WO2011023753A1

WO2011023753A1 - Benzoxazine derivatives as glycine transport inhibitors

Info

Publication number: WO2011023753A1
Application number: PCT/EP2010/062459
Authority: WO
Inventors: Richard Blunt; Andrew John Eatherton; Vincenzo Garzya; Mark Patrick Healy; James Myatt; Roderick Alan Porter
Original assignee: Glaxo Group Limited
Priority date: 2009-08-27
Filing date: 2010-08-26
Publication date: 2011-03-03

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 Gly T1, including neurological and neuropsychiatric disorders, in particular psychoses, dementia or attention deficit disorder.

Description

BENZOXAZINE DERIVATIVES AS GLYCINE TRANSPORT INHIBITORS

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 benzoxazinine 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 of certain neurological and neuropsychiatric disorders, including schizophrenia.

In a first aspect, there is provided a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein

(I)

R¹ is selected from

a) 5 to 6 memberec ] 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, C_1-4alkyl, Ci_-4alkoxy, cyano, hydroxy, hydroxyC_1-4alkyl, -(CH₂)_n-(NR^1aR^1b), -(CO)NR^1aR^1b, -(CO)O-Ci_-4alkyl, -(CHO), haloC_1-4alkyl and haloCi_-4alkoxy;

c) R¹ is phenyl which is unsubstituted or substituted with 1 to 3 substituents

independently selected from halo, C_1-4alkyl, C_1-4alkoxy, cyano, hydroxy, hydroxyCi_-4alkyl, -(CH₂)_n-(NR^1aR^1b), -(CO)NR^1aR^1b, -(CO)O-Ci_-4alkyl, -(CO)OH, -(CHO), -SO₂(NR^1aR^1b), haloCi_₄alkyl, haloCi_-4alkoxy, -(CO)Ci_-4alkyl, C_2-4alkenyl, -SCi_-4alkyl and 5 to 6 membered heteroaryl ring which contains 1 to 4 heteroatoms independently selected from O, N and

S;

n is 1 , 2, 3 or 4;

R^1a and R^1b are independently selected from hydrogen, C_1-4alkyl and haloC_1-4alkyl;

R² is selected from hydrogen, halo, cyano, C_1-4alkyl, haloC_1-4alkyl, C_1-4alkoxy and FIaIoC_1-

₄alkoxy;

R³ is selected from hydrogen, halo, cyano and haloC_1-4alkyl;

R⁴ is selected from hydrogen, halo, cyano, C_1-4alkyl, haloC_1-4alkyl, C_1-4alkoxy and FIaIoC_1- ₄alkoxy;

R⁵ is selected from -C(OH)R⁶ and -C(O)Me; and

R⁶ is selected from -CF₃, -CHF₂ and -CH₂F,

for use in therapy. According to a further aspect, there is provided a compound of formula (I), or a pharmaceutically acceptable salt thereof, for the treatment of a disorder mediated by GIyTL

According to a further aspect, there is provided the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a disorder mediated by GIyTI .

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), or a pharmaceutically acceptable salt thereof. According to a further aspect, there is provided a pharmaceutical composition comprising (a) a compound of formula (I), or a pharmaceutically acceptable salt thereof, and (b) a pharmaceutically acceptable excipient.

According to a further aspect, there is provided a compound of formula (I), or a salt thereof, wherein

(IA)

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_-4alkoxy, cyano, hydroxy,

-(CH₂)_n-(NR^1aR^1b), -(CO)NR^1aR^1b, -(CO)O-Ci_-4alkyl, -(CHO), haloC^alkyl and haloCi_-4alkoxy;

c) R¹ is phenyl which is unsubstituted or substituted with 1 to 3 substituents

independently selected from halo, C_1-4alkyl, C_1-4alkoxy, cyano, hydroxy, hydroxyC_1-4alkyl, -(CH₂)_n-(NR^1aR^1b), -(CO)NR^1aR^1b, -(CO)O-C_1-4alkyl, -(CO)OH, -(CHO), -SO₂(NR^1aR^1b), haloC_1-4alkyl, haloC_1-4alkoxy, -(CO)C_1-4alkyl, C_2-4alkenyl, -SC_1-4alkyl and 5 to 6 membered heteroaryl ring which contains 1 to 4 heteroatoms independently selected from O, N and S;

n is 1 , 2, 3 or 4;

₄alkoxy;

R³ is selected from hydrogen, halo, cyano and haloCi_-4alkyl;

R⁴ is selected from hydrogen, halo, cyano, Ci_-4alkyl, haloC_1-4alkyl, Ci_-4alkoxy and halod. ₄alkoxy; R⁵ is selected from -C(OH)R⁶ and -C(O)Me; and

R⁶ is selected from -CF₃, -CHF₂ and -CH₂F,

with the proviso that the compound of formula (I) is other than:-

8-acetyl-2,2-difluoro-4-[(2-methyl-1 ,3-thiazol-4-yl)methyl]-2H-1 ,4-benzoxazin-3(4H)-one; 8-acetyl-2,2-difluoro-4-{[6-(trifluoromethyl)-3-pyridinyl]methyl}-2H-1 ,4-benzoxazin-3(4/-/)- one;

methyl 5-[(8-acetyl-2,2-difluoro-3-oxo-2,3-dihydro-4H-1 ,4-benzoxazin-4-yl)methyl]-2- furancarboxylate;

8-acetyl-2,2-difluoro-4-(2-pyridinylmethyl)-2H-1 ,4-benzoxazin-3(4H)-one;

3-[(8-acetyl-2,2-difluoro-3-oxo-2,3-dihydro-4H-1 ,4-benzoxazin-4-yl)methyl]benzonitrile;

2-[(8-acetyl-2,2-difluoro-3-oxo-2,3-dihydro-4H-1 ,4-benzoxazin-4-yl)methyl]benzonitrile;

8-acetyl-4-{[5-acetyl-2-(methyloxy)phenyl]methyl}-2,2-difluoro-2H-1 ,4-benzoxazin-3(4H)- one;

8-acetyl-4-[(4-chlorophenyl)methyl]-2,2-difluoro-2H-1 ,4-benzoxazin-3(4H)-one;

8-acetyl-2,2-difluoro-4-[(4-methylphenyl)methyl]-2H-1 ,4-benzoxazin-3(4H)-one;

8-acetyl-2,2-difluoro-4-[(2-fluorophenyl)methyl]-2H-1 ,4-benzoxazin-3(4H)-one;

8-acetyl-2,2-difluoro-4-[(4-fluorophenyl)methyl]-2H-1 ,4-benzoxazin-3(4H)-one;

8-acetyl-2,2-difluoro-4-[(3-fluorophenyl)methyl]-2H-1 ,4-benzoxazin-3(4H)-one;

8-acetyl-2,2-difluoro-4-[(2-chlorophenyl)methyl]-2H-1 ,4-benzoxazin-3(4H)-one;

8-acetyl-4-[(4-ethenylphenyl)methyl]-2,2-difluoro-2H-1 ,4-benzoxazin-3(4H)-one; and

8-acetyl-2,2-difluoro-4-{[4-(methylthio)phenyl]methyl}-2H-1 ,4-benzoxazin-3(4H)-one.

Description of the embodiments

In a further aspect, there is provided a compound of formula (IA), or a salt thereof, as defined above, with the proviso that the compound of formula (I) is not 8-acetyl-2,2- difluoro-4-(2-pyridinylmethyl)-2H-1 ,4-benzoxazin-3(4/-/)-one.

In a further aspect, there is provided a compound of formula (I), or a salt thereof, wherein

(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;

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, C_1-4alkyl, Ci_-4alkoxy, cyano, hydroxy, hydroxyC_1-4alkyl, -(CH₂)_n-(NR^1aR^1b),

-(CO)NR^1aR^1b, -(CO)O-Ci_-4alkyl, -(CHO), haloC_1-4alkyl and haloCi_-4alkoxy;

c) R¹ is phenyl which is unsubstituted or substituted with 1 to 3 substituents

independently selected from halo, C_1-4alkyl, C_1-4alkoxy, cyano, hydroxy, hydroxyCi_-4alkyl,

-(CH₂)_n-(NR^1aR^1b), -(CO)NR^1aR^1b, -(CHO), -SO₂(NR^1aR^1b), haloCi_-4alkyl, haloCi_-4alkoxy, -

(CO)Ci_-4alkyl, C₂-₄alkenyl, -SCi_-4alkyl and 5 to 6 membered heteroaryl ring which contains 1 to 4 heteroatoms independently selected from O, N and S;

n is 1 , 2, 3 or 4;

₄alkoxy;

R³ is selected from hydrogen, halo, cyano and haloC_1-4alkyl;

R⁴ is selected from hydrogen, halo, cyano, C_1-4alkyl, haloC_1-4alkyl, C_1-4alkoxy and FIaIoC_1-

₄alkoxy;

R⁵ is selected from -C(OH)R⁶ and -C(O)Me; and

R⁶ is selected from -CF₃, -CHF₂ and -CH₂F,

with the proviso that (i) when R¹ is phenyl which is monosubstituted in the para position relative to its attachment to the -CH₂- group, the substituent is other than -cyano, -CF₃, -

NH₂, -CONH₂, -SO₂NH₂ or -SO₂NHMe, and (ii) the compound of formula (I) is other than:-

8-acetyl-2,2-difluoro-4-[(2-methyl-1 ,3-thiazol-4-yl)methyl]-2H-1 ,4-benzoxazin-3(4H)-one;

