 0 0 20 0 60 80
Rice 55 25 0 20 60 45 25 35 0 20 0 25 0 55
Sedge, Umbrella 90 80 0 85 95 95 80 90 40 0 65 40 75 80
Table C Compounds
250 g ai/ha 33 35 36
Flood
Barnyardgrass 25 45 45
Ducksalad 90 70 90 Rice 60 65 55
Sedge, Umbrella 85 90 80
Table C Compounds
125 g ai/ha 7 10 12 14 16 17 18 19 23 26 27 28 31 32
Flood
Barnyardgrass 50 10 0 20 35 25 10 10 10 0 0 0 0 0
Ducksalad 60 0 0 0 85 90 15 50 0 0 20 0 0 45
Rice 55 25 0 0 50 20 0 30 0 0 0 0 0 15
Sedge, Umbrella 85 60 0 85 95 95 50 90 40 0 35 0 60 75
Table C Compounds
125 g ai/ha 33 35 36
Flood
Barnyardgrass 10 10 30
Ducksalad 0 60 25
Rice 35 50 40
Sedge, Umbrella 80 85 75
Table C Compounds
62 g ai/ha 7 10 12 14 16 17 18 19 23 26 27 28 31 32
Flood
Barnyardgrass 35 0 0 0 30 10 5 0 10 0 0 0 0 0
Ducksalad 20 0 0 0 85 25 0 45 0 0 0 0 0 0
Rice 40 20 0 0 15 15 0 0 0 0 0 0 0 15
Sedge, Umbrella 85 25 0 85 95 95 10 90 20 0 0 0 55 70
Table C Compounds
62 g ai/ha 33 35 36
Flood
Barnyardgrass 5 5 15
Ducksalad 0 25 20
Rice 5 50 25
Sedge, Umbrella 80 85 70
Table C Compounds
500 g ai/ha 1 4 14 16 17 18 19 23 25 26 27 28 29 33
Postemergence
Barley - - 35 30 30 30 40 40 30 35 30 35 35 40
Bermudagrass 30 20
Blackgrass - - 70 65 60 65 65 60 45 75 60 45 50 55 Bromegrass, Downy - - 35 60 50 60 55 40 65 60 60 40 45 40
Canarygrass - - 70 55 65 60 55 40 50 55 60 50 55 60
Chickweed 90 100 _ _ _ _ _ _ _ _ _ _ _ _
Cocklebur 40 5 - - - - - - - - - - - -
Corn 30 10 - - - - - - - - - - - -
Crabgrass, Large 60 30
Cupgrass, Woolly 50 o - - - - - - - - - - - -
Foxtail, Giant 40 10 - - - - - - - - - - - -
Foxtail, Green - - 80 75 75 80 65 70 60 65 65 65 60 65
Goosegrass 50 30 - - - - - - - - - - - -
Johnsongrass 30 0 - - - - - - - - - - - -
Kochia 80 70 - - - - - - - - - - - -
Lambsquarters 100 80 - - - - - - - - - - - -
Morningglory 60 10 - - - - - - - - - - - -
Nutsedge, Yellow o o - - - - - - - - - - - -
Oat, Wild - - 65 40 65 55 65 60 55 60 65 55 55 55
Pigweed 100 85 - - - - - - - - - - - -
Ragweed 70 - - - - - - - - - - - - -
Ryegrass, Italian - - - 50 65 60 65 55 60 60 60 60 45 60
Soybean 70 15 - - - - - - - - - - - -
Surinam Grass 70 5 - - - - - - - - - - - -
Velvetleaf 30 20 - - - - - - - - - - - -
Wheat - - 40 30 35 30 40 40 35 35 30 35 35 35
Windgrass - - 60 60 65 65 60 65 40 60 60 40 45 40
Table C Compounds
250 g ai/ha 1 4 14 16 17 18 19 23 25 26 27 28 29 31
Postemergence
Barley - - 35 30 30 30 35 30 20 25 30 35 25 35
Bermudagrass 20 0 - - - - - - - - - - - -
Blackgrass - - 70 55 60 65 55 60 45 55 40 40 40 40
Bromegrass, Downy - - 35 60 40 40 55 35 45 45 55 40 30 30
Canarygrass - - 50 45 55 60 55 40 45 55 45 45 45 45
Chickweed 90 100 _ _ _ _ _ - - _ _ _ - _
Cocklebur 30 0 - - - - - - - - - - - -
Corn 30 10 - - - - - - - - - - - -
Crabgrass, Large 50 10 - - - - - - - - - - - -
Cupgrass, Woolly 50 0 - - - - - - - - - - - -
Foxtail, Giant 40 10 - - - - - - - - - - - - Foxtail, Green - - 75 65 65 65 65 65 60 60 60 60 45 60
Goosegrass 40 110 - - - - - - - - - - - -
Johnsongrass 20 0 - - - - - - - - - - - -
Kochia 20 660 - - - - - - - - - - - -
Lambsquarters 100 770 - - - - - - - - - - - -
Morningglory 60 110 - - - - - - - - - - - -
Nutsedge, Yellow 0 0 - - - - - - - - - - - -
Oat, Wild - - 60 40 65 45 65 60 45 55 60 50 50 55
Pigweed 100 770 - - - - - - - - - - - -
Ragweed 60 880 - - - - - - - - - - - -
Ryegrass, Italian - - 75 45 65 55 50 50 55 45 60 60 40 65
Soybean 70 11.5 _ _ _ _ _ _ _ _ _ _ _ _
Surinam Grass 60 0 _ - - - - - - _ _ - _ -
Velvetleaf 30 5 _ _ _ _ _ _ _ _ _ _ _ _
Wheat - - 35 30 35 25 40 40 30 35 30 35 30 40
Windgrass - - 60 60 60 65 60 65 40 60 60 40 40 40
Table C Compound
250 g ai/ha 33
Postemergence
Barley 35
Bermudagrass -
Blackgrass 35
Bromegrass, Downy 40
Canarygrass 60
Chickweed -
Cocklebur -
Corn -
Crabgrass, Large -
Cupgrass, Woolly -
Foxtail, Giant -
Foxtail, Green 65
Goosegrass -
Johnsongrass -
Kochia -
Lambsquarters -
Morningglory -
Nutsedge, Yellow -
Oat, Wild 45 Pigweed -
Ragweed -
Ryegrass, Italian 45
Soybean -
Surinam Grass -
Velvetleaf -
Wheat 35
Windgrass 40
Table C Compounds
125 g ai/ha 1 3 4 14 16 17 18 19 23 25 26 27 28 29
Postemergence
Barley - - - 30 25 25 20 30 30 20 25 20 35 20
Bermudagrass 20 10 0 - - - - - - - - - - -
Blackgrass - - - 55 40 50 65 50 45 35 40 40 40 35
Bromegrass, Downy - - - 35 60 40 35 45 35 40 45 45 40 30
Canarygrass - - - 45 40 40 45 55 35 35 45 45 45 40
Chickweed 80 100 80 - - - - - - - - - - -
Cocklebur 20 35 0 - _ - _ - _ _ - - - -
Corn 20 20 10 - - - - - - - - - - -
Crabgrass, Large 30 10 5 _ _ _ _ _ _ _ _ _ _ _
Cupgrass, Woolly 40 40 0 _ _ - - - _ _ - - _ -
Foxtail, Giant - 30 0 - - - - - - - - - - -
Foxtail, Green - - - 65 45 55 55 65 65 60 60 6Q 45 40
Goosegrass 20 30 0 - - - - - - - - - - -
Johnsongrass 20 10 0 - _ _ - - - _ - _ - _
Kochia 20 70 55 _ _ _ _ _ _ _ _ _ _ _
Lambsquarters 90 100 50 - - - - - - - - - - -
Morningglory - 5 5 _ _ _ _ _ _ _ _ _ _ _
Nutsedge, Yellow 0 0 0 _ _ _ _ - - _ _ _ - _
Oat, Wild - - - 55 40 45 40 60 40 35 45 45 45 45
Pigweed 100 90 70 - - - - - - - - - - -
Ragweed 60 80 70 - - - - - - - - - - -
Ryegrass, Italian - - - 60 45 60 45 40 45 55 40 45 45 35
Soybean 60 50 10 - - - - - - - - - - -
Surinam Grass 20 5 0 _ _ - _ - - _ - _ - _
Velvetleaf 20 100 5 _ _ _ _ _ _ _ - _ _ _
Wheat - - - 30 20 20 20 35 35 30 30 25 35 25
Windgrass - - - 60 60 50 55 35 55 40 60 40 35 35 Table C Compounds
125 g ai/ha 31 33
Postemergence
Barley 30 30
Bermudagrass - -
Blackgrass 30 35
Bromegrass, Downy 30 35
Canarygrass 35 40
Chickweed - -
Cocklebur - -
Corn - -
Crabgrass , Large - -
Cupgrass, Woolly - -
Foxtail, Giant - -
Foxtail, Green 45 60
Goosegrass - -
Johnsongrass - -
Kochia - -
Lambsquarters - -
Morningglory - -
Nutsedge, Yellow - -
Oat, Wild 45 40
Pigweed - -
Ragweed - -
Ryegrass, Italian 65 45
Soybean - -
Surinam Grass - -
Velvetleaf - -
Wheat 35 30
Windgrass 35 30
Table C Compounds
62 g ai/ha 1 3 4 14 16 17 18 19 23 25 26 27 28 29
Postemergence
Barley - - - 20 20 15 20 30 30 20 25 20 25 10
Bermudagrass 10 0
Blackgrass - - 45 40 40 65 40 35 35 35 40 35 35
Bromegrass, Downy - - 35 40 35 35 40 35 35 35 35 35 0
Canarygrass - - 40 40 35 45 45 35 35 45 35 40 20 Chickweed 70 100 5 - - _ _ - - - _ _ _ -
Cocklebur 20 35 0 - - - - - - - - - - -
Corn 20 15 5 - - - - - - - - - - -
Crabgrass, Large 30 5 0 - - - - - - - - - - -
Cupgrass, Woolly 20 20 0 - - - - - - - - - - -
Foxtail , Giant 20 15 0 - - - - - - - - - - -
Foxtail, Green - 60 35 35 40 65 60 60 40 45 45 30
Goosegrass 20 5 0 - - - - - - - - - - -
Johnsongrass 20 0 0 - - - - - - - - - - -
Kochia 20 50 40 - - - - - - - - - - -
Lambsquarters 90 100 50 - - - - - - - - - - -
Morningglory 60 5 5 - - - - - - - - - - -
Nutsedge, Yellow 0 0 0 - - - - - - - - - - -
Oat, Wild - 45 40 45 40 50 40 35 40 45 45 30
Pigweed 100 80 65 - - - - - - - - - - -
Ragweed 20 70 60 - - - - - - - - - - -
Ryegrass, Italian - 50 35 60 45 40 40 35 35 40 40 30
Soybean 60 45 10 - - - - - - - - - - -
Surinam Grass 20 0 0 - - - - - - - - - - -
Velvetleaf 20 80 0 - - - - - - - - - - -
Wheat - 25 20 15 20 35 35 30 30 20 25 10
Windgrass - 40 60 50 40 35 55 35 60 35 30 20
Table C Compounds Table C Compounds
62 g ai/ha 31 33 31 g ai/ha 3 31
Postemergence Postemergence
Barley 30 30 Barley - 30
Bermudagrass Bermudagrass 0
Blackgrass 30 30 Blackgrass - 0
Bromegrass, Downy 30 35 Bromegrass, Downy - 30
Canarygrass 35 35 Canarygrass - 35
Chickweed Chickweed 95
Cocklebur Cocklebur 35
Corn Corn 15
Crabgrass, Large Crabgrass, Large 5
