Patent Application
20160007606
The present invention relates to microbiocidal pyrazole derivatives, e.g. as active ingredients, which have microbiocidal activity, in particular fungicidal activity. The invention also relates to preparation of these pyrazole derivatives, to pyrazole derivatives used as intermediates in the preparation of these pyrazole derivatives, to preparation of these intermediates, to agrochemical compositions which comprise at least one of the pyrazole derivatives, to preparation of these compositions and to use of the pyrazole derivatives or compositions in agriculture or horticulture for controlling or preventing infestation of plants, harvested food crops, seeds or non-living materials by phytopathogenic microorganisms, preferably fungi.
Certain compounds for use as fungicides are described in WO 2007/014290, WO 2008/013622, WO 2008/013925, WO 2008/091580, WO 2008/091594 and WO 2009/055514.
The present invention provides compounds of formula I:
wherein,
G1 and G2 are independently O or S;
Y1 and Y2 are independently CR11 or N;
n is 1 or 2;
p is 1 or 2, providing that when n is 2, p is 1;
R1 and R2 each independently are C1-C4alkyl, C3-C5cycloalkyl or C1-C4haloalkyl;
R3, R4, R5, R6, R7 and R8 each independently are hydrogen, C1-C4alkylcarbonyl, C3-C5cycloalkylcarbonyl, C1-C4haloalkylcarbonyl, carboxyl, C1-C4alkoxycarbonyl, C3-C5cycloalkoxycarbonyl, C1-C4haloalkoxycarbonyl, aminocarbonyl, (C1-C4alkyl)aminocarbonyl, (C3-C5cycloalkyl)aminocarbonyl, (C1-C4haloalkyl)aminocarbonyl, (C1-C4alkyl)2aminocarbonyl, (C3-C5cycloalkyl)2aminocarbonyl or (C1-C4haloalkyl)2aminocarbonyl, providing that at least one of R3, R4, R5, R6, R7 or R8 is C1-C4alkylcarbonyl, C3-C5cycloalkylcarbonyl, C1-C4haloalkylcarbonyl, carboxyl, C1-C4alkoxycarbonyl, C3-C5cycloalkoxycarbonyl, C1-C4haloalkoxycarbonyl, aminocarbonyl, (C1-C4alkyl)aminocarbonyl, (C3-C5cycloalkyl)aminocarbonyl, (C1-C4haloalkyl)aminocarbonyl, (C1-C4alkyl)2aminocarbonyl, (C3-C5cycloalkyl)2aminocarbonyl or (C1-C4haloalkyl)2aminocarbonyl;
R9 is C(═O)—OR12, C(═O)—NR12R13 or a 4- to 15-membered mono-, bi- or tricyclic, saturated, partially unsaturated or aromatic heterocyclic ringsystem optionally substituted by one or more R14;
R10 is hydrogen, halogen or hydroxyl;
R11 is hydrogen, halogen or cyano;
R12 is arylalkyl, heteroarylalkyl or a 4- to 11-membered mono- or bicyclic, saturated, partially unsaturated or aromatic carbocyclic ringsystem, wherein the arylalkyl, heteroarylalkyl and 4- to 11-membered carbocyclic ringsystem are optionally substituted by one or more R14;
R13 is hydrogen, C1-C4alkyl, C3-C5cycloalkyl or C1-C4alkoxy;
each R14 independently is halogen, cyano, amino, nitro, hydroxyl, mercapto, C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C3-C8cycloalkyl, C3-C8cycloalkyl-C1-C4alkyl, C3-C8cycloalkyl-C1-C4alkoxy, C3-C8cycloalkyl-C1-C4alkylthio, C1-C8alkoxy, C3-C8cycloalkoxy, C1-C8alkenyloxy, C2-C8alkynyloxy, C1-C8alkylthio, C1-C8alkylsulfonyl, C1-C8alkylsulfinyl, C3-C8cycloalkylthio, C3-C8cycloalkylsulfonyl, C3-C8cycloalkylsulfinyl, aryl, aryloxy, arylthio, arylsulfonyl, arylsulfinyl, aryl-C1-C4alkyl, aryl-C1-C4alkoxy, aryl-C1-C4alkylthio, heterocyclyl, heterocycyl-C1-C4alkyl, heterocycyl-C1-C4alkoxy, heterocycyl-C1-C4alkylthio, NH(C1-C8alkyl), N(C1-C8alkyl)2, C1-C4alkylcarbonyl, C3-C8cycloalkylcarbonyl, C2-C8alkenylcarbonyl, C2-C8alkynylcarbonyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, alkenyloxy, alkynyloxy and cycloalkoxy are optionally substituted by halogen, and wherein aryl and heterocyclyl are optionally substituted by one or more R15; and
each R15 independently is halogen, cyano, C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy or C1-C4haloalkoxy; or a salt or a N-oxide thereof.
For the avoidance of doubt, by the expression “providing that at least one of R3, R4, R5, R6, R7 or R8 is C1-C4alkylcarbonyl, C3-C5cycloalkylcarbonyl, C1-C4haloalkylcarbonyl, carboxyl, C1-C4alkoxycarbonyl, C3-C5cycloalkoxycarbonyl, C1-C4haloalkoxycarbonyl, aminocarbonyl, (C1-C4alkyl)aminocarbonyl, (C3-C5cycloalkyl)aminocarbonyl, (C1-C4haloalkyl)aminocarbonyl, (C1-C4alkyl)2aminocarbonyl, (C3-C5cycloalkyl)2aminocarbonyl or (C1-C4haloalkyl)2aminocarbonyl”, it is intended herein that at least one of R3, R4, R5, R6, R7 or R8 is not hydrogen.
Where substituents are indicated as being optionally substituted, this means that they may or may not carry one or more identical or different substituents, e.g. one to five substituents, e.g. one to three substituents. Normally not more than three such optional substituents are present at the same time. Where a group is indicated as being substituted, e.g. alkyl, unless stated otherwise this includes those groups that are part of other groups, e.g. the alkyl in alkylthio.
The term “halogen” refers to fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or bromine.
Alkyl substituents may be straight-chained or branched. Alkyl on its own or as part of another substituent is, depending upon the number of carbon atoms mentioned, for example, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl and the isomers thereof, for example, iso-propyl, iso-butyl, sec-butyl, tert-butyl, iso-amyl or pivaloyl.
Alkenyl substituents can be in the form of straight or branched chains, and the alkenyl moieties, where appropriate, can be of either the (E)- or (Z)-configuration. Examples are vinyl and allyl. The alkenyl groups are preferably C2-C6, more preferably C2-C4 and most preferably C2-C3 alkenyl groups.
Alkynyl substituents can be in the form of straight or branched chains. Examples are ethynyl and propargyl. The alkynyl groups are preferably C2-C6, more preferably C2-C4 and most preferably C2-C3 alkynyl groups.
Haloalkyl groups may contain one or more identical or different halogen atoms and, for example, may stand for CH2Cl, CHCl2, CCI3, CH2F, CHF2, CF3, CF3CH2, CH3CF2, CF3CF2 or CCl3CCl2.
Haloalkenyl groups are alkenyl groups, respectively, which are substituted with one or more of the same or different halogen atoms and are, for example, 2,2-difluorovinyl or 1,2-dichloro-2-fluoro-vinyl.
Haloalkynyl groups are alkynyl groups, respectively, which are substituted with one or more of the same or different halogen atoms and are, for example, 1-chloro-prop-2-ynyl.
Alkoxy means a radical —OR, where R is alkyl, e.g. as defined above. Alkoxy groups include, but are not limited to, methoxy, ethoxy, 1-methylethoxy, propoxy, butoxy, 1-methylpropoxy and 2-methylpropoxy.
Cyano means a —CN group.
Amino means an NH2 group.
Hydroxyl or hydroxy stands for a —OH group.
Aryl means a ring system which may be mono-, bi- or tricyclic. Examples of such rings include phenyl, naphthalenyl, anthracenyl, indenyl or phenanthrenyl. A preferred aryl group is phenyl.
Heteroaryl stands for aromatic ring systems comprising mono-, bi- or tricyclic systems wherein at least one oxygen, nitrogen or sulfur atom is present as a ring member. Monocyclic and bicyclic aromatic ring systems are preferred, monocyclic ring systems are more preferred. For example, monocyclic heteoraryl may be a 5- to 7-membered aromatic ring containing one to three heteroatoms selected from oxygen, nitrogen and sulfur, more preferably selected from nitrogen and sulfur. Bicyclic heteroaryl may be a 9- to 11-membered bicyclic ring containing one to five heteroatoms, preferably one to three heteroatoms, selected from oxygen, nitrogen and sulfur. Examples are furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, tetrazinyl, indolyl, benzothiophenyl, benzofuranyl, benzimidazolyl, indazolyl, benzotriazolyl, benzothiazolyl, benzoxazolyl, imiazothiazoyl, quinolinyl, quinoxalinyl, isoquinolinyl, phthalazinyl, quinoxalinyl, quinazolinyl, cinnolinyl and naphthyridinyl, preferably pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, furanyl, thienyl thiazolyl or thiadiazolyl. Heteroaryl rings do not contain adjacent oxygen ring atoms, adjacent sulfur ring atoms or adjacent oxygen and sulfur ring atoms. A link to a heteroaryl group can be via a carbon atom or via a nitrogen atom.
Heterocyclyl is defined to include heteroaryl and in addition their saturated or partially unsaturated analogues. The different rings of bi- or tricyclic heterocyclic ring systems may be linked via one atom belonging to two different rings (spiro), via two adjacent ring atoms belonging to two different rings (annelated) or via two different, not adjacent ring atoms belonging to two different rings (bridged).
The presence of one or more possible asymmetric carbon atoms in a compound of formula I means that the compounds may occur in optically isomeric forms, i.e. enantiomeric or diastereomeric forms. Also atropisomers may occur as a result of restricted rotation about a single bond. Formula I is intended to include all those possible isomeric forms and mixtures thereof. The present invention includes all those possible isomeric forms and mixtures thereof for a compound of formula I. Likewise, formula I is intended to include all possible tautomers. The present invention includes all possible tautomeric forms for a compound of formula I.
In each case, the compounds of formula I according to the invention are in free form, in oxidized form as a N-oxide or in salt form, e.g. an agronomically usable salt form.
N-oxides are oxidized forms of tertiary amines or oxidized forms of nitrogen containing heteroaromatic compounds. They are described for instance in the book “Heterocyclic N-oxides” by A. Albini and S. Pietra, CRC Press, Boca Raton 1991.
The following list provides definitions, including preferred definitions, for substituents G1, G2, T, Y1, Y2, n, p, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14 and R15 with reference to compounds of formula I and other compounds of the invention carrying the same substituents. For any one of these substituents, any of the definitions given below may be combined with any definition of any other substituent given below or elsewhere in this document.
G1 and G2 are independently 0 or S.
G1 is preferably O.
G2 is preferably S.
T is CR10 or N, preferably CH or N, more preferably CH.
Y1 and Y2 are independently CR11 or N.
Y1 is preferably CH or N, more preferably N.
Y2 is preferably CH or N; more preferably CH.
n is 1 or 2, preferably 2.
p is 1 or 2, providing that when n is 2, p is 1, preferably p is 1.