8-acetyl-2,2-difluoro-4-{[6-(trifluoromethyl)-3-pyridinyl]methyl}-2H-1 ,4-benzoxazin-3(4/-/)- one;

8-acetyl-2,2-difluoro-4-(2-pyridinylmethyl)-2H-1 ,4-benzoxazin-3(4H)-one;

3-[(8-acetyl-2,2-difluoro-3-oxo-2,3-dihydro-4H-1 ,4-benzoxazin-4-yl)methyl]benzonitrile; 2-[(8-acetyl-2,2-difluoro-3-oxo-2,3-dihydro-4H-1 ,4-benzoxazin-4-yl)methyl]benzonitrile;

8-acetyl-4-{[5-acetyl-2-(methyloxy)phenyl]methyl}-2,2-difluoro-2H-1 ,4-benzoxazin-3(4H)- one; 8-acetyl-4-[(4-chlorophenyl)methyl]-2,2-difluoro-2/-/-1 ,4-benzoxazin-3(4/-/)-one;

8-acetyl-2_!2-difluoro-4-[(4-methylphenyl)methyl]-2H-1 _!4-benzoxazin-3(4/-/)-one;

8-acetyl-2,2-difluoro-4-[(2-fluorophenyl)methyl]-2/-/-1 ,4-benzoxazin-3(4/-/)-one;

8-acetyl-2,2-difluoro-4-[(4-fluorophenyl)methyl]-2/-/-1 ,4-benzoxazin-3(4/-/)-one;

8-acetyl-2,2-difluoro-4-[(3-fluorophenyl)methyl]-2/-/-1 ,4-benzoxazin-3(4/-/)-one;

8-acetyl-2,2-difluoro-4-[(2-chlorophenyl)methyl]-2/-/-1 ,4-benzoxazin-3(4/-/)-one;

8-acetyl-4-[(4-ethenylphenyl)methyl]-2,2-difluoro-2/-/-1 ,4-benzoxazin-3(4/-/)-one; and 8-acetyl-2,2-difluoro-4-{[4-(methylthio)phenyl]methyl}-2/-/-1 ,4-benzoxazin-3(4/-/)-one. In a further aspect, R², R³ and R⁴ are independently selected from hydrogen, halo, cyano and haloCi_-4alkyl. In a further aspect, R², R³ and R⁴ are independently selected from hydrogen, halo and cyano. In a yet further aspect, R², R³ and R⁴ are independently selected from hydrogen and halo. In a further aspect, R² is halo or hydrogen and R³ and R⁴ are hydrogen. In a further aspect, R² is fluoro or hydrogen and R³ and R⁴ are hydrogen. In a further aspect, R² is fluoro and R³ and R⁴ are hydrogen. In a further aspect, R², R³ and R⁴ are hydrogen.

In a further aspect, R⁵ is-C(O)Me. In a yet further aspect, R⁵ is -C(OH)R⁶. In a further aspect, R⁵ is

wherein R⁶ is as defined above. In a further aspect, R⁵ is

wherein R⁶ is as defined above.

In a further aspect, R⁶ is -CH₂F or -CF₃. In a yet further aspect, R⁶ is -CHF₂ or -CF₃. In a further aspect, R⁶ is -CHF₂ or CH₂F. In a further aspect, R⁶ is -CF₃.

In a further aspect, R¹ is

(a) a 5 to 6 membered heteroaryl ring which contains 1 to 4 heteroatoms independently selected from O, N and S, wherein the 5 to 6 membered heteroaryl ring is unsubstituted or substituted with 1 to 3 substituents independently selected from halo, oxo, Ci^alkyl, C_1-4alkoxy, cyano, hydroxyl, hydroxy C_1-4alkyl, -(CH₂)_n-(NR^1aR^1b), -(C0)NR^1aR^1b, -(CO)O- C_1-4alkyl, -(CHO), haloC_1-4alkyl and haloC_1-4alkoxy;

(b) 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_1-4alkyl, C_1-4alkoxy, cyano, hydroxyl, hydroxy C_1-4alkyl, -(CH₂)_n-(NR^1aR^1b), -(C0)NR^1aR^1b, -(CO)O-C_1-4alkyl, - (CHO), haloCi_₄alkyl and haloCi_-4alkoxy; or

(c) phenyl which is unsubstituted or substituted with 1 to 2 substituents independently selected from halo,

Ci_-4alkoxy, cyano, hydroxy, hydroxyCi_-4alkyl, -(CH₂)_n- (NR^1aR^1b), -(C0)NR^1aR^1b, -(CO)O-Ci_-4alkyl, -(CO)OH, -(CHO), -S0₂(NR^1aR^1b), haloCi. ₄alkyl, haloCi_-4alkoxy, -(CO)Ci_-4alkyl, C_2-4alkenyl, -SCi_-4alkyl and 5 to 6 membered heteroaryl ring which contains 1 to 4 heteroatoms independently selected from O, N and S.

In a further aspect, R¹ is

(a) 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_1-4alkyl, C_1-4alkoxy, cyano, hydroxyl, hydroxy C_1-4alkyl, -(CH₂)_n-(NR^1aR^1b), -(C0)NR^1aR^1b, -(CO)O- C_1-4alkyl, -(CHO), haloC_1-4alkyl and haloC_1-4alkoxy;

(b) 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_-4alkyl, Ci_-4alkoxy, cyano, hydroxyl, hydroxy Ci_-4alkyl, -(CH₂)_n-(NR^1aR^1b), - (C0)NR^1aR^1b, -(COp-C^alkyl, -(CHO), haloC^alkyl and haloCi_-4alkoxy; or

Ci_-4alkoxy, cyano, hydroxy, hydroxyCi_-4alkyl, -(CH₂)_n- (NR^1aR^1b), -(C0)NR^1aR^1b, -(CO)O-Ci_-4alkyl, -(CO)OH, -(CHO), -S0₂(NR^1aR^1b), haloCi. ₄alkyl, haloCi_-4alkoxy, -(CO)Ci_-4alkyl, C_2-4alkenyl, -SCi_-4alkyl and 5 to 6 membered heteroaryl ring which contains 1 to 4 heteroatoms independently selected from O, N and S; and wherein at least one substituent is attached to the 3-position relative to the bond attaching the phenyl to the rest of the molecule.

In a further aspect, R¹ is

(a) 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_1-4alkyl, C_1-4alkoxy, cyano, hydroxyl, hydroxy C_1-4alkyl, -(CH₂)_n- (NR^1aR^1b), -(CO)NR^1aR^1b, -(CO)O-C_1-4alkyl, -(CHO), haloC_1-4alkyl and haloC_1-4alkoxy;

(b) 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_-4alkyl, Ci_-4alkoxy, cyano, hydroxyl, hydroxy Ci_-4alkyl, -(CH₂)_n-(NR^1aR^1b), - (CO)NR^1aR^1b, -(CO)O-C_1-4alkyl, -(CHO), haloC_1-4alkyl and haloCi_-4alkoxy; or

(c) phenyl which is unsubstituted or substituted with 1 to 2 substituents independently selected from halo, C_1-4alkyl, Ci_-4alkoxy, cyano, hydroxy, hydroxyCi_-4alkyl, -(CH₂)_n-

(NR^1aR^1b), -(CO)NR^1aR^1b, -(CO)O-Ci_-4alkyl, -(CO)OH, -(CHO), -SO₂(NR^1aR^1b), halod. ₄alkyl, haloCi_-4alkoxy, -(CO)Ci_-4alkyl, C_2-4alkenyl, -SCi_-4alkyl and 5 to 6 membered heteroaryl ring which contains 1 to 4 heteroatoms independently selected from O, N and S; and wherein at least one substituent is attached to the 3-position relative to the bond attaching the phenyl to the rest of the molecule.

In a further aspect, R¹ is

(a) - furanyl which is unsubstituted or substituted with 1 substituent selected from C_1- ₄alkyl, -(CO)O-C_1-4alkyl, -(CHO) and haloC_1-4alkyl;

- thiazolyl which is unsubstituted or substituted with 1 substituent selected from C_1-4alkyl;

- thienyl which is unsubstituted or substituted with 1 substituent selected from -(CO)O-C_1- ₄alkyl,

- unsubstituted oxazolyl,

- pyridyl which is unsubstituted or substituted with 1 or 2 substituents independently selected from halo, haloC_1-4alkyl, -(CO)O-C_1-4alkyl, C_1-4alkyl, C_1-4alkoxy and cyano;

- unsubstituted pyrimidinyl;

- unsubstituted pyrazinyl; or

- unsubstituted pyridazinyl;

(b) 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_1-4alkyl, C_1-4alkoxy, cyano, hydroxyl, hydroxy C_1-4alkyl, -(CH₂)_n-(NR^1aR^1b), - (C0)NR^1aR^1b, -(CO)O-C_1-4alkyl, -(CHO), haloC_1-4alkyl and haloC_1-4alkoxy; or

(c) phenyl which is unsubstituted or substituted with 1 to 2 substituents independently selected from halo, C_1-4alkyl, C_1-4alkoxy, cyano, hydroxy, hydroxyC_1-4alkyl, -(CH₂)_n- (NR^1aR^1b), -(C0)NR^1aR^1b, -(CO)O-C_1-4alkyl, -(CO)OH, -(CHO), -S0₂(NR^1aR^1b), halod. ₄alkyl, haloC_1-4alkoxy, -(CO)C_1-4alkyl, C_2-4alkenyl, -SC_1-4alkyl and 5 to 6 membered heteroaryl ring which contains 1 to 4 heteroatoms independently selected from O, N and S; and wherein at least one substituent is attached to the 3-position relative to the bond attaching the phenyl to the rest of the molecule.

