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    • 专利摘要:
    bis (difluoromethyl) pyrazols as fungicides. bis (difluormethyl) derivatives of formula (i), in which the symbols r1, xeg have the meanings given in the descriptive report, as well as agrochemicals salts, metal complexes and n-oxides thereof and their use in combating harmful phytopathogenic fungi as well as processes for the production of compounds of formula (i).
    公开号:BR112012015152B1
    申请号:R112012015152-5
    申请日:2010-12-17
    公开日:2018-07-03
    发明作者:Cristau Pierre；Kluth Joachim；Tsuchiya Tomoki；Wasnaire Pierre；Benting Jürgen；Portz Daniela；Wachendorff-Neumann Ulrike；Hoffman Sebastian
    申请人:Bayer Cropscience Ag；
    IPC主号:
    专利说明:

    (54) Title: COMPOUNDS DERIVED FROM BIS (DIFLUORMETHIL) PIRAZÓIS, THEIR USES AND THEIR PREPARATION PROCESS, AGENT UNDERSTANDING THE REFERRED COMPOUNDS AND THEIR PRODUCTION PROCESS, AND PROCESS FOR THE COMBAT OF HARMFUL PHYTOPHOGENIC FUNGI: 51). C07D 417/04; C07D 417/14; A01N 43/78 (30) Unionist Priority: 12/21/2009 US 61 / 288,484, 12/21/2009 EP 09180073.0 (73) Holder (s): BAYER CROPSCIENCE AG (72) Inventor (s): PIERRE CRISTAU; JOACHIM KLUTH; TOMOKI TSUCHIYA; PIERRE WASNAIRE; JÜRGEN BENTING; DANIELA PORTZ; ULRIKE WACHENDORFF-NEUMANN; SEBASTIAN HOFFMAN
    1/108 “BIS DIFFERENTIAL COMPOUNDS (DIFLUORMETHIL) PIRAZÓIS, ITS USES AND THEIR PREPARATION PROCESS, AGENT UNDERSTANDING THE COMPOUND COMPOUNDS AND THEIR PRODUCTION PROCESS, AND PROCESS FOR COMBATING HARMFUL PHYTOPHOGENIC FUNGI”.
    The invention relates to bis (difluormethyl) pyrazole derivatives, their agrochemically effective salts, their use as well as processes and agents for combating harmful phytopathogenic fungi in and / or in plants or in and / or in plant seed , processes for the production of these agents and treated seed, as well as their use to fight harmful phytopathogenic fungi in agriculture, horticulture and forestry, in animal health, in material protection, as well as in the domestic and hygienic sector. In addition, the present invention relates to a process for the production of bis (difluormethyl) pyrazole derivatives.
    It is already known that certain substituted pyrazole derivatives can be used as fungicidal preparations for plant protection (see WO 07/014290, WO 08/013925, WO 08/013622, WO 08/091594, WO 08/091580, WO 09 / 055514, WO 09/094407, WO 09/94445, WO
    09/132785, WO 10/037479, WO 10/065579, WO 10/066353, WO 10/123791, see also patent applications with the registration numbers: Del02010000662.9, PCT / EP2010 / 003499, EP09174510.9, EP09174614.9, EP09180073.0, EP10161264.6, EP10163067.1, EP10164099.3, EP10172486.2, EP10174012.4, EP10189067.1). However, the fungicidal efficacy of these compounds, precisely in smaller amounts of application, is not always satisfactory.
    Since the ecological and economic requirements of modern plant protection preparations are continually increasing, for example, with regard to the spectrum of action, toxicity, selectivity, amount of application, formation of residues and favorable production capacity and, in addition, for example, problems with resistance can occur, the constant objective is to develop new preparations for the protection of plants, particularly fungicides, which, at least in part, present advantages compared to those known.
    Surprisingly, it has now been found that the present bis (difluormethyl) pyrazole derivatives solve the mentioned objectives in at least some ways and that they are suitable as preparations for plant protection, especially as fungicides.
    The purpose of the invention are compounds of the formula (I)

    in which the symbols have the following meanings:
    Petition 870180026317, of 04/02/2018, p. 17/27
    2/108
    X represents oxygen or sulfur,

    G represents G1 =, G2 = -G3 =
    R 1 represents hydrogen or halogen,
    R 2 represents C ^ Cg alkyl or C 1 -C 6 haloalkyl
    or
    R 2 represents a C 3 -C 8 cycloalkyl, which can contain up to two substituents, in which the substituents independently of each other, are selected from the following list:
    cyano, halogen, hydroxy, oxo, C r C 4 alkyl, C 1 -C 4 halogenoalquila, CAC4 alkoxy, C r C 4 haloalkoxy, C 4 -C 4 alkylthio, Ci-C4 haloalkylthio or phenyl or
    R 2 represents a C 5 -C 8 cycloalkenyl, which can contain up to two substituents, where the substituents independently of each other are selected from the following list:
    cyano, halogen, hydroxy, oxo, -C 4 alkyl, C halogenoalquila Ci-4 alkoxy, Ci-C4, haloalkoxy θ! -θ 4, C-4 alkylthio, Ci-C4 haloalkylthio or phenyl or
    R 2 represents a phenyl, which can contain up to two substituents, where the substituents independently of each other are selected from the following list:
    amino, halogen, cyano, hydroxy, SH, nitro, C (= O) H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 O 6 alkynyl, C ^ -C halogenoalquila, C 2 -C halogenoalquenila 6, halogenoalquinila C 2 -C 6 alkyl , C 3 -C 8 cycloalkyl, C 3 -C 8 halogenocicloalquila, alquilcicloalquila C 4 -C 10, C 4 C 10 cycloalkylalkyl, C 6 -C 14 cicloalquilcicloalquila, halogenocicloalquilalquila C 4 -C 10, alkylcicioalkylalkyl C 5 C 10 , cycloalkenyl C 3 -C 8 , halogenocycloalkenyl C 3 -C 8 , alkoxyalkyl C 2 -C 6 , cycloalkoxyalkyl C 4 -Ci 0 , alkoxyalkoxyalkyl C 3 -C 8 , alkylalkylalkylC 2 -C 6 alkylsulfinyl 2 -C 6 alquilsulfonilalquila C 2 -C 6 alkyl , C 2 -C 6 alkylaminoalkyl, C 3 -C 8 dialkylaminoalkyl, C 2 -C 6 halogenoalquilaminoalquila, cicloalquilaminoalquila C 4 -C 10, C 2 -C 6 alkylcarbonyl, C 2 halogenoalquilcarbonila -C 6 , C 4 -C 8 cycloalkylcarbonyl, C 2 -C 6 alkoxycarbonyl, C 4 -C 8 cycloalkoxycarbonyl, C 5 -C 10 cycloalkylalkoxycarbonyl, alkylam inocarbonila C 2 -C 6 alkyl , C 3 -C 8 dialquilaminocarbonila, cicloalquilaminocarbonila C 4 -C 8 halogenoalcoxialquila C 2 -C 6 hydroxyalkyl C ^ alkyl, Ci-C6 alkoxy, haloalkoxy Ch-alkyl, C 3 -C 8 cycloalkoxy , halogenocicloalcoxi C 3 -C 8 -cycloalkyl , C 4 -C cicioalquilalcoxi 0, C 2 -C 6 alkenyloxy, C 2 -C 6 halogenoalqueniloxi, C 2 -C 6 alkynyloxy, C 2 -C 6 halogenoalquiniloxi, C 2 -C 6 alkoxyalkoxy, alkylcarbonyloxy C 2 -C 6 alkyl , C 2 -C 6 halogenoalquilcarboniloxi, C4-C8 cycloalkylcarbonyloxy, C3-C6 alquilcarbonilalcoxi, C₁ to C₆ alkylthio, Ci-C6 haloalkylthio, C 3 -C 6 cycloalkylthio, alquilsulfinila CVCE, halogenoalquilsulfinila C 1 -C 6 , C 2 C-alkylsulfonyl, Ch-Cg haloalkylsulfonyl,
    3/108 cicloalquilsulfonila C 3 -C 8 -cycloalkyl , tri- (Ci-C4 alkyl) silyl, C r C 6 alkylsulfonylamino, C halogenoalquilsulfonilamino / or C6 or -LQ
    R 2 represents naphthyl, dihydronaphthalenyl, tetrahydronaphthalenyl, hexahydronaphthalenyl, octahydronaphthalenyl or indenyl, which can contain up to two substituents, where the substituents independently of each other are selected from the following list:
    cyano, nitro, halogen, alkyl C / -C6 alkyl, C1 -C4 halogenoalquila, cicioalquila C 3 -C 6 alkyl , C 2 -C 6 alkenyl, C 2 -C 6 halogenoalquenila, C 2 -C 6 alkynyl, C 2 -C halogenoalquinila 6, tri (Ci-C4 alkyl) silyl, benzyl, phenyl, hydroxy, SH, oxo, Ci-C6 alkoxy, C ^ Ce haloalkoxy, C 2 -C 6 alkenyloxy, C 2 -C 6 alkynyloxy, alkylthio C Ce or C 1 -C 6 haloalkylthio or
    R 2 represents a 5- or 6-membered heteroaryl radical, which can contain up to two substituents, where the substituents independently of each other are selected from the following list:
    Substituents on the carbon: halogen, cyano, nitro, hydroxy, SH, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 6 -C halogenoalquila, halogenoalquenila C 2 -C 6, C 2 halogenoalquinila C6, cicioalquila C 3 -C 6 alkyl , C 3 -C 6 halogenocicloalquila, alquilcicloalquila C 4 -C 0 -C 0 -C 4 cycloalkylalkyl, C 6 -C 14 cicloalquilcicloalquila, alquilcicloalquila C5-C10 alkyl, C2-C4 alkoxyalkyl , C 2 -C 4 alkylcarbonyl, C 2 -C 6 alkoxycarbonyl, C 2 -C 6 alquilaminocarbonila, dialquilaminocarbonila C 3 -C 8 hydroxyalkyl, C 4 alkoxy, Ci-C4 haloalkoxy, C2-C6 alkylcarbonyloxy, alquilcarboniltio C 2 -C 6 -alkyl, Ci-C 4 alkylthio, haloalkylthio C r C 4 -C alquilsulfinila 4 halogenoalquilsulfinila C1-C4 alquilsulfonila C r C 4, C r C 4 halogenoalquilsulfonila, tri (alkyl or Ci-Cúsilila -LQ substituents in nitrogen: Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 6 halogenoalquila C r, C 2 -C 6 halogenoalquenila, halogenoalquinil C 2 -C 6 cicioalquila C 3 -C 6 alkyl , C 3 -C 6 halogenocicloalquila, alquilcicloalquila C 4 -C 0 -C 0 -C 4 cycloalkylalkyl, alquilsulfonila Ci-C 4, C (= O) H, C ( = O) Me, C (= O) 0Me, benzyl or phenyl or
    R 2 and R 3 form, together with the carbon atom to which they are attached, a 5- to 12-membered mono- or bicyclic ring system, unsubstituted or substituted, partially saturated or unsaturated, which can contain up to three other heteroatoms , selected from N, O and S, in which two oxygen atoms are not adjacent and in which possible substituents independently of each other, are selected from halogen, C r C 4 alkyl, CrC 4 haloalkyl, Ci-C 4 alkoxy, haloalkoxy C ^, oxo, hydroxy, benzyl or phenyl,
    R 3 represents hydrogen, cyano, C1-C3 alkyl or C 1 -C 3 haloalkyl,
    R Tz represents halogen or hydrogen,
    4/108
    L represents a direct bond, -CH 2 -, - (C = O) -, sulfur or oxygen,
    Q represents phenyl, which can contain up to two substituents, where the substituents independently of each other are selected from the following list:
    halogen, cyano, nitro, hydroxy, SH, -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogenoalquila -C 6, C 2 -C 6 halogenoalquenila, halogenoalquinila C 2 -C 6, cycloalkyl C 3 - C 8 halogenocicloalquila C 3 -C 8, C 2 -C 6 alkoxyalkyl, C 2 -C 6 alkylcarbonyl, C 2 -C 6 halogenoalquilcarbonila, C 2 -C 6 alkoxycarbonyl, CRCE alkoxy, haloalkoxy Ο ^ Οβ, cyclo C 3 - C 8 , C 3 -C 8 halo-cycloalkoxy, C 2 -C 6 alkenyloxy, C 2 -C 6 alkynyloxy, C 2 -C 6 alkoxyalkyl, C r C 6 alkylthio, C 1 -C 6 haloalkylalkyl, C / -C 6 alkylsulfinyl, haloalkylsulfinyl CiC 6 , Ci-C 6 alkylsulfonyl, halogenoalkylsulfonyl Ο ^ Οβ, tri (CrC 4 alkyl) silyl or phenyl or
    Q represents a 5- or 6-membered heteroaryl radical, which can contain up to two substituents, where the substituents independently of each other are selected from the following list:
    Substituents on the carbon: halogen, cyano, nitro, hydroxy, SH, Ci-C 8 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 6 -C halogenoalquila, halogenoalquenila C 2 -C 8, C 2 halogenoalquinila -C 6 alkyl , C 3 -C 6 cycloalkyl, C 3 -C 6 halogenocicloalquila, alquilcicloalquila C 4 -C 10 cycloalkylalkyl , C 4 -C 10, C 6 -C cicloalquilcicloalquila 4 alquilcicloalquilalquila C5-C10 alkyl, C2-C4 alkoxyalkyl , C 2 -C 4 alkylcarbonyl, C 2 -C 6 alkoxycarbonyl, Ci-C4 alkoxy, haloalkoxy CrCzt, C 2 -C 6 alkylcarbonyloxy, C 2 -C 6 alquilcarboniltio, C r C 4 alkylthio, Ci-C4 haloalkylthio, alquilsulfinila CU-O, C-C 4 halogenoalquilsulfinila, alquilsulfonila halogenoalquilsulfonila ^ Cr, tri (C r C 4 alkyl) silyl or phenyl substituents at nitrogen: Ci-C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C alkynyl 4, halogenoalquila -C 4 halogenoalquenila C 2 -C 4 halogenoalquinila C 2 -C 4 alkyl , C 3 -C 6 cycloalkyl, C 4 -C alquilsulfonila, C (= O) H, C (= O) Me, C (= O) OMe or phenyl, as well as salts, metal complexes and agrochemically effective N-oxides thereof.
    Another objective is to use the compounds of formula (I) as a fungicide.
    Bis (difluormethyl) pyrazole derivatives of the formula (I) according to the invention, as well as their agrochemically effective salts, metal complexes and N-oxides are very well suited to combat harmful phytopathogenic fungi. The compounds according to the invention mentioned above show mainly a strong fungicidal efficacy and can be used both in plant protection, in the domestic and hygienic sector, as well as in material protection.
    The compounds of the formula (I) can be present both in pure form, and also as mixtures of different possible isomeric forms, particularly stereoisomers, such as E and Z isomers, threus and erythro, as well as optical isomers, such as
    5/108 as R and S isomers or atropoisomers, but optionally also of tautomers. Both the E isomers, as well as the Z, are also claimed, as well as the thromus and erythro isomers, as well as the optical, desired mixtures of these isomers, as well as the possible tautomeric forms.
    Bis (difluormethyl) pyrazole derivatives which can be used according to the invention are generally defined by formula (I). Preferred definitions of the radicals of the formulas mentioned above and below are given below. These definitions apply in the same way for the final products of formula (I), as well as for all intermediate products (see also below for explanations of the processes and intermediate products).
    X preferably represents oxygen,
    R 1 preferably represents hydrogen or fluorine,
    G preferably represents G1, G3 and G4,
    G is particularly preferred
    6/108

    G4-10 =, G4-11 =
    7/108
    R 2 preferably represents a C 3 -C 8 cycloalkyl, which can contain up to two substituents, where the substituents independently of each other are selected from the following list:
    cyano, halogen, hydroxy, oxo, C / -C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, CGC4 alkylthio, C r C 4 haloalkylthio or phenyl,
    R 2 furthermore preferably represents a phenyl, which may contain up to two substituents, in which the substituents independently of each other are selected from the following list:
    amino, halogen, cyano, hydroxy, SH, nitro, C (= O) H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 6 -C halogenoalquila, C 2 -C halogenoalquenila 6, halogenoalquinila C 2 -C 6 alkyl , C 3 -C 8 cycloalkyl, C 3 -C 8 halogenocicloalquila, alquilcicloalquila C4 -C10 alkyl, C4 -C10 cycloalkylalkyl, C 6 -C 14 cicloalquilcicloalquila, halogenocicloalquilalquila C4-C10 alkyl, C5 alquilcicloalquilalquila Cw, C 3 -C 8 cycloalkenyl, C 3 -C 8 halogenocicloalquenila, C 2 -C 6 alkoxyalkyl, C 4 -C 10 cicloalcoxialquila, alcoxialcoxialquila C 3 -C 8 alquiltioalquila C 2 -C 6 alkyl , C 2 -C 6 alquilsulfinilalquila, alquilsulfonilalquila C 2 -C 6 alkyl , C 2 -C 6 alkylaminoalkyl, C 3 -C 8 dialkylaminoalkyl, C 2 -C 6 halogenoalquilaminoalquila, cicloalquilaminoalquila C 4 -C 10, C 2 -C 6 alkylcarbonyl, C 2 -C 6 halogenoalquilcarbonila, cicloalquilcarbonila C 4 -C 8, C 2 -C 6 alkoxycarbonyl, C 4 -C 8 cicloalcoxicarbonila, cicloalquilalcoxicarbonila C5-C10 alkyl, C2 alquilaminocarbonila -C 6 alkyl , C 3 -C 8 dialquilaminocarbonila, cicloalquilaminocarbonila C 4 -C 8, C 2 -C 6 halogenoalcoxialquila, Ci-C6 hydroxyalkyl, Ci-C6 alkoxy, Ci-C 6 haloalkoxy, C 3 -C 8 cycloalkoxy, halogenocycloalkoxy C 3 -C 8 , cycloalkylalkoxy C 4 -C 10 , alkenyloxy C 2 -C 6 , halogenoalkenyloxy C 2 C 6 , alkynyloxy C 2 -C 6 , halogenoalkynoxy C 2 -C 6 , alkoxyalkoxy C 2 -C 6 , alkylcarbonyloxy C 2 -C 6 alkyl , C 2 -C 6 halogenoalquilcarboniloxi, C4-C8 cycloalkylcarbonyloxy, C3-C6 alquilcarbonilalcoxi, Ci-C6 alkylthio, haloalkylthio L-Ce, C3-C6 cycloalkylthio, C r C alquilsulfinila 6 halogenoalquilsulfinila Ci-C 6, C 6 -C alquilsulfonila, Ci-C6 halogenoalquilsulfonila, C 3 -C 8 cicloalquilsulfonila, tri (04-04 alkyl) 3) 1113, aiquilsulfonilamino Ci-C 6, C 6 and R halogenoalquilsulfonilamino or -LQ ,
    R 2 furthermore preferably represents a 5- or 6-membered heteroaryl radical, which can contain up to two substituents, where the substituents independently of each other are selected from the following list:
    Substituents on the carbon: halogen, cyano, nitro, hydroxy, SH, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogenoalquila L-EC halogenoalquenila C 2 -C 6, C 2 halogenoalquinila - C 6, C 3 -C 6 cycloalkyl, C 3 -C 6 halogenocicloalquila, alquilcicloalquila C 4 -C 10 cycloalkylalkyl Ο 4 -Ο 10, 14 cicloalquilcicloalquila C6, C5 -C10 alquilcicloalquilalquila, C 2 -C 4 alkoxyalkyl, C 2 -C 4 alkylcarbonyl, C 2 -C 6 alkoxycarbonyl, C 2 -C 6 alquilaminocarbonila, dialquilaminocarbonila C 3 -C 8 -cycloalkyl , C1 -C4 hydroxyalkyl, C1 -C4 alkoxy, C1 -C4 haloalkoxy, C2-C6 alkylcarbonyloxy, C 2 -C 6 alkylcarbonylthio, C1-C4 alkylthio, C1-C4 haloalkylthio,
    Alquilsulfinila 8/108 (A-4 alkyl, Ci-C4 halogenoalquilsulfinila, alquilsulfonila C / -C4 alkyl, C1 -C4 halogenoalquilsulfonila, tri (Ci-C4 alkyl) silyl or -LQ, the nitrogen substituents: C r C 6 alkyl, alkenyl C 2 -C 6, C 2 -C 6 alkynyl, halogenoalquila CPCE, halogenoalquenila C 2 -C 6 halogenoalquinila C 2 -C 6 alkyl , C 3 -C 6 cycloalkyl, C 3 -C 6 halogenocicloalquila, alquilcicloalquila C 4 -C 10, C4-C10 cycloalkylalkyl, C1-4 alkylsulfonyl, C (= O) H, C (= O) Me, C (= O) OMe, benzyl or phenyl,
    R 2 particularly preferably represents a phenyl, which may contain two substituents, in which the substituents independently of each other, are selected from the following list:
    amino, halogen, cyano, nitro, C r C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, Q-Ce halogenoalquila, halogenoalquenila C 2 -C 6 halogenoalquinila C 2 -C 6, cycloalkyl C 3 C8, halogenocicloalquila C 3 -C 8, C 2 -C 6 alkoxyalkyl, C 2 -C 6 alkylcarbonyl, C 2 -C 6 halogenoalquilcarbonila, C 2 -C 6 alkoxycarbonyl, Ci-C6 alkoxy, C1-C5 haloalkoxy, C 3 -C 8 cycloalkoxy, C 3 -C 8 halogenocicloalcoxi, C 2 -C 6 alkenyloxy, C 2 -C 6 alkynyloxy, C 2 -C 6 alkoxyalkoxy, C-C6 alkylthio, Ci-C6 haloalkylthio, alquilsulfinila (^ -Οε, halogenoalkylsulfinyl C r C 6 , alkylsulfonyl Ο ^ Οε, halogenoalkylsulfonyl (Ξ ^ -Οε or phenyl,
    R 2 most particularly represents a phenyl, which may contain two substituents, in which the substituents independently of each other, are selected from the following list:
    chlorine, fluorine, bromine, iodine, cyano, nitro, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH (CH 3 ) 2 , CH 2 CH 2 CH 2 CH 3 , -CH ( CH 3 ) CH 2 CH 3 , -CH 2 CH (CH 3 ) CH 3 , -C (CH 3 ) 3 , -CH = CH 2 , -CH = CHCH 3 , ch 2 ch = ch 3 , -ch = chch 2 ch 3 , -ch 2 ch = chch 3 , -ch 2 ch 2 ch = ch 2 , -c = ch, -occh 3 , ch 2 c = ch, -c = cch 2 ch 3 , -ch 2 occh 3 , -ch 2 ch 2 och, -cf 2 , -cfh 2 , -cf 2 h, -cf 2 cf 3 , CCI 3 , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH 2 OCH 3 , -CH 2 OCH 2 CH 3i CH 2 CH 2 OCH 3 , -CH 2 OCH 2 CH 2 CH 3 , -CH 2 CH 2 OCH 2 CH 3 , -CH 2 CH 2 CH 2 OCH 3i -C (= O) CH 3i C (= O) CH 2 CH 3 , C (= O) CH 2 CH 2 CH 3 , C (= O) CH (CH 3 ) 2i -C (= O) CF 3 , -C (= O) OCH 3 , C (= O ) OCH 2 CH 3 , -C (= O) OCH 2 CH 2 CH 3 , -C (= O) OCH (CH 3 ) 2 , -och 3 , -och 2 ch 3 , OCH 2 CH 2 CH 3 , - OCH (CH 3 ) 2j -OCH 2 CH 2 CH 2 CH 3i -OCH 2 CH (CH 3 ) 2i -OCH (CH 3 ) CH 2 CH 3i OC (CH 3 ) 3 , -OCF 3 , -OCF 2 H, -OCH 2 CF 3i -OCF 2 CF 3i O-cyclohexyl, O-cyclopentyl, Ociclopropyl, -SCH 3 , -SCH 2 CH 3 , -SCH 2 CH 2 CH 3 , -SCH ( CH 3 ) 2 , -SCH 2 CH 2 CH 2 CH 3 , SCH 2 CH (CH 3 ) 2 , -SCH (CH 3 ) CH 2 CH 3j -SC (CH 3 ) 3 , -scf 3 , -scf 2 h , -sch 2 cf 3 , -scf 2 cf 3 , S (= O) Me, -S (O) CF 3 , -S (= O) 2 Me, -S (O) 2 CF 3 , -OCH 2 CH = CH 2 , -OCH 2 OCH, -OCH 2 OCH 3 , OCH 2 OCH 2 CH 3 , -OCH 2 CH 2 OCH 3 , -OCH 2 OCH (CH 3 ) 2 , trimethylsilyl or phenyl,
    R 2 particularly preferably represents a phenyl, which may contain two substituents, in which the substituents independently of each other, are selected from the following list:
    fluorine, chlorine, bromine, -CH 3 or phenyl,
    9/108
    R 3 preferably represents hydrogen, cyano or CrC 3 alkyl,
    R 3 represents particularly preferably hydrogen or methyl, ethyl, npropyl, iso-propyl,
    R 3 most particularly represents hydrogen,
    R Tz preferably represents chlorine or hydrogen and particularly preferably hydrogen,
    L preferably represents a direct bond or oxygen,
    Q preferably represents a phenyl, which can contain up to two substituents, where the substituents independently of each other are selected from the following list:
    halogen, cyano, hydroxy, nitro, SH, Ci-C6 alkyl, Ci-C6 halogenoalquila, C 3 -C 6 cycloalkyl, C 1 -C 4 alkoxy, C -C 4 haloalkoxy, C r C 4 alkylthio, haloalkylthio C 1 -C 4 or phenyl,
    In addition, Q preferably represents a 5- or 6-membered heteroaryl radical, which may contain up to two substituents, where the substituents independently of each other are selected from the following list:
    Substituents on the carbon: halogen, cyano, hydroxy, nitro, SH, Ci-C6 alkyl, Ci-C6 halogenoalquila, C 3 -C 6 cycloalkyl, -C 4 alkoxy, C -C 4 haloalkoxy, -C 4 alkylthio, haloalkylthio C! C4 alkyl or phenyl substituents at nitrogen: C r C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl or phenyl, and salts, metal complexes and N-oxides agrochemically effective.
    The definitions or clarifications of radicals mentioned above in general or cited in preferential scopes, however, can also be arbitrarily combined with each other, therefore, between the respective scopes and preferential scopes. They are applied to the final products, as well as to the pre-products and intermediate products correspondingly. In addition, individual definitions can be dispensed with.
    Preferred are those compounds of the formula (I), in which all radicals each have the preferred meanings mentioned above.
    Particularly preferred are those compounds of the formula (I), in which all the radicals each have the particularly preferred meanings mentioned above.
    Most particularly preferred are those compounds of the formula (I), in which all the radicals each have the meanings in a very particularly preferred way cited above.
    Especially preferred are those compounds of the formula (I), in which all the radicals each have the meanings in a very particularly preferred way cited above.
    10/108
    In addition, the compounds of formula (I), in which
    X represents oxygen,
    G represents G3 and / or G4 and especially G3,
    R 1 represents fluorine or hydrogen and especially hydrogen,
    R 2 represents phenyl, 2-fluorophenyl, 2,6-difluorphenyl, 2-acetylphenyl, 3-acetylphenyl, 2-hydroxyphenyl, 2-nitrophenyl, 2 - [(2-methoxyethoxy) methyl] phenyl, 2 - [(ethylsulfanyl) methyl] phenyl , 2 [(cyclopropylmethoxy) carbonyl] phenyl, 2- (allyloxy) phenyl, 3- (but-2-in-1-yloxy) phenyl, 2 (butoxymethyl) phenyl, 2-fluor-6-formylphenyl, 2 - [( 2-methylprop-2-en-1-yl) oxy] phenyl, 2- (2-methoxyethoxy) phenyl, 2 - [(3-methylbut-2-en-1-yl) oxy] phenyl, 3- (prop-2- in-1 -yloxy) phenyl, 4- (prop-2-in-1-yloxy) phenyl, 3-formylphenyl, 2- (cyclohexylmethoxy) phenyl, 2- (pent-2-in-1-yloxy) phenyl, 2- fluorphenyl, 29cyclopropylcarbamoyl) phenyl, 2- (but-2-in-1-yloxy) -6-fluorophenyl, 2-fluor-6- (prop-2-2-in-1 yloxy) phenyl, 2 - [(cyclohexylcarbonyl ) oxy] phenyl, 2 - [(cyclopropylcarbonyl) oxy] phenyl, 3- (pent-2-in-1-yloxy) phenyl, 2- (but-2-in-1-yloxy) -6-fluorphenyl, 2-fluorine -6- (prop-2-in-1-yloxy) phenyl, 2 [(cyclohexylcarbonyl) oxy] phenyl, 2 - [(cyclopropylcarbonyl) oxy] phenyl, 3- (pent-2-in-1-yloxy) phenyl, 2 (but-2-in-1-yloxy) phenyl, 2 - [(3,3,3-trifluorpropanoyl) oxy] phenyl, 2 - [(methylsulfonyl) amino] phenyl, 2etynylphenyl, 2- (prop-2-in-1-yloxy) phenyl, 4 - [(methylsulfonyl) amino] phenyl, 2-aminophenyl, 3hydroxyphenyl, 2- ( methoxycarbonyl0phenyl, 2- (chloromethyl) phenyl, 4- (pent-2-in-1-yloxy) phenyl, 4- (but-2in-1-yloxy) phenyl, 2-chloro-6- (prop-2-in- 1 -yloxy) phenyl, 2-chloro-6- (2-methoxyethoxy) phenyl, 2- (allyloxy) -6chlorophenyl, 2 - [(2,2,2-trifluorethoxy) methyl] phenyl, 2 - [(ethylsulfonyl) methyl ] phenyl or 2 (hydroxymethyl) phenyl and R 2 represents particularly phenyl, 2-fluorophenyl or 2,6-difluorphenyl,
    R 3 represents hydrogen,
    R Tz represents hydrogen, as well as salts, metal complexes and agrochemically effective N-oxides.
    Depending on the nature of the substituents defined above, the compounds of formula (I) have acidic or basic properties and with inorganic or organic acids or with bases or metal ions, they can form salts, optionally also internal salts or addition products. If the compounds of formula (I) carry amino, alkylamino or other groups that induce basic properties, then these compounds can be reacted with acids for salts or through synthesis, they are directly obtained as salts. If the compounds of formula (I) carry hydroxy, carboxy or other groups that induce acidic properties, then these compounds can be reacted with bases for salts. Suitable gases are, for example, hydroxides, carbonates, alkali and alkaline earth metal bicarbonates, particularly those of sodium, potassium, magnesium and calcium, in addition, ammonia, primary, secondary and tertiary amines with C / -C4 alkyl groups, alkanol mono-, di- and trialcanolamines (L-C4, choline as well as chlorocholine.
    Salts obtainable in this way also have fungicidal properties,
    11/108 herbicides and insecticides.
