WO2021058595A1 - Herbicidal compounds - Google Patents

Herbicidal compounds Download PDF

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Publication number
WO2021058595A1
WO2021058595A1 PCT/EP2020/076614 EP2020076614W WO2021058595A1 WO 2021058595 A1 WO2021058595 A1 WO 2021058595A1 EP 2020076614 W EP2020076614 W EP 2020076614W WO 2021058595 A1 WO2021058595 A1 WO 2021058595A1
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alkyl
group
formula
phenyl
hydrogen
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PCT/EP2020/076614
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French (fr)
Inventor
James Nicholas Scutt
Nigel James Willetts
Sunil CHAKAVE
Vanitha ACHARYA
Mangala Phadte
Swarnendu SASMAL
Sandeep Reddy KANDUKURI
Joseph Andrew TATE
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Syngenta Crop Protection Ag
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Publication of WO2021058595A1 publication Critical patent/WO2021058595A1/en

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    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/34—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom
    • A01N43/40—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom six-membered rings
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/90—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having two or more relevant hetero rings, condensed among themselves or with a common carbocyclic ring system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • the present invention relates to herbicidally active pyridinium derivatives, as well as to processes and intermediates used for the preparation of such derivatives.
  • the invention further extends to herbicidal compositions comprising such derivatives, as well as to the use of such compounds and compositions for controlling undesirable plant growth: in particular the use for controlling weeds, in crops of useful plants.
  • the present invention is based on the finding that pyridinium derivatives of formula (I) as defined herein, exhibit surprisingly good herbicidal activity.
  • R 1 is selected from the group consisting of hydrogen, halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 1 -C 6 haloalkyl, -OR 7 , -OR 15a , -N(R 6 )S(O) 2 R 15 , -N(R 6 )C(O)R 15 , -N(R 6 )C(O)OR 15 , - N(R 6 )C(O)NR 16 R 17 , -N(R 6 )CHO, -N(R 7a ) 2 and -S(O) r R 15 ;
  • R 2 is selected from the group consisting of hydrogen, halogen, C 1 -C 6 alkyl and C 1 -C 6 haloalkyl; and wherein when R 1 is selected from the group consisting of -OR 7 , -OR 15a , -N(R 6 )S(O) 2 R 15 , - N(R 6 )C(O)R 15 , -N(R 6 )C(O)OR 15 , -N(R 6 )C(O)NR 16 R 17 , -N(R 6 )CHO, -N(R 7a ) 2 and -S(O) r R 15 , R 2 is selected from the group consisting of hydrogen and C 1 -C 6 alkyl; or
  • R 1 and R 2 together with the carbon atom to which they are attached form a C 3 -C 6 cycloalkyl ring or a 3- to 6- membered heterocyclyl, which comprises 1 or 2 heteroatoms individually selected from N and O; and
  • Q is (CR 1a R 2b ) m ; m is 0, 1 , 2 or 3; each R 1a and R 2b are independently selected from the group consisting of hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -OH, -OR 7 , -OR 15a , -NH 2 , -NHR 7 , -NHR 15a , -N(R 6 )CHO, -NR 7b R 7c and -S(O) r R 15 ; or each R 1a and R 2b together with the carbon atom to which they are attached form a C 3 -C 6 cycloalkyl ring or a 3- to 6- membered heterocyclyl, which comprises 1 or 2 heteroatoms individually selected from N and O; and
  • R 3 , R 3a , R 4 and R 5 are independently selected from the group consisting of hydrogen, halogen, cyano, nitro, -S(O)rR 15 , C 1 -C 6 alkyl, C 1 -C 6 fluoroalkyl, C 1 -C 6 fluoroalkoxy, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl and - N(R 6 ) 2 ; each R 6 is independently selected from hydrogen and C 1 -C 6 alkyl; each R 7 is independently selected from the group consisting of C 1 -C 6 alkyl, -S(O) 2 R 15 , -C(O)R 15 , - C(O)OR 15 and -C(O)NR 16 R 17 ; each R 7a is independently selected from the group consisting of -S(O) 2 R 15 , -C(O)R 15 , -C(O)OR 15 - C(O)NR 16 R 17 and
  • R 7b and R 7c are independently selected from the group consisting of C 1 -C 6 alkyl, -S(O) 2 R 15 , -C(O)R 15 , - C(O)OR 15 , -C(O)NR 16 R 17 and phenyl, and wherein said phenyl is optionally substituted by 1 , 2 or 3 R 9 substituents, which may be the same or different; or
  • R 7b and R 7c together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclyl ring which optionally comprises one additional heteroatom individually selected from N, O and S; and
  • A is a fused bicyclic structure of general formula; in which:
  • ring A 1 has 5 members and ring A 2 has 6 members;
  • A includes at least one heteroatom selected from N, O and S, with the remainder being carbon atoms;
  • one of the carbon atoms is optionally a carbonyl
  • A is optionally substituted in any available position in either or both of ring A 1 or ring A 2 by p substituents R 8 , which may be the same or different;
  • each R 8 is independently selected from the group consisting of halogen, nitro, cyano, -NH 2 , -NHR 7 , -N(R 7 ) 2 , -OH, -OR 7 , -S(O) r R 15 , - NR 6 S(O) 2 R 15 , -C(O)OR 10 , -C(O)R 15 , -C(O)NR 16 R 17 , -S(O) 2 NR 16 R 17 , C 1 - C a y, C 1 -C 6 haloalkyl, C 3 - C 6 cycloalkyl, C 3 -C 6 halocycloalkyl, C 3 -C 6 cycloalkoxy, C 2 -C 6 alkenyl, C 2 -C 6 haloalkenyl, C 2 -C 6 alkenyl, C 2 -C 6 haloalkenyl, C 2 -C 6 alkenyl,
  • X is selected from the group consisting of C 3 -C 6 cycloalkyl, phenyl, a 5- or 6- membered heteroaryl, which comprises 1 , 2, 3 or 4 heteroatoms individually selected from N, O and S, and a 4- to 6- membered heterocyclyl, which comprises 1 , 2 or 3 heteroatoms individually selected from N, O and S, and wherein said cycloalkyl, phenyl, heteroaryl or heterocyclyl moieties are optionally substituted by 1 or 2 substituents, which may be the same or different, selected from R 9 , and wherein the aforementioned CR 1 R 2 , Q and Z moieties may be attached at any position of said cycloalkyl, phenyl, heteroaryl or heterocyclyl moieties; n is 0 or 1 ; Z is selected from the group consisting of -C(O)OR 10 , -CH 2 OH, -CHO, -C(O)NHOR 11 , -C
  • R 10 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, phenyl and benzyl, and wherein said phenyl or benzyl are optionally substituted by 1 , 2 or 3 R 9 substituents, which may be the same or different;
  • R 11 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl and phenyl, and wherein said phenyl is optionally substituted by 1 , 2 or 3 R 9 substituents, which may be the same or different;
  • R 12 is selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, -OH, -N(R 6 ) 2 and phenyl, and wherein said phenyl is optionally substituted by 1 , 2 or 3 R 9 substituents, which may be the same or different;
  • R 13 is selected from the group consisting of -OH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy and phenyl;
  • R 14 is C 1 -C 6 haloalkyl
  • R 15 is selected from the group consisting of C 1 -C 6 alkyl and phenyl, and wherein said phenyl is optionally substituted by 1 , 2 or 3 R 9 substituents, which may be the same or different;
  • R 15a is phenyl, wherein said phenyl is optionally substituted by 1 , 2 or 3 R 9 substituents, which may be the same or different;
  • R 16 and R 17 are independently selected from the group consisting of hydrogen and C 1 -C 6 alkyl; or R 16 and R 17 together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclyl ring which optionally comprises one additional heteroatom individually selected from N, O and S; and
  • R 18 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, -N(R 6 ) 2 and phenyl, and wherein said phenyl is optionally substituted by 1 , 2 or 3 R 9 substituents, which may be the same or different; and r is 0, 1 or 2.
  • an agrochemical composition comprising a herbicidally effective amount of a compound of formula (I) and an agrochemically-acceptable diluent or carrier.
  • Such an agricultural composition may further comprise at least one additional active ingredient.
  • a method of controlling or preventing undesirable plant growth wherein a herbicidally effective amount of a compound of formula (I), or a composition comprising this compound as active ingredient, is applied to the plants, to parts thereof or the locus thereof.
  • halogen refers to fluorine (fluoro), chlorine (chloro), bromine (bromo) or iodine (iodo), preferably fluorine, chlorine or bromine.
  • cyano means a -CN group.
  • hydroxy means an -OH group.
  • nitro means an -NO 2 group.
  • C 1 -C 6 alkyl refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to six carbon atoms, and which is attached to the rest of the molecule by a single bond.
  • C 1 -C 4 alkyl and C 1 - C 2 alkyl are to be construed accordingly.
  • Examples of C 1 -C 6 alkyl include, but are not limited to, methyl (Me), ethyl (Et), n-propyl, 1-methylethyl (iso-propyl), n-butyl, and 1-dimethylethyl (t-butyl).
  • C 1 -C 6 alkoxy refers to a radical of the formula -OR a where R a is a C 1 - C 6 alkyl radical as generally defined above.
  • R a is a C 1 - C 6 alkyl radical as generally defined above.
  • C 1 -C 4 alkoxy is to be construed accordingly. Examples of C 1 - 4 alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, iso-propoxy and -butoxy.
  • C 1 -C 6 haloalkyl refers to a C 1 -C 6 alkyl radical as generally defined above substituted by one or more of the same or different halogen atoms.
  • C 1 -C 4 haloalkyl is to be construed accordingly.
  • Examples of C 1 -C 6 haloalkyl include, but are not limited to chloromethyl, fluoromethyl, fluoroethyl, difluoromethyl, trifluoromethyl and 2,2,2-trifluoroethyl.
  • C 2 -C 6 alkenyl refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one double bond that can be of either the (E)- or (Z)-configuration, having from two to six carbon atoms, which is attached to the rest of the molecule by a single bond.
  • C 2 -C 4 alkenyl is to be construed accordingly.
  • Examples of C 2 -C 6 alkenyl include, but are not limited to, prop-1 -enyl, allyl (prop-2-enyl) and but-1-enyl.
  • C 2 -C 6 haloalkenyl refers to a C 2 -C 6 alkenyl radical as generally defined above substituted by one or more of the same or different halogen atoms.
  • Examples of C 2 -C 6 haloalkenyl include, but are not limited to chloroethylene, fluoroethylene, 1 ,1-difluoroethylene, 1 ,1-dichloroethylene and 1 ,1 ,2-trichloroethylene.
  • C 2 -C 6 alkynyl refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one triple bond, having from two to six carbon atoms, and which is attached to the rest of the molecule by a single bond.
  • C 2 -C 4 alkynyl is to be construed accordingly.
  • Examples of C 2 -C 6 alkynyl include, but are not limited to, prop-1-ynyl, propargyl (prop-2-ynyl) and but-1-ynyl.
  • C 1 -C 6 haloalkoxy refers to a C 1 -C 6 alkoxy group as defined above substituted by one or more of the same or different halogen atoms.
  • C 1 -C 4 haloalkoxy is to be construed accordingly.
  • Examples of C 1 -C 6 haloalkoxy include, but are not limited to, fluoromethoxy, difluoromethoxy, fluoroethoxy, trifluoromethoxy and trifluoroethoxy.
  • C 1 -C 3 haloalkoxyC 1 -C 3 alkyl refers to a radical of the formula R b -O-R a - where R b is a C 1 -C 3 haloalkyl radical as generally defined above, and R a is a C 1 -C 3 alkylene radical as generally defined above.
  • C 1 -C 3 alkoxyC 1 -C 3 alkyl refers to a radical of the formula R b -O-R a - where R b is a C 1 -C 3 alkyl radical as generally defined above, and R a is a C 1 -C 3 alkylene radical as generally defined above.
  • C 1 -C 3 alkoxyC 1 -C 3 alkoxy- refers to a radical of the formula R b -O-R a - O- where R b is a C 1 -C 3 alkyl radical as generally defined above, and R a is a C 1 -C 3 alkylene radical as generally defined above.
  • C 3 -C 6 alkenyloxy refers to a radical of the formula -OR a where R a is a C 3 -C 6 alkenyl radical as generally defined above.
  • C 3 -C 6 alkynyloxy refers to a radical of the formula -OR a where R a is a C 3 -C 6 alkynyl radical as generally defined above.
  • hydroxyC 1 -C 6 alkyl refers to a C 1 -C 6 alkyl radical as generally defined above substituted by one or more hydroxy groups.
  • C 1 -C 6 alkylcarbonyl refers to a radical of the formula -C(O)R a where R a is a C 1 -C 6 alkyl radical as generally defined above.
  • C 1 -C 6 alkoxycarbonyl refers to a radical of the formula -C(O)OR a where R a is a C 1 -C 6 alkyl radical as generally defined above.
  • aminocarbonyl refers to a radical of the formula -C(O)NH 2 .
  • C 3 -C 6 cycloalkyl refers to a stable, monocyclic ring radical which is saturated or partially unsaturated and contains 3 to 6 carbon atoms.
  • C 3 -C 4 cycloalkyl is to be construed accordingly. Examples of C 3 -C 6 cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • C 3 -C 6 halocycloalkyl refers to a C 3 -C 6 cycloalkyl radical as generally defined above substituted by one or more of the same or different halogen atoms.
  • C 3 -C 4 halocycloalkyl is to be construed accordingly.
  • C 3 -C 6 cycloalkoxy refers to a radical of the formula -OR a where R a is a C 3 -C 6 cycloalkyl radical as generally defined above.
  • N-C 3 -C 6 cycloalkylamino refers to a radical of the formula -NHR a where R a is a C 3 -C 6 cycloalkyl radical as generally defined above.
  • heteroaryl refers to a 5- or 6- membered monocyclic aromatic ring which comprises 1 , 2, 3 or 4 heteroatoms individually selected from nitrogen, oxygen and sulfur.
  • the heteroaryl radical may be bonded to the rest of the molecule via a carbon atom or heteroatom.
  • heteroaryl include, furyl, pyrrolyl, imidazolyl, thienyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrazinyl, pyridazinyl, pyrimidyl or pyridyl.
  • heterocyclyl refers to a stable 4- to 6-membered non-aromatic monocyclic ring radical which comprises 1 , 2, or 3 heteroatoms individually selected from nitrogen, oxygen and sulfur.
  • the heterocyclyl radical may be bonded to the rest of the molecule via a carbon atom or heteroatom.
  • heterocyclyl examples include, but are not limited to, pyrrolinyl, pyrrolidyl, tetrahydrofuryl, tetrahydrothienyl, tetrahydrothiopyranyl, piperidyl, piperazinyl, tetrahydropyranyl, dihydroisoxazolyl, dioxolanyl, morpholinyl or d-lactamyl.
  • asymmetric carbon atoms in a compound of formula (I) means that the compounds may occur in chiral 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).
  • formula (I) is intended to include all possible tautomers (including lactam-lactim tautomerism and keto-enol tautomerism) where present.
  • the present invention includes all possible tautomeric forms for a compound of formula (I).
  • where there are di-substituted alkenes these may be present in E or Z form or as mixtures of both in any proportion.
  • the present invention includes all these possible isomeric forms and mixtures thereof for a compound of formula (I).
  • the compounds of formula (I) will typically be provided in the form of an agronomically acceptable salt, a zwitterion or an agronomically acceptable salt of a zwitterion.
  • This invention covers all such agronomically acceptable salts, zwitterions and mixtures thereof in all proportions.
  • a compound of formula (I) wherein Z comprises an acidic proton may exist as a zwitterion, a compound of formula (l-l), or as an agronomically acceptable salt, a compound of formula (l-ll) as shown below:
  • Y represents an agronomically acceptable anion and j and k represent integers that may be selected from 1 , 2 or 3, dependent upon the charge of the respective anion Y.
  • a compound of formula (I) may also exist as an agronomically acceptable salt of a zwitterion, a compound of formula (l-lll) as shown below: wherein, Y represents an agronomically acceptable anion, M represents an agronomically acceptable cation (in addition to the pyridazinium cation) and the integers j, k and q may be selected from 1 , 2 or 3, dependent upon the charge of the respective anion Y and respective cation M.
  • a compound of formula (l-ll) wherein k is 2, j is 1 and Y is selected from the group consisting of halogen, trifluoroacetate and pentafluoropropionate.
  • a nitrogen atom in ring A may be protonated or a nitrogen atom comprised in R 1 , R 2 , R 8 , Q orX may be protonated.
  • k is 2, j is 1 and Y is chloride, wherein a nitrogen atom in ring A is protonated.
  • Suitable agronomically acceptable salts of the present invention include but are not limited chloride, bromide, iodide, fluoride, 2-naphthalenesulfonate, acetate, adipate, methoxide, ethoxide, propoxide, butoxide, aspartate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, butylsulfate, butylsulfonate, butyrate, camphorate, camsylate, caprate, caproate, caprylate, carbonate, citrate, diphosphate, edetate, edisylate, enanthate, ethanedisulfonate, ethanesulfonate, ethylsulfate, formate, fumarate, gluceptate, gluconate, glucoronate, glutamate, glycerophosphate, hepta
  • Suitable cations represented by M include, but are not limited to, metals, conjugate acids of amines and organic cations.
  • suitable metals include aluminium, calcium, cesium, copper, lithium, magnesium, manganese, potassium, sodium, iron and zinc.
  • Suitable amines include allylamine, ammonia, amylamine, arginine, benethamine, benzathine, butenyl-2-amine, butylamine, butylethanolamine, cyclohexylamine, decylamine, diamylamine, dibutylamine, diethanolamine, diethylamine, diethylenetriamine, diheptylamine, dihexylamine, diisoamylamine, diisopropylamine, dimethylamine, dioctylamine, dipropanolamine, dipropargylamine, dipropylamine, dodecylamine, ethanolamine, ethylamine, ethylbutylamine, ethylenediamine, ethylheptylamine, ethyloctylamine, ethylpropanolamine, heptadecylamine, heptylamine, hexadecylamine, he
  • Suitable organic cations include benzyltributylammonium, benzyltrimethylammonium, benzyltriphenylphosphonium, choline, tetrabutylammonium, tetrabutylphosphonium, tetraethylammonium, tetraethylphosphonium, tetramethylammonium, tetramethylphosphonium, tetrapropylammonium, tetrapropylphosphonium, tributylsulfonium, tributylsulfoxonium, triethylsulfonium, triethylsulfoxonium, trimethylsulfonium, trimethylsulfoxonium, tripropylsulfonium and tripropylsulfoxonium.
  • Preferred compounds of formula (I), wherein Z comprises an acidic proton can be represented as either (l-l) or (l-ll).
  • Y is chloride, bromide, iodide, hydroxide, bicarbonate, acetate, pentafluoropropionate, triflate, trifluoroacetate, methylsulfate, tosylate and nitrate, wherein j and k are 1.
  • Y is chloride, bromide, iodide, hydroxide, bicarbonate, acetate, trifluoroacetate, methylsulfate, tosylate and nitrate, wherein j and k are 1.
  • R 1 , R 2 , R 1a , R 2b , R 3 , R 3a , R 4 , R 5 , A and Z are as defined for compounds of formula (I).
  • the following list provides definitions, including preferred definitions, for substituents n, m, r, A, Q, X, Z, R 1 , R 2 ,R 1a , R 2b , R 3 , R 3a , R 4 , R 5 , R 6 , R 7 ,R 7a , R 7b ,R 7c ,R 8 ,R 9 , R 10 , R 1 1 , R 12 , R 13 , R 1 4 , R 15 ,R 15a ,R 16 , R 17 and R 18 with reference to the compounds of formula (I) according to the invention.
  • R 1 is selected from the group consisting of hydrogen, halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 1 -C 6 haloalkyl, -OR 7 , -OR 15a , -N(R 6 )S(O) 2 R 15 , -N(R 6 )C(O)R 15 , -N(R 6 )C(O)OR 15 , -N(R 6 )C(O)NR 16 R 17 , -N(R 6 )CHO, -N(R 7a ) 2 and -S(O) r R 15 .
  • R 1 is selected from the groupconsisting of hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 fluoroalkyl, -OR 7 , -NHS(O) 2 R 15 , -NHC(O)R 15 , -NHC(O)OR 15 , -NHC(O)NR 16 R 17 , -N(R 7a ) 2 and -S(O) r R 15 . More preferably, R 1 is selected from the group consisting of hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 fluoroalkyl, -OR 7 and -N(R 7a ) 2 .
  • R 1 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, -OR 7 and -N(R 7a ) 2 . Even more preferably still, R 1 is hydrogen or C 1 -C 6 alkyl. Yet even more preferably still, R 1 is hydrogen or methyl. Most preferably R 1 is hydrogen.
  • R 2 is selected from the group consisting of hydrogen, halogen, C 1 -C 6 alkyl and C 1 -C 6 haloalkyl. Preferably, R 2 is selected from the group consisting of hydrogen, halogen, C 1 -C 6 alkyl and C 1 -C 6 fluoroalkyl. More preferably, R 2 is hydrogen or C 1 -C 6 alkyl.
  • R 2 is hydrogen or methyl. Most preferably R 2 is hydrogen.
  • R 1 is selected from the group consisting of -OR 7 , -OR 15a , -N(R 6 )S(O) 2 R 15 , -N(R 6 )C(O)R 15 ,-N(R 6 )C(O)OR 15 , -N(R 6 )C(O)NR 16 R 17 , -N(R 6 )CHO, -N(R 7a ) 2 and -S(O) r R 15 , R 2 is selected from the group consisting of hydrogen and C 1 -C 6 alkyl.
  • R 1 is selected from the group consisting of -OR 7 , -NHS(O) 2 R 15 , -NHC(O)R 15 , -NHC(O)OR 15 , -NHC(O)NR 16 R 17 , -N(R 7a ) 2 and -S(O) r R 15
  • R 2 is selected from the group consisting of hydrogen and methyl.
  • R 1 and R 2 together with the carbon atom to which they are attached form a C 3 -C 6 cycloalkyl ring or a 3- to 6- membered heterocyclyl, which comprises 1 or 2 heteroatoms individually selected fromN and O.
  • R 1 and R 2 together with the carbon atom to which they are attached form a C 3 -C 6 cycloalkyl ring. More preferably, R 1 and R 2 together with the carbon atom to which they are attached form a cyclopropyl ring. In one embodiment R 1 and R 2 are hydrogen.
  • R 1 is methyl and R 2 is hydrogen.
  • R 1 is methyl and R 2 is methyl.
  • Q is (CR 1a R 2b ) m .
  • m is 0, 1 , 2 or 3.
  • m is 0,1 or 2. More preferably, m is 1 or 2. Most preferably, m is 1.
  • Each R 1a and R 2b are independently selected from the group consisting of hydrogen, halogen, C 1 - C 6 alkyl, C 1 -C 6 haloalkyl, -OH, -OR 7 , -OR 15a , -NH 2 , -NHR 7 , -NHR 15a , -N(R 6 )CHO, -NR 7b R 7c and -S(O) r R 15 .
  • each R 1a and R 2b are independently selected from the group consisting of hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 fluoroalkyl, -OH, -NH 2 and -NHR 7 .
  • each R 1a and R 2b are independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, -OH and -NH 2 . Even more preferably, each R 1a and R 2b are independently selected from the group consisting of hydrogen, methyl, -OH and -NH 2 . Even more preferably still, each R 1a and R 2b are independently selected from the group consisting of hydrogen and methyl. Most preferably R 1a and R 2b are hydrogen.
  • each R 1a and R 2b are independently selected from the group consisting of hydrogen and C 1 -C 6 alkyl.
  • each R 1a and R 2b together with the carbon atom to which they are attached form a C 3 - C 6 cycloalkyl ring or a 3- to 6- membered heterocyclyl, which comprises 1 or 2 heteroatoms individually selected from N and O.
  • each R 1a and R 2b together with the carbon atom to which they are attached form a C 3 -C 6 cycloalkyl ring.
  • each R 1a and R 2b together with the carbon atom to which they are attached form a cyclopropyl ring.
  • R 3 , R 3a , R 4 and R 5 are independently selected from the group consisting of hydrogen, halogen, cyano, nitro, -S(O)rR 15 , C 1 -C 6 alkyl, C 1 -C 6 fluoroalkyl, C 1 -C 6 fluoroalkoxy, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl and - N(R 6 ) 2 .
  • R 3 , R 3a , R 4 and R 5 are independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 1 -C 6 fluoroalkyl, C 1 -C 6 fluoroalkoxy, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl and -N(R 6 ) 2 . More preferably, R 3 , R 3a , R 4 and R 5 are independently selected from the group consisting of hydrogen, C 1 - C 6 alkyl and C 1 -C 6 alkoxy. Even more preferably, R 3 , R 3a , R 4 and R 5 are independently selected from the group consisting of hydrogen and C 1 -C 6 alkyl. Even more preferably still, R 3 , R 3a , R 4 and R 5 are independently selected from the group consisting of hydrogen and methyl. Most preferably, R 3 , R 3a , R 4 and R 5 are hydrogen.
  • Each R 6 is independently selected from hydrogen and C 1 -C 6 alkyl. Preferably, each R 6 is independently selected from hydrogen and methyl.
  • Each R 7 is independently selected from the group consisting of C 1 -C 6 alkyl, -S(O) 2 R 15 , -C(O)R 15 , - C(O)OR 15 and -C(O)NR 16 R 17 .
  • each R 7 is independently selected from the group consisting of C 1 -C 6 alkyl, -C(O)R 15 and -C(O)NR 16 R 17 . More preferably, each R 7 is C 1 -C 6 alkyl. Most preferably, each R 7 is methyl.
  • Each R 7a is independently selected from the group consisting of -S(O) 2 R 15 , -C(O)R 15 , -C(O)OR 15 - C(O)NR 16 R 17 and -C(O)NR 6 R 15a .
  • each R 7a is independently -C(O)R 15 or -C(O)NR 16 R 17 .
  • R 7b and R 7c are independently selected from the group consisting of C 1 -C 6 alkyl, -S(O) 2 R 15 , -C(O)R 15 , - C(O)OR 15 , -C(O)NR 16 R 17 and phenyl, and wherein said phenyl is optionally substituted by 1 , 2 or 3 R 9 substituents, which may be the same or different.
  • R 7b and R 7c are independently selected from the group consisting of C 1 -C 6 alkyl, -C(O)R 15 and -C(O)NR 16 R 17 . More preferably, R 7b and R 7c are C 1 -C 6 alkyl. Most preferably, R 7b and R 7c are methyl.
  • R 7b and R 7c together with the nitrogen atom to which they are attached form a 4- to 6- membered heterocyclyl ring which optionally comprises one additional heteroatom individually selected from N, O and S.
  • R 7b and R 7c together with the nitrogen atom to which they are attached form a 5- to 6-membered heterocyclyl ring which optionally comprises one additional heteroatom individually selected from N and O.
  • R 7b and R 7c together with the nitrogen atom to which they are attached form an pyrrolidyl, oxazolidinyl, imidazolidinyl, piperidyl, piperazinyl or morpholinyl group.
  • A is a fused bicyclic structure of general formula; in which:
  • ring A 1 has 5 members and ring A 2 has 6 members;
  • A includes at least one heteroatom selected from N, O and S, with the remainder being carbon atoms;
  • At least one of ring A 1 and ring A 2 is aromatic, or A as a whole is aromatic;
  • A is attached to the remainder of the compound of formula (I) at any available position of ring A 2 provided it is a carbon atom;
  • one of the carbon atoms is optionally a carbonyl;
  • A is optionally substituted in any available position in either or both of ring A 1 or ring A 2 by p substituents R 8 , which may be the same or different; and
  • A comprises at least one nitrogen atom in either ring A 1 or A 2 .
  • a as a whole is aromatic.
  • a as a whole is aromatic, and ring A 1 includes at least one heteroatom selected from N, O and S, with the remainder being carbon atoms, and ring A 2 includes at least one heteroatom selected from N with the remainder being carbon atoms.
  • A contains 1 , 2, 3, 4, 5 or 6 heteroatoms, more preferably A contains 2, 3, 4, 5 or 6 heteroatoms.
  • A includes at least one N heteroatom with the remainder being carbon atoms.
  • A contains 1 , 2, 3, 4, 5 or 6 N heteroatoms with the remainder being carbon atoms.
  • A is selected from the group consisting of formula A-l to A-CXIV below (the skilled person would appreciate that if p is 3 1 then R 8 may be substituted on any available position of rings A- I to A-CXIV) ,
  • A is selected from the group consisting of formula A-l to A-LXXI.
  • A is selected from the group consisting of formula A-XLIII to A-LXXI.
  • A is selected from the group consisting of formula A-a, A-b, A-c, A-d, A-e, A-f, A- g, A-h, A-j, A-k, A-m, A-n, A-o, A-p, A-q and A-r below (preferably, A-a, A-b, A-c, A-d, A-e, A-g, A-h, A- j, A-n, A-o, A-p, A-q and A-r, more preferably, A-a, A-c, A-o and A-p) ,
  • X 1 is CH or N
  • W 1 is O, S or N(Me); each A 3 is independently selected from the group consisting of CH, N, O, S and N(Me);
  • R 8a is selected from the group consisting of hydrogen, -NH 2 , -NMe 2 , -OH and methyl; and wherein the jagged line defines the point of attachment to the remaining part of a compound of formula (I).
  • A is selected from the group consisting of formula A-VIII, A-IX, A-X, A-XLIX, A-LIII, A-LVII, A-LVIII, A-LXXII, A-LXXIII, A-LXXV, A-LXXVI, A-LXXX, A-LXXXI, A-LXXII, A-LXXIII, A-XCII and A-XCVI below,
  • A is selected from the group consisting of formula A-IX, A-LVII, A-LVIII, A-LXXV, A-LXXVI,
  • each R 8 is independently selected from the group consisting of halogen, nitro, cyano, -NH 2 , -NHR 7 , -N(R 7 ) 2 , -OH, -OR 7 , -S(O) r R 15 , - NR 6 S(O) 2 R 15 , -C(O)OR 10 , -C(O)R 15 , -C(O)NR 16 R 17 , -S(O) 2 NR 16 R 17 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 - C 6 cycloalkyl, C 3 -C 6 halocycloalkyl, C 3 -C 6 cycloalkoxy, C 2 -C 6 alkenyl, C 2 -C
  • each R 8 is independently selected from the group consisting of halogen, nitro, cyano, -NH 2 , -NHR 7 , -N(R 7 ) 2 , -OH, -OR 7 , -S(O) r R 15 , - NR 6 S(O) 2 R 15 , -C(O)OR 10 , -C(O)R 15 , -C(O)NR 16 R 17 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl, C 1 - C 3 alkoxyC 1 -C 3 alkyl-, hydroxyC 1 -C 6 alkyl- and C 1 -C 6 haloalkoxy.
  • each R 8 is independently selected from the group consisting of chloro, fluoro, cyano, -NH 2 , -N(Me) 2 , -OH, -OMe, -S(O) 2 Me, - C(O)OMe, -C(O)OH, -C(O)Me, -C(O)NH 2 , -C(O)NHMe, -C(O)N(Me) 2 , methyl, ethyl and trifluoromethyl.
  • each R 8 is independently selected from the group consisting of -NH 2 , -N(Me) 2 , -OH, and methyl. Even more preferably still, when A is substituted on one or more ring carbon atoms, each R 8 is independently selected from the group consisting of -N(Me) 2 , -OH, and methyl. Most preferably, when A is substituted on one or more ring carbon atoms, each R 8 is methyl.
  • each R 8 is independently selected from the group consisting of -OR 7 , -S(O) r R 12 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl, C 3 - C 6 halocycloalkyl, C 3 -C 6 cycloalkoxy, C 2 -C 6 alkenyl, C 2 -C 6 haloalkenyl, C 2 -C 6 alkynyl, C 1 -C 3 alkoxyC 1 - C 3 alkyl-, hydroxyC 2 -C 6 alkyl-, C 1 -C 6 haloalkoxy, C 1 -C 3 haloalkoxyC 1 -C 3 alkyl-, C 1 -C 6 alkoxycarbonyl, C 3 - C 6 alkenyloxy, C 3 -C 6 alkyl
  • each R 8 is independently selected from the group consisting of -OR 7 , C 1 -C 6 alkyl and C 1 -C 6 haloalkyl. More preferably, R 8 is C 1 -C 6 alkyl. Even more preferably still, each R 8 is methyl or ethyl. Most preferably R 8 is methyl.
  • each R 9 is independently selected from the group consisting of halogen, cyano, -N(R 6 ) 2 , C 1 - C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkyl and C 1 -C 4 haloalkoxy. More preferably, each R 9 is independently selected from the group consisting of halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy and C 1 -C 4 haloalkyl. Even more preferably, each R 9 is independently selected from the group consisting of halogen and C 1 -C 4 alkyl.
  • X is selected from the group consisting of C 3 -C 6 cycloalkyl, phenyl, a 5- or 6- membered heteroaryl, which comprises 1 , 2, 3 or 4 heteroatoms individually selected from N, O and S, and a 4- to 6- membered heterocyclyl, which comprises 1 , 2 or 3 heteroatoms individually selected from N, O and S, and wherein said cycloalkyl, phenyl, heteroaryl or heterocyclyl moieties are optionally substituted by 1 or 2 substituents, which may be the same or different, selected from R 9 , and wherein the aforementioned CR 1 R 2 , Q and Z moieties may be attached at any position of said cycloalkyl, phenyl, heteroaryl or heterocyclyl moieties.
  • X is selected from the group consisting of phenyl and a 4- to 6- membered heterocyclyl, which comprises 1 or 2 heteroatoms individually selected from N and O, and wherein said phenyl or heterocyclyl moieties are optionally substituted by 1 or 2 substituents, which may be the same or different, selected from R 9 , and wherein the aforementioned CR 1 R 2 , Q and Z moieties may be attached at any position of said phenyl or heterocyclyl moieties.
  • X is a 4- to 6- membered heterocyclyl, which comprises 1 or 2 heteroatoms individually selected from N and O, and wherein said heterocyclyl moieties is optionally substituted by 1 or 2 substituents, which may be the same or different, selected from R 9 , and wherein the aforementioned CR 1 R 2 , Q and Z moieties may be attached at any position of said heterocyclyl moiety.
  • X is a 5-membered heterocyclyl, which comprises 1 heteroatom, wherein said heteroatom is N, and wherein the aforementioned CR 1 R 2 , Q and Z moieties may be attached at any position of said heterocyclyl moiety.
  • X is a 5-membered heterocyclyl, which comprises 1 heteroatom, wherein said heteroatom is N, and wherein the aforementioned CR 1 R 2 and Q moieties are attached adjacent to the N atom and the Z moiety is attached to the N atom.
  • X is phenyl optionally substituted by 1 or 2 substituents, which may be the same or different, selected from R 9 , and wherein the aforementioned CR 1 R 2 , Q and Z moieties may be attached at any position of said phenyl moiety.
  • X is phenyl and the aforementioned CR 1 R 2 and Q moieties are attached in a postion para to the Z moiety.
  • n is 0 or 1 .
  • n is 0.
  • Z is selected from the group consisting of -C(O)OR 10 , -CH 2 OH, -CHO, -C(O)NHOR 11 , -C(O)NHCN, - OC(O)NHOR 11 , -OC(O)NHCN, -NR 6 C(O)NHOR 11 , -NR 6 C(O)NHCN, -C(O)NHS(O) 2 R 12 , - OC(O)NHS(O) 2 R 12 , -NR 6 C(O)NHS(O) 2 R 12 , -S(O) 2 OR 10 , -OS(O) 2 OR 10 , -NR 6 S(O) 2 OR 10 , -NR 6 S(O)OR 10 , -NHS(O) 2 R 14 , -S(O)OR 10 , -OS(O)OR 10 , -S(O) 2 NHCN, -S(O) 2 NHC(O)R 18 , -
  • Z is selected from the group consisting of -C(O)OR 10 , -C(O)NHOR 11 , -C(O)NHCN, - OC(O)NHOR 11 , -NR 6 C(O)NHOR 11 , -C(O)NHS(O) 2 R 12 , -OC(O)NHS(O) 2 R 12 , -NR 6 C(O)NHS(O) 2 R 12 , - S(O) 2 OR 10 , -OS(O) 2 OR 10 , -NR 6 S(O) 2 OR 10 , -NR 6 S(O)OR 10 , -NHS(O) 2 R 14 , -S(O)OR 10 , -OS(O)OR 10 , - S(O) 2 NHC(O)R 18 , -S(O) 2 NHS(O) 2 R 12 , -OS(O) 2 NHS(O) 2 R 12 , -OS(O) 2 NHC(O)R
  • Z is selected from the group consisting of -C(O)OR 10 , -C(O)NHOR 11 , -C(O)NHCN, - C(O)NHS(O) 2 R 12 , -S(O) 2 OR 10 , -OS(O) 2 OR 10 , -NR 6 S(O) 2 OR 10 , -NHS(O) 2 R 14 , -S(O)OR 10 , -
  • Z is selected from the group consisting of -C(O)OR 10 , -C(O)NHCN, - C(O)NHS(O) 2 R 12 , -S(O) 2 OR 10 , and -P(O)(R 13 )(OR 10 ).
  • Z is selected from the group consisting of -C(O)OH, -C(O)OCH3, - C(O)OCH 2 CH 3 , -C(O)OCH(CH 3 ) 2 , -C(O)OC(CH 3 ) 3 , -C(O)OCH 2 C 6 H 5 , -C(O)OC 6 H 5 , -C(O)NHS(O) 2 CH 3 , - S(O) 2 OH, -P(O)(OH)( OCH 2 CH 3 ) and -P(O)(OCH 2 CH 3 )(OCH 2 CH 3 ).
  • Z is selected from the group consisting of -C(O)OH, -C(O)OCH 3 , - C(O)OC(CH 3 ) 3 and -S(O) 2 OH.
  • Z is -C(O)OH or -S(O) 2 OH.
  • R 10 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, phenyl and benzyl, and wherein said phenyl or benzyl are optionally substituted by 1 , 2 or 3 R 9 substituents, which may be the same or different.
  • R 10 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, phenyl and benzyl. More preferably, R 10 is selected from the group consisting of hydrogen and C 1 -C 6 alkyl. Most preferably, R 10 is hydrogen.
  • R 11 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl and phenyl, and wherein said phenyl is optionally substituted by 1 , 2 or 3 R 9 substituents, which may be the same or different.
  • R 11 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl and phenyl. More preferably, R 11 is selected from the group consisting of hydrogen and C 1 -C 6 alkyl. Even more preferably, R 11 is C 1 -C 6 alkyl. Most preferably, R 11 is methyl.
  • R 12 is selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, -OH, -N(R 6 ) 2 and phenyl, and wherein said phenyl is optionally substituted by 1 , 2 or 3 R 9 substituents, which may be the same or different.
  • R 12 is selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 - C 6 alkoxy, -OH, -N(R 6 ) 2 and phenyl.
  • R 12 is selected from the group consisting of C 1 - C 6 alkyl, C 1 -C 6 haloalkyl and -N(R 6 ) 2 . Even more preferably, R 12 is selected from the group consisting of methyl, -N(Me) 2 and trifluoromethyl. Most preferably, R 12 is methyl.
  • R 13 is selected from the group consisting of -OH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy and phenyl.
  • R 13 is selected from the group consisting of -OH, C 1 -C 6 alkyl and C 1 -C 6 alkoxy. More preferably, R 13 is selected from the group consisting of -OH and C 1 -C 6 alkoxy. Even more preferably, R 13 is selected from the group consisting of -OH, methoxy and ethoxy. Most preferably, R 13 is -OH.
  • R 14 is C 1 -C 6 haloalkyl. Preferably, R 14 is trifluoromethyl.
  • R 15 is selected from the group consisting of C 1 -C 6 alkyl and phenyl, and wherein said phenyl is optionally substituted by 1 , 2 or 3 R 9 substituents, which may be the same or different.
  • R 15 is selected from the group consisting of C 1 -C 6 alkyl and phenyl. More preferably, R 15 is C 1 -C 6 alkyl. Most preferably R 15 is methyl.
  • R 15a is phenyl, wherein said phenyl is optionally substituted by 1 , 2 or 3 R 9 substituents, which may be the same or different.
  • R 15a is phenyl optionally substituted by 1 R 9 substituent. More preferably, R 15a is phenyl.
  • R 16 and R 17 are independently selected from the group consisting of hydrogen and C 1 -C 6 alkyl. Preferably, R 16 and R 17 are independently selected from the group consisting of hydrogen and methyl.
  • R 16 and R 17 together with the nitrogen atom to which they are attached form a 4- to 6- membered heterocyclyl ring which optionally comprises one additional heteroatom individually selected from N, O and S.
  • R 16 and R 17 together with the nitrogen atom to which they are attached form a 5- to 6-membered heterocyclyl ring which optionally comprises one additional heteroatom individually selected from N and O.
  • R 16 and R 17 together with the nitrogen atom to which they are attached form an pyrrolidyl, oxazolidinyl, imidazolidinyl, piperidyl, piperazinyl or morpholinyl group.
  • R 18 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, -N(R 6 ) 2 and phenyl, and wherein said phenyl is optionally substituted by 1 , 2 or 3 R 9 substituents, which may be the same or different.
  • R 18 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, -N(R 6 ) 2 and phenyl.
  • R 18 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl and C 1 -C 6 haloalkyl. Further more preferably, R 18 is selected from the group consisting of C 1 -C 6 alkyl and C 1 -C 6 haloalkyl. Most preferably, R 18 is methyl or trifluoromethyl. r is 0, 1 or 2. Preferably, r is 0 or 2.
