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WO2010046215A2 - Diaza-indole derivatives and their use as fungicides - Google Patents

Diaza-indole derivatives and their use as fungicides Download PDF

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Publication number
WO2010046215A2
WO2010046215A2 PCT/EP2009/062673 EP2009062673W WO2010046215A2 WO 2010046215 A2 WO2010046215 A2 WO 2010046215A2 EP 2009062673 W EP2009062673 W EP 2009062673W WO 2010046215 A2 WO2010046215 A2 WO 2010046215A2
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Prior art keywords
optionally substituted
hydrogen
alkyl
halogen
alkenyl
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PCT/EP2009/062673
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French (fr)
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WO2010046215A3 (en
Inventor
Patrice Selles
Nityakalyani Srinivas
Raphael Dumeunier
Frederik Cederbaum
Jayant Umarye
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Syngenta Participations AG
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Syngenta Participations AG
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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
    • A01N43/90—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
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • 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

Definitions

  • the present invention relates to novel fungicidally active diaza-indoles, compositions comprising these novel compounds and their use in methods for the control and/or prevention of fungal infection in plants.
  • the invention relates to processes for preparing the novel compounds of the invention.
  • the present invention provides a method of preventing and/or controlling a fungal infection in a plant and/or plant propagation material, comprising applying to the plant or plant propagation material a compound of formula (I):
  • any one of G 1 , G 2 and G 3 is N and the other two of G 1 , G 2 and G 3 are CR 8 , CR 1 or CR 2 , such that when G 1 is not N, G 1 is CR 8 ; when G 2 is not N, G 2 is CR 1 ; when G 3 is not N, G 3 is CR 2 ;
  • X 1 is N or CH
  • X 2 is N or CR 5 ;
  • R 1 Is:
  • R 2 is:
  • R 3 is:
  • R 4 is:
  • R 5 is: (i) hydrogen, halogen, hydro xyl, cyano or nitro,
  • R 6 is:
  • R 7 is:
  • R 8 is:
  • R 10 , R 11 , R 14 , R 15 , R 16 and R 17 are, independently: (i) hydrogen, halogen, hydroxyl, cyano or nitro; (ii) optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkenyl or optionally substituted alkynyl, or (iii) optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl or optionally substituted cycloalkenyl;
  • R 12 and R 13 are, independently:
  • R 18 and R 19 are, independently: (i) hydrogen, (ii) optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl,
  • R 20 is: (i) hydroxyl
  • R 21 and R 22 are, independently: (i) hydrogen,
  • R 23 and R 24 are, independently:
  • R 25 is optionally susbstituted alkyl, optionally susbstituted alkenyl or optionally susbstituted alkynyl;
  • R 1 and R 2 optionally: independently, (i) R 1 and R 2 , (ii) R 1 and R 3 (iii) R 2 and R 3 , (iv) R 3 and R 5 , (v) R 5 : and R 6 , (vi) R 5 and R 18 , (vii) R 5 and R 19 , (viii) R 14 and R 15 and/or (ix) R 18 and R 19 form an optionally substituted aryl, optionally susbstituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl or optionally substituted cycloalkenyl containing from 5 to 18 ring atoms;
  • Alkyl means a linear saturated monovalent hydrocarbon radical of one to eight carbon atoms or a branched saturated monovalent hydrocarbon radical of three to eight carbon atoms, e.g. methyl, ethyl, n-propyl, ⁇ o-propyl, n-butyl, sec-butyl, ⁇ o-butyl, tert- butyl, n-pentyl, n-hexyl and the like.
  • linear alkyl groups contain one to six carbon atoms, more preferably one to four carbon atoms and most preferably are selected from methyl, ethyl or n-propyl.
  • branched alkyl groups contain three to six carbon atoms and more preferably are selected from ⁇ o-propyl, sec-butyl, ⁇ o-butyl or tert- butyl.
  • alkenyl means a linear monovalent hydrocarbon radical of two to eight carbon atoms, or a branched monovalent hydrocarbon radical of three to eight carbon atoms containing at least one double bond, e.g. ethenyl, propenyl and the like. Where appropriate, an alkenyl group can be of either the (E)- or (Z)-configuration.
  • linear alkenyl groups contain two to six carbon atoms and more preferably are selected from ethenyl, prop- 1-enyl, prop-2-enyl, prop-l,2-dienyl, but-1-enyl, but-2-enyl, but-3-enyl, but-l,2-dienyl and but-l,3-dienyl.
  • branched alkenyl groups contain three to six carbon atoms and more preferably are selected from 1-methylethenyl, 1-methylprop- 1-enyl, l-methylprop-2- enyl, 2-methylprop- 1-enyl and 2-methylprop-2-enyl.
  • an alkenyl group may contain at least two double bonds between three contiguous carbon atoms, e.g. prop- 1,2 dienyl, penta-1,2 dienyl, penta-2,3 dienyl, hexa-l,2-dienyl and the like.
  • such an alkenyl group can be of either the (R)- or ( ⁇ -configuration.
  • Preferred is prop- 1,2- dienyl.
  • Alkynyl means a linear monovalent hydrocarbon radical of two to eight carbon atoms, or a branched monovalent hydrocarbon radical of four to eight carbon atoms, containing at least one triple bond, e.g. ethynyl, propynyl and the like.
  • linear alkynyl groups contain two to six carbon atoms and more preferably are selected from ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl and but-3-ynyl.
  • branched alkynyl groups contain four to six carbon atoms and more preferably are selected from l-methylprop-2-ynyl, 3-methylbut-l-ynyl, l-methylbut-2-ynyl, l-methylbut-3-ynyl and 2-methylbut-3 -ynyl.
  • Alkylene means a linear saturated divalent hydrocarbon radical of one to six carbon atoms or a branched saturated divalent hydrocarbon radical or three to six carbon atoms, e.g. methylene, ethylene, propylene, 2-methylpropylene and the like.
  • Preferred alkylene groups are the divalent radicals of the alkyl groups defined above.
  • alkenylene means a linear divalent hydrocarbon radical of two to six carbon atoms or a branched divalent hydrocarbon radical of three to six carbon atoms, containing at least one double bond, e.g. ethenylene, propenylene and the like.
  • Preferred alkenylene groups are the divalent radicals of the alkenyl groups defined above.
  • Cycloalkyl means a saturated monovalent cyclic hydrocarbon radical of three to eight ring carbons.
  • cycloalkyl groups contain three to six ring carbons, more preferably they are selected from cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • Cycloalkenyl means a monovalent cyclic mono- or di-unsaturated hyrodcarbon radical of three to eight ring carbons, preferably four to six ring carbons, e.g. cyclobutenyl, cyclopentenyl and cyclohexenyl.
  • Heterocycloalkyl means a monovalent cyclic radical of three to eight ring atoms, preferably 3-6 or 4-6 ring atoms, containing one, two or three ring heteroatoms independently selected from N, O and S(O) n (where n is an integer from 0 to 2), the remaining ring atoms being carbon where one or two carbon atoms may be a carbonyl group, in which there are no double or triple double bonds linking the ring atoms.
  • rings include, but are not limited to, oxirane, oxetane, tetrahydrofuran, tetrahydropyran, 1,3- dioxolane, 1 ,4-dioxane, aziridine, azetidine, pyrrolidine, piperidine, oxazinane, morpholine, thiomorpholine, imidazolidine, pyrazolidine and piperazine. More preferably, the heterocycloalkyl group contains three to five ring atoms including one O and/or one N ring atom.
  • Aryl means a monovalent moncyclic or bicyclic aromatic hydrocarbon radical of six to ten ring carbons atoms. Suitable aryl groups include phenyl and naphthyl, in particular, phenyl.
  • Heteroaryl means a monovalent monocyclic or bicyclic aromatic hydrocarbon radical of five to ten ring atoms, preferably five or six ring atoms, containing one, two, three or four ring heteroatoms selected, independently, from N, O or S, the remaining ring atoms being carbon.
  • heteroaryl groups include, but are not limited to pyridyl, pyrimidinyl, pyrazolyl, thiazolyl, thiophenyl, isoazolyl, and tetrazolyl groups.
  • Heterocyclic ring or “ heterocycle” means a saturated or fully unsaturated or partially unsaturated monovalent cyclic radical of three to eight ring atoms, preferably 3-6 or 4-6 ring atoms, containing one, two or three ring heteroatoms independently selected from N, O and S(O) n (where n is an integer from 0 to 2).
  • a heterocyclic ring may be a heteroaryl group or a heterocycloalkyl group as defined above.
  • Alkoxy means a monovalent radical -OR, where R is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, or optionally substituted heteroaryl.
  • R may be an optionally substituted Ci_6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-6 cycloalkyl, optionally substituted 3-6 membered heterocycloalkyl, optionally substituted C 4 - 6 cycloalkenyl, optionally substituted phenyl, or optionally substituted heterophenyl.
  • R may be an optionally substituted aralkyl or optionally substituted heteroaralkyl group.
  • an alkoxy group is selected from methoxy, ethoxy, 1-methylethoxy, propoxy, 1-methylpropoxy and 2-methylpropoxy. More preferably alkoxy means methoxy or ethoxy.
  • Alkoxyalkyl means a monovalent linear radical -R a OR b , wherein R a is an optionally substituted alkyl group, e.g. optionally substituted Ci_6 alkyl, and R b is an optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl group, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl or optionally substituted heteroaryl group.
  • R b may be an optionally substituted Ci_6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C 3-6 cycloalkyl, optionally substituted 3-6 membered heterocycloalkyl, optionally substituted C4-6 cycloalkenyl, optionally substituted phenyl, or optionally substituted heterophenyl.
  • R b may be an optionally substituted aralkyl or optionally substituted heteroaralkyl group, as defined herein.
  • Halo or halogen means fluoro, chloro, bromo or iodo, preferably chloro or fluoro.
  • Haloalkyl means alkyl as defined above substituted with one or more of the same or different halo atoms.
  • a substituted alkyl group may be a haloalkyl group.
  • haloalkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2-trifluoroethyl, 2-chloro-ethyl, 2-iodoethyl, 3-fluoropropyl, 3-chloropropyl, 2-trifluoro-l-chloroethyl and l-difluoro-2-difluoro-3-trifluoropropyl.
  • Haloalkenyl means alkenyl as defined above substituted with one or more of the same or different halo atoms.
  • a substituted alkenyl group may be a haloalkenyl group.
  • haloalkenyl groups include, but are not limited to 2-dibromoethenyl, 2-fluoro-2- bromoethenyl, 5-bromopent-3-enyl and 3-dichloroprop-2-enyl.
  • Alkyl means a monovalent radical -R a R b , wherein R a is an alkylene or alkenylene group and R b is an aryl group, each as defined above.
  • Hetero aralkyl means a monovalent radical -R a R b where R a is an alkylene or alkenylene group and R b is a heteroaryl group, each as defined above.
  • Acyl means a monovalent radical -C(O)R, wherein R is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl or optionally substituted heteroaryl.
  • R may be an optionally substituted Ci_6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C 3-6 cycloalkyl, optionally substituted 3-6 membered heterocycloalkyl, optionally substituted C 4-6 cycloalkenyl, optionally substituted phenyl, or optionally substituted heterophenyl.
  • Acyloxy means a monovalent radical -OC(O)R, wherein R is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl or optionally substituted heteroaryl.
  • R may be an optionally substituted Ci_6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C 3-6 cycloalkyl, optionally substituted 3-6 membered heterocycloalkyl, optionally substituted C 4-6 cycloalkenyl, optionally substituted phenyl, or optionally substituted heterophenyl.
  • alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl and heteroaryl groups may be unsubstitued, or may be substituted by one or more substituents independently selected from halogen, hydroxyl, cyano, alkyl (optionally substituted by cyano), e.g. d- 4 alkyl, haloalkyl, e.g. d- 4 haloalkyl, alkenyl, e.g. C2-4 alkenyl, haloalkenyl, e.g.
  • R and R' are, independently, hydrogen or alkyl (in particular, methyl or ethyl).
  • Preferred optional substituents are alkoxy (in particular, methoxy or ethoxy), hydroxyl, cyano, halogen (in particular, fluoro, chloro or bromo), heterocycloalkyl (in particular, oxirane or tetrahydrofuran), heteroaryl (in particular, pyridyl), -C(O)OR (wherein R is hydrogen or alkyl (in particular, methyl or ethyl)) and trialkylsilyl (in particular, trimethylsilyl).
  • alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl and heteroaryl groups may be independently selected from halogen, hydroxyl, Ci_ 4 alkyl, Ci_ 4 haloalkyl, -NH 2 , and cyano; in particular halogen.
  • the compounds of formula (I) may exist in different geometric or optical isomeric forms or in different tautomeric forms.
  • One or more centres of chirality may be present, in which case compounds of the formula (I) may be present as pure enantiomers, mixtures of enantiomers, pure diastereomers or mixtures of diastereomers.
  • Centres of tautomerisation may be present. This invention covers all such isomers and tautomers and mixtures thereof in all proportions as well as isotopic forms such as deuterated compounds.
  • Suitable salts of the compounds of formula (I) include acid addition salts such as those with an inorganic acid such as hydrochloric, hydrobromic, sulfuric, nitric or phosphoric acid, or an organic carboxylic acid such as oxalic, tartaric, lactic, butyric, toluic, hexanoic or phthalic acid, or a sulphonic acid such as methane, benzene or toluene sulphonic acid.
  • organic carboxylic acids include haloacids such as trifluoroacetic acid. This invention covers all such salts of compounds of formula (I).
  • N-oxides are oxidised forms of tertiary amines or oxidised forms of nitrogen containing heteroaromatic compounds. They are described in many books for example in "Heterocyclic N-oxides" by Angelo Albini and Silvio Pietra, CRC Press, Boca Raton, Florida, 1991. This invention covers all such N-oxide forms of compounds of formula (I).
  • the preferred groups for X 1 and X 2 and R 1 to R 25 are as set out below.
  • G 1 is CR 8
  • G 2 is CR 1
  • G 3 is N.
  • X 1 is CH.
  • X 2 is CR 5 . More preferably, X 2 is CH.
  • R 1 is:
  • R 1 is hydrogen, halogen, cyano, optionally substituted Ci_6 alkyl, optionally substituted C 2 -6 alkenyl, optionally substituted C 2 -6 alkynyl, optionally substituted aryl, e.g. optionally substituted phenyl, or -C(O)R 10 .
  • R 1 is hydrogen, chloro, bromo, cyano, methyl or 2-trimethylsilyl-ethynyl.
  • R 1 is hydrogen, chloro or methyl.
  • R 2 is: (i) hydrogen, or
  • R 2 is hydrogen or Ci_6 alkyl.
  • R 3 is: (i) hydrogen or hydroxyl, (ii) optionally substituted Ci_6 alkyl, optionally substituted C 2 -6 alkenyl or optionally substituted C 2 -6 alkynyl,
  • optionally substituted cycloalkyl e.g. optionally substituted C 3-6 cycloalkyl, or (iv) -C(O)R 12 , -OR 12 , -C(O)OR 12 , -OC(O)R 12 or -S(O) 2 R 12 ; wherein the optional substitutents in all cases are as defined above and, more preferably, are selected from cyano, halogen, hydroxyl, Ci_ 4 alkyl, C 2 - 4 alkenyl, alkoxy, e.g. -O-Ci_ 4 alkyl (optionally substituted by alkoxy, e.g.
  • acyl e.g. -(O)C-C 1-3 alkyl
  • cycloalkyl e.g. C3-6 cycloalkyl
  • cycloalkenyl e.g. C3-6 cycloalkenyl
  • heterocycloalkyl e.g. 3-6-membered heterocycloalkyl
  • aryl e.g. phenyl, heteroaryl, e.g. heterophenyl, -NH 2 , trialkylsilyl, -C(O)R and -C(O)OR
  • R is hydrogen, methyl or ethyl
  • R 3 is hydrogen, hydroxyl, -C(O)R 12 , -OR 12 , -C(O)OR 12 , -OC(O)R 12 ,
  • Ci_6 alkyl optionally substituted C 2 -6 alkenyl, optionally substituted C 2 -6 alkynyl, optionally substituted cycloalkyl, e.g. optionally substituted C 3 _6 cycloalkyl.
  • R 3 may be optionally substituted Ci_6 alkyl, optionally substituted C 2 -6 alkenyl or optionally susbtituted C 2 -6 alkynyl, wherein the optional substituents of the alkyl, alkenyl and alkynyl are selected from cyano, methoxy, and halogen.
  • R is C 3 _ 4 alkenyl or C 3 _ 4 alkynyl.
  • R 4 is: (i) hydrogen or halogen, (ii) optionally substituted C 2 -6 alkynyl, or (iii) optionally substituted aryl, e.g. optionally substituted phenyl, or optionally substituted heteroaryl, e.g. optionally substituted heterophenyl; wherein the optional substituents in all cases are as defined above and, more preferably, are selected from hydroxyl, halogen (in particular, fluoro or chloro), haloalkyl, e.g. Ci_ 4 haloalkyl, acyl, e.g. -(O)C-C 1-3 alkyl, and Ci_ 4 alkyl (in particular, methyl).
  • the Ci_ 4 alkyl may be Ci_ 4 haloalkyl.
  • R 4 is hydrogen, halogen, optionally substituted C 2 -6 alkynyl or optionally substituted aryl, e.g. optionally substituted phenyl, or optionally substituted heteroaryl, e.g. optionally substituted heterophenyl. Even more preferably, R 4 is phenyl, 3- methylphenyl, 3-trifluoromethylphenyl, 2-fluorophenyl, 3 -fluorophenyl, 4-fluorophenyl, 2,5- difluorophenyl, 3-methyl-4-fluorophenyl, 2,4-difluorophenyl, 2,6-diflurophenyl, or 2,4,6- diflurophenyl.
  • R 4 may be phenyl optionally substituted by 1 to 3 groups independently selected from Ci_ 4 alkyl, Ci_ 4 haloalkyl and halogen, e.g. R4 is phenyl optionally substituted by 1-3 halogen atoms.
  • R 5 is: (i) hydrogen, or halogen
  • Ci_6 alkyl optionally substituted C 2 -6 alkenyl or optionally substituted C 2 -6 alkynyl, or
  • optionally substituted aryl e.g. optionally substituted phenyl, optionally substituted heteroaryl, e.g. optionally substituted heterophenyl, optionally substituted cycloalkyl, e.g. optionally substituted C 3-6 cycloalkyl, optionally substituted cycloalkenyl, e.g. optionally substituted C 4 -6 cycloalkenyl, or an optionally substituted heterocycylic ring formed with R 6 , e.g. a 5 or 6 membered heterocycle; wherein the optional substituents in all cases are as defined above and, more preferably, are selected from halogen, cyano, hydroxyl, Ci_ 4 haloalkyl and Ci_ 4 alkyl.
  • R 5 is hydrogen or halogen.
  • R 6 is:
  • optionally substituted aryl e.g. optionally substituted phenyl, optionally substituted heteroaryl, e.g. optionally substituted heterophenyl, optionally substituted cycloalkyl, e.g. optionally substituted C3-6 cycloalkyl, optionally substituted cycloalkenyl, e.g. optionally substituted C4-6 cycloalkenyl, or an optionally substituted heterocyclic ring formed with R 5 as defined above, e.g. a 5 or 6 membered heterocycle; or (iii) -C(O)OR 18 , -NR 18 R 19 (e.g.
  • R 6 is hydrogen or -NR 18 R 19 , e.g. -NHR 19 .
  • R 6 is -
  • R 23 is preferably Ci_4 alkyl, e.g. ethyl, isopropyl, or cyclopropyl or cyclobutyl.
  • R 6 may be hydrogen or -NHR 19 in which R 19 is hydrogen, Ci_ 4 alkyl optionally substituted with hydroxy or Ci_4 alkoxy which in turn may be substituted by hydroxy, or R 19 is -C(O)R 23 , and R 23 is Ci_ 4 alkyl, C 2 - 4 alkenyl, C 2 - 4 alkynyl, or C 3 - 4 cycloalkyl.
  • R 7 and R 8 are, independently: (i) hydrogen, hydroxyl, or cyano, optionally substituted Ci_6 alkyl, wherein the optional subsituents are as defined above and, more preferably, are selected from halogen, cyano, hydroxyl and haloalkyl e.g. Ci_ 4 haloalkyl, or (ii) -NR 21 R 22 ;
  • R 7 and R 8 are, independently, hydrogen, hydroxyl, cyano -NR 21 R 22 , or optionally substituted Ci_6 alkyl. Most preferably, R 7 and R 8 are, independently, hydrogen, hydroxyl or NR 21 R 22 .
  • R 10 , R 11 , R 14 , R 15 , R 16 and R 17 are, independently: (i) hydrogen, or (ii) optionally substituted Ci_6 alkyl, optionally substituted C 2 _6 alkenyl or optionally substituted C 2 _6 alkynyl, wherein the optional substituents are as defined above and, more preferably, are selected from hydroxyl, halogen, cyano and alkoxy, e.g. -O-Ci_4 alkyl.
  • R 10 , R 11 , R 14 , R 15 , R 16 and R 17 are, independently, hydrogen or optionally substituted Ci_ 3 alkyl. Most preferably, R 10 , R 11 , R 14 , R 15 , R 16 and R 17 are, independently, hydrogen, methyl or ethyl.
  • R 12 and R 13 are, independently: (i) optionally substituted Ci_6 alkyl, optionally substituted C 2 -6 alkenyl, optionally substituted C2-6 alkynyl, or (ii) optionally substituted C3-6 cycloalkyl or optionally substituted C 4 -6 cycloalkenyl; wherein optional substituents in all cases are as defined above and, more preferably are selected from hydroxyl, halogen, cyano, alkoxy, e.g. -O-Ci_ 4 alkyl, cycloalkyl (optionally substituted with hydroxyl or methyl), e.g.
  • R 12 and R 13 are, independently, optionally substituted Ci_ 4 alkyl, including Ci_ 4 alkyl-0-Ci_ 4 alkyl, optionally substituted C 2 - 4 alkenyl or optionally substituted C 2 - 4 alkynyl. Most preferably, R 12 and R 13 are, independently, cyanomethyl, (1-methyl)- cyanomethyl, prop-2-enyl, prop-2-ynyl or methoxymethyl.
  • R 18 is:
  • an optionally substituted heterocyclic ring formed with R 19 e.g. a 5 or 6 membered heterocyclic ring, or
  • R 18 is hydrogen, Ci_ 4 alkyl, C 2 - 4 alkenyl, or C 2 - 4 alkynyl. More preferably Ri 8 is hydrogen, ethyl, ⁇ o-propyl, prop-2-enyl, prop-2ynyl or but-2-ynyl.
  • R 19 is: (i) hydrogen
  • Ci_6 alkyl optionally substituted C 2 -6 alkenyl or optionally substituted C 2 -6 alkynyl
  • optionally substituted aryl e.g. optionally substituted phenyl, optionally substituted heteroaryl, e.g. optionally substituted heterophenyl, optionally substituted cycloalkyl, e.g. optionally substituted C3-6 cycloalkyl, optionally substituted cycloalkenyl, e.g. optionally substituted C 4 -6 cycloalkenyl, or optionally substituted heterocycloalkyl, e.g. a 3-6 member optionally substituted heterocycloalkyl, or an optionally substituted heterocyclic ring formed with R 18 , e.g. a 5 or 6 membered heterocyclic ring, or
  • R 19 is hydrogen, -C(S)R 23 , -C(O)R 23 or -C(O)OR 23 or optionally substituted d_ 4 alkyl. Most preferably, R 19 is hydrogen, ⁇ o-butyl, -C(O)R 23 or -C(O)OR 23 .
  • R 20 is -NR 21 R 22 ;
  • R 21 and R 22 are, independently: (i) hydrogen,
  • Ci_6 alkyl e.g. Ci_ 4 alkyl
  • optional substituents are as defined above and, more preferably, are selected from hydroxyl, cyano, halogen, alkoxy, e.g. -O-Ci_ 4 alkyl, acyl, e.g. -(O)C-C 1-3 acyl, cycloalkyl, e.g. C3-6 cycloalkyl, cycloalkenyl, e.g. C 4 -6 cycloalkenyl, heterocycloalkyl, e.g. a 3-6-membered heterocycloalkyl, or
  • R 21 and R 22 are, independently, hydrogen or optionally substituted
  • R 21 and R 22 are, independently, hydrogen, methyl or ethyl.
  • R 23 and R 24 are, independently:
  • optionally substituted cycloalkyl e.g. optionally substituted C 3 _6 cycloalkyl, optionally substituted cycloalkenyl, e.g. optionally substituted C 4 _ 6 cycloalkenyl or optionally substituted aryl, e.g. optionally substituted phenyl; wherein the optional substituents in all cases are as defined above and, more preferably, are selected from hydroxyl, halogen, cyano, Ci_ 4 alkyl, alkoxy, e.g. -O-Ci_ 4 alkyl, cycloalkyl, e.g. C3-6 cycloalkenyl, cycloalkenyl e.g.
  • R is cycloalkyl, e.g. C3-6 cycloalkyl, or cycloalkenyl, e.g. C4-6 cycloalkenyl).
  • R 23 and R 24 are, independently, hydrogen, hydroxyl, optionally substituted Ci_6 alkyl, e.g. Ci-6 alkyl-O-Ci_6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted cycloalkyl, e.g. optionally substituted C 3-6 cycloalkyl, or optionally substituted cycloalkenyl, e.g. optionally substituted C 4-6 cycloalkenyl.
  • Ci_6 alkyl e.g. Ci-6 alkyl-O-Ci_6 alkyl
  • C2-6 alkenyl optionally substituted cycloalkyl, e.g. optionally substituted C 3-6 cycloalkyl
  • optionally substituted cycloalkenyl e.g. optionally substituted C 4-6 cycloalkenyl.
  • R 23 and R 24 are, independently, methyl, ethyl, ⁇ o-propyl, methoxymethyl, cyclopropyl or cyclo butyl, in which the cyclopropyl or cyclo butyl group may be substituted with one or more substituents being selected from cyano, halogen (preferably fluoro), Ci_4 alkyl (preferably methyl or ethyl) or haloalkenyl.
  • R 25 is Ci_4 alkyl. More preferably, R 25 is methyl, ethyl, propyl or 2- dimethylethyl.
  • R 3 when R 3 is hydrogen, R 6 is other than hydrogen. More preferably, R 3 is hydrogen and R 6 is -NR 18 R 19 . More preferably, R 3 is hydrogen and R 6 is -NHR 19 . More preferably, R 3 is hydrogen and R 6 is -NHC(O)R 23 .
  • R 6 is hydrogen and R 3 is other than hydrogen. More preferably, R 6 is hydrogen and R 3 is -OR 12 or optionally substituted Ci_6 alkyl, C2-4 alkenyl, e.g. C3_4 allenyl, or C2-4 alkynyl. Most preferably, R 6 is hydrogen and R 3 is cyanomethyl, aminoethyl, aminopropyl, prop-2-enyl, prop-2-ynyl, prop-l,2-dienyl, methoxymethyl, 2-fluoromethyl, -OCH 2 C ⁇ CH, -OCH 2 OCH 3 , -OCH 2 CN, -OCH(CH 3 )CN.
  • the method of the invention may utilise a compound of the formula (Ia):
  • X 1 , X 2 , R 1 , R 2 , R 3 , R 4 , R 6 , and R 7 are as defined above for the compound of formula (I), in any combination thereof.
  • the method of the invention may utilise a compound of the formula (Ib):
  • the method of the invention may utilise a compound of the formula (Ic):
  • the method of the invention utilises a compound of formula (Id):
  • any one of G 1 , G 2 and G 3 is N and the other two of G 1 , G 2 and G 3 are CR 8 , CR 1 or CR 2 , such that when G 1 is not N, G 1 is CR 8 ; when G 2 is not N, G 2 is CR 1 ; when G 3 is not N, G 3 is CR 2 ; R 1 , R 2 , R 3 , R 4 , R 6 and R 8 are as defined for formula (I) above, in any combination thereof; and, preferably, in any combination:
  • R 1 is hydrogen, halogen, cyano, optionally substituted Ci_ 6 alkyl (in particular, optionally substituted Ci_ 4 alkyl and, most particularly, optionally substituted methyl or ethyl, wherein the optional substitutent is as defined above and more preferably is hydroxyl, e.g. 1-hydroxylethyl) or -C(O)R 10 in which R 10 is hydrogen or Ci_ 4 alkyl;
  • R 2 is hydrogen, halogen or Ci_ 4 alkyl
  • R 3 is hydrogen, hydroxyl, cyano, optionally substituted Ci_6 alkyl, optionally substituted C2-6 alkenyl, including optionally substituted C 3-6 allenyl, optionally substituted C2-6 alkynyl, -NR 12 R 13 , -OR 12 or -C(O)R 12 , wherein:
  • the optional substituents on the alkyl, alkenyl and alkynyl groups are as defined above and, more preferably, are independently selected from halo, cyano, hydroxyl, alkoxy (optionally substituted by alkoxy or acyl), e.g. -O-Ci_ 4 alkyl, Ci_ 4 alkyl, C 2 - 4 alkenyl, cycloalkyl, e.g. C3-6 cycloalkyl, cycloalkenyl, e.g. C 4 -6 cycloalkenyl, heterocycloalkyl, e.g. 3-6 membered heterocycloalkyl, aryl, e.g. phenyl, heteroaryl, e.g. heterophenyl,
  • R is hydrogen, Ci_ 4 alkyl, C 2 - 4 alkenyl or C 2 - 4 alkynyl, and
  • R 12 and R 13 are, independently, optionally substituted alkyl, e.g. optionally substituted Ci_6 alkyl, optionally substituted alkenyl, e.g. optionally substituted C 2 -6 alkenyl, optionally substituted alkynyl, e.g. optionally substituted C 2 -6 alkenyl, optionally substituted cycloalkyl, e.g. optionally substituted C3-6 cycloalkyl, or optionally substituted cycloalkenyl, e.g. optionally substituted C 4 _6 cycloalkenyl; the optional substituents being as defined above and, more preferably, halo, cyano, hydroxyl, alkoxy, e.g.
  • cycloalkyl e.g. C 3-6 cycloalkyl
  • cycloalkenyl e.g. C 4 _6 cycloalkenyl
  • heterocycloalkyl e.g. 3-6 membered heterocycloalkyl, -C(O)R, -C(O)OR or -OS(O)NRR', wherein R and R' are, independently, hydrogen or alkyl, e.g.
  • Ci_ 4 alkyl is optionally substituted aryl (in particular, optionally substituted phenyl or optionally substituted naphthyl), the optional substituents being as defined above and, more preferably halogen or Ci_4 alkyl;
  • R 6 is hydrogen, halogen or -NR 18 R 19 , wherein:
  • R 18 is hydrogen, -C(O)R 23 , -C(O)OR 23 or optionally substituted Ci_ 4 alkyl, optionally substituted C2-4 alkenyl or optionally substituted C2-4 alkynyl, in which R 23 is optionally substituted Ci_4 alkyl, the optional substituents being as defined above, and
  • R 19 is hydrogen, optionally substituted Ci_4 alkyl, optionally substituted C2-4 alkenyl, optionally substituted C 2 - 4 alkynyl, -C(S)R 23 -C(O)R 23 or -C(O)OR 23 , in which R 23 is hydrogen, optionally substituted Ci_4 alkyl, optionally substituted C2-4 alkenyl, optionally substituted C2-4 alkynyl, optionally substituted C 3-6 cycloalkyl or optionally substituted C 3-6 cycloalkenyl, the optional substituents being as defined above;
  • R 8 is hydrogen, halogen or Ci_4 alkyl.