R1 and R2 each independently are C1-C4alkyl, C3-C5cycloalkyl or C1-C4haloalkyl. Preferably R1 and R2 are each independently methyl or halomethyl, more preferably methyl, difluoromethyl or trifluoromethyl.
Preferably R1 is difluoromethyl or trifluoromethyl. Preferably R2 is methyl or difluoromethyl. In one group of compounds R1 is trifluoromethyl and R2 is methyl. In another group of compounds R1 and R2 are both difluoromethyl.
R3, R4, R5, R6, R7 and R8 each independently are hydrogen, C1-C4alkylcarbonyl, C3-C5cycloalkylcarbonyl, C1-C4haloalkylcarbonyl, carboxyl, C1-C4alkoxycarbonyl, C3-C5cycloalkoxycarbonyl, C1-C4haloalkoxycarbonyl, aminocarbonyl, (C1-C4alkyl)aminocarbonyl, (C3-C5cycloalkyl)aminocarbonyl, (C1-C4haloalkyl)aminocarbonyl, (C1-C4alkyl)2aminocarbonyl, (C3-C5cycloalkyl)2aminocarbonyl or (C1-C4haloalkyl)2aminocarbonyl, providing that at least one of R3, R4, R5, R6, R7 or R8 is C1-C4alkylcarbonyl, C3-C5cycloalkylcarbonyl, C1-C4haloalkylcarbonyl, carboxyl, C1-C4alkoxycarbonyl, C3-C5cycloalkoxycarbonyl, C1-C4haloalkoxycarbonyl, aminocarbonyl, (C1-C4alkyl)aminocarbonyl, (C3-C5cycloalkyl)aminocarbonyl, (C1-C4haloalkyl)aminocarbonyl, (C1-C4alkyl)2aminocarbonyl, (C3-C5cycloalkyl)2aminocarbonyl or (C1-C4haloalkyl)2aminocarbonyl.
Preferably one of R3 and R5 is carboxyl, C1-C4alkoxycarbonyl, C1-C4haloalkoxycarbonyl, aminocarbonyl, (C1-C4alkyl)aminocarbonyl, (C1-C4haloalkyl)aminocarbonyl, (C1-C4alkyl)2aminocarbonyl or (C1-C4haloalkyl)2aminocarbonyl and R4, R6, R7 and R8 are hydrogen;
More preferably one of R3 and R5 is carboxyl, C1-C4alkoxycarbonyl, aminocarbonyl, (C1-C4alkyl)aminocarbonyl, (C1-C4alkyl)2aminocarbonyl and R4, R6, R7 and R8 are hydrogen.
Even more preferably, one of R3 and R5 is carboxyl or C1-C4alkoxycarbonyl and R4, R6, R7 and R8 are hydrogen.
R9 is C(═O)—OR12, C(═O)—NR12R13 or a 4- to 15-membered mono-, bi- or tricyclic, saturated, partially unsaturated or aromatic heterocyclic ringsystem optionally substituted by one or more R14. Preferably R9 is C(═O)—NR12R13 or a 5-membered heterocyclic ringsystem optionally substituted by one or more R14. More preferably R9 is C(═O)—NR12R13 or a isoxazoline optionally substituted by one or more R14.
R10 is hydrogen, halogen or hydroxyl; preferably hydrogen, fluoro or hydroxyl, more preferably hydrogen.
R11 is hydrogen, halogen or cyano; preferably hydrogen or cyano, more preferably hydrogen.
R12 is arylalkyl, heteroarylalkyl or a 4- to 11-membered mono- or bicyclic, saturated, partially unsaturated or aromatic carbocyclic ringsystem, wherein the arylalkyl, heteroarylalkyl and 4- to 11-membered carbocyclic ringsystem are optionally substituted by one or more R14. Preferably R12 is arylalkyl or a 9- to 10-membered bicyclic carbocyclic ringsystem, wherein the arylalkyl and 9- to 10-membered bicyclic carbocyclic ringsystem are optionally substituted by one or more R14. More preferably R12 is benzyl or a 10-membered bicyclic carbocyclic ringsystem, wherein the benzyl and 10-membered bicyclic carbocyclic ringsystem are optionally substituted by one or more R14.
R13 is hydrogen, C1-C4alkyl, C3-C5cycloalkyl or C1-C4alkoxy. Preferably R13 is hydrogen or C1-C4alkyl. More preferably R13 is hydrogen or methyl.
Each R14 is independently, halogen, cyano, amino, nitro, hydroxyl, mercapto, C1-C8 alkyl, C2-C8alkenyl, C2-C8alkynyl, C3-C8cycloalkyl, C3-C8cycloalkyl-C1-C4alkyl, C3-C8cycloalkyl-C1-C4alkyloxy, C3-C8cycloalkyl-C1-C4alkylthio, C1-C8alkoxy, C3-C8cycloalkyloxy, C2-C8alkenyloxy, C2-C8alkynyloxy, C1-C8alkylthio, C1-C8alkylsulfonyl, C1-C8alkylsulfinyl, C3-C8cycloalkylthio, C3-C8cycloalkylsulfonyl, C3-C8cycloalkylsulfinyl, aryl, aryloxy, arylthio, arylsulfonyl, arylsulfinyl, aryl-C1-C4alkyl, aryl-C1-C4alkoxy, aryl-C1-C8alkylthio, heterocyclyl, heterocycyl-C1-C4alkyl, heterocycyl-C1-C4alkoxy, heterocycyl-C1-C4alkylthio, NH(C1-C8alkyl), N(C1-C8alkyl)2, C1-C4alkylcarbonyl, C3-C8cycloalkylcarbonyl, C2-C8alkenylcarbonyl, C2-C8alkynylcarbonyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, alkenyloxy, alkynyloxy and cycloalkoxy are optionally substituted by halogen, and wherein the aryl and heterocyclyl are optionally substituted by one or more R15.
Preferably each R14 independently is halogen, cyano, amino, nitro, hydroxyl, mercapto, C1-C8 alkyl, C2-C8alkenyl, C2-C8alkynyl, C3-C8cycloalkyl, C3-C8cycloalkyl-C1-C4alkyl, C3-C8cycloalkyl-C1-C4alkylthio, C1-C8alkoxy, C3-C8cycloalkoxy, C2-C8alkenyloxy, C2-C8alkynyloxy, C1-C8alkylthio, C1-C8alkylsulfonyl, C1-C8alkylsulfinyl, C3-C8cycloalkylthio, C3-C8cycloalkylsulfonyl, C3-C8cycloalkylsulfinyl, phenyl, phenyloxy, phenylthio, phenylsulfonyl, phenylsulfinyl, phenyl-C1-C4alkyl, phenyl-C1-C4alkyloxy, phenyl-C1-C4alkylthio, heterocyclyl, heterocycyl-C1-C4alkyl, heterocycyl-C1-C4alkyloxy, heterocycyl-C1-C4alkylthio, NH(C1-C8alkyl), N(C1-C8alkyl)2, C1-C4alkylcarbonyl, C3-C8cycloalkylcarbonyl, C2-C8alkenylcarbonyl, C2-C8alkynylcarbonyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, alkenyloxy, alkynyloxy and cycloalkoxy are optionally substituted by halogen, and wherein aryl and heterocyclyl are optionally substituted by one or more R15; and wherein heterocyclyl is independently selected from pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, furanyl, thienyl, thiazolyl, thiadiazolyl, pyrrolidinyl, piperazinyl, piperidinyl, morpholinyl, and tetrahydropyranyl.
More preferably each R14 independently is halogen, cyano, amino, mercapto, C1-C8alkyl, C3-C8cycloalkyl, C3-C8cycloalkyl-C1-C4alkyloxy, C3-C8cycloalkyl-C1-C4alkylthio, C1-C8alkoxy, C1-C8alkylthio, phenyl, phenyloxy, phenylthio, phenyl-C1-C4alkoxy, phenyl-C1-C4alkylthio, heterocyclyl, heterocyclyl-C1-C4alkoxy, heterocyclyl-C1-C4alkylthio, NH(C1-C8alkyl), N(C1-C8alkyl)2, and wherein heterocyclyl is indepedendently selected from pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, furanyl, thienyl, thiazolyl, thiadiazolyl, pyrrolidinyl, piperazinyl, piperidinyl, morpholinyl, and tetrahydroyranyl, and wherein alkyl, cycloalkyl and alkoxy are optionally substituted by halogen, and wherein aryl and heterocyclyl moieties are optionally substituted by one or more R15.
Even more preferably each R14 independently is halogen, cyano, amino, mercapto, C1-C4alkyl, C3-C6cycloalkyl, C3-C6cycloalkyl-C1-C4alkylthio, C1-C4alkoxy, C1-C4alkylthio, phenyl and phenyloxy, and wherein alkyl, cycloalkyl and alkoxy are optionally substituted by halogen, and wherein phenyl is optionally substituted by one or more R15.
Each R15 is independently halogen, cyano, C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy or C1-C4haloalkoxy, preferably each R15 independently is halogen, cyano, methyl, halomethyl, methoxy or halomethoxy, more preferably each R15 independently is halogen, methyl or halomethyl.
The compound of the invention may be a compound of formula I-a
wherein Z is selected from Z-1 to Z-12
and G1, G2, T, Y1, Y2, n, p, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14 and R15 are as defined for formula I. The preferred substituent definitions are the same as for compounds of formula I. Preferably Z is selected from Z-1, Z-4, Z-8, Z-10 and Z-12.
Preferably, in compounds according to formula I-a, R14 and R15 are independently C1-C4alkyl, C1-C4haloalkyl or halogen.
In one group of compounds of the invention G1 and G2 are independently O or S; T is CR10 or N; Y1 is N; Y2 is CR11 or N; n is 1 or 2; p is 1; R1 and R2 each independently are C1-C4alkyl, C3-C5cycloalkyl or C1-C4haloalkyl; one of R3 and R5 is carboxyl, C1-C4alkoxycarbonyl, C1-C4haloalkoxycarbonyl, aminocarbonyl, (C1-C4alkyl)aminocarbonyl, (C1-C4haloalkyl)aminocarbonyl, (C1-C4alkyl)2aminocarbonyl or (C1-C4haloalkyl)2aminocarbonyl; R4, R6, R7 and R8 are hydrogen; R9 is C(═O)—OR12, C(═O)—NR12R13 or a 4- to 15-membered mono-, bi- or tricyclic, saturated, partially unsaturated or aromatic heterocyclic ringsystem optionally substituted by one or more R14; R10 is hydrogen, halogen or hydroxyl; R11 is hydrogen, halogen or cyano; R12 is arylalkyl, heteroarylalkyl or a 4- to 11-membered mono- or bicyclic, saturated, partially unsaturated or aromatic carbocyclic ringsystem, wherein the arylalkyl, heteroarylalkyl and 4- to 11-membered carbocyclic ringsystem are optionally substituted by one or more R14; R13 is hydrogen, C1-C4alkyl, C3-C5cycloalkyl or C1-C4alkoxy; each R14 independently is halogen, cyano, amino, nitro, hydroxyl, mercapto, C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C3-C8cycloalkyl, C3-C8cycloalkyl-C1-C4alkyl, C3-C8cycloalkyl-C1-C4alkoxy, C3-C8cycloalkyl-C1-C4alkylthio, C1-C8alkoxy, C3-C8cycloalkoxy, C1-C8alkenyloxy, C2-C8alkynyloxy, C1-C8alkylthio, C1-C8alkylsulfonyl, C3-C8cycloalkylthio, C3-C8cycloalkylsulfonyl, C3-C8cycloalkylsulfinyl, aryl, aryloxy, arylthio, arylsulfonyl, arylsulfinyl, aryl-C1-C4alkyl, aryl-C1-C4alkoxy, aryl-C1-C4alkylthio, heterocyclyl, heterocycyl-C1-C4alkyl, heterocycyl-C1-C4alkoxy, heterocycyl-C1-C4alkylthio, NH(C1-C8alkyl), N(C1-C8alkyl)2, C1-C4alkylcarbonyl, C3-C8cycloalkylcarbonyl, C2-C8alkenylcarbonyl, C2-C8alkynylcarbonyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, alkenyloxy, alkynyloxy and cycloalkoxy are optionally substituted by halogen, and wherein aryl and heterocyclyl are optionally substituted by one or more R15; and
each R15 independently is halogen, cyano, C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy or C1-C4haloalkoxy.