In one aspect, R¹ is

(a) - 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; or

- unsubstituted pyridazinyl;

(b) 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_1-4alkyl, C_1-4alkoxy, cyano, haloC_1-4alkyl and haloC_1-4alkoxy, particularly oxo and C_1-4alkyl, more particularly oxo and methyl; or

(c) phenyl which is unsubstituted or substituted with 1 or 2 substituents independently selected from halo, C_1-4alkyl, C_1-4alkoxy, cyano, -SO₂(NR^1aR^1b), haloCi_-4alkyl, haloCi.

₄alkoxy, -(C0)NR^1aR^1b, -(CO)Ci_-4alkyl, C_2-4alkenyl, -SC^alkyl and 5 to 6 membered heteroaryl ring which contains 1 to 4 heteroatoms independently selected from O, N and S. In a further aspect, R¹ is

(a) - 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 (b) 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,

Ci_-4alkoxy, cyano, haloCi_-4alkyl and

particularly oxo and

more particularly oxo or methyl; or

(c) phenyl which is unsubstituted or substituted with 1 or 2 substituents independently selected from fluoro, chloro, cyano, methyl, methoxy, imidazolyl, ethenyl, -(CO)N(CH₃)₂, - (CO)(CH₃), -SCH₃ and -SO₂(NR^1aR^1b).

In a further aspect, R¹ is

(a) 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_1-4alkyl, C_1-4alkoxy, cyano, hydroxyl, hydroxy C_1-4alkyl, -(CH₂)_n-(NR^1aR^1b), -(CO)NR^1aR^1b, -(CO)O- C_1-4alkyl, -(CHO), haloC_1-4alkyl and haloC_1-4alkoxy;

(b) 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_1-4alkyl, C_1-4alkoxy, cyano, haloC_1-4alkyl and haloC_1-4alkoxy, particularly oxo and more particularly oxo and methyl; or

(c) phenyl which is unsubstituted or substituted with 1 or 2 substituents independently selected from halo,

Ci_-4alkoxy, cyano, hydroxy, hydroxyCi_-4alkyl, -(CH₂)_n- (NR^1aR^1b), -(CO)NR^1aR^1b, -(CO)O-Ci_-4alkyl, -(CHO), -SO₂(NR^1aR^1b), haloCi_-4alkyl, haloCi. ₄alkoxy, -(CO)Ci_-4alkyl, C_2-4alkenyl, -SCi_-4alkyl and 5 to 6 membered heteroaryl ring which contains 1 to 4 heteroatoms independently selected from O, N and S;

R², R³ and R⁴ are independently selected from hydrogen, halo, cyano and haloCi_-4alkyl; R⁵ is -C(O)Me or -C(OH)R⁶, and

R⁶ is CF₃, CHF₂ or CH₂F, in particular CF₃.

In a further aspect, R¹ is

(a) 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_1-4alkyl, C_1-4alkoxy, cyano, hydroxyl, hydroxy C_1-4alkyl, -(CH₂)_n- (NR^1aR^1b), -(CO)NR^1aR^1b, -(CO)O-C_1-4alkyl, -(CHO), haloC_1-4alkyl and haloC_1-4alkoxy,

(b) 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, Ci_-4alkoxy, cyano, haloCi. ₄alkyl and haloCi_-4alkoxy, particularly oxo and

more particularly oxo and methyl;

₄alkoxy, -(CO)Ci_-4alkyl, C_2-4alkenyl, -SCi_-4alkyl and 5 to 6 membered heteroaryl ring which contains 1 to 4 heteroatoms independently selected from O, N and S;

R², R³ and R⁴ are independently selected from hydrogen, halo and cyano;

R⁵ is -C(O)Me or -C(OH)R⁶, and

R⁶ is CF₃, CHF₂ or CH₂F, in particular CF₃.

In a further aspect, R¹ is

- 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;

(b) 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_1-4alkyl, C_1-4alkoxy, cyano, haloC_1-4alkyl and haloC_1-4alkoxy, particularly oxo and C_1-4alkyl, more particularly oxo and methyl;

(c) phenyl which is unsubstituted or substituted with 1 or 2 substituents independently selected from fluoro, chloro, cyano, methyl, methoxy, imidazolyl, ethenyl, -(CO)N(CH₃)₂, - (CO)(CH₃), -SCH₃ and -SO₂(NR^1aR^1b); R², R³ and R⁴ are independently selected from hydrogen and halo, particularly fluoro;

R⁵ is -C(O)Me or -C(OH)R⁶, and

R⁶ is CF₃, CHF₂ or CH₂F, in particular CF₃. In a further aspect, R¹ is

(a) - 3-pyridyl which is unsubstituted or substituted with 1 or 2 substituents selected from fluoro, chloro, methoxy, cyano, trifluoromethyl, methyl and -(CO)O-CH₃;

- 4-pyridyl which is unsubstituted or substituted with 1 or 2 substituents independently selected from fluoro, methyl, chloro and cyano;

(b) 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_1-4alkyl, C_1-4alkoxy, cyano, haloC_1-4alkyl and haloC_1-4alkoxy, particularly oxo and C_1-4alkyl more particularly oxo and methyl;

(c) 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, R⁴ is hydrogen or halo, in particular fluoro;

R⁵ is -C(O)Me or -C(OH)R⁶, and

R⁶ is CF₃, CHF₂ or CH₂F, in particular CF₃. In a further aspect, there is provided a compound of formula I represented by a formula (IA), or a salt thereof, wherein

(IA)

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;

Ci_-4alkoxy, cyano, hydroxy,

-(CH₂)_n-(NR^1aR^1b),

-(CO)NR^1aR^1b, -(CO)O-Ci_-4alkyl, -(CHO), haloC^alkyl and haloCi_-4alkoxy;

n is 1 , 2, 3 or 4;

R^1a and R^1b are independently selected from hydrogen, Ci_-4alkyl and haloCi_-4alkyl;

R² is selected from hydrogen, halo, cyano, Ci_-4alkyl,

Ci_-4alkoxy and haloCi.

₄alkoxy;

R³ is selected from hydrogen, halo, cyano and haloCi_-4alkyl;

R⁴ is selected from hydrogen, halo, cyano, Ci_-4alkyl,

Ci_-4alkoxy and haloCi.

₄alkoxy; and

R⁶ is selected from -CF₃, -CHF₂ and -CH₂F.

In a further aspect, there is provided a compound of formula I as represented by formula (IA'), or a salt thereof, wherein

(IA')

R¹, R², R³, R⁴ and R⁶ are as defined for a compound of formula (IA).

In a further aspect, there is provided a compound of formula I as represented by (IA"), or a salt thereof, wherein

(IA")

R¹, R², R³, R⁴ and R⁶ are as defined for a compound of formula (IA).

In a further aspect, there is provided a compound of formula (IA), or a salt thereof wherein R², R³ and R⁴ are independently selected from hydrogen, halo, cyano and haloCi_₄alkyl. In a further aspect, R², R³ and R⁴ are independently selected from hydrogen, halo and cyano. In an even more particular aspect, R², R³ and R⁴ are independently selected from hydrogen and halo. In yet an even more particular aspect, R² is halo or hydrogen and R³ and R⁴ are hydrogen. In a most particular aspect, R² is fluoro or hydrogen and R³ and R⁴ are hydrogen, more particularly, R², R³ and R⁴ are hydrogen.

In a further aspect, there is provided a compound of formula (IA), or a salt thereof wherein R⁶ is CF₃.

In a further aspect, there is provided a compound of formula (IA), or a salt thereof 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, C_1-4alkyl, C_1-4alkoxy, cyano, hydroxy, hydroxy C_1-4alkyl, -(CH₂)_n-(NR^1aR^1b), - (CO)NR^1aR^1b, -(CO)O-C_1-4alkyl, -(CHO), haloC_1-4alkyl and haloC_1-4alkoxy.

In a further aspect, there is provided a compound of formula (IA), or a salt thereof 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, Ci_-4alkoxy, cyano, hydroxyl, hydroxy Ci_-4alkyl, -(CH₂)_n-(NR^1aR^1b), - (CO)NR^1aR^1b, -(CO)O-Ci.₄alkyl, -(CHO), haloC^alkyl and haloCi_-4alkoxy. In another particular aspect, there is provided a compound of formula (IA), or a salt thereof 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, C_1-4alkyl, C_1-4alkoxy, cyano, hydroxyl, hydroxy C_1-4alkyl, -(CH₂)_n-(NR^1aR^1b), -(CO)NR^1aR^1b, -(CO)O-C_1-4alkyl, -(CHO), haloC_1-4alkyl and haloC_1-4alkoxy. In a further aspect, R¹ is selected from

- furanyl which is unsubstituted or substituted with 1 substituent selected from C_1-4alkyl, - (CO)O-C_1-4alkyl, -(CHO) and haloC_1-4alkyl; - thiazolyl which is unsubstituted or substituted with 1 substituent selected from C_1-4alkyl;

- 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; and

- unsubstituted pyridazinyl.

