Thiazol-4-Carboxylic Acid Esters and Thioesters as Plant Protection Agents

Information

  • Patent Application
  • 20150237859
  • Publication Number
    20150237859
  • Date Filed
    April 03, 2015
    9 years ago
  • Date Published
    August 27, 2015
    8 years ago
Abstract
The use of thiazole-4-carboxylic esters and thioesters of the formula (I)
Description

The invention relates to thiazole-4-carboxylic esters and thioesters or agrochemically active salts thereof, to their use and to methods and compositions for controlling phytopathogenic harmful fungi in and/or on plants or in and/or on seed of plants, to processes for preparing such compositions and to treated seed, and to their use for controlling phytopathogenic harmful fungi in agriculture, horticulture and forestry, in animal health, in the protection of materials and in the domestic and hygiene field. The present invention furthermore relates to a process for preparing thiazole-4-carboxylic esters and thioesters.


It is already known that certain piperidinyl-substituted thiazole-4-carboxamides can be used as fungicidal crop protection agents (see WO 07/014290, WO08/091594). However, in particular at relatively low application rates, the fungicidal activity of these compounds is not always sufficient.


Furthermore, in many cases the activity spectrum of these amides is insufficient. Moreover, some carboxylic esters are described as intermediates; however, a biological activity is not described.


WO 04/058751 describes piperidinyl-substituted thiazole-4-carboxylic esters and thioesters which can be used as pharmaceutics for modulating blood pressure.


WO 05/003128 describes further piperidinyl-substituted thiazole-4-carboxylic esters and thioesters which are likewise suitable for medicinal applications, here as inhibitors on the microsomal triglyceride transfer protein (MTP inhibitors). However, an effect on fungal pathogens is not described.


Since the ecological and economical demands made on modern crop protection agents are increasing constantly, for example with respect to activity spectrum, toxicity, selectivity, application rate, formation of residues and favorable manufacture, and there can furthermore be problems, for example, with resistances, there is a constant need to develop novel crop protection agents which, at least in some areas, have advantages over the known ones.


Surprisingly, it has now been found that the present thiazole-4-carboxylic esters and thioesters achieve at least some aspects of the objects mentioned and are suitable for use as crop protection agents, in particular as fungicides.


The invention relates to compounds of the formulas (I)




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in which the symbols have the following meanings:

  • R1 and R3 independently of one another are H, C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C3-C6-cycloalkyl, C3-C6-halocycloalkyl, optionally substituted phenyl, C1-C4-alkoxy, C1-C4-haloalkyl, C1-C4-haloalkoxy, (C1-C4-alkyl)carbonyl, formyl, CR8═NOR9, CONR10R11, (C1-C4-alkoxy)carbonyl, COOH, halogen, hydroxyl or cyano
  • R2 is H, substituted or unsubstituted phenyl, C1-C4-alkyl, C2-C4-alkenyl. C2-C4-alkynyl, C3-C6-cycloalkyl, C3-C6-halocycloalkyl, C1-C4-alkoxy, C1-C4-haloalkyl, C1-C4-haloalkoxy, (C1-C4-alkyl)carbonyl, formyl, CR8═NOR9, CONR10R11, (C1-C4-alkoxy)carbonyl, COOH, halogen, hydroxyl, cyano, nitro or NR10R11

    or
  • R1 and R2 or R2 and R3 together with the carbon atoms to which they are attached form a 5- to 7-membered unsubstituted or substituted, partially saturated or unsaturated cycle which may contain up to three further heteroatoms selected from the group consisting of N, O and S, where two oxygen atoms are not adjacent,


    possible substituents independently of one another being selected from the group consisting of C1-C4-alkyl, C1-C4-alkoxy, oxo, hydroxyl and halogen
  • R4 and R5 independently of one another are H, C1-C4-alkyl, C3-C6-cycloalkyl or C1-C4-haloalkyl,


    or
  • R4 and R5 together with the carbon atom to which they are attached form a 3- to 7-membered unsubstituted or substituted saturated cycle which may contain up to three heteroatoms selected from the group consisting of N, O and S, where two oxygen atoms are not adjacent, possible substituents independently of one another being selected from the group consisting of C1-C4-alkyl, C1-C4-alkoxy, oxo, hydroxyl, halogen
  • Y1, Y2, Y3 independently of one another are sulfur or oxygen
  • X is a direct bond or an unsubstituted or substituted C1- to C3-carbon chain, where the carbon atoms carry, independently of one another, H, C1-C4-alkyl or oxo as substituents
  • W is an unsubstituted or substituted C1- to C3-carbon chain, where the carbon atoms carry, independently of one another, H, C1-C4-alkyl or oxo as substituents
  • R6 is H, C1-C4-alkyl, C1-C4-haloalkyl, (C1-C4-alkyl)carbonyl, formyl, CR8═NOR9, CONR10R11, (C1-C4-alkoxy)carbonyl, COOH, NR10R11, nitro, halogen or cyano
  • G is (C(R12)2)m

    where m=0 to 6
  • R7 is unsubstituted or substituted C5-C10-alkyl, C2-C16-alkenyl, C2-C16-alkynyl, C3-C15-cycloalkyl, C5-C15-cycloalkenyl, C3-C15-heterocyclyl, aryl, hetaryl or Si(C1-C4-alkyl)3,


    possible substituents independently of one another being selected from the list below:


    halogen, cyano, nitro, nitroso, C1-C4-alkyl, C1-C4-haloalkyl, arylalkyl, arylhaloalkyl, hydroxyl, oxo, C1-C4-alkoxy, O(C1-C6-alkyl)mOC1-C6-alkyl, O—C3-C6-cycloalkyl, O-phenyl, C1-C4-haloalkoxy, SH, C1-C6-thioalkyl, C1-C6-thiohaloalkyl, S-phenyl, SO2—C1-C6-alkyl, SO2—C1-C6-haloalkyl, SO—C1-C6-alkyl, SO—C1-C6-haloalkyl, CO2H, (C1-C4-alkyl)carbonyl, (C1-C4-haloalkyl)carbonyl, formyl, CR8═NOR9, CONR10R11, (C1-C4-alkoxy)carbonyl, COOH, NR10R11, cyclopropylamino, CH2COCH3, (CH2)mO—C1-C6-alkyl, CH2OH, CH2SMe, (CH2)2SMe, C3-C6-cycloalkyl, 1-methoxycyclopropyl, 1-chlorocyclopropyl, cyclohexylmethyl, C2-C6-alkenyl, C2-C6-alkynyl, Si(C1-C4-alkyl)3, phenyl or benzyl


    or


    two adjacent substituents form an optionally methyl- or halogen-substituted dioxolane or dioxane ring,
  • R8, R9, R10, R11 independently of one another are H, C1-C4-alkyl or C3-C6-cycloalkyl,


    or
  • R10 and R11 together with the nitrogen atom to which they are attached form a 3- to 7-membered unsubstituted or substituted saturated cycle which may contain up to two further heteroatoms selected from the group consisting of N, O and S, where two oxygen atoms are not adjacent,


    possible substituents independently of one another being selected from the group consisting of C1-C4-alkyl, C1-C4-alkoxy, halogen and oxo
  • R12 is identical or different independently of one another H, halogen, C1-C4-alkyl, C1-C4-alkoxy, C3-C6-cycloalkyl or C1-C4-haloalkyl,


    or


    two or four R12, in each case on two adjacent carbon atoms, are direct bonds,


    and also agrochemically active salts thereof.


The thiazole-4-carboxylic esters and thioesters of the formula (I) according to the invention and their agrochemically active salts are highly suitable for controlling phytopathogenic harmful fungi. The compounds according to the invention mentioned above have potent fungicidal activity and can be used both in crop protection, in the domestic and hygiene field and in the protection of materials.


The compounds of the formula (I) can be present both in pure form and as mixtures of various possible isomeric forms, in particular of stereoisomers, such as E and Z, threo and erythro, endo or exo, and also optical isomers, such as R and S isomers or atropisomers, and, if appropriate, also of tautomers. What is claimed are both the E and the Z isomers, and also the threo and erythro, and also the optical isomers, any mixtures of these isomers, and also the possible tautomeric forms.


Preference is given to compounds of the formula (I) in which one or more of the symbols have one of the meanings below:

  • R1 and R3 independently of one another are H, C1-C4-alkyl, C3-C6-cycloalkyl, C1-C3-alkoxy, C1-C3-haloalkyl, C1-C3-haloalkoxy, halogen, hydroxyl, cyano or phenyl,
  • R2 is H, phenyl, C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C3-C6-cycloalkyl, C1-C3-alkoxy, C1-C3-haloalkyl, C1-C3-haloalkoxy, halogen, hydroxyl, cyano or NR10R11.


    or
  • R1 and R2 together with the carbon atoms to which they are attached form a phenyl ring,
  • R4 and R5 independently of one another are H, C1-C3-alkyl, cyclopropyl, cyclopentyl, cylohexyl, or C1-C3-haloalkyl,


    or
  • R4 and R5 together with the carbon atom to which they are attached form a cyclopropyl ring,
  • Y1 and Y2 are oxygen,
  • Y3 is sulfur or oxygen,
  • X is a direct bond, CH2 or CH2CH2,
  • W is CH2, CH2CH2 or CH2CH2CH2,
  • R6 is H, C1-C3-alkyl, C1-C3-haloalkyl, NH2, NHMe, NMe2, chlorine, fluorine or cyano,
  • G is (C(R12)2)m.


    where m=0 to 4
  • R7 is unsubstituted or substituted C5-C10-alkyl, C2-C16-alkenyl, C2-C16-alkynyl, C3-C15-cycloalkyl, C5-C15-cycloalkenyl, C3-C15-heterocyclyl, aryl, hetaryl or Si(C1-C4-alkyl)3,


    possible substituents independently of one another being selected from the list below:


    fluorine, chlorine, bromine, iodine, cyano, nitro, CF3, CFH2, CF2H, C2F5, CCl3, hydroxyl, OMe, OEt, OPr, OisoPr, OBu, OsecBu, OlsoBu, OtertBu, O(CH2)2OCH3, O(CH2)3OCH3, O-cyclohexyl, O-cylopentyl, O-cyclopropyl, O-phenyl, OCF3, OCF2H, OCH2CF3, OCF2CF3, SH, SMe, SEt, SCF3, SCF2H, S-phenyl, SO2Me, SO2CF3, SOMe, SOEt, CO2H, CO2CH3, CO2Et, CO2Pr, CO2isoPr, CO2tertBu, COMe, COCF3, NH2, NHMe, NMe2, NHEt, NEt2, NHPr, NHisoPr, NHnBu, NHtertBu, NHisoBu, NHsecBu, cyclopropylamino, morpholinyl, piperidinyl, piperazinyl, pyrrolidinyl, aziridinyl, azetidinyl, formyl, CH2COCH3, CH2OMe, (CH2)2OMe, (CH2)3OMe, CH2OH, CH2SMe, (CH2)2SMe, methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, 1-methoxycyclopropyl, 1-chlorocyclopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexylmethyl, prop-2-en-1-yl, 1-methylprop-2-en-1-yl, but-3-en-1-yl, trimethylsilyl)methyl, phenyl, benzyl, —CH═CH2, —CH2CH═CH2, —CH(CH3)CH—CH2, —CH2C≡CH, —C≡CH,


    or


    two adjacent substituents form an optionally methyl- or halogen-substituted dioxolane or dioxane ring,
  • R10,R11 independently of one another are H, methyl, ethyl, isopropyl or cyclopropyl,


    or
  • R10 and R11 together with the nitrogen atom to which they are attached form an aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl or morpholinyl ring,
  • R12 is identical or different independently of one another H, methyl, ethyl, chlorine, fluorine, trifluoromethyl, methoxy or cyclopropyl,


    or


    two or four R12, in each case on two adjacent carbon atoms, are direct bonds,


    and the agrochemically active salts thereof.


Particular preference is given to compounds of the formula (I) in which one or more of the symbols have one of the meanings below:

  • R1 is C1-C2-alkyl or C1-C2-haloalkyl,
  • R2 is H, C1-C2-haloalkyl or halogen,


    or
  • R1 and R2 together with the carbon atoms to which they are attached form a phenyl ring,
  • R3 is H, C1-C2-alkyl, C1-C2-haloalkyl or phenyl,
  • R4 is H, C1-C2-alkyl or C1-C2-haloalkyl,
  • R5 is H, C1-C2-alkyl, C1-C2-haloalkyl or cyclopropyl,


    or
  • R4 and R5 together with the carbon atom to which they are attached form a cyclopropyl ring,
  • Y1 is oxygen,
  • Y2 is oxygen,
  • Y3 is sulfur or oxygen,
  • X is CH2 or CH2CH2,
  • W is CH2, CH2CH2 or CH2CH2CH2,
  • R6 is H or methyl,
  • G is (C(R12)),


    where m=0 to 4
  • R7 is unsubstituted or substituted C5-C10-alkyl, C2-C16-alkenyl, C2-C16-alkynyl, C3-C15-cycloalkyl, C5-C15-cycloalkenyl, C3-C15-heterocyclyl, aryl, hetaryl or Si(C1-C4-alkyl)3,


    possible substituents independently of one another being selected from the list below:


    fluorine, chlorine, bromine, iodine, cyano, nitro, CF3, hydroxyl, OMe, O-phenyl, OCF3, OCF2H, OCH2CF3, OCF2CF3, SMe, S-phenyl, methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, phenyl, benzyl, —CH—CH2, —CH2CH—CH2 or —C≡CH,
  • R12 is identical or different independently of one another H, methyl or ethyl,


    and the agrochemically active salts thereof.


Very particular preference is given to compounds of the formula (I) in which one or more of the symbols have one of the meanings below:

  • R1 is methyl, ethyl, 1-methylethyl, 1,1-dimethylethyl, difluoromethyl, trifluoromethyl or pentafluoroethyl,
  • R2 is H or chlorine,


    or
  • R1 and R2 together with the carbon atoms to which they are attached form a phenyl ring,
  • R3 is H, methyl, 1,1-dimethylethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl or phenyl,
  • R4 is H or methyl,
  • R5 is H, methyl or cyclopropyl,


    or
  • R4 and R5 together with the carbon atom to which they are attached form a cyclopropyl ring,
  • Y1 is oxygen,
  • Y2 is oxygen,
  • Y3 is sulfur or oxygen,
  • X is CH2 or CH2CH2,
  • W is CH2, CH2CH2 or CH2CH2CH2,
  • R6 is H or methyl,
  • G is a direct bond, CH2, CH2CH2, CH(CH3), CH(CH2CH3) or CH(CF3),
  • R7 is methyl, tert-butyl, heptan-3-yl, octyl, (1Z)-prop-1-en-1-yl, (E)-2-phenylethenyl, hex-1-en-3-yl, diphenylmethyl, 1,2,3,4-tetrahydronaphthalen-1-yl, (1R)-1,2,3,4-tetrahydronaphthalen-1-yl, (1S)-1,2,3,4-tetrahydronaphthalen-1-yl, 1,2,3,4-tetrahydronaphthalen-2-yl, 5,6,7,8-tetrahydronaphthalen-1-yl, 5,6,7,8-tetrahydronaphthalen-2-yl, decahydronaphthalen-1-yl, 1,4-dioxaspiro[4.5]dec-8-yl, 2,3-dihydro-1H-inden-1-yl, 2,3-dihydro-1H-inden-2-yl, cyclopropyl, 2,2-dichlorocyclopropyl, cyclopentyl, 1-ethynylcyclopentyl, cyclohexyl, 2-methylcyclohexyl, 2,6-dimethylcyclohexyl, 4-tert-butylcyclohexyl, 5-methyl-2-(propan-2-yl)cyclohexyl, 3-methyl-5-(propan-2-yl)cyclohexyl, 1-cyanocyclohexyl, 1-ethynylcyclohexyl, cycloheptyl, cyclopropyl(phenyl)methyl, (1S,2R)-1,7,7-trimethylbicyclo[2.2.1]hept-2-yl, phenyl, 4-fluorophenyl, 2-bromophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,4-dichlorophenyl, 2,6-dichlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 2,4,6-trichlorophenyl, 2,4,6-trifluorophenyl, 2-methoxyphenyl, 4-methoxyphenyl, 2,4-dimethoxyphenyl, 2,6-dimethoxyphenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 4-nitrophenyl, 2-(trifluoromethyl)phenyl, 3-(trifluoromethyl)phenyl, 4-(trifluoromethyl)phenyl, 2-(trifluoromethoxy)phenyl, 4-(trifluoromcthoxy)phenyl, 4-tert-butylphenyl, biphenyl-2-yl, biphenyl-3-yl, biphenyl-4-yl, 3-phenoxyphenyl, 4-phenoxyphenyl, 2-[1-methoxy-2-(methylamino)-2-oxoethyl]phenyl, 2-[(methylaminoxoxo)acetyl]phenyl 1-naphthyl, 2-naphthyl, phenylethynyl, 2-thienyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, quinolin-5-yl, quinolin-6-yl, quinolin-7-yl, quinolin-8-yl, isoquinolin-5-yl, 1,3-benzoxazol-4-yl, trifluoromethyl, morpholin-4-yl, piperidin-1-yl, pyrrolidin-1-yl, 4-methylpiperazin-1-yl, dimethylamino or trimethylsilyl,


    and the agrochemically active salts thereof.


Most preference is given to compounds of the formula (I) in which one or more of the symbols have one of the meanings below:

  • R1 is methyl, ethyl, 1-methylethyl, 1,1-dimethylethyl, difluoromethyl, trifluoromethyl or pentafluoroethyl,
  • R2 is H or chlorine,
  • R3 is H, methyl, 1,1-dimethylethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl or phenyl,
  • R4 is H or methyl,
  • R5 isH or methyl,
  • Y1 is oxygen,
  • Y2 is oxygen,
  • Y3 is sulfur or oxygen,
  • X is CH2 or CH2CH2,
  • W is CH2 or CH2CH2,
  • R6 is H,
  • G is a direct bond, CH2, CH2CH2, CH(CH3) or CH(CH2CH3),
  • R7 is heptan-3-yl, octyl, (1Z)-prop-1-en-1-yl, (E)-2-phenylethenyl, hex-1-en-3-yl, diphenylmethyl, 1,2,3,4-tetrahydronaphthalen-1-yl, (1R)-1,2,3,4-tetrahydronaphthalen-1-yl, (1S)-1,2,3,4-tetrahydronaphthalen-1-yl, 1,2,3,4-tetrahydronaphthalen-2-yl, 5,6,7,8-tetrahydronaphthalen-1-yl, 5,6,7,8-tetrahydronaphthalen-2-yl, decahydronaphthalen-1-yl, 1,4-dioxaspiro[4.5]dec-8-yl, 2,3-dihydro-1H-inden-1-yl, 2,3-dihydro-1H-inden-2-yl, cyclopropyl, cyclopentyl, 1-ethynylcyclopentyl, cyclohexyl, 2-methylcyclohexyl, 2,6-dimethylcyclohexyl, 4-tert-butylcyclohexyl, 5-methyl-2-(propan-2-yl)cyclohexyl, 3-methyl-5-(propan-2-yl)cyclohexyl. 1-cyanocyclohexyl, 1-ethynylcyclohexyl, cycloheptyl, cyclopropyl(phenyl)methyl, (1S,2R)-1,7,7-trimethylbicyclo[2.2.1]hept-2-yl, phenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,4-dichlorophenyl, 2,6-dichlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 2,4,6-trichlorophenyl, 2,4,6-trifluorophenyl, 2-methoxyphenyl, 4-methoxyphenyl, 2,4-dimethoxyphenyl, 2,6-dimethoxyphenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 4-nitrophenyl, 2-(trifluoromethyl)phenyl, 3-(trifluoromethyl)phenyl, 4-(trifluoromethyl)phenyl, 2-(trifluoromethoxy)phenyl, 4-(trifluoromethoxy)phenyl, 4-tert-butylphenyl, biphenyl-2-yl, biphenyl-3-yl, biphenyl-4-yl, 3-phenoxyphenyl, 4-phenoxyphenyl, 1-naphthyl, 2-naphthyl, phenylethynyl, 2-thienyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, quinolin-5-yl, quinolin-6-yl, quinolin-7-yl, quinolin-8-yl, isoquinolin-5-yl, 1,3-benzoxazol-4-yl, trifluoromethyl, dimethylamino or trimethylsilyl,


    and the agrochemically active salts thereof.


Special preference is furthermore given to compounds of the formula (I) in which one or more of the symbols have one of the meanings below:

  • R1 is C1-C4-alkyl or C1-C2-haloalkyl,
  • R2 is H and
  • R3 is C1-C4-alkyl or C1-C2-haloalkyl,


    where the other substituents have one or more of the meanings mentioned above,


    and the agrochemically active salts thereof.


Special preference is furthermore given to compounds of the formula (I) in which one or more of the symbols have one of the meanings below:

  • R1 is methyl, ethyl, 1-methylethyl, 1,1-dimethylethyl, difluoromethyl, trifluoromethyl or pentafluoroethyl,
  • R2 is H and
  • R3 is methyl, 1,1-dimethylethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl or phenyl,


    where the other substituents have one or more of the meanings mentioned above, and the agrochemically active salts thereof.


Special preference is furthermore given to compounds of the formula (I) in which one or more of the symbols have one of the meanings below:

  • X is CH2CH2 and
  • W is CH2,


    where the other substituents have one or more of the meanings mentioned above, and the agrochemically active salts thereof.


Special preference is furthermore given to compounds of the formula (I) in which

  • Y3 is oxygen,


    where the other substituents have one or more of the meanings mentioned above, and the agrochemically active salts thereof.


Special preference is furthermore given to compounds of the formula (I) in which

  • R6 is H,


    where the other substituents have one or more of the meanings mentioned above, and the agrochemically active salts thereof.


Special preference is furthermore given to compounds of the formula (I) in which

  • G is CH2, CH2CH2, CH(CH3) or CH(CH2CH3).


    where the other substituents have one or more of the meanings mentioned above, and the agrochcmically active salts thereof.


Special preference is furthermore given to compounds of the formula (I) in which

  • R7 is C5-C10-alkyl,


    where the other substituents have one or more of the meanings mentioned above, and the agrochemically active salts thereof.


Special preference is furthermore given to compounds of the formula (I) in which

  • R7 is C5-C8-alkyl,


    where the other substituents have one or more of the meanings mentioned above, and the agrochemically active salts thereof.


Very particular preference is furthermore given to compounds of the formula (I) in which

  • R7 is heptan-3-yl or octyl,


    where the other substituents have one or more of the meanings mentioned above, and the agrochemically active salts thereof.


Special preference is furthermore given to compounds of the formula (I) in which

  • R7 is C2-C16-alkenyl,


    where the other substituents have one or more of the meanings mentioned above, and the agrochemically active salts thereof.


Special preference is furthermore given to compounds of the formula (I) in which

  • R7 is C2-C6-alkenyl,


    where the other substituents have one or more of the meanings mentioned above, and the agrochemically active salts thereof.


Special preference is furthermore given to compounds of the formula (I) in which

  • R7 is (1Z)-prop-1-en-1-yl or hex-1-en-3-yl,


    where the other substituents have one or more of the meanings mentioned above, and the agrochemically active salts thereof.


Special preference is furthermore given to compounds of the formula (I) in which

  • R7 is C2-C16-alkynyl,


    where the other substituents have one or more of the meanings mentioned above, and the agrochemically active salts thereof.


Special preference is furthermore given to compounds of the formula (I) in which

  • R7 is C2-C6-alkynyl,


    where the other substituents have one or more of the meanings mentioned above, and the agrochemically active salts thereof.


Special preference is furthermore given to compounds of the formula (I) in which

  • R7 is C3-C15-cycloalkyl,


    where the other substituents have one or more of the meanings mentioned above, and the agrochemically active salts thereof.


Special preference is furthermore given to compounds of the formula (I) in which

  • R7 is C3-C8-cycloalkyl,


    where the other substituents have one or more of the meanings mentioned above, and the agrochemically active salts thereof.


Special preference is furthermore given to compounds of the formula (I) in which

  • R7 is cyclopropyl, cyclopentyl, cyclohexyl or cycloheptyl,


    where the other substituents have one or more of the meanings mentioned above, and the agrochemically active salts thereof.


Special preference is furthermore given to compounds of the formula (I) in which

  • R7 is C5-C15-cycloalkenyl,


    where the other substituents have one or more of the meanings mentioned above, and the agrochemically active salts thereof.


Special preference is furthermore given to compounds of the formula (I) in which

  • R7 is C5-C8-cycloalkenyl,


    where the other substituents have one or more of the meanings mentioned above, and the agrochemically active salts thereof.


Special preference is furthermore given to compounds of the formula (I) in which

  • R7 is C3-C15-heterocyclyl,


    where the other substituents have one or more of the meanings mentioned above, and the agrochemically active salts thereof.


Special preference is furthermore given to compounds of the formula (I) in which

  • R7 is C5-C6-heterocyclyl,


    where the other substituents have one or more of the meanings mentioned above, and the agrochemically active salts thereof.


Special preference is furthermore given to compounds of the formula (I) in which

  • R7 is aryl,


    where the other substituents have one or more of the meanings mentioned above, and the agrochemically active salts thereof.


Special preference is furthermore given to compounds of the formula (I) in which

  • R7 is phenyl, or saturated or partially or fully unsaturated unsubstituted or substituted naphthyl or indenyl,


    where the other substituents have one or more of the meanings mentioned above, and the agrochemically active salts thereof.


Special preference is furthermore given to compounds of the formula (I) in which

  • R7 is phenyl, 1-naphthyl, 2-naphthyl, 1,2,3,4-tetrahydronaphthalen-1-yl, (1R)-1,2,3,4-tetrahydronaphthalen-1-yl, (1S)-1,2,3,4-tetrahydronaphthalen-1-yl, 1,2,3,4-tetrahydronaphthalen-2-yl, 5,6,7,8-tetrahydronaphthalen-1-yl, 5,6,7,8-tetrahydronaphthalen-2-yl, decahydronaphthalen-1-yl, 2,3-dihydro-1H-inden-1-yl or 2,3-dihydro-1H-inden-2-yl,


    where the other substituents have one or more of the meanings mentioned above, and the agrochemically active salts thereof.


Special preference is furthermore given to compounds of the formula (I) in which

  • R7 is hetaryl,


    where the other substituents have one or more of the meanings mentioned above, and the agrochemically active salts thereof.


Special preference is furthermore given to compounds of the formula (I) in which

  • R7 is furan-2-yl, furan-3-yl, thiophen-2-yl, thiophen-3-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, pyrrol-1-yl, pyrrol-2-yl, pyrrol-3-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, imidazol-1-yl, imidazol-2-yl, imidazol-4-yl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 1,3,4-oxadiazol-2-yl, 1,2,4-thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl, 1,3,4-thiadiazol-2-yl, 1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl, 1,2,3-triazol-4-yl, 1,2,4-triazol-1-yl, 1,2,4-triazol-3-yl, 1,2,4-triazol-4-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyridazin-3-yl, pyridazin-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyrazin-2-yl, 1,3,5-triazin-2-yl, 1,2,4-triazin-3-yl, indol-1-yl, indol-2-yl, indol-3-yl, indol-4-yl, indol-5-yl, indol-6-yl, indol-7-yl, benzimidazol-1-yl, benzimidazol-2-yl, benzimidazol-4-yl, benzimidazol-5-yl, indazol-1-yl, indazol-3-yl, indazol-4-yl, indazol-5-yl, indazol-6-yl, indazol-7-yl, indazol-2-yl, 1-benzofuran-2-yl, 1-benzofuran-3-yl, 1-benzofuran-4-yl, 1-benzofuran-5-yl, 1-benzofuran-6-yl, 1-benzofuran-7-yl, 1-benzothiophen-2-yl, 1-benzothiophen-3-yl, 1-benzothiophen-4yl, 1-benzothiophen-5-yl, 1-benzothiophen-6-yl, 1-benzothiophen-7-yl. 1,3-bcnzothiazol-2-yl, 1,3-benzothiazol-4-yl, 1,3-benzothiazol-5-yl, 1,3-benzothiazol-6-yl, 1,3-benzothiazol-7-yl, 1,3-benzoxazol-2-yl, 1,3-benzoxazol-4-yl, 1,3-benzoxazol-5-yl, 1,3-benzoxazol-6-yl, 1,3-benzoxazol-7-yl, quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-5-yl, quinolin-6-yl, quinolin-7-yl, quinolin-8-yl, isoquinolin-1-yl, isoquinolin-3-yl, isoquinolin-4-yl, isoquinolin-5-yl, isoquinolin-6-yl, isoquinolin-7-yl or isoquinolin-8-yl,


    where the other substituents have one or more of the meanings mentioned above, and the agrochemically active salts thereof.


Special preference is furthermore given to compounds of the formula (I) in which

  • R7 is pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, quinolin-5-yl, quinolin-6-yl, quinolin-7-yl, quinolin-8-yl, isoquinolin-5-yl or 1,3-benzoxazol-4-yl,


    where the other substituents have one or more of the meanings mentioned above, and the agrochemically active salts thereof.


Special preference is furthermore given to compounds of the formula (I) in which

  • R7 is Si(C1-C4-alkyl)3,


    where the other substituents have one or more of the meanings mentioned above, and the agrochemically active salts thereof.


Special preference is furthermore given to compounds of the formula (I) in which

  • R7 is Si(C1-C2-alkyl)3,


    where the other substituents have one or more of the meanings mentioned above, and the agrochemically active salts thereof.


Special preference is furthermore given to compounds of the formula (I) in which

  • R7 is trimethylsilyl,


    where the other substituents have one or more of the meanings mentioned above, and the agrochemically active salts thereof.


Depending on the nature of the substituents defined above, the compounds of the formula (I) have acidic or basic properties and can form salts, if appropriate also inner salts, or adducts with inorganic or organic acids or with bases or with metal ions. If the compounds of the formula (I) carry amino, alkylamino or other groups which induce basic properties, these compounds can be reacted with acids to give salts, or they are directly obtained as salts in the synthesis. If the compounds of the formula (I) carry hydroxyl, carboxyl or other groups which induce acidic properties, these compounds can be reacted with bases to give salts. Suitable bases are, for example, hydroxides, carbonates, bicarbonates of the alkali metals and alkaline earth metals, in particular those of sodium, potassium, magnesium and calcium, furthermore ammonia, primary, secondary and tertiary amines having (C1-C4)-alkyl groups, mono-, di- and trialkanolamines of (C1-C4)-alkanols, choline and also chlorocholine.


The salts obtainable in this manner also have fungicidal properties.


Examples of inorganic acids are hydrohalic acids, such as hydrogen fluoride, hydrogen chloride, hydrogen bromide and hydrogen iodide, sulphuric acid, phosphoric acid and nitric acid, and acidic salts, such as NaHSO4 and KHSO4. Suitable organic acids are, for example, formic acid, carbonic acid and alkanoic acids, such as acetic acid, trifluoroacetic acid, trichloroacetic acid and propionic acid, and also glycolic acid, thiocyanic acid, lactic acid, succinic acid, citric acid, benzoic acid, cinnamic acid, oxalic acid, alkylsulphonic acids (sulphonic acids having straight-chain or branched alkyl radicals of 1 to 20 carbon atoms), arylsulphonic acids or aryldisulphonic acids (aromatic radicals, such as phenyl and naphthyl, which carry one or two sulphonic acid groups), alkylphosphonic acids (phosphonic acids having straight-chain or branched alkyl radicals of 1 to 20 carbon atoms), arylphosphonic acids or aryldiphosphonic acids (aromatic radicals, such as phenyl and naphthyl, which carry one or two phosphonic acid radicals), where the alkyl and aryl radicals may carry further substituents, for example p-toluenesulphonic acid, salicylic acid, p-aminosalicylic acid, 2-phenoxybenzoic acid, 2-acetoxybenzoic acid, etc.


Suitable metal ions are in particular the ions of the elements of the second main group, in particular calcium and magnesium, of the third and fourth main group, in particular aluminum, tin and lead, and also of the first to eighth transition group, in particular chromium, manganese, iron, cobalt, nickel, copper, zinc and others. Particular preference is given to the metal ions of the elements of the fourth period. Here, the metals can be present in various valencies that they can assume.


Optionally substituted groups can be mono- or polysubstituted, where in the case of polysubstitutions the substituents can be identical or different.