  • R 1 is hydrogen or C 1 -C 6 alkyl
  • R 2 is hydrogen or C 1 -C 6 alkyl
  • Q is (CR 1a R 2b ) m ; m is 0, 1 or 2;
  • R 1a and R 2b are independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, -OH and - NH 2 ;
  • R 3 , R 3a , R 4 and R 5 are independently selected from the group consisting of hydrogen and methyl; each R 6 is independently selected from hydrogen and methyl; each R 7 is C 1 -C 6 alkyl;
  • A is a fused bicyclic structure of general formula; in which:
  • ring A 1 has 5 members and ring A 2 has 6 members;
  • A contains 2,3,4 or 5 heteroatoms selected from N, O and S, with the remainder being carbon atoms;
  • A is attached to the remainder of the compound of formula (I) at any available position of ring A 2 provided it is a carbon atom;
  • one of the carbon atoms is optionally a carbonyl
  • A is optionally substituted in any available position in either or both of ring A 1 or ring A 2 by p substituents R 8 , which may be the same or different;
  • each R 8 is independently selected from the group consisting of halogen, nitro, cyano, -NH 2 , -NHR 7 , -N(R 7 ) 2 , -OR 7 , -S(O) r R 15 , -NR 6 S(O) 2 R 15 , - C(O)OR 10 , -C(O)R 15 , -C(O)NR 16 R 17 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl, C 1 -C 3 alkoxyC 1 -C 3 alkyl- , hydroxyC 1 -C 6 alkyl- and C 1 -C 6 haloalkoxy; when A is substituted on one or more N atoms by one or more R 8 , then each R 8 is C 1 -C 6 alkyl
  • Z is selected from the group consisting of -C(O)OR 10 , -C(O)NHCN, -C(O)NHS(O) 2 R 12 , -S(O) 2 OR 10 , and -P(O)(R 13 )(OR 10 );
  • R 10 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, phenyl and benzyl;
  • R 12 is selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 6 haloalkyl and -N(R 6 ) 2 ;
  • R 13 is selected from the group consisting of -OH and C 1 -C 6 alkoxy
  • R 15 is C 1 -C 6 alkyl
  • R 16 and R 17 are independently selected from the group consisting of hydrogen and methyl; and r is 0 or 2.
  • R 1 is hydrogen or methyl
  • R 2 is hydrogen or methyl
  • Q is (CR 1a R 2b ) m ; m is 0, 1 or 2;
  • R 1a and R 2b are independently selected from the group consisting of hydrogen and methyl;
  • R 3 , R 3a , R 4 and R 5 are hydrogen
  • A is selected from the group consisting of formula A-l to A-LXXI and p is 0, 1 , or 2, more preferably 0 or 1 , most preferably 0; when A is substituted on one or more ring carbon atoms, each R 8 is independently selected from the group consisting of chloro, fluoro, cyano, -NH 2 , -N(Me) 2 , -OMe, -S(O) 2 Me, -C(O)OMe, -C(O)OH, - C(O)Me, -C(O)NH 2 , -C(O)NHMe, -C(O)N(Me) 2 , methyl, ethyl and trifluoromethyl, even more preferably methyl; when A is substituted on one or more N atoms by one or more R 8 , then each R 8 is C 1 -C 6 alkyl, or most preferably methyl; n is 0; and
  • Z is selected from the group consisting of -C(O)OH, -C(O)OCH 3 , -C(O)OCH 2 CH 3 , -C(O)OCH(CH 3 ) 2 , - C(O)OC(CH 3 ) 3 , -C(O)OCH 2 C 6 H 5 , -C(O)OC 6 H 5 , -C(O)NHS(O) 2 CH 3 , -S(O) 2 OH, -P(O)(OH)( OCH 2 CH 3 ) and -P(O)(OCH 2 CH 3 )(OCH 2 CH 3 ).
  • the compound according to formula (I) is selected from a compound of formula (l-aa) to (l-dj) below
  • each R 8 is independently selected from the group consisting of chloro, fluoro, cyano, -NH 2 , -N(Me) 2 , - OH, -OMe, -S(O) 2 Me, -C(O)OMe, -C(O)OH, -C(O)Me, -C(O)NH 2 , -C(O)NHMe, -C(O)N(Me) 2 , methyl and trifluoromethyl; and
  • Z is selected from the group consisting of -C(O)OH, -C(O)OCH 3 , -C(O)OCH 2 CH 3 , -C(O)OCH(CH 3 ) 2 , - C(O)OC(CH 3 ) 3 , -C(O)OCH 2 C 6 H 5 , -C(O)OC 6 H 5 , -C(O)NHS(O) 2 CH 3 , -S(O) 2 OH, -P(O)(OH)( OCH 2 CH 3 ) and -P(O)(OCH 2 CH 3 )( OCH 2 CH 3 ), preferably Z is -C(O)OH or -S(O) 2 OH.
  • R 1 is hydrogen or methyl;
  • R 2 is hydrogen or methyl
  • Q is (CR 1a R 2b ) m ; m is 0, 1 or 2; R 1a and R 2b are independently selected from the group consisting of hydrogen and methyl;
  • R 3 , R 3a , R 4 and R 5 are hydrogen
  • A is selected from the group consisting of formula A-l to A-CXIV and p is 0, 1 , or 2, more preferably 0 or 1 , most preferably 0; when A is substituted on one or more ring carbon atoms, each R 8 is independently selected from the group consisting of -NH 2 , -N(Me) 2 , -OH, and methyl, even more preferably methyl; when A is substituted on one or more N atoms by one or more R 8 , then each R 8 is C 1 -C 6 alkyl, or most preferably methyl; n is 0; and
  • Z is selected from the group consisting of -C(O)OH, -C(O)OCH 3 , -C(O)OC(CH 3 ) 3 and -S(O) 2 OH.
  • R 1 is hydrogen
  • R 2 is hydrogen
  • Q is (CR 1a R 2b ) m ; m is 0, 1 or 2;
  • R 1a and R 2b are hydrogen
  • R 3 , R 3a , R 4 and R 5 are hydrogen
  • A is selected from the group consisting of formula A-VIII, A-IX, A-X, A-XLIX, A-LIII, A-LVII, A-LVIII, A- LXXII, A-LXXIII, A-LXXV, A-LXXVI, A-LXXX, A-LXXXI, A-LXXII, A-LXXIII, A-XCII and A-XCVI and p is 0 or 1 (preferably p is 0); when p is 1 A is substituted on a ring carbon atom, and each R 8 is independently selected from the group consisting of -NH 2 , -N(Me) 2 , -OH, and methyl, even more preferably methyl; n is 0; and
  • Z is selected from the group consisting of -C(O)OH, -C(O)OCH 3 , -C(O)OC(CH 3 ) 3 and -S(O) 2 OH (preferably, Z is -C(O)OH or -S(O) 2 OH).
  • R 1 is hydrogen
  • R 2 is hydrogen
  • Q is (CR 1a R 2b ) m ; m is 0, 1 or 2;
  • R 1a and R 2b are hydrogen
  • R 3 , R 3a , R 4 and R 5 are hydrogen
  • A is selected from the group consisting of formula A-IX, A-LVII, A-LVIII, A-LXXV, A-LXXVI, A-LXXXI and A-XCVI, and p is 0 or 1 (preferably p is 0); when p is 1 A is substituted on a ring carbon atom, and each R 8 is independently selected from the group consisting of -NH 2 , -N(Me) 2 , -OH, and methyl, even more preferably methyl; n is 0; and Z is selected from the group consisting of -C(O)OH, -C(O)OCH 3 , -C(O)OC(CH 3 ) 3 and -S(O) 2 OH (preferably, Z is -C(O)OH or -S(O) 2 OH).
  • R 1 is hydrogen
  • R 2 is hydrogen
  • Q is (CR 1a R 2b ) m ; m is 0, 1 or 2;
  • R 1a and R 2b are hydrogen
  • R 3 , R 3a , R 4 and R 5 are hydrogen
  • A is selected from the group consisting of formula A-a, A-b, A-c, A-d, A-e, A-f, A-g, A-h, A-j, A-k, A-m, A-n, A-o, A-p, A-q and A-r below (preferably, A-a, A-b, A-c, A-d, A-e, A-g, A-h, A-j, A-n, A-o, A-p, A-q and A-r, more preferably, A-a, A-c, A-o and A-p) , wherein X 1 is CH or N;
  • W 1 is O, S or N(Me); each A 3 is independently selected from the group consisting of CH, N, O, S and N(Me);
  • R 8a is selected from the group consisting of hydrogen, -NH 2 , -N(Me) 2 , -OH and methyl; and wherein the jagged line defines the point of attachment to the remaining part of a compound of formula (I); n is 0; and
  • Z is selected from the group consisting of -C(O)OH, -C(O)OCH 3 , -C(O)OC(CH 3 ) 3 and -S(O) 2 OH (preferably, Z is -C(O)OH or -S(O) 2 OH).
  • the compound according to formula (I) is selected from a compound selected from the group consisting of A1 to A73 listed in Table A. It should be understood that compounds of formula (I) may exist/be manufactured in "procidal form", wherein they comprise a group "G". Such compounds are referred to herein as compounds of formula (l-IV).
  • G is a group which may be removed in a plant by any appropriate mechanism including, but not limited to, metabolism and chemical degradation to give a compound of formula (l-l), (l-ll) or (l-lll) wherein Z contains an acidic proton, for example see the scheme below: Whilst such G groups may be considered as ‘procidal’, and thus yield active herbicidal compounds once removed, compounds comprising such groups may also exhibit herbicidal activity in their own right. In such cases in a compound of formula (l-IV), Z-G may include but is not limited to, any one of (G1) to (G7) below and E indicates the point of attachment to the remaining part of a compound of formula (I):
  • G, R 19 , R 20 , R 21 , R 22 and R 23 are defined as follows:
  • G is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, -C(R 21 R 22 )OC(O)R 19 , phenyl or phenyl-C 1 -C 4 alkyl-, wherein said phenyl moiety is optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl or C 1 -C 6 alkoxy.
  • R 19 is C 1 -C 6 alkyl or phenyl
  • R 20 is hydroxy, C 1 -C 6 alkyl, C 1 -C 6 alkoxy or phenyl,
  • R 21 is hydrogen or methyl
  • R 22 is hydrogen or methyl
  • R 23 is hydrogen or C 1 -C 6 alkyl.
  • This table discloses 181 specific compounds of the formula (T-1): (T-1) wherein A is as defined in Table 1 and R 3 , R 3a , R 4 and R 5 are hydrogen.
  • This table discloses 181 specific compounds of the formula (T-3): wherein A is as defined in Table 1 and R 3 , R 3a , R 4 and R 5 are hydrogen.
  • This table discloses 181 specific compounds of the formula (T-4): wherein A is as defined in Table 1 and R 3 , R 3a , R 4 and R 5 are hydrogen.
  • This table discloses 181 specific compounds of the formula (T-7): wherein A is as defined in Table 1 and R 3 , R 3a , R 4 and R 5 are hydrogen.
  • Table 8 This table discloses 181 specific compounds of the formula (T-8): wherein A is as defined in Table 1 and R 3 , R 3a , R 4 and R 5 are hydrogen.
  • Table 9 discloses 181 specific compounds of the formula (T-7): wherein A is as defined in Table 1 and R 3 , R 3a , R 4 and R 5 are hydrogen.
  • This table discloses 181 specific compounds of the formula (T-11): wherein A is as defined in Table 1 and R 3 , R 3a , R 4 and R 5 are hydrogen.
  • This table discloses 181 specific compounds of the formula (T-14): wherein A is as defined in Table 1 and R 3 , R 3a , R 4 and R 5 are hydrogen.
  • Table 15 This table discloses 181 specific compounds of the formula (T-15): wherein A is as defined in Table 1 and R 3 , R 3a , R 4 and R 5 are hydrogen.
  • Table 16 This table discloses 181 specific compounds of the formula (T-15): wherein A is as defined in Table 1 and R 3 , R 3a , R 4 and R 5 are hydrogen.
  • This table discloses 181 specific compounds of the formula (T-17): wherein A is as defined in Table 1 and R 3 , R 3a , R 4 and R 5 are hydrogen.
  • This table discloses 181 specific compounds of the formula (T-21): wherein A is as defined in Table 1 and R 3 , R 3a , R 4 and R 5 are hydrogen.
  • Table 22 This table discloses 181 specific compounds of the formula (T-22): wherein A is as defined in Table 1 and R 3 , R 3a , R 4 and R 5 are hydrogen.
  • This table discloses 181 specific compounds of the formula (T-24): wherein A is as defined in Table 1 and R 3 , R 3a , R 4 and R 5 are hydrogen.
  • This table discloses 181 specific compounds of the formula (T-25): wherein A is as defined in Table 1 and R 3 , R 3a , R 4 and R 5 are hydrogen.
  • This table discloses 181 specific compounds of the formula (T-27): wherein A is as defined in Table 1 and R 3 , R 3a , R 4 and R 5 are hydrogen.
  • This table discloses 181 specific compounds of the formula (T-28): wherein A is as defined in Table 1 and R 3 , R 3a , R 4 and R 5 are hydrogen.
  • Table 29 This table discloses 181 specific compounds of the formula (T-29): wherein A is as defined in Table 1 and R 3 , R 3a , R 4 and R 5 are hydrogen.
  • Table 30
  • This table discloses 181 specific compounds of the formula (T-31): wherein A is as defined in Table 1 and R 3 , R 3a , R 4 and R 5 are hydrogen.
  • This table discloses 181 specific compounds of the formula (T-34): wherein A is as defined in Table 1 and R 3 , R 3a , R 4 and R 5 are hydrogen.
  • the compounds of the present invention may be prepared according to the following schemes in which the substituents n, m, r, A, Q, X, Z, R 1 , R 2 , R 1a , R 2b , R 2 , R 3 , R 3a , R 4 , R 5 , R 6 , R 7 , R 7a , R 7b R 7c , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 15a , R 16 , R 17 and R 18 are as defined hereinbefore unless explicitly stated otherwise.
  • the compounds of the preceeding Tables 1 to 34 may thus be obtained in an analogous manner.
  • the compounds of formula (I) may be prepared by the alkylation of compounds of formula (X), wherein R 3 , R 3a , R 4 , R 5 and A are as defined for compounds of formula (I), with a suitable alkylating agent of formula (W), wherein R 1 , R 2 , Q, X, n and Z are as defined for compounds of formula (I) and LG is a suitable leaving group, for example, halide or pseudohalide such as triflate, mesylate or tosylate, in a suitable solvent at a suitable temperature, as described in reaction scheme 1.
  • Example conditions include stirring a compound of formula (X) with an alkylating agent of formula (W) in a solvent, or mixture of solvents, such as acetone, dichloromethane, dichloroethane, N,N-dimethylformamide, acetonitrile, 1 ,4-dioxane, water, acetic acid or triflu roacetic acid at a temperature between -78°C and 150°C.
  • solvent such as acetone, dichloromethane, dichloroethane, N,N-dimethylformamide, acetonitrile, 1 ,4-dioxane, water, acetic acid or triflu roacetic acid at a temperature between -78°C and 150°C.
  • An alkylating agent of formula (W) may include, but is not limited to, bromoacetic acid, methyl bromoacetate, 3-bromopropionoic acid, methyl 3-bromopropionate, 2-bromo-N-methoxyacetamide, sodium 2- bromoethanesulphonate, 2,2-dimethylpropyl 2-(trifluoromethylsulfonyloxy)ethanesulfonate, 2-bromo-N- methanesulfonylacetamide, 3-bromo-N-methanesulfonylpropanamide, dimethoxyphosphorylmethyl trifluoromethanesulfonate, dimethyl 3-bromopropylphosphonate, 3-chloro-2, 2-dimethyl-propanoic acid and diethyl 2-bromoethylphosphonate.
  • esters of N- alkyl acids which include, but are not limited to, esters of carboxylic acids, phosphonic acids, phosphinic acids, sulfonic acids and sulfinic acids, may be subsequently partially or fully hydrolysed by treament with a suitable reagent, for example, aqueous hydrochloric acid or trimethylsilyl bromide, in a suitable solvent at a suitable temperature between 0°C and 100°C.
  • a suitable reagent for example, aqueous hydrochloric acid or trimethylsilyl bromide
  • compounds of formula (I) may be prepared by reacting compounds of formula (X), wherein R 3 , R 3a , R 4 , R 5 and A are as defined for compounds of formula (I), with a suitably activated electrophilic alkene of formula (B), wherein Z is -S(O) 2 OR 10 , -P(O)(R 13 )(OR 10 ) or -C(O)OR 10 and R 1 , R 2 , R 1a , R 10 and R 13 are as defined for compounds of formula (I), in a suitable solvent at a suitable temperature.
  • Compounds of formula (B) are known in the literature, or may be prepared by known methods.
  • Example reagents include, but are not limited to, acrylic acid, methacrylic acid, crotonic acid, 3,3-dimethylacrylic acid, methyl acrylate, ethene sulfonic acid, isopropyl ethylenesulfonate, 2,2-dimethylpropyl ethenesulfonate and dimethyl vinylphosphonate.
  • esters of N-alkyl acids which include, but are not limited to, esters of carboxylic acids, phosphonic acids, phosphinic acids, sulfonic acids and sulfinic acids, may be subsequently partially or fully hydrolysed by treament with a suitable reagent in a suitable solvent at a suitable temperature, as described in reaction scheme 2.
  • An alkylating agent of formula (E) or (F) may include, but is not limited to, 1 ,3-propanesultone, 1 ,4-butanesultone, ethylenesulfate, 1 ,3-propylene sulfate and 1 ,2,3-oxathiazolidine 2,2-dioxide.
  • alkylating agents and related compounds are either known in the literature or may be prepared by known literature methods.
  • a compound of formula (I), wherein m is 0, n is 0 and Z is -S(O) 2 OH may be prepared from a compound of formula (I), wherein m is 0, n is 0 and Z is C(O)OR 10 , by treatment with trimethylsilylchlorosulfonate in a suitable solvent at a suitable temperature, as described in reaction scheme 4.
  • Preferred conditions include heating the carboxylate precursor in neat trimethylsilylchlorosulfonate at a temperature between 25°C and 150°C.
  • compounds of formula (I) may be prepared by reacting compounds of formula (X), wherein R 3 , R 3a , R 4 , R 5 and A are as defined for compounds of formula (I), with a suitable alcohol of formula (WW), wherein R 1 , R 2 , Q, X, n and Z are as defined for compounds of formula (I), under Mitsunobu-type conditions such as those reported by Petit et al, Tet. Lett. 2008, 49 (22), 3663.
  • Suitable phosphines include triphenylphosphine
  • suitable azodicarboxylates include diisopropylazodicarboxylate
  • suitable acids include fluoroboric acid, triflic acid and bis(trifluoromethylsulfonyl)amine, as described in reaction scheme 5.
  • Such alcohols are either known in the literature or may be prepared by known literature methods.
  • a compound of formula (I), wherein n, Q, Z, X, R 1 , R 2 , R 3 , R 3a , R 4 , R 5 and A are as defined for compounds of formula (I), may be prepared from a compound of formula (R) and an oxidant, in a suitable solvent at a suitable temperature, as outlined in reaction scheme 6.
  • oxidants include, but are not limited to, tetrachloro-p-benzoquinone, 2,3-dichloro-5,6- dicyanobenzoquinone, bromine, N-bromosuccinimide, manganese dioxide, selenium dioxide, potassium permanganate or biocatalysts.
  • Related reactions are known in the literature.
  • a compound of formula (R), wherein n, Q, Z, X, R 1 , R 2 , R 3 , R 3a , R 4 , R 5 and A are as defined for compounds of formula (I), may be prepared from a compound of formula (S) and an organometallic of formula (T), wherein M' includes, but is not limited to, organomagnesium, organolithium, organocopper and organozinc reagents, in a suitable solvent at a suitable temperature, optionally in the presence of an additonal transition metal additive, as outlined in reaction scheme 7.
  • Example conditions include treating a compound of formula (S) with a Grignard of formula (T), in the presence of 0.05-100 mol% copper iodide, in a solvent such as tetrahydrofuran at a temperature between -78°C and 100°C.
  • Organometallics of formula (T) are known in the literature, or may be prepared by known literature methods.
  • Compounds of formula (S) may be prepared by analogous reactions to those for the preparation of compounds of formula (I) from a compound of formula (X). Reaction scheme 7
  • Compounds of formula (I) may also be prepared by oxidation of a compound of formula (BB), wherein A, R 3 , R 3a , R 4 and R 5 are as defined for compounds of formula (I), as outlined in reaction scheme 8.
  • Example conditions include stirring a compound of formula (BB) in a suitable solvent at a suitable temperature in the presence of a suitable oxidant.
  • oxidants include, but are not limited to, tetrachloro-p-benzoquinone, 2,3-dichloro-5,6-dicyanobenzoquinone, bromine, N- bromosuccinimide, manganese dioxide, selenium dioxide, potassium permanganate or biocatalysts.
  • Compounds of formula (BB) may be prepared from a compound of formula (CC), wherein A, R 3 , R 3a , R 4 and R 5 are as defined for compounds of formula (I), by analogous N-alkylation methods previously described in schemes 1 , 2 and 3, using reagents (W), (B), (E), (F), (AF) and (WW).
  • Reaction scheme 9 Compounds of formula (X) are known in the literature or may be prepared using literature methods. Example methods include, but are not limited to, the transition metal cross-coupling of compounds of formula (H) and formula (J), or alternatively compounds of formula (K) and formula (L), as outlined in scheme 10.
  • M' is either an organostannane, organoboronic acid or ester, organotrifluoroborate, organomagnesium, organocopper or organozinc, and for compounds of formula (H) and (K) Hal is defined as a halogen or pseudo halogen, for example triflate, mesylate and tosylate.
  • Such cross-couplings include Stille (for example Sauer, J.; Heldmann, D. K.
  • Suzuki-Miyaura for example Luebbers, T.; Flohr, A.; Jolidon, S.; David- Pierson, P.; Jacobsen, H.; Ozmen, L.; Baumann, K. Bioorg. Med. Chem. Lett., 2011 , 6554
  • Negishi for example Imahori, T.; Suzawa, K.; Kondo, Y. Heterocycles, 2008, 1057
  • Kumada for example Heravi, M. M.; Hajiabbasi, P. Monatsh. Chem., 2012, 1575.
  • the coupling partners may be selected with reference to the specific cross-coupling reaction and target product.
  • Transition metal catalysts may be selected with reference to the desired cross-coupling and are known in the literature.
  • Compounds of formula (H), formula (K) and formula (L) are known in the literature, or may be prepared by known literature methods.
  • a compound of formula (J), wherein M' is either an organostannane, organoboronic acid or ester, organotrifluoroborate, organomagnesium, organocopper or organozinc, may be prepared from a compound of formula (K), wherein R 3 , R 3a , R 4 and R 5 are as defined for compounds of formula (I), and Hal is defined as a halogen or pseudo halogen, for example triflate, mesylate and tosylate, as described in scheme 11 .
  • Example conditions are well known in the literature, for example halogen-metal exchange (wherein Hal is iodine, bromide and chlorine), or transition metal mediated cross-coupling of either a diboron or distannane reagent (wherein Hal is iodine, bromide, chlorine, triflate, mesylate and tosylate).
  • Example halogen-metal exchange conditions to prepare a compound of formula (J), wherein M' is an organostannane include treatment of a compound of formula (K) with butyl lithium then tri-n-butyltin chloride in an appropriate solvent at an appropriate temperature (for example see Koch, V.; Nieger, M.; Braese, S., Adv. Synth.
  • Example halogen-metal exchange conditions to prepare a compound of formula (J), wherein M’ is an organoboronic acid include treatment of a compound of formula (K) with butyl lithium then triisopropyl borate in an appropriate solvent at an appropriate temperature (for example see Fudickar, W.; Linker, T., J. Org. Chem., 2017, 9258).
  • Example halogen- metal exchange conditions to prepare a compound of formula (J), wherein M’ is an organomagnesium include treatment of a compound of formula (K) with isopropyl magnesium chloride in an appropriate solvent at an appropriate temperature (for example see Salituro et al.
  • Example halogen-metal exchange conditions to prepare a compound of formula (J), wherein M’ is an organozinc include treatment of a compound of formula (K) with isopropyl magnesium chloride then dichloro(N,N,N',N'-tetramethylethylenediamine)zinc in an appropriate solvent at an appropriate temperature (for example see Baba et al. JP 2013227251).
  • Example transition metal mediated conditions to prepare a compound of formula (J), wherein M’ is an organostannane include treatment of a compound of formula (K) with hexamethyldistannane and bis(triphenylphosphine)palladium(ll) dichloride in an appropriate solvent at an appropriate temperature (for example see Barbachyn, M. R. et al., J. Med. Chem., 2003, 284).
  • Example transition metal mediated conditions to prepare a compound of formula (J), wherein M’ is an organboronic acid include treatment of a compound of formula (K) with bis(pinacolato)diboron, bis(triphenylphosphine)palladium(ll) dichloride and potassium acetate in an appropriate solvent at an appropriate temperature (for example see Meng et al. CN 104276997).
  • Compounds of formula (K) are either known in the literature or can be prepared by known methods.
  • compounds of formula (X) may be prepared by classical ring synthesis approaches starting from a compound of formula (ZZ), wherein R 3 , R 3a , R 4 and R 5 are as defined for compounds of formula (I) and T is a functional group which can be converted through one or more chemical steps into a bicylic fused heteroaromatic A, wherein A is as defined for compounds of formula (I).
  • Example functional groups include, but are not limited to, -CO2H, -C(O)NH 2 , -C(O)Me, -C(O)H, -CN and -Hal, and such transformations are are known in the literature.
  • a compound of formula (X) may also be prepared from a compound of formula (DD) or a compound of formula (CC) using similar oxidation conditions as described previously, as outlined in reaction scheme 13.
  • Compounds of formula (CC) may be prepared by deprotection of a compound of formula (DD), wherein A, R 3 , R 3a , R 4 and R 5 are as defined for compounds of formula (I) and G 1 is a suitable protecting group, as outlined in reaction scheme 14. Examples of suitable protecting groups and conditions are well known in the literature.
  • Compounds of formula (DD) are known in the literature or may be prepared using literature methods, (for example see Dyckman et al. WO 2019126082).
  • Example methods include, but are not limited to, the transition metal cross-coupling of compounds of formula (H) and formula (EE), wherein M' is either an organostannane, organoboronic acid or ester, organotrifluoroborate, organomagnesium, organocopper or organozinc, as outlined in reaction scheme 14.
  • Such cross-couplings include Stille, see for example Lee, Ju-Hyeon et al, European Journal of Medicinal Chemistry, 74, 246-257; 2014, Suzuki-Miyaura, see for example Kim, Eunkyung et al, Bioorganic & Medicinal Chemistry Letters, 18(18), 4993-4996; 2008 and Negishi, see for example Baskaran, Subramanian et al, PCT Int. Appl. , 2010091409.
  • the coupling partners may be selected with reference to the specific cross-coupling reaction and target product. Transition metal catalysts, ligands, bases, solvents and temperatures may be selected with reference to the desired cross-coupling and are known in the literature.
  • Compounds of formula (H) and formula (EE) are known in the literature, or may be prepared by known literature methods.
  • the compounds according to the invention can be used as herbicidal agents in unmodified form, but they are generally formulated into compositions in various ways using formulation adjuvants, such as carriers, solvents and surface-active substances.
  • formulation adjuvants such as carriers, solvents and surface-active substances.
  • the formulations can be in various physical forms, e.g.
  • soluble liquids soluble liquids, water-soluble concentrates or water soluble granules are preferred.
  • Such formulations can either be used directly or diluted prior to use.
  • the dilutions can be made, for example, with water, liquid fertilisers, micronutrients, biological organisms, oil or solvents.
  • the formulations can be prepared e.g. by mixing the active ingredient with the formulation adjuvants in order to obtain compositions in the form of finely divided solids, granules, solutions, dispersions or emulsions.
  • the active ingredients can also be formulated with other adjuvants, such as finely divided solids, mineral oils, oils of vegetable or animal origin, modified oils of vegetable or animal origin, organic solvents, water, surface-active substances or combinations thereof.
  • the active ingredients can also be contained in very fine microcapsules.
  • Microcapsules contain the active ingredients in a porous carrier. This enables the active ingredients to be released into the environment in controlled amounts (e.g. slow-release).
  • Microcapsules usually have a diameter of from 0.1 to 500 microns. They contain active ingredients in an amount of about from 25 to 95 % by weight of the capsule weight.
  • the active ingredients can be in the form of a monolithic solid, in the form of fine particles in solid or liquid dispersion or in the form of a suitable solution.
  • the encapsulating membranes can comprise, for example, natural or synthetic rubbers, cellulose, styrene/butadiene copolymers, polyacrylonitrile, polyacrylate, polyesters, polyamides, polyureas, polyurethane or chemically modified polymers and starch xanthates or other polymers that are known to the person skilled in the art.
  • very fine microcapsules can be formed in which the active ingredient is contained in the form of finely divided particles in a solid matrix of base substance, but the microcapsules are not themselves encapsulated.
  • liquid carriers there may be used: water, toluene, xylene, petroleum ether, vegetable oils, acetone, methyl ethyl ketone, cyclohexanone, acid anhydrides, acetonitrile, acetophenone, amyl acetate, 2-butanone, butylene carbonate, chlorobenzene, cyclohexane, cyclohexanol, alkyl esters of acetic acid, diacetone alcohol, 1 ,2-dichloropropane, diethanolamine, p- diethylbenzene, diethylene glycol, diethylene glycol abietate, diethylene glycol butyl ether, diethylene glycol ethyl ether, diethylene glycol methyl ether, N,N-dimethylformamide, dimethyl sulfoxide, 1 ,4- dioxane, dipropy
  • Suitable solid carriers are, for example, talc, titanium dioxide, pyrophyllite clay, silica, attapulgite clay, kieselguhr, limestone, calcium carbonate, bentonite, calcium montmorillonite, cottonseed husks, wheat flour, soybean flour, pumice, wood flour, ground walnut shells, lignin and similar substances.
  • a large number of surface-active substances can advantageously be used in both solid and liquid formulations, especially in those formulations which can be diluted with a carrier prior to use.
  • Surface- active substances may be anionic, cationic, non-ionic or polymeric and they can be used as emulsifiers, wetting agents or suspending agents or for other purposes.
  • Typical surface-active substances include, for example, salts of alkyl sulfates, such as diethanolammonium lauryl sulfate; salts of alkylarylsulfonates, such as calcium dodecylbenzenesulfonate; alkylphenol/alkylene oxide addition products, such as nonylphenol ethoxylate; alcohol/alkylene oxide addition products, such as tridecylalcohol ethoxylate; soaps, such as sodium stearate; salts of alkylnaphthalenesulfonates, such as sodium dibutylnaphthalenesulfonate; dialkyl esters of sulfosu coin ate salts, such as sodium di(2- ethylhexyl)sulfosuccinate; sorbitol esters, such as sorbitol oleate; quaternary amines, such as lauryltrimethylammonium chloride, polyethylene glycol esters
  • Further adjuvants that can be used in pesticidal formulations include crystallisation inhibitors, viscosity modifiers, suspending agents, dyes, anti-oxidants, foaming agents, light absorbers, mixing auxiliaries, antifoams, complexing agents, neutralising or pH-modifying substances and buffers, corrosion inhibitors, fragrances, wetting agents, take-up enhancers, micronutrients, plasticisers, glidants, lubricants, dispersants, thickeners, antifreezes, microbicides, and liquid and solid fertilisers.
  • compositions according to the invention can include an additive comprising an oil of vegetable or animal origin, a mineral oil, alkyl esters of such oils or mixtures of such oils and oil derivatives.
  • the amount of oil additive in the composition according to the invention is generally from 0.01 to 10 %, based on the mixture to be applied.
  • the oil additive can be added to a spray tank in the desired concentration after a spray mixture has been prepared.
  • Preferred oil additives comprise mineral oils or an oil of vegetable origin, for example rapeseed oil, olive oil or sunflower oil, emulsified vegetable oil, alkyl esters of oils of vegetable origin, for example the methyl derivatives, or an oil of animal origin, such as fish oil or beef tallow.
  • Preferred oil additives comprise alkyl esters of C 8 -C 22 fatty acids, especially the methyl derivatives of C 12 -C 18 fatty acids, for example the methyl esters of lauric acid, palmitic acid and oleic acid (methyl laurate, methyl palmitate and methyl oleate, respectively).
  • Many oil derivatives are known from the Compendium of Herbicide Adjuvants, 10 th Edition, Southern Illinois University, 2010.
  • the herbicidal compositions generally comprise from 0.1 to 99 % by weight, especially from 0.1 to 95 % by weight, compounds of formula (I) and from 1 to 99.9 % by weight of a formulation adjuvant which preferably includes from 0 to 25 % by weight of a surface-active substance.
  • the inventive compositions generally comprise from 0.1 to 99 % by weight, especially from 0.1 to 95 % by weight, of compounds of the present invention and from 1 to 99.9 % by weight of a formulation adjuvant which preferably includes from 0 to 25 % by weight of a surface-active substance. Whereas commercial products may preferably be formulated as concentrates, the end user will normally employ dilute formulations.
  • the rates of application vary within wide limits and depend on the nature of the soil, the method of application, the crop plant, the pest to be controlled, the prevailing climatic conditions, and other factors governed by the method of application, the time of application and the target crop.
  • a general guideline compounds may be applied at a rate of from 1 to 2000 l/ha, especially from 10 to 1000 l/ha.
  • Preferred formulations can have the following compositions (weight %):
  • Emulsifiable concentrates active ingredient: 1 to 95 %, preferably 60 to 90 % surface-active agent: 1 to 30 %, preferably 5 to 20 % liquid carrier: 1 to 80 %, preferably 1 to 35 %
  • Dusts active ingredient: 0.1 to 10 %, preferably 0.1 to 5 % solid carrier: 99.9 to 90 %, preferably 99.9 to 99 %
  • Suspension concentrates active ingredient: 5 to 75 %, preferably 10 to 50 % water: 94 to 24 %, preferably 88 to 30 % surface-active agent: 1 to 40 %, preferably 2 to 30 %
  • Wettable powders active ingredient: 0.5 to 90 %, preferably 1 to 80 % surface-active agent: 0.5 to 20 %, preferably 1 to 15 % solid carrier: 5 to 95 %, preferably 15 to 90 %
  • Granules active ingredient: 0.1 to 30 %, preferably 0.1 to 15 % solid carrier: 99.5 to 70 %, preferably 97 to 85 %
  • composition of the present may further comprise at least one additional pesticide.
  • additional pesticide is a herbicide and/or herbicide safener.
  • compounds of formula (I) can be used in combination with one or more other herbicides to provide various herbicidal mixtures.
  • specific examples of such mixtures include (wherein “I” represents a compound of formula (I)): I + acetochlor, I + acifluorfen (including acifluorfen-sodium), I + aclonifen, I + ametryn, I + amicarbazone, I + aminopyralid, I + aminotriazole, I + atrazine, I + beflubutamid-M, I + benquitrione, I + bensulfuron (including bensulfuron-methyl), I + bentazone, I + bicyclopyrone, I + bilanafos, I + bispyribac-sodium, I + bixlozone, I + bromacil, I + bromoxynil, I + butachlor, I + butafenacil, I + carfentrazone (including carfentrazone-ethyl),
  • the mixing partners of the compound of formula (I) may also be in the form of esters or salts, as mentioned e.g. in The Pesticide Manual, Fourteenth Edition, British Crop Protection Council, 2006.
  • the compound of formula (I) can also be used in mixtures with other agrochemicals such as fungicides, nematicides or insecticides, examples of which are given in The Pesticide Manual.
  • the mixing ratio of the compound of formula (I) to the mixing partner is preferably from 1 : 100 to 1000:1 .
  • mixtures can advantageously be used in the above-mentioned formulations (in which case "active ingredient” relates to the respective mixture of compound of formula (I) with the mixing partner).
  • Compounds of formula (I) of the present invention may also be combined with herbicide safeners.
  • Preferred combinations include:- I + benoxacor, I + cloquintocet (including cloquintocet-mexyl); I + cyprosulfamide; I + dichlormid; I + fenchlorazole (including fenchlorazole-ethyl); I + fenclorim; I + fluxofenim; l+ furilazole I + isoxadifen (including isoxadifen-ethyl); I + mefenpyr (including mefenpyr-diethyl); I + metcamifen; I + N-(2-methoxybenzoyl)- 4-[(methylaminocarbonyl)amino] benzenesulfonamide and I + oxabetrinil.
  • the safeners of the compound of formula (I) may also be in the form of esters or salts, as mentioned e.g. in The Pesticide Manual, 14 th Edition (BCPC), 2006.
  • the reference to cloquintocet-mexyl also applies to a lithium, sodium, potassium, calcium, magnesium, aluminium, iron, ammonium, quaternary ammonium, sulfonium or phosphonium salt thereof as disclosed in WO 02/34048, and the reference to fenchlorazole-ethyl also applies to fenchlorazole, etc.
  • the mixing ratio of compound of formula (I) to safener is from 100:1 to 1 :10, especially from 20:1 to 1 :1.
  • mixtures can advantageously be used in the above-mentioned formulations (in which case "active ingredient” relates to the respective mixture of compound of formula (I) with the safener).
  • the compounds of formula (I) of this invention are useful as herbicides.
  • the present invention therefore further comprises a method for controlling unwanted plants comprising applying to the said plants or a locus comprising them, an effective amount of a compound of the invention or a herbicidal composition containing said compound.
  • Controlling means killing, reducing or retarding growth or preventing or reducing germination.
  • the plants to be controlled are unwanted plants (weeds).
  • Locus means the area in which the plants are growing or will grow.
  • the rates of application of compounds of formula (I) may vary within wide limits and depend on the nature of the soil, the method of application (pre-emergence; post-emergence; application to the seed furrow; no tillage application etc.), the crop plant, the weed(s) to be controlled, the prevailing climatic conditions, and other factors governed by the method of application, the time of application and the target crop.
  • the compounds of formula (I) according to the invention are generally applied at a rate of from 10 to 2000 g/ha, especially from 50 to 1000 g/ha.
  • the application is generally made by spraying the composition, typically by tractor mounted sprayer for large areas, but other methods such as dusting (for powders), drip or drench can also be used.
  • composition according to the invention can be used include crops such as cereals, for example barley and wheat, cotton, oilseed rape, sunflower, maize, rice, soybeans, sugar beet, sugar cane and turf.
  • crops such as cereals, for example barley and wheat, cotton, oilseed rape, sunflower, maize, rice, soybeans, sugar beet, sugar cane and turf.
  • Crop plants can also include trees, such as fruit trees, palm trees, coconut trees or other nuts. Also included are vines such as grapes, fruit bushes, fruit plants and vegetables. Crops are to be understood as also including those crops which have been rendered tolerant to herbicides or classes of herbicides (e.g. ALS-, GS-, EPSPS-, PPO-, ACCase- and HPPD-inhibitors) by conventional methods of breeding or by genetic engineering.
  • herbicides or classes of herbicides e.g. ALS-, GS-, EPSPS-, PPO-, ACCase- and HPPD-inhibitors
  • An example of a crop that has been rendered tolerant to imidazolinones, e.g. imazamox, by conventional methods of breeding is Clearfield® summer rape (canola).
  • crops that have been rendered tolerant to herbicides by genetic engineering methods include e.g. glyphosate- and glufosinate-resistant maize varieties
  • Crops are also to be understood as being those which have been rendered resistant to harmful insects by genetic engineering methods, for example Bt maize (resistant to European corn borer), Bt cotton (resistant to cotton boll weevil) and also Bt potatoes (resistant to Colorado beetle).
  • Bt maize are the Bt 176 maize hybrids of NK® (Syngenta Seeds).
  • the Bt toxin is a protein that is formed naturally by Bacillus thuringiensis soil bacteria.
  • Examples of toxins, or transgenic plants able to synthesise such toxins are described in EP-A-451 878, EP-A-374 753, WO 93/07278, WO 95/34656, WO 03/052073 and EP-A-427 529.
  • transgenic plants comprising one or more genes that code for an insecticidal resistance and express one or more toxins are KnockOut® (maize), Yield Gard® (maize), NuCOTIN33B® (cotton), Bollgard® (cotton), NewLeaf® (potatoes), NatureGard® and Protexcta®.
  • Plant crops or seed material thereof can be both resistant to herbicides and, at the same time, resistant to insect feeding ("stacked" transgenic events).
  • seed can have the ability to express an insecticidal Cry3 protein while at the same time being tolerant to glyphosate.
  • Crops are also to be understood to include those which are obtained by conventional methods of breeding or genetic engineering and contain so-called output traits (e.g. improved storage stability, higher nutritional value and improved flavour).
  • output traits e.g. improved storage stability, higher nutritional value and improved flavour.
  • turf grass for example in golf-courses, lawns, parks and roadsides, or grown commercially for sod
  • ornamental plants such as flowers or bushes.
  • Compounds of formula (I) and compositions of the invention can typically be used to control a wide variety of monocotyledonous and dicotyledonous weed species.
  • monocotyledonous species that can typically be controlled include Alopecurus myosuroides, Avena fatua, Brachiaria plantaginea, Bromus tectorum, Cyperus esculentus, Digitaria sanguinalis, Echinochloa crus-galli, Lolium perenne, Lolium multiflorum, Panicum miliaceum, Poa annua, Setaria viridis, Setaria faberi and Sorghum bicolor.
  • dicotyledonous species that can be controlled include Abutilon theophrasti, Amaranthus retroflexus, Bidens pilosa, Chenopodium album, Euphorbia heterophylla, Galium aparine, Ipomoea hederacea, Kochia scoparia, Polygonum convolvulus, Sida spinosa, Sinapis arvensis, Solanum nigrum, Stellaria media, Veronica persica and Xanthium strumarium.
  • the compounds of formula (I) are also useful for pre-harvest desiccation in crops, for example, but not limited to, potatoes, soybean, sunflowers and cotton. Pre-harvest desiccation is used to desiccate crop foliage without significant damage to the crop itself to aid harvesting. Compounds/compositions of the invention are particularly useful in non-selective burn-down applications, and as such may also be used to control volunteer or escape crop plants.
  • Wettable powders a) b) c) active ingredients 25 % 50 % 75 % sodium lignosulfonate 5 % 5 % sodium lauryl sulfate 3 % - 5 % sodium diisobutylnaphthalenesulfonate 6 % 10 % phenol polyethylene glycol ether 2 %
  • the combination is thoroughly mixed with the adjuvants and the mixture is thoroughly ground in a suitable mill, affording wettable powders that can be diluted with water to give suspensions of the desired concentration.
  • Emulsifiable concentrate active ingredients 10 % octylphenol polyethylene glycol ether 3 %
  • Emulsions of any required dilution, which can be used in plant protection, can be obtained from this concentrate by dilution with water. Dusts a) b) c)
  • Ready-for-use dusts are obtained by mixing the combination with the carrier and grinding the mixture in a suitable mill.
  • the combination is mixed and ground with the adjuvants, and the mixture is moistened with water.
  • the mixture is extruded and then dried in a stream of air.
  • Active ingredients 8 % polyethylene glycol (mol. wt. 200) 3 %
  • the finely ground combination is uniformly applied, in a mixer, to the kaolin moistened with polyethylene glycol.
  • Non-dusty coated granules are obtained in this manner.
  • the finely ground combination is intimately mixed with the adjuvants, giving a suspension concentrate from which suspensions of any desired dilution can be obtained by dilution with water.
  • 28 parts of the combination are mixed with 2 parts of an aromatic solvent and 7 parts of toluene diisocyanate/polymethylene-polyphenylisocyanate-mixture (8:1).
