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WO2018193387A1 - Heterocyclic compounds with microbiocidal properties - Google Patents

Heterocyclic compounds with microbiocidal properties Download PDF

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Publication number
WO2018193387A1
WO2018193387A1 PCT/IB2018/052681 IB2018052681W WO2018193387A1 WO 2018193387 A1 WO2018193387 A1 WO 2018193387A1 IB 2018052681 W IB2018052681 W IB 2018052681W WO 2018193387 A1 WO2018193387 A1 WO 2018193387A1
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WO
WIPO (PCT)
Prior art keywords
piperidin
thiazol
dihydroisoxazol
pyridin
trifluoromethyl
Prior art date
Application number
PCT/IB2018/052681
Other languages
French (fr)
Inventor
Gajanan SHANBHAG
Ranga Prasad DODDA
Ganesh Tatya KAMBLE
Yuvraj Navanath KALE
G. Renugadevi
Sulur G MANJUNATHA
Mohan Kumar S.P.
Santosh Shridhar AUTKAR
Ruchi GARG
Hagalavadi M VENKATESHA
Jagadeesh Nanjegowda MAVINAHALLI
Alexander G.M. KLAUSENER
Original Assignee
Pi Industries Ltd.
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 Pi Industries Ltd. filed Critical Pi Industries Ltd.
Publication of WO2018193387A1 publication Critical patent/WO2018193387A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the present invention relates to compounds containing one or more heterocyclic rings and salts, metal complexes, N-oxides, enantiomers, stereoisomers and polymorphs thereof; compositions and methods of use for controlling or preventing phytopathogenic micro-organisms.
  • the compounds and compositions thereof of the present invention have the potential of overcoming drawbacks and are suitable for crop protection against phytopathogenic micro-organisms causing plant diseases.
  • compositions comprising, “comprising”, “includes”, “including”, “has”, “having”, “contains”, “containing”, “characterized by” or any other variation thereof, are intended to cover a nonexclusive inclusion, subject to any limitation is explicitly indicated.
  • a composition, mixture, process or method that comprises a list of elements is not necessarily limited to only those elements but may include other elements not expressly listed or inherent to such composition, mixture, process or method.
  • the term "invertebrate pest” includes arthropods, gastropods and nematodes of economic importance as pests.
  • arthropod includes insects, mites, spiders, scorpions, centipedes, millipedes, pil l bugs and symphylans.
  • gastropod includes snails, sl ugs and other Stylommatophora.
  • nematode refers to a living organism of the Phylum Nematoda.
  • helminths includes roundworms, heartworms, phytophagous nematodes (Nematoda), flukes (Tematoda), acanthocephala and tapeworms (Cestoda).
  • invertebrate pest control means inhibition of invertebrate pest development (including mortality, feeding reduction, and/or mating disruption), and related expressions are defined analogously.
  • agronomic refers to the production of field crops such as for food and fiber and includes the growth of corn, soybeans and other legumes, rice, cereal (e.g., wheat, oats, barley, rye, rice, maize), leafy vegetables (e.g., lettuce, cabbage, and other cole crops), fruiting vegetables (e.g., tomatoes, pepper, eggplant, crucifers and cucurbits), potatoes, sweet potatoes, grapes, cotton, tree fruits (e.g., pome, stone and citrus), small fruit (berries, cherries) and biofuel crops such as, jatropha, palm trees, other specialty crops (e.g., canola, sunflower, olives).
  • nonagronomic refers to other than field crops, such as horticultural crops (e.g., greenhouse, nursery or ornamental plants not grown in a field), residential, agricultural, commercial and industrial structures, turf (e.g., sod farm, pasture, golf course, lawn, sports field, etc.), wood products, stored product, agro-forestry and vegetation management, public health (i.e. human) and animal health (e.g., domesticated animals such as pets, livestock and poultry, undomesticated animals such as wildlife) applications.
  • horticultural crops e.g., greenhouse, nursery or ornamental plants not grown in a field
  • turf e.g., sod farm, pasture, golf course, lawn, sports field, etc.
  • wood products e.g., stored product, agro-forestry and vegetation management
  • public health i.e. human
  • animal health e.g., domesticated animals such as pets, livestock and poultry, undomesticated animals such as wildlife
  • Nonagronomic applications include protecting an animal from an invertebrate parasitic pest by administering a parasiticidally effective (i.e. biologically effective) amount of a compound of the present invention, typically in the form of a composition formulated for veterinary use, to the animal to be protected.
  • a parasiticidally effective (i.e. biologically effective) amount of a compound of the present invention typically in the form of a composition formulated for veterinary use, to the animal to be protected.
  • parasiticidal i.e. biologically effective
  • Parasiticidally refers to observable effects on an invertebrate parasite pest to provide protection of an animal from the pest. Parasiticidal effects typical ly relate to diminishing the occurrence or activity of the target invertebrate parasitic pest.
  • Such effects on the pest include necrosis, death, retarded growth, diminished mobility or lessened ability to remain on or in the host animal, reduced feeding and inhibition of reproduction.
  • These effects on invertebrate parasite pests provide control (including prevention, reduction or elimination) of parasitic infestation or infection of the animal.
  • Stereoisomers of the present invention may be present either in pure form or as mixtures of different possible isomeric forms such as stereoisomers or constitutional isomers.
  • the various stereoisomers include enantiomers, diastereomers, chiral isomers, atropisomers, conformers, rotamers, tautomers, optical isomers, polymorphs, and geometric isomers. Any desired mixtures of these isomers fall within the scope of the claims of the present invention.
  • one stereoisomer may be more active and/or may exhibit beneficial effects when enriched relative to the other isomer(s) or when separated from the other isomer(s). Additional ly, the person ski lled in the art knows processes or methods or technology to separate, enrich, and/or to selectively prepare said isomers.
  • alkyl used either alone or in compound words such as “alkylthio” or “haloalkyl” or -N(aikyl) or alkylcarbonylalkyl or alkylsuphonylamino includes straight-chain or branched C, to C 24 alkyl, preferably C
  • alkyl include methyl, ethyl, propyl, 1 -methylethyl, butyl, 1 -methylpropyl, 2-methylpropyl, 1 , 1 -dimethylethyl, pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1 - ethylpropyl, hexyl, 1 , 1 -dimethylpropyl, 1 ,2-dimethylpropyl, 1 -methylpentyl, 2-methylpentyl, 3- methylpentyl, 4-methylpentyl, 1 , 1 -dimethylbutyi, 1 ,2-dimethylbutyl, 1 ,3-dimethylbutyl, 2,2- dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1 -ethylbutyl, 2-ethylbutyl, 1 , 1 , 1
  • the alkyl is at the end of a composite substituent, as, for example, in alkylcycloalkyl
  • the part of the composite substituent at the start for example the cycloalkyl
  • other radicals for example alkenyl, alkynyl, hydroxyl, halogen, carbonyl, carbonyloxy and the like, are at the end.
  • alkenyl used either alone or in compound words includes straight-chain or branched C 2 to C 24 alkenes, preferably C 2 to C J5 alkenes, more preferably C 2 to C 10 alkenes, most preferably C 2 to C 6 alkenes.
  • alkenes include ethenyl, 1 -propenyl, 2-propenyl, 1 -methylethenyl, 1 -butenyl,
  • Alkenyl also includes polyenes such as 1 ,2-propadienyl and 2,4-hexadienyl. This definition also applies to alkenyl as a part of a composite substituent, for example haloalkenyl and the like, unless defined specifically elsewhere.
  • alkynes used either alone or in compound words include ethynyl, 1 -propynyl, 2-propynyl, 1 -butynyl, 2-butynyl, 3-butynyl, l -methyl-2-propynyl, 1 -pentynyl, 2-pentynyl, 3-pentynyl, 4- pentynyl, l-methyl-2-butynyl, l-methyl-3-butynyl, 2-methyl-3-butynyl, 3-methyl-l-butynyl, 1 , 1 -dimethyl- 2-propynyl, 1 -ethyl -2-propynyl, 1 -hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, l -methyl-2- pentynyl, l-methyl-3-pentynyl,
  • alkynyl as a part of a composite substituent, for example haloalkynyl etc., unless specifically defined elsewhere.
  • Alkynyl can also include moieties comprised of multiple triple bonds such as 2,5-hexadiynyl.
  • Cycloalkyl means alkyl closed to form a ring. Representative examples include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. This definition also applies to cycloalkyl as a part of a composite substituent, for example cycloalkylalkyl etc., unless specifically defined elsewhere.
  • Cycloalkenyl means alkenyl closed to form a ring including monocyclic, partially unsaturated hydrocarbyl groups. Representative examples include but are not limited to cyclopropenyl, cyclobutenyl, cyclopentenyl and cyclohexenyl. This definition also applies to cycloalkenyl as a part of a composite substituent, for example cycloalkenylalkyl etc., unless specifically defined elsewhere.
  • Cycloalkoxy, cycloalkenyloxy and the like are defined analogously.
  • Non limiting examples of cycloalkoxy include cyclopropyloxy, cyclopentyloxy and cyclohexyloxy. This definition also applies to cycloalkoxy as a part of a composite substituent, for example cycloalkoxyalkyl etc., unless specifically defined elsewhere.
  • halogen either alone or in compound words such as “haloalkyl”, includes fluorine, chlorine, bromine or iodine. Further, when used in compound words such as “haloalkyl”, said alkyl may be partially or fully substituted with halogen atoms which may be the same or different.
  • haloalkyl examples include chloromethyl, bromomethyl, iodomethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chlorofluoromethyl, dichlorofluoromethyl, chlorodifluoromethyl, 1 -chloroethyl, 1 -bromoethyl, 1 -fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2- trifluoroethyl, 2-chloro-2-fluoroethyl, 2-chloro-2,2-difluoroethyl, 2,2-dichloro-2-fluoroethyl, 2,2,2- trichloroethyl, pentafiuoroetbyl, ] , l -dichloro-2,2,2-trifluoroethyl, and l , l , l l
  • haloalkenyl and “haloalkynyl” are defined analogously except that, instead of alkyl groups, alkenyl and alkynyl groups are present as a part of the substituent.
  • ha!oalkoxy means straight-chain or branched alkoxy groups where at least one up to all of the hydrogen atoms in these groups may be replaced by halogen atoms as specified above.
  • haloalkoxy include chloromethoxy, iodomethoxy, bromomethoxy, dichloromethoxy, trichloromethoxy, fluoromethoxy, difluoromefhoxy, trifluoromethoxy, chlorofluoromethoxy, dichlorofluoromethoxy, chlorodifluoromethoxy, 1 -chloroethoxy, 1 -bromoethoxy, 1 -fluoroethoxy, 2- fluoroethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, 2-chloro-2-fluoroethoxy, 2-chloro-2,2- difluoroethoxy, 2,2-dichloro-2-fluoroethoxy, 2,2,2-trichloro
  • haloalkylthio means straight-chain or branched alkylthio groups where at least one up to all of the hydrogen atoms in these groups may be replaced by halogen atoms as specified above.
  • Non-limiting examples of haloalkylthio include chloromethylthio, iodomethylthio, bromomethylthio, dichloromethylthio, trichloromethylthio, fluoromethylthio, difluoromethylthio, trifluoromethylthio, chlorofluoromethylthio, dichlorofluoromethylthio, chlorodifluoromethylthio, 1 -chloroethylthio, 1 - bromoethylthio, 1 - fluoroethylthio, 2-fluoroethylthio, 2,2-difluoroethylthio, 2,2,2-trifluoroethylthio, 2- chloro-2- fluoroethylthio, 2-ch
  • haloalkylsulfinyl examples include CF 3 S(0), CC1 3 S(0), CF 3 CH 2 S(0) and CF 3 CF 2 S(0).
  • haloalkylsulfonyl examples include CF 3 S(0) 2 , CC1 3 S(0) 2 , CF 3 CH 2 S(0) 2 and CF 3 CF 2 S(0) 2 .
  • Hydroxy means -OH, amino means -NRR, wherein R can be H or any possible substituent such as alkyl.
  • Carbonyl means -C(O)-, carbonyloxy means -OC(O)-, sulfinyl means SO, sulfonyl means S(0) 2 .
  • alkoxy used either alone or in compound words included Cj to C 24 alkoxy, preferably C , to C is alkoxy, more preferably C
  • alkoxy include methoxy, ethoxy, propoxy, 1 -methyl ethoxy, butoxy, 1 -methylpropoxy, 2-methylpropoxy, 1 , 1 - dimethylethoxy, pentoxy, 1 -methyl butoxy, 2-methylbutoxy, 3-methylbutoxy, 2,2-dimethylpropoxy, 1 - ethylpropoxy, hexoxy, 1 , 1 -dimethylpropoxy, 1 ,2-dimethylpropoxy, 1 -methylpentoxy, 2-methylpentoxy, 3-methylpentoxy, 4-methy I pentoxy, 1 , 1 -dimethylbutoxy, 1 ,2-dimethylbutoxy, 1 ,3-dimethylbutoxy, 2,2- dimethylbutoxy, 2,3
  • Alkoxyalkyl denotes alkoxy substitution on alkyl.
  • alkoxyalkyl include CH 3 OCH 2 , CH 3 OCH 2 CH 2 , CH 3 CH 2 OCH 2 , CH 3 CH 2 CH 2 CH 2 OCH 2 and CH 3 CH 2 OCH 2 CH 2 .
  • alkoxyalkoxy denotes alkoxy substitution on alkoxy.
  • alkylthio includes branched or straight-chain alkylthio moieties such as methylthio, ethylthio, propylthio, 1 -methylethylthio, butylthio, 1 -methylpropylthio, 2-methylpropylthio, 1 , 1 -dimethylethylthio, pentylthio, 1 -methylbutylthio, 2-methylbutylthio, 3-methylbutylthio, 2,2-dimethylpropylthio, 1 - ethylpropylthio, hexylthio, 1 , 1 -dimethylpropylthio, 1 ,2-dimethylpropylthio, 1 -methylpentylthio, 2- methylpentylthio, 3-methylpentylthio, 4-rnethylpentylthio, 1 , 1 -dimethylbutylthio, 1 ,2-di
  • Halocycloalkyl, halocycloalkenyl, alkylcycloalkyl, cycloalkylalkyl, cycloalkoxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, haloalkylcarbonyl, cycloalkylcarbonyl, haloalkoxylalkyl, and the like, are defined analogously to the above examples.
  • alkylthioalkyl denotes alkylthio substitution on alkyl.
  • Representative examples of “alkylthioalkyl” include -CH 2 SCH 2 , -CH 2 SCH 2 CH 2 , CH 3 CH 2 SCH 2 , CH 3 CH 2 CH 2 CH 2 SCH 2 and CH 3 CH 2 SCH 2 CH 2 .
  • Alkylthioalkoxy denotes alkylthio substitution on alkoxy.
  • cycloalkylalkylamino denotes cycloalkyl substitution on alkyl amino.
  • alkoxyalkoxyalkyl alkylaminoalkyl, dialkylaminoalkyl, cycloalkylaminoalkyl, cycloalkylaminocarbonyl and the like, are defined analogously to "alkylthioalkyl” or cycloalkylalkylamino.
  • alkoxycarbonyl is an alkoxy group bonded to a skeleton via a carbonyl group (-CO-). This definition also applies to alkoxycarbonyl as a part of a composite substituent, for example cycloalkylalkoxycarbonyl and the like, unless specifically defined elsewhere.
  • alkoxycarbonylalkylamino denotes alkoxy carbonyl substitution on alkyl amino.
  • Alkylcarbonylalkylamino denotes alkyl carbonyl substitution on alkyl amino.
  • alkylthioalkoxycarbonyl, cycloalkylalkylaminoalkyl and the like are defined analogously.
  • alkylsulfinyl examples include but are not limited to methylsulphinyl, ethylsulphinyl, propylsulphinyl, 1 -methylethylsulphinyl, butylsulphinyl, 1 -methylpropylsulphinyl, 2- methylpropylsulphinyl, 1 , 1 -dimethylethyIsulphinyl, pentylsulphinyl, 1 -methylbutylsulphinyl, 2- methylbutylsulphinyl, 3-methylbutylsulphinyl, 2,2-dimethylpropylsulphinyl, 1 -ethylpropylsulphinyl, hexylsu!phinyi, 1 , 1 -dimethylpropylsulphinyl, 1 ,2-dimethylpropylsulphinyl, 1 -methylpentylsulphinyl, 2- methylpentyl
  • arylsulfinyl includes Ar-S(O), wherein Ar can be any carbocyle or heterocylcle. This definition also appl ies to alkylsulphinyl as a part of a composite substituent, for example haloalkylsulphinyl etc., unless specifically defined elsewhere.
  • alkylsulfonyl examples include but are not l imited to methylsulphonyl, ethylsulphonyl, propylsulphonyl, 1 -methylethylsulphonyl, butylsulphonyl, 1 -methylpropylsulphonyl, 2- methylpropylsulphonyl, 1 , 1 -dimcthylethylsulphonyl, pentylsulphonyl, 1 -methylbutylsulphonyl, 2- methylbutylsulphonyl, 3-methy!butylsulphonyl, 2,2-dimethylpropylsulphonyl, 1 -ethylpropylsulphonyl, hexylsulphonyl, 1 , 1 -dimethylpropylsulphonyl, 1 ,2-dimethylpropylsulphonyl, 1 -methylpentylsulphonyl,
  • arylsulfonyl includes Ar-S(0) 2 , wherein Ar can be any carbocyle or heterocylcle. This definition also applies to alkylsulphonyl as a part of a composite substituent, for example alkylsulphonylalkyl etc., unless defined elsewhere.
  • Alkylamino "dialkylamino”, and the like, are defined analogously to the above examples.
  • carrier or “carbocyclic” or “carbocyclyl” include “aromatic carbocyclic ring system” and “nonaromatic carbocylic ring system” or polycyclic or bicyclic (spiro, fused, bridged, nonfused) ring compounds in which the ring may be aromatic or non-aromatic (where aromatic indicates that the Hueckel rule is satisfied and non-aromatic indicates that the Hueckel rule is not statisfied).
  • non-aromatic heterocycle means three- to fifteen-membered, preferably three- to twelve- membered, saturated or partially unsaturated heterocycles containing one to four heteroatoms from the group of oxygen, nitrogen and sulphur: mono, bi- or tricyclic heterocycles which contain, in addition to carbon ring members, one to three n atoms and/or one oxygen or sulphur atom or one or two oxygen and/or sulphur atoms; if the ring contains more than one oxygen atom, they are not directly adjacent; for example (but not limited to) oxiranyl, aziridinyl, 2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2- tetrahydrothienyl, 3-tetrahydrothienyl, 2-pyrrolidinyl, 3-pyrrol idinyl, 3-isoxazolidinyl, 4-isoxazolidinyl, 5-isoxazolidinyl, 3-isothiazo
  • heteroaryl means 5 or 6-membered, fully unsaturated monocyclic ring system containing one to four heteroatoms from the group of oxygen, n and sulphur; if the ring contains more than one oxygen atom, they are not directly adjacent; 5-membered heteroaryl containing one to four n atoms or one to three n atoms and one sulphur or oxygen atom: 5-membered heteroaryl groups which, in addition to carbon atoms, may contain one to four n atoms or one to three n atoms and one sulphur or oxygen atom as ring members, for example (but not limited thereto) 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyrrolyl, 3- pyrrolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 3- pyrazolyl
  • 6-membered heteroaryl which contains one to four n atoms: 6-membered heteroaryl groups which, in addition to carbon atoms, may contain, respectively, one to three and one to four n atoms as ring members, for example (but not limited thereto) 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 3-pyridazinyl, 4- pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 2-pyrazinyl, I,3,5-triazin-2-yl, l,2,4-triazin-3-yl and l,2,4,5-tetrazin-3-yl; benzofused 5-membered heteroaryl containing one to three n atoms or one n atom and one oxygen or sulphur atom: for example (but not limited to) indol-l-yl, indol-2-yl, indol-3-yl, indo
  • heteroaryl as a part of a composite substituent, for example heteroarylalkyl etc., unless specifically defined elsewhere.
  • Trialkylsilyl includes 3 branched and/or straight-chain alkyl radicals attached to and linked through a silicon atom such as trimethylsilyl, triethylsilyl and t-butyl-dimethylsilyl.
  • Hydrochalotrialkylsilyl denotes at least one of the three alkyl radicals is partially or fully substituted with halogen atoms which may be the same or different.
  • Alkoxytrialkylsilyl denotes at least one of the three alkyl radicals is substituted with one or more alkoxy radicals which may be the same or different.
  • Trialkylsilyloxy denotes a trialkylsilyl moiety attached through oxygen.
  • Examples of “a!kylcarbonyl” include C(0)CH 3 , C(0)CH 2 CH 2 CH 3 and C(0)CH(CH 3 ) 2 .
  • haloalkylsufonylaminocarbonyl, alkylsulfonylaminocarbonyl, alkylthioalkoxycarbonyl, alkoxycarbonylalkyl amino and the like are defined analogously
  • the total number of carbon atoms in a substituent group is indicated by the "Q-C " prefix where i and j are numbers from 1 to 21 .
  • C 1 -C 3 alkylsulfonyl designates methylsulfonyl through propylsulfonyl
  • 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 .
  • all substituents are attached to these rings through any available carbon or n by replacement of a hydrogen on said carbon or n
  • fragments 1 , 3 and 5 are capable of forming two double bonds inside the ring by tautomerization as shown below and exist in tautomeric forms 2, 4 and 6 respectively, fragments 1 , 3 and 5 and tautomers thereof i.e., 2, 4 and 6 are included within the definition of the term "fragments and tautomeric forms thereof having two double bonds inside the ring".
  • pest for the purpose of the present invention includes but is not limited to fungi, stramenopiles (oomycetes), bacteria, nematodes, mites, ticks, insects and rodents.
  • Plant is understood here to mean all plants and plant populations, such as desired and undesired wild plants or crop plants (including naturally occurring crop plants).
  • Crop plants may be plants which can be obtained by conventional breeding and optimization methods or by biotechnological and genetic engineering methods or combinations of these methods, including the transgenic plants and including the plant cultivars which are protectable and non-protectable by plant breeders' rights.
  • plant includes a living organism of the kind exemplified by trees, shrubs, herbs, grasses, ferns, and mosses, typically growing in a site, absorbing water and required substances through its roots, and synthesizing nutrients in its leaves by photosynthesis.
  • plant for the purpose of the present invention include but are not limited to agricultural crops such as wheat, rye, barley, triticale, oats or rice; beet, e.g. sugar beet or fodder beet; fruits and fruit trees, such as pomes, stone fruits or soft fruits, e.g.
  • leguminous plants such as lenti ls, peas, alfalfa or soybeans; oil plants, such as rape, mustard, olives, sunflowers, coconut, cocoa beans, castor oil plants, oil palms, ground nuts or soybeans; cucurbits, such as squashes, cucumber or melons; fiber plants, such as cotton, flax, hemp or jute; citrus fruit and citrus trees, such as oranges, lemons, grapefruits or mandarins; any horticultural plants, vegetables, such as spinach, lettuce, asparagus, cabbages, carrots, onions, tomatoes, potatoes, cucurbits or paprika; lauraceous plants, such as avocados, cinnamon or camphor; cucurbitaceae; oleaginous plants; energy and raw material plants, such as cereals, corn, soybean, other leguminous plants, rape, sugar cane or oil palm; tobacco; nuts;
  • the plant for the purpose of the present invention include but is not limited to cereals, corn, rice, soybean and other leguminous plants, fruits and fruit trees, grapes, nuts and nut trees, citrus and citrus trees, any horticultural plants, cucurbitaceae, oleaginous plants, tobacco, coffee, tea, cacao, sugar beet, sugar cane, cotton, potato, tomato, onions, peppers and vegetables, ornamentals, any floricultural plants and other plants for use of human and animals.
  • plant parts is understood to mean all parts and organs of plants above and below the ground.
  • plant parts includes but is not limited to cuttings, leaves, twigs, tubers, flowers, seeds, branches, roots including taproots, lateral roots, root hairs, root apex, root cap, rhizomes, slips, shoots, fruits, fruit bodies, bark, stem, buds, auxiliary buds, meristems, nodes and internodes.
  • locus thereof includes soil, surroundings of plant or plant parts and equipment or tools used before, during or after sowing/planting a plant or a plant part.
  • compositions optionally comprising other compatible compounds to a plant or a plant material or locus thereof include application by a technique known to a person skilled in the art which include but is not limited to spraying, coating, dipping, fumigating, impregnating, injecting and dusting.
  • adhered means adhered to a plant or plant part either physically or chemically including impregnation.
  • the present invention relates to a compound of Formula I,
  • the present invention is inclusive of salts, metal complexes, N-oxides, isomers, and polymorphs of the compound of Formula I.
  • compound of formula I containing fragment of Formula II and tautormeric forms of such fragments having two double bonds inside the ring of Formula II when v is 1 are excluded from the scope of the present invention.
  • the compound X is excluded from the scope of the present invention since the compound X undergoes tautomerization to have two double bonds as shown in Y.
  • v is an integer ranging from 0 to 3.
  • the fragment of Formula II is a four membered ring.
  • the fragment of Formula II is a five, six and seven membered ring respectively.
  • the subsequent ring members of the fragment of Formula II being added as a result of definition of "v" have the same meaning as defined for X 1 , X 2 , X 3 and X 4 .
  • X 4a is the new ring member and has the same meaning as defined for X', X 2 , X 3 and X 4 .
  • v is an integer ranging from 0 to 2.
  • p is an integer ranging from 0 to 10. Particularly, p is an integer ranging from 0 to 8.
  • the indication for example for the purpose of this invention shall mean to include the rings with all the single bonds or all the possible double bonds, depending on the valency of the ring member or the possible combinations of single and double bonds.
  • T is selected from Tl to Tl 17
  • Non-limiting representative examples of T are depicted herein below wherein the bond at the right is attached to A as shown.
  • the substituent R' may be attached to at least one possible position.
  • the substituent R" has the same meaning as R' excluding hydrogen.
  • A is C(R I 5 ) 2 or C(R 15 ) 2 -C(R l5 ) 2 or NR 16 .
  • the substituent R 15 is independently selected from hydrogen, halogen, cyano, hydroxy, -CHO, C 1 - C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 haloalkyl, C 2 -C 4 haloalkenyl, C 2 -C 4 haloalkynyl, C 2 -C 4 alkoxyalkyl, C 2 -C 4 alkylthioalkyl, C 2 -C 4 alkylsulfinylalkyl, C 2 -C 4 alkylsulfonylalkyl, C 2 -C 4 alkylcarbonyl, C 2 -C 4 haloalkylcarbonyl, C 2 -C 5 alkoxycarbonyl, C 3 -C 5 alkoxycarbonylalkyl, C 2 -C 5 alkylaminocarbonyl, C 3 -C 5 dialkylaminocarbonyl
  • the substituent R 15 is hydrogen, halogen, cyano, hydroxy, -CHO, C 1 -C 4 alkyl, C 1 - C 4 haloalkyl or C 2 -C 5 alkoxycarbonyl.
  • the substituent R 16 is hydrogen, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 haloalkyl, C 2 -C 4 haloalkenyl, C 2 -C 4 haloalkynyl, C 2 -C 4 alkoxyalkyl, C 2 -C 4 alkylthioalkyl, C 2 -C 4 alkylsulfinylalkyl, C 2 - C 4 alkylsulfonylalkyl, C 2 -C 4 alkylcarbonyl, C 2 -C 4 haloalkylcarbonyl, C 2 -C 5 alkoxycarbonyl, C 3 - C 5 alkoxycarbonylalkyl, C 2 -C 5 alkylaminocarbonyl, C 3 -C 5 dialkylaminocarbonyl, C 1 -C 4 alkylsulfonyl and C
  • the substituent R 16 is hydrogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 2 -C 4 alkylcarbonyl, C 2 -C 4 haloalkylcarbonyl or C 2 -C 4 alkoxycarbonyl.
  • W is O or S.
  • R 2 is independently hydrogen, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, halogen, cyano or hydroxyl .
  • R 2 are taken together as C 1 -C 4 alkylene or C 2 -C 4 alkenylene to form a bridged bicyclic or fused bicyclic ring system.
  • R 2 independently is selected from C 1 -C 2 alkyl, C 1 -C 2 haloalkyl, C 1 -C 2 alkoxy, halogen, cyano and hydroxy.
  • Z is C or N.
  • n is an integer ranging from 0 to 9 with a proviso that when Z is N, "n” is an integer ranging from 0 to 8; and when the presentation in ring D is a double bond then "n" is an integer
  • G is an optionally substituted 5- or 6- membered heteroaromatic ring or 5- or 6-membered saturated or partially saturated or unsaturated heterocyclic ring.
  • G is a 5- or 6 membered heteroaromatic ring or 5- or 6- membered saturated or partially saturated or unsaturated heterocyclic ring, each ring optionally substituted with up to 2 substituents in case of 5- membered ring and up to 3 substituents in case of 6- membered ring, each substituent selected from R 3 on carbon ring members and R 1 1 on n ring members.
  • G is a 5- or 6 membered heteroaromatic ring each ring optionally substituted with up to 2 substituents in case of 5- membered ring and up to 3 substituents in case of 6- membered ring, wherein in at least one of the hetero atoms is N; and the other heteroatom is N or S or O.
  • the substituents on G are R 3 on carbon ring members and R l ! on n ring members.
  • G is a 5- membered heteroaromatic ring each ring optionally substituted with up to 1 substituents, wherein in at least one of the hetero atoms is N; and the other heteroatom is S or O.
  • G is selected from the G l to G62 as de icted herein below:
  • each R 3a is independently H or R 3 and each R l l a is independently H or R".
  • R 3 and R" may be attached to any or all of the possible position/s.
  • the substituent R 3 is a phenyl or 5- or 6-membered heteroaromatic ring optionally substituted with 1 to 2 substituents independently selected from R 4a on carbon ring members and R 4b on n ring members.
  • R 3 is independently C 1 -C 3 alkyl, C 1 -C 3 haloalkyl or halogen.
  • the substituent R 4a is independently C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 - Cio cycloalkylalkyl, C 4 -C 10 alkylcycloalkyl, C 5 -C 10 alkylcycloalkylalkyl, C 1 -C 6 haloalkyl, C 2 - C 6 haloalkenyl, C 2 -C 6 haloalkynyl, C 3 -C 6 halocycloalkyl, halogen, hydroxy, amino, cyano, nitro, C 1 - C 4 alkoxy, Ci-C 4 haloalkoxy, C 1 -C 4 alkyl thio, C 1 -C 4 alkyl sulfinyl, C 1 -C 4 alkylsulfonyl, C 1 - C 4 haloalky
  • the substituent R 4b is independently C 1 -C 6 alkyl, C 3 -C 6 alkenyl, C 3 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 1 - C 6 haloalkyl, C 3 -C 6 haloalkenyl, C 3 -C 6 haloalkynyl, C 3 -C 6 halocycloalkyl or C 2 -C 4 alkoxyalkyl .
  • the substituent R" is independently C 1 -C 3 alkyl.
  • J is a 5- or 6- membered ring, wherein ring members are selected from carbon, up to 3 N and up to 2 O.
  • J is a 5- or 6- membered ring, wherein ring members are selected from carbon, 1 N and 1 O.
  • J is selected from J l to J86 as depicted herein below:
  • bond on the left is attached to Z 1 and R 3 may be substituted at any or all of the possible position/s and is a single or a double bond.
  • J is selected from and wherein W is C(R 5 ) 2 or CO or O or S or SO or S0 2 or NR 5 .
  • R 5 is -Z 2 Q.
  • the substituents R 25 and R 26 are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, C 2 -C 6 alkylcarbonyl, C 2 -C 6 haloalkylcarbonyl, C 2 -C 6 alkoxycarbonyl, C 2 -C 6 haloalkoxycarbonyl.
  • R 25 and R 26 can be -Z 4 Q.
  • the carbon to which Q is attached may be chiral or non-chiral carbon.
  • the substituents R 17 and R 18 are independently C 1 -C 5 alkyl, C 2 -C 5 alkenyl, C 2 -C 5 alkynyl, C 3 - C 5 cycloalkyl, C 3 -C 6 halocycloalkyl, C 4 -C 10 cycloalkylalkyl, C 4 -C 7 alkylcycloalkyl, C 5 - C 7 alkylcycloalkylalkyl, C 1 -C 5 haloalkyl, C 1 -C 5 alkoxy and C 1 -C 5 haloalkoxy.
  • Q are depicted herein below wherein the bond at the left is attached to J or Z as the case may be.
  • the substituent R 7 may be attached to any possible position/s and the presentation " is a single or a double bond.
  • J & Q together forms aryl or heterocyclic dioxepine ring system.
  • J & Q together forms a fragment selected from M l and M2.
  • the substituents R 5 , R 7 and R 12 may be attached at one or more possible position/s.
  • x is an integer ranging from 0 to 2 and Y is selected from O, S & N.
  • Two R' of Formula II may form a bridged ring system.
  • X' and X 3 may be connected through for example either of -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 - or -CH 2 CH 2 CH 2 CH 2 - to form a bridged ring system.
  • X 2 and X 3 may be connected to either of -CH 2 -, -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH 2 (CH 3 )CFI 2 -, or -CH 2 (CH 3 )CH 2 (CH 3 )-.
  • the substituent R 8 is independently selected from C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 - C 6 cycloalkyl, C 4 -C 10 cycloalkylalkyl, C 4 -C 10 alkylcycloalkyl, C 5 -C 10 alkylcycloalkylalkyl, C 1 - C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, C 3 -C 6 halocycloalkyl, halogen, hydroxy, amino, cyano, nitro, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, C 1 -C 4 alkylthio, C 1 -C 4 alkylsulfinyl, C 1 -C 4 alkylsulfonyl, C 1 -C 4 haloal
  • the substituent R 20 is independently hydrogen, C 1 -C 4 alkyl or C 1 -C 4 haloalkyl.
  • the substituent R 21 is independently hydrogen, C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, C 3 -C 8 cycloalkyl, C 2 -C 6 alkylcarbonyl, C 2 -C 8 haloalkylcarbonyl, C 2 -C 8 alkoxycarbonyl or C 2 -C 8 haloalkoxycarbonyl.
  • a is an integer independently ranging from 0 to 2.
  • Non-limiting compounds of the present invention comprise:
  • Compound No.360 l-(2-(4-(4-(5-(2,5-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l- yl)-2-oxoethyl)-3-isocyano-5-(trifluoiOmethyl)pyridin-2(lH)-one;
  • Compound No.361 3-bromo-l-(2-(4- (4-(l,5-dihydrobenzo[e][l,3]dioxepin-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-5- (trifluoromethyl)pyridin-2(lH)-one;
  • Compound No.360 l-(2-(4-(4-(4-(5-(2,5-difluorophenyl)-4,5-dihydroisoxazol-3-
  • Compound No. 402 l-(2-(4-(4-(5-(2-bromo-5-fluorophenyl)-4,5-dihydroisoxazol-3- yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-3-(trifluoromethyl)pyridin-2(lH)-one;
  • Compound No.403 1- (2-(4-(4-(4-(5-(3,5-dichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-5- (trif]uoromethyl)pyridin-2(lH)-one; Compound No.
  • Compound No. 506 l-(2-(4-(4-(3-(2,6-difluorophenyl)-lH-pyrazol-l-yl)thiazol-2-yl)piperidin-l-yl)-2- oxoethyl)-3-(trifluoromethyl)pyridin-2(lH)-one;
  • Compound No. 507 5-chloro-l-(2-(4-(4-(4-(3-(2,6- difluorophenyl)-! H-pyrazol-l-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-3-(trifluoromethyl)pyridin-
  • 641 6-chloro-l-(2-(4-(4-(5-(2,6- difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-3- (trifluoromethyl)pyridin-2(lH)-one; Compound No.
  • 642 6-chloro-l-(2-(4-(4-(5-(2,6-dichlorophenyl)- 4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-3-(trifluoromethyl)pyridin-2(
  • R 22 is hyrdoxy, bromine, chlorine, iodine or O- C 1 -C 4 alkyl.
  • corresponding C 1 -C 3 alkyl ester or acyl chloride can prepared by alkylating 2-oxo compound (equivalent to C of example 16) using C 1 -C 3 alkyl 2-haloacetate to obtain C 1 -C 3 alkylated 2-oxo compound (equivalent to D of example 16).
  • C 1 -C 3 alkylated 2-oxo compound is then optionally hydrolyzed to obtain an acid (equivalent to E of example 16).
  • the C 1 -C 3 alkylated 2-oxo compound obtained in the first step or the acid obtained in the second step is halogenated using suitable halogenating agent to obtain acyl halide.
  • novel and inventive compounds of the present invention are effective in preventing against and controlling phytopathogenic micro-organisms.
  • An anion part of the salt in case the compound of Formula I is cationic or capable of forming a cation can be inorganic or organic.
  • a cation part of the salt in case the compound of Formula I is an anionic or capable of forming anion can be inorganic or organic.
  • inorganic anion part of the salt examples include but are not limited to chloride, bromide, iodide, fluoride, sulfate, phosphate, nitrate, nitrite, hydrogen carbonates, hydrogen sulfate.
  • organic anion part of the salt examples include but are not limited to formate, alkanoates, carbonates, acetates, trifluoroacetate, trichloroacetate, propionate, glycolate, thiocyanate, lactate, succinate, malate, citrates, benzoates, cinnamates, oxalates, alkylsulphates, alkylsulphonates, arylsulphonates aryldisulphonates, alkylphosphonates, arylphosphonates, aryldiphosphonates, p-toluenesulphonate, and salicylate.
  • inorganic cation part of the salt examples include but are not limited to alkali and alkaline earth metals.
  • organic cation part of the salt include but are not limited to pyridine, methyl amine, imidazole, benzimidazole, hitidine, phosphazene, tetramethyl ammonium, tetrabutylammonium, choline and tri methyl amine.
  • Metal ions in metal complexes of the compound of Formula I are especially the ions of the elements of the second main group, especially calcium and magnesium, of the third and fourth main group, especially aluminium, tin and lead, and also of the first to eighth transition groups, especially chromium, manganese, iron, cobalt, nickel, copper, zinc and others. Particular preference is given to the metal ions of the elements of the fourth period and the first to eighth transition groups.
  • the metals can be present in the various valencies that they can assume.
  • the present invention also relates to the compound of Formula I, in the composition with one or more inert carriers for controlling or preventing against phytopathogenic micro-organisms.
  • the compound of Formula I of the present invention in the composition can be agriculturally acceptable salts, metal complexes, constitutional isomers, stereo-isomers. diastereoisomers, enantiomers, chiral isomers, atropisomers, conformers, rotamers, tautomers, optical isomers, polymorphs, geometric isomers, or N-oxides thereof.
  • the excipient can be an inert carrier or any other essential ingredient such as surfactants, additives, solid diluents and liquid diluents.
  • the present invention also relates to the compound of Formula I in the composition comprising at least one active compatible compound selected from fungicides, insecticides, nematicides, acaricides, biopesticides, herbicides, plant growth regulators, antibiotics, fertiliers and nutrients.
  • active compatible compounds selected from fungicides, insecticides, nematicides, acaricides, biopesticides, herbicides, plant growth regulators, antibiotics, fertiliers and nutrients.
  • active compatible compounds selected from fungicides, insecticides, nematicides, acaricides, biopesticides, herbicides, plant growth regulators, antibiotics, fertiliers and nutrients.
  • the concentration of the compound of present invention in the composition ranges from 1 to 90% by weight with respect to the total weight of the composition, preferably from 5 to 50% by weight with respect to the total weight of the composition.
  • fungicides, insecticides, nematicides, acaricides, biopesticides, herbicides, plant growth regulators, antibiotics and nutrients can be combined with at least one compound of the Formula I of the present invention.
  • fungicides, insecticides, nematicides, acaricides, biopesticides, herbicides, plant growth regulators, antibiotics, fertilizers and nutrients disclosed and reported in WO2016156129 can be combined with at least one compound of the Formula I of the present invention.
  • fungicides insecticides, nematicides, acaricides, biopesticides, herbicides, plant growth regulators, antibiotics, fertilizers and nutrients reported in WO20161 56129 are incorporated herein by way of reference as non-limiting examples to be combined with at least one compound of the Formula I of the present invention.
  • the present invention also relates to a use of the compound of Formula 1 or of the compound of Formula 1 in the composition for control ling or preventing against phytopathogenic micro-organisms such as fungi, stramenopiles, bacteria, insects, nematodes, mites in agricultural crops and or horticultural crops.
  • phytopathogenic micro-organisms such as fungi, stramenopiles, bacteria, insects, nematodes, mites in agricultural crops and or horticultural crops.
  • the present invention also relates to a use of the compound of Formula I or of the compound of Formula I in the composition for controlling or preventing against phytopathogenic fungi and oomycetes in agricultural crops and or horticulture crops.
  • the compound of Formula I or the compound of Formula I in the composition may be used to treat several fungal pathogens.
  • pathogens of fungal diseases include:
  • Albugo species for example Albugo Candida
  • Bremia species for example Bremia lactucae
  • Peronospora species for example Peronospora pisi or P. brassicae
  • Phytophthora species for example Phytophthora infestans
  • Plasmopara species for example Plasmopara viticola
  • Pseiidoperonospora species for example Pseudoperonospora hiimuli or Pseiidoperonospora cubensis
  • Pythium species for example Pythhim 8%
  • Blumeria species for example Blumeria graminis
  • Podosphaera species for example Podosphaera leucotricha
  • Sphaerotheca species for example Sphaerotheca fuliginea
  • Uncinula species for example Uncinula necator
  • Erysiphe species for example Erysiphe cichoracearu
  • Gymnosporangium species for example Gymnosporangium sabinae
  • Hemileia species for example Hemileia vastatrix
  • Phakopsora species for example Phakopsora pachyrhizi or Phakopsora meibomiae
  • Puccinia species for example Puccinia recondita, Puccinia graminis oder Puccinia striiformis
  • Uromyces species for example Uromyces appendiculatus
  • ear and panicle diseases caused, for example, by Alternaria species, for example Alternaria spp.; Aspergillus species, for example Aspergillus flavus; Cladosporium species, for example Cladosporium cladosporioides; Claviceps species, for example Claviceps purpurea; Fusarium species, for example Fusarium culmorum; Gibberella species, for example Gibberella zeae; Monographella species, for example Monographella nivalis; Stagnospora species, for example Stagnospora nodorum; diseases caused by smut fungi, for example Sphacelotheca species, for example Sphacelotheca reiliana; Tilletia species, for example Tilletia caries or Tilletia controversa; Urocystis species, for example Urocystis occulta; Ustilago species, for example Ustilago nuda;
  • Alternaria species for example Alternaria brassicicola
  • Aphanomyces species for example Aphanomyces euteiches
  • Ascochyta species for example Ascochyta lends
  • Aspergillus species for example Aspergillus flavus
  • Cladosporium species for example Cladosporium herbarum
  • Cochliobolus species for example Cochliobolus sativus (conidial form: Drechslera, Bipolaris Syn: Helminthosporium);
  • Colletolrichum species for example Colletolrichum coccodes
  • Fusarium species for example Fusarium culmorum
  • Gibberella species for example Gibberella zeae
  • Macrophomina species for example Macrophomina phaseolina
  • Microdochium species for example Microdochium nivale
  • Monographella species for example,
  • wi lt diseases caused, for example, by Monilinia species, for example Monilinia laxa;
  • Exobasidium species for example Exobasidium vexans
  • Taphrina species for example Taphrina deformans
  • degenerative diseases in woody plants caused, for example, by Esca species, for example Phaeomoniella chlamydospora, Phaeoacremonhim aleophilum or Fomitiporia mediterranea; Ganoderma species, for example Ganoderma boninense;
  • Botrytis species for example Botrytis cinerea
  • diseases of plant tubers caused, for example, by Rhizoctonia species, for example Rhizoctonia solani
  • Helminthosporhim species for example Helminthosporium solani
  • diseases caused by bacterial pathogens for example Xanthomonas species, for example Xanthomonas campestris pv. oryzae; Pseiidomonas species, for example Pse domonas syringae pv. lachrymans; Erwinia species, for example Erwinia amylovora; Ralstonia species, for example Ralstonia solanacearam;
  • phytophthora rot (Phytophthora megasperma), brown stem rot ⁇ Phialophora gregata), pythium rot (Pythium aphanidermatum, Pythium irregulare, Pythium debaryanum, Pythium myriotylum, Pythium ultimum), rhizoctonia root rot, stem decay, and damping-off (Rhizoctonia solani), sclerotinia stem decay (Sclerotmia sclerotiorum), sclerotinia southern blight (Sclerotinia rolfsii), thielaviopsis root rot (Thielaviopsis basicola).
  • Plants which can be treated in accordance with the invention include the following: Rosaceae sp (for example pome fruits such as apples, pears, apricots, cherries, almonds and peaches), Ribesioidae sp. , Juglandaceae sp. , Betulaceae sp. , Anacardiaceae sp., Fagaceae sp., Moraceae sp. , Oleaceae sp. , Actinidaceae sp. , Lauraceae sp. , Musaceae sp. (for example banana trees and plantations), Rubiaceae sp. (for example coffee), Tlteaceae sp.
  • Rosaceae sp for example pome fruits such as apples, pears, apricots, cherries, almonds and peaches
  • Ribesioidae sp. Juglandaceae sp.
  • Sterculiceae sp. for example lemons, oranges and grapefruit
  • Vitaceae sp. for example grapes
  • Solanaceae sp. for example tomatoes, peppers
  • Liliaceae sp. Aster aceae sp.
  • Umbelliferae sp. for example lettuce
  • Cibashaceae sp. for example cucumber
  • Alliaceae sp. for example leek, onion
  • Papilionaceae sp. for example peas
  • major crop plants such as PoaceaelGramineae sp.
  • Asteraceae sp. for example sunflower
  • Brassicaceae sp. for example white cabbage, red cabbage, broccoli, cauliflower, Brussels sprouts, pak choi, kohlrabi, radishes, and oilseed rape, mustard, horseradish and cress
  • Fabacae sp. for example bean, peanuts
  • Papilionaceae sp. for example soya bean
  • Solanaceae sp. for example potatoes), Chenopodiaceae sp.
  • the agricultural crops are cereals, corn, rice, soybean and other leguminous plants, fruits and fruit trees, nuts and nut trees, citrus and citrus trees, any horticultural plants, cucurbitaceae, oleaginous plants, tobacco, coffee, tea, cacao, sugar beet, sugar cane, cotton, potato, tomato, onions, peppers and other vegetables, and ornamentals.
  • the present invention further relates to the use of the compound of Formula I or the compound of Formula I in the composition optionally comprising at least one active compatible compound for treating seeds with the purpose of protecting the seeds, the germinating plants and emerged seedlings against phytopathogenic micro-organisms.
  • the present invention further relates to seeds which have been treated with the compound of the Formula I or the compound of Formula I in the composition optionally comprising at least one active compatible compound for protection from phytopathogenic micro-organisms.
  • the present invention also relates to a method of controlling or preventing infestation of useful plants by phytopathogenic micro-organisms in agricultural crops and or horticultural crops wherein the compound of Formula I or the compound of Formula 1 in the composition optionally comprising at least one active compatible compound, is applied to the plants, to parts thereof or the locus thereof.
  • the effective amount of compound of Formula 1 or the compound of Formula I in the composition optionally comprising at least one active compatible compound ranges from 1 gai to 5000 gai per hectare in agriculture or horticulture crops.
  • the present invention relates to the compound of the Formula I or the compound of the Formula I in the composition optionally comprising at least one active compatible compound applied to a plant, plant parts or locus thereof.
  • the present invention furthermore includes a method for treating seed, particularly seeds (dormant, primed, pregerminated or even with emerged roots and leaves) treated with the compound of the Formula I or the compound of the Formula I in the composition optionally comprising at least one active compatible compound.
  • seed particularly seeds (dormant, primed, pregerminated or even with emerged roots and leaves) treated with the compound of the Formula I or the compound of the Formula I in the composition optionally comprising at least one active compatible compound.
  • the compound of Formula I or the compound of Formula I in the composition optionally comprising at least one active compatible compound is applied to the seeds of plants for controlling or preventing infestation of useful plants by phytopathogenic micro-organisms in agricultural and or horticultural corps.
  • methods for the treatment of seed should also take into consideration the intrinsic phenotypes of transgenic plants in order to achieve optimum protection of the seed and the germinating plant with a minimum of crop protection compositions being employed.
  • One of the advantages of the present invention is that the treatment of the seeds with the compound of Formula I or the compound of Formula I in the composition optionally comprising at least one active compatible compound not only protects the seed itself, but also the resulting plants after emergence, from animal pests and/or phytopathogenic harmful micro-organisms. In this way, the immediate treatment of the crop at the time of sowing or shortly thereafter protect plants as well as seed treatment in prior to sowing. It is likewise considered to be advantageous that the compound of Formula I or the compound of Formula I in the composition optionally comprising at least one active compatible compound can be used especially also for transgenic seed, in which case the plant which grows from this seed is capable of expressing a protein which acts against pests, herbicidal damage or abiotic stress.
  • the compound of Formula I or the compound of Formula I in the composition optionally comprising at least one active compatible compound are suitable for protection of seed of any plant variety which is used in agriculture, in the greenhouse, i n forests or in horticulture. More particularly, the seed is that of cereals (such as wheat, barley, rye, millet and oats), oilseed rape, maize, cotton, soybeen, rice, potatoes, sunflower, beans, coffee, beet (e.g. sugar beet and fodder beet), peanut, vegetables (such as tomato, cucumber, onions and lettuce), lawns and ornamental plants. Of particular significance is the treatment of the seed of wheat, soybean, oi lseed rape, maize and rice. ;
  • transgenic seed with the compound of Formula I or the compound of Formula I in the composition optionally comprising at least one active compatible compound
  • heterologous genes in transgenic seeds may originate, for example, from microorganisms of the species Bacillus, Rhizobhim, Pseitdomonas, Serratia, Trichoderma, Clavibacter, Glomus or Gliocladiiim.
  • These heterologous genes preferably originate from Bacillus sp., in which case the gene product is effective against the European corn borer and/or the Western corn rootworm.
  • the heterologous genes originate from Bacillus thuringiensis.
  • the compound of Formula I or the compound of Formula I in the composition optional ly comprising at least one active compatible compound is applied to seeds.
  • the seed is treated in a state in which it is sufficiently stable for no damage to occur in the course of treatment.
  • seeds can be treated at any time between harvest and some time after sowing. It is customary to use seed which has been separated from the plant and freed from cobs, shells, stalks, coats, hairs or the flesh of the fruits. For example, it is possible to use seed which has been harvested, cleaned and dried down to a moisture content of less than 15% by weight.
  • seed which, after drying, for example, has been treated with water and then dried again or seeds just after priming, or seeds stored in primed conditions or pre-germinated seeds, or seeds sown on nursery trays, tapes or paper.
  • the amount of the compound of Formula I or the compound of Formula I in the composition optionally comprising at least one active compatible compound applied to the seed and/or the amount of further additives is selected such that the germination of the seed is not impaired, or that the resulting plant is not damaged.
  • the compound of Formula I or the compound of Formula I in the composition optionally comprising at least one active compatible compound can be applied directly, i.e. without containing any other components and without having been diluted.
  • the compounds of the Formula I can be converted to the customary Formulations relevant to on-seed applications, such as solutions, emulsions, suspensions, powders, foams, slurries or combined with other coating compositions for seed, such as film forming materials, pelleting materials, fine iron or other metal powders, granules, coating material for inactivated seeds, and also ULV Formulations.
  • seeds can be coated with polymer.
  • the polymer coating is comprised of a binder, a wax and a pigment, and one or more stabilizers in an amount effective to stabilize the suspension.
  • the binder can be a polymer selected from the group consisting of vinyl acetate- ethylene copolymer, vinyl acetate homopolymer, vinyl acetate-acrylic copolymer, vinylacrylic, acrylic, ethylene-vinyl chloride, vinyl ether maleic anhydride, or butadiene styrene. Other similar polymers can be used.
  • Formulations are prepared in a known manner, by mixing the active ingredients or active ingredient combinations with customary additives, for example customary extenders and solvents or diluents, dyes, wetting agents, dispersants, emulsifiers, antifoams, preservatives, secondary thickeners, adhesives, gibberellins, and also water.
  • customary additives for example customary extenders and solvents or diluents, dyes, wetting agents, dispersants, emulsifiers, antifoams, preservatives, secondary thickeners, adhesives, gibberellins, and also water.
  • Useful dyes which may be present in the seed dressing Formulations usable in accordance with the invention are all dyes which are customary for such purposes. It is possible to use either pigments, which are sparingly soluble in water, or dyes, which are soluble in water. Examples include the dyes known by the names Rhodamine B, C.I. Pigment Red 1 12 and C.I. Solvent Red 1 .
  • Useful wetting agents which may be present in the seed dressing Formulations usable in accordance with the invention are all substances which promote wetting and which are conventionally used for the Formulation of active agrochemical ingredients.
  • Usable with preference are alkylnaphthalenesulphonates, such as diisopropyl- or diisobutylnaphthalenesulphonates.
  • Useful dispersants and/or emulsifiers which may be present in the seed dressing Formulations usable in accordance with the invention are all nonionic, anionic and cationic dispersants conventionally used for the Formulation of active agrochemical ingredients. Usable with preference are nonionic or anionic dispersants or mixtures of nonionic or anionic dispersants.
  • Useful nonionic dispersants include especially ethylene oxide/propylene oxide block polymers, alkylphenol polyglycol ethers and tristryrylphenol polyglycol ether, and the phosphated or sulphated derivatives thereof.
  • Suitable anionic dispersants are especially lignosulphonates, polyacrylic acid salts and arylsulphonate/formaldehyde condensates.
  • Antifoams which may be present in the seed dressing Formulations usable in accordance with the invention are all foam-inhibiting substances conventionally used for the Formulation of active agrochemical ingredients. Silicone antifoams and magnesium stearate can be used with preference.
  • Preservatives which may be present in the seed dressing Formulations usable in accordance with the invention are all substances usable for such purposes in agrochemical compositions. Examples include dichlorophene and benzyl alcohol hemiformal.
  • Secondary thickeners which may be present in the seed dressing Formulations usable in accordance with the invention are all substances usable for such purposes in agrochemical compositions.
  • Preferred examples include cellulose derivatives, acrylic acid derivatives, xanthan, modified clays and finely divided silica.
  • Adhesives which may be present in the seed dressing Formulations usable in accordance with the invention are all customary binders usable in seed dressing products.
  • Preferred examples include polyvinylpyrrolidone, polyvinyl acetate, polyvinyl alcohol and tylose.
  • the Formulations for on-seed applications usable in accordance with the invention can be used to treat a wide variety of different kinds of seed either directly or after prior dilution with water.
  • the concentrates or the preparations obtainable therefrom by dilution with water can be used to dress the seed of cereals, such as wheat, barley, rye, oats, and triticale, and also seeds of maize, soybean, rice, oilseed rape, peas, beans, cotton, sunflowers, and beets, or else a wide variety of different vegetable seeds.
  • the Formulations usable in accordance with the invention, or the di lute preparations thereof can also be used for seeds of transgenic plants. In this case, enhanced effects may also occur in interaction with the substances formed by expression.
  • the application rate of the Formulations usable in accordance with the invention can be varied within a relatively wide range. It is guided by the particular content of the active ingredients in the Formulations and by the seeds.
  • the application rates of each single active ingredient are generally between 0.001 and 15 gai per kilogram of seed, preferably between 0.01 and 5 gai per kilogram of seed.
  • the application rate of the compound of Formula I or the compound of Formula 1 in a composition optionally comprising at least one active compatible compound is: in the case of treatment of plant parts, for example leaves: from 0. 1 to 10000 gai/ha, preferably from 5 to 1000 gai/ha, more preferably from 5 to 100 gai/ha (in the case of application by watering or dripping, it is even possible to reduce the application rate, especially when inert substrates such as rockwool or perlite are used);
  • the compound of the Formula I can, at particular concentrations or application rates, also be used as safeners, growth regulators or agents to improve plant properties, or as microbicides, for example as fungicides, antimycotics, bactericides, viricides (including compositions against viroids) or as compositions against phytoplasmas ML O (Mycoplasma-like organisms) and RLO (Rickettsia-like organisms).
  • the compounds of the Formula I intervene in physiological processes of plants and can therefore also be used as plant growth regulators.
  • Plant growth regulators may exert various effects on plants. The effect of the substances depends essentially on the time of application in relation to the developmental stage of the plant, the plant variety and also on the amounts of active ingredient applied to the plants or their environment and on the type of application. In each case, growth regulators should have a particular desired effect on the crop plants.
  • Growth regulating effects comprise earlier germination, better emergence, more developed root system and/or improved root growth, increased ability of tillering, more productive tillers, earl ier flowering, increased plant height and/or biomass, shorting of stems, improvements in shoot growth, number of kernels/ear, number of ears/m 2 , number of stolons and/or number of flowers, enhanced harvest index, bigger leaves, less dead basal leaves, improved phyllotaxy, earlier maturation/ earlier fruit finish, homogenous riping, increased duration of grain filling, better fruit finish, bigger fruit/vegetable size, sprouting resistance and reduced lodging.
  • Increased or improved yield is referring to total biomass per hectare, yield per hectare, kernel/fruit weight, seed size and/or hectolitre weight as well as to improved product quality, comprising:
  • improved marketability relating to improved fruit/grain quality, size distribution (kernel, fruit, etc.), increased storage/shelf-life, firmness /softness, taste (aroma, texture, etc.), grade (size, shape, number of berries, etc.), number of berries/fruits per bunch, crispness, freshness, coverage with wax, frequency of physiological disorders, colour, etc.;
  • decreased undesired ingredients such as e.g. less mycotoxines, less aflatoxines, geosmin level, phenol ic aromas, lacchase, polyphenol oxidases and peroxidases, nitrate content etc.
  • Plant growth-regulating compounds can be used, for example, to slow down the vegetative growth of the plants.
  • Such growth depression is of economic interest, for example, in the case of grasses, since it is thus possible to reduce the frequency of grass cutting in ornamental gardens, parks and sport facilities, on roadsides, at airports or in fruit crops.
  • Also of significance is the inhibition of the growth of herbaceous and woody plants on roadsides and in the vicinity of pipelines or overhead cables, or quite generally in areas where vigorous plant growth is unwanted.
  • growth regulators for inhibition of the longitudinal growth of cereal. This reduces or completely eliminates the risk of lodging of the plants prior to harvest.
  • growth regulators in the case of cereals can strengthen the culm, which also counteracts lodging.
  • the employment of growth regulators for shortening and strengthening culms allows the deployment of higher fertilizer volumes to increase the yield, without any risk of lodging of the cereal crop.
  • vegetative growth depression allows denser planting, and it is thus possible to achieve higher yields based on the soil surface.
  • Another advantage of the smaller plants obtained in this way is that the crop is easier to cultivate and harvest.
  • Reduction of the vegetative plant growth may also lead to increased or improved yields because the nutrients and assimilates are of more benefit to flower and fruit formation than to the vegetative parts of the plants.
  • growth regulators can also be used to promote vegetative growth. This is of great benefit when harvesting the vegetative plant parts. However, promoting vegetative growth may also promote generative growth in that more assimilates are formed, resulting in more or larger fruits.
  • beneficial effects on growth or yield can be achieved through improved nutrient use efficiency, especially n (N)-use efficiency, phosphours (P)-use efficiency, water use efficiency, improved transpiration, respiration and/or C0 2 assimilation rate, better nodulation, improved Ca-metabolism etc.
  • growth regulators can be used to alter the composition of the plants, which in turn may result in an improvement in quality of the harvested products. Under the influence of growth regulators, parthenocarpic fruits may be formed. In addition, it is possible to influence the sex of the flowers. It is also possible to produce sterile pollen, which is of great importance in the breeding and production of hybrid seed.
  • growth regulators can control the branching of the plants.
  • by breaking apical dominance it is possible to promote the development of side shoots, which may be highly desirable particularly in the cultivation of ornamental plants, also in combination with an inhibition of growth.
  • side shoots which may be highly desirable particularly in the cultivation of ornamental plants, also in combination with an inhibition of growth.
  • the amount of leaves on the plants can be controlled such that defoliation of the plants is achieved at a desired time.
  • defoliation plays a major role in the mechanical harvesting of cotton, but is also of interest for facilitating harvesting in other crops, for example in viticulture.
  • Defoliation of the plants can also be undertaken to lower the transpiration of the plants before they are transplanted.
  • growth regulators can modulate plant senescence, which may result in prolonged green leaf area duration, a longer grain filling phase, improved yield quality, etc.
  • Growth regulators can likewise be used to regulate fruit dehiscence. On the one hand, it is possible to prevent premature fruit dehiscence. On the other hand, it is also possible to promote fruit dehiscence or even flower abortion to achieve a desired mass ("thinning"). In addition, it is possible to use growth regulators at the time of harvest to reduce the forces required to detach the fruits, in order to allow mechanical harvesting or to facilitate manual harvesting.
  • Growth regulators can also be used to achieve faster or else delayed ripening of the harvested material before or after harvest. This is particularly advantageous as it allows optimal adjustment to the requirements of the market. Moreover, growth regulators in some cases can improve the fruit colour. In addition, growth regulators can also be used to synchronize maturation within a certain period of time. This establishes the prerequisites for complete mechanical or manual harvesting in a single operation, for example in the case of tobacco, tomatoes or coffee.
  • growth regulators By using growth regulators, it is additionally possible to influence the resting of seed or buds of the plants, such that plants such as pineapple or ornamental plants in nurseries, for example, germinate, sprout or flower at a time when they are normally not inclined to do so. In areas where there is a risk of frost, it may be desirable to delay budding or germination of seeds with the aid of growth regulators, in order to avoid damage resulting from late frosts.
  • growth regulators can induce resistance of the plants to frost, drought or high salinity of the soil. This allows the cultivation of plants in regions which are normally unsuitable for this purpose.
  • the compound of Formula I or the compound of Formula I in the composition optionally comprising at least one active compatible compound also exhibit potent strengthening effect in plants. Accordingly, they can be used for mobilizing the defences of the plant against attack by undesirable micro-organisms.
  • Plant-strengthening (resistance-inducing) substances in the present context are substances capable of stimulating the defence system of plants in such a way that the treated plants, when subsequently inoculated with undesirable micro-organisms, develop a high degree of resistance to these microorganisms.
  • plant physiology effects comprise the following:
  • Abiotic stress tolerance comprising tolerance to high or low temperatures, drought tolerance and recovery after drought stress, water use efficiency (correlating to reduced water consumption), flood tolerance, ozone stress and UV tolerance, tolerance towards- chemicals like heavy metals, salts, pesticides etc.
  • Biotic stress tolerance comprising increased fungal resistance and increased resistance against nematodes, viruses and bacteria.
  • biotic stress tolerance preferably comprises increased fungal resistance and increased resistance against nematodes.
  • the compound of Formula 1 or the compound of Formula 1 in the composition optionally comprising at least one active compatible compound can reduce the mycotoxin content in the harvested material and the foods and feeds prepared therefrom.
  • Mycotoxins include particularly, but not exclusively, the following: deoxynivalenol (DON), nivalenol, 15-Ac-DON, 3-Ac-DON, T2- and HT2- toxin, fumonisins, zearalenon, moniliformin, fusarin, diaceotoxyscirpenol (DAS), beauvericin, enniatin, fusaroproliferin, fusarenol, ochratoxins, patulin, ergot alkaloids and aflatoxins which can be produced, for example, by the following fungi : Fusarium spec, such as F. acuminatum, F. asialicum, F. avenaceum, F.
  • Penicillium spec such as P. verrucosum, P. viridicatum, P. citrinum, P. expansum, P. claviforme, P. roqueforti, Claviceps spec, such as C. purpurea, C. fusiformis, C. paspali, C. africana, Stachybotrys spec, and others.
  • the compound of Formula I or the compound of Formula I in the composition optionally comprising at least one active compatible compound can also be used in the protection of materials, for protection of industrial materials against attack and destruction by phytopathogenic micro-organisms.
  • the compounds of the Formula I can be used as antifouling compositions, alone or in combinations with other active ingredients.
  • Industrial materials in the present context are understood to mean inanimate
  • industrial materials which are to be protected by inventive compositions from microbial alteration or destruction may be adhesives, glues, paper, wallpaper and board/cardboard, textiles, carpets, leather, wood, fibers and tissues, paints and plastic articles, cooling lubricants and other materials which can be infected with or destroyed by micro-organisms.
  • Parts of production plants and buildings, for example cooling-water circuits, cooling and heating systems and ventilation and air- conditioning units, which may be impaired by the proliferation of micro-organisms may also be mentioned within the scope of the materials to be protected.
  • Industrial materials within the scope of the present invention preferably include adhesives, sizes, paper and card, leather, wood, paints, cooling lubricants and heat transfer fluids, more preferably wood.
  • the compound of Formula I or the compound of Formula I in the composition optionally comprising at least one active compatible compound may prevent adverse effects, such as rotting, decay, discoloration, decoloration or formation of mould.
  • the compound of Formula I or the compound of Formula I in the composition optionally comprising at least one active compatible compound may also be used against fungal diseases liable to grow on or inside timber.
  • the term "timber" means all types of species of wood, and all types of working of this wood intended for construction, for example solid wood, high-density wood, laminated wood, and plywood.
  • the method for treating timber according to the invention mainly consists in contacting a composition according to the invention; this includes for example direct application, spraying, dipping, injection or any other suitable means.
  • the compound of Formula I or the compound of Formula I in the composition optionally comprising at least one active compatible compound can be used to protect objects which come into contact with saltwater or brackish water, especially hulls, screens, nets, buildings, moorings and signalling systems, from fouling.
  • the compound of Formula I or the compound of Formula I in the composition optionally comprising at least one active compatible compound can also be employed for protecting storage goods.
  • Storage goods are understood to mean natural substances of vegetable or animal origin or processed products thereof which are of natural origin, and for which long-term protection is desired.
  • Storage goods of vegetable origin for example plants or plant parts, such as stems, leaves, tubers, seeds, fruits, grains, can be protected freshly harvested or after processing by (pre)drying, moistening, comminuting, grinding, pressing or roasting.
  • Storage goods also include timber, both unprocessed, such as construction timber, electricity poles and barriers, or in the form of finished products, such as furniture.
  • Storage goods of animal origin are, for example, hides, leather, furs and hairs.
  • the inventive compositions may prevent adverse effects, such as rotting, decay, discoloration, decoloration or formation of mould.
  • Micro-organisms capable of degrading or altering the industrial materials include, for example, bacteria, fungi, yeasts, algae and slime organisms.
  • the compound of Formula I or the compound of Formula I in the composition optionally comprising at least one active compatible compound preferably act against fungi, especially moulds, wood-discoloring and wood-destroying fungi (Ascomycetes, Basidiomycetes, Deiiteromycetes and Zygomycetes), and against slime organisms and algae.
  • micro-organisms of the following genera Alternaria, such as Alternaria tenuis; Aspergillus, such as Aspergillus niger; Chaetomium, such as Chaetomium globosum; Coniophora, such as Coniophora puetana; Lentinus, such as Lenlinus tigriniis; Penicillium, such as Penicillium glaucum; Polyporus, such as Polyporus versicolor, Aureobasidium, such as Aureobasidium pullulans; Sclerophoma, such as Sclerophoma pityophila; Trichoderma, such as Trichoderma viride; Ophiostoma spp., Ceratocystis spp., Humicola spp., Petriella spp., Trichurus spp., Coriohis spp., Gloeophyllwn spp., Pleurotits spp.
  • the compound of Formula I or the compound of Formula 1 in the composition optionally comprising at least one active compatible compound also has very good anti mycotic effects.
  • the compound of Formula 1 or the compound of Formula I in the composition optionally comprising at least one active compatible compound can be used also to control important fungal pathogens in fish and Crustacea farming, e.g. saprolegnia diclina in trouts, saprolegnia parasitica in crayfish.
  • the compound of Formula I or the compound of Formula I in the composition optionally comprising at least one active compatible compound can therefore be used both in medical and in non-medical applications.
  • the compound of Formula I or the compound of Formula I in the composition optionally comprising at least one active compatible compound can be used as such, in the form of their Formulations or the use forms prepared therefrom, such as ready-to-use solutions, suspensions, wettable powders, pastes, soluble powders, dusts and granules.
  • Application is accomplished in a customary manner, for example by watering, spraying, atomizing, broadcasting, dusting, foaming, spreading-on and the like. It is also possible to deploy the active ingredients by the ultra-low volume method or to inject the active ingredient preparation/the active ingredient itself into the soil. It is also possible to treat the seed of the plants.
  • plants and their parts in accordance with the invention, preferably with wild plant species and plant cultivars, or those obtained by conventional biological breeding methods, such as crossing or protoplast fusion, and also parts thereof.
  • transgenic plants and plant cultivars obtained by genetic engineering methods if appropriate in combination with conventional methods (Genetically Modified Organisms), and parts thereof are treated.
  • the terms "parts” or “parts of plants” or “plant parts” have been explained above. More preferably, plants of the plant cultivars which are commercially available or are in use are treated in accordance with the invention.
  • Plant cultivars are understood to mean plants which have new properties ("traits") and have been obtained by conventional breeding, by mutagenesis or by recombinant DNA techniques. They can be cultivars, varieties, bio- or genotypes.
  • the method of treatment according to the invention can be used in the treatment of genetically modified organisms (GMOs), e.g. plants or seeds.
  • GMOs genetically modified organisms
  • Genetically modified plants are plants of which a heterologous gene has been stably integrated into genome.
  • the expression "heterologous gene” essentially means a gene which is provided or assembled outside the plant and when introduced in the nuclear, chloroplastic or mitochondrial genome gives the transformed plant new or improved agronomic or other properties by expressing a protein or polypeptide of interest or by downregulating or silencing other gene(s) which are present in the plant (using for example, antisense technology, cosuppression technology, RNA interference - RNAi - technology or microRNA - miRNA - technology).
  • a heterologous gene that is located in the genome is also called a transgene.
  • a transgene that is defined by its particular location in the plant genome is called a transformation or transgenic event.
  • Plants and plant cultivars which are preferably to be treated according to the invention include all plants which have genetic material which impart particularly advantageous, useful traits to these plants (whether obtained by breeding and/or biotechnological means).
  • Plants and plant cultivars which are also preferably to be treated according to the invention are resistant against one or more biotic stresses, i.e. said plants show a better defense against ani mal and microbial pests, such as against nematodes, insects, mites, phytopathogenic fungi, bacteria, viruses and/or viroids. Plants and plant cultivars which may also be treated according to the invention are those plants which are resistant to one or more abiotic stresses.
  • Abiotic stress conditions may include, for example, drought, cold temperature exposure, heat exposure, osmotic stress, flooding, increased soil salinity, increased mineral exposure, ozone exposure, high light exposure, limited availability of n nutrients, limited availability of phosphorus nutrients, shade avoidance.
  • Plants and plant cultivars which may also be treated according to the invention are those plants characterized by enhanced yield characteristics. Increased yield in said plants can be the result of, for example, improved plant physiology, growth and development, such as water use efficiency, water retention efficiency, improved n use, enhanced carbon assimilation, improved photosynthesis, increased germination efficiency and accelerated maturation.
  • Yield can furthermore be affected by improved plant architecture (under stress and non-stress conditions), including but not limited to, early flowering, flowering control for hybrid seed production, seedling vigor, plant size, internode number and distance, root growth, seed size, fruit size, pod size, pod or ear number, seed number per pod or ear, seed mass, enhanced seed filling, reduced seed dispersal, reduced pod dehiscence and lodging resistance.
  • Further yield traits include seed composition, such as carbohydrate content and composition for example cotton or starch, protein content, oil content and composition, nutritional value, reduction in anti-nutritional compounds, improved processability and better storage stability.
  • Plants that may be treated according to the invention are hybrid plants that already express the characteristic of heterosis or hybrid vigor which results in generally higher yield, vigor, health and resistance towards biotic and abiotic stresses).
  • Plants or plant cultivars obtained by plant biotechnology methods such as genetic engineering which may be treated according to the invention are herbicide-tolerant plants, i.e. plants made tolerant to one or more given herbicides. Such plants can be obtained either by genetic transformation, or by selection of plants containing a mutation imparting such herbicide tolerance.
  • Plants or plant cultivars obtained by plant biotechnology methods such as genetic engineering which may also be treated according to the invention are insect-resistant transgenic plants, i.e. plants made resistant to attack by certain target insects. Such plants can be obtained by genetic transformation, or by selection of plants containing a mutation imparting such insect resistance.
  • Plants or plant cultivars which may also be treated according to the invention are tolerant to abiotic stresses. Such plants can be obtained by genetic transformation, or by selection of plants containing a mutation imparting such stress resistance. Plants or plant cultivars (obtained by plant biotechnology methods such as genetic engineering) which may also be treated according to the invention show altered quantity, quality and/or storage-stability of the harvested product and/or altered properties of specific ingredients of the harvested product.
  • Plants or plant cultivars which may also be treated according to the invention are plants, such as cotton plants, with altered fiber characteristics. Such plants can be obtained by genetic transformation, or by selection of plants contain a mutation imparting such altered fiber characteristics.
  • Plants or plant cultivars which may also be treated according to the invention are plants, such as oilseed rape or related Brassica plants, with altered oil profile characteristics. Such plants can be obtained by genetic transformation, or by selection of plants contain a mutation imparting such altered oil profile characteristics.
  • Plants or plant cultivars which may also be treated according to the invention are plants, such as oilseed rape or related Brassica plants, with altered seed shattering characteristics. Such plants can be obtained by genetic transformation, or by selection of plants contain a mutation imparting such altered seed shattering characteristics and include plants such as oilseed rape plants with delayed or reduced seed shattering. Plants or plant cultivars (that can be obtained by plant biotechnology methods such as genetic engineering) which may also be treated according to the invention are plants, such as tobacco plants, with altered post-translational protein modification patterns.
  • a compound of Formula 3 is prepared by coupling corresponding acid of Formula 1 with an amine of Formula 2 (or its salt) in the presence of a dehydrative coupling reagent such as dicyclohexylcarbodiimide (DCC), l -(3-dimethy!aminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) 3- [Bis(dimethylamino)methyliumyl]-3FI-benzotriazol-l -oxide hexafluorophosphate (HBTU), or 1 - [Bis(dimethylamino)methylene]-l FI- l ,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU).
  • DCC dicyclohexylcarbodiimide
  • EDC l -(3-dimethy!aminopropyl)-3-ethylcarbodiimide hydrochloride
  • Polymer-supported reagents are also useful here, such as polymer-bound cyclohexylcarbodiimide. These reactions are typically carried out at 0-40 °C in a solvent such as dichloromethane, acetonitrile or dimethylformamide in the presence of a base such as triethylamine or diisopropylethylamine.
  • amides of Formula 3 wherein W is O can be converted to thioamides of Formula 3a wherein W is S using a variety of standard thionating reagents such as phosphorus pentasulfide or 2,4-bis(4-methoxyphenyl)-l,3-dithia-2,4- diphosphetane-2,4-disulfide (Lawesson's reagent).
  • standard thionating reagents such as phosphorus pentasulfide or 2,4-bis(4-methoxyphenyl)-l,3-dithia-2,4- diphosphetane-2,4-disulfide (Lawesson's reagent).
  • R 2 CH 2 COOH where R 2 is a heterocyclic ring linked through n can be prepared by reacting the corresponding R 2 H compound with a haloacetic acid or ester in the presence of base; followed by hydrolysis.
  • the amine compound of Formula 2 can be prepared from the protected amine compound of Formula 4 where ⁇ ' is an amine-protecting group.
  • a compound of the Formula 4 is converted to a compound of the Formula 2 by suitable methods for removing protecting groups described in the literature (Protective Groups in Organic Synthesis; Theodora W. Greene, Peter G. M. Wilts; Wiley-lnterscience; Third Edition; 1999; 494-653).
  • tert-butoxycarbonyl and benzyloxycarbonyl protecting groups can be removed in an acidic medium (for example with hydrochloric acid or trifiuoroacetic acid).
  • Acetyl protecting groups can be removed under basic conditions (for example with potassium carbonate or caesium carbonate).
  • Benzylic protecting groups can be removed hydrogenolytically with hydrogen in the presence of a catalyst (for example palladium on activated carbon).
  • the compound of Formula 2 is separated from the reaction mixture by one of the customary separation techniques. If necessary, the compounds are purified by recrystallization or chromatography, or can, if desired, also be used in the next step without prior purification. It is also possible to isolate the compound of the general Formula 2 as a salt, for example as a salt of hydrochloric acid or of trifluoroacetic acid.
