BRPI0713833B1 - COMPOUND, PLANT DISEASE CONTROL METHOD AND FUNGICIDAL COMPOSITIONS - Google Patents

Abstract

COMPOUNDS, METHOD FOR CONTROLLING PLANT DISEASES AND FUNGICIDAL COMPOSITIONS. The present invention describes compounds of Formulas 1, 1A, 1B and 1C that include all their geometric isomers, stereoisomers, N-oxides and salts, wherein R1, R2, R4a1, R4a2, A, Aa, G, M, W, Z1, Z3, X, J, J1 and n are as defined in the specification. Also described are compositions containing the compounds of Formula 1 and methods of controlling plant diseases caused by fungal pathogens, which comprise applying an effective amount of a compound or composition according to the present invention.

Description

FIELD OF INVENTION

[001] The present invention relates to certain carboxamides, their N-oxides, salts and compositions, as well as methods of using them as fungicides.

BACKGROUND OF THE INVENTION

[002] The control of plant diseases caused by fungal plant pathogens is extremely important to achieve high production efficiency. Plant disease damage to ornamental, vegetable, field, cereal and fruit crops can cause significant reduction in productivity and thus result in increased costs for the consumer. Many products are commercially available for these purposes, but there remains a need for new compounds that are more effective, less expensive, less toxic, environmentally safer or have different sites of action.

[003] International Publication No. WO 05/003128 describes thiazolylpiperidine derivatives of Formula I as MTP (microsomal triglyceride transfer protein) inhibitors: where: A is a radical selected from the radicals a1 and a2 below: or and R1, R2, R3, R4 and R5 are as defined in the specification.

[004] International Patent No. WO 04/058751 describes piperidinyl-thiazole carboxamide derivatives for changing vascular tone.

BRIEF DESCRIPTION OF THE INVENTION

[005] The present invention relates to compounds of Formula 1, including all their geometric isomers, stereoisomers, N-oxides and salts, agricultural compositions that contain them and their use as fungicides: wherein: - R1 is optionally substituted phenyl, naphthalenyl or five- or six-membered heteroaromatic ring; - A is CHR15 or NR16; - R15 is H, 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, alkylthioalkyl C2-C4 alkylsulfinylalkyl C1-C4 alkylthio, C1-C4 haloalkylthio, C1-C4 alkylsulfinyl, C1-C4 haloalkylsulfinyl, C1-C4 alkylsulfonyl or C1-C4 haloalkylsulfonyl; - R16 is H, 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 or C1-C4 haloalkylsulfonyl; W is O or S; X is a radical selected from: in which the bond of X1, X2, X3, X4, X5, X6, X7, X8 or “u” is connected to the carbon atom identified with “r” in Formula 1 and the bond that is identified with “v” is connected to G; - each R2 is independently C1-C4 alkyl, C1 C4 alkenyl, C1-C4 haloalkyl, C1-C4 alkoxy, halogen, cyano or hydroxy; or - two R2 are taken together as C1-C3 alkylene or C2-C3 alkenylene to form a bridged bicyclic or fused bicyclic ring system; or - two R2 bonded to carbon atoms of adjacent rings linked by a double bond are taken together as -CH=CH- CH=CH- optionally substituted with one to three substituents selected from C1-C4 alkyl, C1 haloalkyl- C4, C1-C4 alkoxy, C1-C4 haloalkoxy, halogen, hydroxy, amino, cyano and nitro; - G is an optionally substituted five-membered heteroaromatic ring or a saturated or partially saturated five-membered heterocyclic ring; - J is a five-, six-, or seven-membered ring, an eight- to eleven-membered bicyclic ring system, or a seven- to eleven-membered spirocyclic ring system, wherein each ring or ring system contains ring members selected from carbon and optionally one to four heteroatoms selected from up to 2 O, up to 2 S and up to 4 N and optionally including one to three ring members selected from the group consisting of C(=O), C(=S), S(O), S(O)2 and SiR17R18, wherein each ring or ring system is optionally substituted with one to five substituents selected independently from R5; - each R5 is independently H, halogen, cyano, hydroxy, amino, nitro, -CHO, -C(=O)OH, -C(=O)NH2, -NR25R26, C1-C6 alkyl, C2-C6 alkenyl, alkynyl C2-C6, C1-C6 haloalkyl, C2-C6 haloalkenyl, C2C6 haloalkynyl, C3-C8 cycloalkyl, C3-C8 halocycloalkyl, C4-C10 alkylcycloalkyl, C4-C10 cycloalkylalkyl, C6-C14 cycloalkylcycloalkyl, C4C10 halocycloalkylalkyl, C4-C10 alkylcycloalkylalkyl la C5-C10, C3-C8 cycloalkenyl, C3C8 halocycloalkenyl, C2-C6 alkoxyalkyl, C4-C10 cycloalkoxyalkyl, C3-C8 alkoxyalkoxyalkyl, C2-C6 alkylthioalkyl, C2-C6 alkylsulfinylalkyl, C2-C6 alkylsulfonylalkyl, C2-C6 alkylaminoalkyl, C2-dialkylaminoalkyl 3-C8, C2C6 haloalkylaminoalkyl , C4-C10 cycloalkylaminoalkyl, C2-C6 alkylcarbonyl, C2C6 haloalkylcarbonyl, C4-C8 cycloalkylcarbonyl, C2-C6 alkoxycarbonyl, C4-C8 cycloalkoxycarbonyl, C5-C10 cycloalkylalkoxycarbonyl, C2-C6 alkylaminocarbonyl, C3-C8 dialkylaminocarbonyl, C4-C8 cycloalkylaminocarbonyl, halo alkoxyalkyl C2-C6, 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, haloalkynyloxy C2-C6, C2-C6 alkoxyalkoxy, C2-C6 alkylcarbonyloxy, C2-C6 haloalkylcarbonyloxy, C4-C8 cycloalkylcarbonyloxy, C3-C6 alkylcarbonylalkoxy, C1-C6 alkylthio, C1-C6 haloalkylthio, C3C8 cycloalkylthio, C1-C6 alkylsulfinyl, C1- C6, C1-C6 alkylsulfonyl, C1-C6 haloalkylsulfonyl, C3-C8 cycloalkylsulfonyl, C3-C10 trialkylsilyl, C1-C6 alkylsulfonylamino, C1-C6 or -Z2Q haloalkylsulfonylamino; - R25 is H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, C2-C6 alkylcarbonyl, C2-C6 haloalkylcarbonyl, C2-C6 alkoxycarbonyl or C2-C6 haloalkoxycarbonyl; - R26 is C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, C2-C6 alkylcarbonyl, C2-C6 haloalkylcarbonyl, C2-C6 alkoxycarbonyl, C2-C6 haloalkoxycarbonyl or -Z4Q; - each R17 and R18 is 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- haloalkyl C5, C1-C5 alkoxy or C1-C5 haloalkoxy; - each Q is independently phenyl, benzyl, naphthalenyl, a five- or six-membered heteroaromatic ring or an eight- to eleven-membered heteroaromatic bicyclic ring system, each optionally substituted with one to five substituents independently selected from R7 on members of rings of carbon atoms and R12 on members of rings of nitrogen atoms; or - each Q is independently a three- to seven-membered non-aromatic carbocyclic ring, a five-, six- or seven-membered non-aromatic heterocyclic ring, or an eight- to eleven-membered non-aromatic bicyclic ring system, each of which optionally includes members of rings selected from the group consisting of C(=O), C(=S), S(O), S(O)2 and SiR17R18 and optionally substituted with one to five substituents selected independently from R7 on members of rings of carbon atoms and R12 on members of rings of nitrogen atoms; - each R7 is independently 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-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 trialkylsilyl; or - R5 and R7 are taken together with the atoms linking R5 and R7 to form an optionally substituted five to seven membered ring containing ring members selected from carbon and optionally one to three heteroatoms selected from up to 1 O, up to 1 S and up to 1 N and which optionally include one to three ring members selected from the group consisting of C(=O), C(=S), S(O), S(O )2 and SiR17R18; - R12 is H, C1-C3 alkyl, C1-C3 alkylcarbonyl, C1-C3 alkoxy or C1-C3 alkoxycarbonyl; - each Z1 and Z2 is independently a direct bond, O, C(=O), S(O)m, CHR20 or NR21; - each Z4 is independently O, C(=O), S(O)m or CHR20; - each R20 is independently H, C1-C4 alkyl or C1-C4 haloalkyl; - each R21 is independently H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, C2-C6 alkylcarbonyl, C2-C6 haloalkylcarbonyl, C2-C6 alkoxycarbonyl or C2-C6 haloalkoxycarbonyl; - each m is independently 0, 1 or 2; e - n is 0, 1 or 2; provided that: (a) when R1 is unsubstituted thienyl, X is X1 and the ring containing X is saturated, G is an unsubstituted thiazole ring connected at its 2-position to A is CHR15, R15 is H and J is an isoxazole ring connected in its 4th position to Z1, substituted in its 5th position with methyl and in its 3rd position with meta-substituted phenyl, Z1 is O, C(=O), S (O)m, CHR20 or NR21.

[006] More specifically, the present invention relates to compounds of Formula 1 that include all their geometric isomers and stereoisomers, N-oxides and salts; provided that (b) when A is NR16, and (c) when A is CHR15, R15 is H, W is O, X is X1, n is 0, G is a thiazole ring connected at its 2-position to its 5th position to H, F, Cl or Br, Z1 is a direct bond and R1 is: when J is a substituted phenyl or substituted pyrimidin-4-yl, it is substituted with at least one R5 other than H, SCF3, OCF3, C(CH3)3, S(O)2CF3, OCH3, CF3, Br, cyclopropyl, 1-methylcyclopropyl, OH or CF2CH3 and, when J is a 2,3-dihydro-1H-inden-4-yl or 5,6,7,8-tetrahydronaphthalen-2-yl, it is substituted with at least one R5 is different from H, CH3 or C(CH3)3.

[007] The present invention also relates to a compound of Formula 1A: wherein: - each R4a1 and R4a2 is independently C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, cyclopropyl, C1-C3 haloalkyl, C2-C3 haloalkenyl, C2-C3 haloalkynyl, halocyclopropyl, halogen, cyano, nitro, C1-C2 alkoxy, C1-C2 haloalkoxy, C1-C2 alkylthio, C1-C2 haloalkylthio, C2-C3 alkoxyalkyl, C2-C3 alkylcarbonyl, C2-C3 alkoxycarbonyl, C2-C3 alkylaminocarbonyl or C3-C4 dialkylaminocarbonyl; - Aa is H, CH2CO2H, CH2CO2R30 or CH2C(=O)Cl; and - R30 is C1-C3 alkyl.

[008] The present invention also relates to a compound of Formula 1B: wherein: - each R4a1 and R4a2 is independently C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, cyclopropyl, C1-C3 haloalkyl, C2-C3 haloalkenyl, C2-C3 haloalkynyl, halocyclopropyl, halogen, cyano, nitro, C1-C2 alkoxy, C1-C2 haloalkoxy, C1-C2 alkylthio, C1-C2 haloalkylthio, C2-C3 alkoxyalkyl, C2-C3 alkylcarbonyl, C2-C3 alkoxycarbonyl, C2-C3 alkylaminocarbonyl or C3-C4 dialkylaminocarbonyl; and - Z3 is CN or C(=S)NH2.

[009] The present invention also relates to a compound of Formula 1C: where: - M is C1-C3 alkyl, C1-C3 haloalkyl, hydroxy, C1-C4 alkoxy, C1-C2 haloalkoxy, C1-C4 alkylamino, C2-C8 dialkylamino, 1-piperidinyl, 1-pyrrolidinyl or 4-morpholinyl; and - J1 is J-29-1 through J-29-58 shown in Illustration A as described below.

[010] More specifically, the present invention relates to compounds of Formulas 1A, 1B and 1C, including all their geometric isomers and stereoisomers, N-oxides or salts (except that the compounds of Formula 1C according to the present invention are limited to the stereoisomer embodiments illustrated for J1 in the Summary Description of the Invention above).

[011] The present invention also relates to a fungicidal composition comprising a fungicidal effective amount of a compound of Formula 1 and at least one additional component selected from the group consisting of surfactants, solid diluents or liquid diluents.

[012] The present invention also relates to a fungicidal composition comprising a mixture of a compound of Formula 1 (including all its geometric isomers, stereoisomers, N-oxides and salts) and at least one other fungicide (such as at least another fungicide that has a different site of action).

[013] The present invention further relates to a method of controlling plant diseases caused by fungal plant pathogens which comprises applying to the plant or part thereof, or to the plant seed, an amount effective as a fungicide of Formula 1 ( including all geometric isomers, stereoisomers, N-oxides and salts) (such as in the form of composition described herein).

[014] The present invention also relates to fungicidal plant disease control methods and compositions as described above, except for the proviso that (a) is removed from the definition of the scope of Formula 1.

DETAILED DESCRIPTION OF THE INVENTION

[015] As used herein, the expressions “comprises”, “which comprises”, “includes”, “which includes”, “contains”, “which contains” or any other of their variations, are intended to cover a non-exclusive inclusion. A composition, process, method, article or apparatus comprising a list of elements, for example, is not necessarily limited to just those elements, but may include other elements not expressly related to or inherent in that composition, process, method, article or apparatus . Furthermore, unless expressly indicated otherwise, “or” indicates inclusive or and not or exclusive. Condition A or B, for example, is satisfied by any of the following: A is true (or present) and B is false (or absent), A is false (or absent) and B is true (or present), and both, A and B are true (or present).

[016] Furthermore, the use of “a” or “an” is used to describe elements and components according to the present invention. This is done merely for convenience and to provide a general sense of the present invention. The present specification should be read as including one or at least one and the singular also includes the plural, unless it is obvious to indicate otherwise.

[017] As indicated in the present specification and in the claims, “plant” includes members of the plant kingdom, particularly seed plants (Spermatopsida), in all stages of life, including young plants (such as germinating seeds that develop into seedlings) and mature reproductive stages (such as flower and seed-producing plants). Plant parts include geotropic members that typically grow below the surface of the growing medium (such as soil), such as roots, tubers, bulbs, and underground stems, as well as members that grow above the growing medium, such as foliage (including stems and leaves), flowers, fruits and seeds.

[018] In the descriptions above, the term “alkyl”, used alone or in compound words such as “alkylthio” or “haloalkyl”, includes straight-chain or branched alkyl, such as methyl, ethyl, n-propyl, i-propyl or the different isomers of butyl, pentyl or hexyl. “Alkenyl” includes straight-chain or branched alkenes such as ethenyl, 1-propenyl, 2-propenyl and the different isomers of butenyl, pentenyl and hexenyl. “Alkenyl” also includes polyenes such as 1,2-propadienyl and 2,4-hexadienyl. “Alkynyl” includes straight-chain or branched alkynes such as ethynyl, 1-propynyl, 2-propynyl and the different isomers of butynyl, pentynyl and hexinyl. "Alkynyl" may also include moieties composed of several triple bonds such as 2,5-hexadiinyl. “Alkylene” indicates straight-chain or branched alkanediyl. Examples of “alkylene” include CH2, CH2CH2, CH(CH3), CH2CH2CH2, CH2CH(CH3) and the different isomers of butylene. “Alkenylene” indicates straight-chain or branched alkenediyl that contains an olefinic bond. Examples of “alkenylene” include CH=CH, CH2CH=CH, CH=C(CH3),CH2CH=CH and CH2CH=CHCH2. “Alkoxy” includes, for example, methoxy, ethoxy, n-propyloxy, isopropyloxy and the different isomers butoxy, pentoxy and hexyloxy. “Alkoxyalkyl” indicates alkoxy over alkyl substitution. Examples of “alkoxyalkyl” include CH3OCH2, CH3OCH2CH2, CH3CH2OCH2, CH3CH2CH2CH2OCH2 and CH3CH2OCH2CH2. “Alkylthio” includes straight-chain or branched alkylthio moieties such as methylthio, ethylthio and the different isomers propylthio, butylthio, pentylthio and hexylthio. “Alkylsulfinyl” includes both enantiomers of an alkylsulfinyl group. Examples of “alkylsulfinyl” include CH3S(O), CH3CH2S(O), CH3CH2CH2S(O), (CH3)2CHS(O), and the different isomers of butylsulfinyl, pentylsulfinyl, and hexylsulfinyl. Examples of “alkylsulfonyl” include CH3S(O)2, CH3CH2S(O)2, CH3CH2CH2S(O)2, (CH3)2CHS(O)2, and the different isomers of butylsulfonyl, pentylsulfonyl, and hexylsulfonyl. Examples of “alkylcarbonyl” include C(O)CH3, C(O)CH2CH2CH3 and C(O)CH(CH3)2. Examples of “alkoxycarbonyl” include CH3OC(=O), CH3CH2OC(=O), CH3CH2CH2OC(=O), (CH3)2CHOC(=O), and the different isomers of butoxy or pentoxycarbonyl. Examples of “alkylaminocarbonyl” include CH3NHC(=O)-, CH3CH2CH2NHC(=O), (CH3)2CH2CH2NHC(=O)-, (CH3)2CHNHC(=O)- and the different isomers of butylamino or pentylaminocarbonyl. Examples of “dialkylaminocarbonyl” include (CH3)2NC(=O)-, (CH3CH2)2NC(=O)-, CH3CH2(CH3)NC(=O)-, (CH3)2CHN(CH3)C(=O)- and CH3CH2CH2(CH3)NC(=O)-. “Alkylamino”, “dialkylamino” and the like are defined analogously to the examples above. "Trialkylsilyl" includes three straight-chain and/or branched alkyl radicals connected and linked through a silicon atom, such as trimethylsilyl, triethylsilyl and tert-butyldimethylsilyl. “Cycloalkyl” includes, for example, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Examples of “cycloalkylalkyl” include cyclopropylmethyl, cyclopentylethyl and other cycloalkyl moieties attached to branched or straight-chain alkyl groups. “Alkylcycloalkyl” includes alkyl substitution on a cycloalkyl moiety. Examples include 4-methylcyclohexyl and 3-ethylcyclopentyl.

[019] Unless otherwise indicated, “ring” or “ring system” as a component of Formula 1 (such as substituent J and Q) is carbocyclic or heterocyclic. The term “ring system” indicates two or more connected rings. The term “spirocyclic ring system” indicates a ring system consisting of two rings connected by a single atom (such that the rings contain a single atom in common). Illustrates a portion J1 which is a spirocyclic ring system is J-29-28 illustrated in the definition of Formula 1C. The term “bicyclic ring system” indicates a ring system consisting of two rings that share two or more common atoms. In a “fused bicyclic ring system,” the common atoms are adjacent, and therefore the rings share two adjacent atoms and the bond that connects them. In a “bridged bicyclic ring system”, the common atoms are not adjacent (i.e., there is no bond between the bridgehead atoms). A “bridged bicyclic ring system” is conceptually formed by bonding a segment of one or more atoms to non-adjacent ring members of a ring.

[020] A ring, bicyclic ring system or spirocyclic ring system may be part of an extended ring system that contains more than two rings in which substituents on the ring, bicyclic or spirocyclic ring system are taken together to form the additional rings, which may have bicyclic and/or spirocyclic relationships with other rings in the extended ring system. The specific J1 portion J-29-26 illustrated in the definition of Formula 1C, for example, consists of a dihydro isoxazoline ring that contains a substituent R5 as Z2Q, which is a cyclobutyl ring substituted with two methyl groups as R7 and also a group R7 taken together with another substituent R5 on the isoxazoline dihydro ring as -CH2CH2- to form the additional six-membered ring component in the ring system.

[021] The expression “ring member” indicates an atom (such as C, O, N or S) or another moiety (such as C(=O), C(=S), S(O) or S(O )2) that forms the main chain of a ring or system of rings. The term “carbocyclic ring” indicates a ring in which the atoms forming the main ring chain are selected from carbon only. The term “carbocyclic ring system” indicates two or more fused rings in which the atoms forming the main chain of the rings are selected from carbon only. The term “heterocyclic ring” indicates a ring in which at least one of the atoms forming the main ring chain is other than carbon. The term “heterocyclic ring system” indicates two or more fused rings in which at least one of the atoms forming the main chain of the rings is other than carbon. “Aromatic” indicates that each of the ring atoms lies essentially in the same plane and has a p-orbital perpendicular to the ring plane, in which (4n + 2) π electrons, where n is a positive integer, are associated to the ring to satisfy Hückel's law. The term “heteroaromatic ring” indicates a heterocyclic ring that is aromatic. The term “saturated heterocyclic ring” indicates a heterocyclic ring that contains only single bonds between ring members. The term “partially saturated heterocyclic ring” indicates a heterocyclic ring that contains at least one double bond but is not aromatic.

[022] The dotted line in Formula 1 and in other rings illustrated in the present specification (such as J-44, J-45, J-48 and J-49 in Illustration 3) represent that the indicated bond may be a simple bond or a double bond. Unless otherwise indicated, heterocyclic rings and ring systems are linked to the remainder of Formula 1 through any available carbon or nitrogen by substituting a hydrogen on said carbon or nitrogen and all substituents on the heterocyclic rings and ring systems. Rings are bonded through any available carbon or nitrogen by substituting a hydrogen on said carbon or nitrogen.

[023] As already described, J is a ring with five, six or seven members, a bicyclic ring system with eight to eleven members or a spirocyclic ring system with seven to eleven members, in which each ring or ring system contains ring members selected from carbon and optionally one to four heteroatoms selected from up to 2 O, up to 2 S and up to 4 N and optionally including one to three ring members selected from the group consisting of C (=O), C(=S), S(O), S(O)2 and SiR17R18, wherein each ring or ring system is optionally substituted with one to five substituents selected independently from R5. Since heteroatoms are optional, zero to four heteroatoms can be present. In the present specification, the heteroatoms selected from up to 2 S are atoms and not the S(O) or S(O)2 moieties. Heteroatoms selected from up to 4 N may be oxidized to the form of N-oxides, as the present invention also relates to N-oxide derivatives of the compounds of Formula 1. The one to three optional ring members selected from group consisting of C(=O), C(=S), S(O), S(O)2 and SiR17R18 are therefore in addition to the one to four optional heteroatoms selected from up to 2 O, up to 2 S and up to 4 N. It is worth noting that when the total amount of unoxidized sulfur atoms (i.e., S) and portions of oxidized sulfur (i.e., S(O) and S(O)2) does not exceed 2, such that at most two ring members are selected from S, S(O) and S(O)2 are present in the ring or ring system. When none of the optional heteroatoms and none of the optional ring members selected from S(O), S(O)2 and SiR17R18 are present, the ring or ring system is carbocyclic. R5 substituents can be attached to carbon ring members and nitrogen ring members that have an available attachment point. The carbon-based ring members C(=O) and C(=S) have no available attachment points. Furthermore, in SiR17R18 ring systems, the substituents R17 and R18 are defined separately otherwise and these ring members cannot be additionally substituted with R5. Since the R5 substituents are optional, zero to five substituents can be present, limited by the number of available attachment points.

[024] Similarly, R5 and R7 can be taken together with the atoms linking R5 to R7 to form an optionally substituted five- to seven-membered ring containing ring members selected from carbon and optionally one to three heteroatoms selected from up to 1 O, up to 1 S and up to 1 N and optionally including one to three ring members selected from the group consisting of C(=O), C(=S), S(O ), S(O)2 and SiR17R18. Since heteroatoms are optional, zero to three heteroatoms can be present. In the present specification, the heteroatom selected from up to 1 S is an atom and not the S(O) or S(O)2 moieties. The heteroatom selected from up to 1 N can be oxidized as an N-oxide, as the present invention also relates to N-oxide derivatives of the compounds of Formula 1. The one to three optional ring members selected from the group which consists of C(=O), C(=S), S(O), S(O)2 and SiR17R18 are therefore in addition to the one to three optional heteroatoms selected from up to 1 O, up to 1 S and up to 1 N. It is worth noting that when the total amount of unoxidized sulfur atoms (i.e. S) and oxidized sulfur portions (i.e. S(O) and S(O)2) does not exceed 1 at most a ring member selected from S, S(O) and S(O)2 is present in the ring. When none of the optional heteroatoms and none of the optional ring members selected from S(O), S(O)2 and SiR17R18 are present, the ring is carbocyclic. The five- to seven-membered ring is optionally replaced. The substituents on the atoms linking R5 and R7 are described in the definition of the components linking R5 and R7. When the linker Z2 is CHR20, for example, the substituent R20 is defined as being H, C1-C4 alkyl or C1-C4 haloalkyl. With reference to optional substituents attached to the part of the ring consisting of R5 and R7 taken together, an optional substituent is a non-hydrogen substituent that does not eliminate fungicidal activity. Optional substituents may be attached to carbon ring members and nitrogen ring members that have an available attachment point. The carbon-based ring members C(=O) and C(=S) have no available attachment points. Furthermore, in SiR17R18 ring members, the substituents R17 and R18 are otherwise defined separately and these ring members cannot be further substituted.

[025] The term “halogen”, alone or in compound words such as “haloalkyl”, includes fluorine, chlorine, bromine or iodine. Furthermore, when used in compound words such as “haloalkyl”, said alkyl may be fully or partially replaced with halogen atoms that may be identical or different. Examples of “haloalkyl” include F3C, ClCH2, CF3CH2 and CF3CCl2. The terms “haloalkenyl”, “haloalkynyl”, “halocycloalkyl”, “haloalkoxy”, “haloalkylthio” and the like are defined analogously to the term “haloalkyl”. Examples of “haloalkenyl” include (Cl)2C=CHCH2 and CF3CH2CH=CHCH2. Examples of “haloalkynyl” include HCECCHCI, CF3CEC, CCI3CEC and FCH2CECCH2. Examples of “haloalkoxy” include CF3O, CCl3CH2O, HCF2CH2CH2O and CF3CH2O. Examples of “haloalkylthio” include CCl3S, CF3S, CCl3CH2S and ClCH2CH2CH2S. Examples of “haloalkylsulfinyl” include CF3S(O), CCl3S(O), CF3CH2S(O) and CF3CF2S(O). Examples of “haloalkylsulfonyl” include CF3S(O)2, CCl3S(O)2, CF3CH2S(O)2 and CF3CF2S(O)2.

[026] The total number of carbon atoms in the substituent group is indicated by the suffix “Ci-Cj” where i and j are numbers from 1 to 10. C1-C4 alkylsulfonyl designates, for example, methylsulfonyl to butylsulfonyl; C2 alkoxyalkyl means 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 of which include CH3CH2CH2OCH2 and CH3CH2OCH2CH2.

[027] When a compound is substituted with a substituent that contains a subscript indicating that the amount of said substituents may vary, when the amount of said substituents is greater than 1, said substituents are independently selected from the group of defined substituents . Furthermore, when a range is indicated (such as i-j substituents), the number of substituents can be selected from the integers i to j, inclusive. When a group (such as J) contains a substituent (such as R5) which may be hydrogen, when that substituent is taken as hydrogen, it is recognized as being equivalent to said unsubstituted group. When showing a variable group as optionally attached to a position, such as (R2)n where n may be 0 or, as a further example, (R4)k where k may be 0 in Illustration 1, hydrogen may be in the position even if not indicated in the variable group definition (such as R2 and R4). When a position on a group is stated to be “unsubstituted”, the hydrogen atoms are bonded to absorb any free valence. The expression “optionally substituted”, with respect to groups related to R1, R2, R5, R7, G, J and Q, designates groups that are not substituted or that contain at least one non-hydrogen substituent. Unless otherwise indicated, these groups may be replaced with as many optional substituents as can be accommodated by replacing a hydrogen atom with a non-hydrogen substituent on any available nitrogen or carbon atom. Commonly, the number of optional substituents (when present) ranges from 1 to 3. When a specified range for the number of substituents (such as where x is an integer from 0 to 5 in Illustration 3) exceeds the number of available positions for substituents on a ring (such as two available positions for (R5)x on J-1 in Illustration 3), the actual upper end of the range is recognized as the number of available positions. The expression “optionally substituted” indicates that the number of substituents can be zero. The expression “optionally substituted with up to two substituents selected from R3 on carbon ring members and selected from R11 on nitrogen ring members”, for example, indicates that zero, one or two substituents may be present (if the number of potential connection points allows) and, therefore, the number of substituents R3 and R11 can be zero. Similarly, the expression “optionally substituted with one to five substituents” indicates that 0, 1, 2, 3, 4 or 5 substituents may be present if the number of available connection points allows it. The expression “unsubstituted”, with respect to a group such as a ring or ring system, indicates that the group does not contain any substituent other than its one or more bonds to the remainder of Formula 1. The expression “meta-substituted phenyl” indicates a phenyl ring substituted with a non-hydrogen substituent in a meta position with respect to the bond of the phenyl ring to the remainder of Formula 1.

[028] As indicated above, R1 is an optionally substituted phenyl, naphthalenyl or a five- or six-membered heteroaromatic ring; G is an optionally substituted five-membered heteroaromatic ring or a saturated or partially saturated five-membered heterocyclic ring; and R5 and R7 may be taken together with the atoms linking R5 and R7 to form an optionally substituted five to seven membered ring containing ring members selected from carbon and optionally one to three heteroatoms selected from up to 1 O, up to 1 S and up to 1 N and optionally includes one to three ring members selected from the group consisting of C(=O), C(=S), S(O), S(O)2 and SiR17R18. The term “substituted”, with respect to the definitions of R1, G, R5 and R7, designates groups that have at least one non-hydrogen substituent that does not eliminate fungicidal activity. Because these groups are optionally substituted, they need not contain any non-hydrogen substituents. Because these groups are “optionally substituted” without the indicated number of substituents, these groups can be replaced with as many optional substituents as can be accommodated by replacing a hydrogen atom with a non-hydrogen substituent on any carbon or nitrogen atom. available.

[029] The nomenclature of substituents in this specification uses recognized terminology that provides conciseness in the precise guidance of the chemical structure for those skilled in the art. For brevity, location descriptions may be omitted; “pyrazol-1-yl” indicates “1H-pyrazol-1-yl” according to the Chemical Abstracts nomenclature system. The term “pyridyl” is synonymous with “pyridinyl”. The order of relationship of substituents may be different from the Chemical Abstracts system if the difference does not affect the meaning.

[030] The compounds according to the present invention can exist in the form of one or more stereoisomers. The various stereoisomers include enantiomers, diastereomers, atropisomers, and geometric isomers. Those skilled in the art will appreciate that a stereoisomer may be more active and/or may exhibit beneficial effects when enriched with respect to the other stereoisomer(s) or when separated from the other stereoisomer(s). . Furthermore, those skilled in the art know how to selectively separate, enrich and/or prepare said stereoisomers. The compounds according to the present invention may be present in the form of a mixture of stereoisomers, individual stereoisomers or as an optically active form. When J is J-29 (see Illustration 3) linked in position 3 to the rest of Formula 1 and J-29 contains a substituent R5 other than H in position 5, for example, Formula 1 has a chiral center on the carbon atom next to it. which R5 is on. The two enantiomers are illustrated as Formula 1' and Formula 1” with the chiral center identified with an asterisk (*).

[031] The present invention comprises racemic mixtures, such as equal amounts of the enantiomers of Formulas 1' and 1”. Furthermore, the present invention includes compounds that are enriched compared to the racemic mixture in one enantiomer of Formula 1. Also included are essentially pure enantiomers of compounds of Formula 1, such as Formula 1' and Formula 1”.

[032] When enantiomerically enriched, one enantiomer is present in greater quantities than the other and the extent of enrichment can be defined by an expression of enantiomeric excess (“ee”), which is defined as (2x-1/100%, where x is the mole fraction of the dominant enantiomer in the mixture (ee of 20%, for example, corresponds to a 60:40 ratio of enantiomers).

[033] Preferably, the compositions according to the present invention have an enantiomeric excess of at least 50%; more preferably, enantiomeric excess of at least 75%; preferably even greater, enantiomeric excess of at least 90% and, more preferably, enantiomeric excess of at least 94% of the most active isomer. Enantiomerically pure realizations of the most active isomer deserve specific observation.

[034] Compounds of Formula 1 may comprise additional chiral centers. Substituents and other molecular components such as R4, R5, R7, G, J, Q and X1 through X9, for example, may contain chiral centers. The present invention comprises racemic mixtures as well as enriched and essentially pure stereoconfigurations at these additional chiral centers.

[035] The compounds according to the present invention can exist in the form of one or more conformational isomers due to restricted rotation around the amide bond (such as C(W)-N) in Formula 1. The present invention comprises mixtures of conformational isomers. Furthermore, the present invention includes compounds that are enriched in one conformer relative to the others.

[036] Some of the rings and unsaturated ring systems shown in Illustrations 1, 2, 3 and 4 may have an arrangement of single and double unions between ring members different from that illustrated. These different arrangements of unions for a specific arrangement of ring atoms correspond to different tautomers. For these rings and unsaturated ring systems, the specific tautomer illustrated should be considered representative of all possible tautomers for the ring atom arrangement shown. Tables listing specific compounds that incorporate the ring and ring systems shown in the Illustrations may involve a tautomer other than the tautomer shown in the Illustrations.