In another group of compounds of the invention G1 is O; G2 is S; T is CH or N; Y′ is N; Y2 is CH; n is 2; p is 1; R1 is difluoromethyl or trifluoromethyl; R2 is methyl or difluoromethyl; R3 is C1-C4alkylcarbonyl, C3-C5cycloalkylcarbonyl, C1-C4haloalkylcarbonyl, carboxyl, C1-C4alkoxycarbonyl, C3-C5cycloalkoxycarbonyl, C1-C4haloalkoxycarbonyl, aminocarbonyl, (C1-C4alkyl)aminocarbonyl, (C3-C5cycloalkyl)aminocarbonyl, (C1-C4haloalkyl)aminocarbonyl, (C1-C4alkyl)2aminocarbonyl, (C3-C5cycloalkyl)2aminocarbonyl or (C1-C4haloalkyl)2aminocarbonyl; R4, R5, R6, R7 and R8 are hydrogen; R9 is C(═O)—NR12R13 or a 5-membered heterocyclic ringsystem optionally substituted by one or more R14; R12 is arylalkyl or a 9- to 10-membered bicyclic carbocyclic ringsystem, wherein the arylalkyl and 9- to 10-membered bicyclic carbocyclic ringsystem are optionally substituted by one or more R14; R13 is hydrogen or methyl; each R14 is halogen, cyano, amino, mercapto, C1-C4alkyl, C3-C6cycloalkyl, C3-C6cycloalkyl-C1-C4alkylthio, C1-C4alkoxy, C1-C4alkylthio, phenyl and phenyloxy, and wherein alkyl, cycloalkyl and alkoxy are optionally substituted by halogen, and wherein phenyl is optionally substituted by one or more R15 and R15 is halogen, methyl or halomethyl.
In another group of compounds of the invention G1 is O; G2 is S; T is CH or N; Y1 is N; Y2 is CH; n is 2; p is 1; R1 is difluoromethyl or trifluoromethyl; R2 is methyl or difluoromethyl; R3 is carboxyl, C1-C4alkoxycarbonyl, C1-C4haloalkoxycarbonyl, aminocarbonyl, (C1-C4alkyl)aminocarbonyl, (C1-C4haloalkyl)aminocarbonyl, (C1-C4alkyl)2aminocarbonyl or (C1-C4haloalkyl)2aminocarbonyl; R4, R5, R6, R7 and R8 are hydrogen; R9 is C(═O)—NR12R13 or a 5-membered heterocyclic ringsystem optionally substituted by one or more R14; R12 is arylalkyl or a 9- to 10-membered bicyclic carbocyclic ringsystem, wherein the arylalkyl and 9- to 10-membered bicyclic carbocyclic ringsystem are optionally substituted by one or more R14; R13 is hydrogen or methyl; each R14 is halogen, cyano, amino, mercapto, C1-C4alkyl, C3-C6cycloalkyl, C3-C6cycloalkyl-C1-C4alkylthio, C1-C4alkoxy, C1-C4alkylthio, phenyl and phenyloxy, and wherein alkyl, cycloalkyl and alkoxy are optionally substituted by halogen, and wherein phenyl is optionally substituted by one or more R15 and R15 is halogen, methyl or halomethyl.
In another group of compounds of the invention G1 is O; G2 is S; T is CH or N; Y1 is N; Y2 is CH; n is 2; p is 1; R1 is difluoromethyl or trifluoromethyl; R2 is methyl or difluoromethyl; R3 is carboxyl, C1-C4alkoxycarbonyl, aminocarbonyl, (C1-C4alkyl)aminocarbonyl, or (C1-C4alkyl)2aminocarbonyl; R4, R5, R6, R7 and R8 are hydrogen; R9 is C(═O)—NR12R13 or a 5-membered heterocyclic ringsystem optionally substituted by one or more R14; R12 is arylalkyl or a 9- to 10-membered bicyclic carbocyclic ringsystem, wherein the arylalkyl and 9- to 10-membered bicyclic carbocyclic ringsystem are optionally substituted by one or more R14; R13 is hydrogen or methyl; each R14 is halogen, cyano, amino, mercapto, C1-C4alkyl, C3-C6cycloalkyl, C3-C6cycloalkyl-C1-C4alkylthio, C1-C4alkoxy, C1-C4alkylthio, phenyl and phenyloxy, and wherein alkyl, cycloalkyl and alkoxy are optionally substituted by halogen, and wherein phenyl is optionally substituted by one or more R15 and R15 is halogen, methyl or halomethyl.
In another group of compounds of the invention G1 is O; G2 is S; T is CH or N; Y1 is N; Y2 is CH; n is 2; p is 1; R1 is difluoromethyl or trifluoromethyl; R2 is methyl or difluoromethyl; R5 is C1-C4alkylcarbonyl, C3-C5cycloalkylcarbonyl, C1-C4haloalkylcarbonyl, carboxyl, C1-C4alkoxycarbonyl, C3-C5cycloalkoxycarbonyl, C1-C4haloalkoxycarbonyl, aminocarbonyl, (C1-C4alkyl)aminocarbonyl, (C3-C6cycloalkyl)aminocarbonyl, (C1-C4haloalkyl)aminocarbonyl, (C1-C4alkyl)2aminocarbonyl, (C3-C5cycloalkyl)2aminocarbonyl or (C1-C4haloalkyl)2aminocarbonyl; R3, R4, R6, R7 and R8 are hydrogen; R9 is C(═O)—NR12R13 or a 5-membered heterocyclic ringsystem optionally substituted by one or more R14; R12 is arylalkyl or a 9- to 10-membered bicyclic carbocyclic ringsystem, wherein the arylalkyl and 9- to 10-membered bicyclic carbocyclic ringsystem are optionally substituted by one or more R14; R13 is hydrogen or methyl; each R14 is halogen, cyano, amino, mercapto, C1-C4alkyl, C3-C6cycloalkyl, C3-C6cycloalkyl-C1-C4alkylthio, C1-C4alkoxy, C1-C4alkylthio, phenyl and phenyloxy, and wherein alkyl, cycloalkyl and alkoxy are optionally substituted by halogen, and wherein phenyl is optionally substituted by one or more R15 and R15 is halogen, methyl or halomethyl.
In another group of compounds of the invention G1 is O; G2 is S; T is CH or N; Y1 is N; Y2 is CH; n is 2; p is 1; R1 is difluoromethyl or trifluoromethyl; R2 is methyl or difluoromethyl; R5 is carboxyl, C1-C4alkoxycarbonyl, C1-C4haloalkoxycarbonyl, aminocarbonyl, (C1-C4alkyl)aminocarbonyl, (C1-C4haloalkyl)aminocarbonyl, (C1-C4alkyl)2aminocarbonyl or (C1-C4haloalkyl)2aminocarbonyl; R3, R4, R6, R7 and R8 are hydrogen; R9 is C(═O)—NR12R13 or a 5-membered heterocyclic ringsystem optionally substituted by one or more R14; R12 is arylalkyl or a 9- to 10-membered bicyclic carbocyclic ringsystem, wherein the arylalkyl and 9- to 10-membered bicyclic carbocyclic ringsystem are optionally substituted by one or more R14; R13 is hydrogen or methyl; each R14 is halogen, cyano, amino, mercapto, C1-C4alkyl, C3-C6cycloalkyl, C3-C6cycloalkyl-C1-C4alkylthio, C1-C4alkoxy, C1-C4alkylthio, phenyl and phenyloxy, and wherein alkyl, cycloalkyl and alkoxy are optionally substituted by halogen, and wherein phenyl is optionally substituted by one or more R15 and R15 is halogen, methyl or halomethyl.
In another group of compounds of the invention G1 is O; G2 is S; T is CH or N; Y1 is N; Y2 is CH; n is 2; p is 1; R1 is difluoromethyl or trifluoromethyl; R2 is methyl or difluoromethyl; R5 is carboxyl, C1-C4alkoxycarbonyl, aminocarbonyl, (C1-C4alkyl)aminocarbonyl, or (C1-C4alkyl)2aminocarbonyl; R3, R4, R6, R7 and R8 are hydrogen; R9 is C(═O)—NR12R13 or a 5-membered heterocyclic ringsystem optionally substituted by one or more R14; R12 is arylalkyl or a 9- to 10-membered bicyclic carbocyclic ringsystem, wherein the arylalkyl and 9- to 10-membered bicyclic carbocyclic ringsystem are optionally substituted by one or more R14; R13 is hydrogen or methyl; each R14 is halogen, cyano, amino, mercapto, C1-C4alkyl, C3-C6cycloalkyl, C3-C6cycloalkyl-C1-C4alkylthio, C1-C4alkoxy, C1-C4alkylthio, phenyl and phenyloxy, and wherein alkyl, cycloalkyl and alkoxy are optionally substituted by halogen, and wherein phenyl is optionally substituted by one or more R15 and R15 is halogen, methyl or halomethyl.
In another group of compounds the compound of the invention is a compound of formula I.a, wherein G1 is O; G2 is S; T is CH or N; Y1 is N; Y2 is CH; Z is selected from Z-1 to Z-12 (above); preferably Z-1, Z-4, Z-8, Z-10 and Z-12; n is 2; p is 1; R1 is difluoromethyl or trifluoromethyl; R2 is methyl or difluoromethyl; R3 is C1-C4alkylcarbonyl, C3-C5cycloalkylcarbonyl, C1-C4haloalkylcarbonyl, carboxyl, C1-C4alkoxycarbonyl, C3-C5cycloalkoxycarbonyl, C1-C4haloalkoxycarbonyl, aminocarbonyl, (C1-C4alkyl)aminocarbonyl, (C3-C5cycloalkyl)aminocarbonyl, (C1-C4haloalkyl)aminocarbonyl, (C1-C4alkyl)2aminocarbonyl, (C3-C5cycloalkyl)2aminocarbonyl or (C1-C4haloalkyl)2aminocarbonyl and R4, R5, R6, R7 and R8 are hydrogen.