  • a compound of the general Formula 6 is obtained by condensation of an aldehyde of the Formula 5 with hydroxylamine and subsequent chlorination (see, for example, WO05/0040159, WO08/013622 and Synthesis, 1987, 1 1 , 998- 1001 ).
  • aldehyde 5 and hydroxylamine are first reacted to obtain corresponding oxime which is subsequently chlorinated in the presence of a suitable chlorinating agent.
  • a suitable chlorinating agent Preferred chlorinating reagents are N-chlorosuccinimide, NaOCl, HCIO and chlorine.
  • the step (a) is performed using one or more diluents preferably with protic solvents, for example ethanol.
  • the reaction mixture is diluted in step (b) with a further solvent, for example tetrahydrofuran, and then aqueous sodium hypochlorite is added.
  • the chlorination can likewise be effected with the aid of N-chlorosuccinimide in N,N-dimethyl formamide (DMF) or Ethyl acetate.
  • DMF N,N-dimethyl formamide
  • Ethyl acetate Ethyl acetate
  • alkenes and alkynes 7a and 7b are commercially available or can be prepared from commercially available precursors by methods described in the literature (for example from ketones or aldehydes by a Wittig or Horner-Wadsworth-Emmons olefination: Chem. Rev. 1989, 89, 863-927 and Julia olefination: Tetrahedron Lett., 1973, 14, 4833-4836; Peterson olefmation: J. Org. Chem. 1968, 33, 780; with the Bestmann-Ohira reagent: Synthesis 2004, 1 , 59-62).
  • a compound of the general Formula 4a is obtained from an alkyne of the general Formula 7a and and compound 6; and a compound of the general Formula 4b is obtained from an alkene of the general Formula 7b and compound 6 by a cycloaddition reaction (see, for example, WO 08/013622 and Synthesis, 1987, 1 1 , 998- 1001 ).
  • the step c is performed in the presence of a suitable base.
  • bases are tertiary amines (e.g. triethylamine), and alkali metal or alkaline earth metal carbonates (for example potassium or sodium carbonate), hydrogencarbonates and phosphates.
  • the step c is preferably performed using one or more diluents.
  • inert organic solvents are a preferred option (for example toluene and ethyl acetate). Water is likewise a possible solvent.
  • process can be performed in an excess of the alkene 7a or of the alkyne
  • the workup is carried out by customary methods. If necessary, the compounds are purified by recrystallization or chromatography.
  • a compound of Formula 5 is prepared (step a) by reducing corresponding ester 8 into the corresponding alcohol using NaBH -MeOH system.
  • the aromatic alcohols are obtained by the method explained in the ARKIVOC 2006, 128- 133, involving the reduction of aromatic ethyl, esters within 15 - 60 minutes after refluxing in THF.
  • the respective alcohol products were isolated after aqueous workup in good yield.
  • Corresponding alcohol is oxidized to aldehyde compound of Formula 5 (Scheme 4, Step b) using oxidizing agents like Mn0 2 , Dess-Martin periodinane, IBX, TEMPO.
  • Preferred solvents for the conversion were acetonitrile or dichloromethane.
  • a Compound of Formula 8 is prepared using the well-known Suzuki reaction involving Pd-catalyzed cross-coupling of Formula 10 with a boronic acid Formula 9 or corresponding ester.
  • Many catalysts are useful for this type of transformation; a typical catalyst is tetrakis(triphenylphosphine)palladium, or bis(triphenylphosphine)palladium chloride Solvents such as tetrahydrofuran, acetonitrile, diethyl ether and dioxane or dioxane: water mixture are suitable.
  • the Suzuki reaction and related coupling procedures offer many alternatives for creation of the C-G bond. For leading references see for example C. A. Zificsak and D. J.
  • Reduction of the compound of Formula 8 is carried out by catalytic hydrogenation to obtain compound of Formula 8a.
  • Pd/C, Pt/C, Raney Ni are the preferred catalyst.
  • For synthetic procedure refer Bioorganic & Medicinal Chemistry 23 (201 5) 2129-21 38.
  • Substituted compound of Formula 17 can be further functionalized using known methods in the literature like chlorionation, bromination, trifluromethylation to obtain appropriately substituted heterocyclic ring l ike pyridone (Formula 11).
  • References for the said transformations are Zhang, Pei-Zhi et al Tetrahedron, 72(23), 3250-3255; 2016 Canibano; Rodriguez; Santos; Sanz-Tejedor; Carreno; Gonzalez; Garcia-Ruano Synthesis, 2001 , 14,2175 - 2179, WO2004/50637.
  • the substituted functional ized heterocyclic ring containing a pyridone-like moiety can be acylated by reaction with an alkyl ester containing a suitable leaving group such as halogen, mesylate or tosylate, in the presence of a base such as potassium carbonate or cesium carbonate, in a polar solvent such as N,N- dimethyl formamide (DMF) or N-methyl-2-pyrrolidone (NMP), with or without heating to obtain the compound of Formula 12.
  • a polar solvent such as N,N- dimethyl formamide (DMF) or N-methyl-2-pyrrolidone (NMP)
  • DMF N,N- dimethyl formamide
  • NMP N-methyl-2-pyrrolidone
  • mixtures of O- and N-alkylated products are obtained, and the two regio-isomeric products can be separated by means of SiO z gel or reverse phase chromatography.
  • lithium salts for example LiCl
  • the addition of lithium salts, for example LiCl, to the reaction mixture can be employed to favor N- vs. O- alkylation.
  • the obtained alkyl ester can be further hydrolyzed to the corresponding acids by heating or stirring at room temperature in the presence of lithium hydroxide or sodium hydroxide in solvents like ethanol and water to obtain compound of Formula 1.
  • a compound of Formula 14 can be prepared by treating substituted acetoacetic ester with alkyl hydrazine of Formula 13. Compound of Formula 14 can then be selectively alkylated using alkyl halides with or without base to obtain compound of Formula 15.
  • Substituted compound of Formula 15 can be further functionalized using known methods in the literature l ike chlorionation, bromination and trifluromethylation to obtain appropriately substituted heterocyclic ring like pyrazolone of Formula 16.
  • the pyrazolone of Formula 16 can be further hydrolyzed to the corresponding acids by heating or stirring at room temperature in the presence of lithium hydroxide or sodium hydroxide in solvents like ethanol and water to obtain compound of Formula la.
  • a compound of Formula 6b can be prepared by reacting a compound of Formula 11 and a compound of Formula 10 in the presence of a base.
  • Suitable bases include sodium hydride or potassium carbonate, and the reaction is carried out in a solvent such as ⁇ , ⁇ -dimethylformamide or acetonitrile at 0 to 80 °C.
  • Suitable leaving groups Y 2 in the compound of Formula 11 include bromide, iodide, mesylate (OS(0) 2 CH 3 ), triflate (OS(0) 2 CF 3 ) and the like, and the compound of Formula 11 can be prepared from the corresponding compounds wherein Y is OH, using general methods known in the art.
  • a compound of Formula 3a wherein W is O involves coupling of an acid of Formula 1 or la with an amine of Formula 20 (or its acid salt) in the presence of a dehydrative coupling reagent such as dicyclohexylcarbodiimide (DCC), l -(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) O-benzotriazol-l-yl-tetramethyluronium hexafluoro-phosphate (HBTU), or 1 - [Bis(dimethylamino)methylene]- l H- l ,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU).
  • DCC dicyclohexylcarbodiimide
  • EDC O-benzotriazol-l-yl-tetramethyluronium hexafluoro-phosphate
  • HATU 1 - [
  • Polymer-supported reagents are again useful here, such as polymer-bound cyclohexylcarbodiimide. These reactions are typically run at 0-40 °C in a solvent such as dichloromethane, acetonitrile or ⁇ , ⁇ -dimethylformamide in the presence of a base such as triethylamine or ⁇ , ⁇ -diisopropylethylamine.
  • amides of Formula 3a wherein W is O can be converted to thioamides of Formula 3a wherein W is S using a variety of standard thiating reagents such as phosphorus pentasulfide or 2, 4-bis(4-methoxyphenyl)-l,3-dithia-2,4-diphosphetane-2,4-disulfide (Lawesson's reagent).
  • standard thiating reagents such as phosphorus pentasulfide or 2, 4-bis(4-methoxyphenyl)-l,3-dithia-2,4-diphosphetane-2,4-disulfide (Lawesson's reagent).
  • a compound of Formula 3a can be prepared by reacting the compound of Formula 21 with compound of the formula 22 in the presence of an acid or a Lewis acid, preferably in the presence of an acid.
  • the acid which can be used in this step include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid and the like, organic acids such as acetic acid, trifluoroacetic acid, p-toluenesulfonic acid, trifluoromethanesulfonic acid and the like.
  • Lewis acid examples include zinc chloride, aluminum chloride, tin chloride, boron trichloride, boron trifluoride, trimethylsi lyltrifluoromethane sulfonate and the like.
  • the solvent which can be used in this step may be any solvent which does not inhibit the progress of this reaction and examples thereof include nitriles such as acetonitrile; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, monoglyme, diglyme, etc.; dichloromethane, dichloroethane , Halogenated hydrocarbons such as chloroform, carbon tetrachloride and tetrachloroethane; aromatic hydrocarbons such as benzene, chlorobenzene, nitrobenzene and toluene; amides such as N,N- dimethylformamide and ⁇ , ⁇ -dimethylacetamide; imidazolinones such as l ,3-dimethyl-2-imidazolinone, sulfur compounds such as dimethylsulfoxide and the like can be used, and mixed solvents thereof can also be used.
  • nitriles such as ace
  • the reaction temperature may be selected from the range of -20 °C to the boiling point of the inert solvent to be used, preferably in the range of 0 °C to 150 °C.
  • the reaction time varies depending on the reaction temperature, the reaction substrate, the reaction amount and the like, but is usually from 10 minutes to 48 hours.
  • the compound of Formula 22 can be prepared by reducing the compound of Formula 23 with a reducing agent in a solvent.
  • Reducing agent suitable in this step are lithium aluminum hydride, diisobutylaluminum hydride, borane and the like.
  • Preferred solvent that can be used in this step is tetrahydrofuran, dioxane or the like.
  • the reaction temperature may be selected from the range of from -20 °C to the boiling point range of the inert solvent to be used, preferably in the range of 0 °C to 100 °C.
  • the compound of Formula 22 can also be prepared by reducing the compound of Formula 24 with a reducing agent in a solvent.
  • Reducing agent suitable in this step are lithium aluminum hydride, diisobutylaluminum hydride, borane and the like.
  • Preferred solvent that can be used in this step is tetrahydrofuran, dioxane or the l ike.
  • the reaction temperature may be selected from the range of from -20 °C. to the boiling point range of the inert solvent to be used, preferably in the range of 0°C to 100 °C.
  • Synthesis of compounds of Formula 26 involves palladium-catalyzed cross-coupling reaction of terminal alkynes of Formula 25 and organic electrophiles such as alkyl bromides or chlorides. The most widely used of these is a cross between the Cu-promoted Castro-Stephens reaction and the Heck alkynylation, known as the Sonogashira reaction.
  • the compound of Formula 26 can also be obtained using palladium- based systems to catalyze the reaction of aryl halides and terminal alkynes.
  • alkynylation of aldehydes can be achieved by Corey-Fuchs reaction (Tetrahedron Lett, 1 972, 36, 3769) or a Seyferth-Gilbert homologization (see, for example, J. Org. Chem., 1 996, 61 , 2540).
  • the alkyne of Formula 19 can also be prepared from the aldehyde of Formula 5 with Bestmann-Ohira's reagent analogously to the literature instructions (see, for example, Synthesis, 2004, 59).
  • Alkynylation with Bestmann-Ohira's reagent in methanol or ethanol is preferably used in the equivalent of potassium carbonate or sodium carbonate.
  • the aldehyde of Formula 5 and the alkynylation reagent are used in equimolar amounts, but the Bestmann-Ohira's reagent can be used in excess if necessary.
  • the reaction is preferably carried out at from -100 °C to 60 °C and more preferably at from -78 °C to 40 °C.
  • the reaction time varies depending on the scale of the reaction and the reaction temperature, but is generally between a few minutes and 48 hours.
  • the compounds of Formula 25 are separated from the reaction mixture by one of the conventional separation techniques. If necessary, the compounds are purified by recrystallization, distillation or chromatography or, if desired, can also be used in the next step without prior purification.
  • Step A Preparation of ethyl 2-bromo-l,3-thiazole-4-carboxylate
  • Step B Preparation of ethyl 2-(l-(tert-butoxycarbonyl)-l,2,3,6-tetrahydropyridin-4-yI)thiazole-4- carboxylate
  • Step C Preparation of ethyl 2-(l-(tert-butoxycarbonyl)piperidin-4-yl)thiazole-4-carboxylate
  • Step D Preparation of tert-butyl 4-(4-(hydroxymethyl)thiazol-2-yl)piperidine-l-carboxylate
  • Step E Preparation of tert-butyl 4-(4-formylthiazol-2-yl)piperidine-l-carboxylate
  • Step G Preparation of tert-butyl 4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2- yl)piperidine-l-carboxylate
  • Step Gl Alternate preparation of tert-butyl 4-(4-(5-(2,6-difIuorophenyl)-4,5-dihydroisoxazol-3- yl)thiazol-2-yl)piperidine-l-carboxylate
  • Step H Preparation of 5-(2,6-difluorophenyl)-3-(2-(piperidin-4-yI)thiazol-4-yl)-4,5- dihydroisoxazole
  • reaction mixture was concentrated under reduced pressure and partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution and the ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated to obtain the 160 mg of 5-(2,6-difluorophenyl)-3- (2-(piperidin-4-yl)thiazol-4-yl)-4,5-dihydroisoxazole.
  • Step I Preparation of 3-chloro-l-(2-(4-(4-(5-(2,6-difIuorophenyl)-4,5-dihydroisoxazol-3-yl)thiazoI- 2-yl)piperidin-l-yl)-2-oxoethyl)-5-(trifluoromethyl)pyridin-2(lH)-one
  • the reaction mixture was diluted with dichloromethane (10 ml), and washed with IN aqueous Hydrogen chloride and saturated aqueous sodium bicarbonate solution.
  • the dichloromethane layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 3-chloro-l-(2-(4-(4-(5-(2,6-difluorophenyl)-4,5- dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxo (100 mg, 0.170 mmol, 36% yield).
  • Step A Preparation of 2-(l-(tert-butoxycarbonyl)piperidin-4-yl)thiazoIe-4-carboxylic acid
  • Step B Preparation of tert-butyl 4-(4-((l, 2, 3, 4-tetrahydronaphthalen-l-yl)carbamoyl)thiazol-2- yl)piperidine-l-carboxy!ate
  • the reaction mixture was diluted with dichloromethane ( 10 ml), and washed with 1 N aqueous Hydrogen chloride and saturated aqueous sodium bicarbonate solution.
  • the dichloromethane layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 2-( l -(2-(3-chloro-2-oxo-5- (trifluoromethyl)pyridin- l (2H)-yl)acetyl)piperidin-4-yl)-N-( l ,2,3,4-tetrahydronaphth ⁇
  • reaction mixture was diluted with water (20 ml) and extracted twice with dichloromethane (30 ml). The combined dichloromethane layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure which was purified by column chromatography using ethyl acetate and hexane (80:20) as eluents to obtain 5-(difluoromethyl)-2-(2-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3- yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-l-methyl-l,2-dihydro-3H-pyrazol-3-one (0.075 g, 0.140 mmol, 24% yield).
  • Step A Preparation of tert-butyl (E)-4-(4-(((benzyloxy) imino) methyl) thiazol-2-yl) piperidine-1- carboxylate
  • Step B Preparation of (E)-2-(piperidin-4-yl) thiazole-4-carbaldehyde O-benzyl oxime
  • Step C Preparation of (E/Z)-2-(l-(2-(2-oxo-5-(trifluoromethyl) pyridin-l(2H)-yl) acetyl) piperidin- 4-yl) thiazole-4-carbaldehyde O-benzyl oxime
  • reaction mixture was allowed to stirr at room temperature for 3h.
  • the reaction mixture was quenched with water, extracted thrice with ethyl acetate (30 ml).
  • the ethyl acetate layer was dried over sodium sulphate filtered and concentrated under reduced pressure.
  • Step B Preparation of tert-butyl 4-(4-(3-(2, 6-difluorophenyI)-4, 5-dihydroisoxazol-5-yl) thiazoI-2- yl) piperidine-l-carboxylate
  • the resulting mixture was stirred at 60 °C for 3h.
  • the reaction mixture was diluted with water (50 ml) and extracted twice with ethyl acetate (20 ml). The comined ethyl acetate layers were dried over anhydrous sodium sulfate and evaporated.
  • Step C Preparation of 3-(2, 6-difluorophenyl)-5-(2-(piperidin-4-yl) thiazol-4-yl ⁇ -4, 5- dihydroisoxazole 2, 2, 2-trifluoroacetate
  • Step D Preparation of l-(2-(4-(4-(3-(2, 6-difluorophenyl)-4, 5-dihydroisoxazol-5-yl) thiazol-2-yl) piperidin-l-yl)-2-oxoethyl)-3-(trifluoromethyl) pyridin-2(lH)-one
  • the reaction mixture was stirred at room temperature for l h.
  • the reaction was quenched with cold water and the solid obtained was filtered.
  • the crude prodcut was purified by prep- chromatography to obtain l -(2-(4-(4-(3-(2, 6-difluorophenyl)-4, 5-dihydroisoxazol-5-yl) thiazol-2-yl) piperidin- l -yl)-2-oxoethyl)-3-(trifluoromethyl) pyridin-2( l H)-one ( 100 mg, 0.1 81 mmol, 34% yield).
  • Step 2 Preparation of 4-(l, 5-dihydrobenzo[e] [1,3] dioxepin-3-yl)-2-(piperidin-4-yi) thiazole
  • Step 3 Preparation of l-(2-(4-(4-(l, 5-dihydrobenzo[e] [1 ,3] dioxepin-3-yl) thiazol-2-yl) piperidin-1- yl)-2-oxoethyi)-3-(trifluoromethyl) pyridin-2(lH)-one
  • reaction mixture was stirred for 12h. After completion of the reaction, the reaction mixture was diluted with water (50 ml) and extracted twice with ethyl acetate ( 10 ml). The combined ethyl acetate layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure.
  • Step 1 Preparation of 2-(piperidin-4-yl) thiazole-4-carbaldehyde
  • Step 2 Preparation of 2-(l-(2-(2-oxo-5-(tritluoromethyl) pyridin-l(2H)-yl) acetyl) piperidin-4-yl) thiazole-4-carbaldehyde
  • Step 3 Preparation of l-(2-oxo-2-(4-(4-(3-phenyl-4,8-dihydro-[l,3]dioxepino[5,6-d]isoxazol-6- yl)thiazoI-2-yl)piperidin-l-yl)ethyl)-5-(trifluoromethyl)pyridin-2(l H)-one
  • 3-phenyl isoxazole-4,5-diyl)dimethanol (0. 185 g, 0.901 mmol) and p-toluene sulfonic acid monohydrate (0.071 g, 0.376 mmol) were dissolved in a solution of dry toluene (20 ml) and dry N,N-dimethyl formamide (5 ml) and stirred with odium sulfate under n atmosphere.
  • Step B Preparation of dimethyl 3-phenylisoxazole-4, 5-dicarboxylate
  • Step B l-chloro-2-ethenyl-3-(methoxymethoxy)benzene
  • Step D 3-chloro-2-ethenylphenyl methanesulfonate
  • Step B Preparation of ethyl 2-(3-(difluoromethyl)-2-methyI-5-oxo-2,5-dihydro-lH-pyrazol-l- yl)acetate
  • Step C Preparation of 2-(3-(difluoromethyl)-2-methyl-5-oxo-2,5-dihydro-lH-pyrazol-l-yl)acetic acid
  • Step A Preparation of ethyl 2-(4-bromo-3-(difluoromethyl)-2-niethyl-5-oxo-2,5-dihydro-lH- pyrazol-l-yl)acetate
  • Step B Preparation of 2-(4-bromo-3-(difluoroniethyl)-2-methyl-5-oxo-2,5-dihydro-lH-pyrazol-l- yl)acetic acid

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Abstract

The present disclosure relates to a compound of Formula I, wherein the substituents T, A, W, R2, n, Z, G, Z1 and J are as defined in the description.

Description

HETEROCYCLIC COMPOUNDS WITH MICROBIOCIDAL PROPERTIES
FIELD OF THE INVENTION: The present invention relates to compounds containing one or more heterocyclic rings and salts, metal complexes, N-oxides, enantiomers, stereoisomers and polymorphs thereof; compositions and methods of use for controlling or preventing phytopathogenic micro-organisms.
PRIOR ART AND PROBLEM TO BE SOLVED:
The performance of reported compounds for controlling or preventing phytopathogenic micro-organisms is not always satisfactory. Further, the performance of these compounds in terms of activity spectrum, toxicity, selective activity, application rate, environmental demands, economical demands, cannot always be achieved. Moreover, due to prolong use of these compounds it is likely that pests may have developed resistance to these compounds thus rendering them ineffective in crop protection.
Various compounds have been reported in the literature for preventing against and controlling particularly, phytopathogenic micro-organisms. Some of the literature are WO200801 3622, WO2008013925, WO2009094407, WO2009094445, WO2010065579, WO201 1076699, WO201 1085170, WO2012025557, WO2012055837, WO2012104273, WO2013037768, WO2013098229, WO2013127808, WO2014075874, WO2014206896, WO2015028457, WO201 5144571 , WO2016024350, WO2016024434, WO2017109855, WO2017109858, and WO2017138069.
Surprisingly, it is now found that the compounds and compositions thereof of the present invention have the potential of overcoming drawbacks and are suitable for crop protection against phytopathogenic micro-organisms causing plant diseases.
SUMMARY OF THE INVENTION: ;
The present invention relates to compound of Formula I,
Figure imgf000002_0001
wherein the substituents are as defined in the description and claims. The present invention will now be described in detail in the description.
DETAILED DESCRIPTION:
DEFINITIONS:
The definitions provided herein for the terminologies used in the present invention are for illustrative purpose only and in no manner limit the scope of the present invention disclosed in the present invention.
As used herein, the terms "comprises", "comprising", "includes", "including", "has", "having", "contains", "containing", "characterized by" or any other variation thereof, are intended to cover a nonexclusive inclusion, subject to any limitation is explicitly indicated. For example, a composition, mixture, process or method that comprises a list of elements is not necessarily limited to only those elements but may include other elements not expressly listed or inherent to such composition, mixture, process or method.
The transitional phrase "consisting of excludes any element, step or ingredient not specified. If in the claim, such would close the claim to the inclusion of materials other than those recited except for impurities ordinarily associated therewith. When the phrase "consisting of appears in a clause of the body of a claim, rather than immediately following the preamble, it limits only the element set forth in that clause; other elements are not excluded from the claim as a whole.
The transitional phrase "consisting essentially of is used to define a composition or method that includes materials, steps, features, components or elements, in addition to those literally disclosed, provided that these additional materials, steps, features, components or elements do not materially affect the basic and novel characteristic(s) of the claimed invention. The term "consisting essentially of occupies a middle ground between "comprising" and "consisting of.
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 present invention are intended to be nonrestrictive regarding the number of instances (i.e. occurrences) of the element or component. Therefore "a" or "an" should be read to include one or at least one, and the singular word form of the element or component also includes the plural unless the number is obviously meant to be singular.
As referred to in this invention, the term "invertebrate pest" includes arthropods, gastropods and nematodes of economic importance as pests. The term "arthropod" includes insects, mites, spiders, scorpions, centipedes, millipedes, pil l bugs and symphylans. The term "gastropod" includes snails, sl ugs and other Stylommatophora. The term "nematode" refers to a living organism of the Phylum Nematoda. The term "helminths" includes roundworms, heartworms, phytophagous nematodes (Nematoda), flukes (Tematoda), acanthocephala and tapeworms (Cestoda).
In the context of this invention "invertebrate pest control" means inhibition of invertebrate pest development (including mortality, feeding reduction, and/or mating disruption), and related expressions are defined analogously.
The term "agronomic" refers to the production of field crops such as for food and fiber and includes the growth of corn, soybeans and other legumes, rice, cereal (e.g., wheat, oats, barley, rye, rice, maize), leafy vegetables (e.g., lettuce, cabbage, and other cole crops), fruiting vegetables (e.g., tomatoes, pepper, eggplant, crucifers and cucurbits), potatoes, sweet potatoes, grapes, cotton, tree fruits (e.g., pome, stone and citrus), small fruit (berries, cherries) and biofuel crops such as, jatropha, palm trees, other specialty crops (e.g., canola, sunflower, olives).
The term "nonagronomic" refers to other than field crops, such as horticultural crops (e.g., greenhouse, nursery or ornamental plants not grown in a field), residential, agricultural, commercial and industrial structures, turf (e.g., sod farm, pasture, golf course, lawn, sports field, etc.), wood products, stored product, agro-forestry and vegetation management, public health (i.e. human) and animal health (e.g., domesticated animals such as pets, livestock and poultry, undomesticated animals such as wildlife) applications.
Nonagronomic applications include protecting an animal from an invertebrate parasitic pest by administering a parasiticidally effective (i.e. biologically effective) amount of a compound of the present invention, typically in the form of a composition formulated for veterinary use, to the animal to be protected. As referred to in the present invention and claims, the terms "parasiticidal" and "parasiticidally" refers to observable effects on an invertebrate parasite pest to provide protection of an animal from the pest. Parasiticidal effects typical ly relate to diminishing the occurrence or activity of the target invertebrate parasitic pest. Such effects on the pest include necrosis, death, retarded growth, diminished mobility or lessened ability to remain on or in the host animal, reduced feeding and inhibition of reproduction. These effects on invertebrate parasite pests provide control (including prevention, reduction or elimination) of parasitic infestation or infection of the animal.
Compounds of the present invention may be present either in pure form or as mixtures of different possible isomeric forms such as stereoisomers or constitutional isomers. The various stereoisomers include enantiomers, diastereomers, chiral isomers, atropisomers, conformers, rotamers, tautomers, optical isomers, polymorphs, and geometric isomers. Any desired mixtures of these isomers fall within the scope of the claims of the present invention. 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 isomer(s) or when separated from the other isomer(s). Additional ly, the person ski lled in the art knows processes or methods or technology to separate, enrich, and/or to selectively prepare said isomers.
The meaning of various terms used in the description shall now be illustrated.
The term "alkyl", used either alone or in compound words such as "alkylthio" or "haloalkyl" or -N(aikyl) or alkylcarbonylalkyl or alkylsuphonylamino includes straight-chain or branched C, to C24 alkyl, preferably C | to Cj5 alkyl, more preferably C i to C i0 alkyl, most preferably C , to Q, alkyl. Representative examples of alkyl include methyl, ethyl, propyl, 1 -methylethyl, butyl, 1 -methylpropyl, 2-methylpropyl, 1 , 1 -dimethylethyl, pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1 - ethylpropyl, hexyl, 1 , 1 -dimethylpropyl, 1 ,2-dimethylpropyl, 1 -methylpentyl, 2-methylpentyl, 3- methylpentyl, 4-methylpentyl, 1 , 1 -dimethylbutyi, 1 ,2-dimethylbutyl, 1 ,3-dimethylbutyl, 2,2- dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1 -ethylbutyl, 2-ethylbutyl, 1 , 1 ,2-trimethylpropyl, 1 ,2,2-trimethylpropyl, 1 -ethyl- 1 -methylpropyl and l-ethyl-2-methylpropyl or the different isomers. If the alkyl is at the end of a composite substituent, as, for example, in alkylcycloalkyl, the part of the composite substituent at the start, for example the cycloalkyl, may be mono- or polysubstituted identically or differently and independently by alkyl. The same also applies to composite substituents in which other radicals, for example alkenyl, alkynyl, hydroxyl, halogen, carbonyl, carbonyloxy and the like, are at the end.
The term "alkenyl", used either alone or in compound words includes straight-chain or branched C2 to C24 alkenes, preferably C2 to CJ5 alkenes, more preferably C2 to C 10 alkenes, most preferably C2 to C6 alkenes. Representative examples of alkenes include ethenyl, 1 -propenyl, 2-propenyl, 1 -methylethenyl, 1 -butenyl,
2- butenyl, 3-butenyl, 1 -methyl- 1 -propenyl, 2-methyI-l-propenyl, l-methyl-2 -propenyl, 2-methyl-2- propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1 -methyl- 1 -butenyl, 2-methyl- 1 -butenyl, 3- methyl- 1 -butenyl, l-methyl-2-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, l-methyl-3-butenyl, 2- methyl-3-butenyl, 3-methyl-3-butenyl, l , l -dimethyl-2-propenyl, 1 ,2-dimethyl-l -propenyl, l ,2-dimethyl-2 -propenyl, 1 -ethyl- 1 -propenyl, l-ethyl-2-propenyl, 1 -hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1 -methyl- 1 -pentenyl, 2-methyl- 1 -pentenyl, 3-methyl- 1 -pentenyl, 4-methyl-l -pentenyl, l -methyl-2- pentenyl, 2-methyl -2-pentenyl, 3-methyl-2-pentenyl, 4-methyl-2-pentenyl, l-methyl-3-pentenyl, 2-methyl-
3- pentenyl, 3-methyl-3-pentenyl, 4-methyl-3-pentenyl, l -methyl-4-pentenyl, 2-methyl-4-pentenyl, 3- methyl-4-pentenyl, 4-m ethyl -4-pentenyl, l , l -dimethyl-2-butenyl, l,l-dimethyl-3-butenyl, 1 ,2-dimethyl-l- butenyl, l ,2-dimethyl-2-butenyl, l ,2-dimethyl-3-butenyl, 1 ,3-dimethyl- l -butenyl, l,3-dimethyl-2-butenyl, l,3-dimethyl-3-butenyl, 2,2-dimethyl-3-butenyl, 2,3-dimethyl- 1 -butenyl, 2,3-dimethyl-2-butenyl, 2,3- dimethyl-3-butenyl, 3,3-dimethyl-l-butenyl, 3,3-dimethyl-2-butenyl, 1 -ethyl-l -butenyl, l -ethyl-2-butenyl, l-ethyI-3-butenyl, 2-ethyl- 1 -butenyl, 2-ethyl-2-butenyl, 2-ethyl-3-butenyl, l,l,2-trimethyl-2-propenyI, I - ethyl-l-methyl-2-propenyl, l-ethyl-2-niethyl-l-propenyl and l-ethyl-2-methyl-2-propenyl and the different isomers. "Alkenyl" also includes polyenes such as 1 ,2-propadienyl and 2,4-hexadienyl. This definition also applies to alkenyl as a part of a composite substituent, for example haloalkenyl and the like, unless defined specifically elsewhere.
Representative examples of alkynes used either alone or in compound words include ethynyl, 1 -propynyl, 2-propynyl, 1 -butynyl, 2-butynyl, 3-butynyl, l -methyl-2-propynyl, 1 -pentynyl, 2-pentynyl, 3-pentynyl, 4- pentynyl, l-methyl-2-butynyl, l-methyl-3-butynyl, 2-methyl-3-butynyl, 3-methyl-l-butynyl, 1 , 1 -dimethyl- 2-propynyl, 1 -ethyl -2-propynyl, 1 -hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, l -methyl-2- pentynyl, l-methyl-3-pentynyl, l -methyl-4-pentynyl, 2-methyl-3-pentynyl, 2-methyl-4-pentynyl, 3- methyl-l-pentynyl, 3-methyl-4-pentynyl, 4-methyl-l-pentynyl, 4-methyl-2-pentynyl, l , l -dimethyl-2- butynyl, l,l-dimethyl-3-butynyl, l,2-dimethyl-3-butynyl, 2,2-dimcthyl-3-butynyl, 3,3-dimethyl-l-butynyl, l-ethyl-2-butynyl, 1 -ethyl -3 -but ny 1 , 2-ethyl-3-butynyl and l -ethyl-l-methyl-2-propynyl and the different isomers. This definition also applies to alkynyl as a part of a composite substituent, for example haloalkynyl etc., unless specifically defined elsewhere. "Alkynyl" can also include moieties comprised of multiple triple bonds such as 2,5-hexadiynyl.
Cycloalkyl means alkyl closed to form a ring. Representative examples include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. This definition also applies to cycloalkyl as a part of a composite substituent, for example cycloalkylalkyl etc., unless specifically defined elsewhere.
Cycloalkenyl means alkenyl closed to form a ring including monocyclic, partially unsaturated hydrocarbyl groups. Representative examples include but are not limited to cyclopropenyl, cyclobutenyl, cyclopentenyl and cyclohexenyl. This definition also applies to cycloalkenyl as a part of a composite substituent, for example cycloalkenylalkyl etc., unless specifically defined elsewhere.
Cycloalkoxy, cycloalkenyloxy and the like are defined analogously. Non limiting examples of cycloalkoxy include cyclopropyloxy, cyclopentyloxy and cyclohexyloxy. This definition also applies to cycloalkoxy as a part of a composite substituent, for example cycloalkoxyalkyl etc., unless specifically defined elsewhere.
The term "halogen", either alone or in compound words such as "haloalkyl", includes fluorine, chlorine, bromine or iodine. Further, when used in compound words such as "haloalkyl", said alkyl may be partially or fully substituted with halogen atoms which may be the same or different. Examples of "haloalkyl" include chloromethyl, bromomethyl, iodomethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chlorofluoromethyl, dichlorofluoromethyl, chlorodifluoromethyl, 1 -chloroethyl, 1 -bromoethyl, 1 -fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2- trifluoroethyl, 2-chloro-2-fluoroethyl, 2-chloro-2,2-difluoroethyl, 2,2-dichloro-2-fluoroethyl, 2,2,2- trichloroethyl, pentafiuoroetbyl, ] , l -dichloro-2,2,2-trifluoroethyl, and l , l , l -trifiuoroprop-2-yl. This definition also applies to haloalkyl as a part of a composite substituent, for example haloalkylami noalkyl etc., unless specifically defined elsewhere.
The terms "haloalkenyl" and "haloalkynyl" are defined analogously except that, instead of alkyl groups, alkenyl and alkynyl groups are present as a part of the substituent.
The term "ha!oalkoxy" means straight-chain or branched alkoxy groups where at least one up to all of the hydrogen atoms in these groups may be replaced by halogen atoms as specified above. Non-limiting examples of haloalkoxy include chloromethoxy, iodomethoxy, bromomethoxy, dichloromethoxy, trichloromethoxy, fluoromethoxy, difluoromefhoxy, trifluoromethoxy, chlorofluoromethoxy, dichlorofluoromethoxy, chlorodifluoromethoxy, 1 -chloroethoxy, 1 -bromoethoxy, 1 -fluoroethoxy, 2- fluoroethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, 2-chloro-2-fluoroethoxy, 2-chloro-2,2- difluoroethoxy, 2,2-dichloro-2-fluoroethoxy, 2,2,2-trichloroethoxy, pentafluoroethoxy and 1,1,1- trifluoroprop-2-oxy. This definition also applies to haloalkoxy as a part of a composite substituent, for example haloalkoxyalkyl etc., unless specifically defined elsewhere.
The term "haloalkylthio" means straight-chain or branched alkylthio groups where at least one up to all of the hydrogen atoms in these groups may be replaced by halogen atoms as specified above. Non-limiting examples of haloalkylthio include chloromethylthio, iodomethylthio, bromomethylthio, dichloromethylthio, trichloromethylthio, fluoromethylthio, difluoromethylthio, trifluoromethylthio, chlorofluoromethylthio, dichlorofluoromethylthio, chlorodifluoromethylthio, 1 -chloroethylthio, 1 - bromoethylthio, 1 - fluoroethylthio, 2-fluoroethylthio, 2,2-difluoroethylthio, 2,2,2-trifluoroethylthio, 2- chloro-2- fluoroethylthio, 2-chloro-2,2-difluoroethylthio, 2,2-dichloro-2-fluoroethylthio, 2,2,2- trichloroethylthio, pentafluoroethylthio and l,l,l-trifluoroprop-2-ylthio. This definition also applies to haloalkylthio as a part of a composite substituent, for example haloalkylthioalkyl etc., unless specifically defined elsewhere.
Examples of "haloalkylsulfinyl" include CF3S(0), CC13S(0), CF3CH2S(0) and CF3CF2S(0). Examples of "haloalkylsulfonyl" include CF3S(0)2, CC13S(0)2, CF3CH2S(0)2 and CF3CF2S(0)2.
Hydroxy means -OH, amino means -NRR, wherein R can be H or any possible substituent such as alkyl. Carbonyl means -C(O)-, carbonyloxy means -OC(O)-, sulfinyl means SO, sulfonyl means S(0)2.
The term "alkoxy" used either alone or in compound words included Cj to C24 alkoxy, preferably C , to C is alkoxy, more preferably C | to C i o alkoxy, most preferably C | to C6 alkoxy. Examples of alkoxy include methoxy, ethoxy, propoxy, 1 -methyl ethoxy, butoxy, 1 -methylpropoxy, 2-methylpropoxy, 1 , 1 - dimethylethoxy, pentoxy, 1 -methyl butoxy, 2-methylbutoxy, 3-methylbutoxy, 2,2-dimethylpropoxy, 1 - ethylpropoxy, hexoxy, 1 , 1 -dimethylpropoxy, 1 ,2-dimethylpropoxy, 1 -methylpentoxy, 2-methylpentoxy, 3-methylpentoxy, 4-methy I pentoxy, 1 , 1 -dimethylbutoxy, 1 ,2-dimethylbutoxy, 1 ,3-dimethylbutoxy, 2,2- dimethylbutoxy, 2,3-dimethylbutoxy, 3,3-dimethylbutoxy, 1 -ethylbutoxy, 2-ethylbutoxy, 1 , 1 ,2- trimethylpropoxy, 1 ,2,2-trimethylpropoxy, 1 -ethyl-l -methylpropoxy and l-ethyl-2-methylpropoxy and the different isomers. This definition also applies to alkoxy as a part of a composite substituent, for example haloalkoxy, alkynylalkoxy, etc., unless specifically defined elsewhere.
"Alkoxyalkyl" denotes alkoxy substitution on alkyl. Examples of "alkoxyalkyl" include CH3OCH2, CH3OCH2CH2, CH3CH2OCH2, CH3CH2CH2CH2OCH2 and CH3CH2OCH2CH2.
The term "alkoxyalkoxy" denotes alkoxy substitution on alkoxy.
The term "alkylthio" includes branched or straight-chain alkylthio moieties such as methylthio, ethylthio, propylthio, 1 -methylethylthio, butylthio, 1 -methylpropylthio, 2-methylpropylthio, 1 , 1 -dimethylethylthio, pentylthio, 1 -methylbutylthio, 2-methylbutylthio, 3-methylbutylthio, 2,2-dimethylpropylthio, 1 - ethylpropylthio, hexylthio, 1 , 1 -dimethylpropylthio, 1 ,2-dimethylpropylthio, 1 -methylpentylthio, 2- methylpentylthio, 3-methylpentylthio, 4-rnethylpentylthio, 1 , 1 -dimethylbutylthio, 1 ,2-dimethylbutylthio, 1 ,3-dimethylbutylthio, 2,2-dimethylbutylthio, 2,3-dimethylbutylthio, 3,3-dimethylbutylthio, 1 - ethylbutylthio, 2-ethylbutylthio, 1 , 1 ,2-trimethylpropylthio, 1 ,2,2-trimethylpropylthio, 1 -ethyl-l - methylpropylthio and l-ethyl-2-methylpropylthio and the different isomers.
Halocycloalkyl, halocycloalkenyl, alkylcycloalkyl, cycloalkylalkyl, cycloalkoxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, haloalkylcarbonyl, cycloalkylcarbonyl, haloalkoxylalkyl, and the like, are defined analogously to the above examples.
The term "alkylthioalkyl" denotes alkylthio substitution on alkyl. Representative examples of "alkylthioalkyl" include -CH2SCH2, -CH2SCH2CH2, CH3CH2SCH2, CH3CH2CH2CH2SCH2 and CH3CH2SCH2CH2. "Alkylthioalkoxy" denotes alkylthio substitution on alkoxy. The term "cycloalkylalkylamino" denotes cycloalkyl substitution on alkyl amino.
The terms alkoxyalkoxyalkyl, alkylaminoalkyl, dialkylaminoalkyl, cycloalkylaminoalkyl, cycloalkylaminocarbonyl and the like, are defined analogously to "alkylthioalkyl" or cycloalkylalkylamino.
The term "alkoxycarbonyl" is an alkoxy group bonded to a skeleton via a carbonyl group (-CO-). This definition also applies to alkoxycarbonyl as a part of a composite substituent, for example cycloalkylalkoxycarbonyl and the like, unless specifically defined elsewhere.
The term "alkoxycarbonylalkylamino" denotes alkoxy carbonyl substitution on alkyl amino. "Alkylcarbonylalkylamino" denotes alkyl carbonyl substitution on alkyl amino. The terms alkylthioalkoxycarbonyl, cycloalkylalkylaminoalkyl and the like are defined analogously.
Examples of "alkylsulfinyl" include but are not limited to methylsulphinyl, ethylsulphinyl, propylsulphinyl, 1 -methylethylsulphinyl, butylsulphinyl, 1 -methylpropylsulphinyl, 2- methylpropylsulphinyl, 1 , 1 -dimethylethyIsulphinyl, pentylsulphinyl, 1 -methylbutylsulphinyl, 2- methylbutylsulphinyl, 3-methylbutylsulphinyl, 2,2-dimethylpropylsulphinyl, 1 -ethylpropylsulphinyl, hexylsu!phinyi, 1 , 1 -dimethylpropylsulphinyl, 1 ,2-dimethylpropylsulphinyl, 1 -methylpentylsulphinyl, 2- methylpentylsulphinyl, 3-methylpentylsulphinyl, 4-methylpentylsulphinyI, 1 , 1 -dimethylbutylsulphinyl, 1 ,2-dimethylbutylsulphinyl, 1 ,3-dimethylbutylsulphinyl, 2,2-dimethylbutylsulphinyl, 2,3- dimethylbutylsulphinyl, 3,3-dimethylbutylsulphinyl, 1 -ethylbutylsulphinyl, 2-ethylbutylsulphinyl, 1 , 1 ,2- trimethylpropylsulphinyl, 1 ,2,2-trimethylpropy!sulphinyl, 1 -ethyl-l -methylpropylsulphinyl and l -ethyl-2- methylpropylsulphinyl and the different isomers. The term "arylsulfinyl" includes Ar-S(O), wherein Ar can be any carbocyle or heterocylcle. This definition also appl ies to alkylsulphinyl as a part of a composite substituent, for example haloalkylsulphinyl etc., unless specifically defined elsewhere.
Examples of "alkylsulfonyl" include but are not l imited to methylsulphonyl, ethylsulphonyl, propylsulphonyl, 1 -methylethylsulphonyl, butylsulphonyl, 1 -methylpropylsulphonyl, 2- methylpropylsulphonyl, 1 , 1 -dimcthylethylsulphonyl, pentylsulphonyl, 1 -methylbutylsulphonyl, 2- methylbutylsulphonyl, 3-methy!butylsulphonyl, 2,2-dimethylpropylsulphonyl, 1 -ethylpropylsulphonyl, hexylsulphonyl, 1 , 1 -dimethylpropylsulphonyl, 1 ,2-dimethylpropylsulphonyl, 1 -methylpentylsulphonyl, 2- methylpentylsulphonyl, 3-methylpentylsulphonyl, 4-methylpentylsulphonyl, 1 , 1 -dimethylbutylsulphonyl, 1 ,2-dimethylbutylsulphonyl, 1 ,3-dimethylbutylsulphonyl, 2,2-dimethylbutylsulphonyl, 2,3- dimethylbutylsulphonyl, 3,3-dimethylbutylsulphonyl, 1 -ethylbutylsulphonyl, 2-ethylbutylsulphonyl, 1 , 1 ,2-trimethylpropylsulphonyl, 1 ,2,2-trimethylpropylsulphonyl, 1 -ethyl- 1 -methylpropylsulphonyl and 1- ethyl-2-methylpropylsulphonyl and the different isomers. The term "arylsulfonyl" includes Ar-S(0)2, wherein Ar can be any carbocyle or heterocylcle. This definition also applies to alkylsulphonyl as a part of a composite substituent, for example alkylsulphonylalkyl etc., unless defined elsewhere.
"Alkylamino", "dialkylamino", and the like, are defined analogously to the above examples.
The terms "carbocycle" or "carbocyclic" or "carbocyclyl" include "aromatic carbocyclic ring system" and "nonaromatic carbocylic ring system" or polycyclic or bicyclic (spiro, fused, bridged, nonfused) ring compounds in which the ring may be aromatic or non-aromatic (where aromatic indicates that the Hueckel rule is satisfied and non-aromatic indicates that the Hueckel rule is not statisfied).
The terms "heterocycle" or "heterocyclic" or "heterocyclyl" include "aromatic heterocycle or heteroaryl ring system" and "nonaromatic heterocycle ring system" or polycyclic or bicyclic (spiro, fused, bridged, nonfused) ring compounds in which the ring may be aromatic or non-aromatic, wherein the heterocycle ring contains at least one heteroatom selected from N, O, S(O)0_2, and or C ring member of the heterocycle may be replaced by C(=0), C(=S), C(=CR*R*) and C=NR*, * indicates integers (where aromatic heterocycle or heteroaryl ring indicates that the Hueckel rule is satisfied).
The term "non-aromatic heterocycle" means three- to fifteen-membered, preferably three- to twelve- membered, saturated or partially unsaturated heterocycles containing one to four heteroatoms from the group of oxygen, nitrogen and sulphur: mono, bi- or tricyclic heterocycles which contain, in addition to carbon ring members, one to three n atoms and/or one oxygen or sulphur atom or one or two oxygen and/or sulphur atoms; if the ring contains more than one oxygen atom, they are not directly adjacent; for example (but not limited to) oxiranyl, aziridinyl, 2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2- tetrahydrothienyl, 3-tetrahydrothienyl, 2-pyrrolidinyl, 3-pyrrol idinyl, 3-isoxazolidinyl, 4-isoxazolidinyl, 5-isoxazolidinyl, 3-isothiazolidinyl, 4-isothiazolidinyl, 5-isothiazolidinyl, 3-pyrazolidinyl, 4- pyrazolidinyl, 5-pyrazolidinyl, 2-oxazolidinyl, 4-oxazolidinyl, 5-oxazolidinyl, 2-thiazolidinyl, 4- thiazolidinyl, 5-thiazolidinyl, 2-imidazol idinyl, 4-imidazolidinyl, l ,2,4-oxadiazolidin-3-yl, 1,2,4- oxadiazolidin-5-yl, l,2,4-thiadiazolidin-3-yl, l ,2,4-thiadiazolidin-5-yl, l,2,4-triazolidin-3-yl, 1,3,4- oxadiazolidin-2-yl, l,3,4-thiadiazolidin-2-yl, l ,3,4-triazolidin-2-yl, 2,3-dihydrofur-2-yl, 2,3-dihydrofur-3- yl, 2,4-dihydrofur-2-yl, 2,4-dihydrofur-3-yl, 2,3-dihydrothien-2-yl, 2,3-dihydrothien-3-yl, 2,4- dihydrothien-2-yl, 2,4-dihydrothien-3-yl, 2-pyrrolin-2-yl, 2-pyrrolin-3-yl, 3-pyrrolin-2-yl, 3-pyrrolin-3-yl, 2-isoxazolin-3-yl, 3-isoxazol in-3-yl, 4-isoxazolin-3-yl, 2-isoxazolin-4-yl, 3-isoxazolin-4-yl, 4-isoxazolin- 4-yl, 2-isoxazolin-5-yl, 3-isoxazolin-5-yl, 4-isoxazolin-5-yl, 2-isothiazolin-3-yl, 3-isothiazolin-3-yl, 4- isothiazolin-3-yl, 2-isothiazolin-4-yl, 3-isothiazolin-4-yl, 4-isothiazolin-4-yl, 2-isothiazolin-5-yl, 3- isothiazolin-5-yl, 4-isothiazolin-5-yl, 2,3-dihydropyrazol-l-yl, 2,3-dihydropyrazol-2-yl, 2,3- dihydropyrazol-3-yl, 2,3-dihydropyrazol-4-yl, 2,3-dihydropyrazol-5-yl, 3,4-dihydropyrazol-l-yl, 3,4- dihydropyrazol-3-yl, 3,4-dihydropyrazol-4-yl, 3,4-dihydropyrazol-5-yl, 4,5-dihydropyrazol-l-yl, 4,5- dihydropyrazol-3-yl, 4,5-dihydropyrazol-4-yl, 4,5-dihydropyrazol-5-yl, 2,3-dihydrooxazol-2-yl, 2,3- dihydrooxazol-3-yl, 2,3-dihydrooxazol-4-yl, 2,3-dihydrooxazol-5-yl, 3,4-dihydrooxazol-2-yl, 3,4- dihydrooxazol-3-yl, 3,4-dihydrooxazol-4-yl, 3,4-dihydrooxazol-5-yl, 3,4-dihydrooxazol-2-yl, 3,4- dihydrooxazol-3-yl, 3,4-dihydrooxazol-4-yl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, l,3-dioxan-5-yl, 2-tetrahydropyranyl, 4-tetrahydropyranyl, 2-tetrahydrothienyl, 3-hexahydropyridazinyl, 4- hexahydropyridazinyl, 2-hexahydropyrimidinyl, 4-hexahydropyrimidinyl, 5-hexahydropyrimidinyl, 2- piperazinyl, l,3,5-hexahydrotriazin-2-yl, l,2,4-hexahydrotriazin-3-yl and cycloserines. This definition also applies to heterocyclyl as a part of a composite substituent, for example heterocyclylalkyl etc., unless specifically defined elsewhere.
The term "heteroaryl" means 5 or 6-membered, fully unsaturated monocyclic ring system containing one to four heteroatoms from the group of oxygen, n and sulphur; if the ring contains more than one oxygen atom, they are not directly adjacent; 5-membered heteroaryl containing one to four n atoms or one to three n atoms and one sulphur or oxygen atom: 5-membered heteroaryl groups which, in addition to carbon atoms, may contain one to four n atoms or one to three n atoms and one sulphur or oxygen atom as ring members, for example (but not limited thereto) 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyrrolyl, 3- pyrrolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 3- pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 2-thiazolyl, 4-thiazolyl, 5- thiazolyl, 2-imidazolyl, 4-imidazolyl, I,2,4-oxadiazol-3-yl, l,2,4-oxadiazol-5-yl, l,2,4-thiadiazol-3-yl, l,2,4-thiadiazol-5-yl, l,2,4-triazol-3-yl, I,3,4-oxadiazol-2-yl, l,3,4-thiadiazol-2-yl and l,3,4-triazol-2-yl; n- bonded 5-membered heteroaryl containing one to four n atoms, or benzofused n-bonded 5-membered heteroaryl containing one to three n atoms: 5-membered heteroaryl groups which, in addition to carbon atoms, may contain one to four n atoms or one to three n atoms as ring members and in which two adjacent carbon ring members or one n and one adjacent carbon ring member may be bridged by a buta- l,3-diene-l,4-diyl group in which one or two carbon atoms may be replaced by n atoms, where these rings are attached to the skeleton via one of the n ring members, for example (but not limited to) 1 -pyrrolyl, 1 - pyrazolyl, 1 ,2,4-triazol-l- yl, 1 -imidazolyl, 1 ,2,3-triazol-l-yl and 1 ,3,4-triazol-l-yl.
6-membered heteroaryl which contains one to four n atoms: 6-membered heteroaryl groups which, in addition to carbon atoms, may contain, respectively, one to three and one to four n atoms as ring members, for example (but not limited thereto) 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 3-pyridazinyl, 4- pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 2-pyrazinyl, I,3,5-triazin-2-yl, l,2,4-triazin-3-yl and l,2,4,5-tetrazin-3-yl; benzofused 5-membered heteroaryl containing one to three n atoms or one n atom and one oxygen or sulphur atom: for example (but not limited to) indol-l-yl, indol-2-yl, indol-3-yl, indol-4-yl, indol-5-yl, indol-6-yl, indol-7-yl, benzimidazol-l-yl, benzimidazol-2-yl, benzimidazol-4-yl, benzimidazol-5-yl, indazol-l-yl, indazol-3-yl, indazol-4-yl, indazol-5-yl, indazol-6-yl, indazol-7-yl, indazol-2-yl, l-benzofuran-2-yl, l-benzofuran-3-yl, l-benzofuran-4-yl, l-benzofuran-5-yl, 1 -benzofuran- 6- yl, l-benzofuran-7-yl, l-benzothiophen-2-yl, l-benzothiophen-3-yl, l-benzothiophen-4-yl, 1 - benzothiophen-5-yl, l-benzothiophen-6-yl, l-benzothiophen-7-yl, l,3-benzothiazol-2-yl, 1 ,3- benzothiazol- 4-yl, l,3-benzothiazoI-5-yl, l,3-benzothiazol-6-yl, l,3-benzothiazol-7-yl, l,3-benzoxazol-2-yl, 1,3- benzoxazol-4-yl, l,3-benzoxazol-5-yl, l ,3-benzoxazol-6-yl and l,3-benzoxazol-7-yl; benzofused 6- membered heteroaryl which contains one to three n atoms: for example (but not limited to) quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-5-yl, quinolin-6-yl, quinolin-7-yl, quinolin-8-yl, isoquinolin-l-yl, isoquinolin-3-yl, isoquinolin-4-yl, isoquinolin-5-yl, isoquinolin-6-yl, isoquinolin-7-yl and isoquinolin-8- yi-
This definition also applies to heteroaryl as a part of a composite substituent, for example heteroarylalkyl etc., unless specifically defined elsewhere.
The term "aromatic" indicates that the Hueckel rule is satisfied and the term "non-aromatic" indicates that the Hueckel rule is not satisfied.
"Trialkylsilyl" includes 3 branched and/or straight-chain alkyl radicals attached to and linked through a silicon atom such as trimethylsilyl, triethylsilyl and t-butyl-dimethylsilyl. "Halotrialkylsilyl" denotes at least one of the three alkyl radicals is partially or fully substituted with halogen atoms which may be the same or different. "Alkoxytrialkylsilyl" denotes at least one of the three alkyl radicals is substituted with one or more alkoxy radicals which may be the same or different. "Trialkylsilyloxy" denotes a trialkylsilyl moiety attached through oxygen.
Examples of "a!kylcarbonyl" include C(0)CH3, C(0)CH2CH2CH3 and C(0)CH(CH3)2. Examples of "alkoxycarbonyl" include CH3OC(=0), CH3CH2OC(=0), CH3CH2CH2OC(=0), (CH3)2CHOC(=0) and the different butoxy -or pentoxycarbonyl isomers. Examples of "alkylaminocarbonyl" include CH3NHC(=0), CH3CH2NFIC(=0), CH3CH2CH2NHC(=0), (CH3)2CHNHC(=0) and the different butylamino -or pentylaminocarbonyl isomers. Examples of "dialkylaminocarbonyl" include (CH3)2NC(=0), (CH3CEI2)2NC(=0), CH3CH2(CH3)NC(=0), CH3CH2CH2(CH3)NC(=0) and (CH3)2CHN(CH3)C(=0). Examples of "alkoxyalkylcarbonyl" include CH3OCH2C(=0), CH3OCH2CH2C(=0), CH3CH2OCH2C(=0), CFI3CH2CH2CH2OCH2C(=0) and CH3CH2OCH2CH2C(=0). Examples of "alkylthioalkylcarbonyl" include CI I3SCI I2C(=0), CH3SCH2CH2C(=0), CH3CH2SCH2C(=0), CH3CH2CH2CH2SCH2C(=0) and CH3CH2SCH2CH2C(=0). The term haloalkylsufonylaminocarbonyl, alkylsulfonylaminocarbonyl, alkylthioalkoxycarbonyl, alkoxycarbonylalkyl amino and the like are defined analogously
Examples of "alkylaminoalkylcal-bonyΓ, include CH3NHCH2C(=0), CH3NHCH2CH2C(=0), CH3CH2NHCH2C(=0), CH3CH2CH2CH2NHCH2C(=0) and CH3CH2NHCH2CH2C(=0).
The term "amide" means A-R'C=ONR"-B, wherein R' and R" indicate substituents and A and B indicate any group.
The term "thioamide" means A-R'C=SNR"-B, wherein R' and R" indicate substituents and A and B indicate any group.
The total number of carbon atoms in a substituent group is indicated by the "Q-C " prefix where i and j are numbers from 1 to 21 . For example, C1-C3 alkylsulfonyl designates methylsulfonyl through propylsulfonyl; 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. In the above recitations, when a compound of Formula I is comprised of one or more heterocyclic rings, all substituents are attached to these rings through any available carbon or n by replacement of a hydrogen on said carbon or n.
When a compound is substituted with a substituent bearing a subscript that indicates that the number of said substituents can exceed 1 , said substituents (when they exceed 1 ) are independently selected from the group of defined substituents. Further, when the subscript m in (R)m indicates an integer ranging from for example 0 to 4, then the number of substituents may be selected from the integers from 0 and 4 inclusive. When a group contains a substituent which can be hydrogen, then, when this substituent is taken as hydrogen, it is recognized that said group is being un-substituted. The term "fragments and tautomeric forms thereof having two double bonds inside the ring" means and includes the fragments capable of forming two double bonds inside the ring by tautomerization.
For example, since the fragments 1 , 3 and 5 are capable of forming two double bonds inside the ring by tautomerization as shown below and exist in tautomeric forms 2, 4 and 6 respectively, fragments 1 , 3 and 5 and tautomers thereof i.e., 2, 4 and 6 are included within the definition of the term "fragments and tautomeric forms thereof having two double bonds inside the ring".
Figure imgf000013_0001
The term "tautomer" has the same meaning as defined and elaborated in Organic Chemistry by Jonathan Clayden, Nick Geeves, Stuart Warren, chapter 21.
The embodiments herein and the various features and advantageous details thereof are explained with reference to the non-limiting embodiments in the description. Descriptions of well-known components and processing techniques are omitted so as to not unnecessarily obscure the embodiments herein. The examples used herein are intended merely to facilitate an understanding of ways in which the embodiments herein may be practiced and to further enable those of skilled in the art to practice the embodiments herein. Accordingly, the examples should not be construed as limiting the scope of the embodiments herein.
The description of the specific embodiments will so fully reveal the general nature of the embodiments herein that others can, by applying current knowledge, readily modify and/or adapt for various applications such specific embodiments without departing from the generic concept, and, therefore, such adaptations and modifications should and are intended to be comprehended within the meaning and range of equivalents of the disclosed embodiments. It is to be understood that the phraseology or terminology employed herein is for the purpose of description and not of limitation. Therefore, while the embodiments herein have been described in terms of preferred embodiments, those skilled in the art wil l recognize that the embodiments herein can be practiced with modification within the spirit and scope of the embodiments as described herein.
Any discussion of documents, acts, materials, devices, articles and the like that has been included in this specification is solely for the purpose of providing a context for the invention. It is not to be taken as an admission that any or all of these matters form a part of the prior art base or were common general knowledge in the field relevant to the invention as it existed anywhere before the priority date of this application. The numerical values mentioned in the description and the claims though might form a critical part of the present invention of the present invention, any deviation from such numerical values shall still fall within the scope of the present invention if that deviation follows the same scientific principle as that of the present invention disclosed in the present invention.
The term "pest" for the purpose of the present invention includes but is not limited to fungi, stramenopiles (oomycetes), bacteria, nematodes, mites, ticks, insects and rodents.
The term "plant" is understood here to mean all plants and plant populations, such as desired and undesired wild plants or crop plants (including naturally occurring crop plants). Crop plants may be plants which can be obtained by conventional breeding and optimization methods or by biotechnological and genetic engineering methods or combinations of these methods, including the transgenic plants and including the plant cultivars which are protectable and non-protectable by plant breeders' rights.
For the purpose of the present invention the term "plant" includes a living organism of the kind exemplified by trees, shrubs, herbs, grasses, ferns, and mosses, typically growing in a site, absorbing water and required substances through its roots, and synthesizing nutrients in its leaves by photosynthesis. Examples of "plant" for the purpose of the present invention include but are not limited to agricultural crops such as wheat, rye, barley, triticale, oats or rice; beet, e.g. sugar beet or fodder beet; fruits and fruit trees, such as pomes, stone fruits or soft fruits, e.g. apples, pears, plums, peaches, almonds, cherries, strawberries, raspberries, blackberries or gooseberries; leguminous plants, such as lenti ls, peas, alfalfa or soybeans; oil plants, such as rape, mustard, olives, sunflowers, coconut, cocoa beans, castor oil plants, oil palms, ground nuts or soybeans; cucurbits, such as squashes, cucumber or melons; fiber plants, such as cotton, flax, hemp or jute; citrus fruit and citrus trees, such as oranges, lemons, grapefruits or mandarins; any horticultural plants, vegetables, such as spinach, lettuce, asparagus, cabbages, carrots, onions, tomatoes, potatoes, cucurbits or paprika; lauraceous plants, such as avocados, cinnamon or camphor; cucurbitaceae; oleaginous plants; energy and raw material plants, such as cereals, corn, soybean, other leguminous plants, rape, sugar cane or oil palm; tobacco; nuts; coffee; tea; cacao; bananas; peppers; vines (table grapes and grape juice grape vines); hop; turf; sweet leaf (also called Stevia); natural rubber plants or ornamental and forestry plants, sueh as flowers, shrubs, broad-leaved trees or evergreens, e.g. conifers; and on the plant propagation material, such as seeds, and the crop material of these plants.
Preferably, the plant for the purpose of the present invention include but is not limited to cereals, corn, rice, soybean and other leguminous plants, fruits and fruit trees, grapes, nuts and nut trees, citrus and citrus trees, any horticultural plants, cucurbitaceae, oleaginous plants, tobacco, coffee, tea, cacao, sugar beet, sugar cane, cotton, potato, tomato, onions, peppers and vegetables, ornamentals, any floricultural plants and other plants for use of human and animals. The term "plant parts" is understood to mean all parts and organs of plants above and below the ground. For the purpose of the present invention the term plant parts includes but is not limited to cuttings, leaves, twigs, tubers, flowers, seeds, branches, roots including taproots, lateral roots, root hairs, root apex, root cap, rhizomes, slips, shoots, fruits, fruit bodies, bark, stem, buds, auxiliary buds, meristems, nodes and internodes.
The term "locus thereof includes soil, surroundings of plant or plant parts and equipment or tools used before, during or after sowing/planting a plant or a plant part.
Application of the compounds of the present invention or the compound of the present invention in a composition optionally comprising other compatible compounds to a plant or a plant material or locus thereof include application by a technique known to a person skilled in the art which include but is not limited to spraying, coating, dipping, fumigating, impregnating, injecting and dusting.
The term "applied" means adhered to a plant or plant part either physically or chemically including impregnation.
The present invention relates to a compound of Formula I,
Figure imgf000015_0001
The present invention is inclusive of salts, metal complexes, N-oxides, isomers, and polymorphs of the compound of Formula I.
The substituent T in the Formula 1 is a fragment of Formula II,
Figure imgf000015_0002
The ring members ', X2', X3 and X4 are independently C, N, O, S(0)a, C=S, C=0, S=NR" and S(0)=NR6 , and at least one of X ' , X2', X3 and X4 is C=0. Particularly, at least one of X1 and X4 is C=0 and when v=0 then at least one of X1 and X3 is C=0.
Provided when v is 1 , then the fragments of Formula II and tautomeric forms thereof having two double bonds inside the ring of Formula II are excluded from the definition of the fragment of Formula II.
Therefore, compound of formula I containing fragment of Formula II and tautormeric forms of such fragments having two double bonds inside the ring of Formula II when v is 1 , are excluded from the scope of the present invention. For example, the compound X is excluded from the scope of the present invention since the compound X undergoes tautomerization to have two double bonds as shown in Y.
Figure imgf000016_0001
v is an integer ranging from 0 to 3. When v is 0 the fragment of Formula II is a four membered ring. Similarly, when v is 1 , 2 and 3, the fragment of Formula II is a five, six and seven membered ring respectively. The subsequent ring members of the fragment of Formula II being added as a result of definition of "v" have the same meaning as defined for X 1, X2, X3 and X4. For example, when v is an integer 2, X4a is the new ring member and has the same meaning as defined for X', X2, X3 and X4. Particularly, v is an integer ranging from 0 to 2.
p is an integer ranging from 0 to 10. Particularly, p is an integer ranging from 0 to 8.
The indication, for example
Figure imgf000016_0002
for the purpose of this invention shall mean to include the rings with all the single bonds or all the possible double bonds, depending on the valency of the ring member or the possible combinations of single and double bonds.
In one of the embodiments T is selected from Tl to Tl 17
Non-limiting representative examples of T are depicted herein below wherein the bond at the right is attached to A as shown. The substituent R' may be attached to at least one possible position. The substituent R" has the same meaning as R' excluding hydrogen.
Figure imgf000016_0003
Figure imgf000017_0001
Figure imgf000018_0001
Figure imgf000019_0001
A is C(RI 5)2 or C(R15)2-C(Rl5)2 or NR16.
The substituent R15 is independently selected from hydrogen, halogen, cyano, hydroxy, -CHO, C1- C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C2-C4 haloalkenyl, C2-C4 haloalkynyl, C2-C4 alkoxyalkyl, C2-C4 alkylthioalkyl, C2-C4 alkylsulfinylalkyl, C2-C4 alkylsulfonylalkyl, C2-C4 alkylcarbonyl, C2-C4 haloalkylcarbonyl, C2-C5 alkoxycarbonyl, C3-C5 alkoxycarbonylalkyl, C2-C5 alkylaminocarbonyl, C3-C5 dialkylaminocarbonyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylthio, C1-C4 haloalkylthio, C1- C4 alkylsulfinyl, C1-C4 haloalkylsulfinyl, C1-C4 alkyl sulfonyl and C1-C4 haloalkylsulfonyl .
Particularly, the substituent R 15 is hydrogen, halogen, cyano, hydroxy, -CHO, C1-C4 alkyl, C 1- C4 haloalkyl or C2-C5 alkoxycarbonyl.
The substituent R16 is hydrogen, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C2-C4 haloalkenyl, C2-C4 haloalkynyl, C2-C4 alkoxyalkyl, C2-C4 alkylthioalkyl, C2-C4 alkylsulfinylalkyl, C2- C4 alkylsulfonylalkyl, C2-C4 alkylcarbonyl, C2-C4 haloalkylcarbonyl, C2-C5 alkoxycarbonyl, C3- C5 alkoxycarbonylalkyl, C2-C5 alkylaminocarbonyl, C3-C5 dialkylaminocarbonyl, C1-C4 alkylsulfonyl and C1-C4 haloalkylsulfonyl.
Particularly, the substituent R16 is hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C2-C4 alkylcarbonyl, C2-C4 haloalkylcarbonyl or C2-C4 alkoxycarbonyl. W is O or S.
R2 is independently hydrogen, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 alkoxy, halogen, cyano or hydroxyl .
Alternatively, two R2 are taken together as C1-C4 alkylene or C2-C4 alkenylene to form a bridged bicyclic or fused bicyclic ring system.
In another alternative, two R2 attached to adjacent ring carbon atoms are taken together as -CH=CH- CH=CH- optionally substituted with 1 to 3 substituents selected from C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, halogen, hydroxy, amino, cyano and nitro.
Particularly, R2 independently is selected from C1-C2 alkyl, C1-C2 haloalkyl, C 1-C2 alkoxy, halogen, cyano and hydroxy.
Z is C or N. "n" is an integer ranging from 0 to 9 with a proviso that when Z is N, "n" is an integer ranging from 0 to 8; and when the presentation in ring D is a double bond then "n" is an integer
Figure imgf000020_0002
ranging from 0 to 7.
G is an optionally substituted 5- or 6- membered heteroaromatic ring or 5- or 6-membered saturated or partially saturated or unsaturated heterocyclic ring.
Particularly, G is a 5- or 6 membered heteroaromatic ring or 5- or 6- membered saturated or partially saturated or unsaturated heterocyclic ring, each ring optionally substituted with up to 2 substituents in case of 5- membered ring and up to 3 substituents in case of 6- membered ring, each substituent selected from R3 on carbon ring members and R1 1 on n ring members.
More particularly, G is a 5- or 6 membered heteroaromatic ring each ring optionally substituted with up to 2 substituents in case of 5- membered ring and up to 3 substituents in case of 6- membered ring, wherein in at least one of the hetero atoms is N; and the other heteroatom is N or S or O. The substituents on G are R3 on carbon ring members and Rl ! on n ring members.
Most particularly, G is a 5- membered heteroaromatic ring each ring optionally substituted with up to 1 substituents, wherein in at least one of the hetero atoms is N; and the other heteroatom is S or O.
In one of the embodiments G is selected from the G l to G62 as de icted herein below:
Figure imgf000020_0001
Figure imgf000021_0001
Figure imgf000022_0001
wherein the bond to the left is attached to ring D and the bond to the right is attached to Z' ; each R3a is independently H or R3 and each Rl l a is independently H or R". R3 and R" may be attached to any or all of the possible position/s.
The substituent R3 is a phenyl or 5- or 6-membered heteroaromatic ring optionally substituted with 1 to 2 substituents independently selected from R4a on carbon ring members and R4b on n ring members. Alternatively, R3 is independently C1-C3 alkyl, C1-C3 haloalkyl or halogen.
The substituent R4a is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4- Cio cycloalkylalkyl, C4-C10 alkylcycloalkyl, C5-C10 alkylcycloalkylalkyl, C1-C6 haloalkyl, C2- C6 haloalkenyl, C2-C6 haloalkynyl, C3-C6 halocycloalkyl, halogen, hydroxy, amino, cyano, nitro, C1- C4 alkoxy, Ci-C4 haloalkoxy, C1-C4 alkyl thio, C1-C4 alkyl sulfinyl, C1-C4 alkylsulfonyl, C1- C4 haloalkylthio, C1-C4 haloalkylsulfinyl, C1-C4 haloalkylsulfonyl, C1-C4 alkylamino, C2-C8 dialkylamino, C3-C6 cycloalkylamino, C2-C4 alkoxyalkyl, C1-C4 hydroxyalkyl, C2-C4 alkylcarbonyl, C2- C6 alkoxycarbonyl, C2-C6 alkylcarbonyloxy, C2-C6 alkylcarbonylthio, C2-C6 alkylaminocarbonyl, C3-C8 dialkylaminocarbonyl or C3-C6 trialkylsi lyl.
The substituent R4b is independently C1-C6 alkyl, C3-C6 alkenyl, C3-C6 alkynyl, C3-C6 cycloalkyl, C 1- C6 haloalkyl, C3-C6 haloalkenyl, C3-C6 haloalkynyl, C3-C6 halocycloalkyl or C2-C4 alkoxyalkyl .
The substituent R" is independently C1-C3 alkyl.
J is a 5-, 6- or 7-membered ring, a 8- to 1 1 -membered bicyclic ring system or a 7- to 1 1 -membered spirocyclic ring system, each ring member of ring or ring system is selected from C, N, O, S(0)a, C=0, C=S, and each ring or ring system optionally substituted with 1 to 5 substituents independently selected from R5.
Particularly, J is a 5- or 6- membered ring, wherein ring members are selected from carbon, up to 3 N and up to 2 O.
More particularly, J is a 5- or 6- membered ring, wherein ring members are selected from carbon, 1 N and 1 O.
In one of the embodiments J is selected from J l to J86 as depicted herein below:
Figure imgf000023_0001
Figure imgf000024_0001
wherein bond on the left is attached to Z1 and R3 may be substituted at any or all of the possible position/s and is a single or a double bond.
Alternatively, J is selected from
Figure imgf000024_0002
and
Figure imgf000024_0003
wherein W is C(R5)2 or CO or O or S or SO or S02 or NR5.
The subsituent R5 is independently hydrogen, halogen, cyano, hydroxy, nitro, -CHO, -C(=0)OH, - C(=0)NH2, -NR25R26, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, cycloalkyl, halocycloalkyl, alkylcycloalkyl, cycloalkylalkyi, cycloalkylcycloalkyl, halocycloalkylalkyl, alkylcycloalkylalkyl, cycloalkenyl, halocycloalkenyl, alkoxyalkyl, cycloalkoxyalkyl, alkoxyalkoxyalkyl, alkylthioalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, alkylaminoalkyl, dialkylaminoalkyl, haloalkylaminoalkyl, cycloalkylaminoalkyl, alkylcarbonyl, haloalkylcarbonyl, cycloalkylcarbonyl, alkoxycarbonyl, cycloalkoxycarbonyl, cycloalkylalkoxycarbonyl, alkylaminocarbonyl, dialkylarninocarbonyl, cycloalkylaminocarbonyl, haioalkoxyalkyl, hydroxyalkyl, aikoxy, haloalkoxy, cycloalkoxy, halocycloalkoxy, cycloalkylalkoxy, alkenyloxy, haloalkenyloxy, alkynyloxy, haloalkynyloxy, alkoxyalkoxy, alkylcarbonyloxy, haloalkylcarbonyloxy, cyc!oalkylcarbonyloxy, alkylcarbonylalkoxy, alkylthio, haloalkylthio, cycloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, trialkylsilyl, alkylsulfonylamino, haloalkylsulfonylamino or -Z2Q.
Particularly, the substituent R5 is independently hydrogen, halogen, cyano, hydroxy, nitro, -CHO, - C(=0)OH, -C(=0)NH2, -NR25R26, C , -C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C2- C6 haloalkenyl, C2-C6 haloalkynyl, C3-C8 cycloalkyl, C3-C8 halocycloalkyl, C4-C10 alkylcycloalkyl, C4- C 10 cycloalkylalkyi, C6-C 14 cycloalkylcycloalkyl, C4-C10 halocycloalkylalkyl, C5-C10 alkylcycloalkylalkyl, C3-C8 cycloalkenyl, C3-C8 halocycloalkenyl, C2-C6 alkoxyalkyl, C4-C10 cycloalkoxyalkyl, C3- C8 alkoxyalkoxyalkyl, C2-C6 alkylthioalkyl, C2-C6 alkylsulfinylalkyl, C2-C6 alkylsulfonylalkyl, C2- C6 alkylaminoalkyl, C3-C8 dialkylaminoalkyl, C2-C6 haloalkylaminoalkyl, C4-C10 cycloalkylaminoalkyl, C2-C8 alkylcarbonyl, C2-C6 haloalkylcarbonyl, C4-C8 cycloalkylcarbonyl, C2-C8 alkoxycarbonyl, C4-C8 cycloalkoxycarbonyl, C3-C10 cycloalkylalkoxycarbonyl, C2-C6 alkylaminocarbonyl, C3-C8 dialkylarninocarbonyl, C4-C8 cycloalkylaminocarbonyl, C2-C6 haloal koxyalkyl, C1-C6 hydroxyalkyl, C 1- C6 alkoxy, C1-C6 haloalkoxy, C3-C8 cycloalkoxy, C3-C8 halocycloalkoxy, C4-C10 cycloalkylalkoxy, C2- C6 alkenyloxy, C2-C6 haloalkenyloxy, C2-C6 alkynyloxy, C2-C6 haloalkynyloxy, C2-C6 alkoxyalkoxy, C2- C6 alkylcarbonyloxy, C2-C6 haloalkylcarbonyloxy, C4-C8 cycloalkylcarbonyloxy, C3- C6 alkylcarbonylalkoxy, C1-C6 alkylthio, C1-C6 haloalkylthio, C3-C8 cycloalkylthio, C1-C6 alkylsulfinyl, C1-C6 haloalkylsulfmyl, C1-C6 alkylsulfonyl, C1-C6 haloalkylsulfonyl, C3-C8 cycloalkylsulfonyl, C3-C10 trialkylsilyl, C1-C6 alkylsulfonylamino and Q^ haloalkylsulfonylamino. Alternatively, R5 is -Z2Q. The substituents R25 and R26 are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, C2-C6 alkylcarbonyl, C2-C6 haloalkylcarbonyl, C2-C6 alkoxycarbonyl, C2-C6 haloalkoxycarbonyl. Alternatively, R25 and R26 can be -Z4Q.