    Examples of inorganic acids are halogen acids, such as hydrofluoric acid, hydrochloric acid, hydrobromic acid and hydroiodic acid, sulfuric acid, phosphoric acid and nitric acid and acid salts, such as NaHSO 4 and KHSO 4 . Organic acids include, for example, formic acid, carbonic acid and alkanoic acids, such as acetic acid, trifluoroacetic acid, trichloroacetic acid and propionic acid, as well as glycolic acid, thiocyanic acid, lactic acid, succinic acid, citric acid, benzoic acid , cinnamic acid, oxalic acid, C 6 -C 20 saturated or one or double unsaturated fatty acids, alkyl sulfuric monoester, alkyl sulfonic acids (sulfonic acids with straight or branched chain alkyl radicals with 1 to 20 carbon atoms), aryl sulfonic acids or arildisulfonic acids (aromatic radicals, such as phenyl and naphthyl, which carry one or two groups of sulfonic acids), alkylphosphonic acids (phosphonic acids with linear or branched alkyl radicals with 1 to 20 carbon atoms), arylsulfonic acids or acids arildiphosphonic (aromatic radicals, such as phenyl and naphthyl, which carry one or two phosphonic acid radicals), in which the radicals alkyl or aryl may carry other substituents, for example, p-toluenesulfonic acid, salicylic acid, paminosalicylic acid, 2-phenoxybenzoic acid, 2-acetoxybenzoic acid and so on.
    Metal ions include particularly the ions of the elements of the second main group, particularly calcium and magnesium, of the third and fourth main group, particularly aluminum, tin and lead, as well as of the first to the eighth subgroup, particularly chromium, manganese, iron , cobalt, nickel, copper, zinc and others. Particularly preferred are the metal ions of the elements of the fourth period. In this case, the metals can be present in the different valences that compete with them.
    Optionally substituted groups can be substituted one or more times, with multiple substitutions the substituents can be the same or different.
    In the definitions of the symbols indicated in the formulas above, collective terms are used, which are generally representative for the following substituents:
    halogen: fluorine, chlorine, bromine and iodine;
    alkyl: saturated hydrocarbon radicals, in a straight or branched chain with 1 to 8 carbon atoms, for example, (but not limited to) C 1 -C 6 alkyl, such as methyl, ethyl, propyl, 1-methylethyl, butyl, 1- methyl-propyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl, 1-methyl-butyl, 2-methyl-butyl, 3-methyl-butyl, 2,2-di-methylpropyl, 1-ethyl-propyl, hexyl, 1,1-dimethyl-propyl, 1,2-dimethyl- propyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3, 3dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1methylpropyl and 1-ethyl-2-methylpropyl;
    alkenyl: unsaturated hydrocarbon radicals, in a straight or branched chain with 2
    12/108 to 8 carbon atoms and with a double bond in a desired position, for example (but not limited to) C 2 -C 6 alkenyl, such as ethylene, 1-propenyl, 2-propenyl, 1methylethyl, 1-butenyl , 2-butenyl, 3-butenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl, 1methyl-2-propenyl, 2-methyl-2-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl , 4-pentenyl, 1methyl-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-2propenyl, 1,2-dimethyl-1-propenyl, 1,2-dimethyl-2 -propenyl, 1-ethyl-1-propenyl, 1-ethyl-2propenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl, 2methyl-1-pentenyl , 3-methyl-1-pentenyl, 4-methyl-1-pentenyl, 1-methyl-2-pentenyl, 2-methyl-2pentenyl, 3-methyl-2-pentenyl, 4-methyl-2-pentenyl, l-methyl -3- pentenyl, 2-methyl-3-pentenyl, 3methyl-3-pentenyl, 4-methyl-3-pentenyl, 1-methyl-4-penteni la, 2-methyl-4-pentenyl, 3-methyl-4pentenyl, 4-methyl-4-pentenyl, 1,1-dimethyl-2-butenyl, 1,1-dimethyl-3-butenyl, 1,2-dimethyl- 1butenyl, 1,2-dimethyl-2-butenyl, 1,2-dimethyl-3-butenyl, 1,3-dimethyl-1-butenyl, 1,3-dimethyl-2butenyl, 1,3-dimethyl-3-butenyl, 2,2-dimethyl-3-butenyl, 2,3-dimethyl-1-butyl, 2,3-dimethyl-2-butyl, 2,3-dimethyl-3-butenyl, 3,3-dimethyl-1-butyl, 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-2propenyl;
    alkynyl: straight or branched chain hydrocarbon groups with 2 to 8 carbon atoms and a triple bond in a desired position, for example (but not limited to) C 2 -C 6 alkynyl, such as ethynyl, 1-propynyl, 2- propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1methyl-2-propynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-methyl-2-butynyl, 1methyl-3-butynyl, 2-methyl-3-butynyl, 3-methyl-1-butynyl, 1,1-dimethyl-2-propynyl, 1-ethyl-2propynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5- hexynyl, 1-methyl-2-pentynyl, 1-methyl3-pentynyl, 1-methyl-4-pentynyl, 2-methyl-3-pentynyl, 2-methyl-4-pentynyl, 3-methyl-1-pentynyl, 3methyl- 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 alkoxy radicals, linear or branched with 1 to 8 carbon atoms, for example (but not limited to) C 1 -C 6 alkoxy, such as methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy, 1-methyl -propoxy, 2-methylpropoxy, 1,1-dimethylethoxy, pentoxy, 1methylbutoxy, 2-methylbutoxy, 3-methylbutoxy, 2,2-di-methylpropoxy, 1-ethylpropoxy, hexoxy, 1,1dimethylpropoxy, 1,2-dimethylpropoxy, 1 -methylpentoxy, 2-methylpentoxy, 3-methylpentoxy, 4-methylpentoxy, 1,1-dimethylbutoxy, 1,2-dimethylbutoxy, 1,3-dimethylbutoxy, 2,2-dimethylbutoxy, 2,3dimethylbutoxy, 3,3-dimethylbutoxy, 1-ethylbutoxy, 1-ethylbutoxy , 2-ethylbutoxy, 1,1,2-trimethylpropoxy, 1,2,2-trimethylpropoxy, 1-ethyl-1-methylpropoxy and 1-ethyl-2-methyl-propoxy;
    alkylthio: saturated alkylthio radicals, linear or branched with 1 to 8
    13/108 carbon atoms, for example (but not limited to) C 1 -C 6 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-di-methylpropylthio, 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, 2,2dimethylbutylthio, 2,3-dimethylbutylthio, 3,3-dimethylbutylthio, 1-ethylbutylthio, 2-ethylbutyl, 1 , 1,2trimethylpropylthio, 1,2,2-trimethylpropylthio, 1-ethyl-1-methylpropylthio and 1-ethyl-2-methylpropylthio;
    alkoxycarbonyl: an alkoxy group with 1 to 6 carbon atoms (as mentioned above), which is attached to the structure through a carbonyl group (-CO-);
    alkylsulfinyl: saturated alkylsulfinyl radicals, linear or branched with 1 to 8 carbon atoms, for example (but not limited to) C 1 -C 6 alkylsulfinyl, such as methylsulfinyl, ethylsulfinyl, propylsulfinyl, 1-methylethylsulfinyl, butylsulfinyl, 1-methyl -propylsulfinyl, 2-methylpropylsulfinyl, 1,1-dimethylethylsulfinyl, pentylsulfinyl, 1-methylbutylsulfinyl, 2methylbuti Isu If ini Ia, 3-methylbuti Isu If inila, 2,2-di-methylpropilsu If inila, 1-methylpropylsulfinyl, hexils 1-dimethylpropylsulfinyl, 1,2-dimethylpropylsulfinyl, 1-methylpentylsulfinyl, 2-methylpentylsulfinyl, 3-methylpentylsulfinyl, 4-methylpentylsultinyl, 1,1-dimethylbutylsulfinyl, 1,2-dimethylbutylsulfinyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2,3-dimethylbutyl dimethyl-butylsulfinyl,
    3.3- dimethylbutylsulfinyl, 1-ethylbutylsulfinyl, 2-ethylbutylsulfinyl, 1,1,2-trimethylpropylsulfinyl, 1,2,2trimethylpropylsulfinyl, 1-ethyl-1-methylpropylsulfinyl and 1-ethyl-2-methylpropylsulfinyl;
    alkylsulfonyl: saturated alkylsulfonyl radicals, in a straight or branched chain with 1 to 8 carbon atoms, for example (but not limited to) C- | -C 6 alkylsulfonyl, such as methylsulfonyl, ethylsulfonyl, propylsulfonyl, 1-methylethylsulfonyl, butylsulfonyl, 1 -methylpropylsulfonyl, 2-methylpropylsulfonyl, 1,1-dimethylethylsulfonyl, pentylsulfonyl, 1-methylbutylsulfonyl, 2-methylbutylsulfonyl, 3-methylbutylsulfonyl, 2,2-di-methylpropylsulfonyl, 1ethylpropylsulfonyl, hexylsulfonyl, 1-methylsulfonyl, 1,1-dimethylsulfonyl , 2-methylpentylsulfonyl, 3-methylpentylsulfonyl, 4-methylpentylsulfonyl, 1,1dimethylbutylsulfonyl, 1,2-dimethylbutylsulfonyl, 1,3-dimethylbutylsulfonyl, 2,2-dimethylbutylsulfonyl,
    2.3-dimethyl-butylsulfonyl, 3,3-dimethylbutylsulfonyl, 1-ethylbutylsulfonyl, 2-ethylbutylsulfonyl, 1,1,2trimethylpropylsulfonyl, 1,2,2-trimethylpropylsulfonyl, 1-ethyl-1-methylpropylsulfonyl and 1-ethyl-2-methylpropyl;
    cycloalkyl: monocyclic hydrocarbon groups, saturated with 3 to 10 carbon ring members, for example (but not limited to) cyclopropyl, cyclopentyl and cyclohexyl;
    halogenoalkyl: straight or branched chain alkyl groups with 1 to 8 carbon atoms (as mentioned above), in which in these groups, partially or completely, the hydrogen atoms can be substituted as mentioned above, for example (but not limited) a) halogenoalkyl Cj-Cs, such as chloromethyl, bromomethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chlorofluoromethyl, dichlorofluoromethyl,
    14/108 chlorodifiuormethyl, 1-chloroethyl, 1-bromoethyl, 1-fluorethyl, 2-fluorethyl, 2,2-difluorethyl, 2,2,2trifluorethyl, 2-chloro-2-fluorethyl, 2-chloro-2,2-difluorethyl , 2,2-dichloro-2-fluorethyl, 2,2,2trichloroethyl, pentafluorethyl and 1,1,1-trifluorprop-2-yl;
    halogenoalkoxy: straight or branched chain alkoxy groups with 1 to 8 carbon atoms (as mentioned above), and in these groups, partially or completely, the hydrogen atoms can be replaced by halogen atoms, as mentioned above, by example (but not limited to) C1-C3 halogenoalkoxy, such as chloromethoxy, bromomethoxy, dichloromethoxy, trichloromethoxy, fluormethoxy, difluormethoxy, trifluormethoxy, chlorofluormethoxy, 1-chloroethoxy, 1-chloroethoxy, 1-chloroethoxy, 1-chloroethoxy, 1-chloroethoxy 2-difluorethoxy, 2,2,2-trifluorethoxy, 2-chloro-2-fluorethoxy, 2-chloro-2,2difluorethoxy, 2,2-dichloro-2-fluorethoxy, 2,2,2-trichlorethoxy, pentafluor-ethoxy and 1,1,1 -trifluorprop-2oxy;
    halogenoalkylthio: straight or branched chain alkylthio groups with 1 to 8 carbon atoms (as mentioned above), in which in these groups, partially or completely, the hydrogen atoms can be replaced by halogen atoms, as mentioned above, by example (but not limited to) halogenoalkylthio CfoCa, such as chloromethylthio, bromomethylthio, dichloromethylthio, trichloromethylthio, fluormethylthio, difluormethylthio, trifluoromethyl, chlorofluoromethyl, dichlorofluoromethyl, chlorodifluorethylthio, 1-fluorethyl, 1-fluorethyl difluorethylthio, 2,2,2-trifluorethylthio, 2-chloro-2-fluorethylthio, 2-chloro-2,2di-fluorethylthio, 2,2-dichloro-2-fluorethylthio, 2,2,2-trichlorethylthio, pentafluorethylthio and 1,1,1-trifluorprop2-ylthium;
    heteroaryl: a 5- or 6-membered, completely unsaturated monocyclic ring system containing one to four heteroatoms of the oxygen, nitrogen or sulfur group, if the ring contains several oxygen atoms, then these are not directly adjacent;
    5-membered heteroaryl; containing one to four nitrogen atoms or one to three nitrogen atoms and one sulfur or oxygen atom: 5 ring heteroaryl groups, which, in addition to carbon atoms, can contain one to four nitrogen atoms or one to three atoms nitrogen and a sulfur or oxygen atom as ring members, for example (but not limited to) 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-pyrazole, 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, 1,2,4oxadiazol-5-yl, 1,2,4-thiadiazol-3-yl, 1,2,4-thiadiazole- 5-yl, 1,2,4-triazol-3-yl, 1,3,4-oxadiazol-2yl, 1,3,4-thiadiazol-2-yl and 1,3,4-triazol-2-yl;
    5-membered heteroaryl through nitrogen, containing one to four nitrogen atoms or 5-membered benzocondensed heteroaryl through nitrogen, containing one to three nitrogen atoms: 5-ring heteroaryl groups,
    15/108 which, in addition to carbon atoms, can 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 ring member and one adjacent carbon can be bridged by a buta-1,3-dien-1,4-diyl group, in which one or two carbon atoms can be replaced by nitrogen atoms, these rings being attached to the structure via one of the nitrogen ring members, for example (but not limited to) 1-pyrrolyl, 1-pyrazolyl, 1,2,4-triazol-1-yl, 1-imidazolyl, 1,2,3triazole -1 -yl and 1,3,4-triazole-1 -yl;
    6-membered heteroaryl, containing one to four nitrogen atoms: 6-ringed heteroaryl groups, which, in addition to carbon atoms, can contain one to three or one to four nitrogen atoms as ring members, for example (but not limited a) 2pyridinyl, 3-pyridinyl, 4-pyridinyl, 3-pyridazinyl, 4-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5pyrimidinyl, 2-pyrazinyl, 1,3,5-triazin-2-yl, 1,2 , 4-triazin-3-yl and 1,2,4,5-tetrazin-3-yl;
    5-membered benzocondensed heteroaryl, containing one to three nitrogen atoms or one nitrogen atom and one oxygen or sulfur atom: for example (but not limited to) indole-1-yl, indole-2-ion, indole-3- ila, indol-4-yl, indol-5-yl, indol6-yl, indol-7-yl, benzimidazol-1-yl, benzimidazol-2-yl, benzimidazol-4-yl, benzimidazol-5ila, indazol-1 - ila, indazol-3-yl, indazol-4-yl, indazol-5-yl, indazol-6-yl, indazol-7-yl, indazoi2-yl, 1-benzofuran-2-yl, 1-benzofuran-3- yl, 1-benzofuran-4-yl, 1-benzofuran-5-yl, 1benzofuran-6-yl, 1-benzofuran-7-yl, 1-benzothiophen-2-yl, 1,1-benzothiophen-3-yl, 1benzothiophen-4-yl, 1-benzothiophen-5-yl, 1-benzothiophen-6-yl, 1-benzothiophen-7-yl, 1,3benzothiazol-2-yl, 1,3-benzothiazole-4-yl, 1, 3-benzothiazol-5-yl, 1,3-benzothiazol-6-yl, 1,1,3benzothiazol-7-yl, 1,3-benzoxazol-2-yl, 1,3-benzoxazol-4-yl, 1, 3-benzoxazol-5-yl, 1,3-benzoxazol-6-yl and 1,3-benzoxazol-7-yl;
    6-membered benzocondensed heteroaryl, containing one to three nitrogen atoms: for example (but not limited to) quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-5-yl, quinolin-6- ila, quinolin-7-yl, quinolin-8-yl, isoquinolin-1-yl, isoquinolin-3-yl, isoquinolin-4-yl, isoquinolin-5-yl, isoquinolin-6-yl, isoquinolin-7-yl and isoquinolin-8-yl;
    heterocyclic: saturated or partially unsaturated heterocycle with three to fifteen members, containing one to four heteroatoms of the oxygen, nitrogen or sulfur group: mono-, bi- or tricyclic heterocycles containing, in addition to carbon ring members, one to three nitrogen atoms and / or an oxygen or sulfur atom or one or two oxygen and / or sulfur atoms; if the ring contains several oxygen atoms, then these are not directly adjacent, such as, for example (but not limited to) oxiranyl, aziridinyl,
    2- tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-tetrahydrothienyl, 3-tetrahydrothienyl, 2-pyrrolidinyl,
    3-pyrrolidinyl, 3-isoxazolidinyl, 4-isoxazolidinyl, 5-isozazolidinyl, 3-isothiazolidinyl, 4-isothiazolidinyl, 5-isothiazolidinyl, 3-pyrazolidinyl, 4-pyrazolidinyl, 5-pyrazolidinyl, 216/108 oxazolidinyl, 5-oxazolidin , 2-thiazolidinyl, 4-thiazolidinyl, 5-thiazolidinyl, 2imidazolidinyl, 4-imidazolidinyl, 1,2,4-oxadiazolidin-3-yl, 1,2,4-oxadiazolidin-5-yl, 1,2,4tiad iazolidin- 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, 2,4dihydrofur-2-yl, 2, 4-dihydrofur-3-yl, 1,2,3-dihydrothien-2-yl, 2,3-dihydrothien-3-yl, 2,4dihydrothien-2-yl, 2,4-dihydrotien-3-yl, 2- pyrrolin-2-yl, 2-pyrrolin-3-yl, 3-pyrrolin-2-yl, 3-pyrrolin3-yl, 2-isoxazolin-3-yl, 3-isoxazolin-3-yl, 4-isoxazolin-3- ila, 2-isoxazolin-4-yl, 3-isoxazolin-4yl, 4-isoxazolin-4-yl, 2-isoxazolin-5-yl, 3-isoxazolin-5-yl, 4-isoxazolin-5-yl, 2- isothiazolin-3yl, 3-isothiazolin-3-yl, 4-isothiazolin-3-yl, 2-iso-thiazolin-4-yl, 3-isothiazolin-4-yl, 4-isothiazolin-4ila, 2-isothiazolin-5- ila, 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-5yl, 4,5-dihydropyrazol-1-yl, 4,5- dihydropyrazol-3-yl, 4,5-dihydropyrazol-4-yl, 4,5-dihydropyrazol-5-yl, 2,3-dihydro-oxazol-2-yl, 2,3-dihydro-oxazol-3-yl, 2, 3-dihydro-oxazol-4-yl, 2,3-dihydrooxazol-5-yl, 3,4-dihydro-oxazol-2-yl, 3,4-dihydro-oxazol-3-yl, 3,4-dihydro- oxazol-4-yl, 3,4-dihydro-oxazol-5-yl, 3,4-dihydro-oxazol-2-yl, 3,4-dihydro-oxazol-3-yl, 3,4-dihydro-oxazol-4- ila, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 1,3-dioxan-5-yl, 2-tetrahydropyranyl, 4tetrahydropyranyl, 2-tetrahydrothienyl, 3-hexahydro-pyridazinyl, 4-hexahydropyridazinyl, 4-hexahydridine 5-hexahydropyrimidinyl, 2-piperazinyl, 1.5hexahydrotriazin-2-yl and 1,2,4-hexahydrotriazin-3-yl;
    leaving group: leaving group S N 1 or S N 2, for example, chlorine, bromine, iodine, alkylsulfonates (-OSO 2 -alkyl, for example, -OSO 2 CH 3 , -OSO 2 CF 3 ) or arylsulfonates ( 0SO 2 -aryl, for example, -OSO 2 Ph, -OSO 2 PhMe).
    When mentioning combinations of various radicals, such as, for example, Cx-Cy alkylcarbonyl or Cx-Cy alkoxyalkyl, the expression Cx-Cy designates in each case the sum of all carbon atoms, which are respectively present in the entire fragment . In this case, X and Y each represent an integer, where the number Y is greater than that of X.
    Those combinations, which are opposed to natural laws and which the specialist would have excluded, therefore, due to his technical knowledge, are not understood. For example, ring structures with three or more adjacent O atoms are excluded.
    Clarification of intermediate products and processes
    The bis (difluormethyl) pyrazole derivatives of formula (I) can be produced in a different way. Next, the possible processes are initially represented by means of schemes. When not indicated otherwise, the radicals indicated have the meanings indicated above.
    Process A
    10/178
    Scheme 1: Process A

    (m)
    W 1 —N
    OH S, Br (H) (IV)
    W 1 represents acetyl, C / -C4 alkoxycarbonyl, benzyl, benzyloxycarbonyl or [3,5bis (difluormethyl) -1 H-pyrazol-1-yl] acetyl
    Process A describes the preparation of compounds of structure (IV) by reacting compounds of structure (II) with (III).
    One possibility of producing the intermediate product (IV) from compound (II) is shown in scheme 1 (process A). A compound of the general formula (IV) is obtained from a compound of the general formula (III) by changing the halogen metal and subsequently adding a compound of the formula (II) (see, for example, Org. Lett. 2004, 6, 3083-3085).
    Process A is carried out in the presence of a suitable metal-organic compound. Suitable metalorganic compounds are organolithium compounds (such as, for example, butyl lithium) or Grignard reagents (such as, for example, isopropylmagnesium halide).
    Process A is preferably carried out using one or more diluents. In carrying out the process, aprotic solvents are preferably included, such as, for example, dioxane, glyme, diethyl ether or tetrahydrofuran. Particularly preferred is the use of tetrahydrofuran.
    In the execution of process A, the reaction temperatures may vary over a wider range. In the case of halogen-metal exchange reactions, it is generally carried out at temperatures from -120 ° C to + 150 ° C, preferably at temperatures from -120 ° C to + 60 ° C, most particularly preferably at - 120 ° C to 0 ° C. After the addition of compound (II), it is preferably used at -80 ° C to + 50 ° C.
    In order to carry out process A, 1 mole of the compound of the formula (III) is used, in general, 1 to 2 moles, preferably 1 mole of the metal-organic compound. The duration of the reaction matters from 1 to 48 hours. Processing is carried out by conventional methods. If necessary, the compounds are purified by means of recrystallization, distillation or chromatography or can optionally also be used in the next step without prior purification.
    Process B
    10/188
    W - N
    (IV)
    Scheme 2: Process B Halogenation
    W 1 —N
    (Go)
    Br
    W 1 represents acetyl, C1-C4 alkoxycarbonyl, benzyl, benzyloxycarbonyl or [3,5bis (difluoromethyl) -1 H-pyrazol-1-yl] acetyl R 1a represents F, Cl, Br, I
    Process B describes the preparation of compounds of the structure (V-a) by means of halogenation of compounds of the structure (IV).
    A compound of the general formula (Va), in which R 1a is F, Cl, Br and I, is obtained from a compound of the general formula (IV) by means of halogenation (see, for example, WO 06/133216, WO 04/108692, J. Med. Chem., 1991, 34, 108-122, EP0796846, J. Antibiot., 1988, 41, 134-138, Bioorg. Med. Chem. Lett., 2008, 18, 5209-5212 , Chem. Eur..J, 2004, 5640-5648, Russ. J. Org. Chem., 2007, 50-55).
    As solvents, all conventional solvents, inert in the reaction conditions, can be used, or the reaction can be carried out in mixtures of two or more of these solvents. Preferably, the dichloromethane solvent is used.
    As a halogen source, it is possible to use, for example, diethylamino sulfur trifluoride, selectfluor, deoxofluor, thionyl chloride, PBr 3 and methanesulfonyl chloride.
    The starting materials and the halogenating agent are used in equimolar amounts. The halogenating agent can also be used in excess. The reaction is normally carried out at temperatures of -80 ° C to + 80 ° C and preferably at 0 ° C to + 40 ° C, but it can also be carried out at the reflux temperature of the reaction mixture. The reaction time varies depending on the reaction scale and the reaction temperature, but is usually between a few minutes and 48 hours.
    After completion of the reaction, the compounds (V-a) are separated from the reaction mixture by one of the conventional separation techniques. If necessary, the compounds are purified by recrystallization, distillation or chromatography or can optionally also be used in the next step without prior purification.
    Process C
    Scheme 3: Process C
    10/198
    Carbonylation
    W — Ν
    R (V-a) ο
    W - N
    Ή (Vl-a)
    W 1 represents acetyl, C 1 -C 4 alkoxycarbonyl, benzyl, benzyloxycarbonyl or [3,5bis (difluormethyl) -1 H-pyrazol-1-yl] acetyl R 1a represents f, Cl, Br, I
    One possibility of producing the intermediate product (Vl-a) from the compound (Va) is shown in scheme 3 (process C).
    A compound of the general formula (Vl-a) is obtained from a compound of the general formula (Va) by means of halogen-metal exchange and subsequent addition of an electrophile (eg DMF), see, for example, Tetrahedron , 2006, 62, 9017-9037; Org. Lett. 2005, 7, 339-342; Synthesis, 1987, 11,998-1001.
    Process C is carried out in the presence of a suitable metal-organic compound. Preferred metalorganic compounds are organolithium compounds (such as, for example, butyl lithium).
    Process C is preferably carried out using one or more diluents. In carrying out process C, aprotic solvents are preferably included (such as, for example, dioxane, dimethoxyethane (glyme), diethyl ether or tetrahydrofuran). Diethyl ether is particularly preferred.
    In the execution of process A, the reaction temperatures may vary over a wider range. In the case of halogen-metal exchange reactions, it is generally carried out at temperatures from -120 ° C to + 150 ° C, preferably at temperatures from -120 ° C to + 60 ° C, most particularly preferably at - 120 ° C to -70 ° C. After adding compound (II), work is preferably done at -80 ° C to + 50 ° C.
    In order to carry out process C, 1 to 2 mol, preferably 1 mol of the metal-organic compound and the electrophilic compound, is usually used per mol of the compound (V-a). The duration of the reaction matters from 1 to 48 hours. Processing is carried out by conventional methods. If necessary, the compounds are purified by means of recrystallization, distillation or chromatography or optionally they can also be used in the next step without prior purification.
    Process D
    Scheme 4: Process D
    10/20
    One possibility of producing the intermediate product (VIII) from the compound (VI) is shown in scheme 4 (process D).
    A compound of the general formula IVIII) is obtained by condensing an aldehyde of the formula (VI) with hydroxylamine (VII) and subsequent chlorination (see, for example, WO 05/0040159, WO 08/013622 and Synthesis 1987, 11,998 -1001).
    In process D, aldehyde (VI) (VI with R 1 = H is available in Maybridge) and hydroxylamine (VII) are initially taken to the reaction (scheme 4, step (a)). The corresponding oxime is subsequently chlorinated in the presence of a suitable chlorinating agent. Preferred chlorination reagents are N-chlorosuccinimide, HCIO and chlorine. After step (a) of process D, the reaction mixture can be processed by conventional methods or directly further reacted in step (b).
    Process D is preferably carried out using one or more diluents. In step (a) of process D according to the invention, practical solvents, such as, for example, ethanol, are preferably used as the solvent. After the formation of the corresponding oxime of compound (VI), the reaction mixture is diluted in step (b) with another solvent, for example, tetrahydrofuran, and then it is provided with aqueous sodium hypochlorite. Likewise, chlorination can be performed with the aid of Nchlorosuccinimide in DMF.
    In the execution of process D, the reaction temperatures may vary over a wider range. In general, work is carried out at temperatures from -10 ° C to + 150 ° C, preferably at temperatures from 0 ° C to + 100 ° C, most particularly preferably at the reflux temperature of the solvent in step (a) and at 0 ° C to 30 ° C in step (b).
    In order to carry out process D, 1 to 2 mol, preferably 1 mol of hydroxylamine (VII) and, in general, 1 to 5 mol, preferably 1 mol of a reagent, is used per mol of compound (VI) chlorination. The duration of the reaction matters from 1 to 48 hours. Processing is carried out by conventional methods. If necessary, the compounds are purified by means of recrystallization, distillation or chromatography or can optionally also be used in the next step without prior purification.
    Process E
    10/21
    One possibility of producing the intermediate product (X-a) or the compounds of the formula (l-a) according to the invention from the compound (VIII) is shown in scheme 5 (process E).
    A compound of the general formula (Xa) or (la) is obtained from an alkene of the general formula (IX) and the compound (VIII) by means of a cycloaddition reaction (see, for example, WO 08/013622 and Synthesis, 1987, 11,998-1001).
    Alkenes (IX) are commercially available or can be produced from commercially available pre-steps according to instructions described in the literature (for example, from ketones or aldehydes by an olefinization by Wittig or HornerWadsworth-Emmons: Chem. Rev. 1989, 89, 863-927 and Julia olefination: Tetrahedron Lett., 1973, 14, 4833-4836; Peterson olefin: J. Org. Chem. 1968, 33, 780).
    Process E is carried out in the presence of an appropriate base. Preferred bases are tertiary amines (e.g., triethylamine), alkali metal or alkaline earth metal carbonates, bicarbonates and phosphates.
    Process E is preferably carried out using one or more diluents. In carrying out process E, inert organic solvents (such as, for example, toluene and hexane) are preferably included. Likewise, water is included as a solvent. Alternatively, process E can be carried out on an excess of alkene (IX).
    Typically, a suitable base and olefin (IX) are previously introduced and compound (VIII) is added. Alternatively, compounds (VIII) and (IX) are previously introduced and a suitable base is added.
    In the execution of process E, the reaction temperatures may vary over a wider range. In general, it is operated at temperatures of -120 ° C to + 150 ° C, preferably at temperatures of -10 ° C to + 100 ° C, most particularly preferably at 0 ° C to 30 ° C.
    To carry out process E, 0.5 to 5 mol per compound of formula (VIII), preferably 1 mol of the alkene (IX) is generally used. The duration of the reaction matters from 1 to 48 hours. Processing is carried out by conventional methods. If necessary, the compounds are purified by means of recrystallization, distillation or chromatography or can optionally also be used in the next step without prior purification.
    10/22
    Process F
    Figure 6: Process F
    W 1 represents acetyl, alkoxycarbonyl CrC ^ benzyl, benzyloxycarbonyl or [3,5 bis (difluormethyl) -1 H-pyrazol-1-yl] acetyl
    One possibility of producing the intermediate product (X-b) or the compounds of the formula (l-b) according to the invention from the compound (VIII) is shown in scheme 6 (process F).
    A compound of the general formula (Xb) or (lb) is obtained from an alkaline of the general formula (XI) and the compound (VIII) by means of a cycloaddition reaction (see, for example, WO 08/013622, WO 05/040159 and Synthesis, 1987, 11,998-1001).
    Alkines (XI) are either commercially available or can be produced from commercially available pre-steps according to instructions described in the literature (for example, from ketones or aldehydes by a Corey-Fuchs reaction: Tetrahedron Lett. 1972, 36, 3769-3772, Seyferth-Gilbert homologation: J. Org. Chem. 1996, 61, 2540-2541 or with the Bestmann-Ohira reagent: Synthesis 2004, 1, 59-62).
    Process F is carried out in the presence of an appropriate base. Preferred bases are tertiary amines (e.g., triethylamine), alkali metal and alkaline earth metal carbonates, bicarbonates and phosphates.
    Process F is preferably carried out using one or more diluents. In carrying out process F, preferably inert organic solvents, such as, for example, toluene and hexane. Likewise, water is included as a solvent. Alternatively, process F can be performed on an excess of alkaline (XI).