  • R 1 is hydrogen, halo or optionally substituted Ci_4 alkyl, wherein the optional substituent is preferably hydro xyl;
  • R 2 and R 8 are, independently: hydrogen, methyl, ethyl or chloro;
  • R 3 is hydrogen, -OR 12 , optionally substituted Ci_4 alkyl, optionally substituted C2-4 alkenyl, or optionally substituted C2-4 alkynyl;
  • R 4 is phenyl, which is optionally substituted by at least one substituent selected from halogen and Ci_ 4 alkyl (in particular, methyl);
  • R 6 is halogen or -NR 18 R 19 , wherein R 18 is hydrogen, prop-2-enyl or prop-2-ynyl, and R 19 is -C(O)R 23 , in which R 23 is hydrogen, methyl, ethyl, ⁇ o-propyl, 1-methylethyl, 1-methylpropyl, 2-dimethylethyl, propyl, 1-
  • R 1 is hydrogen, chloro or methyl
  • R 2 and R 8 are, independently, hydrogen, methyl, ethyl or chloro
  • R 3 is hydrogen, cyanomethyl, prop- 2-enyl or prop-2-ynyl
  • R 4 is phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 4- chlorophenyl, 3-methylphenyl or 3-methyl-4-fluorophenyl
  • R 6 is -NR 18 R 19 in which R 18 is hydrogen and R 19 is -C(O)R 23 , in which R 23 is methyl, ethyl, ⁇ o-propyl, cyclopropyl, eye Io butyl or 1-methylcyclopropyl.
  • the method of the invention may utilise a compound of formula (Ie):
  • R 1 , R 2 , R 3 , R 4 and R 6 are as defined above for compound (Id), in any combination thereof.
  • the method of the invention may utilise a compound of formula (If):
  • R 2 , R 3 , R 4 , R 6 and R 8 are as defined above for compound (Id), in any combination thereof.
  • the method of the invention may utilise a compound of formula (Ig):
  • R 1 , R 3 , R 4 , R 6 and R 8 are as defined above for compound (Id), in any combination thereof.
  • the method of the invention utilises a compound of formula (Ih):
  • any one of G 1 , G 2 and G 3 is N and the other two of G 1 , G 2 and G 3 are CR 8 , CR 1 or CR 2 , such that when G 1 is not N, G 1 is CR 8 ; when G 2 is not N, G 2 is CR 1 ; when G 3 is not N, G 3 is CR 2 ;
  • R 1 , R 2 , R 3 , R 4 , R 6 , R 7 and R 8 are as defined for formula (I) above, in any combination thereof; and preferably:
  • R 1 is hydrogen, halogen, optionally substituted Ci_ 6 alkyl or -C(O)R 10 , in which R 10 is hydrogen or Ci_4 alkyl, the optional substituents being as defined above;
  • R is hydrogen or Ci_ 4 alkyl
  • R 3 is hydrogen, hydroxyl, optionally substituted Ci_6 alkyl, optionally substituted C2-6 alkenyl or optionally substituted C2-6 alkynyl, -C(O)R 12 or -OR 12 , in which R 12 is optionally substituted Ci .4 alkyl, optionally substituted C3-6 cycloalkyl, or optionally substituted C4-6 cycloalkenyl, the optional substituents in all cases being as defined above and, more preferably, selected from halogen, cyano, hydroxyl, alkoxy, e.g. -O-Ci_4 alkyl, cycloalkyl, e.g.
  • C3_6 cycloalkyl cycloalkenyl, e.g. C4_6 cycloalkenyl, heterocycloalkyl, e.g. 3-6- membered cycloalkyl, aryl, e.g. phenyl, heteroaryl, e.g. heterophenyl, -NH 2 , trialkylsilyl and C(O)OR, wherein R is hydrogen, Ci_4 alkyl, C2-4 alkenyl or C2-4 alkynyl;
  • R 4 is optionally substituted aryl, the optional substituents being as defined above and, more preferably halogen or Ci_4 alkyl;
  • R 6 is hydrogen, halogen, hydroxyl, -O-Ci_6 alkyl, or -NR 18 R 19 , wherein:
  • R 18 is hydrogen, -C(O)R 23 , -C(O)OR 23 , optionally substituted Ci_ 4 alkyl, optionally substituted C2-4 alkenyl or optionally substituted C2-4 alkynyl, in which R 23 is optionally substituted Ci_4 alkyl, the optional substituents being as defined above, and
  • R 19 is hydrogen, optionally substituted Ci_4 alkyl, optionally substituted C2-4 alkenyl, optionally substituted C 2 - 4 alkynyl, -C(S)R 23 -C(O)R 23 or -C(O)OR 23 , in which R 23 is hydrogen, optionally substituted Ci_4 alkyl, optionally substituted C2-4 alkenyl, optionally substituted C2-4 alkynyl, optionally substituted C 3-6 cycloalkyl or optionally substituted C4-6 cycloalkenyl, the optional substituents being as defined above;
  • R is hydrogen, halogen or Ci_ 4 alkyl
  • R is hydrogen, halogen, Ci _4 alkyl or NR R , in which R and R are, independently, hydrogen or Ci_4 alkyl.
  • R 1 is hydrogen, halo or optionally substituted Ci_4 alkyl, the optional substituents being as defined above;
  • R 2 is hydrogen or methyl;
  • R 3 is hydrogen, optionally substituted Ci_ 4 alkyl, optionally substituted C 2 - 4 alkenyl, optionally substituted C2-4 alkynyl, or -OR 12 , in which R 12 is optionally substituted Ci_4 alkyl, optionally substituted C 3-6 cycloalkyl or optionally substituted C4_6 cycloalkenyl, the optional substituents in all cases being as defined above;
  • R 4 is phenyl, which is optionally substituted by at least one substituent selected from halogen and Ci_ 4 alkyl;
  • R 6 is halogen or -NR 18 R 19 , in which R 18 is hydrogen, prop-2-enyl or prop-2-ynyl, and R 19 is -C(O)R 23 , in which R 23 is hydrogen, methyl, ethyl,
  • R 1 is hydrogen, chloro or methyl
  • R 2 is hydrogen or methyl
  • R 3 is hydrogen, cyanomethyl, prop-2-enyl, prop-2-ynyl or benzyl
  • R 4 is 2-fluorophenyl, 3 -fluorophenyl, 4-fluorophenyl, 4-chlorophenyl, 3-methylphenyl or 3- methyl-4-fluorophenyl
  • R 6 is -NR 18 R 19 , in which R 18 is hydrogen, and R 19 is -C(O)R 23 , in which R 23 is methyl, ethyl, ⁇ o-propyl, cyclopropyl, eye Io butyl or 1-methylcyclopropyl
  • R 7 is hydrogen, chloro, fluoro or methyl
  • R 8 is hydrogen, chloro or methyl.
  • the method of the invention may utilise a compound of formula l(h) in which: R 1 is hydrogen, halogen, -NH-C M alkyl, -NH-C M haloalkyl, wherein the Ci_ 4 alkyl and Ci_ 4 haloalkyl are optionally substituted by Ci_4 alkoxy or Ci_4 haloalkoxy; R 2 is hydrogen, halogen, hydroxy, -NH-Ci_ 4 alkyl, -NH-Ci_ 4 haloalkyl, -N(Ci -4 alkyl)-Ci_ 4 alkyl, -N(Ci -4 haloalkyl)-Ci_ 4 alkyl, -N(Ci -4 alkyl)-C M haloalkyl, -N(Ci -4 haloalkyl)-C M haloalkyl, -NH-C3_6 cycloalkyl, -NH-C3_6 halocyclo
  • R 6 is hydrogen, halogen, hydroxy, Ci_4 alkoxy, Ci_4 haloalkoxy, -NH 2 , -NH-C M alkyl, -NH- Ci_ 4 haloalkyl, wherein the alkyl and haloalkyl are optionally substituted by hydroxy or Ci_ 4 alkoxy, which in turn may be substituted by hydroxy, or R 6 is -NH-C(O)-C 1-4 alkyl, -NH- C(O)-CL 4 haloalkyl, -NH-C(O)-C 3-6 cycoalkyl, -NH-C(O)-C 3-6 halocycloalkyl, -NH-C(O)- C2-4 alkenyl, NH-C(O)-C 2 - 4 haloalkenyl, -NH-C(O)-C 2-4 alkynyl, or -NH-C(O)-C 2-4 haloalkynyl
  • R 7 is hydrogen or halogen
  • R 8 is hydrogen or halogen
  • the method of the invention may utilise a compound of formula l(h) in which: R 1 is hydrogen, -NH-C M alkyl, wherein the C M alkyl is optionally substituted by methoxy; R 2 is hydrogen or halogen;
  • R 3 is hydrogen, C M alkyl, C 3 _ 4 alkenyl, C 3 _ 4 alkynyl, wherein the C M alkyl is optionally substited by cyano or methoxy;
  • R 4 is phenyl optionally substituted with 1-3 halogen atoms;
  • R 6 is hydrogen,-NH-Ci_4 alkyl, wherein the alkyl is optionally substituted by hydroxy or C M alkoxy, which in turn may be substituted by hydroxy, or R 6 is -NH-C(O)-C 1-4 alkyl, NH- C(O)-C 3-4 cycoalkyl, -NH-C(O)-C 3-4 alkenyl, or -NH-C(O)-C 2-4 alkynyl; R 7 is hydrogen or halogen; R 8 is hydrogen or halogen.
  • the method of the invention may utilise a compound of formula (Ii):
  • R 1 , R 2 , R 3 , R 4 , R 6 , and R 7 are as defined for formula (Ih) above, in any combination thereof.
  • the method of the invention may utilise a compound of formula (Ij):
  • R 2 , R 3 , R 4 , R 6 , R 7 , and R 8 are as defined for formula (Ih) above, in any combination thereof.
  • the method of the invention may utilise a compound of formula (Ik):
  • R 1 , R 3 , R 4 , R 6 , R 7 , and R 8 are as defined for formula (Ih) above, in any combination thereof.
  • the method of the invention utilises a compound of formula (II)
  • any one of G 1 , G 2 and G 3 is N and the other two of G 1 , G 2 and G 3 are CR 8 , CR 1 or CR 2 , such that when G 1 is not N, G 1 is CR 8 ; when G 2 is not N, G 2 is CR 1 ; when G 3 is not N, G 3 is CR 2 ; and preferably, in any combination:
  • R 1 is hydrogen, halogen or Ci_4 alkyl
  • R 2 is hydrogen, halogen or Ci_4 alkyl
  • R , 3 is hydrogen, optionally substituted Ci_6 alkyl, optionally substituted C2-6 alkenyl or optionally substituted C2-6 alkynyl, the optional substituents being as defined above and, more preferably, halogen or alkoxy, e.g. -O-Ci_4 alkyl;
  • R 4 is optionally substituted aryl, e.g. optionally substituted phenyl, the optional subsituents being as defined above and, more preferably, halogen;
  • R 6 is hydrogen, -SR 18 or -NR 18 R 19 , wherein R 18 is hydrogen or Ci_ 4 alkyl, and R 19 is optionally substituted C 1-4 alkyl, -C(S)R 23 or -C(O)R 23 , and R 23 is hydrogen or Ci_ 4 alkyl, the optional substituents being as defined above;
  • R 7 is hydrogen, halogen or Ci_4 alkyl
  • R 8 is hydrogen, halogen or Ci_4 alkyl. More preferably, in any combination thereof: R 1 is hydrogen, methyl, ethyl or chloro; R 2 is hydrogen, methyl, ethyl or chloro; R 3 is hydrogen, halo-Ci_4 alkyl, Ci_4 alkyl-O-Ci_4 alkyl, Ci_ 4 alkyl, C 2 - 4 alkenyl or C 2 - 4 alkynyl, in particular hydrogen, 2-fluoroethyl, methoxymethyl, prop-l,2-diene or prop-2-ynyl; R 4 is optionally substituted phenyl, the optional substituent being halogen, e.g.
  • R 6 is hydrogen or -NR 18 R 19 , wherein R 18 is hydrogen, and R 19 is 2-methoxy-l-methylethyl, -C(S)R 23 or -C(O)R 23 , and R 23 is Ci_ 4 alkyl, in particular 1- methylethyl, 1-dimethylethyl or 3-methylpropyl;
  • R 7 is hydrogen, methyl, ethyl or chloro; and
  • R 8 is hydrogen, methyl, ethyl or chloro.
  • the method of the invention may utilise a compound of formula (Im):
  • R 1 , R 2 , R 3 , R 4 , R 6 and R 7 are as defined for formula (II) above, in any combination thereof.
  • the method of the invention may utilise a compound of formula (In):
  • R 2 , R 3 , R 4 , R 6 , R 7 and R 8 are as defined for formula (II) above, in any combination thereof.
  • the method of the invention may utilise a compound of formula (Io):
  • R 1 , R 3 , R 4 , R 6 , R 7 and R 8 are as defined for formula (II) above, in any combination thereof.
  • the present invention provides a compound of formula (I) as defined above with the provisos that:
  • the compound of formula (I) is not: 7-phenyl-6-(pyridin-4-yl)-5H-pyrrolo[3,2-c]pyridazine; 7-phenyl-6-(pyridin-4-yl)-5H-pyrrolo[3,2-d]pyrimidine; 7-phenyl-6-(pyridin-4-yl)-5H-pyrrolo[2,3-b]pyrazine;
  • the also invention provides a compound of formula (Ia) as defined above, with the proviso that the compound of formula (Ia) is not: 7-phenyl-6-(pyridin-4-yl)-5H-pyrrolo[3,2-c]pyridazine.
  • the invention also provides a compound of formula (Ib) as defined above, with the proviso that the compound of formula (Ib) is not: 7-phenyl-6-(pyridin-4-yl)-5H-pyrrolo[3,2-d]pyrimidine; or 7-(4-fluorophenyl)-6-(pyridine-4-yl)-5H-pyrrolo[3,2-d]pyrimidine.
  • the invention also provides a compound of formula (Ic) as defined above, with the provisos that:
  • the compound of formula (Ic) is not: 7-phenyl-6-(pyridin-4-yl)-5H-pyrrolo[2,3-b]pyrazine.
  • the invention also provides a compound of formula (Id), (Ih) or (II) as defined above, with the provisos that:
  • the invention also provides a compound of formula (Ie), (Ii) or (Im) as defined above, with the proviso that the compound of formula (Ie), (Ii) or (Im) is not:
  • the invention also provides a compound of formula (If), (Ij) or (In) as defined above, with the proviso that the compound of formula (If), (ij) or (In) is not:
  • the invention also provides a compound of formula (Ig), (Ik) or (Io) as defined above, with the provisos that:
  • R 4 is not 4-fluorophenyl; and (ii) the compound of formula (Ig), (Ik) or (Io) is not: 7-phenyl-6-(pyridin-4-yl)-5H-pyrrolo[2,3-b]pyrazine;
  • the present invention provides a compound of any one of formulas (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (II), (Im), (In), and (Io) with the proviso that the compound is not one that is disclosed in WO 99/20624.
  • the compounds listed above are named according to the scheme outlined on pages 17 and 18 of WO 99/20624.
  • WO 99/20624 is incorporated herein by reference.
  • the invention also provides a compound of any one of formulas (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (II), (Im), (In), and (Io), wherein, when present: G 1 , G 2 , G 3 , X 1 , X 2 , R 1 , R 2 , R 3 , R 4 , R 5 , R 7 , R 8 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 20 , R 21 , R 22 , R 23 , R 24 , and R 25 are as defined above for formula (I), in any combination thereof, and, in any combination:
  • R 6 is:
  • aryl e.g. optionally substituted phenyl, optionally substituted heteroaryl, e.g. optionally substituted heterophenyl, optionally substituted cycloalkyl, e.g. optionally
  • R 6 is -NR 18 R 19 , e.g. -NHR 19 .
  • R 6 is -NHC(O)R 23 , in which R 23 is preferably Ci_ 4 alkyl, e.g. ethyl, isopropyl, or cyclopropyl or cyclobutyl.
  • R 18 is: (i) hydrogen
  • Ci_6 alkyl optionally substituted C 2 -6 alkenyl or optionally substituted C 2 -6 alkynyl
  • an optionally substituted heterocyclic ring formed with R 19 e.g. a 5 or 6 membered heterocycle, or
  • R 18 is hydrogen, Ci_ 4 alkyl, C 2 - 4 alkenyl, or C 2 - 4 alkynyl. More preferably Ri 8 is hydrogen, ethyl, ⁇ o-propyl, prop-2-enyl, prop-2ynyl or but-2-ynyl.
  • R 19 is:
  • Ci_6 alkyl optionally substituted C 2 -6 alkenyl or optionally substituted C 2 -6 alkynyl
  • optionally substituted aryl e.g. optionally substituted phenyl, optionally substituted heteroaryl, e.g. optionally substituted heterophenyl
  • optionally substituted cycloalkyl e.g. optionally substituted C3-6 cycloalkyl
  • optionally substituted cycloalkenyl e.g. optionally substituted C 4 -6 cycloalkenyl, or optionally substituted heterocycloalkyl, e.g.
  • R 19 is hydrogen, -C(S)R 23 , -C(O)R 23 or -C(O)OR 23 or Ci -4 alkyl.
  • R 19 is hydrogen, wo-butyl, -C(O)R 23 or -C(O)OR 23 .
  • the invention also provides a compound of any one of formulas (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (II), (Im), (In), and (Io), wherein, when present: G 1 , G 2 , G 3 , X 1 , X 2 , R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , R 8 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , and R 25 are as defined above for formula (I), in any combination thereof, and:
  • R 3 is: (v) hydroxyl
  • Ci_6 alkyl optionally substituted C 2 -6 alkenyl or optionally substituted C 2 -6 alkynyl
  • optionally substituted cycloalkyl e.g. optionally substituted C 3-6 cycloalkyl, or (viii) -C(O)R 12 , -OR 12 , -C(O)OR 12 , -OC(O)R 12 or -S(O) 2 R 12 ; wherein the optional substitutents in all cases are as defined above and, more preferably, are selected from cyano, halogen, hydroxyl, Ci_ 4 alkyl, C 2 - 4 alkenyl, alkoxy, e.g. -O-Ci_ 4 alkyl (optionally substituted by alkoxy, e.g.
  • acyl e.g. -(O)C-C 1-3 alkyl
  • cycloalkyl e.g. C 3-6 cycloalkyl
  • cycloalkenyl e.g. C 3 _ 6
  • heterocycloalkyl e.g. 3-6-membered heterocycloalkyl
  • aryl e.g. phenyl, heteroaryl, e.g. heterophenyl, -NH 2 , trialkylsilyl, -C(O)R and -C(O)OR (wherein R is hydrogen, methyl or ethyl).
  • R 3 is hydroxyl, -C(O)R 12 , -OR 12 , -C(O)OR 12 , -OC(O)R 12 , -S(O) 2 R 12 , optionally substituted Ci_6 alkyl, optionally substituted C 2 -6 alkenyl, optionally substituted C 2 -6 alkynyl, optionally substituted cycloalkyl, e.g. optionally substituted C 3 _6 cycloalkyl.
  • the invention relates to a process for the preparation of a compound the of the invention, e.g. compounds of formula (I), as defined according to any of the aspects above, comprising: a) cyclising a compound of formula (F)
  • G 1 , G 2 , G 3 , R 1 , R 2 , R 4 and R 8 are as defined for formula (I), X is a halogen, and R is a group of formula:
  • R 3 is as defined for formula (I); preferably said derivatisation is by reaction with R -LG, wherein LG is a leaving group and R 3 is an alkyl group, or by reaction with R 12 CO-LG, wherein R 12 is as defined for formula (I) and LG is a leaving group; or b) reacting an azaindole of formula (K)
  • G 1 , G 2 , G 3 , R 1 , R 2 and R 8 are as defined for formula (I), R is as defined above, and LG is a leaving group,
  • R 3 is as defined for formula (I); preferably said derivatisation is by reaction with R 3 -LG, wherein LG is a leaving group and R 3 is an alkyl group, or by reaction with R 12 CO-LG, wherein R 12 is as defined for formula (I) and LG is a leaving group; or
  • G 1 , G 2 , G 3 , R 1 , R 2 , R 4 , and R 8 are defined for formula (I), and R is as defined above,
  • Suitable leaving groups are well known in the art and may be, for example, halogen, triflate or mesylate.
  • a method of the present invention may include converting a compound of formula (I) to a salt of N-oxide thereof.
  • R is:
  • X 1 and X 2 , R 1 to R 8 are as defined above and X is halogen.
  • Compounds of formula C can be obtained by reaction between an ester of formula A and an acetonitrile derivative of formula B in the presence of a base such as sodium methoxide or potassium t-butoxide in suitable alcoholic solvent, (see J. Med. Chem. 2003, 46, 4702-4713).
  • a base such as sodium methoxide or potassium t-butoxide in suitable alcoholic solvent
  • compound F may exist as its enamine-imine equilibrium; both compounds might be separated under state of the art purification condition such as chromatography.
  • Heterocycle of formula E such as 3-chloro-pyridazin-4-ylamine or 3-Bromo- pyrazin-2-ylamine, may be commercially available or may be prepared by known methodologies. For example, by reduction of the corresponding nitro derivative (see J. Chem. Soc, 1952, 2042). As further example, pyridazine derivatives can be prepared according to the procedures reported in Journal of Heterocyclic Chemistry 1964, 1(5), 247-50 .
  • the di-azaindole (5H-Pyrrolo[3,2-c]pyridazine; 5H-Pyrrolo[3,2-d]pyrimidine or 5H- Pyrrolo[2,3-b]pyrazine) of formula G is obtained by cyclisation of the enamine F in the presence of a tertiary amine base such as DABCO and a palladium catalyst such as palladium acetate (II) or dichlorobis(triphenylphosphine) palladium (II) in an inert solvent such as dimethylformamide or dimethylacetamide (see J. Org. Chem. 1997, 62, 2676-2677).
  • a tertiary amine base such as DABCO
  • a palladium catalyst such as palladium acetate (II) or dichlorobis(triphenylphosphine) palladium (II) in an inert solvent such as dimethylformamide or dimethylacetamide
  • Compounds of formula H, where R 3 is not hydrogen may be obtained by alkylation or acylation of compounds of formula G.
  • This alkylation can be realized with an alkylating agent of formula R -Y (where Y is a leaving group such as halogen, triflate, mesylate and the like) in the presence of a base such as sodium hydride or lithium hexamethyldisilazane in an aprotic solvent such as dimethylformamide or tetrahydrofuran.
  • Compounds of formula J may be obtained in a single step condensation-cyclisation of a compound of formula E and compound of formula I.
  • the reaction is carried out in the presence of a base, such as potassium phosphate or potassium carbonate, a dehydrating agent, such as magnesium or sodium sulphate, and a palladium catalyst, preferably (di-t- butylphoshino) palladium, in an inert solvent, such as dimethylformamide or dimethylacetamide, under an inert atmosphere in a closed vessel, (see: Angew. Chem. Int. Ed. Eng. 2004, 4526-4528).
  • Compounds of formula J can be regioselectively brominated in the presence of bromine or N-bromosuccinimide in a solvent, such as carbon tetrachloride or DMF, to give a compound of formula K (see: Synthesis, 1982, 1096).
  • Compounds of formula G can be obtained by further treatment of a compound of formula K in the presence of a boronic acid of formula R 4 B(OH) 2 (where R 4 is as previously defined) under Suzuki cross coupling conditions (see: Chem. Comm. 1979, 866) under thermal or microwave conditions.
  • Compounds of formula L may be obtained by sequential protection of the corresponding heterocycle E (see “Protective groups in organic chemistry” Greene and Wuts 4 th edition, Wiley Interscience).
  • Compounds of formula L can be coupled with compounds of formula M under Sonogashira coupling conditions (see: Synthesis 1980, (8) 627-630) and subsequently treated with iodine in an inert solvent, such as dichloromethane, to undergo direct iodo cyclisation and formation of N (see: Org. Letters 2004, 6(6) 1037-1040).
  • Compounds of formula M can be prepared from the parent halogenated compound by reaction under Sonogashira conditions (see: Synthesis, 1980, (8) 627-630) with trimethylsilyl acetylene, followed by deprotection under basic conditions of the trimethyl silyl group.
  • Compounds of formula M may also be prepared from the parent aldehyde under Corey- Fuchs reaction conditions (see: Tet. Lett. 1972, (36) 3769).
  • Compounds of formula O may be obtained by treatment of N under the same conditions as the ones described above for K in scheme 2 in the presence of a boronic acid.
  • acetate as protective group can be deprotected under acidic conditions such as HCl or basic conditions such as LiOH. It is to be noted that weak protecting groups may be deprotected during the course of reactions to generate compounds of formula N or O. It is also to be noticed that PG and R 3 may be the same from the beginning of the preparation thus the deprotection step may not be required.
  • Compounds of formula J may also be obtained by direct treament of the amino heterocycle E in two steps by reacting with a compound of formula M under Sonogashira conditions followed by a cyclisation under basic conditions (NEt 3 , KOH) as described in Tet. Lett., 2007, 48, 6951-6953. The remaining sequence to reach G and H may be as previously described.
  • Scheme 4 describes an alternative method for the preparation of compound of formula (I) where R 3 is OR 12 as described previously:
  • Compounds of formula Q can be selectively reduced at the nitro position under alternative conditions to generate the 1 -hydroxy fused pyrrole of formula S.
  • compounds of formula Q can be treated under Bechamp conditions in the presence of iron in an acidic aqueous media to give compounds of formula S. Under these conditions, the complete reduced form of the azaindole may also be formed.
  • Compounds of formula Q can also be treated under catalytic hydrogenation conditions, in the presence of hydrogen, with or without pressure, with a catalyst such as palladium on charcoal in an alcoholic solvent such as ethanol.
  • Compounds of formula S can then be treated under the same conditions as those discribed for G in scheme 1 in order to generate compound of formula T, where R 12 is as previously described.
  • Scheme 5 describes an alternative method for the preparation of compound of formula (I) where R is not hydrogen.
  • a pyridine of formula U where R is as previously described can be transformed into its acetal V by treating the corresponding aldehyde in methanol or in suitable trialkyl ortho formate, such as trimethylortho formate (for the preparation of the dimethylacetal), in the presence of a catalytic amount of an acid such as sulfuric acid.
  • Compounds of formula U may be commercially available, for example 4-pyridine carboxaldehyde, 3-nitro isonicotinaldehyde and 3-chloro-4-pyridine carboxaldehyde, but may also be prepared by state of the art methodology, for example by starting from the hydroxymethyl derivative and using an oxidation procedure (see: Aus. J.
  • the compound of formula U may also be prepared from the halogen or unsubstituted analogue by halogen-metal or hydrogen-metal exchange followed by treatment with a suitable electrophile such as dimethylformamide (see: Synthesis 1999, 306-311).
  • Compounds of formula Z can be obtained by treating compounds of formula V with a suitable base, such a n-butyl lithium, sodium hydride or lithium hexamethyldisilazane, in an aprotic solvent, such a tetrahydrofuran or diethyl ether, preferably at low temperature followed by the treatment of the anion by a compound of formula W where X is a leaving group such as halogen (chlorine, bromine or iodide) or a mesylate and R 4 is as previously described.
  • a suitable base such as a n-butyl lithium, sodium hydride or lithium hexamethyldisilazane
  • an aprotic solvent such as a tetrahydrofuran or diethyl ether
  • Compounds of formula Z can be oxidized to generate compounds of formula AA, for example in the presence of hydrogen peroxide in a solvent, such as dichloromethane, in the presence of a catalyst, such as methyl trioxorhenium (see Tet. Lett., 1996, 37(6), 805-808), or in the presence of hydrogen peroxide-urea complex in a solvent such as dichloromethane (see Chem. Ber. 1992, 125(8), 1965-1966).
  • a solvent such as dichloromethane
  • a catalyst such as methyl trioxorhenium
  • Compounds of formula AA can be treated by the previously described amino heterocycle of formula E under the conditions described for the preparation of F in scheme 1 to generate compound of formula AB.
  • compounds of formula AB can be obtained by reacting compounds of formula AA and E together in the absence of solvent at a temperature allowing the distillation of the alcohol formed (see: Synthesis 1993, 12, 1227- 1229).
  • compounds of formula AB can exist as two isomers, imine and enamine, that may also be separated for example by chromatography.
  • Compounds of formula AD where X is halogen such as chlorine or bromine can be prepared by treating compounds of formula AC with POCI3 or POBr 3 under conditions used in state of the art methodology such as chlorination of substituted pyridines in Chem. and Pharm. Bull. 1994, 42(9), 1841-1849.
  • Compounds of formula AE can be prepared from compounds of formula AD by Buchwald amination or amidation reaction in the presence of a primary amide or amine, a palladium (II) catalyst such as palladium diacetate, a ligand such as Xantphos®, a base such as potassium or cesium carbonate, in an aprotic solvent such as dioxane or tetrahydrofuran, under thermal or microwave conditions (see Org. Let. 2001, 3(21) 3417-3419).
  • a palladium (II) catalyst such as palladium diacetate
  • a ligand such as Xantphos®
  • a base such as potassium or cesium carbonate
  • Compounds of formula AE may also be prepared from AD by direct treatment with an amine such as benzyl amine under thermal or microwave conditions, followed by treatment with a strong acid such as concentrated sulphuric acid to generate the compound where R 6 is NH 2 .
  • Such an intermediate can be further treated by an appropriate non nucleophilic base, such as pyridine, in a solvent, such as dimethylformamide or tetrahydrofuran, and an acylating agent, such as R 20 COX, where X is chlorine or fluorine and R 20 is as previously described. It can also be treated with an alkylating agent, such as R 18 -X where X is a leaving group such as halogen or a mesylate, under the same conditions.
  • R 6 is neither an amine nor an amide
  • compounds of formula AC may be treated with an activator such as benzoyl chloride in the presence of a cyanide source such as trimethylsilyl-cyanide in an aprotic solvent such as dimethylformamide or tetrahydrofuran (See J. Org. Chem. 1983, 48, 1375-1377).
  • an activator such as benzoyl chloride
  • a cyanide source such as trimethylsilyl-cyanide in an aprotic solvent such as dimethylformamide or tetrahydrofuran
  • Compounds of formula AE where R 6 is cyanide can be further modified by state of the art methods to generate all the possible derivatives of the cyanide group: for example, reduction to the acid or ester, reduction to the amide or reduction to the amine, addition on cyanide by an alkyl or aryl Grignard to generate the ketone.
  • Compounds of formula AI can be prepared from compounds of formula AD following the methodology described in scheme 1 for the preparation of compounds of formula H from compounds of formula G.
  • Compounds of formula AG can be prepared from compounds of formula AE following the methodology used for the preparation of compounds of formula AI.
  • Compounds of formula AG can also be prepared from compounds of formula AI following the methodologies used for the preparation of compounds of formula AE from compounds of formula AD.
  • Compounds of formula AF can be prepared from compounds of formula AE by the following treatment: oxidation of the pyridine following the preparation described for compounds of formula AA from compounds of formula Z direct reaction to introduce R 7 as described for the introduction of R 6 in the preparation of compounds of formula AE from compounds of formula AD - R 7 may also be introduced by the methodologies described for the introduction of
  • Scheme 6 describes an alternative method for the preparation of compounds of formula (I) where X 1 is CH and X 2 is N (compounds of formula (Ic), for example, where G 1 , G 2 , G 3 , R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , and R 8 are defined for formula (I).
  • Compounds of formula AL can be prepared by treatment of a pyrimidine of formula AJ, where X is a halogen such as bromine, chlorine or iodide and R 7 is as previously described, in the presence of a suitable base to realize the metal halogen exchange, n-butyl lithium or s-butyl lithium may be used in an aprotic solvent, such as tetrahydrofuran, preferably at low temperature.
  • the acyl chloride of formula AK can then react with the previously formed anion of the pyrimidine to give compounds of formula AL.
  • Compounds of formula AJ may be commercially available such as the 4-iodo-2- methylthio- pyrimidine or obtained by state of the art methods (see for examples Tet. Lett. 2001, 42(2), 311-313).
  • Compounds of formula AK are usually commercially available, for example phenylacetyl chloride, m-tolylacetyl chloride or 4-fluoro benzeneacetyl chloride, but may also be prepared from the corresponding acid.
  • Compounds of formula AM can be prepared from the condensation between compounds of formula E and AL under the conditions described for the formation of compound F in scheme 1, followed by the cyclisation of the imine or enamine obtained under the conditions described in scheme 1 for the formation of compound G.
  • an oxidant such as m-chloroperbenzoique acid
  • a solvent such as dichloromethane
  • Compounds of formula AN may be obtained by treatment of compounds of formula AM following the same procedure as the one previously described for the formation of compounds of formula H from compound of formula G.
  • Compounds of formula AO can be prepared from compounds of formula AN using methodology as previously described for the preparation of compounds of formula AP from compounds of formula AM .