  • This mixture is emulsified in a mixture of 1 .2 parts of polyvinylalcohol, 0.05 parts of a defoamer and 51 .6 parts of water until the desired particle size is achieved.
  • To this emulsion a mixture of 2.8 parts 1 ,6-diaminohexane in 5.3 parts of water is added. The mixture is agitated until the polymerization reaction is completed.
  • the obtained capsule suspension is stabilized by adding 0.25 parts of a thickener and 3 parts of a dispersing agent.
  • the capsule suspension formulation contains 28% of the active ingredients.
  • the medium capsule diameter is 8-15 microns.
  • the resulting formulation is applied to seeds as an aqueous suspension in an apparatus suitable for that purpose.
  • Electrospray positive and negative Capillary (kV) 3.0, Cone (V) 35.0, Source Temperature (°C) 150, Cone Gas Flow (L/Hr.) 10, Desolvation Gas Flow (L/Hr.) 500.
  • Solvent A H 2 O with 0.05% TFA
  • Solvent B CH 3 CN with 0.05% TFA
  • Electrospray positive and negative Cone (V) 20.00, Source Temperature (°C) 120, Cone Gas Flow (L/Hr.) 50
  • the preparative HPLC was conducted using an 11.4 minute run time (not using at column dilution, bypassed with the column selector), according to the following gradient table:
  • Step 1 Preparation of 3-(dimethylamino)-1-(4-pyridyl)prop-2-en-1-one
  • Step 3 Preparation of 3-[4-([1 ,2,4]triazolo[1 ,5-a]pyrimidin-7-yl)pyridin-1-ium-1-yl]propanoic acid 2,2,2- trifluoroacetate A1
  • Step 1 Preparation of 3-chloro-6-(4-pyridyl)pyridazine
  • Step 3 Preparation of 3-[4-(tetrazolo[1 ,5-b]pyridazin-6-yl)pyridin-1-ium-1-yl]propanoic acid 2,2,2- trifluoroacetate A3
  • Step 1 Preparation of 8-(4-pyridyl)-[1 ,2,4]triazolo[4,3-b]pyridazine
  • Step 2 Preparation of 3-[4-([1 ,2,4]triazolo[4,3-b]pyridazin-8-yl)pyridin-1-ium-1-yl]propanoic acid bromide A2
  • a microwave vial was charged with tributyl(4-pyridyl)stannane (0.257 g), 7-chlorothiazolo[5,4- d]pyrimidine (0.1 g), tetrakis(triphenylphosphine)palladium(0) (0.067 g) and 1 ,4-dioxane (2.62 mL).
  • the mixture was heated at 140°C under microwave irradiation for 1 hour.
  • the reaction mixture was concentrated and purified by silica gel chromatography eluting with a mixture of acetonitrile and dichloromethane to give 7-(4-pyridyl)thiazolo[5,4-d]pyrimidine as a brown solid.
  • a microwave vial was charged, under nitrogen atmosphere, with 4-iodopyridine (0.1 g), 5-(4,4,5,5- tetramethyl-1 ,3, 2-dioxaborolan-2-yl)-2,1 ,3-benzoxadiazole (0.132 g), cesium carbonate (0.238 g), 1 ,1'- bis(diphenylphosphino)ferrocene-palladium(ll)dichloride dichloromethane complex (0.04 g), 1 ,4- dioxane (0.805 mL) and water (0.268 mL). The mixture was heated at 120°C under microwave irradiation for 30 minutes.
  • the reaction mixture was diluted with dichloromethane, filtered through a pad of celite, which was washed with further dichloromethane.
  • the filtrate was concentrated and purified by silica gel chromatography eluting with a mixture of ethyl acetate and hexanes to give 5-(4- pyridyl)-2,1 ,3-benzoxadiazole as a yellow solid.
  • a microwave vial was charged, under nitrogen atmosphere, with 4-iodopyridine (0.1 g), 5-(4, 4,5,5- tetramethyl-1 ,3, 2-dioxaborolan-2-yl)-2,1 ,3-benzothiadiazole (0.141 g), 1 ,1'- bis(diphenylphosphino)ferrocene-palladium(ll)dichloride dichloromethane complex (0.04 g), cesium carbonate (0.239 g), 1 ,4-dioxane (0.805 mL) and water (0.268 mL). The mixture was heated at 120°C under microwave irradiation for 30 minutes.
  • reaction mixture was diluted with dichloromethane, filtered through a pad of celite, which was washed with further dichloromethane.
  • the filtrate was concentrated and purified by silica gel chromatography eluting with a mixture of ethyl acetate and hexanes to give 5-(4-pyridyl)-2,1 ,3-benzothiadiazole as an off-white solid.
  • a microwave vial was charged with tributyl(4-pyridyl)stannane (0.286 g), 4-chloro-2,1 ,3- benzoxadiazole (0.1 g), tetrakis(triphenylphosphine)palladium(0) (0.0748 g) and 1 ,4-dioxane (2.91 mL).
  • the mixture was heated at 140°C under microwave irradiation for 1 hour.
  • the reaction mixture was concentrated and purified by silica gel chromatography eluting with a mixture of ethyl acetate and hexanes to give 4-(4-pyridyl)-2,1 ,3-benzoxadiazole as an off-white solid.
  • Example 8 Preparation of 6-(4-pyridyl)-[1 ,2,41triazolo[1 ,5-a]pyrimidine A microwave vial was charged with 4H-1 ,2,4-triazol-3-amine (0.1 g), 2-(4-pyridyl)propanedial (0.177 g) and acetic acid (2.02 mL). The mixture was heated at 150°C under microwave irradiation for 1 hour. The reaction mixture was concentrated and purified by silica gel chromatography eluting with a mixture of methanol in dichloromethane to give 6-(4-pyridyl)-[1 ,2,4]triazolo[1 ,5-a]pyrimidine as a white solid.
  • Step 2 Preparation of N'-[5-bromo-3-(methylamino)pyrazin-2-yl]-N,N-dimethyl-formamidine
  • N,N-dimethylformamide dimethyl acetal 8.36 g
  • the reaction mixture was heated at 50°C for 8 hours.
  • the reaction mixture was cooled and concentrated to give crude N'-[5- bromo-3-(methylamino)pyrazin-2-yl]-N,N-dimethyl-formamidine as a brown solid, which was used without further purification.
  • Step 5 Preparation of tert-butyl 3-[4-(3-methylimidazo[4,5-b]pyrazin-5-yl)pyridin-1-ium-1-yl]propanoate bromide A9 To a mixture of 3-methyl-5-(4-pyridyl)imidazo[4,5-b]pyrazine (0.5 g), tetrahydrofuran (5 mL) and acetonitrile (5 mL) was added tert-butyl 3-bromopropanoate (0.705 g) at room temperature. The reaction mixture was heated at 80°C for 16 hours, then cooled and concentrated.
  • Step 6 Preparation of 3-[4-(3-methylimidazo[4,5-b]pyrazin-5-yl)pyridin-1-ium-1-yl]propanoic acid chloride A8
  • Step 1 Preparation of 5-chlorothiazolo[5,4-b]pyridin-2-amine To a mixture of 2,6-dichloropyridin-3-amine (10 g) in acetic acid (100 mL) was added potassium thiocyanate (14.4 g) and this mixture was heated at 90°C for 16 hours. The resulting mixture was poured onto ice and this mixture was adjusted to pH 6 with aqueous ammonia and extracted with ethyl acetate (2x150 mL).
  • Step 1 Preparation of 3-amino-6-chloro-pyridine-2-thiol
  • a mixture of 5-chlorothiazolo[5,4-b]pyridin-2-amine (2.7 g) in 20% aqueous sodium hydroxide (100 mL) was added sodium sulfite (3.59 g) and this mixture was heated at 100°C for 16 hours.
  • the reaction mixture was cooled and neutralized with formic acid ( ⁇ 3 mL).
  • the resulting precipitate was filtered off to give 3-amino-6-chloro-pyridine-2-thiol as a yellow solid, which was used without further purification.
  • Step 1 Preparation of N'-(6-chloropyridazin-3-yl)-N,N-dimethyl-formamidine
  • Step 3 Preparation of 6-chloro-[1 ,2,4]triazolo[1 ,5-b]pyridazine
  • Step 4 Preparation of 6-(4-pyridyl)-[1 ,2,4]triazolo[1 ,5-b]pyridazine
  • reaction mixture was filtered through celite, washing with 5% methanol in dichloromethane (2x30 mL). The filtrate was concentrated and the residue purified by silica gel chromatography eluting with a mixture of methanol and dichloromethane to afford 6-(4- pyridyl)-[1 ,2,4]triazolo[1 ,5-b]pyridazine as an off-white solid.
  • Step 5 Preparation of tert-butyl 3-[4-([1 ,2,4]triazolo[1 ,5-b]pyridazin-6-yl)pyridin-1-ium-1-yl]propanoate bromide A18
  • Step 6 Preparation of 3-[4-([1 ,2,4]triazolo[1 ,5-b]pyridazin-6-yl)pyridin-1-ium-1-yl]propanoic acid chloride A13
  • Example 13 Preparation of 3-[4-([1 ,2,4]triazolo[1 ,5-a]pyrazin-5-yl)pyridin-1 -ium-1 -yl]propanoic acid chloride A14 Step 1 : Preparation of 6-(4-pyridyl)pyrazin-2-amine
  • Step 3 Preparation of N'-hydroxy-N-[6-(4-pyridyl)pyrazin-2-yl]formamidine
  • methanol 50 mL
  • hydroxylamine hydrochloride 1.16 g
  • sodium acetate 1 .36 g
  • Step 4 Preparation of 5-(4-pyridyl)-[1 ,2,4]triazolo[1 ,5-a]pyrazine
  • Step 5 Preparation of tert-butyl 3-[4-([1 ,2,4]triazolo[1 ,5-a]pyrazin-5-yl)pyridin-1-ium-1-yl]propanoate bromide A19
  • Step 6 Preparation of 3-[4-([1 ,2,4]triazolo[1 ,5-a]pyrazin-5-yl)pyridin-1-ium-1-yl]propanoic acid chloride A14
  • Step 1 Preparation of 5-chloro-1-oxido-[1 ,2,5]oxadiazolo[3,4-b]pyridin-1-ium
  • Step 3 Preparation of 5-(4-pyridyl)-[1 ,2,5]oxadiazolo[3,4-b]pyridine
  • Step 4 Preparation of methyl 3-[4-([1 ,2,5]oxadiazolo[3,4-b]pyridin-5-yl)pyridin-1-ium-1-yl]propanoate bromide A17
  • Step 5 Preparation of 3-[4-([1 ,2,5]oxadiazolo[3,4-b]pyridin-5-yl)pyridin-1-ium-1-yl]propanoic acid chloride A10
  • Step 3 Preparation of 5-(4-pyridyl)-[1 ,2,4]triazolo[1 ,5-a]pyrimidine
  • Step 1 Preparation of 3-methylsulfanyl-5-(4-pyridyl)-1 ,2,4-triazine
  • Step 3 Preparation of 7-(4-pyridyl)-[1 ,2,4]triazolo[4,3-b][1 ,2,4]triazine
  • Step 1 Preparartion of 1-(4-pyridyl)-N-(1 ,2,4-triazol-4-yl)ethanimine
  • Step 3 Preparation of 6-(4-pyridyl)-[1 ,2,4]triazolo[4,3-b]pyridazine
  • Step 1 Preparation of 3-(dimethylamino)-1-(4-pyridyl)prop-2-en-1-one
  • Step 2 Preparation of 7-(4-pyridyl)pyrazolo[1 ,5-a]pyrimidine
  • a microwave vial was charged with 1 H-pyrazol-5-amine (0.2 g), 3-(dimethylamino)-1-(4-pyridyl)prop-2- en-1-one (0.424 g) and acetic acid (3 mL) and heated at 150°C under microwave irradiation for 30 minutes.
  • the reaction mixture was concentrated and triturated with methyl t-butyl ether and the residue was purified by silica gel chromatography eluting with a mixture of ethyl acetate and methanol to give 7-(4-pyridyl)pyrazolo[1 ,5-a]pyrimidine as a light yellow solid.
  • a microwave vial was charged with 4-pyridylboronic acid (0.44 g), 5-chloropyrazolo[1 ,5-a]pyrimidine (0.5 g), 1 ,4-dioxane (5 mL) and water (2.5 mL) then tripotassium phosphate (1 .38 g) was added. After degassing for 10 minutes with nitrogen, tetrakis(triphenylphosphine)palladium(0) (0.188 g) was added and the reaction mass was degassed for a further 10 minutes. The mixture was heated at 120°C under microwave irradiation for 45 minutes then diluted with water and extracted with ethyl acetate.
  • a microwave vial was charged with 4-amino-4H-1 ,2,4-triazole (1 g), 3-(dimethylamino)-1-(4- pyridyl)prop-2-en-1-one (2.05 g) and acetic acid (20 mL) and heated at 150°C under microwave irradiation for 60 minutes.
  • the reaction mixture was concentrated and the residue was purified by silica gel chromatography eluting with a mixture of ethyl acetate and methanol to give 8-(4-pyridyl)- [1 ,2,4]triazolo[4,3-b]pyridazine as a yellow solid.
  • Step 1 Preparation of 1-(4-pyridyl)-N-pyrrol-1-yl-ethanimine
  • Step 2 Preparation of N,N-dimethyl-3-(4-pyridyl)-3-pyrrol-1-ylimino-prop-1-en-1 -amine
  • Example 22 Preparation of 4-(4-pyridyl)pyrrolo[1 ,2-b]pyridazine A microwave vial was charged with 1-aminopyrrole (0.7 g), 3-(dimethylamino)-1-(4-pyridyl)prop-2-en- 1 -one (1.5 g) and acetic acid (12.5 mL) and heated at 150°C under microwave irradiation for 60 minutes.
  • reaction mixture was concentrated and triturated with methyl t-butyl ether and the residue was purified by silica gel chromatography eluting with a mixture of ethyl acetate and cyclohexane to give 4-(4-pyridyl)pyrrolo[1 ,2-b]pyridazine as a light yellow solid.
  • Step 1 Preparation of 7-(4-pyridyl)-[1 ,2,4]triazolo[1 ,5-a]pyrimidine
  • reaction mixture was concentrated and purified by silica gel chromatography eluting with a mixture of ethyl acetate and methanol to give 7-(4-pyridyl)- [1 ,2,4]triazolo[1 ,5-a]pyrimidine as a light yellow solid.
  • Step 2 Preparation of tert-butyl 2-[4-([1 ,2,4]triazolo[1 ,5-a]pyrimidin-7-yl)pyridin-1-ium-1-yl]acetate bromide A41
  • Step 3 Preparation of 2-[4-([1 ,2,4]triazolo[1 ,5-a]pyrimidin-7-yl) pyridin-1 -ium-1 -yl]acetic acid 2,2,2- trifluoroacetate A34
  • reaction mixture was concentrated and the residue was purified by using reverse phase chromatography eluting with a mixture of acetonitrile and water (trifluoroacetic acid was present in the eluent) to give 2-[4-([1 ,2,4]triazolo[1 ,5-a]pyrimidin-7-yl)pyridin-1- ium-1-yl]acetic acid 2,2,2-trifluoroacetate.
  • a microwave vial was charged with 4-pyridylboronic acid (0.5 g), 6-chloroimidazo[1 ,2-b]pyridazine (0.5 g), 1 ,4-dioxane (5 mL) and water (2.5 mL) then tripotassium phosphate (1 .38 g) was added. After degassing for 10 minutes with nitrogen, tetrakis(triphenylphosphine)palladium(0) (0.188 g) was added and the reaction mass was degassed for a further 10 minutes. The mixture was heated at 120°C under microwave irradiation for 30 minutes then diluted with water and extracted with ethyl acetate.
  • Step 1 Preparation of N-imidazol-1-yl-1-(4-pyridyl)ethanimine
  • Step 2 Preparation of 3-imidazol-1-ylimino-N,N-dimethyl-3-(4-pyridyl)prop-1-en-1 -amine
  • Step 3 Preparation of 2-(4-pyridyl)imidazo[1 ,5-b]pyridazine
  • the aqueous layer was concentrated and purified by reverse phase HPLC eluting with a mixture of water and acetonitrile to give 2-[4-([1 ,2,4]triazolo[1 ,5-b]pyridazin-6- yl)pyridin-1-ium-1-yl]ethanesulfonate as an off-white solid.
  • Step 2 Preparation of 8-chloro-[1 ,2,4]triazolo[4,3-a]pyrazine
  • Step 3 Preparation of 8-(4-pyridyl)-[1 ,2,4]triazolo[4,3-a]pyrazine
  • a microwave vial was charged with 8-chloro-[1 ,2,4]triazolo[4,3-a]pyrazine (0.5 g), 2- methyltetrahydrofuran (10 mL) and water (10 mL). After degassing for 10 minutes with nitrogen, tetrakis(triphenylphosphine)palladium(0) (0.578 g) and 4-pyridylboronic acid (0.47 g) was added and the reaction mass was degassed for a further 10 minutes. The mixture was heated at 120°C under microwave irradiation for 1 hour then diluted with water and extracted with ethyl acetate (3x30 mL).
  • Step 4 Preparation of 3-[4-([1 ,2,4]triazolo[4,3-a]pyrazin-8-yl)pyridin-1-ium-1-yl]propanoic acid bromide A42
  • Step 1 Preparation of tert-butyl 2-[4-([1 ,2,4]triazolo[4,3-b]pyridazin-6-yl)pyridin-1-ium-1-yl]acetate bromide A48
  • Step 2 Preparation of [4-([1 ,2,4]triazolo[4,3-b]pyridazin-6-yl)pyridin-1-ium-1-yl]methanesulfonate A45 [Chlorosulfonyloxy(dimethyl)silyl]methane (10 mL) was heated at 120°C, in order to have an internal temperature of 105°C, then tert-butyl 2-[4-([1 ,2,4]triazolo[4,3-b]pyridazin-6-yl)pyridin-1-ium-1-yl]acetate bromide (0.76 g) was added portion wise. After heating for 24 hours, the reaction mixture was cooled to room temperature.
  • Step 1 Preparation of 5-(4-pyridyl)-1 ,2,4-triazin-3-amine
  • Step 2 Preparation of 3-(4-pyridyl)imidazo[1 ,2-b][1 ,2,4]triazine
  • Step 3 Preparation of 5-chloro-[1 ,2,4]triazolo[4,3-a]pyrazine
  • Step 4 Preparation of 5-(4-pyridyl)-[1 ,2,4]triazolo[4,3-a]pyrazine
  • Step 1 Preparation of N-(1H-1 ,2,4-triazol-5-yl)pyridine-4-carboxamidine
  • Step 2 Preparation of 7-methyl-5-(4-pyridyl)-[1 ,2,4]triazolo[1 ,5-a][1 ,3,5]triazine
  • Step 1 Preparation of N'-(1 ,2,4-triazol-4-yl)pyridine-4-carboxamidine
  • Step 2 Preparation of N-(dimethylaminomethylene)-N'-(1 ,2,4-triazol-4-yl)pyridine-4-carboxamidine
  • N'-(1 ,2,4-triazol-4-yl)pyridine-4-carboxamidine (1 g) in N,N-dimethylformamide (11 mL), under nitrogen atmosphere, was added tert-butoxy bis(dimethylamino)methane (3.4 mL) and the mixture was heated at 100°C for 2 hours.
  • the reaction mass was cooled to room temperature, concentrated and the residue was triturated with methyl t-butyl ether to give N- (dimethylaminomethylene)-N'-(1 ,2,4-triazol-4-yl)pyridine-4-carboxamidine as a light brown solid.
  • Step 3 Preparation of N,N-dimethyl-6-(4-pyridyl)-[1 ,2,4]triazolo[3,4-f][1 ,2,4]triazin-8-amine
  • Step 1 Preparation of 3-chloro-N-[(2,4-dimethoxyphenyl)methyl]pyrazin-2-amine
  • 2,3-dichloropyrazine (5 g) and (2,4-dimethoxyphenyl)methanamine (16.8 g) was stirred at room temperature for 16 hours.
  • the reaction was partitioned between water and ethyl acetate.
  • the organic layer was dried over sodium sulfate, concentrated and the residue was purified by silica gel chromatography eluting with a mixture of ethyl acetate and cyclohexane to give 3-chloro-N-[(2,4- dimethoxyphenyl)methyl]pyrazin-2-amine.
  • Step 2 Preparation of N-[(2,4-dimethoxyphenyl)methyl]-3-(4-pyridyl)pyrazin-2-amine
  • tetrakis(triphenylphosphine)palladium(0) 5.11 g
  • Step 5 Preparation of N-hydroxy-N'-[3-(4-pyridyl)pyrazin-2-yl]formamidine
  • hydroxylamine hydrochloride 0.672 g
  • reaction mixture was concentrated and the residue was purified by silica gel chromatography eluting with a mixture of ethyl acetate and cyclohexane to give N-hydroxy-N'-[3-(4- pyridyl)pyrazin-2-yl]formamidine.
  • Step 6 Preparation of 8-(4-pyridyl)-[1 ,2,4]triazolo[1 ,5-a]pyrazine
  • Step 2 Preparation of 5-chloro-2-methyl-triazolo[4,5-d]pyrimidine
  • iodomethane 2.5 mL
  • the reaction mass was cooled to ⁇ 0°C and sodium bis(trimethylsilyl)amide (1 M in tetrahydrofuran, 30 mL) was added over 15 minutes.
  • the reaction was stirred at room temperature for 12 hours.
  • the mixture was quenched with saturated aqueous ammonium chloride, diluted with water and extracted with ethyl acetate.
  • a microwave vial was charged with tributyl(4-pyridyl)stannane (1 .075 g), 5-chloro-2-methyl- triazolo[4,5-d]pyrimidine (0.45 g), tetrakis(triphenylphosphine)palladium(0) (0.307 g) and 1 ,4-dioxane (9 mL) and the reaction mass was degassed with nitrogen for 15 minutes. The mixture was heated at 120°C under microwave irradiation for 1 hour. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (2x50 mL).
  • a microwave vial was charged with tributyl(4-pyridyl)stannane (1 .146 g), 5-chloro-3-methyl- triazolo[4,5-d]pyrimidine (0.48 g), tetrakis(triphenylphosphine)palladium(0) (0.328 g) and 1 ,4-dioxane (10 mL) and the reaction mass was degassed with nitrogen for 15 minutes. The mixture was heated at 120°C under microwave irradiation for 1 hour. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (2x50 mL).
  • Example 36 Preparation of 7-(4-pyridyl)-[1 ,2,4]triazolo[1 ,5-b][1 ,2,4]triazine
  • Step 1 Preparation of N,N-dimethyl-N'-[5-(4-pyridyl)-1 ,2,4-triazin-3-yl]formamidine
  • a microwave vial was charged with 5-(4-pyridyl)-1 ,2,4-triazin-3-amine (1 .7 g) and 1 ,1-dimethoxy-N,N- dimethyl-methanamine (17 mL). The mixture was heated at 100°C under microwave irradiation for 1 hour. The reaction mixture was concentrated to give crude N,N-dimethyl-N'-[5-(4-pyridyl)-1 ,2,4-triazin- 3-yl]formamidine, which was used without further purification.
  • Step 2 Preparation of N-hydroxy-N'-[5-(4-pyridyl)-1 ,2,4-triazin-3-yl]formamidine
  • Step 3 Preparation of 7-(4-pyridyl)-[1 ,2,4]triazolo[1 ,5-b][1 ,2,4]triazine
  • Step 1 Preparation of ethyl-2-(4-pyridyl)-2-(1 H-1 ,2,4-triazol-5-ylhydrazono)acetate
  • Step 2 Preparation of 3-(4-pyridyl)-[1 ,2,4]triazolo[5,1-c][1 ,2,4]triazin-4-ol
  • Step 2 Preparation of N-[1-(dimethylamino)ethylidene]-N'-(1 ,2,4-triazol-4-yl)pyridine-4-carboxamidine
  • a microwave vial was charged with N'-(1 ,2,4-triazol-4-yl)pyridine-4-carboxamidine (0.5 g), toluene (7.5 mL) and 1 ,1-dimethoxy-N,N-dimethyl-ethanamine (0.43 mL). The mixture was heated at 140°C under microwave irradiation for 1 hour. The reaction mixture was concentrated and the resulting residue was triturated with tert-butyl methyl etherto give N-[1-(dimethylamino)ethylidene]-N'-(1 ,2,4-triazol-4- yl)pyridine-4-carboxamidine as a light brown gummy mass.
  • Step-3 Preparation of 8-methyl-6-(4-pyridyl)-[1 ,2,4]triazolo[3,4-f][1 ,2,4]triazine
  • reaction mixture was concentrated and purified by silica gel chromatography eluting with a mixture of ethyl acetate and cyclohexane to give 8- methyl-6-(4-pyridyl)-[1 ,2,4]triazolo[3,4-f][1 ,2,4]triazine as an off-white solid.
  • Example 39 Preparation of 5-(4-pyridyl)-[1 ,2,4]triazolo[1 ,5-c]pyrimidine To a microwave vial, purged with nitrogen, was added the 5-chloro-[1 ,2,4]triazolo[1 ,5-c]pyrimidine (0.2 g), 1 ,T-bis(diphenylphosphino)ferrocene-palladium(ll)dichloride dichloromethane complex (0.109 g), 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridine (0.328 g) and potassium phosphate tribasic (0.841 g).
  • IF50 11.12% Emulsogen EL360 TM + 44.44% N-methylpyrrolidon
  • Test plants Ipomoea hederacea (IPOHE), Euphorbia heterophylla (EPHHL), Chenopodium album (CHEAL), Amaranthus palmeri (AMAPA), Lolium perenne (LOLPE), Digitaria sanguinalis (DIGSA), Eleusine indica (ELEIN), Echinochloa crus-galli (ECHCG), Setaria faberi (SETFA)

Abstract

Compounds of the formula (I) wherein the substituents are as defined in claim 1, useful as a pesticides, especially as herbicides.

Description

Herbicidal Compounds
The present invention relates to herbicidally active pyridinium derivatives, as well as to processes and intermediates used for the preparation of such derivatives. The invention further extends to herbicidal compositions comprising such derivatives, as well as to the use of such compounds and compositions for controlling undesirable plant growth: in particular the use for controlling weeds, in crops of useful plants.
The present invention is based on the finding that pyridinium derivatives of formula (I) as defined herein, exhibit surprisingly good herbicidal activity. Thus, according to the present invention there is provided the use of a compound of formula (I) or an agronomically acceptable salt or zwitterionic species thereof, as a herbicide:
Figure imgf000002_0001
wherein
R1 is selected from the group consisting of hydrogen, halogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, C1-C6haloalkyl, -OR7, -OR15a, -N(R6)S(O)2R15, -N(R6)C(O)R15, -N(R6)C(O)OR15, - N(R6)C(O)NR16R17, -N(R6)CHO, -N(R7a)2 and -S(O)rR15;
R2 is selected from the group consisting of hydrogen, halogen, C1-C6alkyl and C1-C6haloalkyl; and wherein when R1 is selected from the group consisting of -OR7, -OR15a, -N(R6)S(O)2R15, - N(R6)C(O)R15, -N(R6)C(O)OR15, -N(R6)C(O)NR16R17, -N(R6)CHO, -N(R7a)2 and -S(O)rR15, R2 is selected from the group consisting of hydrogen and C1-C6alkyl; or
R1 and R2 together with the carbon atom to which they are attached form a C3-C6cycloalkyl ring or a 3- to 6- membered heterocyclyl, which comprises 1 or 2 heteroatoms individually selected from N and O; and
Q is (CR1aR2b)m; m is 0, 1 , 2 or 3; each R1a and R2b are independently selected from the group consisting of hydrogen, halogen, C1-C6alkyl, C1-C6haloalkyl, -OH, -OR7, -OR15a, -NH2, -NHR7, -NHR15a, -N(R6)CHO, -NR7bR7c and -S(O)rR15; or each R1a and R2b together with the carbon atom to which they are attached form a C3-C6cycloalkyl ring or a 3- to 6- membered heterocyclyl, which comprises 1 or 2 heteroatoms individually selected from N and O; and
R3, R3a, R4 and R5 are independently selected from the group consisting of hydrogen, halogen, cyano, nitro, -S(O)rR15, C1-C6alkyl, C1-C6fluoroalkyl, C1-C6fluoroalkoxy, C1-C6alkoxy, C3-C6cycloalkyl and - N(R6)2; each R6 is independently selected from hydrogen and C1-C6alkyl; each R7 is independently selected from the group consisting of C1-C6alkyl, -S(O)2R15, -C(O)R15, - C(O)OR15 and -C(O)NR16R17; each R7a is independently selected from the group consisting of -S(O)2R15, -C(O)R15, -C(O)OR15 - C(O)NR16R17 and -C(O)NR6R15a;
R7b and R7c are independently selected from the group consisting of C1-C6alkyl, -S(O)2R15, -C(O)R15, - C(O)OR15, -C(O)NR16R17 and phenyl, and wherein said phenyl is optionally substituted by 1 , 2 or 3 R9 substituents, which may be the same or different; or
R7b and R7c together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclyl ring which optionally comprises one additional heteroatom individually selected from N, O and S; and
A is a fused bicyclic structure of general formula;
Figure imgf000003_0001
in which:
(i) ring A1 has 5 members and ring A2 has 6 members;
(ii) A includes at least one heteroatom selected from N, O and S, with the remainder being carbon atoms;
(ill) at least one of ring A1 and ring A2 is aromatic, or A as a whole is aromatic; (iv) A is attached to the remainder of the compound of formula (I) at any available position of ring A2 provided it is a carbon atom;
(v) one of the carbon atoms is optionally a carbonyl;
(vi) A is optionally substituted in any available position in either or both of ring A1 or ring A2 by p substituents R8, which may be the same or different; and
(vii) p is 0 to 6; when A is substituted on one or more carbon atoms by R8, then each R8 is independently selected from the group consisting of halogen, nitro, cyano, -NH2, -NHR7, -N(R7)2, -OH, -OR7, -S(O)rR15, - NR6S(O)2R15, -C(O)OR10, -C(O)R15, -C(O)NR16R17, -S(O)2NR16R17, C1- C a y, C1-C6haloalkyl, C3- C6cycloalkyl, C3-C6halocycloalkyl, C3-C6cycloalkoxy, C2-C6alkenyl, C2-C6haloalkenyl, C2-C6alkynyl, C1- C3alkoxyC1-C3alkyl-, hydroxyC1-C6alkyl-, C1-C3alkoxyC1-C3alkoxy-, C1-C6haloalkoxy, C1- C3haloalkoxyC1-C3alkyl-, C3-C6alkenyloxy, C3-C6alkynyloxy, N-C3-C6cycloalkylamino, -C(R6)=NOR6, phenyl, a 3- to 6- membered heterocyclyl, which comprises 1 or 2 heteroatoms individually selected from N and O, and a 5- or 6- membered heteroaryl, which comprises 1 , 2, 3 or 4 heteroatoms individually selected from N, O and S, and wherein said phenyl, heterocyclyl or heteroaryl moieties are optionally substituted by 1 , 2 or 3 substituents, which may be the same or different, selected from R9; and when A is substituted on one or more N atoms by one or more R8, then each R8 is independently selected from the group consisting of -OR7, -S(O)rR12, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, C3-C6halocycloalkyl, C3-C6cycloalkoxy, C2-C6alkenyl, C2-C6haloalkenyl, C2-C6alkynyl, C1-C3alkoxyC1- C3alkyl-, hydroxyC2-C6alkyl-, C1-C6haloalkoxy, C1-C3haloalkoxyC1-C3alkyl-, C1-C6alkoxycarbonyl, C3- C6alkenyloxy, C3-C6alkynyloxy, C1-C6alkylcarbonyl, C1-C6alkylaminocarbonyl, di-C1- C6alkylaminocarbonyl, phenyl and heteroaryl, wherein the heteroaryl moiety is a 5- or 6-membered monocyclic aromatic ring which comprises 1 , 2, 3 or 4 heteroatoms individually selected from N, O and S, and wherein any of said phenyl or heteroaryl moieties are optionally substituted by 1 , 2 or 3 substituents, which may be the same or different, selected from R9; each R9 is independently selected from the group consisting of halogen, cyano, -OH, -N(R6)2, C1-C4alkyl, C1-C4alkoxy, C1-C4haloalkyl and C1-C4haloalkoxy;
X is selected from the group consisting of C3-C6cycloalkyl, phenyl, a 5- or 6- membered heteroaryl, which comprises 1 , 2, 3 or 4 heteroatoms individually selected from N, O and S, and a 4- to 6- membered heterocyclyl, which comprises 1 , 2 or 3 heteroatoms individually selected from N, O and S, and wherein said cycloalkyl, phenyl, heteroaryl or heterocyclyl moieties are optionally substituted by 1 or 2 substituents, which may be the same or different, selected from R9, and wherein the aforementioned CR1R2, Q and Z moieties may be attached at any position of said cycloalkyl, phenyl, heteroaryl or heterocyclyl moieties; n is 0 or 1 ; Z is selected from the group consisting of -C(O)OR10, -CH2OH, -CHO, -C(O)NHOR11, -C(O)NHCN, - OC(O)NHOR11, -OC(O)NHCN, -NR6C(O)NHOR11, -NR6C(O)NHCN, -C(O)NHS(O)2R12, - OC(O)NHS(O)2R12, -NR6C(O)NHS(O)2R12, -S(O)2OR10, -OS(O)2OR10, -NR6S(O)2OR10, -NR6S(O)OR10, -NHS(O)2R14, -S(O)OR10, -OS(O)OR10, -S(O)2NHCN, -S(O)2NHC(O)R18, -S(O)2NHS(O)2R12, - OS(O)2NHCN, -OS(O)2NHS(O)2R12, -OS(O)2NHC(O)R18, -NR6S(O)2NHCN, -NR6S(O)2NHC(O)R18, - N(OH)C(O)R15, -ONHC(O)R15, -NR6S(O)2NHS(O)2R12, -P(O)(R13)(OR10), -P(O)H(OR10), - OP(O)(R13)(OR10), -NR6P(O)(R13)(OR10) and tetrazole;
R10 is selected from the group consisting of hydrogen, C1-C6alkyl, phenyl and benzyl, and wherein said phenyl or benzyl are optionally substituted by 1 , 2 or 3 R9 substituents, which may be the same or different;
R11 is selected from the group consisting of hydrogen, C1-C6alkyl and phenyl, and wherein said phenyl is optionally substituted by 1 , 2 or 3 R9 substituents, which may be the same or different;
R12 is selected from the group consisting of C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, -OH, -N(R6)2 and phenyl, and wherein said phenyl is optionally substituted by 1 , 2 or 3 R9 substituents, which may be the same or different;
R13 is selected from the group consisting of -OH, C1-C6alkyl, C1-C6alkoxy and phenyl;
R14 is C1-C6haloalkyl;
R15 is selected from the group consisting of C1-C6alkyl and phenyl, and wherein said phenyl is optionally substituted by 1 , 2 or 3 R9 substituents, which may be the same or different;
R15a is phenyl, wherein said phenyl is optionally substituted by 1 , 2 or 3 R9 substituents, which may be the same or different;
R16 and R17 are independently selected from the group consisting of hydrogen and C1-C6alkyl; or R16 and R17 together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclyl ring which optionally comprises one additional heteroatom individually selected from N, O and S; and
R18 is selected from the group consisting of hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, -N(R6)2 and phenyl, and wherein said phenyl is optionally substituted by 1 , 2 or 3 R9 substituents, which may be the same or different; and r is 0, 1 or 2. According to a second aspect of the invention, there is provided a compound of formula (I) or an agronomically acceptable salt or zwitterionic species thereof, as defined herein, with the proviso that the compound of formula (I) is not,
Figure imgf000006_0001
2-[4-(3-aminopyrazolo[1 ,5-a]pyridin-5-yl)pyridin-1-ium-1-yl]ethanol .
According to a third aspect of the invention, there is provided an agrochemical composition comprising a herbicidally effective amount of a compound of formula (I) and an agrochemically-acceptable diluent or carrier. Such an agricultural composition may further comprise at least one additional active ingredient.
According to a fourth aspect of the invention, there is provided a method of controlling or preventing undesirable plant growth, wherein a herbicidally effective amount of a compound of formula (I), or a composition comprising this compound as active ingredient, is applied to the plants, to parts thereof or the locus thereof.
As used herein, the term "halogen" or "halo" refers to fluorine (fluoro), chlorine (chloro), bromine (bromo) or iodine (iodo), preferably fluorine, chlorine or bromine.
As used herein, cyano means a -CN group.
As used herein, hydroxy means an -OH group.
As used herein, nitro means an -NO2 group.
As used herein, the term "C1-C6alkyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to six carbon atoms, and which is attached to the rest of the molecule by a single bond. C1-C4alkyl and C1- C2alkyl are to be construed accordingly. Examples of C1-C6alkyl include, but are not limited to, methyl (Me), ethyl (Et), n-propyl, 1-methylethyl (iso-propyl), n-butyl, and 1-dimethylethyl (t-butyl).
As used herein, the term "C1-C6alkoxy" refers to a radical of the formula -ORa where Ra is a C1- C6alkyl radical as generally defined above. C1-C4alkoxy is to be construed accordingly. Examples of C1- 4alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, iso-propoxy and -butoxy.
As used herein, the term "C1-C6haloalkyl" refers to a C1-C6alkyl radical as generally defined above substituted by one or more of the same or different halogen atoms. C1-C4haloalkyl is to be construed accordingly. Examples of C1-C6haloalkyl include, but are not limited to chloromethyl, fluoromethyl, fluoroethyl, difluoromethyl, trifluoromethyl and 2,2,2-trifluoroethyl.
As used herein, the term "C2-C6alkenyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one double bond that can be of either the (E)- or (Z)-configuration, having from two to six carbon atoms, which is attached to the rest of the molecule by a single bond. C2-C4alkenyl is to be construed accordingly. Examples of C2-C6alkenyl include, but are not limited to, prop-1 -enyl, allyl (prop-2-enyl) and but-1-enyl.
As used herein, the term “C2-C6haloalkenyl” refers to a C2-C6alkenyl radical as generally defined above substituted by one or more of the same or different halogen atoms. Examples of C2-C6haloalkenyl include, but are not limited to chloroethylene, fluoroethylene, 1 ,1-difluoroethylene, 1 ,1-dichloroethylene and 1 ,1 ,2-trichloroethylene.
As used herein, the term "C2-C6alkynyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one triple bond, having from two to six carbon atoms, and which is attached to the rest of the molecule by a single bond. C2-C4alkynyl is to be construed accordingly. Examples of C2-C6alkynyl include, but are not limited to, prop-1-ynyl, propargyl (prop-2-ynyl) and but-1-ynyl.
As used herein, the term "C1-C6haloalkoxy" refers to a C1-C6alkoxy group as defined above substituted by one or more of the same or different halogen atoms. C1-C4haloalkoxy is to be construed accordingly. Examples of C1-C6haloalkoxy include, but are not limited to, fluoromethoxy, difluoromethoxy, fluoroethoxy, trifluoromethoxy and trifluoroethoxy.
As used herein, the term "C1-C3haloalkoxyC1-C3alkyl" refers to a radical of the formula Rb-O-Ra- where Rb is a C1-C3haloalkyl radical as generally defined above, and Ra is a C1-C3alkylene radical as generally defined above.
As used herein, the term "C1-C3alkoxyC1-C3alkyl" refers to a radical of the formula Rb-O-Ra- where Rb is a C1-C3alkyl radical as generally defined above, and Ra is a C1-C3alkylene radical as generally defined above.
As used herein, the term " C1-C3alkoxyC1-C3alkoxy-" refers to a radical of the formula Rb-O-Ra- O- where Rb is a C1-C3alkyl radical as generally defined above, and Ra is a C1-C3alkylene radical as generally defined above.
As used herein, the term "C3-C6alkenyloxy" refers to a radical of the formula -ORa where Ra is a C3-C6alkenyl radical as generally defined above.
As used herein, the term "C3-C6alkynyloxy" refers to a radical of the formula -ORa where Ra is a C3-C6alkynyl radical as generally defined above.
As used herein, the term “hydroxyC1-C6alkyl” refers to a C1-C6alkyl radical as generally defined above substituted by one or more hydroxy groups.
As used herein, the term "C1-C6alkylcarbonyl" refers to a radical of the formula -C(O)Ra where Ra is a C1-C6alkyl radical as generally defined above.
As used herein, the term "C1-C6alkoxycarbonyl" refers to a radical of the formula -C(O)ORa where Ra is a C1-C6alkyl radical as generally defined above.
As used herein, the term “aminocarbonyl” refers to a radical of the formula -C(O)NH2. As used herein, the term "C3-C6cycloalkyl" refers to a stable, monocyclic ring radical which is saturated or partially unsaturated and contains 3 to 6 carbon atoms. C3-C4cycloalkyl is to be construed accordingly. Examples of C3-C6cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
As used herein, the term "C3-C6halocycloalkyl" refers to a C3-C6cycloalkyl radical as generally defined above substituted by one or more of the same or different halogen atoms. C3-C4halocycloalkyl is to be construed accordingly.
As used herein, the term "C3-C6cycloalkoxy" refers to a radical of the formula -ORa where Ra is a C3-C6cycloalkyl radical as generally defined above.
As used herein, the term “N-C3-C6cycloalkylamino” refers to a radical of the formula -NHRa where Ra is a C3-C6cycloalkyl radical as generally defined above.
As used herein, except where explicitly stated otherwise, the term "heteroaryl" refers to a 5- or 6- membered monocyclic aromatic ring which comprises 1 , 2, 3 or 4 heteroatoms individually selected from nitrogen, oxygen and sulfur. The heteroaryl radical may be bonded to the rest of the molecule via a carbon atom or heteroatom. Examples of heteroaryl include, furyl, pyrrolyl, imidazolyl, thienyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrazinyl, pyridazinyl, pyrimidyl or pyridyl.
As used herein, except where explicitly stated otherwise, the term "heterocyclyl" or "heterocyclic" refers to a stable 4- to 6-membered non-aromatic monocyclic ring radical which comprises 1 , 2, or 3 heteroatoms individually selected from nitrogen, oxygen and sulfur. The heterocyclyl radical may be bonded to the rest of the molecule via a carbon atom or heteroatom. Examples of heterocyclyl include, but are not limited to, pyrrolinyl, pyrrolidyl, tetrahydrofuryl, tetrahydrothienyl, tetrahydrothiopyranyl, piperidyl, piperazinyl, tetrahydropyranyl, dihydroisoxazolyl, dioxolanyl, morpholinyl or d-lactamyl.
