WO2011023753A1 - Dérivés de benzoxazine inhibiteurs du transport de glycine - Google Patents

Dérivés de benzoxazine inhibiteurs du transport de glycine Download PDF

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Publication number
WO2011023753A1
WO2011023753A1 PCT/EP2010/062459 EP2010062459W WO2011023753A1 WO 2011023753 A1 WO2011023753 A1 WO 2011023753A1 EP 2010062459 W EP2010062459 W EP 2010062459W WO 2011023753 A1 WO2011023753 A1 WO 2011023753A1
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Prior art keywords
difluoro
methyl
benzoxazin
alkyl
hydroxyethyl
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PCT/EP2010/062459
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English (en)
Inventor
Richard Blunt
Andrew John Eatherton
Vincenzo Garzya
Mark Patrick Healy
James Myatt
Roderick Alan Porter
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Glaxo Group Limited
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Publication of WO2011023753A1 publication Critical patent/WO2011023753A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/34—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings
    • C07D265/36—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings condensed with one six-membered ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
    • 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
    • C07D417/06—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 carbon chain containing only aliphatic carbon atoms

Definitions

  • the present invention relates to benzoxazinone derivatives, processes for their preparation, pharmaceutical compositions and medicaments containing them and to their use in treating disorders mediated by GIyTI , including neurological and neuropsychiatric disorders, in particular psychoses, dementia or attention deficit disorder.
  • GIyTI is found throughout the brain and may be located at NMDA glutamate receptor synapses as well as in areas containing inhibitory glycine receptors (Cubelos et al., Cerebral Cortex, 15, 2005: 448-459; Zafra et al., Eur. J. Neurosci. 7, 1995: 1342-1352).
  • GIyT-Ia three variants of GIyTI , termed GIyT-Ia, GIyT-I b and GIyT-Ic (Kim et al., Molecular Pharmacology, 45, 1994: 608-617), each of which displays a unique distribution in the brain and peripheral tissues.
  • the variants arise by differential splicing and exon usage, and differ in their N-terminal regions.
  • GlyT2 in contrast, is found predominantly in the brain stem and spinal cord, and its distribution corresponds closely to that of inhibitory glycine receptors (Liu et al., J. Biological Chemistry, 268, 1993: 22802-22808; Jursky and Nelson, J.
  • GlyT2 Another distinguishing feature of glycine transport mediated by GlyT2 is that it is not inhibited by sarcosine as is the case for glycine transport mediated by GIyTL.
  • GIyTI the role of GIyTI is to regulate glycine levels at both NMDA glutamate receptors and inhibitory glycine receptors, whereas the main role of GlyT2 may be to replenish glycine in presynaptic terminals of inhibitory glycinergic synapses (Gomeza et al., Neuron 40, 2003, 785-796 & 797-806).
  • NMDA receptors are critically involved in memory and learning (Rison and Staunton, Neurosci. Biobehav. Rev., 19 533-552 (1995); Danysz et al, Behavioral Pharmacol., 6 455-474 (1995)); and, furthermore, decreased function of NMDA-mediated
  • agents that inhibit GIyTI and thereby increase glycine activation of NMDA receptors can be used as novel antipsychotics and anti- dementia agents, and to treat other diseases in which cognitive processes are impaired, such as attention deficit disorders and organic brain syndromes.
  • Glycine transport inhibitors are already known in the art, for example as disclosed in published international patent application WO03/055478 (SmithKline Beecham).
  • WO06/050054 (Nuada) and WO07/134169 (Nuada) disclose benzolactam boronic acid compounds and analogs thereof for inhibiting an inflammatory cytokine such as TNF- ⁇ .
  • WO07/086504 discloses benzoxazinine compounds which are inhibitors of URAT1 activity and effective for treating diseases associated with uric acid.
  • R 1 is selected from
  • heteroaryl ring which contains 1 to 4 heteroatoms independently selected from O, N and S;
  • the 5 to 6 membered heteroaryl ring and 8 to 10 membered fused bicyclic ring system are unsubstituted or substituted with 1 to 3 substituents independently selected from halo, oxo, C 1-4 alkyl, Ci -4 alkoxy, cyano, hydroxy, hydroxyC 1-4 alkyl, -(CH 2 ) n -(NR 1a R 1b ), -(CO)NR 1a R 1b , -(CO)O-Ci -4 alkyl, -(CHO), haloC 1-4 alkyl and haloCi -4 alkoxy;
  • R 1 is phenyl which is unsubstituted or substituted with 1 to 3 substituents
  • halo independently selected from halo, C 1-4 alkyl, C 1-4 alkoxy, cyano, hydroxy, hydroxyCi -4 alkyl, -(CH 2 ) n -(NR 1a R 1b ), -(CO)NR 1a R 1b , -(CO)O-Ci -4 alkyl, -(CO)OH, -(CHO), -SO 2 (NR 1a R 1b ), haloCi_ 4 alkyl, haloCi -4 alkoxy, -(CO)Ci -4 alkyl, C 2-4 alkenyl, -SCi -4 alkyl and 5 to 6 membered heteroaryl ring which contains 1 to 4 heteroatoms independently selected from O, N and
  • n 1 , 2, 3 or 4;
  • R 1a and R 1b are independently selected from hydrogen, C 1-4 alkyl and haloC 1-4 alkyl;
  • R 2 is selected from hydrogen, halo, cyano, C 1-4 alkyl, haloC 1-4 alkyl, C 1-4 alkoxy and FIaIoC 1-
  • R 3 is selected from hydrogen, halo, cyano and haloC 1-4 alkyl
  • R 4 is selected from hydrogen, halo, cyano, C 1-4 alkyl, haloC 1-4 alkyl, C 1-4 alkoxy and FIaIoC 1- 4 alkoxy;
  • R 5 is selected from -C(OH)R 6 and -C(O)Me;
  • R 6 is selected from -CF 3 , -CHF 2 and -CH 2 F,
  • a compound of formula (I), or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of a disorder mediated by GIyTI .
  • a method for the treatment of a disorder mediated by GIyTI in a human in need thereof comprising administering to said human a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof.
  • a pharmaceutical composition comprising (a) a compound of formula (I), or a pharmaceutically acceptable salt thereof, and (b) a pharmaceutically acceptable excipient.
  • R 1 is selected from
  • R 1 is phenyl which is unsubstituted or substituted with 1 to 3 substituents
  • halo independently selected from halo, C 1-4 alkyl, C 1-4 alkoxy, cyano, hydroxy, hydroxyC 1-4 alkyl, -(CH 2 ) n -(NR 1a R 1b ), -(CO)NR 1a R 1b , -(CO)O-C 1-4 alkyl, -(CO)OH, -(CHO), -SO 2 (NR 1a R 1b ), haloC 1-4 alkyl, haloC 1-4 alkoxy, -(CO)C 1-4 alkyl, C 2-4 alkenyl, -SC 1-4 alkyl and 5 to 6 membered heteroaryl ring which contains 1 to 4 heteroatoms independently selected from O, N and S;
  • n 1 , 2, 3 or 4;
  • R 1a and R 1b are independently selected from hydrogen, C 1-4 alkyl and haloC 1-4 alkyl;
  • R 2 is selected from hydrogen, halo, cyano, C 1-4 alkyl, haloC 1-4 alkyl, C 1-4 alkoxy and FIaIoC 1-
  • R 3 is selected from hydrogen, halo, cyano and haloCi -4 alkyl
  • R 4 is selected from hydrogen, halo, cyano, Ci -4 alkyl, haloC 1-4 alkyl, Ci -4 alkoxy and halod. 4 alkoxy;
  • R 5 is selected from -C(OH)R 6 and -C(O)Me;
  • R 6 is selected from -CF 3 , -CHF 2 and -CH 2 F,
  • a compound of formula (IA), or a salt thereof, as defined above with the proviso that the compound of formula (I) is not 8-acetyl-2,2- difluoro-4-(2-pyridinylmethyl)-2H-1 ,4-benzoxazin-3(4/-/)-one.
  • R 1 is selected from a) 5 to 6 membered heteroaryl ring which contains 1 to 4 heteroatoms independently selected from O, N and S;
  • R 1 is phenyl which is unsubstituted or substituted with 1 to 3 substituents
  • n 1 , 2, 3 or 4;
  • R 1a and R 1b are independently selected from hydrogen, C 1-4 alkyl and haloC 1-4 alkyl;
  • R 2 is selected from hydrogen, halo, cyano, C 1-4 alkyl, haloC 1-4 alkyl, C 1-4 alkoxy and FIaIoC 1-
  • R 3 is selected from hydrogen, halo, cyano and haloC 1-4 alkyl
  • R 4 is selected from hydrogen, halo, cyano, C 1-4 alkyl, haloC 1-4 alkyl, C 1-4 alkoxy and FIaIoC 1-
  • R 5 is selected from -C(OH)R 6 and -C(O)Me;
  • R 6 is selected from -CF 3 , -CHF 2 and -CH 2 F,
  • R 2 , R 3 and R 4 are independently selected from hydrogen, halo, cyano and haloCi -4 alkyl. In a further aspect, R 2 , R 3 and R 4 are independently selected from hydrogen, halo and cyano.
  • R 2 , R 3 and R 4 are independently selected from hydrogen and halo. In a further aspect, R 2 is halo or hydrogen and R 3 and R 4 are hydrogen. In a further aspect, R 2 is fluoro or hydrogen and R 3 and R 4 are hydrogen. In a further aspect, R 2 is fluoro and R 3 and R 4 are hydrogen. In a further aspect, R 2 , R 3 and R 4 are hydrogen.
  • R 5 is-C(O)Me. In a yet further aspect, R 5 is -C(OH)R 6 . In a further aspect, R 5 is
  • R 6 is as defined above.
  • R 5 is
  • R 6 is as defined above.
  • R 6 is -CH 2 F or -CF 3 . In a yet further aspect, R 6 is -CHF 2 or -CF 3 . In a further aspect, R 6 is -CHF 2 or CH 2 F. In a further aspect, R 6 is -CF 3 .
  • R 1 is
  • a 5 to 6 membered heteroaryl ring which contains 1 to 4 heteroatoms independently selected from O, N and S, wherein the 5 to 6 membered heteroaryl ring is unsubstituted or substituted with 1 to 3 substituents independently selected from halo, oxo, Ci ⁇ alkyl, C 1-4 alkoxy, cyano, hydroxyl, hydroxy C 1-4 alkyl, -(CH 2 ) n -(NR 1a R 1b ), -(C0)NR 1a R 1b , -(CO)O- C 1-4 alkyl, -(CHO), haloC 1-4 alkyl and haloC 1-4 alkoxy;
  • phenyl which is unsubstituted or substituted with 1 to 2 substituents independently selected from halo, Ci -4 alkoxy, cyano, hydroxy, hydroxyCi -4 alkyl, -(CH 2 ) n - (NR 1a R 1b ), -(C0)NR 1a R 1b , -(CO)O-Ci -4 alkyl, -(CO)OH, -(CHO), -S0 2 (NR 1a R 1b ), haloCi.
  • R 1 is
  • a 5 to 6 membered heteroaryl ring which contains 1 to 2 heteroatoms independently selected from O, N and S, wherein the 5 to 6 membered heteroaryl ring is unsubstituted or substituted with 1 to 3 substituents independently selected from halo, oxo, C 1-4 alkyl, C 1-4 alkoxy, cyano, hydroxyl, hydroxy C 1-4 alkyl, -(CH 2 ) n -(NR 1a R 1b ), -(C0)NR 1a R 1b , -(CO)O- C 1-4 alkyl, -(CHO), haloC 1-4 alkyl and haloC 1-4 alkoxy;
  • pyridopyrimidinyl benzoxadiazolyl, benzoxazolyl, imidazopyridinyl, oxazolopyridinyl, benzothiadiazolyl, indazolyl, imidazothiazolyl, furopyridinyl and thienopyrazolyl, each of which is unsubstituted or substituted with 1 to 3 substituents independently selected from halo, oxo, Ci -4 alkyl, Ci -4 alkoxy, cyano, hydroxyl, hydroxy Ci -4 alkyl, -(CH 2 ) n -(NR 1a R 1b ), - (C0)NR 1a R 1b , -(COp-C ⁇ alkyl, -(CHO), haloC ⁇ alkyl and haloCi -4 alkoxy; or
  • phenyl which is unsubstituted or substituted with 1 to 2 substituents independently selected from halo, Ci -4 alkoxy, cyano, hydroxy, hydroxyCi -4 alkyl, -(CH 2 ) n - (NR 1a R 1b ), -(C0)NR 1a R 1b , -(CO)O-Ci -4 alkyl, -(CO)OH, -(CHO), -S0 2 (NR 1a R 1b ), haloCi.
  • R 1 is
  • pyridopyrimidinyl benzoxadiazolyl, benzoxazolyl, imidazopyridinyl, oxazolopyridinyl, benzothiadiazolyl, indazolyl, imidazothiazolyl, furopyridinyl and thienopyrazolyl, each of which is unsubstituted or substituted with 1 to 3 substituents independently selected from halo, oxo, Ci -4 alkyl, Ci -4 alkoxy, cyano, hydroxyl, hydroxy Ci -4 alkyl, -(CH 2 ) n -(NR 1a R 1b ), - (CO)NR 1a R 1b , -(CO)O-C 1-4 alkyl, -(CHO), haloC 1-4 alkyl and haloCi -4 alkoxy; or
  • phenyl which is unsubstituted or substituted with 1 to 2 substituents independently selected from halo, C 1-4 alkyl, Ci -4 alkoxy, cyano, hydroxy, hydroxyCi -4 alkyl, -(CH 2 ) n -
  • R 1 is
  • - pyridyl which is unsubstituted or substituted with 1 or 2 substituents independently selected from halo, haloC 1-4 alkyl, -(CO)O-C 1-4 alkyl, C 1-4 alkyl, C 1-4 alkoxy and cyano;
  • pyridopyrimidinyl benzoxadiazolyl, benzoxazolyl, imidazopyridinyl, oxazolopyridinyl, benzothiadiazolyl, indazolyl, imidazothiazolyl, furopyridinyl and thienopyrazolyl, each of which is unsubstituted or substituted with 1 to 3 substituents independently selected from halo, oxo, C 1-4 alkyl, C 1-4 alkoxy, cyano, hydroxyl, hydroxy C 1-4 alkyl, -(CH 2 ) n -(NR 1a R 1b ), - (C0)NR 1a R 1b , -(CO)O-C 1-4 alkyl, -(CHO), haloC 1-4 alkyl and haloC 1-4 alkoxy; or
  • phenyl which is unsubstituted or substituted with 1 to 2 substituents independently selected from halo, C 1-4 alkyl, C 1-4 alkoxy, cyano, hydroxy, hydroxyC 1-4 alkyl, -(CH 2 ) n - (NR 1a R 1b ), -(C0)NR 1a R 1b , -(CO)O-C 1-4 alkyl, -(CO)OH, -(CHO), -S0 2 (NR 1a R 1b ), halod.