  • Compounds of formula AO may also be prepared by the direct introduction of R 3 at the indole ring of the compounds of formula AP following the procedure previously described for the formation of compounds of formula H from compounds of formula G in scheme 1.
  • the compounds of formula I are useful in controlling plant pathogenic fungi when they are applied to a plant or plant propagation material in a fungicidally effective amount.
  • Plant propagation material is meant generative parts of a plant including seeds of all kinds (fruit, tubers, bulbs, grains etc), roots, rhizomes, cuttings, cut shoots and the like. Plant propagation material may also include plants and young plants which are to be transplanted after germination or after emergence from the soil.
  • a compound that "controls fungal infection" in plants and/or plant propagation material is, for example, a compound that inhibits, e.g. selectively inhibits, an existing fungal infection in a plant or plant propagation material.
  • the compound may slow the rate of fungal growth and/or reduce fungal growth in a plant or plant propagation material, e.g. compared to the absence of the compound.
  • a compound that "prevents fungal infection” in plants or plant propagation material is, for example, a compound that inhibits e.g. selectively inhibits, the emergence of a fungal infection in a plant or plant propagation material.
  • the compound may slow the appearance of a fungal infection and/or reduce the rate of fungal emergence in a plant or plant propagation material, e.g. compared to the absence of the compound.
  • a compound that controls and/or prevents a fungal infection in a plant or plant propagation material may reduce the ability of a fungus to grow in and/or on a plant or plnat propagation material and/or reduce the rate at which the fungal infection spreads to any neighbouring plants.
  • the compound may be biologically active, e.g. it may impede the normal internal biochemistry of the fungus.
  • the compound is toxic for the fungus, e.g. it kills the fungus on contact.
  • Applying the compound to a plant or plant propagation material means, for example, contacting the compound with a plant or plant propagation material to be treated.
  • the methods, compounds and compositions of the present invention are, for example, effective against the phytopathogenic fungi of the following classes: Fungi imperfecti (e.g. Botrytis, Pyricularia, Helminthosporium, Fusarium, Septoria, Cercospora and Alternaria), Basidiomycetes (e.g. Rhizoctonia, Hemileia, Puccinia), Ascomycetes (e.g. Venturia and Erysiphe, Podosphaera, Monilinia, Uncinula and Pyrenophora) and Oomycetes (e.g. Phytophthora, Pythium, Plasmopara).
  • Fungi imperfecti e.g. Botrytis, Pyricularia, Helminthosporium, Fusarium, Septoria, Cercospora and Alternaria
  • Basidiomycetes e.g. Rhizoctonia, Hemileia, Puccinia
  • Ascomycetes
  • the methods, compounds and compositions of the present invention are effective against Botrytis spp., Pyricularia spp., Fusarium spp. Septoria spp., Rhizoctonia spp., Puccinia spp., Erysiphe spp., Phytophthoria spp., Pythium spp. and Plasmopara spp.
  • the methods, compounds and compositions of the present invention are effective against Botrytis cinerea, Pyricularia oryzae, Fusarium culmorum, Septoria nodurum and Septoria tritici, Rhizoctonia solani, Puccinia recondite, Erysiphe graminis, Pyrenophora teres, Phytophthora infestans, Pythium ultimum and Plasmopara viticola.
  • the methods, compounds and compositions of the present invention are suitable for controlling such disease on a number of plants and their propagation material including, but not limited to the following target crops: cereals (wheat, barley, rye, oats, maize (including field corn, pop corn and sweet corn), rice, sorghum and related crops); beet (sugar beet and fodder beet); leguminous plants (beans, lentils, peas, soybeans); oil plants (rape, mustard, sunflowers); cucumber plants (marrows, cucumbers, melons); fibre plants (cotton, flax, hemp, jute); vegetables (spinach, lettuce, asparagus, cabbages, carrots, eggplants, onions, pepper, tomatoes, potatoes, paprika, okra); plantation crops (bananas, fruit trees, rubber trees, tree nurseries), ornamentals (flowers, shrubs, broad-leaved trees and evergreens, such as conifers); as well as other plants such as vines, bushberries (such as blue
  • ryegrasses such as perennial ryegrass (Lolium perenne L.) and annual (Italian) ryegrass (Lolium multiflorum Lam.)) and warm-season turf grasses (for example, Bermudagrasses (Cynodon L. C. Rich), including hybrid and common Bermudagrass; Zoysiagrasses (Zoysia Willd ), St. Augustinegrass (Stenotaphrum secundatum (Walt.) Kuntze); and centipedegrass (Eremochloa ophiuroides (Munro.) hack.)).
  • Crops' are to be understood to include those crops that have been made tolerant to pests and pesticides, including herbicides or classes of herbicides, as a result of conventional methods of breeding or genetic engineering.
  • Tolerance to e.g. herbicides means a reduced susceptibility to damage caused by a particular herbicide compared to conventional crop breeds.
  • Crops can be modified or bred so as to be tolerant, for example, to HPPD inhibitors such as mesotrione or EPSPS inhibitors such as glyphosate.
  • the compounds of formula I find general use as fungicides and may therefore also be used to control pathogenic fungi in related areas, for example in the protection of technical materials, including wood and wood related technical products, in food storage or in hygiene management.
  • the present invention further provides the use of a compound of formula I for controlling fungi.
  • the compound of the invention is normally applied to plants and/or plant propagation material in a fungicidally effective amount. The amount used will of course depend on several factors such as the plant or propagation material, the type of fungus and the particular compound of the invention.
  • the compounds of formula I may be in unmodified form or, preferably, formulated together with carriers and adjuvants conventionally employed in the art of formulation.
  • the invention therefore also relates to a composition for the control of fungal infection comprising a compound of formula I as defined above and an agriculturally acceptable carrier or diluent.
  • the agrochemical composition will usually contain from 0.1 to 99% by weight, preferably from 0.1 to 95% by weight, of the compound of formula I, 99.9 to 1% by weight, preferably 99.8 to 5% by weight, of a solid or liquid adjuvant, and from 0 to 25% by weight, preferably from 0.1 to 25% by weight, of a surfactant.
  • the agrochemical compositions and formulations of the present invention are applied prior to disease development.
  • Rates and frequency of use of the formulations are those conventionally used in the art and will depend on the risk of infestation by the fungal pathogen, the developmental stage of the plant and on the location, timing and application method.
  • Advantageous rates of application are normally from 5g to 2kg of active ingredient (a.i.) per hectare (ha), preferably from 1Og to lkg a.i./ha, most preferably from 2Og to 60Og a.i./ha.
  • convenient rates of application are from 1 Omg to 1 g of active substance per kg of seeds.
  • the agrochemical compositions comprising compound of formula (I) are usually applied as a formulation containing the various adjuvants and carriers known to or used in the industry. They may thus be formulated as granules, as wettable or soluble powders, as emulsifiable concentrates, as coatable pastes, as dusts, as flowables, as solutions, as suspensions or emulsions, or as controlled release forms such as microcapsules. These formulations are described in more detail below and may contain as little as about 0.5% to as much as about 95% or more by weight of the active ingredient. The optimum amount will depend on formulation, application equipment and nature of the plant pathogenic fungi to be controlled.
  • Suspension concentrates are aqueous formulations in which finely divided solid particles of the active compound are suspended. Such formulations include anti-settling agents and dispersing agents and may further include a wetting agent to enhance activity as well an anti-foam and a crystal growth inhibitor. In use, these concentrates are diluted in water and normally applied as a spray to the area to be treated. The amount of active ingredient may range from about 0.5% to about 95% of the concentrate.
  • Wettable powders are in the form of finely divided particles which disperse readily in water or other liquid carriers.
  • the particles contain the active ingredient retained in a solid matrix.
  • Typical solid matrices include fuller's earth, kaolin clays, silicas and other readily wet organic or inorganic solids. Wettable powders normally contain about 5% to about 95% of the active ingredient plus a small amount of wetting, dispersing or emulsifying agent.
  • Emulsif ⁇ able concentrates are homogeneous liquid compositions dispersible in water or other liquid and may consist entirely of the active compound with a liquid or solid emulsifying agent, or may also contain a liquid carrier, such as xylene, heavy aromatic naphthas, isophorone and other non-volatile organic solvents. In use, these concentrates are dispersed in water or other liquid and normally applied as a spray to the area to be treated. The amount of active ingredient may range from about 0.5% to about 95% of the concentrate.
  • Granular formulations include both extrudates and relatively coarse particles and are usually applied without dilution to the area in which control of plant pathogenic fungi is required.
  • Typical carriers for granular formulations include sand, fuller's earth, attapulgite clay, bentonite clays, montmorillonite clay, vermiculite, perlite, calcium carbonate, brick, pumice, pyrophyllite, kaolin, dolomite, plaster, wood flour, ground corn cobs, ground peanut hulls, sugars, sodium chloride, sodium sulphate, sodium silicate, sodium borate, magnesia, mica, iron oxide, zinc oxide, titanium oxide, antimony oxide, cryolite, gypsum, diatomaceous earth, calcium sulphate and other organic or inorganic materials which absorb or which can be coated with the active compound.
  • Granular formulations normally contain about 5% to about 25% active ingredients which may include surface-active agents such as heavy aromatic naphthas, kerosene and other petroleum fractions, or vegetable oils; and/or stickers such as dextrins, glue or synthetic resins.
  • active ingredients which may include surface-active agents such as heavy aromatic naphthas, kerosene and other petroleum fractions, or vegetable oils; and/or stickers such as dextrins, glue or synthetic resins.
  • Dusts are free-flowing admixtures of the active ingredient with finely divided solids such as talc, clays, flours and other organic and inorganic solids which act as dispersants and carriers.
  • Microcapsules are typically droplets or granules of the active ingredient enclosed in an inert porous shell which allows escape of the enclosed material to the surroundings at controlled rates.
  • Encapsulated droplets are typically about 1 to 50 microns in diameter.
  • the enclosed liquid typically constitutes about 50 to 95% of the weight of the capsule and may include solvent in addition to the active compound.
  • Encapsulated granules are generally porous granules with porous membranes sealing the granule pore openings, retaining the active species in liquid form inside the granule pores.
  • Granules typically range from 1 millimetre to 1 centimetre and preferably 1 to 2 millimetres in diameter. Granules are formed by extrusion, agglomeration or prilling, or are naturally occurring.
  • Shell or membrane materials include natural and synthetic rubbers, cellulosic materials, styrene-butadiene copolymers, polyacrylonitriles, polyacrylates, polyesters, polyamides, polyureas, polyurethanes and starch xanthates.
  • compositions for agrochemical applications include simple solutions of the active ingredient in a solvent in which it is completely soluble at the desired concentration, such as acetone, alkylated naphthalenes, xylene and other organic solvents.
  • Pressurised sprayers wherein the active ingredient is dispersed in finely-divided form as a result of vaporisation of a low boiling dispersant solvent carrier, may also be used.
  • Suitable agricultural adjuvants and carriers that are useful in formulating the compositions of the invention in the formulation types described above are well known to those skilled in the art. Suitable examples of the different classes are found in the non- limiting list below.
  • Liquid carriers that can be employed include water, toluene, xylene, petroleum naphtha, crop oil, acetone, methyl ethyl ketone, cyclohexanone, acetic anhydride, acetonitrile, acetophenone, amyl acetate, 2-butanone, chlorobenzene, cyclohexane, cyclohexanol, alkyl acetates, diacetonalcohol, 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-dimethyl formamide, dimethyl sulfoxide, 1 ,4-dioxane, dipropylene glycol, dipropylene glycol methyl ether, dipropylene glycol dibenzoate, di
  • Suitable solid carriers include talc, titanium dioxide, pyrophyllite clay, silica, attapulgite clay, kieselguhr, chalk, diatomaxeous earth, lime, calcium carbonate, bentonite clay, fuller's earth, cotton seed hulls, wheat flour, soybean flour, pumice, wood flour, walnut shell flour, lignin and the like.
  • a broad range of surface-active agents are advantageously employed in both said liquid and solid compositions, especially those designed to be diluted with carrier before application. These agents, when used, normally comprise from 0.1% to 15% by weight of the formulation. They can be anionic, cationic, non- ionic or polymeric in character and can be employed as emulsifying agents, wetting agents, suspending agents or for other purposes.
  • Typical surface active agents include salts of alkyl sulfates, such as diethanolammonium lauryl sulphate; alkylarylsulfonate salts, such as calcium dodecylbenzenesulfonate; alkylphenol-alkylene oxide addition products, such as nonylphenol-C.sub.
  • alcohol-alkylene oxide addition products such as tridecyl alcohol-C.sub. 16 ethoxylate
  • soaps such as sodium stearate
  • alkylnaphthalenesulfonate salts such as sodium dibutylnaphthalenesulfonate
  • dialkyl esters of sulfosuccinate salts such as sodium di(2- ethylhexyl) sulfosuccinate
  • sorbitol esters such as sorbitol oleate
  • quaternary amines such as lauryl trimethylammonium chloride
  • polyethylene glycol esters of fatty acids such as polyethylene glycol stearate
  • salts of mono and dialkyl phosphate esters such as mono and dialkyl phosphate esters.
  • adjuvants commonly utilized in agricultural compositions include crystallisation inhibitors, viscosity modifiers, suspending agents, spray droplet modifiers, pigments, antioxidants, foaming agents, anti-foaming agents, light-blocking agents, compatibilizing agents, antifoam agents, sequestering agents, neutralising agents and buffers, corrosion inhibitors, dyes, odorants, spreading agents, penetration aids, micronutrients, emollients, lubricants, sticking agents, and the like.
  • biocidally active ingredients or compositions may be used in the methods of the invention and applied simultaneously or sequentially with the compound of formula (I). When applied simultaneously, these further active ingredients may be formulated together with the compound of the invention or mixed in, for example, the spray tank. These further biocidally active ingredients may be fungicides, herbicides, insecticides, bactericides, acaricides, nematicides and/or plant growth regulators.
  • formulations of the invention and for use in the methods of the invention can be applied to the areas where control is desired by conventional methods such as spraying atomising, dusting, scattering, coating or pouring.
  • Dust and liquid compositions for example, can be applied by the use of power-dusters, broom and hand sprayers and spray dusters.
  • the formulations can also be applied from airplanes as a dust or a spray or by rope wick applications.
  • Both solid and liquid formulations may also be applied to the soil in the locus of the plant to be treated allowing the active ingredient to penetrate the plant through the roots.
  • the formulations of the invention may also be used for dressing applications on plant propagation material to provide protection against fungus infections on the plant propagation material as well as against phytopathogenic fungi occurring in the soil.
  • the active ingredient may be applied to plant propagation material to be protected by impregnating the plant propagation material, in particular, seeds, either with a liquid formulation of the fungicide or coating it with a solid formulation.
  • plant propagation material in particular, seeds
  • other types of application are also possible, for example, the specific treatment of plant cuttings or twigs serving propagation.
  • the compounds of formula (I) as defined above can be used in the treatment of fungal infections of human and animal subjects.
  • the active compounds as described herein may be combined with a pharmaceutically acceptable carrier and administered or applied to such subjects or infections in an amount effective to treat the infection in accordance with known techniques.
  • the present invention also provides the use of a compound of formula (I) as defined above in the manufacture of a medicament for the treatment of a fungal infection in a human or animal.
  • the present invention also provides a compound of formula (I) for use in the treatment of a fungal infection in a human or animal.
  • reaction mixture is poured into ice-water (1.2L) and the pH is adjusted to 7 with a 25% solution of ammonium hydroxide. After extraction in ethyl acetate, the organic layers are dried over magnesium sulfate and the residue after concentration is purified by chromatography on silica gel (ethylacetate/hexane 2/1) to give 133 g of 2-(4- fluorophenyl)-l-(pyridine-4-yl)ethanone as a yellowish solid.
  • Step 2 A mixture of hydrazine monohydrate (2.95g), 2-(4-fluorophenyl)-l-(pyridine- 4-yl)ethanone (5 g, 23 mmoles) are dissolved in 500 rnL of ethanol in the presence of a catalytic amount of acetic acid. The reaction is heated to reflux for 2 hours. The reaction mixture is then concentrated to 25% of the original volume and extracted in ethyl acetate / saturated ammonium chloride solution. The organic phase is washed with water and dried over magnesium sulfate.
  • Step 3 2.73 g of [2-(4-Fluoro-phenyl)-l-pyridin-4-yl-ethylidene]-hydrazine are dissolved in 20 mL of toluene under argon. 2.95 g of 5-bromopyrimidine (18mmoles) and 1.8 g of sodium tert-butylate (18.5 mmoles) are then added to the mixture, followed by Ig of DPPF ([l-l '-bis-(diphenylphosphine)ferrocene]) and 0.48 g of PdC12(DPPF) dichloro- methane complex. The reaction mixture is heated at 100 0 C for 12 hours..
  • DPPF [l-l '-bis-(diphenylphosphine)ferrocene]
  • Step 4 1.1 g ofN-[2-(4-Fluoro-phenyl)-l-pyridin-4-yl-ethylidene]-N'-pyrimidin-5- yl-hydrazine 4 mL of diethylene glycol under nitrogen is heated at 250 0 C for 4 hours in a metal bath. The cooled reaction mixture is then poured into concentrated NaCl solution and extracted with ethyl acetate. The organic phase is washed with water and dried over magnesium sulfate. Chrommatography of the solid residue after concentration affords 250 mg of 7-(4-Fluoro-phenyl)-6-pyridin-4-yl-5H-pyrrolo[3,2-d]pyrimidine as beige crystals.
  • Step 5 Sodium hydride (52mg, 1.29 mmole 60% in oil) is added to a solution of 125 mg (0.43 mmole) of 7-(4-Fluoro-phenyl)-6-pyridin-4-yl-5H-pyrrolo[3,2-d]pyrimidine in 6 mL of dimethylformamide at room temperature. After 30 min. at room temperature, 547 mg of l-bromo-2-fluoroethane is added to the reaction mixture. After 90min. at room temperature, the reaction mixture is poured into ammonium chloride solution and extracted with ethyl acetate. The organic phase is washed with water and dried over magnesium sulfate.
  • Step 1 To 2,3-dichloropyrazine (100 g, 0.671 mol) in dioxane (150 rnL), was added benzylamine (86.3 g, 0.805 mol), triethylamine (140 mL, 1.0 mol), and the reaction mixture was heated at 100 0 C for 6-7 h. After completion of the reaction, most of the solvent was evaporated under reduced pressure, the reaction mass was diluted with water, and extracted with dichloromethane.
  • Step 2 To 2-chloro-3-iodopyridine (100 g, 0.418 mol) in dry DMF (250 mL) under an atmosphere of nitrogen was added Pd 2 (dba)3 (19.1 g, 0.021 mol, 5 mol%), triethylamine (300 mL), and CuI (0.398 g, 0.0021 mol, 0.5 mol%). The reaction mixture was cooled to O 0 C and to this was added trimethylsilylacetylene (35.1 mL, 0.459 mol) dropwise. The reaction mixture was allowed to stir at room temperature (25 0 C) for 3-4 h. After completion of the reaction, the reaction mixture was diluted with cold water, and filtered over a celite bed.
  • Step 3 To 2-benzylamino-3-chloropyrazine (50 g, 0.228 mol) in dimethyl formamide
  • reaction mixture was heated at HO 0 C for 4-5h. After completion of the reaction, the reaction mixture was filtered through a celite bed, the filtrate diluted with cold water, and extracted with dichloromethane. The combined organic layers were dried over sodium sulfate, concentrated under reduced pressure, and purified by chromatography on neutral alumina (ethylacetate/hexane, 1/5) to yield 32.8 g (45%) of 2-(2-chloro-4-ethynylpyridine)- 3-benzylaminopyrazine.
  • Step 4 A solution of 2-(2-chloro-4-ethynyl pyridine)-3-benzylaminopyrazine (37 g,
  • Step 5 A mixture of palladium acetate (1.23 g, 0.00547 mol, 5 mol%), X-Phos (5.21 g, 0.011 mol, 10 mol%), and potassium tertiary butoxide (18.4 g, 0.164 mol) in toluene/ethanol (2:1, 10OmL) under an atmosphere of nitrogen was heated to 7O 0 C. To this was added 2-(2-chloro pyridyl)-l-benzyl-4,7-diazaindole (35 g, 0.11 mol) as a solution in toluene/ethanol (2:1, 15OmL) dropwise. After completion of addition the reaction mixture was heated at 90-100 0 C for 1-2 h.
  • Step 6 2-(2-ethoxy pyridyl)-l-benzyl-4,7-diazaindole (35 g, 0.11 mol) in dicholoromehtane (150 mL) under an atmosphere of nitrogen was cooled to O 0 C, to this was added bromine (1.47 mL, 0.11 mol) dissolved in dichloromethane (100 mL) dropwise. After addition was complete the reaction mixture was allowed to stir at room temperature (25 0 C) for 1 h. After completio of the reaction, the reaction mass was quenched with aqueous solution of sodium thiosulfate, extracted with dichloromethane, and the combined organic layers were washed with aqueous sodium bicarbonate.
  • Step 7 A mixture of palladium acetate (0.55 g, 0.0025 mol, 5 mol%), X-Phos (2.33 g, 0.0049 mol, 10 mol%), and cesium carbonate (48 g, 0.147 mol) in toluene/ethanol (3:1, 60 mL) under an atmosphere of nitrogen was allowed to stir for 5-10 min. To this was added a solution of phenyl boronic acid (6.58 g, 0.054 mol) and 2-(2-ethoxy pyridyl)-3-bromo-l- benzyl-4,7-diazaindole (20 g, 0.049 mol) in toluene/ethanol (3:1, 60 mL), dropwise.
  • reaction mixture was heated at 6O 0 C for 5 h.
  • solvent was evaporated under reduced pressure, the reaction mass diluted with water, and extracted with ehtylacetate. The combine organic layers were dried over sodium sulfate and evaporated under reduced pressure to yield 17 g (85%) of 2-(2-ethoxy pyridyl)-3- phenyl-l-benzyl-4,7-diazaindole, which was pure enough to be used as such for the next step.
  • Step 1 2-(2-ethoxy pyridyl)-3-phenyl-l-benzyl-4,7-diazaindole (17 g, 0.042 mol) in 33% HBr in glacial acetic acid (50 mL) was heated at 100-11O 0 C for 6-7 h.
  • Step 2 2-(2-hydroxy pyridyl)-3-phenyl-l-benzyl-4,7-diazaindole (13 g, 0.035 mol) in phosphorous oxychloride (50 mL) was heated at 100-11O 0 C for 7 h. After completion of the reaction, the phosphorous oxy chloride was distilled out, the reaction mass neutralized with aqueous IN sodium hydroxide solution, and the aqueous phase extracted with dichloromethane.
  • Step 3 2-(2-chloro pyridyl)-3-phenyl-N-benzyl-4,7-diazaindole (11 g, 0.028 mol) in cone sulfuric acid (20 mL) was heated at 8O 0 C for 8 h. After completion of the reaction, the reaction mixture was cooled to room temperature (25 0 C), diluted with ice, extracted with dichloromethane by adjusting the aqueous layer to neutral and basic pH.
  • Step 4 A mixture of para methoxy benzylamine (3.6 g, 0.026 mol), palladium acetate (0.18 g, 0.00065 mol, 5 mol%), X-Phos (0.62 g, 0.0013 mol, 10 mol%), and potassium tertiary butoxide (3.67 g, 0.033 mol) in toluene (25 mL) under an atmosphere of nitrogen was heated to 7O 0 C.
  • Step 5 To 2-[2-(p-methoxy benzylamino) pyridyl]-3-phenyl-4,7-diazaindole (2 g, 0.0049 mol) in dimethyl formamide (10 mL) was added cesium carbonate (4 g, 0.012 mol) and the mixture was allowed to stir at room temperature (25 0 C) for 10 min. To this was added allyl bromide (0.65 g, 0.0054 mol) dropwise and the reaction mixture was stirred at room temperature (25 0 C) for 15 min. After completion of the reaction, the reaction mixture was diluted with water and extracted with dichloromethane.
  • Step 6 2-[2-(p-methoxy benzylamino) pyridyl]-3-phenyl-N-propargyl-4,7- diazaindole (1.8 g, 0.004 mol) in trifluoro acetic acid (5 mL) was heated at 50-60 0 C under an atmosphere of nitrogen for 2 h. After completion of the reaction, the excess trifluoroacetic acid was distilled out under reduced pressure. The reaction mass was diluted with water, adjusted to basic pH using IN sodium hydroxide, and extracted with dichloromethane.
  • Step 7 To 2-(2-amino pyridyl)-3-phenyl-l-allyl-4,7-diazaindole (0.2 g, 0.0006 mol) in pyridine (2 mL) was added propionyl chloride (0.06 g, 0.00067 mol) dropwise and the reaction mixture was stirred at room temperature (25 0 C) for 15 min. After completion of the reaction, pyridine was evaporated under reduced pressure, the reaction mass diluted with water, and extracted with dichloromethane. The combined organic layers were washed with IN hydrochloric acid, water, dried over sodium sulfate, and concentrated under reduced pressure.
  • Ethyl formate (14.17g, 0.19 mol) is added dropwise to a solution of sodium methoxide in methanol (prepared by dissolving 10.3g sodium in 100ml methanol).
  • Benzyl cyanide (2Og, 0.17 mol) in methanol is then added dropwise to the above mixture.
  • the reaction mixture is then heated to reflux till complete precipitation of white salt. After cooling down to room temperature, the reaction mixture is filtered through buchner funnel, washed with diethyl ether and dried to obtain the white solid (21 g).
  • 3-Amino-4-phenyl-lH-pyrrole-2-carboxylic acid ethyl ester (27g, 0.12 mol) is dissolved in ethanol and stirred at room temperature for 10 minutes.
  • Formamidine acetate (27g, 0.258 mol) is then added to the above mixture and stirred for 10 minutes at room temperature.
  • the reaction mixture is then heated to reflux for 8h. Cooled reaction mixture is filtered, washed with ethanol (25ml x 4) and dried to yield 7-Phenyl-5H-pyrrolo[3,2-d]pyrimidin-4-ol as white solid (2Ig).
  • Step 5 4-Chloro-7-phenyl-5H-pyrrolo[3,2-d]pyrimidine
  • Phosphorus oxy chloride 120ml, 10 vol
  • phenyl-5H-pyrrolo[3,2-d]pyrimidin-4-ol (12g, 0.056 mol)
  • the reaction mixture is then refluxed at 105 0 C for 4 hours.
  • the organic layer is washed with water, aq. NaHCO 3 solution, dried with Na 2 SO 4 and concentrated under vacuum to afford 4-Chloro-7-phenyl-5H-pyrrolo[3,2-d]pyrimidine (9.8g.)
  • Step 8 7-Phenyl-6-pyridin-4-yl-5H-pyrrolo[3,2-d]pyrimidine
  • Example 6 Biological activity of the compounds of the invention
  • the compounds of the invention were tested in a leaf disk assay, as described below to determine their preventative action against a number of fungal species.
  • the test compounds were dissolved in DMSO and diluted into water to 200 ppm.
  • the final test solution contained 2% DMSO and 0.025% Tween ® 20.
  • Botrytis cinerea grey mould: Bean leaf disks were placed on agar in a 24-well plate and sprayed with a solution of the test compound. After allowing the disks to dry completely (24 hours), they were inoculated with a spore suspension of the fungus. After appropriate incubation the activity of a compound was assessed three days after inoculation as preventive fungicidal activity.
  • Tomato leaf disks were placed on water agar in a 24-well plate and sprayed with a solution of the test compound. After allowing the disks to dry completely (24 hours), they were inoculated with a spore suspension of the fungus. After appropriate incubation the activity of a compound was assessed four days after inoculation as preventive fungicidal activity.
  • Plasmopara viticola downy mildew of grapevine: Grapevine leaf disks were placed on agar in a 24-well plate and sprayed a solution of the test compound. After allowing the disks to dry completely (for between 12 and 24 hours), they were inoculated with a spore suspension of the fungus. After appropriate incubation the activity of a compound was assessed seven days after inoculation as preventive fungicidal activity.
  • the compounds of the invention were also tested for their ability to inhibit the growth of fungal spores in nutrient broth.
  • test plates were incubated at 24 C and the inhibition of growth was determined photometrically after 72 hrs (Septoria tritici, Botrytis cinerea, Pyricularia oryzae) or 48 hrs (Rhizoctonia solani, Fusarium culmorum).
  • Type of column Water atlantis del 8; Column length: 20 mm; Internal diameter of column: 3 mm; Particle Size: 3 micron; Temperature: 40 0 C.
  • Method B (Agilentl 100 Series LC) with the following HPLC gradient conditions : Solvent A: 0.1% formic acid in water / acetonitrile (9:1) Solvent B: 0.1% formic acid in acetonitrile)
  • Type of column Water atlantis dcl8; Column length: 20 mm; Internal diameter of column: 3 mm; Particle Size: 3 micron; Temperature: 40 0 C.
  • Type of column Waters, symmetry C-18; Column length: 50mm; Internal diameter of column: 4.6mm; Particle Size: 3.5 micron;
  • Method D Thermo HPLC with the following HPLC gradient conditions: Solvent A: 0.25 % formic acid in water Solvent B: 0.025% formic acid in acetonitrile
  • Type of column Waters, symmetry C-18; Column length: 50mm; Internal diameter of column: 4.6mm; Particle Size: 3.5 micron;

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Abstract

The present invention relates to novel compounds of the formula (I) in which any one of G1, G2 and G3 is N and the other two of G1, G2 and G3 are CR8, CR1 or CR2, such that when G1 is not N, G1 is CR8; when G2 is not N, G2 is CR1; when G3 is not N, G3 is CR2; and X1, X2, R1, R2, R3, R4, R6, R7, and R8 are as defined in the claims. In particular, the invention relates to use of these compounds in methods for the control and/or prevention of fungal infection in plants. The invention also relates to compositions containing these compounds as well as methods for preparing these compounds.

Description

DIAZA-INDOLE DERIVATIVES AND THEIR USE AS FUNGICIDES
The present invention relates to novel fungicidally active diaza-indoles, compositions comprising these novel compounds and their use in methods for the control and/or prevention of fungal infection in plants. In addition, the invention relates to processes for preparing the novel compounds of the invention.
Certain diaza-indoles and their use in the prevention and treatment of human and animal disease, although not that caused by fungi, are described in WO 99/20624. Related compounds are also described in WO 2007/110868, WO 2007/047207, and WO 98/022457 but these also do not relate to the control of fungi in plants. It has now been found that certain diaza-indoles have fungicidal activity and, in particular, activity against plant pathogenic fungi.