In the definitions of the symbols given in the formulae above, collective terms were used which are generally representative of the following substituents:


halogen: fluorine, chlorine, bromine and iodine;


aryl: unsubstituted or optionally substituted 5- to 15S-membered partially or filly unsaturated mono-, bi- or tricyclic ring system having up to 3 ring members selected from the groups C(O), (C═S), where at least one of the rings of the ring system is fully unsaturated, such as, for example (but not limited to), benzene, naphthalene, tetrahydronaphthalene, anthracene, indane, phenantlirene, azulene;


alkyl: saturated, straight-chain or branched hydrocarbon radicals having 1 to 10 carbon atoms, for example (but not limited thereto) methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl and 1-ethyl-2-methylpropyl, heptyl, 1-methylhexyl, octyl, 1,1-diniethylhexyl, 2-ethylbexyl, 1-ethylhexyl, nonyl, 1,2,2-trimethylhexyl, decyl;

  • haloalkyl: straight-chain or branched alkyl groups having 1 to 4 carbon atoms (as mentioned above), where in these groups some or all of the hydrogen atoms may be replaced by halogen atoms as mentioned above, for example (but not limited thereto) C1-C2-haloalkyl, such as chloro-methyl, bromomethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chlorofluoromethyl, dichlorofluoromethyl, chlorodifluoromethyl, 1-chloroethyl, 1-bromoethyl, 1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-chloro-2-fluoroethyl, 2-chloro-2,2-difluoroethyl, 2,2-dichloro-2-fluoroethyl, 2,2,2-trichloroethyl, pentafluoroethyl and 1,1,1-trifluoroprop-2-yl;


    alkenyl: unsaturated, straight-chain or branched hydrocarbon radicals having 2 to 16 carbon atoms and at least one double bond in any position, for example (but not limited thereto) C2-C6-alkenyl, such as ethenyl, 1-propenyl, 2-propenyl, 1-methylethenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl, 3-methyl-1-butenyl, 1-methyl-2-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 1-methyl-3-butenyl, 2-methyl-3-butenyl, 3-methyl-3-butenyl, 1,1-dimethyl-2-propenyl, 1,2-dimethyl-1-propenyl, 1,2-dimethyl-2-propenyl, 1-ethyl-propenyl, 1-ethyl-2-propenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 3 methyl-1-pentenyl, 4-methyl-1-pentenyl, 1-methyl-2-pentenyl, 2-methyl-2-pentenyl, 3-methyl-2-pentenyl, 4-methyl-2-pentenyl, 1-methyl-3-pentenyl, 2-methyl-3-pentenyl, 3-methyl-3-pentenyl, 4-methyl-3-pentenyl, 1-methyl-4-pentenyl, 2-methyl-4-pentenyl, 3-methyl-4-pentenyl, 4-methyl-4-pentenyl, 1,1-dimethyl-2-butenyl, 1,1-dimethyl-3-butenyl, 1,2-dimethyl-1-butenyl, 1,2-dimethyl-2-butenyl, 1,2-dimethyl-3-butenyl, 1,3-dimethyl-1-butenyl, 1,3-dimethyl-2-butenyl, 1,3-dimethyl-3-butenyl, 2,2-dimethyl-3-butenyl, 2,3-dimethyl-1-butenyl, 2,3-dimethyl-2-butenyl, 2,3-dimethyl-3-butenyl, 3,3-dimethyl-1-butenyl, 3,3-dimethyl-2-butenyl, 1-ethyl-1-butenyl, 1-ethyl-2-butenyl, 1-ethyl-3-butenyl, 2-ethyl-1-butenyl, 2-ethyl-2-butenyl, 2-ethyl-3-butenyl, 1,1,2-trimethyl-2-propenyl, 1-ethyl-1-methyl-2-propenyl, 1-ethyl-2-methyl-1-propenyl and 1-ethyl-2-methyl-2-propenyl;


    alkynyl: straight-chain or branched hydrocarbon groups having 2 to 16 carbon atoms and at least one triple bond in any position, for example (but not limited thereto) C2-C6-alkynyl, such as ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-methyl-2-butynyl, 1-methyl-3-butynyl, 2-methyl-3-butynyl, 3-methyl-1-butynyl, 1,1-dimethyl-2-propynyl, 1-ethyl-2-propynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-methyl-2-pentynyl, 1-methyl-3-pentynyl, 1-methyl-4-pentynyl, 2-methyl-3-pentynyl, 2-methyl-4-pentynyl, 3-methyl-1-pentynyl, 3-methyl-4-pentynyl, 4-methyl-1-pentynyl, 4-methyl-2-pentynyl, 1,1-dimethyl-2-butynyl, 1,1-dimethyl-3-butynyl, 1,2-dimethyl-3-butynyl, 2,2-dimethyl-3-butynyl, 3,3-dimethyl-1-butynyl, 1-ethyl-2-butynyl, 1-ethyl-3-butynyl, 2-ethyl-3-butynyl and 1-ethyl-1-methyl-2-propynyl;


    alkoxy: saturated, straight-chain or branched alkoxy radicals having 1 to 4 carbon atoms, for example (but not limited thereto) C1-C4-alkoxy, such as methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy, 1,1-dimethylethoxy;


    haloalkoxy: straight-chain or branched alkoxy groups having 1 to 4 carbon atoms (as mentioned above), where in these groups some or all of the hydrogen atoms may be replaced by halogen atoms as mentioned above, for example (but not limited thereto) C1-C2-haloalkoxy, such as chloro-methoxy, bromomethoxy, dichloromethoxy, trichloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chlorofluoromethoxy, dichlorofluoromethoxy, chlorodifluoromethoxy, 1-chloroethoxy, 1-bromoethoxy, 1-fluoroethoxy, 2-fluoroethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, 2-chloro-2-fluoroethoxy, 2-chloro-2,2-difluoroethoxy. 2,2-dichloro-2-fluoroethoxy, 2,2,2-trichloroethoxy, pentafluoroethoxy and 1,1,1-trifluoroprop-2-oxy;


    thioalkyl: saturated, straight-chain or branched alkylthio radicals having 1 to 6 carbon atoms, for example (but not limited thereto) C1-C6-alkylthio, such as methylthio, ethylthio, propylthio, 1-methylethylthio, butylthio, 1-methylpropylthio, 2-methylpropylthio, 1,1-dimethylethylthio, pentylthio, 1-methylbutylthio, 2-methylbutylthio, 3-methylbutylthio, 2,2-dimethylpropylthio, 1-ethylpropylthio, hexylthio, 1,1-dimethylpropylthio, 1,2-dimethylpropylthio, 1-methylpentylthio, 2-methylpentylthio, 3-methylpentylthio, 4-methylpentylthio, 1,1-dimethylbutylthio, 1,2-dimethylbutylthio, 1,3-dimethylbutylthio, 2,2-dimethylbutylthio, 2,3-dimethylbutylthio, 3,3-dimethylbutylthio, 1-ethylbutylthio, 2-ethylbutylthio, 1,1,2-trimethylpropylthio, 1,2,2-trimethyl-propylthio, 1-ethyl-1-methylpropylthio and 1-ethyl-2-methylpropylthio;


    thiohaloalkyl: straight-chain or branched alkylthio groups having 1 to 6 carbon atoms (as mentioned above), where in these groups some or all of the hydrogen atoms may be replaced by halogen atoms as mentioned above, for example (but not limited thereto) C1-C2-haloalkylthio, such as chloromethylthio, bromomethylthio, dichloromethylthio, trichloromethylthio, fluoromethylthio, difluoromethylthio, trifluoromethylthio, chlorofluoromethylthio, dichlorofluoromethylthio, chlorodifluoromethylthio, 1-chloroethylthio, 1-bromoethylthio, 1-fluoroethylthio, 2-fluoroethylthio. 2,2-difluoroethylthio, 2,2,2-trifluoroethylthio, 2-chloro-2-fluoroethylthio, 2-chloro-2,2-difluoroethylthio, 2,2-dichloro-2-fluoroethylthio, 2,2,2-trichloroethylthio, pentafluoroethylthio and 1,1,1-trifluoroprop-2-ylthio;


    cycloalkyl: mono-, bi- or tricyclic saturated hydrocarbon groups having 3 to 12 carbon ring members, for example (but not limited thereto) cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, bicyclo[1.0.1]butane, decalinyl, norbornyl:


    cycloalkenyl: mono-, bi- or tricyclic non-aromatic hydrocarbon groups having 5 to 15 carbon ring members and at least one double bond, for example (but not limited thereto) cyclopenten-1-yl, cyclohexen-1-yl, cyclohepta-1,3-dien-1-yl, norbornen-1-yl;


    (alkoxy)carbonyl: an alkoxy group having 1 to 4 carbon atoms (as mentioned above) which is attached to the skeleton via a carbonyl group (—CO—);


    heterocyclyl: a three- to fifteen-membered saturated or partially unsaturated heterocycle which contains one to four heteroatoms from the group consisting of oxygen, nitrogen and sulfur: mono-, bi- or tricyclic heterocycles which contain, in addition to carbon ring members, one to three nitrogen atoms and/or one oxygen or sulphur atom or one or two oxygen and/or sulphur atoms; if the ring contains a plurality of oxygen atoms, these are not directly adjacent; such as, for example (but not limited thereto), oxiranyl, aziridinyl, 2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-tetrahydrothienyl, 3-tetrahydrothienyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 3-isoxazolidinyl, 4-isoxazolidinyl, 5-isoxazolidinyl, 3-isothiazolidinyl, 4-isothiazolidinyl, 5-isothiazolidinyl, 3-pyrazolidinyl, 4-pyrazolidinyl, 5-pyrazolidinyl, 2-oxazolidinyl, 4-oxazolidinyl, 5-oxazolidinyl, 2-thiazolidinyl, 4-thiazolidinyl, 5-thiazolidinyl, 2-imidazolidinyl, 4-imidazolidinyl, 1,2,4-oxadiazolidin-3-yl, 1,2,4-oxadiazolidin-5-yl, 1,2,4-thiadiazolidin-3-yl, 1,2,4-thiadiazolidin-5-yl, 1,2,4-triazolidin-3-yl, 1,3,4-oxadiazolidin-2-yl, 1,3,4-thiadiazolidin-2-yl, 1,3,4-triazolidin-2-yl, 2,3-dihydrofur-2-yl, 2,3-dihydrofur-3-yl, 2,4-dihydrofur-2-yl, 2,4-dihydrofur-3-yl, 2,3-dihydrothien-2-yl, 2,3-dihydrothien-3-yl, 2,4-dihydrothien-2-yl, 2,4-dihydrothien-3-yl, 2-pyrrolin-2-yl, 2-pyrrolin-3-yl, 3-pyrrolin-2-yl, 3-pyrrolin-3-yl, 2-isoxazolin-3-yl, 3-isoxazolin-3-yl, 4-isoxazolin-3-yl, 2-isoxazolin-4-yl, 3-isoxazolin-4-yl, 4-isoxazolin-4-yl, 2-isoxazolin-5-yl, 3-isoxazolin-5-yl, 4-isoxazolin-5-yl, 2-isothiazolin-3-yl, 3-isothiazolin-3-yl, 4-isothiazolin-3-yl, 2-isothiazolin-4-yl, 3-isothiazolin-4-yl, 4-isothiazolin-4-yl, 2-isothiazolin-5-yl, 3-isothiazolin-5-yl, 4-isothiazolin-5-yl, 2,3-dihydropyrazol-1-yl, 2,3-dihydropyrazol-2-yl, 2,3-dihydropyrazol-3-yl, 2,3-dihydropyrazol-4-yl, 2,3-dihydropyrazol-5-yl, 3,4-dihydropyrazol-1-yl, 3,4-dihydropyrazol-3-yl, 3,4-dihydropyrazol-4-yl, 3,4-dihydropyrazol-5-yl, 4,5-dihydropyrazol-1-yl, 4,5-dihydropyrazol-3-yl, 4,5-dihydropyrazol-4-yl, 4,5-dihydropyrazol-5-yl, 2,3-dihydrooxazol-2-yl, 2,3-dihydrooxazol-3-yl, 2,3-dihydrooxazol-4-yl, 2,3-dihydrooxazol-5-yl, 3,4-dihydrooxazol-2-yl, 3,4-dihydrooxazol-3-yl, 3,4-dihydrooxazol-4-yl, 3,4-dihydrooxazol-5-yl, 3,4-dihydrooxazol-2-yl, 3,4-dihydrooxazol-3-yl, 3,4-dihydrooxazol-4-yl, 2.piperidinyl, 3-piperidinyl, 4-piperidinyl, 1,3-dioxan-5-yl, 2-tetra-hydropyranyl, 4-tetrahydropyranyl, 2-tetrahydrothienyl, 3-hexahydropyridazinyl, 4-hexahy-dropyridazinyl, 2-hexahydropyrimidinyl, 4-hexahydropyrimidinyl, 5-hexahydropyrimidinyl, 2-piperazinyl, 1,3,5-hexahydrotriazin-2-yl and 1,2,4-hexahydrotriazin-3-yl;


    hetaryl: an unsubstituted or optionally substituted 5- to 15-membered partially or fully unsaturated mono-, bi- or tricyclic ring system where at least one of the rings of the ring system is fully unsaturated and which contains one to four heteroatoms from the group consisting of oxygen, nitrogen and sulfur; if the ring contains a plurality of oxygen atoms, these are not directly adjacent;


    such as, for example (but not limited thereto)
    • 5-membered heteroaryl which contains one to four nitrogen atoms or one to three nitrogen atoms and one sulfur or oxygen atom: 5-membered heteroaryl groups which, in addition to carbon atoms, may contain one to four nitrogen atoms or one to three nitrogen atoms and one sulfur or oxygen atom as ring members, for example 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyrrolyl, 3-pyrrolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-imidazolyl, 4-imidazolyl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 1,2,4-thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl, 1,2,4-triazol-3-yl, 1,3,4-oxadiazol-2-yl, 1,3,4-thiadiazol-2-yl and 1,3,4-triazol-2-yl;
    • benzo-fused 5-membered heteroaryl which contains one to three nitrogen atoms or one nitrogen atom and one oxygen or sulfur atom: 5-membered heteroaryl groups which, in addition to carbon atoms, may contain one to four nitrogen atoms or one to three nitrogen atoms and one sulfur or oxygen atom as ring members and in which two adjacent carbon ring members or one nitrogen and one adjacent carbon ring member may be bridged by a buta-1,3-diene-1,4-diyl group in which one or two carbon atoms may be replaced by nitrogen atoms; for example benzindolyl, benzimidazolyl, benzothiazolyl, benzopyrazolyl, benzofuryl;
    • 5-membered heteroaryl which contains one to four nitrogen atoms and is attached via nitrogen or benzo-fused 5-membered heteroaryl which contains one to three nitrogen atoms and is attached via nitrogen: 5-membered heteroaryl groups which, in addition to carbon atoms, may contain one to four nitrogen atoms or one to three nitrogen atoms as ring members and in which two adjacent carbon ring members or one nitrogen and one adjacent carbon ring member may be bridged by a buta-1,3-diene-1,4-diyl group in which one or two carbon atoms may be replaced by nitrogen atoms, where these rings are attached to the skeleton via one of the nitrogen ring members, for example 1-pyrrolyl, 1-pyrazolyl, 1,2,4-triazol-1-yl, 1-imidazolyl, 1,2,3-triazol-1-yl, 1,3,4-triazol-1-yl;
    • 6-membered heteroaryl which contains one to three or one to four nitrogen atoms: 6-membered heteroaryl groups which, in addition to carbon atoms, may contain, respectively, one to three and one to four nitrogen atoms as ring members, for example 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 3-pyridazinyl, 4-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 2-pyrazinyl, 1,3,5-triazin-2-yl and 1,2,4-triazin-3-yl;


Not included are combinations which are against natural laws and which the person skilled in the art would therefore exclude based on his/her expert knowledge. Ring structures having three or more adjacent oxygen atoms, for example, are excluded.


The present invention furthermore provides a process for preparing the thiazole-4-carboxylic esters and thioesters of the formula (I) according to the invention, which comprises at least one of steps (a) to (c) below:

  • (a) the conversion of a compound of the formula (VII) or (IX) into a compound of the formula (VI) or (X), optionally in each case in the presence of a solvent and, if appropriate, in the presence of an acid or, if appropriate, in the presence of a base or, if appropriate, in the presence of a hydrogen source, according to the reaction scheme below (Scheme 1):




embedded image


where

    • L=—O—C1-C2-alkyl for compounds of the formulae (VII) and (VI),
    • L=—Y3−G-R7 for compounds of the formulae (IX) and (X),
    • PG=acetyl, C1-C4-alkoxycarbonyl, benzyl or benzyloxycarbonyl,
    • W, X and R6 are as defined above for formula (I).
  • (b) the reaction of a compound of the formula (VI) or (X) with a compound of the formula (V) to give a compound of the formula (IV) or (I), in each case, if appropriate, in the presence of a coupling agent, a base and a solvent, according to the reaction scheme below (Scheme 2):




embedded image




    • where

    • Z═Cl or OH,

    • L=—O—C1-C2-alkyl for compounds of the formulae (VI) and (IV),

    • L=—Y3-G-R7 for compounds of the formulae (X) and (I),

    • W, X, Y3, G, R, R2, R3, R4, R5, R6 and R7 are as defined above for formula (I).



  • (c) the conversion of a compound of the formula (IV) or (VII) into a compound of the formula (III) or (VIII), in each case by hydrolysis in the presence of a base and, if appropriate, in the presence of a solvent, according to the reaction scheme below (Scheme 3):





embedded image




    • where







embedded image


for compounds of the formulae (IV) and (III),

    • Q=acetyl, C1-C4-alkoxycarbonyl, benzyl or benzyloxycarbonyl (corresponds to PG), for compounds of the formulae (VII) and (VIII),
    • W, X, R1, R2, R3, R4, R5 and R6 are as defined above for formula (I).
  • (d) the reaction of a compound of the formula (III) or (VIII) with a compound of the formula


(II) to give a compound of the formula (I) or (IX), in each case, if appropriate, in the presence of a coupling agent, a base and a solvent, according to the reaction scheme below (Scheme 4):




embedded image


where




embedded image


for compounds of the formulae (III) and (I),

    • Q=acetyl, C1-C4-alkoxycarbonyl, benzyl or benzyloxycarbonyl (corresponds to PG), for compounds of the formulae (VIII) and (IX),
    • Z═OH or chlorine,
    • W, X, Y3, G, R, R2, R3, R4, R5, R6 and R7 are as defined above for formula (I).
  • (e) the conversion of a compound of the formula (I) into a compound of the formula (I) in the presence of a sulfurizing agent and, if appropriate, in the presence of a solvent, according to the reaction scheme below (Scheme 5):




embedded image




    • where

    • Y1=sulfur or oxygen,

    • Y2=sulfur or oxygen,

    • W, X, Y3, G, R1, R2, R3, R4, R5, R6 and R7 are as defined above for formula (I).





A general overview of the synthesis paths is given in Scheme 6.


The protective group is removed from compounds of the formula (VII), giving compounds of the formula (VI) or the corresponding salt (Scheme 1). A compound of the formula (VI) or a corresponding salt is coupled with a substrate of the formula (V), which gives compounds of the formula (IV) (Scheme 2). The hydrolysis of compounds of the formula (IV) leads to carboxylic acids of the formula (III) (Scheme 3), followed by a coupling reaction in the presence of an alcohol or thiol of the general formula (II), which gives compounds of the formula (I) (Scheme 4). Alternatively, the hydrolysis of the compound of the formula (VII) leads to a carboxylic acid of the general formula (VIII) (Scheme 3), followed by a coupling reaction in the presence of an alcohol or thiol of the general formula (II), which gives a compound of the formula (IX) (Scheme 4). The protective group marked PG of a compound of the formula (IX) is removed, so that a compound of the formula (X) or the corresponding salt is formed (Scheme 1). A compound of the formula (X) or a corresponding salt is coupled with a substrate of the formula (V), which gives a compound of the formula (I) (Scheme 2). A sulfurizing agent is added to a compound of the formula (I) to form a compound of the formula (I) (Y1=sulfur or oxygen, Y2=sulfur or oxygen) (Scheme 5).




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One way of preparing the intermediate (VI) from corresponding compounds (VII) is shown in Scheme 1.


A compound of the formula (VII) is converted into a compound of the formula (VI) a using suitable methods for removing protective groups, which methods are described in the literature (“Protective Groups in Organic Synthesis”; Third Edition; Theodora W. Greene, Peter G. M. Wuts; 494-653, and the literature cited therein).


tert-Butoxycarbonyl and benzyloxycarbonyl protective groups can be removed in an acidic medium (for example using hydrochloric acid or trifluoroacetic acid). Acetyl protective groups can be removed under basic conditions (using, for example, potassium carbonate or cesium carbonate). Benzylic protective groups can be removed hydrogenolytically using hydrogen in the presence of a catalyst (for example palladium on activated carbon).


Suitable for use as solvents are all customary solvents which are inert under the reaction conditions, such as, for example, alcohols (for example methanol, ethanol, propanol), cyclic and acyclic ethers (for example diethyl ether, tetrahydrofuran, dioxane), aromatic hydrocarbons (for example benzene, toluene, xylene), halogenated hydrocarbons (for example dichloromethane, chloroform, carbon tetrachloride), halogenated aromatic hydrocarbons (for example chlorobenzene, dichlorobenzene), nitriles (for example acetonitrile), carboxylic esters (for example ethyl acetate), amides (for example N,N-dimethylformamide, N,N-dimethylacetamide), dimethyl sulfoxide, 1,3-dimethyl-2-imidazolinone, water and acetic acid, or the reaction can be carried out in mixtures of two or more of these solvents.


Acids which can be used for this reaction of deprotecting t-butoxycarbonyl and benzyloxycarbonyl groups are, for example, trifluoroacetic acid, hydrochloric acid or other acids, as described in the literature (for example “Protective Groups in Organic Synthesis”; Third Edition; Theodora W. Greene, Peter G. M. Wuts; pp. 494-653).


The reaction is usually carried out at temperatures of 0° C.-150° C. and preferably at room temperature, but it can also be carried out at the reflux temperature of the reaction mixture. The reaction time varies depending on the scale of the reaction and the reaction temperature, but is generally between half an hour and 72 hours.


After the reaction has ended, the compounds (VI) are removed from the reaction mixture using one of the customary separation techniques. If required, the compounds are purified by recrystallisation, distillation or chromatography, or they can, if appropriate, also be used for the next step without prior purification. Moreover, it is possible to isolate the compound of the general formula (VI) as a salt, for example as a salt of hydrochloric acid or trifluoroacetic acid.


The same process is used to convert a compound of the formula (IX) into a compound of the formula (X).


C1-C2-Alkyl esters (VII) are known and can be prepared from commercially available precursors according to procedures described in the literature, for example from nitriles of the formula (XI), carboxylic acids of the formula (XII), carbonyl chlorides of the formula (XIII), amides of the formula (XIV) or thioamides of the formula (XV) (FIG. 1). A preferred method is the Hantzsch thiazole synthesis. Starting with (XIV) and commercially available ethyl or methyl halpyruvate in ethanol or in N,N-dimethylformamide in the presence of, for example, triethylamine at room temperature (for examples see WO 07/014290 and the references cited therein).




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where

    • Q=H or acid-labile amine protective groups, such as, for example, t-butoxycarbonyl (tBoc) or benzyloxycarbonyl (Cbz), or a benzyl protective group, such as, for example, benzyl (Bn).


      W and X are as defined above for formula (I).


One way of preparing compounds of the formula (IV) from corresponding compounds (VI) is shown in Scheme 2.


A compound of the formula (IV) is synthesized by a coupling reaction of a compound of the formula (VI) with a substrate of the formula (V) where Z═Cl, if appropriate in the presence of an acid scavenger/a base.


Acid halides (V) (Z═Cl) or the corresponding carboxylic acids (V) (Z═OH) are commercially available or can be prepared by processes described in the literature (for examples see WO 07/014290 and the references cited therein). A preferred method is shown in Scheme 7. Pyrazoles (XVIII) can be prepared from diketones (XXI) and commercially available hydrazine (XX) or the corresponding HCl salt in ethanol or in N,N-dimethylformamide, if appropriate in the presence of bases, for example triethylamine at reflux. Compounds (XVI) can be prepared by alkylation of compounds (XVIII) with commercially available α-halo esters (XVII) in acetonitrile or in N,N-dimethylformamide in the presence of bases, for example potassium carbonate at room temperature. Alternatively, compounds (XVI) can be prepared directly from diketones (XXI) and commercially available hydrazine (XIX) or the corresponding HCl salts in ethanol or in N,N-dimethylformamide, if appropriate in the presence of bases, for example triethylamine at reflux. Carboxylic acids (V) (Z═OH) can be prepared by hydrolysis of the esters (XVI) in THF/water mixtures using lithium hydroxide at room temperature. Moreover, a substrate of the general formula (V) where Z═Cl can be prepared from the corresponding acid (Z═OH) by chlorination using processes known from the literature (for example Tetrahedron 2005, 61, 10827-10852, and the literature cited therein).




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Suitable for use as solvents are all customary solvents which are inert under the reaction conditions, such as, for example, alcohols (for example methanol, ethanol, propanol), cyclic and acyclic ethers (for example diethyl ether, tetrahydrofuran, dioxane), aromatic hydrocarbons (for example benzene, toluene, xylene), halogenated hydrocarbons (for example dichloromethane, chloroform, carbon tetrachloride), halogenated aromatic hydrocarbons (for example chlorobenzene, dichlorobenzene) and nitriles (for example acetonitrile), or the reaction can be carried out in mixtures of two or more of these solvents. The preferred solvents are tetrahydrofuran and dichloromethane.


At least one equivalent of an acid scavenger/a base (for example Hünig base, triethylamine or commercially available polymeric acid scavengers), based on the starting material of the general formula (V), is employed. If the starting material is a salt, at least two equivalents of the acid scavenger are required.


The reaction is usually carried out at temperatures of 0° C.-100° C. and preferably at 20° C.-30° C., but it can also be carried out at the reflux temperature of the reaction mixture. The reaction time varies depending on the scale of the reaction and the reaction temperature, but is generally between a few minutes and 48 hours.


After the reaction has ended, the compounds (IV) are removed from the reaction mixture using one of the customary separation techniques. If required, the compounds are purified by recrystallisation, distillation or chromatography, or they can, if appropriate, also be used for the next step without prior purification.


Alternatively, a compound of the formula (IV) can also be synthesized from the corresponding compound of the formula (VI) using a substrate of the formula (V) where Z═OH in the presence of a coupling agent analogously to procedures described in the literature (for example Tetrahedron 2005, 61, 10827-10852, and the references cited therein).


Suitable coupling agents are, for example, peptide coupling agents (for example N-(3-dimethylaminopropyl)-N-ethylcarbodiimide mixed with 4-dimethylaminopyridine, N-(3-dimethylaminopropyl)-N-ethylcarbodiimide mixed with 1-hydroxybenzotriazole, bromotripyrrolidinophosphonium hexafluorophosphate, O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate, etc.).


If appropriate, a base, such as, for example, triethylamine or Hünig base can be employed in the reaction.


Suitable for use as solvents are all customary solvents which are inert under the reaction conditions, such as, for example, alcohols (for example methanol, ethanol, propanol), cyclic and acyclic ethers (for example diethyl ether, tetrahydrofuran, dioxane), aromatic hydrocarbon s (for example benzene, toluene, xylene), halogenated hydrocarbons (for example dichloromethane, chloroform, carbon tetrachloride), halogenated aromatic hydrocarbons (for example chlorobenzene, dichlorobenzene), nitriles (for example acetonitrile) and amides (for example N,N-dimethylformamide, N,N-dimethylacetamide), or the reaction can be carried out in mixtures of two or more of these solvents. The preferred solvent is dichloromethane.


The reaction is usually carried out at temperatures of 0° C.-100° C. and preferably at 0° C.-30° C., but it can also be carried out at the reflux temperature of the reaction mixture. The reaction time varies depending on the scale of the reaction and the reaction temperature, but is generally between a few minutes and 48 hours.


After the reaction has ended, the compounds (IV) are removed from the reaction mixture using one of the customary separation techniques. If required, the compounds are purified by recrystallisation, distillation or chromatography, or they can, if appropriate, also be used for the next step without prior purification.


Analogously, it is possible to convert compounds of the formula (X) into compounds of the formula (I).


One way of preparing the intermediate (III) from corresponding compounds (IV) is shown in Scheme 3.


The carboxylic acid of the formula (III) can be prepared by hydrolysis of the corresponding C1-C2-alkyl ester of the formula (IV). It is possible to use, for example, the method described in WO2007/014290.


Suitable for use as solvents are all customary solvents which are inert under the reaction conditions, such as, for example, alcohols (for example methanol, ethanol, propanol), cyclic and acyclic ethers (for example diethyl ether, tetrahydrofuran, dioxane), aromatic hydrocarbons (for example benzene, toluene, xylene), halogenated hydrocarbons (for example dichloromethane, chloroform, carbon tetrachloride) and halogenated aromatic hydrocarbons (for example chlorobenzene, dichlorobenzene), or the reaction can be carried out in mixtures of two or more of these solvents.


Suitable alkali metal hydroxides are, for example, LiOH, NaOH or KOH, usually in the presence of water together with a cosolvent, preferably THF and/or methanol, to facilitate dissolution of the ester. The starting material and the alkali metal hydroxide are employed in equimolar amounts; however, the alkali metal hydroxide may, if required, also be used in excess. The carboxylate salt formed is converted into the free acid by treatment with a slight excess of mineral acids, such as, for example, hydrochloric acid or sulfuric acid.


The reaction is usually carried out at temperatures of 0° C.-60° C., but it can also be carried out at the reflux temperature of the reaction mixture. The reaction time varies depending on the scale of the reaction and the reaction temperature, but is generally between a few minutes and 48 hours.


After the reaction has ended, the compounds (Ill) are removed from the reaction mixture using one of the customary separation techniques. If required, the compounds are purified by recrystallisation, distillation or chromatography.


Analogously, it is possible to convert compounds of the formula (VII) into compounds of the formula (VIII).


One way of preparing compounds of the formula (I) from corresponding compounds (III) is shown in Scheme 4.


A compound of the formula (I) is synthesized by a coupling reaction of a compound of the formula (III) with a substrate of the formula (II), by chlorination using processes known from the literature (for example Tetrahedron 2005, 61, 10827-10852, and the literature cited therein), if appropriate in the presence of an acid scavenger/a base.


Substrates of the general formula (II) are commercially available or can be prepared by processes described in the literature (see, for example, “The Chemistry of Functional groups”; “The Chemistry of the Thiol Group”; John Wiley & Sons, 1974, 163-269, and the references cited therein).


Suitable for use as solvents are all customary solvents which are inert under the reaction conditions, such as, for example, alcohols (for example methanol, ethanol, propanol), cyclic and acyclic ethers (for example diethyl ether, tetrahydrofuran, dioxane), aromatic hydrocarbons (for example benzene, toluene, xylene), halogenated hydrocarbons (for example dichloromethane, chloroform, carbon tetrachloride), halogenated aromatic hydrocarbons (for example chlorobenzene, dichlorobenzene) and nitriles (for example acetonitrile), or the reaction can be carried out in mixtures of two or more of these solvents. The preferred solvents are tetrahydrofuran and dichloromethane.


At least one equivalent of an acid scavenger/a base (for example Hünig base, triethylamine or commercially available polymeric acid scavengers), based on the starting material of the general formula (II), is employed. If the starting material is a salt, at least two equivalents of the acid scavenger are required.


The reaction is usually carried out at temperatures of 0° C.-100° C. and preferably at 20° C.-30° C., but it can also be carried out at the reflux temperature of the reaction mixture. The reaction time varies depending on the scale of the reaction and the reaction temperature, but is generally between a few minutes and 48 hours.


After the reaction has ended, the compounds (I) are removed from the reaction mixture using one of the customary separation techniques. If required, the compounds are purified by recrystallisation, distillation or chromatography, or they can, if appropriate, also be used for the next step without prior purification.


Alternatively, a compound of the formula (I) can also be synthesized from the corresponding compound of the formula (III) (Z═OH) using a substrate of the formula (II) in the presence of a coupling agent analogously to procedures described in the literature (for example Tetrahedron 2005, 61, 10827-10852, and the references cited therein).


Suitable coupling agents are, for example, peptide coupling agents (for example N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide mixed with 4-dimethylaminopyridine, N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide mixed with 1-hydroxybenzotriazole, bromotripyrrolidinophosphonium hexafluorophosphate, O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate, etc.).


If appropriate, a base, such as, for example, triethylamine or Hünig base can be employed in the reaction.


Suitable for use as solvents are all customary solvents which are inert under the reaction conditions, such as, for example, alcohols (for example methanol, ethanol, propanol), cyclic and acyclic ethers (for example diethyl ether, tetrahydrofuran, dioxane), aromatic hydrocarbons (for example benzene, toluene, xylene), halogenated hydrocarbons (for example dichloromethane, chloroform, carbon tetrachloride), halogenated aromatic hydrocarbons (for example chlorobenzene, dichlorobenzene), nitriles (for example acetonitrile) and amides (for example N,N-dimethylformamide, N,N-dimethylacetamide), or the reaction can be carried out in mixtures of two or more of these solvents. The preferred solvents are N,N-dimethylformamide and dichloromethane.


The reaction is usually carried out at temperatures of 0° C.-100° C. and preferably at 0° C.-30° C., but it can also be carried out at the reflux temperature of the reaction mixture. The reaction time varies depending on the scale of the reaction and the reaction temperature, but is generally between a few minutes and 48 hours.


After the reaction has ended, the compounds (I) are removed from the reaction mixture using one of the customary separation techniques. If required, the compounds are purified by recrystallisation, distillation or chromatography, or they can, if appropriate, also be used for the next step without prior purification.


The same process can be used to convert a compound of the general formula (VIII) into a compound of the general formula (IX).


One way to prepare compounds of the formula (I) in which Y1 and Y2═S from corresponding compounds (I) in which Y1 and Y2═O is shown in Scheme 5.


A sulfurizing agent, such as, for example, Lawesson's reagent or, for example, phosphorus pentasulfide, is added to a compound of the formula (I) to form a compound of the formula (I) (Y1 and Y2=sulfur). Here, it is possible, for example, to use the method described in Tetrahedron Lett 2002, 43 (3), 371-373.


Suitable for use as solvents are all customary solvents which are inert under the reaction conditions, such as, for example, alcohols (for example methanol, ethanol, propanol), cyclic and acyclic ethers (for example diethyl ether, tetrahydrofuran, dioxane), aromatic hydrocarbons (for example benzene, toluene, xylene), halogenated hydrocarbons (for example dichloromethane, chloroform, carbon tetrachloride), halogenated aromatic hydrocarbons (for example chlorobenzene, dichlorobenzene), nitriles (for example acetonitrile), carboxylic esters (for example ethyl acetate) and amides (for example N,N-dimethylformamide, N,N-dimethylacetamide), and the reaction can be carried out in mixtures of two or more of these solvents. The preferred solvents are chloroform, toluene and 1,2-dimethoxyethane.


Suitable sulfurizing agents are, for example, Lawesson's reagent (see Tetrahedron 1986, 42, 6555-6564, Tetrahedron Lett. 1993, 46, 7459-7462) and phosphorus pentasultide. The starting material and the sulfurizing agent are employed in equimolar amounts; however, the sulfurizing agent may, if required, also be used in excess.


The reaction is usually carried out at temperatures of 0° C.-150° C. and preferably at 0° C.-100° C., but it can also be carried out at the reflux temperature of the reaction mixture. The reaction time varies depending on the scale of the reaction and the reaction temperature, but is generally between a few minutes and 48 hours.


After the reaction has ended, the compounds (I) are removed from the reaction mixture using one of the customary separation techniques. If required, the compounds are purified by recrystallisation, distillation or chromatography.


The compound of the formula (XVIII-1)




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and salts thereof are novel.


The compounds of the formulae (XVI-1), (XVI-2), (XVI-3), (XVI-4) and (XVI-5),




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and salts thereof are novel.


The compounds of the formulae (V-1), (V-2), (V-3), (V-4) and (V-5),




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and salts thereof novel.


The compounds of the formulae (IV-1), (IV-2) and (IV-3),




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and salts thereof are novel.


The compounds of the formulae (III-1), (III-2) and (III-3) in which




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Z═OH or chlorine


and salts thereof are novel.


The compounds of the formula (IX) in which




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the symbols have the meanings below

  • PG is acetyl, C1-C2-alkoxycarbonyl, benzyl or benzyloxycarbonyl,
  • W, X, Y3, G, R6 and R7 have the general, preferred, particularly preferred or very particularly preferred meanings given above


    and salts thereof are novel.




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The compounds of the formula (X) in which




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the symbols have the meanings below

  • W, X, Y3, G, R6 and R7 have the general, preferred, particularly preferred or very particularly preferred meanings given above


    and salts thereof are novel.




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The invention furthermore provides the non-medicinal use of the thiazole-4-carboxylic esters and thioesters according to the invention or mixtures thereof for controlling unwanted microorganisms.


The invention furthermore relates to a composition for controlling unwanted microorganisms which comprises at least one thiazole-4-carboxylic ester or thioester according to the present invention.


Moreover, the invention relates to a method for controlling unwanted microorganisms, characterized in that the thiazole-4-carboxylic esters and thioesters according to the invention are applied to the microorganisms and/or in their habitat.


The invention furthermore relates to seed treated with at least one thiazole-4-carboxylic ester or thioester according to the invention.


A last subject matter of the invention relates to a method for protecting seed against unwanted microorganisms by using seed treated with at least one thiazole-4-carboxylic ester or thioester according to the present invention.


The substances according to the invention have potent microbicidal activity and can be employed for controlling unwanted microorganisms, such as fungi and bacteria, in crop protection and in the protection of materials.


The thiazole-4-carboxylic esters and thioesters of the formula (I) according to the invention have very good fungicidal properties and can be used in crop protection, for example, for controlling Plasmodiophoromycetes, Oomycetes, Chytridiomycetes, Zygomycetes, Ascomycetes, Basidiomycetes and Deuteromycctcs.


Bactericides can be employed in crop protection, for example, for controlling Pseudomonadaceae, Rhizobiaceae, Enterobacteriaceae, Corynebacteriaceae and Streptomycetaceae.


The fungicidal compositions according to the invention can be used for the curative or protective control of phytopathogenic fungi. Accordingly, the invention also relates to curative and protective methods for controlling phytopathogenic fungi using the active compounds or compositions according to the invention, which are applied to the seed, the plant or plant parts, the fruit or the soil in which the plants grow.


The compositions according to the invention for controlling phytopathogenic fungi in crop protection comprise an effective, but non-phytotoxic amount of the active compounds according to the invention. “Effective, but non-phytotoxic amount” means an amount of the composition according to the invention which is sufficient to control the fungal disease of the plant in a satisfactory manner or to eradicate the fungal disease completely, and which, at the same time, does not cause any significant symptoms of phytotoxicity. In general, this application rate may vary within a relatively wide range. It depends on a plurality of factors, for example on the fungus to be controlled, the plant, the climatic conditions and the ingredients of the compositions according to the invention.


All plants and plant parts can be treated in accordance with the invention. By plants are understood here all plants and plant populations such as desired and undesired wild plants or crop plants (including naturally occurring crop plants). Crop plants can be plants which can be obtained by conventional breeding and optimization methods or by biotechnological and genetic engineering methods or combinations of these methods, including the transgenic plants and including the plant varieties which can or cannot be protected by varietal property rights. Plant parts are to be understood as meaning all parts and organs of plants above and below the ground, such as shoot, leaf, flower and root, examples which may be mentioned being leaves, needles, stalks, stems, flowers, fruit bodies, fruits, seeds, roots, tubers and rhizomes. Parts of plants also include harvested plants and vegetative and generative propagation material, for example seedlings, tubers, rhizomes, cuttings and seeds.


The following plants may be mentioned as plants which can be treated according to the invention: cotton, flax, grapevines, fruit, vegetables, such as Rosaceae sp. (for example pomaceous fruit, such as apples and pears, but also stone fruit, such as apricots, cherries, almonds and peaches and soft fruit such as strawberries), Ribesioidae sp., Juglandaceae sp., Betulaceae sp., Anacardiaceae sp., Fagaceae sp., Moraceae sp., Oleaceae sp., Actinidaceae sp., Lauraceae sp., Musaceae sp. (for example banana trees and plantations), Rubiaceae sp. (for example coffee), Theaceae sp., Sterculiceae sp., Rutaceae sp. (for example lemons, oranges and grapefruit), Solanaceae sp. (for example tomatoes), Liliaceae sp., Asteraceae sp. (for example lettuce), Umbelliferae sp., Cruciferae sp., Chenopodiaceae sp., Cucurbitaceae sp. (for example cucumbers), Alliaceae sp. (for example leek, onions), Papilionaceae sp. (for example peas); major crop plants, such as Gramineae sp. (for example maize, lawn, cereals such as wheat, rye, rice, barley, oats, millet and triticale), Asteraceae sp. (for example sunflowers), Brassicaceae sp. (for example white cabbage, red cabbage, broccoli, cauliflowers, brussels sprouts, pak choi, kohlrabi, garden radish, and also oilseed rape, mustard, horseradish and cress), Fabacae sp. (for example beans, peanuts), Papilionaceae sp. (for example soya beans), Solanaceae sp. (for example potatoes), Chenopodiaceae sp. (for example sugarbeet, fodderbeet, swiss chard, beetroot); crop plants and ornamental plants in garden and forest; and also in each case genetically modified varieties of these plants. Preference is given to treating cereal plants according to the invention.