[037] The compounds according to the present invention include N-oxide derivatives. Those skilled in the art will appreciate that not all nitrogen-containing heterocycles can form N-oxides, as nitrogen requires a lone pair of electrons available for oxidation to the oxide; Those skilled in the art will recognize nitrogen-containing heterocycles that can form N-oxides. Those skilled in the art will also recognize that tertiary amines can form N-oxides. Synthetic methods of preparing N-oxides of heterocycles and tertiary amines are well known to those skilled in the art, including the oxidation of heterocycles and tertiary amines with peroxy acids such as peracetic and m-chloroperbenzoic acid (MCPBA), hydrogen peroxide, hydroperoxides alkyl compounds such as tert-butyl hydroperoxide, sodium perborate and dioxiranes such as dimethyldioxirane. These N-oxide preparation methods have been extensively described and analyzed in the literature; see, for example: T. L. Gilchrist in Comprehensive Organic Synthesis, vol. 7, pp. 748-750, S. V. Ley, Ed., Pergamon Press; M. Tisler and B. Stanovnik in Comprehensive Heterocyclic Chemistry, vol. 3, pp. 1820, A. J. Boulton and A. McKillop, Eds., Pergamon Press; M. R. Grimmett and B. R. T. Keene in Advances in Heterocyclic Chemistry, vol. 43, pp. 149161, A. R. Katritzky, Ed., Academic Press; M. Tisler and B. Stanovnik in Advances in Heterocyclic Chemistry, vol. 9, pp. 285-291, A. R. Katritzky and A. J. Boulton, Eds., Academic Press; and G. W. H. Cheeseman and E. S. G. Werstiuk in Advances in Heterocyclic Chemistry, vol. 22, pp. 390-392, A. R. Katritzky and A. J. Boulton, Eds., Academic Press.

[038] The compounds of Formula 1 herein may be in the form of salts suitable for agricultural use. Those skilled in the art recognize that, because in the environment and under physiological conditions the salts of chemical compounds are in equilibrium with their corresponding non-salt forms, the salts share the biological utility of the non-salt forms. Thus, a wide variety of salts of Formula 1 compounds are useful for controlling plant diseases caused by fungal plant pathogens (i.e., they are suitable for agricultural use). Salts of the compounds of Formula 1 include acid addition salts with organic or inorganic acids such as hydrobromic, hydrochloric, nitric, phosphoric, sulfuric, acetic, butyric, fumaric, lactic, maleic, malonic, oxalic, propionic, salicylic, tartaric acids. , 4-toluenesulfonic or valeric. When a compound of Formula 1 contains an acid moiety such as carboxylic acid or phenol, the salts also include those formed with organic or inorganic bases such as pyridine, triethylamine or ammonia, or amides, hydrides, hydroxides or carbonates of sodium, potassium, lithium , calcium, magnesium or barium. Consequently, the present invention comprises compounds selected from Formulas 1, 1A, 1B and 1C, their N-oxides and salts.

[039] Embodiments of the present invention include:

[040] Realization 1. Formula 1 compound in which A is CHR15.

[041] Achievement 1a. Compound according to Embodiment 1 wherein R15 is H, halogen, cyano, hydroxy, -CHO, C1-C4 alkyl, C1-C4 haloalkyl or C2-C5 alkoxycarbonyl.

[042] Achievement 1b. Compound according to Embodiment 1a wherein R15 is H, cyano, hydroxy, methyl or methoxycarbonyl.

[043] Achievement 1c. Compounded according to Realization 1b wherein R15 is H.

[044] Achievement 2. Formula 1 compound in which A is NR16.

[045] Achievement 2a. Compound according to Embodiment 2 wherein R16 is H, C1-C4 alkyl, C1-C4 haloalkyl, C2C4 alkylcarbonyl, C2-C4 haloalkylcarbonyl or C2-C4 alkoxycarbonyl.

[046] Achievement 2b. Compound according to Embodiment 2a wherein R16 is H, methyl, methylcarbonyl or methoxycarbonyl.

[047] Realization 2c. Compounded according to Realization 2b, wherein R16 is H.

[048] Realization 3. Formula 1 compound in which W is O.

[049] Realization 4. Formula 1 compound where W is S.

[050] Realization 5. Compound of Formula 1 in which each R2 is independently C1-C2 alkyl, C1-C2 haloalkyl, C1-C2 alkoxy, halogen, cyano or hydroxy.

[051] Achievement 5a. Compound according to Realization 5 wherein each R2 is independently methyl, methoxy, cyano or hydroxy.

[052] Achievement 5b. Compound according to Realization 5a wherein each R2 is methyl.

[053] Realization 6. Compound of Formula 1 in which n is 0 or 1.

[054] Realization 7. Composed according to Realization 6 where n is 0.

[055] Achievement 7a. Composed according to Realization 6 where n is 1.

[056] Realization 8. Formula 1 compound in which X is X1, X2 or X3.

[057] Realization 9. Composed according to Realization 8 wherein X is X1 or X2.

[058] Realization 10. Composed according to Realization 9 where X is X1.

[059] Realization 11. Compound of Formula 1 in which the ring comprising X is saturated (that is, it contains only simple unions).

[060] Realization 12. Compound of Formula 1 in which R1 is a five- or six-membered phenyl or heteroaromatic ring optionally substituted with non-bonding substituents to make R1 a fused ring system.

[061] Achievement 12a. Compound according to Embodiment 12, wherein: - R1 is phenyl or a five- or six-membered heteroaromatic ring optionally substituted with one to three substituents independently selected from R4a on carbon ring members and R4b on carbon ring members. nitrogen; - each R4a is independently 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-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 trialkylsilyl; and - each R4b is independently C1-C6 alkyl, C3-C6 alkenyl, C3-C6 alkynyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, C3-C6 haloalkenyl, C3-C6 haloalkynyl, C3-C6 halocycloalkyl or C2-C4 alkoxyalkyl .

[062] Realization 12b. Compound according to Embodiment 12a wherein R1 is phenyl or a five- or six-membered heteroaromatic ring optionally substituted with one or two substituents independently selected from R4a on carbon ring members and R4b on nitrogen ring members.

[063] Realization 13. Composed according to Realization 12b, wherein R1 is one of U-1 to U-50 shown in Illustration 1; ILLUSTRATION 1 wherein: - when R4 is bonded to a carbon ring member, said R4 is selected from R4a and, when R4 is bonded to a nitrogen ring member (such as in U-4, U-11 a U-15, U-24 to U-26, U-31 or U-35), the aforementioned R4 is selected from R4b; e-k is 0, 1 or 2.

[064] Realization 14. Composed according to Realization 13, wherein R1 is selected from U-1 to U-5, U-8, U-11, U-13, U-15, U-20 to U-28, U-31, U-36 to U-39 and U-50.

[065] Realization 15. Composed according to Realization 14, wherein R1 is selected from U-1 to U-3, U-5, U-8, U-11, U-13, U-20, U-22, U-23, U-25 to U-28, U-36 to U-39 and U-50.

[066] Realization 16. Composed according to Realization 15, wherein R1 is selected from U-1 to U-3, U-11, U-13, U-20, U-22, U-23, U-36 to U-39 and U-50.

[067] Realization 17. Composed according to Realization 16, where R1 is U-1 or U-50.

[068] Realization 18. Composed according to Realization 17, where R1 is U-1.

[069] Realization 19. Composed according to Realization 17, where R1 is U-50.

[070] Realization 20. Compound according to any of Realizations 12 and 13, wherein each R4a is independently C1C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, cyclopropyl, C1-C3 haloalkyl, C2-C3 haloalkenyl, C2 haloalkynyl -C3, halocyclopropyl, halogen, cyano, nitro, C1-C2 alkoxy, C1-C2 haloalkoxy, C1-C2 alkylthio, C1-C2 haloalkylthio, C2-C3 alkoxyalkyl, C2-C3 alkylcarbonyl, C2-C3 alkoxycarbonyl, C2-C3 alkylaminocarbonyl or C3-C4 dialkylaminocarbonyl.

[071] Realization 21. Compound according to Realization 20, wherein each R4a is independently C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, cyclopropyl, C1-C3 haloalkyl, C2-C3 haloalkenyl, C2-haloalkynyl C3, halocyclopropyl, halogen, cyano, nitro, C1-C2 alkoxy or C1-C2 haloalkoxy.

[072] Realization 22. Compound according to Realization 21, wherein each R4a is independently halogen, C1-C3 alkyl, C1C3 haloalkyl, C1-C2 alkoxy or C1-C2 haloalkoxy.

[073] Realization 23. Compound according to Realization 21, wherein each R4a is independently halogen, C1-C2 alkyl, C1C2 haloalkyl or C1-C2 alkoxy.

[074] Realization 24. Compound according to Realization 23, wherein each R4a is independently C1-C2 alkyl, trifluoromethyl, Cl, Br, I or methoxy.

[075] Realization 25. Compound according to Realization 24, wherein each R4a is independently C1-C2 alkyl, trifluoromethyl, Cl or Br.

[076] Realization 26. Compound according to any of Realizations 12 and 13, wherein each R4b is independently C1-C3 alkyl, C3 alkenyl (such as allyl), C3 alkynyl (such as propargyl), cyclopropyl, C1-C3 haloalkyl , C3 haloalkenyl, C3 haloalkynyl, halocyclopropyl or C2-C3 alkoxyalkyl.

[077] Realization 27. Compound according to Realization 26, wherein each R4b is independently C1-C3 alkyl, C3 alkenyl, C3 alkynyl, cyclopropyl, C1-C3 haloalkyl, C3 haloalkenyl or halocyclopropyl.

[078] Realization 28. Compound according to Realization 27, wherein each R4b is independently C1-C2 alkyl or C1-C2 haloalkyl.

[079] Realization 29. Compound according to Realization 28, wherein each R4b is independently C1-C2 alkyl or trifluoromethyl.

[080] Realization 30. Compound according to Realization 29, in which each R4b is independently C1-C2 alkyl.

[081] Realization 31. Compound according to Realization 13, wherein k is 1 or 2 and at least one R4 is Cl.

[082] Realization 32. Composed according to Realization 13, where k is 1 or 2 and at least one R4 is Br.

[083] Realization 33. Compound according to Realization 13, wherein k is 1 or 2 and at least one R4 is methyl.

[084] Realization 34. Compound according to Realization 13, wherein k is 1 or 2 and at least one R4 is ethyl.

[085] Realization 35. Compound according to Realization 13, wherein k is 1 or 2 and at least one R4 is trifluoromethyl.

[086] Realization 36. Compound according to Realization 13, wherein k is 1 or 2 and at least one R4 is methoxy.

[087] Realization 37. Composed according to Realization 18, where k is 1 and R4 is connected to position 3 or 5 of U-1.

[088] Realization 38. Composed according to Realization 18, where k is 2 and one R4 is connected to position 3 and the other R4 is connected to position 5 of U-1.

[089] Realization 39. Composed according to Realization 19, where k is 1 and R4 is connected to position 2 or 3 of U-50.

[090] Realization 40. Composed according to Realization 19, wherein k is 2 and one R4 is connected to position 2 and the other R4 is connected to position 5 of U-50.

[091] Realization 41. Compound of Formula 1 in which: - G is a five-membered heteroaromatic ring or a saturated or partially saturated five-membered heterocyclic ring, in which each ring is optionally substituted with up to two substituents selected from R3 on carbon ring members and selected from R11 on nitrogen ring members; each R3 is independently C1-C3 alkyl, C1-C3 haloalkyl or halogen; and each R11 is independently C1-C3 alkyl.

[092] Realization 42. Composite of Realization 41, where G is one of G-1 to G-59 shown in Illustration 2: ILLUSTRATION 2 wherein the link projecting to the left is linked to X and the link projecting to the right is linked to Z1; each R3a is independently selected from H or R3; and R11a is selected from H and R11; provided that: - when G is G-6, G-16 or G-42 and each R3a is different from H, R11a is H; - when G is G-25 or G-31, at least one R3a is H; and - when G is one of G-31 to G-35, Z1 is a direct bond or CHR20.

[093] Realization 43. Composed according to Realization 42, wherein G is selected from G-1 to G-3, G-7, G-8, G-10, G-11, G-14, G-15, G-23, G-24, G-26 to G-28, G-30, G-36 to G-38 and G-49 to G-55.

[094] Realization 44. Composed according to Realization 43, wherein G is selected from G-1, G-2, G-7, G-8, G-14, G-15, G-23, G-24, G-26, G-27, G-36, G-37, G-38, G-49, G-50 and G-55.

[095] Realization 45. Composed according to Realization 44, wherein G is selected from G-1, G-2, G-15, G-26, G-27, G-36, G-37 and G-38.

[096] Realization 46. Composed according to Realization 45, wherein G is selected from G-1, G-2, G-15, G-26 and G-36.

[097] Realization 47. Composed according to Realization 46, where G is G-1. Realizations of these compounds in Realizations 1 to 40, Realizations 52 to 83 and Realizations A1 to A5 are worth noting.

[098] Realization 48. Composed according to Realization 46, where G is G-2. Realizations of these compounds in Realizations 1 to 40, Realizations 52 to 83 and Realizations A1 to A5 are worth noting.

[099] Realization 49. Composed according to Realization 46, where G is G-15. Realizations of these compounds in Realizations 1 to 40, Realizations 52 to 83 and Realizations A1 to A5 are worth noting.

[0100] Realization 50. Composed according to Realization 46, where G is G-26. Realizations of these compounds in Realizations 1 to 40, Realizations 52 to 83 and Realizations A1 to A5 are worth noting.

[0101] Realization 51. Composed according to Realization 46, where G is G-36. Realizations of these compounds in Realizations 1 to 40, Realizations 52 to 83 and Realizations A1 to A5 are worth noting.

[0102] Realization 52. Compound according to any of Realizations 41 to 51, wherein R3a is H, C1-C3 alkyl or halogen.

[0103] Realization 53. Compound according to Realization 52, wherein R3a is H or methyl.

[0104] Embodiment 54. Compound according to any of Embodiments 41 to 51, wherein R3a is H and R11a is H or methyl.

[0105] Realization 55. Composed according to any of Formula 1 and Realizations 41 to 51, where G is unsubstituted.

[0106] Realization 56. Compound of Formula 1, where J is one of J-1 to J-82 shown in Illustration 3: wherein the connection shown projecting to the left is connected to Z1; ex is an integer from 0 to 5.

[0107] Achievement 56a. Composite, according to Realization 56, where J is one of J-29-1 to J-29-58 shown in Illustration A: ILLUSTRATION A

[0108] Realization 57. Composed according to Realization 56, wherein J is selected from J-1, J-2, J-3, J-4, J-5, J-7, J-8, J-9, J-10, J-11, J-12, J-14, J-15, J-16, J-20, J-24, J-25, J-26, J-29, J- 30, J-37, J-38, J-45 and J-69.

[0109] Realization 58. Composed according to Realization 57, wherein J is selected from J-4, J-5, J-8, J-11, J-15, J-16, J-20, J-29, J-30, J-37, J-38 and J-69.

[0110] Realization 59. Composed according to Realization 58, wherein J is selected from J-4, J-5, J-11, J-20, J-29, J-37, J-38 and J-69.

[0111] Realization 60. Composed according to Realization 59, where J is J-11.

[0112] Realization 61. Composed according to Realization 59, where J is J-29.

[0113] Achievement 61a. Composed according to Realization 61, where J is any of J-29-1 to J-29-58 (illustrated in Illustration A).

[0114] Realization 62. Composed according to Realization 59, where J is J-69.

[0115] Realization 63. Composed according to Realization 60, wherein position 3 of J-11 is connected to Z1 and position 5 of J-11 is connected to R5 other than H.

[0116] Achievement 63a. Composed according to Realization 63, wherein position 3 of J-11 is connected to Z1 and position 5 of J-11 is connected to Z2Q.

[0117] Realization 64. Composed according to Realization 61, wherein position 3 of J-29 is connected to Z1 and position 5 of J-29 is connected to R5 other than H.

[0118] Achievement 64a. Composed according to Realization 65, wherein position 3 of J-29 is connected to Z1 and position 5 of J-29 is connected to Z2Q.

[0119] Realization 65. Compound of Formula 1 or Realization 56, wherein each R5 is independently H, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C2-C6 haloalkenyl, haloalkynyl C2-C6, C3-C8 cycloalkyl, C3-C8 halocycloalkyl, C4-C10 alkylcycloalkyl, C4-C10 cycloalkylalkyl, C2-C6 alkoxyalkyl, C4-C10 cycloalkoxyalkyl, C3-C8 alkoxyalkoxyalkyl, C2-C6 alkylthioalkyl, C2-C6 alkoxycarbonyl, alkoxy C1-C6, C1-C6 haloalkoxy, C3-C8 cycloalkoxy, C3-C8 halocycloalkoxy, C4-C10 cycloalkylalkoxy, C2-C6 alkenyloxy, C2C6 haloalkenyloxy, C2-C6 alkynyloxy, C2-C6 haloalkynyloxy, C2-C6 alkoxyalkoxy, C2-alkylcarbonyloxy C6, C2-C6 haloalkylcarbonyloxy, C4-C8 cycloalkylcarbonyloxy, C3-C6 alkylcarbonylalkoxy, C1-C6 alkylthio, C1-C6 haloalkylthio, C3-C8 cycloalkylthio, C3-C10 trialkylsilyl, -NR25R26 or Z2Q.

[0120] Embodiment 66. Compound according to Embodiment 65, wherein each R5 is independently H, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, C3-C8 halocycloalkyl, C2-C6 alkoxyalkyl, alkoxy C1-C6, C1-C6 haloalkoxy, C3-C8 cycloalkoxy, C2-C6 alkenyloxy, C2-C6 haloalkenyloxy, C2-C6 alkynyloxy, C2-C6 alkoxyalkoxy, C2-C6 alkylcarbonyloxy, C2-C6 haloalkylcarbonyloxy, C1C6 alkylthio, C1- haloalkylthio C6, trialkylsilyl C3-C10, -NR25R26 or Z2Q.

[0121] Realization 67. Compound according to Realization 66, wherein each R5 is independently H, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -NR25R26 or Z2Q.

[0122] Realization 68. Compound of Formula 1 or according to Realization 56, wherein, in one case, R5 is Z2Q and, in other cases, R5 is independently selected from H, cyano, C1-C4 alkyl, C1C4 haloalkyl, C2-C4 alkylcarbonyl and halogen.

[0123] Realization 69. Compound according to Realization 68, wherein, in other cases, R5 is independently selected from H and C1-C3 alkyl.

[0124] Realization 70. Composed according to Realization 56, where x is 1 or 2.

[0125] Realization 71. Composed according to Realization 70, where x is 1.

[0126] Realization 72. Composed according to Realization 71, wherein R5 is Z2Q.

[0127] Realization 73. Formula 1 compound in which Z1 is a direct bond.

[0128] Realization 74. Formula 1 compound in which Z2 is a direct bond.

[0129] Realization 75. Formula 1 compound in which Q is one of Q-1 to Q-102 shown in Illustration 4: ILLUSTRATION 4 where p is 0, 1, 2, 3, 4 or 5.

[0130] Realization 76. Composed in accordance with Realization 75, wherein Q is selected from Q-1, Q-20, Q-32 to Q-34, Q-45 to Q-47, Q-60 to Q-73, Q-76 to Q-79, Q-84 to Q-94 and Q-98 to Q-102.

[0131] Realization 77. Composed according to Realization 76, wherein Q is Q-1, Q-45, Q-63, Q-64, Q-65, Q-68, Q-69, Q-70, Q-71, Q-72, Q-73, Q-76, Q-78, Q-79, Q-84, Q-85, Q-98, Q-99, Q-100, Q-101 or Q- 102.

[0132] Realization 78. Composed according to Realization 77, wherein Q is Q-45, Q-63, Q-64, Q-65, Q-68, Q-69, Q-70, Q-71, Q-72 or Q-85.

[0133] Achievement 78a. Composed according to Realization 78, wherein Q is Q-45, Q-63, Q-65, Q-70, Q-71, Q-72, or Q-85.

[0134] Realization 78b. Composed according to Realization 78, where Q is Q-45, Q-63, Q-65, or Q-70.

[0135] Realization 79. Compound of Formula 1 or according to Realization 75, wherein each R7 is independently C1-C3 alkyl, C1-C3 haloalkyl, halogen, hydroxy, amino, cyano, nitro, C1-C2 alkoxy or haloalkoxy C1-C2.

[0136] Realization 80. Compound according to Realization 79, wherein each R7 is independently C1-C3 alkyl, halogen, hydroxy, cyano or C1-C2 alkoxy.

[0137] Realization 81. Compound according to Realization 80, wherein each R7 is independently methyl, F, Cl, Br, hydroxy, cyano or methoxy.

[0138] Realization 82. Compound of Formula 1 in which, when R5 and R7 are taken together with the atoms linking R5 and R7 to form an optionally substituted five- to seven-membered ring, the ring members are selected from carbon and optionally one to three heteroatoms selected from up to 1 O, up to 1 S and up to 1 N and optionally include one to three ring members selected from the group consisting of C(=O), C( =S), S(O), S(O)2 and SiR17R18.

[0139] Achievement 82a. Compound according to Embodiment 82, wherein, when R5 and R7 are taken together with the atoms linking R5 and R7 to form an optionally substituted five- to seven-membered ring, R5 and R7 are taken together with the atoms that connect R5 and R7 to form a five- to seven-membered ring that contains as ring members carbon atoms and, optionally, one to three heteroatoms selected from up to 1 O, up to 1 S, and up to 1 N and optionally includes from one to three ring members selected from the group consisting of C(=O), C(=S), S(O), S(O)2 and SiR17R18, optionally substituted with up to two substituents selected from R8; and each R8 is independently C1-C3 alkyl.

[0140] Realization 82b. A compound of Formula 1, wherein, when R5 and R7 are taken together with the atoms linking R5 and R7 to form an optionally substituted five- to seven-membered ring, R5 and R7 are taken together with the atoms linking R5 and R7 to form a five- to seven-membered ring that contains ring members selected from carbon and optionally one to three heteroatoms selected from up to 1 O, up to 1 S, and up to 1 N and optionally includes one to three ring members selected from the group consisting of C(=O), C(=S), S(O), S(O)2 and SiR17R18, wherein the ring is optionally substituted on ring members other than atoms which link R5 and R7 with substituents selected from R8; and each R8 is independently 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, C3C6 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 haloalkylsulfinyl -C4, 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 alkylcarbonylthio -C6, C2-C6 alkylaminocarbonyl, C3-C8 dialkylaminocarbonyl or C3-C6 trialkylsilyl;

[0141] Realization 82c. A compound of Formula 1, wherein, when R5 and R7 are taken together with the atoms linking R5 and R7 to form an optionally substituted five- to seven-membered ring, R5 and R7 are taken together with the atoms linking R5 and R7 to form a five to seven membered ring containing as ring members two to seven carbon atoms and, optionally, one to three heteroatoms selected from up to 1 O, up to 1 S, up to 1 Si and up to 1 N, wherein the silicon atom ring member is selected from SiR9R10, the ring is optionally substituted on ring members other than the atoms linking R5 and R7 with substituents selected from R8; and each R8 is independently 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, C3C6 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 haloalkylsulfinyl -C4, 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 alkylcarbonylthio -C6, C2-C6 alkylaminocarbonyl, C3-C8 dialkylaminocarbonyl or C3-C6 trialkylsilyl.

[0142] Realization 82d. Compound according to any of Embodiments 82b or 82c, wherein the ring is optionally substituted on ring members other than the atoms linking R5 and R7 with up to four substituents selected from R8.

[0143] Realization 82e. Compound according to Embodiment 82d, wherein the ring is optionally substituted on ring members other than the atoms linking R5 and R7 with up to two substituents selected from R8.

[0144] Realization 82f. Compound according to either Embodiment 82b or 82c, wherein each R8 is independently C1-C3 alkyl.

[0145] Achievement 82g. Compound according to Embodiment 82b, wherein, when R5 and R7 are taken together with the atoms linking R5 and R7 to form an optionally substituted five- to seven-membered ring, R5 and R7 are taken together with the atoms that connect R5 and R7 to form a five- to seven-membered ring that contains ring members selected from carbon and optionally one to three heteroatoms selected from up to 1 O, up to 1 S, and up to 1 N and optionally including from one to three ring members selected from the group consisting of C(=O), C(=S), S(O), S(O)2 and SiR17R18, optionally substituted with up to two substituents selected from R8 ; and each R8 is C1-C3 alkyl.

[0146] Realization 82h. Compound according to Embodiment 82c, wherein, when R5 and R7 are taken together with the atoms linking R5 and R7 to form an optionally substituted five- to seven-membered ring, R5 and R7 are taken together with the atoms that bind R5 and R7 to form a five- to seven-membered ring containing as ring members two to seven carbon atoms and optionally one to three heteroatoms selected from up to 1 O, up to 1 S, and up to 1 N, optionally substituted with up to two substituents selected from R8; and each R8 is C1-C3 alkyl.

[0147] Realization 83. Compound of Formula 1 or according to Realization 75, where p is 0, 1, 2 or 3.

[0148] Realization 84. Compound of Formula 1 in which R1 is optionally substituted phenyl or a five- or six-membered heteroaromatic ring.

[0149] Realization 85. Compound of Formula 1 in which A is CH2 or NH.

[0150] Realization 86. Formula 1 compound in which X is selected from X1, X2, X3, X4, X5, X6, X7 and X8.

[0151] Realization 87. Compound of Formula 1 in which J is a five- or six-membered ring, an eight- to eleven-membered bicyclic ring system, or a seven- to eleven-membered spirocyclic ring system, in which each ring or system of rings contains ring members selected from carbon and optionally one to three heteroatoms selected from up to 1 O, up to 1 S and up to 3 N and optionally includes one to three ring members selected from group consisting of C(=O), C(=S), S(O) and S(O)2, each ring or ring system optionally substituted with one to five substituents selected independently from R5.

[0152] Realization 88. Compound of Formula 1 wherein J is phenyl, five- or six-membered heteroaromatic ring, naphthalenyl or an eight- to eleven-membered heteroaromatic bicyclic ring system, wherein each ring or ring system is optionally substituted with one to five substituents independently selected from R5; or J is a five-, six- or seven-membered non-aromatic ring, an eight- to eleven-membered non-aromatic bicyclic or seven to eleven-membered spirocyclic ring system, wherein each ring or ring system optionally includes one to three members of rings selected from the group consisting of C(=O), C(=S), S(O), S(O)2 and SiR17R18, optionally substituted with one to five substituents selected independently from R5.

[0153] Realization 89. Compound of Formula 1, in which each R5 is independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C10 cycloalkylalkyl, C4-C10 alkylcycloalkyl, alkylcycloalkylalkyl C5-C10, C1-C6 haloalkyl, C2-C6 haloalkenyl,C2-C6 haloalkynyl, C3-C6 halocycloalkyl, halogen, hydroxy, amino, cyano, nitro, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylthio, alkylsulfinyl C1-C6 alkylsulfonyl C1-C6, C2-C6 alkylcarbonyl, C2-C6 alkoxycarbonyl, C2-C6 alkylcarbonyloxy, C2-C6 alkylaminocarbonyl, C3C8 dialkylaminocarbonyl, C3-C6 or -Z2Q trialkylsilyl; each R7 is independently 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, haloalkynyl C2-C6, 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, haloalkylsulfinyl C1-C4, 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, alkylcarbonylthio C2-C6, C2-C6 alkylaminocarbonyl, C3-C8 dialkylaminocarbonyl or C3-C6 trialkylsilyl; or R5 and R7 are taken together with the atoms linking R5 and R7 to form an optionally substituted five- to seven-membered ring containing, as ring members, two to seven carbon atoms and, optionally, one to three selected heteroatoms. from up to 1 O, up to 1 S and up to 1 N.

[0154] Realization 90. Compound of Formula 1 in which each Q is independently an optionally substituted phenyl, benzyl, naphthalenyl, C3-C6 cycloalkyl, C3-C6 cycloalkenyl or five- or six-membered heteroaromatic ring, each optionally substituted with an a three substituents selected from R7 on carbon ring members and R12 on nitrogen ring members.

[0155] Achievement 90a. A compound of Formula 1 wherein each Q is independently a three- to seven-membered non-aromatic carbocyclic ring, a five-, six-, or seven-membered non-aromatic heterocyclic ring, or an eight- to eleven-membered non-aromatic bicyclic ring system, wherein each which optionally includes ring members selected from the group consisting of C(=O), C(=S), S(O), S(O)2 and SiR17R18, optionally substituted with one to five substituents independently selected from of R7 over carbon atom ring members and R12 over nitrogen atom ring members.

[0156] Realization 91. Formula 1 compound in which each Z1 and Z2 is independently a direct union, O, C(=O), S(O)m, CHR20 or NR21.

[0157] Realization 92. Compound of Formula 1 in which R21 is H, C1-C3 alkyl, C2-C3 alkylcarbonyl or C2-C3 alkoxycarbonyl.

[0158] Realization 93. Compound of Formula 1 wherein, when G is an optionally substituted thiazole ring connected at its 2-position to X and at its 4-position to Z1 in Formula 1, A is CHR15 and J is an optionally substituted isoxazole ring connected in position 4 to Z1, Z1 is O, C(=O), S(O)m, CHR20 or NR21.

[0159] Realization 94. Compound of Formula 1 wherein, when G is an optionally substituted thiazole ring connected at its 2 position to X and at its 4 position to Z1 in Formula 1 and J is an optionally substituted isoxazole ring connected at its position 4 to Z1, Z1 is O, C(=O), S(O)m, CHR20 or NR21.

[0160] Realization 95. Compound of Formula 1 wherein, when G is an optionally substituted thiazole ring connected at its 2-position to X and at its 4-position to Z1 in Formula 1, A is CHR15, Z1 is a direct union and J is an optionally substituted isoxazole ring, J is connected to the remainder of Formula 1 at position 3 or 5 of the isoxazole ring.

[0161] Realization 96. Compound of Formula 1 wherein, when G is an optionally substituted thiazole ring connected at its 2-position to X and at its 4-position to Z1 in Formula 1, A is CHR15, Z1 is a direct union and J is an optionally substituted isoxazole ring, J is connected to the remainder of Formula 1 at position 3 of the isoxazole ring.

[0162] Realization 97. Compound of Formula 1 wherein, when G is an optionally substituted thiazole ring connected at its 2-position to X and at its 4-position to Z1 in Formula 1, Z1 is a direct union and J is an isoxazole ring optionally substituted, J is connected to the remainder of Formula 1 at position 3 of the isoxazole ring.

[0163] Realization 98. Compound of Formula 1 in which, when X is X2 and the ring containing X is saturated, A is CHR15, G is an optionally substituted five-membered heteroaromatic ring, Z1 is a direct union and J is phenyl , five- or six-membered heteroaromatic ring, naphthalenyl, or an eight- to eleven-membered heteroaromatic bicyclic ring system, the J ring or ring system is substituted with at least one R5 that is other than H.

[0164] Realization 99. Compound of Formula 1 in which, when X is X2 and the ring containing X is saturated, A is CHR15, G is an optionally substituted five-membered heteroaromatic ring, Z1 is a direct union and J is phenyl , five- or six-membered heteroaromatic ring, naphthalenyl or an eight- to eleven-membered heteroaromatic bicyclic ring system, the J ring or ring system is substituted with at least one R5 which is Z2Q.

[0165] Realization 100. Compound of Formula 1 in which, when X is X1 and the ring containing X is saturated, A is NH, G is an optionally substituted thiazole ring connected at its 2 position to Z1 in Formula 1 and J is an optionally substituted imidazole ring connected at its 2 position to the remainder of Formula 1, Z1 is O, C(=O), S(O)m, CHR20 or NR21.

[0166] Realization 101. Compound of Formula 1 in which, when X is X1 and the ring containing X is saturated, A is NR16, G is an optionally substituted thiazole ring connected at its 2 position to Z1 in Formula 1 and J is an optionally substituted imidazole ring connected at its 2 position to the remainder of Formula 1, Z1 is O, C(=O), S(O)m, CHR20 or NR21.

[0167] Realization 102. Compound of Formula 1 wherein, when G is an optionally substituted thiazole ring connected at its 2-position to X and at its 4-position to Z1 in Formula 1, J is other than optionally substituted imidazolyl.

[0168] Realization 103. Compound of Formula 1 in which each Z4 is independently C(=O) or S(O)2.

[0169] Realization 104. Composed according to Realization 103, wherein each Z4 is C(=O).

[0170] Realization 105. Compound of Formula 1 in which: - each R2 is independently C1-C4 alkyl, C1 C4 alkenyl, C1-C4 haloalkyl, C1-C4 alkoxy, halogen, cyano or hydroxy; or - two R2 are taken together as C1-C3 alkylene or C2-C3 alkenylene to form a bridged bicyclic ring system; or - two R2 bonded to carbon atoms of adjacent rings linked by a double bond are taken together as -CH=CH-CH=CH- optionally substituted with one to three substituents selected from C1-C4 alkyl, C1 haloalkyl- C4, C1-C4 alkoxy, C1-C4 haloalkoxy, halogen, hydroxy, amino, cyano and nitro.