  • R 1 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • - pyridyl which is unsubstituted or substituted with 1 or 2 substituents independently selected from fluoro, chloro, trifluoromethyl, -(CO)O-CH 3 , methyl, methoxy and cyano; - unsubstituted pyrimidinyl;
  • pyridopyrimidinyl benzoxadiazolyl, benzoxazolyl, imidazopyridinyl, oxazolopyridinyl, benzothiadiazolyl, indazolyl, imidazothiazolyl, furopyridinyl and thienopyrazolyl, each of which is unsubstituted or substituted with 1 to 3 substituents independently selected from halo, oxo, C 1-4 alkyl, C 1-4 alkoxy, cyano, haloC 1-4 alkyl and haloC 1-4 alkoxy, particularly oxo and C 1-4 alkyl, more particularly oxo and methyl; or
  • phenyl which is unsubstituted or substituted with 1 or 2 substituents independently selected from halo, C 1-4 alkyl, C 1-4 alkoxy, cyano, -SO 2 (NR 1a R 1b ), haloCi -4 alkyl, haloCi.
  • R 1 is
  • pyridopyrimidin-2-yl benzoxadiazol-5-yl, benzoxazol-6-yl, benzoxazol-2-yl, benzotriazol- 6-yl, benzotriazol-1-yl, imidazopyridin-2-yl, oxazolopyridin-2-yl, indazol-3-yl,
  • phenyl which is unsubstituted or substituted with 1 or 2 substituents independently selected from fluoro, chloro, cyano, methyl, methoxy, imidazolyl, ethenyl, -(CO)N(CH 3 ) 2 , - (CO)(CH 3 ), -SCH 3 and -SO 2 (NR 1a R 1b ).
  • R 1 is
  • a 5 to 6 membered heteroaryl ring which contains 1 to 4 heteroatoms independently selected from O, N and S, wherein the 5 to 6 membered heteroaryl ring is unsubstituted or substituted with 1 to 3 substituents independently selected from halo, oxo, C 1-4 alkyl, C 1-4 alkoxy, cyano, hydroxyl, hydroxy C 1-4 alkyl, -(CH 2 ) n -(NR 1a R 1b ), -(CO)NR 1a R 1b , -(CO)O- C 1-4 alkyl, -(CHO), haloC 1-4 alkyl and haloC 1-4 alkoxy;
  • pyridopyrimidinyl benzoxadiazolyl, benzoxazolyl, imidazopyridinyl, oxazolopyridinyl, benzothiadiazolyl, indazolyl, imidazothiazolyl, furopyridinyl and thienopyrazolyl, each of which is unsubstituted or substituted with 1 to 3 substituents independently selected from halo, oxo, C 1-4 alkyl, C 1-4 alkoxy, cyano, haloC 1-4 alkyl and haloC 1-4 alkoxy, particularly oxo and more particularly oxo and methyl; or
  • phenyl which is unsubstituted or substituted with 1 or 2 substituents independently selected from halo, Ci -4 alkoxy, cyano, hydroxy, hydroxyCi -4 alkyl, -(CH 2 ) n - (NR 1a R 1b ), -(CO)NR 1a R 1b , -(CO)O-Ci -4 alkyl, -(CHO), -SO 2 (NR 1a R 1b ), haloCi -4 alkyl, haloCi.
  • R 2 , R 3 and R 4 are independently selected from hydrogen, halo, cyano and haloCi -4 alkyl; R 5 is -C(O)Me or -C(OH)R 6 , and
  • R 6 is CF 3 , CHF 2 or CH 2 F, in particular CF 3 .
  • R 1 is
  • phenyl which is unsubstituted or substituted with 1 or 2 substituents independently selected from halo, C 1-4 alkyl, C 1-4 alkoxy, cyano, -SO 2 (NR 1a R 1b ), haloCi -4 alkyl, haloCi.
  • R 2 , R 3 and R 4 are independently selected from hydrogen, halo and cyano;
  • R 5 is -C(O)Me or -C(OH)R 6 .
  • R 6 is CF 3 , CHF 2 or CH 2 F, in particular CF 3 .
  • R 1 is
  • - pyridyl which is unsubstituted or substituted with 1 or 2 substituents independently selected from fluoro, chloro, trifluoromethyl, -(CO)O-CH 3 , methyl, methoxy and cyano;
  • pyridopyrimidinyl benzoxadiazolyl, benzoxazolyl, imidazopyridinyl, oxazolopyridinyl, benzothiadiazolyl, indazolyl, imidazothiazolyl, furopyridinyl and thienopyrazolyl, each of which is unsubstituted or substituted with 1 to 3 substituents independently selected from halo, oxo, C 1-4 alkyl, C 1-4 alkoxy, cyano, haloC 1-4 alkyl and haloC 1-4 alkoxy, particularly oxo and C 1-4 alkyl, more particularly oxo and methyl;
  • phenyl which is unsubstituted or substituted with 1 or 2 substituents independently selected from fluoro, chloro, cyano, methyl, methoxy, imidazolyl, ethenyl, -(CO)N(CH 3 ) 2 , - (CO)(CH 3 ), -SCH 3 and -SO 2 (NR 1a R 1b );
  • R 2 , R 3 and R 4 are independently selected from hydrogen and halo, particularly fluoro;
  • R 5 is -C(O)Me or -C(OH)R 6 .
  • R 6 is CF 3 , CHF 2 or CH 2 F, in particular CF 3 .
  • R 1 is
  • R 2 is halo, in particular fluoro
  • R 3 is hydrogen
  • R 4 is hydrogen or halo, in particular fluoro
  • R 5 is -C(O)Me or -C(OH)R 6 .
  • R 6 is CF 3 , CHF 2 or CH 2 F, in particular CF 3 .
  • a compound of formula I represented by a formula (IA), or a salt thereof, wherein
  • R 1 is selected from
  • n 1 , 2, 3 or 4;
  • R 1a and R 1b are independently selected from hydrogen, Ci -4 alkyl and haloCi -4 alkyl;
  • R 2 is selected from hydrogen, halo, cyano, Ci -4 alkyl, Ci -4 alkoxy and haloCi.
  • R 3 is selected from hydrogen, halo, cyano and haloCi -4 alkyl
  • R 4 is selected from hydrogen, halo, cyano, Ci -4 alkyl, Ci -4 alkoxy and haloCi.
  • R 6 is selected from -CF 3 , -CHF 2 and -CH 2 F.
  • R 1 , R 2 , R 3 , R 4 and R 6 are as defined for a compound of formula (IA).
  • R 1 , R 2 , R 3 , R 4 and R 6 are as defined for a compound of formula (IA).
  • a compound of formula (IA), or a salt thereof wherein R 2 , R 3 and R 4 are independently selected from hydrogen, halo, cyano and haloCi_ 4 alkyl.
  • R 2 , R 3 and R 4 are independently selected from hydrogen, halo and cyano.
  • R 2 , R 3 and R 4 are independently selected from hydrogen and halo.
  • R 2 is halo or hydrogen and R 3 and R 4 are hydrogen.
  • R 2 is fluoro or hydrogen and R 3 and R 4 are hydrogen, more particularly, R 2 , R 3 and R 4 are hydrogen.
  • a compound of formula (IA), or a salt thereof wherein R 1 is a 5 to 6 membered heteroaryl ring which contains 1 to 4 heteroatoms independently selected from O, N and S, wherein the 5 to 6 membered heteroaryl ring is unsubstituted or substituted with 1 to 3 substituents independently selected from halo, oxo, C 1-4 alkyl, C 1-4 alkoxy, cyano, hydroxy, hydroxy C 1-4 alkyl, -(CH 2 ) n -(NR 1a R 1b ), - (CO)NR 1a R 1b , -(CO)O-C 1-4 alkyl, -(CHO), haloC 1-4 alkyl and haloC 1-4 alkoxy.
  • a compound of formula (IA), or a salt thereof wherein R 1 is a 5 to 6 membered heteroaryl ring which contains 1 to 2 heteroatoms independently selected from O, N and S, wherein the 5 to 6 membered heteroaryl ring is unsubstituted or substituted with 1 to 3 substituents independently selected from halo, oxo, Ci -4 alkoxy, cyano, hydroxyl, hydroxy Ci -4 alkyl, -(CH 2 ) n -(NR 1a R 1b ), - (CO)NR 1a R 1b , -(CO)O-Ci.
  • R 1 is selected from furanyl, thiazolyl, thienyl, oxazolyl, pyridyl, pyridazinyl, pyrimidinyl and pyrazinyl, each of which is unsubstituted or substituted with 1 to 3 substituents independently selected from halo, oxo, C 1-4 alkyl, C 1-4 alkoxy, cyano, hydroxyl, hydroxy C 1-4 alkyl, -(CH 2 ) n -(NR 1a R 1b ), -(CO)NR 1a R 1b , -(CO)O-C 1-4 alkyl, -(CHO), haloC 1-4 alkyl and haloC 1-4 alkoxy.
  • R 1 is selected from furanyl, thiazolyl, thienyl, oxazolyl, pyridyl, pyridazinyl, pyrimidinyl and pyrazinyl, each
  • - pyridyl which is unsubstituted or substituted with 1 or 2 substituents independently selected from halo, haloCi -4 alkyl, -(CO)O-Ci -4 alkyl, Ci -4 alkyl, Ci -4 alkoxy and cyano;
  • - pyridyl which is unsubstituted or substituted with 1 or 2 substituents independently selected from fluoro, chloro, trifluoromethyl, -(CO)O-CH 3 , methyl, methoxy and cyano;
  • a compound of formula (IA), or a salt thereof wherein R 1 is a 5 to 6 membered heteroaryl ring which contains 1 to 4 heteroatoms independently selected from O, N and S, wherein the 5 to 6 membered heteroaryl ring is unsubstituted or substituted with 1 to 3 substituents independently selected from halo, oxo, C 1-4 alkyl, C 1-4 alkoxy, cyano, hydroxyl, hydroxy C 1-4 alkyl, -(CH 2 ) n -(NR 1a R 1b ), - (CO)NR 1a R 1b , -(CO)O-C 1-4 alkyl, -(CHO), haloC 1-4 alkyl and haloC 1-4 alkoxy, R 2 is hydrogen or halo, in particular hydrogen, R 3 is hydrogen and R 4 is hydrogen or halo, in particular hydrogen, R 6 is CF 3 , CHF 2 or CH 2 F, in particular CF
  • a compound of formula (IB), or a salt thereof wherein R 1 is a 5 to 6 membered heteroaryl ring which contains 1 to 4 heteroatoms independently selected from O, N and S, wherein the 5 to 6 membered heteroaryl ring is unsubstituted or substituted with 1 to 3 substituents independently selected from halo, oxo, C 1-4 alkyl, Ci -4 alkoxy, cyano, hydroxyl, hydroxy C 1-4 alkyl, -(CH 2 ) n -(NR 1a R 1b ), - (C0)NR 1a R 1b , -(COp-C ⁇ alkyl, -(CHO), haloC ⁇ alkyl and haloCi -4 alkoxy, R 2 is hydrogen or halo, R 3 is hydrogen, R 4 is hydrogen or halo.
  • R 1 is selected from furanyl, thiazolyl, thienyl, oxazolyl, pyridyl, pyridazinyl, pyrimidinyl and pyrazinyl,
  • R 2 is hydrogen or halo, in particular hydrogen
  • R 3 is hydrogen and R 4 is hydrogen or halo, in particular hydrogen
  • R 6 is CF 3 , CHF 2 or CH 2 F, in particular CF 3 .
  • R 2 is hydrogen or halo, in particular fluoro
  • R 3 is hydrogen
  • R 4 is hydrogen or halo, in particular fluoro.
  • R 2 is hydrogen or halo, in particular hydrogen
  • R 3 is hydrogen and R 4 is hydrogen or halo, in particular hydrogen
  • R 6 is CF 3 , CHF 2 or CH 2 F, in particular CF 3 .
  • - pyridyl which is unsubstituted or substituted with 1 or 2 substituents selected from halo, haloC 1-4 alkyl, -(CO)O-C 1-4 alkyl, C 1-4 alkyl, C 1-4 alkoxy and cyano;
  • R 2 is hydrogen or halo, in particular fluoro
  • R 3 is hydrogen
  • R 4 is hydrogen or halo, in particular fluoro.
  • - pyridyl which is unsubstituted or substituted with 1 or 2 substituents independently selected from fluoro, chloro, trifluoromethyl, -(CO)O-CH 3 , methyl, methoxy and cyano; - unsubstituted pyrimidinyl;
  • R 2 is hydrogen or halo, in particular hydrogen
  • R 3 is hydrogen
  • R 4 is hydrogen or halo, in particular hydrogen
  • R 6 is CF 3 , CHF 2 or CH 2 F, in particular CF 3 .
  • - pyridyl which is unsubstituted or substituted with 1 or 2 substituents independently selected from fluoro, chloro, trifluoromethyl, -(CO)O-CH 3 , methyl, methoxy and cyano;
  • R 2 is hydrogen or halo, in particular fluoro
  • R 3 is hydrogen
  • R 4 is hydrogen or halo, in particular fluoro
  • R 6 is CF 3 , CHF 2 or CH 2 F, in particular CF 3 .
  • R 2 is hydrogen or halo, in particular hydrogen
  • R 3 is hydrogen
  • R 4 is hydrogen or halo, in particular hydrogen
  • R 6 is CF 3 , CHF 2 or CH 2 F, in particular CF 3 .