Some pathogens of fungal diseases which can be treated according to the invention may be mentioned by way of example, but not by way of limitation:


diseases caused by powdery mildew pathogens, such as, for example, Blumeria species, such as, for example, Blumeria graminis; Podosphaera species, such as, for example, Podosphacra leuco-tricha; Sphaerotheca species, such as, for example, Sphaerotheca fuliginea; Uncinula species, such as, for example, Uncinula necator, diseases caused by rust disease pathogens, such as, for example, Gymnosporangium species, such as, for example, Gymnosporangium sabinae; Hemileia species, such as, for example, Hemileia vastatrix; Phakopsora species, such as, for example, Phakopsora pachyrhizi and Phakopsora meibomiae; Puccinia species, such as, for example, Puccinia recondita or Puccinia triticina; Uromyces species, such as, for example, Uromyces appendiculatus;

diseases caused by pathogens from the group of the Oomycetes, such as, for example, Bremia species, such as, for example, Bremia lactucae; Peronospora species, such as, for example, Peronospora pisi or P. brassicae; Phytophthora species, such as, for example, Phytophthora infestans; Plasmopara species, such as, for example, Plasmopara viticola; Pseudoperonospora species, such as, for example, Pseudoperonospora humuli or Pseudoperonospora cubensis; Pythium species, such as, for example, Pythium ultimum;

leaf blotch diseases and leaf wilt diseases caused, for example, by Alternaria species, such as, for example, Alternaria solani; Cercospora species, such as, for example, Cercospora beticola; Cladiosporium species, such as, for example, Cladiosporium cucumerinum; Cochliobolus species, such as, for example, Cochliobolus sativus (conidia form: Drechslera, syn: Helminthosporium); Colletotrichum species, such as, for example, Colletotrichum lindemuthanium; Cycloconium species, such as, for example, Cycloconium oleaginum; Diaporthe species, such as, for example, Diaporthe citri; Elsinoe species, such as, for example, Elsinoe fawcettii; Gloeosporium species, such as, for example, Gloeosporium laeticolor, Glomerella species, such as, for example, Glomerella cingulata: Guignardia species, such as, for example, Guignardia bidwelli; Leptosphaeria species, such as, for example, Leptosphaeria maculans; Magnaporthe species, such as, for example, Magnaporthe grisea; Microdochium species, such as, for example, Microdochium nivale; Mycosphaerella species, such as, for example, Mycosphaerella graminicola and M. fijiensis; Phaeosphaeria species, such as, for example, Phaeosphaeria nodorum; Pyrenophora species, such as, for example, Pyrenophora teres; Ramularia species, such as, for example, Ramularia collo-cygni; Rhynchosporium species, such as, for example, Rhynchosporium secalis; Septoria species, such as, for example, Septoria apii; Typhula species, such as, for example, Typhula incamata; Venturia species, such as, for example, Venturia inaequalis;

root and stem diseases caused, for example, by Corticium species, such as, for example, Corticium graminearum; Fusarium species, such as, for example, Fusarium oxysporum; Gaeumannomyces species, such as, for example, Gaeumannomyces graminis; Rhizoctonia species, such as, for example Rhizoctonia solani; Tapesia species, such as, for example, Tapesia acuformis; Thielaviopsis species, such as, for example, Thielaviopsis basicola;

ear and panicle diseases (including corn cobs) caused, for example, by Alternaria species, such as, for example, Alternaria spp.; Aspergillus species, such as, for example, Aspergillus flavus; Cladosporium species, such as, for example, Cladosporium cladosporioides; Claviceps species, such as, for example, Claviceps purpurea; Fusarium species, such as, for example, Fusarium culmorum; Gibberella species, such as, for example, Gibberella zeae; Monographella species, such as, for example, Monographella nivalis; Septoria species, such as, for example, Septoria nodorum; diseases caused by smut fungi, such as, for example, Sphacclotheca species, such as, for example, Sphacelotheca reiliana; Tilletia species, such as, for example, Tilletia caries, T. controversa; Urocystis species, such as, for example, Urocystis occulta; Ustilago species, such as, for example, Ustilago nuda, U. nuda tritici;

Fruit rot caused, for example, by Aspergillus species, such as, for example, Aspergillus flavus; Botrytis species, such as, for example, Botrytis cinerea; Penicillium species, such as, for example, Penicillium expansum and P. purpurogenum; Sclerotinia species, such as, for example, Sclerotinia sclerotiorum;
Verticilium species, such as, for example, Verticilium alboatrum;

seed- and soil-borne rot and wilt diseases, and also diseases of seedlings, caused, for example, by Fusarium species, such as, for example, Fusarium culmorum; Phytophthora species, such as, for example, Phytophthora cactorum; Pythium species, such as, for example, Pythium ultimum; Rhizoctonia species, such as, for example, Rhizoctonia solani; Sclerotium species, such as, for example, Sclerotium rolfsii;

cancerous diseases, galls and witches' broom caused, for example, by Nectria species, such as, for example, Nectria galligena;

wilt diseases caused, for example, by Monilinia species, such as, for example, Monilinia laxa;

deformations of leaves, flowers and fruits caused, for example, by Taphrina species, such as, for example, Taphrina deformans;


degenerative diseases of woody plants caused, for example, by Esca species, such as, for example, Phaeomoniella chlamydospora and Phaeoacremonium aleophilum and Fomitiporia mediterranea; diseases of flowers and seeds caused, for example, by Botrytis species, such as, for example, Botrytis cinerea;

diseases of plant tubers caused, for example, by Rhizoctonia species, such as, for example, Rhizoctonia solani; Helminthosporium species, such as, for example, Helminthosporium solani;

diseases caused by bacterial pathogens, such as, for example, Xanthomonas species, such as, for example, Xanthomonas campestris pv. oryzae; Pseudomonas species, such as, for example, Pseudomonas syringae pv. lachrymans; Erwinia species, such as, for example, Erwinia amylovora;


Preference is given to controlling the following diseases of soybeans:


Fungal diseases on leaves, stems, pods and seeds caused, for example, by alternaria leaf spot (Alternaria spec. atrans tenuissima), anthracnose (Colletotrichum gloeosporoides dematium var. truncatum), brown spot (Septoria glycines), cercospora leaf spot and blight (Cercospora kikuchii), choanephora leaf blight (Choanephora infundibulifera trispora (Syn.)), dactuliophora leaf spot (Dactuliophora glycines), downy mildew (Peronospora manshurica), drechslera blight (Drechslera glycini), frogeye leaf spot (Cercospora sojina), leptosphaerulina leaf spot (Leptosphaerulina trifolii), phyllostica leaf spot (Phyllosticta sojaecola), pod and stem blight (Phomopsis sojae), powdery mildew (Microsphaera diffusa), pyrenochaeta leaf spot (Pyrenochaeta glycines), rhizoctonia aerial, foliage, and web blight (Rhizoctonia solani), rust (Phakopsora pachyrhizi Phakopsora meibomiae), scab (Sphaceloma glycines), stemphylium leaf blight (Stemphylium botryosum), target spot (Corynespora cassiicola).


Fungal diseases on roots and the stem base caused, for example, by black root rot (Calonectria crotalariae), charcoal rot (Macrophomina phaseolina), fusarium blight or wilt, root rot, and pod and collar rot (Fusarium oxysporum, Fusarium orthoceras, Fusarium semitectum, Fusarium equiseti), mycoleptodiscus root rot (Mycoleptodiscus terrestris), neocosmospora (Neocosmospora vasinfecta), pod and stem blight (Diaporthe phaseolorum), stem canker (Diaporthe phaseolorum var. caulivora), phytophthora rot (Phytophthora megasperma), brown stem rot (Phialophora gregata), pythium rot (Pythium aphanidcrmatum, Pythium irregulare, Pythium debaryanum, Pythium myriotylum, Pythium ultimum), rhizoctonia root rot, stem decay, and damping-off (Rhizoctonia solani), sclerotinia stem decay (Sclerotinia sclerotiorum), sclerotinia southern blight (Sclerotinia rolfsii), thielaviopsis root rot (Thielaviopsis basicola).


The active compounds according to the invention also have very good fortifying action in plants. Accordingly, they can be used for mobilizing the defenses of the plant against attack by undesirable microorganisms.


Plant-strengthening (resistance-inducing) substances are to be understood as meaning, in the present context, those substances which are capable of stimulating the defense system of plants in such a way that the treated plants, when subsequently inoculated with undesired microorganisms, develop a high degree of resistance to these microorganisms.


In the present case, undesirable microorganisms are to be understood as meaning phytopathogenic fungi and bacteria. Accordingly, the substances according to the invention can be used to protect plants for a certain period after the treatment against attack by the pathogens mentioned. The period for which protection is provided generally extends over 1 to 10 days, preferably 1 to 7 days, after the treatment of the plants with the active compounds.


The fact that the active compounds are well tolerated by plants at the concentrations required for controlling plant diseases permits the treatment of above-ground parts of plants, of propagation stock and seeds, and of the soil.


The active compounds according to the invention can be employed particularly successfully for controlling diseases in viticulture and fruit and vegetable growing such as, for example, against Botrytis, Venturia, Sphaerotheca, Podosphaera, Phythophthora and Plasmopara species.


The active compounds according to the invention are also suitable for increasing the yield of crops. In addition, they show reduced toxicity and are well tolerated by plants.


If appropriate, the compounds according to the invention can, at certain concentrations or application rates, also be used as herbicides, safeners, growth regulators or agents to improve plant properties, or as microbicidcs, for example as fungicides, antimycotics, bactericides, viricides (including agents against viroids) or as agents against MLO (Mycoplasma-like organisms) and RLO (Rickettsia-like organisms). If appropriate, they can also be used as intermediates or precursors for the synthesis of other active compounds.


If appropriate, the active compounds according to the invention can also be employed in specific concentrations and application rates as herbicides, for influencing plant growth, and for controlling animal pests. If appropriate, they can also be used as intermediates and precursors for the synthesis of further active compounds.


The active compounds according to the invention, in combination with good plant tolerance and favourable toxicity to warm-blooded animals and being tolerated well by the environment, are suitable for protecting plants and plant organs, for increasing the harvest yields, for improving the quality of the harvested material and for controlling animal pests, in particular insects, arachnids, helminths, nematodes and molluscs, which are encountered in agriculture, in horticulture, in animal husbandry, in forests, in gardens and leisure facilities, in the protection of stored products and of materials, and in the hygiene sector. They may be preferably employed as plant protection agents.


The treatment according to the invention of the plants and plant parts with the active compounds or compositions is carried out directly or by action on their surroundings, habitat or storage space using customary treatment methods, for example by dipping, spraying, atomizing, irrigating, evaporating, dusting, fogging, broadcasting, foaming, painting, spreading-on, watering (drenching), drip irrigating and, in the case of propagation material, in particular in the case of seeds, furthermore as a powder for dry seed treatment, a solution for seed treatment, a water-soluble powder for slurry treatment, by incrusting, by coating with one or more coats, etc. It is furthermore possible to apply the active compounds by the ultra-low volume method or to inject the active compound preparation or the active compound itself into the soil.


The active compounds according to the invention can also be used as defoliants, desiccants, haulm killers and, especially, as weedkillers. Weeds in the broadest sense are understood to mean all plants which grow in locations where they are undesired. Whether the substances according to the invention act as total or selective herbicides depends essentially on the amount used.


Moreover, in the protection of materials, the active compounds or compositions according to the invention can be employed for protecting industrial materials against attack and destruction by unwanted microorganisms, such as, for example, fungi.


Industrial materials in the present context are understood as meaning non-living materials which have been prepared for use in industry. For example, industrial materials which are intended to be protected by active compounds according to the invention from microbial change or destruction can be adhesives, sizes, paper and board, textiles, leather, wood, paints and plastic articles, cooling lubricants and other materials which can be infected with, or destroyed by, microorganisms. Parts of production plants, for example cooling-water circuits, which may be impaired by the proliferation of microorganisms may also be mentioned within the scope of the materials to be protected. Industrial materials which may be mentioned within the scope of the present invention are preferably adhesives, sizes, paper and board, leather, wood, paints, cooling lubricants and heat-transfer liquids particularly preferably wood. The active compounds or compositions according to the invention may prevent disadvantageous effects, such as rotting, decay, discoloration, decoloration or formation of mold.


The method according to the invention for controlling unwanted fungi can also be employed for protecting storage goods. Here, storage goods are to be understood as meaning natural substances of vegetable or animal origin or processed products thereof of natural origin, for which long-term protection is desired. Storage goods of vegetable origin, such as, for example, plants or plant parts, such as stems, leaves, tubers, seeds, fruits, grains, can be protected freshly harvested or after processing by (pre)drying, moistening, comminuting, grinding, pressing or roasting. Storage goods also include timber, both unprocessed, such as construction timber, electricity poles and barriers, or in the form of finished products, such as furniture. Storage goods of animal origin are, for example, hides, leather, furs and hairs. The active compounds according to the invention may prevent disadvantageous effects, such as rotting, decay, discoloration, decoloration or formation of mold.


Microorganisms capable of degrading or changing the industrial materials which may be mentioned are, for example, bacteria, fungi, yeasts, algae and slime organisms. The active compounds according to the invention preferably act against fungi, in particular molds, wood-discoloring and wood-destroying fungi (Basidiomycetes), and against slime organisms and algae. Microorganisms of the following genera may be mentioned as examples: Alternaria, such as Alternaria tenuis; Aspergillus, such as Aspergillus niger, Chaetomium, such as Chaetomium globosum; Coniophora, such as Coniophora puetana; Lentinus, such as Lentinus tigrinus; Penicillium, such as Penicillium glaucum; Polyporus, such as Polyporus versicolor, Aureobasidium, such as Aureobasidium pullulans; Sclerophoma, such as Sclerophoma pityophila; Trichoderma, such as Trichoderma viride; Escherichia, such as Escherichia coli; Pseudomonas, such as Pseudomonas aeruginosa; Staphylococcus, such as Staphylococcus aureus.


The present invention furthermore relates to a composition for controlling unwanted microorganisms, which composition comprises at least one of the thiazole-4-carboxylic ester or thiocsters according to the invention. These are preferably fungicidal composition which comprise agriculturally suitable auxiliaries, solvents, carriers, surfactants or extenders.


According to the invention, a carrier is a natural or synthetic organic or inorganic substance with which the active compounds are mixed or bonded for better applicability, in particular for application to plants or plant parts or seed. The carrier, which may be solid or liquid, is generally inert and should be suitable for use in agriculture.


As solid carriers these are suitable: for example ammonium salts and ground natural minerals such as kaolins, clays, talc, chalk, quartz, attapulgite, niontmorillonite or diatomaceous earth, and ground synthetic materials such as highly-disperse silica, alumina and silicates; suitable solid carriers for granules are: for example, crushed and fractionated natural rocks such as calcite, marble, pumice, sepiolite and dolomite, and also synthetic granules of inorganic and organic meals, and granules of organic material such as paper, sawdust, coconut shells, maize cobs and tobacco stalks; suitable emulsifiers and/or foam-formers are: for example, nonionic and anionic emulsifiers, such as polyoxyethylene fatty acid esters, polyoxyethylene fatty alcohol ethers, for example alkylaryl polyglycol ethers, alkylsulfonates, alkyl sulphates, arylsulfonates and also protein hydrolysates; suitable dispersants are nonionic and/or ionic substances, for example from the classes of the alcohol-POE and/or -POP ethers, acid and/or POP POE esters, alkylaryl and/or POP POE ethers, fat and/or POP POE adducts, POE- and/or POP-polyol derivatives, POE- and/or POP-sorbitan or -sugar adducts, alkyl or aryl sulphates, alkyl- or arylsulphonates and alkyl or aryl phosphates or the corresponding PO-ether adducts. Furthermore, suitable oligo- or polymers, for example those derived from vinylic monomers, from acrylic acid, from EO and/or PO alone or in combination with, for example, (poly)alcohols or (poly)amines. It is also possible to employ lignin and its sulphonic acid derivatives, unmodified and modified celluloses, aromatic and/or aliphatic sulphonic acids and their adducts with formaldehyde.


The active compounds can be converted into the customary formulations, such as solutions, emulsions, wettable powders, water- and oil-based suspensions, powders, dusts, pastes, soluble powders, soluble granules, granules for broadcasting, suspoemulsion concentrates, natural compounds impregnated with active compound, synthetic substances impregnated with active compound, fertilizers and also microencapsulations in polymeric substances.


The active compounds can be applied as such, in the form of their formulations or the use forms prepared therefrom, such as ready-to-use solutions, emulsions, water- or oil-based suspensions, powders, wettable powders, pastes, soluble powders, dusts, soluble granules, granules for broadcasting, suspoemulsion concentrates, natural products impregnated with active compound, synthetic materials impregnated with active compound, fertilizers and also microencapsulations in polymeric substances. Application is carried out in a customary manner, for example by watering, spraying, atomizing, broadcasting, dusting, foaming, spreading, etc. It is furthermore possible to apply the active compounds by the ultra-low volume method, or to inject the active compound preparation or the active compound itself into the soil. It is also possible to treat the seeds of the plants.


The formulations mentioned can be prepared in a manner known per se, for example by mixing the active compounds with at least one customary extender, solvent or diluent, emulsifier, dispersant, and/or binder or fixative, wetting agent, water-repellent, if appropriate desiccants and UV stabilizers and, if appropriate, dyes and pigments, defoamers, preservatives, secondary thickeners, adhesives, gibberellins and also further processing auxiliaries.


The compositions according to the invention include not only formulations which are already ready for use and can be applied with a suitable apparatus to the plant or the seed, but also commercial concentrates which have to be diluted with water prior to use.


The active compounds according to the invention can be present as such or in their (commercial) formulations and in the use forms prepared from these formulations as a mixture with other (known) active compounds, such as insecticides, attractants, sterilants, bactericides, acaricides, nematicides, fungicides, growth regulators, herbicides, fertilizers, safeners and/or semiochemicals.


Suitable for use as auxiliaries are substances which are suitable for imparting to the composition itself and/or to preparations derived therefrom (for example spray liquors, seed dressings) particular properties such as certain technical properties and/or also particular biological properties. Typical suitable auxiliaries are: extenders, solvents and carriers.


Suitable extenders are, for example, water, polar and nonpolar organic chemical liquids, for example from the classes of the aromatic and non-aromatic hydrocarbons (such as paraffins, alkylbenzenes, alkylnaphthalenes, chlorobenzenes), the alcohols and polyols (which, if appropriate, may also be substituted, etherified and/or esterified), the ketones (such as acetone, cyclohexanone), esters (including fats and oils) and (poly)ethers, the unsubstituted and substituted amines, amides, lactams (such as N-alkylpyrrolidones) and lactones, the sulphones and sulphoxides (such as dimethyl sulphoxide).


Liquefied gaseous extenders or carriers are to be understood as meaning liquids which are gaseous at standard temperature and under atmospheric pressure, fix example aerosol propellants such as halogenated hydrocarbons, or else butane, propane, nitrogen and carbon dioxide.


Tackifiers such as carboxymethylcellulose and natural and synthetic polymers in the form of powders, granules or latices, such as gum arabic, polyvinyl alcohol and polyvinyl acetate, or else natural phospholipids such as cephalins and lecithins and synthetic phospholipids can be used in the formulations. Other possible additives are mineral and vegetable oils.


If the extender used is water, it is also possible to employ, for example, organic solvents as auxiliary solvents. Essentially, suitable liquid solvents are: aromatics such as xylene, toluene or alkylnaphthalenes, chlorinated aromatics or chlorinated aliphatic hydrocarbons such as chlorobenzenes, chloroethylenes or methylene chloride, aliphatic hydrocarbons such as cyclohexane or paraffins, for example petroleum fractions, alcohols such as butanol or glycol and their ethers and esters, ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone or cyclohexanone, strongly polar solvents such as dimethylformamide or dimethyl sulphoxide, or else water.


The compositions according to the invention may comprise additional further components, such as, for example, surfactants. Suitable surfactants are emulsifiers and/or foam formers, dispersants or wetting agents having ionic or nonionic properties, or mixtures of these surfactants. Examples of these are salts of polyacrylic acid, salts of lignosulphonic acid, salts of phenolsulphonic acid or naphthalenesulphonic acid, polycondensates of ethylene oxide with fatty alcohols or with fatty acids or with fatty amines, substituted phenols (preferably alkylphenols or arylphenols), salts of sulphosuccinic esters, taurine derivatives (preferably alkyl taurates), phosphoric esters of polyethoxylated alcohols or phenols, fatty esters of polyols, and derivatives of the compounds containing sulphates, sulphonates and phosphates, for example alkylaryl polyglycol ethers, alkylsulphonates, alkyl sulphates, arylsulphonates, protein hydrolysates, lignosulphite waste liquors and methylcellulose. The presence of a surfactant is required if one of the active compounds and/or one of the inert carriers is insoluble in water and when the application takes place in water. The proportion of surfactants is between 5 and 40 per cent by weight of the composition according to the invention.


It is possible to use colorants such as inorganic pigments, for example iron oxide, titanium oxide and Prussian Blue, and organic dyestuffs such as alizarin dyestuffs, azo dyestuffs and metal phthalocyanine dyestuffs, and trace nutrients such as salts of iron, manganese, boron, copper, cobalt, molybdenum and zinc.


Other possible additives are perfumes, mineral or vegetable, optionally modified oils, waxes and nutrients (including trace nutrients), such as salts of iron, manganese, boron, copper, cobalt, molybdenum and zinc.


Stabilizers, such as low-temperature stabilizers, preservatives, antioxidants, light stabilizers or other agents which improve chemical and/or physical stability may also be present.


If appropriate, other additional components may also be present, for example protective colloids, binders, adhesives, thickeners, thixotropic substances, penetrants, stabilizers, sequestering agents, complex formers. In general, the active compounds can be combined with any solid or liquid additive customarily used for formulation purposes.


The formulations generally comprise between 0.05 and 99% by weight. 0.01 and 98% by weight, preferably between 0.1 and 95% by weight, particularly preferably between 0.5 and 90% of active compound, very particularly preferably between 10 and 70% by weight. The formulations described above can be used in a method according to the invention for controlling unwanted microorganisms, where the thiazole-4-carboxylic esters and thioestcrs according to the invention are applied to the microorganisms and/or to their habitat.


The active compounds according to the invention can be used as such or in their formulations, also in a mixture with known fungicides, bactericides, acaricides, nematicides or insecticides, to broaden, for example, the activity spectrum or to prevent development of resistance.


Suitable mixing partners are, for example, known fungicides, insecticides, acaricides, nematicides or else bactericides (see also Pesticide Manual, 13th ed.).


A mixture with other known active compounds, such as herbicides, or with fertilizers and growth regulators, safeners and/or semiochemicals is also possible.


The compounds are employed in a customary manner appropriate for the use forms.


The invention furthermore includes a method for treating seed.


A further aspect of the present invention relates in particular to seed treated with at least one of the thiazole-4-carboxylic esters or thioesters according to the invention. The seed according to the invention is used in methods for protecting seed against animal pests and/or phytopathogenic harmful fungi. In these methods, seed treated with at least one active compound according to the invention is employed.


The active compounds or compositions according to the invention are also suitable for treating seed. A large part of the damage to crop plants caused by harmful organisms is triggered by the infection of the seed during storage or after sowing both during and after germination of the plant.


This phase is particularly critical since the roots and shoots of the growing plant are particularly sensitive, and even small damage may result in the death of the plant. Accordingly, there is great interest in protecting the seed and the germinating plant by using appropriate compositions.


The control of animal pests and/or phytopatlogenic harmful fungi by tr-eating the seed of plants has been known for a long time and is the subject of continuous improvements. However, the treatment of seed entails a series of problems which cannot always be solved in a satisfactory manner. Thus, it is desirable to develop methods for protecting the seed and the germinating plant which dispense with, or at least reduce considerably, the additional application of crop protection agents after planting or after emergence of the plants. It is furthermore desirable to optimize the amount of active compound employed in such a way as to provide optimum protection for the seed and the germinating plant from attack by phytopathogenic fungi, but without damaging the plant itself by the active compound employed. In particular, methods for the treatment of seed should also take into consideration the intrinsic fungicidal properties of transgenic plants in order to achieve optimum protection of the seed and the germinating plant with a minimum of crop protection agents being employed.


Accordingly, the present invention also relates to a method for protecting seed and germinating plants against attack by animal pests and/or phytopathogenic harmful fungi by treating the seed with a composition according to the invention. The invention also relates to the use of the compositions according to the invention for treating seed for protecting the seed and the germinating plant against phytopathogenic fungi. Furthermore, the invention relates to seed treated with a composition according to the invention for protection against phytopathogenic fungi.


The control of animal pests and/or phytopathogenic harmful fungi which damage plants post-emergence is carried out primarily by treating the soil and the above-ground parts of plants with plant protection agents. Owing to the concerns regarding a possible impact of the plant protection agent on the environment and the health of humans and animals, there are efforts to reduce the amount of active compounds applied.


One of the advantages of the present invention is that, because of the particular systemic properties of the compositions according to the invention, treatment of the seed with these compositions not only protects the seed itself, but also the resulting plants after emergence, from animal pests and/or phytopathogenic harmful fungi. In this manner, the immediate treatment of the crop at the time of sowing or shortly thereafter can be dispensed with.


It is also considered to be advantageous that the active compounds or compositions according to the invention can be used irn particular also for transgenic seed where the plant growing from this seed is capable of expressing a protein which acts against pests. By treating such seed with the active compounds or compositions according to the invention, even by the expression of the, for example, insecticidal protein, certain pests may be controlled. Surprisingly, a further synergistic effect may be observed here, which additionally increases the effectiveness of the protection against attack by pests.


The compositions according to the invention are suitable for protecting seed of any plant variety which is employed in agriculture, in the greenhouse, in forests or in horticulture. In particular, this takes the form of seed of cereals (such as wheat, barley, rye, millet and oats), maize, cotton, soybeans, rice, potatoes, sunflowers, beans, coffee, beets (for example sugarbeets and fodder beets), peanuts, vegetables (such as such as tomatoes, cucumbers, onions and lettuce), lawn and ornamental plants. The treatment of the seed of cereals (such as wheat, barley, rye and oats), maize and rice is of particular importance.


As also described further below, the treatment of transgenic seed with the active compounds or compositions according to the invention is of particular importance. This refers to the seed of plants containing at least one heterologous gene which allows the expression of a polypeptide or protein having insecticidal properties. The heterologous gene in transgenic seed can originate, for example, from microorganisms of the species Bacillus, Rhizobium, Pseudomonas, Serratia, Trichoderma, Clavibacter, Glomus or Gliocladium. Preferably, this heterologous gene is from Bacillus sp., the gene product having activity against the European corn borer and/or the Western corn rootworm. Particularly preferably, the heterologous gene originates from Bacillus thuringiensis.


Within the context of the present invention, the composition according to the invention is applied to the seed either alone or in suitable formulation. Preferably, the seed is treated in a state in which it is stable enough to avoid damage during treatment. In general, the seed may be treated at any point in time between harvest and sowing. The seed usually used has been separated from the plant and freed from cobs, shells, stalks, coats, hairs or the flesh of the fruits. Thus, it is possible to use, for example, seed which has been harvested, cleaned and dried to a moisture content of less than 15% by weight. Alternatively, it is also possible to use seed which, after drying, has been treated, for example, with water and then dried again.


When treating the seed, care must generally be taken that the amount of the composition according to the invention applied to the seed and/or the amount of further additives is chosen in such a way that the germination of the seed is not adversely affected, or that the resulting plant is not damaged. This must be borne in mind in particular in the case of active compounds which can have phytotoxic effects at certain application rates.


The compositions according to the invention can be applied directly, i.e. without any other components and undiluted. In general, it is preferred to apply the compositions to the seed in the form of a suitable formulation. Suitable formulations and methods for treating seed are known to the person skilled in the art and are described, for example, in the following documents: U.S. Pat. No. 4,272,417 A, U.S. Pat. No. 4,245,432 A, U.S. Pat. No. 4,808,430 A, U.S. Pat. No. 5,876,739 A, US 2003/0176428 A1, WO 2002/080675 A1, WO 2002/028186 A2.


The active compounds which can be used in accordance with the invention can be converted into the customary seed-dressing formulations, such as solutions, emulsions, suspensions, powders, foams, slurries or other coating compositions for seed, and also ULV formulations These formulations are prepared in a known manner, by mixing the active compounds or active compound combinations with customary additives such as, for example, customary extenders and also solvents or diluents, colorants, wetting agents, dispersants, emulsifiers, antifoams, preservatives, secondary thickeners, adhesives, gibberellins and also water.


Colorants which may be present in the seed-dressing formulations which can be used in accordance with the invention are all colorants which are customary for such purposes. In this context, not only pigments, which are sparingly soluble in water, but also dyes, which are soluble in water, may be used. Examples which may be mentioned are the colorants known by the names Rhodamin B, C.I. Pigment Red 112 and C.I. Solvent Red 1.


Suitable wetting agents which may be present in the seed-dressing formulations which can be used in accordance with the invention are all substances which promote wetting and which are conventionally used for the formulation of agrochemical active compounds. Preference is given to using alkylnaphthalenesulphonates, such as diisopropyl- or diisobutylnaphthalenesulphonates.


Suitable dispersants and/or emulsifiers which may be present in the seed-dressing formulations which can be used in accordance with the invention are all nonionic, anionic and cationic dispersants conventionally used for the formulation of agrochemical active compounds. Preference is given to using nonionic or anionic dispersants or mixtures of nonionic or anionic dispersants. Suitable nonionic dispersants which may be mentioned are, in particular, ethylene oxide/propylene oxide block polymers, alkylphenol polyglycol ethers and tristryrylphenol polyglycol ether, and their phosphated or sulphated derivatives. Suitable anionic dispersants are, in particular, lignlosulphonates, polyacrylic acid salts and arylsulphonate/formaldehyde condensates.


Antifoams which may be present in the seed-dressing formulations which can be used in accordance with the invention are all foam-inhibiting substances conventionally used for the formulation of agrochemical active compounds. Silicone antifoams and magnesium stearate can preferably be used.


Preservatives which may be present in the seed-dressing formulations which can be used in accordance with the invention are all substances which can be employed for such purposes in agrochemical compositions. Dichlorophene and benzyl alcohol hemiformal may be mentioned by way of example.


Secondary thickeners which may be present in the seed-dressing formulations which can be used in accordance with the invention are all substances which can be employed for such purposes in agrochemical compositions. Cellulose derivatives, acrylic acid derivatives, xanthan, modified clays and finely divided silica are preferred.


Adhesives which may be present in the seed-dressing formulations which can be used in accordance with the invention are all customary binders which can be employed in seed-dressing products. Polyvinylpyrrolidone, polyvinyl acetate, polyvinyl alcohol and tylose may be mentioned as being preferred.


Gibberellins which can be present in the seed-dressing formulations which can be used in accordance with the invention are preferably the gibberellins A1, A3 (=gibberellic acid), A4 and A7; gibberellic acid is especially preferably used. The gibberellins are known (cf. R. Wegler “Chemie der Pflanzenschutz-und Schdlingsbekämpfungsmittel” [Chemistry of plant protection agents and pesticides], vol. 2, Springer Verlag, 1970, p. 401-412).


The seed-dressing formulations which can be used in accordance with the invention can be employed for the treatment of a wide range of seed, either directly or after previously having been diluted with water. Thus, the concentrates or the preparations obtainable therefrom by dilution with water may be used to dress the seed of cereals, such as wheat, barley, rye, oats, and triticale, and also the seed of maize, rice, oilseed rape, peas, beans, cotton, sunflowers, and beets, or else vegetable seed of any of a very wide variety of kinds. The seed-dressing formulations which can be used according to the invention or their dilute preparations may also be used to dress seed of transgenic plants. In this context, additional synergistic effects may also occur in cooperation with the substances formed by expression.


All mixers which can conventionally be employed for the seed-dressing operation are suitable for treating seed with the seed-dressing formulations which can be used in accordance with the invention or with the preparations prepared therefrom by addition of water. Specifically, a procedure is followed during the seed-dressing operation in which the seed is placed into a mixer, the specific desired amount of seed-dressing formulations, either as such or after previously having been diluted with water, is added, and everything is mixed until the formulation is distributed uniformly on the seed. If appropriate, this is followed by a drying process.


The application rate of the seed dressing formulations which can be used according to the invention may be varied within a relatively wide range. It depends on the respective content of the active compounds in the formulations and on the seed. The active compound combination application rates are generally between 0.001 and 50 g per kilogram of seed, preferably between 0.01 and 15 g per kilogram of seed.


In addition, the compounds of the formula (I) according to the invention also have very good antimycotic activity. They have a very broad antimycotic activity spectrum in particular against dermatophytes and yeasts, molds and diphasic fungi, (for example against Candida species, such as Candida albicans, Candida glabrata), and Epidermophyton floccosum, Aspergillus species, such as Aspergillus niger and Aspergillus fumigatus, Trichophyton species, such as Trichophyton mentagrophytes, Microsporon species such as Microsporon canis and audouinii. The list of these fungi by no means limits the mycotic spectrum covered, but is only for illustration.


Accordingly, the active compounds of the formula (I) according to the invention can be used both in medical and in non-medical applications.


The active compounds can be used as such, in the form of their formulations or the use forms prepared therefrom, such as ready-to-use solutions, suspensions, wettable powders, pastes, soluble powders, dusts and granules. Application is carried out in a customary manner, for example by watering, spraying, atomizing, broadcasting, dusting, foaming, spreading, etc. It is furthermore possible to apply the active compounds by the ultra-low volume method, or to inject the active compound preparation or the active compound itself into the soil. It is also possible to treat the seed of the plants.


When using the active compounds according to the invention as fungicides, the application rates can be varied within a relatively wide range, depending on the kind of application. The application rate of the active compounds according to the invention is

    • when treating plant parts, for example leaves: from 0,1 to 10 000 g/ha, preferably from 10 to 1 000 g/ha, particularly preferably from 50 to 300 g/ha (when the application is carried out by watering or dripping, it is even possible to reduce the application rate, especially when inert substrates such as rock wool or perlite are used);
    • when treating seed: from 2 to 200 g per 100 kg of seed, preferably from 3 to 150 g per 100 kg of seed, particularly preferably from 2.5 to 25 g per 100 kg of seed, very particularly preferably from 2.5 to 12.5 g per 100 kg of seed;
    • when treating the soil: from 0.1 to 10 000 g/ha, preferably from 1 to 5000 g/ha.


These application rates are mentioned only by way of example and are not limiting in the sense of the invention.


With respect to possible additional partners for mixing, reference is made to the insecticides and fungicides mentioned above.


The compounds according to the invention can at the same time be employed for protecting objects which come into contact with saltwater or brackish water, such as hulls, screens, nets, buildings, moorings and signaling systems, against fouling.


Furthermore, the compounds according to the invention can be used alone or in combinations with other active compounds as antifouling compositions.


The method of treatment according to the invention can be used in the treatment of genetically modified organisms (GMOs), e.g. plants or seeds. Genetically modified plants (or transgenic plants) are plants in which a heterologous gene has been stably integrated into the genome. The expression “heterologous gene” essentially means a gene which is provided or assembled outside the plant and when introduced in the nuclear, chloroplastic or hypochondrial genome gives the transformed plant new or improved agronomic or other properties by expressing a protein or polypeptide of interest or by downregulating or silencing other gene(s) which are present in the plant (using for example antisense technology, cosuppression technology or RNAi technology [RNA interference]). A heterologous gene that is located in the genome is also called a transgene. A transgene that is defined by its particular location in the plant genome is called a transformation or transgenic event.


Depending on the plant species or plant varieties, their location and growth conditions (soils, climate, vegetation period, diet), the treatment according to the invention may also result in superadditive (“synergistic”) effects. Possible are thus, for example, the following effects which exceed the effects which were to be expected: reduced application rates and/or a widening of the activity spectrum and/or an increase in the activity of the active compounds and compositions which can be used according to the invention, better plant growth, increased tolerance to high or low temperatures, increased tolerance to drought or to water or soil salt content, increased flowering performance, easier harvesting, accelerated maturation, higher harvest yields, bigger fruits, larger plant height, greener leaf color, earlier flowering, higher quality and/or a higher nutritional value of the harvested products, higher sugar concentration within the fruits, better storage stability and/or processability of the harvested products.


At certain application rates, the active compound combinations according to the invention may also have a strengthening effect in plants. Accordingly, they are suitable for mobilizing the defense system of the plant against attack by unwanted phytopathogenic fungi and/or microorganisms and/or viruses. This may, if appropriate, be one of the reasons for the enhanced activity of the combinations according to the invention, for example against fungi. Plant-strengthening (resistance-inducing) substances are to be understood as meaning, in the present context, also those substances or combinations of substances which are capable of stimulating the defence system of plants in such a way that, when subsequently inoculated with unwanted phytopathogenic fungi and/or microorganisms and/or viruses, the treated plants display a substantial degree of resistance to there unwanted phytopathogenic fungi and/or microorganisms and/or viruses. In the present case, unwanted phytopathogenic fungi and/or microorganisms and/or viruses are understood as meaning phytopathogenic fungi, bacteria and viruses. Thus, the substances according to the invention can be employed for protecting plants against attack by the abovementioned pathogens within a certain period of time after the treatment. The period within which protection is brought about generally extends from 1 to 10 days, preferably 1 to 7 days, after the treatment of the plants with the active compounds.


Plants and plant varieties which are preferably treated according to the invention include all plants which have genetic material which imparts particularly advantageous, useful traits to these plants (whether obtained by breeding and/or biotechnological means).


Plants and plant varieties which are also preferably treated according to the invention are resistant against one or more biotic stresses, i.e. said plants have a better defence against animal and microbial pests, such as against nematodes, insects, mites, phytopathogcnic fungi, bacteria, viruses and/or viroids.


Plants and plant varieties which may also be treated according to the invention are those plants which are resistant to one or more abiotic stress factors. Abiotic stress conditions may include, for example, drought, cold temperature exposure, heat exposure, osmotic stress, waterlogging, increased soil salinity, increased exposure to minerals, exposure to ozone, exposure to strong light. limited availability of nitrogen nutrients, limited availability of phosphorus nutrients or shade avoidance.


Plants and plant varieties which may also be treated according to the invention are those plants characterized by enhanced yield characteristics. Enhanced yield in said plants can be the result of, for example, improved plant physiology, growth and development, such as water use efficiency, water retention efficiency, improved nitrogen use, enhanced carbon assimilation, improved photosynthesis, increased germination efficiency and accelerated maturation. Yield can furthermore be affected by improved plant architecture (under stress and non-stress conditions), including early flowering, flowering control for hybrid seed production, seedling vigour, plant size, internode number and distance, root growth, seed size, fruit size, pod size, pod or ear number, seed number per pod or ear, seed mass, enhanced seed filling, reduced seed dispersal, reduced pod dehiscence and lodging resistance. Further yield traits include seed composition, such as carbohydrate content, protein content, oil content and composition, nutritional value, reduction in anti-nutritional compounds, improved processability and better storage stability.


Plants that may be treated according to the invention are hybrid plants that already express the characteristics of heterosis, or hybrid vigour, which results in generally higher yield, vigour, health and resistance towards biotic and abiotic stress factors. Such plants are typically made by crossing an inbred male-sterile parent line (the female parent) with another inbred male-fertile parent line (the male parent). Hybrid seed is typically harvested from the male sterile plants and sold to growers. Male sterile plants can sometimes (e.g. in corn) be produced by detasseling (i.e. the mechanical removal of the male reproductive organs or male flowers) but, more typically, male sterility is the result of genetic determinants in the plant genome. In that case, and especially when seed is the desired product to be harvested from the hybrid plants, it is typically useful to ensure that male fertility in the hybrid plants, which contain the genetic determinants responsible for male sterility, is fully restored. This can be accomplished by ensuring that the male parents have appropriate fertility restorer genes which are capable of restoring the male fertility in hybrid plants that contain the genetic determinants responsible for male sterility. Genetic determinants for male sterility may be located in the cytoplasm. Examples of cytoplasmic male sterility (CMS) were for instance described for Brassica species. However, genetic determinants for male sterility can also be located in the nuclear genome. Male sterile plants can also be obtained by plant biotechnology methods such as genetic engineering. A particularly useful means of obtaining male sterile plants is described in WO 89/10396 in which, for example, a ribonuclease such as barnase is selectively expressed in the tapetum cells in the stamens. Fertility can then be restored by expression in the tapetum cells of a ribonuclease inhibitor such as barstar.