In a further aspect, there is provided a compound of formula (IA), or a salt thereof wherein R¹ is selected from

- furanyl which is unsubstituted or substituted with 1 substituent selected from methyl, - (CO)O-CH₃, -(CHO) and trifluoromethyl;

- unsubstituted oxazolyl,

- unsubstituted pyrimidinyl;

- unsubstituted pyrazinyl; and

- unsubstituted pyridazinyl. In a further aspect, there is provided a compound of formula (IA), or a salt thereof wherein 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;

- 4-pyridyl which is unsubstituted or substituted with 1 or 2 substituents independently selected from fluoro, methyl, chloro and cyano.

In a further aspect, there is provided a compound of formula (IA), or a salt thereof 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, C_1-4alkyl, C_1-4alkoxy, cyano, hydroxyl, hydroxy C_1-4alkyl, -(CH₂)_n-(NR^1aR^1b), - (CO)NR^1aR^1b, -(CO)O-C_1-4alkyl, -(CHO), haloC_1-4alkyl and haloC_1-4alkoxy, R² is hydrogen or halo, in particular hydrogen, R³ is hydrogen and R⁴ is hydrogen or halo, in particular hydrogen, R⁶ is CF₃, CHF₂ or CH₂F, in particular CF₃.

In a further aspect, there is provided a compound of formula (IB), or a salt thereof 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, C_1-4alkyl, Ci_-4alkoxy, cyano, hydroxyl, hydroxy C_1-4alkyl, -(CH₂)_n-(NR^1aR^1b), - (C0)NR^1aR^1b, -(COp-C^alkyl, -(CHO), haloC^alkyl and haloCi_-4alkoxy, R² is hydrogen or halo, R³ is hydrogen, R⁴ is hydrogen or halo.

In a further aspect, there is provided a compound of formula (IA), or a salt thereof 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, C_1-4alkyl, C_1-4alkoxy, cyano, hydroxyl, hydroxy C_1-4alkyl, -(CH₂)_n-(NR^1aR^1b), -(C0)NR^1aR^1b, -(CO)O-C_1-4alkyl, -(CHO), halod. ₄alkyl and haloC_1-4alkoxy, R² is hydrogen or halo, in particular hydrogen, R³ is hydrogen and R⁴ is hydrogen or halo, in particular hydrogen, R⁶ is CF₃, CHF₂ or CH₂F, in particular CF₃.

In a further aspect, there is provided a compound of formula (IA), or a salt thereof 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, Ci_-4alkyl, Ci_-4alkoxy, cyano, hydroxyl, hydroxy C_1-4alkyl, -(CH₂)_n-(NR^1aR^1b), -(CO)NR^1aR^1b, -(COp-C^alkyl, -(CHO), haloCi. ₄alkyl and haloCi_-4alkoxy, R² is hydrogen or halo, in particular fluoro, R³ is hydrogen and R⁴ is hydrogen or halo, in particular fluoro. In a further aspect, there is provided a compound of formula (IA), or a salt thereof wherein R¹ is selected from

- furanyl which is unsubstituted or substituted with 1 substituent selected from Ci_-4alkyl, - (CO)O-C_1-4alkyl, -(CHO) and haloC_1-4alkyl;

- thiazolyl which is unsubstituted or substituted with 1 substituent selected from C_1-4alkyl; - thienyl which is unsubstituted or substituted with 1 substituent selected from -(CO)O-C_1-

₄alkyl,

- unsubstituted oxazolyl, - pyridyl which is unsubstituted or substituted with 1 or 2 substituents selected from halo, haloC_1-4alkyl, -(CO)O-C_1-4alkyl, C_1-4alkyl, C_1-4alkoxy and cyano;

- unsubstituted pyrimidinyl;

- unsubstituted pyrazinyl; and

- unsubstituted pyridazinyl;

R² is hydrogen or halo, in particular hydrogen, R³ is hydrogen and R⁴ is hydrogen or halo, in particular hydrogen, R⁶ is CF₃, CHF₂ or CH₂F, in particular CF₃.

- furanyl which is unsubstituted or substituted with 1 substituent selected from Ci_-4alkyl, - (CO)O-Ci-4alkyl, -(CHO) and haloC^alkyl;

- thiazolyl which is unsubstituted or substituted with 1 substituent selected from

- 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, haloC_1-4alkyl, -(CO)O-C_1-4alkyl, C_1-4alkyl, C_1-4alkoxy 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 a further aspect, there is provided a compound of formula (IA), or a salt thereof wherein R¹ is selected from

CH₃,

- unsubstituted oxazolyl,

- unsubstituted pyrazinyl; and

- unsubstituted pyridazinyl; R² is hydrogen or halo, in particular hydrogen, R³ is hydrogen, R⁴ is hydrogen or halo, in particular hydrogen, and R⁶ is CF₃, CHF₂ or CH₂F, in particular CF₃.

- unsubstituted oxazolyl,

- unsubstituted pyrimidinyl;

- unsubstituted pyrazinyl; and

- unsubstituted pyridazinyl;

R² is hydrogen or halo, in particular fluoro, R³ is hydrogen, R⁴ is hydrogen or halo, in particular fluoro and R⁶ is CF₃, CHF₂ or CH₂F, in particular CF₃. In a further aspect, there is provided a compound of formula (IA), or a salt thereof 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;

R² is hydrogen or halo, in particular hydrogen, R³ is hydrogen, R⁴ is hydrogen or halo, in particular hydrogen, and R⁶ is CF₃, CHF₂ or CH₂F, in particular CF₃.

- 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, R⁴ is hydrogen or halo, in particular fluoro, and R⁶ is CF₃, CHF₂ or CH₂F, in particular CF₃.

In a further aspect, there is provided a compound of formula (IB), or a salt thereof wherein R¹ is selected from

- furanyl which is unsubstituted or substituted with 1 substituent selected from C_1-4alkyl, - (CO)O-C_1-4alkyl, -(CHO) and haloC_1-4alkyl;

- unsubstituted oxazolyl,

- pyridyl which is unsubstituted or substituted with 1 or 2 substituents selected from halo, haloCi_₄alkyl, -(CO)O-Ci_-4alkyl, Ci_-4alkyl,

and cyano;

- unsubstituted pyrimidinyl;

- unsubstituted pyrazinyl; and

- unsubstituted pyridazinyl;

R², R³ and R⁴ are hydrogen, and R⁶ is CF₃, CHF₂ or CH₂F, in particular CF₃.

In a further aspect, there is provided a compound of formula (IA), or a salt thereof wherein, R¹ is selected from

- thienyl which is unsubstituted or substituted with 1 substituent selected from -(CO)O- CH₃, - unsubstituted oxazolyl,

- unsubstituted pyrimidinyl;

- unsubstituted pyrazinyl; and

- unsubstituted pyridazinyl;

In a further aspect, there is provided a compound of formula (IA), or a salt thereof 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, C_1-4alkyl, C_1- ₄alkoxy, cyano, hydroxyl, hydroxy C_1-4alkyl, -(CH₂)_n-(NR^1aR^1b), -(CO)NR^1aR^1b, -(CO)O-C_1- ₄alkyl, -(CHO), haloC_1-4alkyl and haloC_1-4alkoxy. In a further aspect, there is provided a compound of formula (IA), or a salt thereof 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, C_1-4alkyl, C_1-4alkoxy, cyano, hydroxyl, hydroxy C_1- ₄alkyl, -(CH₂)_n-(NR^1aR^1b), -(CO)NR^1aR^1b, -(CO)O-C_1-4alkyl, -(CHO), haloC_1-4alkyl and haloC_1-4alkoxy.

In a further aspect, there is provided a compound of formula (IA), or a salt thereof 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, C_1-4alkyl, C_1-4alkoxy, cyano, haloC_1-4alkyl and haloC_1-4alkoxy, particularly oxo and C_1-4alkyl, more particularly oxo and methyl. In a further aspect, there is provided a compound of formula (IA), or a salt thereof wherein 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, Ci_-4alkoxy, cyano, haloCi_-4alkyl and

particularly oxo and Ci_-4alkyl, more particularly oxo and methyl. In a further aspect, there is provided a compound of formula (IA), or a salt thereof 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, C_1-4alkyl, C_1-4alkoxy, cyano, haloC_1-4alkyl and haloC_1-4alkoxy, particularly oxo and C_1-4alkyl, more particularly oxo and methyl; R², R³ and R⁴ are hydrogen, and R⁶ is CF₃, CHF₂ or CH₂F, in particular CF₃.

In a further aspect, there is provided a compound of formula (IA), or a salt thereof 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, Ci_-4alkyl, Ci_-4alkoxy, cyano,

and haloCi_-4alkoxy, particularly oxo and Ci_-4alkyl more particularly oxo and methyl; R², R³ and R⁴ are hydrogen, and R⁶ is CF₃, CHF₂ or CH₂F, in particular CF₃.

In a further aspect, there is provided a compound of formula (IA), or a salt thereof 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, C_1-4alkyl, C_1-4alkoxy, cyano, haloC_1-4alkyl and haloC_1-4alkoxy, particularly oxo and C_1-4alkyl, more particularly oxo and methyl; R² is halo, in particular fluoro, R³ is hydrogen, R⁴ is hydrogen or halo, in particular fluoro, and R⁶ is CF₃, CHF₂ or CH₂F, in particular CF₃.

and haloCi_-4alkoxy, particularly oxo and Ci_-4alkyl more particularly oxo and methyl; R² is halo, in particular fluoro, R³ is hydrogen, R⁴ is hydrogen or halo, in particular fluoro, and R⁶ is CF₃, CHF₂ or CH₂F, in particular CF₃.

