WO2002059118A1 - Process for n-(oxyalkylation) of carboxamides - Google Patents

Process for n-(oxyalkylation) of carboxamides Download PDF

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Publication number
WO2002059118A1
WO2002059118A1 PCT/GB2002/000313 GB0200313W WO02059118A1 WO 2002059118 A1 WO2002059118 A1 WO 2002059118A1 GB 0200313 W GB0200313 W GB 0200313W WO 02059118 A1 WO02059118 A1 WO 02059118A1
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optionally substituted
alkyl
hydrogen
alkoxy
cycloalkyl
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PCT/GB2002/000313
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French (fr)
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Alfred Glyn Williams
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Syngenta Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to a process for the production of biologically active ether derivatives of amides, in particular of fungicidal, insecticidal, acaricidal, molluscicidal and nematicidal compounds, as well as to methods of using them to combat fungal diseases (especially fungal diseases of plants) and to methods of using them to combat and control insect, acarine, mollusc and nematode pests.
  • a number of pesticidal compounds comprising a heteroaryl ring system linked via a chain which includes an amide or sulphonamide group, to a second aromatic ring system which may be aryl or heteroaryl and in which the nitrogen atom of the amide or sulphonamide bears an alkoxymethyl substituent.
  • Examples of such compounds are given for example in WO 00/06566, copending British Patent Application Nos 00/02029.7, 00/02032.1, 00/02035.4, 00/02037.0, 00/02041.2, 00/02031.3 and 00/02036.2 as well as WO96/31448 and in the J. Agric. Food Chem 1997, 45,1920-1930.
  • A is an optionally substituted heteroaryl group
  • B is an optionally substituted aryl or heteroaryl group
  • X is oxygen or sulphur
  • R la and R lb are independently selected from hydrogen, C(O)OC 1 . alkyl or aryl;
  • R 2 is a bond, optionally substituted . 6 alkylene, optionally substituted C 2 . 6 alkenylene, optionally substituted C 2 . 6 alkynylene, optionally substituted C 2 . 6 cycloalkylene, optionally substituted - 6 alkylenoxy, optionally substituted oxy(C 1 .
  • R 3 is optionally substituted Ci- ⁇ alkyl, optionally substituted C ⁇ alkyl- carbonyl, optionally substituted C 2 . 6 alkenyl, optionally substituted C 2 - 6 alkynyl, optionally substituted C ⁇ ocycloalkyl, optionally substituted aryl or optionally substituted aroyl; said process comprising reacting a compound of formula (IT)
  • (m) which is a liquid or a low melting point solid at room temperature and where R la , R lb and R 3 are as defined in relation to formula (I) and Z is a leaving group, in the presence of a base but in the absence of a further solvent.
  • low melting point solid refers to a solid which will form a liquid at the temperature of the reaction.
  • the reaction is suitably effected at moderate temperatures, for example, at from 20 to 90°C, and preferably at about 60°C. Reaction times may vary, but in general the reaction will be completed within 5 hours and in some cases, within as little as 2 hours.
  • Suitable bases are weak bases including trialkylamines (such as triethylamine), cyclic amines (such as l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), l,8-diazabicyclo[4.3.0]non-5-ene (DBN) and l,4-diazobicyclo[2.2.2]octane (DABCO)), pyridine, N-methylmorpholine and ⁇ oly-4-vinylpyridine.
  • trialkylamines such as triethylamine
  • cyclic amines such as l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), l,8-diazabicyclo[4.3.0]non-5-ene (DBN) and l,4-diazobicyclo[2.2.2]octane (DABCO)
  • DBU l,8-diazabicyclo[
  • Suitable leaving groups Z include halo, mesylate and tosylate; and in particular are halo (such as chloro or bromo) and in particular chloro.
  • R la and R lb is hydrogen and the other is hydrogen, carboethoxy or phenyl. Most preferably both R la and R lb are hydrogen.
  • R 3 is . 6 alkylcarbonyl, benzoyl (where the phenyl ring is optionally substituted with halogen or C ⁇ alkyl), (C 1 . 6 )alkyl (where the alkyl group is optionally substituted by aryl or . 4 alkoxycarbonyl), C 2 . 6 alkenyl, C 2 . 6 alkynyl or benzyl (where the phenyl ring is optionally substituted with halogen or ⁇ alkyl).
  • R 3 is C ⁇ . ⁇ alkylcarbonyl, benzoyl (where the phenyl ring is optionally substituted with halogen or C ⁇ alkyl), -6 alkyl, C 2 . 6 alkenyl or C 2 -6 alkynyl.
  • R 3 is C e alkyl or . 6 alkylcarbonyl.
  • R 3 is a alkyl group such as methyl, ethyl, propyl, 2- butyl, 2-methylpropyl and n-pentyl, in particular ethyl.
  • a preferred example of a compound of formula (HI) is chloromethylethylether (CMEE).
  • the product is suitably recovered from the reaction mixture by dissolution into an organic solvent, such as hexane, which may then be filtered to remove impurities. Pure product may then be extracted from the solvent by evaporation.
  • an organic solvent such as hexane
  • heteroaryl refers to aromatic heterocyclic groups which suitably contain from 4 to 20 ring atoms, and in particular from 5 to 12 atoms, up to five, suitably up to three of which are heteroatoms such as sulphur, oxygen or nitrogen.
  • Heteroaryl groups are suitably mono- or bicyclic rings.
  • heteroaryl rings are aromatic rings containing up to 10 atoms including one or more heteroatoms (preferably one or two heteroatoms) selected from O, S and N. Examples of such rings which are monocyclic include pyridine, pyiimidine, furan, pyrazole, thiophene, thiazole, isothiazole, oxazole and isoxazole.
  • Bicyclic rings include quinoline, isoquinoline, quinazoline, indole, benzothiazole, benzotriazole, benzoxazole, indole, benzisoxazole and benzimidazole.
  • heteroaryl rings may comprise an aromatic heterocyclic group fused to a non-aromatic ring.
  • heterocycle and “heterocyclyl” and these refer to both aromatic and non-aromatic rings containing up to 10 atoms including one or more (preferably one or two) heteroatoms selected from O, S and N.
  • non-aromatic rings include 1,3-dioxolane, tetrahydrofuran and morpholine.
  • alkyl group or moiety is suitably a straight or branched chain which, unless otherwise specified suitably has from 1-10, and preferably from 1-6, carbon atoms.
  • alkyl groups are methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, w ⁇ -propyl, n-butyl, sec-butyl, ⁇ o-butyl, tert-butyl and neo-pentyl.
  • Alkenyl and alkynyl moieties can be in the form of straight or branched chains, and the alkenyl moieties, where appropriate, can be of either the (E)- or ⁇ -configuration. Examples are vinyl, allyl and propargyl. In the context of this specification acyl is optionally substituted C ⁇ alkylcarbonyl
  • halogen includes fluorine, chlorine, bromine and iodine.
  • Haloalkyl groups are alkyl groups which are substituted with one or more of the same or different halogen atoms and are, for example, CF 3 , CH 2 CF 3 or CH 2 CHF .
  • Phenyl(C 1 . 4 )alkyl is, for example, 1-phenyleth-l-yl, 2-phenyleth-l-yl, 2-phenylprop-2-yl or 3-phenylprop-l-yl but is preferably benzyl.
  • aryl includes naphthyl, anthracyl, fluorenyl and indenyl but is preferably phenyl.
  • Cycloalkyl includes cyclopropyl, cyclopentyl and cyclohexyl.
  • Cycloalkenyl includes cyclopentenyl and cyclohexenyl. Suitable optional substituents for cycloalkenyl groups include d- 3 alkyl, halogen and cyano.
  • Carbocyclic rings include aryl, cycloalkyl and cycloalkenyl groups. When heterocyclic rings are formed by joining two groups on an N atom, the resulting rings are suitably pyrrolidine, piperidine, thiomorpholine and morpholine each of which may be substituted by one or two (C ⁇ . 6 ) alkyl groups. Where present, and unless otherwise stated, suitable optional substitutents for alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl and non-aromatic heterocyclyl groups include halogen, nitro, cyano, NCS-, C 3 . cycloalkyl (which itself is optionally substituted with d.
  • heterocyclyloxy (which itself is optionally substituted with d- 6 alkyl or halogen), C ⁇ . 6 alkylcarbonylamino and N-(C 1 . 6 )alkyl- carbonyl-N-(C 1 . 6 )alkylamino.
  • Suitable further substituents for aryl or heteroaryl groups of these substitutents include halogen, d- ⁇ alkyl, d_6 haloalkyl, d- 6 alkoxy(d. 6 )alkyl, C ⁇ _ 6 alkoxy, . 6 haloalkoxy, d-6 alkylthio, d_6 haloalkylthio, _6 alkylsulfinyl, C ⁇ . 6 haloalkylsulfinyl, d_ 6 alkylsulfonyl, haloalkylsulfonyl, C 2 _ 6 alkenyl, C 2 .
  • Suitable optional substitutents for aryl or heteroaryl groups such as the heteroaryl group A and the aryl or heteroaryl group B include halogen, nitro, cyano, NCS-, d. 6 alkyl, d- 6 haloalkyl, d. 6 alkoxy(d. 6 )alkyl, C 2 . 6 alkenyl, C 2 .
  • alkyldiarylsilyl triarylsilyl, C O alkylcarbonyl, CM O alkoxycarbonyl, aminocarbonyl, d.6 alkylaminocarbonyl, di(d_ 6 alkylaminocarbonyl, N-(d. 3 alkyl)-N-(d. 3 alkoxy)aminocarbonyl, d. 6 alkylcarbonyloxy, arylcarbonyloxy (where the aryl group itself is optionally substituted), di(d_ 6 )alkylaminocarbonyloxy, aryl (which itself is optionally substituted), heteroaryl (which itself is optionally substituted), heterocyclyl (which itself is optionally substituted with .
  • Suitable further substitutents for aryl or heteroaryl groups or moities in the substitutents on A or B include halogen, d.6 alkyl, d_6 haloalkyl, C ⁇ .e alkoxy(C 1 . 6 )alkyl, d. 6 alkoxy, d. 6 haloalkoxy, d_ 6 alkylthio, d_ 6 haloalkylthio, C ⁇ -6 alkylsulfinyl, d. 6 haloalkylsulfinyl, d.
  • A is an optionally substituted heteroaryl group and most preferably A is, or includes, an optionally substituted 5-membered aromatic ring such as thiazole, isothiazole, triazole, imidazole, pyrazole, pyrrole, tetrazole, or where appropriate, N-oxides thereof. Most preferably A is or includes an optionally substituted isothiazole group, in particular a 5 isothiazole, such as a group of sub-formula (i).
  • R 20 is hydrogen, halogen, optionally substituted C ⁇ . 6 alkyl, optionally substituted C - 6 alkenyl, optionally substituted C 2 . 6 alkynyl, optionally substituted d. 6 alkoxy, optionally substituted d_ 6 alkylthio, optionally substituted C 3 . 7 cycloalkyl, cyano or SF 5 .
  • R 20 is hydrogen, halogen, d. 6 alkyl, C ⁇ . 6 cyanoalkyl, d- 6 haloalkyl, C 3 . cycloalkyl(C ⁇ . 4 )alkyl, C ⁇ . 6 alkoxy(C 1 . 6 )alkyl, C 2 . 6 alkenyl, C 2 . 6 alkynyl,Ci- 6 alkoxy, d_ 6 haloalkoxy, d_6 alkylthio, d_ 6 haloalkylthio, C 3 . 6 cycloalkyl or cyano.
  • R 20 is hydrogen, halogen, C ⁇ - 6 alkyl, d- 6 haloalkyl, d_ 6 alkoxy(C ⁇ . 6 )alkyl, C . 6 alkenyl, C ⁇ -6 alkoxy, C ⁇ _ 6 haloalkoxy, C ⁇ -6 alkylthio, _6 haloalkylthio, C 3 .e cycloalkyl or cyano.
  • R 20 is halogen, Ci. 6 alkyl, d-6 haloalkyl, C ⁇ - 6 alkoxy or d- 6 haloalkoxy.
  • R is hydrogen, halogen, optionally substituted d- 6 alkyl, optionally substituted C 2 - 6 alkenyl, optionally substituted C 2 . 6 alkynyl, optionally substituted d_ 6 alkoxy, optionally substituted d. 6 alkylthio, optionally substituted d_ 6 alkylsulfinyl, optionally substituted d- 6 alkylsulfonyl, cyano, nitro, formyl, optionally substituted d.