Plants or plant varieties (obtained by plant biotechnology methods such as genetic engineering) which may be treated according to the invention are herbicide-tolerant plants, i.e. plants made tolerant to one or more given herbicides. Such plants can be obtained either by genetic transformation, or by selection of plants containing a mutation imparting such herbicide tolerance.


Herbicide-tolerant plants are for example glyphosate-tolerant plants, i.e. plants made tolerant to the herbicide glyphosate or salts thereof. For example, glyphosate-tolerant plants can be obtained by transforming the plant with a gene encoding the enzyme 5-enolpyruvylshikimate-3-phosphate synthase (EPSPS). Examples of such EPSPS genes are the AroA gene (mutant CT7) of the bacterium Salmonella typhimurium, the CP4 gene of the bacterium Agrobacterium sp., the genes encoding a petunia EPSPS, a tomato EPSPS, or an Eleusine EPSPS. It can also be a mutated EPSPS. Glyphosate-tolerant plants can also be obtained by expressing a gene that encodes a glyphosate oxidoreductase enzyme. Glyphosate-tolerant plants can also be obtained by expressing a gene that encodes a glyphosate acetyl transferase enzyme. Glyphosate-tolerant plants can also be obtained by selecting plants containing naturally-occurring mutations of the above-mentioned genes.


Other herbicide-resistant plants are for example plants which have been made tolerant to herbicides inhibiting the enzyme glutamine synthase, such as bialaphos, phosphinothricin or glufosinate. Such plants can be obtained by expressing an enzyme detoxifying the herbicide or a mutant glutamine synthase enzyme that is resistant to inhibition. One such efficient detoxifying enzyme is, for example, an enzyme encoding a phosphinothricin acetyltransferase (such as the bar or pat protein from Streptomyces species). Plants expressing an exogenous phosphinothricin acetyltransferase have been described.


Further herbicide-tolerant plants are also plants that are made tolerant to the herbicides inhibiting the enzyme hydroxyphenylpyruvatedioxygenase (HPPD). Hydroxyphenylpyruvatedioxygenases are enzymes that catalyse the reaction in which para-hydroxyphenylpyruvate (HPP) is transformed into homogentisate. Plants tolerant to HPPD-inhibitors can be transformed with a gene encoding a naturally-occurring resistant HPPD enzyme, or a gene encoding a mutated HPPD enzyme. Tolerance to HPPD-inhibitors can also be obtained by transforming plants with genes encoding certain enzymes enabling the formation of homogentisate despite the inhibition of the native HPPD enzyme by the HPPD-inhibitor. Tolerance of plants to HPPD inhibitors can also be improved by transforming plants with a gene encoding an enzyme prephenate dehydrogenase in addition to a gene encoding an HPPD-tolerant enzyme.


Further herbicide-resistant plants are plants that have been made tolerant to acetolactate synthase (ALS) inhibitors. Known ALS inhibitors include, for example, sulphonylurea, imidazolinone, triazolopyrimidines, pyrimidinyloxy(thio)benzoates, and/or sulphonylaminocarbonyltriazolinone herbicides. Different mutations in the ALS enzyme (also known as acetohydroxyacid synthase, AHAS) are known to confer tolerance to different herbicides and groups of herbicides. The production of sulphonylurea-tolerant plants and imidazolinone-tolerant plants has been described in the international publication WO 1996/033270. Further sulphonylurea- and imidazolinone-tolerant plants have also been described, for example in WO 2007/024782.


Other plants tolerant to imidazolinone and/or sulphonylurea can be obtained by induced mutagenesis, by selection in cell cultures in the presence of the herbicide or by mutation breeding.


Plants or plant varieties (obtained by plant biotechnology methods such as genetic engineering) which may also be treated according to the invention are insect-resistant transgenic plants, i.e. plants made resistant to attack by certain target insects. Such plants can be obtained by genetic transformation, or by selection of plants containing a mutation imparting such insect resistance.


In the present context, the term “insect-resistant transgenic plant” includes any plant containing at least one transgene comprising a coding sequence encoding:

  • 1) an insecticidal crystal protein from Bacillus thuringiensis or an insecticidal portion thereof, such as the insecticidal crystal proteins listed online at: http://www.lifesci.sussex.ac.uk/Home/Neil_Crickmore/Bt/, or insecticidal portions thereof, for example proteins of the Cry protein classes Cry1Ab, Cry1Ac, Cry1F, Cry2Ab, Cry3Ae or Cry3Bb or insecticidal portions thereof; or
  • 2) a crystal protein from Bacillus thuringiensis or a portion thereof which is insecticidal in the presence of a second other crystal protein from Bacillus thuringiensis or a portion thereof, such as the binary toxin made up of the Cy34 and Cy35 crystal proteins; or
  • 3) a hybrid insecticidal protein comprising parts of two different insecticidal crystal proteins from Bacillus thuringiensis, such as a hybrid of the proteins of 1) above or a hybrid of the proteins of 2) above, for example the Cry1A.105 protein produced by maize event MON98034 (WO 2007/027777): or
  • 4) a protein of any one of 1) to 3) above wherein some, particularly 1 to 10, amino acids have been replaced by another amino acid to obtain a higher insecticidal activity to a target insect species, and/or to expand the range of target insect species affected, and/or because of changes induced in the encoding DNA during cloning or transformation, such as the Cry3Bbl protein in maize events MON863 or MON88017, or the Cry3A protein in maize event MIR604;
  • 5) an insecticidal secreted protein from Bacillus thuringiensis or Bacillus cereus, or an insecticidal portion thereof, such as the vegetative insecticidal proteins (VIP) listed at: http://www.lifesci.sussex.ac.uk/home/Neil_Crickmore/Bt/vip.html, for example proteins from the VIP3Aa protein class; or
  • 6) a secreted protein from Bacillus thuringiensis or Bacillus cereus which is insecticidal in the presence of a second secreted protein from Bacillus thuringiensis or B. cereus, such as the binary toxin made up of the VIP1A and VIP2A proteins.
  • 7) a hybrid insecticidal protein comprising parts from different secreted proteins from Bacillus thuringiensis or Bacillus cereus, such as a hybrid of the proteins in 1) above or a hybrid of the proteins in 2) above; or
  • 8) a protein of any one of 1) to 3) above wherein some, particularly 1 to 10, amino acids have been replaced by another amino acid to obtain a higher insecticidal activity to a target insect species, and/or to expand the range of target insect species affected, and/or because of changes induced in the encoding DNA during cloning or transformation (while still encoding an insecticidal protein), such as the VIP3Aa protein in cotton event COT102.


Of course, insect-resistant transgenic plants, as used herein, also include any plant comprising a combination of genes encoding the proteins of any one of the above classes 1 to 8. In one embodiment, an insect-resistant plant contains more than one transgene encoding a protein of any one of the above classes 1 to 8, to expand the range of target insect species affected or to delay insect resistance development to the plants, by using different proteins insecticidal to the same target insect species but having a different mode of action, such as binding to different receptor binding sites in the insect.


Plants or plant varieties (obtained by plant biotechnology methods such as genetic engineering) which may also be treated according to the invention are tolerant to abiotic stress factors. Such plants can be obtained by genetic transformation, or by selection of plants containing a mutation imparting such stress resistance. Particularly useful stress-tolerant plants include the following:

    • a. plants which contain a transgene capable of reducing the expression and/or the activity of the poly(ADP-ribose)polymerase (PARP) gene in the plant cells or plants.
    • b. plants which contain a stress tolerance-enhancing transgcne capable of reducing the expression and/or the activity of the PARG encoding genes of the plants or plants cells;
    • c. plants which contain a stress tolerance-enhancing transgene coding for a plant-functional enzyme of the nicotinamide adenine dinucleotide salvage biosynthesis pathway, including nicotinamidase, nicotinate phosphoribosyltransferase, nicotinic acid mononucleotide adenyl transferase, nicotinamide adenine dinucleotide synthetase or nicotinamide phosphoribosyltransferase.


Plants or plant varieties (obtained by plant biotechnology methods such as genetic engineering) which may also be treated according to the invention show altered quantity, quality and/or storage-stability of the harvested product and/or altered properties of specific ingredients of the harvested product such as, for example:

  • 1) Transgenic plants which synthesize a modified starch which is altered with respect to its chemophysical traits, in particular the amylose content or the amylose/amylopectin ratio, the degree of branching, the average chain length, the distribution of the side chains, the viscosity behavior, the gel resistance, the grain size and/or grain morphology of the starch in comparison to the synthesized starch in wild-type plant cells or plants, such that this modified starch is better suited for certain applications.
  • 2) Transgenic plants which synthesize non-starch carbohydrate polymers or which synthesize non-starch carbohydrate polymers with altered properties in comparison to wild type plants without genetic modification. Examples are plants which produce polyfructose, especially of the inulin and levan type, plants which produce alpha-1,4-glucans, plants which produce alpha-1,6 branched alpha-1,4-glucans, and plants producing alternan.
  • 3) Transgenic plants which produce hyaluronan.


Plants or plant varieties (obtained by plant biotechnology methods such as genetic engineering) which may also be treated according to the invention are plants, such as cotton plants, with altered fiber characteristics. Such plants can be obtained by genetic transformation, or by selection of plants containing a mutation imparting such altered fiber characteristics and include:

  • a) plants, such as cotton plants, which contain an altered form of cellulose synthase genes,
  • b) plants, such as cotton plants, which contain an altered form of rsw2 or rsw3 homologous nucleic acids;
  • c) plants, such as cotton plants, with an increased expression of sucrose phosphate synthase;
  • d) plants, such as cotton plants, with an increased expression of sucrose synthase;
  • e) plants, such as cotton plants, wherein the timing of the plasmodesmatal gating at the basis of the fiber cell is altered, for example through downregulation of fiber-selective β-1,3-glucanase;
  • f) plants, such as cotton plants, which have fibers with altered reactivity, for example through the expression of the N-acetylglucosaminetransferase gene including nodC and chitin synthase genes.


Plants or plant cultivars (that can be obtained by plant biotechnology methods such as genetic engineering) which may also be treated according to the invention are plants, such as oilseed rape or related Brassica plants, with altered oil profile characteristics. Such plants can be obtained by genetic transformation or by selection of plants containing a mutation imparting such altered oil characteristics and include:

  • a) plants, such as oilseed rape plants, which produce oil having a high oleic acid content;
  • b) plants, such as oilseed rape plants, which produce oil having a low linolenic acid content.
  • c) plants, such as oilseed rape plants, which produce oil having a low level of saturated fatty acids.


Particularly useful transgenic plants which may be treated according to the invention are plants which comprise one or more genes which encode one or more toxins are the transgenic plants available under the following trade names: YIELD GARD® (for example maize, cotton, soya beans), KnockOut® (for example maize), BiteGard® (for example maize), BT-Xtra® (for example maize), StarLink® (for example maize), Bollgard® (cotton), Nucotn® (cotton), Nucotn 33B® (cotton), NatureGard® (for example maize), Protecta® and NewLeaf@(potato). Examples of herbicide-tolerant plants which may be mentioned are maize varieties, cotton varieties and soya bean varieties which are available under the following trade names: Roundup Ready® (tolerance to glyphosate, for example maize, cotton, soya beans), Liberty Link® (tolerance to phosphinothricin, for example oilseed rape), IMI® (tolerance to imidazolinone) and SCS® (tolerance to sulphonylurea, for example maize). Herbicide-resistant plants (plants bred in a conventional manner for herbicide tolerance) which may be mentioned include the varieties sold under the name Clearfield® (for example maize).


Particularly useful transgenic plants which may be treated according to the invention are plants containing transformation events, or a combination of transformation events, that are listed for example in the databases for various national or regional regulatory agencies (see for example http://gmoinfo.jrc.it/gmp_browse.aspx and http://www.agbios.com/dbase.php).


The plants listed can be treated according to the invention in a particularly advantageous manner with the compounds of the general formula (I) and/or the active compound mixtures according to the invention. The preferred ranges stated above for the active compounds or mixtures also apply to the treatment of these plants. Particular emphasis is given to the treatment of plants with the compounds or mixtures specifically mentioned in the present text.


The active compounds or compositions according to the invention can thus be employed for protecting plants for a certain period of time after treatment against attack by the pathogens mentioned. The period for which protection is provided extends generally for 1 to 28 days, preferably 1 to 14 days, particularly preferably for 1 to 10 days, very particularly preferably for 1 to 7 days after the treatment of the plants with the active compounds, or up to 200 days after a seed treatment.


The preparation and the use of the active compounds of the formula (I) according to the invention is illustrated by the examples below. However, the invention is not limited to these examples.


General note: Unless indicated otherwise, all chromatographic purification and separation steps are carried out on silica gel and using a solvent gradient of from 0:100 ethyl acetate/cyclohexane to 100:0 ethyl acetate/cyclohexane.


General note: Unless indicated otherwise, all chromatographic purification and separation steps are carried out on silica gel and using a solvent gradient of from 0:100 ethyl acetate/hexane to 100:0 ethyl acetate/hexane.


Preparation of Starting Materials of the Formula (XVIII)
3-tert-Butyl-5-(pentafluoroethyl)-1H-pyrazole (XVIII-1)

At room temperature, hydrazine hydrate (2.06 g) is added to a solution of 1,1,1,2,2-pentafluoro-6,6-dimethylheptane-3,5-dione (10.1 g) in ethanol (100 ml). The reaction mixture is stirred at room temperature overnight. After removal of the solvents under reduced pressure, 3-tert-butyl-5-(pentafluoroethyl)-1H-pyrazole (7.9 g, 79%) is obtained.


log P (pH 2.7): 3.23



1H NMR (DMSO-d6, 400 MHz): δppm: 1.30 (s, 9H), 6.40 (s, 1H) 13.3 (s, 1H)


MS (ESI): 243 ([M+H]+)


5-tert-Butyl-3-(trifluoromethyl)-1H-pyrazole (XVIII-2)

1,1,1-Trifluoro-5,5-dimethylhexane-2,4-dione (14.1 g) is reacted analogously to Example XVIII-1 with hydrazine hydrate (3.61 g). This gives 5-tert-butyl-3-(trifluoromethyl)-1H-pyrazole (10.7 g. 77%)



1H NMR (DMSO-d6, 400 MHz): δppm: 1.30 (s, 9H), 6.39 (s, 1H), 13.1 (s, 1H)


MS (ESI): 192 ([M]+)


3-Isopropyl-5-(trifluoromethyl)-1H-pyrazole (XVIII-3)

1,1,1-Trifluoro-5-methylhexane-2,4-dione (24.9 g) is reacted analogously to Example XVIII-1 with hydrazine hydrate (6.84 g). This gives 3-isopropyl-5-(trifluoromethyl)-1H-pyrazole (19 g, 78%)



1H NMR (DMSO-d6, 400 MHz): δppm: 1.23 (d, 6H), 3.02 (septet, 1H), 6.39 (s, 1H), 13.1 (s, 1H)


MS (ESI): 178 ([M]+)


Preparation of Starting Materials of the Formula (XVI)
Ethyl [3-tert-butyl-5-(trifluoromethyl)-1H-pyrazol-1-yl]acetate (XVI-1) and ethyl [5-tert-butyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetate (XVI-2)

Potassium carbonate (15.4 g) is added to a solution of 5-tert-butyl-3-(trifluoromethyl)-1H-pyrazole (XVIII-2, 10.7 g) in acetonitrile (150 ml). Ethyl bromoacetate (13.9 g) is then added dropwise at room temperature. The reaction mixture is stirred at room temperature overnight and then filtered and concentrated under reduced pressure. The residue is purified chromatographically. This gives ethyl [3-tert-butyl-5-(trifluoromethyl)-1H-pyrazol-1-yl]acetate (7.84 g, 50%) and ethyl[5-tert-butyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetate (4.53 g, 29%).


Ethyl [3-tert-butyl-5-(trifluoromethyl)-1H-pyrazol-1-yl]acetate (XVI-1)


log P (pH 2.7): 3.89



1H NMR (DMSO-d6, 400 MHz): δppm: 1.18 (t, 3H), 1.26 (s, 9H), 4.15 (q, 2H), 5.06 (s, 2H), 6.79 (s, 1H)


MS (ESI): 279 ([M+H]+)


Ethyl [5-tert-butyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetate (XVI-2)


log P (pH 2.7): 3.48



1H NMR (DMSO-d6, 400 MHz): δppm: 1.20 (t, 3H), 1.31 (s, 9H), 4.17 (q, 2H), 5.18 (s, 2H), 6.47 (s, 1H)


MS (ESI): 279 ([M+H]+)


Ethyl [3-tert-butyl-5-(pentafluoroethyl)-1H-pyrazol-1-yl]acetate (XVI-3) and ethyl [5-tert-butyl-3-(pentafluoroethyl)-1H-pyrazol-1-yl]acetate (XVI-4)

3-tert-Butyl-5-(pentafluoroethyl)-1H-pyrazole (XVIII-1, 7.90 g) is reacted analogously to Examples XVI-1 and XVI-2 with ethyl bromoacetate (8.17 g). This gives, after chromatographic purification, ethyl[3-tert-butyl-5-(pentafluoroethyl)-1H-pyrazol-1-yl]acetate (2.50 g, 23%) and ethyl[5-tert-butyl-3-(pentafluoroethyl)-1H-pyrazol-1-yl]acetate (4.80 g, 45%).


Ethyl [3-tert-butyl-5-(pentafluoroethyl)-1H-pyrazol-1-yl]acetate (XVI-3)


log P (pH 2.7): 4.45



1H NMR (DMSO-d6, 400 MHz): δppm: 1.18 (t, 3H), 1.26 (s, 9H), 4.15 (q, 2H), 5.07 (s, 2H), 6.75 (s, 1H)


MS (ESI): 329 ([M+H]+)


Ethyl [5-tert-butyl-3-(pentafluoroethyl)-1H-pyrazol-1-yl]acetate (XVI-4)

log P (pH 2.7): 4.05



1H NMR (DMSO-d6, 400 MHz): δppm: 1.18 (t, 3H), 1.32 (s, 9H), 4.16 (q, 2H), 5.20 (s, 2H), 6.47 (s, 1H)


MS (ESI): 329 ([M+H]+)


Ethyl [3-isopropyl-5-(trifluoromethyl)-1H-pyrazol-1-yl]acetate (XVI-5)

3-Isopropyl-5-(trifluoromethyl)-1H-pyrazole (XVIII-3, 19.3 g) is reacted analogously to Examples XVI-1 and XVI-2 with ethyl bromoacetate (27.1 g). This gives ethyl[3-isopropyl-5-(trifluoromethyl)-1H-pyrazol-1-yl]acetate (26.2 g, 92%)


log P (pH 2.7): 3.22



1H NMR (DMSO-d6, 400 MHz): δppm: 1.18-1.22 (m, 3H), 1.20 (d, 6H), 3.0 (septet, 1H), 4.17 (q, 2H), 5.11 (s, 2H), 6.54 (s, 1H)


MS (ESI): 265 ([M+H]+)


Ethyl [4-chloro-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetate (XVI-6)

4-Chloro-5-methyl-3-(trifluoromethyl)-1H-pyrazole (14.9 g) is reacted analogously to Examples XVI-1 and XVI-2 with ethyl bromoacetate (20.3 g). This gives ethyl[4-chloro-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetate (19.5 g, 89%)


log P (pH 2.7): 3.11



1H NMR (DMSO-d6, 400 MHz): δppm: 1.22 (t, 311), 2.25 (s, 311), 4.18 (q, 2H), 5.24 (s, 2H) MS (ESI): 271 ([M+H]+)


Preparation of Starting Materials of the Formula (V)
[3-tert-Butyl-5-(trifluoromethyl)-1H-pyrazol-1-yl]acetic acid (V−1)

At room temperature, a solution of lithium hydroxide monohydrate (2.35 g) in water (20 ml) is added dropwise to a solution of ethyl[3-tert-butyl-5-(trifluoromethyl)-1H-pyrazol-1-yl]acetate (XVI-1, 7.80 g) in tetrahydrofuran (80 ml). The reaction mixture is stirred for 2 hours. After removal of the solvent under reduced pressure, the residue is, at 0° C., slowly adjusted to pH 2-3 using dilute hydrochloric acid (1M). This gives, after filtration and drying, [3-tert-butyl-5-(trifluoromethyl)-1H-pyrazol-1-yl]acetic acid as a white solid (7.1 g, 100%).


log P (pH 2.7): 2.45



1H NMR (DMSO-d6, 400 MHz): δppm: 1.26 (s, 9H), 4.95 (s, 2H), 6.76 (s, 1H)


MS (ESI): 251 ([M+H]+)


[5-tert-Butyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetic acid (V-2)

Ethyl [5-tert-butyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetate (XVI-2, 4.50 g) is reacted analogously to Example V-1. This gives, after filtration and drying, [5-tert-butyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetic acid (3.9 g, 95%).


log P (pH 2.7): 2.45



1H NMR (DMSO-d6, 400 MHz): δppm: 1.26 (s, 9H), 4.95 (s, 2H), 6.76 (s, 1H) MS (ESI): 251 ([M+H]+)


[3-tert-Butyl-5-(pentafluoroethyl)-1H-pyrazol-1-yl]acetic acid (V-3)

Ethyl [3-tert-butyl-5-(pentafluoroethyl)-1H-pyrazol-1-yl]acetate (XVI-3, 2.50 g) is reacted analogously to Example V-1. This gives, after filtration and drying. [3-tert-butyl-5-(pentafluoroethyl)-1H-pyrazol-1-yl]acetic acid (1.8 g. 79%).


log P (pH 2.7): 2.92



1H NMR (DMSO-d6, 400 MHz): δppm: 1.27 (s, 9H), 4.96 (s, 2H), 6.72 (s, 1H)


MS (ESI): 301 ([M+H]+)


[5-tert-Butyl-3-(pentafluoroethyl)-1H-pyrazol-1-yl]acetic acid (V-4)

Ethyl [5-tert-butyl-3-(pentafluoroethyl)-1H-pyrazol-1-yl]acetate (XVI-4, 4.80 g) is reacted analogously to Example V-1. This gives, after filtration and drying, [5-tert-butyl-3-(pentafluoroethyl)-1H-pyrazol-1-yl]acetic acid (3.5 g, 80%).


log P (pH 2.7): 2.75



1H NMR (DMSO-d6, 400 MHz): δppm: 1.33 (s, 9H), 5.09 (s, 2H), 6.45 (s, 1H)


MS (ESI): 301 ([M+H]+)


[3-Isopropyl-5-(trifluoromethyl)-1H-pyrazol-1-yl]acetic acid (V-5)

Ethyl [3-isopropyl-5-(trifluoromethyl)-1H-pyrazol-1-yl]acetate (XVI-5, 26.2 g) is reacted analogously to Example V-1. This gives, after filtration and drying [3-isopropyl-5-(trifluoromethyl)-1H-pyrazol-1-yl]acetic acid (22 g, 94%).


log P (pH 2.7): 2.05



1H NMR (DMSO-d6, 400 MHz): δppm: 1.21 (d, 6H), 2.99 (septet, 1H), 4.99 (s, 2H), 6.51 (s, 1H)


MS (ESI): 237 ([M+H]+)


[4-Chloro-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetic acid (V-6)

Ethyl [4-chloro-5-methyl-3-(trifluoromethyl)-1H-pyrazo-1-yl]acetate (XVI-6, 18.0 g) is reacted analogously to Example V-1. This gives, after filtration and drying, [4-chloro-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetic acid (15.5 g, 96%).


log P (pH 7.8): 0.68



1H NMR (DMSO-d6, 400 MHz): δppm: 2.24 (s, 3H), 3.13 (bs, 1H), 5.04 (s, 2H)


Preparation of Starting Materials of the Formula (VI)
4-[4-(Ethoxycarbonyl)-1,3-thiazol-2-yl]piperidinium chloride (VI-1)

Under argon and at 0° C., a 2-molar solution of hydrogen chloride in diethyl ether (370 ml) is added dropwise to a solution of tert-butyl 4-[4-(ethoxycarbonyl)-1,3-thiazol-2-yl]piperidine-1-carboxylate (25.0 g) in diethyl ether (200 ml). The reaction mixture is stirred at 0° C. and then slowly warmed to room temperature. After stirring overnight, the solvent and excess hydrogen chloride are removed. This gives 4-[4-(ethoxycarbonyl)-1,3-thiazol-2-yl]piperidinium chloride (20.0 g, 98%)


log P (pH 2.7): 0.42



1H NMR (DMSO-d6, 400 MHz): δppm: 1.31 (t, 3H), 1.97-2.04 (m, 2H), 2.18-2.23 (m, 2H), 2.98-3.08 (m, 2H), 3.31-3.39 (m, 2H), 3.42 (m, 1H), 4.30 (q, 2H), 839 (s, 1H). 8.90 (bs, 1H), 9.13 (bs, 1H)


MS (ESI): 241 ([M−Cl]+)


3-[4-(Ethoxycarbonyl)-1,3-thiazol-2-yl]piperidinium chloride (VI-2)

tert-Butyl 3-[4-(ethoxycarbonyl)-1,3-thiazol-2-yl]piperidine-1-carboxylate (13.8 g) is reacted analogously to Example VI-1. This gives 3-[4-(ethoxycarbonyl)-1,3-thiazol-2-yl]piperidinium chloride (10.4 g, 93%)


log P (pH 2.7): 0.54



1H NMR (DMSO-d6, 400 MHz): δppm: 1.31 (t, 3H). 1.75-1.82 (m. 1H), 1.87-1.92 (m, 2H), 2.17-2.20 (m, 1H), 2.90-2.94 (m, 111), 3.10-3.25 (m, 1H), 3.25-3.28 (m, 1H), 3.57 (m, 1H), 3.62 (m, 1H), 4.30 (q, 2H), 8.43 (s, 1H), 9.29-9.34 (m, 2H)


MS (ESI): 241 ([M−Cl]+)


Preparation of Starting Materials of the Formula (IV)
Ethyl 2-(1-{[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carboxylate (IV-1)

Oxalyl chloride (6.91 g) and a drop of N,N-dimethylformamide are added to a solution of [3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]acetic acid (8.00 g) in dichloromethane (200 ml). The reaction mixture is stirred at room temperature overnight, and excess oxalyl chloride is then removed under reduced pressure. The residue is redissolved in dichloromethane (20 ml) and added to a solution of 4-[4-(ethoxycarbonyl)-1,3-thiazol-2-yl]piperidinium chloride (VI-1, 7.53 g) and Hünig base (10.6 g) in dichloromethane (80 ml). The reaction mixture is stirred at room temperature for 24 hours, added to a mixture of ice and water, neutralized with saturated bicarbonate solution and extracted with ethyl acetate. The combined organic phases are dried over sodium sulphate and concentrated under reduced pressure. The residue is purified chromatographically. This gives ethyl 2-(1-{[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carboxylate (10 g, 63%).


log P (pH 2.7): 2.52



1H NMR (DMSO-d6, 400 MHz): δppm: 1.31 (t, 3H), 1.55-1.85 (m, 2H), 2.10 (m, 2H), 3.20-3.60 (m, 4H), 3.99 (bs, 1H), 4.30 (q, 2H), 5.35 (s, 2H), 6.83-7.30 (m, 3H), 8.37 (s, 1H)


MS (ESI): 449 ([M+H]+)


Ethyl 2-(1-{[3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carboxylate (IV-2)

4-[4-(Ethoxycarbonyl)-1,3-thiazol-2-yl]piperidinium chloride (VI-1, 5.50 g) is reacted analogously to Example IV-1 with [3-(trifluoromethyl)-1H-pyrazol-1-yl]acetic acid (3.86 g). This gives, after chromatographic purification, ethyl 2-(1-{[3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carboxylate (5.1 g, 62%).


log P (pH 2.7): 2.41



1H NMR (DMSO-d6, 400 MHz): δppm: 1.31 (t, 3H), 1.63 (bs, 1H), 1.75 (bs, 1H), 2.05-2.15 (m, 2H), 2.88 (bs, 1H), 3.26 (bs, 1H). 3.36 (m, 1H), 3.98 (bs, 1H), 4.30 (q, 2H), 4.35 (bs, 1H), 5.28 (s, 2H), 6.67 (d. 1H), 7.85 (dd, 1H), 8.36 (s, 1H)


MS (ESI): 417 ([M+H]+)


Ethyl 2-(1-{[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-3-yl)-1,3-thiazole-4-carboxylate (IV-3)

3-[4-(Ethoxycarbonyl)-1,3-thiazol-2-yl]piperidinium chloride (VI-2, 5.32 g) is reacted analogously to Example IV-1 with [5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetic acid (4.00 g). This gives, after chromatographic purification, ethyl 2-(1-{[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-3-yl)-1,3-thiazole-4-carboxylate (5.7 g, 69%).


log P (pH 2.7): 2.78



1H NMR (DMSO-d6, 400 MHz): δppm: 1.29 (t, 3H), 1.50-1.74 (m, 2H), 1.79-1.89 (m, 2H), 2.20 (s, 3H), 3.18 (m, 1H), 3.39 (m, 0.5H), 3,69 (m, 0.5H), 3.86-3.89 (m, 1H), 4.00 (m, 0.5H), 4.30 (q, 2H), 4.45 (m, 0.5H), 4.90 (m, 1H), 5.25-5.30 (m, 2H), 6.44 (s, 1H), 8.40 (s, 1H)


MS (ESI): 431 ([M+H]+)


Ethyl 2-{1-[2-(3,5-dimethyl-1H-pyrazol-1-yl)-2-methylpropanoyl]piperidin-4-yl}-1,3-thiazole-4-carboxylate (IV-4)

4-[4-(Ethoxycarbonyl)-1,3-thiazol-2-yl]piperidinium chloride (VI-1, 8.23 g) is reacted analogously to Example IV-1 with 2-(3,5-dimethyl-1H-pyrazol-1-yl)-2-methylpropanoic acid (5.42 g). This gives, after chromatographic purification, ethyl 2-{1-[2-(3,5-dimethyl-1H-pyrazol-1-yl)-2-methylpropanoyl]piperidin-4-yl}-1,3-thiazole-4-carboxylate (9.64 g, 80%) log P (pH 7.8): 2.34



1H NMR (DMSO-d6, 400 MHz): δppm: 1.29 (t, 3H), 1.41 (m, 2H), 1.66 (s, 6H), 1.90 (m, 2H), 2.11 (s, 3H), 2.12 (s, 3H), 2.81 (m, 2H), 3.22 (m, 1H), 3.59 (m, 1H), 4,10 (m, 1H), 4.28 (q, 2H), 5.89 (s, 1H), 8.32 (s, 1H)


MS (ESI): 405 ([M+H]+)


Ethyl 2-(1-{[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidn-4-yl)-1,3-thazole-4-carboxylate (IV-5)

4-[4-(Ethoxycarbonyl)-1,3-thiazol-2-yl]piperidinium chloride (VI-1, 4.65 g) is reacted analogously to Example IV-1 with [5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetic acid (3.50 g). This gives, after chromatographic purification, ethyl 2-(1-{[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carboxylate (5.00 g, 69%).


log P (pH 2.7): 2.62



1H NMR (DMSO-d6, 400 MHz): δppm: 1.31 (t, 3H), 1.62 (bs, 1H), 1.80 (bs, 1H), 2.06-2.16 (m, 2H), 2.22 (s, 3H), 2.88 (bs, 1H), 3.28 (bs, 1H), 3.37 (m, 1H), 3.99 (bs, 1H), 4.30 (q, 2H), 4.33 (bs, 1H), 5.22 (bs, 2H), 6.45 (s, 1H), 8.37 (s, 1H)


MS (ESI): 431 ([M+H]+)


Ethyl 2-(1-{[4-chloro-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carboxylate (IV-6)

4-[4-(Ethoxycarbonyl)-1,3-thiazol-2-yl]piperidinium chloride (VI-1, 5.50 g) is reacted analogously to Example IV-1 with [4-chloro-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetic acid (4.82 g). This gives, after chromatographic purification, ethyl 2-(1-{[4-chloro-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carboxylate (6.00 g, 65%).


log P (pH 2.7): 3.17



1H NMR (DMSO-d6, 400 MHz): δppm: 1.31 (t, 3H), 1.61 (bs, 1H), 1.81 (bs, 1H), 2.05-2.15 (m, 2H), 2.20 (s, 3H), 2.88 (bs, 1H), 3.27 (bs, 1H), 3.37 (m, 1H), 3.95 (bs, 1H), 4.30 (q, 2H), 4.32 (bs, 1H), 5.27-5.35 (3, 2H), 8.37 (s, 1H)


MS (ESI): 465 ([M+H]+)


Preparation of Starting Materials of the Formula (III)
2-(1-{[3,5-Bis(difluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carboxylic acid (III-1)

Ethyl 2-(1-{[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carboxylate (IV-1, 13.3 g) is dissolved in tetrahydrofuran (80 ml). LiOH monohydrate (1.86 g) dissolved in water (20 ml) is then added. After 3 hours, water is added, the pH is adjusted to 2-3 with dilute hydrochloric acid (1M), the mixture is then extracted with ethyl acetate and the combined organic phases are dried with sodium sulfate. The solid is filtered off and the solvent is removed by distillation. This gives 2-(1-{[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carboxylic acid (11.7 g, 94%).


log P (pH 2.7): 1.71



1H NMR (DMSO-d6, 400 MHz): δppm: 1.55-1.85 (m, 2H), 2.09-2.13 (m, 2H), 2.80-3.30 (m, 3H), 3.36 (m, 1H), 3.99 (bs, 1H), 4.30 (bs, 1H), 5.34 (s, 2H), 6.85 (s, 1H), 6.98 (t, 1H), 7.14 (t, 1H), 8.29 (s, 1H)


MS (ESI): 421 ([M+H]+)


2-(1-{[3-(Trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carboxylic acid (III-2)

Ethyl 2-(1-{[3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carboxylate (IV-2, 5.20 g) is reacted analogously to Example III-1. This gives, after drying, 2-(1-{[3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carboxylic acid (4.6 g, 95%).


log P (pH 2.7): 1.65



1H NMR (DMSO-d6, 400 MHz): δppm: 1.64 (bs, 1H), 1.76 (bs, 1H), 2.05-2.15 (m, 2H), 2.88 (bs, 1H), 3.23 (bs, 1H), 3.36 (m, 1H), 3.98 (bs, 1H), 4.34 (bs, 1H), 5.28 (s, 2H), 6.67 (d, 1H), 7.85 (dd. 1H), 8.29 (s, 1H)


MS (ESI): 389 ([M+H]+)


2-(1-{[5-Methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-3-yl)-1,3-thiazole-4-carboxylic acid (III-3)

Ethyl 2-(1-{[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-3-yl)-1,3-thiazole-4-carboxylate (IV-3, 5.70 g) is reacted analogously to Example III-1. This gives, after drying, 2-(1-{[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-3-yl)-1,3-thiazole-4-carboxylic acid (5.4 g, 100%).


log P (pH 2.7): 1.90



1H NMR (DMSO-d6, 400 MHz): δppm: 1.48-1.88 (m. 4H), 2.20 (s, 3H), 3.38 (m, 0.5H), 3.60 (m, 0.5H), 3.87 (m, 2H), 4.01 (m, 0.5H), 4.45 (m, 0.5H), 5.24-5.28 (m, 3H), 6.44 (s, 1H), 8.32 (s, 1H)


MS (ESI): 403 ([M+H])


2-(1-{[5-Methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carboxylic acid (III-4)

Ethyl 2-(1-{[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-5-yl)-1,3-thiazole-4-carboxylate (IV-3, 5.10 g) is reacted analogously to Example III-1. This gives, after drying, 2-(1-{[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carboxylic acid (4.63 g, 97%).


log P (pH 2.7): 1.82



1H NMR (DMSO-d6, 400 MHz): δppm: 1.62 (bs, 1H), 1.79 (bs, 1H), 2.06-2.16 (m, 2H), 2.22 (s, 3H), 2.88 (bs, 1H), 3.28 (bs, 1H), 3.37 (m, 1H), 3.99 (bs, 1H), 4.33 (bs, 1H), 5.21 (bs, 2H), 6.45 (d, 1H), 8.30 (s, 1H)


MS (ESI): 403 ([M+H]+)


2-(1-{[4-Chloro-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carboxylic acid (III-5)

Ethyl 2-(1-{[4-chloro-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-5-yl)-1,3-thiazole-4-carboxylate (IV-6, 6.00 g) is reacted analogously to Example III-1. This gives, after drying, 2-(1-{[4-chloro-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carboxylic acid (3.10 g, 55%).


log P (pH 2.7): 2.26



1H NMR (DMSO-d6, 400 MHz): δppm: 1.61 (bs, 1H), 1.81 (bs, 1H), 2.05-2.17 (m, 2H), 2.20 (s, 3H), 2.89 (bs, 1H), 3.27 (bs, 1H), 3.37 (m, 1H), 3.95 (bs, 1H), 4.32 (bs, 1H), 5.27-5.34 (m, 2H), 8.29 (s, 1H)


MS (ESI): 437 ([M+H]+)


Preparation of the compounds of the formula (I)
Cyclohexyl 2-(1-{[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carboxylate (I-811)

At room temperature, cyclohexanol (2.17 g), dimethylaminopyridine (0.20 g) and 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide (3.35 g) are added to a solution of 2-(1-{[3,5-bis(difluoromethyl)-H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carboxylic acid (III-1, 7.00 g) in dichloromethane (80 ml). The mixture is stirred overnight, and water is then added. The aqueous phase is separated off and extracted with ethyl acetate. The combined organic phases are dried with sodium sulfate. The solid is filtered off and the solvent is removed by distillation. The residue is purified chromatographically. This gives cyclohexyl 2-(1-{[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carboxylate (2.83 g, 34%).