Accordingly, the present invention provides a method of preventing and/or controlling a fungal infection in a plant and/or plant propagation material, comprising applying to the plant or plant propagation material a compound of formula (I):
Figure imgf000002_0001
wherein:
any one of G1, G2 and G3 is N and the other two of G1, G2 and G3 are CR8, CR1 or CR2, such that when G1 is not N, G1 is CR8; when G2 is not N, G2 is CR1; when G3 is not N, G3 is CR2;
X1 is N or CH;
X2 is N or CR5; R1 Is:
(i) hydrogen, halogen, hydroxyl, cyano or nitro,
(ii) optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl, (iii) optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl or optionally substituted cycloalkenyl, or (iv) -C(O)R10, -C(O)NR10R11, -C(S)NR10R11, -C(NOR10)Rπ, -C(O)OR10, -OR10, -SR10,
-S(O)R10, -S(O)NR10R11, -S(O)2NR10R11, -S(O)2R10, -NR10R11, -P(O)(OR10XOR11) or -OP(O)(OR10)(ORn);
R2 is:
(i) hydrogen, halogen, hydroxyl, cyano or nitro,
(ii) optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl or optionally substituted alkoxy,
(iii) optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl or optionally substituted cycloalkenyl, or
(iv) -C(O)R10, -C(O)NR10R11, -C(S)NR10R11, -C(NOR10)Rπ, -C(O)OR10, -OR10, - SR10, -S(O)R10, -S(O)NR10R11, -S(O)2NR10R11, -S(O)2R10, -NR10R11, -
P(O)(OR10XOR11) or -OP(O)(OR1 °)(0R11);
R3 is:
(i) hydrogen, hydroxyl, cyano or nitro, (ii) optionally substituted alkyl, optionally substituted alkenyl, including optionally substituted allenyl, or optionally substituted alkynyl,
(iii) optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl or optionally substituted cycloalkenyl, or (iv) -C(O)R12, -C(O)OR12, -OR12, -OC(O)R12, -S(O)2R12 or -NR12R13;
R4 is:
(i) hydrogen, halogen, hydroxyl, cyano or nitro, (ii) optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl, (iii) optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl or optionally substituted cycloalkenyl, or
(iv) -C(O)R14, -C(O)OR14, -C(NOR14)R15, -OR14, -SR14, -S(O)NR14R15, -S(O)2R14, or
-NR14R15;
R5 is: (i) hydrogen, halogen, hydro xyl, cyano or nitro,
(ii) optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl, (iii) -C(O)R16, -C(O)OR16, -OR16, -SR16, -S(O)R16, -S(O)NR16R17, -S(O)2R16, or -NR16R17;
R6 is:
(i) hydrogen, halogen, hydroxyl optionally substituted alkoxy or cyano, (ii) optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl or optionally substituted cycloalkenyl, or (iii) -C(O)OR18, -SR18, -NR18R19, -C(O)NR18R19, -N=CR20 or -C(=NR18)NR19R20 ;
R7 is:
(i) hydrogen, halogen, hydroxyl, cyano, or nitro, (ii) optionally substituted alkyl, or (iii) -NR21R22;
R8 is:
(i) hydrogen, halogen, hydroxyl, cyano, or nitro, (ii) optionally substituted alkyl, or (iii) -NR21R22;
R10, R11, R14, R15, R16 and R17 are, independently: (i) hydrogen, halogen, hydroxyl, cyano or nitro; (ii) optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkenyl or optionally substituted alkynyl, or (iii) optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl or optionally substituted cycloalkenyl;
R12 and R13 are, independently:
(i) hydrogen, halogen, hydroxyl, cyano, nitro or -NR21R22;
(ii) optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkenyl or optionally substituted alkynyl, or
(iii) optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl or optionally substituted cycloalkenyl;
R18 and R19 are, independently: (i) hydrogen, (ii) optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl,
(iii) optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl or optionally substituted cycloalkenyl, or (iv) -C(S)R23, -C(O)R23, -S(O2)R23, -C(O)OR23, -OR23 or C(O)NR23R24;
R20 is: (i) hydroxyl,
(ii) optionally substituted alkyl or optionally substituted alkoxy, or (iii) -NR21R22, or -N=CR21R22;
R21 and R22 are, independently: (i) hydrogen,
(ii) optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl, (iii) optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl or optionally substituted cycloalkenyl, or
(iv) -C(O)OR25;
R23 and R24 are, independently:
(i) hydrogen or hydroxyl,
(ii) optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl, or (iii) optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl or optionally substituted cycloalkenyl; and
R25 is optionally susbstituted alkyl, optionally susbstituted alkenyl or optionally susbstituted alkynyl;
and
optionally: independently, (i) R1 and R2, (ii) R1 and R3 (iii) R2 and R3, (iv) R3 and R5, (v) R 5: and R6, (vi) R5 and R18, (vii) R5 and R19, (viii) R14 and R15 and/or (ix) R18 and R19 form an optionally substituted aryl, optionally susbstituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl or optionally substituted cycloalkenyl containing from 5 to 18 ring atoms;
or an isomer, tautomer, N-oxide or salt (including N-oxide salt), thereof.
Unless otherwise stated, the following terms used in the specification and claims have the meanings given below:
"Alkyl" means a linear saturated monovalent hydrocarbon radical of one to eight carbon atoms or a branched saturated monovalent hydrocarbon radical of three to eight carbon atoms, e.g. methyl, ethyl, n-propyl, ώo-propyl, n-butyl, sec-butyl, ώo-butyl, tert- butyl, n-pentyl, n-hexyl and the like. Preferably, linear alkyl groups contain one to six carbon atoms, more preferably one to four carbon atoms and most preferably are selected from methyl, ethyl or n-propyl. Preferably, branched alkyl groups contain three to six carbon atoms and more preferably are selected from ώo-propyl, sec-butyl, ώo-butyl or tert- butyl.
"Alkenyl" means a linear monovalent hydrocarbon radical of two to eight carbon atoms, or a branched monovalent hydrocarbon radical of three to eight carbon atoms containing at least one double bond, e.g. ethenyl, propenyl and the like. Where appropriate, an alkenyl group can be of either the (E)- or (Z)-configuration. Preferably, linear alkenyl groups contain two to six carbon atoms and more preferably are selected from ethenyl, prop- 1-enyl, prop-2-enyl, prop-l,2-dienyl, but-1-enyl, but-2-enyl, but-3-enyl, but-l,2-dienyl and but-l,3-dienyl. Preferably, branched alkenyl groups contain three to six carbon atoms and more preferably are selected from 1-methylethenyl, 1-methylprop- 1-enyl, l-methylprop-2- enyl, 2-methylprop- 1-enyl and 2-methylprop-2-enyl. In some cases an alkenyl group may contain at least two double bonds between three contiguous carbon atoms, e.g. prop- 1,2 dienyl, penta-1,2 dienyl, penta-2,3 dienyl, hexa-l,2-dienyl and the like. Where appropriate, such an alkenyl group can be of either the (R)- or (^-configuration. Preferred is prop- 1,2- dienyl.
"Alkynyl" means a linear monovalent hydrocarbon radical of two to eight carbon atoms, or a branched monovalent hydrocarbon radical of four to eight carbon atoms, containing at least one triple bond, e.g. ethynyl, propynyl and the like. Preferably, linear alkynyl groups contain two to six carbon atoms and more preferably are selected from ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl and but-3-ynyl. Preferably, branched alkynyl groups contain four to six carbon atoms and more preferably are selected from l-methylprop-2-ynyl, 3-methylbut-l-ynyl, l-methylbut-2-ynyl, l-methylbut-3-ynyl and 2-methylbut-3 -ynyl.
"Alkylene" means a linear saturated divalent hydrocarbon radical of one to six carbon atoms or a branched saturated divalent hydrocarbon radical or three to six carbon atoms, e.g. methylene, ethylene, propylene, 2-methylpropylene and the like. Preferred alkylene groups are the divalent radicals of the alkyl groups defined above.
"Alkenylene" means a linear divalent hydrocarbon radical of two to six carbon atoms or a branched divalent hydrocarbon radical of three to six carbon atoms, containing at least one double bond, e.g. ethenylene, propenylene and the like. Preferred alkenylene groups are the divalent radicals of the alkenyl groups defined above.
"Cycloalkyl" means a saturated monovalent cyclic hydrocarbon radical of three to eight ring carbons. Preferably, cycloalkyl groups contain three to six ring carbons, more preferably they are selected from cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
"Cycloalkenyl" means a monovalent cyclic mono- or di-unsaturated hyrodcarbon radical of three to eight ring carbons, preferably four to six ring carbons, e.g. cyclobutenyl, cyclopentenyl and cyclohexenyl.
"Heterocycloalkyl" means a monovalent cyclic radical of three to eight ring atoms, preferably 3-6 or 4-6 ring atoms, containing one, two or three ring heteroatoms independently selected from N, O and S(O)n (where n is an integer from 0 to 2), the remaining ring atoms being carbon where one or two carbon atoms may be a carbonyl group, in which there are no double or triple double bonds linking the ring atoms. Examples of such rings include, but are not limited to, oxirane, oxetane, tetrahydrofuran, tetrahydropyran, 1,3- dioxolane, 1 ,4-dioxane, aziridine, azetidine, pyrrolidine, piperidine, oxazinane, morpholine, thiomorpholine, imidazolidine, pyrazolidine and piperazine. More preferably, the heterocycloalkyl group contains three to five ring atoms including one O and/or one N ring atom.
"Aryl" means a monovalent moncyclic or bicyclic aromatic hydrocarbon radical of six to ten ring carbons atoms. Suitable aryl groups include phenyl and naphthyl, in particular, phenyl.
"Heteroaryl" means a monovalent monocyclic or bicyclic aromatic hydrocarbon radical of five to ten ring atoms, preferably five or six ring atoms, containing one, two, three or four ring heteroatoms selected, independently, from N, O or S, the remaining ring atoms being carbon. Examples of heteroaryl groups include, but are not limited to pyridyl, pyrimidinyl, pyrazolyl, thiazolyl, thiophenyl, isoazolyl, and tetrazolyl groups.
"Heterocyclic ring" or " heterocycle" means a saturated or fully unsaturated or partially unsaturated monovalent cyclic radical of three to eight ring atoms, preferably 3-6 or 4-6 ring atoms, containing one, two or three ring heteroatoms independently selected from N, O and S(O)n (where n is an integer from 0 to 2). A heterocyclic ring may be a heteroaryl group or a heterocycloalkyl group as defined above.
"Alkoxy" means a monovalent radical -OR, where R is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, or optionally substituted heteroaryl. In particular, R may be an optionally substituted Ci_6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-6 cycloalkyl, optionally substituted 3-6 membered heterocycloalkyl, optionally substituted C4-6 cycloalkenyl, optionally substituted phenyl, or optionally substituted heterophenyl. R may be an optionally substituted aralkyl or optionally substituted heteroaralkyl group. Preferably, an alkoxy group is selected from methoxy, ethoxy, 1-methylethoxy, propoxy, 1-methylpropoxy and 2-methylpropoxy. More preferably alkoxy means methoxy or ethoxy.
"Alkoxyalkyl" means a monovalent linear radical -RaORb, wherein Ra is an optionally substituted alkyl group, e.g. optionally substituted Ci_6 alkyl, and Rb is an optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl group, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl or optionally substituted heteroaryl group. In particular, Rb may be an optionally substituted Ci_6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-6 cycloalkyl, optionally substituted 3-6 membered heterocycloalkyl, optionally substituted C4-6 cycloalkenyl, optionally substituted phenyl, or optionally substituted heterophenyl. Rb may be an optionally substituted aralkyl or optionally substituted heteroaralkyl group, as defined herein.
"Halo" or "halogen" means fluoro, chloro, bromo or iodo, preferably chloro or fluoro.
"Haloalkyl" means alkyl as defined above substituted with one or more of the same or different halo atoms. A substituted alkyl group may be a haloalkyl group. Examples of haloalkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2-trifluoroethyl, 2-chloro-ethyl, 2-iodoethyl, 3-fluoropropyl, 3-chloropropyl, 2-trifluoro-l-chloroethyl and l-difluoro-2-difluoro-3-trifluoropropyl.
"Haloalkenyl" means alkenyl as defined above substituted with one or more of the same or different halo atoms. A substituted alkenyl group may be a haloalkenyl group.
Examples of haloalkenyl groups include, but are not limited to 2-dibromoethenyl, 2-fluoro-2- bromoethenyl, 5-bromopent-3-enyl and 3-dichloroprop-2-enyl.
"Aralkyl" means a monovalent radical -RaRb, wherein Ra is an alkylene or alkenylene group and Rb is an aryl group, each as defined above.
"Hetero aralkyl" means a monovalent radical -RaRb where Ra is an alkylene or alkenylene group and Rb is a heteroaryl group, each as defined above.
"Acyl" means a monovalent radical -C(O)R, wherein R is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl or optionally substituted heteroaryl. In particular, R may be an optionally substituted Ci_6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-6 cycloalkyl, optionally substituted 3-6 membered heterocycloalkyl, optionally substituted C4-6 cycloalkenyl, optionally substituted phenyl, or optionally substituted heterophenyl.
"Acyloxy" means a monovalent radical -OC(O)R, wherein R is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl or optionally substituted heteroaryl. In particular, R may be an optionally substituted Ci_6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-6 cycloalkyl, optionally substituted 3-6 membered heterocycloalkyl, optionally substituted C4-6 cycloalkenyl, optionally substituted phenyl, or optionally substituted heterophenyl.
The groups defined above, in particular, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl and heteroaryl groups, may be unsubstitued, or may be substituted by one or more substituents independently selected from halogen, hydroxyl, cyano, alkyl (optionally substituted by cyano), e.g. d-4 alkyl, haloalkyl, e.g. d-4 haloalkyl, alkenyl, e.g. C2-4 alkenyl, haloalkenyl, e.g. C2-4 haloalkenyl, alkynyl (optionally substituted by -C(O)OR), e.g. C2-4 alkynyl, haloalkynyl, e.g. C2-4 haloalkynyl, cycloalkyl (optionally substituted by cyano, halogen, hydroxyl or methyl), e.g. C3-6 cycloalkyl, heterocycloalkyl, e.g. 3-6 membered heterocycloalkyl, aryl (optionally substituted by halogen), e.g. phenyl, heteroaryl, e.g. heterophenyl, alkoxy (optionally substituted by alkoxy or acyl), e.g. O- C1 -4 alkyl, -C(O)R, -C(O)OR, -SR, -S(O)R, -S(O)2R, -S(O)NRR', -OS(O)NRR', -P(O)(OR)(OR'), -0(P)(O)(OR)(OR'), -NRR', -NRC(O)OR', -C(O)NRR', -0-N=CRR' or trialkylsilyl, wherein R and R' are, independently, hydrogen or alkyl, e.g. C1 -4 alkyl, alkoxy, e.g. -O-Ci-4 alkyl, haloalkyl, e.g. C1 -4 haloalkyl, alkenyl, e.g. C2-4 alkenyl, haloalkenyl, e.g. C2-4 haloalkenyl, alkynyl, e.g. C2-4 alkynyl, cycloalkyl, e.g. C3-6 cycloalkyl, heterocycloalkyl, aryl, e.g. phenyl, or heteroaryl, e.g. heterophenyl. In particular, R and R' are, independently, hydrogen or alkyl (in particular, methyl or ethyl). Preferred optional substituents are alkoxy (in particular, methoxy or ethoxy), hydroxyl, cyano, halogen (in particular, fluoro, chloro or bromo), heterocycloalkyl (in particular, oxirane or tetrahydrofuran), heteroaryl (in particular, pyridyl), -C(O)OR (wherein R is hydrogen or alkyl (in particular, methyl or ethyl)) and trialkylsilyl (in particular, trimethylsilyl). For example, the optional substituents of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl and heteroaryl groups may be independently selected from halogen, hydroxyl, Ci_4 alkyl, Ci_4 haloalkyl, -NH2, and cyano; in particular halogen.
For the avoidance of doubt, a group that is "optionally substituted" is either unsubstitued or is substitued with one or more substituents selected from those listed in the above paragraph.
The compounds of formula (I) may exist in different geometric or optical isomeric forms or in different tautomeric forms. One or more centres of chirality may be present, in which case compounds of the formula (I) may be present as pure enantiomers, mixtures of enantiomers, pure diastereomers or mixtures of diastereomers. There may be double bonds present in the molecule, such as C=C or C=N bonds, in which case compounds of formula (I) may be present as single isomers or mixtures of isomers. Centres of tautomerisation may be present. This invention covers all such isomers and tautomers and mixtures thereof in all proportions as well as isotopic forms such as deuterated compounds. Suitable salts of the compounds of formula (I) include acid addition salts such as those with an inorganic acid such as hydrochloric, hydrobromic, sulfuric, nitric or phosphoric acid, or an organic carboxylic acid such as oxalic, tartaric, lactic, butyric, toluic, hexanoic or phthalic acid, or a sulphonic acid such as methane, benzene or toluene sulphonic acid. Other examples of organic carboxylic acids include haloacids such as trifluoroacetic acid. This invention covers all such salts of compounds of formula (I).
N-oxides are oxidised forms of tertiary amines or oxidised forms of nitrogen containing heteroaromatic compounds. They are described in many books for example in "Heterocyclic N-oxides" by Angelo Albini and Silvio Pietra, CRC Press, Boca Raton, Florida, 1991. This invention covers all such N-oxide forms of compounds of formula (I).
In particularly preferred embodiments of the invention, the preferred groups for X1 and X2 and R1 to R25, in any combination thereof, are as set out below.
Preferably, G1 is CR8, G2 is CR1, and G3 is N.
Preferably, X1 is CH.
Preferably, X2 is CR5. More preferably, X2 is CH.
Preferably, R1 is:
(i) hydrogen, halogen, or cyano, (ii) optionally substituted Ci_6 alkyl, optionally substituted C2-6 alkenyl or optionally substituted C2-6 alkynyl, or (iii) optionally substituted aryl, e.g. optionally substituted phenyl, or -C(O)R10; wherein optional substituents in all cases are as defined above and, more preferably, are selected from hydroxyl, alkoxy, e.g. -0-C1-4 alkyl, halogen and trialkylsilyl. More preferably, R1 is hydrogen, halogen, cyano, optionally substituted Ci_6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted aryl, e.g. optionally substituted phenyl, or -C(O)R10. Even more preferably, R1 is hydrogen, chloro, bromo, cyano, methyl or 2-trimethylsilyl-ethynyl. Most preferably, R1 is hydrogen, chloro or methyl. Preferably, R2 is: (i) hydrogen, or
(ii) optionally substituted Ci_6 alkyl or optionally substituted O-Ci_6 alkyl, wherein the optional substituents are as defined above.
More preferably, R2 is hydrogen or Ci_6 alkyl.
Preferably, R3 is: (i) hydrogen or hydroxyl, (ii) optionally substituted Ci_6 alkyl, optionally substituted C2-6 alkenyl or optionally substituted C2-6 alkynyl,
(iii) optionally substituted cycloalkyl, e.g. optionally substituted C3-6 cycloalkyl, or (iv) -C(O)R12, -OR12, -C(O)OR12, -OC(O)R12 or -S(O)2R12; wherein the optional substitutents in all cases are as defined above and, more preferably, are selected from cyano, halogen, hydroxyl, Ci_4 alkyl, C2-4 alkenyl, alkoxy, e.g. -O-Ci_4 alkyl (optionally substituted by alkoxy, e.g. -O-Ci_4 alkyl, or acyl, e.g. -(O)C-C1-3 alkyl), cycloalkyl, e.g. C3-6 cycloalkyl, cycloalkenyl, e.g. C3-6 cycloalkenyl, heterocycloalkyl, e.g. 3-6-membered heterocycloalkyl, aryl, e.g. phenyl, heteroaryl, e.g. heterophenyl, -NH2, trialkylsilyl, -C(O)R and -C(O)OR (wherein R is hydrogen, methyl or ethyl). More preferably, R3 is hydrogen, hydroxyl, -C(O)R12, -OR12, -C(O)OR12, -OC(O)R12,
-S(O)2R12, optionally substituted Ci_6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted cycloalkyl, e.g. optionally substituted C3_6 cycloalkyl. Most preferably, R is hydrogen, cyanomethyl, aminoethyl, aminopropyl, ethenyl, prop-2-enyl, prop-2-ynyl, prop-l,2-dienyl, methoxymethyl, 2-fluoromethyl, 2- fluoroethyl, -0CH2C≡CH, -OCH2OCH3, -OCH2CN, -OCH(CH3)CN, -OCH2CH=CH2, or benzyl.
R3 may be optionally substituted Ci_6 alkyl, optionally substituted C2-6 alkenyl or optionally susbtituted C2-6 alkynyl, wherein the optional substituents of the alkyl, alkenyl and alkynyl are selected from cyano, methoxy, and halogen. For example, R is C3_4 alkenyl or C3_4 alkynyl.
Preferably, R4 is: (i) hydrogen or halogen, (ii) optionally substituted C2-6 alkynyl, or (iii) optionally substituted aryl, e.g. optionally substituted phenyl, or optionally substituted heteroaryl, e.g. optionally substituted heterophenyl; wherein the optional substituents in all cases are as defined above and, more preferably, are selected from hydroxyl, halogen (in particular, fluoro or chloro), haloalkyl, e.g. Ci_4 haloalkyl, acyl, e.g. -(O)C-C1-3 alkyl, and Ci_4 alkyl (in particular, methyl). The Ci_4 alkyl may be Ci_4 haloalkyl.
More preferably, R4 is hydrogen, halogen, optionally substituted C2-6 alkynyl or optionally substituted aryl, e.g. optionally substituted phenyl, or optionally substituted heteroaryl, e.g. optionally substituted heterophenyl. Even more preferably, R4 is phenyl, 3- methylphenyl, 3-trifluoromethylphenyl, 2-fluorophenyl, 3 -fluorophenyl, 4-fluorophenyl, 2,5- difluorophenyl, 3-methyl-4-fluorophenyl, 2,4-difluorophenyl, 2,6-diflurophenyl, or 2,4,6- diflurophenyl.
R4 may be phenyl optionally substituted by 1 to 3 groups independently selected from Ci_4 alkyl, Ci_4 haloalkyl and halogen, e.g. R4 is phenyl optionally substituted by 1-3 halogen atoms.
Preferably, R5 is: (i) hydrogen, or halogen,
(ii) optionally substituted Ci_6 alkyl, optionally substituted C2-6 alkenyl or optionally substituted C2-6 alkynyl, or
(iii) optionally substituted aryl, e.g. optionally substituted phenyl, optionally substituted heteroaryl, e.g. optionally substituted heterophenyl, optionally substituted cycloalkyl, e.g. optionally substituted C3-6 cycloalkyl, optionally substituted cycloalkenyl, e.g. optionally substituted C4-6 cycloalkenyl, or an optionally substituted heterocycylic ring formed with R6, e.g. a 5 or 6 membered heterocycle; wherein the optional substituents in all cases are as defined above and, more preferably, are selected from halogen, cyano, hydroxyl, Ci_4 haloalkyl and Ci_4 alkyl.
More preferably, R5 is hydrogen or halogen.
Preferably, R6 is:
(i) hydrogen, chloro, hydroxyl, or ethoxy,
(ii) optionally substituted aryl, e.g. optionally substituted phenyl, optionally substituted heteroaryl, e.g. optionally substituted heterophenyl, optionally substituted cycloalkyl, e.g. optionally substituted C3-6 cycloalkyl, optionally substituted cycloalkenyl, e.g. optionally substituted C4-6 cycloalkenyl, or an optionally substituted heterocyclic ring formed with R5 as defined above, e.g. a 5 or 6 membered heterocycle; or (iii) -C(O)OR18, -NR18R19 (e.g. NH2) or -N=CR20; wherein the optional substituents in all cases are as defined above. More preferably, R6 is hydrogen or -NR18R19, e.g. -NHR19. Most preferably, R6 is -
NHC(O)R23, in which R23 is preferably Ci_4 alkyl, e.g. ethyl, isopropyl, or cyclopropyl or cyclobutyl.
For example, R6 may be hydrogen or -NHR19 in which R19 is hydrogen, Ci_4 alkyl optionally substituted with hydroxy or Ci_4 alkoxy which in turn may be substituted by hydroxy, or R19 is -C(O)R23, and R23 is Ci_4 alkyl, C2-4 alkenyl, C2-4 alkynyl, or C3-4 cycloalkyl.
Preferably, R7 and R8 are, independently: (i) hydrogen, hydroxyl, or cyano, optionally substituted Ci_6 alkyl, wherein the optional subsituents are as defined above and, more preferably, are selected from halogen, cyano, hydroxyl and haloalkyl e.g. Ci_4 haloalkyl, or (ii) -NR21R22;
More preferably, R7 and R8 are, independently, hydrogen, hydroxyl, cyano -NR21R22, or optionally substituted Ci_6 alkyl. Most preferably, R7 and R8 are, independently, hydrogen, hydroxyl or NR21R22.
Preferably, R10, R11, R14, R15, R16 and R17 are, independently: (i) hydrogen, or (ii) optionally substituted Ci_6 alkyl, optionally substituted C2_6 alkenyl or optionally substituted C2_6 alkynyl, wherein the optional substituents are as defined above and, more preferably, are selected from hydroxyl, halogen, cyano and alkoxy, e.g. -O-Ci_4 alkyl.
More preferably R10, R11, R14, R15, R16 and R17 are, independently, hydrogen or optionally substituted Ci_3 alkyl. Most preferably, R10, R11, R14, R15, R16 and R17 are, independently, hydrogen, methyl or ethyl.
Preferably, R12 and R13 are, independently: (i) optionally substituted Ci_6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, or (ii) optionally substituted C3-6 cycloalkyl or optionally substituted C4-6 cycloalkenyl; wherein optional substituents in all cases are as defined above and, more preferably are selected from hydroxyl, halogen, cyano, alkoxy, e.g. -O-Ci_4 alkyl, cycloalkyl (optionally substituted with hydroxyl or methyl), e.g. C3-6 cycloalkyl, cycloalkenyl (optionally substituted with hydroxyl or methyl), e.g. C4-6 cycloalkenyl, -C(O)OR, and -OS(O)NRR' (wherein R and R' are, independently, hydrogen, alkyl, e.g. Ci_4 alkyl, alkenyl, e.g. Ci_4 alkenyl or alkynyl, e.g. Ci_4 alkynyl). More preferably, R12 and R13 are, independently, optionally substituted Ci_4 alkyl, including Ci_4 alkyl-0-Ci_4 alkyl, optionally substituted C2-4 alkenyl or optionally substituted C2-4 alkynyl. Most preferably, R12 and R13 are, independently, cyanomethyl, (1-methyl)- cyanomethyl, prop-2-enyl, prop-2-ynyl or methoxymethyl.
Preferably, R18 is:
(i) hydrogen, (ii) optionally substituted Ci_6 alkyl, optionally substituted C2-6 alkenyl or optionally substituted C2-6 alkynyl,
(iii) an optionally substituted heterocyclic ring formed with R19, e.g. a 5 or 6 membered heterocyclic ring, or
(iv) -C(O)R23, -C(O)OR23, -S(O)2R23 or -C(O)NR23R24; wherein the optional substituents in all cases are as defined above and, more preferably, are selected from hydroxyl, cyano, halogen and alkoxy, e.g. -O-Ci_4 alkyl.
More preferably, R18 is hydrogen, Ci_4 alkyl, C2-4 alkenyl, or C2-4 alkynyl. More preferably Ri 8 is hydrogen, ethyl, ώo-propyl, prop-2-enyl, prop-2ynyl or but-2-ynyl.
Preferably, R19 is: (i) hydrogen,
(ii) optionally substituted Ci_6 alkyl, optionally substituted C2-6 alkenyl or optionally substituted C2-6 alkynyl,
(iii) optionally substituted aryl, e.g. optionally substituted phenyl, optionally substituted heteroaryl, e.g. optionally substituted heterophenyl, optionally substituted cycloalkyl, e.g. optionally substituted C3-6 cycloalkyl, optionally substituted cycloalkenyl, e.g. optionally substituted C4-6 cycloalkenyl, or optionally substituted heterocycloalkyl, e.g. a 3-6 member optionally substituted heterocycloalkyl, or an optionally substituted heterocyclic ring formed with R18, e.g. a 5 or 6 membered heterocyclic ring, or
(iv) -C(S)R23, -C(O)R23, -C(O)OR23, -S(O)2R23 or -C(O)NR23R24, wherein the optional substituents in all case are as defined above and, more preferably, are selected from hydroxyl, cyano, halogen, alkoxy, e.g. -O-Ci_4 alkyl, cycloalkyl, e.g. C3-6 cycloalkyl, cycloalkenyl, e.g. C4-6 cycloalkenyl, and heterocycloalkyl, e.g. a 3-6-membered heterocycloalkyl;
More preferably, R19 is hydrogen, -C(S)R23, -C(O)R23 or -C(O)OR23 or optionally substituted d_4 alkyl. Most preferably, R19 is hydrogen, ώo-butyl, -C(O)R23 or -C(O)OR23.
Preferably, R20 is -NR21R22;
Preferably, R21 and R22 are, independently: (i) hydrogen,
(ii) optionally substituted Ci_6 alkyl, e.g. Ci_4 alkyl, wherein optional substituents are as defined above and, more preferably, are selected from hydroxyl, cyano, halogen, alkoxy, e.g. -O-Ci_4 alkyl, acyl, e.g. -(O)C-C1-3 acyl, cycloalkyl, e.g. C3-6 cycloalkyl, cycloalkenyl, e.g. C4-6 cycloalkenyl, heterocycloalkyl, e.g. a 3-6-membered heterocycloalkyl, or
(iii) -C(O)OR25.
More preferably, R21 and R22 are, independently, hydrogen or optionally substituted
Ci_4 alkyl. Most preferably, R21 and R22 are, independently, hydrogen, methyl or ethyl.
Preferably, R23 and R24 are, independently:
(i) hydrogen or hydroxyl, (ii) optionally substituted Ci_6 alkyl, optionally substituted C2-6 alkenyl or optionally substituted C2-6 alkynyl, or
(iii) optionally substituted cycloalkyl, e.g. optionally substituted C3_6 cycloalkyl, optionally substituted cycloalkenyl, e.g. optionally substituted C4_6 cycloalkenyl or optionally substituted aryl, e.g. optionally substituted phenyl; wherein the optional substituents in all cases are as defined above and, more preferably, are selected from hydroxyl, halogen, cyano, Ci_4 alkyl, alkoxy, e.g. -O-Ci_4 alkyl, cycloalkyl, e.g. C3-6 cycloalkenyl, cycloalkenyl e.g. C4-6 cycloalkenyl, and -C(O)OR (wherein R is cycloalkyl, e.g. C3-6 cycloalkyl, or cycloalkenyl, e.g. C4-6 cycloalkenyl).
More preferably, R23 and R24 are, independently, hydrogen, hydroxyl, optionally substituted Ci_6 alkyl, e.g. Ci-6 alkyl-O-Ci_6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted cycloalkyl, e.g. optionally substituted C3-6 cycloalkyl, or optionally substituted cycloalkenyl, e.g. optionally substituted C4-6 cycloalkenyl. Most preferably R23 and R24 are, independently, methyl, ethyl, ώo-propyl, methoxymethyl, cyclopropyl or cyclo butyl, in which the cyclopropyl or cyclo butyl group may be substituted with one or more substituents being selected from cyano, halogen (preferably fluoro), Ci_4 alkyl (preferably methyl or ethyl) or haloalkenyl.
Preferably, R25 is Ci_4 alkyl. More preferably, R25 is methyl, ethyl, propyl or 2- dimethylethyl.
In a particularly preferred embodiment, when R3 is hydrogen, R6 is other than hydrogen. More preferably, R3 is hydrogen and R6 is -NR18R19. More preferably, R3 is hydrogen and R6 is -NHR19. More preferably, R3 is hydrogen and R6 is -NHC(O)R23.
In an alternative preferred embodiment, R6 is hydrogen and R3 is other than hydrogen. More preferably, R6 is hydrogen and R3 is -OR12 or optionally substituted Ci_6 alkyl, C2-4 alkenyl, e.g. C3_4 allenyl, or C2-4 alkynyl. Most preferably, R6 is hydrogen and R3 is cyanomethyl, aminoethyl, aminopropyl, prop-2-enyl, prop-2-ynyl, prop-l,2-dienyl, methoxymethyl, 2-fluoromethyl, -OCH2C≡CH, -OCH2OCH3, -OCH2CN, -OCH(CH3)CN.
For example, the method of the invention may utilise a compound of the formula (Ia):
Figure imgf000018_0001
wherein X1, X2, R1, R2, R3, R4, R6, and R7 are as defined above for the compound of formula (I), in any combination thereof. The method of the invention may utilise a compound of the formula (Ib):
Figure imgf000019_0001
wherein X1, X2, R2, R3, R4, R6, R7, and R8 are as defined above for the compound of formula (I), in any combination thereof.
The method of the invention may utilise a compound of the formula (Ic):
Figure imgf000019_0002
wherein X1, X2, R1, R3, R4, R6, R7, and R8 are as defined above for the compound of formula (I), in any combination thereof.