In a further aspect, there is provided a compound of formula (I) represented by formula (IB), or a pharmaceutically acceptable salt thereof, for use in therapy, wherein

(IB)

R¹ is selected from

Ci_-4alkoxy, cyano, hydroxy,

-(CH₂)_n-(NR^1aR^1b), -(CO)NR^1aR^1b, -(CO)O-C_1-4alkyl, -(CHO), haloC_1-4alkyl and haloC_1-4alkoxy;

n is 1 , 2, 3 or 4; R^1a and R^1b are independently selected from hydrogen, C_1-4alkyl and haloC_1-4alkyl;

₄alkoxy;

R³ is selected from hydrogen, halo, cyano and haloC_1-4alkyl;

₄alkoxy.

According to a further aspect, there is provided a compound of formula (IB), or a salt thereof, with the proviso that the compound of formula (IB) is not

Methyl 5-[(8-acetyl-2,2-difluoro-3-oxo-2,3-dihydro-4H-1 ,4-benzoxazin-4-yl)methyl]-2- furancarboxylate; and

8-acetyl-2,2-difluoro-4-(2-pyridinylmethyl)-2H-1 ,4-benzoxazin-3(4H)-one.

In a further aspect, the compound of formula (IB) is not 8-acetyl-2,2-difluoro-4-(2- pyridinylmethyl)-2H-1 ,4-benzoxazin-3(4H)-one. In a further aspect, there is provided a compound of formula (IB), or a salt thereof wherein R², R³ and R⁴ are independently selected from hydrogen, halo, cyano and haloC_1-4alkyl. In a more particular aspect, R², R³ and R⁴ are independently selected from hydrogen, halo and cyano. In an even more particular aspect, R², R³ and R⁴ are independently selected from hydrogen and halo. In yet an even more particular aspect, R² is halo and R³ and R⁴ are hydrogen. In a most particular aspect, R² is fluoro and R³ and R⁴ are hydrogen. In another aspect, R², R³ and R⁴ are hydrogen.

In a further aspect, there is provided a compound of formula (IB), or a salt thereof 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, C_1-4alkyl, Ci_-4alkoxy, cyano, hydroxyl, hydroxy C_1-4alkyl, -(CH₂)_n-(NR^1aR^1b), - (CO)NR^1aR^1b, -(CO)O-C_1-4alkyl, -(CHO), haloC_1-4alkyl and haloC_1-4alkoxy. In one particular aspect, there is provided a compound of formula (IB), or a salt thereof 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, C_1-4alkyl, C_1-4alkoxy, cyano, hydroxyl, hydroxy C_1-4alkyl, -(CH₂)_n-(NR^1aR^1b), - (CO)NR^1aR^1b, -(CO)O-C_1-4alkyl, -(CHO), haloC_1-4alkyl and haloC_1-4alkoxy. In a further aspect, there is provided a compound of formula (IB), or a salt thereof 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, Ci_-4alkyl, Ci_-4alkoxy, cyano, hydroxyl, hydroxy C_1-4alkyl, -(CH₂)_n-(NR^1aR^1b), -(CO)NR^1aR^1b, -(COp-C^alkyl, -(CHO), haloCi. ₄alkyl and haloCi_-4alkoxy. In a further aspect, R¹ is selected from

- furanyl which is unsubstituted or substituted with 1 substituent selected from Ci_-4alkyl, - (COp-C^alkyl, -(CHO) and haloCi_-4alkyl;

- unsubstituted oxazolyl,

- unsubstituted pyrimidinyl;

- unsubstituted pyrazinyl; and

- unsubstituted pyridazinyl.

In a further aspect, there is provided a compound of formula (IB), or a salt thereof wherein, R¹ is selected from

- unsubstituted oxazolyl,

- unsubstituted pyrimidinyl;

- unsubstituted pyrazinyl; and

- unsubstituted pyridazinyl. In a further aspect, there is provided a compound of formula (IB), or a salt thereof wherein, 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 a further aspect, there is provided a compound of formula (IB), or a salt thereof 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, Ci_-4alkoxy, cyano, hydroxyl, hydroxy Ci_-4alkyl, -(CH₂)_n-(NR^1aR^1b), - (C0)NR^1aR^1b, -(CO)O-C_1-4alkyl, -(CHO), haloC_1-4alkyl and haloC_1-4alkoxy, R² is hydrogen or halo, R³ is hydrogen and R⁴ is hydrogen or halo.

In a further aspect, there is provided a compound of formula (IB), or a salt thereof 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, C_1-4alkyl, C_1-4alkoxy, cyano, hydroxyl, hydroxy C_1-4alkyl, -(CH₂)_n-(NR^1aR^1b), -(CO)NR^1aR^1b, -(CO)O-C_1-4alkyl, -(CHO), halod.

₄alkyl and haloC_1-4alkoxy, R² is hydrogen or halo, in particular fluoro, R³ is hydrogen and

R⁴ is hydrogen or halo, in particular fluoro.

- unsubstituted oxazolyl,

- unsubstituted pyrimidinyl;

- unsubstituted pyrazinyl; and - unsubstituted pyridazinyl;

RR²² iiss hhyyddrrooggeenn oor halo, in particular fluoro, R³ is hydrogen and R⁴ is hydrogen or halo, in particular fluoro. In a further aspect, there is provided a compound of formula (IB), or a salt thereof wherein, R¹ is selected from

CH₃,

- unsubstituted oxazolyl,

- unsubstituted pyrazinyl; and

- unsubstituted pyridazinyl;

R² is hydrogen or halo, in particular fluoro, R³ is hydrogen, R⁴ is hydrogen or halo, in particular fluoro.

- thiazolyl which is unsubstituted or substituted with 1 substituent selected from C_1-4alkyl; - thienyl which is unsubstituted or substituted with 1 substituent selected from -(CO)O-C_1- ₄alkyl,

- unsubstituted oxazolyl,

- unsubstituted pyrimidinyl;

- unsubstituted pyrazinyl; and

- unsubstituted pyridazinyl;

R², R³ and R⁴ are hydrogen.

- unsubstituted oxazolyl,

- unsubstituted pyrimidinyl;

- unsubstituted pyrazinyl; and

- unsubstituted pyridazinyl;

R², R³ and R⁴ are hydrogen.

In a further aspect, there is provided a compound of formula (IB), or a salt thereof 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, C_1-4alkyl, C_1- ₄alkoxy, cyano, hydroxyl, hydroxy C_1-4alkyl, -(CH₂)_n-(NR^1aR^1b), -(CO)NR^1aR^1b, -(CO)O-C_1- ₄alkyl, -(CHO), haloC_1-4alkyl and haloC_1-4alkoxy. In a further aspect, there is provided a compound of formula (IB), or a salt thereof 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, C_1-4alkyl, C_1-4alkoxy, cyano, hydroxyl, hydroxy C_1- ₄alkyl, -(CH₂)_n-(NR^1aR^1b), -(CO)NR^1aR^1b, -(CO)O-C_1-4alkyl, -(CHO), haloC_1-4alkyl and haloC_1-4alkoxy.

In a further aspect, there is provided a compound of formula (IB), or a salt thereof 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, C_1-4alkyl, C_1-4alkoxy, cyano, haloC_1-4alkyl and haloC_1-4alkoxy, particularly oxo and C_1-4alkyl, more particularly oxo and methyl.

In a further aspect, there is provided a compound of formula (IB), or a salt thereof wherein, 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, C_1-4alkyl, C_1-4alkoxy, cyano, haloC_1-4alkyl and haloC_1-4alkoxy, particularly oxo and C_1-4alkyl, more particularly oxo and methyl.

In a further aspect, there is provided a compound of formula (IB), or a salt thereof 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, C_1-4alkyl, C_1-4alkoxy, cyano, haloC_1-4alkyl and haloC_1-4alkoxy, particularly oxo and C_1-4alkyl, more particularly oxo and methyl; R², R³ and R⁴ are hydrogen.

In a further aspect, there is provided a compound of formula (IB), or a salt thereof 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, Ci_-4alkyl, Ci_-4alkoxy, cyano,

and haloCi_-4alkoxy, particularly oxo and Ci_-4alkyl more particularly oxo and methyl; R², R³ and R⁴ are hydrogen.

In a further aspect, there is provided a compound of formula (IB), or a salt thereof 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, C_1-4alkyl, C_1-4alkoxy, cyano, haloC_1-4alkyl and haloC_1-4alkoxy, particularly oxo and C_1-4alkyl, more particularly oxo and methyl; R² is halo, in particular fluoro, R³ is hydrogen, R⁴ is hydrogen or halo, in particular fluoro.

and haloCi_-4alkoxy, particularly oxo and Ci_-4alkyl more particularly oxo and methyl; R² is halo, in particular fluoro, R³ is hydrogen, R⁴ is hydrogen or halo, in particular fluoro.

In a further aspect, there is provided a compound of formula (I) represented by formula (IC), or a pharmaceutically acceptable salt thereof, for use in therapy, wherein

(IC)

R¹ is phenyl which is unsubstituted or substituted with 1 to 3 substituents independently selected from halo,

Ci_-4alkoxy, cyano, hydroxy, hydroxyCi_-4alkyl, -(CH₂)_n- (NR^1aR^1b), -(CO)NR^1aR^1b, -(CO)O-Ci_-4alkyl, -(CO)OH, -(CHO), -S0₂(NR^1aR^1b), haloCi.