    Typically, a suitable base and alkaline (XI) are previously introduced and compound (VIII) is added. Alternatively, compounds (VIII) and (XI) are previously introduced and a suitable base is added.
    In the execution of process F, the reaction temperatures may vary over a wider range. In general, it is operated at temperatures of -120 ° C to + 150 ° C, preferably at temperatures of -10 ° C to + 100 ° C, most particularly preferably at 0 ° C to 30 ° C.
    To carry out process F, 0.5 to 5 mol per compound of the formula (VIII) is used, preferably 1 mol of the alkaline (XI). The duration of the reaction matters from 1 to 48 hours. Processing is carried out by conventional methods. If necessary, the compounds are purified by recrystallization, distillation or chromatography or
    23/108 can optionally also be used in the next step without prior purification. Process G
    One possibility of producing compounds of formula (XII) from corresponding compounds (X) is shown in scheme 7.
    A compound of the formula (X) is converted to a compound of the formula (XII) by means of suitable methods to remove protection groups, which are described in the literature (“Protective Groups in Organic Synthesis, Third Edition; 1999; 494-653 and literature cited there).
    Protection groups of tert-butoxycarbonyl and benzyloxycarbonyl can be removed in an acidic medium (for example, with hydrochloric acid or trifluoroacetic acid). Acetyl protecting groups can be removed under basic conditions (for example, with potassium carbonate or cesium carbonate). Benzyl protecting groups can be removed hydrogenolytically with hydrogen in the presence of a catalyst (eg, palladium on activated carbon).
    As solvents can be used all conventional solvents, inert in 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), ester of carboxylic acid (eg, acetic acid ethyl ester), amides (eg, Ν, Ν-dimethylformamide, N, N-dimethylacetamide), dimethylsulfoxide, 1,3-dimethyl-2-imidazolinone, water and acetic acid or the reaction can be made in mixtures of two or more of these solvents.
    Acids, which can be used for this deprotection reaction of tbutoxycarbonyl 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; 1999; pages 494-653).
    The reaction is normally carried out at temperatures from 0 ° C to + 150 ° C and preferably at room temperature, but it can also be carried out at
    24/108 reflux temperature of the reaction mixture. The reaction time varies depending on the scale of the reaction and the reaction temperature, but is usually between half an hour and 72 hours.
    Upon completion of the reaction, compounds (XII) are separated from the reaction mixture by one of the conventional separation techniques. If necessary, the compounds are purified by means of recrystallization, distillation or chromatography or, if desired, can also be used in the next step without prior purification. In addition, it is possible to isolate the compound of the general formula (XII) as a salt, for example, as a salt of hydrochloric acid or trifluoroacetic acid.
    Process H
    One possibility of producing compounds of formula (Ia) from corresponding compounds (XII) is shown in scheme 8.
    A compound with the general formula (Ia) can be synthesized in a manner analogous to the instructions described in the literature (see, for example, WO 07/147336), by means of a coupling reaction of a compound with the corresponding general formula (XII ) with a substrate of the general formula (X11la) with W 2a = chlorine, optionally in the presence of an acid / base trap.
    (Xllla) (W 2a = chlorine) or (Xlllb) (W 2b = OH) compounds are either commercially available or can be prepared by processes described in the literature (see, for example, WO 08/013662 and WO 08/13925) . In addition, a substrate with the general formula (Xllla), with W 2a = chlorine, can be produced from the corresponding acid (W 2b = OH) by means of chlorination using processes known from the literature (for example, Tetrahedron 2005, 61, 10827-10852 and literature cited there).
    R 2 substituents can be modified at all stages of synthesis, in which they occur, according to reaction instructions generally known to the
    25/108 expert. In this way, for example, the OH, NH2 or SH functionalities can be alkylated by known methods with suitable halides or sulfates (see, for example, J. March: Advanced Organic Chemistry - Reactions, Mechanisms and Structures, 4th. Ed. (1992 ), Wiley, New York, pages 388-390, 406-407, 411-415), acylated using suitable carboxylic acids, carboxylic acid chlorides or carboxylic acid anhydrides (see J. March: Advanced Organic Chemistry - Reactions, Mechanisms and Structures, 4th Ed. (1992), Wiley, New York, pages 392-400, 409, 417-419) or sulfonated using suitable sulfonyl chlorides (see J. March: Advanced Organic Chemistry - Reactions, Mechanisms and Structures, 4th Ed. (1992), Wiley, New York, pages 496-500). Also, by means of hydroxy compounds with halogenating agents, they can be converted into corresponding halides (see, for example, J. March: Advanced Organic Chemistry - Reactions, Mechanisms and Structures, 4th. Ed. (1992), Wiley, New York , pages 431-434). These halides, in turn, can be etherified with the aid of suitable hydroxy compounds (see, for example, J. March: Advanced Organic Chemistry - Reactions, Mechanisms and Structures, 4th. Ed. (1992), Wiley, New York, pages 388-390). In addition, carbonyl functionalities can be reduced according to common methods for corresponding hydroxy compounds (see, for example, J. March: Advanced Organic Chemistry - Reactions, Mechanisms and Structures, 4th. Ed. (1992), Wiley, New York , pages 443, 910-918) or, in the case of aldehydes, can be oxidized to carboxylic acids (see, for example, J. March: Advanced Organic Chemistry - Reactions, Mechanisms and Structures, 4th. Ed. (1992), Wiley , New York, pages 701-703), which in turn can be converted into the corresponding esters (see, for example, J. March: Advanced Organic Chemistry Reactions, Mechanisms and Structures, 4th. Ed. (1992), Wiley, New York, pages 393396). Finally, thioethers can be oxidized using oxidizing agents suitable for sulfoxides or sulfones (see, for example, J. March: Advanced Organic Chemistry Reactions, Mechanisms and Structures, 4th. Ed. (1992), Wiley, New York, pages 12011202 ). Examples of such reactions are found in the synthesis part of this application.
    As solvents can be used all common solvents, inert in the reaction conditions, such as, for example, 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. Preferred solvents are tetrahydrofuran and dichloromethane.
    At least an equivalent of an acid trap / base is used (for example,
    26/108 (Hünig's base, triethylamine or commercially available polymeric acid scavengers) in proportion to the starting material of the general formula (XII). If the starting material is a salt, at least two equivalents of the acid trap are required.
    The reaction is normally carried out at temperatures from 0 ° C to 100 ° C and preferably at 20 ° C to 30 ° C, but it can also be carried out at the reflux temperature of the reaction mixture. The reaction time varies depending on the reaction scale and the reaction temperature, but is usually between a few minutes and 48 hours.
    Upon completion of the reaction, compounds (I) are separated from the reaction mixture by one of the conventional separation techniques. If necessary, the compounds are purified by recrystallization, distillation or chromatography or can optionally also be used in the next step without prior purification.
    Alternatively, a compound of formula (Ia) can also be synthesized from the corresponding compound of formula (XII) with a substrate of formula (Xlllb) with W 2b = OH in the presence of a coupling reagent in a manner analogous to the instructions described in the literature ( for example, Tetrahedron 2005, 61, 10827-10852 and references cited therein).
    Suitable coupling reagents are, for example, peptide coupling reagents (for example, N- (3-dimethylaminopropyl) -Netyl-carbodiimide mixed with 4-dimethylamino-pyridine, N- (3-dimethylaminopropyl) -N'-ethyl- carbodiimide mixed with 1-hydroxybenzotriazole, bromo-tripyrrolidinophosphonium hexafluorphosphate, O- (7azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorphosphate and so on).
    Optionally, a base, such as, for example, triethylamine or Hünig's base can be used in the reaction.
    As solvents can be used all common solvents, inert in 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, Ν, Ν-dimethylformamide, N, Ndimethylacetamide) or the reaction can be carried out in mixtures of two or more of these solvents. The preferred solvent is dichloromethane.
    The reaction is normally 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 reaction scale and the reaction temperature, but is usually between a few minutes and 48 hours.
    After completion of the reaction, compounds (l-a) are separated from the mixture of
    27/108 reaction by one of the conventional separation techniques. If necessary, the compounds are purified by recrystallization, distillation or chromatography or can optionally also be used in the next step without prior purification.
    from corresponding compounds (Ia), in which X a is oxygen, is shown in scheme 9.
    As solvents can be used all conventional solvents, inert in 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), ester of carboxylic acid (for example, ethyl ester of acetic acid) and amides (for example, N, N-dimethylformamide, Ν, Ν-dimethylacetamide and the reaction can be carried out in mixtures of two or more of these solvents. The preferred solvents are chloroform and 1,2-dimethoxyethane.
    Suitable sulfurating reagents are, for example, Lawesson's reagent (see Tetrahedron 1986, 42, 6555-6564, Tetrahedron Lett. 1993, 46, 7459-7462) and phosphorus pentasulfide. The starting material and the sulfurizing reagent are used in equimolar amounts, but the sulfurizing reagent can also optionally be used in excess.
    The reaction is normally carried out at temperatures of 0 ° C to 150 ° C and preferably at 0 ° C to 100 ° C, but it can also be carried out at the reflux temperature of the reaction mixture. The reaction time varies depending on the reaction scale and the reaction temperature, but is usually between a few minutes and 48 hours.
    After the completion of the reaction, the compounds (Ib), in which X b is sulfur, are separated from the reaction mixture by one of the conventional separation techniques. If necessary, the compounds are purified by recrystallization, distillation or chromatography.
    Process J
    10/288
    Figure 10: Process J
    W 1 —N
    Halogenation reagent
    W 1 —N
    , G (X-a) or (I-a) (X-d) or (I-d)
    W 1 represents acetyl, C1-C4 alkoxycarbonyl, benzyl, benzyloxycarbonyl or [3.5bis (d if luormeti I) -1 H-pyrazol-1-yljacetyl R Tz represents a halogen
    A possibility of producing the intermediate product (Xd) or the compounds of the formula (ld) according to the invention from the compound (Xa) or (ld) from the compound (Xa) is shown in scheme 10 (process J) .
    A compound of the general formula (Xd) or (ld) is obtained from the compound (Xa) or (la) by means of halogenation (see, for example, WO 08/013622, WO 05/040159 and Synthesis 1987, 11 , 998-1001).
    As solvents can be used all conventional solvents, inert in the reaction conditions, such as, for example, cyclic and acyclic ethers (for example, diethyl ether, tetrahydrofuran, dioxanes), 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 acids (for example, acetic acid) and carboxylic acid esters (eg, acetic acid ethyl ester) and the reaction can be carried out in mixtures of two or more of these solvents. Preferred solvents are chloroform and acetic acid.
    Preferred halogenating reagents are, for example, N-chlorosuccinimide, HCIO and chlorine (chlorination reagents), N-bromosuccinimide, HBrO and bromine (bromination reagents, N-fluordibenzenesulfonimides (NFSI) and F 2 (fluorination reagents) or Niodosuccinimide , ICI and iodine (iodination reagents, see J. March: Advanced Organic Chemistry - Reactions, Mechanisms and Structures, 4th Ed. (1992), Wiley, New York, pages 531-534; D. Kikelj. U. Urleb in Science of Synthesis, 11 (2001), pages 749-751) The starting material and halogenating reagent are used in equimolar amounts, but the halogenating reagent can optionally also be used in excess.
    The reaction is normally carried out at temperatures from -10 ° C to + 200 ° C and preferably at 0 ° C to 100 ° C, but it can also be carried out at the reflux temperature of the reaction mixture. The reaction time varies depending on the reaction scale and the reaction temperature, but is usually between a few minutes and 48 hours.
    Upon completion of the reaction, the compounds (X-d) or (l-d) are separated from the reaction mixture by one of the conventional separation techniques. If necessary,
    29/108 compounds are purified by recrystallization, distillation or chromatography.
    Another object of the invention relates to the non-medical use of the bis (difluormethyl) pyrazole derivatives according to the invention to combat unwanted microorganisms.
    Another object of the invention relates to an agent for combating unwanted microorganisms, comprising at least one bis (difluormethyl) pyrazole derivative according to the present invention.
    In addition, the invention relates to a process for combating unwanted microorganisms, characterized by the fact that the bis (difluormethyl) pyrazole derivatives according to the invention are applied on the microorganisms and / or in their habitat.
    In addition, the invention relates to a seed, which has been treated with at least one bis (difluormethyl) pyrazole derivative according to the invention.
    A final object of the invention relates to a process for protecting the seed against unwanted microorganisms by using a seed treated with at least one bis (difluormethyl) pyrazole derivative according to the present invention.
    The substances according to the invention have a strong microbicidal effect and can be used to combat unwanted microorganisms, such as fungi and bacteria, in plant protection and material protection.
    The bis (difluormethyl) pyrazole derivatives of formula (I) according to the invention, have very good fungicidal properties and can be used in plant protection, for example, to combat Plasmodiophoromycetes, Oomycetes, Chytridiomycetes, Zygomycetes, Ascomycetes, Basidiomycetes and Deuteromycetes.
    Bactericides can be used to protect plants, for example, to combat Pseudomonadaceae, Rhizobiaceae, Enterobacteriaceae, Corynebacteriaceae and Streptomycetaceae.
    The fungicidal agents according to the invention can be used to combat phytopathogenic fungi in a curative or protective way. Consequently, the invention also relates to curative and protective processes to combat phytopathogenic fungi through the use of the active substances or agents according to the invention, which are applied to the seed, plant or parts of the plant, fruits or soil , in which the plants grow.
    The agents according to the invention for combating phytopathogenic fungi in plant protection comprise an effective, but not phytotoxic, amount of the active substances according to the invention. Effective but non-phytotoxic amount means an amount of the agent according to the invention, which is sufficient to sufficiently control the fungal disease of the plant or kill it completely and, at the same time, does not bring with it any phytotoxicity symptoms worthy of mention. mention. In
    30/108 Overall, this amount of application may vary over a wider range. It depends on several factors, for example, the fungus to be combated, the plant, the climatic conditions and the constituent substances of the agents according to the invention.
    According to the invention, all plants and parts of the plants can be treated. In this case, plants are understood to mean all plants and plant populations, such as wild plants or desirable and undesirable crop plants (including crop plants of natural origin). Cultivation plants can be plants, which can be obtained by conventional cultivation and optimization methods or by biotechnological and genetic engineering methods or combinations of these methods, including transgenic plants and even the varieties of plants that are protected or not protected by protection laws. variety. By plant parts must be understood all aerial and underground parts and plant organs, such as bud, leaf, flower and root, being listed, for example, leaves, needles, stems, trunks, flowers, fruit pulp, fruits and seeds , as well as roots, tubers and rhizomes. Plant parts also include harvest material as well as vegetative and generative propagation material, for example, cuttings, tubers, rhizomes, seedlings and seeds.
    As plants, which can be treated according to the invention, the following are mentioned: cotton, flax, grapevine, fruits, vegetables, such as Rosaceae sp. (for example, stone fruits, such as apples and pears, but also drupes, such as apricots, cherries, almonds and peaches and berries, 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 banana 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, salad), Umbelliferae sp., Cruciferae sp., Chenopodiaceae sp., Cucurbitaceae sp. (e.g., cucumber), Alliaceae sp. (for example, leeks, onions), Papilionaceae sp. (for example, peas); major useful plants, such as Gramineae sp. (for example, maize, lawn, cereals, such as wheat, rye, rice, barley, oats, millet and triticale), Asteraceae sp. (for example, sunflower), Brassicaceae sp. (for example, white cabbage, red cabbage, broccoli, cauliflower. Brussels sprouts, pak choi, kohlrabi, radishes, as well as rapeseed. mustard, horseradish and watercress). Fabacae sp. (for example, beans, peanuts), Papilionaceae sp. (for example, soy), Solanaceae sp. (for example, potatoes), Chenopodiaceae sp. (eg sugar beet, fodder beet, chard, beet), useful plants and ornamental plants in the garden and forest; as well as species of these plants in each case genetically modified.
    For example, but not limited to, mentioning some pathogens of
    31/108 fungal diseases, which can be treated according to the invention:
    diseases, caused by powdery mildew pathogens, such as, for example, Blumeria species, such as, for example, Blumeria graminis; Podosphaera species, such as, for example, Podosphaera leucotricha; Sphaerotheca species, such as, for example, Sphaerotheca fuliginea; Uncinula species, such as, for example, Uncinula necator;
    diseases, caused by pathogens of rust diseases, 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, Puccinia graminis or Puccinia striiformis; Uromyces species, such as, for example, Uromyces appendiculatus;
    diseases, caused by pathogens from the Oomycetes group, such as, for example, Albugo species, such as, for example, Albugo candida; 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 diseases and leaf wilting, caused, for example, by Alternaria species, such as, for example, Alternaria solani; Cercospora species, such as, for example, Cercospora beticola; Cladiosporum species, such as, for example, Cladiosporium cucumerinum; Cochliobolus species, such as, for example, Cochliobolus sativus (form of conidia: Drechslera, synonym: Helminthosporium) or cochliobolus miyabeanus; 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 fawcetii; Gloeosporium species, such as, for example, Gloeosporium laeticolor; Glomerella species, such as, for example, Glomerella cingulata; Guignardia species, such as, for example, Guignardia bidwelii; Leptosphaeria species, such as, for example, Leptosphaeria maculans; Magnaporthe species, such as, for example, Magnaporthe grisea; Microdochium species, such as, for example, Microdochiium nivale; Mycosphaerella species, such as, for example, Mycosphaerella graminicola, Mycosphaerella arachidicola or Mycosphaerella fijiensis; species of Phaeosphaeria, such as, for example,
    10/328
    Phaeosphaeria nodorum; Pyrenophora species, such as, for example, Pyrenophora teres or Pyrenophora tritici repentis; Ramularia species, such as, for example, Ramularia collo-cygni or Ramularia areola; Rhynchosporium species, such as, for example, Rhynchosporium secalis; Septoria species, such as, for example, Septoria apii or Septoria lycopersici; Stagonospora species, such as, for example, Stagonospora nodorum; Typhula species, such as, for example, Typhula incarnata; 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; Piasmodiophora species, such as, for example, Piasmodiophora brassicae; Rhizoctonia species, such as, for example, Rhizoctonia solani; Sarocladium species, such as, for example, Sarocladium oryzae; Sclerotium species, such as, for example, Sclerotium oryzae; Tapesia species, such as, for example, Tapesia acuformis; Thielaviopsis species, such as, for example, Thielaviopsis basicola;
    ear and panicle diseases (including ears of corn), 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; Stagonospora species, such as, for example, Stagonospora nodorum;
    diseases, caused by coal (fungi), such as, for example, Sphacelotheca species, such as, for example, Sphacelotheca reiliana; Tilletia species, such as, for example, Tilletia caries or controversial Tilletia; Urocystis species, such as, for example, Urocystis occulta; Ustilago species, such as, for example, Ustilago nuda, 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 or Penicillium purpurogenum; Rhizopus species, such as, for example, Rhizopus stolonifer; Sclerotinia species, such as, for example, Sclerotinia sclerotiorum; Verticilium species, such as, for example, Verticilium alboatrum;
    seed rot and wilting and natural from the soil, as well as plant-born diseases of the seed, caused, for example, by Alternaria species, such as,
    33/108 for example, Alternaria brassicicola; Aphanomyces species, such as, for example, Aphanomyces euteiches; Ascochyta species, such as, for example, Ascochyta lentis; Aspergillus species, such as, for example, Aspergillus flavus; Cladosporium species, such as, for example, Cladosporium herbarum; Cochliobolus species, such as, for example, Cochliobolus sativus (form of conifers: Drechslera, Bipolaris; synonym: Helminthosporium); Colletotrichum species, such as, for example, Colletotrichum coccodes; Fusarium species, such as, for example, Fusarium culmorum; Gibberella species, such as, for example, Gibberella zeae; Macrophomina species, such as, for example, Macrophomina phaseolina, Microdochium species, such as, for example, Microdochium nivale; Monographella species, such as, for example, Monographella nivalis; Penicillium species, such as, for example, Penicillium expansum; Phoma species, such as, for example, Phoma lingam; Phomopsis species, such as, for example, Phomopsisoyae; Phytophthora species, such as, for example, Phytophthora cactorum;
    Pythium species, such as, for example, Pythium ultimum; Pyrenophora species, such as, for example, Pyrenophora graminea; Pyricularia species, such as, for example, Pyricularia oryzae; Pythium species, such as, for example, Pythium ultimum; Rhizoctonia species, such as, for example, Rhizoctonia solani; Rhizopus species, such as, for example, Rhizopus oryzae; Sclerotium species, such as, for example, Sclerotium rolfsii; Septoria species, such as, for example, Septoria nodorum; Typhula species, such as, for example, Typhula incarnata; Verticillium species, such as, for example, Verticillium dahliae;
    diseases of cancer, vesicles and witches' broom caused, for example, by Nectria species, such as, for example, Nectria galligena;
    wilting diseases caused, for example, by Monilinia species, such as, for example, Monilinia laxa;
    deformations of leaves, flowers and fruits caused, for example, by species of Exobasidium, such as, for example, Exobasidium vexans; Taphrina species, such as, for example, Taphrina deformans;
    degenerative diseases of woody plants caused, for example, by species of Esca, such as, for example, Phaemoniella clamydospora, Phaemoniella aleophilum or Fomitiporia mediterrânea; Ganoderma species, such as, for example, Ganoderma boninense;
    flower and seed diseases caused, for example, by Botrytis species, such as, for example, Botrytis cinerea;
    plant tuber diseases caused, for example, by Rhizoctonia species, such as, for example, Rhizoctonia solani; Helminthosporium species, such as
    34/108 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.
    The following soybean diseases can preferably be combated: fungal diseases on leaves, stems, pods and seeds caused by, for example, alternaria leaf spot (Alternaria spec. Atrans tenuissima), anthracnose (Colletotrichum gloeosporoides dematium var. Truncatum), brown spot (Septoria glycínes), cercospora leaf spot and blight (Cercospora kikuchii), choanephora leaf blight (Choanephora infundibulifera trispora (Syn.)), dactuliophora leaf spot (Dactuliophora glycínes), downy mildew (Peronospora manshurica), drechslera, drechsl spot (Cercospora sojina), leptosphaerulina leaf spot (Leptosphaerulina trifolii), phyllostica leaf spot (Phyllostictaoyaecola), pod and stem blight (Phomopsis soye), powdery mildew (Microsphaera diffusa), pyrenochaeta leaf spot (Pyrenochaeta foliage glycines), rh , and web blight (Rhizoctonia solani), rust (Phakopsora pachyrhizi), scabies (Sphaceloma glycínes), Stemphylium leaf blight (Stemphyliu botryosum), target spot (Corynespora cassiicola).
    Fungal diseases at the roots and at the base of the stems, 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 rot) (Phialophora gregata), pythium rot (Pythium aphanidermatum, Pythium irregulare, Pythium debaryanum, Pythium myriotylum, Pythium ultimum), rhizoctonia root rot, stem decay, and damping-off (Rhizoctonia solani), sclerotinia stem decay (Sclerotinia sclerotinia sclerotinia sclerotler sclerotinia sclerotinia sclerotinia sclerotinia sclerotinia sclerotinia sclerotinia sclerotinia sclerotinia sclerotinia sclerotinia sclerotinia sclerotinia sclerotinia sclerotinia sclerotinia sclerotinia sclerotinia sclerotinia sclerotinia sclerotinia sclerotinia sclerotinia sclerotinia sclerotinia sclerotinia sclerotinia sclerotinia sclerotinia sclerotinia sclerotinia sclerotinia sclerotinia sclerotinia sclerotinia blight (Sclerotinia rolfsii), thielaviopsis root rot (Thielaviopsis basicola).
    The active substances according to the invention also have a very good strengthening effect on plants. Therefore, they are suitable for mobilizing the plant's own defense forces against attack by unwanted microorganisms.
    By plant-fortifying substances (resistance inducers) in the present context, those substances, which are capable of stimulating the plant defense system in such a way, that the treated plants, when subsequently inoculated with the unwanted microorganisms, should be understood feature a
    35/108 broad resistance against these microorganisms.
    By unwanted microorganisms in the present case, phytopathogenic fungi and bacteria must be understood. Therefore, the substances according to the invention can be used to protect plants against infestation by the aforementioned pathogens within a certain period of time after treatment. The period of time, during which protection is obtained, generally extends from 1 to 10 days, preferably 1 to 7 days, after the treatment of the plants with the active substances.
    The good compatibility of the active substances by plants in the concentrations necessary to combat plant diseases allows treatment of aerial parts of plants, plant material and seeds and soil.
    In that case, the active substances according to the invention can be used with particularly good success to combat diseases in wine growing, fruit growing, growing potatoes and vegetables and growing vegetables, such as, for example, particularly against false fungi of the powdery mildew, oomycetes, such as, for example, species of Phytophthora, Plasmopara, Pseudoperonospora and Pythium.
    The active substances according to the invention are also suitable for increasing the yield of the crop. In addition, they are less toxic and have good plant compatibility.
    The compounds according to the invention, optionally in certain concentrations or application amounts, can also be used as herbicides, protectors, growth regulators or agents to improve the properties of plants or as microbicides, for example, as fungicides, antimycotics, bactericides , viricidal (including agents against viroids) or as agents against MLO (Mycoplasma-like organism) and RLO (Rickettsia-like organism). Optionally, they can also be used as insecticides. Optionally they can also be used as intermediate products or precursors for the synthesis of other active substances.
    With good compatibility with plants, favorable toxicity for warm-blooded animals and good compatibility with the environment, the active substances according to the invention are suitable to protect plants and plant organs, to increase the yield of the harvest, to improve the quality of the crop. harvesting in agriculture, horticulture, livestock, forests, gardens and leisure facilities, in the protection of stored food and materials, as well as in the hygiene sector. Preferably, they can be used as preparations for plant protection. They can preferably be used as preparations for plant protection. They are effective against normally sensitive and resistant species, as well as against all or some stages of development.
    The treatment according to the invention of plants and parts of plants with
    36/108 the active substances or agents are carried out directly or through action on their environment, living space or deposit by conventional treatment methods, for example, by immersion, spraying, spraying, spraying, evaporation, dusting, nebulization, dispersion, foaming , coating, spreading, watering (drainage), drip irrigation and in the case of propagating material, particularly in the case of seeds, in addition, by means of dry disinfection, wet disinfection, suspension disinfection, incrustation, coating of one or more layers. In addition, it is possible to apply the active substances by the ultra low volume process or to inject the active substance preparation or the active substance itself into the soil.
    The active substances according to the invention or agents can also be used in the protection of material to protect technical materials from attack and destruction by unwanted microorganisms, such as, for example, fungi.
    By technical materials in the present context, we mean non-living materials, which have been prepared for use in technology. For example, technical materials, which must be protected by the active substances according to the invention against microbial alteration or destruction can be adhesives, glues, papers and cardboard, fabrics, leather, wood, paint products and plastic articles, lubricants refrigerators and other materials, which can be attacked or destroyed by microorganisms. In the scope of the materials to be protected, parts of production facilities are also mentioned, for example, water cooling circuits, which can be harmed by the proliferation of microorganisms. In the context of the present invention, technical materials, preferably adhesives, glues, paper and cardboard, leather, wood, paint products, cooling lubricants and heat-transmitting fluids, preferably wood, are mentioned. The active substances or agents according to the invention can prevent disadvantageous effects, such as rotting, degradation, fading, discoloration or mold.
    The process according to the invention to combat unwanted fungi can also be used to protect so-called storage goods. In this case, storage goods are understood to mean natural substances of plant or animal origin or their processing products, which have been removed from nature and desired for long-term protection. Storage goods of plant origin, such as, for example, plants or parts of plants, such as stems, leaves, tubers, seeds, fruits, grains, can be protected in the freshly harvested state or after processing by (pre) drying , moistening, crushing, grinding, pressing or roasting. Storage goods also comprise useful wood, whether unprocessed, such as construction wood, electricity poles and cabinets or in the form of finished products, such as furniture. Animal storage goods are, for example, fur, leather, pelts and hair.
    37/108
    The active substances according to the invention can prevent disadvantageous effects, such as rotting, degradation, fading, discoloration or mold.
    As microorganisms, which can cause a change in technical materials, mention is made, for example, of bacteria, fungi, yeasts, algae and mucus. Preferably, the active substances according to the invention act against fungi, particularly mold fungi, fungi that discolor wood and destroy wood (basidiomycetes), as well as against mucus and algae. For example, microorganisms of the following genera are mentioned: 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 puliulans, Sclerophoma, such as Sclerophoma pityophila, Trichoderma, such as Trichoderma viride, Escherichia, such as Escherichia coli, Pseudoccus, such as such as Staphylococcus aureus.
    The present invention also relates to an agent for combating unwanted microorganisms, comprising at least one of the bis (difluormethyl) pyrazole derivatives according to the invention. Preferably, these are fungicidal agents, which contain adjuvants, solvents, vehicles, surfactants or thinners usable in agriculture.
    According to the invention, vehicle means an organic or inorganic substance, natural or synthetic, with which the active substances, for the best applicability, are mixed or bonded mainly to be applied to plants or parts of plants or seed. The vehicle, which can be solid or liquid, is generally inert and should be usable in agriculture.
    Solid vehicles include: for example, ammonium salts and natural stone powders, such as kaolin, clays, talc, chalk, quartz, atapulgite, montmorillonite or infusory earth and synthetic stone powders, such as highly dispersed silicic acid, aluminum oxide and silicates, as solid vehicles for granules are included: for example, broken and fractionated natural stones, such as calcite, marble, gravel, sepiolite, dolomite as well as synthetic granules of inorganic and organic flours as well as granules of organic material, such as paper, sawdust, coconut shells, corn cobs and tobacco stalks; as emulsifiers and / or foaming agents are included: for example, non-ionogenic and anionic emulsifiers, such as polyoxyethylene-fatty acid ester, polyoxyethylene-fatty alcohol ether, for example, alkylaryl-polyglycolic ether, alkyl sulfonates, sulphates alkyl, aryl sulfonates as well as albumin hydrolysates; non-ionic and / or ionic substances are included as dispersants, for example, from the classes of alcohol-POE and / or POP ethers,
    38/108 acid and / or POP-POE, alkyl-aryl- and / or POP-POE ether, grease and / or POP-POE addition products, POE and / or POP-polyol derivatives, POE addition products - and / or POPsorbitan or sugar, alkyl or aryl sulphates, sulphonates and phosphates or the corresponding PO-ether addition products. Suitable oligomers and polymers are furthermore, for example, those starting from vinyl monomers, acrylic acid, EO and / or PO alone or in combination with, for example, (poly-) alcohols or (poly-) amines. In addition, lignin and its derivatives of sulfonic acid, simple and modified celluloses, aromatic and / or aliphatic sulfonic acids, as well as their addition products with formaideide, can be found.
    The active substances can be converted into conventional formulations, such as solutions, emulsions, spray powders, water and oil based suspensions, powders, dusting powders, pastes, soluble powders, soluble pellets, spreading pellets, suspension concentrates- emulsion, natural substances impregnated with active substance, synthetic substances impregnated with active substance, fertilizers, as well as very fine encapsulations in polymeric substances.