In a particular embodiment, the method of the invention utilises a compound of formula (Id):
Figure imgf000019_0003
wherein:
any one of G1, G2 and G3 is N and the other two of G1, G2 and G3 are CR8, CR1 or CR2, such that when G1 is not N, G1 is CR8; when G2 is not N, G2 is CR1; when G3 is not N, G3 is CR2; R1, R2, R3, R4, R6 and R8 are as defined for formula (I) above, in any combination thereof; and, preferably, in any combination:
R1 is hydrogen, halogen, cyano, optionally substituted Ci_6 alkyl (in particular, optionally substituted Ci_4 alkyl and, most particularly, optionally substituted methyl or ethyl, wherein the optional substitutent is as defined above and more preferably is hydroxyl, e.g. 1-hydroxylethyl) or -C(O)R10 in which R10 is hydrogen or Ci_4 alkyl;
R2 is hydrogen, halogen or Ci_4 alkyl;
R3 is hydrogen, hydroxyl, cyano, optionally substituted Ci_6 alkyl, optionally substituted C2-6 alkenyl, including optionally substituted C3-6 allenyl, optionally substituted C2-6 alkynyl, -NR12R13, -OR12 or -C(O)R12, wherein:
(a) the optional substituents on the alkyl, alkenyl and alkynyl groups are as defined above and, more preferably, are independently selected from halo, cyano, hydroxyl, alkoxy (optionally substituted by alkoxy or acyl), e.g. -O-Ci_4 alkyl, Ci_4 alkyl, C2-4 alkenyl, cycloalkyl, e.g. C3-6 cycloalkyl, cycloalkenyl, e.g. C4-6 cycloalkenyl, heterocycloalkyl, e.g. 3-6 membered heterocycloalkyl, aryl, e.g. phenyl, heteroaryl, e.g. heterophenyl,
-C(O)R, -C(O)OR and -SR, wherein R is hydrogen, Ci_4 alkyl, C2-4 alkenyl or C2-4 alkynyl, and
(b) R12 and R13 are, independently, optionally substituted alkyl, e.g. optionally substituted Ci_6 alkyl, optionally substituted alkenyl, e.g. optionally substituted C2-6 alkenyl, optionally substituted alkynyl, e.g. optionally substituted C2-6 alkenyl, optionally substituted cycloalkyl, e.g. optionally substituted C3-6 cycloalkyl, or optionally substituted cycloalkenyl, e.g. optionally substituted C4_6 cycloalkenyl; the optional substituents being as defined above and, more preferably, halo, cyano, hydroxyl, alkoxy, e.g. -O-Ci_4 alkyl, cycloalkyl, e.g. C3-6 cycloalkyl, cycloalkenyl, e.g. C4_6 cycloalkenyl, heterocycloalkyl, e.g. 3-6 membered heterocycloalkyl, -C(O)R, -C(O)OR or -OS(O)NRR', wherein R and R' are, independently, hydrogen or alkyl, e.g. Ci_4 alkyl; R4 is optionally substituted aryl (in particular, optionally substituted phenyl or optionally substituted naphthyl), the optional substituents being as defined above and, more preferably halogen or Ci_4 alkyl;
R6 is hydrogen, halogen or -NR18R19, wherein:
(a) R18 is hydrogen, -C(O)R23, -C(O)OR23 or optionally substituted Ci_4 alkyl, optionally substituted C2-4 alkenyl or optionally substituted C2-4 alkynyl, in which R23 is optionally substituted Ci_4 alkyl, the optional substituents being as defined above, and
(b) R19 is hydrogen, optionally substituted Ci_4 alkyl, optionally substituted C2-4 alkenyl, optionally substituted C2-4 alkynyl, -C(S)R23 -C(O)R23 or -C(O)OR23, in which R23 is hydrogen, optionally substituted Ci_4 alkyl, optionally substituted C2-4 alkenyl, optionally substituted C2-4 alkynyl, optionally substituted C3-6 cycloalkyl or optionally substituted C3-6 cycloalkenyl, the optional substituents being as defined above;
R8 is hydrogen, halogen or Ci_4 alkyl.
More preferably, in any combination thereof, R1 is hydrogen, halo or optionally substituted Ci_4 alkyl, wherein the optional substituent is preferably hydro xyl; R2 and R8 are, independently: hydrogen, methyl, ethyl or chloro; R3 is hydrogen, -OR12, optionally substituted Ci_4 alkyl, optionally substituted C2-4 alkenyl, or optionally substituted C2-4 alkynyl; R4 is phenyl, which is optionally substituted by at least one substituent selected from halogen and Ci_4 alkyl (in particular, methyl); R6 is halogen or -NR18R19, wherein R18 is hydrogen, prop-2-enyl or prop-2-ynyl, and R19 is -C(O)R23, in which R23 is hydrogen, methyl, ethyl, ώo-propyl, 1-methylethyl, 1-methylpropyl, 2-dimethylethyl, propyl, 1- methylethenyl, 2-methylprop-l-enyl, but-3-enyl, cyclopropyl, 1-methylcyclopropyl, 1- fluorocyclopropyl or cyclobutyl.
Even more preferably, in any combination thereof, R1 is hydrogen, chloro or methyl; R2 and R8 are, independently, hydrogen, methyl, ethyl or chloro; R3 is hydrogen, cyanomethyl, prop- 2-enyl or prop-2-ynyl; R4 is phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 4- chlorophenyl, 3-methylphenyl or 3-methyl-4-fluorophenyl; R6 is -NR18R19 in which R18 is hydrogen and R19 is -C(O)R23, in which R23 is methyl, ethyl, ώo-propyl, cyclopropyl, eye Io butyl or 1-methylcyclopropyl.
For example, the method of the invention may utilise a compound of formula (Ie):
Figure imgf000022_0001
wherein R1, R2, R3, R4 and R6 are as defined above for compound (Id), in any combination thereof.
The method of the invention may utilise a compound of formula (If):
Figure imgf000022_0002
wherein R2, R3, R4, R6 and R8 are as defined above for compound (Id), in any combination thereof.
The method of the invention may utilise a compound of formula (Ig):
Figure imgf000022_0003
wherein R1, R3, R4, R6 and R8 are as defined above for compound (Id), in any combination thereof. In a particular embodiment, the method of the invention utilises a compound of formula (Ih):
Figure imgf000023_0001
wherein:
any one of G1, G2 and G3 is N and the other two of G1, G2 and G3 are CR8, CR1 or CR2, such that when G1 is not N, G1 is CR8; when G2 is not N, G2 is CR1; when G3 is not N, G3 is CR2;
wherein R1, R2, R3, R4, R6, R7 and R8 are as defined for formula (I) above, in any combination thereof; and preferably:
R1 is hydrogen, halogen, optionally substituted Ci_6 alkyl or -C(O)R10, in which R10 is hydrogen or Ci_4 alkyl, the optional substituents being as defined above;
R is hydrogen or Ci_4 alkyl;
R3 is hydrogen, hydroxyl, optionally substituted Ci_6 alkyl, optionally substituted C2-6 alkenyl or optionally substituted C2-6 alkynyl, -C(O)R12 or -OR12, in which R12 is optionally substituted Ci .4 alkyl, optionally substituted C3-6 cycloalkyl, or optionally substituted C4-6 cycloalkenyl, the optional substituents in all cases being as defined above and, more preferably, selected from halogen, cyano, hydroxyl, alkoxy, e.g. -O-Ci_4 alkyl, cycloalkyl, e.g. C3_6 cycloalkyl, cycloalkenyl, e.g. C4_6 cycloalkenyl, heterocycloalkyl, e.g. 3-6- membered cycloalkyl, aryl, e.g. phenyl, heteroaryl, e.g. heterophenyl, -NH2, trialkylsilyl and C(O)OR, wherein R is hydrogen, Ci_4 alkyl, C2-4 alkenyl or C2-4 alkynyl;
R4 is optionally substituted aryl, the optional substituents being as defined above and, more preferably halogen or Ci_4 alkyl; R6 is hydrogen, halogen, hydroxyl, -O-Ci_6 alkyl, or -NR18R19, wherein:
(a) R18 is hydrogen, -C(O)R23, -C(O)OR23, optionally substituted Ci_4 alkyl, optionally substituted C2-4 alkenyl or optionally substituted C2-4 alkynyl, in which R23 is optionally substituted Ci_4 alkyl, the optional substituents being as defined above, and
(b) R19 is hydrogen, optionally substituted Ci_4 alkyl, optionally substituted C2-4 alkenyl, optionally substituted C2-4 alkynyl, -C(S)R23 -C(O)R23 or -C(O)OR23, in which R23 is hydrogen, optionally substituted Ci_4 alkyl, optionally substituted C2-4 alkenyl, optionally substituted C2-4 alkynyl, optionally substituted C3-6 cycloalkyl or optionally substituted C4-6 cycloalkenyl, the optional substituents being as defined above;
R is hydrogen, halogen or Ci_4 alkyl; and
R is hydrogen, halogen, Ci _4 alkyl or NR R , in which R and R are, independently, hydrogen or Ci_4 alkyl.
More preferably, in any combination thereof, R1 is hydrogen, halo or optionally substituted Ci_4 alkyl, the optional substituents being as defined above; R2 is hydrogen or methyl; R3 is hydrogen, optionally substituted Ci_4 alkyl, optionally substituted C2-4 alkenyl, optionally substituted C2-4 alkynyl, or -OR12, in which R12 is optionally substituted Ci_4 alkyl, optionally substituted C3-6 cycloalkyl or optionally substituted C4_6 cycloalkenyl, the optional substituents in all cases being as defined above; R4 is phenyl, which is optionally substituted by at least one substituent selected from halogen and Ci_4 alkyl; R6 is halogen or -NR18R19, in which R18 is hydrogen, prop-2-enyl or prop-2-ynyl, and R19 is -C(O)R23, in which R23 is hydrogen, methyl, ethyl, ώo-propyl, 1-methylethyl, 1-methylpropyl, 2-dimethylethyl, propyl, 1-methylethenyl, 2-methylprop-l-enyl, but-3-enyl, cyclopropyl, 1-methylcyclopropyl, 1- fluorocyclopropyl or cyclobutyl; R7 is hydrogen, chloro, fluoro or methyl; and R8 is hydrogen, chloro, methyl or 2-methoxy-l-ethylamino.
Even more preferably, in any combination thereof, R1 is hydrogen, chloro or methyl; R2 is hydrogen or methyl; R3 is hydrogen, cyanomethyl, prop-2-enyl, prop-2-ynyl or benzyl; R4 is 2-fluorophenyl, 3 -fluorophenyl, 4-fluorophenyl, 4-chlorophenyl, 3-methylphenyl or 3- methyl-4-fluorophenyl; R6 is -NR18R19, in which R18 is hydrogen, and R19 is -C(O)R23, in which R23 is methyl, ethyl, ώo-propyl, cyclopropyl, eye Io butyl or 1-methylcyclopropyl; R7 is hydrogen, chloro, fluoro or methyl; and R8 is hydrogen, chloro or methyl.
For example the method of the invention may utilise a compound of formula l(h) in which: R1 is hydrogen, halogen, -NH-CM alkyl, -NH-CM haloalkyl, wherein the Ci_4 alkyl and Ci_4 haloalkyl are optionally substituted by Ci_4 alkoxy or Ci_4 haloalkoxy; R2 is hydrogen, halogen, hydroxy, -NH-Ci_4 alkyl, -NH-Ci_4 haloalkyl, -N(Ci-4 alkyl)-Ci_4 alkyl, -N(Ci-4 haloalkyl)-Ci_4 alkyl, -N(Ci-4 alkyl)-CM haloalkyl, -N(Ci-4 haloalkyl)-CM haloalkyl, -NH-C3_6 cycloalkyl, -NH-C3_6 halocycloalkyl; R3 is hydrogen, Ci_4 alkyl, Ci_4 haloalkyl, C2-4 alkenyl, C2-4 haloalkenyl, C2-4 alkynyl, C2-4 haloalkynyl, wherein the alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl and haloalkynyl are optionally substited by a substituent selected from cyano, Ci_4 alkoxy and Ci_4 haloalcoxy, or R3 is benzyl optionally substituted with 1-3 substituents selected from halogen, cyano, Ci_4 alkoxy and Ci_4 haloalkoxy; R4 is phenyl optionally substituted with 1-3 halogen atoms;
R6 is hydrogen, halogen, hydroxy, Ci_4 alkoxy, Ci_4 haloalkoxy, -NH2, -NH-CM alkyl, -NH- Ci_4 haloalkyl, wherein the alkyl and haloalkyl are optionally substituted by hydroxy or Ci_4 alkoxy, which in turn may be substituted by hydroxy, or R6 is -NH-C(O)-C 1-4 alkyl, -NH- C(O)-CL4 haloalkyl, -NH-C(O)-C3-6 cycoalkyl, -NH-C(O)-C3-6 halocycloalkyl, -NH-C(O)- C2-4 alkenyl, NH-C(O)-C2-4 haloalkenyl, -NH-C(O)-C2-4 alkynyl, or -NH-C(O)-C2-4 haloalkynyl;
R7 is hydrogen or halogen; R8 is hydrogen or halogen.
For example the method of the invention may utilise a compound of formula l(h) in which: R1 is hydrogen, -NH-CM alkyl, wherein the CM alkyl is optionally substituted by methoxy; R2 is hydrogen or halogen;
R3 is hydrogen, CM alkyl, C3_4 alkenyl, C3_4 alkynyl, wherein the CM alkyl is optionally substited by cyano or methoxy; R4 is phenyl optionally substituted with 1-3 halogen atoms;
R6 is hydrogen,-NH-Ci_4 alkyl, wherein the alkyl is optionally substituted by hydroxy or CM alkoxy, which in turn may be substituted by hydroxy, or R6 is -NH-C(O)-C1-4 alkyl, NH- C(O)-C3-4 cycoalkyl, -NH-C(O)-C3-4 alkenyl, or -NH-C(O)-C2-4 alkynyl; R7 is hydrogen or halogen; R8 is hydrogen or halogen.
The method of the invention may utilise a compound of formula (Ii):
Figure imgf000026_0001
wherein R1, R2, R3, R4, R6, and R7 are as defined for formula (Ih) above, in any combination thereof.
The method of the invention may utilise a compound of formula (Ij):
Figure imgf000026_0002
wherein R2, R3, R4, R6, R7, and R8 are as defined for formula (Ih) above, in any combination thereof.
The method of the invention may utilise a compound of formula (Ik):
Figure imgf000026_0003
wherein R1, R3, R4, R6, R7, and R8 are as defined for formula (Ih) above, in any combination thereof. In a particular embodiment, the method of the invention utilises a compound of formula (II)
Figure imgf000027_0001
wherein:
any one of G1, G2 and G3 is N and the other two of G1, G2 and G3 are CR8, CR1 or CR2, such that when G1 is not N, G1 is CR8; when G2 is not N, G2 is CR1; when G3 is not N, G3 is CR2; and preferably, in any combination:
R1 is hydrogen, halogen or Ci_4 alkyl;
R2 is hydrogen, halogen or Ci_4 alkyl;
R , 3 is hydrogen, optionally substituted Ci_6 alkyl, optionally substituted C2-6 alkenyl or optionally substituted C2-6 alkynyl, the optional substituents being as defined above and, more preferably, halogen or alkoxy, e.g. -O-Ci_4 alkyl;
R4 is optionally substituted aryl, e.g. optionally substituted phenyl, the optional subsituents being as defined above and, more preferably, halogen;
R6 is hydrogen, -SR18 or -NR18R19, wherein R18 is hydrogen or Ci_4 alkyl, and R19 is optionally substituted C1-4alkyl, -C(S)R23 or -C(O)R23, and R23 is hydrogen or Ci_4 alkyl, the optional substituents being as defined above;
R7 is hydrogen, halogen or Ci_4 alkyl; and
R8 is hydrogen, halogen or Ci_4 alkyl. More preferably, in any combination thereof: R1 is hydrogen, methyl, ethyl or chloro; R2 is hydrogen, methyl, ethyl or chloro; R3 is hydrogen, halo-Ci_4 alkyl, Ci_4 alkyl-O-Ci_4 alkyl, Ci_4 alkyl, C2-4 alkenyl or C2-4 alkynyl, in particular hydrogen, 2-fluoroethyl, methoxymethyl, prop-l,2-diene or prop-2-ynyl; R4 is optionally substituted phenyl, the optional substituent being halogen, e.g. fluoro; R6 is hydrogen or -NR18R19, wherein R18 is hydrogen, and R19 is 2-methoxy-l-methylethyl, -C(S)R23 or -C(O)R23, and R23 is Ci_4 alkyl, in particular 1- methylethyl, 1-dimethylethyl or 3-methylpropyl; R7 is hydrogen, methyl, ethyl or chloro; and R8 is hydrogen, methyl, ethyl or chloro.
The method of the invention may utilise a compound of formula (Im):
Figure imgf000028_0001
wherein R1, R2, R3, R4, R6 and R7 are as defined for formula (II) above, in any combination thereof.
The method of the invention may utilise a compound of formula (In):
Figure imgf000028_0002
wherein R2, R3, R4, R6, R7 and R8 are as defined for formula (II) above, in any combination thereof.
The method of the invention may utilise a compound of formula (Io):
Figure imgf000029_0001
wherein R1, R3, R4, R6, R7 and R8 are as defined for formula (II) above, in any combination thereof.
Examples of compounds for use in the present invention are shown in Tables I, II and III below:
Figure imgf000030_0001
Figure imgf000031_0001
Figure imgf000032_0001
Figure imgf000033_0001
Figure imgf000034_0001
Table Ia - HPLC-MS or MS data of Certain Compounds of Table I
Figure imgf000035_0001
Method: see under "Examples" for details of Method A; Method B; Method C and Method D.
Figure imgf000036_0001
Figure imgf000037_0001
Figure imgf000038_0001
Figure imgf000038_0002
In a further aspect, the present invention provides a compound of formula (I) as defined above with the provisos that:
(i) when G1 is CR8, G2 is CR1, G3 is N, X1 is CH, X2 is CR5, and R5 and R6 are both H, then R4 is not 4-fluorophenyl; and
(ii) the compound of formula (I) is not: 7-phenyl-6-(pyridin-4-yl)-5H-pyrrolo[3,2-c]pyridazine; 7-phenyl-6-(pyridin-4-yl)-5H-pyrrolo[3,2-d]pyrimidine; 7-phenyl-6-(pyridin-4-yl)-5H-pyrrolo[2,3-b]pyrazine;
7-(3-chlorophenyl)-6-[2-(2-methylthioethylamino)-4-pyridyl]-5H-pyrrolo[2,3-b]pyrazine; 7-(3-chlorophenyl)-6-(2-chloropyridin-4-yl)-5H-pyrrolo[2,3-b]pyrazine; or 7-(4-fluorophenyl)-6-(pyridine-4-yl)-5H-pyrrolo[3,2-d]pyrimidine.
The also invention provides a compound of formula (Ia) as defined above, with the proviso that the compound of formula (Ia) is not: 7-phenyl-6-(pyridin-4-yl)-5H-pyrrolo[3,2-c]pyridazine.
The invention also provides a compound of formula (Ib) as defined above, with the proviso that the compound of formula (Ib) is not: 7-phenyl-6-(pyridin-4-yl)-5H-pyrrolo[3,2-d]pyrimidine; or 7-(4-fluorophenyl)-6-(pyridine-4-yl)-5H-pyrrolo[3,2-d]pyrimidine.
The invention also provides a compound of formula (Ic) as defined above, with the provisos that:
(i) when X1 is CH, X2 is CR5, and R5 and R6 are both H, then R4 is not 4- fluorophenyl; and
(ii) the compound of formula (Ic) is not: 7-phenyl-6-(pyridin-4-yl)-5H-pyrrolo[2,3-b]pyrazine.
7-(3-chlorophenyl)-6-[2-(2-methylthioethylaminjo)-4-pyridyl]-5H-pyrrolo[2,3-b]pyrazine; or 7-(3-chlorophenyl)-6-(2-chloropyridin-4-yl)-5H-pyrrolo[2,3-b]pyrazine. The invention also provides a compound of formula (Id), (Ih) or (II) as defined above, with the provisos that:
(i) when G1 is CR8, G2 is CR1, G3 is N, then R4 is not 4-fluorophenyl; and (ii) the compound of formula (Id), (Ih) or (II) is not: 7-phenyl-6-(pyridin-4-yl)-5H-pyrrolo[3,2-c]pyridazine; 7-phenyl-6-(pyridin-4-yl)-5H-pyrrolo[3,2-d]pyrimidine; 7-phenyl-6-(pyridin-4-yl)-5H-pyrrolo[2,3-b]pyrazine;
7-(3-chlorophenyl)-6-[2-(2-methylthioethylamino)-4-pyridyl]-5H-pyrrolo[2,3-b]pyrazine; 7-(3-chlorophenyl)-6-(2-chloropyridin-4-yl)-5H-pyrrolo[2,3-b]pyrazine; or 7-(4-fluorophenyl)-6-(pyridine-4-yl)-5H-pyrrolo[3,2-d]pyrimidine.
The invention also provides a compound of formula (Ie), (Ii) or (Im) as defined above, with the proviso that the compound of formula (Ie), (Ii) or (Im) is not:
7-phenyl-6-(pyridin-4-yl)-5H-pyrrolo[3,2-c]pyridazine.
The invention also provides a compound of formula (If), (Ij) or (In) as defined above, with the proviso that the compound of formula (If), (ij) or (In) is not:
7-phenyl-6-(pyridin-4-yl)-5H-pyrrolo[3,2-d]pyrimidine; or
7-(4-fluorophenyl)-6-(pyridine-4-yl)-5H-pyrrolo[3,2-d]pyrimidine.
The invention also provides a compound of formula (Ig), (Ik) or (Io) as defined above, with the provisos that:
(i) R4 is not 4-fluorophenyl; and (ii) the compound of formula (Ig), (Ik) or (Io) is not: 7-phenyl-6-(pyridin-4-yl)-5H-pyrrolo[2,3-b]pyrazine;
7-(3-chlorophenyl)-6-[2-(2-methylthioethylamino)-4-pyridyl]-5H-pyrrolo[2,3-b]pyrazine; or
7-(3-chlorophenyl)-6-(2-chloropyridin-4-yl)-5H-pyrrolo[2,3-b]pyrazine.
Generally, the present invention provides a compound of any one of formulas (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (II), (Im), (In), and (Io) with the proviso that the compound is not one that is disclosed in WO 99/20624. For the avoidance of doubt, the compounds listed above are named according to the scheme outlined on pages 17 and 18 of WO 99/20624. WO 99/20624 is incorporated herein by reference. The invention also provides a compound of any one of formulas (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (II), (Im), (In), and (Io), wherein, when present: G1, G2, G3, X1, X2, R1, R2, R3, R4, R5, R7, R8, R10, R11, R12, R13, R14, R15, R16, R17, R20, R21, R22, R23, R24, and R25 are as defined above for formula (I), in any combination thereof, and, in any combination:
R6 is:
(i) hydroxyl, or ethoxy,
(ii) optionally substituted aryl, e.g. optionally substituted phenyl, optionally substituted heteroaryl, e.g. optionally substituted heterophenyl, optionally substituted cycloalkyl, e.g. optionally substituted C3-6 cycloalkyl, optionally substituted cycloalkenyl, e.g. optionally substituted C4-6 cycloalkenyl, or an optionally substituted heterocyclic ring formed with R5 as defined above, e.g. a 5 or 6 membered heterocycle; or (iii) -C(O)OR18, -NR18R19 (e.g. NH2) or -N=CR20; wherein the optional substituents in all cases are as defined above.
More preferably, R6 is -NR18R19, e.g. -NHR19. Most preferably, R6 is -NHC(O)R23, in which R23 is preferably Ci_4 alkyl, e.g. ethyl, isopropyl, or cyclopropyl or cyclobutyl.
R18 is: (i) hydrogen,
(ii) Ci_6 alkyl, optionally substituted C2-6 alkenyl or optionally substituted C2-6 alkynyl, (iii) an optionally substituted heterocyclic ring formed with R19, e.g. a 5 or 6 membered heterocycle, or
(iv) -C(O)R23, -C(O)OR23, -S(O)2R23 or -C(O)NR23R24; wherein optional substituents in all cases are as defined above and, more preferably, are selected from hydroxyl, cyano, halogen and alkoxy, e.g. -O-Ci_4 alkyl.
More preferably, R18 is hydrogen, Ci_4 alkyl, C2-4 alkenyl, or C2-4 alkynyl. More preferably Ri 8 is hydrogen, ethyl, ώo-propyl, prop-2-enyl, prop-2ynyl or but-2-ynyl.
R19 is:
(i) hydrogen,
(ii) Ci_6 alkyl, optionally substituted C2-6 alkenyl or optionally substituted C2-6 alkynyl, (iii) optionally substituted aryl, e.g. optionally substituted phenyl, optionally substituted heteroaryl, e.g. optionally substituted heterophenyl, optionally substituted cycloalkyl, e.g. optionally substituted C3-6 cycloalkyl, optionally substituted cycloalkenyl, e.g. optionally substituted C4-6 cycloalkenyl, or optionally substituted heterocycloalkyl, e.g. a 3-6 membered optionally substituted heterocycloalkyl, or an optionally substituted heterocyclic ring formed with R18, e.g. a 5 or 6 membered heterocycle, or (iv) -C(S)R23, -C(O)R23, -C(O)OR23, -S(O)2R23 or -C(O)NR23R24, wherein the optional substituents in all case are as defined above and, more preferably, are selected from hydroxyl, cyano, halogen, alkoxy, e.g. -O-Ci_4 alkyl, cycloalkyl, e.g. C3-6 cycloalkyl, cycloalkenyl, e.g. C4-6 cycloalkenyl, and heterocycloalkyl, e.g. a 3-6-membered heterocycle; More preferably, R19 is hydrogen, -C(S)R23, -C(O)R23 or -C(O)OR23 or Ci-4 alkyl.
Most preferably, R19 is hydrogen, wo-butyl, -C(O)R23 or -C(O)OR23.
The invention also provides a compound of any one of formulas (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (II), (Im), (In), and (Io), wherein, when present: G1, G2, G3, X1, X2, R1, R2, R4, R5, R6, R7, R8, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, and R25 are as defined above for formula (I), in any combination thereof, and:
R3 is: (v) hydroxyl,
(vi) optionally substituted Ci_6 alkyl, optionally substituted C2-6 alkenyl or optionally substituted C2-6 alkynyl,
(vii) optionally substituted cycloalkyl, e.g. optionally substituted C3-6 cycloalkyl, or (viii) -C(O)R12, -OR12, -C(O)OR12, -OC(O)R12 or -S(O)2R12; wherein the optional substitutents in all cases are as defined above and, more preferably, are selected from cyano, halogen, hydroxyl, Ci_4 alkyl, C2-4 alkenyl, alkoxy, e.g. -O-Ci_4 alkyl (optionally substituted by alkoxy, e.g. -O-Ci_4 alkyl, or acyl, e.g. -(O)C-C1-3 alkyl), cycloalkyl, e.g. C3-6 cycloalkyl, cycloalkenyl, e.g. C3_6 cycloalkenyl, heterocycloalkyl, e.g. 3-6-membered heterocycloalkyl, aryl, e.g. phenyl, heteroaryl, e.g. heterophenyl, -NH2, trialkylsilyl, -C(O)R and -C(O)OR (wherein R is hydrogen, methyl or ethyl).
More preferably, R3 is hydroxyl, -C(O)R12, -OR12, -C(O)OR12, -OC(O)R12, -S(O)2R12, optionally substituted Ci_6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted cycloalkyl, e.g. optionally substituted C3_6 cycloalkyl. Most preferably, R3 is cyanomethyl, aminoethyl, aminopropyl, ethenyl, prop-2- enyl, prop-2-ynyl, prop-l,2-dienyl, methoxymethyl, 2-fluoromethyl, 2-fluoroethyl, - OCH2C≡CH, -OCH2OCH3, -OCH2CN, -OCH(CH3)CN, -OCH2CH=CH2, or benzyl.
In a further aspect, the invention relates to a process for the preparation of a compound the of the invention, e.g. compounds of formula (I), as defined according to any of the aspects above, comprising: a) cyclising a compound of formula (F)
Figure imgf000043_0001
wherein G1, G2, G3, R1, R2, R4 and R8 are as defined for formula (I), X is a halogen, and R is a group of formula:
Figure imgf000043_0002
and X1, X2, R6 and R7 are as defined for formula (I),
to give an azaindole of formula (G):
Figure imgf000043_0003
and, optionally, derivitising at the secondary amine position with a group R3, wherein R3 is as defined for formula (I); preferably said derivatisation is by reaction with R -LG, wherein LG is a leaving group and R3 is an alkyl group, or by reaction with R12CO-LG, wherein R12 is as defined for formula (I) and LG is a leaving group; or b) reacting an azaindole of formula (K)
Figure imgf000044_0001
wherein G1, G2, G3, R1, R2 and R8 are as defined for formula (I), R is as defined above, and LG is a leaving group,
with a compound of formula R4-B(OH)2, wherein R4 is as defined for formula (I), to give a compound of formula (G) as defined above,
and, optionally, derivitising at the secondary amine position with a group R3, wherein R3 is as defined for formula (I); preferably said derivatisation is by reaction with R3-LG, wherein LG is a leaving group and R3 is an alkyl group, or by reaction with R12CO-LG, wherein R12 is as defined for formula (I) and LG is a leaving group; or
c) reacting a compound of formula (S)
Figure imgf000044_0002
wherein G1, G2, G3, R1, R2, R4, and R8 are defined for formula (I), and R is as defined above,
with a compound of formula R12-LG, wherein R12 is as defined for formula (I) and LG is a leaving group to give a compound of formula (T)
Figure imgf000044_0003
Suitable leaving groups, as mentioned in (a), (b), and (c), are well known in the art and may be, for example, halogen, triflate or mesylate.
A method of the present invention may include converting a compound of formula (I) to a salt of N-oxide thereof.
For the avoidance of doubt, the compounds of the invention cover all possible combinations of substituents, as defined herein.
The skilled person will, or course, appreciate that the compounds of the invention can be made by various other methods.
Compounds of the invention and compounds for use in the methods of the invention can be made, for example, by following the reaction scheme and the methods detailed below. The starting materials used for the preparation of the compounds of the invention may be purchased from usual commercial suppliers or may be prepared according to procedures known to the person skilled in the art. The starting materials as well as the intermediates may be purified before use in the next step by state of the art methodologies such as chromatography, crystallization, distillation and filtration.
The schemes listed below to exemplify the possible preparation methods for the compounds of general formula I are suggestions that might be modified by those skilled in the art to reach the disclosed compounds. Many of the steps detailed below can be found with detailed operating procedure in the following references: J. Med. Chem. 2003, 46, 4702- 4713 ; Synlett 2005, 20, 3121-3125; Tet. Lett. 2004 (45), 8087-8090
Compounds of general formula (I) previously described and listed in the tables above may be prepared following the procedure described in scheme 1 : Scheme 1
Figure imgf000046_0001
wherein R is:
Figure imgf000046_0002
and X1 and X2, R1 to R8 are as defined above and X is halogen.
Compounds of formula C can be obtained by reaction between an ester of formula A and an acetonitrile derivative of formula B in the presence of a base such as sodium methoxide or potassium t-butoxide in suitable alcoholic solvent, (see J. Med. Chem. 2003, 46, 4702-4713).
Compounds of formula A are generally commercially available but might be prepared by state of the art procedures from the corresponding acid, nitrile, or methyl derivative by esterification, hydrolysis or oxidation reactions, respectively.
Compounds of formula B, such as phenyl acetonitrile, 4-fluorophenyl acetonitrile or 3-methylphenyl acetonitrile and related compounds are commercially available. Acidic treatment of compounds of formula C in suitable aqueous acid such as hydrobromic acid results in hydrolysis and decarboxylation leading to compound of formula D.
Further condensation of D with an amino heterocycle of formula E results in a formation of an enamine of formula F where X is a halogen such as bromo, chloro or iodo. The reaction may be performed in an aromatic solvent such as benzene, toluene or xylene in the presence of a catalytic amount of acid such as p-toluene sulfonic acid.
Alternatively, compound F may exist as its enamine-imine equilibrium; both compounds might be separated under state of the art purification condition such as chromatography.
Heterocycle of formula E, such as 3-chloro-pyridazin-4-ylamine or 3-Bromo- pyrazin-2-ylamine, may be commercially available or may be prepared by known methodologies. For example, by reduction of the corresponding nitro derivative (see J. Chem. Soc, 1952, 2042). As further example, pyridazine derivatives can be prepared according to the procedures reported in Journal of Heterocyclic Chemistry 1964, 1(5), 247-50 .
The di-azaindole (5H-Pyrrolo[3,2-c]pyridazine; 5H-Pyrrolo[3,2-d]pyrimidine or 5H- Pyrrolo[2,3-b]pyrazine) of formula G is obtained by cyclisation of the enamine F in the presence of a tertiary amine base such as DABCO and a palladium catalyst such as palladium acetate (II) or dichlorobis(triphenylphosphine) palladium (II) in an inert solvent such as dimethylformamide or dimethylacetamide (see J. Org. Chem. 1997, 62, 2676-2677).