  • R 50 is hydrogen, optionally substituted phenyl or optionally substituted d- 6 alkyl and R 52 is hydrogen, optionally substituted phenyl (d_ 2 )alkyl or optionally substituted d- 20 alkyl; or R 20 and R 21 together with the atoms to which they are attached may be joined to form a five, six or seven-membered saturated or unsaturated, carbocylic or heterocyclic ring which may contain one or two heteroatoms selected from O, N or S and which is optionally substituted by d_ 6 alkyl, C1-6 haloalkyl or halogen.
  • R 21 is hydrogen, halogen, d_ 6 alkyl, C ⁇ _ 6 haloalkyl, d-6 alkoxy (C 1 . 6 )alkyl, C 2 -6 alkenyl, d. 6 alkynyl, C ⁇ . 6 alkoxy, d. 6 haloalkoxy, d_ 6 alkylthio, d. 6 haloalkylthio, d. 6 alkylsulfinyl, C ⁇ - 6 haloalkylsulfinyl, d.
  • R is hydrogen, halogen, C ⁇ . 6 alkyl, d- 6 haloalkyl, d- 6 alkoxy (d- 6 )alkyl, d_ 6 alkoxy, d_ 6 haloalkoxy or d_ 6 alkylthio; or R 20 and R 21 together with the atoms to which they are attached form a cyclopentane or benzene ring optionally substituted by Cj- 6 alkyl, d- 6 haloalkyl or halogen.
  • R is hydrogen, halogen, C ⁇ _ 6 alkyl, C ⁇ - 6 haloalkyl, C ⁇ _ 6 alkoxy(d- 6 )alkyl, C ⁇ . 6 alkoxy or d_ 6 haloalkoxy; or R 21 and R 20 together with the atoms to which they are attached form a cyclopentane ring optionally substituted by d_ 6 alkyl, d. 6 haloalkyl or halogen.
  • R y is an optional substituent for A as defined above, and in particular is halo or d- ⁇ haloalkyl.
  • A may be a 6-membered heteroaryl ring (such as pyridyl or pyrimidinyl), a 5- membered heteroaryl ring fused to a cycloalkyl ring or a bicyclic heteroaryl group such as quinolinyl group.
  • 6-membered heteroaryl ring such as pyridyl or pyrimidinyl
  • 5- membered heteroaryl ring fused to a cycloalkyl ring or a bicyclic heteroaryl group such as quinolinyl group.
  • Particular examples of such groups are groups of sub-formulae (iii), (iv) and (v):
  • R 53 is d- 6 alkyl or phenyl(d- 2 )alkyl (where the phenyl group is optionally substituted by halo, nitro, cyano, C ⁇ - 6 alkyl, d_ 6 haloalkyl, d_ 6 alkoxy or d- 6 haloalkoxy);
  • R 16 is hydrogen, d_ 6 alkyl or d_ 6 haloalkyl; and
  • R 17 is hydrogen, C ⁇ . 6 alkyl, d- 6 haloalkyl, d_6 alkoxy, cyano, d-6 alkoxycarbonyl or d- 6 alkylcarbonyl .
  • R 2 is d_ alkylene (which may be optionally substituted by halogen, d_ 3 alkyl or C ⁇ _ 3 alkoxy), -C(O)- or C 1 - 4 alkyleneoxy (which is optionally substituted by d_ 3 alkyl).
  • R 2 is CH 2 , CH(CH 3 ), CHF, CH(OCH 3 ), CH 2 O or CH(CH 3 )O and even more preferably CH 2 , CHF or CH(CH 3 ).
  • B is an optionally substituted heteroaryl group, in particular is heteroaryl bicyclic ring.
  • Particularly preferred rings comprise a phenyl ring fused to a 5-membered heteroaryl ring of sub-formula (vi)
  • D is N, N-oxide or CR 18 where R 18 is hydrogen, halogen, nitro, cyano, optionally substituted C 1 -8 alkyl, optionally substituted C 2 . 6 alkenyl, optionally substituted C 2 - 6 alkynyl, optionally substituted C 3 . 7 cycloalkyl, optionally substituted d_ 6 alkoxycarbonyl, optionally substituted d_ 6 alkylcarbonyl, optionally substituted C ⁇ -6 alkylaminocarbonyl, optionally substituted di(C ⁇ - 6 )alkylaminocarbonyl, optionally substituted phenyl or optionally substituted heteroaryl;
  • E is O, S or NR 24 where R 24 is hydrogen, cyano, optionally substituted d. 8 alkyl, optionally substituted [C 2 _6 alkenyl(C 1 . 6 )alkyl], optionally substituted [C 2 _6 alkynyl(C 1 . 6 )alkyl], optionally substituted C 3 . 7 cycloalkyl, optionally substituted [C 3 . cycloalkyl(C ⁇ . 6 )alkyl], C ⁇ .
  • R is hydrogen, halogen, cyano, optionally substituted d_ 2 o alkyl, optionally substituted C 2 . 2 o alkenyl, optionally substituted C 2 .
  • R 27 is hydrogen, optionally substituted phenyl or optionally substituted d- 6 alkyl
  • R 28 and R 29 are, independently, hydrogen, optionally substituted d. 20 alkyl, optionally substituted C 3 . 7 cycloalkyl, optionally substituted [C 2 . 20 alkenyl(C ⁇ . 6 )alkyl], optionally substituted [C 2 . 20 alkynyl(d.
  • R 31 is hydrogen, optionally substituted phenyl (d_ 2 )alkyl or optionally substituted d_ 20 alkyl; and R 41 , R 42 and R 43 are , independently, hydrogen, halogen, optionally substituted d- 6 alkyl, optionally substituted d- ⁇ alkoxy, optionally substituted Ci. 6 alkylthio, optionally substituted d- 6 alkylsulfinyl, optionally substituted d-6 alkylsulfonyl, cyano, nitro, optionally substituted C ⁇ _ 6 alkylcarbonyl, optionally substituted Ci. 6 alkoxycarbonyl or SF 5 .
  • D is N.
  • R is preferably hydrogen, halogen, nitro, cyano, d- 8 alkyl, d- ⁇ haloalkyl, _ 6 cyanoalkyl, C 3 . 7 cycloalkyl(C 1 -6)alkyl, C ⁇ _ 6 alkoxy(C 1 _6)alkyl, C ⁇ _ 6 alkoxycarbonyl(d. 6 )alkyl, d_ 6 alkylcarbonyl(C 1 - 6 )alkyl, C ⁇ . 6 alkylaminocarbonyl(C 1 _ 6 )alkyl, di(Ci. 6 )alkylaminocarbonyl(C 1 .
  • phenyl(C 1 _ 6 )alkyl phenyl(C 1 _ 6 )alkyl (wherein the phenyl group may be optionally substituted by halo, nitro, cyano, d_ alkyl, d_ 6 haloalkyl, C ⁇ _ 6 alkoxy or C ⁇ - 6 haloalkoxy), heteroaryl(d- 6 )alkyl (wherein the heteroaryl group may be optionally substituted by halo, nitro, cyano, d-6 alkyl, d_6 haloalkyl, Cj.
  • R 18 is hydrogen, halogen, d. 8 alkyl or d. 6 haloalkyl.
  • R 24 is hydrogen, d. 8 alkyl, Ci. 6 haloalkyl, C ⁇ . 6 cyanoalkyl, C 2 . 6 alkenyl, C 2 - 6 haloalkenyl, C 2 . 6 alkynyl, C 3 . 7 cycloalkyl, C 3 . 7 cycloalkyl(C ⁇ . 6 )alkyl, d. 6 alkoxy(C ⁇ . 6 )alkyl, d.6 alkoxycarbonyl, C ⁇ - 6 alkylcarbonyl, d_ 6 alkylaminocarbonyl, di(C ⁇ .
  • R 24 is hydrogen, C ⁇ . 8 alkyl or C ⁇ . 6 haloalkyl; E is preferably O or S, and more preferably O._
  • R 22 is cyano, d. 8 alkyl, C ⁇ - 8 haloalkyl, C ⁇ - 8 cyanoalkyl, C 3 . 7 cycloalkyl(C 1 . 6 )alkyl, C 5 . 6 cycloalkenyl(C 1 .6)alkyl, Ci_ 6 alkoxy(Ci. 6 )alkyl, C 3 . 6 alkenyloxy(Ci- 6 )alkyl, C 3 .
  • heteroaryl group may be optionally substituted by halo, nitro, cyano, d_6 alkyl, d_ 6 haloalkyl, C ⁇ - 6 alkoxy or d_ 6 haloalkoxy
  • heterocyclyl(C ⁇ _ 4 )alkyl where the heterocyclyl group may be optionally substituted by halo, cyano, d_ 6 alkyl, d_ 6 haloalkyl, d. 6 alkoxy or C ⁇ . 6 haloalkoxy
  • heterocyclyl(C ⁇ - )alkyl (wherein the heterocyclyl group may be optionally substituted by halo, nitro, cyano, d-6 alkyl, d_ 6 haloalkyl, C ⁇ _6 alkoxy or Ci.6 haloalkoxy), d. 6 alkoxycarbonyl(C ⁇ . 6 )alkyl, C 2 . 6 alkenyl, C 2 .
  • R 27 is phenyl (which may be optionally substituted by halo, nitro, cyano, C ⁇ _ 6 alkyl, C ⁇ _ 6 haloalkyl, d_ 6 alkoxy or C ⁇ - 6 haloalkoxy), d- 6 alkyl or d_ 6 haloalkyl
  • R 28 and R 29 are, independently, hydrogen, C ⁇ . 8 alkyl, C 3 . cycloalkyl(Ci. )alkyl,
  • R 22 is d. 8 alkyl, C ⁇ . 8 haloalkyl, C ⁇ . 8 cyanoalkyl, C 3 . 7 cycloalkyl(d_6)alkyl, C5. 6 cycloalkenyl(d-6)alkyl, d.6 alkoxy(d. 6 )alkyl, C 3 . 6 alkenyloxy(d_ 6 )alkyl, C 3 . 6 alkynyloxy(d. 6 )alkyl, aryloxy(d.6)alkyl, C1.6 carboxyalkyl, Ci. 6 alkylcarbonyl(C ⁇ . 6 )alkyl, C .6 alkenylcarbonyl(C ⁇ .
  • Ci- 6 alkyl or C ⁇ _ 6 haloalkyl, R 28 and R 29 are, independently, hydrogen, C ⁇ _ 8 alkyl, C 3 . 7 cycloalkyl(d. 4 )alkyl, C 2 . 6 haloalkyl, Ci. 6 alkoxy(C ⁇ . 6 )alkyl, C 3 . cycloalkyl, C 3 . 6 alkenyl, C 3 . 6 alkynyl or Ci.
  • R 28 and R 29 together with the N atom to which they are attached form a five, six or seven-membered heterocyclic ring which may contain one or two further hetero atoms selected from O, N or S and which may be optionally substituted by one or two Ci- 6 alkyl groups; and R 31 is phenyl(C ⁇ _ 2 )alkyl (wherein the phenyl group may be optionally substituted by halo, nitro, cyano, - 6 alkyl, d. 6 haloalkyl, d_ 6 alkoxy or d_ 6 haloalkoxy) or Ci. 6 alkyl. Most preferably, R 22 is d.
  • R 41 , R 42 and R 43 are, independently, hydrogen, halogen, - 6 alkyl, Ci. 6 haloalkyl, Ci-6 alkoxy, Ci-6 haloalkoxy, Ci-e alkylthio, d_ 6 haloalkylthio, - 6 alkylsulfinyl, Ci- 6 haloalkylsulfinyl, C ⁇ _6 alkylsulfonyl, d- 6 haloalkylsulfonyl, cyano, nitro, d. 6 alkylcarbonyl or d.6 alkoxycarbonyl.
  • R 41 , R 42 and R 43 are, independently, hydrogen, halogen or C ⁇ _ 3 alkyl, and most preferably R 41 , R 42 and R 43 are, independently, hydrogen or halogen (especially fluorine).
  • B is a phenyl group, optionally substituted by a phenoxy group.
  • a particular example of a group B is a group of sub-formula (vi)
  • R z is an optional substituent as described above in relation to aryl groups, and in particular C ⁇ _ 6 alkyl, haloCi. 6 alkyl, cyano or nitro.
  • X is preferably oxygen.
  • Certain compounds of formula (I) may exist in different isomeric or tautomeric forms. This invention covers all such isomers and tautomers and mixtures thereof in all proportions, including racemic mixtures, as well as isotopic forms such as deuterated compounds.