In another group of compounds the compound of the invention is a compound of formula I.a, wherein G1 is O; G2 is S; T is CH or N; Y1 is N; Y2 is CH; Z is selected from Z-1 to Z-12 (above); preferably Z-1, Z-4, Z-8, Z-10 and Z-12; n is 2; p is 1; R1 is difluoromethyl or trifluoromethyl; R2 is methyl or difluoromethyl; R3 is carboxyl, C1-C4alkoxycarbonyl, C1-C4haloalkoxycarbonyl, aminocarbonyl, (C1-C4alkyl)aminocarbonyl, (C1-C4haloalkyl)aminocarbonyl, (C1-C4alkyl)2aminocarbonyl or (C1-C4haloalkyl)2aminocarbonyl; and R4, R5, R6, R7 and R8 are hydrogen.
In another group of compounds the compound of the invention is a compound of formula I.a, wherein G1 is O; G2 is S; T is CH or N; Y1 is N; Y2 is CH; Z is selected from Z-1 to Z-12 (above); preferably Z-1, Z-4, Z-8, Z-10 and Z-12; n is 2; p is 1; R1 is difluoromethyl or trifluoromethyl; R2 is methyl or difluoromethyl; R3 is carboxyl, C1-C4alkoxycarbonyl, aminocarbonyl, (C1-C4alkyl)aminocarbonyl, or (C1-C4alkyl)2aminocarbonyl; and R4, R5, R6, R7 and R8 are hydrogen.
In another group of compounds the compound of the invention is a compound of formula I.a, wherein G1 is O; G2 is S; T is CH or N; Y1 is N; Y2 is CH; Z is selected from Z-1 to Z12 (above); preferably Z-1, Z-4, Z-8, Z-10 and Z-12; n is 2; p is 1; R1 is difluoromethyl or trifluoromethyl; R2 is methyl or difluoromethyl; R5 is C1-C4alkylcarbonyl, C3-C5cycloalkylcarbonyl, C1-C4haloalkylcarbonyl, carboxyl, C1-C4alkoxycarbonyl, C3-C5cycloalkoxycarbonyl, C1-C4haloalkoxycarbonyl, aminocarbonyl, (C1-C4alkyl)aminocarbonyl, (C3-C5cycloalkyl)aminocarbonyl, (C1-C4haloalkyl)aminocarbonyl, (C1-C4alkyl)2aminocarbonyl, (C3-C5cycloalkyl)2aminocarbonyl or (C1-C4haloalkyl)2aminocarbonyl and R3, R4, R6, R7 and R8 are hydrogen.
In another group of compounds the compound of the invention is a compound of formula I.a, wherein G1 is O; G2 is S; T is CH or N; Y1 is N; Y2 is CH; Z is selected from Z-1 to Z-12 (above); preferably Z-1, Z-4, Z-8, Z-10 and Z-12; n is 2; p is 1; R1 is difluoromethyl or trifluoromethyl; R2 is methyl or difluoromethyl; R5 is carboxyl, C1-C4alkoxycarbonyl, C1-C4haloalkoxycarbonyl, aminocarbonyl, (C1-C4alkyl)aminocarbonyl, (C1-C4haloalkyl)aminocarbonyl, (C1-C4alkyl)2aminocarbonyl or (C1-C4haloalkyl)2aminocarbonyl; and R3, R4, R6, R7 and R8 are hydrogen.
In another group of compounds the compound of the invention is a compound of formula I.a, wherein G1 is O; G2 is S; T is CH or N; Y1 is N; Y2 is CH; Z is selected from Z-1 to Z-12 (above); preferably Z-1, Z-4, Z-8, Z-10 and Z-12; n is 2; p is 1; R1 is difluoromethyl or trifluoromethyl; R2 is methyl or difluoromethyl; R5 is carboxyl, C1-C4alkoxycarbonyl, aminocarbonyl, (C1-C4alkyl)aminocarbonyl, or (C1-C4alkyl)2aminocarbonyl; and R3, R4, R6, R7 and R8 are hydrogen.
For the avoidance of doubt, when n is 1 and p is 1 compounds of formula I have the formula according to formula I-b:
in which R1, R2, R3, R4, R5, R6, R7, R8, R9, G1, G2, T, Y1 and Y2 have the definitions as described for formula I.
When n is 2 and p is 1, compounds of formula I have the formula according to formula I-c:
in which R1, R2, R3, R4, R5, R6, R7, R8, R9, G1, G2, T, Y1 and Y2 have the definitions as described for formula I.
When n is 1 and p is 2, compounds of formula I have the formula according to formula I-d:
in which R1, R2, R3, R4, R5, R6, R7, R8, R9, G1, G2, T, Y1 and Y2 have the definitions as described for formula I.
The invention also relates to compounds of formula I-b, formula I-c and formula l-d as shown above.
The invention also relates to compounds of formula I-e:
in which R1, R2, R3, R4, R5, R6, R7, R8, R9, G2, Y1 and Y2 have the definitions as described for formula I. Preferred definitions of R1, R2, R3, R4, R5, R6, R7, R8, R9, G2, Y1 and Y2 are as defined for formula I.
The invention also relates to compounds of formula I-f:
in which R1, R2, R3, R4, R5, R6, R7, R8 and R9 have the definitions as described for formula I. Preferred definitions of R1, R2, R3, R4, R5, R6, R7, R8 and R9 are as defined for formula I.
The invention also relates to compounds of formula I-g:
wherein R3, R4, R5, R6, R7, R8, R9, G1, G2, T, Y1, Y2, n and p have the definition as described for formula I. Preferred definitions of R3, R4, R5, R6, R7, R8, R9, G1, G2, T, Y1, Y2, n and p are as defined for formula I.
The invention also relates to compounds of formula I-h:
in which R3, R4, R5, R6, R7, R8, R9, G1, G2, T, Y1, Y2, n and p have the definitions as described for formula I. Preferred definitions of R3, R4, R5, R6, R7, R8, R9, G1, G2, T, Y1, Y2, n and p are as defined for formula I.
The invention includes compounds of formula II:
wherein R3, R4, R5, R6, R7, R8, R9, G2, T, Y1, Y2, n and p are as defined for a compound of formula I and R16 is hydrogen, a protecting group, such as alkylcarbonyl, benzyl or alkoxycarbonyl, e.g. C1-C4 alkylcarbonyl, benzyl or C1-C4 alkoxycarbonyl, in particular acetyl, benzyl or tert-butoxycarbonyl. These compounds, including salts and N-oxides thereof, are useful as intermediates in the synthesis of compounds of formula I. Preferred definitions of R3, R4, R5, R6, R7, R8, R9, G2, T, Y1, Y2, n and p are as defined for formula I.
The invention also includes compounds of formula Ill
wherein E is hydrogen, a protecting group such as alkylcarbonyl, benzyl or alkoxycarbonyl, e.g. C1-C4 alkylcarbonyl, benzyl or C1-C4 alkoxycarbonyl, in particular acetyl, benzyl or tert-butoxycarbonyl; or group M,
R1, R2, R3, R4, R5, R6, R7, R8, G1, G2, T, Y1, Y2, n and p are as defined for a compound of formula I and R17 is C1-C6alkyl. These compounds, including salts and N-oxides thereof, are useful as intermediates in the synthesis of compounds of formula I. Preferred definitions of R1, R2, R3, R4, R5, R6, R7, R8, G1, G2, T, Y1, Y2, n and p are as defined for formula I.
The invention also includes compounds of formula IV
wherein E is hydrogen, a protecting group such as alkylcarbonyl, benzyl or alkoxycarbonyl, e.g. C1-C4 alkylcarbonyl, benzyl or C1-C4 alkoxycarbonyl, in particular acetyl, benzyl or tert-butoxycarbonyl; or group M
and R1, R2, R3, R4, R5, R6, R7, R8, G1, G2, T, Y1, Y2, n and p are as defined for a compound of formula I. These compounds, including salts and N-oxides thereof, are useful as intermediates in the synthesis of compounds of formula I. Preferred definitions of R1, R2, R3, R4, R5, R6, R7, R8, G1, G2, T, Y1, Y2, n and p are as defined for formula I.
The invention also includes compounds of formula V
wherein E is hydrogen, a protecting group such as alkylcarbonyl, benzyl or alkoxycarbonyl, e.g. C1-C4 alkylcarbonyl, benzyl or C1-C4 alkoxycarbonyl, in particular acetyl, benzyl or tert-butoxycarbonyl; or group M,
R1, R2, R3, R4, R5, R6, R7, R8, G1, G2, T, Y1, Y2, n and p are as defined for a compound of formula I and Hal is halogen, preferably chloro. These compounds, including salts and N-oxides thereof, are useful as intermediates in the synthesis of compounds of formula I. Preferred definitions of R1, R2, R3, R4, R5, R6, R7, R8, G1, G2, T, Y1, Y2, n and p are as defined for formula I.
The invention also includes compounds of formula VI
wherein E is hydrogen, a protecting group such as alkylcarbonyl, benzyl or alkoxycarbonyl, e.g. C1-C4 alkylcarbonyl, benzyl or C1-C4 alkoxycarbonyl, in particular acetyl, benzyl or tert-butoxycarbonyl; or group M
and R1, R2, R3, R4, R5, R6, R7, R8, G1, G2, T, Y1, Y2, n and p are as defined for a compound of formula I. These compounds, including salts and N-oxides thereof, are useful as intermediates in the synthesis of compounds of formula I. Preferred definitions of R1, R2, R3, R4, R5, R6, R7, R8, G1, G2, T, Y1, Y2, n and p are as defined for formula I.
The invention also includes compounds of formula VII
wherein E is hydrogen or a protecting group such as alkylcarbonyl, benzyl or alkoxycarbonyl, e.g. C1-C4 alkylcarbonyl, benzyl or C1-C4 alkoxycarbonyl, in particular acetyl, benzyl or tert-butoxycarbonyl; and R3, R4, R5, R7, R8, R9, G2, Y1, Y2, n and p are as defined for a compound of formula I. These compounds, including salts and N-oxides thereof, are useful as intermediates in the synthesis of compounds of formula I. Preferred definitions of R3, R4, R5, R7, R8, R9, G2, Y1, Y2, n and p are as defined for formula I.
Preferred individual compounds of formula I are:
Compounds of the present invention can be made as shown in the following schemes. Throughout this description, the group M, wherein R1, R2 and G1 are as defined for formula I, stands for:
The compounds of formula IX, wherein R3, R4, R5, R6, R7, R8, R12, G2, T, Y1, Y2, n and p are as defined for formula I and E is hydrogen, a protecting group such as acetyl, benzyl or tert-butoxycarbonyl or a group M, can be obtained by transformation of a compound of formula V, wherein R3, R4, R5, R6, R7, R8, G2, T, Y1, Y2, n and p are as defined for formula I, Hal is halogen, preferably chloro, and E is hydrogen, a protecting group such as acetyl, benzyl or tert-butoxycarbonyl or a group M, with a compound of formula VIII, wherein R12 is as defined for formula I and a base, such as pyridine, triethylamine, ethyl diisopropylamine. This is shown in Scheme 1.
The compounds of formula V, wherein R3, R4, R5, R6, R7, R8, G2, T, Y1, Y2, n and p are as defined for formula I, Hal is halogen, preferably chloro, and E is hydrogen, a protecting group such as acetyl, benzyl or tert-butoxycarbonyl or a group M, can be obtained by transformation of a compound of formula IV, wherein R3, R4, R5, R6, R7, Ra, G2, T, Y1, Y2, n and p are as defined for formula I and E is hydrogen, a protecting group such as acetyl, benzyl or tert-butoxycarbonyl or a group M, with a thionyl halide, such as thionyl chloride, or a phosphoryl halide, such as phosphoryl chloride. This is shown in Scheme 2.