Cupgrass, Woolly Cupgrass, Woolly 5
Foxtail, Giant Foxtail, Giant 10
Foxtail, Green 45 45 Foxtail, Green - 45
Goosegrass Goosegrass 0 Johnsongrass - Johnsongrass 0 -
Kochia - Kochia 30 -
Lambsquarters - Lambsquarters 70 -
Morningglory - Morningglory 5 -
Nutsedge, Yellow - Nutsedge, Yellow 0 -
Oat, Wild 35 40 Oat, Wild - 35
Pigweed - Pigweed 50 -
Ragweed - Ragweed 0 -
Ryegrass, Italian 45 35 Ryegrass, Italian - 35
Soybean - Soybean 20 -
Surinam Grass _ Surinam Grass 0 -
Velvetleaf - Velvetleaf 30 -
Wheat 35 25 Wheat - 30
Windgrass 30 20 Windgrass - 20
Table C Compound
16 g ai/ha 3
Postemergence
Bermudagrass 0
Chickweed 80
Cocklebur 20
Corn 10
Crabgrass, Large 5
Cupgrass , Woo1ly 0
Foxtail, Giant 0
Goosegrass 0
Johnsongrass 0
Kochia 10
Lambsquarters 50
Morningglory 0
Nutsedge, Yellow 0
Pigweed 40
Ragweed 0
Soybean 20
Surinam Grass 0
Velvetleaf 0 Table C Compounds
500 g ai/ha 1 14 16 17 18
Preemergence
Bermudagrass 100 100 100 100 90
Cocklebur 10 0 0 5 5
Corn 30 30 30 25 10
Crabgrass , Large 100 100 100 100 100
Cupgrass , Woo1ly 20 50 80 100 50
Foxtail, Giant 100 100 100 100 100
Goosegrass 100 100 100 100 100
Johnsongrass 60 50 65 40 30
Kochia - 100 100 100 100
Lambsquarters 100 100 100 100 100
Morningglory 100 50 10 5 10
Nightshade 100 100 100 100 100
Nutsedge, Yellow 0 0 0 0 0
Pigweed 100 100 100 100 100
Ragweed 80 50 55 100 100
Soybean 0 10 5 5 5
Sunflower 0 30 0 0 5
Surinam Grass 100 65 60 70 10
Velvetleaf 30 70 70 70 60
Table C Compounds
250 g ai/ha 1 14 16 17 18
Preemergence
Bermudagrass 90 100 100 100 90
Cocklebur 0 0 0 0 0
Corn 10 10 10 10 10
Crabgrass, Large 100 100 100 100 100
Cupgrass, Woolly 20 10 30 95 50
Foxtail, Giant 90 80 95 100 95
Goosegrass 90 95 100 100 100
Johnsongrass 40 10 60 40 5
Kochia 100 100 100 100 100
Lambsquarters 100 100 100 100 100
Morningglory 90 0 0 0 0
Nightshade 100 100 100 100 100
Nutsedge, Yellow 0 0 0 0 0 Pigweed 100 100 100 100 100
Ragweed 70 0 50 - 5
Soybean 0 10 5 5 0
Sunflower 0 0 0 0 0
Surinam Grass 90 50 40 15 5
Velvetleaf 30 5 70 - 20
Table C Compounds
125 g ai/ha 1 14 16 17 18
Preemergence
Bermudagrass 90 100 90 85 90
Cocklebur 0 0 0 0 0
Corn 0 0 10 5 5
Crabgrass, Large 100 100 85 95 95
Cupgrass, Woolly - 10 5 40 10
Foxtail, Giant 90 70 50 80 50
Goosegrass 20 45 65 95 50
Johnsongrass 30 5 20 5 0
Kochia 90 100 100 100 100
Lambsquarters 100 100 100 100 100
Morningglory 60 0 0 0 0
Nightshade 100 100 100 100 100
Nutsedge, Yellow 0 0 0 0 0
Pigweed 100 100 100 100 1 0
Ragweed 70 0 0 80 0
Soybean 0 0 0 0 0
Sunflower 0 0 0 0 0
Surinam Grass 40 10 5 10 0
Velvetleaf 10 - 0 0 0
Table C Compounds
62 g ai/ha 1 14 16 17 18
Preemergence
Bermudagrass 0 60 60 85 40
Cocklebur 0 0 0 0 0
Corn 0 0 0 0 0
Crabgrass, Large 100 80 80 85 60
Cupgrass, Woolly 20 0 0 5 5
Foxtail, Giant 90 30 50 60 30 Goosegrass 20 40 60 40 20
Johnsongrass 20 5 10 0 0
Kochia 0 0 100 100 100
Lambsquarters 100 100 100 100 100
Morningglory 0 0 0 0 0
Nightshade 100 95 95 95 90
Nutsedge, Yellow 0 0 0 0 0
Pigweed 100 100 90 100 100
Ragweed 0 0 0 10 0
Soybean - 0 0 0 0
Sunflower 0 0 0 0 0
Surinam Grass - 5 5 0 0
Velvetleaf 10 5 0 0 0
TESTD Seeds of plant species selected from annual blugrass (Poa annua), blackgrass (Alopecurus myosuroides), catchweed bedstraw (Galium aparine), common chickweed (Stellaria media), downy bromegrass (Bromus tectorum), green foxtail (Setaria viridis), Italian ryegrass (Lolium multiflorum), kochia (Kochia scoparia , lambsquarters (Chenopodium album), littleseed canarygrass (Phalaris minor), pigweed (Amaranthus retroflexus), Russian thistle (Salsola kali), wild buckwheat (Polygonum convolvulus), wild mustard (Sinapis arvensis), wild oat (Avena fatua), windgrass (Apera spica-venti), winter barley (Hordeum vulgar e), and wheat (Triticum aestivum) were planted and treated preemergence with test chemicals formulated in a non-phytotoxic solvent mixture which included a surfactant. At the same time, plants selected from these crop and weed species were treated with postemergence applications of some of the test chemicals formulated in the same manner. Plants ranged in height from 2 to 18 cm (1- to 4-leaf stage) for postemergence treatments. Treated plants and controls were maintained in a controlled growth environment for 15 to 25 days after which time all species were compared to controls and visually evaluated. Plant response ratings, summarized in Table D, are based on a scale of 0 to 100 where 0 is no effect and 100 is complete control. A dash (-) response means no test result.
Table D Compounds Table D Compounds
250 g ai/ha 10 14 125 g ai/ha lO 14
Postemergence Postemergence
Barley 40 40 Barley 25 40
Blackgrass 80 70 Blackgrass 70 70
Bluegrass 65 70 Bluegrass 65 65 Bromegrass, Downy 40 75 Bromegras s , Downy 40 65
Buckwheat, Wild 75 100 Buckwhea , Wild 70 85
Canarygrass 75 70 Canarygrass 65 70
Chickweed 90 100 Chickweed. 80 100
Foxtail, Green 50 80 Foxtail, Green 40 75
Galium 65 100 Galium 60 80
Kochia 95 98 Kochia 90 100
Lambsquarters 95 100 Lambsquar-ters 85 100
Mustard, Wild 100 100 Mustard, Wild 80 100
Oat, Wild 65 65 Oat, Wild. 45 65
Pigweed 90 100 Pigweed 80 100
Russian Thistle 75 98 Russian Thistle 75 75
Ryegrass, Italian 65 65 Ryegrass, Italian 65 60
Wheat 20 45 Wheat 10 40
Windgrass 65 75 Windgrass 65 70
Table D Compounds Table D Compound
62 g ai/ha 10 14 31 g ai/tia 10
Postemergence Early Postemergence
Barley 15 35 Barley 10
Blackgrass 50 60 Blackgrass 40
Bluegrass 50 65 Bluegrass 40
Bromegrass, Downy 40 60 Bromegrass, Downy 40
Buckwheat, Wild 60 75 Buckwheat, Wild 45
Canarygrass 50 65 Canarygrass 40
Chickweed 70 100 Chickweed. 50
Foxtail, Green 40 60- Foxtail, Green 40
Galium 60 65 Galium 40
Kochia 65 98 Kochia 50
Lambsquarters 70 100 Lambsqua- ters 60
Mustard, Wild 80 100 Mustard, Wild 70
Oat, Wild 40 65 Oat, Wild. 35
Pigweed 80 100 Pigweed 70
Russian Thistle 60 70 Russian Thistle 45
Ryegrass, Italian 60 60 Ryegrass , Italian 35
Wheat 5 40 Wheat 5
Windgrass 50 60 Windgrass 40 Table D Compounds Table D Compc>unds
250 g ai/ha 10 14 125 g ai/ha 10 14
Preemergence Preemergence
Barley 35 20 Barley 10 20
Blackgrass 100 65 Blackgrass 85 65
Bluegrass 95 65 Bluegrass 95 60
Bromegrass, Downy 65 65 Bromegrass, Downy 60 65
Buckwheat, Wild 90 65 Buckwheat, Wild 70 60
Canarygrass 98 60 Canarygrass 98 45
Chickweed 100 100 Chickweed 100 100
Foxtail, Green 100 85 Foxtail, Green 100 65
Galium 40 70 Galium 30 60
Kochia 100 100 Kochia 95 100
Lambsquarters 100 65 Lambsquarters 100 60
Mustard, Wild 100 100 Mustard, Wild 100 45
Oat, Wild 70 70 Oat, Wild 65 65
Pigweed 100 100 Pigweed 100 100
Russian Thistle 60 65 Russian Thistle 60 65
Ryegrass, Italian 100 65 Ryegrass, Italian 65 65
Wheat 25 60 Wheat 0 35
Windgrass 100 75 Windgrass 100 75
Table D Compounds Table D Compound
62 g ai/ha 10 14 31 g ai/ha 10
Preemergence Preemergence
Barley 0 0 Barley 0
Blackgrass 75 45 Blackgrass 60
Bluegrass 80 40 Bluegrass 60
Bromegrass, Downy 50 40 Bromegrass, Downy 50
Buckwheat, Wild 60 40 Buckwheat, Wild 50
Canarygrass 95 25 Canarygrass 60
Chickweed 100 100 Chickweed 100
Foxtail, Green 100 55 Foxtail, Green 85
Galium 30 40 Galium 20
Kochia 80 100 Kochia 65
Lambsquarters 100 50 Lambsquarters 80
Mustard, Wild 100 45 Mustard, Wild 60
Oat, Wild 65 55 Oat, Wild 60 Pigweed 100 100 Pigweed 100
Russian Thistle 60 65 Russian Thistle 40
Ryegrass, Italian 60 60 Ryegrass, Italian 50
Wheat 0 35 Wheat 0
Windgrass 100 65 Windgrass 90