[0171] Combinations of Realizations 1 to 105 are illustrated by:

[0172] Achievement A1. Compound of Formula 1 wherein: - G is a five-membered heteroaromatic ring or a saturated or partially saturated five-membered heterocyclic ring, wherein each ring is optionally substituted with up to two substituents selected from R3 on carbon ring members and selected from R11 on nitrogen ring members; - R1 is phenyl or a five- or six-membered heteroaromatic ring optionally substituted with one to two substituents independently selected from R4a on carbon ring members and R4b on nitrogen ring members; - each R2 is independently C1-C2 alkyl, C1 C2 haloalkyl, C1-C2 alkoxy, halogen, cyano or hydroxy; - each R3 is independently C1-C3 alkyl, C1 C3 haloalkyl or halogen; - each R4a is independently 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, haloalkynyl C2-C6, 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, haloalkylsulfinyl C1-C4, 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, alkylcarbonylthio C2-C6, C2-C6 alkylaminocarbonyl, C3-C8 dialkylaminocarbonyl or C3-C6 trialkylsilyl; - each R4b is independently C1-C6 alkyl, C2 C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, C3-C6 haloalkenyl, C3-C6 haloalkynyl, C3-C6 halocycloalkyl or C2-C4 alkoxyalkyl; - each R11 is independently C1-C3 alkyl; - 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 alkylcarbonyl, C2-C4 haloalkylcarbonyl or C2-C4 alkoxycarbonyl; - when R5 and R7 are taken together with the atoms linking R5 and R7 to form an optionally substituted five- to seven-membered ring, R5 and R7 are taken together with the atoms linking R5 and R7 to form a five-membered ring to seven members that contain ring members selected from carbon and optionally one to three heteroatoms selected from up to 1 O, up to 1 S and up to 1 N and that optionally include one to three ring members selected from the group which consists of C(=O), C(=S), S(O), S(O)2 and SiR17R18, in which the ring is optionally substituted on ring members other than the atoms linking R5 and R7 with up to four substituents selected from R8; - each R8 is independently 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-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 trialkylsilyl; and - each Z4 is independently C(=O) or S(O)2. Achievement A2. Composed according to Realization A1, where: - G is one of G-1 to G-59 (as shown in Illustration 2), where the union projecting to the left is linked to projects to the right is linked to Z1; - J is one of J-1 to J-82 (as shown in Illustration 3), where the union shown projecting to the left is connected to Z1; - Q is one of Q-1 to Q-102 (as shown in Illustration 4); - R1 is one of U-1 to U-50 (as shown in Illustration 1); - each R2 is independently methyl, methoxy, cyano or hydroxy; - each R3a is selected independently from H and R3; - each R5 is independently H, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C2-C6 haloalkenyl, C2-C6 haloalkynyl, C3-C8 cycloalkyl, C3-C8 halocycloalkyl, alkylcycloalkyl C4-C10, C4-C10 cycloalkylalkyl, C2-C6 alkoxyalkyl, C4-C10 cycloalkoxyalkyl, C3-C8 alkoxyalkoxyalkyl, C2-C6 alkylthioalkyl, C2-C6 alkoxycarbonyl, C1C6 alkoxy, C1-C6 haloalkoxy, C3-C8 cycloalkoxy, C3-halocycloalkoxy C8, 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, C3C6 alkylcarbonylalkoxy, C1-C6 alkylthio, C1-C6 haloalkylthio, C3-C8 cycloalkylthio, C3-C10 trialkylsilyl, - NR25R26 or Z2Q; - R11a is selected from H and R11; - R15 is H, cyano, hydroxy, methyl or methoxycarbonyl; - R16 is H, methyl, methylcarbonyl or methoxycarbonyl; - each Z4 is C(=O); - k is 0, 1 or 2; - p is 0, 1, 2 or 3; e - x is an integer from 0 to 5; provided that: (a) when R4 is attached to a carbon ring member, said R4 is selected from R4a; (b) when R4 is attached to a nitrogen ring member (such as in U-4, U-11 to U-15, U-24 to U-26, U-31 or U-35), said R4 is selected from R4b; (c) when G is G-6, G-16 or G-42 and each R3a is different from H, R11a is H; (d) when G is G-25 or G-31, at least one R3a is H; and (e) when G is one of G-31 to G-35, Z1 is a direct union or CHR20.

[0173] Achievement A3. Compound of Realization A2, where: - G is selected from G-1, G-2, G-7, G-8, G-14, G-15, G-23, G-24, G-26 , G-27, G-36, G-37, G-38, G-49, G-50 and G-55; - J is selected from J-1, J-2, J-3, J-4, J-5, J-7, J-8, J- 9, J-10, J-11, J-12 , J-14, J-15, J-16, J-20, J-24, J-25, J-26, J-29, J-30, J-37, J-38, J-45 and J -69; - each Q is independently Q-1, Q-20, Q-32 to Q-34, Q-45 to Q-47, Q-60 to Q-73, Q-76 to Q-79, Q-84 to Q -94 and Q-98 to Q-102; - A is CH2 or NH; - W is O; - X is X1, X2 or X3; - each R5 is independently H, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C3-C8 halocycloalkyl, C2-C6 alkoxyalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C8 cycloalkoxy, alkenyloxy C2-C6, C2-C6 haloalkenyloxy, C2-C6 alkynyloxy, C2-C6 alkoxyalkoxy, C2C6 alkylcarbonyloxy, C2-C6 haloalkylcarbonyloxy, C1-C6 alkylthio, C1-C6 haloalkylthio, C3-C10 trialkylsilyl, -NR25R26 or Z2Q; - Z1 is a direct union; - Z2 is a direct union or NR21; - R1 is selected from U-1 to U-3, U-11, U-13, U-20, U-22, U-23, U-36 to U-39 and U-50; - each R3 is independently methyl or halogen; - each R4a is independently C1-C2 alkyl, C1-C2 haloalkyl, halogen, C1-C2 alkoxy or C1-C2 haloalkoxy; - each R4b is independently C1-C2 alkyl or C1-C2 haloalkyl; - each R7 is independently halogen, cyano, C1 C3 alkyl, C1-C3 haloalkyl, hydroxy, C1-C2 alkoxy or C1-C2 haloalkoxy; - k is 1 or 2; e - n is 0.

[0174] Worth noting are compounds of Realization A3 in which one R5 is Z2Q and any other R5 substituents are independently selected from H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, C3-C8 halocycloalkyl, C2 alkoxyalkyl -C6, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C8 cycloalkoxy, C2-C6 alkenyloxy, C2-C6 haloalkenyloxy, C2-C6 alkynyloxy, C2-C6 alkoxyalkoxy, C2-C6 alkylcarbonyloxy, C2-C6 haloalkylcarbonyloxy, C1 alkylthio -C6, C1-C6 haloalkylthio, C3-C10 trialkylsilyl and -NR25R26. Also worthy of note are compounds of Realization A3 in which all R5 substituents are different from Z2Q (each R5 is selected independently, for example, from H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, C3-halocycloalkyl C8, C2-C6 alkoxyalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C8 cycloalkoxy, C2-C6 alkenyloxy, C2-C6 haloalkenyloxy, C2-C6 alkynyloxy, C2-C6 alkoxyalkoxy, C2-C6 alkylcarbonyloxy, C2- haloalkylcarbonyloxy C6, C1-C6 alkylthio, C1-C6 haloalkylthio, C3-C10 trialkylsilyl and -NR25R26).

[0175] A4 Achievement. Compound according to Realization A3, wherein: - A is CH2; - G is selected from G-1, G-2, G-15, G-26, G-27, G-36, G-37 and G-38; and G is unsubstituted; - J is selected from J-4, J-5, J-8, J-11, J-15, J-16, J-20, J-29, J-30, J-37, J-38 and J-69; - Q is selected from Q-1, Q-45, Q-63, Q-64, Q-65, Q-68, Q-69, Q-70, Q-71, Q-72, Q-73 , Q-76, Q-78, Q-79, Q-84, Q-85, Q-98, Q-99, Q-100, Q-101 and Q-102; - X is X1 or X2; and the ring comprising X is saturated; - R1 is U-1 or U-50; - each R4a is independently C1-C2 alkyl, trifluoromethyl, Cl, Br, I or methoxy; - each R4b is independently C1-C2 alkyl or trifluoromethyl; and - each R5 is independently H, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C4 haloalkoxy, -NR25R26 or Z2Q.

[0176] Achievement A5. Composed according to Realization A4, where: - G is selected from G-1, G-2, G-15, G-26 and G-36; - J is selected from J-4, J-5, J-11, J-20, J-29, J-37, J-38 and J-69; - Q is selected from Q-45, Q-63, Q-64, Q-65, Q-68, Q-69, Q-70, Q-71, Q-72 and Q-85; and - X is X1.

[0177] Achievement A6. Compound of Formula 1 in which: - R1 is optionally substituted phenyl or a five- or six-membered heteroaromatic ring; - A is CH2 or NH; - X is X1, X2, X3, X4, X5, X6, X7 or X8; - each R2 is independently C1-C4 alkyl, C1 C4 alkenyl, C1-C4 haloalkyl, C1-C4 alkoxy, halogen, cyano or hydroxy; or - two R2 are taken together as C1-C3 alkylene or C2-C3 alkenylene to form a bridged bicyclic ring system; or - two R2 bonded to carbon atoms of adjacent rings linked by a double bond are taken together as -CH=CH-CH=CH- optionally substituted with one to three substituents selected from C1-C4 alkyl, C1 haloalkyl- C4, C1-C4 alkoxy, C1-C4 haloalkoxy, halogen, hydroxy, amino, cyano and nitro; - G is an optionally substituted five-membered heteroaromatic ring or saturated or partially saturated five-membered heterocyclic ring; - J is a five- or six-membered ring or an eight- to eleven-membered bicyclic ring system, wherein each ring or ring system contains ring members selected from carbon and, optionally, one to three heteroatoms selected from of up to 1 O, up to 1 S and up to 3 N and which optionally includes one to three ring members selected from the group consisting of C(=O), C(=S), S(O) or S( O)2, wherein each ring or ring system is optionally substituted with one to five substituents selected independently from R5; - each R5 is independently H, 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- haloalkenyl C6, C2-C6 haloalkynyl, C3-C6 cycloalkyl, halogen, hydroxy, amino, cyano, nitro, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylthio, C1-C6 alkylsulfinyl, C1-C6 alkylsulfonyl, C1- haloalkylthio C6, C1-C6 haloalkylsulfinyl, C1-C6 haloalkylsulfonyl, C1-C6 alkylamino, C2-C8 dialkylamino, C3-C6 cycloalkylamino, C2-C6 alkoxyalkyl, C1-C6 haloalkoxyalkyl, C1-C6 hydroxyalkyl, C2-C6 alkylcarbonyl, C2-alkoxycarbonyl C6, C2-C6 alkylcarbonyloxy, C2-C6 alkylaminocarbonyl, C3C8 dialkylaminocarbonyl, C3-C6 trialkylsilyl or -Z2Q; - each Q is independently phenyl, benzyl, naphthalenyl, C3-C6 cycloalkyl, C3-C6 cycloalkenyl or an optionally substituted five- or six-membered heteroaromatic ring, each optionally substituted with one to three substituents independently selected from R7 on members of carbon rings and R12 on nitrogen ring members; - each R7 is independently 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, haloalkynyl C2-C6, C3-C6 halocycloalkyl, nitrogen, hydroxy, amino, cyano, nitro, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylthio, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl, C1-C4 haloalkylthio, haloalkylsulfinyl C1-C4, 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, alkylcarbonylthio C2-C6, C2-C6 alkylaminocarbonyl, C3-C8 dialkylaminocarbonyl or C3-C6 trialkylsilyl; or - R5 and R7 are taken together with the linking atoms R5 and R7 to form an optionally substituted five to seven membered ring containing as ring members two to seven carbon atoms and optionally one to three heteroatoms selected from from up to 1 O, up to 1 S and up to 1 N; - R12 is C1-C3 alkyl; - each Z1 and Z2 is independently a direct union, O, S(O)m, CHR20 or NR21; and - R21 is H or C1-C3 alkyl.

[0178] Achievement A7. Compound according to Embodiment A6, wherein: - G is a five-membered heteroaromatic ring or saturated or partially saturated five-membered heterocyclic ring, each ring optionally substituted with up to two substituents selected from R3 on carbon ring members and selected from R11 on nitrogen ring members; - R1 is phenyl or a five- or six-membered heteroaromatic ring optionally substituted with one to two substituents independently selected from R4a on carbon ring members and R4b on nitrogen ring members; - each R3 is independently C1-C3 alkyl, C1 C3 haloalkyl or halogen; - each R4a is independently 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, haloalkynyl C2-C6, 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, haloalkylsulfinyl C1-C4, 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, alkylcarbonylthio C2-C6, C2-C6 alkylaminocarbonyl, C3-C8 dialkylaminocarbonyl or C3-C6 trialkylsilyl; - each R4b is independently C1-C6 alkyl, C3 C6 alkenyl, C3-C6 alkynyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, C3-C6 haloalkenyl, C3-C6 haloalkynyl, C3-C6 halocycloalkyl or C2-C4 alkoxyalkyl; - each R11 is independently C1-C3 alkyl; and - when R5 and R7 are taken together with the atoms linking R5 and R7 to form an optionally substituted five- to seven-membered ring, R5 and R7 are taken together with the atoms linking R5 and R7 to form a ring with five to seven members containing as ring members two to seven carbon atoms and optionally one to three heteroatoms selected from up to 1 O, up to 1 S and up to 1 N optionally substituted with up to two substituents selected from R8; and each R8 is independently C1-C3 alkyl.

[0179] Achievement A8. Composed according to Realization A7, where: - G is one of G-1 to G-55 (as shown in Illustration 2), where the union projecting to the left is connected to projects to the right is linked to Z1; - J is one of J-1 to J-82 (as shown in Illustration 3) in which the shown joint projecting to the left is connected to Z1; - Q is one of Q-1 to Q-55 (as shown in Illustration 4); - R1 is one of U-1 to U-50 (as shown in Illustration 1); - each R3a is selected independently from H and R3; - R11a is selected from H and R11; - k is 0, 1 or 2; - p is 0, 1 or 2; e - x is an integer from 0 to 5; provided that: (a) when R4 is attached to a carbon ring member, said R4 is selected from R4a; (b) when R4 is attached to a nitrogen ring member (such as in U-4, U-11 to U-15, U-24 to U-26, U-31 or U-35), said R4 is selected from R4b; (c) when G is G-6, G-16 or G-42 and each R3a is different from H, R11a is H; (d) when G is G-25 or G-31, the at least one R3a is H; and (e) when G is one of G-31 to G-35, Z1 is a direct union or CHR20.

[0180] Achievement A9. Composed according to Realization A8, where: - G is selected from G-1, G-2, G-15, G-26, G-27, G-36, G-37 and G-38; - J is selected from J-1, J-2, J-3, J-4, J-5, J-7, J-8, J- 9, J-10, J-11, J-12 , J-14, J-15, J-16, J-20, J-24, J-25, J-26, J-29, J-30, J-45 and J-69; - each Q is independently Q-1, Q-20, Q-32 to Q-34, Q-45, Q-46 or Q-47; - W is O; - X is X1, X2 or X3; - each Z1 and Z2 is a direct union; - R1 is selected from U-1 to U-3, U-11, U-13, U-20, U-22, U-23, U-36 to U-39 and U-50; - each R3 is independently methyl or halogen; - each R4a is independently C1-C2 alkyl, C1-C2 haloalkyl, halogen or C1-C2 alkoxy; - each R4b is independently C1-C2 alkyl or C1-C2 haloalkyl; - one case of R5 is Z2Q and the other cases of R5 are independently selected from H, C1-C4 alkyl, C1-C4 haloalkyl and halogen; - each R7 is independently halogen, C1-C3 alkyl, C1-C3 haloalkyl, hydroxy, C1-C2 alkoxy or C1-C2 haloalkoxy; - k is 1 or 2; e - n is 0.

[0181] Achievement A10. Compound according to Realization A9, wherein: - A is CH2; - G is selected from G-1, G-2, G-15, G-26 and G-36; and G is unsubstituted; - J is selected from J-11, J-25, J-26, J-29 and J-30; - Q is selected from Q-1 and Q-45; - X is X1 or X2; and the ring comprising X is saturated; - R1 is U-1 or U-50; - each R4a is independently C1-C2 alkyl, trifluoromethyl, Cl, Br, I or methoxy; and - each R4b is independently C1-C2 alkyl or trifluoromethyl.

[0182] Achievement A11. Composed according to Realization A10, where: - J is selected from J-11 and J-29; - X is X1; and - each R4a is independently C1-C2 alkyl, trifluoromethyl or Cl.

[0183] Achievement A12. Compound of Formula 1, wherein: - R1 is U-1 or U-50 (as shown in Illustration 1) wherein, when R4 is attached to a carbon ring member, said R4 is selected from R4a and , when R4 is attached to a nitrogen ring member, said R4 is selected from R4b; - each R4a is independently C1-C2 alkyl, trifluoromethyl, Cl, Br, I or methoxy; - each R4b is independently C1-C2 alkyl or trifluoromethyl; - A is CH2; - W is O; - X is X1 or X2 and the ring comprising X is saturated; - each R2 is independently ethyl, methoxy, cyano or hydroxy; - G is selected from G-1, G-2, G-15, G-26 and G-36 (as shown in Illustration 2), where the union projecting to the left is connected to union that projects to the right is connected to Z1; and G is unsubstituted; - each R3a is selected independently from H and R3; - each R3 is independently methyl or halogen; - J is selected from J-11, J-25, J-26, J-29 and J-30 (as shown in Illustration 3), where the union shown projecting to the left is connected to Z1; - each R5 is independently H, cyano, hydroxy, amino, nitro, -CHO, -C(=O)OH, -C(=O)NH2, -NR25R26, C1-C6 alkyl, C2-C6 alkenyl, C2-alkynyl C6, C1-C6 haloalkyl, C2-C6 haloalkenyl, C2-C6 haloalkynyl, C3C8 cycloalkyl, C3-C8 halocycloalkyl, C4-C10 alkylcycloalkyl, C4-C10 cycloalkylalkyl, C6-C14 cycloalkylcycloalkyl, C4-C10 halocycloalkylalkyl, C4-alkylcycloalkylalkyl 5-C10, cycloalkenyl C3-C8, C2-C6 haloalkylaminoalkyl, C4-C10 cycloalkylaminoalkyl, C2-C6 alkylcarbonyl, C2-C6 haloalkylcarbonyl, C4C8 cycloalkylcarbonyl, C2-C6 alkoxycarbonyl, C4-C8 cycloalkoxycarbonyl, C5-C10 cycloalkylalkoxycarbonyl, C4-C8 alkylaminocarbonyl, C1-C6 alkoxy, haloalk oxy C1 -C6, C3C8 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 haloalkylsulfinyl, C1-C6 alkylsulfonyl, C1-C6 haloalkylsulfonyl, C3-C8 cycloalkylsulfonyl , C3-C10 trialkylsilyl, C1-C6 alkylsulfonylamino, C1-C6 or -Z2Q haloalkylsulfonylamino; - R25 is H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, C2-C6 alkylcarbonyl, C2-C6 haloalkylcarbonyl, C2-C6 alkoxycarbonyl or C2-C6 haloalkoxycarbonyl; - R26 is C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, C2-C6 alkylcarbonyl, C2-C6 haloalkylcarbonyl, C2-C6 alkoxycarbonyl, C2-C6 haloalkoxycarbonyl or -Z4Q; - each Q is selected from Q-1, Q-45 and Q-63 (as shown in Illustration 4); - each R7 is independently 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, haloalkynyl C2-C6, 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, haloalkylsulfinyl C1-C4, 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, alkylcarbonylthio C2-C6, C2-C6 alkylaminocarbonyl, C3-C8 dialkylaminocarbonyl or C3-C6 trialkylsilyl; or - R5 and R7 are taken together with the linking atoms R5 and R7 to form a five to seven membered ring containing as ring members two to seven carbon atoms and, optionally, one to three heteroatoms selected from up to 1 O, up to 1 S, up to 1 Si and up to 1 N, wherein the silicon atom ring member is selected from SiR9R10, wherein the ring is optionally substituted on ring members other than the atoms linking R5 and R7 with up to four substituents selected from R8; - each R8 is independently 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, haloalkynyl C2-C6, 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, haloalkylsulfinyl C1-C4, 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, alkylcarbonylthio C2-C6, C2-C6 alkylaminocarbonyl, C3-C8 dialkylaminocarbonyl or C3-C6 trialkylsilyl; - R12 is C1-C3 alkyl; - each Z1 and Z2 is a direct union; - each Z4 is independently C(=O) or S(O)2; - n is 0, 1 or 2; - k is 0, 1 or 2; - p is 0, 1 or 2; and - x is an integer from 0 to 5; provided that when R1 is unsubstituted thienyl, X is X1, G is an unsubstituted thiazole ring connected at its 2-position to and J is an isoxazole ring connected at its 4-position to Z1 and substituted at its 5-position with methyl, J is unsubstituted at its 3-position with meta-substituted phenyl.

[0184] Embodiments of the present invention also include:

[0185] Achievement B1. Compound of Formula 1A wherein each R4a1 and R4a2 is independently C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, cyclopropyl, C1-C3 haloalkyl, halocyclopropyl, halogen, cyano, nitro, C1-C2 alkoxy or C1- haloalkoxy C2.

[0186] Achievement B2. Compound of Realization B1 wherein each R4a1 and R4a2 is independently C1-C3 alkyl, C1-C3 haloalkyl, halogen, cyano, C1-C2 alkoxy or C1-C2 haloalkoxy.

[0187] Achievement B3. Compound according to Embodiment B2 wherein each R4a1 and R4a2 are independently C1-C3 alkyl, C1C3 haloalkyl or halogen.

[0188] Achievement B4. Formula 1A compound where Aa is H.

[0189] Achievement B5. Compound of Formula 1A where Aa is CH2CO2H.

[0190] Achievement B6. Formula 1A compound where Aa is CH2CO2R30.

[0191] Achievement B7. Compound of Formula 1A where Aa is CH2C(=O)Cl.

[0192] Achievement B8. Compound of Formula 1B wherein each R4a1 and R4a2 is independently C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, cyclopropyl, C1-C3 haloalkyl, halocyclopropyl, halogen, cyano, nitro, C1-C2 alkoxy or C1- haloalkoxy C2.

[0193] Achievement B9. Compound according to Realization B8, wherein each R4a1 and R4a2 is independently C1-C3 alkyl, C1-C3 haloalkyl, halogen, cyano, C1-C2 alkoxy or C1-C2 haloalkoxy.

[0194] Achievement B10. Compound according to Realization B9, wherein each R4a1 and R4a2 is independently C1-C3 alkyl, C1-C3 haloalkyl or halogen.

[0195] Achievement B11. Formula 1B compound where Z3 is CN.

[0196] Achievement B12. Compound of Formula 1B where Z3 is C(=S)NH2.

[0197] With regard to the compounds of Formula 1C according to the present invention, it is observed that various embodiments of J-29 can be present in two or more enantiomeric forms. The enantiomeric forms of J-29 embodiments for compounds of Formula 1C according to the present invention are those shown in Illustration A above. All enantiomers of J-29 are included in compounds of Formula 1C in the present invention for embodiments in which no specific enantiomeric form of J-29 is illustrated (such as J-29-33 enantiomers and J-29-22 enantiomers based on position of the methyl group).

[0198] Achievement B13. Compound of Formula 1C wherein M is C1-C2 alkyl, C1-C2 haloalkyl, hydroxy, C1-C4 alkoxy, C1-C2 haloalkoxy, C1-C3 alkylamino, C2-C6 dialkylamino, 1-piperidinyl, 1-pyrrolidinyl or 4- morpholinyl.

[0199] Specific embodiments include compounds of Formula 1 selected from the group consisting of: - 4-[4-[(5R)-4,5-dihydro-5-phenyl-3-isoxazolyl]-2-thiazolyl ]-1-[[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl]piperidine and its enantiomer (Compound 1); - 1-[[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl]-4-[4-(5-phenyl-3-isoxazolyl)-2-thiazolyl]piperidine (Compound 2) ; - 1-[4-[4-[(5R)-4,5-dihydro-5-methyl-5-phenyl-3-isoxazolyl]-2-thiazolyl]-1-piperidinyl]-2-[5- methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]ethanone and its enantiomer (Compound 15); - 2-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]-1-[4-[4-[(3aS, 9bR),3a,4,5,9b-tetrahydronaphth[2, 1-d]isoxazol-3-yl]-2-thiazolyl]-1-piperidinyl]ethanone and its enantiomer (Compound 16); - 1-[4-[4-[(5R)-4,5-dihydro-5-phenyl-3-isoxazolyl]-2-thiazolyl]-1-piperidinyl]-2-[5-ethyl-3- (trifluoromethyl)-1H-pyrazol-1-yl]ethanone and its enantiomer (Compound 19); - 2-[3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl]-1-[4-[4-[(5R)-4,5-dihydro-5-phenyl-3-isoxazolyl ]-2-thiazolyl]-1-piperidinyl]ethanone and its enantiomer (Compound 22); - 1-[4-[4-[(5R)-3',4'-dihydrospiro[isoxazol-5(4H),1',(2'H)-naphthalen]-3-yl]-2- thiazolyl]-1-piperidinyl]-2-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]ethanone and its enantiomer (Compound 37); - 1-[4-[4-[(5R)-2,3-dihydrospiro[1H-indene-1,5'(4'H)-isoxazole]- 3'-yl]-2-thiazolyl]- 1-piperidinyl]-2-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]ethanone and its enantiomer (Compound 44); - 2-[5-chloro-3-(trifluoromethyl)-1H-pyrazol-1-yl]-1-[4-[4-[(5R)-4,5-dihydro-5-phenyl-3- isoxazolyl]-2-thiazolyl]-1-piperidinyl]ethanone and its enantiomer (Compound 107); - 2-[(5R)-4,5-dihydro-3-[2-[1-[2-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl]-4 -piperidinyl]-4-thiazolyl]-5-isoxazolyl]-1H-isoindol-1,3(2H)-dione and its enantiomer (Compound 129); - 2-[5-chloro-3-(trifluoromethyl)-1H-pyrazol-1-yl]-1-[4-[4-[(1R)-2,3-dihydrospiro[1H-indene-1, 5'(4'H)-isoxazol]-3'-yl]-2-thiazolyl]-1-piperidinyl]ethanone and its enantiomer (Compound 232); - 2-[5-chloro-3-(trifluoromethyl)-1H-pyrazol-1-yl]-1-[4-[4-[(1'R)- 3',4'-dihydrospiro[isoxazole- 5(4H),1'(2'H)naphthalen]-3-yl]-2-thiazolyl]-1-piperidinyl]ethanone and its enantiomer (Compound 230); - 2-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]-1-[4-[4-[(3R)-spiro[benzofuran-3(2H),5'(4' H)-isoxazol-3'-yl-2-thiazolyl]-1-piperidinyl]ethanone and its enantiomer (Compound 185); - 1-[4-[4-[(1R)-2,3-dihydrospiro[1H-indene-1,5'(4'H)-isoxazole]- 3'-yl]-2-thiazolyl]- 1-piperidinyl]-2-(3,5-dimethyl-1H-pyrazol-1-yl)ethanone and its enantiomer (Compound 165); - 2-[3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl]-1-[4-[4-[(1'R)-3',4'-dihydrospiro[isoxazol-5 (4H),1'(2'H)-naphthalen]-3-yl]-2-thiazolyl]-1-piperidinyl]ethanone and its enantiomer (Compound 229); - 2-[3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl]-1-[4-[4-[(1R)-2,3-dihydrospiro[1H-indene-1,5 '(4'H)-isoxazol]-3'-yl]-2-thiazolyl]-1-piperidinyl]ethanone and its enantiomer (Compound 231); - 1-[4-[4-[(5R)-5-(2,6-dichlorophenyl)-4,5-dihydro-3-isoxazolyl]-2-thiazolyl]-1-piperidinyl]-2-[ 5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]ethanone and its enantiomer (Compound 135); - 1-[4-[4-[(5R)-4,5-dihydro-5-(2fluorophenyl)-3-isoxazolyl]-2-thiazolyl]-1-piperidinyl]-2-[5-methyl- 3-(trifluoromethyl)-1H-pyrazol-1-yl]ethanone and its enantiomer (Compound 79); - 1-[4-[4-[(5R)-4,5-dihydro-5-(2-methylphenyl)-3-isoxazolyl]-2-thiazolyl]-1-piperidinyl]-2-[5- methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]ethanone and its enantiomer (Compound 161); - 1-[4-[4-[(5R)-5-(2,6-dimethylphenyl)-4,5-dihydro-3-isoxazolyl]-2-thiazolyl]-1-piperidinyl]-2-[ 5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]ethanone and its enantiomer (Compound 178); - 1-[4-[4-[(5R)-4,5-dihydro-5-(2,4,6-trimethylphenyl)-3-isoxazolyl]-2-thiazolyl]-1-piperidinyl]-2 -[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]ethanone and its enantiomer (Compound 179); - 1-[4-[4-[(1'R)-3',4'-dihydrospiro[isoxazol-5(4H),1'(2'H)-naphthalen]-3-yl]-2 -thiazolyl]-1-piperidinyl]-2-(3,5-dimethyl-1H-pyrazol-1-yl) ethanone and its enantiomer (Compound 164); - 1-[4-[4-[(5R)-4,5-dihydro-5-(2,4,6-trimethoxyphenyl)-3-isoxazolyl]-2-thiazolyl]-1-piperidinyl]-2 -[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]ethanone and its enantiomer (Compound 155); - 3-[(5R)-4,5-dihydro-3-[2-[1-[2-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl]-4 -piperidinyl]-4-thiazolyl]-5-isoxazolyl]-2(3H)benzoxazolone and its enantiomer (Compound 225); - 1-[4-[4-[(5R)-5-(2,6-difluorophenyl)-4,5-dihydro-3-isoxazolyl]-2-thiazolyl]-1-piperidinyl]-2-[ 5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]ethanone and its enantiomer (Compound 214); - 2-[(5R)-4,5-dihydro-3-[2-[1-[2-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl]-4 -piperidinyl]-4-thiazolyl]-5-isoxazolyl]benzonitrile and its enantiomer (Compound 220); - 2-[5-chloro-3-(trifluoromethyl)-1H-pyrazol-1-yl]-1-[4-[4-[(5R)-4,5-dihydro-5-methyl-5- phenyl-3-isoxazolyl]-2-thiazolyl]-1-piperidinyl]ethanone and its enantiomer (Compound 261); - 2-[3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl]-1-[4-[4-[(5R)-4,5-dihydro-5-methyl-5-phenyl -3-isoxazolyl]-2-thiazolyl]-1-piperidinyl]ethanone and its enantiomer (Compound 260); - 1-[4-[4-[(5R)-5-(2-chlorophenyl)-4,5-dihydro-3-isoxazolyl]-2-thiazolyl]-1-piperidinyl]-2-[5- methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]ethanone and its enantiomer (Compound 8); - 1-[4-[4-[(5R)-4,5-dihydro-5-phenyl-3-isoxazolyl]-2-thiazolyl]-1-piperidinyl]-2-[3-methyl-5- (trifluoromethyl)-1H-pyrazol-1-yl]ethanone and its enantiomer (Compound 128); - 1-[4-[4-[(4S)-2,3-dihydrospiro[4H-1-benzopyran-4,5'(4'H)-isoxazol]-3'-yl]-2-thiazolyl ]-1-piperidinyl]-2-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]ethanone and its enantiomer (Compound 137); and - (5R)-4,5-dihydro-3-[2-[1-[2-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl]-4-piperidinyl ]-4-thiazolyl]-5-phenyl-5-isoxazolocarbonitrile and its enantiomer (Compound 265). Specific embodiments also include compounds of Formula 1B selected from the group consisting of: - 1-[2-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl]-4-piperidinecarbothioamide; - 1-[2-[3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl]acetyl]-4-piperidinecarbothioamide; - 1-[2-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl]-4-piperidinecarbonitrile; and - 1-[2-[3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl]acetyl]-4-piperidinecarbonitrile.