The substituent Q is independently phenyl, benzyl, naphthalenyl, a 5- or 6-membered aromatic ring, an 8- to 1 1 -membered aromatic multi-cyclic ring system, an 8- to 1 1 -membered aromatic fused ring system, a 5- or 6-membered heteroaromatic ring, an 8- to 1 1 -membered heteroaromatic multi-cyclic ring system or an 8- to 1 1 -membered heteroaromatic fused ring system, each ring member of the ring or the ring system is selected from C, N, O, S(0)a, C=0, C=S, and SiRl7R18, and each ring or ring system is optionally substituted with 1 to 8 substituents independently selected from R7 on carbon atoms of the rings and R 12 on n atoms of the rings.
Alternatively, Q is independently a 3- to 7-membered nonaromatic carbocyclic ring, a 5-, 6- or 7- membered nonaromatic heterocyclic ring, an 8- to 15-membered nonaromatic multi-cyclic ring system or an 8- to 1 5-membered nonaromatic fused ring system, each ring member of the ring or the ring system is selected from C, N, O, S(0)a, C=0, C=S and SiRl7R18, and each ring or ring system is optionally substituted with 1 to 8 substituents independently selected from R7 on carbon atom ring members and R12 on n atom ring members. The carbon to which Q is attached may be chiral or non-chiral carbon. The substituents R 17 and R18 are independently C 1-C5 alkyl, C2-C5 alkenyl, C2-C5 alkynyl, C3- C5 cycloalkyl, C3-C6 halocycloalkyl, C4-C10 cycloalkylalkyl, C4-C7 alkylcycloalkyl, C5- C7 alkylcycloalkylalkyl, C1-C5 haloalkyl, C 1-C5alkoxy and C 1-C5 haloalkoxy. Non-limiting examples of Q are depicted herein below wherein the bond at the left is attached to J or Z as the case may be. The substituent R7 may be attached to any possible position/s and the presentation "
Figure imgf000026_0002
is a single or a double bond.
Figure imgf000026_0001
Figure imgf000027_0001
Figure imgf000028_0001
Alternatively, J & Q together forms aryl or heterocyclic dioxepine ring system.
In one of the preferred embodiments J & Q together forms a fragment selected from M l and M2. The substituents R5, R7 and R12 may be attached at one or more possible position/s. x is an integer ranging from 0 to 2 and Y is selected from O, S & N.
Figure imgf000028_0002
The substituents R' and R7 are independently hydrogen, halogen, hydroxy, cyano, -OR25, -NR25R26, -N02, -SH, -SCN, -COR25, -C(=0)OR25, -C(=0)NR25R26, -NR25C(=0)R25, -0(C=0)R25, -0(C=0)NR25R26, - C(=NOR25)R26, -NR25S02R26, -CSR25, -C(=S)OR25, -C(=S)NR25R26, -NR25C(=S)R26, -0(C=S)R25, - 0(C=S)NR25R26, -0(C=S)SR25, -N=C(R25)2, -NHCN, -S02NHCN, -C(=0)NHCN, -C(=S)NHCN, - C(=S(0))NHCN, -S02NR25R26, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, cycloalkyl, halocycloalkyl, alkylcycloalkyl, cycloalkylalkyl, cycloalkylcycloalkyl, halocycloalkylalkyl, alkylcycloalkylalkyl, cycloaikenyl, halocycloalkenyl, alkoxyalkyl, cycloalkoxyalkyl, alkoxyalkoxyalkyl, alkylthioalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, alkylamino, dialkylamino, alkylaminoalkyl, dialkylaminoalkyl, haloalkylaminoalkyl, cycloalkylamino, cycloalkylaminoalkyl, alkylcarbonyl, haloalkylcarbonyi, cycloalkylcarbonyl, alkoxycarbonyl, cycloalkoxycarbonyl, cycloalkylalkoxycarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, cycloalkylaminocarbonyl, haloalkoxyalkyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, alkoxy, haloalkoxy, cycloalkoxy, halocycloalkoxy, cycloalkylalkoxy, alkenyloxy, haloalkenyloxy, alkynyloxy, haloalkynyloxy, alkoxyalkoxy, alkylcarbonyloxy, haloalkylcarbonyloxy, cycloalkylcarbonyloxy, alkylcarbonylalkoxy, alkylthio, haloalkylthio, cycloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, cycloalkylsulfinyl, trialkylsilyl, alkylsulfonylamino, haloalkylsulfonylamino, alkylcarbonylthio, alkylsulfonyloxy, alkylsulfinyloxy, arylsulfonyloxy, arylsulfinyloxy, arylsulfonyl, arylsulfinyl, cyanoalkyl, alkenylcarbonyloxy, alkoxyalkylthio, alkylthioalkoxy, haloalkenylcarbonyloxy, alkoxycarbonylalkyl, alkoxyalkynyl, alkynylthio, halocycloalkylcarbonyloxy, alkenylamino, alkynylamino, haloalkylamino, cycloalkylalkylamino, alkoxyamino, haloalkoxyamino, alkylcarbonylamino, haloalkylcarbonylamino, alkoxycarbonylamino, alkylcarbonyialkylamino, haloalkylcarbonylalkylamino, alkoxycarbonylaikylamino, alkenylthio, haloalkoxycarbonyl, alkoxyalkylcarbonyl, haloalkoxycarbonylamino, di(haloalkyl)aminoalkyl, halocycloalkenyloxyalkyl, alkoxy(alkyl)aminocarbonyl, haloalkylsulfonylaminocarbonyl, alkylsulfonylaminocarbonyl, alkoxycarbonylalkoxy, alkylaminothiocarbonylamino, cycloalkylalkylaminoalkyl, alkylthiocarbonyl, cycloalkenyloxyalkyl, alkoxyalkoxycarbonyl, dialkylaminothiocarbonylamino, haloalkoxyhaloalkoxy, alkoxyhaloalkoxy, halocycloalkoxyalkyl, dialkylaminocarbonylamino, alkoxyalkenyl, alkylthiocarbonyloxy, haloalkoxyalkoxy, haloalkylsulfonyloxy, alkoxyhaloalkyl, di(haloalkyl)amino, dialkoxyalkyl, alkylaminocarbonylamino, haloalkoxyhaloalkyl, alkylaminocarbonylalkylamino, trialkylsilylalkynyloxy, trialkylsilyloxy, trialkylsilylalkynyl, cyano(alkoxy)alkyl, dialkylthioalkyl, alkoxysulfonyl, halocycloalkoxycarbonyl, alkylcycloalkylcarbonyl, halocycloalkylcarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, cyanoalkoxycarbonyl, alkylthioalkoxycarbonyl, alkynylcarbonyloxy, haloalkynylcarbonyloxy, cyanocarbonyloxy, cyanoalkylcarbonyloxy, cycloalkylsulphonyloxy, cycloalkylalkylsulphonyloxy, halocycloalkylsulphonyloxy, alkenylsulphonyloxy, alkynylsulphonyloxy, cyanoalkylsulphonyloxy, haloalkenylsulphonyloxy, haloalkynylsulphonyloxy, alkynylcycloalkyloxy, cyanoalkenyloxy, cyanoalkynyloxy, alkoxycarbonyloxy, alkenyloxycarbonyloxy, alkynyloxycarbonyloxy, alkoxyalkylcarbonyloxy, sulfilimines, sulfoximines and -SF5. Alternatively, R1 and R7 can be -Z2Q.
Two R' of Formula II may form a bridged ring system. For instance, X' and X3 may be connected through for example either of -CH2-, -CH2CH2-, -CH2CH2CH2- or -CH2CH2CH2CH2- to form a bridged ring system. Similarly, in case when v is 3, X2 and X3 may be connected to either of -CH2-, -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, -CH2CH2(CH3)CFI2-, or -CH2(CH3)CH2(CH3)-.
Q is particularly Q45 or Q99 and the substituent R7 is independently selected from fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxyl, amino, -SH, -C(=0)H, methyl, ethyl, propyl, 1 -methylethyl, n- butyl, 1 , 1 -dimethylethyl, 1 ,2-dimethylethyl, ethenyl, ethynyl, trifluoromethyl, difluoromethyl, trichloromethyl, dichloromethyl, cyclopropyl, methoxy, ethoxy, n-propoxy, l -methyl-ethoxy, 1 , 1 - dimethylethoxy, methylcarbonyl, ethylcarbonyl, trifluoromethylcarbonyl, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, 1 -methylethoxycarbonyl, 1 , 1 -dimethylethoxycarbonyl, 1 - ethenyloxy, 2-propenyloxy, 2-propynyloxy, methylcarbonyloxy, trifluoromethylcarbonyloxy, chloromethylcarbonyloxy, methylthio, ethylthio and methylsulphonyl.
The substituent R12 is hydrogen, -OR25, -COR25, -C(=0)OR25, -C(=0)NR25R26, -C(=NOR25)R2<> j -CSR25, - C(=S)OR25, -C(=S)NR25R26, -S02NHCN, -C(=0)NHCN, -C(=S)NHCN, -C(=S(0))NHCN, -S02NR25R26, alkyl, alkenyl, alkynyl, haloalkyi, haloalkenyl, haloalkynyl, cycloalkyl, halocycloalkyl, alkylcycloalkyl, cycloalkylalkyl, cycloalkylcycloalkyl, halocycloalkylalkyl, alkylcycloalkylalkyl, cycloalkenyl, halocycloalkenyl, alkoxyalkyl, cycloalkoxyalkyl, alkoxyalkoxyalky!, alkylthioalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, alkylamino, dialkylamino, alkylaminoalkyl, dialkylaminoalkyl, haloalkylaminoalkyl, cycloalkylamino, cycloalkylaminoalkyl, alkylcarbonyl, haloalkylcarbonyl, cycloalkylcarbonyl, alkoxycarbonyl, cycloalkoxycarbonyl, cycloalkylalkoxycarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, cycloalkylaminocarbonyl, haloalkoxyalkyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, alkoxy, haloalkoxy, cycloalkoxy, halocycloalkoxy, cycloalkylalkoxy, alkenyloxy, haloalkenyloxy, alkynyloxy, haloalkynyloxy, alkoxyalkoxy, alkylcarbonyloxy, haloalkylcarbonyloxy, cycloalkylcarbonyloxy, alkylcarbonylalkoxy, alkylthio, haloalkylthio, cycloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, cycloalkylsulfinyl, trialkylsilyl, alkylsulfonylamino, haloalkylsulfonylamino, alkylcarbonylthio, alkylsulfonyloxy, alkylsulfinyloxy, arylsulfonyloxy, arylsulfmyloxy, arylsulfonyl, arylsulfinyl, cyanoalkyl, alkenylcarbonyloxy, alkoxyalkylthio, haloalkenylcarbonyloxy, alkoxycarbonylalkyl, alkoxyalkynyl, alkynylthio, halocycloalkylcarbonyloxy, alkenylamino, alkynylamino, haloalkyiamino, cycloalkylalkylamino, alkoxyamino, haloalkoxyamino, alkylcarbonylamino, haloalkylcarbonylamino, alkoxycarbonylamino, alkylcarbonylalkylamino, haloalkylcarbonylalkylamino, alkoxycarbonylalkylamino, alkenylthio, haloalkoxycarbonyl, alkoxyalkylcarbonyl, haloalkoxycarbonylamino, di(haloaIkyl)aminoalkyl, halocycloalkenyloxyalkyl, alkoxy(alkyl)aminocarbonyl, haloalkylsulfonylaminocarbonyl, alkylsulfonylaminocarbonyl, alkoxycarbonylalkoxy, alkylaminothiocarbonylamino, cycloalkylalkylaminoalkyl, alkylthiocarbonyl, cycloalkenyloxyalkyl, alkoxyalkoxycarbonyl, dialkylaminothiocarbonylamino, haloalkoxyhaloalkoxy, alkoxyhaloalkoxy, halocycloalkoxyalkyl, dialkylaminocarbonylamino, alkoxyalkenyl, alkylthiocarbonyloxy, haloalkoxyalkoxy, haloalkylsulfonyloxy, alkoxyhaloalkyl, di(haloalkyl)amino, dialkoxyalkyl, alkylaminocarbonylamino, haloalkoxyhaloalkyl, alkylaminocarbonylalkylamino, trialkylsi lylalkynyloxy, trialkylsilyloxy, trialkylsilylalkynyl, cyano(alkoxy)alkyl, dialkyltbioalkyl, alkoxysulfonyl, halocycloalkoxycarbonyl, alkylcycloalkylcarbonyl, halocycloalkylcarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, cyanoalkoxycarbonyl, alkylthioalkylcarbonyl, alkylthioalkoxycarbonyl, alkylaminoalkylcarbonyl, alkynylcarbonyloxy, haloalkynylcarbonyloxy, cyanocarbonyloxy, cyanoalkylcarbonyloxy, cycloalkylsulphonyloxy, cycloalkylalkylsulphonyloxy, halocycloalkylsulphonyloxy, alkenylsulphonyloxy, alkynylsulphonyloxy, cyanoalkylsulphonyloxy, haloalkenylsulphonyloxy, haloalkynylsulphonyloxy, alkynylcycloalkyloxy, cyanoalkenyloxy, cyanoalkynyloxy, alkoxycarbonyloxy, alkenyloxycarbonyloxy, alkynyloxycarbonyloxy, alkoxyalkylcarbonyloxy, sulfilimines, sulfoximines, and -SF5. Alternatively, Rl2 can be -Z2Q.
R5 and R7 or R12 taken together with the atoms linking R5 and R7 or R12 to form a saturated, unsaturated or partially unsaturated 4- to 7-membered ring, each ring members selected from C, N, O, S(0)a,C=0, C=S, S=NR6 and S(0)=NR6, and said ring optionally substituted by R7 on carbon atom ring members and R 12 on n atom ring members.
Two R' taken together with the atoms to which they are attached form saturated, unsaturated or partially unsaturated 4- to 7-membered ring containing ring members selected from C, S, N, O, C=0, C=S, S(O), S(0)2j and S(0)=NR12, and said ring optionally substituted by R7 on carbon atom ring members and R 12 on n atom ring members.
Particularly, R5 and R7 or R12 taken together with the atoms linking R5 and R7 or R i 2 to foi τη a saturated, unsaturated or patially unsaturated substituted 5- to 7-membered ring, each ring members selected from C, N, O, S, C=0, C=S, S(O), S(0)2 and S(0)=NR12, the ring optionally substituted on ring members other than the atoms linking R5 and R7 or R12 with up to 4 substituents selected from R8.
The substituent R8 is independently selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3- C6 cycloalkyl, C4-C10 cycloalkylalkyl, C4-C10 alkylcycloalkyl, C5-C10 alkylcycloalkylalkyl, C1- C6 haloalkyl, C2-C6 haloalkenyl, C2-C6 haloalkynyl, C3-C6 halocycloalkyl, halogen, hydroxy, amino, cyano, nitro, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylthio, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl, C1-C4 haloalkylthio, C1-C4 haloalkylsulfinyl, C1-C4 haloalkylsulfonyl, C1-C4alkylamino, C2-C8 dialkylamino, C3-C6 cycloalkylamino, C2-C4 alkoxyalkyl, C1-C4 hydroxyalkyl, C2-C4 alkylcarbonyl, C2- C6 alkoxycarbonyl, C2-C6 alkylcarbonyloxy, C2-C6 alkylcarbonylthio, C2-C6 alkylaminocarbonyl, C3-C8 dialkylaminocarbonyl and C3-C6 trialkylsilyl.
The substituents Z1 and Z2 are independently a direct bond, O, C=0, C=S, S(0)a, CHR20 or NR21.
The substituent Z4 is independently O, C=0, C=S, S(0)a or CHR20.
The substituent R20 is independently hydrogen, C1-C4 alkyl or C1-C4 haloalkyl. The substituent R21 is independently hydrogen, C1-C8 alkyl, C1-C8 haloalkyl, C3-C8 cycloalkyl, C2-C6 alkylcarbonyl, C2-C8 haloalkylcarbonyl, C2-C8 alkoxycarbonyl or C2-C8 haloalkoxycarbonyl.
a is an integer independently ranging from 0 to 2.
Non-limiting compounds of the present invention comprise:
Compound No. 1 : 3-chloro-l -(2-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2- yl)piperidin- l -yl)-2-oxoethyl)-5-(trifluoromethyl)pyridin-2( l H)-one; Compound No. 2: 2-(2-(4-(4-(5- (2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin- l -yl)-2-oxoethyl)isoindoline- l ,3- dione; Compound No. 3 : 3,4-dichloro-l -(2-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3- yl)thiazol-2-yl)piperidin- l -yl)-2-oxoethyl)-l H-pyrrole-2,5-dione; Compound No. 4: l -(2-(4-(4-(5-(2,6- difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin- l -yl)-2-oxoethyl)- l H-pyrrole-2,5-dione; Compound No. 5: 3-chloro-2-(3-(2-( l -(2-(5,5-dimethyl-l -oxido-4-phenyl- l ,2,3-thiadiazol-2(5H)- yl)acetyl)piperidin-4-yl)thiazol-4-yl)-4,5-dihydroisoxazol-5-yl)phenyl methanesulfonate; Compound No. 6: 3-chloro-2-(3-(2-( l -(2-(3-chloro-2-oxo-5-(trifluoromethyI)pyridin- l (2H)-yI)acetyl)piperidin-4- yl)thiazol-4-yl)-4,5-dihydroisoxazol-5-yl)phenyl methanesulfonate; Compound No. 7: 3-chloro-l-(2-(4- (4-(5-(2-chloiOphenyl)-4,5-dihydroisoxazol-3-yi)thiazol-2-yl)piperidin-]-yl)-2-oxoethyl)-5- (trifluoromethyI)pyridin-2(lH)-one; Compound No. 8: l-(2-(4-(4-(5-(2-chIorophenyI)-4,5- dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-5-(trifluoromethyl)pyridin-2
Compound No. 9: 5-biOmo-l-(2-(4-(4-(5-(2-chlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2- yl)piperidin-l-yl)-2-oxoethyl)pyridin-2(lH)-one; Compound No. 10: l-(2-oxo-2-(4-(4-(5-phenyl-4,5- dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)ethyl)-5-(trifluoromethyl)pyridin-2(lH)-one; Compound No. 11 : 4-chloro-5-methoxy-2-(2-oxo-2-(4-(4-(5-phenyl-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-
1- yl)ethyl)pyridazin-3(2H)-one; Compound No. 12: 5-bromo-l -(2-oxo-2-(4-(4-(5-phenyl-4,5- dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)ethyl)pyridin-2(lH)-one; Compound No.13: 3-chloro-l- (2-oxo-2-(4-(4-(5-phenyl-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)ethyl)-5- (trifluoromethyl)pyridin-2(lH)-one; Compound No. 14: 5-bromo-l-(2-(4-(4-(5-(2,6-ditluorophenyl)-4,5- dihydroisoxazol-3-yl)thiazol-2-yl)pipendin-l-yl)-2-oxoethyl)pyridin-2(lH)-one; Compound No.15: l-(2- (4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-^ (trifluoromethyl)pyridin-2(lH)-one; Compound No. 16: 4-chloro-2-(2-(4-(4-(5-(2,6-difluorophenyl)-4,5- dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-5-methoxypyndazin-3(2H)-one; Compound No.17: 3-chloro-l-(2-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)^
2- oxoethyl)-5-((trifluoromethyl)thio)pyridin-2(lH)-one; Compound No. 18: l-(2-oxo-2-(4-(4-(5-(2,4,6- trichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)etbyl)-5-(trifluoroniethyl)pyridi 2(lH)-one; Compound No.19: 3-chloro-l-(2-oxo-2-(4-(4-(5-(2,4,6-trichlorophenyl)-4,5-dihydroisoxazol-
3- yl)thiazol-2-yl)piperidin-l-yl)ethyl)-5-(trifluoromethyl)pyridin-2(lH)-one; Compound No.20: l-(2-(4- (4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-4- methylpyridin-2(lH)-one; Compound No. 21: 5-((dimethyl(oxo)-X6-sulfaneyIidene)amino)-l-(2-oxo-2- (4-(4-(5-phenyl-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)ethyl)pyridin-2(lH)-one; Compound No. 22: 4Hnethyl-l-(2-oxo-2-(4-(4-(5-(2,4,64nchlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2- yl)piperidin-l-yI)ethyl)pyridin-2(lH)-one; Compound No. 23: 3-chIoro-2-(3-(2-(l-(2-(2-oxo-5- (trifluoromethyl)pyridin-l(2H)-yl)acetyl)piperidin-4-yl)thiazol-4-yl)-4,5-dihydroisoxazol-5^^ methanesulfonate; Compound No.24: 2-(3-(2-(l-(2-(5-bromo-2-oxopyridin-l(2H)-yl)acetyl)piperidin-4- yl)thiazol-4-yl)-4,5-dihydroisoxazol-5-yl)-3-chlorophenyl methanesulfonate; Compound No. 25: 3- chloro-2K3-(2-(l-(2-(4-methyl-2-oxopyridin-l(2H)-yl)acetyl)piperidii>4-yl)thiazol-4-yl)-4^
dihydroisoxazol-5-yl)phenyl methanesulfonate; Compound No. 26: 3-chloro-2-(3-(2-(l-(2-(5-chloro-2- oxopyridin-l(2H)-yl)acetyl)piperidin-4-yl)thiazol-4-yl)-4,5-dihydroisoxazol-5-yl)phenyl
methanesulfonate; Compound No. 27: 5-chloiO-l-(2-(4-(4-(5-(2-chlorophenyl)-4,5-dihydroisoxazol-3- yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)pyridin-2(lH)-one; Compound No. 28: l-(2-(4-(4-(5-(2- chIorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)pipendin-l-yl)-2-oxoethyl)-4-meth one; Compound No. 29: 4-chloro-2-(2-(4-(4-(5-(2-chlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2- yl)piperidin-l-yl)-2-oxoethyl)-5-methoxypyridazin-3(2H)-one; Compound No. 30: 5-chloro-l-(2-(4-(4-
(5-(2,6-difIuorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)pyridi one; Compound No. 31: l-(2-(4-(4-(5-(2-chlorophenyl)-4,5-dihydroisoxazol-3-yi)thiazol-2-yl)piperidin- l-yl)-2-oxoethyl)quinolin-2(lH)-one; Compound No. 32: l-(2-oxo-2-(4-(4-(5-(2-
(trifluoromethyI)phenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)ethyl)-5-
(trifluoromethyl)pyridin-2(lH)-one; Compound No. 33: 3-chloro-l-(2-oxo-2-(4-(4-(5-(2-
(trifluoromethyl)phenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)ethyl)-5-
(trifluoromethyl)pyridin-2(lH)-one; Compound No. 34: l-(2-(4-(4-(5-(2,6-difluorophenyl)-4,5- dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)quinolin-2(lH)-one; Compound No. 35: 3- chloro-l-(2-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2- thioxoethy])-5-(trifluoromethyl)pyridin-2(lH)-one; Compound No. 36: 3-chloro-l-(2-(4-(4-(5-(2,6- difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl^
Compound No.37: 5-chloro-1-(2-oxo-2-(4-(4-(5-phenyl-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin- l-yl)ethyI)pyridin-2(lH)-one; Compound No. 38: 4-methyl-l-(2-oxo-2-(4-(4-(5-phenyl-4,5- dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)ethyl)pyridin-2(lH)-one; Compound No.39: l-(2-(4-(4- (5-(2,6-dichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-5- (trifluoromethyl)pyridin-2(lH)-one; Compound No.40: 3-chloro-l-(2-(4-(4-(5-(2,6-dichlorophenyl)-4,5- dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-5-(trifluoromethyl)pyridin-2(lH)-o Compound No. 41: l-(2-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l- yl)-2-oxoethyl)pyridin-2(lH)-one; Compound No. 42: 3,5-dichloro-l-(2-(4-(4-(5-(2,6-difluorophenyl)- 4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)pyridin-4(lH)-one; Compound No. 43: l-(2-oxo-2-(4-(4-(5-phenyl-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)ethyl)azetidin
Compound No. 44: 1 -(2-oxo-2-(4-(4-(5-phenyl-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l - yl)ethyl)pyridin-2(lH)-one; Compound No. 45: l-(2-oxo-2-(4-(4-(5-phenyl-4,5-dihydroisoxazol-3- yl)thiazol-2-yl)piperidin-l-yl)ethyl)pyridin-2(lH)-one; Compound No. 46: 2-(2-(4-(4-(5-(2,6- difluoropheny])-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin- l-yl)-2-oxoethyl)-l -methyl- 1,2-dihydro- 3H-pyrazol-3-one; Compound No.47: 3-chloro-2-(3-(2-(l-(2-(3-chloro-2-oxo-5-(trifluoromethyl)pyridin- l(2H)-yl)acetyl)-l,2,3,6-tetrahydropyridin-4-yl)thiazol-4-yl)-4,5-dihydroisoxazol-5-yl)phenyl methanesulfonate; Compound No. 48: 2-(3-(2-(l-(2-(5-bromo-2-oxopyridin-l(2H)-yl)acetyl)-l,2,3,6- tetrahydropyridin-4-yl)thiazol-4-yl)-4,5-dihydroisoxazol-5-yl)-3-chlorophenyl methanesulfonate; Compound No. 49: 1 -methyl-2-(2-oxo-2-(4-(4-(5-(2-(trifluoromethyl)phenyl)-4,5-dihydroisoxazo]-3- yI)thiazol-2-yl)piperidin-l-yI)ethyl)-l,2-dihydro-3H-pyrazol-3-one; Compound No. 50: 2-(2-(4-(4-(5- (2,6-dichlorophenyl)-4,5-dihydroiso
dihydro-3H-pyrazol-3-one; Compound No. 51: 3-bromo-l-(2-(4-(4-(5-(2,6-dichlorophenyl)-4,5- dihydroisoxazol-3-yl)thiazoI-2-y])piperidin-l-y])-2-oxoeth^
Compound No. 52: l-(2-(4-(4-(5-(2,6-dichIoiOphenyl)-4,5-dihydroisoxazoI-3-yl)thiazol-2-yl)piperidin-l- yl)-2-oxoethyl)-3-(trifluoromethyl)pyridin-2(lH)-one; Compound No. 53: 5-bromo-l-(2-(4-(4-(5-(2,6- dichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazo]-2-yl)piperidin-l-yl)-2-oxoethyl)-3-
(trifluoromethyl)pyridin-2(lH)-one; Compound No. 54: l-(2-(4-(4-(5-(2,6-difluorophenyl)-4,5- dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-3-(trifluoromethyl)pyridin-2(] H)-one;
Compound No. 55: 5-biOmo-l-(2-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazoi-3-y!)thiazol-2- yl)piperidin-l-yl)-2-oxoethyl)-3-(tnfluoromethyl)pyridin-2(lH)-one; Compound No. 56: 3-chloro-2-(3-
(2-(l-(2-(6HTiethyl-2-oxo-3-(trifluoromethyl)pyridin-l(2H)-yl)acetyl)piperidin-4-y])th
dihydroisoxazol-5-yl)phenyl methanesulfonate; Compound No. 57: 3-chloro-2-(3-(2-(l-(2-(6-methyl-2- oxo-3-(trifluoromethyl)pyridin-l(2H)-yl)acetyl)piperidin-4-yl)thiazol-4-yl)-4,5-dih
yl)phenyl methanesulfonate; Compound No.58: l-(2-(4-(4-(5-(2,6-dichlorophenyl)-4,5-dihydroisoxazol-
3- yl)thiazol-2-yl)piperidh>l-yl)-2-oxoethyl)-6-me Compound No.59: 5-chloro-l-(2-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)- 2-oxoethyl)-6-methyl-3-(tnfluoromethyl)pyridin-2(lH)-one; Compound No. 60: 3-chloro-2-(3-(2-(l-(2- (3,5-dibromo-2-oxopyridin-l(2H)-yl)acetyl)piperidin-4-yl)thiazol-4-yl)-4,5-dihydroisoxazol-5-yl)phenyl methanesulfonate; Compound No. 61: 3,5-dibromo-l-(2-(4-(4-(5-(2,6-dichlorophenyl)-4,5- dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)pyridin-2(lH)-one; Compound No.62: 3,5- dibromo-l-(2-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)pipendin-l-yl)-2- oxoethyl)pyridin-2(lH)-one; Compound No.63: 3-chloro-2-(3-(2-(l-(2-(2-methyl-5-oxo-2,5-dihydro-lH- pyrazo]-l-yl)acetyl)piperidin-4-yl)thiazol-4-yl)-4,5-dihydroisoxazol-5-yl)phenyl methanesulfonate; Compound No. 64: 3-bromo-l-(2-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2- yl)piperidin-l-yl)-2-oxoethyl)-5-(trifluoromethyl)pyridin-2(lH)-one; Compound No.65: 2-(3-(2-(l-(2-(3- bromo-2-oxo-5-(trifluoiOmethyl)pyridin-l(2H)-yl)acetyl)piperidin-4-yl)thiazol-4-yl)-4,5- dihydroisoxazol-5-yl)-3-chloiOphenyl methanesulfonate; Compound No. 66: 5-bromo-3-chloro-l-(2-(4- (4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)pyridi 2(lH)-one; Compound No.67: 2-(3-(2-(l-(2-(5-biOmo-3-chloro-2-oxopyridin-l(2H)-yl)acetyl)piperidin-
4- yl)thiazol-4-yl)-4,5-dihydroisoxazol-5-yl)-3-chlorophenyl methanesulfonate; Compound No. 68: 5- bromo-3-chloro-l-(2-(4-(4-(5-(2,6-dichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l -yl)- 2-oxoethyl)pyridin-2(lH)-one; Compound No.69: 5-(difluoromethyl)-2-(2-(4-(4-(5-(2,6-difluorophenyl)- 4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-l-methyl-l,2-dihydro-3H-pyrazol-3- one; Compound No. 70: 2-(2-(4-(4-(5-(2,6-dichlorophenyl)-4,5-dihydroisoxazol-3-yI)thiazoI-2- yl)piperidin- 1 -yl)-2-oxoethyl)-5-(difluoromethyl)-l -methyl- l,2-dihydro-3H-pyrazol-3-one; Compound No. 71: 3-chloro-2-(3-(2-(l-(2-(3-(difluoromethy])-2-methyl-5-oxo-2,5-dihydro-lH-pyrazol-l- yl)acetyl)piperidin-4-yI)thiazol-4-yl)-4,5-dihydroisoxazol-5-yl)phenyl methanesulfonate; Compound No. 72: 3-chloro-2-(3-(2-(l-(2-(2-oxo-3-(trifluoromethyl)pyridin-l(2H)-yl)acetyl)piperidin-4-yl)thiazol-4-yl)- 4,5-dihydroisoxazol-5-yl)phenyl methanesulfonate; Compound No.73: 2-(3-(2-(l-(2-(5-bromo-2-oxo-3- (triiluoromethyl)pyridin-l(2H)-yl)acetyl)piperidin-4-yl)thiazol-4-yl)-4,5-dihydroisoxazol-5-yl)-3- chlorophenyl methanesulfonate; Compound No. 74: 3-chloro-2-(3-(2-(l-(2-(3,5-dichloro-2-oxopyridin- l(2H)-yl)acetyl)piperidin-4-yl)thiazol-4-yl)-4,5-dihydroisoxazol-5-yl)phenyl methanesulfonate; Compound No.75: 2-(l-(2-(3-chloro-2-oxo-5-(trifluoromethyl)pyridin-l(2H)-yl)acetyl)piperidin-4-yl)-N- (l,2,3,4-tetrahydronaphthalen-l-yl)thiazole-4-carboxamide; Compound No.76: 3-chloro-2-(3-(2-(l-(2-(6- methyl-2-oxopyridin-l(2H)-yl)acetyl)piperidin-4-yl)thiazol-4-yl)-4,5-dihydroisoxazol-5-yl)phenyl methanesulfonate; Compound No. 77: l-(2-(4-(4-(5-(2,6-difiuorophenyl)-4,5-dihydroisoxazol-3- yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-6-methylpyridin-2(lH)-one; Compound No.78: l-(2-(4-(4-(5- (2,6-dichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-6-methylpyridin- 2(lH)-one; Compound No. 79: 3-chloro-2-(3-(2-(l-(2-(3-cyano-2-oxopyridin-l(2H)-yl)acetyl)piperidin- 4-yl)thiazol-4-yl)-4,5-dihydroisoxazol-5-yl)phenyl methanesulfonate; Compound No. 80: l-(2-(4-(4-(5- (2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-2-oxo-l,2- dihydropyridine-3-carbonitrile; Compound No. 81: l-(2-(4-(4-(5-(2,6-dichlorophenyl)-4,5- dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-2-oxo-l,2-dihydropyridine-3-carbonitrile; Compound No. 82: 4-bromo-2-(2-(4-(4-(5-(2,6-dichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2- yl)piperidin-l-yl)-2-oxoethyl)-5-(difluoromethyl)-l-methyl-l,2-dihydro-3H-pyrazol-3-one; Compound No. 83: 4-bromo-5-(difluoromethyl)-2-(2-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol- 2-yl)piperidin-l-yl)-2-oxoethyl)-l-methyl-l,2-dihydro-3H-pyrazol-3-one; Compound No.84: 2-(3-(2-(l- (2-(4-bromo-3-(difluoi methyl)-2-methyl-5-oxo-2,5-dihydro-lH-pyrazol-l-yl)acetyl)piperidin-4- yl)thiazol-4-yl)-4,5-dihydroisoxazol-5-yl)-3-chlorophenyl methanesulfonate; Compound No. 85: 3,5- dichloro-l-(2-(4-(4-(5-(2,6-dichlorophenyl)-4,5-dihydi isoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2- oxoethyl)pyridin-2(lH)-one; Compound No. 86: 3-bromo-5-chloro-l-(2-(4-(4-(5-(2,6-difluorophenyl)- 4,5-dihydroisoxazol-3-yl)thiazol-2-yI)pipendin-l-yl)-2-oxoethyl)pyridin-2(lH)-one; Compound No. 87: l-(2-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-6- (trifluoromethyl)pyridin-2(lH)-one; Compound No. 88: 3-bromo-5-chloro-l-(2-(4-(4-(5-(2,6- dichloi'ophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)pyridin-2(lH)-one; Compound No. 89: 1 -(2-(4-(4-(5-(2,6-dichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l- yl)-2-oxoethyl)-6-(trifluoromethyl)pyridin-2(lH)-one; Compound No. 90: 2-(3-(2-(l-(2-(3-bromo-5- chloro-2-oxopyridin-l(2H)-yl)acetyl)piperidin-4-yl)thiazol-4-yI)-4,5-dihydroisoxazol-5-yl)-3- chlorophenyl methanesulfonate; Compound No. 91: 3-chloro-2-(3-(2-(l-(2-(2-oxo-6- (trifluoromethyl)pyridin-l(2H)-yl)acetyl)pipendin-4-yl)thiazol-4-yl)-4,5-dihydroi
methanesulfonate; Compound No.92: 3-bromo-5-methyl-l-(2-oxo-2-(4-(4-(5-(2,4,6-trichlorophenyl)-4,5- dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-]-yl)elhyl)pyridin-2(]H)-one; Compound No.93: 3-bromo-l- (2-(4-(4-(5-(2,6-dichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-5- methylpyridin-2(lH)-one; Compound No. 94: l-(2-(4-(4-(5-(2,6-dichlorophenyl)-4,5-dihydroisoxazol-3- yl)thiazoI-2-yl)piperidin-l-yl)-2-oxoethyl)-5-methylpyridin-2(]H)-one; Compound No.95: 2-(3-(2-(l-(2- (3-bromo-5-methyl-2-oxopyridin-l(2H)-yl)acetyl)piperidin-4-yl)thiazol-4-yl)-4,5-dihydroisoxazol-5-yl)^ 3-chlorophenyl methanesulfonate; Compound No. 96: 5-methyl-l-(2-oxo-2-(4-(4-(5-(2,4,6- tnchlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)ethyl)pyridin-2(lH)-one
Compound No. 97: 3,5-dichloro-l -(2-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2- yl)piperidin-l-yI)-2-oxoethyl)pyndin-2(lH)-one; Compound No. 98: l-(2-(4-(4-(5-(2,6-difluotOphenyl)- 4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-5-methyl-3-(trifluoromethyl)pyri 2(lH)-one; Compound No. 99: 2-(l-(2-(5-bromo-2-oxopyridin-l(2H)-yl)acetyl)piperidin-4-yl)-N- (l,2,3,4-tetrahydronaphthalen-l-yl)thiazoie-4-carboxamide; Compound No. 100: 3-chloro-l-(2-oxo-2-(4- (4-(5-(2,4,64richlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)ethyl)pyridi one; Compound No. 101: l-(2-(4-(4-(5-(2,6-dichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2- yl)piperidin-l-yl)-2-oxoethyl)-4-(trifluoromethyl)pyridin-2(lH)-one; Compound No. 102: l-(2-(4-(4-(5- (2,6-dichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-5-fluoropyr^ 2(lH)-one; Compound No. 103: l-(2-oxo-2-(4-(4-(5-(2,4,6-trichlorophenyl)-4,5-dihydroisoxazol-3- yl)thiazol-2-yl)piperidin-l-yl)ethyl)-4-(trifluoromethyl)pyridin-2(lH)-one; Compound No. 104: 5-fluoro- l-(2-oxo-2-(4-(4-(5-(2,4,64richlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-N yl)ethyl)pyridin-2(lH)-one; Compound No. 105: 3-chloro-2-(3-(2-(l-(2-(2-oxo-4- (trifluoromethyl)pyridin-l(2H)-yl)acetyl)piperidi
methanesulfonate; Compound No. 106: l-(2-oxo-2-(4-(4-(5-(2,4,6-trichlorophenyl)-4,5-dihydroisoxazol- 3-yl)thiazol-2-yl)piperidin-l-yl)ethyl)pyridin-2(lH)-one; Compound No. 107: 5-bromo-l-(2-oxo-2-(4-(4- (5-(2,4,64richloiOphenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)ethyl)pyridin-^
Compound No. 108: 3-chloiO-2-(3-(2-(l-(2-(2-oxopiperidin-l-yl)acetyI)piperidin-4-yl)thiazol-4-yl)-4,5- dihydroisoxazol-5-yl)phenyl methanesulfonate; Compound No. 109: 3-chloro-2-(3-(2-(l-(2-(2-oxo-3,5- bis(trifluoromethyl)pyridin-l(2H)-yl)acetyl)piperidin-4-yl)thiazol-4-yl)-4,5-dihydroisoxazol-5 methanesulfonate; Compound No. 110: l-(2-(4-(4-(5-(2,6-dichloiOphenyl)-4,5-dihydroisoxazol-3- yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)piperidin-2-one; Compound No. Ill: l-(2-(4-(4-(5-(2,6- dichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-3,5- bis(tnfluoromethyl)pyridin-2(lH)-one; Compound No. 112: 6-(difluoromethyl)-l-(2-oxo-2-(4-(4-(5- (2,4,6-trichlorophenyl)-4,5-dihydroisoxaz
Compound No. 113: 3-bromo-l-(2-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydiOisoxazol-3-yl)thiazol-2- yl)piperidin-l-yl)-2-oxoethyl)-5-methylpyridin-2(lH)-one; Compound No. 114: l-(2-(4-(4-(5-(2,6- difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-5-methylpyridin- 2(lH)-one; Compound No. 115: 6-(difluoromethy])-l-(2-(4-(4-(5-(2,6-difluoiOphenyl)-4,5- dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)pyridin-2(lH)-one; Compound No. 116: 1- (2-(4-(4-(5-(2,6-dichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-6- (difluoromethyl)pyridin-2(lH)-one; Compound No. 117: 3-chloro-2-(3-(2-(l-(2-(6-(difluoromethyl)-2- oxopyridin-l(2H)-yl)acetyl)piperidin-4-yl)thiazol-4-yl)-4,5-dihydroisoxazol-5-yl)phenyl
methanesulfonate; Compound No. 118: 3-chloro-2-(3-(2-(l-(2-(5-methyl-2-oxopyridin-l(2H)- yl)acetyl)piperidin-4-yl)thiazol-4-yl)-4,5-dihydroisoxazol-5-yl)phenyl methanesulfonate; Compound No. 119: l-(2-oxo-2-(4-(4-(5-(2,4,6-trichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l- yl)ethyl)-6-(trifluoromethyl)pyridin-2(lH)-one; Compound No. 120: 3-bromo-l-(2-oxo-2-(4-(4-(5-(2,4,6- trichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)ethyl)-5-(trifluoromethyl)pyri 2(lH)-one; Compound No. 121: 5-chloro-l-(2-(4-(4-(5-(2,6-dichlorophenyl)-4,5-dihydroisoxazol-3- yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-3-(trifluoromethyl)pyridin-2(lH)-one; Compound No. 122: 3- chloro-2-(3-(2-(l-(2-(5-fluoro-2-oxopyridin-l(2H)-yl)acetyl)piperidin-4-yl)thiazol-4-yl)-4,5- dihydroisoxazol-5-yl)phenyl methanesulfonate; Compound No. 123: l-(2-(4-(4-(5-(2,6-difluorophenyl)- 4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-4-(trifluoromethyl)pyridin-2(lH)-one; Compound No.124: l-(2-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l- yl)-2-oxoethyl)-5-fluoropyridin-2(lH)-one; Compound No. 125: l-(2-(4-(4-(5-(2,6-dichlorophenyl)-4,5- dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-3-methylpyridin-2(lH)-one; Compound No. 126: l-(2-(4-(4-(5-(2,6-dichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2- oxoethyl)-3,6-bis(trifluoromethyl)pyridin-2(lH)-one; Compound No. 127: l-(2-(4-(4-(5-(2,6- difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-3-methylpyridin- 2(lH)-one; Compound No. 128: l-(2-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2- yl)piperidin-l-yl)-2-oxoethyI)-3,6-bis(trifluoromethyl)pyridin-2(lH)-one; Compound No. 129: 1-methyl- 2-(2-oxo-2-(4-(4-(5-(2,4,6-trichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)ethyl)- l,2-dihydro-3H-pyrazol-3-one; Compound No. 130: 3,5-dichloro-l-(2-oxo-2-(4-(4-(5-(2,4,6- trichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)ethyl)pyridin-2(1H)-one;
Compound No. 131 : l-(2-oxo-2-(4-(4-(5-(2,4,6-trichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2- yl)piperidin-l-yl)ethyl)-3-(tnfluoromethyl)pyridin-2(lH)-one; Compound No. 132: methyl l-(2-(4-(4-(5- (2,6-dichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-2-oxo-5- (trifluoromethyl)-l,2-dihydropyridine-3-carboxylate; Compound No.133: methyl l-(2-(4-(4-(5-(2-chloro- 6-((methylsulfonyl)oxy)phenyl)-4,5-dihydroisoxazol-3-yl)th^
5-(trifluoromethyl)-],2-dihydropyridine-3-carboxylate; Compound No. 134: methyl l-(2-(4-(4-(5-(2,6- difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-2-oxo-5- (trifluoromethyl)-l,2-dihydropyridine-3-carboxylate; Compound No. 135: l-(2-(4-(4-(5-(2,6- difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)piperidin-2-one;
Compound No. 136: 2-oxo-l-(2-oxo-2-(4-(4-(5-(2,4,6-trichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-
2- yl)piperidin-l-yl)ethyl)-l,2-dihydropyridine-3-carbonitrile; Compound No. 137: 6-methyl-l-(2-oxo-2- (4-(4-(5-(2,4,6 richlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)ethyl)pyridi one; Compound No. 138: l-(2-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2- yl)piperidin-l-yl)-2-oxoethyl)pyrrolidin-2-one; Compound No. 139: l-(2-(4-(4-(5-(2,6-dichlorophenyl)- 4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)pyrrolidin-2-one; Compound No. 140:
3- chloro-2-(3-(2-(l-(2-(2-oxopyrrolidin-l-yl)acetyl)piperidin-4-yl)thiazol-4-yl)-4,5-dihydroisoxazol-5- yl)phenyl methanesulfonate; Compound No. 141: l-(2-oxo-2-(4-(4-(5-(2,4,6-trichlorophenyl)-4,5- dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)ethyl)pyrrolidin-2-one; Compound No. 142: l-(2-oxo-2- (4-(4-(5-(2,4,6-trichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)ethyl)piperi one; Compound No.143: l-(2-oxo-2-(4-(4-(5-(2,4,6-trichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2- yl)piperidin-l-yl)ethyl)piperidin-2-one; Compound No. 144: 3-chloro-2-(3-(2-(l-(2-(3-chloro-2- oxopyridin-l(2H)-yl)acetyl)piperidin-4-yl)thiazol-4-yl)-4,5-dihydroisoxazol-5-yl)phenyl
methanesulfonate; Compound No. 145: 5-chloro-l-(2-oxo-2-(4-(4-(5-(2,4,6-trichlorophenyl)-4,5- dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)ethyl)pyridin-2(lH)-one; Compound No. 146: l-(2-(4- (4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-3,5- bis(trifluoromethyl)pyridin-2(lH)-one; Compound No. 147: l-(2-(4-(4-(5-(2,6-dichlorophenyl)-4,5- dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-5-methyl-3-(trifluoromethyl)pyridin-^ one; Compound No.148: 2-(l-(2-(3-bromo-2-oxo-5-(trifluoromethyl)pyridin-l(2H)-yl)acetyl)pipendin-4- yl)-N-(l,2,3,4-tetrahydronaphthalen-l-yl)thiazole-4-carboxamide; Compound No. 149: 3-cyclopropyl-l- (2-(4-(4-(5-(2,6-diiluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-5- (trifluoromethyl)pyridin-2(lH)-one; Compound No. 150: l-(2-(4-(4-(5-(2,6-difluorophenyl)-4,5- dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-3-methyl-5-(trifluoromethyl)pyridin^ one; Compound No.151: 3-cyclopropyl-l-(2-oxo-2-(4-(4-(5-(2,4,6-trichlorophenyl)-4,5-dihydroisoxazol- 3-yl)thiazol-2-yl)piperidin-l-yl)ethyl)-5-(trifluoromethyl)pyridin-2(lH)-one; Compound No. 152: 3- methyl-l-(2-oxo-2-(4-(4-(5-(2,4,6 nchlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-y])piperidin-l- yl)ethyl)-5-(trifluoromethy])pyridin-2(lH)-one; Compound No. 153: 3-chloro-2-(3-(2-(l-(2-(3- cyclopropyl-2-oxo-5-(trifluoromethyl)pyridin-l(2H)-yl)acetyl)piperidin-4-yl)thiazol-4-yi)-4,5- dihydroisoxazol-5-yl)phenyl methanesulfonate; Compound No. 154: 5-bromo-2-oxo-l-(2-oxo-2-(4-(4-(5- (2,4,64richlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)pipendin-l -yl)ethyl)-l ,2-dihydropyridine-3- carbonitrile; Compound No. 155: 3-methyl-l-(2-oxo-2-(4-(4-(5-(2,4,6-trichlorophenyl)-4,5- dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)ethyl)pyridin-2(lH)-one; Compound No. 156: l-(2-oxo-
2- (4-(4-(5-(2,4,6-trichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)ethyl)-3,6- bis(tnfluoromethyl)pyridin-2(lH)-one; Compound No. 157: 3-chloro-2-(3-(2-(l-(2-(3-methyl-2- oxopyridin-l(2H)-yl)acetyl)piperidin-4-yl)thiazot-4-yl)-4,5-dihydroisoxazol-5-yl)phenyl
methanesulfonate; Compound No. 158: 3-chloro-2-(3-(2-(l-(2-(2-oxo-3,6-bis(trifluoromethyl)pyridin- l(2H)-yl)acetyl)piperidin-4-yl)thiazol-4-yl)-4,5-dihydroisoxazol-5-yl)phenyl methanesulfonate; Compound No. 159: 3-bromo-5-chloro-l-(2-oxo-2-(4-(4-(5-(2,4,6-trichlorophenyl)-4,5-dihydroisoxazol-
3- yl)thiazol-2-yl)piperidin-l-yl)ethyl)pyridin-2(lH)-one; Compound No. 160: 5-bromo-3-methyl-l-(2- oxo-2-(4-(4-(5-(2,4,64richlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazoI-2-yl)piperidin-l-yI)ethyl)pyridi 2(lH)-one; Compound No. 161: 5-bromo-l-(2-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3- yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-3-methylpyridin-2(lH)-one; Compound No. 162: 3-chloro-2- (3-(2-(l-(2-(3-methyl-2-oxo-5-(trifIuoromem^
dihydroisoxazol-5-yl)phenyl methanesulfonate; Compound No. 163: 3,5-dibromo-l-(2-oxo-2-(4-(4-(5- (2,4,64richlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)ethyl)pyridin-2(lH)-one; Compound No. 164: 6-methyl-l-(2-oxo-2-(4-(4-(5-(2,4,6-trichlorophenyl)-4,5-dihydroisoxazol-3- yl)thiazol-2-yl)piperidin-l-yl)ethyl)-3-(trifluoromethyl)pyridin-2(lH)-one; Compound No.165: 5-bromo-
1- (2-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyI)-2- oxo-l,2-dihydropyridine-3-carbonitrile; Compound No. 166: 5-methyl-l-(2-oxo-2-(4-(4-(5-(2,4,6- trichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)ethyl)-3-(trifluoromethyl)py^^ 2(lH)-one; Compound No. 167: 3-chloro-2-(3-(2-(l-(2-(5-methy]-2-oxo-3-(trifluoromethyl)pyridin- l(2H)-yl)acetyl)piperidin-4-yl)thiazol-4-yl)-4,5-dihydroisoxazoI-5-yl)phenyl methanesulfonate; Compound No. 168: 3-cyclopropyl-l-(2-(4-(4-(5-(2,6-dichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-
2- yl)piperidin-l-yl)-2-oxoethyl)-5-(trifluoiOmethyl)pyndin-2(lH)-one; Compound No. 169: l-(2-(4-(4- (5-(2,6-dichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-3-methyl-5- (trifluoromethyl)pyndin-2(lH)-one; Compound No. 170: 5-bromo-l-(2-(4-(4-(5-(2,6-dichlorophenyl)- 4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-3-nitropyridin-2(lH)-one; Compound No. 171 : 5-bromo-l-(2-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l- y])-2-oxoethy])-3-nitropyridin-2(lH)-one; Compound No. 172: 5-bromo-l-(2-(4-(4-(5-(2,6- dichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-2-oxo-l,2- dihydropyridine-3-carbonitrile; Compound No. 173: 5-chloro-l-(2-(4-(4-(5-(2,6-difluorophenyl)-4,5- dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyI)-2-oxo-l,2-dihydropyridine-3-carbonitrile; Compound No. 174: 5-chloro-l -(2-(4-(4-(5-(2,6-dichlorophenyl)-4,5-dihydiOisoxazol-3-yl)thiazol-2- yl)piperidin-l-yl)-2-oxoethyl)-2-oxo-l,2-dihydropyridine-3-carbonitrile; Compound No.175: 5-chloro-2- oxo-l-(2-oxo-2-(4-(4-(5-(2,4,6 richlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)pipendin-l- yl)ethyl)-l,2-dihydropyridine-3-carbonitrile; Compound No. 176: 3-chloro-2-(3-(2-(l-(2-(5-chloro-3- cyano-2-oxopyridin-l(2H)-yI)acetyl)piperidin-4-yl)thiazol-4-yl)-4,5-dihydroisoxazol-5-yl)phenyl methanesuifonate; Compound No. 177: 6-(difluoromethyl)-l-(2-(4-(4-(5-(2,6-difluorophenyI)-4,5- dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-3-(trifluoromethyl)pyridin-2(lH
Compound No. 178: l-(2-(4-(4-(5-(2,6-dichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin- l-yl)-2-oxoethyl)-6-(difluoromethyl)-3-(trifluoromethyl)pyridin-2(lH)-one; Compound No. 179: 6- (difluoromethyl)-l-(2-oxo-2-(4-(4-(5-(2,4,6-trichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2- yl)piperidin-l-yl)ethyl)-3-(trifluoromethyl)pyridin-2(lH)-one; Compound No. 180: 3-chloro-2-(3-(2-(l- (2-(6-(difluoromethyl)-2-oxo-3-(trifluoromethyl)pyridin-l(2H)-yl)acetyl)piperidin-4-yl)thiazol^ dihydroisoxazol-5-yl)phenyl methanesuifonate; Compound No. 181: 5-bromo-l-(2-(4-(4-(5-(2,6- dichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-3-methyIpyridi 2(lH)-one; Compound No. 182: 2-(3-(2-(l-(2-(5-bromo-3-methyl-2-oxopyridin-l (2H)- yl)acetyl)piperidin-4-yl)thiazol-4-yl)-4,5-dihydroisoxazol-5-yl)-3-chlorophenyl methanesuifonate; Compound No. 183: 5-cyclopropyl-l-(2-oxo-2-(4-(4-(5-(2,4,6-trichlorophenyl)-4,5-dihydroisoxazol-3- yl)thiazol-2-yl)piperidin-l-yl)ethyl)-3-(trifluoromethyl)pyridin-2(lH)-one; Compound No. 184: l-(2-(4- (4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-5-fl
(trifluoromethyl)pyridin-2(lH)-one; Compound No. 185: 3-chloro-2-(3-(2-(l-(2-(5-fluoro-2-oxo-3- (tritluoromethyl)pyridin-l(2H)-yl)acetyl)piperidin-4-yl)thiazol-4-yl)-4,5-dihydroisoxazol-5-yl)phenyl methanesuifonate; Compound No. 186: 2-(3-(2-(l-(2-(5-bromo-3-nitro-2-oxopyridin-l(2H)- yl)acetyI)piperidin-4-yl)thiazol-4-yl)-4,5-dihydroisoxazol-5-yl)-3-chlorophenyl methanesuifonate; Compound No. 187: 5-bromo-3-nitro-l -(2-oxo-2-(4-(4-(5-(2,4,6-trichlorophenyl)-4,5-dihydroisoxazol-3- yl)thiazol-2-yl)piperidin-l-yl)ethyl)pyridin-2(lH)-one; Compound No.188: 5-fluoro-l-(2-oxo-2-(4-(4-(5- (2,4,6-trichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)ethyl)-3- (trifluoromethyl)pyridin-2(lH)-one; Compound No. 189: l-(2-(4-(4-(5-(2,6-dichlorophenyl)-4,5- dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-5-fluoro-3-(trifluoromethyl)pyridi one; Compound No. 190: 3-(difluoromethyl)-l-(2-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3- yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)pyridin-2(lH)-one; Compound No. 191: l-(2-(4-(4-(5-(2,6- dichloiOphenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-y])-2-oxoethyl)-3- (difluoromethyl)pyridin-2(lH)-one; Compound No. 192: 3-(difluoromethyl)-l-(2-oxo-2-(4-(4-(5-(2,4,6- trichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)ethyl)pyridin-2(lH)-one;
Compound No. ] 93: 3-chloro-2-(3-(2-(] -(2-(3-(diiluoromethyl)-2-oxopyridin-l (2H)-yl)acetyl)piperidin- 4-yl)thiazol-4-yl)-4,5-dihydroisoxazol-5-yl)phenyl methanesuifonate; Compound No.194: 5-chloro-l-(2- (4-(4-(5-(2,6-difluorophenyl)-4,5-dihydro
(trifluoromethyI)pyridin-2(lH)-one; Compound No. 195: 5-chloro-l-(2-oxo-2-(4-(4-(5-(2,4,6- trichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)pipei din-l-yl)ethyl)-3-(trifluorome
2(lH)-one; Compound No. 196: 3-chloro-2-(3-(2-(l-(2-(5-chloro-2-oxo-3-(trifluoromethyl)pyridin- l(2H)-yl)acetyl)piperidin-4-yl)thiazol-4-yl)-4,5-dihydroisoxazol-5-yl)phenyl methanesulfonate; Compound No. 197: 1 -(2-(4-(4-(5-(2,6-dichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin- l-yl)-2-oxoethyl)-5-nitro-3-(trifluoromethyl)pyridin-2(lH)-one; Compound No. 198: 3-chloro-2-(3-(2-(l- (2-(5-nitro-2-oxo-3-(trifluoromethyl)pyridin-l(2H)-yl)acety])piperidin-4-yl)thiazol-4-yl)^
dihydroisoxazol-5-yl)phenyl methanesulfonate; Compound No. 199: 5-cyclopropyl-l-(2-(4-(4-(5-(2,6- difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-3-
(trifluoromethyl)pyridin-2(lII)-one; Compound No. 200: 5-cyclopropyl-l-(2-(4-(4-(5-(2,6- dichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-3- (trifluoromethyl)pyridin-2(lH)-one; Compound No.201: 3-bromo-5-(difluoromethyl)-l-(2-(4-(4-(5-(2,6- difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)pyridin-2(lH)-one Compound No. 202: 3-bromo-l-(2-(4-(4-(5-(2,6-dichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2- yl)piperidin-l-yl)-2-oxoethyl)-5-(difluoromethyl)pyridin-2(lH)-one; Compound No. 203: 3-bromo-5- (difluoromethyl)-l-(2-oxo-2-(4-(4-(5-(2,4,6-trichlorophenyl)-4,5-dihydroisoxazol-3-y])thiazol-2- yl)piperidin-l-yl)ethyl)pyridin-2(lH)-one; Compound No. 204: 5-(difluoromethyl)-l-(2-oxo-2-(4-(4-(5- (2,4,6-trichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)ethyl)pyridin-2(l^
Compound No.205: l-(2-(4-(4-(5-(4-chlorophenyl)isoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)- 3-(trifluoromethyl)pyridin-2(lH)-one; Compound No. 206: l-(2-(4-(4-(5-(4-chlorophenyl)isoxazol-3- yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-5-(difluoromethyl)pyridin-2(lH)-one; Compound No.207: 1- (2-(4-(4-(5-(2,6-dichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)^ (difluoromethyl)pyridin-2(lH)-one; Compound No. 208: 5-(difluoromethyl)-l-(2-(4-(4-(5-(2,6- difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)pyridin-2(lH^^
Compound No. 209: 3-chloro-l-(2-(4-(4-(5-(2-chloro-6-hydroxyphenyl)-4,5-dihydroisoxazol-3- yI)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-5-(trifluoromethyl)pyridin-2(lH)-one; Compound No.210: 3- bromo-l-(2-(4-(4-(5-(2-chloro-6-hydiOxyphenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2- oxoethyl)-5-(trifluoromethyl)pyridin-2(lH)-one; Compound No.211: l-(2-(4-(4-(5-(2,6-difluorophenyl)- 4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-6-oxo-5-(trifluoromethyl)-l,6- dihydropyridine-3-carbonitrile; Compound No. 212: 5-bromo-l-(2-(4-(4-(5-(2,6-dichlorophenyl)-4,5- dihydroisoxazol-3-yl)thiazol-2-yI)piperidin-l-yl)-2-oxoethyI)-6-oxo-l,6-dihydropyridine-3 arbonitrile; Compound No. 213: 5-bromo-l-(2-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2- yl)piperidin-l-yI)-2-oxoethyl)-6-oxo-l,6-dihydropyridine-3-carbonitrile; Compound No.214: 5-chloro-l- (2-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoe^ l,6-dihydropyridine-3-carbonitn'le; Compound No.215: 5-chloro-l-(2-(4-(4-(5-(2,6-dichlorophenyl)-4,5- dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2^
Compound No.216: 3-chloro-2-(3-(2-( 1 -(2-(3-chloro-5-cyano-2-oxopyridin-l (2H)-yl)acetyl)piperidin-4- yl)thiazol-4-yl)-4,5-dihydroisoxazol-5-yl)phenyl methanesulfonate; Compound No. 217: 3-chloro-l-(2- (4-(4-(5-(2-chloro-6-(prop-2-yn-l-yloxy)phenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2- oxoethyl)-5-(trifluoromethyl)pyridin-2(lH)-one; Compound No.218: 3-bromo-l-(2-(4-(4-(5-(2-chloro-6- (prop-2-yn-l-yloxy)phenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-5- (trifluoromethyl)pyridin-2(lH)-one; Compound No. 219: 3-nitro-l-(2-oxo-2-(4-(4-(5-(2,4,6- trichlorophenyl)-4,5-dihydroisoxaz.ol-3-yl)thiazol-2-yl)piperidin-l-yl)ethyl)-5-(trifluorometh^
2(lH)-one; Compound No. 220: 5-biOmo-3-(difluoiOmethyI)-l-(2-(4-(4-(5-(2,6-difluorophenyl)-4;5- dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)pyridin-2(lH)-one; Compound No. 221: 5- bromo-3-(difluoromethyl)-l-(2-oxo-2-(4-(4-(5-(2,4,04richlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-
2- yl)piperidin-l-yl)ethyl)pyridin-2(lH)-one; Compound No. 222: 5-bromo-l-(2-(4-(4-(5-(2,6- dichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-3-
(difluoromethyl)pyridin-2(lH)-one; Compound No. 223: 2-(3-(2-(l-(2-(3-bromo-5-cyano-2-oxopyridin- l(2H)-yl)acetyl)piperidin-4-yl)thiazol-4-yl)-4,5-dihydroisoxazol-5-yl)-3-chlorophenyl methanesulfonate; Compound No.224: 2-(2-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l- yl)-2-oxoethyl)-2-azabicyclo[2.2.1]hept-5-en-3-one; Compound No.225: 3-bromo-5-isocyano-l-(2-oxo- 2-(4-(4-(5-(2,4,64richlorophenyI)-4,5-dihydroisoxazol-3-yl)thiazoI-2-yl)piperidin-l-yl)ethyl)pyridin-
2(lH)-one; Compound No. 226: 3-chloro-5-isocyano-l-(2-oxo-2-(4-(4-(5-(2,4,6-trichlorophenyl)-4,5- dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)ethyl)pyridin-2(lH)-one; Compound No. 227: 2-(3-(2- (l-(2-(5-bromo-3-(difluoromethyl)-2-oxopyridin-l(2H)-yl)acetyl)piperidin-4-yl)thiazol-4-yl)-4,5 dihydroisoxazol-5-yl)-3-chlorophenyl methanesulfonate; Compound No.228: 3-chloro-2-(3-(2-(l-(2-(5- (difluoromethyl)-2-oxopyridin-l(2H)-yl)acetyl)piperidin-4-yl)thiazol-4-yl)-4,5-dihydroisoxazol-5- yOphenyl methanesulfonate; Compound No.229: l-(2-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-
3- yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-3-nitiO-5-(trifluoromethyl)pyridin-2(lH)-one; Compound No. 230: 3-chloro-2-(3K2-(l-(2-(3-nitro-2-oxo-5-(trifluoromethyl)pyndin-l(2H)-yl)acetyl)pi yI)thiazol-4-yl)-4,5-dihydroisoxazol-5-yI)phenyl methanesulfonate; Compound No. 231: l-(2-(4-(4-(5- (2,6-dichloiOphenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-3-nitro-5-
(trifluoromethyl)pyridin-2(lH)-one; Compound No. 232: 5-nitro-l-(2-oxo-2-(4-(4-(5-(2,4,6- trichlorophenyl)-4,5-dihydroisoxazoI-3-yl)thiazol-2-yl)piperidin-l-yl)ethyl)-3-(tnfluorometh
2(lH)-one; Compound No. 233: 1 -(2-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2- yl)piperidii>l-yl)-2-oxoethyl)-5Miitro-3-(trifluoiOmethyl)pyridin-2(lH)-one; Compound No.234: 2-(2-(4- (4-(5-(2,6-difluorophenyl)-4,5-dihydroiso
(trifluoromethyl)-l,2-dihydro-3H-pyrazol-3-one; Compound No.235: l-(2-(4-(4-(5-(2,6-difluorophenyl)- 4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yI)-2-oxoethyl)-2-oxo-5-(trifluoromethyl)-l,2- dihydropyridine-3-carbonitrile; Compound No. 236: l-(2-(4-(4-(5-(2,6-difluorophenyl)-4,5- dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)azepan-2-one; Compound No.237: l-(2-(4- (4-(5-(2,6-dichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)azepan-2- one; Compound No.238: l-(2-oxo-2-(4-(4-(5-(2,4,6-tricblorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2- yl)piperidin-l-yl)ethyl)azepan-2-one; Compound No. 239: 3-chloro-2-(3-(2-(l-(2-(2-oxoazepan-l- yl)acetyl)piperidin-4-yl)thiazol-4-yl)-4,5-dihydroisoxazol-5-yl)phenyl methanesulfonate; Compound No. 240: 3-chloro-2-(3-(2-(l-(2-(3-isocyano-2-oxo-5-(trifluoromethyl)pyridin-l(2H)-yl)acetyl)piperidin-4- yl)thiazol-4-y])-4,5-dihydroisoxazol-5-yl)phenyl methanesulfonate; Compound No. 241: 3-bromo-l-(2- (4-(4-(5-mesityl-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-5- (trifluoromethyl)pyridin-2(lH)-one; Compound No. 242: 3-bromo-l-(2-oxo-2-(4-(4-(5-(3- (trifluoromethyl)phenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)ethyl)-5- (trifluoromethyl)pyridin-2(lH)-one; Compound No. 243: 3-bromo-l-(2-(4-(4-(5-(4-(tert-butyl)phenyl)- 4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-5-(trifluoromethyl)pyridin-2(lH)-o Compound No.244: l-(2-(4-(4-(5-(4-(tert-butyl)phenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin- l-yl)-2-oxoethyl)-3-(trifluoromethyl)pyridin-2(lH)-one; Compound No. 245: l-(2-(4-(4-(5-mesityl-4,5- dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-3-(triiluoromethyl)pyridin-2(lH)-one; Compound No.246: l-(2-oxo-2-(4-(4-(5-(3-(trifluoromethyl)phenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2- yl)piperidin-l-yl)ethyl)-3-(trifluoromethyl)pyridin-2(lH)-one; Compound No. 247: 3-chloro-l-(2-(4-(4- (5-mesityl-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)pipe
2(lH)-one; Compound No. 248: l-(2-(4-(4-(5-(4-(tert-butyl)phenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2- yl)piperidin-l-yl)-2-oxoethyl)-3-chloro-5-(trifluoromethyl)pyridin-2(lH)-one; Compound No. 249: 3- ch!oro-l-(2-oxo-2-(4-(4-(5-(3-(trifluoromethyl)phenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidi yl)ethyl)-5-(trifluoromethyl)pyridin-2(lH)-one; Compound No. 250: 2-oxo-l-(2-oxo-2-(4-(4-(5-(2,4,6- trichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)ethyl)-5-(trifluoromethy;l)-l,2- dihydropyridine-3-carbonitrile; Compound No. 251: l-(2-(4-(4-(5-(2,6-dichlorophenyl)-4,5- dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-3-isocyano-5-(trifluoromethyl)pyndin- 2(lH)-one; Compound No. 252: l-(2-(4-(4-(l,5-dihydrobenzo[e][l,3]dioxepin-3-yl)thiazol-2- yl)piperidin-l-yl)-2-oxoethyl)-3-(trifluoromethyl)pyridin-2(lH)-one; Compound No. 253: l-(2-(4-(4-(5- (2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yI)piperidin-l-yl)-2-oxoethyl)-2,5-dimethyl-l,2- dihydro-3H-pyrazol-3-one; Compound No. 254: l-(2-(4-(4-(l,5-dihydrobenzo[e][l,3]dioxepin-3- yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-5-(trifluoromethyl)pyridin-2(lH)-one; Compound No.255: 6- methyl- l-(2-oxo-2-(4-(4-(5-(3-(trifluoromethyl)phenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl) l-yl)ethyl)-3-(trifluoromethyl)pyridin-2(lH)-one; Compound No. 256: l-(2-(4-(4-(5-mesityl-4,5- dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-5-(trifluoromethyl)pyridin-2(lH)-one; Compound No. 257: l-(2-oxo-2-(4-(4-(3-phenyl-4,8-dihydro-[l,3]dioxepino[5,6-d]isoxazol-6-yl)thiazol- 2-yl)piperidin-l-yl)ethyl)-5-(trifluoromethyl)pyridin-2(lH)-one; Compound No. 258: 1 -(2-oxo-2-(4-(4- (5-(3-(trifluoromethyl)phenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)ethyl)-5- (trifluoromethyl)pyridin-2(lH)-one; Compound No. 259: l-(2-(4-(4-(5-(4-(tert-butyl)phenyl)-4,5- dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-5-(trifluoromethyl)pyridin-2(lH)-one; Compound No. 260: l-(2-(4-(4-(5-(4-(tert-butyl)phenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin- l-yl)-2-oxoethyl)-6-methyl-3-(trifluoromethyl)pyridin-2(lH)-one; Compound No. 261: l-(2-(4-(4-(5- mesityl-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-6-methyl-3- (trifluoromethyl)pyridin-2(lH)-one; Compound No. 262: l-(2-(4-(4-(5-(2,6-dichlorophenyl)-4,5- dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-2,5-dimethyl-l,2-dihydro-3H-pyrazol-3- one; Compound No.263: 5-chloro-l-(2-oxo-2-(4-(4-(5-(3-(trifluoromethyl)phenyl)-4,5-dihydroisoxazol- 3-yl)thiazol-2-yl)piperidin-l-yl)ethyl)-3-(trifluoromethyl)pyridin-2(lH)-one; Compound No. 264: 5- chloro-l-(2-(4-(4-(5-mesityl-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-3- (trifluoromethyl)pyridin-2(lH)-one; Compound No. 265: 3-(2-(l-(2-(5-chloro-2-oxo-3- (trifluoromethyl)pyridin-l(2H)-yl)acetyl)piperidin-4-yl)thiazol-4-yl)-4,5-dihydroisoxazole-5- carboxamide; Compound No. 266: l-(2-(4-(4-(5-(2-chlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2- yl)piperidin-l-yl)-2-oxoethyl)-3-(trifluoromethyl)pyridin-2(lH)-one; Compound No. 267: l-(2-(4-(4-(5- (2-chlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-6-methyl-3- (trifluoromethyl)pyridin-2(lH)-one; Compound No. 268: 3-bromo-l-(2-(4-(4-(5-(2-chlorophenyl)-4,5- dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-5-(trifluoromethyl)pyridin-2(lH)-one; Compound No.269: l-(2-oxo-2-(4-(4-(5-(2-(trifluoromethyl)phenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2- yl)piperidin-l-yl)ethyl)-3-(trifluoromethyl)pyridin-2(lH)-one; Compound No.270: 6-methyl-l-(2-oxo-2- (4-(4-(5-(2-(trifluoromethyl)phenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)ethyl)-3- (trifluoromethyl)pyridin-2(lH)-one; Compound No. 271: 3-bromo-l-(2-oxo-2-(4-(4-(5-(2- (trifluoromethyl)phenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)ethyl)-5- (trifluoromethyl)pyridin-2(lH)-one; Compound No. 272: ethyl 3-(2-(l-(2-(2-oxo-5- (trifluoromethyl)pyridin-l(2H)-yl)acetyl)piperidin-4-yl)thiazol-4-yl)-4,5-dihydroisoxazole^
Compound No. 273: ethyl 3-(2-(l-(2-(2-oxo-3-(trifluoiOmethyl)pyridin-](2H)-yl)acetyl)pipendin-4- yl)thiazol-4-yl)-4,5-dihydroisoxazole-5-carboxylate; Compound No. 274: methyl 3-(2-(l-(2-(2-oxo-3- (trifluoromethyl)pyridin-l(2H)-yl)acetyl)piperidin-4-yl)thiazol-4-yl)-4,5-dihydroisoxazole-5-carboxy Compound No. 275: l-(2-oxo-2-(4-(4-(5-(3,4,5-trifluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2- yl)piperidin-l-yl)ethyl)-3-(trifluoromethyl)pyridin-2(lH)-one; Compound No. 276: 3-(2-(l-(2-(2-oxo-3- (trifluoromethyl)pyridin-l (2H)-yl)acetyl)piperidin-4-yl)thiazol-4-yl)-4,5-dihydroisoxazole-5- carboxamide; Compound No. 277: 6-methyl-l-(2-oxo-2-(4-(4-(5-(3,4,5-trifluoiOphenyl)-4,5- dihydroisoxazol-3-y!)thiazol-2-yl)piperidin-l-yl)ethyl)-3-(trifluoromethyl)pyridii>2( Compound No. 278: l-(2-oxo-2-(4-(4-(5-(3,4,54nf]uorophenyl)-4,5-dihydiOisoxazol-3-yl)thiazol-2-yl)piperidin-l- y])ethyl)-5-(trif!uoromethyl)pyridin-2(lH)-one; Compound No.279: 3-bromo-l-(2-oxo-2-(4-(4-(5-(3,4,5- trifluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol^
2(lH)-one; Compound No. 280: 3-(2-(l-(2-(2-oxo-5-(trifluoiOmethyl)pyridin-l(2H)-yl)acetyl)piperidin-
4-yl)thiazol-4-yl)-4,5-dihydroisoxazole-5-carboxamide; Compound No. 281: l-(2-oxo-2-(4-(4-(5-(o- tolyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)pipendin-l-yl)ethyl)-3-(trifluoromethyl)pyridi
Compound No. 282: 6-methyl-l -(2-oxo-2-(4-(4-(5-(o-tolyl)-4,5-dihydroisoxazol-3-yl)thiazol-2- yl)piperidin-l-yl)ethyl)-3-(tnf]uoromethyl)pyridin-2(lH)-one; Compound No. 283: l-(2-oxo-2-(4-(4-(5-
(o4olyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperi
one; Compound No. 284: 3-bromo-l-(2-oxo-2-(4-(4-(5-(o-tolyl)-4,5-dihydroisoxazoI-3-yl)thiazol-2- yl)piperidin-l-yl)ethyI)-5-(trifluoiOmethyl)pyridin-2(lH)-one; Compound No. 285: l-(2-(4-(4-(5-(2,5- difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-3-
(trifluoromethyl)pyridin-2(lH)-one; Compound No. 286: l-(2-(4-(4-(5-(2,5-difluorophenyl)-4,5- dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-6-methyl-3-(trifluoromethyl)pyri one; Compound No. 287: l-(2-(4-(4-(5-(2,5-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2- yl)piperidin-l-y])-2-oxoethyl)-5-(trifluoiOmethyl)pyndin-2(lH)-one; Compound No.288: 3-bromo-l-(2-
(4-(4-(5-(2,5-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-5-
(trifluoromethyl)pyridin-2(lH)-one; Compound No. 289: l-(2-(4-(4-(5-(2-fluorophenyl)-4,5- dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-3-(trifluoromethyl)pyridin-2(lH^
Compound No.290: 1 -(2-(4-(4-(5-(2-fluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazoi-2-yl)piperidin- 1 -yl)-
2-oxoethyl)-5-(trifluoromethy])pyridin-2(lH)-one; Compound No. 291: 3-bromo-l-(2-(4-(4-(5-(2- fluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-y])-2-oxoethyl)-5-
(trifluoromethyl)pyridin-2(lH)-one; Compound No. 292: l-(2-(4-(4-(5-(2-fluorophenyl)-4,5- dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-6-methyl-3-(trifluoromethyl)pyridi one; Compound No. 293: l-(2-(4-(4-(5-(4-methoxyphenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2- yl)piperidin-l-yl)-2-oxoethyl)-3-(trifluoiOmethyl)pyridin-2(lH)-one; Compound No. 294: l-(2-(4-(4-(5-
(4-methoxyphenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-5-
(trifluoromethyl)pyridin-2(lH)-one; Compound No.295: 3-bromo-l-(2-(4-(4-(5-(4-methoxyphenyl)-4,5- dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-5-(trifluoromethyl)pyridin-2(lH
Compound No. 296: 1 -(2-(4-(4-(5-(4-methoxyphenyl)-4,5-dihydraisoxazol-3-yl)thiazo]-2-yI)piperidin-l - y!)-2-oxoethyl)-6-methyl-3-(trifluoromethyl)pyridin-2(lH)-one; Compound No. 297: l-(2-(4-(4-(5-(2- chloro-6-(trifluoromethyl)phenyI)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-I-yl)-2-oxoethyl)-3-
(trifluoromethyl)pyridin-2(lH)-one; Compound No. 298: l-(2-(4-(4-(5-(2-chloro-6-
(trifluoromethyl)phenyl)-4,5-dihydroisoxazoI-3-yI)thiazoI-2-yI)piperidin-l-yl)-2-oxoethyI)-6-meth
(trifluoromethyl)pyridin-2(lH)-one; Compound No. 299: 5-chloro-l-(2-(4-(4-(5-(2-chloro-6-
(tril1uoromethyl)phenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-3-
(trifluoromethyl)pyridin-2(lH)-one; Compound No. 300: l-(2-(4-(4-(5-(2-chloro-6-
(trifluoromethyl)phenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-5-
(trifluoromethyl)pyridin-2(lH)-one; Compound No. 301: 3-chloro-l-(2-(4-(4-(5-(2-chloro-6-
(trifluoromethyl)phenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-5-
(trifluoromethyl)pyridin-2(lH)-one; Compound No. 302: 3-bromo-l-(2-(4-(4-(5-(2-chloro-6
(trifluoromethyl)phenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-5-
(trifluoromethyl)pyridin-2(lH)-one; Compound No. 303: l-(2-(4-(4-(5-(2-bromo-6-fluorophenyl)-4,5- dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-3-(trifluoromethyl)pyridin-2(lH
Compound No. 304: 1 -(2-(4-(4-(5-(2-bromo-6-fluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2- yl)piperidin-l-yl)-2-oxoethyl)-6-methyl-3-(trifluoromethyl)pyridin-2(lH)-one; Compound No.305: l-(2-
(4-(4-(5-(2-bromo-6-fluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-5- chloro-3-(trifluoromethyl)pyridin-2(lH)-one; Compound No. 306: l-(2-(4-(4-(5-(2-bromo-6- fluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yI)-2-oxoethyl)-5-