log P (pH 2.7): 3.64



1H NMR (DMSO-d6, 400 MHz): δppm: 1.29-1.90 (m, 12H), 2.09-2.12 (m, 2H), 2.88 (bs, 1H), 3.25 (bs, 1H), 3.39 (m, 1H), 4.01 (bs, 1H), 4.30 (bs, 1H), 4.88-4.93 (m, 1H), 5.35 (s, 2H), 6.85 (s, 1H), 6.96 (t, 1H), 7.14 (t, 1H), 8.34 (s, 1H) MS (ESI): 503 ([M+H])


1-Naphthyl 2-(1-{[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carboxylate (I-813)

2-(1-{[3,5-Bis(difluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carboxylic acid (III-1, 7.00 g) is reacted analogously to Example I-811 with 1-naphthol (3.12 g). This gives, after chromatographic purification, 1-naphthyl-2-(1l-{[3,5-bis(difluoromcthyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carboxylate (4.0 g, 44%).


log P (pH 2.7): 3.64



1H NMR (DMSO-d6, 400 MHz): δppm: 1.70 (bs, 1H), 1.87 (bs, 1H), 2.18 (m, 2H), 2.91 (bs, 1H), 3.31 (bs, 1H), 3.48 (m, 1H), 4.03 (bs, 1H), 4.36 (bs, 1H), 5.36 (s, 2H), 6.85 (s, 1H), 6.97 (t, 1H), 7.15 (t, 1H), 7.45 (dd, 1H), 7.54-7.61 (m, 3H), 7.89 (m, 2H), 8.01 (m, 1H), 8.84 (s, 1H)


MS (ESI): 547 ([M+H]+)


1-Naphthyl 2-(1-{[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carboxylate (I-227)

Oxalyl chloride (189 mg) and a drop of N,N-dimethylformamide are added to a solution of 2-(1-{[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carboxylic acid (III-4, 200 mg) in dichloromethane (2 ml). The reaction mixture is stirred at room temperature overnight, and excess oxalyl chloride is then removed under reduced pressure. The residue is re-dissolved in dichloromethane (2 ml) and added to a solution of 1-naphthol (79 mg) and pyridine (489 mg) in dichloromethane (4 ml). The mixture is stirred at room temperature for one hour, and dilute hydrochloric acid (1M) is then added. The aqueous phase is separated off and extracted with ethyl acetate, and the combined organic phases are then dried with sodium sulfate. The solid is filtered off and the solvent is removed by distillation. The residue is purified chromatographically. This gives 1-naphthyl 2-(1-{[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carboxylate (100 mg, 38%).


log P (pH 2.7): 3.75



1H NMR (CD3CN, 400 MHz): δppm: 1.72-2.00 (m, 2H), 2.19-2.27 (m, 2H), 2.24 (s, 3H), 2.92 (bs, 1H), 3.34 (bs, 1H), 3.42 (m, 1H), 3.98 (bs, 1H), 4.49 (bs, 1H), 5.06 (bs, 2H), 6.37 (s, 1H), 7.40 (d. 1H), 7.52-7.60 (m, 3H), 7.86 (d, 1H), 7.92-7.99 (m, 2H), 8.55 (s, 1H)


MS (ESI): 529 ([M+H])


1,2,3,4-Tetrahydronaphthalen-1-yl 2-(1-{[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carboxylate (I-224)

At room temperature, 1,2,3,4-tetrahydronaphthalen-1-ol (155 mg) and triphenylphosphine (758 mg) are added to a solution of 2-(1-{[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carboxylic acid (III-4, 380 mg) in tetrahydrofuran (2.5 ml). The mixture is stirred at 0 C under argon for 5 minutes, and diethyldiazene 1,2-dicarboxylate (383 mg) is then added dropwise. The reaction mixture is slowly warmed to room temperature. After 2 hours, the solvent is removed under reduced pressure and the residue is purified chromatographically. This gives 1,2,3,4-tetrahydronaphthalen-1-yl 2-(1-{[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carboxylate (196 mg, 39%).


log P (pH 2.7): 4.01



1H NMR (DMSO-d6, 400 MHz): δppm: 1.52-1.88 (m, 3H), 1.88-2.15 (m, 4H), 2.22 (s, 3H), 2.70-2.99 (m, 4H), 3.25 (bs, 1H), 3.38 (m, 1H), 3.98 (bs, 1H), 4.33 (bs, 1H), 5.21 (bs, 2H), 6.12 (t, 1H), 6.44 (s, 1H), 7.15-7.19 (m, 2H), 7.21-7.30 (m, 2H), 8.35 (s, 1H)


MS (ESI): 403 ([M+H-1,2,3,4-tetrahydronaphthalen-1-ol]+)


Cyclohexyl 2-(1-{[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carboxylate (I-220)

A solution of 2-(1-{[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carboxylic acid (III-4, 6.00 g) is reacted analogously to Example I-811 with cyclohexanol (1.94 g). This gives, after chromatographic purification, cyclohexyl 2-(1-{[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carboxylate (5.00 g, 69%).


log P (pH 2.7): 3.74



1H NMR (DMSO-d6, 400 MHz): δppm: 1.25-1.48 (m, 3H), 1.50-2.00 (broad m, 2H), 1.50-1.51 (m, 3H). 1.70-1.80 (m, 2H), 1.85-1.92 (m, 2H), 2.06-2.16 (m, 2H), 2.22 (s, 3H), 2.88 (bs, 1H), 3.28 (bs, 1H), 3.38 (m, 1H), 3.98 (bs, 1H), 4.34 (bs, 1H). 4.91 (septet, 1H), 5.21 (bs, 2H), 6.44 (s, 1H), 8.34 (s, 1H)


MS (ESI): 485 ([M+H]+)


2-Bromohenzyl 2-(1-{[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carboxylate (I-820)

A solution of 2-(1-{[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carboxylic acid (III-4, 100 mg) is reacted analogously to Example I-811 with (2-bromophenyl)methanol (49.0 mg). This gives, after chromatographic purification, 2-bromobenzyl 2-(1-{[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carboxylate (123 mg, 89%).


log P (pH 2.7): 3.80



1H NMR (DMSO-d6, 400 MHz): δppm: 1.62 (bs, 1H), 1.80 (bs, 1H), 2.07-2.19 (m, 2H), 2.22 (s, 3H), 2.88 (bs, 1H), 3.27 (bs, 1H), 3.38 (m, 1H), 3.99 (bs, 1H), 4.43 (bs, 1H), 5.22 (bs, 2H), 5.38 (s, 2H), 6.44 (s, 1H), 7.32 (td, 1H), 7.43 (td, 1H), 7.56 (dd, 1H), 7.67 (dd, 1H), 8.46 (s, 1H) MS (ESI): 571, 573 ([M+H])


3,3-Dimethylbutyl 2-(1-{[3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carboxylate (I-767)

A solution of 2-(1-{[3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carboxylic acid (III-2, 200 mg) is reacted analogously to Example I-811 with 3,3-dimethylbutan-1-ol (68.0 mg). This gives, after chromatographic purification, 3,3-dimethylbutyl 2-(1-{[3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carboxylate (98 mg, 40%).


log P (pH 2.7): 3.82



1H NMR (DMSO-d6, 400 MHz): δppm: 0.96 (s, 9H), 1.50-1.85 (broad m+t, 4H), 2.06-2.13 (m, 2H), 2.88 (bs, 1H), 3.28 (bs, 1H), 3.38 (m, 1H), 3.98 (bs, 1H), 4.31 (t, 2H), 4.34 (bs, 1H), 5.28 (bs, 21H), 6.66 (d, 1H), 7.85 (s, 1H), 8.34 (s, 1H)


MS (ESI): 473 ([M+H]+)


S-(4-Fluorobenzyl) 2-(1-{[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carbothioate (I-27)

A solution of 2-(1-{[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carboxylic acid (III-4, 200 mg) is reacted analogously to Example I-227 with (4-fluorophenyl)methanethiol (78.0 mg). This gives, after chromatographic purification, S-(4-fluorobenzyl) 2-(1-{[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carbothioate (110 mg, 42%).


log P (pH 2.7): 4.00



1H NMR (CD3CN, 400 MHz): δppm: 1.64-1.88 (broad m, 2H), 2.12-2.18 (m, 2H), 2.23 (s, 3H), 2.92 (bs, 1H), 3.30 (bs, 1H), 3.33 (m, 1H), 3.97 (bs, 1H), 4.24 (s, 2H), 4.41 (bs, 1H), 5.04 (bs, 2H), 6.36 (s, 1H), 7.00-7.07 (m, 2H), 7.36-7.42 (m, 2H), 8.11 (s, 1H)


MS (ESI): 527 ([M+H])


S-Cyclohexyl 2-(1-{[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carbothioate (I-76)

A solution of 2-(1-{[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carboxylic acid (Ill-4, 200 mg) is reacted analogously to Example I-227 with cyclohexanethiol (64.0 mg). This gives, after chromatographic purification, S-cyclohexyl 2-(1-{[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carbothioate (110 mg, 44%).


log P (pH 2.7): 4.51



1H NMR (CD3CN, 400 MHz): δppm: 1.30-1.40 (m, 2H), 1.42-1.90 (m, 10H), 2.12-2.19 (m, 2H), 2.24 (s, 3H), 2.91 (bs, 1H), 3.30 (bs, 1H), 3.34 (m, 1H), 3.65 (m, 1H), 3.95 (bs, 1H), 4.44 (bs, 1H), 5.04 (bs, 2H), 6.36 (s, 1H), 8.05 (s, 1H)


MS (ESI): 501 ([M+H]+)


S-1-Naphthyl 2-(1-{[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carbothioate (I-77)

A solution of 2-(1-{[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carboxylic acid (III-4, 200 mg) is reacted analogously to Example I-227 with naphthalene-1-thiol (88.0 mg). This gives, after chromatographic purification, S-1-naphthyl 2-(1-{[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4.carbothioate (100 mg, 37%).


log P (pH 2.7): 4.22



1H NMR (CD3CN, 400 MHz): δppm: 1.74-1.90 (m, 2H), 2.20-2.26 (m, 2H), 2.25 (s, 3H), 2.93 (bs, 1H), 3.34 (bs, 1H), 3.42 (m, 1H), 4.04 (bs, 1H), 4.48 (bs, 1H), 5.07 (bs, 2H), 6.37 (s, 1H), 7.54-7.60 (m, 3H), 7.80 (dd, 1H), 7.98 (dd, 1H), 8.05 (d, 1H), 8.13 (s, 1H), 8.20 (dd, 1H)


MS (ESI): 545 ([M+H]+)


Preparation of Starting Materials of the Formula (VIII)
2-[1-(tert-Butoxycarbonyl)piperidin-4-yl]-1,3-thiazole-4-carboxylic acid (VIII-1)

At room temperature, lithium hydroxide monohydrate (8.88 g) is added in one portion to a solution of tert-butyl 4-[4-(ethoxycarbonyl)-1,3-thiazol-2-yl]piperidine-1-carboxylate (24.0 g) in tetrahydrofuran (240 ml) and water (60 ml). The mixture is stirred for 4 hours and then stirred with dilute hydrochloric acid (1M) (100 ml) and ethyl acetate (100 ml). The aqueous phase is separated off and extracted with ethyl acetate, and the combined organic phases are then dried with sodium sulfate. The solid is filtered off and the solvent is removed by distillation. This gives 2-[1-(tert-Butoxycarbonyl)piperidin-4-yl]-1,3-thiazole-4-carboxylic acid (21 g, 94%)


log P (pH 2.7): 2.04



1H NMR (DMSO-d6, 400 MHz): δppm: 1.41 (s, 9H), 1.59 (qd, 2H), 2.02 (dd, 2H), 2.91 (m, 2H), 3.23 (m, 1H), 3.97-4.02 (m, 2H), 8.27 (s, 1H)


MS (ESI): 256 ([M+H−C(CH3)3]+)


Preparation of Starting Materials of the Formula (IX)
tert-Butyl 4-{4-[(cyclohexyloxy)carbonyl]-1,3-thiazol-2-yl}piperidine-1-carboxylate (IX-1)

At room temperature, cyclohexanol (1.21 g), dimethylaminopyridine (113 mg) and 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide (1.87 g) are added to a solution of 2-[1-(tert-butoxycarbonyl)piperidin-4-yl]-1,3-thiazole-4-carboxylic acid (VII-I, 2.90 g) in dichloromethane (30 ml). The mixture is stirred at room temperature overnight, and water is then added. The aqueous phase is separated off and extracted with ethyl acetate, and the combined organic phases are then dried with sodium sulfate. The solid is filtered off and the solvent is removed by distillation. The residue is purified chromatographically. This gives tert-butyl 4-{4-[(cyclohexyloxy)carbonyl]-1,3-thiazol-2-yl}piperidine-1-carboxylate (2.63 g, 72%)


log P (pH 2.7): 4.62



1H NMR (DMSO-d6, 400 MHz): δppm: 1.13-1.81 (m+s, 21H), 2.02 (m, 2H), 2.90 (m, 2H), 3.40 (m, 1H), 3.98-4.01 (m, 2H), 4.90 (m, 1H), 8.32 (s, 1H)


MS (ESI): 339 ([M+2H−C(CH3)3]+)


tert-Butyl 4-{4-[(1-naphthyloxy)carbonyl]-1,3-thiazol-2-yl}piperidine-1-carboxylate (IX-2)

A solution of 2-[1-(tert-butoxycarbonyl)piperidin-4-yl]-1,3-thiazole-4-carboxylic acid (VIII-1, 12.0 g) is reacted analogously to Example IX-1 with 1-naphthol (7.20 g). This gives, after chromatographic purification, tert-butyl 4-{4-[(1-naphthyloxy)carbonyl]-1,3-thiazol-2-yl}piperidine-1-carboxylate (12.3 g, 73%)


log P (pH 2.7): 4.50



1H NMR (DMSO-d6, 400 MHz): δppm: 1.42 (s, 9H), 1.67 (qd, 2H), 2.10 (dd, 2H), 2.95 (m, 2H), 3.35 (m, 1H), 4.00-4.08 (m, 2H), 7.45 (dd, 1H), 7.55-7.62 (m, 3H), 7.89 (d, 2H), 8.01 (dd, 1H), 8.83 (s, 1H)


MS (ESI): 383 ([M+2H−C(CH3)3]+)


Preparation of Starting Materials of the Formula (X)
4-{4-[(Cyclohexyloxy)carbonyl]-1,3-thiazol-2-yl}piperidinium chloride (X-1)

Under argon and at 0° C, a 2-molar solution of hydrogen chloride in diethyl ether (50 ml) is added dropwise to a solution of tert-butyl 4-{4-[(cyclohexyloxy)carbonyl]-1,3-thiazol-2-yl}piperidine-1-carboxylate (IX-1, 2.63 g) in dioxane (20 ml). The reaction mixture is stirred at 0° C. and then slowly warmed to room temperature. After stirring overnight, the solvent and excess hydrogen chloride are removed. This gives 4-{4-[(cyclohexyloxy)carbonyl]-1,3-thiazol-2-yl}piperidinium chloride (2.19 g, 99%)


log P (pH 2.7): 1.25



1H NMR (DMSO-d6, 400 MHz): δppm: 1.15-1.55 (m, 6H), 1.71-1.75 (m, 2H), 1.85-1.90 (m, 2H), 1.98-2.04 (m, 2H), 2.20 (dd, 2H), 3.01-3.03 (m, 2H), 3.14-3.34 (m, 2H), 3.40 (m, 1H), 4.90 (m, 1H), 8.36 (s, 1H), 9.05 (bs, 1H), 9.25 (bs, 1H) MS (ESI): 295 ([M−Cl]+)


4-{4-[(1-Naphthyloxy)carbonyl]-1,3-thiazol-2-yl}piperidinium chloride (X-2)

tert-Butyl 4-{4-[(1-naphthyloxy)carbonyl]-1,3-thiazol-2-yl}piperidine-1-carboxylate (IX-2, 3.20 g) is reacted analogously to Example X-1. This gives, after drying, 4-{4-[(1-naphthyloxy)carbonyl]-1,3-thiazol-2-yl}piperidinium chloride (2.93 g, 100%)


log P (pH 2.7): 1.42



1H NMR (DMSO-d6, 400 MHz): δppm: 2.02-2.15 (m, 2H), 2.25-2.34 (m, 2H), 3.00-3.12 (m, 2H), 3.34-3.40 (m, 2H), 3.51 (m, 1H), 7.46 (dd, 1H), 7.53-7.62 (m, 3H), 7.89 (d, 2H), 8.00-5.05 (m, 1H), 8.87 (s, 1H), 9.05 (bs, 1H), 9.25 (bs, 1H)


MS (ESI): 339 ([M−Cl]+)


Preparation of the Compounds of the Formula (I)

Cyclohexyl 2-(1-({[3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carboxylate (I-772)


[3,5-Bis(trifluoromethyl)-1H-pyrazol-1-yl]acetic acid (288 mg) and Hünig base (323 mg) are dissolved in dichloromethane (10 ml) and stirred at room temperature for 30 min. 4-{4-[(Cyclohexyloxy)carbonyl]-1,3-thiazol-2-yl}piperidinium chloride (X-1, 330 mg) is added, and the mixture is stirred for a further 5 min before bromo-tris-pyrrolidinophosphonium hexafluorophosphate (559 mg) is added. The reaction mixture is stirred at room temperature overnight. After removal of the solvent under reduced pressure, the residue is purified chromatographically. This gives cyclohexyl 2-(1-{[3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carboxylate (348 mg, 65%).


log P (pH 2.7): 4.39



1H NMR (DMSO-d6, 400 MHz): δ: 1.20-1.60 (m, 8H), 1.71-1.75 (m, 2H), 1.85-1.88 (m, 2H), 2.04 (m, 2H), 2.90 (bs, 1H), 3.30 (bs, 1H), 3.38 (m, 1H), 3.95 (bs, 1H), 4.30 (bs, 1H), 4.91 (m, 1H), 5.48 (bs, 2H), 7.47 (s, 1H), 8.34 (s, 1H)


MS (ESI): 539 ([M+H]+)


1-Naphthyl 2-(1-{[3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carboxylate (I-771)

4-{4-[(1-Naphthyloxy)carbonyl]-1,3-thiazol-2-yl}piperidinium chloride (X-2, 375 mg) is reacted analogously to Example I-772 with [3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl]acetic acid (288 mg). This gives, after chromatographic purification, 1-naphthyl 2-(1-{[3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carboxylate (356 mg, 61%).


log P (pH 2.7): 4.35



1H NMR (DMSO-d6, 400 MHz): δppm: 1.65 (m, 1H), 1.90 (m, 1H), 2.19 (m, 2H), 2.95 (m, 1H), 3.32 (m, 1H), 3.48 (m, 1H), 4.01 (m, 1H), 4.35 (m, 1H), 5.50 (m, 2H), 7.45 (m, 2H), 7.56-7.61 (m, 3H), 7.89 (m, 2H), 8.02 (m, 1H), 8.84 (s, 1H)


MS (ESI): 583 ([M+H]+)


1-Naphthyl 2-(1-{[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carboxylate (I-813)

Oxalyl chloride (6.78 g) and a drop of N,N-dimethylformamide are added to a solution of [3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]acetic acid (10.8 g) in dichloromethane (150 ml). The reaction mixture is stirred at room temperature overnight, and excess oxalyl chloride is then removed under reduced pressure. The residue is redissolved in dichloromethane (50 ml) and added to a solution of 4-{4-[(1-naphthyloxy)carbonyl]-1,3-thiazol-2-yl]piperidinium chloride (X-2, 7.25 g) and Hünig base (10.4 g) in dichloromethane (100 ml) at 0° C. The reaction mixture is stirred at room temperature overnight. After addition of cone ammonium chloride solution, the aqueous phase is separated off and extracted with ethyl acetate. The combined organic phases are dried over sodium sulfate. The solid is filtered off and the solvent is removed by distillation. The residue is purified chromatographically. This gives 1-naphthyl 2-(1-{[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carboxylate (11.3 g, 64%).


log P (pH 2.7): 3.64



1H NMR (DMSO-d6, 400 MHz): δppm: 1.70 (bs, 1H), 1.87 (bs, 1H), 2.18 (m, 2H), 2.91 (bs, 1H), 3.31 (bs, 1H), 3.48 (m, 1H), 4.03 (bs, 1H), 4.36 (bs, 1H), 5.36 (s, 2H), 6.85 (s, 1H), 6.97 (t, 1H), 7.15 (t, 1H), 7.45 (dd, 1H): 7.54-7.61 (m, 3H), 7.89 (m, 2H), 8.01 (m, 1H), 8.84 (s, 1H)


MS (ESI): 547 ([M+H]+)


Cyclohexyl 2-(1-{2-[3,5-bis(diluoromethyl)-1H-pyrazol-1-yl]ethanethioyl}piperidin-4-yl)-1,3-thiazole-4-carboxylate (I-854)

At room temperature, 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane 2,4-disulfide (88 mg) is added to a solution of cyclohexyl 2-(l-{[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carboxylate (I-811. 200 mg) in 1.2-dimethoxyethane (1 ml) and chloroform (0.4 ml). The reaction mixture is stirred at 70-80° C. overnight. After removal of the solvent under reduced pressure, the residue is purified chromatographically. This gives cyclohexyl 2-(1-{2-[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]ethanethioyl}piperidin-4-yl)-1,3-thiazole-4-carboxylate (80 mg, 39%).


log P (pH 2.7): 4.23



1H NMR (DMSO-d6, 400 MHz): δppm; 1.30-1.58 (m, 6H), 1.75-1.92 (m, 4H), 2.10-2.30 (m, 4H), 3.32 (m, 1H), 3.50 (m, 2H), 4.39 (m, 1H), 4.93 (m, 1H), 5.39 (s, 2H), 5.42 (m, 1H), 6.79 (t, 1H), 6.83 (s, 1H), 7.01 (t, 1H), 8.16 (s, 1H)


MS (ESI): 519 ([M+H]+)







EXAMPLES

Table 1 shows the compounds of the formula (I) whose use as fungicides is claimed.












(I)




