WO2011012622A1 - Benzoxazinone derivatives for the treatment of glytl mediated disorders - Google Patents

Benzoxazinone derivatives for the treatment of glytl mediated disorders Download PDF

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Publication number
WO2011012622A1
WO2011012622A1 PCT/EP2010/060886 EP2010060886W WO2011012622A1 WO 2011012622 A1 WO2011012622 A1 WO 2011012622A1 EP 2010060886 W EP2010060886 W EP 2010060886W WO 2011012622 A1 WO2011012622 A1 WO 2011012622A1
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alkyl
methyl
unsubstituted
alkoxy
compound
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PCT/EP2010/060886
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French (fr)
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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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    • 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
    • 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
    • C07D419/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms
    • C07D419/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D419/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen, oxygen, and sulfur 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
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • the present invention relates to 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 neurotransmission appears to contribute to the symptoms of schizophrenia (Lisman et al., Trends Neurosci. 31 , 234-242 (2008); Olney and Farber, Archives General Psychiatry, 52, 998-1007 (1996)).
  • 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 benzoxazinone compounds which are inhibitors of URAT1 activity and effective for treating diseases associated with uric acid.
  • R 1 is selected from
  • phenyl which is unsubstituted or substituted with 1 to 3 substituents independently selected from halo, cyano, hydroxy, -(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 and haloCi_ 4 alkoxy;
  • 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 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 alkoxy and haloCi. 4 alkoxy.
  • 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) as defined in the first aspect, or a pharmaceutically acceptable salt thereof.
  • a pharmaceutical composition comprising (a) a compound of formula (I) as defined in the first aspect, or a pharmaceutically acceptable salt thereof, and (b) a pharmaceutically acceptable excipient.
  • R 1 is selected from
  • 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 - (NR 1a R 1b ), -(C0)NR 1a R 1b , -(CO)O-C 1-4 alkyl, -(CHO), -SO 2 (NR 1a R 1b ), haloC 1-4 alkyl and haloC 1-4 alkoxy;
  • 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, 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 alkoxy and haloCi.
  • alkyl refers to a straight or branched hydrocarbon chain containing the specified number of carbon atoms.
  • C 1-6 alkyl means a straight or branched hydrocarbon chain containing at least 1 and at most 6 carbon atoms.
  • alkyl include, but are not limited to; methyl (Me), ethyl (Et), n-propyl, i-propyl, t-butyl, n-hexyl and i-hexyl.
  • Other examples of alkyl include, but are not limited to; n-butyl, isobutyl, sec-butyl, n-pentyl, isopentyl or neopentyl.
  • 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).
  • haloCi -4 alkyl refers to a Ci -4 alkyl group as defined herein substituted with one or more halo groups as defined herein, which halo groups may be the same or different.
  • haloCi -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. -O-CF 3 or difluoromethoxy.
  • -(CO)O-C 1-4 alkyl refers an carboxylic acid ester group wherein C 1-4 alkyl is defined herein. Examples of haloC 1-4 alkyl include, but are not limited to; - (CO)O-methyl or -(CO)O-ethyl.
  • hydroxyCi -4 alkyl refers to a Ci -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 independently selected from oxygen, nitrogen or sulphur.
  • 5-membered heteroaryl rings in this instance include, but are not limited to, 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.
  • the term 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
  • the term independently means that where more than one substituent is selected from a number of possible substituents, those substituents may be the same or different.
  • the term comprise, and variations such as comprises and comprising will be understood to imply the inclusion of a stated integer or step or group of integers but not to the exclusion of any other integer or step or group of integers or steps.
  • R 1 , R 2 , R 3 and R 4 are as defined in the first aspect.
  • R 1 , R 2 , R 3 and R 4 are as defined in the first aspect.
  • the compound as defined in the first to third aspect is not 2,2- difluoro-8-(1 -hydroxyethyl)-4-[(5-oxo-5H-[1 ,3]thiazolo[3,2-a]pyrimidin-7-yl)methyl]-2H-1 ,4- benzoxazin-3(4H)-one and 2,2-difluoro-8-(1-hydroxyethyl)-4-[(1-methyl-4-oxo-1 ,4- dihydro-2-quinolinyl)methyl]-2H-1 ,4-benzoxazin-3(4H)-one.
  • R 2 , R 3 and R 4 are independently selected from hydrogen, halo, cyano and In a more particular embodiment of the first to third aspect, R 2 , R 3 and R 4 are independently selected from hydrogen, halo and cyano. In an even more particular embodiment of the first to third aspect, R 2 , R 3 and R 4 are independently selected from hydrogen and halo. In yet an even more particular embodiment, R 2 is halo and R 3 and R 4 are hydrogen. In a most particular embodiment, R 2 is fluoro and R 3 and R 4 are hydrogen. In a most particular embodiment, R 2 , R 3 and R 4 are hydrogen.
  • 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 ), -(CO)NR 1a R 1b , -(CO)O-Ci -4 alkyl, -(CHO), haloCi -4 alkyl and haloCi_ 4 alkoxy, or R 1 is phenyl which is unsubstituted or substituted with 1 or 2 substituents independently selected from halo, Ci -4 alkyl, Ci -4 alkoxy, cyano, hydroxyl, hydroxy C 1-4 alkyl, -(CH 2
  • 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 or 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, hydroxyl, hydroxy C 1-4 alkyl, -(CH 2 )
  • 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, Ci- 4 alkoxy, cyano, hydroxyl, hydroxy C 1-4 alkyl, -(CH 2 ) n -(NR 1a R 1b ), -(C0)NR 1a R 1b , -(CO)O-Ci- 4 alkyl, -(CHO), haloCi -4 alkyl and haloCi -4 alkoxy or R 1 is phenyl which is unsubstituted or substituted with 1 or 2 substituents independently selected from halo, C 1-4 alkyl, Ci- 4 alkoxy, cyano, -S0 2 (NR 1a R
  • R 1 is selected from - furanyl which is unsubstituted or substituted with 1 substituent selected from C 1-4 alkyl, - (CO)O-C 1-4 alkyl, -(CHO) and haloC 1-4 alkyl;
  • - 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;
  • R 1 is selected from
  • - 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 1 is selected from
  • 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-Ci -4 alkyl, -(CHO), haloCi -4 alkyl and haloCi_ 4 alkoxy or R 1 is phenyl which is unsubstituted or substituted with 1 or 2 substituents independently selected from halo, Ci -4 alkyl, Ci -4 alkoxy, cyano, hydroxyl, hydroxy C 1-4 alkyl, -(CH 2
  • 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 ), -(C0)NR 1a R 1b , -(CO)O-C 1-4 alkyl, -(CHO), haloC 1-4 alkyl and haloC 1-4 alkoxy or 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 ), hal
  • 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-Ci -4 alkyl, -(CHO), haloCi -4 alkyl and haloCi_ 4 alkoxy or R 1 is phenyl which is unsubstituted or substituted with 1 or 2 substituents independently selected from halo, Ci -4 alkyl, Ci -4 alkoxy, cyano, hydroxyl, hydroxy C 1-4 alkyl, -(CH 2
  • 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 2 is hydrogen or halo, in particular fluoro, R 3 is hydrogen and R 4 is hydrogen or halo, in particular fluoro.
  • R 1 is selected from
  • - 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.
  • R 1 is selected from
  • - 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 1 is selected from
  • R 2 is hydrogen or halo, in particular fluoro
  • R 3 is hydrogen
  • R 4 is hydrogen or halo, in particular fluoro.
  • R 1 is selected from
  • - 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.
  • R 1 is selected from
  • - 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 1 is selected from
  • 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 or R 1 is phenyl which is unsubstituted or substituted with 1 or 2 substituents independently selected from halo, Ci -4 alkyl, Ci -4 alkoxy, cyano, hydroxyl, hydroxy C 1-4 alkyl, -(CH 2 ) n - (NR 1a R 1b
  • 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-
  • R 1 is phenyl which is unsubstituted or substituted with 1 or 2 substituents independently selected from halo, C 1-4 alkyl, C 1-
  • 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, Ci- 4 alkoxy, cyano, haloCi -4 alkyl and haloCi -4 alkoxy, particularly oxo and Ci -4 alkyl, more particularly oxo and methyl or R 1 is phenyl which is unsubstituted or substituted with 1 or 2 substituents independently selected from halo
  • 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, benzimidazol-2-yl, 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, 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 hal
  • 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, Ci- 4 alkoxy, cyano, haloCi -4 alkyl and haloCi -4 alkoxy, particularly oxo and Ci -4 alkyl, more particularly oxo and methyl or R 1 is phenyl which is unsubstituted or substituted with 1 or 2 substituents independently selected from halo
  • 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, cyano, and haloCi -4 alkoxy, particularly oxo and Ci -4 alkyl more particularly oxo and methyl or R 1 is selected from quinolin-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 or R 1 is phenyl which is unsubstituted or substituted with 1 or 2 substituents independently
  • 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, cyano, and haloCi -4 alkoxy, particularly oxo and Ci -4 alkyl more particularly oxo and methyl or R 1 is selected from quinolin-6-yl,
  • 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, C 1-4 alkyl, C 1-4 alkoxy, cyano, haloC 1-4 alkyl and haloC 1-4 alkoxy, particularly oxo and C 1-4 alky
  • compounds as defined in the first to third aspect, or salts thereof are selected from supporting compounds 1 to 224, or salts thereof.
  • compounds as defined in the first to third aspect, or salts thereof are selected from supporting compounds 1 to 100 and 197 to 224, or salts thereof. More particularly, compounds as defined in the first to third aspect, or salts thereof, are selected from
  • 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- 4 alkoxy;
  • 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 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 2 , R 3 and R 4 are as defined in the first aspect.
  • R 1 is selected from
  • R 2 , R 3 and R 4 are as defined in the first aspect.
  • the compound as defined in the fourth to sixth aspect is not 2,2- difluoro-8-(1 -hydroxyethyl)-4-[(5-oxo-5H-[1 ,3]thiazolo[3,2-a]pyrimidin-7-yl)methyl]-2H-1 ,4- benzoxazin-3(4H)-one and 2,2-difluoro-8-(1-hydroxyethyl)-4-[(1-methyl-4-oxo-1 ,4- dihydro-2-quinolinyl)methyl]-2H-1 ,4-benzoxazin-3(4H)-one.
  • R 2 , R 3 and R 4 are independently selected from hydrogen, halo, cyano and haloC 1-4 alkyl. In a more particular embodiment of the fourth to sixth aspect, R 2 , R 3 and R 4 are independently selected from hydrogen, halo and cyano. In an even more particular embodiment of the fourth to sixth aspect, R 2 , R 3 and R 4 are independently selected from hydrogen and halo. In yet an even more particular embodiment, R 2 is halo and R 3 and R 4 are hydrogen. In a most particular embodiment, R 2 is fluoro and R 3 and R 4 are hydrogen.
  • 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 ), -(CO)NR 1a R 1b , -(CO)O-Ci -4 alkyl, -(CHO), haloCi -4 alkyl and haloC 1-4 alkoxy.
  • 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.
  • 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 , -(CHO), haloCi -4 alkyl and haloCi -4 alkoxy.
  • R 1 is selected from furanyl, thiazolyl, thienyl, oxazolyl, pyridyl, pyridazinyl, pyrimidinyl and pyrazinyl, each of which is unsubstituted or substituted
  • - pyridyl which is unsubstituted or substituted with 1 or 2 substituents independently selected from halo, haloCi -4 alkyl, -(CO)O-Ci -4 alkyl, C 1-4 alkyl, Ci -4 alkoxy and cyano;
  • R 1 is selected from
  • - 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 1 is selected from
  • 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-Ci -4 alkyl, -(CHO), haloCi -4 alkyl and haloCi_ 4 alkoxy, R 2 is hydrogen or halo, R 3 is hydrogen and R 4 is hydrogen or halo.
  • 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, Ci -4 alkoxy, cyano, hydroxyl, hydroxy C 1-4 alkyl, -(CH 2 ) n -(NR 1a R 1b ), -
  • R 1 is selected from - furanyl which is unsubstituted or substituted with 1 substituent selected from C 1-4 alkyl, - (CO)O-C 1-4 alkyl, -(CHO) and haloC 1-4 alkyl;
  • - 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 is hydrogen or halo, in particular fluoro
  • R 3 is hydrogen
  • R 4 is hydrogen or halo, in particular fluoro.
  • R 1 is selected from
  • - 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 1 is selected from
  • R 2 is hydrogen or halo, in particular fluoro
  • R 3 is hydrogen
  • R 4 is hydrogen or halo, in particular fluoro.
  • R 1 is selected from
  • - 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.
  • R 1 is selected from
  • - 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 1 is selected from
  • 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, Ci -4 alkyl, cyano, hydroxyl, hydroxy Ci -4 alkyl, -(CH 2 ) n - (NR 1a R 1b ), -(CO)NR 1a R 1b , -(CO)O-Ci -4 alkyl, -(CHO), haloCi -4 alkyl and haloCi -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-C 1-4 alkyl, -(CHO), haloC
  • 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 Ci -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, benzimidazol-2-yl, 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, 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
  • 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 alky
  • 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, cyano, and haloCi -4 alkoxy, particularly oxo and more particularly oxo and methyl; and R 2 , R 3 and R 4
  • 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 fluoro, R 3 is hydrogen and R 4 is hydrogen or halo
  • 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, cyano, and haloCi -4 alkoxy, particularly oxo and Ci -4 alkyl more particularly oxo and methyl; R 2 is selected from quinolin-6-yl,
  • compounds as defined in the fourth to sixth aspect, or salts thereof are selected from supporting compounds 1 to 100, or salts thereof. More particularly, compounds as defined in the fourth to sixth aspect, or salts thereof, are selected from S ⁇ P ⁇ -Difluoro- ⁇ -ti-hydroxyethyO-S-oxo ⁇ .S-dihydro ⁇ H-i ⁇ -benzoxazin ⁇ -yOmethylJ-S- pyridinecarbonitrile;
  • 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, hydroxyl, hydroxy C 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, haloCUalkyl, 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, haloCUalkyl, Ci -4 alkoxy and haloCi.
  • R 5 I 1 nR2 1 nR3 and R are as defined in the first aspect.
  • R 5 I 1 n R2 1 n R3 and R are as defined in the first aspect.
  • 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, 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), -SO 2 (NR 1a R 1b ), haloC 1-4 alkyl and haloC 1-4 alkoxy.
  • 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, 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), -S0 2 (NR 1a R 1b ), haloC 1-4 alkyl and haloC 1-4 alkoxy; and wherein at least one substituent is attached to the 3-position relative to the bond attaching the phenyl to the rest of the molecule.
  • substituents independently selected from halo, C 1-4 alkyl, C 1- 4 alkoxy, cyano, hydroxyl, hydroxy C 1-4 alkyl, -(CH 2 ) n -(NR 1a R 1b ), -(C0)NR 1
  • 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 ), haloC 1-4 alkyl and haloC 1-4 alkoxy.
  • R 1 is phenyl which is unsubstituted or substituted with 1 or 2 substituents independently selected from fluoro, chloro, cyano, methyl, methoxy 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, Ci -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), -SO 2 (NR 1a R 1b ), halod ⁇ alkyl and haloC 1-4 alkoxy;
  • 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 ), haloC 1-4 alkyl and haloC 1-4 alkoxy; 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 and -SO 2 (NR 1a R 1b ); R 2 , R 3 and R 4 are independently selected from hydrogen and halo.
  • 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.
  • R 1 is phenyl which is unsubstituted or substituted with 1 or 2 substituents independently selected from fluoro, cyano, methyl and methoxy; and R 2 , R 3 and R 4 are hydrogen.
  • compounds as defined in the seventh to ninth aspect, or salts thereof are selected from compounds 197 to 224, or salts thereof. More particularly, compounds as defined in the seventh to ninth aspect, or salts thereof, are selected from
  • Certain compounds as defined in the first to ninth aspect may in some circumstances form acid addition salts thereof. It will be appreciated that for use in medicine compounds as defined in the first to ninth aspect may be used as salts, in which case the salts should be pharmaceutically acceptable.
  • Pharmaceutically acceptable salts include those described by Berge, Bighley and Monkhouse , J. Pharm. ScL, 1977, 66, 1-19.
  • pharmaceutically acceptable 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, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid, and the like.
  • 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.
  • pro-drugs examples include Drugs of Today, Volume 19, Number 9, 1983, pp 499 - 538 and in Topics in Chemistry, Chapter 31 , pp 306 - 316 and in "Design of Prodrugs" by H. Bundgaard, Elsevier, 1985, Chapter 1 (the disclosures in which documents are incorporated herein by reference). It will further be appreciated by those skilled in the art, that certain moieties, known to those skilled in the art as “pro- moieties”, for example as described by H. Bundgaard in "Design of Prodrugs” (the disclosure in which document is incorporated herein by reference) may be placed on appropriate functionalities when such functionalities are present within the compounds as defined in the first to ninth aspects. Therefore, in a further aspect, the invention provides a prodrug of a compound as defined in the first to ninth aspect, for example in the fourth to sixth aspect or the seventh to ninth aspect.
  • Certain compounds as defined in the first to ninth aspect 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 in the first to ninth aspect may also exhibit tautomerism within the R 1 moiety, and the present invention includes each such tautomer.
  • An example of a compound as defined in the first to ninth aspect which exhibits tautomerism is
  • the subject invention also includes isotopically-labelled compounds, which are identical to the compounds as defined in the first to ninth 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 ninth 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 in the first to ninth aspect or salts thereof are not isotopically labelled.
  • general formulae are designated by Roman numerals (I), (II), (III), (IV), etc.
  • R 5 is chloro, iodo or bromo, suitably bromo, or when R 5 is hydrogen, R 2 is fluoro, and L is a suitable leaving group such as halogen or methanesulfonate.
  • 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, in a suitable solvent, for example N,N-dimethylformamide, in the presence of a suitable base, for example sodium hydride.
  • compounds of formula (Vl) 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 acetaldehyde, in a suitable solvent and at a suitable temperature, for example diethyl ether at -78 0 C.
  • compounds of formula (I) may be prepared by reacting compounds of formula (Vl) with compounds of formula (VII), in a suitable solvent, for example N, N- dimethylformamide or acetonitrile, in the presence of a suitable base, for example potassium carbonate or triethylamine.
  • R 1 is as defined in the first aspect, and A is hydrogen, hydroxy or d ⁇ alkyloxy.
  • compounds of formula (IX) can be prepared by treating compounds of formula (VIII) with a suitable reducing agent, for example borane, sodium borohydride, lithium borohydride or lithium aluminium hydride, in a suitable solvent, for example tetrahydrofuran or methanol. Alternatively they may be commercially available or may be prepared by known methods.
  • a suitable reducing agent for example borane, sodium borohydride, lithium borohydride or lithium aluminium hydride
  • a suitable solvent for example tetrahydrofuran or methanol.
  • a suitable solvent for example tetrahydrofuran or methanol.
  • compounds of formula (Vila) may be prepared by treating compounds of formula (IX) 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.
  • R 1 is as defined in the first aspect, and L 2 is chloro or bromo when R 1 is a heteroaryl or a fused bicyclic ring system and bromo when R 1 is phenyl.
  • Compounds of formula (VIIb) may be prepared by reacting compounds of formula (X) with a suitable halogenating agent, such as ⁇ /-bromosuccinimide or ⁇ /-chlorosuccinimide, in the presence of a suitable radical initiator, such as 2,2'-azobis(2-methylpropionitrile) or dibenzoyl peroxide, in a suitable solvent, such as carbon tetrachloride.
  • a suitable radical initiator such as 2,2'-azobis(2-methylpropionitrile) or dibenzoyl peroxide
  • R 1 is as defined in the first aspect.
  • Compounds of formula (VIIc) may be prepared by treating compounds of formula (IX) with a suitable mesylating agent, for example methanesulfonyl chloride or methanesulfonic anhydride, in the presence of a suitable base, for example triethylamine or polystyrene-supported diethylamine, in a suitable solvent, for example ethyl acetate or dichloromethane.
  • a suitable mesylating agent for example methanesulfonyl chloride or methanesulfonic anhydride
  • a suitable base for example triethylamine or polystyrene-supported diethylamine
  • a suitable solvent for example ethyl acetate or dichloromethane.
  • R 5 I', n R2 z , n R3 ⁇ and R 4 are as defined in the first aspect, R 5 is chloro, iodo or bromo, suitably bromo, and L is a suitable leaving group such as halogen, suitably bromo or chloro, or methanesulfonate.
  • compounds of formula (Xl) 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- methyl-N-(methoxy)acetamide, 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- methyl-N-(methoxy)acetamide
  • compounds of formula (XII) may be prepared by reacting compounds of formula (Xl) with compounds of formula (VII) 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
  • compounds of formula (I) may be prepared by treating compounds of formula (XII) with a suitable reducing agent, for example sodium triacetoxyborohydride or sodium borohydride, in a suitable solvent, for example tetrahydrofuran or dichloromethane, at a suitable temperature, for example room temperature.
  • a suitable reducing agent for example sodium triacetoxyborohydride or sodium borohydride
  • a suitable solvent for example tetrahydrofuran or dichloromethane
  • R 1 , R 2 , R 3 and R 4 are as defined in the first aspect and L is a suitable leaving group such as halogen or methanesulfonate.
  • compounds of formula (XIII) can be prepared by treating compounds of formula (Xl) with a suitable reducing agent, for example 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 tetrahydrofuran, at a suitable temperature, for example room temperature.
  • a suitable reducing agent for example a combination of (3aS)-1-methyl- 3,3-diphenyltetrahydro-3H-pyrrolo[1 ,2-c][1 ,3,2]oxazaborole
  • a suitable solvent for example tetrahydrofuran
  • compounds of formula (I) can be prepared by reacting compounds of formula (XIII) with compounds of formula (VII), where L indicates a suitable leaving group such as bromo, chloro or methanesulfonate, 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
  • a te/t-butoxycarbonyl group can be removed by treating the compound with a suitable acid, for example hydrogen chloride in dioxane, in a suitable solvent, for example dichloromethane, at a suitable temperature, for example room temperature.
  • a suitable acid for example hydrogen chloride in dioxane
  • a suitable solvent for example dichloromethane
  • the compounds as defined in the first to ninth aspect inhibit the GIyTI transporter.
  • Such compounds are therefore of potential utility for the treatment or prophylaxis of certain neurological and neuropsychiatric disorders.
  • the compounds as defined in the first to ninth aspect 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.
  • 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
  • psychosis NOS "schizophrenia-spectrum” disorders such as schizo
  • disorders include Parkinson's disease, dyskinetic disorders, cognitive impairment, emesis, movement disorders, amnesia, circadian rhythm disorders, aggression and vertigo.
  • treatment refers to symptomatic or prodromal treatment.
  • treatment refers to symptomatic treatment.
  • treatment refers to prodromal treatment.
  • the disorder mediated by GIyTI to be treated is a psychosis, including schizophrenia, dementia and attention deficit disorders.
  • 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 Alzheimer's disease.
  • the term "effective amount" means that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal or human that is being sought, for instance, by a researcher or clinician.
  • DSM-IV American Psychiatric Association
  • the compounds as defined in the first to ninth aspect be of use in the treatment or prophylaxis of schizophrenia including the subtypes Paranoid Type (295.30), Disorganised Type (295.10), Catatonic Type (295.20), Undifferentiated Type (295.90) and Residual Type (295.60); Schizophreniform Disorder (295.40); Schizoaffective Disorder (295.70) including the subtypes Bipolar Type and Depressive Type; Delusional Disorder (297.1 ) including the subtypes Erotomanic Type, Grandiose Type, Jealous Type, Persecutory Type, Somatic Type, Mixed Type and Unspecified Type; Brief Psychotic Disorder (298.8); Shared Psychotic Disorder (297.3); Psychotic Disorder Due to a General Medical Condition including the subtypes With Delusions and With Hallucinations; Substance-Induced Psychotic Disorder including the subtypes With Delusions (293.81 ) and With Hallucinations (293.82); and Psychotic Disorder Not Otherwise Spec
  • the compounds as defined in the first to ninth aspect may be also of use in the treatment or prophylaxis 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 (31 1 ); 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 as defined in the first to ninth aspect may also be of use in the treatment or prophylaxis 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- Injury Type, Situational Type and Other Type), Social Phobia (300.23), Obsessive- Compulsive Disorder (300.3), Posttraumatic Stress Disorder (309.81 ), Acute Stress Disorder (308.3), Generalized Anxiety Disorder (300.02), Anxiety Disorder Due to a General Medical Condition (293.84), Substance-Induced Anxiety Disorder and Anxiety Disorder Not Otherwise Specified (300.00).
  • 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- Injury Type, Situational Type and Other Type), Social Phobia (300.
  • the compounds as defined in the first to ninth aspect may also be of use in the treatment or prophylaxis 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
  • the compounds as defined in the first to ninth aspect may also be of use in the treatment or prophylaxis 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
  • Another Mental Disorder (307.44); Sleep Disorder Due to a General Medical Condition; and Substance-Induced Sleep Disorder including the subtypes Insomnia Type, Hypersomnia Type, Parasomnia Type and Mixed Type.
  • the compounds as defined in the first to ninth aspect may also be of use in the treatment or prophylaxis 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 as defined in the first to ninth aspect may also be of use in the treatment or prophylaxis 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 /Hyperactivity Disorder Not Otherwise Specified (314.9); Hyperkinetic Disorder; 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 as defined in the first to ninth aspect may also be of use in the treatment or prophylaxis 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).
  • 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)
  • the compounds as defined in the first to ninth aspect may also be of use in the treatment or prophylaxis of cognitive impairment.
  • cognitive impairment includes for example the treatment or prophylaxis of impairment of cognitive functions including attention, orientation, learning disorders, memory (i.e.
  • cognia amnesia, amnesic disorders, transient global amnesia syndrome and age-associated memory impairment
  • cognitive impairment as a result of stroke, Alzheimer's disease, Huntington's disease, Pick disease, Aids-related dementia or other dementia states such as M ulti infarct 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 (pseudodementia states) 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 as defined in the first to ninth aspect may also be of use for the treatment or prophylaxis 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 as defined in the first to ninth aspect may also be of use in the treatment or prophylaxis of sexual dysfunctions including sexual Desire Disorders such as
  • Erectile Disorder (302.72); orgasmic disorders such as Female Orgasmic Disorder
  • the compounds as defined in the first to ninth aspect may also be of use as anticonvulsants.
  • the compounds as defined in the first to ninth aspect are thus useful in the treatment or prophylaxis 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 or prophylaxis of epilepsy may be carried out by the administration of a nontoxic anticonvulsant effective amount of a compound of the formula (I) or a salt thereof.
  • the compounds as defined in the first to ninth aspect may also be useful in the treatment or prophylaxis 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 as defined in the first to ninth aspect 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 compound as defined in the first to ninth aspect, or a pharmaceutically acceptable salt thereof, for use in the treatment or prophylaxis of a disorder mediated by GIyTL More particularly, there is provided a compound as defined in the first to ninth aspect, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disorder mediated by GIyTI .
  • a method of treatment or prophylaxis of a disorder mediated by GIyTI which method comprises the administration of a compound as defined in the first to ninth aspect, or a pharmaceutically acceptable salt thereof. More particularly, there is provided a method of treatment of a disorder mediated by GIyTI , which method comprises the administration of a compound as defined in the first to ninth aspect, or a pharmaceutically acceptable salt thereof.
  • a compound as defined in the first to ninth aspect, or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in the treatment or prophylaxis of a disorder mediated by GIyTL More particularly, there is provided the use of a compound as defined in the first to ninth aspect, 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.
  • a pharmaceutical composition comprising a compound as defined in the first to ninth aspect, 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 as defined in the first to ninth aspect, 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.
  • a flavoured base such as sugar and acacia or tragacanth
  • 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 suppositories comprising the active ingredient and one or more solid carriers forming the suppository base, for example, cocoa butter.
  • 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, sub- lingual, 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 as defined in the first to ninth aspect 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 ninth 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 as defined in the first to ninth aspect, 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 as defined in the first to ninth aspect 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).
  • anticholinergics such as benztropine, biperiden, procyclidine and trihexyphenidyl
  • antihistamines such as diphenhydramine
  • dopaminergics such as amantadine
  • iii) antidepressants iv) anxiolytics
  • the compounds as defined in the first to ninth aspect may be used in combination with antidepressants to treat or prevent depression and mood disorders.
  • the compounds as defined in the first to ninth aspect 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 as defined in the first to ninth aspect may be used in combination with the following agents to treat or prevent anxiety disorders: i) anxiolytics; and ii) antidepressants.
  • the compounds as defined in the first to ninth aspect 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.
  • the compounds as defined in the first to ninth aspect may be used in combination with the following agents to improve alcohol withdrawal and reduce alcohol craving: i) NMDA receptor antagonists for example acamprosate; ii) GABA receptor agonists for example tetrabamate; and iii) Opioid receptor antagonists for example naltrexone.
  • NMDA receptor antagonists for example acamprosate
  • GABA receptor agonists for example tetrabamate
  • Opioid receptor antagonists for example naltrexone.
  • the compounds as defined in the first to ninth aspect 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 as defined in the first to ninth aspect 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 as defined in the first to ninth aspect 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 as defined in the first to ninth aspect 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 as defined in the first to ninth aspect 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 as defined in the first to ninth aspect 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 as defined in the first to ninth aspect 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 as defined in the first to ninth aspect 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
  • the compounds as defined in the first to ninth aspect may be used in combination with the same agents specified for male sexual dysfunction to treat or prevent female sexual dysfunction, and in addition an estrogen agonist such as estradiol.
  • antipsychotic drugs examples 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 ; benzisothiazolyl-piperazines; triazine such as lamotrigine; dibenzoxazepines, such as loxapine; dihydroindolones, such as
  • 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 as defined in the first to ninth aspect 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 as defined in the first to ninth aspect or a pharmaceutically acceptable salt thereof may be used in combination with other medicaments indicated to be useful in the treatment or prophylaxis 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
  • NSAIDs non-steroidal anti-inflammatory drugs
  • NSAIDs non-steroidal anti-inflammatory drugs
  • 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
  • ligands for the ⁇ 2 ⁇ -subunit of voltage gated calcium channels such as gabapentin, pregabalin and solzira
  • tricyclic antidepressants such as amitriptyline
  • neurone stabilising antiepileptic drugs cholinesterase inhibitors such as galantamine
  • mono-aminergic uptake inhibitors such as venlafaxine
  • the compound as defined in the first to ninth aspect or a pharmaceutically acceptable salt thereof may be used in combination with other medicaments indicated to be useful as either disease modifying or symptomatic treatments of Alzheimer's disease.
  • 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 antagonists, M1 muscarinic agonists, M2 muscarinic antagonist, acetylcholinesterase inhibitors (e.g. tetrahydroaminoacridine, donepezil or rivastigmine), or allosteric modulators, nicotinic receptor agonists or allosteric modulators, symptomatic agents such as 5-HT6 receptor antagonists, e.g. SB742457, H3 receptor antagonists e.g.
  • 5-HT 1A antagonists e.g. lecozotan
  • 5-HT6 antagonists e.g. lecozotan
  • M1 muscarinic agonists e.g. M2 muscarinic antagonist
  • acetylcholinesterase inhibitors e.g. tetrahydroaminoa
  • 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 cooling bath was removed and 1 M hydrochloric acid (100 mL) was added dropwise while temperature was allowed to rise to 25 0 C. Water (100 mL) was added and then further 1 M hydrochloric acid (50 mL) in order to adjust the pH of the aqueous phase to 5. The phases were separated. The aqueous phase was back-extracted with EtOAc (250 ml_). The combined organic layers were dried over sodium sulphate and were evaporated to give a residue (10.7 g) that was dissolved in EtOAc (200 ml_). Silica (230- 400 Mesh, 20 g) was added.
  • 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 7) 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).
  • a solution of 2,2,7-trifluoro-2H-1 ,4-benzoxazin-3(4H)-one (200 mg, 0.985 mmol, may be prepared as described in intermediate 10) in dry THF (10 ml.) was cooled to -65 0 C under argon. BuLi (1.4 mL, 2.240 mmol, 1.6 M in hexanes) was added and the mixture was stirred for 1 hr. Acetaldehyde (0.6 mL, 10.62 mmol) was added and the mixture was stirred for 3 hr, with the temperature rising to 5 0 C. Saturated ammonium chloride solution (10 ml.) and ethyl acetate (10 ml.) were added.
  • 2,3-Dimethylpyridine 1-oxide (1.440 g, 1 1.69 mmol, may be prepared as described in intermediate 31 ), trimethylsilyl cyanide (4.70 ml, 35.1 mmol) and triethylamine (2.445 ml, 17.54 mmol) were dissolved in acetonitrile (23.39 ml) in a 50 ml. round-bottomed flask flushed with argon and stirred at 9O 0 C for 5 days. The reaction mixture was cooled to O 0 C and treated with 5M aqueous sodium hydroxide (30ml).
  • the crude product was purified on a 40+S Biotage silica cartridge, eluting with a 0 to 20 % mixture of EtOAc in hexane.
  • the product was dissolved in MeOH (10 ml), cooled to 0 0 C and sulfuric acid (250 ⁇ l, 4.69 mmol) was added dropwise and the reaction was stirred at 90 0 C overnight.
  • the reaction mixture was cooled to room temperature, evaporated to dryness and the pH adjusted to 9 using saturated aqueous sodium bisulfate solution.
  • Methyl 5,6-dimethyl-2-pyridinecarboxylate (167 mg, may be prepared as described in intermediate 33) and sodium borohydride (191 mg, 5.05 mmol) were dissolved in MeOH (5 ml) and stirred at room temperature overnight. The reaction mixture was evaporated to dryness, redissolved in DCM (30 ml) and treated with saturated aqueous sodium bicarbonate solution (30 ml). The aqueous layer was extracted with DCM (2 x 30 ml) and the organic layers were combined, washed with brine, dried over magnesium sulfate, filtered and evaporated to dryness to give the crude product (114 mg) as a colourless oil.
  • the crude product was dissolved in MeOH (5 ml), sodium borohydride (191 mg, 5.05 mmol) was added and the reaction mixture stirred at room temperature overnight.
  • the reaction mixture was evaporated to dryness, redissolved in DCM (30 ml) and treated with saturated aqueous sodium bicarbonate solution (30 ml).
  • the aqueous layer was extracted with DCM (2 x 30 ml) and the organic layers were combined, washed with brine, dried over magnesium sulfate, filtered and evaporated to dryness to give the crude product (93 mg) as a colourless oil.
  • the crude product was purified on a 25+S Biotage silica cartridge, eluting with a 0 to 30 % mixture of EtOAc in hexane.
  • 2-Amino-3-(methylamino)benzonitrile (441 mg; may be prepared as described in intermediate 65) was dissolved in 2-chloro-1 ,1 ,1-trimethoxyethane (3 ml_, Aldrich). Concentrated hydrochloric acid (0.6 ml.) was added dropwise and the mixture was stirred at RT for 3 days. It was basified with aqueous sodium bicarbonate solution and then extracted with DCM (3 x 100 ml_). The combined organic layers were dried over soldium sulphate, filtered and evaporated to obtain a light red solid. This was purified by chromatography on silica gel (eluent petroleum ether / EtOAc 1 :1 ) to give the title compound (300 mg).
  • [2-Amino-3-(methoxy)phenyl]methylamine (4.0 g; may be prepared as described in intermediate 70) and chloroacetic acid (5.0 g) were dissolved in hydrochloric acid (5 N, 100 ml.) and heated to reflux overnight. After cooling to room temperature the mixture was basified with aqueous sodium bicarbonate solution (10% w/v) then extracted with DCM (x 2). The combined organic layers were dried and concentrated to give the crude product. This was purified by chromatography on silica gel to give the title compound (3 g)-
  • a mixture of 1 ,2-dimethyl-1 /-/-indole-3-carbaldehyde oxime (5.65 g; may be prepared as described in intermediate 76) and acetic anhydride (200 ml.) was heated to reflux for 2 hr. The mixture was cooled and water (600 ml.) was added. It was extracted with EtOAc. The organic extractions were purified by column chromatography to obtain the title compound (5 g) as a yellow solid.
  • 3-amino- ⁇ /-methyl-4-pyridinecarboxamide (68 mg; may be prepared as described in intermediate 86) was dissolved in THF under stirring, and under an argon atmosphere. Chloroacetyl chloride (0.038 ml.) was then added, and the reaction mixture was left overnight, still under stirring and argon atmosphere and at RT. Another portion of chloroacetyl chloride (0.038 ml.) was added. The reaction mixture was left under stirring for 2 hr. Sodium bicarbonate (60.5 mg) was added, and the reaction mixture was left under stirring for 5 min ( the argon atmosphere was removed). Then DCM (20 ml.) and water (10 ml.) were added, and the reaction mixture was stirred for 5 min.
  • the reaction mixture was cooled to room temperature.
  • the reaction mixture was diluted with saturated aqueous sodium bicarbonate solution (5 ml.) and then with DCM (10 ml_).
  • the layers were separated and the aqueous was extracted with DCM (2 x 10 ml_).
  • the combined organic layers were washed with water (10 ml.) and brine (15 ml_), dried through a phase separating cartridge and evaporated to give the title compound (46 mg) as a pink solid, m/z [M+H] + : 210.0 / 212.0. Retention time 0.63 min (LC/MS method 4).
  • a mixture of 6-fluoro-3-methyl-2-[(methoxy)methyl]-4(3/-/)-quinazolinone (1.2 g; may be prepared as described in intermediate 95) and 48% aqueous hydrobromic acid (100 ml.) was placed in a preheated hotplate (120 0 C) for 2 days. The reaction was cooled and evaporated to dryness to give the title compound (1.3 g) as a mixture with 6-fluoro-2- (hydroxymethyl)-3-methyl-4(3H)-quinazolinone. m/z [M+H] + : 271.0 / 273.0. Retention time 0.87 min (LC/MS method 3).
  • Chloroacetyl chloride (0.21 1 ml.) was added to a solution of 2-amino- ⁇ /-methyl-3- pyridinecarboxamide (380 mg; may be prepared as described in intermediate 117) in dry THF (20 ml.) under argon. The mixture was stirred overnight. More THF (20 ml.) and chloroacetyl chloride (0.5 ml.) were added and the mixture was stirred overnight. More chloroacetyl chloride (0.5 ml.) were added and the mixture was heated to reflux overnight. It was cooled to room temperature. Water (20 ml.) and sodium bicarbonate (2 g) were added. DCM (80 ml.) was added and the layers were separated (hydrophobic membrane).
  • 2-Amino-3-bromobenzoic acid (1.5 g; may be prepared as described in intermediate 136) in a solution of acetic anhydride (6 ml.) was heated at 12O 0 C for 2 hr. The reaction mixture was then cooled down to RT and the solvent was removed by rotary evaporation. Aqueous ammonia solution (28%) (12 ml.) was then added to the dry mixture and this was refluxed at 65 0 C for 2 hrs. During the reflux, another 6 ml. of aqueous ammonia solution (28%) was added. A precipitate was formed which was filtered off, then washed with water, and then with diethyl ether. The title compound thus obtained (1.042 g) was dried in the oven overnight, m/z [M+H] + : 238.8 / 240.8. Retention time 0.67 min (LC/MS method 3).
  • 8-Bromo-2,3-dimethyl-4(3/-/)-quinazolinone (795 mg; may be prepared as described in intermediate 138), zinc cyanide (443 mg; Aldrich), palladium(ll) trifluoroacetate (41.8 mg; Aldrich), 1 ,1'-binaphthalen-2-yl[bis(1 ,1-dimethylethyl)]phosphane (110 mg; Aldrich) and zinc (103 mg) were charged to a 25 ml. flask and dissolved in ⁇ /, ⁇ /-dimethylacetamide (15 ml_). The mixture was purged through with argon, and heated to 80 0 C overnight.
  • a mixture of 2,3-dimethyl-4-oxo-3,4-dihydro-8-quinazolinecarbonitrile (50 mg; may be prepared as described in intermediate 139), NBS (44.7 mg) and benzoyl peroxide (0.608 mg) in carbon tetrachloride (2 ml.) was heated to reflux for 2 hr. NBS (44.7 mg) was added followed by benzoyl peroxide (0.608 mg) and the mixture was refluxed overnight. Further NBS (44.7 mg) and benzoyl peroxide (0.608 mg) were added. The mixture was refluxed for 3 hr. AIBN (0.412 mg) was added to the hot mixture that was refluxed overnight.