  • R la , R lb ,R 3 , and X are as defined in relation to formula (I); n is O or 1;
  • Y is O, S or ⁇ R , where R is hydrogen, cyano, d- 8 alkyl, d- 6 haloalkyl, Ci-6 cyanoalkyl, C 2 . 6 alkenyl, C 2 _6 alkynyl, C 3 . 7 cycloalkyl, C 2 . 6 haloalkenyl, C 3 -g cycloalkyl(Ci.6)alkyl, Ci_ 6 alkoxy(d.
  • R 4 is hydrogen, halogen, d_6 alkyl, d-6 haloalkyl, Ci- 6 alkoxy, Ci-6 haloalkoxy, d_ 6 alkylthio, Ci.6 haloalkylthio, C 3 .6 cycloalkyl, d- 6 alkoxy(d-6)alkyl or SF 5 ;
  • R 5 is hydrogen, halogen, C ⁇ .
  • R 4 and R 5 together with the carbon atoms to which they are attached form a five or six membered saturated or unsaturated heterocyclic or carbocyclic ring, optionally substituted by one or two Ci-6 alkyl groups;
  • R 6 is hydrogen, halogen, cyano, d. 8 alkyl, d. 6 haloalkyl, d. 6 cyanoalkyl, C 2 - 6 alkenyl, C 2 . 6 alkynyl, C3-7 cycloalkyl, C 3 . 7 halocycloalkyl, C 3 - 7 cyanocycloalkyl, d_ 3 alkyl(C 3 . 7 )cycloalkyl, .3 alkyl(C 3 . 7 )halocycloalkyl, C 3 .
  • Suitable optional substituents for optionally substituted phenyl or optionally substituted heteroaryl groups mentioned above includes substituents listed above in relation to group A.
  • Compounds of formula (IN) are described and claimed in WO 00/06566. Particularly preferred examples of compounds of formula (IN) are also set out in that patent application.
  • bridging group in the compounds of formula (IV) is attached at the 5-position of the bicyclic ring assuming that Y is at position 1.
  • suitable compounds of formula (IN) are compounds of formula (IV A)
  • R 4 is C ⁇ _ 2 alkyl, especially, methyl.
  • R 5 is hydrogen, cyano or halogen, especially, halogen (especially bromo or chloro).
  • R 6 is d_ 6 alkoxy(d.6)alkyl, d- 6 haloalkyl, morpholino, d. 6 alkyl or d. 6 alkoxy, especially morpholino, d- ⁇ alkyl or d- 6 alkoxy. It is preferred that n is 0.
  • X is oxygen
  • Y is oxygen or sulphur.
  • the process of the invention produces a compound of formula (IV) wherein R 1 and R 3 are as defined in relation to formula (I), R 4 is d ⁇ alkyl (especially methyl or ethyl); R 5 is hydrogen, halogen (especially chloro or bromo) or cyano; or R 4 and R 5 together with the carbon atoms to which they are attached form a cyclopentyl, cyclohexyl or phenyl ring; n is 0; X and Y are both oxygen; and R 6 is Ci_ 6 alkyl [optionally substituted with halogen, C ⁇ _ alkoxy, phenyl (itself optionally substituted with halogen), CONH 2 (itself optionally substituted with d. 4 alkyl), cyano, C 3 . 6 cycloalkyl or
  • R 2 is a group R 2 as defined in relation to formula (I) provided that it is not CH or CH 2 O.
  • Compounds of formula (N) are disclosed in particular in copending British Patent Application No. 00/02037.0.
  • Particular examples of compounds of formula (V) are compounds of formula (VA)
  • Preferred groups E, D, X, R 20 , R 21 , R 1 , R 3 , R 22 , R 41 , R 42 and R 43 are as set out above.
  • Particular examples of compounds of formula (I) are listed in Table 1.
  • the reaction is effected in the presence of a known coupling agent such as 1,3-dicyclohexylcarbodiimide, 1,3-d ⁇ .yopropylcarbodiimide or l-(3-dimethylaminopropyl)-3-ethylcarbodiimide.
  • a compound of formula (XI) may first be converted to an acid chloride, anhydride or chloroformate suitable for reaction with an amine to form an amide; such procedures are well known and are described, for example, in J. March, Advanced Organic Chemistry, Third Edition, John Wiley and Sons, New York, 1985, pages 370-376 and references therein.
  • Compounds of formula (X) are either known compounds or may be prepared from commercially available starting materials by methods described in the literature (see, for example, C. Oliver Kappe, Robert Flammang, and Curt Wentrup, Heterocycles, Vol. 37, No. 3, 1615, (1994); A. Adams andR. Slack, J. Chem. Soc, 3061, (1959); and Ronald E Haclder, Kenneth W. Burow, Jr., Sylvester V. Kaster and David I. Wickiser, J. Heterocyclic Chem, 26, 1575, (1989)).
  • B is a bicyclic ring
  • they may be prepared by acylation followed by cyclisation of a compound of formula (XII)
  • R 1 , R 2 , R 3 , X, Y and n are as described in claim 1, using methods analogous to those described in WO 00/06566.
  • Compounds of formula (III) are known compounds or may be prepared from known compounds by conventional methods.
  • the mixture was maintained at a temperature of 74° to76°C for 135 minutes, after which hexane (20ml) was added.
  • Example 1 The reaction of Example 1 was repeated using different reaction conditions. On this occasion, chloromethyl ethyl ether (CMEE) (12ml) was charged first into a reaction vessel at a temperature of 14°C. Triethylamine (3.0ml, 0.0054mol) was added and a very rapid exothermic reaction took place, increasing the temperature to 61 °C. The mixture was allowed to cool to 41°C, and starting material (A) in the form of a solid (4.0g, 0.0027mol) was added
  • CMEE chloromethyl ethyl ether
  • Triethylamine (0.75ml) was added in one portion to a cooled flask (water bath) of chloromethyl ethyl ether, under nitrogen. A white precipitate formed immediately, and then starting material of structure B (lg) was added.
  • the mixture was heated to 105-110°C for lhour, and then poured into a saturated aqueous sodium bicarbonate solution. This was then extracted three times using ethyl acetate, once with water and once with brine, before being dried over magnesium sulphate and concentrated. The concentrated was chromatographed on a silica column, which was eluted with a 4:1 hexane:ethylacetate mixture. The desired product was obtained from the eluent.

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Abstract

A process for preparing a compound of general formula (I) where A is aryl, X is O or S, R² is a bond or a specified linker, and R³ is a specified substituent attached through a C atom, said process comprising reacting a compounds of formula (II) where a compound of formula (III) which is a liquid or a low melting point solid at room temperature and where Z is a leaving group, in the presence of a base but in the absence of a further solvent. The compounds (I) are useful as pesticides.

Description

PROCESS FOR N- (OXYALKY ATION) OF CARBOXAMIDES
The present invention relates to a process for the production of biologically active ether derivatives of amides, in particular of fungicidal, insecticidal, acaricidal, molluscicidal and nematicidal compounds, as well as to methods of using them to combat fungal diseases (especially fungal diseases of plants) and to methods of using them to combat and control insect, acarine, mollusc and nematode pests.
A number of pesticidal compounds are known comprising a heteroaryl ring system linked via a chain which includes an amide or sulphonamide group, to a second aromatic ring system which may be aryl or heteroaryl and in which the nitrogen atom of the amide or sulphonamide bears an alkoxymethyl substituent. Examples of such compounds are given for example in WO 00/06566, copending British Patent Application Nos 00/02029.7, 00/02032.1, 00/02035.4, 00/02037.0, 00/02041.2, 00/02031.3 and 00/02036.2 as well as WO96/31448 and in the J. Agric. Food Chem 1997, 45,1920-1930. The preparation of such compounds has in the past been effected using a method in which solutions of the secondary amides in organic solvents such as tetrahydrofuran, have been reacted with a suitable ether reagent in the presence of N,O-bis(trimethyl- silyl)acetamide (see Example 10 of WO 00/06566).
The applicants have found that by modifying the conditions used, improved yields of products are obtained more efficiently and simply.
According to the present invention there is provided a process for preparing a compound of general formula (I)
Figure imgf000003_0001
(I) where
A is an optionally substituted heteroaryl group,
B is an optionally substituted aryl or heteroaryl group, X is oxygen or sulphur,
Rla and Rlb are independently selected from hydrogen, C(O)OC1. alkyl or aryl; R2 is a bond, optionally substituted .6 alkylene, optionally substituted C2.6 alkenylene, optionally substituted C2.6 alkynylene, optionally substituted C2.6 cycloalkylene, optionally substituted -6 alkylenoxy, optionally substituted oxy(C1.6)alkylene, optionally substituted .e alkylenethio, optionally substituted thio(C1_6)alkylene, optionally substituted d-6 alkylenamino, optionally substituted amino^ϊ^alkylene, optionally substituted [Cι.6 alkyleneoxy(Cι_6)alkylene], optionally substituted [Ci-β alkylenethio(Cι_6)alkylene], optionally substituted [ .6 alkylenesulfinyl(C1_6)alkylene], optionally substituted [d-6 alkylenesulfonyl(Cι.6)alkylene] or optionally substituted [Cι.β alkyleneamino-
(C1.6)alkylene]; and R3 is optionally substituted Ci-βalkyl, optionally substituted C^alkyl- carbonyl, optionally substituted C2.6alkenyl, optionally substituted C2-6alkynyl, optionally substituted C^ocycloalkyl, optionally substituted aryl or optionally substituted aroyl; said process comprising reacting a compound of formula (IT)
Figure imgf000004_0001
(")
where A, B, X, and R2 are as defined in relation to formula (I), with a compound of formula (III)
Figure imgf000004_0002
R1a
(m) which is a liquid or a low melting point solid at room temperature and where Rla , Rlb and R3 are as defined in relation to formula (I) and Z is a leaving group, in the presence of a base but in the absence of a further solvent. The expression "low melting point solid" refers to a solid which will form a liquid at the temperature of the reaction. The reaction is suitably effected at moderate temperatures, for example, at from 20 to 90°C, and preferably at about 60°C. Reaction times may vary, but in general the reaction will be completed within 5 hours and in some cases, within as little as 2 hours.
Suitable bases are weak bases including trialkylamines (such as triethylamine), cyclic amines (such as l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), l,8-diazabicyclo[4.3.0]non-5-ene (DBN) and l,4-diazobicyclo[2.2.2]octane (DABCO)), pyridine, N-methylmorpholine and ρoly-4-vinylpyridine.
Suitable leaving groups Z include halo, mesylate and tosylate; and in particular are halo (such as chloro or bromo) and in particular chloro. Suitably at least one of Rla and Rlb is hydrogen and the other is hydrogen, carboethoxy or phenyl. Most preferably both Rla and Rlb are hydrogen.
Suitably R3 is .6 alkylcarbonyl, benzoyl (where the phenyl ring is optionally substituted with halogen or C^ alkyl), (C1.6)alkyl (where the alkyl group is optionally substituted by aryl or .4 alkoxycarbonyl), C2.6 alkenyl, C2.6 alkynyl or benzyl (where the phenyl ring is optionally substituted with halogen or ^ alkyl).
Preferably R3 is C\.^ alkylcarbonyl, benzoyl (where the phenyl ring is optionally substituted with halogen or C^ alkyl), -6 alkyl, C2.6 alkenyl or C2-6 alkynyl.
Most preferably, R3 is C e alkyl or .6 alkylcarbonyl. In particular R3 is a
Figure imgf000005_0001
alkyl group such as methyl, ethyl, propyl, 2- butyl, 2-methylpropyl and n-pentyl, in particular ethyl.
Thus a preferred example of a compound of formula (HI) is chloromethylethylether (CMEE).
When the reaction is complete, the product is suitably recovered from the reaction mixture by dissolution into an organic solvent, such as hexane, which may then be filtered to remove impurities. Pure product may then be extracted from the solvent by evaporation.
As used herein, the term "heteroaryl" refers to aromatic heterocyclic groups which suitably contain from 4 to 20 ring atoms, and in particular from 5 to 12 atoms, up to five, suitably up to three of which are heteroatoms such as sulphur, oxygen or nitrogen. Heteroaryl groups are suitably mono- or bicyclic rings. In particular, heteroaryl rings are aromatic rings containing up to 10 atoms including one or more heteroatoms (preferably one or two heteroatoms) selected from O, S and N. Examples of such rings which are monocyclic include pyridine, pyiimidine, furan, pyrazole, thiophene, thiazole, isothiazole, oxazole and isoxazole. Bicyclic rings include quinoline, isoquinoline, quinazoline, indole, benzothiazole, benzotriazole, benzoxazole, indole, benzisoxazole and benzimidazole. In addition, heteroaryl rings may comprise an aromatic heterocyclic group fused to a non-aromatic ring.