Compounds of formula H, where R3 is not hydrogen may be obtained by alkylation or acylation of compounds of formula G. This alkylation can be realized with an alkylating agent of formula R -Y (where Y is a leaving group such as halogen, triflate, mesylate and the like) in the presence of a base such as sodium hydride or lithium hexamethyldisilazane in an aprotic solvent such as dimethylformamide or tetrahydrofuran. Compounds of formula G may also be obtained by acylation in the presence of an acylating agent such as R3COX (where X is a halogen) in the presence of a base such as sodium hydride or lithium hexamethyldisilazane in an aprotic solvent such as dimethylformamide or tetrahydrofuran. Scheme 2 describes an alternative method for the preparation of compound of formula (I):
Scheme 2
Figure imgf000048_0001
Compounds of formula J may be obtained in a single step condensation-cyclisation of a compound of formula E and compound of formula I. The reaction is carried out in the presence of a base, such as potassium phosphate or potassium carbonate, a dehydrating agent, such as magnesium or sodium sulphate, and a palladium catalyst, preferably (di-t- butylphoshino) palladium, in an inert solvent, such as dimethylformamide or dimethylacetamide, under an inert atmosphere in a closed vessel, (see: Angew. Chem. Int. Ed. Eng. 2004, 4526-4528).
Compounds of formula J can be regioselectively brominated in the presence of bromine or N-bromosuccinimide in a solvent, such as carbon tetrachloride or DMF, to give a compound of formula K (see: Synthesis, 1982, 1096). Compounds of formula G can be obtained by further treatment of a compound of formula K in the presence of a boronic acid of formula R4B(OH)2 (where R4 is as previously defined) under Suzuki cross coupling conditions (see: Chem. Comm. 1979, 866) under thermal or microwave conditions.
Compounds of type H may then be obtained following the procedure described above for scheme 1. Scheme 3 describes a further alternative method for the preparation of compound of formula (I).
Scheme 3
Figure imgf000049_0001
Compounds of formula L (where PG is a protective group such as methyl, acetate, benzyl, mesylate, tosylate and the like) may be obtained by sequential protection of the corresponding heterocycle E (see "Protective groups in organic chemistry" Greene and Wuts 4th edition, Wiley Interscience). Compounds of formula L can be coupled with compounds of formula M under Sonogashira coupling conditions (see: Synthesis 1980, (8) 627-630) and subsequently treated with iodine in an inert solvent, such as dichloromethane, to undergo direct iodo cyclisation and formation of N (see: Org. Letters 2004, 6(6) 1037-1040).
Compounds of formula M can be prepared from the parent halogenated compound by reaction under Sonogashira conditions (see: Synthesis, 1980, (8) 627-630) with trimethylsilyl acetylene, followed by deprotection under basic conditions of the trimethyl silyl group. Compounds of formula M may also be prepared from the parent aldehyde under Corey- Fuchs reaction conditions (see: Tet. Lett. 1972, (36) 3769). Compounds of formula O may be obtained by treatment of N under the same conditions as the ones described above for K in scheme 2 in the presence of a boronic acid.
Compounds of formula G may be obtained by deprotection of compounds of formula
O under state of the art methods depending on the nature of the protective group. As an example, acetate as protective group can be deprotected under acidic conditions such as HCl or basic conditions such as LiOH. It is to be noted that weak protecting groups may be deprotected during the course of reactions to generate compounds of formula N or O. It is also to be noticed that PG and R3 may be the same from the beginning of the preparation thus the deprotection step may not be required.
Compounds of formula H may be obtained following the procedure described above in scheme 1.
Compounds of formula J may also be obtained by direct treament of the amino heterocycle E in two steps by reacting with a compound of formula M under Sonogashira conditions followed by a cyclisation under basic conditions (NEt3, KOH) as described in Tet. Lett., 2007, 48, 6951-6953. The remaining sequence to reach G and H may be as previously described.
Scheme 4 describes an alternative method for the preparation of compound of formula (I) where R3 is OR12 as described previously:
Scheme 4
Figure imgf000051_0001
Reaction of a ketone of formula D (as already described) and a nitro heterocyclic compound of formula P in the presence of a base, such as sodium hydride or potassium t- butoxide, in an aprotic solvent, such as dimethylformamide, gives a compound of formula Q that may also exist as its enol form.
Compounds of formula P, where X is a halogen such as chlorine or bromine are either commercially available or may be prepared by known methods. For example, compounds such as 4-chloro-6-methoxy-5-nitro-Pyrimidine and 3-Chloro-2-nitropyrazine are commercially available. For the preparation of compounds of formula P, the person skilled in the art may follow examples such those described in Ingenieur Chimiste (Brussels), 1967, 49 244-245 for the preparation of pyridazynes.
Compounds of formula Q can be selectively reduced at the nitro position under alternative conditions to generate the 1 -hydroxy fused pyrrole of formula S. For example, compounds of formula Q can be treated under Bechamp conditions in the presence of iron in an acidic aqueous media to give compounds of formula S. Under these conditions, the complete reduced form of the azaindole may also be formed. Compounds of formula Q can also be treated under catalytic hydrogenation conditions, in the presence of hydrogen, with or without pressure, with a catalyst such as palladium on charcoal in an alcoholic solvent such as ethanol. Compounds of formula S can then be treated under the same conditions as those discribed for G in scheme 1 in order to generate compound of formula T, where R12 is as previously described.
Scheme 5 describes an alternative method for the preparation of compound of formula (I) where R is not hydrogen.
Scheme 5
Figure imgf000052_0001
For this sequence, a pyridine of formula U where R is as previously described can be transformed into its acetal V by treating the corresponding aldehyde in methanol or in suitable trialkyl ortho formate, such as trimethylortho formate (for the preparation of the dimethylacetal), in the presence of a catalytic amount of an acid such as sulfuric acid. Compounds of formula U may be commercially available, for example 4-pyridine carboxaldehyde, 3-nitro isonicotinaldehyde and 3-chloro-4-pyridine carboxaldehyde, but may also be prepared by state of the art methodology, for example by starting from the hydroxymethyl derivative and using an oxidation procedure (see: Aus. J. Chem 1993, 46(7) 987-993) and also by the reduction of the corresponding ester. The compound of formula U may also be prepared from the halogen or unsubstituted analogue by halogen-metal or hydrogen-metal exchange followed by treatment with a suitable electrophile such as dimethylformamide (see: Synthesis 1999, 306-311).
Compounds of formula Z can be obtained by treating compounds of formula V with a suitable base, such a n-butyl lithium, sodium hydride or lithium hexamethyldisilazane, in an aprotic solvent, such a tetrahydrofuran or diethyl ether, preferably at low temperature followed by the treatment of the anion by a compound of formula W where X is a leaving group such as halogen (chlorine, bromine or iodide) or a mesylate and R4 is as previously described.
Compounds of formula W are usually commercially available, for example A- fluorobenzyl chloride, 3 -methyl benzyl chloride or benzyl bromide, but may also be prepared by state of the art methodologies.
Compounds of formula Z can be oxidized to generate compounds of formula AA, for example in the presence of hydrogen peroxide in a solvent, such as dichloromethane, in the presence of a catalyst, such as methyl trioxorhenium (see Tet. Lett., 1996, 37(6), 805-808), or in the presence of hydrogen peroxide-urea complex in a solvent such as dichloromethane (see Chem. Ber. 1992, 125(8), 1965-1966).
Compounds of formula AA can be treated by the previously described amino heterocycle of formula E under the conditions described for the preparation of F in scheme 1 to generate compound of formula AB. Alternatively compounds of formula AB can be obtained by reacting compounds of formula AA and E together in the absence of solvent at a temperature allowing the distillation of the alcohol formed (see: Synthesis 1993, 12, 1227- 1229). As previously mentioned, compounds of formula AB can exist as two isomers, imine and enamine, that may also be separated for example by chromatography.
Cyclisation of compounds of formula AB under the conditions described in scheme 1 for the formation of G allows the preparation of the azaindole AC.
Compounds of formula AD where X is halogen such as chlorine or bromine can be prepared by treating compounds of formula AC with POCI3 or POBr3 under conditions used in state of the art methodology such as chlorination of substituted pyridines in Chem. and Pharm. Bull. 1994, 42(9), 1841-1849.
Compounds of formula AE can be prepared from compounds of formula AD by Buchwald amination or amidation reaction in the presence of a primary amide or amine, a palladium (II) catalyst such as palladium diacetate, a ligand such as Xantphos®, a base such as potassium or cesium carbonate, in an aprotic solvent such as dioxane or tetrahydrofuran, under thermal or microwave conditions (see Org. Let. 2001, 3(21) 3417-3419).
Compounds of formula AE may also be prepared from AD by direct treatment with an amine such as benzyl amine under thermal or microwave conditions, followed by treatment with a strong acid such as concentrated sulphuric acid to generate the compound where R6 is NH2. Such an intermediate can be further treated by an appropriate non nucleophilic base, such as pyridine, in a solvent, such as dimethylformamide or tetrahydrofuran, and an acylating agent, such as R20COX, where X is chlorine or fluorine and R20 is as previously described. It can also be treated with an alkylating agent, such as R18-X where X is a leaving group such as halogen or a mesylate, under the same conditions.
Another alkylation or acylation will provide, under the same conditions, compounds where R6 is NR18R19, as previously described.
Compounds of formula AE where R6 is neither an amine nor an amide can be prepared directly by treating compounds of formula AC with an activating agent followed by a nucleophile as described in the review from Science of Synthesis 2005, 15, 285-387 (Georg Thiem Verlag Publisher). For example, if R6 is cyanide, compounds of formula AC may be treated with an activator such as benzoyl chloride in the presence of a cyanide source such as trimethylsilyl-cyanide in an aprotic solvent such as dimethylformamide or tetrahydrofuran (See J. Org. Chem. 1983, 48, 1375-1377).
Compounds of formula AE where R6 is cyanide can be further modified by state of the art methods to generate all the possible derivatives of the cyanide group: for example, reduction to the acid or ester, reduction to the amide or reduction to the amine, addition on cyanide by an alkyl or aryl Grignard to generate the ketone.
Compounds of formula AI can be prepared from compounds of formula AD following the methodology described in scheme 1 for the preparation of compounds of formula H from compounds of formula G.
Compounds of formula AG can be prepared from compounds of formula AE following the methodology used for the preparation of compounds of formula AI. Compounds of formula AG can also be prepared from compounds of formula AI following the methodologies used for the preparation of compounds of formula AE from compounds of formula AD.
Compounds of formula AF can be prepared from compounds of formula AE by the following treatment: oxidation of the pyridine following the preparation described for compounds of formula AA from compounds of formula Z direct reaction to introduce R7 as described for the introduction of R6 in the preparation of compounds of formula AE from compounds of formula AD - R7 may also be introduced by the methodologies described for the introduction of
R6 in the preparation of compounds of formula AE from compounds of formula
AC via compounds of formula AD.
Compounds of formula AH may be prepared from compounds of formula AF following the treatment described for the preparation of compounds of formula H in scheme 1.
Further steps may be realized that are not disclosed in scheme 5 from compounds of formula AC, AD, AI, AE, AF, AG and AH. These reactions may result in further transformation of R to R , for example, cyclisation between R 6 a „„nd i T R-) 3 or between R and
R2
Scheme 6 describes an alternative method for the preparation of compounds of formula (I) where X1 is CH and X2 is N (compounds of formula (Ic), for example, where G1, G2, G3, R1, R2, R3, R4, R6, R7, and R8 are defined for formula (I).
Figure imgf000056_0001
Scheme 6
Figure imgf000056_0002
Compounds of formula AL can be prepared by treatment of a pyrimidine of formula AJ, where X is a halogen such as bromine, chlorine or iodide and R7 is as previously described, in the presence of a suitable base to realize the metal halogen exchange, n-butyl lithium or s-butyl lithium may be used in an aprotic solvent, such as tetrahydrofuran, preferably at low temperature. The acyl chloride of formula AK can then react with the previously formed anion of the pyrimidine to give compounds of formula AL. Compounds of formula AJ may be commercially available such as the 4-iodo-2- methylthio- pyrimidine or obtained by state of the art methods (see for examples Tet. Lett. 2001, 42(2), 311-313).
Compounds of formula AK are usually commercially available, for example phenylacetyl chloride, m-tolylacetyl chloride or 4-fluoro benzeneacetyl chloride, but may also be prepared from the corresponding acid.
Compounds of formula AM can be prepared from the condensation between compounds of formula E and AL under the conditions described for the formation of compound F in scheme 1, followed by the cyclisation of the imine or enamine obtained under the conditions described in scheme 1 for the formation of compound G.
Compound E is as previously described.
Oxidation of the pyrimidine compounds of formula AM in the presence of an oxidant, such as m-chloroperbenzoique acid, in a solvent, such as dichloromethane, results in the formation of the sulfoxide intermediate. Further treatment of this intermediate with an amine, such as benzyl amine, followed by treatment in concentrated sulphuric acid results in the formation of a compound of formula AP where R6 is NH2. Further treatment as previously described for the formation of compound AE in scheme 5 results in the formation of AP with R6 as previously described.
Compounds of formula AN may be obtained by treatment of compounds of formula AM following the same procedure as the one previously described for the formation of compounds of formula H from compound of formula G.
Compounds of formula AO can be prepared from compounds of formula AN using methodology as previously described for the preparation of compounds of formula AP from compounds of formula AM .
Compounds of formula AO may also be prepared by the direct introduction of R3 at the indole ring of the compounds of formula AP following the procedure previously described for the formation of compounds of formula H from compounds of formula G in scheme 1.
Specific procedures for the preparation of intermediates of type E related to the preparation of compounds of formula (Ii) or (Im) can be found in Recueil des Travaux Chimiques des Pays-Bas 1974, 93(8), 236-9; Yakugaku Zasshi, 1965, 85(4), 344-52; Journal of Pharmaceutical Sciences 1963, 52(6), 539-41; and Chemistry Letters, 2001, 54. The obtained compounds E can then be transformed to compounds of formula I(i) or I(m) following the previously described procedures.
The previously described processes will enable those skilled in the art to understand the general conditions and techniques that may be used to obtain the compounds utilised in this invention. If desired, further modification of groups R1 to R8 may be undertaken to obtain compounds having a cyclic structure between R1 and R2, R1 and R3, R2 and R3, R3 and R5, or R5 and R6. Such further modification steps are routine for a person skilled in the art. In particular, it will be recognized by those skilled in the art that these modifications might be realized by more than one step, involving for example reduction, oxidation, coupling reaction with or without catalyst, nucleophilic substitution, latonisation, lactamisation and the like.
As indicated above, it has now been found that the compounds of formula I are useful in controlling plant pathogenic fungi when they are applied to a plant or plant propagation material in a fungicidally effective amount.
By 'plant propagation material' is meant generative parts of a plant including seeds of all kinds (fruit, tubers, bulbs, grains etc), roots, rhizomes, cuttings, cut shoots and the like. Plant propagation material may also include plants and young plants which are to be transplanted after germination or after emergence from the soil.
A compound that "controls fungal infection" in plants and/or plant propagation material is, for example, a compound that inhibits, e.g. selectively inhibits, an existing fungal infection in a plant or plant propagation material. For example, the compound may slow the rate of fungal growth and/or reduce fungal growth in a plant or plant propagation material, e.g. compared to the absence of the compound. A compound that "prevents fungal infection" in plants or plant propagation material is, for example, a compound that inhibits e.g. selectively inhibits, the emergence of a fungal infection in a plant or plant propagation material. For example, the compound may slow the appearance of a fungal infection and/or reduce the rate of fungal emergence in a plant or plant propagation material, e.g. compared to the absence of the compound.
Generally, a compound that controls and/or prevents a fungal infection in a plant or plant propagation material may reduce the ability of a fungus to grow in and/or on a plant or plnat propagation material and/or reduce the rate at which the fungal infection spreads to any neighbouring plants. The compound may be biologically active, e.g. it may impede the normal internal biochemistry of the fungus. Preferably the compound is toxic for the fungus, e.g. it kills the fungus on contact.
"Applying" the compound to a plant or plant propagation material means, for example, contacting the compound with a plant or plant propagation material to be treated.
The methods, compounds and compositions of the present invention are, for example, effective against the phytopathogenic fungi of the following classes: Fungi imperfecti (e.g. Botrytis, Pyricularia, Helminthosporium, Fusarium, Septoria, Cercospora and Alternaria), Basidiomycetes (e.g. Rhizoctonia, Hemileia, Puccinia), Ascomycetes (e.g. Venturia and Erysiphe, Podosphaera, Monilinia, Uncinula and Pyrenophora) and Oomycetes (e.g. Phytophthora, Pythium, Plasmopara). In particular, the methods, compounds and compositions of the present invention are effective against Botrytis spp., Pyricularia spp., Fusarium spp. Septoria spp., Rhizoctonia spp., Puccinia spp., Erysiphe spp., Phytophthoria spp., Pythium spp. and Plasmopara spp. Most particularly, the methods, compounds and compositions of the present invention are effective against Botrytis cinerea, Pyricularia oryzae, Fusarium culmorum, Septoria nodurum and Septoria tritici, Rhizoctonia solani, Puccinia recondite, Erysiphe graminis, Pyrenophora teres, Phytophthora infestans, Pythium ultimum and Plasmopara viticola.
The methods, compounds and compositions of the present invention are suitable for controlling such disease on a number of plants and their propagation material including, but not limited to the following target crops: cereals (wheat, barley, rye, oats, maize (including field corn, pop corn and sweet corn), rice, sorghum and related crops); beet (sugar beet and fodder beet); leguminous plants (beans, lentils, peas, soybeans); oil plants (rape, mustard, sunflowers); cucumber plants (marrows, cucumbers, melons); fibre plants (cotton, flax, hemp, jute); vegetables (spinach, lettuce, asparagus, cabbages, carrots, eggplants, onions, pepper, tomatoes, potatoes, paprika, okra); plantation crops (bananas, fruit trees, rubber trees, tree nurseries), ornamentals (flowers, shrubs, broad-leaved trees and evergreens, such as conifers); as well as other plants such as vines, bushberries (such as blueberries), caneberries, cranberries, peppermint, rhubarb, spearmint, sugar cane and turf grasses including, but not limited to, cool-season turf grasses (for example, bluegrasses (Poa L.), such as Kentucky bluegrass (Poa pratensis L.), rough bluegrass (Poa trivialis L.), Canada bluegrass (Poa compressa L.) and annual bluegrass (Poa annua L.); bentgrasses (Agrostis L.), such as creeping bentgrass (Agrostis palustris Huds.), colonial bentgrass (Agrostis tenius Sibth.), velvet bentgrass (Agrostis canina L.) and redtop (Agrostis alba L.); fescues (Festuca L.), such as tall fescue (Festuca arundinacea Schreb.), meadow fescue (Festuca elatior L.) and fine fescues such as creeping red fescue (Festuca rubra L.), chewings fescue (Festuca rubra var. commutata Gaud.), sheep fescue (Festuca ovina L.) and hard fescue (Festuca longifolia); and ryegrasses (Lolium L.), such as perennial ryegrass (Lolium perenne L.) and annual (Italian) ryegrass (Lolium multiflorum Lam.)) and warm-season turf grasses (for example, Bermudagrasses (Cynodon L. C. Rich), including hybrid and common Bermudagrass; Zoysiagrasses (Zoysia Willd ), St. Augustinegrass (Stenotaphrum secundatum (Walt.) Kuntze); and centipedegrass (Eremochloa ophiuroides (Munro.) Hack.)).
In addition 'crops' are to be understood to include those crops that have been made tolerant to pests and pesticides, including herbicides or classes of herbicides, as a result of conventional methods of breeding or genetic engineering. Tolerance to e.g. herbicides means a reduced susceptibility to damage caused by a particular herbicide compared to conventional crop breeds. Crops can be modified or bred so as to be tolerant, for example, to HPPD inhibitors such as mesotrione or EPSPS inhibitors such as glyphosate.
Furthermore, the compounds of formula I find general use as fungicides and may therefore also be used to control pathogenic fungi in related areas, for example in the protection of technical materials, including wood and wood related technical products, in food storage or in hygiene management. As such, the present invention further provides the use of a compound of formula I for controlling fungi. The compound of the invention is normally applied to plants and/or plant propagation material in a fungicidally effective amount. The amount used will of course depend on several factors such as the plant or propagation material, the type of fungus and the particular compound of the invention. When used in the methods of the invention, the compounds of formula I may be in unmodified form or, preferably, formulated together with carriers and adjuvants conventionally employed in the art of formulation.
The invention therefore also relates to a composition for the control of fungal infection comprising a compound of formula I as defined above and an agriculturally acceptable carrier or diluent.
The agrochemical composition will usually contain from 0.1 to 99% by weight, preferably from 0.1 to 95% by weight, of the compound of formula I, 99.9 to 1% by weight, preferably 99.8 to 5% by weight, of a solid or liquid adjuvant, and from 0 to 25% by weight, preferably from 0.1 to 25% by weight, of a surfactant.
Suitably, the agrochemical compositions and formulations of the present invention are applied prior to disease development. Rates and frequency of use of the formulations are those conventionally used in the art and will depend on the risk of infestation by the fungal pathogen, the developmental stage of the plant and on the location, timing and application method. Advantageous rates of application are normally from 5g to 2kg of active ingredient (a.i.) per hectare (ha), preferably from 1Og to lkg a.i./ha, most preferably from 2Og to 60Og a.i./ha. When used as seed drenching agent, convenient rates of application are from 1 Omg to 1 g of active substance per kg of seeds.
In practice, as indicated above, the agrochemical compositions comprising compound of formula (I) are usually applied as a formulation containing the various adjuvants and carriers known to or used in the industry. They may thus be formulated as granules, as wettable or soluble powders, as emulsifiable concentrates, as coatable pastes, as dusts, as flowables, as solutions, as suspensions or emulsions, or as controlled release forms such as microcapsules. These formulations are described in more detail below and may contain as little as about 0.5% to as much as about 95% or more by weight of the active ingredient. The optimum amount will depend on formulation, application equipment and nature of the plant pathogenic fungi to be controlled.
Suspension concentrates are aqueous formulations in which finely divided solid particles of the active compound are suspended. Such formulations include anti-settling agents and dispersing agents and may further include a wetting agent to enhance activity as well an anti-foam and a crystal growth inhibitor. In use, these concentrates are diluted in water and normally applied as a spray to the area to be treated. The amount of active ingredient may range from about 0.5% to about 95% of the concentrate.
Wettable powders are in the form of finely divided particles which disperse readily in water or other liquid carriers. The particles contain the active ingredient retained in a solid matrix. Typical solid matrices include fuller's earth, kaolin clays, silicas and other readily wet organic or inorganic solids. Wettable powders normally contain about 5% to about 95% of the active ingredient plus a small amount of wetting, dispersing or emulsifying agent.
Emulsifϊable concentrates are homogeneous liquid compositions dispersible in water or other liquid and may consist entirely of the active compound with a liquid or solid emulsifying agent, or may also contain a liquid carrier, such as xylene, heavy aromatic naphthas, isophorone and other non-volatile organic solvents. In use, these concentrates are dispersed in water or other liquid and normally applied as a spray to the area to be treated. The amount of active ingredient may range from about 0.5% to about 95% of the concentrate.
Granular formulations include both extrudates and relatively coarse particles and are usually applied without dilution to the area in which control of plant pathogenic fungi is required. Typical carriers for granular formulations include sand, fuller's earth, attapulgite clay, bentonite clays, montmorillonite clay, vermiculite, perlite, calcium carbonate, brick, pumice, pyrophyllite, kaolin, dolomite, plaster, wood flour, ground corn cobs, ground peanut hulls, sugars, sodium chloride, sodium sulphate, sodium silicate, sodium borate, magnesia, mica, iron oxide, zinc oxide, titanium oxide, antimony oxide, cryolite, gypsum, diatomaceous earth, calcium sulphate and other organic or inorganic materials which absorb or which can be coated with the active compound. Granular formulations normally contain about 5% to about 25% active ingredients which may include surface-active agents such as heavy aromatic naphthas, kerosene and other petroleum fractions, or vegetable oils; and/or stickers such as dextrins, glue or synthetic resins.
Dusts are free-flowing admixtures of the active ingredient with finely divided solids such as talc, clays, flours and other organic and inorganic solids which act as dispersants and carriers.
Microcapsules are typically droplets or granules of the active ingredient enclosed in an inert porous shell which allows escape of the enclosed material to the surroundings at controlled rates. Encapsulated droplets are typically about 1 to 50 microns in diameter. The enclosed liquid typically constitutes about 50 to 95% of the weight of the capsule and may include solvent in addition to the active compound. Encapsulated granules are generally porous granules with porous membranes sealing the granule pore openings, retaining the active species in liquid form inside the granule pores. Granules typically range from 1 millimetre to 1 centimetre and preferably 1 to 2 millimetres in diameter. Granules are formed by extrusion, agglomeration or prilling, or are naturally occurring. Examples of such materials are vermiculite, sintered clay, kaolin, attapulgite clay, sawdust and granular carbon. Shell or membrane materials include natural and synthetic rubbers, cellulosic materials, styrene-butadiene copolymers, polyacrylonitriles, polyacrylates, polyesters, polyamides, polyureas, polyurethanes and starch xanthates.
Other useful formulations for agrochemical applications include simple solutions of the active ingredient in a solvent in which it is completely soluble at the desired concentration, such as acetone, alkylated naphthalenes, xylene and other organic solvents. Pressurised sprayers, wherein the active ingredient is dispersed in finely-divided form as a result of vaporisation of a low boiling dispersant solvent carrier, may also be used.
Suitable agricultural adjuvants and carriers that are useful in formulating the compositions of the invention in the formulation types described above are well known to those skilled in the art. Suitable examples of the different classes are found in the non- limiting list below.
Liquid carriers that can be employed include water, toluene, xylene, petroleum naphtha, crop oil, acetone, methyl ethyl ketone, cyclohexanone, acetic anhydride, acetonitrile, acetophenone, amyl acetate, 2-butanone, chlorobenzene, cyclohexane, cyclohexanol, alkyl acetates, diacetonalcohol, 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-dimethyl formamide, dimethyl sulfoxide, 1 ,4-dioxane, dipropylene glycol, dipropylene glycol methyl ether, dipropylene glycol dibenzoate, diproxitol, alkyl pyrrolidinone, ethyl acetate, 2-ethyl hexanol, ethylene carbonate, 1,1,1-trichloroethane, 2-heptanone, alpha pinene, d-limonene, ethylene glycol, ethylene glycol butyl ether, ethylene glycol methyl ether, gamma-butyrolactone, glycerol, glycerol diacetate, glycerol monoacetate, glycerol triacetate, hexadecane, hexylene glycol, isoamyl acetate, isobornyl acetate, isooctane, isophorone, isopropyl benzene, isopropyl myristate, lactic acid, laurylamine, mesityl oxide, methoxy-propanol, methyl isoamyl ketone, methyl isobutyl ketone, methyl laurate, methyl octanoate, methyl oleate, methylene chloride, m- xylene, n-hexane, n-octylamine, octadecanoic acid, octyl amine acetate, oleic acid, oleylamine, o-xylene, phenol, polyethylene glycol (PEG400), propionic acid, propylene glycol, propylene glycol monomethyl ether, p-xylene, toluene, triethyl phosphate, triethylene glycol, xylene sulfonic acid, paraffin, mineral oil, trichloroethylene, perchloroethylene, ethyl acetate, amyl acetate, butyl acetate, methanol, ethanol, isopropanol, and higher molecular weight alcohols such as amyl alcohol, tetrahydrofurfuryl alcohol, hexanol, octanol, etc. ethylene glycol, propylene glycol, glycerine, N-methyl-2- pyrrolidinone, and the like. Water is generally the carrier of choice for the dilution of concentrates.
Suitable solid carriers include talc, titanium dioxide, pyrophyllite clay, silica, attapulgite clay, kieselguhr, chalk, diatomaxeous earth, lime, calcium carbonate, bentonite clay, fuller's earth, cotton seed hulls, wheat flour, soybean flour, pumice, wood flour, walnut shell flour, lignin and the like.
A broad range of surface-active agents are advantageously employed in both said liquid and solid compositions, especially those designed to be diluted with carrier before application. These agents, when used, normally comprise from 0.1% to 15% by weight of the formulation. They can be anionic, cationic, non- ionic or polymeric in character and can be employed as emulsifying agents, wetting agents, suspending agents or for other purposes. Typical surface active agents include salts of alkyl sulfates, such as diethanolammonium lauryl sulphate; alkylarylsulfonate salts, such as calcium dodecylbenzenesulfonate; alkylphenol-alkylene oxide addition products, such as nonylphenol-C.sub. 18 ethoxylate; alcohol-alkylene oxide addition products, such as tridecyl alcohol-C.sub. 16 ethoxylate; soaps, such as sodium stearate; alkylnaphthalenesulfonate salts, such as sodium dibutylnaphthalenesulfonate; dialkyl esters of sulfosuccinate salts, such as sodium di(2- ethylhexyl) sulfosuccinate; sorbitol esters, such as sorbitol oleate; quaternary amines, such as lauryl trimethylammonium 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 dialkyl phosphate esters.
Other adjuvants commonly utilized in agricultural compositions include crystallisation inhibitors, viscosity modifiers, suspending agents, spray droplet modifiers, pigments, antioxidants, foaming agents, anti-foaming agents, light-blocking agents, compatibilizing agents, antifoam agents, sequestering agents, neutralising agents and buffers, corrosion inhibitors, dyes, odorants, spreading agents, penetration aids, micronutrients, emollients, lubricants, sticking agents, and the like.
In addition, further, other biocidally active ingredients or compositions may be used in the methods of the invention and applied simultaneously or sequentially with the compound of formula (I). When applied simultaneously, these further active ingredients may be formulated together with the compound of the invention or mixed in, for example, the spray tank. These further biocidally active ingredients may be fungicides, herbicides, insecticides, bactericides, acaricides, nematicides and/or plant growth regulators.
Examples of insecticidal compounds for use in the compositions/methods of the present invention include, but are not limited to, pyrethroids (such as permethrin, cypermethrin, fenvalerate, esfenvalerate, deltamethrin, cyhalothrin (in particular, lambda-cyhalothrin), bifenthrin, fenpropathrin, cyfluthrin, tefluthrin, fish safe pyrethroids (for example ethofenprox), natural pyrethrin, tetramethrin, s-bioallethrin, fenfluthrin, prallethrin and 5-benzyl-3-furylmethyl-(E)-(lR,3S)-2,2-dimethyl-3-(2-oxothiolan-3- ylidenemethyl)cyclopropane carboxylate), organophosphates (such as, profenofos, sulprofos, acephate, methyl parathion, azinphos-methyl, demeton-s-methyl, heptenophos, thiometon, fenamiphos, monocrotophos, profenofos, triazophos, methamidophos, dimethoate, phosphamidon, malathion, chlorpyrifos, phosalone, terbufos, fensulfothion, fonofos, phorate, phoxim, pirimiphos-methyl, pirimiphos-ethyl, fenitrothion, fosthiazate and diazinon); carbamates, including aryl carbamates, (such as pirimicarb, triazamate, cloethocarb, carbofuran, furathiocarb, ethiofencarb, aldicarb, thiofurox, carbosulfan, bendiocarb, fenobucarb, propoxur, methomyl and oxamyl), benzoyl ureas (such as diflubenzuron, triflumuron, hexaflumuron, flufenoxuron and chlorfluazuron), organic tin compounds (such as cyhexatin, fenbutatin oxide and azocyclotin), pyrazoles (such as tebufenpyrad and fenpyroximate), macrolides (such as avermectins or milbemycins, for example abamectin, emamectin benzoate, ivermectin, milbemycin, spinosad and azadirachtin), hormones or pheromones, organochlorine compounds (such as endosulfan, benzene hexachloride, DDT, chlordane and dieldrin), amidines (such as chlordimeform and amitraz), fumigant agents (such as chloropicrin, dichloropropane, methyl bromide and metam); chloronicotinyl compounds (such as imidacloprid, thiacloprid, acetamiprid, nitenpyram and thiamethoxam), diacylhydrazines (such as tebufenozide, chromafenozide and methoxyfenozide), diphenyl ethers (such as diofenolan and pyriproxifen), indoxacarb, chlorfenapyr and pymetrozine.