The presence of one or more possible asymmetric carbon atoms in a compound of formula (I) means that the compounds may occur in chiral 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 (including lactam-lactim tautomerism and keto-enol tautomerism) where present. The present invention includes all possible tautomeric forms for a compound of formula (I). Similarly, where there are di-substituted alkenes, these may be present in E or Z form or as mixtures of both in any proportion. The present invention includes all these possible isomeric forms and mixtures thereof for a compound of formula (I).
The compounds of formula (I) will typically be provided in the form of an agronomically acceptable salt, a zwitterion or an agronomically acceptable salt of a zwitterion. This invention covers all such agronomically acceptable salts, zwitterions and mixtures thereof in all proportions.
For example a compound of formula (I) wherein Z comprises an acidic proton, may exist as a zwitterion, a compound of formula (l-l), or as an agronomically acceptable salt, a compound of formula (l-ll) as shown below:
Figure imgf000009_0001
wherein, Y represents an agronomically acceptable anion and j and k represent integers that may be selected from 1 , 2 or 3, dependent upon the charge of the respective anion Y.
A compound of formula (I) may also exist as an agronomically acceptable salt of a zwitterion, a compound of formula (l-lll) as shown below:
Figure imgf000009_0002
wherein, Y represents an agronomically acceptable anion, M represents an agronomically acceptable cation (in addition to the pyridazinium cation) and the integers j, k and q may be selected from 1 , 2 or 3, dependent upon the charge of the respective anion Y and respective cation M.
Thus where a compound of formula (I) is drawn in protonated form herein, the skilled person would appreciate that it could equally be represented in unprotonated or salt form with one or more relevant counter ions.
In one embodiment of the invention there is provided a compound of formula (l-ll) wherein k is 2, j is 1 and Y is selected from the group consisting of halogen, trifluoroacetate and pentafluoropropionate. In this embodiment a nitrogen atom in ring A may be protonated or a nitrogen atom comprised in R1, R2, R8, Q orX may be protonated. Preferably, in a compound of formula (l-ll), k is 2, j is 1 and Y is chloride, wherein a nitrogen atom in ring A is protonated.
Suitable agronomically acceptable salts of the present invention, represented by an anion Y, include but are not limited chloride, bromide, iodide, fluoride, 2-naphthalenesulfonate, acetate, adipate, methoxide, ethoxide, propoxide, butoxide, aspartate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, butylsulfate, butylsulfonate, butyrate, camphorate, camsylate, caprate, caproate, caprylate, carbonate, citrate, diphosphate, edetate, edisylate, enanthate, ethanedisulfonate, ethanesulfonate, ethylsulfate, formate, fumarate, gluceptate, gluconate, glucoronate, glutamate, glycerophosphate, heptadecanoate, hexadecanoate, hydrogen sulfate, hydroxide, hydroxynaphthoate, isethionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methanedisulfonate, methylsulfate, mucate, myristate, napsylate, nitrate, nonadecanoate, octadecanoate, oxalate, pelargonate, pentadecanoate, pentafluoropropionate, perchlorate, phosphate, propionate, propylsulfate, propylsulfonate, succinate, sulfate, tartrate, tosylate, tridecylate, triflate, trifluoroacetate, undecylinate and valerate.
Suitable cations represented by M include, but are not limited to, metals, conjugate acids of amines and organic cations. Examples of suitable metals include aluminium, calcium, cesium, copper, lithium, magnesium, manganese, potassium, sodium, iron and zinc. Examples of suitable amines include allylamine, ammonia, amylamine, arginine, benethamine, benzathine, butenyl-2-amine, butylamine, butylethanolamine, cyclohexylamine, decylamine, diamylamine, dibutylamine, diethanolamine, diethylamine, diethylenetriamine, diheptylamine, dihexylamine, diisoamylamine, diisopropylamine, dimethylamine, dioctylamine, dipropanolamine, dipropargylamine, dipropylamine, dodecylamine, ethanolamine, ethylamine, ethylbutylamine, ethylenediamine, ethylheptylamine, ethyloctylamine, ethylpropanolamine, heptadecylamine, heptylamine, hexadecylamine, hexenyl-2-amine, hexylamine, hexylheptylamine, hexyloctylamine, histidine, indoline, isoamylamine, isobutanolamine, isobutylamine, isopropanolamine, isopropylamine, lysine, meglumine, methoxyethylamine, methylamine, methylbutylamine, methylethylamine, methylhexylamine, methylisopropylamine, methylnonylamine, methyloctadecylamine, methylpentadecylamine, morpholine, N,N-diethylethanolamine, N- methylpiperazine, nonylamine, octadecylamine, octylamine, oleylamine, pentadecylamine, pentenyl-2- amine, phenoxyethylamine, picoline, piperazine, piperidine, propanolamine, propylamine, propylenediamine, pyridine, pyrrolidine, sec-butylamine, stearylamine, tallowamine, tetradecylamine, tributylamine, tridecylamine, trimethylamine, triheptylamine, trihexylamine, triisobutylamine, triisodecylamine, triisopropylamine, trimethylamine, tripentylamine, tripropylamine, tris(hydroxymethyl)aminomethane, and undecylamine. Examples of suitable organic cations include benzyltributylammonium, benzyltrimethylammonium, benzyltriphenylphosphonium, choline, tetrabutylammonium, tetrabutylphosphonium, tetraethylammonium, tetraethylphosphonium, tetramethylammonium, tetramethylphosphonium, tetrapropylammonium, tetrapropylphosphonium, tributylsulfonium, tributylsulfoxonium, triethylsulfonium, triethylsulfoxonium, trimethylsulfonium, trimethylsulfoxonium, tripropylsulfonium and tripropylsulfoxonium.
Preferred compounds of formula (I), wherein Z comprises an acidic proton, can be represented as either (l-l) or (l-ll). For compounds of formula (l-ll) emphasis is given to salts when Y is chloride, bromide, iodide, hydroxide, bicarbonate, acetate, pentafluoropropionate, triflate, trifluoroacetate, methylsulfate, tosylate and nitrate, wherein j and k are 1. Preferably, Y is chloride, bromide, iodide, hydroxide, bicarbonate, acetate, trifluoroacetate, methylsulfate, tosylate and nitrate, wherein j and k are 1. For compounds of formula (l-ll) emphasis is also given to salts when Y is carbonate and sulfate, wherein j is 2 and k is 1 , and when Y is phosphate, wherein j is 3 and k is 1 . Where appropriate compounds of formula (I) may also be in the form of (and/or be used as) an N-oxide.
Compounds of formula (I) wherein m is 0 and n is 0 may be represented by a compound of formula (I- la) as shown below:
Figure imgf000011_0003
I-Ia) wherein R1, R2, R3, R3a, R4, R5, A and Z are as defined for compounds of formula (I).
Compounds of formula (I) wherein m is 1 and n is 0 may be represented by a compound of formula (I-
Ib) as shown below:
Figure imgf000011_0001
(I-Ib) wherein R1, R2, R1a, R2b, R3, R3a, R4, R5, A and Z are as defined for compounds of formula (I).
Compounds of formula (I) wherein m is 2 and n is 0 may be represented by a compound of formula (I- lc) as shown below:
Figure imgf000011_0002
(l-lc) wherein R1, R2, R1a, R2b, R3, R3a, R4, R5, A and Z are as defined for compounds of formula (I).
Compounds of formula (I) wherein m is 3 and n is 0 may be represented by a compound of formula (I-
Id) as shown below:
Figure imgf000012_0001
Figure imgf000012_0004
Figure imgf000012_0003
Figure imgf000012_0002
wherein R1, R2, R1a, R2b, R3, R3a, R4, R5, A and Z are as defined for compounds of formula (I). The following list provides definitions, including preferred definitions, for substituents n, m, r, A, Q, X, Z, R1 , R2 ,R1a, R2b , R3 , R3a, R4
Figure imgf000012_0005
, R5, R6 , R7,R7a, R7b ,R7c,R8,R9, R10 , R1 1, R12 , R 13, R1 4, R15 ,R15a,R16 , R17and R18 with reference to the compounds of formula (I) according to the invention. For anyone 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. R1 is selected from the group consisting of hydrogen, halogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, C1-C6haloalkyl, -OR7, -OR15a, -N(R6)S(O)2R15, -N(R6)C(O)R15, -N(R6)C(O)OR15, -N(R6)C(O)NR16R17, -N(R6)CHO, -N(R7a)2 and -S(O)rR15. Preferably, R1 is selected from the groupconsisting of hydrogen, halogen, C1-C6alkyl, C1-C6fluoroalkyl, -OR7, -NHS(O)2R15, -NHC(O)R15, -NHC(O)OR15, -NHC(O)NR16R17, -N(R7a)2 and -S(O)rR15. More preferably, R1 is selected from the group consisting of hydrogen, halogen, C1-C6alkyl, C1-C6fluoroalkyl, -OR7and -N(R7a)2. Even more preferably,R1 is selected from the group consisting of hydrogen, C1-C6alkyl, -OR7 and -N(R7a)2. Even more preferably still, R1 is hydrogen or C1-C6alkyl. Yet even more preferably still, R1 is hydrogen or methyl. Most preferably R1 is hydrogen. R2 is selected from the group consisting of hydrogen, halogen, C1-C6alkyl and C1-C6haloalkyl. Preferably, R2 is selected from the group consisting of hydrogen, halogen, C1-C6alkyl and C1-C6fluoroalkyl. More preferably, R2 is hydrogen or C1-C6alkyl. Even more preferably, R2 is hydrogen or methyl. Most preferably R2 is hydrogen. Wherein when R1 is selected from the group consisting of -OR7, -OR15a, -N(R6)S(O)2R15, -N(R6)C(O)R15,-N(R6)C(O)OR15, -N(R6)C(O)NR16R17, -N(R6)CHO, -N(R7a)2 and -S(O)rR15, R2 is selected from the group consisting of hydrogen and C1-C6alkyl. Preferably, when R1 is selected from the group consisting of -OR7, -NHS(O)2R15, -NHC(O)R15, -NHC(O)OR15, -NHC(O)NR16R17, -N(R7a)2 and -S(O)rR15, R2 is selected from the group consisting of hydrogen and methyl. Alternatively, R1 and R2 together with the carbon atom to which they are attached form a C3-C6cycloalkyl ring or a 3- to 6- membered heterocyclyl, which comprises 1 or 2 heteroatoms individually selected fromN and O. Preferably, R1 and R2 together with the carbon atom to which they are attached form a C3-C6cycloalkyl ring. More preferably, R1 and R2 together with the carbon atom to which they are attached form a cyclopropyl ring. In one embodiment R1 and R2 are hydrogen.
In another embodiment R1 is methyl and R2 is hydrogen.
In another embodiment R1 is methyl and R2 is methyl.
Q is (CR1aR2b)m. m is 0, 1 , 2 or 3. Preferably, m is 0,1 or 2. More preferably, m is 1 or 2. Most preferably, m is 1.
Each R1a and R2b are independently selected from the group consisting of hydrogen, halogen, C1- C6alkyl, C1-C6haloalkyl, -OH, -OR7, -OR15a, -NH2, -NHR7, -NHR15a, -N(R6)CHO, -NR7bR7c and -S(O)rR15. Preferably, each R1a and R2b are independently selected from the group consisting of hydrogen, halogen, C1-C6alkyl, C1-C6fluoroalkyl, -OH, -NH2 and -NHR7. More preferably, each R1a and R2b are independently selected from the group consisting of hydrogen, C1-C6alkyl, -OH and -NH2. Even more preferably, each R1a and R2b are independently selected from the group consisting of hydrogen, methyl, -OH and -NH2. Even more preferably still, each R1a and R2b are independently selected from the group consisting of hydrogen and methyl. Most preferably R1a and R2b are hydrogen.
In another embodiment each R1a and R2b are independently selected from the group consisting of hydrogen and C1-C6alkyl.
Alternatively, each R1a and R2b together with the carbon atom to which they are attached form a C3- C6cycloalkyl ring or a 3- to 6- membered heterocyclyl, which comprises 1 or 2 heteroatoms individually selected from N and O. Preferably, each R1a and R2b together with the carbon atom to which they are attached form a C3-C6cycloalkyl ring. More preferably, each R1a and R2b together with the carbon atom to which they are attached form a cyclopropyl ring.
R3, R3a, R4 and R5 are independently selected from the group consisting of hydrogen, halogen, cyano, nitro, -S(O)rR15, C1-C6alkyl, C1-C6fluoroalkyl, C1-C6fluoroalkoxy, C1-C6alkoxy, C3-C6cycloalkyl and - N(R6)2. Preferably, R3, R3a, R4 and R5 are independently selected from the group consisting of hydrogen, C1-C6alkyl, C1-C6fluoroalkyl, C1-C6fluoroalkoxy, C1-C6alkoxy, C3-C6cycloalkyl and -N(R6)2. More preferably, R3, R3a, R4 and R5 are independently selected from the group consisting of hydrogen, C1- C6alkyl and C1-C6alkoxy. Even more preferably, R3, R3a, R4 and R5 are independently selected from the group consisting of hydrogen and C1-C6alkyl. Even more preferably still, R3, R3a, R4 and R5 are independently selected from the group consisting of hydrogen and methyl. Most preferably, R3, R3a, R4 and R5 are hydrogen.
Each R6 is independently selected from hydrogen and C1-C6alkyl. Preferably, each R6 is independently selected from hydrogen and methyl. Each R7 is independently selected from the group consisting of C1-C6alkyl, -S(O)2R15, -C(O)R15, - C(O)OR15 and -C(O)NR16R17. Preferably, each R7 is independently selected from the group consisting of C1-C6alkyl, -C(O)R15 and -C(O)NR16R17. More preferably, each R7 is C1-C6alkyl. Most preferably, each R7 is methyl.
Each R7a is independently selected from the group consisting of -S(O)2R15, -C(O)R15, -C(O)OR15 - C(O)NR16R17 and -C(O)NR6R15a. Preferably, each R7a is independently -C(O)R15 or -C(O)NR16R17.
R7b and R7c are independently selected from the group consisting of C1-C6alkyl, -S(O)2R15, -C(O)R15, - C(O)OR15, -C(O)NR16R17 and phenyl, and wherein said phenyl is optionally substituted by 1 , 2 or 3 R9 substituents, which may be the same or different. Preferably, R7b and R7c are independently selected from the group consisting of C1-C6alkyl, -C(O)R15 and -C(O)NR16R17. More preferably, R7b and R7c are C1-C6alkyl. Most preferably, R7b and R7care methyl.
Alternatively, R7b and R7c together with the nitrogen atom to which they are attached form a 4- to 6- membered heterocyclyl ring which optionally comprises one additional heteroatom individually selected from N, O and S. Preferably, R7b and R7c together with the nitrogen atom to which they are attached form a 5- to 6-membered heterocyclyl ring which optionally comprises one additional heteroatom individually selected from N and O. More preferably, R7b and R7c together with the nitrogen atom to which they are attached form an pyrrolidyl, oxazolidinyl, imidazolidinyl, piperidyl, piperazinyl or morpholinyl group.
A is a fused bicyclic structure of general formula;
Figure imgf000014_0001
in which:
(i) ring A1 has 5 members and ring A2 has 6 members;
(ii) A includes at least one heteroatom selected from N, O and S, with the remainder being carbon atoms;
(ill) at least one of ring A1 and ring A2 is aromatic, or A as a whole is aromatic;
(iv) A is attached to the remainder of the compound of formula (I) at any available position of ring A2 provided it is a carbon atom;
(v) one of the carbon atoms is optionally a carbonyl; (vi) A is optionally substituted in any available position in either or both of ring A1 or ring A2 by p substituents R8, which may be the same or different; and
(vii) p is 0 to 6. Preferably A comprises at least one nitrogen atom in either ring A1 or A2.
Preferably A as a whole is aromatic.
In one embodiment, A as a whole is aromatic, and ring A1 includes at least one heteroatom selected from N, O and S, with the remainder being carbon atoms, and ring A2 includes at least one heteroatom selected from N with the remainder being carbon atoms.
Preferably A contains 1 , 2, 3, 4, 5 or 6 heteroatoms, more preferably A contains 2, 3, 4, 5 or 6 heteroatoms.
In one embodiment A includes at least one N heteroatom with the remainder being carbon atoms. Preferably (in this embodiment), A contains 1 , 2, 3, 4, 5 or 6 N heteroatoms with the remainder being carbon atoms. Even more preferably A is selected from the group consisting of formula A-l to A-CXIV below (the skilled person would appreciate that if p is ³ 1 then R8 may be substituted on any available position of rings A- I to A-CXIV) ,
Figure imgf000016_0001
Figure imgf000017_0001
Figure imgf000018_0001
Figure imgf000019_0001
wherein the jagged line defines the point of attachment to the remaining part of a compound of formula
(I)· Even more preferably still, A is selected from the group consisting of formula A-l to A-LXXI.
Yet even more preferably still, A is selected from the group consisting of formula A-XLIII to A-LXXI.
In one embodiment, A is selected from the group consisting of formula A-a, A-b, A-c, A-d, A-e, A-f, A- g, A-h, A-j, A-k, A-m, A-n, A-o, A-p, A-q and A-r below (preferably, A-a, A-b, A-c, A-d, A-e, A-g, A-h, A- j, A-n, A-o, A-p, A-q and A-r, more preferably, A-a, A-c, A-o and A-p) ,
Figure imgf000020_0001
wherein X1 is CH or N;
W1 is O, S or N(Me); each A3 is independently selected from the group consisting of CH, N, O, S and N(Me);
R8a is selected from the group consisting of hydrogen, -NH2, -NMe2, -OH and methyl; and wherein the jagged line defines the point of attachment to the remaining part of a compound of formula (I). In another embodiment, A is selected from the group consisting of formula A-VIII, A-IX, A-X, A-XLIX, A-LIII, A-LVII, A-LVIII, A-LXXII, A-LXXIII, A-LXXV, A-LXXVI, A-LXXX, A-LXXXI, A-LXXXII, A-LXXXIII, A-XCII and A-XCVI below,
Figure imgf000021_0002
wherein the jagged line defines the point of attachment to the remaining part of a compound of formula
(I)· Preferably, A is selected from the group consisting of formula A-IX, A-LVII, A-LVIII, A-LXXV, A-LXXVI,
A-LXXXI and A-XCVI below,
Figure imgf000021_0001
wherein the jagged line defines the point of attachment to the remaining part of a compound of formula
(I)· Preferably p is 0, 1 or 2, more preferably 0 or 1 , most preferably 0. when A is substituted on one or more carbon atoms by R8, then each R8 is independently selected from the group consisting of halogen, nitro, cyano, -NH2, -NHR7, -N(R7)2, -OH, -OR7, -S(O)rR15, - NR6S(O)2R15, -C(O)OR10, -C(O)R15, -C(O)NR16R17, -S(O)2NR16R17, C1-C6alkyl, C1-C6haloalkyl, C3- C6cycloalkyl, C3-C6halocycloalkyl, C3-C6cycloalkoxy, C2-C6alkenyl, C2-C6haloalkenyl, C2-C6alkynyl, C1- C3alkoxyC1-C3alkyl-, hydroxyC1-C6alkyl-, C1-C3alkoxyC1-C3alkoxy-, C1-C6haloalkoxy, C1- C3haloalkoxyC1-C3alkyl-, C3-C6alkenyloxy, C3-C6alkynyloxy, N-C3-C6cycloalkylamino, -C(R6)=NOR6, phenyl, a 3- to 6- membered heterocyclyl, which comprises 1 or 2 heteroatoms individually selected from N and O, and a 5- or 6- membered heteroaryl, which comprises 1 , 2, 3 or 4 heteroatoms individually selected from N, O and S, and wherein said phenyl, heterocyclyl or heteroaryl moieties are optionally substituted by 1 , 2 or 3 substituents, which may be the same or different, selected from R9.
Preferably, when A is substituted on one or more ring carbon atoms, each R8 is independently selected from the group consisting of halogen, nitro, cyano, -NH2, -NHR7, -N(R7)2, -OH, -OR7, -S(O)rR15, - NR6S(O)2R15, -C(O)OR10, -C(O)R15, -C(O)NR16R17, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, C1- C3alkoxyC1-C3alkyl-, hydroxyC1-C6alkyl- and C1-C6haloalkoxy.
More preferably, when A is substituted on one or more ring carbon atoms, each R8 is independently selected from the group consisting of chloro, fluoro, cyano, -NH2, -N(Me)2, -OH, -OMe, -S(O)2Me, - C(O)OMe, -C(O)OH, -C(O)Me, -C(O)NH2, -C(O)NHMe, -C(O)N(Me)2, methyl, ethyl and trifluoromethyl.
Even more preferably, when A is substituted on one or more ring carbon atoms, each R8 is independently selected from the group consisting of -NH2, -N(Me)2, -OH, and methyl. Even more preferably still, when A is substituted on one or more ring carbon atoms, each R8 is independently selected from the group consisting of -N(Me)2, -OH, and methyl. Most preferably, when A is substituted on one or more ring carbon atoms, each R8 is methyl.
When A is substituted on one or more N atoms by one or more R8, then each R8 is independently selected from the group consisting of -OR7, -S(O)rR12, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, C3- C6halocycloalkyl, C3-C6cycloalkoxy, C2-C6alkenyl, C2-C6haloalkenyl, C2-C6alkynyl, C1-C3alkoxyC1- C3alkyl-, hydroxyC2-C6alkyl-, C1-C6haloalkoxy, C1-C3haloalkoxyC1-C3alkyl-, C1-C6alkoxycarbonyl, C3- C6alkenyloxy, C3-C6alkynyloxy, C1-C6alkylcarbonyl, C1-C6alkylaminocarbonyl, di-C1- C6alkylaminocarbonyl, phenyl and heteroaryl, wherein the heteroaryl moiety is a 5- or 6-membered monocyclic aromatic ring which comprises 1 , 2, 3 or 4 heteroatoms individually selected from N, O and S, and wherein any of said phenyl or heteroaryl moieties are optionally substituted by 1 , 2 or 3 substituents, which may be the same or different, selected from R9.
Preferably, when A is substituted on one or more N atoms by one or more R8, then each R8 is independently selected from the group consisting of -OR7, C1-C6alkyl and C1-C6haloalkyl. More preferably, R8 is C1-C6alkyl. Even more preferably still, each R8 is methyl or ethyl. Most preferably R8 is methyl.
Preferably, each R9 is independently selected from the group consisting of halogen, cyano, -N(R6)2, C1- C4alkyl, C1-C4alkoxy, C1-C4haloalkyl and C1-C4haloalkoxy. More preferably, each R9 is independently selected from the group consisting of halogen, C1-C4alkyl, C1-C4alkoxy and C1-C4haloalkyl. Even more preferably, each R9 is independently selected from the group consisting of halogen and C1-C4alkyl.
X is selected from the group consisting of C3-C6cycloalkyl, phenyl, a 5- or 6- membered heteroaryl, which comprises 1 , 2, 3 or 4 heteroatoms individually selected from N, O and S, and a 4- to 6- membered heterocyclyl, which comprises 1 , 2 or 3 heteroatoms individually selected from N, O and S, and wherein said cycloalkyl, phenyl, heteroaryl or heterocyclyl moieties are optionally substituted by 1 or 2 substituents, which may be the same or different, selected from R9, and wherein the aforementioned CR1R2, Q and Z moieties may be attached at any position of said cycloalkyl, phenyl, heteroaryl or heterocyclyl moieties.
Preferably, X is selected from the group consisting of phenyl and a 4- to 6- membered heterocyclyl, which comprises 1 or 2 heteroatoms individually selected from N and O, and wherein said phenyl or heterocyclyl moieties are optionally substituted by 1 or 2 substituents, which may be the same or different, selected from R9, and wherein the aforementioned CR1R2, Q and Z moieties may be attached at any position of said phenyl or heterocyclyl moieties.
More preferably, X is a 4- to 6- membered heterocyclyl, which comprises 1 or 2 heteroatoms individually selected from N and O, and wherein said heterocyclyl moieties is optionally substituted by 1 or 2 substituents, which may be the same or different, selected from R9, and wherein the aforementioned CR1R2, Q and Z moieties may be attached at any position of said heterocyclyl moiety.
In one embodiment, X is a 5-membered heterocyclyl, which comprises 1 heteroatom, wherein said heteroatom is N, and wherein the aforementioned CR1R2, Q and Z moieties may be attached at any position of said heterocyclyl moiety. Preferably, X is a 5-membered heterocyclyl, which comprises 1 heteroatom, wherein said heteroatom is N, and wherein the aforementioned CR1R2 and Q moieties are attached adjacent to the N atom and the Z moiety is attached to the N atom.
In another embodiment, X is phenyl optionally substituted by 1 or 2 substituents, which may be the same or different, selected from R9, and wherein the aforementioned CR1R2, Q and Z moieties may be attached at any position of said phenyl moiety. Preferably, X is phenyl and the aforementioned CR1R2 and Q moieties are attached in a postion para to the Z moiety. n is 0 or 1 . Preferably, n is 0. Z is selected from the group consisting of -C(O)OR10, -CH2OH, -CHO, -C(O)NHOR11, -C(O)NHCN, - OC(O)NHOR11, -OC(O)NHCN, -NR6C(O)NHOR11, -NR6C(O)NHCN, -C(O)NHS(O)2R12, - OC(O)NHS(O)2R12, -NR6C(O)NHS(O)2R12, -S(O)2OR10, -OS(O)2OR10, -NR6S(O)2OR10, -NR6S(O)OR10, -NHS(O)2R14, -S(O)OR10, -OS(O)OR10, -S(O)2NHCN, -S(O)2NHC(O)R18, -S(O)2NHS(O)2R12, - OS(O)2NHCN, -OS(O)2NHS(O)2R12, -OS(O)2NHC(O)R18, -NR6S(O)2NHCN, -NR6S(O)2NHC(O)R18, - N(OH)C(O)R15, -ONHC(O)R15, -NR6S(O)2NHS(O)2R12, -P(O)(R13)(OR10), -P(O)H(OR10), - OP(O)(R13)(OR10), -NR6P(O)(R13)(OR10) and tetrazole.
Preferably, Z is selected from the group consisting of -C(O)OR10, -C(O)NHOR11, -C(O)NHCN, - OC(O)NHOR11, -NR6C(O)NHOR11, -C(O)NHS(O)2R12, -OC(O)NHS(O)2R12, -NR6C(O)NHS(O)2R12, - S(O)2OR10, -OS(O)2OR10, -NR6S(O)2OR10, -NR6S(O)OR10, -NHS(O)2R14, -S(O)OR10, -OS(O)OR10, - S(O)2NHC(O)R18, -S(O)2NHS(O)2R12, -OS(O)2NHS(O)2R12, -OS(O)2NHC(O)R18, -NR6S(O)2NHC(O)R18, -N(OH)C(O)R15, -ONHC(O)R15, -NR6S(O)2NHS(O)2R12, -P(O)(R13)(OR10), -P(O)H(OR10), - OP(O)(R13)(OR10), -NR6P(O)(R13)(OR10) and tetrazole.
More preferably, Z is selected from the group consisting of -C(O)OR10, -C(O)NHOR11, -C(O)NHCN, - C(O)NHS(O)2R12, -S(O)2OR10, -OS(O)2OR10, -NR6S(O)2OR10, -NHS(O)2R14, -S(O)OR10, -
P(O)(R13)(OR10) and tetrazole.
Even more preferably Z is selected from the group consisting of -C(O)OR10, -C(O)NHCN, - C(O)NHS(O)2R12, -S(O)2OR10, and -P(O)(R13)(OR10).
Even more preferably still Z is selected from the group consisting of -C(O)OH, -C(O)OCH3, - C(O)OCH2CH3, -C(O)OCH(CH3)2, -C(O)OC(CH3)3, -C(O)OCH2C6H5, -C(O)OC6H5, -C(O)NHS(O)2CH3, - S(O)2OH, -P(O)(OH)( OCH2CH3) and -P(O)(OCH2CH3)(OCH2CH3).
Yet even more preferably still, Z is selected from the group consisting of -C(O)OH, -C(O)OCH3, - C(O)OC(CH3)3 and -S(O)2OH.
Most preferably Z is -C(O)OH or -S(O)2OH.
R10 is selected from the group consisting of hydrogen, C1-C6alkyl, phenyl and benzyl, and wherein said phenyl or benzyl are optionally substituted by 1 , 2 or 3 R9 substituents, which may be the same or different. Preferably, R10 is selected from the group consisting of hydrogen, C1-C6alkyl, phenyl and benzyl. More preferably, R10 is selected from the group consisting of hydrogen and C1-C6alkyl. Most preferably, R10 is hydrogen.
R11 is selected from the group consisting of hydrogen, C1-C6alkyl and phenyl, and wherein said phenyl is optionally substituted by 1 , 2 or 3 R9 substituents, which may be the same or different. Preferably, R11 is selected from the group consisting of hydrogen, C1-C6alkyl and phenyl. More preferably, R11 is selected from the group consisting of hydrogen and C1-C6alkyl. Even more preferably, R11 is C1-C6alkyl. Most preferably, R11 is methyl.
R12 is selected from the group consisting of C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, -OH, -N(R6)2 and phenyl, and wherein said phenyl is optionally substituted by 1 , 2 or 3 R9 substituents, which may be the same or different. Preferably, R12 is selected from the group consisting of C1-C6alkyl, C1-C6haloalkyl, C1- C6alkoxy, -OH, -N(R6)2 and phenyl. More preferably, R12 is selected from the group consisting of C1- C6alkyl, C1-C6haloalkyl and -N(R6)2. Even more preferably, R12 is selected from the group consisting of methyl, -N(Me)2 and trifluoromethyl. Most preferably, R12 is methyl.
R13 is selected from the group consisting of -OH, C1-C6alkyl, C1-C6alkoxy and phenyl. Preferably R13 is selected from the group consisting of -OH, C1-C6alkyl and C1-C6alkoxy. More preferably, R13 is selected from the group consisting of -OH and C1-C6alkoxy. Even more preferably, R13 is selected from the group consisting of -OH, methoxy and ethoxy. Most preferably, R13 is -OH.
R14 is C1-C6haloalkyl. Preferably, R14 is trifluoromethyl.
R15 is selected from the group consisting of C1-C6alkyl and phenyl, and wherein said phenyl is optionally substituted by 1 , 2 or 3 R9 substituents, which may be the same or different. Preferably, R15 is selected from the group consisting of C1-C6alkyl and phenyl. More preferably, R15 is C1-C6alkyl. Most preferably R15 is methyl.
R15a is phenyl, wherein said phenyl is optionally substituted by 1 , 2 or 3 R9 substituents, which may be the same or different. Preferably, R15a is phenyl optionally substituted by 1 R9 substituent. More preferably, R15a is phenyl.
R16 and R17 are independently selected from the group consisting of hydrogen and C1-C6alkyl. Preferably, R16 and R17 are independently selected from the group consisting of hydrogen and methyl.
Alternatively, R16 and R17 together with the nitrogen atom to which they are attached form a 4- to 6- membered heterocyclyl ring which optionally comprises one additional heteroatom individually selected from N, O and S. Preferably, R16 and R17 together with the nitrogen atom to which they are attached form a 5- to 6-membered heterocyclyl ring which optionally comprises one additional heteroatom individually selected from N and O. More preferably, R16 and R17 together with the nitrogen atom to which they are attached form an pyrrolidyl, oxazolidinyl, imidazolidinyl, piperidyl, piperazinyl or morpholinyl group.
R18 is selected from the group consisting of hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, -N(R6)2 and phenyl, and wherein said phenyl is optionally substituted by 1 , 2 or 3 R9 substituents, which may be the same or different. Preferably, R18 is selected from the group consisting of hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, -N(R6)2 and phenyl. More preferably, R18 is selected from the group consisting of hydrogen, C1-C6alkyl and C1-C6haloalkyl. Further more preferably, R18 is selected from the group consisting of C1-C6alkyl and C1-C6haloalkyl. Most preferably, R18 is methyl or trifluoromethyl. r is 0, 1 or 2. Preferably, r is 0 or 2.
In a set of preferred embodiments, in a compound according to formula (I) of the invention,
R1 is hydrogen or C1-C6alkyl;
R2 is hydrogen or C1-C6alkyl;
Q is (CR1aR2b)m; m is 0, 1 or 2;
R1a and R2b are independently selected from the group consisting of hydrogen, C1-C6alkyl, -OH and - NH2;
R3, R3a, R4 and R5 are independently selected from the group consisting of hydrogen and methyl; each R6 is independently selected from hydrogen and methyl; each R7 is C1-C6alkyl;
A is a fused bicyclic structure of general formula;
Figure imgf000026_0001
in which:
(i) ring A1 has 5 members and ring A2 has 6 members;
(ii) A contains 2,3,4 or 5 heteroatoms selected from N, O and S, with the remainder being carbon atoms;
(iii) A as a whole is aromatic;
(iv) A is attached to the remainder of the compound of formula (I) at any available position of ring A2 provided it is a carbon atom;
(v) one of the carbon atoms is optionally a carbonyl;
(vi) A is optionally substituted in any available position in either or both of ring A1 or ring A2 by p substituents R8, which may be the same or different; and
(vii) p is 0, 1 or 2; when A is substituted on one or more ring carbon atoms, each R8 is independently selected from the group consisting of halogen, nitro, cyano, -NH2, -NHR7, -N(R7)2, -OR7, -S(O)rR15, -NR6S(O)2R15, - C(O)OR10, -C(O)R15, -C(O)NR16R17, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, C1-C3alkoxyC1-C3alkyl- , hydroxyC1-C6alkyl- and C1-C6haloalkoxy; when A is substituted on one or more N atoms by one or more R8, then each R8 is C1-C6alkyl, most preferably methyl; n is 0;
Z is selected from the group consisting of -C(O)OR10, -C(O)NHCN, -C(O)NHS(O)2R12, -S(O)2OR10, and -P(O)(R13)(OR10);
R10 is selected from the group consisting of hydrogen, C1-C6alkyl, phenyl and benzyl;
R12 is selected from the group consisting of C1-C6alkyl, C1-C6haloalkyl and -N(R6)2;
R13 is selected from the group consisting of -OH and C1-C6alkoxy;
R15 is C1-C6alkyl;
R16 and R17 are independently selected from the group consisting of hydrogen and methyl; and r is 0 or 2.
More preferably,
R1 is hydrogen or methyl;
R2 is hydrogen or methyl;
Q is (CR1aR2b)m; m is 0, 1 or 2;
R1a and R2b are independently selected from the group consisting of hydrogen and methyl;
R3, R3a, R4 and R5 are hydrogen;
A is selected from the group consisting of formula A-l to A-LXXI and p is 0, 1 , or 2, more preferably 0 or 1 , most preferably 0; when A is substituted on one or more ring carbon atoms, each R8 is independently selected from the group consisting of chloro, fluoro, cyano, -NH2, -N(Me)2, -OMe, -S(O)2Me, -C(O)OMe, -C(O)OH, - C(O)Me, -C(O)NH2, -C(O)NHMe, -C(O)N(Me)2, methyl, ethyl and trifluoromethyl, even more preferably methyl; when A is substituted on one or more N atoms by one or more R8, then each R8 is C1-C6alkyl, or most preferably methyl; n is 0; and
Z is selected from the group consisting of -C(O)OH, -C(O)OCH3, -C(O)OCH2CH3, -C(O)OCH(CH3)2, - C(O)OC(CH3)3, -C(O)OCH2C6H5, -C(O)OC6H5, -C(O)NHS(O)2CH3, -S(O)2OH, -P(O)(OH)( OCH2CH3) and -P(O)(OCH2CH3)(OCH2CH3).
In a further set of preferred embodiments, the compound according to formula (I) is selected from a compound of formula (l-aa) to (l-dj) below
Figure imgf000028_0001
Figure imgf000029_0001
Figure imgf000030_0001
Figure imgf000031_0001
Figure imgf000032_0001
wherein p is 0, 1 or 2; preferably 0 or 1 , more preferably 0, each R8 is independently selected from the group consisting of chloro, fluoro, cyano, -NH2, -N(Me)2, - OH, -OMe, -S(O)2Me, -C(O)OMe, -C(O)OH, -C(O)Me, -C(O)NH2, -C(O)NHMe, -C(O)N(Me)2, methyl and trifluoromethyl; and
Z is selected from the group consisting of -C(O)OH, -C(O)OCH3, -C(O)OCH2CH3, -C(O)OCH(CH3)2, - C(O)OC(CH3)3, -C(O)OCH2C6H5, -C(O)OC6H5, -C(O)NHS(O)2CH3, -S(O)2OH, -P(O)(OH)( OCH2CH3) and -P(O)(OCH2CH3)( OCH2CH3), preferably Z is -C(O)OH or -S(O)2OH. In another preferred embodiment, R1 is hydrogen or methyl;
R2 is hydrogen or methyl;
Q is (CR1aR2b)m; m is 0, 1 or 2; R1a and R2b are independently selected from the group consisting of hydrogen and methyl;
R3, R3a, R4 and R5 are hydrogen;
A is selected from the group consisting of formula A-l to A-CXIV and p is 0, 1 , or 2, more preferably 0 or 1 , most preferably 0; when A is substituted on one or more ring carbon atoms, each R8 is independently selected from the group consisting of -NH2, -N(Me)2, -OH, and methyl, even more preferably methyl; when A is substituted on one or more N atoms by one or more R8, then each R8 is C1-C6alkyl, or most preferably methyl; n is 0; and
Z is selected from the group consisting of -C(O)OH, -C(O)OCH3, -C(O)OC(CH3)3 and -S(O)2OH.
Preferably, in this embodiment,
R1 is hydrogen;
R2 is hydrogen;
Q is (CR1aR2b)m; m is 0, 1 or 2;
R1a and R2b are hydrogen;
R3, R3a, R4 and R5 are hydrogen;
A is selected from the group consisting of formula A-VIII, A-IX, A-X, A-XLIX, A-LIII, A-LVII, A-LVIII, A- LXXII, A-LXXIII, A-LXXV, A-LXXVI, A-LXXX, A-LXXXI, A-LXXXII, A-LXXXIII, A-XCII and A-XCVI and p is 0 or 1 (preferably p is 0); when p is 1 A is substituted on a ring carbon atom, and each R8 is independently selected from the group consisting of -NH2, -N(Me)2, -OH, and methyl, even more preferably methyl; n is 0; and
Z is selected from the group consisting of -C(O)OH, -C(O)OCH3, -C(O)OC(CH3)3 and -S(O)2OH (preferably, Z is -C(O)OH or -S(O)2OH).
More preferably, in this embodiment,
R1 is hydrogen;
R2 is hydrogen;
Q is (CR1aR2b)m; m is 0, 1 or 2;
R1a and R2b are hydrogen;
R3, R3a, R4 and R5 are hydrogen;
A is selected from the group consisting of formula A-IX, A-LVII, A-LVIII, A-LXXV, A-LXXVI, A-LXXXI and A-XCVI, and p is 0 or 1 (preferably p is 0); when p is 1 A is substituted on a ring carbon atom, and each R8 is independently selected from the group consisting of -NH2, -N(Me)2, -OH, and methyl, even more preferably methyl; n is 0; and Z is selected from the group consisting of -C(O)OH, -C(O)OCH3, -C(O)OC(CH3)3 and -S(O)2OH (preferably, Z is -C(O)OH or -S(O)2OH).
In another preferred set of embodiments,
R1 is hydrogen;
R2 is hydrogen;
Q is (CR1aR2b)m; m is 0, 1 or 2;
R1a and R2b are hydrogen;
R3, R3a, R4 and R5 are hydrogen;
A is selected from the group consisting of formula A-a, A-b, A-c, A-d, A-e, A-f, A-g, A-h, A-j, A-k, A-m, A-n, A-o, A-p, A-q and A-r below (preferably, A-a, A-b, A-c, A-d, A-e, A-g, A-h, A-j, A-n, A-o, A-p, A-q and A-r, more preferably, A-a, A-c, A-o and A-p) ,
Figure imgf000034_0001
wherein X1 is CH or N;
W1 is O, S or N(Me); each A3 is independently selected from the group consisting of CH, N, O, S and N(Me);
R8a is selected from the group consisting of hydrogen, -NH2, -N(Me)2, -OH and methyl; and wherein the jagged line defines the point of attachment to the remaining part of a compound of formula (I); n is 0; and
Z is selected from the group consisting of -C(O)OH, -C(O)OCH3, -C(O)OC(CH3)3 and -S(O)2OH (preferably, Z is -C(O)OH or -S(O)2OH). In one set of embodiments, the compound according to formula (I) is selected from a compound selected from the group consisting of A1 to A73 listed in Table A. It should be understood that compounds of formula (I) may exist/be manufactured in "procidal form", wherein they comprise a group "G". Such compounds are referred to herein as compounds of formula (l-IV).
G is a group which may be removed in a plant by any appropriate mechanism including, but not limited to, metabolism and chemical degradation to give a compound of formula (l-l), (l-ll) or (l-lll) wherein Z contains an acidic proton, for example see the scheme below:
Figure imgf000035_0001
Whilst such G groups may be considered as ‘procidal’, and thus yield active herbicidal compounds once removed, compounds comprising such groups may also exhibit herbicidal activity in their own right. In such cases in a compound of formula (l-IV), Z-G may include but is not limited to, any one of (G1) to (G7) below and E indicates the point of attachment to the remaining part of a compound of formula (I):
In embodiments where Z-G is (G1) to (G7), G, R19, R20, R21, R22 and R23 are defined as follows:
G is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, -C(R21R22)OC(O)R19, phenyl or phenyl-C1-C4alkyl-, wherein said phenyl moiety is optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, C1-C6alkyl, C1-C6haloalkyl or C1-C6alkoxy.
R19 is C1-C6alkyl or phenyl,
R20 is hydroxy, C1-C6alkyl, C1-C6alkoxy or phenyl,
R21 is hydrogen or methyl, R22 is hydrogen or methyl,
R23 is hydrogen or C1-C6alkyl.
The compounds in Tables 1 to 34 below illustrate the compounds of the invention. The skilled person would understand that the compounds of formula (I) may exist as an agronomically acceptable salt, a zwitterion or an agronomically acceptable salt of a zwitterion as described hereinbefore.
Table 1 :
This table discloses 181 specific compounds of the formula (T-1):
Figure imgf000036_0001
(T-1) wherein A is as defined in Table 1 and R3, R3a, R4 and R5 are hydrogen.
Figure imgf000037_0001
Figure imgf000038_0001
Figure imgf000039_0001
Figure imgf000040_0001
Figure imgf000041_0001
Figure imgf000042_0001
Figure imgf000043_0001
Figure imgf000044_0001
Figure imgf000045_0001
Table 2:
This table discloses 181 specific compounds of the formula (T-2):
Figure imgf000046_0003
wherein A is as defined in Table 1 and R3, R3a, R4 and R5 are hydrogen. Table 3:
This table discloses 181 specific compounds of the formula (T-3):
Figure imgf000046_0001
wherein A is as defined in Table 1 and R3, R3a, R4 and R5 are hydrogen.