Other expressions used herein include the terms "heterocycle" and "heterocyclyl" and these refer to both aromatic and non-aromatic rings containing up to 10 atoms including one or more (preferably one or two) heteroatoms selected from O, S and N. Examples of non-aromatic rings include 1,3-dioxolane, tetrahydrofuran and morpholine.
Any alkyl group or moiety is suitably a straight or branched chain which, unless otherwise specified suitably has from 1-10, and preferably from 1-6, carbon atoms. Particular examples of alkyl groups are methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, wø-propyl, n-butyl, sec-butyl, ώo-butyl, tert-butyl and neo-pentyl.
Alkenyl and alkynyl moieties can be in the form of straight or branched chains, and the alkenyl moieties, where appropriate, can be of either the (E)- or ©-configuration. Examples are vinyl, allyl and propargyl. In the context of this specification acyl is optionally substituted C^ alkylcarbonyl
(for example acetyl), optionally substituted C2.6 alkenylcarbonyl, optionally substituted C2.6 alkynylcarbonyl, optionally substituted arylcarbonyl (for example benzoyl) or optionally substituted heteroarylcarbonyl.
The term "halogen" includes fluorine, chlorine, bromine and iodine. Haloalkyl groups are alkyl groups which are substituted with one or more of the same or different halogen atoms and are, for example, CF3, CH2CF3 or CH2CHF .
Phenyl(C1.4)alkyl is, for example, 1-phenyleth-l-yl, 2-phenyleth-l-yl, 2-phenylprop-2-yl or 3-phenylprop-l-yl but is preferably benzyl.
As used herein, the term "aryl" includes naphthyl, anthracyl, fluorenyl and indenyl but is preferably phenyl.
"Cycloalkyl" includes cyclopropyl, cyclopentyl and cyclohexyl.
"Cycloalkenyl" includes cyclopentenyl and cyclohexenyl. Suitable optional substituents for cycloalkenyl groups include d-3 alkyl, halogen and cyano.
"Carbocyclic" rings include aryl, cycloalkyl and cycloalkenyl groups. When heterocyclic rings are formed by joining two groups on an N atom, the resulting rings are suitably pyrrolidine, piperidine, thiomorpholine and morpholine each of which may be substituted by one or two (Cι.6) alkyl groups. Where present, and unless otherwise stated, suitable optional substitutents for alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl and non-aromatic heterocyclyl groups include halogen, nitro, cyano, NCS-, C3. cycloalkyl (which itself is optionally substituted with d.6 alkyl or halogen), Cs- cycloalkenyl (which itself is optionally substituted with d.6 alkyl or halogen), CMO alkoxy, CMO alkoxy(C1.1o)alkoxy, tri(C1.4)alkylsilyl(C1.6)alkoxy, d.6 alkoxycarbonyl(C1.1o)alkoxy, Cι_10 haloalkoxy, aryl(d.4)alkoxy (where the aryl group is itself optionally substituted), C3.7 cycloalkyloxy (where the cycloalkyl group is optionally substituted with Cι.6 alkyl or halogen), CHO alkenyloxy, CMO alkynyloxy, CMO alkylthio, C O haloalkylthio, aryl(d.4)alkylthio (where the aryl group itself is optionally substituted), C3. cycloalkylthio (where the cycloalkyl group is optionally substituted with d_6 alkyl or halogen), tri(C1. )alkylsilyl(C1_6)alkylthio, arylthio (where the aryl group itself is optionally substituted), d-6 alkylsulfonyl, d_6 haloalkylsulfonyl, d-6 alkylsulfinyl, d-6 haloalkylsulfinyl, arylsulfonyl (where the aryl group itself is optionally substituted), tri(d. )alkylsilyl, aryldi(Cι^)alkylsilyl, (d.4)alkyldiarylsilyl, triarylsilyl, CMO alkylcarbonyl, HO2C, CMO alkoxycarbonyl, aminocarbonyl, Cι.6 alkylaminocarbonyl, di(d_6 alkyl)aminocarbonyl, N-(d_3 alkyl)-N-(d_3 alkoxy)aminocarbonyl,
Figure imgf000007_0001
alkylcarbonyloxy, arylcarbonyloxy (where the aryl group itself is optionally substituted), di(d„6)alkylaminocarbonyloxy, aryl (which itself is optionally substituted), heteroaryl (which itself is optionally substituted), heterocyclyl (which itself is optionally substituted with d-6 alkyl or halogen), aryloxy (which itselfis optionally substituted), heteroaryloxy,
(which itself is optionally substituted), heterocyclyloxy (which itself is optionally substituted with d-6 alkyl or halogen), Cι.6 alkylcarbonylamino and N-(C1.6)alkyl- carbonyl-N-(C1.6)alkylamino.
Suitable further substituents for aryl or heteroaryl groups of these substitutents include halogen, d-β alkyl, d_6 haloalkyl, d-6 alkoxy(d.6)alkyl, Cι_6 alkoxy, .6 haloalkoxy, d-6 alkylthio, d_6 haloalkylthio, _6 alkylsulfinyl, Cι.6 haloalkylsulfinyl, d_6 alkylsulfonyl,
Figure imgf000007_0002
haloalkylsulfonyl, C2_6 alkenyl, C2.6 haloalkenyl, C2.β alkynyl, C3. cycloalkyl, C5-6 cycloalkenyl. nitro, cyano, Ci-β alkylcarbonyl, d_6 alkoxycarbonyl, amido and mono- and di-d-δalkylamido. Suitable optional substitutents for aryl or heteroaryl groups such as the heteroaryl group A and the aryl or heteroaryl group B include halogen, nitro, cyano, NCS-, d.6 alkyl, d-6 haloalkyl, d.6 alkoxy(d.6)alkyl, C2.6 alkenyl, C2.6 haloalkenyl, C2.6 alkynyl, C3.7 cycloalkyl (which itself is optionally substituted with d.6 alkyl or halogen), C5.7 cycloalkenyl (which itself is optionally substituted with d-6 alkyl or halogen), CMO alkoxy, CMO alkoxy(CMo)alkoxy, tri(C1. )alkylsilyl(C1.6)alkoxy, d.6 alkoxycarbonyl(CMo)alkoxy, CMO haloalkoxy, aryl(d.4)alkoxy (where the aryl group itself is optionally substituted), C3.7 cycloalkyloxy (where the cycloalkyl group is optionally substituted with d-β alkyl or halogen), CMO alkenyloxy, CMO alkynyloxy, CMO alkylthio, CMO haloalkylthio, aryl(d- )alkylthio (where the aryl group itself is optionally substituted), C3.7 cycloalkylthio (where the cycloalkyl group is optionally substituted with d_6 alkyl or halogen), tri(C1. )alkylsilyl(C1.6)alkylthio, arylthio (where the aryl group itself is optionally substituted), d.6 alkylsulfonyl, d_6 haloalkylsulfonyl, d.6 alkylsulfinyl, Cι-6 haloalkylsulfinyl, arylsulfonyl (where the aryl group itself is optionally substituted), tri(d. )alkylsilyl, aryldi(C1.4)alkylsilyl, (Cι.4)alkyldiarylsilyl, triarylsilyl, C O alkylcarbonyl, CMO alkoxycarbonyl, aminocarbonyl, d.6 alkylaminocarbonyl, di(d_6 alkylaminocarbonyl, N-(d.3 alkyl)-N-(d.3 alkoxy)aminocarbonyl, d.6 alkylcarbonyloxy, arylcarbonyloxy (where the aryl group itself is optionally substituted), di(d_6)alkylaminocarbonyloxy, aryl (which itself is optionally substituted), heteroaryl (which itself is optionally substituted), heterocyclyl (which itself is optionally substituted with .6 alkyl or halogen), aryloxy (which itself is optionally substituted), heteroaryloxy, (which itself is optionally substituted), heterocyclyloxy (which itself is optionally substituted with Cι_6 alkyl or halogen), d_6 alkylcarbonylamino and N-(d_6)- alkylcarbonyl-N-(d_6)alkylamino.
Suitable further substitutents for aryl or heteroaryl groups or moities in the substitutents on A or B include halogen, d.6 alkyl, d_6 haloalkyl, Cι.e alkoxy(C1.6)alkyl, d.6 alkoxy, d.6 haloalkoxy, d_6 alkylthio, d_6 haloalkylthio, Cι-6 alkylsulfinyl, d.6 haloalkylsulfinyl, d.6 alkylsulfonyl, d_6 haloalkylsulfonyl, C2_6 alkenyl, C2_6 haloalkenyl, C2.6 alkynyl, C3.7 cycloalkyl, C5.6 cycloalkenyl. nitro, cyano, d.6 alkylcarbonyl, d.6 alkoxycarbonyl, amido and mono- and di-d-βalkylamido.
Preferably A is an optionally substituted heteroaryl group and most preferably A is, or includes, an optionally substituted 5-membered aromatic ring such as thiazole, isothiazole, triazole, imidazole, pyrazole, pyrrole, tetrazole, or where appropriate, N-oxides thereof. Most preferably A is or includes an optionally substituted isothiazole group, in particular a 5 isothiazole, such as a group of sub-formula (i).
Figure imgf000009_0001
0) where * indicates the point of attachment to the amide group and R20 and R21 are optional substituents as described above.
In particular, R20 is hydrogen, halogen, optionally substituted Cι.6 alkyl, optionally substituted C -6 alkenyl, optionally substituted C2.6 alkynyl, optionally substituted d.6 alkoxy, optionally substituted d_6 alkylthio, optionally substituted C3.7 cycloalkyl, cyano or SF5.
Preferably, R20 is hydrogen, halogen, d.6 alkyl, Cι.6 cyanoalkyl, d-6 haloalkyl, C3. cycloalkyl(Cι.4)alkyl, Cι.6 alkoxy(C1.6)alkyl, C2.6 alkenyl, C2.6 alkynyl,Ci-6 alkoxy, d_6 haloalkoxy, d_6 alkylthio, d_6 haloalkylthio, C3.6 cycloalkyl or cyano.
More preferably, R20 is hydrogen, halogen, Cι-6 alkyl, d-6 haloalkyl, d_6 alkoxy(Cι.6)alkyl, C .6 alkenyl, Cι-6 alkoxy, Cι_6 haloalkoxy, Cι-6 alkylthio, _6 haloalkylthio, C3.e cycloalkyl or cyano.
Most preferably R20 is halogen, Ci.6 alkyl, d-6 haloalkyl, Cι-6 alkoxy or d-6 haloalkoxy.
Suitably R is hydrogen, halogen, optionally substituted d-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2.6 alkynyl, optionally substituted d_6 alkoxy, optionally substituted d.6 alkylthio, optionally substituted d_6 alkylsulfinyl, optionally substituted d-6 alkylsulfonyl, cyano, nitro, formyl, optionally substituted d.6 alkylcarbonyl, optionally substituted d-6 alkoxycarbonyl, SF5 or R52ON=C(R50) where R50 is hydrogen, optionally substituted phenyl or optionally substituted d-6 alkyl and R52 is hydrogen, optionally substituted phenyl (d_2)alkyl or optionally substituted d-20 alkyl; or R20 and R21 together with the atoms to which they are attached may be joined to form a five, six or seven-membered saturated or unsaturated, carbocylic or heterocyclic ring which may contain one or two heteroatoms selected from O, N or S and which is optionally substituted by d_6 alkyl, C1-6 haloalkyl or halogen.
Preferably, R21 is hydrogen, halogen, d_6 alkyl, Cι_6 haloalkyl, d-6 alkoxy (C1.6)alkyl, C2-6 alkenyl, d.6 alkynyl, Cι.6 alkoxy, d.6 haloalkoxy, d_6 alkylthio, d.6 haloalkylthio, d.6 alkylsulfinyl, Cι-6 haloalkylsulfinyl, d.6 alkylsulfonyl, d_6 haloalkylsulfonyl, cyano, nitro, formyl, d-6 alkylcarbonyl, d.6 alkoxycarbonyl or CH=NOR ; where R is phenyl(d_2)alkyl (wherein the phenyl group may be optionally substituted by halo, nitro, cyano, d_6 alkyl, Cι.6 haloalkyl, C]_6 alkoxy or d_6 haloalkoxy) or d-6 alkyl; or R and R together with the atoms to which they are attached may be joined to form a five, six or seven-membered saturated or unsaturated, carbocylic or heterocyclic ring which may contain one or two heteroatoms selected from O, N or S and which is optionally substituted by Cι-6 alkyl, d-6 haloalkyl or halogen.