    The active substances can be applied as such, in the form of their formulations or in the application forms prepared from them, such as ready-to-use solutions, emulsions, water or oil based suspensions, powders, spray powders, pastes, soluble powders, dusting powders, soluble pellets, spreading pellets, suspension-emulsion concentrates, natural substances impregnated with active substance, synthetic substances impregnated with active substance, fertilizers, as well as very fine encapsulations in polymeric substances. The application takes place in a conventional way, for example, by watering, spraying, spraying, spreading, dusting, foaming, coating and so on. In addition, it is possible to apply the active substances by the ultra-low volume process or to inject the preparation of the active substance or the active substance itself into the soil. Plant seeds can also be treated.
    The aforementioned formulations can be prepared in a known manner, for example, by mixing the active substances with at least one diluent, solvent or diluent, emulsifier, dispersant and / or adhesive or fixing agent, humectant, conventional water repellent, optionally drying agents and stabilizers UV and optionally dyes and pigments, defoamers, preservatives, secondary thickeners, glues, gibberellins, as well as other adjuvants.
    The agents according to the invention comprise not only formulations, which are ready for use and which can be applied to the plant or seeds with suitable equipment, but also commercial concentrates, which must be diluted with water before use. use.
    10/39
    The active substances according to the invention can be present as such or in their (commercial) formulations, as well as in the application forms prepared from these formulations in mixture with other (known) active substances, such as insecticides, baits, sterilizers, bactericides, acaricides, nematicides, fungicides, growth regulators, herbicides, fertilizers, protectors or semi-chemicals.
    As adjuvants, those substances, which are suitable, can be used to give the agent itself and / or the preparations derived therefrom (for example, spray broths, seed disinfectants), particular properties, such as certain technical properties and / or also particular biological properties. Typical adjuvants are included: thinners, solvents and vehicles.
    Suitable diluents are, for example, water, polar organic chemical liquids and supports, for example, from the classes of aromatic and non-aromatic hydrocarbons (such as paraffins, alkylbenzenes, alkylnaphthalenes, chlorobenzenes), of alcohols and polyols (which optionally can also be substituted, etherified and / or esterified), ketones (such as acetone, cyclohexanone), esters 9 also greases and oils) and (poly-) ethers, amines, amides, lactams (such as N-alkylpyrrolidones) and simple and substituted lactones , sulfones and sulfoxides (such as dimethyl sulfoxide).
    Liquefied gaseous diluents or vehicles are understood to mean those liquids, which are gaseous at normal temperature and under normal pressure, for example, aerosol propellant gases, such as halogenated hydrocarbons, as well as butane, propane, nitrogen and carbon dioxide.
    Adhesives such as carboxymethylcellulose, powdered and granulated synthetic or synthetic polymers, such as gum arabic, polyvinyl alcohol, polyvinyl acetate, as well as natural phospholipids such as cephalins and lecithins and synthetic phospholipids can be used in the formulations. Other additives can be mineral and vegetable oils.
    In the case of using water as a diluent, for example, organic solvents can also be used as auxiliary solvents. As liquid solvents are essentially included: aromatic compounds, such as xylene, toluene or alkylnaphthalenes, chlorinated aromatic compounds or chlorinated aliphatic hydrocarbons, such as chlorobenzenes, chloroethylenes or methylene chloride, aliphatic hydrocarbons, such as cyclohexane or paraffins, for example, fractions of petroleum, alcohols, such as butanol or glycol, as well as their ethers and esters, ketones, such as acetone, methyl ethyl ketone, methyl isobutyl ketone or cyclohexanone, strongly polar solvents, such as dimethylformamide and dimethyl sulfoxide, as well as water.
    The agents according to the invention can additionally contain other components, such as, for example, surfactants. As substances
    40/108 surfactants may include emulsifiers and / or foaming agents, dispersants or humectants with ionic or non-ionic properties or mixtures of these surfactants. Examples for this purpose are salts of polyacrylic acid, salts of lignosulfonic acid, salts of phenolsulfonic acid or naphthalenesulfonic acid, polycondensates of ethylene oxide with fatty alcohols or with fatty acids or with fatty amines, substituted phenols (preferably alkylphenols or arylphenols), salts of sulfosuccinic acid esters, taurine derivatives (preferably alkyltaurates), phosphoric acid esters of polyethoxyl alcohols or phenols, polyol fatty acid esters and derivatives of compounds containing sulphates, sulphonates and phosphates, for example, alkylaryl polyglycolic ether, alkyl sulphonates , alkyl sulfates, aryl sulfonates, albumin hydrolysates, residual lignin and methylcellulose bleaches. The presence of a surfactant substance is necessary when one of the active substances and / or an inert vehicle is not soluble in water and when the application is carried out in water. The proportion of surfactants is between 5 and 40% by weight of the agent according to the invention.
    Dyes, such as inorganic pigments, for example, iron oxide, titanium oxide, ferrocyan blue and organic dyes, such as alizarin, azo and phthalocyanine dyes of metals and trace elements, such as iron, manganese salts, can be used , boron, copper, cobalt, molybdenum and zinc.
    Other additives can be flavorings, optionally modified mineral or vegetable oils, waxes and nutritious substances (also trace elements), such as iron, manganese, boron, copper, cobalt, molybdenum and zinc salts.
    In addition, stabilizers, such as low temperature stabilizers, preservatives, oxidation protection agents, sun protection agents or other agents that improve chemical and / or physical stability, may be contained.
    Optionally, other additional components may also be contained, for example, protective colloids, adhesives, glues, thickeners, thixotropic substances, penetration enhancers, stabilizers, sequestrants, complex builders. In general, the active substances can be combined with each solid or liquid additive, which is conventionally used for formulation purposes.
    In general, the formulations contain 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 substances active, most particularly preferably, between 10 and 70% by weight.
    The formulations described above can be used in a process according to the invention to combat unwanted microorganisms, in which the bis (difluormethyl) pyrazole derivatives according to the invention are applied to the microorganisms and / or
    41/108 in its habitat.
    The active substances according to the invention can be used as such or in their formulations also in admixture with known fungicides, bactericides, acaricides, nematicides or insecticides to thus, for example, broaden the spectrum of action or prevent resistance developments.
    As a mix of participants are included, for example, fungicides, insecticides, acaricides, nematicides or bactericides also known (see also Pesticide Manual, 14th edition).
    It is also possible to mix with other known active substances, such as herbicides or with fertilizers and growth regulators, protectors or semi-chemicals.
    The application takes place in a conventional manner adapted to the application forms.
    In addition, the invention comprises a process for treating seeds.
    Another aspect of the present invention relates particularly to a seed, which is treated with at least one of the bis (difluormethyl) pyrazole derivatives according to the invention. The seeds according to the invention find application in processes to protect the seed against harmful phytopathogenic fungi. In the case of these, a seed treated with at least one active substance according to the invention is used.
    The active substances or agents according to the invention are also suitable for seed treatment. A large part of the damage caused by harmful organisms in crop plants is caused by infestation of the seed during storage or after sowing, as well as during and after germination of the plant. This phase is particularly critical, because the roots and shoots of the growing plant are particularly sensitive and also only minor damage can lead to the death of the plant. Therefore, there is a great interest in protecting the seed and the growing plant through the use of suitable agents.
    The fight against harmful phytopathogenic fungi through the treatment of plant seeds has been known for a long time and is the subject of constant improvements. However, in the treatment of the seed, a series of problems result, which cannot always be solved satisfactorily. In this way, it is desirable to develop processes to protect the seed and the germinating plant, which dispense or, at least, clearly reduce the additional application of preparations for plant protection after sowing or after the emergence of the plants. In addition, it is desirable to optimize the amount of active substance used in such a way that the seed and plant in
    42/108 germination are protected as well as possible against infestation by phytopathogenic fungi, without, however, harming the plant itself due to the active substance used. In particular, seed treatment processes should also consider the intrinsic fungicidal properties of transgenic plants, in order to obtain optimum protection for the seed and the germinating plant with a minimum amount of preparations for plant protection.
    Therefore, the present invention also relates to a process for the protection of germinating seed and plants against infestation of harmful animal parasites and / or harmful phytopathogenic fungi, in which the seed is treated with an agent according to the invention. The invention relates, likewise, to the use of the agents according to the invention for the treatment of seed for the protection of seed and germinating plants against phytopathogenic fungi. In addition, the invention relates to the seed, which, for protection against phytopathogenic fungi, has been treated with an agent according to the invention.
    The combat of harmful animal parasites and / or harmful phytopathogenic fungi, which damage plants after emergence, is carried out, in the first line, by treating the soil and aerial parts of plants with preparations for plant protection. Based on considerations regarding the possible influence of preparations for plant protection on the environment and the health of humans and animals, efforts are being made to decrease the amount of active substances applied.
    One of the advantages of the present invention is that, based on the particular systemic properties of the agents according to the invention, the treatment of the seed with these agents does not only protect the seed itself, but also the resulting plants after emergence against parasites harmful phytopathogenic animals and / or fungi. In this way, immediate treatment of the crop can be dispensed at the time of sowing or shortly thereafter.
    Likewise, it is considered to be advantageous, that the active substances or agents according to the invention can also be used particularly in the transgenic seed, since the plants that grow from that seed are able to express a protein, which acts against parasites. Through the treatment of this seed with the active substances or agents according to the invention, certain parasites can already be combated through the expression, for example, of the insecticidal protein. Surprisingly, in this case, another synergistic effect can be observed, which further increases the effectiveness for protection against parasite infestation.
    The agents according to the invention, are suitable for the protection of the seed of any plant variety, which is used in agriculture, greenhouse, forestry or horticulture. In that case, it is particularly cereal seed
    43/108 (such as wheat, barley, rye, millet and oats), corn, cotton, soybeans, rice, potatoes, sunflower, beans, coffee, turnips (for example, beet and fodder beet), peanuts, vegetables (such as tomato, cucumber, onions and salad), lawns and ornamental plants. The treatment of cereal seed (such as wheat, barley, rye and oats), corn and rice is of particular importance.
    As written below, the treatment of transgenic seed with the active substances or agents according to the invention is of particular importance. This refers to the seed of plants, which contain at least one heterologous gene, which allows the expression of a polypeptide or protein with insecticidal properties. The heterologous gene in transgenic seed may come, for example, from microorganisms of the species Bacillus, Rhizobium, Pseudomonas, Serratia, Trichoderma, Clavibacter, Glomus or Gliocladium. Preferably, this heterologous gene comes from Bacillus sp., And the gene product has an effect against the European corn borer (European corn borer) and / or against the corn root coieopteran (western corn rootworm). Most preferably, the heterologous gene comes from Bacillus thuringiensis.
    In the context of the present invention, the agent according to the invention is applied to the seed alone or in a suitable formulation. Preferably, the seed is treated in a state, in which it is so stable, that no damage occurs in the treatment. In general, seed treatment can be carried out at any time between harvest and sowing. Conventionally, seed is used, which is separated from the plant and has been released from tubers, barks, stems, pods, wool or pulp. Thus, for example, seed, which has been harvested, cleaned and dried to a moisture content of less than 15% by weight, can be used. Alternatively, seed can also be used, which after drying has been treated, for example, with water and then dried again.
    In general, during treatment, care must be taken to ensure that the amount of the agent according to the invention and / or other additives applied to the seed is selected in such a way that the germination of the seed is not impaired or the resulting plant is not damaged. This is mainly seen in active substances, which in certain amounts of application may show phytotoxic effects.
    The agents according to the invention can be applied directly, that is, without containing other components and without having been diluted. In general, it is preferable to apply the agents in the form of a suitable formulation on the seed. Suitable formulations and processes for treating the seed are known to the skilled person and are described, for example, in the following documents: US 4,272,417, US 4,245,432 A, US 4,808,430 A, US 5,876,739 A, US 2003 / 0176428 A1, WO 2002/080675 A1, WO 2002/028186 A2.
    The active substances usable according to the invention can be
    44/108 converted into conventional disinfectant formulations, such as solutions, emulsions, suspensions, powders, foams, slurries or other seed coatings, as well as ultra-low volume (ULV) formulations.
    These formulations are prepared in a known manner, in which the active substances or combinations of active substances are mixed with conventional additives, such as, for example, conventional thinners, as well as solvents or thinners, dyes, humectants, dispersants, emulsifiers, defoamers, preservatives, secondary thickeners, glues, gibberellins and also water.
    As dyes, which can be contained in the disinfectant formulations usable according to the invention, all conventional dyes for such purposes are included. In this case, both water-soluble pigments and water-soluble dyes can be used. As examples, the dyes known by the names Rhodamin B, C.l. Pigment Red 112 and C.l. Solvent Red 1.
    As humectants, which can be contained in the disinfectant formulations usable according to the invention, all the wetting agents conventional for the formulation of agrochemical active substances are included. Preferably, alkylnaphthalene sulfonates, such as diisopropyl- or diisobutylnaphthalene sulfonates, can be used.
    As dispersants and / or emulsifiers, which may be contained in disinfectant formulations usable according to the invention, all conventional nonionic, anionic and cationic dispersants for the formulation of agrochemical active substances are included. Preferably, nonionic or anionic dispersants or mixtures of nonionic or anionic dispersants are usable. Suitable nonionic dispersants include block copolymers of ethylene oxide, propylene oxide, alkylphenol polyglycolic ether as well as tristyrylphenol polyglycolic ether and its phosphate or sulfate derivatives. Suitable anionic dispersants are particularly ligninosulfonates, polyacrylic acid salts and arylsulfonatoformaldehyde condensates.
    As defoamers in disinfectant formulations usable in accordance with the invention, all conventional foam inhibiting substances for the formulation of agrochemical active substances can be contained. Preferably, silicone defoamer and magnesium stearate are used.
    As preservatives in disinfectant formulations usable according to the invention, all substances usable for such purposes in agrochemicals can be present. For example, mention dichlorophene and hemiformal benzyl alcohol.
    As secondary thickeners, which may be contained in formulations
    45/108 disinfectants usable according to the invention, all substances usable for such purposes in agrochemicals are included. Preferably, cellulose derivatives, derivatives of acrylic acid, xanthan, modified clays and highly dispersed silicic acid are included.
    As adhesives, which may be contained in disinfectant formulations usable in accordance with the invention, all adhesives usable in disinfectants are included. Preferably, polyvinylpyrrolidone, polyvinyl acetate, polyvinyl alcohol and tylose are mentioned.
    As gibberellins, which can be contained in the disinfectant formulations usable according to the invention, gibberellins A1, A3 (= gibberellinic acid), A4 and A7 are preferably included, particularly preferably gibberellinic acid is used. Gibberellins are known (compare R. Wegler Chemie der Pflanzenschutz- und Schádlingsbekãmpfungsmittel, volume 2, Springer Verlag, 1970, page 401-412).
    The disinfectant formulations usable according to the invention, can be used either directly or after previous dilution with water, for the treatment of seeds of the most different nature. Thus, the concentrates or preparations that can be obtained from these by diluting with water can be used for the disinfection of cereal seeds, such as wheat, barley, rye, oats and triticale, as well as corn, rice, rapeseed, peas, beans, cotton, sunflowers and turnips or also the seed of vegetables of the most different nature. Disinfectant formulations usable according to the invention or their diluted preparations can also be used to disinfect the seed of transgenic plants. In this case, in addition to the substances formed through expression, additional synergistic effects may also occur.
    For the treatment of the seed with the disinfectant formulations usable in accordance with the invention or of the preparations prepared therefrom by means of the addition of water, all the mixers generally usable for disinfection are included. In disinfection, it is specifically done in such a way that the disinfectant formulations that can be used according to the invention can be used either directly or after previous dilution with water, for the treatment of seeds of the most different nature, also of seeds of transgenic plants. . In this case, additional synergistic effects can also occur in cooperation with the substances formed through expression.
    For the treatment of the seed with the disinfectant formulations usable in accordance with the invention or of the preparations prepared therefrom by adding water, all the mixers generally usable for disinfection are included. In disinfection, it is specifically done in such a way that the seed is placed in a mixer, the respectively desired amount of disinfectant formulations is
    46/108 added or as such or after previous dilution with water and mixed until uniform distribution of the formulation in the seed. Optionally, it follows a drying process.
    The amount of application of disinfectant formulations usable according to the invention can vary within a broader range. It varies according to the respective content of the active substances in the formulations and according to the seed. The application amounts of the active substance combination 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 formula (I) according to the invention also have very good antimycotic effects. They have a very broad spectrum of antimycotic action, particularly against dermatophytes and yeasts, mold and diphasic fungi (for example, against Candida species, such as Candida albicans, Candida glabrata), as well as 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 enumeration of these fungi does not represent any limitation of the scope of the mycotic spectrum, but rather, it is only elucidatory.
    The active substances of formula (I) according to the invention can therefore be used both in medicinal and non-medicinal applications.
    The active substances can be applied as such, in the form of their formulations or in the application forms prepared from them, such as ready-to-use solutions, suspensions, spray powders, pastes, soluble powders, dusting agents and granules. The application takes place in a conventional manner, for example, by watering, spraying, spraying, spacing, dusting, foaming, coating and so on. In addition, it is possible to apply the active substances by the ultra low volume process or to inject the active substance preparation or the active substance itself into the soil. Plant seed can also be treated.
    When using the active substances according to the invention as fungicides, the application amounts, depending on the type of application, can vary over a wider range. The amount of application of the active substances according to the invention is important in the • treatment of 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 applied via irrigation or dripping, the amount of application can even be reduced, especially when inert substrates, such as mineral wool or perlite) are used;
    • in seed treatment: from 2 to 200 g per 100 kg of seed, preferably from
    47/108 to 150 g for 100 kg of seed, particularly preferred, from 2.5 to 25 g for 100 kg of seed, most particularly preferred, from 2.5 to 12.5 g for 100 kg of seed ;
    • in soil treatment: from 0.1 to 10,000 g / kg, preferably from 1 to 5,000 g / ha.
    These application amounts are given by way of example only and are not limited in the sense of the invention.
    The application of the active substances according to the invention in the veterinary medicine and livestock sector occurs in a known way through enteral administration in the form, for example, of tablets, capsules, drinks, drains, granules, pastes, cakes, of the process feed-through, suppositories, through parenteral administration, such as, for example, by injections (intramuscular, subcutaneous, intravenous, intraperitoneal and others), implants, through nasal application, through dermal application in the form, for example, of immersion or bathing (diving), spraying (spray), infusion (pour-on and spot-on), washing, dusting as well as with the aid of molded articles containing active substance, such as collar, ear tags, flow tags, bands articulators, halters, marking devices and others.
    For application in livestock, poultry, domestic animals and others, the active substances of the formula (I) can be used as formulations (for example, powders, emulsions, flowable agents), which contain the active substances in an amount from 1 to 80 % by weight, directly or after dilution of 100 to 10,000 times or they can be used as a chemical bath.
    The ready-to-use agents can optionally contain still other insecticides and optionally still one or more fungicides.
    With respect to possible additional participants, reference should be made to the insecticides and fungicides mentioned above.
    At the same time, the compounds according to the invention can be used to protect against the encrustation of objects, particularly ship bodies, sieves, nets, constructions, anchorages and signals, which come into contact with sea water or water brackish.
    In addition, the compounds according to the invention, can be used alone or in combinations with other active substances as anti-fouling agents.
    The treatment process according to the invention, can be used for the treatment of genetically modified organisms (GMOs), for example, plants or seeds. Genetically modified plants (or transgenic plants) are plants, in which a heterologous gene has been stably integrated into the genome. The term heterologous gene essentially means a gene, which is made available or assembled outside the
    48/108 plant and when introduced into the nuclear genome of the cell, the chloroplastic genome or the mitochondrial genome, thus gives the transformed plant new or improved agronomic properties or others, so that it expresses an interesting protein or polypeptide or that it regulates for low or turn off another gene that is present in the plant or other genes that are present in the plant (for example, through antisense technology, cosuppression technology or RNAi [RNA Interference] technology). A heterologous gene, which is present in the genome, is also called a transgene. A transgene, which is defined by its specific presence in the plant's genome, is referred to as a transformation event or transgenic event.
    Depending on the species of plants or varieties of plants, their location and their growing conditions (soils, climate, vegetation period, nutrition), the treatment according to the invention can also lead to superadditive (synergistic) effects. Thus, for example, the following effects are possible, which exceed the effects actually expected: reduced amounts of application and / or broadened spectrum of action and / or high effectiveness of active substances and compositions, which can be used according to the invention, better plant growth, greater tolerance against high or low temperatures, greater tolerance against drought or water or salt content in the soil, greater flowering, easier harvesting, accelerated ripening, higher yields, larger fruits, greater plant height, green color more intense leaf, premature flowering, higher quality and / or higher nutritional value of the harvested products, higher concentration of sugar in the fruits, better storage and / or processability of the harvested products.
    In certain application amounts, combinations of active substances according to the invention can also have a strengthening effect on plants. Consequently, they are suitable for mobilizing the plant defense system against attack by phytopathogenic fungi and / or unwanted microorganisms and / or viruses. This can optionally be one of the reasons for the greater effectiveness of the combinations according to the invention, for example, against fungi. Plant fortifying substances (resistance inducers) in the present context, should also mean those substances or combinations of substances, which are capable of stimulating the plant defense system in such a way that treated plants, when subsequently inoculated with phytopathogenic fungi and / or unwanted microorganisms and / or viruses, have a considerable degree of resistance against phytopathogenic fungi and / or unwanted microorganisms and / or viruses. In the present case, phytopathogenic fungi and / or unwanted microorganisms and / or viruses are understood, phytopathogenic fungi, bacteria and viruses. Therefore, the substances according to the invention, can be used to protect plants against attack by the mentioned pathogens within a certain period of time after treatment. The period of time, during which a protective effect is obtained, generally extends from 1 to
    49/108 days, preferably 1 to 7 days after treatment of the plants with the active substances.
    Plants and plant varieties, which are preferably treated according to the invention, are included all plants, which have a hetereditary factor, which gives useful characteristics, particularly advantageous to these plants (regardless, if obtained through cultivation and / or biotechnology).
    Plants and plant varieties, which are also preferably treated according to the invention, are resistant to one or more biotic stress factors, that is, these plants have a better defense against animal and microbial parasites, such as nematodes, insects, mites , phytopathogenic fungi, bacteria, viruses and / or viroids.
    Plants and plant varieties, which can also be treated according to the invention, are those plants, which are resistant against one or more abiotic stress factors. Abiotic stress conditions include, for example, drought, cold and hot conditions, osmotic stress, flooding, increased soil salinity, increased exposure to minerals, ozone conditions, strong light conditions, limited availability of nitrogen nutrients, availability limited amount of phosphorus nutrients or shade impediment.
    Plants and plant varieties, which can also be treated according to the invention, are those plants, which are characterized by increased production properties. Increased production in these plants can be based, for example, on better plant physiology, better plant growth and better plant development, such as water use efficiency, water retention efficiency, better nitrogen utilization, carbon assimilation increased, better photosynthesis, increased germination strength and accelerated ripening. In addition, production can be influenced by better plant architecture (under stress and non-stress conditions), including premature flowering, flower control for hybrid seed production, seedling vigor, plant size, number and internode distance, root growth, seed size, fruit size, pod size, number of pods or ears, number of seeds per pod or ear, seed mass, reinforced seed filling, reduced seed drop, reduced burst of pods, as well as stability. Other production characteristics include the composition of the seed, such as carbohydrate content, protein content, oil content and oil composition, nutritional value, reduction of anti-nutritional compounds, better processability and better storage capacity.
    Plants, which can be treated according to the invention, are hybrid plants, which already express the properties of heterosis or the hybrid effect, which leads
    50/108 generally to greater production, increased vigor, better health and better resistance to biotic and abiotic stress factors. Such plants are typically produced by crossing a line of inbreeding parents of sterile pollen (the female crossing participant) with another line of inbreeding parents of fertile pollen (the male crossing participant). Hybrid seed is typically harvested from sterile pollen plants and sold to growers. Sterile pollen plants can sometimes be produced (for example, in the case of corn) by removing pollen-producing flowers (ie, mechanical removal of male sexual organs or male flowers); however, it is common that pollen sterility is based on genetic determinants in the plant's genome. In this case, particularly when the desired product is about seeds, since it is desired to harvest from hybrid plants, it is conventionally favorable to ensure that pollen fertility in hybrid plants, which contain the genetic determinants responsible for pollen sterility, is completely restored. This can be achieved by ensuring that male breeding participants have corresponding fertility restoring genes, which are capable of restoring pollen fertility in hybrid plants, which contain the genetic determinants, which are responsible for pollen sterility. Genetic determinants for pollen sterility may be located in the cytoplasm. Examples of cytoplasmic pollen sterility (CMS) have been described, for example, for Brassica species. Genetic determinants for pollen sterility, however, may also be located in the cell's nuclear genome. Sterile pollen plants can also be obtained with methods of plant biotechnology, such as genetic engineering. A particularly favorable medium for the production of sterile pollen plants is described in WO 89/10396, in which, for example, a ribonuclease, such as a barnase, is selectively expressed in the tapetum cells in the stamens. Fertility can then be restored through the expression of a ribonuclease inhibitor, as needed, in tapetum cells.
    Plants or varieties of plants (which are obtained with methods of plant biotechnology, such as genetic engineering), which can be treated according to the invention, are plants tolerant to herbicides, ie plants, which have been made tolerant against a or more herbicides given. Such plants can be obtained either through genetic transformation or through the selection of plants, which contain a mutation, which gives such a tolerance to herbicides.
    Herbicide-tolerant plants are, for example, glyphosate-tolerant plants, that is, plants, which have been made tolerant against the herbicide glyphosate or its salts. Thus, for example, glyphosate-tolerant plants can be obtained by transforming the plant with a gene, which encodes the enzyme 5-enolpiruvilshikimat-3-phosphate
    51/108 synthase (EPSPS). Examples of such EPSPS genes are the AroA gene (CT7 mutant) of the bacteria Salmonella typhimuríum, the CP4 gene of the bacterium Agrobacteríum sp., The genes, which encode an EPSPS of petunia, an EPSPS of tomatoes or an EPSPS of eleusin. It may also be a mutated EPSPS. Glyphosate tolerant plants can also be obtained by expressing a gene, which encodes a glyphosate oxidoreductase enzyme. Glyphosate-tolerant plants can also be obtained by expressing a gene, which encodes a glyphosate-acetyltransferase enzyme. Glyphosate-tolerant plants can also be obtained by selecting plants, which contain naturally occurring mutations in the genes mentioned above.
    Other herbicide-resistant plants are, for example, plants, which have been made tolerant to herbicides, which inhibit the enzyme glutamine synthase, such as bialaphos, phosphinothricin or giufosinate. Such plants can be obtained by expressing an enzyme, which detoxifies the herbicide or a mutant in the enzyme glutamine synthase, which is resistant to inhibition. Such a detoxifying enzyme is, for example, an enzyme, which encodes a phosphinothricin-acetyltransferase (such as, for example, the bar or pat protein of Streptomyces species). Plants, which express an exogenous phosphinothricin-acetyltransferase, are described.
    Other herbicide-tolerant plants are also plants, which have been made tolerant to herbicides, which inhibit the enzyme hydroxyphenylpyruvatodioxigenase (HPPD). In the case of hydroxyphenylpyruvatodioxigenases these are enzymes, which catalyze the reaction, in which parahydroxyphenylpyruvate (HPP) is transformed into homogentisate. Plants, which are tolerant of HPPD inhibitors, can be transformed with a gene, which encodes a naturally occurring resistant HPPD enzyme, or with a gene, which encodes a mutated HPPD enzyme. A tolerance to HPPD inhibitors can also be obtained by the fact that they transform plants with genes, which encode certain enzymes, which allow the formation of homogenized despite the inhibition of the native HPPD enzyme through the HPPD inhibitor. Plant tolerance to HPPD inhibitors can also be improved by the fact that they transform plants in addition to a gene, which encodes an HPPD-tolerant enzyme, with a gene, which encodes a prefenatodehydrogenase enzyme.
    Other herbicide-resistant plants are plants, which have been made tolerant to acetolactate synthase (ALS) inhibitors. Known ALS inhibitors include, for example, sulfonylurea, imidazolinone, triazolopyrimidines, pyrimidinyloxy (thio) benzoates and / or sulfonylaminocarbonyltriazolinone herbicides. It is known that different mutations in the ALS enzyme (also known as acetohydroxy acid synthase, AHAS) give a tolerance to different herbicides or groups of herbicides. The production of plants tolerant to sulfonylurea and plants tolerant to imidazolinone is
    52/108 described in the international publication WO 1996/033270. Other plants tolerant to sulfonylurea and imidazolinone are also described, for example, in WO 2007/024782.
    Other plants, which are tolerant to imidazolinone and / or sulfonylurea, can be obtained through induced mutagenesis, selection in cell cultures in the presence of the herbicide or through mutation culture.
    Plants or varieties of plants (which were obtained by the method of plant biotechnology, such as genetic engineering), which can also be treated according to the invention, are transgenic plants resistant to insects, that is, plants, which have been made resistant to infestation with certain target insects. Such plants can be obtained through genetic transformation or through the selection of plants, which contain a mutation, which confers such resistance against insects.
    In the present context, the term insect resistant transgenic plant includes any plant, which contains at least one transgene, which comprises a coding sequence, which encodes the following:
    1) an insecticidal crystalline protein from Bacillus thuringiensis or an insecticidal part of it, as well as the insecticidal crystalline proteins, which were listed online at: http://www.lifesci.sussex.ac.uk/Horrie/Neil Crickmore / Bt / or insecticidal parts thereof, for example, proteins of the Cry, CrylAb, CrylAc, Cry1 F, Cry2Ab, Cry3Ae or Cry3Bb protein classes or insecticidal portions thereof; or
    2) a crystalline protein from Bacillus thuringiensis or a part of it, which in the presence of another, second crystalline protein in addition to Bacillus thuringiensis or a portion thereof, has an insecticidal action, such as the binary toxin, which consists of the crystalline proteins Cy34 and Cy35; or
    3) an insecticidal hybrid protein, comprising parts of two different crystalline insecticidal proteins from Bacillus thuringiensis, such as, for example, a hybrid of the proteins of 1) above or a hybrid of the proteins of 2) above, for example, the CrylA protein .105, which is produced by the MON98034 corn event (WO 2007/027777); or
    4) a protein according to one of points 1) to 3) above, in which some, particularly 1 to 10 amino acids have been replaced by another amino acid, in order to obtain a greater insecticidal efficacy in relation to a target insect species and / or to broaden the spectrum of the corresponding target insect species and / or because of changes, which were induced in the coding DNA during cloning or transformation, such as the Cry3Bb1 protein in MON863 or MON88017 corn events or the Cry3A protein in the MIR 604 corn; or
    5) an insecticidal protein secreted from Bacillus thuringiensis or Bacillus cereus or an insecticidal part of it, such as vegetative insecticidal proteins, VIP, which are listed under
    53/108 http://www.lifesci.sussex.ac.uk/home/Neil Crickmore / Bt / vip.html. for example, proteins of the VIP3Aa protein class; or
    6) a secreted protein from Bacillus thuringiensis or Bacillus cereus, which in the presence of a second secreted protein from Bacillus thuringiensis or Bacillus cereus has an insecticidal action, such as the binary toxin, which consists of the VIP1A and VIP2A proteins;
    7) an insecticidal hybrid protein, comprising parts of different proteins secreted from Bacillus thuringiensis or Bacillus cereus, such as a hybrid of the proteins of 1) or a hybrid of the proteins of 2) above; or
    8) a protein according to one of points 1) to 3) above, in which some, particularly 1 to 10 amino acids have been replaced by another amino acid, to obtain a greater insecticidal efficacy in relation to a target insect species and / or to broaden the spectrum of the corresponding target insect species and / or because of changes, which were induced in the coding DNA during cloning or transformation (where the coding remains for an insecticidal protein), such as the VIP3Aa protein in the event of cotton COT 102.