(trifluoromethyl)pyridin-2(lH)-one; Compound No. 307: l-(2-(4-(4-(5-(2-bromo-6-fluorophenyl)-4,5 dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-3-chloro-5-(trifluoromethyl)pyri one; Compound No. 308: 3-bromo-l-(2-(4-(4-(5-(2-bromo-6-fluorophenyl)-4,5-dihydroisoxazol-3- yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-5-(trifluoromethyl)pyridin-2(lH)-one; Compound No.309: 1-
(2-(4-(4-(5-(2,6-dimethoxyphenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-
(trifluoiOmethyl)pyridin-2(lH)-one; Compound No. 310: l-(2-(4-(4-(5-(2,6-dimethoxyphenyl)-4,5- dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-6-methyl-3-(trifluoromethyl)pyridin-2 one; Compound No. 311: 5-chloro-l-(2-(4-(4-(5-(2,6-dimethoxyphenyl)-4,5-dihydroisoxazol-3- yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-3-(trifluoromethyl)pyridin-2(lH)-one; Compound No.312: 3- chloro-l-(2-oxo-2-(4-(4-(5-(3,4,5-trifluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin- yl)ethyl)-5-(trifluoromethyl)pyridin-2(lH)-one; Compound No.313: 5-chloro-l-(2-oxo-2-(4-(4-(5-(3,4,5- trifluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)ethyl)-3-(trifluoromethyl)pyri
2(lH)-one; Compound No. 314: l-(2-(4-(4-(5-(3,4-dichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2- yl)piperidin-]-yl)-2-oxoethyl)-5-(trifluoromethyl)pyridin-2(lH)-one; Compound No. 315: l-(2-(4-(4-(5-
(3,4-dichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-3- (trifluoromethyl)pyridin-2(lH)-one; Compound No. 316: 3-chloro- l-(2-(4-(4-(5-(3,4-dich!orophenyl)- 4,5-dihydroisoxazo!-3-yl)thiazol-2-yl)pipendin-l-yl)-2-oxoethyl)-5-(trifluoromethyl)pyridin-2(lH) Compound No. 317: 5-chloro- 1 -(2-(4-(4-(5-(3,4-dichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2- yl)piperidin-l-yl)-2-oxoethyl)-3-(trifluoromethy])pyridin-2(lH)-one; Compound No.318: 3-bromo-l-(2- (4-(4-(5-(3,4-dichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-5- (trifluoromethyl)pyridin-2(lH)-one; Compound No.319: 2-(3-(2-(l-(2-(2-oxo-5-(trifluoromethyl)pyridin- 1 (2H)-yl)acetyl)piperidin-4-yl)thiazol-4-yl)-4,5-dihydroisoxazol-5-yl)benzonitrile; Compound No. 320: 2-(3-(2-(l-(2-(2-oxo-3-(trifluoromethyl)pyridin-l(2H)-yl)acetyl)piperidin-4-yl)thiazol-4-yl)-4,5- dihydroisoxazol-5-yl)benzonitrile; Compound No. 321: l-(2-oxo-2-(4-(4-(5-(5-(trifluoromethyl)pyridin- 2-yl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l^
Compound No. 322: l-(2-oxo-2-(4-(4-(5-(5-(trifluoromethyl)pyridin-2-yl)-4,5-dihydroisoxazol-3- yl)thiazol-2-yl)piperidin-l-yl)ethy!)-5-(trifluoromethyl)pyridin-2(lH)-one; Compound No.323: 3-bromo- l-(2-oxo-2-(4-(4-(5-(5-(trifluoromethyl)pyridin-2-yl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l- yl)ethyl)-5-(trifluoromethyl)pyridin-2(lH) -one; Compound No. 324: 6-methyl-l-(2-oxo-2-(4-(4-(5-(5- (trifluoromethyl)pyridin-2-yl)-4,5-dihy^
(trifluoromethyl)pyridin-2(lH)-one; Compound No. 325: 5-chloro- 1 -(2-oxo-2-(4-(4-(5-(5- (trifluoromethyl)pyridin-2-yl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)ethyl)-3- (trifluoromethyl)pyridin-2(lH)-one; Compound No. 326: l-(2-(4-(4-(5-(2-chloro-6-fluorophenyl)-4,5- dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-3-(trifluoromethyl)pyridin-2(lH)-one; Compound No. 327: l-(2-(4-(4-(5-(2-chloro-6-fluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2- yl)piperidin-l-yl)-2-oxoethyl)-5-(trifluoromethyl)pyridin-2(lH)-one; Compound No.328: 3-bromo-l-(2- (4-(4-(5-(2-chloro-6-fluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-5- (trifluoiOmethyl)pyridin-2(lH)-one; Compound No. 329: l-(2-(4-(4-(5-(2-chloro-6-fluorophenyl)-4,5- dihydroisoxazol-3-yI)thiazol-2-yl)piperidin-l-yl^
one; Compound No. 330: 5-chloro-l-(2-(4-(4-(5-(2-chloro-6-fluorophenyl)-4,5-dihydroisoxazol-3- yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-3-(trifluoromethyl)pyridin-2(lH)-one; Compound No.331: 5- chloro-l-(2-(4-(4-(5-(2,6-dimethoxyphenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2- oxoethyl)-3-(trifluoromethyl)pyridin-2(lH)-one; Compound No. 332: 6-methyl-l-(2-oxo-2-(4-(4-(5- (2,3,5-trichloiOphenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)ethyl)-3- (trifluoiOmethyl)pyridin-2(lH)-one; Compound No. 333: 5-chloro- 1 -(2-oxo-2-(4-(4-(5-(2,3,5- trichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yI)ethyl)-3-(trifluoromethyl)pyridin- 2(lH)-one; Compound No. 334: l-(2-oxo-2-(4-(4-(5-(2,3,5-trichlorophenyl)-4,5-dihydroisoxazol-3- yl)thiazol-2-yl)piperidin-l-yl)ethyl)-5-(trifluoromethyl)pyridin-2(lH)-one; Compound No.335: 3-chloro- l-(2-oxo-2-(4-(4-(5-(2,3,5-trichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)ethyl)-5- (trifluoromethyl)pyridin-2(lH)-one; Compound No. 336: 3-bromo-l -(2-oxo-2-(4-(4-(5-(2,3, 5- trichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)ethyl)-5-(trifl
2(lH)-one; Compound No. 337: l-(2-(4-(4-(5-(3-(difluoromethyl)-l -methyl- 1 H-pyrazol-4-yl)-4,5- dihydroisoxazoI-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-3-(trifluoromethyl)pyridin-2(lH)-one Compound No. 338: 5-chloro-l-(2-(4-(4-(5-(3-(difluoromethyl)-l-methyl-lH-pyrazol-4-yl)-4,5- dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoem^
Compound No.339: l-(2-(4-(4-(5-(3-(difluoromethyl)-l-methyl-lH-pyrazol-4-yl)-4,5-dihydroisoxazol-3- yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyI)-5-(trifluoromethyl)pyridin-2(lH)-one; Compound No.340: 3- chloro-l-(2-(4-(4-(5-(3-(difluoromethyl)-l-methyl-lH-pyrazol-4-yl)-4,5-dihydroisoxazol-3-yl)thiazol-2- yl)piperidin-l-yl)-2-oxoethyl)-5-(tnfluoromethyl)pyridin-2(lH)-one; Compound No.341: 3-bromo-l-(2- (4-(4-(5-(3-(difluoromethyl)-l -methyl- lH-pyrazol-4-yl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin- l-yl)-2-oxoethyl)-5-(trifluoromethyl)pyridin-2(lH)-one; Compound No. 342: l-(2-(4-(4-(5-(3- (difluoromethyl)-l -methyl- lH-pyrazol-4-yl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2- oxoethyl)-2-oxo-5-(trifluoromethyl)-l,2-dihydropyridine-3-carbonitrile; Compound No. 343: l-(2-(4-(4- (5-(2,6-dimethoxyphenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-5-
(trifluoromethyl)pyridin-2(lH)-one; Compound No.344: 3-chloro-l-(2-(4-(4-(5-(2,6-dimethoxyphenyl)- 4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-5-(trifluoromethyl)pyrH
Compound No. 345: 3-bromo-l -(2-(4-(4-(5-(2,6-dimethoxyphenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2- yl)piperidin-l-yl)-2-oxoethyl)-5-(trifluoromethyl)pyridin-2(lH)-one; Compound No. 346: 2-(3-(2-(l-(2- (3-chloro-2-oxo-5-(trifluoromethyl)pyridin-l(2H)-yl)acetyl)piperidin-4-yl)thiazol-4-yl)-4,5- dihydroisoxazol-5-yl)benzonitrile; Compound No. 347: 2-(3-(2-(l-(2-(5-chloro-2-oxo-3- (trifluoromethyl)pyridin-l(2H)-yl)acetyl)piperidin-4-yl)thiazol-4-yl)-4,5-dihydroisoxazol-5- yl)benzonitrile; Compound No. 348: 2-(3-(2-(l-(2-(3-bromo-2-oxo-5-(trifluoromethyl)pyridin-l(2H)- yl)acetyl)piperidin-4-yl)thiazol-4-yl)-4,5-dihydroisoxazol-5-yl)benzonitrile; Compound No.349: l-(2-(4- (4-(5-(2,6-dimethylphenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-5-
(trifluoromethyI)pyridin-2(lH)-one; Compound No. 350: l-(2-(4-(4-(5-(2,6-dimethylphenyl)-4,5- dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-3-(trifluoromethyl)pyridi
Compound No. 351 : 3-chloro-l-(2-(4-(4-(5-(2,6-dimethylphenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2- yl)piperidin-l-yl)-2-oxoethyl)-5-(trifluoromethyl)pyridin-2(lH)-one; Compound No.352: 5-chloro-l-(2- (4-(4-(5-(2,6-dimethylphenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yI)piperidin-l-yl)-2-oxoethyl)-3-
(trifluoromethyl)pyridin-2(lH)-one; Compound No. 353: 3-bromo-l -(2-(4-(4-(5-(2,6-dimethylphenyl)- 4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-5-(trifluoromethyl)pyridin-2(lH Compound No. 354: 1 -(2-(4-(4-(5-(2,6-dimethylphenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin- l-yl)-2-oxoethyl)-6-methyl-3-(trifluoromethyl)pyridin-2(lH)-one; Compound No. 355: 5-chloro-l-(2- oxo-2-(4-(4-(5-(o-tolyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)ethyl)-3- (trifluoromethyl)pyridin-2(lH)-one; Compound No. 356: 3-chloro-l-(2-oxo-2-(4-(4-(5-(o-tolyl)-4,5- dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)ethyl)-5-(tnfluoromethyl)pyndin-2(lH)-one; Compound No. 357: 2-oxo-l-(2-oxo-2-(4-(4-(5-(o-tolyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)ethyl)- 5-(trifluoromethyl)-l,2-dihydropyridine-3-carbonitrile; Compound No. 358: 5-chloro-l-(2-(4-(4-(5-(2,5- difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-3- (trifluoromethyl)pyridin-2(lH)-one; Compound No.359: 3-chloro-l-(2-(4-(4-(5-(2,5-difluorophenyl)-4,5- dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-o^
Compound No.360: l-(2-(4-(4-(5-(2,5-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l- yl)-2-oxoethyl)-3-isocyano-5-(trifluoiOmethyl)pyridin-2(lH)-one; Compound No.361: 3-bromo-l-(2-(4- (4-(l,5-dihydrobenzo[e][l,3]dioxepin-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-5- (trifluoromethyl)pyridin-2(lH)-one; Compound No. 362: l-(2-(4-(4-(l,5-dihydrobenzo[e][l,3]dioxepin- 3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-6-methyl-3-(trifluoromethyl)pyridin-2(lH)-one; Compound No. 363: l-(2-(4-(4-(l,5-dihydrobenzo[e][l,3]dioxepin-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-2- oxo-5-(trifluoromethyl)-l,2-dihydropyridine-3-carbonitrile; Compound No.364: 3-chloro-l-(2-(4-(4-(l,5- dihydrobenzo[e][l,3]dioxepin-3-yI)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-5-(trifluoromethy
2(lH)-one; Compound No. 365: l-(2-(4-(4-(5-(2-bromo-5-fluorophenyl)-4,5-dihydroisoxazol-3- yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-6-methyl-3-(trifluoromethyl)pyridin-2(lH)-one; Compound No.366: l-(2-(4-(4-(5-(2-bromo-5-fluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2- oxoethyl)-3-chloro-5-(trifluoromethy])pyridin-2(lH)-one; Compound No.367: 3-bromo-l-(2-(4-(4-(5-(2- chloro-5-(trifluoromethyl)phenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yI)piperidin-l-yl)-2-ox
(trifluoromethyl)pyridin-2(lH)-one; Compound No. 368: 5-chloro-l-(2-(4-(4-(5-(2-chloro-5- (trifluoromethyl)phenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-3- (trifluoromethyl)pyridin-2(lH)-one; Compound No. 369: 3-chloro-l-(2-(4-(4-(5-(2-chloro-5- (trifluoromethyl)phenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-5- (trifluoromethyl)pyridin-2(lH)-one; Compound No. 370: l-(2-(4-(4-(5-(2-chloro-6-(prop-2-yn-l- yloxy)phenyl)-4,5-dihydiOisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-3- (triiluoromethyl)pyridin-2(lH)-one; Compound No. 371: ]-(2-(4-(4-(5-(2-chloro-6-(prop-2-yn-l- yloxy)phenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-5- (trifluoromethyl)pyridin-2(lH)-one; Compound No. 372: l-(2-(4-(4-(5-(2-chloro-6-(prop-2-yn-l- yIoxy)phenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-] -y])-2-oxoethyl)-6-methyl-3- (trifluoromethyl)pyridin-2(lH)-one; Compound No. 373: l-(2-(4-(4-(5-(2-chloro-6-(prop-2-yn-l- yloxy)phenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyI)-2-oxo-5- (trifluoromethyl)-l,2-dihydropyridine-3-carbonitrile; Compound No. 374: l-(2-(4-(4-(5-(2-(allyloxy)-6- chlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-3-bromo-5-
(trifluoromethyl)pyridin-2(lH)-one; Compound No.375: l-(2-(4-(4-(5-(2-(allyloxy)-6-chlorophenyl)-4,5 dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-3-chloro-5-(trifluoromethyl)pyridi one; Compound No. 376: l-(2-(4-(4-(5-(2-chloro-5-(trifluoromethyi)phenyl)-4,5-dihydroisoxazol-3 yl)thiazo]-2-y])piperidin-l-yl)-2-oxoethyl)-5-(triiluoromethyl)pyridin-2(lH)-one; Compound No.377: 1
(2-(4-(4-(5-(2-chloro-5-(trifluoromethyl)phenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperi oxoethyl)-6-methyl-3-(trifluoromethyl)pyridin-2(lH)-one; Compound No.378: l-(2-(4-(4-(5-(2-chloro-5
(trifluoromethyl)phenyl)-4,5-dihydroisoxazoI-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-3-
(trifluoromethyl)pyridin-2(lH)-one; Compound No.379: 5-chloro-l-(2-oxo-2-(4-(4-(3-phenylprop-l-yn- l-yl)thiazol-2-yl)piperidin-l-yl)ethyl)-3-(trifluoiOmethyl)pyridin-2(lH)-one; Compound No. 380: l-(2-
(4-(4-(5-(2-bromo-5-fluorophenyl)-4,5-dihydroisoxazoW
chloro-3-(difluoromethyl)pyridin-2(lH)-one; Compound No. 381: l-(2-(4-(4-(5-(2,6-dimethoxyphenyl)- 4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l -yl)-2-oxoethyl)-2-oxo-5-(trifluoromethyl)-l,2- dihydropyridine-3-carbonitrile; Compound No. 382: 5-chloro-l-(2-(4-(4-(5-(2-fluorophenyl)-4,5- dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-ox^
Compound No. 383: 5-chloro-l-(2-(4-(4-(5-(4-methoxyphenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2- yl)piperidin-l-yl)-2-oxoethyl)-3-(trifluoromethyl)pyridin-2(lH)-one; Compound No.384: 3-chloro-l-(2- (4-(4-(5-(2-fluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-5- (trifluoromethyl)pyridin-2(lH)-one; Compound No.385: 3-chloro-l-(2-(4-(4-(5-(4-methoxyphenyl)-4,5- dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-5-(trifluoromethyl)pyridin-2(lH)-one; Compound No. 386: 3-chloro-l-(2-oxo-2-(4-(4-(5-(5-(trifluoromethyl)pyndin-2-yI)-4,5-dihydroisoxazol- 3-yl)thiazol-2-yl)pipei'idin-l-yl)ethyl)-5-(trifluoromethyl)pyridin-2(lH)-one; Compound No. 387: 3- chloro-l-(2-(4-(4-(5-(2-chloro-6-fluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-y^ oxoethyl)-5-(trifluoromethyl)pyridin-2(lH)-one; Compound No. 388: 3-bromo-l-(2-(4-(4-(5-(2,6- dichloro-4-(trifluoromethyl)phenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoeth^ (trifluoromethyl)pyridin-2(lH)-one; Compound No. 389: 5-chloro-l-(2-(4-(4-(5-(2,6-dichloro-4- (trifluoiOmethy])phenyl)-4,5-dihydroisoxazol-3-yl)thiazo]-2-yl)piperidin-l-yl)-2-oxoethyl)-3- (trifluoromethyl)pyridin-2(lH)-one; Compound No. 390: 3-chloro-l-(2-(4-(4-(5-(2,6-dichloro-4- (trifluoiOmethyl)phenyl)-4,5-dihydroisoxazoi-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-5- (tnfluoromethyl)pyridin-2(lH)-one; Compound No. 391: l-(2-(4-(4-(5-(2,6-dichloro-4- (trifluoiOmethyl)phenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)pipendin-l-yl)-2-oxoethyl)-5- (trifluoromethyl)pyridin-2(lH)-one; Compound No. 392: l-(2-(4-(4-(5-(2,6-dichloro-4- (trifluoromethyl)phenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-6-methyl-3- (tnfluoiOmethyl)pyridin-2(lH)-one; Compound No. 393: 1 -(2-(4-(4-(5-(2,6-dichloro-4- (trifluoromethyl)phenyl)-4,5-dihydroisoxazol-3^
(trifluoromethyl)pyridin-2(lH)-one; Compound No. 394: 5-chloro-l-(2-(4-(4-(5-(2-chloro-5- (trifluoiOiTiethyl)phenyI)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-3- (difIuoromethyl)pyridin-2(lH)-one; Compound No. 395: l-(2-(4-(4-(5-(2-bromo-5-fluorophenyl)-4,5- dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-5-(trifluoromethyl)pyridin-2(lH)-one; Compound No. 396: 3-bromo-l-(2-(4-(4-(5-(2-bromo-5-fluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol- 2-yl)piperidin-l-yl)-2-oxoethyl)-5-(trifluoromethyl)pyridin-2(lH)-one; Compound No. 397: 1-(2-(4-(4· (5-(2-bromo-5-fluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-2-oxo-5- (trifluoromethyl)-l ,2-dihydropyridine-3-carbonitrile; Compound No. 398: l-(2-(4-(4-(5-(2-bromo-5 fluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-5-chloro-3- (trifluoromethyl)pyridin-2(lH)-one; Compound No. 399: l-(2-(4-(4-(5-(2,6-dichlorophenyl)-4,5 dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-6-oxo-5-(trifluoromethyl)-l,6- dihydropyridine-3-carbonitrile; Compound No. 400: 3-chloro-2-(3-(2-(l-(2-(5-cyano-2-oxo-3- (trifluoromethyl)pyridin-l(2H)-yl)acetyl)piperidin-4-yl)thiazol-4-yl)-4,5-dihydroisoxazol- methanesulfonate; Compound No. 401: 6-oxo-l-(2-oxo-2-(4-(4-(5-(2,4,6-trichlorophenyl)-4,5' dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)ethyl)-5-(trifliioromethyl)-l,6-dihydropyn
carbonitrile; Compound No. 402: l-(2-(4-(4-(5-(2-bromo-5-fluorophenyl)-4,5-dihydroisoxazol-3- yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-3-(trifluoromethyl)pyridin-2(lH)-one; Compound No.403: 1- (2-(4-(4-(5-(3,5-dichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-5- (trif]uoromethyl)pyridin-2(lH)-one; Compound No. 404: l-(2-(4-(4-(5-(3,5-dichlorophenyl)-4,5- dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-3-(trifluoromethyl)pyndin-2(lH
Compound No. 405: 3-chloiO-l-(2-(4-(4-(5-(3,5-dichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2 yl)piperidin-l-yl)-2-oxoethyl)-5-(trifluoromethyl)pyridin-2(lH)-one; Compound No.406: 5-chloro-l-(2- (4-(4-(5-(3,5-dichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-3- (trifluoromethyl)pyridin-2(lH)-one; Compound No. 407: 3-bromo-l-(2-(4-(4-(5-(3,5-dichlorophenyl} 4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-5-(trifluoromethyl)pyridin-2(l^ Compound No. 408: l-(2-[4-(4-(5-(3,5-dichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin- l-yl)-2-oxoethyl)-6-methyl-3-(trifluoromethyl)pyridin-2(lH)-one; Compound No. 409: l-(2-(4-(4-(5-(4- (tert-butyl)phenyI)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yI)-2-oxoethyl)-5-chloro-3- (difluoromethyl)pyridin-2(lH)-one; Compound No. 410: l-(2-(4-(4-(5-(2,6-dichloro-4- (trifluoromethyl)phenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-2-oxo-5- (trifluoromethyl)-l,2-dihydropyridine-3-carbonitrile; Compound No.411: 5-chloro-3-(difluoromethyl)-l- (2-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2- oxoethyl)pyridin-2(lH)-one; Compound No.412: l-(2-(4-(4-(5-(2-chIoro-5-(trifluoromethyl)phenyl)-4,5- dihydroisoxazol-3-yl)thiazol-2-yl)piperi
dihydropyridine-3-carbonitrile; Compound No. 413: 3-bromo-l-(2-(4-(4-(5-(2,5-dichlorophenyl)-4,5- dihydroisoxazol-3-yl)thiazol-2-yI)piperidin-l-yl)-2-oxoethyl)-5-(tri†1uoromethyI)pyridin-2(l H)-one; Compound No. 414: ]-(2-(4-(4-(5-(2,5-dichlorophenyl)-4,5-dihydiOisoxazol-3-yl)thiazol-2-yl)pipendin- l-yl)-2-oxoethyl)-5-(trifluoromethyl)pyridin-2(lH)-one; Compound No. 415: 1 -(2-(4-(4-(5-(2,5- dichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-6-methyl-3- (trifluoromethyl)pyridin-2(lH)-one; Compound No. 416: 3-chloro-l-(2-(4-(4-(5-(2,5-dichlorophenyl)- 4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-5-(trifluoromethyl)pyridin-2
Compound No. 417: l-(2-(4-(4-(5-(2,5-dichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin- l-yl)-2-oxoethyl)-3-(trifluoromethyl)pyridin-2(lH)-one; Compound No. 418: l-(2-(4-(4-(5-(2,5- dichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-2-oxo-5- (trifluoromethyl)-l,2-dihydropyridine-3-carbonitrile; Compound No. 419: 5-chloro-l-(2-(4-(4-(5-(2,5- dichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-3- (trifluoromethyl)pyridin-2(lH)-one; Compound No. 420: 3-chloro-l-(2-(4-(4-(5-(3-methylpyridin-2-yl)- 4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-5-(triiluoromethyl)pyridin-2(lH)-one; Compound No. 421: 5-chloro-l-(2-(4-(4-(5-(3-methylpyridin-2-yl)-4,5-dihydroisoxazol-3-yl)thiazol-2- yl)piperidin-l-yl)-2-oxoethyl)-3-(trifluoromethyl)pyridin-2(lH)-one; Compound No. 422: 3-isocyano-l- (2-(4-(4-(5-(3-methylpyridin-2-yl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoeth^ (trifluoromethyl)pyridin-2(lH)-one; Compound No. 423: 5-chloro-l-(2-(4-(4-(5-(2,6-dichlorophenyl)- 4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-3-(difluoromethyi)pyridin-2(lH)-
Compound No. 424: 5-chloro-l-(2-(4-(4-(5-(2,6-dichloro-4-(triiluoromethyl)phenyl)-4,5- dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-3-(difluoromethyl)pyridin-2(lH
Compound No. 425: 3-chloro-2-(3-(2-(l-(2-(5-chloro-3-(difluoromethyl)-2-oxopyridin-l(2H)- yl)acetyl)piperidin-4-yl)thiazol-4-yl)-4,5-dihydroisoxazol-5-yl)pbenyl methanesulfonate; Compound No. 426: l-(2-(4-(4-(5-(3,5-dichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2- oxoethyl)-2-oxo-5-(trifluoromethyl)-l,2-dihydropyridine-3-carbonitrile; Compound No.427: l-(2-(4-(4- (5-(4-(tert-butyl)phenyl)-4,5-dihydroisoxazoI-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-2-oxo-5- (trifluoromethyl)-l,2-dihydropyridine-3-carbonitrile; Compound No.428: l-(2-(4-(4-(5-(2-cyanophenyl)- 4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-2-oxo-5-(trifIuoromethyl)-l,2- dihydiOpyridine-3-carbonitrile; Compound No.429: (E)-2-(l-(2-(2-oxo-5-(trifluoromethyI)pyridin-l(2h)- yl)acetyl)piperidin-4-yl)thiazole-4-carbaldehyde o-benzyl oxime; Compound No. 430: (Z)-2-(l -(2-(2- oxo-5-(trifluoromethyl)pyridin-l(2H)-yl)acetyl)piperidin-4-yl)thiazole-4-carbaldehyde O-benzyl oxime; Compound No. 431 : (E)-2-(l-(2-(2-oxo-3-(trifluoromethyl)pyridin-l(2H)-yl)acetyl)piperidin-4- yl)thiazole-4-carbaldehyde O-benzyl oxime; Compound No. 432: (Z)-2-(l-(2-(2-oxo-3- (trifluoromethyl)pyridin-l(2H)-yl)acetyl)piperidin-4-yl)thiazoIe-4-carbaldehyde O-benzyl oxime; Compound No. 433: 3-chloro-2-(3-(2-(l-(2-(5-chioro-3-(difluoromethyl)-2-oxopyridin-l(2H)- yl)acetyl)piperidin-4-yl)thiazol-4-yl)-4,5-dihydroisoxazol-5-yl)phenyl methanesulfonate; Compound No. 434: l-(2-(4-(4-(5-(2-(allyioxy)-6-chlorophenyl)-4,5-dihydroisoxazol-3-y])thiazol-2-yl)piperidin-l-yI)-2- oxoethyl)-3-(trifluoromethyl)pyridin-2(lH)-one; Compound No. 435: l-(2-(4-(4-(5-(2-(allyloxy)-6- chloiOphenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-6-methyl-3- (trifluoromethyl)pyridin-2(lH)-one; Compound No.436: l-(2-(4-(4-(5-(2-(allyloxy)-6-chlorophenyl)-4,5- dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoem^
Compound No. 437: l-(2-(4-(4-(5-(2-(allyloxy)-6-chlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2- yl)piperidin-l-yl)-2-oxoethyl)-5-chloro-3-(trifluoromethyl)pyridin-2(lH)-one; Compound No.438: l-(2- (4-(4-(5-(2-(allyloxy)-6-chlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)- 2-oxo-5-(tnfluoromethyl)-l,2-dihydropyridine-3-carbonitrile; Compound No.439: 2-oxo-l-(2-oxo-2-(4- (4-(5-(2-(trifluoromethyl)phenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)ethyl)-5- (trittuoromethyl)-l,2-dihydropyridine-3-carbonitnle; Compound No.440: l-(2-(4-(4-(5-(2-fluorophenyI)- 4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-2-oxo-5-(trifluoromethyl)-l,2- dihydropyridine-3-carbonitrile; Compound No. 441: l-(2-(4-(4-(5-(4-methoxyphenyl)-4,5- dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-2-oxo-5-(trifluoromethyl)-l,2- dihydropyridine-3-carbonitrile; Compound No. 442: l-(2-(4-(4-(5-(2-chloro-6-fluorophenyl)-4,5- dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-2-oxo-5-(trifluoiOmethyl)-l,2- dihydropyridine-3-carbonitrile; Compound No. 443: 2-oxo-l-(2-oxo-2-(4-(4-(5-(5- (trifluoromethyl)pyridin-2-yl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin -yl)ethyl)-5- (trifluoromethyl)-l,2-dihydropyridine-3-carbonitrile; Compound No. 444: l-(2-(4-(4-(5-(2-chloro-3- (trifluoromethyl)phenyl)-4,5-dihydroisoxazol-3-yl)thiazoI-2-yl)piperidin-l-yl)-2-oxoethyl)-3- (trifluoromethyl)pyridin-2(lH)-one; Compound No. 445: l-(2-(4-(4-(5-(2-chIoro-3- (trifluoromethyl)phenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-6-methyl^
(trifluoromethyl)pyridin-2(lH)-one; Compound No. 446: 5-chloro-l-(2-(4-(4-(5-(2-cbloro-3- (trifluoromethyl)phenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-3- (trit1uoromethyl)pyridin-2(lH)-one; Compound No. 447: l-(2-(4-(4-(5-(2-chloro-3- (trifluoiOmethyl)pheny!)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-5- (trifluoromethyl)pyridin-2(lH)-one; Compound No. 448: 3-cbloro-l-(2-(4-(4-(5-(2-chloro-3- (trifluoromethyl)phenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-5- (trifluoromethyl)pyridin-2(lH)-one; Compound No. 449: 3-bromo-l-(2-(4-(4-(5-(2-chIoro-3- (trifluoroiTiethyl)phenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-5- (trifluoromethyl)pyridin-2(lH)-one; Compound No. 450: l-(2-(4-(4-(5-(2-chloro-3- (trifluoromethyl)phenyl)-4,5-dihydro
(trifluoromethyl)-l,2-dihydropyridine-3-carbonitrile; Compound No. 451: 5-chloro-l-(2-(4-(4-(5-(2- chloro-3-(trifluoromethyl)phenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoed (difluoromethyl)pyridin-2(lH)-one; Compound No. 452: l-(2-(4-(4-(5-(2,6-difluorophenyl)-5-methyl- 4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-3-(trifluoromethyl)pyridin-2(lH Compound No. 453: l-(2-(4-(4-(5-(4-chloro-2-fluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2- yl)piperidin-l-yl)-2-oxoethyl)-5-(trifluoromethyl)pyridin-2(lH)-one; Compound No. 454: l-(2-(4-(4-(5- (4-chloro-2-fluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-3- (trifluoromethyl)pyridin-2(lH)-one; Compound No. 455: 3-chloro-l-(2-(4-(4-(5-(4-chloro-2- fluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-5- (trifluoromethyl)pyridin-2(lH)-one; Compound No. 456: 5-chloro-l-(2-(4-(4-(5-(4-chloro-2- fluorophenyl)-4,5-dihydroisoxazoI-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-3- (trifluoromethyl)pyridin-2(]H)-one; Compound No. 457: 3-bromo-l-(2-(4-(4-(5-(4-chloro-2- fluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-5- (trifluoromethyl)pyridin-2(lH)-one; Compound No. 458: l-(2-(4-(4-(5-(4-chloro-2-fluorophenyl)-4,5- dihydiOisoxazol-3-yl)thiazo]-2-yI)piperidin-] -yl)-2-oxoethyl)-6-methyl-3-(trifluoiOmethy])pyndin-2(] H)- one; Compound No. 459: l-(2-(4-(4-(5-(4-chloro-2-fluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2- yl)piperidin-l-yl)-2-oxoethyI)-2-oxo-5-(tnfluoromethyl)-l,2-dihydropyridine-3-carbonitrile; Compound No. 460: methyl 5-cyano-l-(2-(4-(4-(5-(2,6-dichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2- yl)piperidin-l-yl)-2-oxoethyl)-6-oxo-l,6-dihydropyridine-3-carboxylate; Compound No.461: l-(2-(4-(4- (5-(2,6-dichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-2-oxo-5- (trifluoromethyl)-l,2-dihydropyridine-3-carboxamide; Compound No. 462: l-(2-(4-(4-(5-(2,6- dichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-2-oxo-5- (trifluoromethyl)-l,2-dihydropyridine-3-carboxylic acid; Compound No.463: l-(2-(4-(4-(5-(6-chloro-2,3- difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-6-oxo-5- (trifluoromethyl)-l,6-dihydropyridine-3-carbonitrile; Compound No. 464: 3-bromo-l-(2-(4-(4-(5-(6- chloro-2,3-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-5- (trifluoromethyl)pyridin-2(l H)-one; Compound No.465: l-(2-(4-(4-(5-(6-chloro-2,3-difluorophenyl)-4,5- dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yI)-2-oxoethyl)-5-(trifluoromethyl)pyridin-2(lH)- Compound No. 466: 3-chIoro-l -(2-(4-(4-(5-(6-chloro-2,3-difluorophenyl)-4,5-dihydroisoxazol-3- yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-5-(trifluoromethyl)pyridin-2(lH)-one; Compound No.467: 5- bromo-l-(2-(4-(4-(5-(6-chloro-2,3-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)- 2-oxoethyl)-3-(trifluoromethy])pyridin-2(lH)-one; Compound No. 468: l-(2-(4-(4-(5-(6-chloro-2,3- difluorophenyI)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-3- (trifluoromethyl)pyridin-2(lH)-one; Compound No.469: l-(2-(4-(4-(5-(6-chloro-2,3-difluorophenyl)-4,5- dihydroisoxazol-3-yl)thiazoI-2-yl)piperidin-l-yl)-2-oxoethyl)-6-methyl-3-(trifluoromethyl)pyridin one; Compound No. 470: (E)-2-(l-(2-(5-chloro-2-oxo-3-(trifluoromethyl)pyridin-l(2H)- yl)acetyl)piperidin-4-yl)thiazole-4-carba!dehyde O-benzyl oxime; Compound No. 471: (Z)-2-(l-(2-(5- chloro-2-oxo-3-(trifluoromethyl)pyridin-l(2H)-yl)acetyl)piperidin-4-yl)thiazole-4-carbaldehyde O-benzyl oxime; Compound No. 472: l-(2-(4-(4-(3-(2,6-difluorophenyl)-4,5-dihydroisoxazol-5-yl)thiazol-2- yl)piperidin-l-yl)-2-oxoethyl)-3-(trifluoromethyl)pyridin-2(lH)-one; Compound No. 473: l-(2-(4-(4-(3- (2,6-difluorophenyl)-4,5-dihydroisoxazol-5-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-6-methyl-3- (trifluoromethyl)pyridin-2(lH)-one; Compound No.474: 5-bromo-l-(2-(4-(4-(3-(2,6-difluorophenyl)-4,5- dihydroisoxazol-5-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-3-(trifluoromethyl)pyridin-2(lH)-one; Compound No.475: l-(2-(4-(4-(3-(2,6-difluorophenyl)-4,5-dihydroisoxazol-5-yl)thiazol-2-yl)piperidin-l- yl)-2-oxoethyl)-5-(trifluoromethyl)pyridin-2(lH)-one; Compound No. 476: 3-bromo-l-(2-(4-(4-(3-(2,6- difluorophenyl)-4,5-dihydroisoxazol-5-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-5- (trifluoromethyl)pyridin-2(lH)-one; Compound No. 477: 1-(2-(4-(4-(3-(2,6-difluorophenyl)-4,5- dihydroisoxazol-5-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-2-oxo-5-(trifluoromethyl)-l,2- dihydiOpyridine-3-carbonitrile; Compound No. 478: 3-chloro-l-(2-(4-(4-(3-(2,6-difluorophenyl)-4,5- dihydroisoxazol-5-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-5-(trifluoromethyl)pyridin-2(lH)-^ Compound No. 479: 5-cyano-l-(2-(4-(4-(5-(2,6-dichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2- yl)piperidin-l-yl)-2-oxoethyl)-6-oxo-l,6-dihydropyridine-3-carboxylic acid; Compound No. 480: l-(2- oxo-2-(4-(4-(5-(2,4,6-trifluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)ethyl)-3- (trifluoromethyl)pyridin-2(lH)-one; Compound No. 481: l-(2-(4-(4-(5-(5-chloro-l-methyl-3- (trifluoromethyl)-lH-pyrazol-4-yl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)- (trifluoromethyl)pyridin-2(lH)-one; Compound No.482: and 5-bromo-l-(2-(4-(4-(5-(5-chloro-l-methyl- 3-(trifluoromethyl)-lH-pyrazol-4-yl)-4,5-dihydro
(trifluoromethyl)pyridin-2(lH)-one; Compound No. 483: l-(3-(4-(4-(5-(2,6-difluorophenyl)-4,5- dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-3-oxopropyl)-3-(trifluoromethyl)pyridin-2(lH)-one; Compound No. 484: 5-chloro-l -(3-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydiO;,soxazol-3-yl)thiazol-2- yl)piperidin-l-yl)-3-oxopropyl)-3-(trifluoromethyl)pyridin-2(lH)-one; Compound No.485: l-(3-(4-(4-(5- (2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-3-oxopropyl)-5- (trifluoromethyl)pyridin-2(lH)-one; Compound No.486: 3-chloro-l-(3-(4-(4-(5-(2,6-difluorophenyl)-4,5- dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-3-oxopropyI)-5-(trifluoromethyl)pyridin-2(lH)-one; Compound No. 487: N-(5-chloro-2-oxo-3-(trifluoiOmethyl)pyridin-l(2H)-yl)-4-(4-(5-(2,6- difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidine-l-carboxamide; Compound No.488: N- (5-chloro-2-oxo-3-(trifluoromethyl)pyiidin-l(2H)-yl)-4-(4-(5-(2,6-difluoiOphenyl)-4,5-dihydroisoxazol- 3-yl)thiazol-2-yl)piperidine-l-carboxamide; Compound No. 489: 4-(4-(5-(2,6-difluorophenyl)-4,5- dihydroisoxazol-3-yl)thiazol-2-yl)-N-(2-oxo-5-(trifluoromethyl)pyridin-l(2H)-yl)piperidine-l- carboxamide; Compound No.490: N-(3-chIoiO-2-oxo-5-(trifluoromethyl)pyridin-l(2H)-yl)-4-(4-(5-(2,6- difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidine-l-carboxamide; Compound No.491: 5- chloro-l-(2-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperazin-l-yl)-2- oxoethyl)-3-(trifluoromethyl)pyridin-2(lH)-one; Compound No.492: l-(2-(4-(4-(5-(2,6-difluorophenyl)- 4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperazin-l-yl)-2-oxoem^
Compound No. 493: 3-chloro-l-(2-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2- yl)piperazin-l-yl)-2-oxoethy])-5-(trifluoromethy])pyridin-2(]H)-one; Compound No.494: l-(2-(4-(5-(5- (2,6-difluoiOphenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-3- (trifluoromethyI)pyridin-2(lH)-one; Compound No.495: 5-chloro-l-(2-(4-(5-(5-(2,6-difluorophenyl)-4,5- dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-o^
Compound No.496: l-(2-(4-(5-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-y])piperidin-l- yl)-2-oxoetbyl)-5-(trifluoromethyl)pyridin-2(lH)-one; Compound No. 497: 3-chloro-l-(2-(4-(5-(5-(2,6- difluorophenyl)-4,5-dihydroisoxazoI-3-yl)thiazol-2-yl)piperidin-l-yI)-2-oxoethyl)-5-
(trifluoromethyl)pyridin-2(lH)-one; Compound No. 498: l-(2-(4-(4-(5-(2,6-difluorophenyl)-l-methyl-
4,5-dihydro-lH-pyrazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-3-(trifluoromethyl)pyri one; Compound No.499: 5-chloro-l-(2-(4-(4-(5-(2,6-difluorophenyl)-l-methyl-4,5-dihydro-lH-pyrazol-
3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethy])-3-(trifluoromethyl)pyndin-2(lH)-one; Compound No. 500:
5-chloro-l-(2-(4-(4-(5-(2,6-difluorophenyl)-]-methyl-4,5-dihydro-lH^yrazol-3-yl)thiazol-2-yl)piperidin- l-yl)-2-oxoethyl)-3-(trifluoromethyl)pyridin-2(lH)-one; Compound No. 501: l-(2-(4-(4-(5-(2,6- difluorophenyl)-l-methy]-4,5-dihydro-lH-pyrazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-5-
(trifluoromethyl)pyridin-2(lH)-one; Compound No. 502: l-(2-(4-(4-(5-(2,6-difluorophenyl)-l-methyl- lH-pyrazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-3-(trifluoromethyl)pyridin-2(
Compound No. 503: 5-chloro-l-(2-(4-(4-(5-(2,6-difluorophenyI)-l -methyl- 1 H-pyrazol-3-yl)thiazol-2- yl)piperidin-]-yl)-2-oxoethyl)-3-(trifluorometbyl)pyridin-2(lH)-one; Compound No. 504: l-(2-(4-(4-(5-
(2,6-difluorophenyl)-l-methyl-lH-pyrazol-3-yl)thiazol-2-y!)piperidin-l-yl)-2-oxoethyl)-5-
(trifluoromethyl)pyridin-2(lH)-one; Compound No. 505: 3-chloro-l-(2-(4-(4-(5-(2,6-difluorophenyl)-l- methyI-lH-pyrazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-5-(trifluoromethyI)pyridin-2(lH
Compound No. 506: l-(2-(4-(4-(3-(2,6-difluorophenyl)-lH-pyrazol-l-yl)thiazol-2-yl)piperidin-l-yl)-2- oxoethyl)-3-(trifluoromethyl)pyridin-2(lH)-one; Compound No. 507: 5-chloro-l-(2-(4-(4-(3-(2,6- difluorophenyl)-! H-pyrazol-l-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-3-(trifluoromethyl)pyridin-
2(lH)-one; Compound No. 508: l-(2-(4-(4-(3-(2,6-difluorophenyl)-lH-pyrazol-l-yl)thiazol-2- yl)piperidin-l-yl)-2-oxoethyl)-5-(trifluoromethyl)pyridin-2(lH)-one; Compound No.509: 3-chloro-l-(2- (4-(4-(3-(2,6-difluorophenyl)-lH-pyrazol-l-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-5- (trifluoromethyl)pyridin-2(lH)-one; Compound No. 510: l-(2-(4-(5-(5-(naphthalen-l-yl)-4,5- dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-3-(trifluoromethyl)pyridin-2(l H)-one; Compound No. 511: 5-chloro-l-(2-(4-(5-(5-(naphthalen-l-yI)-4,5-dihydroisoxazol-3-yl)thiazol-2- yl)piperidin-l-yl)-2-oxoethyl)-3-(trifluoromethyl)pyridin-2(lH)-one; Compound No. 512: l-(2-(4-(5-(5- (naphthalen-l-yl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-5- (trifluoromethyl)pyridin-2(lH)-one; Compound No. 513: 3-chloro-l -(2-(4-(5-(5-(naphthalen-l-yl)-4,5- dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-5-(trifluoromethyl)pyridin-2(lH)-^ Compound No.514: 1 -(2-(4-(4-(3-(2,6-dichlorophenyl)-3-oxoprop- 1 -yn- 1 -yl)thiazol-2-yl)piperidin- 1 -yl)- 2-oxoethyl)-3-(trifluoromethyl)pyridin-2(lH)-one; Compound No. 515: 5-chloro-l-(2-(4-(4-(3-(2,6- dichlorophenyl)-3-oxoprop- 1 -yn- 1 -yl)thiazol-2-yl)piperidin-l -yl)-2-oxoethyI)-3-(trifluoromethyl)pyridin- 2(lH)-one; Compound No. 516: l-(2-(4-(4-(3-(2,6-dichlorophenyl)-3-oxoprop-l-yn-l-yl)thiazol-2- yl)piperidin-l-yl)-2-oxoethyl)-5-(trifluoiOmethyl)pyridin-2(lH)-one; Compound No. 517: 3-chloro-l-(2- (4-(4-(3-(2,6-dichlorophenyl)-3-oxoprop-l-yn-l-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-5- (trifiuoromethyl)pyridin-2(lH)-one; Compound No.518: l-(2-(4-(4-(3-(4-bromophenyl)-3-oxoprop-l-yn- l-yl)thiazol-2-yl)pipendin-l-yl)-2-oxoethyl)-3-(trifluoromethyl)pyridin-2(lH)-one; Compound No. 519: l-(2-(4-(4-(3-(4-bromophenyl)-3-oxoprop-l-yn-l-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-5-chloro-3- (trifluoromethyl)pyridin-2(lH)-one; Compound No.520: l-(2-(4-(4-(3-(4-bromophenyl)-3-oxoprop-l-yn- 1 -yl)thiazol-2-yl)piperidin-l -yl)-2-oxoethyl)-5-(trifluoromethyl)pyridin-2( 1 H)-one; Compound No. 521 :
1- (2-(4-(4-(3-(4-bromophenyl)-3-oxoprop-l-yn-l-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-3-chloro-5- (trifluoromethyl)pyridin-2(lH)-one; Compound No. 522: l-(2-oxo-2-(4-(4-(3-phenylprop-l-yn-l- yl)thiazol-2-yl)piperidin-l-yl)ethyl)-3-(trifluoromethyl)pyridin-2(lH)-one; Compound No.523: l-(2-oxo-
2- (4-(4-(3-phenylprop- 1 -yn- 1 -yl)thiazol-2-yl)piperidin-l -yl)ethyl)-5-(trifluoromethyl)pyridin-2( 1 H)-one; Compound No.524: Compound No. :; Compound No.525: 3-chloro-l-(2-oxo-2-(4-(4-(3-phenylprop-l- yn-l-yl)thiazol-2-yl)piperidin-l-yl)ethyl)-5-(trifluoromethyl)pyridin-2(lH)-one; Compound No. 526: 1- (2-(4-(4-(3-(2,6-dichlorophenyl)prop-l-yn-l-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-3- (trifluoiOmethyl)pyridin-2(lH)-one; Compound No. 527: 5-chloro-l-(2-(4-(4-(3-(2,6- dichlorophenyl)prop-l-yn-l-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-3-(trifluoromethyl)pyridin-2(lH)- one; Compound No.528: l-(2-(4-(4-(3-(2,6-dichlorophenyl)prop-l-yn-l -yl)thiazol-2-yl)piperidin-l-yl)-2- oxoethyl)-5-(trifluoromethyl)pyridin-2(lH)-one; Compound No. 529: 3-chloro-l-(2-(4-(4-(3-(2,6- dichlorophenyl)prop- 1 -yn- 1 -yl)thiazol-2-yl)piperidin-l -yl)-2-oxoethyl)-5-(trifluoromethyl)pyridin-2( 1 H)- one; Compound No. 530: l-(2-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2- yl)piperidin-l-yl)-2-thioxoethyl)-3-(trifluoromethyl)pyridin-2(lH)-one; Compound No. 531: 5-chloro-l- (2-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yI)piperidin-l-yl)-2-thioxoethyl)-3- (trifIuoromethyl)pyridin-2(lH)-one; Compound No. 532: l-(2-(4-(4-(5-(2,6-difluorophenyl)-4,5- dihydiOisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-24hioxoethyl)-5-(trifluoromethyl)pyridi
Compound No. 533: 2-(2,6-difluorophenyl)-N-(2-(l-(2-(2-oxo-3-(tnfluoromethy])pyridin-l(2H)- yl)acetyl)piperidin-4-yl)thiazol-4-yl)ethanethioamide; Compound No.534: N-(2-(l-(2-(5-chloro-2-oxo-3-
(trifluoiOmethyl)pyridin-l(2H)-yl)acetyl)piperidin-4-yl)thiazol-4-yl)-2-(2,6- difluorophenyl)ethanethioamide; Compound No. 535: 2-(2,6-difluorophenyl)-N-(2-(l-(2-(2-oxo-5- (trifluoromethyl)pyridin-l(2H)-yl)acetyl)piperidin-4-yl)thiazol-4-yl)ethanethioamide; Compound No. 536: N-(2-(l-(2-(3-chloro-2K)xo-5-(trifluoromethy
2- (2,6-difluorophenyl)ethanethioamide; Compound No. 537: l-(3-(4-(4-(5-(2,6-dichlorophenyl)-4,5- dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yI)-3-oxopropyl)-3-(trifluoromethyl)pyridin-2(lH
Compound No. 538: 5-chloro-l-(3-(4-(4-(5-(2,6-dichlorophenyl)-4,5-dihydroisoxazol-3-yl)lhiazol-2- yl)piperidin-l-yl)-3-oxopiOpyl)-3-(trifluoromethyl)pyridin-2(lH)-one; Compound No.539: l-(3-(4-(4-(5- (2,6-dichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-3-oxopropyI)-5- (trifluoromethyl)pyridin-2(lH)-one; Compound No. 540: 3-chloro-l-(3-(4-(4-(5-(2,6-dichlorophenyl)- 4,5-dihydroisoxazo]-3-yl)thiazol-2-yl)piperidin-K
Compound No. 541: N-(5-chloro-2-oxo-3-(trifluoromethyl)pyridin-l(2H)-yl)-4-(4-(5-(2,6- dichloropheny])-4,5-dihydiOisoxazol-3-yl)thiazol-2-yl)piperidine-l-carboxamide; Compound No.542: N- (5<hloro-2-oxo-3-(trifluoromethyl)pyridin-l(2H)-yl)-4-(4-(5-(2,6-dichlorophenyl)-4,5-dihydroisox
3- yl)thiazol-2-yl)piperidine-l-carboxamide; Compound No. 543: 4-(4-(5-(2,6-dichlorophenyl)-4,5- dihydroisoxazoI-3-yI)thiazol-2-yl)-N-(2-oxo-5-(trifluoromethyl)pyridin-l(2H)-yl)piperidine-1- carboxamide; Compound No. 544: N-(3-chloro-2-oxo-5-(trifluoromethyl)pyridin-l(2H)-yl)-4-(4-(5-(2,6- dicblorophenyl)-4,5-dihydroisoxazol-3-y])thiazol-2-yI)piperidine-l-carboxamide; Compound No.545: 5- chloro-l-(2-(4-(4-(5-(2,6-dichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperazin-l-yl)-2- oxoethyl)-3-(trifluoromethyl)pyridin-2(lH)-one; Compound No.546: l-(2-(4-(4-(5-(2,6-dichlorophenyl)- 4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperazin- 1 -yl)-2-oxoethyl)-5-(trifluoromethyl)pyridin-2( 1 H)-one; Compound No. 547: 3-chloro-l-(2-(4-(4-(5-(2,6-dichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2- yl)piperazin-l-yl)-2-oxoethyl)-5-(trifluoromethyl)pyridin-2(lH)-one; Compound No.548: 5-ch!oro-l -(2- (4-(5-(5-(2,6-dichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yI)piperidin-l-yl)-2-oxoethyl)-3- (trifluoromethyl)pyridin-2(lH)-one; Compound No. 549: l-(2-(4-(5-(5-(2,6-dicblorophenyl)-4,5- dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-5-(trifluoromethyl)pyridin-2(lH)- Compound No. 550: 3-chloiO-l-(2-(4-(5-(5-(2,6-dichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2- yl)piperidin-l-yl)-2-oxoethyl)-5-(trifluoromethyl)pyridin-2(lH)-one; Compound No. 551: l-(2-(4-(4-(5- (2,6-dichlorophenyl)-l-methyl-4,5-dihydro-lH-pyrazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-3- (tnfluoromethyl)pyridin-2(lH)-one; Compound No. 552: 5-chloiO-l-(2-(4-(4-(5-(2,6-difluorophenyl)-l- methyl-4,5-dihydro-lH-pyrazol-3-yl)thiazo
2(lH)-one; Compound No. 553: 5-chloro-l-(2-(4-(4-(5-(2,6-dichlorophenyl)-l-methyl-4,5-dihydro-lH- pyrazo]-3-yl)thiazol-2-yl)piperidin-1-yl)-2-oxoethyl)-3-(trifluoromethyl)pyridin-2(lH)-one; Compound No. 554: 1 -(2-(4-(4-(5-(2,6-dichlorophenyl)- 1 -methyl-4,5-dihydro- 1 H-pyrazol-3-yl)thiazol-2- yl)piperidin-l-yl)-2-oxoethyl)-3-(trifluoromethyl)pyridin-2(lH)-one; Compound No. 555: l-(2-(4-(4-(5- (2,6-dichlorophenyl)-l -methyl- lH-pyrazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-3- (trifluoromethyl)pyridin-2(lH)-one; Compound No. 556: 5-chloro-l-(2-(4-(4-(5-(2,6-dichlorophenyl)-l- methyl-lH-pyrazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-3-(trifluoromethyl)pyridin-2(lH)-one; Compound No.557: l-(2-(4-(4-(5-(2,6-dichlorophenyl)-l-methyl-lH-pyrazol-3-yl)thiazol-2-yl)piperidin- l-yl)-2-oxoethyl)-5-(trifluoromethyl)pyridin-2(lH)-one; Compound No.558: 3-chloro-l-(2-(4-(4-(5-(2,6- dichlorophenyl)-l -methyl- lH-pyrazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-5- (trifluoromethyl)pyridin-2(lH)-one; Compound No.559: l-(2-(4-(4-(3-(2,6-dichlorophenyl)-lH-pyrazol- l-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-3-(trifluoiOmethyl)pyridin-2(lH)-one; Compound No. 560: 5-chloro-l-(2-(4-(4-(3-(2,6-dichlorophenyl)-lH-pyrazol-l-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-3- (trifluoromethyl)pyridin-2(lH)-one; Compound No.561: l-(2-(4-(4-(3-(2,6-dichlorophenyl)-lH-pyrazol- l-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-5-(trifluoromethyl)pyndin-2(lH)-one; Compound No. 562: 3-chloro-l-(2-(4-(4-(3-(2,6-dichlorophenyl)-lH-pyrazol-l-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-5- (trifluoromethyl)pyridin-2(lH)-one; Compound No. 563: 5-bromo-l-(2-(4-(5-(5-(naphthalen-l-yl)-4,5- dihydroisoxazol-3-yl)thiazoI-2-y])piperidin-l-yl)-2-oxo
Compound No. 564: l-(2-(4-(4-(3-(2,6-difluorophenyl)prop-l-yn-l-yl)thiazol-2-yl)piperidin-l-yl)-2- oxoethyl)-3-(tnfluoromethyl)pyridin-2(lH)-one; Compound No. 565: 5-chloro-l-(2-(4-(4-(3-(2,6- difluorophenyl)prop-l-yn-l-yl)thiazol-2-yl)pipendin-l-yl)-2-oxoethyl)-3-(trifluoromethyl)pyridin-2(lH)- one; Compound No. 566: 3-chloro-l-(2-(4-(4-(3-(2,6-difluorophenyl)prop-l-yn-l-yl)thiazol-2- yl)piperidin-l-yl)-2-oxoethyl)-5-(trifluoromethyl)pyridin-2(lH)-one; Compound No. 567: l-(2-(4-(4-(5- (2,6-dichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-thioxoethyl)-3-
(trifluoromethyl)pyridin-2(lH)-one; Compound No. 568: N-(2-(l-(2-(5-chloro-2-oxo-3- (trifluoromethyl)pyridin-l(2H)-yl)acetyl)piperidin-4-yl)thiazol-4-yl)-2-(2,6- dichlorophenyl)ethanethioamide; Compound No. 569: 2-(2,6-dichlorophenyl)-N-(2-(l-(2-(2-oxo-3- (trifluoromethyl)pyridin-l(2H)-yl)acetyl)piperidin-4-yl)thiazol-4-yl)ethanethioamide; Compound No. 570: 5-chloro-l-(2-(4-(4-(5-(2,6-dichlorophenyI)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2- thioxoethyl)-3-(trifluoromethyl)pyridin-2(lH)-one; Compound No. 571: l-(2-(4-(4-(5-(2,6- dichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-thioxoethyl)-3- (trifluoromethyl)pyridin-2(lH)-one; Compound No. 572: l-(2-(4-(6-(5-(2,6-difluorophenyl)-4,5- dihydroisoxazol-3-yl)pyridin-2-yl)piperidin-l-yl)-2-oxoethyl)-3-(trifluoromethyl)pyridin-2(lH)-one; Compound No. 573: 5-ch]oro-l-(2-(4-(6-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)pyridin-2- yl)piperidin-]-yl)-2-oxoethyl)-3-(trifluoromethyl)pyridin-2(lH)-one; Compound No. 574: ]-(2-(4-(6-(5- (2,6-dichlorophenyl)-4,5-dihydroisoxazol-3-yl)pyridin-2-yl)piperidin-l-yl)-2-oxoethyl)-3- (trifluoromethyl)pyridin-2(lH)-one; Compound No. 575: 5-chloro-l-(2-(4-(6-(5-(2,6-dichlorophenyl)- 4,5-dihydroisoxazol-3-yl)pyridin-2-yl)piperidin-l-yl)-2-oxoethyl)-3-(trifluoromethyl)pyri
Compound No. 576: l-(2-(4-(6-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)pyridin-2-yl)piperidin- l-yl)-2-oxoethyl)-5-(trifluoromethyl)pyridin-2(lH)-one; Compound No.577: 3-chloro-l-(2-(4-(6-(5-(2,6- difluoiOphenyI)-4,5-dihydroisoxazoI-3-y])pyridin-2-yl)piperidin-l-yI)-2-oxoethyl)-5- (trifluoromethyl)pyridin-2(lH)-one; Compound No. 578: l-(2-(4-(6-(5-(2,6-dichlorophenyl)-4,5- dihydroisoxazol-3-yl)pyridii>2-yl)piperidin-l-yl)-2-oxoethyl)-5-(trifluoromethyl)pyridin-2(l^
Compound No. 579: 3-chloro-l-(2-(4-(6-(5-(2,6-dichlorophenyl)-4,5-dihydroisoxazol-3-yl)pyridin-2- yl)piperidin-]-yl)-2-oxoethyl)-5-(trifluoromethyl)pyridin-2(lH)-one; Compound No. 580: l-(2-(4-(2-(5- (2,6-dichlorophenyI)-4,5-dihydroisoxazoI-3-yl)pyndin-4-yI)piperidin-l-yI)-2-oxoethyl)-5- (trifluoromethyl)pyridin-2(lH)-one; Compound No. 581: 3-chloro-l-(2-(4-(2-(5-(2,6-dichlorophenyl)- 4,5-dihydroisoxazol-3-yl)pyridin-4-yl)piperidin-l-yl)-2-oxoethyl)-5-(trifluoromethyl)pyri
Compound No. 582: l-(2-(4-(2-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)pyridin-4-yl)piperidin- l-yl)-2-oxoethyl)-5-(trifluoromethy])pyridin-2(lH)-one; Compound No.583: 3-chloro-l-(2-(4-(2-(5-(2,6- difluorophenyl)-4,5-dihydiOisoxazol-3-yl)pyridin-4-yl)piperidin-l-yl)-2-oxoethyl)-5- (trifluoromethy])pyridin-2(lH)-one; Compound No. 584: l-(2-(4-(2-(5-(2,6-dichlorophenyl)-4,5- dihydroisoxazol-3-yl)pyridin-4-yl)piperidin-l-yl)-2-oxoethyl)-3-(trifluoromethyl)pyridi
Compound No. 585: 5-chloro-l-(2-(4-(2-(5-(2,6-dichlorophenyl)-4,5-dihydroisoxazol-3-yl)pyridin-4- yl)piperidin-]-y])-2-oxoethyI)-3-(trifluoromethyl)pyridin-2(lH)-one; Compound No. 586: l-(2-(4-(2-(5- (2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)pyndin-4-yl)piperidin-l-yl)-2-oxoethyl)-3- (trifluoromethyl)pyridin-2(lH)-one; Compound No.587: 5-chloro-l-(2-(4-(2-(5-(2,6-difluorophenyl)-4,5- dihydroisoxazol-3-yl)pyridin-4-yl)piperidin-l-yl)-2-oxoethyl)-3-(trifluoromethyl)pyridin^
Compound No.588: 3-chloro-l-(2-(4-(3-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)-lH-pyrazol-l- yl)piperidin-]-yl)-2-oxoethyl)-5-(trifluoiOmethyl)pyi:idin-2(lH)-one; Compound No.589: 3-chloro-]-(2- (4-(3-(5-(2,6-dichlorophenyl)-4,5-dihydroisoxazol-3-yl)-lH-pyrazol-l-yl)piperidin-l-yI)-2-oxoethyl)-5- (trifluoromethyl)pyridin-2(lH)-one; Compound No. 590: 3-chloro-2-(3-(l-(l-(2-(3-chloro-2-oxo-5- (trifluoromethyl)pyridin-l(2H)-yl)acetyl)piperidin-4-yl)-lH-pyrazol-3-yl)-4,5-dihydroisoxa^
yl)phenyl methanesulfonate; Compound No. 591: 3-chloro-l-(2-oxo-2-(4-(3-(5-(2,4,6-trichlorophenyl)- 4,5-dihydroisoxazol-3-yl)-lH-pyrazol-]-yl)piperidin-l-yl)ethyl)-5-(trifluoromethy])pyridin-2(]H)-oi^ Compound No. 592: 3-chloro-l -(2-(4-(3-(5-(2-chloro-6-(tnfluoromethyl)phenyl)-4,5-dihydroisoxazo!-3- yl)-lH-pyrazoI-l-yl)piperidin-l-yl)-2-oxoethyl)-5-(trifluoromethyl)pyndin-2(lH)-one; Compound No. 593: l-(2-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2- oxoethyl)-5-methoxy-3-(trifluoromethyl)pyridin-2(lH)-one; Compound No. 594: l-(2-(4-(4-(5-(2,6- dichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-y])piperidin-l-yl)-2-oxoethyl)-5-methoxy-3- (trifIuoromethyl)pyridin-2(lH)-one; Compound No. 595: 5-methoxy-l-(2-oxo-2-(4-(4-(5-(2,4,6- trichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)ethyl)-3-(trifluorometh^
2(lH)-one; Compound No. 596: 3-chloiO-2-(3-(2-(l-(2-(5-methoxy-2-oxo-3-(trifluoromethyl)pyridin- l(2H)-yl)acetyl)piperidin-4-yl)thiazol-4-yl)-4,5-dihydroisoxazol-5-yl)phenyl methanesulfonate; Compound No. 597: 5-(difluoromethoxy)-l-(2-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3- yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-3-(trifluoromethyl)pyridin-2(lH)-one; Compound No.598: 1- (2-(4-(4-(5-(2,6-dichlorophenyl)-4,5-dihydroisoxazol-3-yI)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-5-
(difluoromethoxy)-3-(trifluoromethyl)pyridin-2(lH)-one; Compound No.599: 5-(difluoromethoxy)-l-(2- oxo-2-(4-(4-(5-(2,4,64richlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)ethyl)-3 (tnfluoromethyl)pyridin-2(lH)-one; Compound No.600: 3-chloro-2-(3-(2-(l-(2-(5-(difluoromethoxy)-2- oxo-3-(trifluoromethyl)pyridin-l(2H)-yl)acetyl)piperidin-4-yl)thiazol-4-yl)-4,5-dihydrois
yl)phenyl methanesulfonate; Compound No.601: l-(2-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol- 3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-5-(fr^
Compound No. 602: l-(2-(4-(4-(5-(2,6-dichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin- l-yl)-2-oxoethyl)-5-(trifluoromethoxy)-3-(trifluoromethyl)pyridin-2(lH)-one; Compound No.603: l-(2- oxo-2-(4-(4-(5-(2,4,6-trichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)ethyl)-5- (trifluoromethoxy)-3-(trifluoromethyl)pyridin-2(lH)-one; Compound No.604: 3-chloro-2-(3-(2-(l-(2-(2- oxo-5-(trifluoromethoxy)-3-(tnfluoromethyl)pyridin-l(2H)-yl)acetyl)piperidin-4-yl)thi
dihydroisoxazol-5-yl)phenyl methanesulfonate; Compound No. 605: l-(2-(4-(4-(5-(2,6-difluorophenyl)- 4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-5-(dimethylamino)-3- (trifluoromethyl)pyridin-2(lH)-one; Compound No. 606: l-(2-(4-(4-(5-(2,6-dichlorophenyl)-4,5- dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-5-(dimethylamino)-3-
(trifiuoromethyl)pyridin-2(lH)-one; Compound No. 607: 5-(dimethylamino)-l-(2-oxo-2-(4-(4-(5-(2,4,6- trichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)ethyl)-3-(triflu
2(lH)-one; Compound No. 608: 3-chloro-2-(3-(2-(l-(2-(5-(dimethylamino)-2-oxo-3-
(trifluoromethyl)pyridin-l(2H)-yl)acetyl)piperidin-4-yl)thiazol-4-yl)-4,5-dihydroisoxazol-5-yl^^ methanesulfonate; Compound No. 609: l-(2-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3- yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-3-(trifluoromethyl)-5-((trifluoromethyl)thio)pyridin-2(lH one; Compound No. 610: l-(2-(4-(4-(5-(2,6-dichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2- yl)piperidin-l-yl)-2-oxoethyl)-3-(trifluoromethyl)-5-((trifluoromethyl)thio)pyridin-2(l H)-one; Compound No. 611: l-(2-oxo-2-(4-(4-(5-(2,4,6-trichloiOphenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l- yl)ethyl)-3-(trifluoromethyl)-5-((trifluoromethyl)thio)pyndin-2(lH)-one; Compound No.612: 3-chloro-2- (3-(2-(l-(2-(2-oxo-3-(trifluoromethyl)-5-((tiifluoromethyl)thio)pyridin-l(2H)-yl)acetyl)pipen yl)thiazol-4-yl)-4,5-dihydroisoxazol-5-yl)phenyl methanesulfonate; Compound No. 613: l-(2-(4-(4-(5- (2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-3-methoxy-5- (trifluoromethyl)pyridin-2(lH)-one; Compound No. 614: l-(2-(4-(4-(5-(2,6-dichlorophenyl)-4,5- dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-3-methoxy-5-(trifluoromethyl)pyn 2(lH)-one; Compound No. 615: 3-methoxy-l -(2-oxo-2-(4-(4-(5-(2,4,6-trichlorophenyl)-4,5- dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)ethyl)^^ Compound No. 616: 3-chloro-2-(3-(2-(l-(2-(3-methoxy-2-oxo-5-(trifluoromethyI)pyridin-l(2H)-yl)acetyl)piperidin- 4-yl)thiazol-4-yl)-4,5-dihydroisoxazol-5-yl)phenyl methanesulfonate; Compound No. 617: 3- (difluoromethoxy)-l-(2-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydiOisoxazol-3-yl)thiazol-2-yl)piperidin-l- yl)-2-oxoethyl)-5-(trifluoromethyl)pyridin-2(lH)-one; Compound No. 618: l-(2-(4-(4-(5-(2,6- dichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-3-(difluorometh 5-(tnfluoromethyl)pyridin-2(lH)-one; Compound No. 619: 3-(difluoromethoxy)-l-(2-oxo-2-(4-(4-(5- (2,4,6-trichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)ethyl)-5-
(trifluoromethyl)pyridin-2(lH)-one; Compound No.620: 3-chloro-2-(3-(2-(l-(2-(3-(difluoromethoxy)-2- oxo-5-(trifluoromethyl)pyridin-l(2H)~yl)acetyl)pi
yl)phenyl methanesulfonate; Compound No.621: l-(2-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol- 3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-3-(trifluoromethoxy)-5-(trifluoromethyl)pyridin-2(lH)-one; Compound No. 622: l-(2-(4-(4-(5-(2,6-dichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin- l-yl)-2-oxoethyl)-3-(trifluoromethoxy)-5-(trifluoromethyl)pyridin-2(lH)-one; Compound No.623: l-(2- oxo-2-(4-(4-(5-(2,4,64richlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)ethyl)-3- (trifluoromethoxy)-5-(tnfluoromethyl)pyridin-2(lH)-one; Compound No.624: 3-chloro-2-(3-(2-(l-(2-(2- oxo-3-(trifluoromethoxy)-5-(trifluoromethyl)pyridin-l(2H)-yl)acetyl)piperidin-4-yl)thiazol-4-yl)-4,5- dihydroisoxazol-5-yl)phenyl methanesulfonate; Compound No. 625: l-(2-(4-(4-(5-(2,6-difluorophenyl)- 4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-3-(dimethylamino)-5- (trifluoiOmethyl)pyridin-2(lH)-one; Compound No. 626: l-(2-(4-(4-(5-(2,6-dichlorophenyl)-4,5- dihydroisoxazoI-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-3-(dimethylamino)-5- (tnfluoromethyl)pyridin-2(lH)-one; Compound No. 627: 3-(dimethylamino)-l-(2-oxo-2-(4-(4-(5-(2,4,6- trichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)ethyl)-5-(trifluoromethyl)^^
2(lH)-one; Compound No. 628: 3-chloro-2-(3-(2-(l-(2-(3-(dimethylamino)-2-oxo-5- (trifluoromethyl)pyridin-l(2H)-yl)acetyl)pi
methanesulfonate; Compound No. 629: l-(2-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazoI-3- yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-5-(trifiuoromethyl)-3-((trifluoromethyl)thi one; Compound No. 630: l-(2-(4-(4r(5-(2,6-dichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2- yl)piperidin-l-yl)-2-oxoethyl)-5-(trifluoromethyl)-3-((trifluoromethyl)thio)pyridi Compound No. 631 : l-(2-oxo-2-(4-(4-(5-(2,4,6-trichloiOphenyI)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l- yl)ethyl)-5-(trifluoromethyl)-3-((trifluoromethyl)thio)pyridin-2(lH)-one; Compound No.632: 3-chloro-2- (3-(2-(l-(2-(2-oxo-5-(trif!uoromethyl)-3-((trifluoromethyl)thio)pyridin-l(2H)-yl)acetyl)piperidi yl)thiazol-4-yl)-4,5-dihydroisoxazol-5-yl)pheny] methanesulfonate; Compound No. 633: l-(2-(4-(4-(5- (2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yI)-2-oxoethyI)-3-f!uoi -5- (tnfluoromethyl)pyridin-2(lH)-one; Compound No. 634: l-(2-(4-(4-(5-(2,6-dichlorophenyl)-4,5- dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-3-fluoro-5-(trifluoromethyl)pyr one; Compound No. 635: 3-fluoro-l-(2-oxo-2-(4-(4-(5-(2,4,6-trichlorophenyl)-4,5-dihydroisoxazol-3- y])thiazol-2-yl)piperidin-l-yl)ethyl)-5-(trifluoromethyl)pyridin-2(lH)-one; Compound No.636: 3-chloro- 2-(3-(2-(l-(2-(3-fluoro-2-oxo-5-(trifluoromethyl)pyridin-l(2H)-yl)acetyl)piperidin-4-yl)thi
dihydroisoxazol-5-yl)phenyl methanesulfonate; Compound No. 637: 3-(difluoromethyl)-l-(2-(4-(4-(5- (2,6-diiluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-6-methylpyridin- 2(lH)-one; Compound No. 638: l-(2-(4-(4-(5-(2,6-dichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2- yl)piperidin-l-yl)-2-oxoethyl)-3-(difluoromethyl)-6-methylpyridin-2(lH)-one; Compound No. 639: 3- (difluoromethyl)-6-methyl-l-(2-oxo-2-(4-(4-(5-(2,4,6-tnchlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol- 2-yl)piperidin-l-yl)ethyl)pyridin-2(lH)-one; Compound No. 640: 3-chloro-2-(3-(2-(l-(2-(3- (difluoromethyl)-6-methyl-2-oxopyridin-l(2H)-yl)acetyl)piperidin-4-yl)thiazol-4-yl)-4,5- dihydroisoxazol-5-yl)phenyl methanesulfonate; Compound No. 641: 6-chloro-l-(2-(4-(4-(5-(2,6- difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-3- (trifluoromethyl)pyridin-2(lH)-one; Compound No. 642: 6-chloro-l-(2-(4-(4-(5-(2,6-dichlorophenyl)- 4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-3-(trifluoromethyl)pyridin-2(
Compound No. 643: 6-chloro-l-(2-oxo-2-(4-(4-(5-(2,4,6-trichlorophenyl)-4,5-dihydroisoxazol-3- yl)thiazol-2-yl)piperidin-l-yl)ethyl)-3-(trifluoromethyl)pyridin-2(]H)-one; Compound No.644: 3-chloro- 2-(3-(2-(l-(2-(6-chloro-2-oxo-3-(trifluoromethyl)pyridin-l(2H)-yl)acetyl)piperidin-4-yl)thiazol-^ dihydroisoxazol-5-yl)phenyl methanesulfonate; Compound No. 645: 5-(difluoromethyl)-l-(2-(4-(4-(5- (2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-6-oxo-l,6- dihydropyridine-3-carbonitrile; Compound No. 646: l-(2-(4-(4-(5-(2,6-dichlorophenyl)-4,5- dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-5-(difluoromethyl)-6-oxo-l ,6- dihydropyridine-3-carbonitrile; Compound No.647: 5-(difluoromethyl)-6-oxo-l-(2-oxo-2-(4-(4-(5-(2,4,6- trichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)ethyl)-l,6-dihydiOpyridine-3- carbonitrile; Compound No. 648: 3-chloro-2-(3-(2-(l-(2-(5-cyano-3-(difluoromethyl)-2-oxopyridin- l(2H)-yl)acetyl)piperidin-4-yl)thiazol-4-yl)-4,5-dihydroisoxazol-5-yl)phenyl methanesulfonate; Compound No. 649: 3-(2-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l - yl)-2-oxoethyl)-l ,4-dimethyI-l ,3-dihydro-2H-imidazol-2-one; Compound No. 650: 3-(2-(4-(4-(5-(2,6- dichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin- l -yl)-2-oxoethyl)- l ,4-dimethyl- l ,3- dihydro-2H-imidazol-2-one; Compound No. 651 : l ,4-dimethyl-3-(2-oxo-2~(4-(4-(5-(2,4,6- trichlorophenyl)-4,5-dihydroisoxazoI-3-yI)thiazoI-2-yl)piperidin- l -yI)ethyI)- ] ,3-dihydro-2H-ii^^ one; Compound No. 652: 3-chloro-2-(3-(2-( l -(2-(3,5-dimethyl-2-oxo-2)3-dihydro- l H-imidazol-l - yl)acetyl)piperidin-4-yl)thiazol-4-yl)-4,5-dihydroisoxazol-5-yl)phenyl methanesulfonate; Compound No. 653 : 3-(2-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l -yl)-2- oxoethyl)- l -methyl-4-(trifluoromethyl)-l ,3-dihydiO-2H-imidazol-2-one; Compound No. 654: 3-(2-(4-(4- (5-(2,6-dichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l -yl)-2-oxoethyl)-l -methyl-4-
(trifluoromethyl)- l ,3-dihydro-2H-imidazol-2-one; Compound No. 655 : l -methyl-3-(2-oxo-2-(4-(4-(5- (2,4,64richiorophenyl)-4,5-dihydroisoxazol-3-yl)thiazo!-2-y])pipendiiv l -y])ethyl)-4-(tri
l ,3-dihydro-2H-imidazo]-2-one; Compound No. 656: 3-chloro-2-(3-(2-(l -(2-(3-methyl-2-oxo-5- (trifIuoromethyl)-2,3-dihydro- l H-imidazol- l -yl)acetyl)piperidin-4-yl)thiazol-4-yI)-4,5-dihydroi
5-yl)phenyl methanesulfonate; Compound No. 657: 4-(difluoromefhyl)-3-(2-(4-(4-(5-(2,6- difluorophenyl)-4,5-dihydiOisoxazol-3-yl)thiazol-2-yl)piperidin- l -yl)-2-oxoethyl)- l -methyl- 1 ,3-dihydro- 2H-imidazol-2-one; Compound No. 658: 3-(2-(4-(4-(5-(2,6-dichlorophenyl)-4,5-dihydroisoxazol-3- yl)thiazol-2-yl)piperidin- l -yl)-2-oxoethyl)-4-(difluoromethyl)- l -methyl-13-dihydro-2H-imi
Compound No. 659: 4-(difluoromethyl)-l -methyl-3-(2-oxo-2-(4-(4-(5-(2,4,6-trichlorophenyl)-4,5- dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l -yl)ethyl)- l ,3-dihydro-2H-imidazol-2-one; Compound No. 660: 3-chloro-2-(3-(2-( l -(2-(5-(difluoromethyl)-3-methyl-2-oxo-2,3-dihydro-l H-imidazol-l - yl)acetyl)piperidin-4-yl)thiazol-4-yl)-4,5-dihydroisoxazol-5-yl)phenyl methanesulfonate; Compound No. 661 : 2-(2-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydiOisoxazol-3-yl)thiazol-2-yl)piperidin- l -yl)-2- oxoethyl)-5-methylisoxazol-3(2H)-one; Compound No. 662: 2-(2-(4-(4-(5-(2,6-dichlorophenyl)-4,5- dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l -yl)-2-oxoethyl)-5-methyl isoxazol-3(2H)-one; Compound No. 663 : 5-methyl-2-(2-oxo-2-(4-(4-(5-(2,4,6-trichloiOphenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2- yl)piperidin-l -yl)ethyl)isoxazol-3(2H)-one; Compound No. 664: 3-chloro-2-(3-(2-( l -(2-(5-methyl-3- . oxoisoxazol-2(3H)-yl)acetyl)piperidin-4-yl)thiazol-4-yl)-4,5-dihydroisoxazol-5-yl)phenyl
methanesulfonate; Compound No. 665 : 2-(2-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3- yl)thiazol-2-yl)piperidin-l -yl)-2-oxoethyl)-5-(trifluoromethyl)isoxazol-3(2H)-one; Compound No. 666: 2-(2-(4-(4-(5-(2,6-dichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin- l -yl)-2-oxoethyl)-5- (trifluoromethyl)isoxazol-3(2H)-one; Compound No. 667: 2-(2-oxo-2-(4-(4-(5-(2,4,6-trichlorophenyl)- 4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l -yl)ethyl)-5-(trifluoromethyl)isoxazol-3(2H)-one;
Compound No. 668: 3-chloro-2-(3-(2-( l -(2-(3-oxo-5-(trifluoromethyl )isoxazol-2(3H)-yl)acetyl)piperidin- 4-yl)thiazol-4-yl)-4,5-dihydroisoxazol-5-yl)phenyl methanesulfonate; Compound No. 669: 5- (difluoromethyl)-2-(2-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yi)piperi 2-oxoethyl)isoxazol-3(2H)-one; Compound No. 670: 2-(2-(4-(4-(5-(2,6-dichlorophenyl)-4,5- dihydroisoxazol-3-yl)thiazol-2-yI)piperidin-l -yl)-2^^
Compound No. 671 : 2-(2-oxo-2-(4-(4-(5-(2,4,6-trichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2- yI)piperidin-l -yl)ethyl)-5-(trifluoromethyl)isoxazol-3(2H)-one; Compound No. 672: and Compound No. 673 : 3-chloro-2-(3-(2-( l -(2-(3-oxo-5-(trifluoromethyl)isoxazo]-2(3H)-yl)acetyl)piperidin-4-yl)thiazol-4- yl)-4,5-dihydroisoxazol-5-yl)phenyl methanesulfonate.