More preferably R is hydrogen, halogen, Cι.6 alkyl, d-6 haloalkyl, d-6 alkoxy (d-6)alkyl, d_6 alkoxy, d_6 haloalkoxy or d_6 alkylthio; or R20 and R21 together with the atoms to which they are attached form a cyclopentane or benzene ring optionally substituted by Cj-6 alkyl, d-6 haloalkyl or halogen.
Most preferably, R is hydrogen, halogen, Cι_6 alkyl, Cι-6 haloalkyl, Cι_6 alkoxy(d-6)alkyl, Cι.6 alkoxy or d_6 haloalkoxy; or R21 and R20 together with the atoms to which they are attached form a cyclopentane ring optionally substituted by d_6 alkyl, d.6 haloalkyl or halogen.
An example of a system where R21 and R20 together with the atoms to which they are attached form a ring is a group of sub-formula (ii)
Figure imgf000010_0001
(ϋ)
where Ry is an optional substituent for A as defined above, and in particular is halo or d-δhaloalkyl.
Alternatively, A may be a 6-membered heteroaryl ring (such as pyridyl or pyrimidinyl), a 5- membered heteroaryl ring fused to a cycloalkyl ring or a bicyclic heteroaryl group such as quinolinyl group. Particular examples of such groups are groups of sub-formulae (iii), (iv) and (v):
Figure imgf000011_0001
(iv)
(iϋ) (v) where R20, R21 and Ry are as defined above.
Suitably, in the compound of formula (I), R2 is d_6 alkylene, d_6 alkenylene, d-6 alkylenoxy, oxy(d-6)alkylene or d-6 alkylenamino; each of which is optionally substituted by Cι-3 alkyl, d.3 haloalkyl, d.3 cyanoalkyl, halogen, d-3 alkoxy, Ci -6 alkoxycarbonyl, cyano, =O, =NR15 or =CR16R17; where R15 is d.6 alkyl or OR53 and R53 is d-6 alkyl or phenyl(d-2)alkyl (where the phenyl group is optionally substituted by halo, nitro, cyano, Cι-6 alkyl, d_6 haloalkyl, d_6 alkoxy or d-6 haloalkoxy); R16 is hydrogen, d_6 alkyl or d_6 haloalkyl; and R17 is hydrogen, Cι.6 alkyl, d-6 haloalkyl, d_6 alkoxy, cyano, d-6 alkoxycarbonyl or d-6 alkylcarbonyl .
More preferably, R2 is d_ alkylene (which may be optionally substituted by halogen, d_3 alkyl or Cι_3 alkoxy), -C(O)- or C1-4 alkyleneoxy (which is optionally substituted by d_3 alkyl).
Most preferably, R2 is CH2, CH(CH3), CHF, CH(OCH3), CH2O or CH(CH3)O and even more preferably CH2, CHF or CH(CH3).
Suitably B is an optionally substituted heteroaryl group, in particular is heteroaryl bicyclic ring. Particularly preferred rings comprise a phenyl ring fused to a 5-membered heteroaryl ring of sub-formula (vi)
Figure imgf000011_0002
(vi) where * indicates the point of attachment,
D is N, N-oxide or CR18 where R18 is hydrogen, halogen, nitro, cyano, optionally substituted C1-8 alkyl, optionally substituted C2.6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3.7 cycloalkyl, optionally substituted d_6 alkoxycarbonyl, optionally substituted d_6 alkylcarbonyl, optionally substituted Cι-6 alkylaminocarbonyl, optionally substituted di(Cι-6)alkylaminocarbonyl, optionally substituted phenyl or optionally substituted heteroaryl;
E is O, S or NR24 where R24 is hydrogen, cyano, optionally substituted d.8 alkyl, optionally substituted [C2_6 alkenyl(C1.6)alkyl], optionally substituted [C2_6 alkynyl(C1.6)alkyl], optionally substituted C3.7 cycloalkyl, optionally substituted [C3. cycloalkyl(Cι.6)alkyl], Cι.6 alkoxy(d-6)alkyl, optionally substituted d-6 alkoxycarbonyl, optionally substituted d_6 alkylcarbonyl, optionally substituted d_6 alkylaminocarbonyl, optionally substituted di(Cι-6)alkylaminocarbonyl, optionally substituted phenyl, optionally substituted heteroaryl, optionally substituted alkylsulfonyl or optionally substituted arylsulfonyl; R is hydrogen, halogen, cyano, optionally substituted d_2o alkyl, optionally substituted C2.2o alkenyl, optionally substituted C2.2o alkynyl, optionally substituted C3. cycloalkyl, optionally substituted C5.6 cycloalkenyl, formyl, optionally substituted d.2o alkoxycarbonyl, optionally substituted d.2o alkylcarbonyl, aminocarbonyl, optionally substituted d_2o alkylaminocarbonyl, optionally substituted di(C1.2o)alkylaminocarbonyl, optionally substituted aryloxycarbonyl, optionally substituted arylcarbonyl, optionally substituted arylaminocarbonyl, optionally substituted N-(C1.6)alkyl-N-arylaminocarbonyl, optionally substituted diarylaminocarbonyl, optionally substituted heteroaryloxycarbonyl, optionally substituted heteroarylcarbonyl, optionally substituted heteroarylaminocarbonyl, optionally substituted N-(Cι-6)alkyl-N-heteroarylaminocarbonyl, optionally substituted diheteroarylaminocarbonyl, optionally substituted phenyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, HS, optionally substituted C1.2o alkylthio, optionally substituted Cι_2o alkylsulfinyl, optionally substituted d_2o alkylsulfonyl, optionally substituted arylthio, optionally substituted arylsulfinyl, optionally substituted arylsulfonyl, R26O, R28R29N or R31ON=C(R27), where R26 is optionally substituted Cι.20 alkyl, optionally substituted [C2-2o alkenyl(C1.6)alkyl], optionally substituted [C2.2o alkynyl(d.6) alkyl], optionally substituted C3.7 cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted [heterocyclyl(C1.6)alkylCH=N] or di(d.6) alkylC=N, R27 is hydrogen, optionally substituted phenyl or optionally substituted d-6 alkyl, R28 and R29 are, independently, hydrogen, optionally substituted d.20 alkyl, optionally substituted C3.7 cycloalkyl, optionally substituted [C2.20 alkenyl(Cι.6)alkyl], optionally substituted [C2.20 alkynyl(d.6)alkyl], optionally substituted d.20 alkoxycarbonyl, optionally substituted phenoxycarbonyl, formyl, optionally substituted Cι_2o alkylcarbonyl, optionally substituted d.2o alkylsulfonyl or optionally substituted phenylsulfonyl, or R28 and R29 together with the N atom to which they are attached form a five, six or seven-membered heterocyclic ring which may contain one or two further hetero atoms selected from O, N or S and which may be optionally substituted by one or two d-6 alkyl groups;
R31 is hydrogen, optionally substituted phenyl (d_2)alkyl or optionally substituted d_20 alkyl; and R41, R42 and R43 are , independently, hydrogen, halogen, optionally substituted d-6 alkyl, optionally substituted d-β alkoxy, optionally substituted Ci.6 alkylthio, optionally substituted d-6 alkylsulfinyl, optionally substituted d-6 alkylsulfonyl, cyano, nitro, optionally substituted Cι_6 alkylcarbonyl, optionally substituted Ci.6 alkoxycarbonyl or SF5. Preferably, D is N.
IS IS
However, when D is CR , R is preferably hydrogen, halogen, nitro, cyano, d-8 alkyl, d-β haloalkyl, _6 cyanoalkyl, C3.7 cycloalkyl(C1-6)alkyl, Cι_6 alkoxy(C1_6)alkyl, Cι_6 alkoxycarbonyl(d.6)alkyl, d_6 alkylcarbonyl(C1-6)alkyl, Cι.6 alkylaminocarbonyl(C1_6)alkyl, di(Ci.6)alkylaminocarbonyl(C1.6)alkyl, phenyl(C1_6)alkyl (wherein the phenyl group may be optionally substituted by halo, nitro, cyano, d_ alkyl, d_6 haloalkyl, Cι_6 alkoxy or Cι-6 haloalkoxy), heteroaryl(d-6)alkyl (wherein the heteroaryl group may be optionally substituted by halo, nitro, cyano, d-6 alkyl, d_6 haloalkyl, Cj.6 alkoxy or d-6 haloalkoxy), C2.6 alkenyl, C2_6 haloalkenyl, C2.6 alkynyl, C3. cycloalkyl, d_6 alkoxycarbonyl, d_6 alkylcarbonyl, d.6 alkylaminocarbonyl, di(Ci-6)alkylaminocarbonyl, phenyl (which may be optionally substituted by halo, nitro, cyano, Cι_6 alkyl, d-e haloalkyl, d_6 alkoxy or d-6 haloalkoxy) or heteroaryl (which may be optionally substituted by halo, nitro, cyano, d_6 alkyl, d_6 haloalkyl, _6 alkoxy or d_6 haloalkoxy). More preferably, R18 is hydrogen, halogen, d.8 alkyl or d.6 haloalkyl.
When E is NR24, R24 is hydrogen, d.8 alkyl, Ci.6 haloalkyl, Cι.6 cyanoalkyl, C2.6 alkenyl, C2-6 haloalkenyl, C2.6 alkynyl, C3.7 cycloalkyl, C3.7 cycloalkyl(Cι.6)alkyl, d.6 alkoxy(Cι.6)alkyl, d.6 alkoxycarbonyl, Cι-6 alkylcarbonyl, d_6 alkylaminocarbonyl, di(Cι.6)alkylaminocarbonyl, phenyl (which may be optionally substituted by halo, nitro, cyano, Ci.6 alkyl, d.6 haloalkyl, Ci.6 alkoxy or d.6 haloalkoxy) or heteroaryl (which may be optionally substituted by halo, nitro, cyano, Ci.6 alkyl, Ci.6 haloalkyl, d_6 alkoxy or Ci-e haloalkoxy).