Examples of herbicidal compounds for use in the compositions/methods of the present invention include, but are not limited to, 2,3,6-TBA, 2,4-D, 2,4-DB, acetochlor, acifluorfen-sodium, aclonifen, acrolein, alachlor, alloxydim, ametryn, amicarbazone, amidosulfuron, aminopyralid, aminotriazol, amitrole, ammonium sulfamate, anilofos, asulam, atrazine, aviglycine, azafenidin, azimsulfuron, BAY FOE 5043, beflubutamid, benazolin, bencarbazone, benfluralin, benfuresate, bensulfuron-methyl, bensulide, bentazone, benzfendizone, benzobicyclon, benzofenap, bialaphos, bifenox, bispyribac- sodium, borax, bromacil, bromobutide, bromophenoxim, bromoxynil, butachlor, butafenacil, butamifos, butralin, butroxydim, butylate, cafenstrole, carbetamide, carfentrazone-ethyl, chloransulam methyl, chlorbromuron, chlorflurenol-methyl, chloridazon, chlorimuron-ethyl, chloroacetic acid, chlorotoluron, chlorpropham, chlorsulfuron, chlorthal-dimethyl, cinidon- ethyl, cinmethylin, cinosulfuron, clefoxydim profoxidim, clethodim, clodinafop-propargyl, clomazone, clomeprop, clopyralid, cloransulam, cloransulam-methyl, cumuluron, cumyluron, cyanamide, cyanazine, cyclanilide, cycloate, cyclosulfamuron, cycloxydim, cyhalofop, cyhalofop-butyl, cyprosulfamide, daimuron, dalapon, dazomet, desmedipham, ,desmetryn, dicamba, dichlobenil, dichlorprop, dichlorprop-P, diclofop-methyl, diclosulam, difenzoquat metilsulfate, diflufenican, diflufenzopyr, dimefuron, dimepiperate, dimethachlor, dimethametryn, dimethenamid, dimethenamid-P, dimethipin, dimethylarsinic acid, dinitramine, dinoterb, diphenamid, dipropetryn, diquat, ibromide, dithiopyr, diuron, DNOC, DSMA, endothal, EPTC, esprocarb, ethalfluralin, ethametsulfuron-methyl, ethephon, ethofumesate, ethoxyfen-ethyl, ethoxysulfuron, etobenzanid, fenclorim, fenoxaprop-P-ethyl, fentrazamide, ferrous sulfate, flamprop, flamprop-M, flazasulfuron, florasulam, fluazifop- butyl, fluazifop-P-butyl, fluazolate, flucarbazone sodium, flucetosulfuron, fluchloralin, flufenacet, flufenpyr-thyl, flumetralin, flumetsulam, flumiclorac-pentyl, flumioxazin, flumipropin, fluometuron, fluoroglycofen-ethyl, fluoxaprop, flupoxam, flupropacil, flupropanate, flupyrsulfuron-methyl-sodium, flurenol, fluridone, flurochloridone, fluroxypyr, flurtamone, fluthiacet-methyl, fluxofenim, fomesafen, foramsulfuron, fosamine, glufosinate- ammonium, glyphosate, halosulfuron-methyl, haloxyfop, haloxyfop-P, HC-252, hexazinone, imazamethabenz-methyl, imazamox, imazapic, imazapyr, imazaquin, imazethapyr, imazosulfuron, indanofan, iodosulfuron, iodosulfuron-methyl- sodium, ioxynil, isopropazol, isoproturon, isouron, isoxaben, isoxachlortole, isoxadifen, isoxaflutole, isoxapyrifop, karbutylate, KIH-485, lactofen, lenacil, linuron, MCPA, MCPA-thioethyl, MCPB, mecoprop, mecoprop-P, mefenacet, mefenpyr diethyl, mefluidide, mesosulfuron methyl, mesotrione, metam, metamifop (mefluoxafop), metamitron, metazachlor, methabenzthiazuron, methazole, methyl isothiocyanate, methylarsonic acid, methyldymron, metobenzuron, metobromuron, metolachlor, metosulam, metoxuron, metribuzin, metsulfuron-methyl, MK-616, molinate, mono linuron, MSMA, naproanilide, napropamide, naptalam, NDA-402989, neburon, nefenacet, nicosulfuron, nipyraclofen, n-methyl- glyphosate, nonanoic acid, norflurazon, oleic acid (fatty acids), orbencarb, orthosulfamuron, oryzalin, oxaciclomefone, oxadiargyl, oxadiazon, oxasulfuron, oxaziclomefone, oxyfluorfen, pebulate, pendimethalin, penoxsulam, pentachlorophenol, pentanochlor, pentoxazone, pethoxamid, petrolium oils, phenmedipham, phenoxaprop-P-ethyl (R), picloram, picolinafen, pinoxaden, piperophos, pretilachlor, primisulfuron, primisulfuron-methyl, procarbazone, prodiamine, profluazol, profoxydim, prohexcadion calcium, prometon, prometryn, propachlor, propanil, propaquizafop, propazine, propham, propisochlor, propoxycarbazone, propoxycarbazone-sodium, propyzamide, prosulfocarb, prosulfuron, pyraclonil pyrazogyl, pyraflufen-ethyl, pyrasulfotole, pyrazolynate, pyrazosulfuron-ethyl, pyrazoxyfen, pyribenzoxim, pyributicarb, pyridafol, pyridate, pyriftalid, pyriminobac-methyl, pyrimisulfan, pyrithiobac-sodium, quinclorac, quinmerac, quinoclamine, quizalofop, quizalofop-P, rimsulfuron, sequestren, sethoxydim, siduron, simazine, simetryn, S- metolachlor, sodium chlorate, sulcotrione, sulfentrazone, sulfometuron-methyl, sulfosate, sulfosulfuron, sulfuric acid, tar oils, TCA-sodium, tebutam, tebuthiuron, tefuryltrione, tembotrione, tepraloxydim, terbacil, terbumeton, terbuthylazine, terbutryn, thenylchlor, thiazafluron, thiazimin, thiazopyr, thiencarbazone, thifensulfuron-methyl (thiameturon- methyl), thiobencarb, tiocarbazil, topramezone, tralkoxydim, tri-allate, triasulfuron, triaziflam, tribenuron-methyl, triclopyr, trietazine, triflosulam, trifloxysulfuron, trifloxysulfuron-sodium, trifluralin, triflusulfuron-methyl, trinexapac-ethyl and tritosulfuron.
Examples of fungicidal compounds for use in the compositions/methods of the present invention include, but are not limited to, acibenzolar (CGA245704), ancymidol, alanycarb, aldimorph, amisulbrom anilazine, azaconazole, azoxystrobin, benalaxyl, benthiavalicarb, benomyl, biloxazol, bitertanol, bixafen blasticidin S, boscalid, bromuconazole, bupirimate, captafol, captan, carbendazim, carbendazim chlorhydrate, carboxin, carpropamid, carvone, CGA41396, CGA41397, chinomethionate, chloroneb, chlorothalonil, chlorozolinate, clozylacon, copper containing compounds such as copper oxychloride, copper oxyquinolate, copper sulphate, copper tallate and Bordeaux mixture, cyflufenamid, cymoxanil, cyproconazole, cyprodinil, debacarb, di-2-pyridyl disulphide 1,1 '-dioxide, dichlofluanid, diclomezine, dichlozoline, dichlone, dicloran, diclocymet, diethofencarb, difenoconazole, difenzoquat, diflumetorim, 0,0-di-ώo-propyl-lS'-benzyl thiophosphate, dimefluazole, dimetconazole, dimethomorph, dimethirimol, dimoxystrobin, diniconazole, dinocap, dithianon, dodecyl dimethyl ammonium chloride, dodemorph, dodine, doguadine, edifenphos, enestrobin, epoxiconazole, ethaboxam, ethirimol, etridiazole, famoxadone, fenamidone (RPA407213), fenarimol, fenbuconazole, fenfuram, fenhexamid (KBR2738), fenoxanil, fenpiclonil, fenpropidin, fenpropimorph, fentin acetate, fentin hydroxide, ferbam, ferimzone, fluazinam, fluopicolide, fludioxonil, fluoxastrobin, flumetover, SYP-LI90 (flumorph), fluopyram fluoroimide, fluquinconazole, flusilazole, flusulfamide, flutolanil, flutriafol, folpet, fosetyl-aluminium, fuberidazole, furalaxyl, furametpyr, guazatine, hexaconazole, hydroxyisoxazole, hymexazole, IKF-916 (Cyazofamid), imazalil, imibenconazole, iminoctadine, iminoctadine triacetate, ipconazole, iprobenfos, iprodione, iprovalicarb (SZX0722), isopropanyl butyl carbamate, isoprothiolane, kasugamycin, kresoxim-methyl, LY186054, LY211795, LY248908, maneb, mancopper, mancozeb, mandipropamid, maneb, mefenoxam, mepanipyrim, mepronil, metalaxyl, metconazole, methasulfocarb, metiram, metiram-zinc, metominostrobin, metrafenone, myclobutanil, myclozoline, neoasozin, nickel dimethyldithiocarbamate, nitrothal-ώopropyl, nuarimol, ofurace, organomercury compounds, orysastrobin, oxadixyl, oxasulfuron, oxine- copper, oxolinic acid, oxpoconazole, oxycarboxin, pefurazoate, penconazole, pencycuron, penthiopyrad, phenazin oxide, phosdiphen, phosphorus acids, phthalide, picoxystrobin (ZAl 963), polyoxin D, polyram, probenazole, prochloraz, procymidone, propamocarb, prop- iconazole, propineb, propionic acid, proquinazid, prothioconazole, pyraclostrobin, pyrazophos, Pyribencarb pyrifenox, pyrimethanil, pyroquilon, pyroxyflir, pyrrolnitrin, quaternary ammonium compounds, quinomethionate, quinoxyfen, quintozene, silthiofam simeconazole, sipconazole (F- 155), sodium pentachlorophenate, spiroxamine, streptomycin, sulphur, schwefel, tebuconazole, tecloftalam, tecnazene, tetraconazole, thiabendazole, thifluzamid, 2-(thiocyanomethylthio)benzothiazole, thiophanate-methyl, thiram, tiadinil timibenconazole, tolclofos-methyl, tolylfluanid, triadimefon, triadimenol, triazbutil, triazoxide, tricyclazole, tridemorph, trifloxystrobin (CGA279202), triforine, triflumizole, triticonazole, validamycin A, vapam, valiphenal vinclozolin, zineb, ziram, zoxamide, 3-[5- (4-chlorophenyl)-2,3-dimethylisoxazolidin-3-yl]pyridine, 5-chloro-7-(4-methylpiperidine-l- yl)-6-(2,4,6-trifluorophenyl)[l ,2,4]triazolo[l ,5-a]pyrimidine and N-(4-chloro-2-nitrophenyl)- N-ethyl-4-methyl-benzsulfonamide.
These formulations of the invention and for use in the methods of the invention can be applied to the areas where control is desired by conventional methods such as spraying atomising, dusting, scattering, coating or pouring. Dust and liquid compositions, for example, can be applied by the use of power-dusters, broom and hand sprayers and spray dusters. The formulations can also be applied from airplanes as a dust or a spray or by rope wick applications. Both solid and liquid formulations may also be applied to the soil in the locus of the plant to be treated allowing the active ingredient to penetrate the plant through the roots. The formulations of the invention may also be used for dressing applications on plant propagation material to provide protection against fungus infections on the plant propagation material as well as against phytopathogenic fungi occurring in the soil. Suitably, the active ingredient may be applied to plant propagation material to be protected by impregnating the plant propagation material, in particular, seeds, either with a liquid formulation of the fungicide or coating it with a solid formulation. In special cases, other types of application are also possible, for example, the specific treatment of plant cuttings or twigs serving propagation.
In addition, the compounds of formula (I) as defined above can be used in the treatment of fungal infections of human and animal subjects. The active compounds as described herein may be combined with a pharmaceutically acceptable carrier and administered or applied to such subjects or infections in an amount effective to treat the infection in accordance with known techniques. Accordingly, therefore, the present invention also provides the use of a compound of formula (I) as defined above in the manufacture of a medicament for the treatment of a fungal infection in a human or animal. The present invention also provides a compound of formula (I) for use in the treatment of a fungal infection in a human or animal.
The present invention will now be described by way of the following non- limiting examples. Those skilled in the art will promptly recognize appropriate variations from the procedures both as to reactants and as to reaction conditions and techniques.
EXAMPLES
Example 1 - Preparation of 5-(2-Fluoro-ethyl)-7-(4-fluoro-phenyl)-6-pyridin-4-yl-5H- pyrrolor3,2-d1pyrimidine
Figure imgf000070_0001
Step 1 : 50.6 g of sodium metal (2.1 moles) are dissolved in 1.5 L of absolute ethanol under refluxing conditions. A mixture of 205 g of methyl isonicotinate (1.5 moles) and 202 g of 4-fluorophenyl in 0.5 L of absolute ethanol are added once the temperature has cooled to 300C. The reaction mixture is refluxed for 4 hours, then cooled and poured into 1.2 L of ice- water. HCl 2N is added to reach pH=3 and the resulting yellow precipitate filtered and dried (271 g). This material is suspended in 1.1 L of 48% HBr solution and heated at 1000C for 8 hours. Once cooled, the reaction mixture is poured into ice-water (1.2L) and the pH is adjusted to 7 with a 25% solution of ammonium hydroxide. After extraction in ethyl acetate, the organic layers are dried over magnesium sulfate and the residue after concentration is purified by chromatography on silica gel (ethylacetate/hexane 2/1) to give 133 g of 2-(4- fluorophenyl)-l-(pyridine-4-yl)ethanone as a yellowish solid. Step 2: A mixture of hydrazine monohydrate (2.95g), 2-(4-fluorophenyl)-l-(pyridine- 4-yl)ethanone (5 g, 23 mmoles) are dissolved in 500 rnL of ethanol in the presence of a catalytic amount of acetic acid. The reaction is heated to reflux for 2 hours. The reaction mixture is then concentrated to 25% of the original volume and extracted in ethyl acetate / saturated ammonium chloride solution. The organic phase is washed with water and dried over magnesium sulfate. The solid residue after concentration is recrystallized into ethyl acetate to 3.6 g of [2-(4-Fluoro-phenyl)-l-pyridin-4-yl-ethylidene]-hydrazine as brown crystals.
Step 3: 2.73 g of [2-(4-Fluoro-phenyl)-l-pyridin-4-yl-ethylidene]-hydrazine are dissolved in 20 mL of toluene under argon. 2.95 g of 5-bromopyrimidine (18mmoles) and 1.8 g of sodium tert-butylate (18.5 mmoles) are then added to the mixture, followed by Ig of DPPF ([l-l '-bis-(diphenylphosphine)ferrocene]) and 0.48 g of PdC12(DPPF) dichloro- methane complex. The reaction mixture is heated at 1000C for 12 hours.. The cooled reaction mixture is concentrated under vaccuo and directly chrommatographied on silica gel (Hexane/acetone 3/2 + Triethylamine 1%) to afford 0.25 g of N-[2-(4-Fluoro-phenyl)-l- pyridin-4-yl-ethylidene]-N'-pyrimidin-5-yl- hydrazine as brownish solid.
Step 4: 1.1 g ofN-[2-(4-Fluoro-phenyl)-l-pyridin-4-yl-ethylidene]-N'-pyrimidin-5- yl-hydrazine 4 mL of diethylene glycol under nitrogen is heated at 2500C for 4 hours in a metal bath. The cooled reaction mixture is then poured into concentrated NaCl solution and extracted with ethyl acetate. The organic phase is washed with water and dried over magnesium sulfate. Chrommatography of the solid residue after concentration affords 250 mg of 7-(4-Fluoro-phenyl)-6-pyridin-4-yl-5H-pyrrolo[3,2-d]pyrimidine as beige crystals.
Step 5: Sodium hydride (52mg, 1.29 mmole 60% in oil) is added to a solution of 125 mg (0.43 mmole) of 7-(4-Fluoro-phenyl)-6-pyridin-4-yl-5H-pyrrolo[3,2-d]pyrimidine in 6 mL of dimethylformamide at room temperature. After 30 min. at room temperature, 547 mg of l-bromo-2-fluoroethane is added to the reaction mixture. After 90min. at room temperature, the reaction mixture is poured into ammonium chloride solution and extracted with ethyl acetate. The organic phase is washed with water and dried over magnesium sulfate. The solid residue is purified by chromatography on silica gel (ethylacetate/methanol 9/1) to give lOmg of 5-(2-Fluoro-ethyl)-7-(4-fluoro-phenyl)-6-pyridin-4-yl-5H-pyrrolo[3,2- d]pyrimidine. Example 2: Preparation of 6-(2-Ethoxy-pwidin-4^1)-7-phenyl-5H-pyrrolor2,3-b1pyrazine
Figure imgf000072_0001
Step 1 : To 2,3-dichloropyrazine (100 g, 0.671 mol) in dioxane (150 rnL), was added benzylamine (86.3 g, 0.805 mol), triethylamine (140 mL, 1.0 mol), and the reaction mixture was heated at 1000C for 6-7 h. After completion of the reaction, most of the solvent was evaporated under reduced pressure, the reaction mass was diluted with water, and extracted with dichloromethane. The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure to yield the desired product which was purified by chromatography on neutral alumina (ethylacetate/hexane, 1/20) to yield 126 g (86%) of 2-benzylamino-3-chloropyrazine.
Step 2: To 2-chloro-3-iodopyridine (100 g, 0.418 mol) in dry DMF (250 mL) under an atmosphere of nitrogen was added Pd2(dba)3 (19.1 g, 0.021 mol, 5 mol%), triethylamine (300 mL), and CuI (0.398 g, 0.0021 mol, 0.5 mol%). The reaction mixture was cooled to O0C and to this was added trimethylsilylacetylene (35.1 mL, 0.459 mol) dropwise. The reaction mixture was allowed to stir at room temperature (250C) for 3-4 h. After completion of the reaction, the reaction mixture was diluted with cold water, and filtered over a celite bed. The filtrate was then extracted with ethylacetate, the combined organic layers were washed with brine, dried over sodium sulfate. The crude product was concentrated from the organic layer and purified by chromatography on neutral alumina (ethylacetate/hexane, 4/96) to yield 71 g (81%) of 2-chloro-3-trimethylsiliyacetylenopyridine.
Step 3: To 2-benzylamino-3-chloropyrazine (50 g, 0.228 mol) in dimethyl formamide
(300 mL) under an atmosphere of nitrogen was added tetrakis (triphenyl phosphine) palladium(O) (13.2 g, 0.0114 mol, 5 mol%). The mixture was heated to 7O0C for 15 min. to this was added CuI (190.4 g, 0.217 mol) and triethylamine (500 mL). After stirring the mixture for 10 min a solution of 2-chloro-3-trimethylsiliyacetylenopyridine in dimethylformamide was added dropwise, followed by addition of tetrabutylammoniumfluoride (119.2 g, 0.457 mol) and tetramethylethylenediamine (20 mL). The reaction mixture was heated at HO0C for 4-5h. After completion of the reaction, the reaction mixture was filtered through a celite bed, the filtrate diluted with cold water, and extracted with dichloromethane. The combined organic layers were dried over sodium sulfate, concentrated under reduced pressure, and purified by chromatography on neutral alumina (ethylacetate/hexane, 1/5) to yield 32.8 g (45%) of 2-(2-chloro-4-ethynylpyridine)- 3-benzylaminopyrazine.
Step 4: A solution of 2-(2-chloro-4-ethynyl pyridine)-3-benzylaminopyrazine (37 g,
0.115 mol) in dichloromethane (350 mL) was cooled to O0C. To this was added potassium tertiarybutoxide (38.9 g, 0.347 mol) under an atmosphere on nitrogen. The reaction mixture was allowed to stir at room temperature (250C) for 1 h. After completion of the reaction, the reaction mixture was diluted with dichloromethane, washed with water and the aqueous layer extracted again with dichloromethane. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to yield 35 g (95%) of 2-(2-chloro pyridyl)- 1 -benzyl-4,7-diazaindole.
Step 5: A mixture of palladium acetate (1.23 g, 0.00547 mol, 5 mol%), X-Phos (5.21 g, 0.011 mol, 10 mol%), and potassium tertiary butoxide (18.4 g, 0.164 mol) in toluene/ethanol (2:1, 10OmL) under an atmosphere of nitrogen was heated to 7O0C. To this was added 2-(2-chloro pyridyl)-l-benzyl-4,7-diazaindole (35 g, 0.11 mol) as a solution in toluene/ethanol (2:1, 15OmL) dropwise. After completion of addition the reaction mixture was heated at 90-1000C for 1-2 h. After completion of the reaction, the solvent was evaporated under reduced pressure, the reaction mass was diluted with cold water, filtered over a celite bed, and the aqueous filtrate was extracted with dichloromethane. The combined organic layers were dried over sodium sulfate, concentrated under reduced pressure to yield 35 g (96%) of 2-(2-ethoxy pyridyl)-l-benzyl-4,7-diazaindole.
Step 6: 2-(2-ethoxy pyridyl)-l-benzyl-4,7-diazaindole (35 g, 0.11 mol) in dicholoromehtane (150 mL) under an atmosphere of nitrogen was cooled to O0C, to this was added bromine (1.47 mL, 0.11 mol) dissolved in dichloromethane (100 mL) dropwise. After addition was complete the reaction mixture was allowed to stir at room temperature (250C) for 1 h. After completio of the reaction, the reaction mass was quenched with aqueous solution of sodium thiosulfate, extracted with dichloromethane, and the combined organic layers were washed with aqueous sodium bicarbonate. The organic layer was dried sodiun sulfate and concentrated under reduced pressure to yield 40 g (92%) of 2-(2-ethoxy pyridyl)- 3-bromo-l-benzyl-4,7-diazaindole, which was pure enough to be used as such for the next step.
Step 7: A mixture of palladium acetate (0.55 g, 0.0025 mol, 5 mol%), X-Phos (2.33 g, 0.0049 mol, 10 mol%), and cesium carbonate (48 g, 0.147 mol) in toluene/ethanol (3:1, 60 mL) under an atmosphere of nitrogen was allowed to stir for 5-10 min. To this was added a solution of phenyl boronic acid (6.58 g, 0.054 mol) and 2-(2-ethoxy pyridyl)-3-bromo-l- benzyl-4,7-diazaindole (20 g, 0.049 mol) in toluene/ethanol (3:1, 60 mL), dropwise. After completion of addition, the reaction mixture was heated at 6O0C for 5 h. Upon completion of the reaction, solvent was evaporated under reduced pressure, the reaction mass diluted with water, and extracted with ehtylacetate. The combine organic layers were dried over sodium sulfate and evaporated under reduced pressure to yield 17 g (85%) of 2-(2-ethoxy pyridyl)-3- phenyl-l-benzyl-4,7-diazaindole, which was pure enough to be used as such for the next step.
Example 3: Preparation of N-[4-(5-Allyl-7-phenyl-5H-pyrrolo[2,3-blpyrazin-6-yl)-pyridin-2- yll -propionamide
Figure imgf000074_0001
Step 1 : 2-(2-ethoxy pyridyl)-3-phenyl-l-benzyl-4,7-diazaindole (17 g, 0.042 mol) in 33% HBr in glacial acetic acid (50 mL) was heated at 100-11O0C for 6-7 h. Upon completion of the reaction, the excess HBr in glacial acetic acid was evaporated under educed pressure, the reaction mass was diluted with water, extracted with dichloromethane, the organic layer dried over sodium sulfate, and concentrated under reduced pressure to yield 13 g (82%) of 2- (2-hydroxy pyridyl)-3-phenyl-l-benzyl-4,7-diazaindole, which was pure enough to be used as such for the next step.
Step 2: 2-(2-hydroxy pyridyl)-3-phenyl-l-benzyl-4,7-diazaindole (13 g, 0.035 mol) in phosphorous oxychloride (50 mL) was heated at 100-11O0C for 7 h. After completion of the reaction, the phosphorous oxy chloride was distilled out, the reaction mass neutralized with aqueous IN sodium hydroxide solution, and the aqueous phase extracted with dichloromethane. The combine organic layers were dried over sodium sulfate and concentrated under reduced pressure to yield H g (81%) of 2-(2-chloro pyridyl)-3 -phenyl- 1- benzyl-4,7-diazaindole, which was used for the next step without further purification.
Step 3: 2-(2-chloro pyridyl)-3-phenyl-N-benzyl-4,7-diazaindole (11 g, 0.028 mol) in cone sulfuric acid (20 mL) was heated at 8O0C for 8 h. After completion of the reaction, the reaction mixture was cooled to room temperature (250C), diluted with ice, extracted with dichloromethane by adjusting the aqueous layer to neutral and basic pH. The combined organic layers were washed with aqueous sodium bicarbonate solution, dried over sodium sulfate, and concentrated under reduced pressure to yield 4.1 g (48%) of 2-(2-chloro pyridyl)-3-phenyl-4,7-diazaindole which was used without further purification for the next step.
Step 4: A mixture of para methoxy benzylamine (3.6 g, 0.026 mol), palladium acetate (0.18 g, 0.00065 mol, 5 mol%), X-Phos (0.62 g, 0.0013 mol, 10 mol%), and potassium tertiary butoxide (3.67 g, 0.033 mol) in toluene (25 mL) under an atmosphere of nitrogen was heated to 7O0C. To this was added a solution of 2-(2-chloro pyridyl)-3-phenyl-4,7- diazaindole (4 g, 0.013 mol) in toluene (25 mL) dropwise, after completion of addition the reaction mixture was heated at HO0C for 7-8 h. After completion of the reaction, the reaction mixture was filtered through a celite bed, most of the solvent evaporated under reduced pressure, diluted with water, and extracted with dichloromethane. The combined organic layers were dried over sodium sulfate, concentrated under reduced pressure, and purified by chromatography on neutral alumina (methanol/dicholromethane, 1/20) to yield 2.5 g (47%) of 2-[2-(p-methoxy benzylamino) pyridyl]-3-phenyl-4,7-diazaindole.
Step 5: To 2-[2-(p-methoxy benzylamino) pyridyl]-3-phenyl-4,7-diazaindole (2 g, 0.0049 mol) in dimethyl formamide (10 mL) was added cesium carbonate (4 g, 0.012 mol) and the mixture was allowed to stir at room temperature (250C) for 10 min. To this was added allyl bromide (0.65 g, 0.0054 mol) dropwise and the reaction mixture was stirred at room temperature (250C) for 15 min. After completion of the reaction, the reaction mixture was diluted with water and extracted with dichloromethane. The combined organic layers were washed with water, dried over sodium sulfate, and concentrated under reduced pressure to yield 1.8 g (82%) of 2-[2-(p-methoxy benzylamino) pyridyl]-3-phenyl-l-allyl-4,7- diazaindole, which was used without further purification for the next step.
Step 6: 2-[2-(p-methoxy benzylamino) pyridyl]-3-phenyl-N-propargyl-4,7- diazaindole (1.8 g, 0.004 mol) in trifluoro acetic acid (5 mL) was heated at 50-600C under an atmosphere of nitrogen for 2 h. After completion of the reaction, the excess trifluoroacetic acid was distilled out under reduced pressure. The reaction mass was diluted with water, adjusted to basic pH using IN sodium hydroxide, and extracted with dichloromethane. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to yield 1.3 g (83%) of 2-(2amino pyridyl)-3-phenyl-l-allyl-4,7-diazaindole, which was used without further purification for the next step.
Step 7: To 2-(2-amino pyridyl)-3-phenyl-l-allyl-4,7-diazaindole (0.2 g, 0.0006 mol) in pyridine (2 mL) was added propionyl chloride (0.06 g, 0.00067 mol) dropwise and the reaction mixture was stirred at room temperature (250C) for 15 min. After completion of the reaction, pyridine was evaporated under reduced pressure, the reaction mass diluted with water, and extracted with dichloromethane. The combined organic layers were washed with IN hydrochloric acid, water, dried over sodium sulfate, and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel (ethylacetate/hexane, 3/20) to yield 0.06 g (25%) of 2-(2-propionamido pyridyl)-3 -phenyl- 1- allyl-4,7-diazaindole.
Example 4: 5-Allyl-7-phenyl-6-pyridin-4-yl-5H-pyrrolo[3,2-dlpyrimidine Step 1 : Sodium salt of 3-Hydroxy-2-phenyl-acrylonitrile
Ethyl formate (14.17g, 0.19 mol) is added dropwise to a solution of sodium methoxide in methanol (prepared by dissolving 10.3g sodium in 100ml methanol). Benzyl cyanide (2Og, 0.17 mol) in methanol is then added dropwise to the above mixture. The reaction mixture is then heated to reflux till complete precipitation of white salt. After cooling down to room temperature, the reaction mixture is filtered through buchner funnel, washed with diethyl ether and dried to obtain the white solid (21 g).
Step 2: 2-[2-Cyano-2-phenyl-eth-ylideneamino]-malonic acid diethyl ester
sodium salt of 3-Hydroxy-2-phenyl-acrylonitrile (2Og, 0.138 mol) is dissolved in water (700ml) to form a clear solution. Acetic acid (100ml) is then added dropwise and mixture is stirred at room temperature for 10 minutes. Solution of diethyl amino malonate (5Og, 0.22 mol) in methanol (300ml) and triethylamine (20ml) is then added dropwise to the previously made solution of sodium salt of 3-hydroxy-2-phenyl-acrylonitrile and the mixture is heated at 7O0C for 8 hours. After cooling down to room temperature, methanol is evaporated, the mixture is quenched with water and extracted with dichloromethane. The combined organic extracts are washed with water, dried with Na2SO4 and concentrated under vacuum to afford 2-[2-Cyano-2-phenyl-eth-ylideneamino]-malonic acid diethyl ester (28g).
Step 3: 3-Amino-4-phenyl-lH-pyrrole-2-carboxylic acid ethyl ester
To a solution of (28g, 0.093 mol) 2-[2-Cyano-2-phenyl-eth-ylideneamino]-malonic acid diethyl ester in methanol is added slowly sodium methoxide (prepared by dissolving 5.4g sodium in 50ml methanol) at O0C. The reaction mixture is then stirred at room temperature overnight. Methanol is evaporated, residue is diluted in water and extracted twice with ethyl acetate. The combined organic extracts are dried with Na2SO4, concentrated under vacuum to yield Amino-4-phenyl-lH-pyrrole-2-carboxylic acid ethyl ester (27g).
Step 4: 7-Phenyl-5H-pyrrolo[3,2-d]pyrimidin-4-ol
3-Amino-4-phenyl-lH-pyrrole-2-carboxylic acid ethyl ester (27g, 0.12 mol) is dissolved in ethanol and stirred at room temperature for 10 minutes. Formamidine acetate (27g, 0.258 mol) is then added to the above mixture and stirred for 10 minutes at room temperature. The reaction mixture is then heated to reflux for 8h. Cooled reaction mixture is filtered, washed with ethanol (25ml x 4) and dried to yield 7-Phenyl-5H-pyrrolo[3,2-d]pyrimidin-4-ol as white solid (2Ig).
Step 5: 4-Chloro-7-phenyl-5H-pyrrolo[3,2-d]pyrimidine Phosphorus oxy chloride (120ml, 10 vol) is added to phenyl-5H-pyrrolo[3,2-d]pyrimidin-4-ol (12g, 0.056 mol) under inert atmosphere at 0 0C. The reaction mixture is then refluxed at 105 0C for 4 hours. After cooling the reaction mixture to room temperature, it is quenched by adding crushed ice slowly and then extracted twice with ethyl acetate. The organic layer is washed with water, aq. NaHCO3 solution, dried with Na2SO4 and concentrated under vacuum to afford 4-Chloro-7-phenyl-5H-pyrrolo[3,2-d]pyrimidine (9.8g.)