  • R 2 is hydrogen or halo, in particular fluoro
  • R 3 is hydrogen
  • R 4 is hydrogen or halo, in particular fluoro
  • R 6 is CF 3 , CHF 2 or CH 2 F, in particular CF 3 .
  • R 2 is hydrogen or halo, in particular fluoro
  • R 3 is hydrogen
  • R 4 is hydrogen or halo, in particular fluoro
  • R 6 is CF 3 , CHF 2 or CH 2 F, in particular CF 3 .
  • - pyridyl which is unsubstituted or substituted with 1 or 2 substituents selected from halo, haloCi_ 4 alkyl, -(CO)O-Ci -4 alkyl, Ci -4 alkyl, and cyano;
  • R 2 , R 3 and R 4 are hydrogen, and R 6 is CF 3 , CHF 2 or CH 2 F, in particular CF 3 .
  • - pyridyl which is unsubstituted or substituted with 1 or 2 substituents independently selected from fluoro, chloro, trifluoromethyl, -(CO)O-CH 3 , methyl, methoxy and cyano;
  • R 2 , R 3 and R 4 are hydrogen, and R 6 is CF 3 , CHF 2 or CH 2 F, in particular CF 3 .
  • R 2 , R 3 and R 4 are hydrogen, and R 6 is CF 3 , CHF 2 or CH 2 F, in particular CF 3 .
  • a compound of formula (IA), or a salt thereof wherein R 1 is a 8 to 10 membered fused bicyclic ring system which is unsubstituted or substituted with 1 to 3 substituents independently selected from halo, oxo, C 1-4 alkyl, C 1- 4 alkoxy, cyano, hydroxyl, hydroxy C 1-4 alkyl, -(CH 2 ) n -(NR 1a R 1b ), -(CO)NR 1a R 1b , -(CO)O-C 1- 4 alkyl, -(CHO), haloC 1-4 alkyl and haloC 1-4 alkoxy.
  • R 1 is selected from quinolin-3-yl, quinolin-2-yl, quinolin-6-yl, quinazolin-2-yl, benzotriazol-5-yl, benzothiazol-3-yl, benzothiazol-2-yl, benzothiadiazol-6-yl,
  • a compound of formula (IA), or a salt thereof wherein R 1 is selected from quinolinyl, quinazolinyl, benzotriazolyl, benzothiazolyl, benzimidazolyl, pyridopyrimidinyl, benzoxadiazolyl, benzoxazolyl, imidazopyridinyl, oxazolopyridinyl, benzothiadiazolyl, indazolyl, imidazothiazolyl, furopyridinyl and thienopyrazolyl, each of which is unsubstituted or substituted with 1 to 3 substituents independently selected from halo, oxo, C 1-4 alkyl, C 1-4 alkoxy, cyano, haloC 1-4 alkyl and haloC 1-4 alkoxy, particularly oxo and C 1-4 alkyl, more particularly oxo and methyl; R 2 , R 3 and R 4 are hydrogen
  • a compound of formula (IA), or a salt thereof wherein R 1 is selected from quinolin-6-yl, quinazolin-2-yl, benzotriazol-5-yl, benzothiazol- 3-yl, benzothiazol-2-yl, benzimidazol-2-yl, pyridopyrimidin-2-yl, benzoxadiazol-4-yl, benzoxazol-2-yl, imidazopyridin-2-yl, oxazolopyridin-2-yl, indazol-3-yl, imidazothiazol-6- yl, furopyridin-5-yl and thienopyrazol-5-yl, each of which is unsubstituted or substituted with 1 to 3 substituents independently selected from halo, oxo, Ci -4 alkyl, Ci -4 alkoxy, cyano, and haloCi -4 alkoxy, particularly ox
  • a compound of formula (IA), or a salt thereof wherein R 1 is selected from quinolinyl, quinazolinyl, benzotriazolyl, benzothiazolyl, benzimidazolyl, pyridopyrimidinyl, benzoxadiazolyl, benzoxazolyl, imidazopyridinyl, oxazolopyridinyl, benzothiadiazolyl, indazolyl, imidazothiazolyl, furopyridinyl and thienopyrazolyl, each of which is unsubstituted or substituted with 1 to 3 substituents independently selected from halo, oxo, C 1-4 alkyl, C 1-4 alkoxy, cyano, haloC 1-4 alkyl and haloC 1-4 alkoxy, particularly oxo and C 1-4 alkyl, more particularly oxo and methyl; R 2 is halo, in particular fluor
  • a compound of formula (IA), or a salt thereof wherein R 1 is selected from quinolin-6-yl, quinazolin-2-yl, benzotriazol-5-yl, benzothiazol- 3-yl, benzothiazol-2-yl, benzimidazol-2-yl, pyridopyrimidin-2-yl, benzoxadiazol-4-yl, benzoxazol-2-yl, imidazopyridin-2-yl, oxazolopyridin-2-yl, indazol-3-yl, imidazothiazol-6- yl, furopyridin-5-yl and thienopyrazol-5-yl, each of which is unsubstituted or substituted with 1 to 3 substituents independently selected from halo, oxo, Ci -4 alkyl, Ci -4 alkoxy, cyano, and haloCi -4 alkoxy, particularly ox
  • R 1 is selected from
  • n 1 , 2, 3 or 4;
  • R 1a and R 1b are independently selected from hydrogen, C 1-4 alkyl and haloC 1-4 alkyl;
  • R 2 is selected from hydrogen, halo, cyano, C 1-4 alkyl, haloC 1-4 alkyl, C 1-4 alkoxy and FIaIoC 1-
  • R 3 is selected from hydrogen, halo, cyano and haloC 1-4 alkyl
  • R 4 is selected from hydrogen, halo, cyano, C 1-4 alkyl, haloC 1-4 alkyl, C 1-4 alkoxy and FIaIoC 1-
  • the compound of formula (IB) is not 8-acetyl-2,2-difluoro-4-(2- pyridinylmethyl)-2H-1 ,4-benzoxazin-3(4H)-one.
  • a compound of formula (IB), or a salt thereof wherein R 2 , R 3 and R 4 are independently selected from hydrogen, halo, cyano and haloC 1-4 alkyl.
  • R 2 , R 3 and R 4 are independently selected from hydrogen, halo and cyano.
  • R 2 , R 3 and R 4 are independently selected from hydrogen and halo.
  • R 2 is halo and R 3 and R 4 are hydrogen.
  • R 2 is fluoro and R 3 and R 4 are hydrogen.
  • R 2 , R 3 and R 4 are hydrogen.
  • a compound of formula (IB), or a salt thereof wherein R 1 is a 5 to 6 membered heteroaryl ring which contains 1 to 4 heteroatoms independently selected from O, N and S, wherein the 5 to 6 membered heteroaryl ring is unsubstituted or substituted with 1 to 3 substituents independently selected from halo, oxo, C 1-4 alkyl, Ci -4 alkoxy, cyano, hydroxyl, hydroxy C 1-4 alkyl, -(CH 2 ) n -(NR 1a R 1b ), - (CO)NR 1a R 1b , -(CO)O-C 1-4 alkyl, -(CHO), haloC 1-4 alkyl and haloC 1-4 alkoxy.
  • a compound of formula (IB), or a salt thereof wherein R 1 is a 5 to 6 membered heteroaryl ring which contains 1 to 2 heteroatoms independently selected from O, N and S, wherein the 5 to 6 membered heteroaryl ring is unsubstituted or substituted with 1 to 3 substituents independently selected from halo, oxo, C 1-4 alkyl, C 1-4 alkoxy, cyano, hydroxyl, hydroxy C 1-4 alkyl, -(CH 2 ) n -(NR 1a R 1b ), - (CO)NR 1a R 1b , -(CO)O-C 1-4 alkyl, -(CHO), haloC 1-4 alkyl and haloC 1-4 alkoxy.
  • R 1 is selected from furanyl, thiazolyl, thienyl, oxazolyl, pyridyl, pyridazinyl,
  • - pyridyl which is unsubstituted or substituted with 1 or 2 substituents independently selected from halo, haloC 1-4 alkyl, -(CO)O-C 1-4 alkyl, C 1-4 alkyl, C 1-4 alkoxy and cyano;
  • - pyridyl which is unsubstituted or substituted with 1 or 2 substituents independently selected from fluoro, chloro, trifluoromethyl, -(CO)O-CH 3 , methyl, methoxy and cyano;
  • 3-pyridyl which is unsubstituted or substituted with 1 or 2 substituents independently selected from fluoro, chloro, methoxy, cyano, trifluoromethyl, methyl and -(CO)O-CH 3 ;
  • 2-pyridyl which is unsubstituted or substituted with 1 or 2 substituents independently selected from methyl, chloro, fluoro, methoxy and cyano;
  • R 1 is a 5 to 6 membered heteroaryl ring which contains 1 to 4 heteroatoms independently selected from O, N and S, wherein the 5 to 6 membered heteroaryl ring is unsubstituted or substituted with 1 to 3 substituents independently selected from halo, oxo, Ci -4 alkoxy, cyano, hydroxyl, hydroxy Ci -4 alkyl, -(CH 2 ) n -(NR 1a R 1b ), - (C0)NR 1a R 1b , -(CO)O-C 1-4 alkyl, -(CHO), haloC 1-4 alkyl and haloC 1-4 alkoxy, R 2 is hydrogen or halo, R 3 is hydrogen
  • R 1 is selected from furanyl, thiazolyl, thienyl, oxazolyl, pyridyl, pyridazinyl, pyrimidinyl and pyrazinyl, each of which is unsubstituted or substituted with 1 to 3 substituents independently selected from halo, oxo, C 1-4 alkyl, C 1-4 alkoxy, cyano, hydroxyl, hydroxy C 1-4 alkyl, -(CH 2 ) n -(NR 1a R 1b ), -(CO)NR 1a R 1b , -(CO)O-C 1-4 alkyl, -(CHO), halod.
  • R 2 is hydrogen or halo, in particular fluoro
  • R 3 is hydrogen
  • R 4 is hydrogen or halo, in particular fluoro.
  • - pyridyl which is unsubstituted or substituted with 1 or 2 substituents selected from halo, haloC 1-4 alkyl, -(CO)O-C 1-4 alkyl, C 1-4 alkyl, C 1-4 alkoxy and cyano;
  • RR 22 i iss hhyyddrrooggeenn oor halo, in particular fluoro
  • R 3 is hydrogen
  • R 4 is hydrogen or halo, in particular fluoro.
  • - pyridyl which is unsubstituted or substituted with 1 or 2 substituents independently selected from fluoro, chloro, trifluoromethyl, -(CO)O-CH 3 , methyl, methoxy and cyano; - unsubstituted pyrimidinyl;
  • R 2 is hydrogen or halo, in particular fluoro
  • R 3 is hydrogen
  • R 4 is hydrogen or halo, in particular fluoro.
  • R 2 is hydrogen or halo, in particular fluoro
  • R 3 is hydrogen
  • R 4 is hydrogen or halo, in particular fluoro.
  • - pyridyl which is unsubstituted or substituted with 1 or 2 substituents selected from halo, haloC 1-4 alkyl, -(CO)O-C 1-4 alkyl, C 1-4 alkyl, C 1-4 alkoxy and cyano;
  • R 2 , R 3 and R 4 are hydrogen.
  • - pyridyl which is unsubstituted or substituted with 1 or 2 substituents independently selected from fluoro, chloro, trifluoromethyl, -(CO)O-CH 3 , methyl, methoxy and cyano;
  • R 2 , R 3 and R 4 are hydrogen.
  • R 2 , R 3 and R 4 are hydrogen.
  • R 1 is a 8 to 10 membered fused bicyclic ring system which is unsubstituted or substituted with 1 to 3 substituents independently selected from halo, oxo, C 1-4 alkyl, C 1- 4 alkoxy, cyano, hydroxyl, hydroxy C 1-4 alkyl, -(CH 2 ) n -(NR 1a R 1b ), -(CO)NR 1a R 1b , -(CO)O-C 1- 4 alkyl, -(CHO), haloC 1-4 alkyl and haloC 1-4 alkoxy.
  • R 1 is selected from quinolinyl, quinazolinyl, benzotriazolyl, benzothiazolyl, benzimidazolyl, pyridopyrimidinyl, benzoxadiazolyl, benzoxazolyl, imidazopyridinyl, oxazolopyridinyl, benzothiadiazolyl, indazolyl, imidazothiazolyl, furopyridinyl and thienopyrazolyl, each of which is unsubstituted or substituted with 1 to 3 substituents independently selected from halo, oxo, C 1-4 alkyl, C 1-4 alkoxy, cyano, hydroxyl, hydroxy C 1- 4 alkyl, -(CH 2 ) n -(NR 1a R 1b ), -(CO)NR 1a R 1b , -(CO)O-
  • R 1 is selected from quinolinyl, quinazolinyl, benzotriazolyl, benzothiazolyl, benzimidazolyl, pyridopyrimidinyl, benzoxadiazolyl, benzoxazolyl, imidazopyridinyl, oxazolopyridinyl, benzothiadiazolyl, indazolyl, imidazothiazolyl, furopyridinyl and thienopyrazolyl, each of which is unsubstituted or substituted with 1 to 3 substituents independently selected from halo, oxo, C 1-4 alkyl, C 1-4 alkoxy, cyano, haloC 1-4 alkyl and haloC 1-4 alkoxy, particularly oxo and C 1-4 alkyl, more particularly oxo and methyl.