embedded image
























EX NO
R1
R2
R3
R4
R5
Y1
X





1
CF3
H
CH3
H
H
O
—CH2CH2


2
CF3
H
CH3
H
H
O
—CH2CH2


3
CF3
H
CH3
H
H
O
—CH2CH2


4
CF3
H
CH3
H
H
O
—CH2CH2


5
CF3
H
CH3
H
H
O
—CH2CH2


6
CF3
H
CH3
H
H
O
—CH2CH2


7
CF3
H
CH3
H
H
O
—CH2CH2


8
CF3
H
CH3
H
H
O
—CH2CH2


9
CF3
H
CH3
H
H
O
—CH2CH2


10
CF3
H
CH3
H
H
O
—CH2CH2


11
CF3
H
CH3
H
H
O
—CH2CH2


12
CF3
H
CH3
H
H
O
—CH2CH2


13
CF3
H
CH3
H
H
O
—CH2CH2


14
CF3
H
CH3
H
H
O
—CH2CH2


15
CF3
H
CH3
H
H
O
—CH2CH2


16
CF3
H
CH3
H
H
O
—CH2CH2


17
CF3
H
CH3
H
H
O
—CH2CH2


18
CF3
H
CH3
H
H
O
—CH2CH2


19
CF3
H
CH3
H
H
O
—CH2CH2


20
CF3
H
CH3
H
H
O
—CH2CH2


21
CF3
H
CH3
H
H
O
—CH2CH2


22
CF3
H
CH3
H
H
O
—CH2CH2


23
CF3
H
CH3
H
H
O
—CH2CH2


24
CF3
H
CH3
H
H
O
—CH2CH2


25
CF3
H
CH3
H
H
O
—CH2CH2


26
CF3
H
CH3
H
H
O
—CH2CH2


27
CF3
H
CH3
H
H
O
—CH2CH2


28
CF3
H
CH3
H
H
O
—CH2CH2


29
CF3
H
CH3
H
H
O
—CH2CH2


30
CF3
H
CH3
H
H
O
—CH2CH2


31
CF3
H
CH3
H
H
O
—CH2CH2


32
CF3
H
CH3
H
H
O
—CH2CH2


33
CF3
H
CH3
H
H
O
—CH2CH2


34
CF3
H
CH3
H
H
O
—CH2CH2


35
CF3
H
CH3
H
H
O
—CH2CH2


36
CF3
H
CH3
H
H
O
—CH2CH2


37
CF3
H
CH3
H
H
O
—CH2CH2


38
CF3
H
CH3
H
H
O
—CH2CH2


39
CF3
H
CH3
H
H
O
—CH2CH2


40
CF3
H
CH3
H
H
O
—CH2CH2


41
CF3
H
CH3
H
H
O
—CH2CH2


42
CF3
H
CH3
H
H
O
—CH2CH2


43
CF3
H
CH3
H
H
O
—CH2CH2


44
CF3
H
CH3
H
H
O
—CH2CH2


45
CF3
H
CH3
H
H
O
—CH2CH2


46
CF3
H
CH3
H
H
O
—CH2CH2


47
CF3
H
CH3
H
H
O
—CH2CH2


48
CF3
H
CH3
H
H
O
—CH2CH2


49
CF3
H
CH3
H
H
O
—CH2CH2


50
CF3
H
CH3
H
H
O
—CH2CH2


51
CF3
H
CH3
H
H
O
—CH2CH2


52
CF3
H
CH3
H
H
O
—CH2CH2


53
CF3
H
CH3
H
H
O
—CH2CH2


54
CF3
H
CH3
H
H
O
—CH2CH2


55
CF3
H
CH3
H
H
O
—CH2CH2


56
CF3
H
CH3
H
H
O
—CH2CH2


57
CF3
H
CH3
H
H
O
—CH2CH2


58
CF3
H
CH3
H
H
O
—CH2CH2


59
CF3
H
CH3
H
H
O
—CH2CH2


60
CF3
H
CH3
H
H
O
—CH2CH2


61
CF3
H
CH3
H
H
O
—CH2CH2


62
CF3
H
CH3
H
H
O
—CH2CH2


63
CF3
H
CH3
H
H
O
—CH2CH2


64
CF3
H
CH3
H
H
O
—CH2CH2


65
CF3
H
CH3
H
H
O
—CH2CH2


66
CF3
H
CH3
H
H
O
—CH2CH2


67
CF3
H
CH3
H
H
O
—CH2CH2


68
CF3
H
CH3
H
H
O
—CH2CH2


69
CF3
H
CH3
H
H
O
—CH2CH2


70
CF3
H
CH3
H
H
O
—CH2CH2


71
CF3
H
CH3
H
H
O
—CH2CH2


72
CF3
H
CH3
H
H
O
—CH2CH2


73
CF3
H
CH3
H
H
O
—CH2CH2


74
CF3
H
CH3
H
H
O
—CH2CH2


75
CF3
H
CH3
H
H
O
—CH2CH2


76
CF3
H
CH3
H
H
O
—CH2CH2


77
CF3
H
CH3
H
H
O
—CH2CH2


78
CF3
H
CH3
H
H
O
—CH2CH2


79
CF3
H
CH3
H
H
O
—CH2CH2


80
CF3
H
CH3
H
H
O
—CH2CH2


81
CF3
H
CH3
H
H
O
—CH2CH2


82
CF3
H
CH3
H
H
O
—CH2CH2


83
CF3
H
CH3
H
H
O
—CH2CH2


84
CF3
H
H
H
H
O
—CH2CH2


85
CF3
H
H
H
H
O
—CH2CH2


86
CF3
H
H
H
H
O
—CH2CH2


87
CF3
H
H
H
H
O
—CH2CH2


88
CF3
H
H
H
H
O
—CH2CH2


89
CF3
H
H
H
H
O
—CH2CH2


90
CF3
H
H
H
H
O
—CH2CH2


91
CF3
H
H
H
H
O
—CH2CH2


92
CF3
H
H
H
H
O
—CH2CH2


93
CF3
H
H
H
H
O
—CH2CH2


94
CF3
H
H
H
H
O
—CH2CH2


95
CF3
H
H
H
H
O
—CH2CH2


96
CF3
H
H
H
H
O
—CH2CH2


97
CF3
H
H
H
H
O
—CH2CH2


98
CF3
H
H
H
H
O
—CH2CH2


99
CF3
H
H
H
H
O
—CH2CH2


100
CF3
H
H
H
H
O
—CH2CH2


101
CF3
H
H
H
H
O
—CH2CH2


102
CF3
H
H
H
H
O
—CH2CH2


103
CF3
H
H
H
H
O
—CH2CH2


104
CF3
H
H
H
H
O
—CH2CH2


105
CF3
H
H
H
H
O
—CH2CH2


106
CF3
H
H
H
H
O
—CH2CH2


107
CF3
H
H
H
H
O
—CH2CH2


108
CF3
H
H
H
H
O
—CH2CH2


109
CF3
H
H
H
H
O
—CH2CH2


110
CF3
H
H
H
H
O
—CH2CH2


111
CF3
H
H
H
H
O
—CH2CH2


112
CF3
H
H
H
H
O
—CH2CH2


113
CF3
H
H
H
H
O
—CH2CH2


114
CF3
H
H
H
H
O
—CH2CH2


115
CF3
H
H
H
H
O
—CH2CH2


116
CF3
H
H
H
H
O
—CH2CH2


117
CF3
H
H
H
H
O
—CH2CH2


118
CF3
H
H
H
H
O
—CH2CH2


119
CF3
H
H
H
H
O
—CH2CH2


120
CF3
H
H
H
H
O
—CH2CH2


121
CF3
H
H
H
H
O
—CH2CH2


122
CF3
H
H
H
H
O
—CH2CH2


123
CF3
H
H
H
H
O
—CH2CH2


124
CF3
H
H
H
H
O
—CH2CH2


125
CF3
H
H
H
H
O
—CH2CH2


126
CF3
H
H
H
H
O
—CH2CH2


127
CF3
H
H
H
H
O
—CH2CH2


128
CF3
H
H
H
H
O
—CH2CH2


129
CF3
H
H
H
H
O
—CH2CH2


130
CF3
H
H
H
H
O
—CH2CH2


131
CF3
H
H
H
H
O
—CH2CH2


132
CF3
H
H
H
H
O
—CH2CH2


133
CF3
H
H
H
H
O
—CH2CH2


134
CF3
H
H
H
H
O
—CH2CH2


135
CF3
H
H
H
H
O
—CH2CH2


136
CF3
H
H
H
H
O
—CH2CH2


137
CF3
H
H
H
H
O
—CH2CH2


138
CF3
H
H
H
H
O
—CH2CH2


139
CF3
H
H
H
H
O
—CH2CH2


140
CF3
H
H
H
H
O
—CH2CH2


141
CF3
H
H
H
H
O
—CH2CH2


142
CF3
H
H
H
H
O
—CH2CH2


143
CF3
H
H
H
H
O
—CH2CH2


144
CF3
chlorine
CH3
H
H
O
—CH2CH2


145
CF3
chlorine
CH3
H
H
O
—CH2CH2


146
CF3
chlorine
CH3
H
H
O
—CH2CH2


147
CF3
chlorine
CH3
H
H
O
—CH2CH2


148
CF3
chlorine
CH3
H
H
O
—CH2CH2


149
CF3
chlorine
CH3
H
H
O
—CH2CH2


150
CF3
chlorine
CH3
H
H
O
—CH2CH2


151
CF3
chlorine
CH3
H
H
O
—CH2CH2


152
CF3
chlorine
CH3
H
H
O
—CH2CH2


153
CF3
chlorine
CH3
H
H
O
—CH2CH2


154
CF3
chlorine
CH3
H
H
O
—CH2CH2


155
CF3
chlorine
CH3
H
H
O
—CH2CH2


156
CF3
chlorine
CH3
H
H
O
—CH2CH2


157
CF3
chlorine
CH3
H
H
O
—CH2CH2


158
CF3
chlorine
CH3
H
H
O
—CH2CH2


159
CF3
chlorine
CH3
H
H
O
—CH2CH2


160
CF3
chlorine
CH3
H
H
O
—CH2CH2


161
CF3
chlorine
CH3
H
H
O
—CH2CH2


162
CF3
chlorine
CH3
H
H
O
—CH2CH2


163
CF3
chlorine
CH3
H
H
O
—CH2CH2


164
CF3
chlorine
CH3
H
H
O
—CH2CH2


165
CF3
chlorine
CH3
H
H
O
—CH2CH2


166
CF3
chlorine
CH3
H
H
O
—CH2CH2


167
CF3
chlorine
CH3
H
H
O
—CH2CH2


168
CF3
chlorine
CH3
H
H
O
—CH2CH2


169
CF3
chlorine
CH3
H
H
O
—CH2CH2


170
CF3
chlorine
CH3
H
H
O
—CH2CH2


171
CF3
chlorine
CH3
H
H
O
—CH2CH2


172
CF3
chlorine
CH3
H
H
O
—CH2CH2


173
CF3
chlorine
CH3
H
H
O
—CH2CH2


174
CF3
chlorine
CH3
H
H
O
—CH2CH2


175
CF3
chlorine
CH3
H
H
O
—CH2CH2


176
CF3
chlorine
CH3
H
H
O
—CH2CH2


177
CF3
chlorine
CH3
H
H
O
—CH2CH2


178
CF3
chlorine
CH3
H
H
O
—CH2CH2


179
CF3
chlorine
CH3
H
H
O
—CH2CH2


180
CF3
chlorine
CH3
H
H
O
—CH2CH2


181
CF3
chlorine
CH3
H
H
O
—CH2CH2


182
CF3
chlorine
CH3
H
H
O
—CH2CH2


183
CF3
chlorine
CH3
H
H
O
—CH2CH2


184
CF3
chlorine
CH3
H
H
O
—CH2CH2


185
CF3
chlorine
CH3
H
H
O
—CH2CH2


186
CF3
chlorine
CH3
H
H
O
—CH2CH2


187
CF3
chlorine
CH3
H
H
O
—CH2CH2


188
CF3
chlorine
CH3
H
H
O
—CH2CH2


189
CF3
chlorine
CH3
H
H
O
—CH2CH2


190
CF3
chlorine
CH3
H
H
O
—CH2CH2


191
CF3
chlorine
CH3
H
H
O
—CH2CH2


192
CF3
chlorine
CH3
H
H
O
—CH2CH2


193
CF3
chlorine
CH3
H
H
O
—CH2CH2


194
CF3
chlorine
CH3
H
H
O
—CH2CH2


195
CF3
chlorine
CH3
H
H
O
—CH2CH2


196
CF3
chlorine
CH3
H
H
O
—CH2CH2


197
CF3
chlorine
CH3
H
H
O
—CH2CH2


198
CF3
chlorine
CH3
H
H
O
—CH2CH2


199
CF3
chlorine
CH3
H
H
O
—CH2CH2


200
CF3
chlorine
CH3
H
H
O
—CH2CH2


201
CF3
chlorine
CH3
H
H
O
—CH2CH2


202
CF3
chlorine
CH3
H
H
O
—CH2CH2


203
CF3
chlorine
CH3
H
H
O
—CH2CH2


204
CF3
chlorine
CH3
H
H
O
—CH2CH2


205
CF3
chlorine
CH3
H
H
O
—CH2CH2


206
CF3
chlorine
CH3
H
H
O
—CH2CH2


207
CF3
chlorine
CH3
H
H
O
—CH2CH2


208
CF3
chlorine
CH3
H
H
O
—CH2CH2


209
CF3
chlorine
CH3
H
H
O
—CH2CH2


210
CF3
chlorine
CH3
H
H
O
—CH2CH2


211
CF3
chlorine
CH3
H
H
O
—CH2CH2


212
CF3
chlorine
CH3
H
H
O
—CH2CH2


213
CF3
chlorine
CH3
H
H
O
—CH2CH2


214
CF3
chlorine
CH3
H
H
O
—CH2CH2


215
CF3
chlorine
CH3
H
H
O
—CH2CH2


216
CF3
chlorine
CH3
H
H
O
—CH2CH2


217
CF3
chlorine
CH3
H
H
O
—CH2CH2


218
CF3
chlorine
CH3
H
H
O
—CH2CH2


219
CF3
H
CH3
H
H
O
—CH2


220
CF3
H
CH3
H
H
O
—CH2


221
CF3
H
CH3
H
H
O
—CH2


222
CF3
H
CH3
H
H
O
—CH2


223
CF3
H
CH3
H
H
O
—CH2


224
CF3
H
CH3
H
H
O
—CH2


225
CF3
H
CH3
H
H
O
—CH2


226
CF3
H
CH3
H
H
O
—CH2


227
CF3
H
CH3
H
H
O
—CH2


228
CF3
H
CH3
H
H
O
—CH2


229
CF3
H
CH3
H
H
O
—CH2


230
CF3
H
CH3
H
H
O
—CH2


231
CF3
H
CH3
H
H
O
—CH2


232
CF3
H
CH3
H
H
O
—CH2


233
CF3
H
CH3
H
H
O
—CH2


234
CF3
H
CH3
H
H
O
—CH2


235
CF3
H
CH3
H
H
O
—CH2


236
CF3
H
CH3
H
H
O
—CH2


237
CF3
H
CH3
H
H
O
—CH2


238
CF3
H
CH3
H
H
O
—CH2


239
CF3
H
CH3
H
H
O
—CH2


240
CF3
H
CH3
H
H
O
—CH2


241
CF3
H
CH3
H
H
O
—CH2


242
CF3
H
CH3
H
H
O
—CH2


243
CF3
H
CH3
H
H
O
—CH2


244
CF3
H
CH3
H
H
O
—CH2


245
CF3
H
CH3
H
H
O
—CH2


246
CF3
H
CH3
H
H
O
—CH2


247
CF3
H
CH3
H
H
O
—CH2


248
CF3
H
CH3
H
H
O
—CH2


249
CF3
H
CH3
H
H
O
—CH2


250
CF3
H
CH3
H
H
O
—CH2


251
CF3
H
CH3
H
H
O
—CH2


252
CF3
H
CH3
H
H
O
—CH2


253
CF3
H
CH3
H
H
O
—CH2


254
CF3
H
CH3
H
H
O
—CH2


255
CF3
H
CH3
H
H
O
—CH2


256
CF3
H
CH3
H
H
O
—CH2


257
CF3
H
CH3
H
H
O
—CH2


258
CF3
H
CH3
H
H
O
—CH2


259
CF3
H
CH3
H
H
O
—CH2


260
CF3
H
CH3
H
H
O
—CH2


261
CF3
H
CH3
H
H
O
—CH2


262
CF3
H
CH3
H
H
O
—CH2


263
CF3
H
CH3
H
H
O
—CH2


264
CF3
H
CH3
H
H
O
—CH2


265
CF3
H
CH3
H
H
O
—CH2


266
CF3
H
CH3
H
H
O
—CH2


267
CF3
H
CH3
H
H
O
—CH2


268
CF3
H
CH3
H
H
O
—CH2


269
CF3
H
CH3
H
H
O
—CH2


270
CF3
H
CH3
H
H
O
—CH2


271
CF3
H
CH3
H
H
O
—CH2


272
CF3
H
CH3
H
H
O
—CH2


273
CF3
H
CH3
H
H
O
—CH2


274
CF3
H
CH3
H
H
O
—CH2


275
CF3
H
CH3
H
H
O
—CH2


276
CF3
H
CH3
H
H
O
—CH2


277
CF3
H
CH3
H
H
O
—CH2


278
CF3
H
CH3
H
H
O
—CH2


279
CF3
H
CH3
H
H
O
—CH2


280
CF3
H
CH3
H
H
O
—CH2


281
CF3
H
CH3
H
H
O
—CH2


282
CF3
H
CH3
H
H
O
—CH2


283
CF3
H
CH3
H
H
O
—CH2


284
CF3
H
CH3
H
H
O
—CH2


285
CF3
H
CH3
H
H
O
—CH2


286
CF3
H
CH3
H
H
O
—CH2


287
CF3
H
CH3
H
H
O
—CH2


288
CF3
H
CH3
H
H
O
—CH2


289
CF3
H
CH3
H
H
O
—CH2


290
CF3
H
CH3
H
H
O
—CH2


291
CF3
H
CH3
H
H
O
—CH2


292
CF3
H
CH3
H
H
O
—CH2


293
CF3
H
CH3
H
H
O
—CH2


294
CH3
H
CH3
H
H
O
—CH2CH2


295
CH3
H
CH3
H
H
O
—CH2CH2


296
CH3
H
CH3
H
H
O
—CH2CH2


297
CH3
H
CH3
H
H
O
—CH2CH2


298
CH3
H
CH3
H
H
O
—CH2CH2


299
CH3
H
CH3
H
H
O
—CH2CH2


300
CH3
H
CH3
H
H
O
—CH2CH2


301
CH3
H
CH3
H
H
O
—CH2CH2


302
CH3
H
CH3
H
H
O
—CH2CH2


303
CH3
H
CH3
H
H
O
—CH2CH2


304
CH3
H
CH3
H
H
O
—CH2CH2


305
CH3
H
CH3
H
H
O
—CH2CH2


306
CH3
H
CH3
H
H
O
—CH2CH2


307
CH3
H
CH3
H
H
O
—CH2CH2


308
CH3
H
CH3
H
H
O
—CH2CH2


309
CH3
H
CH3
H
H
O
—CH2CH2


310
CH3
H
CH3
H
H
O
—CH2CH2


311
CH3
H
CH3
H
H
O
—CH2CH2


312
CH3
H
CH3
H
H
O
—CH2CH2


313
CH3
H
CH3
H
H
O
—CH2CH2


314
CH3
H
CH3
H
H
O
—CH2CH2


315
CH3
H
CH3
H
H
O
—CH2CH2


316
CH3
H
CH3
H
H
O
—CH2CH2


317
CH3
H
CH3
H
H
O
—CH2CH2


318
CH3
H
CH3
H
H
O
—CH2CH2


319
CH3
H
CH3
H
H
O
—CH2CH2


320
CH3
H
CH3
H
H
O
—CH2CH2


321
CH3
H
CH3
H
H
O
—CH2CH2


322
CH3
H
CH3
H
H
O
—CH2CH2


323
CH3
H
CH3
H
H
O
—CH2CH2


324
CH3
H
CH3
H
H
O
—CH2CH2


325
CH3
H
CH3
H
H
O
—CH2CH2


326
CH3
H
CH3
H
H
O
—CH2CH2


327
CH3
H
CH3
H
H
O
—CH2CH2


328
CH3
H
CH3
H
H
O
—CH2CH2


329
CH3
H
CH3
H
H
O
—CH2CH2


330
CH3
H
CH3
H
H
O
—CH2CH2


331
CH3
H
CH3
H
H
O
—CH2CH2


332
CH3
H
CH3
H
H
O
—CH2CH2


333
CH3
H
CH3
H
H
O
—CH2CH2


334
CH3
H
CH3
H
H
O
—CH2CH2


335
CH3
H
CH3
H
H
O
—CH2CH2


336
CH3
H
CH3
H
H
O
—CH2CH2


337
CH3
H
CH3
H
H
O
—CH2CH2


338
CH3
H
CH3
H
H
O
—CH2CH2


339
CH3
H
CH3
H
H
O
—CH2CH2


340
CH3
H
CH3
H
H
O
—CH2CH2


341
CH3
H
CH3
H
H
O
—CH2CH2


342
CH3
H
CH3
H
H
O
—CH2CH2


343
CH3
H
CH3
H
H
O
—CH2CH2


344
CH3
H
CH3
H
H
O
—CH2CH2


345
CH3
H
CH3
H
H
O
—CH2CH2


346
CH3
H
CH3
H
H
O
—CH2CH2


347
CH3
H
CH3
H
H
O
—CH2CH2


348
CH3
H
CH3
H
H
O
—CH2CH2


349
CH3
H
CH3
H
H
O
—CH2CH2


350
CH3
H
CH3
H
H
O
—CH2CH2


351
CH3
H
CH3
H
H
O
—CH2CH2


352
CH3
H
CH3
H
H
O
—CH2CH2


353
CH3
H
CH3
H
H
O
—CH2CH2


354
CH3
H
CH3
H
H
O
—CH2CH2


355
CH3
H
CH3
H
H
O
—CH2CH2


356
CH3
H
CH3
H
H
O
—CH2CH2


357
CH3
H
CH3
H
H
O
—CH2CH2


358
CH3
H
CH3
H
H
O
—CH2CH2


359
CH3
H
CH3
H
H
O
—CH2CH2


360
CH3
H
CH3
H
H
O
—CH2CH2


361
CH3
H
CH3
H
H
O
—CH2CH2


362
CH3
H
CH3
H
H
O
—CH2CH2


363
CH3
H
CH3
H
H
O
—CH2CH2


364
CH3
H
CH3
H
H
O
—CH2CH2


365
CH3
H
CH3
CH3
CH3
O
—CH2CH2


366
CH3
H
CH3
H
H
O
—CH2CH2


367
CH3
H
CH3
H
H
O
—CH2CH2


368
CH3
H
CH3
CH3
CH3
O
—CH2CH2


369
CH3
H
CH3
CH3
CH3
O
—CH2CH2


370
CH3
H
CH3
CH3
CH3
O
—CH2CH2


371
CH3
H
CH3
H
H
O
—CH2CH2


372
CH3
H
CH3
CH3
CH3
O
—CH2CH2


373
CH3
H
CH3
CH3
CH3
O
—CH2CH2


374
CH3
H
CH3
H
H
O
—CH2CH2


375
CH3
H
CH3
CH3
CH3
O
—CH2CH2


376
CH3
H
CH3
CH3
CH3
O
—CH2CH2


377
CH3
H
CH3
CH3
CH3
O
—CH2CH2


378
CH3
H
CH3
CH3
CH3
O
—CH2CH2


379
CH3
H
CH3
CH3
CH3
O
—CH2CH2


380
CH3
H
CH3
CH3
CH3
O
—CH2CH2


381
CH3
H
CH3
CH3
CH3
O
—CH2CH2


382
CH3
H
CH3
CH3
CH3
O
—CH2CH2


383
CH3
H
CH3
CH3
CH3
O
—CH2CH2


384
CH3
H
CH3
CH3
CH3
O
—CH2CH2


385
CH3
H
CH3
CH3
CH3
O
—CH2CH2


386
CH3
H
CH3
CH3
CH3
O
—CH2CH2


387
CH3
H
CH3
CH3
CH3
O
—CH2CH2


388
CH3
H
CH3
CH3
CH3
O
—CH2CH2


389
CH3
H
CH3
CH3
CH3
O
—CH2CH2


390
CH3
H
CH3
CH3
CH3
O
—CH2CH2


391
CH3
H
CH3
CH3
CH3
O
—CH2CH2


392
CH3
H
CH3
CH3
CH3
O
—CH2CH2


393
CH3
H
CH3
CH3
CH3
O
—CH2CH2


394
CH3
H
CH3
CH3
CH3
O
—CH2CH2


395
CH3
H
CH3
CH3
CH3
O
—CH2CH2


396
CH3
H
CH3
CH3
CH3
O
—CH2CH2


397
CH3
H
CH3
CH3
CH3
O
—CH2CH2


398
CH3
H
CH3
CH3
CH3
O
—CH2CH2


399
CH3
H
CH3
CH3
CH3
O
—CH2CH2


400
CH3
H
CH3
CH3
CH3
O
—CH2CH2


401
CH3
H
CH3
CH3
CH3
O
—CH2CH2


402
CH3
H
CH3
CH3
CH3
O
—CH2CH2


403
CH3
H
CH3
CH3
CH3
O
—CH2CH2


404
CH3
H
CH3
CH3
CH3
O
—CH2CH2


405
CH3
H
CH3
CH3
CH3
O
—CH2CH2


406
CH3
H
CH3
CH3
CH3
O
—CH2CH2


407
CH3
H
CH3
CH3
CH3
O
—CH2CH2


408
CH3
H
CH3
CH3
CH3
O
—CH2CH2


409
CH3
H
CH3
CH3
CH3
O
—CH2CH2


410
CH3
H
CH3
CH3
CH3
O
—CH2CH2


411
CH3
H
CH3
CH3
CH3
O
—CH2CH2


412
CH3
H
CH3
CH3
CH3
O
—CH2CH2


413
CH3
H
CH3
CH3
CH3
O
—CH2CH2


414
CH3
H
CH3
CH3
CH3
O
—CH2CH2


415
CH3
H
CH3
CH3
CH3
O
—CH2CH2


416
CH3
H
CH3
CH3
CH3
O
—CH2CH2


417
CH3
H
CH3
CH3
CH3
O
—CH2CH2


418
CH3
H
CH3
CH3
CH3
O
—CH2CH2


419
CH3
H
CH3
CH3
CH3
O
—CH2CH2


420
CH3
H
CH3
CH3
CH3
O
—CH2CH2


421
CH3
H
CH3
CH3
CH3
O
—CH2CH2


422
CH3
H
CH3
CH3
CH3
O
—CH2CH2


423
CH3
H
CH3
CH3
CH3
O
—CH2CH2


424
CH3
H
CH3
CH3
CH3
O
—CH2CH2


425
CH3
H
CH3
CH3
CH3
O
—CH2CH2


426
CH3
H
CH3
CH3
CH3
O
—CH2CH2


427
CH3
H
CH3
CH3
CH3
O
—CH2CH2


428
CH3
H
CH3
CH3
CH3
O
—CH2CH2


429
CH3
H
CH3
CH3
CH3
O
—CH2CH2


430
CH3
H
CH3
CH3
CH3
O
—CH2CH2


431
CH3
H
CH3
CH3
CH3
O
—CH2CH2


432
CH3
H
CH3
CH3
CH3
O
—CH2CH2


433
CH3
H
CH3
CH3
CH3
O
—CH2CH2


434
CH3
H
CH3
CH3
CH3
O
—CH2CH2


435
CH3
H
CH3
CH3
CH3
O
—CH2CH2


436
CH3
H
CH3
CH3
CH3
O
—CH2CH2


437
CH3
H
CH3
CH3
CH3
O
—CH2CH2


438
CH3
H
CH3
CH3
CH3
O
—CH2CH2


439
CH3
H
CH3
CH3
CH3
O
—CH2CH2


440
CH3
H
CH3
CH3
CH3
O
—CH2CH2


441
CH3
H
CH3
CH3
CH3
O
—CH2CH2


442
CH3
H
CH3
CH3
CH3
O
—CH2CH2


443
CH3
H
CH3
CH3
CH3
O
—CH2CH2


444
CF3
H
CH3
H
H
O
—CH2CH2


445
CF3
H
CH3
H
H
O
—CH2CH2


446
CF3
H
CH3
H
H
O
—CH2CH2


447
CF3
H
CH3
H
H
O
—CH2CH2


448
CF3
H
CH3
H
H
O
—CH2CH2


449
CF3
H
CH3
H
H
O
—CH2CH2


450
CF3
H
CH3
H
H
O
—CH2CH2


451
CF3
H
CH3
H
H
O
—CH2CH2


452
CF3
H
CH3
H
H
O
—CH2CH2


453
CF3
H
CH3
H
H
O
—CH2CH2


454
CF3
H
CH3
H
H
O
—CH2CH2


455
CF3
H
CH3
H
H
O
—CH2CH2


456
CF3
H
CH3
H
H
O
—CH2CH2


457
CF3
H
CH3
H
H
O
—CH2CH2


458
CF3
H
CH3
H
H
O
—CH2CH2


459
CF3
H
CH3
H
H
O
—CH2CH2


460
CF3
H
CH3
H
H
O
—CH2CH2


461
CF3
H
CH3
H
H
O
—CH2CH2


462
CF3
H
CH3
H
H
O
—CH2CH2


463
CF3
H
CH3
H
H
O
—CH2CH2


464
CF3
H
CH3
H
H
O
—CH2CH2


465
CF3
H
CH3
H
H
O
—CH2CH2


466
CF3
H
CH3
H
H
O
—CH2CH2


467
CF3
H
CH3
H
H
O
—CH2CH2


468
CF3
H
CH3
H
H
O
—CH2CH2


469
CF3
H
CH3
H
H
O
—CH2CH2


470
CF3
H
CH3
H
H
O
—CH2CH2


471
CF3
H
CH3
H
H
O
—CH2CH2


472
CF3
H
CH3
H
H
O
—CH2CH2


473
CF3
H
CH3
H
H
O
—CH2CH2


474
CF3
H
CH3
H
H
O
—CH2CH2


475
CF3
H
CH3
H
H
O
—CH2CH2


476
CF3
H
CH3
H
H
O
—CH2CH2


477
CF3
H
CH3
H
H
O
—CH2CH2


478
CF3
H
CH3
H
H
O
—CH2CH2


479
CF3
H
CH3
H
H
O
—CH2CH2


480
CF3
H
CH3
H
H
O
—CH2CH2


481
CF3
H
CH3
H
H
O
—CH2CH2


482
CF3
H
CH3
H
H
O
—CH2CH2


483
CF3
H
CH3
H
H
O
—CH2CH2


484
CF3
H
CH3
H
H
O
—CH2CH2


485
CF3
H
CH3
H
H
O
—CH2CH2


486
CF3
H
CH3
H
H
O
—CH2CH2


487
CF3
H
CH3
H
H
O
—CH2CH2


488
CF3
H
CH3
H
H
O
—CH2CH2


489
CF3
H
CH3
H
H
O
—CH2CH2


490
CF3
H
CH3
H
H
O
—CH2CH2


491
CF3
H
CH3
H
H
O
—CH2CH2


492
CF3
H
CH3
H
H
O
—CH2CH2


493
CF3
H
CH3
H
H
O
—CH2CH2


494
CF3
H
CH3
H
H
O
—CH2CH2


495
CF3
H
CH3
H
H
O
—CH2CH2


496
CF3
H
CH3
H
H
O
—CH2CH2


497
CF3
H
CH3
H
H
O
—CH2CH2


498
CF3
H
CH3
H
H
O
—CH2CH2


499
CF3
H
CH3
H
H
O
—CH2CH2


500
CF3
H
CH3
H
H
O
—CH2CH2


501
CF3
H
CH3
H
H
O
—CH2CH2


502
CF3
H
CH3
H
H
O
—CH2CH2


503
CF3
H
CH3
H
H
O
—CH2CH2


504
CF3
H
CH3
H
H
O
—CH2CH2


505
CF3
H
CH3
H
H
O
—CH2CH2


506
CF3
H
CH3
H
H
O
—CH2CH2


507
CF3
H
CH3
H
H
O
—CH2CH2


508
CF3
H
CH3
H
H
O
—CH2CH2


509
CF3
H
CH3
H
H
O
—CH2CH2


510
CF3
H
CH3
H
H
O
—CH2CH2


511
CF3
H
CH3
H
H
O
—CH2CH2


512
CF3
H
CH3
H
H
O
—CH2CH2


513
CF3
H
CH3
H
H
O
—CH2CH2


514
CF3
H
CH3
H
H
O
—CH2CH2


515
CF3
H
CH3
H
H
O
—CH2CH2


516
CF3
H
CH3
H
H
O
—CH2CH2


517
CF3
H
CH3
H
H
O
—CH2CH2


518
CF3
H
CH3
H
H
O
—CH2CH2


519
CF3
H
CH3
H
H
O
—CH2CH2


520
CF3
H
CH3
H
H
O
—CH2CH2


521
CF3
H
CH3
H
H
O
bond


522
CF3
H
CH3
H
H
O
bond


523
CF3
H
CH3
H
H
O
bond


524
CF3
H
CH3
H
H
O
bond


525
CF3
H
CH3
H
H
O
bond


526
CF3
H
CH3
H
H
O
bond


527
CF3
H
CH3
H
H
O
bond


528
CF3
H
CH3
H
H
O
bond


529
CF3
H
CH3
H
H
O
bond


530
CF3
H
CH3
H
H
O
bond


531
CF3
H
CH3
H
H
O
bond


532
CF3
H
CH3
H
H
O
bond


533
CF3
H
CH3
H
H
O
bond


534
CF3
H
CH3
H
H
O
bond


535
CF3
H
CH3
H
H
O
bond


536
CF3
H
CH3
H
H
O
bond


537
CF3
H
CH3
H
H
O
bond


538
CF3
H
CH3
H
H
O
bond


539
CF3
H
CH3
H
H
O
bond


540
CF3
H
CH3
H
H
O
bond


541
CF3
H
CH3
H
H
O
bond


542
CF3
H
CH3
H
H
O
bond


543
CF3
H
CH3
H
H
O
bond


544
CF3
H
CH3
H
H
O
bond


545
CF3
H
CH3
H
H
O
bond


546
CF3
H
CH3
H
H
O
bond


547
CF3
H
CH3
H
H
O
bond


548
CF3
H
CH3
H
H
O
bond


549
CF3
H
CH3
H
H
O
bond


550
CF3
H
CH3
H
H
O
bond


551
CF3
H
CH3
H
H
O
bond


552
CF3
H
CH3
H
H
O
bond


553
CF3
H
CH3
H
H
O
bond


554
CF3
H
CH3
H
H
O
bond


555
CF3
H
CH3
H
H
O
bond


556
CF3
H
CH3
H
H
O
bond


557
CF3
H
CH3
H
H
O
bond


558
CF3
H
CH3
H
H
O
bond


559
CF3
H
CH3
H
H
O
bond


560
CF3
H
CH3
H
H
O
bond


561
CF3
H
CH3
H
H
O
bond


562
CF3
H
CH3
H
H
O
bond


563
CF3
H
CH3
H
H
O
bond


564
CF3
H
CH3
H
H
O
bond


565
CF3
H
CH3
H
H
O
bond


566
CF3
H
CH3
H
H
O
bond


567
CF3
H
CH3
H
H
O
bond


568
CF3
H
CH3
H
H
O
bond


569
CF3
H
CH3
H
H
O
bond


570
CF3
H
CH3
H
H
O
bond


571
CF3
H
CH3
H
H
O
bond


572
CF3
H
CH3
H
H
O
bond


573
CF3
H
CH3
H
H
O
bond


574
CF3
H
CH3
H
H
O
bond


575
CF3
H
CH3
H
H
O
bond


576
CF3
H
CH3
H
H
O
bond


577
CF3
H
CH3
H
H
O
bond


578
CF3
H
CH3
H
H
O
bond


579
CF3
H
CH3
H
H
O
bond


580
CF3
H
CH3
H
H
O
bond


581
CF3
H
CH3
H
H
O
bond


582
CF3
H
CH3
H
H
O
bond


583
CF3
H
CH3
H
H
O
bond


584
CF3
H
CH3
H
H
O
bond


585
CF3
H
CH3
H
H
O
bond


586
CF3
H
CH3
H
H
O
bond


587
CF3
H
CH3
H
H
O
bond


588
CF3
H
CH3
H
H
O
bond


589
CF3
H
CH3
H
H
O
bond


590
CF3
H
CH3
H
H
O
bond


591
CF3
H
CH3
H
H
O
bond


592
CF3
H
CH3
H
H
O
bond


593
CF3
H
CH3
H
H
O
bond


594
CF3
H
CH3
H
H
O
bond


595
CF3
H
CH3
H
H
O
bond


596
CF3
H
CH3
H
H
O
bond


597
CF3
H
CH3
H
H
O
bond


598
CF3
H
CH3
H
CH3
O
—CH2CH2


599
CF3
H
CH3
H
CH3
O
—CH2CH2


600
CF3
H
CH3
H
CH3
O
—CH2CH2


601
CF3
H
CH3
H
CH3
O
—CH2CH2


602
CF3
H
CH3
H
CH3
O
—CH2CH2


603
CF3
H
CH3
H
CH3
O
—CH2CH2


604
CF3
H
CH3
H
CH3
O
—CH2CH2


605
CF3
H
CH3
H
CH3
O
—CH2CH2


606
CF3
H
CH3
H
CH3
O
—CH2CH2


607
CF3
H
CH3
H
CH3
O
—CH2CH2


608
CF3
H
CH3
H
CH3
O
—CH2CH2


609
CF3
H
CH3
H
CH3
O
—CH2CH2


610
CF3
H
CH3
H
CH3
O
—CH2CH2


611
CF3
H
CH3
H
CH3
O
—CH2CH2


612
CF3
H
CH3
H
CH3
O
—CH2CH2


613
CF3
H
CH3
H
CH3
O
—CH2CH2


614
CF3
H
CH3
H
CH3
O
—CH2CH2


615
CF3
H
CH3
H
CH3
O
—CH2CH2


616
CF3
H
CH3
H
CH3
O
—CH2CH2


617
CF3
H
CH3
H
CH3
O
—CH2CH2


618
CF3
H
CH3
H
CH3
O
—CH2CH2


619
CF3
H
CH3
H
CH3
O
—CH2CH2


620
CF3
H
CH3
H
CH3
O
—CH2CH2


621
CF3
H
CH3
H
CH3
O
—CH2CH2


622
CF3
H
CH3
H
CH3
O
—CH2CH2


623
CF3
H
CH3
H
CH3
O
—CH2CH2


624
CF3
H
CH3
H
CH3
O
—CH2CH2


625
CF3
H
CH3
H
CH3
O
—CH2CH2


626
CF3
H
CH3
H
CH3
O
—CH2CH2


627
CF3
H
CH3
H
CH3
O
—CH2CH2


628
CF3
H
CH3
H
CH3
O
—CH2CH2


629
CF3
H
CH3
H
CH3
O
—CH2CH2


630
CF3
H
CH3
H
CH3
O
—CH2CH2


631
CF3
H
CH3
H
CH3
O
—CH2CH2


632
CF3
H
CH3
H
CH3
O
—CH2CH2


633
CF3
H
CH3
H
CH3
O
—CH2CH2


634
CF3
H
CH3
H
CH3
O
—CH2CH2


635
CF3
H
CH3
H
CH3
O
—CH2CH2


636
CF3
H
CH3
H
CH3
O
—CH2CH2


637
CF3
H
CH3
H
CH3
O
—CH2CH2


638
CF3
H
CH3
H
CH3
O
—CH2CH2


639
CF3
H
CH3
H
CH3
O
—CH2CH2


640
CF3
H
CH3
H
CH3
O
—CH2CH2


641
CF3
H
CH3
H
CH3
O
—CH2CH2


642
CF3
H
CH3
H
CH3
O
—CH2CH2


643
CF3
H
CH3
H
CH3
O
—CH2CH2


644
CF3
H
CH3
H
CH3
O
—CH2CH2


645
CF3
H
CH3
H
CH3
O
—CH2CH2


646
CF3
H
CH3
H
CH3
O
—CH2CH2


647
CF3
H
CH3
H
CH3
O
—CH2CH2


648
CF3
H
CH3
H
CH3
O
—CH2CH2


649
CF3
H
CH3
H
CH3
O
—CH2CH2


650
CF3
H
CH3
H
CH3
O
—CH2CH2


651
CF3
H
CH3
H
CH3
O
—CH2CH2


652
CF3
H
CH3
H
CH3
O
—CH2CH2


653
CF3
H
CH3
H
CH3
O
—CH2CH2


654
CF3
H
CH3
H
CH3
O
—CH2CH2


655
CF3
H
CH3
H
CH3
O
—CH2CH2


656
CF3
H
CH3
H
CH3
O
—CH2CH2


657
CF3
H
CH3
H
CH3
O
—CH2CH2


658
CF3
H
CH3
H
CH3
O
—CH2CH2


659
CF3
H
CH3
H
CH3
O
—CH2CH2


660
CF3
H
CH3
H
CH3
O
—CH2CH2


661
CF3
H
CH3
H
CH3
O
—CH2CH2


662
CF3
H
CH3
H
CH3
O
—CH2CH2


663
CF3
H
CH3
H
CH3
O
—CH2CH2


664
CF3
H
CH3
H
CH3
O
—CH2CH2


665
CF3
H
CH3
H
CH3
O
—CH2CH2


666
CF3
H
CH3
H
CH3
O
—CH2CH2


667
CF3
H
CH3
H
CH3
O
—CH2CH2


668
CF3
H
CH3
H
CH3
O
—CH2CH2


669
CF3
H
CH3
H
CH3
O
—CH2CH2


670
CF3
H
CH3
H
CH3
O
—CH2CH2


671
CF3
H
CH3
H
CH3
O
—CH2CH2


672
CF3
H
CH3
H
CH3
O
—CH2CH2


673
CF3
H
CH3
H
CH3
O
—CH2CH2


674
CF3
H
CH3
H
CH3
O
—CH2CH2













675
(1Z,3Z)-buta-
CH3
H
H
O
—CH2CH2



1,3-diene-1,4-diyl







676
(1Z,3Z)-buta-
CH3
H
H
O
—CH2CH2



1,3-diene-1,4-diyl







677
(1Z,3Z)-buta-
CH3
H
H
O
—CH2CH2



1,3-diene-1,4-diyl







678
(1Z,3Z)-buta-
CH3
H
H
O
—CH2CH2



1,3-diene-1,4-diyl







679
(1Z,3Z)-buta-
CH3
H
H
O
—CH2CH2



1,3-diene-1,4-diyl







680
(1Z,3Z)-buta-
CH3
H
H
O
—CH2CH2



1,3-diene-1,4-diyl







681
(1Z,3Z)-buta-
CH3
H
H
O
—CH2CH2



1,3-diene-1,4-diyl







682
(1Z,3Z)-buta-
CH3
H
H
O
—CH2CH2



1,3-diene-1,4-diyl







683
(1Z,3Z)-buta-
CH3
H
H
O
—CH2CH2



1,3-diene-1,4-diyl







684
(1Z,3Z)-buta-
CH3
H
H
O
—CH2CH2



1,3-diene-1,4-diyl







685
(1Z,3Z)-buta-
CH3
H
H
O
—CH2CH2



1,3-diene-1,4-diyl







686
(1Z,3Z)-buta-
CH3
H
H
O
—CH2CH2



1,3-diene-1,4-diyl







687
(1Z,3Z)-buta-
CH3
H
H
O
—CH2CH2



1,3-diene-1,4-diyl







688
(1Z,3Z)-buta-
CH3
H
H
O
—CH2CH2



1,3-diene-1,4-diyl







689
(1Z,3Z)-buta-
CH3
H
H
O
—CH2CH2



1,3-diene-1,4-diyl







690
(1Z,3Z)-buta-
CH3
H
H
O
—CH2CH2



1,3-diene-1,4-diyl







691
(1Z,3Z)-buta-
CH3
H
H
O
—CH2CH2



1,3-diene-1,4-diyl







692
(1Z,3Z)-buta-
CH3
H
H
O
—CH2CH2



1,3-diene-1,4-diyl







693
(1Z,3Z)-buta-
CH3
H
H
O
—CH2CH2



1,3-diene-1,4-diyl







694
(1Z,3Z)-buta-
CH3
H
H
O
—CH2CH2



1,3-diene-1,4-diyl







695
(1Z,3Z)-buta-
CH3
H
H
O
—CH2CH2



1,3-diene-1,4-diyl







696
(1Z,3Z)-buta-
CH3
H
H
O
—CH2CH2



1,3-diene-1,4-diyl







697
(1Z,3Z)-buta-
CH3
H
H
O
—CH2CH2



1,3-diene-1,4-diyl







698
(1Z,3Z)-buta-
CH3
H
H
O
—CH2CH2



1,3-diene-1,4-diyl







699
(1Z,3Z)-buta-
CH3
H
H
O
—CH2CH2



1,3-diene-1,4-diyl







700
(1Z,3Z)-buta-
CH3
H
H
O
—CH2CH2



1,3-diene-1,4-diyl







701
(1Z,3Z)-buta-
CH3
H
H
O
—CH2CH2



1,3-diene-1,4-diyl







702
(1Z,3Z)-buta-
CH3
H
H
O
—CH2CH2



1,3-diene-1,4-diyl







703
(1Z,3Z)-buta-
CH3
H
H
O
—CH2CH2



1,3-diene-1,4-diyl







704
(1Z,3Z)-buta-
CH3
H
H
O
—CH2CH2



1,3-diene-1,4-diyl







705
(1Z,3Z)-buta-
CH3
H
H
O
—CH2CH2



1,3-diene-1,4-diyl







706
(1Z,3Z)-buta-
CH3
H
H
O
—CH2CH2



1,3-diene-1,4-diyl







707
(1Z,3Z)-buta-
CH3
H
H
O
—CH2CH2



1,3-diene-1,4-diyl







708
(1Z,3Z)-buta-
CH3
H
H
O
—CH2CH2



1,3-diene-1,4-diyl







709
(1Z,3Z)-buta-
CH3
H
H
O
—CH2CH2



1,3-diene-1,4-diyl







710
(1Z,3Z)-buta-
CH3
H
H
O
—CH2CH2



1,3-diene-1,4-diyl







711
(1Z,3Z)-buta-
CH3
H
H
O
—CH2CH2



1,3-diene-1,4-diyl







712
(1Z,3Z)-buta-
CH3
H
H
O
—CH2CH2



1,3-diene-1,4-diyl







713
(1Z,3Z)-buta-
CH3
H
H
O
—CH2CH2



1,3-diene-1,4-diyl







714
(1Z,3Z)-buta-
CH3
H
H
O
—CH2CH2



1,3-diene-1,4-diyl







715
(1Z,3Z)-buta-
CH3
H
H
O
—CH2CH2



1,3-diene-1,4-diyl







716
(1Z,3Z)-buta-
CH3
H
H
O
—CH2CH2



1,3-diene-1,4-diyl







717
(1Z,3Z)-buta-
CH3
H
H
O
—CH2CH2



1,3-diene-1,4-diyl







718
(1Z,3Z)-buta-
CH3
H
H
O
—CH2CH2



1,3-diene-1,4-diyl







719
(1Z,3Z)-buta-
CH3
H
H
O
—CH2CH2



1,3-diene-1,4-diyl







720
(1Z,3Z)-buta-
CH3
H
H
O
—CH2CH2



1,3-diene-1,4-diyl







721
(1Z,3Z)-buta-
CH3
H
H
O
—CH2CH2



1,3-diene-1,4-diyl







722
(1Z,3Z)-buta-
CH3
H
H
O
—CH2CH2



1,3-diene-1,4-diyl







723
(1Z,3Z)-buta-
CH3
H
H
O
—CH2CH2



1,3-diene-1,4-diyl







724
(1Z,3Z)-buta-
CH3
H
H
O
—CH2CH2



1,3-diene-1,4-diyl







725
(1Z,3Z)-buta-
CH3
H
H
O
—CH2CH2



1,3-diene-1,4-diyl







726
(1Z,3Z)-buta-
CH3
H
H
O
—CH2CH2



1,3-diene-1,4-diyl







727
(1Z,3Z)-buta-
CH3
H
H
O
—CH2CH2



1,3-diene-1,4-diyl







728
(1Z,3Z)-buta-
CH3
H
H
O
—CH2CH2



1,3-diene-1,4-diyl







729
(1Z,3Z)-buta-
CH3
H
H
O
—CH2CH2



1,3-diene-1,4-diyl







730
(1Z,3Z)-buta-
CH3
H
H
O
—CH2CH2



1,3-diene-1,4-diyl







731
(1Z,3Z)-buta-
CH3
H
H
O
—CH2CH2



1,3-diene-1,4-diyl







732
(1Z,3Z)-buta-
CH3
H
H
O
—CH2CH2



1,3-diene-1,4-diyl







733
(1Z,3Z)-buta-
CH3
H
H
O
—CH2CH2



1,3-diene-1,4-diyl







734
(1Z,3Z)-buta-
CH3
H
H
O
—CH2CH2



1,3-diene-1,4-diyl







735
(1Z,3Z)-buta-
CH3
H
H
O
—CH2CH2



1,3-diene-1,4-diyl







736
(1Z,3Z)-buta-
CH3
H
H
O
—CH2CH2



1,3-diene-1,4-diyl







737
(1Z,3Z)-buta-
CH3
H
H
O
—CH2CH2



1,3-diene-1,4-diyl







738
(1Z,3Z)-buta-
CH3
H
H
O
—CH2CH2



1,3-diene-1,4-diyl







739
(1Z,3Z)-buta-
CH3
H
H
O
—CH2CH2



1,3-diene-1,4-diyl







740
(1Z,3Z)-buta-
CH3
H
H
O
—CH2CH2



1,3-diene-1,4-diyl







741
(1Z,3Z)-buta-
CH3
H
H
O
—CH2CH2



1,3-diene-1,4-diyl







742
(1Z,3Z)-buta-
CH3
H
H
O
—CH2CH2



1,3-diene-1,4-diyl