Table 4:
This table discloses 181 specific compounds of the formula (T-4):
Figure imgf000046_0002
wherein A is as defined in Table 1 and R3, R3a, R4 and R5 are hydrogen.
Table 5:
This table discloses 181 specific compounds of the formula (T-5):
Figure imgf000046_0004
wherein A is as defined in Table 1 and R3, R3a, R4 and R5 are hydrogen. Table 6:
This table discloses 181 specific compounds of the formula (T-6):
Figure imgf000047_0003
wherein A is as defined in Table 1 and R3, R3a, R4 and R5 are hydrogen. Table 7:
This table discloses 181 specific compounds of the formula (T-7):
Figure imgf000047_0001
wherein A is as defined in Table 1 and R3, R3a, R4 and R5 are hydrogen. Table 8: This table discloses 181 specific compounds of the formula (T-8):
Figure imgf000047_0002
wherein A is as defined in Table 1 and R3, R3a, R4 and R5 are hydrogen. Table 9:
This table discloses 181 specific compounds of the formula (T-9):
Figure imgf000048_0003
wherein A is as defined in Table 1 and R3, R3a, R4 and R5 are hydrogen. Table 10:
This table discloses 181 specific compounds of the formula (T-10):
Figure imgf000048_0001
wherein A is as defined in Table 1 and R3, R3a, R4 and R5 are hydrogen. Table 11 :
This table discloses 181 specific compounds of the formula (T-11):
Figure imgf000048_0002
wherein A is as defined in Table 1 and R3, R3a, R4 and R5 are hydrogen.
Table 12:
This table discloses 181 specific compounds of the formula (T-12):
Figure imgf000048_0004
wherein A is as defined in Table 1 and R3, R3a, R4 and R5 are hydrogen. Table 13:
This table discloses 181 specific compounds of the formula (T-13):
Figure imgf000049_0002
wherein A is as defined in Table 1 and R3, R3a, R4 and R5 are hydrogen. Table 14:
This table discloses 181 specific compounds of the formula (T-14):
Figure imgf000049_0001
wherein A is as defined in Table 1 and R3, R3a, R4 and R5 are hydrogen.
Table 15: This table discloses 181 specific compounds of the formula (T-15):
Figure imgf000049_0003
wherein A is as defined in Table 1 and R3, R3a, R4 and R5 are hydrogen. Table 16:
This table discloses 181 specific compounds of the formula (T-16):
Figure imgf000050_0003
wherein A is as defined in Table 1 and R3, R3a, R4 and R5 are hydrogen. Table 17:
This table discloses 181 specific compounds of the formula (T-17):
Figure imgf000050_0001
wherein A is as defined in Table 1 and R3, R3a, R4 and R5 are hydrogen.
Table 18:
This table discloses 181 specific compounds of the formula (T-18):
Figure imgf000050_0002
wherein A is as defined in Table 1 and R3, R3a, R4 and R5 are hydrogen. Table 19:
This table discloses 181 specific compounds of the formula (T-19):
Figure imgf000050_0004
wherein A is as defined in Table 1 and R3, R3a, R4 and R5 are hydrogen. Table 20:
This table discloses 181 specific compounds of the formula (T-20):
Figure imgf000051_0002
wherein A is as defined in Table 1 and R3, R3a, R4 and R5 are hydrogen. Table 21 :
This table discloses 181 specific compounds of the formula (T-21):
Figure imgf000051_0001
wherein A is as defined in Table 1 and R3, R3a, R4 and R5 are hydrogen.
Table 22: This table discloses 181 specific compounds of the formula (T-22):
Figure imgf000051_0003
wherein A is as defined in Table 1 and R3, R3a, R4 and R5 are hydrogen. Table 23:
This table discloses 181 specific compounds of the formula (T-23):
Figure imgf000052_0003
wherein A is as defined in Table 1 and R3, R3a, R4 and R5 are hydrogen. Table 24:
This table discloses 181 specific compounds of the formula (T-24):
Figure imgf000052_0001
wherein A is as defined in Table 1 and R3, R3a, R4 and R5 are hydrogen.
Table 25:
This table discloses 181 specific compounds of the formula (T-25):
Figure imgf000052_0002
wherein A is as defined in Table 1 and R3, R3a, R4 and R5 are hydrogen.
Table 26:
This table discloses 181 specific compounds of the formula (T-26):
Figure imgf000052_0004
wherein A is as defined in Table 1 and R3, R3a, R4 and R5 are hydrogen. Table 27:
This table discloses 181 specific compounds of the formula (T-27):
Figure imgf000053_0003
wherein A is as defined in Table 1 and R3, R3a, R4 and R5 are hydrogen.
Table 28:
This table discloses 181 specific compounds of the formula (T-28):
Figure imgf000053_0001
wherein A is as defined in Table 1 and R3, R3a, R4 and R5 are hydrogen. Table 29: This table discloses 181 specific compounds of the formula (T-29):
Figure imgf000053_0002
wherein A is as defined in Table 1 and R3, R3a, R4 and R5 are hydrogen. Table 30:
This table discloses 181 specific compounds of the formula (T-30):
Figure imgf000054_0002
wherein A is as defined in Table 1 and R3, R3a, R4 and R5 are hydrogen. Table 31 :
This table discloses 181 specific compounds of the formula (T-31):
Figure imgf000054_0001
wherein A is as defined in Table 1 and R3, R3a, R4 and R5 are hydrogen.
Table 32:
This table discloses 181 specific compounds of the formula (T-32):
Figure imgf000054_0003
wherein A is as defined in Table 1 and R3, R3a, R4 and R5 are hydrogen. Table 33:
This table discloses 181 specific compounds of the formula (T-33):
Figure imgf000054_0004
wherein A is as defined in Table 1 and R3, R3a, R4 and R5 are hydrogen. Table 34:
This table discloses 181 specific compounds of the formula (T-34):
Figure imgf000055_0001
wherein A is as defined in Table 1 and R3, R3a, R4 and R5 are hydrogen.
The compounds of the present invention may be prepared according to the following schemes in which the substituents n, m, r, A, Q, X, Z, R1, R2, R1a, R2b, R2, R3, R3a, R4, R5, R6, R7, R7a, R7b R7c, R8, R9, R10, R11, R12, R13, R14, R15, R15a, R16, R17 and R18 are as defined hereinbefore unless explicitly stated otherwise. The compounds of the preceeding Tables 1 to 34 may thus be obtained in an analogous manner.
The compounds of formula (I) may be prepared by the alkylation of compounds of formula (X), wherein R3, R3a, R4, R5 and A are as defined for compounds of formula (I), with a suitable alkylating agent of formula (W), wherein R1, R2, Q, X, n and Z are as defined for compounds of formula (I) and LG is a suitable leaving group, for example, halide or pseudohalide such as triflate, mesylate or tosylate, in a suitable solvent at a suitable temperature, as described in reaction scheme 1. Example conditions include stirring a compound of formula (X) with an alkylating agent of formula (W) in a solvent, or mixture of solvents, such as acetone, dichloromethane, dichloroethane, N,N-dimethylformamide, acetonitrile, 1 ,4-dioxane, water, acetic acid or triflu roacetic acid at a temperature between -78°C and 150°C. An alkylating agent of formula (W) may include, but is not limited to, bromoacetic acid, methyl bromoacetate, 3-bromopropionoic acid, methyl 3-bromopropionate, 2-bromo-N-methoxyacetamide, sodium 2- bromoethanesulphonate, 2,2-dimethylpropyl 2-(trifluoromethylsulfonyloxy)ethanesulfonate, 2-bromo-N- methanesulfonylacetamide, 3-bromo-N-methanesulfonylpropanamide, dimethoxyphosphorylmethyl trifluoromethanesulfonate, dimethyl 3-bromopropylphosphonate, 3-chloro-2, 2-dimethyl-propanoic acid and diethyl 2-bromoethylphosphonate. Such alkylating agents and related compounds are either known in the literature or may be prepared by known literature methods. Compounds of formula (I) which may be described as esters of N- alkyl acids, which include, but are not limited to, esters of carboxylic acids, phosphonic acids, phosphinic acids, sulfonic acids and sulfinic acids, may be subsequently partially or fully hydrolysed by treament with a suitable reagent, for example, aqueous hydrochloric acid or trimethylsilyl bromide, in a suitable solvent at a suitable temperature between 0°C and 100°C. Reaction scheme 1
Figure imgf000056_0001
Additionally, compounds of formula (I) may be prepared by reacting compounds of formula (X), wherein R3, R3a, R4, R5 and A are as defined for compounds of formula (I), with a suitably activated electrophilic alkene of formula (B), wherein Z is -S(O)2OR10, -P(O)(R13)(OR10) or -C(O)OR10 and R1, R2, R1a, R10 and R13 are as defined for compounds of formula (I), in a suitable solvent at a suitable temperature. Compounds of formula (B) are known in the literature, or may be prepared by known methods. Example reagents include, but are not limited to, acrylic acid, methacrylic acid, crotonic acid, 3,3-dimethylacrylic acid, methyl acrylate, ethene sulfonic acid, isopropyl ethylenesulfonate, 2,2-dimethylpropyl ethenesulfonate and dimethyl vinylphosphonate. The direct products of these reactions, which may be described as esters of N-alkyl acids, which include, but are not limited to, esters of carboxylic acids, phosphonic acids, phosphinic acids, sulfonic acids and sulfinic acids, may be subsequently partially or fully hydrolysed by treament with a suitable reagent in a suitable solvent at a suitable temperature, as described in reaction scheme 2.
Reaction scheme 2
Figure imgf000056_0002
In a related reaction compounds of formula (I), wherein Q is C(R1aR2b), m is 1 , 2 or 3, n=0 and Z is - S(O)2OH, -OS(O)2OH or -NR6S(O)2OH, may be prepared by the reaction of compounds of formula (X), wherein R3, R3a, R4, R5 and A are as defined for compounds of formula (I), with a cyclic alkylating agent of formula (E), (F) or (AF), wherein Ya is C(R1aR2b), O or NR6 and R1, R2, R1a and R2b are as defined for compounds of formula (I), in a suitable solvent at a suitable temperature, as described in reaction scheme 3. Suitable solvents and suitable temperatures are as previously described. An alkylating agent of formula (E) or (F) may include, but is not limited to, 1 ,3-propanesultone, 1 ,4-butanesultone, ethylenesulfate, 1 ,3-propylene sulfate and 1 ,2,3-oxathiazolidine 2,2-dioxide. Such alkylating agents and related compounds are either known in the literature or may be prepared by known literature methods.
Reaction scheme 3
Figure imgf000057_0001
A compound of formula (I), wherein m is 0, n is 0 and Z is -S(O)2OH, may be prepared from a compound of formula (I), wherein m is 0, n is 0 and Z is C(O)OR10, by treatment with trimethylsilylchlorosulfonate in a suitable solvent at a suitable temperature, as described in reaction scheme 4. Preferred conditions include heating the carboxylate precursor in neat trimethylsilylchlorosulfonate at a temperature between 25°C and 150°C.
Reaction scheme 4
Figure imgf000057_0002
Furthermore, compounds of formula (I) may be prepared by reacting compounds of formula (X), wherein R3, R3a, R4, R5 and A are as defined for compounds of formula (I), with a suitable alcohol of formula (WW), wherein R1 , R2, Q, X, n and Z are as defined for compounds of formula (I), under Mitsunobu-type conditions such as those reported by Petit et al, Tet. Lett. 2008, 49 (22), 3663. Suitable phosphines include triphenylphosphine, suitable azodicarboxylates include diisopropylazodicarboxylate and suitable acids include fluoroboric acid, triflic acid and bis(trifluoromethylsulfonyl)amine, as described in reaction scheme 5. Such alcohols are either known in the literature or may be prepared by known literature methods.
Reaction scheme 5
Figure imgf000058_0002
In another approach a compound of formula (I), wherein n, Q, Z, X, R1, R2, R3, R3a, R4, R5 and A are as defined for compounds of formula (I), may be prepared from a compound of formula (R) and an oxidant, in a suitable solvent at a suitable temperature, as outlined in reaction scheme 6. Examples of such oxidants include, but are not limited to, tetrachloro-p-benzoquinone, 2,3-dichloro-5,6- dicyanobenzoquinone, bromine, N-bromosuccinimide, manganese dioxide, selenium dioxide, potassium permanganate or biocatalysts. Related reactions are known in the literature.
Reaction scheme 6
Figure imgf000058_0001
A compound of formula (R), wherein n, Q, Z, X, R1, R2, R3, R3a, R4, R5 and A are as defined for compounds of formula (I), may be prepared from a compound of formula (S) and an organometallic of formula (T), wherein M' includes, but is not limited to, organomagnesium, organolithium, organocopper and organozinc reagents, in a suitable solvent at a suitable temperature, optionally in the presence of an additonal transition metal additive, as outlined in reaction scheme 7. Example conditions include treating a compound of formula (S) with a Grignard of formula (T), in the presence of 0.05-100 mol% copper iodide, in a solvent such as tetrahydrofuran at a temperature between -78°C and 100°C. Organometallics of formula (T) are known in the literature, or may be prepared by known literature methods. Compounds of formula (S) may be prepared by analogous reactions to those for the preparation of compounds of formula (I) from a compound of formula (X). Reaction scheme 7
Figure imgf000059_0001
Compounds of formula (I) may also be prepared by oxidation of a compound of formula (BB), wherein A, R3, R3a, R4 and R5 are as defined for compounds of formula (I), as outlined in reaction scheme 8. Example conditions include stirring a compound of formula (BB) in a suitable solvent at a suitable temperature in the presence of a suitable oxidant. Examples of such oxidants include, but are not limited to, tetrachloro-p-benzoquinone, 2,3-dichloro-5,6-dicyanobenzoquinone, bromine, N- bromosuccinimide, manganese dioxide, selenium dioxide, potassium permanganate or biocatalysts. See, for example, Toscani, Anita et al, ACS Catalysis, 8(9), 8781-8787; 2018, Chang, Meng-Yang et al, Tetrahedron Letters, 51 (37), 4886-4889; 201.
Reaction scheme 8
Figure imgf000059_0002
Compounds of formula (BB) may be prepared from a compound of formula (CC), wherein A, R3, R3a, R4 and R5 are as defined for compounds of formula (I), by analogous N-alkylation methods previously described in schemes 1 , 2 and 3, using reagents (W), (B), (E), (F), (AF) and (WW). Reaction scheme 9
Figure imgf000059_0003
Compounds of formula (X) are known in the literature or may be prepared using literature methods. Example methods include, but are not limited to, the transition metal cross-coupling of compounds of formula (H) and formula (J), or alternatively compounds of formula (K) and formula (L), as outlined in scheme 10. For organometallics of formula (J) and formula (L), M' is either an organostannane, organoboronic acid or ester, organotrifluoroborate, organomagnesium, organocopper or organozinc, and for compounds of formula (H) and (K) Hal is defined as a halogen or pseudo halogen, for example triflate, mesylate and tosylate. Such cross-couplings include Stille (for example Sauer, J.; Heldmann, D. K. Tetrahedron, 1998, 4297), Suzuki-Miyaura (for example Luebbers, T.; Flohr, A.; Jolidon, S.; David- Pierson, P.; Jacobsen, H.; Ozmen, L.; Baumann, K. Bioorg. Med. Chem. Lett., 2011 , 6554), Negishi (for example Imahori, T.; Suzawa, K.; Kondo, Y. Heterocycles, 2008, 1057), and Kumada (for example Heravi, M. M.; Hajiabbasi, P. Monatsh. Chem., 2012, 1575). The coupling partners may be selected with reference to the specific cross-coupling reaction and target product. Transition metal catalysts, ligands, bases, solvents and temperatures may be selected with reference to the desired cross-coupling and are known in the literature. Compounds of formula (H), formula (K) and formula (L) are known in the literature, or may be prepared by known literature methods.
Reaction scheme 10
Figure imgf000060_0001
A compound of formula (J), wherein M' is either an organostannane, organoboronic acid or ester, organotrifluoroborate, organomagnesium, organocopper or organozinc, may be prepared from a compound of formula (K), wherein R3, R3a, R4 and R5 are as defined for compounds of formula (I), and Hal is defined as a halogen or pseudo halogen, for example triflate, mesylate and tosylate, as described in scheme 11 . Example conditions are well known in the literature, for example halogen-metal exchange (wherein Hal is iodine, bromide and chlorine), or transition metal mediated cross-coupling of either a diboron or distannane reagent (wherein Hal is iodine, bromide, chlorine, triflate, mesylate and tosylate). Example halogen-metal exchange conditions to prepare a compound of formula (J), wherein M' is an organostannane, include treatment of a compound of formula (K) with butyl lithium then tri-n-butyltin chloride in an appropriate solvent at an appropriate temperature (for example see Koch, V.; Nieger, M.; Braese, S., Adv. Synth. Catal., 2017, 832). Example halogen-metal exchange conditions to prepare a compound of formula (J), wherein M’ is an organoboronic acid, include treatment of a compound of formula (K) with butyl lithium then triisopropyl borate in an appropriate solvent at an appropriate temperature (for example see Fudickar, W.; Linker, T., J. Org. Chem., 2017, 9258). Example halogen- metal exchange conditions to prepare a compound of formula (J), wherein M’ is an organomagnesium, include treatment of a compound of formula (K) with isopropyl magnesium chloride in an appropriate solvent at an appropriate temperature (for example see Salituro et al. WO 2018075699), or alternatively activated magnesium in an appropriate solvent at an appropriate temperature (for example see Tang et al. CN 107417486). Example halogen-metal exchange conditions to prepare a compound of formula (J), wherein M’ is an organozinc, include treatment of a compound of formula (K) with isopropyl magnesium chloride then dichloro(N,N,N',N'-tetramethylethylenediamine)zinc in an appropriate solvent at an appropriate temperature (for example see Baba et al. JP 2013227251). Example transition metal mediated conditions to prepare a compound of formula (J), wherein M’ is an organostannane, include treatment of a compound of formula (K) with hexamethyldistannane and bis(triphenylphosphine)palladium(ll) dichloride in an appropriate solvent at an appropriate temperature (for example see Barbachyn, M. R. et al., J. Med. Chem., 2003, 284). Example transition metal mediated conditions to prepare a compound of formula (J), wherein M’ is an organboronic acid, include treatment of a compound of formula (K) with bis(pinacolato)diboron, bis(triphenylphosphine)palladium(ll) dichloride and potassium acetate in an appropriate solvent at an appropriate temperature (for example see Meng et al. CN 104276997). Compounds of formula (K) are either known in the literature or can be prepared by known methods.
Reaction scheme 11
Figure imgf000061_0001
In an addtional approach, outlined in reaction scheme 12, compounds of formula (X) may be prepared by classical ring synthesis approaches starting from a compound of formula (ZZ), wherein R3, R3a, R4 and R5 are as defined for compounds of formula (I) and T is a functional group which can be converted through one or more chemical steps into a bicylic fused heteroaromatic A, wherein A is as defined for compounds of formula (I). Example functional groups include, but are not limited to, -CO2H, -C(O)NH2, -C(O)Me, -C(O)H, -CN and -Hal, and such transformations are are known in the literature.
Reaction scheme 12
Figure imgf000062_0002
A compound of formula (X) may also be prepared from a compound of formula (DD) or a compound of formula (CC) using similar oxidation conditions as described previously, as outlined in reaction scheme 13.
Reaction scheme 13
Figure imgf000062_0003
Compounds of formula (CC) may be prepared by deprotection of a compound of formula (DD), wherein A, R3, R3a, R4 and R5 are as defined for compounds of formula (I) and G1 is a suitable protecting group, as outlined in reaction scheme 14. Examples of suitable protecting groups and conditions are well known in the literature.
Reaction scheme 14
Figure imgf000062_0001
Compounds of formula (DD) are known in the literature or may be prepared using literature methods, (for example see Dyckman et al. WO 2019126082). Example methods include, but are not limited to, the transition metal cross-coupling of compounds of formula (H) and formula (EE), wherein M' is either an organostannane, organoboronic acid or ester, organotrifluoroborate, organomagnesium, organocopper or organozinc, as outlined in reaction scheme 14. Such cross-couplings include Stille, see for example Lee, Ju-Hyeon et al, European Journal of Medicinal Chemistry, 74, 246-257; 2014, Suzuki-Miyaura, see for example Kim, Eunkyung et al, Bioorganic & Medicinal Chemistry Letters, 18(18), 4993-4996; 2008 and Negishi, see for example Baskaran, Subramanian et al, PCT Int. Appl. , 2010091409. The coupling partners may be selected with reference to the specific cross-coupling reaction and target product. Transition metal catalysts, ligands, bases, solvents and temperatures may be selected with reference to the desired cross-coupling and are known in the literature. Compounds of formula (H) and formula (EE) are known in the literature, or may be prepared by known literature methods.
Reaction scheme 15
Figure imgf000063_0001
The compounds according to the invention can be used as herbicidal agents in unmodified form, but they are generally formulated into compositions in various ways using formulation adjuvants, such as carriers, solvents and surface-active substances. The formulations can be in various physical forms, e.g. in the form of dusting powders, gels, wettable powders, water-dispersible granules, water- dispersible tablets, effervescent pellets, emulsifiable concentrates, microemulsifiable concentrates, oil- in-water emulsions, oil-flowables, aqueous dispersions, oily dispersions, suspo-emulsions, capsule suspensions, emulsifiable granules, soluble liquids, water-soluble concentrates (with water or a water- miscible organic solvent as carrier), impregnated polymer films or in other forms known e.g. from the Manual on Development and Use of FAO and WHO Specifications for Pesticides, United Nations, First Edition, Second Revision (2010). For water-soluble compounds, soluble liquids, water-soluble concentrates or water soluble granules are preferred. Such formulations can either be used directly or diluted prior to use. The dilutions can be made, for example, with water, liquid fertilisers, micronutrients, biological organisms, oil or solvents.
The formulations can be prepared e.g. by mixing the active ingredient with the formulation adjuvants in order to obtain compositions in the form of finely divided solids, granules, solutions, dispersions or emulsions. The active ingredients can also be formulated with other adjuvants, such as finely divided solids, mineral oils, oils of vegetable or animal origin, modified oils of vegetable or animal origin, organic solvents, water, surface-active substances or combinations thereof.
The active ingredients can also be contained in very fine microcapsules. Microcapsules contain the active ingredients in a porous carrier. This enables the active ingredients to be released into the environment in controlled amounts (e.g. slow-release). Microcapsules usually have a diameter of from 0.1 to 500 microns. They contain active ingredients in an amount of about from 25 to 95 % by weight of the capsule weight. The active ingredients can be in the form of a monolithic solid, in the form of fine particles in solid or liquid dispersion or in the form of a suitable solution. The encapsulating membranes can comprise, for example, natural or synthetic rubbers, cellulose, styrene/butadiene copolymers, polyacrylonitrile, polyacrylate, polyesters, polyamides, polyureas, polyurethane or chemically modified polymers and starch xanthates or other polymers that are known to the person skilled in the art. Alternatively, very fine microcapsules can be formed in which the active ingredient is contained in the form of finely divided particles in a solid matrix of base substance, but the microcapsules are not themselves encapsulated.
The formulation adjuvants that are suitable for the preparation of the compositions according to the invention are known per se. As liquid carriers there may be used: water, toluene, xylene, petroleum ether, vegetable oils, acetone, methyl ethyl ketone, cyclohexanone, acid anhydrides, acetonitrile, acetophenone, amyl acetate, 2-butanone, butylene carbonate, chlorobenzene, cyclohexane, cyclohexanol, alkyl esters of acetic acid, diacetone alcohol, 1 ,2-dichloropropane, diethanolamine, p- diethylbenzene, diethylene glycol, diethylene glycol abietate, diethylene glycol butyl ether, diethylene glycol ethyl ether, diethylene glycol methyl ether, N,N-dimethylformamide, dimethyl sulfoxide, 1 ,4- dioxane, dipropylene glycol, dipropylene glycol methyl ether, dipropylene glycol dibenzoate, diproxitol, alkylpyrrolidone, ethyl acetate, 2-ethylhexanol, ethylene carbonate, 1 ,1 ,1 -trichloroethane, 2-heptanone, alpha-pinene, d-limonene, ethyl lactate, ethylene glycol, ethylene glycol butyl ether, ethylene glycol methyl ether, gamma-butyrolactone, glycerol, glycerol acetate, glycerol diacetate, glycerol triacetate, hexadecane, hexylene glycol, isoamyl acetate, isobornyl acetate, isooctane, isophorone, isopropylbenzene, isopropyl myristate, lactic acid, laurylamine, mesityl oxide, methoxypropanol, methyl isoamyl ketone, methyl isobutyl ketone, methyl laurate, methyl octanoate, methyl oleate, methylene chloride, m-xylene, n-hexane, n-octylamine, octadecanoic acid, octylamine acetate, oleic acid, oleylamine, o-xylene, phenol, polyethylene glycol, propionic acid, propyl lactate, propylene carbonate, propylene glycol, propylene glycol methyl ether, p-xylene, toluene, triethyl phosphate, triethylene glycol, xylenesulfonic acid, paraffin, mineral oil, trichloroethylene, perchloroethylene, ethyl acetate, amyl acetate, butyl acetate, propylene glycol methyl ether, diethylene glycol methyl ether, methanol, ethanol, isopropanol, and alcohols of higher molecular weight, such as amyl alcohol, tetrahydrofurfuryl alcohol, hexanol, octanol, ethylene glycol, propylene glycol, glycerol, N-methyl-2-pyrrolidone and the like.
Suitable solid carriers are, for example, talc, titanium dioxide, pyrophyllite clay, silica, attapulgite clay, kieselguhr, limestone, calcium carbonate, bentonite, calcium montmorillonite, cottonseed husks, wheat flour, soybean flour, pumice, wood flour, ground walnut shells, lignin and similar substances.
A large number of surface-active substances can advantageously be used in both solid and liquid formulations, especially in those formulations which can be diluted with a carrier prior to use. Surface- active substances may be anionic, cationic, non-ionic or polymeric and they can be used as emulsifiers, wetting agents or suspending agents or for other purposes. Typical surface-active substances include, for example, salts of alkyl sulfates, such as diethanolammonium lauryl sulfate; salts of alkylarylsulfonates, such as calcium dodecylbenzenesulfonate; alkylphenol/alkylene oxide addition products, such as nonylphenol ethoxylate; alcohol/alkylene oxide addition products, such as tridecylalcohol ethoxylate; soaps, such as sodium stearate; salts of alkylnaphthalenesulfonates, such as sodium dibutylnaphthalenesulfonate; dialkyl esters of sulfosu coin ate salts, such as sodium di(2- ethylhexyl)sulfosuccinate; sorbitol esters, such as sorbitol oleate; quaternary amines, such as lauryltrimethylammonium chloride, polyethylene glycol esters of fatty acids, such as polyethylene glycol stearate; block copolymers of ethylene oxide and propylene oxide; and salts of mono- and di- alkylphosphate esters; and also further substances described e.g. in McCutcheon's Detergents and Emulsifiers Annual, MC Publishing Corp., Ridgewood New Jersey (1981).
Further adjuvants that can be used in pesticidal formulations include crystallisation inhibitors, viscosity modifiers, suspending agents, dyes, anti-oxidants, foaming agents, light absorbers, mixing auxiliaries, antifoams, complexing agents, neutralising or pH-modifying substances and buffers, corrosion inhibitors, fragrances, wetting agents, take-up enhancers, micronutrients, plasticisers, glidants, lubricants, dispersants, thickeners, antifreezes, microbicides, and liquid and solid fertilisers.
The compositions according to the invention can include an additive comprising an oil of vegetable or animal origin, a mineral oil, alkyl esters of such oils or mixtures of such oils and oil derivatives. The amount of oil additive in the composition according to the invention is generally from 0.01 to 10 %, based on the mixture to be applied. For example, the oil additive can be added to a spray tank in the desired concentration after a spray mixture has been prepared. Preferred oil additives comprise mineral oils or an oil of vegetable origin, for example rapeseed oil, olive oil or sunflower oil, emulsified vegetable oil, alkyl esters of oils of vegetable origin, for example the methyl derivatives, or an oil of animal origin, such as fish oil or beef tallow. Preferred oil additives comprise alkyl esters of C8-C22 fatty acids, especially the methyl derivatives of C12-C18 fatty acids, for example the methyl esters of lauric acid, palmitic acid and oleic acid (methyl laurate, methyl palmitate and methyl oleate, respectively). Many oil derivatives are known from the Compendium of Herbicide Adjuvants, 10th Edition, Southern Illinois University, 2010.
The herbicidal compositions generally comprise from 0.1 to 99 % by weight, especially from 0.1 to 95 % by weight, compounds of formula (I) and from 1 to 99.9 % by weight of a formulation adjuvant which preferably includes from 0 to 25 % by weight of a surface-active substance. The inventive compositions generally comprise from 0.1 to 99 % by weight, especially from 0.1 to 95 % by weight, of compounds of the present invention and from 1 to 99.9 % by weight of a formulation adjuvant which preferably includes from 0 to 25 % by weight of a surface-active substance. Whereas commercial products may preferably be formulated as concentrates, the end user will normally employ dilute formulations.
The rates of application vary within wide limits and depend on the nature of the soil, the method of application, the crop plant, the pest to be controlled, the prevailing climatic conditions, and other factors governed by the method of application, the time of application and the target crop. As a general guideline compounds may be applied at a rate of from 1 to 2000 l/ha, especially from 10 to 1000 l/ha. Preferred formulations can have the following compositions (weight %):
Emulsifiable concentrates: active ingredient: 1 to 95 %, preferably 60 to 90 % surface-active agent: 1 to 30 %, preferably 5 to 20 % liquid carrier: 1 to 80 %, preferably 1 to 35 %
Dusts: active ingredient: 0.1 to 10 %, preferably 0.1 to 5 % solid carrier: 99.9 to 90 %, preferably 99.9 to 99 %
Suspension concentrates: active ingredient: 5 to 75 %, preferably 10 to 50 % water: 94 to 24 %, preferably 88 to 30 % surface-active agent: 1 to 40 %, preferably 2 to 30 %
Wettable powders: active ingredient: 0.5 to 90 %, preferably 1 to 80 % surface-active agent: 0.5 to 20 %, preferably 1 to 15 % solid carrier: 5 to 95 %, preferably 15 to 90 %
Granules: active ingredient: 0.1 to 30 %, preferably 0.1 to 15 % solid carrier: 99.5 to 70 %, preferably 97 to 85 %
The composition of the present may further comprise at least one additional pesticide. For example, the compounds according to the invention can also be used in combination with other herbicides or plant growth regulators. In a preferred embodiment the additional pesticide is a herbicide and/or herbicide safener.
Thus, compounds of formula (I) can be used in combination with one or more other herbicides to provide various herbicidal mixtures. Specific examples of such mixtures include (wherein “I” represents a compound of formula (I)): I + acetochlor, I + acifluorfen (including acifluorfen-sodium), I + aclonifen, I + ametryn, I + amicarbazone, I + aminopyralid, I + aminotriazole, I + atrazine, I + beflubutamid-M, I + benquitrione, I + bensulfuron (including bensulfuron-methyl), I + bentazone, I + bicyclopyrone, I + bilanafos, I + bispyribac-sodium, I + bixlozone, I + bromacil, I + bromoxynil, I + butachlor, I + butafenacil, I + carfentrazone (including carfentrazone-ethyl), I + cloransulam (including cloransulam-methyl), I + chlorimuron (including chlorimuron-ethyl), I + chlorotoluron, I + chlorsulfuron, I + cinmethylin, I + clacyfos, I + clethodim, I + clodinafop (including clodinafop-propargyl), I + clomazone, I + clopyralid, I + cyclopyranil, I + cyclopyrimorate, I + cyclosulfamuron, I + cyhalofop (including cyhalofop-butyl), I + 2,4- D (including the choline salt and 2-ethylhexyl ester thereof), I + 2,4-DB, I + desmedipham, I + dicamba (including the aluminium, aminopropyl, bis-aminopropylmethyl, choline, dichloroprop, diglycolamine, dimethylamine, dimethylammonium, potassium and sodium salts thereof), I + diclosulam, I + diflufenican, I + diflufenzopyr, I + dimethachlor, I + dimethenamid-P, I + diquat dibromide, I + diuron, I + epyrifenacil, I + ethalfluralin, I + ethofumesate, I + fenoxaprop (including fenoxaprop-P-ethyl), I + fenoxasulfone, I + fenquinotrione, I + fentrazamide, I + flazasulfuron, I + florasulam, I + florpyrauxifen (including florpyrauxifen-benzyl), I + fluazifop (including fluazifop-P-butyl), I + flucarbazone (including flucarbazone-sodium), I + flufenacet, I + flumetsulam, I + flumioxazin, I + fluometuron, I + flupyrsulfuron (including flupyrsulfuron-methyl-sodium), I + fluroxypyr (including fluroxypyr-meptyl), I + fomesafen, I + foramsulfuron, I + glufosinate (including L- glufosinate and the ammonium salts of both), I + glyphosate (including the diammonium, isopropylammonium and potassium salts thereof), I + halauxifen (including halauxifen-methyl), I + haloxyfop (including haloxyfop-methyl), I + hexazinone, I + hydantocidin, I + imazamox (including R- imazamox), I + imazapic, I + imazapyr, I + imazethapyr, I + indaziflam, I + iodosulfuron (including iodosulfuron-methyl-sodium), I + iofensulfuron (including iofensulfuron- sodium), I + ioxynil, I + isoproturon, I + isoxaflutole, I + lancotrione, I + MCPA, I + MCPB, I + mecoprop- P, I + mesosulfuron (including mesosulfuron-methyl), I + mesotrione, I + metamitron, I + metazachlor, I + methiozolin, I + metolachlor, I + metosulam, I + metribuzin, I + metsulfuron, I + napropamide, I + nicosulfuron, I + norflurazon, I + oxadiazon, I + oxasulfuron, I + oxyfluorfen, I + paraquat dichloride, I + pendimethalin, I + penoxsulam, I + phenmedipham, I + picloram, I + pinoxaden, I + pretilachlor, I + primisulfuron-methyl, I + prometryne, I + propanil, I + propaquizafop, I + propyrisulfuron, I + propyzamide, I + prosulfocarb, I + prosulfuron, I + pyraclonil, I + pyraflufen (including pyraflufen-ethyl), I + pyrasulfotole, I + pyridate, I + pyriftalid, I + pyrimisulfan, I + pyroxasulfone, I + pyroxsulam, I + quinclorac, I + quinmerac, I + quizalofop (including quizalofop-P-ethyl and quizalofop-P-tefuryl), I + rimsulfuron, I + saflufenacil, I + sethoxydim, I + simazine, I + S-metalochlor, I + sulfentrazone, I + sulfosulfuron, I + tebuthiuron, I + tefuryltrione, I + tembotrione, I + terbuthylazine, I + terbutryn, I + tetflupyrolimet, I + thiencarbazone, I + thifensulfuron, I + tiafenacil, I + tolpyralate, I + topramezone, I + tralkoxydim, I + triafamone, I + triallate, I + triasulfuron, I + tribenuron (including tribenuron-methyl), I + triclopyr, I + trifloxysulfuron (including trifloxysulfuron-sodium), I + trifludimoxazin, I + trifluralin, I + triflusulfuron, I + 3-(2-chloro-4-fluoro-5-(3-methyl-2,6-dioxo-4-trifluoromethyl-3,6-dihydropyrimidin- 1 (2H)-yl)phenyl)-5-methyl-4,5-dihydroisoxazole-5-carboxylic acid ethyl ester, I + 4-hydroxy-1-methoxy-
5-methyl-3-[4-(trifluoromethyl)-2-pyridyl]imidazolidin-2-one, I + 4-hydroxy-1 ,5-dimethyl-3-[4-
(trifluoromethyl)-2-pyridyl]imidazolidin-2-one, I + 5-ethoxy-4-hydroxy-1-methyl-3-[4-(trifluoromethyl)-2- pyridyl]imidazolidin-2-one, I + 4-hydroxy-1-methyl-3-[4-(trifluoromethyl)-2-pyridyl]imidazolidin-2-one, I + 4-hydroxy-1 ,5-dimethyl-3-[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]imidazolidin-2-one, I + (4R)1-(5-tert- butylisoxazol-3-yl)-4-ethoxy-5-hydroxy-3-methyl-imidazolidin-2-one, I + 3-[2-(3,4-dimethoxyphenyl)-6- methyl-3-oxo-pyridazine-4-carbonyl]bicyclo[3.2.1]octane-2,4-dione, I + 2-[2-(3,4-dimethoxyphenyl)-6- methyl-3-oxo-pyridazine-4-carbonyl]-5-methyl-cyclohexane-1 ,3-dione, I + 2-[2-(3,4-dimethoxyphenyl)-
6-methyl-3-oxo-pyridazine-4-carbonyl]cyclohexane-1 ,3-dione, I + 2-[2-(3,4-dimethoxyphenyl)-6-methyl-
3-oxo-pyridazine-4-carbonyl]-5,5-dimethyl-cyclohexane-1 ,3-dione, I + 6-[2-(3,4-dimethoxyphenyl)-6- methyl-3-oxo-pyridazine-4-carbonyl]-2,2,4,4-tetramethyl-cyclohexane-1 ,3,5-trione, I + 2-[2-(3,4- dimethoxyphenyl)-6-methyl-3-oxo-pyridazine-4-carbonyl]-5-ethyl-cyclohexane-1 ,3-dione, I + 2-[2-(3,4- dimethoxyphenyl)-6-methyl-3-oxo-pyridazine-4-carbonyl]-4,4,6,6-tetramethyl-cyclohexane-1 ,3-dione, I + 2-[6-cyclopropyl-2-(3,4-dimethoxyphenyl)-3-oxo-pyridazine-4-carbonyl]-5-methyl-cyclohexane-1 ,3- dione, I + 3-[6-cyclopropyl-2-(3,4-dimethoxyphenyl)-3-oxo-pyridazine-4-carbonyl]bicyclo[3.2.1]octane-
2.4-dione, I + 2-[6-cyclopropyl-2-(3,4-dimethoxyphenyl)-3-oxo-pyridazine-4-carbonyl]-5, 5-dimethyl- cyclohexane-1 ,3-dione, I + 6-[6-cyclopropyl-2-(3,4-dimethoxyphenyl)-3-oxo-pyridazine-4-carbonyl]-
2.2.4.4-tetramethyl-cyclohexane-1 ,3,5-trione, I + 2-[6-cyclopropyl-2-(3,4-dimethoxyphenyl)-3-oxo- pyridazine-4-carbonyl]cyclohexane-1 ,3-dione, I + 4-[2-(3,4-dimethoxyphenyl)-6-methyl-3-oxo- pyridazine-4-carbonyl]-2,2,6,6-tetramethyl-tetrahydropyran-3,5-dione, I + 4-[6-cyclopropyl-2-(3,4- dimethoxyphenyl)-3-oxo-pyridazine-4-carbonyl]-2,2,6,6-tetramethyl-tetrahydropyran-3,5-dione, I + 4- amino-3-chloro-5-fluoro-6-(7-fluoro-1 H-indol-6-yl)pyridine-2-carboxylic acid (including agrochemically acceptable esters thereof, for example, methyl 4-amino-3-chloro-5- fluoro-6-(7-fluoro-1 H-indol-6-yl)pyridine-2-carboxylate, prop-2-ynyl 4-amino-3-chloro-5-fluoro-6-(7- fluoro-1 H-indol-6-yl)pyridine-2-carboxylate and cyanomethyl 4-amino-3-chloro-5-fluoro-6-(7-fluoro-1 H- indol-6-yl)pyridine-2-carboxylate), I + 3-ethylsulfanyl-N-(1 ,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)- [1 ,2,4]triazolo[4,3-a]pyridine-8-carboxamide, I + 3-(isopropylsulfanylmethyl)-N-(5-methyl-1 ,3,4- oxadiazol-2-yl)-5-(trifluoromethyl)-[1 ,2,4]triazolo[4,3-a]pyridine-8-carboxamide, I + 3-
(isopropylsulfonylmethyl)-N-(5-methyl-1 ,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-[1 ,2,4]triazolo[4,3- a]pyridine-8-carboxamide, I + 3-(ethylsulfonylmethyl)-N-(5-methyl-1 ,3,4-oxadiazol-2-yl)-5- (trifluoromethyl)-[1 ,2,4]triazolo[4,3-a]pyridine-8-carboxamide, I + ethyl 2-[[3-[[3-chloro-5-fluoro-6-[3- methyl-2,6-dioxo-4-(trifluoromethyl)pyrimidin-1-yl]-2-pyridyl]oxy]acetate, I + 6-chloro-4-(2,7-dimethyl-1- naphthyl)-5-hydroxy-2-methyl-pyridazin-3-one, I + 1-[2-chloro-6-(5-chloropyrimidin-2-yl)oxy-phenyl]-
4.4.4-trifluoro-butan-1-one and I + 5-[2-chloro-6-(5-chloropyrimidin-2-yl)oxy-phenyl]-3-
(difluoromethyl)isoxazole.
The mixing partners of the compound of formula (I) may also be in the form of esters or salts, as mentioned e.g. in The Pesticide Manual, Fourteenth Edition, British Crop Protection Council, 2006.
The compound of formula (I) can also be used in mixtures with other agrochemicals such as fungicides, nematicides or insecticides, examples of which are given in The Pesticide Manual.
The mixing ratio of the compound of formula (I) to the mixing partner is preferably from 1 : 100 to 1000:1 .
The mixtures can advantageously be used in the above-mentioned formulations (in which case "active ingredient" relates to the respective mixture of compound of formula (I) with the mixing partner).
Compounds of formula (I) of the present invention may also be combined with herbicide safeners. Preferred combinations (wherein "I" represents a compound of formula (I)) include:- I + benoxacor, I + cloquintocet (including cloquintocet-mexyl); I + cyprosulfamide; I + dichlormid; I + fenchlorazole (including fenchlorazole-ethyl); I + fenclorim; I + fluxofenim; l+ furilazole I + isoxadifen (including isoxadifen-ethyl); I + mefenpyr (including mefenpyr-diethyl); I + metcamifen; I + N-(2-methoxybenzoyl)- 4-[(methylaminocarbonyl)amino] benzenesulfonamide and I + oxabetrinil. Particularly preferred are mixtures of a compound of formula (I) with cyprosulfamide, isoxadifen (including isoxadifen-ethyl), cloquintocet (including cloquintocet-mexyl) and/or N-(2-methoxybenzoyl)-4- [(methyl-aminocarbonyl)amino]benzenesulfonamide.