  • R 1 is selected from quinolin-3-yl, quinolin-2-yl, quinolin-6-yl, quinazolin-2-yl, benzotriazol-5-yl, benzothiazol-3-yl, benzothiazol-2-yl, benzothiadiazol-6-yl,
  • R 1 is selected from quinolinyl, quinazolinyl, benzotriazolyl, benzothiazolyl, benzimidazolyl, pyridopyrimidinyl, benzoxadiazolyl, benzoxazolyl, imidazopyridinyl, oxazolopyridinyl, benzothiadiazolyl, indazolyl, imidazothiazolyl, furopyridinyl and thienopyrazolyl, each of which is unsubstituted or substituted with 1 to 3 substituents independently selected from halo, oxo, C 1-4 alkyl, C 1-4 alkoxy, cyano, haloC 1-4 alkyl and haloC 1-4 alkoxy, particularly oxo and C 1-4 alkyl, more particularly oxo and methyl; R 2 , R 3 and R 4 are
  • R 1 is selected from quinolin-6-yl, quinazolin-2-yl, benzotriazol-5-yl, benzothiazol- 3-yl, benzothiazol-2-yl, benzimidazol-2-yl, pyridopyrimidin-2-yl, benzoxadiazol-4-yl, benzoxazol-2-yl, imidazopyridin-2-yl, oxazolopyridin-2-yl, indazol-3-yl, imidazothiazol-6- yl, furopyridin-5-yl and thienopyrazol-5-yl, each of which is unsubstituted or substituted with 1 to 3 substituents independently selected from halo, oxo, Ci -4 alkyl, Ci -4 alkoxy, cyano, and haloCi -4 alkoxy, particularly o
  • R 1 is selected from quinolinyl, quinazolinyl, benzotriazolyl, benzothiazolyl, benzimidazolyl, pyridopyrimidinyl, benzoxadiazolyl, benzoxazolyl, imidazopyridinyl, oxazolopyridinyl, benzothiadiazolyl, indazolyl, imidazothiazolyl, furopyridinyl and thienopyrazolyl, each of which is unsubstituted or substituted with 1 to 3 substituents independently selected from halo, oxo, C 1-4 alkyl, C 1-4 alkoxy, cyano, haloC 1-4 alkyl and haloC 1-4 alkoxy, particularly oxo and C 1-4 alkyl, more particularly oxo and methyl; R 2 is halo, in particular fluorine fluoride, pyridopyrimidinyl, benzoxadiazolyl,
  • R 1 is selected from quinolin-6-yl, quinazolin-2-yl, benzotriazol-5-yl, benzothiazol- 3-yl, benzothiazol-2-yl, benzimidazol-2-yl, pyridopyrimidin-2-yl, benzoxadiazol-4-yl, benzoxazol-2-yl, imidazopyridin-2-yl, oxazolopyridin-2-yl, indazol-3-yl, imidazothiazol-6- yl, furopyridin-5-yl and thienopyrazol-5-yl, each of which is unsubstituted or substituted with 1 to 3 substituents independently selected from halo, oxo, Ci -4 alkyl, Ci -4 alkoxy, cyano, and haloCi -4 alkoxy, particularly o
  • R 1 is phenyl which is unsubstituted or substituted with 1 to 3 substituents independently selected from halo, Ci -4 alkoxy, cyano, hydroxy, hydroxyCi -4 alkyl, -(CH 2 ) n - (NR 1a R 1b ), -(CO)NR 1a R 1b , -(CO)O-Ci -4 alkyl, -(CO)OH, -(CHO), -S0 2 (NR 1a R 1b ), haloCi.
  • R 1a and R 1b are independently selected from hydrogen, Ci -4 alkyl and haloCi -4 alkyl;
  • n 1 , 2, 3 or 4;
  • R 2 is selected from hydrogen, halo, cyano, Ci -4 alkyl, Ci -4 alkoxy and haloCi.
  • R 3 is selected from hydrogen, halo, cyano and haloC 1-4 alkyl
  • R 4 is selected from hydrogen, halo, cyano, C 1-4 alkyl, haloC 1-4 alkyl, C 1-4 alkoxy and FIaIoC 1- 4 alkoxy, with the proviso that
  • R 1 when R 1 is phenyl which is monosubstituted in the para position relative to its attachment to the -CH 2 - group, the substituent is other than -cyano, -CF 3 , -NH 2 , -CONH 2 , -SO 2 NH 2
  • R 1 is phenyl which is unsubstituted or substituted with 1 to 3 substituents independently selected from halo, C 1-4 alkyl, C 1-4 alkoxy, cyano, hydroxy, hydroxyC 1-4 alkyl, -(CH 2 ) n -
  • R 1a and R 1b are independently selected from hydrogen, Ci -4 alkyl and haloCi -4 alkyl;
  • n 1 , 2, 3 or 4;
  • R 2 is selected from hydrogen, halo, cyano, Ci -4 alkyl, Ci -4 alkoxy and haloCi. 4 alkoxy;
  • R 3 is selected from hydrogen, halo, cyano and haloCi -4 alkyl
  • R 4 is selected from hydrogen, halo, cyano, Ci -4 alkyl, Ci -4 alkoxy and haloCi.
  • R 1 when R 1 is phenyl which is monosubstituted in the para position relative to its attachment to the -CH 2 - group, the substituent is other than -cyano, -CF 3 , -NH 2 , -
  • R 1 is phenyl which is unsubstituted or substituted with 1 to 3 substituents independently selected from halo, Ci -4 alkoxy, cyano, hydroxy, hydroxyCi -4 alkyl, -(CH 2 ) n - (NR 1a R 1b ), -(C0)NR 1a R 1b , -(CO)O-Ci -4 alkyl, -(CO)OH, -(CHO), -S0 2 (NR 1a R 1b ), haloCi.
  • R 1a and R 1b are independently selected from hydrogen, Ci -4 alkyl and haloCi -4 alkyl;
  • n 1 , 2, 3 or 4;
  • R 2 is selected from hydrogen, halo, cyano, Ci -4 alkyl, Ci -4 alkoxy and haloCi.
  • R 3 is selected from hydrogen, halo, cyano and haloC 1-4 alkyl
  • R 4 is selected from hydrogen, halo, cyano, C 1-4 alkyl, haloC 1-4 alkyl, C 1-4 alkoxy and FIaIoC 1- 4 alkoxy.
  • the compound of formula (IE) is not 3-[(8-acetyl-2,2-difluoro-3-oxo- 2,3-dihydro-4H-1 ,4-benzoxazin-4-yl)methyl]- ⁇ /, ⁇ /-dimethylbenzamide and 2-[(8-acetyl- 2,2-difluoro-3-oxo-2,3-dihydro-4H-1 ,4-benzoxazin-4-yl)methyl]benzonitrile.
  • a compound of formula (IE), or a salt thereof, as defined above with the proviso that the compound of formula (IE) is not 3-[(8-acetyl-2,2-difluoro-3-oxo-2,3-dihydro-4H-1 ,4-benzoxazin-4-yl)methyl]benzonitrile; 2-[(8-acetyl-2,2-difluoro-3-oxo-2,3-dihydro-4H-1 ,4-benzoxazin-4-yl)methyl]benzonitrile; 8-acetyl-4- ⁇ [5-acetyl-2-(methyloxy)phenyl]methyl ⁇ -2,2-difluoro-2H-1 ,4-benzoxazin-3(4H)- one;
  • R 2 , R 3 and R 4 are independently selected from hydrogen, halo and cyano. In a further aspect, R 2 , R 3 and R 4 are independently selected from hydrogen and halo. In yet further aspect, R 2 is halo and R 3 and R 4 are hydrogen. In a further aspect, R 2 is fluoro and R 3 and R 4 are hydrogen. In a further aspect, R 2 , R 3 and R 4 are hydrogen.
  • R 1 is phenyl which is unsubstituted or substituted with 1 to 2 substituents independently selected from halo, C 1-4 alkyl, C 1-4 alkoxy, cyano, hydroxy, hydroxyC 1-4 alkyl, -(CH 2 ) n -(NR 1a R 1b ), -(CO)NR 1a R 1b , -(CO)O-C 1-4 alkyl, -(CO)OH, -(CHO), -SO 2 (NR 1a R 1b ), haloC 1-4 alkyl, haloC 1-4 alkoxy, -(CO)C 1-4 alkyl, C 2-4 alkenyl, -SC 1-4 alkyl and 5 to 6 membered heteroaryl ring which contains 1 to 4 heteroatoms independently selected from O, N and S.
  • R 1 is phenyl which is unsubstituted or substituted with 1 to 2 substituents independently selected from halo, C 1-4 alkyl, C
  • R 1 is phenyl which is unsubstituted or substituted with 1 to 2 substituents independently selected from halo, C 1-4 alkyl, C 1-4 alkoxy, cyano, hydroxy, hydroxyC 1-4 alkyl, -(CH 2 ) n -(NR 1a R 1b ), -(CO)NR 1a R 1b , -(CO)O-Ci -4 alkyl, -(CO)OH, -(CHO), -S0 2 (NR 1a R 1b ), haloCi_ 4 alkyl, haloCi -4 alkoxy, -(CO)Ci -4 alkyl, C 2-4 alkenyl, -SCi -4 alkyl and 5 to 6 membered heteroaryl ring which contains 1 to 4 heteroatoms independently selected from O, N and S; and wherein at least one substituent is attached to the 3-
  • R 1 is phenyl which is unsubstituted or substituted with 1 or 2 substituents independently selected from halo, cyano, -S0 2 (NR 1a R 1b ), haloCi. 4 alkyl, haloC 1-4 alkoxy, -(C0)NR 1a R 1b , -(CO)C 1-4 alkyl, C 2-4 alkenyl, -SC 1-4 alkyl and 5 to 6 membered heteroaryl ring which contains 1 to 4 heteroatoms independently selected from O, N and S.
  • R 1 is phenyl which is unsubstituted or substituted with 1 or 2 substituents independently selected from halo, cyano, -S0 2 (NR 1a R 1b ), haloCi. 4 alkyl, haloC 1-4 alkoxy, -(C0)NR 1a R 1b , -(CO)C 1-4 alkyl, C 2-4 alkenyl, -SC 1-4
  • R 1 is phenyl which is unsubstituted or substituted with 1 or 2 substituents independently selected from fluoro, chloro, cyano, methyl, methoxy, imidazolyl, ethenyl, - (CO)N(CH 3 ) 2 , -(CO)(CH 3 ), -SCH 3 and -SO 2 (NR 1a R 1b ).
  • R 1 is phenyl which is unsubstituted or substituted with 1 or 2 substituents independently selected from fluoro, cyano, methyl and methoxy.
  • R 1 is phenyl which is unsubstituted or substituted with 1 or 2 substituents independently selected from halo, cyano, hydroxy, hydroxyCi -4 alkyl, -(CH 2 ) n -(NR 1a R 1b ), -(CO)NR 1a R 1b , -(CO)O-Ci -4 alkyl, -(CHO), -SO 2 (NR 1a R 1b ), haloC ⁇ alkyl, haloCi_ 4 alkoxy, -(CO)Ci -4 alkyl, C 2-4 alkenyl, and 5 to 6 membered heteroaryl ring which contains 1 to 4 heteroatoms independently selected from O, N and S; R 2 , R 3 and R 4 are independently selected from hydrogen, halo, cyano and haloC 1-4 alkyl.
  • R 1 is phenyl which is unsubstituted or substituted with 1 or 2 substituents independently selected from halo, C 1-4 alkyl, C 1-4 alkoxy, cyano, -SO 2 (NR 1a R 1b ), FIaIoC 1- 4 alkyl, haloC 1-4 alkoxy, -(CO)C 1-4 alkyl, C 2-4 alkenyl, -SC 1-4 alkyl and 5 to 6 membered heteroaryl ring which contains 1 to 4 heteroatoms independently selected from O, N and S; R 2 , R 3 and R 4 are independently selected from hydrogen, halo and cyano.
  • R 1 is phenyl which is unsubstituted or substituted with 1 or 2 substituents independently selected from fluoro, chloro, cyano, methyl, methoxy, imidazolyl, ethenyl, - (CO)N(CH 3 ) 2 , -(CO)(CH 3 ), -SCH 3 and -S0 2 (NR 1a R 1b );
  • R 2 , R 3 and R 4 are independently selected from hydrogen and halo.
  • IE formula (IE), or a salt thereof wherein, R 1 is phenyl which is unsubstituted or substituted with 1 or 2 substituents independently selected from fluoro, cyano, methyl and methoxy; R 2 is halo and R 3 and R 4 are hydrogen, more particularly, R 2 is fluoro and R 3 and R 4 are hydrogen.
  • alkyl when used as a group or as part of a group refers to a straight or branched hydrocarbon chain containing the specified number of carbon atoms.
  • Ci -6 alkyl means a straight or branched hydrocarbon chain containing at least 1 and at most 6 carbon atoms.
  • alkyl examples include, but are not limited to; methyl (Me), ethyl (Et), n-propyl, i-propyl, t-butyl, n-hexyl and i-hexyl.
  • alkoxy when used as a group or as part of a group refers to an -O-alkyl group wherein alkyl is as defined hereinbefore.
  • alkoxy include, but are not limited to; methoxy, ethoxy, propoxy, butoxy, pentoxy or hexoxy.
  • halo is used herein to describe, unless otherwise stated, a group selected from fluoro (fluorine), chloro (chlorine), bromo (bromine) or iodo (iodine).
  • haloC 1-4 alkyl refers to a C 1-4 alkyl group as defined herein substituted with one or more halo groups which halo groups may be the same or different,.
  • haloC 1-4 alkyl include, but are not limited to; -CF 3 .CF 2 H or - CF 3 CH 2 .
  • haloC 1-4 alkoxy refers to a C 1-4 alkoxy group as defined herein substituted with one or more halo groups which halo groups may be the same or different, e.g. -0-CF 3 or difluoromethoxy.
  • -(CO)O-Ci -4 alkyl refers to a carboxylic acid ester group wherein Ci -4 alkyl is defined herein. Examples of include, but are not limited to; - (CO)O-methyl or -(CO)O-ethyl.
  • hydroxyC 1-4 alkyl refers to a C 1-4 alkyl group as defined herein substituted with one hydroxy group, e.g. -CH 2 CH 2 OH.
  • 5 to 6 membered heteroaryl ring refers to a 5 to 6 membered aromatic ring system which contains 1 to 3 heteroatoms selected from oxygen, nitrogen or sulphur.
  • 5-membered heteroaryl rings in this instance include furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, isothiazolyl, isoxazolyl, thienyl, pyrazolyl and tetrazolyl.
  • 6-membered heteroaryl rings include pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl and triazinyl.