The compounds of formula IV, wherein R3, R4, R5, R6, R7, R8, G2, T, Y1, Y2, n and p are as defined for formula I and E is hydrogen, a protecting group such as acetyl, benzyl or tert-butoxycarbonyl or a group M, can be obtained by transformation of a compound of formula Ill, wherein R3, R4, R5, R6, R7, R8, G2, T, Y1, Y2, n and p are as defined for formula I, R17 is C1-C6alkyl and E is hydrogen, a protecting group such as acetyl, benzyl or tert-butoxycarbonyl or a group M, with a base, such as lithium hydroxide, sodium hydroxide, sodium carbonate, potassium hydroxide or potassium carbonate. This is shown in Scheme 3.
Alternatively, the compounds of formula IX, wherein R3, R4, R5, R6, R7, R8, R12, G2, T, Y1, Y2, n and p are as defined for formula I and E is hydrogen, a protecting group such as acetyl, benzyl or tert-butoxycarbonyl or a group M, can be obtained by transformation of a compound of formula IV, wherein R3, R4, R5, R6, R7, R8, G2, T, Y1, Y2, n and p are as defined for formula I and E is hydrogen, a protecting group such as acetyl, benzyl or tert-butoxycarbonyl or a group M, with a compound of formula VIII, wherein R12 is as defined for formula I and an acid, such as hydrochloric acid or sulphuric acid. This is shown in Scheme 4.
The compounds of formula XI, wherein R3, R4, R5, R6, R7, R8, R12, R13, G2, T, Y1, Y2, n and p are as defined for formula I and E is hydrogen, a protecting group such as acetyl, benzyl or tert-butoxycarbonyl or a group M, can be obtained by transformation of a compound of formula V, wherein R3, R4, R5, R6, R7, R8, G2, T, Y1, Y2, n and p are as defined for formula I, Hal is halogen, preferably chloro, and E is hydrogen, a protecting group such as acetyl, benzyl or tert-butoxycarbonyl or a group M, with a compound of formula X, wherein R12 and R13 are as defined for formula I and a base, such as pyridine, triethylamine, ethyl diisopropylamine. This is shown in Scheme 5.
Alternatively, the compounds of formula XI, wherein R3, R4, R5, R6, R7, R8, R12, R13, G2, T, Y1, Y2, n and p are as defined for formula I and E is hydrogen, a protecting group such as acetyl, benzyl or tert-butoxycarbonyl or a group M, can be obtained by transformation of a compound of formula IV, wherein R3, R4, R5, R6, R7, R8, G2, T, Y1, Y2, n and p are as defined for formula I and E is hydrogen, a protecting group such as acetyl, benzyl or tert-butoxycarbonyl or a group M, with a compound of formula X, wherein R12 and R13 are as defined for formula I, an activating reagent, such as BOP, PyBOP, EDCI, CDI or HATU, and a base, such as pyridine, triethylamine, ethyl diisopropylamine. This is shown in Scheme 6.
The compounds of formula XIII, wherein R3, R4, R5, R6, R7, R8, R14, G2, T, Y1, Y2, n and p are as defined for formula I and E is hydrogen, a protecting group such as acetyl, benzyl or tert-butoxycarbonyl or a group M, can be obtained by transformation of a compound of formula VI, wherein R3, R4, R5, R6, R7, R8, G2, T, Y1, Y2, n and p are as defined for formula I and E is hydrogen, a protecting group such as acetyl, benzyl or tert-butoxycarbonyl or a group M, with a compound of formula XII, wherein R14 is as defined for formula, and hydroxylamine and sodium hypochlorite. This is shown in Scheme 7.
The compounds of formula XIV, wherein R3, R4, R5, R6, R7, R8, R9, G2, T, Y1, Y2, n and p are as defined for formula I and E is hydrogen, a protecting group such as acetyl, benzyl or tert-butoxycarbonyl, can be obtained by transformation of a compound of formula VII, wherein R3, R4, R5, R7, R8, R9, G2, Y1, Y2, n and p are as defined for formula I and E is hydrogen or a protecting group such as acetyl, benzyl or tert-butoxycarbonyl, with hydrogen and a catalyst, such as palladium on charcoal or Raney-nickel, or with a hydride, such as lithium aluminium hydride. This is shown in Scheme 8.
The compounds of formula VII, wherein R3, R4, R5, R7, R8, R9, G2, Y1, Y2, n and p are as defined for formula I and E is hydrogen or a protecting group such as acetyl, benzyl or tert-butoxycarbonyl, can be obtained by transformation of a compound of formula XV, wherein R3, R4, R5, R7, R8, n and p are as defined for formula I, R18 and R19 each independently are hydroxyl or C1-4alkoxy or together with the interjacent boron atom form a five- or six-membered saturated heterocyclic ring, and E is hydrogen or a protecting group such as acetyl, benzyl or tert-butoxycarbonyl, with a compound of formula XVI, wherein R9, G2, Y1, Y2 and Hal is halogen, preferably bromo or iodo, and a transition metal catalyst, such as tetrakis(triphenylphosphine)palladium, and a ligand. This is shown in Scheme 9.
The compounds of formula XVIII, wherein R3, R4, R5, R6, R7, R8, R9, G2, Y1, Y2, n and p are as defined for formula I and E is hydrogen, a protecting group such as acetyl, benzyl or tert-butoxycarbonyl or a group M, can be obtained by transformation of a compound of formula XVII, wherein R3, R4, R5, R6, R7, R8, n and p are as defined for formula I and E is hydrogen, a protecting group such as acetyl, benzyl or tert-butoxycarbonyl or a group M, with a compound of formula XVI, wherein R9, G2, Y1, Y2 and Hal is halogen, preferably chloro, bromo or iodo, with a transition metal catalyst and a ligand or with a base. This is shown in Scheme 10.
Surprisingly, it has now been found that the novel compounds of formula I have, for practical purposes, a very advantageous level of biological activity for protecting plants against diseases that are caused by fungi.
The compounds of formula I can be used in the agricultural sector and related fields of use e.g. as active ingredients for controlling plant pests or on non-living materials for control of spoilage microorganisms or organisms potentially harmful to man. The novel compounds are distinguished by excellent activity at low rates of application, by being well tolerated by plants and by being environmentally safe. They have very useful curative, preventive and systemic properties and may be used for protecting numerous cultivated plants. The compounds of formula I can be used to inhibit or destroy the pests that occur on plants or parts of plants (fruit, blossoms, leaves, stems, tubers, roots) of different crops of useful plants, while at the same time protecting also those parts of the plants that grow later e.g. from phytopathogenic microorganisms.
It is also possible to use compounds of formula I as dressing agents for the treatment of plant propagation material, e.g., seed, such as fruits, tubers or grains, or plant cuttings (for example rice), for the protection against fungal infections as well as against phytopathogenic fungi occurring in the soil. The propagation material can be treated with a composition comprising a compound of formula I before planting: seed, for example, can be dressed before being sown. The active ingredients according to the invention can also be applied to grains (coating), either by impregnating the seeds in a liquid formulation or by coating them with a solid formulation. The composition can also be applied to the planting site when the propagation material is being planted, for example, to the seed furrow during sowing. The invention relates also to such methods of treating plant propagation material and to the plant propagation material so treated.
Furthermore the compounds according to present invention can be used for controlling fungi in related areas, for example in the protection of technical materials, including wood and wood related technical products, in food storage, in hygiene management.
In addition, the invention could be used to protect non-living materials from fungal attack, e.g. lumber, wall boards and paint.
The compounds of formula I are, for example, effective against the phytopathogenic fungi of the following classes: Fungi imperfecti (e.g. Alternaria spp.), Basidiomycetes (e.g. Corticium spp., Ceratobasidium spp., Waitea spp., Thanatephorus spp., Rhizoctonia spp., Hemileia spp., Puccinia spp., Phakopsora spp., Ustilago spp., Tilletia spp.), Ascomycetes (e.g. Venturia spp., Blumeria spp., Erysiphe spp., Podosphaera spp., Uncinula spp., Monilinia spp., Sclerotinia spp., Colletotrichum spp., Glomerella spp., Fusarium spp., Gibberella spp., Monographella spp., Phaeosphaeria spp., Mycosphaerella spp., Cercospora spp., Pyrenophora spp., Rhynchosporium spp., Magnaporthe spp., Gaeumannomyces spp., Oculimacula spp., Ramularia spp., Botryotinia spp.) and Oomycetes (e.g. Phytophthora spp., Pythium spp., Plasmopara spp., Peronospora spp., Pseudoperonospora spp. Bremia spp).
Outstanding activity is observed against downy mildew (e.g. Plasmopara viticola) and late blight (e.g. Phytophthora infestans). Furthermore, the novel compounds of formula I are effective against phytopathogenic gram negative and gram positive bacteria (e.g. Xanthomonas spp, Pseudomonas spp, Erwinia amylovora, Ralstonia spp.) and viruses (e.g. tobacco mosaic virus).
Within the scope of present invention, target crops and/or useful plants to be protected typically comprise the following species of plants: cereal (wheat, barley, rye, oat, rice, maize, sorghum and related species); beet (sugar beet and fodder beet); pomes, drupes and soft fruit (apples, pears, plums, peaches, almonds, cherries, strawberries, raspberries and blackberries); leguminous plants (beans, lentils, peas, soybeans); oil plants (rape, mustard, poppy, olives, sunflowers, coconut, castor oil plants, cocoa beans, groundnuts); cucumber plants (pumpkins, cucumbers, melons); fibre plants (cotton, flax, hemp, jute); citrus fruit (oranges, lemons, grapefruit, mandarins); vegetables (spinach, lettuce, asparagus, cabbages, carrots, onions, tomatoes, potatoes, paprika); lauraceae (avocado, cihnamomum, camphor) or plants such as tobacco, nuts, coffee, eggplants, sugar cane, tea, pepper, vines, hops, bananas and natural rubber plants, as well as turf and ornamentals.
The useful plants and/or target crops in accordance with the invention include conventional as well as genetically enhanced or engineered varieties such as, for example, insect resistant (e.g. Bt. and VIP varieties) as well as disease resistant, herbicide tolerant (e.g. glyphosate- and glufosinate-resistant maize varieties commercially available under the trade names RoundupReady® and LibertyLink®) and nematode tolerant varieties. By way of example, suitable genetically enhanced or engineered crop varieties include the Stoneville 5599BR cotton and Stoneville 4892BR cotton varieties.
The term “useful plants” and/or “target crops” is to be understood as including also useful plants that have been rendered tolerant to herbicides like bromoxynil or classes of herbicides (such as, for example, HPPD inhibitors, ALS inhibitors, for example primisulfuron, prosulfuron and trifloxysulfuron, EPSPS (5-enol-pyrovyl-shikimate-3-phosphate-synthase) inhibitors, GS (glutamine synthetase) inhibitors or PPO (protoporphyrinogen-oxidase) inhibitors) as a result of conventional methods of breeding or genetic engineering. An example of a crop that has been rendered tolerant to imidazolinones, e.g. imazamox, by conventional methods of breeding (mutagenesis) is Clearfield® summer rape (Canola). Examples of crops that have been rendered tolerant to herbicides or classes of herbicides by genetic engineering methods include glyphosate- and glufosinate-resistant maize varieties commercially available under the trade names RoundupReady®, Herculex I® and LibertyLink®.