In accordance with the present invention compound of Formula I or the compounds specifically mentioned herein above can be prepared by using a compound represented by Formula 111 and polymorphs thereof:
Figure imgf000065_0001
wherein, R', p, X 1, X2, X3, X4 and v are as defined above. R22 is hyrdoxy, bromine, chlorine, iodine or O- C1-C4 alkyl.
Representative and non-l imiting examples of the intermediates useful for preparing the compounds of the present invention are:
2-(2-oxopyridin-l (2H)-yl)acetic acid; 2-(5-chloro-2-oxopyridin-l (2H)-yl)acetic acid; 2-(3-chloro-2- oxopyridin-l (2H)-yl)acetic acid; 2-(5-bromo-2-oxopyridin-l (2H)-yl)acetic acid; 2-(5-fluoro-2- oxopyridin- l (2H)-yl)acetic acid; 2-(2-oxo-5-(trifluoromethyl)pyridin-l (2H)-yl)acetic acid; 2-(2-oxo-3- (trifluoromethyl)pyridin- l (2H)-yl)acetic acid; 2-(2-oxo-6-(trifluoromethyl)pyridin- l (2H)-yl)acetic acid; 2-(2-oxo-4-(trifluoromethyl)pyridin-l (2H)-yl)acetic acid; 2-(4-methyl-2-oxopyridin-l (2H)-yl)acetic acid; 2-(5-methyl-2-oxopyridin-l (2H)-yl)acetic acid; 2-(6-methyl-2-oxopyridin-l (2H)-yl)acetic acid; 2-(3- methyi-2-oxopyridin-l (2H)-yl)acetic acid; 2-(3-(difluoromethyl)-2-oxopyridin- l (2H)-yl)acetic acid; 2-(5- (difluoromethyl)-2-oxopyridin- l (2H)-yl)acetic acid; 2-(5-bromo-2-oxo-3-(trifluoromethyl)pyridin- l (2H)- yl)acetic acid; 2-(3-bromo-2-oxo-5-(trifluoromethyl)pyridin-l (2H)-yl)acetic acid; 2-(3-chloro-2-oxo-5- (trifluoromethyl)pyridin- l (2H)-yl)acetic acid; 2-(5-chloro-2-oxo-3-(trifluoromethyl)pyridin- l (2H)- yl)acetic acid; 2-(5-methyl-2-oxo-3-(trifluoromethyl)pyridin- l (2H)-yl)acetic acid; 2-(6-methyl-2-oxo-3- (trifluoromethyl)pyridin- l (2H)-yl)acetic acid; 2-(5-fluoro-2-oxo-3-(trifluoromethyl)pyridin- l (2H)- yl)acetic acid; 2-(3-methyl-2-oxo-5-(trifluoromethyl)pyridin- l (2H)-yl)acetic acid; 2-(5-cyclopropyl-2- oxo-3-(trifluoromethyl)pyridin- l (2H)-yl)acetic acid; 2-(3-cyclopropyl-2-oxo-5-(trifluoromethyl)pyridin- I (2H)-yl)acetic acid; 2-(3-bromo-5-cyano-2-oxopyndin- l (2H)-yl)acetic acid; 2-(3-chloro-2-oxo-5- ((trifluoromethyl)thio)pyridin-l (2H)-yl)acetic acid; 2-(6-(difluoromethyl)-2-oxo-3-
(trifluoromethyl)pyridin- l (2H)-yl)acetic acid; 2-(2-oxo-3,5-bis(trifluoromethyl)pyridin- l (2H)-y])acetic acid; 2-(5-chloro-3-(difluoromethyl)-2-oxopyridin- l (2H)-yl)acetic acid; 2-(3,5-dichloro-2-oxopyridin- l (2H)-yl)acetic acid; 2-(3,5-dibromo-2-oxopyridin- l (2H)-yl)acetic acid; 2-(3-bromo-5-chloro-2- oxopyridin- l (2H)-yl)acetic acid; 2-(3-bromo-5-methyl-2-oxopyridin- l (2H)-yl)acetic acid; 2-(5-chloro-3- cyano-2-oxopyridin- l (2H)-y])acetic acid; 2-(5-bromo-3-cyano-2-oxopyridin- l (2H)-yl)acetic acid;
2-(2-oxo-3,6-bis(trifluoromethyl)pyridin- l (2H)-yl)acetic acid; 2-(3-bromo-5-(difluoromethyl)-2- oxopyridin- l (2H)-yl)acetic acid; 2-(5-(difluoromethyl)-2-oxopyridin-l (2H)-yl)acetic acid; 2-(5-cyano-2- oxo-3-(trifluoromethyl)pyridin- l (2H)-yl)acetic acid; 2-(5-chloro-6-methyl-2-oxo-3-
(trifluoromethyl)pyridin- l (2H)-yl)acetic acid; 2-(3-((dimethyl(oxo)^6-sulfaneylidene)amino)-2- oxopyridin- l (2H)-yl)acetic acid; 2-(5-bromo-3-chloro-2-oxopyridin- l (2H)-yl)acetic acid;
2-(3-cyano-2-oxopyridin- l (2H)-yl)acetic acid; 2-(6-(difluoromethyl)-2-oxopyridin-l (2H)-yl)acetic acid 2-(5-methyl-2-oxopyridin- l (2H)-yl)acetic acid; 2-(2-oxo-6-(trifluoromethyl)pyridin- l (2H)-yl)acetic acid; 2-(3-(ethoxycarbonyl)-2-oxo-5-(trifluoromethyl)pyridin-l (2H)-yl)acetic acid; 2-(3-cyano-2-oxopyridin- l (2H)-yl)acetic acid; 2-(5-chloro-2-oxopyridin-l (2H)-yl)acetic acid; 2-(5-bromo-3-methyl-2-oxopyridin- l (2H)-yl)acetic acid; 2-(5-methy]-2-oxo-3-(trifluoromethyl)pyridin-l (2H)-yl)acetic acid; 2-(5-bromo-3- nitro-2-oxopyridin- l (2H)-yl)acetic acid; 2-(5-nitro-2-oxo-3-(trifluoromethyl)pyridin- l (2H)-yl)acetic acid; 2-(3-bromo-5-(difluoromethyl)-2-oxopyridin-l (2H)-yl)acetic acid; 2-(3-chloro-5-cyano-2-oxopyridin- l (2H)-yl)acetic acid; 2-(3-nitro-2-oxo-5-(trifluoromethyl)pyridin-l (2H)-yi)acetic acid; 2-(3-cyano-2-oxo- 5-(trifluoromethyl)pyridin- l (2H)-yl)acetic acid; 2-(3-cyano-5-(methoxycarbonyl)-2-oxopyridin- l (2H)- yl)acetic acid; 2-(3-carbamoyl-2-oxo-5-(trifluoromethyl)pyridin-l(2H)-yl)acetic acid; l -(carboxymethyl)- 2-oxo-5-(trifluoromethyl)- l ,2-dihydropyridine-3-carboxylic acid; l -(carboxymethyl)-5-cyano-6-oxo-l ,6- dihydropyridine-3-carboxylic acid; 2-(3-chloro-5-(difluoromethyl)-2-oxopyridin- l (2H)-yl)acetic acid; 2- (3-(tert-butylcarbamoyl)-2-oxo-5-(trifluoromethyl)pyridin-l (2H)-yl)acetic acid; 2-(5,5-dimethyl-l -oxido- 4-phenyl- 1 ,2,3-thiadiazoI-2(5H)-yl)acetic acid; 2-(2-methyl-5-oxo-2,5-dihydro- 1 H-pyrazol- 1 -yl)acetic acid; 2-(3-(difluoromethyl)-2-methyl-5-oxo-2,5-dihydro-l H-pyrazol- l -yl)acetic acid; 2-(4-bromo-3- (difluoromethyI)-2-methy Ι-5-ΟΧΟ-2, 5-dihydro- l H-pyrazol- l -yl)acetic acid; 2-(2-methyl-5-oxo-3- (trifluoromethyl)-2,5-dihydro- l H-pyrazol- l -yl)acetic acid; and 2-(2,5-dimethyl-3-oxo-2,3-dihydro-l H- pyrazol- l -yl)acetic acid. The compound of Formula III also includes corresponding C1-C3 alkyl ester, acyl halides and polymorphs thereof.
For example, methyl 2-(3-carbamoyl-2-oxo-5-(trifluoromethyl)pyridin- l (2H)-yl)acetate; or ethyl 2-(3-carbamoyl-2-oxo-5-(trifluoromethyl)pyridin-l (2H)-yl)acetate; or 2-(3-carbamoyl-2-oxo-5-(trifluoromethyl)pyridin- l (2H)-yl)acetyl chloride
and corresponding methyl ester or ethyl ester or acyl chloride of 2-(3-carbamoyl-2-oxo-5- (tnfluoromethyl)pyridin- l (2H)-yl)acetic acid are also included in the scope of the present invention. The compound of Formula III can be prepared by any of the processes described in the experimental section.
In one of the embodiment of the present i nvention compound of Formula III, corresponding C1-C3 alkyl ester or acyl chloride can prepared by alkylating 2-oxo compound (equivalent to C of example 16) using C1-C3 alkyl 2-haloacetate to obtain C1-C3 alkylated 2-oxo compound (equivalent to D of example 16). C1-C3 alkylated 2-oxo compound is then optionally hydrolyzed to obtain an acid (equivalent to E of example 16).
The C1-C3 alkylated 2-oxo compound obtained in the first step or the acid obtained in the second step is halogenated using suitable halogenating agent to obtain acyl halide.
The novel and inventive compounds of the present invention, the salts, isomers, metal complexes and N- oxides thereof are effective in preventing against and controlling phytopathogenic micro-organisms. An anion part of the salt in case the compound of Formula I is cationic or capable of forming a cation can be inorganic or organic.
Alterntively, a cation part of the salt in case the compound of Formula I is an anionic or capable of forming anion can be inorganic or organic.
Examples of inorganic anion part of the salt include but are not limited to chloride, bromide, iodide, fluoride, sulfate, phosphate, nitrate, nitrite, hydrogen carbonates, hydrogen sulfate.
Examples of organic anion part of the salt include but are not limited to formate, alkanoates, carbonates, acetates, trifluoroacetate, trichloroacetate, propionate, glycolate, thiocyanate, lactate, succinate, malate, citrates, benzoates, cinnamates, oxalates, alkylsulphates, alkylsulphonates, arylsulphonates aryldisulphonates, alkylphosphonates, arylphosphonates, aryldiphosphonates, p-toluenesulphonate, and salicylate.
Examples of inorganic cation part of the salt include but are not limited to alkali and alkaline earth metals. Examples of organic cation part of the salt include but are not limited to pyridine, methyl amine, imidazole, benzimidazole, hitidine, phosphazene, tetramethyl ammonium, tetrabutylammonium, choline and tri methyl amine.
Metal ions in metal complexes of the compound of Formula I are especially the ions of the elements of the second main group, especially calcium and magnesium, of the third and fourth main group, especially aluminium, tin and lead, and also of the first to eighth transition groups, especially chromium, manganese, iron, cobalt, nickel, copper, zinc and others. Particular preference is given to the metal ions of the elements of the fourth period and the first to eighth transition groups. Here, the metals can be present in the various valencies that they can assume.
The present invention also relates to the compound of Formula I, in the composition with one or more inert carriers for controlling or preventing against phytopathogenic micro-organisms.
The compound of Formula I of the present invention in the composition can be agriculturally acceptable salts, metal complexes, constitutional isomers, stereo-isomers. diastereoisomers, enantiomers, chiral isomers, atropisomers, conformers, rotamers, tautomers, optical isomers, polymorphs, geometric isomers, or N-oxides thereof. The excipient can be an inert carrier or any other essential ingredient such as surfactants, additives, solid diluents and liquid diluents.
The present invention also relates to the compound of Formula I in the composition comprising at least one active compatible compound selected from fungicides, insecticides, nematicides, acaricides, biopesticides, herbicides, plant growth regulators, antibiotics, fertiliers and nutrients. The compounds used in the composition and in combination with the compound of Formula I are also termed as active compatible compounds.
The concentration of the compound of present invention in the composition ranges from 1 to 90% by weight with respect to the total weight of the composition, preferably from 5 to 50% by weight with respect to the total weight of the composition.
The known and reported fungicides, insecticides, nematicides, acaricides, biopesticides, herbicides, plant growth regulators, antibiotics and nutrients can be combined with at least one compound of the Formula I of the present invention. For example, fungicides, insecticides, nematicides, acaricides, biopesticides, herbicides, plant growth regulators, antibiotics, fertilizers and nutrients disclosed and reported in WO2016156129 can be combined with at least one compound of the Formula I of the present invention. The fungicides, insecticides, nematicides, acaricides, biopesticides, herbicides, plant growth regulators, antibiotics, fertilizers and nutrients reported in WO20161 56129 are incorporated herein by way of reference as non-limiting examples to be combined with at least one compound of the Formula I of the present invention.
The present invention also relates to a use of the compound of Formula 1 or of the compound of Formula 1 in the composition for control ling or preventing against phytopathogenic micro-organisms such as fungi, stramenopiles, bacteria, insects, nematodes, mites in agricultural crops and or horticultural crops.
Particularly, the present invention also relates to a use of the compound of Formula I or of the compound of Formula I in the composition for controlling or preventing against phytopathogenic fungi and oomycetes in agricultural crops and or horticulture crops. The compound of Formula I or the compound of Formula I in the composition may be used to treat several fungal pathogens. Non-limiting examples of pathogens of fungal diseases which can be treated in accordance with the invention include:
diseases caused by pathogens from the group of the Oomycetes, for example Albugo species, for example Albugo Candida; Bremia species, for example Bremia lactucae; Peronospora species, for example Peronospora pisi or P. brassicae; Phytophthora species, for example Phytophthora infestans; Plasmopara species, for example Plasmopara viticola; Pseiidoperonospora species, for example Pseudoperonospora hiimuli or Pseiidoperonospora cubensis; Pythium species, for example Pythhim ultimitm;
diseases caused by powdery mildew pathogens, for example Blumeria species, for example Blumeria graminis; Podosphaera species, for example Podosphaera leucotricha; Sphaerotheca species, for example Sphaerotheca fuliginea; Uncinula species, for example Uncinula necator; Erysiphe species, for example Erysiphe cichoracearu;
diseases caused by rust disease pathogens, for example Gymnosporangium species, for example Gymnosporangium sabinae; Hemileia species, for example Hemileia vastatrix; Phakopsora species, for example Phakopsora pachyrhizi or Phakopsora meibomiae; Puccinia species, for example Puccinia recondita, Puccinia graminis oder Puccinia striiformis; Uromyces species, for example Uromyces appendiculatus;
leaf blotch diseases and leaf wilt diseases caused, for example, by Alternaria species, for example Alternaria solani; Cercospora species, for example Cercospora beticola; Cladiosporium species, for example Cladiosporium cucumerinum; Cochliobolus species, for example Cochliobolus sativus (conidial form: Drechslera, syn: Helminthosporium) or Cochliobolus miyabeanus; Colletotrichum species, for example Colletotrichum lindemuthanium; Cycloconium species, for example Cycloconium oleaginum; Diaporthe species, for example Diaporthe citri; Elsinoe species, for example Elsinoe fawcettii; Gloeosporium species, for example Gloeosporium laeticolor; Glo erella species, for example Glomerella cingulata; Gitignardia species, for example Gitignardia bidwelli; Leptosphaeria species, for example Leptosphaeria macidans; Magnaporthe species, for example Magnaporthe grisea; Microdochium species, for example Microdochium nivale; Mycosphaerella species, for example Mycosphaerella graminicola, Mycosphaerella arachidicola or Mycosphaerella fijiensis; Phaeosphaeria species, for example Phaeosphaeria nodorum; Pyrenophora species, for example Pyrenophora teres or Pyrenophora tritici repentis; Ramularia species, for example Ramularia collo-cygni or Ramularia areola; Rhynchosporium species, for example Rhynchosporium secalis; Septoria species, for example Septoria apii or Septoria lycopersici; Stagonospora species, for example Stagonospora nodorum; Typhula species, for example Typhida incarnata; Venturia species, for example Venturia inaequalis; root and stem diseases caused, for example, by Corticium species, for example Corticium graminearum; Fusarium species, for example Fusarium oxysporum; Gaeumcmnomyces species, for example Gaeumannomyces graminis; Plasmodiophora species, for example Plasmodiophora brassicae; Rhizoctonia species, for example Rhizoctonia solani; Sarocladium species, for example Sarocladium oryzae; Sclerotiwn species, for example Sclerotium oryzae; Tapesia species, for example Tapesia acuformis; Thielaviopsis species, for example Thielaviopsis basicola; Ganoderma species, for example Ganoderma lucidum;
ear and panicle diseases (including corn cobs) caused, for example, by Alternaria species, for example Alternaria spp.; Aspergillus species, for example Aspergillus flavus; Cladosporium species, for example Cladosporium cladosporioides; Claviceps species, for example Claviceps purpurea; Fusarium species, for example Fusarium culmorum; Gibberella species, for example Gibberella zeae; Monographella species, for example Monographella nivalis; Stagnospora species, for example Stagnospora nodorum; diseases caused by smut fungi, for example Sphacelotheca species, for example Sphacelotheca reiliana; Tilletia species, for example Tilletia caries or Tilletia controversa; Urocystis species, for example Urocystis occulta; Ustilago species, for example Ustilago nuda;
fruit rot caused, for example, by Aspergillus species, for example Aspergillus flavus; Botrytis species, for example Botrytis cinerea; Penicillium species, for example Penicillium expansion or Penicillium purpurogenum; Rhizopus species, for example Rhizopus stolonifer; Sclerotinia species, for example Sclerotinia sulerotiorum; Verticilium species, for example Verticilium alboatrum;
seed- and son -borne rot and wilt diseases, and also diseases of seedlings, caused, for example, by Alternaria species, for example Alternaria brassicicola; Aphanomyces species, for example Aphanomyces euteiches; Ascochyta species, for example Ascochyta lends; Aspergillus species, for example Aspergillus flavus; Cladosporium species, for example Cladosporium herbarum; Cochliobolus species, for example Cochliobolus sativus (conidial form: Drechslera, Bipolaris Syn: Helminthosporium); Colletolrichum species, for example Colletolrichum coccodes; Fusarium species, for example Fusarium culmorum; Gibberella species, for example Gibberella zeae; Macrophomina species, for example Macrophomina phaseolina; Microdochium species, for example Microdochium nivale; Monographella species,, for example Monographella nivalis; Penicillium species, for example Penicillium expansum; Phoma species, for example Phoma lingam; Phomopsis species, for example Phomopsis sojae; Phytophlhora species, for example Phytophlhora cactorum; Pyrenophora species, for example Pyrenophora graminea; Pyricularia species, for example Pyricularia oryzae; Pythium species, for example Pythhim ultimum; Rhizoctonia species, for example Rhizoctonia solani; Rhizopus species, for example Rhizopus oryzae; Sclerotium species, for example Sclerotium rolfsii; Septoria species, for example Septoria nodorum; Typhula species, for example Typhula incarnata; Verticillium species, for example Verticillium dahliae; cancers, galls and witches' broom caused, for example, by Nectria species, for example Nectria galligena;
wi lt diseases caused, for example, by Monilinia species, for example Monilinia laxa;
deformations of leaves, flowers and fruits caused, for example, by Exobasidium species, for example Exobasidium vexans; Taphrina species, for example Taphrina deformans;
degenerative diseases in woody plants, caused, for example, by Esca species, for example Phaeomoniella chlamydospora, Phaeoacremonhim aleophilum or Fomitiporia mediterranea; Ganoderma species, for example Ganoderma boninense;
diseases of flowers and seeds caused, for example, by Botrytis species, for example Botrytis cinerea; diseases of plant tubers caused, for example, by Rhizoctonia species, for example Rhizoctonia solani; Helminthosporhim species, for example Helminthosporium solani;
diseases caused by bacterial pathogens, for example Xanthomonas species, for example Xanthomonas campestris pv. oryzae; Pseiidomonas species, for example Pse domonas syringae pv. lachrymans; Erwinia species, for example Erwinia amylovora; Ralstonia species, for example Ralstonia solanacearam;
Fungal diseases on roots and the stem base caused, for example, by black root rot (Calonectria crotalariae), charcoal rot (Macrophomina phaseolina), fusarium blight or wilt, root rot, and pod and collar rot (Fusarium oxysporum, Fusarium orthoceras, Fusarium semitectum, Fusarium equiseti), mycoleptodiscus root rot (Mycoleptodiscus terrestris), neocosmospora (Neocosmospora vasinfecta), pod and stem blight (Diaporthe phaseolorum), stem canker {Diaporthe phaseolorum var. caulivora), phytophthora rot (Phytophthora megasperma), brown stem rot {Phialophora gregata), pythium rot (Pythium aphanidermatum, Pythium irregulare, Pythium debaryanum, Pythium myriotylum, Pythium ultimum), rhizoctonia root rot, stem decay, and damping-off (Rhizoctonia solani), sclerotinia stem decay (Sclerotmia sclerotiorum), sclerotinia southern blight (Sclerotinia rolfsii), thielaviopsis root rot (Thielaviopsis basicola).
Plants which can be treated in accordance with the invention include the following: Rosaceae sp (for example pome fruits such as apples, pears, apricots, cherries, almonds and peaches), Ribesioidae sp. , Juglandaceae sp. , Betulaceae sp. , Anacardiaceae sp., Fagaceae sp., Moraceae sp. , Oleaceae sp. , Actinidaceae sp. , Lauraceae sp. , Musaceae sp. (for example banana trees and plantations), Rubiaceae sp. (for example coffee), Tlteaceae sp. , Sterculiceae sp., Rutaceae sp. (for example lemons, oranges and grapefruit); Vitaceae sp. (for example grapes); Solanaceae sp. (for example tomatoes, peppers), Liliaceae sp., Aster aceae sp. (for example lettuce), Umbelliferae sp. , Cruciferae sp., Chenopodiaceae sp. , Cucurbitaceae sp. (for example cucumber), Alliaceae sp. (for example leek, onion), Papilionaceae sp. (for example peas); major crop plants, such as PoaceaelGramineae sp. (for example maize, turf, cereals such as wheat, rye, rice, barley, oats, millet and triticale), Asteraceae sp. (for example sunflower), Brassicaceae sp. (for example white cabbage, red cabbage, broccoli, cauliflower, Brussels sprouts, pak choi, kohlrabi, radishes, and oilseed rape, mustard, horseradish and cress), Fabacae sp. (for example bean, peanuts), Papilionaceae sp. (for example soya bean), Solanaceae sp. (for example potatoes), Chenopodiaceae sp. (for example sugar beet, fodder beet, swiss chard, beetroot); Malvaceae (for example cotton); useful plants and ornamental plants for gardens and wooded areas; and genetically modified varieties of each of these plants.
The agricultural crops are cereals, corn, rice, soybean and other leguminous plants, fruits and fruit trees, nuts and nut trees, citrus and citrus trees, any horticultural plants, cucurbitaceae, oleaginous plants, tobacco, coffee, tea, cacao, sugar beet, sugar cane, cotton, potato, tomato, onions, peppers and other vegetables, and ornamentals.
The present invention further relates to the use of the compound of Formula I or the compound of Formula I in the composition optionally comprising at least one active compatible compound for treating seeds with the purpose of protecting the seeds, the germinating plants and emerged seedlings against phytopathogenic micro-organisms.
The present invention further relates to seeds which have been treated with the compound of the Formula I or the compound of Formula I in the composition optionally comprising at least one active compatible compound for protection from phytopathogenic micro-organisms.
The present invention also relates to a method of controlling or preventing infestation of useful plants by phytopathogenic micro-organisms in agricultural crops and or horticultural crops wherein the compound of Formula I or the compound of Formula 1 in the composition optionally comprising at least one active compatible compound, is applied to the plants, to parts thereof or the locus thereof. The effective amount of compound of Formula 1 or the compound of Formula I in the composition optionally comprising at least one active compatible compound ranges from 1 gai to 5000 gai per hectare in agriculture or horticulture crops.
Also, the present invention relates to the compound of the Formula I or the compound of the Formula I in the composition optionally comprising at least one active compatible compound applied to a plant, plant parts or locus thereof.
The present invention furthermore includes a method for treating seed, particularly seeds (dormant, primed, pregerminated or even with emerged roots and leaves) treated with the compound of the Formula I or the compound of the Formula I in the composition optionally comprising at least one active compatible compound. In these methods, the compound of Formula I or the compound of Formula I in the composition optionally comprising at least one active compatible compound is applied to the seeds of plants for controlling or preventing infestation of useful plants by phytopathogenic micro-organisms in agricultural and or horticultural corps. It is also desirable to optimize the amount of the active ingredient used so as to provide the best possible protection for the plants, the plant parts, or the seeds, the germinating plants and emerged seedl ings from attack by phytopathogenic micro-organisms, but without damaging the plants themselves by the active ingredient used. In particular, methods for the treatment of seed should also take into consideration the intrinsic phenotypes of transgenic plants in order to achieve optimum protection of the seed and the germinating plant with a minimum of crop protection compositions being employed.
One of the advantages of the present invention is that the treatment of the seeds with the compound of Formula I or the compound of Formula I in the composition optionally comprising at least one active compatible compound not only protects the seed itself, but also the resulting plants after emergence, from animal pests and/or phytopathogenic harmful micro-organisms. In this way, the immediate treatment of the crop at the time of sowing or shortly thereafter protect plants as well as seed treatment in prior to sowing. It is likewise considered to be advantageous that the compound of Formula I or the compound of Formula I in the composition optionally comprising at least one active compatible compound can be used especially also for transgenic seed, in which case the plant which grows from this seed is capable of expressing a protein which acts against pests, herbicidal damage or abiotic stress. The treatment of such seeds with the compound of Formula I or the compound of Formula I in the composition optionally comprising at least one active compatible compound, for example an insecticidal protein, can result in control of certain pests. Surprisingly, a further enhanced effect can be observed in this case, which additionally increases the effectiveness for protection against attack by pests, micro-organisms, weeds or abiotic stress.
The compound of Formula I or the compound of Formula I in the composition optionally comprising at least one active compatible compound are suitable for protection of seed of any plant variety which is used in agriculture, in the greenhouse, i n forests or in horticulture. More particularly, the seed is that of cereals (such as wheat, barley, rye, millet and oats), oilseed rape, maize, cotton, soybeen, rice, potatoes, sunflower, beans, coffee, beet (e.g. sugar beet and fodder beet), peanut, vegetables (such as tomato, cucumber, onions and lettuce), lawns and ornamental plants. Of particular significance is the treatment of the seed of wheat, soybean, oi lseed rape, maize and rice. ;
As also described below, the treatment of transgenic seed with the compound of Formula I or the compound of Formula I in the composition optionally comprising at least one active compatible compound, is of particular significance. This refers to the seed of plants containing at least one heterologous gene which allows the expression of a polypeptide or protein, e.g. having insecticidal properties. These heterologous genes in transgenic seeds may originate, for example, from microorganisms of the species Bacillus, Rhizobhim, Pseitdomonas, Serratia, Trichoderma, Clavibacter, Glomus or Gliocladiiim. These heterologous genes preferably originate from Bacillus sp., in which case the gene product is effective against the European corn borer and/or the Western corn rootworm. Particularly preferably, the heterologous genes originate from Bacillus thuringiensis.
In the context of the present invention, the compound of Formula I or the compound of Formula I in the composition optional ly comprising at least one active compatible compound is applied to seeds. Preferably, the seed is treated in a state in which it is sufficiently stable for no damage to occur in the course of treatment. In general, seeds can be treated at any time between harvest and some time after sowing. It is customary to use seed which has been separated from the plant and freed from cobs, shells, stalks, coats, hairs or the flesh of the fruits. For example, it is possible to use seed which has been harvested, cleaned and dried down to a moisture content of less than 15% by weight. Alternatively, it is also possible to use seed which, after drying, for example, has been treated with water and then dried again, or seeds just after priming, or seeds stored in primed conditions or pre-germinated seeds, or seeds sown on nursery trays, tapes or paper.
When treating the seeds, it generally has to be ensured that the amount of the compound of Formula I or the compound of Formula I in the composition optionally comprising at least one active compatible compound applied to the seed and/or the amount of further additives is selected such that the germination of the seed is not impaired, or that the resulting plant is not damaged.
The compound of Formula I or the compound of Formula I in the composition optionally comprising at least one active compatible compound can be applied directly, i.e. without containing any other components and without having been diluted. In general, it is preferable to apply the compositions comprising compound of Formula I to the seed in the form of a suitable Formulation. Suitable Formulations and methods for seed treatment are known to those skilled in the art. The compounds of the Formula I can be converted to the customary Formulations relevant to on-seed applications, such as solutions, emulsions, suspensions, powders, foams, slurries or combined with other coating compositions for seed, such as film forming materials, pelleting materials, fine iron or other metal powders, granules, coating material for inactivated seeds, and also ULV Formulations.
In the treatment of seeds to faci litate plantability seeds can be coated with polymer. The polymer coating is comprised of a binder, a wax and a pigment, and one or more stabilizers in an amount effective to stabilize the suspension. The binder can be a polymer selected from the group consisting of vinyl acetate- ethylene copolymer, vinyl acetate homopolymer, vinyl acetate-acrylic copolymer, vinylacrylic, acrylic, ethylene-vinyl chloride, vinyl ether maleic anhydride, or butadiene styrene. Other similar polymers can be used.
These Formulations are prepared in a known manner, by mixing the active ingredients or active ingredient combinations with customary additives, for example customary extenders and solvents or diluents, dyes, wetting agents, dispersants, emulsifiers, antifoams, preservatives, secondary thickeners, adhesives, gibberellins, and also water.
Useful dyes which may be present in the seed dressing Formulations usable in accordance with the invention are all dyes which are customary for such purposes. It is possible to use either pigments, which are sparingly soluble in water, or dyes, which are soluble in water. Examples include the dyes known by the names Rhodamine B, C.I. Pigment Red 1 12 and C.I. Solvent Red 1 .
Useful wetting agents which may be present in the seed dressing Formulations usable in accordance with the invention are all substances which promote wetting and which are conventionally used for the Formulation of active agrochemical ingredients. Usable with preference are alkylnaphthalenesulphonates, such as diisopropyl- or diisobutylnaphthalenesulphonates.
Useful dispersants and/or emulsifiers which may be present in the seed dressing Formulations usable in accordance with the invention are all nonionic, anionic and cationic dispersants conventionally used for the Formulation of active agrochemical ingredients. Usable with preference are nonionic or anionic dispersants or mixtures of nonionic or anionic dispersants. Useful nonionic dispersants include especially ethylene oxide/propylene oxide block polymers, alkylphenol polyglycol ethers and tristryrylphenol polyglycol ether, and the phosphated or sulphated derivatives thereof. Suitable anionic dispersants are especially lignosulphonates, polyacrylic acid salts and arylsulphonate/formaldehyde condensates.
Antifoams which may be present in the seed dressing Formulations usable in accordance with the invention are all foam-inhibiting substances conventionally used for the Formulation of active agrochemical ingredients. Silicone antifoams and magnesium stearate can be used with preference.
Preservatives which may be present in the seed dressing Formulations usable in accordance with the invention are all substances usable for such purposes in agrochemical compositions. Examples include dichlorophene and benzyl alcohol hemiformal.
Secondary thickeners which may be present in the seed dressing Formulations usable in accordance with the invention are all substances usable for such purposes in agrochemical compositions. Preferred examples include cellulose derivatives, acrylic acid derivatives, xanthan, modified clays and finely divided silica.
Adhesives which may be present in the seed dressing Formulations usable in accordance with the invention are all customary binders usable in seed dressing products. Preferred examples include polyvinylpyrrolidone, polyvinyl acetate, polyvinyl alcohol and tylose.
The Formulations for on-seed applications usable in accordance with the invention can be used to treat a wide variety of different kinds of seed either directly or after prior dilution with water. For instance, the concentrates or the preparations obtainable therefrom by dilution with water can be used to dress the seed of cereals, such as wheat, barley, rye, oats, and triticale, and also seeds of maize, soybean, rice, oilseed rape, peas, beans, cotton, sunflowers, and beets, or else a wide variety of different vegetable seeds. The Formulations usable in accordance with the invention, or the di lute preparations thereof, can also be used for seeds of transgenic plants. In this case, enhanced effects may also occur in interaction with the substances formed by expression.
For treatment of seeds with the Formulations usable in accordance with the invention, or the preparations prepared therefrom by adding water, all mixing units usable customarily for on-seed applications are useful. Specifically, the procedure in on-seed applications is to place the seeds into a mixer, to add the particular desired amount of the Formulations, either as such or after prior dilution with water, and to mix everything until all applied Formulations are distributed homogeneously on the seeds. If appropriate, this is followed by a drying operation.
The application rate of the Formulations usable in accordance with the invention can be varied within a relatively wide range. It is guided by the particular content of the active ingredients in the Formulations and by the seeds. The application rates of each single active ingredient are generally between 0.001 and 15 gai per kilogram of seed, preferably between 0.01 and 5 gai per kilogram of seed.
When using the compound of Formula I as fungicides, the application rates can be varied within a relatively wide range, depending on the kind of application. The application rate of the compound of Formula I or the compound of Formula 1 in a composition optionally comprising at least one active compatible compound, is: in the case of treatment of plant parts, for example leaves: from 0. 1 to 10000 gai/ha, preferably from 5 to 1000 gai/ha, more preferably from 5 to 100 gai/ha (in the case of application by watering or dripping, it is even possible to reduce the application rate, especially when inert substrates such as rockwool or perlite are used);
in the case of seed treatment: from 0.1 to 200 gai per 100 kg of seed, preferably from 1 to 150 gai per 100 kg of seed, more preferably from 2.5 to 25 gai per 100 kg of seed,
in the case of soil treatment: from 0.1 to 10000 gai/ha, preferably from 1 to 1000 gai/ha.
These application rates are merely by way of example and are not limiting for the purposes of the invention.
In some cases, the compound of the Formula I can, at particular concentrations or application rates, also be used as safeners, growth regulators or agents to improve plant properties, or as microbicides, for example as fungicides, antimycotics, bactericides, viricides (including compositions against viroids) or as compositions against phytoplasmas ML O (Mycoplasma-like organisms) and RLO (Rickettsia-like organisms).
The compounds of the Formula I intervene in physiological processes of plants and can therefore also be used as plant growth regulators. Plant growth regulators may exert various effects on plants. The effect of the substances depends essentially on the time of application in relation to the developmental stage of the plant, the plant variety and also on the amounts of active ingredient applied to the plants or their environment and on the type of application. In each case, growth regulators should have a particular desired effect on the crop plants.
Growth regulating effects, comprise earlier germination, better emergence, more developed root system and/or improved root growth, increased ability of tillering, more productive tillers, earl ier flowering, increased plant height and/or biomass, shorting of stems, improvements in shoot growth, number of kernels/ear, number of ears/m2, number of stolons and/or number of flowers, enhanced harvest index, bigger leaves, less dead basal leaves, improved phyllotaxy, earlier maturation/ earlier fruit finish, homogenous riping, increased duration of grain filling, better fruit finish, bigger fruit/vegetable size, sprouting resistance and reduced lodging.
Increased or improved yield is referring to total biomass per hectare, yield per hectare, kernel/fruit weight, seed size and/or hectolitre weight as well as to improved product quality, comprising:
improved processability relating to size distribution (kernel, fruit, etc.), homogenous riping, grain moisture, better milling, better vinification, better brewing, increased juice yield, harvestability, digestibility, sedimentation value, falling number, pod stability, storage stability, improved fiber length/strength/uniformity, increase of milk and/or meet quality of silage fed animals, adaption to cooking and frying;
further comprising improved marketability relating to improved fruit/grain quality, size distribution (kernel, fruit, etc.), increased storage/shelf-life, firmness /softness, taste (aroma, texture, etc.), grade (size, shape, number of berries, etc.), number of berries/fruits per bunch, crispness, freshness, coverage with wax, frequency of physiological disorders, colour, etc.;
further comprising increased desired ingredients such as e.g. protein content, fatty acids, oi l content, oil quality, aminoacid composition, sugar content, acid content (pH), sugar/acid ratio (Brix), polyphenols, starch content, nutritional quality, gluten content/index, energy content, taste, etc.;
and further comprising decreased undesired ingredients such as e.g. less mycotoxines, less aflatoxines, geosmin level, phenol ic aromas, lacchase, polyphenol oxidases and peroxidases, nitrate content etc.
Plant growth-regulating compounds can be used, for example, to slow down the vegetative growth of the plants. Such growth depression is of economic interest, for example, in the case of grasses, since it is thus possible to reduce the frequency of grass cutting in ornamental gardens, parks and sport facilities, on roadsides, at airports or in fruit crops. Also of significance is the inhibition of the growth of herbaceous and woody plants on roadsides and in the vicinity of pipelines or overhead cables, or quite generally in areas where vigorous plant growth is unwanted.
Also important is the use of growth regulators for inhibition of the longitudinal growth of cereal. This reduces or completely eliminates the risk of lodging of the plants prior to harvest. In addition, growth regulators in the case of cereals can strengthen the culm, which also counteracts lodging. The employment of growth regulators for shortening and strengthening culms allows the deployment of higher fertilizer volumes to increase the yield, without any risk of lodging of the cereal crop.
In many crop plants, vegetative growth depression allows denser planting, and it is thus possible to achieve higher yields based on the soil surface. Another advantage of the smaller plants obtained in this way is that the crop is easier to cultivate and harvest.
Reduction of the vegetative plant growth may also lead to increased or improved yields because the nutrients and assimilates are of more benefit to flower and fruit formation than to the vegetative parts of the plants.
Alternatively, growth regulators can also be used to promote vegetative growth. This is of great benefit when harvesting the vegetative plant parts. However, promoting vegetative growth may also promote generative growth in that more assimilates are formed, resulting in more or larger fruits.
Furthermore, beneficial effects on growth or yield can be achieved through improved nutrient use efficiency, especially n (N)-use efficiency, phosphours (P)-use efficiency, water use efficiency, improved transpiration, respiration and/or C02 assimilation rate, better nodulation, improved Ca-metabolism etc.
Likewise, growth regulators can be used to alter the composition of the plants, which in turn may result in an improvement in quality of the harvested products. Under the influence of growth regulators, parthenocarpic fruits may be formed. In addition, it is possible to influence the sex of the flowers. It is also possible to produce sterile pollen, which is of great importance in the breeding and production of hybrid seed.
Use of growth regulators can control the branching of the plants. On the one hand, by breaking apical dominance, it is possible to promote the development of side shoots, which may be highly desirable particularly in the cultivation of ornamental plants, also in combination with an inhibition of growth. On the other hand, however, it is also possible to inhibit the growth of the side shoots. This effect is of particular interest, for example, in the cultivation of tobacco or in the cultivation of tomatoes.
Under the influence of growth regulators, the amount of leaves on the plants can be controlled such that defoliation of the plants is achieved at a desired time. Such defoliation plays a major role in the mechanical harvesting of cotton, but is also of interest for facilitating harvesting in other crops, for example in viticulture. Defoliation of the plants can also be undertaken to lower the transpiration of the plants before they are transplanted.
Furthermore, growth regulators can modulate plant senescence, which may result in prolonged green leaf area duration, a longer grain filling phase, improved yield quality, etc.
Growth regulators can likewise be used to regulate fruit dehiscence. On the one hand, it is possible to prevent premature fruit dehiscence. On the other hand, it is also possible to promote fruit dehiscence or even flower abortion to achieve a desired mass ("thinning"). In addition, it is possible to use growth regulators at the time of harvest to reduce the forces required to detach the fruits, in order to allow mechanical harvesting or to facilitate manual harvesting.
Growth regulators can also be used to achieve faster or else delayed ripening of the harvested material before or after harvest. This is particularly advantageous as it allows optimal adjustment to the requirements of the market. Moreover, growth regulators in some cases can improve the fruit colour. In addition, growth regulators can also be used to synchronize maturation within a certain period of time. This establishes the prerequisites for complete mechanical or manual harvesting in a single operation, for example in the case of tobacco, tomatoes or coffee.
By using growth regulators, it is additionally possible to influence the resting of seed or buds of the plants, such that plants such as pineapple or ornamental plants in nurseries, for example, germinate, sprout or flower at a time when they are normally not inclined to do so. In areas where there is a risk of frost, it may be desirable to delay budding or germination of seeds with the aid of growth regulators, in order to avoid damage resulting from late frosts.
Finally, growth regulators can induce resistance of the plants to frost, drought or high salinity of the soil. This allows the cultivation of plants in regions which are normally unsuitable for this purpose.
The compound of Formula I or the compound of Formula I in the composition optionally comprising at least one active compatible compound also exhibit potent strengthening effect in plants. Accordingly, they can be used for mobilizing the defences of the plant against attack by undesirable micro-organisms. Plant-strengthening (resistance-inducing) substances in the present context are substances capable of stimulating the defence system of plants in such a way that the treated plants, when subsequently inoculated with undesirable micro-organisms, develop a high degree of resistance to these microorganisms.
Further, in context with the present invention plant physiology effects comprise the following:
Abiotic stress tolerance, comprising tolerance to high or low temperatures, drought tolerance and recovery after drought stress, water use efficiency (correlating to reduced water consumption), flood tolerance, ozone stress and UV tolerance, tolerance towards- chemicals like heavy metals, salts, pesticides etc.
Biotic stress tolerance comprising increased fungal resistance and increased resistance against nematodes, viruses and bacteria. In context with the present invention, biotic stress tolerance preferably comprises increased fungal resistance and increased resistance against nematodes.
Increased plant vigor, comprising plant health / plant quality and seed vigor, reduced stand fai lure, improved appearance, increased recovery after periods of stress, improved pigmentation (e.g. chlorophyll content, stay-green effects, etc.) and improved photosynthetic efficiency. In addition, the compound of Formula 1 or the compound of Formula 1 in the composition optionally comprising at least one active compatible compound can reduce the mycotoxin content in the harvested material and the foods and feeds prepared therefrom. Mycotoxins include particularly, but not exclusively, the following: deoxynivalenol (DON), nivalenol, 15-Ac-DON, 3-Ac-DON, T2- and HT2- toxin, fumonisins, zearalenon, moniliformin, fusarin, diaceotoxyscirpenol (DAS), beauvericin, enniatin, fusaroproliferin, fusarenol, ochratoxins, patulin, ergot alkaloids and aflatoxins which can be produced, for example, by the following fungi : Fusarium spec, such as F. acuminatum, F. asialicum, F. avenaceum, F. crookM'ellense, F. culmorum, F. graminearum (Gibberella zeae), F. equiseti, F. fujikoroi, F. musarum, F. oxysporum, F. proliferation, F. poae, F. pseudograminearum, F. sambucinum, F. scirpi, F. semitectum, F. solani, F. sporotrichoides, F. langsethiae, F. subglutinans, F. tricinctum, F. verticillioid.es etc., and also by Aspergillus spec, such as A. flavus, A. parasiticus, A. nomius, A. ochraceus, A. clavatus, A. terreus, A. versicolor, Penicillium spec, such as P. verrucosum, P. viridicatum, P. citrinum, P. expansum, P. claviforme, P. roqueforti, Claviceps spec, such as C. purpurea, C. fusiformis, C. paspali, C. africana, Stachybotrys spec, and others.
The compound of Formula I or the compound of Formula I in the composition optionally comprising at least one active compatible compound can also be used in the protection of materials, for protection of industrial materials against attack and destruction by phytopathogenic micro-organisms.
In addition, the compounds of the Formula I can be used as antifouling compositions, alone or in combinations with other active ingredients.
Industrial materials in the present context are understood to mean inanimate| materials which have been prepared for use in industry. For example, industrial materials which are to be protected by inventive compositions from microbial alteration or destruction may be adhesives, glues, paper, wallpaper and board/cardboard, textiles, carpets, leather, wood, fibers and tissues, paints and plastic articles, cooling lubricants and other materials which can be infected with or destroyed by micro-organisms. Parts of production plants and buildings, for example cooling-water circuits, cooling and heating systems and ventilation and air- conditioning units, which may be impaired by the proliferation of micro-organisms may also be mentioned within the scope of the materials to be protected. Industrial materials within the scope of the present invention preferably include adhesives, sizes, paper and card, leather, wood, paints, cooling lubricants and heat transfer fluids, more preferably wood.
The compound of Formula I or the compound of Formula I in the composition optionally comprising at least one active compatible compound may prevent adverse effects, such as rotting, decay, discoloration, decoloration or formation of mould.
In the case of treatment of wood the compound of Formula I or the compound of Formula I in the composition optional ly comprising at least one active compatible compound may also be used against fungal diseases liable to grow on or inside timber. The term "timber" means all types of species of wood, and all types of working of this wood intended for construction, for example solid wood, high-density wood, laminated wood, and plywood. The method for treating timber according to the invention mainly consists in contacting a composition according to the invention; this includes for example direct application, spraying, dipping, injection or any other suitable means.
In addition, the compound of Formula I or the compound of Formula I in the composition optionally comprising at least one active compatible compound can be used to protect objects which come into contact with saltwater or brackish water, especially hulls, screens, nets, buildings, moorings and signalling systems, from fouling.
The compound of Formula I or the compound of Formula I in the composition optionally comprising at least one active compatible compound can also be employed for protecting storage goods. Storage goods are understood to mean natural substances of vegetable or animal origin or processed products thereof which are of natural origin, and for which long-term protection is desired.
Storage goods of vegetable origin, for example plants or plant parts, such as stems, leaves, tubers, seeds, fruits, grains, can be protected freshly harvested or after processing by (pre)drying, moistening, comminuting, grinding, pressing or roasting. Storage goods also include timber, both unprocessed, such as construction timber, electricity poles and barriers, or in the form of finished products, such as furniture. Storage goods of animal origin are, for example, hides, leather, furs and hairs. The inventive compositions may prevent adverse effects, such as rotting, decay, discoloration, decoloration or formation of mould.
Micro-organisms capable of degrading or altering the industrial materials include, for example, bacteria, fungi, yeasts, algae and slime organisms. The compound of Formula I or the compound of Formula I in the composition optionally comprising at least one active compatible compound preferably act against fungi, especially moulds, wood-discoloring and wood-destroying fungi (Ascomycetes, Basidiomycetes, Deiiteromycetes and Zygomycetes), and against slime organisms and algae. Examples include micro-organisms of the following genera: Alternaria, such as Alternaria tenuis; Aspergillus, such as Aspergillus niger; Chaetomium, such as Chaetomium globosum; Coniophora, such as Coniophora puetana; Lentinus, such as Lenlinus tigriniis; Penicillium, such as Penicillium glaucum; Polyporus, such as Polyporus versicolor, Aureobasidium, such as Aureobasidium pullulans; Sclerophoma, such as Sclerophoma pityophila; Trichoderma, such as Trichoderma viride; Ophiostoma spp., Ceratocystis spp., Humicola spp., Petriella spp., Trichurus spp., Coriohis spp., Gloeophyllwn spp., Pleurotits spp., Poria spp., Serpula spp. and Tyromyces spp., Cladosporium spp., Paecilomyces spp. Mucor spp., Escherichia, such as Escherichia coli; P eudomonas, such as Pseudomonas aeruginosa; Staphylococcus, such as Staphylococcus aureus, Candida spp. and Saccharomyces spp., such as Saccharomyces cerevisae. In addition, the compound of Formula I or the compound of Formula 1 in the composition optionally comprising at least one active compatible compound also has very good anti mycotic effects. They have a very broad antimycotic activity spectrum, especially against dermatophytes and yeasts, moulds and diphasic fungi (for example against Candida species, such as Candida albicans, Candida glabrata), and Epidermophyton floccosum, Aspergillus species, such as Aspergillus niger and Aspergillus fumigatus, Trichophyton species, such as Trichophyton mentagi'ophytes, Microsporon species such as Microsporon canis and audouinii. The enumeration of these fungi by no means constitutes a restriction of the mycotic spectrum covered, and is merely of illustrative character.
The compound of Formula 1 or the compound of Formula I in the composition optionally comprising at least one active compatible compound can be used also to control important fungal pathogens in fish and Crustacea farming, e.g. saprolegnia diclina in trouts, saprolegnia parasitica in crayfish.
The compound of Formula I or the compound of Formula I in the composition optionally comprising at least one active compatible compound can therefore be used both in medical and in non-medical applications.
The compound of Formula I or the compound of Formula I in the composition optionally comprising at least one active compatible compound can be used as such, in the form of their Formulations or the use forms prepared therefrom, such as ready-to-use solutions, suspensions, wettable powders, pastes, soluble powders, dusts and granules. Application is accomplished in a customary manner, for example by watering, spraying, atomizing, broadcasting, dusting, foaming, spreading-on and the like. It is also possible to deploy the active ingredients by the ultra-low volume method or to inject the active ingredient preparation/the active ingredient itself into the soil. It is also possible to treat the seed of the plants.
It is possible to treat all plants and their parts in accordance with the invention, preferably with wild plant species and plant cultivars, or those obtained by conventional biological breeding methods, such as crossing or protoplast fusion, and also parts thereof. In a further preferred embodiment, transgenic plants and plant cultivars obtained by genetic engineering methods, if appropriate in combination with conventional methods (Genetically Modified Organisms), and parts thereof are treated. The terms "parts" or "parts of plants" or "plant parts" have been explained above. More preferably, plants of the plant cultivars which are commercially available or are in use are treated in accordance with the invention. Plant cultivars are understood to mean plants which have new properties ("traits") and have been obtained by conventional breeding, by mutagenesis or by recombinant DNA techniques. They can be cultivars, varieties, bio- or genotypes.
The method of treatment according to the invention can be used in the treatment of genetically modified organisms (GMOs), e.g. plants or seeds. Genetically modified plants (or transgenic plants) are plants of which a heterologous gene has been stably integrated into genome. The expression "heterologous gene" essentially means a gene which is provided or assembled outside the plant and when introduced in the nuclear, chloroplastic or mitochondrial genome gives the transformed plant new or improved agronomic or other properties by expressing a protein or polypeptide of interest or by downregulating or silencing other gene(s) which are present in the plant (using for example, antisense technology, cosuppression technology, RNA interference - RNAi - technology or microRNA - miRNA - technology). A heterologous gene that is located in the genome is also called a transgene. A transgene that is defined by its particular location in the plant genome is called a transformation or transgenic event.
Plants and plant cultivars which are preferably to be treated according to the invention include all plants which have genetic material which impart particularly advantageous, useful traits to these plants (whether obtained by breeding and/or biotechnological means).
Plants and plant cultivars which are also preferably to be treated according to the invention are resistant against one or more biotic stresses, i.e. said plants show a better defense against ani mal and microbial pests, such as against nematodes, insects, mites, phytopathogenic fungi, bacteria, viruses and/or viroids. Plants and plant cultivars which may also be treated according to the invention are those plants which are resistant to one or more abiotic stresses. Abiotic stress conditions may include, for example, drought, cold temperature exposure, heat exposure, osmotic stress, flooding, increased soil salinity, increased mineral exposure, ozone exposure, high light exposure, limited availability of n nutrients, limited availability of phosphorus nutrients, shade avoidance.
Plants and plant cultivars which may also be treated according to the invention, are those plants characterized by enhanced yield characteristics. Increased yield in said plants can be the result of, for example, improved plant physiology, growth and development, such as water use efficiency, water retention efficiency, improved n use, enhanced carbon assimilation, improved photosynthesis, increased germination efficiency and accelerated maturation. Yield can furthermore be affected by improved plant architecture (under stress and non-stress conditions), including but not limited to, early flowering, flowering control for hybrid seed production, seedling vigor, plant size, internode number and distance, root growth, seed size, fruit size, pod size, pod or ear number, seed number per pod or ear, seed mass, enhanced seed filling, reduced seed dispersal, reduced pod dehiscence and lodging resistance. Further yield traits include seed composition, such as carbohydrate content and composition for example cotton or starch, protein content, oil content and composition, nutritional value, reduction in anti-nutritional compounds, improved processability and better storage stability.
Plants that may be treated according to the invention are hybrid plants that already express the characteristic of heterosis or hybrid vigor which results in generally higher yield, vigor, health and resistance towards biotic and abiotic stresses).
Plants or plant cultivars (obtained by plant biotechnology methods such as genetic engineering) which may be treated according to the invention are herbicide-tolerant plants, i.e. plants made tolerant to one or more given herbicides. Such plants can be obtained either by genetic transformation, or by selection of plants containing a mutation imparting such herbicide tolerance.
Plants or plant cultivars (obtained by plant biotechnology methods such as genetic engineering) which may also be treated according to the invention are insect-resistant transgenic plants, i.e. plants made resistant to attack by certain target insects. Such plants can be obtained by genetic transformation, or by selection of plants containing a mutation imparting such insect resistance.
Plants or plant cultivars (obtained by plant biotechnology methods such as genetic engineering) which may also be treated according to the invention are tolerant to abiotic stresses. Such plants can be obtained by genetic transformation, or by selection of plants containing a mutation imparting such stress resistance. Plants or plant cultivars (obtained by plant biotechnology methods such as genetic engineering) which may also be treated according to the invention show altered quantity, quality and/or storage-stability of the harvested product and/or altered properties of specific ingredients of the harvested product.
Plants or plant cultivars (that can be obtained by plant biotechnology methods such as genetic engineering) which may also be treated according to the invention are plants, such as cotton plants, with altered fiber characteristics. Such plants can be obtained by genetic transformation, or by selection of plants contain a mutation imparting such altered fiber characteristics.
Plants or plant cultivars (that can be obtained by plant biotechnology methods such as genetic engineering) which may also be treated according to the invention are plants, such as oilseed rape or related Brassica plants, with altered oil profile characteristics. Such plants can be obtained by genetic transformation, or by selection of plants contain a mutation imparting such altered oil profile characteristics.
Plants or plant cultivars (that can be obtained by plant biotechnology methods such as genetic engineering) which may also be treated according to the invention are plants, such as oilseed rape or related Brassica plants, with altered seed shattering characteristics. Such plants can be obtained by genetic transformation, or by selection of plants contain a mutation imparting such altered seed shattering characteristics and include plants such as oilseed rape plants with delayed or reduced seed shattering. Plants or plant cultivars (that can be obtained by plant biotechnology methods such as genetic engineering) which may also be treated according to the invention are plants, such as tobacco plants, with altered post-translational protein modification patterns.
The invention disclosed in the present invention shall now be elaborated with the help of non-limiting schemes and examples.
SCHEMES:
Scheme 1
Figure imgf000085_0001
A compound of Formula 3, is prepared by coupling corresponding acid of Formula 1 with an amine of Formula 2 (or its salt) in the presence of a dehydrative coupling reagent such as dicyclohexylcarbodiimide (DCC), l -(3-dimethy!aminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) 3- [Bis(dimethylamino)methyliumyl]-3FI-benzotriazol-l -oxide hexafluorophosphate (HBTU), or 1 - [Bis(dimethylamino)methylene]-l FI- l ,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU). Polymer-supported reagents are also useful here, such as polymer-bound cyclohexylcarbodiimide. These reactions are typically carried out at 0-40 °C in a solvent such as dichloromethane, acetonitrile or dimethylformamide in the presence of a base such as triethylamine or diisopropylethylamine. In a subsequent step, amides of Formula 3 wherein W is O can be converted to thioamides of Formula 3a wherein W is S using a variety of standard thionating reagents such as phosphorus pentasulfide or 2,4-bis(4-methoxyphenyl)-l,3-dithia-2,4- diphosphetane-2,4-disulfide (Lawesson's reagent).
The acids of Formula 1 are known or can be prepared by methods known to one skilled in the art. For example, R2CH2COOH where R2 is a heterocyclic ring linked through n can be prepared by reacting the corresponding R2H compound with a haloacetic acid or ester in the presence of base; followed by hydrolysis.
Scheme 2
Figure imgf000085_0002
The amine compound of Formula 2 can be prepared from the protected amine compound of Formula 4 where Υ ' is an amine-protecting group.
A compound of the Formula 4 is converted to a compound of the Formula 2 by suitable methods for removing protecting groups described in the literature (Protective Groups in Organic Synthesis; Theodora W. Greene, Peter G. M. Wilts; Wiley-lnterscience; Third Edition; 1999; 494-653).
For example, tert-butoxycarbonyl and benzyloxycarbonyl protecting groups can be removed in an acidic medium (for example with hydrochloric acid or trifiuoroacetic acid). Acetyl protecting groups can be removed under basic conditions (for example with potassium carbonate or caesium carbonate). Benzylic protecting groups can be removed hydrogenolytically with hydrogen in the presence of a catalyst (for example palladium on activated carbon). After completion of the reaction, the compound of Formula 2 is separated from the reaction mixture by one of the customary separation techniques. If necessary, the compounds are purified by recrystallization or chromatography, or can, if desired, also be used in the next step without prior purification. It is also possible to isolate the compound of the general Formula 2 as a salt, for example as a salt of hydrochloric acid or of trifluoroacetic acid.
Scheme 3
Figure imgf000086_0001
A compound of the general Formula 6 is obtained by condensation of an aldehyde of the Formula 5 with hydroxylamine and subsequent chlorination (see, for example, WO05/0040159, WO08/013622 and Synthesis, 1987, 1 1 , 998- 1001 ).
In the process, aldehyde 5 and hydroxylamine are first reacted to obtain corresponding oxime which is subsequently chlorinated in the presence of a suitable chlorinating agent. Preferred chlorinating reagents are N-chlorosuccinimide, NaOCl, HCIO and chlorine. After step (a), the reaction mixture can be worked up by customary methods or converted further directly in step (b).
The step (a) is performed using one or more diluents preferably with protic solvents, for example ethanol. After the formation of the corresponding oxime from compound (5), the reaction mixture is diluted in step (b) with a further solvent, for example tetrahydrofuran, and then aqueous sodium hypochlorite is added. The chlorination can likewise be effected with the aid of N-chlorosuccinimide in N,N-dimethyl formamide (DMF) or Ethyl acetate. The workup is carried out by customary methods. The compounds can be used in the next step without prior purification.
A particular means of preparing compounds of the Formula 4 from corresponding compound of Formula 6 by reaction with the compound of Formula 7a or 7b is shown in Scheme 3 step c.
The alkenes and alkynes 7a and 7b are commercially available or can be prepared from commercially available precursors by methods described in the literature (for example from ketones or aldehydes by a Wittig or Horner-Wadsworth-Emmons olefination: Chem. Rev. 1989, 89, 863-927 and Julia olefination: Tetrahedron Lett., 1973, 14, 4833-4836; Peterson olefmation: J. Org. Chem. 1968, 33, 780; with the Bestmann-Ohira reagent: Synthesis 2004, 1 , 59-62).
A compound of the general Formula 4a is obtained from an alkyne of the general Formula 7a and and compound 6; and a compound of the general Formula 4b is obtained from an alkene of the general Formula 7b and compound 6 by a cycloaddition reaction (see, for example, WO 08/013622 and Synthesis, 1987, 1 1 , 998- 1001 ).
The step c is performed in the presence of a suitable base. Preferred bases are tertiary amines (e.g. triethylamine), and alkali metal or alkaline earth metal carbonates (for example potassium or sodium carbonate), hydrogencarbonates and phosphates.
The step c is preferably performed using one or more diluents. In the performance of process, inert organic solvents are a preferred option (for example toluene and ethyl acetate). Water is likewise a possible solvent. Alternatively, process can be performed in an excess of the alkene 7a or of the alkyne
7b.
The workup is carried out by customary methods. If necessary, the compounds are purified by recrystallization or chromatography.
Scheme 4
Figure imgf000087_0001
A compound of Formula 5 is prepared (step a) by reducing corresponding ester 8 into the corresponding alcohol using NaBH -MeOH system. The aromatic alcohols are obtained by the method explained in the ARKIVOC 2006, 128- 133, involving the reduction of aromatic ethyl, esters within 15 - 60 minutes after refluxing in THF. The respective alcohol products were isolated after aqueous workup in good yield.
Corresponding alcohol is oxidized to aldehyde compound of Formula 5 (Scheme 4, Step b) using oxidizing agents like Mn02, Dess-Martin periodinane, IBX, TEMPO. Preferred solvents for the conversion were acetonitrile or dichloromethane. For leading references see for example Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 1 13, 7277, Quesada, E.; Taylor, R. J. K., Tetrahedron Lett. 2005, 46, 6473-6476. Naik, N.; Braslau, R. Tetrahedron 1998, 54,667)
Scheme 5
Figure imgf000088_0001
A Compound of Formula 8 is prepared using the well-known Suzuki reaction involving Pd-catalyzed cross-coupling of Formula 10 with a boronic acid Formula 9 or corresponding ester. Many catalysts are useful for this type of transformation; a typical catalyst is tetrakis(triphenylphosphine)palladium, or bis(triphenylphosphine)palladium chloride Solvents such as tetrahydrofuran, acetonitrile, diethyl ether and dioxane or dioxane: water mixture are suitable. The Suzuki reaction and related coupling procedures offer many alternatives for creation of the C-G bond. For leading references see for example C. A. Zificsak and D. J. Hlasta, Tetrahedron 2004, 60, 8991 -9016. For a thorough review of palladium chemistry applicable to the synthesis of C-G bonds see J. J. Li and G. W. Gribble, editors, Palladium in Heterocyclic Chemistry: A Guide for the Synthetic Chemist, Elsevier: Oxford, UK, 2000. Many variations of catalyst type, base and reaction conditions are known in the art for this general method.
Scheme 6
Figure imgf000088_0002
8
Reduction of the compound of Formula 8 is carried out by catalytic hydrogenation to obtain compound of Formula 8a. Pd/C, Pt/C, Raney Ni are the preferred catalyst. For synthetic procedure refer Bioorganic & Medicinal Chemistry 23 (201 5) 2129-21 38.
Scheme 7
Figure imgf000088_0003
Outline for the preparation of acid of Formula 1 is described in Scheme 7. Suitably substituted compound of Formula 17 was sourced commercially or can be prepared from the corresponding chloro derivatives using known methods in the literature. Preferred reagents for these conversions are sulfuric acid, hydrochloric acid and sodium hydroxide. Please refer WO2007/39563, WO2014/71044 Lavecchia; Berteina-Raboin; Guillaumet, Tetrahedron Letters, 2004, vol .45, 35 .6633 - 6636.
Substituted compound of Formula 17 can be further functionalized using known methods in the literature like chlorionation, bromination, trifluromethylation to obtain appropriately substituted heterocyclic ring l ike pyridone (Formula 11). References for the said transformations are Zhang, Pei-Zhi et al Tetrahedron, 72(23), 3250-3255; 2016 Canibano; Rodriguez; Santos; Sanz-Tejedor; Carreno; Gonzalez; Garcia-Ruano Synthesis, 2001 , 14,2175 - 2179, WO2004/50637.
The substituted functional ized heterocyclic ring containing a pyridone-like moiety can be acylated by reaction with an alkyl ester containing a suitable leaving group such as halogen, mesylate or tosylate, in the presence of a base such as potassium carbonate or cesium carbonate, in a polar solvent such as N,N- dimethyl formamide (DMF) or N-methyl-2-pyrrolidone (NMP), with or without heating to obtain the compound of Formula 12. Typically, mixtures of O- and N-alkylated products are obtained, and the two regio-isomeric products can be separated by means of SiOz gel or reverse phase chromatography. The addition of lithium salts, for example LiCl, to the reaction mixture can be employed to favor N- vs. O- alkylation. The obtained alkyl ester can be further hydrolyzed to the corresponding acids by heating or stirring at room temperature in the presence of lithium hydroxide or sodium hydroxide in solvents like ethanol and water to obtain compound of Formula 1.
Scheme 8
Figure imgf000089_0001
A compound of Formula 14 can be prepared by treating substituted acetoacetic ester with alkyl hydrazine of Formula 13. Compound of Formula 14 can then be selectively alkylated using alkyl halides with or without base to obtain compound of Formula 15.
Substituted compound of Formula 15 can be further functionalized using known methods in the literature l ike chlorionation, bromination and trifluromethylation to obtain appropriately substituted heterocyclic ring like pyrazolone of Formula 16.
The pyrazolone of Formula 16 can be further hydrolyzed to the corresponding acids by heating or stirring at room temperature in the presence of lithium hydroxide or sodium hydroxide in solvents like ethanol and water to obtain compound of Formula la.
Scheme 9
Figure imgf000089_0002
A compound of Formula 6b can be prepared by reacting a compound of Formula 11 and a compound of Formula 10 in the presence of a base. Suitable bases include sodium hydride or potassium carbonate, and the reaction is carried out in a solvent such as Ν,Ν-dimethylformamide or acetonitrile at 0 to 80 °C. Suitable leaving groups Y2 in the compound of Formula 11 include bromide, iodide, mesylate (OS(0)2CH3), triflate (OS(0)2CF3) and the like, and the compound of Formula 11 can be prepared from the corresponding compounds wherein Y is OH, using general methods known in the art.
Scheme 10
Figure imgf000090_0001
A compound of Formula 3a wherein W is O involves coupling of an acid of Formula 1 or la with an amine of Formula 20 (or its acid salt) in the presence of a dehydrative coupling reagent such as dicyclohexylcarbodiimide (DCC), l -(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) O-benzotriazol-l-yl-tetramethyluronium hexafluoro-phosphate (HBTU), or 1 - [Bis(dimethylamino)methylene]- l H- l ,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU). Polymer-supported reagents are again useful here, such as polymer-bound cyclohexylcarbodiimide. These reactions are typically run at 0-40 °C in a solvent such as dichloromethane, acetonitrile or Ν,Ν-dimethylformamide in the presence of a base such as triethylamine or Ν,Ν-diisopropylethylamine. In a subsequent step, amides of Formula 3a wherein W is O can be converted to thioamides of Formula 3a wherein W is S using a variety of standard thiating reagents such as phosphorus pentasulfide or 2, 4-bis(4-methoxyphenyl)-l,3-dithia-2,4-diphosphetane-2,4-disulfide (Lawesson's reagent).
Scheme 1 1
Figure imgf000090_0002
A compound of Formula 3a can be prepared by reacting the compound of Formula 21 with compound of the formula 22 in the presence of an acid or a Lewis acid, preferably in the presence of an acid. Examples of the acid which can be used in this step include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid and the like, organic acids such as acetic acid, trifluoroacetic acid, p-toluenesulfonic acid, trifluoromethanesulfonic acid and the like. Examples of the Lewis acid which can be used in this step include zinc chloride, aluminum chloride, tin chloride, boron trichloride, boron trifluoride, trimethylsi lyltrifluoromethane sulfonate and the like.
The solvent which can be used in this step may be any solvent which does not inhibit the progress of this reaction and examples thereof include nitriles such as acetonitrile; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, monoglyme, diglyme, etc.; dichloromethane, dichloroethane , Halogenated hydrocarbons such as chloroform, carbon tetrachloride and tetrachloroethane; aromatic hydrocarbons such as benzene, chlorobenzene, nitrobenzene and toluene; amides such as N,N- dimethylformamide and Ν,Ν-dimethylacetamide; imidazolinones such as l ,3-dimethyl-2-imidazolinone, sulfur compounds such as dimethylsulfoxide and the like can be used, and mixed solvents thereof can also be used.
The reaction temperature may be selected from the range of -20 °C to the boiling point of the inert solvent to be used, preferably in the range of 0 °C to 150 °C.
The reaction time varies depending on the reaction temperature, the reaction substrate, the reaction amount and the like, but is usually from 10 minutes to 48 hours.
Scheme 12
Figure imgf000091_0001
The compound of Formula 22 can be prepared by reducing the compound of Formula 23 with a reducing agent in a solvent. Reducing agent suitable in this step, are lithium aluminum hydride, diisobutylaluminum hydride, borane and the like. Preferred solvent that can be used in this step is tetrahydrofuran, dioxane or the like.
The reaction temperature may be selected from the range of from -20 °C to the boiling point range of the inert solvent to be used, preferably in the range of 0 °C to 100 °C.
Scheme 13
Figure imgf000091_0002
The compound of Formula 22 can also be prepared by reducing the compound of Formula 24 with a reducing agent in a solvent. Reducing agent suitable in this step, are lithium aluminum hydride, diisobutylaluminum hydride, borane and the like. Preferred solvent that can be used in this step is tetrahydrofuran, dioxane or the l ike.
The reaction temperature may be selected from the range of from -20 °C. to the boiling point range of the inert solvent to be used, preferably in the range of 0°C to 100 °C.
Scheme 14
Figure imgf000092_0001
Synthesis of compounds of Formula 26 involves palladium-catalyzed cross-coupling reaction of terminal alkynes of Formula 25 and organic electrophiles such as alkyl bromides or chlorides. The most widely used of these is a cross between the Cu-promoted Castro-Stephens reaction and the Heck alkynylation, known as the Sonogashira reaction. The compound of Formula 26 can also be obtained using palladium- based systems to catalyze the reaction of aryl halides and terminal alkynes. For leading references see for example Metal-Catalyzed Cross-Coupling Reactions, Vol. 2; de Meijere, A.; Diederich, F., Eds.; Wiley- VCH: Weinheim, 2004.,Negishi, E.; Anastasia, L. Chem. Rev. 2003, 103, 1979,Castro, C. E.; Stephens, R. D. J. Org. Chem. 1963, 28, 2163,Dieck, H. A.; Heck, F. R. J. Organomet. Chem. 1975, 93, 259, Sonogashira, K. J. Organomet. Chem. 2002, 653, 46. Scheme 1 5
Figure imgf000092_0002
One possibility of preparing the intermediate of Formula 25 from the compound of Formula 5 is shown in Scheme 1 5.
In the literature, it is known that alkynylation of aldehydes can be achieved by Corey-Fuchs reaction (Tetrahedron Lett, 1 972, 36, 3769) or a Seyferth-Gilbert homologization (see, for example, J. Org. Chem., 1 996, 61 , 2540). Alternatively, the alkyne of Formula 19 can also be prepared from the aldehyde of Formula 5 with Bestmann-Ohira's reagent analogously to the literature instructions (see, for example, Synthesis, 2004, 59). Alkynylation with Bestmann-Ohira's reagent in methanol or ethanol is preferably used in the equivalent of potassium carbonate or sodium carbonate.
The aldehyde of Formula 5 and the alkynylation reagent are used in equimolar amounts, but the Bestmann-Ohira's reagent can be used in excess if necessary. The reaction is preferably carried out at from -100 °C to 60 °C and more preferably at from -78 °C to 40 °C. The reaction time varies depending on the scale of the reaction and the reaction temperature, but is generally between a few minutes and 48 hours.
After completion of the reaction, the compounds of Formula 25 are separated from the reaction mixture by one of the conventional separation techniques. If necessary, the compounds are purified by recrystallization, distillation or chromatography or, if desired, can also be used in the next step without prior purification.
EXAMPLE 1
Preparation of 3-chloro-l-(2-(4-(4-(5-(2, 6-difluorophenyl)-4, 5-dihydroisoxazol-3-yl) thiazol-2-yl) piperidin-l-yl)-2-oxoethyl)-5-(trifluoromethyl) pyridin-2(lH)-one (Compound 1)
Step A: Preparation of ethyl 2-bromo-l,3-thiazole-4-carboxylate
To a solution of ethyl 2-aminothiazole-4-carboxylate ( 100 g, 581 mmol) and copper (II) bromide ( 195 g, 871 mmol) in acetonitrile ( 1000 ml) at 0 °C, tert-butylnitrite ( 104 ml, 871 mmol) was added dropwise. The reaction mixture was warmed to room temperature and stirred for 12h. After completion of the reaction, the reaction mixture was diluted with a mixture of ethyl acetate (1000 ml) and water (3000 ml) and then acidified to pH 2 using IN hydrochloric acid. The two layers were separated and the aqueous layer was again extracted three times with ethyl acetate (500 ml). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by recrystallization from hexane to obtain pure ethyl 2-bromo-l ,3-thiazole-4-carboxylate ( 1 1 5 g, 84% yield).
Ή-NMR (400 MHz, DMSO-d6) δ 8.52 (s, 1 H), 4.29 (q, J = 7.1 Hz, 2H), 1.29 (t, J = 7.1 Hz, 3H) MS: m/z = 235.90. [M+l ].
Step B: Preparation of ethyl 2-(l-(tert-butoxycarbonyl)-l,2,3,6-tetrahydropyridin-4-yI)thiazole-4- carboxylate
To a solution of ethyl 2-bromo- l ,3-thiazole-4-carboxylate (63.6 g, 270 mmol) in 200 ml of dioxane, bis(triphenylphosphine)palladium(II)chloride (9.46 g, 13.48 mmol), tert-butyl 4-(4,4,5,5-tetramethyl- l ,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine- l (2H)-carboxylate ( 100 g, 323 mmol) and a solution of sodium carbonate (86 g, 809 mmol) in 100 ml of water were consecutively added at room temperature. The reaction mixture was heated to 85 °C for 12h cooled to room temperature, filtered through celite bed and washed with methanol. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography using ethyl acetate and hexane (30:70) as eluents to obtain ethyl 2-
( l -(tert-butoxycarbonyl)- l , 2, 3, 6-tetrahydropyridin-4-yl) thiazole-4-carboxylate (50 g, 55% yield).