  • 8 to 10 membered fused bicyclic ring system includes but is not limited to the following ring systems indolinyl, indolyl, isoindolinyl, isoindolyl, indenyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, benzoxadiazolyl,
  • benzotriazolyl benzoxazinyl, benzopyranyl, benzothiopyranyl, benzothiadiazolyl, quinolinyl, isoquinolinyl, chromenyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, furopyridinyl, naphthyl, dihydroquinolinyl, dihydroquinazolinyl,
  • dihydrobenzothienyl dihydrodioxinopyridinyl, dihydroindenyl, dihydropyrrolopyridinyl, dihydropyrrolopyrimidinyl, dihydropyrrolopyrazinyl, dihydropyrrolopyridazinyl,
  • pyrrolopyridinyl pyrrolopyrazinyl, pyrrolopyridazinyl, pyrrolopyrimidinyl, furopyrimidinyl, furopyrazinyl, furopyridazinyl, thienopyridinyl, thienopyrazinyl, thienopyrimidinyl, pyrazolopyridinyl, pyrazolopyrazinyl, pyrazolopyridazinyl,
  • pyridopyrimidinyl pyridooxazinyl, pyrazinooxazinyl, pyridazinooxazinyl, pyrimidooxazinyl, dihydropyridooxazinyl, dihydropyrazinooxazinyl, dihydropyridazinooxazinyl,
  • dihydrothienopyrimidinyl dihydrocyclopentapyridinyl, dihydrocyclopentapyrazinyl, dihydrocyclopentapyridazinyl, dihydrocyclopentapyrimidinyl, imidazothiazolyl and dihydrothienopyrazolyl.
  • salts includes salts prepared from pharmaceutically acceptable acids, including inorganic and organic acids. Such acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic,
  • Examples of pharmaceutically acceptable salts include those formed from maleic, fumaric, benzoic, ascorbic, pamoic, succinic, hydrochloric, sulfuric, bismethylenesalicylic, methanesulfonic, ethanedisulfonic, propionic, tartaric, salicylic, citric, gluconic, aspartic, stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, cyclohexylsulfamic, phosphoric and nitric acids.
  • the invention provides a prodrug of a compound as defined above.
  • Certain compounds as defined above are capable of existing in stereoisomeric forms (e.g. diastereomers and enantiomers) and the invention extends to each of these stereoisomeric forms and to mixtures thereof including racemates.
  • the different stereoisomeric forms may be separated one from the other by the usual methods, or any given isomer may be obtained by stereospecific or asymmetric synthesis.
  • the invention also extends to any tautomeric forms and mixtures thereof.
  • Certain compounds as defined above may also exhibit tautomerism within the R 1 moiety, and the present invention includes each such tautomer.
  • An example of a compound as defined above which exhibits tautomerism is
  • the subject invention also includes isotopically-labelled compounds, which are identical to the compounds as defined in the first to third aspect, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number most commonly found in nature.
  • isotopes that can be incorporated into compounds as defined in the first to third aspect include isotopes of hydrogen, carbon, nitrogen, fluorine, such as 3 H, 11 C, 14 C and 18 F.
  • isotopically-labelled compounds of the present invention for example those into which radioactive isotopes such as 3 H, 14 C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3 H, and carbon-14, i.e., 14 C, isotopes are particularly preferred for their ease of preparation and detectability. 11 C and 18 F isotopes are particularly useful in PET (positron emission tomography). PET is useful in brain imaging.
  • lsotopically labelled compounds of formula (I) and following of this invention can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples below, by substituting a readily available isotopically labelled reagent for a non-isotopically labelled reagent.
  • compounds as defined above or salts thereof are not isotopically labelled.
  • R 7 is chloro, iodo or bromo, for example bromo, or when R 7 is hydrogen, R 2 is fluoro, and L is a suitable leaving group such as halogen or methanesulfonate, for example bromo.
  • compounds of formula (III) may be prepared by the reduction of compounds of formula (II) under standard conditions, for example zinc in acetic acid and methanol, sodium hydrosulfite in ethanol and water, hydrogenation with palladium on carbon and Raney nickel with hydrazine. Alternatively they may be commercially available.
  • compounds of formula (IV) may be prepared by reacting compounds of formula (III) with an appropriate acylating agent, for example ethyl bromo(difluoro)acetate or bromo(difluoro)acetyl chloride, in a suitable solvent, for example ethyl acetate, tetrahydrofuran or 1 ,4-dioxane, in the presence of a suitable base, for example triethylamine or trimethylaluminium, at elevated temperature, for example at reflux.
  • an appropriate acylating agent for example ethyl bromo(difluoro)acetate or bromo(difluoro)acetyl chloride
  • a suitable solvent for example ethyl acetate, tetrahydrofuran or 1 ,4-dioxane
  • a suitable base for example triethylamine or trimethylaluminium
  • compounds of formula (V) may be prepared by heating compounds of formula (IV) at elevated temperature, for example 50 0 C, in a suitable solvent, for example N,N-dimethylformamide, in the presence of a suitable base, for example potassium carbonate.
  • compounds of formula (V) may be prepared by treating compounds of formula (III) with an appropriate acylating agent, for example ethyl bromo(difluoro)acetate or bromo(difluoro)acetyl chloride, in a suitable solvent, for example ⁇ /, ⁇ /-dimethylformamide, in the presence of a suitable base, for example sodium hydride.
  • organolithium compound for example n- butyllithium
  • an appropriate electrophile for example ethyl trifluoroacetate, ethyl difluoroacetate, ethyl fluoroacetate or 2,
  • compounds of formula (Vl), wherein R 6 may be -CH 3 or -CH 2 , -CHF 2 or - CF 3 may be prepared from compounds of formula (V) by treating compounds of formula (V) with an organolithium compound, for example n-butyllithium, and reacting the product with an appropriate electrophile, for example ethyl trifluoracetate, ethyl difluoroacetate or ethyl fluoroacetate, in a suitable solvent and at a suitable temperature, for example diethyl ether at -78 0 C.
  • organolithium compound for example n-butyllithium
  • an appropriate electrophile for example ethyl trifluoracetate, ethyl difluoroacetate or ethyl fluoroacetate
  • compounds of formula (Vl) may be prepared by treating compounds of formula (V) with a suitable reducing agent, for example sodium triacetoxyborohydride or a combination of (3aS)-1-methyl-3,3-diphenyltetrahydro-3H- pyrrolo[1 ,2-c][1 ,3,2]oxazaborole with borane-tetrahydrofuran complex, in a suitable solvent, for example 1 ,2-dichloroethane or tetrahydrofuran, at a suitable temperature, for example room temperature.
  • a suitable reducing agent for example sodium triacetoxyborohydride or a combination of (3aS)-1-methyl-3,3-diphenyltetrahydro-3H- pyrrolo[1 ,2-c][1 ,3,2]oxazaborole
  • a suitable solvent for example 1 ,2-dichloroethane or tetrahydrofuran
  • step (iv)a compounds of formula (VII) wherein R 6 is -CH 2 F, -CHF 2 or -CF 3 , may be prepared by treating compounds of formula (Vl) with a suitable reducing agent, for example sodium triacetoxyborohydride, in a suitable solvent, for example 1 ,2- dichloroethane, at a suitable temperature, for example room temperature.
  • a suitable reducing agent for example sodium triacetoxyborohydride
  • step (v) compounds of formula (I), wherein R 6 may be -CH 3 or -CH 2 , -CHF 2 or -CF 3 , may be prepared by reacting compounds of formula (Vl) or formula (VII) with compounds of formula (VIII), in a suitable solvent, for example ⁇ /, ⁇ /-dimethylformamide or acetonitrile, in the presence of a suitable base, for example potassium carbonate or triethylamine.
  • a suitable solvent for example ⁇ /, ⁇ /-dimethylformamide or acetonitrile
  • Compounds of formula (II) may be prepared according to known methods or may be commercially available.
  • R 1 is as defined in the first aspect, and A is hydrogen or
  • compounds of formula (X) can be prepared by treating compounds of formula (IX) with a suitable reducing agent, for example borane or sodium borohydride, in a suitable solvent, for example tetrahydrofuran or methanol. Alternatively they may be commercially available.
  • a suitable reducing agent for example borane or sodium borohydride
  • compounds of formula (Villa) may be prepared by treating compounds of formula (X) with a suitable brominating agent, for example concentrated hydrobromic acid at a suitable temperature, for example reflux, or phosphorus tribromide or bromo(trimethyl)silane in a suitable solvent, for example chloroform or diethyl ether.
  • a suitable brominating agent for example concentrated hydrobromic acid at a suitable temperature, for example reflux, or phosphorus tribromide or bromo(trimethyl)silane in a suitable solvent, for example chloroform or diethyl ether.
  • R 1 is as defined in the first aspect.
  • Compounds of formula (Villa) may be prepared by reacting compounds of formula (Xl) with a suitable brominating agent, such as N-bromosuccinimide, in the presence of suitable radical initiators, such as 2,2'-azobis(2-methylpropionitrile) or dibenzoyl peroxide, in a suitable solvent, such as carbon tetrachloride.
  • a suitable brominating agent such as N-bromosuccinimide
  • suitable radical initiators such as 2,2'-azobis(2-methylpropionitrile) or dibenzoyl peroxide
  • R 1 is as defined in the first aspect.
  • Compounds of formula (VIIIb) may be prepared by treating compounds of formula (X) with a suitable mesylating agent, for example methanesulfonyl chloride or
  • R 7 is chloro, iodo or bromo, for example bromo
  • L is a suitable leaving group such as halogen, for example bromo or chloro, or methanesulfonate.
  • compounds of formula (XII) may be prepared from compounds of formula (V) by treating compounds of formula (V) with an organolithium compound, for example n- butyllithium, and reacting the product with an appropriate electrophile, for example N, N- dimethylformamide, at a suitable temperature, for example -78 0 C, in a suitable solvent, for example diethyl ether.
  • organolithium compound for example n- butyllithium
  • an appropriate electrophile for example N, N- dimethylformamide
  • compounds of formula (Vila) may be prepared from compounds of formula (XII) by treating compounds of formula (XII) with a suitable source of trifluoromethyl anion, for example trimethyl(trifluoromethyl)silane in the presence of cesium fluoride, in a suitable solvent, for example tetrahydrofuran, at a suitable temperature, for example room temperature.
  • a suitable source of trifluoromethyl anion for example trimethyl(trifluoromethyl)silane in the presence of cesium fluoride, in a suitable solvent, for example tetrahydrofuran, at a suitable temperature, for example room temperature.
  • compounds of formula (Ia) may be prepared by reacting compounds of formula (Vila) with compounds of formula (VIII), in a suitable solvent, for example N, N- dimethylformamide, in the presence of a suitable base, for example potassium carbonate.
  • a suitable solvent for example N, N- dimethylformamide
  • the compounds as defined above inhibit the GIyTI transporter. Such compounds are therefore of potential utility for the treatment or prophylaxis of certain neurological and neuropsychiatric disorders. Furthermore, the compounds as defined above selectively inhibit the GIyTI transporter over the GlyT2 transporter.
  • disorders mediated by GIyTI refers to disorders that may be treated by the administration of a medicament that alters the activity of the GIyTI transporter.
  • disorders include neurological and neuropsychiatric disorders, including psychoses such as schizophrenia, dementia and other forms of impaired cognition such as attention deficit disorders and organic brain syndromes.
  • neuropsychiatric disorders include drug-induced (phencyclidine, ketamine and other dissociative anesthetics, amphetamine and other psychostimulants and cocaine) psychosis, psychosis associated with affective disorders, brief reactive psychosis, schizoaffective psychosis, and psychosis NOS, "schizophrenia-spectrum” disorders such as schizoid or schizotypal personality disorders, or illness associated with psychosis (such as major depression, manic depressive (bipolar) disorder, Alzheimer's disease and post-traumatic stress disorder), and NMDA receptor-related disorders such as autism, depression, benign forgetfulness, childhood learning disorders and closed head injury.
  • Other disorders include Parkinson's disease, dyskinetic disorders, cognitive impairment, emesis, movement disorders, amnesia, circadian rhythm disorders, aggression and vertigo.
  • the term “treatment” refers to symptomatic or prodromal treatment . In one embodiment, the term “treatment” refers to symptomatic treatment. In another embodiment, the term “treatment” refers to prodromal treatment.
  • the disorder mediated by GIyTI to be treated is a psychosis, including schizophrenia, dementia and attention deficit disorders. In one aspect, the disorder is schizophrenia.
  • the disorder mediated by GIyTI to be treated is posttraumatic stress disorder.
  • the disorder mediated by GIyTI to be treated is pain, epilepsy or
  • the term “effective amount” means that amount of a drug or
  • the compounds of formula (I) as defined above be of use in the treatment of schizophrenia including the subtypes Paranoid Type (295.30), Disorganised Type
  • Substance-Induced Psychotic Disorder including the subtypes With Delusions (293.81 ) and With Hallucinations (293.82); and Psychotic Disorder Not Otherwise Specified (298.9).
  • the compounds of formula (I) as defined above may be also of use in the treatment of mood disorders including Major Depressive Episode, Manic Episode, Mixed Episode and Hypomanic Episode; Depressive Disorders including Major Depressive Disorder, Dysthymic Disorder (300.4), Depressive Disorder Not Otherwise Specified (311 ); Bipolar Disorders including Bipolar I Disorder, Bipolar Il Disorder (Recurrent Major Depressive Episodes with Hypomanic Episodes) (296.89), Cyclothymic Disorder (301.13) and Bipolar Disorder Not Otherwise Specified (296.80); Other Mood Disorders including Mood Disorder Due to a General Medical Condition (293.83) which includes the subtypes With Depressive Features, With Major Depressive-like Episode, With Manic Features and With Mixed Features), Substance-Induced Mood Disorder (including the subtypes With Depressive Features, With Manic Features and With Mixed Features) and Mood Disorder Not Otherwise Specified (296.90).