[0200] Compounds of Formula 1 deserve attention, including all their geometric isomers, stereoisomers, N-oxides and salts suitable for agricultural use, agricultural compositions that contain them and their use as fungicides, in which: - R1 is an optionally substituted phenyl or five- or six-membered heteroaromatic ring; - A is CH2 or NH; - X is X1, X2, X3, X4, X5, X6, X7 or X8; - each R2 is independently C1-C4 alkyl, C1 C4 alkenyl, C1-C4 haloalkyl, C1-C4 alkoxy, halogen, cyano or hydroxy; or - two R2 are taken together as C1-C3 alkylene or C2-C3 alkenylene to form a bridged bicyclic ring system; or - two R2 bonded to carbon atoms of adjacent rings linked by a double bond are taken together as -CH=CH-CH=CH- optionally substituted with one to three substituents selected from C1-C4 alkyl, C1 haloalkyl- C4, C1-C4 alkoxy, C1-C4 haloalkoxy, halogen, hydroxy, amino, cyano and nitro; - J is a five- or six-membered ring or an eight- to eleven-membered bicyclic ring system, wherein each ring or ring system containing ring members selected from carbon and, optionally, one to three heteroatoms selected from starting from up to 1 O, up to 1 S and up to 3 N and optionally including one to three ring members selected from the group consisting of C(=O), C(=S), S(O) or S( O)2, wherein each ring or ring system is optionally substituted with one to five substituents selected independently from R5; - each R5 is independently H, 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- haloalkenyl C6, C2-C6 haloalkynyl, C3-C6 halocycloalkyl, halogen, hydroxy, amino, cyano, nitro, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylthio, C1-C6 alkylsulfinyl, C1-C6 alkylsulfonyl, C1- haloalkylthio C6, C1-C6 haloalkylsulfonyl, C1-C6 alkylamino, C2-C8 dialkylamino, C3-C6 cycloalkylamino, C2-C6 alkoxyalkyl, C2-C6 haloalkoxyalkyl, C1-C6 hydroxyalkyl, C2-C6 alkylcarbonyl, C2-C6 alkoxycarbonyl, C2-alkylcarbonyloxy C6, C2C6 alkylaminocarbonyl, C3-C8 dialkylaminocarbonyl, C3-C6 trialkylsilyl or -Z2Q; - each Q is independently phenyl, benzyl, naphthalenyl, C3-C6 cycloalkyl, C3-C6 cycloalkenyl or an optionally substituted five- or six-membered heteroaromatic ring, each optionally substituted with one to three substituents selected from R7 on ring members of carbon and R12 on nitrogen ring members; - each R7 is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 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-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 trialkylsilyl; or - R5 and R7 are taken together with the linking atoms R5 and R7 to form an optionally substituted five- to seven-membered ring containing as ring members two to seven carbon atoms and optionally one to three heteroatoms selected from from up to 1 O, up to 1 S and up to 1 N wherein the silicon atom ring member is selected from SiR9R10; - R12 is C1-C3 alkyl; - each Z1 and Z2 is independently a direct union, O, S(O)m, CHR20 or NR21; - m is 0, 1 or 2 (which is understood as indicating that each m is independently 0, 1 or 2); and - R21 is H or C1-C3 alkyl (subject to proviso (b) and/or proviso (c) as applicable).

[0201] Compounds of Formula 1 also deserve attention, which include all their geometric isomers and stereoisomers, N-oxides and salts, agricultural compositions that contain them and their use as fungicides, in which: - each R5 is independently H, halogen, cyano, hydroxy, amino, nitro, -CHO, -C(=O)OH, -C(=O)NH2, -NR25R26, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C2-C6 haloalkenyl, C2C6 haloalkynyl, C3-C8 cycloalkyl, C3-C8 halocycloalkyl, C4-C10 alkylcycloalkyl, C4-C10 cycloalkylalkyl, C6-C14 cycloalkylcycloalkyl, C4-C10 halocycloalkylalkyl, C5-C10 alkylcycloalkylalkyl, C3-cycloalkenyl C8, halocycloalkenyl C3C8 , 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, cycloalkyl C4-C10 kylaminoalkyl , C2-C6 alkylcarbonyl, C2-C6 haloalkylcarbonyl, C4-C8 cycloalkylcarbonyl, C2-C6 alkoxycarbonyl, C4-C8 cycloalkoxycarbonyl, C5-C10 cycloalkylalkoxycarbonyl, C2-C6 alkylaminocarbonyl, C3-C8 dialkylaminocarbonyl, C4-C8 cycloalkylaminocarbonyl, C1-C6 alkoxy , Haloalócóxi C1-C6, Cycloalcloxi C3-C8, Halocycloalclolaci C3-C8, Cycloalchilalóxi C4C10, Alchenyloxi C2-C6, Haloalchenilóxi C2-C6, Alchinylóxi C2-C6, Haloalchinylolox C2-C6, Alcoxialciolócoxi C2-C6, Alkycarbonilox -C6, haloalquilcarboniloxi C2-C6, C4-C8 cycloalkylcarbonyloxy, C3-C6 alkylcarbonylalkoxy, C1-C6 alkylthio, C1-C6 haloalkylthio, C3-C8 cycloalkylthio, C1-C6 alkylsulfinyl, C1-C6 haloalkylsulfinyl, C1-C6 alkylsulfonyl, C1-C6 haloalkylsulfonyl, cycloalkylsulfonyl C3-C8, C3-C10 trialkylsilyl, C1-C6 alkylsulfonylamino, C1-C6 haloalkylsulfonylamino or - Z2Q; - each R7 is independently 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, haloalkynyl C2-C6, 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, haloalkylsulfinyl C1-C4, 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, alkylcarbonylthio C2-C6, C2-C6 alkylaminocarbonyl, C3-C8 dialkylaminocarbonyl or C3-C6 trialkylsilyl; or - R5 and R7 are taken together with the linking atoms R5 and R7 to form an optionally substituted five- to seven-membered ring containing as ring members two to seven carbon atoms and optionally one to three heteroatoms selected from from up to 1 O, up to 1 S, up to 1 Si and up to 1 N; and - R12 is C1-C3 alkyl (subject to proviso (b) and/or proviso (c) as applicable).

[0202] The present invention provides a fungicidal composition comprising a compound of Formula 1 (which includes all its geometric isomers, stereoisomers, N-oxides and salts) and at least one other fungicide. Compositions comprising a compound corresponding to any of the compound embodiments described above deserve notice as embodiments of these compositions.

[0203] The present invention provides a fungicidal composition comprising a fungicidal effective amount of a compound of Formula 1 (which includes all its geometric and stereoisomers, N-oxides and salts suitable for agricultural use) and at least one additional component selected from the group consisting of surfactants, solid diluents and liquid diluents. Compositions comprising a compound corresponding to any of the compound embodiments described above deserve notice as embodiments of these compositions.

[0204] The present invention provides a method of controlling plant diseases caused by fungal plant pathogens which comprises applying to the plant or a part thereof, or to the seed of the plant, a fungicide-effective amount of a compound of Formula 1 (which includes all its geometric isomers, stereoisomers, N-oxides and salts suitable for agricultural use). Worthy of note as an embodiment of these methods are methods comprising applying a fungicidal effective amount of a compound corresponding to any of the compound embodiments described above. The embodiments in which the compounds are applied as compositions of the present invention deserve specific observations.

[0205] The compounds of Formulas 1, 1A, 1B and 1C can be prepared by one of the following methods and variations, as described in Schemes 1 to 20. The definitions of A, G, J, W, X, Q , Z1, R1, R2, R15, R16 and n in the compounds of Formulas 1 to 38 below are as described above in the Summary Description of the Invention, unless otherwise indicated. Formulas 1a through 1e and Formulas 1Ba and 1Bb are various subsets of Formula 1 and 1B, respectively.

[0206] As shown in Scheme 1, compounds of Formula 1a (Formula 1 where A is CHR15) where W is O can be prepared by coupling an acid chloride of Formula 2 with an amine of Formula 3 in the presence of an acid extractor. Typical acid extractants include amine bases such as triethylamine, N,N-diisopropylethylamine and pyridine. Other extractants include hydroxides such as sodium and potassium hydroxide and carbonates such as sodium carbonate and potassium carbonate. In certain cases, it is useful to employ polymer-supported acid extractants such as polymer-bound N,N-diisopropylethylamine and polymer-bound 4-(dimethylamino)pyridine. Acid salts of the amines of Formula 3 can also be used in this reaction, provided that at least two equivalents of the acid extractant are present. Typical acids used to form salts with amines include hydrochloric acid, oxalic acid, and trifluoroacetic acid. In a subsequent step, amides of Formula 1a where W is O can be converted to thioamides of Formula 1a where W is S using a series of standard thiating reagents such as phosphorus pentasulfide or 2,4-disulfide. bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetan (Lawesson reagent).

[0207] An alternative procedure for preparing compounds of Formula 1a in which W is O is illustrated in Scheme 2 and involves coupling an acid of Formula 4 with an amine of Formula 3 (or its salt) in the presence of a coupling reagent dehydrant such as dicyclohexylcarbodiimide (DCC), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) or O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU). Polymer-supported reagents are again useful at present, such as polymer-bound cyclohexylcarbodiimide. These reactions are typically conducted at 0-40°C in a solvent such as dichloromethane or acetonitrile in the presence of a base such as triethylamine or N,N-diisopropylethylamine. The acids of Formula 4 are known or can be prepared by methods known to those skilled in the art. R1CH2COOH where R1 is a nitrogen-linked heteroaromatic ring can be prepared, for example, by reacting the corresponding compound R1H with an ester or haloacetic acid in the presence of base; see, for example, U.S. Patent No. ° 4,084,955. R1CH2COOH wherein R1 is phenyl or a carbon-bonded heteroaromatic ring can be prepared from the corresponding R1CH2-halogen compounds by displacement of the halogen with cyanide followed by hydrolysis; see, for example, K. Adachi, Yuki Gosei Kagaku Kyokaishi, 1969, 27, 875-876; of R1C(=O)CH3 through the Willgerodt-Kindler reaction; see, for example, HR Darabi et al, Tetrahedron Letters 1999, 40, 7549-7552 and MM Alam and SR Adapa, Synthetic Communications 2003, 33, 59-63 and references therein; or of R1Br or R1I via palladium-catalyzed coupling with tert-butyl acetate or diethyl malonate, followed by ester hydrolysis; see, for example, WA Moradi and SL Buchwald, J. Am. Chem. Soc. 2001, 123, 7996-8002 and JF Hartwig et al, J. Am. Chem. Soc. 2002, 124, 12557-12565.

[0208] As the synthetic literature includes many methods of amide formation, the synthetic procedures of Schemes 1 and 2 are only representative examples of a wide variety of useful methods of preparing compounds of Formula 1. Those skilled in the art also understand that chlorides Formula 2 acids can be prepared from Formula 4 acids by several well-known methods.

[0209] Certain compounds of Formula 1b (Formula 1 in which A is CHR15 and W is O) in which R1 is a heteroaromatic ring containing five-membered nitrogen bonded through the nitrogen atom can be prepared through the heterocycle reaction original formula of Formula 5 and a haloacetamide of Formula 6 as shown in Scheme 3. The reaction is conducted in the presence of a base such as sodium hydride or potassium carbonate in a solvent such as tetrahydrofuran, N,N-dimethylformamide or acetonitrile at 0 up to 80°C. The haloacetamide of Formula 6 can be prepared by reacting an amine of Formula 3 with an α-halo carboxylic acid halide or an α-halo carboxylic acid or anhydride thereof, analogous to the amide formation reactions described in Schemes 1 and 2, respectively. wherein R1 is an unsubstituted five-membered nitrogen-containing heteroaromatic ring on N; and Y1 is Cl, Br or I.

[0210] Compounds of Formula 1c (Formula 1 where A is NH), where R1 is phenyl, naphthalenyl or a five- or six-membered heteroaromatic ring and W is O or S, can be prepared by reacting an amine of Formula 3 with an isocyanate or isothiocyanate, respectively, of Formula 7 as illustrated in Scheme 4. This reaction is typically conducted at room temperature in an aprotic solvent such as dichloromethane or acetonitrile.

[0211] Compounds of Formula 1c can also be prepared by reacting an amine of Formula 8 with a carbamoyl or thiocarbamoyl chloride or imidazole of Formula 9 as shown in Scheme 5. When Y is chlorine, the reaction is typically conducted in the presence of an acid extractant. Typical acid extractants include amine bases such as triethylamine, N,N-diisopropylethylamine and pyridine. Other extractants include hydroxides such as sodium and potassium hydroxide and carbonates such as sodium carbonate and potassium carbonate. Carbamoyl or thiocarbamoyl chlorides of Formula 9 (where Y is Cl) can be prepared from amines of Formula 3 by treatment with phosgene or thiophosgene, respectively, or their equivalents, while carbamoyl or thiocarbamoyl imidazoles of Formula 9 ( where Y is imidazol-1-yl) can be prepared from amines of Formula 3 by treatment with 1,1'-carbonyldiimidazole or 1,1'-thiocarbonyldiimidazole, respectively, according to general methods known to those skilled in the art. subject. where W is O or S; and Y is Cl or imidazol-1-yl.

[0212] Certain compounds of Formula 1d (i.e., Formula 1 in which the X-containing ring is saturated) can be prepared from compounds of Formula 1e in which the X-containing ring is unsaturated through catalytic hydrogenation, as per shown in Scheme 6. Typical conditions involve exposure of a compound of Formula 1e to hydrogen gas under pressure of 70 to 700 kPa, preferably 270 to 350 kPa, in the presence of a metallic catalyst such as palladium supported on an inert vehicle such as activated carbon, in a weight ratio of 5 to 20% metal to vehicle, suspended in a solvent such as ethanol at room temperature. This type of reduction is very well known; see, for example, Catalytic Hydrogenation, L. Cerveny, Ed., Elsevier Science, Amsterdam, 1986. Those skilled in the art will recognize that some other functionalities that may be present in compounds of Formula 1e may also be reduced under conditions of catalytic hydrogenation, so as to require appropriate selection of catalyst and conditions. where X is X1, X2, X5. X8 or X9.

[0213] Certain compounds of Formula 1 in which X is X1, X5, X7 or X9 and G is attached to the ring containing ring containing the X of Formula 10 with a nitrogen-containing heterocycle of Formula 11 in the presence of a base as illustrated in Scheme 7. Suitable bases include sodium hydride or potassium carbonate and the reaction is conducted in a solvent such as N, N-dimethylformamide or acetonitrile at 0 to 80 °C. Suitable residual groups in compounds of Formula 10 include bromide, iodide, mesylate (OS(O)2CH3), triflate (OS(O)2CF3) and the like and compounds of Formula 10 can be prepared from the corresponding compounds where Y2 is OH , using general methods known in the art. where W is O or S; X is X1, X5, X7 or X9; and Y2 is a residual group such as Br, I, OS(O)2Me or OS(O)2CF3.

[0214] Compounds of Formula 1 in which X is X2 or X8 can be prepared by reacting a compound of Formula 12 with a heterocyclic triflate or halide (OS(O)2CF3) of Formula 13 as shown in Scheme 8. The reaction is conducted in the presence of a base such as potassium carbonate in a solvent such as dimethyl sulfoxide, N,N-dimethylformamide or acetonitrile at 0 to 80 °C. Compounds of Formula 13 wherein Y2 is triflate can be prepared from corresponding compounds wherein Y2 is OH by methods known to those skilled in the art. where W is O or S; X is X2 or X8; and Y2 is a residual group such as Br, I, OS(O)2Me or OS(O)2CF3.

[0215] The amine compounds of Formula 3 can be prepared from the protected amine compounds of Formula 14 wherein Y3 is an amine protecting group as shown in Scheme 9. A wide variety of amine protecting groups are available (see, for example, example, TW Greene and PGM Wuts, Protective Groups in Organic Synthesis, second edition; Wiley: New York, 1991) and the use and selection of appropriate protecting groups will be evident to those skilled in chemical synthesis. The protecting group can be removed and the amine isolated as its acid salt or free amine by general methods known in the art. Those skilled in the art will also recognize that the protected amines of Formula 14 can be prepared by methods analogous to those described in Schemes 6, 7 and 8 above in which the R1AC(=W) group is replaced by Y3 to generate useful intermediates of Formula 14 for preparing Formula 1 compounds. where Y3 is an amine protecting group.

[0216] Compounds of Formula 14 can also be prepared by reacting a suitably functionalized compound of Formula 15 with a suitably functionalized compound of Formula 16 as shown in Scheme 10. Functional groups Y4 and Y5 are selected, without limitation, from moieties such as aldehydes, ketones, esters, acids, amides, thioamides, nitriles, amines, alcohols, thiols, hydrazines, oximes, amidines, amidooximes, olefins, acetylenes, halides, alkyl halides, methanesulfonates, trifluoromethanesulfonates, boronic acids , boronates and the like, which, under appropriate reaction conditions, will allow the construction of the various heterocyclic rings G. The reaction of a compound of Formula 15 in which Y4 is a thioamide group with a compound of Formula 16 in which Y5 is a bromoacetyl will generate a compound of Formula 14 in which G is a thiazole ring. The synthetic literature describes many general methods of forming five-membered heteroaromatic rings and five-membered partially saturated heterocyclic rings (such as G-1 to G-59); see, for example, Comprehensive Heterocyclic Chemistry, Vol. 4-6, AR Katritzky and CW Rees, editors, Pergamon Press, New York, 1984; Comprehensive Heterocyclic Chemistry II, Vol. 2-4, AR Katrizky, CW Rees and EF Scriven, editors, Pergamon Press, New York, 1996; and The Chemistry of Heterocyclic Compounds series, EC Taylor, editor, Wiley, New York. The use of intermediates of Formula 15 wherein X is X1 and Y4 is Br, I, methanesulfonate or trifluoromethanesulfonate has been described to prepare organozinc reagents for use in cross-coupling reactions with aromatic rings; see, for example, S. Bellotte, Synlett 1998, 379-380, and M. Nakamura et al, Synlett 2005, 1794-1798. Those skilled in the art know how to select the appropriate functional groups to construct the desired heterocyclic rings such as G. The compounds of Formulas 15 and 16 are known or can be prepared by those skilled in the art. where Y4 and Y5 are functional groups suitable for constructing the desired heterocycle G.

[0217] Certain compounds of Formula 14 in which Z1 is O, S or NR21 can be prepared by displacing an appropriate residual group Y2 on G of Formula 17 with a compound of Formula 18 in the presence of a base as illustrated in the Scheme 11. Suitable bases include sodium hydride or potassium carbonate and the reaction is conducted in a solvent such as N,N-dimethylformamide or acetonitrile at 0 to 80 °C. Suitable residual groups in compounds of Formula 17 include bromide, iodide, mesylate (OS(O)2CH3), triflate (OS(O)2CF3) and the like. The compounds of Formula 17 can be prepared from corresponding compounds where Y2 is OH by general methods known in the art. Many of the compounds of Formula 18 are known or can be prepared by general methods known in the art. wherein Y2 is a residual group such as Br, I, OS(O)2Me or OS(O)2CF3; and Z1 is O, S or NR21.

[0218] Certain compounds of Formula 14 in which Z1 is O, S or NR21 can also be prepared by displacing an appropriate residual group Y2 on J of Formula 20 with a compound of Formula 19 in the presence of a base as illustrated in Scheme 12. Suitable bases include sodium hydride or potassium carbonate and the reaction is conducted in a solvent such as N,N-dimethylformamide or acetonitrile at 0 to 80 °C. Suitable residual groups in compounds of Formula 20 include bromide, iodide, mesylate (OS(O)2CH3), triflate (OS(O)2CF3) and the like. Compounds of Formula 20 can be prepared from corresponding compounds where Y2 is OH using general methods known in the art. wherein Y2 is a residual group such as Br, I, OS(O)2Me or OS(O)2CF3; and Z1 is O, S or NR21.

[0219] Compounds of Formula 14 can also be prepared by reacting a suitably functionalized compound of Formula 21 with a suitably functionalized compound of Formula 22 as shown in Scheme 13. Functional groups Y6 and Y7 are selected, but without limitation , from moieties such as aldehydes, ketones, esters, acids, amides, thioamides, nitriles, amines, alcohols, thiols, hydrazines, oximes, amidines, amide oximes, olefins, acetylenes, halides, alkyl halides, methanesulfonates, trifluoromethanesulfonates, boronic acids, boronates and the like, which, under appropriate reaction conditions, will permit the construction of the various J heterocyclic rings. The reaction of a compound of Formula 21 in which Y6 is a chloro oxime moiety with a compound of Formula 22 in which Y7 is a vinyl or acetylene group in the presence of a base, for example, will generate a compound of Formula 14 in which J is an isoxazoline or isoxazole, respectively. The synthetic literature includes many general methods of forming carbocyclic and heterocyclic rings and ring systems (such as J-1 to J-82); see, for example, Comprehensive Heterocyclic Chemistry, Vol. 4-6, AR Katritzky and CW Rees, editors, Pergamon Press, New York, 1984; Comprehensive Heterocyclic Chemistry II, Vol. 2-4, AR Katritzky, CW Rees and EF Scriven, editors, Pergamon Press, New York, 1996; the series The Chemistry of Heterocyclic Compounds, EC Taylor, editor, Wiley, New York, and Rodd's Chemistry of Carbon Compounds, VOL. 2-4, Elsevier, New York. General procedures for cycloaddition of nitrile oxides with olefins are well documented in the chemical literature. For relevant references, see Lee, Synthesis 1982, 6, 508-509 and Kanemasa et al, Tetrahedron 2000, 56, 10571064, as well as the references cited therein. Those skilled in the art know how to select the appropriate functional groups to construct the desired heterocyclic ring J. The compounds of Formula 22 are known or can be prepared by general methods known in the art. where Y6 and Y7 are functional groups suitable for constructing the desired heterocycle J.

[0220] An alternative preparation of the compounds of Formula 14 in which Z1 is a union includes the well-known Suzuki reaction which involves Pd-catalyzed cross-coupling of an iodide or bromide of Formula 23 or 26 with a boronic acid of Formula 24 or 25 , respectively, as shown in Scheme 14. Many catalysts are useful for this type of transformation; a typical catalyst is tetrakis(triphenylphosphine)palladium. Solvents such as tetrahydrofuran, acetonitrile, diethyl ether and dioxane are suitable. The Suzuki reaction and related coupling procedures offer many alternatives for creating the GJ Union. For important references, see, for example, CA Zificsak and DJ Hlasta, Tetrahedron 2004, 60, 8991-9016. For a complete review of palladium chemistry applicable to the synthesis of GJ unions, see JJ Li and GW Gribble, editors, Palladium in Heterocyclic Chemistry: A Guide for the Synthetic Chemist, Elsevier: Oxford, Great Britain, 2000. Many type variations Catalyst, base and reaction conditions are known in the art for this general method.

[0221] Those skilled in the art will recognize that many compounds of Formula 1 can be prepared directly by methods analogous to those described in Schemes 10 to 14 above in which the Y3 group is replaced by R1AC(=W). Thus, the compounds corresponding to Formulas 15, 17, 19, 21, 23 and 25 in which Y3 is replaced by R1AC(=W) are useful intermediates for the preparation of compounds of Formula 1.

[0222] Thioamides of Formula 1Bb are particularly useful intermediates for the preparation of compounds of Formula 1 in which X is X1. A thioamide of Formula 1Bb can be prepared by adding hydrogen sulfide to the corresponding nitrile of Formula 1Ba as shown in Scheme 15. where R1 is as defined for Formula 1.

[0223] The method of Scheme 15 can be conducted by contacting a compound of Formula 1Ba with hydrogen sulfide in the presence of an amine such as pyridine, diethylamine or diethanolamine. Alternatively, hydrogen sulfide can be used in the form of its disulfide salt with an alkali metal or ammonia. This type of reaction is well documented in the literature (such as A. Jackson et al, EP 696,581 (1996)).

[0224] Certain compounds of Formula 1Ba in which R1 is a five-membered nitrogen-containing heteroaromatic ring bonded through a nitrogen atom can be prepared by reacting the original heterocycle of Formula 5 and a halocetamide of Formula 27 as shown in Scheme 16. The reaction is conducted in the presence of a base such as sodium hydride or potassium carbonate in a solvent such as tetrahydrofuran, N,N-dimethylformamide or acetonitrile at 0 to 80 ° C. wherein R1 is an unsubstituted five-membered nitrogen-containing heteroaromatic ring on N (i.e., a five-membered heteroaromatic ring comprising a ring member of the formula -(NH)-); and Y1 is Cl, Br or I.

[0225] The haloacetamides of Formula 27 can be prepared using the two methods shown in Scheme 17. where Y1 is Cl, Br or I; and R31 is a tertiary alkyl group such as - C(Me)3.

[0226] In one method, 4-cyanopiperidine of Formula 29 is haloacetylated through contact with the appropriate haloacetyl chloride, typically in the presence of a base according to standard methods. Preferred conditions involve the use of an aqueous solution of an inorganic base such as an alkali or alkaline earth metal phosphate, bicarbonate or carbonate and a water-immiscible organic solvent such as toluene, ethyl acetate or 1,2-dichloroethane. . In the second method illustrated in Scheme 17, a 1-(haloacetyl)-N-substituted isonipecotamide derivative of Formula 28, wherein R31 is tertiary alkyl such as C(Me)3, is dehydrated using a standard amide dehydrating agent such as thionyl chloride or phosphorus oxychloride in an appropriate solvent. A particularly preferred solvent for this transformation is an N,N-dialkylamide such as N,N-dimethylformamide. The reaction is typically conducted by adding 0.9 to 2 equivalents, preferably 1.1 equivalents, of phosphorus oxychloride or thionyl chloride, to a mixture of a compound of Formula 28 and 0.5 to 10 parts by weight. of solvent, at a temperature at which the reaction proceeds rapidly during addition. The addition time for this reaction is typically about twenty to ninety minutes under typical temperatures of about 35 to 55 °C.

[0227] As shown in Scheme 18, the compounds of Formula 28 can be prepared from the compound of Formula 30 by analogy with the haloacetylation reaction described for Scheme 17.

[0228] The compounds of Formula 30 are known or can be prepared from 4-cyanopyridine or isonicotinic acid using methods well known in the art; see, for example, G. Marzolph et al, DE 3,537,762 (1986) for the preparation of N-t-butyl pyridinecarboxamides from cyanopyridines and t-butanol and S. F. Nelsen et al, J. Org. Chem., 1990, 55 , 3825 for hydrogenation of N-methylisonicotinamide with a platinum catalyst.

[0229] Halomethyl isoxazole ketones of Formula 35 are particularly useful intermediates for the preparation of certain chiral compounds of Formula 1, wherein J is, for example, selected from J-29-1 to J-29-12 as shown in Illustration A. Halomethyl isoxazole ketones of Formula 35 can be prepared using the multistep reaction sequences shown in Scheme 19. wherein R32 is C2-C8 dialkylamino, C2-C6 haloalkylamino, 1-piperidinyl, 1-pyrrolidinyl or 4-morpholinyl; and R5 are as defined above in the Summary Description of the Invention.

[0230] The preparation of the racemic carboxylic acids of Formula 32 can be carried out according to well-known methods of acid or basic hydrolysis of the corresponding compounds of Formula 31, preferably using a slight excess of sodium hydroxide in a co-solvent miscible in water such as methanol or tetrahydrofuran at about 25 to 45°C. The product can be isolated by adjusting the pH to about 1 to 3 and then filtering or extracting, optionally after removing the organic solvent by evaporation. The racemic carboxylic acids of Formula 32 can be resolved by classical fractional crystallization of diastereomeric salts of appropriate chiral amine bases such as cinchonine, dihydrocinchonine or a mixture thereof. A mixture of cinchonine and dihydrocinchonine in a ratio of about 85:15 is particularly useful because it provides, for example, the (R)-configured carboxylic acids of Formula 33, wherein R5 is a substituted phenyl group, such as less soluble salt. Furthermore, these chiral amine bases are readily available on a commercial scale. The (R)-configured halomethyl ketone intermediates of Formula 35 generate the most active final products as a Formula 1 fungicide after coupling with thioamides of Formula 1Bb. The halomethyl ketones of Formula 35 can be prepared by first reacting the corresponding amides of Formula 31, either in the form of pure enantiomers (i.e., Formula 31a) or in racemic or enantiomerically enriched mixtures, with a molar equivalent of a methylmagnesium halide (Grignard reagent) in a suitable solvent or mixture of solvents such as tetrahydrofuran and toluene at about 0 to 20 ° C and the crude ketone products of Formula 34 can be isolated by quenching with aqueous acid, extraction and concentration. Next, the crude ketones of Formula 34 are halogenated with a reagent such as sulfuryl chloride to generate the chloromethyl ketones of Formula 35 in which Y1 is Cl or molecular bromine to generate the corresponding bromomethyl ketones of Formula 35 in which Y1 is Br. The halomethyl ketones of Formula 35 can be purified by crystallization from a solvent such as hexanes or methanol, or can be used without further purification in the condensation reaction with thioamides.

[0231] The isoxazole carboxamides of Formula 31 can be prepared by cycloaddition of the corresponding hydroxamoyl chlorides of Formula 36 with olefin derivatives of Formula 37, as shown in Scheme 20.

[0232] In this method, all three reaction components (the compounds of Formulas 36 and 37 and the base) are brought into contact so as to minimize hydrolysis or dimerization of the hydroxamoyl chloride of Formula 36. In a typical procedure, the base, which may be a tertiary amine base such as triethylamine or an inorganic base such as an alkali or alkaline earth metal carbonate, bicarbonate or phosphate, is mixed with the olefin derivative of Formula 37 and the hydroxamoyl chloride of Formula 36 it is added gradually at a temperature at which the cycloaddition proceeds at a relatively high speed, typically 5 to 25 °C. Alternatively, the base can be added gradually to the other two components (the compounds of Formulas 36 and 37). This alternative procedure is preferable when the hydroxamoyl chloride of Formula 36 is substantially insoluble in the reaction medium. The solvent in the reaction medium can be water or an inert organic solvent such as toluene, hexane or even the olefin derivative used in excess. The product can be separated from the salt co-product by filtering or washing with water, followed by evaporation of the solvent. The crude product can be purified by crystallization or the crude product can be used directly in the methods of Scheme 19. The compounds of Formula 31 are useful precursors to the corresponding methyl ketones of Formula 34 and halomethyl ketones of Formula 35 and are also useful for the preparation of the resolved enantiomers of the compounds of Formulas 34 and 35 through hydrolysis, resolution, methyl ketone synthesis, and halogenation, as shown in Scheme 19.

[0233] It is recognized that some reagents and reaction conditions described above for the preparation of compounds of Formulas 1, 1A, 1B and 1C may not be compatible with certain functionalities present in the intermediates. In these cases, the incorporation of protection and deprotection sequences or interconversions of functional groups in the synthesis will help to obtain the desired products. The use and selection of protecting groups will be evident to those skilled in chemical synthesis (see, for example, T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, second edition; Wiley: New York, 1991). Those skilled in the art will recognize that, in some cases, after introducing a given reagent as illustrated in any individual scheme, it may be necessary to perform additional routine synthetic steps not described in detail to complete the synthesis of compounds of Formulas 1, 1A, 1B. and 1C. Those skilled in the art will also recognize that it may be necessary to perform a combination of the steps illustrated in the above schemes in a different order than indicated by the specific sequence shown to prepare the compounds of Formulas 1, 1A, 1B and 1C.

[0234] Those skilled in the art will also recognize that the compounds of Formulas 1, 1A, 1B and 1C and the intermediates described herein can be subjected to various electrophilic, nucleophilic, radical, organometallic, oxidation and reduction reactions to add substituents or modify existing substituents.

[0235] Without further elaboration, it is believed that those skilled in the art, employing the above description, can utilize the present invention to the fullest extent possible. The following Examples should, therefore, be interpreted as merely illustrative and not limiting the specification in any way. The steps in the following Examples illustrate a procedure for each step in a general synthetic transformation and the starting material for each step may not necessarily have been prepared through a specific preparative conduction whose procedure is described in other Examples or Steps. Percentages are by weight, except for mixtures of chromatographic solvents or when otherwise indicated. Parts and percentages for chromatographic solvent mixtures are by volume unless otherwise noted. 1H NMR spectra are reported in ppm from tetramethylsilane; “s” indicates isolated, “d” indicates double, “t” indicates trio”, “m” indicates multiple, “q” indicates quartet, “br s” indicates broad isolated, “br d” indicates broad double, “br t ” indicates broad triple and “br m” indicates broad multiple.EXAMPLE 1

[0236] Preparation of 4-[4-[4,5-dihydro-5-phenyl-3-isoxazolyl]-2-thiazolyl]-1-[[5-methyl-3-(trifluoromethyl)-1H-pyrazole -1-yl]acetyl]piperidine (Compound 1):Step A: Preparation of 4-[4-(4,5-dihydro-5-phenyl-3-isoxazolyl)-2-thiazolyl]-1-piperidinecarboxylate 1,1-dimethylethyl

[0237] To a suspension of 1,1-dimethylethyl 4-(4-formyl-2-thiazolyl)-1-piperidinecarboxylate (1.0 g, 3.4 mmol) in ethanol (5 ml), one aqueous hydroxylamine solution (50% by weight, 0.25 ml, 4.0 mmol). The reaction mixture was heated to 60 °C for one hour, during which time the reaction mixture became homogeneous. The resulting solution was cooled to room temperature and diluted with tetrahydrofuran (10 ml). Styrene (0.57 ml, 5 mmol) was added to the reaction mixture, followed by the gradual addition of Clorox® aqueous sodium hypochlorite solution (10.5 ml) over three hours. The reaction mixture was stirred overnight at room temperature and the resulting solid was filtered, washed with water and diethyl ether and dried in air to give the title compound as a white powder (610 mg). The filtrate was diluted with saturated aqueous sodium bicarbonate solution and extracted with diethyl ether. The extract was dried (MgSO4) and concentrated under reduced pressure to give 850 mg of the title compound as a yellow oil. The oil was diluted with diethyl ether (4 ml) and allowed to stand to give an additional 233 mg of product as a white solid.