Claims

What is claimed is: 1. A compound selected from Formula I, an N-oxide or an agriculturally suitable salt thereof,
Figure imgf000147_0001
wherein
Figure imgf000147_0002
J-9 T is CR6 or Ν; UisCR7orΝ; YisCRsorN; ZisCR9orN; Rla is H, C1-C4 alkyl, C]-C4 fluoroalkyl, C2-C4 alkenyl, C2-C4 fluoroalkenyl, C2-C4 alkynyl or C2-C4 fluoroalkynyl; Rlb is halogen, -CN, ^-€4. alkyl, Cj- fluoroalkyl, C2-C4 alkenyl, C2-C4 fluoroalkenyl, C2-C4 alkynyl or C2-C4 fluoroalkynyl; R2a is C C6 alkyl, C]-C6 haloalkyl, C2-C6 alkoxyalkyl, C2-C6 alkylthioalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-Ce alkynyl, C2-C6 haloalkynyl, C3-C6 cycloalkyl, C4-C5 alkylcycloalkyl, Cβ-Cg halocycloalkyl, C4-C6 cycloalkylalkyl, C5-C6 alkylcycloalkylalkyl or SiR10RnR12; R2b is C C6 alkyl, Cj-C6 haloalkyl, C2-C6 alkoxyalkyl, C2-C6 alkylthioalkyl, C2-C6 alkenyl, C2-Cg haloalkenyl, C2-C6 alkynyl, C2-Cg haloalkynyl, C3-C6 cycloalkyl, C4-C6 alkylcycloalkyl, C3-C6 halocycloalkyl, C4-C6 cycloalkylalkyl or C5~C6 alkylcycloalkylalkyl; R3 is H, F or Ci-C2 alkyl; or
R2a or R2b 1S taken together with R3 as -C(R13)(R14)-(Y1)s-(CH2)t-(Y2)u- or -C(R13)CR14)-(Y1)V-CH=CH-(Y2)W- wherein the left end of the radical is connected as R2a or R2b, and the right end of the radical is connected as R3; R4 is H, -C2 alkyl, C2-C6 alkylcarbonyl, C2-C6 alkoxycarbonyl, C2-C6 alkoxyalkyl or C2-Cg alkylthioalkyl; R5 is a phenyl ring or a 5- or 6-membered heteroaromatic ring which includes at least one heteroatom selected from N, O and S, each ring optionally substituted with one or more substituents selected from R15; or R5 is a 5- or 6-membered partially unsaturated heterocyclic ring which includes at least one heteroatom selected from N, O and S, the ring connected through a nitrogen atom or an sp2 carbon atom to the remainder of Formula I and optionally substituted by one or more substituents selected from R16;
R6 is H, F, C]— C2 alkyl, C2-C2 fluoroalkyl,
Figure imgf000148_0001
fluoroalkoxy, C!-C2 alkylthio or CJ-C2 fluoroalkylthio; R7 is H, F, C]— C2 alkyl, C]-C2 fluoroalkyl, C]-C2 fluoroalkoxy, Cx-C2 alkylthio or Cι-C2 fluoroalkylthio; R8 and R9 are independently selected from H, F, C -C2 alkyl, Cι~C2 fluoroalkyl, Cι-C2 fluoroalkoxy, C -C2 alkylthio and C1-C2 fluoroalkylthio; R10 is Cj-C2 alkyl or haloalkyl; R11 is C C2 alkyl or
Figure imgf000148_0002
haloalkyl; R12 is C!-C2 alkyl or Cj-C2 haloalkyl; R13 and R14 are independently H or C2-C2 alkyl; each R15 is independently halogen, -CN, C]-C2 alkyl, C -C2 haloalkyl, C^-C2 alkoxy, Cj-^ haloalkoxy, C1-C2 alkylthio, C!-C2 alkylsulfinyl, Cι~C2 alkylsulfonyl, -SCHF2 or -SCF3; each R16 is independently C]-C alkyl; is O or S; Y1 and Y2 are independently CH2, 0, S, NH or NCH3; s is 0 or 1; t is 1 or 2; and u is 0 or 1; provided that the sum of s, t and u is 2 or 3; and v is 0 or 1; w is 0 or 1; provided that the sum of v and w is 0 or 1; provided that (a) when J is J-1, Rla is CH3, R2a is C(CH3)3, R3 is H, T is CH, U is CH, Y is CH and Z is CH, then R5 is other than phenyl and 5-oxazolyl; (b) when a R15 or R16 substituent is attached to a nitrogen atom, said substituent is C!-C2 alkyl; (c) when R5 comprises a tetrazole ring, said ring is connected through the carbon atom to the remainder of Formula I and substituted on a nitrogen atom with Cι~C2 alkyl; (d) when R7 is F and R5 comprises a 1-pyrazolyl ring, no more than one substituent R15 attached to said ring is haloalkyl; (e) when J is J-2 or J-6, then R7 and R9 are H; (f) when J is J-2 or J-6, and R2b is C1-C2 alkyl, then Rlb is halogen, C2-C4 alkyl, C]-C4 fluoroalkyl, C2-C4 alkenyl, C2-C4 fluoroalkenyl, C2-C4 alkynyl or C2-C fluoroalkynyl; (g) when T is N, then Z is CR9; and (h) when J is J-8, then R2b is other than C5-C6 cycloalkyl.
2. The compound of Claim 1 wherein at most one of T, U, Y and Z is N; Rla or Rlb is selected from a radical in the group consisting of C1-C3 alkyl, C1-C3 fluoroalkyl, C2-C3 alkenyl, C -C3 fluoroalkenyl, C2-C3 alkynyl and C2-C3 fluoroalkynyl, each radical unbranched and connected through a terminal end carbon atom to the azole ring; R6 is H or F; R7 is H or F; R8 is H or F; R9 is H or F; R4 is H; R13 is Cj-C2 alkyl; W is O; Y1 and Y2 are independently CH2 or O; the sum of s, t and u is 2; and the sum of v and w is 0.
3. The compound of Claim 2 wherein J is J-1, J-2, J-3, J-5 or J-8.
4. The compound of Claim 3 wherein Rla or Rlb is CH2CH3, CH2CH2F, CH2CHF2, CH2CF3 or CH=CH2, R2a or R2b is tert-butyl, isopropyl or cyclopropyl, and R3 is H.
5. The compound of Claim 4 wherein each R15 is independently halogen, -CN, C1-C2 alkyl, C^ fluoroalkyl or C^ alkoxy.
6. The compound of Claim 5 wherein R5 is a phenyl ring optionally substituted with 1-2 substituents selected from R15.
7. The compound of Claim 5 wherein R5 is a 5- or 6-membered partially unsaturated heterocyclic ring which includes at least one heteroatom selected from N, O and S and optionally substituted with 1-2 substituents selected from R16.
8. The compound of Claim 5 wherein R5 is a 5- or 6-membered heteroaromatic ring which includes at least one heteroatom selected from N, O and S and optionally substituted with 1-2 substituents selected from R15.
9. The compound of Claim 8 wherein the 5- or 6-membered heteroaromatic ring is 2-pyridinyl.
10. The compound of Claim 5 which is 3-(l,l-dimethylethyl)-l-ethyl- N-[3-(2-pyridinyl)phenyl]-lH-pyrazole-5-carboxamide.
11. A herbicidal composition comprising a herbicidally effective amount of a compound of Claim 1 and at least one of a surfactant, a solid diluent or a liquid diluent.
12. A method for controlling the growth of undesired vegetation comprising contacting the vegetation or its environment with a herbicidally effective amount of a compound of Claim 1.
13. A herbicidal mixture comprising a herbicidally effective amount of a compound of Claim 1 and an effective amount of at least one additional active ingredient selected from the group consisting of an other herbicide and a herbicide safener.
14. A herbicidal composition comprising the herbicidal mixture of Claim 13 and at least one of a surfactant, a solid diluent or a liquid diluent.
15. A herbicidal mixture of Claim 13 wherein the other herbicide is selected from isoproturon, flupyrsulfuron-methyl and metsulfuron-methyl, or an agriculturally suitable salt thereof.
16. A herbicidal mixture of Claim 13 wherein the safener is selected from benoxacor, l-bromo-4-[(chloromethyl)sulfonyl]benzene, cloquintocet-mexyl, cyometrinil, dichlormid, 2-(dichloromethyl)-2-methyl-l,3-dioxolane, fenchlorazole-ethyl, fenclorim, flurazole, fluxofenim, furilazole, isoxadifen-ethyl, mefenpyr-ethyl, (4-methoxy- 3-methylphenyl)(3-methylphenyl)methanone, 1,8-naphthalic anhydride and oxabetrinil.
17. A method for selectively controlling the growth of undesired vegetation in a crop comprising contacting the locus of the crop with a herbicidally effective amount of a compound of Claim 1 and an antidotally effective amount of a safener.
18. A method for selectively controlling the growth of undesired vegetation in a crop comprising contacting the locus of the crop with a herbicidally effective amount of a compound of Claim 1 wherein seed from which the crop is grown is treated with an antidotally effective amount of a safener.
PCT/US2004/035045 2003-10-20 2004-10-20 Heteroyclylphenyl-and heterocyclylpyridyl-substituted azolecarboxamides as herbicides WO2005040152A1 (en)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US51266503P 2003-10-20 2003-10-20
US60/512,665 2003-10-20
US55781604P 2004-03-30 2004-03-30
US60/557,816 2004-03-30