  • the compounds of formula (I) as defined above may also be of use in the treatment of anxiety disorders including Panic Attack, Agoraphobia, Panic Disorder, Agoraphobia Without History of Panic Disorder (300.22), Specific Phobia (300.29) including the subtypes Animal Type, Natural Environment Type, Blood-lnjection-lnjury Type,
  • the compounds of formula (I) as defined above may also be of use in the treatment of substance-related disorders including Substance Use Disorders such as Substance Dependence and Substance Abuse; Substance-Induced Disorders such as Substance Intoxication, Substance Withdrawal, Substance-Induced Delirium, Substance-Induced Persisting Dementia, Substance-Induced Persisting Amnestic Disorder, Substance- Induced Psychotic Disorder, Substance-Induced Mood Disorder, Substance-Induced Anxiety Disorder, Substance-Induced Sexual Dysfunction, Substance-Induced Sleep Disorder and Hallucinogen Persisting Perception Disorder (Flashbacks); Alcohol-Related Disorders such as Alcohol Dependence (303.90), Alcohol Abuse (305.00), Alcohol Intoxication (303.00), Alcohol Withdrawal (291.81 ), Alcohol Intoxication Delirium, Alcohol Withdrawal Delirium, Alcohol-Induced Persisting Dementia, Alcohol-Induced Persisting Amnes
  • Amphetamine (or Amphetamine-I_ike)-Related Disorders such as Amphetamine
  • Amphetamine Induced Psychotic Disorder Amphetamine-Induced Mood Disorder, Amphetamine-Induced Anxiety Disorder, Amphetamine-Induced Sexual Dysfunction, Amphetamine-Induced Sleep Disorder and Amphetamine-Related Disorder Not
  • Caffeine Related Disorders such as Caffeine Intoxication (305.90), Caffeine-Induced Anxiety Disorder, Caffeine-Induced Sleep Disorder and Caffeine-Related Disorder Not Otherwise Specified (292.9); Cannabis-Related Disorders such as Cannabis Dependence (304.30), Cannabis Abuse (305.20), Cannabis
  • Nicotine-Related Disorders such as Nicotine Dependence (305.1 ), Nicotine Withdrawal (292.0) and Nicotine-Related Disorder Not Otherwise Specified (292.9); Opioid-Related Disorders such as Opioid Dependence (304.00), Opioid Abuse (305.50), Opioid Intoxication (292.89), Opioid Withdrawal (292.0), Opioid Intoxication Delirium, Opioid-lnduced Psychotic Disorder, Opioid-lnduced Mood Disorder, Opioid-lnduced Sexual Dysfunction, Opioid-lnduced Sleep Disorder and Opioid-Related Disorder Not Otherwise Specified (292.9);
  • Phencyclidine or Phencyclidine-Like-Related Disorders such as Phencyclidine
  • Sedative-, Hypnotic-, or Anxiolytic-Related Disorders such as Sedative, Hypnotic, or Anxiolytic Dependence (304.10), Sedative, Hypnotic, or Anxiolytic Abuse (305.40), Sedative, Hypnotic, or Anxiolytic Intoxication (292.89), Sedative, Hypnotic, or Anxiolytic Withdrawal (292.0), Sedative, Hypnotic, or Anxiolytic Intoxication Delirium, Sedative, Hypnotic, or Anxiolytic Withdrawal Delirium, Sedative-, Hypnotic-, or Anxiolytic-Persisting
  • Anxiolytic-lnduced Sexual Dysfunction Sedative-, Hypnotic-, or Anxiolytic-lnduced Sleep Disorder and Sedative-, Hypnotic-, or Anxiolytic-Related Disorder Not Otherwise
  • the compounds of formula (I) as defined above may also be of use in the treatment of sleep disorders including primary sleep disorders such as Dyssomnias such as Primary Insomnia (307.42), Primary Hypersomnia (307.44), Narcolepsy (347), Breathing-Related Sleep Disorders (780.59), Circadian Rhythm Sleep Disorder (307.45) and Dyssomnia Not Otherwise Specified (307.47); primary sleep disorders such as Parasomnias such as Nightmare Disorder (307.47), Sleep Terror Disorder (307.46), Sleepwalking Disorder (307.46) and Parasomnia Not Otherwise Specified (307.47); Sleep Disorders Related to Another Mental Disorder such as Insomnia Related to Another Mental Disorder (307.42) and Hypersomnia Related to Another Mental Disorder (307.44); Sleep Disorder Due to
  • the compounds of formula (I) as defined above may also be of use in the treatment of eating disorders such as Anorexia Nervosa (307.1 ) including the subtypes Restricting Type and Binge-Eating/Purging Type; Bulimia Nervosa (307.51 ) including the subtypes Purging Type and Nonpurging Type; Obesity; Compulsive Eating Disorder; and Eating Disorder Not Otherwise Specified (307.50).
  • eating disorders such as Anorexia Nervosa (307.1 ) including the subtypes Restricting Type and Binge-Eating/Purging Type; Bulimia Nervosa (307.51 ) including the subtypes Purging Type and Nonpurging Type; Obesity; Compulsive Eating Disorder; and Eating Disorder Not Otherwise Specified (307.50).
  • the compounds of formula (I) as defined above may also be of use in the treatment of Autistic Disorder (299.00); Attention-Deficit /Hyperactivity Disorder including the subtypes Attention-Deficit /Hyperactivity Disorder Combined Type (314.01 ), Attention-Deficit /Hyperactivity Disorder Predominantly Inattentive Type (314.00), Attention-Deficit /Hyperactivity Disorder Hyperactive-Impulse Type (314.01 ) and Attention-Deficit
  • Disruptive Behaviour Disorders such as Conduct Disorder including the subtypes childhood-onset type (321.81 ), Adolescent-Onset Type (312.82) and Unspecified Onset (312.89), Oppositional Defiant Disorder (313.81 ) and Disruptive Behaviour Disorder Not Otherwise Specified; and Tic Disorders such as Tourette's Disorder (307.23).
  • the compounds of formula (I) as defined above may also be of use in the treatment of Personality Disorders including the subtypes Paranoid Personality Disorder (301.0), Schizoid Personality Disorder (301.20), Schizotypal Personality Disorder (301 ,22), Antisocial Personality Disorder (301.7), Borderline Personality Disorder (301 ,83), Histrionic Personality Disorder (301.50), Narcissistic Personality Disorder (301 ,81 ), Avoidant Personality Disorder (301.82), Dependent Personality Disorder (301.6), Obsessive-Compulsive Personality Disorder (301.4) and Personality Disorder Not Otherwise Specified (301.9).
  • the compounds of formula (I) as defined above may also be of use in the treatment of cognitive impairment.
  • the term cognitive impairment includes for example the treatment or prophylaxis of impairment of cognitive functions including attention, orientation, learning disorders, memory (i.e. memory disorders, amnesia, amnesic disorders, transient global amnesia syndrome and age- associated memory impairment) and language function; cognitive impairment as a result of stroke, Alzheimer's disease, Huntington's disease, Pick disease, Aids-related dementia or other dementia states such as Multiinfarct dementia, alcoholic dementia, hypotiroidism-related dementia, and dementia associated to other degenerative disorders such as cerebellar atrophy and amyotropic lateral sclerosis; other acute or sub-acute conditions that may cause cognitive decline such as delirium or depression
  • Parkinson's disease trauma, head trauma, age related cognitive decline, stroke, neurodegeneration, drug-induced states, neurotoxic agents, mild cognitive impairment, age related cognitive impairment, autism related cognitive impairment, Down's syndrome, cognitive deficit related to psychosis, and post-electroconvulsive treatment or prophylaxis related cognitive disorders; and dyskinetic disorders such as Parkinson's disease, neuroleptic-induced parkinsonism, and tardive dyskinesias.
  • the compounds of formula (I) as defined above may also be of use for the treatment of cognition impairment which arises in association or as a result of other diseases such as schizophrenia, bipolar disorder, depression, other psychiatric disorders and psychotic conditions associated with cognitive impairment.
  • the compounds of formula (I) as defined above may also be of use in the treatment of sexual dysfunctions including sexual Desire Disorders such as Hypoactive Sexual Desire Disorder (302.71 ), and sexual Aversion Disorder (302.79); sexual arousal disorders such as Female Sexual Arousal Disorder (302.72) and Male Erectile Disorder (302.72);
  • orgasmic disorders such as Female Orgasmic Disorder (302.73), Male Orgasmic
  • the compounds of formula (I) as defined above may also be of use as anticonvulsants.
  • the compounds of formula (I) as defined above are thus useful in the treatment of convulsions in mammals, and particularly epilepsy in humans. "Epilepsy” is intended to include the following seizures: simple partial seizures, complex partial seizures, secondary generalised seizures, generalised seizures including absence seizures, myoclonic seizures, clonic seizures, tonic seizures, tonic clonic seizures and atonic seizures.
  • the invention also provides a method of treating convulsions, which comprises administering to a mammal in need thereof an effective amount of a compound of the invention as hereinbefore described or a salt thereof.
  • Treatment of epilepsy may be carried out by the administration of a non-toxic anticonvulsant effective amount of a compound of the formula (I) or a salt thereof.
  • the compounds of formula (I) as defined above may also be useful in the treatment of pain, including acute pain, chronic pain, chronic articular pain, musculoskeletal pain, neuropathic pain, inflammatory pain, visceral pain, pain associated with cancer, pain associated with migraine, tension headache and cluster headaches, pain associated with functional bowel disorders, lower back and neck pain, pain associated with sprains and strains, sympathetically maintained pain; myositis, pain associated with influenza or other viral infections such as the common cold, pain associated with rheumatic fever, pain associated with myocardial ischemia, post operative pain, cancer chemotherapy, headache, toothache and dysmenorrhea.
  • 'Chronic articular pain' conditions include rheumatoid arthritis, osteoarthritis, rheumatoid spondylitis, gouty arthritis and juvenile arthritis.
  • 'Pain associated with functional bowel disorders' includes non-ulcer dyspepsia, non- cardiac chest pain and irritable bowel syndrome.
  • 'Neuropathic pain' syndromes include: diabetic neuropathy, sciatica, non-specific lower back pain, trigeminal neuralgia, multiple sclerosis pain, fibromyalgia, HIV-related neuropathy, post-herpetic neuralgia, trigeminal neuralgia, and pain resulting from physical trauma, amputation, phantom limb syndrome, spinal surgery, cancer, toxins or chronic inflammatory conditions.
  • neuropathic pain conditions include pain associated with normally non-painful sensations such as "pins and needles" (paraesthesias and dysesthesias), increased sensitivity to touch (hyperesthesia), painful sensation following innocuous stimulation (dynamic, static, thermal or cold allodynia), increased sensitivity to noxious stimuli (thermal, cold, mechanical hyperalgesia), continuing pain sensation after removal of the stimulation (hyperpathia) or an absence of or deficit in selective sensory pathways (hypoalgesia).
  • normally non-painful sensations such as "pins and needles” (paraesthesias and dysesthesias), increased sensitivity to touch (hyperesthesia), painful sensation following innocuous stimulation (dynamic, static, thermal or cold allodynia), increased sensitivity to noxious stimuli (thermal, cold, mechanical hyperalgesia), continuing pain sensation after removal of the stimulation (hyperpathia) or an absence of or deficit in selective sensory pathways (hypoalgesia).
  • neurodegenerative diseases and neurodegeneration include neurodegenerative diseases and neurodegeneration, neurodegeneration following trauma, tinnitus, dependence on a dependence-inducing agent such as opioids (e.g. morphine), CNS depressants (e.g. ethanol), psychostimulants (e.g. cocaine) and nicotine.
  • opioids e.g. morphine
  • CNS depressants e.g. ethanol
  • psychostimulants e.g. cocaine
  • Neurodegenerative diseases include dementia, particularly degenerative dementia (including senile dementia, dementia with Lewy bodies, Alzheimer's disease, Pick's disease, Huntingdon's chorea, Parkinson's disease and Creutzfeldt-Jakob disease, ALS, motor neuron disease); vascular dementia (including multi-infarct dementia); as well as dementia associated with intracranial space occupying lesions; trauma; infections and related conditions (including HIV infection, meningitis and shingles); metabolism; toxins; anoxia and vitamin deficiency; and mild cognitive impairment associated with ageing, particularly Age Associated Memory Impairment.
  • degenerative dementia including senile dementia, dementia with Lewy bodies, Alzheimer's disease, Pick's disease, Huntingdon's chorea, Parkinson's disease and Creutzfeldt-Jakob disease, ALS, motor neuron disease
  • vascular dementia including multi-infarct dementia
  • dementia associated with intracranial space occupying lesions trauma
  • infections and related conditions including HIV infection, meningitis and shingles
  • Another condition which could potentially be treated by compounds of formula (I) as defined above is spasticity or muscular hypertonicity.
  • disorders include benign forgetfulness, childhood learning disorders and closed head injury, Parkinson's disease, dyskinetic disorders, cognitive impairment, emesis, movement disorders, amnesia, circadian rhythm disorders, aggression and vertigo.
  • a method of treatment of a disorder mediated by GIyTI comprises the administration of a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof.
  • a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in the treatment of a disorder mediated by GIyTI .
  • the disorder mediated by GIyTI to be treated by the use or method as hereinbefore described is a psychosis, including schizophrenia, dementia and attention deficit disorders.
  • the disorder is schizophrenia.
  • composition comprising a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, adapted for use in human or veterinary medicine.
  • the present invention also provides a pharmaceutical composition, which comprises a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable excipient.
  • a pharmaceutical composition of the invention is usually adapted for oral, sub-lingual, buccal, parenteral (for example, subcutaneous, intramuscular, or intravenous), rectal, topical and intranasal administration and in forms suitable for administration by inhalation or insufflation (either through the mouth or nose).
  • parenteral for example, subcutaneous, intramuscular, or intravenous
  • rectal topical and intranasal administration and in forms suitable for administration by inhalation or insufflation (either through the mouth or nose).
  • inhalation or insufflation either through the mouth or nose.
  • oral administration is provided.
  • compositions suitable for oral administration may be provided as discrete units, such as tablets, capsules, cachets, or lozenges, each containing a predetermined amount of the active compound; as powders or granules; as solutions or suspensions in aqueous or non-aqueous liquids; or as oil-in-water or water-in-oil emulsions.
  • Compositions suitable for sublingual or buccal administration include lozenges comprising the active compound and, typically, a flavoured base, such as sugar and acacia or tragacanth and pastilles comprising the active compound in an inert base, such as gelatin and glycerin or sucrose and acacia.