₄alkyl, haloCi_-4alkoxy, -(CO)Ci_-4alkyl, C_2-4alkenyl, -SCi_-4alkyl and 5 to 6 membered heteroaryl ring which contains 1 to 4 heteroatoms independently selected from O, N and

S;

n is 1 , 2, 3 or 4;

R² is selected from hydrogen, halo, cyano, Ci_-4alkyl,

Ci_-4alkoxy and haloCi.

₄alkoxy;

R³ is selected from hydrogen, halo, cyano and haloC_1-4alkyl;

R⁴ is selected from hydrogen, halo, cyano, C_1-4alkyl, haloC_1-4alkyl, C_1-4alkoxy and FIaIoC_1- ₄alkoxy, with the proviso that

when R¹ is phenyl which is monosubstituted in the para position relative to its attachment to the -CH₂- group, the substituent is other than -cyano, -CF₃, -NH₂, -CONH₂, -SO₂NH₂

Or -SO₂NHMe. In a further aspect, there is provided a compound of formula (I) represented by formula (ID), or a pharmaceutically acceptable salt thereof, for use in therapy, wherein

(ID) R¹ is phenyl which is unsubstituted or substituted with 1 to 3 substituents independently selected from halo, C_1-4alkyl, C_1-4alkoxy, cyano, hydroxy, hydroxyC_1-4alkyl, -(CH₂)_n-

(NR^1aR^1b), -(CO)NR^1aR^1b, -(CO)O-C_1-4alkyl, -(CO)OH, -(CHO), -S0₂(NR^1aR^1b), halod.

₄alkyl, haloC_1-4alkoxy, -(CO)C_1-4alkyl, C_2-4alkenyl, -SC_1-4alkyl and 5 to 6 membered heteroaryl ring which contains 1 to 4 heteroatoms independently selected from O, N and

S;

n is 1 , 2, 3 or 4;

R² is selected from hydrogen, halo, cyano, Ci_-4alkyl,

Ci_-4alkoxy and haloCi. ₄alkoxy;

R³ is selected from hydrogen, halo, cyano and haloCi_-4alkyl;

R⁴ is selected from hydrogen, halo, cyano, Ci_-4alkyl,

Ci_-4alkoxy and haloCi.

₄alkoxy, with the proviso that

(i) when R¹ is phenyl which is monosubstituted in the para position relative to its attachment to the -CH₂- group, the substituent is other than -cyano, -CF₃, -NH₂, -

CONH₂, -SO₂NH₂ Or -SO₂NHMe; and (ii) the compound of formula (IC) is not

8-acetyl-4-[(4-chlorophenyl)methyl]-2,2-difluoro-2H-1 ,4-benzoxazin-3(4H)-one;

8-acetyl-2,2-difluoro-4-[(4-methylphenyl)methyl]-2H-1 ,4-benzoxazin-3(4H)-one;

8-acetyl-2,2-difluoro-4-[(2-fluorophenyl)methyl]-2H-1 ,4-benzoxazin-3(4H)-one;

8-acetyl-2,2-difluoro-4-[(4-fluorophenyl)methyl]-2H-1 ,4-benzoxazin-3(4H)-one;

8-acetyl-2,2-difluoro-4-[(3-fluorophenyl)methyl]-2H-1 ,4-benzoxazin-3(4H)-one;

8-acetyl-2,2-difluoro-4-[(2-chlorophenyl)methyl]-2H-1 ,4-benzoxazin-3(4H)-one;

8-acetyl-2,2-difluoro-4-{[4-(methylthio)phenyl]methyl}-2H-1 ,4-benzoxazin-3(4H)-one. In a further aspect, there is provided a compound of formula (I) represented by formula (IE), or a pharmaceutically acceptable salt thereof, for use in therapy, wherein

(IE)

Ci_-4alkoxy, cyano, hydroxy, hydroxyCi_-4alkyl, -(CH₂)_n- (NR^1aR^1b), -(C0)NR^1aR^1b, -(CO)O-Ci_-4alkyl, -(CO)OH, -(CHO), -S0₂(NR^1aR^1b), haloCi.

S;

n is 1 , 2, 3 or 4;

R² is selected from hydrogen, halo, cyano, Ci_-4alkyl,

Ci_-4alkoxy and haloCi.

₄alkoxy;

R³ is selected from hydrogen, halo, cyano and haloC_1-4alkyl;

R⁴ is selected from hydrogen, halo, cyano, C_1-4alkyl, haloC_1-4alkyl, C_1-4alkoxy and FIaIoC_1- ₄alkoxy.

In a further aspect, the compound of formula (IE) is not 3-[(8-acetyl-2,2-difluoro-3-oxo- 2,3-dihydro-4H-1 ,4-benzoxazin-4-yl)methyl]-Λ/,Λ/-dimethylbenzamide and 2-[(8-acetyl- 2,2-difluoro-3-oxo-2,3-dihydro-4H-1 ,4-benzoxazin-4-yl)methyl]benzonitrile.

According to a further aspect, there is provided a compound of formula (IE), or a salt thereof, as defined above, with the proviso that the compound of formula (IE) is not 3-[(8-acetyl-2,2-difluoro-3-oxo-2,3-dihydro-4H-1 ,4-benzoxazin-4-yl)methyl]benzonitrile; 2-[(8-acetyl-2,2-difluoro-3-oxo-2,3-dihydro-4H-1 ,4-benzoxazin-4-yl)methyl]benzonitrile; 8-acetyl-4-{[5-acetyl-2-(methyloxy)phenyl]methyl}-2,2-difluoro-2H-1 ,4-benzoxazin-3(4H)- one;

8-acetyl-4-[(4-chlorophenyl)methyl]-2,2-difluoro-2H-1 ,4-benzoxazin-3(4H)-one;

8-acetyl-2,2-difluoro-4-[(4-methylphenyl)methyl]-2H-1 ,4-benzoxazin-3(4H)-one;

8-acetyl-2,2-difluoro-4-[(2-fluorophenyl)methyl]-2H-1 ,4-benzoxazin-3(4H)-one;

8-acetyl-2,2-difluoro-4-[(4-fluorophenyl)methyl]-2H-1 ,4-benzoxazin-3(4H)-one;

8-acetyl-2,2-difluoro-4-[(3-fluorophenyl)methyl]-2H-1 ,4-benzoxazin-3(4H)-one; 8-acetyl-2,2-difluoro-4-[(2-chlorophenyl)methyl]-2/-/-1 ,4-benzoxazin-3(4/-/)-one;

8-acetyl-4-[(4-ethenylphenyl)methyl]-2,2-difluoro-2/-/-1 ,4-benzoxazin-3(4/-/)-one; and 8-acetyl-2,2-difluoro-4-{[4-(methylthio)phenyl]methyl}-2/-/-1 ,4-benzoxazin-3(4/-/)-one. In a further aspect, there is provided a compound of formula (IE), or a salt thereof wherein, R², R³ and R⁴ are independently selected from hydrogen, halo, cyano and haloCi_-4alkyl. In a more particular aspect, R², R³ and R⁴ are independently selected from hydrogen, halo and cyano. In a further aspect, R², R³ and R⁴ are independently selected from hydrogen and halo. In yet further aspect, R² is halo and R³ and R⁴ are hydrogen. In a further aspect, R² is fluoro and R³ and R⁴ are hydrogen. In a further aspect, R², R³ and R⁴ are hydrogen.

In a further aspect, there is provided a compound of formula (IE), or a salt thereof wherein, R¹ is phenyl which is unsubstituted or substituted with 1 to 2 substituents independently selected from halo, C_1-4alkyl, C_1-4alkoxy, cyano, hydroxy, hydroxyC_1-4alkyl, -(CH₂)_n-(NR^1aR^1b), -(CO)NR^1aR^1b, -(CO)O-C_1-4alkyl, -(CO)OH, -(CHO), -SO₂(NR^1aR^1b), haloC_1-4alkyl, haloC_1-4alkoxy, -(CO)C_1-4alkyl, C_2-4alkenyl, -SC_1-4alkyl and 5 to 6 membered heteroaryl ring which contains 1 to 4 heteroatoms independently selected from O, N and S.

In a further aspect, there is provided a compound of formula (IE), or a salt thereof wherein, R¹ is phenyl which is unsubstituted or substituted with 1 to 2 substituents independently selected from halo, C_1-4alkyl, C_1-4alkoxy, cyano, hydroxy, hydroxyC_1-4alkyl, -(CH₂)_n-(NR^1aR^1b), -(CO)NR^1aR^1b, -(CO)O-Ci_-4alkyl, -(CO)OH, -(CHO), -S0₂(NR^1aR^1b), haloCi_₄alkyl, haloCi_-4alkoxy, -(CO)Ci_-4alkyl, C_2-4alkenyl, -SCi_-4alkyl and 5 to 6 membered heteroaryl ring which contains 1 to 4 heteroatoms independently selected from O, N and S; and wherein at least one substituent is attached to the 3-position relative to the bond attaching the phenyl to the rest of the molecule. In a further aspect, there is provided a compound of formula (IE), or a salt thereof wherein, R¹ is phenyl which is unsubstituted or substituted with 1 or 2 substituents independently selected from halo,

cyano, -S0₂(NR^1aR^1b), haloCi. ₄alkyl, haloC_1-4alkoxy, -(C0)NR^1aR^1b, -(CO)C_1-4alkyl, C_2-4alkenyl, -SC_1-4alkyl and 5 to 6 membered heteroaryl ring which contains 1 to 4 heteroatoms independently selected from O, N and S. In a further aspect, there is provided a compound of formula (IE), or a salt thereof wherein, R¹ is phenyl which is unsubstituted or substituted with 1 or 2 substituents independently selected from fluoro, chloro, cyano, methyl, methoxy, imidazolyl, ethenyl, - (CO)N(CH₃)₂, -(CO)(CH₃), -SCH₃ and -SO₂(NR^1aR^1b).