    Naturally, insect resistant transgenic plants in the present context also include any plant, which comprises a combination of genes, which encode the proteins of one of the classes 1 to 8 mentioned above. In one embodiment, an insect resistant plant contains more than one transgene, which encodes a protein according to one of the 1 to 8 mentioned above, to broaden the spectrum of the corresponding target insect species or to delay the development of a resistance of insects against plants, due to the fact that they use different proteins, which are insecticides for the same species of target insect, however, they present a different mode of action, such as binding to different points of attachment of the receptor on the insect.
    Plants or varieties of plants (which were obtained by methods of plant biotechnology, such as genetic engineering), which can also be treated according to the invention, are tolerant against abiotic stress factors. Such plants can be obtained through genetic transformation or through the selection of plants, which contain a mutation, which confers such resistance against stress. Particularly useful plants with tolerance to stress are included the following:
    The. plants, which contain a transgene, capable of reducing the expression and / or activity of the gene for poly (ADP-ribose) polymerase (PARP) in the cells of plants or plants;
    B. plants, which contain a stress tolerance promoting transgene, capable of reducing the expression and / or activity of genes encoding PARG of plants or plant cells;
    ç. plants, which contain a stress tolerance promoting transgene, which
    54/108 encodes a functional enzyme in plants of the nicotinamide-indinucleotide salvage biosynthesis pathway, among them nicotinamidase, nicotinatophosphorphosphoramide transferase, nicotinamidadenindinucleotide synthase or nicotinamide transfer.
    Plants or varieties of plants (which were obtained by methods of plant biotechnology, such as genetic engineering), which can also be treated according to the invention, have a modified quantity, quality and / or storage capacity of the harvested product and / or modified properties of certain components of the harvested product, such as, for example:
    1) transgenic plants, which synthesize a modified starch, which with respect to its chemical-physical properties, particularly the amylose content or the amylose / amylopectin ratio, the degree of branching, the average length of the chain, the distribution of the side chains , the behavior of viscosity, resistance to gel, starch grain size and / or starch grain morphology compared to starch synthesized in plant cells or wild type plants, is altered in such a way that this modified starch is more suitable for certain applications.
    2) Transgenic plants, which synthesize polymers of non-starch carbohydrates or polymers of non-starch carbohydrates, whose properties are altered in comparison with wild type plants without genetic modification. Examples are plants, which produce polyfructose, particularly of the inulin and levan type, plants, which produce alpha-1,4-glucans, plants, which produce alpha-1,4-branched alpha-1,6-glucans and plants, which produce alternan .
    3) Transgenic plants, which produce hyaluronan.
    Plants or varieties of plants (which were obtained by methods of plant biotechnology, such as genetic engineering), which can also be treated according to the invention, are plants, such as cotton plants with modified fibrous properties. Such plants can be obtained by means of genetic transformation or by selecting plants, which contain a mutation, which confers such modified fibrous properties; these are included:
    a) plants, such as cotton plants, that contain a modified form of cellulose synthase genes,
    b) plants, such as cotton plants, that contain a modified form of homologous nucleic acids rsw2 or rsw3;
    c) plants, such as cotton plants with increased expression of sacarosphosphate synthase;
    d) plants, such as cotton plants with an increased expression of sucrose synthase;
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    e) plants, such as cotton plants, in which the timing of the control of the passage of plasmodesms is modified at the base of the fibrous cell, for example, through the downward regulation of the β-1,3-glucosase-selective;
    f) plants, such as cotton plants with fibers with modified reactivity, for example, through the expression of the N-acetylgiucosamine transferase gene, also including nodC and chitin synthase genes.
    Plants or varieties of plants (which have been obtained by methods of plant biotechnology, such as genetic engineering), which can also be treated according to the invention, are plants, such as rapeseed or Brassica plants related to modified properties of the composition of the oil. Such plants can be obtained through genetic transformation or through the selection of plants, which contain a mutation, which confers such modified oily properties; these include:
    a) plants, such as rapeseed plants, which produce oil with a high oleic acid content;
    b) plants, such as rapeseed plants, which produce oil with a low acid content;
    c) plants, such as rapeseed plants, which produce oil with a low saturated fatty acid content.
    Particularly useful transgenic plants, which can be treated according to the invention, are plants with one or more genes, which encode one or more toxins, are transgenic plants, which are offered by the following trade names: YIELD GARD® (for example, corn, cotton, soybeans), KnockOut® (eg corn), BiteGard® (eg corn), BT-Xtra® (eg corn), StarLink® (eg corn), Bollgard® (cotton) , Nucotn® (cotton), Nucotn 33B® (cotton), NatureGard® (for example, corn), Protecta® and New Leaf® (potato). Herbicide-tolerant plants that can be cited are, for example, corn varieties, cotton varieties and soy varieties, which are offered by the following trade names: Roundup Ready® (glyphosate tolerance, for example, corn, cotton, soy ), Liberty Link® (tolerance to phosphinothricin, for example, rapeseed), IMI® (tolerance to imidazolinone) and SCS® (tolerance to sulfonylurea), for example, corn. Herbicide-resistant plants (plants traditionally grown for herbicide tolerance), which can be cited, include the varieties offered by the designation Clearfield® (for example, maize).
    Particularly useful transgenic plants, which can be treated according to the invention, are plants, which contain transformation events or a combination of transformation events and which are listed, for example, in the archives of various national or regional regulatory agencies (see, for example, http://gmoinfo.jrc.it/gmp_browse.aspx and http://www.agbios.com/dbase.php).
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    The listed plants can be treated in a particularly advantageous manner according to the invention with compounds of the general formula (I) or with the mixtures of active substances according to the invention. The preferred areas indicated above in the active substances or mixtures, also apply to the treatment of these plants. Particularly noteworthy is the treatment of plants with the compounds or mixtures particularly listed in this text.
    Therefore, the active substances or agents according to the invention can be used to protect plants against attack by the mentioned harmful pathogens within a certain period of time after treatment. The period of time, within which protection is carried out, generally extends to 1 to 28 days, preferably 1 to 14 days, particularly preferably 1 to 10 days, most particularly preferably 1 to 7 days after treating the plants with the active substances or for up to 200 days after treating the seed.
    The production and use of the active substances of formulas (I) according to the invention is shown in the following examples. However, the invention is not limited to these examples.
    General: Unless otherwise specified, all purification or chromatographic separation steps were carried out on silica gel and with a solvent gradient from 0: 100 acetic acid / cyclohexane ethyl ester to 100: 0 acetic acid / hexane ethyl ester .
    Preparation of compounds of formula (I)
    2- (3,5-bis (difluormethyl) -1 H-pyrazol-1-yl] -1 - {4-fluor-4- [4- (5-phenyl-4,5-dihydro-1,2-oxazole -3yl) -1,3-thiazol-2-yl] piperidin-1-yl} ethanone (I-5)
    Process A
    7erc-butyl-4- (4-bromo-1,3-thiazol-2-yl) -4-hydroxypiperidin-1-carboxylate (IV-1)
    To a solution of 2,4-dibromo-1,3-thiazole (8.8 g) in dichloromethane (180 ml) was added n-butyllithium (1.6 M in tetrahydrofuran, 25 ml) by dripping at - 78 ° C under argon. The reaction mixture was stirred at -78 ° C for 20 minutes and then ferc-butyl-4-oxopiperidin-1-carboxylate was added. The mixture was stirred at room temperature for 30 minutes. Then, the reaction mixture was mixed with saturated ammonium chloride solution at -30 ° C and the aqueous phase was separated. After the extraction of the aqueous phase with dichloromethane, the combined organic phases were dried over sodium sulfate and concentrated under low pressure. The residue was purified by chromatography. Tert-butyl-4- (4-bromo-1,3-thiazol-2-yl) -4-hydroxypiperidin-1 carboxylate (15.3 g) was obtained.
    1 H NMR (DMSO-d 6 ): 6 ppm : 1.43 (s, 9H), 1.70 (d, 2H), 1.88 (ddd, 2H0, 3.11 (bs, 2H), 3 , 83 (d, 2H), 6.31 (s, 1H), 7.72 (s, 1H).
    57/108 logP (HCOOH): 2.74.
    MS (ESI): 363 and 365 ([M + H] + )
    Process B
    7erc-butyl-4- (4-bromo-1,3-thiazol-2-yl) -4-fluorpiperidin-1-carboxylate (V-1)
    7erc-butyl-4- (4-bromo-1,3-thiazol-2-yl) -4-hydroxypiperidin-1-carboxylate (17.7 g) was previously introduced into a PE flask, with argon, at 0 ° C in dichloromethane and diethylamino sulfur trifluoride (DAST) (7.08 ml) was added by dripping. The cooling has been removed. After stirring overnight, it was mixed with saturated aqueous sodium bicarbonate solution and extracted with dichloromethane. The organic extracts were dried over sodium sulfate and concentrated under low pressure. The residue was purified by chromatography. Ferc-butyl-4- (4-bromo-1,3-thiazol-2-yl) -4fluorpiperidin-1-carboxylate (18.0 g) was obtained.
    1 H NMR (DMSO-d 6 ): 6 ppm : 1.42 (s, 9H), 2.13-2.00 (m, 4H), 3.14 (bs, 2H), 3,953.87 (m , 2H), 7.95 (s, 1H).
    logP (HCOOH): 3.94.
    MS (ESI): 309 and 311 ([MC (CH 3 ) 3 + 2H] + )
    Process C
    7erc-butyl-4-fluor-4- (4-formyl-1,3-thiazol-2-yl) -piperidin-1-carboxylate (VI-1)
    To a solution of tert-butyl-4- (4-bromo-1,3-thiazol-2-yl) -4-fluorpiperidin-1carboxylate (245 mg) in dichloromethane (5 ml) was added n-butyl lithium ( 1.6 M in tetrahydrofuran, 0.42 ml) by dripping at -78 ° C. After 20 minutes Ν, Ν-dimethylformamide (0.16 ml) was added dropwise. After stirring for 30 minutes at 78 ° C, saturated ammonium chloride solution was mixed and extracted with dichloromethane. The organic extracts were dried over sodium sulfate and concentrated under low pressure. The residue was purified by chromatography. Ferc-butyl-4-fluor- (4-formyl1,3-thiazol-2-yl) piperidin-1-carboxylate (75 mg) was obtained.
    1 H NMR (DMSO-d 6 ): 6 ppm : 1.43 (s, 9H), 2.18-2.04 (m, 4H), 3.17 (bs, 2H), 3,973.89 (m , 2H), 8.80 (s, 1H), 9.92 (s, 1H) logP (HCOOH): 2.80
    MS (ESI): 259 ([MC (CH 3 ) 3 + 2H] + ).
    Process D and E erc-butyl-4-fluor-4- {4 - [(E / Z) - (hydroxyimino) methyl] -1,3-thiazol-2-yl} piperidin-1-carboxylate
    To a solution of tert-butyl-4-fluor- (4-formyl-1,3-thiazol-2-yl) piperidin-1carboxylate (3.49 g) in ethanol (50 ml) was added by dripping hydroxylamine (a 50% in water, 0.81 ml) at room temperature. The reaction mixture was stirred at 60 ° C for 1 hour, then the solvent was removed under low pressure. Ferc-butyl-4-fluor-4- {4 [(E / Z) - (hydroxyimino) methyl] -1,3-thiazol-2-yl} piperidin-1-carboxylate (3.49 g ).
    58/108
    1 H NMR (DMSO-d 6 ): 6 ppm : 1.42 (s, 9H), 2.17-2.03 (m, 4H), 3.16 (bs, 2H), 3,943.86 (m , 2H), 7.96 (s, 1H), 8.17 (s, 1H) logP (HCOOH): 2.53
    MS (ESI): 230 ([M-COOC (CH 3 ) 3 + 2H] + )
    7erc-butyl-4-fluor-4- [4- (5-phenyl-4,5-dihydro-1,2-oxazol-3-yl) -1,3-thiazol-2-yl] piperidin-1carboxylate (Xa -1)
    To a solution of ferc-butyl-4-fluor-4- {4 - [(E / Z) - (hydroxyimino) methyl] -1,3-thiazol-2yl} piperidin-1-carboxylate (500 mg) in tetrahydrofuran (5 ml), styrene (0.21 ml) was added by dripping at room temperature and then chlorine bleach (13% in water). After stirring for 4 hours at room temperature, the solvent was removed under low pressure. The residue was mixed with dichloromethane and water and extracted with dichloromethane. The organic extracts were dried over sodium sulfate and concentrated under low pressure. The residue was purified by chromatography. Tert-Butyl-4fluor-4- [4- (5-phenyl! -4,5-dihydro-1,2-oxazol-3-yl) -1,3-thiazol-2-yl] piperidin-1 was obtained -carboxylate (380 mg).
    1 H NMR (DMSO-d 6 ): 6 ppm : 1.42 (s, 9H), 2.14-2.07 (m, 4H), 3.15 (bs, 2H), 3.38 (dd , 1H), 3.89 (dd, 1H), 3.93 (bs, 2H), 5.75 (dd, 1H), 7.34 (m, 1H), 7.42-7.39 (m, 4H), 8.21 (s,
    IH) logP (HCOOH): 4.28
    MS (ESI): 332 ([M-COOC (CH 3 ) 3 + 2H] + ).
    Process G
    4-fluor-4- [4- (5-phenyl-4,5-dihydro-1,2-oxazol-3-yl) -1,3-thiazol-2-yl] piperidinium chloride (XII1)
    To a solution of ether-butyl-4-fluor-4- [4- (5-phenyl-4,5-dihydro-1,2-oxazol-3-yl) -1,3thiazol-2-yl] piperidin-1 -carboxylate (380 mg) a 4 molar solution of hydrochloric acid in 1,4-dioxane at 0 ° C was added dropwise. The reaction mixture was stirred at 0 ° C and then it was slowly warmed to room temperature. After stirring overnight, the excess solvent and hydrogen chloride were removed. 4fluor-4- [4- (5-phenyl-4,5-dihydro-1,2-oxazol-3-yl) -1,3-thiazol2-yl] piperidinium chloride (374 mg) was obtained.
    1 H NMR (DMSO-d 6 ): 6 ppm : 2.58-2.30 (m, 4H), 3.23-3.14 (m, 2H), 3.38 (dd, 1H), 3 , 56 (s, 2H), 3.90 (dd, 1H), 5.76 (dd, 1H), 7.42-7.33 (m, 5H), 8.25 (s, 1H), 9, 08 (bs, 1H), 9.24 (bs, 1H) logP (HCOOH): 1.17
    MS (ESI): 332 ([M-CI] + )
    Process H
    2- [3,5-bis (difluormethyl) -1 H-pyrazol-1 -II] -1 - {4-fluor-4- [4- (5-phenyl-4,5-dihydro-1,2-oxazole -3II) -1,3-thiazol-2-yl] piperidin-1-yl} ethanone (I-5)
    To a solution of [bis-3,5- (difluormethyl) -1 H-pyrazol-1-yljacetic acid (230 mg)
    59/108 in dichloromethane (5 ml) were added oxalyl chloride (387 mg) and a drop of Ν, Ν-dimethylformamide. The reaction mixture was stirred at room temperature overnight. After removing the solvents under low pressure, the residue was then dissolved in dichloromethane (5 ml) and at 0 ° C, added dropwise with a solution of 4fluor-4- [4- (5-phenyl-4-chloride) , 5-dihydro-1,2-oxazol-3-yl) -1,3-thiazol-2-yl] piperidinium (374 mg) and Hünig's base (394 mg) in dichloromethane (5 ml). The reaction mixture was stirred at room temperature for 3 hours. After adding concentrated ammonium chloride solution, the aqueous phase was separated and extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated under low pressure. The residue was purified by chromatography. 2- [3,5-bis (difluormethyl) -1H-pyrazol-1yl] -1 - {4-fluor-4- [4- (5-phenyl-4,5-dihydro-1,2-oxazole) was obtained -3-yl) -1,3-thiazol-2-yl] piperidin-1-yl} ethanone (250 mg).
    1 H NMR (DMSO-d 6 ): δ ppm : 2.45-2.05 (m, 4H), 3.11 (m, 1H), 3.38 (dd, 1H), 3.48 (m , 1H), 3.95-3.86 (m, 2H), 4.26 (m, 1H), 5.39 (d, 1H), 5.50 (d, 1H), 5.76 (dd, 1H), 6.91 (s, 1H), 7.03 (t, 1H), 7.18 (t, 1H), 7.42-7.33 (m, 5H), 8.22 (s, 1H ) logP (HCOOH): 3.41
    MS (ESI): 540 ([M + H] +)
    1- (4- {4- [5- (2-acetylphenyl) -4,5-dihydro-1,2-oxazol-3-yl] -1,3-thiazol-2-yl} piperidin-1-yl) -2- [3,5bis (difluormethyl) -1 H-pyrazol-1-ethanone (I-7)
    Process D and E
    7erc-butyl-4- {4- [5- (2-acetylphenyl) -4,5-dihydro-1,2-oxazol-3-yl] -1,3-thiazol-2-yl} piperidin-1carboxylate (Xa -2)
    To a solution of tert-butyl-4- {4 - [(E / Z) - (hydroxyimino) methyl] -1,3-thiazol-2yl} piperidin-1-carboxylate (4.5 g) and 1- (2-vinylphenyl) ethanone (2.32 g) in ethyl acetate (70 ml), potassium bicarbonate (7.23 g) and N-chlorosuccinimide (2.31 g) were added at room temperature and then three drops of water. The reaction mixture was stirred at 60 ° C for 3 hours, then it was mixed with ethyl acetate and water and extracted with ethyl acetate. The organic extracts were dried over sodium sulfate and concentrated under low pressure. The residue was purified by chromatography. Tert-Butyl-4- {4 [5-2-acetylphenyl) -4,5-dihydro-1,2-oxazol-3-ii] -1,3-thiazol-2-yl} piperidin-1 - was obtained carboxylate (4.64 g).
    1 H NMR (DMSO-d 6 ): 6 ppm : 1.41 (s, 9H), 1.60-1.48 (m, 2H), 2.04-1.98 (m, 2H), 2 , 63 (s, 3H), 2.89 (bs, 2H), 3.13 (dd, 1H), 3.27-3.18 (m, 1H), 4.07-3.95 (m, 3H ), 6.12 (dd, 1H), 7.48 (dd, 1H), 7.56 (d, 1H), 7.61 (dd, 1H), 7.98 (s, 1H), 8.00 (d, 1H).
    Process G
    1 - (2- {3- [2- (pyridin-4-i) -1,3-thiazol-4-yl] -4,5-dihydro-1,2-oxazol-5- hydrochloride il} ethanona
    To a solution of ferc-butyl-4- {4- [5-2-acetylphenyl) -4,5-dihydro-1,2-oxazol-3-yl] -1,3thiazol-2-yl} piperidin-1- carboxylate (500 mg) in 1,4-dioxane 95 ml) was added by
    60/108 dripping a 4 molar solution of hydrogen chloride in 1,4-dioxane (4.2 ml), at 0 ° C. The reaction mixture was stirred at 0 ° C and then slowly warmed up to room temperature. After stirring overnight, the excess solvent and hydrogen chloride were removed. 1- (2- {3- [2- (piperidin-4-yl) -1,3-thiazol-4-yl] -4,5-dihydro1,2-oxazol-5-yl} phenyl hydrochloride was obtained ) ethanone (430 mg).
    NMR-'Ή (DMSO-d 6 ): δ ppm : 1.99-1.85 (m, 2H), 2.23-2.15 (m, 2H), 2.63 (s, 3H), 3 , 08-2.97 (m, 2H), 3.14 (dd, 1H), 3.43-3.30 (m, 3H), 4.00 (dd, 1H), 6.12 (dd, 1H ), 7.98 (dd, 1H), 7.56 (d, 1H), 7.62 (dd, 1H), 8.00 (d, 1H), 8.03 (s, 1H), 8.75 (bs, 1H), 9.03 (bs, 1H) logP (HCOOH): 0.96
    MS (ESI): 358 ([M-CI] + )
    Process H
    1- (4- {4- [5- (2-acetylphenyl) -4,5-dihydro-1,2-oxazol-3-yl] -1,3-thiazol-2-yl] piperidin-1-yl) -2- [3,5bis (difluormethyl) -1 H-pyrazol-1-yl] ethanone (I-7)
    Solution A: To a solution of [3,5-bis (difluormethyl) -1 H-pyrazol-1-yljacetic acid (280 mg) in dichloromethane (10 ml), a drop of N, N-dimethylformamide and chloride of oxalyl (0.295 ml) at room temperature. After stirring for 2 hours at room temperature, the solvent was removed and the residue was redissolved in dichloromethane (10 ml) (solution A).
    To a hydrochloride solution of 1 - (2- {3- [2- (piperidin-4-yl) -1,3-thiazol-4-yl] -4,5dihydro-1,2-oxazol-5-yl} phenyl) ethanone (441 mg) in dichloromethane (5 ml) was added diisopropylethylamine (588 ml) at room temperature. After 15 minutes, solution A was added by dripping. After stirring overnight at room temperature, the reaction mixture was mixed with water and extracted with ethyl acetate. The organic extracts were dried over sodium sulfate and extracted under low pressure. The residue was purified by chromatography. 1- (4- {4- [5- (2-acetylphenyl) -4,5-dihydro-1,2-oxazol-3yl] -1,3-thiazol-2-yl} piperidin-1-yl was obtained ) -2- [3,5-bis (difluormethyl) -1 H-pyrazol-1-yljetanone (590 mg).
    2- {3- [2- (1 - {[3,5-bis (difluormethyl) -1 H-pyrazol-1-yl] acetyl} piperidin-4-yl) -1,3-thiazol-4-yl] -4,5dihydro-1,2-oxazol-5-yl} benzaldehyde (I-26)
    Process D and E
    7erc-butyl-4- {4- [5- (2-formylphenyl) -4,5-dihydro-1,2-oxazol-3-yl] -1,3-thiazol-2-yl} piperidin-1carboxylate (Xa -3)
    7erc-butyl-4- {4 - [(E / Z) - (hydroxyimino) methyl] -1,3-thiazol-2-yl} piperidin-1-carboxylate (5.6 g) and 2-vinylbenzaldehyde ( 2.61 g) were reacted in a manner analogous to i-7 (process D and E). Tert-Butyl-4- {4- [5- (2-formylphenyl) -4,5-dihydro-1,2-oxazol-3-yl] -1,3-thiazol-2yl} piperidin-1- carboxylate (5.69 g).
    1 H NMR (DMSO-d 6 ): 6 ppm : 1.41 (s, 9H), 1.60-1.48 (m, 2H), 2.04-1.98 (m, 2H), 2 , 89 (bs, 2H), 3,283.15 (m, 2H), 4.07-3.95 (m, 3H), 6.42 (dd, 1H), 7.64-7.57 (m, 2H ), 7.72
    61/108 (dd, 1H), 7.99 (s, 1H), 8.03 (d, 1H), 10.18 (s, 1H) logP (HCOOH): 3.76 MS (ESI): 342 ( [M-COOC (CH 3 ) 3 + 2H] + ).
    Process G
    2- {3- [2- (piperidin-4-yl) -1,3-thiazol-4-yl] -4,5-dihydro-1,2-oxazol-5ylbenzaldehyde (XII-3) hydrochloride
    7erc-butyl-4- {4- [5- (2-formylphenyl) -4,5-dihydro-1,2-oxazol-3-yl] -1,3-thiazol-2yl} piperidin-1-carboxylate (5 , 1 g) were reacted in a manner analogous to I-7 (process G). 2- {3- [2- (piperidin-4-yl) -1,3-thiazol-4-yl] -4,5-dihydro-1,2-oxazol-5yl} benzaldehyde hydrochloride (4, 35 g).
    1 H NMR (DMSO-d 6 ): δ ppm : 2.02-1.89 (m, 2H), 2.23-2.15 (m, 2H), 3.08-2.97 (m, 2H), 3.18 (dd, 1H), 3.35-3.29 (m, 2H), 3.41-3.35 (m, 1H), 4.05 (dd, 1H), 6.42 (dd, 1H), 7,647.57 (m, 2H), 7.72 (dd, 1H), 8.02 (d, 1H), 8.03 (s, 1H), 10.19 (s, 1H) logP (HCOOH): 0.76
    MS (ESI): 342 ([M-CI] + ).
    Process H
    2- {3- [2- (1 - {[3,5-bis (difluormethyl) -1 H-pyrazol-1-yl] acetyl} piperidin-4-yl) -1,3-thiazol-4-yl] -4,5dihydro-1,2-oxazol-5-yl} benzaldehyde (1 -26)
    2- {3- [2- (piperidin-4-yl) -1,3-thiazol-4-yl] -4,5-dihydro-1,2-oxazol-5yl} benzaldehyde hydrochloride (432 mg) was reacted similarly to I-7 (case G). 2- {3 [2- (1 - {[3,5-bis (difluormethyl) -1 H-pyrazol-1-yl] acetyl} piperidin-4-yl) -1,3-thiazol-4- was obtained yl] -4,5-dihydro-1,2oxazol-5-yl} -benzaldehyde (330 mg).
    2- [3,5-bis (difluormethyl) -1 H-pyrazol-1-yl] -1 - (4- {4- [5- (2-ethynylphenyl) -4,5-dihydro-1,2-oxazole -3iI] -1,3-thiazol-2-yl} piperidin-1-yl) ethanone (1 -38)
    To a solution of 4-acetamidobenzenesulfonylazide (140 mg) in acetonitrile (10 ml) was added dimethyl-2-oxopropylphosphonate (97 mg) at room temperature. After stirring for 2 hours, 2- {3- [2- (1 - {[3,5-bis (difluormethyl) -1 H-pyrazol-1yl] acetyl} piperidin-4-yl) -1 was added, 3-thiazol-4-yl] -4,5-dihydro-1,2-oxazol-5-yl} benzaldehyde (267 mg) in methanol (2 ml) to the reaction mixture. After stirring for 8 hours, the reaction mixture was mixed with ethyl acetate and water and extracted with ethyl acetate. The organic extracts were dried over sodium sulfate and concentrated under low pressure. The residue was purified by chromatography. Tert-2- [3,5-bis (difluormethyl) -1Hpyrazol-1-yl] -1 - (4- {4- [5- (2-ethynylphenyl) -4,5-dihydro-1,2 -oxazol-3-yl] -1,3-thiazol-2-yl} piperidin-1 yl) ethanone (50 mg).
    N- (2- {3- [2- (1 - {[3,5-bis (difluormethyl) -1 H-pyrazol-1-ii1acetinoiperidin-4-yl) -1,3-thiazol-4-in4,5 -dihydro-1.2-oxazol-5-ii) phenyl) methanesulfonamide (i-37)
    Process D and E
    62/108 rerc-butyl-4- [4- (5- {2 - [(methylsulfonyl) amino] phenyl} -4,5-dihydro-1,2-oxazol-3-yl) -1,3-thiazole- 2il] pi peridin-1-carboxylate (Xa-4)
    7erc-butyl-4- {4 - [(Z / E) - (hydroxyimino) methyl] -1,3-thiazol-2-yl} piperidin-1-carboxylate (1.35 g) and N- (2 -vinylphenyl) methanesulfonamide (1.11 g) were reacted in a manner analogous to I-7 (process D and E). Tert-butyl-4- [4- (5- {2 - [(methylsulfonyl) amino] phenyl} -4,5-dihydro1,2-oxazol-3-yl) -1,3-thiazol-2- useful] piperidin-1-carboxylate (0.94 g).
    1 H NMR (DMSO-d 6 ): 6 ppm : 1.41 (s, 9H), 1.51-1.49 (m, 2H), 2.08-2.00 (m, 2H), 2 , 95-2.84 (m, 2H), 3.03 (s, 3H), 3.38-3.21 (m, 2H), 3.90 (dd, 1H), 4.05-3.96 (m, 2H), 6.09 (dd, 1H), 7.43-7.30 (m, 4H), 8.00 (s, 1H), 9.18 (bs, 1H) logP (HCOOH): 3.00
    MS (ESI): 407 ([M-COOC (CH 3 ) 3 + 2H] + )
    Process G
    4- [4- (5- {2 - [(methylsulfonyl) amino] phenyl} -4,5-dihydro-1,2-oxazol-3-yl) -1,3-thiazol-2yl] piperidinium chloride (XII -4)
    7erc-butyl-4- [4- (5- {2 - [(methylsulfonyl) amino] phenyl} -4,5-dihydro-1,2-oxazol-3-yl) -1,3thiazol-2-yl] piperidin -1-carboxylate (900 mg) was reacted in a manner analogous to I-7 (process G). 4- [4- (5- {2 - [(methylsulfonyl) amino] phenyl} -4,5-dihydro-1,2-oxazol-3-yl) -1,3thiazol-2-yl] chloride was obtained piperidinium (1.00 g).
    logP (HCOOH): 0.72
    MS (ESI): 407 ([M-CI + 2H] + ).
    Process H
    N- (2- (3- [2- (1 - {[3,5-bis (difluormethyl) -1 H-pyrazol-1-yl] acetyl} piperidin-4-yl) -1,3-thiazol-4 -yl] 4,5-dihydro-1,2-oxazoi-5-yl} phenyl) methanesulfonamide (I-37)
    4- [4- (5- {2 - [(methylsulfonyl) amino] phenyl} -4,5-dihydro-1,2-oxazol-3-yl) -1,3thiazol-2-yl] piperidinium chloride (299 mg) was reacted in a manner analogous to I-7 (process G). N- (2- {3- [2- (1 - {[3,5-bis (difluormethyl) -1 H-pyrazol-1-yl] acetyl} piperidin-4-yl) -1,3- thiazol-4-yl] -4,5-dihydro-1,2-oxazol-5-yl} phenyl) methanesulfonamide (215 mg).
    2- [3,5-bis (difluormethyl) -1 H-pyrazol-1-yl] -1- (4- {4- [5- (2-hydroxyphenyl) -4,5dihydro-1,2-oxazol-3 -il] -1,3-thiazol-2-yl} piperidin-1-yl) ethanone (I-9)
    Process D and E
    7erc-butyl-4- {4- [5- (2-hydroxyphenyl) -4,5-dihydro-1,2-oxazol-3-yl] -1,3-thiazol-2-yl} -piperidin-1carboxylate ( Xa-5)
    To a solution of tert-butyl-4- {4 - [(hydroxyimino) methyl] -1,3-thiazol-2-yl} piperidin-1carboxylate (3.46 g) and 2-vinylphenol (1.60 g ) in ethyl acetate (50 ml), potassium bicarbonate (5.55 g) and N-chlorosuccinimide (1.78 g) were added at room temperature and then a drop of water. After stirring overnight at 60 ° C, the reaction mixture was mixed with ethyl acetate and water and extracted with ethyl acetate. The
    63/108 organic extracts were dried over sodium sulfate and concentrated under low pressure. The residue was purified by chromatography. Tert-butyl-4- {4- [5- (2-hydroxyphenyl) 4,5-dihydro-1,2-oxazol-3-yl] -1,3-thiazol-2-yl} piperidin-1 was obtained -carboxylate (1.70 g).