  • ethyl 4H-thieno[3,2-b]pyrrole-5-carboxylate (642 mg; may be prepared as described in intermediate 153) was dissolved in THF (20 ml_). This mixture was left under stirring and under argon for 10 min, and then lithium aluminium hydride (3 ml) was added slowly through a septum. The reaction mixture was left under stirring overnight. The reaction was stopped with the slow addition of wet THF (20 ml_), then the ice bath and argon atmosphere were removed, and aqueous sodium hydroxide (20 ml.) was added. Water (5 ml.) was poured into the reaction mixture, and the mixture was extracted with DCM (3 x 50 ml_).
  • 2-Methyl-1 ,6-naphthyridine (450 mg; may be prepared as described in intermediate 161 ) was dissolved in carbon tetrachloride (15 ml_). Benzoyl peroxide (37.8 mg) and N- chlorosuccinimide (500 mg) were added and the mixture was heated to reflux for 2 hr. The solvent was evaporated to give a black viscous oil that was filtered through a plug of silica (eluting with DCM). The fraction containing UV-visible material was evaporated and residue was purified by silica gel chromatography using 0-10% MeOH in EtOAc (12CV).
  • 3-Amino-2-nitrobenzonitrile (100 mg; may be prepared as described in intermediate 163) was taken up in ethanol (10 ml.) and then hydrogenated using the H-Cube Hydrogenator, using Full H 2 mode and catalytic palladium on carbon. The output solution was concentrated under vacuum to afford the title compound (73 mg) as a pale yellow solid, m/z [M+H] + : 134.1. Retention time 0.48 min (LC/MS method 3).
  • 2,3-Diaminobenzonitrile (80 mg; may be prepared as described in intermediate 164) was taken up in ethanol (10 ml). Ethyl 3-bromo-2-oxopropanoate (0.076 ml; Aldrich) was added and left to stir at room temperature overnight. The reaction mixture was filtered, leaving a light orange solid as the residue (15mg). The filtrate was concentrated under vacuum. It was then diluted with DCM and purified, along with the residue, using silica chromatography (10 - 70% EtOAc / isohexane) to give the title compound (70 mg) as an orange solid, m/z [M+H] + : 264.0 / 266.0. Retention time 0.72 min (LC/MS method 3).
  • Lithium borohydride (small amounts portionwise over six hours, approximately 300 mg) was added and the mixture was heated at 5O 0 C for 24 hr. The reaction mixture was cooled and left at RT for 2 days. The solvent was evaporated and the residue dissolved in aqueous hydrochloric acid (2 N, 20 ml). The aqueous was washed with EtOAc (2 x 30 ml). The aqueous was basified with 12.5 N aqueous sodium hydroxide to pH 14 and then extracted with DCM (3 x 25 ml). The organic layer was dried over magnesium sulfate, filtered and evaporated to give an off-white solid (42mg). This was purified by MDAP to afford the title compound (32 mg) as a white solid.
  • NBS (200 mg) was added to a solution of 2-methylquinazoline (200 mg, ACES) in carbon tetrachloride (8 ml_). The mixture was heated to 75 0 C under argon and then AIBN (23 mg) was added. Heating continued for 4 hr. The mixture was cooled then diluted with saturated aqueous sodium bicarbonate solution (10 ml_). The layers were separated and the aqueous was extracted with DCM (2 x 10 ml_). The combined organic layers were dried (hydrophobic frit) and evaporated to give a brown oil. Mass: 260 mg.
  • racemates were prepared by a similar procedure to that used for compound 2, from racemic 2,2-difluoro-8-(1-hydroxyethyl)-2H-1 ,4- benzoxazin-3(4H)-one (may be prepared as described in intermediate 4) and the appropriate alkylating agent. Purification was by MDAP (formic acid method or high pH method) or chromatography on silica. * indicates that catalytic potassium iodide was added to the reaction mixture.
  • Racemic 8-bromo-2,2-difluoro-2H-1 ,4-benzoxazin-3(4H)-one (50 mg, 0.189 mmol, intermediate 4), 5-(bromomethyl)-3-pyridinecarbonitrile (37.3 mg, 0.189 mmol, intermediate 24), potassium carbonate (52.3 mg, 0.379 mmol) and potassium iodide (0.314 mg, 1.894 ⁇ mol) were dissolved in DMF (3000 ⁇ l) in a 10 ml. round-bottomed flask open to the atmosphere and stirred at room temperature overnight. The reaction mixture was evaporated to dryness, redissolved in EtOAc (30ml) and treated with saturated aqueous sodium bicarbonate (30ml).
  • 2,2-Difluoro-8-[(1S)-1-hydroxyethyl]-2H-1 ,4-benzoxazin-3(4H)-one (75 mg, may be prepared as described in intermediate 5), 5-(bromomethyl)-3-pyridinecarbonitrile (233 mg, may be prepared as described in intermediate 24), potassium carbonate (90 mg, 0.655 mmol) and potassium iodide (0.543 mg, 3.27 ⁇ mol) were dissolved in DMF (5000 ⁇ l) in a 25 ml. round-bottomed flask open to the atmosphere and stirred at room temperature overnight. The reaction mixture was evaporated to dryness, redissolved in EtOAc (30ml) and treated with saturated aqueous sodium bicarbonate (30ml).
  • the aqueous layer was extracted with EtOAc (2x30ml) and the organic layers were combined, washed with brine (30ml), dried over magnesium sulfate, filtered and evaporated to dryness to give the crude product (194mg) as a light brown oil.
  • the crude product was purified on a 25+S Biotage silica cartridge, eluting with a 0 to 75 % mixture of EtOAc in hexane. The title compound was obtained (87 mg) as an cream solid.
  • 2,2-Difluoro-8-[(1 S)-1-hydroxyethyl]-2H-1 ,4-benzoxazin-3(4H)-one (5.4g; may be prepared as described in intermediate 5) was dissolved in dry DMF (200 ml.) and (2- cyano-4-pyridinyl)methyl methanesulfonate (5.00 g; may be prepared as described in intermediate 194) and potassium carbonate (6.51 g) were added at 25 0 C. The mixture (suspension) was stirred at 25 0 C overnight.
  • Racemic 2,2-difluoro-8-(1-hydroxyethyl)-2H-1 ,4-benzoxazin-3(4H)-one (50 mg; may be prepared as described in intermediate 4), 6-(bromomethyl)-2-pyridinecarbonitrile (64.5 mg, may be prepared as described in intermediate 39), potassium carbonate (60.3 mg, 0.436 mmol) and potassium iodide (0.362 mg, 2.182 ⁇ mol) were dissolved in DMF (2000 ⁇ l) in a 10 ml. round-bottomed flask open to the atmosphere and stirred at room temperature overnight. The reaction mixture was evaporated to dryness, redissolved in EtOAc (30ml) and treated with saturated aqueous sodium bicarbonate (30ml).
  • the aqueous layer was extracted with EtOAc (2x30ml) and the organic layers were combined, washed with brine (30ml), dried over magnesium sulfate, fiitered and evaporated to dryness to give the crude product (94mg) as a pale yellow oil.
  • the crude product was purified on a 25+S Biotage silica cartridge, eluting with a 0 to 70 % mixture of EtOAc in hexane to give a colourless oil (67 mg). 53 mg of this racemic mixture was resolved using a Chiralpak IA column eluting with heptane: ethanol (80:20) v/v pump- mixed.
  • racemates were prepared by a similar procedure to that used for compound 2, from racemic 2,2-difluoro-8-(1-hydroxyethyl)-2H-1 ,4- benzoxazin-3(4H)-one (may be prepared as described in intermediate 4) and the appropriate alkylating agent. Purification was by MDAP or chromatography on silica. * indicates that catalytic potassium iodide was added to the reaction mixture.
  • the following compounds 117 to 177 were prepared by a similar procedure to that used for compound 91 , from 2,2-difluoro-8-[(1 S)-1-hydroxyethyl]-2H-1 ,4-benzoxazin-3(4/-/)-one (may be prepared as described in intermediate 5) and the appropriate alkylating agent.
  • Achiral purification was by MDAP (formic acid method) or chromatography on silica.

Abstract

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 GlyT1, including neurological and neuropsychiatric disorders, in particular psychoses, dementia or attention deficit disorder.

Description

Title
BENZOXAZ INONE DERIVATIVES FOR THE TREATMENT OF GLYTI MEDIATED DISORDERS
Technical field
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. Background
Molecular cloning has revealed the existence in mammalian brains of two classes of glycine transporters, termed GIyTI and GlyT2. 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). Molecular cloning has further revealed the existence of 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. Neurochemistry, 64, 1995 : 1026-1033). 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 Studies involving selective knockout of either GIyTI or GlyT2 have also suggested that 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 neurotransmission appears to contribute to the symptoms of schizophrenia (Lisman et al., Trends Neurosci. 31 , 234-242 (2008); Olney and Farber, Archives General Psychiatry, 52, 998-1007 (1996)). Thus, 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-α.
WO07/086504 (Japan Tobacco Inc.) discloses benzoxazinone compounds which are inhibitors of URAT1 activity and effective for treating diseases associated with uric acid.
However, there still remains the need to identify further compounds that can inhibit GIyTI transporters, including those that inhibit GIyTI transporters selectively over GlyT2 transporters.
Summary of the invention
It has now been found that a class of compounds inhibit GIyTI transporters and are thus of potential utility in the treatment or prophylaxis of certain neurological and neuropsychiatric disorders, including schizophrenia.
In a first aspect, there is provided a compound of formula (I), or a salt thereof, wherein
Figure imgf000003_0001
(I)
R1 is selected from
a) 5 to 6 membered heteroaryl ring which contains 1 to 4 heteroatoms independently selected from O, N and S;
b) 8 to 10 membered fused bicyclic ring system containing 0, 1 , 2, 3 or 4 heteroatoms independently selected from O, N and S, with a maximum of 3 heteroatoms present in each of the two rings; wherein 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, C1-4alkyl, C1-4alkoxy, cyano, hydroxy, hydroxyC1-4alkyl, -(CH2)n-(NR1aR1b), -(CO)NR1aR1b, -(CO)O-C1-4alkyl, -(CHO), haloC1-4alkyl and haloC1-4alkoxy; or
(c) phenyl which is unsubstituted or substituted with 1 to 3 substituents independently selected from halo,
Figure imgf000004_0001
cyano, hydroxy,
Figure imgf000004_0002
-(CH2)n- (NR1aR1b), -(CO)NR1aR1b, -(CO)O-Ci-4alkyl, -(CHO), -SO2(NR1aR1b), haloCi-4alkyl and haloCi_4alkoxy;
n is 1 , 2, 3 or 4;
R1a and R1b are independently selected from hydrogen, Ci-4alkyl and haloCi-4alkyl;
R2 is selected from hydrogen, halo, cyano,
Figure imgf000004_0003
Ci-4alkoxy and haloCi.
4alkoxy;
R3 is selected from hydrogen, halo, cyano and haloCi-4alkyl; and
R4 is selected from hydrogen, halo, cyano,
Figure imgf000004_0004
Ci-4alkoxy and haloCi. 4alkoxy.
According to a further aspect, there is provided a compound of formula (I) as defined in the first aspect, or a pharmaceutically acceptable salt thereof, for use in therapy. According to a further aspect, there is provided a compound of formula (I) as defined in the first aspect, or a pharmaceutically acceptable salt thereof, for use in treating a disorder mediated by GIyTL
According to a further aspect, there is provided the use of a compound of formula (I) as defined in the first aspect, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a disorder mediated by GIyTI .
According to a further aspect, there is provided 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) as defined in the first aspect, or a pharmaceutically acceptable salt thereof.
According to a further aspect, there is provided a pharmaceutical composition comprising (a) a compound of formula (I) as defined in the first aspect, or a pharmaceutically acceptable salt thereof, and (b) a pharmaceutically acceptable excipient.
Description of the embodiments In a first aspect, there is provided a compound of formula (I), or a salt thereof, wherein
Figure imgf000005_0001
R1 is selected from
a) 5 to 6 membered heteroaryl ring which contains 1 to 4 heteroatoms independently selected from O, N and S;
b) 8 to 10 membered fused bicyclic ring system containing O, 1 , 2, 3 or 4 heteroatoms independently selected from O, N and S, with a maximum of 3 heteroatoms present in each of the two rings;
wherein 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, C1-4alkyl, C1-4alkoxy, cyano, hydroxy, hydroxyC1-4alkyl, -(CH2)n-(NR1aR1b),
-(CO)NR1aR1b, -(CO)O-C1-4alkyl, -(CHO), haloC1-4alkyl and haloC1-4alkoxy; or
(c) phenyl which is unsubstituted or substituted with 1 to 3 substituents independently selected from halo, C1-4alkyl, C1-4alkoxy, cyano, hydroxy, hydroxyC1-4alkyl, -(CH2)n- (NR1aR1b), -(C0)NR1aR1b, -(CO)O-C1-4alkyl, -(CHO), -SO2(NR1aR1b), haloC1-4alkyl and haloC1-4alkoxy;
n is 1 , 2, 3 or 4;
R1a and R1b are independently selected from hydrogen, C1-4alkyl and haloC1-4alkyl;
R2 is selected from hydrogen, halo, cyano,
Figure imgf000005_0002
Ci-4alkoxy and haloCi. 4alkoxy;
R3 is selected from hydrogen, halo, cyano and haloCi-4alkyl; and
R4 is selected from hydrogen, halo, cyano,
Figure imgf000005_0003
Ci-4alkoxy and haloCi.
4alkoxy. Definitions
As used herein, the term 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. For example, C1-6 alkyl means a straight or branched hydrocarbon chain containing at least 1 and at most 6 carbon atoms. Examples of alkyl include, but are not limited to; methyl (Me), ethyl (Et), n-propyl, i-propyl, t-butyl, n-hexyl and i-hexyl. Other examples of alkyl include, but are not limited to; n-butyl, isobutyl, sec-butyl, n-pentyl, isopentyl or neopentyl.
As used herein, the term alkoxy (when used as a group or as part of a group) refers to an -O-alkyl group wherein alkyl is as defined hereinbefore. Examples of alkoxy include, but are not limited to; methoxy, ethoxy, propoxy, butoxy, pentoxy or hexoxy.
The term halo is used herein to describe, unless otherwise stated, a group selected from fluoro (fluorine), chloro (chlorine), bromo (bromine) or iodo (iodine).
The term haloCi-4alkyl as used herein refers to a Ci-4alkyl group as defined herein substituted with one or more halo groups as defined herein, which halo groups may be the same or different. Examples of haloCi-4alkyl include, but are not limited to; CF3, CF2H or CF3CH2.
The term haloC1-4alkoxy as used herein refers to a C1-4alkoxy group as defined herein substituted with one or more halo groups which halo groups may be the same or different, e.g. -O-CF3 or difluoromethoxy. The term -(CO)O-C1-4alkyl as used herein refers an carboxylic acid ester group wherein C1-4alkyl is defined herein. Examples of haloC1-4alkyl include, but are not limited to; - (CO)O-methyl or -(CO)O-ethyl.
The term oxo as used herein refers to a bivalent oxygen substituent, i.e. =0.
The term hydroxyCi-4alkyl as used herein refers to a Ci-4alkyl group as defined herein substituted with one hydroxy group, e.g. -CH2CH2OH.
The term -(CO)NR1aR1b as used herein refers to an amide group wherein an amine group NR1aR1b is attached to a carbonyl group C=O. The term -SO2(NR1aR1b) as used herein refers to a sulphonamide group wherein an amine group NR1aR1b is attached to a sulfon group S(=O)2.
The term 5 to 6 membered heteroaryl ring refers to a 5 to 6 membered aromatic ring system which contains 1 to 3 heteroatoms independently selected from oxygen, nitrogen or sulphur. Examples of 5-membered heteroaryl rings in this instance include, but are not limited to, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, isothiazolyl, isoxazolyl, thienyl, pyrazolyl and tetrazolyl. Examples of 6- membered heteroaryl rings include pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl and triazinyl. The term 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, dihydrobenzoxazinyl, dihydrochromenyl, dihydrobenzodioxinyl, tetrahydroquinolinyl, tetrahydroquinoxalinyl, tetrahydronaphthalenyl dihydrobenzoxazolyl, dihydrobenzofuranyl, dihydrobenzopyranyl, dihydrobenzothiopyranyl, dihydrobenzothienyl, dihydrodioxinopyridinyl, dihydroindenyl, dihydropyrrolopyridinyl, dihydropyrrolopyrimidinyl, dihydropyrrolopyrazinyl, dihydropyrrolopyridazinyl, pyrrolopyridinyl, pyrrolopyrazinyl, pyrrolopyridazinyl, pyrrolopyrimidinyl, furopyrimidinyl, furopyrazinyl, furopyridazinyl, thienopyridinyl, thienopyrazinyl, thienopyridazinyl, thienopyrimidinyl, pyrazolopyridinyl, pyrazolopyrazinyl, pyrazolopyridazinyl, pyrazolopyrimidinyl, imidazopyridinyl, imidazopyrazinyl, imidazopyridazinyl, imidazopyrimidinyl, indazolyl, thiazolopyridinyl, thiazolopyrazinyl, thiazolopyridazinyl, thiazolopyrimidinyl, thienopyrazolyl, oxazolopyridinyl, oxazolopyrazinyl, oxazolopyridazinyl, oxazolopyrimidinyl, pyridopyrazinyl, pyridopyridazinyl, pyridopyrimidinyl, pyridooxazinyl, pyrazinooxazinyl, pyridazinooxazinyl, pyrimidooxazinyl, dihydropyridooxazinyl, dihydropyrazinooxazinyl, dihydropyridazinooxazinyl, dihydropyrimidooxazinyl, dihydropyranopyridinyl, dihydropyranopyrazinyl, dihydropyranopyridazinyl, dihydropyrimidinyl, pyranopyridinyl, pyranopyrimidinyl, pyranopyrazinyl, pyranopyridazinyl, dihydrodioxinopyridinyl, dihydrodioxinopyrazinyl, dihydrodioxinopyridazinyl, dihydrodioxinopyrimidinyl, tetrahydronaphthyridinyl, tetrahydropyridopyridazinyl, tetrahydropyridopyrazinyl, tetrahydropyridopyrimidinyl, tetrahydropyrazinopyridazinyl, tetrahydropteridinyl, tetrahydropyrazinopyrazinyl, tetrahydroquinolinyl, tetrahydrocinnolinyl, tetrahydroquinazolinyl, tetrahydroquinoxalinyl, thiinopyridinyl, thiinopyrazinyl, thiinopyridazinyl, thiinopyrimidinyl, dihydrothiinopyridinyl, dihydrothiinopyrazinyl, dihydrothiinopyridazinyl, dihydrothiinopyrimidinyl, dihydrofuropyridinyl, dihydrofuropyrazinyl, dihydrofuropyridazinyl, dihydrofuropyrimidinyl, dihydrothienopyridinyl, dihydrothienopyrazinyl, dihydrothienopyridazinyl, dihydrothienopyrimidinyl, dihydrocyclopentapyridinyl, dihydrocyclopentapyrazinyl, dihydrocyclopentapyridazinyl, dihydrocyclopentapyrimidinyl, imidazothiazolyl and dihydrothienopyrazolyl. For the avoidance of doubt, the term independently means that where more than one substituent is selected from a number of possible substituents, those substituents may be the same or different. Throughout the specification and the claims which follow, unless the context requires otherwise, the term comprise, and variations such as comprises and comprising, will be understood to imply the inclusion of a stated integer or step or group of integers but not to the exclusion of any other integer or step or group of integers or steps.
In a second aspect, there is provided a compound of formula I as represented by formula (Ia), or a salt thereof, wherein
Figure imgf000008_0001
(Ia)
R1, R2, R3 and R4 are as defined in the first aspect.
In a third aspect, there is provided a compound of formula I as represented by formula (Ib), or a salt thereof, wherein
Figure imgf000008_0002
(Ib)
R1, R2, R3 and R4 are as defined in the first aspect.
In one embodiment, the compound as defined in the first to third aspect is not 2,2- difluoro-8-(1 -hydroxyethyl)-4-[(5-oxo-5H-[1 ,3]thiazolo[3,2-a]pyrimidin-7-yl)methyl]-2H-1 ,4- benzoxazin-3(4H)-one and 2,2-difluoro-8-(1-hydroxyethyl)-4-[(1-methyl-4-oxo-1 ,4- dihydro-2-quinolinyl)methyl]-2H-1 ,4-benzoxazin-3(4H)-one.
In one embodiment of the first to third aspect, R2, R3 and R4 are independently selected from hydrogen, halo, cyano and
Figure imgf000008_0003
In a more particular embodiment of the first to third aspect, R2, R3 and R4 are independently selected from hydrogen, halo and cyano. In an even more particular embodiment of the first to third aspect, R2, R3 and R4 are independently selected from hydrogen and halo. In yet an even more particular embodiment, R2 is halo and R3 and R4 are hydrogen. In a most particular embodiment, R2 is fluoro and R3 and R4 are hydrogen. In a most particular embodiment, R2, R3 and R4 are hydrogen.
In one embodiment of the first to third aspect, R1 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,
Figure imgf000009_0001
Ci-4alkoxy, cyano, hydroxyl, hydroxy Ci- 4alkyl, -(CH2)n-(NR1aR1b), -(CO)NR1aR1b, -(CO)O-Ci-4alkyl, -(CHO), haloCi-4alkyl and haloCi_4alkoxy, or R1 is phenyl which is unsubstituted or substituted with 1 or 2 substituents independently selected from halo, Ci-4alkyl, Ci-4alkoxy, cyano, hydroxyl, hydroxy C1-4alkyl, -(CH2)n-(NR1aR1b), -(CO)NR1aR1b, -(CO)O-Ci-4alkyl, -(CHO), - SO2(NR1aR1b), haloC1-4alkyl and haloC1-4alkoxy.
In one particular embodiment, R1 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, C1-4alkyl, C1-4alkoxy, cyano, hydroxyl, hydroxy C1-4alkyl, -(CH2)n- (NR1aR1b), -(CO)NR1aR1b, -(CO)O-C1-4alkyl, -(CHO), haloC1-4alkyl and haloC1-4alkoxy or R1 is phenyl which is unsubstituted or substituted with 1 or 2 substituents independently selected from halo, C1-4alkyl, C1-4alkoxy, cyano, hydroxyl, hydroxy C1-4alkyl, -(CH2)n- (NR1aR1b), -(C0)NR1aR1b, -(CO)O-Ci-4alkyl, -(CHO), -SO2(NR1aR1b), haloCi-4alkyl and haloCi_4alkoxy; and wherein at least one substituent is attached to the 3-position relative to the bond attaching the phenyl to the rest of the molecule.
In another particular embodiment, R1 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,
Figure imgf000009_0002
Ci- 4alkoxy, cyano, hydroxyl, hydroxy C1-4alkyl, -(CH2)n-(NR1aR1b), -(C0)NR1aR1b, -(CO)O-Ci- 4alkyl, -(CHO), haloCi-4alkyl and haloCi-4alkoxy or R1 is phenyl which is unsubstituted or substituted with 1 or 2 substituents independently selected from halo, C1-4alkyl, Ci- 4alkoxy, cyano, -S02(NR1aR1b), haloCi-4alkyl and haloCi-4alkoxy.
In a further embodiment, R1 is selected from - furanyl which is unsubstituted or substituted with 1 substituent selected from C1-4alkyl, - (CO)O-C1-4alkyl, -(CHO) and haloC1-4alkyl;
- thiazolyl which is unsubstituted or substituted with 1 substituent selected from C1-4alkyl;
- thienyl which is unsubstituted or substituted with 1 substituent selected from -(CO)O-C1- 4alkyl,
- unsubstituted oxazolyl,
- pyridyl which is unsubstituted or substituted with 1 or 2 substituents independently selected from halo, haloCi-4alkyl, -(CO)O-Ci-4alkyl, Ci-4alkyl, Ci-4alkoxy and cyano;
- unsubstituted pyrimidinyl;
- unsubstituted pyrazinyl;
- unsubstituted pyridazinyl; and
- phenyl which is unsubstituted or substituted with 1 or 2 substituents independently selected from fluoro, chloro, cyano, methyl, methoxy and -SO2(NR1aR1b). In one embodiment of the first to third aspect, R1 is selected from
- furanyl which is unsubstituted or substituted with 1 substituent selected from methyl, - (CO)O-CH3, -(CHO) and trifluoromethyl;
- thiazolyl which is unsubstituted or substituted with 1 substituent selected from methyl;
- thienyl which is unsubstituted or substituted with 1 substituent selected from -(CO)O- CH3,
- unsubstituted oxazolyl,
- pyridyl which is unsubstituted or substituted with 1 or 2 substituents independently selected from fluoro, chloro, trifluoromethyl, -(CO)O-CH3, methyl, methoxy and cyano;
- unsubstituted pyrimidinyl;
- unsubstituted pyrazinyl; and
- unsubstituted pyridazinyl; and
- phenyl which is unsubstituted or substituted with 1 or 2 substituents independently selected from fluoro, chloro, cyano, methyl, methoxy and -S02(NR1aR1b). In one embodiment of the first to third aspect, R1 is selected from
- 3-pyridyl which is unsubstituted or substituted with 1 or 2 substituents independently selected from fluoro, chloro, methoxy, cyano, trifluoromethyl, methyl and -(CO)O-CH3;
- 2-pyridyl which is unsubstituted or substituted with 1 or 2 substituents independently selected from methyl, chloro, fluoro, methoxy and cyano;
- 4-pyridyl which is unsubstituted or substituted with 1 or 2 substituents independently selected from fluoro, methyl, chloro and cyano; and - phenyl which is unsubstituted or substituted with 1 or 2 substituents independently selected from fluoro, cyano, methyl and methoxy.
In one embodiment of the first to third aspect, R1 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,
Figure imgf000011_0001
Ci-4alkoxy, cyano, hydroxyl, hydroxy Ci- 4alkyl, -(CH2)n-(NR1aR1b), -(C0)NR1aR1b, -(CO)O-Ci-4alkyl, -(CHO), haloCi-4alkyl and haloCi_4alkoxy or R1 is phenyl which is unsubstituted or substituted with 1 or 2 substituents independently selected from halo, Ci-4alkyl, Ci-4alkoxy, cyano, hydroxyl, hydroxy C1-4alkyl, -(CH2)n-(NR1aR1b), -(C0)NR1aR1b, -(CO)O-Ci-4alkyl, -(CHO), - S02(NR1aR1b), haloCi-4alkyl and haloCi-4alkoxy; R2, R3 and R4 are independently selected from hydrogen, halo, cyano and haloCi-4alkyl. In one embodiment of the first to third aspect, R1 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, C1-4alkyl, C1-4alkoxy, cyano, hydroxyl, hydroxy C1- 4alkyl, -(CH2)n-(NR1aR1b), -(C0)NR1aR1b, -(CO)O-C1-4alkyl, -(CHO), haloC1-4alkyl and haloC1-4alkoxy or R1 is phenyl which is unsubstituted or substituted with 1 or 2 substituents independently selected from halo, C1-4alkyl, C1-4alkoxy, cyano, - SO2(NR1aR1b), haloC1-4alkyl and haloC1-4alkoxy; R2, R3 and R4 are independently selected from hydrogen, halo and cyano. In one embodiment of the first to third aspect, R1 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,
Figure imgf000011_0002
Ci-4alkoxy, cyano, hydroxyl, hydroxy Ci- 4alkyl, -(CH2)n-(NR1aR1b), -(C0)NR1aR1b, -(CO)O-Ci-4alkyl, -(CHO), haloCi-4alkyl and haloCi_4alkoxy or R1 is phenyl which is unsubstituted or substituted with 1 or 2 substituents independently selected from halo, Ci-4alkyl, Ci-4alkoxy, cyano, hydroxyl, hydroxy C1-4alkyl, -(CH2)n-(NR1aR1b), -(C0)NR1aR1b, -(CO)O-Ci-4alkyl, -(CHO), - S02(NR1aR1b), haloCi^alkyl and haloCi-4alkoxy; R2, R3 and R4 are independently selected from hydrogen, halo, cyano and haloC^alkyl, R2 is hydrogen or halo, R3 is hydrogen and R4 is hydrogen or halo. In one embodiment of the first to third aspect, R1 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, C1-4alkyl, C1-4alkoxy, cyano, hydroxyl, hydroxy C1-4alkyl, -(CH2)n-(NR1aR1b), - (CO)NR1aR1b, -(CO)O-C1-4alkyl, -(CHO), haloC1-4alkyl and haloC1-4alkoxy, R2 is hydrogen or halo, in particular fluoro, R3 is hydrogen and R4 is hydrogen or halo, in particular fluoro.
In one embodiment of the first to third aspect, R1 is selected from
- furanyl which is unsubstituted or substituted with 1 substituent selected from C-^alkyl, - (CO)O-Ci.4alkyl, -(CHO) and haloCi-4alkyl;
- thiazolyl which is unsubstituted or substituted with 1 substituent selected from
Figure imgf000012_0001
- thienyl which is unsubstituted or substituted with 1 substituent selected from -(CO)O-Ci- 4alkyl,
- unsubstituted oxazolyl,
- pyridyl which is unsubstituted or substituted with 1 or 2 substituents selected from halo, haloC1-4alkyl, -(CO)O-C1-4alkyl, C1-4alkyl, C1-4alkoxy and cyano;
- unsubstituted pyrimidinyl;
- unsubstituted pyrazinyl;
- unsubstituted pyridazinyl; and
-phenyl which is unsubstituted or substituted with 1 or 2 substituents independently selected from fluoro, cyano, methyl and methoxy;
R2 is hydrogen or halo, in particular fluoro, R3 is hydrogen and R4 is hydrogen or halo, in particular fluoro.
In one embodiment of the first to third aspect, R1 is selected from
- furanyl which is unsubstituted or substituted with 1 substituent selected from methyl, - (CO)O-CH3, -(CHO) and trifluoromethyl;
- thiazolyl which is unsubstituted or substituted with 1 substituent selected from methyl; - thienyl which is unsubstituted or substituted with 1 substituent selected from -(CO)O-
CH3,
- unsubstituted oxazolyl,
- pyridyl which is unsubstituted or substituted with 1 or 2 substituents independently selected from fluoro, chloro, trifluoromethyl, -(CO)O-CH3, methyl, methoxy and cyano; - unsubstituted pyrimidinyl;
- unsubstituted pyrazinyl;
- unsubstituted pyridazinyl; and -phenyl which is unsubstituted or substituted with 1 or 2 substituents independently selected from fluoro, cyano, methyl and methoxy;
R2 is hydrogen or halo, in particular fluoro, R3 is hydrogen and R4 is hydrogen or halo, in particular fluoro.
In one embodiment of the first to third aspect, R1 is selected from
- 3-pyridyl which is unsubstituted or substituted with 1 or 2 substituents selected from fluoro, chloro, methoxy, cyano, trifluoromethyl, methyl and -(CO)O-CH3;
- 2-pyridyl which is unsubstituted or substituted with 1 or 2 substituents independently selected from methyl, chloro, fluoro, methoxy and cyano;
- 4-pyridyl which is unsubstituted or substituted with 1 or 2 substituents independently selected from fluoro, methyl, chloro and cyano; and
-phenyl which is unsubstituted or substituted with 1 or 2 substituents independently selected from fluoro, cyano, methyl and methoxy;
R2 is hydrogen or halo, in particular fluoro, R3 is hydrogen and R4 is hydrogen or halo, in particular fluoro.
In one embodiment of the first to third aspect, R1 is selected from
- furanyl which is unsubstituted or substituted with 1 substituent selected from C1-4alkyl, - (CO)O-C1-4alkyl, -(CHO) and haloC1-4alkyl;
- thiazolyl which is unsubstituted or substituted with 1 substituent selected from C1-4alkyl;
- thienyl which is unsubstituted or substituted with 1 substituent selected from -(CO)O-C1- 4alkyl,
- unsubstituted oxazolyl,
- pyridyl which is unsubstituted or substituted with 1 or 2 substituents selected from halo, haloCi_4alkyl, -(CO)O-Ci-4alkyl, Ci-4alkyl,
Figure imgf000013_0001
and cyano;
- unsubstituted pyrimidinyl;
- unsubstituted pyrazinyl;
- unsubstituted pyridazinyl; and
-phenyl which is unsubstituted or substituted with 1 or 2 substituents independently selected from fluoro, cyano, methyl and methoxy;
R2, R3 and R4 are hydrogen.
In one embodiment of the first to third aspect, R1 is selected from
- furanyl which is unsubstituted or substituted with 1 substituent selected from methyl, - (CO)O-CH3, -(CHO) and trifluoromethyl;
- thiazolyl which is unsubstituted or substituted with 1 substituent selected from methyl; - thienyl which is unsubstituted or substituted with 1 substituent selected from -(CO)O- CH3,
- unsubstituted oxazolyl,
- pyridyl which is unsubstituted or substituted with 1 or 2 substituents independently selected from fluoro, chloro, trifluoromethyl, -(CO)O-CH3, methyl, methoxy and cyano;
- unsubstituted pyrimidinyl;
- unsubstituted pyrazinyl; and
- unsubstituted pyridazinyl; and
R2, R3 and R4 are hydrogen.
In one embodiment of the first to third aspect, R1 is selected from
- 3-pyridyl which is unsubstituted or substituted with 1 or 2 substituents selected from fluoro, chloro, methoxy, cyano, trifluoromethyl, methyl and -(CO)O-CH3;
- 2-pyridyl which is unsubstituted or substituted with 1 or 2 substituents independently selected from methyl, chloro, fluoro, methoxy and cyano; and
- 4-pyridyl which is unsubstituted or substituted with 1 or 2 substituents independently selected from fluoro, methyl, chloro and cyano; and
R2, R3 and R4 are hydrogen. In one embodiment of the first to third aspect, R1 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, C1-4alkyl, C1-4alkoxy, cyano, hydroxyl, hydroxy C1-4alkyl, -(CH2)n- (NR1aR1b), -(CO)NR1aR1b, -(CO)O-C1-4alkyl, -(CHO), haloC1-4alkyl and haloC1-4alkoxy or R1 is phenyl which is unsubstituted or substituted with 1 or 2 substituents independently selected from halo, Ci-4alkyl, Ci-4alkoxy, cyano, hydroxyl, hydroxy C1-4alkyl, -(CH2)n- (NR1aR1b), -(C0)NR1aR1b, -(CO)O-Ci-4alkyl, -(CHO), -SO2(NR1aR1b), haloCUalkyl and haloCi_4alkoxy.
In one embodiment of the first to third aspect, R1 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, C1-4alkyl, C1-
4alkoxy, cyano, hydroxyl, hydroxy C1-4alkyl, -(CH2)n-(NR1aR1b), -(CO)NR1aR1b, -(CO)O-C1- 4alkyl, -(CHO), haloC1-4alkyl and haloC1-4alkoxy or R1 is phenyl which is unsubstituted or substituted with 1 or 2 substituents independently selected from halo, C1-4alkyl, C1-
4alkoxy, cyano, hydroxyl, hydroxy C1-4alkyl, -(CH2)n-(NR1aR1b), -(C0)NR1aR1b, -(CO)O-C1- 4alkyl, -(CHO), -SO2(NR1aR1b), haloC1-4alkyl and haloC1-4alkoxy; and wherein at least one substituent is attached to the 3-position relative to the bond attaching the phenyl to the rest of the molecule. In one embodiment of the first to third aspect, R1 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,
Figure imgf000015_0001
Ci- 4alkoxy, cyano, haloCi-4alkyl and haloCi-4alkoxy, particularly oxo and Ci-4alkyl, more particularly oxo and methyl or R1 is phenyl which is unsubstituted or substituted with 1 or 2 substituents independently selected from halo, Ci-4alkyl, Ci-4alkoxy, cyano, - SO2(NR1aR1b),
Figure imgf000015_0002
and haloCi-4alkoxy. In one embodiment of the first to third aspect, R1 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, benzimidazol-2-yl, 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, 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, C1-4alkyl, C1-4alkoxy, cyano, haloC1-4alkyl and haloC1-4alkoxy, particularly oxo and C1-4alkyl, more particularly oxo and methyl or R1 is phenyl which is unsubstituted or substituted with 1 or 2 substituents independently selected from halo,
Figure imgf000015_0003
cyano, -SO2(NR1aR1b), haloCi-4alkyl and haloCi. 4alkoxy.
In one embodiment of the first to third aspect, R1 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,
Figure imgf000015_0004
Ci- 4alkoxy, cyano, haloCi-4alkyl and haloCi-4alkoxy, particularly oxo and Ci-4alkyl, more particularly oxo and methyl or R1 is phenyl which is unsubstituted or substituted with 1 or 2 substituents independently selected from halo, C1-4alkyl, Ci-4alkoxy, cyano, - SO2(NR1aR1b), haloC^alkyl and haloCi-4alkoxy; and R2, R3 and R4 are hydrogen. In one embodiment of the first to third aspect, R1 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-4alkyl,
Figure imgf000016_0001
cyano,
Figure imgf000016_0002
and haloCi-4alkoxy, particularly oxo and Ci-4alkyl more particularly oxo and methyl or R1 is phenyl which is unsubstituted or substituted with 1 or 2 substituents independently selected from halo, Ci-4alkyl, C^alkoxy, cyano, hydroxyl, hydroxy C1-4alkyl, -(CH2)n-(NR1aR1b), -(CO)NR1aR1b, -(CO)O-Ci-4alkyl, -(CHO), -SO2(NR1aR1b), haloCi-4alkyl and haloC^alkoxy; and wherein at least one substituent is attached to the 3-position relative to the bond attaching the phenyl to the rest of the molecule; and R2, R3 and R4 are hydrogen.
In one embodiment of the first to third aspect, R1 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, C1-4alkyl, C1- 4alkoxy, cyano, haloC1-4alkyl and haloC1-4alkoxy, particularly oxo and C1-4alkyl, more particularly oxo and methyl or R1 is phenyl which is unsubstituted or substituted with 1 or 2 substituents independently selected from halo, C1-4alkyl, C1-4alkoxy, cyano, - SO2(NR1aR1b), haloC1-4alkyl and haloC1-4alkoxy; R2 is halo, in particular fluoro, R3 is hydrogen and R4 is hydrogen or halo, in particular fluoro. In one embodiment of the first to third aspect, R1 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-4alkyl,
Figure imgf000016_0003
cyano,
Figure imgf000016_0004
and haloCi-4alkoxy, particularly oxo and Ci-4alkyl more particularly oxo and methyl or R1 is phenyl which is unsubstituted or substituted with 1 or 2 substituents independently selected from fluoro, chloro, cyano, methyl, methoxy and -SO2(NR1aR1b); R2 is halo, in particular fluoro, R3 is hydrogen and R4 is hydrogen or halo, in particular fluoro.