Ή-NMR (400 MHz, DMSO-c¾ δ 8.40 (s, 1 H), 6.63 (s, 1 H), 4.26 (q, J = 7.0 Hz, 2H), 4.01 (s, 2H), 3.49 (t, J = 5.7 Hz, 2H), 2.54 (d, ./ = 1 .7 Hz, 2H), 1 .39 (d, J = 6.4 Hz, 9H), 1 .24- 1.28 (m, 3H). MS: m/z = 339 [M+l ].
Step C: Preparation of ethyl 2-(l-(tert-butoxycarbonyl)piperidin-4-yl)thiazole-4-carboxylate
To a solution of ethyl 2-( l -(tert-butoxycarbonyl)- l ,2,3,6-tetrahydiOpyridin-4-yl)thiazole-4-carboxylate ( 12.8 g, 37.8 mmol) in 200 ml of ethanol, a suspension of 10% Palladium on charcoal (16.10 g, 1 5.13 mmol) in 100 ml of ethanol was added. The reaction mixture was maintained under hydrogen pressure of 70 bar at 65 °C for 12h and was cooled to room temperature and filtered. The filtrate was concentrated to obtain ethyl 2-( l -(tert-butoxycarbonyl) piperidin-4-yl) thiazole-4-carboxylate (9.3g, 72% yield).
Ή-NMR (400 MHz, DMSO-c/6) δ 8.41 (s, 1 H), 4.28 (q, J = 7.1 Hz, 2H), 4.00 (d, J = 12.5 Hz, 2H), 3.20-
3.27 (m, 1 H), 2.87 (s, 2H), 2.00-2.03 (m, 2H), 1.53 (ddd, J = 24.7, 12.2, 4.1 Hz, 2H), 1.37-1.43 (m, 9H),
1 .28 (t, J = 7.1 Hz, 3H). MS: m/z = 341 .10 [M+l ].
Step D: Preparation of tert-butyl 4-(4-(hydroxymethyl)thiazol-2-yl)piperidine-l-carboxylate
To a stirred solution of ethyl 2-( l -(tert-butoxycarbonyl) piperidin-4-yl) thiazole-4-carboxylate (30 g, 88 mmol) in tetrahydrofuran (500 ml), sodium borohydride (NaBH4) ( 16.67 g, 441 mmol) was added. The reaction mixture was heated to 60 °C and methanol (40 ml) was added slowly into the reaction mixture until it becomes clear solution. The reaction was quenched with ammonium chloride (NH4C1) solution (200 ml) and extracted twice with dichloromethane (200 ml). The combined dichloromethane layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 4-(4- (hydroxymethyl) thiazol-2-yl) piperidine- l -carboxylate (21 g, 80% yield).
MS: m/z = 299.401 [M+l ].
Step E: Preparation of tert-butyl 4-(4-formylthiazol-2-yl)piperidine-l-carboxylate
To a stirred solution of tert-butyl 4-(4-(hydroxymethyl) thiazol-2-yl) piperidine- l -carboxylate (8.4 g, 28.2 mmol) in dichloromethane (350 ml), Dess-Martin periodinane (23.88 g, 56.3 mmol) was added. The reaction mixture was stirred for 12h at room temperature and the reaction was quenched with aq. NaHC03 solution and aqueous layer was extracted twice with dichlorornethanei(200 ml). Dichloromethan layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by column chromatography using ethyl acetate and hexane (30:70) as eluents to obtain tert-butyl 4-(4-formylthiazol-2-yl)piperidine- l -carboxylate (5.3g, 52% yield).
Ή-NMR (400 MHz, DMSO-d6) δ 9.87 (s, 1 H), 8.63 (s, 1 H), 4.00 (d, ./ = 13.0 Hz, 2H), 3.24-3.29 (m, 1 H), 2.89 (s, 2H), 2.04 (dd, ./ = 12.7, 1 .8 Hz, 2H), 1 .56 (ddd, J = 24.6, 12. 1 , 4.1 Hz, 2H), 1.38-1 .43 (m, 9H). MS: m/z = 297.385 [M+l ]. Step F: Preparation of tert-butyl (E/Z) -4-(4-((hydroxyimino)methyI)thiazoI-2-yl)piperidine-l- carboxylate
To a stirred solution of hydroxylamine hydrochloride (0.563 g, 8. 10 mmol) in ethanol ( 15 ml), pyridine ( 1 .31 ml 16.2 mmol) was added. After 10 min, tert-butyl 4-(4-formylthiazol-2-yl) piperidine- 1 - carboxylate (2g, 6.75 mmol) was added and stirred for 1 hr at room temperature. The reaction mixture was concentrated under reduced pressure; residue was taken in aqueous ammonium chloride (NH4C1) solution (20 ml) and extracted twice with ethyl acetate (50 ml). Ethyl acetate layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure to obtain tert-butyl (E/Z)-4-(4- ((hydroxyimino) methyl) thiazol-2-yl) piperidine-l -carboxylate (2g, 95% yield).
Ή-NMR (400 MHz, DMSO-c/6) δ 12.05-1 1.09 ( 1 H), 8.49-7.96 ( l H), 7.87-7.54 ( 1 H), 3.99 (d, J = 14.1
Hz, 2H), 3.25-3.1 3 (m, 1 H), 2.88 (s, 2H), 2.01 (dd, J = 12.8, 2.1 Hz, 2H), 1 .61 - 1 .45 (m, 2H), 1.39 (s, 9H). MS: m/z = 312.400 [M+l ].
Step G: Preparation of tert-butyl 4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2- yl)piperidine-l-carboxylate
To a stirred solution of tert-butyl (E/Z)-4-(4-((hydroxyimino)methyl)thiazol-2-yl)piperidine- l -carboxylate (0.525 g, 1.686 mmol) in dry tetrahydrofuran (30 ml) at 0 °C, 2,6-difluorostyrene (0.41 8 ml , 3.37 mmol) was added followed by the addition of 4% aqueous sodium hypochlorite (6.24 ml , 5.06 mmol) and stirred for 1 hr. The reaction mass was quenched with water and the aqueous layer was extracted with ethyl acetate (50 ml x 2). The combined ethyl acetate layers were dried over anhydrous sodium sulfate. concentrated under reduced pressure and the residue was purified by column chromatography using ethyl acetate and hexane (40:60) as eluents to obtain the tert-butyl 4-(4-(5-(2,6-difluorophenyl)-4,5- dihydroisoxazol-3-yl)thiazol-2-yl)piperidine- l -carboxylate (250 mg, 0.556 mmol, 33% yield).
Step Gl : Alternate preparation of tert-butyl 4-(4-(5-(2,6-difIuorophenyl)-4,5-dihydroisoxazol-3- yl)thiazol-2-yl)piperidine-l-carboxylate
To a stirred solution of tert-butyl (E/Z)-4-(4-((hydroxyimino)methyl)thiazol-2-yl) piperidine- l - carboxylate (4 g, 12.85 mmol) in ethyl acetate (100 ml), N-chlorosuccinimide (3.43 g, 25.7 mmol) was added followed by the addition of sodium bicarbonate (7.55 g, 90 mmol). To the reaction mixture 1 :3- difluoro-2-vinylbenzene (3.60 g, 25.7 mmol) and 10 ml of water were added. The reaction mixture was heated to 65 °C for 3h and was cooled to 1 5 °C. The reaction was quenched using water. The aqueous layer was extracted twice with ethyl acetate (50 ml). The combined ethyl acetate layers were dried over anhydrous sodium sulfate, concentrated under reduced pressure and the residue was purified by column chromatography using ethyl acetate and hexane (40:60) as eluents to obtain tert-butyl 4-(4-(5-(2, 6- difluorophenyl)-4, 5-dihydroisoxazol-3-yl) thiazol-2-yl) piperidine- l -carboxylate (3g, 6.67 mmol, 52% yield). Ή-NMR (400 MHz, DMSO-c¾ δ 8.00 (s, 1H), 7.46-7.51 (m, 1H), 7.15 (t, J= 8.5 Hz, 2H), 5.99 (dd, ./ = 12.1, 8.6 Hz, lH), 4.00 (d, J= 12.5 Hz, 2H), 3.88 (dd, ./= 17.3, 12.1 Hz, 1H), 3.47-3.55 (m, 1H), 3.24- 3.28 (m, 1H), 3.05-2.74 (m, 2H), 2.03 (dd, J = 12.8, 2.1 Hz, 2H), 1.55 (dd, J= 12.2, 4.1 Hz, 2H), 1.40 (s,9H) MS: m/z = 450.20 [M+l].
Step H: Preparation of 5-(2,6-difluorophenyl)-3-(2-(piperidin-4-yI)thiazol-4-yl)-4,5- dihydroisoxazole
To a solution of tert-butyl 4-(4-(5-(2, 6-difluorophenyl)-4, 5-dihydroisoxazoI-3-yl) thiazol-2-yl) piperidine-l-carboxylate (0.21 lg, 0.469 mmol) in dichloromethane (20 ml), trifluoroacetic acid (TFA) (1.447 ml , 18.78 mmol) was added. The reaction mixture was stirred at room temperature for 1 h to obtain a clear solution. The reaction mixture was concentrated under reduced pressure and partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution and the ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated to obtain the 160 mg of 5-(2,6-difluorophenyl)-3- (2-(piperidin-4-yl)thiazol-4-yl)-4,5-dihydroisoxazole.
Step I: Preparation of 3-chloro-l-(2-(4-(4-(5-(2,6-difIuorophenyl)-4,5-dihydroisoxazol-3-yl)thiazoI- 2-yl)piperidin-l-yl)-2-oxoethyl)-5-(trifluoromethyl)pyridin-2(lH)-one
A mixture of 5-(2,6-difluoiOphenyl)-3-(2-(piperidin-4-yl)thiazol-4-yl)-4,5-dihydroisoxazole (164mg, 0.469 mmol), 2-(3-chloro-2-oxo-5-(trifluoromethyl)pyridin-l(2H)-yl)acetic acid (132 mg, 0.516 mmol), 1 -[Bis(dimethylamino)methylene]-lH-l ,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU) (214 mg, 0.563 mmol) and Ν,Ν-diisopropyl ethyl amine (DIEA) (0.492 ml , 2.82 mmol) in Dimethylformamide (5 ml) was stirred at room temperature for 16h. The reaction mixture was diluted with dichloromethane (10 ml), and washed with IN aqueous Hydrogen chloride and saturated aqueous sodium bicarbonate solution. The dichloromethane layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 3-chloro-l-(2-(4-(4-(5-(2,6-difluorophenyl)-4,5- dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxo (100 mg, 0.170 mmol, 36% yield).
Ή-NMR (400 MHz, DMSO-c/6) δ 8.36 (q, J= 1.2 Hz, 1H), 8.16 (d, J = 2.4 Hz, 1H), 8.02 (s, 1H), 7.45- 7.52 (m, 1H), 7.12,7.18 (m, 2H), 5.99 (dd, J= 12.1, 8.6 Hz, 1H), 5.00 (dd, J= 21.0, 15.8 Hz, 2H), 4.35 (d, J = 13.1 Hz, 1H), 4.01 (q,J=7.1 Hz, 1H), 3.85-3.96 (m, 2H), 3.37-3.56 (m, 2H), 2.81-2.87 (m, 1H), 2.12 (dd, J = 25.1, 12.3 Hz, 2H), 1.80(dd,J= 12.1,3.4 Hz, 1H), 1.57(dd,./= 12.2, 3.8 Hz, 1H) MS: m/z = 587.15 [M+l].
EXAMPLE 2
Preparation of 3-chloro-l-(2-(4-(4-(5-(2, 6-difluorophenyl)-4, 5-dihydroisoxazol-3-yl) thiazol-2-yl) piperidin-l-yl)-2-thioxoethyl)-5-(trifluoromethyl) pyridin-2(lH)-one (Compound 36) To a stirred solution of 3-chloro- l -(2-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2- yl)piperidin- l -yl)-2-oxoethyl)-5-(trifluoromethyl)pyridin-2( l H)-one (0.3 g, 0.51 1 mmol) in toluene (20 ml), Lawesson's reagent ( 1.034 g, 2.56 mmol) was added and heated at 100 °C for 16h. After completion of the reaction, the reaction mixture was filtered and concentrated under reduced pressure. Crude product was purified by column chromatography using ethyl acetate and hexane (80:20) as eluents to obtain 3- chloro- l -(2-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin- l -yl)-2- thioxoethyl)-5 (trifluoromethyl) pyridin-2( l H)-one (0.15 g, 0.249 mmol, 49% yield).
Ή-NMR (400 MHz, CDC13-<f) δ 7.91 (s, 1H), 7.68-7.71 (m, 2H), 7.28-7.33 (m, 1 H), 6.92 (t, J = 8.3 Hz, 2H), 6.08 (dd, J = 1 1 .9, 9.3 Hz, 1 H), 5.39 (d, J = 13.4 Hz, 1 H), 5.06 (dd, J = 22.2, 14.9 Hz, 2H), 4.58 (d, J = 1 3.1 Hz, 1 H), 3.81 (dd, J = 17.0, 12.2 Hz, 1 H), 3.60-3.66 (m, 2H), 3.47-3.53 (m, 2H), 2.28-2.39 (m, 2H), 2.01 -2.04 (m, 2H)
EXAMPLE 3
Preparation of 2-(l-(2-(3-chloro-2-oxo-5-(trifluoromethyl) pyridin-l(2H)-yl) acetyl) piperidin-4-yl)- N-(l, 2, 3, 4-tetrahydronaphthalen-l-yl) thiazoIe-4-carboxamide (Compound 86)
Step A: Preparation of 2-(l-(tert-butoxycarbonyl)piperidin-4-yl)thiazoIe-4-carboxylic acid
To a stirred solution of ethyl 2-( l -(tert-butoxycarbonyl)piperidin-4-yl)thiazole-4-carboxylate ( l . l g, 3.23 mmol) in a mixture of methanol and water (40 ml), lithium hydroxide (LiOH) (0.310 g, 12.92 mmol) was added. The reaction mass was stirred for 2h. The reaction mixture was concentrated, diluted with water and acidified with IN Hydrogen chloride. The precipitated acid was filtered and dried to obtain 2-(l -(tert- butoxycarbonyl)piperidin-4-yl)thiazole-4-carboxylic acid (0.9g, 89% yield).
Step B: Preparation of tert-butyl 4-(4-((l, 2, 3, 4-tetrahydronaphthalen-l-yl)carbamoyl)thiazol-2- yl)piperidine-l-carboxy!ate
To a stirred solution of 2-( l -(tert-butoxycarbonyl)piperidin-4-yl)thiazole-4-carboxylic acid ( 1 g, 3.20 mmol) in 5 ml of dry dimethylformamide, l -[Bis(dimethylamino)methylene]-l H- l ,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphate (HATU) (1 .217 g, 3.20 mmol) was added and the resulting clear solution was stirred for 10 mins at room temperature. 1 , 2, 3, 4-tetrahydronaphthalen- l -amine (0.518 g, 3.52 mmol) and Ν,Ν-diisopropyl ethyl amine (DIEA) (2.80 ml , 16.01 mmol) were added and the resulting yellow solution was stirred for 16h at room temperature. The reaction was quenched with 100 ml of a saturated solution of NaCl and extracted with ethyl acetate (200 ml). The combined ethyl acetate layers were evaporated and the residue was column purified using ethyl acetate and hexane (30:70) as eluents to obtain tert-butyl 4-(4-(( l , 2, 3, 4-tetrahydronaphthalen- l -yl) carbamoyl) thiazol-2-yl) piperidine- l -carboxylate ( 1 . 1 57 g, 2.62 mmol, 82% yield). Step C: Preparation of 2-(piperidin-4-yl)-N-(l, 2, 3, 4-tetrahydronaphthalen-l-yl)thiazole-4- carboxamide
To a solution of tert-butyl 4-(4-(( l , 2, 3, 4-tetrahydronaphthalen- l -yl) carbamoyl) thiazol-2-yl) piperidine- 1 -carboxylate ( 1 .1 57g, 2.62 mmol) in dichloromethane (20 ml), trifluoroacetic acid (8.07 ml , 105 mmol) was added. The reaction mixture was stirred at room temperature for 1 h to obtain a clear solution. The solution was concentrated under reduced pressure and partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The ethyl acetate layer was dried anhydrous sodium sulfate and concentrated to obtain 2-(piperidin-4-yl)-N-( l , 2, 3, 4-tetrahydronaphthalen- l -yl)thiazole-4-carboxamide. Step D: Preparation of 2-(piperidin-4-yl)-N-(l, 2, 3, 4-tetrahydronaphthalen-l-yl)thiazole-4- carboxamide
A mixture of 2-(piperidin-4-yl)-N-( l ,2,3,4-tetrahydiOnaphthalen- l -yl)thiazole-4-carboxamide ( 1 50mg, 0.439 mmol), 2-(3-chloro-2-oxo-5-(trifluoromethyl)pyridin-l (2H)-yl)acetic acid (123 mg, 0.483 mmol), l -[Bis(dimethylamino)methylene]-l H-l ,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU) (200 mg, 0.527 mmol), and Ν,Ν-diisopropyl ethyl amine (DIEA) (0.460 ml , 2.64 mmol) in dimethylformamide (5 ml) was swirled to form a vortex and held at room temperature for 16 h. The reaction mixture was diluted with dichloromethane ( 10 ml), and washed with 1 N aqueous Hydrogen chloride and saturated aqueous sodium bicarbonate solution. The dichloromethane layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 2-( l -(2-(3-chloro-2-oxo-5- (trifluoromethyl)pyridin- l (2H)-yl)acetyl)piperidin-4-yl)-N-( l ,2,3,4-tetrahydronaphth^
carboxamide (74mg, 0.128 mmol, 29% yield).
Ή-NMR (400 MHz, DMSO-i/6) δ 8.37 (d, J = 9.2 Hz, 1 H), 8.33 (s, 1 H), 8.24 (s, 1 H), 8.16 (d, J = 2.4 Hz, 1 H), 7. 10-7.1 8 (m, 4H), 5. 19 (dd, J = 14.0, 8.3 Hz, 1 H), 4.94-5.02 (m, 2H), 4.33 (d, J = 13.0 Hz, 1 H), 3.94 (d, J = 13.8 Hz, 1 H), 3.35-3.39 (m, 1 H), 3.22-3.28 (m, 1H), 2.69-2.84 (m, 3H), 2.06-2.16 (m, 211), 1 .86-1 .97 (m, 3H), 1 .73- 1 .82 (m, 2H), 1 .58 (dd, J = 23.7, 1 1.6 Hz, 1 H) MS: m/z = 579.40 [M+l ].
EXAMPLE 4
Preparation of 2-(2-(4-(4-(5-(2, 6-difluorophenyl)-4, 5-dihydroisoxazol-3-yl) thiazol-2-yl) piperidin- l-yl)-2-oxoethyl)-l-methyl-l , 2-dihydro-3H-pyrazol-3-one (Compound 47) To a solution of 5-(2, 6-difluorophenyl)-3-(2-(piperidin-4-yl) thiazol-4-yl)-4, 5-dihydroisoxazole (0.2 g, 0.572 mmol) in dimethylformamide (5 ml), Ν,Ν-diisopropyl ethyl amine (DIEA) (0.500 ml , 2.86 mmol) was added. To the resulting mixture, l -[Bis(dimethylamino)methylene]- l H- l ,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphate (HATU) (0.326 g, 0.859 mmol) and 2-(2-methyl-5-oxo-2, 5- dihydro- l H-pyrazol-l -yl) acetic acid (0.107 g, 0.687 mmol) were added and the reaction mixture was allowed to stir at room temperature overnight. The reaction mixture was diluted with water (20 ml) and extracted twice with dichloromethane (30 ml). The combined dichloromethane layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure which was column purified using ethyl acetate and hexane (80:20) as eluents to obtain 2-(2-(4-(4-(5-(2,6-difluorophenyl)- 4,5-dihydroisoxazol-3-yl)thiazol-2-yi)piperidin-l-yl)-2-oxoethyl)-l-methyl-l,2-dihydro-3H-pyrazol-3- one (0.110 g, 0.226 mmol, 39% yield).
Ή-NMR (400 MHz, DMSO-i/6) δ 8.02 (s, 1H), 7.60 (d, ./ = 3.4 Hz, 1H), 7.47-7.51 (m, 1H), 7.15 (t, J = 8.6 Hz, 2H), 5.99 (dd, J = 12.1, 8.6 Hz, 1H), 5.12 (d, ./= 3.5 Hz, 1H), 4.72 (dd, J= 37.3, 17.1 Hz, 2H), 4.35 (d, J = 12.8 Hz, 1H), 4.04 (d, ./= 13.3 Hz, 1H), 3.89 (dd,./= 17.3, 12.2 Hz, 1H), 3.46-3.56 (m, 1H), 3.35-3.39 (m, 1H), 3.33 (s, 3H), 3.26 (d, ./= 24.6 Hz, 1H), 2.79 (d, J= 1.2 Hz, 1H), 2.06-2.12 (m, 2H), 1.74 (s, 1H), 1.55 (d, .7=3.7 Hz, 1H) MS: m/z = 488.20 (M+l)
EXAMPLE 5
Preparation of 5-(difluoromethyl)-2-(2-(4-(4-(5-(2, 6-difluorophenyl)-4, 5-dihydroisoxazol-3-yl) thiazol-2-yl) piperidin-l-yl)-2-oxoethyl)-l-methyl-l, 2-dihydro-3H-pyrazol-3-one (Compound 70) To a solution of 5-(2, 6-difluorophenyl)-3-(2-(piperidin-4-yl) thiazol-4-yl)-4, 5-dihydroisoxazole (0.2 g, 0.572 mmol) in dimethylformamide (6 ml), Ν,Ν-diisopropyl ethyl amine (DIEA) (0.500 ml , 2.86 mmol) was added. To the resulting mixture, l-[Bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphate (HATU) (0.326 g, 0.859 mmol) and 2-(3-(difluoromethyl)-2- methyl-5-oxo-2, 5-dihydro-lH-pyrazol-l-yl) acetic acid (0.142 g, 0.687 mmol) were added and the reaction mixture was allowed to stir at room temperature overnight under n atmosphere. The reaction mixture was diluted with water (20 ml) and extracted twice with dichloromethane (30 ml).The combined dichloromethane layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure which was purified by column chromatography using ethyl acetate and hexane (80:20) as eluents to obtain 5-(difluoromethyl)-2-(2-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3- yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-l-methyl-l,2-dihydro-3H-pyrazol-3-one (0.075 g, 0.140 mmol, 24% yield).
'H-NMR (400 MHz, DMSO-i/6) δ 8.03 (d, J= 3.2 Hz, 1H), 7.48-7.52 (m, 1H), 7.04-7.31 (m, 3H), 6.00 (dd, J= 12.1, 8.6 Hz, 1H), 5.57 (s, 1H), 4.84 (q, ./= 17.4 Hz, 2H), 4.36 (d, J= 13.1 Hz, 1H), 4.02 (d, J = 13.4 Hz, 1H), 3.90 (dd, 7= 17.3, 12.2 Hz, 1H), 3.53 (q, J= 8.6 Hz, 1H), 3.37-3.41 (m, 4H), 3.22-3.26 (m, 1H), 2.81 (t,J = 11.5 Hz, 1H), 2.07-2.14 (m, 2H), 1.76-1.80 (m, 1H), 1.56(dd,j = 12.6, 3.9 Hz, 1H)MS: m/z = 538.20 (M+l)
EXAMPLE 6
Preparation of (E)-2-(l-(2-(2-oxo-5-(trifluoromethyl)pyridin-l(2H)-yl)acetyl)piperidin-4-yl)thiazole- 4-carbaldehyde O-benzyl oxime & (Z)-2-(l-(2-(2-oxo-5-(trifluoromethyl)pyridin-l(2H)- yl)acetyl)piperidin-4-yl)thiazole-4-carbaldehyde O-benzyl oxime (Compound 429 & Compound
430) Step A: Preparation of tert-butyl (E)-4-(4-(((benzyloxy) imino) methyl) thiazol-2-yl) piperidine-1- carboxylate
To a stirred solution of tert-butyl 4-(4-formylthiazol-2-yl)piperidine- l -carboxylate ( 1.0 g, 3.37 mmol) in ethanoi ( 10 ml), O-benzylhydroxylamine (0.393 ml , 3.37 mmol) and catalytic amount of conc.Hydrogen chloride were added. The reaction mixture was stirred overnight at room temperature. After completion of the reaction, ethanoi was evaporated under reduced pressure. The residue was purified by recrystalhzation using hexane and ethyl acetate to obtain tert-butyl (E)-4-(4-(((benzyloxy)imino)methy!)thiazol-2- yl)piperidine- l -carboxylate (0.89g, 3.37 mmol, 66% yield).
Step B: Preparation of (E)-2-(piperidin-4-yl) thiazole-4-carbaldehyde O-benzyl oxime
To a stirred solution of tert-butyl (E)-4-(4-(((benzyloxy) imino) methyl) thiazol-2-yl) piperidine-1 - carboxylate (0.6 g, 1 .469 mmol) in dichloromethane (3 ml), trifluoroacetic acid (TFA) (3.40 ml , 44.1 mmol) was added. The reaction mixture was stirred for 1 hr at room temperature. After completion of the reaction, the reaction mixture was evaporated under reduced pressure to obtain (E)-2-(piperidin-4-yl) thiazole-4-carbaldehyde O-benzyl oxime (0.412 g, 1 .367 mmol, 93% yield).
Step C: Preparation of (E/Z)-2-(l-(2-(2-oxo-5-(trifluoromethyl) pyridin-l(2H)-yl) acetyl) piperidin- 4-yl) thiazole-4-carbaldehyde O-benzyl oxime
To a stirred solution of (E)-2-(piperidin-4-yl)thiazole-4-carbaldehyde O-benzyl oxime (300 mg, 0.995 mmol) in Ν,Ν-dimethyl formamide ( 10 ml), Ν,Ν-diisopropyl ethyl amine (DIEA) ( 1 .043 ml , 5.97 mmol), 2-(2-oxo-5-(trifluoromethyl)pyridin- l (2H)-yl)acetic acid (220 mg, 0.995 mmol) and 1 - [Bis(dimethylamino)methylene]-l H- l ,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU) (568 mg, 1.493 mmol) were added. The reaction mixture was allowed to stirr at room temperature for 3h. The reaction mixture was quenched with water, extracted thrice with ethyl acetate (30 ml). The ethyl acetate layer was dried over sodium sulphate filtered and concentrated under reduced pressure. The residue was column purified using ethyl acetate and hexane (70:30) as eluents to obtain (E)-2-( l -(2-(2- oxo-5-(trifluoromethyl)pyridin- l (2H)-yl)acetyl)piperidin-4-yl)thiazole-4-carbaldehyde O-benzyl oxime (130 mg, 0.258 mmol, 25.9 % yield) and (Z)-2-( l-(2-(2-oxo-5-(trifluoromethyl)pyridin-l (2H)- yl)acetyl)piperidin-4-yl)thiazole-4-carbaldehyde O-benzyl oxime (90 mg, .0.178 mmol, 18% yield).
Ή-NMR (400 MHz, DMSO-t/6) 0 8.41 (s, 1 H), 8.30 (s, 1 H), 7.74 (s, 1 H), 7.70 (dd, ./ = 9.5, 2.7 Hz, 1 H), 7.31 -7.43 (m, 5H), 6.55 (d, J = 9.5 Hz, 1 H), 5.28 (s, 2H), 4.88-4.94 (m, 2H), 4.34-4.37 (m, 1H), 3.99 (d, J = 14.7 Hz, 1 H), 3.37-3.42 (m, 1 H), 3.25-3.28 (m, 1 H), 2.80-2.87 (m, 1 H), 2.06-2.15 (m, 2H), 1.76- 1 .83 (m, 1 H), 1 .51 - 1.57 (m, 1 H)
Ή-NMR (400 MHz, DMSO-c/6) δ 8.32 (d, J = 1 1 .7 Hz, 1 H), 8.28 (d, J = 1 1.7 Hz, 1 H), 7.89 (s, 1 H), 7.70 (dd, J = 9.5, 2.9 Hz, 1 H), 7.30-7.45 (m, 5H), 6.55 (d, J = 9.5 Hz, 1 H), 5. 18 (s, 2H), 4.88-5.00 (m, 2H), 4.37 (d, J = 12.7 Hz, 1 H), 4.00 (d, J = 12.5 Hz, l H), 3.24-3.43 (m, 2H), 2.68-2.85 (m, 1 H),2.0- 2.18(m,2H), l .78-1.85 (m, 1 H), 1.53- 1 .61 (m, 1 H)
EXAMPLE 7
Preparation of l-(2-(4-(4-(3-(2, 6-difIuorophenyl)-4, 5-dihydroisoxazol-5-yl) thiazol-2-yl) piperidin- l-yl)-2-oxoethyI)-3-(trifluoromethyl) pyridin-2(lH)-one (Compound 472) Step A: Preparation of tert-butyl 4-(4-(((benzyloxy) imino) methyl) thiazol-2-yl) piperidine-1- carboxylate
To a stirred suspension of tert-butyl 4-(4-formylthiazol-2-yl)piperidine- l -carboxylate (6.0 g, 20.24 mmol) and methyltnphenylphosphonium bromide ( 10.85 g, 30.4 mmol) in tetrahydrofuran (50 ml), sodium hydride (1.619 g, 40.5 mmol) was added under n at 0 °C. The reaction mixture was stirred at room temperature for 12h. The reaction mixture was poured on to ice and washed thrice with brine (30 ml), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography using ethyl acetate and hexane (20:80) as eluents to obtain the title compound tert-butyl 4-(4-vinylthiazol-2-yl)piperidine- l -carboxylate (5 g, 16.98 mmol, 84% yield).
Step B: Preparation of tert-butyl 4-(4-(3-(2, 6-difluorophenyI)-4, 5-dihydroisoxazol-5-yl) thiazoI-2- yl) piperidine-l-carboxylate
To a stirred solution of (E)-2, 6-difluorobenzaldehyde oxime (0.7 g, 4.46 mmol) in ethyl acetate (30 ml), N-chlorosuccinimide (0.81 1 g, 6.08 mmol) and sodium bicarbonate (2.382 g, 28.4 mmol) were added at room temperature. After 5 mins, tert-butyl 4-(4-vinylthiazol-2-yl) piperidine- l -carboxylate ( 1.192 g, 4.05 mmol) in ethyl aceatate (5 ml) and water (5 ml) were added to the reaction mixture. The resulting mixture was stirred at 60 °C for 3h. The reaction mixture was diluted with water (50 ml) and extracted twice with ethyl acetate (20 ml). The comined ethyl acetate layers were dried over anhydrous sodium sulfate and evaporated. The residue was purified by column chromatography using ethyl acetate and hexane (40:60) as eluents to obtain tert-butyl 4-(4-(3-(2, 6-difluorophenyl)-4, 5-dihydroisoxazol-5-yl) thiazol-2-yl) piperidine-l -carboxylate ( 1.274 g, 2.84 mmol, 70% yield).
Step C: Preparation of 3-(2, 6-difluorophenyl)-5-(2-(piperidin-4-yl) thiazol-4-yl}-4, 5- dihydroisoxazole 2, 2, 2-trifluoroacetate
To the stirred solution of tert-butyl 4-(4-(3-(2, 6-difluorophenyl)-4, 5-dihydroisoxazol-5-yl) thiazol-2-yl) piperidine-l -carboxylate (2.2 g, 4.89 mmol) in dichloromethane (20 ml), trifluoroacetic acid ( 10.91 ml , 147 mmol) was added. The reaction mixture was stirred for I hr at 0 °C and it was concentrated under reduced pressure to obtain 3-(2, 6-difluorophenyl)-5-(2-(piperidin-4-yI) thiazol-4-yl)-4, 5- dihydroisoxazole 2, 2, 2-trifluoroacetate. Step D: Preparation of l-(2-(4-(4-(3-(2, 6-difluorophenyl)-4, 5-dihydroisoxazol-5-yl) thiazol-2-yl) piperidin-l-yl)-2-oxoethyl)-3-(trifluoromethyl) pyridin-2(lH)-one
To a stirred solution of 3-(2,6-difluorophenyl)-5-(2-(piperidin-4-yl) thiazol-4-y])-4, 5-dihydroisoxazole 2, 2, 2-trifluoroacetate (250 mg, 0.539 mmol) in Ν,Ν-dimethyl formamide (5 mi ), Ν,Ν-diisopropyl ethyl amine (DIEA) (0.471 ml , 2.70 mmol), l -[Bis(dimethylamino)methylene]- l H- l ,2,3-triazolo[4,5- bjpyridinium 3-oxid hexafluorophosphate (HATU) (308 mg, 0.809 mmol) and 2-(2-oxo-3- (trifluoromethyl) pyridin-l (2H)-yl) acetic acid ( 155 mg, 0.699 mmol) were added drop wise at room temperature. The reaction mixture was stirred at room temperature for l h. The reaction was quenched with cold water and the solid obtained was filtered. The crude prodcut was purified by prep- chromatography to obtain l -(2-(4-(4-(3-(2, 6-difluorophenyl)-4, 5-dihydroisoxazol-5-yl) thiazol-2-yl) piperidin- l -yl)-2-oxoethyl)-3-(trifluoromethyl) pyridin-2( l H)-one ( 100 mg, 0.1 81 mmol, 34% yield). Ή-NMR (400 MHz, DMSO-J6) δ 8.01 -7.87 (m, 2H), 7.69 (s, 1 H), 7.64-7.53 (m, 1 H), 7.3 1 -7.21 (m, 2H), 6.42-6.35 (m, 1H), 5.89-5.79 (m, 1H), 5.06-4.80 (m, 2H), 4.39-4.24 (m, 1 H), 4.06-3.94 (m, 1H), 3.85- 3.73 (m, I H), 3.70-3.57 (m, 1 H), 3.42-3.22 (m, 2H), 2.92-2.78 (m, 1 H), 2.20-2.03 (m, 2H), 1.86-1.73 (m, 1 H), 1 .61 -1.49 (m, 1H).
Example 8
Preparation of l-(2-(4-(4-(l, 5-dihydrobenzo[e] [1,3] dioxepin-3-yl) thiazol-2-yl) piperidin-l-yl)-2- oxoethyl)-3-(trifluoromethyl) pyridin-2(lH)-one (Compound 252)
Step 1 : Preparation of 2-(piperidin-4-yI) thiazole-4-carbaldehyde
To a stirred solution of tert-butyl 4-(4-formylthiazol-2-yl)piperidine- l -carboxylate (2 g, 6.75 mmol) in dichloromethane (20 ml) , trifluoro acetic acid (18.2 ml 236 mmol) was added at 0°C. The reaction mixture was stirred for 4 h at 0 °C and it was concentrated under reduced pressure to obtain 2-(piperidin- 4-yl) thiazole-4-carbaldehyde ( 1 .3 g, 5.60 mmol, 83 % yield).
Step 2: Preparation of 4-(l, 5-dihydrobenzo[e] [1,3] dioxepin-3-yl)-2-(piperidin-4-yi) thiazole
To a stirred solution of 2-(piperidin-4-yl) thiazole-4-carbaldehyde ( 1 .0 g, 5.10 mmol) in dichloromethane (1 5 ml), 1 , 2-phenylenedimethanol ( 1.408 g, 10.19 mmol) was added. After stirring the reaction mixture for 5 minutes, sodium sulphate ( l g) and paratoluene sulfonic acid ( 10%) were added. The reaction mixture was stirred for 12h at room temperature. The reaction mixture was fi ltered to remove inorganics. The filtrate was concentrated under reduced pressure to obtain 4-(l ,5-dihydrobenzo[e] [1 ,3] dioxepin-3- yl)-2-(piperidin-4-yl) thiazole (810 mg, 2.56 mmol, 50% yield).
Step 3: Preparation of l-(2-(4-(4-(l, 5-dihydrobenzo[e] [1 ,3] dioxepin-3-yl) thiazol-2-yl) piperidin-1- yl)-2-oxoethyi)-3-(trifluoromethyl) pyridin-2(lH)-one
To a stirred solution of 4-( l ,5-dihydrobenzo[e][ l ,3]dioxepin-3-yl)-2-(piperidin-4-yl)thiazole ( 1.264 mmol, 400 mg) in N,N-dimethylformamide ( 1 5 ml), Ν,Ν-diisopropyl ethyl amine (DIEA) ( 1 2.64 mmol, 2.208 ml), 2-(2-oxo-3-(trifluoromethyl) pyridin- 1 (2H)-yi) acetic acid ( 1 .264 mmol, 280 mg) and 1 - [Bis(dimethylamino)methylene]-l H- l ,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU) ( 1 .517 mmol, 577 mg) were added. The reaction mixture was stirred for 12h. After completion of the reaction, the reaction mixture was diluted with water (50 ml) and extracted twice with ethyl acetate ( 10 ml). The combined ethyl acetate layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was column purified using ethyl acetate and hexane (70:30) as eluents to obtain 1 -(2-(4-(4-( 1 ,5-dihydrobenzo[e][ 1 ,3]dioxepin-3-yl)thiazol-2-yl)piperidin- 1 -yl)-2-oxoethyl)-3- (trifluoromethyl)pyridin-2( l H)-one (380 mg ,0.731 mmol, 90% yield).
'H-NMR (400 MHz, DMSO-i/6) δ 7.91 -7.96 (m, 2H), 7.58 (d, J = 4.9 Hz, 1 H), 7.25 (t, J = 9.5 Hz, 4H), 6.38 (t, J = 6.7 Hz, 1 H), 6.04 (d, J = 7.3 Hz, 1 H), 4.90-5.03 (m, 6H), 4.36 (d, J = 13.4 Hz, I H), 3.99 (d, J = 13.4 Hz, 1 H), 3.33-3.37 (m, 1 H), 3.27 (t, J = 1 1.6 Hz, 1 H), 2.82 (t, J = 1 1.6 Hz, I H), 2.09 (dd, J = 22.3, 1 2.5 Hz, 2H), 1 .78 (qd, J = 12.2, 3.7 Hz, I H), 1.47-1.59 (m, I H)
Example 9
Preparation of l-(2-oxo-2-(4-(4-(3-phenyl-4,8-dihydro-[l,3]dioxepino[5,6-d]isoxazol-6-yl)thiazol-2- yl)piperidin-l-yl)ethyl)-5-(trifluoromethyl)pyridin-2(lH)-one (Compound 257)
Step 1 : Preparation of 2-(piperidin-4-yl) thiazole-4-carbaldehyde
To a solution of tert-butyl 4-(4-formylthiazol-2-yl) piperidine-l -carboxylate (0.5 g, 1.687 mol) in dichloromethane ( 10 ml), trifluoro acetic acid (5.20 ml , 67.5 mol) was added.The reaction mixture was stirred at room temperature for lh. The reaction mixture was concentrated under reduced pressure to obtain 2-(piperidin-4-yl) thiazole-4-carbaldehyde (0.285 g, 1.451 mmol, 86% yield). MS: m/z = 197.00 [M+l ].
Step 2: Preparation of 2-(l-(2-(2-oxo-5-(tritluoromethyl) pyridin-l(2H)-yl) acetyl) piperidin-4-yl) thiazole-4-carbaldehyde
To a solution of 2-(piperidin-4-yl) thiazole-4-carbaldehyde (0.3g, 1.529 mmol) in N,N-dimethyl formamide (DMF) (8 ml), Ν,Ν-diisopropyl ethyl amine (DIEA) ( 1.335 ml , 7.64 mmol), 1 - [Bis(dimethylamino)methylene]-l H-l ,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU) (0.872 g, 2.293 mmol) and 2-(2-oxq-5-(trifluoromethyl) pyridin-1 (2H)-yl) acetic acid (0.406 g, 1.834 mmol) were added to the reaction mixture and was allowed to stir at room temperature overnight under n atmosphere. The reaction mixture was diluted with water and extracted twice with ethyl acetate (30 ml). The combined ethyl acetate layers were washed with brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude product was purified by preparative HPLC to obtain 2-( l - (2-(2-oxo-5-(trifluoromethyl) pyridine l (2H)-yl) acetyl) piperidin-4-yl) thiazole-4-carba!dehyde ( 1 95mg, 0.488 mmol, 32% yield). MS: m/z 400 [M+l ]. Step 3:Preparation of l-(2-oxo-2-(4-(4-(3-phenyl-4,8-dihydro-[l,3]dioxepino[5,6-d]isoxazol-6- yl)thiazoI-2-yl)piperidin-l-yl)ethyl)-5-(trifluoromethyl)pyridin-2(l H)-one
3-phenyl isoxazole-4,5-diyl)dimethanol (0. 185 g, 0.901 mmol) and p-toluene sulfonic acid monohydrate (0.071 g, 0.376 mmol) were dissolved in a solution of dry toluene (20 ml) and dry N,N-dimethyl formamide (5 ml) and stirred with odium sulfate under n atmosphere. 2-( l -(2-(2-oxo-5- (trifluoromethyl)pyridin-l (2H)-yl)acetyl)piperidin-4-yl)thiazole-4-carbaldehyde (0.3 g, 0.751 mmol) was added drop wise to the resulting mixture at room temperature and stirred overnight at 80 °C. The reaction mixture was filtered and concentrated. The residue was purified to obtain l -(2-oxo-2-(4-(4-(3-phenyl-4,8- dihydro-[ l ,3]dioxepino[5,6-d]isoxazol-6-yl)thiazol-2-yl)piperidin- l -yl)ethyl)-5-(tiMfluoromethy0 2( l H)-one ( 100 mg, 0.170 mmol, 23% yield). MS: m/z = 587.15 [M+l ].
Ή-NMR (400 MHz, DMSO- d6) δ 8.30 (s, 1 H), 7.69-7.75 (m, 1H), 7.55-7.62 (m, 2H), 7.46 (t, ./ = 7.3 Hz, 1 H), 7.37 (t, .7 = 7.5 Hz, 2H), 7.22 (s, 1 H), 6.55 (d, .7 = 9.8 Hz, 1H), 5.21 (d, J = 1.2 Hz, 1 H), 4.91 (dd, J = 1 8.8, 16.1 Hz, 2H), 4.55 (td, ./ = 8.7, 3.5 Hz, 1 H), 4.20 (q, .7 = 8.6 Hz, 2H), 3.88-3.91 (m, 1 H), 3.17-3.29 (m, 2H), 2.72-2.89 (m, 2H), 2.59-2.68 (m, 1 H), 1 .87- 1.99 (m, 2H), 1.56-1 .67 (m, 1 H), 1 .33-1.48 (m, 1 H)
Example 10
Preparation of (3-phenylisoxazole-4, 5-diyl) dimethanol
Step A: Preparation of (E/Z)-benzaldehyde oxime
To a stirred solution of hydroxylamine hydrochloride (2.357 g, 33.9 mmol) in ethanol (20 ml), pyridine (5.49 ml , 67.8 mmol) was added at 0 °C. Benzaldehyde (3 g, 28.3 mmol) was added slowly and the reaction mixture was stirred at room temperature for 20 mins. The reaction mixture was evaporated and the residue was purified by column chromatography using ethyl acetate and hexane (20:80) as eluents to obtain (E/Z)-benzaldehyde oxime. MS: m/z = 122.25 [M+l ].
Step B: Preparation of dimethyl 3-phenylisoxazole-4, 5-dicarboxylate
To a solution of (E/Z)-benzaldehyde oxime (2 g, 16.51 mmol) in ethyl acetate (20 ml), N- chlorosuccinimide (4.41 g, 33.0 mmol) and sodium bicarbonate (9.71 g, 1 16 mmol) were added at room temperature. Then dimethyl but-2-ynedioate (2.448 ml , 19.81 mmol) and 2 ml of water were added. The reaction mixture was stirred at 60 °C for 2h. After completion of the reaction, the reaction mass was di luted with water ( 1 5 ml) and extracted twice with ethyl acetate ( 100 ml). The combined ethyl acetate extracts were evaporated and purified by column chromatography using ethyl acetate and hexane (30:70) as eluents to obtain dimethyl 3-phenylisoxazole-4, 5-dicarboxylate ( 1.3 g, 4.98 mmol, 30% yield).
Ή-NMR (400 MHz, DMSO-d6) δ 7.65-7.69 (m, 2H), 7.55-7.63 (m, 3H), 3.97 (s, 3H), 3.86 (s, 3H)
Step C: Preparation of (3-phenylisoxazole-4, 5-diyl) dimethanol
To a stirred solution of lithium aluminum hydride (7.66 ml , 7.66 mmol) in tetrahydrofuran (20 ml ) at 0 °C, dimethyl 3-phenylisoxazoIe-4,5-dicarboxylate ( 1 g, 3.83 mmo!) was added portion wise and stirred for 2h. The reaction was quenched with ammonium chloride solution and extracted thrice with dichloromethane (30 ml). The combined dichloromethane layers were evaporated to obtain (3- phenylisoxazole-4, 5-diyl) dimethanol (0.35 g, 1 .706 mmol, 45% yield). MS: m/z = 206.10 [M+l ].
Example 11
Preparation of 1, 2-phenylenedimethanol
To a stirred solution of lithium aluminium hydride (0.782 g, 20.60 mmol) in tetrahydrofuran (20 ml) at 0 °C, a solution of dimethyl phthalate ( 1 .681 ml , 10.30 mmol) in tetrahydrofuran (5 ml) was added drop wise. The reaction mixture was stirred for 3h at room temperature. The reaction mixture was quenched with 10% dil. hydrogen chloride (20 ml) and aqueous layer was extracted twice with ethyl acetate ( 10 ml). The combined ethyl acetate layers were dried over sodium sulphate and evaporated to obtain 1 , 2- phenylenedimethanol ( 1 g, 7.24 mmol, 70% yield).
EXAMPLE 12
Preparation of 3-chloro-2-ethenylphenyl methanesulfonate Step A: 2-chloro-6-(methoxymethoxy)benzaldehyde
To a stirred solution of 2-chloro-6-hydroxybenzaldehyde (25 g, 160 mmol) in dichloromethane (500 ml), Ν,Ν-diisopropyl ethyl amine (D1EA) ( 139 ml , 798 mmol) was added at 0 °C. Chloromethoxymethane (36.4 ml , 479 mmol) was added dropwise to the reaction mixture at the same temperature. The reaction mixture was allowed to attain room temperature and stirred for another 3h. After completion of the reaction, water (400 ml) was added and extracted twice with dichloromethane (200 ml). The combined dichloromethane layers were dried over anhydrous sodium sulfate, concentrated under reduced pressure and residue was purified by column chromatography using using ethyl acetate and hexane (20:80) as eluents to obtain 2-chloro-6-(methoxymethoxy)benzaldehyde (25 g, 78% yield).
Ή-NMR (400 MHz, DMSO-i/6) δ 10.39 (s, 1 H), 7.55 (t, J = 8.3 Hz, 1H), 7.25 (dd, J = 8.6, 0.8 Hz, 1 H), 7.18 (d, .7 = 8.1 Hz, 1 H), 5.33 (s, 2H), 3.41 (s, 3H).
Step B: l-chloro-2-ethenyl-3-(methoxymethoxy)benzene
To a stirred solution of 2-chloro-6-(methoxymethoxy)benzaldehyde (25 g, 125 mmol) in tetrahydrofuran (500 ml), methyltriphenylphosphonium bromide (67 g, 1 87 mmol) was added at 0 °C. Sodium hydride 60% ( 1 1 g, 274 mmol) was added portionwise to the reaction mixture at the same temperature. The reaction mixture was allowed to attain room temperature and stirred overnight. After completion of the reaction, saturated ammonium chloride solution (400 ml) was added and extracted twice with ethyl acetate (300 ml). The combined ethyl acetate layers were dried over anhydrous sodium sulfate, concentrated under reduced pressure and residue was purified by column chromatography using ethyl acetate and hexane (05 :95) as eluents to give l -chloro-2-ethenyl-3-(methoxymethoxy)benzene (23 g, 92% yield). Ή-NMR (400 MHz, DMSO-afe) δ 7.20-7.24 (m, 1 H), 7.09-7.12 (m, 2H), 6.79 (dd, ./ = 17.8, 12.0 Hz, 1 H), 5.98 (dd, J = 1 7.8, 2.2 Hz, ] H), 5.62 (dd, .7 = 1 1 .9, 2.1 Hz, 1 H), 5.26 (s, 2H), 3.38 (s, 3H).
Step C: 3-chloro-2-ethenylphenol
To a stirred solution of l -chloro-2-ethenyl-3-(methoxymethoxy)benzene ( 1 0 g, 50.3 mmol), in methanol (400 ml), acetyl chloride (6.1 ml , 85 mmol) was added dropwise over l h at 0 °C. The reaction mixture was allowed to attain room temperature and stirred for another 3h. After completion of the reaction, triethylamine was added to adjust to pH 7-8. The reaction mixture was concentrated under reduced pressure and residue was purified by column chromatography using ethyl acetate and hexane (05 :95) as eluents to obtain 3-chIoro-2-ethenylphenol (6.9 g, 89% yield).
Ή-NMR (400 MHz, DMSO-4) δ 10.20 (s, 1 H), 7.05 (t, J = 8.0 Hz, 1 H), 6.76-6.89 (m, 3H), 6.10 (dd, J = 17.8, 2.5 Hz, 1 H), 5.52 (dd, J = 12.1 , 2.4 Hz, 1 H).
Step D: 3-chloro-2-ethenylphenyl methanesulfonate
To a stirred solution of 3-chloro-2-ethenylphenol (6.9 g, 44.6 mmol) in dichloromethane (250 ml), triethylamine (8 ml , 58 mmol) was added at 0 °C. Methanesulfonyl chloride (4.89 ml , 62.5 mmol) was added dropwise to the reaction mixture at the same temperature. The reaction mixture was allowed to attain room temperature and stirred for 4h. The reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography using ethyl acetate and hexane (05:95) as eluents to obtain 3-chloro-2-vinylphenyl methanesulfonate (9 g, 87% yield).
'H-NMR (400 MHz, DMSO-40 δ 7.48-7.52 (m, 1 H), 7.37-7.43 (m, 2H), 6.71 (dd, .7 = 18.0, 1 1.8 Hz, 1 H), 5.84 (dd, J = 1 8.0, 1.5 Hz, 1 H), 5.74 (dd, J = 1 1.8, 1.5 Hz, 1H), 3.42 (s, 3H).
EXAMPLE 13
Preparation of l,3-difluoro-2-vinylbenzene
To a stirred suspension of 2, 6-difluorobenzaldehyde (7.59 ml , 70.4 mmol) and methyltriphenylphosphonium bromide (37.7 g, 106 mmol) in tetrahydrofuran (50 ml), sodium hydride ( 1 1.26 g, 281 mmol) was added under n atmosphere at 0 °C. The resulting mixture was stirred at room temperature for 5h. The reaction mixture was washed thrice with brine (30 ml) dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was. purified by column chromatography using ethyl acetate and hexane (05 :95) as eluents to obtain l ,3-difluoro-2-vinylbenzene (9g, 64.2 mmol, 91 % yield).
Ή-NMR (400 MHz, DMSCM,) δ 7.35-7.39 (m, 1 H), 7.1 3 (t, .7 = 8.6 Hz, 2H), 6.70 (dd, J = 17.9, 1 1 .9 Hz, 1 H), 5.97 (d, .7 = 1 8.0 Hz, 1 H), 5.66 (d, .7 = 1 1 .9 Hz, 1 H)
EXAMPLE 14
Preparation of 2-(3-(difluoroniethyl)-2-methyl-5-oxo-2, 5-dihydro-lH-pyrazol-l-yl) acetic acid Step A: Preparation of ethyl 2-(3-(difluoromethyl)-5-oxo-2, 5-dihydro-lH-pyrazol-l-yl)acetate A solution of ethyl aminoglycinate hydrochloride (5.000 g, 32.3 mmol) and ethyl 4, 4-difluoro-3- oxobutanoate (5.37 g, 32.3 mmol) in ethanol (50 ml) was stirred at 85 °C overnight. The reaction mixture was concentrated under reduced pressure to obtain ethyl 2-(3-(difluoromethyl)-5-oxo-2, 5-dihydro- l H- pyrazol- l -yl) acetate (5.2 g, 23.62 mmol, 73% yield).
Ή-NMR (400 MHz, DMSO-i/6) δ 12.32- 10.95 ( 1 H), 6.96-6.54 ( 1 H), 5.61 -5.53 ( 1 H), 4.80-4.74 (2H), 4.19-4.08 (2H), 1 .22- 1.1 5 (3H) MS: m/z = 221 . 10 (M+l )
Step B: Preparation of ethyl 2-(3-(difluoromethyl)-2-methyI-5-oxo-2,5-dihydro-lH-pyrazol-l- yl)acetate
To a solution of ethyl 2-(3-(difluoromethyl)-5-oxo-2, 5-dihydro- l H-pyrazol- l -yl) acetate ( 1.0 g, 4.54 mmol) in 10 ml of acetonitrile, iodomethane (1.420 ml , 22.71 mmol) was added. The reaction mixture was stirred for 16h at 1 10 °C under in a sealed vial. The reaction mixture was concentrated under reduced pressure to obtain ethyl 2-(3-(difluoromethyl)-2-methyI-5-oxo-2, 5-dihydro-lH-pyrazol-l -yl) acetate (1.0 g, 4.27 mmol, 94% yield).
Ή-NMR (400 MHz, DMSO- d6) δ 7.05-7.32 (m, 1 H), 5.66 (s, 1 H), 4.69 (d, J = 14.1 Hz, 2H), 4.07-4.19 (m, 2H), 3.37 (S, 3H), 1.14-1.21 (m, 3H) MS: m/z = 234.95 (M+l)
Step C: Preparation of 2-(3-(difluoromethyl)-2-methyl-5-oxo-2,5-dihydro-lH-pyrazol-l-yl)acetic acid
To a solution of ethyl 2-(3-(difluoromethyl)-2-methyl-5-oxo-2,5-dihydro- l H-pyrazol- l -yl)acetate (2.0 g, 8.54 mmol) in a mixture of tetrahydrofuran ( 16 ml), ethanol (4 ml) and water ( 1 ml), lithium hydroxide monohydrate (1.792 g, 42.7 mmol) was added. The resulting mixture was stirred at room temperature for 3h. The reaction mixture was concentrated under reduced pressure, diluted with water (5 ml) and acidified with cone hydrogen chloride to pH 2. The reaction mixture was extracted twice with n-butanol (50 ml), the combined extracts were concentratd to obtain 2-(3-(difluoromethyl)-2-methyl-5-oxo-2,5-dihydro- lH- pyrazol- l -yl)acetic acid ( 1.2g, 5.82 mmol, 68% yield).
MS: m/z = 206.90 (M+l )
EXAMPLE 15
Preparation of 2-(4-bromo-3-(difluoromethyl)-2-methyl-5-oxo-2, 5-dihydro-lH-pyrazoJ-l-yl) acetic acid
Step A: Preparation of ethyl 2-(4-bromo-3-(difluoromethyl)-2-niethyl-5-oxo-2,5-dihydro-lH- pyrazol-l-yl)acetate
To a solution of ethyl 2-(3-(difluoromethyl)-2-methyl-5-oxo-2,5-dihydro- l H-pyrazol-l -yl)acetate (2.0 g, 8.54 mmol) in chloroform (30 ml), N-bromosuccinamide (2.280 g, 12.81 mmol) was added and the reaction mixture was allowed to stir at 50 °C for 4h. The reaction mixture was diluted with water ( 100 ml) and extracted twice with dichloromethane ( 100 ml). The combined dichloromethane layers were dried over anhydrous sodium sulfate and concentrated to obtain ethyl 2-(4-bromo-3-(difluoromethyl)-2-methyl- 5-oxo-2,5-dihydro- l H-pyrazol- l -yl)acetate (2.0 g, 6.39 mmol, 75 % yield).
Ή-NMR (400 MHz, DMSO--¾ δ 7.10-7.37 (m, 1 H), 4.77 (d, J = 7.3 Hz, 2H), 4.10-4.18 (m, 2H), 3.41 (s, 3H), 1.15- 1.21 (m, 3H) MS: m/z = 3 12.85 (M+l )
Step B: Preparation of 2-(4-bromo-3-(difluoroniethyl)-2-methyl-5-oxo-2,5-dihydro-lH-pyrazol-l- yl)acetic acid
To a solution of ethyl 2-(4-biOmo-3-(difluoromethyl)-2-methyl-5-oxo-2,5-di hydtO- l H-pyrazol- 1 - yl)acetate (2.0 g, 6.39 mmol) in tetrahydrofuran ( 16.00 ml), ethanol (4.0 ml) and water (1 ml), lithium hydroxide monohydrate ( 1.340 g, 31.9 mmol) was added. The resulting mixture was stirred at room temperature for 3h. The reaction mixture was concentrated under reduced pressure and the residue was diluted with water (5 ml) and acidified with 5N hydrogen chloride to pH 2, solid obtained was filtered and dried to obtain 2-(4-bromo-3-(difiuoromethyl)-2-iT)ethyl-5-oxo-2,5-dihydro- l//-pyrazol-l -yl)acetic acid ( l .Og, 3.51 mmol, 55% yield).
Ή-NMR (400 MHz, DMSO-i/6) δ 1 3.30 (s, 1 H), 7.1 1 -7.37 (m, 1 H), 4.68 (d, J = 5.7 Hz, 2H), 3.43 (s, 3H) MS: m/z = 284.85 (M+l )
EXAMPLE 16
General scheme for synthesis of pyridone acid
Figure imgf000108_0001
Step A: Preparation of B
A solution of substituted or unsubstituted 2-chloropyridine ( 13.51 mmol), potassium hydroxide (40.5 mmol) in tert- butanol (20 ml) was refluxed at 100 °C for 2h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was diluted with water ( 10 ml) and washed with dichloromethane ( 1 5 ml) to remove unreacted product. The aqueous layer was acidified with 10 % hydrogen chloride to pH 2 and extracted with dichloromethane. The combined dichloromethane layers were dried over anhydrous sodium sulfate, concentrated under reduced pressure to give resultant 2-pyridone derivative.
Step B: Preparation of C (Halogenation)
To a stirred solution of substituted or unsubstituted 2-pyridone ( 1 eqiv) in acetic acid ( 10 ml) was added N-halosuccinamide ( 1 .5 eqiv) and heated to 120 °C overnight. The recation mixture was filtered, concentrated, diluted with saturated aqueous NaHC03 and extracted twice with ethyl acetate. The combined ethyl acetate layers were washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated and purified by combiflash to give C in good to excellent yields.
Step Bl : Alternative preparation of C (Halogenation)
To a solution of substituted or unsubstituted 2-pyridone ( 1 eqiv) in dichloromethane ( 1 5 ml), bromine ( 1.2 eqiv) was slowely added. After addition, the mixture was stirred at room temperature for 1 8h. The reaction mixture was cooled to 0 °C and quenched with saturated aqueous sodium bicarbonate (5 ml). The mixture was then extracted twice with ethyl acetate. The combined ethyl acetate layers were dried over anhydrous sodium sulfate, concentrated and the residue was purified by coloumn chromatography to give compound C.
Step B2: Alternative preparation of C (Trifluoromethylation)
To a solution of substituted or unsubstituted 2-pyridone (9.20 mmol, 1 eqiv) and sodium trifluoromethanesulfinate (27.6 mmol, 3 equivalent) in acetic acid ( 10 ml), manganese triacetate hydrate (27.6 mmol, 3 equivalent) was added in batches. The mixture was stirred at 25 °C in the presence of air for 12h. Water (20 ml) was added to the reaction mixture, extracted twice with ethyl acetate. The combined ethyl acetate extracts were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography using ethyl acetate and hexane as eluents to give compound C.
Step C: Preparation of D (Alkylation)
To a stirred solution of compound C (8.84 mmol, 1 eqiv) in Ν,Ν-dimethylformamide, potassium carbonate ( 17.68 mmol, 2 eqiv) was added followed by the addition of ethyl 2-bromoacetate ( 10.61 mmol, 1 .2 eqiv). The resulting mixture was stirred at ambient temperature for 1 2h then diluted with water. The aqueous phase was extracted thrice with ethyl acetate and the combined ethyl acetate layers were washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by combiflash chromatography to afford the compound D.
Step D: Preparation of E (Hydrolysis)
To a solution of compound D (9.23 mmol, 1 eqiv) in ethanol and water, sodium hydroxide ( 18.46 mmol, 2 eqiv) was added and the resulting mixture was stirred at ambient temperature for 2h. The reaction mixture was concentrated under reduced pressure, diluted with water and acidified with cone hydrogen chloride upto pH 4. The precipitated solid product was filtered, washed with water followed by n-hexane and dried to obtain corresponding pyridone acid E in good to excellent yields.
The following representative and non-limiting pyridone acids were prepared by procedures described in the Example 16.
Figure imgf000109_0001
Figure imgf000110_0001
Figure imgf000111_0001
Figure imgf000112_0001
Figure imgf000113_0001
Figure imgf000114_0001
BIOLOGY EXAMPLES:
Phytophthora infestans (Late blight of potato & tomato):
IN VITRO TEST: Compounds were dissolved in 0.3% DMSO & then added to Rye Agar medium just prior to dispensing it into petri dishes.5 ml medium with compound in the desired concentration was dispensed into 60 mm sterile petri-plates. After solidification each plate was seeded with 5mm size mycelial disc taken form periphery of actively growing virulent culture plate. Plates were incubated in growth chambers at 18 °C temperature and 95% relative humidity for seven days and radial growth was measured. Compounds 1 4 6 7 8 9 10 12 13 14
15 17 18 19 20 23 24 26 27 30 32 33
34 35 36 37 39 40 41 47 48 51 52 53
54 55 56 57 58 59 60 61 62 64 65 66
67 68 72 73 74 76 77 78 80 81 85 86
88 89 90 92 93 94 95 96 98 99 100 101
102 104 106 107 109 110 111 112 113 114 115 116
117 118 120 121 123 124 125 126 127 128 130 131
132 133 134 135 136 137 138 139 141 142 144 145
146 147 149 150 151 152 153 154 155 156 157 158
159 160 161 162 163 164 165 166 167 168 169 170 171 172 173 174 175 176 177 178 179 1 80 1 81 1 82
1 83 1 84 185 186 187 188 1 89 1 90 1 91 1 92 193 1 94
1 95 196 197 198 199 200 201 202 203 204 205 207
208 209 210 21 1 212 213 21 4 21 5 216 217 21 8 219
220 221 222 223 224 225 226 227 228 229 230 231
232 233 235 236 237 238 240 241 242 243 244 245
246 247 248 249 250 251 252 254 255 256 258 259
260 261 262 263 264 266 267 268 269 270 271 275
277 278 279 281 282 283 284 285 286 287 288 289
290 291 292 293 294 295 296 297 298 299 300 301
302 303 304 305 306 307 308 309 3 10 31 1 3 12 313
314 315 316 317 318 319 320 321 322 323 324 325
326 327 328 329 330 331 332 333 334 335 336 337
338 339 340 341 342 343 344 345 346 347 348 349
350 351 352 353 354 355 356 357 358 359 360 361
362 363 364 365 366 367 368 369 370 371 372 373
374 375 376 377 378 380 381 382 383 384 385 386
387 388 389 390 391 392 393 394 395 396 397 398
399 400 401 402 403 404 405 406 407 408 410 41 1
412 41 3 414 415 4 16 417 418 419 420 421 422 423
424 425 426 428 433 434 435 436 437 438 439 440
441 442 445 448 452 453 454 455 456 457 458 459
460 461 462 463 464 465 466 467 468 469 473 474
476 478 480 481 482 at 30 ppm gave 70% control in these tests when compared to the untreated check which showed extensive disease development.
GREENHOUSE: Compounds were dissolved in 2% DMSO/Acetone & then mixed with water to calibrated spray volume of 50 ml . This 50 ml spray solution was poured into the spray bottles for further applications. To test the preventive activity of compounds, healthy young Tomato plants raised in the greenhouse were sprayed with active compound preparation at the stated application rates inside the spray cabinets using hal low-cone nozzles. One day after treatment, the plants were inoculated with sporangial suspension (Cold sterile water) containing 0.24x106 Phytophthora infestans inoculum. After inoculation the plants were kept in darkness at 15°C during 24 hours, and then they were kept in greenhouse chamber at 1 8°C temperature and 95- 100 % relative humidity for disease expression. A visual assessment of compound's performance was carried by rating the disease severity (0- 100% scale) on treated plants on 3, 7, 10 and 1 5 days after application. Efficacy (% control) of the compounds was calculated by comparing the disease rating in the treatment with untreated control. The sprayed plants were also assessed for compound's phytotoxic effects by recording symptoms like necrosis, chlorosis and stunting. Compounds 1 8, 19, 33, 40, 47, 51 , 52, 53, 54, 55, 56, 57, 58, 61 , 62, 64, 65, 66, 67, 68, 72, 73, 74, 84, 85, 88, 89 & 90 at 20ppm gave 90% control in these tests when compared to the untreated check which showed extensive disease development. None of the compounds showed any negative crop response to any of the compounds tested.

Claims

We Claim :
1 . A compound of Formula I,
Figure imgf000117_0001
wherein
T is a fragment of Formula II
Figure imgf000117_0002
wherein, X 1, X2', X3 and X4 are independently C, N, O, 8(0),, C=S, C=0, S=NR6 and S(0)=NRc , and at least one of X1, X2·, X3 and X4 is C=0;
v is an integer ranging from 0 to 3;
p is an integer ranging from 0 to 10;
provided that when v is 1 , then the fragments of Formula II and tautomeric forms thereof having two double bonds inside the ring of Formula II are excluded from the definition of the fragment of Formula II,
A is C(R! 5)2 or C(RI5)2-C(R'5)2 or NR16;
R15 is independently hydrogen, halogen, cyano, hydroxy, -CHO, C1-C4 alkyl, C2- C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C2-C4 haloalkenyl, C2-C4 haloalkynyl, C2-C4 alkoxyalkyl, C2-C4 alkylthioalkyl, C2-C4 alkylsulfinylalkyl, C2-C4 alkylsulfonylalkyl, C2- C4 alkylcarbonyl, C2-C4 haloa!kylcarbonyl, C2-C5 alkoxycarbonyl, C3- C5 alkoxycarbonylalkyi, C2-C5 alkylaminocarbonyl, C3-C5 dialkylaminocarbonyl, C 1- C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylthio, C1-C4 haloalkylthio, C1-C4 alkylsulfinyl, C1-C4 haloalkylsulfinyl, C1-C4 alkylsulfonyl or C1-C4 haloalkylsulfonyl;
Rl6 is hydrogen, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C2-C4 haloalkenyl, C2-C4 haloalkynyl, C2-C4 alkoxyalkyl, C2-C4 alkylthioalkyl, C2- C4 alkylsulfinylalkyl, C2-C4 alkylsulfonylalkyl, C2-C4 alkylcarbonyl, C2-C4 haloalkylcarbony!, C2-C5 alkoxycarbonyl, C3-C5 alkoxycarbonylalkyi, C2-C5 alkylaminocarbonyl, C3-C5 dialkylaminocarbonyl, C1-C4 alkylsulfonyl or C 1-
C4 haloalkylsulfonyl;
W is O or S;
R2 is independently
hydrogen, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 alkoxy, halogen, cyano or hydroxy; or
two R2 are taken together as C1-C4 alkylene or C2-C4 alkenylene to form a bridged bicyclic or fused bicyclic ring system; or
two R2 attached to adjacent ring carbon atoms are taken together as -CH=CH-CH=CH- optionally substituted with 1 to 3 substituents selected from C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, halogen, hydroxy, amino, cyano and nitro;
Z is C or N, "n" is an integer ranging from 0 to 9 with a proviso that when Z is N, "n" is an integer ranging from 0 to 8; and when the presentation
Figure imgf000118_0001
in ring D is a double bond then
"n" is an integer ranging from 0 to 7,
Figure imgf000118_0004
is a single or a double bond;
G is an optionally substituted 5- or 6- membered heteroaromatic ring or 5- or 6-membered saturated or partially saturated or unsaturated heterocyclic ring;
J is a 5-, 6- or 7-membered ring, a 8- to 1 1 -membered bicyclic ring system or a 7- to 1 1 - membered spirocyclic ring system, each ring member of the ring or the ring system is selected from C, N, O, S(0)a, C=0, C=S, and each ring or ring system optionally substituted with 1 to 5 substituents independently selected from R5; or and
Figure imgf000118_0002
wherein W1 is C(R5)2 or CO or O or S or
Figure imgf000118_0003
SO or S02 or NR ;
R is independently hydrogen, halogen, cyano, hydroxy, nitro, -CHO, -C(=0)OH, -C(=0)NH2, - NR25R26, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, cycloalkyl, halocycloalkyi, alkylcycloalkyl, cycloalkylalkyl, cycloalkylcycloalkyl, halocycloalkylalkyl, alkylcycloalkylalkyl, cycloalkenyl, halocycloalkenyl, alkoxyalkyl, cycloalkoxyalkyl, alkoxyalkoxyalkyl, alkylthioalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, alkylaminoalkyl, dialkylaminoalkyl, haloalkylaminoalkyl, cycloalky!aminoalkyl, alkylcarbonyl, haloalkylcarbonyl, cycloalkylcarbonyl, alkoxycarbonyl, cycloalkoxycarbonyl, cycloalkylalkoxycarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, cycloalkylaminocarbonyl, haloalkoxyalkyl, hydroxyalkyl, alkoxy, haloalkoxy, cycloalkoxy, halocycloalkoxy, cycloalkylalkoxy, alkenyl oxy, haloalkenyloxy, alkynyloxy, haloalkynyloxy, aikoxyalkoxy, alkylcarbonyloxy, haloalkylcarbonyloxy, cycloalkylcarbonyloxy, alkylcarbonylalkoxy, alkyltbio, haloalkylthio, cycloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, trialkylsilyl, alkylsul fonylamino, haloalkylsulfonylamino or -Z2Q;
R25 and R26 are independently hydrogen, C1-C6 aIkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, C2-C6 alkylcarbonyl, C2-C6 haloalkylcarbonyl, C2-C6 alkoxycarbonyl, C2- C6 haloalkoxycarbonyl or -Z4Q;
Q is independently phenyl, benzyl, naphthalenyl, a 5- or 6-membered aromatic ring, an 8- to 1 1 -membered aromatic multi-cyclic ring system, an 8- to 1 1 -membered aromatic fused ring system, a 5- or 6-membered heteroaromatic ring, an 8- to 1 1-membered heteroaromatic multi-cyclic ring system or an 8- to 1 1 -membered heteroaromatic fused ring system, each ring member of the ring or the ring system is selected from C, N, O, 8(0).,, C=0, C=S, and SiR l7R 18, and each ring or ring system is optionally substituted with 1 to 8 substituents independently selected from R7 on carbon atom of the rings and R12 on n atom of the rings; or
Q is independently a 3- to 7-membered nonaromatic carbocyclic ring, a 5-, 6- or 7- membered nonaromatic heterocyclic ring, an 8- to 15-membered nonaromatic multi- cyclic ring system or an 8- to 1 5-membered nonaromatic fused ring system, each ring member of the ring or the ring system is selected from C, N, O, S(0)a, C=0, C=S and SiRl7Ri8, and each ring or ring system is optionally substituted with 1 to 8 substituents independently selected from R7 on carbon atom ring members and R12 on n atom ring members; or
J & Q together forms aryl or heterocyclic dioxepine ring system M l and M2
Figure imgf000119_0001
wherein, R5, R7 and R 12 may be attached at one or more possible position/s, x is an integer ranging from 0 to 2 and Y is selected from O, S & N;
R' and R7 are independently hydrogen, halogen, hydroxy, cano, -OR25, -NR25R26, -N02, - SH, -SF5, -SCn, -COR25, -C(=0)OR25, -C(=0)NR25R26, -NR25C(=0)R25, -0(C=0)R25, - 0(C=0)NR25R26, -C(=NOR25)R26, -NR25S02R26, -CSR25, -C(=S)OR25, -C(=S)NR25R26, - NR25C(=S)R26, -0(C=S)R25, -0(C=S)NR25R26, -0(C=S)SR25, -N=C(R25)2, -NHCN, - S02NHCN, -C(=0)NHCN, -C(=S)NHCN, -C(=S(0))NHCN, -S02NR25R , alkyl, alkenyl, alkyny], haloalkyl, haloalkenyl, haloalkynyl, cycloalkyl, halocycloalkyl, alkylcycloalkyl, cycloalkylalkyl, cycloalkylcycloalkyl, halocycloalkylalkyl, alkylcycloalkylalkyl, cycloalkenyl, halocycloalkenyl, alkoxyalkyl, cycloalkoxyalkyl, alkoxyalkoxyalkyl, alkylthioalkyl, alkylsulflnylalkyl, alkylsulfonylalkyl, alkylamino, dialkylamino, alkylaminoalkyl, dialkylaminoalkyl, haloalkylaminoalkyl, cycloalkylamino, cycloalkylaminoalkyl, alkylcarbonyl, haloalkylcarbonyl, cycloalkylcarbonyl, alkoxycarbonyl, cycloalkoxycarbonyl, cycloalkylalkoxycarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, cycloalkylaminocarbonyl, haloalkoxyalkyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, alkoxy, haloalkoxy, cycloalkoxy, halocycloalkoxy, cycloalkylalkoxy, alkenyloxy, haloalkenyloxy, alkynyloxy, haloalkynyloxy, alkoxyalkoxy, alkylcarbonyloxy, haloalkylcarbonyloxy, cycloalkylcarbonyloxy, alkylcarbonyialkoxy, alkylthio, haloalkylthio, cycloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, cycloalkylsulfinyl, trialkylsilyl, alkylsulfonylamino, haloalkylsulfonylamino, alkylcarbonylthio, alkylsulfonyloxy, alkylsulfinyloxy, arylsulfonyloxy, arylsulfinyloxy, arylsulfonyl, arylsulfinyl, cyanoalkyl, a!kenylcarbonyloxy, alkoxyalkylthio, alkylthioalkoxy, haloalkenylcarbonyloxy, alkoxycarbonylalkyl, alkoxyalkynyl, alkynylthio, halocycloalkylcarbonyloxy, alkenylamino, alkynylamino, haloalkylamino, cycloalkylalkylamino, alkoxyamino, haloalkoxyamino, alkylcarbonylamino, haloalkylcarbonylamino, alkoxycarbonylamino, alkylcarbonylalkylamino, haloalkylcarbonylalkylamino, alkoxycarbonylalkylamino, alkenylthio, haloalkoxycarbonyl, alkoxyalkylcarbonyl, haloalkoxycarbonylamino, di(haloalkyl)aminoalkyl, halocycloalkenyloxyalkyl, alkoxy(alkyI)aminocarbonyl, haloalkylsulfonylaminocarbonyl, alkylsulfonylaminocarbonyl, alkoxycarbonylalkoxy, alkylaminothiocarbonylamino, cycloalkylalkylaminoalkyl, alkylthiocarbonyl, cycloalkenyloxyalkyl, alkoxyalkoxycarbonyl, dialkylaminothiocarbonylamino, haloalkoxyhaloalkoxy, alkoxyhaloalkoxy, halocycloalkoxyalkyl, dialkylaminocarbonylamino, alkoxyalkenyl, alkylthiocarbonyloxy, haloalkoxyalkoxy, haloalkylsulfonyloxy, alkoxyhaloalkyl, di(haloalkyl)amino, dialkoxyalkyl, alkylaminocarbonylamino, haloalkoxyhaloalkyl, alkylaminocarbonylalkylamino, trialkylsi lylalkynyloxy, trialkylsily!oxy, trialkylsilylalkynyl, cyano(alkoxy)alkyl, dialkylthioalkyl, alkoxysulfonyl, halocycloalkoxycarbonyl, alkylcycloalky!carbonyl, halocycloalkylcarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, cyanoalkoxycarbonyl, alkylthioalkoxycarbonyl, alkynylcarbonyloxy, haloalkynylcarbonyloxy, cyanocarbonyloxy, cyanoalkylcarbonyloxy, cycloalkylsulphonyloxy, cycloalkylalkylsulphonyloxy, halocycloalkylsuiphonyloxy, alkenylsulphonyloxy, alkynylsulphonyloxy, cyanoalkylsulphonyloxy, haloalkenylsulphonyloxy, haloalkynylsulphonyloxy, alkynylcycloalkyloxy, cyanoalkenyloxy, cyanoalkynyloxy, alkoxycarbonyloxy, alkenyloxycarbonyloxy, alkynyloxycarbonyloxy, alkoxyalkylcarbonyloxy, sulfilimines, sulfoximines, or -Z2Q; or
R12 is hydrogen, -OR25, -COR25, -C(=0)OR25, -C(=0)NR25R26, -C(=NOR25)R26. -CSR25, - C(=S)0R25, -C(=S)NR25R26, -S02NHCN, -C(=0)NHCN, -C(=S)NHCN, - C(=S(0))NHCN, -S02NR25R26, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, cycloalkyl, halocycloalkyl, alkylcycloalkyl, cycloalkylalkyl, cycloalkylcycloalkyl, halocycloalkylalkyl, alkylcycloalkylalkyl, cycloalkenyl, halocycloalkenyl, alkoxyalkyl, cycloalkoxyalkyl, alkoxyalkoxyalkyl, alkylthioalkyl, alkylsulfmylalkyl, alkylsulfonylalkyl, alkylamino, dialkylamino, alkylaminoalkyl, dialkylaminoalkyl, haloalkylaminoalkyl, cycloalkylamino, cycloalkylaminoalkyl, alkylcarbonyl, haloalkylcarbonyl, cycloalkylcarbonyl, alkoxycarbonyl, cycloalkoxycarbonyl, cycloalkylalkoxycarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, cycloalkylaminocarbonyl, haloalkoxyalkyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, alkoxy, haloalkoxy, cycloalkoxy, halocycloalkoxy, cycloalkylalkoxy, alkenyloxy, haloalkenyloxy, alkynyloxy, haloalkynyloxy, alkoxyalkoxy, alkylcarbonyloxy, haloalkylcarbonyloxy, cycloalkylcarbonyloxy, alkylcarbonylalkoxy, alkylthio, haloalkylthio, cycloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, cycloalkylsulfinyl, trialkylsilyl, alkylsulfonylamino, haloalkylsulfonylamino, alkylcarbonylthio, alkylsulfonyloxy, alkylsulfinyloxy, arylsulfonyloxy, arylsulfmyloxy, arylsulfonyl, arylsulfinyl, cyanoalkyl, alkenylcarbonyloxy, alkoxyalkylthio, haloalkenylcarbonyloxy, alkoxycarbonylalkyl, alkoxyalkynyl, alkynylthio, halocycloalkylcarbonyloxy, alkenylamino, alkynylamino, haloalkylamino, cycloalkylalkylamino, alkoxyamino, haloalkoxyamino, alkylcarbonylamino, haloalkylcarbonylamino, alkoxycarbonylamino, alkylcarbonylalkylamino, haloalkylcarbonylalkylamino, alkoxycarbonylalkylamino, alkenylthio, haloalkoxycarbonyl, alkoxyalkylcarbonyl, haloalkoxycarbonylamino, di(haloalkyl)aminoalkyl, halocycloalkenyloxyalkyl, alkoxy(alkyl)aminocarbonyl, haloalkylsulfonylaminocarbonyl, alkylsulfonylaminocarbonyl, alkoxycarbonylalkoxy, alkylaminothiocarbonylamino, cycloalkylalkylaminoalkyl, alkylthiocarbonyl, cycloalkenyloxyalkyl, alkoxyalkoxycarbonyl, dial kylaminothiocarbonylamino, haloalkoxyhaloalkoxy, alkoxyhaloalkoxy, halocycloalkoxyalkyl, dialkylaminocarbonylamino, alkoxyalkenyl, alkylthiocarbonyloxy, haloalkoxyalkoxy, haloalkylsulfonyloxy, alkoxyhaloal kyl, di(haIoalkyl)amino, dialkoxyalkyl, alkylaminocarbonylamino, haloalkoxyhaloalkyl, alkylaminocarbonylalkylamino, trialkylsilylalkynyloxy, trialkylsilyloxy, trialkylsilylalkynyl, cyano(alkoxy)aIkyl, dialkylthioalkyl, alkoxysulfonyl, halocycloalkoxycarbonyl, alkylcycloalkylcarbonyl, halocycloalkylcarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, cyanoalkoxycarbonyl, alkylthioalkylcarbonyl, alkylthioalkoxycarbonyl, alkylaminoalkylcarbonyl, alkynylcarbonyloxy, haloalkynylcarbonyloxy, cyanocarbonyloxy, cyanoalkylcarbonyloxy, cycloalkylsulphonyloxy, cycloalkylalkylsulphonyloxy, halocycloalkylsulphonyloxy, alkenylsulphonyloxy, alkynylsulphonyloxy, cyanoalkylsulphonyloxy, haloalkenylsulphonyloxy, haloalkynylsulphonyloxy, alkynylcycloalkyloxy, cyanoalkenyloxy, cyanoalkynyloxy, alkoxycarbonyloxy, alkenyloxycarbonyloxy, alkynyloxycarbonyloxy, alkoxyalkylcarbonyloxy, sulfilimines, sulfoximines, -SF5 or -Z'Q; or
R17 and R18 are independently C1-C5 alkyl, C2-C5 alkenyl, C2-C5 alkynyl, C3- C5 cycloalkyl, C3-C6 halocycloalkyl, C4-C10 cycloalkylalkyl, C4-C7 alkylcycloalkyl, C5- C7 alkylcycloalkylalkyl, C1-C5 haloalkyl, C1-C5 alkoxy or C1-C5 haloalkoxy; R5 and R7 or R12 taken together with the atoms linking R5 and R7 or R12 to form a saturated, unsaturated or partially unsaturated 4- to 7-membered ring, each ring members selected from C, N, O, S(0)a,C=0, C=S, S=NR12 and S(0)=NR 12, and said ring optionally substituted by R7 on carbon atom ring members and R12 on n atom ring members;
Two R' taken together with the atoms to which they are attached form saturated, unsaturated or partially unsaturated 4- to 7-membered ring containing ring members selected from C, N, O, S(0)a,C=0, C=S, S=NR12 and S(0)=NR12, and said ring optionally substituted by R7 on carbon atom ring members and R12 on n atom ring members;
Z1 and Z2 are independently a direct bond, O, C=0, C=S, S(0)a, CHR20 or NR2' ;
Z4 is independently O, C=0, C=S, S(0)a or CHR20;
R20 is independently H, C1-C4 alkyl or C1-C4 haloalkyl;
R2 ' is independently H, C 1-C8 alkyl, C 1-C8 haloalkyl, C3-C8 cycloalkyl, C2-C6 alkylcarbonyl, C2- C8 haloalkylcarbonyl, C2-C8 alkoxycarbonyl or C2-C8 haloalkoxycarbonyl;
a is independently 0, 1 or 2,
salts, metal complexes, N-oxides, isomers, and polymorphs of the compound of Formula ] .