Step 6: 7-Phenyl-5H-pyrrolo[3,2-d]pyrimidine
4-Chloro-7-phenyl-5H-pyrrolo[3,2-d]pyrimidine (5.1g, 0.022 mol) is dissolved in methanol (50ml) and (8.4g, 0.13 mol) of ammonium formate is added. The mixture is degassed and then (0.47g, 10 mol%) of 10% Pd/C is added carefully under nitrogen. The reaction mixture is stirred at room temperature overnight. Reaction mixture is then filtered over celite bed, methanol is then evaporated, residue is diluted with water and extracted with dichloromethane. The organic layer is washed with water, dried with Na2SO4 and concentrated under vacuum to afford 7-Phenyl-5H-pyrrolo[3,2-d]pyrimidine (3g).
Step 7: 6-Bromo-7-phenyl-5H-pyrrolo[3,2-d]pyrimidine
7-Phenyl-5H-pyrrolo[3,2-d]pyrimidine (1Og, 0.047 mol) is dissolved in methanol (60ml) and cooled to O0C. Cold solution of bromine (7.68g, 0.042 mol) in acetic acid (20ml) is then added dropwise to the reaction mixture at O0C. The reaction mixture is stirred at room temperature overnight. Reaction mixture is then filtered through buchner funnel, solid obtained is washed with diethyl ether and dried under vacuum to afford 6-Bromo-7-phenyl- 5H-pyrrolo[3,2-d]pyrimidine (10.9g).
Step 8: 7-Phenyl-6-pyridin-4-yl-5H-pyrrolo[3,2-d]pyrimidine
Mixture of 6-Bromo-7-phenyl-5H-pyrrolo[3,2-d]pyrimidine (l .Og 0.003 mol), 4-pyridyl boronic acid (0.53g, 0.004 mol), (Ph3P)2PdCl2 (0.25g, 10 mol%) and sodium carbonate (0.77g, 0.0073 mol) are dissolved in of DME:H2O :Ethanol (10ml/ 7:3:2) and heated in microwave at HO0C for 20 minutes. The reaction mixture is then filtered over celite bed. Filtrate is then quenched with water and extracted with dichloromethane. The organic layer is washed with water, dried over Na2SO4 and concentrated under vacuum. The residue is purified by column chromatography to yield 7-Phenyl-6-pyridin-4-yl-5H-pyrrolo[3,2- d]pyrimidine (0.558g).
Step 9 5-Allyl-7-phenyl-6-pyridin-4-yl-5H-pyrrolo[3,2-d]pyrimidine
7-Phenyl-6-pyridin-4-yl-5H-pyrrolo[3,2-d]pyrimidine (0.2g, 0.0007 mol) is dissolved in tetrahydrofuran (10ml). Sodium hydroxide (0.088g, 0.0022 mol) dissolved in water is then added dropwise followed by addition of (0.132g, 0.0011 mol) of allyl bromide. The reaction mixture is then stirred at room temperature for 2 hours. THF is then evaporated, mixture diluted with ethyl acetate, dried with Na2SO4 and concentrated under vacuum. The residue is purified by column chromatography to yield 5-Allyl-7-phenyl-6-pyridin-4-yl-5H- pyrrolo[3,2-d]pyrimidine (O.lg).
Figure imgf000079_0001
Example 5: 7-Phenyl-5-prop-2-ynyl-6-pyridin-4-yl-5H-pyrrolo[3,2-clpyridazine 4-Amino- pyridazin-3-ol
To a solution of 4,5-dichloro-3-hydroxypyridazine (53.69 g; 0.325 mol) in ethanol (1.8 L) is added 158 mL of Hydrazine. hydrate (10 eqs; 3.25 mol). The reaction mixture is then heated to reflux overnight (over which period of time it changes from white to yellow suspension, then to orange suspension and finally to orange solution). The reaction mixture is allowed to cool down to room temperature, and 90 grams of Isolute are added. The solvent is removed under vacuum and the residue is purified by column chromatography (2 kg silica gel), eluting with ethyl acetate, then EtOAc: MeOH: Et3N (95 :4: 1) and finally EtOAc: MeOH: Et3N
(90:9:1). The 44.1 grams of solid materials obtained from the column are mixed with 22 mL of water and cooled down to 00C overnight. 16.32 grams of orange crystals are obtained by filtration, washing with cold water and drying at 45°C at a reduced pressure of 14mm(Hg) overnight.
IH NMR (400Mhz, CDCl3) 7.45ppm, IH, d, J=4.64Hz; 6.30ppm, 2H, bs; 6.16ppm, IH, d, J=4.75Hz.
4-[2-Phenyl- 1 -pyridin-4-yl-ethylideneamino]-pyridazin-3-ol
0.5 grams of 4-(l,l-Dimethoxy-2-phenyl-ethyl)-pyridine are dissolved in 1 mL DMF, 1 drop of cc. sulfuric acid is added, and the mixture heated to 900C. 1.09 grams of 4-Amino- pyridazin-3-ol in 2.5 ml of DMF are added during 20 minutes, and the reaction mixture is heated further to 1250C overnight. After cooling down to room temperature, the mixture is washed with a saturated aqueous solution Of NaHCO3 and extracted three times with ethyl acetate. The combined organic extracts are dried with Na2SO4, filtered and concentrated under vacuum. The residue is purified by column chromatography (elution with ethyl acetate + 1 % triethylamine). 400 mg of the title compound are obtained as a mixture of imine/enamine.
IH NMR (400Mhz, D6-DMSO) 12.8ppm, IH, bs; 12.5ppm, IH, bs; 8.58ppm, 2H, dd, J=I .4 and 4.7Hz; 8.51ppm, IH, s; 7.95ppm, IH, s; 7.56ppm, 2H, d, J=7.3Hz; 7.49ppm, 2H, dd, J=I .6 and 4.6Hz; 7.46ppm, IH, d, J=4.7Hz; 7.41ppm, IH, d, J=4.7Hz; 7.36ppm, 2H, t, J=7.2Hz; 7.30ppm, IH, t, J=7.2Hz; 7.24ppm, IH, bs; 6.3ppm, IH, bs; 6.17ppm, IH, d, J=4.7Hz; 5.61ppm, IH, d, J=4.8Hz.
(3 -Chloro-pyridazin-4-yl)- [2-phenyl- 1 -pyridin-4-yl-ethylidene] -amine
91 mg of 4-[2-Phenyl-l-pyridin-4-yl-ethylideneamino]-pyridazin-3-ol and 11.4 mg of Me3NHCl are heated in 0.6 mL of POCl3 at 1000C for 2 hours. After cooling down to room temperature, the mixture is poured on ice, stirred for 30 minutes and neutralised with sodium hydroxide 4M. It is then extracted with ethyl acetate, washed with sat. NaHCO3, and extracted again with EtOAc. The combined organic extracts are dried over Na2SO4, filtered and concentrated under vacuum. The residue is purified by column chromatography (elution with ethyl acetate/methanol 19/1 + 1% triethylamine). 53.5 mg of the title compound are obtained.
IH NMR (400Mhz, CDC13) 8.61ppm, 2H, bs; 8.44ppm, IH, d, J=5.8Hz; 7.37-7.22ppm, 6H, m; 6.82ppm, IH, s; 6.53ppm, IH, bs; 6.13ppm, IH, d, J=5.8Hz.
7-Phenyl-6-pyridin-4-yl-5H-pyrrolo[3,2-c]pyridazine
387 mg of (3-Chloro-pyridazin-4-yl)-[2-phenyl-l-pyridin-4-yl-ethylidene]-amine, 444 mg DABCO and 88 mg (Ph3P)2PdCl2 are dissolved in DMF (5.8 mL) and stirred at 1100C for
3.5 hours. After cooling down to room temperature, the mixture is washed with a saturated aqueous solution OfNaHCO3 and extracted twice with ethyl acetate. The combined organic extracts are dried with Na2SO4, filtered and concentrated under vacuum. 221 mg of solid material are obtained but they contain very little product. The aqueous phase is then filtrated, the solid obtained is dried at 400C at a reduced pressure of 14 mm(Hg) overnight. 168.5 mg of the title compound are then obtained.
IH NMR (400Mhz, D6-DMS0) 12.48ppm, IH, bs; 9.01ppm, IH, d, J=5.8Hz; 8.65ppm, 2H, d, J=5.8Hz; 7.71ppm, IH, d, J=5.9Hz; 7.57ppm, 2H, d, J=7.2Hz; 7.51ppm, 2H, d, J=5.9Hz; 7.46ppm, 2H, t, J=7.2Hz; 7.39ppm, IH, t, J=7.2Hz.
7-Phenyl-5-prop-2-ynyl-6-pyridin-4-yl-5H-pyrrolo[3,2-c]pyridazine
108 mg of 7-Phenyl-6-pyridin-4-yl-5H-pyrrolo[3,2-c]pyridazine are dissolved in DMF (1.2 mL), and 19 mg NaH (60%, 1.2 eq.) are added portionwise under slight cooling. The mixture is stirred 15 minutes, before 40 μL of propargyl bromide are added. After 3 hours at room temperature, a saturated aqueous solution OfNaHCO3 is added dropwise, and the mixture is further diluted with dichloromethane. Extraction, drying over Na2SO4, filtration and evaporation afford the crude compound. The latter is purified twice by column chromatography (10 g silica gel, elution with EtOAc/MeOH/Et3N 89: 10: 1 then 10 g silica gel, , elution with EtOAc/MeOH/Et3N 93:6:1). 6 mg of the pure title compound are obtained.
IH NMR (400Mhz, CDC13) 9.16ppm, IH, d, J=5.9Hz; 8.77ppm, 2H, dd, J=I.3 and 4.6Hz; 7.59ppm, IH, d, J=5.9Hz; 7.56ppm, 2H, d, J=7.7Hz; 7.42ppm, 2H, dd, J=I.5 and 4.4Hz; 7.33ppm, 2H, t, J=7.6Hz; 7.28ppm, IH, t, J=7.6Hz; 4.77ppm, 2H, d, J=2.5Hz; 2.47ppm, IH, t, J=2.5Hz.
Based on similar synthesis following derivatives were prepared:
7-(4-Fluoro-phenyl)-6-pyridin-4-yl-5H-pyrrolo[3,2-c]pyridazine
IH NMR (400Mhz, CD3OD) 8.98ppm, IH, d, J=5.9Hz; 8.60ppm, 2H, dd, J=I.5 and 4.8Hz;
7.77ppm, IH, d, J=5.9Hz; 7.59-7.56ppm, 4H, m; 7.2ppm, 2H, t, J=8.8Hz.
5-Allyl-7-(4-fluoro-phenyl)-6-pyridin-4-yl-5H-pyrrolo[3,2-clpyridazine
IH NMR (400Mhz, CDCl3) 9.11ppm, IH, d, J=5.9Hz; 8.73ppm, 2H, d, J=5.5Hz; 7.55ppm, 2H, dd, J=5.4 and 8.8Hz; 7.42ppm, IH, d, J=5.9Hz; 7.33ppm, 2H, d, J=6Hz; 7.02ppm, 2H, t, J=8.8Hz; 5.91ppm, IH, tdd, J= 4.6 and 10.5 and 17.1Hz; 5.27ppm, IH, d, J=10.5Hz; 4.93ppm, IH, d, J=17.1Hz; 4.66ppm, 2H, m.
Example 6: Biological activity of the compounds of the invention
The compounds of the invention were tested in a leaf disk assay, as described below to determine their preventative action against a number of fungal species. In all cases, the test compounds were dissolved in DMSO and diluted into water to 200 ppm. The final test solution contained 2% DMSO and 0.025% Tween® 20.
a) Erysiphe graminis f.sp. hordei (barley powdery mildew) and Pyrenophora teres (barley net blotch): Barley leaf segments were placed on agar in a 24-well plate and sprayed with a solution of the test compound. After allowing the segments to dry completely (24 hours) they were inoculated with a spore suspension of the fungus. After appropriate incubation the activity of a compound was assessed four {Pyrenophora teres) or seven {Erysiphe graminis f.sp. hordei) days after inoculation as preventive fungicidal activity.
b) Erysiphe graminis f.sp. tritici (wheat powdery mildew), Puccinia reconditafsp. tritici (wheat brown rust) and Septoria nodorum (wheat glume blotch): Wheat leaf segments were placed on agar in a 24-well plate and sprayed with a solution of the test compound. After allowing the segments to dry completely (24 hours), they were inoculated with a spore suspension of the fungus. After appropriate incubation the activity of a compound was assessed four (Septoria nodorum), seven (Erysiphe graminis f.sp. tritici) or eight (Puccinia reconditaf.sp. tritici) days after inoculation as preventive fungicidal activity.
c) Pyricularia oryzae (rice blast): Rice leaf segments were placed on agar in a 24- well plate and sprayed with a solution of the test compound. After allowing the segments to dry completely (24 hours), they were inoculated with a spore suspension of the fungus. After appropriate incubation the activity of a compound was assessed five days after inoculation as preventive fungicidal activity.
d) Botrytis cinerea (grey mould): Bean leaf disks were placed on agar in a 24-well plate and sprayed with a solution of the test compound. After allowing the disks to dry completely (24 hours), they were inoculated with a spore suspension of the fungus. After appropriate incubation the activity of a compound was assessed three days after inoculation as preventive fungicidal activity.
e) Phytophthora infestans (late blight of potato/tomato): Tomato leaf disks were placed on water agar in a 24-well plate and sprayed with a solution of the test compound. After allowing the disks to dry completely (24 hours), they were inoculated with a spore suspension of the fungus. After appropriate incubation the activity of a compound was assessed four days after inoculation as preventive fungicidal activity.
f) Plasmopara viticola (downy mildew of grapevine): Grapevine leaf disks were placed on agar in a 24-well plate and sprayed a solution of the test compound. After allowing the disks to dry completely (for between 12 and 24 hours), they were inoculated with a spore suspension of the fungus. After appropriate incubation the activity of a compound was assessed seven days after inoculation as preventive fungicidal activity.
The following compounds (numbering corresponds to Tables 1, 2 and 3 above) gave at least 80% control of the following fungal infection at 200ppm in the leaf disc assays described above:
Plasmopara viticola: l.l;1.2;1.3;1.4;1.18;1.19;1.20;1.21;1.22;1.23;1.34;1.37;1.38;1.39;1.42;1.43;1.44;1.45;2.6;2.7
;2.8;2.9;2.12 Erysiphe graminis f.sp. triticϊ.
1.3;1.4;1.18;1.19;1.20;1.21;1.22;1.36;1.37;1.38;1.39;1.42;1.43;1.44;1.45;2.5;2.12;2.13 Puccinia reconditaf.sp. triticϊ. 1.3;1.4;1.5;1.18;1.19;1.20;1.21;1.22;1.23;1.31;1.34;1.36;1.37;1.38;1.39;1.42;1.43;1.44,1.45; 2.3;2.4;2.7;2.8;2.12
In addition, the compounds of the invention were also tested for their ability to inhibit the growth of fungal spores in nutrient broth.
a) Septoria tritici (wheat leaf blotch), Botrytis cinerea (grey mould), Pyricularia oryzae (rice blast), Rhizoctonia solani (foot rot and damping off), Fusarium culmorum (foot rot of cereals): Conidia of the fungus from cryogenic storage were directly mixed into nutrient broth (PDB potato dextrose broth). After placing a (DMSO) solution of the test compounds at 20 ppm into a microtiter plate (96-well format) the nutrient broth containing the fungal spores was added. The test plates were incubated at 24 C and the inhibition of growth was determined photometrically after 72 hrs (Septoria tritici, Botrytis cinerea, Pyricularia oryzae) or 48 hrs (Rhizoctonia solani, Fusarium culmorum).
b) Pythium ultimum (Damping off): Mycelial fragments of the fungus, prepared from a fresh liquid culture, were mixed into potato dextrose broth. A (DMSO) solution of the test compound at 20ppm was then placed into a 96-well microtiter plate and the nutrient broth containing the fungal spores was added. The test plate was incubated at 240C and the inhibition of growth was determined photometrically after 48 hours.
The following compounds (numbering corresponds to Tables I and II above) gave at least 80% control of the following fungal infection at 20ppm in the liquid culture assays described above:
Septoria tritici: 1.3;1.6;1.7;1.8;1.19;1.20;1.21;1.22;1.23;1.29;1.31;1.36;1.37;1.38;1.39;.142,1.43,1.44;1.45;2. 8;2.12;3.2 Pythium ultimum: 1.3;1.4;1.7;1.8,1.9;1.20;1.24;1.40;1.42;1.43;1.44;1.45;2.1;2.2;2.5;2.6;2.10;2.12;3.2;3.4 Example 7 - HPLC Methods Used
Method A (Water Alliance 2795 LC) with the following HPLC gradient conditions: Solvent A: 0.1% formic acid in water/ acetonitrile (9:1) Solvent B: 0.1% formic acid in acetonitrile)
Figure imgf000085_0001
Type of column: Water atlantis del 8; Column length: 20 mm; Internal diameter of column: 3 mm; Particle Size: 3 micron; Temperature: 400C.
The characteristic values obtained for each compound were the retention time ("RT", recorded in minutes) and the molecular ion, typically the cation MH+ as listed in Tables 1, 2 and 3. The HPLC-MS method used is indicated in brackets.
Method B (Agilentl 100 Series LC) with the following HPLC gradient conditions : Solvent A: 0.1% formic acid in water / acetonitrile (9:1) Solvent B: 0.1% formic acid in acetonitrile)
Figure imgf000085_0002
Type of column: Water atlantis dcl8; Column length: 20 mm; Internal diameter of column: 3 mm; Particle Size: 3 micron; Temperature: 400C.
Method C (Thermo HPLC) with the following HPLC gradient conditions: Solvent A: 0.25 % formic acid in water Solvent B: 0.025% formic acid in acetonitrile
Figure imgf000086_0001
Type of column: Waters, symmetry C-18; Column length: 50mm; Internal diameter of column: 4.6mm; Particle Size: 3.5 micron;
Method D (Thermo HPLC) with the following HPLC gradient conditions: Solvent A: 0.25 % formic acid in water Solvent B: 0.025% formic acid in acetonitrile
Figure imgf000086_0002
Type of column: Waters, symmetry C-18; Column length: 50mm; Internal diameter of column: 4.6mm; Particle Size: 3.5 micron;
The characteristic values obtained for each compound were the retention time ("RT", recorded in minutes) and the molecular ion, typically the cation MH+ as listed in Tables 1,2 and 3. The HPLC-MS method used is indicated in brackets.
Although the invention has been described with reference to preferred embodiments and examples thereof, the scope of the present invention is not limited only to those described embodiments. As will be apparent to persons skilled in the art, modifications and adaptations to the above-described invention can be made without departing from the spirit and scope of the invention, which is defined and circumscribed by the appended claims. All publications cited herein are hereby incorporated by reference in their entirety for all purposes to the same extent as if each individual publication were specifically and individually indicated to be so incorporated by reference.

Claims

1. A method of preventing and/or controlling fungal infection in plants and/or plant propagation material comprising applying to the plant or plant propagation material a compound of formula (I) :
Figure imgf000088_0001
wherein:
any one of G1, G2 and G3 is N and the other two of G1, G2 and G3 are CR8, CR1 or CR2, such that when G1 is not N, G1 is CR8; when G2 is not N, G2 is CR1; when G3 is not N, G3 is CR2;
X1 is N or CH;
X2 is N or CR5;
R1 is:
(i) hydrogen, halogen, hydroxyl, cyano or nitro, (ii) optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, or optionally substituted alkoxy, (iii) optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl or optionally substituted cycloalkenyl, or (iv) -C(O)R10, -C(O)NR10R11, -C(S)NR10R11, -C(NOR10)Rπ, -C(O)OR10, -OR10, -
SR10, -S(O)R10, -S(O)NR10R11, -S(O)2NR10R11, -S(O)2R10, -NR10R11, -
P(O)(OR10XOR11) or -OP(O)(OR1 °)(0R11);
R2 is: (i) hydrogen, halogen, hydroxyl, cyano or nitro, (ii) optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl, (iii) optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl or optionally substituted cycloalkenyl, or
(iv) -C(O)R10, -C(O)NR10R11, -C(S)NR10R11, -C(NOR10)Rπ, -C(O)OR10, -OR10, -
SR10, -S(O)R10, -S(O)NR10R11, -S(O)2NR10R11, -S(O)2R10, -NR10R11, -
P(O)(OR10XOR11) or -OP(O)(OR1 °)(0R11);
R3 is:
(i) hydrogen, hydroxyl, cyano or nitro,
(ii) optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl,
(iii) optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl or optionally substituted cycloalkenyl, or (iv) -C(O)R12, -C(O)OR12, -OR12, -OC(O)R12, -S(O)2R12 or -NR12R13;
R4 is: (i) hydrogen, halogen, hydroxyl, cyano or nitro,
(ii) optionally substituted alkyl, optionally substituted alkenyl or optionally substituted, (iii) optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl or optionally substituted cycloalkenyl, or
(iv) -C(O)R14, -C(O)OR14, -C(NOR14)R15, -OR14, -SR14, -S(O)NR14R15, -
S(O)2R14, or -NR14R15;
R5 is: (i) hydrogen, halogen, hydroxyl, cyano or nitro,
(ii) optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl, (iii) -C(O)R16, -C(O)OR16, -OR16, -SR16, -S(O)R16, -S(O)NR16R17, -S(O)2R16, or -
NR16R17; R6 is:
(i) hydrogen, halogen, hydroxy, ethoxy or cyano,
(ii) optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl or optionally substituted cycloalkenyl, or (iii) -C(O)OR18, -SR18, -NR18R19, -C(O)NR18R19, -N=CR20 or -C(=NR18)NR19R20 ;
R7 is: (i) hydrogen, halogen, hydroxyl, cyano, or nitro, (ii) optionally substituted alkyl, or (iii) -NR21R22;
R8 is: (i) hydrogen, halogen, hydroxyl, cyano, or nitro, (ii) optionally substituted alkyl, or (iii) -NR21R22;
R10, R11, R14, R15, R16 and R17 are, independently: (i) hydrogen, halogen, hydroxyl, cyano or nitro;
(ii) optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkenyl or optionally substituted alkynyl, or (iii) optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl or optionally substituted cycloalkenyl;
R12 and R13 are, independently:
(i) hydrogen, halogen, hydroxyl, cyano, nitro or -NR21R22;
(ii) optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkenyl or optionally substituted alkynyl, or
(iii) optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl or optionally substituted cycloalkenyl; R18 and R19 are, independently:
(i) hydrogen,
(ii) optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl, (iii) optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl or optionally substituted cycloalkenyl, or (iv) -C(S)R23 -C(O)R23, -SO2R23, -C(O)OR23, -OR23 or C(O)NR23R24;
R20 is:
(i) hydroxyl,
(ii) optionally substituted alkyl or optionally substituted alkoxy, or
(iii) -NR21R22 or -N=CR21R22;
R21 and R22 are, independently: (i) hydrogen, (ii) optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl,
(iii) optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl or optionally substituted cycloalkenyl, or (iv) -C(O)OR25;
R23 and R24 are, independently: (i) hydrogen or hydroxyl,
(ii) optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl, or (iii) optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl or optionally substituted cycloalkenyl; and
R25 is optionally susbstituted alkyl, optionally susbstituted alkenyl or optionally susbstituted alkynyl; and
optionally: independently, (i) R1 and R2, (ii) R1 and R3 (iii) R2 and R3, (iv) R3 and R5, (v) R 5 and R6, (vi) R5 and R18, (vii) R5 and R19, (viii) R14 and R15 and/or (ix) R18 and R19 form an optionally substituted aryl, optionally susbstituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl or optionally substituted cycloalkenyl containing from 5 to 18 ring atoms;
or an isomer, tautomer, N-oxide or salt (including N-oxide salt), thereof.
2. The method of claim 1 , wherein G1 is CR8, G2 is CR1 , and G3 is N.
3. The method of claim 1 or claim 2, wherein X1 is CH and X2 is CH;
4. The method any one of claims 1 to 3, wherein
R1 is hydrogen, halogen, cyano, optionally substituted Ci_6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted phenyl or -C(O)R10;
R2 is hydrogen, or Ci_6 alkyl;
R3 is hydrogen, hydroxyl, -C(O)R12, -OR12, -C(O)OR12, -OC(O)R12, -S(O)2R12, optionally substituted Ci_6 alkyl, optionally substituted C2-6 alkenyl, or optionally substituted C2-6 alkynyl, optionally substituted C3-6 cycloalkyl;
R4 is hydrogen, halogen, optionally substituted C2-6 alkynyl, optionally substituted aryl or optionally substituted heteroaryl;
R5 is halogen, cyano, hydroxyl, Ci_4 haloalkyl or Ci_4 alkyl; R6 is hydrogen or -NR18R19;
R7 is hydrogen, hydroxyl, cyano, -NR21R22 or optionally substituted Ci_6 alkyl;
R8 is hydrogen, hydroxyl, cyano, -NR21R22 or optionally substituted Ci_6 alkyl;
R18 is hydrogen, Ci_4 alkyl, C2-4 alkenyl, or C2-4 alkynyl;
R19 is hydrogen, ώo-butyl, -C(O)R23 or -C(O)OR23; R21 and R22 are independently selected from hydrogen, methyl and ethyl;
R23 is hydrogen, hydroxyl, optionally substituted Ci_6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C3-6 cycloalkyl, or optionally substituted C4_6 cycloalkenyl.
5. The method of claim 4, wherein the optional substituents of the alkyl, alkenyl, alkynyl, phenyl, cycloalkyl, cycloalkenyl, aryl, and heteroaryl groups are selected from methoxy, ethoxy, hydroxyl, cyano, halogen, pyridyl, oxirane, tetrahydrofuran, trimethylsilyl and -C(O)OR, wherein R is hydrogen, methyl or ethyl.
6. The method of any one of claims 1 to 5, wherein R1 is hydrogen, chloro, or methyl;
R2 is hydrogen, or Ci_6 alkyl; R5 is hydrogen or halogen; R7 and R8 are independently hydrogen, hydroxyl or NR21R22; R21 and R22 are independently hydrogen, methyl or ethyl.
7. The method of any one of claims 1 to 6, wherein
R3 is optionally substituted Ci_6 alkyl, optionally substituted C2-6 alkenyl or optionally susbtituted C2-6 alkynyl, wherein the optional substituents of the alkyl, alkenyl and alkynyl are independently selected from cyano, methoxy, and halogen.
8. The method of any one of claims 1 to 6, wherein
R3 is hydrogen, cyanomethyl, aminoethyl, aminopropyl, ethenyl, prop-2-enyl, prop-2-ynyl, prop-l,2-dienyl, methoxymethyl, 2-fluoromethyl, 2-fluoroethyl, -OCH2C≡CH, -OCH2OCH3, -OCH2CN, -OCH(CH3)CN, -OCH2CH=CH2, or benzyl.
9. The method of any one of claims 1 to 8, wherein
R4 is phenyl optionally substituted by 1 to 3 groups independently selected from Ci_4 alkyl, Ci_4 haloalkyl and halogen.
10. The method of any one of claims 1 to 8, wherein
R4 is phenyl, 3-methylphenyl, 3-trifluoromethylphenyl, 2-fluorophenyl, 3 -fluorophenyl, 4- fluorophenyl, 2,5-difluorophenyl, 3-methyl-4-fluorophenyl, 2,4-difluorophenyl, 2,6- diflurophenyl, or 2,4,6-diflurophenyl.
11. The method of any one of claims 1 to 10, wherein R6 is hydrogen or -NHR19; R19 is hydrogen, Ci_4 alkyl optionally substituted by hydroxy or Ci_4 alkoxy which in turn may be substituted by hydroxy, or R19 is -C(O)R23;
R23 is Ci_4 alkyl, C2-4 alkenyl, C2-4 alkynyl, or C3-4 cycloalkyl.
12. The method of any one of claims 1 to 11, wherein
R6 is NHC(O)R23, in which R23 is Ci_4 alkyl, cyclopropyl or cyclobutyl.
13. The method of claim 1 , wherein X1 is CH and X2 is CH; R1 is hydrogen, halo or optionally substituted Ci_4 alkyl,
R2 is hydrogen or methyl;
R3 is hydrogen, Ci_4 alkyl, C2-4 alkenyl, C2-4 alkynyl, or -OR12, in which R12 is Ci_4 alkyl, C3-6 cycloalkyl or C4_6 cycloalkenyl;
R4 is phenyl, which is optionally substituted by at least one substituent selected from halogen and Ci_4 alkyl;
R6 is halogen or -NR18R19, in which R18 is hydrogen, prop-2-enyl or prop-2-ynyl, and R19 is -
C(O)R23, in which R23 is hydrogen, methyl, ethyl, ώo-propyl, 1-methylethyl, 1-methylpropyl,
2-dimethylethyl, propyl, 1-methylethenyl, 2-methylprop-l-enyl, but-3-enyl, cyclopropyl, 1- methylcyclopropyl, 1-fluorocyclopropyl or cyclobutyl; R7 is hydrogen, chloro, fluoro or methyl; and
R8 is hydrogen, chloro, methyl or 2-methoxy-l-ethylamino.
14. The method of claim 1, wherein X1 is CH and X2 is CH; R1 is hydrogen, chloro or methyl;
R2 is hydrogen or methyl;
R3 is hydrogen, cyanomethyl, prop-2-enyl, prop-2-ynyl or benzyl;
R4 is 2-fluorophenyl, 3 -fluorophenyl, 4-fluorophenyl, 4-chlorophenyl, 3-methylphenyl or 3- methyl-4-fluorophenyl; R6 is -NR18R19, in which R18 is hydrogen, and R19 is -C(O)R23, in which R23 is methyl, ethyl, ώo-propyl, cyclopropyl, cyclobutyl or 1-methylcyclopropyl;
R7 is hydrogen, chloro, fluoro or methyl; and
R8 is hydrogen, chloro or methyl.
15. The method of claim 1 , wherein X1 is CH and X2 is CH;
R1 is hydrogen, -NH-CM alkyl, wherein the Ci_4 alkyl is optionally substituted by methoxy; R2 is hydrogen or halogen; R3 is hydrogen, Ci_4 alkyl, C3-4 alkenyl, C3-4 alkynyl, wherein the Ci_4 alkyl is optionally substited by cyano or methoxy;
R4 is phenyl optionally substituted by 1-3 halogen atoms;
R6 is hydrogen,-NH-Ci_4 alkyl, wherein the alkyl is optionally substituted by hydroxy or Ci_4 alkoxy, which in turn may be substituted by hydroxy, or R6 is -NH-C(O)-C 1-4 alkyl, NH- C(O)-C3-4 cycoalkyl, -NH-C(O)-C3-4 alkenyl, or -NH-C(O)-C2-4 alkynyl; R7 is hydrogen or halogen; R8 is hydrogen or halogen.
16. The method of claim 1, wherein the compound is one of the compounds set out in Table I, Table II, or Table III.
17. A compound of formula (I) as defined in any one of claims 1 to 16, with the provisos that:
(i) when G1 is CR8, G2 is CR1, G3 is N, X1 is CH, X2 is CR5, and R5 and R6 are both H, then R4 is not 4-fluorophenyl; and
(ii) the compound of formula (I) is not: 7-phenyl-6-(pyridin-4-yl)-5H-pyrrolo[3,2-c]pyridazine; 7-phenyl-6-(pyridin-4-yl)-5H-pyrrolo[3,2-d]pyrimidine; 7-phenyl-6-(pyridin-4-yl)-5H-pyrrolo[2,3-b]pyrazine; 7-(3-chlorophenyl)-6-[2-(2-methylthioethylamino)-4-pyridyl]-5H-pyrrolo[2,3-b]pyrazine; 7-(3-chlorophenyl)-6-(2-chloropyridin-4-yl)-5H-pyrrolo[2,3-b]pyrazine; or 7-(4-fluorophenyl)-6-(pyridine-4-yl)-5H-pyrrolo[3,2-d]pyrimidine.
18. A composition for the control of fungal infection comprising a compound of formula (I) as defined in any one of claims 1 to 16 and an agriculturally acceptable carrier or diluent.
19. The composition of claim 18, wherein the composition further comprises at least one active ingredient selected from a fungicide, a herbicide, an insecticide, a bactericide, an acaricide, a nematicide and/or a plant growth regulator.
PCT/EP2009/062673 2008-10-21 2009-09-30 Diaza-indole derivatives and their use as fungicides Ceased WO2010046215A2 (en)

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