In one embodiment of the first to third aspect, R1 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, C1-4alkyl, C1-4alkoxy, cyano, haloC1-4alkyl and haloC1-4alkoxy, particularly oxo and C1-4alkyl more particularly oxo and methyl or R1 is phenyl which is unsubstituted or substituted with 1 or 2 substituents independently selected from fluoro, cyano, methyl and methoxy; R2 is halo, in particular fluoro, R3 is hydrogen and R4 is hydrogen or halo, in particular fluoro. In one particular embodiment, compounds as defined in the first to third aspect, or salts thereof, are selected from supporting compounds 1 to 224, or salts thereof. In a more particular embodiment, compounds as defined in the first to third aspect, or salts thereof, are selected from supporting compounds 1 to 100 and 197 to 224, or salts thereof. More particularly, compounds as defined in the first to third aspect, or salts thereof, are selected from
5-{[2,2-Difluoro-8-[1-hydroxyethyl]-3-oxo-2,3-dihydro-4H-1 ,4-benzoxazin-4-yl]methyl}-3- pyridinecarbonitrile;
2,2-Difluoro-8-[(1S)-1-hydroxyethyl)-4-[(3-methyl-4-oxo-3,4-dihydro-2- quinazolinyl)methyl]-2H-1 ,4-benzoxazin-3(4H)-one;
2,2-Difluoro-4-[(5-fluoro-3-pyridinyl)methyl]-8-[(1 S)-1-hydroxyethyl]-2H-1 ,4-benzoxazin-
3(4H)-one;
4-{[2,2-Difluoro-8-[1-hydroxyethyl)-3-oxo-2,3-dihydro-4H-1 ,4-benzoxazin-4-yl]methyl}-2- pyridinecarbonitrile;
6-({2,2-Difluoro-8-[1-hydroxyethyl]-3-oxo-2,3-dihydro-4H-1 ,4-benzoxazin-4-yl}methyl)-2- pyridinecarbonitrile; and
2,2,7-Trifluoro-4-[(5-fluoro-3-pyridinyl)methyl]-8-[(1 S)-1 -hydroxyethyl]-2H-1 ,4-benzoxazin-
3(4H)-one;
3-{[2,2-Difluoro-8-[(1 S)-1-hydroxyethyl]-3-oxo-2,3-dihydro-4H-1 ,4-benzoxazin-4- yl]methyl}benzonitrile and
3-{[2,2-difluoro-8-[(1 R)-1-hydroxyethyl]-3-oxo-2,3-dihydro-4H-1 ,4-benzoxazin-4- yl]methyl}benzonitrile;
or a salt thereof.
In a fourth aspect, there is provided a compound of formula (I) as represented by formula (Ic), or a salt thereof, wherein
Figure imgf000018_0001
R1 is selected from
a) 5 to 6 membered heteroaryl ring which contains 1 to 4 heteroatoms independently selected from O, N and S;
b) 8 to 10 membered fused bicyclic ring system containing 0, 1 , 2, 3 or 4 heteroatoms independently selected from O, N and S, with a maximum of 3 heteroatoms present in each of the two rings;
wherein 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, C1-4alkyl, C1-4alkoxy, cyano, hydroxy, hydroxyC1-4alkyl, -(CH2)n-(NR1aR1b),
-(CO)NR1aR1b, -(CO)O-C1-4alkyl, -(CHO), haloC1-4alkyl and haloC1-4alkoxy; or
n is 1 , 2, 3 or 4;
R1a and R1b are independently selected from hydrogen, C1-4alkyl and haloC1-4alkyl;
R2 is selected from hydrogen, halo, cyano, C1-4alkyl, haloC1-4alkyl, C1-4alkoxy and FIaIoC1- 4alkoxy;
R3 is selected from hydrogen, halo, cyano and haloC1-4alkyl; and
R4 is selected from hydrogen, halo, cyano, C1-4alkyl, haloC1-4alkyl, C1-4alkoxy and FIaIoC1-
4alkoxy. In a fifth aspect, there is provided a compound of formula I as represented by formula (Id), or a salt thereof, wherein
Figure imgf000018_0002
(Id)
R1 is selected from a) 5 to 6 membered heteroaryl ring which contains 1 to 4 heteroatoms independently selected from O, N and S; and
b) 8 to 10 membered fused bicyclic ring system containing 0, 1 , 2, 3 or 4 heteroatoms independently selected from O, N and S, with a maximum of 3 heteroatoms present in each of the two rings;
wherein 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, Ci-4alkyl,
Figure imgf000019_0001
cyano, hydroxy, hydroxyCi-4alkyl, -(CH2)n-(NR1aR1b), -(CO)NR1aR1b, -(CO)O-Ci-4alkyl, -(CHO), haloC^alkyl and haloCi-4alkoxy;
and R2, R3 and R4 are as defined in the first aspect.
In a sixth aspect, there is provided a compound of formula I as represented by formula (Ie), or a salt thereof, wherein
Figure imgf000019_0002
(Ie)
R1 is selected from
a) 5 to 6 membered heteroaryl ring which contains 1 to 4 heteroatoms independently selected from O, N and S;
b) 8 to 10 membered fused bicyclic ring system containing 0, 1 , 2, 3 or 4 heteroatoms independently selected from O, N and S, with a maximum of 3 heteroatoms present in each of the two rings;
wherein 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, Ci-4alkyl,
Figure imgf000019_0003
cyano, hydroxy, hydroxyCi-4alkyl, -(CH2)n-(NR1aR1b), -(CO)NR1aR1b, -(CO)O-Ci-4alkyl, -(CHO), haloC^alkyl and haloCi-4alkoxy;
and R2, R3 and R4 are as defined in the first aspect.
In one embodiment, the compound as defined in the fourth to sixth aspect is not 2,2- difluoro-8-(1 -hydroxyethyl)-4-[(5-oxo-5H-[1 ,3]thiazolo[3,2-a]pyrimidin-7-yl)methyl]-2H-1 ,4- benzoxazin-3(4H)-one and 2,2-difluoro-8-(1-hydroxyethyl)-4-[(1-methyl-4-oxo-1 ,4- dihydro-2-quinolinyl)methyl]-2H-1 ,4-benzoxazin-3(4H)-one. In one embodiment of the fourth to sixth aspect, R2, R3 and R4 are independently selected from hydrogen, halo, cyano and haloC1-4alkyl. In a more particular embodiment of the fourth to sixth aspect, R2, R3 and R4 are independently selected from hydrogen, halo and cyano. In an even more particular embodiment of the fourth to sixth aspect, R2, R3 and R4 are independently selected from hydrogen and halo. In yet an even more particular embodiment, R2 is halo and R3 and R4 are hydrogen. In a most particular embodiment, R2 is fluoro and R3 and R4 are hydrogen. In one embodiment of the fourth to sixth aspect, R1 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,
Figure imgf000020_0001
Ci-4alkoxy, cyano, hydroxyl, hydroxy Ci- 4alkyl, -(CH2)n-(NR1aR1b), -(CO)NR1aR1b, -(CO)O-Ci-4alkyl, -(CHO), haloCi-4alkyl and haloC1-4alkoxy. In one particular embodiment, R1 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, C1-4alkyl, C1-4alkoxy, cyano, hydroxyl, hydroxy C1- 4alkyl, -(CH2)n-(NR1aR1b), -(C0)NR1aR1b, -(CO)O-C1-4alkyl, -(CHO), haloC1-4alkyl and haloC1-4alkoxy. In another particular embodiment, R1 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, C1-4alkyl, C1-4alkoxy, cyano, hydroxyl, hydroxy C1-4alkyl, -(CH2)n-(NR1aR1b), - (CO)NR1aR1b,
Figure imgf000020_0002
-(CHO), haloCi-4alkyl and haloCi-4alkoxy. In a further embodiment, R1 is selected from
- furanyl which is unsubstituted or substituted with 1 substituent selected from - (COp-C^alkyl, -(CHO) and haloCi-4alkyl;
- thiazolyl which is unsubstituted or substituted with 1 substituent selected from
Figure imgf000020_0003
- thienyl which is unsubstituted or substituted with 1 substituent selected from -(CO)O-Ci- 4alkyl,
- unsubstituted oxazolyl,
- pyridyl which is unsubstituted or substituted with 1 or 2 substituents independently selected from halo, haloCi-4alkyl, -(CO)O-Ci-4alkyl, C1-4alkyl, Ci-4alkoxy and cyano;
- unsubstituted pyrimidinyl;
- unsubstituted pyrazinyl; and
- unsubstituted pyridazinyl. In one embodiment of the fourth to sixth aspect, R1 is selected from
- furanyl which is unsubstituted or substituted with 1 substituent selected from methyl, - (CO)O-CH3, -(CHO) and trifluoromethyl;
- thiazolyl which is unsubstituted or substituted with 1 substituent selected from methyl; - thienyl which is unsubstituted or substituted with 1 substituent selected from -(CO)O- CH3,
- unsubstituted oxazolyl,
- pyridyl which is unsubstituted or substituted with 1 or 2 substituents independently selected from fluoro, chloro, trifluoromethyl, -(CO)O-CH3, methyl, methoxy and cyano; - unsubstituted pyrimidinyl;
- unsubstituted pyrazinyl; and
- unsubstituted pyridazinyl.
In one embodiment of the fourth to sixth aspect, R1 is selected from
- 3-pyridyl which is unsubstituted or substituted with 1 or 2 substituents independently selected from fluoro, chloro, methoxy, cyano, trifluoromethyl, methyl and -(CO)O-CH3;
- 2-pyridyl which is unsubstituted or substituted with 1 or 2 substituents independently selected from methyl, chloro, fluoro, methoxy and cyano; and
- 4-pyridyl which is unsubstituted or substituted with 1 or 2 substituents independently selected from fluoro, methyl, chloro and cyano.
In one embodiment of the fourth to sixth aspect, R1 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,
Figure imgf000021_0001
Ci-4alkoxy, cyano, hydroxyl, hydroxy Ci- 4alkyl, -(CH2)n-(NR1aR1b), -(C0)NR1aR1b, -(CO)O-Ci-4alkyl, -(CHO), haloCi-4alkyl and haloCi_4alkoxy, R2 is hydrogen or halo, R3 is hydrogen and R4 is hydrogen or halo.
In one embodiment of the fourth to sixth aspect, R1 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, C1-4alkyl, Ci-4alkoxy, cyano, hydroxyl, hydroxy C1-4alkyl, -(CH2)n-(NR1aR1b), -
(C0)NR1aR1b, -(CO)O-C1-4alkyl, -(CHO), haloC1-4alkyl and haloC1-4alkoxy, R2 is hydrogen or halo, in particular fluoro, R3 is hydrogen and R4 is hydrogen or halo, in particular fluoro.
In one embodiment of the fourth to sixth aspect, R1 is selected from - furanyl which is unsubstituted or substituted with 1 substituent selected from C1-4alkyl, - (CO)O-C1-4alkyl, -(CHO) and haloC1-4alkyl;
- thiazolyl which is unsubstituted or substituted with 1 substituent selected from C1-4alkyl;
- thienyl which is unsubstituted or substituted with 1 substituent selected from -(CO)O-C1- 4alkyl,
- unsubstituted oxazolyl,
- pyridyl which is unsubstituted or substituted with 1 or 2 substituents selected from halo, haloCi_4alkyl, -(CO)O-Ci-4alkyl, Ci-4alkyl,
Figure imgf000022_0001
and cyano;
- unsubstituted pyrimidinyl;
- unsubstituted pyrazinyl; and
- unsubstituted pyridazinyl;
R2 is hydrogen or halo, in particular fluoro, R3 is hydrogen and R4 is hydrogen or halo, in particular fluoro. In one embodiment of the fourth to sixth aspect, R1 is selected from
- furanyl which is unsubstituted or substituted with 1 substituent selected from methyl, - (CO)O-CH3, -(CHO) and trifluoromethyl;
- thiazolyl which is unsubstituted or substituted with 1 substituent selected from methyl;
- thienyl which is unsubstituted or substituted with 1 substituent selected from -(CO)O- CH3,
- unsubstituted oxazolyl,
- pyridyl which is unsubstituted or substituted with 1 or 2 substituents independently selected from fluoro, chloro, trifluoromethyl, -(CO)O-CH3, methyl, methoxy and cyano;
- unsubstituted pyrimidinyl;
- unsubstituted pyrazinyl; and
- unsubstituted pyridazinyl;
R2 is hydrogen or halo, in particular fluoro, R3 is hydrogen and R4 is hydrogen or halo, in particular fluoro. In one embodiment of the fourth to sixth aspect, R1 is selected from
- 3-pyridyl which is unsubstituted or substituted with 1 or 2 substituents selected from fluoro, chloro, methoxy, cyano, trifluoromethyl, methyl and -(CO)O-CH3;
- 2-pyridyl which is unsubstituted or substituted with 1 or 2 substituents independently selected from methyl, chloro, fluoro, methoxy and cyano; and
- 4-pyridyl which is unsubstituted or substituted with 1 or 2 substituents independently selected from fluoro, methyl, chloro and cyano; R2 is hydrogen or halo, in particular fluoro, R3 is hydrogen and R4 is hydrogen or halo, in particular fluoro.
In one embodiment of the fourth to sixth aspect, R1 is selected from
- furanyl which is unsubstituted or substituted with 1 substituent selected from C1-4alkyl, - (CO)O-Ci-4alkyl, -(CHO) and haloC^alkyl;
- thiazolyl which is unsubstituted or substituted with 1 substituent selected from
Figure imgf000023_0001
- thienyl which is unsubstituted or substituted with 1 substituent selected from -(CO)O-Ci- 4alkyl,
- unsubstituted oxazolyl,
- pyridyl which is unsubstituted or substituted with 1 or 2 substituents selected from halo, haloCi-4alkyl, -(CO)O-Ci-4alkyl, Ci-4alkyl,
Figure imgf000023_0002
and cyano;
- unsubstituted pyrimidinyl;
- unsubstituted pyrazinyl; and
- unsubstituted pyridazinyl; and
R2, R3 and R4 are hydrogen.
In one embodiment of the fourth to sixth aspect, R1 is selected from
- furanyl which is unsubstituted or substituted with 1 substituent selected from methyl, - (CO)O-CH3, -(CHO) and trifluoromethyl;
- thiazolyl which is unsubstituted or substituted with 1 substituent selected from methyl;
- thienyl which is unsubstituted or substituted with 1 substituent selected from -(CO)O- CH3,
- unsubstituted oxazolyl,
- pyridyl which is unsubstituted or substituted with 1 or 2 substituents independently selected from fluoro, chloro, trifluoromethyl, -(CO)O-CH3, methyl, methoxy and cyano;
- unsubstituted pyrimidinyl;
- unsubstituted pyrazinyl; and
- unsubstituted pyridazinyl; and
R2, R3 and R4 are hydrogen.
In one embodiment of the fourth to sixth aspect, R1 is selected from
- 3-pyridyl which is unsubstituted or substituted with 1 or 2 substituents selected from fluoro, chloro, methoxy, cyano, trifluoromethyl, methyl and -(CO)O-CH3;
- 2-pyridyl which is unsubstituted or substituted with 1 or 2 substituents independently selected from methyl, chloro, fluoro, methoxy and cyano; and - 4-pyridyl which is unsubstituted or substituted with 1 or 2 substituents independently selected from fluoro, methyl, chloro and cyano; and
R2, R3 and R4 are hydrogen. In one embodiment of the fourth to sixth aspect, R1 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, Ci-4alkyl,
Figure imgf000024_0001
cyano, hydroxyl, hydroxy Ci-4alkyl, -(CH2)n- (NR1aR1b), -(CO)NR1aR1b, -(CO)O-Ci-4alkyl, -(CHO), haloCi-4alkyl and haloCi-4alkoxy. In one embodiment of the fourth to sixth aspect, R1 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, C1-4alkyl, C1-4alkoxy, cyano, hydroxyl, hydroxy C1-4alkyl, -(CH2)n-(NR1aR1b), - (CO)NR1aR1b, -(CO)O-C1-4alkyl, -(CHO), haloC1-4alkyl and haloC1-4alkoxy.
In one embodiment of the fourth to sixth aspect, R1 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, C1-4alkyl, C1-4alkoxy, cyano, haloC1-4alkyl and haloC1-4alkoxy, particularly oxo and Ci-4alkyl, more particularly oxo and methyl.
In one embodiment of the fourth to sixth aspect, R1 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, benzimidazol-2-yl, 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, 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,
Figure imgf000024_0002
Ci-4alkoxy, cyano, haloCi. 4alkyl and haloC1-4alkoxy, particularly oxo and C1-4alkyl, more particularly oxo and methyl. In one embodiment of the fourth to sixth aspect, R1 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, C1-4alkyl, C1-4alkoxy, cyano, haloC1-4alkyl and haloC1-4alkoxy, particularly oxo and C1-4alkyl, more particularly oxo and methyl; and R2, R3 and R4 are hydrogen.
In one embodiment of the fourth to sixth aspect, R1 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-4alkyl,
Figure imgf000025_0001
cyano,
Figure imgf000025_0002
and haloCi-4alkoxy, particularly oxo and
Figure imgf000025_0003
more particularly oxo and methyl; and R2, R3 and R4 are hydrogen. In one embodiment of the fourth to sixth aspect, R1 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, C1-4alkyl, C1-4alkoxy, cyano, haloC1-4alkyl and haloC1-4alkoxy, particularly oxo and C1-4alkyl, more particularly oxo and methyl; R2 is halo, in particular fluoro, R3 is hydrogen and R4 is hydrogen or halo, in particular fluoro.
In one embodiment of the fourth to sixth aspect, R1 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-4alkyl,
Figure imgf000025_0004
cyano,
Figure imgf000025_0005
and haloCi-4alkoxy, particularly oxo and Ci-4alkyl more particularly oxo and methyl; R2 is halo, in particular fluoro, R3 is hydrogen and R4 is hydrogen or halo, in particular fluoro.
In one particular embodiment, compounds as defined in the fourth to sixth aspect, or salts thereof, are selected from supporting compounds 1 to 100, or salts thereof. More particularly, compounds as defined in the fourth to sixth aspect, or salts thereof, are selected from S^P^-Difluoro-δ-ti-hydroxyethyO-S-oxo^.S-dihydro^H-i ^-benzoxazin^-yOmethylJ-S- pyridinecarbonitrile;
2,2-Difluoro-8-[(1S)-1-hydroxyethyl)-4-[(3-methyl-4-oxo-3,4-dihydro-2- quinazolinyl)methyl]-2H-1 ,4-benzoxazin-3(4H)-one;
2!2-Difluoro-4-[(5-fluoro-3-pyridinyl)methyl]-8-[(1 S)-1-hydroxyethyl]-2H-1 ,4-benzoxazin- 3(4H)-one;
4-{[2!2-Difluoro-8-[1-hydroxyethyl)-3-oxo-2!3-dihydro-4H-1 ,4-benzoxazin-4-yl]methyl}-2- pyridinecarbonitrile;
Figure imgf000026_0001
pyridinecarbonitrile; and
2,2,7-Trifluoro-4-[(5-fluoro-3-pyridinyl)methyl]-8-[(1 S)- 1 -hydroxyethyl]-2H-1 ,4-benzoxazin-
3(4H)-one;
or a salt thereof. In a seventh aspect, there is provided a compound of formula (I) as represented by formula (If), or a salt thereof, wherein
Figure imgf000026_0002
(if)
R1 is phenyl which is unsubstituted or substituted with 1 to 3 substituents independently selected from halo, C1-4alkyl, C1-4alkoxy, cyano, hydroxyl, hydroxy C1-4alkyl, -(CH2)n-
(NR1aR1b), -(CO)NR1aR1b, -(CO)O-Ci-4alkyl, -(CHO), -SO2(NR1aR1b), haloCUalkyl and haloCi_4alkoxy;
R1a and R1b are independently selected from hydrogen, Ci-4alkyl and haloCi-4alkyl;
n is 1 , 2, 3 or 4;
R2 is selected from hydrogen, halo, cyano,
Figure imgf000026_0003
haloCUalkyl, Ci-4alkoxy and haloCi.
4alkoxy;
R3 is selected from hydrogen, halo, cyano and haloCi-4alkyl;
R4 is selected from hydrogen, halo, cyano,
Figure imgf000026_0004
haloCUalkyl, Ci-4alkoxy and haloCi.
4alkoxy. In an eighth aspect, there is provided a compound of formula I as represented by formula (Ig), or a salt thereof, wherein
Figure imgf000027_0001
(ig)
R 5I 1 nR21 nR3 and R are as defined in the first aspect.
In a ninth aspect, there is provided a compound of formula I as represented by formula (Ih), or a salt thereof, wherein
Figure imgf000027_0002
(Ih)
R 5I 1 n R21 n R3 and R are as defined in the first aspect.
In one embodiment of the seventh to ninth aspect, R1 is phenyl which is unsubstituted or substituted with 1 or 2 substituents independently selected from halo, C1-4alkyl, C1- 4alkoxy, cyano, hydroxyl, hydroxy C1-4alkyl, -(CH2)n-(NR1aR1b), -(CO)NR1aR1b, -(CO)O-C1- 4alkyl, -(CHO), -SO2(NR1aR1b), haloC1-4alkyl and haloC1-4alkoxy.
In one embodiment of the seventh to ninth aspect, R1 is phenyl which is unsubstituted or substituted with 1 or 2 substituents independently selected from halo, C1-4alkyl, C1- 4alkoxy, cyano, hydroxyl, hydroxy C1-4alkyl, -(CH2)n-(NR1aR1b), -(C0)NR1aR1b, -(CO)O-C1- 4alkyl, -(CHO), -S02(NR1aR1b), haloC1-4alkyl and haloC1-4alkoxy; and wherein at least one substituent is attached to the 3-position relative to the bond attaching the phenyl to the rest of the molecule. In one embodiment of the seventh to ninth aspect, R1 is phenyl which is unsubstituted or substituted with 1 or 2 substituents independently selected from halo, C1-4alkyl, C1- 4alkoxy, cyano, -SO2(NR1aR1b), haloC1-4alkyl and haloC1-4alkoxy. In one embodiment of the seventh to ninth aspect, R1 is phenyl which is unsubstituted or substituted with 1 or 2 substituents independently selected from fluoro, chloro, cyano, methyl, methoxy and -SO2(NR1aR1b).
In one embodiment of the seventh to ninth aspect, R1 is phenyl which is unsubstituted or substituted with 1 or 2 substituents independently selected from fluoro, cyano, methyl and methoxy.
In one embodiment of the seventh to ninth aspect, R1 is phenyl which is unsubstituted or substituted with 1 or 2 substituents independently selected from halo, Ci-4alkyl, C1- 4alkoxy, cyano, hydroxyl, hydroxy C1-4alkyl, -(CH2)n-(NR1aR1b), -(CO)NR1aR1b, -(CO)O-C1- 4alkyl, -(CHO), -SO2(NR1aR1b), halod^alkyl and haloC1-4alkoxy; R2, R3 and R4 are independently selected from hydrogen, halo, cyano and haloC1-4alkyl.
In one embodiment of the seventh to ninth aspect, R1 is phenyl which is unsubstituted or substituted with 1 or 2 substituents independently selected from halo, C1-4alkyl, C1- 4alkoxy, cyano, -SO2(NR1aR1b), haloC1-4alkyl and haloC1-4alkoxy; R2, R3 and R4 are independently selected from hydrogen, halo and cyano.
In one embodiment of the seventh to ninth aspect, R1 is phenyl which is unsubstituted or substituted with 1 or 2 substituents independently selected from fluoro, chloro, cyano, methyl, methoxy and -SO2(NR1aR1b); R2, R3 and R4 are independently selected from hydrogen and halo.
In one embodiment of the seventh to ninth aspect, R1 is phenyl which is unsubstituted or substituted with 1 or 2 substituents independently selected from fluoro, cyano, methyl and methoxy; R2 is halo and R3 and R4 are hydrogen, more particularly, R2 is fluoro and R3 and R4 are hydrogen.
In one embodiment of the seventh to ninth aspect, R1 is phenyl which is unsubstituted or substituted with 1 or 2 substituents independently selected from fluoro, cyano, methyl and methoxy; and R2, R3 and R4 are hydrogen. In one particular embodiment, compounds as defined in the seventh to ninth aspect, or salts thereof, are selected from compounds 197 to 224, or salts thereof. More particularly, compounds as defined in the seventh to ninth aspect, or salts thereof, are selected from
3-{[2,2-Difluoro-8-[(1 S)-1-hydroxyethyl]-3-oxo-2,3-dihydro-4H-1 ,4-benzoxazin-4- yl]methyl}benzonitrile and
3-{[2,2-difluoro-8-[(1 R)-1-hydroxyethyl]-3-oxo-2,3-dihydro-4H-1 ,4-benzoxazin-4- yl]methyl}benzonitrile;
or a salt thereof.
Certain compounds as defined in the first to ninth aspect may in some circumstances form acid addition salts thereof. It will be appreciated that for use in medicine compounds as defined in the first to ninth aspect may be used as salts, in which case the salts should be pharmaceutically acceptable. Pharmaceutically acceptable salts include those described by Berge, Bighley and Monkhouse , J. Pharm. ScL, 1977, 66, 1-19. The term "pharmaceutically acceptable 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, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid, and the like.
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.
It will be appreciated by those skilled in the art that certain protected derivatives of the compounds as defined in the first to ninth aspect, which may be made prior to a final deprotection stage, may not possess pharmacological activity as such, but may, in certain instances, be administered orally or parenterally and thereafter metabolised in the body to form compounds as defined in the first to ninth aspect which are pharmacologically active. Such derivatives may therefore be described as "prodrugs". All protected derivatives and prodrugs of compounds defined in the first to ninth aspect are included within the scope of the invention. Examples of suitable pro-drugs for the compounds of the present invention are described in Drugs of Today, Volume 19, Number 9, 1983, pp 499 - 538 and in Topics in Chemistry, Chapter 31 , pp 306 - 316 and in "Design of Prodrugs" by H. Bundgaard, Elsevier, 1985, Chapter 1 (the disclosures in which documents are incorporated herein by reference). It will further be appreciated by those skilled in the art, that certain moieties, known to those skilled in the art as "pro- moieties", for example as described by H. Bundgaard in "Design of Prodrugs" (the disclosure in which document is incorporated herein by reference) may be placed on appropriate functionalities when such functionalities are present within the compounds as defined in the first to ninth aspects. Therefore, in a further aspect, the invention provides a prodrug of a compound as defined in the first to ninth aspect, for example in the fourth to sixth aspect or the seventh to ninth aspect.
It will be appreciated that certain compounds as defined in the first to ninth aspect, or their salts, may exist as solvates, such as hydrates. Where solvates exist, this invention includes within its scope stoichiometric and non-stoichiometric solvates.
It will be appreciated that certain compounds as defined in the first to ninth aspect, or their salts, may exist in more than one polymorphic form. The invention extends to all such forms whether in a pure polymorphic form or when admixed with any other material, such as another polymorphic form.
Certain compounds as defined in the first to ninth aspect 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 in the first to ninth aspect may also exhibit tautomerism within the R1 moiety, and the present invention includes each such tautomer. An example of a compound as defined in the first to ninth aspect which exhibits tautomerism is
Figure imgf000031_0001
Each of the above isomers is included within the scope of the present invention.
The subject invention also includes isotopically-labelled compounds, which are identical to the compounds as defined in the first to ninth 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. Examples of isotopes that can be incorporated into compounds as defined in the first to ninth aspect include isotopes of hydrogen, carbon, nitrogen, fluorine, such as 3H, 11C, 14C and 18F.
Compounds as defined in the first to ninth aspect and salts of said compounds that contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of the present invention. Isotopically-labelled compounds of the present invention, for example those into which radioactive isotopes such as 3H, 14C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3H, and carbon- 14, i.e., 14C, isotopes are particularly preferred for their ease of preparation and detectability. 11C and 18F isotopes are particularly useful in PET (positron emission tomography). PET is useful in brain imaging. Further, substitution with heavier isotopes such as deuterium, i.e., 2H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances, 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. In one embodiment, compounds as defined in the first to ninth aspect or salts thereof are not isotopically labelled. Throughout the specification, general formulae are designated by Roman numerals (I), (II), (III), (IV), etc. Subsets of these general formulae are defined as (Ia), (Ib), (Ic), etc. ... (IVa), (IVb), (IVc), etc. Compounds as defined in the first to ninth aspect may be prepared as set forth in the following Schemes and in the Supporting Compounds section. The following processes form another aspect of the present invention.
Compounds as defined in the first to ninth aspect may be prepared in accordance with the following Scheme 1.
Scheme 1
Figure imgf000032_0001
wherein R1, R2, R3 and R4 are as defined in the first aspect, R5 is chloro, iodo or bromo, suitably bromo, or when R5 is hydrogen, R2 is fluoro, and L is a suitable leaving group such as halogen or methanesulfonate. In step (i), 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. In step (ii), 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.
In step (iii), compounds of formula (V) may be prepared by heating compounds of formula (IV) at elevated temperature, for example 50 0C, in a suitable solvent, for example N,N-dimethylformamide, in the presence of a suitable base, for example potassium carbonate. Alternatively, compounds of formula (V) may be prepared by treating compounds of formula (III) with an appropriate acylating agent, for example ethyl bromo(difluoro)acetate, in a suitable solvent, for example N,N-dimethylformamide, in the presence of a suitable base, for example sodium hydride.
In step (iv), compounds of formula (Vl) 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 acetaldehyde, in a suitable solvent and at a suitable temperature, for example diethyl ether at -78 0C. In step (v), compounds of formula (I) may be prepared by reacting compounds of formula (Vl) with compounds of formula (VII), in a suitable solvent, for example N, N- dimethylformamide or acetonitrile, in the presence of a suitable base, for example potassium carbonate or triethylamine. Compounds of formula (II) may be prepared according to known methods or may be commercially available. Compounds of formula (VII) can be prepared in accordance with the following Schemes 2, 3 and 4. Alternatively they may be commercially available or may be prepared according to known methods. Scheme 2
R,ΛA 818P O. R'^OH -SteP ®- R1^Br
(VIII) <IX) (Vila)
wherein R1 is as defined in the first aspect, and A is hydrogen, hydroxy or d^alkyloxy.
In Step (i), compounds of formula (IX) can be prepared by treating compounds of formula (VIII) with a suitable reducing agent, for example borane, sodium borohydride, lithium borohydride or lithium aluminium hydride, in a suitable solvent, for example tetrahydrofuran or methanol. Alternatively they may be commercially available or may be prepared by known methods. In step (ii), compounds of formula (Vila) may be prepared by treating compounds of formula (IX) 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. Scheme 3
Figure imgf000034_0001
(X) (VIIb)
wherein R1 is as defined in the first aspect, and L2 is chloro or bromo when R1 is a heteroaryl or a fused bicyclic ring system and bromo when R1 is phenyl. Compounds of formula (VIIb) may be prepared by reacting compounds of formula (X) with a suitable halogenating agent, such as Λ/-bromosuccinimide or Λ/-chlorosuccinimide, in the presence of a suitable radical initiator, such as 2,2'-azobis(2-methylpropionitrile) or dibenzoyl peroxide, in a suitable solvent, such as carbon tetrachloride. Compounds of formula (X) are commercially available or may be prepared by known methods.
Scheme 4 R1^^OH *" R OMs
(IX) (VIIc)
wherein R1 is as defined in the first aspect.
Compounds of formula (VIIc) may be prepared by treating compounds of formula (IX) with a suitable mesylating agent, for example methanesulfonyl chloride or methanesulfonic anhydride, in the presence of a suitable base, for example triethylamine or polystyrene-supported diethylamine, in a suitable solvent, for example ethyl acetate or dichloromethane. Compounds of formula (IX) may be prepared as described in scheme 2 or may be commercially available.
Compounds as defined in the first to ninth aspect may also be prepared in accordance with the following Scheme 5.
Scheme 5
Figure imgf000035_0001
(XII) (I)
wherein R 5I', n R2z, n R3ό and R4 are as defined in the first aspect, R5 is chloro, iodo or bromo, suitably bromo, and L is a suitable leaving group such as halogen, suitably bromo or chloro, or methanesulfonate. In Step (i), compounds of formula (Xl) 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- methyl-N-(methoxy)acetamide, at a suitable temperature, for example -78 0C, in a suitable solvent, for example diethyl ether.
In Step (ii), compounds of formula (XII) may be prepared by reacting compounds of formula (Xl) with compounds of formula (VII) in a suitable solvent, for example N, N- dimethylformamide, in the presence of a suitable base, for example potassium carbonate.
In Step (iii), compounds of formula (I) may be prepared by treating compounds of formula (XII) with a suitable reducing agent, for example sodium triacetoxyborohydride or sodium borohydride, in a suitable solvent, for example tetrahydrofuran or dichloromethane, at a suitable temperature, for example room temperature.
Scheme 6
Figure imgf000036_0001
(I)
wherein R1, R2, R3 and R4 are as defined in the first aspect and L is a suitable leaving group such as halogen or methanesulfonate.
In Step (i), compounds of formula (XIII) can be prepared by treating compounds of formula (Xl) with a suitable reducing agent, for example 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 tetrahydrofuran, at a suitable temperature, for example room temperature. In Step (ii), compounds of formula (I) can be prepared by reacting compounds of formula (XIII) with compounds of formula (VII), where L indicates a suitable leaving group such as bromo, chloro or methanesulfonate, in a suitable solvent, for example N, N- dimethylformamide, in the presence of a suitable base, for example potassium carbonate.
Compounds of formula (Xl) may be prepared as described in Scheme 5.
Compounds of formula (I) containing protecting groups may be deprotected using known methods. For example, a te/t-butoxycarbonyl group can be removed by treating the compound with a suitable acid, for example hydrogen chloride in dioxane, in a suitable solvent, for example dichloromethane, at a suitable temperature, for example room temperature. The compounds as defined in the first to ninth aspect 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 in the first to ninth aspect selectively inhibit the GIyTI transporter over the GlyT2 transporter.
As used herein, the term "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. These 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. Other 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. In the context of the present invention, 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. In one embodiment, the disorder mediated by GIyTI to be treated is a psychosis, including schizophrenia, dementia and attention deficit disorders. In one embodiment, the disorder is schizophrenia.
In one embodiment, the disorder mediated by GIyTI to be treated is posttraumatic stress disorder.
In one embodiment, the disorder mediated by GIyTI to be treated is pain, epilepsy or Alzheimer's disease. As used herein, the term "effective amount" means that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal or human that is being sought, for instance, by a researcher or clinician.
Within the context of the present invention, the terms used herein are classified in the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, published by the
American Psychiatric Association (DSM-IV) and/or the International Classification of
Diseases, 10th Edition (ICD-10). Treatment or prophylaxis of the various subtypes of the disorders mentioned herein using the compounds as defined in the first to ninth aspect are contemplated as part of the present invention. Numbers in brackets after the listed diseases below refer to the classification code in DSM-IV.
In particular, the compounds as defined in the first to ninth aspect be of use in the treatment or prophylaxis of schizophrenia including the subtypes Paranoid Type (295.30), Disorganised Type (295.10), Catatonic Type (295.20), Undifferentiated Type (295.90) and Residual Type (295.60); Schizophreniform Disorder (295.40); Schizoaffective Disorder (295.70) including the subtypes Bipolar Type and Depressive Type; Delusional Disorder (297.1 ) including the subtypes Erotomanic Type, Grandiose Type, Jealous Type, Persecutory Type, Somatic Type, Mixed Type and Unspecified Type; Brief Psychotic Disorder (298.8); Shared Psychotic Disorder (297.3); Psychotic Disorder Due to a General Medical Condition including the subtypes With Delusions and With Hallucinations; 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 as defined in the first to ninth aspect may be also of use in the treatment or prophylaxis 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 (31 1 ); 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 as defined in the first to ninth aspect may also be of use in the treatment or prophylaxis 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- Injury Type, Situational Type and Other Type), Social Phobia (300.23), Obsessive- Compulsive Disorder (300.3), Posttraumatic Stress Disorder (309.81 ), Acute Stress Disorder (308.3), Generalized Anxiety Disorder (300.02), Anxiety Disorder Due to a General Medical Condition (293.84), Substance-Induced Anxiety Disorder and Anxiety Disorder Not Otherwise Specified (300.00).
The compounds as defined in the first to ninth aspect may also be of use in the treatment or prophylaxis 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 Amnestic Disorder, Alcohol-Induced Psychotic Disorder, Alcohol-Induced Mood Disorder, Alcohol-Induced Anxiety Disorder, Alcohol-Induced Sexual Dysfunction, Alcohol-Induced Sleep Disorder and Alcohol-Related Disorder Not Otherwise Specified (291.9); Amphetamine (or Amphetamine-I_ike)-Related Disorders such as Amphetamine Dependence (304.40), Amphetamine Abuse (305.70), Amphetamine Intoxication (292.89), Amphetamine Withdrawal (292.0), Amphetamine Intoxication Delirium, 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 Otherwise Specified (292.9); 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 Intoxication (292.89), Cannabis Intoxication Delirium, Cannabis-lnduced Psychotic Disorder, Cannabis-lnduced Anxiety Disorder and Cannabis-Related Disorder Not Otherwise Specified (292.9); Cocaine-Related Disorders such as Cocaine Dependence (304.20), Cocaine Abuse (305.60), Cocaine Intoxication (292.89), Cocaine Withdrawal (292.0), Cocaine Intoxication Delirium, Cocaine-Induced Psychotic Disorder, Cocaine-Induced Mood Disorder, Cocaine-Induced Anxiety Disorder, Cocaine-Induced Sexual Dysfunction, Cocaine-Induced Sleep Disorder and Cocaine-Related Disorder Not Otherwise Specified (292.9); Hallucinogen-Related Disorders such as Hallucinogen Dependence (304.50), Hallucinogen Abuse (305.30), Hallucinogen Intoxication (292.89), Hallucinogen Persisting Perception Disorder (Flashbacks) (292.89), Hallucinogen Intoxication Delirium, Hallucinogen-Induced Psychotic Disorder, Hallucinogen-Induced Mood Disorder, Hallucinogen-Induced Anxiety Disorder and Hallucinogen-Related Disorder Not Otherwise Specified (292.9); Inhalant-Related Disorders such as Inhalant Dependence (304.60), Inhalant Abuse (305.90), Inhalant Intoxication (292.89), Inhalant Intoxication Delirium, Inhalant-Induced Persisting Dementia, Inhalant-Induced Psychotic Disorder, Inhalant-Induced Mood Disorder, Inhalant-Induced Anxiety Disorder and Inhalant-Related Disorder Not Otherwise Specified (292.9); 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 Dependence (304.60), Phencyclidine Abuse (305.90), Phencyclidine Intoxication (292.89), Phencyclidine Intoxication Delirium, Phencyclidine-lnduced Psychotic Disorder, Phencyclidine-lnduced Mood Disorder, Phencyclidine-lnduced Anxiety Disorder and Phencyclidine-Related Disorder Not Otherwise Specified (292.9); 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 Dementia, Sedative-, Hypnotic-, or Anxiolytic- Persisting Amnestic Disorder, Sedative-, Hypnotic-, or Anxiolytic- lnduced Psychotic Disorder, Sedative-, Hypnotic-, or Anxiolytic-lnduced Mood Disorder, Sedative-, Hypnotic-, or Anxiolytic-lnduced Anxiety Disorder Sedative-, Hypnotic-, or Anxiolytic-lnduced Sexual Dysfunction, Sedative-, Hypnotic-, or Anxiolytic-lnduced Sleep Disorder and Sedative-, Hypnotic-, or Anxiolytic-Related Disorder Not Otherwise Specified (292.9); Polysubstance-Related Disorder such as Polysubstance Dependence (304.80); and Other (or Unknown) Substance-Related Disorders such as Anabolic Steroids, Nitrate Inhalants and Nitrous Oxide.
The compounds as defined in the first to ninth aspect may also be of use in the treatment or prophylaxis 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 a General Medical Condition; and Substance-Induced Sleep Disorder including the subtypes Insomnia Type, Hypersomnia Type, Parasomnia Type and Mixed Type.
The compounds as defined in the first to ninth aspect may also be of use in the treatment or prophylaxis 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). The compounds as defined in the first to ninth aspect may also be of use in the treatment or prophylaxis 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 /Hyperactivity Disorder Not Otherwise Specified (314.9); Hyperkinetic Disorder; 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 as defined in the first to ninth aspect may also be of use in the treatment or prophylaxis 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 as defined in the first to ninth aspect may also be of use in the treatment or prophylaxis of cognitive impairment. Within the context of the present invention, 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 M ulti infarct 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 (pseudodementia states) 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 as defined in the first to ninth aspect may also be of use for the treatment or prophylaxis 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 as defined in the first to ninth aspect may also be of use in the treatment or prophylaxis 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 Disorder (302.74) and Premature Ejaculation (302.75); sexual pain disorder such as Dyspareunia (302.76) and Vaginismus (306.51 ); Sexual
Dysfunction Not Otherwise Specified (302.70); paraphilias such as Exhibitionism (302.4),
Fetishism (302.81 ), Frotteurism (302.89), Pedophilia (302.2), Sexual Masochism
(302.83), Sexual Sadism (302.84), Transvestic Fetishism (302.3), Voyeurism (302.82) and Paraphilia Not Otherwise Specified (302.9); gender identity disorders such as Gender Identity Disorder in Children (302.6) and Gender Identity Disorder in Adolescents or Adults (302.85); and Sexual Disorder Not Otherwise Specified (302.9).