[0238] NMR 1H (CDCl3) δ 1.47 (s, 9H), 1.7 (m, 2H), 2.1 (m, 2H), 2.85 (m, 2H), 3.2 (m , 1H), 3.45 (m, 1H), 3.84 (m, 1H), 4.2 (br s, 2H), 5.75 (m, 1H), 7.25-7.40 (m , 5H), 7.61 (s, 1H).

[0239] Step B: Preparation of 4-[4-[4,5-dihydro-5-phenyl-3-isoxazolyl]-2-thiazolyl]-1-[[5-methyl-3-(trifluoromethyl)- 1H-pyrazol-1-yl]acetyl]piperidine

[0240] To a solution of 1,1-dimethylethyl 4-[4-(4,5-dihydro-5-phenyl-3-isoxazolyl)-2-thiazolyl]-1-piperidinecarboxylate (i.e., the product of Example 1, Step A) (0.815 g, 1.97 mmol) in dichloromethane (50 ml), a solution of hydrogen chloride in diethyl ether (2 M, 10 ml, 20 mmol) was added. The reaction mixture was stirred at room temperature for one hour to generate a gum-like precipitate. Methanol was added to dissolve the precipitate and the reaction mixture was stirred for an additional hour. The reaction mixture was concentrated under reduced pressure and partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution and the organic layer was dried (MgSO4) and concentrated to give the free amine as a clear oil (0.31 g ), which solidified upon rest. A mixture of the resulting free amine (0.31 g, 1.0 mmol), 5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-acetic acid (0.208 g, 1.0 mmol), 1- [3-(dimethylamino)propyl]-3-ethylcarbodiimide (0.25 g, 1.3 mmol), triethylamine (150 μl, 1.08 mmol), and a catalytic amount of 1-hydroxy-benzotriazole hydrate (about 1 mg) in dichloromethane (5 ml) was stirred to form a whirlpool and kept at room temperature for sixteen hours. The reaction mixture was diluted with dichloromethane (10 ml), washed with 1N aqueous hydrochloric acid and saturated aqueous sodium bicarbonate solution. The organic layer was dried (MgSO4) and concentrated under reduced pressure to generate 0.47 g of the title product, a compound according to the present invention, in the form of a white foam.

[0241] NMR 1H (CDCl3) δ 1.8 (m, 2H), 2.2 (m, 2H), 2.32 (s, 3H), 2.9 (m, 1H), 3.3 (m , 2H), 3.42 (m, 1H), 3.85 (m, 1H), 4.05 (m, 1H), 4.55 (m, 1H), 4.98 (m, 2H), 5 .75 (m, 1H), 6.33 (s, 1H), 7.25-7.42 (m, 5H), 7.63 (s, 1H).

[0242] The following compounds were prepared using procedures analogous to Step B of Example 1: - 1-[4-[4-(4,5-dihydro-5-phenyl-3-isoxazolyl)-2- thiazolyl]-1-piperidinyl]-2-[3-methyl-5-(trifluoromethyl)-1H-pyrazol-1-yl]ethanone (Compound 128): 1H NMR (CDCl3) δ 1.7-1.9 (m , 2H), 2.16 (m, 1H), 2.24 (m, 1H), 2.29 (s, 3H), 2.84-2.92 (br t, 1H), 3.30 (m , 2H), 3.43 (m, 1H), 3.86 (m, 2H), 4.59 (br d, 1H), 5.04 (s, 2H), 5.75 (m, 1H), 6.47 (s, 1H), 7.29-7.39 (m, 6H), 7.64 (s, 1H). - 1-[4-[4-(4,5-dihydro-5-phenyl-3-isoxazolyl)-2-thiazolyl]-1-piperidinyl]-2-[5-ethyl-3-(trifluoromethyl)- 1H-pyrazol-1-yl]ethanone (Compound 19): melting point 128-133 °C (crystallized from methyl acetate/petroleum ether): NMR 1H (CDCl3) δ 1.28 (t, 3H) , 1.8 (m, 2H), 2.2 (m, 2H), 2.62 (q, 2H), 2.9 (m, 1H), 3.3 (m, 2H), 3.42 ( m, 1H), 3.85 (m, 1H), 4.05 (m, 1H), 4.55 (m, 1H), 4.98 (m, 2H), 5.75 (m, 1H), 6.33 (s, 1H), 7.25-7.42 (m, 5H), 7.63 (s, 1H). - 2-[3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl]-1-[4-[4-(4,5-dihydro-5-phenyl-3-isoxazolyl)-2- thiazolyl]-1-piperidinyl]ethanone (Compound 22): melting point 130-133 °C (crystallized from methyl acetate/petroleum ether); 1H NMR (CDCl3) δ 1.8 (m, 2H), 2.2 (m, 2H), 2.9 (m, 1H), 3.3 (m, 2H), 3.42 (m, 1H) , 3.85 (m, 2H), 4.55 (m, 1H), 5.10 (s, 2H), 5.77 (m, 1H), 6.95 (s, 1H), 7,257.42 ( m, 5H), 7.64 (s, 1H). - 1-[4-[4-(2,3-dihydrospiro[4H-1-benzopyran-4,5'(4'H)-isoxazol]-3'-yl)-2-thiazolyl]-1- piperidinyl]-2-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]ethanone (Compound 137): 1H NMR (CDCl3) δ 1.83 (m, 2H), 2.18 (m , 3H), 2.33 (s, 3H), 2.42 (m, 1H), 2.90 (m, 1H), 3.31 (m, 2H), 3.47 (d, 1H), 3 .83 (d, 1H), 4.05 (m, 1H), 4.27 (m, 1H), 4.40 (m, 1H), 4.58 (d, 1H), 4.97 (m, 2H), 6.33 (s, 1H), 6.87 (d, 1H), 6.95 (dd, 1H), 7.21 (dd, 1H), 7.38 (d, 1H), 7, 67 (s, 1H). - 1-[4-[4-(2,3-dihydrospiro[4H-1-benzothiopyran-4,5'(4'H)-isoxazol]-3'-yl)-2-thiazolyl]-1- piperidinyl]-2-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]ethanone (Compound 102): 1H NMR (CDCl3) δ 1.82 (m, 2H), 2.23 (m , 2H), 2.31 (s, 3H), 2.37 (m, 1H), 2.50 (m, 1H), 2.90 (m, 1H), 3.14 (m, 1H), 3 .17 (m, 1H), 3.27 (m, 2H), 3.48 (d, 1H), 3.66 (d, 1H), 4.05 (m, 1H), 4.57 (d, 1H), 4.97 (m, 2H), 6.33 (s, 1H), 7.06 (m, 3H), 7.45 (d, 1H), 7.65 (s, 1H). EXAMPLE 2

[0243] Preparation of 1-[[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl]-4-[4-(5-phenyl-3-isoxazolyl)-2-thiazolyl]piperidine (Compound 2)

[0244] Step A: Preparation of 2-(4-piperidinyl)-4-thiazolocarboxaldehyde monohydrochloride

[0245] To a solution of 1,1-dimethylethyl 4-(4-formyl-2-thiazolyl)-1-piperidinecarboxylate (1.0 g, 3.4 mmol) in dichloromethane (20 ml), one hydrogen chloride solution in diethyl ether (2.0 ml, 15 mol, 30 mmol). The reaction mixture was stirred under nitrogen at room temperature for two hours and then evaporated under reduced pressure to give 1.2 g of the title compound as a white solid.

[0246] NMR 1H (CDCl3) δ 2.31-2.38 (m, 2H), 2.44-2.50 (m, 2H), 3.11-3.20 (m, 2H), 3, 36-3.44 (m, 1H), 3.57-3.65 (m, 2H), 8.14 (s, 1H), 10.01 (s, 1H).

[0247] Step B: Preparation of 4-(4-formyl-2-thiazolyl)-1-[[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl]piperidine

[0248] To a solution of 5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-acetic acid (0.8 g, 3.8 mmol) in dichloromethane (10 ml), oxalyl chloride ( 2.4 g, 19.2 mmol) and two drops of N,N-dimethylformamide, resulting in slight exothermicity. The reaction mixture was then heated under reflux for fifteen minutes. The reaction mixture was concentrated in vacuo and the residue was suspended in tetrahydrofuran (10 ml) and treated with a solution of 2-(4-piperidinyl)-4-thiazolocarboxaldehyde monohydrochloride (i.e., the product of Example 2, Step A ) (1.1 g, 5.1 mmol) in tetrahydrofuran (10 ml), followed by dropwise addition of triethylamine (1.2 g, 11.9 mmol). The reaction mixture was stirred overnight at room temperature and then partitioned between 1 N aqueous hydrochloric acid and ethyl acetate. The organic layer was separated and the aqueous layer was extracted with additional ethyl acetate (2 x 30 ml). The combined organic layers were washed with 1N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate solution and brine. The organic layer was dried (MgSO4) and evaporated under reduced pressure to give 0.8 g of the title compound as a yellow oil.

[0249] NMR 1H (CDCl3) δ 1.79-1.90 (m, 2H), 2.18-2.29 (m, 2H), 2.33 (s, 3H), 2.87-2, 94 (m, 1H), 3.28-3.40 (m, 2H), 4.05-4.15 (m, 1H), 4.56-4.64 (m, 1H), 4.99- 5.02 (m, 2H), 6.35 (s, 1H), 8.12 (s, 1H), 10.01 (s, 1H).

[0250] Step C: Preparation of 4-[4-[(hydroxyimino)methyl]-2-thiazolyl]-1-[[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl]piperidine

[0251] To a solution of 4-(4-formyl-2-thiazolyl)-1-[[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl]piperidine (i.e., the product of Example 2, Step B) (0.8 g, 2.07 mmol) in ethyl alcohol (15 ml), hydroxylamine (50% aqueous solution, 0.136 g, 4.1 mmol) was added and the reaction mixture was stirred at room temperature for ten minutes. The reaction mixture was concentrated under reduced pressure to give a yellow oil, which was purified by flash column chromatography on silica gel using 50% ethyl acetate in hexanes as eluent to give 0.7 g of the title compound in white solid form.

[0252] NMR 1H (CDCl3) δ 1.72-1.85 (m, 2H), 2.17-2.27 (m, 2H), 2.32 (s, 3H), 2.82-2, 91 (m, 1H), 3.25-3.37 (m, 2H), 4.02-4.09 (m, 1H), 4.58-4.63 (m, 1H), 4.95- 5.03 (m, 2H), 6.35 (s, 1H), 7.43 (s, 1H), 7.71 (s, 1H), 8.19 (s, 1H).

[0253] Step D: Preparation of 1-[[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl]-4-[4-(5-phenyl-3-isoxazolyl)-2- thiazolyl]piperidine

[0254] 4-[4-[(Hydroxyimino)methyl]-2-thiazolyl]-1-[[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl]piperidine (i.e., the product of Example 2, Step C) (0.2 g, 0.5 mmol) was suspended in tetrahydrofuran (20 ml) and phenylacetylene (1.1 ml, 1 mmol) was added, followed by a slow dropwise addition of Clorox® whitening solution (6.15% by weight sodium hypochlorite, 10 ml) for one hour. The reaction mixture was partitioned between saturated aqueous sodium bicarbonate solution and ethyl acetate. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (3 x 30 ml). The combined organic layers were washed with brine, dried (MgSO4) and concentrated under reduced pressure to give an oil, which was purified by flash column chromatography on silica gel using 10% methanol in ethyl acetate as eluent to give 70 mg of the title product, a compound according to the present invention, in the form of a light yellow oil.

[0255] NMR 1H (CDCl3) δ 1.80-1.92 (m, 2H), 2.22-2.32 (m, 2H), 2.34 (s, 3H), 2.90-2, 98 (m, 1H), 3.31-3.41 (m, 2H), 4.05-4.11 (m, 1H), 4.58-4.65 (m, 1H), 4.97- 5.07 (m, 2H), 6.36 (s, 1H), 6.98 (s, 1H), 7.47-7.53 (m, 3H), 7.84 (s, 2H), 7 .88 (m, 1H).EXAMPLE 3

[0256] Preparation of 4-[4-(4,5-dihydro-1-methyl-5-phenyl-1H-imidazol-2-yl)-2-thiazolyl]-1-[[5-methyl-3 -(trifluoromethyl)-1H-pyrazol-1-yl]acetyl]piperidine (Compound 7)

[0257] To a solution of 4-(4-formyl-2-thiazolyl)-1-[[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl]piperidine (i.e., the product of Example 2, Step B) (0.8 g, 2.07 mmol) in tert-butanol (5 ml), N1-methyl-1-phenyl-1,2-ethanediamine (43.57 mg, 0 .29 mmol). The reaction mixture was stirred at room temperature under a nitrogen atmosphere for thirty minutes, and then potassium carbonate (107.8 mg, 0.78 mmol) and iodine (43.57 mg, 0.33 mmol) were added. mmol). The reaction mixture was stirred at 70 °C for three hours and then cooled by adding saturated aqueous sodium sulfite solution until the iodine color almost completely disappeared. The reaction mixture was extracted with chloroform and the organic layer was washed with saturated aqueous sodium bicarbonate solution and brine, dried (Na2SO4), filtered and concentrated. The residue was purified by means of preparative thin layer chromatography on silica gel using a mixture of 94% ethyl acetate, 5% methanol and 1% triethylamine as eluent to give 64 mg of the title product, a compound according to the present invention, in oil form.

[0258] NMR 1H (CDCl3) δ 1.72-1.87 (m, 2H), 2.15-2.28 (m, 2H), 2.31 (s, 3H), 2.86-2, 92 (m, 1H), 2.97 (s, 3H), 3.26-3.37 (m, 2H), 3.62-4.39 (m, 2H), 4.0-4.6 ( m, 2H), 4.93-5.05 (m, 2H), 6.31 (s, 1H), 7.30-7.41 (m, 5H), 7.88 (s, 1H).EXAMPLE 4

[0259] Preparation of 4-[4-(4,5-dihydro-3-phenyl-5-isoxazolyl)-2-thiazolyl]-1-[(5-methyl-3-(trifluoromethyl)-1H-pyrazole -1-yl)acetyl]piperidine (Compound 6)

[0260] Step A: Preparation of 1,1-dimethylethyl 4-(4-ethenyl-2-thiazolyl)-1-piperidinecarboxylate

[0261] To a cold suspension (-50 °C) of methyltriphenylphosphonium bromide (1.2 g, 3.3 mmol) in tetrahydrofuran (5 ml), a solution of sodium bis(trimethylsilyl)amide (3 .4 ml, 3.4 mmol) and the resulting mixture was stirred for one hour at room temperature. The resulting opaque yellow solution was cooled again to -30°C and 1,1-dimethylethyl 4-(4-formyl-2-thiazolyl)-1-piperidinecarboxylate (0.5 g, 1.68 mmol) was added. The resulting slightly yellow solution was stirred at room temperature for three hours, then diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried (MgSO4), filtered and purified by silica gel column chromatography using 15 to 30% ethyl acetate in hexanes as eluent to give 471 mg of the title compound as a colorless oil. .

[0262] NMR 1H (CDCl3) δ 1.47 (s, 9H), 1.68 (m, 2H), 2.10 (m, 2H), 2.88 (m, 2H), 3.15 (m , 1H), 4.18 (m, 2H), 5.34 (d, 1H), 6.02 (d, 1H), 6.68 (dd, 1H), 6.99 (s, 1H).

[0263] Step B: Preparation of 4-(4-ethenyl-2-thiazolyl)piperidine

[0264] To a solution of 1,1-dimethylethyl 4-(4-ethenyl-2-thiazolyl)-1-piperidinecarboxylate (i.e., the product of Example 4, Step A) (471 mg, 1.6 mmol) in dichloromethane (5 ml), a solution of hydrogen chloride in diethyl ether (2.0 M, 7 ml, 14 mmol) was added. The reaction mixture was stirred under nitrogen at room temperature for four hours, and then an aqueous solution of 1 N sodium hydroxide was added until the pH of the reaction mixture increased to about 10. The resulting mixture was extracted with dichloromethane (2x). The organic layers were combined, washed with brine, dried (MgSO4), filtered and concentrated in vacuo to give 302 mg of the title compound as an oil.

[0265] NMR 1H (CDCl3) δ 1.70 (m, 2H), 1.82 (br s, 1H), 2.12 (br d, 2H), 2.76 (br t, 2H), 3, 11 (m, 1H), 3.18 (m, 2H), 5.32 (d, 1H), 6.02 (d, 1H), 6.70 (dd, 1H), 6.99 (s, 1H ).

[0266] Step C: Preparation of 4-(4-ethenyl-2-thiazolyl)-1-[[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl]piperidine

[0267] To a solution of 5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-acetic acid (0.5 g, 2.4 mmol) in dichloromethane (4 ml), oxalyl chloride ( 0.3 ml, 3.6 mmol) and a drop of N,N-dimethylformamide, resulting in slight exothermicity. The reaction mixture was then heated under reflux for fifteen minutes. The reaction mixture was evaporated and the resulting residue was suspended in dichloromethane (4 ml) and treated with a solution of 4-(4-ethenyl-2-thiazolyl)piperidine (i.e., the product of Example 4, Step B) ( 302 mg, 1.5 mmol) in dichloromethane (2 ml), followed by addition of triethylamine (0.32 ml, 2.3 mmol). The reaction mixture was stirred overnight at room temperature, then concentrated and purified by silica gel column chromatography using 30-40% ethyl acetate in hexanes as eluent to give 414 mg of the title compound as white solid.

[0268] NMR 1H (CDCl3) δ 1.78 (m, 2H), 2.18 (m, 2H), 2.32 (s, 3H), 2.90 (br t, 1H), 3.30 ( m, 2H), 4.03 (d, 1H), 4.55 (d, 1H), 5.00 (m, 2H), 5.35 (d, 1H), 6.02 (d, 1H), 6.33 (s, 1H), 6.68 (dd, 1H), 7.01 (s, 1H).

[0269] Step D: Preparation of 4-[4-(4,5-dihydro-3-phenyl-5-isoxazolyl)-2-thiazolyl]-1-[(5-methyl-3-(trifluoromethyl)- 1H-pyrazol-1-yl)acetyl]pyridine

[0270] To a solution of benzaldehyde oxime (49 mg, 0.4 mmol) in N,N-dimethylformamide (3 ml), N-chlorosuccinimide (54 mg, 0.4 mmol) was added, followed by the addition of 4 -(4-ethenyl-2-thiazolyl)-1-[[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl]piperidine (i.e., the product of Example 4, Step C) (103 mg, 0.27 mmol) and triethylamine (41 mg, 0.4 mmol). The resulting mixture was stirred at room temperature for five hours, then diluted with water and extracted with dichloromethane (2x). The organic layers were combined, dried (MgSO4) and filtered. The filtrate was concentrated and the residue was purified by column chromatography on silica gel using 55-70% ethyl acetate in hexanes as eluent to give 90 mg of the title product, a compound according to the present invention in the form of white solid.

[0271] NMR 1H (CDCl3) δ 1.76 (m, 2H), 2.17 (m, 2H), 2.31 (s, 3H), 2.88 (br t, 1H), 3.25 ( m, 2H), 3.65 (m, 1H), 3.78 (m, 1H), 4.02 (br d, 1H), 4.56 (br d, 1H), 4.99 (m, 2H ), 5.84 (dd, 1H), 6.32 (s, 1H), 7.28 (s, 1H), 7.40-7.42 (m, 3H), 7.69-7.71 ( m, 2H).EXAMPLE 5

[0272] Preparation of 1-[4-[4-[5-(2-chlorophenyl)-4,5-dihydro-3-isoxazolyl]-2-thiazolyl]-1-piperidinyl]-2-[5- methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]ethanone (Compound 8)

[0273] To a solution of 1-chloro-2-ethenylbenzene (0.035 g, 0.25 mmol), triethylamine (2.5 mg, 0.025 mmol) and aqueous solution of Clorox® sodium hypochlorite (1 ml, 16.1 mmol) in dichloromethane (5 ml), 4-[4-[(hydroxyimino)methyl]-2-thiazolyl]-1-[[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1- was added yl]acetyl]piperidine (i.e., the product of Example 2, Step C (0.10 g, 0.25 mmol) in dichloromethane (5 ml) dropwise for one hour at 0 °C. The reaction mixture was kept stirring for one hour, then filtered through Celite® diatomaceous filter aid and concentrated under reduced pressure to generate an oil, which was purified by column chromatography on silica gel using 50% ethyl acetate in hexane as eluent to generate 73 mg of the title compound in the form of white foam, which melts at 115-122 °C (crystallized from methyl acetate and petroleum ether).

[0274] NMR 1H (CDCl3) δ 1.74-1.80 (m, 2H), 2.14-2.22 (m, 2H), 2.32 (s, 3H), 2.85-2, 91 (m, 1H), 3.26-3.30 (m, 2H), 3.31-3.32 (m, 1H), 4.05-4.07 (m, 1H), 4.55- 4.58 (m, 1H), 4.93-5.03 (q, 2H), 6.01-6.06 (m, 1H), 6.331 (s, 1H), 7.25-7.29 ( m, 2H), 7.38-7.40 (m, 1H), 7.56-7.58 (m, 1H), 7.62 (s, 1H).EXAMPLE 6

[0275] Preparation of 1-[4-[4-(4,5-dihydro-5-phenyl-3-isoxazolyl)-2-thiazolyl]-1-piperidinyl]-2-[5-methyl-3- (trifluoromethyl)-1H-pyrazol-1-yl]ethanethione (Compound 130)

[0276] A solution of 4-[4-[4,5-dihydro-5-phenyl-3-isoxazolyl]-2-thiazolyl]-1-[[5-methyl-3-(trifluoromethyl)-1 H -pyrazol-1-yl]acetyl]piperidine (i.e., the product of Example 1, Step B) (235 mg, 0.47 mmol) and phosphorus pentasulfide (104.5 mg, 0.235 mmol) in pyridine (5 ml ) was heated under reflux for two hours. The reaction mixture was then concentrated under reduced pressure and the residue was partitioned between dichloromethane (10 ml) and water (10 ml). The organic layer was washed with 1N hydrochloric acid, water, saturated aqueous sodium bicarbonate solution and brine, dried (MgSO4) and concentrated under reduced pressure to give 240 mg of the title product, a compound according to the present invention, in the white foam form.

[0277] NMR 1H (CDCl3) δ 1.80-2.00 (m, 2H), 2.20-2.28 (m, 2H), 2.45 (s, 3H), 3.35-3, 46 (3H, m), 3.50-3.61 (m, 1H), 3.80-3.88 (m, 1H), 4.70-4.80 (m, 1H), 5.30- 5.33 (m, 2H), 5.35-5.40 (m, 1H), 5.74-5.80 (m, 1H), 6.32 (s, 1H), 7.30-7, 40 (m, 5H), 7.65 (s, 1H).EXAMPLE 7

[0278] Preparation of 1-[4-[4-(4,5-dihydro-5-phenyl-3-isoxazolyl)-2-thiazolyl]-1-piperazinyl]-2-[5-methyl-3- (trifluoromethyl)-1H-pyrazol-1-yl]ethanone (Compound 154)

[0279] Step A: Preparation of 1,1-dimethylethyl 4-(aminothioxomethyl)-1-piperazine-carboxylate

[0280] To a solution of thiocarbonyldiimidazole (2.1 g, 11.8 mmol) in tetrahydrofuran (30 ml) at room temperature, 1,1-dimethylethyl 1-piperazinecarboxylate (2 g, 10.75 mmol) was added . The reaction mixture was stirred at room temperature for two hours and then heated at 55 °C for an additional two hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure until about 20 ml of tetrahydrofuran remained. The residue was then treated with a solution of 2 M ammonia in methanol (10 ml) and stirred at room temperature for 24 hours. The reaction mixture was concentrated under reduced pressure and the residue was triturated with diethyl ether (25 ml) to give a white precipitate. The precipitate was filtered and dried to give 1.5 g of the title compound as a white solid.

[0281] 1H NMR (CDCl3) δ 1.39 (s, 9H), 3.32 (m, 4H), 3.73 (m, 4H), 7.49 (br s, 2H).

[0282] Step B: Preparation of 3-chloro-N-hydroxy-2-oxo-propanimidoyl chloride

[0283] To a solution of 1,3-dichloroacetone (100 g, 0.79 mol) in a solution of 2 M hydrogen chloride in diethyl ether (400 ml) at 15 ° C, t-nitrite was added. butyl (55 g, 0.534 mol) over ten minutes. The progress of the reaction was monitored using 1H NMR to obtain about 85% conversion with no more than 3% bis-nitrosation byproduct. The reaction mixture was concentrated under reduced pressure to leave a semi-solid, which was then rinsed thoroughly with n-BuCl. The resulting solid was collected under filtration to give 77 g of the title compound as a white solid. The filtrate was further concentrated under reduced pressure to generate a semisolid residue, which was rinsed with additional n-BuCl. The resulting solid was collected under filtration to generate an additional 15 g of the title compound as a white solid.

[0284] 1H NMR (DMSO-d6) δ 4.96 (s, 2H), 13.76 (s, 1H).

[0285] Step C: Preparation of 2-chloro-1-(4,5-dihydro-5-phenyl)-3-isoxazolyl)ethanone

[0286] To a mixture of styrene (6.79 g, 65.3 mmol) and sodium bicarbonate (32.1 g, powder) in acetonitrile (100 ml), 3-chloro-N-hydroxy chloride was added -2-oxo-propanimidoyl (i.e., the product of Example 7, Step B) (10 g, 64.1 mmol) in ten installments for twenty minutes. The reaction mixture was then stirred for an additional hour and filtered. The filtered solid was rinsed with acetonitrile and the combined filtrates were concentrated under reduced pressure to leave an oil, which was triturated first with hexanes and then with 1-chlorobutane to give 13.6 g of the title compound as a white solid.

[0287] NMR 1H (CDCI3) δ 3.13 (m, 1H), 3.66 (m, 1H), 4.96 (s, 2H), 5.83 (m, 1H), 7.34-7 .44 (m, 5H).

[0288] Step D: Preparation of 1,1-dimethylethyl 4-[4-(4,5-dihydro-5-phenyl-3-isoxazoIiI)-2-thiazoIiI]-1-piperazinoacetate

[0289] To a solution of 2-chloro-1-(4,5-dihydro-5-phenyl-3-isoxazoIiI)ethanone (i.e., the product of Example 7, Step C) (0.450 g, 2.018 mmol ) and 1,1-dimethylethyl 4-(amino-thioxomethyl)-1-piperazinecarboxylate (i.e., the product of Example 7, Step A) (0.5 g, 2.04 mmol) in ethanol (10 ml), triethylamine (0.204 g, 2.013 mmol) was added and the reaction mixture was stirred at room temperature for twelve hours. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between ethyl acetate (30 ml) and water (30 ml). The organic layer was separated and washed with brine (25 ml), dried (Na2SO4) and concentrated under reduced pressure. The crude residue was purified by column chromatography using 20% ethyl acetate in petroleum ether as eluent to give 700 mg of the title compound as a white solid.

[0290] NMR 1H (CDCl3) δ 1.48 (s, 9H), 3.30 (m, 1H), 3.54 (m, 8H), 3.74 (m, 1H), 5.71 (m , 1H), 6.91 (s, 1H), 7.40-7.29 (m, 5H).

[0291] Step E: Preparation of 1-[4-(4,5-dihydro-5-phenyl-3-isoxazolyl)-2-thiazolyl]piperazine hydrochloride

[0292] To a solution of 1,1-dimethylethyl 4-[4-(4,5-dihydro-5-phenyl-3-isoxazolyl)-2-thiazolyl]-1-piperazinoacetate (i.e., the product of Example 7, Step D) (0.7 g, 1.686 mmol) in diethyl ether (10 ml), a solution of 2 M hydrogen chloride in methanol (10 ml) was added at room temperature. The reaction mixture was stirred at room temperature for eight hours. The resulting white precipitate was filtered and dried to give 500 mg of the title compound as a white solid.

[0293] NMR 1H (CDCl3) δ 3.21 (m, 4H), 3.27 (m, 1H), 3.68 (m, 4H), 3.79 (m, 1H), 5.68 (m , 1H), 7.41-7.29 (m, 6H), 9.49 (br s, 2H).

[0294] Step F: Preparation of 1-[4-[4-(4,5-dihydro-5-phenyl-3-isoxazolyl)-2-thiazolyl]-1-piperazinyl]-2-[5-methyl -3-(trifluoromethyl)-1H-pyrazol-1-yl]ethanone

[0295] To a solution of 1-[4-(4,5-dihydro-5-phenyl-3-isoxazolyl)-2-thiazolyl]piperazine hydrochloride (i.e., the product of Example 7, Step E) (200 mg, 0.57 mmol) and 5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-acetic acid (0.120 g, 0.57 mmol) in dichloromethane (10 ml) at room temperature were added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.110 g, 0.57 mmol), triethylamine (0.086 g, 0.85 mmol) and 1-hydroxy-benzotriazole hydrate (0.020 g, 0. 14 mmol). The reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was diluted with dichloromethane (30 ml) and washed with water (20 ml) and brine (20 ml). The organic layer was dried (Na2SO4) and concentrated under reduced pressure. The crude residue was purified by column chromatography using 3% methanol in chloroform as eluent to give 180 mg of the title product, a compound according to the present invention, as a white solid.

[0296] NMR 1H (CDCl3) δ 2.32 (s, 3H), 3.29 (m, 1H), 3.52 (m, 2H), 3.61 (m, 2H), 3.79-3 .72 (m, 5H), 4.98 (m, 2H), 5.69 (m, 1H), 6.33 (s, 1H), 6.93 (s, 1H), 7.38-7, 28 (m, 5H).

[0297] Mass spectrum at 505.5 (M+1). EXAMPLE 8

[0298] Preparation of 1-[4-[4-(3',4'-dihydrospiro[isoxazol-5 (4H),1', (2'H)-naphthalen]-3-yl)-2- thiazolyl]-1-piperidinyl]-2-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]ethanone (Compound 37)

[0299] Step A: Preparation of 1-(2-chloroacetyl)-4-piperidinecarbonitrile

[0300] A mixture of 4-piperidinecarbonitrile (200 g, 1.80 mol) and 40% aqueous potassium carbonate solution (342 g, 0.99 mol) in dichloromethane (1 ml) was cooled to -10 °C and a solution of chloroacetyl chloride (210 g, 1.86 mol) in dichloromethane (300 ml) was added for about 75 minutes, while maintaining the reaction mixture at -10 to 0 ° C. After completion of the addition, the reaction mixture was separated, the upper aqueous phase was extracted with dichloromethane (2 x 300 ml) and the combined organic phases were concentrated under reduced pressure to give 312 g of the title compound as a liquid which was slowly crystallized upon standing. This compound showed sufficient purity for use in subsequent reactions.

[0301] NMR 1H (CDCl3) δ 1.8-2.1 (m, 4H), 2.95 (m, 1H), 3.5-3.8 (m, 4H), 4.08 (q, 2H).

[0302] Step A1: Alternative preparation of 1-(2-chloroacetyl)-4-piperidinecarbonitrile

[0303] A solution of N-(1,1-dimethylethyl)-4-piperidinecarboxamide (201 g, 1.0 mol) in dichloromethane (1 l) was cooled under nitrogen to -5 ° C and chloroacetyl chloride was added (124 g, 1.1 mol) in 300 ml of dichloromethane drops for thirty minutes, while maintaining the reaction mixture at 0 to 5 °C. Then, 20% aqueous potassium carbonate solution (450 g, 0.65 mol) was added in drops for thirty minutes, while maintaining the reaction temperature at 0 to 5 °C. The reaction mixture was stirred for an additional thirty minutes at 0 ° C and then kept warm at room temperature. The layers were separated and the aqueous layer was extracted with dichloromethane (200 ml). The combined dichloromethane layers were concentrated under reduced pressure to give a solid, which was triturated with 400 ml of hexanes. The slurry was filtered and the filter pad was washed with 100 ml of hexanes and dried in a vacuum oven overnight at 50 °C to generate 185.5 g of 1-(2-chloroacetyl)-N-(1, 1-dimethylethyl)-4-piperidinecarboxamide in the form of a solid, which melts at 140.5-141.5 °C.

[0304] 1H NMR (CDCl3) δ 1.35 (s, 9H), 1.6-2.0 (m, 4H), 2.25 (m, 1H), 2.8 (t, 1H), 3 .2 (t, 1H), 3.9 (d, 1H), 4.07 (s, 2H), 4.5 (d, 1H), 5.3 (br s, 1H).

[0305] To a solution of 1-(2-chloroacetyl)-N-(1,1-dimethylethyl)-4-piperidinecarboxamide (26.1 g, 0.10 mol) in N,N-dimethylformamide (35 ml), Phosphorus oxychloride (18.8 g, 0.123 mol) was added in drops for thirty minutes, while maintaining the temperature of the reaction mixture rising to 37 °C. The reaction mixture was heated to 55 °C for one hour and then ice-cooled water (about 150 g) was slowly added to maintain a temperature of about 10 °C. The pH of the reaction mixture was adjusted to 5.5 with 50% aqueous NaOH solution. The mixture was extracted with dichloromethane (4 x 100 ml) and the combined extract was concentrated under reduced pressure to give 18.1 g of the title compound as a solid. This compound showed sufficient purity for use in subsequent reactions.