The term “useful plants” and/or “target crops” is to be understood as including also useful plants which have been so transformed by the use of recombinant DNA techniques that they are capable of synthesising one or more selectively acting toxins, such as are known, for example, from toxin-producing bacteria, especially those of the genus Bacillus.
The term “useful plants” and/or “target crops” is to be understood as including also useful plants which have been so transformed by the use of recombinant DNA techniques that they are capable of synthesising antipathogenic substances having a selective action, such as, for example, the so-called “pathogenesis-related proteins” (PRPs, see e.g. EP-A-0 392 225). Examples of such antipathogenic substances and transgenic plants capable of synthesising such antipathogenic substances are known, for example, from EP-A-0 392 225, WO 95/33818, and EP-A-0 353 191. The methods of producing such transgenic plants are generally known to the person skilled in the art and are described, for example, in the publications mentioned above.
The term “locus” of a plant as used herein is intended to embrace the place on which the plants are growing, where the plant propagation materials of the plants are sown or where the plant propagation materials of the plants will be placed into the soil. An example for such a locus is a field, on which crop plants are growing.
The term “plant propagation material” is understood to denote generative parts of the plant, such as seeds, which can be used for the multiplication of the latter, and vegetative material, such as cuttings or tubers, for example potatoes. There may be mentioned for example seeds (in the strict sense), roots, fruits, tubers, bulbs, rhizomes and parts of plants. Germinated plants and young plants which are to be transplanted after germination or after emergence from the soil, may also be mentioned. These young plants may be protected before transplantation by a total or partial treatment by immersion. Preferably “plant propagation material” is understood to denote seeds.
The compounds of formula I may be used in unmodified form or, preferably, together with the adjuvants conventionally employed in the art of formulation. To this end they may be conveniently formulated in known manner to emulsifiable concentrates, coatable pastes, directly sprayable or dilutable solutions or suspensions, dilute emulsions, wettable powders, soluble powders, dusts, granulates, and also encapsulations e.g. in polymeric substances. As with the type of the compositions, the methods of application, such as spraying, atomising, dusting, scattering, coating or pouring, are chosen in accordance with the intended objectives and the prevailing circumstances. The compositions may also contain further adjuvants such as stabilizers, antifoams, viscosity regulators, binders or tackifiers as well as fertilizers, micronutrient donors or other formulations for obtaining special effects.
Suitable carriers and adjuvants, e.g. for agricultural use, can be solid or liquid and are substances useful in formulation technology, e.g. natural or regenerated mineral substances, solvents, dispersants, wetting agents, tackifiers, thickeners, binders or fertilizers. Such carriers are for example described in WO 97/33890.
The compounds of formula I are normally used in the form of compositions and can be applied to the crop area or plant to be treated, simultaneously or in succession with further compounds. These further compounds can be e.g. fertilizers or micronutrient donors or other preparations, which influence the growth of plants. They can also be selective herbicides or non-selective herbicides as well as insecticides, fungicides, bactericides, nematicides, molluscicides or mixtures of several of these preparations, if desired together with further carriers, surfactants or application promoting adjuvants customarily employed in the art of formulation.
The compounds of formula I may be used in the form of (fungicidal) compositions for controlling or protecting against phytopathogenic microorganisms, comprising as active ingredient at least one compound of formula I or of at least one preferred individual compound as above-defined, in free form or in agrochemically usable salt form, and at least one of the above-mentioned adjuvants.
The invention provides a composition, preferably a fungicidal composition, comprising at least one compound formula I an agriculturally acceptable carrier and optionally an adjuvant. An agricultural acceptable carrier is for example a carrier that is suitable for agricultural use. Agricultural carriers are well known in the art. Preferably said composition may comprise at least one or more pesticidally active compounds, for example an additional fungicidal active ingredient in addition to the compound of formula I.
The compound of formula (I) may be the sole active ingredient of a composition or it may be admixed with one or more additional active ingredients such as a pesticide, fungicide, synergist, herbicide or plant growth regulator where appropriate. An additional active ingredient may, in some cases, result in unexpected synergistic activities. Examples of suitable additional active ingredients include the following: Azoxystrobin (131860-33-8), Dimoxystrobin (149961-52-4), Enestrobin (238410-11-2), Fluoxastrobin (193740-76-0), Kresoxim-methyl (143390-89-0), Metominostrobin (133408-50-1), Orysastrobin (248593-16-0), Picoxystrobin (117428-22-5), Pyraclostrobin (175013-18-0), trifloxystrobin (141517-21-7), Azaconazole (60207-31-0), Bromuconazole (116255-48-2), Cyproconazole (94361-06-5), Difenoconazole (119446-68-3), Diniconazole (83657-24-3), Diniconazole-M (83657-18-5), Epoxiconazole (13385-98-8), Fenbuconazole (114369-43-6), Fluquinconazole (136426-54-5), Flusilazole (85509-19-9), Flutriafol (76674-21-0), Hexaconazole (79983-71-4), Imazalil (58594-72-2), Imibenconazole (86598-92-7), Ipconazole (125225-28-7), Metconazole (125116-23-6), Myclobutanil (88671-89-0), Oxpoconazole (174212-12-5), Pefurazoate (58011-68-0), Penconazole (66246-88-6), Prochloraz (67747-09-5), Propiconazole (60207-90-1), Prothioconazole (178928-70-6), Simeconazole (149508-90-7), Tebuconazole (107534-96-3), Tetraconazole (112281-77-3), Triadimefon (43121-43-3), Triadimenol (55219-65-3), Triflumizole (99387-89-0), Triticonazole (131983-72-7), Diclobutrazol (76738-62-0), Etaconazole (60207-93-4), Fluconazole (86386-73-4), Fluconazole-cis (112839-32-4), Thiabendazole (148-79-8), Quinconazole (103970-75-8), Fenpiclonil (74738-17-3), Fludioxonil (131341-86-1), Cyprodinil (121552-61-2), Mepanipyrim (110235-47-7), Pyrimethanil (53112-28-0), Aldimorph (91315-15-0), Dodemorph (1593-77-7), Fenpropimorph (67564-91-4), Tridemorph (81412-43-3), Fenpropidin (67306-00-7), Spiroxamine (118134-30-8), Isopyrazam (881685-58-1), Sedaxane (874967-67-6), Bixafen (581809-46-3), Penthiopyrad (183675-82-3), Fluxapyroxad (907204-31-3), Boscalid (188425-85-6), Penflufen (494793-67-8), Fluopyram (658066-35-4), Mandipropamid (374726-62-2), Benthiavalicarb (413615-35-7), Dimethomorph (110488-70-5), Chlorothalonil (1897-45-6), Fluazinam (79622-59-6), Dithianon (3347-22-6), Metrafenone (220899-03-6), Tricyclazole (41814-78-2), Mefenoxam (70630-17-0), Metalaxyl (57837-19-1), Acibenzolar (126448-41-7) (Acibenzolar-S-methyl (126448-41-7)), Mancozeb (8018-01-7), Ametoctradine (865318-97-4) Cyflufenamid (180409-60-3), and Kresoxim-methyl (143390-89-0), Ipconazole (125225-28-7), Amisulbrom (348635-87-0), Cyflufenamid (180409-60-3), Ethaboxam (16650-77-3), Fluopicolide (239110-15-7), Fluthianil (304900-25-2), Isotianil (224049-04-1), Proquinazid (189278-12-4), Valiphenal (283159-90-0), 1-methyl-cyclopropene (3100-04-7), Trifloxystrobin (141517-21-7), Sulfur (7704-34-9), Copper ammoniumcarbonate (CAS 33113-08-5); Copper oleate (CAS 1120-44-1); Folpet (133-07-3), Quinoxyfen (124495-18-7), Captan (133-06-2), Fenhexamid (126833-17-8), Glufosinate and its salts (51276-47-2, 35597-44-5 (S-isomer)), Glyphosate (1071-83-6) and its salts (69254-40-6 (Diammonium), 34494-04-7 (Dimethylammonium), 38641-94-0 (Isopropylammonium), 40465-66-5 (Monoammonium), 70901-20-1 (Potassium), 70393-85-0 (Sesquisodium), 81591-81-3 (Trimesium)), 1-methyl-3-difluoromethyl-1H-pyrazole-4-carboxylic acid (2-dichloromethylene-3-ethyl-1-methyl-indan-4-yl)-amide (1072957-71-1), 1-methyl-3-difluoromethyl-1H-pyrazole-4-carboxylic acid (4′-methylsulfanyl-biphenyl-2-yl)-amide, 1-methyl-3-difluoromethyl-4H-pyrazole-4-carboxylic acid [2-(2,4-dichloro-phenyl)-2-methoxy-1-methyl-ethyl]-amide, (5-Chloro-2,4-dimethyl-pyridin-3-yl)-(2,3,4-trimethoxy-6-methyl-phenyl)-methanone, (5-Bromo-4-chloro-2-methoxy-pyridin-3-yl)-(2,3,4-trimethoxy-6-methyl-phenyl)-methanone, 2-{2-[(E)-3-(2,6-Dichloro-phenyl)-1-methyl-prop-2-en-(E)-ylideneaminooxymethyl]-phenyl}-2-[(Z)-methoxyimino]-N-methyl-acetamide, 3-[5-(4-Chloro-phenyl)-2,3-dimethyl-isoxazolidin-3-yl]-pyridine.
Another aspect of invention is related to the use of a compound of formula I or of a preferred individual compound as above-defined, of a composition comprising at least one compound of formula I or at least one preferred individual compound as above-defined, or of a fungicidal mixture comprising at least one compound of formula I or at least one preferred individual compound as above-defined, in admixture with other fungicides, as described above, for controlling or preventing infestation of plants, e.g. useful plants such as crop plants, propagation material thereof, e.g. seeds, harvested crops, e.g. harvested food crops, or non-living materials by phytopathogenic microorganisms, preferably fungal organisms.
A further aspect of invention is related to a method of controlling or preventing an infestation of plants, e.g. useful plants such as crop plants, propagation material thereof, e.g. seeds, harvested crops, e.g. harvested food crops, or of non-living materials by phytopathogenic or spoilage microorganisms or organisms potentially harmful to man, especially fungal organisms, which comprises the application of a compound of formula I or of a preferred individual compound as above-defined as active ingredient to the plants, to parts of the plants or to the locus thereof, to the propagation material thereof, or to any part of the non-living materials.
Controlling or preventing means reducing infestation by phytopathogenic or spoilage microorganisms or organisms potentially harmful to man, especially fungal organisms, to such a level that an improvement is demonstrated.
A preferred method of controlling or preventing an infestation of crop plants by phytopathogenic microorganisms, especially fungal organisms, which comprises the application of a compound of formula I, or an agrochemical composition which contains at least one of said compounds, is foliar application. The frequency of application and the rate of application will depend on the risk of infestation by the corresponding pathogen. However, the compounds of formula I can also penetrate the plant through the roots via the soil (systemic action) by drenching the locus of the plant with a liquid formulation, or by applying the compounds in solid form to the soil, e.g. in granular form (soil application). In crops of water rice such granulates can be applied to the flooded rice field. The compounds of formula I may also be applied to seeds (coating) by impregnating the seeds or tubers either with a liquid formulation of the fungicide or coating them with a solid formulation.