The compounds as defined in the first to ninth aspect may also be of use as anticonvulsants. The compounds as defined in the first to ninth aspect are thus useful in the treatment or prophylaxis 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 or prophylaxis of epilepsy may be carried out by the administration of a nontoxic anticonvulsant effective amount of a compound of the formula (I) or a salt thereof. The compounds as defined in the first to ninth aspect may also be useful in the treatment or prophylaxis 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. In addition, 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).
Other conditions which could potentially be treated by compounds as defined in the first to ninth aspect 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.
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.
Another condition which could potentially be treated by compounds as defined in the first to ninth aspect is spasticity or muscular hypertonicity.
Other 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.
Thus, in a further aspect, there is provided a compound as defined in the first to ninth aspect, or a pharmaceutically acceptable salt thereof, for use in therapy.
In one aspect, there is provided a compound as defined in the first to ninth aspect, or a pharmaceutically acceptable salt thereof, for use in the treatment or prophylaxis of a disorder mediated by GIyTL More particularly, there is provided a compound as defined in the first to ninth aspect, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disorder mediated by GIyTI . In a further aspect, there is provided a method of treatment or prophylaxis of a disorder mediated by GIyTI , which method comprises the administration of a compound as defined in the first to ninth aspect, or a pharmaceutically acceptable salt thereof. More particularly, there is provided a method of treatment of a disorder mediated by GIyTI , which method comprises the administration of a compound as defined in the first to ninth aspect, or a pharmaceutically acceptable salt thereof.
In a further aspect, there is provided the use of a compound as defined in the first to ninth aspect, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment or prophylaxis of a disorder mediated by GIyTL More particularly, there is provided the use of a compound as defined in the first to ninth aspect, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of a disorder mediated by GIyTI .
In one embodiment, 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. In one embodiment, the disorder is schizophrenia. In order to use a compound as defined in the first to ninth aspect or a pharmaceutically acceptable salt thereof for the treatment or prophylaxis of humans and other mammals it is normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition. Therefore in another aspect of the invention there is provided a pharmaceutical composition comprising a compound as defined in the first to ninth aspect, or a pharmaceutically acceptable salt thereof, adapted for use in human or veterinary medicine.
In order to use compounds as defined in the first to ninth aspect in therapy, they will normally be formulated into a pharmaceutical composition in accordance with standard pharmaceutical practice. The present invention also provides a pharmaceutical composition, which comprises a compound as defined in the first to ninth aspect, 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). The most suitable means of administration for a particular patient will depend on the nature and severity of the conditions being treated and on the nature of the active compound. In one embodiment, 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 suppositories comprising the active ingredient and one or more solid carriers forming the suppository base, for example, cocoa butter. 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.
The 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.
For example, 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.
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.
It will be appreciated that the precise dose administered will depend on the age and condition of the patient and the frequency and route of administration and will be at the ultimate discretion of the attendant physician. 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, sub- lingual, 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 as defined in the first to ninth aspect 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. However, as a general guide 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 comprising 0.05 to IOOOmg of a compound as defined in the first to ninth aspect or a pharmaceutically acceptable salt thereof, and 0 to 3 g more suitably 0 to 2g of at least one pharmaceutically acceptable carrier.
In a further aspect, a compound as defined in the first to ninth aspect, or a pharmaceutically acceptable salt thereof, may be suitable for combination with other active ingredients. When a compound as defined in the first to ninth aspect or a pharmaceutically acceptable salt thereof is used in combination with another therapeutic agent, the compounds may be administered either sequentially or simultaneously by any convenient route. The compounds as defined in the first to ninth aspect 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 as defined in the first to ninth aspect may be used in combination with antidepressants to treat or prevent depression and mood disorders. The compounds as defined in the first to ninth aspect 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 as defined in the first to ninth aspect may be used in combination with the following agents to treat or prevent anxiety disorders: i) anxiolytics; and ii) antidepressants.
The compounds as defined in the first to ninth aspect 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.
The compounds as defined in the first to ninth aspect may be used in combination with the following agents to improve alcohol withdrawal and reduce alcohol craving: i) NMDA receptor antagonists for example acamprosate; ii) GABA receptor agonists for example tetrabamate; and iii) Opioid receptor antagonists for example naltrexone.
The compounds as defined in the first to ninth aspect 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. The compounds as defined in the first to ninth aspect 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.
The compounds as defined in the first to ninth aspect 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 as defined in the first to ninth aspect 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 as defined in the first to ninth aspect 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 as defined in the first to ninth aspect 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).
The compounds as defined in the first to ninth aspect 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 as defined in the first to ninth aspect 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.
The compounds as defined in the first to ninth aspect may be used in combination with the same agents specified for male sexual dysfunction to treat or prevent female sexual dysfunction, and in addition an estrogen agonist such as estradiol.
Examples of antipsychotic drugs that may be useful in combination with a compound as defined in the first to ninth 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 ; benzisothiazolyl-piperazines; triazine such as lamotrigine; dibenzoxazepines, such as loxapine; dihydroindolones, such as molindone; aripiprazole; and derivatives thereof that have antipsychotic activity.
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); thiothixene (available under the tradename NAVANE®;, from Pfizer); trifluoperazine (10- [3-(4-methyl-1 -piperazinyl)propyl]-2-(trifluoromethyl)phenothiazine dihydrochloride, available under the tradename STELAZINE®, from Smith Klein Beckman; perphenazine (available under the tradename TRILAFON®; from Schering); thioridazine (available under the tradename MELLARIL®; from Novartis, Roxane, HiTech, Teva, and Alpharma) ; molindone (available under the tradename MOBAN®, from Endo); and loxapine (available under the tradename LOXITANE®; from Watson). Furthermore, 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. 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/divalproex, carbamazepine, lamotrigine, gabapentin, topiramate and tiagabine.
Anxiolytics include benzodiazepines such as alprazolam and lorazepam. It will be appreciated by those skilled in the art that the compounds as defined in the first to ninth aspect 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. When used in the treatment or prophylaxis of pain, the compound as defined in the first to ninth aspect or a pharmaceutically acceptable salt thereof may be used in combination with other medicaments indicated to be useful in the treatment or prophylaxis 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) receptor modulators, such as glycine receptor antagonists or memantine; ligands for the α2δ-subunit of voltage gated calcium channels, such as gabapentin, pregabalin and solzira; tricyclic antidepressants such as amitriptyline; neurone stabilising antiepileptic drugs; cholinesterase inhibitors such as galantamine; mono-aminergic uptake inhibitors such as venlafaxine; opioid analgesics; local anaesthetics; 5HT1 agonists, such as triptans, for Compound sumatriptan, naratriptan, zolmitriptan, eletriptan, frovatriptan, almotriptan or rizatriptan; nicotinic acetyl choline (nACh) receptor modulators; glutamate receptor modulators, for Compound modulators of the NR2B subtype; EP4 receptor ligands; EP2 receptor ligands; EP3 receptor ligands; EP4 agonists and EP2 agonists; EP4 antagonists; EP2 antagonists and EP3 antagonists; cannabinoid receptor ligands; bradykinin receptor ligands; vanilloid receptor or Transient Receptor Potential (TRP) ligands; and purinergic receptor ligands, including antagonists at P2X3, P2X2/3, P2X4, P2X7 or P2X4/7; KCNQ/Kv7 channel openers, such as retigabine; Additional COX-2 inhibitors are disclosed in US Patent Nos. 5,474,995, US5,633,272; US5,466,823, US6,310,099 and US6.291.523; and in WO 96/25405, WO 97/38986, WO 98/03484, WO 97/14691 , WO99/12930, WO00/26216, WO00/52008, WO00/38311 , WO01/58881 and WO02/18374.
When used in the treatment or prophylaxis of Alzheimer's disease, the compound as defined in the first to ninth aspect or a pharmaceutically acceptable salt thereof may be used in combination with other medicaments indicated to be useful as either disease modifying or symptomatic treatments of Alzheimer's disease.
Suitable examples of such other therapeutic agents may be agents known to modify cholinergic transmission such as 5-HT1A antagonists, (e.g. lecozotan), 5-HT6 antagonists, M1 muscarinic agonists, M2 muscarinic antagonist, acetylcholinesterase inhibitors (e.g. tetrahydroaminoacridine, donepezil or rivastigmine), or 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 β or v- secretase inhibitors (e.g. R-flurbiprofen), also AMPA positive modulators.
All publications, including but not limited to patents and patent applications, cited in this specification are herein incorporated by reference as if each individual publication were specifically and individually indicated to be incorporated by reference herein as though fully set forth. Abbreviations
MeOH methanol
EtOAc ethyl acetate
HCI hydrochloric acid
Et2O diethyl ether
MDAP mass-directed auto-purification system
THF tetrahydrofuran
DCM / MDC dichloromethane / methylene dichloride
DMF N,N-dimethylformamide
DMSO dimethyl sulfoxide
BuLi n-butyllithium
AIBN 2,2'-azobis(2-methylpropionitrile)
EDC N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide
HOBt 1 H-1 ,2,3-benzotriazol-i-ol
DCE 1 ,2-dichloroethane
MP macroporous polystyrene
CV column volume
Ms methanesulfonyl
hr hour(s)
RT room temperature
Cpd compound
HOAt 1-hydroxy-7-azabenzotriazole
NBS Λ/-bromosuccinimide Supporting Compounds
The preparation of a number of supporting compounds as defined in the first to ninth aspect are described below.
In the procedures that follow, after each starting material, reference to an intermediate is typically provided. This is provided merely for assistance to the skilled chemist. The starting material may not necessarily have been prepared from the batch referred to. The LC/MS method numbers refer to the Experimental section.
Intermediate 1 : 2-Amino-6-bromophenol
Figure imgf000055_0001
Method A
To a solution of 2-bromo-6-nitrophenol (5g; Aldrich) in MeOH (459ml) and acetic acid
(115ml) was added portionwise with stirring zinc powder (7.5Og), and the reaction mixture stirred at room temperature for fifteen minutes. The reaction mixture was filtered through a pad of celite and washed with water (500ml) and the filtrate evaporated to remove the methanol. The aqueous layer was extracted with DCM (2x 500ml) and the combined organic layers washed with saturated sodium bicarbonate (2x 500ml) and brine (500ml), then dried and evaporated to afford the title compound (3.45g) as a dark brown solid, m/z [M+H]+: 188.0 /190.0. Retention time 0.51 min (LC/MS method 3).
Method B
To a solution of 2-bromo-6-nitrophenol (25g) in ethanol (250ml) was added dropwise with stirring a solution of sodium hydrosulfite (8Og) in water (500ml), and the reaction mixture stirred at 6O0C for three hours then cooled overnight. The reaction mixture was evaporated to remove the ethanol. The aqueous was extracted with DCM (500ml and 250ml) and the combined organic layers washed with brine (300ml), then dried and evaporated to afford the title compound (13.2g) as a brown solid. Intermediate 2: 2-Bromo-N-(3-bromo-2-hydroxyphenyl)-2,2-difluoroacetamide
Figure imgf000055_0002
A mixture of 2-amino-6-bromophenol (13.2g, may be prepared as described in intermediate 1 ), ethyl bromo(difluoro)acetate (15.7g; Aldrich) and triethylamine (10.8ml) in ethyl acetate (80ml) was refluxed (9O0C) under argon for two hours. The reaction mixture was diluted with EtOAc (400ml) and washed with water (3x 200ml).The combined aqueous was extracted with EtOAc (200ml) and the combined organic layers dried and evaporated. The residue was dissolved in DCM and loaded onto four Biotage Si 40+M columns and purified using the Biotage SP4 eluting with 0-20% EtOAc/isohexane over twenty column volumes to afford the title compound (12.5g) as an orange oil. m/z [M-H]": 343.8 / 345.7. Retention time 1.01 min (LC/MS method 3). Intermediate 3: 8-Bromo-2,2-difluoro-2H-1 ,4-benzoxazin-3(4H)-one
Figure imgf000056_0001
Method A
To a solution of 2-bromo-N-(3-bromo-2-hydroxyphenyl)-2,2-difluoroacetamide (12.5g, may be prepared as described intermediate 2) in DMF (140ml) was added potassium carbonate (1 Og) and the reaction mixture was heated at 500C for two hours. The reaction mixture was diluted with EtOAc (500ml) and washed with water (2x 200ml).The combined aqueous was adjusted to pH7 and extracted with EtOAc (2 x 200ml) and the combined organic layers washed with water (2x 500ml) then dried and evaporated to afford the title compound (9.12g) as an orange solid, m/z [M-H]": 261.9 / 263.9. Retention time 1.00 min (LC/MS method 3).
Method B
To a solution of 2-amino-6-bromophenol (2.00 g, 10.70 mmol, may be prepared as described in intermediate 1 ) in DMF (20 ml) was added sodium hydride (60%, 560 mg, 13.90 mmol) at 00C under nitrogen. The mixture was stirred for 30 min then ethyl bromo(difluoro)acetate (2.61 g, 12.84 mmol, Aldrich) was added dropwise at 00C and stirred for 30 min at 00C, then stirred for 3 hr at 300C. The mixture was diluted with EtOAc (50 ml), washed with water three times, then washed with brine, dried over sodium sulfate, filtered and concentrated. It was purified via column chromatography on silica gel (eluting with petroleum ether / ethyl acetate 10:1 ) to give the title compound (1.18 g) as a brown solid.
Intermediate 4: 2,2-Difluoro-8-(1 -hydroxyethyl)-2H-1 ,4-benzoxazin-3(4H)-one
Figure imgf000056_0002
Method A
To a solution of 8-bromo-2,2-difluoro-2H-1 ,4-benzoxazin-3(4H)-one (12g, may be prepared as described in intermediate 3) in diethyl ether (300ml) was added BuLi (63ml; 1.6M in hexane) dropwise at -780C under argon. The mixture was stirred for thirty minutes; acetaldehyde (25ml) was added and stirred at -780C warming to room temperature overnight. The reaction mixture was treated with 2N hydrochloric acid to adjust the pH to 1. The organic and aqueous layers were separated and the aqueous extracted with EtOAc (200ml). The combined organic layers were washed with water and brine, then dried and evaporated to a red oil (18g). The oil was dissolved in DCM and purified using the Biotage SP4 using three 40+M columns and eluting with 0 to 50% EtOAc/isohexane over 20CV then stirred overnight in isohexane (500ml), filtered off and dried to afford the title compound (6.74g) as a white solid, m/z [M-H]": 228.0. Retention time 0.66 min (LC/MS method 3).
Method B
(3aR)-1-Methyl-3,3-diphenyltetrahydro-3H-pyrrolo[1 ,2-c][1 ,3,2]oxazaborole (8.80 ml_, 1 M in toluene; Aldrich) was dissolved in dry THF (20 ml.) and borane-THF complex (4.40 ml_, 1 M in THF) was added. The mixture was stirred at 250C for 15 min. A solution of 8- acetyl-2,2-difluoro-2H-1 ,4-benzoxazin-3(4H)-one (2.0 g) in dry THF (20 ml.) was added dropwise (in 10 min). The mixture was stirred at 250C for 30 min. From UPLC: reaction not completed. Further borane-THF complex (2.20 ml.) was added and the mixture was stirred for 30 min at 250C. Saturated aqueous ammonium chloride (40 ml.) was added dropwise at 250C to the reaction mixture. Then EtOAc (40 ml.) and water (20 ml.) were added. The phases were separated. The aqueous phase was back-extracted with EtOAc (40 ml_). The combined organic layers were dried over sodium sulphate and evaporated and the residue (6 g, white) was dissolved in EtOAc (150 ml.) and MeOH (50 ml_). Silica (230-400 Mesh, 20 g) was added and solvent was evaporated to give a white powder that was charged on a top of a column (silica 230-400 Mesh) and eluted with cyclohexane / EtOAc 9:1 to 6:4 to give the title compound (1.635 g) as a white solid. Analysis by chiral HPLC (column - Chiralpak AS-H; eluent - hexane / isopropanol 85:15 v/v) showed that 2,2-difluoro-[(1 S)-1-hydroxyethyl]-2H-1 ,4-benzoxazin-3(4H)-one (faster- running enantiomer) was present in 72.9% enantiomeric excess over 2,2-difluoro-[(1 R)-1- hydroxyethyl]-2H-1 ,4-benzoxazin-3(4H)-one (slower-running enantiomer), by comparison with an authentic sample of 2,2-difluoro-[(1 /?)-1-hydroxyethyl]-2H-1 ,4-benzoxazin-3(4H)- one (may be prepared as described in intermediate 6).
Intermediates 5: 2,2-Difluoro-8-[(1S)-1-hydroxyethyl]-2H-1,4-benzoxazin-3(4H)-one and Intermediate 6: 2,2-difluoro-8-[(1R)-1-hydroxyethyl]-2H-1 ,4-benzoxazin-3(4H)- one
Figure imgf000058_0001
Racemic mixture 2,2-difluoro-8-(1-hydroxyethyl)-2H-1 ,4-benzoxazin-3(4H)-one (1g, may be prepared as described in intermediate 4) was resolved using a Chiralpak AS column (20mm x 250mm, 10μm) eluting with heptane: isopropyl alcohol (90:10) v/v pump-mixed. Flow rate: 17 ml/min. UV detection: 215 nm. Using these conditions, the faster running enantiomer 2,2-difluoro-8-[(1 S)- 1 -hydroxyethyl]-2H-1 ,4-benzoxazin-3(4H)-one (415mg, intermediate 5) and the slower running enantiomer 2,2-difluoro-8-[(1 R)-1-hydroxyethyl]- 2H-1 ,4-benzoxazin-3(4H)-one (416mg, intermediate 6) were obtained in >99% enantiomeric excess, m/z [M-H]": 228.0. Retention time 0.66 min (LC/MS method 3). The absolute configurations were determined by ab initio vibrational circular dichroism.
Intermediate 7: 8-Acetyl-2,2-difluoro-2H-1 ,4-benzoxazin-3(4H)-one
Figure imgf000058_0002
Method A
The title compound (1.96 g) was made in a similar manner to the preparation of intermediate 4, method A, replacing acetaldehyde with N-methyl-N-(methoxy)acetamide (Aldrich). m/z [M-H]": 226.0. Retention time 0.84 min (LC/MS method 3).
Method B
To a solution of 8-bromo-2,2-difluoro-2H-1 ,4-benzoxazin-3(4H)-one (10.0 g, may be prepared as described in intermediate 3) in dry Et2O (260 ml.) was added BuLi (47.3 mL, 2.0 M in cyclohexane) dropwise (in 35 min, maintaining internal temperature below - 7O0C) at -730C under argon. A white suspension was formed. The mixture was mechanically stirred for 1 hr at -730C (internal temperature). Λ/-Methyl-/V- (methoxy)acetamide (8.05 mL; Aldrich) was added and stirred at -730C for 2 hr.
The cooling bath was removed and 1 M hydrochloric acid (100 mL) was added dropwise while temperature was allowed to rise to 250C. Water (100 mL) was added and then further 1 M hydrochloric acid (50 mL) in order to adjust the pH of the aqueous phase to 5. The phases were separated. The aqueous phase was back-extracted with EtOAc (250 ml_). The combined organic layers were dried over sodium sulphate and were evaporated to give a residue (10.7 g) that was dissolved in EtOAc (200 ml_). Silica (230- 400 Mesh, 20 g) was added. The solvent was evaporated to give a powder that was charged on the top of a silica column and eluted with cyclohexane / EtOAc 9:1 to 6:4 to give the title compound (4.428 g) as a white powder.
Intermediate 8: 8-Acetyl-2,2-difluoro-4-(3-pyridinylmethyl)-2H-1 ,4-benzoxazin-3(4H)- one
Figure imgf000059_0001
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 7) 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 combined extract was dried (magnesium sulfate) and concentrated under vacuum to leave a yellow solid. This was purified by Biotage (12+M column) eluting with 0-100% EtOAc/isohexane to afford the title compound as a white solid (50mg). m/z [M+H]+: 319.0. Retention time 0.74 min (LC/MS method 3).
Intermediate 9: 2-Bromo-2,2-difluoro-N-(4-fluoro-2-hydroxyphenyl)acetamide
Figure imgf000059_0002
Bromo(difluoro)acetyl chloride (2.28 g, 11.79 mmol, Fluorochem) and triethylamine (2.2 ml_, 15.87 mmol) were added to a solution of 2-amino-5-fluorophenol (1.00 g, 7.87 mmol, Apollo) in dry THF (15 ml_). The mixture was heated to 100 0C for 10 min in a microwave. It was cooled to room temperature then diluted with EtOAc (50 ml.) and water (50 ml_). The layers were separated and the aqueous was extracted with EtOAc (1 x 50 ml_). The combined organic layers were washed with aqueous citric acid solution (1 x 50 ml_; 10% w/v) and brine (1 x 50 ml_), dried (sodium sulfate), filtered and evaporated to give a black solid. Mass: 3.26 g. This was purified by Biotage (100 g silica cartridge; eluent isohexane / EtOAc 0 to 20%; collection by UV trigger). The main peak was collected and the fractions were combined and evaporated to give the title compound (1.82 g) as an orange solid, m/z [M-H]": 281.7 / 283.7. Retention time 0.91 min (LC/MS method 3).
Intermediate 10: 2,2,7-Trifluoro-2H-1,4-benzoxazin-3(4H)-one
Figure imgf000060_0001
The title compound (1.23 g) was made in a similar fashion to the preparation of 8-bromo- 2,2-difluoro-2H-1 ,4-benzoxazin-3(4H)-one (may be prepared as described in intermediate 3, method A), replacing 2-bromo-N-(3-bromo-2-hydroxyphenyl)-2,2- difluoroacetamide with 2-bromo-2,2-difluoro-N-(4-fluoro-2-hydroxyphenyl)acetamide (may be prepared as describe in intermediate 9). m/z [M-H]": 201.8. Retention time 0.85 min (LC/MS method 3).
Intermediate 11 : 2,2,7-Trifluoro-8-(1 -hydroxyethyl)-2H-1 ,4-benzoxazin-3(4H)-one
Figure imgf000060_0002
A solution of 2,2,7-trifluoro-2H-1 ,4-benzoxazin-3(4H)-one (200 mg, 0.985 mmol, may be prepared as described in intermediate 10) in dry THF (10 ml.) was cooled to -65 0C under argon. BuLi (1.4 mL, 2.240 mmol, 1.6 M in hexanes) was added and the mixture was stirred for 1 hr. Acetaldehyde (0.6 mL, 10.62 mmol) was added and the mixture was stirred for 3 hr, with the temperature rising to 5 0C. Saturated ammonium chloride solution (10 ml.) and ethyl acetate (10 ml.) were added. The layers were separated and the aqueous layer extracted with ethyl acetate (2 x 20 ml_). The combined organic layers were washed with water (1 x 10 mL) and brine (1 x 10 ml_), dried (sodium sulphate), filtered and evaporated to give an orange oil (602 mg). This was purified by Biotage (25M silica cartridge; eluent isohexane / ethyl acetate 0 to 40%; collection by UV trigger) to give 2,2,7-trifluoro-8-(1-hydroxyethyl)-2H-1 ,4-benzoxazin-3(4H)-one as an orange oil, crystallising slowly (277 mg). The product was used in the next step without further purification, m/z [M-H]": 245.9. Retention time 0.65 min (LC/MS method 3). Intermediate 12: 3-(Bromomethyl)quinoline hydrobromide
Figure imgf000061_0001
A solution of 3-quinolinylmethanol (150mg, AKos) in 48% aqueous hydrobromic acid (1.5ml) was heated at 1100C for three hours. The reaction mixture was cooled and evaporated to give the title compound as a green solid (285 mg), which was used immediately in the next reaction, m/z [M+H]+: 222.0 / 223.9. Retention time 0.82 min (LC/MS method 3).
The following intermediates were prepared by a similar procedure to that described for intermediate 12 from the appropriate alcohol.
Figure imgf000061_0002
Figure imgf000062_0001
Intermediate 16: 2-(bromomethyl)-6-chloropyridine
Figure imgf000062_0002
2-Chloro-6-methylpyridine (1 10mg, Aldrich), N-bromosuccinimide (153mg) and AIBN (14.16mg) were dissolved in carbon tetrachloride (2ml) and the reaction mixture stirred at 80 0C under argon for three hours. The reaction mixture was allowed to cool to room temperature, filtered through Kieselguhr, washed with dichloromethane and evaporated to afford the title compound (98mg; crude material used directly in the next step), m/z [M+H]+: 205.9 / 207.9 / 210.1. Retention time 0.89 min (LC/MS method 3).
The following intermediates were prepared by a similar procedure to that described for intermediate 16 from the appropriate methylpyridine, and used crude in the following step.
Figure imgf000062_0003
Figure imgf000063_0001
26 Br 2-(bromomethyl)-3-fluoropyridine
27 Br 2-(bromomethyl)-3-chloropyridine
28 Br 4-(bromomethyl)-3-fluoropyridine
29 2-(bromomethyl)-3-pyridinecarbonitrile
Figure imgf000064_0001
30 Br 6-(bromomethyl)-3-pyridinecarbonitrile
Intermediate 31 : 2,3-Dimethylpyridine 1 -oxide
Figure imgf000064_0002
2,3-dimethylpyridine (1 g, 9.33 mmol, Aldrich) and hydrogen peroxide (1.059 ml, 9.33 mmol) were dissolved in acetic acid (4.67 ml) in a 25 ml. round-bottomed flask open to the atmosphere and stirred at 90 0C for 7 hours. The reaction mixture was allowed to cool to room temperature and evaporated to dryness to give the title compound (1.440 g) as a colourless oil. The product was directly used in the following reaction, m/z [M+H]+ : 123.8. Retention time 0.35 min (LC/MS method 3).
Intermediate 32: 5,6-Dimethyl-2-pyridinecarbonitrile
Figure imgf000065_0001
2,3-Dimethylpyridine 1-oxide (1.440 g, 1 1.69 mmol, may be prepared as described in intermediate 31 ), trimethylsilyl cyanide (4.70 ml, 35.1 mmol) and triethylamine (2.445 ml, 17.54 mmol) were dissolved in acetonitrile (23.39 ml) in a 50 ml. round-bottomed flask flushed with argon and stirred at 9O0C for 5 days. The reaction mixture was cooled to O0C and treated with 5M aqueous sodium hydroxide (30ml). The aqueous layer was extracted with DCM (3x30ml) and the organic layers were combined, washed with brine (30ml), dried over magnesium sulfate, filtered and evaporated to dryness to give the crude product (748mg) as a black/brown oil. The crude product was purified on a 40+S Biotage silica cartridge, eluting with a 0 to 50 % mixture of EtOAc in hexane. This gave the target compound (172 mg) as an off-white solid, m/z [M+H]+ : 132.9. Retention time 0.69 min (LC/MS method 3).
Intermediate 33: Methyl 5,6-dimethyl-2-pyridinecarboxylate
Figure imgf000065_0002
5,6-Dimethyl-2-pyridinecarbonitrile (170 mg, may be prepared as described in intermediate 32) was dissolved in hydrochloric acid (2 ml, 65.8 mmol) and stirred at 1 10 0C overnight. The reaction mixture was allowed to cool to room temperature, evaporated to dryness, redissolved in EtOAc (30 ml) and treated with saturated aqueous sodium bicarbonate solution (30 ml). The aqueous layer was extracted with ethyl acetate (2 x 30 ml) and the organic layers were combined, washed with brine, dried over magnesium sulfate, filtered and evaporated to dryness to give the crude product (1.48 g) as a light brown oil. The crude product was purified on a 40+S Biotage silica cartridge, eluting with a 0 to 20 % mixture of EtOAc in hexane. The product was dissolved in MeOH (10 ml), cooled to 0 0C and sulfuric acid (250 μl, 4.69 mmol) was added dropwise and the reaction was stirred at 90 0C overnight. The reaction mixture was cooled to room temperature, evaporated to dryness and the pH adjusted to 9 using saturated aqueous sodium bisulfate solution. The aqueous layer was extracted with EtOAc (3 x 30 ml) and the organic layers were combined, washed with brine, dried over magnesium sulfate and filtered to give the title compound (165 mg) as an off-white solid, m/z [M+H]+: 166.1. Retention time 0.56 min (LC/MS method 3). Intermediate 34: (5,6-Dimethyl-2-pyridinyl)methanol
Figure imgf000066_0001
Methyl 5,6-dimethyl-2-pyridinecarboxylate (167 mg, may be prepared as described in intermediate 33) and sodium borohydride (191 mg, 5.05 mmol) were dissolved in MeOH (5 ml) and stirred at room temperature overnight. The reaction mixture was evaporated to dryness, redissolved in DCM (30 ml) and treated with saturated aqueous sodium bicarbonate solution (30 ml). The aqueous layer was extracted with DCM (2 x 30 ml) and the organic layers were combined, washed with brine, dried over magnesium sulfate, filtered and evaporated to dryness to give the crude product (114 mg) as a colourless oil. The crude product was dissolved in MeOH (5 ml), sodium borohydride (191 mg, 5.05 mmol) was added and the reaction mixture stirred at room temperature overnight. The reaction mixture was evaporated to dryness, redissolved in DCM (30 ml) and treated with saturated aqueous sodium bicarbonate solution (30 ml). The aqueous layer was extracted with DCM (2 x 30 ml) and the organic layers were combined, washed with brine, dried over magnesium sulfate, filtered and evaporated to dryness to give the crude product (93 mg) as a colourless oil. The crude product was purified on a 25+S Biotage silica cartridge, eluting with a 0 to 30 % mixture of EtOAc in hexane. This gave the title compound (59 mg) as a colourless oil. 1H NMR (MeOD) δ: 2.29 (3H, s), 2.46 (3H, s), 4.62 (2H, s), 7.27 (1 H, d), 7.56 (1 H, d).
Intermediate 35: (2-chloro-6-methyl-4-pyridinyl)methanol
Figure imgf000066_0002
2-Chloro-6-methyl-4-pyridinecarboxylic acid (200 mg, 1.166 mmol; Aldrich) was dissolved in THF (5.83 ml) in a 50 ml. round-bottomed flask flushed with argon and cooled to 0 0C. This solution was treated with 1 M borane-tetrahydrofuran complex (5.828 ml, 5.83 mmol) and stirred at room temperature overnight. The reaction mixture was cooled in an ice bath, treated with concentrated hydrochloric acid (2 ml), stirred for 30 minutes then basified with 50 % w/w aqueous sodium hydroxide. This solution was extracted with EtOAc (3 x 30 ml) and the combined organic solutions were washed with brine (30 ml), dried over magnesium sulfate, filtered and evaporated to dryness to give the crude product (172 mg) as a white solid. The crude product was purified on a 25+S Biotage silica cartridge, eluting with a 0 to 5 % mixture of MeOH in DCM. The title compound was obtained (144 mg) as a white solid, m/z [M+H]+: 158.1 / 160.1 Retention time 0.52 min (LC/MS method 3). Intermediate 36: 6-(bromomethyl)-2,3-dimethylpyridine
Figure imgf000067_0001
(5,6-Dimethyl-2-pyridinyl)methanol (50 mg, may be prepared as described in intermediate 34) was dissolved in chloroform (6075 μl) in a 100 ml. round-bottomed flask flushed with argon and phosphorus tribromide (34.4 μl, 0.364 mmol) was added slowly at O0C. The reaction mixture was stirred at room temperature for 2 hr. The reaction mixture was cooled to O0C and treated with saturated aqueous sodium bicarbonate solution (30ml). The aqueous layer was extracted with DCM (3x30ml) and the organic layers were combined, washed with brine (30ml), dried over magnesium sulfate, filtered and evaporated to dryness to give the title compound (59 mg) as a pale pink oil. m/z [M+H]+: 199.9 / 201.9. Retention time 0.84 min (LCMS method 3).
The following intermediates were prepared by a similar procedure to that described for intermediate 36 from the appropriate alcohol.
Figure imgf000067_0002
Figure imgf000068_0004
Intermediate 43: 6-(bromomethyl)-3-methyl-1 ,3-benzoxazol-2(3H)-one
Figure imgf000068_0001
For a preparation see Liacha, M; Yous, S; Depreux, P; Poupaert, J. H; Lesieur, D; Heterocycles, 1999, 51 , 1929-1943.
Intermediate 44: 1,2,3-Benzothiadiazol-6-ylmethanol
Figure imgf000068_0002
For a preparation method see international patent application WO2005/082859, published on 09 Sep 2005.
Intermediate 45: (5-Bromo-2-nitrophenyl)methylamine
Figure imgf000068_0003
To a stirred partial solution of 4-bromo-2-fluoronitrobenzene (9.2 g; Aldrich) in acetonitrile (140 ml) was added a solution of 8M methylamine in ethanol (86 ml). The reaction was stirred at room temperature for 4 hr and then evaporated to dryness. The residue was partitioned between EtOAc (500 ml) and water (500 ml). The aqueous phase was separated off and extracted with EtOAc (500 ml). The organic phases were combined, washed with water (500 ml) and brine, dried (magnesium sulphate) and evaporated to give the title compound (9.47 g) as an orange-brown solid.
Intermediate 46: (2-Amino-5-bromophenyl)methylamine
Figure imgf000069_0001
To a stirred solution of (5-bromo-2-nitrophenyl)methylamine (9.46 g, may be prepared as described in intermediate 45) in ethanol (300 ml) was added tin (II) chloride (47.35 g) and the resulting mixture was heated at reflux for 2.5 hr. More tin (II) chloride (30.05 g) was added and reflux was continued for 1 hr. The mixture was allowed to cool then poured into stirred ice / water (2I). The mixture was basified to pH 8 using saturated aqueous sodium bicarbonate and then EtOAc was added. The resultant thick white suspension was filtered through Celite. The aqueous phase was separated off and extracted with EtOAc. The organic phases were combined, washed with brine and dried (sodium sulfate) and evaporated to give the target compound as a dark brown oil (9.50 g).
Intermediate 47: 6-Bromo-1-methyl-1 H-1 ,2,3-benzotriazole
Figure imgf000069_0002
To a cooled (0 0C) and stirred suspension of (2-amino-5-bromophenyl)methylamine (9.5g, may be prepared as described in intermediate 46) in 2M hydrobromic acid was added dropwise a cooled (5 0C) solution of sodium nitrite (4.02 g) in water (50 ml). The resultant mixture was stirred at 5 0C for 0.5 hr and then at 15-20 0C for 4 hr. The mixture was partitioned between EtOAc (500 ml) and saturated aqueous sodium bicarbonate (500 ml). The aqueous phase was separated off and extracted with EtOAc (500 ml). The organic phases were combined, washed with water and brine, dried (magnesium sulphate) and adsorbed on to silica gel prior to flash chromatography over silica gel, eluting with EtOAc / cyclohexane (1 :3). Fractions containing the target compound were combined and evaporated to give a brown solid (4.48 g). 2.61 g of this was further purified by chromatography over silica gel, eluting with 2% MeOH in chloroform. The appropriate fractions were combined and evaporated to give the target compound as a pale brown solid (1.3O g).
Intermediate 48: (1 -methyl-1H-1,2,3-benzotriazol-6-yl)methanol
Figure imgf000070_0001
To a cooled (-78 0C) and stirred solution of 6-bromo-1-methyl-1 H-1 ,2,3-benzotriazole (0.25 g, may be prepared as described in intermediate 47) in dry THF was added a solution of tert-butyllithium in pentane (0.83 ml, 1.7M). This mixture was stirred at -78 0C for 1 hr and then methyl formate (0.036 ml, Aldrich) was added. The mixture was stirred at -78 0C for 0.5 hr and then allowed to warm to room temperature. The reaction was quenched with water and acidified with a few drops of 2N hydrochloric acid. The resultant mixture was extracted with EtOAc (2 x 50 ml), the extracts were combined, washed with water, dried (magnesium sulphate) and evaporated to give a brown oil (0.22 g). This was purified by flash chromatography over silica gel eluting with cyclohexane / EtOAc 50 to 100% to give the target compound (0.017 g) as a brown oil.
Intermediate 49: (2-Fluoro-4-pyridinyl)methyl methanesulfonate
Figure imgf000070_0002
(2-Fluoro-4-pyridinyl)methanol (500 mg, 3.93 mmol, Molekula) and triethylamine (806 μl, 5.78 mmol) were dissolved in EtOAc (7.87 ml) and stirred at 0 0C. Methanesulfonyl chloride (391 μl, 5.03 mmol) was added slowly at 0 0C and stirred for 2 h. The reaction mixture was diluted with EtOAc (50 ml) and treated with water (50 ml). The aqueous layer was then extracted with EtOAc (2 x 50 ml) and the organic layers were combined, washed with brine (50 ml), dried over magnesium sulfate, filtered and evaporated to dryness to give a pale yellow oil. The oil was redissolved in EtOAc (2.62 ml), diluted with heptane (1.75 ml), cooled to 0 0C and stirred for 2 h. The resultant white crystals were filtered and washed with cold heptane to give the title compound (390 mg) as a white solid, m/z [M+H]+: 206.0. Retention time 0.64 min (LC/MS method 3). Intermediate 50: 1,2,3-Benzothiadiazol-6-ylmethyl methanesulfonate
Figure imgf000071_0001
1 ,2,3-Benzothiadiazol-6-ylmethanol (29 mg, 0.175 mmol) was dissolved in DCM (2 ml.) and THF (2 ml_). Polystyrene-supported diethylamine (150 mg, 0.525 mmol) and methanesulfonyl chloride (0.027 ml_, 0.350 mmol) were added and the mixtures were stirred for 2hr at room temperature under argon. The resin was filtered off and washed with DCM and THF, and the collected washings were evaporated. The product was taken forward without purification. The following intermediates were prepared by a similar procedure to that described for intermediate 50 from the appropriate alcohol and used crude in the following step.
Figure imgf000072_0001
Figure imgf000073_0001
Intermediate 58: 1,3-Oxazol-2-ylmethyl methanesulfonate
Figure imgf000073_0002
To a solution of 1 ,3-oxazol-2-ylmethanol (364mg; Apollo) in dry DCM (20ml) at O0C was added triethylamine (0.573ml), followed by methanesulfonyl chloride (0.321 ml). The mixture was stirred for 1 hr, then diluted with DCM, washed with water, saturated aqueous sodium bicarbonate solution and brine, dried over magnesium sulfate, filtered and concentrated under vacuum to afford the title compound (573mg), as an orange oil. 1H NMR (CDCI3): 3.11 (3H, s), 5.32 (2H, s), 7.20 (1 H, d), 7.74 (1 H, d).
Intermediate 59: 2-(Hydroxymethyl)-1-methyl-4(1H)-quinolinone
Figure imgf000073_0003
For a preparation see Coppola G. M., J. Heterocyclic Chem., 1986, 23, 1717-1719. Intermediate 60: (1 -Methyl-4-oxo-1,4-dihydro-2-quinolinyl)methyl methanesulfonate
Figure imgf000073_0004
The title compound (33 mg) was made in a similar manner to 1 ,2,3-benzothiadiazol-6- ylmethyl methanesulfonate (may be prepared as described in intermediate 50) and used in the next step without purification. Intermediate 61 : 2-(bromomethyl)-4,5-dimethyl-1,3-oxazole
Figure imgf000074_0001
The title compound (319 mg) was made in a similar manner to 2-(bromomethyl)-6- chloropyridine (may be prepared as described in intermediate 16), replacing 2-chloro-6- methylpyridine with 2,4,5-trimethyl-1 ,3-oxazole (Aldrich).
Intermediate 62: 5-(bromomethyl)-3-methyl-1 ,3-benzoxazol-2(3H)-one
Figure imgf000074_0002
For a preparation see Liacha, M.; Yous, S.; Depreux, P.; Poupaert, J. H.; Lesieur, D. Heterocycles 1999, 51, 1929 - 1943.
Intermediate 63: (3-iodo-2-nitrophenyl)methylamine
Figure imgf000074_0003
1-Fluoro-3-iodo-2-nitrobenzene (2.67 g, 10 mmol; Apollo) and methylamine (2.87 g, 27% w/w solution in MeOH) were dissolved in MeOH (50 ml.) and stirred at RT overnight. The mixture was concentrated to afford the title compound (2.22 g) as a red solid.