Publications (1)

Publication Number Publication Date
WO2005040152A1 true WO2005040152A1 (en) 2005-05-06

Family

ID=34526753

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2004/035045 WO2005040152A1 (en) 2003-10-20 2004-10-20 Heteroyclylphenyl-and heterocyclylpyridyl-substituted azolecarboxamides as herbicides

Country Status (1)

Country Link
WO (1) WO2005040152A1 (en)

Cited By (67)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006028958A3 (en) * 2004-09-02 2006-04-13 Genentech Inc Pyridyl inhibitors of hedgehog signalling
WO2007009717A1 (en) * 2005-07-18 2007-01-25 Syngenta Participations Ag Pyrazole-4- carboxamide derivatives as microbiocides
JP2009542771A (en) * 2006-07-07 2009-12-03 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング Phenyl-substituted heteroaryl derivatives and their use as anticancer agents
WO2011003796A1 (en) 2009-07-06 2011-01-13 Basf Se Pyridazine compounds for controlling invertebrate pests
US20110130380A1 (en) * 2009-09-04 2011-06-02 Barsanti Paul A Heteroaryl Kinase Inhibitors
EP2352723A2 (en) * 2008-11-05 2011-08-10 Bayer CropScience AG Halogen-substituted compounds used as pesticides
WO2011117806A2 (en) 2010-03-23 2011-09-29 Basf Se Pyridazine compounds for controlling invertebrate pests
WO2012034960A1 (en) * 2010-09-13 2012-03-22 Basf Se Pyridine compounds for controlling invertebrate pests ii
EP2563759A2 (en) * 2010-04-27 2013-03-06 Calcimedica, Inc. Compounds that modulate intracellular calcium
WO2013040021A1 (en) 2011-09-13 2013-03-21 Monsanto Technology Llc Methods and compositions for weed control
WO2013040117A1 (en) 2011-09-13 2013-03-21 Monsanto Technology Llc Methods and compositions for weed control
WO2013039990A1 (en) 2011-09-13 2013-03-21 Monsanto Technology Llc Methods and compositions for weed control
US8642597B2 (en) 2007-08-27 2014-02-04 Basf Se Pyrazole compounds for controlling invertebrate pests
US8710056B2 (en) 2009-07-06 2014-04-29 Basf Se Pyridazine compounds for controlling invertebrate pests
US8710055B2 (en) 2010-12-21 2014-04-29 Boehringer Ingelheim International Gmbh Triazolylphenyl sulfonamides as serine/threonine kinase inhibitors
US8729083B2 (en) 2008-09-24 2014-05-20 Basf Se Pyrazole compounds for controlling invertebrate pests
US8778929B2 (en) 2008-09-29 2014-07-15 Boehringer Ingelheim International Gmbh Substituted heteroaryl inhibitors of B-RAF
CN103998446A (en) * 2011-11-28 2014-08-20 诺华股份有限公司 Novel trifluoromethyl-oxadiazole derivatives and their use in the treatment of disease
WO2014151255A1 (en) 2013-03-15 2014-09-25 Monsanto Technology Llc Methods and compositions for weed control
US8853125B2 (en) 2008-09-24 2014-10-07 Basf Se Pyrazole compounds for controlling invertebrate pests
US8865703B2 (en) 2010-03-26 2014-10-21 Boehringer Ingelheim International Gmbh Pyridyltriazoles
US8889665B2 (en) 2007-07-02 2014-11-18 Boehringer Ingelheim International Gmbh Chemical compounds
US8981084B2 (en) 2010-01-13 2015-03-17 Tempero Pharmaceuticals, Inc. Oxadiazole HDAC inhibitors
US9056843B2 (en) 2011-07-08 2015-06-16 Novartis Ag Trifluoromethyl-oxadiazole derivatives and their use in the treatment of disease
WO2015108982A2 (en) 2014-01-15 2015-07-23 Monsanto Technology Llc Methods and compositions for weed control using epsps polynucleotides
US9121022B2 (en) 2010-03-08 2015-09-01 Monsanto Technology Llc Method for controlling herbicide-resistant plants
US9125414B2 (en) 2009-07-24 2015-09-08 Basf Se Pyridine derivatives compounds for controlling invertebrate pests
US9290507B2 (en) 2010-03-26 2016-03-22 Boehringer Ingelheim International Gmbh B-RAF kinase inhibitors
US9416363B2 (en) 2011-09-13 2016-08-16 Monsanto Technology Llc Methods and compositions for weed control
US9422558B2 (en) 2011-09-13 2016-08-23 Monsanto Technology Llc Methods and compositions for weed control
US9422557B2 (en) 2011-09-13 2016-08-23 Monsanto Technology Llc Methods and compositions for weed control
EP3048099A3 (en) * 2006-11-15 2016-09-21 YM BioSciences Australia Pty Ltd Inhibitors of kinase activity
US9540642B2 (en) 2013-11-04 2017-01-10 The United States Of America, As Represented By The Secretary Of Agriculture Compositions and methods for controlling arthropod parasite and pest infestations
US9777288B2 (en) 2013-07-19 2017-10-03 Monsanto Technology Llc Compositions and methods for controlling leptinotarsa
US9850496B2 (en) 2013-07-19 2017-12-26 Monsanto Technology Llc Compositions and methods for controlling Leptinotarsa
WO2018029242A1 (en) * 2016-08-11 2018-02-15 Syngenta Participations Ag Microbiocidal oxadiazole derivatives
JP2018521110A (en) * 2015-07-27 2018-08-02 チョン クン ダン ファーマシューティカル コーポレーション 1,3,4-oxadiazolamide derivative compounds as histone deacetylase 6 inhibitors and pharmaceutical compositions containing them,
US10041068B2 (en) 2013-01-01 2018-08-07 A. B. Seeds Ltd. Isolated dsRNA molecules and methods of using same for silencing target molecules of interest
US10240161B2 (en) 2012-05-24 2019-03-26 A.B. Seeds Ltd. Compositions and methods for silencing gene expression
US10378012B2 (en) 2014-07-29 2019-08-13 Monsanto Technology Llc Compositions and methods for controlling insect pests
US10492494B2 (en) 2015-11-13 2019-12-03 Basf Se Substituted oxadiazoles for combating phytopathogenic fungi
US10499644B2 (en) 2015-11-19 2019-12-10 Basf Se Substituted oxadiazoles for combating phytopathogenic fungi
US10555526B2 (en) 2015-11-05 2020-02-11 Basf Se Substituted oxadiazoles for combating phytopathogenic fungi
US10557138B2 (en) 2013-12-10 2020-02-11 Beeologics, Inc. Compositions and methods for virus control in Varroa mite and bees
US10612019B2 (en) 2013-03-13 2020-04-07 Monsanto Technology Llc Methods and compositions for weed control
US10609930B2 (en) 2013-03-13 2020-04-07 Monsanto Technology Llc Methods and compositions for weed control
US10655136B2 (en) 2015-06-03 2020-05-19 Monsanto Technology Llc Methods and compositions for introducing nucleic acids into plants
US10674727B2 (en) 2015-11-19 2020-06-09 Basf Se Substituted oxadiazoles for combating phytopathogenic fungi
US10683505B2 (en) 2013-01-01 2020-06-16 Monsanto Technology Llc Methods of introducing dsRNA to plant seeds for modulating gene expression
US10687532B2 (en) 2015-11-13 2020-06-23 Basf Se Substituted oxadiazoles for combating phytopathogenic fungi
WO2020151589A1 (en) * 2019-01-25 2020-07-30 北京赛特明强医药科技有限公司 Acylamino bridged heterocyclic compound, and composition and application thereof
US10760086B2 (en) 2011-09-13 2020-09-01 Monsanto Technology Llc Methods and compositions for weed control
US10785980B2 (en) 2016-06-09 2020-09-29 Basf Se Substituted oxadiazoles for combating phytopathogenic fungi
US10801028B2 (en) 2009-10-14 2020-10-13 Beeologics Inc. Compositions for controlling Varroa mites in bees
US10808249B2 (en) 2011-09-13 2020-10-20 Monsanto Technology Llc Methods and compositions for weed control
US10806146B2 (en) 2011-09-13 2020-10-20 Monsanto Technology Llc Methods and compositions for weed control
US10829828B2 (en) 2011-09-13 2020-11-10 Monsanto Technology Llc Methods and compositions for weed control
CN112119063A (en) * 2018-05-18 2020-12-22 富士胶片株式会社 Method for producing 3-difluoromethylpyrazole compound, method for producing 3-difluoromethylpyrazole-4-carboxylic acid compound, and pyrazolidine compound
US10883103B2 (en) 2015-06-02 2021-01-05 Monsanto Technology Llc Compositions and methods for delivery of a polynucleotide into a plant
US10888579B2 (en) 2007-11-07 2021-01-12 Beeologics Inc. Compositions for conferring tolerance to viral disease in social insects, and the use thereof
US10968449B2 (en) 2015-01-22 2021-04-06 Monsanto Technology Llc Compositions and methods for controlling Leptinotarsa
US10986839B2 (en) 2016-04-11 2021-04-27 Basf Se Substituted oxadiazoles for combating phytopathogenic fungi
US10988764B2 (en) 2014-06-23 2021-04-27 Monsanto Technology Llc Compositions and methods for regulating gene expression via RNA interference
US11091770B2 (en) 2014-04-01 2021-08-17 Monsanto Technology Llc Compositions and methods for controlling insect pests
US20210317103A1 (en) * 2018-08-14 2021-10-14 Biogen Ma Inc. Ask1 inhibiting agents
US11807857B2 (en) 2014-06-25 2023-11-07 Monsanto Technology Llc Methods and compositions for delivering nucleic acids to plant cells and regulating gene expression
US11999715B2 (en) * 2019-08-13 2024-06-04 Biogen Ma Inc. ASK1 inhibiting agents