The safeners of the compound of formula (I) may also be in the form of esters or salts, as mentioned e.g. in The Pesticide Manual, 14th Edition (BCPC), 2006. The reference to cloquintocet-mexyl also applies to a lithium, sodium, potassium, calcium, magnesium, aluminium, iron, ammonium, quaternary ammonium, sulfonium or phosphonium salt thereof as disclosed in WO 02/34048, and the reference to fenchlorazole-ethyl also applies to fenchlorazole, etc.
Preferably the mixing ratio of compound of formula (I) to safener is from 100:1 to 1 :10, especially from 20:1 to 1 :1.
The mixtures can advantageously be used in the above-mentioned formulations (in which case "active ingredient" relates to the respective mixture of compound of formula (I) with the safener).
The compounds of formula (I) of this invention are useful as herbicides. The present invention therefore further comprises a method for controlling unwanted plants comprising applying to the said plants or a locus comprising them, an effective amount of a compound of the invention or a herbicidal composition containing said compound. ‘Controlling’ means killing, reducing or retarding growth or preventing or reducing germination. Generally the plants to be controlled are unwanted plants (weeds). ‘Locus’ means the area in which the plants are growing or will grow.
The rates of application of compounds of formula (I) may vary within wide limits and depend on the nature of the soil, the method of application (pre-emergence; post-emergence; application to the seed furrow; no tillage application etc.), the crop plant, the weed(s) to be controlled, the prevailing climatic conditions, and other factors governed by the method of application, the time of application and the target crop. The compounds of formula (I) according to the invention are generally applied at a rate of from 10 to 2000 g/ha, especially from 50 to 1000 g/ha.
The application is generally made by spraying the composition, typically by tractor mounted sprayer for large areas, but other methods such as dusting (for powders), drip or drench can also be used.
Useful plants in which the composition according to the invention can be used include crops such as cereals, for example barley and wheat, cotton, oilseed rape, sunflower, maize, rice, soybeans, sugar beet, sugar cane and turf.
Crop plants can also include trees, such as fruit trees, palm trees, coconut trees or other nuts. Also included are vines such as grapes, fruit bushes, fruit plants and vegetables. Crops are to be understood as also including those crops which have been rendered tolerant to herbicides or classes of herbicides (e.g. ALS-, GS-, EPSPS-, PPO-, ACCase- and HPPD-inhibitors) by conventional methods of breeding or by genetic engineering. An example of a crop that has been rendered tolerant to imidazolinones, e.g. imazamox, by conventional methods of breeding is Clearfield® summer rape (canola). Examples of crops that have been rendered tolerant to herbicides by genetic engineering methods include e.g. glyphosate- and glufosinate-resistant maize varieties commercially available under the trade names RoundupReady® and LibertyLink®.
Crops are also to be understood as being those which have been rendered resistant to harmful insects by genetic engineering methods, for example Bt maize (resistant to European corn borer), Bt cotton (resistant to cotton boll weevil) and also Bt potatoes (resistant to Colorado beetle). Examples of Bt maize are the Bt 176 maize hybrids of NK® (Syngenta Seeds). The Bt toxin is a protein that is formed naturally by Bacillus thuringiensis soil bacteria. Examples of toxins, or transgenic plants able to synthesise such toxins, are described in EP-A-451 878, EP-A-374 753, WO 93/07278, WO 95/34656, WO 03/052073 and EP-A-427 529. Examples of transgenic plants comprising one or more genes that code for an insecticidal resistance and express one or more toxins are KnockOut® (maize), Yield Gard® (maize), NuCOTIN33B® (cotton), Bollgard® (cotton), NewLeaf® (potatoes), NatureGard® and Protexcta®. Plant crops or seed material thereof can be both resistant to herbicides and, at the same time, resistant to insect feeding ("stacked" transgenic events). For example, seed can have the ability to express an insecticidal Cry3 protein while at the same time being tolerant to glyphosate.
Crops are also to be understood to include those which are obtained by conventional methods of breeding or genetic engineering and contain so-called output traits (e.g. improved storage stability, higher nutritional value and improved flavour).
Other useful plants include turf grass for example in golf-courses, lawns, parks and roadsides, or grown commercially for sod, and ornamental plants such as flowers or bushes.
Compounds of formula (I) and compositions of the invention can typically be used to control a wide variety of monocotyledonous and dicotyledonous weed species. Examples of monocotyledonous species that can typically be controlled include Alopecurus myosuroides, Avena fatua, Brachiaria plantaginea, Bromus tectorum, Cyperus esculentus, Digitaria sanguinalis, Echinochloa crus-galli, Lolium perenne, Lolium multiflorum, Panicum miliaceum, Poa annua, Setaria viridis, Setaria faberi and Sorghum bicolor. Examples of dicotyledonous species that can be controlled include Abutilon theophrasti, Amaranthus retroflexus, Bidens pilosa, Chenopodium album, Euphorbia heterophylla, Galium aparine, Ipomoea hederacea, Kochia scoparia, Polygonum convolvulus, Sida spinosa, Sinapis arvensis, Solanum nigrum, Stellaria media, Veronica persica and Xanthium strumarium.
The compounds of formula (I) are also useful for pre-harvest desiccation in crops, for example, but not limited to, potatoes, soybean, sunflowers and cotton. Pre-harvest desiccation is used to desiccate crop foliage without significant damage to the crop itself to aid harvesting. Compounds/compositions of the invention are particularly useful in non-selective burn-down applications, and as such may also be used to control volunteer or escape crop plants. Various aspects and embodiments of the present invention will now be illustrated in more detail by way of example. It will be appreciated that modification of detail may be made without departing from the scope of the invention.
EXAMPLES
The Examples which follow serve to illustrate, but do not limit, the invention.
Formulation Examples
Wettable powders a) b) c) active ingredients 25 % 50 % 75 % sodium lignosulfonate 5 % 5 % sodium lauryl sulfate 3 % - 5 % sodium diisobutylnaphthalenesulfonate 6 % 10 % phenol polyethylene glycol ether 2 %
(7-8 mol of ethylene oxide) highly dispersed silicic acid 5 % 10 % 10 %
Kaolin 62 % 27 %
The combination is thoroughly mixed with the adjuvants and the mixture is thoroughly ground in a suitable mill, affording wettable powders that can be diluted with water to give suspensions of the desired concentration.
Emulsifiable concentrate active ingredients 10 % octylphenol polyethylene glycol ether 3 %
(4-5 mol of ethylene oxide) calcium dodecylbenzenesulfonate 3 % castor oil polyglycol ether (35 mol of ethylene oxide) 4 %
Cyclohexanone 30 % xylene mixture 50 %
Emulsions of any required dilution, which can be used in plant protection, can be obtained from this concentrate by dilution with water. Dusts a) b) c)
Active ingredients 5 % 6 % 4 %
Talcum 95 %
Kaolin - 94 % mineral filler - - 96 %
Ready-for-use dusts are obtained by mixing the combination with the carrier and grinding the mixture in a suitable mill.
Extruder granules
Active ingredients 15 % sodium lignosulfonate 2 % carboxymethylcellulose 1 %
Kaolin 82 %
The combination is mixed and ground with the adjuvants, and the mixture is moistened with water. The mixture is extruded and then dried in a stream of air.
Coated granules
Active ingredients 8 % polyethylene glycol (mol. wt. 200) 3 %
Kaolin 89 %
The finely ground combination is uniformly applied, in a mixer, to the kaolin moistened with polyethylene glycol. Non-dusty coated granules are obtained in this manner.
Suspension concentrate active ingredients 40 % propylene glycol 10 % nonylphenol polyethylene glycol ether (15 mol of ethylene oxide) 6 %
Sodium lignosulfonate 10 % carboxymethylcellulose 1 % silicone oil (in the form of a 75 % emulsion in water) 1 %
Water 32 %
The finely ground combination is intimately mixed with the adjuvants, giving a suspension concentrate from which suspensions of any desired dilution can be obtained by dilution with water. Slow Release Capsule Suspension
28 parts of the combination are mixed with 2 parts of an aromatic solvent and 7 parts of toluene diisocyanate/polymethylene-polyphenylisocyanate-mixture (8:1). This mixture is emulsified in a mixture of 1 .2 parts of polyvinylalcohol, 0.05 parts of a defoamer and 51 .6 parts of water until the desired particle size is achieved. To this emulsion a mixture of 2.8 parts 1 ,6-diaminohexane in 5.3 parts of water is added. The mixture is agitated until the polymerization reaction is completed. The obtained capsule suspension is stabilized by adding 0.25 parts of a thickener and 3 parts of a dispersing agent. The capsule suspension formulation contains 28% of the active ingredients. The medium capsule diameter is 8-15 microns.
The resulting formulation is applied to seeds as an aqueous suspension in an apparatus suitable for that purpose.
List of Abbreviations:
Boc = tert-butyloxycarbonyl br = broad
CDCI3 = chloroform-d
CD3OD = methanol-d
°C = degrees Celsius
D2O = water-d
DCM = dichloromethane d = doublet dd = double doublet dt = double triplet
DMSO = dimethylsulfoxide
EtOAc = ethyl acetate h = hour(s)
HCI = hydrochloric acid
HPLC = high-performance liquid chromatography (description of the apparatus and the methods used for HPLC are given below) m = multiplet
M = molar min = minutes
MHz = mega hertz mL = millilitre mp = melting point ppm = parts per million q = quartet quin = quintet rt = room temperature s = singlet t = triplet
THF = tetrahydrofuran
LC/MS = Liquid Chromatography Mass Spectrometry
Analyticals were run on a Waters ACQUITY UPLC-MS using a Sample Organizer with Sample Manager FTN+, H-class QSM, Column Manager, 2 x Column Manager Aux, photodiode array, ELSD (Wavelength range (nm): 210 to 400) and SQD 2.
Ionisation method: Electrospray positive and negative: Capillary (kV) 3.0, Cone (V) 35.0, Source Temperature (°C) 150, Cone Gas Flow (L/Hr.) 10, Desolvation Gas Flow (L/Hr.) 500.
Mass range (Da): positive 95 to 800, negative 115 to 800.
Injection volume 1 ul in acetonitrile for columns.
Column
Waters ACQUITY UPLC HSS T3 1 .8μm 2.1x50mm
Columns used the following gradient at 40°C.
Figure imgf000074_0001
Solvent A: H2O with 0.05% TFA, Solvent B: CH3CN with 0.05% TFA
Preparative Reverse Phase HPLC Method:
Compounds purified by mass directed preparative HPLC using ES+/ES- on a Waters FractionLynx Autopurification system comprising a 2767 injector/collector with a 2545 gradient pump, two 515 isocratic pumps, SFO, 2998 photodiode array (Wavelength range (nm): 210 to 400), 2424 ELSD and QDa mass spectrometer. A Waters Atlantis T3 5micron 19x10mm guard column was used with a Waters Atlantis T3 OBD, 5micron 30x100mm prep column.
Ionisation method: Electrospray positive and negative: Cone (V) 20.00, Source Temperature (°C) 120, Cone Gas Flow (L/Hr.) 50
Mass range (Da): positive 100 to 800, negative 115 to 800.
The preparative HPLC was conducted using an 11.4 minute run time (not using at column dilution, bypassed with the column selector), according to the following gradient table:
Figure imgf000074_0002
Figure imgf000075_0004
515 pump Oml/min Acetonitrile (ACD)
515 pump 1 ml/min 90% Methanol/10% Water (make up pump) Solvent A: Water with 0.05% Trifluoroacetic Acid Solvent B: Acetonitrile with 0.05% Trifluoroacetic Acid
Preparation Examples
Example 1 : Preparation of 3-[4-([1 ,2,4]triazolo[1 ,5-a]pyrimidin-7-yl)pyridin-1 -ium-1 -yl]propanoic acid
2,2.2-trifluoroacetate A1
Figure imgf000075_0001
Step 1 : Preparation of 3-(dimethylamino)-1-(4-pyridyl)prop-2-en-1-one
Figure imgf000075_0002
A microwave vial, under nitrogen atmosphere, was charged with 1-(4-pyridyl)ethanone (2 g) and 1 ,1- dimethoxy-N,N-dimethyl-methanamine (10 mL) and heated at 150°C under microwave irradiation for 30 minutes. The reaction mixture was concentrated and triturated with methyl t-butyl ether to give 3- (dimethylamino)-1-(4-pyridyl)prop-2-en-1-one as a yellow solid.
1H NMR (400 MHz, CDCI3) 8.67 (d, 2H), 7.82 (br, 1 H), 7.66 (d, 2H), 5.63 (d, 1 H), 3.16 (s, 3H), 2.93 (s, 3H) Step 2: Preparation of 7-(4-pyridyl)-[1 ,2,4]triazolo[1 ,5-a]pyrimidine
Figure imgf000075_0003
A microwave vial, under nitrogen atmosphere, was charged with 3-(dimethylamino)-1-(4-pyridyl)prop- 2-en-1-one (0.31 g), 4H-1 ,2,4-triazol-3-amine (0.15 g) and acetic acid (2.5 mL) and heated at 150°C under microwave irradiation for 60 minutes. The reaction mixture was concentrated and purified on silica using a gradient from 0 to 5% methanol in ethyl acetate to give 7-(4-pyridyl)-[1 ,2,4]triazolo[1 ,5- a]pyrimidine as a light yellow solid.
1H NMR (400 MHz, DMSO-d6) 9.03 (d, 1 H), 8.85 - 8.90 (m, 2H), 8.78 (s, 1 H), 8.13 - 8.18 (m, 2H), 7.77 (d, 1 H)
Step 3: Preparation of 3-[4-([1 ,2,4]triazolo[1 ,5-a]pyrimidin-7-yl)pyridin-1-ium-1-yl]propanoic acid 2,2,2- trifluoroacetate A1
To a solution of 7-(4-pyridyl)-[1 ,2,4]triazolo[1 ,5-a]pyrimidine (0.25 g) in acetonitrile (6.3 mL) was added 3-bromopropionic acid (0.29 g). The mixture was heated at 80°C for 70 hours, then cooled and concentrated. The crude product was triturated with methyl t-butyl ether to afford a brown gum which was purified by preparative reverse phase HPLC (trifluoroacetic acid was present in the eluent) to give 3-[4-([1 ,2,4]triazolo[1 ,5-a]pyrimidin-7-yl)pyridin-1-ium-1-yl]propanoic acid 2,2,2-trifluoroacetate as an off-white solid. 1H NMR (400 MHz, D2O) 9.22 (d, 2H), 9.05 (d, 1 H), 8.78 (d, 2H), 8.66 (s, 1 H), 7.83 (d, 1 H), 5.01 (t, 2H), 3.25 (t, 2H) (CO2H proton missing)
Example 2: Preparation of 3-[4-(tetrazolo[1 ,5-b]pyridazin-6-yl)pyridin-1-ium-1-yl]propanoic acid 2,2,2- trifluoroacetate A3
Figure imgf000076_0001
Step 1 : Preparation of 3-chloro-6-(4-pyridyl)pyridazine
Figure imgf000076_0002
To a solution of 4-pyridylboronic acid (4.5 g), 3,6-dichloropyridazine (6.5g), 1 ,4-dioxane (45 mL) and water (18 mL) was added potassium carbonate (12 g) at room temperature, under nitrogen atmosphere. To this mixture was added cyclopentyl(diphenyl)phosphane;dichloropalladium;iron (PdCI2dppf ) (2.7 g) and the reaction mass was heated at 90°C for 3h. The reaction mixture was filtered through celite and washed through with ethyl acetate (200 mL). The filtrate was washed with brine, dried over sodium sulfate, concentrated and purified by silica gel chromatography using an ethyl acetate and cyclohexane mixture as eluent to give 3-chloro-6-(4-pyridyl)pyridazine as a beige solid. 1H NMR (400 MHz, CDCl3) 8.82 (d, 2H), 7.97 (d, 2H), 7.92 (d, 1 H), 7.67 (d, 1 H) Step 2: Preparation of 6-(4-pyridyl)tetrazolo[1 ,5-b]pyridazine
Figure imgf000077_0001
A microwave vial, under nitrogen atmosphere, was charged with 3-chloro-6-(4-pyridyl)pyridazine (0.1 g), sodium azide (0.10 g) and N,N-dimethylformamide (1 mL). The reaction mass was heated at 90°C under microwave irradiation for 1 hour. The reaction mass was diluted with water (10 mL), concentrated and purified by silica gel chromatography using a dichloromethane and ethyl acetate mixture to give 6-(4-pyridyl)tetrazolo[1 ,5-b]pyridazine as a white solid.
1H NMR (400 MHz, DMSO-d6) 9.02 (d, 1 H), 8.88 (d, 2H), 8.55 (d, 1 H), 8.20 (d, 2H)
Step 3: Preparation of 3-[4-(tetrazolo[1 ,5-b]pyridazin-6-yl)pyridin-1-ium-1-yl]propanoic acid 2,2,2- trifluoroacetate A3
To a solution of 6-(4-pyridyl)tetrazolo[1 ,5-b]pyridazine (0.045g) in acetonitrile (1 mL) was added 3- bromopropanoic acid (0.035 g) and the mixture was heated at 80°C for 24 hours. The reaction mass was concentrated, triturated with methyl t-butyl ether and purified by preparative reverse phase HPLC (trifluoroacetic acid was present in the eluent) to give 3-[4-(tetrazolo[1 ,5-b]pyridazin-6-yl) pyridin-1 -ium- 1-yl]propanoic acid 2,2,2-trifluoroacetate as a white solid.
1H NMR (400 MHz, D2O) 9.20 (d, 2H), 8.86 (d, 1 H), 8.81 (d, 2H), 8.51 (d, 1 H), 4.99 (t, 2H), 3.23 (t, 2H) (CO2H proton missing)
Example 3: Preparation of 3-[4-([1 .2.4]triazolo[4.3-b]pyridazin-8-yl)pyridin-1-ium-1-yl]propanoic acid bromide A2
Figure imgf000077_0002
Step 1 : Preparation of 8-(4-pyridyl)-[1 ,2,4]triazolo[4,3-b]pyridazine
Figure imgf000077_0003
A microwave vial, under nitrogen atmosphere, was charged with 3-(dimethylamino)-1-(4-pyridyl)prop- 2-en-1-one (1.027 g), 4-amino-4H-1 ,2,4-triazole (0.5 g) and acetic acid (10 mL) and heated at 150°C under microwave irradiation for 60 minutes. The reaction mixture was concentrated and purified on silica using a gradient from 0 to 5% methanol in ethyl acetate to give 8-(4-pyridyl)-[1 ,2,4]triazolo[4,3- b]pyridazine as an off-white solid.
1H NMR (400 MHz, DMSO-de) 9.82 (s, 1 H) 8.79 - 8.87 (m, 3H) 8.40 (d, 2H) 7.90 (d, 1 H)
Step 2: Preparation of 3-[4-([1 ,2,4]triazolo[4,3-b]pyridazin-8-yl)pyridin-1-ium-1-yl]propanoic acid bromide A2
To a solution of 8-(4-pyridyl)-[1 ,2,4]triazolo[4,3-b]pyridazine (0.25 g) in acetonitrile (5 mL) was added
3-bromopropionic acid (0.38 g) and the mixture was heated at reflux for 40 hours. The reaction mass was concentrated, triturated with methyl t-butyl ether and dried under vacuum to give 3-[4-
([1 ,2,4]triazolo[4,3-b]pyridazin-8-yl)pyridin-1-ium-1-yl]propanoic acid bromide as an off-white solid.
1H NMR (400 MHz, D2O) 9.51 (s, 1 H), 9.13 (d, 2H), 8.73 - 8.79 (m, 3H), 7.87 (d, 1 H), 4.96 (t, 2H), 3.23 (t, 2H) (CO2H proton missing)
Example 4: Preparation of 7-(4-pyridvl)thiazolo[5,4-d]pyrimidine
Figure imgf000078_0001
A microwave vial was charged with tributyl(4-pyridyl)stannane (0.257 g), 7-chlorothiazolo[5,4- d]pyrimidine (0.1 g), tetrakis(triphenylphosphine)palladium(0) (0.067 g) and 1 ,4-dioxane (2.62 mL). The mixture was heated at 140°C under microwave irradiation for 1 hour. The reaction mixture was concentrated and purified by silica gel chromatography eluting with a mixture of acetonitrile and dichloromethane to give 7-(4-pyridyl)thiazolo[5,4-d]pyrimidine as a brown solid.
1H NMR (400 MHz, CDCl3) 9.30 (s, 1 H), 9.28 (s, 1 H), 8.90 (d, 2H), 8.64 (d, 2H)
Example 5: Preparation of 5-(4-pyridyl)-2,1 ,3-benzoxadiazole
Figure imgf000078_0002
A microwave vial was charged, under nitrogen atmosphere, with 4-iodopyridine (0.1 g), 5-(4,4,5,5- tetramethyl-1 ,3, 2-dioxaborolan-2-yl)-2,1 ,3-benzoxadiazole (0.132 g), cesium carbonate (0.238 g), 1 ,1'- bis(diphenylphosphino)ferrocene-palladium(ll)dichloride dichloromethane complex (0.04 g), 1 ,4- dioxane (0.805 mL) and water (0.268 mL). The mixture was heated at 120°C under microwave irradiation for 30 minutes. The reaction mixture was diluted with dichloromethane, filtered through a pad of celite, which was washed with further dichloromethane. The filtrate was concentrated and purified by silica gel chromatography eluting with a mixture of ethyl acetate and hexanes to give 5-(4- pyridyl)-2,1 ,3-benzoxadiazole as a yellow solid.
1H NMR (400 MHz, CDCl3) 8.82 - 8.74 (m, 2H), 8.08 (t, 1 H), 8.00 (dd, 1 H), 7.70 (dd, 1 H), 7.61 - 7.52 (m, 2H)
Example 6: Preparation of 5-(4-pyridyl)-2,1 ,3-benzothiadiazole
Figure imgf000079_0001
A microwave vial was charged, under nitrogen atmosphere, with 4-iodopyridine (0.1 g), 5-(4, 4,5,5- tetramethyl-1 ,3, 2-dioxaborolan-2-yl)-2,1 ,3-benzothiadiazole (0.141 g), 1 ,1'- bis(diphenylphosphino)ferrocene-palladium(ll)dichloride dichloromethane complex (0.04 g), cesium carbonate (0.239 g), 1 ,4-dioxane (0.805 mL) and water (0.268 mL). The mixture was heated at 120°C under microwave irradiation for 30 minutes. The reaction mixture was diluted with dichloromethane, filtered through a pad of celite, which was washed with further dichloromethane. The filtrate was concentrated and purified by silica gel chromatography eluting with a mixture of ethyl acetate and hexanes to give 5-(4-pyridyl)-2,1 ,3-benzothiadiazole as an off-white solid.
1H NMR (400 MHz, CDCl3) 8.77 (br s, 2H), 8.28 (dd, 1 H), 8.14 (dd, 1 H), 7.89 (dd, 1 H), 7.63 (d, 2H) Example 7: Preparation of 4-(4-pyridyl)-2,1 ,3-benzoxadiazole
Figure imgf000079_0002
A microwave vial was charged with tributyl(4-pyridyl)stannane (0.286 g), 4-chloro-2,1 ,3- benzoxadiazole (0.1 g), tetrakis(triphenylphosphine)palladium(0) (0.0748 g) and 1 ,4-dioxane (2.91 mL). The mixture was heated at 140°C under microwave irradiation for 1 hour. The reaction mixture was concentrated and purified by silica gel chromatography eluting with a mixture of ethyl acetate and hexanes to give 4-(4-pyridyl)-2,1 ,3-benzoxadiazole as an off-white solid.
1H NMR (400 MHz, CDCl3) 8.84 - 8.75 (m, 2H), 7.97 - 7.90 (m, 3H), 7.75 (d, 1 H), 7.57 (dd, 1 H)
Example 8: Preparation of 6-(4-pyridyl)-[1 ,2,41triazolo[1 ,5-a]pyrimidine A microwave vial was charged with 4H-1 ,2,4-triazol-3-amine (0.1 g), 2-(4-pyridyl)propanedial (0.177 g) and acetic acid (2.02 mL). The mixture was heated at 150°C under microwave irradiation for 1 hour. The reaction mixture was concentrated and purified by silica gel chromatography eluting with a mixture of methanol in dichloromethane to give 6-(4-pyridyl)-[1 ,2,4]triazolo[1 ,5-a]pyrimidine as a white solid.
1H NMR (400 MHz, CDCl3) 9.13 (d, 1 H), 9.12 (d, 1 H), 8.84 - 8.81 (m, 2H), 8.61 (s, 1 H), 7.56 (d, 2H)
Example 9: Preparation of 3-[4-(3-methylimidazo[4.5-b]pyrazin-5-yl)pyridin-1-ium-1-yl]propanoic acid chloride A8
Figure imgf000080_0001
Step 1 : Preparation of 5-bromo-N3-methyl-pyrazine-2, 3-diamine
Figure imgf000080_0002
To a mixture of 3,5-dibromopyrazin-2-amine (7 g) in ethanol (50 mL) was added methylamine (40% solution in water, 70 mL) at room temperature. The reaction mixture was heated at 90°C in a sealed tube for 16 hours. The reaction mixture was concentrated to give crude 5-bromo-N3-methyl-pyrazine- 2, 3-diamine as an off-white solid, which was used without further purification.
1H NMR (400 MHz, DMSO-d6) 7.16 (s, 1 H), 6.62 - 6.60 (d, 1 H), 6.11 (s, 2H), 2.82 - 2.80 (d, 3H) Step 2: Preparation of N'-[5-bromo-3-(methylamino)pyrazin-2-yl]-N,N-dimethyl-formamidine
Figure imgf000080_0003
To a mixture of 5-bromo-N3-methyl-pyrazine-2, 3-diamine (5 g) in dichloromethane (50 mL) was added N,N-dimethylformamide dimethyl acetal (8.36 g) at room temperature. The reaction mixture was heated at 50°C for 8 hours. The reaction mixture was cooled and concentrated to give crude N'-[5- bromo-3-(methylamino)pyrazin-2-yl]-N,N-dimethyl-formamidine as a brown solid, which was used without further purification.
1H NMR (400 MHz, CDCl3) 8.40 (s, 1 H), 7.36 (s, 1 H), 5.85 (s, 1 H), 3.11 (s, 3H), 3.07 (s, 3H), 3.01 - 3.00 (d, 3H)
Step 3: Preparation of 5-bromo-3-methyl-imidazo[4,5-b]pyrazine
Figure imgf000081_0001
A mixture of N'-[5-bromo-3-(methylamino)pyrazin-2-yl]-N,N-dimethyl-formamidine (4 g), 1 ,4-dioxane (50 mL) and acetic acid (4 mL) was heated at 100°C for 16 hours. The reaction mixture was concentrated and the residue was purified by silica gel chromatography eluting with a mixture of methanol and dichloromethane to afford 5-bromo-3-methyl-imidazo[4,5-b]pyrazine as an off-white solid.
1H NMR (400 MHz, CDCl3) 8.63 (s, 1 H), 8.30 (s, 1 H), 3.95 (s, 3H)
Step 4: Preparation of 3-methyl-5-(4-pyridyl)imidazo[4,5-b]pyrazine
Figure imgf000081_0002
To a mixture of 5-bromo-3-methyl-imidazo[4,5-b]pyrazine (2.4 g), 1 ,4-dioxane (80 mL) and water (20 mL) was added pyridine-4-boronic acid (1 .58 g) and potassium carbonate (2.95 g) at room temperature. The mixture was purged with argon for 10 minutes and tetrakis(triphenylphosphine)palladium(0) (1.24 g) was added, followed by further purging with argon for 10 minutes. The resulting reaction mixture was heated at 100°C for 16 hours. The reaction mixture was filtered through celite and washed with 5% methanol in dichloromethane (200 mL). The filtrate was concentrated and the residue purified by silica gel chromatography eluting with a mixture of methanol and dichloromethane to afford 3-methyl-5-(4-pyridyl)imidazo[4,5-b]pyrazine as an off-white solid.
1H NMR (400 MHz, CDCl3) 9.12 (s, 1 H), 8.79 - 8.77 (t, 2H), 8.39 (s, 1 H), 8.01 - 8.0 (dd, 2H), 4.03 (s, 3H)
Step 5: Preparation of tert-butyl 3-[4-(3-methylimidazo[4,5-b]pyrazin-5-yl)pyridin-1-ium-1-yl]propanoate bromide A9 To a mixture of 3-methyl-5-(4-pyridyl)imidazo[4,5-b]pyrazine (0.5 g), tetrahydrofuran (5 mL) and acetonitrile (5 mL) was added tert-butyl 3-bromopropanoate (0.705 g) at room temperature. The reaction mixture was heated at 80°C for 16 hours, then cooled and concentrated. The resulting residue was dissolved in water (20 mL) and washed with dichloromethane (2x20 mL). The aqueous layer was concentrated and the residue was purified by using reverse phase chromatography eluting with a mixture of water and acetonitrile to afford tert-butyl 3-[4-(3-methylimidazo[4,5-b]pyrazin-5- yl)pyridin-1-ium-1-yl]propanoate bromide as an off-white solid.
1H NMR (400 MHz, D2O) 9.16 (s, 1 H), 8.92 (d, 2H), 8.72 - 8.67 (m, 3H), 4.81 (t, 2H), 3.93 (s, 3H), 3.08 (t, 2H), 1.29 (s, 9H)
Step 6: Preparation of 3-[4-(3-methylimidazo[4,5-b]pyrazin-5-yl)pyridin-1-ium-1-yl]propanoic acid chloride A8
A solution of tert-butyl 3-[4-(3-methylimidazo[4,5-b]pyrazin-5-yl)pyridin-1-ium-1-yl]propanoate bromide (0.12 g) and 6M aqueous hydrochloric acid (3 mL) was stirred at room temperature for 16 hours. The reaction mixture was diluted with water (10 mL) and washed with dichloromethane (2x10 mL). The aqueous layer was concentrated and the residue was purified by using reverse phase chromatography eluting with a mixture of water and acetonitrile to afford 3-[4-(3-methylimidazo[4,5-b]pyrazin-5- yl)pyridin-1-ium-1-yl]propanoic acid chloride as an off-white solid.
1H NMR (400 MHz, D2O) 9.18 (s, 1H), 8.93 (d, 2H), 8.78 (s, 1H), 8.66 (d, 2H), 4.82 (t, 2H), 3.94 (s,
3H), 3.13 (t, 2H) (CO2H proton missing)
Example 10: Preparation of 3-(4-thiazolo[5,4-b]pyridin-5-ylpyridin-1-ium-1-yl)propanoic acid chloride
A12
Figure imgf000082_0001
Step 1 : Preparation of 5-chlorothiazolo[5,4-b]pyridin-2-amine To a mixture of 2,6-dichloropyridin-3-amine (10 g) in acetic acid (100 mL) was added potassium thiocyanate (14.4 g) and this mixture was heated at 90°C for 16 hours. The resulting mixture was poured onto ice and this mixture was adjusted to pH 6 with aqueous ammonia and extracted with ethyl acetate (2x150 mL). The combined organic layers were dried over sodium sulfate, concentrated and the residue was purified by silica gel chromatography eluting with a mixture of ethyl acetate and petroleum ether to give 5-chlorothiazolo[5,4-b]pyridin-2-amine as an off-white solid.
Step 2: Preparation of 5-chlorothiazolo[5,4-b]pyridine
Figure imgf000083_0001
To a solution of 5-chlorothiazolo[5,4-b]pyridin-2-amine (3.3 g) in tetrahydrofuran (60 mL), cooled to ~0°C, was added tert-butyl nitrite (2.98 mL) over 5 minutes. The reaction mixture was then heated at 70°C for 1 hour. After cooling, the reaction mixture was quenched with ice cold water (50 mL) and extracted with ethyl acetate (2x75 mL). The combined organic layers were dried over sodium sulfate, concentrated and the residue was purified by silica gel chromatography eluting with a mixture of ethyl acetate and hexanes to afford 5-chlorothiazolo[5,4-b]pyridine as an off-white solid.
1H NMR (400 MHz, DMSO-d6) 9.59 (s, 1 H), 8.56 - 8.53 (d, 1 H), 7.72 - 7.69 (d, 1 H)
Step 3: Preparation of 5-(4-pyridyl)thiazolo[5,4-b]pyridine
Figure imgf000083_0002
A mixture of 5-chlorothiazolo[5,4-b]pyridine (1.3 g), toluene (20 mL) and tributyl(4-pyridyl)stannane (2.75 g) was purged with argon for 10 minutes. To this mixture was added tetrakis(triphenylphosphine)palladium(0) (0.863 g) followed by purging further with argon for 10 minutes. The resulting reaction mixture was heated at 110°C for 16 hours, cooled and filtered through celite, washing through with 5% methanol in dichloromethane (100 mL). The resulting filtrate was concentrated and the residue purified by silica gel chromatography eluting with a mixture of ethyl acetate and hexanes to afford 5-(4-pyridyl)thiazolo[5,4-b] pyridine as an off-white solid.
1H NMR (400 MHz, DMSO-d6) 9.64 (s, 1 H), 8.75 - 8.74 (dd, 2H), 8.65 - 8.63 (d, 1 H), 8.36 - 8.33 (d,
1 H), 8.16 - 8.14 (dd, 2H) Step 4: Preparation of tert-butyl 3-(4-thiazolo[5,4-b]pyridin-5-ylpyridin-1-ium-1-yl)propanoate bromide A35
Figure imgf000084_0001
To a mixture of 5-(4-pyridyl)thiazolo[5,4-b] pyridine (0.1 g), tetrahydrofuran (2 mL) and acetonitrile (2 mL) was added tert-butyl 3-bromopropanoate (0.114 g) at room temperature. The reaction mixture was heated at 90°C for 2 hours, then cooled and concentrated. The resulting residue was dissolved in water (20 mL) and washed with dichloromethane (2x20 mL). The aqueous layer was concentrated and the residue was purified by using reverse phase chromatography eluting with a mixture of water and acetonitrile to afford tert-butyl 3-(4-thiazolo[5,4-b]pyridin-5-ylpyridin-1-ium-1-yl)propanoate bromide as an off-white solid.
1H NMR (400 MHz, D2O) 9.45 (s, 1 H), 8.92 (d, 2H), 8.61 (d, 2H), 8.54 (d, 1 H), 8.28 (d, 1 H), 4.80 (t, 2H), 3.06 (t, 2H), 1.27 (s, 9H)
Step 5 Preparation of 3-(4-thiazolo[5,4-b]pyridin-5-ylpyridin-1-ium-1-yl)propanoic acid chloride A12
A solution of tert-butyl 3-(4-thiazolo[5,4-b]pyridin-5-ylpyridin-1-ium-1-yl)propanoate bromide (0.08 g) and 6M aqueous hydrochloric acid (5 mL) was stirred at room temperature for 1 hour. The reaction mixture was diluted with water (10 mL) and washed with dichloromethane (2x10 mL). The aqueous layer was concentrated to afford 3-(4-thiazolo[5,4-b]pyridin-5-ylpyridin-1-ium-1-yl)propanoic acid chloride as a red solid.
1H NMR (400 MHz, D2O) 9.46 (s, 1 H), 8.98 (d, 2H), 8.58 (d, 2H), 8.50 (d, 1 H), 8.25 (d, 1 H), 4.89 (t, 2H), 3.20 (t, 2H) (CO2H proton missing)
Example 11 : Preparation of 3-[4-(thiadiazolo[5.4-b]pyridin-5-yl)pyridin-1-ium-1-yl]propanoic acid chloride A11
Figure imgf000084_0002
Step 1 : Preparation of 3-amino-6-chloro-pyridine-2-thiol To a mixture of 5-chlorothiazolo[5,4-b]pyridin-2-amine (2.7 g) in 20% aqueous sodium hydroxide (100 mL) was added sodium sulfite (3.59 g) and this mixture was heated at 100°C for 16 hours. The reaction mixture was cooled and neutralized with formic acid (~3 mL). The resulting precipitate was filtered off to give 3-amino-6-chloro-pyridine-2-thiol as a yellow solid, which was used without further purification.
Step 2: Preparation of 5-chlorothiadiazolo[5,4-b]pyridine
Figure imgf000085_0001
A solution of 3-amino-6-chloro-pyridine-2-thiol (1 g) in concentrated hydrochloric acid (2 mL) was cooled to ~0°C and a solution of sodium nitrite (2.1 g) in water (8 mL) was added drop wise. The resulting reaction mixture was then stirred at room temperature for 2 hours. Water (50 mL) was added to the reaction mixture and the resulting solution was extracted with dichloromethane (2x100 mL).
The combined organic layers were dried over sodium sulfate and concentrated to afford 5- chlorothiadiazolo[5,4-b]pyridine as a light brown solid.
1H NMR (400 MHz, DMSO-d6) 9.23 - 9.21 (d, 1 H), 7.95 - 7.93 (d, 1 H)
Step 3: Preparation of 5-(4-pyridyl)thiadiazolo[5,4-b]pyridine
Figure imgf000085_0002
To a mixture of 5-chlorothiadiazolo[5,4-b]pyridine (0.43 g), 1 ,4-dioxane (10 mL) and water (0.5 mL) was added pyridine-4-boronic acid (0.362 g) and potassium carbonate (0.679 g) at room temperature. The mixture was purged with argon for 10 minutes and tetrakis(triphenylphosphine)palladium(0)
(0.284 g) was added, followed by further purging with argon for 10 minutes. The resulting reaction mixture was heated at 100°C for 1 hour. The reaction mixture was filtered through celite, washing through with 5% methanol in dichloromethane (100 mL). The filtrate was concentrated and the residue purified by silica gel chromatography eluting with a mixture of ethyl acetate and hexanes to afford 5-(4-pyridyl)thiadiazolo[5 ,4- b] pyridine as an off-white solid.
1H NMR (400 MHz, DMSO-d6) 9.35 - 9.32 (d, 1 H), 8.82 - 8.81 (dd, 2H), 8.57 - 8.55 (d, 1 H), 8.25 - 8.24 (dd, 2H)
Preparation of tert-butyl 3-[4-(thiadiazolo[5,4-b]pyridin-5-yl)pyridin-1-ium-1-yl]propanoate bromide A36 To a mixture of 5-(4-pyridyl)thiadiazolo[5,4-b] pyridine (0.09 g), tetrahydrofuran (2 mL) and acetonitrile (2 mL) was added tert-butyl 3-bromopropanoate (0.161 g) at room temperature. The reaction mixture was heated at 90°C for 2 hours, then cooled and concentrated. The resulting residue was dissolved in water (20 mL) and washed with dichloromethane (2x20 mL). The aqueous layer was concentrated and the residue was purified by using reverse phase chromatography eluting with water to afford tert- butyl 3-[4-(thiadiazolo[5,4-b]pyridin-5-yl)pyridin-1-ium-1-yl]propanoate bromide as an off white solid.
1H NMR (400 MHz, D2O) 9.11 (br d, 1 H), 9.00 (br d, 2H), 8.68 (br d, 2H), 8.39 (br d, 1 H), 4.84 (brt, 2H), 3.09 (br t, 2H), 1.27 (s, 9H)
Preparation of 3-[4-(thiadiazolo[5,4-b]pyridin-5-yl)pyridin-1-ium-1-yl]propanoic acid chloride A11
A solution of tert-butyl 3-[4-(thiadiazolo[5,4-b]pyridin-5-yl)pyridin-1-ium-1-yl]propanoate bromide (0.08 g) and 6M aqueous hydrochloric acid (5 mL) was stirred at room temperature for 3 hours. The reaction mixture was diluted with water (10 mL) and washed with dichloromethane (2x10 mL). The aqueous layer was concentrated to afford 3-[4-(thiadiazolo[5,4-b]pyridin-5-yl)pyridin-1 -ium-1 - yl]propanoic acid chloride as an off-white solid.
1H NMR (400 MHz, D2O) 9.09 (d, 1 H), 9.00 (d, 2H), 8.64 (d, 2H), 8.38 (d, 1 H), 4.86 (t, 2H), 3.14 (t, 2H) (CO2H proton missing)
Example 12: Preparation of 3-[4-([1 ,2,4]triazolo[1 ,5-b]pyridazin-6-yl)pyridin-1-ium-1-yl]propanoic acid chloride A13
Figure imgf000086_0001
Step 1 : Preparation of N'-(6-chloropyridazin-3-yl)-N,N-dimethyl-formamidine
Figure imgf000086_0002
A mixture of 6-chloropyridazin-3-amine (3.5 g), toluene (70 mL) and N,N-dimethylformamide dimethyl acetal (4.83 g) was heated at 100°C for 16 hours. The reaction mixture was cooled to room temperature and concentrated to obtain N'-(6-chloropyridazin-3-yl)-N,N-dimethyl-formamidine as a white solid, which was used without further purification.
1H NMR (400 MHz, DMSO-d6) 8.48 (s, 1 H), 7.59 - 7.57 (d, 1 H), 7.17 - 7.15 (d, 1 H), 3.13 (s, 3H), 3.02 (s, 3H)
Step 2: Preparation of N-(6-chloropyridazin-3-yl)-N'-hydroxy-formamidine
Figure imgf000087_0001
To a solution of N'-(6-chloropyridazin-3-yl)-N,N-dimethyl-formamidine (3.9 g) in methanol (100 mL), cooled to ~0°C, was added hydroxylamine hydrochloride (1 .76 g) followed by sodium acetate (2.08 g). The reaction mixture was allowed to warm to room temperature and stirred for 16 hours.
Dichloromethane (50 mL) was added and the resulting solid was filtered off, washed with 10% methanol in dichloromethane and dried under vacuum to afford N-(6-chloropyridazin-3-yl)-N'-hydroxy- formamidine as a white solid.
1H NMR (400 MHz, DMSO-d6) 8.50 (s, 1 H), 8.14 - 8.12 (d, 1 H), 7.47 - 7.44 (d, 1 H) (NH and OH protons missing)
Step 3: Preparation of 6-chloro-[1 ,2,4]triazolo[1 ,5-b]pyridazine
Figure imgf000087_0002
A mixture of N-(6-chloropyridazin-3-yl)-N'-hydroxy-formamidine (4.5 g) and polyphosphoric acid (9.20 g) was heated at 100°C for 3 hours. The reaction mixture was cooled, diluted with 50% aqueous ammonia solution and extracted with dichloromethane (2x150 mL). The combined organic layers were washed with water (25 mL), followed by brine (20 mL), dried over sodium sulfate and concentrated. The resulting residue was purified by silica gel chromatography eluting with a mixture of ethyl acetate in hexanes to afford 6-chloro-[1 ,2,4]triazolo[1 ,5-b]pyridazine as an off-white solid.