More preferably, R24 is hydrogen, Cι.8 alkyl or Cι.6 haloalkyl; E is preferably O or S, and more preferably O._ Suitably R22 is cyano, d.8 alkyl, Cι-8 haloalkyl, Cι-8 cyanoalkyl, C3.7 cycloalkyl(C1.6)alkyl, C5.6 cycloalkenyl(C1.6)alkyl, Ci_6 alkoxy(Ci.6)alkyl, C3.6 alkenyloxy(Ci-6)alkyl, C3.6 alkynyloxy(Cι-6)alkyl, aryloxy(Ci.6)alkyl, d-6 carboxyalkyl, Cι.6 alkylcarbonyl(Ci-6)alkyl, C2.6 alkenylcarbonyl(Cι.6)alkyl, C2.6 alkynylcarbonyl(d.6)alkyl, Ci. alkoxycarbonyl(Cι-6)alkyl, C3_6 alkenyloxycarbonyl(Cι-6)alkyl, C3.6 alkynyloxycarbonyl(Ci.6)alkyl, aryloxycarbonyl(Cι.6)alkyl, Cι.6 alkylthio(Ci.6)alkyl, Ci.6 alkylsulfinyl(C1.6)alkyl, d.6 alkylsulfonyl(d.6)alkyl, aminocarbonyl(d-6)alkyl, Ci.6 alkylarninocarbonyl(Ci.6)alkyl, di(C1-6)alkylaminocarbonyl(Cι.6)alkyl, phenyl(Cι^)alkyl (wherein the phenyl group may be optionally substituted by halo, nitro, cyano, Cι_6 alkyl, Cι-6 haloalkyl, -6 alkoxy or d-6 haloalkoxy), heteroaryl(d.4)alkyl (where the heteroaryl group may be optionally substituted by halo, nitro, cyano, d_6 alkyl, d_6 haloalkyl, Cι-6 alkoxy or d_6 haloalkoxy), heterocyclyl(Cι_4)alkyl (where the heterocyclyl group may be optionally substituted by halo, cyano, d_6 alkyl, d_6 haloalkyl, d.6 alkoxy or Cι.6 haloalkoxy), C2.6 alkenyl, C2.6 haloalkenyl, d.6 cyanoalkenyl, C5.6 cycloalkenyl, aminocarbonyl(C2.6)alkenyl, Ci.6 alkylaminocarbonyl(Cι_6)alkenyl, di(C1.6)alkylaminocarbonyl(Cι-6)alkenyl, phenyl(C2. )alkenyl, (wherein the phenyl group may be optionally substituted by halo, nitro, cyano, d.6 alkyl, d-6 haloalkyl, Ci.6 alkoxy or Cι-6 haloalkoxy), C2-6 alkynyl, aminocarbonyl (C2.6)alkynyl, alkylaminocarbonyl(C1.6)alkynyl, di(Ci.6)alkylaminocarbonyl(Cι.6)alkynyl, C3.7 cycloalkyl, C3. halocycloalkyl, C3.7 cyanocycloalkyl, d_3 alkyl(C .7)cycloalkyl, C1.3 alkyl(C3. )halocycloalkyl, C5.6 cycloalkenyl, formyl, d_6 alkoxycarbonyl, d-6 alkylcarbonyl, aminocarbonyl, d_6 alkylaminocarbonyl, di(C1.6)alkylaminocarbonyl, phenyl (which may be optionally substituted by halo, nitro, cyano, d_6 alkyl, d-6 haloalkyl, C1-6 alkoxy or C1.6 haloalkoxy), heteroaryl (which may be optionally substituted by halo, nitro, cyano, d_6 alkyl, d-6 haloalkyl, d.6 alkoxy or Ci.6 haloalkoxy), heterocyclyl (which may be optionally substituted by halo, nitro, cyano, d.6 alkyl, d_6 haloalkyl, Ci.6 alkoxy or Ci.6 haloalkoxy), Ci-g alkylthio, R26O, R28R29N or R31ON=C(R27), where R26 is d.8 alkyl, Cw haloalkyl, Cw cyanoalkyl, Cι_6 alkoxy(d.6)alkyl, phenyl(Ci.4)alkyl , (wherein the phenyl group may be optionally substituted by halo, nitro, cyano, Cι_6 alkyl, d-6 haloalkyl, d-6 alkoxy or d-6 haloalkoxy), heteroaryl(d.4)alkyl (wherein the heteroaryl group may be optionally substituted by halo, nitro, cyano, d-6 alkyl, Cι-6 haloalkyl, d.6 alkoxy or Cι-6 haloalkoxy), heterocyclyl(Cι- )alkyl (wherein the heterocyclyl group may be optionally substituted by halo, nitro, cyano, d-6 alkyl, d_6 haloalkyl, Cι_6 alkoxy or Ci.6 haloalkoxy), d.6 alkoxycarbonyl(Cι.6)alkyl, C2.6 alkenyl, C2.6 alkynyl or N=C(CH3)2, and where R27 is phenyl (which may be optionally substituted by halo, nitro, cyano, Cι_6 alkyl, Cι_6 haloalkyl, d_6 alkoxy or Cι-6 haloalkoxy), d-6 alkyl or d_6 haloalkyl, R28 and R29 are, independently, hydrogen, Cι.8 alkyl, C3. cycloalkyl(Ci. )alkyl,
C2-6 haloalkyl, d_6 alkoxy(Ci-6)alkyl, C3. cycloalkyl, C3_6 alkenyl, C3.6 alkynyl or Ci_6 alkoxycarbonyl, or R and R together with the N atom to which they are attached form a five, six or seven-membered heterocyclic ring which may contain one or two further hetero atoms selected from O, N or S and which may be optionally substituted by one or two d-e alkyl groups, and R31 is phenyl(d.2)alkyl (wherein the phenyl group may be optionally substituted by halo, nitro, cyano, d-β alkyl, Cι_6 haloalkyl, d.6 alkoxy or d.6 haloalkoxy) or Ci.6 alkyl.
More preferably, R22 is d.8 alkyl, Cι.8 haloalkyl, Cι.8 cyanoalkyl, C3.7 cycloalkyl(d_6)alkyl, C5.6 cycloalkenyl(d-6)alkyl, d.6 alkoxy(d.6)alkyl, C3.6 alkenyloxy(d_6)alkyl, C3.6 alkynyloxy(d.6)alkyl, aryloxy(d.6)alkyl, C1.6 carboxyalkyl, Ci.6 alkylcarbonyl(Cι.6)alkyl, C .6 alkenylcarbonyl(Cι.6)alkyl, C2_6 alkynylcarbonyl(Ci-6)alkyl, Ci.6 alkoxycarbonyl(C1.6)alkyl, C3.6 alkenyloxycarbonyl(Cι-6)alkyl, C3.6 alkynyloxycarbonyl(Ci-6)alkyl, aryloxycarbonyl(Cι_6)alkyl, Ci-6 alkylthio(Ci.6)alkyl, Ci-6 alkylsulfinyl(Cι_6)alkyl, d_6 alkylsulfonyl(Ci.6)alkyl, aminocarbonyl(Cι.6)alkyl, -6 alkylaminocarbonyl(Ci.6)alkyl, di(Cι-6)alkylaminocarbonyl(Ci.6)alkyl, phenyl(Cι^)alkyl (wherein the phenyl group may be optionally substituted by halo, nitro, cyano, Ci.6 alkyl, Cj.6 haloalkyl, d.6 alkoxy or Cι_6 haloalkoxy), heteroaryl(Cι.4)alkyl (wherein the heteroaryl group may be optionally substituted by halo, nitro, cyano, d.6 alkyl, Ci.6 haloalkyl, d.6 alkoxy or Ci.6 haloalkoxy),
Figure imgf000015_0001
(wherein the heterocyclyl group may be optionally substituted by halo, nitro, cyano, Ci-6 alkyl, d-6 haloalkyl, Cι_6 alkoxy or d-6 haloalkoxy), C2.β alkenyl, C2-e haloalkenyl, d_6 cyanoalkenyl, C5-6 cycloalkenyl, aminocarbonyl(C2.6)alkenyl, Ci-6 alkylaminocarbonyl(Ci-6)alkenyl, di(C1.6)alkylaminocarbonyl(C1-6)alkenyl, phenyl(C2.4)alkenyl, (wherein the phenyl group may be optionally substituted by halo, nitro, cyano, Ci-6 alkyl, Ci.6 haloalkyl, C1.6 alkoxy or d.6 haloalkoxy), C2.6 alkynyl, aminocarbonyl(C2-6)aIkynyl, alkylaminocarbonyl(Ci.6)alkynyl, di(Cι.6)alkylaminocarbonyl(Cι.6)alkynyl, C3.7 cycloalkyl, C3.7 halocycloalkyl, C3.7 cyanocycloalkyl, Cι.3 alkyl(C3.7)cycloalkyl, Cι.3 alkyl(C3.7)halocycloalkyl, phenyl (which may be optionally substituted by halo, nitro, cyano, Cι-6 alkyl, d-6 haloalkyl, d.6 alkoxy or d-6 haloalkoxy), heteroaryl (which may be optionally substituted by halo, nitro, cyano, Ci-6 alkyl, d.6 haloalkyl, .6 alkoxy or Cι_6 haloalkoxy), heterocyclyl (which may be optionally substituted by halo, nitro, cyano, Cι_6 alkyl, d.6 haloalkyl, d.6 alkoxy or Ci-e haloalkoxy), d.8 alkylthio, R26O, R28R29N or R31ON=C(R27), where R26 is d.8 alkyl or d-e haloalkyl, R27 is phenyl (which may be optionally substituted by halo, nitro, cyano, Ci-β alkyl, Cι.6 haloalkyl, .6 alkoxy or d-6 haloalkoxy), Ci-6 alkyl or Cι_6 haloalkyl, R28 and R29 are, independently, hydrogen, Cι_8 alkyl, C3.7 cycloalkyl(d.4)alkyl, C2.6 haloalkyl, Ci.6 alkoxy(Cι.6)alkyl, C3. cycloalkyl, C3.6 alkenyl, C3.6 alkynyl or Ci.6 alkoxycarbonyl, or R28 and R29 together with the N atom to which they are attached form a five, six or seven-membered heterocyclic ring which may contain one or two further hetero atoms selected from O, N or S and which may be optionally substituted by one or two Ci-6 alkyl groups; and R31 is phenyl(Cι_2)alkyl (wherein the phenyl group may be optionally substituted by halo, nitro, cyano, -6 alkyl, d.6 haloalkyl, d_6 alkoxy or d_6 haloalkoxy) or Ci.6 alkyl. Most preferably, R22 is d.8 alkyl, d_8 haloalkyl, d_8 cyanoalkyl, Ci-6 alkoxy (Ci.6) alkyl, C3.7 cycloalkyl, d.3 alkyl (C3.7) cycloalkyl or heterocyclyl (which may be optionally substituted by halo, nitro, cyano, d.6 alkyl, d-6 haloalkyl, d-6 alkoxy or d.6 haloalkoxy.
Suitably, R41, R42 and R43 are, independently, hydrogen, halogen, -6 alkyl, Ci.6 haloalkyl, Ci-6 alkoxy, Ci-6 haloalkoxy, Ci-e alkylthio, d_6 haloalkylthio, -6 alkylsulfinyl, Ci-6 haloalkylsulfinyl, Cι_6 alkylsulfonyl, d-6 haloalkylsulfonyl, cyano, nitro, d.6 alkylcarbonyl or d.6 alkoxycarbonyl.
Preferably, R41, R42 and R43 are, independently, hydrogen, halogen or Cι_3 alkyl, and most preferably R41, R42 and R43 are, independently, hydrogen or halogen (especially fluorine). Alternatively B is a phenyl group, optionally substituted by a phenoxy group. A particular example of a group B is a group of sub-formula (vi)
Figure imgf000016_0001
(vi) where and * represents the point of attachment to the R2 group of formula (I) and Rz is an optional substituent as described above in relation to aryl groups, and in particular Cι_6alkyl, haloCi.6alkyl, cyano or nitro. X is preferably oxygen.
Certain compounds of formula (I) may exist in different isomeric or tautomeric forms. This invention covers all such isomers and tautomers and mixtures thereof in all proportions, including racemic mixtures, as well as isotopic forms such as deuterated compounds.
Particularly preferred examples of compounds of formula (I) are compounds of formula (IV)
Figure imgf000017_0001
(IN) wherein Rla, Rlb,R3, and X are as defined in relation to formula (I); n is O or 1;
7 7
Y is O, S or ΝR , where R is hydrogen, cyano, d-8 alkyl, d-6 haloalkyl, Ci-6 cyanoalkyl, C2.6 alkenyl, C2_6 alkynyl, C3.7 cycloalkyl, C2.6 haloalkenyl, C3-g cycloalkyl(Ci.6)alkyl, Ci_6 alkoxy(d.6)alkyl, Ci-6 alkoxycarbonyl, Ci-6 alkylcarbonyl, Ci-6 alkylaminocarbonyl, di(Ci_6)alkylaminocarbonyl, optionally substituted phenyl or optionally substituted heteroaryl;
R4 is hydrogen, halogen, d_6 alkyl, d-6 haloalkyl, Ci-6 alkoxy, Ci-6 haloalkoxy, d_6 alkylthio, Ci.6 haloalkylthio, C3.6 cycloalkyl, d-6 alkoxy(d-6)alkyl or SF5; R5 is hydrogen, halogen, Cι.6 alkyl, Ci-6 alkoxy, Ci-6 haloalkoxy, d-6 alkylthio, Cι_6 haloalkylthio, Ci-6 alkylsulfinyl, d-6 haloalkylsulfinyl, d-6 alkylsulfonyl, d-6 haloalkylsulfonyl, Ci-6 haloalkyl, cyano, nitro, CHO, CH=ΝOR12, Ci-6 alkylcarbonyl, Ci-6 alkoxycarbonyl or SF5, where R12 is Ci-β alkyl, optionally substituted phenyl or optionally substituted phenyl(d.4)alkyl; or R4 and R5 together with the carbon atoms to which they are attached form a five or six membered saturated or unsaturated heterocyclic or carbocyclic ring, optionally substituted by one or two Ci-6 alkyl groups;
R6 is hydrogen, halogen, cyano, d.8 alkyl, d.6 haloalkyl, d.6 cyanoalkyl, C2-6 alkenyl, C2.6 alkynyl, C3-7 cycloalkyl, C3.7 halocycloalkyl, C3-7 cyanocycloalkyl, d_3 alkyl(C3.7)cycloalkyl, .3 alkyl(C3.7)halocycloalkyl, C3.6 cycloalkyl(Cι-6)alkyl, C5-6 cycloalkenyl, C5-6cycloalkenyl(Ci-6)alkyl, C2.6 haloalkenyl, Cι.6cyanoalkenyl, Ci-6 alkoxy(Ci_6)alkyl, formyl, d-6 carboxyalkyl, d_6 alkylcarbonyl(C1_6)alkyl, d-6 alkoxycarbonyl(Ci_6)alkyl, Ci-6 alkylthio(Ci-6)alkyl, CM alkylsulfϊnyl(d.6)alkyl, d-e alkylsulfonyl(Ci.6)alkyl, aminocarbonyl(d-6)alkyl, Ci-6 alkylaminocarbonyl(d.6)alkyl, di(Cι-6)alkylaminocarbonyl(Cι.6)alkyl, Ci-6 alkoxycarbonyl, Ci.6 alkylcarbonyl, aminocarbonyl, d_6 alkylaminocarbonyl, di(Cι-6)alkylaminocarbonyl, optionally substituted phenyl, optionally substituted phenyl(d.4)alkyl, optionally substituted phenyl(C2. )alkenyl, optionally substituted heteroaryl, optionally substituted heteroaryl(d_ )alkyl, optionally substituted non-aromatic heterocyclyl or heterocyclyl(Cι_ )alkyl, a group OR , a group S(O)pR9, a group NR10Rπ or a group C(R14)=NOR13; where R8 , R9, R10, R11, R13 and R14 are as defined above and p is 0, 1 or 2.