[0306] Step B: Preparation of 1-[2-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl]-4-piperidinecarbonitrile

[0307] A solution of 3-methyl-5-trifluoromethylpyrazole (9.3 g, 52 mmol) and 45% aqueous potassium hydroxide solution (7.79 g, 62 mmol) in N,N-dimethylformamide (25 ml ) was cooled to 5°C and 1-(2-chloroacetyl)-4-piperidinecarbonitrile (i.e., the product of Example 8, Step A or A1) (11.2 g, 60 mmol) was added. The reaction mixture was stirred for eight hours at 5-10 °C, then diluted with water (100 ml) and filtered. The filter cluster was washed with water and dried at 50 °C in a vacuum oven to generate 15 g of the title compound in the form of a solid containing 3% of its regioisomer, i.e., 1 -[2-[3- methyl-5-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl]-4-piperidinecarbonitrile.

[0308] NMR 1H (CDCl3) δ 1.88 (m, 4H), 2.32 (s, 3H), 2.95 (m, 1H), 3.7 (m, 4H), 5.0 (q , 2H), 6.34 (s, 1H).

[0309] Step C: Preparation of 1-[2-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl]-4-piperidinecarbothioamide

[0310] Hydrogen sulfide gas was passed into a solution of 1-[2-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl]-4-piperidinecarbonitrile (i.e., the product of Example 8, Step B) (9.0 g, 30 mmol) and diethanolamine (3.15 g, 30 mmol) in N, N -dimethylformamide (15 ml) at 50 ° C in a flask equipped with a dry ice condenser. The hydrogen sulfide feed was stopped when the reaction mixture became saturated with hydrogen sulfide, as indicated by condensation on the cold finger. The reaction mixture was stirred for an additional thirty minutes at 50 °C. Then, excess hydrogen sulfide gas was sprayed into the scrubber via a subsurface nitrogen stream and water (70 ml) was gradually added. The reaction mixture was cooled to 5 °C, filtered and washed with water (2 x 30 ml). The filter cake was dried at 50 °C in a vacuum oven to generate 8.0 g of the title compound as a solid, which melts at 185-186 °C.

[0311] NMR 1H (CDCl3) δ 1.7 (m, 2H), 2.0 (m, 2H), 2.29 (m, 3H), 2.65 (t, 1H), 3.0 (m , 3H), 3.2 (t, 1H), 4.0 (d, 1H), 4.6 (d, 1H), 4.96 (d, 1H), 5.4 (d, 1H), 6 .35 (s, 1H), 7.4 (br s, 1H), 7.5 (br s, 1H).

[0312] Step D: Preparation of 1-[4-[4-(3',4'-dihydrospiro[isoxazol-5 (4H),1',(2'H)-naphthalen]-3-yl) -2-thiazolyl]-1-piperidinyl]-2-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]ethanone

[0313] A solution of 1-[2-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl]-4-piperidine-carbothioamide (i.e., the product of Example 8, Step C ) (0.5 g, 1.5 mmol), 2-chloro-1-(3',4'-dihydrospiro[isoxazol-5(4H),1',(2'H)-naphthalen]-3 -yl)ethanone (prepared by a method analogous to Example 7, Step C) (0.4 g, 1.5 mmol) and tetrabutylammonium bromide (0.030 g, 0.10 mmol) in tetrahydrofuran (15 ml) were stirred overnight at room temperature and then heated at 55-60 °C for three hours. The reaction mixture was diluted with water and extracted with dichloromethane. The extract was washed with brine, dried (MgSO4) and concentrated under reduced pressure. The crude product was further purified by medium pressure liquid chromatography using 50% ethyl acetate in hexanes as eluent to generate 260 mg of the title product, a compound according to the present invention, as an off-white solid which melts at 81 -84 °C.

[0314] NMR 1H (CDCl3) δ 1.76-1.86 (m, 3H), 2.04-2.08 (m, 2H), 2.16-2.26 (m, 2H), 2, 32 (s, 3H), 2.83-2.87 (m, 2H), 2.88-2.93 (m, 1H), 3.27-3.35 (m, 2H), 3.48- 3.65 (m, 2H), 4.02-4.06 (m, 1H), 4.55-4.59 (m, 1H), 4.94-5.04 (q, 2H), 6, 33 (s, 1H), 7.10-7.12 (m, 1H), 7.19-7.21 (m, 2H), 7.40-7.43 (m, 1H), 7.62 ( s, 1H).

[0315] The following compounds were prepared using procedures analogous to Step D of Example 8: - 1-[4-[4-(4,5-dihydro-5-methyl-5-phenyl-3-isoxazolyl )-2-thiazolyl]-1-piperidinyl]-2-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]ethanone (Compound 15): melting point 97-100 °C (crystallized at from methyl acetate/petroleum ether); NMR 1H (CDCl3) δ 1.74-1.80 (m, 1H), 1.81 (s, 3H), 2.14-2.20 (m, 2H), 2.32 (s, 3H), 2.85-2.91 (m, 1H), 3.26-3.32 (m, 2), 3.52-3.62 (m, 2H), 4.01-4.05 (m, 1H ), 4.54-4.58 (m, 1H), 4.94-5.04 (q, 2H), 6.33 (s, 1H), 7.26-7.29 (m, 1H), 7.35-7.38 (m, 2H), 7.48-7.50 (m, 2H), 7.58 (s, 1H). - 2-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]-1-[4-[4-(3a,4,5,9b-tetrahydronaphth[2,1-d]isoxazole- 3-yl)-2-thiazolyl]-1-piperidinyl]ethanone (Compound 16): melting point 162-165 °C (crystallized from methyl acetate/petroleum ether); NMR 1H (CDCl3) δ 1.79-1.85 (m, 2H), 2.00-2.05 (m, 2H), 2.20-2.26 (m, 2H), 2.33 (s , 3H), 2.68-2.72 (m, 2H), 2.88-2.94 (m, 1H), 3.303.35 (m, 2H), 3.92-3.98 (m, 1H ), 4.06-4.10 (m, 1H), 4.58-4.60 (m, 1H), 4.945.06 (m, 2H), 5.58-5.60 (d, 1H), 6.34 (s, 1H), 7.17-7.20 (m, 1H), 7.28-7.30 (m, 2H), 7.47-7.49 (m, 1H), 7, 72 (s, 1H). - 1-[4-[4-(2,3-dihydrospiro[1H-indene-1,5'(4'H)-isoxazol]-3'-yl)- 2-thiazolyl]-1-piperidinyl] -2-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]ethanone (Compound 44): 1H NMR (CDCl3) δ 1.77-1.84 (m, 2H), 2.17 -2.25 (m, 2H), 2.33 (s, 3H), 2.61-2.68 (m, 1H), 2.90-2.96 (m, 2H), 3.12-3 .20 (m, 1H), 3.31-3.35 (m, 2H), 3.54-3.75 (m, 2H), 4.04-4.10 (m, 1H), 4.56 -4.60 (m, 1H), 4.94-5.04 (q, 2H), 6.34 (s, 1H), 7.28-7.30 (m, 3H), 7.37-7 .38 (m, 1H), 7.64 (s, 1H). - 1-[4-[4-[4,5-dihydro-5-(4-methoxyphenyl)-3-isoxazolyl]-2-thiazolyl]- 1-piperidinyl]-2-[5-methyl-3- (trifluoromethyl)-1H-pyrazol-1-yl]ethanone (Compound 18): melting point 119-124 °C (crystallized from methyl acetate and petroleum ether); NMR 1H (CDCl3) δ 1.76-1.82 (m, 2H), 2.16-2.24 (m, 2H), 2.32 (s, 3H), 2.86-2.92 (m , 1H), 3.28-3.34 (m, 2H), 3.37-3.43 (m, 1H), 3.76-3.83 (m, 1H), 3.81 (s, 3H ), 4.03-4.06 (m, 1H), 4.56-4.59 (m, 1H), 4.94-5.04 (q, 2H), 5.67-5.72 (m , 1H), 6.33 (s, 1H), 6.89-6.91 (d, 2H), 7.31-7.33 (d, 2H), 7.62 (s, 1H).EXAMPLE 9

[0316] Preparation of 1-[4-[4-(4,5-dihydro-5-(2-pyridinyl)-3-isoxazolyl)-2-thiazolyl]-1-piperidinyl]-2-[5- methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]ethanone (Compound 98)

[0317] To a solution of 1-[2-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl]-4-piperidinecarbothioamide (i.e., the product of Example 8, Step C) (200 mg, 0.6 mmol) in tetrahydrofuran (8 ml), 3-chloro-N-hydroxy-2-oxopropanimidoyl chloride (i.e., the product of Example 7, Step B) (93 mg, 0 .6 mmol), followed by tetrabutylammonium bromide (15 mg, 0.05 mmol). The reaction mixture was heated at 50 °C for four hours. The reaction mixture was cooled and concentrated under reduced pressure. To the resulting residue, acetonitrile (8 ml) and finely powdered sodium bicarbonate (151 mg, 1.0 mmol) were added followed by 2-ethenylpyridine (63 mg, 0.6 mmol) and the resulting mixture was stirred at temperature environment for one night. The reaction mixture was concentrated under reduced pressure and purified by flash chromatography on a Varian Bond Elute SI® silica gel (20 g) column using 0 to 75% ethyl acetate in hexanes as eluent to generate 80 mg of the title product, a compound according to the present invention, in the form of a yellow semisolid.

[0318] NMR 1H (CDCl3) δ 1.47-1.62 (m, 1H), 1.70-1.85 (m, 1H), 2.01-2.18 (m, 2H), 2, 49 (s, 3H), 2.82 (t, 1H), 3.20-3.42 (m, 2H), 3.73 (dd, 1H), 3.82 (dd, 1H), 3.98 (D, 1H), 4.38 (d, 1H), 5.26 (m, 2H), 5.80 (dd, 1H), 6.50 (s, 1H), 7.38 (dd, 1H) , 7.50 (d, 1H), 7.82 (t, 1H), 8.05 (s, 1H), 8.60 (d, 1H).EXAMPLE 10

[0319] Preparation of 2-[5-chloro-3-(trifluoromethyl)-1H-pyrazol-1-yl]- 1-[4-[4-(4,5-dihydro-5-phenyl-3- isoxazolyl)-2-thiazolyl]-1-piperidinyl]ethanone (Compound 107)

[0320] Step A: Preparation of N,N-dimethyl-3-(trifluoromethyl)-1H-pyrazol-1-sulfonamide

[0321] To a solution of 3-trifluoromethylpyrazole (5.0 g, 36 mmol), triethylamine (7.0 ml, 50 mmol) in dichloromethane (40 ml), dimethylsulfamoyl chloride (5.5 ml, 51 ml) was added. mmol) and the reaction mixture was heated under reflux for two days. The resulting mixture was cooled to room temperature and filtered through a pad of silica gel using dichloromethane as eluent. The filtrate was then concentrated under reduced pressure to generate an amber residue. The resulting residue was dissolved in diethyl ether. The ether solution was washed with water, dried (MgSO4) and concentrated under reduced pressure to give 8.71 g of the title compound.

[0322] 1H NMR (CDCls) δ 3.01 (s, 6H), 6.65 (s, 1H), 8.03 (s, 1H).

[0323] Step B: Preparation of 5-chloro-N,N-dimethyl-3-(trifluoromethyl)-1H-pyrazoI-1-sulfonamide

[0324] A stirred solution of N,N-dimethyl-3-(trifluoromethyl)-1H-pyrazol-1-sulfonamide (i.e., the product of Example 10, Step A) (4.0 g, 16 mmol) in tetrahydrofuran (25 ml) was cooled to -78 ° C and then treated dropwise with 2 M n-butyl lithium in cyclohexane (8.6 mI, 17.2 mmoI). The reaction mixture was stirred for an additional thirty minutes and then a solution of hexachloroethane (4.2 g, 18 mmol) in tetrahydrofuran (15 ml) was added dropwise. The reaction mixture was stirred for one hour, warmed to room temperature and cooled with water (50 ml). The resulting solution was extracted with dichloromethane, dried (MgSO4) and concentrated under reduced pressure to give 4.38 g of the title compound. This compound showed sufficient purity for use in subsequent reactions.

[0325] 1H NMR (CDCl3) δ 3.15 (s, 6H), 6.58 (s, 1H).

[0326] Step C: Preparation of 5-chloro-3-(trifluoromethyl)-1H-pyrazole

[0327] A solution of 5-chloro-N,N-dimethyl-3-(trifluoromethyl)-1H-pyrazol-1-sulfonamide (i.e., the product of Example 10, Step B) (4.38 g, 15. 8 mmol) and trifluoroacetic acid (2.7 ml, 35 mmol) was stirred at 0 °C for one and a half hours. The reaction mixture was diluted with water (15 ml) and sodium carbonate was added to raise the pH to 12. The solution was extracted with diethyl ether, dried (MgSO4) and concentrated under reduced pressure to give 2.1 g of the title compound. This compound showed sufficient purity for use in subsequent reactions.

[0328] NMR 1H (CDCl3) δ 6.57 (m, 1H).

[0329] Step D: Preparation of ethyl 5-chloro-3-(trifluoromethyl)-1H-pyrazol-1-acetate

[0330] To a suspension of 5-chloro-3-(trifluoromethyl)-1H-pyrazole (i.e., the product of Example 10, Step C) (2.1 g, 12.3 mmol) and potassium carbonate (3 .6 g, 26.0 mmol) in 20 ml of N,N-dimethylformamide, ethyl bromoacetate (2.1 ml, 18.8 mmol) was added and the resulting mixture was stirred at room temperature for twelve hours. The resulting mixture was diluted with ethyl acetate, washed with water and dried (MgSO4). The reaction mixture was concentrated in vacuo and further purified by medium pressure liquid chromatography using 0 to 50% ethyl acetate in hexanes as eluent to give 940 mg of the title compound as an oil.

[0331] 1H NMR (CDCl3) δ 1.29 (m, 3H), 4.27 (q, 2H), 4.96 (m, 2H), 6.55 (s, 1H).

[0332] Step D1: Alternative preparation of ethyl 5-chloro-3-(trifluoromethyl)-1H-pyrazol-1-acetate

[0333] To a solution of aluminum chloride (3.0 g, 22.5 mmol) in dichloromethane (100 ml), a solution of trifluoroacetyl chloride (3 g, 22.6 mmol) in dichloromethane was added dropwise (5 ml) while maintaining the temperature of the reaction mixture below -30 °C. The reaction mixture was stirred for fifteen minutes at -50 °C. Then, a solution of vinylidene chloride (2.2 g, 22.7 mmol) in dichloromethane (10 ml) was added dropwise over two hours to the reaction mixture. The reaction mixture was stirred for an additional two hours at -50 °C and then gradually warmed to room temperature. The reaction mixture was diluted with water and the aqueous layer was extracted with dichloromethane. The organic layers were combined, dried (MgSO4) and concentrated under reduced pressure to generate 4,4-dichloro-1,1,1-trifluoro-3-buten-2-one as an oil which was used in the next step without additional purification.

[0334] NMR 1H (CDCl3) δ 5.30 (s, 1H).

[0335] 19F NMR (CDCl3) δ -63.6.

[0336] A mixture of ethyl hydrazinoacetate hydrochloride (2.8 g, 18.1 mmol) and triethylamine (9.2 g, 91 mmol) in a solution of ethanol (20 ml) and N,N-dimethylformamide (1 ml), a solution of crude 4,4-dichloro-1,1,1-trifluoro-3-buten-2-one in dichloromethane (20 ml) was added in drops, while maintaining the temperature of the mixture reaction rate below 10 °C. After stirring for an additional two hours at less than 10 °C, the reaction mixture was concentrated under reduced pressure. The residue was diluted with diethyl ether and the mixture was filtered. The resulting filtrate was concentrated to give 4.34 g of the title compound as a solid. This compound had sufficient purity for use in subsequent reactions.

[0337] 1H NMR (CDCl3) δ 1.29 (t, 3H), 4.27 (q, 2H), 4.97 (s, 1H), 6.55 (s, 1H).

[0338] 19F NMR (CDCl3) δ -63.4.

[0339] Step E: Preparation of 5-chloro-3-(trifluoromethyl)-1H-pyrazol-1-acetic acid

[0340] A solution of ethyl 5-chloro-3-(trifluoromethyl)-1H-pyrazol-1-acetate (i.e., the intermediate product of Example 10, Step D or D1) (218 mg, 0.85 mmol) in tetrahydrofuran (1 ml) was treated with a 50% by weight aqueous solution of sodium hydroxide (0.2 ml) in water (0.6 ml). The reaction mixture was stirred at room temperature for four hours. The reaction mixture was treated with concentrated aqueous hydrochloric acid to reduce the pH to 1 and then extracted with ethyl acetate. The extract was dried (MgSO4) and concentrated under pressure to give 140 mg of the title compound. This compound showed sufficient purity for use in subsequent reactions.

[0341] 1H NMR (DMSO-d6) δ 5.41 (s, 2H), 7.09 (s, 1H).

[0342] Step F: Preparation of 2-[5-chloro-3-(trifluoromethyl)-1H-pyrazol-1-yl]-1-[4-[4-(4,5-dihydro-5-phenyl -3-isoxazolyl)-2-thiazolyl]-1-piperidinyl]ethanone

[0343] To a solution of 1,1-dimethylethyl 4-[4-(4,5-dihydro-5-phenyl-3-isoxazolyl)-2-thiazolyl]-1-piperidinecarboxylate (i.e., the product of Example 1, Step A) (1.026 g, 2.48 mmol) in ethanol (10 ml), a solution of 2 M hydrogen chloride in diethyl ether (4.2 ml, 12.6 mmol) was added. The reaction mixture was stirred at room temperature overnight. Then, the reaction mixture was heated at 60 °C for two hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to give 0.710 g of 4-[4-(4,5-dihydro-5-phenyl-3-isoxazolyl)-2-thiazolyl]-1 hydrochloride -piperidine in the form of a white solid.

[0344] 5-Chloro-3-(trifluoromethyl)-1H-pyrazol-1-acetic acid (i.e., the product of Example 10, Step E) (0.14 g, 0.61 mmol) in dichloromethane (5 ml), N,N-dimethylformamide (one drop) was added followed by oxalyl chloride (0.07 ml, 0.80 mmol) at room temperature. The reaction mixture was stirred at room temperature for one hour and then concentrated under reduced pressure. The resulting crude 5-chloro-3-(trifluoromethyl)-1H-pyrazol-1-acetyl chloride was taken up in 5 ml of dichloromethane and the resulting solution was added dropwise to a mixture of 4-[4-(4 ,5-dihydro-5-phenyl-3-isoxazolyl)-2-thiazolyl]-1-piperidine (0.20 g, 0.57 mmol) prepared above and triethylamine (0.40 ml, 2.85 mmol) in 10 ml of dichloromethane at 0 °C. The reaction mixture was stirred overnight at room temperature and then diluted with 1.0 N aqueous hydrochloric acid solution. The organic layer was separated, washed with water, dried (MgSO4), concentrated under reduced pressure and purified by medium pressure liquid chromatography using ethyl acetate in hexanes as eluent to give 40 mg of the title product, a compound according to with the present invention, in the form of a solid that melts at 128-131 °C.

[0345] NMR 1H (CDCl3) δ 1.81 (m, 2H), 2.20 (m, 2H), 2.89 (m, 1H), 3.31 (m, 2H), 3.46 (m , 1H), 3.87 (m, 2H), 4.55 (m, 1H), 5.08 (m, 2H), 5.75 (m, 1H), 6.54 (s, 1H), 7 .25-7.42 (m, 5H), 7.63 (s, 1H).EXAMPLE 11

[0346] Preparation of 2-[5-bromo-3-(trifluoromethyl)-1H-pyrazol-1-yl]-1-[4-[4-(4,5-dihydro-5-phenyl-3- isoxazolyl)-2-thiazolyl]-1-piperidinyl]ethanone (Compound 126)

[0347] Step A: Preparation of 5-bromo-N,N-dimethyl-3-(trifluoromethyl)-1H-pyrazol-1-sulfonamide

[0348] A stirred solution of N,N-dimethyl-3-(trifluoromethyl)-1H-pyrazol-1-sulfonamide (i.e., the product of Example 10, Step A) (4.25 g, 17.5 mmol) in tetrahydrofuran (50 ml) was cooled to -78 °C and then 2 M n-butyllithium in cyclohexane (10.0 ml, 20.0 mmol) was added dropwise. The reaction mixture was stirred for an additional thirty minutes and then bromine (1.0 ml, 3.1 g, 18.7 mmol) was added dropwise. The reaction mixture was stirred for ten minutes, warmed to room temperature and cooled with brine (50 ml). The resulting solution was extracted with diethyl ether, dried (MgSO4) and concentrated under reduced pressure to give 6.77 g of the title compound as a light yellow oil. This compound showed sufficient purity for use in subsequent reactions.

[0349] 1H NMR (CDCIs) δ 3.15 (s, 6H), 6.69 (s, 1H).

[0350] Step B: Preparation of 5-bromo-3-(trifluoromethyl)-1H-pyrazole

[0351] A solution of 5-bromo-N,N-dimethyl-3-(trifluoromethyl)-1H-pyrazol-1-sulfonamide (i.e., the product of Example 11, Step A) (4.50 g, 14. 0 mmol) and trifluoroacetic acid (2.0 ml, 26 mmol) was stirred at 25 °C for four hours. The reaction mixture was diluted with water (20 ml) and sodium hydroxide was added to raise the pH to 12. The solution was extracted with chloroform, dried (MgSO4) and concentrated under reduced pressure to give 2.73 g of the compound title in the form of light yellow oil. This compound showed sufficient purity for use in subsequent reactions.

[0352] NMR 1H (CDCl3) δ 6.63 (m, 1H).

[0353] Step C: Preparation of ethyl 5-bromo-3-(trifluoromethyl)-1H-pyrazol-1-acetate

[0354] A suspension of 5-bromo-3-(trifluoromethyl)-1H-pyrazole (i.e., the product of Example 11, Step B) (2.73 g, 12.7 mmol) and potassium carbonate (2. 0 g, 14.5 mmol) in N,N-dimethylformamide (20 ml) was treated with ethyl iodoacetate (3.0 ml, 25.3 mmol) and the resulting mixture was stirred at 95 ° C for three hours. The resulting mixture was diluted with ethyl acetate, washed with water and dried (MgSO4). The reaction mixture was concentrated in vacuo and further purified by medium pressure liquid chromatography using 0 to 50% ethyl acetate in hexanes as eluent to give 2.84 g of the title compound as a brown oil.

[0355] 1H NMR (CDCl3) δ 1.29 (m, 3H), 4.26 (q, 2H), 5.00 (m, 2H), 6.64 (s, 1H).

[0356] Step D: Preparation of 5-bromo-3-(trifluoromethyl)-1H-pyrazol-1-acetic acid

[0357] A solution of ethyl 5-bromo-3-(trifluoromethyl)-1H-pyrazol-1-acetate (i.e., the product of Example 11, Step C) (2.84 g, 9.4 mmol) in Tetrahydrofuran (10 ml) was treated with a 50% by weight aqueous solution of sodium hydroxide solution (1.0 ml). The reaction mixture was stirred at room temperature for two hours. The reaction mixture was treated with concentrated aqueous hydrochloric acid to reduce the pH to 1 and then extracted with ethyl acetate. The extract was dried (MgSO4) and concentrated under pressure to give 2.26 g of the title compound as a light brown solid. Recrystallization from 1-chlorobutane (20 ml) gave 0.68 g of the title compound as glossy light pink plates.

[0358] NMR 1H (CDCl3) δ 5.08 (s, 2H), 6.65 (s, 1H).

[0359] Step E: Preparation of 2-[5-bromo-3-(trifluoromethyl)-1H-pyrazol-1-yl]-1-[4-[4-(4,5-dihydro-5-phenyl -3-isoxazoli)-2-thiazolyl]-1-piperidinyl]ethanone

[0360] To a solution of 5-bromo-3-(trifluoromethyl)-1H-pyrazol-1-acetic acid (i.e., the product of Example 11, Step D) (0.12 g, 0.61 mmol) in dichloromethane (5 ml), N,N-dimethylformamide (one drop) was added followed by oxalyl chloride (0.25 ml, 2.86 mmol). The reaction mixture was stirred at room temperature for one hour and then concentrated under reduced pressure. The residue containing crude acid chloride was taken up in dichloromethane (5 ml) and the solution was added dropwise to a mixture of 4-[4-(4,5-dihydro-5-phenyl-3-isoxazolyl) hydrochloride -2-thiazolyl]-1-piperidine (i.e., the product of Example 10, Step F) (0.15 g, 0.43 mmol) and triethylamine (0.25 ml, 1.8 mmol) in dichloromethane (5 ml) at 0°C. The reaction mixture was kept warm at room temperature and then stirred overnight at room temperature. The mixture was then partitioned between 1.0 N aqueous hydrochloric acid solution and dichloromethane. The organic layer was washed with water, dried (MgSO4), concentrated under reduced pressure and purified by medium pressure liquid chromatography using ethyl acetate in hexanes as eluent to give 90 mg of the title product, a compound according to present invention, in the form of an amorphous solid.

[0361] NMR 1H (CDCl3) δ 1.84 (m, 2H), 2.20 (m, 2H), 2.89 (m, 1H), 3.31 (m, 2H), 3.46 (m , 1H), 3.89 (m, 2H), 4.58 (m, 1H), 5.11 (m, 2H), 5.75 (m, 1H), 6.63 (s, 1H), 7 .25-7.42 (m, 5H), 7.66 (s, 1H).EXAMPLE 12

[0362] Preparation of 1-[4-[4-[(5R)-4,5-dihydro-5-phenyl-3-isoxazolyl]-2-thiazolyl]-1-piperidinyl]-2-[5- methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]ethanone (Compound 3)

[0363] Step A: Preparation of 4,5-dihydro-N,N-dimethyl-5-phenyl-3-isoxazolocarboxamide

[0364] To a solution of 2-(dimethylamino)-N-hydroxy-2-oxoethanimidoyl chloride (prepared according to the procedure of E. Raleigh, US Patent No. 3,557,089 (6.0 g, 40 mmol), styrene (6.0 g, 60 mmol) in toluene (15 ml), a solution of potassium hydrogen carbonate (5.0 g, 50 mmol) in water (25 ml) was added for one hour, keeping at the same time the reaction temperature was 7 to 10 °C. The reaction mixture was diluted with 10 ml of toluene and stirred for an additional ten minutes. The organic layer was separated and washed with water. The organic layer was concentrated under reduced pressure until no styrene remained to generate 8.7 g of the title compound as a light yellow oil.This compound was of sufficient purity for use in subsequent reactions.

[0365] NMR 1H (CDGls) δ 3.08 (s, 3H), 3.32 (s, 3H), 3.35 (dd, 1H), 3.71 (dd, 1H), 5.65 (dd , 1H), 7.35 (m, 5H).

[0366] Step B: Preparation of 4,5-dihydro-5-phenyl-3-isoxazolecarboxylic acid

[0367] To a solution of 4,5-dihydro-N,N-dimethyl-5-phenyl-3-isoxazolecarboxamide (i.e., the product of Example 12, Step A) (60.0 g, 275 mmol) in methane (300 mI), an aqueous solution of sodium hydroxide (44 g of 50% aqueous NaOH in 50 mI of water) was added in drops for thirty minutes, while maintaining the temperature of the reaction mixture at 45°C. The reaction mixture was kept cooled to room temperature and stirred overnight. The resulting mixture was concentrated under reduced pressure and treated with 200 mL of water. The pH of the reaction mixture was adjusted using concentrated hydrochloric acid to about 1.0. The crude product was extracted into ethyl acetate (200 ml). The ethyl acetate solution was concentrated under reduced pressure and the residue was triturated with hexanes. The resulting precipitate was filtered, washed with hexanes (2 x 20 mL) and dried in vacuo to give 46.5 g of the title compound as a solid.

[0368] NMR 1H (CDCI3) δ 3.25 (dd, 1H), 3.75 (dd, 1H), 5.85 (dd, 1H), 7.35 (m, 5H), 8.1 (br s, 1H).

[0369] Step C: Preparation of (5R)-4,5-dihydro-5-phenyl-3-isoxazolecarboxylic acid cinchonine salt

[0370] A mixture of racemic 4,5-dihydro-5-phenyl-3-isoxazolecarboxylic acid (i.e., the product of Example 12, Step B) (9.5 g, 50 mmol) in methanol (70 ml ) was heated to 55°C and cinchonine (containing about 15% dihydrocinchonine, 14.5 g, 50 mmol) was added over twenty minutes, maintaining the temperature of the reaction mixture at 53 to 57° W. The reaction mixture was kept cooled at room temperature for sixty minutes and then water (35 ml) was added dropwise for thirty minutes. The resulting syrup was cooled to 10 °C and filtered. The filter pad was washed twice with 10 ml of 25% methanol in water and dried in air to give 8.52 g of the title compound as a solid. The diastereomeric ratio of the product was determined using chiral high performance liquid chromatography (HPLC) analysis on a Daicel Chiralcel® OD HPLC column to be about 99:1.

[0371] NMR 1H (CDCl3) δ 3.25 (dd, 1H), 3.75 (dd, 1H), 5.85 (dd, 1H), 7.35 (m, 5H), 8.1 (br s, 1H).

[0372] Step D: Preparation of (5R)-4,5-dihydro-N,N-dimethyl-5-phenyl-3-isoxazolocarboxamide

[0373] The cinchonine salt of (5R)-4,5-dihydro-5-phenyl-3-isoxazolocarboxylic acid (i.e., the product of Example 12, Step C) (98% diastereomeric excess, 16, 5 g, 34.3 mmol) was syruped in a mixture of 1 N hydrochloric acid (90 ml), cyclohexane (100 ml) and ethyl acetate (40 ml). After all solids had dissolved, the phases were separated and the organic layer was washed with brine (20 ml) and concentrated under reduced pressure to give 5.6 g of white solid. To a solution of the resulting free acid (5.0 g, 26.2 mmol) in ethyl acetate (100 ml) at room temperature was added N,N-dimethylformamide (one drop), followed by thionyl chloride (4 .25 g, 35.7 mmol). The reaction mixture was then heated under reflux for three hours. The resulting mixture was cooled and concentrated under reduced pressure. The crude acid chloride-containing residue was dissolved in ethyl acetate (25 ml) and this solution was added in portions to a previously cooled (5°C) mixture of dimethylamine in tetrahydrofuran (29 ml of a 2.0 M solution). , while maintaining the temperature of the mixture at 5 to 10 °C. At the end of the addition, the reaction mixture was concentrated under reduced pressure and diluted with water (50 ml). The resulting precipitate was filtered, washed with water and dried by suction overnight to give 4.1 g of the title compound as a light brown solid, which melts at 59-61 °C. This compound showed sufficient purity for use in subsequent reactions.

[0374] Step E: Preparation of 2-bromo-1-[(5R)-4,5-dihydro-5-phenyl-3-isoxazolyl]ethanone

[0375] A solution of (5R)-4,5-dihydro-N,N-dimethyl-5-phenyl-3-isoxazolocarboxamide (i.e., the product of Example 12, Step D) (3.5 g, 16.0 mmol) in a mixture of tetrahydrofuran (5 ml) and toluene (10 ml) was cooled to - 15 °C and methyl magnesium bromide (3.0 M solution in tetrahydrofuran, 8.8 ml, 26.4 mmol) was added for one hour at -15 °C. Then, the reaction mixture was poured over a mixture of 20 g of concentrated hydrochloric acid and 80 g of ice and the organic phase was separated. The aqueous phase was extracted with ethyl acetate (100 ml) and the combined extract was washed with brine (40 ml) and concentrated under reduced pressure to give 3.2 g of 1-[(5R)-4,5-di- hydro-5-phenyl-3-isoxazolyl]ethanone.

[0376] 1H NMR (CDCle) δ 2.55 (s, 3H), 3.17 (dd, 1H), 3.54 (dd, 1H), 5.75 (dd, 1H), 7.35 (m , 5H).

[0377] 1-[(5R)-4,5-dihydro-5-phenyl-3-isoxazolyl]ethanone (3.2 g, 16.7 mmol) was dissolved in 1,2-dichloroethane (15 ml) and a solution of bromine (2.13 g, 13.3 mmol) in dichloroethane (5 ml) was added for thirty minutes, while maintaining the temperature of the reaction mixture at about 30 ° C. The reaction mixture was diluted with water (10 ml) and the organic layer was concentrated under reduced pressure and purified by medium pressure liquid chromatography using 35% dichloromethane in hexanes as eluent to give 2.6 g of the title compound. in the form of a white solid, which melts at 31 -33 °C.

[0378] NMR 1H (CDCl3) δ 3.20 (dd, 1H), 3.60 (dd, 1H), 4.49 (s, 2H), 5.80 (dd, 1H), 7.35 (m , 5H).