743
(1Z,3Z)-buta-
CH3
H
H
O
—CH2CH2



1,3-diene-1,4-diyl







744
(1Z,3Z)-buta-
CH3
H
H
O
—CH2CH2



1,3-diene-1,4-diyl







745
(1Z,3Z)-buta-
CH3
H
H
O
—CH2CH2



1,3-diene-1,4-diyl







746
(1Z,3Z)-buta-
CH3
H
H
O
—CH2CH2



1,3-diene-1,4-diyl







747
(1Z,3Z)-buta-
CH3
H
H
O
—CH2CH2



1,3-diene-1,4-diyl







748
(1Z,3Z)-buta-
CH3
H
H
O
—CH2CH2



1,3-diene-1,4-diyl







749
(1Z,3Z)-buta-
CH3
H
H
O
—CH2CH2



1,3-diene-1,4-diyl







750
(1Z,3Z)-buta-
CH3
H
H
O
—CH2CH2



1,3-diene-1,4-diyl







751
(1Z,3Z)-buta-
CH3
H
H
O
—CH2CH2



1,3-diene-1,4-diyl


















752
CF3
H
CH3
—CH2CH2
O
—CH2CH2


753
CF3
H
CH3
—CH2CH2
O
—CH2CH2


754
CF3
H
CH3
—CH2CH2
O
—CH2CH2


755
CF3
H
CH3
—CH2CH2
O
—CH2CH2


756
CF3
H
CH3
—CH2CH2
O
—CH2CH2


757
CF3
H
CH3
—CH2CH2
O
—CH2CH2


758
CF3
H
CH3
—CH2CH2
O
—CH2CH2














759
CF3
H
CH3
H
cyclopropyl
O
—CH2CH2


760
CF3
H
CH3
H
cyclopropyl
O
—CH2CH2


761
CF3
H
CH3
H
cyclopropyl
O
—CH2CH2


762
CF3
H
CH3
H
cyclopropyl
O
—CH2CH2


763
CF3
H
CH3
H
cyclopropyl
O
—CH2CH2


764
CF3
H
CH3
H
cyclopropyl
O
—CH2CH2


765
CF3
H
CH3
H
cyclopropyl
O
—CH2CH2


766
CF3
H
CH3
H
H
O
—CH2CH2


767
CF3
H
H
H
H
O
—CH2CH2


768
CF3
chlorine
CH3
H
H
O
—CH2CH2


769
CF3
chlorine
CH3
H
CH3
O
—CH2CH2


770
CF3
chlorine
CH3
H
CH3
O
—CH2CH2


771
CF3
H
CF3
H
H
O
—CH2CH2


772
CF3
H
CF3
H
H
O
—CH2CH2


773
CF3
H
H
H
CH3
O
—CH2CH2


774
CF3
H
H
H
CH3
O
—CH2CH2


775
CF3
H
CH3
H
H
O
—CH2CH2


776
CF3
H
CH3
H
H
O
—CH2CH2


777
CF3
H
phenyl
H
H
O
—CH2CH2


778
CF3
H
ethyl
H
H
O
—CH2CH2


779
CF3
H
CH3
H
H
O
—CH2CH2


780
CF3
H
CH3
H
H
O
—CH2CH2


781
CF3
H
CH3
H
H
O
—CH2CH2


782
CF3
H
CH3
H
H
O
—CH2CH2


783
CF3
H
CH3
H
H
O
—CH2CH2


784
CF3
H
CH3
H
H
O
—CH2CH2


785
CF3
H
CH3
H
H
O
—CH2CH2


786
CF3
H
CH3
H
H
O
—CH2CH2


787
CF3
H
CH3
H
H
O
—CH2CH2


788
CF3
H
CH3
H
H
O
—CH2CH2


789
CF3
H
CH3
H
H
O
—CH2CH2


790
CF3
H
CH3
H
H
O
—CH2CH2


791
CF3
H
CH3
H
H
O
—CH2CH2


792
CF3
H
CH3
H
H
O
—CH2CH2


793
CF3
H
CH3
H
H
O
—CH2CH2


794
CF3
H
CH3
H
H
O
—CH2CH2


795
CF3
H
CH3
H
H
O
—CH2CH2


796
CH3
H
difluoro-
H
H
O
—CH2CH2





methyl






797
CH3
H
CH3
CH3
CH3
O
—CH2CH2


798
CH3
H
CH3
CH3
CH3
O
—CH2CH2


799
CH3
H
CH3
CH3
CH3
O
—CH2CH2


800
CH3
H
CH3
CH3
CH3
O
—CH2CH2


801
CH3
H
CH3
CH3
CH3
O
—CH2CH2


802
CH3
H
CH3
CH3
CH3
O
—CH2CH2


803
CH3
H
CH3
CH3
CH3
O
—CH2CH2


804
CH3
H
CH3
CH3
CH3
O
—CH2CH2


805
CH3
H
CH3
CH3
CH3
O
—CH2CH2


806
CH3
H
CH3
CH3
CH3
O
—CH2CH2


807
CF3
H
CH3
H
H
O
—CH2CH2


808
CF3
H
CH3
H
H
O
—CH2CH2


809
CF3
H
CH3
H
H
O
—CH2CH2


810
ethyl
H
ethyl
H
H
O
—CH2CH2


811
difluoro-
H
difluoro-
H
H
O
—CH2CH2



methyl

methyl






812
ethyl
H
ethyl
H
H
O
—CH2CH2


813
difluoro-
H
difluoro-
H
H
O
—CH2CH2



methyl

methyl






814
CF3
H
CH3
H
H
O
—CH2CH2


815
CF3
H
CH3
H
H
O
—CH2CH2


816
CF3
H
CH3
H
H
O
—CH2CH2


817
CF3
H
CH3
H
H
O
—CH2CH2


818
CF3
H
CH3
H
H
O
—CH2CH2


819
CF3
H
CH3
H
H
O
—CH2CH2


820
CF3
H
CH3
H
H
O
—CH2CH2


821
CF3
H
CH3
H
H
O
—CH2CH2


822
CF3
H
CH3
H
H
O
—CH2CH2


823
CF3
H
CH3
H
H
O
—CH2CH2


824
CF3
H
CH3
H
H
O
—CH2CH2


825
CF3
H
CH3
H
H
O
—CH2CH2


826
CF3
H
CH3
H
H
O
—CH2CH2


827
CF3
H
CH3
H
H
O
—CH2CH2


828
CF3
H
CH3
H
H
O
—CH2CH2


829
CF3
H
CH3
H
H
O
—CH2CH2


830
CF3
H
CH3
H
H
O
—CH2CH2


831
CF3
H
CH3
H
H
O
—CH2CH2


832
CF3
H
CH3
H
H
O
—CH2CH2


833
CF3
H
CH3
H
H
O
—CH2CH2


834
CF3
H
CH3
H
H
O
—CH2CH2


835
CF3
H
CH3
H
H
O
—CH2CH2


836
CF3
H
CH3
H
H
O
—CH2CH2


837
CF3
H
CH3
H
H
O
—CH2CH2


838
CF3
H
CH3
H
H
O
—CH2CH2


839
H
CF3
CH3
H
H
O
—CH2CH2


840
CF3
H
H
H
H
O
—CH2CH2


841
CF3
chlorine
CH3
H
H
O
—CH2CH2


842
CH3
H
CH3
CH3
CH3
O
—CH2CH2


843
CF3
H
CH3
H
H
O
—CH2


844
CH3
H
difluoro-
H
H
O
—CH2CH2





methyl






845
CF3
H
CH3
H
H
O
—CH2CH2


846
CF3
H
CH3
H
H
O
—CH2CH2


847
tBu
H
CF3
H
H
O
—CH2CH2


848
CF3
H
tBu
H
H
O
—CH2CH2


849
tBu
H
CF2CF3
H
H
O
—CH2CH2


850
CF2CF3
H
tBu
H
H
O
—CH2CH2


851
iPr
H
CF3
H
H
O
—CH2CH2


852
ethyl
H
CF3
H
H
O
—CH2CH2


853
CF3
H
CH3
H
H
O
—CH2CH2


854
difluoro-
H
difluoro-
H
H
S
—CH2CH2



methyl

methyl

















EX NO
W
R6
Y2
Y3
G
R7
log p





1
—CH2
H
O
O
—CH2
trimethylsilyl



2
—CH2
H
O
O
bond
cyclohexyl



3
—CH2
H
O
O
bond
cyclopentyl
3.40*


4
—CH2
H
O
O
—CH2
cyclopropyl



5
—CH2
H
O
O
—CH2
2,2-dicholoro-









cyclopropyl



6
—CH2
H
O
O
bond
1,2,3,4-tetra-
4.01**








hydronaphthalen-









1-yl



7
—CH2
H
O
O
bond
decahydro-









naphthalen-1-yl



8
—CH2
H
O
O
bond
2,3-dihydro-1H-
3.76*








inden-1-yl



9
—CH2
H
O
O
bond
1-naphthyl



10
—CH2
H
O
O
bond
2-naphthyl
3.84*


11
—CH2
H
O
O
—CH2CH2
morpholin-4-yl



12
—CH2
H
O
O
—CH2
4-fluorophenyl
3.35*


13
—CH2
H
O
O
—CH2CH2
piperidin-1-yl



14
—CH2
H
O
O
—CH2CH2
pyrrolidin-1-yl



15
—CH2
H
O
O
—CH2
phenyl
3.37*


16
—CH2
H
O
O
—CH2CH2
4-methylpiperazin-









1-yl



17
—CH2
H
O
O
—CH2
4-chlorophenyl
3.73*


18
—CH2
H
O
O
—CH2
4-methylphenyl
4.21*


19
—CH2
H
O
O
—CH2
4-methoxyphenyl
3.30*


20
—CH2
H
O
O
—CH2
2,4-dichlorophenyl
3.69*


21
—CH2
H
O
O
—CH2
3,5-dichlorophenyl
4.24*


22
—CH2
H
O
O
—CH2
2,6-dichlorophenyl
3.94*


23
—CH2
H
O
O
—CH2
2-chlorophenyl
3.70*


24
—CH2
H
O
O
—CH2
3-chlorophenyl
3.72*


25
—CH2
H
O
O
—CH2
3-(trifluoromethyl)
3.81*








phenyl



26
—CH2
H
O
O
—CH2
3-methylphenyl
3.68*


27
—CH2
H
O
S
—CH2
4-fluorophenyl
4.00*


28
—CH2
H
O
O
—CH2
4-nitrophenyl
3.22*


29
—CH2
H
O
O
—CH2
4-tert-butylphenyl
4.57*


30
—CH2
H
O
S
—CH2
phenyl



31
—CH2
H
O
O
—CH2
2-methylphenyl
3.62*


32
—CH2
H
O
S
—CH2
4-chlorophenyl



33
—CH2
H
O
S
—CH2
4-methylphenyl



34
—CH2
H
O
S
—CH2
4-methoxyphenyl



35
—CH2
H
O
S
—CH2
2,4-dicholorphenyl



36
—CH2
H
O
S
—CH2
3,5-dichlorophenyl



37
—CH2
H
O
S
—CH2
2,6-dichlorophenyl



38
—CH2
H
O
S
—CH2
2-chlorophenyl



39
—CH2
H
O
S
—CH2
3-chlorophenyl



40
—CH2
H
O
S
—CH2
3-(trifluoromethyl)









phenyl



41
—CH2
H
O
O
—CH(CH3)—
4-fluorophenyl
3.60*


42
—CH2
H
O
O
—CH(CH2CH3)—
4-fluorophenyl
3.89*


43
—CH2
H
O
O
—CH2CH2
4-fluorophenyl
3.55*


44
—CH2
H
O
O
bond
phenyl
3.20*


45
—CH2
H
O
O
bond
4-fluorophenyl
3.26*


46
—CH2
H
O
S
—CH2
2-methylphenyl



47
—CH2
H
O
O
—CH(CF3)—
phenyl



48
—CH2
H
O
S
—CH2
4-nitrophenyl



49
—CH2
H
O
S
—CH2
4-tert-butlyphenyl



50
—CH2
H
O
S
—CH2
3-methlyphenyl



51
—CH2
H
O
O
bond
4-chlorophenyl



52
—CH2
H
O
O
bond
4-methylphenyl



53
—CH2
H
O
O
bond
3-chlorophenyl



54
—CH2
H
O
O
bond
3,5-dichlorophenyl



55
—CH2
H
O
O
bond
3,4-dichlorophenyl



56
—CH2
H
O
O
bond
2,4-dichlorophenyl



57
—CH2
H
O
O
bond
2-chlorophenyl



58
—CH2
H
O
O
bond
2,6-dichlorophenyl



59
—CH2
H
O
O
bond
3-(trifluoromethyl)









phenyl



60
—CH2
H
O
O
bond
3-methlyphenyl



61
—CH2
H
O
O
bond
2-methylphenyl



62
—CH2
H
O
O
bond
4-tert-butylphenyl



63
—CH2
H
O
O
bond
4-nitrophenyl



64
—CH2
H
O
S
bond
phenyl



65
—CH2
H
O
S
bond
4-fluorophenyl



66
—CH2
H
O
S
bond
4-chlorophenyl



67
—CH2
H
O
S
bond
4-methylphenyl



68
—CH2
H
O
S
bond
3-chlorophenyl



69
—CH2
H
O
S
bond
3,5-dichlorophenyl



70
—CH2
H
O
S
bond
3,4-dichlorophenyl



71
—CH2
H
O
S
bond
2,4-dichlorophenyl



72
—CH2
H
O
S
bond
2-chlorophenyl



73
—CH2
H
O
S
bond
2,6-dichlorophenyl



74
—CH2
H
O
S
bond
3-(trifluoromethyl)









phenyl



75
—CH2
H
O
S
bond
3-methylphenyl



76
—CH2
H
O
S
bond
cyclohexyl
4.51*


77
—CH2
H
O
S
bond
1-naphthyl
4.22*


78
—CH2
H
O
S
bond
4-nitrophenyl



79
—CH2
H
O
O
—CH2
pyridin-4-yl



80
—CH2
H
O
O
—CH2
pyridin-2-yl
2.21*


81
—CH2
H
O
O
—CH2
2-thienyl
3.22*


82
—CH2
H
O
S
bond
2-methylphenyl



83
—CH2
H
O
S
bond
4-tert-butylphenyl



84
—CH2
H
O
O
—CH2
trimethylsilyl
3.53*


85
—CH2
H
O
O
bond
cyclohexyl
3.42*


86
—CH2
H
O
O
bond
cyclopentyl



87
—CH2
H
O
O
—CH2
cyclopropyl



88
—CH2
H
O
O
—CH2
2,2-dichlorocyclo-









propyl



89
—CH2
H
O
O
bond
1,2,3,4-tetrahydro-
3.68*








naphthalen-1-yl



90
—CH2
H
O
O
bond
decahydro-









naphthalen-1-yl



91
—CH2
H
O
O
bond
2,3-dihydro-1H-
3.37*








inden-1-yl



92
—CH2
H
O
O
bond
1-naphthyl
3.42*


93
—CH2
H
O
O
bond
2-naphthyl



94
—CH2
H
O
O
—CH2
phenyl
2.99*


95
—CH2
H
O
O
—CH2
4-fluorophenyl
3.04*


96
—CH2
H
O
O
—CH2
4-chlorophenyl



97
—CH2
H
O
O
—CH2
4-methylphenyl



98
—CH2
H
O
O
—CH2
4-methoxyphenyl



99
—CH2
H
O
O
—CH2
2,4-dichlorophenyl



100
—CH2
H
O
O
—CH2
3,5-dichlorophenyl



101
—CH2
H
O
O
—CH2
2,6-dichlorophenyl



102
—CH2
H
O
O
—CH2
2-chlorophenyl



103
—CH2
H
O
O
—CH2
3-chlorophenyl



104
—CH2
H
O
O
—CH2
3-(trifluoromethyl)









phenyl



105
—CH2
H
O
O
—CH2
3-methylphenyl



106
—CH2
H
O
O
—CH2
2-methylphenyl



107
—CH2
H
O
O
—CH2
4-nitrophenyl



108
—CH2
H
O
O
—CH2
4-tert-butylphenyl



109
—CH2
H
O
S
—CH2
phenyl



110
—CH2
H
O
S
—CH2
4-fluorophenyl



111
—CH2
H
O
S
—CH2
4-chlorophenyl



112
—CH2
H
O
S
—CH2
4-methylphenyl



113
—CH2
H
O
S
—CH2
4-methoxyphenyl



114
—CH2
H
O
S
—CH2
2,4-dichlorophenyl



115
—CH2
H
O
S
—CH2
3,5-dichlorophenyl



116
—CH2
H
O
S
—CH2
2,6-dichlorophenyl



117
—CH2
H
O
S
—CH2
2-chlorophenyl



118
—CH2
H
O
S
—CH2
3-chlorophenyl



119
—CH2
H
O
S
—CH2
3-(trifluoromethyl)









phenyl



120
—CH2
H
O
S
—CH2
3-methylphenyl



121
—CH2
H
O
S
—CH2
2-methlyphenyl



122
—CH2
H
O
S
—CH2
4-nitrophenyl



123
—CH2
H
O
S
—CH2
4-tert-butylphenyl



124
—CH2
H
O
O
—CH(CH3)—
4-fluorophenyl
3.18*


125
—CH2
H
O
O
—CH(CH2CH3)—
4-fluorophenyl



126
—CH2
H
O
O
—CH2CH2
4-fluorophenyl
3.27*


127
—CH2
H
O
O
bond
phenyl
2.85*


128
—CH2
H
O
O
bond
4-fluorophenyl
2.89*


129
—CH2
H
O
O
bond
4-chlorophenyl



130
—CH2
H
O
O
bond
4-methylphenyl



131
—CH2
H
O
O
bond
3-chlorophenyl



132
—CH2
H
O
O
bond
3,5-dichlorophenyl



133
—CH2
H
O
O
bond
3,4-dichlorophenyl



134
—CH2
H
O
O
bond
2,4-dichlorophenyl



135
—CH2
H
O
O
bond
2-chlorophenyl



136
—CH2
H
O
O
bond
2,6-dichlorophenyl



137
—CH2
H
O
O
bond
3-(trifluoromethyl)









phenyl



138
—CH2
H
O
O
bond
3-methylphenyl



139
—CH2
H
O
O
bond
2-methylphenyl



140
—CH2
H
O
O
bond
4-tert-butlyphenyl



141
—CH2
H
O
O
bond
4-nitrophenyl



142
—CH2
H
O
O
—CH2
pyridin-4-yl
1.32*


143
—CH2
H
O
O
—CH2
2-thienyl
2.85*


144
—CH2
H
O
O
—CH2
trimethylsilyl
4.28*


145
—CH2
H
O
O
bond
cyclohexyl
4.17*


146
—CH2
H
O
O
bond
cyclopentyl
3.84*


147
—CH2
H
O
O
—CH2
cyclopropyl



148
—CH2
H
O
O
—CH2
2,2-dichlorocyclo-









propyl



149
—CH2
H
O
O
bond
1,2,3,4-tetrahydro-
4.40*








naphthalen-1-yl



150
—CH2
H
O
O
bond
decahydro-
5.44*








naphthalen-1-yl



151
—CH2
H
O
O
bond
2,3-dihydro-1H-
4.17*








inden-1-yl



152
—CH2
H
O
O
bond
1-naphthyl
4.17*


153
—CH2
H
O
O
bond
2-naphthyl
4.17*


154
—CH2
H
O
O
—CH2
phenyl
3.73*


155
—CH2
H
O
O
—CH2
4-fluorophenyl
3.73*


156
—CH2
H
O
O
—CH2
4-chlorophenyl



157
—CH2
H
O
O
—CH2
4-methylphenyl



158
—CH2
H
O
O
—CH2
4-methoxyphenyl



159
—CH2
H
O
O
—CH2
2,4-dichlorophenyl



160
—CH2
H
O
O
—CH2
3,5-dichlorophenyl



161
—CH2
H
O
O
—CH2
2,6-dichlorophenyl



162
—CH2
H
O
O
—CH2
2-chlorophenyl



163
—CH2
H
O
O
—CH2
3-chlorophenyl



164
—CH2
H
O
O
—CH2
3-(trifluoromethyl)









phenyl



165
—CH2
H
O
O
—CH2
3-methylphenyl



166
—CH2
H
O
O
—CH2
2-methylphenyl



167
—CH2
H
O
O
—CH2
4-nitrophenyl



168
—CH2
H
O
O
—CH2
4-tert-butylphenyl



169
—CH2
H
O
S
—CH2
phenyl



170
—CH2
H
O
S
—CH2
4-fluorophenyl



171
—CH2
H
O
S
—CH2
4-chlorophenyl



172
—CH2
H
O
S
—CH2
4-methylphenyl



173
—CH2
H
O
S
—CH2
4-methoxyphenyl



174
—CH2
H
O
S
—CH2
2,4-dichlorophenyl



175
—CH2
H
O
S
—CH2
3,5-dichlorophenyl



176
—CH2
H
O
S
—CH2
2,6-dichlorophenyl



177
—CH2
H
O
S
—CH2
2-chlorophenyl



178
—CH2
H
O
S
—CH2
3-chlorophenyl



179
—CH2
H
O
S
—CH2
3-(trifluoromethyl)









phenyl



180
—CH2
H
O
S
—CH2
3-methylphenyl



181
—CH2
H
O
S
—CH2
2-methylphenyl



182
—CH2
H
O
S
—CH2
4-nitrophenyl



183
—CH2
H
O
S
—CH2
4-tert-butylphenyl



184
—CH2
H
O
O
—CH(CH3)—
4-fluorophenyl
3.89*


185
—CH2
H
O
O
—CH(CH2CH3)—
4-fluorophenyl



186
—CH2
H
O
O
—CH2CH2
4-fluorophenyl
3.94*


187
—CH2
H
O
O
bond
phenyl
3.58*


188
—CH2
H
O
O
bond
4-fluorophenyl
3.63*


189
—CH2
H
O
O
bond
4-chlorophenyl



190
—CH2
H
O
O
bond
4-methylphenyl



191
—CH2
H
O
O
bond
3-chlorophenyl



192
—CH2
H
O
O
bond
3,5-dichlorophenyl



193
—CH2
H
O
O
bond
3,4-dichlorophenyl



194
—CH2
H
O
O
bond
2,4-dichlorophenyl



195
—CH2
H
O
O
bond
2-chlorophenyl



196
—CH2
H
O
O
bond
2,6-dichlorophenyl



197
—CH2
H
O
O
bond
3-(trifluoromethyl)









phenyl



198
—CH2
H
O
O
bond
3-methylphenyl



199
—CH2
H
O
O
bond
2-methylphenyl



200
—CH2
H
O
O
bond
4-tert-butylphenyl



201
—CH2
H
O
O
bond
4-nitrophenyl



202
—CH2
H
O
S
bond
phenyl



203
—CH2
H
O
S
bond
4-fluorophenyl



204
—CH2
H
O
S
bond
4-chlorophenyl



205
—CH2
H
O
S
bond
4-methylohenyl



206
—CH2
H
O
S
bond
3-chlorophenyl



207
—CH2
H
O
S
bond
3,5-dichlorophenyl



208
—CH2
H
O
S
bond
3,4-dichlorophenyl



209
—CH2
H
O
S
bond
2,4-dichlorophenyl



210
—CH2
H
O
S
bond
2-chlorophenyl



211
—CH2
H
O
S
bond
2,6-dichlorophenyl



212
—CH2
H
O
S
bond
3-(trifluoromethyl)









phenyl



213
—CH2
H
O
S
bond
3-methylphenyl



214
—CH2
H
O
S
bond
2-methylphenyl



215
—CH2
H
O
S
bond
4-tert-butylphenyl



216
—CH2
H
O
S
bond
4-nitrophenyl



217
—CH2
H
O
O
—CH2
pyridin-4-yl
1.82*


218
—CH2
H
O
O
—CH2
2-thienyl
3.58*


219
—CH2CH2
H
O
O
—CH2
trimethylsilyl
3.89*


220
—CH2CH2
H
O
O
bond
cyclohexyl
3.74*


221
—CH2CH2
H
O
O
bond
cyclopentyl
3.47*


222
—CH2CH2
H
O
O
—CH2
cyclopropyl



223
—CH2CH2
H
O
O
—CH2
2,2-dichlorocyclo-









propyl



224
—CH2CH2
H
O
O
bond
1,2,3,4-tetrahydro-
4.01*








naphthalen-1-yl



225
—CH2CH2
H
O
O
bond
decahydro-
5.08*








naphthalen-1-yl



226
—CH2CH2
H
O
O
bond
2,3-dihydro-1H-
3.78*








inden-1-yl



227
—CH2CH2
H
O
O
bond
1-naphthyl
3.75*


228
—CH2CH2
H
O
O
bond
2-naphthyl
3.84*


229
—CH2CH2
H
O
O
—CH2
phenyl
3.37*


230
—CH2CH2
H
O
O
—CH2
4-fluorophenyl
3.37*


231
—CH2CH2
H
O
O
—CH2
4-chlorophenyl



232
—CH2CH2
H
O
O
—CH2
4-methylphenyl



233
—CH2CH2
H
O
O
—CH2
4-methoxyphenyl



234
—CH2CH2
H
O
O
—CH2
2,4-dichlorophenyl



235
—CH2CH2
H
O
O
—CH2
3,5-dichlorophenyl



236
—CH2CH2
H
O
O
—CH2
2,6-dichlorophenyl



237
—CH2CH2
H
O
O
—CH2
2-chlorophenyl



238
—CH2CH2
H
O
O
—CH2
3-chlorophenyl



239
—CH2CH2
H
O
O
—CH2
3-(trifluoromethyl)









phenyl



240
—CH2CH2
H
O
O
—CH2
3-methylphenyl



241
—CH2CH2
H
O
O
—CH2
2-methylphenyl



242
—CH2CH2
H
O
O
—CH2
4-nitrophenyl



243
—CH2CH2
H
O
O
—CH2
4-tert-butylphenyl



244
—CH2CH2
H
O
S
—CH2
phenyl



245
—CH2CH2
H
O
S
—CH2
4-fluorophenyl



246
—CH2CH2
H
O
S
—CH2
4-chlorophenyl



247
—CH2CH2
H
O
S
—CH2
4-methylphenyl



248
—CH2CH2
H
O
S
—CH2
4-methoxyphenyl



249
—CH2CH2
H
O
S
—CH2
2,4-dichlorophenyl



250
—CH2CH2
H
O
S
—CH2
3,5-dichlorophenyl



251
—CH2CH2
H
O
S
—CH2
2,6-dichlorophenyl



252
—CH2CH2
H
O
S
—CH2
2-chlorophenyl



253
—CH2CH2
H
O
S
—CH2
3-chlorophenyl



254
—CH2CH2
H
O
S
—CH2
3-(trifluoromethyl)









phenyl



255
—CH2CH2
H
O
S
—CH2
3-methylphenyl



256
—CH2CH2
H
O
S
—CH2
2-methylphenyl



257
—CH2CH2
H
O
S
—CH2
4-nitrophenyl



258
—CH2CH2
H
O
S
—CH2
4-tert-butylphenyl



259
—CH2CH2
H
O
O
—CH(CH3)—
4-fluorophenyl
3.53*


260
—CH2CH2
H
O
O
—CH(CH2CH3)—
4-fluorophenyl



261
—CH2CH2
H
O
O
—CH2CH2
4-fluorophenyl
3.63*


262
—CH2CH2
H
O
O
bond
phenyl
3.18*


263
—CH2CH2
H
O
O
bond
4-fluorophenyl
3.27*


264
—CH2CH2
H
O
O
bond
4-chlorophenyl



265
—CH2CH2
H
O
O
bond
4-methylphenyl



266
—CH2CH2
H
O
O
bond
3-chlorophenyl



267
—CH2CH2
H
O
O
bond
3,5-dichlorophenyl



268
—CH2CH2
H
O
O
bond
3,4-dichlorophenyl



269
—CH2CH2
H
O
O
bond
2,4-dichlorophenyl



270
—CH2CH2
H
O
O
bond
2-chlorophenyl



271
—CH2CH2
H
O
O
bond
2,6-dichlorophenyl



272
—CH2CH2
H
O
O
bond
3-(trifluoromethyl)




—CH2CH2




phenyl



273
—CH2CH2
H
O
O
bond
3-methylphenyl



274
—CH2CH2
H
O
O
bond
2-methylphenyl



275
—CH2CH2
H
O
O
bond
4-tert-butylphenyl



276
—CH2CH2
H
O
O
bond
4-nitrophenyl



277
—CH2CH2
H
O
S
bond
phenyl



278
—CH2CH2
H
O
S
bond
4-fluorophenyl



279
—CH2CH2
H
O
S
bond
4-chlorophenyl



280
—CH2CH2
H
O
S
bond
4-methylphenyl



281
—CH2CH2
H
O
S
bond
3-chlorophenyl



282
—CH2CH2
H
O
S
bond
3,5-dichlorophenyl



283
—CH2CH2
H
O
S
bond
3,4-dichlorophenyl



284
—CH2CH2
H
O
S
bond
2,4-dichlorophenyl



285
—CH2CH2
H
O
S
bond
2-chlorophenyl



286
—CH2CH2
H
O
S
bond
2,6-dichlorophenyl



287
—CH2CH2
H
O
S
bond
3-(trifluoromethyl)









phenyl



288
—CH2CH2
H
O
S
bond
3-methylphenyl



289
—CH2CH2
H
O
S
bond
2-methylphenyl



290
—CH2CH2
H
O
S
bond
4-tert-butylphenyl



291
—CH2CH2
H
O
S
bond
4-nitrophenyl



292
—CH2CH2
H
O
O
—CH2
pyridin-4-yl



293
—CH2CH2
H
O
O
—CH2
2-thienyl



294
—CH2
H
O
O
—CH2
trimethylsilyl



295
—CH2
H
O
O
bond
cyclohexyl



296
—CH2
H
O
O
bond
cylcopentyl



297
—CH2
H
O
O
—CH2
cyclopropyl



298
—CH2
H
O
O
—CH2
2,2-dichlorophenyl



299
—CH2
H
O
O
bond
1,2,3,4-tetrahydro-









naphthalen-1-yl



300
—CH2
H
O
O
bond
decahydro-









naphthalen-1-yl



301
—CH2
H
O
O
bond
2,3-dihydro-1H-









inden-1-yl



302
—CH2
H
O
O
bond
1-naphthyl



303
—CH2
H
O
O
bond
2-naphthyl



304
—CH2
H
O
O
—CH2
phenyl



305
—CH2
H
O
O
—CH2
4-fluorophenyl



306
—CH2
H
O
O
—CH2
4-chlorophenyl



307
—CH2
H
O
O
—CH2
4-methylphenyl



308
—CH2
H
O
O
—CH2
4-methoxyphenyl



309
—CH2
H
O
O
—CH2
2,4-dichlorophenyl



310
—CH2
H
O
O
—CH2
3,5-dichlorophenyl



311
—CH2
H
O
O
—CH2
2,6-dichlorophenyl



312
—CH2
H
O
O
—CH2
2-chlorophenyl



313
—CH2
H
O
O
—CH2
3-chlorophenyl



314
—CH2
H
O
O
—CH2
3-(trifluoromethyl)









phenyl



315
—CH2
H
O
O
—CH2
3-methylphenyl



316
—CH2
H
O
O
—CH2
2-methylphenyl



317
—CH2
H
O
O
—CH2
4-nitrophenyl



318
—CH2
H
O
O
—CH2
4-tert-butylphenyl



319
—CH2
H
O
S
—CH2
phenyl



320
—CH2
H
O
S
—CH2
4-fluorophenyl



321
—CH2
H
O
S
—CH2
4-chlorophenyl



322
—CH2
H
O
S
—CH2
4-methylphenyl



323
—CH2
H
O
S
—CH2
4-methoxyphenyl



324
—CH2
H
O
S
—CH2
2,4-dichlorophenyl



325
—CH2
H
O
S
—CH2
3,5-dichlorophenyl



326
—CH2
H
O
S
—CH2
2,6-dichlorophenyl



327
—CH2
H
O
S
—CH2
2-chlorophenyl



328
—CH2
H
O
S
—CH2
3-chlorophenyl



329
—CH2
H
O
S
—CH2
3-(trifluoromethyl)









phenyl



330
—CH2
H
O
S
—CH2
3-methylphenyl



331
—CH2
H
O
S
—CH2
2-methylphenyl



332
—CH2
H
O
S
—CH2
4-nitrophenyl



333
—CH2
H
O
S
—CH2
4-tert-butylphenyl



334
—CH2
H
O
O
—CH(CH3)—
4-fluorophenyl



335
—CH2
H
O
O
—CH(CH2CH3)—
4-fluorophenyl



336
—CH2
H
O
O
—CH2CH2
4-fluorophenyl



337
—CH2
H
O
O
bond
phenyl



338
—CH2
H
O
O
bond
4-fluorophenyl



339
—CH2
H
O
O
bond
4-chlorophenyl



340
—CH2
H
O
O
bond
4-methylphenyl



341
—CH2
H
O
O
bond
3-chlorophenyl



342
—CH2
H
O
O
bond
3,5-dichlorophenyl



343
—CH2
H
O
O
bond
3,4-dichlorophenyl



344
—CH2
H
O
O
bond
2,4-dichlorophenyl



345
—CH2
H
O
O
bond
2-chlorophenyl



346
—CH2
H
O
O
bond
2,6-dichlorophenyl



347
—CH2
H
O
O
bond
3-(trifluoromethyl)









phenyl



348
—CH2
H
O
O
bond
3-methylphenyl



349
—CH2
H
O
O
bond
2-methylphenyl



350
—CH2
H
O
O
bond
4-tert-butylphenyl



351
—CH2
H
O
O
bond
4-nitrophenyl



352
—CH2
H
O
S
bond
phenyl



353
—CH2
H
O
S
bond
4-fluorophenyl



354
—CH2
H
O
S
bond
4-chlorophenyl



355
—CH2
H
O
S
bond
4-methylphenyl



356
—CH2
H
O
S
bond
3-chlorophenyl



357
—CH2
H
O
S
bond
3,5-dichlorophenyl



358
—CH2
H
O
S
bond
3,4-dichlorophenyl



359
—CH2
H
O
S
bond
2,4-dichlorophenyl



360
—CH2
H
O
S
bond
2-chlorophenyl



361
—CH2
H
O
S
bond
2,6-dichlorophenyl



362
—CH2
H
O
S
bond
3-(trifluoromethyl)









phenyl



363
—CH2
H
O
S
bond
3-methylphenyl



364
—CH2
H
O
S
bond
2-methylphenyl



365
—CH2
H
O
O
bond
cyclopentyl



366
—CH2
H
O
S
bond
4-nitrophenyl



367
—CH2
H
O
O
—CH2
pyridin-4-yl



368
—CH2
H
O
O
bond
1,2,3,4-tetrahydro-
4.04*








naphthalen-1-yl



369
—CH2
H
O
O
—CH2
trimethylsilyl
3.84*


370
—CH2
H
O
O
bond
cyclohexyl
3.78*


371
—CH2
H
O
S
bond
4-tert-butylphenyl



372
—CH2
H
O
O
—CH2
cyclopropyl
3.86*


373
—CH2
H
O
O
—CH2
2,2-dichlorocyclo-









propyl



374
—CH2
H
O
O
—CH2
2-thienyl



375
—CH2
H
O
O
bond
decahydro-









naphthalen-1-yl



376
—CH2
H
O
O
bond
2,3-dihydro-1H-
3.68*








inden-1-yl



377
—CH2
H
O
O
bond
1-naphthyl
3.82*


378
—CH2
H
O
O
bond
2-naphthyl
3.73*


379
—CH2
H
O
O
—CH2
phenyl
3.19*


380
—CH2
H
O
O
—CH2
4-fluorophenyl
3.35*


381
—CH2
H
O
O
—CH2
4-chlorophenyl



382
—CH2
H
O
O
—CH2
4-methylphenyl



383
—CH2
H
O
O
—CH2
4-methoxyphenyl



384
—CH2
H
O
O
—CH2
2,4-dichlorophenyl



385
—CH2
H
O
O
—CH2
3,5-dichlorophenyl



386
—CH2
H
O
O
—CH2
2,6-dichlorophenyl



387
—CH2
H
O
O
—CH2
2-chlorophenyl



388
—CH2
H
O
O
—CH2
3-chlorophenyl



389
—CH2
H
O
O
—CH2
3-(trifluoromethyl)









phenyl



390
—CH2
H
O
O
—CH2
3-methylphenyl



391
—CH2
H
O
O
—CH2
2-methylphenyl



392
—CH2
H
O
O
—CH2
4-nitrophenyl



393
—CH2
H
O
O
—CH2
4-tert-butylphenyl



394
—CH2
H
O
S
—CH2
phenyl



395
—CH2
H
O
S
—CH2
4-fluorophenyl



396
—CH2
H
O
S
—CH2
4-chlorophenyl



397
—CH2
H
O
S
—CH2
4-methylphenyl



398
—CH2
H
O
S
—CH2
4-methoxyphenyl



399
—CH2
H
O
S
—CH2
2,4-dichlorophenyl



400
—CH2
H
O
S
—CH2
3,5-dichlorophenyl



401
—CH2
H
O
S
—CH2
2,6-dichlorophenyl



402
—CH2
H
O
S
—CH2
2-chlorophenyl



403
—CH2
H
O
O
—CH(CH3)—
4-fluorophenyl
3.47*


404
—CH2
H
O
O
—CH(CH2CH3)—
4-fluorophenyl



405
—CH2
H
O
O
—CH2CH2
4-fluorophenyl
3.42*


406
—CH2
H
O
S
—CH2
2-methylphenyl



407
—CH2
H
O
S
—CH2
4-nitrophenyl



408
—CH2
H
O
S
—CH2
4-tert-butylphenyl



409
—CH2
H
O
S
—CH2
3-chlorophenyl



410
—CH2
H
O
S
—CH2
3-(trifluoromethyl)









phenyl



411
—CH2
H
O
S
—CH2
3-methylphenyl



412
—CH2
H
O
O
bond
phenyl
3.06*


413
—CH2
H
O
O
bond
4-fluorophenyl
3.21*


414
—CH2
H
O
O
bond
4-chlorophenyl



415
—CH2
H
O
O
bond
4-methylphenyl



416
—CH2
H
O
O
bond
3-chlorophenyl



417
—CH2
H
O
O
bond
3,5-dichlorophenyl



418
—CH2
H
O
O
bond
3,4-dichlorophenyl



419
—CH2
H
O
O
bond
2,4-dichlorophenyl



420
—CH2
H
O
O
bond
2-chlorophenyl



421
—CH2
H
O
O
bond
2,6-dichlorophenyl



422
—CH2
H
O
O
bond
3-(trifluoromethyl)









phenyl



423
—CH2
H
O
O
bond
3-methylphenyl



424
—CH2
H
O
O
bond
2-methylphenyl



425
—CH2
H
O
O
bond
4-tert-butylphenyl



426
—CH2
H
O
O
bond
4-nitrophenyl



427
—CH2
H
O
S
bond
phenyl



428
—CH2
H
O
S
bond
4-fluorophenyl



429
—CH2
H
O
S
bond
4-chlorophenyl



430
—CH2
H
O
S
bond
4-methylphenyl



431
—CH2
H
O
S
bond
3-chlorophenyl



432
—CH2
H
O
S
bond
3,5-dichlorophenyl



433
—CH2
H
O
S
bond
3,4-dichlorophenyl



434
—CH2
H
O
S
bond
2,4-dichlorophenyl



435
—CH2
H
O
S
bond
2-chlorophenyl



436
—CH2
H
O
S
bond
2,6-dichlorophenyl



437
—CH2
H
O
S
bond
3-(trifluoromethyl)









phenyl



438
—CH2
H
O
S
bond
3-methylphenyl



439
—CH2
H
O
S
bond
2-methylphenyl



440
—CH2
H
O
S
bond
4-tert-butylphenyl



441
—CH2
H
O
S
bond
4-nitrophenyl



442
—CH2
H
O
O
—CH2
pyridin-4-yl
1.33*


443
—CH2
H
O
O
—CH2
2-thienyl
3.06*


444
—CH2
CH3
O
O
—CH2
trimethylsilyl



445
—CH2
CH3
O
O
bond
cyclohexyl



446
—CH2
CH3
O
O
bond
cyclopentyl



447
—CH2
CH3
O
O
—CH2
cyclopropyl



448
—CH2
CH3
O
O
—CH2
2,2-dichlorocyclo-









propyl



449
—CH2
CH3
O
O
bond
1,2,3,4-tetrahydro-









naphthalen-1-yl



450
—CH2
CH3
O
O
bond
decahydro-









naphthalen-1-yl



451
—CH2
CH3
O
O
bond
2,3-dihydro-1H-









inden-1-yl



452
—CH2
CH3
O
O
bond
1-naphthyl



453
—CH2
CH3
O
O
bond
2-naphthyl



454
—CH2
CH3
O
O
—CH2
phenyl



455
—CH2
CH3
O
O
—CH2
4-fluorophenyl



456
—CH2
CH3
O
O
—CH2
4-chlorophenyl



457
—CH2
CH3
O
O
—CH2
4-methylphenyl



458
—CH2
CH3
O
O
—CH2
4-methoxyphenyl



459
—CH2
CH3
O
O
—CH2
2,4-dichlorophenyl



460
—CH2
CH3
O
O
—CH2
3,5-dichlorophenyl



461
—CH2
CH3
O
O
—CH2
2,6-dichlorophenyl



462
—CH2
CH3
O
O
—CH2
2-chlorophenyl



463
—CH2
CH3
O
O
—CH2
3-chlorophenyl



464
—CH2
CH3
O
O
—CH2
3-(trifluoromethyl)









phenyl



465
—CH2
CH3
O
O
—CH2
3-methylphenyl



466
—CH2
CH3
O
O
—CH2
2-methylphenyl



467
—CH2
CH3
O
O
—CH2
4-nitrophenyl



468
—CH2
CH3
O
O
—CH2
4-tert-butylphenyl



469
—CH2
CH3
O
S
—CH2
phenyl



470
—CH2
CH3
O
S
—CH2
4-fluorophenyl



471
—CH2
CH3
O
S
—CH2
4-chlorophenyl



472
—CH2
CH3
O
S
—CH2
4-methylphenyl



473
—CH2
CH3
O
S
—CH2
4-methoxyphenyl



474
—CH2
CH3
O
S
—CH2
2,4-dichlorophenyl



475
—CH2
CH3
O
S
—CH2
3,5-dichlorophenyl



476
—CH2
CH3
O
S
—CH2
2,6-dichlorophenyl



477
—CH2
CH3
O
S
—CH2
2-chlorophenyl



478
—CH2
CH3
O
S
—CH2
3-chlorophenyl



479
—CH2
CH3
O
S
—CH2
3-(trifluoromethyl)









phenyl



480
—CH2
CH3
O
S
—CH2
3-methylphenyl



481
—CH2
CH3
O
S
—CH2
2-methylphenyl



482
—CH2
CH3
O
S
—CH2
4-nitrophenyl



483
—CH2
CH3
O
S
—CH2
4-tert-butylphenyl



484
—CH2
CH3
O
O
—CH(CH3)—
4-fluorophenyl



485
—CH2
CH3
O
O
—CH(CH2CH3)—
4-fluorophenyl



486
—CH2
CH3
O
O
—CH2CH2
4-fluorophenyl



487
—CH2
CH3
O
O
bond
phenyl



488
—CH2
CH3
O
O
bond
4-fluorophenyl



489
—CH2
CH3
O
O
bond
4-chlorophenyl



490
—CH2
CH3
O
O
bond
4-methylphenyl



491
—CH2
CH3
O
O
bond
3-chlorophenyl



492
—CH2
CH3
O
O
bond
3,5-dichlorophenyl



493
—CH2
CH3
O
O
bond
3,4-dichlorophenyl



494
—CH2
CH3
O
O
bond
2,4-dichlorophenyl



495
—CH2
CH3
O
O
bond
2-chlorophenyl



496
—CH2
CH3
O
O
bond
2,6-dichlorophenyl



497
—CH2
CH3
O
O
bond
3-(trifluoromethyl)