Intermediate 64: 3-(methylamino)-2-nitrobenzonitrile
Figure imgf000074_0004
(3-lodo-2-nitrophenyl)methylamine (1.9Og; may be prepared as described in intermediate 63), zinc cyanide (1.60 g) and tetrakis(triphenylphosphine)palladium(0) (789 mg) were suspended in DMF (40 ml_). The resulting mixture was stirred at 80 0C under nitrogen overnight. It was cooled to room temperature and diluted with DCM (200 ml_), then poured into ice-water (1000 ml_). The layers were separated and the aqueous was extracted with DCM (2 x 200 ml_). The combined organic layers were washed with aqueous sodium bicarbonate solution (1 x 500 ml.) and water (2 x 500 ml_), dried over sodium sulphate, filtered and concentrated to afford a red solid. This was purified by chromatography over silica gel (eluent petroleum ether / EtOAc / triethylamine 60:40:2) to afford the title compound (847 mg) as a solid.
Intermediate 65: 2-amino-3-(methylamino)benzonitrile
Figure imgf000075_0001
3-(Methylamino)-2-nitrobenzonitrile (797 mg; may be prepared as described in intermediate 64) was dissolved in EtOAc (50 ml.) and MeOH (50 ml_). Palladium on carbon (160 mg, 10% w/w) was added and the mixture was stirred at RT under a hydrogen atmosphere for 2.5 hr. The mixture was filtered and concentrated to afford the title compound (530 mg) as a grey solid. Intermediate 66: 2-(chloromethyl)-1 -methyl-1H-benzimidazole-4-carbonitrile
Figure imgf000075_0002
2-Amino-3-(methylamino)benzonitrile (441 mg; may be prepared as described in intermediate 65) was dissolved in 2-chloro-1 ,1 ,1-trimethoxyethane (3 ml_, Aldrich). Concentrated hydrochloric acid (0.6 ml.) was added dropwise and the mixture was stirred at RT for 3 days. It was basified with aqueous sodium bicarbonate solution and then extracted with DCM (3 x 100 ml_). The combined organic layers were dried over soldium sulphate, filtered and evaporated to obtain a light red solid. This was purified by chromatography on silica gel (eluent petroleum ether / EtOAc 1 :1 ) to give the title compound (300 mg).
Intermediate 67: 2-(chloromethyl)-1 -methyl-1H-benzimidazole-6-carbonitrile
Figure imgf000076_0001
For a preparation see international patent application WO2005/082901 , published on 09 Sep 2005. Intermediate 68: 3-(chloromethyl)-2-methyl-4H-chromen-4-one
Figure imgf000076_0002
For a preparation see Nakazumi, Hiroyuki; Ueyama, Tamio; Sonoda, Hikaru; Kitao, Teijiro. Bull. Chem. Soc. Jpn. 1984, 24, 2323 - 2324 Intermediate 69: Λ/-Methyl-3-(methoxy)-2-nitroaniline
Figure imgf000076_0003
3-Fluoro-2-nitroanisole (4.5 g; Apollo) was mixed with methylamine (50 ml_, 27% w/w solution in MeOH) and the mixture was heated to reflux for 10 hr. After cooling to room temperature the solvent was evaporated to give the title compound (4.0 g).
Intermediate 70: [2-amino-3-(methoxy)phenyl]methylamine
Figure imgf000076_0004
To a Parr bottle was added palladium on carbon (1.0 g, 10% w/w) and MeOH (300 ml.) under nitrogen, followed by Λ/-methyl-3-(methoxy)-2-nitroaniline (4.0 g; may be prepared as described in intermediate 69). The mixture was hydrogenated at 50 psi at RT for 48 hr. The mixture was filtered and the filtrate was evaporated to give the title compound (4.1 g). Intermediate 71 : 2-(chloromethyl)-1 -methyl -4-(methoxy)-1 H-benzimidazole
Figure imgf000077_0001
[2-Amino-3-(methoxy)phenyl]methylamine (4.0 g; may be prepared as described in intermediate 70) and chloroacetic acid (5.0 g) were dissolved in hydrochloric acid (5 N, 100 ml.) and heated to reflux overnight. After cooling to room temperature the mixture was basified with aqueous sodium bicarbonate solution (10% w/v) then extracted with DCM (x 2). The combined organic layers were dried and concentrated to give the crude product. This was purified by chromatography on silica gel to give the title compound (3 g)-
Intermediate 72: 1-(methoxy)-2,3-dinitrobenzene
Figure imgf000077_0002
3-Nitroanisole (4.5 g; Aldrich) was dissolved in DCM (200 ml.) and cooled to 5 0C. Concentrated nitric acid (40 ml.) was added slowly. The mixture was stirred for 30 min at 5 0C, then washed with water and aqueous sodium bicarbonate solution (6 N). The organic layer was evaporated and the crude product was purified by chromatography on silica gel (eluent petroleum ether / ethyl acetate 5:1 ) to give the title compound (4.0 g). Intermediate 73: Λ/-methyl-2-(methoxy)-6-nitroaniline
Figure imgf000077_0003
The title compound (4.1 g) was made in a similar fashion to the preparation of Λ/-methyl- 3-(methoxy)-2-nitroaniline (may be prepared as described in intermediate 69), replacing 3-fluoro-2-nitroanisole with 1-(methoxy)-2,3-dinitrobenzene (may be prepared as described in intermediate 72).
Intermediate 74: [2-amino-6-(methoxy)phenyl]methylamine
Figure imgf000078_0001
The title compound (7.8 g) was made in a similar fashion to the preparation of [2-amino- 3-(methoxy)phenyl]methylamine (may be prepared as described in intermediate 70), replacing Λ/-methyl-3-(methoxy)-2-nitroaniline with Λ/-methyl-2-(methoxy)-6-nitroaniline (may be prepared as described in intermediate 73).
Intermediate 75: 2-(chloromethyl)-1 -methyl -7-(methoxy)-1 H-benzimidazole
Figure imgf000078_0002
The title compound (2.0 g) was made in a similar fashion to the preparation of 2- (chloromethyl)-1-methyl-4-(methoxy)-1 H-benzimidazole (may be prepared as described in intermediate 71 ), replacing [2-amino-3-(methoxy)phenyl]methylamine with [2-amino-6- (methoxy)phenyl]methylamine (may be prepared as described in intermediate 74).
Intermediate 76: 1,2-dimethyl-1H-indole-3-carbaldehyde oxime
Figure imgf000078_0003
Hydroxylamine hydrochloride (5.7 g) was added to a solution of potassium hydroxide (6.3 g) in water (25 ml_). A solution of 1 ,2-dimethyl-1 H-indole-3-carbaldehyde (6.5 g; Apollo) in ethanol (400 ml.) was added and the mixture was heated to reflux for 1.5 hr. The solvent was evaporated to give the title compound as a mixture with potassium salts (5.65 g). Intermediate 77: 1,2-dimethyl-1H-indole-3-carbonitrile
Figure imgf000079_0001
A mixture of 1 ,2-dimethyl-1 /-/-indole-3-carbaldehyde oxime (5.65 g; may be prepared as described in intermediate 76) and acetic anhydride (200 ml.) was heated to reflux for 2 hr. The mixture was cooled and water (600 ml.) was added. It was extracted with EtOAc. The organic extractions were purified by column chromatography to obtain the title compound (5 g) as a yellow solid.
Intermediate 78: 2-(bromomethyl)-1-methyl-1H-indole-3-carbonitrile
Figure imgf000079_0002
The title compound (3.5 g) was made in a similar fashion to the preparation of 2- (bromomethyl)-6-chloropyridine (may be prepared as described in intermediate 16), replacing 2-chloro-6-methylpyridine with 1 ,2-dimethyl-1H-indole-3-carbonitrile (may be prepared as described in intermediate 78).
Intermediate 79: (2-bromo-6-nitrophenyl)methylamine
Figure imgf000079_0003
The title compound (2.1 g) was made in a similar fashion to the preparation of (3-iodo-2- nitrophenyl)methylamine (may be prepared as described in intermediate 63), replacing 1- fluoro-3-iodo-2-nitrobenzene with 1-bromo-2-fluoro-3-nitrobenzene (Apollo).
Intermediate 80: 2-(methylamino)-3-nitrobenzonitrile
Figure imgf000079_0004
A mixture of (2-bromo-6-nitrophenyl)methylamine (2.10 g; may be prepared as described in intermediate 79) and copper (I) cyanide (1.62 g) in 1-methyl-2-pyrrolidinone (60 ml.) was heated at 150 0C under an argon atmosphere for 3 hr. It was cooled to RT, diluted with Et2O and filtered. The filtrate was washed with water, hydrochloric acid (1 /V), saturated aqueous sodium bicarbonate solution and brine. It was dried over sodium sulphate, filtered and evaporated to give the title compound (1.13 g) as a red solid.
Intermediate 81 : 3-amino-2-(methylamino)benzonitrile
Figure imgf000080_0001
The title compound (0.83 g) was made in a similar fashion to the preparation of 2-amino- 3-(methylamino)benzonitrile (may be prepared as described in intermediate 65), replacing 3-(methylamino)-2-nitrobenzonitrile with 2-(methylamino)-3-nitrobenzonitrile (may be prepared as described in intermediate 80). Intermediate 82: 2-(chloromethyl)-1 -methyl-1H-benzimidazole-7-carbonitrile
Figure imgf000080_0002
The title compound (0.82 g) was made in a similar fashion to the preparation of 2- (chloromethyl)-1-methyl-4-(methoxy)-1 H-benzimidazole (may be prepared as described in intermediate 71 ), replacing [2-amino-3-(methoxy)phenyl]methylamine with 3-amino-2- (methylamino)benzonitrile (may be prepared as described in intermediate 81 ).
Intermediate 83: Λ/-methyl-5-(methoxy)-2-nitroaniline
Figure imgf000080_0003
The title compound (4.0 g) was made in a similar fashion to the preparation of (3-iodo-2- nitrophenyl)methylamine (may be prepared as described in intermediate 63), replacing 1- fluoro-3-iodo-2-nitrobenzene with 1-fluoro-5-methoxy-2-nitrobenzene (Apin). Intermediate 84: [2-amino-5-(methyloxy)phenyl]methylamine
Figure imgf000081_0001
The title compound (4.0 g) was made in a similar fashion to the preparation of [2-amino- 3-(methoxy)phenyl]methylamine (may be prepared as described in intermediate 70), replacing Λ/-methyl-3-(methoxy)-2-nitroaniline with Λ/-methyl-5-(methoxy)-2-nitroaniline (may be prepared as described in intermediate 83).
Intermediate 85: 2-(chloromethyl)-1 -methyl-6-(methyloxy)-1H-benzimidazole
Figure imgf000081_0002
The title compound (0.05 g) was made in a similar fashion to the preparation of 2- (chloromethyl)-1-methyl-4-(methoxy)-1H-benzimidazole (may be prepared as described in intermediate 71 ), replacing [2-amino-3-(methoxy)phenyl]methylamine with [2-amino-5- (methyloxy)phenyl]methylamine (may be prepared as described in intermediate 84). Intermediate 86: 3-amino-Λ/-methyl-4-pyridinecarboxamide
Figure imgf000081_0003
S-Amino^-pyridinecarboxylic acid (500 mg; Maybridge) was dissolved in DMF (20 ml.) under stirring. To this solution, EDC (833 mg) and HOAt (591 mg) were added. Triethylamine (1.514 ml.) and methylamine hydrochloride (293 mg) were added, and the reaction mixture was stirred at RT for 3 days. The solvent was removed by rotary evaporation. After addition of water, the mixture was then extracted with EtOAc (3 x 20 ml.) and the combined organic extracts were washed with aqueous citric acid solution (10% w/v, 1 x 20 ml_), followed by saturated aqueous sodium bicarbonate solution (1 x 20 ml.) and then brine (1 x 20 ml_). The organic layer was dried over magnesium sulfate and the solvent removed by rotary evaporation. The aqueous layer was extracted with a mixture of DCM and MeOH (4:1 ). The combined organic layers were dried with a phase separation cartridge, and the solvent removed by rotary evaporation. The mixture was purified by Biotage (100 g silica cartridge; eluent DCM / MeOH 0 to 20%). Two peaks were observed and the fractions from the second one were combined and evaporated to give the title compound (78 mg). m/z [M+H]+: 152.1. Retention time 0.40 min (LC/MS method 4).
Intermediate 87: 3-[(chloroacetyl)amino]-Λ/-methyl-4-pyridinecarboxamide
Figure imgf000082_0001
3-amino-Λ/-methyl-4-pyridinecarboxamide (68 mg; may be prepared as described in intermediate 86) was dissolved in THF under stirring, and under an argon atmosphere. Chloroacetyl chloride (0.038 ml.) was then added, and the reaction mixture was left overnight, still under stirring and argon atmosphere and at RT. Another portion of chloroacetyl chloride (0.038 ml.) was added. The reaction mixture was left under stirring for 2 hr. Sodium bicarbonate (60.5 mg) was added, and the reaction mixture was left under stirring for 5 min ( the argon atmosphere was removed). Then DCM (20 ml.) and water (10 ml.) were added, and the reaction mixture was stirred for 5 min. The phases were separated with a phase separating cartridge. The solvent from the organic layer was removed by rotary evaporation, giving the title compound (78 mg) as a white solid, m/z [M+H]+: 228.0 / 230.0. Retention time 0.53 min (LC/MS method 4).
Intermediate 88: 2-(chloromethyl)-3-methylpyrido[3,4-cflpyrimidin-4(3H)-one
Figure imgf000082_0002
A mixture of 3-[(chloroacetyl)amino]-Λ/-methyl-4-pyridinecarboxamide (74 mg; may be prepared as described in intermediate 87) and p-toluenesulfonic acid monohydrate (124 mg) in toluene (6 ml.) was heated to reflux for 4.25 hours.
The reaction mixture was cooled to room temperature. The reaction mixture was diluted with saturated aqueous sodium bicarbonate solution (5 ml.) and then with DCM (10 ml_). The layers were separated and the aqueous was extracted with DCM (2 x 10 ml_). The combined organic layers were washed with water (10 ml.) and brine (15 ml_), dried through a phase separating cartridge and evaporated to give the title compound (46 mg) as a pink solid, m/z [M+H]+: 210.0 / 212.0. Retention time 0.63 min (LC/MS method 4).
Intermediate 89: 2-(hydroxymethyl)-4(1W)-quinolinone
Figure imgf000083_0001
For a preparation see international patent application WO2008/144865, published on 04 Dec 2008.
Intermediate 90: 2-(bromomethyl)-4(1H)-quinolinone
Figure imgf000083_0002
A mixture of 2-(hydroxymethyl)-4(1 /-/)-quinolinone (4.666 g; may be prepared as described in intermediate 90) and carbon tetrabromide (15.01 g) in DCM (200 ml.) at 0 0C under nitrogen was treated portionwise with triphenylphosphine over 0.5 hr. The mixture was stirred at 0 0C for 0.5 hr, then at RT for 18 hr. The mixture was cooled to 0 0C and MeOH (20 ml.) was added. The mixture was stirred at 0 0C for 0.5 hr, then at RT for 0.5 hr. More MeOH (50 ml.) was added to dissolve all the material. Silica gel (100 g) was added and the solvent was removed under vacuum. The residue was chromatographed on silica gel. Elution with MeOH / DCM 0.5:10 then 1 :10 gave the title compound (5.8 g) as a slightly impure beige solid, plus some pure title compound (800 mg) as a white solid. The impure solid was further purified by chromatography on silica gel. Elution with MeOH / EtOAc 0.3:10 gave title compound which was combined with the pure compound from the previous purification to afford the title compound (2.12 g) as a pale straw-coloured solid. Intermediate 91 : 2-amino-Λ/-ethylbenzamide
Figure imgf000083_0003
A solution of isatoic anhydride (0.50 g; Aldrich) in ethylamine (10 mL) (2M solution in MeOH) was heated to reflux overnight. The solvent was evaporated to give a pink solid. Mass: 0.59g. This was purified by Biotage (100 g silica cartridge; eluent isohexane / ethyl acetate 10 to 50%; collection by UV trigger). Fractions corresponding to the main peak were combined and evaporated to give the title compound (0.38 g) as a white solid, m/z [M+H]+: 165.0. Retention time 0.51 min (LC/MS method 3).
Intermediate 92: 2-[(chloroacetyl)amino]-Λ/-ethylbenzamide
Figure imgf000084_0001
A solution of 2-amino-Λ/-ethylbenzamide (0.38 g; may be prepared as described in intermediate 91 ) in dry DCM (20 mL) was cooled with an ice bath under argon. Chloroacetyl chloride (0.195 mL) was added and the mixture was stirred for 2 hr, and allowed to rise to RT. During this time all the solvent evaporated, so more DCM (20 mL) was added, followed by sodium bicarbonate (0.31 1 g). Water (20 mL) was added, the mixture was stirred for 5 min, and the layers were separated (phase separation cartridge). The organic layer was evaporated to give the title compound (0.53 g) as a white solid, m/z [M+H]+: 241.0 / 242.0. Retention time 0.75 min (LC/MS method 3).
Intermediate 93: 2-(chloromethyl)-3-ethyl-4(3H)-quinazolinone
Figure imgf000084_0002
The title compound (0.34 g) was made in a similar fashion to the preparation of 2-
(chloromethyl)-3-methylpyrido[3,4-c/]pyrimidin-4(3/-/)-one (may be prepared as described in intermediate 88), replacing 3-[(chloroacetyl)amino]-Λ/-methyl-4-pyridinecarboxamide with 2-[(chloroacetyl)amino]-Λ/-ethylbenzamide may be prepared as described in intermediate 92). m/z [M+H]+: 222.9 / 225.0. Retention time 0.87 min (LC/MS method 3).
Intermediate 94: methyl 5-fluoro-2-{[(methoxy)acetyl]amino}benzoate
Figure imgf000085_0001
To a solution of methyl 2-amino-5-fluorobenzoate (5 g; Alfa Aesar) in anhydrous DMF (74 mL) was added methoxyacetyl chloride (5 ml_; Aldrich) followed by the addition of pyridine (12 mL), and the reaction mixture was stirred at RT under argon for 45 min. The reaction mixture was partioned between EtOAc (200 mL) and hydrochloric acid (1 M, 100 mL), and the organic layer was washed with hydrochloric acid (1 M, 2 x 100 mL) and brine (1 x 100 mL), dried over magnesium sulfate, filtered and evaporated to give a yellow solid. This was dissolved in DCM and purified on the Biotage SP4 using a silica 40+M column (x2) and eluting with 0 to 50% EtOAc / isohexane over 20CV to afford the title compound as a white solid (6.632 g). m/z [M+H]+: 242.0. Retention time 0.94 min (LC/MS method 3).
Intermediate 95: 6-fluoro-3-methyl-2-[(methoxy)methyl]-4(3H)-quinazolinone
Figure imgf000085_0002
To a mixture of methyl 5-fluoro-2-{[(methoxy)acetyl]amino}benzoate (1.7 g; may be prepared as described in intermediate 94) and 2 M methylamine in MeOH (72 mL) was added 2M methylamine in THF (41 mL). The clear solution was stirred at RT overnight, and then the solvents were removed under vacuum. The residue was dissolved in DCM and purified on the Biotage SP4 using a silica 40+M column and eluting with 20 to 50% EtOAc / isohexane over 10CV and then 50% EtOAc / isohexane over 10 CV to afford the title compounds as a white solid (722.1 mg). m/z [M+H]+: 223.2. Retention time 0.73 min (LC/MS method 3).
Intermediate 96: 2-(bromomethyl)-6-fluoro-3-methyl-4(3H)-quinazolinone
Figure imgf000085_0003
A mixture of 6-fluoro-3-methyl-2-[(methoxy)methyl]-4(3/-/)-quinazolinone (1.2 g; may be prepared as described in intermediate 95) and 48% aqueous hydrobromic acid (100 ml.) was placed in a preheated hotplate (120 0C) for 2 days. The reaction was cooled and evaporated to dryness to give the title compound (1.3 g) as a mixture with 6-fluoro-2- (hydroxymethyl)-3-methyl-4(3H)-quinazolinone. m/z [M+H]+: 271.0 / 273.0. Retention time 0.87 min (LC/MS method 3).
Intermediate 97: 2-(chloromethyl)-7-(methoxy)-4(1 H)-quinazolinone
Figure imgf000086_0001
To a solution of sodium methoxide in anhydrous MeOH (10 ml.) was added chloroacetonitrile (1.039 g; Aldrich) and the clear solution was stirred at RT for 30 min under argon. A solution of 2-amino-5-(methoxy)benzoic acid (2 g; Aldrich) in anhydrous MeOH (50 ml.) was then added and the reaction mixture was stirred at RT for 90 min. The reaction mixture was then heated to 80 0C and stirred for 1 hr. The mixture was allowed to cool to room temperature and the solid was filtered off and washed with MeOH (20 ml.) to afford the title compound (1.86 g) as an off white solid, m/z [M+H]+: 225.1 / 227.1. Retention time 0.67 min (LC/MS method 3).
Intermediate 98: 2-(iodomethyl)-3-methyl-7-(methoxy)-4(3H)-quinazolinone
Figure imgf000086_0002
To a solution of 2-(chloromethyl)-6-(methoxy)-4(1 H)-quinazolinone (200 mg; may be prepared as described in intermediate 97) in anhydrous DMF (20 ml.) was added methyl iodide (2.5 g) followed by cesium carbonate (435 mg) and the solution was stirred at RT for 30 min. The reaction mixture was diluted with EtOAc (100 ml.) and washed with water (3 x 50 ml.) then dried over magnesium sulfate, filtered and evaporated to give a brown solid (302 mg). The solid was dissolved in DCM and purified on the Biotage SP4 using a 25+M silica column and eluting with 0 to 50% EtOAc / isohexane over 20CV to afford the title compound (190mg) as a white solid with approximately 10% 2-(chloromethyl)-3- methyl-7-(methoxy)-4(3H)-quinazolinone. m/z [M+H]+: 331.0. Retention time 0.85 min (LC/MS method 3). Intermediate 99: methyl 4-fluoro-2-{[(methoxy)acetyl]amino}benzoate
Figure imgf000087_0001
The title compound (453 mg) was made in a similar fashion to the preparation of methyl 5-fluoro-2-{[(methoxy)acetyl]amino}benzoate (may be prepared as described in intermediate 94), replacing methyl 2-amino-5-fluorobenzoate with methyl 2-amino-4- fluorobenzoate (Enamine). m/z [M+H]+: 242.2. Retention time 0.98 min (LC/MS method 3).
Intermediate 100: 7-fluoro-3-methyl-2-[(methoxy)methyl]-4(3H)-quinazolinone
Figure imgf000087_0002
The title compound (336 mg) was made in a similar fashion to the preparation of 6-fluoro- 3-methyl-2-[(methoxy)methyl]-4(3H)-quinazolinone (may be prepared as described in intermediate 95), replacing methyl 5-fluoro-2-{[(methoxy)acetyl]amino}benzoate with methyl 4-fluoro-2-{[(methoxy)acetyl]amino}benzoate (may be prepared as described in intermediate 99). m/z [M+H]+: 223.2. Retention time 0.70 min (LC/MS method 3).
Intermediate 101 : 2-(bromomethyl)-7-fluoro-3-methyl-4(3H)-quinazolinone
Figure imgf000087_0003
The title compound (662 mg) was made in a similar fashion to the preparation of 2- (bromomethyl)-6-fluoro-3-methyl-4(3H)-quinazolinone (may be prepared as described in intermediate 95), replacing 6-fluoro-3-methyl-2-[(methoxy)methyl]-4(3H)-quinazolinone with 7-fluoro-3-methyl-2-[(methoxy)methyl]-4(3H)-quinazolinone (may be prepared as described in intermediate 100). m/z [M+H]+: 271.0 / 273.0. Retention time 0.86 min (LC/MS method 3). Intermediate 102: 3-amino-Λ/-methyl-2-pyridinecarboxamide
Figure imgf000088_0001
The title compound (404 mg) was made in a similar fashion to the preparation of 3- amino-Λ/-methyl-4-pyridinecarboxamide (may be prepared as described in intermediate 86), replacing S-amino^-pyridinecarboxylic acid with 3-amino-2-pyridinecarboxylic acid (Apollo), m/z [M+H]+: 152.0. Retention time 0.56 min (LC/MS method 4).
Intermediate 103: 3-[(chloroacetyl)amino]-Λ/-methyl-2-pyridinecarboxamide
Figure imgf000088_0002
The title compound (609 mg) was made in a similar fashion to the preparation of 3- [(chloroacetyl)amino]-Λ/-methyl-4-pyridinecarboxamide (may be prepared as described in intermediate 87), replacing 3-amino-Λ/-methyl-4-pyridinecarboxamide with 3-amino-/V- methyl-2-pyridinecarboxamide (may be prepared as described in intermediate 102), and DCM with THF as the reaction solvent, m/z [M+H]+: 228.0 / 229.0. Retention time 0.72 min (LC/MS method 3).
Intermediate 104: 2-(chloromethyl)-3-methylpyrido[3,2-cflpyrimidin-4(3H)-one
Figure imgf000088_0003
The title compound (581 mg) was made in a similar fashion to the preparation of 2- (chloromethyl)-3-methylpyrido[3,4-c/]pyrimidin-4(3/-/)-one (may be prepared as described in intermediate 88), replacing 3-[(chloroacetyl)amino]-Λ/-methyl-4-pyridinecarboxamide with 3-[(chloroacetyl)amino]-Λ/-methyl-2-pyridinecarboxamide (may be prepared as described in intermediate 103). m/z [M+H]+: 210.1 / 212.1. Retention time 0.51 min (LC/MS method 3). Intermediate 105: 2-(chloromethyl)-6-(methoxy)-4(1 H)-quinazolinone
Figure imgf000089_0001
The title compound (1.86 g) was made in a similar fashion to the preparation of 2- (chloromethyl)-7-(methoxy)-4(1 H)-quinazolinone (may be prepared as described in intermediate 97), replacing 2-amino-5-(methoxy)benzoic acid with 2-amino-4- (methoxy)benzoic acid (Fluorochem). m/z [M+H]+: 225.1 / 227.1. Retention time 0.65 min (LC/MS method 3).
Intermediate 106: 2-(iodomethyl)-3-methyl-6-(methoxy)-4(3H)-quinazolinone
Figure imgf000089_0002
The title compound (190 mg) was made in a similar fashion to the preparation of 2- (iodomethyl)-3-methyl-7-(methoxy)-4(3H)-quinazolinone (may be prepared as described in intermediate 98), replacing 2-(chloromethyl)-7-(methoxy)-4(1 H)-quinazolinone with 2- (chloromethyl)-6-(methoxy)-4(1 H)-quinazolinone (may be prepared as described in intermediate 105). m/z [M+H]+: 331.1. Retention time 0.85 min (LC/MS method 3).
Intermediate 107: 2-(chloromethyl)-7-methyl-4(1H)-quinazolinone
Figure imgf000089_0003
The title compound (893 mg) was made in a similar fashion to the preparation of 2- (chloromethyl)-7-(methoxy)-4(1 H)-quinazolinone (may be prepared as described in intermediate 97), replacing 2-amino-5-(methoxy)benzoic acid with 2-amino-4- methylbenzoic acid (Maybridge). m/z [M+H]+: 209.1 / 211.1. Retention time 0.71 min (LC/MS method 3). Intermediate 108: 2-(iodomethyl)-3,7-dimethyl-4(3H)-quinazolinone
Figure imgf000090_0001
The title compound (66 mg) was made in a similar fashion to the preparation of 2- (iodomethyl)-3-methyl-7-(methoxy)-4(3H)-quinazolinone (may be prepared as described in intermediate 98), replacing 2-(chloromethyl)-7-(methoxy)-4(1 H)-quinazolinone with 2- (chloromethyl)-7-methyl-4(1 H)-quinazolinone (may be prepared as described in intermediate 107). m/z [M+H]+: 315.1. Retention time 0.89 min (LC/MS method 3).
Intermediate 109: 2-(chloromethyl)-6-methyl-4(1H)-quinazolinone
Figure imgf000090_0002
The title compound (878 mg) was made in a similar fashion to the preparation of 2- (chloromethyl)-7-(methoxy)-4(1 H)-quinazolinone (may be prepared as described in intermediate 97), replacing 2-amino-5-(methoxy)benzoic acid with 2-amino-5- methylbenzoic acid (Aldrich). m/z [M+H]+: 209.2 / 21 1.1. Retention time 0.70 min (LC/MS method 3).
Intermediate 110: 2-(iodomethyl)-3,6-dimethyl-4(3H)-quinazolinone
Figure imgf000090_0003
The title compound (56 mg) was made in a similar fashion to the preparation of 2- (iodomethyl)-3-methyl-7-(methoxy)-4(3H)-quinazolinone (may be prepared as described in intermediate 98), replacing 2-(chloromethyl)-7-(methoxy)-4(1 H)-quinazolinone with 2- (chloromethyl)-6-methyl-4(1 H)-quinazolinone (may be prepared as described in intermediate 109). m/z [M+H]+: 315.1. Retention time 0.90 min (LC/MS method 3).
Intermediate 111 : 2-(chloromethyl)-5-(methoxy)-4(1 H)-quinazolinone
Figure imgf000091_0001
The title compound (1.6 g) was made in a similar fashion to the preparation of 2- (chloromethyl)-7-(methoxy)-4(1 H)-quinazolinone (may be prepared as described in intermediate 97), replacing 2-amino-5-(methoxy)benzoic acid with 2-amino-6- (methoxy)benzoic acid (Fluka). m/z [M+H]+: 225.1 / 227.1. Retention time 0.56 min (LC/MS method 3).
Intermediate 112: 2-(iodomethyl)-3-methyl-5-(methoxy)-4(3H)-quinazolinone
Figure imgf000091_0002
The title compound (128 mg) was made in a similar fashion to the preparation of 2- (iodomethyl)-3-methyl-7-(methoxy)-4(3H)-quinazolinone (may be prepared as described in intermediate 98), replacing 2-(chloromethyl)-7-(methoxy)-4(1 H)-quinazolinone with 2- (chloromethyl)-5-(methoxy)-4(1 H)-quinazolinone (may be prepared as described in intermediate 11 1 ). m/z [M+H]+: 331.1. Retention time 0.71 min (LC/MS method 3).
Intermediate 113: 6-chloro-2-(chloromethyl)-4(1H)-quinazolinone
Figure imgf000091_0003
The title compound (873 mg) was made in a similar fashion to the preparation of 2- (chloromethyl)-7-(methoxy)-4(1 H)-quinazolinone (may be prepared as described in intermediate 97), replacing 2-amino-5-(methoxy)benzoic acid with 2-amino-5- chlorobenzoic acid (Aldrich). m/z [M+H]+: 229.0 / 231.0. Retention time 0.77 min (LC/MS method 3).
Intermediate 114: 6-chloro-2-(iodomethyl)-3-methyl-4(3H)-quinazolinone
Figure imgf000092_0001
The title compound (128 mg) was made in a similar fashion to the preparation of 2- (iodomethyl)-3-methyl-7-(methoxy)-4(3H)-quinazolinone (may be prepared as described in intermediate 98), replacing 2-(chloromethyl)-7-(methoxy)-4(1 H)-quinazolinone with 6- chloro-2-(chloromethyl)-4(1 H)-quinazolinone (may be prepared as described in intermediate 113). m/z [M+H]+: 335.0 / 336.9. Retention time 0.99 min (LC/MS method 3).
Intermediate 115: 7-chloro-2-(chloromethyl)-4(1H)-quinazolinone
Figure imgf000092_0002
The title compound (606 mg) was made in a similar fashion to the preparation of 2- (chloromethyl)-7-(methoxy)-4(1 H)-quinazolinone (may be prepared as described in intermediate 97), replacing 2-amino-5-(methoxy)benzoic acid with 2-amino-4- chlorobenzoic acid (Aldrich). m/z [M+H]+: 229.0 / 231.0. Retention time 0.79 min (LC/MS method 3).
Intermediate 116: 7-chloro-2-(iodomethyl)-3-methyl-4(3H)-quinazolinone
Figure imgf000092_0003
The title compound (209 mg) was made in a similar fashion to the preparation of 2- (iodomethyl)-3-methyl-7-(methoxy)-4(3H)-quinazolinone (may be prepared as described in intermediate 98), replacing 2-(chloromethyl)-7-(methoxy)-4(1 H)-quinazolinone with 7- chloro-2-(chloromethyl)-4(1 H)-quinazolinone (may be prepared as described in intermediate 115). m/z [M+H]+: 335.0 / 337.0. Retention time 1.00 min (LC/MS method 3).
Intermediate 117: 2-amino-Λ/-methyl-3-pyridinecarboxamide
Figure imgf000093_0001
The title compound (380 mg) was made in a similar fashion to the preparation of 3- amino-Λ/-methyl-4-pyridinecarboxamide (may be prepared as described in intermediate 86), replacing S-amino^-pyridinecarboxylic acid with 2-amino-3-pyridinecarboxylic acid (Aldrich), and HOAt with HOBt. m/z [M+H]+: 152.1. Retention time 0.43 min (LC/MS method 4).
Intermediate 118: 2-(chloromethyl)-3-methylpyrido[2,3-c/]pyrimidin-4(3H)-one
Figure imgf000093_0002
Chloroacetyl chloride (0.21 1 ml.) was added to a solution of 2-amino-Λ/-methyl-3- pyridinecarboxamide (380 mg; may be prepared as described in intermediate 117) in dry THF (20 ml.) under argon. The mixture was stirred overnight. More THF (20 ml.) and chloroacetyl chloride (0.5 ml.) were added and the mixture was stirred overnight. More chloroacetyl chloride (0.5 ml.) were added and the mixture was heated to reflux overnight. It was cooled to room temperature. Water (20 ml.) and sodium bicarbonate (2 g) were added. DCM (80 ml.) was added and the layers were separated (hydrophobic membrane). The organic layer was evaporated to give a brown solid. Mass: 654 mg. The aqueous layer was extracted again with 5:1 DCM / MeOH (2 x 60 ml_). The combined organic layers were dried (hydrophobic membrane) and evaporated to give a reddish solid. Mass: 37 mg. The two solids were combined and purified by Biotage (100g silica cartridge; eluent DCM / MeOH 0 to 5%; collection by UV trigger) to give the title compound (120 mg) as a brown solid, m/z [M+H]+: 210.1 / 212.2. Retention time 0.53 min (LC/MS method 3). Intermediate 119: 2-(chloromethyl)-8-(methoxy)-4(1H)-quinazolinone
Figure imgf000094_0001
The title compound (512 mg) was made in a similar fashion to the preparation of 2- (chloromethyl)-7-(methoxy)-4(1 H)-quinazolinone (may be prepared as described in intermediate 97), replacing 2-amino-5-(methoxy)benzoic acid with 2-amino-3- (methoxy)benzoic acid (Aldrich). m/z [M+H]+: 225.1 / 227.2. Retention time 0.58 min (LC/MS method 3).
Intermediate 120: 2-(iodomethyl)-3-methyl-8-(methoxy)-4(3H)-quinazolinone
Figure imgf000094_0002
The title compound (52 mg) was made in a similar fashion to the preparation of 2- (iodomethyl)-3-methyl-7-(methoxy)-4(3H)-quinazolinone (may be prepared as described in intermediate 98), replacing 2-(chloromethyl)-7-(methoxy)-4(1 H)-quinazolinone with 2- (chloromethyl)-8-(methoxy)-4(1 H)-quinazolinone (may be prepared as described in intermediate 119). m/z [M+H]+: 331.0. Retention time 0.76 min (LC/MS method 3).
Intermediate 121 : 4-amino-Λ/-methyl-3-pyridinecarboxamide
Figure imgf000094_0003
The title compound (630 mg) was made in a similar fashion to the preparation of 3- amino-Λ/-methyl-4-pyridinecarboxamide (may be prepared as described in intermediate 86), replacing 3-amino-4-pyridinecarboxylic acid with 4-amino-3-pyridinecarboxylic acid (Aldrich), and HOAt with HOBt. m/z [M+H]+: 152.0. Retention time 0.38 min (LC/MS method 4).
Intermediate 122: 4-[(chloroacetyl)amino]-Λ/-methyl-3-pyridinecarboxamide
Figure imgf000095_0001
4-Amino-Λ/-methyl-3-pyridinecarboxamide (200 mg; may be prepared as described in intermediate 121 ) was dissolved in DMF (20.00 ml_). DMAP (8.08 mg), N,N- diisopropylethylamine (0.462 ml.) and chloroacetyl chloride (0.212 ml.) were added at room temperature under stirring. The mixture was heated in the microwave for 10 min at
100 0C. The mixture was diluted with EtOAc (10 ml) and washed with water and brine ( x
3). Organics were dried over sodium sulphate, filtered and the solvent was evaporated to afford the crude product that was purified by silica chromatography to afford the title compound (100 mg, 0.395 mmol). m/z [M+H]+: 228.1 / 230.1. Retention time 0.44 min (LC/MS method 3).
Intermediate 123: 2-(chloromethyl)-3-methylpyrido[4,3-c/]pyrimidin-4(3H)-one
Figure imgf000095_0002
The title compound (581 mg) was made in a similar fashion to the preparation of 2- (chloromethyl)-3-methylpyrido[3,4-c/]pyrimidin-4(3/-/)-one (may be prepared as described in intermediate 88), replacing 3-[(chloroacetyl)amino]-Λ/-methyl-4-pyridinecarboxamide with 4-[(chloroacetyl)amino]-Λ/-methyl-3-pyridinecarboxamide (may be prepared as described in intermediate 122). m/z [M+H]+: 209.9 / 212.0. Retention time 0.61 min (LC/MS method 4).
Intermediate 124: 2-(chloromethyl)-5-fluoro-4(1H)-quinazolinone
Figure imgf000095_0003
The title compound (0.8 g) was made in a similar fashion to the preparation of 2-
(chloromethyl)-7-(methoxy)-4(1 H)-quinazolinone (may be prepared as described in intermediate 97), replacing 2-amino-5-(methoxy)benzoic acid with 2-amino-6- fluorobenzoic acid (Apollo), m/z [M+H]+: 213.1 / 215.1. Retention time 0.61 min (LC/MS method 3).
Intermediate 125: 5-fluoro-2-(iodomethyl)-3-methyl-4(3H)-quinazolinone
Figure imgf000096_0001
The title compound (221 mg) was made in a similar fashion to the preparation of 2-
(iodomethyl)-3-methyl-7-(methoxy)-4(3H)-quinazolinone (may be prepared as described in intermediate 98), replacing 2-(chloromethyl)-7-(methoxy)-4(1 H)-quinazolinone with 2- (chloromethyl)-5-fluoro-4(1 H)-quinazolinone (may be prepared as described in intermediate 124). m/z [M+H]+: 319.0. Retention time 1.04 min (LC/MS method 3).
Intermediate 126: 2-(chloromethyl)-8-fluoro-4(1H)-quinazolinone
Figure imgf000096_0002
The title compound (659 mg) was made in a similar fashion to the preparation of 2- (chloromethyl)-7-(methoxy)-4(1 H)-quinazolinone (may be prepared as described in intermediate 97), replacing 2-amino-5-(methoxy)benzoic acid with 2-amino-3- fluorobenzoic acid (Matrix Scientific), m/z [M+H]+: 213.1 / 215.0. Retention time 0.63 min (LC/MS method 3). Intermediate 127: 8-fluoro-2-(iodomethyl)-3-methyl-4(3H)-quinazolinone
Figure imgf000096_0003
The title compound (206 mg) was made in a similar fashion to the preparation of 2- (iodomethyl)-3-methyl-7-(methoxy)-4(3H)-quinazolinone (may be prepared as described in intermediate 98), replacing 2-(chloromethyl)-7-(methoxy)-4(1 H)-quinazolinone with 2- (chloromethyl)-8-fluoro-4(1 H)-quinazolinone (may be prepared as described in intermediate 126). m/z [M+H]+: 319.0. Retention time 1.07 min (LC/MS method 3).