In a further aspect, there is provided a compound of formula (IE), or a salt thereof wherein, R¹ is phenyl which is unsubstituted or substituted with 1 or 2 substituents independently selected from fluoro, cyano, methyl and methoxy. In a further aspect, there is provided a compound of formula (IE), or a salt thereof wherein, R¹ is phenyl which is unsubstituted or substituted with 1 or 2 substituents independently selected from halo,

cyano, hydroxy, hydroxyCi_-4alkyl, -(CH₂)_n-(NR^1aR^1b), -(CO)NR^1aR^1b, -(CO)O-Ci_-4alkyl, -(CHO), -SO₂(NR^1aR^1b), haloC^alkyl, haloCi_₄alkoxy, -(CO)Ci_-4alkyl, C_2-4alkenyl,

and 5 to 6 membered heteroaryl ring which contains 1 to 4 heteroatoms independently selected from O, N and S; R², R³ and R⁴ are independently selected from hydrogen, halo, cyano and haloC_1-4alkyl.

In a further aspect, there is provided a compound of formula (IE), or a salt thereof wherein, R¹ is phenyl which is unsubstituted or substituted with 1 or 2 substituents independently selected from halo, C_1-4alkyl, C_1-4alkoxy, cyano, -SO₂(NR^1aR^1b), FIaIoC_1- ₄alkyl, haloC_1-4alkoxy, -(CO)C_1-4alkyl, C_2-4alkenyl, -SC_1-4alkyl and 5 to 6 membered heteroaryl ring which contains 1 to 4 heteroatoms independently selected from O, N and S; R², R³ and R⁴ are independently selected from hydrogen, halo and cyano. In a further aspect, there is provided a compound of formula (IE), or a salt thereof wherein, R¹ is phenyl which is unsubstituted or substituted with 1 or 2 substituents independently selected from fluoro, chloro, cyano, methyl, methoxy, imidazolyl, ethenyl, - (CO)N(CH₃)₂, -(CO)(CH₃), -SCH₃ and -S0₂(NR^1aR^1b); R², R³ and R⁴ are independently selected from hydrogen and halo.

In a further aspect, there is provided a compound of formula (IE), or a salt thereof wherein, 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.

Each of the aspects of the invention are independent unless stated otherwise. Nevertheless the skilled person will understand that all the permutations of the aspects herein described are within the scope of the invention. Thus it is to be understood that the present invention covers all combinations of suitable, convenient and exemplified aspects described herein. 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, Ci_-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.

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 haloC_1-4alkyl as used herein refers to a C_1-4alkyl group as defined herein substituted with one or more halo groups which halo groups may be the same or different,. Examples of haloC_1-4alkyl include, but are not limited to; -CF₃ .CF₂H or - CF₃CH₂.

The term haloC_1-4alkoxy as used herein refers to a C_1-4alkoxy group as defined herein substituted with one or more halo groups which halo groups may be the same or different, e.g. -0-CF₃ or difluoromethoxy.

The term -(CO)O-Ci_-4alkyl as used herein refers to a carboxylic acid ester group wherein Ci_-4alkyl is defined herein. Examples of

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 hydroxyC_1-4alkyl as used herein refers to a C_1-4alkyl group as defined herein substituted with one hydroxy group, e.g. -CH₂CH₂OH.

The term -(CO)NR^1aR^1b as used herein refers to an amide group wherein an amine group NR^1aR^1b is attached to a carbonyl group C=O. The term -SO₂(NR^1aR^1b) as used herein refers to a sulphonamide group wherein an amine group NR^1aR^1b 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 selected from oxygen, nitrogen or sulphur. Examples of 5-membered heteroaryl rings in this instance include 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.

In a further aspect, compounds of formula (I), or salts thereof, are selected from

4-[(5-Chloro-3-pyridinyl)methyl]-2,2-difluoro-8-(2,2,2-trifluoro-1-hydroxyethyl)-2H-1 ,4- benzoxazin-3(4H)-one (racemate);

6-{[2,2-Difluoro-3-oxo-8-(2,2,2-trifluoro-1-hydroxyethyl)-2,3-dihydro-4H-1 ,4-benzoxazin-4- yl]methyl}-2-pyridinecarbonitrile (racemate);

4-[(5-Chloro-3-pyridinyl)methyl]-2,2-difluoro-8-[(1 S)-2,2,2-trifluoro-1-hydroxyethyl]-2H- 1 ,4-benzoxazin-3(4H)-one;

4-[(5-chloro-3-pyridinyl)methyl]-2,2-difluoro-8-[(1 R)-2,2,2-trifluoro-1-hydroxyethyl]-2H-1 ,4- benzoxazin-3(4H)-one;

6-({2,2-Difluoro-3-oxo-8-[(1 S)-2,2,2-trifluoro-1-hydroxyethyl]-2,3-dihydro-4H-1 ,4- benzoxazin-4-yl}methyl)-2-pyridinecarbonitrile;

6-({2,2-difluoro-3-oxo-8-[(1 R)-2,2,2-trifluoro-1-hydroxyethyl]-2,3-dihydro-4H-1 ,4- benzoxazin-4-yl}methyl)-2-pyridinecarbonitrile;

2,2-difluoro-4-[(5-fluoro-3-pyridinyl)methyl]-8-(2,2,2-trifluoro-1-hydroxyethyl)-2H-1 ,4- benzoxazin-3(4H)-one;

4-{[2,2-difluoro-3-oxo-8-(2,2,2-trifluoro-1-hydroxyethyl)-2,3-dihydro-4H-1 ,4-benzoxazin-4- yl]methyl}-2-pyridinecarbonitrile;

2,2-difluoro-4-[(2-fluoro-4-pyridinyl)methyl]-8-(2,2,2-trifluoro-1-hydroxyethyl)-2H-1 ,4- benzoxazin-3(4H)-one;

4-[(5-chloro-3-pyridinyl)methyl]-8-(2,2-difluoro-1-hydroxyethyl)-2,2-difluoro-2H-1 ,4- benzoxazin-3(4H)-one;

4-[(5-chloro-3-pyridinyl)methyl]-2,2-difluoro-8-(2-fluoro-1-hydroxyethyl)-2H-1 ,4- benzoxazin-3(4H)-one;

2,2-difluoro-4-[(5-fluoro-3-pyridinyl)methyl]-8-[(1 R)-2,2,2-trifluoro-1-hydroxyethyl]-2H-1 ,4- benzoxazin-3(4H)-one;

2,2-difluoro-4-[(5-fluoro-3-pyridinyl)methyl]-8-[(1 S)-2,2,2-trifluoro-1-hydroxyethyl]-2H-1 ,4- benzoxazin-3(4H)-one;

4-({2,2-difluoro-3-oxo-8-[(1 R)-2,2,2-trifluoro-1-hydroxyethyl]-2,3-dihydro-4H-1 ,4- benzoxazin-4-yl}methyl)-2-pyridinecarbonitrile; 4-({2,2-difluoro-3-oxo-8-[(1 S)-2,2,2-trifluoro-1 -hydroxyethyl]-2,3-dihydro-4H-1 ,4- benzoxazin-4-yl}methyl)-2-pyridinecarbonitrile;

2_!2-difluoro-4-[(2-fluoro-4-pyridinyl)methyl]-8-[(1 R)-2_!2_!2-trifluoro-1-hydroxyethyl]-2H-1 _!4- benzoxazin-3(4H)-one;

2,2-difluoro-4-[(2-fluoro-4-pyridinyl)methyl]-8-[(1 S)-2,2,2-trifluoro-1 -hydroxyethyl]-2H-1 ,4- benzoxazin-3(4H)-one;

4-[(5-chloro-3-pyridinyl)methyl]-8-[(1 R)-2,2-difluoro-1 -hydroxyethyl]-2,2-difluoro-2H-1 ,4- benzoxazin-3(4H)-one;

4-[(5-chloro-3-pyridinyl)methyl]-8-[(1 S)-2_!2-difluoro-1-hydroxyethyl]-2_!2-difluoro-2H-1 _!4- benzoxazin-3(4H)-one;

4-({8-[(1 R)-2_!2-difluoro-1-hydroxyethyl]-2,2-difluoro-3-oxo-2_!3-dihydro-4H-1 ,4- benzoxazin-4-yl}methyl)-2-pyridinecarbonitrile;

4-({8-[(1 S)-2,2-difluoro-1-hydroxyethyl]-2_!2-difluoro-3-oxo-2_!3-dihydro-4H-1 ,4- benzoxazin-4-yl}methyl)-2-pyridinecarbonitrile;

4-[(5-chloro-3-pyridinyl)methyl]-2_!2-difluoro-8-[(1 R)-2-fluoro-1-hydroxyethyl]-2H-1 _!4- benzoxazin-3(4H)-one;

4-[(5-chloro-3-pyridinyl)methyl]-2_!2-difluoro-8-[(1 S)-2-fluoro-1-hydroxyethyl]-2H-1 _!4- benzoxazin-3(4H)-one;

4-({2,2-difluoro-8-[(1 R)-2-fluoro-1 -hydroxyethyl]-3-oxo-2,3-dihydro-4H-1 ,4-benzoxazin-4- yl}methyl)-2-pyridinecarbonitrile;

4-({2_!2-difluoro-8-[(1 S)-2-fluoro-1-hydroxyethyl]-3-oxo-2_!3-dihydro-4H-1 _!4-benzoxazin-4- yl}methyl)-2-pyridinecarbonitrile;

8-Acetyl-2,2-difluoro-4-(3-pyridinylmethyl)-2H-1 ,4-benzoxazin-3(4H)-one; and

8-Acetyl-2_!2-difluoro-4-[(5-fluoro-3-pyridinyl)methyl]-2H-1 _!4-benzoxazin-3(4/-/)-one.