498
—CH2
CH3
O
O
bond
phenyl









3-methylphenyl



499
—CH2
CH3
O
O
bond
2-methylphenyl



500
—CH2
CH3
O
O
bond
4-tert-butylphenyl



501
—CH2
CH3
O
O
bond
4-nitrophenyl



502
—CH2
CH3
O
S
bond
phenyl



503
—CH2
CH3
O
S
bond
4-fluorophenyl



504
—CH2
CH3
O
S
bond
4-chlorophenyl



505
—CH2
CH3
O
S
bond
4-methylphenyl



506
—CH2
CH3
O
S
bond
3-chlorophenyl



507
—CH2
CH3
O
S
bond
3,5-dichlorophenyl



508
—CH2
CH3
O
S
bond
3,4-dichlorophenyl



509
—CH2
CH3
O
S
bond
2,4-dichlorophenyl



510
—CH2
CH3
O
S
bond
2-chlorophenyl



511
—CH2
CH3
O
S
bond
2,6-dichlorophenyl



512
—CH2
CH3
O
S
bond
3-(trifluoromethyl)









phenyl



513
—CH2
CH3
O
S
bond
3-methylphenyl



514
—CH2
CH3
O
S
bond
2-methylphenyl



515
—CH2
CH3
O
S
bond
4-tert-butylphenyl



516
—CH2
CH3
O
S
bond
4-nitrophenyl



517
—CH2
CH3
O
O
—CH2
pyridin-4-yl



518
—CH2
CH3
O
O
—CH2
2-thienyl



519
—CH2
CH3
O
S
bond
cyclohexyl



520
—CH2
CH3
O
S
bond
1-naphthyl



521
—CH2CH2CH2
H
O
O
—CH2
trimethylsilyl



522
—CH2CH2CH2
H
O
O
bond
cyclohexyl



523
—CH2CH2CH2
H
O
O
bond
cyclopentyl



524
—CH2CH2CH2
H
O
O
—CH2
cyclopropyl



525
—CH2CH2CH2
H
O
O
—CH2
2,2-dichlorocyclo-









propyl



526
—CH2CH2CH2
H
O
O
bond
1,2,3,4-tetrahydro-









naphthalen-1-yl



527
—CH2CH2CH2
H
O
O
bond
decahydro-









naphthalen-1-yl



528
—CH2CH2CH2
H
O
O
bond
2,3-dihydro-1H-









inden-1-yl



529
—CH2CH2CH2
H
O
O
bond
1-naphthyl



530
—CH2CH2CH2
H
O
O
bond
2-naphthyl



531
—CH2CH2CH2
H
O
O
—CH2
phenyl



532
—CH2CH2CH2
H
O
O
—CH2
4-fluorophenyl



533
—CH2CH2CH2
H
O
O
—CH2
4-chlorophenyl



534
—CH2CH2CH2
H
O
O
—CH2
4-methylphenyl



535
—CH2CH2CH2
H
O
O
—CH2
4-methoxyphenyl



536
—CH2CH2CH2
H
O
O
—CH2
2,4-dichlorophenyl



537
—CH2CH2CH2
H
O
O
—CH2
3,5-dichlorophenyl



538
—CH2CH2CH2
H
O
O
—CH2
2,6-dichlorophenyl



539
—CH2CH2CH2
H
O
O
—CH2
2-chlorophenyl



540
—CH2CH2CH2
H
O
O
—CH2
3-chlorophenyl



541
—CH2CH2CH2
H
O
O
—CH2
3-(trifluoromethyl)









phenyl



542
—CH2CH2CH2
H
O
O
—CH2
3-methylphenyl



543
—CH2CH2CH2
H
O
O
—CH2
2-methylphenyl



544
—CH2CH2CH2
H
O
O
—CH2
4-nitrophenyl



545
—CH2CH2CH2
H
O
O
—CH2
4-tert-butylphenyl



546
—CH2CH2CH2
H
O
S
—CH2
phenyl



547
—CH2CH2CH2
H
O
S
—CH2
4-fluorophenyl



548
—CH2CH2CH2
H
O
S
—CH2
4-chlorophenyl



549
—CH2CH2CH2
H
O
S
—CH2
4-methylphenyl



550
—CH2CH2CH2
H
O
S
—CH2
4-methoxyphenyl



551
—CH2CH2CH2
H
O
S
—CH2
2,4-dichlorophenyl



552
—CH2CH2CH2
H
O
S
—CH2
3,5-dichlorophenyl



553
—CH2CH2CH2
H
O
S
—CH2
2,6-dichlorophenyl



554
—CH2CH2CH2
H
O
S
—CH2
2-chlorophenyl



555
—CH2CH2CH2
H
O
S
—CH2
3-chlorophenyl



556
—CH2CH2CH2
H
O
S
—CH2
3-(trifluoromethyl)









phenyl



557
—CH2CH2CH2
H
O
S
—CH2
3-methylphenyl



558
—CH2CH2CH2
H
O
S
—CH2
2-methylphenyl



559
—CH2CH2CH2
H
O
S
—CH2
4-nitrophenyl



560
—CH2CH2CH2
H
O
S
—CH2
4-tert-butylphenyl



561
—CH2CH2CH2
H
O
O
—CH(CH3)—
4-fluorophenyl



562
—CH2CH2CH2
H
O
O
—CH(CH2CH3)—
4-fluorophenyl



563
—CH2CH2CH2
H
O
O
—CH2CH2
4-fluorophenyl



564
—CH2CH2CH2
H
O
O
bond
phenyl



565
—CH2CH2CH2
H
O
O
bond
4-fluorophenyl



566
—CH2CH2CH2
H
O
O
bond
4-chlorophenyl



567
—CH2CH2CH2
H
O
O
bond
4-methylphenyl



568
—CH2CH2CH2
H
O
O
bond
3-chlorophenyl



569
—CH2CH2CH2
H
O
O
bond
3,5-dichlorophenyl



570
—CH2CH2CH2
H
O
O
bond
3,4-dichlorophenyl



571
—CH2CH2CH2
H
O
O
bond
2,4-dichlorophenyl



572
—CH2CH2CH2
H
O
O
bond
2-chlorophenyl



573
—CH2CH2CH2
H
O
O
bond
2,6-dichlorophenyl



574
—CH2CH2CH2
H
O
O
bond
3-(trifluoromethyl)









phenyl



575
—CH2CH2CH2
H
O
O
bond
3-methylphenyl



576
—CH2CH2CH2
H
O
O
bond
2-methylphenyl



577
—CH2CH2CH2
H
O
O
bond
4-tert-butylphenyl



578
—CH2CH2CH2
H
O
O
bond
4-nitrophenyl



579
—CH2CH2CH2
H
O
S
bond
phenyl



580
—CH2CH2CH2
H
O
S
bond
4-fluorophenyl



581
—CH2CH2CH2
H
O
S
bond
4-chlorophenyl



582
—CH2CH2CH2
H
O
S
bond
4-methylphenyl



583
—CH2CH2CH2
H
O
S
bond
3-chlorophenyl



584
—CH2CH2CH2
H
O
S
bond
3,5-dichlorophenyl



585
—CH2CH2CH2
H
O
S
bond
3,4-dichlorophenyl



586
—CH2CH2CH2
H
O
S
bond
2,4-dichlorophenyl



587
—CH2CH2CH2
H
O
S
bond
2-chlorophenyl



588
—CH2CH2CH2
H
O
S
bond
2,6-dichlorophenyl



589
—CH2CH2CH2
H
O
S
bond
3-(trifluoromethyl)




—CH2CH2CH2




phenyl



590
—CH2CH2CH2
H
O
S
bond
3-methylphenyl



591
—CH2CH2CH2
H
O
S
bond
2-methylphenyl



592
—CH2CH2CH2
H
O
S
bond
4-tert-butylphenyl



593
—CH2CH2CH2
H
O
S
bond
4-nitrophenyl



594
—CH2CH2CH2
H
O
O
—CH2
pyridin-4-yl



595
—CH2CH2CH2
H
O
O
—CH2
2-thienyl



596
—CH2CH2CH2
H
O
S
bond
cyclohexyl



597
—CH2CH2CH2
H
O
S
bond
1-naphthyl



598
—CH2
H
O
O
—CH2
trimethylsilyl



599
—CH2
H
O
O
bond
cyclohexyl



600
—CH2
H
O
O
bond
cyclopentyl



601
—CH2
H
O
O
—CH2
cyclopropyl



602
—CH2
H
O
O
—CH2
2,2-dichlorocyclo-









propyl



603
—CH2
H
O
O
bond
1,2,3,4-tetrahydro-









naphthalen-1-yl



604
—CH2
H
O
O
bond
decahydro-









naphthalen-1-yl



605
—CH2
H
O
O
bond
2,3-dihydro-1H-









inden-1-yl



606
—CH2
H
O
O
bond
1-naphthyl



607
—CH2
H
O
O
bond
2-naphthyl



608
—CH2
H
O
O
—CH2
phenyl



609
—CH2
H
O
O
—CH2
4-fluorophenyl



610
—CH2
H
O
O
—CH2
4-chlorophenyl



611
—CH2
H
O
O
—CH2
4-methylphenyl



612
—CH2
H
O
O
—CH2
4-methoxyphenyl



613
—CH2
H
O
O
—CH2
2,4-dichlorophenyl



614
—CH2
H
O
O
—CH2
3,5-dichlorophenyl



615
—CH2
H
O
O
—CH2
2,6-dichlorophenyl



616
—CH2
H
O
O
—CH2
2-chlorophenyl



617
—CH2
H
O
O
—CH2
3-chlorophenyl



618
—CH2
H
O
O
—CH2
3-(trifluoromethyl)









phenyl



619
—CH2
H
O
O
—CH2
3-methylphenyl



620
—CH2
H
O
O
—CH2
2-methylphenyl



621
—CH2
H
O
O
—CH2
4-nitrophenyl



622
—CH2
H
O
O
—CH2
4-tert-butylphenyl



623
—CH2
H
O
S
—CH2
phenyl



624
—CH2
H
O
S
—CH2
4-fluorophenyl



625
—CH2
H
O
S
—CH2
4-chlorophenyl



626
—CH2
H
O
S
—CH2
4-methylphenyl



627
—CH2
H
O
S
—CH2
4-methoxyphenyl



628
—CH2
H
O
S
—CH2
2,4-dichlorophenyl



629
—CH2
H
O
S
—CH2
3,5-dichlorophenyl



630
—CH2
H
O
S
—CH2
2,6-dichlorophenyl



631
—CH2
H
O
S
—CH2
2-chlorophenyl



632
—CH2
H
O
S
—CH2
3-chlorophenyl



633
—CH2
H
O
S
—CH2
3-(trifluoromethyl)









phenyl



634
—CH2
H
O
S
—CH2
3-methylphenyl



635
—CH2
H
O
S
—CH2
2-methylphenyl



636
—CH2
H
O
S
—CH2
4-nitrophenyl



637
—CH2
H
O
S
—CH2
4-tert-butylphenyl



638
—CH2
H
O
O
—CH(CH3)—
4-fluorophenyl



639
—CH2
H
O
O
—CH(CH2CH3)—
4-fluorophenyl



640
—CH2
H
O
O
—CH2CH2
4-fluorophenyl



641
—CH2
H
O
O
bond
phenyl



642
—CH2
H
O
O
bond
4-fluorophenyl



643
—CH2
H
O
O
bond
4-chlorophenyl



644
—CH2
H
O
O
bond
4-methylphenyl



645
—CH2
H
O
O
bond
3-chlorophenyl



646
—CH2
H
O
O
bond
3,5-dichlorophenyl



647
—CH2
H
O
O
bond
3,4-dichlorophenyl



648
—CH2
H
O
O
bond
2,4-dichlorophenyl



649
—CH2
H
O
O
bond
2-chlorophenyl



650
—CH2
H
O
O
bond
2,6-dichlorophenyl



651
—CH2
H
O
O
bond
3-(trifluoromethyl)









phenyl



652
—CH2
H
O
O
bond
3-methylphenyl



653
—CH2
H
O
O
bond
2-methylphenyl



654
—CH2
H
O
O
bond
4-tert-butylphenyl



655
—CH2
H
O
O
bond
4-nitrophenyl



656
—CH2
H
O
S
bond
phenyl



657
—CH2
H
O
S
bond
4-fluorophenyl



658
—CH2
H
O
S
bond
4-chlorophenyl



659
—CH2
H
O
S
bond
4-methylphenyl



660
—CH2
H
O
S
bond
3-chlorophenyl



661
—CH2
H
O
S
bond
3,5-dichlorophenyl



662
—CH2
H
O
S
bond
3,4-dichlorophenyl



663
—CH2
H
O
S
bond
2,4-dichlorophenyl



664
—CH2
H
O
S
bond
2-chlorophenyl



665
—CH2
H
O
S
bond
2,6-dichlorophenyl



666
—CH2
H
O
S
bond
3-(trifluoromethyl)









phenyl



667
—CH2
H
O
S
bond
3-methylphenyl



668
—CH2
H
O
S
bond
2-methylphenyl



669
—CH2
H
O
S
bond
4-tert-butylphenyl



670
—CH2
H
O
S
bond
4-nitrophenyl



671
—CH2
H
O
O
—CH2
pyridin-4-yl



672
—CH2
H
O
O
—CH2
2-thienyl



673
—CH2
H
O
S
bond
cyclohexyl



674
—CH2
H
O
S
bond
1-naphthyl



675
—CH2
H
O
O
—CH2
trimethylsilyl



676
—CH2
H
O
O
bond
cyclohexyl



677
—CH2
H
O
O
bond
cyclopentyl



678
—CH2
H
O
O
—CH2
cyclopropyl



679
—CH2
H
O
O
—CH2
2,2-dichlorocyclo-









propyl



680
—CH2
H
O
O
bond
1,2,3,4-tetrahydro-









naphthalen-1-yl



681
—CH2
H
O
O
bond
decahydro-









naphthalen-1-yl



682
—CH2
H
O
O
bond
2,3-dihydro-1H-









inden-1-yl



683
—CH2
H
O
O
bond
1-naphthyl



684
—CH2
H
O
O
bond
2-naphthyl



685
—CH2
H
O
O
—CH2
phenyl



686
—CH2
H
O
O
—CH2
4-fluorophenyl



687
—CH2
H
O
O
—CH2
4-chlorophenyl



688
—CH2
H
O
O
—CH2
4-methylphenyl



689
—CH2
H
O
O
—CH2
4-methoxyphenyl



690
—CH2
H
O
O
—CH2
2,4-dichlorophenyl



691
—CH2
H
O
O
—CH2
3,5-dichlorophenyl



692
—CH2
H
O
O
—CH2
2,6-dichlorophenyl



693
—CH2
H
O
O
—CH2
2-chlorophenyl



694
—CH2
H
O
O
—CH2
3-chlorophenyl



695
—CH2
H
O
O
—CH2
3-(trifluoromethyl)









phenyl



696
—CH2
H
O
O
—CH2
3-methylphenyl



697
—CH2
H
O
O
—CH2
2-methylphenyl



698
—CH2
H
O
O
—CH2
4-nitrophenyl



699
—CH2
H
O
O
—CH2
4-tert-butylphenyl



700
—CH2
H
O
S
—CH2
phenyl



701
—CH2
H
O
S
—CH2
4-fluorophenyl



702
—CH2
H
O
S
—CH2
4-chlorophenyl



703
—CH2
H
O
S
—CH2
4-methylphenyl



704
—CH2
H
O
S
—CH2
4-methoxyphenyl



705
—CH2
H
O
S
—CH2
2,4-dichlorophenyl



706
—CH2
H
O
S
—CH2
3,5-dichlorophenyl



707
—CH2
H
O
S
—CH2
2,6-dichlorophenyl



708
—CH2
H
O
S
—CH2
2-chlorophenyl



709
—CH2
H
O
S
—CH2
3-chlorophenyl



710
—CH2
H
O
S
—CH2
3-(trifluoromethyl)









phenyl



711
—CH2
H
O
S
—CH2
3-methylphenyl



712
—CH2
H
O
S
—CH2
2-methylphenyl



713
—CH2
H
O
S
—CH2
4-nitrophenyl



714
—CH2
H
O
S
—CH2
4-tert-butylphenyl



715
—CH2
H
O
O
—CH(CH3)—
4-fluorophenyl



716
—CH2
H
O
O
—CH(CH2CH3)—
4-fluorophenyl



717
—CH2
H
O
O
—CH2CH2
4-fluorophenyl



718
—CH2
H
O
O
bond
phenyl



719
—CH2
H
O
O
bond
4-fluorophenyl



720
—CH2
H
O
O
bond
4-chlorophenyl



721
—CH2
H
O
O
bond
4-methylphenyl



722
—CH2
H
O
O
bond
3-chlorophenyl



723
—CH2
H
O
O
bond
3,5-dichlorophenyl



724
—CH2
H
O
O
bond
3,4-dichlorophenyl



725
—CH2
H
O
O
bond
2,4-dichlorophenyl



726
—CH2
H
O
O
bond
2-chlorophenyl



727
—CH2
H
O
O
bond
2,6-dichlorophenyl



728
—CH2
H
O
O
bond
3-(trifluoromethyl)









phenyl



729
—CH2
H
O
O
bond
3-methylphenyl



730
—CH2
H
O
O
bond
2-methylphenyl



731
—CH2
H
O
O
bond
4-tert-butylphenyl



732
—CH2
H
O
O
bond
4-nitrophenyl



733
—CH2
H
O
S
bond
phenyl



734
—CH2
H
O
S
bond
4-fluorophenyl



735
—CH2
H
O
S
bond
4-chlorophenyl



736
—CH2
H
O
S
bond
4-methylphenyl



737
—CH2
H
O
S
bond
3-chlorophenyl



738
—CH2
H
O
S
bond
3,5-dichlorophenyl



739
—CH2
H
O
S
bond
3,4-dichlorophenyl



740
—CH2
H
O
S
bond
2,4-dichlorophenyl



741
—CH2
H
O
S
bond
2-chlorophenyl



742
—CH2
H
O
S
bond
2,6-dichlorophenyl



743
—CH2
H
O
S
bond
3-(trifluoromethyl)









phenyl



744
—CH2
H
O
S
bond
3-methylphenyl



745
—CH2
H
O
S
bond
2-methylphenyl



746
—CH2
H
O
S
bond
4-tert-butylphenyl



747
—CH2
H
O
S
bond
4-nitrophenyl



748
—CH2
H
O
O
—CH2
pyridin-4-yl



749
—CH2
H
O
O
—CH2
2-thienyl



750
—CH2
H
O
S
bond
cylcohexyl



751
—CH2
H
O
S
bond
1-naphthyl



752
—CH2
H
O
O
bond
cyclohexyl



753
—CH2
H
O
O
bond
1,2,3,4-tetrahydro-









naphthalen-1-yl



754
—CH2
H
O
O
bond
decahydro-









naphthalen-1-yl



755
—CH2
H
O
O
bond
2,3-dihydro-1H-









inden-1-yl



756
—CH2
H
O
O
bond
1-naphthyl



757
—CH2
H
O
O
bond
2-naphthyl



758
—CH2
H
O
O
—CH2
phenyl



759
—CH2
H
O
O
bond
cyclohexyl



760
—CH2
H
O
O
bond
1,2,3,4-tetrahydro-









naphthalen-1-yl



761
—CH2
H
O
O
bond
decahydro-









naphthalen-1-yl



762
—CH2
H
O
O
bond
2,3-dihydro-1H-









inden-1-yl



763
—CH2
H
O
O
bond
1-naphthyl



764
—CH2
H
O
O
bond
2-naphthyl



765
—CH2
H
O
O
—CH2
phenyl



766
—CH2
H
O
O
—CH2CH2
tert-butyl



767
—CH2
H
O
O
—CH2CH2
tert-butyl
3.82*


768
—CH2
H
O
O
—CH2CH2
tert-butyl



769
—CH2
H
O
O
bond
cyclohexyl
4.58*


770
—CH2
H
O
O
bond
1-naphthyl
4.50*


771
—CH2
H
O
O
bond
1-naphthyl
4.35*


772
—CH2
H
O
O
bond
cyclohexyl
4.39*


773
—CH2
H
O
O
bond
1-naphthyl
3.87*


774
—CH2
H
O
O
bond
cyclohexyl
3.88*


775
—CH2
H
O
O
—CH2
3,4-dichlorophenyl
4.09*


776
—CH2
H
O
O
—CH2
4-(trifluoromethyl)
3.86*








phenyl



777
—CH2
H
O
O
bond
1-naphthyl
4.50*


778
—CH2
H
O
O
bond
1-naphthyl



779
—CH2
H
O
O
—CH2
(E)-2-phenylethenyl
3.74*


780
—CH2
H
O
O
—CH2
pyridin-3-yl
1.74*


781
—CH2
H
O
O
bond
quinolin-7-yl
2.42*


782
—CH2
H
O
O
bond
quinolin-8-yl
2.88*


783
—CH2
H
O
O
—CH2
1-naphthyl
3.90*


784
—CH2
H
O
O
—CH2
2-naphthyl
3.92*


785
—CH2
H
O
O
—CH(CH3)—
1-naphthyl
4.16*


786
—CH2
H
O
O
—CH(CH3)—
2-naphthyl
4.18*


787
—CH2
H
O
O
—CH2
phenylethynyl
3.70*


788
—CH2
H
O
O
bond
cycloheptyl
4.09*


789
—CH2
H
O
O
bond
1,2,3,4-tetrahydro-
3.94*








naphthalen-2-yl



790
—CH2
H
O
O
bond
5,6,7,8-tetrahydro-
4.21*








naphthalen-1-yl



791
—CH2
H
O
O
bond
2,3-dihydro-1H-
3.67*








inden-2-yl



792
—CH2
H
O
O
bond
5,6,7,8-tetrahydro-
4.30*








naphthalen-2-yl



793
—CH2
H
O
O
bond
quinolin-6-yl
2.37*


794
—CH2
H
O
O
bond
isoquinolin-5-yl
2.18*


795
—CH2
H
O
O
bond
(1R)-1,2,3,4-tetra-
4.06*








hydronaphthalen-1-yl



796
—CH2
H
O
O
bond
cyclohexyl
3.28*


797
—CH2
H
O
O
bond
5-methyl-2-(propan-
5.51*








2-yl)cyclohexyl



798
—CH2
H
O
O
bond
1-ethynyl-
3.28*








cyclopentyl



799
—CH2
H
O
O
—CH(CH2CH3)—
(1Z)-prop-1-en-1-yl
3.78*


800
—CH2
H
O
O
bond
(1S,2R)-1,7,7-
5.08*








trimethylbicyclo









[2.2.1]hept-2-yl



801
—CH2
H
O
O
bond
hex-1-en-3-yl
3.78*


802
—CH2
H
O
O
bond
3-methyl-5-(propan-
5.58*








2-yl)cyclohexyl



803
—CH2
H
O
O
—CH2CH2
dimethylamino
1.03*


804
—CH2
H
O
O
bond
1-ethynyl-
3.73*








cyclohexyl



805
—CH2
H
O
O
—CH(CH3)—
CF3
3.19*


806
—CH2
H
O
O
—CH2
heptan-3-yl
5.08*


807
—CH2
H
O
O
bond
quinolin-5-yl
2.59*


808
—CH2
H
O
O
bond
diphenylmethyl
4.17*


809
—CH2
H
O
O
bond
1,3-benzoxazol-4-yl
2.81*


810
—CH2
H
O
O
bond
cyclohexyl



811
—CH2
H
O
O
bond
cyclohexyl
3.64*


812
—CH2
H
O
O
bond
1-naphthyl



813
—CH2
H
O
O
bond
1-naphthyl
3.64*


814
—CH2
H
O
O
bond
2-methoxyphenyl
3.17*


815
—CH2
H
O
O
bond
cyclopropyl(phenyl)
3.87*








methyl



816
—CH2
H
O
O
bond
2,6-dimethoxyphenyl
3.12*


817
—CH2
H
O
O
—CH2
2-methoxyphenyl
3.44*


818
—CH2
H
O
O
—CH2
2,4,6-trichlorophenyl
4.53*


819
—CH2
H
O
O
—CH2
4-(trifluoromethoxy)
3.99*








phenyl



820
—CH2
H
O
O
—CH2
2-bromophenyl
3.80*


821
—CH2
H
O
O
bond
biphenyl-2-yl
3.96*


822
—CH2
H
O
O
bond
biphenyl-3-yl
4.16*


823
—CH2
H
O
O
bond
biphenyl-4-yl
4.17*


824
—CH2
H
O
O
bond
3-phenoxyphenyl
4.18*


825
—CH2
H
O
O
bond
4-phenoxyphenyl
4.14*


826
—CH2
H
O
O
bond
1-ethynylcyclohexyl
3.76*


827
—CH2
H
O
O
bond
1-cyanocyclohexyl
3.33*


828
—CH2
H
O
O
bond
4-tert-butylcyclohexl
5.19*


829
—CH2
H
O
O
bond
5-methyl-2-(propan-
5.22*








2-yl)-cyclohexyl



830
—CH2
H
O
O
bond
1,4-dioxaspiro[4.5]
2.90*








dec-8-yl



831
—CH2
H
O
O
bond
2,6-dimethylcyclo-
4.40*








hexyl



832
—CH2
H
O
O
bond
2-methcyclohexyl
4.12*


833
—CH2
H
O
O
bond
octyl
5.02*


834
—CH2
H
O
O
—CH2
2,4-dimethoxyphenyl
3.33*


835
—CH2
H
O
O
—CH2
2,4,6-trifluorophenyl
3..53*


836
—CH2
H
O
O
—CH2
2-(trifluoromethyl)
3.84*








phenyl



837
—CH2
H
O
O
—CH2
2-(trifluoromethoxy)
3.95*








phenyl



838
—CH2
H
O
O
—CH2
CH3



839
—CH2
H
O
O
—CH2
CH3



840
—CH2
H
O
O
—CH2
CH3



841
—CH2
H
O
O
—CH2
CH3



842
—CH2
H
O
O
—CH2
CH3



843
—CH2CH2
H
O
O
—CH2
CH3



844
—CH2
H
O
O
bond
1-naphthyl



845
—CH2
H
O
O
—CH2
2-[1-methoxy-2-









(methylamino)-2-









oxoethyl]phenyl



846
—CH2
H
O
O
—CH2
2-[(methylamino)-









(oxo)acetyl]phenyl



847
—CH2
H
O
O
—CH2
cyclohexyl
4.75*


848
—CH2
H
O
O
—CH2
cyclohexyl
4.51*


849
—CH2
H
O
O
—CH2
cyclohexyl
5.08*


850
—CH2
H
O
O
—CH2
cyclohexyl
4.94*


851
—CH2
H
O
O
—CH2
cyclohexyl
4.35*


852
—CH2
H
O
O
—CH2
cyclohexyl
3.99*


853
—CH2
H
O
O
bond
(1S)-1,2,3,4-tetra-
4.06*








hydronaphthalen-1-yl



854
—CH2
H
O
O
bond
cyclohexyl
4.23*





The logP values were measured according to EEC directive 79/831 Annex V.A8 by HPLC (High Performance Liquid Chromatography) on reversed-phase columns (C 18), using the methods below:


**The determination in the acidic range is carried out at pH 2.3 using the mobile phases 0.1% aqueous phosphoric acid and acetonitrile linear gradient from 10% acetonitrile to 95% acetonitrile.


*The LC-MS determination in the acidic range is carried out at pH 2.7 using the mobile phases 0.1% aqueous formic acid and acetonitrile (contains 0.1% formic acid) linear gradient from 10% acetonitrile to 95% acetonitrile


***The LC-MS determination in the neutral range is carried out at pH 7.8 using the mobile phases 0.001 molar aqueous ammonium bicarbonate solution and acetonitrile linear gradient from 10% acetonitrile to 95% acetonitrile.


The calibration is carried out using unbranched alkan-2-ones (having 3 to 16 carbon atoms) with known logP values (determination of the logP values by the retention times using linear interpolation between two successive alkanones). The lambda-maX values were determined in the maxima of the chromatographic signals using the UV spectra from 200 nm to 400 nm.






Use Examples
Example A

Phytophthora Test (Tomato)/Protective

Solvent: 24.5 parts by weight of acetone

    • 24.5 parts by weight of dimethylacetamide


      Emulsifier: 1 part by weight of alkylaryl polyglycol ether


To produce a suitable preparation of active compound, 1 part by weight of active compound is mixed with the stated amounts of solvent and emulsifier, and the concentrate is diluted with water to the desired concentration.


To test for protective activity, young plants are sprayed with the preparation of active compound at the stated application rate. After the spray coating has dried on, the plants are inoculated with an aqueous spore suspension of Phytophthora infestans. The plants are then placed in an incubation cabin at about 20° C. and 100% relative atmospheric humidity.


Evaluation is carried out 3 days after the inoculation. 0% means an efficacy which corresponds to that of the control, whereas an efficacy of 100% means that no infection is observed.


In this test, the compounds according to the invention of the formulae below show, at an active compound concentration of 100 ppm, an efficacy of 70% or more.


Ex. Nos. 44, 45, 8, 10, 766, 772, 771, 774, 773, 18, 20, 19, 775, 17, 23, 24, 776, 29, 21, 26, 28, 15, 31, 25, 778, 81, 3, 779, 781, 782, 783, 784, 785, 788, 790, 789, 791, 792, 795, 794, 796, 811, 813


Example B

Plasmopara Test (Grapevine)/Protective

Solvent: 24.5 parts by weight of acetone

    • 24.5 parts by weight of dimethylacetamide


      Emulsifier: 1 part by weight of alkylaryl polyglycol ether


To produce a suitable preparation of active compound, 1 part by weight of active compound is mixed with the stated amounts of solvent and emulsifier, and the concentrate is diluted with water to the desired concentration.


To test for protective activity, young plants are sprayed with the preparation of active compound at the stated application rate. After the spray coating has dried on, the plants are inoculated with an aqueous spore suspension of Plasmopara viticola and then remain in an incubation cabin at about 20° C. and 100% relative atmospheric humidity for 1 day. The plants are then placed in a greenhouse at about 21 C and about 90% atmospheric humidity for 4 days. The plants are then moistened and placed in an incubation cabin for 1 day.


Evaluation is carried out 6 days after the inoculation. 0% means an efficacy which corresponds to that of the control, whereas an efficacy of 100% means that no infection is observed.


In this test, the compounds according to the invention of the formulae below show, at an active compound concentration of 100 ppm, an efficacy of 70% or more.


Ex. Nos. 44, 45, 8, 10, 766, 772, 771, 774, 773, 18, 20, 19, 775, 17, 23, 24, 776, 21, 26, 28, 15, 31, 25, 778, 81, 3, 779, 781, 782, 783, 784, 785, 788, 790, 789, 791, 792, 795, 794, 796, 811, 813


Example C

Phytophthora Test (Tomato)/Protective

Solvent: 24.5 parts by weight of acetone

    • 24.5 parts by weight of dimethylacetamide


      Emulsifier: 1 part by weight of alkylaryl polyglycol ether


To produce a suitable preparation of active compound, 1 part by weight of active compound is mixed with the stated amounts of solvent and emulsifier, and the concentrate is diluted with water to the desired concentration.


To test for protective activity, young plants are sprayed with the preparation of active compound at the stated application rate. After the spray coating has dried on, the plants are inoculated with an aqueous spore suspension of Phytophthora Infestans. The plants are then placed in an incubation cabin at about 20° C. and 100% relative atmospheric humidity.


Evaluation is carried out 3 days after the inoculation. 0% means an efficacy which corresponds to that of the control, whereas an efficacy of 100% means that no infection is observed.









TABLE







Phytophthora test (tomato) / protective










Active




compound




application rate



Active compound
in ppm
Efficacy in %





Known from W02007014290















embedded image


10
65












According the invention:












Ex. 23


embedded image


10
94









Example D

Plasmopara Test (Grapevine)/Protective

Solvent: 24.5 parts by weight of acetone

    • 24.5 parts by weight of dimethylacetamide


      Emulsifier: 1 part by weight of alkylaryl polyglycol ether


To produce a suitable preparation of active compound, 1 part by weight of active compound is mixed with the stated amounts of solvent and emulsifier, and the concentrate is diluted with water to the desired concentration.


To test for protective activity, young plants are sprayed with the preparation of active compound at the stated application rate. After the spray coating has dried on, the plants are inoculated with an aqueous spore suspension of Plasmopara viticola and then remain in an incubation cabin at about 20° C. and 100% relative atmospheric humidity for 1 day. The plants are then placed in a greenhouse at about 21° C. and about 90% atmospheric humidity for 4 days. The plants are then moistened and placed in an incubation cabin for 1 day.


Evaluation is carried out 6 days after the inoculation. 0% means an efficacy which corresponds to that of the control, whereas an efficacy of 100/% means that no infection is observed.









TABLE







Plasmopara test (grapevine) / protective










Active




compound




application rate



Active compound
in ppm
Efficacy in %





Known from W02007014290















embedded image


1
72












According the invention:












Ex. 6


embedded image


1
91









Example E

Plasmopara Test (Grapevine)/Curative

Solvent: 24.5 parts by weight of acetone

    • 24.5 parts by weight of dimethylacetamide


      Emulsifier: 1 part by weight of alkylaryl polyglycol ether


To produce a suitable preparation of active compound, 1 part by weight of active compound is mixed with the stated amounts of solvent and emulsifier, and the concentrate is diluted with water to the desired concentration.


To test for curative activity, young plants are inoculated with an aqueous spore suspension of Plasmopara viticola. The plants remain in an incubation cabin at about 20° C. and 100% relative atmospheric humidity for 24 hours, and after a further 24 hours at about 21° C. and about 90% relative atmospheric humidity, the plants are sprayed with the active compound preparation at the stated application rate.


5 days after the inoculation, the plants are moistened and placed in an incubation cabin for 1 day.


Evaluation is carried out 6 days after the inoculation. 0% means an efficacy which corresponds to that of the control, whereas an efficacy of 100% means that no infection is observed.









TABLE







Plasmopara test (grapevine) / curative










Active




compound




application rate



Active compound
in ppm
Efficacy in %





Known from W02007014290















embedded image


100
37












According the invention:












Ex. 6


embedded image


100
84








Claims
  • 1-6. (canceled)
  • 7. A compound of formula (XVI-1), (XVI-2), (XVI-3), (XVI-4) or (XVI-5):
  • 8. A compound of formula (V-1), (V-2), (V-3), (V-4) or (V-5):
  • 9-10. (canceled)
  • 11. A compound of formula (IX):
  • 12. A compound of formula (X):
  • 13-14. (canceled)
  • 15. A compound of formula (IX-1) or (IX-2) according to claim 11,
  • 16. A compound of formula (X-1) or (X-2) according to claim 12,
Priority Claims (1)
Number Date Country Kind
08155472.7 Apr 2008 EP regional
Divisions (2)
Number Date Country
Parent 14039806 Sep 2013 US
Child 14678174 US
Parent 12990358 Oct 2010 US
Child 14039806 US