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0419917A1 (en) * 1989-09-23 1991-04-03 BASF Aktiengesellschaft Pyrazol-3-carboxylic acid amides
WO1993025535A1 (en) * 1992-06-11 1993-12-23 Rhone Poulenc Agriculture Ltd. Herbicidal pyrazole-(thio)-carboxamides

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0419917A1 (en) * 1989-09-23 1991-04-03 BASF Aktiengesellschaft Pyrazol-3-carboxylic acid amides
WO1993025535A1 (en) * 1992-06-11 1993-12-23 Rhone Poulenc Agriculture Ltd. Herbicidal pyrazole-(thio)-carboxamides

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
PARLOW J J: "Synthesis of pyrazolecarbonylaminopyridinecarboxamides as herbicides", JOURNAL OF HETEROCYCLIC CHEMISTRY, HETEROCORPORATION. PROVO, US, vol. 35, 1998, pages 1493 - 1499, XP002273124, ISSN: 0022-152X *
PARLOW JOHN J ET AL: "Utility of Complementary Molecular Reactivity and Molecular Recognition (CMR/R) Technology and Polymer -Supported Reagents in the Solution-Phase Synthesis of Heterocyclic Carboxamides", JOURNAL OF ORGANIC CHEMISTRY, AMERICAN CHEMICAL SOCIETY. EASTON, US, vol. 62, 1997, pages 5908 - 5919, XP002213047, ISSN: 0022-3263 *