    1 H NMR (DMSO-dg): δ ppm : 1.41 (s, 9H), 1.49-1.61 (m, 2H), 1.98-2.06 (m, 2H), 2, 82-2.96 (m, 2H), 3.80 (dd, 1H), 3.96-4.05 (m, 2H), 5.82 (dd, 1H), 6.79 (t, 1H) , 6.85 (d, 1H), 7.13 (t, 1H), 7.20 (d, 1H), 7.98 (s, 1H), 9.70 (s, 1H) logP (pH2.7 ): 3.22
    MS (ESI): 330 ([M + HC 4 H 9 OCO] + ) ·
    Process G
    4- {4- [5- (2-hydroxyphenyl) -4,5-dihydro-1,2-oxazol-3-yl] -1,3-thiazol-2-yl} piperidium chloride (XII-5)
    To a solution of ferc-butyl-4- {4- [5- (2-hydroxyphenyl) -4,5-dihydro-1,2-oxazol-3-yl] 1,3-thiazol-2-yl} piperidin- 1-carboxylate (1.70 g) in dichloromethane a 4 molar solution of hydrogen chloride (4.0 eq.) In 1,4-dioxane at 0 ° C was added dropwise. The reaction mixture was stirred at 0 ° C and then slowly warmed up to room temperature. After stirring overnight, the excess solvent and hydrogen chloride were removed. 4- {4- [5- (2-hydroxyphenyl) -4,5-dihydro-1,2-oxazol-3-yl] -1,3-thiazol2-yl} piperidinium chloride (1.45 g ).
    1 H NMR (DMSO-de): 6 ppm : 1.85-1.98 (m, 2H), 2.15-2.23 (m, 2H), 2.98-3.09 (m, 2H ), 3.26 (dd, 1H), 3.81 (dd, 1H), 5.83 (dd, 1H), 6.79 (t, 1H), 6.86 (d, 1H), 7.13 (t, 1H), 7.20 (d, 1H), 8.02 (s, 1H), 8.58 (bs, 1H), 8.87 (bs, 1H), 9.74 (s, 1H) logP (pH2.7): 0.69
    MS (ESI): 330 ([M + H] + ).
    Process H
    2- [3,5-bis (difluormethyl) -1 H-pyrazol-1 -i] -1 - (4- {4- [5- (2-hydroxyphenyl) -4,5-dihydro-1,2-oxazol3 - yl] -1,3-thiazol-2-yl} piperidin-1-yl) ethanone (I-9)
    To a solution of [3,5-bis- (difluormethyl) -1 H-pyrazol-1-yljacetic acid (982 mg) in dichloromethane (10 ml) is added oxalyl chloride (1.50 g) and a drop of N, Ndimethylformamide at 0 ° C. The reaction mixture is stirred at room temperature for 60 minutes. The excess solvent and reagent are removed under low pressure. The solid residue is again dissolved in dichloromethane and at 0 ° C, added dropwise to a solution of 4- {4- [5- (2-hydroxyphenyl) -4,5-dihydro-1,2-oxazol-3 chloride -il] -1,3-thiazol-2il} piperidinium (1.45 g) and triethylamine (5.5 ml) in dichloromethane (14 ml). The reaction mixture is stirred at room temperature for 3 hours. Then, it is mixed with concentrated sodium bicarbonate solution, the aqueous phase is separated and extracted with ethyl ester of acetic acid. The combined organic phases are dried over sodium sulfate and concentrated. After column chromatographic purification, 2- [3,564 / 108 bis (difluormethyl) -1 H-pyrazol-1-iij-1 - (4- {4- [5- (2-hydroxyphenyl) -4 is obtained -4 , 5-dihydro-1,2-oxazol-3-yl] -1,3thiazol-2-yl} piperidin-1-yl) ethanone (900 mg).
    2- [3,5-bis (difluormethyl) -1-pyrazol-1-yl] -1- [4- (4- {5- [2- (prop-2-in-1-yloxy) phenyl] -4 , 5-dihydro1,2-oxazol-3-yl} -1,3-thiazol-2-yl) piperidin-1-yl] ethanone (1-21)
    To a solution of 2- [3,5-bis (difluormethyl) -1 H-pyrazol-1-yl] -1- (4- {4- [5- (2hydroxyphenyl) -4,5-dihydro-1,2 -oxazol-3-yl] -1,3-thiazol-2-yl} piperidin-1-yl) ethanone (60 mg) and potassium carbonate (23 mg) in DMF (3 ml), are added at room temperature potassium iodide (10 mg) and 3-bromoprop-1 -ine (21 mg). The reaction mixture is stirred at 80 ° C for 9 hours. Then, the mixture is mixed with dilute hydrochloric acid and extracted with acetic ester. The combined organic phases are dried over sodium sulfate and concentrated. After column chromatographic purification, 2- [3,5bis (difluormethyl) -1 H-pyrazol-1-yl] -1- [4- (4- {5- [2- (prop-2-in -1-yloxy) phenyl] -4,5-dihydro-1,2-oxazol-3yl} -1,3-thiazol-2-yl) piperidin-1-yl) ethanone (40 mg).
    2- {3- [2- (1 - {[3,5-bis (difluormethyl) -1 H-pyrazol-1-yl] acetyl} piperidin-4-yl) -1,3-thiazol-4-yl] -4,5dihydro-1,2-oxazol-5-yl} phenylcyclohexanecarboxylate (I-32)
    To a solution of 2- [3,5-bis (difluormethyl) -1 H-pyrazol-1-yl] -1- (4- {4- {5- [2 (hydroxyphenyl) -4,5-dihydro-1 , 2-oxazol-3-yl] -1,3-thiazol-2-yl} piperidin-1-yl) ethanone (150 mg) and triethylamine (33 mg) in methylene chloride (10 ml) is added to 0 ° C, a solution of cyclohexanocarbonyl chloride in methylene chloride (2 ml). The ice bath is removed and the reaction mixture is stirred for 3 hours at 0 ° C - room temperature. Then, the mixture is mixed with diluted sodium bicarbonate solution and extracted with methylene chloride. The combined organic phases are dried over sodium sulfate and concentrated. After column chromatographic purification, 2- {3- [2- (1 - {[3,5bis (d if fluoromethyl) -1 H-pyrazol-1 -yl] acetyl} pi peridin-4-i I is obtained ) -1,3-thiazol-4-yl] -4,5-dihydro-1,2-oxazol ~ 5yl} phenylcyclohexanecarboxylate (150 mg).
    2- [3,5-bis (difluormethyl) -1 H-pyrazol-1-yl] -1- (4- {4- [5- (2-nitrophenyl) -4,5-dihydro-1,2-oxazole -3yl] -1,3-thiazol-2-yl} piperidin-1-yl) ethanone (1-10)
    Process D and E
    7erc-butyl-4- {4- [5- (2-nitrophenyl) -4,5-dihydro-1,2-oxazol-3-yl] -1,3-thiazol-2yl} piperidin-1-carboxylate (Xa -6)
    To a solution of ferc-butyl-4- {4 - [(hydroxyimino) methyl] -1,3-thiazol-2-yl} piperidin-1carboxylate (2.80 g) and 1-nitro-2-vinylbenzene ( 1.60 g) in ethyl acetate (50 ml), potassium bicarbonate (4.50 g) and N-chlorosuccinimide (1.44 g) were added at room temperature and then a drop of water. After stirring overnight at 60 ° C, the reaction mixture was mixed with ethyl acetate and water and extracted with ethyl acetate. The organic extracts were dried over sodium sulfate and concentrated under low pressure. The residue was purified by chromatography. Tert-butyl-4- {4- [5- (2-nitrophenyl) -4,565 / 108 dihydro-1,2-oxazol-3-yl] -1,3-thiazol-2-yl} piperidin-1 was obtained -carboxylate (2.10 g).
    1 H NMR (DMSO-d 6 , 400 MHz): 6 ppm : 1.40 (s, 9H), 1.48-1.60 (m, 2H), 1.98-2.06 (m, 2H ), 2.81 - 2.96 (m, 2H), 3.40 (dd, 1H), 3.96-4.04 (m, 2H), 4.09 (dd, 1H), 6.24 ( dd, 1H), 7.64 (t, 1H), 7.66 (d, 1H), 7.79 (t, 1H), 8.02 (s, 1H), 8.15 (d, 1H) logP (pH2.7): 4.01
    MS (ESI): 359 ([M + HC 4 H 9 OCO] + )
    Process G
    4- {4- [5- (2-nitrophenyl) -4,5-dihydro-1,2-oxazol-3-yl] -1,3-thiazol-2-yl} piperidinium (XII6) chloride
    To a solution of tert-butyl-4- {4- [5- (2-nitrophenyl) -4,5-dihydro-1,2-oxazol-3-yl] -1,3thiazol-2-yl} piperidin-1 -carboxylate (2.10 g) in dichloromethane a 4 molar solution of hydrogen chloride (4.0 eq.) was added by dripping in 1,4-dioxane. The reaction mixture was stirred at 0 ° C and then slowly warmed up to room temperature. After stirring overnight, the excess solvent and hydrogen chloride were removed. 4- {4- [5- (2-nitrophenyl) -4,5-dihydro-1,2-oxazol-3-yl] 1,3-thiazol-2yl} piperidinium chloride (1.60 g) was obtained .
    1 H NMR (DMSO-d 6 , 400 MHz): 6 ppm : 1.86-1.97 (m, 2H), 2.15-2.23 (m, 2H), 2,983.09 (m, 2H ), 4.10 (dd, 1H), 6.24 (dd, 1H), 7.62 (t, 1H), 7.67 (d, 1H), 7.81 (t, 1H), 8.07 (s, 1H), 8.16 (d, 1H), 8.63 (bs, 1H), 8.91 (bs, 1H) logP (pH2.7): 1.09
    MS (ESI): 359 ([M + H] + )
    Process H
    2- [3,5-bis (difluormethyl) -1 H-pyrazol-1-yl] -1 - (4- {4- [5- (2-nitrophenyl) -4,5-dihydro-1,2-oxazole -3yl] -1,3-thiazol-2-yl} piperidin-1-yl) ethanone (1-10)
    To a solution of [3,5-bis- (difluormethyl) -1 H-pyrazol-1-yljacetic acid (0.37 g) in dichloromethane (10 ml) is added, at 0 ° C, oxalyl chloride (0 , 57 g) and a drop of Ν, Ν-dimethylformamide. The reaction mixture is stirred at room temperature for 60 minutes. The excess solvent and reagent are removed under low pressure. The solid residue is again dissolved in dichloromethane and, at 0 ° C, added dropwise to a solution of 4- {4- [5- (2-nitrophenyl) -4,5-dihydro-1,2-oxazole- 3-yl] -1,3-thiazol-2yl} piperidinium (0.59 g) and triethylamine (2.1 ml) in dichloromethane (14 ml). The reaction mixture is stirred at room temperature for 20 hours. Then, it is mixed with concentrated sodium bicarbonate solution, the aqueous phase is separated and extracted with ethyl ester of acetic acid. The combined organic phases are dried over sodium sulfate and concentrated. After column chromatographic purification, 2- [3,5bis (difluormethyl) -1 H-pyrazol-1-yl] -1 - (4- {4- [5- (2-nitrophenyl) -4.5 is obtained -dihydro-1,2-oxazol-3-yl] -1,3-thiazol2-yl} piperidin-1-yl) ethanone (170 mg).
    66/108
    1- (4- {4- [5- (2-aminophenyl) -4,5-dihydro-1,2-oxazol-3-yl] -1,3-thiazol-2-yl} piperidin-1-yl) -2- [3,5bis (difluormethyl) -1 H-pyrazol-1-yljetanone (1-41)
    To a solution of 2- [3,5-bis (difluoromethyl) -1 H-pyrazol-1-yl] -1 - (4- {4- [5- (2-nitrophenyl) 4,5-dihydro-1,2 -oxazol-3-yl] -1,3-thiazol-2-yl} piperidin-1-yljetanone (80 mg) in methanol (10 ml) Pd / C (20 mg, 10%) is added at room temperature The reaction mixture is stirred for 3 hours at room temperature under a hydrogen atmosphere, then the volatile components are removed under low pressure After column chromatographic purification, 1- (4- {4- [5 - (2-aminophenyl) -4,5-dihydro-1,2-oxazol-3-yl] -1,3thiazol-2-yl} piperidin-1-yl) -2- [3,5-bis (difluormethyl) -1 H-pyrazol-1-yljetanone (25 mg).
    2- [3,5-bis (difluormethyl) -1 H-pyrazol-1-yl] -1 - [4- (4- {5- [2- (cyclohexylmethoxy) phenylJ-4,5-dihydro1,2-oxazole -3-yl} -1,3-thiazol-2-yl) piperidin-1-yljetanone (I-24)
    Process D and E
    7erc-butyl-4- (4- {5- [2- (cyclohexylmethoxy) phenyl] -4,5-dihydro-1,2-oxazol-3-yl} -1,3-thiazol-2yl) piperidin-1 - carboxylate (Xa-7)
    To a solution of tert-butyl-4- {4 - [(hydroxyimino) methylj-1,3-thiazol-2-yl} piperidin-1carboxylate (2.90 g) and 1- (cyclohexylmethoxy) -2-vinylbenzene (2.40 g) in ethyl acetate (300 ml), potassium bicarbonate (4.60 g) and N-chlorosuccinimide (1.48 g) were added at room temperature and then a drop of water. The reaction mixture was stirred at 60 ° C for 6 hours, then it was mixed with ethyl acetate and water and extracted with ethyl acetate. The organic extracts were dried over sodium sulfate and concentrated under low pressure. The residue was purified by chromatography. Tert-Butyl-4- (4- {5- [2- (cyclohexylmethoxy) phenyl] -4,5-dihydro-1,2-oxazol-3-yl} -1,3-thiazol-2-yl was obtained ) piperidin1-carboxylate (3.40 g).
    1 H NMR (DMSO-d 6 , 400 MHz): 6 ppm : 0.97-1.12 (m, 5H), 1.40 (s, 9H), 1.50-1.80 (m, 8H ), 1.98-2.06 (m, 2H), 2.81-2.96 (m, 2H), 3.74-3.81 (m, 3H), 3.95-4.03 (m , 2H), 5.78 (dd, 1H), 6.92 (t, 1H), 7.00 (d, 1H), 7.26-7.33 (m, 2H), 7.97 (s, 1H) logP (pH2.7): 6.30
    MS (ESI): 426 ([M + HC 4 H 9 OCO] + )
    Process G
    4- (4- {5- [2- (cyclohexylmethoxy) phenyl] -4,5-dihydro-1,2-oxazol-3-yl} -1,3-thiazol-2yl) piperidinium chloride (XII-7)
    To a solution of ether-butyl-4- (4- {5- [2- (cyclohexylmethoxy) phenyl] -4,5-dihydro-1,2oxazol-3-yl} -1,3-thiazol-2-yl) piperidin-1-carboxylate (3.20 g) in dichloromethane a 4 molar solution of hydrogen chloride (4.0 eq.) was added by dripping in 1,4-dioxane at 0 ° C. The reaction mixture was stirred at 0 ° C and then slowly warmed to room temperature. After stirring overnight, the excess solvent and hydrogen chloride were removed. 4- (4- {5- [2- (cyclohexylmethoxy) phenyl] -4,5-dihydro-1,2-oxazol-3-yl} 67/108
    1,3-thiazol-2-yl) piperidinium (2.50 g).
    1 H NMR (DMSO-d 6 , 400 MHz): 6 ppm : 0.92-1.14 (m, 5H), 1.51-1.81 (m, 6H), 1,932.07 (m, 2H ), 2.14-2.27 (m, 2H), 2.92-3.10 (m, 2H), 3.26-3.47 (m, 4H), 3.71-3.86 (m , 3H), 5.80 (dd, 1H), 6.91 (t, 1H), 7.01 (d, 1H), 7.25-7.34 (m, 2H), 8.01 (s, 1H), 9.30 (s, 1H), 9.52 (s, 1H) logP (pH2.7): 1.90
    MS (ESI): 426 ([M + H] + )
    Process H
    2- [3,5-bis (difluormethyl) -1 H-pyrazol-1-yl] -1- [4- (4- {5- [2- (cyclohexylmethoxy) phenyl] -4,5-dihydro1,2- oxazol-3-yl} -1,3-thiazol-2-yl) piperidin-1-yl] ethanone (I-24)
    To a solution of [3,5-bis- (difluormethyl) -1H-pyrazol-1-yl] acetic acid (1.49 g) in dichloromethane (10 ml) is added oxalyl chloride (2.29 g) and a drop of N, Ndimethylformamide, at 0 ° C. The reaction mixture is stirred at room temperature for 60 minutes. The excess solvent and reagent are removed under low pressure. The solid residue is again dissolved in dichloromethane and at 0 ° C is added dropwise to a 4- (4- {5- [2- (cyclohexylmethoxy) phenyl] -4,5-dihydro-1,2- chloride solution oxazol-3-yl} -1,3thiazol-2-yl) piperidinium (2.55 g) and triethylamine (8.36 ml) in dichloromethane (14 ml). The reaction mixture is stirred at room temperature for 20 hours. Then it is mixed with concentrated sodium bicarbonate solution, the aqueous phase is separated and extracted with ethyl ester of acetic acid. The combined organic phases are dried over sodium sulfate and concentrated. After column chromatographic purification, 2- [3,5-bis (difluormethyl) -1 H-pyrazol-1-yl] -1 - [4- (4- {5- [2- (cyclohexylmethoxy) phenyl) is obtained ] -4,5-dihydro-1,2oxazol-3-yl} -1,3-thiazol-2-yl) piperidin-1-yl] ethanone (1.87 g).
    2- {3- [2- (1 - {[3,5-bis (difluormethyl) -1 H-pyrazol-1-yl] acetyl} piperidin-4-yl) -1,3-thiazol-4-yl] -1,2oxazol-5-yl} benzaldehyde (1-31)
    Process D and E
    7erc-butyl-4- {4- [5- (2-formylphenyl) -1,2 ~ oxazol-3-yl] -1,3-thiazol-2-yl} piperidin-1-carboxylate (Xb-1)
    To a solution of tert-butyl-4- {4 - [(hydroxyimino) methyl] -1,3-thiazol-2-yl} piperidin-1 carboxylate (1.00 g) in DMF (10 ml) was added N-chlorosuccinimide (0.51 g) at 50 ° C and stirred for 30 minutes. To the reaction mixture, triethylamine (1.34 ml) and 2-ethynylbenzaldehyde (0.54 g) were added at room temperature. After stirring at 50 ° C for 2 hours, the reaction mixture was mixed with ethyl acetate and water and extracted with ethyl acetate. The extracts were dried over sodium sulfate and concentrated under low pressure. The residue was purified by chromatography. Tert-butyl-4- {4- [5- (2-formylphenyl) -1,2oxazol-3-yl] -1,3-thiazol-2-yl} piperidin-1-carboxylate (95 mg) was obtained.
    1 H NMR (DMSO-d 6 ): 6 ppm : 1.42-1.41 (m, 9H), 1.69-1.50 (m, 2H), 2.12-1.98 (m,
    68/108
    2Η), 2.90 (bs, 2H), 3.40-3.28 (m, 1H), 4.10-3.95 (m, 2H), 7.44 (s, 1H), 7.77 (dd, 1H), 7.87 (dd, 1H), 7.94 (d, 1H), 8.02 (d, 1H), 8.29 (s, 1H), 10.29 (s, 1H) logP (HCOOH): 4.10
    MS (ESI): 340 ([M-COOC (CH 3 ) 3 + 2H] + )
    Process G and H
    2- {3- [2- (1 - {[3,5-bis (difluormethyl) -1 H-pyrazol-1-yl] acetyl} piperidin-4-yl) -1,2-thiazol-4-yl] -1,2oxazol-5-ii} benzaldehyde (1-31)
    To a solution of tert-butyl-4- {4- [5- (2-formylphenyl) -1,2-oxazol-3-yl] -1,3-thiazol-2yl} piperidin-1-carboxylate (95 mg) in dichloromethane a 4-molar solution of hydrogen chloride (2 ml) in 1,4-dioxane was added dropwise at 0 ° C. The reaction mixture was stirred at 0 ° C and then it was slowly warmed to room temperature. After stirring overnight, the excess solvent and hydrogen chloride were removed. 4- {4- [5- (2-formylphenyl) -1,2-oxazol-3-yl] -1,3-thiazol-2-yl} -piperidinium chloride (XII-8) was obtained.
    To a solution of [3,5-bis- (difluormethyl) -1 H-pyrazol-1-yljacetic acid (51 mg) in dichloromethane (2 ml) is added oxalyl chloride (57 μΙ) and a drop of N, Ndimethylformamide at 0 ° C. The reaction mixture is stirred at room temperature for 60 minutes. The excess solvent and reagent are removed under low pressure. The solid residue is again dissolved in dichloromethane and at 0 ° C is added dropwise to a 4- {4- [5- (2-formylphenyl) -1,2-oxazol-3-yl] -1 chloride solution, 3-thiazol-2-yl} piperidinium and triethylamine (90 μΙ) in dichloromethane (2 ml). The reaction mixture is stirred at room temperature for 3 hours. Then, it is mixed with concentrated sodium bicarbonate solution, the aqueous phase is separated and extracted with ethyl ester of acetic acid. The combined organic phases are dried over sodium sulfate and concentrated. After column chromatographic purification, 2- {3- [2- (1 - {[3,5-bis (difluormethyl) 1 H-pyrazol-1-yl] acetyl} piperidin-4-yl) -1 is obtained, 3-thiazol-4-yl] -1,2-oxazol-5-yl} benzaldehyde (36 mg). Cyclopropylmethyl-2- {3- [2- (1 - {[3,5-bis (difluormethyl) -1 H-pyrazol-1 -yl] acetyl} piperidin-4-yl) -1,3thiazol-4-yl] -4,5-dihydro-1,2-oxazol-5-yl} benzoate (1-13)
    Process D and E
    7erc-butyl-4- (4- {5- [2- (methoxycarbonyl) phenyl] -4,5-dihydro-1,2-oxazol-3-yl} -1,3-thiazol-2iI) piperidin-1 - carboxylate (Xa-8)
    7erc-butyl-4- {4 - [(Z / E) - (hydroxyimino) methyl] -1,3-thiazol-2-yl} piperidin-1-carboxylate (600 mg) and methyl-2-vinylbenzoate ( 406 mg) were reacted in a manner analogous to 1-31 (process D and D). Tert-butyl-4- (4- {5- [2- (methoxycarbonyl) phenyl] -4,5-dihydro-1,2oxazol-3-yl} -1,3-thiazol-2-yl) piperidin was obtained -1-carboxylate (643 mg).
    1 H NMR (DMSO-d 6 ): 6 ppm : 1.40 (s, 9H), 1.60-1.49 (m, 2H), 2.05-1.96 (m, 2H), 2 , 98-2.75 (m, 2H), 3.20 (dd, 1H), 3.26-3.20 (m, 1H), 3.88 (s, 3H), 4.02 (dd, 1H ), 4.05-3.93 (m, 2H), 6.30 (dd, 1H), 7.48 (dd, 1H), 7.55 (d, 1H), 7.65 (dd, 1H) , 7.96 (d, 1H), 8.00 (s, 1H)
    69/108 logP (HCOOH): 4.14
    MS (ESI): 372 ([M-COOC (CH 3 ) 3 + 2H] + ).
    2- (3- {2- [1 - (ferc-butoxycarbonyl) piperidin-4-yl] -1,3-thiazol-4-yl} -4,5-dihydro-1,2oxazol-5-yl) benzoic acid (Xa-9)
    To a solution of tert-butyl-4- (4- {5- [2- (methoxycarbonyl) phenyl] -4,5-dihydro-1,2oxazol-3-yl} -1,3-thiazol-2-yl) piperidin-1-carboxylate (643 mg) in tetrahydrofuran (4 ml) and water (0.8 ml) lithium hydroxide monohydrate (86 mg) is added at room temperature. The mixture is stirred at room temperature for 2 hours and then mixed with an ice-cold HC11N solution. The aqueous phase is extracted with ethyl acetate and then the combined organic phases are dried with sodium sulfate. The solid is filtered and the solvent is distilled, 2- (3- {2- [1 - (tert-butoxycarbonyl) piperidin-4-yl] -1,3-thiazol-4-yl} -4 acid is obtained, 5dihydro-1,2-oxazol-5-yl) benzoic (377 mg).
    1 H NMR (DMSO-de): δ ppm : 1.40 (s, 9H), 1.56-1.48 (m, 2H), 2.04-1.99 (m, 2H), 2, 88 (bs, 2H), 3.18 (dd, 1H), 3.28-3.19 (m, 1H), 4.04-3.98 (m, 3H), 6.48 (dd, 1H) , 7.43 (d, 1H), 7.52 (d, 1H), 7.60 (dd, 1H), 7.96 (d, 1H), 8.01 (s, 1H) logP (HCOOH): 3.18
    MS (ESI): 358 ([M-COOC (CH 3 ) 3 + 2H] + ).
    7erc-butyl-4- [4- (5- {2 - [(cicIopropylmethoxy) carbonyl] phenyl} -4,5-dihydro-1,2-oxazol-3-i 1) -1,3 thiazol-2-yl] piperidin-1-carboxylate (Xa-10)
    To a solution of 2- (3- {2- [1- (tert-butoxycarbonyl) piperidin-4-yl] -1,3-thiazol4-yl} -4,5-dihydro-1,2-oxazol-5 -yl) benzoic acid (300 mg) in dichloromethane (10 ml), cyclopropylmethanol (47 mg), 4-dimethylaminopyridine (8 mg) and 1-ethyl-3- (3'dimethylaminopropyl) carbodiimide (132 mg) are added to room temperature. The mixture is stirred at room temperature for 3 hours and then mixed with water. The aqueous phase is separated and extracted with ethyl acetate. The combined organic phases are dried over sodium sulfate and concentrated under low pressure. The residue is purified by chromatography. Ferc-butyl-4- [4- (5- {2 - [(cyclopropylmethoxy) carbonyl] phenyl} -4,5dihydro-1,2-oxazol-3-yl) -1,3-thiazol-2- is obtained useful] piperidin-1-carboxylate (270 mg).
    1 H NMR (DMSO-d 6 ): 6 ppm : 0.40-0.37 (m, 2H), 0.61-0.56 (m, 2H), 1.30-1.22 (m, 1H), 1.40 (s, 9H), 1.59-1.48 (m, 2H), 2.05-1.98 (m, 2H), 2.88 (bs, 2H), 3.26 -3.18 (m, 2H), 4.08-3.96 (m, 3H), 4.15 (dd, 2H), 6.31 (dd, 1H), 7.48 (dd, 1H), 7.56 (d, 1H), 7.65 (dd, 1H), 7.96 (d, 1H), 8.00 (s, 1H) logP (HCOOH): 4.99
    MS (ESI): 412 ([M-COOC (CH,). + 2H] + )
    Process G and H
    Cyclopropylmethyl-2- {3- [2- (1 - {[3,5-bis (difluormethyl) -1 H-pyrazol-1 -yl] acetyl} piperidin-4-yl) -1,3thiazol-4-yl] -4,5-dihydro-1,2-oxazol-5-yl} benzoate (1-13)
    70/108 tert-butyl-4- [4- (5- {2 - [(cyclopropylmethoxy) carbonyl] phenyl} -4,5-dihydro-1,2-oxazol-3-yl) 1,3-thiazol-2 -yl] piperidin-1-carboxylate (270 mg) was reacted in a manner analogous to 1-31 (process G and H). Cyclopropylmethyl-2- {3- [2- (1 - {[3,5-bis (difluormethyl) -1H-pyrazol-1yl] acetyl} piperidin-4-yl) -1,3-thiazol-4- was obtained yl] -4,5-dihydro-1,2-oxazol-5-yl} benzoate (136 mg).
    Methyl-2- {3- [2- (1 - {[3,5-bis (difluormethyl) -1 H-pyrazol-1-yl] acetyl} piperidin-4-yl) -1,3-thiazol-4- yl] 4,5-dihydro-1,2-oxazol-5-yl} benzoate (1-43) and Methyl-2- {3- [2- (1 - {[3,5-bis (difluormethyl) -1Hpírazol -1-yl] acetyl} piperidin-4-yl) -5-chloro-1,3-thiazol-4-yl] -4,5-dihydro-1,2-oxazol-5yl} benzoate (I-46)
    4- (4-Formyl-1,3-thiazol-2-yl) piperidinium chloride
    A tert-butyl-4- (4-formyl-1,3-thiazol-2-yl) piperidin-1-carboxylate (10 g) was added by dropping, at 0 ° C, a 4 molar solution of hydrogen chloride in 1,4diaxane (100 ml). The reaction mixture was stirred at 0 ° C and then it was slowly warmed up to room temperature. After stirring overnight, the excess solvent and hydrogen chloride were removed. 4- (4-Formyl-1,3-thiazol-2-yl) piperidinium chloride (9 g) was obtained.
    1 H NMR (DMSO-d 6 ): δ ppm : 2.05-1.94 (m, 2H), 2.25-2.17 (m, 2H), 3.09-2.97 (m, 2H), 3.37-3.30 (m, 2H), 3.48-3.40 (m, 1H), 8.68 (s, 1H), 9.15 (bs, 1H), 9.32 (bs, 1H), 9.90 (s, 1H).
    2- (1 - {[3,5-bis (difluormethyl) -1 H-pyrazol-1 -I l] acetyl} pi peridi η-4-yl) -1,3-thiazol-4-carbaldehyde (VI- 2)
    To a solution of [3,5-bis- (difluormethyl) -1 H-pyrazole-1-yl] acetic acid (3.64 g) in dichloromethane (20 ml), oxalyl chloride (3 ml) is added at 0 ° C , 5 ml) and a drop of N, Ndimethylformamide. The reaction mixture is stirred at room temperature for 10 minutes. The excess solvent and reagent are removed under low pressure. The solid residue is again dissolved in dichloromethane and at 0 ° C, it is added dropwise to a solution of 4- (4-formyl-1,3-thiazol-2-yl) piperidinium chloride (3.11 g) and triethylamine (5.6 ml) in dichloromethane (20 ml). The reaction mixture is stirred at room temperature for 3 hours. Then it is mixed with concentrated sodium bicarbonate solution, the aqueous phase is separated and extracted with ethyl ester of acetic acid. The combined organic phases are dried over sodium sulfate and concentrated. After column chromatographic purification, 2- (1 - {[3,5-bis (difluormethyl) -1 H-pyrazol-1 yl] acetyl} piperidin-4-yl) -1,3-thiazol-4 is obtained -carbaldehyde (4.52 g).