A formulation, e.g. a composition containing the compound of formula I, and, if desired, a solid or liquid adjuvant or monomers for encapsulating the compound of formula I, may be prepared in a known manner, typically by intimately mixing and/or grinding the compound with extenders, for example solvents, solid carriers and, optionally, surface active compounds (surfactants).
The agrochemical formulations and/or compositions will usually contain from 0.1 to 99% by weight, preferably from 0.1 to 95% by weight, of the compound of formula I, 99.9 to 1% by weight, preferably 99.8 to 5% by weight, of a solid or liquid adjuvant, and from 0 to 25% by weight, preferably from 0.1 to 25% by weight, of a surfactant.
Advantageous rates of application are normally from 5 g to 2 kg of active ingredient (a.i.) per hectare (ha), preferably from 10 g to 1 kg a.i./ha, most preferably from 20 g to 600 g a.i./ha. When used as seed drenching agent, convenient dosages are from 10 mg to 1 g of active substance per kg of seeds.
Whereas it is preferred to formulate commercial products as concentrates, the end user will normally use dilute formulations.
The following non-limiting examples illustrate the above-described invention in more detail.
5.0 ml of a 50% aqueous solution of hydroxylamine were added to a suspension of 2-bromo-4-formylthiazole (4.0 g, 20 mmol) in 50 ml of ethanol. The reaction mixture was heated to 60 OC for 2 h. The resulting solution was cooled to room temperature and diluted with 80 ml of tetrahydrofuran. 2,6-difluorostyrene (4.3 g, 30 mmol) was added to the reaction mixture, followed by the dropwise addition of 98 ml of a 15% aqueous solution of sodium hypochlorite. The reaction mixture was stirred for 16 h at room temperature and subsequently quenched by addition of water. The phases were separated and the aqueous phase was extracted with ethyl acetate. The combined organic layer was washed with 5% aqueous sodium bicarbonate solution and brine, dried over sodium sulfate and concentrated under reduced pressure. The remainder was purified by column chromatography on silica gel (cyclohexane/ethyl acetate 4:1) to obtain 3-(2-bromo-thiazol-4-yl)-5-(2,6-difluoro-phenyl)-4,5-dihydro-isoxazole as light yellow cristalls. M.p. 135-142° C. 1H-NMR (400 MHz, CDCl3): δ=3.63 (dd, 1H), 3.81 (dd, 1H), 6.09 (dd, 1H), 6.92 (t, 2H), 7.28-7.35 (m, 1H), 7.78 (s, 1H). MS: m/z=347 (M+2).
Potassium carbonate (1.2 g, 8.7 mmol) was added to a solution of 3-(2-bromo-thiazol-4-yl)-5-(2,6-difluoro-phenyl)-4,5-dihydro-isoxazole (1.25 g, 3.6 mmol) and 1-N-Boc-2-piperazinecarboxylic acid methyl ester (1.1 g, 4.4 mmol) in 15 ml of acetonitrile. The reaction mixture was stirred for 150 h at 90° C. and subsequently cooled and filtered. The solid potassium salt was washed with ethyl acetate and the filtrate as well as the washing layers were combined and evaporated. The remainder was purified by column chromatography on silica gel (cyclohexane/ethyl acetate 4:1) to obtain 4-{4-[5-(2,6-difluoro-phenyl)-4,5-dihydro-isoxazol-3-yl]-thiazol-2-yl}-piperazine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester as a light yellow foam. M.p. 68-72° C. 1H-NMR (400 MHz, CDCl3): δ=1.42-1.53 (m, 9H), 3.09 (dd, 1H), 3.33 (dt, 2H), 3.52 (dd, 1H), 3.69 (t, 1H), 3.74 (s, 3H), 3.91-4.08 (m, 2H), 4.42 (dd, 1H), 4.70-4.93 (m, 1H), 6.02 (t, 1H), 6.89 (t, 2H), 7.00 (s, 1H), 7.24-7.31 (m, 1H). MS: m/z=509 (M+1).
12.5 ml of a 1.25 M solution of hydrochloric acid in ethanol were added to a solution of 4-{4-[5-(2,6-difluoro-phenyl)-4,5-dihydro-isoxazol-3-yl]-thiazol-2-yl}-piperazine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (0.8 g, 1.6 mmol) in 13 ml of a 1:1 mixture of dichloromethane and methanol. This reaction mixture was stirred for 16 h at room temperature and then evaporated to directly deliver 4-{4-[5-(2,6-difluoro-phenyl)-4,5-dihydro-isoxazol-3-yl]-thiazol-2-yl}-piperazine-2-carboxylic acid methyl ester hydrochloride as a light orange foam. 1H-NMR (400 MHz, CDCl3): δ=3.21 (dd, 1H), 3.39-3.48 (m, 2H), 3.59 (dd, 1H), 3.68 (t, 1H), 3.77-3.86 (m, 5H), 4.25 (dd, 1H), 4.51-4.57 (m, 1H), 5.99 (t, 1H), 6.32 (bs, 1H), 7.16 (t, 2H), 7.42 (s, 1H), 7.50 (q, 1H). MS: m/z=409 (M+1-HCl).
To a solution of 4-{4-[5-(2,6-difluoro-phenyl)-4,5-dihydro-isoxazol-3-yl]-thiazol-2-yl}-piperazine-2-carboxylic acid methyl ester hydrochloride (0.5 g, 1.0 mmol) in 4 ml of N,N-dimethylformamide were added at 0° C. sequentially ethyl(diisopropyl)amine (0.3 g, 2.5 mmol), (5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid (0.2 g, 1.1 mmol) and benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (0.5 g, 1.1 mmol). The reaction mixture was stirred for 16 h at room temperature, then poured on water and extracted with ethyl acetate. The combined organic layer was washed with saturated aqueous sodium bicarbonate solution and brine, dried over sodium sulfate and evaporated. The residue is purified by column chromatography on silica gel (cyclohexane/ethyl acetate 4:1) to give 4-{4-[5-(2,6-difluoro-phenyl)-4,5-dihydro-isoxazol-3-yl]-thiazol-2-yl}-1-[2-(5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetyl]-piperazine-2-carboxylic acid methyl ester (compound I.az.038) as light yellow foam. 1H-NMR (400 MHz, CDCl3): 8=2.31 (s, 3H), 3.12 (t, 1H), 3.34 (dd, 1H), 3.53 (dd, 1H), 3.64-3.76 (m, 4H), 3.89 (dd, 1H), 4.20 (dt, 1H), 4.44 (dd, 1H), 4.97 (dd, 1H), 5.22 (dd, 1H), 6.02 (t, 1H), 6.33 (d, 1H), 6.91 (t, 2H), 7.02 (s, 1H), 7.29 (q, 1H). MS: m/z=599 (M+1).
To a solution of 4-{4-[5-(2,6-difluoro-phenyl)-4,5-dihydro-isoxazol-3-yl]-thiazol-2-yl}-1-[2-(5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetyl]-piperazine-2-carboxylic acid methyl ester (compound I.az.038, 0.3 g, 0.5 mmol) in 5 ml of tetrahydrofurane was added 0.8 ml of a 1 N sodium hydroxide solution. The reaction mixture was stirred for 2 h at room temperature and then concentrated under reduced pressure. The residue was taken up in water and washed with ethyl acetate. The aqueous phase was acidified with citric acid to pH 3 to 4 and then extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate and evaporated to directly deliver 4-{4-[5-(2,6-difluoro-phenyl)-4,5-dihydro-isoxazol-3-yl]-thiazol-2-yl}-1-[2-(5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetyl]-piperazine-2-carboxylic acid (compound I.az.037) as white cristalls. M.p. 178-185° C. 1H-NMR (400 MHz, CDCl3): δ=2.27 (s, 3H), 3.04-3.20 (m, 2H), 3.33 (dd, 1H), 3.50 (dd, 1H), 3.62-3.71 (m, 2H), 3.89 (dd, 1H), 4.17 (dt, 1H), 4.45 (dd, 1H), 5.04-5.28 (m, 3H), 6.00 (t, 1H), 6.31 (d, 1H), 6.89 (t, 2H), 6.96 (s, 1H), 7.28 (q, 1H). MS: m/z=585 (M+1).
Table 1 below illustrates examples of individual compounds of formula I according to the invention.
where
a) 360 compounds of formula (I.a):
wherein R1, R2, R3, R5, G2, T, Y1 and Y2 are as defined in Table 1.
b) 360 compounds of formula (I.b):
wherein R1, R2, R3, R5, G2, T, Y1 and Y2 are as defined in Table 1.
c) 360 compounds of formula (I.c):
wherein R1, R2, R3, R5, G2, T, Y1 and Y2 are as defined in Table 1.
d) 360 compounds of formula (I.d):
Wherein R1, R2, R3, R5, G2, T, Y1 and Y2 are as defined in Table 1.
e) 360 compounds of formula (I.e):
wherein R1, R2, R3, R5, G2, T, Y1 and Y2 are as defined in Table 1.
f) 360 compounds of formula (I.f):
wherein R1, R2, R3, R5, G2, T, Y1 and Y2 are as defined in Table 1.
g) 360 compounds of formula (I.g):
wherein R1, R2, R3, R5, G2, T, Y1 and Y2 are as defined in Table 1.
h) 360 compounds of formula (I.h):
wherein R1, R2, R3, R5, G2, T, Y1 and Y2 are as defined in Table 1.
i) 360 compounds of formula (I.i):
wherein R1, R2, R3, R5, G2, T, Y1 and Y2 are as defined in Table 1.
j) 360 compounds of formula (I.j):
wherein R1, R2, R3, R5, G2, T, Y1 and Y2 are as defined in Table 1.
k) 360 compounds of formula (I.k):
wherein R1, R2, R3, R5, G2, T, Y1 and Y2 are as defined in Table 1.
m) 360 compounds of formula (I.m):
wherein R1, R2, R3, R5, G2, T, Y1 and Y2 are as defined in Table 1.
n) 360 compounds of formula (I.n):
wherein R1, R2, R3, R5, G2, T, Y1 and Y2 are as defined in Table 1.
o) 360 compounds of formula (I.o):
wherein R1, R2, R3, R5, G2, T, Y1 and Y2 are as defined in Table 1.
p) 360 compounds of formula (I.p):
wherein R1, R2, R3, R5, G2, T, Y1 and Y2 are as defined in Table 1.
q) 360 compounds of formula (I.q):
wherein R1, R2, R3, R5, G2, T, Y1 and Y2 are as defined in Table 1.
r) 360 compounds of formula (I.r):
wherein R1, R2, R3, R5, G2, T, Y1 and Y2 are as defined in Table 1.
s) 360 compounds of formula (I.s):
wherein R1, R2, R3, R5, G2, T, Y1 and Y2 are as defined in Table 1.
t) 360 compounds of formula (I.t):
wherein R1, R2, R3, R5, G2, T, Y1 and Y2 are as defined in Table 1.
u) 360 compounds of formula (I.u):
wherein R1, R2, R3, R5, G2, T, Y1 and Y2 are as defined in Table 1.
v) 360 compounds of formula (I.v):
wherein R1, R2, R3, R5, G2, T, Y1 and Y2 are as defined in Table 1.