Intermediate 128: 2-(chloromethyl)-8-methyl-4(1H)-quinazolinone
Figure imgf000097_0001
The title compound (0.8 g) was made in a similar fashion to the preparation of 2- (chloromethyl)-7-(methoxy)-4(1 H)-quinazolinone (may be prepared as described in intermediate 97), replacing 2-amino-5-(methoxy)benzoic acid with 2-amino-3- methylbenzoic acid (Aldrich). m/z [M+H]+: 209.1 / 21 1.1. Retention time 0.82 min (LC/MS method 3).
Intermediate 129: 2-(iodomethyl)-3,8-dimethyl-4(3H)-quinazolinone
Figure imgf000097_0002
The title compound (230 mg) was made in a similar fashion to the preparation of 2- (iodomethyl)-3-methyl-7-(methoxy)-4(3H)-quinazolinone (may be prepared as described in intermediate 98), replacing 2-(chloromethyl)-7-(methoxy)-4(1 H)-quinazolinone with 2- (chloromethyl)-8-methyl-4(1 H)-quinazolinone (may be prepared as described in intermediate 128). m/z [M+H]+: 315.1. Retention time 1.05 min (LC/MS method 3). Intermediate 130: 8-chloro-2-(chloromethyl)-4(1H)-quinazolinone
Figure imgf000097_0003
The title compound (56 mg) was made in a similar fashion to the preparation of 2-
(chloromethyl)-7-(methoxy)-4(1 H)-quinazolinone (may be prepared as described in intermediate 97), replacing 2-amino-5-(methoxy)benzoic acid with 2-amino-3- chlorobenzoic acid (Aldrich). m/z [M+H]+: 229.1 / 231.1. Retention time 0.87 min (LC/MS method 3).
Intermediate 131 : 8-chloro-2-(iodomethyl)-3-methyl-4(3H)-quinazolinone
Figure imgf000098_0001
The title compound (22 mg) was made in a similar fashion to the preparation of 2-
(iodomethyl)-3-methyl-7-(methoxy)-4(3H)-quinazolinone (may be prepared as described in intermediate 98), replacing 2-(chloromethyl)-7-(methoxy)-4(1 H)-quinazolinone with 8- chloro-2-(chloromethyl)-4(1H)-quinazolinone (may be prepared as described in intermediate 131 ). m/z [M+H]+: 334.9 / 336.9. Retention time 1.17 min (LC/MS method 3).
Intermediate 132: 5-chloro-2-(chloromethyl)-4(1H)-quinazolinone
The title compound (470 mg) was made in a similar fashion to the preparation of 2- (chloromethyl)-7-(methoxy)-4(1 H)-quinazolinone (may be prepared as described in intermediate 97), replacing 2-amino-5-(methoxy)benzoic acid with 2-amino-6- chlorobenzoic acid (Aldrich). m/z [M+H]+: 229.0 / 231.0. Retention time 0.71 min (LC/MS method 3). Intermediate 133: 5-chloro-2-(iodomethyl)-3-methyl-4(3H)-quinazolinone
Figure imgf000098_0002
The title compound (198 mg) was made in a similar fashion to the preparation of 2- (iodomethyl)-3-methyl-7-(methoxy)-4(3H)-quinazolinone (may be prepared as described in intermediate 98), replacing 2-(chloromethyl)-7-(methoxy)-4(1 H)-quinazolinone with 5- chloro-2-(chloromethyl)-4(1 H)-quinazolinone (may be prepared as described in intermediate 132). m/z [M+H]+: 335.0 / 337.0. Retention time 1.00 min (LC/MS method 3).
Intermediate 134: 2-(chloromethyl)-5-methyl-4(1H)-quinazolinone
Figure imgf000099_0001
The title compound (341 mg) was made in a similar fashion to the preparation of 2- (chloromethyl)-7-(methoxy)-4(1 H)-quinazolinone (may be prepared as described in intermediate 97), replacing 2-amino-5-(methoxy)benzoic acid with 2-amino-6- methylbenzoic acid (Fluka). m/z [M+H]+: 209.1 / 211.1. Retention time 0.81 min (LC/MS method 3).
Intermediate 135: 2-(iodomethyl)-3,5-dimethyl-4(3H)-quinazolinone
Figure imgf000099_0002
The title compound (292 mg) was made in a similar fashion to the preparation of 2- (iodomethyl)-3-methyl-7-(methoxy)-4(3H)-quinazolinone (may be prepared as described in intermediate 98), replacing 2-(chloromethyl)-7-(methoxy)-4(1 H)-quinazolinone with 2- (chloromethyl)-5-methyl-4(1 H)-quinazolinone (may be prepared as described in intermediate 134). m/z [M+H]+: 315.0. Retention time 0.97 min (LC/MS method 3).
Intermediate 136: 2-amino-3-bromobenzoic acid
Figure imgf000099_0003
The title compound (406 mg) was made in a similar fashion to the preparation of 2- amino-6-bromophenol (may be prepared as described in intermediate 1 , method A), replacing 2-bromo-6-nitrophenol with 3-bromo-2-nitrobenzoic acid (Chess GmbH), m/z [M+H]+: 216.1 / 218.1. Retention time 0.83 min (LC/MS method 3).
Intermediate 137: 8-bromo-2-methyl-4(1H)-quinazolinone
Figure imgf000100_0001
2-Amino-3-bromobenzoic acid (1.5 g; may be prepared as described in intermediate 136) in a solution of acetic anhydride (6 ml.) was heated at 12O0C for 2 hr. The reaction mixture was then cooled down to RT and the solvent was removed by rotary evaporation. Aqueous ammonia solution (28%) (12 ml.) was then added to the dry mixture and this was refluxed at 650C for 2 hrs. During the reflux, another 6 ml. of aqueous ammonia solution (28%) was added. A precipitate was formed which was filtered off, then washed with water, and then with diethyl ether. The title compound thus obtained (1.042 g) was dried in the oven overnight, m/z [M+H]+: 238.8 / 240.8. Retention time 0.67 min (LC/MS method 3).
Intermediate 138: 8-bromo-2,3-dimethyl-4(3H)-quinazolinone
Figure imgf000100_0002
To a solution of 8-bromo-2-methyl-4(1 H)-quinazolinone (1.083 g; may be prepared as described in intermediate 137) in anhydrous DMF (90 ml.) was added methyl iodide (5.67 ml.) followed by cesium carbonate (2.214 g) and the solution was stirred at room temperature for 1.5 hr. The reaction mixture was diluted with EtOAc (200 ml.) and washed with water (3 x 100 ml.) then dried over magnesium sulfate, filtered and evaporated to give an orange solid (907 mg). This was dissolved in EtOAc (50 ml.) and washed with brine (3 x 50 ml_). The organic was dried over magnesium sulphate, filtered, and the sovent was removed by rotary evaporation to afford the title compound (795 mg). m/z [M+H]+: 253.0 / 255.0. Retention time 0.79 min (LC/MS method 3).
Intermediate 139: 2,3-dimethyl-4-oxo-3,4-dihydro-8-quinazolinecarbonitrile
Figure imgf000101_0001
8-Bromo-2,3-dimethyl-4(3/-/)-quinazolinone (795 mg; may be prepared as described in intermediate 138), zinc cyanide (443 mg; Aldrich), palladium(ll) trifluoroacetate (41.8 mg; Aldrich), 1 ,1'-binaphthalen-2-yl[bis(1 ,1-dimethylethyl)]phosphane (110 mg; Aldrich) and zinc (103 mg) were charged to a 25 ml. flask and dissolved in Λ/,Λ/-dimethylacetamide (15 ml_). The mixture was purged through with argon, and heated to 80 0C overnight. The mixture was cooled to RT, filtered and the filtrate was diluted with EtOAc (50 ml_). The organic mixture was washed with water and brine (x 3). The organic layer was dried over sodium sulfate, filtered and the solvent was evaporated to afford a solid that was purified by silica chromatography (EtOAc / isohexane) to afford the title compound (263 mg). m/z [M+H]+: 200.2. Retention time 0.66 min (LC/MS method 3).
Intermediate 140: 2-(bromomethyl)-3-methyl-4-oxo-3,4-dihydro-8- quinazolinecarbonitrile
Figure imgf000101_0002
A mixture of 2,3-dimethyl-4-oxo-3,4-dihydro-8-quinazolinecarbonitrile (50 mg; may be prepared as described in intermediate 139), NBS (44.7 mg) and benzoyl peroxide (0.608 mg) in carbon tetrachloride (2 ml.) was heated to reflux for 2 hr. NBS (44.7 mg) was added followed by benzoyl peroxide (0.608 mg) and the mixture was refluxed overnight. Further NBS (44.7 mg) and benzoyl peroxide (0.608 mg) were added. The mixture was refluxed for 3 hr. AIBN (0.412 mg) was added to the hot mixture that was refluxed overnight. The mixture was cooled to room temperature, solvent was evaporated and the mixture was partitioned between EtOAc and water. The two phases were separated and the aqueous was extracted with EtOAc (x 2). Organics were combined, dried over sodium sulfate, filtered and the solvent was evaporated to afford the crude product that was purified by silica chromatography (EtOAc / isohexane) to afford the title compound (27 mg). m/z [M+H]+: 277.9 / 279.9. Retention time 0.85 min (LC/MS method 3). Intermediate 141 : 7-bromo-2-methyl-4(1H)-quinazolinone
Figure imgf000102_0001
The title compound (900 mg) was made in a similar fashion to the preparation of 8- bromo-2-methyl-4(1 H)-quinazolinone (may be prepared as described in intermediate 137), replacing 2-amino-3-bromobenzoic acid with 4-amino-3-bromobenzoic acid (Apollo), m/z [M+H]+: 238.8 / 240.8. Retention time 0.70 min (LC/MS method 3).
Intermediate 142: 7-bromo-2,3-dimethyl-4(3H)-quinazolinone
Figure imgf000102_0002
The title compound (500 mg) was made in a similar fashion to the preparation of 8- bromo-2,3-dimethyl-4(3H)-quinazolinone (may be prepared as described in intermediate 138), replacing 8-bromo-2-methyl-4(1 H)-quinazolinone with 7-bromo-2-methyl-4(1 H)- quinazolinone (may be prepared as described in intermediate 136). m/z [M+H]+: 253.0 / 255.0. Retention time 0.78 min (LC/MS method 3).
Intermediate 143: 2,3-dimethyl-4-oxo-3,4-dihydro-7-quinazolinecarbonitrile
Figure imgf000102_0003
The title compound (150 mg) was made in a similar fashion to the preparation of 2,3- dimethyl-4-oxo-3,4-dihydro-8-quinazolinecarbonitrile (may be prepared as described in intermediate 137), replacing 8-bromo-2,3-dimethyl-4(3H)-quinazolinone with 7-bromo- 2,3-dimethyl-4(3H)-quinazolinone (may be prepared as described in intermediate 142). m/z [M+H]+: 200.1. Retention time 0.63 min (LC/MS method 3).
Intermediate 144: 2-(bromomethyl)-3-methyl-4-oxo-3,4-dihydro-7- quinazolinecarbonitrile
Figure imgf000103_0001
The title compound (18 mg) made in a similar fashion to the preparation of 2- (bromomethyl)-3-methyl-4-oxo-3,4-dihydro-8-quinazolinecarbonitrile (may be prepared as described in intermediate 140), replacing 2,3-dimethyl-4-oxo-3,4-dihydro-8- quinazolinecarbonitrile with 2,3-dimethyl-4-oxo-3,4-dihydro-7-quinazolinecarbonitrile (may be prepared as described in intermediate 143). m/z [M+H]+: 278.0 / 280.0. Retention time 0.87 min (LC/MS method 3).
Intermediate 145: 6-(bromomethyl)-1,3-benzoxazole
Figure imgf000103_0002
A mixture of 6-methyl-1 ,3-benzoxazole (300 mg; Apollo), NBS (401 mg) and benzoyl peroxide (5.46 mg) in carbon tetrachloride (8 ml.) was heated at reflux under an atmosphere of argon for 18 hr. The reaction mixture was cooled to RT, filtered and concentrated under reduced pressure to give a brown oil. The crude product was purified by column chromatography (Biotage SP4 25+M silica column) using 0-35% EtOAc in isohexane. The fractions containing product were combined and concentrated under reduced pressure to give the title compound as a pale yellow solid (194 mg). m/z [M+H]+: 212.0 / 214.0. Retention time 0.89 min (LC/MS method 3). The following intermediates 146 to 152 were prepared by a similar procedure to that used for intermediate 145 from the appropriate methyl compound.
Figure imgf000103_0003
/
/ / / / /
Figure imgf000104_0001
Intermediate 153: ethyl 4H-thieno[3,2-fe]pyrrole-5-carboxylate
Figure imgf000104_0002
4H-Thieno[3,2-b]pyrrole-5-carboxylic acid (1 g; Maybridge) was dissolved in ethanol (20 mL) under argon. The mixture was cooled down with an ice water bath, and thionyl chloride (0.873 mL) was slowly added. The reaction mixture was cooled for 0.5 hr and then the ice bath was removed. The reaction mixture was left under stirring overnight, then heated to reflux for 3 hr. The reaction mixture was cooled to RT, then poured into a mixture of ice (100 mL) and sodium acetate (3 g). The mixture was then extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with water (1 x 100 mL) and brine (1 x 100 ml_), dried over magnesium sulfate, filtered, and the solvent was removed by rotary evaporation, giving the title compound as a brown solid (642 mg; m/z [M+H]+: 196.1. Retention time 0.96 min (LC/MS method 3). Intermediate 154: 4H-thieno[3,2-fe]pyrrol-5-ylmethanol
Figure imgf000105_0001
In a 3 necked flask, ethyl 4H-thieno[3,2-b]pyrrole-5-carboxylate (642 mg; may be prepared as described in intermediate 153) was dissolved in THF (20 ml_). This mixture was left under stirring and under argon for 10 min, and then lithium aluminium hydride (3 ml) was added slowly through a septum. The reaction mixture was left under stirring overnight. The reaction was stopped with the slow addition of wet THF (20 ml_), then the ice bath and argon atmosphere were removed, and aqueous sodium hydroxide (20 ml.) was added. Water (5 ml.) was poured into the reaction mixture, and the mixture was extracted with DCM (3 x 50 ml_). In order to facilitate the extraction, the reaction mixture was filtered through Celite. The combined organic layers were washed with water (1 x 100 ml.) then brine (1 x 100 ml_), and dried over magnesium sulfate. The solvent was removed by rotary evaporation to give the title compound (355 mg). m/z [M+H]+: 153.9. Retention time 0.63 min (LC/MS method 3). Intermediate 155: 4H-thieno[3,2-fe]pyrrol-5-ylmethyl methanesulfonate
Figure imgf000105_0002
4H-Thieno[3,2-b]pyrrol-5-ylmethanol (100 mg; may be prepared as described in intermediate 154) was dissolved in EtOAc (10 ml_), under argon. To this mixture, pyridine (0.106 ml.) methanesulfonyl chloride (0.061 ml.) were added. Then DMAP (7.97 mg) was added, and the mixture was left under stirring overnight. Saturated aqueous sodium bicarbonate was poured in the reaction flask, and the layers were separated. The organic layer was dried over magnesium sulfate, and the solvent was removed by rotary evaporation to give the title compound (105 mg) which was taken forward without purification. Intermediate 156: 3-(bromomethyl)-1-methyl-2-oxo-1 ,2-dihydro-6- quinoxalinecarbonitrile
Figure imgf000106_0001
3-Amino-4-(methylamino)benzonitrile (250 mg; Maybridge) was stirred in ethanol (5 ml_). Ethyl 3-bromo-2-oxopropanoate (0.212 ml; Aldrich) was added and left to stir at room temperature overnight. An orange precipitate had formed overnight, which was filtered off and dried to afford the title compound (253 mg) as a light brown solid, m/z [M+H]+: 278.1 / 280.1. Retention time 0.83 min (LC/MS method 3). Intermediate 157: 3-(bromomethyl)-2-oxo-1,2-dihydro-6-quinoxalinecarbonitrile
Figure imgf000106_0002
3,4-Diaminobenzonitrile (250 mg; Aldrich) was stirred in ethanol (5 ml_). Ethyl 3-bromo-2- oxopropanoate (0.235 ml; Aldrich) was added and left to stir at room temperature for 90 min. The solvent was evaporated to afford an orange solid, which was purified via silica chromatography (20 - 100% EtOAc / isohexane) to give two mixtures of isomers, which were enriched with one isomer or the other. These were re-purified using the same system to give the title compound (50 mg) as an approximately 1 :1 mixture with 2- (bromomethyl)-3-oxo-3,4-dihydro-7-quinoxalinecarbonitrile. It was used in the next reaction without further purification, m/z [M+H]+: 262.2 / 264.2. Retention time 0.73 min (LC/MS method 3).
Intermediate 158: 3-(iodomethyl)-1 -methyl-2(1H)-quinoxalinone-c/3
Figure imgf000106_0003
The title compound (1 18 mg) was made in a similar fashion to the preparation of 2- (iodomethyl)-3-methyl-7-(methoxy)-4(3H)-quinazolinone (may be prepared as described in intermediate 98), replacing 2-(chloromethyl)-7-(methoxy)-4(1 H)-quinazolinone with 3- (bromomethyl)-2(1 H)-quinoxalinone (Aldrich), and methyl iodide with iodomethane-c/3 (Aldrich). m/z [M+H]+: 303.9. Retention time 0.88 min (LC/MS method 3).
Intermediate 159: 3-(iodomethyl)-1 -methyl-2(1H)-quinoxalinone
Figure imgf000107_0001
The title compound (109 mg) was made in a similar fashion to the preparation of 2- (iodomethyl)-3-methyl-7-(methoxy)-4(3H)-quinazolinone (may be prepared as described in intermediate 98), replacing 2-(chloromethyl)-7-(methoxy)-4(1 H)-quinazolinone with 3- (bromomethyl)-2(1 H)-quinoxalinone (Aldrich). m/z [M+H]+: 301.0. Retention time 0.86 min (LC/MS method 3).
Intermediate 160: 3-(bromomethyl)-6,7-dimethyl-2(1 H)-quinoxalinone
Figure imgf000107_0002
The title compound (543 mg) was made in a similar fashion to the preparation of 3- (bromomethyl)-1-methyl-2-oxo-1 ,2-dihydro-6-quinoxalinecarbonitrile (may be prepared as described in intermediate 156), replacing 3-amino-4-(methylamino)benzonitrile with 4,5- dimethyl-1 ,2-benzenediamine (Aldrich). m/z [M+H]+: 267.1 / 269.0. Retention time 0.87 min (LC/MS method 3). Intermediate 161 : 2-methyl-1 ,6-naphthyridine
Figure imgf000107_0003
To 4-amino-3-pyridinecarbaldehyde (980 mg; Aldrich) in acetone (20 mL) was added aqueous sodium hydroxide (2 M, 1.324 mL) and the solution was heated to reflux for 2 hr. The solvent was evaporated to give the title compound (1.37 g) as a dark oil contaminated with sodium salts. Used with no further purification, m/z [M+H]+: 144.9. Retention time 0.58 min (LC/MS method 4).
Intermediate 162: 2-(chloromethyl)-1,6-naphthyridine
Figure imgf000108_0001
2-Methyl-1 ,6-naphthyridine (450 mg; may be prepared as described in intermediate 161 ) was dissolved in carbon tetrachloride (15 ml_). Benzoyl peroxide (37.8 mg) and N- chlorosuccinimide (500 mg) were added and the mixture was heated to reflux for 2 hr. The solvent was evaporated to give a black viscous oil that was filtered through a plug of silica (eluting with DCM). The fraction containing UV-visible material was evaporated and residue was purified by silica gel chromatography using 0-10% MeOH in EtOAc (12CV).
The relevant fractions were combined and concentrated to give a the title compound (180 mg) as a yellow solid. 1H NMR (CDCI3) δ: 4.86 (2H, s), 7.77 (1 H, d), 7.89 (1 H, d), 8.35 (1 H, d), 8.79 (1 H, d), 9.30 (1 H, s).
Intermediate 163: 3-amino-2-nitrobenzonitrile
Figure imgf000108_0002
3-Bromo-2-nitroaniline (250mg; Aldrich), potassium hexacyanoferrate (II) trihydrate (107 mg; Aldrich), sodium carbonate (147 mg), palladium(ll) acetate (12.93 mg) and N, N- dimethylacetamide (10 ml.) were placed in a round bottomed flask. A reflux condenser was fitted and the system purged with argon three times and heated at 12O0C for 22 hr.
The reaction mixture was then diluted with EtOAc and washed with water. The organic phases were combined and concentrated under vacuum to afford a dark brown solid, which was taken up in DCM and purified using silica chromatography (5-80% EtOAc / isohexane) to afford the title compound (108 mg) as a yellow / orange solid, m/z [M+H]+:
164.1. Retention time 0.65 min (LC/MS method 3).
Intermediate 164: 2,3-diaminobenzonitrile
Figure imgf000108_0003
3-Amino-2-nitrobenzonitrile (100 mg; may be prepared as described in intermediate 163) was taken up in ethanol (10 ml.) and then hydrogenated using the H-Cube Hydrogenator, using Full H2 mode and catalytic palladium on carbon. The output solution was concentrated under vacuum to afford the title compound (73 mg) as a pale yellow solid, m/z [M+H]+: 134.1. Retention time 0.48 min (LC/MS method 3).
Intermediate 165: 3-(bromomethyl)-2-oxo-1,2-dihydro-5-quinoxalinecarbonitrile
Figure imgf000109_0001
2,3-Diaminobenzonitrile (80 mg; may be prepared as described in intermediate 164) was taken up in ethanol (10 ml). Ethyl 3-bromo-2-oxopropanoate (0.076 ml; Aldrich) was added and left to stir at room temperature overnight. The reaction mixture was filtered, leaving a light orange solid as the residue (15mg). The filtrate was concentrated under vacuum. It was then diluted with DCM and purified, along with the residue, using silica chromatography (10 - 70% EtOAc / isohexane) to give the title compound (70 mg) as an orange solid, m/z [M+H]+: 264.0 / 266.0. Retention time 0.72 min (LC/MS method 3).
Intermediate 166: 7-(bromomethyl)pyrazolo[1 ,5-a]pyridine
Figure imgf000109_0002
Pyrazolo[1 ,5-a]pyridin-7-ylmethanol (100 mg; PharmLab) was treated with 33% w/w hydrogen bromide in acetic acid (5 ml) and heated to 60 0C for 2 hr. The volatiles were removed under vacuum to give the title compound (130 mg). m/z [M+H]+: 211.0 / 213.0. Retention time 0.88 min (LC/MS method 3).
Intermediate 167: 3-methylpyrido[2,3-fe]pyrazine
Figure imgf000109_0003
To a solution of hydroxyacetone (0.566 mL; Aldrich) in DCM (100 mL) was added 2,3- pyridinediamine (1 g; Aldrich), 4A molecular sieves (~5g) and activated manganese dioxide (3.98 g). The resulting reaction mixture was heated to reflux for 2 hr. After this time the reaction mixture was cooled to RT, filtered through Celite and the solid residues were washed with DCM. The solvent was then removed under vacuum and the product purified by column chromatography eluting in 10% MeOH in DCM to yield the title compound (813 mg) as an orange crystalline solid, m/z [M+H]+: 145.8. Retention time 0.43 min (LC/MS method 3).
Intermediate 168: 3-(chloromethyl)pyrido[2,3-fe]pyrazine
Figure imgf000110_0001
The title compound (241 mg) was made in a similar fashion to the preparation of 2- (chloromethyl)-1 ,6-naphthyridine (may be prepared as described in intermediate 162), replacing 2-methyl-1 ,6-naphthyridine with 3-methylpyrido[2,3-b]pyrazine (may be prepared as described in intermediate 167). m/z [M+H]+: 179.8 / 181.7. Retention time 0.56 min (LC/MS method 3).
Intermediate 169: methyl 1H-pyrrolo[2,3-fe]pyridine-6-carboxylate
Figure imgf000110_0002
To a solution of 1 H-pyrrolo[2,3-b]pyridine-6-carboxylic acid (1g; Allweys) in MeOH (30 ml) was added concentrated sulfuric acid (0.2 ml) and the reaction mixture was heated under reflux for 18 hr. The reaction mixture was cooled and partitioned between EtOAc (100 ml) and aqueous sodium bicarbonate (50 ml). The organic layer was dried over magnesium sulphate, filtered and evaporated to afford the title compound (470mg) as a pale brown solid, m/z [M+H]+: 177.0. Retention time 0.70 min (LC/MS method 3).
Intermediate 170: 1H-pyrrolo[2,3-fe]pyridin-6-ylmethanol
Figure imgf000110_0003
To a suspension of methyl 1H-pyrrolo[2,3-b]pyridine-6-carboxylate (200 mg; may be prepared as described in intermediate 169) in MeOH (10 ml) was added lithium borohydride (74 mg) and the reaction mixture was stirred at room temperature for 30 min. Lithium borohydride (74 mg) was added and the mixture was heated at 5O0C for 15 hr. Lithium borohydride (148 mg) and the mixture was heated at 5O0C for 24 hr. Lithium borohydride (small amounts portionwise over six hours, approximately 300 mg) was added and the mixture was heated at 5O0C for 72 hr. Lithium borohydride (small amounts portionwise over six hours, approximately 300 mg) was added and the mixture was heated at 5O0C for 24 hr. The reaction mixture was cooled and left at RT for 2 days. The solvent was evaporated and the residue dissolved in aqueous hydrochloric acid (2 N, 20 ml). The aqueous was washed with EtOAc (2 x 30 ml). The aqueous was basified with 12.5 N aqueous sodium hydroxide to pH 14 and then extracted with DCM (3 x 25 ml). The organic layer was dried over magnesium sulfate, filtered and evaporated to give an off-white solid (42mg). This was purified by MDAP to afford the title compound (32 mg) as a white solid. 1H NMR (CD3OD) δ: 4.74 (2H, s), 6.45 (1 H, d), 7.22 (1 H, d), 7.33 (1 H, d), 7.97 (1 H, d). Retention time 0.57 min (LC/MS method 4).
Intermediate 171 : 6-(bromomethyl)-1H-pyrrolo[2,3-fe]pyridine hydrobromide
Figure imgf000111_0001
The title compound (70 mg) was made in a similar fashion to the preparation of 3- (bromomethyl)quinoline hydrobromide (may be prepared as described in intermediate 12), replacing 3-quinolinylmethanol with 1 H-pyrrolo[2,3-b]pyridin-6-ylmethanol (may be prepared as described in intermediate 170). m/z [M+H]+: 210.9 / 212.8. Retention time 0.81 min (LC/MS method 3). Intermediate 172: 5-(hydroxymethyl)-2(1H)-pyridinone
Figure imgf000111_0002
To a suspension of methyl 6-oxo-1 ,6-dihydro-3-pyridinecarboxylate (400 mg; Fluorochem) in THF (7 mL) was added dropwise 2M lithium borohydride in THF (6.53 mL) and the reaction mixture was heated at 55 0C under an atmosphere of argon for 5 hr. The reaction mixture was allowed to cool to RT and MeOH (4 mL) and water (1 mL) were added carefully. The mixture was stirred at room temperature for 20 min and then concentrated under reduced pressure. The crude product was purified by column chromatography, Biotage SP4, 25+M column, 0 - 30% MeOH / DCM. The fractions containing product were combined and concentrated under reduced pressure to give the title compound (68 mg) as a white solid, m/z [M+H]+: 125.9. Retention time 0.24 min (LC/MS method 3). Intermediate 173: 5-(bromomethyl)-2(1H)-pyridinone hydrobromide
Figure imgf000112_0001
The title compound (128 mg) was made in a similar fashion to the preparation of 3- (bromomethyl)quinoline hydrobromide (may be prepared as described in intermediate 12), replacing 3-quinolinylmethanol with 5-(hydroxymethyl)-2(1 H)-pyridinone (may be prepared as described in intermediate 172). 1H NMR (DMSO-c/6) δ: 4.60 (2H, s), 6.43 (1 H, d), 7.45 (1 H, dd), 7.62 - 7.65 (2H, m).
Intermediate 174: 4-(hydroxymethyl)-2(1H)-pyridinone
Figure imgf000112_0002
The title compound (141 mg) was made in a similar fashion to the preparation of 5- (hydroxymethyl)-2(1 H)-pyridinone (may be prepared as described in intermediate 172), replacing methyl 6-oxo-1 ,6-dihydro-3-pyridinecarboxylate with methyl 2-oxo-1 ,2-dihydro- 4-pyridinecarboxylate (Apollo), m/z [M+H]+: 126.0. Retention time 0.25 min (LC/MS method 3).
Intermediate 175: 4-(bromomethyl)-2(1H)-pyridinone hydrobromide
Figure imgf000112_0003
The title compound (137 mg) was made in a similar fashion to the preparation of 3- (bromomethyl)quinoline hydrobromide (may be prepared as described in intermediate 12), replacing 3-quinolinylmethanol with 4-(hydroxymethyl)-2(1 H)-pyridinone (may be prepared as described in intermediate 174). m/z [M+H]+: 187.9 / 189.9. Retention time 0.49 min (LC/MS method 3). Intermediate 176: methyl 6-oxo-1 ,6-dihydro-2-pyridinecarboxylate
Figure imgf000112_0004
The title compound (431 mg) was made in a similar fashion to the preparation of methyl 1H-pyrrolo[2,3-b]pyridine-6-carboxylate (may be prepared as described in intermediate 169), replacing 1 H-pyrrolo[2,3-b]pyridine-6-carboxylic acid with 6-oxo-1 ,6-dihydro-2- pyridinecarboxylic acid (Aldrich). m/z [M+H]+: 154.1. Retention time 0.44 min (LC/MS method 3).
Intermediate 177: 6-(hydroxymethyl)-2(1H)-pyridinone
Figure imgf000113_0001
The title compound (203 mg) was made in a similar fashion to the preparation of 5- (hydroxymethyl)-2(1 H)-pyridinone (may be prepared as described in intermediate 172), replacing methyl 6-oxo-1 ,6-dihydro-3-pyridinecarboxylate with methyl 6-oxo-1 ,6-dihydro- 2-pyridinecarboxylate (may be prepared as described in intermediate 176). m/z [M+H]+: 126.0. Retention time 0.54 min (LC/MS method 3). Intermediate 178: 6-(bromomethyl)-2(1H)-pyridinone hydrobromide
Figure imgf000113_0002
The title compound (325 mg) was made in a similar fashion to the preparation of 3- (bromomethyl)quinoline hydrobromide (may be prepared as described in intermediate 12), replacing 3-quinolinylmethanol with 6-(hydroxymethyl)-2(1 H)-pyridinone (may be prepared as described in intermediate 177). m/z [M+H]+: 187.9 / 189.9. Retention time 0.46 min (LC/MS method 3).
Intermediate 179: 1H-pyrrolo[3,2-c]pyridin-2-ylmethanol
Figure imgf000113_0003
1H-Pyrrolo[3,2-c]pyridine-2-carbaldehyde (450 mg; Anichem) was dissolved in THF (15 mL). Sodium borohydride (116 mg) was added at 0 0C and the mixture was stirred for 30 min. It was quenched with water, the solvent was evaporated and the residue was applied to an SCX column. It was eluted with MeOH followed by 2M ammonia in MeOH. Fractions containing the desired product were evaporated to give the title compound (390 mg) as a yellow oil. 1H NMR (CD3OD) δ: 4.77 (2H, s), 6.55 (1 H, s), 7.40 (1 H, d), 8.10 (1 H, d), 8.71 (1 H, s).
Intermediate 180: 2-(bromomethyl)-1H-pyrrolo[3,2-c]pyridine
Figure imgf000114_0001
The title compound (68 mg) was made in a similar fashion to the preparation of 3- (bromomethyl)quinoline hydrobromide (may be prepared as described in intermediate 12), replacing 3-quinolinylmethanol with 1 H-pyrrolo[3,2-c]pyridin-2-ylmethanol (may be prepared as described in intermediate 179). 1H NMR (DMSO-c/6) δ: 4.98 (2H, s), 7.14 (1 H, s), 7.92 (1 H, d), 8.43 (1 H, d), 9.25 (1 H, s).
Intermediate 181 : 2-(chloromethyl)-5,6,7,8-tetrahydro-4(1 H)-quinazolinone
Figure imgf000114_0002
1-(1-Cyclohexen-1-yl)pyrrolidine (0.167 ml_; Aldrich) was dissolved in THF (5 ml.) in a 25 ml. round-bottomed flask flushed with argon, cooled to 0 0C, treated dropwise with a solution of chloroacetyl isocyanate (0.085 ml_; Aldrich) in THF (1 ml) and stirred at 0 0C for 30 mins. The reaction mixture was then treated with acetic acid (5.00 ml.) and ammonium acetate (385 mg) and heated to reflux for 2 hr. The reaction mixture was cooled to RT and stood overnight. The reaction mixture was poured into water (50 ml.) and extracted with EtOAc (50 ml. x 2). The combined organic solutions were dried over magnesium sulfate, filtered and evaporated to dryness to give the crude product (134 mg) as a brown solid. The crude product was purified on a 12+M Biotage silica cartridge, eluting with a 0 to 5 % mixture of MeOH in DCM. This gave the title compound (71 mg) as an off-white solid, m/z [M+H]+: 199.0 / 200.9. Retention time 0.60 min (LC/MS method 3).
Intermediate 182: 2-(iodomethyl)-3-methyl-5,6,7,8-tetrahydro-4(3H)-quinazolinone
Figure imgf000115_0001
The title compound (21 mg) was made in a similar fashion to the preparation of 2- (iodomethyl)-3-methyl-7-(methoxy)-4(3H)-quinazolinone (may be prepared as described in intermediate 98), replacing 2-(chloromethyl)-7-(methoxy)-4(1 H)-quinazolinone with 2- (chloromethyl)-5,6,7,8-tetrahydro-4(1 H)-quinazolinone (may be prepared as described in intermediate 181 ). m/z [M+H]+: 304.8. Retention time 0.79 min (LC/MS method 3).
Intermediate 183: 2-(bromomethyl)quinazoline
Figure imgf000115_0002
NBS (200 mg) was added to a solution of 2-methylquinazoline (200 mg, ACES) in carbon tetrachloride (8 ml_). The mixture was heated to 75 0C under argon and then AIBN (23 mg) was added. Heating continued for 4 hr. The mixture was cooled then diluted with saturated aqueous sodium bicarbonate solution (10 ml_). The layers were separated and the aqueous was extracted with DCM (2 x 10 ml_). The combined organic layers were dried (hydrophobic frit) and evaporated to give a brown oil. Mass: 260 mg. This was purified by Biotage (50 g silica cartridge; eluent 0 to 30% ethyl acetate in isohexane; collection by UV trigger) to give the title compound (19 mg) as a white solid, m/z [M+H]+: 222.9 / 224.9. Retention time 0.81 min (LC/MS method 3). Intermediate 184: 1,1-dimethylethyl 4-methyl-1H-benzimidazole-1-carboxylate
Figure imgf000115_0003
4-Methyl-1 H-benzimidazole (328 mg; APAC) was dissolved in DCM (7 ml_), di-te/f-butyl dicarbonate (0.634 ml.) was added and the solution was stirred at RT for 18 hr. The solvent was evaporated to give the title compound (575 mg) as a yellow oil. It was used without further purification, m/z [M+H]+: 233.2. Retention time 1.18 min (LC/MS method 3). Intermediate 185: 1,1 -dimethylethyl 4-(bromomethyl)-1H-benzimidazole-1- carboxylate
Figure imgf000116_0001
The title compound (530 mg) was made in a similar fashion to the preparation of 6- (bromomethyl)-i ,3-benzoxazole (may be prepared as described in intermediate 145), replacing 6-methyl-1 ,3-benzoxazole with 1 ,1-dimethylethyl 4-methyl-1 H-benzimidazole-1- carboxylate (may be prepared as described in intermediate 184). 1H NMR (DMSO-c/β) δ: 1.66 (9H, s), 5.02 (2H, s), 7.42(1 H, t), 7.48, (1 H, d), 7.91 (1 H, d), 8.71 (1 H, s). Retention time 1.19 min (LC/MS method 3).
Intermediate 186: 1 ,1-dimethylethyl 4-({2,2-difluoro-8-[(1 S)-1 -hydroxyethyl]-3-oxo- 2,3-dihydro-4H-1 ,4-benzoxazin-4-yl}methyl)-1H-benzimidazole-1 -carboxylate
Figure imgf000116_0002
The title compound (95 mg) was made in a similar fashion to the preparation of 2,2- difluoro-8-[(1 S)-1-hydroxyethyl)-4-[(3-methyl-4-oxo-3,4-dihydro-2-quinazolinyl)methyl]- 2H-1 ,4-benzoxazin-3(4H)-one (may be prepared as described in compound 91 ), replacing 2-(chloromethyl)-3-methyl-4(3H)-quinazolinone with 1 ,1-dimethylethyl 4- (bromomethyl)-1 H-benzimidazole-1 -carboxylate (may be prepared as described in intermediate 185). m/z [M+H]+: 459.9. Retention time 1.25 min (LC/MS method 3). The crude product was used in the next reaction without purification. Intermediate 187: 1,1-dimethylethyl δ-methyl-IH-i^jS-benzotriazole-i-carboxylate
Figure imgf000117_0001
A solution of 5-methyl-1 /-/-1 ,2,3-benzotriazole (400 mg; Aldrich) in DCM (14 ml.) was cooled to 0 0C under an atmosphere of argon. Di-te/f-butyl dicarbonate (1.046 mL) and triethylamine (0.419 mL) were added and the reaction mixture was allowed to warm to RT and stirred for 3 hr. The reaction mixture was concentrated under reduced pressure to give a dark yellow oil. The crude product was purified by column chromatography (Biotage SP4, 25+M column, 0-50% EtOAc / isohexane). The fractions containing product were combined and concentrated under reduced pressure to give the title compound (721 mg) as a clear oil. m/z [M+H]+: 234.1. Retention time 1.27 min (LC/MS method 3).
Intermediate 188: 1 ,1 -dimethylethyl 5-(bromomethyl)-1H-1,2,3-benzotriazole-1- carboxylate
Figure imgf000117_0002
The title compound (56 mg) was made in a similar fashion to the preparation of 6- (bromomethyl)-i ,3-benzoxazole (may be prepared as described in intermediate 145), replacing 6-methyl-1 ,3-benzoxazole with 1 ,1-dimethylethyl 5-methyl-1H-1 ,2,3- benzotriazole-1-carboxylate (may be prepared as described in intermediate 187). 1H NMR (CDCI3) δ: 1.77 (9H, s), 4.65 (2H, d), 7.60 (1 H, ddd), 8.03-8.16 (2H, m). Retention time 1.32 min (LC/MS method 3).
Intermediate 189: 1 ,1-dimethylethyl 5-({2,2-difluoro-8-[(1 S)-1-hydroxyethyl]-3-oxo- 2,3-dihydro-4H-1,4-benzoxazin-4-yl}methyl)-1H-1,2,3-benzotriazole-1-carboxylate
Figure imgf000118_0001
The title compound (102 mg) was made in a similar fashion to the preparation of 2,2- difluoro-8-[(1 S)-1-hydroxyethyl)-4-[(3-methyl-4-oxo-3,4-dihydro-2-quinazolinyl)methyl]- 2H-1 ,4-benzoxazin-3(4H)-one (may be prepared as described in compound 91 ), replacing 2-(chloromethyl)-3-methyl-4(3H)-quinazolinone with 1 ,1-dimethylethyl 5- (bromomethyl)-1 H-1 ,2,3-benzotriazole-1-carboxylate (may be prepared as described in intermediate 188). m/z [M+H]+: 461.3. Retention time 1.59 min (LC/MS method 3). The crude product was used in the next reaction without purification. Intermediate 190: 1,1-dimethylethyl 4-methyl-1H-indazole-1-carboxylate
Figure imgf000118_0002
The title compound (189 mg) was made in a similar fashion to the preparation of 1 ,1- dimethylethyl 5-methyl-1 H-1 ,2,3-benzotriazole-1-carboxylate (may be prepared as described in intermediate 187), replacing 5-methyl-1 H-1 ,2,3-benzotriazole with 4-methyl- 1H-indazole (ChemBridge). m/z [M+H]+: 233.1. Retention time 1.25 min (LC/MS method 3).