[0379] Step E1: Alternative preparation of 2-bromo-1-(4,5-dihydro-5-phenyl-3-isoxazolyl)ethanone

[0380] To a solution of 4,5-dihydro-N,N-dimethyl-5-phenyl-3-isoxazolocarboxamide (i.e., the product of Example 12, Step A) (17 g, 78.0 mmol) In a mixture of tetrahydrofuran (20 ml) and toluene (80 ml), methyl magnesium bromide (3.0 M solution in tetrahydrofuran, 28 ml, 84 mmol) was added for one hour, while maintaining the temperature reaction temperature from -10 to -15 °C. The reaction mixture was poured into a mixture of concentrated hydrochloric acid (20 g) and ice (80 g) and the organic phase was separated. The aqueous phase was extracted with ethyl acetate (100 ml) and the combined organic extracts were washed with brine (40 ml) and concentrated under reduced pressure to give 14.4 g of 1-(4,5-dihydro-5 -phenyl-3-isoxazolyl)ethanone in the form of a light yellow oil.

[0381] NMR 1H (CDCl3) δ 2.55 (s, 3H), 3.17 (dd, 1H), 3.54 (dd, 1H), 5.75 (dd, 1H), 7.35 (m , 5H).

[0382] 1-(4,5-Dihydro-5-phenyl-3-isoxazolyl)ethanone (11.5 g, 60 mmol) was dissolved in ethyl acetate (45 ml) and a bromine solution (9. 6 g, 60.0 mmol) in ethyl acetate (30 ml) was added for thirty minutes, while maintaining the temperature of the reaction mixture at about 30 ° C. After one hour, the reaction mixture was diluted with water (10 ml) and the organic layer was concentrated under reduced pressure to generate 16.7 g of reddish oil that contained about 10% initial methyl ketone and about 10% dibrominated ketone.

[0383] NMR 1H (CDCl3) δ 3.20 (dd, 1H), 3.60 (dd, 1H), 4.49 (s, 2H), 5.80 (dd, 1H), 7.35 (m , 5H).

[0384] Step F: Preparation of 1-[4-[4-[(5R)-4,5-dihydro-5-phenyl-3-isoxazolyl]-2-thiazolyl]-1-piperidinyl]-2- [5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]ethanone

[0385] A mixture of 1-[2-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl]-4-piperidinecarbothioamide (i.e., the product of Example 8, Step C) ( 1.7 g, 5.0 mmol) and 2-bromo-1-[(5R)-4,5-dihydro-5-phenyl-3-isoxazolyl]ethanone (i.e., the product of Example 12, Step E or E1) (1.35 g, 5 mmol) in ethanol (15 ml) was heated at 50 ° C for thirty minutes. The reaction mixture was diluted with water and extracted with dichloromethane. The extract was washed with brine, dried (MgSO4) and concentrated under reduced pressure to generate the title product, a compound according to the present invention, in the form of a light yellow gum. High-performance liquid chromatography (HPLC) analysis demonstrated that the title product had a purity of about 95% and contained the enantiomer (R) in an enantiomeric excess of about 98%.

[0386] 1H NMR (CDCls) δ 1.8 (m, 2H), 2.2 (m, 2H), 2.32 (s, 3H), 2.9 (m, 1H), 3.3 (m , 2H), 3.42 (dd, 1H), 3.82 (dd, 1H), 4.05 (m, 1H), 4.6 (m, 1H), 5.0 (q, 2H), 5 .78 (dd, 1H), 6.35 (s, 1H), 7.4 (m, 5H), 7.62 (s, 1H).EXAMPLE 13

[0387] Preparation of 1-[4-[4-(4,5-dihydro-5-phenyl-3-isoxazolyl)-2-thiazolyl]-3,6-dihydro-1 (2H)-pyridinyl ]-2-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]ethanone (Compound 217)

[0388] Step A: Preparation of 4-[4-(4,5-dihydro-5-phenyl-3-isoxazolyl)-2-thiazolyl]pyridine

[0389] To a solution of thioisonicotinamide (0.5 g, 3.6 mmol) in 1-methyl-2-pyrrolidinone (25 ml), 2-chloro-1-(4,5-dihydro- 5-phenyl-3-isoxazolyl)ethanone (0.807 g, 3.6 mmol) at room temperature. The reaction mixture was then heated to 100 °C for three hours. The reaction mixture was then cooled to room temperature, quenched with water (100 ml), extracted with ethyl acetate (50 ml x 2). The reaction mixture was diluted with water (50 ml) and brine (50 ml) and the organic layer was concentrated under reduced pressure and purified by medium pressure liquid chromatography using 2% methanol in chloroform as eluent to give 0 .7 g of the title compound as a brown solid.

[0390] NMR 1H (CDCl3) δ 3.5 (m, 1H), 3.9 (m, 1H), 5.8 (m, 1H), 7.35 (m, 5H), 8.16 (s , 1H), 8.3 (d, 2H), 8.8 (d, 2H).

[0391] Step B: Preparation of 4-[4-(4,5-dihydro-5-phenyl-3-isoxazolyl)-2-thiazolyl]-1,2,3,6-tetrahydro-1-(phenylmethyl )pyridine

[0392] To a solution of 4-[4-(4,5-dihydro-5-phenyl-3-isoxazolyl)-2-thiazolyl]pyridine (i.e., the product of Example 13, Step A) (0 60 g, 1.95 mmol) in toluene (10 ml), benzyl bromide (0.670 g, 3.90 mmol) was added and the reaction mixture was heated at 100 ° C for twelve hours. Then, the reaction mixture was cooled to room temperature. The precipitated solid was filtered and dried. The solid was dissolved in methanol (10 ml) and sodium borohydride (0.072 g, 1.95 mmol) was added in portions. The reaction mixture was stirred at room temperature for two hours, diluted with water (50 ml), neutralized with 1.5 N aqueous hydrochloric acid solution and extracted with ethyl acetate (50 ml). The organic layer was separated, washed with brine (25 ml) and concentrated under reduced pressure. The residue was purified by medium pressure liquid chromatography using 3% methanol in chloroform as eluent to give 0.4 g of the title compound as a white solid.

[0393] NMR 1H (CDCl3) δ 3.03-3.1 (m, 2H), 3.4-3.6 (m, 4H), 3.84.0 (m, 2H), 4.25- 4.32 (m, 2H), 5.76-5.79 (m, 1H), 6.47 (s, 1H), 7.34-7.48 (m, 10H), 7.72 (s, 1H).

[0394] Step C: Preparation of 4-[4-(4,5-dihydro-5-phenyl-3-isoxazolIiI)-2-thiazoIiI]-1,2,3,6-tetrahydropyridine hydrochloride

[0395] To a solution of 4-[4-(4,5-dihydro-5-phenyl-3-isoxazoIiI)-2-thiazoIiI]-1,2,3,6-tetrahydro-1-(phenylmethyl) pyridine (i.e., the product of Example 13, Step B) (0.400 g, 0.99 mmol) in dichloroethane (10 ml), 1-chloroethyl chloroformate (0.286 g, 1.99 mmol) was added and the mixture reaction was heated at 80 °C for five hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. Methane (10 mI) was added to the residue and the resulting mixture was heated at 60 ° C for one hour, cooled to room temperature and concentrated under reduced pressure. The residue was triturated with 50% petroleum ether in ethyl acetate and the solid formed was filtered and dried to give 0.25 g of the title compound as a white solid.

[0396] NMR 1H (DMSO-d6) δ 2.50-2.55 (m, 2H), 3.31-3.39 (m, 3H), 3.86-3.91 (m, 3H), 5.73-5.78 (m, 1H), 6.67 (s, 1H), 7.34-7.39 (m, 5H), 7.68 (s, 1H), 9.47 (s, 2H).

[0397] Step D: Preparation of 1-[4-[4-(4,5-dihydro-5-phenyl-3-isoxazolIiI)-2-thiazolIiI]-3,6-dihydro-1 (2H )-pyridinyl]-2-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]ethanone

[0398] To a solution of 4-[4-(4,5-dihydro-5-phenyl-3-isoxazoIiI)-2-thiazoIiI]-1,2,3,6-tetrahydropyridine hydrochloride (i.e. the product of Example 13, Step C) (0.250 g, 0.720 mmoI) and 5-methyl-3-(trifluoromethyl)-1H-pyrazole-1-acetic acid (0.150 g, 0.720 mmoI) in dichloromethane (10 ml), added N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (0.138 g, 0.720 mmol), 1-hydroxybenzotriazole (0.024 g, 0.177 mmol) and triethylamine (0.145 g, 1.44 mmol) were mixed at room temperature. The reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was diluted with dichloromethane (30 ml) and washed with water (20 ml) and brine (20 ml). The organic layer was separated, washed with water, dried (Na2SO4), concentrated under reduced pressure and purified by medium pressure liquid chromatography using 3% methanol in chloroform as eluent to give 200 mg of the title product, a compound according to with the present invention, in the form of a white solid.

[0399] NMR 1H (CDCl3) δ 2.3 (s, 3H), 2.71-2.75 (m, 2H), 3.423.46 (m, 1H), 3.74-3.88 (m, 3H), 4.24-4.27 (m, 2H), 5.02 (s, 2H), 5.71-5.76 (m, 1H), 6.32 (s, 1H), 6.57 (s, 1H), 7.3-7.38 (m, 5H), 7.64 (s, 1H).

[0400] By means of the procedures described herein, together with methods known in the art, the compounds of Tables 1A to 8 below can be prepared. The following abbreviations are used in the following Tables: t indicates tertiary, s indicates secondary, n indicates normal, i indicates iso, c indicates cycle, Ac indicates acetyl, Me indicates methyl, Et indicates ethyl, Pr indicates propyl (i.e. n-propyl), i-Pr indicates isopropyl, c-Pr indicates cyclopropyl, Bu indicates butyl, Pen indicates pentyl, Hex indicates hexyl, Am indicates amyl and CN indicates cyano. Dash (-) indicates absence of substituents.

[0401] The present invention includes, but is not limited to, the following examples of substances.

[0402] * The definitions of J, R5, Q, R7 and R12 in the compounds in this table are as defined in Illustrations 3 and 4 in the Realizations above. A dash “-“ in column (R5)x indicates no substitution on J. A dash in each of columns Z2 and Q indicates that no Z2Q substituent is attached as R5 to J. A dash in columns (R7)p and/ or R12 indicates no substitution over Q.

[0403] ** J orientation indicates the connection points for Z1 and Z2 (or other R5 when Z2 is not present) on ring J. The first number indicates the ring position on J at which Z1 is connected and the second number indicates the ring position on J to which Z2 is attached or, when Z2 is not present, the ring position on J to which the substituent listed under (R5)x is attached.

[0404] Note 1: R5 and R7 taken together to form a CH2CH2 bridge between position 4 of J-29 and position 2 of Q-45.

[0405] Note 2: R5 and R7 taken together to form a CH2 bridge between position 4 of J-29 and position 2 of Q-45.

[0406] Note 3: R5 and R7 taken together to form a CH2CH2 bridge between position 4 of J-26 and position 2 of Q-45.

[0407] Note 4: R5 and R7 taken together to form a CH2CH2 bridge between position 1 of J-3 and position 2 of Q-45.

[0408] * The definitions of X, G, R3a and R11a in the compounds of this table are as defined in the Summary Description of the Invention and Illustration 2 in the Embodiments above.

[0409] A dash “-“ in the (R2)n column indicates the absence of substituents.

[0410] * The definitions of G and J in the compounds of this table are as defined in Illustrations 2 and 3 in the Realizations above. The (R5)y column designates the (R5)x substituents shown on the J groups in Illustration 3 other than the R7a-substituted phenyl ring shown in the structure above this table. R7a can be selected from H (to indicate absence of substitution on the phenyl ring) as well as the substituents defined for R7. A dash “-“ in the (R5)y column indicates no substitution on J other than the phenyl ring substituted by R7a.

[0411] ** The R3a substituent in G is H.

[0412] *** The numbers in parentheses indicate the connection points on the J ring. The first number is the connection point for the G ring; the second number is the attachment point for the phenyl ring. where J is one of J-29-1 to J-29-57 (as shown in Illustration A above).

[0413] R1 is 2,5-dichlorophenyl; X is X1, G* is G-1.

[0414] R1 is 2,5-dichlorophenyl; X is X2; G* is G-1.

[0415] R1 is 2,5-dichlorophenyl; X is X1; G* is G-2.

[0416] R1 is 2,5-dichlorophenyl; X is X2; G* is G-2.

[0417] R1 is 2-chloro-5-(trifluoromethyl)phenyl; X is X1; G* is G-1.

[0418] R1 is 2-chloro-5-(trifluoromethyl)phenyl; X is X2; G* is G-1.

[0419] R1 is 2-chloro-5-(trifluoromethyl)phenyl; X is X1; G* is G-2.

[0420] R1 is 2-chloro-5-(trifluoromethyl)phenyl; X is X2; G* is G-2.

[0421] R1 is 2,5-dimethylphenyl; X is X1; G* is G-1.

[0422] R1 is 2,5-dimethylphenyl; X is X2; G* is G-1.

[0423] R1 is 2 5-dimethylphenyl X is X1; G* is G ;-2.

[0424] R1 is 2 5-dimethylphenyl X is X2; G* is G ;-2.

[0425] R1 is 2-methyl-5-(trifluoromethyl)phenyl; X is X1; G* is G-1.

[0426] R1 is 2-methyl-5-(trifluoromethyl)phenyl; X is X2; G* is G-1.

[0427] R1 is 2-methyl-5-(trifluoromethyl)phenyl; X is X1; G* is G-2.

[0428] R1 is 2-methyl-5-(trifluoromethyl)phenyl; X is X2; G* is G-2.

[0429] R1 is 3,5-dimethylpyrazol-1-yl; X is X1; G* is G-1.

[0430] R1 is 3,5-dimethylpyrazol-1-yl; X is X2; G* is G-1.

[0431] R1 is 3,5-dimethylpyrazol-1-yl; X is X1; G* is G-2.

[0432] R1 is 3,5-dimethylpyrazol-1-yl; X is X2; G* is G-2.

[0433] R1 is 3,5-dichloropyrazol-1-yl; X is X1; G* is G-1.

[0434] R1 is 3,5-dichloropyrazol-1-yl; X is X2; G* is G-1.

[0435] R1 is 3,5-dichloropyrazol-1-yl; X is X1; G* is G-2.

[0436] R1 is 3,5-dichloropyrazol-1-yl; X is X2; G* is G-2.

[0437] R1 is 3,5-dibromopyrazol-1-yl; X is X1; G* is G-1.

[0438] R1 is 3,5-dibromopyrazol-1-yl; X is X2; G* is G-1.

[0439] R1 is 3,5-dibromopyrazol-1-yl; X is X1 G* is G-2.

[0440] R1 is 3,5-dibromopyrazol-1-yl; X is X2; G* is G-2.

[0441] R1 is 5-methyl-3-(trifluoromethyl)pyrazol-1-yl; X is X1; G* is G-1.

[0442] R1 is 5-methyl-3-(trifluoromethyl)pyrazol-1-yl; X is X2; G* is G-1.

[0443] R1 is 5-methyl-3-(trifluoromethyl)pyrazol-1-yl; X is X1; G* is G-2.

[0444] R1 is 5-methyl-3-(trifluoromethyl)pyrazol-1-yl; X is X2; G* is G-2.

[0445] R1 is 5-chloro-3-(trifluoromethyl)pyrazol-1-yl; X is X1; G* is G-1

[0446] R1 is 5-chloro-3-(trifluoromethyl)pyrazol-1-yl; X is X2; G* is G-1.

[0447] R1 is 5-chloro-3-(trifluoromethyl)pyrazol-1-yl; X is X1; G* is G-2.

[0448] R1 is 5-chloro-3-(trifluoromethyl)pyrazol-1-yl; X is X2; G* is G-2

[0449] R1 is 5-bromo-3-(trifluoromethyl)pyrazol-1-yl; X is X1; G* is G- 1.

[0450] R1 is 5-bromo-3-(trifluoromethyl)pyrazol-1-yl; X is X2; G* is G-1.

[0451] R1 is 5-bromo-3-(trifluoromethyl)pyrazol-1-yl; X is X2; G* is G-2.

[0452] R1 is 5-ethyl-3-(trifluoromethyl)pyrazol-1-yl; X is X1; G* is G-1.

[0453] R1 is 5-e)thyl-3-(trifluoromethyl)pyrazol-1-yl a; X is X2; G* is G-1.

[0454] R1 is 5-ethyl-3-(trifluoromethyl)pyrazol-1-yl; X is X1; G* is G-2.

[0455] R1 is 5-ethyl-3-(trifluoromethyl)pyrazol-1-yl; X is X2; G* is G-2.

[0456] R1 is 3,5-bis-(trifluoromethyl)pyrazol-1-yl; X is X1; G* is G-1.

[0457] R1 is 3,5-bis-(trifluoromethyl)pyrazol-1-yl; X is X2; G* is G-1.

[0458] R1 is 3,5-bis-(trifluoromethyl)pyrazol-1-yl; X is X1; G* is G-2.

[0459] R1 is 3,5-bis-(trifluoromethyl)pyrazol-1-yl; X is X2; G* is G-2.

[0460] R1 is 3-methyl-5-(trifluoromethyl)pyrazol-1-yl; X is X1; G* is G-1.

[0461] R1 is 3-methyl-5-(trifluoromethyl)pyrazol-1-yl; X is X2; G* is G-1.

[0462] R1 is 3-methyl-5-(trifluoromethyl)pyrazol-1-yl; X is X1; G* is G-2.

[0463] R1 is 3-methyl-5-(trifluoromethyl)pyrazol-1-yl; X is X2; G* is G-2.

[0464] R1 is 3-chloro-5-(trifluoromethyl)pyrazol-1-yl; X is X1; G* is G-1.

[0465] R1 is 3-chloro-5-(trifluoromethyl)pyrazol-1-yl; X is X2 G* is G-1

[0466] R1 is 3-chloro-5-(trifluoromethyl)pyrazol-1-yl; X is X1; G* is G-2.

[0467] R1 is 3-chloro-5-(trifluoromethyl)pyrazol-1-yl; X is X2; G* is G-2.

[0468] R1 is 3-bromo-5-(trifluoromethyl)pyrazol-1-yl; X is X1; G* is G-1.

[0469] R1 is 3-bromo-5-(trifluoromethyl)pyrazol-1-yl; X is X2; G* is G-1.

[0470] R1 is 3-bromo-5-(trifluoromethyl)pyrazol-1-yl; X is X1; G* is G-2.

[0471] R1 is 3-bromo-5-(trifluoromethyl)pyrazol-1-yl; X is X2; G* is G-2.

[0472] R1 is 5-methoxy-3-(trifluoromethyl)pyrazol-1-yl; X is X1; G* is G-1.

[0473] R1 is 5-methoxy-3-(trifluoromethyl)pyrazol-1-yl; X is X2; G* is G-1.

[0474] R1 is 5-methoxy-3-(trifluoromethyl)pyrazol-1-yl; X is X1; G* is G-2.

[0475] R1 is 5-methoxy-3-(trifluoromethyl)pyrazol-1-yl; X is X2; G* is G-2.

[0476] R1 is 5-difluoromethoxy-3-(trifluoromethyl)pyrazol-1-yl; X is X1;G* is G-1.

[0477] R1 is 5-difluoromethoxy-3-(trifluoromethyl)pyrazol-1-yl; X is X2; G* is G-1.

[0478] R1 is 5-difluoromethoxy-3-(trifluoromethyl)pyrazol-1-yl; X is X1;G* is G-2.

[0479] R1 is 5-difluoromethoxy-3-(trifluoromethyl)pyrazol-1-yl; X is X2; G* is G-2.

[0480] Table 5 above identifies specific compounds that comprise a J group selected from J-29-1 to J-29-57 (i.e., specific examples of J-29). Because many J-29-1 to J-29-57 include a chiral center, these J groups are illustrated in a specific enantiomeric configuration, which in some cases may provide the greatest fungicidal activity. Those skilled in the art immediately recognize the antipode (i.e., opposite enantiomer) for each of the related compounds and further understand that enantiomers may be present in the form of pure enantiomers or in mixtures enriched in one enantiomer or in racemic mixtures.* *substituent R3a in G is H. where J1 is one of J-29-1 to J-29-58 (as shown in Illustration A above).

[0481] Table 8 above identifies specific compounds that comprise a J1 group selected from J-29-1 to J-29-58. Because many J-29-1 to J-29-58 include a chiral center, these J1 groups are illustrated in a specific enantiomeric configuration that in some cases may provide the greatest fungicidal activity for compounds of Formula 1. Those skilled in the art recognize immediately the antipode (i.e., opposite enantiomer) for each of the related compounds and further understands that enantiomers may be present in the form of pure enantiomers or in mixtures enriched in one enantiomer or in racemic mixtures.

FORMULATION/USE

[0482] A compound of Formula 1 according to the present invention will generally be used as a fungicidal active ingredient in a composition, that is, formulation, with at least one additional component selected from the group consisting of surfactants, solid diluents and diluents liquids, which serves as a vehicle. The ingredients of the composition or formulation are selected to be consistent with the physical properties of the active ingredient, mode of application and environmental factors such as soil type, humidity and temperature.

[0483] Useful formulations include liquid and solid compositions. Liquid compositions include solutions (including emulsifiable concentrates), suspensions, emulsions (including microemulsions and/or suspoemulsions) and the like, which may optionally be thickened into gels. The general types of aqueous liquid compositions are soluble concentrate, suspension concentrate, capsule suspension, concentrated emulsion, microemulsion, and suspoemulsion. The general types of non-aqueous liquid compositions are emulsifiable concentrate, microemulsifiable concentrate, dispersible concentrate and oil dispersion.

[0484] General types of solid compositions are dry powders, powders, granules, pellets, pills, lozenges, tablets, filled films (including seed coatings) and the like, which may be water-dispersible (“wettable”) or water-soluble. Films and coatings formed with fluid suspensions or film-forming solutions are particularly useful for seed treatment. The active ingredient can be (micro)encapsulated and additionally shaped into a suspension or solid formulation; alternatively, the entire active ingredient formulation may be encapsulated (or “overcoated”). Encapsulation can control or delay the release of the active ingredient. An emulsifiable granule combines the advantages of an emulsifiable concentrated formulation and a dry granular formulation. High strength compositions are mainly used as intermediates for further formulation.

[0485] Sprayable formulations are typically extended into an appropriate medium prior to spraying. These liquid and solid formulations are formulated so that they are easily diluted in the spray medium, typically water. Spray volumes can range from about one to several thousand liters per hectare, but are more typically in the range of about ten to several hundred liters per hectare. Sprayable formulations can be mixed in the tank with water or other suitable medium for foliar treatment through aerial or soil application, or for application to the plant's growing medium. Liquid and dry formulations can be measured directly into drip irrigation systems or measured in the furrow during planting. Liquid and solid formulations can be applied to vegetable seeds in the form of pre-planting seed treatments to protect developing roots and other underground plant parts and/or foliage through systemic absorption.

[0486] Formulations will typically contain effective amounts of active ingredient, diluent and surfactant within the following approximate ranges, which add up to 100% by weight.

[0487] Solid diluents include, for example, clays such as bentonite, montmorillonite, attapulgite and kaolin, gypsum, cellulose, titanium dioxide, zinc oxide, starch, dextrin, sugars (such as lactose and sucrose), silica, talc , mica, diatomaceous earth, urea, calcium carbonate, sodium carbonate and bicarbonate and sodium sulfate. Typical solid diluents are described in Watkins et al, Handbook of Insecticide Dust Diluents and Carriers, second edition, Dorland Books, Caldwell, New Jersey.

[0488] Liquid diluents include, for example, water, N,N-dimethylalkanamides (such as N,N-dimethylformamide), limonene, dimethyl sulfoxide, N-alkylpyrrolidones (such as N-methylpyrrolidinone), ethylene glycol, triethylene glycol , propylene glycol, dipropylene glycol, polypropylene glycol, propylene carbonate, butylene carbonate, paraffins (such as white mineral oils, normal paraffins, isoparaffins), alkylbenzenes, alkylnaphthalenes, glycerin, glycerol triacetate, sorbitol, triacetin, aromatic hydrocarbons, aliphatic dearomatized, alkylbenzenes, alkylnaphthalenes, ketones such as cyclohexanone, 2-heptanone, isophorone and 4-hydroxy-4-methyl-2-pentanone, acetates such as isoamyl acetate, hexyl acetate, heptyl acetate, octyl acetate, nonyl, tridecyl acetate and isobornyl acetate, other esters such as alkylated lactate esters, dibasic esters and γ-butyrolactone and alcohols, which may be linear, branched, saturated or unsaturated, such as methanol, ethanol, n-propanol, alcohol isopropyl alcohol, n-butanol, isobutyl alcohol, n-hexanol, 2-ethyl hexanol, n-octanol, decanol, isodecyl alcohol, isooctadecanol, cetyl alcohol, lauryl alcohol, tridecyl alcohol, oleyl alcohol, cyclohexanol, tetrahydrofurfuryl alcohol, diacetone alcohol and alcohol benzyl. Liquid diluents also include glycerol esters of saturated and unsaturated fatty acids (typically C6-C22) such as fruit and plant seed oils (such as olive, castor, linseed, sesame, corn, peanut, sunflower, grape seed oils , safflower, cotton seed, soybean, rapeseed, coconut and palm seed), fats from animal sources (such as beef tallow, pork tallow, lard, cod liver oil, fish oil) and mixtures thereof. Liquid diluents also include alkylated fatty acids (such as methylated, ethylated, and butylated), wherein the fatty acids can be obtained through hydrolysis of glycerol esters from plant and animal sources and can be purified through distillation. Typical liquid diluents are described in Marsden, Solvents Guide, second edition, Interscience, New York, 1950.

[0489] Liquid and solid compositions according to the present invention often include one or more surfactants. Surfactants can be classified as non-ionic, anionic or cationic. Nonionic surfactants useful for the compositions herein include, but are not limited to: alkoxylated alcohols such as alkoxylated alcohols based on natural and synthetic alcohols (which may be linear or branched) and prepared from alcohols and ethylene oxide, propylene oxide, butylene oxide or mixtures thereof; ethoxylated amines, alkanolamides and ethoxylated alkanolamides; alkoxylated triglycerides, such as ethoxylated soybean, castor and rapeseed oils; alkylphenol alkoxylates, such as octylphenol ethoxylates, nonylphenol ethoxylates, dinonyl phenol ethoxylates and dodecyl phenol ethoxylates (prepared from phenols and ethylene oxide, propylene oxide, butylene oxide or mixtures thereof); block polymers prepared from ethylene oxide or propylene oxide and reverse block polymers in which the end blocks are prepared from propylene oxide; ethoxylated fatty acids; ethoxylated fatty oils and esters; ethoxylated methyl esters; ethoxylated tristyrylphenol (including those prepared from ethylene oxide, propylene oxide, butylene oxide or mixtures thereof); fatty acid esters, glycerol esters, lanolin-based derivatives, polyethoxylated esters such as polyethoxylated sorbitan fatty acid esters, polyethoxylated sorbitol fatty acid esters and polyethoxylated glycerol fatty acid esters; other sorbitan derivatives such as sorbitan esters; polymeric surfactants, such as random copolymers, block copolymers, alkylated pegylated resins (polyethylene glycol), graft or comb polymers and star polymers; polyethylene glycols (pegs); polyethylene glycol fatty acid esters; silicone-based surfactants; and sugar derivatives, such as sucrose esters, alkyl polyglycosides and alkyl polysaccharides.

[0490] Useful anionic surfactants include, but are not limited to: alkylaryl sulfonic acids and their salts; carboxylated alcohol or alkylphenol ethoxylates; diphenyl sulfonate derivatives; lignin and lignin derivatives such as lignosulfonates; maleic or succinic acids or their anhydrides; olefin sulfonates; phosphate esters such as phosphate esters of alkoxylated alcohols, phosphate esters of alkoxylated alkylphenol and phosphate esters of ethoxylated styryl phenol; protein-based surfactants; sarcosine derivatives; styryl phenol ether sulfate; sulfates and sulfonates of oils and fatty acids; ethoxylated alkylphenol sulfates and sulfonates; alcohol sulfates; ethoxylated alcohol sulfates; amine and amide sulfonates such as N,N-alkyl taurates; benzene, cumene, toluene, xylene and dodecyl and tridecylbenzene sulfonates; condensed naphthalene sulfonates; naphthalene and alkyl naphthalene sulfonates; fractionated petroleum sulfonates; sulfusuccinamates; and sulfosuccinates and derivatives thereof, such as dialkyl sulfosuccinate salts.

[0491] Useful cationic surfactants include, but are not limited to: amides and ethoxylated amides; amines, such as N-alkyl propanediamines, tripropylenetriamines and dipropylenetetramines, and ethoxylated amines, ethoxylated diamines and propoxylated amines (prepared from the amines and ethylene oxide, propylene oxide, butylene oxide or mixtures thereof); amine salts, such as amine acetates and diamine salts; quaternary ammonium salts, such as quaternary salts, ethoxylated quaternary salts and diquaternary salts; and amine oxides, such as alkyldimethylamine oxides and bis-(2-hydroxyethyl)alkylamine oxides.

[0492] Also useful for the present compositions are mixtures of anionic and nonionic surfactants or mixtures of nonionic and cationic surfactants. Nonionic, anionic, and cationic surfactants and their recommended uses are described in a series of published references that include McCutcheon’s Emulsifiers and Detergents, annual North American and international editions published by McCutcheon’s Division, The Manufacturing Confectioner Publishing Co.; Sisely and Wood, Encyclopedia of Surface Active Agents, Chemical Publ. Co., Inc., New York, 1964; and A. S. Davidson and B. Milwidsky, Synthetic Detergents, seventh edition, John Wiley and Sons, New York, 1987.

[0493] The compositions according to the present invention may also contain additives and formulation aids, known to those skilled in the art as formulation aids. These additives and formulation aids can control: pH (buffers), foaming during processing (antifoams such as polyorganosiloxanes (e.g. Rhodorsil® 416)), sedimentation of active ingredients (suspension forming agents), viscosity (thixotropic thickeners ), microbial growth in containers (antimicrobials), product freezing (antifreezes), color (dyes/pigment dispersions (e.g. Pro-Ized® Red Dye)), washing (film formers or binders), evaporation (water retardants) evaporation) and other attributes of the formulation. Film formers include, for example, polyvinyl acetates, polyvinyl acetate copolymers, vinyl acetate polyvinylpyrrolidone copolymer, polyvinyl alcohols, polyvinyl alcohol copolymers and waxes. Examples of additives and formulation aids include those listed in McCutcheon's Volume 2: Functional Materials, annual international and North American editions published by the McCutcheon Division, The Manufacturing Confectioner Publishing Co. and PCT Patent No. WO 03/024222.

[0494] Solutions, including emulsifiable concentrates, can be prepared by simply mixing the ingredients. If the solvent of a liquid composition intended for use as an emulsifiable concentrate is immiscible with water, an emulsifier is typically added to emulsify the active-containing solvent upon dilution with water. Active ingredient slurries, with particle diameters of up to 2000 μm, can be wet milled using media mills to obtain particles with average diameters of less than 3 μm. Aqueous slurries can be prepared into finished suspension concentrates (see, for example, U.S. Patent No. 3,060,084) or further processed by spray drying to form water-dispersible granules. Dry formulations typically require dry milling processes, which produce average particle diameters in the range of 2 to 10 μm. Powders and dry powders can be prepared by mixing and, typically, grinding as in a hammer mill or fluid power mill. Granules and pellets can be prepared by spraying the active material onto previously formed granular vehicles or by agglomeration methods. See Browning, Agglomeration, Chemical Engineering, December 4, 1967, pp. 147-48, Perry’s Chemical Engineer’s Handbook, fourth edition, McGraw-Hill, New York, 1963, pp. 8-57 et seq., and WO 91/13546. Pellets may be prepared as described in US 4,172,714. Water-dispersible and water-soluble granules can be prepared as taught in US 4,144,050, US 3,920,442 and DE 3,246,493. Tablets can be prepared as taught in US 5,180,587, US 5,232,701 and US 5,208,030. Films may be prepared as taught in GB 2,095,558 and US 3,299,566.

[0495] For additional information regarding the formulation technique, see T. S. Woods, The Formulator's Toolbox - Product Forms for Modern Agriculture in Pesticide Chemistry and Bioscience, The FoodEnvironment Challenge, T. Brooks and T. R. Roberts, Eds., Proceedings of the 9th International Congress on Pesticide Chemistry, The Royal Society of Chemistry, Cambridge, 1999, pp. 120-133. See also US 3,235,361, Col. 6, line 16 to Col. 7, line 19 and Examples 10-41; US 3,309,192, Col. 5, line 43 to Col. 7, line 62 and Examples 8, 12, 15, 39, 41, 52, 53, 58, 132, 138-140, 162164, 166, 167 and 169- 182; US 2,891,855, Col. 3, line 66 to Col. 5, line 17 and Examples 1-4; Klingman, Weed Control as a Science, John Wiley and Sons, Inc., New York, 1961, pp. 81-96; Hance et al, Weed Control Handbook, eighth edition, Blackwell Scientific Publications, Oxford, 1989; and Developments in Formulation Technology, PJB Publications, Richmond, Great Britain, 2000.