  • compositions suitable for parenteral administration typically comprise sterile aqueous solutions containing a predetermined concentration of the active compound; the solution may be isotonic with the blood of the intended recipient. Such solutions may be administered intravenously or by subcutaneous or intramuscular injection.
  • compositions suitable for rectal administration may be provided as unit-dose
  • compositions suitable for topical or intranasal application include ointments, creams, lotions, pastes, gels, sprays, aerosols and oils.
  • Suitable carriers for such compositions include petroleum jelly, lanolin, polyethylene glycols, alcohols, and combinations thereof.
  • compositions of the invention may be prepared by any suitable method, typically by uniformly and intimately admixing the active compound(s) with liquids or finely divided solid carriers, or both, in the required proportions and then, if necessary, shaping the resulting mixture into the desired shape.
  • a tablet may be prepared by compressing an intimate mixture comprising a powder or granules of the active ingredient and one or more optional ingredients, such as a binder, lubricant, inert diluent, or surface active dispersing agent, or by moulding an intimate mixture of powdered active ingredient and inert liquid diluent.
  • one or more optional ingredients such as a binder, lubricant, inert diluent, or surface active dispersing agent, or by moulding an intimate mixture of powdered active ingredient and inert liquid diluent.
  • Aqueous solutions for parenteral administration are typically prepared by dissolving the active compound in sufficient water to give the desired concentration and then rendering the resulting solution sterile and isotonic.
  • the compound may be administered in single or divided doses and may be administered one or more times, for example 1 to 4 times per day.
  • a proposed dose of the active ingredient for use according to the invention for oral, sublingual, parenteral, buccal, rectal, intranasal or topical administration to a human (of approximately 70 kg bodyweight) for the treatment of neurological and neuropsychiatric disorders mediated by a GIyTI inhibitor, including schizophrenia, may be about 0.1 to about 1000 mg, for example about 0.5 mg to about 1000mg, or about 1 mg to about 1000 mg, or about 5 mg to about 500 mg, or about 10 mg to about 100 mg of the active ingredient per unit dose, which could be administered, for example, 1 to 4 times per day.
  • the composition may contain from 0.1% to 99% by weight, preferably from 10% to 60% by weight, of the active material, depending on the method of administration.
  • the dose of the compound of formula (I) as defined above or a pharmaceutically acceptable salt thereof used in the treatment or prophylaxis of the aforementioned disorders will vary in the usual way with the seriousness of the disorders, the weight of the sufferer, and other similar factors.
  • suitable unit doses may be 0.05 to 1000 mg, more suitably 1.0 to 200 mg, and such unit doses may be administered more than once a day, for example two or three a day. Such therapy may extend for a number of weeks, months, years or even life.
  • a further aspect to the invention is a pharmaceutical composition
  • a pharmaceutical composition comprising 0.05 to IOOOmg of a compound as defined in the first to third aspect or a pharmaceutically acceptable salt thereof, and 0 to 3 g more suitably 0 to 2g of at least one pharmaceutically acceptable carrier.
  • a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof may be suitable for combination with other active ingredients.
  • the compounds may be administered either sequentially or simultaneously by any convenient route.
  • the compounds of formula (I) as defined above may be used in combination with the following agents to treat or prevent psychotic disorders: i) antipsychotics; ii) drugs for extrapyramidal side effects, for example anticholinergics (such as benztropine, biperiden, procyclidine and trihexyphenidyl), antihistamines (such as diphenhydramine) and dopaminergics (such as amantadine); iii) antidepressants; iv) anxiolytics; and v) cognitive enhancers for example cholinesterase inhibitors (such as tacrine, donepezil, rivastigmine and galantamine).
  • the compounds of formula (I) as defined above may be used in combination with antidepressants to treat or prevent depression and mood disorders.
  • the compounds of formula (I) as defined above may be used in combination with the following agents to treat or prevent bipolar disease: i) mood stabilisers; ii) antipsychotics; and iii) antidepressants.
  • the compounds of formula (I) as defined above may be used in combination with the following agents to treat or prevent anxiety disorders: i) anxiolytics; and ii) antidepressants.
  • the compounds of formula (I) as defined above may be used in combination with the following agents to improve nicotine withdrawal and reduce nicotine craving: i) nicotine replacement therapy for example a sublingual formulation of nicotine beta-cyclodextrin and nicotine patches; and ii) bupropion.
  • NMDA receptor antagonists for example acamprosate
  • GABA receptor agonists for example tetrabamate
  • Opioid receptor antagonists for example naltrexone
  • the compounds of formula (I) as defined above may be used in combination with the following agents to improve opiate withdrawal and reduce opiate craving: i) opioid mu receptor agonist/opioid kappa receptor antagonist for example buprenorphine; ii) opioid receptor antagonists for example naltrexone; and iii) vasodilatory antihypertensives for example lofexidine.
  • opioid mu receptor agonist/opioid kappa receptor antagonist for example buprenorphine
  • opioid receptor antagonists for example naltrexone
  • vasodilatory antihypertensives for example lofexidine.
  • the compounds of formula (I) as defined above may be used in combination with the following agents to treat or prevent sleeping disorders: i) benzodiazepines for example temazepam, lormetazepam, estazolam and triazolam; ii) non-benzodiazepine hypnotics for example Zolpidem, zopiclone, zaleplon and indiplon; iii) barbiturates for example aprobarbital, butabarbital, pentobarbital, secobarbita and phenobarbital; iv) antidepressants; v) other sedative-hypnotics for example chloral hydrate and chlormethiazole.
  • benzodiazepines for example temazepam, lormetazepam, estazolam and triazolam
  • non-benzodiazepine hypnotics for example Zolpidem, zopiclone, zaleplon and indiplon
  • the compounds of formula (I) as defined above may be used in combination with the following agents to treat anorexia: i) appetite stimulants for example cyproheptidine; ii) antidepressants; iii) antipsychotics; iv) zinc; and v) premenstral agents for example pyridoxine and progesterones.
  • the compounds of formula (I) as defined above may be used in combination with the following agents to treat or prevent bulimia: i) antidepressants; ii) opioid receptor antagonists; iii) antiemetics for example ondansetron; iv) testosterone receptor antagonists for example flutamide; v) mood stabilisers; vi) zinc; and vii) premenstral agents.
  • the compounds of formula (I) as defined above may be used in combination with the following agents to treat or prevent autism: i) antipsychotics; ii) antidepressants; iii) anxiolytics; and iv) stimulants for example methylphenidate, amphetamine formulations and pemoline.
  • the compounds of formula (I) as defined above may be used in combination with the following agents to treat or prevent ADHD: i) stimulants for example methylphenidate, amphetamine formulations and pemoline; and ii) non-stimulants for example norepinephrine reuptake inhibitors (such as atomoxetine), alpha 2 adrenoceptor agonists (such as clonidine), antidepressants, modafinil, and cholinesterase inhibitors (such as galantamine and donezepil).
  • stimulants for example methylphenidate, amphetamine formulations and pemoline
  • non-stimulants for example norepinephrine reuptake inhibitors (such as atomoxetine), alpha 2 adrenoceptor agonists (such as clonidine), antidepressants, modafinil, and cholinesterase inhibitors (such as galantamine and donezepil).
  • the compounds of formula (I) as defined above may be used in combination with the following agents to treat personality disorders: i) antipsychotics; ii) antidepressants; iii) mood stabilisers; and iv) anxiolytics.
  • the compounds of formula (I) as defined above may be used in combination with the following agents to treat or prevent male sexual dysfunction: i) phosphodiesterase V inhibitors, for example vardenafil and sildenafil; ii) dopamine agonists/dopamine transport inhibitors for example apomorphine and buproprion; iii) alpha adrenoceptor antagonists for example phentolamine; iv) prostaglandin agonists for example alprostadil; v) testosterone agonists such as testosterone; vi) serotonin transport inhibitors for example serotonin reuptake inhibitors; v) noradrenaline transport inhibitors for example reboxetine and vii) 5-HT1 A agonists, for example flibanserine.
  • phosphodiesterase V inhibitors for example vardenafil and sildenafil
  • dopamine agonists/dopamine transport inhibitors for example apomorphine and buproprion
  • antipsychotic drugs that may be useful in combination with a compound as defined in the first to third aspect include, but are not limited to: butyrophenones, such as haloperidol, pimozide, and droperidol; phenothiazines, such as chlorpromazine, thioridazine, mesoridazine, trifluoperazine, perphenazine, fluphenazine, thiflupromazine, prochlorperazine, and acetophenazine; thioxanthenes, such as thiothixene and chlorprothixene ; thienobenzodiazepines; dibenzodiazepines; benzisoxazoles; dibenzothiazepines; imidazolidinones ; benzisothiazoly
  • Examples of tradenames and suppliers of selected antipsychotic drugs are as follows: amisulpride (SOLIAN(D), clozapine (available under the tradename CLOZARIL®, from Mylan, Zenith Goldline, UDL, Novartis); olanzapine (available under the tradename ZYPREX®, from Lilly; ziprasidone (available under the tradename GEODON®, from Pfizer); risperidone (available under the tradename RISPERDAL®, from Janssen); quetiapine fumarate (available under the tradename SEROQUEL®, from AstraZeneca); haloperidol (available under the tradename HALDOL®, from Ortho-McNeil); chlorpromazine (available under the tradename THORAZINE®, from SmithKline Beecham (GSK); fluphenazine (available under the tradename PROLIXIN®, from Apothecon, Copley, Schering, Teva, and American Pharmaceutical Partners, Pasadena);
  • benperidol (Glianimon®), perazine (Taxilan®) or melperone (Eunerpan®)) may be used.
  • Other antipsychotic drugs include promazine (available under the tradename SPARINE®), triflurpromazine (available under the tradename VESPRIN®), chlorprothixene (available under the tradename TARACTAN®), droperidol (available under the tradename INAPSINE®), acetophenazine (available under the tradename TINDAL®;), prochlorperazine (available under the tradename COMPAZINE®), methotrimeprazine (available under the tradename NOZINAN®), pipotiazine (available under the tradename PIPOTRIL®), ziprasidone, and hoperidone.
  • promazine available under the tradename SPARINE®
  • triflurpromazine available under the tradename VESPRIN®
  • chlorprothixene available under the tradename TARACTAN®
  • droperidol
  • Antidepressant drugs include serotonin reuptake inhibitors (such as citalopram, escitalopram, fluoxetine, paroxetine, dapoxetine and sertraline); dual serotonin/noradrenaline reuptake inhibitors (such as venlafaxine, duloxetine and milnacipran); Noradrenaline reuptake inhibitors (such as reboxetine); tricyclic antidepressants (such as amitriptyline, clomipramine, imipramine, maprotiline, nortriptyline and trimipramine); monoamine oxidase inhibitors (such as isocarboxazide, moclobemide, phenelzine and tranylcypromine); and others (such as bupropion, mianserin, mirtazapine, nefazodone and trazodone).
  • Mood stabiliser drugs include lithium, sodium valproate/valproic acid/divalpro
  • Anxiolytics include benzodiazepines such as alprazolam and lorazepam. It will be appreciated by those skilled in the art that the compounds of formula (I) as defined above may be used in conjunction with one or more other therapeutic agents, for instance, antidepressant agents such as 5HT3 antagonists, serotonin agonists, NK1 antagonists, NK3 antagonists, AMPA modulators, alpha7 positive modulators, 5HT6 antagonists, 5HT2A antagonists, selective serotonin reuptake inhibitors (SSRI), noradrenaline re-uptake inhibitors (SNRI), tricyclic antidepressants, dopaminergic antidepressants, H3 antagonists, 5HT1A antagonists, 5HT1 B antagonists, 5HT1 D antagonists, D1 agonists, M1 and M1/4 muscarinic agonists and/or anticonvulsant agents, as well as cognitive enhancers.
  • antidepressant agents such as 5HT3 antagonists, serotonin
  • the compound of formula (I) as defined above or a pharmaceutically acceptable salt thereof may be used in combination with other medicaments indicated to be useful in the treatment of pain of neuropathic origin including neuralgias, neuritis and back pain, and inflammatory pain including osteoarthritis, rheumatoid arthritis, acute inflammatory pain, back pain and migraine.
  • Such therapeutic agents include for Compound COX-2 (cyclooxygenase-2 ) inhibitors, such as celecoxib, deracoxib, rofecoxib, valdecoxib, parecoxib, COX-189 or 2-(4-ethoxy- phenyl)-3-(4-methanesulfonyl-phenyl)-pyrazolo[1 ,5-b]pyridazine (WO99/012930); 5- lipoxygenase inhibitors; NSAIDs (non-steroidal anti-inflammatory drugs) such as diclofenac, indomethacin, nabumetone or ibuprofen; bisphosphonates, leukotriene receptor antagonists; DMARDs (disease modifying anti-rheumatic drugs) such as methotrexate; adenosine A1 receptor agonists; sodium channel blockers, such as lamotrigine; NMDA (N-methyl-D-aspartate)
  • the compound of formula (I) as defined above or a pharmaceutically acceptable salt thereof may be used in combination with other medicaments indicated to be useful as either disease modifying or
  • Suitable examples of such other therapeutic agents may be agents known to modify cholinergic transmission such as 5-HT 1A antagonists, (e.g. lecozotan), 5-HT6
  • M1 muscarinic agonists M2 muscarinic antagonist
  • acetylcholinesterase inhibitors e.g tetrahydroaminoacridine, donepezil or rivastigmine
  • allosteric modulators nicotinic receptor agonists or allosteric modulators
  • symptomatic agents such as 5-HT6 receptor antagonists, e.g. SB742457, H3 receptor antagonists e.g.
  • GSK189254 and GSK239512 5-HT4 receptor agonist, PPAR agonists, also NMDA receptor antagonists or modulators, also disease modifying agents such as ⁇ or v- secretase inhibitors (e.g. R-flurbiprofen), also AMPA positive modulators.
  • the reaction mixture was quenched with water (20 ml) then acidified with 1 M hydrochloric acid and extracted with EtOAc (50 ml. X 3). The combined organic solutions were washed with brine (50 ml_), dried over magnesium sulfate, filtered and evaporated to dryness to give the crude product as a pale yellow solid.
  • the crude product was purified on a 40+M Biotage silica cartridge, eluting with a 0 to 20 % mixture of EtOAc in hexane, graduated over 10 CV. This gave two batches of material containing the target compound.