1H NMR (400 MHz, DMSO-d6) 8.50 (s, 1 H), 8.14 - 8.12 (d, 1 H), 7.47 - 7.44 (d, 1 H)
Step 4: Preparation of 6-(4-pyridyl)-[1 ,2,4]triazolo[1 ,5-b]pyridazine
Figure imgf000087_0003
To a mixture of 6-chloro-[1 ,2,4]triazolo[1 ,5-b]pyridazine (2 g), 1 ,4-dioxane (75 mL) and water (25 mL) was added pyridine-4-boronic acid (1 .91 g) and potassium carbonate (5.37 g) at room temperature. The mixture was purged with argon for 10 minutes and tetrakis(triphenylphosphine)palladium(0) (2.99 g) was added, followed by further purging with argon for 10 minutes. The resulting reaction mixture was heated at 100°C for 16 hours. The reaction mixture was filtered through celite, washing with 5% methanol in dichloromethane (2x30 mL). The filtrate was concentrated and the residue purified by silica gel chromatography eluting with a mixture of methanol and dichloromethane to afford 6-(4- pyridyl)-[1 ,2,4]triazolo[1 ,5-b]pyridazine as an off-white solid.
1H NMR (400 MHz, DMSO-d6) 8.85 - 8.83 (d, 2H), 8.50 (s, 1 H), 8.32 - 8.30 (d, 1 H), 7.97 - 7.96 (d, 2H), 7.93 - 7.91 (d, 1 H)
Step 5: Preparation of tert-butyl 3-[4-([1 ,2,4]triazolo[1 ,5-b]pyridazin-6-yl)pyridin-1-ium-1-yl]propanoate bromide A18
Figure imgf000088_0001
To a mixture of 6-(4-pyridyl)-[1 ,2,4]triazolo[1 ,5-b]pyridazine (0.4 g) and tetrahydrofuran (20 mL) was added tert-butyl 3-bromopropanoate (0.5 g) at room temperature. The reaction mixture was heated at 80°C for 16 hours, then cooled and concentrated. The resulting residue was dissolved in water (50 mL) and washed with dichloromethane (2x50 mL). The aqueous layer was concentrated and the residue was purified by using reverse phase chromatography eluting with a mixture of acetonitrile and water to afford tert-butyl 3-[4-([1 ,2,4]triazolo[1 ,5-b]pyridazin-6-yl)pyridin-1-ium-1-yl]propanoate bromide as an off-white solid.
1H NMR (400 MHz, D2O) 9.09 (d, 2H), 8.74 (d, 2H), 8.70 (s, 1 H), 8.52 (d, 1 H), 8.36 (d, 1 H), 4.92 (t,
2H), 3.15 (t, 2H), 1.35 (s, 9H)
Step 6: Preparation of 3-[4-([1 ,2,4]triazolo[1 ,5-b]pyridazin-6-yl)pyridin-1-ium-1-yl]propanoic acid chloride A13
A solution of tert-butyl 3-[4-([1 ,2,4]triazolo[1 ,5-b]pyridazin-6-yl)pyridin-1-ium-1-yl]propanoate bromide (0.14 g) and 6M aqueous hydrochloric acid (2 mL) was stirred at room temperature for 16 hours. The reaction mixture was diluted with water (50 mL) and washed with dichloromethane (2x20 mL). The aqueous layer was concentrated to afford 3-[4-([1 ,2,4]triazolo[1 ,5-b]pyridazin-6-yl)pyridin-1 -ium-1 - yl]propanoic acid chloride as a white solid.
1H NMR (400 MHz, D2O) 9.08 (d, 2H), 8.72 - 8.60 (m, 3H), 8.46 (d, 1 H), 8.32 (d, 1 H), 4.92 (t, 2H), 3.19 (t, 2H) (CO2H proton missing)
Example 13: Preparation of 3-[4-([1 ,2,4]triazolo[1 ,5-a]pyrazin-5-yl)pyridin-1 -ium-1 -yl]propanoic acid chloride A14 Step 1 : Preparation of 6-(4-pyridyl)pyrazin-2-amine
Figure imgf000089_0001
To a mixture of 6-chloropyrazin-2-amine (3 g), 1 ,4-dioxane (50 mL) and water (10 mL) was added pyridine-4-boronic acid (2.34 g) and potassium carbonate (4.38 g) at room temperature. The mixture was purged with argon for 5 minutes and tetrakis(triphenylphosphine)palladium(0) (1.83 g) was added, followed by further purging with argon for 5 minutes. The resulting reaction mixture was heated at 100°C for 16 hours. The reaction mixture was filtered through celite, washing with 15% methanol in dichloromethane (300 mL). The filtrate was concentrated and purified by silica gel chromatography eluting with a mixture of methanol and dichloromethane to afford 6-(4-pyridyl)pyrazin-2-amine as a brown solid.
1H NMR (400 MHz, DMSO-d6) 8.68 - 8.67 (d, 2H), 8.42 (s, 1 H), 7.97 (s, 1 H), 7.96 - 7.95 (d, 2H), 6.70 (s, 2H) Step 2: Preparation of N,N-dimethyl-N'-[6-(4-pyridyl)pyrazin-2-yl]formamidine
Figure imgf000089_0002
A mixture of 6-(4-pyridyl)pyrazin-2-amine (3.2 g), toluene (100 mL) and N,N-dimethylformamide dimethyl acetal (3.16 g) was heated at 100°C for 2 hours. The reaction mixture was cooled to room temperature and concentrated to obtain N,N-dimethyl-N'-[6-(4-pyridyl)pyrazin-2-yl]formamidine as a light orange sticky liquid, which was used without further purification.
1H NMR (400 MHz, CDCl3) 8.73 - 8.72 (dd, 2H), 8.62 (s, 1 H), 8.33 (s, 1 H), 7.91 - 7.89 (dd, 2H), 7.27 - 7.15 (m, 1 H), 3.19 (s, 3H), 3.17 (s, 3H)
Step 3: Preparation of N'-hydroxy-N-[6-(4-pyridyl)pyrazin-2-yl]formamidine To a solution of N,N-dimethyl-N'-[6-(4-pyridyl)pyrazin-2-yl]formamidine (3.5 g) in methanol (50 mL), cooled to ~0°C, was added hydroxylamine hydrochloride (1.16 g) followed by sodium acetate (1 .36 g). The reaction mixture was allowed to warm to room temperature and stirred for 16 hours. Dichloromethane (100 mL) was added and the resulting solid was filtered off, washed with 10% methanol in dichloromethane and dried under vacuum to afford N'-hydroxy-N-[6-(4-pyridyl)pyrazin-2- yl]formamidine as a pale white solid.
1H NMR (400 MHz, DMSO-d6) 8.83 (s, 1 H), 8.72 - 8.71 (d, 2H), 8.52 (s, 1 H), 8.14 - 8.12 (d, 2H), 8.06 - 8.04 (d, 1 H), 2.48 (s, 2H)
Step 4: Preparation of 5-(4-pyridyl)-[1 ,2,4]triazolo[1 ,5-a]pyrazine
Figure imgf000090_0001
A mixture of N'-hydroxy-N-[6-(4-pyridyl)pyrazin-2-yl]formamidine (3 g) and polyphosphoric acid (8.41 g) was heated at 100°C for 2 hours. The reaction mixture was cooled, diluted with aqueous ammonia solution to adjust the pH to ~10 and extracted with dichloromethane (2x150 mL). The combined organic layers were washed with brine (150 mL), dried over sodium sulfate and concentrated. The resulting residue was purified by silica gel chromatography eluting with a mixture of methanol in dichloromethane to afford 5-(4-pyridyl)-[1 ,2,4]triazolo[1 ,5-a]pyrazine as an off-white solid.
1H NMR (400 MHz, DMSO-d6) 9.53 (s, 1 H), 8.86 (s, 1 H), 8.86 - 8.84 (dd, 2H), 8.69 (s, 1 H), 8.15 - 8.13 (dd, 2H)
Step 5: Preparation of tert-butyl 3-[4-([1 ,2,4]triazolo[1 ,5-a]pyrazin-5-yl)pyridin-1-ium-1-yl]propanoate bromide A19
Figure imgf000090_0002
To a mixture of 5-(4-pyridyl)-[1 ,2,4]triazolo[1 ,5-a]pyrazine (0.4 g), acetonitrile (10 mL) and tetrahydrofuran (10 mL) was added tert-butyl 3-bromopropanoate (0.446 g) at room temperature. The reaction mixture was heated at 80°C for 16 hours, then cooled and concentrated. The resulting residue was dissolved in water (20 mL) and washed with dichloromethane (2x30 mL). The aqueous layer was concentrated and the residue was purified by using reverse phase chromatography eluting with a mixture of acetonitrile and water to afford tert-butyl 3-[4-([1 ,2,4]triazolo[1 ,5-a]pyrazin-5- yl)pyridin-1-ium-1-yl]propanoate bromide as a light brown solid.
1H NMR (400 MHz, D2O) 9.40 (s, 1 H), 9.06 (d, 2H), 8.74 (d, 2H), 8.67 (s, 1 H), 8.65 (s, 1 H), 4.87 (t,
2H), 3.10 (t, 2H), 1.29 (s, 9H)
Step 6: Preparation of 3-[4-([1 ,2,4]triazolo[1 ,5-a]pyrazin-5-yl)pyridin-1-ium-1-yl]propanoic acid chloride A14
A solution of tert-butyl 3-[4-([1 ,2,4]triazolo[1 ,5-a]pyrazin-5-yl)pyridin-1-ium-1-yl]propanoate bromide (0.15 g) and 6M aqueous hydrochloric acid (5 mL) was stirred at room temperature for 16 hours. The reaction mixture was diluted with water (10 mL) and washed with dichloromethane (2x20 mL). The aqueous layer was concentrated and the residue was purified by using reverse phase chromatography eluting with a mixture of acetonitrile and water to afford 3-[4-([1 ,2,4]triazolo[1 ,5-a]pyrazin-5-yl) pyridin- 1-ium-1-yl]propanoic acid chloride as a light grey solid.
1H NMR (400 MHz, D2O) 9.46 (s, 1 H), 9.13 (d, 2H), 8.82 - 8.67 (m, 4H), 4.96 (t, 2H), 3.23 (t, 2H)
(CO2H proton missing)
Example 14: Preparation of 3-[4-([1 .2.5]oxadiazolo[3.4-b]pyridin-5-yl)pyridin-1-ium-1-yl]propanoic acid chloride A10
Figure imgf000091_0001
Step 1 : Preparation of 5-chloro-1-oxido-[1 ,2,5]oxadiazolo[3,4-b]pyridin-1-ium
Figure imgf000091_0002
To a mixture of 6-chloro-3-nitro-pyridin-2-amine (8 g) in acetone (500 mL) was added iodobenzene diacetate (36.4 g) and the resulting mixture was heated at 80°C for 6 hours. The reaction mixture was cooled and concentrated. The resulting residue was dissolved in water (100 mL) and extracted with ethyl acetate (2x500 mL). The combined organic layers were dried over sodium sulfate, concentrated and the residue was purified by silica gel chromatography eluting with a mixture of ethyl acetate and hexanes to give 5-chloro-1-oxido-[1 ,2,5]oxadiazolo[3,4-b]pyridin-1-ium as a pale brown solid.
1H NMR (400 MHz, CDCl3) 7.79 - 7.77 (d, 1 H), 7.18 - 7.16 (d, 1 H) Step 2: Preparation of 5-chloro-[1 ,2,5]oxadiazolo[3,4-b]pyridine
Figure imgf000092_0001
To a mixture of 5-chloro-1-oxido-[1 ,2,5]oxadiazolo[3,4-b]pyridin-1-ium (2 g) in dichloromethane (300 mL), cooled to ~0°C, was added triphenylphosphine (4.49 g). The reaction was stirred at ~0°C for 1 hour, quenched with 1 M aqueous sodium hydroxide (150 mL) and extracted with ethyl acetate (2x150 mL). The combined organic layers were dried over sodium sulfate, concentrated and the residue was purified by silica gel chromatography eluting with a mixture of ethyl acetate and hexanes to give 5- chloro-[1 ,2,5]oxadiazolo[3,4-b]pyridine as a dark green solid.
1H NMR (400 MHz, CDCl3) 8.17 - 8.14 (d, 1 H), 7.35 - 7.32 (d, 1 H)
Step 3: Preparation of 5-(4-pyridyl)-[1 ,2,5]oxadiazolo[3,4-b]pyridine
Figure imgf000092_0002
A mixture of 5-chloro-[1 ,2,5]oxadiazolo[3,4-b]pyridine (0.5 g), 1 ,4-dioxane (20 mL) and tributyl(4- pyridyl)stannane (1.16 g) was purged with argon for 10 minutes. To this mixture was added tetrakis(triphenylphosphine)palladium(0) (0.364 g) followed by purging further with argon for 5 minutes. The resulting reaction mixture was heated at 110°C for 16 hours, cooled and filtered through celite, washing through with 5% methanol in dichloromethane (100 mL). The resulting filtrate was concentrated and the residue purified by silica gel chromatography eluting with a mixture of ethyl acetate and hexanes to afford 5-(4-pyridyl)-[1 ,2,5]oxadiazolo[3,4-b]pyridine as a dark green solid.
1H NMR (400 MHz, CDCl3) 8.82 - 8.80 (d, 2H), 8.35 - 8.33 (d, 1 H), 8.00 - 7.98 (d, 2H), 7.90 - 7.88 (d,
1 H)
Step 4: Preparation of methyl 3-[4-([1 ,2,5]oxadiazolo[3,4-b]pyridin-5-yl)pyridin-1-ium-1-yl]propanoate bromide A17
Figure imgf000092_0003
To a solution of 5-(4-pyridyl)-[1 ,2,5]oxadiazolo[3,4-b]pyridine (0.1 g), acetonitrile (5 mL) and tetrahydrofuran (5 mL) was added 3-bromopropanoic acid (0.121 g) and the mixture was heated at 90°C for 16 hours. The reaction mass was concentrated, diluted with water (10 mL) and washed with dichloromethane (2x20 mL). The aqueous layer was concentrated and the residue was purified by using reverse phase chromatography eluting with water to afford methyl 3-[4-([1 ,2,5]oxadiazolo[3,4- b]pyridin-5-yl)pyridin-1-ium-1-yl]propanoate bromide as a dark brown liquid.
1H NMR (400 MHz, D2O) 9.09 (d, 2H), 8.69 (d, 2H), 8.60 (d, 1 H), 8.19 (d, 1 H), 4.92 (t, 2H), 3.59 (s,
3H), 3.19 (t, 2H)
Step 5: Preparation of 3-[4-([1 ,2,5]oxadiazolo[3,4-b]pyridin-5-yl)pyridin-1-ium-1-yl]propanoic acid chloride A10
A solution of methyl 3-[4-([1 ,2,5]oxadiazolo[3,4-b]pyridin-5-yl)pyridin-1-ium-1-yl]propanoate bromide (0.08 g) and 6M aqueous hydrochloric acid (2 mL) was stirred at room temperature for 16 hours. The reaction mixture was diluted with water (50 mL) and washed with dichloromethane (2x20 mL). The aqueous layer was concentrated to afford 3-[4-([1 ,2,5]oxadiazolo[3,4-b]pyridin-5-yl)pyridin-1-ium-1- yl]propanoic acid chloride as a pale brown solid.
1H NMR (400 MHz, D2O) 9.11 (br d, 2H), 8.70 (br d, 2H), 8.66 - 8.57 (m, 1 H), 8.20 (d, 1 H), 4.92 (t, 2H), 3.19 (brt, 2H) (CO2H proton missing)
Example 15: Preparation of 5-(4-pyridyl)-[1 ,2,4]triazolo[1 ,5-a]pyrimidine
Figure imgf000093_0001
Step 1 : Preparation of 2-chloro-4-(4-pyridyl)pyrimidine
Figure imgf000093_0002
To a solution of 4-pyridylboronic acid (4.95 g), 2,4-dichloropyrimidine (5 g) and 1 ,4-dioxane (134.25 mL), was added water (33.5 mL) and sodium carbonate (10.672 g). After purging with nitrogen for 10 minutes, [1 , 1'-bis(diphenylphosphino)ferrocene]dichloropalladium(ll) (1 .228 g) was added and the reaction mixture was heated at 90°C for 16 hours. The reaction mass was cooled, diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, concentrated and purified by silica gel chromatography eluting with a mixture of ethyl acetate in cyclohexane to give 2-chloro-4-(4-pyridyl)pyrimidine as a light brown solid.
1H NMR (400 MHz, CDCl3) 8.86 - 8.78 (m, 3H), 8.00 (d, 2H), 7.74 (d, 1 H)
Step 2: Preparation of 2-hydrazinyl-4-(4-pyridinyl)pyrimidine
Figure imgf000094_0002
To a solution of 2-chloro-4-(4-pyridyl)pyrimidine (0.8 g) in pyridine (8.35 mL) was added hydrazine hydrate (2.09 g) and the mixture was stirred at room temperature for 16 hours. After cooling the reaction mixture was concentrated and the residue was washed with tert-butyl methyl ether to give 2- hydrazinyl-4-(4-pyridinyl)pyrimidine as a brown solid.
1H NMR (400 MHz, DMSO-d6) 8.73 (d, 2H), 8.48 (br, 1 H), 8.39 (s, 1 H), 8.07 (d, 1 H), 7.28 (d, 2H), 3.16 (s, 2H)
Step 3: Preparation of 5-(4-pyridyl)-[1 ,2,4]triazolo[1 ,5-a]pyrimidine
A mixture of [4-(4-pyridyl)pyrimidin-2-yl]hydrazine (0.5 g) and triethyl orthoformate (4.44 mL) was heated at 120°C for 5 hours. The reaction mixture was concentrated and the residue was washed with tert-butyl methyl ether and purified by silica gel chromatography eluting with a mixture of ethyl acetate and methanol to give 5-(4-pyridyl)-[1 ,2,4]triazolo[1 ,5-a]pyrimidine as a light brown solid.
1H NMR (400 MHz, DMSO-d6) 9.02 (d, 1 H), 8.85 - 8.90 (m, 2H), 8.77 (s, 1 H), 8.13 - 8.18 (m, 2H), 7.76 (d, 1 H)
Example 16: Preparation of 7-(4-pyridyl)-[1 ,2,4]triazolo[4,3-b][1,2,4]triazine
Figure imgf000094_0001
Step 1 : Preparation of 3-methylsulfanyl-5-(4-pyridyl)-1 ,2,4-triazine
Figure imgf000094_0003
To a solution of 1-(4-pyridyl)ethanone (1 .5 g) in dimethyl sulfoxide (15 mL) was added hydrobromic acid (48% in water, 15 mL) at room temperature and the mixture was heated at 55°C for 2 hours. The reaction mixture was cooled to room temperature and added drop wise to a mixture of [(methylsulfanylcarbonimidoyl)amino]ammonium iodide (3.36 g) and potassium carbonate (16.59 g) in ethanol (50 mL). The reaction mixture was heated at 80°C for 1 hour. The reaction mixture was diluted with ethyl acetate (100 mL) and washed with brine (2x100 mL). The organic layer was dried over anhydrous sodium sulfate, concentrated and purified by silica gel column chromatography eluting with a mixture of ethyl acetate and cyclohexane to give 3-methylsulfanyl-5-(4-pyridyl)-1 ,2,4-triazine as a yellow solid.
1H NMR (400 MHz, CDCl3) 9.42 (s, 1 H), 8.84 (d, 2H), 7.99 (d, 2H), 2.72 (s, 3H) Step 2: Preparation of [5-(4-pyridyl)-1 ,2,4-triazin-3-yl]hydrazine
Figure imgf000095_0001
To a solution of 3-methylsulfanyl-5-(4-pyridyl)-1 ,2,4-triazine (0.05 g) in 1 ,4-dioxane (1 mL), under nitrogen atmosphere, was added hydrazine hydrate (0.05 mL) and the mixture was heated at 100°C for 8 hours. The reaction mass was concentrated and the resulting solid was washed with tert-butyl methyl ether to give [5-(4-pyridyl)-1 ,2,4-triazin-3-yl]hydrazine as a yellow solid.
1H NMR (400 MHz, DMSO-d6) 9.34 (s, 1 H), 8.81 (d, 2H), 8.16 (d, 2H), 3.37 (br s, 3H)
Step 3: Preparation of 7-(4-pyridyl)-[1 ,2,4]triazolo[4,3-b][1 ,2,4]triazine A mixture of 5-(4-pyridyl)-1 ,2,4-triazin-3-yl]hydrazine (0.05 g) in trimethyl orthoformate (2 mL), under nitrogen atmosphere, was heated at 100°C for 15 hours. The reaction mass was concentrated and washed with tert-butyl methyl ether to give 7-(4-pyridyl)-[1 ,2,4]triazolo[4,3-b][1 ,2,4]triazine as a solid.
1H NMR (400 MHz, DMSO-d6) 9.80 (s, 1 H), 9.53 (s, 1 H), 8.85 - 8.91 (m, 2H), 8.24 - 8.30 (m, 2H) Example 17: Preparation of 6-(4-pyridyl)-[1 ,2, 4]triazolo[4,3-b]pyridazine
Figure imgf000095_0002
Step 1 : Preparartion of 1-(4-pyridyl)-N-(1 ,2,4-triazol-4-yl)ethanimine
Figure imgf000095_0003
To a mixture of 1 ,2,4-triazol-4-amine (1 .6 g) and 1-(4-pyridyl)ethanone (1 .5 g) in toluene (60 mL) was added p-toluenesulfonic acid (0.11 g). The reaction mixture was heated at 130°C for 5 hours. After cooling the reaction mass was concentrated to give 1-(4-pyridyl)-N-(1 ,2,4-triazol-4-yl)ethanimine, which was used without further purification.
LCMS: 188 (M+H), Retention time 0.16 min Step 2: Preparation of N,N-dimethyl-3-(4-pyridyl)-3-(1 ,2,4-triazol-4-ylimino)prop-1-en-1 -amine
Figure imgf000096_0001
To a solution of 1-(4-pyridyl)-N-(1 ,2,4-triazol-4-yl)ethanimine (0.61 g) in tetrahydrofuran (8.0 mL) was added tert-butoxy bis(dimethylamino)methane (1 .74 mL) and the mixture was heated at 80°C for 5 hours. After cooling the reaction mass was concentrated to give N,N-dimethyl-3-(4-pyridyl)-3-(1 ,2,4- triazol-4-ylimino)prop-1-en-1 -amine as a gummy mass, which was used without further purification. LCMS: 243 (M+H), Retention time 0.13 min
Step 3: Preparation of 6-(4-pyridyl)-[1 ,2,4]triazolo[4,3-b]pyridazine
A solution of N,N-dimethyl-3-(4-pyridyl)-3-(1 ,2,4-triazol-4-ylimino)prop-1-en-1 -amine (0.06 g) in acetic acid (2 mL) was heated at 130°C for 4 hours. The reaction mixture was concentrated and the residue was purified by silica gel chromatography eluting with a mixture of ethyl acetate and methanol to give 6-(4-pyridyl)-[1 ,2,4]triazolo[4,3-b]pyridazine as a light brown solid.
1H NMR (400 MHz, DMSO-d6) 9.79 (s, 1 H), 8.82 (d, 2H), 8.57 (d, 1 H), 8.02 - 8.09 (m, 3H)
Example 18: Preparation of 7-(4-pyridyl)pyrazolo[1 ,5-a]pyrimidine
Figure imgf000096_0002
Step 1 : Preparation of 3-(dimethylamino)-1-(4-pyridyl)prop-2-en-1-one
Figure imgf000096_0003
A microwave vial was charged with 1-(4-pyridyl)ethanone (1 g) and 1 ,1-dimethoxy-N,N-dimethyl- methanamine (10 mL) and heated at 150°C under microwave irradiation for 15 minutes. The reaction mixture was concentrated and triturated with methyl t-butyl ether to give 3-(dimethylamino)-1-(4- pyridyl)prop-2-en-1-one as a brown solid. 1H NMR (400 MHz, DMSO-d6) 8.68 (d, 2H), 7.82 - 7.73 (m, 3H), 5.84 (d, 1 H), 3.18 (s, 3H), 2.95 (s, 3H)
Step 2: Preparation of 7-(4-pyridyl)pyrazolo[1 ,5-a]pyrimidine
A microwave vial was charged with 1 H-pyrazol-5-amine (0.2 g), 3-(dimethylamino)-1-(4-pyridyl)prop-2- en-1-one (0.424 g) and acetic acid (3 mL) and heated at 150°C under microwave irradiation for 30 minutes. The reaction mixture was concentrated and triturated with methyl t-butyl ether and the residue was purified by silica gel chromatography eluting with a mixture of ethyl acetate and methanol to give 7-(4-pyridyl)pyrazolo[1 ,5-a]pyrimidine as a light yellow solid.
1H NMR (400 MHz, DMSO-d6) 8.84 (d, 2H), 8.68 (d, 1 H), 8.31 (d, 1 H), 8.12 (d, 2H), 6.90 (d, 1 H), 7.40 (d, 1 H)
Example 19: Preparation of 5-(4-pyridyl)pyrazolo[1 ,5-a]pyrimidine
Figure imgf000097_0001
A microwave vial was charged with 4-pyridylboronic acid (0.44 g), 5-chloropyrazolo[1 ,5-a]pyrimidine (0.5 g), 1 ,4-dioxane (5 mL) and water (2.5 mL) then tripotassium phosphate (1 .38 g) was added. After degassing for 10 minutes with nitrogen, tetrakis(triphenylphosphine)palladium(0) (0.188 g) was added and the reaction mass was degassed for a further 10 minutes. The mixture was heated at 120°C under microwave irradiation for 45 minutes then diluted with water and extracted with ethyl acetate. The organic layer was concentrated and the residue was purified by silica gel chromatography eluting with a mixture of ethyl acetate and cyclohexane to give 5-(4-pyridyl)pyrazolo[1 ,5-a]pyrimidine.
1H NMR (400 MHz, DMSO-d6) 9.31 (d, 1 H), 8.78 (d, 2H), 8.32 (d, 1 H), 8.16 (d, 2H), 7.76 (d, 1 H), 6.87 (d, 1 H)
Example 20: Preparation of 8-(4-pyridyl)-[1.2.4]triazolo[4,3-b]pyridazine
Figure imgf000097_0002
A microwave vial was charged with 4-amino-4H-1 ,2,4-triazole (1 g), 3-(dimethylamino)-1-(4- pyridyl)prop-2-en-1-one (2.05 g) and acetic acid (20 mL) and heated at 150°C under microwave irradiation for 60 minutes. The reaction mixture was concentrated and the residue was purified by silica gel chromatography eluting with a mixture of ethyl acetate and methanol to give 8-(4-pyridyl)- [1 ,2,4]triazolo[4,3-b]pyridazine as a yellow solid.
1H NMR (400 MHz, DMSO-d6) 9.82 (s, 1 H), 8.79 - 8.87 (m, 3H), 8.38 - 8.41 (m, 2H), 7.90 (d, 1 H) Example 21 : Preparation of 2-(4-pyridyl)pyrrolo[1 ,2-b]pyridazine
Figure imgf000098_0001
Step 1 : Preparation of 1-(4-pyridyl)-N-pyrrol-1-yl-ethanimine
Figure imgf000098_0002
To a mixture of 1-aminopyrrole (0.349 g), 4-acetylpyridine (0.5 g) and toluene (25 mL) was added p- toluenesulfonic acid (0.039 g) and this mixture was heated at 120°C for 5 hours. The reaction mass was cooled and concentrated to give 1-(4-pyridyl)-N-pyrrol-1-yl-ethanimine, which was used without further purification.
1H NMR (400 MHz, CDCl3) 8.71 (d, 2H), 7.75 (d, 2H), 6.87 (t, 2H), 6.26 (t, 2H), 2.50 (s, 3H)
Step 2: Preparation of N,N-dimethyl-3-(4-pyridyl)-3-pyrrol-1-ylimino-prop-1-en-1 -amine
Figure imgf000098_0003
A mixture of 1-(4-pyridyl)-N-pyrrol-1-yl-ethanimine (0.1 g), tetrahydrofuran (1.5 mL) and tert-butoxy bis(dimethylamino)methane (0.35 mL) was heated at 90°C for 5 hours. The reaction mass was cooled and concentrated to give N,N-dimethyl-3-(4-pyridyl)-3-pyrrol-1-ylimino-prop-1-en-1 -amine as a gummy mass, which was used without further purification.
LCMS: 241 (M+H), Retention time 0.15 min
Step 3: Preparation of 2-(4-pyridyl)pyrrolo[1 ,2-b]pyridazine
A mixture of N,N-dimethyl-3-(4-pyridyl)-3-pyrrol-1-ylimino-prop-1-en-1 -amine (0.2 g) and acetic acid (2 mL) was heated at 130°C for 4 hours. The reaction mixture was concentrated and the residue was purified by silica gel chromatography eluting with a mixture of ethyl acetate and cyclohexane to give 2- (4- py ridy I) py rrolo [1 ,2-b]pyridazine as a light yellow solid.
1H NMR (400 MHz, CDCl3) 8.74 (d, 2H), 7.83 - 7.88 (m, 4H), 6.99 (d, 1 H), 6.94 (dd, 1 H), 6.58 (dd, 1 H)
Example 22: Preparation of 4-(4-pyridyl)pyrrolo[1 ,2-b]pyridazine
Figure imgf000099_0003
A microwave vial was charged with 1-aminopyrrole (0.7 g), 3-(dimethylamino)-1-(4-pyridyl)prop-2-en- 1 -one (1.5 g) and acetic acid (12.5 mL) and heated at 150°C under microwave irradiation for 60 minutes. The reaction mixture was concentrated and triturated with methyl t-butyl ether and the residue was purified by silica gel chromatography eluting with a mixture of ethyl acetate and cyclohexane to give 4-(4-pyridyl)pyrrolo[1 ,2-b]pyridazine as a light yellow solid.
1H NMR (400 MHz, DMSO-d6) 8.77 (d, 2H), 8.29 (d, 1H), 8.01 (dd, 1H), 7.77 (d, 2H), 6.97 (dd, 1 H), 6.87 (d, 1 H), 6.71 (dd, 1H) Example 23: Preparation of 2-[4-([1 ,2,4]triazolo[1 ,5-a]pyrimidin-7-yl)pyridin-1-ium-1-yl]acetic acid 2,2.2-trifluoroacetate A34
Figure imgf000099_0001
Step 1 : Preparation of 7-(4-pyridyl)-[1 ,2,4]triazolo[1 ,5-a]pyrimidine
Figure imgf000099_0002
A microwave vial, under nitrogen atmosphere, was charged with 3-(dimethylamino)-1-(4-pyridyl)prop- 2-en-1-one (0.31 g), 4H-1 ,2,4-triazol-3-amine (0.15 g) and acetic acid (2.5 mL) and heated at 150°C under microwave irradiation for 60 minutes. The reaction mixture was concentrated and purified by silica gel chromatography eluting with a mixture of ethyl acetate and methanol to give 7-(4-pyridyl)- [1 ,2,4]triazolo[1 ,5-a]pyrimidine as a light yellow solid.
1H NMR (400 MHz, DMSO-d6) 9.03 (d, 1H), 8.85 - 8.90 (m, 2H), 8.78 (s, 1H), 8.13 - 8.18 (m, 2H), 7.77 (d, 1 H)
Step 2: Preparation of tert-butyl 2-[4-([1 ,2,4]triazolo[1 ,5-a]pyrimidin-7-yl)pyridin-1-ium-1-yl]acetate bromide A41
Figure imgf000100_0002
To a solution of 7-(4-pyridyl)-[1 ,2,4]triazolo[1 ,5-a]pyrimidine (0.5 g) in acetonitrile (12 mL) was added tert-butyl bromoacetate (0.742 g). The reaction mass was heated at 80°C for 2 days. The reaction mixture was cooled to room temperature, diluted with water and washed with dichloromethane. The aqueous layer was concentrated to give tert-butyl 2-[4-([1 ,2,4]triazolo[1 ,5-a]pyrimidin-7-yl)pyridin-1- ium-1-yl]acetate bromide as a light brown solid.
1H NMR (400 MHz, D2O) 9.10 - 9.15 (m, 3H), 8.89 (d, 2H), 8.73 (s, 1 H), 7.90 (d, 1 H), 5.61 (s, 2H),
1.50 (s, 9H)
Step 3: Preparation of 2-[4-([1 ,2,4]triazolo[1 ,5-a]pyrimidin-7-yl) pyridin-1 -ium-1 -yl]acetic acid 2,2,2- trifluoroacetate A34
To a mixture of tert-butyl 2-[4-([1 ,2,4]triazolo[1 ,5-a]pyrimidin-7-yl) pyridin-1 -ium-1 -yl]acetate bromide (0.3 g) and 1 ,4-dioxane (1 .5 mL) was added trifluoroacetic acid (6 mL) and the reaction mass was stirred at room temperature for 24 hours. The reaction mixture was concentrated and the residue was purified by using reverse phase chromatography eluting with a mixture of acetonitrile and water (trifluoroacetic acid was present in the eluent) to give 2-[4-([1 ,2,4]triazolo[1 ,5-a]pyrimidin-7-yl)pyridin-1- ium-1-yl]acetic acid 2,2,2-trifluoroacetate.
1H NMR (400 MHz, D2O) 8.98 - 9.18 (m, 3H), 8.83 (d, 2H), 8.70 (s, 1 H), 7.88 (d, 1 H), 5.38 (s, 2H) (CO2H proton missing)
Example 24: Preparation of 6-(4-pyridyl)imidazo[1 ,2-b]pyridazine
Figure imgf000100_0001
A microwave vial was charged with 4-pyridylboronic acid (0.5 g), 6-chloroimidazo[1 ,2-b]pyridazine (0.5 g), 1 ,4-dioxane (5 mL) and water (2.5 mL) then tripotassium phosphate (1 .38 g) was added. After degassing for 10 minutes with nitrogen, tetrakis(triphenylphosphine)palladium(0) (0.188 g) was added and the reaction mass was degassed for a further 10 minutes. The mixture was heated at 120°C under microwave irradiation for 30 minutes then diluted with water and extracted with ethyl acetate. The organic layer was concentrated and the residue was purified by silica gel chromatography eluting with a mixture of ethyl acetate and cyclohexane to give 6-(4-pyridyl)imidazo[1 ,2-b]pyridazine.
1H NMR (400 MHz, DMSO-d6) 8.77 (d, 2H), 8.42 (s, 1 H), 8.31 (d, 1 H), 8.05 (d, 2H), 7.90 (d, 2H) Example 25: Preparation of 2-(4-pyridyl)imidazo[1 ,5-b]pyridazine
Figure imgf000101_0001
Step 1 : Preparation of N-imidazol-1-yl-1-(4-pyridyl)ethanimine
Figure imgf000101_0002
To a mixture of imidazol-1 -amine hydrochloride (0.2 g) and 4-acetylpyridine (0.217 g) in toluene (16 mL) was added p-toluenesulfonic acid (0.016 g). The reaction mass was heated at 130°C for 10 hours then concentrated to give N-imidazol-1-yl-1-(4-pyridyl)ethanimine, which was used without further purification.
LCMS: 187 (M+H), Retention time 0.13 min
Step 2: Preparation of 3-imidazol-1-ylimino-N,N-dimethyl-3-(4-pyridyl)prop-1-en-1 -amine
Figure imgf000101_0003
A mixture of N-imidazol-1-yl-1-(4-pyridyl)ethanimine (1 g), tetrahydrofuran (12 mL) and tert-butoxy bis(dimethylamino)methane (1 .84 g) was heated at 80°C for 5 hours. The reaction mass was cooled and concentrated to give 3-imidazol-1-ylimino-N,N-dimethyl-3-(4-pyridyl)prop-1-en-1 -amine, which was used without further purification.
Step 3: Preparation of 2-(4-pyridyl)imidazo[1 ,5-b]pyridazine
A mixture of 3-imidazol-1-ylimino-N,N-dimethyl-3-(4-pyridyl)prop-1-en-1 -amine (0.75 g) and acetic acid (2.5 mL) was heated at 130°C for 4 hours. The reaction mixture was concentrated and partitioned between water and ethyl acetate. The organic layer was concentrated and the residue was purified by silica gel chromatography eluting with a mixture of ethyl acetate and cyclohexane to give 2-(4- pyridyl)imidazo[1 ,5-b]pyridazine as a yellow solid.
1H NMR (400 MHz, DMSO-d6) 8.77 - 8.89 (m, 3H), 8.33 (d, 1 H), 8.04 (d, 2H), 7.60 (s, 1 H), 7.44 (d, 1 H) Example 26: Preparation of 2-[4-([1 ,2,4]triazolo[1 ,5-b]pyridazin-6-yl)pyridin-1-ium-1-yl]ethanesulfonate
A24
Figure imgf000102_0001
A mixture of 6-(4-pyridyl)-[1 ,2,4]triazolo[1 ,5-b]pyridazine (0.2 g), sodium 2-bromoethanesulfonate (0.289 g) and water (10 mL) was heated at 100°C for 16 hours. The reaction mixture was cooled, concentrated and the resulting residue was diluted with water (50 mL) and washed with dichloromethane (2x50 mL). The aqueous layer was concentrated and purified by reverse phase HPLC eluting with a mixture of water and acetonitrile to give 2-[4-([1 ,2,4]triazolo[1 ,5-b]pyridazin-6- yl)pyridin-1-ium-1-yl]ethanesulfonate as an off-white solid.
1H NMR (400 MHz, D2O) 9.03 (d, 2H), 8.66 (d, 2H), 8.62 (s, 1 H), 8.44 (d, 1 H), 8.30 (d, 1 H), 5.00 (t, 2H), 3.59 - 3.52 (m, 2H)
Example 27: Preparation of 3-[4-([1 .2.4]triazolo[4,3-a]pyrazin-8-yl)pyridin-1-ium-1-yl]propanoic acid bromide A42
Figure imgf000102_0002
Step 1 : Preparation of (3-chloropyrazin-2-yl)hydrazine
Figure imgf000102_0003
To a solution of 2,3-dichloropyrazine (6 g) in ethanol (60 mL) was added hydrazine hydrate (4.07 g) and the reaction mass was heated at reflux for 3 hours. The reaction mass was cooled and the resulting precipitate was filtered off and washed with tert-butyl methyl ether to give (3-chloropyrazin-2- yl)hydrazine as a white solid.
1H NMR (400 MHz, DMSO-d6) 8.30 (br d, 1 H), 8.06 (d, 1 H), 7.56 (d, 1 H), 4.31 - 4.57 (m, 2H)
Step 2: Preparation of 8-chloro-[1 ,2,4]triazolo[4,3-a]pyrazine
Figure imgf000103_0002
A suspension of (3-chloropyrazin-2-yl)hydrazine (5 g) in diethoxymethoxyethane (5.28 g) was heated at 100°C for 1 hour. The brown solid formed in the reaction mixture was filtered off, washed with cyclohexane and dried under vacuum to give 8-chloro-[1 ,2,4]triazolo[4,3-a]pyrazine.
1H NMR (400 MHz, DMSO-d6) 9.55 (s, 1 H), 8.64 (d, 1 H), 7.78 (d, 1 H)
Step 3: Preparation of 8-(4-pyridyl)-[1 ,2,4]triazolo[4,3-a]pyrazine
Figure imgf000103_0001
A microwave vial was charged with 8-chloro-[1 ,2,4]triazolo[4,3-a]pyrazine (0.5 g), 2- methyltetrahydrofuran (10 mL) and water (10 mL). After degassing for 10 minutes with nitrogen, tetrakis(triphenylphosphine)palladium(0) (0.578 g) and 4-pyridylboronic acid (0.47 g) was added and the reaction mass was degassed for a further 10 minutes. The mixture was heated at 120°C under microwave irradiation for 1 hour then diluted with water and extracted with ethyl acetate (3x30 mL). The combined organic layers were dried over sodium sulfate, concentrated and the residue was purified by silica gel chromatography eluting with a mixture of ethyl acetate and cyclohexane to give 8- (4-pyridyl)-[1 ,2,4]triazolo[4,3-a]pyrazine.
1H NMR (400 MHz, CD3OD) 9.44 (s, 1 H), 8.79 (br d, 4H), 8.59 (d, 1 H), 8.15 (d, 1 H)
Step 4: Preparation of 3-[4-([1 ,2,4]triazolo[4,3-a]pyrazin-8-yl)pyridin-1-ium-1-yl]propanoic acid bromide A42
To a solution of 8-(4-pyridyl)-[1 ,2,4]triazolo[1 ,5-a]pyrazine (0.02 g) in acetonitrile (0.4 mL) was added 3-bromopropionic acid (0.02 g). The mixture was heated at 60°C for 24 hours, then cooled and concentrated. The crude product was triturated with methyl t-butyl ether to give 3-[4- ([1 ,2,4]triazolo[4,3-a]pyrazin-8-yl)pyridin-1-ium-1-yl]propanoic acid bromide as a grey solid.
1H NMR (400 MHz, D2O) 9.48 (s, 1 H), 9.16 (d, 2H), 9.10 (d, 2H), 8.69 (d, 1 H), 8.24 (d, 1 H), 4.98 (t, 2H), 3.22 (t, 2H) (CO2H proton missing)
Example 28: Preparation of [4-([1 ,2,4]triazolo[4.3-b]pyridazin-6-yl)pyridin-1-ium-1-yl]methanesulfonate A45
Figure imgf000104_0003
Step 1 : Preparation of tert-butyl 2-[4-([1 ,2,4]triazolo[4,3-b]pyridazin-6-yl)pyridin-1-ium-1-yl]acetate bromide A48
Figure imgf000104_0001
To a mixture of 6-(4-pyridyl)-[1 ,2,4]triazolo[4,3-b]pyridazine (0.5 g) in acetonitrile (10 mL) was added tert-butyl 2-bromoacetate (0.56 mL) and the reaction was stirred for 2 days. More tert-butyl 2- bromoacetate (0.56 mL) was added and the mixture was stirred for a further 3 days. The reaction mixture was concentrated and the residue was triturated with acetone to give tert-butyl 2-[4- ([1 ,2,4]triazolo[4,3-b]pyridazin-6-yl)pyridin-1-ium-1-yl]acetate bromide as a cream solid.