[0496] In the following Examples, all percentages are by weight and all formulations are prepared in conventional ways. Compound numbers designate compounds in Index Table A. EXAMPLE A EXAMPLE B EXAMPLE C EXAMPLE D EXAMPLE E EXAMPLE F EXAMPLE G

[0497] The compounds of Formula 1 according to the present invention are useful as plant disease control agents. The present invention therefore further comprises a method of controlling plant diseases caused by fungal plant pathogens which comprises applying to the plant or part thereof to be protected, or to the seed of the plant to be protected, an effective amount of a compound according to the present invention or a fungicidal composition containing said compound. The compounds and/or compositions according to the present invention provide control of diseases caused by a broad spectrum of fungal plant pathogens in the classes basidiomycetes, ascomycetes, oomycetes and deuteromycetes. They are effective in controlling a broad spectrum of plant diseases, particularly foliar pathogens of ornamentals, grass, legumes, field crops, cereals and fruits. These pathogens include: oomycetes, including Phytophthora diseases such as Phytophthora infestans, Phytophthora megasperma, Phytophthora parasitica, Phytophthora cinnamoni, Phytophthora capsici; Pythium diseases such as Pythium aphanidermatum; and diseases in the peronosporaceae family, such as Plasmopara viticola, Peronospora spp. (including Peronospora tabacina and Peronospora parasitica), Pseudoperonospora spp. (including Pseudoperonospora cubensis) and Bremia lactucae; Ascomycetes, including Alternaria diseases such as Alternaria solani and Alternaria brassicae; Guignardia diseases such as Guignardia bidwell; Venturia diseases such as Venturia inaequalis; Septoria diseases such as Septoria nodorum and Septoria tritici; powdery mildew diseases such as Erysiphe spp. (including Erysiphe graminis and Erysiphe polygoni), Uncinula necatur, Sphaerotheca fuligena and Podosphaera leucotricha; Pseudocercosporella herpotrichoides; Botrytis diseases such as Botrytis cinerea; Monilinia fructicola; Sclerotinia diseases such as Sclerotinia sclerotiorum; Magnaporthe grisea; Phomopsis viticola; Helminthosporium diseases such as Helminthosporium tritici repentis; Pyrenophora teres; anthracnose diseases such as Glomerella or Colletotrichum spp. (such as Colletotrichum graminicola and Colletotrichum orbiculare); and Gaeumannomyces graminis; Basidiomycetes, including rust diseases caused by Puccinia spp. (such as Puccinia recondita, Puccinia striiformis, Puccinia hordei, Puccinia graminis and Puccinia arachidis); Hemileia uvatrix; and Phakopsora pachyrhizi; other pathogens that include Rhizoctonia spp (such as Rhizoctonia solani); Fusarium diseases such as Fusarium roseum, Fusarium graminearum and Fusarium oxysporum; Verticillium dahliae; Sclerotium rolfsii; Rynchosporium secalis; Cercosporidium personatum, Cercospora arachidicola and Cercospora beticola; and other genera and species closely related to these pathogens. In addition to their activity as a fungicide, the compositions or combinations also have activity against bacteria such as Erwinia amylovora; Xanthomonas compestris; Pseudomonas syringae and other related species. The control provided to diseases caused by the ascomycetes and oomycetes classes deserves observation. The control provided to diseases caused by the oomycetes class deserves specific observation.

[0498] Control of plant diseases is normally achieved by applying an effective amount of a compound according to the present invention before or after infection, to the part of the plant to be protected such as the roots, stem, foliage , fruits, seeds, tubers or bulbs, or to the media (soil or sand) in which the plants to be protected are growing. Compounds can also be applied to seeds to protect the seeds and the seedlings that develop from the seeds. The compounds can also be applied through irrigation water to treat plants.

[0499] Application rates for these compounds can be influenced by various environmental factors and must be determined under actual use conditions. Foliage can normally be protected when treated at a rate of less than about 1 g/ha to about 5000 g/ha of active ingredient. Seeds and seedlings can usually be protected when the seed is treated at a rate of about 0.1 to about 10 g/kg of seed.

[0500] The compounds according to the present invention can also be mixed with one or more other insecticides, fungicides, nematicides, bactericides, acaricides, growth regulators, chemosterilants, semiochemicals, repellents, attractants, pheromones, feeding stimulants or other compounds biologically active ingredients to form a multi-component pesticide generating an even broader spectrum of agricultural protection. Examples of such agricultural protectants with which the compounds according to the present invention can be formulated are: insecticides such as abamectin, acephate, acetamiprid, amidoflumet (S-1955), avermectin, azadirachtin, azinphos-methyl, bifenthrin, bifenazate, buprofezin, carbofuran, cartap, chlorantraniliprole (DPX-E2Y45), chlorfenapyr, chlorfluazuron, chlorpyrifos, chlorpyrifos-methyl, chromafenozide, clothianidin, cyflumetofen, cyfluthrin, beta-cyfluthrin, cyhalothrin, lambda-cyhalothrin, cypermethrin, cyromazine, deltamethrin, diafenthiuron, diazinon, dieldrin , diflubenzuron, dimefluthrin, dimethoate, dinotefuran, diofenolan, emamectin, endosulfan, esfenvarelate, etiprol, fenothiocarb, fenoxycarb, fenpropathrin, fenvarelate, fipronil, flonicamid, flubendiamide, flucitrinate, tau-fluvalinate, flufenerim (UR-50701), flufenoxuron, phonofos, halofenozide, hexaflumuron, hydramethylnon, imidacloprid, indoxacarb, isofenphos, lufenuron, malathion, metaflumizone, metaldehyde, methamidophos, methidathion, methomyl, methoprene, methoxychlor, metofluthrin, monocrotophos, methoxyfenozide, nitenpyram, nithiazine, novaluron, noviflumuron (XDE-007), oxa thousand BSN 2060); fungicides such as acibenzolar, aldimorph, amisulbrom, anilazine, azaconazole, azoxystrobin, benalaxyl, benodanil, benomyl, bentiavalicarb, bentiavalicarb- isopropyl, binapacryl, biphenyl, bitertanol, bixafen, blasticidin-S, Bordeaux mixture (tribasic copper sulfate), boscalid /nicobifen, bromuconazole, bupyrimate, butiobate, carboxin, carpropamid, Captafol, Captan, Carbendazim, Chloroneb, Chlorothalonil, 5-chloro-6-(2,4,6-trifluorophenyl)-7-(4-methylipiperidin-1-yl) [1,2,4]triazolo[1,5-a]pyrimidine, clozolinate, clotrimazole, copper oxychloride, copper salts such as copper sulfate and copper hydroxide, cyazofamid, ciflufenamid, cymoxanil, cyproconazole, cyprodinil, diclofluanid , diclocimet, diclomezin, dichloran, dietofencarb, difenoconazole, diflumetrim, dimetirimol, N-[2-(1,3-dimethylbutyl)phenyl]-5-fluoro-1,3-dimethyl-1H-pyrazolo-4-carboxamide, dimethomorph, dimoxystrobin, diniconazole, diniconazole-M, dinocap, discostrobin, ditianon, dodemorph, dodina, econazole, edifenfos, enestroburin, epoxiconazole, etaconazole, etaboxam, ethyrimole, etridiazole, famoxadone, fenamidone, fenarimol, fenbuconazole, fencaramid, fenfuram, fenhexamide, fenoxanil, fenpiclonil, fenpropidin, fenpropimorph, fentin acetate, fentin hydroxide, ferbam, ferfurazoate, ferimzone, fluazinam, fludioxonil, flumetover, flumorph, fluopicolide, fluopyram, fluoxastrobin, fluquinconazole, flusilazole, flusulfamide, flutolanil, flutriafol, folpet, fosetyl-aluminum, fuberidazole, furalaxil, furametapyr, hexaconazole, himexazole, guazatine, imazalil, imibenconazole, iminoctadine, iodicarb, ipconazole, iprobenfos, iprodione, iprovalicarb, isoconazole, isoprothiolane, isotianil, casugamycin, cresoxim-methyl, mancozeb, mandipropamid, maneb, mapanipirin, mefenoxam, mepronil, meptildinocap, metalaxyl, metconazole, metasulfocarb, metiram, metominostrobin, mepanipyrim, metiram, metrafenone, miconazole, myclobutanil, naftifine, neo-asozin (ferric methanoarsonate), nuarimol, octilinone, ofurace, orisastrobin, oxadixyl, oxalinic acid, oxpoconazole, oxycarboxin , paclobutrazol, penconazole, pencycuron, penthiopyrad, perforazoate, phosphonic acid, phthalide, picobenzamid, picoxystrobin, piperaline, polyoxin, probenazole, prochloraz, procymidone, propamocarb, propamocarb hydrochloride, propiconazole, propineb, proquinazid, prothiocarb, prothioconazole, pyraclostrobin, priazophos, Piribencarb, pirifenox, pirimetanil, pyrifenox, pirolnitrin, pyrocilon, quinchonazole, quinoxifen, fifth, sileciofam, symeconazole, spiroxamine, sulfur, tebuconazole, tebrazen, tecloftalam, teethnazene, terbinafin, tetraconazole , tifluzamide, thiophanate, thiophanate-methyl, thiram, thiadinil, tolclofos-methyl, tolifluanid, triadimefon, triadimenol, triarimol, triazoxide, tricyclazole, tridemorph, triflumizole, tricyclazole trimorphamide, trifloxystrobin, triporin, triticonazole, uniconazole, validamycin, vinclozolin, zineb, ziram and zoxamide, nematicides such as aldoxycarb, aldoxycarb, fenamiphos, imiciaphos and oxamyl; bactericides such as streptomycin; acaricides such as amitraz, chinomethionat, chlorobenzylate, cyenopirafen, cyhexatin, dicofol, dienochlor, etoxazole, fenazaquin, fenbutatin oxide, fenpropathrin, fenpyroximate, hexithiazox, propargite, pyridaben and tebufenpyrad; and biological agents such as Bacillus thuringiensis, Bacillus thuringiensis delta endotoxin, bacillovirus and entomopathogenic bacteria, viruses and fungi. Descriptions of several commercially available compounds listed above can be found in The Pesticide Manual, thirteenth edition, C. D. S. Thomlin, ed., British Crop Protection Council, 2003. For embodiments in which one or more of these various mixing partners are used, the Weight ratio between these various mixing partners (in total) and the Formula 1 compound is typically from about 1:100 to about 3000:1. Weight ratios of about 1:30 to about 300:1 (such as ratios of about 1:1 to about 30:1) are worth noting. It will be evident that the inclusion of these additional components can expand the spectrum of diseases controlled beyond the spectrum controlled by the Formula 1 compound alone.

[0501] In a mixing embodiment, granules of a solid composition comprising a compound of Formula 1 are mixed with granules of a solid composition comprising another agricultural protectant. These granule mixtures may be in accordance with the general granule mixture description of PCT Patent No. WO 94/24861 or, more preferably, the homogeneous granule mixture teaching of U.S. Patent No. 6,022,552.

[0502] Combinations (such as in the form of compositions) of a compound of Formula 1 with at least one other fungicide are worth noting. Compositions in which the other fungicide has a different site of action than the Formula 1 compound deserve specific observation. In certain cases, combinations with other fungicides that have a similar spectrum of control but different site of action will be particularly advantageous for administering resistance. Compositions that, in addition to the compound of Formula 1, include at least one compound selected from the group consisting of: (1) alkylenebis (dithiocarbamate) fungicides deserve specific observation; (2) cymoxanil; (3) phenylamide fungicides; (4) pyrimidinone fungicides; (5) chlorothalonil; (6) carboxamides that act on complex II of the fungal mitochondrial respiratory electron transfer site; (7) quinoxifen; (8) metrafenone; (9) ciflufenamid; (10) cyprodinil; (11) copper compounds; (12) phthalimide fungicides; (13) fosetyl aluminum; (14) benzimidazole fungicides; (15) cyazofamid; (16) fluazinam; (17) iprovalicarb; (18) propamocarb; (19) validomycin; (20) dichlorophenyl dicarboximide fungicides; (21) zoxamide; (22) fluopicolide; (23) mandipropamid; (24) carboxylic acid amides that act on phospholipid biosynthesis and deposition on cell walls; (25) dimethomorph; (26) non-DMI sterol biosynthesis inhibitors; (27) demethylase inhibitors in sterol biosynthesis; (28) bc1 complex fungicides; and salts of compounds (1) to (28).

[0503] Additional descriptions of classes of fungicidal compounds are provided below.

[0504] Pyrimidinone fungicides (group (4)) include the compounds of Formula A1: wherein M forms a fused phenyl, thiophene or pyridine ring; R11 is C1-C6 alkyl; R12 is C1-C6 alkyl or C1-C6 alkoxy; R13 is halogen; and R14 is hydrogen or halogen.

[0505] Pyrimidinone fungicides are described in Published PCT Patent Application No. WO 94/26722 and in U.S. Patents No. 6,066,638, 6,245,770, 6,262,058 and 6,277,858. Pyrimidinone fungicides selected from the group are worth noting: 6-bromo-3-propyl-2-propyloxy-4 (3H)-quinazolinone; 6,8-diiodo-3-propyl-2-propyloxy-4(3H)-quinazolinone; 6-iodo-3-propyl-2-propyloxy-4(3H)-quinazolinone (proquinazid); 6-chloro-2-propoxy-3-propylthieno[2,3-d]pyrimidin-4(3H)-one; 6-bromo-2-propoxy-3-propylthieno[2,3-d]pyrimidin-4(3H)-one; 7-bromo-2-propoxy-3-propylthieno[2,3-d]pyrimidin-4(3H)-one; 6-bromo-2-propoxy-3-propylpyrido[2,3-d]pyrimidin-4(3H)-one; 6,7-dibromo-2-propoxy-3-propylthieno[3,2-d]pyrimidin-4(3H)-one; and 3-(cyclopropylmethyl)-6-iodo-2-(propylthio)pyrido[2,3-d]pyrimidin-4(3H)-one.

[0506] Sterol biosynthesis inhibitors (group (27)) control fungi by inhibiting enzymes in the sterol biosynthesis process. Demethylase inhibitor fungicides have a common site of action in the fungal sterol biosynthesis process, which involves inhibition of demethylation at position 14 of lanosterol or 24-methylene dihydrolanosterol, which are sterol precursors in fungi. Compounds that act at this site are often called demethylase inhibitors, DMI fungicides, or DMIs. The demethylase enzyme is sometimes indicated by other names in the biochemical literature, which include cytochrome P-450 (14DM). The demethylase enzyme is described, for example, in J. Biol. Chem. 1992, 267, 13175-79 and references cited therein. DMI fungicides are divided into several chemical classes: azoles (including triazoles and imidazoles), pyrimidines, piperazines and pyridines. Triazoles include azaconazole, bromuconazole, cyproconazole, difenoconazole, diniconazole (including diniconazole-M), epoxiconazole, etaconazole, fenbuconazole, fluquinconazole, flusilazole, flutriafol, hexaconazole, imibenconazole, ipconazole, metconazole, myclobutanil, penconazole, propiconazole, prothioconazole, quinconazole, simeconazole , tebuconazole, tetraconazole, triadimefon, triadimenol, triticonazole and uniconazole. Imidazoles include clotrimazole, econazole, imazalil, isoconazole, miconazole, oxpoconazole, prochloraz, and triflumizole. Pyrimidines include fenarimol, nuarimol and triarimol. Piperazines include triporin. Pyridines include buthiobate and pyrifenox. Biochemical research has demonstrated that all of the fungicides mentioned above are DMI fungicides as described by K. H. Kuck et al in Modern Selective Fungicides - Properties, Applications and Mechanisms of Action, H. Lyr (Ed.), Gustav Fischer Verlag: New York, 1995, 205 -258.

[0507] Fungicides from the bc1 complex (group (28)) have a fungicidal mode of action that inhibits the bc1 complex in the mitochondrial respiration chain. The bc1 complex is sometimes indicated by other names in the biochemical literature, which include electron transfer chain complex III, and ubihydroquinone: cytochrome c oxidoreductase. This complex is uniquely identified by Enzyme Commission number EC1.10.2.2. The bc 1 complex is described, for example, in J. Biol. Chem. 1989, 264, 14543-48; Methods Enzymol. 1986, 126, 253-71; and references mentioned there. Strobilurin fungicides such as azoxystrobin, dimoxystrobin, enestroburin (SYP-Z7071), fluoxastrobin, kresoxim-methyl, metominostrobin, orisastrobin, picoxystrobin, pyraclostrobin and trifloxystrobin are known to have this mode of action (H. Sauter et al, Angew. Chem. Int. Ed. 1999, 38, 1328-1349). Other fungicidal compounds that inhibit the bc1 complex in the mitochondrial respiration chain include famoxadone and fenamidone.

[0508] Alkylenebis(dithiocarbamate) fungicides (group (1)) include compounds such as mancozeb, maneb, propineb and zineb. Phenylamide fungicides (group (3)) include compounds such as metalaxyl, benalaxyl, furalaxyl and oxadixyl. Carboxamides (group (6)) include compounds such as boscalid, carboxin, fenfuram, flutolanil, furamethpyr, mepronil, oxycarboxin, tifluzamide, penthiopyrad and N-[2-(1,3-dimethylbutyl)phenyl]-5-fluoro-1, 3-dimethyl-1H-pyrazolo-4-carboxamide (PCT Patent No. WO 2003/010149) and are known to inhibit mitochondrial function through disruption of complex II (succinate dehydrogenase) in the respiratory electron transport chain. Copper compounds (group (11)) include compounds such as copper oxychloride, copper sulfate and copper hydroxide, including compositions such as Bordeaux mixture (tribasic copper sulfate). Phthalimide fungicides (group (12)) include compounds such as folpet and pegon. Benzimidazole fungicides (group (14)) include benomyl and carbendazim. Dichlorophenyl dicarboximide fungicides (group (20)) include clozolinate, diclozolin, iprodione, isovaledione, myclozolin, procymidone and vinclozolin.

[0509] Non-DMI sterol biosynthesis inhibitors (group (26)) include morpholine and piperidine fungicides. Morpholines and piperidines are sterol biosynthesis inhibitors that have been shown to inhibit steps in the sterol biosynthesis process subsequent to the inhibitions achieved by DMI sterol biosynthesis (group (27)). Morpholines include aldimorph, dodemorph, fenpropimorph, tridemorph and trimorphamide. Piperidines include fenpropidine.

[0510] The methods in which plant diseases caused by oomycete fungal plant pathogens are controlled deserve attention.

[0511] The above discussion with reference to the use of compounds of Formula 1 in compositions (such as certain compositions comprising surfactants, solid diluents, liquid diluents and/or biologically active compounds) and in methods of controlling plant diseases (such as control of plant diseases caused by oomycete fungal plant pathogens) also applies to compounds within the exclusion scope of proviso (a) of Formula 1.

[0512] The following Tests demonstrate the control effectiveness of compounds according to the present invention on specific pathogens. The pathogen control protection generated by the compounds is not limited, however, to these species. See Tables Index A for compound descriptions. Stereocenters labeled “R” (straight) and “S” (sinister) are based on the Cahn-Ingold-Prelog system as used by Chemical Abstracts; a stereocenter mark followed by asterisks “**” indicates that the stereochemical description is relative to other stereocenters and the compound is racemic. The abbreviation “Ex.” indicates “Example” and is followed by a number that indicates in which example the compound is prepared. Table Index A lists the molecular weight of the parent ion with the highest isotopic abundance (M+1) formed by the addition of H+ (molecular weight of 1) to the molecule, observed through mass spectrometry using chemical ionization under atmospheric pressure (AP+ ). Chiral separation of Compound 1 into Compounds 3 and 4 was performed using a preparative AD-RH CHIRALPAK® column (Chiral Technologies, Inc., Wester Chester PA, United States) containing silica gel coated with amylose-tris(3.5 carbamate -dimethylphenyl) and eluted with a gradient of water and methanol. Specific rotation ([α]D) was measured in an ethanol solution at 25 °C using a 100 mm path cell.

[0513] G is as defined in Illustration 2; R3a in G is H. L groups are defined as illustrated below.

[0514] Note 1: enantiomer with faster elution from the AD-RH CHIRALPAK® column using methanol in water as eluent, specific rotation = -98.8°. Analysis using AD-RH CHIRALPAK® analytical column indicated approximately 100% optical purity.

[0515] Note 2: enantiomer with slower elution from the AD-RH CHIRALPAK® reverse phase column using methanol in water as eluent, specific rotation = +88°. Analysis using an AD-RH CHIRALPAK® analytical column indicated approximately 93% optical purity.

[0516] Note 3: Diastereomer A.

[0517] Note 4: Diastereomer B.

[0518] Note 5: Mixture of isomers.

BIOLOGICAL EXAMPLES OF THE INVENTION

[0519] General protocol for preparing test suspensions for Tests A to C: The test compounds were first dissolved in acetone in an amount equal to 3% of the final volume and then suspended at the desired concentration (in ppm) in acetone and purified water (50/50 mixture by volume) containing 250 ppm of the surfactant Trem® 014 (polyhydric alcohol esters). The resulting test suspensions were then used in Tests A to C. Spraying a 200 ppm test suspension to the soaking point of the test plants was equivalent to a rate of 500 g/ha.

TEST A

[0520] Grape seedlings were inoculated with a spore suspension of Plasmopara viticola (the causative agent of grape downy mildew) and incubated in a saturated atmosphere at 20 ° C for 24 hours. After a short drying period, the test suspension was sprayed to the soaking point onto the grape seedlings, which were then moved to a growth chamber at 20°C for five days, after which the grape seedling was placed back in a saturated atmosphere at 20°C for 24 hours. Upon removal, visual assessments of the disease were performed.

TEST B

[0521] The test suspension was sprayed to the point of drenching on tomato seedlings. The next day, the seedlings were inoculated with a spore suspension of Phytophthora infestans (the causative agent of tomato back blight), incubated in a saturated atmosphere at 20°C for 24 hours and then moved to a growth chamber at 20°C. °C for five days, after which visual assessments of the disease were carried out.

TEST C

[0522] Tomato seedlings were inoculated with a spore suspension of Phytophthora infestans (the causative agent of tomato later blight) and incubated in a saturated atmosphere at 20 ° C for seventeen hours. After a short drying period, the test suspension was sprayed to the point of soaking onto the tomato seedlings, which were then moved to a growth chamber at 20°C for four days, after which visual assessments of the quality were carried out. illness.

[0523] In addition to Tests A to C, the compounds were also sprayed on two separate sets of tomato plants, which were inoculated with Botrytis cinerea or Alternaria solani 24 hours after treatment, bluegrass plants, which were inoculated with Pythium aphanidermatum 24 hours after treatment and three separate sets of wheat plants, which were inoculated with Erysiphe graminis f. sp. tritici, Puccinia recondita or Septoria nodorum 24 hours after treatment. The compounds tested did not exhibit observable activity against these additional pathogens under the test conditions at the application rates tested.

[0524] The results of Tests A to C are provided in Table A. In the table, a rating of 100 indicates 100% disease control and a rating of 0 indicates no disease control (relative to controls). Dash (-) indicates absence of substituents. TABLE OF BIOLOGICAL TESTS RESULTS

Claims (8)

1. COMPOUND, characterized by being selected from the group consisting of: - 4-[4-[(5R)-4,5-dihydro-5-phenyl-3-isoxazolyl]-2-thiazolyl]-1 -[[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl]piperidine and its enantiomer; - 1-[[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl]-4-[4-(5-phenyl-3-isoxazolyl)-2-thiazolyl]piperidine; - 1-[4-[4-[(5R)-4,5-dihydro-5-methyl-5-phenyl-3-isoxazolyl]-2-thiazolyl]-1-piperidinyl]-2-[5- methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]ethanone and its enantiomer; - 1-[4-[4-[(5R)-4,5-dihydro-5-phenyl-3-isoxazolyl]-2-thiazolyl]- 1-piperidinyl]-2-[5-ethyl-3- (trifluoromethyl)-1H-pyrazol-1-yl]ethanone and its enantiomer; - 2-[3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl]-1-[4-[4-[(5R)- 4,5-dihydro-5-phenyl-3- isoxazolyl]-2-thiazolyl]-1-piperidinyl]ethanone and its enantiomer; - 1-[4-[4-[(5R)-3',4'-dihydrospiro[isoxazol-5(4H),1',(2'H)-naphthalen]-3-yl]-2- thiazolyl]-1-piperidinyl]-2-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]ethanone and its enantiomer; - 2-[5-chloro-3-(trifluoromethyl)-1H-pyrazol-1-yl]-1-[4-[4-[(5R)- 4,5-dihydro-5-phenyl-3 -isoxazolyl]-2-thiazolyl]-1-piperidinyl]ethanone and its enantiomer; - 1-[4-[4-[(5R)-5-(2,6-dichlorophenyl)-4,5-dihydro-3-isoxazolyl]-2-thiazolyl]-1-piperidinyl]-2-[ 5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]ethanone and its enantiomer; - 1-[4-[4-[(5R)-4,5-dihydro-5-(2-fluorophenyl)-3-isoxazolyl]-2-thiazolyl]-1-piperidinyl]-2-[5- methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]ethanone and its enantiomer; - 1-[4-[4-[(5R)-4,5-dihydro-5-(2-methylphenyl)-3-isoxazolyl]-2-thiazolyl]-1-piperidinyl]-2-[5- methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]ethanone and its enantiomer; - 1-[4-[4-[(5R)-5-(2,6-dimethylphenyl)-4,5-dihydro-3-isoxazolyl]-2-thiazolyl]-1-piperidinyl]-2-[ 5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]ethanone and its enantiomer; - 1-[4-[4-[(1'R)-3',4'-dihydrospiro[isoxazol-5(4H),1'(2'H)-naphthalen]-3-yl]-2 -thiazolyl]-1-piperidinyl]-2-(3,5-dimethyl-1H-pyrazol-1-yl) ethanone and its enantiomer; - 1-[4-[4-[(5R)-5-(2,6-difluorophenyl)-4,5-dihydro-3-isoxazolyl]-2-thiazolyl]-1-piperidinyl]-2-[ 5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]ethanone and its enantiomer; - 2-[3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl]-1-[4-[4-[(5R)-4,5-dihydro-5-methyl-5-phenyl -3-isoxazolyl]-2-thiazolyl]-1-piperidinyl]ethanone and its enantiomer; - 1-[4-[4-[(5R)-5-(2-chlorophenyl)-4,5-dihydro-3-isoxazolyl]-2-thiazolyl]-1-piperidinyl]-2-[5- methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]ethanone and its enantiomer; - 1-[4-[4-[(5R)-4,5-dihydro-5-phenyl-3-isoxazolyl]-2-thiazolyl]-1-piperidinyl]-2-[3-methyl-5- (trifluoromethyl)-1H-pyrazol-1-yl]ethanone and its enantiomer; - 2-[5-chloro-3-(trifluoromethyl)-1H-pyrazol-1-yl]-1-[4-[4-[(5R)-4,5-dihydro-5-methyl-5- phenyl-3-isoxazolyl]-2-thiazolyl]-1-piperidinyl]ethanone and its enantiomer. 2. COMPOUND, according to claim 1, characterized in that it is 1-[4-[4-[(5R)-5-(2,6-difluorophenyl)-4,5-dihydro-3-isoxazolyl]- 2-thiazolyl]-1-piperidinyl]-2-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]ethanone and its enantiomer. 3. METHOD FOR CONTROLLING PLANT DISEASES, caused by Oomycete fungal plant pathogens, characterized by applying to the plant or part thereof, or to the seed of the plant, an amount effective as a fungicide of a compound selected from the group consisting of the compounds as defined in any one of claims 1 to 2. 4. FUNGICIDAL COMPOSITION, characterized in that it comprises (1) a fungicidal effective amount of a compound selected from the group consisting of the compounds as defined in any one of claims 1 to 2; and (2) at least one additional component selected from the group consisting of surfactants, solid diluents and liquid diluents. 5. FUNGICIDAL COMPOSITION, characterized in that it comprises (1) a compound selected from the group consisting of the compounds as defined in any one of claims 1 to 2; and (2) at least one other fungicide. 6. FUNGICIDAL COMPOSITION, according to claim 5, characterized in that the at least one other fungicide is selected from acibenzolar, aldimorph, amisulbrom, anilazine, azaconazole, azoxystrobin, benalaxyl, benodanil, benomyl, bentiavalicarb, bentiavalicarb-isopropyl, binapacryl , biphenyl, bitertanol, bixafen, blasticidin-S, Bordeaux mixture (tribasic copper sulfate), boscalid/nicobifen, bromuconazole, bupyrimate, butiobate, carboxin, carpropamid, Captafol, Captan, carbendazim, cloloneb, chlorothalonil, 5-chloro-6 -(2,4,6-trifluorophenyl)-7-(4-methylpiperidin-1-yl)[1,2,4]triazolo[1,5-a]pyrimidine, clozolinate, clotrimazole, copper oxychloride, copper salts , such as copper sulfate and copper hydroxide, cyazofamid, ciflufenamid, cymoxanil, cyproconazole, cyprodinil, diclofluanid, diclocimet, diclomezin, dichloran, diethofencarb, difenoconazole, diflumetrim, dimethirimol, N-[2-(1,3-dimethylbutyl)phenyl ]-5-fluoro-1,3-dimethyl-1H-pyrazolo-4-carboxamide, dimethomorph, dimoxystrobin, diniconazole, diniconazole M, dinocap, discostrobin, dithianon, dodemorph, dodine, econazole, edifenphos, enestroburin, epoxiconazole, etaconazole, etaboxam , ethyrimole, etridiazole, famoxadone, fenamidone, fenarimol, fenbuconazole, fencaramid, fenfuram, fenhexamide, fenoxanil, fenpiclonil, fenpropidin, fenpropimorph, fentin acetate, fentin chloride, fentin hydroxide, ferbam, ferfurazoate, ferimzone, fluazinam, fludioxonil, flumetover , flumorph, fluopicolide, fluopyram, fluoxastrobin, fluquinconazole, flusilazole, flusulfamide, flutolanil, flutriafol, folpet, fosetyl-aluminum, fuberidazole, furalaxil, furametapyr, hexaconazole, himexazole, guazatine, imazalil, imibenconazole, iminoctadine, iodicarb, ipconazole, iprobenfos, iprodium in , ipovalicarb, isoconazole, isoprotiolane, isotianyl, casugamycin, cresoxim-methyl, mancozeb, mandipropamid, dineb, mapanipirin, mefenoxam, mepronil, metalldinocap, metalaxil, metconazole, metasulfocarb, metominostrobin, mepanipirim, metrafen na, mycone, microbutanil, naftifine , neo-asozin (ferric methanoarsonate), nuarimol, octilinone, ofurace, orisastrobin, oxadixyl, oxalinic acid, oxpoconazole, oxycarboxin, oxytetracycline, paclobutrazol, penconazole, pencycuron, penthiopyrad, perforazoate, phosphonic acid, phthalide, picobenzamid, picoxystrobin, piperaline, polyoxin , probenazole, prochloraz, procymidone, propamocarb, propamocarb hydrochloride, propiconazole, propineb, proquinazid, prothiocarb, prothioconazole, pyraclostrobin, priazophos, piribencarb, pyrifenox, pyrimethanil, pyrifenox, pyrolnitrin, piroquilon, quinconazole, quinoxifen, Fifthozene, siltiofam, simeconazole , spiroxamine , streptomycin, sulfur, tebuconazole, tecrazene, tecloftalam, technazene, terbinafine, tetraconazole, thiabendazole, thifluzamide, thiophanate, thiophanate-methyl, thiram, tiadinil, tolclofos-methyl, tolifluanid, triadimefon, triadimenol, triarimol, triazoxide, tricyclazole, tridemorph, triflumizole , tricyclazole trimorphamide, trifloxystrobin, triporin, triticonazole, uniconazole, validamycin, vinclozolin, zineb, ziram and zoxamide. 7. FUNGICIDAL COMPOSITION, according to claim 5, characterized in that the at least one other fungicide includes at least one compound selected from the group consisting of: (1) alkylenebis (dithiocarbamate) fungicides; (2) cymoxanil; (3) phenylamide fungicides; (4) pyrimidinone fungicides; (5) chlorothalonil; (6) carboxamides that act on complex II of the fungal mitochondrial respiratory electron transfer site; (7) quinoxifen; (8) metrafenone; (9) ciflufenamid; (10) cyprodinil; (11) copper compounds; (12) phthalimide fungicides; (13) fosetyl aluminum; (14) benzimidazole fungicides; (15) cyazofamid; (16) fluazinam; (17) iprovalicarb; (18) propamocarb; (19) validomycin; (20) dichlorophenyl dicarboximide fungicides; (21) zoxamide; (22) fluopicolide; (23) mandipropamid; (24) carboxylic acid amides that act on phospholipid biosynthesis and deposition on cell walls; (25) dimethomorph; (26) non-DMI sterol biosynthesis inhibitors; (27) demethylase inhibitors in sterol biosynthesis; (28) bc1 complex fungicides; and salts of compounds (1) to (28). 8. FUNGICIDAL COMPOSITION, according to any one of claims 4 to 7, characterized in that component (1) is 1-[4-[4-[5-(2,6-difluorophenyl)-4,5-dihydro- 3-isoxazolyl]-2-thiazolyl]-1-piperidinyl]-2-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]ethanone.