Cited By (109)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9278961B2 (en) 2004-09-02 2016-03-08 Genentech, Inc. Pyridyl inhibitors of hedgehog signalling
US9321761B2 (en) 2004-09-02 2016-04-26 Curis, Inc. Pyridyl inhibitors of hedgehog signalling
EA017262B1 (en) * 2004-09-02 2012-11-30 Дженентек, Инк. Compounds of 2-(2-halogen-4-aminophenyl)pyridyl inhibitors of hedgehog signaling (embodiments), process for preparing same, composition and methods for treating cancer and inhibiting angiogenesis and hedgehog pathway signaling in cells based thereon
US9790183B2 (en) 2004-09-02 2017-10-17 Genentech, Inc. Pyridyl inhibitors of hedgehog signalling
US7888364B2 (en) 2004-09-02 2011-02-15 Curis, Inc. Pyridyl inhibitors of hedgehog signalling
WO2006028958A3 (en) * 2004-09-02 2006-04-13 Genentech Inc Pyridyl inhibitors of hedgehog signalling
WO2007009717A1 (en) * 2005-07-18 2007-01-25 Syngenta Participations Ag Pyrazole-4- carboxamide derivatives as microbiocides
US8003626B2 (en) 2005-07-18 2011-08-23 Syngenta Crop Protection, Inc. Pyrazole-4-carboxamide derivatives as microbiocides
US8198308B2 (en) 2006-07-07 2012-06-12 Boehringer Ingelheim International Gmbh Chemical compounds
JP2009542771A (en) * 2006-07-07 2009-12-03 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング Phenyl-substituted heteroaryl derivatives and their use as anticancer agents
EP3048099A3 (en) * 2006-11-15 2016-09-21 YM BioSciences Australia Pty Ltd Inhibitors of kinase activity
US8889665B2 (en) 2007-07-02 2014-11-18 Boehringer Ingelheim International Gmbh Chemical compounds
US8642597B2 (en) 2007-08-27 2014-02-04 Basf Se Pyrazole compounds for controlling invertebrate pests
US9204647B2 (en) 2007-08-27 2015-12-08 Basf Se Pyrazole compounds for controlling invertebrate pests
US10888579B2 (en) 2007-11-07 2021-01-12 Beeologics Inc. Compositions for conferring tolerance to viral disease in social insects, and the use thereof
US9375008B2 (en) 2008-09-24 2016-06-28 Basf Se Pyrazole compounds for controlling invertebrate pests
US8853125B2 (en) 2008-09-24 2014-10-07 Basf Se Pyrazole compounds for controlling invertebrate pests
US8729083B2 (en) 2008-09-24 2014-05-20 Basf Se Pyrazole compounds for controlling invertebrate pests
US8778929B2 (en) 2008-09-29 2014-07-15 Boehringer Ingelheim International Gmbh Substituted heteroaryl inhibitors of B-RAF
JP2012507482A (en) * 2008-11-05 2012-03-29 バイエル・クロップサイエンス・アーゲー New halogen-substituted compounds
EP2352723B1 (en) * 2008-11-05 2016-11-23 Bayer Intellectual Property GmbH Pesticidal n-aryl- or n-heteroaryl pyrazole carboxamide compounds
EP2352723A2 (en) * 2008-11-05 2011-08-10 Bayer CropScience AG Halogen-substituted compounds used as pesticides
US9029639B2 (en) 2009-07-06 2015-05-12 Basf Se Pyridazine compounds for controlling invertebrate pests
WO2011003796A1 (en) 2009-07-06 2011-01-13 Basf Se Pyridazine compounds for controlling invertebrate pests
US8710056B2 (en) 2009-07-06 2014-04-29 Basf Se Pyridazine compounds for controlling invertebrate pests
US9125414B2 (en) 2009-07-24 2015-09-08 Basf Se Pyridine derivatives compounds for controlling invertebrate pests
US20110130380A1 (en) * 2009-09-04 2011-06-02 Barsanti Paul A Heteroaryl Kinase Inhibitors
US10801028B2 (en) 2009-10-14 2020-10-13 Beeologics Inc. Compositions for controlling Varroa mites in bees
US8981084B2 (en) 2010-01-13 2015-03-17 Tempero Pharmaceuticals, Inc. Oxadiazole HDAC inhibitors
US9121022B2 (en) 2010-03-08 2015-09-01 Monsanto Technology Llc Method for controlling herbicide-resistant plants
US11812738B2 (en) 2010-03-08 2023-11-14 Monsanto Technology Llc Polynucleotide molecules for gene regulation in plants
US9988634B2 (en) 2010-03-08 2018-06-05 Monsanto Technology Llc Polynucleotide molecules for gene regulation in plants
WO2011117806A2 (en) 2010-03-23 2011-09-29 Basf Se Pyridazine compounds for controlling invertebrate pests
US8937177B2 (en) 2010-03-23 2015-01-20 Basf Se Pyridazine compounds for controlling invertebrate pests
WO2011117213A1 (en) 2010-03-23 2011-09-29 Basf Se Pyridazine compounds for controlling invertebrate pests
WO2011117806A3 (en) * 2010-03-23 2012-03-01 Basf Se Pyridazine compounds for controlling invertebrate pests
US20130012382A1 (en) * 2010-03-23 2013-01-10 Basf Se Pyridazine Compounds for Controlling Invertebrate Pests
US9290507B2 (en) 2010-03-26 2016-03-22 Boehringer Ingelheim International Gmbh B-RAF kinase inhibitors
US8865703B2 (en) 2010-03-26 2014-10-21 Boehringer Ingelheim International Gmbh Pyridyltriazoles
US9090612B2 (en) 2010-04-27 2015-07-28 Calcimedica, Inc. Compounds that modulate intracellular calcium
EP2563759A2 (en) * 2010-04-27 2013-03-06 Calcimedica, Inc. Compounds that modulate intracellular calcium
US8754219B2 (en) 2010-04-27 2014-06-17 Calcimedica, Inc. Compounds that modulate intracellular calcium
US9353099B2 (en) 2010-04-27 2016-05-31 Calcimedica, Inc. Compounds that modulate intracellular calcium
EP2563759A4 (en) * 2010-04-27 2013-10-23 Calcimedica Inc Compounds that modulate intracellular calcium
US10206401B2 (en) 2010-09-13 2019-02-19 Basf Se Pyridine compounds for controlling invertebrate pests II
CN103097376A (en) * 2010-09-13 2013-05-08 巴斯夫欧洲公司 Pyridine compounds for controlling invertebrate pests ii
WO2012034960A1 (en) * 2010-09-13 2012-03-22 Basf Se Pyridine compounds for controlling invertebrate pests ii
US8710055B2 (en) 2010-12-21 2014-04-29 Boehringer Ingelheim International Gmbh Triazolylphenyl sulfonamides as serine/threonine kinase inhibitors
US9056843B2 (en) 2011-07-08 2015-06-16 Novartis Ag Trifluoromethyl-oxadiazole derivatives and their use in the treatment of disease
US10808249B2 (en) 2011-09-13 2020-10-20 Monsanto Technology Llc Methods and compositions for weed control
WO2013040117A1 (en) 2011-09-13 2013-03-21 Monsanto Technology Llc Methods and compositions for weed control
EP3382027A2 (en) 2011-09-13 2018-10-03 Monsanto Technology LLC Methods and compositions for weed control
US10806146B2 (en) 2011-09-13 2020-10-20 Monsanto Technology Llc Methods and compositions for weed control
US9422557B2 (en) 2011-09-13 2016-08-23 Monsanto Technology Llc Methods and compositions for weed control
US9422558B2 (en) 2011-09-13 2016-08-23 Monsanto Technology Llc Methods and compositions for weed control
WO2013039990A1 (en) 2011-09-13 2013-03-21 Monsanto Technology Llc Methods and compositions for weed control
US9416363B2 (en) 2011-09-13 2016-08-16 Monsanto Technology Llc Methods and compositions for weed control