2. The compound of Formula I as claimed in claim 1 , wherein
at least one of X ', and X4 is C=0, and when v=0 then at least one of X 1 and X3 is C=0,
v is an integer ranging from 0 to 2,
p is an integer ranging from 0 to 8,
R5 is independently H, halogen, cyano, hydroxy, nitro, -CHO, -C(=0)OH, -C(=0)NH2, -NR25R26, C ,- C6 alky 1, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C2-C6 haloalkenyl, C2-C6 haloalkynyl, C3- C8 cycloaikyl, C3-C8 halocycloalkyl, C4-Cl 0 alkylcycloalkyl, C4-C10 cycloalkylalkyl, C6-C u cycloalkylcycloalkyl, C4-C10 halocycloalkylalkyl, C5-C10 alkylcycloalkylalkyl, C3-C8 cycloalkenyl, C3-C8 halocycloalkenyl, C2-C6 alkoxyalkyl, C4-C10 cycloalkoxyalkyl, C3-C8 alkoxyalkoxyalkyl, C2- C6 alkylthioalkyl, C2-C6 alkylsulflnylalkyl, C2-C6 alkylsulfonylalkyl, C2-C6 alkylaminoalkyl, C3-C8 dialkylaminoalkyl, C2-C6 haloalkylaminoalkyl, C4-C10 cycloalkylaminoalkyl, C2-C8 alkylcarbonyl, C2-C6 haloalkylcarbonyl, C4-C8 cycloalkylcarbonyl, C2-C8 alkoxycarbonyl, C4-C8 cycloalkoxycarbonyl, C3-C10 cycloalkylalkoxycarbonyl, C2-C6 alkylaminocarbonyl, C3-C8 dialkylarninocarbonyl, C4-C8 cycloalkylaminocarbonyl, C2-C6 haloalkoxyalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C8 cycloalkoxy, C3-C8 halocycloalkoxy, C4-C10 cycloalkylalkoxy, C2-C6 alkenyloxy, C2-C6 haloalkenyloxy, C2-C6 alkynyloxy, C2-C6 haloalkynyloxy, C2- C6 alkoxyalkoxy, C2-C6 alkylcarbonyloxy, C2-C6 haloalkylcarbonyloxy, C4-C3 cycloalkylcarbonyloxy, C3-C6 alkylcarbonylalkoxy, C1-C6 alkylthio, C1-C6 haloalkylthio, C3- C8 cycloalkylthio, C1-C6 alkylsulfinyl, C1-C6 haloalkylsulfinyl, C1-C6 alkylsulfonyl, C ,- C6 haloalkylsulfonyl, C3-C8 cycloalkylsulfonyl, C3-C10 trialkylsilyl, C1-C6 alkylsulfonylamino and C 1- C6 haloalkylsulfonylamino or -Z2Q;
G is a 5- or 6 membered heteroaromatic ring or 5- or 6- membered saturated or partially saturated heterocyclic ring, each ring optionally substituted with up to 2 substituents in case of 5- membered ring and up to 3 substituents in case of 6- membered ring, each substitiient selected from R3:' on carbon ring members and RUa on n ring members;
R3a is hydrogen or R3; R3 is a phenyl or 5- or 6-membered heteroaromatic ring optionally substituted with 1 to 2 substituents independently selected from R4a on carbon ring members and R',b on n ri ng members; or
R3 is independently C1-C3 alky], C1-C3 haloalkyl or halogen;
R4a is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloaikyl, C4- C 10 cycloalkylalkyl, C4-C10 alkylcycloalkyl, C5-C10 alkylcycloalkylalkyl, C1-C6 haloalkyl, C2- C6 haloalkenyl, C2-C6 haloalkynyl, C3-C6 halocycloalkyl, halogen, hydroxy, amino, cyano, nitro, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylthio, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl, C 1- C4 haloalkylthio, C1-C4 haloalkylsulfinyl, C1-C4 haloalkylsulfonyl, C1-C4 alkylamino, C2-C8 dialkylamino, C3-C6 cycloalkylamino, C2-C4 alkoxyalkyl, C1-C4 hydroxyalkyl, C2-
C4 aikylcarbonyl, C2-C6 alkoxycarbonyl, C2-C6 alkylcarbonyloxy, C2-C6 alkylcarbonylthio, C2-
C6 alkylaminocarbonyl, C3-C8 dialkylaminocarbonyl or C3-C6 trialkylsi lyl;
R4b is independently C1-C6 alkyl, C3-C6 alkenyl, C3-C6 alkynyl, C3-C6 cycloalkyl, C1-C6 haloalkyl,
C3-C6 haloalkenyl, C3-C6 haloaikynyi, C3-C6 haiocycloalkyl or C2-C4 alkoxyalkyl;
R l l a is hydrogen or R" ; R" is independently C ,-C3 alkyl;
R2 is independently C1-C2 alkyl, C1-C2 haloalkyl, C1-C2 alkoxy, halogen, cyano or hydroxy;
R15 is H, halogen, cyano, hydroxy, -CHO, C1-C4 alkyl, C1-C4 haloalkyl or C2-C5 alkoxycarbonyl ;
R16 is H, C1-C4 alkyl, C1-C4 haloalkyl, C2-C4 aikylcarbonyl, C2-C4 haloalkylcarbonyl or C2-
C4 alkoxycarbonyl;
Rs and R7 or R 12 taken together with the atoms linking R5 and R7 or R12 to form a saturated, unsaturated or patially unsaturated substituted 5- to 7-membered ring, each ring members selected from C, N, O, S, C=0, C=S, S(O), S(0)2 and S(0)=NR12, the ring optionally substituted on ring members other than the atoms linking R5 and R7 or R12 with up to 4 substituents selected from R8; R8 is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4- Cio cycloalkylalkyl, C4-C10 alkylcycloalkyl, C5-C10 alkylcycloalkylalkyl, C1-C6 haloalkyl, C2- C6 haloalkenyl, C2-C6 haloaikynyi, C3-C6 haiocycloalkyl, halogen, hydroxy, amino, cyano, nitro, C1- C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylthio, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl, C 1- C4 haloalkylthio, C1-C4 haloalkylsulfmyl, C1-C4 haloalkylsulfonyl, C1-C4 alkylamino, C2-C8 dialkylamino, C3-C6 cycloalkylamino, C2-C4 alkoxyalkyl, C1-C4 hydroxyalkyl, C2-C4 aikylcarbonyl, C2-C6 alkoxycarbonyl, C2-C6 alkylcarbonyloxy, C2-C6 alkylcarbonylthio, C2-C6 alkylaminocarbonyl, C3-C8 dialkylaminocarbonyl or C3-C6 trialkylsilyl;
J is a 5- or 6- membered ring, wherein ring members are selected from carbon, up to 3 N and up to 2 O;
Z1 and Z2 are independently a direct bond, O or C=0; and
Z4 is independently C=0 or S(0)2.
3. The compound as claimed in claim 1 , wherein
T is selected from T l to Tl 1 7,
G is selected from G 1 to G62,
J is selected from J l to J86, and
Q is selected from Q l to Q99.
4. The compound as claimed in claim 1, is at least one selected from the group of:
3-chloro-l -(2-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2- oxoethyl)-5-(trifluoromethyl)pyridin-2(lH)-one; 2-(2-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol- 3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)isoindoline-l,3-dione; 3,4-dichloro-l-(2-(4-(4-(5-(2,6- difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-lH-pyrrole-2,5-dione; l-(2-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yI)-2-oxoethyl)-lH- pyrrole-2,5-dione; 3-chloro-2-(3-(2-( 1 -(2-(5,5-dimethyl- 1 -oxido-4-phenyl- 1 ,2,3-thiadiazol-2(5H)- yl)acetyl)piperidin-4-yl)thiazol-4-yl)-4,5-dihydroisoxazol-5-yl)phenyl methanesulfonate; 3-chloro-2-(3- (2-(l-(2-(3-chloro-2-oxo-5-(tritluoromethyl)pyridin-l(2H)-yl)acetyl)piperidin-4-yl)thiazol-4-yl)-4,5- dihydroisoxazol-5-yl)phenyl methanesulfonate; 3-chloro-l-(2-(4-(4-(5-(2-chlorophenyl)-4,5- dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yI)-2-oxoethyl)-5-(trifluoromethyl)pyndin-2(lH)-one l-(2- (4-(4-(5-(2-chlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-5- (trifluoromethyl)pyridin-2(lH)-one; 5-bromo-l-(2-(4-(4-(5-(2-chlorophenyl)-4,5-dihydroisoxazol-3- yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)pyridin-2(lH)-one; l-(2-oxo-2-(4-(4-(5-phenyl-4,5- dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)ethyl)-5-(trifluoromethyl)pyridin-2(lH)-one; 4-chloro-5- methoxy-2-(2-oxo-2-(4-(4-(5-phenyl-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l- yl)ethyl)pyridazin-3(2H)-one; 5-bromo-l -(2-oxo-2-(4-(4-(5-phenyl-4,5-dihydroisoxazol-3-yl)thiazol-2- yl)piperidin-l-yl)ethyl)pyridin-2(lH)-one; 3-chloro-l -(2-oxo-2-(4-(4-(5-phenyl-4,5-dihydroisoxazol-3- yl)thiazol-2-yl)piperidin-l-yl)ethyl)-5-(trii1uoromethyl)pyridin-2(lH)-one; 5-bromo-l -(2-(4-(4-(5-(2,6- difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)pyridin-2(lH)-one; 1- (2-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-5- (trifluoromethyl)pyridin-2(lH)-one; 4-chloro-2-(2-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3- yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-5-methoxypyridazin-3(2H)-one; 3-chloro-l -(2-(4-(4-(5-(2,6- difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-5-
((trifluoromethyl)thio)pyridin-2(lH)-one; l-(2-oxo-2-(4-(4-(5-(2,4,6-trichlorophenyl)-4,5- dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)ethyl)-5-(trifluoromethyl)pyridin-2(lH)-one; 3-chloro-l- (2-oxo-2-(4-(4-(5-(2,4,6-trichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)ethyl)-5- (trifluoromethyl)pyridin-2(lH)-one; l-(2-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol- 2-yl)piperidin-l-yl)-2-oxoethyl)-4-methylpyridin-2(lH)-one; 5-((dimethyl(oxo)- 6- sulfaneylidene)amino)-l-(2-oxo-2-(4-(4-(5-phenyl-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l- yl)ethy!)pyridin-2(lH)-one; 4-methyl-l -(2-oxo-2-(4-(4-(5-(2,4,6-trichlorophenyl)-4,5-dihydroisoxazol-3- yl)thiazol-2-yl)piperidin- 1 -yl)ethyl)pyridin-2( 1 H)-one; 3-chloro-2-(3-(2-( 1 -(2-(2-oxo-5-
(trifluoromethyl)pyridirvl(2H)-yl)acetyl)piperidin-4-yl)thiazol-4-yl)-4,5-dihydroisoxazol-5-yl) methanesulfonate; 2-(3-(2-(l-(2-(5-bromo-2-oxopyridin-l(2H)-yl)acetyl)piperidin-4-yl)thiazol-4-yl)-4,5- dihydroisoxazol-5-y])-3-chlorophenyl methanesulfonate; 3-chloro-2-(3-(2-(] -(2-(4-methyl-2-oxopyridin- l(2H)-yl)acetyl)piperidin-4-yl)thiazol-4-yl)-4,5-dihydroisoxazol-5-yl)phenyl methanesulfonate; 3-chloro- 2-(3-(2-(l-(2-(5-chloro-2-oxopyridin-l(2H)-yl)acetyl)piperidin-4-yl)thiazol-4-yl)-4,5-dihydroisoxazol-5- yl)phenyl methanesulfonate; 5-chloro-l-(2-(4-(4-(5-(2-chlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2- yl)piperidin-l-yl)-2-oxoethyl)pyridin-2(lH)-one; 1 -(2-(4-(4-(5-(2-chlorophenyl)-4,5-dihydiOisoxazol-3- yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-4-methylpyridin-2(lH)-one; 4-chloro-2-(2-(4-(4-(5-(2- chlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-5-methoxypyridazin- 3(2H)-one; 5-chloro-l-(2-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l- yl)-2-oxoethyl)pyridin-2(lH)-one; l-(2-(4-(4-(5-(2-chlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2- yl)piperidin-l-yi)-2-oxoethyl)quinolin-2(lH)-one; l-(2-oxo-2-(4-(4-(5-(2-(trifluoromethyl)phenyl)-4,5- dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)ethy 3-chloro-l- (2-oxo-2-(4-(4-(5-(2-(trifiuoromethyl)phenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)ethyl)- 5-(trifluoroinethyl)pyridin-2(lH)-one; l-(2-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3- yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)quinolin-2(lH)-one; 3-chloro-l-(2-(4-(4-(5-(2,6- difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-thioxoethyl)-5- (trifluoromethyl)pyridin-2(lH)-one; 3-chloro-l-(2-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3- yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)pyridin-2(lH)-one; 5-chloro-l-(2-oxo-2-(4-(4-(5-phenyl-4,5- dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)ethyl)pyridin-2(lH)-one; 4-methyl-l-(2-oxo-2-(4-(4-(5- phenyl-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)ethyl)pyridin-2(lH)-one; l-(2-(4-(4-(5-(2,6- dichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-5- (trifluoiOmethyl)pyridin-2(lH)-one; 3-chloro-l-(2-(4-(4-(5-(2,6-dichlorophenyl)-4,5-dihydroisoxazol-3- yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-5-(trifluoromethyl)pyridin-2(lH)-one; l-(2-(4-(4-(5-(2,6- diiluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)pyridin-2(lH)-on 3,5- dichloro-l-(2-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2- oxoethyl)pyridin-4(lH)-one; l-(2-oxo-2-(4-(4-(5-phenyl-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin- l-yl)ethyl)azetidin-2-one; l-(2-oxo-2-(4-(4-(5-phenyl-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l- yl)ethyl)pyridin-2(lH)-one; l-(2-oxo-2-(4-(4-(5-phenyl-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-
1- yl)ethyl)pyridin-2(lH)-one; 2-(2-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazoI-2- yl)piperidin-l-yl)-2-oxoethyl)-l -methyl- l,2-dihydro-3H-pyrazol-3-one; 3-chloro-2-(3-(2-(l-(2-(3-chloro-
2- oxo-5-(triinuoromethyl)pyridin-l(2H)-yl)acetyl)-l,2,3,6-tetrahydropyridin-4-yl)thiazol-4-yl)-^ dihydroisoxazol-5-yl)phenyl methanesulfonate; 2-(3-(2-(l-(2-(5-bi mo-2-oxopyridin-l(2H)-yl)acetyl)- 1 ,2,3,6-tetrahydiOpyridin-4-yl)thiazol-4-yl)-4,5-dihydroisoxazol-5-yl)-3-chlorophenyl methanesulfonate; l-methyl-2-(2-oxo-2-(4-(4-(5-(2-(trifluoi methyl)phenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2- yl)piperidin-l-yl)ethyl)-l,2-dihydro-3H-pyrazol-3-one; 2-(2-(4-(4-(5-(2,6-dichlorophenyl)-4,5- dihydroisoxazol-3-yl)thiazol-2-yl)piperidin- l-yl)-2-oxoethyl)-l -methyl- 1 ,2-dihydro-3H-pyrazol-3-one; 3- bromo-l-(2-(4-(4-(5-(2,6-dichlorophenyl)-4,5-dihydroisoxazoI-3-yl)thiazol-2-yl)piperidin-l-yl)-2- oxoethyl)-5-(trifluoromethyl)pyridin-2( 1 H)-one; 1 -(2-(4-(4-(5-(2,6-dichlorophenyl)-4,5-dihydroisoxazol- 3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-3-(trifluoromethyl)pyridin-2(lH)-one; 5-bromo-l-(2-(4-(4- (5-(2,6-dichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yI)piperidin-l-yl)-2-oxoethyl)-3- (trifluoromethyl)pyridin-2(lH)-one; l-(2-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol- 2-yl)piperidin-l-yl)-2-oxoethyl)-3-(tri†luoromethyl)pyridin-2(lH)-one; 5-bromo-l-(2-(4-(4-(5-(2,6- difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yi)piperidin-l-yl)-2-oxoethyl)-3- (trifluoromethyl)pyndin-2(lH)-one; 3-chloro-2-(3-(2-(l-(2-(6-methyl-2-oxo-3-(trifluoromethyl)pyridin- l(2H)-yl)acetyl)piperidin-4-yl)thiazol-4-yl)-4,5-dihydroisoxazol-5-yl)phenyl methanesulfonate; 3-chloro- 2-(3-(2-(l-(2-(6-methyl-2-oxo-3-(trifluoromethyl)pyridin-l(2H)-yl)acetyl)piperidin-4-yl)thiazo]-4-yl)- 4,5-dihydroisoxazol-5-yl)phenyl methanesulfonate; l-(2-(4-(4-(5-(2,6-dichlorophenyl)-4,5- dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-6-methyl-3-(trifluoromethyl)pyridi one; 5-chloro-l-(2-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2- oxoethyl)-6-methyl-3-(trifluoiOmethyl)pyridin-2(lH)-one; 3-chloro-2-(3-(2-(l-(2-(3,5-dibromo-2- oxopyridin-l(2H)-yl)acetyl)piperidin-4-yl)thiazol-4-yl)-4,5-dihydiOisoxazol-5-yl)phenyl
methanesulfonate; 3,5-dibromo-l-(2-(4-(4-(5-(2,6-dichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2- yl)piperidin-l-yl)-2-oxoethyl)pyridin-2(lH)-one; 3,5-dibromo-l-(2-(4-(4-(5-(2,6-difluorophenyl)-4,5- dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)pyridin-2(lH)-one; 3-chloro-2-(3-(2-(l-(2- (2-methyl-5-oxo-2,5-dihydro-lH-pyrazol-l-yl)acetyl)piperidin-4-yl)thiazol-4-yl)-4,5-dihydroisoxazol-5- yl)phenyl methanesulfonate; 3-bromo-l-(2-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3- yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-5-(trifluoromethyl)pyridin-2(lH)-one; 2-(3-(2-(l-(2-(3-bromo-
2- oxo-5-(trifluoromethyl)pyridin-l(2H)-yl)acetyl)piperidin-4-yl)thiazol-4-yl)-4,5-dihyd
3- chlorophenyl methanesulfonate; 5-bromo-3-chloro-l-(2-(4-(4-(5-(2,6-difluorophenyl)-4,5- dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)pyridin-2(lH)-one; 2-(3-(2-(l-(2-(5-bromo-
3- chloro-2-oxo|pyridin-l(2H)-yl)acetyl)pipendin-4-yl)thiazol-4-yl)-4,5-dihydroisoxazol-5-yl)-3- chlorophenyl methanesulfonate; 5-bromo-3-chloro-l-(2-(4-(4-(5-(2,6-dichlorophenyl)-4,5- dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)pyridin-2(lH)-one; 5-(difluoromethy])-2-(2- (4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-l -methyl- l,2-dihydro-3H-pyrazol-3-one; 2-(2-(4-(4-(5-(2,6-dichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2- yl)piperidin-l-yl)-2-oxoethyl)-5-(difluoromethyl)-l -methyl- l,2-dihydro-3H-pyrazol-3-one; 3-chloro-2-(3- (2-(l-(2-(3-(difluoromethyl)-2-methyl-5-oxo-2,5-dihydro-lH-pyrazol-l-yl)acetyl)piperidin-4-yl)thiazol-
4- yl)-4,5-dihydroisoxazol-5-yl)phenyl methanesulfonate; 3-chloro-2-(3-(2-( 1 -(2-(2-oxo-3- (trifluoromethyl)pyridin-l(2H)-yl)acetyl)piperidin-4-yl)thiazo]-4-yl)-4,5-dih
methanesulfonate; 2-(3-(2-(l-(2-(5-bromo-2-oxo-3-(trifluoromethyl)pyridin-l (2H)-yl)acetyl)piperidin-4- yl)thiazol-4-yl)-4,5-dihydroisoxazol-5-yl)-3-chlorophenyl methanesulfonate; 3-chloro-2-(3-(2-(l-(2-(3,5- dichloro-2-oxopyridii>l(2H)-yl)acetyl)piperidin-4-y^
methanesulfonate; 2-(l-(2-(3-chloro-2-oxo-5-(trifluoromethyl)pyridin-l(2H)-yl)acetyl)piperidin-4-yl)-N- (l,2,3,4-tetrahydronaphthalen-l-yl)thiazole-4-carboxamide; 3-chloro-2-(3-(2-(l-(2-(6-methyl-2- oxopyridin-l(2H)-yl)acetyl)piperidin-4-yl)thiazol-4-yl)-4,5-dihydroisoxazol-5-yl)phenyl
methanesulfonate; l-(2-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydiOisoxazol-3-yl)thiazol-2-yl)piperidin-l- yl)-2-oxoethyl)-6-methylpyridin-2(lH)-one; l-(2-(4-(4-(5-(2,6-dichloiOphenyl)-4,5-dihydroisoxazol-3- yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-6-methylpyridin-2(lH)-one; 3-chloro-2-(3-(2-(l-(2-(3-cyano- 2-oxopyridin-l(2H)-yl)acetyl)piperidin-4-yl)thiazol-4-yl)-4,5-dihydroisoxazol-5-yl)phenyl
methanesulfonate; l-(2-(4-(4-(5-(2,6-difluoiOphenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-] - yl)-2-oxoethyl)-2-oxo-l,2-dihydropyridine-3-carbonitrile; l-(2-(4-(4-(5-(2,6-dichlorophenyl)-4,5- dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-2-oxo-l,2-dihydropyridine-3-carbonM 4-bromo-2-(2-(4-(4-(5-(2,6-dichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2- oxoethyl)-5-(difluoromethyl)-l-methyl-l,2-dihydro-3H-pyrazol-3-one; 4-bromo-5-(difluoromethyl)-2-(2- (4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-l -methyl- l,2-dihydro-3H-pyrazol-3-one; 2-(3-(2-(l-(2-(4-bromo-3-(difluoromethyl)-2-methyl-5-oxo-2,5-dihydiO- lH-pyrazol-l-yl)acetyl)piperidin-4-yl)thiazol-4-yl)-4,5-dihydroisoxazol-5-yl)-3-chlorophenyl methanesulfonate; 3,5-dichloro-l-(2-(4-(4-(5-(2,6-dichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2- yl)piperidin-l-yl)-2-oxoethyl)pyridin-2(lH)-one; 3-bromo-5-chloro-l-(2-(4-(4-(5-(2,6-difluorophenyl)- 4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)pyridin-2(lH)-one; l-(2-(4-(4-(5-(2,6- difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-6- (trifluoromethyl)pyridin-2(lH)-one; 3-bromo-5-chloro-l-(2-(4-(4-(5-(2,6-dichlorophenyl)-4,5- dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)pyridin-2(lH)-one; l-(2-(4-(4-(5-(2,6- dichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-6- (trifluoromethyl)pyridin-2(lH)-one; 2-(3-(2-(l-(2-(3-biOmo-5-chloiO-2-oxopyridin-l(2H)-. yl)acetyl)piperidin-4-yl)thiazol-4-yl)-4,5-dihydroisoxazol-5-yi)-3-chlorophenyl methanesulfonate; 3- chloro-2-(3-(2-(l-(2-(2-oxo-6-(trifluoromethyl)pyridin-l(2H)-yl)acetyl)piperidin-4-yl)thiazol-4-y dihydroisoxazol-5-yl)phenyl methanesulfonate; 3-bromo-5-methyl-l-(2-oxo-2-(4-(4-(5-(2,4,6- trichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)ethyl)pyridin-2(lH)-one^ 3-bromo- l-(2-(4-(4-(5-(2,6-dichlorophenyl)-4,5-dihydiOisoxazol-3-yl)thiazol-2-yl)piperidin-l -yl)-2-oxoethy!)-5- methylpyridin-2(lH)-one; l-(2-(4-(4-(5-(2,6-dichlorophenyl)-4,5-dihydiOisoxazol-3-yl)thiazol-2- yl)piperidin-l-yl)-2-oxoethyl)-5-methylpyridin-2(lH)-one; 2-(3-(2-(l-(2-(3-bromo-5-methyl-2- oxopyridin-l(2H)-yI)acetyl)pipendin-4-yl)thiazol-4-y])-4,5-dihydroisoxazol-5-yl)-3-ch methanesulfonate; 5-methyI-l-(2-oxo-2-(4-(4-(5-(2,4,6-trichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol- 2-yl)piperidin-l-yl)ethyl)pyridin-2(lH)-one; 3,5-dichloro-l-(2-(4-(4-(5-(2,6-difluorophenyl)-4,5- dihydroisoxazol-3-y])thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)pyridin-2(lH)-one; l-(2-(4-(4-(5-(2,6- difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-5-methyl-3- (trif1uoromethyl)pyridin-2(lH)-one; 2-(l-(2-(5-bromo-2-oxopyridin-l(2H)-yl)acetyl)piperidin-4-yl)-N- (l,2,3,4-tetrahydronaphthalen-l-yl)thiazole-4-carboxamide; 3-chloro-l-(2-oxo-2-(4-(4-(5-(2,4,6- trichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)ethyl)pyridin-2(lH)-one; l-(2-(4- (4-(5-(2,6-dichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-4- (trifluoromethyl)pyridin-2(lH)-one; l-(2-(4-(4-(5-(2,6-dichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol- 2-yl)piperidin-l-yl)-2-oxoethyI)-5-fluoropyridin-2(lH)-one; l-(2-oxo-2-(4-(4-(5-(2,4,6-trichlorophenyl)- 4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)ethyl)-4-(trifluoromethyl)pyridin-2( 5- fluoro-l-(2-oxo-2-(4-(4-(5-(2,4,6-trichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l- yl)ethyl)pyridin-2(lH)-one; 3-chloro-2-(3-(2-(l-(2-(2-oxo-4-(trifluoromethyl)pyridin-l(2H)- yl)acetyl)piperidin-4-yl)thiazol-4-yl)-4,5-dihydroisoxazol-5-yl)phenyl methanesulfonate; l-(2-oxo-2-(4- (4-(5-(2,4,64richlorophenyl)-4,5-dihydroisoxazol-3-y0
one; 5-bromo-l-(2-oxo-2-(4-(4-(5-(2,4,6-trichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2- yl)piperidin-l-yl)ethyl)pyridin-2(lH)-one; 3-chloro-2-(3-(2-(l-(2-(2-oxopiperidin-l-yl)acetyl)piperidin-4- yl)thiazol-4-yl)-4,5-dihydroisoxazol-5-yl)phenyl methanesulfonate; 3-chloro-2-(3-(2-(l-(2-(2-oxo-3,5- bis(trifluoromethyl)pyridin-l(2H)-yl)acetyl)piperidin-4-yl)thiazol-4-yl)-4,5-dihydroisoxa
methanesulfonate; l-(2-(4-(4-(5-(2,6-dichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l- yl)-2-oxoethyl)piperidin-2-one; l-(2-(4-(4-(5-(2,6-dichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2- yl)pipendin-l-yl)-2-oxoethyl)-3,5-bis(trifluoromethyl)pyridin-2(lH)-one; 6-(difluoromethyl)-l-(2-oxo-2- (4-(4-(5-(2,4,6-trichlorophenyl)-4,5-dihydroisox
one; 3-bromo-l-(2-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2- oxoethyl)-5-methylpyridin-2(lH)-one; l-(2-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3- yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-5-methylpyridin-2(lH)-one; 6-(difluoromethyl)-l-(2-(4-(4-(5- (2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)pyridin-2(lH)-one; l-(2-(4-(4-(5-(2,6-dichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-6- (difluoromethyl)pyridin-2(lH)-one; 3-chloro-2-(3-(2-(l-(2-(6-(difluoromethyl)-2-oxopyridin-l(2H)- yl)acetyl)piperidin-4-yl)thiazol-4-yl)-4,5-dihydroisoxazol-5-yl)phenyl methanesulfonate; 3-chloro-2-(3- (2-( l-(2-(5-methyl-2-oxopyridin-l(2H)-yl)acetyl)piperidin-4-yl)thiazol-4-yl)-4,5-dihydroisoxazol-5- yl)phenyl methanesulfonate; l-(2-oxo-2-(4-(4-(5-(2,4,6-trichlorophenyl)-4,5-dihydroisoxazol-3- yl)thiazol-2-yI)piperidin-l-yl)ethyl)-6-(trifluoromethyl)pyridin-2(lH)-one; 3-bromo-l -(2-oxo-2-(4-(4-(5- (2,4,6-trichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)ethyl)-5- (trifluoromethyl)pyridin-2(lH)-one; 5-chloiO-l-(2-(4-(4-(5-(2,6-dichlorophenyl)-4,5-dihydroisoxazol-3- yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-3-(trifluoromethyl)pyridin-2(lH)-one; 3-chloro-2-(3-(2-(l-(2- (5-fluoro-2-oxopyridin-l(2H)-yl)acetyl)piperidin-4-yl)thiazol-4-yl)-4,5-dihydroisoxazol-5-yl)pheny^ methanesulfonate; ]-(2-(4-(4-(5-(2,6-difluoropheny!)-4,5-dihydroisoxazol-3-y])thiazol-2-y])piperidin-l- yl)-2-oxoethyl)-4-(trifluoromethyl)pyridin-2(lH)-one; l-(2-(4-(4-(5-(2,6-difluorophenyl)-4,5- dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-5-fluoropyridin-2(lH)-one; l-(2-(4-(4-(5- (2,6-dichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)pipendin-l-yl)-2-oxoethyl)-3-methylpyridi 2(lH)-one; l-(2-(4-(4-(5-(2,6-dichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2- oxoethyl)-3,6-bis(tnfluoiOinethyl)pyridin-2(lH)-one; l-(2-(4-(4-(5-(2,6-difluorophenyl)-4,5- dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-3-methylpyridin-2(lH)-one; l-(2-(4-(4-(5- (2,6-difluoiOphenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethy])-3,6- bis(trifluoromethyl)pyridin-2(lH)-one; l-methyl-2-(2-oxo-2-(4-(4-(5-(2,4,6-trichlorophenyl)-4,5- dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)ethyl)-l,2-dihydro-3H-pyrazol-3-one; 3,5-dichloro-l-(2- oxo-2-(4-(4-(5-(2,4,64nchlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)pipendin-l-yl)ethyl^ 2(lH)-one; l-(2-oxo-2-(4-(4-(5-(2,4,64richlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-^ yl)ethyl)-3-(trifluoiOmethyl)pyridin-2(lH)-one; methyl l-(2-(4-(4-(5-(2,6-dichlorophenyl)-4,5- dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-2-oxo-5-(trifluoromethyl)-l,2- dihydropyridine-3-carboxylate; methyl l-(2-(4-(4-(5-(2-chloro-6-((methylsulfonyl)oxy)phenyl)-4,5- dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-2-oxo-5-(trifluoiOmethyl)-l,2- dihydropyridine-3-carboxylate; methyl l-(2-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3- yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-2-oxo-5-(tnfluoromethyl)-l,2-dihydropyridine-3-^
1 -(2-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin- 1 -yl)-2- oxoethyl)piperidin-2-one; 2-oxo-l-(2-oxo-2-(4-(4-(5-(2,4,6-trichlorophenyl)-4,5-dihydroisoxazol-3- yl)thiazol-2-yl)piperidin-l-yl)ethyl)-l,2-dihydropyridine-3-carbonitrile; 6-methyl-l-(2-oxo-2-(4-(4-(5- (2,4,64richlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)ethyl)pyridin-2(lH)-on 1- (2-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydiOisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2- oxoethyl)pyrrolidin-2-one; l-(2-(4-(4-(5-(2,6-dichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2- yl)piperidin-l-yl)-2-oxoethyl)pyrrolidin-2-one; 3-chloro-2-(3-(2-(l-(2-(2-oxopyiTolidin-l- yl)acetyl)piperidin-4-yl)thiazoI-4-yI)-4,5-dihydroisoxazol-5-yl)phenyl methanesulfonate; l-(2-oxo-2-(4- (4-(5-(2,4,64richlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)ethy!)pyrrolidi ]-(2-oxo-2-(4-(4-(5-(2,4,64richloiOphenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-]- yl)ethyl)piperidin-2-one; l-(2-oxo-2-(4-(4-(5-(2,4,6-trichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2- yl)piperidin-l-yl)ethyl)piperidin-2-one; 3-chloro-2-(3-(2-(l-(2-(3-chloro-2-oxopyridin-l(2H)- yl)acetyl)piperidin-4-yl)thiazol-4-yl)-4,5-dihydroisoxazol-5-yl)phenyl methanesulfonate; 5-chloro-l-(2- oxo-2-(4-(4-(5-(2,4,6-trichlorophenyl)-4,5-dihydroisoxazol-3-yI)thiazol-2-yl)piperidin-l-yl)ethyl)pyridin- 2(lH)-one; l-(2-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2- oxoethyl)-3,5-bis(trifluoromethyl)pyridin-2(lH)-one; l-(2-(4-(4-(5-(2,6-dichlorophenyl)-4,5- dihydroisoxazol-3-yl)thiazol-2-yI)piperidin-l-yl)-2-oxoethyl)-5-methyl-3-(trifluoromethyl)pyri one; 2-(l-(2-(3-bromo-2-oxo-5-(trifluoromethyl)pyridin-l(2H)-yl)acetyl)piperidin-4-yl)-N-( 1,2,3,4- tetrahydronaphthaIen-l-yl)thiazole-4-carboxamide; 3-cyclopropyl-l-(2-(4-(4-(5-(2,6-difluorophenyl)-4,5- dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-5-(trifluoromethyl)pyridin-2(lH)-one; l-(2- (4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-3-methy 5-(trifluoromethyl)pyridin-2(lH)-one; 3-cyclopropyl-l-(2-oxo-2-(4-(4-(5-(2,4,6-trichlorophenyl)-4,5- dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)ethyl)-5-(trifluoromethyl)pyridin-2(lH)-one; 3-methyl-
1- (2-oxo-2-(4-(4-(5-(2,4,6-trichlorophenyl)-4,5-dihyd
(trifluoromethyl)pyridin-2(lH)-one; 3-chloro-2-(3-(2-(l-(2-(3-cyclopropyI-2-oxo-5- (trifluoromethyl)pyridin-l(2H)-yl)acetyl)piperidin-4-yl)thiazol-4-yl)-4,5-dihydroisoxazol-5-yl)ph methanesulfonate; 5-bromo-2-oxo- 1 -(2-oxo-2-(4-(4-(5-(2,4,6-trichlorophenyl)-4,5-dihydroisoxazol-3- yl)thiazol-2-yl)piperidin-l-yl)ethyl)-l,2-dihydropyridine-3-carbonitrile; 3-methyl-l-(2-oxo-2-(4-(4-(5- (2,4,6-trichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)ethyl)pyridin-2(lH)-one; 1- (2-oxo-2-(4-(4-(5-(2,4,6-trichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)ethyl)-3,6- bis(trifluoromethyl)pyridin-2(]H)-one; 3-chloro-2-(3-(2-(l-(2-(3-methyl-2-oxopyridin-l(2H)- yl)acetyl)piperidin-4-yI)thiazol-4-yl)-4,5-dihydroisoxazol-5-yl)phenyl methanesulfonate; 3-chloro-2-(3- (2-(l-(2-(2-oxo-3,6-bis(trifluoromethyl)pyridin-l(2H)-yl)acetyl)piperidin-4-yl)thiazol-4-yl)-4,5- dihydroisoxazol-5-yl)phenyl methanesulfonate; 3-bromo-5-chloro-l-(2-oxo-2-(4-(4-(5-(2,4,6- trichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)ethyl)pyridin-2(lH)-one; 5-bromo- 3-methyl-l-(2-oxo-2-(4-(4-(5-(2,4,6-trichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l- yl)ethyl)pyridin-2(lH)-one; 5-bromo-l-(2-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-
2- yl)piperidin-l-yl)-2-oxoethyl)-3-methylpyridin-2(lH)-one; 3-chloro-2-(3-(2-(l-(2-(3-methyl-2-oxo-5- (trifluoromethyl)pyridin-l(2H)-yi)acetyl)piperidin-4-yl)thiazol-4-yl)-4,5-dihydroisoxazol-5-yl)pheny^ methanesulfonate; 3,5-dibromo-l-(2-oxo-2-(4-(4-(5-(2,4,6-trichlorophenyl)-4,5-dihydroisoxazol-3- yl)thiazol-2-yl)piperidin-l-yl)ethyl)pyridin-2(lH)-one; 6-methyl-l-(2-oxo-2-(4-(4-(5-(2,4,6- trichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)ethyl)-3-(trifluoromethyl)pyridi
2(lH)-one; 5-bromo-l-(2-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin- l-yl)-2-oxoethyl)-2-oxo-l,2-dihydropyridine-3-carbonitrile; 5-methyl-l-(2-oxo-2-(4-(4-(5-(2,4,6- tnchlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)ethyl)-3-(trifiuoromethyl)pyridin- 2(lH)-one; 3-chloro-2-(3-(2-(l-(2-(5-methyl-2-oxo-3-(trifluoromethyl)pyridin-l(2H)-yl)acetyl)piperidin- 4- yl)thiazol-4-yl)-4,5-dihydroisoxazol-5-yI)phenyl methanesulfonate; 3-cyclopropyl-l-(2-(4-(4-(5-(2,6- dichloiOphenyl)-4,5-dihydroisoxazol-3-y!)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-5- (trifluoromethyI)pyndin-2(lH)-one; 1 -(2-(4-(4-(5-(2,6-dichlorophenyl)-4,5-dihydroisoxazoI-3-yl)thiazol- 2-yl)pipendin-l-yl)-2-oxoethyl)-3-methyl-5-(tnfluoroiTiethyl)pyridin-2(lH)-one; 5-bromo-l-(2-(4-(4-(5- (2,6-dichlorophenyI)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-3-nitropyn
2(lH)-one; 5-bromo-l-(2-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-
1- yl)-2-oxoethyl)-3-nitropyridin-2(lH)-one; 5-bromo-l-(2-(4-(4-(5-(2,6-dichlorophenyl)-4,5- dihydroisoxazol-3-yl)thiazol-2-yl)pipendin-l-yl)-2-oxoethy])-2-oxo-l,2-dihydropyridine-3-car^^
5- chloro-l-(2-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yI)-2- oxoethyl)-2-oxo-l,2-dihydropyridine-3-carbonitrile; 5-chloro-l-(2-(4-(4-(5-(2,6-dichlorophenyl)-4,5- dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-2-oxo-l,2-dihydropyridine-3-carbonto^ 5-chloro-2-oxo-l-(2-oxo-2-(4-(4-(5-(2,4,6-trichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2- yl)piperidin-l-yl)ethyl)-l,2-dihydropyridine-3-carbonitrile; 3-chloro-2-(3-(2-(l-(2-(5-chloro-3-cyano-2- oxopyridin-](2H)-yl)acetyl)piperidin-4-y])thiazol-4-yl)-4,5-dihydiOisoxazol-5-yl)pheny]
methanesulfonate; 6-(difluoromethyI)-l-(2-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3- yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-3-(trifluoromethyl)pyridin-2(lH)-one; l-(2-(4-(4-(5-(2,6- dichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-6-(difluoiOmethyl)-3- (trifluoromethyl)pyridin-2(lH)-one; 6-(difluoromethyl)-l-(2-oxo-2-(4-(4-(5-(2,4,6-trichlorophenyl)-4,5- dihydroisoxazol-3-yI)thiazol-2-yl)piperidin-l-yl)ethyl)-3-(trifluoromethyl)pyridin-^ 3-chloro-2- (3-(2-(l-(2-(6-(difluoromethy])-2-oxo-3-(trifluoromethyl)pyridin-l(2H)-yl)acetyl)piperidin-^
4-yl)-4,5-dihydroisoxazol-5-yl)phenyl methanesulfonate; 5-bromo-l-(2-(4-(4-(5-(2,6-dichlorophenyl)- 4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-3-methylpyridin-2(lH)-one; 2-(3-(2-(l- (2-(5-bromo-3-methyl-2-oxopyridin-l(2H)-yl)acetyl)piperidin-4-yl)thiazol-4-yl)-4,5-dihydroisoxazol-5- yl)-3-chlorophenyl methanesulfonate; 5-cyclopropyl-l-(2-oxo-2-(4-(4-(5-(2,4,6-trichlorophenyl)-4,5- dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)ethyl)-3-(trifluoromethyl)pyridin-2(lH)-one l-(2-(4-(4- (5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-5-fluoro-3^ (trifluoromethyl)pyridin-2(lH)-one; 3-chloiO-2-(3-(2-(l-(2-(5-fluoro-2-oxo-3-(trifluoromethyl)pyridin- l(2H)-yl)acetyl)piperidin-4-yl)thiazol-4-yl)-4,5-dihydroisoxazol-5-yl)phenyl methanesulfonate; 2-(3-(2- (l-(2-(5-bromo-3-nitro-2-oxopyndin-l(2H)-yl)acetyl)piperidin-4-yl)thiazol-4-yl)-4,5-dihydroi yl)-3-chlorophenyl methanesulfonate; 5-bromo-3-nitro-l -(2-oxo-2-(4-(4-(5-(2,4,6-trichlorophenyl)-4,5- dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)ethyl)pyridin-2(lH)-one; 5-fluoro-l-(2-oxo-2-(4-(4-(5- (2,4,6-trichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)ethyl)-3- (trifluoiOmethyl)pyridin-2(lH)-one; l-(2-(4-(4-(5-(2,6-dichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-
2- yl)piperidii>l-yl)-2-oxoethyl)-5-fluoro-3-(trifluoromethyl)pyridin-2(lH)-one; 3-(difluoromethyl)-l-(2- (4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazo!-2-yl)piperidin-l-yl)-2-oxo
2(lH)-one; l-(2-(4-(4-(5-(2,6-dichloiOphenyI)-4,5-dihydiOisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2- oxoethyl)-3-(dif!uoromethyl)pyridin-2(l H)-one; 3-(diflLioromethy])-l -(2-oxo-2-(4-(4-(5-(2,4,6- trichlorophenyl)-4,5-dihydiOisoxazol-3-yl)thiazoI-2-yl)piperidin- 1 -yl)ethyl)pyridin-2( 1 H)-one; 3-chloro-
2-(3-(2-(l-(2-(3-(difluoromethyl)-2-oxopyridin-l(2H)-yl)acetyI)piperidin-4-yl)thiazol-4-y0
dihydroisoxazol-5-yl)phenyl methanesulfonate; 5-chloro-l-(2-(4-(4-(5-(2,6-difluorophenyl)-4,5- dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-3-(trifluoromethyl)pyridin-2(lH 5- chloro-l-(2-oxo-2-(4-(4-(5-(2,4,64richlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l- yl)ethyl)-3-(tnfluoromethyl)pyridin-2(lH)-one; 3-chloro-2-(3^2-(l-(2-(5-chloro-2-oxo-3-
(trifluoromethyl)pyridin-l(2H)-yl)acetyl)piperidin-4-yl)thiazol-4-yl)-4,5-dihydiOi
methanesulfonate; l-(2-(4-(4-(5-(2,6-dichIoiOphenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l- yl)-2-oxoethyl)-5-nitro-3-(trifluoromethyl)pyridin-2(lH)-one; 3-chIoro-2-(3-(2-(l-(2-(5-nitro-2-oxo-3- (trifluoromethyl)pyridin-l(2H)-yl)acetyl)piperidin-4-yl)thiazoI-4-yl)-4,5-dihydroisox
methanesulfonate; 5-cyclopropyl-l-(2-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2- yl)piperidin-l-yl)-2-oxoethyl)-3-(trifluoromethyl)pyridin-2(lH)-one; 5-cyclopropyl-l-(2-(4-(4-(5-(2,6- dichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-3- (trifluoromethyl)pyridin-2( 1 H)-one; 3-bromo-5-(difluoromethyl)- 1 -(2-(4-(4-(5-(2,6-difluorophenyl)-4,5- dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)pyridin-2(lH)-one; 3-bromo-l-(2-(4-(4-(5- (2,6-dichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-5- (difluoromethyl)pyridin-2(lH)-one; 3-biOmo-5-(diiluoromethyl)-l-(2-oxo-2-(4-(4-(5-(2,4,6- trichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)ethyl)pyridin-2(lH)-one; 5- (difluoromethyl)-l-(2-oxo-2-(4-(4-(5-(2,4,6-trichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2- yl)piperidin-l-yl)ethyl)pyridin-2(lH)-one; l-(2-(4-(4-(5-(4-chlorophenyl)isoxazol-3-yl)thiazol-2- yl)piperidin-l-yl)-2-oxoethyl)-3-(trifluoromethyl)pyndin-2(lH)-one; l-(2-(4-(4-(5-(4- chlorophenyl)isoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-5-(difluoromethyl)pyridin-2(lH)- one; l-(2-(4-(4-(5-(2,6-dichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2- oxoethyl^S-CdifluoromethyOpyridin^ilH^one; 5-(difluoromethyl)-l-(2-(4-(4-(5-(2,6-difluorophenyl)- 4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)pyridin-2(lH)-one; 3-chloro-l-(2-(4-(4- (5-(2-chloro-6-hydroxyphenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-5- (trifluoromethyl)pyridin-2(lH)-one; 3-bromo-l-(2-(4-(4-(5-(2-chloiO-6-hydiOxyphenyl)-4,5- dihydroisoxazol-3-yl)thiazoI-2-yl)piperidin-l-yl)-2-oxoethyI)-5-(trifluoromethyl)pyndin-2(lH)-one; l-(2- (4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-6-oxo-5- (trifluoromethyl)-l,6-dihydropyridine-3-carbonitrile; 5-bromo-l -(2-(4-(4-(5-(2,6-dichlorophenyl)-4,5- dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-6-oxo-l,6-dihydropyridine-3-carbonitrile; 5-bromo-l-(2-(4^4-(5-(2,6-difluorophenyl)-4,5-dihyd
oxoethyl)-6-oxo-l,6-dihydropyridine-3-carbonitrile; 5-chloro-l-(2-(4-(4-(5-(2,6-difluorophenyl)-4,5- dihydroisoxazol-3-yl)thiazol-2-y])piperidin-] -yl)-2-oxoethyl)-6-oxo-l,6-dihydropyridine-3-carbonitrile; 5-chloro-l-(2-(4-(4-(5-(2,6-dichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2- oxoethyl)-6-oxo-l,6-dihydropyridine-3-carbonitrile; 3-chloro-2-(3-(2-(l-(2-(3-chloro-5-cyano-2- oxopyridin-l(2H)-yl)acetyl)piperidin-4-yl)thiazol-4-yl)-4,5-dihydroisoxazol-5-yl)phenyl
methanesulfonate; 3-chloro-l-(2-(4-(4-(5-(2-chloro-6-(prop-2-yn-l-yloxy)phenyl)-4,5-dihydroisoxazol-3- yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-5-(trifluoromethyl)pyridin-2(lH)-one; 3-bromo-l-(2-(4-(4-(5- (2-chloro-6-(prop-2-yn-l-yloxy)phenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2- oxoethyl)-5-(trifluoromethyl)pyridin-2(lH)-one; 3-nitro-l-(2-oxo-2-(4-(4-(5-(2,4,6-trichlorophenyl)-4,5- dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)ethyl)-5-(trifluoromethyl)pyridin-2(lH)-o 5-bromo-3- (difluoromethyl)-l-(2-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperi 2-oxoethyl)pyridin-2(lH)-one; 5-bromo-3-(difluoromethyl)-l-(2-oxo-2-(4-(4-(5-(2,4,6-trichlorophenyl)- 4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)ethyl)pyridin-2(lH)-one; 5-bromo-l-(2-(4-(4-(5- (2,6-dichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-3-
(difluoromethyl)pyridin-2(lH)-one; 2-(3-(2-(l-(2-(3-bromo-5-cyano-2-oxopyndin-l(2H)- yl)acetyl)piperidin-4-yl)thiazol-4-yl)-4,5-dihydroisoxazol-5-yl)-3-chlorophenyi methanesulfonate; 2-(2- (4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-2- azabicyclo[2.2.1]hept-5-en-3-one; 3-bromo-5-isocyano-l-(2-oxo-2-(4-(4-(5-(2,4,6-trichlorophenyl)-4,5- dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)ethyl)pyridin-2(lH)-one; 3-chloro-5-isocyano-l-(2-oxo- 2-(4-(4-(5-(2,4,6 richlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)ethyl)pyridin- 2( 1 H)-one; 2-(3-(2-( 1 -(2-(5-bromo-3-(difluoromethy l)-2-oxopyridin- 1 (2H)-y l)acetyl)piperidin-4- yl)thiazol-4-yl)-4,5-dihydroisoxazol-5-yl)-3-chlorophenyl methanesulfonate; 3-chloro-2-(3-(2-(l-(2-(5- (difluoromethyl)-2-oxopyridin-l(2H)-yl)acetyl)piperidin-4-yl)thiazol-4-yl)-4,5-dihydroisoxazol-5- yl)phenyl methanesulfonate; 1 -(2-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2- yl)piperidin-l-yl)-2-oxoethyl)-3-nitro-5-(trifluoromethyl)pyridin-2(lH)-one; 3-chloro-2-(3-(2-(l-(2-(3- nitro-2-oxo-5-(trifluoromethyl)pyridin-l(2H)-yl)acetyl)piperidin-4-yl)thiazol-4-yl)-4,5-di
5-yl)phenyl methanesulfonate; l-(2-(4-(4-(5-(2,6-dichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2- yl)piperidin-l-yl)-2-oxoethyl)-3-nitro-5-(trifluoromethyl)pyridin-2(lH)-one; 5-nitro-l-(2-oxo-2-(4-(4-(5- (2,4,6-trichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)ethyl)-3-
(trifluoromethyl)pyridin-2(lH)-one; l-(2-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol- 2-yI)piperidin-l-yI)-2-oxoethyI)-5-nitro-3-(trifluoromethy[)pyridin-2(IH)-one; 2-(2-(4-(4-(5-(2,6- difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-l-methyl-5- (trifluoromethyl)-l,2-dihydro-3H-pyrazol-3-one; l-(2-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol- 3- yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-2-oxo
carbonitrile; l-(2-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2- oxoethyl)azepan-2-one; l-(2-(4-(4-(5-(2,6-dichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazoI-2- yl)piperidin-l-yl)-2-oxoethyl)azepan-2-one; l-(2-oxo-2-(4-(4-(5-(2,4,6-trichlorophenyl)-4,5- dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)ethyl)azepan-2-one; 3-chloro-2-(3-(2-(l-(2-(2- oxoazepan-l-yl)acetyl)piperidin-4-yl)thiazol-4-y])-4,5-dihydroisoxazol-5-yl)phenyl methanesulfonate; 3- chloro-2-(3-(2-( 1 -(2-(3-isocyano-2-oxo-5-(trifluoro
4- yl)-4,5-dihydroisoxazol-5-yl)phenyl methanesulfonate; 3-bromo-l-(2-(4-(4-(5-mesityl-4,5- dihydroisoxazol-3-yI)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-5-(trifluoromethyl)pyridi 3- bromo-l-(2-oxo-2-(4-(4-(5-(3-(trifluoromethyl)phenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin^ yl)ethyl)-5-(trifluoromethyl)pyridin-2(lH)-one; 3-bromo-l-(2-(4-(4-(5-(4-(tert-butyl)phenyl)-4,5- dihydroisoxazoi-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-5-(tnfluoromethyl)pyridi l-(2- (4-(4-(5-(4-(tert-butyl)phenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-y])piperidin-l-yl)-2-oxoethyl)-3- (trifluoromethyl)pyridin-2(lH)-one; l-(2-(4-(4-(5-mesityl-4,5-dihydroisoxazol-3-yl)thiazol-2- yl)piperidin-l-yl)-2-oxoethyl)-3-(tnfluoromethyl)pyridin-2(lH)-one; l-(2-oxo-2-(4-(4-(5-(3- (trifluoromethyl)phenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)ethyl)-3- (trifluoiOmethyl)pyridin-2(lH)-one; 3-chloro-l-(2-(4-(4-(5-mesityl-4,5-dihydroisoxazol-3-yl)thiazol-2- yl)piperidin-l-yl)-2-oxoethyl)-5-(trifluoromethyl)pyridin-2(lH)-one; l-(2-(4-(4-(5-(4-(tert-butyl)phenyl)- 4,5-dihydroisoxazol-3-y])thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-3-chloro-5-(trifluoromethyl)p^ 2(lH)-one; 3-chloro-l-(2-oxo-2-(4-(4-(5-(3-(trifluoromethyl)phenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2- yl)piperidin- 1 -yl)ethyl)-5-(trifluoromethyl)pyridin-2( l H)-one; 2-oxo- 1 -(2-oxo-2-(4-(4-(5-(2,4,6- trichlorophenyl)-4,5-dihydiOisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)ethyl)-5-(trifl
dihydropyridine-3-carbonitrile; l-(2-(4-(4-(5-(2,6-dichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2- yl)piperidin-l-yl)-2-oxoethyl)-3-isocyano-5-(trifluoromethyl)pyridin-2(lH)-one; I -(2-(4-(4-( l ,5- dihydrobenzo[e][l,3]dioxepin-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-3-(tnfluoromethyr
2(lH)-one; l-(2-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yI)-2- oxoethyl)-2,5-dimethyl- 1 ,2-dihydro-3H-pyrazol-3-one; l -(2-(4-(4-( l ,5-dihydrobenzo[e][ l ,3]dioxepin-3- yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-5-(trifluoromethyl)pyridin-2(lH)-one; 6-methyl-l-(2-oxo-2- (4-(4-(5-(3-(trifluoromethyl)phenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)ethyl)-3- (triiluoromethyl)pyridin-2(lH)-one; l-(2-(4-(4-(5-mesityl-4,5-dihydroisoxazol-3-yl)thiazol-2- yI)piperidin-l-yl)-2-oxoethyl)-5-(trifluoromethyl)pyridin-2(lH)-one; l-(2-oxo-2-(4-(4-(3-phenyI-4,8- dihydro-[l3]dioxepino[5,6-d]isoxazol-6-yl)thiazol-2-yl)piperidin-l-yl)ethyl)-5-(trifluoromethyl)^^ 2(lH)-one; l-(2-oxo-2-(4-(4-(5-(3-(trifluoromethyl)phenyl)-4,5-dihydroisoxazol-3-y])thiazol-2- y])piperidin-l-yl)ethyl)-5-(trifluoromethyl)pyridin-2(lH)-one; l-(2-(4-(4-(5-(4-(tei1-butyl)phenyl)-4,5- dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-5-(trifliuoromethyl)pyri l-(2- (4-(4-(5-(4-(tert-butyl)phenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyI)-6- methyl-3-(trifluoromethyl)pyridin-2(lH)-one; l-(2-(4-(4-(5-mesityl-4,5-dihydroisoxazoI-3-yl)thiazol-2- yl)piperidin-l-yl)-2-oxoethyl)-6-methyl-3-(trifluoromethyl)pyridin-2(lH)-one; l-(2-(4-(4-(5-(2,6- dichloropheny!)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-2,5-dimethyl-l,2- dihydro-3H-pyrazol-3-one; 5-chloro-l-(2-oxo-2-(4-(4-(5-(3-(trifluoromethyl)phenyl)-4,5- dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)ethyl)-3-(trilluoromethyl)pyridin-2(lH)-one; 5-chloro-l- (2-(4-(4-(5-mesityl-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-3- (trifluoromethyl)pyridin-2(lH)-one; 3-(2-(l-(2-(5-ch]oro-2-oxo-3-(trifluoromethy])pyridin-l(2H)- yl)acetyl)piperidin-4-yl)thiazol-4-yl)-4,5-dihydroisoxazole-5-carboxamide; l-(2-(4-(4-(5-(2- chlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-3- (trifluoromethyl)pyridin-2(lH)-one; l-(2-(4-(4-(5-(2-chlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2- yl)piperidin-l-yl)-2-oxoethyl)-6-methyl-3-(trifluoromethyl)pyridin-2(lH)-one; 3-bromo-l-(2-(4-(4-(5-(2- chlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-5- (trifluoromethyl)pyridin-2(lH)-one; l-(2-oxo-2-(4-(4-(5-(2-(trifluoromethyl)phenyl)-4,5-dihydroisoxazol- 3-yl)thiazol-2-yl)piperidin-l-yl)ethyl)-3-(trifluoromethyl)pyridin-2(lH)-one; 6-methyl-l-(2-oxo-2-(4-(4- (5-(2-(trifluoromethy])phenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-y])ethyl)-3- (trifluoromethyl)pyridin-2(lH)-one; 3-bromo-l-(2-oxo-2-(4-(4-(5-(2-(trifluoromethyl)phenyi)-4,5- dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)ethyl)-5-(trifluoromethyl)pyridin-2(lH)-one; ethyl 3-(2- (l-(2-(2-oxo-5-(trifluoromethyl)pyridin-l(2H)-yl)acetyl)piperidin-4-yl)thiazol-4-yl)-4,5- dihydroisoxazole-5-carboxylate; ethyl 3-(2-(l-(2-(2-oxo-3-(trifluoromethyl)pyridin-l(2H)- yl)acetyl)piperidin-4-yl)thiazol-4-yl)-4,5-dihydroisoxazole-5-carboxyIate; methyl 3-(2-(l-(2-(2-oxo-3- (trifluoromethyl)pyridin-l(2H)-yl)acetyl)piperidin-4-yl)thiazol-4-yl)-4,5-dihydroisoxazo
l-(2-oxo-2-(4-(4-(5-(3,4,54rifluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)e^ (trifluoromethyl)pyridin-2(lH)-one; 3-(2-(l-(2-(2-oxo-3-(trifluoromethyl)pyridin-l(2H)- yl)acetyl)piperidin-4-yl)thiazol-4-yl)-4,5-dihydroisoxazole-5-carboxamide; 6-methyl-l-(2-oxo-2-(4-(4-(5- (3,4,5-trifluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)ethyl)-3- (trifluoromethyl)pyridin-2(lH)-one; l-(2-oxo-2-(4-(4-(5-(3,4,5-trifluorophenyl)-4,5-dihydroisoxazol-3- yl)thiazol-2-yl)piperidin-l-yl)ethyl)-5-(trif]uoromethyl)pyridin-2(lH)-one; 3-bromo-l-(2-oxo-2-(4-(4-(5- (3,4,5-trifluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)ethyl)-5- (trifluoromethyl)pyridin-2(lH)-one; 3-(2-(l-(2-(2-oxo-5-(trifluoromethyl)pyridin-l(2H)- yl)acetyl)piperidin-4-yl)thiazol-4-yl)-4,5-dihydroisoxazole-5-carboxamide; l-(2-oxo-2-(4-(4-(5-(o-tolyl)- 4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)ethyl)-3-(trifluoromethyl)pyridin-2(lH)-one; 6- methyl-l-(2-oxo-2-(4-(4-(5-(o-tolyl)-4,5-dihydiOisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)ethyl)-3- (trifluoromethyl)pyridin-2( 1 H)-one; 1 -(2-oxo-2-(4-(4-(5-(o-tolyl)-4,5-dihydroisoxazol-3-yl)thiazol-2- yl)piperidin-l-yI)ethyl)-5-(trifluoromethyl)pyridin-2(lH)-one; 3-bromo-l-(2-oxo-2-(4-(4-(5-(o-tolyl)-4,5- dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)ethyl)-5-(trifluoromethyl)pyridin-2(lH)-one; 1-(2-(4-(4- (5-(2,5-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-3- (trifluoromethyl)pyridin-2(lH)-one ; l-(2-(4-(4-(5-(2,5-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol- 2-yl)piperidin-l-yl)-2-oxoethyl)-6-methyl-3-(trifluoromethyl)pyridin-2(lH)-one; l-(2-(4-(4-(5-(2,5- difluorophenyl)-4,5-dihydroisoxazoI-3-yI)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-5- (trifluoromethyl)pyridin-2(lH)-one; 3-bromo-l-(2-(4-(4-(5-(2,5-difluorophenyl)-4,5-dihydroisoxazol-3- yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-5-(trifluoromethyl)pyridin-2(lH)-one; l-(2-(4-(4-(5-(2- fluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-3-
(trifluoromethyl)pyridin-2(lH)-one; l-(2-(4-(4-(5-(2-fluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2- yl)piperidin-l-yl)-2-oxoethyl)-5-(trifluoromethyl)pyridin-2(lH)-one; 3-bromo-l-(2-(4-(4-(5-(2- fluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-5-
(trifluoromethyl)pyridin-2(lH)-one; l-(2-(4-(4-(5-(2-fluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2- yl)piperidin-l-yl)-2-oxoethyI)-6-methyl-3-(trifluoromethyl)pyridin-2(lH)-one; l-(2-(4-(4-(5-(4- methoxyphenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-3- (triiluoromethyl)pyridin-2( 1 H)-one; 1 -(2-(4-(4-(5-(4-methoxyphenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2- yl)piperidin-l-yl)-2-oxoethyl)-5-(tnfluoromethyl)pyridin-2(lH)-one; 3-bromo-l-(2-(4-(4-(5-(4- methoxyphenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-5- (trifluoromethyl)pyridin-2(lH)-one; l-(2-(4-(4-(5-(4-methoxyphenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2- yl)piperidin-l-yl)-2-oxoethyl)-6-methyI-3-(trifluoromethyl)pyridin-2(lH)-one; l-(2-(4-(4-(5-(2-chloro-6- (trifluoromethyI)phenyl)-4,5-dihydiOisoxazol-3-yt)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-3- (trifluoromethyl)pyridin-2(lH)-one; l-(2-(4-(4-(5-(2-chloro-6-(trifluoromethyl)phenyl)-4,5- dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-6-methyl-3-(trifluoromethyl)pyridi one; 5-chloro- 1 -(2-(4-(4-(5-(2-chloro-6-(trifluoromethyl)phenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2- yl)piperidin-l-y])-2-oxoethyl)-3-(trifluoromethyl)pyridin-2(lH)-one; l-(2-(4-(4-(5-(2-chloro-6- (trifluoromethyl)phenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)pjperidin-l-yl)-2-oxoethyl)-5- (trifluoromethyl)pyridin-2(lH)-one; 3-chloro-l-(2-(4-(4-(5-(2-chloro-6-(trifluoromethyl)phenyl)-4,5- dihydroisoxazol-3-y])thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-5-(trifluoromethyl)pyridin-2(]H)- 3- bromo-l-(2-(4-(4-(5-(2-chloro-6-(trifluoromethyl)pheny])-4,5-dihydroisoxazol-3-yl)thiazol-2- yl)piperidin-l-yl)-2-oxoethyI)-5-(trifluoromethyl)pyridin-2(lH)-one; l-(2-(4-(4-(5-(2-bromo-6- fluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-3- (trifluoromethyl)pyridin-2(l H)-one; ] -(2-(4-(4-(5-(2-bromo-6-fluorophenyl)-4,5-dihydroisoxazol-3- yl)thiazo]-2-yl)piperidin-l-yl)-2-oxoethyl)-6-methyl-3-(trifluoromethyl)pyridin-2(lH)-one; l-(2-(4-(4-(5- (2-bromo-6-fluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-5-chloro-3- (trifluoromethyl)pyridin-2(l H)-one; l-(2-(4-(4-(5-(2-bromo-6-fluorophenyl)-4,5-dihydroisoxazol-3- yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-5-(trifluoromethyl)pyridin-2(lH)-one; l-(2-(4-(4-(5-(2-bromo- 6-fluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-3-chloro-5- (trifluoromethyl)pyridin-2(lH)-one; 3-bromo-]-(2-(4-(4-(5-(2-bromo-6-fluorophenyl)-4,5- dihydroisoxazol-3-yl)thiazol-2-yI)pipendin-l-y])-2-oxoethyl)-5-(trifluoromethyl)pyridin l-(2- (4-(4-(5-(2,6-dimethoxyphenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-3- (trifluoromethyl)pyridin-2(lH)-one; l-(2-(4-(4-(5-(2,6-dimethoxyphenyl)-4,5-dihydroisoxazol-3- yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-6-methyl-3-(trifluoromethyl)pyridin-2(lH 5-chloro-l -(2- (4-(4-(5-(2,6-dimethoxyphenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-3-
(trifluoromethyl)pyridin-2(lH)-one; 3-chloro-l-(2-oxo-2-(4-(4-(5-(3,4,5-trifluorophenyl)-4,5- dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)ethyl)-5-(trifluoromethyl)pyridin-2(lH)-one; 5-chloro-l - (2-oxo-2-(4-(4-(5-(3,4,5-trifluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)ethy0^ (trifluoromethyl)pyndin-2(lH)-one; l-(2-(4-(4-(5-(3,4-dichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol- 2-yl)piperidin-l-yl)-2-oxoethyl)-5-(trifluoromethyl)pyridin-2(lH)-one; l-(2-(4-(4-(5-(3,4- dichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-3- (trifluoromethyl)pyridin-2(lH)-one; 3-chloro-l-(2-(4-(4-(5-(3,4-dichlorophenyl)-4,5-dihydroisoxazol-3- yl)thiazol-2-y])piperidin-l-yl)-2-oxoethyl)-5-(trifluoromethyl)pyridin-2(lH)-one; 5-chloro-l -(2-(4-(4-(5- (3,4-dichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-3- (trifluoiOmethyl)pyridin-2(lH)-one; 3-bromo-l-(2-(4-(4-(5-(3,4-dichlorophenyl)-4,5-dihydroisoxazol-3- yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-5-(trifluoromethyl)pyridin-2(lH)-one; 2-(3-(2-(l-(2-(2-oxo-5- (trifluoromethyl)pyridin-l(2H)-yl)acetyl)piperidin-4-yl)thiazol-4-yl)-4,5-dihydroisoxazol-5- yl)benzonitrile; 2-(3-(2-(l-(2-(2-oxo-3-(trifluoromethyl)pyridin-l(2H)-yl)acetyl)piperidin-4-yl)thiazol-4- yl)-4,5-dihydroisoxazol-5-yl)benzonitrile; l-(2-oxo-2-(4-(4-(5-(5-(trifluoromethyl)pyridin-2-yl)-4,5- dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)ethyl)-3-(trifluoromethyl)pyridin-2(lH)-one; l-(2-oxo-2- (4-(4-(5-(5-(trifluoromethyl)pyridin-2-yl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)ethy0 (trifluoromethyl)pyridin-2(lH)-one; 3-bromo-l-(2-oxo-2-(4-(4-(5-(5-(trifluoromethyl)pyridin-2-yl)-4,5- dihydroisoxazol-3-yl)thiazoI-2-yl)piperidin-l-yl)ethyl)-5-(trifluoromethyl)pyridin-2(lH)-one; 6-methyl-
1- (2-oxo-2-(4-(4-(5-(5-(trifluoromethy!)pyridin-2-yl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperi yl)ethyl)-3-(trifluoiOmethyl)pyridin-2(lH)-one; 5-chloro-l-(2-oxo-2-(4-(4-(5-(5-(trifluoromethyl)pyridin-
2- yl)-4,5-dihydroisoxazol-3-yl)thiazol-2-y])piperidin-l-yl)ethyl)-3-(trifluoromethyl)pyridi 1- (2-(4-(4-(5-(2-chloro-6-fluorophenyl)-4,5-dihydiOisoxazol-3-yl)thiazoI-2-yl)piperidin-l-yl)-2-oxoethyl)-
3- (trifluoromethyl)pyridin-2(lH)-one; l-(2-(4-(4-(5-(2-chloro-6-fluorophenyl)-4,5-dihydroisoxazol-3- yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-5-(trifluoromethyl)pyridin-2(lH)-one; 3-bromo-l-(2-(4-(4-(5- (2-chloiO-6-fluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)pipendin-l -yl)-2-oxoethyl)-5- (trifluoromethyl)pyridin-2(lH)-one; l-(2-(4-(4-(5-(2-chloiO-6-fluorophenyl)-4,5-dihydroisoxazol-3- yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-6-methyl-3-(trifluoromethyl)pyridin-2(lH)-on^ 5-chloro-l-(2- (4-(4-(5-(2-chloro-6-fluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-3- (trifluoromethyl)pyridin-2(lH)-one; 5-chloro-l-(2-(4-(4-(5-(2,6-dimethoxyphenyl)-4,5-dihydroisoxazol- 3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-3-(trifluoromethyl)pyridin-2(lH)-one; 6-methyl-l-(2-oxo-2- (4-(4-(5-(2,3,5-trichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazoI-2-yl)piperidin-l-yI)ethyl)-3- (trifluoiOmethyl)pyridin-2(lH)-one; 5-chloro-l-(2-oxo-2-(4-(4-(5-(2,3,5-trichlorophenyl)-4,5- dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)ethyl)-3-(trifluoromethyl)pyridin-2( l-(2-oxo-2- (4-(4-(5-(2,3,54richlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)ethyl)-5- (trifluoromethyl)pyridin-2(lH)-one; 3-chloro-l-(2-oxo-2-(4-(4-(5-(2,3,5-trichlorophenyl)-4,5- dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)ethyl)-5-(trifluoromethyl)pyridin-2(lH)-on 3-bromo-l- (2-oxo-2-(4-(4-(5-(23,5-trichlorophenyl)-4,5-d^
(trifluoromethyl)pyridin-2(lH)-one; l-(2-(4-(4-(5-(3-(difluoromethyl)-l -methyl- 1 H-pyrazol-4-yl)-4,5- dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-3-(trifluoromethyl)pyridin-2(lH)-one; 5- chloro- l-(2-(4-(4-(5-(3-(difluoromethyl)-l -methyl- 1 H-pyrazoI-4-yl)-4,5-dihydroisoxazol-3-yl)thiazol-2- yl)piperidin-l-yl)-2-oxoethyl)-3-(trifluoromethyl)pyridin-2(lH)-one; l-(2-(4-(4-(5-(3-(difluoromethyl)-l- methyl-lH-pyrazol-4-yl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-5- (trifluoromethyl)pyridin-2(lH)-one; 3-chloro-l-(2-(4-(4-(5-(3-(difluoromethyl)-l-methyl-lH-pyrazol-4- yl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l^
one; 3-bromo-l-(2-(4-(4-(5-(3-(difluoromethyl)-l -methyl- 1 H-pyrazol-4-yl)-4,5-dihydroisoxazol-3- yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-5-(trifluoromethyl)pyridin-2(lH)-one; l-(2-(4-(4-(5-(3- (difluoromethyl)-l-methyl-lH-pyrazol-4-yl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2- oxoethyl)-2-oxo-5-(trifluoromethyl)-l,2-dihydropyridine-3-carbonitrile; l-(2-(4-(4-(5-(2,6- dimethoxyphenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-5- (trifluoromethyl)pyridin-2(lH)-one; 3-chloro-l-(2-(4-(4-(5-(2,6-dimethoxyphenyl)-4,5-dihydroisoxazol- 3-yl}thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-5-(trii1uoromethyl)pyridin-2(lH)-one; 3-bromo-l-(2-(4-(4- (5-(2,6-dimethoxyphenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-5- (trif!uoromethyl)pyridin-2(lH)-one; 2-(3-(2-(l-(2-(3-chloro-2-oxo-5-(trifluoromethyl)pyridin-l(2H)- yl)acetyl)piperidin-4-yl)thiazol-4-yl)-4,5-dihydroisoxazol-5-yl)benzonitrile; 2-(3-(2-(l-(2-(5-chloro-2- oxo-3-(trifluoiOmethyl)pyridin-l(2H)-yl)acetyl)piperidin-4-yl)thiazol-4-yl)-4,5-dihydroisoxazol-5- yl)benzonitrile; 2-(3-(2-(l-(2-(3-bromo-2-oxo-5-(trifluoromethyl)pyridin-l(2H)-yl)acetyl)piperidin-4- yl)thiazol-4-yl)-4,5-dihydroisoxazol-5-yl)benzonitrile; l-(2-(4-(4-(5-(2,6-dimethylphenyl)-4,5- dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-5-(trifluoromethyl)pyiMdin-2(lH)-one; l-(2- (4-(4-(5-(2,6-dimethylphenyl)-4,5-dihydro