    1 H NMR (DMSO-d 6 ): δ ppm : 1.65-1.53 (m, 1H), 1.89-1.77 (m, 1H), 2.18-2.08 (m, 2H), 2.90-2.80 (m, 1H), 3.48-3.22 (m, 2H), 4.00-3.93 (m, 1H), 4.38-4.31 ( m, 1H), 5.34 (d, 1H), 5.39 (d, 1H), 6.90 (s, 1H), 7.02 (t, 1H), 7.18 (t, 1H), 8.65 (s, 1H), 9.90 (s, 1H) logP (HCOOH): 1.93
    MS (ESI): 405 ([M + H] + )
    Process D and E
    71/108
    2- (1 - {[3,5-bis (difl uormeti I) -1 H-pyrazol-1 -i I] acetyl l} pi peridi η-4-i I) -1,3-thiazol-4carbaldeidoxima
    To a solution of 2- (1 - {[3,5-bis (difluormethyl) -1 H-pyrazol-1-yl] acetyl} piperidin-4-yl) -1,3thiazol-4-carbaldehyde (485 mg) in ethanol (5 ml) hydroxylamine (50% in water, 44 μΙ) was added by dripping at room temperature. The reaction mixture was stirred at 60 ° C for 2 hours, then the solvent was removed under low pressure. 2- (1 - {[3,5 bis (difluoromethyl) -1 H-pyrazol-1-yl] acetyl} piperidin-4-yl) -1,3-thiazol-4-carbaldehydexime (454 mg) was obtained.
    logP (HCOOH): 1.93 and 1.98 (2 isomers)
    MS (ESI): 420 ([M + H] + ).
    Methyl-2- {3- [2- (1 - {[3,5-bis (difluormethyl) -1 H-pyrazol-1-yl] acetyl} piperidin-4-yl) -1,3-thiazol-4- yl] 4,5-dihydro-1,2-oxazol-5-yl} benzoate (1-43) and Methyl-2- {3- [2- (1 - {[3,5-bis (difluormethyl) -1Hpi razol-1-yl] acetyl} pi peridi n-4-yl) -5-chloro-1,3-thiazol-4-yl] -4,5-dihydro-1,2-oxazol-5yl} benzoate (1- 46)
    To a solution of 2- (1 - {[3,5-bis (difluormethyl) -1 H-pyrazol-1-yl] acetyl} piperidin-4-yl) -1,3thiazol-4-carbaldehydexima (1.00 g ) in DMF (4 ml), Nchlorosuccinimide (382 mg) was added at 50 ° C and stirred for 30 minutes. To the reaction mixture, triethylamine (1 ml) and methyl-2-vinylbenzoate (0.50 g) were added at room temperature. After stirring for 2 hours at 50 ° C, the reaction mixture was mixed with ethyl acetate and water and extracted with ethyl acetate. The organic extracts were dried over sodium sulfate and concentrated under low pressure. The residue was purified by chromatography. Methyl-2- {3- [2- (1 - {[3,5-bis (difluormethyl) -1 H-pyrazol-1yl] acetyl} piperidin-4-yl) -1,3-thiazole-4 was obtained -il] -4,5-dihydro-1,2-oxazol-5-yl} benzoate (287 mg) and methyl-2 {3- (2- (1 - {[3,5-bis (difluormethyl) - 1 H-pyrazol-1 -yl] acetyl} piperidin-4-yl) -5-chloro-1,3-thiazol-4-yl] -4,5dihydro-1,2-oxazol-5-yl} benzoate (193 mg).
    2- {3- [2- (1 - {[3,5-bis (difluormethyl) -1 H-pyrazol-1-yl] acetyl} piperidin-4-yl) -1,3-thiazol-4-yl] -4,5dihydro-1,2-oxazol-5-yl} -N-cyclopropylbenzamide (I-27)
    Acid 2- {3- [2- (1 - {[3,5-bis (difluormethyl) -1 H-pyrazol-1-yl] acetyl} piperidin-4-yl) -1,3-thiazol-4yl] - 4,5-dihydro-1,2-oxazol-5-yl} benzoic
    To a solution of methyl-2- {3- [2- (1 - {[3,5-bis (difluormethyl) -1 H-pyrazol-1-yl] acetyl} piperidin441) -1,3-thiazole-4- il] -4,5-dihydro-1,2-oxazol-5-yl} benzoate (208 mg) in tetrahydrofuran (1 ml) and water (0.2 ml) lithium hydroxide monohydrate (23 mg) is added at room temperature. The mixture is stirred at room temperature for 2 hours and then mixed with ice cold 1N HCI solution. The aqueous phase is extracted with ethyl acetate and then, the combined organic phases are dried with sodium sulfate. The solid is filtered and the solvent is distilled. 2- {3- [2- (1 - {[3,5-bis (difluormethyl) -1 H-pyrazol-1 yl] acetyl} piperidin-4-yl) -1,3-thiazole-4 acid is obtained -yl] -4,5-dihydro-1,2-oxazol-5-yl} benzoic (158 mg).
    1 H NMR (DMSO-d 6 ): δ ppm : 1.61-1.50 (m, 1H), 1.59-1.73 (m, 1H), 2.15-2.02 (m, 2H),
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    2.87-2.78 (m, 1H), 3.48-3.15 (m, 3H), 4.05-3.92 (m, 2H), 4.38-4.30 (m, 1H ), 5.34 (d, 1H), 5.42 (d, 1H), 6.38 (dd, 1H), 6.89 (s, 1H), 7.02 (t, 1H), 7.17 (t, 1H), 7.43 (dd, 1H), 7.54 (d, 1H), 7.60 (dd, 1H), 7.96 (d, 1H), 8.02 (s, 1H) logP (HCOOH): 2.63
    MS (ESI): 566 ([M + H] + ).
    2- {3- [2- (1 - {[3,5-bis (difluormethyl) -1 H-pyrazol-1-i Ijaceti I} piperid in -4-yl) -1,3-thiazol-4-yl ] -4,5dihydro-1,2-oxazol-5-yl} -N-cyclopropylbenzamide (I-27)
    To a solution of 2- {3- [2- (1 - {[3,5-bis (difluormethyl) -1H-pyrazol-1yl] acetyl} piperidin-4-yl) -1,3-thiazole-4- il] -4,5-dihydro-1,2-oxazol-5-yl} benzoic acid (105 mg) in dichloromethane (10 ml), cyclopropanamine (11 mg), 4-dimethylaminopyridine (2 mg) and 1-ethyl -3- (3'-dimethylaminopropyl) carbodiimide (37 mg) at room temperature. The mixture is stirred at room temperature for 3 hours and then mixed with water. The aqueous phase is separated and extracted with ethyl acetate. The combined organic phases are dried over sodium sulfate and concentrated under low pressure. The residue is purified by chromatography. 2- {3- [2- (1 - {[3,5-bis (difluormethyl) -1 H-pyrazol-1 yl] acetyl} piperidin-4-yl) -1,3-thiazol-4- is obtained yl] -4,5-dihydro-1,2-oxazol-5-yl} -N-cyclopropylbenzamide (78 mg).
    2- [3,5-bis (difluormethyl) -1 H-pyrazol-1-yl] -1 - [4- (4- {5- [2- (hydroxymethyl) phenyl] -4,5-dihydro-1, 2oxazoi-3-yl} -1,3-thiazol-2-yl) piperidin-1-yljetanone (I-45)
    To a solution of 2- {3- [2- (1 - {[3,5-bis (difiuormethyl) -1 H-pyrazol-1-yl] acetyl} piperidin-4-yl) 1,3-thiazol-4 -il] -4,5-dihydro-1,2-oxazol-5-yl} benzaldehyde (1.9 g) in methanol (50 ml), sodium borohydride (0.16 g) was added at 0 ° C and then, it was stirred at room temperature for 2 hours. Then, the reaction mixture was mixed at 0 ° C with 0.1 molar hydrochloric acid and ethyl acetate. organic extracts were dried over sodium sulfate and concentrated under low pressure. The residue was purified by chromatography. 2- [3,5-bis (difluormethyl) -1 H-pyrazol-1-yl] -1 - [4- (4- {5- [2- (hydroxymethyl) phenyl] -4,5-dihydro1 was obtained .2- oxazol-3-yl} -1,3-thiazol-2-yl) piperidin-1-yljetanone (1.1 g).
    2- [3,5-bis (difluormethyl) -1 H-pyrazol-1-yl] -1 - [4- (4- {5- [2- (chloromethyl) phenyl] -4,5-dihydro-1, 2oxazol-3-yl} -1,3-thiazol-2-yl) piperidin-1-yljetanone (I-44)
    To a solution of 2- [3,5-bis (difluormethyl) -1 H-pyrazol-1-yl] -1- [4- (4- {5- [2 (hydroxymethyl) phenyl] -4,5-dihydro -1,2-oxazol-3-yl} -1,3-thiazol-2-yl) piperidin-1-yljetanone (0.55 g) in dichloromethane (10 ml) thionyl chloride (0.24 g) was added and a drop of DMF at room temperature, and then the mixture was refluxed for 2 hours. Then, the reaction mixture was concentrated under low pressure. Without further purification, 2 [3,5-bis (difluormethyl) -1 H-pyrazol-1-yl] -1 - [4- (4- {5- [2- (chloromethyl) phenyl] -4, was obtained, 5-dihydro-1,2-oxazol-3-yl} 1.3-thiazol-2-yl) piperidin-1-yl] ethanone (0.59 g).
    2- [3,5-bis (difluormethyl) -1 H-pyrazol-1-i] -1 - {4- [4- {5- [2- (methoxyethoxy) phenyl] -4,5-dihydro-1,273 / 108 oxazol-3-yl} -1,3-thiazol-2-yl) piperidin-1-yl] ethanone (1-11)
    2-methoxyethanol (1.5 ml) was mixed at room temperature with sodium hydride (60%, 17 mg) and then stirred at room temperature for 2 hours. To this mixture, a solution of 2- [3,5-bis (difluormethyl) -1 H-pyrazol-1-yl] -1 - [4 (4- {5- [2- (chloromethyl) phenyl] was added by dripping -4,5-dihydro-1,2-oxazol-3-yl} -1,3-thiazol-2-yl) piperidin-1-yl] ethanone (0.20 g) in 2-methoxyethanol (1.5 g ) and then, the mixture was stirred at room temperature for 16 hours. Then, the reaction mixture was mixed with water and dichloromethane. The organic extracts were dried over sodium sulfate and concentrated under low pressure. The residue was purified by chromatography. 2- [3,5-bis (difluormethyl) -1H-pyrazol1 -yl] -1 - {4- [4- (5- {2 - [(2-methoxyethoxy) methyl] phenyl} -4.5 was obtained -dihydro-1,2-oxazol-3-yl) -1,3-thiazol-2yl] piperidin-1-yljetanone (0.11 g).
    2- [3,5-bis (difluormethyl) -1 H-pyrazol-1-yl] -1 - {4- [4- (5- {2- (ethylsulfanyl) phenyl} -4,5-dihydro-1, 2oxazol-3-yl) -1,3-thiazol-2-yl] piperidin-1-yl} ethanone (1-12)
    2- {3- [2- (1 - {[3,5-bis (difluormethyl) -1 H-pyrazol-1-yl] acetyl} pi peridin-4-yl) -1,3-thiazol-4-yl ] -4,5dihydro-1,2-oxazol-5-yl} benzylimidothiocarbamate
    A mixture of 2- [3,5-bis (difluormethyl) -1H-pyrazoyl-1-yl] -1- [4- (4- {5- [2- (chloromethyl) phenyl] 4,5-dihydro-1 , 2-oxazol-3-yl} -1,3-thiazol-2-yl) piperidin-1-yl] ethanone (0.20 g) and thiourea (29 mg) in ethanol (5 ml) are refluxed for 1 hour . Then, the reaction mixture is concentrated under low pressure and the residue is mixed with 5% sodium bicarbonate solution and acetic ester. The organic extracts were dried over sodium sulfate and concentrated under low pressure. The residue was filtered through a mixture of cyclohexane and acetic ester (1: 2) through silica gel. 2- {3- [2- (1 - {[3,5-bis (difluormethyl) -1H-pyrazol-1yl] acetyl} piperidin-4-yl) -1,3-thiazol-4-yl- 4,5-dihydro-1,2-oxazol ~ 5-yl} benzylimidothiocarbamate (0.15
    g) ·
    1 H NMR (DMSO-de): δ ppm : 1.58 (m, 1H), 1.80 (m, 1H), 2.18-2.05 (m, 2H), 2.82 (m, 1H), 3.42-3.20 (m, 3H), 3.97 (m, 2H), 4.32 (m, 2H), 5.40 (dd, 2H), 6.06 (dd, 1H ), 6.59 (bs, 1H), 6.91 (s, 1H), 7.03 (t, 1H), 7.18 (t, 1H), 7.45-7.25 (m, 4H) , 8.03 (s, 1H) logP (HCOOH): 1.68
    2- [3,5-bis (difluormethyl) -1 H-pyrazol-1-yl] -1- {4- [4- (5- {2- (ethylsulfanyl) methyl] phenyl} -4,5-dihydro1. 2-oxazol-3-yl) -1,3-thiazol-2-yl] piperidin-1-yl} ethanone (1-12)
    To a solution of 2- {3- [2- (1 - {[3,5-bis (difluormethyl) -1 H-pyrazol-1-yl] acetyl} piperidin-4-yl) 1.3-thiazol-4-yl ] -4,5-dihydro-1,2-oxazol-5-yl} benzylimidothiocarbamate (0.15 g) in toluene (5 ml) 50% caustic soda (0.5 ml), iodethane (42 mg) was added and a drop of tetra-n-butylammonium bromide. Then, the mixture was vigorously stirred at room temperature for 2 hours. Then, the reaction mixture was mixed with water and acetic ester. The organic extracts were dried over sodium sulfate and concentrated under low pressure. The residue was purified by chromatography. 2- [3,5-bis (difluormethyl) -1H74 / 108 pyrazol-1 -yl] -1 - {4- [4- (5- {2- (ethylsulfanyl) methyl] phenyl} -4.5 was obtained -dihydro-1,2-oxazol-3-yl) -1,3-thiazol-2yl] piperidin-1-yljetanone (50 mg).
    - [4- (4- {5- [2- (allyloxy) phenyl] -4,5-dihydro-1,2-oxazol-3-yl} -1,3-thiazol-2-yl) piperidin-1 - yl] -2- {3,5bis (difluormethyl) -1 H-pyrazol-1-yl] eta ninth (1-14)
    To a solution of 2- [3,5-bis (difluormethyl) -1 H-pyrazol-1-yl] -1 - (4- {4- [5- (2-hydroxyphenyl) 4,5-dihydro-1, 2-oxazol-3-yl] -1,3-thiazol-2-yl} piperidin-1-yl} ethanone (81 mg) and potassium carbonate (105 mg) in acetone (5 ml), allyl bromide is added (73 mg) at room temperature The reaction mixture is stirred for 5 hours at reflux, then the mixture is mixed with water and extracted with acetic ester.The combined organic phases are dried over sodium sulfate and concentrated. chromatographic purification, 1 - [4- (4- {5- [2- (allyloxy) phenyl] -4,5-dihydro-1,2-oxazol-3-yl} -1,3-thiazol-2 is obtained -il} piperidin-1 -yl] -2 [3,5-bís (difluormethyl) -1 H-pyrazol-1-yljetanone (48 mg).
    2- [3,5-bis (difluormethyl) -1 H-pyrazol-1-yl] -1- {4- [4- (5- {2 - [(3-methylbut-2-en-1-yl) oxy] phenyl} -4,5dihydro-1,2-oxazol-3-yl) -1,3-thiazol-2-yl] piperidin-1-yl} ethanone (I-20) and 2- [3,5bis ( difluormethyl) -1 H-pyrazol-1-yl] -1 - {4- [4- (5- {2 - [(2-methylprop-2-en-1 -yl) oxy] phenyl} -4,5dihydro- 1,2-oxazol-3-yl) -1,3-thiazol-2-yl] piperidin-1-yl} ethanone (1-18) were reacted in a manner analogous to 1-14.
    2- [3,5-bis (difluormethyl) -1 H-pyrazol-1-yl] -1 - [4- (4- {5- [2- (2-methoxyethoxy) phenyl] -4,5-dihydro- 1,2oxazol-3-yl} -1,3-thiazol-2-yl) ethanone (1-19)
    To a solution of 2- [3,5-bis (difluormethyl) -1 H-pyrazol-1-yl] -1 - (4- {4- [5- (2-hydroxyphenyl) 4,5-dihydro-1, 2-oxazol-3-yl] -1,3-thiazol-2-yl} piperidin-1-yl} ethanone (81 mg) and potassium carbonate (105 mg) in Ν, Ν-dimethylformamide (5 ml) 1-bromo-2-methoxyethane (84 mg) and potassium iodide (2.5 mg) at room temperature The reaction mixture is stirred at 80 ° C for 3 hours, then the mixture is mixed with water and extracted with acetic ester. The combined organic phases are dried over sodium sulfate and concentrated. After column chromatographic purification, 2- [3,5bis (difluoromethyl) -1 H-pyrazol-1-yl] -1 is obtained. - [4- (4- {5- [2- (2-methoxyethoxy) phenyl-4,5-dihydro-1,2-oxazol-3-yl} 1,3-thiazol-2-yl) piperidin-1 - iljetanone (41 mg).
    2- [3,5-bis (difluormethyl) -1 H-pyrazol-1-yl] -1 - [4- (4- {5- [2- (2-methoxyethoxy) phenyl-4,5-dihydro-1, 2oxazol-3-yl} -1,3-thiazol-2-yl) piperidin-1-yl] ethanone (I-28)
    Process D and E ferc-butyl-4- (4- {5- [3- (2-methoxyethoxy) phenyl] -4,5-dihydro-1,2-oxazol-3-yl} -thiazol-2-yl) piperidin1-carboxylate (Xa-11) ferc-butyl-4- {4 - [(hydroxyimino) methyl] -1,3-thiazol-2-yl} piperidin-1-carboxylate (250 mg) and 1 (2- methoxyethoxy) -3-vinylbenzene were reacted in a manner analogous to 1-31 (process D and E). Ferc-butyl-4- (4- {5- [3- (2-methoxyethoxy) phenyl] -4,5-dihydro-1,2-oxazol-3-yl} -thiazol-2yl) piperidin-1 was obtained -carboxylate (170 mg).
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    1 H NMR (DMSO-de): 6 ppm : 8.00 (s, 1H), 7.29 (t, 1H), 7.10-6.80 (m, 3H), 5.68 (dd, 1H), 4.15-3.95 (m, 4H), 3.84 (dd, 1H), 3.70-3.60 (m, 2 H), 3.45-3.20 (m), 2.95-2.80 (m, 2H), 2.081.98 (m, 2H), 1.63-1.48 (m, 2H), 1.40 (s, 9H).
    The 1- (2-methoxyethoxy) -3-vinylbenzene reagent was synthesized from 3- (2methoxyethoxy) -benzaldehyde according to standard instructions to the specialist (Wittig Reaktion: Chem. Rev 1989, 89, 863-927).
    Process G and H
    2- [3,5-bis (difluormethyl) -1 H-pyrazol-1-yl] -1 - [4- (4- {5- [3- (2-methoxyethoxy) phenyl-4,5-dihydro-1 , 2oxazol-3-yl} -1,3-thiazoi-2-yl) piperidin-1-yl] ethanone (I-28) tert-butyl-4- (4- {5- [3- (2-methoxyethoxy) -phenyl] -4,5-dihydro-1,2-oxazol-3-yl} -1,3-thiazol-2yl) piperidin-1-carboxylate (279 mg) was reacted analogously to 1-31 (process G and H). 2- [3,5-bis (difluormethyl) -1 H-pyrazol-1-yl] -1 - [4- (4- {5- [3- (2-methoxyethoxy) phenyl-4,5-dihydro- 1,2-oxazol-3-yl} -1,3-thiazol-2-yl) piperidin-1-yl] ethanone (180 mg).
    2- [3,5-bis (difluormethyl) -1 H-pyrazol-1-i] -1 - (4- {4- [5- (2-chloro-6-hydroxyphenyl) -4,5-dihydro- 1,2oxazol-3-yl} -1,3-thiazol-2-yl} piperidin-1-yl) ethanone (I-54)
    Process D and E ferc-butyl-4- {4- [5- (2-chloro-6-hydroxyphenyl) -4,5-dihydro-1,2-oxazol-3-yl] -1,3-thiazol-2il } piperidin-1-carboxylate (Xa-12)
    To a solution of tert-butyl-4- {4 - [(hydroxyimino) methyl] -1,3-thiazol-2-yl} piperidin-1 carboxylate (400 mg) in ethyl acetate (10 ml) was added N-chlorosuccinimide (206 mg). The reaction mixture was stirred for 30 minutes at reflux. To the reaction mixture were added 3-chloro-2-vinylphenol (397 mg) and potassium bicarbonate (257 mg) at room temperature and then a drop of water. After stirring at room temperature overnight, the reaction mixture is mixed with ethyl acetate and water and extracted with ethyl acetate. The organic extracts were dried over sodium sulfate and concentrated under low pressure. The residue was purified by chromatography. Tert-Butyl-4- {4- [5- (2-chloro-6-hydroxyphenyl) -4,5-dihydro-1,2-oxazol-3-yl] -1,3-thiazol-2- il} piperidin-1carboxylate (345 mg).
    1 H NMR (DMSO-d 6 ): 6 ppm : 7.95 (s, 1H), 7.18 (t, 1H), 6.92 (d, 1H), 6.82 (d, 1H), 6.17 (dd, 1H), 4.13.95 (m), 3.30-3.15 (m), 3.05-2.75 (m, 2H), 2.08-2.0 ( m, 2H), 1.62-1.50 (m, 2H), 1.40 (s, 9H).
    Also in this case, the reagent 3-chloro-2-vinylphenol was synthesized starting from 2chloro-6-hydroxybenzaldehyde according to the current instructions to the specialist (Wittig Reaktion: Chem. Rev. 1989, 89, 863-927).
    Process G and H
    2- [3,5-bis (difluormethyl) -1 H-pyrazol-1-i] -1 - (4- {4- [5- (2-chloro-6-hydroxyphenyl) -4,5-dihydro- 1,2oxazol-3-yl] -1,3-thiazol-2-yl} piperidin-1-yl) ethanone (I-54)
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    To a solution of ferc-butyl-4- {4- [5- (2-chloro-6-hydroxyphenyl) -4,5-dihydro-1,2-oxazol-3-yl] 1,3-thiazol-2- il} piperidin-1-carboxylate (346 mg) in dichloromethane, a 4 molar solution of hydrogen chloride (4.0 eq.) in 1,4-dioxane was added dropwise at 0 ° C. The reaction mixture was stirred at 0 ° C and then it was slowly warmed up to room temperature. After stirring for 5 hours, the excess solvent and hydrogen chloride were removed. 4- {4- [5- (2-chloro-6-hydroxyphenyl) -4,5-dihydro1,2-oxazol-3-yl] 1,3-thiazol-2-yl} pyridinium chloride (XII -9).
    To a solution of [3,5-bis- (difluormethyl) -1 H-pyrazol-1-yljacetic acid (177 mg) in dichloromethane (40 ml), add oxalyl chloride (290 mg) and a drop of N , N10 dimethylformamide, at 0 ° C. The reaction mixture is stirred at room temperature for 2 hours. The excess solvent and reagent are removed under low pressure. The solid residue is again dissolved in dichloromethane and at 0 ° C is added dropwise to a solution of 4- {4- [5- (2-chloro-6-hydroxyphenyl) -4,5-dihydro-1,2 -oxazol-3-yl] -1,3thiazol-2-yl} piperidinium and triethylamine (5.0 eq.) in dichloromethane (25 ml). The reaction mixture is stirred at room temperature overnight. Then, it is mixed with concentrated sodium bicarbonate solution, the aqueous phase is separated and extracted with ethyl ester of acetic acid. The combined organic phases are dried over sodium sulfate and concentrated. After column chromatographic purification, 2- [3,5bis (difluormethyl) -1H-pyrazol-1-yl] -1- (4- {4- [5- (2-chloro-6-hydroxyphenyl) - 4,5-dihydro-1,2-oxazol-3-yl] 20 1,3-thiazol-2-yl} piperidin-1-yl) ethanone (110 mg).
    1 H NMR (DMSO-d 6 ): 6 ppm : 10.28 (s, 1H), 7.98 (s, 1H), 7.30-6.80 (m, 6H), 6.17 (dd ,
    1H), 5.40 (dd, 2H), 4.36 (d, 1H), 3.97 (d, 1H), 3.71-3.55 (m, 2H), 3.32-3.24 (m, 1H), 2.84 (t, 1H), 2.16-2.08 (m, 2H), 1.85-1.75 (m, 1H), 1.62-1.53 (m , 1H).
    Log P (HCOOH): 2.94
    1- [4- (4- {5- [2- (aIi! Oxy) -6-chlorophenyl] -4,5-dihydro-1,2-oxazol-3-yl} -1,3-thiazol-2- il) piperidin-1yl] -2- [3,5-bis (difluormethyl) -1 H-pyrazol-1-yljetanone (1-51)
    To a solution of 2- [3,5-bis (difluormethyl) -1 H-pyrazol-1-yl] -1- (4- {4- [5- (2-chloro-6-hydroxyphenyl) -4,5- dihydro-1,2-oxazol-3-yl-1,3-thiazol-2-yl} piperidin-1-yl) ethanone (39 mg) and potassium carbonate (47 mg) in acetone (5 ml) allyl bromide (33 mg) at room temperature. The reaction mixture is stirred for 5 hours at reflux. Then, the mixture is mixed with water and extracted with acetic ester. The combined organic phases are dried over sodium sulfate and concentrated. After column chromatographic purification, 1- [4- (4- {5- [2- (allyloxy) -6-chlorophenyl] -4,5-dihydro-1,2-oxazol-3-yl} - 1,3-thiazol-2yl) piperidin-1-yl] -2- [3,5-bis (difluormethyl) -1 H-pyrazol-1-yljetanone (26 mg).
    2- [3,5-bis (difluormethyl) -1 H-pyrazol-1-yl] -1 - [4- (4- {5- [2-chloro-6- (prop-2-in-1-yloxy ) phenyl] -4,5dihydro-1,2-oxazol-3-yl} -1,3-thiazol-2-yl) piperidin-1-yljetanone (i-49)
    To a solution of 2- [3,5-bis (difluormethyl) -1 H-pyrazol-1-yl] -1- (4- {4- [5- (2-chloro-6-hydroxy77 / 108 phenyl) - 4,5-dihydro-1,2-oxazol-3-yl] -1,3-thiazol-2-yl} piperidin-1-yl) ethanone (33 mg) and potassium carbonate (12 mg) in Ν, Ν -dimethylformamide (5 ml) potassium iodide (5 mg) and 3-bromoprop-1 -ine (11 mg) are added at room temperature. The reaction mixture is stirred at 80 ° C for 9 hours. Then, the mixture is mixed with dilute hydrochloric acid and extracted with acetic ester. The combined organic phases are dried over sodium sulfate and concentrated. After column chromatographic purification, 2- [3,5bis (difluormethyl) -1 H-pyrazol-1-yl] -1 - [4- (4- {5- [2-chloro-6- (prop-2-in-1-yloxy) phenyl] -4,5-dihydro-1,2oxazol-3-yl} -1,3-thiazol-2-yl) piperidin-1-yl] ethanone (19 mg) .
    2- [3,5-bis (difluormethyl) -1 H-pyrazol-1-i] -1 - [4- (4- {5- [2-chloro-6- (2-methoxyethoxy) phenyl] -4,510 dihydro-1,2-oxazol-3-yl} -thiazol-2-yl} piperidin-1-yl] ethanone (I-50)
    To a solution of 2- [3,5-bis (difluormethyl) -1H-pyrazol-1-yl] -1- (4- {4- [5- (2-chloro-6-hydroxyphenyl) -4,5- dihydro-1,2-oxazol-3-yl] -1,3-thiazol-2-yl} piperidin-1-yl) ethanone (39 mg) and potassium carbonate (47 mg) in Ν, Ν-dimethylformamide (5 ml) are added 1-bromo-2-methoxyethane (38 mg) and potassium iodide (1.1 mg) at room temperature. The reaction mixture is stirred at 80 ° C for 3 hours. Then, the mixture is mixed with water and extracted with acetic ester. The combined organic phases are dried over sodium sulfate and concentrated. After column chromatographic purification, 2- [3,5bis (difluormethyl) -1 H-pyrazol-1-yl] -1 - [4- (4- {5- [2-chloro-6- ( 2-methoxyethoxy) phenyl] -4,5-dihydro-1,2oxazol-3-yl} -1,3-thiazol-2-yl) piperidin-1-yl] ethanone (17 mg).
    2- {3- [2- (1 - {[3,5-bis (difluormethyl) -1 H-pyrazol-1-i Iacetyl} piperidi n-4-yl) -1,3-thiazol-4-yl] -4,5dihydro-1,2-oxazol-5-yl} -3-fluorbenzaldehyde (1-17)
    3-fluor-2-vinylbenzaldehyde
    To a solution of 1-bromo-3-fluor-2-vinylbenzene (900 mg) in THF (40 ml) was added by dropping n-butyl lithium (3.4 ml 1.6 M / hexane) at -78 ° C. After stirring for 60 minutes at -78 ° C, the reaction mixture was mixed with water and then heated to room temperature. Then, the mixture was mixed with water and extracted with acetic ester. The combined organic phases were dried over sodium sulfate and concentrated. After column chromatographic purification, 3-fluor-2-vinyl benzaldehyde (160 mg) is obtained.
    Also in this case, the reagent 1-bromo-3-fluor-2-vinylbenzene was synthesized starting from 2-bromo-6-fluorbenzaldehyde according to current instructions for the specialist (Wittig Reaktion: Chem. Rev 1989, 89, 863-927 ).
    Process D and E tert-butyl-4- {4- [5- (2-fluor-6-formylphenyl) -4,5-dihydro-1,2-oxazol-3-yl] -1,3-thiazol-235 il} piperidin-1-carboxylate (Xa-13)
    To a solution of ferc-butyl-4- {4 - [(hydroxyimino) methyl] -1,3-thiazol-2-yl} piperidin-1carboxylate (166 mg) in ethyl acetate (10 ml) was added N -chlorosuccinimide (85.5
    78/108 mg). The reaction mixture was stirred for 30 minutes at reflux. To this reaction mixture were added 3-fluor-2-vinylbenzaldehyde (160 mg) and potassium bicarbonate (106.7 mg) at room temperature and then a drop of water. After stirring at room temperature overnight, the reaction mixture was mixed with ethyl acetate and water and extracted with ethyl acetate. The organic extracts were dried over sodium sulfate and concentrated under low pressure. The residue was purified by chromatography. Tert-butyl-4- {4- [5- (2-fluor-6-formylphenyl) -4,5-dihydro-1,2oxazol-3-yl] -1,3-thiazol-2-yl was obtained} piperidin-1-carboxylate (110 mg).
    1 H NMR (DMSO-d 6 ): 6 ppm : 10.26 (s, 1H), 8.03 (s, 1H), 7.76 (dd, 1 H), 7.68-7.64 ( m, 1H), 7.62-7.57 (m, 1H), 6.55 (t, 1H), 4.08-3.90 (m, 3H), 3.53 (dd, 1H), 3 , 40-3.30 (m, 1H), 2.05-2.00 (m, 2H), 1.62-1.52 (m, 2H), 1.40 (s, 9H), logP (HC02H ): 3.62 Process G and H
    2- {3- [2- (1 - {[3,5-bis (difluormethyl) -1 H-pyrazol-1-yl] acetyl} piperidin-4-yl) -1,3-thiazol-4-yl] -4,5dihydro-1,2-oxazol-5-yl} -3-fluorbenzaldehyde (1-17)
    To a solution of ferc-butü-4- {4- [5- (2-fluor-6-formylphenyl) -4,5-dihydro-1,2-oxazol-3-yl] 1,3-thiazol-2- il} piperidin-1-carboxylate (112 mg) in dichloromethane a 4 molar solution of hydrogen chloride (4.0 eq.) in 1,4-dioxane at 0 ° C was added dropwise. The reaction mixture was stirred at 0 ° C and then it was slowly warmed to room temperature. After stirring for 5 hours, the excess solvent and hydrogen chloride were removed. 4- {4- [5- (2-fluor-6-formylphenyl) -4,5-dihydro-1,2oxazol-3-yl] -1,3-thiazol-2-yl} piperidinium chloride ( XI1-10).