Suitable optional substituents for optionally substituted phenyl or optionally substituted heteroaryl groups mentioned above includes substituents listed above in relation to group A. Compounds of formula (IN) are described and claimed in WO 00/06566. Particularly preferred examples of compounds of formula (IN) are also set out in that patent application.
Suitably, the bridging group in the compounds of formula (IV) is attached at the 5-position of the bicyclic ring assuming that Y is at position 1. Thus suitable compounds of formula (IN) are compounds of formula (IV A)
Figure imgf000018_0001
(INA) where R1, R3, R4, R5, R6, X, Y and n are as defined in relation to formula (IV).
In particular, in the compounds of formula (IV) or (IV A), one or more of the following preferences apply: It is preferred that R4 is Cι_2 alkyl, especially, methyl.
It is preferred that R5 is hydrogen, cyano or halogen, especially, halogen (especially bromo or chloro).
It is preferred that R6 is d_6 alkoxy(d.6)alkyl, d-6 haloalkyl, morpholino, d.6 alkyl or d.6 alkoxy, especially morpholino, d-β alkyl or d-6 alkoxy. It is preferred that n is 0.
It is preferred that X is oxygen.
It is preferred that Y is oxygen or sulphur.
In one particular embodiment, the process of the invention produces a compound of formula (IV) wherein R1 and R3 are as defined in relation to formula (I), R4 is d^ alkyl (especially methyl or ethyl); R5 is hydrogen, halogen (especially chloro or bromo) or cyano; or R4 and R5 together with the carbon atoms to which they are attached form a cyclopentyl, cyclohexyl or phenyl ring; n is 0; X and Y are both oxygen; and R6 is Ci_6 alkyl [optionally substituted with halogen, Cι_ alkoxy, phenyl (itself optionally substituted with halogen), CONH2 (itself optionally substituted with d.4 alkyl), cyano, C3.6 cycloalkyl or
CO d^alkoxy)], C3-6 alkenyl, C3-6 alkynyl, C3_6 cycloalkyl, phenyl [optionally substituted with halogen, d^ haloalkyl (especially CF3), nitro, or cyano] or heteroaryl (especially pyridyl or pyrimidinyl) [optionally substituted with d.4 alkyl or C1.4 haloalkyl].
Yet a further preferred group of compounds which may be prepared by the method of the present invention are compounds of formula (V)
Figure imgf000019_0001
(V) wherein Rla, Rlb, X and R3 are as defined in relation to formula (I), R20 and R21 are as defined in relation to sub-formula (ii), R22, R41, R42, R43, D and E are as defined in relation to sub-formula (vi)
R2 is a group R2 as defined in relation to formula (I) provided that it is not CH or CH2O. Compounds of formula (N) are disclosed in particular in copending British Patent Application No. 00/02037.0.
Particular examples of compounds of formula (V) are compounds of formula (VA)
Figure imgf000020_0001
(VA) wherein R2', E, D, X, R20, R21, R1, R3, R22, R41, R42 and R43 are as defined above for a compound of formula (V).
Preferred groups E, D, X, R20, R21, R1, R3, R22, R41, R42 and R43 are as set out above. Particular examples of compounds of formula (I) are listed in Table 1.
Table 1
Figure imgf000020_0002
Figure imgf000020_0003
Compounds of formula (II) are known compounds or they can be prepared from known compounds by conventional methods. For example, compounds of formula (II) may be prepared by acylation of a compound of formula (X)
A-NH2
(X) where A is as defined in relation to formula (I), with a compound of formula (XI) HO-C(X)-R2-B
(XI) where X, R2 and B are as defined in relation to formula (I).
Preferably the reaction is effected in the presence of a known coupling agent such as 1,3-dicyclohexylcarbodiimide, 1,3-dπ.yopropylcarbodiimide or l-(3-dimethylaminopropyl)-3-ethylcarbodiimide. Alternatively a compound of formula (XI) may first be converted to an acid chloride, anhydride or chloroformate suitable for reaction with an amine to form an amide; such procedures are well known and are described, for example, in J. March, Advanced Organic Chemistry, Third Edition, John Wiley and Sons, New York, 1985, pages 370-376 and references therein.
Compounds of formula (X) are either known compounds or may be prepared from commercially available starting materials by methods described in the literature (see, for example, C. Oliver Kappe, Robert Flammang, and Curt Wentrup, Heterocycles, Vol. 37, No. 3, 1615, (1994); A. Adams andR. Slack, J. Chem. Soc, 3061, (1959); and Ronald E Haclder, Kenneth W. Burow, Jr., Sylvester V. Kaster and David I. Wickiser, J. Heterocyclic Chem, 26, 1575, (1989)).
Alternatively, where B is a bicyclic ring, they may be prepared by acylation followed by cyclisation of a compound of formula (XII)
Figure imgf000021_0001
wherein R1, R2, R3, X, Y and n are as described in claim 1, using methods analogous to those described in WO 00/06566.
Compounds of formula (III) are known compounds or may be prepared from known compounds by conventional methods.
The invention will now be particular described by way of example. Example 1
Preparation of Compound No 1 in Table 1
Figure imgf000022_0001
Starting material (A) (l.Og, 0.0027 mol), prepared as described in WO 00/06566, was charged to a 5ml round bottomed flask. Chloromethylethyl ether (CMEE) (3ml) was added followed by triethylamine (0.75ml, 0.0054mol) with stirring to form a dark brown slurry.
The mixture was maintained at a temperature of 74° to76°C for 135 minutes, after which hexane (20ml) was added.
A heavy brown precipitate formed and this was filtered off and washed well with hexane. The hexane filtrates were combined, and evaporated under reduced pressure at 40°C to produce the desired product (B) (0.84g, 69.4% yield). The structure of the product was confirmed by n.m.r.
1H NMR (CDC13) δ:7.4(m)(2H), 7.05(m)(broad 1H), 5.1(s)(broad)(2H), 3.6(q)(2H), 2.80(s)(2H), 2.50(s)(3H), 1.2(t) (3H), l.l(s)(9H). Example 2
Preparation of Compound No 1 in Table 1
The reaction of Example 1 was repeated using different reaction conditions. On this occasion, chloromethyl ethyl ether (CMEE) (12ml) was charged first into a reaction vessel at a temperature of 14°C. Triethylamine (3.0ml, 0.0054mol) was added and a very rapid exothermic reaction took place, increasing the temperature to 61 °C. The mixture was allowed to cool to 41°C, and starting material (A) in the form of a solid (4.0g, 0.0027mol) was added
The reaction mixture was heated to 92 °C over an oil bath . After 2 hours, hexane (25ml) was added and the heavy brown precipitate formed was filtered off and washed well with hexane. Hexane filtrates combined were combined and evaporated under reduced pressure to give the desired product (as confirmed by n.m.r (2.62g, 55% yield). Example 3
Preparation of Compound No 3 in Table 1
Starting material A (see Example l)(0.566g) was stirred in chloromethyl isobutyl ether
(1.5ml) at room temperature and triethylamine (0.304g) added dropwise. The mixture was warmed to 70°C for 1 hour, cooled to room temperature and partitioned between sodium bicarbonate solution (15ml) and dichloromethane (20ml). The organic layer was separated, further washed with sodium bicarbonate solution (25ml), dried (MgSO4), filtered and the filtrate evaporated to give a light brown liquid. This dissolved in a minimum amount of dichloromethane and applied to a silica column. The column was then washed with hexane
(20ml), and eluted with a mixture of ethylacetate and hexane (3:7), collecting approximately
20ml fractions. Combined fractions were evaporated at 40°C to give a pale yellow liquid
(0.713g)
MS : Mrf" 464,466
1H NMR (CDC13) δ:7.41(s)broad(lH), 7.39(d)(lH), 7.05(d)(broad 1H), 5.09(s)(broad)(2H),
3.72(s)(broad) (2H), 3.29(d)(2H), 2.80(s)(2H), 2.50(s)(3H), 1.83(sept)(lH), 1.08(s) (3H),
0.88(d)(6H).
Example 4
Preparation of Compound No 2 in Table 1
Triethylamine (0.75ml) was added in one portion to a cooled flask (water bath) of chloromethyl ethyl ether, under nitrogen. A white precipitate formed immediately, and then starting material of structure B (lg) was added.
Figure imgf000023_0001
B
The mixture was heated to 105-110°C for lhour, and then poured into a saturated aqueous sodium bicarbonate solution. This was then extracted three times using ethyl acetate, once with water and once with brine, before being dried over magnesium sulphate and concentrated. The concentrated was chromatographed on a silica column, which was eluted with a 4:1 hexane:ethylacetate mixture. The desired product was obtained from the eluent. 1H NMR (CDCI3) δ:7.38(m)(2H), 7.04(broad 1H), 5.10(broad)(2H),3.71(broad) (2H), 3.62(q)(2H), 2.52(s)(3H), 2.29(m)(lH), 1.21(t)(3H), 1.04(s), 1.02(s)(3H). Example 5
Preparation of Compound No. 4 in Table 1 The procedure of Example 3 was repeated using starting material A (see example l)(0.566g) and neopentylchloromethyl ether (1.5ml) to yield the target compound. 1H NMR (CDCI3) 6: 7.39(d)(lH), 7.41(s)(broad)(lH), 7.05(d)(v. broad 1H), 5.10(s)(v broad),3.72(s)(v. broad) (2H), 3.18(s)(2H), 2.80(s)(2H), 2.51(s)(3H), 1.08(s)(9H), 0.88(s)(9H). Example 6
Preparation of Compound No. 5 in Table 1
Starting material (A) (see Example l)(0.566g) was stirred in chloromethyl sec-butyl ether (1.5ml) and triethylamine (0.304g) added. The mixture was heated to 70-80°C for 75 minutes, cooled to room temperature, diluted with dichloromethane (25ml) and washed with sodium bicarbonate solution (3x20ml). The organic layer was dried over magnesium sulphate, filtered and the filtrate evaporated to give a deep red-brown oil. This was dissolved in a minimum amount of dichloromethane and applied to a silica column. The column was then washed with a further minimum amount of dichloromethane, hexane (20ml), and eluted with a mixture of ethylacetate and hexane (1:4), collecting approximately 20ml fractions. Combined fractions were evaporated at 40°C to give the desired product as a pale yellow liquid (0.713g)
1H NMR (CDCI3) δ: 7.40(s)broad(lH), 7.39(d)(lH), 7.04(d)(v. broad 1H), 5.10(broad)(2H),3.71(s)(broad) (2H), 3.59(m)(lH), 2.80(s)(2H), 2.50(s)(3H), 1.36- 1.63(m)(2H), 1.15(d)(3H), 1.08(s)(9H), 0.86(t)(3H). Example 7
Preparation of Compound No. 6 in Table 1
Starting material (A) (see Example l)(0.566g) was stirred in chloromethyl isopropyl ether (1.5ml) and triethylamine (0.304g) added. The mixture was heated to 75°C for 90 minutes, and then at to 95-100°C for a further 60 minutes. The mixture was then cooled to room temperature, diluted with dichloromethane (30ml) and washed with sodium bicarbonate solution (3x30ml). The organic layer was dried over magnesium sulphate, filtered and the filtrate evaporated to give a brown oil. This was dissolved in a minimum amount of dichloromethane and applied to a silica column. The column was then washed with hexane (20ml), and eluted with a mixture of ethylacetate and hexane (1:4), collecting approximately 20ml fractions. Combined fractions were evaporated at 40°C to give the desired product as a pale yellow oil (0.287g)
1HNMR (CDC13) δ: 7.41(s)broad(lH), 7.40(d)(lH), 7.05(d)(v. broad 1H), 5.10(s)(broad)(2H), 3.81(m)(lH), 3.70(s)(v. broad) (2H), 2.80(s)(2H), 2.51(s)(3H), 1.18(d)(6H), 1.08(s)(9H). Example 8
Preparation of Compound No.7 in Table 1 Starting material (A) (see Example l)(0.566g) was stirred in chloromethyl n-propyl ether (1.5ml) and triethylamine (0.304g) added dropwise. The mixture was heated to 70-80°C for 75 minutes, and then at to 100-1100°C for a further 90 minutes. The mixture was then cooled to room temperature, diluted with dichloromethane (30ml) and washed with sodium bicarbonate solution (3x20ml). The organic layer was dried over magnesium sulphate, filtered and the filtrate evaporated to give a brown liquid. This was dissolved in a minimum amount of dichloromethane and applied to a silica column. The column was then washed with hexane (20ml), and eluted with a mixture of ethylacetate and hexane (3:7), and then with a 1:1 mixture ethylacetate:hexane, collecting approximately 20ml fractions. Combined fractions were evaporated to give the desired product as a pale yellow oil (0.287g) 1H NMR (CDC13) δ: 7.41(s)broad(lH), 7.40(d)(lH), 7.05(d)(broad 1H), 5.10(s)(broad)(2H), 3.71(s)broad(2H), 3.50(f) (2H), 2.80(s)(2H), 2.51(s)(3H), 1.59(sext)(2H), 0.90(t)(3H).