(trifluoromethyl)pyridin-2(lH)-one; 3-chloro-l-(2-(4-(4-(5-(2,6-dimethylphenyl)-4,5-dihydroisoxazol-3- yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-5-(trifluoromethyl)pyridin-2(lH)-one; 5-chIoro-l-(2-(4-(4-(5- (2,6-dimethylphenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-3- (trifluoromethyl)pyridin-2(lH)-one; 3-bromo-l-(2-(4-(4-(5-(2,6-dimethylphenyl)-4,5-dihydroisoxazol-3- yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-5-(trifluoromethyl)pyridin-2(lH)-one; l-(2-(4-(4-(5-(2,6- dimethylphenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yI)piperidin-l-yl)-2-oxoethyI)-6-methyl-3- (trifluoromethyl)pyridin-2(lH)-one; 5-chloro-l-(2-oxo-2-(4-(4-(5-(o-tolyl)-4,5-dihydroisoxazol-3- yl)thiazol-2-yl)piperidin-l-yl)ethyl)-3-(trifluoromethyl)pyridin-2(]H)-one; 3-chloro-l-(2-oxo-2-(4-(4-(5- (o olyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)ethyl)-5-(trifluoromethyl)pyridin-2(lH)- one; 2-oxo-l-(2-oxo-2-(4-(4-(5-(o-tolyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)ethyl)-5- (trifluoromethyl)-l,2-dihydropyridine-3-carbonitrile; 5-chIoro-l-(2-(4-(4-(5-(2,5-difluorophenyl)-4,5- dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-3-(trifluoi methyI)pyridin-2(lH)-one; 3- chloro-l-(2-(4-(4-(5-(2,5-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yI)piperidin-l-yl)-2- oxoethyl)-5-(trifluoromethyl)pyridin-2(lH)-one; ]-(2-(4-(4-(5-(2,5-difluoiOphenyl)-4,5-dihydroisoxazol- 3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-3-isocyano-5-(trifluoromethyl)pyridin-2(lH)-one; 3-bromo- l-(2-(4-(4-(l,5-dihydrobenzo[e][l,3]dioxepin-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-5- (trifluoromethyl)pyridin-2(lH)-one; l-(2-(4-(4-(l,5-dihydrobenzo[e][l,3]dioxepin-3-yl)thiazol-2- yl)piperidin- 1 -yl)-2-oxoethyl)-6-methyl-3-(trifluoromethyl)pyridin-2( 1 H)-one; 1 -(2-(4-(4-(l ,5- dihydrobenzo[e][l,3]dioxepin-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-2-oxo-5-(trifluorom l,2-dihydropyridine-3-carbonitrile; 3-chloro-l-(2-(4-(4-(l,5-dihydrobenzo[e][l,3]dioxepin-3-yl)thiazol-2- yl)piperidin-l-yl)-2-oxoethyl)-5-(trifluoromethyl)pyridin-2(lH)-one; l-(2-(4-(4-(5-(2-bromo-5- fluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-6-methyl-3- (trifluoromethyl)pyridin-2(lH)-one; l-(2-(4-(4-(5-(2-bromo-5-fluorophenyl)-4,5-dihydroisoxazol-3- yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-3-chloro-5-(trifluoromethyI)pyridin-2(lH)-one; 3-bromo-l-(2- (4-(4-(5-(2-chloro-5-(tnfluoromethyl)phenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperi
oxoethyl)-5-(trifluoromethyl)pyridin-2(lH)-one; 5-chloro-l-(2-(4-(4-(5-(2-chloro-5- (trifluoromethyl)phenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-3- (trifluoromethyl)pyridin-2(lH)-one; 3-chloro-l-(2-(4-(4-(5-(2-chloro-5-(trifluoromethyl)phenyl)-4,5- dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-5-(trifluoiOmethyl)pyridin-2(lH l-(2- (4-(4-(5-(2-chloro-6-(prop-2-yn-l-yloxy)phenyl)-4,5-dihydroisoxazol-3-yI)thiazol-2-yl)piperidin-l-yl)-2- oxoethyl)-3-(trifluoromethyl)pyridin-2(lH)-one; l-(2-(4-(4-(5-(2-chloro-6-(prop-2-yn-l-yloxy)phenyl)- 4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-5-(tni1uoromethyl)pyridin-2(lH l-(2-(4-(4-(5-(2-chloro-6-(prop-2-yn-l-yloxy)phenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l- yl)-2-oxoethyl)-6-methyl-3-(trifluoromethyl)pyridin-2(lH)-one; l-(2-(4-(4-(5-(2-chloro-6-(prop-2-yn-l- yloxy)phenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yI)piperidin-l-yl)-2-oxoethyl)-2-oxo-5-
(tri†luoromethyl)-l,2-dihydropyridine-3-carbonitrile; l-(2-(4-(4-(5-(2-(allyloxy)-6-chlorophenyl)-4,5- dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-3-bromo-5-(trifluoromethyl)pyn one; l-(2-(4-(4-(5-(2-(allyloxy)-6-chlorophenyl)-4,5-dihydroisoxazol-3-yI)thiazol-2-yl)piperidin-l-yl)-2- oxoethyl)-3-chIoro-5-(trifluoromethyl)pyridin-2(lH)-one; l-(2-(4-(4-(5-(2-chloro-5-
(trifluoromethyl)phenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-5-
(trifluoromethyl)pyridin-2(lH)-one; l-(2-(4-(4-(5-(2-chloro-5-(trifluoromethyl)ph dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-6-methyl-3-(trifluoromethyl)pyridi one; 1 -(2-(4-(4-(5-(2-chloro-5-(trifluoromethyl)phenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-
1 -yl)-2-oxoethyl)-3-(trifluoromethyl)pyridin-2( 1 H)-one; 5-chloro- 1 -(2-oxo-2-(4-(4-(3-phenylprop- 1 -yn- l-yl)thiazol-2-yl)piperidin-l-yl)ethyl)-3-(trifluoromethyl)pyridin-2(lH)-one; l-(2-(4-(4-(5-(2-bromo-5- fluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-5-chloro-3-
(difluoromethyl)pyridin-2(lH)-one; l-(2-(4-(4-(5-(2,6-dimethoxyphenyl)-4,5-dihydroisoxazol-3- yl)thiazoi-2-yl)piperidin-l-yl)-2-oxoethyl)-2-oxo-5-(trifluoromethyl)-l,2-dihydropyridine-3-ca
5-chloro- l-(2-(4-(4-(5-(2-fluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazo]-2-yl)piperidin-l-yl)-2- oxoethyI)-3-(trifluoromethyl)pyridin-2(lH)-one; 5-chloro-l-(2-(4-(4-(5-(4-methoxyphenyl)-4,5- dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-3-(trifluoromethyl)pyndin-2(lH)-o^ 3- chloro-l-(2-(4-(4-(5-(2-fluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-
5-(trifluoromethyl)pyridin-2(lH)-one; 3-chloro-l-(2-(4-(4-(5-(4-methoxyphenyl)-4,5-dihydroisoxazol-3- yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-5-(trifluorornethyl)pyridin-2(lH)-one; 3-chloro-l-(2-oxo-2-(4-
(4-(5-(5-(trifluoromethyl)pyridin-2-yl)-4,5-di
(trifluoiOmethyl)pyridin-2(lH)-one; 3-chloro-l-(2-(4-(4-(5-(2-chloro-6-fluorophenyl)-4,5- dihydroisoxazo]-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-5-(trifluoromethyl)pyridin-2(lH 3- bromo-l-(2-(4-(4-(5-(2,6-dichloro-4-(trifluoiOmethyl)phenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2- yl)piperidin-l-yl)-2-oxoethyl)-5-(trifluoromethyl)pyridin-2(lH)-one; 5-chloro-l-(2-(4-(4-(5-(2,6- dichloro-4-(trifluoromethyl)phenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin- (trifluoiOmethyl)pyridin-2(lH)-one; 3-chloro-l-(2-(4-(4-(5-(2,6-dichIoro-4-(trifluoromethyl)phenyl)-4,5- dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-5-(trifluoromethyl)pyridin-2(lH)-one; l-(2- (4-(4-(5-(2,6-dichloro-4-(trifluoromethyl)phenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidi oxoethyl)-5-(trifluoromethy])pyridin-2(lH)-one; l-(2-(4-(4-(5-(2,6-dichloro-4-(trif!uoromethyl)phenyl)- 4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-6-methyl-3-(trifluoromethyl)pyridin- 2( 1 H)-one; 1 -(2-(4-(4-(5-(2,6-dichloro-4-(trifluoromethyl)phenyl)-4,5-dihydiOisoxazol-3-yl)thiazoi-2- y])piperidin-l-y])-2-oxoethy])-3-(trifluoromethyl)pyridin-2(lH)-one; 5-chloro- l-(2-(4-(4-(5-(2-chloro-5- (trifluoromethyl)phenyl)-4,5-dihydroisoxazo
(difluoromethyl)pyridin-2( 1 H)-one; 1 -(2-(4-(4-(5-(2-biOmo-5-fluorophenyI)-4,5-dihydroisoxazol-3- yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-5-(trifluoromethyl)pyridin-2(lH)-one; 3-bromo-l-(2-(4-(4-(5- (2-bromo-5-fluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yI)-2-oxoethyl)-5- (trifluoromethyl)pyridin-2(lH)-one; l-(2-(4-(4-(5-(2-bromo-5-fluorophenyl)-4,5-dihydroisoxa yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-2-oxo-5-(tnfluoromethyl)-l,2-dihydropyridin
1- (2-(4-(4-(5-(2-bromo-5-fluorophenyl)-4,5-dibydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2- oxoethyl)-5-chloro-3-(trifluoromethyl)pyridin-2(lH)-one; l-(2-(4-(4-(5-(2,6-dichlorophenyl)-4,5- dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-6-oxo-5-(trifluoromethyl)-l,6- dihydropyridine-3-carbonitrile; 3-chloro-2-(3-(2-(l-(2-(5-cyano-2-oxo-3-(trifluoromethyl)pyridin-l(2H)- yl)acetyl)piperidin-4-yl)thiazol-4-yl)-4,5-dihydroisoxazol-5-yl)phenyl methanesulfonate; 6-oxo-l-(2-oxo-
2- (4-(4-(5-(2,4,64richloiOphenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-]-yl)ethyl)-5- (trifluoromethyl)-l,6-dihydropyridine-3-carbonitrile; l-(2-(4-(4-(5-(2-bromo-5-fluorophenyl)-4,5- dihydroisoxazo]-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-3-(trifluoromethyl)pyndin-2 l-(2- (4-(4-(5-(3,5-dichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-5- (trifluoromethyl)pyridin-2(lH)-one; l-(2-(4-(4-(5-(3,5-dichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol- 2-y])piperidin-l-yl)-2-oxoethyl)-3-(trifluoromethyl)pyridin-2(lH)-one; 3-chloro-l-(2-(4-(4-(5-(3,5- dichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-5- (trifluoromethyl)pyridin-2(lH)-one; 5-chloro-l-(2-(4-(4-(5-(3,5-dichlorophenyl)-4,5-dihydroisoxazol-3- yl)thiazol-2-yl)pipendin-l-yl)-2-oxoethyl)-3-(trifluoromethyl)pyridin-2(lH)-one; 3-bromo-l-(2-(4-(4-(5- (3,5-dichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-5- (trifluoromethyl)pyridin-2(lH)-one; l-(2-(4-(4-(5-(3,5-dichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol- 2-yl)piperidin-l-yl)-2-oxoethyl)-6-methyl-3-(trifluoromethyl)pyridin-2(lH)-one; 1 -(2-(4-(4-(5-(4-(tert- butyl)phenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-5-chloro-3- (difluoromethyl)pyridin-2(lH)-one; l-(2-(4-(4-(5-(2,6-dichloro-4-(trifluoromethyl)phenyl)-4,5- dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-2-oxo-5-(trifluoromethyl)-l,2- dihydropyridine-3-carbonitrile; 5-chloro-3-(difluoromethyl)-l-(2-(4-(4-(5-(2,6-difluorophenyl)-4,5- dihydroisoxazol-3-yI)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)pyridin-2(lH)-one; l-(2-(4-(4-(5-(2-ch!oro- 5-(trifluoromethyl)phenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-]-yl)-2-oxoethyl)-2-oxo-5- (trifluoromethy])-l,2-dihydropyridine-3-carbonitrile; 3-bromo-l-(2-(4-(4-(5-(2,5-dichlorophenyl)-4,5- dihydroisoxazol-3-yl)thiazoI-2-yl)piperidin-l-yl)-2-oxoethyl)-5-(trifluoromethyl)pyridin-2(lH l-(2- (4-(4-(5-(2,5-dichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-y])piperidin-l-yl)-2-oxoethyl)-5- (trifluoromethyl)pyridin-2(lH)-one; l-(2-(4-(4-(5-(2,5-dichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol- 2-yl)piperidin-]-yl)-2-oxoethyl)-6-methyl-3-(trifluoromethyl)pyridin-2(lH)-one; 3-chloro-l-(2-(4-(4-(5- (2,5-dichloropheny])-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yi)-2-oxoethyl)-5- (trifluoromethyl)pyridin-2(lH)-one; l-(2-(4-(4-(5-(2,5-dichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-
2- yl)piperidin-l-yl)-2-oxoethyl)-3-(tnfluoromediyl)pyridin-2(lH)-one; l-(2-(4-(4-(5-(2,5- dichIorophenyl)-4,5-dihydroisoxazol-3-yi)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-2-oxo-5- (trifluoiOmethyl)-l,2-dihydiOpyridine-3-carbonitrile; 5-chloro-l-(2-(4-(4-(5-(2,5-dichlorophenyl)-4,5- dihydroisoxazol-3-yl)thiazol-2-y l)piperidin- 1 -yl)-2-oxoethyl)-3-(trifluoromethyl)pyridin-2( 1 H)-one; 3- chloro-l-(2-(4-(4-(5-(3-methy]pyridin-2-yl)-4,5-dihy^
oxoethyl)-5-(trifluoromethyI)pyridin-2(lH)-one; 5-chloro-l-(2-(4-(4-(5-(3-methylpyridin-2-yl)-4,5- dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yI)-2-oxoe 3- isocyano-l-(2-(4-(4-(5-(3-methylpyridin-2-yl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)- oxoethyl)-5-(trifluoromethyl)pyridin-2(lH)-one; 5-chloro-l-(2-(4-(4-(5-(2,6-dichlorophenyl)-4,5- dihydroisoxazoI-3-yl)thiazol-2-yl)piperidin-l-yl)-2-^ 5- chloro-l-(2-(4-(4-(5-(2,6-dichloro-4-(trif!uoromethyl)phenyl)-4,5-dihydroisoxazol-3-yl)thiazo]-2- yl)piperidin-l-yl)-2-oxoethyl)-3-(difluoromethyl)pyridin-2(lH)-one; 3-chloro-2-(3-(2-(l-(2-(5-chIoro-3- (difluoromethyl)-2-oxopyridin-l(2H)-yl)acetyl)piperidin-4-yl)thiazol-4-yl)-4,5-dihydroisoxazol^ yl)phenyl methanesulfonate; l-(2-(4-(4-(5-(3,5-dichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2- yl)piperidin-l-yl)-2-oxoethyl)-2-oxo-5-(trifluoromethyl)-l,2-dihydropyridine-3-carbonitrile; 1 -(2-(4-(4· (5-(4-(tert-butyl)phenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-2-oxo^ (trifluoiOmethyI)-l,2-dihydropyridine-3-carbonitrile; l-(2-(4-(4-(5-(2-cyanophenyl)-4,5-dihydroisoxazol-
3- yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-2-oxo-5-(trifluoromethyl)-l,2-dihydropyridi
carbonitrile; (E)-2-(l-(2-(2-oxo-5-(trifluoromethyl)pyridin-l(2h)-yl)acetyl)piperidin-4-yl)thiazole-4- carbaldehyde o-benzyl oxime; (Z)-2-(l-(2-(2-oxo-5-(trifluoromethyl)pyndin-l(2H)-yl)acetyl)pipendin-4- yl)thiazole-4-carbaldehyde O-benzyl oxime; (E)-2-(l-(2-(2-oxo-3-(trifluoromethyl)pyridin-1(2H) yl)acetyl)piperidin-4-yl)thiazoIe-4-carbaldehyde O-benzyl oxime; (Z)-2-(l-(2-(2-oxo-3- (trifluoromethyl)pyridin-l(2H)-yl)acetyl)piperidin-4-yl)thiazole-4-carbaldehyde O-benzyl oxime; 3· chloro-2-(3-(2-(l-(2-(5-chloro-3-(difluoromethyl)-2-oxopyridin-l(2H)-yl)acetyl)piperidin-4-yl)thiazol-4- yl)-4,5-dihydroisoxazol-5-yl)phenyl methanesulfonate; l-(2-(4-(4-(5-(2-(allyloxy)-6-chlorophenyl)-4,5- dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-3-(trifluoiOmethyl)pyridin-2(lH)-one; l-(2- (4-(4-(5-(2-(allyloxy)-6-chlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)pipendin-l-yl)-2-oxoethyl)- 6-methyl-3-(trifluoiOmethyl)pyridin-2(lH)-one; l-(2-(4-(4-(5-(2-(allyloxy)-6-chlorophenyl)-4,5' dihydroisoxazol-3-yl)th)azol-2-yl)piperidin-l-yl)-2-oxoethyl)-5-(trifluoromethyl)pyridin-2(lH)-one; l-(2- (4-(4-(5-(2-(allyloxy)-6-chloropheny!)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)pipendin-l-yl)-2-oxoethyl)- 5-chloro-3-(trifluoromethyl)pyridin-2(lH)-one; l-(2-(4-(4-(5-(2-(allyloxy)-6-chlorophenyl)-4,5- dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-2-oxo-5-(trifluoromethyl)-l,2- dihydropyridine-3-carbonitrile; 2-oxo-l-(2-oxo-2-(4-(4-(5-(2-(trifluoromethyl)phenyl)-4,5- dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)ethyl)-5-(trifluoromethyl)-l,2-dihydropyridi carbonitrile; 1 -(2-(4-(4-(5-(2-fluorophenyl)-4,5-di]iydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2- oxoethyl)-2-oxo-5-(trifluoiOinethyl)-l,2-dihydropyridine-3-carbonitrile; l-(2-(4-(4-(5-(4- methoxyphenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-2-oxo-5- (trifluoromethyl)-l,2-dihydropyridine-3-carbonitrile; l-(2-(4-(4-(5-(2-chloro-6-fluorophenyl)-4,5- dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-2-oxo-5-(trifluoromethyl)-l,2- dihydropyridine-3-carbonitrile; 2-oxo-l-(2-oxo-2-(4-(4-(5-(5-(trifluoiOmethyl)pyridin-2-yl)-4,5- dihydroisoxazol-3-yl)thiazol-2-yI)piperidin-l-yl)ethyl)-5-(trifluoromethyl)-l,2-dihydropyridine-3- carbonitrile; l-(2-(4-(4-(5-(2-chloro-3-(trifluoromethyl)phenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2- yl)pipendin-l-yl)-2-oxoethyl)-3-(trifIuoromethyl)pyndin-2(lH)-one; l-(2-(4-(4-(5-(2-chloro-3- (triiluoromethyl)phenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-6
(trifluoromethyl)pyridin-2(]H)-one; 5-chloro-l-(2-(4-(4-(5-(2-chloro-3-(trifluoromethyl)phenyl)-4,5- dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-3-(trifluoromethyl)py l-(2- (4-(4-(5-(2-chloro-3-(trifluoromethyl)phenyl)-4,5-dihydroisoxazol-3-yI)thiazol-2-yl)pi
oxoethyl)-5-(trifluoromethyl)pyridin-2(lH)-one; 3-chloro-l-(2-(4-(4-(5-(2-chloro-3- (tnfluoromethyl)phenyl)-4,5-dibydroisoxazol-3-yI)thiazol-2-yl)piperidin-l-yl)-2-oxoe
(trifluoromethyl)pyridin-2(lH)-one; 3-bromo-l-(2-(4-(4-(5-(2-chloro-3-(trifluoromethyl)phenyl)-4,5- dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-5-(trifluoromethyl)pyri l-(2- (4-(4-(5-(2-chloro-3-(trifluoromethyl)phenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2- oxoethyl)-2-oxo-5-(trifluoromethyl)-l,2-dihydropyridine-3-carbonitrile; 5-chloro-l-(2-(4-(4-(5-(2-chloro- 3-(trifluoromethyl)phenyl)-4,5-dihydiOisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-3- (difluoromethyl)pyridin-2(lH)-one; l-(2-(4-(4-(5-(2,6-difluorophenyl)-5-methyl-4,5-dihydroisoxazol-3- yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethy])-3-(tnfluoromethyl)pyndin-2(lH)-orie; l-(2-(4-(4-(5-(4-chloro- 2-fluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-5- (trifluoromethyl)pyridin-2(lH)-one; l-(2-(4-(4-(5-(4-chloro-2-fluorophenyl)-4,5-dihydroisoxazol-3- yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-3-(trifluoromethyl)pyridin-2(lH)-one; 3-chloro-l-(2-(4-(4-(5- (4-chloro-2-fluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-5- (trifluoromethyl)pyridin-2(l H)-one; 5-chloro-l-(2-(4-(4-(5-(4-chloro-2-fluorophenyl)-4,5- dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l -yl)-2-oxoethyl)-3-(trifluoromethyl)pyridin-2(lH)-one; 3- bromo-l-(2-(4-(4-(5-(4-chloro-2-fluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2- oxoethyl)-5-(trifluoromethyl)pyridin-2(lH)-one; l-(2-(4-(4-(5-(4-chIoro-2-fluorophenyl)-4,5- dihydroisoxazol-3-yi)thiazol-2-yl)piperidin-l -yl)-2-oxoethyI)-6-methyl-3-(triflLioromethyl)pyridin-2(lH)- one; l-(2-(4-(4-(5-(4-chloro-2-fluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2- oxoethyl)-2-oxo-5-(trifluoromethyl)-l ,2-dihydropyridine-3-carbonitriIe; methyl 5-cyano-l-(2-(4-(4-(5- (2,6-dichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-6-oxo-l,6- dihydropyridine-3-carboxylate; l-(2-(4-(4-(5-(2,6-dichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2- yl)piperidin-l-yl)-2-oxoethyl)-2-oxo-5-(trifluoromethyI)-l,2-dihydropyridine-3-carboxamide; l-(2-(4-(4- (5-(2,6-dichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-2-oxo-5- (trifluoromethyl)-l,2-dihydropyridine-3-carboxylic acid; l-(2-(4-(4-(5-(6-chloro-2,3-difluorophenyl)-4,5- dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-6-oxo-5-(trifluoromethyl)-l ,6- dihydropyridine-3-carbonitrile; 3-bromo-l-(2-(4-(4-(5-(6-chloro-2,3-difluorophenyl)-4,5- dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-5-(trifluoromethyl)pyridin-2(lH)-one; l-(2- (4-(4-(5-(6-chloro-2,3-difluoiOphenyl)-4,5-dihydiOisoxazol-3-yI)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-
5- (trifluoromethyl)pyridin-2(lH)-one; 3-chloro-l-(2-(4-(4-(5-(6-chloro-2,3-difluorophenyl)-4,5- dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2^ 5- bromo-l-(2-(4-(4-(5-(6-chloro-2,3-difluoroph^
2-oxoethyl)-3-(trifluoromethyl)pyridin-2( 1 H)-one; 1 -(2-(4-(4-(5-(6-chloro-2,3-difluorophenyl)-4,5- dihydroisoxazol-3-yl)thiazoI-2-yl)piperidin-l-yl)-2-oxoethyl)-3-(trifluoromethyl)pyridin-2(l^ l-(2- (4-(4-(5-(6-chloro-23-difluorophenyl)-4,5-dihy
6- methyl-3-(trifluoromethyl)pyridin-2(lH)-one; (E)-2-(l-(2-(5-chloro-2-oxo-3-(trifluoromethyl)pyridin- l(2H)-yl)acetyl)piperidin-4-yl)thiazole-4-carbaldehyde O-benzyl oxime; (Z)-2-(l-(2-(5-chloro-2-oxo-3- (tnfluoromethyl)pyridin-l(2H)-yl)acetyl)piperidin-4-yl)thiazole-4-carbaIdehyde O-benzyl oxime; l-(2-(4- (4-(3-(2,6-difluorophenyl)-4,5-dihydroisoxazol-5-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-3- (trifluoromethyl)pyridin-2(lH)-one; l-(2-(4-(4-(3-(2,6-difiuorophenyl)-4,5-dihydroisoxazol-5-yl)thiazol- 2-yl)piperidin-l-yl)-2-oxoethyl)-6-methyl-3-(trifluoromethyl)pyndin-2(lH)-one; 5-bromo-l-(2-(4-(4-(3- (2,6-difluorophenyl)-4,5-dihydroisoxazol-5-yl)thiazol-2-yl)piperidin-l-y])-2-oxoethyl)-3- (trifluoromethyl)pyridin-2(lH)-one; l-(2-(4-(4-(3-(2,6-difluorophenyl)-4,5-dihydroisoxazol-5-yl)thiazol- 2-yl)piperidin- 1 -yl)-2-oxoethyl)-5-(trifluoromethyl)pyridin-2( 1 H)-one; 3-bromo- 1 -(2-(4-(4-(3-(2,6- difluorophenyl)-4,5-dihydroisoxazol-5-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-5- (trifluoromethyl)pyridin-2(lH)-one; l-(2-(4-(4-(3-(2,6-difluorophenyl)-4,5-dihydroisoxazol-5-yl)thiazol- 2-yl)piperidin-l-yl)-2-oxoethyl)-2-oxo-5-(trifluoromethyl)-l,2-dihydropyndine-3-carbonitrile; 3-chloro- l-(2-(4-(4-(3-(2,6-difluoropheny!)-4,5-dihydroisoxazol-5-yl)thiazol-2-yl)piperidin-l-y])-2-oxoethyl)-5- (trifluoromethyl)pyridin-2(lH)-one; 5-cyano-l-(2-(4-(4-(5-(2,6-dichlorophenyl)-4,5-dihydroisoxazol-3- yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-6-oxo-l,6-dihydropyridine-3-carboxylic acid; l-(2-oxo-2-(4- (4-(5-(2,4,6-trifluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazoi-2-yl)piperidin-l-yl)ethyi)-3- (trifluoromethyl)pyridin-2(lH)-one; l-(2-(4-(4-(5-(5-chloro-l-methyl-3-(trifluoro
yl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-y^ one; and 5-bromo-l-(2-(4-(4-(5-(5-chloro-l-rnethyl-3-(trifluorornethyl)-lH-pyrazol-4-yl)-4,5- dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-3-(trifluoromethyl)pyridin-2(lH l-(3- (4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-3-oxopropyl)-3- (tritluoromethyl)pyridin-2(lH)-one; 5-chloro-l-(3-(4-(4-(5-(2,6-difluorophenyI)-4,5-dihydroisoxazol-3- yI)thiazol-2-yI)piperidin-l-yI)-3-oxopropyI)-3-(trifluoiOmethyl)pyridin-2(lH)-one; l-(3-(4-(4-(5-(2,6- difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazo!-2-yl)piperidin-l-yl)-3-oxopropyl)-5- (trifluoromethyl)pyridin-2(lH)-one; 3-chloro-l-(3-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3- yl)thiazol-2-yl)piperidin-l-yl)-3-oxopropyl)-5-(trifluoromethyl)pyridin-2(lH)-one; N-(5-chloro-2-oxo-3- (trifluoromethyl)pyridin-l(2H)-yl)-4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)th
yl)piperidine-l-carboxamide; N-(5-chloro-2-oxo-3-(trifluoromethyl)pyridin-l(2H)-yl)-4-(4-(5-(2,6- difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidine-l-caiboxamide; 4-(4-(5-(2,6- difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol^
yl)piperidine-l-carboxamide; N-(3-chloro-2-oxo-5-(trifluoromethyl)pyridin-l(2H)-yl)-4-(4-(5-(2,6- difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidine-l-carboxamide; 5-chloro- 1-(2-(4-(4-(5- (2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazo]-2-yl)piperazin-l-yl)-2-oxoethyl)-3- (trifluoromethyl)pyridin-2(lH)-one; l-(2-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol- 2-yl)piperazin-l-yl)-2-oxoethyl)-5-(trifluoromethyl)pyridin-2(lH)-one; 3-chloro-l-(2-(4-(4-(5-(2,6- difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperazin-l-yI)-2-oxoethyl)-5- (trifluoromethyl)pyridin-2(lH)-one; l-(2-(4-(5-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol- 2-yl)piperidin- 1 -yl)-2-oxoethyl)-3-(trifluoromethyl)pyridin-2( 1 H)-one; 5-chloro- 1 -(2-(4-(5-(5-(2,6- difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-3- (trifluoromethyl)pyridin-2(lH)-one; l-(2-(4-(5-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol- 2-yl)piperidin-l-yl)-2-oxoethyl)-5-(trifluoromethyl)pyridin-2(lH)-one; 3-chloro-l-(2-(4-(5-(5-(2,6- difluorophenyl)-4,5-dihydroisoxazol-3-y])thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-5- (trifluoromethyl)pyridin-2( 1 H)-one; 1 -(2-(4-(4-(5-(2,6-difluorophenyl)- 1 -methyl-4,5-dihydro 1 H- pyrazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-3-(trifluoromethyl)pyridin-2(lH)-one; 5-chloro- 1 - (2-(4-(4-(5-(2,6-difluorophenyl)-l-methyl-4,5-dihydro-lH-pyrazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2- oxoethyl)-3-(trifluoromethyl)pyridin-2(lH)-one; 5-chloro-l-(2-(4-(4-(5-(2,6-difluorophenyl)-l-methyl- 4,5-dihydro-lH-pyrazol-3-yl)thiazol-2-yl)piperidin-]-yl)-2-oxoethyl)-3-(trifluoromethyl)pyridin-2(lH)- one; ]-(2-(4-(4-(5-(2,6-difluorophenyl)-l-methyl-4,5-dihydro-lH-pyraz.ol-3-yl)thiazol-2-yl)piperidin-]- yl)-2-oxoethyl)-5-(tnfluoromethyl)pyndin-2(lH)-one; l-(2-(4-(4-(5-(2,6-difluorophenyl)-l -methyl- 1 H- pyrazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-3-(trifluoromethyl)pyridin-2(lH)-one; 5-chloro- 1 - (2-(4-(4-(5-(2,6-difluorophenyl)-l -methyl- lH-pyrazol-3-yl)thiazol-2-y!)piperidin-l-yl)-2-oxoethyl)-3- (trifluoromethyl)pyridin-2(lH)-one; l-(2-(4-(4-(5-(2,6-difluorophenyl)-l -methyl-] H-pyrazol-3-yl)thiazol- 2-yl)piperidin-l-yl)-2-oxoethyl)-5-(trifluoromethyl)pyridin-2(lH)-one; 3-chloro-l-(2-(4-(4-(5-(2,6- difluorophenyl)-l -methyl- 1 H-pyrazol-3-yl)thiazol-2-yl)piperidin- 1 -y l)-2-oxoethyl)-5- (trifluoromethyl)pyridin-2(lH)-one; l-(2-(4-(4-(3-(2,6-difluorophenyl)-lH-pyrazol-l-yl)thiazol-2- yl)pipendin-l-yl)-2-oxoethyl)-3-(trifluoromethyl)pyridin-2(lH)-one; 5-chIoro-l-(2-(4-(4-(3-(2,6- difluorophenyl)-lH-pyrazol-l-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-3-(trifluoromethyl)pyridin- 2(lH)-one; l-(2-(4-(4-(3-(2,6-difluorophenyl)-lH-pyrazol-l-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)- 5-(trifluoiOmethyl)pyridin-2(lH)-one; 3-chloro-l-(2-(4-(4-(3-(2,6-difluorophenyl)-lH-pyrazol-l- yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-5-(trifluoromethyl)pyridin-2(lH)-one; l-(2-(4-(5-(5- (naphthalen-l-yl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-3- (trifluoromethyl)pyridin-2(lH)-one; 5-chloro-l -(2-(4-(5-(5-(naphthalen- 1 -yl)-4,5-dihydroisoxazol-3- yI)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-3-(trifluoiOmethyl)pyridin-2(lH)-one; l-(2-(4-(5-(5- (naphthalen-l-yl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-5- (trifluoromethyl)pyridin-2(lH)-one; 3-chloro-l-(2-(4-(5-(5-(naphthalen-l-yl)-4,5-dihydroisoxazol-3- yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-5-(trifluorornethyl)pyridin-2(lH)-one; l-(2-(4-(4-(3-(2,6- dichlorophenyl)-3-oxoprop-l-yn-l-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-3-(tnfluoromethyl)pyri 2( 1 H)-one; 5-chloro-l -(2-(4-(4-(3-(2,6-dichlorophenyl)-3-oxoprop- 1 -yn- 1 -yl)thiazol-2-yl)piperidin-l -yl)- 2-oxoethyl)-3-(trifluoromethyl)pyridin-2(lH)-one; l-(2-(4-(4-(3-(2,6-dichlorophenyl)-3-oxoprop-l-yn-l- yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-5-(trifluoromethyl)pyridiri-2(lH)-one; 3-chloro-l-(2-(4-(4-(3- (2,6-dichlorophenyl)-3-oxoprop-l-yn-l-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-5- (trifluo!Omethyl)pyridin-2(lH)-one; l-(2-(4-(4-(3-(4-bromophenyl)-3-oxoprop-l-yn-l-yl)thiazol-2- yl)piperidin-l-yl)-2-oxoethyl)-3-(trifluoromethyl)pyridin-2(lH)-one; l-(2-(4-(4-(3-(4-bromophenyl)-3- oxoprop-l-yn-l-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-5-chloro-3-(trifluoromethyl)pyridin-2(lH one; 1 -(2-(4-(4-(3-(4-bromophenyl)-3-oxoprop-l -yn- 1 -yl)thiazol-2-yl)piperidin- 1 -yl)-2-oxoethyl)-5- (trif]uoromethyl)pyridin-2(lH)-one; l-(2-(4-(4-(3-(4-bromophenyl)-3-oxoprop-l-yn-l-yl)thiazol-2- yl)piperidin-l -yl)-2-oxoethyl)-3-chloro-5-(trifluoromethyl)pyridin-2( 1 H)-one; 1 -(2-oxo-2-(4-(4-(3- phenylprop-l-yn-l-yl)thiazol-2-yl)piperidin-l-yl)ethyl)-3-(trifluorornethyl)pyridin-2(lH)-one; l-(2-oxo-
2- (4-(4-(3-phenylprop-l-yn-l-yl)thiazol-2-yl)pipendin-l-yl)ethyl)-5-(trifluoromethyl)pyridin-2(lH)-one;
3- chloro-l-(2-oxo-2-(4-(4-(3-phenylprop-l-yn-l-yl)thiazol-2-yl)piperidin-l-yl)ethyl)-5- (trifluoromethyl)pyridin-2(lH)-one; l-(2-(4-(4-(3-(2,6-dichlorophenyl)prop-l-yn-l-yl)thiazol-2- yl)piperidin-l-yl)-2-oxoethyl)-3-(trifluoromethyl)pyridin-2(lH)-one; 5-chloro-l-(2-(4-(4-(3-(2,6- dichlorophenyl)prop-l-yn-l-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-3-(trifluoromethyl)pyridin-2(lH)- one; l-(2-(4-(4-(3-(2,6-dichlorophenyl)prop-l-yn-l-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-5- (ti'ifluoromethyl)pyridin-2(l H)-one; 3-chloro-l-(2-(4-(4-(3-(2,6-dichlorophenyl)piOp-l-yn-l-yl)thiazol-2- yl)piperidin-l-yl)-2-oxoethyl)-5-(trifluoiOmethyl)pyridin-2(lH)-one; l-(2-(4-(4-(5-(2,6-difluorophenyI)- 4,5-dihydroisoxazol-3-yl)thiazol-2-yl)pipen^^
one; 5-chloro-l-(2-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2- thioxoethyl)-3-(trifluoromethyl)pyridin-2(lH)-one; l-(2-(4-(4-(5-(2,6-difluorophenyl)-4,5- dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-24hioxoethyl)-5-(trifluoromethyl)pyridin 2- (2,6-difluorophenyl)-N-(2-(l-(2-(2-oxo-3-(trifluoromethyl)pyridin-l(2H)-yl)acetyl)piperidin-4-yl^ 4-yl)ethanethioamide; N-(2-(l-(2-(5-chloro-2-oxo-3-(trifluoromethyl)pyridin-l(2H)-yl)acetyl)pipendin-4- yl)thiazol-4-yl)-2-(2,6-difluorophenyl)ethanethioamide; 2-(2,6-difluorophenyl)-N-(2-(l-(2-(2-oxo-5- (trifluoromethyl)pyridin-l(2H)-yl)acetyl)piperidin-4-yl)thiazol-4-yl)ethanethioamide; N-(2-(l-(2-(3- chloro-2-oxo-5-(trifluoromethyl)pyridin-l(2H)-yl)acetyl)piperidin-4-yl)thiazol-4-yl)-2-(^
difluorophenyl)ethanethioamide; l-(3-(4-(4-(5-(2,6-dichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2- yl)piperidin-l-yl)-3-oxopropyl)-3-(trifluoromethyl)pyndin-2(l?I)-one; 5-chloro-l -(3-(4-(4-(5-(2,6- dichlorophenyl)-4,5-dihydiOisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-3-oxop!'opyl)-3- (trifluoromethyl)pyridin-2(lH)-one; l-(3-(4-(4-(5-(2,6-dichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol- 2-yl)piperidin-]-yl)-3-oxopropyl)-5-(trinuoromethyl)pyridin-2(lH)-one; 3-chloro-l-(3-(4-(4-(5-(2,6- dichloiOphenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-3-oxopropyl)-5- (trifluoromethyl)pyridin-2(lH)-one; N-(5-chloro-2-oxo-3-(trifluoromethyl)pyridin-l(2H)-yl)-4-(4-(5-(2,6- dichloropheny])-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidine-l-carboxamide; N-(5-chloro-2-oxo-3- (trifluoromethyl)pyridin-l(2H)-yl)-4-(4-(5-(2,6-dichlorophenyl)-4,5-dihydroisoxazol-3-yl)th
yl)piperidine-l-carboxamide; 4-(4-(5-(2,6-dichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)-N-(2- oxo-5-(trifluoiOmethyl)pyridin-l(2H)-yl)piperidine-l-carboxamide; N-(3-chloro-2-oxo-5- (trifluoromethyl)pyridin-l(2H)-yl)-4-(4-(5^
yl)piperidine-]-carboxamide; 5-chloro-l -(2-(4-(4-(5-(2,6-dichlorophenyl)-4,5-dihydroisoxazol-3- yl)thiazol-2-yl)piperazin-]-yl)-2-oxoethyl)-3-(trifluoroiTiethyl)pyridin-2(lH)-one; l-(2-(4-(4-(5-(2,6- dichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperazin-l-yl)-2-oxoethyl)-5- (trifluoromethyl)pyridin-2(lH)-one; 3-chloro-l-(2-(4-(4-(5-(2,6-dichlorophenyl)-4,5-dihydroisoxazol-3- yl)thiazol-2-yl)piperazin-l-yl)-2-oxoethyl)-5-(trifluoromethy])pyridin-2(lH)-one; 5-chloro-l -(2-(4-(5-(5- (2,6-dichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-3- (tnfluoromethyl)pyridin-2(lH)-one; l-(2-(4-(5-(5-(2,6-dichlorophenyl)-4,5-dihydroisoxazoI-3-yl)thiazol- 2-yl)piperidin-l-yl)-2-oxoethyl)-5-(trifluoiOmethyl)pyridin-2(]H)-one; 3-chloro-l -(2-(4-(5-(5-(2,6- dichlorophenyl)-4,5-dihydiOisoxazol-3-yi)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-5- (trifluoromethyI)pyridin-2(lH)-one; l-(2-(4-(4-(5-(2,6-dichlorophenyl)-l-methyl-4,5-dihydro-lH- pyrazol-3-yl)thiazol-2-yl)piperidin-]-y])-2-oxoethyl)-3-(trifluoromethyl)pyndin-2(l H)-one; 5-chloro-l - (2-(4-(4-(5-(2,6-diTluorophenyl)-l-methyl-4,5-dihydro-lH-pyrazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2- oxoethyl)-3-(trif1uoromethyl)pyridin-2(lH)-one; 5-chloro-l -(2-(4-(4-(5-(2,6-dichlorophenyl)-l -methyl- 4,5-dihydro-lH-pyrazol-3-yl)thiazol-2-yl)piperidin-^
one; l-(2-(4-(4-(5-(2,6-dichlorophenyl)-l-methyl-4,5-dihydro-lH-pyrazol-3-yl)thiazol-2-yl)piperidin-l- yl)-2-oxoethyl)-3-(trifluoromethyl)pyridin-2(lH)-one; 1 -(2-(4-(4-(5-(2,6-dichlorophenyl)- 1 -methyl- 1 H- pyrazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-3-(trifluoromethyl)pyridin-2(lH)-one; 5-chloro-l- (2-(4-(4-(5-(2,6-dichlorophenyl)-l -methyl- lH-pyrazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-3- (trifluoromethyl)pyridin-2(lH)-one; l-(2-(4-(4-(5-(2,6-dichlorophenyl)-l -methyl- 1 H-pyrazol-3- yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-5-(trifluoromethyl)pyridin-2(lH)-one; 3-chloro- 1-(2-(4-(4-(5- (2,6-dichlorophenyl)-] -methyl- 1 H-pyrazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-5- (trifluoromethyl)pyridin-2(lH)-one; l-(2-(4-(4-(3-(2,6-dichlorophenyl)-lH-pyrazol-l-yl)thiazol-2- yl)piperidin-l-yl)-2-oxoethyl)-3-(trifluoromethyl)pyridin-2(lH)-one; 5-chloro-l-(2-(4-(4-(3-(2,6- dichlorophcnyl)-lH-pyrazol-l-yl)thiazol-2-yl)pipendin-l-yl)-2-oxoethyl)-3-(trifluoromethyl)pyridi 2(lH)-one; l-(2-(4-(4-(3-(2,6-dichlorophenyl)-lH-pyrazol-l-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)- 5-(trifluoromethyl)pyridin-2(lH)-one; 3-chloro-l-(2-(4-(4-(3-(2,6-dichlorophenyl)-lH-pyrazol-l- yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-5-(trifluoromethyl)pyridin-2(lH)-one; 5-bromo-l-(2-(4-(5-(5- (naphthalen-l-yl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-3- (trifluoromethyl)pyridin-2(lH)-one; l-(2-(4-(4-(3-(2,6-difluorophenyl)prop-l-yn-l-yl)thiazol-2- yl)piperidin-l-yl)-2-oxoethyl)-3-(trifluoromethyl)pyridin-2(lH)-one; 5-chloro-l-(2-(4-(4-(3-(2,6- difluorophenyl)prop-l-yn-l-yl)thiazol-2-yl)piperidii>l-yl)-2-oxoethyl)-3-(trifluoromethyl)pyrid one; 3-chloro- 1 -(2-(4-(4-(3-(2,6-difluorophenyl)prop- 1 -yn- 1 -yl)thiazol-2-yl)piperidin- 1 -yl)-2-oxoethyl)- 5-(trifluoromethyl)pyridin-2(lH)-one; l-(2-(4-(4-(5-(2,6-dichlorophenyl)-4,5-dihydroisoxazol-3- yl)thiazol-2-yl)piperidin-l-yl)-2-thioxoethyl)-3-(tnfluoromethyl)pyridin-2(lH)-one; N-(2-(l-(2-(5-chloro-
2- oxo-3-(trifluoromethyl)pyridin-l(2H)-yl)acetyl)piperidin-4-yl)thiazol-4-yl)-2-(2,6- dichlorophenyl)ethanethioamide; 2-(2,6-dichlorophenyl)-N-(2-(l-(2-(2-oxo-3-(trifluoromethyl)pyridin- l(2H)-yl)acetyl)piperidin-4-yl)thiazol-4-yl)ethanethioamide; 5-chloro-l-(2-(4-(4-(5-(2,6-dichlorophenyl)- 4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-thioxoethyl)-3-(trifluoromethyl)pyridin-2(lH)- one; l-(2-(4-(4-(5-(2,6-dichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2- thioxoethyl)-3-(trifluoromethyl)pyridin-2(lH)-one; ■ l-(2-(4-(6-(5-(2,6-difluorophenyl)-4,5- dihydroisoxazol-3-yl)pyridin-2-yl)piperidin-l-yl)-2-oxoethyl)-3-(trifluoiOmethyl)pyridin-2(lH)-one; 5- chloro-l-(2-(4-(6-(5-(2,6-dif1uoiOphenyl)-4,5-dihydroisoxazol-3-yl)pyridin-2-yl)piperidin-l-yl)-2- oxoethyl)-3-(trifluoromethyl)pyridin-2(lH)-one; l-(2-(4-(6-(5-(2,6-dichlorophenyl)-4,5-dihydroisoxazol-
3- yl)pyridin-2-yl)piperidin-l-yl)-2-oxoethyl)-3-(trifluoromethyl)pyridin-2(lH)-one; 5-chloro-l-(2-(4-(6- (5-(2,6-dichloiOphenyl)-4,5-dihydiOisoxazol-3-yl)pyridin-2-yl)piperidin-l-yl)-2-oxoethyl)-3- (trifluoromethyl)pyridin-2(lH)-one; l-(2-(4-(6-(5-(2,6-difluorophenyl)-4,5-dihydiOisoxazol-3-yl)pyridin- 2-yl)piperidin-l-yl)-2-oxoethyl)-5-(trifluoiOmethyl)pyridin-2(lH)-one; 3-chloro- 1-(2-(4-(6-(5-(2,6- difluorophenyl)-4,5-dihydroisoxazol-3-yl)pyridii>2-yl)piperidin-l-yl)-2-oxoethyl)-5- (trifiuoromethyl)pyridin-2(lH)-one; l-(2-(4-(6-(5-(2,6-dichlorophenyl)-4,5-dihydroisoxazol-3-yl)pyridin- 2-yl)piperidin-l-yl)-2-oxoethyl)-5-(trifluoromethyl)pyridin-2(lH)-one; 3-chloro-l-(2-(4-(6-(5-(2,6- dichlorophenyl)-4,5-dihydroisoxazol-3-yl)pyridin-2-yl)pipendin-l-yl)-2-oxoethyl)-5- (trifluoromethyl)pyridin-2(lH)-one; l-(2-(4-(2-(5-(2,6-dichlorophenyl)-4,5-dihydroisoxazol-3-yl)pyridin- 4-yl)piperidin-l-yl)-2-oxoethyl)-5-(trifiuoromethyl)pyridin-2(lH)-one; 3-chloro-l-(2-(4-(2-(5-(2,6- dichlorophenyl)-4,5-dihydroisoxazol-3-yl)pyridin-4-yl)piperidin-l-yl)-2-oxoethyl)-5- (trifluoromethyl)pyridin-2( 1 H)-one; 1 -(2-(4-(2-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)pyridin- 4-yl)piperidin-l-yl)-2-oxoethyl)-5-(trifluoromethyl)pyridin-2(lH)-one; 3-chloro-l-(2-(4-(2-(5-(2,6- difluorophenyl)-4,5-dihydroisoxazol-3-yl)pyridin-4-yl)piperidin-l-yl)-2-oxoethyl)-5- (trifluoromethyl)pyridin-2( 1 H)-one; 1 -(2-(4-(2-(5-(2,6-dichlorophenyl)-4,5-dihydroisoxazol-3-yl)pyridin- 4-yl)piperidin-l-yl)-2-oxoethyl)-3-(trifluoromethyl)pyridin-2(lH)-one; 5-chloro-l-(2-(4-(2-(5-(2,6- dichlorophenyl)-4,5-dihydroisoxazol-3-yl)pyridin-4-yl)piperidin-l-yl)-2-oxoethyl)-3- (trif!uoromethyl)pyridin-2(lH)-one; l-(2-(4-(2-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)pyridin- 4-yl)piperidin-l-yl)-2-oxoethyl)-3-(trifluoromethyl)pyridin-2(lH)-one; 5-chloro-l-(2-(4-(2-(5-(2,6- difluorophenyl)-4,5-dihydi isoxazol-3-yl)pyridin-4-yl)piperidin-l-yl)-2-oxoethyl)-3- (trifluoromethyl)pyridin-2(lH)-one; 3-chloro-l-(2-(4-(3-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3- yl)- 1 H-pyrazol- 1 -yl)piperidin- 1 -yl)-2-oxoethyl)-5-(trifluoromethyl)pyridin-2( 1 H)-one; 3-chloro- 1 -(2-(4- (3-(5-(2,6-dichlorophenyl)-4,5-dihydroisoxazol-3-yl)-lH^yrazol-l-yl)piperidin-l-yl)-2-oxoethyl)-5- (trifluoromethyl)pyridin-2(lH)-one; 3-chloro-2-(3-(l-(l-(2-(3-chloro-2-oxo-5-(trifluoromethyl)pyridin- l(2H)-yl)acetyl)piperidin-4-yl)-lH-pyrazol-3-yl)-4,5-dihydroisoxazol-5-yl)phenyl methanesulfonate; 3- chloro-l-(2-oxo-2-(4-(3-(5-(2,4,6-trichlorophenyl)-4,5-dihydroisoxazol-3-yl)-lH-pyrazol-l-yl)piperidin-
1- yl)ethyl)-5-(trifluoromethyl)pyridin-2(lH)-one; 3-chloro-l-(2-(4-(3-(5-(2-chloro-6- (trifluoromethyl)phenyl)-4,5-dihydroisoxazol-3-yl)-l H-pyrazol- l-yl)piperidin-l-yl)-2-oxoethy
(trifluoromethyl)pyridin-2(lH)-one; l-(2-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-
2- yl)piperidin-l-yl)-2-oxoethyl)-5-methoxy-3-(trifluoromethyl)pyridin-2(lH)-one; l-(2-(4-(4-(5-(2,6- dichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-5-methoxy-3- (trifluoromethyl)pyridin-2(lH)-one; 5-methoxy-l-(2-oxo-2-(4-(4-(5-(2,4,6-trichlorophenyl)-4,5- dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)ethyl)-3-(trifluoromethyl)pyridin 3-chloro-2- (3-(2-(l-(2-(5-methoxy-2-oxo-3-(tnfluoromethyl)pyridin-l(2H)-yl)acetyl)piperidin-4-yl)th
dihydroisoxazol-5-yl)phenyl methanesulfonate; 5-(difiuoromethoxy)-l-(2-(4-(4-(5-(2,6-difluorophenyl)- 4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-3-(trifluoromethyl)pyridin-2^ l-(2-(4-(4-(5-(2,6-dichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-5- (difluoromethoxy)-3-(trifluoromethyl)pyridin-2(lH)-one; 5-(difluoromethoxy)-l-(2-oxo-2-(4-(4-(5- (2,4,6-trichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)ethyl)-3- (trifluoromethyl)pyridin-2( 1 H)-one; 3-chloro-2-(3-(2-( 1 -(2-(5-(difluoromefhoxy)-2-oxo-3-
(trifluoromethyl)pyridin-l(2H)-yl)acetyl^
methanesulfonate; l-(2-(4-(4-(5-(2,6-difluoiOphenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l- yl)-2-oxoethyI)-5-(ti-ifluoromethoxy)-3-(trifluoromethyl)pyridin-2(lH)-one; l-(2-(4-(4-(5-(2,6- dichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yI)piperidin-l-yl)-2-oxoethyl)-5-(trifluorome 3-(trifluoromethyl)pyridin-2(lH)-one; l-(2-oxo-2-(4-(4-(5-(2,4,6-trichlorophenyl)-4,5-dihydroisoxazol-3- yl)thiazol-2-yl)piperidin-l-yl)ethyl)-5-(trifluoromethoxy)-3-(trifluoromethyl)pyridi 3- chloro-2-(3-(2-(l-(2-(2-oxo-5-(trifluoromethoxy)-3-(trifluoromethyl)pyridin-l(2H)-yl)acety0
yl)thiazol-4-yl)-4,5-dihydroisoxazol-5-yl)phenyl methanesulfonate; l-(2-(4-(4-(5-(2,6-difluorophenyl)- 4,5-dihydroisoxazol-3-yl)thiazol-2-yl)pipendin-l-yl)-2-oxoethyl)-5-(dimethylamino)-3- (trifluoromethyl)pyridin-2(lH)-one; l-(2-(4-(4-(5-(2,6-dichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol- 2-yl)piperidin-l-yl)-2-oxoethyl)-5-(dimethylamino)-3-(trifluoromethyl)pyridin-2(lH)-one; 5- (dimethylamino)-l-(2-oxo-2-(4-(4-(5-(2,4,6-trichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2- yl)piperidin-l-yl)ethyl)-3-(trifluoromethyl)pyridin-2(lH)-one; 3-chloro-2-(3-(2-(l-(2-(5- (dimethylamino)-2-oxo-3-(trifiiioromethyl)pyridin-l(2H)-yl)acetyl)piperidin-4-yl)thiazol^
dihydroisoxazol-5-yl)phenyl methanesulfonate; l-(2-(4-(4^5-(2,6<lifluoiOphenyl)-4,5Hdihydroisoxazol-3- yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-3-(trifluoromethyl)-5-((trifluoromethyl)thi
one; l-(2-(4-(4-(5-(2,6-dichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2- oxoethyl)-3-(trifluoromethyl)-5-((trifiuoromethyl)thio)pyridin-2(lH)-one; l-(2-oxo-2-(4-(4-(5-(2,4,6- trichlorophenyl)-4,5-dihydiOisoxazoI-3-yl)thiazol-2-yl)piperidin-l-yl)ethyl)-3-(tritluoromethyl)-5- ((trifluoromethyl)thio)pyridin-2(lH)-one; 3-chloro-2-(3-(2-(l-(2-(2-oxo-3-(trifluoromethyl)-5- ((trifluoromethyl)thio)pyridin-l(2H)-yl)acetyl)piperidin-4-yl)thiazol-4-yl)-4,5-dihy
yl)phenyl methanesulfonate; l-(2-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2- yl)piperidin-l-yl)-2-oxoethyl)-3-methoxy-5-(trifluoromethyl)pyridin-2(lH)-one; l-(2-(4-(4-(5-(2,6- dichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-3-methoxy-5- (trifluoromethyl)pyridin-2(lH)-one; 3-methoxy-l-(2-oxo-2-(4-(4-(5-(2,4,6-trichlorophenyl)-4,5- dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)ethyl)-5-(trifluoromethyl)pyridin-2(lH)-one; 3-chloro-2- (3-(2-(l-(2-(3-methoxy-2-oxo-5-(trifluoromethyl)py
dihydroisoxazol-5-yl)phenyl methanesulfonate; 3-(difluoromethoxy)-l-(2-(4-(4-(5-(2,6-difluorophenyl)- 4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-5-(trifluoromethyl)pyridin-2(lH)-one l-(2-(4-(4-(5-(2,6-dichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazoI-2-yl)piperidin-l-yl)-2-oxoethyl)-3- (difluoromethoxy)-5-(trifluoromethyl)pyridin-2(lH)-one; 3-(difluoromethoxy)-l-(2-oxo-2-(4-(4-(5- (2,4,6-trichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)ethyl)-5- (trifluoromethyl)pyridin-2( 1 H)-one; 3-chloro-2-(3-(2-( 1 -(2-(3-(difluoromethoxy)-2-oxo-5-
(trifluoromethyl)pyridin-l (2H)-yl)acetyl)piperidin-4-yl)thiazol-4-yl)-4,5-dihydroisoxazo^
methanesulfonate; l -(2-(4-(4-(5-(2,6-difIuorophenyl)-4,5-dihydroisoxazol-3-yI)thiazol-2-yl)piperidin-l - yl)-2-oxoethyl)-3-(trifluoromethoxy)-5-(trifluoromethyl)pyridin-2( 1 H)-one; 1 -(2-(4-(4-(5-(2,6- dichloiOphenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)pipendin-l -yl)-2-oxoethyl)-3-(trifl
5-(trifluoromethyl)pyridin-2( 1 H)-one; 1 -(2-oxo-2-(4-(4-(5-(2,4,6-trichlorophenyI)-4,5-dihydroiso yl)thiazol-2-yl)piperidin- l -yl)ethyl)-3-(trifluoromethoxy)-5-(trifluoromethyl)pyridin 3- chloro-2-(3-(2-( l -(2-(2-oxo-3-(trifluoromethoxy)-5-(trifluoiOmethyl)pyridin-l (2H)-yl)acetyl)piperidin-4- yl)thiazol-4-yl)-4,5-dihydroisoxazol-5-yl)phenyl methanesulfonate; l -(2-(4-(4-(5-(2,6-difluorophenyl)- 4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin- ] -yl)-2-oxoethyl)-3-(dimethylamino)-5- (trifluoromethyl)pyridin-2( ] H)-one; l -(2-(4-(4-(5-(2,6-dichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol- 2-yl)piperidin-l -yl)-2-oxoethyl)-3-(dimethylamino)-5-(trifluoromethyl)pyridin-2( l H)-one; 3- (dimethylamino)-l -(2-oxo-2-(4-(4-(5-(2,4,6-trich^
yl)piperidin-l -yl)ethyl)-5-(trifluoromethyl)pyridin-2( l H)-one; 3-chloro-2-(3-(2-(l -(2-(3- (dimethylamino)-2-oxo-5-(trifluoromethyl)pyridin- l (2H)-yl)acetyl)piperidin-4-yl)thiazol-4-yl)-4,5- dihydroisoxazol-5-yl)phenyl methanesulfonate; 1 -(2-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3- yl)thiazol-2-yl)piperidin-l -yl)-2-oxoethyl)-5^
one; l -(2-(4-(4-(5-(2,6-dichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin- l-yl)-2- oxoethyl)-5-(trifluoromethyl)-3-((trifluoromethyl)thio)pyridin-2( l H)-one; l -(2-oxo-2-(4-(4-(5-(2,4,6- trichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin- l -yl)ethyl)-5-(trifluorom
((trifluoromethyl)thio)pyridin-2( lH)-one; 3-chloro-2-(3-(2-( l -(2-(2-oxo-5-(trifluoromethyl)-3- ((trifluoromethyl)thio)pyridin-l (2H)-yl)acetyl)piperidin-4-yl)thiazol-4-yl)-4,5-dihydroisoxa
yl)phenyl methanesulfonate; l -(2-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2- yl)piperidin-l -yl)-2-oxoethyl)-3-fluoro-5-(trifluoromethyl)pyridin-2( l H)-one; l -(2-(4-(4-(5-(2,6- dichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-3-fluoro-5- (trifluoromethyl)pyridin-2( l H)-one; 3-fluoro-l -(2-oxo-2-(4-(4-(5-(2,4,6-trichlorophenyl)-4,5- dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l -yl)ethyl)-5-(tnfluoiOmethyl)pyridin-2( l H)-o^ 3-chloro-2- (3-(2-( l -(2-(3-fluoro-2-oxo-5-(trifluoromethyl)pyridin- l (2H)-yl)acetyl)piperidin-4-yl)thi
dihydroisoxazol-5-yl)phenyl methanesulfonate; 3-(difluoromethyl)- l -(2-(4-(4-(5-(2,6-difluorophenyl)- 4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin- l -yl)-2-oxoethyl)-6-methylpyridin-2( l H)-one; l -(2-(4-(4- (5-(2,6-dichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin- l -yl)-2-oxoethyl)-3- (difluoromethyl)-6-methylpyridin-2( l H)-one; 3-(di fluoromethyl)-6-methyI- l -(2-oxo-2-(4-(4-(5-(2,4,6- trichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yI)piperidin- l -yl)ethyI)pyridin-2( l H)-one; 3-chloro- 2-(3-(2-( l -(2-(3-(difluoromethyl)-6-methyl-2-oxopyridin- l (2H)-yl)acetyl)piperidin-4-yl)thi dihydroisoxazol-5-yl)phenyl methanesulfonate; 6-chloro-l -(2-(4-(4-(5-(2,6-difluorophenyl)-4,5- dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yI)-2-oxoethyl)-3-(trifluoromethyl)pyridin-2(lH)-one; 6- chloro-l-(2-(4-(4-(5-(2,6-dichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yI)piperidin-l-yl)-2- oxoethyl)-3-(trifluoromethyl)pyridin-2(lH)-one; 6-chloro-l -(2-oxo-2-(4-(4-(5-(2,4,6-trichlorophenyl)- 4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)ethyl)-3-(trifluoromethyl)pyridin-2(lH^ 3- chloro-2-(3-(2-(l-(2-(6-chloro-2-oxo-3-(trifluorom
yl)-4,5-dihydroisoxazol-5-yl)phenyl methanesulfonate; 5-(difluoromethyl)-l-(2-(4-(4-(5-(2,6- difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yI)piperidin-l-yl)-2-oxoethyl)-6-oxo-l,6- dihydropyridine-3-carbonitrile; l-(2-(4-(4-(5-(2,6-dichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2- yl)piperidin-l-yl)-2-oxoethyl)-5-(difluoromethyl)-6-oxo-l,6-dihydropyridine-3-carbonitrile; 5- (difluoromethyl)-6-oxo-]-(2-oxo-2-(4-(4-(5-(2,4,6-trichlorophenyl)-4,5-dihydroisoxazol-3-yl)lhiazol-2- yl)piperidin-l-yl)ethyl)-l,6-dihydropyridine-3-carbonitrile; 3-chloro-2-(3-(2-(l-(2-(5-cyano-3- (difluoromethyl)-2-oxopyridin-l(2H)-yl)acetyl)piperidin-4-yl)thiazol-4-yl)-4,5-dihydroisoxazol-5- yl)phenyl methanesulfonate; 3-(2-(4-(4-(5-(2,6-ditluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2- yl)piperidin-l-yl)-2-oxoethyl)-l,4-dimethyl-l,3-dihydro-2H-imidazol-2-one; 3-(2-(4-(4-(5-(2,6- dichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-l,4-dimethyl-l,3- dihydro-2H-imidazol-2-one; l,4-dimethyl-3-(2-oxo-2-(4-(4-(5-(2,4,6-trichlorophenyl)-4,5- dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)ethyl)-l,3-dihydro-2H-imidazol-2-one; 3-chloro-2-(3-(2- (l-(2-(3,5-dimethyl-2-oxo-2,3-dihydro-lH-imidazol-l-yl)acetyl)piperidin-4-yl)thiazol-4-yl)-4,5- dihydroisoxazol-5-yl)phenyl methanesulfonate; 3-(2-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3- yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-l-methyl-4-(trifluoromethyl)-1 -dihydro-2H-imidazol-2-one; 3-(2-(4-(4-(5-(2,6-dichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-l- methyl-4-(trifluoromethyl)-l,3-dihydro-2H-imidazol-2-one; l-methyl-3-(2-oxo-2-(4-(4-(5-(2,4,6- trichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)ethyl)-4-(trifluorom
dihydro-2H-imidazol-2-one; 3-chloro-2-(3-(2-(l-(2-(3-methyl-2-oxo-5-(trifluoromethyl)-2,3-dihydro-lH- imidazol-l-yl)acetyl)piperidin-4-yl)thiazol-4-yl)-4,5-dihydroisoxazol-5-yl)phenyl methanesulfonate; 4- (difluoromethyl)-3-(2-(4-(4-(5-(2,6-difluorophe ; 2-oxoethyl)-l -methyl- 1 ,3-dihydro-2H-imidazol-2-one; 3-(2-(4-(4-(5-(2,6-dichlorophenyl)-4,5- dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-4-(difluoroiTiethyl)-l -methyl- 1,3-dihydro- 2H-imidazol-2-one; 4-(difluoromethyl)-l-methyl-3-(2-oxo-2-(4-(4-(5-(2,4,6-trichlorophenyl)-4,5- dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)ethyI)-l,3-dihydro-2H-imidazol-2-one; 3-chloro-2-(3-(2- (l-(2-(5-(difluoromethyl)-3-methyI-2-oxo-2,3-dihydro-lH-imidazol-l-yl)acetyl)piperidin-4-yl)thiazol-4- yl)-4,5-dihydroisoxazol-5-yl)phenyl methanesulfonate; 2-(2-(4-(4-(5-(2,6-difluorophenyl)-4,5- dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l-yl)-2-oxoethyl)-5-methylisoxazol-3(2H)-one; 2-(2-(4-(4-(5- (2,6-dichlorophenyl)-4,5-dihydroisoxazo
3(2H)-one; 5-methyl-2^2-oxo-2-(4-(4-(5-(2,4,6-trichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2- yl)piperidin- l -yl)ethyl)isoxazol-3(2H)-one; 3-chloro-2-(3-(2-( l -(2-(5-methyl-3-oxoisoxazol-2(3H)- yl)acetyl)piperidin-4-yl)thiazol-4-yl)-4,5-dihydroisoxazol-5-yl)phenyl methanesulfonate; 2-(2-(4-(4-(5- (2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin- l -yl)-2-oxoethyl)-5- (trifluoromethyl)isoxazol-3(2H)-one; 2-(2-(4-(4-(5-(2,6-dichlorophenyl)-4,5-dihydroisoxazol-3- yl)thiazol-2-yl)piperidin-l -yl)-2-oxoethyl)-5-(trifluoromethyl)isoxazol-3(2H)-one; 2-(2-oxo-2-(4-(4-(5- (2,4,6-trichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin- l -yl)ethyl)-5- (trifluoromethyl)isoxazol-3(2H)-one; 3-chloro-2-(3-(2-( l-(2-(3-oxo-5-(trifluoromethyl)isoxazol-2(3H)- yl)acetyl)piperidin-4-yl)thiazol-4-yl)-4,5-dihydroisoxazol-5-yl)phenyl methanesulfonate; 5-
(dinuoromethyl)-2-(2-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperi 2-oxoethyl)isoxazol-3(2H)-one; 2-(2-(4-(4-(5-(2,6-dichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2- yl)piperidin- l -yl)-2-oxoethyl)-5-(trifluoromethyl)isoxazol-3(2H)-one; 2-(2-oxo-2-(4-(4-(5-(2,4,6- trichlorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-l -yl)ethyl)-5-(trifluoromethyl)isoxazol- 3(2H)-one; and 3-chloro-2-(3-(2-(l -(2-(3-oxo-5-(trifluoromethyl)isoxazol-2(3H)-yl)acetyl)piperidin-4- yl)thiazol-4-yl)-4,5-dihydroisoxazol-5-yl)phenyl methanesulfonate.
5. The compound of Formula I as claimed in claim 1 , in a composition with one or more inert carriers for controlling or preventing phytopathogenic micro-organisms.
6. The compound of Formula I as claimed in claim 1 , in a composition comprising one or more active compatible compounds selected from fungicides, insecticides, nematicides, acaricides, biopesticides, herbicides, plant growth regulators, antibiotics, fertilizers and nutrients.
7. The compound of Formula I as claimed in claims 5 or 6, wherein the concentration of said compound in the composition ranges from 1 to 90% by weight with respect to the total weight of the composition, preferably from 5 to 50% by weight with respect to the total weight of the composition.
8. Use of compound of Formula I as claimed in claims 1 or 5, for controlling or preventing phytopathogenic fungi, stramenopiles, bacteria, insects, nematodes, mites in agricultural crops and or horticultural crops.
9. Use of compound of Formula I as claimed in claim 1 , for controlling or preventing phytopathogenic fungi and oomycetes in agricultural crops and or horticultural crops.
1 0. Use of the compound Formula I as claimed in claim 9, wherein the agricultural crops are cereals, corn, rice, soybean and other leguminous plants, fruits and fruit trees, grapes, nuts and nut trees, citrus and citrus trees, any horticultural plants, cucurbitaceae, oleaginous plants, tobacco, coffee, tea, cacao, sugar beet, sugar cane, cotton, potato, tomato, onions, peppers and other vegetables, and ornamentals.
1 1 . A method of controlling or preventing infestation of useful plants by phytopathogenic microorganisms in agricultural crops and or horticultural crops wherein the compound of Formula I claimed in claim 1 , is appl ied to the plants, to parts thereof or the locus thereof.
12. A method of controlling or preventing infestation of useful plants by phytopathogenic micro- organisms in agricultural crops and or horticultural crops wherein the compound of Formula I claimed in claim 1 , is applied to the seeds of plants.
13. The method as claimed in claim 12, consists of applying effective dosages of compounds claimed in claim 1 in amounts ranging from 1 gai to 5000 gai per hectare in agricultural or horticultural crops.
14. A compound selected from the group comprising:
2-(3-chloro-2-oxopyridin-l (2H)-yl)acetic acid; 2-(2-oxo-4-(trifluoromethyl)pyridin- l (2H)-yl)acetic acid; 2-(3-(difiuoromethyl)-2-oxopyridin- l(2H)-yl)acetic acid; 2-(3-bromo-2-oxo-5- (trii1uoiOmethyl)pyridin-l (2H)-yl)acetic acid; 2-(5-chloro-2-oxo-3-(trifluoromethyl)pyridin- l (2H)- yl)acetic acid; 2-(5-methyl-2-oxo-3-(trifluoromethyl)pyridin-l (2H)-yl)acetic acid; 2-(6-methyl-2-oxo- 3-(trifluoromethyl)pyridin- l (2H)-yI)acetic acid; 2-(5-fluoro-2-oxo-3-(trifluoromethyl)pyridin- l (2H)- yl)acetic acid; 2-(3-methyl-2-oxo-5-(trifluoromethyl)pyridin- l (2H)-yl)acetic acid; 2-(5-cyclopropyl-
2-oxo-3-(trifluoromethyl)pyridin- l (2H)-yl)acetic acid; 2-(3-cyclopropyl-2-oxo-5-
(tnfluoromethyl)pyridin- l (2H)-yl)acetic acid; 2-(3-bromo-5-cyano-2-oxopyridin- l (2H)-yl)acetic acid; 2-(3-chloro-2-oxo-5-((trifluoromethyl)thio)pyridin- l (2H)-yl)acetic acid; 2-(6-(difluoromethyl)- 2-oxo-3-(trifluoromethyl)pyridin- l (2H)-yl)acetic acid; 2-(2-oxo-3,5-bis(trifluoromethyl)pyridin- l (2H)-yl)acetic acid; 2-(5-chloro-3-(difluoromethyl)-2-oxopyridin- l (2H)-yl)acetic acid; 2-(3-bromo-
5-chloro-2-oxopyridin- l (2H)-yl)acetic acid; 2-(5-chloro-3-cyano-2-oxopyridin-l (2H)-yl)acetic acid; 2-(2-oxo-3,6-bis(trifluoromethyl)pyridin- l (2H)-yl)acetic acid; 2-(3-bromo-5-(difluoromethyl)-2- oxopyridin- l (2H)-yl)acetic acid; 2-(5-cyano-2-oxo-3-(trifluoromethyl)pyridin- l (2H)-yl)acetic acid; 2-(5-chloro-6-methyl-2-oxo-3-(trifluoromethyl)pyridin- l (2H)-yl)acetic acid; 2-(3-((dimethyl(oxo)- X6-sulfaneylidene)amino)-2-oxopyridin- l (2H)-yl)acetic acid; 2-(6-(difluoromethyl)-2-oxopyridin- l (2H)-yl)acetic acid; 2-(3-(ethoxycarbonyl)-2-oxo-5-(trifluorornethyl)pyridin- l (2H)-yl)acetic acid; 2-(5-methyl-2-oxo-3-(trifluoromethyl)pyridin-l (2H)-yl)acetic acid; 2-(5-nitro-2-oxo-3-
(trifluoromethyl)pyridin- l (2H)-yl)acetic acid; 2-(3-bromo-5-(difluoromethyl)-2-oxopyridin- l (2H)- yl)acetic acid; 2-(3-chloro-5-cyano-2-oxopyridin- l (2H)-yl)acetic acid; 2-(3-nitro-2-oxo-5- (trifluoroniethyl)pyridin- l (2H)-yl)acetic acid; 2-(3-cyano-2-oxo-5-(trifluoromethyl)pyridin- l (2H)- yl)acetic acid; 2-(3-cyano-5-(methoxycarbonyl)-2-oxopyridin- l (2H)-yl)acetic acid; 2-(3-carbamoyl- 2-oxo-5-(trifluoromethyl)pyridin-] (2H)-yl)acetic acid; 1 -(carboxymethyl)-2-oxo-5-(trifl uoromethyl)- 1 ,2-dihydropyridine-3-carboxylic acid; l -(carboxymethyl)-5-cyano-6-oxo-l ,6-dihydropyridine-3- carboxylic acid; 2-(3-chloro-5-(difluoiOmethyl)-2-oxopyridin-l (2H)-yl)acetic acid; 2-(3-(tert- butylcarbamoyl)-2-oxo-5-(trifluoromethyl)pyridin- l (2H)-yl)acetic acid; 2-(5,5-dimethyl- ] -oxido-4- phenyl- 1 ,2,3-thiadiazol-2(5H)-yl)acetic acid; 2-(2-methyl-5-oxo-2,5-dihydro- l H-pyrazol- l -yl)acetic acid; 2-(3-(difluoromethyl)-2-methyl-5-oxo-2,5-dihydro- l H-pyrazol- l -yl)acetic acid; 2-(4-bromo-3- (difiuoromethyl)-2-methyl-5-oxo-2,5-diliydro-l H-pyrazol- l -yl)acetic acid; 2-(2-methyl-5-oxo-3- (trifluoromethyl)-2,5-dihydiO-l H-pyrazo]- l -yl)acetic acid; and 2-(2,5-dimethyl-3-oxo-2,3-dihydro- l H-pyrazol- l -yl)acetic acid,
corresponding C1-C3 alkyl esters, acyl halides and polymorphs thereof.
15. A process for preparing compound as claimed in claim 14, wherein said process comprises steps of: a. alkylating 2-oxo compound using C1-C3 alkyl 2-haloacetate to obtain C1-C3 alkylated 2-oxo compound,
b. optionally, hydrolyzing C1-C3 alkylated 2-oxo compound to obtain an acid, or
c. halogenating C1-C3 alkylated 2-oxo compound obtained in step (a) or the acid obtained in step (b) to obtain acyl halide.
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