    To a solution of [3,5-bis- (difluormethyl) -1 H-pyrazol-1-yljacetic acid (58 mg) in dichloromethane (20 ml), oxalyl chloride (94.5 mg) and a drop of Ν, Ν-dimethylformamide at 0 ° C. The reaction mixture was stirred at room temperature for 2 hours. The excess solvent and reagent were removed under low pressure. The solid residue was again dissolved in dichloromethane (5 ml) and at 0 ° C, added dropwise to a solution of 4- {4- [5- (2-fluor-6-formylphenyl) -4,5dihydro-1 chloride , 2-oxazol-3-yl] -1,3-thiazol-2-yl} piperidinium in triethylamine (5.0 eq.) In dichloromethane (15 ml). The reaction mixture was stirred at room temperature overnight. Then, it is mixed with concentrated sodium bicarbonate solution, the aqueous phase is separated and extracted with ethyl ester of acetic acid. The combined organic phases were dried over sodium sulfate and concentrated. After column chromatographic purification, 2- {3- [2- (1 - {[3,5-bis (difluormethyl) -1 H-pyrazol-1 -yl] acetyl} -piperidin-4-yl) was obtained -1,3 thiazol-4-yl] -4,5-dihydro-1,2-oxazol-5-yl} -3-fluorbenzaldehyde (55 mg).
    Examples
    Table 1
    79/108
    In table 1, group G occurs particularly in specifications G3 and G4:
    G3 represents G4 represents:
    example X R 1 G R 2 R 5] R Tz llogp 1-1 0 H G3 phenyl H H 3.17, 3.11 Icl 1-2 0 H G3 2,6-difluorphenyl H H 3.14 [bJ 1-3 0 H G4 phenyl H 3.66 [b] 1-4 0 fluorine G3 2-fluorophenyl H H 3.49 [b] 1-5 0 fluorine G3 phenyl H H 3.41 [bl 1-6 0 fluorine G3 2,6-difluorphenyl H H 3.43 [b] 34 [cl 1-7 0 H G3 2-acetylphenyl H H 3.08 BL 1-8 0 H G3 3-acetylphenyl H H 2.78 fbJ 1-9 0 H G3 2-hydroxyphenyl H H 2.58 [to 6 ! C) 1-10 O H G3 2-nitrophenyl H H 3.19 [b) 1-11 0 H G3 2 - [(2-methoxyethoxy) methyl] phenyl H H 3.21 [bl 1-12 O H G3 2- [(ethylsulfanyl) methyl-phenyl H H 3.9 Ibl 1-13 0 H G3 2-[(cyclopropylmethoxy) carbonyl] phenyl H H 3.92 [0] , 399 [bl 1-14 0 H G3 2- (allyloxy) phenyl H H 3.63 [bl ; 3.65 [cl 1-15 0 H G3 3- (but-2-in-1-yloxy) phenyl H H 3.33 [ol ; 3.29 [a) 1-16 0 H G3 2- (butoxymethyl) phenyl H H 4.24 lbJ 1-17 0 H G3 2-fluor-6-formylphenyl H H 2.82 lcl ; 2.92 lbl 1-18 0 H G3 2 - [(2-methylprop-2-en-1-yl) oxy] phenyl H H 3.96 tb] ; 3.92 [cl 1-19 0 H G3 2- (2-methoxyethoxy) phenyl H H 3.18 [c] ; 3.26 [bl 1-20 0 H G3 2 - [(3-methylbut-2-en-1-yl) oxy] phenyl H H 4.19 [bl ; 4.11 lcl 1-21 0 H G3 3- (prop-2-in-1-yloxy) phenyl H H 3.16 [c] ; 3.24 [al 1-22 0 H G3 4- (prop-2-in-1-yloxy) phenyl H H 3.14 [a] ; 3.08 IC]
    80/108
    example X R 1 G eiljllilllliSlliiil R 3 lill logp 1-23 0 H G3 3-formylphenyl H H 2.78 | s | 1-24 0 H G3 2- (cyclohexylmethoxy) phenyl H H 4.9 taI ; 4.9 [c] 1-25 0 H G3 2- (pent-2-in-1-yloxy) phenyl H H 3.91 [b] 1-26 0 H G3 2-formylphenyl H H 2.98 lb] 1-27 0 H G3 2- (cyclopropylcarbamoyl) phenyl H H 2.64 [b] 1-28 0 H G3 3 - (2-methoxyethoxy) phenyl H H 3.03 [bl ; 3.04 [c] 1-29 0 H G3 2- (but-2-in-1-yloxy) -6-fluorophenyl H H 3.46 [ai ; 3.42 [cl 1-30 0 H G3 2-fluor-6- (prop-2-ín-1-yloxy) phenyl H H 3.18 [a] ; 3.15 [c] 1-31 0 H G4 2-formylphenyl H 3.25 [b) 1-32 O H G3 2 - [(cyclohexylcarbonyl) oxy] phenyl H H 4.27 [to 4.19 [c] 1-33 0 H G3 2 - [(cyclopropylcarbonyl) oxy] phenyl H H 3.28 lcl 3.34 lal 1-34 0 H G3 3- (pent-2-in-1-yloxy) phenyl H H 3.74 [cl 3.83 [al O 1-35 0 H G3 2- (but-2-in-1-ioxy) phenyl H H 3.55 [c 3.65 [aJ 1-36 O H G3 2 - [(3,3,3- H H 9.43 [a] 3.52 [c] trifluorpropanoyl) oxy] phenyl j 1-37 O H G3 2 - [(methylsulfonyl) amino] phenyl H H 2.51 [b] 1-38 0 H G3 2-ethinylphenyl H H 3.36 [b) 1-39 0 H G3 2- (prop-2-in-1-yloxy) phenyl H H 3.23 [cl ; 3.28 [a] 1-40 0 H G3 4 - [(methylsulfonyl) amino] phenyl H H 2.41 [bl 1-41 0 H G3 2-aminophenyl H H 2.71 [cl, 2.7 Ial 1-42 0 H G3 3-hydroxyphenyl H H 2.45 [cl ; 2.43 [a] 1-43 0 H G3 2- (methoxycarbonyl) phenyl H H 3.32 [bl 1-44 0 H G3 2- (chloromethyl) phenyl H H 3.36 lbl 1-45 0 H G3 2- (hydroxymethyl) phenyl H H 2.45 [b] 1-46 0 H G3 2- (methoxycarbonyl) phenyl H chlorine 3.98 [bl 1-47 0 H G3 4- (pent-2-in-1-yloxy) phenyl H H 3.74 [c] ; 3.76 la] 1-48 0 H G3 4- (but-2-in-1-yloxy) phenyl H H 3.42 [cl ; 3.43 [al 1-49 0 H G3 2-chloro-6- (prop-2-in-1-yloxy) phenyl H H 3.5 [bl ; 3.34 lcl 1-50 0 H G3 2-chloro-6- (2-methoxyethoxy) phenyl H H 3.36 [bl 1-51 0 H G3 2- (allyloxy) -6-chlorophenyl H H 3.71 l0 | ; 3.82 lb] 1-52 0 H G3 2 - [(2,2,2-trifluorethoxy) methyl] phenyl H H 3.6 [c] ; 3.4 [bl 1-53 0 H G3 2- [(ethylsulfonyl) methyl] phenyl H H 2.76 [bl 1-54 0 H G3 2-chloro-6-hydroxyphenyl H H 2.94 lbl
    The determination of the logP values was carried out in accordance with EEC Directive 79/831 Annex VA8 by means of HPLC (high performance liquid chromatography) and columns of
    81/108 reverse phase (C 18), with the following methods:
    [al The determination was made on the acidity scale at pH 2.3 with 0.1% aqueous phosphoric acid and acetonitrile as eluents; linear gradient from 10% acetonitrile to 95% acetonitrile.
    [bI The determination with LC-MS on the acidity scale was carried out at pH 2.7 with 0.1% aqueous formic acid and acetonitrile (containing 0.1% formic acid) as eluents; linear gradient from 10% acetonitrile to 95% acetonitrile.
    [c] The determination with LC-MS on the neutral scale is performed at pH 7.8 with 0.001 molar aqueous ammonium bicarbonate solution and acetonitrile as eluents; linear gradient from 10% acetonitrile to 95% acetonitrile.
    Calibration is performed with unbranched alkan-2-ones (with 3 to 16 carbon atoms), whose logP values are known (determination of logP values based on retention times by means of linear interpolation between two successive alkanones).
    Lambda-maX values were determined based on UV spectra from 200 nm to 400 nm at the maximum of the chromatographic signals.
    NMR data from selected examples
    example NMR data 1-1 1 H NMR δ ρρπι : 163 (m, 1H), 1.79 (m, 1H), 2.18-2.05 (m, 2H), 2.88 (m, 1H), 3.42-3 , 20 (m, 3H), 3.87 (dd, 1H), 3.98 (m, 1H), 4.32 (m, 1H), 5.35 (bs, 2H), 5.72 (dd, 1H), 6.85 (s, 1H), 6.97 (t, 1H), 7.14 (t, 1H), 7.40-7.30 (m, 5H), 7.97 (S.1H ) 1-2 1 H NMR ppm : 1.58 (m, 1H), 1.83 (m, 1H), 2.18-2.07 (m, 2H), 2.85 (m, 1H), 3.25 (m, 1H), 3.41 (m, 1H), 3.52 (dd, 1H), 3.90 (dd, 1H), 3.98 (m, 1H), 4.36 (m, 1H) , 5.35 (d, 1H), 5.47 (d, 1H), 6.01 (dd, 1H), 6.90 (s, 1H), 7.02 (t, 1H), 7.18 ( t, 1H), 7.19-7.12 (m, 2H), 7.50 (m, 1H), 8.03 (s, 1H) 1-3 1 H NMR ppm : 1.66 (m, 1H), 1.85 (m, 1H), 2.22-2.10 (m, 2H), 2.88 (dd, 1H), 3.50 -3.45 (m, 2H), 4.00 (d, 1H), 4.39 (d, 1H), 5.37 (d, 1H), 5.45 (d, 1H), 6.91 ( S, 1H), 7.03 (t, 1H), 7.19 (t, 1H), 7.44 (s, 1H), 7.60-7.53 (m, 3H), 7.96 (dd , 2H), 8.23 (s, 1H) 1-4 1 H NMR ppm : 2.45-2.05 (m, 4H), 3.10 (m, 1H), 3.44 (dd, 1H), 3.47 (m, 1H), 3.98 -3.90 (m, 2H), 4.28 (m, 1H), 5.40 (d, 1H), 5.51 (d, 1H), 5.94 (dd, 1H), 6.91 ( S, 1H), 7.03 (t, 1H), 7.18 (t, 1H), 7.32-7.20 (m, 2H), 7.48-7.38 (m, 2H), 8 , 24 (s, 1H) 1-5 1 H NMR: δ ppm : 2.45-2.05 (m, 4H), 3.11 (m, 1H), 3.38 (dd, 1H), 3.48 (m, 1H), 3, 95-3.86 (m, 2H), 4.26 (m, 1H), 5.39 (d, 1H), 5.50 (d, 1H), 5.76 (dd, 1H), 6.91 (s, 1H), 7.03 (t, 1H), 7.18 (t, 1H), 7.42-7.33 (m, 5H), 8.22 (s, 1H)
    82/108
    example NMR data 1-6 1 H NMR (CD 3 CN): 6 ppm : 2.50-2.10 (m, 4H), 3.18 (m, 1H), 3.55 (m, 1H), 3.59 (dd, 1H), 3.89-3.78 (m, 2H), 4.36 (m, 1H), 5.22 (d, 1H), 5.29 (d, 1H), 6.07 (dd, 1H ), 6.79 (t, 1H), 6.83 (s, 1H), 6.91 (t, 1H), 7.07-6.99 (m, 2H), 7.42 (m, 1H) , 7.88 (s, 1H)
    Chemical NMR shifts in ppm were measured at 400 MHz unless otherwise indicated in the DMSO-d 6 solvent with tetramethylsilane as an internal standard.
    The following abbreviations describe signal dissociation:
    b = broad, s = singlet, d = doublet, t = triplet, q = quadruple, m = multiplet.
    83/108 o
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    107/108
    Usage examples
    Example A
    Test with Phytophthora (tomato) / protector
    Solvent: 24.5 parts by weight, acetone
    24.5 parts by weight of dimethylformamide
    Emulsifier: 1 part by weight of alkyl-aryl-polyglycolic ether
    To produce a suitable active substance preparation, 1 part by weight of active substance is mixed with the indicated amounts of solvent and emulsifier and dilute the concentrate with water to the desired concentration.
    To test the protective effectiveness, young plants are sprayed with the preparation of the active substance in the amount of application indicated. After drying the sprayed layer, the plants are inoculated with an aqueous spore suspension of Phytophthora infestans. Then, the plants are placed in an incubation cabin at about 20 ° C and 100% relative humidity.
    Three days after inoculation, the evaluation is carried out. In this case, 0% means an efficacy, which corresponds to that of the control, while a 100% efficacy means, that no infestation is observed.
    In this test, the following compounds according to the invention show, with an active substance concentration of 10 ppm, an efficacy of 70% or more: 1-1 (95%), 1-2 (99%), 1-3 (100%), 1-5 (93%), 1-6 (94%), 1-7 (97%), 1-8 (97%), 1-9 (96%), 1-10 (97 %), 1-14 (98%), 1-15 (95%), 1-19 (96%), 1-20 (95%), 1-21 (98%), 1-22 (98%) , 1-23 (97%), 1-25 (95%), 1-26 (97%), 1-35 (88%), 1-39 (99%), 1-40 (95%), 1 -41 (94%), 1-42 (94%).
    Example B
    Test with Plasmopara (grapevine) I protector
    Solvent: 24.5 parts by weight, acetone
    24.5 parts by weight of dimethylformamide
    Emulsifier: 1 part by weight of alkyl-aryl-polyglycolic ether
    To produce a suitable active substance preparation, 1 part by weight of active substance is mixed with the indicated amounts of solvent and emulsifier and dilute the concentrate with water to the desired concentration.
    To test the protective effectiveness, young plants are sprayed with the preparation of the active substance in the amount of application indicated. After drying the sprayed layer, the plants are inoculated with an aqueous spore suspension of Plasmopara viticola and then remain for one day in an incubator at about 20 ° C and 100% relative humidity. Then, the plants are placed in the greenhouse at about 21 ° C and about 90% humidity. The plants are then moistened and placed in a hatchery for one day.
    108/108
    Six days after inoculation, the evaluation is carried out. In this case, 0% means an efficacy, which corresponds to that of the control, while a 100% efficacy means, that no infestation is observed.
    In this test, the following compounds according to the invention show, with a concentration of active substance of 10 ppm, an efficacy of 70% or more: 1-1 (100%), 1-2 (100%), 1- 3 (100%), 1-4 (100%), 1-5 (97%), 1-6 (100%), 1-7 (100%), 1-8 (99%), 1-9 ( 99%), 1-10 (100%), 1-14 (100%), 1-15 (93%), 1-19 (96%), 1-20 (98%), 1-21 (100%) ), 1-22 (97%), 1 „23 (99%), 1-25 (74%), 1-26 (100%), 1-39 (99%), 1-40 (91%), 1-41 (100%), 1-42 (97%).
    Example C «
    10 Peronospora test (rapeseed) / seed treatment
    The test was carried out in greenhouse conditions.
    To produce an active substance preparation, the active substance was dissolved in N-methyl-2-pyrrolidone and the concentrate was diluted with water to the desired concentration. The rapeseed seeds treated with this solution were sown in 6 * 6 cm pots, which were filled with a 1: 1 mixture of plowed earth treated with steam and sand at a height of 4 cm. Then, the plants were grown at 10 ° C.
    After 14 days, the plants were inoculated with an aqueous spore suspension of Peronospora brassicae. Then, the plants were placed for 7 days in the greenhouse at about 15 ° C and 100% humidity.
    The evaluation was carried out by evaluating the leaf area infested by plant. In this case,
    0% means an efficacy, which corresponds to that of the control, while a 100% efficacy means, that no infestation is observed.
    In this test, the following compounds according to the invention, with an active substance concentration of 50 g / dt, show an efficiency of 80% or more: 1-1 (100%), I-6 (100%), I -7 (100%).
    1/6
    权利要求:
    Claims (12)
    [1]
    1. Compounds, characterized by having the formula (I) in which the symbols have the following meanings: X represents oxygen, r
    G4 = I
    R 1 represents hydrogen or halogen,
    R 2 represents a phenyl, which can contain up to two substituents, in which the
    10 substituents independently of each other are selected from the following list:
    amino, halogen, cyano, hydroxyl, SH, nitro, C (= O) H, C1-C6 alkyl, C2C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C2-C6 haloalkenyl, C2-C6 haloalkyl, C3-cycloalkyl C8, halogenocycloalkyl C3-C8, alkylcycloalkyl C4-C10, cycloalkylalkyl C 4 C10, cycloalkylcycloalkyl C6-Ci 4 , halogenocycloalkylalkyl C 4 -Cw, alkylcycloalkylalkylalkyl-C8-cycloalkyl8, cycloalkyl8
    C -cis 4, alcoxialcoxialquila C3-C8 alkyl, C2-C6 alquiltioalquila, alquilsulfinilalquila C2-C6 alkyl, C2-C6 alquilsulfonilalquila, C2-C6 alkylaminoalkyl, dialkylaminoalkyl C3-C8 alkyl, C2-C6 halogenoalquilaminoalquila, cicloalquilaminoalquila -cis C 4, C 2 -C 6 alkylcarbonyl , C2-C6 haloalkylcarbonyl, C 4 -Cs cycloalkylcarbonyl, C2-C6 alkoxycarbonyl,
    20 C 4 -Cs cycloalkoxycarbonyl, C5-C10 cycloalkylalkoxycarbonyl, C2-C6 alkylaminocarbonyl, C3-C8 dialkylaminocarbonyl, C 4 -Cs, C2-C6 haloalkoxyalkyl, C1-C6, hydroxyalkyl, C1-C6, alkoxy, C1-C6, alkoxy -C8, C3-C8 halo-cycloalkoxy, C 4 -Cio cycloalkylalkoxy, C2-C6 alkenyloxy, C2C6 haloalkenyloxy, C2-C6 alkynyloxy, C2-C6 haloalkyloxy, C2-C6 alkoxyalkoxy, C2-C6-alkylcarbonyl
    25 C2-C6 haloalkylcarbonyloxy, C 4 -Cs cycloalkylcarbonyloxy, C3-C6 alkylcarbonylalkoxy, C1-C6 alkylthio, C1-C6 haloalkylthio, C3-C6 cycloalkylthio, C1-C6 alkylsulfinyl,
    Petition 870180026317, of 04/02/2018, p. 18/27
    [2]
    2/6 C1-C6 halogenoalkylsulfinyl, C1-C6 alkylsulfonyl, C1-C6 haloalkylsulfonyl, C3-C8 cycloalkylsulfonyl, tri (C1-C4 alkyl) silyl, C1-C6 alkylsulfonylamino or C1-C6-haloalkylsulfonylamino
    R 3 represents hydrogen,
    5 R Tz represents halogen or hydrogen, as well as their salts, metal complexes and agrochemically effective N-oxides. Compounds of formula (I) according to claim 1, characterized in that the symbols have the following meanings:
    X represents oxygen,
    10 R 1 represents hydrogen or fluorine,
    G represents G3 or G4,
    R 2 represents, in addition, a phenyl, which can contain up to two substituents, in which the substituents independently of each other are selected from the following list:
    amino, halogen, cyano, hydroxyl, SH, nitro, C (= O) H, C1-C6 alkyl, C2-C6 alkenyl, 15 C2-C6 alkynyl, C1-C6 haloalkyl, C2-C6 halogenoalkenyl, C2-C6 halogenoalkyl, C3-C8 cycloalkyl, C3-C8 halogenocycloalkyl, C4-C10 alkylcycloalkyl, C4C10 cycloalkylalkyl, C6-C14 cycloalkylalkyl-C4-C10 halo, cycloalkyl-C3-cycloalkyl, C6-C10alkyl, C8-cycloalkyl, C8-cycloalkyl , C3-C8 alkoxyalkoxyalkyl, C2-C6 alkylthioalkyl, C2-C6 alkylsulfinylalkyl,
    20 C2-C6 alkylsulfonylalkyl, C2-C6 alkylaminoalkyl, C3-C8 dialkylaminoalkyl, C2-C6 haloalkylaminoalkyl, C4-C10 alkylalkyl, C2-C6 alkylcarbonyl, C8-alkylcarbonyl, C2-C6-cycloalkylcarbonyl, cycloalkylcarbonyl , C5-C10 cycloalkylalkoxycarbonyl, C2-C6 alkylaminocarbonyl, C3-C8 dialkylaminocarbonyl, C4-C8 cycloalkylaminocarbonyl, C2-C6 haloalkoxyalkyl,
    25 C1-C6 hydroxyalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C8 cycloalkoxy, C3-C8 halogenocycloalkoxy, C4-C10 cycloalkylalkoxy, C2-C6 alkenyloxy C2C6-alkoxy, C2 -6alkyl, alkoxy C2-C6, C2-C6 alkylcarbonyloxy, C2-C6 haloalkylcarbonyloxy, C4-C8 cycloalkylcarbonyloxy, C3-C6 alkylcarbonylalkoxy, C1-C6 alkylthio, C1-C6 haloalkyl, C1-C6-alkyl, C1-6 alkyl
    30 C1-C6 haloalkylsulfinyl, C1-C6 alkylsulfonyl, C1-C6 haloalkylsulfonyl, C3-C8 cycloalkylsulfonyl, tri (C1-C4 alkyl) silyl, C1-C6 alkylsulfonylamino or C1-C6-haloalkylsulfonylamino
    R 3 represents hydrogen, as well as its salts, metal complexes and agrochemically effective N-oxides.
    Compounds of formula (I) according to claim 1 or 2, characterized in that the symbols have the following meanings:
    G represents G3 or G4 and especially G3,
    Petition 870180026317, of 04/02/2018, p. 19/27
    [3]
    3/6 as well as its salts, metal complexes and agrochemically effective N-oxides.
    [4]
    Compounds of formula (I) according to any one of claims 1 to 3, characterized in that the symbols have the following meanings:
    R 2 represents a phenyl, which can contain up to two substituents, where the 5 substituents independently of each other are selected from the following list:
    amino, halogen, cyano, nitro, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 halogenoalkyl, C2-C6 halogenoalkyl, C2-C6 halogenoalkyl, C3-C8 cycloalkyl, C3-alkyl8 alkyl -C6, C2-C6 alkylcarbonyl, C2-C6 haloalkylcarbonyl, C2-C6 alkoxycarbonyl, C1-C6 alkoxy, C1-C6 haloalkoxy,
    10 C3-C8 cycloalkoxy, C3-C8 halogenocycloalkoxy, C2-C6 alkenyloxy, C2-C6 alkynyloxy, C2-C6 alkoxyalkyl, C1-C6 alkylthio, C1-C6 haloalkylthioalkyl, C1-haloalkylsulfinyl, haloalkyl6 C1-C6, phenyl, as well as their salts, metal complexes and N-oxides agrochemically effective.
    [5]
    Compounds of formula (I) according to claim 4, characterized
    15 by
    R 2 represents phenyl, 2-fluorophenyl, 2,6-difluorphenyl, 2-acetylphenyl, 3-acetylphenyl, 2-hydroxyphenyl, 2-nitrophenyl, 2 - [(2-methoxyethoxy) methyl] phenyl, 2 - [(ethylsulfanyl) methyl] phenyl , 2 [(cyclopropylmethoxy) carbonyl] phenyl, 2- (allyloxy) phenyl, 3- (but-2-in-1-yloxy) phenyl, 2 (butoxymethyl) phenyl, 2-fluor-6-formylphenyl, 2 - [( methylprop-2-en-1-yl) oxy] phenyl, 2- (220 methoxyethoxy) phenyl, 2 - [(3-methylbut-2-en-1-yl) oxy] phenyl, 3- (prop-2-in -1-yloxy) phenyl, 4- (prop-2-in-1yloxy) phenyl, 3-formylphenyl, 2- (cyclohexylmethoxy) phenyl, 2- (pent-2-in-1-yloxy) phenyl, 2-formylphenyl, 2- (cyclopropylcarbamoyl) phenyl, 2- (but-2-in-1-yloxy) -6-fluorphenyl, 2-fluor-6- (prop-2-in-1yloxy) phenyl, 2 - [(cyclohexylcarbonyl) oxy] phenyl, 2 - [(cyclopropylcarbonyl) oxy] phenyl, 3- (pent-2-in-1-yloxy) phenyl, 2- (but-2-in-1-yloxy) phenyl, 2 - [(3,3,3- trifluorpropanoyl) oxy] phenyl, 225 [(methylsulfonyl) amino] phenyl, 2-ethynylphenyl, 2- (prop-2-in-1-yloxy) phenyl, 4 [(methylsulfonyl) amino] phenyl, 2-aminophenyl, 3-hydroxyphenyl , 2- (methoxycarbonyl) phenyl, 2 (chloromethyl) phenyl, 4- (pent-2-in-1-yloxy) phenyl, 4- (but-2-in-1-yloxy) phenyl, 2-chloro-6- (prop-2-in-1yloxy ) phenyl, 2-chloro-6- (2-methoxyethoxy) phenyl, 2- (allyloxy) -6-chlorophenyl, 2 - [(2,2,2trifluorethoxy) methyl] phenyl, 2 - [(ethylsulfonyl) methyl] phenyl or 2- (hydroxymethyl) phenyl,
    30 as well as its salts, metal complexes and agrochemically effective N-oxides.
    [6]
    Compounds of formula (I) according to any one of claims 1 to 5, characterized by
    R Tz represent hydrogen, as well as its salts, metal complexes and N-oxides agrochemically effective.
    35
    [7]
    7. Process for combating harmful phytopathogenic fungi, characterized by applying compounds of formula (I) as defined in any one of claims 1 to 6, on harmful phytopathogenic fungi and / or their habitat.
    Petition 870180026317, of 04/02/2018, p. 20/27
    Λ / Q
    [8]
    8. Agent for combating harmful phytopathogenic fungi, characterized by a content of at least one compound of the formula (I) as defined in any one of claims 1 to 6, in addition to diluents and / or surfactants.
    [9]
    9. Use of bis (difluormethyl) pyrazole derivatives of formula (I) as defined in any one of claims 1 to 6, characterized in that it is used to combat harmful phytopathogenic fungi.
    [10]
    10. Process for the production of agents to combat harmful phytopathogenic fungi, characterized by mixing bis (difluormethyl) pyrazole derivatives of formula (I) as defined in any one of claims 1 to 6 with diluents and / or surfactants.
    [11]
    11. Use of compounds of formula (I) as defined in any one of claims 1 to 6, characterized in that they are used to treat transgenic plants.
    [12]
    Process for preparing the compounds of formula (I) as defined in any one of claims 1 to 6, characterized in that it comprises at least one of the following steps (E) to (H) and (J):
    step (E): cicloaddition of a compound of the general formula (VIII) with a compound of the general formula (IX) to give compounds of the formula (Xa) or (Ia) in the presence of a base and optionally in the presence of a solvent according with the following reaction scheme (scheme 5):
    R
    R 3 (ix)
    Base (X-a) or (Ia)
    W 1 represents acetyl, C1-C4 alkoxycarbonyl, benzyl, benzyloxycarbonyl or [3,5bis (difluormethyl) -1H-pyrazol-1-yl] acetyl, the radicals R 1 , R 2 , R 3 have the same meaning as that of the radicals R 1 , R 2 , R 3 defined in the preceding claims for formula (I), step (F): cycloaddition of a compound of the general formula (VIII) with a compound of the general formula (XI) to give compounds of the formula (Xb) or (Ia) in the presence of a base and optionally in the presence of a solvent according to the following reaction scheme (scheme 6):
    Petition 870180026317, of 04/02/2018, p. 21/27
    5/6
    W 1 represents acetyl, C1-C4 alkoxycarbonyl, benzyl, benzyloxycarbonyl or [3,5bis (difluormethyl) -1 H-pyrazol-1-yl] acetyl, the radicals R 1 , R 2 have the same meaning as that of the radicals R 1 , R 2 in the preceding claims for formula (I);
    5 step (G): removal of the protecting group from the compounds of the general formula (X) to obtain the compounds of the general formula (XII) according to the following reaction scheme (scheme 7):
    W 1 —N
    R Protective group dissociation
    H-N
    R S (XII) (X)
    W 1a represents acetyl, C1-C4 alkoxycarbonyl, benzyl or benzyloxycarbonyl, the 10 radicals R 1 , G have the same meaning as that of the radicals R 1 , G defined in the preceding claims for formula (I);
    step (H): coupling reaction of the compounds of the general formula (XII) with a substrate of the general formula (XIII) to obtain the compounds of the general formula (Ia) according to the following reaction scheme (scheme 8):
    W 2 represents chlorine or OH,
    X a represents oxygen, the radicals R 1 , G have the same meaning as that of the radicals R 1 , G defined in the preceding claims for formula (I);
    step (J): halogenation of the compounds of the general formula (X-a) or (l-a) to obtain the compounds of the general formula (X-d) or (l-d) according to the following reaction scheme (scheme 10):
    Petition 870180026317, of 04/02/2018, p. 22/27
    6/6
    W 1 —Ν / N
    R 1 s (Xa) or (Ia) halogenating reagent
    W 1 represents acetyl, C1-C4 alkoxycarbonyl, benzyl, benzyloxycarbonyl or [3,5bis (difluormethyl) -1 H-pyrazol-1-yl] acetyl,
    R TZ stands for halogen
    5 the radicals R 1 , G have the same meaning as that of the radicals R 1 , G defined in the preceding claims for formula (I).
    Petition 870180026317, of 04/02/2018, p. 23/27
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    同族专利:
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    法律状态:
    2018-01-02| B07A| Technical examination (opinion): publication of technical examination (opinion)|
    2018-02-27| B15K| Others concerning applications: alteration of classification|Ipc: C07D 417/04 (2006.01), C07D 417/14 (2006.01), A01N |
    2018-04-17| B09A| Decision: intention to grant|
    2018-07-03| B16A| Patent or certificate of addition of invention granted|
    优先权:
    申请号 | 申请日 | 专利标题
    US28848409P| true| 2009-12-21|2009-12-21|
    EP09180073.0|2009-12-21|
    US61/288,484|2009-12-21|
    EP09180073|2009-12-21|
    PCT/EP2010/070156|WO2011076699A1|2009-12-21|2010-12-17|Bispyrazoles used as fungicides|
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