US10760086B2 (en) 2011-09-13 2020-09-01 Monsanto Technology Llc Methods and compositions for weed control
US10829828B2 (en) 2011-09-13 2020-11-10 Monsanto Technology Llc Methods and compositions for weed control
EP3296402A2 (en) 2011-09-13 2018-03-21 Monsanto Technology LLC Methods and compositions for weed control
WO2013040021A1 (en) 2011-09-13 2013-03-21 Monsanto Technology Llc Methods and compositions for weed control
EP3434779A1 (en) 2011-09-13 2019-01-30 Monsanto Technology LLC Methods and compositions for weed control
EP3434780A1 (en) 2011-09-13 2019-01-30 Monsanto Technology LLC Methods and compositions for weed control
US9670193B2 (en) 2011-11-28 2017-06-06 Novartis Ag Trifluoromethyl-oxadiazole derivatives and their use in the treatment of disease
CN103998446A (en) * 2011-11-28 2014-08-20 诺华股份有限公司 Novel trifluoromethyl-oxadiazole derivatives and their use in the treatment of disease
US10934555B2 (en) 2012-05-24 2021-03-02 Monsanto Technology Llc Compositions and methods for silencing gene expression
US10240161B2 (en) 2012-05-24 2019-03-26 A.B. Seeds Ltd. Compositions and methods for silencing gene expression
US10240162B2 (en) 2012-05-24 2019-03-26 A.B. Seeds Ltd. Compositions and methods for silencing gene expression
US10041068B2 (en) 2013-01-01 2018-08-07 A. B. Seeds Ltd. Isolated dsRNA molecules and methods of using same for silencing target molecules of interest
US10683505B2 (en) 2013-01-01 2020-06-16 Monsanto Technology Llc Methods of introducing dsRNA to plant seeds for modulating gene expression
US10609930B2 (en) 2013-03-13 2020-04-07 Monsanto Technology Llc Methods and compositions for weed control
US10612019B2 (en) 2013-03-13 2020-04-07 Monsanto Technology Llc Methods and compositions for weed control
WO2014151255A1 (en) 2013-03-15 2014-09-25 Monsanto Technology Llc Methods and compositions for weed control
US10568328B2 (en) 2013-03-15 2020-02-25 Monsanto Technology Llc Methods and compositions for weed control
US9856495B2 (en) 2013-07-19 2018-01-02 Monsanto Technology Llc Compositions and methods for controlling Leptinotarsa
US11377667B2 (en) 2013-07-19 2022-07-05 Monsanto Technology Llc Compositions and methods for controlling Leptinotarsa
US10597676B2 (en) 2013-07-19 2020-03-24 Monsanto Technology Llc Compositions and methods for controlling Leptinotarsa
US9777288B2 (en) 2013-07-19 2017-10-03 Monsanto Technology Llc Compositions and methods for controlling leptinotarsa
US9850496B2 (en) 2013-07-19 2017-12-26 Monsanto Technology Llc Compositions and methods for controlling Leptinotarsa
US10100306B2 (en) 2013-11-04 2018-10-16 Monsanto Technology Llc Compositions and methods for controlling arthropod parasite and pest infestations
US9540642B2 (en) 2013-11-04 2017-01-10 The United States Of America, As Represented By The Secretary Of Agriculture Compositions and methods for controlling arthropod parasite and pest infestations
US10927374B2 (en) 2013-11-04 2021-02-23 Monsanto Technology Llc Compositions and methods for controlling arthropod parasite and pest infestations
US10557138B2 (en) 2013-12-10 2020-02-11 Beeologics, Inc. Compositions and methods for virus control in Varroa mite and bees
WO2015108982A2 (en) 2014-01-15 2015-07-23 Monsanto Technology Llc Methods and compositions for weed control using epsps polynucleotides
US10334848B2 (en) 2014-01-15 2019-07-02 Monsanto Technology Llc Methods and compositions for weed control using EPSPS polynucleotides
US11091770B2 (en) 2014-04-01 2021-08-17 Monsanto Technology Llc Compositions and methods for controlling insect pests
US10988764B2 (en) 2014-06-23 2021-04-27 Monsanto Technology Llc Compositions and methods for regulating gene expression via RNA interference
US11807857B2 (en) 2014-06-25 2023-11-07 Monsanto Technology Llc Methods and compositions for delivering nucleic acids to plant cells and regulating gene expression
US10378012B2 (en) 2014-07-29 2019-08-13 Monsanto Technology Llc Compositions and methods for controlling insect pests
US11124792B2 (en) 2014-07-29 2021-09-21 Monsanto Technology Llc Compositions and methods for controlling insect pests
US10968449B2 (en) 2015-01-22 2021-04-06 Monsanto Technology Llc Compositions and methods for controlling Leptinotarsa
US10883103B2 (en) 2015-06-02 2021-01-05 Monsanto Technology Llc Compositions and methods for delivery of a polynucleotide into a plant
US10655136B2 (en) 2015-06-03 2020-05-19 Monsanto Technology Llc Methods and compositions for introducing nucleic acids into plants
JP2018521110A (en) * 2015-07-27 2018-08-02 チョン クン ダン ファーマシューティカル コーポレーション 1,3,4-oxadiazolamide derivative compounds as histone deacetylase 6 inhibitors and pharmaceutical compositions containing them,
US10555526B2 (en) 2015-11-05 2020-02-11 Basf Se Substituted oxadiazoles for combating phytopathogenic fungi
US10687532B2 (en) 2015-11-13 2020-06-23 Basf Se Substituted oxadiazoles for combating phytopathogenic fungi
US10492494B2 (en) 2015-11-13 2019-12-03 Basf Se Substituted oxadiazoles for combating phytopathogenic fungi
US10674727B2 (en) 2015-11-19 2020-06-09 Basf Se Substituted oxadiazoles for combating phytopathogenic fungi
US10499644B2 (en) 2015-11-19 2019-12-10 Basf Se Substituted oxadiazoles for combating phytopathogenic fungi
US10986839B2 (en) 2016-04-11 2021-04-27 Basf Se Substituted oxadiazoles for combating phytopathogenic fungi
US10785980B2 (en) 2016-06-09 2020-09-29 Basf Se Substituted oxadiazoles for combating phytopathogenic fungi
WO2018029242A1 (en) * 2016-08-11 2018-02-15 Syngenta Participations Ag Microbiocidal oxadiazole derivatives
CN112119063A (en) * 2018-05-18 2020-12-22 富士胶片株式会社 Method for producing 3-difluoromethylpyrazole compound, method for producing 3-difluoromethylpyrazole-4-carboxylic acid compound, and pyrazolidine compound
CN112119063B (en) * 2018-05-18 2023-10-17 富士胶片株式会社 Method for producing 3-difluoromethylpyrazole compound, method for producing 3-difluoromethylpyrazole-4-carboxylic acid compound, and pyrazolidine compound
US20210317103A1 (en) * 2018-08-14 2021-10-14 Biogen Ma Inc. Ask1 inhibiting agents
CN113166116A (en) * 2019-01-25 2021-07-23 北京赛特明强医药科技有限公司 Amido bridged heterocyclic compound, and composition and application thereof
AU2020210455B2 (en) * 2019-01-25 2023-02-02 Beijing Scitech-Mq Pharmaceuticals Limited Acylamino bridged heterocyclic compound, and composition and application thereof
WO2020151589A1 (en) * 2019-01-25 2020-07-30 北京赛特明强医药科技有限公司 Acylamino bridged heterocyclic compound, and composition and application thereof
US11999715B2 (en) * 2019-08-13 2024-06-04 Biogen Ma Inc. ASK1 inhibiting agents