Claims

1. A process for preparing a compound of general formula (I)
Figure imgf000026_0001
(I) where
A is an optionally substituted heteroaryl group, B is an optionally substituted aryl or heteroaryl group, X is oxygen or sulphur, Rla and Rlb are independently selected from hydrogen, C(O)OCι_4alkyl or aryl; R2 is a bond, optionally substituted d-6 alkylene, optionally substituted C2.6 alkenylene, optionally substituted C2.6 alkynylene, optionally substituted C2.6 cycloalkylene, optionally substituted d-6 alkylenoxy, optionally substituted oxy(d-6)alkylene, optionally substituted Ci-6 alkylenethio, optionally substituted thio(Cι.6)alkylene, optionally substituted Ci-6 alkylenamino, optionally substituted amino(Ci_6)alkylene, optionally substituted [Ci-6 alkyleneoxy(Cι_6)alkylene], optionally substituted [Cι_6 alkylenethio(d-6)alkylene], optionally substituted [Ci.6 alkylenesulfinyl(Ci.6)alkylene], optionally substituted [d-6 alkylenesulfonyl(d_6)alkylene] or optionally substituted [Ci-6 alkyleneamino(C i .6)alkylene] ; and R3 is optionally substituted Ci^alkyl, optionally substituted Cι.6alkylcarbonyl, optionally substituted C2.6alkenyl, optionally substituted C2.ealkynyl, optionally substituted C3_ι0cycloalkyl, optionally substituted aryl or optionally substituted aroyl; said process comprising reacting a compound of formula (II)
Figure imgf000027_0001
(ID
where A, B, X, and R2 are as defined in relation to formula (I), with a compound of formula (HI)
Figure imgf000027_0002
Cm) which is a liquid or a low melting point solid at room temperature and where Rla , Rlb and R3 are as defined in relation to formula (I) and Z is a leaving group, in the presence of a base but in the absence of a further solvent.
2. A process according to claim 1 wherein Rla and Rl are hydrogen.
A process according to claim 1 or claim 2 where Z is chlorine.
4. A process according to any one of the preceeding claims where R3 is Ci.6 alkyl.
A process according to any one of the preceding claims where A is a group of sub-formula (i)
Figure imgf000027_0003
(0 where * indicates the point of attachment to the amide group,
R20 is hydrogen, halogen, optionally substituted d.6 alkyl, optionally substituted C2.6 alkenyl, optionally substituted C2.6 alkynyl, optionally substituted d.6 alkoxy, optionally substituted d-6 alkylthio, optionally substituted C3.7 cycloalkyl, cyano or SF5; and
R21 is hydrogen, halogen, optionally substituted d.6 alkyl, optionally substituted C2.6 alkenyl, optionally substituted C2.6 alkynyl, optionally substituted d.6 alkoxy, optionally substituted Ci-6 alkylthio, optionally substituted Ci-6 alkylsulfinyl, optionally substituted d-6 alkylsulfonyl, cyano, nitro, formyl, optionally substituted Cj-6 alkylcarbonyl, optionally substituted d-6 alkoxycarbonyl, SF5 or R52ON=C(R50); where R50 is hydrogen, optionally substituted phenyl or optionally substituted d-6 alkyl and R52 is hydrogen, optionally substituted phenyl (d.2)alkyl or optionally substituted d.2o alkyl; or R20 and R21 together with the atoms to which they are attached may be joined to form a five, six or seven-membered saturated or unsaturated, carbocylic or heterocyclic ring which may contain one or two heteroatoms selected from O, N or S and which is optionally substituted by d.6 alkyl, d-6 haloalkyl or halogen.
A process according to any one of the preceding claims wherein B is a group of sub- formula (vi)
Figure imgf000028_0001
(vi) where * indicates the point of attachment,
D is N, N-oxide or CR18 where R18 is hydrogen, halogen, nitro, cyano, optionally substituted d-8 alkyl, optionally substituted C2_6 alkenyl, optionally substituted C2_6 alkynyl, optionally substituted C3-7 cycloalkyl, optionally substituted Ci-6 alkoxycarbonyl, optionally substituted Ci-6 alkylcarbonyl, optionally substituted d-6 alkylaminocarbonyl, optionally substituted di(Ci_6)alkylaminocarbonyl, optionally substituted phenyl or optionally substituted heteroaryl;
E is O, S or NR24 where R24 is hydrogen, cyano, optionally substituted d.8 alkyl, optionally substituted [C2.6 alkenyl(d-6)alkyl], optionally substituted [C2.6 alkynyl(Cι.6)alkyl], optionally substituted C3.7 cycloalkyl, optionally substituted [d.7 cycloalkyl(Cι.6)alkyl], Ci_6 alkoxy(Cι-6)alkyl, optionally substituted d_6 alkoxycarbonyl, optionally substituted d-β alkylcarbonyl, optionally substituted Ci-6 alkylaminocarbonyl, optionally substituted di(Cι.6)alkylaminocarbonyl, optionally substituted phenyl, optionally substituted heteroaryl, optionally substituted alkylsulfonyl or optionally substituted arylsulfonyl;
R22 is hydrogen, halogen, cyano, optionally substituted Cι.2o alkyl, optionally substituted C2.2o alkenyl, optionally substituted C2.2o alkynyl, optionally substituted d.7 cycloalkyl, optionally substituted C5.6 cycloalkenyl, formyl, optionally substituted Cι.2o alkoxycarbonyl, optionally substituted Cι.2o alkylcarbonyl, aminocarbonyl, optionally substituted Cj.2o alkylaminocarbonyl, optionally substituted di(Cι-2o)alkylaminocarbonyl, optionally substituted aryloxycarbonyl, optionally substituted arylcarbonyl, optionally substituted arylaminocarbonyl, optionally substituted N-(Cι-6)alkyl-N-arylaminocarbonyl, optionally substituted diarylaminocarbonyl, optionally substituted heteroaryloxycarbonyl, optionally substituted heteroarylcarbonyl, optionally substituted heteroarylaminocarbonyl, optionally substituted N-(Cι-6)alkyl-N-heteroarylaminocarbonyl, optionally substituted diheteroarylaminocarbonyl, optionally substituted phenyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, HS, optionally substituted d_2o alkylthio, optionally substituted Cι_ o alkylsulfinyl, optionally substituted d-2o alkylsulfonyl, optionally substituted arylthio, optionally substituted arylsulfinyl, optionally substituted arylsulfonyl, R26O, R28R29N or R31ON=C(R27), where R26 is optionally substituted Cι-2o alkyl, optionally substituted [C2.2o alkenyl(Ci-6)alkyl], optionally substituted [C2.2o alkynyl(Cι.6) alkyl], optionally substituted C3.7 cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted [heterocyclyl(d-6)alkylCH=N] or di(Cι_ ) alkylC=N, R27 is hydrogen, optionally substituted phenyl or optionally substituted Cι.6 alkyl, R28 and R29 are, independently, hydrogen, optionally substituted d_20 alkyl, optionally substituted C3.7 cycloalkyl, optionally substituted
[C2.2o alkenyl(Cι-6)alkyl], optionally substituted [C2.2o alkynyl(Cι_6)alkyl], optionally substituted Cι.20 alkoxycarbonyl, optionally substituted phenoxycarbonyl, formyl, optionally substituted d.20 alkylcarbonyl, optionally substituted Cι_2 alkylsulfonyl or optionally substituted phenylsulfonyl or R28 and R29 together with the N atom to which they are attached form a five, six or seven-membered heterocyclic ring which may contain one or two further hetero atoms selected from O, N or S and which may be optionally substituted by one or two Ci-6 alkyl groups, R31 is hydrogen, optionally substituted phenyl (C1.2)alkyl or optionally substituted
Ci.20 alkyl; and R41, R42 and R43 are , independently, hydrogen, halogen, optionally substituted Ci-6 alkyl, optionally substituted d_6 alkoxy, optionally substituted d-6 alkylthio, optionally substituted d-6 alkylsulfinyl, optionally substituted d-6 alkylsulfonyl, cyano, nitro, optionally substituted Ci-6 alkylcarbonyl, optionally substituted d-6 alkoxycarbonyl or SF5.
PCT/GB2002/000313 2001-01-26 2002-01-25 Process for n-(oxyalkylation) of carboxamides WO2002059118A1 (en)

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Cited By (14)

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Publication number Priority date Publication date Assignee Title
US7141574B2 (en) 2001-07-25 2006-11-28 Boehringer Ingelheim (Canada) Ltd. Viral polymerase inhibitors
US7803944B2 (en) 2001-07-25 2010-09-28 Boehringer Ingelheim International Gmbh Viral polymerase inhibitors
US7767673B2 (en) 2003-08-21 2010-08-03 Osi Pharmaceuticals, Inc. N-substituted imidazopyridine c-Kit inhibitors
WO2005021537A1 (en) 2003-08-21 2005-03-10 Osi Pharmaceuticals, Inc. N-substituted pyrazolyl-amidyl-benzimidazolyl c-kit inhibitors
US7442709B2 (en) 2003-08-21 2008-10-28 Osi Pharmaceuticals, Inc. N3-substituted imidazopyridine c-Kit inhibitors
US7521448B2 (en) 2003-08-21 2009-04-21 Osi Pharmaceuticals, Inc. N-substituted benzimidazolyl c-Kit inhibitors
US8030309B2 (en) 2004-02-20 2011-10-04 Boehringer Ingelheim International Gmbh Viral polymerase inhibitors
US7879851B2 (en) 2004-02-20 2011-02-01 Boehringer Ingelheim International Gmbh Viral polymerase inhibitors
US7419995B2 (en) 2004-12-01 2008-09-02 Osi Pharmaceuticals, Inc. N-substituted benzimidazoyl c-Kit inhibitors and combinatorial benzimidazole library
WO2006060381A2 (en) 2004-12-01 2006-06-08 Osi Pharmaceuticals, Inc. N-substituted benzimidazolyl c-kit inhibitors and combinatorial benzimidazole library
US9732080B2 (en) 2006-11-03 2017-08-15 Vertex Pharmaceuticals Incorporated Azaindole derivatives as CFTR modulators
US10081621B2 (en) 2010-03-25 2018-09-25 Vertex Pharmaceuticals Incorporated Solid forms of (R)-1(2,2-difluorobenzo[D][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide
US10071979B2 (en) 2010-04-22 2018-09-11 Vertex Pharmaceuticals Incorporated Process of producing cycloalkylcarboxamido-indole compounds
US10206877B2 (en) 2014-04-15 2019-02-19 Vertex Pharmaceuticals Incorporated Pharmaceutical compositions for the treatment of cystic fibrosis transmembrane conductance regulator mediated diseases

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