Intermediate 191 : 1,1-dimethylethyl 4-(bromomethyl)-1H-indazole-1 -carboxylate
Figure imgf000119_0001
The title compound (156 mg) was made in a similar fashion to the preparation of 6- (bromomethyl)-i ,3-benzoxazole (may be prepared as described in intermediate 145), replacing 6-methyl-1 ,3-benzoxazole with 1 ,1-dimethylethyl 4-methyl-1 H-indazole-1- carboxylate (may be prepared as described in intermediate 190). 1H NMR (CDCI3) δ: 1.73 (9H, s), 4.77 (2H, s), 7.25 - 7.33 (1 H, m), 7.46 (1 H, t), 8.14 - 8.20 (1 H, m), 8.35 (1 H, s).
Intermediate 192: 1 ,1-dimethylethyl 4-({2,2-difluoro-8-[(1S)-1 -hydroxyethyl]-3-oxo- 2,3-dihydro-4H-1 ,4-benzoxazin-4-yl}methyl)-1H-indazole-1-carboxylate
Figure imgf000119_0002
The title compound (95 mg) was made in a similar fashion to the preparation of 2,2- difluoro-8-[(1 S)-1-hydroxyethyl)-4-[(3-methyl-4-oxo-3,4-dihydro-2-quinazolinyl)methyl]- 2H-1 ,4-benzoxazin-3(4H)-one (may be prepared as described in compound 91 ), replacing 2-(chloromethyl)-3-methyl-4(3H)-quinazolinone with 1 ,1-dimethylethyl 4- (bromomethyl)-1 H-indazole-1-carboxylate (may be prepared as described in intermediate 191 ). m/z [M+H]+: 460.1. Retention time 1.20 min (LC/MS method 3). The crude product was used in the next reaction without purification. Intermediate 193: 2,2-difluoro-8-(1 -hydroxyethyl)-2H-1,4-benzoxazin-3(4H)-one-d4
Figure imgf000120_0001
The title compound (209 mg) was made in a similar fashion to the preparation of 2,2- difluoro-8-(1-hydroxyethyl)-2H-1 ,4-benzoxazin-3(4H)-one (may be prepared as described in intermediate 4), replacing acetaldehyde with acetaldehyde-c/4 (Aldrich). m/z [M-H]": 232.3. Retention time 0.66 min (LC/MS method 3).
Intermediate 194: (2-cyano-4-pyridinyl)methyl methanesulfonate
Figure imgf000120_0002
4-(Hydroxymethyl)-2-pyridinecarbonitrile (0.5g; 3RChem) was suspended in DCM (10 ml.) and triethylamine (0.831 ml.) was added at 250C. The mixture was cooled in an ice bath and methanesulfonic anhydride (0.714 g) dissolved in DCM (3 ml.) was added dropwise. The mixture was stirred at 250C for 1 hr. Further methanesulfonic anhydride
(130 mg, 0.2eq.) was added and stirred for 15 min at 250C. 2% w/v aqueous sodium bicarbonate solution (10 ml.) was added and the phases were separated. The organic layer was washed with water (10 ml_), dried over sodium sulphate and evaporated to leave the title compound (0.761 g) as a pale yellow solid, m/z [M+H]+: 213.1. Retention time 0.58 min (LC/MS method 3).
Intermediate 195: 3-(Bromomethyl)-5-fluorobenzonitrile
Figure imgf000120_0003
3-Fluoro-5-methylbenzonitrile (200 mg, 1.480 mmol, Fluorochem), Λ/-bromosuccinimide (263 mg, 1.480 mmol) and AIBN (2.430 mg, 0.015 mmol) were dissolved in carbon tetrachloride (4 ml, 41.5 mmol) in a 10 ml. round-bottomed flask flushed with argon and stirred at 80 0C overnight. The reaction mixture was cooled to room temperature then filtered through Kieselguhr, washing with DCM, and evaporated under reduced pressure to give the crude product (356 mg) as a colourless oil. The crude product was purified on a 25+M Biotage silica cartridge, eluting with a 0 to 10 % mixture of EtOAc in hexane. This gave the title compound (130 mg) as a colourless oil. 1H NMR (CDCI3) δ: 4.44 (2H, s), 7.31 (1 H, d), 7.37 (1 H, d), 7.49 (1 H, s). Retention time 0.97 min (LC/MS method 3).
Compound 1 : 2,2-Difluoro-8-(1-hydroxyethyl)-4-(3-pyridinylmethyl)-2H-1,4- benzoxazin-3(4H)-one (racemate)
Figure imgf000121_0001
A stirred solution of 8-acetyl-2,2-difluoro-4-(3-pyridinylmethyl)-2H-1 ,4-benzoxazin-3(4H)- one (30 mg, may be prepared as described in intermediate 8) in THF (5 ml.) at room temperature under argon was treated with MP-triacetoxyborohydride (59.2 mg) and maintained for 18 hours. The mixture was treated with solid sodium triacetoxyborohydride (28mg, 0.132 mmol) and stirring continued at room temperature. After 4 hr further solid sodium triacetoxyborohydride (12mg) was added and the mixture stirred at room temperature for 66 hr. The reaction mixture was concentrated under vacuum and the residue treated with ethanol (3ml), plus 2ml of DCM to aid solution, and then solid sodium borohydride (3mg) was added and stirring maintained at room temperature for 2 hr. Further sodium borohydride (6mg) was added and stirring continued overnight. The mixture was treated with additional sodium borohydride (12mg) and stirring continued for 2 hours. The reaction mixture was concentrated under vacuum and the residue treated with 10% sodium carbonate solution (15ml) and extracted with DCM (2 x 15ml). The combined extract was dried (magnesium sulfate) and concentrated under vacuum to leave a white foam. This was purified by MDAP to give the title compound (2.6 mg) as a colourless oil. m/z [M+H]+: 321.0. Retention time 0.66 min (LC/MS method 3).
Compound 2: 2,2-Difluoro-4-[(5-fluoro-3-pyridinyl)methyl]-8-(1 -hydroxyethyl)-2H- 1 ,4-benzoxazin-3(4H)-one (racemate)
Figure imgf000122_0001
To a solution of 2,2-difluoro-8-(1-hydroxyethyl)-2H-1 ,4-benzoxazin-3(4H)-one (70mg; may be prepared as described in intermediate 4) in DMF (2ml) was added potassium carbonate (84mg) followed by 3-(bromomethyl)-5-fluoropyridine hydrochloride (69mg; Sunshine Chemlab) and the reaction mixture was stirred for eighteen hours. The reaction mixture was diluted with ethyl acetate (30ml) and washed with water (3x 15ml) then dried (magnesium sulfate), filtered and evaporated to give an orange oil. The oil was dissolved in DCM and purified on the Biotage SP4 using a 25+S column and eluting with 0 to 100% EtOAc/isohexane over 20CV to afford the title compound (82mg) as a white foam, m/z [M+H]+: 339.0. Retention time 0.90 min (LC/MS method 3).
The following compounds 3 to 53 (racemates) were prepared by a similar procedure to that used for compound 2, from racemic 2,2-difluoro-8-(1-hydroxyethyl)-2H-1 ,4- benzoxazin-3(4H)-one (may be prepared as described in intermediate 4) and the appropriate alkylating agent. Purification was by MDAP (formic acid method or high pH method) or chromatography on silica. * indicates that catalytic potassium iodide was added to the reaction mixture.
Figure imgf000122_0002
Figure imgf000123_0001
Figure imgf000124_0001
Figure imgf000125_0001
Figure imgf000126_0001
Figure imgf000127_0001
Figure imgf000128_0001
Figure imgf000129_0001
Figure imgf000130_0001
Figure imgf000131_0001
Figure imgf000132_0001
Figure imgf000133_0001
Figure imgf000134_0001
Figure imgf000135_0001
Figure imgf000136_0001
Figure imgf000137_0001
Figure imgf000138_0002
Compound 54: 2,2,7-Trifluoro-4-[(5-fluoro-3-pyridinyl)methyl]-8-(1 -hydroxyethyl)- 2H-1 ,4-benzoxazin-3(4H)-one (racemate)
Figure imgf000138_0001
The title compound was made in a similar manner to the preparation described for 2,2- difluoro-4-[(5-fluoro-3-pyridinyl)methyl]-8-(1-hydroxyethyl)-2H-1 ,4-benzoxazin-3(4H)-one (Compound 2), replacing 2,2-difluoro-8-(1-hydroxyethyl)-2H-1 ,4-benzoxazin-3(4H)-one (may be prepared as described in intermediate 4) with 2,2,7-trifluoro-8-(1-hydroxyethyl)- 2H-1 ,4-benzoxazin-3(4H)-one (may be prepared as described in intermediate 11 ). m/z [M+H]+: 357.1. Retention time 0.87 min (LC/MS method 3).
Compound 55: 2,2-Difluoro-4-[(5-fluoro-3-pyridinyl)methyl]-8-[(1S)-1-hydroxyethyl]- 2H-1,4-benzoxazin-3(4H)-one and Compound 56: 2,2-difluoro-4-[(5-fluoro-3- pyridinyl)methyl]-8-[(1R)-1-hydroxyethyl]-2H-1,4-benzoxazin-3(4H)-one
Figure imgf000139_0001
Method A
To a solution of racemic 2,2-difluoro-8-(1-hydroxyethyl)-2H-1 ,4-benzoxazin-3(4H)-one (70mg, may be prepared as described in intermediate 4) in DMF (2ml) was added potassium carbonate (84mg) followed by the addition of 3-(bromomethyl)-5-fluoropyridine hydrochloride (69mg; Sunshine Chemlab) and the reaction mixture stirred for eighteen hours. The reaction mixture was diluted with EtOAc (30ml) and washed with water (3x 15ml) then dried and evaporated. The residue was dissolved in DCM and purified on the Biotage SP4 using a 25+S column and eluting with O to 100% EtOAc/isohexane over 20CV to afford a white foam (82mg). 80mg of this racemic mixture was resolved using a Chiralpak AS column eluting with heptane: ethanol (70:30) v/v pump-mixed. Using these conditions, the faster running enantiomer 2,2-difluoro-4-[(5-fluoro-3-pyridinyl)methyl]-8- [(1 R)-1-hydroxyethyl]-2H-1 ,4-benzoxazin-3(4H)-one (31 mg, Compound 56) and the slower running enantiomer 2,2-difluoro-4-[(5-fluoro-3-pyridinyl)methyl]-8-[(1 S)-1- hydroxyethyl]-2H-1 ,4-benzoxazin-3(4H)-one (30mg, Compound 55) were obtained in >98% enantiomeric excess. 1H NMR (DMSOd6) δ:1.31 - 1.36 (3H, d), 5.01 - 5.09 (1 H, m), 5.31 - 5.45 (3H, m), 7.22 - 7.28 (2H, m), 7.34 - 7.40 (1 H, m), 7.68 - 7.74 (1 H, m), 8.43 - 8.47 (1 H, m), 8.5 - 8.55 (1 H, d). m/z [M+H]+: 338.9. Retention time 0.90 min (LC/MS method 3). The absolute configurations were determined by ab initio vibrational circular dichroism (see Stephens PJ, Devlin FJ; Determination of the structure of chiral molecules using ab initio virational circular dichroism spectroscopy; Chirality 2000; 12: 172-179).
Method B
To a solution of 2,2-difluoro-8-[(1S)-1-hydroxyethyl]-2H-1 ,4-benzoxazin-3(4H)-one (may be prepared as described in intermediate 5) (100mg) in DMF (2ml) was added potassium carbonate (121 mg) followed by the addition of 3-(bromomethyl)-5-fluoropyridine hydrochloride (99mg; Sunshine Chemlab) and the reaction mixture stirred for seven hours. The reaction mixture was diluted with EtOAc (30ml) and washed with water (3x 15ml) then dried and evaporated to an orange solid. The solid was dissolved in DCM and purified on the Biotage SP4 using a 25+M column and eluting with 0 to 100% EtOAc/isohexane over 20CV to afford 2,2-difluoro-4-[(5-fluoro-3-pyridinyl)methyl]-8-[(1 S)- 1-hydroxyethyl]-2H-1 ,4-benzoxazin-3(4H)-one (1 15mg) as a white solid.
To a solution of 2,2-difluoro-8-[(1 R)-1-hydroxyethyl]-2H-1 ,4-benzoxazin-3(4H)-one (may be prepared as described in intermediate 6) (100mg) in DMF (2ml) was added potassium carbonate (121 mg) followed by the addition of 3-(bromomethyl)-5- fluoropyridine hydrochloride (99mg) and the reaction mixture stirred for seven hours. The reaction mixture was diluted with EtOAc (30ml) and washed with water (3x 15ml) then dried and evaporated to an off-white solid. The solid was dissolved in DCM and purified on the Biotage SP4 using a 25+S column and eluting with 0 to 100% EtOAc/isohexane over 20CV to afford 2,2-difluoro-4-[(5-fluoro-3-pyridinyl)methyl]-8-[(1 R)-1-hydroxyethyl]- 2H-1 ,4-benzoxazin-3(4H)-one (1 15mg) as a white solid.
Compound 57: 5-{[2,2-Difluoro-8-[(1 S)-1 -hydroxyethyl]-3-oxo-2,3-dihydro-4H-1 ,4- benzoxazin-4-yl]methyl}-3-pyridinecarbonitrile and Compound 58: 5-{[2,2-difluoro- 8-[(1 R)-1 -hydroxyethyl]-3-oxo-2,3-dihydro-4H-1 ,4-benzoxazin-4-yl]methyl}-3- pyridinecarbonitrile
Figure imgf000140_0001
Racemic 8-bromo-2,2-difluoro-2H-1 ,4-benzoxazin-3(4H)-one (50 mg, 0.189 mmol, intermediate 4), 5-(bromomethyl)-3-pyridinecarbonitrile (37.3 mg, 0.189 mmol, intermediate 24), potassium carbonate (52.3 mg, 0.379 mmol) and potassium iodide (0.314 mg, 1.894 μmol) were dissolved in DMF (3000 μl) in a 10 ml. round-bottomed flask open to the atmosphere and stirred at room temperature overnight. The reaction mixture was evaporated to dryness, redissolved in EtOAc (30ml) and treated with saturated aqueous sodium bicarbonate (30ml). The aqueous layer was extracted with EtOAc (2x30ml) and the organic layers were combined, washed with brine (30ml), dried over magnesium sulfate, filtered and evaporated to dryness to give the crude product (119mg) as a light brown oil. The crude product was purified on a 25+S Biotage silica cartridge, eluting with a 0 to 70% mixture of EtOAc in hexane. This gave an off-white solid (54 mg). 47 mg of this racemic mixture was resolved using a Chiralpak AS column eluting with heptane: ethanol (90:10) v/v pump-mixed. Using these conditions the faster- running enantiomer (20 mg, Compound 57 or 58) and the slower-running enantiomer (15 mg, Compound 57 or 58) were obtained in >99% enantiomeric excess. 1H NMR (CD3OD) δ: 1.45 (3H, d), 5.23 (1 H, q), 5.41 (2H, s), 7.18 (1 H, dd), 7.25 (1 H, t), 7.42 (1 H, dd), 8.14 (1 H, s), 8.78 (1 H, d), 8.84 (1 H, d). m/z [M+H]+: 345.9. Retention time 0.81 min (LC/MS method 3).
Alternative method for Compound 57: 5-{[2,2-Difluoro-8-[(1S)-1-hydroxyethyl]-3- oxo-2,3-dihydro-4H-1 ,4-benzoxazin-4-yl]methyl}-3-pyridinecarbonitrile
Figure imgf000141_0001
2,2-Difluoro-8-[(1S)-1-hydroxyethyl]-2H-1 ,4-benzoxazin-3(4H)-one (75 mg, may be prepared as described in intermediate 5), 5-(bromomethyl)-3-pyridinecarbonitrile (233 mg, may be prepared as described in intermediate 24), potassium carbonate (90 mg, 0.655 mmol) and potassium iodide (0.543 mg, 3.27 μmol) were dissolved in DMF (5000 μl) in a 25 ml. round-bottomed flask open to the atmosphere and stirred at room temperature overnight. The reaction mixture was evaporated to dryness, redissolved in EtOAc (30ml) and treated with saturated aqueous sodium bicarbonate (30ml). The aqueous layer was extracted with EtOAc (2x30ml) and the organic layers were combined, washed with brine (30ml), dried over magnesium sulfate, filtered and evaporated to dryness to give the crude product (194mg) as a light brown oil. The crude product was purified on a 25+S Biotage silica cartridge, eluting with a 0 to 75 % mixture of EtOAc in hexane. The title compound was obtained (87 mg) as an cream solid. 1H NMR (DMSO-de) δ: 1.34 (3H, d), 5.02 - 5.10 (1 H, m), 5.36 - 5.42 (3H, m), 7.21 - 7.25 (2H, m), 7.37 (1 H, dd), 8.32 (1 H, s), 8.87 (1 H, d), 8.95 (1 H, d). m/z [M+H]+: 346.2. Retention time 0.84 min (LC/MS method 3).
Compounds 59: 4-{[2,2-Difluoro-8-[(1S)-1-hydroxyethyl)-3-oxo-2,3-dihydro-4H-1,4- benzoxazin-4-yl]methyl}-2-pyridinecarbonitrile and Compound 60: 4-{[2,2-difluoro- 8-[(1 R)-1 -hydroxyethyl)-3-oxo-2,3-dihydro-4H-1 ,4-benzoxazin-4-yl]methyl}-2- pyridinecarbonitrile
Figure imgf000142_0001
To a solution of racemic 2,2-difluoro-8-(1-hydroxyethyl)-2H-1 ,4-benzoxazin-3(4H)-one (100mg; may be prepared as described in intermediate 4) in DMF (2ml) was added potassium carbonate (121 mg) followed by the addition of 4-(bromomethyl)-2- pyridinecarbonitrile (282mg; may be prepared as described in intermediate 19) in DMF (4ml) and the reaction mixture was stirred over at room temperature for 3 hr. The reaction mixture was diluted with EtOAc (30ml) and washed with water (3x 15ml) then dried (magnesium sulfate), filtered and evaporated to give a red oil. The residue was dissolved in dichloromethane and purified on the Biotage SP4 using a 25+M column and eluting with 0 to 50% EtOAc/isohexane over 20CV to afford a white solid. 138 mg of this racemic mixture was resolved using a Chiralpak AS column eluting with heptane: ethanol (90:10) v/v pump-mixed. Using these conditions the faster-running enantiomer (44 mg, Compound 59 or 60) and the slower-running enantiomer (44 mg, Compound 59 or 60) were obtained in >96% enantiomeric excess as white solids. 1H NMR (DMSO-dβ) δ: 1.35 (3H, d), 5.03 - 5.1 1 (1 H, m), 5.36 - 5.45 (3H, m), 7.08 (1 H, dd), 7.21 (1 H, t), 7.28, (1 H, d), 7.60 (1 H, dd), 8.08 (1 H, s), 8.71 (1 H, d). m/z [M-H]": 344.0. Retention time 0.85 min (LC/MS method 3).
Alternative methods for compound 59: 4-({2,2-difluoro-8-[(1 S)-1-hydroxyethyl]-3- oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl}methyl)-2-pyridinecarbonitrile
Figure imgf000142_0002
Method A To a solution of 2!2-difluoro-8-[(1 S)-1-hydroxyethyl]-2H-1 !4-benzoxazin-3(4/-/)-one (400 mg; may be prepared as described in intermediate 5) in DMF (15 ml.) was added potassium carbonate (482 mg) followed by the addition of 4-(bromomethyl)-2- pyridinecarbonitrile (413 mg; may be prepared as described in intermediate 19) and the reaction mixture was stirred for 6 hr at RT. The reaction mixture was diluted with EtOAc (100 ml.) and washed with water (3 x 50 ml.) then dried over magnesium sulfate, filtered and evaporated. The residue was dissolved in dichloromethane and purified on the Biotage SP4 using a silica 40+M column and eluting with 0 to 50% EtOAc / isohexane over 20CV then 50% EtOAc / isohexane over 10CV to afford the title compound (538mg) as a white solid. 1H NMR (DMSO-d6) δ: 1.36 (3H, d), 5.03 - 5.12 (1 H, m), 5.36 - 5.43 (3H, m), 7.09 (1 H, dd), 7.21 (1 H, t), 7.38 (1 H, d), 7.60 (1 H, dd), 8.07 (1 H, s), 8.71 (1 H, d). m/z [M-H]": 344.3. Retention time 0.87 min (LC/MS method 3).
Method B
2,2-Difluoro-8-[(1 S)-1-hydroxyethyl]-2H-1 ,4-benzoxazin-3(4H)-one (5.4g; may be prepared as described in intermediate 5) was dissolved in dry DMF (200 ml.) and (2- cyano-4-pyridinyl)methyl methanesulfonate (5.00 g; may be prepared as described in intermediate 194) and potassium carbonate (6.51 g) were added at 250C. The mixture (suspension) was stirred at 250C overnight. Et2O (200 ml.) was added followed by saturated aqueous sodium bicarbonate solution (200 ml.) and water (300 ml.) and further Et2O (200 ml_). The phases were separated. The aqueous phase was back-extracted with EtOAc (400 ml.) and Et2O (400 ml_). The combined organic phases were washed with water (4 x 150 ml_), dried over magnesium sulfate and evaporated to give roughly 8.1 g of crude product that was dissolved in EtOAc (300 ml_). Silica (230-400 Mesh, 30 g) was added. The solvent was evaporated to give a white powder that was charged over the top of a silica column (230-400 Mesh) and eluted with cyclohexane / EtOAc 6:4 to 1 :1 to give the title compound (7.1 g). 1H NMR (DMSO-d6) δ: 1.36 (3H, d), 5.03 - 5.12 (1 H, m), 5.36 - 5.44 (3H, m), 7.09 (1 H, dd), 7.22 (1 H, t), 7.38 (1 H, d), 7.60 (1 H, dd), 8.08 (1 H, s), 8.72 (1 H, d). m/z [M-H]": 344.0. Retention time 0.87 min (LC/MS method 3).
Compounds 61 : 6-({2,2-Difluoro-8-[(1S)-1-hydroxyethyl]-3-oxo-2,3-dihydro-4H-1,4- benzoxazin-4-yl}methyl)-2-pyridinecarbonitrile and Compound 62: 6-({2,2-difluoro- 8-[(1 R)-1 -hydroxyethyl]-3-oxo-2,3-dihydro-4H-1 ,4-benzoxazin-4-yl}methyl)-2- pyridinecarbonitrile
Figure imgf000144_0001
Racemic 2,2-difluoro-8-(1-hydroxyethyl)-2H-1 ,4-benzoxazin-3(4H)-one (50 mg; may be prepared as described in intermediate 4), 6-(bromomethyl)-2-pyridinecarbonitrile (64.5 mg, may be prepared as described in intermediate 39), potassium carbonate (60.3 mg, 0.436 mmol) and potassium iodide (0.362 mg, 2.182 μmol) were dissolved in DMF (2000 μl) in a 10 ml. round-bottomed flask open to the atmosphere and stirred at room temperature overnight. The reaction mixture was evaporated to dryness, redissolved in EtOAc (30ml) and treated with saturated aqueous sodium bicarbonate (30ml). The aqueous layer was extracted with EtOAc (2x30ml) and the organic layers were combined, washed with brine (30ml), dried over magnesium sulfate, fiitered and evaporated to dryness to give the crude product (94mg) as a pale yellow oil. The crude product was purified on a 25+S Biotage silica cartridge, eluting with a 0 to 70 % mixture of EtOAc in hexane to give a colourless oil (67 mg). 53 mg of this racemic mixture was resolved using a Chiralpak IA column eluting with heptane: ethanol (80:20) v/v pump- mixed. Using these conditions the faster-running enantiomer (18 mg, Compound 61 or 62) and the slower-running enantiomer (17 mg, Compound 61 or 62) were obtained in >98% enantiomeric excess as white solids. 1H NMR (CD3OD) δ: 1.45 (3H, d), 5.24 (1 H, q), 5.43 (2H, s), 7.10 (1 H, dd), 7.20 (1 H, t), 7.39, (1 H, d), 7.65 (1 H, d), 7.78 (1 H, d), 7.98 (1 H, t). m/z [M+H]+: 346.2. Retention time 0.91 min (LC/MS method 3).
Alternative method for Compound 61 : 6-({2,2-Difluoro-8-[(1S)-1-hydroxyethyl]-3- oxo-2,3-dihydro-4H-1 ,4-benzoxazin-4-yl}methyl)-2-pyridinecarbonitrile
Figure imgf000144_0002
To a solution of 2,2-difluoro-8-[(1S)-1-hydroxyethyl]-2H-1 ,4-benzoxazin-3(4H)-one (100mg; may be prepared as described in intermediate 5) in DMF (2ml) was added potassium carbonate (121 mg) followed by the addition of 6-(bromomethyl)-2- pyridinecarbonitrile (129mg; may be prepared as described in intermediate 39) in DMF (2ml) and the reaction mixture was stirred at room temperature over night. The reaction mixture was diluted with EtOAc (30ml) and and treated with saturated aqueous sodium bicarbonate (30ml). The aqueous layer was extracted with EtOAc (2x30ml) and the organic layers were combined, washed with brine (30ml), then dried (magnesium sulfate), filtered and evaporated to give a yellow oil. The residue was dissolved in DCM and purified on the Biotage SP4 using a 25+M column and eluting with 0 to 70% EtOAc/isohexane over 20CV to afford the title compound (129 mg) as a white solid. 1H NMR (DMSO-d6) δ: 1.35 (3H, d), 5.03 - 5.12 (1 H, m), 5.38 - 5.50 (3H, m), 7.12 (1 H, dd), 7.22 (1 H, t), 7.37 (1 H, d), 7.77 (1 H, d), 7.97 (1 H, d), 8.09 (1 H, t). m/z [M-H]": 344.1. Retention time 0.88 min (LC/MS method 3).
The following Compounds were prepared by a similar procedure to that used for Compounds 57 and 58, from racemic 2,2-difluoro-8-(1-hydroxyethyl)-2H-1 ,4-benzoxazin- 3(4H)-one (may be prepared as described in intermediate 4) and the appropriate alkylating agent. Achiral purification was by MDAP (formic acid method) or chromatography on silica. * indicates that catalytic potassium iodide was added to the reaction mixture.
Figure imgf000146_0001
Figure imgf000147_0001
Figure imgf000148_0001
Figure imgf000149_0001
Figure imgf000150_0001
Figure imgf000151_0001
Figure imgf000152_0001
Figure imgf000153_0002
Compound 91 : 2,2-Difluoro-8-[(1S)-1-hydroxyethyl)-4-[(3-methyl-4-oxo-3,4-dihydro- 2-quinazolinyl)methyl]-2H-1 ,4-benzoxazin-3(4H)-one
Figure imgf000153_0001
2-(Chloromethyl)-3-methyl-4(3H)-quinazolinone (91 mg, 0.436 mmol; Enamine) was added to 2,2-difluoro-8-[(1S)-1-hydroxyethyl)-2H-1 ,4-benzoxazin-3(4H)-one (50 mg, may be prepared as described in intermediate 5) and potassium carbonate (75 mg, 0.545 mmol) in dry DMF (3 ml_). Potassium iodide (2 mg, 0.012 mmol) was added and the mixtures were stirred overnight at room temperature. The solvent was evaporated and the residue was dissolved in 10% w/v aqueous citric acid solution and EtOAc. More EtOAc, water and solid sodium chloride were added to break up the resulting emulsion. The layers were separated and the aqueous was extracted with EtOAc (1 x 3 ml_). The combined organic layers were dried (sodium sulfate) and evaporated. The residue was purified by MDAP (formic acid method) to give the target compound. 1H NMR (CD3OD) δ: 1.50 (3H, d), 3.77 (3H, s), 5.29 (1 H, q), 5.44 (2H, d), 7.14 (1 H, dd), 7.20 (1 H, t), 7.35 (1 H, d), 7.39 (1 H, d), 7.47 (1 H, t), 7.69 (1 H, td), 8.19 (1 H, dd). m/z [M+H]+: 402.0. Retention time 0.91 min (LC/MS method 3).
The following Compounds were prepared by a similar procedure to that used for Compound 91 , from 2,2-difluoro-8-[(1S)-1-hydroxyethyl]-2H-1 ,4-benzoxazin-3(4H)-one (may be prepared as described in intermediate 5) and the appropriate alkylating agent. Achiral purification was by MDAP (formic acid method) or chromatography on silica.
Figure imgf000155_0001
Figure imgf000156_0001
Figure imgf000157_0002
Compounds 99: 2,2,7-Trifluoro-4-[(5-fluoro-3-pyridinyl)methyl]-8-[(1S)-1- hydroxyethyl]-2H-1 ,4-benzoxazin-3(4H)-one and Compound 100: 2,2,7-Trifluoro-4- [(5-fluoro-3-pyridinyl)methyl]-8-[(1 R)-1 -hydroxyethyl]-2H-1 ,4-benzoxazin-3(4H)-one
Figure imgf000157_0001
Potassium carbonate (193 mg, 1.396 mmol) and 3-(bromomethyl)-5-fluoropyridine hydrobromide (151 mg, 0.558 mmol; Sunshine Chemlab) were added to a solution of 2!2!7-trifluoro-8-(1-hydroxyethyl)-2H-1 ,4-benzoxazin-3(4H)-one (138 mg; may be prepared as described in intermediate 1 1 ) in dry DMF (5 ml_). The mixture was stirred at room temperature overnight. The solvent was evaporated and the residue was dissolved in DCM (3 ml.) and 10% w/v aqueous citric acid (2 ml_). The layers were separated and the aqueous was extracted with DCM (2 x 2 ml_). The combined organic layers were dried (hydrophobic frit) and evaporated to give a brown oil (137 mg). This was purified by MDAP (formic acid method) to give a brown oil (104 mg). 96 mg of this racemic mixture was resolved using a Chiralpak AS column eluting with heptane: ethanol (90:10) v/v pump-mixed. Using these conditions the faster-running enantiomer 2,2,7-trifluoro-4-[(5- fluoro-3-pyridinyl)methyl]-8-[(1 S)- 1 -hydroxyethyl]-2H-1 ,4-benzoxazin-3(4H)-one (42 mg, Compound 99) and the slower-running enantiomer 2,2,7-trifluoro-4-[(5-fluoro-3- pyridinyl)methyl]-8-[(1 R)-1-hydroxyethyl]-2H-1 ,4-benzoxazin-3(4H)-one (40 mg, Compound 100) were obtained in >99% enantiomeric excess. 1H NMR (CD3OD) δ: 1.60 (3H, d), 5.32 - 5.40 (1 H, m), 7.01 (1 H, t), 7.18 - 7.25 (1 H, m), 7.57 (1 H, d), 8.38 - 8.45 (2H, m). m/z [M+H]+: 356.9 Retention time 0.85 min (LC/MS method 3). The absolute configurations were determined by ab initio vibrational circular dichroism.
Compound 101 : 2,2-Difluoro-8-(1-hydroxyethyl)-4-[(5-oxo-5H-[1,3]thiazolo[3,2- a]pyrimidin-7-yl)methyl]-2H-1 ,4-benzoxazin-3(4H)-one (racemate)
Figure imgf000158_0001
The title compound (25 mg) was made in a similar manner to 2,2-difluoro-4-[(5-fluoro-3- pyridinyl)methyl]-8-(1-hydroxyethyl)-2H-1 ,4-benzoxazin-3(4/-/)-one (may be prepared as described in compound 2), replacing 3-(bromomethyl)-5-fluoropyridine hydrochloride with 7-(chloromethyl)-5H-[1 ,3]thiazolo[3,2-a]pyrimidin-5-one (Enamine). m/z [M-H]": 391.9. Retention time 0.76 min (LC/MS method 3).
Compound 102: 2,2-Difluoro-8-(1 -hydroxyethyl)-4-[(1 -methyl -4-oxo-1 ,4-dihydro-2- quinolinyl)methyl]-2H-1,4-benzoxazin-3(4H)-one (racemate)
Figure imgf000158_0002
The title compound (2 mg) was made in a similar manner to 2,2-difluoro-4-[(5-fluoro-3- pyridinyl)methyl]-8-(1-hydroxyethyl)-2H-1 ,4-benzoxazin-3(4/-/)-one (may be prepared as described in compound 2), replacing 3-(bromomethyl)-5-fluoropyridine hydrochloride with (1-methyl-4-oxo-1 ,4-dihydro-2-quinolinyl)methyl methanesulfonate (may be prepared as described in intermediate 60). m/z [M-H]": 401.0. Retention time 0.73 min (LC/MS method 3).
The following compounds 103 to 1 16 (racemates) were prepared by a similar procedure to that used for compound 2, from racemic 2,2-difluoro-8-(1-hydroxyethyl)-2H-1 ,4- benzoxazin-3(4H)-one (may be prepared as described in intermediate 4) and the appropriate alkylating agent. Purification was by MDAP or chromatography on silica. * indicates that catalytic potassium iodide was added to the reaction mixture.
Figure imgf000159_0001
Figure imgf000160_0001
Figure imgf000161_0001
Figure imgf000162_0001
Figure imgf000163_0001
The following compounds 117 to 177 were prepared by a similar procedure to that used for compound 91 , from 2,2-difluoro-8-[(1 S)-1-hydroxyethyl]-2H-1 ,4-benzoxazin-3(4/-/)-one (may be prepared as described in intermediate 5) and the appropriate alkylating agent. Achiral purification was by MDAP (formic acid method) or chromatography on silica.
Figure imgf000163_0002
Figure imgf000164_0001
Figure imgf000165_0001
Figure imgf000166_0001
Figure imgf000167_0001
Figure imgf000168_0001
Figure imgf000169_0001
Figure imgf000170_0001
Figure imgf000171_0001
Figure imgf000172_0001
Figure imgf000173_0001
Figure imgf000174_0001
Figure imgf000175_0001
Figure imgf000176_0001
Figure imgf000177_0001
Figure imgf000178_0001
Figure imgf000179_0001
Figure imgf000180_0002
Compound 178: 2-({2,2-difluoro-8-[(1 R)A -hydroxyethyl]-3-oxo-2,3-dihydro-4H-1 ,4- benzoxazin-4-yl}methyl)-1 -methyl-1H-benzimidazole-4-carbonitrile
Figure imgf000180_0001
The title compound (46 mg) was made in a similar fashion to the preparation of 2,2- difluoro-8-[(1 S)-1-hydroxyethyl)-4-[(3-methyl-4-oxo-3,4-dihydro-2-quinazolinyl)methyl]- 2H-1 ,4-benzoxazin-3(4H)-one (may be prepared as described in compound 91 ), replacing 2,2-difluoro-8-[(1 S)-1-hydroxyethyl]-2H-1 ,4-benzoxazin-3(4H)-one with 2,2- difluoro-8-[(1 R)-1-hydroxyethyl]-2H-1 ,4-benzoxazin-3(4H)-one (may be prepared as described in intermediate 6), and replacing 2-(chloromethyl)-3-methyl-4(3H)- quinazolinone with 2-(chloromethyl)-1-methyl-1H-benzimidazole-4-carbonitrile (may be prepared as described in intermediate 66). m/z [M+H]+: 399.0. Retention time 0.97 min (LC/MS method 3). Compound 179: 2,2-difluoro-8-[(1 /?)-1 -hydroxyethyl]-4-{[1 -methyl -4-(methyloxy)-1 H- benzimidazol-2-yl]methyl}-2H-1 ,4-benzoxazin-3(4H)-one
Figure imgf000181_0001
The title compound (34 mg) was made in a similar fashion to the preparation of 2,2- difluoro-8-[(1 S)-1-hydroxyethyl)-4-[(3-methyl-4-oxo-3,4-dihydro-2-quinazolinyl)methyl]- 2H-1 ,4-benzoxazin-3(4H)-one (may be prepared as described in compound 91 ), replacing 2,2-difluoro-8-[(1 S)-1-hydroxyethyl]-2H-1 ,4-benzoxazin-3(4H)-one with 2,2- difluoro-8-[(1 R)-1-hydroxyethyl]-2H-1 ,4-benzoxazin-3(4H)-one (may be prepared as described in intermediate 6), and replacing 2-(chloromethyl)-3-methyl-4(3H)- quinazolinone with 2-(chloromethyl)-1-methyl-4-(methoxy)-1 H-benzimidazole (may be prepared as described in intermediate 71 ). m/z [M+H]+: 404.2. Retention time 0.94 min (LC/MS method 3). Compound 180: 4-(1H-benzimidazol-4-ylmethyl)-2,2-difluoro-8-[(1 S)-1- hydroxyethyl]-2H-1,4-benzoxazin-3(4H)-one
Figure imgf000181_0002
To a suspension of 1 ,1-dimethylethyl 7-({2,2-difluoro-8-[(1 S)-1-hydroxyethyl]-3-oxo-2,3- dihydro-4H-1 ,4-benzoxazin-4-yl}methyl)-1 H-benzimidazole-1-carboxylate (95 mg, 0.207 mmol; may be prepared as described in intermediate 186) in DCM (2 ml.) was added 4 M hydrochloric acid in dioxane (2 ml_, 8.00 mmol). The reaction mixture was stirred at RT under argon for 16 hr. The reaction mixture was diluted with EtOAc and neutralised by the addition of dilute aqueous sodium hydrogen carbonate solution. After separation of the layers, the aqueous phase was re-extracted with EtOAc. The combined organic phases were passed through a hydrophobic frit and then the solvent was evaporated at reduced pressure. The product was purified by silica gel chromatography eluting with 0 - 20% MeOH in EtOAc to give the title compound (62mg, 0.173 mmol, 83 % yield) as a colourless solid, m/z [M+H]+: 359.9. Retention time 0.84 min (LC/MS method 3).
Compound 181 : 4-(1 H-1 ,2,3-benzotriazol-5-ylmethyl)-2,2-difluoro-8-[(1 S)-1 - hydroxyethyl]-2H-1 ,4-benzoxazin-3(4H)-one
Figure imgf000182_0001
The title compound (15.6 mg) was made in a similar fashion to the preparation of 4-(1 H- benzimidazol-4-ylmethyl)-2,2-difluoro-8-[(1 S)-1-hydroxyethyl]-2H-1 ,4-benzoxazin-3(4H)- one (may be prepared as described in compound 180), replacing 1 ,1-dimethylethyl 7- ({2,2-difluoro-8-[(1 S)-1-hydroxyethyl]-3-oxo-2,3-dihydro-4H-1 ,4-benzoxazin-4-yl}methyl)- 1H-benzimidazole-1-carboxylate with 1 ,1-dimethylethyl 5-({2,2-difluoro-8-[(1 S)-1- hydroxyethyl]-3-oxo-2,3-dihydro-4H-1 ,4-benzoxazin-4-yl}methyl)-1 H-1 ,2,3-benzotriazole- 1-carboxylate (may be prepared as described in intermediate 189). m/z [M+H]+: 361.1. Retention time 0.80 min (LC/MS method 3).
Compound 182: 2,2-difluoro-8-[(1 S)-1-hydroxyethyl]-4-(1H-indazol-4-ylmethyl)-2H- 1 ,4-benzoxazin-3(4H)-one
Figure imgf000183_0001
The title compound (60 mg) was made in a similar fashion to the preparation of 4-(1H- benzimidazol-4-ylmethyl)-2,2-difluoro-8-[(1 S)-1-hydroxyethyl]-2/-/-1 ,4-benzoxazin-3(4/-/)- one (may be prepared as described in compound 180), replacing 1 ,1-dimethylethyl 7- ({2,2-difluoro-8-[(1 S)- 1 -hydroxyethyl]-3-oxo-2,3-dihydro-4H-1 ,4-benzoxazin-4-yl}methyl)- 1H-benzimidazole-1-carboxylate with 1 ,1-dimethylethyl 4-({2,2-difluoro-8-[(1 S)-1- hydroxyethyl]-3-oxo-2,3-dihydro-4H-1 ,4-benzoxazin-4-yl}methyl)-1 H-indazole-1- carboxylate (may be prepared as described in intermediate 192). m/z [M+H]+: 360.2. Retention time 1.19 min (LC/MS method 3).