Similar Documents

Publication Publication Date Title
WO2005040152A1 (en) Heteroyclylphenyl-and heterocyclylpyridyl-substituted azolecarboxamides as herbicides
AU2021232774B2 (en) Pyrimidinyloxy benzene derivatives as herbicides
EP2225211B1 (en) Herbicidal pyridazinone derivatives
CA2548058C (en) Herbicidal pyrimidines
AU2016303209B2 (en) Cyclic N-carboxamide compounds useful as herbicides
AU2017378640B2 (en) Nitrone herbicides
AU2014357342A1 (en) Pyrrolidinones as herbicides
US20100099561A1 (en) Heterobicyclic alkylthio-bridged isoxazolines
WO2009158258A1 (en) Herbicidal dihydro oxo six-membered azinyl isoxazolines
WO2005070889A1 (en) Herbicidal amides
AU2016259529A1 (en) Aryl substituted bicyclic compounds as herbicides
AU2016270304A1 (en) Substituted cyclic amides as herbicides
AU2016246410A1 (en) Substituted cyclic amides as herbicides
EP2120939A2 (en) Substituted pyridine n-oxide herbicides
US20060069132A1 (en) Azolecarboxamide herbicides
WO2004035545A2 (en) Azolecarboxamide herbicides
EP3271350A1 (en) Substituted pyrimidinyloxy pyridine derivatives as herbicides
AU2018244357B2 (en) Novel pyridazinone herbicides
AU2018277537A1 (en) Herbicidal amides
WO2014014904A1 (en) Substituted cycloalkyl 1,2,4-triazine-3,5-diones as herbicides
IL269625A (en) Novel pyridazinone herbicides
IL303595A (en) Substituted pyridazinone herbicides
AU2011203576B2 (en) Herbicidal Pyrimidines

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BW BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE EG ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NA NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SY TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): BW GH GM KE LS MW MZ NA SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LU MC NL PL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
122 Ep: pct application non-entry in european phase