1H NMR (400 MHz, D2O) 9.48 (s, 1 H), 8.96 (d, 2H), 8.70 (d, 2H), 8.44 - 8.38 (m, 1 H), 8.04 (d, 1 H),
5.48 (s, 2H), 1.41 (s, 9H)
Step 2: Preparation of [4-([1 ,2,4]triazolo[4,3-b]pyridazin-6-yl)pyridin-1-ium-1-yl]methanesulfonate A45 [Chlorosulfonyloxy(dimethyl)silyl]methane (10 mL) was heated at 120°C, in order to have an internal temperature of 105°C, then tert-butyl 2-[4-([1 ,2,4]triazolo[4,3-b]pyridazin-6-yl)pyridin-1-ium-1-yl]acetate bromide (0.76 g) was added portion wise. After heating for 24 hours, the reaction mixture was cooled to room temperature. The excess solution was decanted from the gummy residue. The gummy residue was triturated sequentially with cyclohexane (5 mL), diethyl ether (5 mL) and finally acetone (5 mL). The resulting residue was purified by preparative reverse phase HPLC to give [4- ([1 ,2,4]triazolo[4,3-b]pyridazin-6-yl)pyridin-1-ium-1-yl]methanesulfonate.
1H NMR (400 MHz, D2O) 9.51 - 9.47 (m, 1 H), 9.11 - 9.06 (m, 2H), 8.74 (br d, 2H), 8.44 - 8.38 (m, 1 H), 8.09 - 8.04 (m, 1 H), 5.72 (s, 2H)
Example 29: Preparation of 3-(4-pyridyl)imidazo[1 ,2-b][1, 2,4]triazine
Figure imgf000104_0002
Step 1 : Preparation of 5-(4-pyridyl)-1 ,2,4-triazin-3-amine
Figure imgf000105_0001
To a solution of 1-(4-pyridyl)ethanone (1 g) in dimethyl sulfoxide (6 mL) was added aqueous hydrobromic acid (48% in water, 9.8 mL) and the mixture was heated at 70°C for 2 hours. The resulting mixture was cooled and added drop wise to a mixture of guanidinoammonium chloride (1 g), ethanol (24 mL) and potassium carbonate (11 g) at room temperature. The reaction mass was then heated at 70°C for 1 hour. The reaction mass was cooled, diluted with water (100 mL) and extracted with ethyl acetate (5x100 mL). The combined organic layers were dried over sodium sulfate and concentrated to give 5-(4-pyridyl)-1 ,2,4-triazin-3-amine, which was a 1 :1 mixture with 6-(4-pyridyl)- 1 ,2,4-triazin-3-amine and was used without further purification.
LCMS: 174 (M+H), Retention time 0.14 min
Step 2: Preparation of 3-(4-pyridyl)imidazo[1 ,2-b][1 ,2,4]triazine
To a solution of 2-chloroacetaldehyde (2.72 g) in ethanol (20 mL) was added the crude 1 :1 mixture of 5-(4-pyridyl)-1 ,2,4-triazin-3-amine (1 g) at room temperature. The reaction mass was heated at 80°C for 5 hours. The reaction mixture was cooled, concentrated and partitioned between water and ethyl acetate. The organic layer was concentrated and the resulting residue was triturated with methyl t- butyl ether to give 3-(4-pyridyl)imidazo[1 ,2-b][1 ,2,4]triazine.
1H NMR (400 MHz, D2O) 9.50 (s, 1 H), 8.78 - 8.89 (m, 2H), 8.49 - 8.52 (m, 1 H), 8.26 (d, 2H), 8.13 (d,
1 H)
Example 30: Preparation of 5-(4-pyridyl)-[1 ,2,4]triazolo[4,3-a]pyrazine
Figure imgf000105_0002
Step 1 : Preparation of (6-chloropyrazin-2-yl)hydrazine
Figure imgf000105_0003
To a solution of 2,6-dichloropyrazine (5 g) in ethanol (50 mL) was added hydrazine hydrate (3.39 g) and the reaction mass was heated at reflux for 10 hours. The reaction mass was concentrated and triturated with methyl t-butyl ether to give (6-chloropyrazin-2-yl)hydrazine.
1H NMR (400 MHz, CD3OD) 7.99 (s, 1 H), 7.71 (s, 1 H) (NH protons missing) Step 2: Preparation of N'-[(6-chloropyrazin-2-yl)amino]-N,N-dimethyl-formamidine
Figure imgf000106_0001
To a solution of (6-chloropyrazin-2-yl)hydrazine (2 g) in toluene (40 mL) was added N,N- dimethylformamide dimethyl acetal (3.66 g) and the mixture was heated at 80°C for 2 hours. The reaction mass was concentrated and dried under vacuum to give N'-[(6-chloropyrazin-2-yl)amino]-N,N- dimethyl-formamidine.
LCMS: 200 (M+H), Retention time 0.17 min
Step 3: Preparation of 5-chloro-[1 ,2,4]triazolo[4,3-a]pyrazine
Figure imgf000106_0002
A solution of N'-[(6-chloropyrazin-2-yl)amino]-N,N-dimethyl-formamidine (2 g) in acetic acid (20 mL) was heated at reflux for 1 hour. The reaction mass was concentrated and partitioned between saturated aqueous sodium carbonate and ethyl acetate. The organic layer was dried over sodium sulfate, concentrated and the resulting residue was triturated with methyl t-butyl ether to give 5-chloro- [1 ,2,4]triazolo[4,3-a]pyrazine.
1H NMR (400 MHz, DMSO-d6) 9.69 (s, 1 H), 9.45 (s, 1 H), 8.17 (s, 1 H)
Step 4: Preparation of 5-(4-pyridyl)-[1 ,2,4]triazolo[4,3-a]pyrazine
A microwave vial charged with 5-chloro-[1 ,2,4]triazolo[4,3-a]pyrazine (1 g), 4-pyridylboronic acid (0.95 g), 1 ,4-dioxane (30 mL) and water (10 mL) was degassed with nitrogen for 20 minutes. Tetrakis(triphenylphosphine)palladium(0) (1 .16 g) was added and the mixture was heated at 100°C under microwave irradiation for 2 hours. The reaction mixture was filtered through a pad of celite and the filtrate was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, concentrated and triturated with methyl t-butyl ether to give 5-(4-pyridyl)-[1 ,2,4]triazolo[4,3-a]pyrazine.
1H NMR (400 MHz, DMSO-d6) 9.64 (s, 1 H), 9.53 (s, 1 H), 8.85 (d, 2H), 8.17 (s, 1 H), 7.89 (d, 2H)
Example 31 : Preparation of 7-methyl-5-(4-pyridyl)-[1 ,2,4]triazolo[1 ,5-a][1 ,3,5]triazine
Figure imgf000107_0001
Step 1 : Preparation of N-(1H-1 ,2,4-triazol-5-yl)pyridine-4-carboxamidine
Figure imgf000107_0002
To a solution of 4-cyanopyridine (5 g) in methanol (237 mL) was added sodium methoxide (25% solution in methanol, 2.22 mL). After stirring at room temperature for 3 hours, the reaction mass was concentrated. To the resulting residue, under nitrogen atmosphere, was added N,N- dimethylformamide (238 mL), 1H-1 ,2,4-triazol-5-amine (4.16 g) and cesium carbonate (62 g) and the mixture was heated at 120°C for 16 hours. The reaction mass was cooled to room temperature, filtered through celite and the filtrate was concentrated. The resulting residue was partitioned between ethyl acetate and water. The organic layer was concentrated to give N'-(1H-1 ,2,4-triazol-5-yl)pyridine- 4-carboxamidine as a light yellow solid.
1H NMR (400 MHz, DMSO-d6) 8.66 - 8.72 (m, 2H), 8.33 (brs, 1 H), 7.76 - 7.80 (m, 2H) (NH protons missing)
Step 2: Preparation of 7-methyl-5-(4-pyridyl)-[1 ,2,4]triazolo[1 ,5-a][1 ,3,5]triazine
A microwave vial, under nitrogen atmosphere, was charged with N-(1 H-1 ,2,4-triazol-5-yl) pyridine-4- carboxamidine (0.5 g), acetic anhydride (1.79 mL) and toluene (8 mL) and was heated under microwave irradiation at 150°C for 60 minutes. The reaction mixture was concentrated and the residue was purified by silica gel chromatography eluting with a mixture of ethyl acetate and methanol to give 7-methyl-5-(4-pyridyl)-[1 ,2,4]triazolo[1 ,5-a][1 ,3,5]triazine as a light brown solid.
1H NMR (400 MHz, DMSO-d6) 8.83 - 8.88 (m, 1H), 8.74 - 8.79 (m, 2H), 7.76 - 7.80 (m, 2H), 2.34 (s, 3H)
Example 32: Preparation of N,N-dimethyl-6-(4-pyridyl)-[1 ,2,4]triazolo[3,4-f][1 ,2,4]triazin-8-amine
Figure imgf000108_0001
Step 1 : Preparation of N'-(1 ,2,4-triazol-4-yl)pyridine-4-carboxamidine
Figure imgf000108_0002
To a solution of 4-cyanopyridine (4 g) in methanol (190 mL), under nitrogen atmosphere, was added sodium methoxide (25% solution in methanol, 1 .77 mL). After stirring at room temperature for 3 hours, 4-amino-4H-1 ,2,4-triazole (3.26 g) was added and the resulting mixture was heated at reflux for 16 hours. The reaction mass was cooled to room temperature, concentrated and the residue was triturated with methyl t-butyl ether to give N'-(1 ,2,4-triazol-4-yl)pyridine-4-carboxamidine as an off- white solid.
1H NMR (400 MHz, DMSO-d6) 8.73 (d, 2H), 8.51 (s, 2H), 7.85 (d, 2H), 7.62 (br s, 2H)
Step 2: Preparation of N-(dimethylaminomethylene)-N'-(1 ,2,4-triazol-4-yl)pyridine-4-carboxamidine
Figure imgf000108_0003
To a solution of N'-(1 ,2,4-triazol-4-yl)pyridine-4-carboxamidine (1 g) in N,N-dimethylformamide (11 mL), under nitrogen atmosphere, was added tert-butoxy bis(dimethylamino)methane (3.4 mL) and the mixture was heated at 100°C for 2 hours. The reaction mass was cooled to room temperature, concentrated and the residue was triturated with methyl t-butyl ether to give N- (dimethylaminomethylene)-N'-(1 ,2,4-triazol-4-yl)pyridine-4-carboxamidine as a light brown solid.
1H NMR (400 MHz, DMSO-d6) 8.91 (s, 2H), 8.68 - 8.73 (m, 2H), 7.78 (s, 1 H), 7.50 - 7.53 (m, 2H), 3.06 (d, 6H)
Step 3: Preparation of N,N-dimethyl-6-(4-pyridyl)-[1 ,2,4]triazolo[3,4-f][1 ,2,4]triazin-8-amine
A microwave vial, under nitrogen atmosphere, was charged with N-(dimethylaminomethylene)-N'- (1 ,2,4-triazol-4-yl)pyridine-4-carboxamidine (0.6 g) and acetic acid (7 mL) and was heated under microwave irradiation at 150°C for 60 minutes. The reaction mixture was concentrated and the residue was purified by silica gel chromatography eluting with a mixture of ethyl acetate and methanol to give N,N-dimethyl-6-(4-pyridyl)-[1 ,2,4]triazolo[3,4-f][1 ,2,4]triazin-8-amine as an off-white solid.
1H NMR (400 MHz, DMSO-d6) 9.58 (s, 1H), 8.75 (d, 2H), 8.13 (d, 2H), 3.96 (s, 3H), 3.45 (s, 3H)
Example 33: Preparation of 8-(4-pyridyl)-[1 ,2,4]triazolo[1 ,5-a]pyrazine
Figure imgf000109_0001
Step 1 : Preparation of 3-chloro-N-[(2,4-dimethoxyphenyl)methyl]pyrazin-2-amine
Figure imgf000109_0002
A mixture of 2,3-dichloropyrazine (5 g) and (2,4-dimethoxyphenyl)methanamine (16.8 g) was stirred at room temperature for 16 hours. The reaction was partitioned between water and ethyl acetate. The organic layer was dried over sodium sulfate, concentrated and the residue was purified by silica gel chromatography eluting with a mixture of ethyl acetate and cyclohexane to give 3-chloro-N-[(2,4- dimethoxyphenyl)methyl]pyrazin-2-amine.
1H NMR (400 MHz, CD3OD) 7.92 (d, 1H), 7.48 (d, 1H), 7.11 (d, 1H), 6.53 (d, 1H), 6.42 (dd, 1H), 4.55 (s, 2H), 3.85 (s, 3H), 3.76 (s, 3H) (NH proton missing)
Step 2: Preparation of N-[(2,4-dimethoxyphenyl)methyl]-3-(4-pyridyl)pyrazin-2-amine
Figure imgf000109_0003
A mixture of 3-chloro-N-[(2,4-dimethoxyphenyl)methyl]pyrazin-2-amine (8 g), 4-pyridylboronic acid (5.27 g), 1 ,4-dioxane (160 mL) and water (80 mL) was degassed with nitrogen for 20 minutes. To this was added tetrakis(triphenylphosphine)palladium(0) (5.11 g) and the reaction mixture was heated at 80°C for 12 hours. The mixture was filtered through celite and the filtrate was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, concentrated and the residue was purified by silica gel chromatography eluting with a mixture of ethyl acetate and cyclohexane to give N-[(2,4- dimethoxyphenyl)methyl]-3-(4-pyridyl)pyrazin-2-amine.
1H NMR (400 MHz, DMSO-d6) 8.62 - 8.81 (m, 2H), 8.02 (d, 1 H), 7.87 (d, 1 H), 7.66 - 7.72 (m, 2H), 7.06 (d, 1 H), 6.88 (t, 1 H), 6.54 (d, 1 H), 6.43 (dd, 1 H), 4.41 (d, 2H), 3.79 (s, 3H), 3.74 (s 3H)
Step 3: Preparation of 3-(4-pyridyl)pyrazin-2-amine
Figure imgf000110_0001
A mixture of N-[(2,4-dimethoxyphenyl)methyl]-3-(4-pyridyl)pyrazin-2-amine (10 g) and 2,2,2- trifluoroacetic acid (200 mL) in toluene (100 mL) was heated at 60°C for 24 hours. The reaction mass was concentrated and the residue was triturated with methyl t-butyl ether to give 3-(4-pyridyl)pyrazin- 2-amine.
LCMS: 173 (M+H), Retention time 0.14 min Step 4: Preparation of N,N-dimethyl-N'-[3-(4-pyridyl)pyrazin-2-yl]formamidine
Figure imgf000110_0002
A mixture of 3-(4-pyridyl)pyrazin-2-amine (1 g) and 1 ,1-dimethoxy-N,N-dimethyl-methanamine (0.692 g) was heated at 100°C for 2 hours. The reaction mixture was concentrated to give N,N-dimethyl-N'-[3- (4-pyridyl)pyrazin-2-yl]formamidine, which was used without further purification.
Step 5: Preparation of N-hydroxy-N'-[3-(4-pyridyl)pyrazin-2-yl]formamidine
Figure imgf000110_0003
To a solution of N,N-dimethyl-N'-[3-(4-pyridyl)pyrazin-2-yl]formamidine (1.45 g) in methanol (29 mL) was added hydroxylamine hydrochloride (0.672 g) and the reaction was stirred at room temperature for 4 hours. The reaction mixture was concentrated and the residue was purified by silica gel chromatography eluting with a mixture of ethyl acetate and cyclohexane to give N-hydroxy-N'-[3-(4- pyridyl)pyrazin-2-yl]formamidine.
1H NMR (400 MHz, DMSO-d6) 10.55 (br s, 1 H), 10.14 (br s, 1 H), 8.80 (d, 2H), 8.34 (s, 2H), 7.90 - 7.96 (m, 1 H), 7.79 (d, 2H)
Step 6: Preparation of 8-(4-pyridyl)-[1 ,2,4]triazolo[1 ,5-a]pyrazine
To a mixture of N-hydroxy-N'-[3-(4-pyridyl)pyrazin-2-yl]formamidine (1 g) and tetrahydrofuran (20 mL) was added propane phosphonic acid anhydride (4.43 g) and the mixture was heated at reflux for 12 hours. The reaction mixture was concentrated and the resulting residue was triturated with methyl t- butyl ether to give 8-(4-pyridyl)-[1 ,2,4]triazolo[1 ,5-a]pyrazine.
1H NMR (400 MHz, DMSO-d6) 9.25 (d, 1 H), 8.91 (s, 1 H), 8.86 (d, 2H), 8.65 (d, 2H), 8.47 (d, 1 H)
Example 34: Preparation of 2-methyl-5-(4-pyridyl)triazolo[4,5-d]pyrimidine
Figure imgf000111_0001
Step 1 : Preparation of 5-chloro-3H-triazolo[4,5-d]pyrimidine
Figure imgf000111_0002
To a suspension of 2-chloropyrimidine-4, 5-diamine (6 g) in water (80 mL), cooled to ~0°C, was added acetic acid (126 mL) and a solution of sodium nitrite (5.727 g) in water (40 mL) over 15 minutes. The reaction mixture was stirred for 30 minutes at ~0°C. The mixture was concentrated to give crude 5- chloro-3H-triazolo[4,5-d]pyrimidine, which was used without further purification.
1H NMR (400 MHz, DMSO-d6) 9.70 (s, 1 H) (NH proton missing)
Step 2: Preparation of 5-chloro-2-methyl-triazolo[4,5-d]pyrimidine
Figure imgf000111_0003
To a solution of 5-chloro-2H-triazolo[4,5-d]pyrimidine (3.1 g) in tetrahydrofuran (90 mL) was added iodomethane (2.5 mL) at room temperature. The reaction mass was cooled to ~0°C and sodium bis(trimethylsilyl)amide (1 M in tetrahydrofuran, 30 mL) was added over 15 minutes. The reaction was stirred at room temperature for 12 hours. The mixture was quenched with saturated aqueous ammonium chloride, diluted with water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, concentrated and purified by silica gel chromatography eluting with a mixture of ethyl acetate and cyclohexane to give 5-chloro-2-methyl-triazolo[4,5-d]pyrimidine.
1H NMR (400 MHz, CDCl3) 9.48 (s, 1 H), 4.63 (s, 3H)
Step 3: Preparation of 2-methyl-5-(4-pyridyl)triazolo[4,5-d]pyrimidine
A microwave vial was charged with tributyl(4-pyridyl)stannane (1 .075 g), 5-chloro-2-methyl- triazolo[4,5-d]pyrimidine (0.45 g), tetrakis(triphenylphosphine)palladium(0) (0.307 g) and 1 ,4-dioxane (9 mL) and the reaction mass was degassed with nitrogen for 15 minutes. The mixture was heated at 120°C under microwave irradiation for 1 hour. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (2x50 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated and purified by silica gel chromatography eluting with a mixture of ethyl acetate and cyclohexane to give 2-methyl-5-(4-pyridyl)triazolo[4,5-d]pyrimidine.
1H NMR (400 MHz, DMSO-d6) 9.99 (s, 1 H), 8.82 (d, 2H), 8.37 (d, 2H), 4.68 (s, 3H)
Example 35: Preparation of 3-methyl-5-(4-pyridyl)triazolo[4,5-d]pyrimidine
Figure imgf000112_0001
Step 1 : Preparation of 5-chloro-3-methyl-triazolo[4,5-d]pyrimidine
Figure imgf000112_0002
To a solution of 5-chloro-2H-triazolo[4,5-d]pyrimidine (3.1 g) in tetrahydrofuran (90 mL) was added iodomethane (2.5 mL) at room temperature. The reaction mass was cooled to ~0°C and sodium bis(trimethylsilyl)amide (1 M in tetrahydrofuran, 30 mL) was added over 15 minutes. The reaction was stirred at room temperature for 12 hours. The mixture was quenched with saturated aqueous ammonium chloride, diluted with water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, concentrated and purified by silica gel chromatography eluting with a mixture of ethyl acetate and cyclohexane to give 5-chloro-3-methyl-triazolo[4,5-d]pyrimidine. 1H NMR (400 MHz, CDCl3) 9.41 (s, 1 H), 4.35 (s, 3H)
Step 2: Preparation of 3-methyl-5-(4-pyridyl)triazolo[4,5-d]pyrimidine
A microwave vial was charged with tributyl(4-pyridyl)stannane (1 .146 g), 5-chloro-3-methyl- triazolo[4,5-d]pyrimidine (0.48 g), tetrakis(triphenylphosphine)palladium(0) (0.328 g) and 1 ,4-dioxane (10 mL) and the reaction mass was degassed with nitrogen for 15 minutes. The mixture was heated at 120°C under microwave irradiation for 1 hour. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (2x50 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated and purified by silica gel chromatography eluting with a mixture of ethyl acetate and cyclohexane to give 3-methyl-5-(4-pyridyl)triazolo[4,5-d]pyrimidine.
1H NMR (400 MHz, DMSO-d6) 9.91 (s, 1 H), 8.83 (d, 2H), 8.40 (d, 2H), 4.39 (s, 3H)
Example 36: Preparation of 7-(4-pyridyl)-[1 ,2,4]triazolo[1 ,5-b][1 ,2,4]triazine
Figure imgf000113_0001
Step 1 : Preparation of N,N-dimethyl-N'-[5-(4-pyridyl)-1 ,2,4-triazin-3-yl]formamidine
Figure imgf000113_0002
A microwave vial was charged with 5-(4-pyridyl)-1 ,2,4-triazin-3-amine (1 .7 g) and 1 ,1-dimethoxy-N,N- dimethyl-methanamine (17 mL). The mixture was heated at 100°C under microwave irradiation for 1 hour. The reaction mixture was concentrated to give crude N,N-dimethyl-N'-[5-(4-pyridyl)-1 ,2,4-triazin- 3-yl]formamidine, which was used without further purification.
LCMS: 229 (M+H), Retention time 0.14 min
Step 2: Preparation of N-hydroxy-N'-[5-(4-pyridyl)-1 ,2,4-triazin-3-yl]formamidine
Figure imgf000113_0003
A mixture of N,N-dimethyl-N'-[5-(4-pyridyl)-1 ,2,4-triazin-3-yl]formamidine (2.2 g), methanol (44 mL) and hydroxylamine hydrochloride (1 .01 g) was stirred at room temperature for 4 hours. The reaction mixture was concentrated and purified by silica gel chromatography eluting with a mixture of ethyl acetate and cyclohexane to give N-hydroxy-N'-[5-(4-pyridyl)-1 ,2,4-triazin-3-yl]formamidine.
LCMS: 217 (M+H), Retention time 0.18 min
Step 3: Preparation of 7-(4-pyridyl)-[1 ,2,4]triazolo[1 ,5-b][1 ,2,4]triazine
A suspension of N'-hydroxy-N-[5-(4-pyridyl)-1 ,2,4-triazin-3-yl]formamidine (1 g) in polyphosphoric acid (10 mL) was heated at 110°C for 2 hours. The reaction mass was quenched with aqueous sodium bicarbonate and extracted with ethyl acetate (3x20 mL). The combined organic layers were dried over sodium sulfate and concentrated to give 7-(4-pyridyl)-[1 ,2,4]triazolo[1 ,5-b][1 ,2,4]triazine, which was used without further purification.
LCMS: 199 (M+H), Retention time 0.17 min
Example 37: Preparation of 3-(4-pyridyl)-[1.2.4]triazolo[5,1-c][1 ,2,4]triazin-4-ol
Figure imgf000114_0001
Step 1 : Preparation of ethyl-2-(4-pyridyl)-2-(1 H-1 ,2,4-triazol-5-ylhydrazono)acetate
Figure imgf000114_0002
To a mixture of 1 H-1 ,2,4-triazol-5-amine (1 g), water (3.57 mL), acetonitrile (2.4 mL) and cone, hydrochloric acid (4.8 mL), cooled to ~-10°C, was added a solution of sodium nitrite (0.903 g) in water (3.5 mL) drop wise. The mixture was stirred at this temperature for 10 minutes. Then a mixture of ethyl 4-pyridylacetate (1 .9 g) and sodium acetate (2.4 g) in water (2.3 mL) and ethanol (6.8 mL) was added drop wise at ~-10°C. The mixture was allowed to warm to room temperature and stirred for 3 hours at room temperature. The crude mixture was used in the next step.
Step 2: Preparation of 3-(4-pyridyl)-[1 ,2,4]triazolo[5,1-c][1 ,2,4]triazin-4-ol
To the mixture of ethyl-2-(4-pyridyl)-2-(1 H-1 ,2,4-triazol-5-ylhydrazono)acetate crude from Step 1 was added acetic acid (60 ml) at room temperature. The resulting reaction mixture was then refluxed at 120°C for 8 hours. The reaction mass was poured into water and the resulting precipitate was filtered off and dried to give 3-(4-pyridyl)-1 H-[1 ,2,4]triazolo[5,1-c][1 ,2,4]triazin-4-one. 1H NMR (400 MHz, DMSO-d6) 8.90 (d, 2H) 8.49 - 8.52 (m, 3H) (OH proton missing)
Example 38: Preparation of 8-methyl-6-(4-pyridyl)-[1,2,4]triazolo[3,4-f][1 ,2,4]triazine
Figure imgf000115_0001
Step 1 : Preparation of N'-(1 ,2,4-triazol-4-yl)pyridine-4-carboxamidine
Figure imgf000115_0002
To a solution of 4-cyanopyridine (4 g) in methanol (190 mL), under nitrogen atmosphere, was added sodium methoxide (25% solution in methanol, 1 .77 mL). After stirring at room temperature for 3 hours 4-amino-4H-1 ,2,4-triazole (3.26 g) was added and the mixture was heated at reflux for 16 hours. The reaction mass was cooled, concentrated and the resulting residue was triturated with tert-butyl methyl ether to give N'-(1 ,2,4-triazol-4-yl)pyridine-4-carboxamidine as an off-white solid.
1H NMR (400 MHz, DMSO-d6) 8.73 (d, 2H), 8.51 (s, 2H), 7.85 (d, 2H), 7.62 (br s, 2H)
Step 2: Preparation of N-[1-(dimethylamino)ethylidene]-N'-(1 ,2,4-triazol-4-yl)pyridine-4-carboxamidine
Figure imgf000115_0003
A microwave vial was charged with N'-(1 ,2,4-triazol-4-yl)pyridine-4-carboxamidine (0.5 g), toluene (7.5 mL) and 1 ,1-dimethoxy-N,N-dimethyl-ethanamine (0.43 mL). The mixture was heated at 140°C under microwave irradiation for 1 hour. The reaction mixture was concentrated and the resulting residue was triturated with tert-butyl methyl etherto give N-[1-(dimethylamino)ethylidene]-N'-(1 ,2,4-triazol-4- yl)pyridine-4-carboxamidine as a light brown gummy mass.
LCMS: 258 (M+H),
Step-3: Preparation of 8-methyl-6-(4-pyridyl)-[1 ,2,4]triazolo[3,4-f][1 ,2,4]triazine A microwave vial, under nitrogen atmosphere, was charged with N-(dimethylaminomethylene)-N'- (1 ,2,4-triazol-4-yl)pyridine-4-carboxamidine (0.6 g) and acetic acid (7 mL). The mixture was heated at 150°C under microwave irradiation for 40 minutes. The reaction mixture was concentrated and purified by silica gel chromatography eluting with a mixture of ethyl acetate and cyclohexane to give 8- methyl-6-(4-pyridyl)-[1 ,2,4]triazolo[3,4-f][1 ,2,4]triazine as an off-white solid.
1H NMR (400 MHz, CD3OD) 9.64 (s, 1 H), 8.77 (d, 2H), 8.39 (d, 2H), 3.08 (s, 3H)
Example 39: Preparation of 5-(4-pyridyl)-[1 ,2,4]triazolo[1 ,5-c]pyrimidine
Figure imgf000116_0001
To a microwave vial, purged with nitrogen, was added the 5-chloro-[1 ,2,4]triazolo[1 ,5-c]pyrimidine (0.2 g), 1 ,T-bis(diphenylphosphino)ferrocene-palladium(ll)dichloride dichloromethane complex (0.109 g), 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridine (0.328 g) and potassium phosphate tribasic (0.841 g). To the resulting mixture was added 1 ,4-dioxane (3.88 mL) and water (1 .29 mL), followed by purging with nitrogen. The mixture was heated under microwave irradiation at 150°C for 20 minutes. Partitioned the mixture between dichloromethane and water, evaporated the organic layer to give 5-(4- pyridyl)-[1 ,2,4]triazolo[1 ,5-c]pyrimidine, which was used without further purification.
1H NMR (400 MHz, DMSO-d6) 8.90 (br d, 2H), 8.82 (s, 1 H), 8.53 (d, 1 H), 8.47 - 8.42 (m, 2H), 8.07 - 8.02 (m, 1 H)
Table A - Physical Data for Compounds of the Invention
Figure imgf000116_0002
Figure imgf000117_0001
Figure imgf000118_0001
Figure imgf000119_0001
Figure imgf000120_0001
Figure imgf000121_0001
Figure imgf000122_0001
Figure imgf000123_0001
Figure imgf000124_0001
Figure imgf000125_0001
Figure imgf000126_0001
Figure imgf000127_0001
Figure imgf000128_0001
Figure imgf000129_0001
Figure imgf000130_0001
Figure imgf000131_0001
BIOLOGICAL EXAMPLES Post-emergence efficacy Seeds of a variety of test species were sown in standard soil in pots. After cultivation for 14 days (post- emergence) under controlled conditions in a glasshouse (at 24/16 °C, day/night; 14 hours light; 65 % humidity), the plants were sprayed with an aqueous spray solution derived from the dissolution of the technical active ingredient formula (I) in a small amount of acetone and a special solvent and emulsifier mixture referred to as IF50 (11.12% Emulsogen EL360 TM + 44.44% N-methylpyrrolidone + 44.44% Dowanol DPM glycol ether), to create a 50g/l solution which was then diluted to required concentration using 0.25% or 1% Empicol ESC70 (Sodium lauryl ether sulphate) + 1% ammonium sulphate as diluent. The test plants were then grown in a glasshouse under controlled conditions (at 24/16 °C, day/night; 14 hours light; 65 % humidity) and watered twice daily. After 13 days the test was evaluated (100 = total damage to plant; 0 = no damage to plant).
The results are shown in Table B (below). A value of n/a indicates that this combination of weed and test compound was not tested/assessed.
Test plants: Ipomoea hederacea (IPOHE), Euphorbia heterophylla (EPHHL), Chenopodium album (CHEAL), Amaranthus palmeri (AMAPA), Lolium perenne (LOLPE), Digitaria sanguinalis (DIGSA), Eleusine indica (ELEIN), Echinochloa crus-galli (ECHCG), Setaria faberi (SETFA)
Table B - Control of weed species by compounds of formula (I) after post-emergence application
Figure imgf000131_0002
Figure imgf000132_0001
Figure imgf000133_0001

Claims

CLAIMS:
1. Use of a compound of formula (I) or an agronomically acceptable salt or zwitterionic species thereof, as a herbicide:
Figure imgf000134_0001
wherein
R1 is selected from the group consisting of hydrogen, halogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, C1-C6haloalkyl, -OR7, -OR15a, -N(R6)S(O)2R15, -N(R6)C(O)R15, -N(R6)C(O)OR15, - N(R6)C(O)NR16R17, -N(R6)CHO, -N(R7a)2 and -S(O)rR15;
R2 is selected from the group consisting of hydrogen, halogen, C1-C6alkyl and C1-C6haloalkyl; and wherein when R1 is selected from the group consisting of -OR7, -OR15a, -N(R6)S(O)2R15, - N(R6)C(O)R15, -N(R6)C(O)OR15, -N(R6)C(O)NR16R17, -N(R6)CHO, -N(R7a)2 and -S(O)rR15, R2 is selected from the group consisting of hydrogen and C1-C6alkyl; or
R1 and R2 together with the carbon atom to which they are attached form a C3-C6cycloalkyl ring or a 3- to 6- membered heterocyclyl, which comprises 1 or 2 heteroatoms individually selected from N and O; and
Q is (CR1aR2b)m; m is 0, 1 , 2 or 3; each R1a and R2b are independently selected from the group consisting of hydrogen, halogen, C1-C6alkyl, C1-C6haloalkyl, -OH, -OR7, -OR15a, -NH2, -NHR7, -NHR15a, -N(R6)CHO, -NR7bR7c and -S(O)rR15; or each R1a and R2b together with the carbon atom to which they are attached form a C3-C6cycloalkyl ring or a 3- to 6- membered heterocyclyl, which comprises 1 or 2 heteroatoms individually selected from N and O; and R3, R3a, R4 and R5 are independently selected from the group consisting of hydrogen, halogen, cyano, nitro, -S(O)rR15, C1-C6alkyl, C1-C6fluoroalkyl, C1-C6fluoroalkoxy, C1-C6alkoxy, C3-C6cycloalkyl and - N(R6)2; each R6 is independently selected from hydrogen and C1-C6alkyl; each R7 is independently selected from the group consisting of C1-C6alkyl, -S(O)2R15, -C(O)R15, - C(O)OR15 and -C(O)NR16R17; each R7a is independently selected from the group consisting of -S(O)2R15, -C(O)R15, -C(O)OR15 - C(O)NR16R17 and -C(O)NR6R15a;
R7b and R7c are independently selected from the group consisting of C1-C6alkyl, -S(O)2R15, -C(O)R15, - C(O)OR15, -C(O)NR16R17 and phenyl, and wherein said phenyl is optionally substituted by 1 , 2 or 3 R9 substituents, which may be the same or different; or
R7b and R7c together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclyl ring which optionally comprises one additional heteroatom individually selected from N, O and S; and
A is a fused bicyclic structure of general formula;
Figure imgf000135_0001
in which:
(i) ring A1 has 5 members and ring A2 has 6 members;
(ii) A includes at least one heteroatom selected from N, O and S, with the remainder being carbon atoms;
(iii) at least one of ring A1 and ring A2 is aromatic, or A as a whole is aromatic;
(iv) A is attached to the remainder of the compound of formula (I) at any available position of ring A2 provided it is a carbon atom;
(v) one of the carbon atoms is optionally a carbonyl;
(vi) A is optionally substituted in any available position in either or both of ring A1 or ring A2 by p substituents R8, which may be the same or different; and
(vii) p is 0 to 6; when A is substituted on one or more carbon atoms by R8, then each R8 is independently selected from the group consisting of halogen, nitro, cyano, -NH2, -NHR7, -N(R7)2, -OH, -OR7, -S(O)rR15, - NR6S(O)2R15, -C(O)OR10, -C(O)R15, -C(O)NR16R17, -S(O)2NR16R17, C1-C6alkyl, C1-C6haloalkyl, C3- C6cycloalkyl, C3-C6halocycloalkyl, C3-C6cycloalkoxy, C2-C6alkenyl, C2-C6haloalkenyl, C2-C6alkynyl, C1- C3alkoxyC1-C3alkyl-, hydroxyC1-C6alkyl-, C1-C3alkoxyC1-C3alkoxy-, C1-C6haloalkoxy, C1- C3haloalkoxyC1-C3alkyl-, C3-C6alkenyloxy, C3-C6alkynyloxy, N-C3-C6cycloalkylamino, -C(R6)=NOR6, phenyl, a 3- to 6- membered heterocyclyl, which comprises 1 or 2 heteroatoms individually selected from N and O, and a 5- or 6- membered heteroaryl, which comprises 1 , 2, 3 or 4 heteroatoms individually selected from N, O and S, and wherein said phenyl, heterocyclyl or heteroaryl moieties are optionally substituted by 1 , 2 or 3 substituents, which may be the same or different, selected from R9; and when A is substituted on one or more N atoms by one or more R8, then each R8 is independently selected from the group consisting of -OR7, -S(O)rR12, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, C3- C6halocycloalkyl, C3-C6cycloalkoxy, C2-C6alkenyl, C2-C6haloalkenyl, C2-C6alkynyl, C1-C3alkoxyC1- C3alkyl-, hydroxyC2-C6alkyl-, C1-C6haloalkoxy, C1-C3haloalkoxyC1-C3alkyl-, C1-C6alkoxycarbonyl, C3- C6alkenyloxy, C3-C6alkynyloxy, C1-C6alkylcarbonyl, C1-C6alkylaminocarbonyl, di-C1- C6alkylaminocarbonyl, phenyl and heteroaryl, wherein the heteroaryl moiety is a 5- or 6-membered monocyclic aromatic ring which comprises 1 , 2, 3 or 4 heteroatoms individually selected from N, O and S, and wherein any of said phenyl or heteroaryl moieties are optionally substituted by 1 , 2 or 3 substituents, which may be the same or different, selected from R9; each R9 is independently selected from the group consisting of halogen, cyano, -OH, -N(R6)2, C1-C4alkyl, C1-C4alkoxy, C1-C4haloalkyl and C1-C4haloalkoxy;
X is selected from the group consisting of C3-C6cycloalkyl, phenyl, a 5- or 6- membered heteroaryl, which comprises 1 , 2, 3 or 4 heteroatoms individually selected from N, O and S, and a 4- to 6- membered heterocyclyl, which comprises 1 , 2 or 3 heteroatoms individually selected from N, O and S, and wherein said cycloalkyl, phenyl, heteroaryl or heterocyclyl moieties are optionally substituted by 1 or 2 substituents, which may be the same or different, selected from R9, and wherein the aforementioned CR1R2, Q and Z moieties may be attached at any position of said cycloalkyl, phenyl, heteroaryl or heterocyclyl moieties; n is 0 or 1 ;
Z is selected from the group consisting 0f -C(O)OR10, -CH2OH, -CHO, -C(O)NHOR11, -C(O)NHCN, - OC(O)NHOR11, -OC(O)NHCN, -NR6C(O)NHOR11, -NR6C(O)NHCN, -C(O)NHS(O)2R12, - OC(O)NHS(O)2R12, -NR6C(O)NHS(O)2R12, -S(O)2OR10, -OS(O)2OR10, -NR6S(O)2OR10, -NR6S(O)OR10, -NHS(O)2R14, -S(O)OR10, -OS(O)OR10, -S(O)2NHCN, -S(O)2NHC(O)R18, -S(O)2NHS(O)2R12, - OS(O)2NHCN, -OS(O)2NHS(O)2R12, -OS(O)2NHC(O)R18, -NR6S(O)2NHCN, -NR6S(O)2NHC(O)R18, - N(OH)C(O)R15, -ONHC(O)R15, -NR6S(O)2NHS(O)2R12, -P(O)(R13)(OR10), -P(O)H(OR10), - OP(O)(R13)(OR10), -NR6P(O)(R13)(OR10) and tetrazole; R10 is selected from the group consisting of hydrogen, C1-C6alkyl, phenyl and benzyl, and wherein said phenyl or benzyl are optionally substituted by 1 , 2 or 3 R9 substituents, which may be the same or different;
R11 is selected from the group consisting of hydrogen, C1-C6alkyl and phenyl, and wherein said phenyl is optionally substituted by 1 , 2 or 3 R9 substituents, which may be the same or different;
R12 is selected from the group consisting of C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, -OH, -N(R6)2 and phenyl, and wherein said phenyl is optionally substituted by 1 , 2 or 3 R9 substituents, which may be the same or different;
R13 is selected from the group consisting of -OH, C1-C6alkyl, C1-C6alkoxy and phenyl;
R14 is C1-C6haloalkyl;
R15 is selected from the group consisting of C1-C6alkyl and phenyl, and wherein said phenyl is optionally substituted by 1 , 2 or 3 R9 substituents, which may be the same or different;
R15a is phenyl, wherein said phenyl is optionally substituted by 1 , 2 or 3 R9 substituents, which may be the same or different;
R16 and R17 are independently selected from the group consisting of hydrogen and C1-C6alkyl; or R16 and R17 together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclyl ring which optionally comprises one additional heteroatom individually selected from N, O and S; and
R18 is selected from the group consisting of hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, -N(R6)2 and phenyl, and wherein said phenyl is optionally substituted by 1 , 2 or 3 R9 substituents, which may be the same or different; and r is 0, 1 or 2.
2. A compound of formula (I) or an agronomically acceptable salt or zwitterionic species thereof, as defined in claim 1 , with the proviso that the compound of formula (I) is not
Figure imgf000138_0001
2-[4-(3-aminopyrazolo[1 ,5-a]pyridin-5-yl)pyridin-1-ium-1-yl]ethanol.
3. A compound according to claim 2, wherein R1 and R2 are independently selected from the group consisting of hydrogen and C1-C6alkyl.
4. A compound according to claim 2 or claim 3, wherein R1 and R2 are hydrogen.
5. A compound according to any one of claims 2 to 4, wherein each R1a and R2b are independently selected from the group consisting of hydrogen, C1-C6alkyl, -OH and -NH2.
6. A compound according to any one of claims 2 to 5, wherein R1a and R2b are hydrogen.
7. A compound according to any one of claims 2 to 6, wherein m is 0, 1 or 2.
8. A compound according to any one of claims 2 to 7, wherein R3, R3a, R4 and R5 are hydrogen.
9. A compound according to any one of claims 2 to 8, wherein A as a whole is aromatic.
10. A compound according to any one of claims 2 to 9, wherein A is selected from the group consisting of formula A-l to A-LXXI below
Figure imgf000139_0001
Figure imgf000140_0001
wherein the jagged line defines the point of attachment to the remaining part of a compound of formula (I).
11. A compound according to any one of claims 2 to 10, wherein A is selected from the group consisting of formula AXLIII to A-LXXI below
Figure imgf000141_0001
wherein the jagged line defines the point of attachment to the remaining part of a compound of formula
(I)·
12. A compound according to any one of claims 2 to 11 , in which when A is substituted on one or more ring carbon atoms, each R8 is independently selected from the group consisting of chloro, fluoro, cyano, -NH2, -N(Me)2, -OH, -OMe, -S(O)2Me, -C(O)OMe, -C(O)OH, -C(O)Me, -C(O)NH2, -C(O)NHMe, -C(O)N(Me)2, methyl, ethyl and trifluoromethyl.
13. A compound according to any one of claims 2 to 12, in which when A is substituted on one or more N atoms by one or more R8, then each R8 is independently methyl or ethyl.
14. A compound according to any one of claims 2 to 13 in which p is 0 or 1 .
15. A compound according to any one of claims 2 to 14, wherein Z is selected from the group consisting of -C(O)OR10, -C(O)NHS(O)2R12, -S(O)2OR10, and -P(O)(R13)(OR10).
16. A compound according to any one of claims 2 to 15, wherein Z is -C(O)OH or -S(O)2OH.
17. A compound according to any one of claims 2 to 16, wherein n is 0.
18. The use of a compound of formula (I) as defined in any one of claims 2 to 17, or an agronomically acceptable salt or zwitterionic species thereof, as a herbicide.
19. An agrochemical composition comprising a herbicidally effective amount of a compound of formula (I) as defined in any one of claims 1 to 17 and an agrochemically-acceptable diluent or carrier.
20. A method of controlling unwanted plant growth, comprising applying a compound of formula (I) as defined in any one of claims 1 to 17, or a composition according to claim 19, to the unwanted plants or to the locus thereof.
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