Compound 183: 2-({2,2-difluoro-8-[(1 S)-1 -hydroxyethyl]-3-oxo-2,3-dihydro-4H-1 ,4- benzoxazin-4-yl}methyl)-3-methylpyrido[3,4-c/]pyrimidin-4(3H)-one and compound 184: 2-({2,2-difluoro-8-[(1/?)-1-hydroxyethyl]-3-oxo-2,3-dihydro-4H-1,4-benzoxazin- 4-yl}methyl)-3-methylpyrido[3,4-cf]pyrimidin-4(3H)-one
Figure imgf000183_0002
A racemic mixture of 2-{[2,2-difluoro-8-(1-hydroxyethyl)-3-oxo-2,3-dihydro-4H-1 ,4- benzoxazin-4-yl]methyl}-3-methylpyrido[3,4-c/]pyrimidin-4(3/-/)-one (34 mg; may be prepared as described in compound 114) was separated using a Chiralpak AS column eluting with heptane / ethanol 80:20 pump-mixed. Using these conditions the faster- running enantiomer (17 mg) and the slower-running enantiomer (21 mg) were obtained in > 99.8 % enantiomeric excess. The two enantiomers were further purified by MDAP to give the faster-running enantiomer (1 1 mg; compound 183 or 184) and the slower- running enantiomer (1 1 mg; compound 183 or 184) as white solids, m/z [M+H]+: 404.2. Retention time 0.79 min (LC/MS method 3).
Compound 185: 4-[(5-chloro-3-pyridinyl)methyl]-2,2-difluoro-8-(1 -hydroxyethyl)-2H- 1 ,4-benzoxazin-3(4H)-one-d4
Figure imgf000184_0001
The title compound (104 mg) was made in a similar fashion to the preparation of 2,2- difluoro-4-[(5-fluoro-3-pyridinyl)methyl]-8-(1-hydroxyethyl)-2H-1 ,4-benzoxazin-3(4H)-one (may be prepared as described in compound 2), replacing 2,2-difluoro-8-(1- hydroxyethyl)-2H-1 ,4-benzoxazin-3(4H)-one with 2,2-difluoro-8-(1-hydroxyethyl)-2H-1 ,4- benzoxazin-3(4H)-one-c/4 (may be prepared as described in intermediate 193), and replacing 3-(bromomethyl)-5-fluoropyridine hydrobromide with 3-(bromomethyl)-5- chloropyridine hydrobromide (Sunshine Chemlab). m/z [M+H]+: 359.2 / 361.2. Retention time 0.93 min (LC/MS method 3).
Compound 186: 4-[(5-fluoro-3-pyridinyl)methyl]-2,2-difluoro-8-(1 -hydroxyethyl)-2H- 1 ,4-benzoxazin-3(4H)-one-d4
Figure imgf000184_0002
The title compound (104 mg) was made in a similar fashion to the preparation of 2,2- difluoro-4-[(5-fluoro-3-pyridinyl)methyl]-8-(1-hydroxyethyl)-2H-1 ,4-benzoxazin-3(4H)-one (may be prepared as described in compound 2), replacing 2,2-difluoro-8-(1- hydroxyethyl)-2H-1 ,4-benzoxazin-3(4H)-one with 2,2-difluoro-8-(1-hydroxyethyl)-2H-1 ,4- benzoxazin-3(4H)-one-c/4 (may be prepared as described in intermediate 193). m/z [M+H]+: 343.2. Retention time 0.86 min (LC/MS method 3).
Compound 187: 4-[(5-chloro-3-pyridinyl)methyl]-2,2-difluoro-8-[(1 S)A - hydroxyethyl]-2H-1,4-benzoxazin-3(4H)-one-c/4 and compound 188: 4-[(5-chloro-3- pyridinyl)methyl]-2,2-difluoro-8-[(1/?)-1-hydroxyethyl]-2H-1,4-benzoxazin-3(4H)-one-
Figure imgf000185_0001
A racemic mixture of 4-[(5-chloro-3-pyridinyl)methyl]-2,2-difluoro-8-(1-hydroxyethyl)-2H- 1 ,4-benzoxazin-3(4/-/)-one-c/4 (may be prepared as described in compound 185) was separated using a Chiralpak AD column eluting with heptane / ethanol 90:10 pump- mixed. Using these the conditions the faster-running enantiomer (36 mg; compound 187 or 188) and the slower-running enantiomer (31 mg; compound 187 or 188) were obtained in > 99.8% enantiomeric excess, m/z [M+H]+: 359.1. Retention time 0.94 min (LC/MS method 3).
Compound 189: 4-[(5-fluoro-3-pyridinyl)methyl]-2,2-difluoro-8-[(1 S)-1 - hydroxyethyl]-2H-1,4-benzoxazin-3(4H)-one-d4 and compound 190: 4-[(5-fluoro-3- pyridinyl)methyl]-2,2-difluoro-8-[(1/?)-1-hydroxyethyl]-2H-1,4-benzoxazin-3(4H)-one- d4
Figure imgf000186_0001
A racemic mixture of 4-[(5-fluoro-3-pyridinyl)methyl]-2,2-difluoro-8-(1-hydroxyethyl)-2H- 1 ,4-benzoxazin-3(4H)-one-c/4 (may be prepared as described in compound 186) was separated using a Chiralpak AD column eluting with heptane / ethanol 70:30 pump- mixed. Using these the conditions the faster-running enantiomer (37 mg; compound 189 or 190) and the slower-running enantiomer (31 mg; compound 189 or 190) were obtained in > 95.4% enantiomeric excess, m/z [M+H]+: 343.1. Retention time 0.87 min (LC/MS method 3). The following compounds were prepared by a similar procedure to that used for compounds 99 and 100, from racemic 2,2,7-trifluoro-8-(1-hydroxyethyl)-2/-/-1 ,4- benzoxazin-3(4H)-one (may be prepared as described in intermediate 10) and the appropriate alkylating agent.
m/z
Figure imgf000187_0001
Figure imgf000188_0002
Compound 197. 2,2-Difluoro-4-[(3-fluorophenyl)methyl]-8-(1 -hydroxyethyl)-2H-1 ,4- benzoxazin-3(4H)-one (racemate)
Figure imgf000188_0001
To a solution of racemic 2,2-difluoro-8-(1-hydroxyethyl)-2H-1 ,4-benzoxazin-3(4H)-one (300mg; may be prepared as described in intermediate 4) in DMF (4ml) was added potassium carbonate (362mg) followed by the dropwise addition of 1-(bromomethyl)-3- fluorobenzene (495mg; Aldrich) in DMF (4ml) and the reaction mixture stirred for one hour. The reaction mixture was diluted with EtOAc (100ml) and washed with water (3x 50ml) then dried (magnesium sulfate), filtered and evaporated to give an orange oil. The crude product was dissolved in DCM and purified on the Biotage SP4 using a 40+M column and eluting with 0 to 30% EtOAc/isohexane over 20CV to afford the title compound (417mg) as a colourless oil. 1H NMR (CD3OD) δ: 1.45 (3H, d), 5.23 (1 H, q), 5.30 (2H, s), 6.99 - 7.06 (2H, m), 7.07 - 7.11 (2H, m), 7.20 (1 H, t), 7.32 - 7.41 (1 H, m). Retention time 1.09 min (LC/MS method 3).
The following Compounds 198 to 207 (racemates) were prepared by a similar procedure to that used for Compound 197, from racemic 2,2-difluoro-8-(1-hydroxyethyl)-2H-1 ,4- benzoxazin-3(4H)-one (may be prepared as described in intermediate 4) and the appropriate alkylating agent. Purification was by MDAP (formic acid method) or chromatography on silica. * indicates that catalytic potassium iodide was added to the reaction mixture.
Figure imgf000190_0001
Figure imgf000191_0001
Figure imgf000192_0001
Figure imgf000193_0002
Compound 208. 2,2,7-Trifluoro-4-[(3-fluorophenyl)methyl]-8-(1 -hydroxyethyl)-2H- 1 ,4-benzoxazin-3(4H)-one (racemate)
Figure imgf000193_0001
The title compound was made in a similar manner to the preparation of Compound 197 (2,2-difluoro-4-[(3-fluorophenyl)methyl]-8-(1-hydroxyethyl)-2/-/-1 ,4-benzoxazin-3(4/-/)- one), replacing 2,2-difluoro-8-(1-hydroxyethyl)-2H-1 ,4-benzoxazin-3(4H)-one (may be prepared as described in intermediate 4) with 2,2,7-trifluoro-8-(1-hydroxyethyl)-2H-1 ,4- benzoxazin-3(4H)-one (may be prepared as described in intermediate 11 ). 1H NMR (CD3OD) δ: 1.60 (3H, d), 5.29 (2H, s), 5.36 (1 H, q), 6.93 - 7.06 (3H, m), 7.07 - 7.15 (2H, m), 7.33 - 7.41 (1 H, m). Retention time 1.05 min (LC/MS method 3).
Compound 209: 3-{[2,2-Difluoro-8-[(1 S)-1-hydroxyethyl]-3-oxo-2,3-dihydro-4H-1,4- benzoxazin-4-yl]methyl}benzonitrile and Compound 210: 3-{[2,2-difluoro-8-[(1/?)-1- hydroxyethyl]-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl]methyl}benzonitrile
Figure imgf000195_0001
To a solution of racemic 2,2-difluoro-8-(1-hydroxyethyl)-2H-1 ,4-benzoxazin-3(4H)-one (110mg; may be prepared as described in intermediate 4) in DMF (1.2ml) was added potassium carbonate (133mg) followed by the dropwise addition of 3- (bromomethyl)benzonitrile (188mg; Aldrich) in DMF (1.2ml) and the reaction mixture was stirred for 20 hr at room temperature. The reaction mixture was diluted with EtOAc (30ml) and washed with water (2x 20ml) then dried (magnesium sulfate), filtered and evaporated. The residue was dissolved in dichloromethane and loaded onto a Biotage Si 25+S column and purified using the Biotage SP4 eluting with 0-50% EtOAc/isohexane over 20CV to afford a yellow oil. This racemic mixture was resolved using a Chiralpak AS column eluting with heptane: ethanol (90:10) v/v pump-mixed. Using these conditions the faster-running enantiomer (54 mg, Compound 13 or 14) and the slower-running enantiomer (51 mg, Compound 13 or 14) were obtained in >99.8% enantiomeric excess. 1H NMR (DMSOd6) δ: 1.29-1.39 (3H, d), 5.01-5.10 (1 H, m), 5.28-5.46 (3H, m), 7.14-7.22 (2H, m), 7.32-7.40 (1 H, m), 7.54-7.63 (2H, m), 7.74-7.82 (1 H, m), 7.83-7.9 (1 H, s). m/z [M+H]+: mass ion not observed. Retention time 0.99 min (LC/MS method 3).
Compounds 211 : 2,2-Difluoro-4-[(3-fluorophenyl)methyl]-8-[(1 S)-1 -hydroxyethyl]- 2H-1,4-benzoxazin-3(4H)-one and Compound 212: 2,2-difluoro-4-[(3- fluorophenyl)methyl]-8-[(1/?)-1-hydroxyethyl]-2H-1,4-benzoxazin-3(4H)-one
Figure imgf000196_0001
To a solution of racemic 2,2-difluoro-8-(1-hydroxyethyl)-2/-/-1 ,4-benzoxazin-3(4/-/)-one (300mg; may be prepared as described in intermediate 4) in DMF (4ml) was added potassium carbonate (362mg) followed by the dropwise addition of 1-(bromomethyl)-3- fluorobenzene (495mg; Aldrich) in DMF (4ml) and the reaction mixture was stirred for one hour. The reaction mixture was diluted with EtOAc (100ml) and washed with water (3x 50ml) then dried and evaporated. The residue was dissolved in DCM and purified on the Biotage SP4 using a 40+M column and eluting with 0 to 30% EtOAc/isohexane over 20CV to afford a colourless oil (417mg). This racemic mixture was resolved using a Chiralpak AS column eluting with heptane: isopropyl alcohol (95:5) v/v pump-mixed. Using these conditions, the faster running enantiomer 2,2-difluoro-8-[(1 S)-1- hydroxyethyl]-2H-1 ,4-benzoxazin-3(4H)-one (128mg, Compound 21 1 ) and the slower running enantiomer 2,2-difluoro-8-[(1 /?)-1-hydroxyethyl]-2H-1 ,4-benzoxazin-3(4H)-one (71 mg, Compound 212) were obtained in >93% enantiomeric excess. The absolute configurations were determined by ab initio vibrational circular dichroism (see Stephens PJ, Devlin FJ; Determination of the structure of chiral molecules using ab initio virational circular dichroism spectroscopy; Chirality 2000; 12: 172-179).
1H NMR (CD3OD) δ : 1.42-1.47 (3H, d), 5.19-5.25 (1 H, m), 5.25-5.36 (2H, m), 6.98-7.06 (2H, m), 7.06-7.12 (2H, m), 7.16-7.23 (1 H, m), 7.33-7.41 (2H, m). Retention time 1.09 min (LC/MS method 3). The following Compounds were prepared by a similar procedure to that used for Compounds 209 and 210, from racemic 2,2-difluoro-8-(1-hydroxyethyl)-2H-1 ,4- benzoxazin-3(4H)-one (may be prepared as described in intermediate 4) and the appropriate alkylating agent. Purification was by MDAP (formic acid method) or chromatography on silica. * indicates that catalytic potassium iodide was added to the reaction mixture.
Figure imgf000197_0001
Figure imgf000198_0001
Figure imgf000199_0001
Figure imgf000200_0001
Figure imgf000201_0001
Compounds 223: 2,2,7-Trifluoro-4-[(3-fluorophenyl)methyl]-8-[(1 S)-1-hydroxyethyl]- 2H-1,4-benzoxazin-3(4H)-one and Compound 224: 2,2,7-trifluoro-4-[(3- fluorophenyl)methyl]-8-[(1/?)-1-hydroxyethyl]-2H-1,4-benzoxazin-3(4H)-one
Figure imgf000202_0001
The title compounds (faster-running enantiomer, compound 223 or 224: 32 mg and slower-running enantiomer, compound 223 or 224: 18 mg) were made in a similar manner to the preparation of Compounds 209 and 210, replacing 2,2-difluoro-8-(1- hydroxyethyl)-2H-1 ,4-benzoxazin-3(4H)-one (may be prepared as described in intermediate 4) with 2,2,7-trifluoro-8-(1-hydroxyethyl)-2H-1 ,4-benzoxazin-3(4H)-one (may be prepared as described in intermediate 11 ), and 3-(bromomethyl)benzonitrile with 1- (bromomethyl)-3-fluorobenzene (Aldrich). 1H NMR (CD3OD) δ: 1.60 (3H, d), 5.29 (2H, s), 5.36 (1 H, q), 6.93 - 7.06 (3H, m), 7.07 - 7.15 (2H, m), 7.33 - 7.41 (1 H, m). Retention time 1.05 min (LC/MS method 3). Experimental
Starting materials, reagents and solvents were obtained from commercial suppliers and used without further purification unless otherwise stated. Chromatography was carried out using pre-packed Biotage™ silica-gel columns as the stationary phase and analytical grade solvents as the eluent unless otherwise stated. Phase separation cartridge or hydrophobic frit refers to Biotage lsolute Phase Separator.
NMR spectra were obtained at 298K, 300K or 303.2K at the frequency stated using either a Bruker™ DPX400 or AV400 machine and run as a dilute solution of CDCI3 unless otherwise stated. All NMR spectra were referenced to tetramethylsilane (TMS δH 0, δc C 0). All coupling constants are reported in hertz (Hz) and multiplicities are labelled s (singlet), bs (broad singlet), d (doublet), t (triplet), q (quartet), dd (doublet of doublets), dt (doublet of triplets), td (triplet of doublets), ddd (double-double-doublet) and m (multiplet). All quoted retention times are measured using LC/MS (Liquid Chromatography / Mass Spectrometry). Where appropriate, these retention times were used as a guide for purification using mass-directed auto-purification (MDAP), which refers to purification by HPLC, wherein fraction collection is triggered by detection of the programmed mass ion for the compound of interest.
Total ion current traces were obtained for electrospray positive and negative ionisation (ES+ / ES-) and / or atmospheric pressure chemical positive and negative ionisation (AP+ / AP-).
Where reactions are described as having been carried out in a similar manner to earlier, more completely described reactions, the general reaction conditions used were essentially the same. Work up conditions used were of the types standard in the art, but may have been adapted from one reaction to another. The starting material may not necessarily have been prepared from the batch referred to. Unless otherwise stated, all compounds with chiral centre(s) are racemic. Compounds synthesised may have various purities ranging from for example 85% to 98%. However, calculations of number of moles and yield are generally not adjusted for this. All reactions were either carried out under argon or may be carried out under argon, unless otherwise stated.
Analytical LC/MS chromatography conditions
Four different methods were used.
Method 1 : Sun~5min_For
The HPLC analysis was conducted on a Sunfire C18 column (30mm x 4.6mm i.d. 3.5μm packing diameter) at 300C.
The solvents employed were:
A = 0.1 % v/v solution of formic acid in water
B = 0.1 % v/v solution of formic acid in acetonitrile
The gradient employed was:
Figure imgf000203_0001
Figure imgf000204_0001
The UV detection was a summed signal from wavelength of 210nm to 350nm.
MS Conditions:
MS Waters ZQ
lonisation mode Alternate-scan Positive and Negative Electrospray
Scan range 100 to 1000 AMU
Scan time 0.50 sec
Inter scan delay 0.20 sec
Method 2: XBr~5min_HpH_ESCI
The HPLC analysis was conducted on an XBridge C18 column (50mm x 4.6mm i.d.
3.5μm packing diameter) at 300C.
The solvents employed were:
A = 10 mM ammonium bicarbonate in water adjusted to pH 10 with ammonia solution
B = acetonitrile
The gradient employed was:
Figure imgf000204_0002
The UV detection was a summed signal from wavelength of 210nm to 350nm.
MS Conditions: MS Waters ZQ
lonisation mode Alternate-scan Positive and Negative Electrospray and APCI Scan range 100 to 1000 AMU
Scan time 0.50 sec
Inter scan delay 0.10 sec
Method 3: Acq~2min_For
The UPLC analysis was conducted on an Acquity UPLC BEH C18 column (50mm x
2.1 mm i.d. 1.7 μm packing diameter at 400C.
The solvents employed were:
A = 0.1 % v/v solution of formic acid in water
B = 0.1 % v/v solution of formic acid in acetonitrile The gradient employed was:
Figure imgf000205_0001
The UV detection was a summed signal from wavelength of 210nm to 350nm. MS Conditions:
MS Waters ZQ
lonisation mode Alternate-scan Positive and Negative Electrospray
Scan range 100 to 1000 AMU
Scan time 0.27 sec
Inter Scan delay 0.10 sec
Method 4: Acq~2min_HpH
The UPLC analysis was conducted on an Acquity UPLC BEH C18 column (50mm x 2.1 mm i.d. 1.7μm packing diameter at 400C. The solvents employed were:
A = 10 mM ammonium bicarbonate in water adjusted to pH 10 with ammonia solution
B = acetonitrile
The gradient employed was:
Figure imgf000206_0001
The UV detection was a summed signal from wavelength of 210nm to 350nm.
MS Conditions:
MS Waters ZQ
lonisation mode Alternate-scan Positive and Negative Electrospray and APCI Scan range 100 to 1000 AMU
Scan time 0.27 sec
Inter Scan delay 0.10 sec
Mass-Directed Auto-Purification System chromatography conditions
Mass-directed HPLC refers to methods where the material was purified by HPLC wherein fraction collection is triggered by detection of the programmed mass ion for the compound of interest. Two different sets of methods were used with the exact method selected depending on the retention time of the compound of interest and the degree of separation from impurities as determined by analytical LCMS.
Method set 1 : formic acid
The HPLC analysis was conducted on a Sunfire C18 column (150mm x 30mm i.d. 5μm packing diameter) at ambient temperature. The solvents employed were:
A = 0.1 % v/v solution of formic acid in water B = 0.1 % v/v solution of formic acid in acetonitrile
Five different gradients were employed:
Method A:
Figure imgf000207_0001
Method E:
Figure imgf000208_0001
The UV detection was a summed signal from wavelength of 210nm to 350nm.
MS Conditions:
MS Waters ZQ
lonisation mode Alternate-scan Positive and Negative Electrospray
Scan range 100 to 1000 AMU
Scan time 0.50 sec
Inter Scan delay 0.20 sec
Method set 2: high pH
The HPLC analysis was conducted on an XBridge C18 column (150mm x 30mm i.d. 5μm packing diameter) at ambient temperature.
The solvents employed were:
A = 10 mM ammonium bicarbonate in water adjusted to pH 10 with ammonia solution
B = acetonitrile
Five different gradients were employed:
Method A:
Figure imgf000208_0002
Method B:
Figure imgf000209_0001
The UV detection was a summed signal from wavelength of 210nm to 350nm.
MS Conditions: MS Waters ZQ
lonisation mode Alternate-scan Positive and Negative Electrospray
Scan range 100 to 1000 AMU
Scan time 0.50 sec
Inter scan delay 0.20 sec
Pharmacological data The affinities of the compounds as defined in the first to ninth aspect for the GIyTI transporter were determined by the following assay. The compounds as defined in the first to ninth aspect were used in the form as described herein. The compounds of the first to ninth aspect were not necessarily from the same batch. The test compound made in one batch may have been combined with other batch(es) for the assay(s).
Whole Cell Preparation for GlyT-1
HEK293 cells expressing GlyT-1 were grown in cell culture medium (DMEM Nut Mix F12 containing 2mM L-Glutamine, 0.8mg/ml_ geneticin and 10% FCS-HI) at 37C and 5% CO2. Cells grown to 70-80% confluency in T175 flasks were harvested and resuspended in freezing media (90% FBS, 10% DMSO) and aliquoted into 1 ml cryotubes. Cells are then frozen in a controlled rate freezer and stored at -14O0C.
[3H]-glycine Uptake SPA Binding Assay for GIyT- 1 Frozen cells are defrosted rapidly and washed with PBS. Cells are resuspended in PBS, counted and then centrifuged (500rpm for 5mins). The cell pellet is gently resuspended in assay buffer (14OmM NaCI, 5.4mM KCI, 1.8mM CaCI2, 0.8mM MgSO4, 2OmM HEPES, 5mM glucose and 5mM alanine, pH 7.4) to give a final density of 1.32x106 cells/ml.
Compounds are serially diluted 2.5-fold in DMSO from a top concentration of 2.5mM with each compound giving an 1 1 data point dose-response. 100nl of test compound at each concentration was added to the assay plate. An equal volume of Leadseeker™ WGA (wheat germ agglutinin) SPA beads (6.5mg/ml suspended in assay buffer) is added to the cell suspension 1.32x106 cells/ml. 5μl_ of this cell/bead suspension transferred to each well of a low volume 384-well white solid bottom plate containing 100nl of test compounds. Glycine substrate solution (5μl_) is added to each well [1 :100 dilution of 100μM [3H]-glycine stock in assay buffer containing 2.5μM glycine). Final DMSO concentration was 1% v/v, final assay concentrations (FAC) 3300 cells/well, 16.25μg/well SPA bead, Glycine 1.25μM. Plates are sealed and incubated for 3 hours at room temperature before being read on the PerkinElmer ViewLux™ imaging plate reader. Activity is determined by measuring luminescent light at 613nm, plC50 (negative Iog10 of the molar IC50) values were calculated using the ActivityBase™ software. Supporting compounds 1 to 224 have been tested in the above assay.
Supporting compounds 1 to 100, 103 to 105, 107 to 1 11 , 1 13 to 133, 135 to 141 , 143 to 153, 155, 157 to 169, 172 to 196 and 197 to 224 have a plC50 of 5.0 or above. Compounds 2 to 22, 24 to 26, 32, 33 to 39, 41 to 45, 47 to 49, 51 to 55, 57, 59 to 70, 71/72 (faster running enantiomer), 73, 74, 75/76 (faster running enantiomer), 77 to 100, 103, 105, 107, 108, 11 1 , 113, 1 14, 1 16 to 121 , 123 to 133, 135 to 138, 140, 141 , 143 to 145, 147 to 153, 155, 157 to 164, 166 to 169, 174 to 180, 183 to 188, 190 to 196, 197 to 206, 208 to 224 have a plCso of 5.6 or above. Compounds 2 to 8, 10 to 19, 21 , 24, 25, 33 to 39, 43, 44, 47, 51 , 54, 55, 57, 60 to 62, 63/64 (faster running enantiomer), 65, 66, 67/68 (faster running enantiomer), 69, 70, 71/72 (faster running enantiomer), 73, 74, 75/76 (faster running enantiomer), 77 to 94, 97 to 100, 103, 105, 108, 111 , 1 13, 114, 1 16 to 121 , 123 to 133, 135 to 138, 140, 143 to 145, 147 to 150, 153, 155, 157 to 162, 164, 166 to 169, 174 to 179, 183 to 188, 190 to 196, 197 to 206, 208 to 215, 217 to 224 have a plC50 of 6.0 or above. Compound 34 has a plC50 of 7.7. Compound 202 has a plC50 of 8.0.
Compounds that are considered to have selectivity for inhibition of the GIyTI transporter over the GlyT2 transporter are those that have a greater activity at the GIyTI transporter than at the the GlyT2 transporter. For example, compounds may be considered to show selectivity for the GIyTI transporter if they have a plC50 of 5.0 or above compared with a plC50 of below 5.0 for the GlyT2 transporter. Compounds considered to be particularly selective for inhibition of the GIyTI transporter over the GlyT2 transporter are those that have a plC50 for the GIyTI transporter that is greater than the plC50 for the GlyT2 transporter by 0.5 or more and compounds considered to be especially selective are those that have a plC50 for the GIyTI transporter that is greater than the plC50 for the GlyT2 transporter by 1.0 or more. Compounds 1 to 25, 27 to 29, 31 to 39, 41 to 100, 197 to 224 have a plC50 for the GIyTI transporter that is greater than the plC50 for the GlyT2 transporter by 0.5 or more. Compounds 2 to 19, 21 , 22, 24, 25, 32, 33 to 39, 41 to 44, 47 to 49, 51 to 55, 57, 59 to 70, 71/72 (faster running enantiomer), 73, 74, 75/76 (faster running enantiomer), 77 to 100, 197 to 206, 208 to 224 have a plC50 for the GIyTI transporter that is greater than the plC50 for the GlyT2 transporter by 1.0 or more. Compound 34 has a plC50 for the GIyTI transporter that is greater than the plC50 for the GlyT2 transporter by 3.1. Compound 202 has a plC50 for the GIyTI transporter that is greater than the plC50 for the GlyT2 transporter by 3.4.

Claims

Claims
1. A compound of formula (I), or a salt thereof, wherein
Figure imgf000213_0001
(I)
R1 is selected from
a) 5 to 6 membered heteroaryl ring which contains 1 to 4 heteroatoms independently selected from O, N and S;
b) 8 to 10 membered fused bicyclic ring system containing 0, 1 , 2, 3 or 4 heteroatoms independently selected from O, N and S, with a maximum of 3 heteroatoms present in each of the two rings;
wherein 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, C1-4alkyl, C1-4alkoxy, cyano, hydroxy, hydroxyC1-4alkyl, -(CH2)n-(NR1aR1b), -(CO)NR1aR1b, -(CO)O-C1-4alkyl, -(CHO), haloC1-4alkyl and haloC1-4alkoxy; or
(c) phenyl which is unsubstituted or substituted with 1 to 3 substituents independently selected from halo, C1-4alkyl, C1-4alkoxy, cyano, hydroxy, hydroxyC1-4alkyl, -(CH2)n-
(NR1aR1b), -(CO)NR1aR1b, -(CO)O-C1-4alkyl, -(CHO), -SO2(NR1aR1b), haloC1-4alkyl and haloC1-4alkoxy;
n is 1 , 2, 3 or 4;
R1a and R1b are independently selected from hydrogen, Ci-4alkyl and haloCi-4alkyl;
R2 is selected from hydrogen, halo, cyano,
Figure imgf000213_0002
Ci-4alkoxy and haloCi.
4alkoxy;
R3 is selected from hydrogen, halo, cyano and haloCi-4alkyl; and
R4 is selected from hydrogen, halo, cyano,
Figure imgf000213_0003
Ci-4alkoxy and haloCi.
4alkoxy.
2. A compound of formula I as represented by formula (Ia) according to claim 1 , or a salt thereof, wherein
Figure imgf000214_0001
R1, R2, R3 and R4 are as defined in claim 1.
3. A compound of formula I as represented by formula (Ib) according to claim 1 , or a salt thereof, wherein
Figure imgf000214_0002
R1, R2, R3 and R4 are as defined in claim 1.
4. The compound according to any one of claims 1 to 3 wherein R2, R3 and R4 are independently selected from hydrogen, halo, cyano and haloCi-4alkyl.
5. The compound according to claim 4 wherein R2, R3 and R4 are independently selected from hydrogen and halo.
6. The compound according to claim 5 wherein R2, R3 and R4 are independently selected from hydrogen and halo.
7. The compound according to claim 6 wherein R2 is halo and R3 and R4 are hydrogen.
8. The compound according to claim 7 wherein R2 is fluoro and R3 and R4 are hydrogen.
9. The compound according to any one of claims 1 to 8 wherein R1 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, C1-4alkyl, C1-4alkoxy, cyano, hydroxyl, hydroxy C1-4alkyl, -(CH2)n-(NR1aR1b), -(CO)NR1aR1b, -(CO)O-C1-4alkyl, -(CHO), halod. 4alkyl and haloC1-4alkoxy.
10. The compound according to claim 9 wherein R1 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,
Figure imgf000215_0001
Ci-4alkoxy, cyano, hydroxyl, hydroxy Ci- 4alkyl, -(CH2)n-(NR1aR1b), -(CO)NR1aR1b, -(CO)O-Ci-4alkyl, -(CHO), haloCi-4alkyl and haloCi_4alkoxy.
11. The compound according to claim 10 wherein R1 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, C1-4alkyl, C1-4alkoxy, cyano, hydroxyl, hydroxy C1-4alkyl, -(CH2)n-(NR1aR1b), - (CO)NR1aR1b, -(CO)O-C1-4alkyl, -(CHO), haloC1-4alkyl and haloC1-4alkoxy.
12. The compound, or a salt thereof, according to claim 11 wherein R1 is selected from - furanyl which is unsubstituted or substituted with 1 substituent selected from C1-4alkyl, -
(CO)O-C1-4alkyl, -(CHO) and haloC1-4alkyl;
- thiazolyl which is unsubstituted or substituted with 1 substituent selected from C1-4alkyl;
- thienyl which is unsubstituted or substituted with 1 substituent selected from -(CO)O-C1- 4alkyl,
- unsubstituted oxazolyl,
- pyridyl which is unsubstituted or substituted with 1 or 2 substituents selected from halo, haloCi_4alkyl, -(CO)O-Ci-4alkyl, Ci-4alkyl,
Figure imgf000215_0002
and cyano;
- unsubstituted pyrimidinyl;
- unsubstituted pyrazinyl; and
- unsubstituted pyridazinyl.
13. The compound, or a salt thereof, according to claim 12 wherein R1 is selected from
- furanyl which is unsubstituted or substituted with 1 substituent selected from methyl, - (CO)O-CH3, -(CHO) and trifluoromethyl;
- thiazolyl which is unsubstituted or substituted with 1 substituent selected from methyl;
- thienyl which is unsubstituted or substituted with 1 substituent selected from -(CO)O- CH3, - unsubstituted oxazolyl,
- pyridyl which is unsubstituted or substituted with 1 or 2 substituents independently selected from fluoro, chloro, trifluoromethyl, -(CO)O-CH3, methyl, methoxy and cyano;
- unsubstituted pyrimidinyl;
- unsubstituted pyrazinyl; and
- unsubstituted pyridazinyl.
14. The compound, or a salt thereof, according to claim 13 wherein R1 is selected from
- 3-pyridyl which is unsubstituted or substituted with 1 or 2 substituents selected from fluoro, chloro, methoxy, cyano, trifluoromethyl, methyl and -(CO)O-CH3;
- 2-pyridyl which is unsubstituted or substituted with 1 or 2 substituents independently selected from methyl, chloro, fluoro, methoxy and cyano; and
- 4-pyridyl which is unsubstituted or substituted with 1 or 2 substituents independently selected from fluoro, methyl, chloro and cyano.
15. The compound, or a salt thereof, according to any one of claim 1 to 8 wherein R1 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, C1-4alkyl, C1-4alkoxy, cyano, hydroxyl, hydroxy C1-4alkyl, -(CH2)n-(NR1aR1b), -(CO)NR1aR1b, -(CO)O-C1-4alkyl, -(CHO), haloC1-4alkyl and haloC1-4alkoxy.
16. The compound, or a salt thereof, according to claim 15 wherein R1 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, Ci-4alkoxy, cyano, hydroxyl, hydroxy Ci-4alkyl, -(CH2)n-(NR1aR1b), - (CO)NR1aR1b, -(COp-C^alkyl, -(CHO), haloC^alkyl and haloCi-4alkoxy.
17. The compound, or a salt thereof, according to claim 16 wherein R1 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, C1-4alkyl, C1-4alkoxy, cyano, haloC1-4alkyl and haloC1-4alkoxy, particularly oxo and C1-4alkyl more particularly oxo and methyl.
18. The compound, or a salt thereof, according to claim 17 wherein R1 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,
Figure imgf000217_0001
Ci-4alkoxy, cyano, haloCi. 4alkyl and haloCi-4alkoxy, particularly oxo and
Figure imgf000217_0002
more particularly oxo and methyl.
19. The compound or salt according to any one of claims 1 to 8, wherein R1 is phenyl which is unsubstituted or substituted with 1 or 2 substitutents independently selected from halo, C1-4alkyl, C1-4alkoxy, cyano, hydroxyl, hydroxy C1-4alkyl, -(CH2)n-(NR1aR1b), - (CO)NR1aR1b, -(COp-C^alkyl, -(CHO), -SO2(NR1aR1b), haloCUalkyl and haloCi-4alkoxy.
20. The compound or salt according to claim 19, wherein R1 is phenyl which is unsubstituted or substituted with 1 or 2 substitutents independently selected from halo,
C1-4alkyl, C1-4alkoxy, cyano, hydroxyl, hydroxy C1-4alkyl, -(CH2)n-(NR1aR1b), -(CO)NR1aR1b, -(CO)O-C1-4alkyl, -(CHO), -SO2(NR1aR1b), halod^alkyl and haloC1-4alkoxy; and wherein at least one substituent is attached to the 3-position relative to the bond attaching the phenyl to the rest of the molecule.
21. The compound or salt according to claim 19 or 20, wherein R1 is phenyl which is unsubstituted or substituted with 1 or 2 substitutents independently selected from halo, C1-4alkyl, C1-4alkoxy, cyano, -SO2(NR1aR1b), haloC1-4alkyl and haloC1-4alkoxy.
22. The compound or salt according to claim 21 , wherein R1 is phenyl which is unsubstituted or substituted with 1 or 2 substitutents independently selected from fluoro, chloro, cyano, methyl, methoxy and -SO2(NR1aR1b).
23 The compound or salt according to claim 22, wherein R1 is phenyl which is unsubstituted or substituted with 1 or 2 substitutents independently selected from fluoro, cyano, methyl and methoxy.
24. The compound, or a salt thereof, according to claim 1 selected from
5-{[2,2-Difluoro-8-[1-hydroxyethyl]-3-oxo-2,3-dihydro-4H-1 ,4-benzoxazin-4-yl]methyl}-3- pyridinecarbonitrile;
2,2-Difluoro-8-[(1S)-1-hydroxyethyl)-4-[(3-methyl-4-oxo-3,4-dihydro-2- quinazolinyl)methyl]-2H-1 ,4-benzoxazin-3(4H)-one; 2!2-Difluoro-4-[(5-fluoro-3-pyridinyl)methyl]-8-[(1 S)-1-hydroxyethyl]-2H-1 ,4-benzoxazin- 3(4H)-one;
4-{[2!2-Difluoro-8-[1-hydroxyethyl)-3-oxo-2!3-dihydro-4H-1 ,4-benzoxazin-4-yl]methyl}-2- pyridinecarbonitrile;
Figure imgf000218_0001
pyridinecarbonitrile;
2!2,7-Trifluoro-4-[(5-fluoro-3-pyridinyl)methyl]-8-[(1 S)- 1 -hydroxyethyl]-2H-1 ,4-benzoxazin- 3(4H)-one;
3-{[2,2-Difluoro-8-[(1 S)-1-hydroxyethyl]-3-oxo-2,3-dihydro-4H-1 ,4-benzoxazin-4- yl]methyl}benzonitrile and
3-{[2,2-difluoro-8-[(1 R)-1-hydroxyethyl]-3-oxo-2,3-dihydro-4H-1 ,4-benzoxazin-4- yl]methyl}benzonitrile;
or a salt thereof.
25. A compound of formula (I) as represented by formula (Ic) according to claim 1 , or a salt thereof, wherein
Figure imgf000218_0002
R1 is selected from
a) 5 to 6 membered heteroaryl ring which contains 1 to 4 heteroatoms independently selected from O, N and S;
b) 8 to 10 membered fused bicyclic ring system containing 0, 1 , 2, 3 or 4 heteroatoms independently selected from O, N and S, with a maximum of 3 heteroatoms present in each of the two rings;
wherein 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, Ci-4alkyl,
Figure imgf000218_0003
cyano, hydroxy, hydroxyCi-4alkyl, -(CH2)n-(NR1aR1b),
-(CO)NR1aR1b, -(CO)O-Ci-4alkyl, -(CHO), haloC^alkyl and haloCi-4alkoxy; or
n is 1 , 2, 3 or 4;
R1a and R1b are independently selected from hydrogen, C1-4alkyl and haloC1-4alkyl;
R2 is selected from hydrogen, halo, cyano, C1-4alkyl, haloC1-4alkyl, C1-4alkoxy and FIaIoC1-
4alkoxy; R3 is selected from hydrogen, halo, cyano and haloC1-4alkyl; and
RR44 iiss sseelected from hydrogen, halo, cyano, C1-4alkyl, haloC1-4alkyl, C1-4alkoxy and haloCi.
4alkoxy.
26. A compound of formula (I) as represented by formula (If), according to claim 1 or a salt thereof, wherein
Figure imgf000219_0001
(if)
R1 is phenyl which is unsubstituted or substituted with 1 to 3 substituents independently selected from halo, Ci-4alkyl, Ci-4alkoxy, cyano, hydroxyl, hydroxy
Figure imgf000219_0002
-(CH2)n-
(NR1aR1b), -(CO)NR1aR1b, -(CO)O-Ci-4alkyl, -(CHO), -SO2(NR1aR1b), haloCUalkyl and haloC1-4alkoxy;
R1a and R1b are independently selected from hydrogen, C1-4alkyl and haloC1-4alkyl;
n is 1 , 2, 3 or 4;
R2 is selected from hydrogen, halo, cyano, C1-4alkyl, haloC1-4alkyl, C1-4alkoxy and FIaIoC1-
4alkoxy;
R3 is selected from hydrogen, halo, cyano and haloC1-4alkyl;
R4 is selected from hydrogen, halo, cyano, C1-4alkyl, haloC1-4alkyl, C1-4alkoxy and FIaIoC1-
4alkoxy.
27. A compound, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 26, for use in therapy.
28. The compound, or a pharmaceutically acceptable salt thereof, according to claim 27, for use in the treatment of a disorder mediated by GIyTI .
29. The compound, or a pharmaceutically acceptable salt thereof, according to claim 28, wherein the disorder is psychosis, including schizophrenia, dementia or attention deficit disorder.
30. Use of a compound, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 26, in the manufacture of a medicament for the treatment of a disorder mediated by GIyTL
31. Use according to claim 30, wherein the disorder is psychosis, including schizophrenia, dementia or attention deficit disorder.
32. 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, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 26.
33. The method according to claim 32 wherein the disorder is psychosis, including schizophrenia, dementia or attention deficit disorder.
34. A pharmaceutical composition comprising (a) a compound, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 26 and (b) a pharmaceutically acceptable excipient.
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