w) 360 compounds of formula (I.w):
wherein R1, R2, R3, R5, G2, T, Y1 and Y2 are as defined in Table 1.
x) 360 compounds of formula (I.x):
wherein R1, R2, R3, R5, G2, T, Y1 and Y2 are as defined in Table 1.
y) 360 compounds of formula (I.y):
wherein R1, R2, R3, R5, G2, T, Y1 and Y2 are as defined in Table 1.
z) 360 compounds of formula (I.z):
wherein R1, R2, R3, R5, G2, T, Y1 and Y2 are as defined in Table 1.
aa) 360 compounds of formula (I.aa):
wherein R1, R2, R3, R5, G2, T, Y1 and Y2 are as defined in Table 1.
ab) 360 compounds of formula (I.ab):
wherein R1, R2, R3, R5, G2, T, Y1 and Y2 are as defined in Table 1.
ac) 360 compounds of formula (I.ac):
wherein R1, R2, R3, R5, G2, T, Y1 and Y2 are as defined in Table 1.
ad) 360 compounds of formula (I.ad):
wherein R1, R2, R3, R5, G2, T, Y1 and Y2 are as defined in Table 1.
ae) 360 compounds of formula (I.ae):
wherein R1, R2, R3, R5, G2, T, Y1 and Y2 are as defined in Table 1.
af) 360 compounds of formula (I.af):
wherein R1, R2, R3, R5, G2, T, Y1 and Y2 are as defined in Table 1.
ag) 360 compounds of formula (I.ag):
wherein R1, R2, R3, R5, G2, T, Y1 and Y2 are as defined in Table 1.
ah) 360 compounds of formula (I.ah):
wherein R1, R2, R3, R5, G2, T, Y1 and Y2 are as defined in Table 1.
ai) 360 compounds of formula (I.ai):
wherein R1, R2, R3, R5, G2, T, Y1 and Y2 are as defined in Table 1.
aj) 360 compounds of formula (I.aj):
wherein R1, R2, R3, R5, G2, T, Y1 and Y2 are as defined in Table 1.
ak) 360 compounds of formula (I.ak):
wherein R1, R2, R3, R5, G2, T, Y1 and Y2 are as defined in Table 1.
am) 360 compounds of formula (I.am):
wherein R1, R2, R3, R5, G2, T, Y1 and Y2 are as defined in Table 1.
an) 360 compounds of formula (I.an):
wherein R1, R2, R3, R5, G2, T, Y1 and Y2 are as defined in Table 1.
ao) 360 compounds of formula (I.ao):
wherein R1, R2, R3, R5, G2, T, Y1 and Y2 are as defined in Table 1.
ap) 360 compounds of formula (I.ap):
wherein R1, R2, R3, R5, G2, T, Y1 and Y2 are as defined in Table 1.
aq) 360 compounds of formula (I.aq):
wherein R1, R2, R3, R5, G2, T, Y1 and Y2 are as defined in Table 1.
ar) 360 compounds of formula (I.ar):
wherein R1, R2, R3, R5, G2, T, Y1 and Y2 are as defined in Table 1.
as) 360 compounds of formula (I.as):
wherein R1, R2, R3, R5, G2, T, Y1 and Y2 are as defined in Table 1.
at) 360 compounds of formula (I.at):
wherein R1, R2, R3, R5, G2, T, Y1 and Y2 are as defined in Table 1.
au) 360 compounds of formula (I.au):
wherein R1, R2, R3, R5, G2, T, Y1 and Y2 are as defined in Table 1.
av) 360 compounds of formula (I.av):
wherein R1, R2, R3, R5, G2, T, Y1 and Y2 are as defined in Table 1.
aw) 360 compounds of formula (I.aw):
wherein R1, R2, R3, R5, G2, T, Y1 and Y2 are as defined in Table 1.
ax) 360 compounds of formula (I.ax):
wherein R1, R2, R3, R5, G2, T, Y1 and Y2 are as defined in Table 1.
ay) 360 compounds of formula (I.ay):
Wherein R1, R2, R3, R5, G2, T, Y1 and Y2 are as defined in Table 1.
az) 360 compounds of formula (I.az):
wherein R1, R2, R3, R5, G2, T, Y1 and Y2 are as defined in Table 1.
ba) 360 compounds of formula (I.ba):
wherein R1, R2, R3, R5, G2, T, Y1 and Y2 are as defined in Table 1.
bb) 360 compounds of formula (I.bb):
wherein R1, R2, R3, R5, G2, T, Y1 and Y2 are as defined in Table 1.
bc) 360 compounds of formula (I.bc):
wherein R1, R2, R3, R5, G2, T, Y1 and Y2 are as defined in Table 1.
bd) 360 compounds of formula (I.bd):
wherein R1, R2, R3, R5, G2, T, Y1 and Y2 are as defined in Table 1.
be) 360 compounds of formula (I.be):
wherein R1, R2, R3, R5, G2, T, Y1 and Y2 are as defined in Table 1.
bf) 360 compounds of formula (I.bf):
wherein R1, R2, R3, R5, G2, T, Y1 and Y2 are as defined in Table 1.
Throughout this description, temperatures are given in degrees Celsius and “m.p.” means melting point. LC/MS means Liquid Chromatography Mass Spectroscopy and the description of the apparatus and the method is: (ACQUITY UPLC from Waters, Phenomenex Gemini C18, 3 μm particle size, 110 Angström, 30×3 mm column, 1.7 mL/min., 60° C., H2O+0.05% HCOOH (95%)/CH3CN/MeOH 4:1+0.04% HCOOH (5%)−2 min.−CH3CN/MeOH 4:1+0.04% HCOOH (5%)−0.8 min., ACQUITY SQD Mass Spectrometer from Waters, ionization method: electrospray (ESI), Polarity: positive ions, Capillary (kV) 3.00, Cone (V) 20.00, Extractor (V) 3.00, Source Temperature (° C.) 150, Desolvation Temperature (° C.) 400, Cone Gas Flow (L/Hr) 60, Desolvation Gas Flow (L/Hr) 700)).
The compounds according to the present invention can be prepared according to the above-mentioned reaction schemes, in which, unless otherwise stated, the definition of each variable is as defined above for a compound of formula (I).
Phytophthora Infestans/Tomato/Leaf Disc Preventative (Tomato Late Blight)
Tomato leaf disks are placed on water agar in multiwell plates (24-well format) and sprayed with the formulated test compound diluted in water. The leaf disks are inoculated with a spore suspension of the fungus 1 day after application. The inoculated leaf disks are incubated at 16° C. and 75% rh under a light regime of 24 h darkness followed by 12 h light/12 h darkness in a climate cabinet and the activity of a compound is assessed as percent disease control compared to untreated when an appropriate level of disease damage appears in untreated check leaf disks (5-7 days after application).
Compounds I.az.038, I.az.044, I.az.254, I.az.259 and I.az.260 at 200 ppm give at least 80% disease control in this test when compared to untreated control leaf disks under the same conditions, which show extensive disease development.
Phytophthora infestans/Potato/Preventative (Potato Late Blight)
2-week old potato plants cv. Bintje are sprayed in a spray chamber with the formulated test compound diluted in water. The test plants are inoculated by spraying them with a sporangia suspension 2 days after application. The inoculated test plants are incubated at 18° C. with 14 h light/day and 100% rh in a growth chamber and the percentage leaf area covered by disease is assessed when an appropriate level of disease appears on untreated check plants (5-7 days after application).
Phytophthora infestans/Potato/Curative (Potato Late Blight)
2-week old potato plants cv. Bintje are inoculated by spraying them with a sporangia suspension one day before application. The inoculated plants are sprayed in a spray chamber with the formulated test compound diluted in water. The inoculated test plants are incubated at 18° C. with 14 h light/day and 100% rh in a growth chamber and the percentage leaf area covered by disease is assessed when an appropriate level of disease appears on untreated check plants (3-4 days after application).
Phytophthora infestans I Potato/Long Lasting (Potato Late Blight)
2-week old potato plants cv. Bintje are sprayed in a spray chamber with the formulated test compound diluted in water. The test plants are inoculated by spraying them with a sporangia suspension 6 days after application. The inoculated test plants are incubated at 18° C. with 14 h light/day and 100% rh in a growth chamber and the percentage leaf area covered by disease is assessed when an appropriate level of disease appears on untreated check plants (9-11 days after application).
Plasmopara viticola/Grape/Leaf Disc Preventative (Grape Downy Mildew)
Grape vine leaf disks are placed on water agar in multiwell plates (24-well format) and sprayed with the formulated test compound diluted in water. The leaf disks are inoculated with a spore suspension of the fungus 1 day after application. The inoculated leaf disks are incubated at 19° C. and 80% rh under a light regime of 12 h light/12 h darkness in a climate cabinet and the activity of a compound is assessed as percent disease control compared to untreated when an appropriate level of disease damage appears in untreated check leaf disks (6-8 days after application).
Compounds I.az.038, I.az.254 and I.az.260 at 200 ppm give at least 80% disease control in this test when compared to untreated control leaf disks under the same conditions, which show extensive disease development.
Plasmopara viticola/Grape/Preventative (Rape Downy Mildew)
5-week old grape seedlings cv. Gutedel are sprayed in a spray chamber with the formulated test compound diluted in water. The test plants plants are inoculated by spraying a sporangia suspension on their lower leaf surface one day after application. The inoculated test plants are incubated at 22° C. and 100% rh in a greenhouse and the percentage leaf area covered by disease is assessed when an appropriate level of disease appears on untreated check plants (6-8 days after application).
Plasmopara viticola/Grape/Curative (Grape Downy Mildew)
5-week-old grape seedlings cv. Gutedel are inoculated by spraying a sporangia suspension on their lower leaf surface one day before application. The inoculated grape plants are sprayed in a spray chamber with the formulated test compound diluted in water. The inoculated test plants are incubated at 22° C. and 100% rh in a greenhouse and the percentage leaf area covered by disease is assessed when an appropriate level of disease appears on untreated check plants (4-6 days after application).
Plasmopara viticola/Grape/Long Lasting (Grape Downy Mildew)
5-week old grape seedlings cv. Gutedel are sprayed in a spray chamber with the formulated test compound diluted in water. The test plants are inoculated by spraying a sporangia suspension on their lower leaf surface 6 days after application. The inoculated test plants are incubated at 22° C. and 100% rh in a greenhouse and the percentage leaf area covered by disease is assessed when an appropriate level of disease appears on untreated check plants (11-13 days after application).
Pythium ultimum/Liquid Culture (Seedling Damping Off)
Mycelia fragments and oospores of a newly grown liquid culture of the fungus are directly mixed into nutrient broth (PDB potato dextrose broth). After placing a (DMSO) solution of test compound into a microtiter plate (96-well format), the nutrient broth containing the fungal mycelia/spore mixture is added. The test plates are incubated at 24° C. and the inhibition of growth is determined photometrically 2-3 days after application.
Compounds I.az.038, I.az.043, I.az.044, I.az.254, Iaz.259 and I.az.260 at 200 ppm give at least 80% disease control in this test when compared to untreated control agar droplets under the same conditions, which show extensive disease development.
| Number | Date | Country | Kind |
|---|---|---|---|
| 620/DELNP/2012 | Mar 2012 | IN | national |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/EP13/53803 | 2/26/2013 | WO | 00 |