  • the second batch was purified again on a 40+M Biotage silica cartridge, eluting with a 0 to 20 % mixture of EtOAc in hexane, graduated over 20 CV. Each batch was triturated three times with hexane to give the target compound (632 mg) as an off-white solid, m/z [M-H] " : 212.2. Retention time 0.75 min (LC/MS method 3).
  • 2,2-Difluoro-3-oxo-3,4-dihydro-2H-1 ,4-benzoxazine-8-carbaldehyde (100 mg; may be prepared as described in intermediate 4) and trimethyl(trifluoromethyl)silane (83 ⁇ l; Aldrich) were dissolved in THF (2 ml) in a 25 ml. round-bottomed flask flushed with argon, cooled to 0 0 C, treated with cesium fluoride (7.13 mg) and stirred at 0 0 C for 1 hr. An excess of cesium fluoride was added, the reaction mixture warmed to room temperature and stirring continued overnight. A further portion of
  • trimethyl(trifluoromethyl)silane (83 ⁇ l) was added and stirring at room temperature continued for 3 hr. A further portion of trimethyl(trifluoromethyl)silane (83 ⁇ l) was added, giving an exotherm and a colour change from opaque yellow to a clear red/brown solution. Stirring continued for 40 minutes. A further portion of
  • 2,2-Difluoro-8-(trifluoroacetyl)-2H-1 ,4-benzoxazin-3(4H)-one (1.45 g; may be prepared as described in intermediate 6) was dissolved in 1 ,2-dichloroethane (25.8 ml) in a 10 ml_ round-bottomed flask flushed with argon, treated with sodium triacetoxyborohydride (1.202 g) and stirred at room temperature for 2 days. Sodium triacetoxyborohydride (1.093g) was added to the reaction mixture and stirred at room temperature for 3 hours. Sodium triacetoxyborohydride (1.093g) was added to the reaction mixture and stirred at room temperature for 2 hours.
  • the title compound (30 mg) was prepared by a similar method to 2,2-difluoro-8-(2,2,2- trifluoro-1-hydroxyethyl)-2H-1 ,4-benzoxazin-3(4H)-one (may be prepared as described in intermediate 5, method B), replacing 2,2-difluoro-8-(trifluoroacetyl)-2H-1 ,4-benzoxazin- 3(4H)-one with 2,2-difluoro-8-(fluoroacetyl)-2H-1 ,4-benzoxazin-3(4H)-one (may be prepared as described in intermediate 9).
  • m/z [M-H] " 246.3. Retention time 0.74 min (LC/MS method 3).
  • Racemic 8-(2,2-difluoro-1-hydroxyethyl)-2-fluoro-2H-1 ,4-benzoxazin-3(4H)-one (470 mg; may be prepared as described in intermediate 10) was resolved using a Chiralcel OJ column eluting with heptane: ethanol (90:10) v/v pump-mixed. Using these conditions the faster-running enantiomer (175 mg, intermediate 15 or 16) and the slower-running enantiomer (145 mg, intermediate 15 or 16) were obtained in >99.8% enantiomeric excess, m/z [M-H] " : 246.0. Retention time 0.66 min (LC/MS method 3).
  • 2,2,7-Trifluoro-2H-1 ,4-benzoxazin-3(4/-/)-one (1.026 g; may be prepared as described in intermediate 19) was dissolved in THF (16 ml.) in a 150 ml. round bottomed flask flushed with argon, and cooled to -78 0 C. BuLi (6.95 ml_, 1.6 M in hexanes) was added dropwise and stirring continued at -78 0 C for 30 min. Ethyl trifluoroacetate (2.404 ml.) was added and stirring at -78 0 C continued for 3 hr. The reaction mixture was warmed to RT and stirred for 1.5 hr.
  • the reaction mixture was quenched with MeOH, poured into 2M hydrochloric acid (25 ml_), treated with water (50 ml.) and extracted with EtOAc (3 x 50 ml_). The organic layers were combined, washed with brine (100 ml_), dried over magnesium sulfate, filtered and evaporated to dryness to give a yellow oil (2.276 g).
  • the crude product was purified on a 10Og Biotage silica cartridge, eluting with a 0 to 50 % mixture of EtOAc in hexane, to give a yellow oil (1.1 g). This was dissolved in 1 ,2- dichloroethane (20 ml.) in a 50 ml.
  • Racemic 2,2-difluoro-8-(2,2,2-trifluoro-1-hydroxyethyl)-2/-/-1 ,4-benzoxazin-3(4/-/)-one (2.49 g; may be prepared as described in intermediate 5) was resolved using a Chiralcel OJ column eluting with heptane (+ 0.1% trifluoroacetic acid) / ethanol (+ 0.1 %
  • a suspension of 8-acetyl-2,2-difluoro-4- ⁇ [3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl]methyl ⁇ -2H-1 ,4-benzoxazin-3(4H)-one (100 mg, 0.23 mmol, may be prepared as described in intermediate 28) and phenylboronic acid (56 mg, 0.46 mmol) in 3 N hydrochloric acid (5 ml.) was stirred for 16 hr at 80 0 C then diluted with EtOAc (15 ml_). It was washed with water (10 ml.
  • the target compound (264 mg) was made in a similar manner to the preparation of 8- bromo-2,2-difluoro-2H-1 ,4-benzoxazin-3(4/-/)-one (may be prepared as described in intermediate 3), replacing 2-bromo- ⁇ /-(3-bromo-2-hydroxyphenyl)-2,2-difluoroacetamide with ⁇ /-(3-acetyl-6-fluoro-2-hydroxyphenyl)-2-bromo-2,2-difluoroacetamide (may be prepared as described in intermediate 9).
  • m/z [M-H] " 243.9. Retention time 0.78 min (LC/MS method 3).
  • the reaction mixture was evaporated to dryness under reduced pressure and the residue redissolved in EtOAc (20 ml.) then washed with a saturated aqueous solution of ammonium chloride (20 ml_). This aqueous solution was extracted with further portions of EtOAc (20 ml. X 2) and the combined organic solutions dried over magnesium sulfate, filtered and evaporated to dryness to give the crude product (155 mg) as a colourless oil.
  • the crude product was purified on a 12+M Biotage silica cartridge, eluting with a 0 to 50 % mixture of ethyl acetate in hexane to give the racemic target compound (95 mg) as a white solid.
  • 2,2-difluoro-8-(2,2,2-trifluoro-1-hydroxyethyl)-2H-1 ,4-benzoxazin-3(4H)-one 150 mg; may be prepared as described in intermediate 5
  • (2-fluoro-4-pyridinyl)methyl methanesulfonate 130 mg; may be prepared as described in intermediate 12
  • potassium carbonate 146 mg, 1.060 mmol
  • the reaction mixture was evaporated to dryness under reduced pressure and the residue redissolved in EtOAc (30 ml) then washed with a saturated aqueous solution of ammonium chloride (30 ml). This aqueous solution was extracted with further portions of EtOAc (30 ml X 2) and the combined organic solutions dried over magnesium sulfate, filtered and evaporated to dryness to give the crude product (216 mg) as a colourless oil.
  • the crude product was purified on a 25+S Biotage silica cartridge, eluting with a 0 to 50 % mixture of ethyl acetate in hexane to give the racemic target compound (169 mg) as a white solid.
  • the reaction mixture was treated with a further portion of 4-(bromomethyl)-2- pyridinecarbonitrile (22 mg) and stirred for 30 minutes.
  • the reaction mixture was diluted with EtOAc (30 ml), washed with a saturated aqueous solution of ammonium chloride (30 ml) followed by water (30 ml x 2), dried over magnesium sulfate, filtered and evaporated to dryness to give the crude product (178 mg) as an off-white solid.
  • the crude product was purified on a 12+M Biotage silica cartridge, eluting with a 0 to 50 % mixture of EtOAc in hexane. This gave the target compound (126 mg, compound 20 or 21 ) as an off-white solid.
  • reaction mixture was left for 5 hr. It was diluted with EtOAc (50 ml.) and water (50 ml_), vigorously shaken, the two phases were separated and the organic phase was washed with water (3x). Organics were dried over sodium sulfate, filtered and the solvent was evaporated to afford the crude product that was triturated with MeOH and purified by silica chromatography (EtOAc - hexane) and by MDAP to afford the target compound (30 mg, compound 20 or 21 ).
  • R-stereoisomer S-stereoisomer 2,2-difluoro-8-(2-fluoro-1-hydroxyethyl)-2H-1 ,4-benzoxazin-3(4H)-one (1 10 mg; may be prepared as described in intermediate 10), 3-(bromomethyl)-5-chloropyridine (153 mg; Sunshine Chemicals) and potassium carbonate (185 mg, 1.335 mmol) were dissolved in DMF (2 ml.) in a 10 mL round-bottomed flask open to the atmosphere and stirred at RT overnight.
  • reaction mixture was diluted with EtOAc (50ml) and washed with water (3x25ml) then dried (magnesium sulfate), filtered and evaporated.
  • the residue was dissolved in DCM and purified on the Biotage SP4 using a 25+M column and eluting with 0 to 50% EtOAc / isohexane over 15CV to afford the title compound (180mg, compound 24 or 25) as a white solid.
  • reaction mixture was diluted with EtOAc (50ml) and washed with water (3x25ml) then dried (magnesium sulfate), filtered and evaporated.
  • the residue was dissolved in DCM and purified on the Biotage SP4 using a 25+M column and eluting with 0 to 50% EtOAc / isohexane over 15CV to afford the title compound (127mg, compound 24 or 25) as a white solid.
  • 6-(Bromomethyl)quinoxaline 50 mg; may be prepared as described in intermediate 17 was added to a solution of 2,2-difluoro-8-(2,2,2-trifluoro-1-hydroxyethyl)-2H-1 ,4- benzoxazin-3(4H)-one (63.5 mg; may be prepared as described in intermediate 5) in DMF (3 ml_). Potassium carbonate (75 mg) and potassium iodide (1.860 mg) were added. The reaction was stirred overnight at RT, under argon. Then water (20 ml.) was added to the reaction mixture, and the new mixture was extracted 3 times with 20 ml. of EtOAc. The combined organic phases were washed 3 times with 20 ml.
  • 4-benzoxazin-3(4/-/)-one with 2,2,7-trifluoro-8-(2-fluoro-1-hydroxyethyl)-2H-1 ,4-benzoxazin-3(4H)-one may be prepared as described in intermediate 22), and replacing 6-(bromomethyl)quinoxaline with 3-(bromomethyl)-5-fluoropyridine hydrobromide (Sunshine Chemicals), m/z [M+H] + : 375.0. Retention time 0.88 min (LC/MS method 3).
  • a stirred solution of 8-acetyl-2,2-difluoro-2H-1 ,4-benzoxazin-3(4H)-one (50 mg, 0.220 mmol, may be prepared as described in intermediate 27) in DMF (3ml) at room temperature under argon was treated with potassium carbonate (60.8 mg, 0.440 mmol) followed by the addition of a solution of 3-(chloromethyl)pyridine hydrochloride (72.2 mg, 0.440 mmol, Aldrich) in DMF (3ml) and the resulting mixture was stirred at room temperature for 42 hours. The reaction mixture was concentrated under vacuum and the residue treated with 10% aqueous sodium carbonate solution (20ml) and extracted with DCM (2 x 20ml).
  • the title compound was (31 mg) made in a similar fashion to the preparation of 8-acetyl- 2,2-difluoro-4-(3-pyridinylmethyl)-2H-1 ,4-benzoxazin-3(4/-/)-one (may be prepared as described in example 36), replacing 3-(chloromethyl)pyridine hydrochloride with 3- (bromomethyl)-5-fluoropyridine hydrochloride (Sunshine Chemlab). Purification was by MDAP (formic acid method), m/z [M+H] + : 336.9. Retention time 0.99 min (LC/MS method 3).
  • the target compound (342 mg) was made in a similar fashion to the preparation of 8- acetyl-4-[(3-bromophenyl)methyl]-2,2-difluoro-2H-1 ,4-benzoxazin-3(4H)-one (may be prepared as described in compound 42), replacing 1-bromo-3-(bromomethyl)benzene with methyl 3-(bromomethyl)benzoate (Aldrich).

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Abstract

Cette invention concerne des dérivés de benzoxazinone, des procédés pour les préparer, des compositions pharmaceutiques et des médicaments les contenant et leur utilisation pour traiter des troubles médiés par Gly T1, comprenant les troubles neurologiques et neuropsychiatriques, en particulier, les psychoses, la démence ou le trouble du déficit de l'attention.
PCT/EP2010/062459 2009-08-27 2010-08-26 Dérivés de benzoxazine inhibiteurs du transport de glycine WO2011023753A1 (fr)

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Cited By (4)

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WO2014150688A1 (fr) * 2013-03-15 2014-09-25 The General Hospital Corporation Glycine, métabolisme mitochondriale monocarboné et cancer
WO2015012400A1 (fr) 2013-07-26 2015-01-29 大正製薬株式会社 Inhibiteur du transporteur de la glycine
WO2020179859A1 (fr) 2019-03-06 2020-09-10 第一三共株式会社 Dérivé de pyrrolopyrazole
WO2023212795A1 (fr) * 2022-05-06 2023-11-09 Richard Bergeron Utilisation d'antagonistes du transporteur-1 de la glycine en tant qu'agents prophylactiques/thérapeutiques de la démence vasculaire et/ou de l'accident vasculaire cérébral

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WO2015012400A1 (fr) 2013-07-26 2015-01-29 大正製薬株式会社 Inhibiteur du transporteur de la glycine
EP3026043A4 (fr) * 2013-07-26 2016-12-14 Taisho Pharmaceutical Co Ltd Inhibiteur du transporteur de la glycine
WO2020179859A1 (fr) 2019-03-06 2020-09-10 第一三共株式会社 Dérivé de pyrrolopyrazole
WO2023212795A1 (fr) * 2022-05-06 2023-11-09 Richard Bergeron Utilisation d'antagonistes du transporteur-1 de la glycine en tant qu'agents prophylactiques/thérapeutiques de la démence vasculaire et/ou de l'accident vasculaire cérébral

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