In a further aspect, there is provided a compound of formula (IA) as defined above, or salts thereof, wherein the compound is selected from

4-[(5-Chloro-3-pyridinyl)methyl]-2,2-difluoro-8-[(1 S)-2,2,2-trifluoro-1-hydroxyethyl]-2H-

1 ,4-benzoxazin-3(4H)-one;

4-[(5-chloro-3-pyridinyl)methyl]-2,2-difluoro-8-[(1R)-2,2,2-trifluoro-1-hydroxyethyl]-2H-1 ,4- benzoxazin-3(4H)-one;

6-({2,2-Difluoro-3-oxo-8-[(1 S)-2,2,2-trifluoro-1-hydroxyethyl]-2,3-dihydro-4H-1 ,4- benzoxazin-4-yl}methyl)-2-pyridinecarbonitrile; 6-({2_!2-difluoro-3-oxo-8-[(1 R)-2_!2_!2-trifluoro-1-hydroxyethyl]-2_!3-dihydro-4H-1 ,4- benzoxazin-4-yl}methyl)-2-pyridinecarbonitrile;

2_!2-difluoro-4-[(5-fluoro-3-pyridinyl)methyl]-8-(2_!2_!2-trifluoro-1-hydroxyethyl)-2H-1 _!4- benzoxazin-3(4H)-one;

4-{[2_!2-difluoro-3-oxo-8-(2_!2_!2-trifluoro-1-hydroxyethyl)-2_!3-dihydro-4H-1 _!4-benzoxazin-4- yl]methyl}-2-pyridinecarbonitrile;

2_!2-difluoro-4-[(2-fluoro-4-pyridinyl)methyl]-8-(2_!2_!2-trifluoro-1-hydroxyethyl)-2H-1 _!4- benzoxazin-3(4H)-one;

4-[(5-chloro-3-pyridinyl)methyl]-8-(2_!2-difluoro-1-hydroxyethyl)-2_!2-difluoro-2H-1 _!4- benzoxazin-3(4H)-one;

4-[(5-chloro-3-pyridinyl)methyl]-2_!2-difluoro-8-(2-fluoro-1-hydroxyethyl)-2H-1 _!4- benzoxazin-3(4H)-one;

2_!2-difluoro-4-[(5-fluoro-3-pyridinyl)methyl]-8-[(1R)-2_!2_!2-trifluoro-1-hydroxyethyl]-2H-1 _!4- benzoxazin-3(4H)-one;

2,2-difluoro-4-[(5-fluoro-3-pyridinyl)methyl]-8-[(1 S)-2,2,2-trifluoro-1 -hydroxyethyl]-2H-1 ,4- benzoxazin-3(4H)-one;

4-({2_!2-difluoro-3-oxo-8-[(1 R)-2_!2_!2-trifluoro-1-hydroxyethyl]-2_!3-dihydro-4H-1 ,4- benzoxazin-4-yl}methyl)-2-pyridinecarbonitrile;

4-({2,2-difluoro-3-oxo-8-[(1 S)-2,2,2-trifluoro-1 -hydroxyethyl]-2,3-dihydro-4H-1 ,4- benzoxazin-4-yl}methyl)-2-pyridinecarbonitrile;

2_!2-difluoro-4-[(2-fluoro-4-pyridinyl)methyl]-8-[(1 S)-2_!2_!2-trifluoro-1-hydroxyethyl]-2H-1 _!4- benzoxazin-3(4H)-one;

4-({8-[(1 R)-2_!2-difluoro-1-hydroxyethyl]-2_!2-difluoro-3-oxo-2_!3-dihydro-4H-1 _!4- benzoxazin-4-yl}methyl)-2-pyridinecarbonitrile;

4-[(5-chloro-3-pyridinyl)methyl]-2,2-difluoro-8-[(1 S)-2-fluoro-1-hydroxyethyl]-2H-1 ,4- benzoxazin-3(4H)-one; 4-({2,2-difluoro-8-[(1 R)-2-fluoro-1 -hydroxyethyl]-3-oxo-2,3-dihydro-4H-1 ,4-benzoxazin-4- yl}methyl)-2-pyridinecarbonitrile; and

4-({2_!2-difluoro-8-[(1 S)-2-fluoro-1-hydroxyethyl]-3-oxo-2_!3-dihydro-4H-1 _!4-benzoxazin-4- yl}methyl)-2-pyridinecarbonitrile.

1 ,4-benzoxazin-3(4H)-one;

6-({2,2-Difluoro-3-oxo-8-[(1 S)-2,2,2-trifluoro-1-hydroxyethyl]-2,3-dihydro-4H-1 ,4- benzoxazin-4-yl}methyl)-2-pyridinecarbonitrile; and

or a salt thereof.

In a further aspect, there is provided a compound of formula (IB), or a salt thereof wherein the compound is selected from

8-Acetyl-2,2-difluoro-4-(3-pyridinylmethyl)-2H-1 ,4-benzoxazin-3(4H)-one; and

8-Acetyl-2,2-difluoro-4-[(5-fluoro-3-pyridinyl)methyl]-2H-1 ,4-benzoxazin-3(4H)-one.

Certain compounds as defined in the above aspects may in some circumstances form acid addition salts thereof. It will be appreciated that for use in medicine compounds as defined above 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 above, 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 third aspect which are pharmacologically active. Such derivatives may therefore be described as "prodrugs". All protected derivatives and prodrugs of compounds defined above 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 and second aspects. Therefore, in a further aspect, the invention provides a prodrug of a compound as defined above.

It will be appreciated that certain compounds as defined above, 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 above, 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 above are capable of existing in stereoisomeric forms (e.g. diastereomers and enantiomers) and the invention extends to each of these stereoisomeric forms and to mixtures thereof including racemates. The different stereoisomeric forms may be separated one from the other by the usual methods, or any given isomer may be obtained by stereospecific or asymmetric synthesis. The invention also extends to any tautomeric forms and mixtures thereof.

Certain compounds as defined above may also exhibit tautomerism within the R¹ moiety, and the present invention includes each such tautomer. An example of a compound as defined above which exhibits tautomerism is

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 third aspect, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number most commonly found in nature. Examples of isotopes that can be incorporated into compounds as defined in the first to third aspect include isotopes of hydrogen, carbon, nitrogen, fluorine, such as ³H, ¹¹C, ¹⁴C and ¹⁸F.

Compounds as defined above 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 above 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 above 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 above may be prepared in accordance with the following Scheme 1. Scheme 1

wherein R¹, R², R³, R⁴ and R⁶ are as defined above, R⁷ is chloro, iodo or bromo, for example bromo, or when R⁷ is hydrogen, R² is fluoro, and L is a suitable leaving group such as halogen or methanesulfonate, for example bromo. 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 or bromo(difluoro)acetyl chloride, in a suitable solvent, for example Λ/,Λ/-dimethylformamide, in the presence of a suitable base, for example sodium hydride. In another alternative method, compounds of formula (V) can be prepared from compounds of formula (IV) where R⁷ = chloro, bromo or iodo, for example bromo, by treating compounds of formula (IV) with an organolithium compound, for example n- butyllithium, and reacting the product with an appropriate electrophile, for example ethyl trifluoroacetate, ethyl difluoroacetate, ethyl fluoroacetate or 2,2,2-trifluoro-Λ/-methyl-/V- (methyloxy)acetamide, at a suitable temperature, for example -78 ⁰C, in a suitable solvent, for example diethyl ether, tetrahydrofuran or methyl te/f-butyl ether.

In step (iv), compounds of formula (Vl), wherein R⁶ may be -CH₃ or -CH₂, -CHF₂ or - CF₃, may be prepared from compounds of formula (V) by treating compounds of formula (V) with an organolithium compound, for example n-butyllithium, and reacting the product with an appropriate electrophile, for example ethyl trifluoracetate, ethyl difluoroacetate or ethyl fluoroacetate, in a suitable solvent and at a suitable temperature, for example diethyl ether at -78 ⁰C. Alternatively, compounds of formula (Vl) may be prepared by treating compounds of formula (V) with a suitable reducing agent, for example sodium triacetoxyborohydride or a combination of (3aS)-1-methyl-3,3-diphenyltetrahydro-3H- pyrrolo[1 ,2-c][1 ,3,2]oxazaborole with borane-tetrahydrofuran complex, in a suitable solvent, for example 1 ,2-dichloroethane or tetrahydrofuran, at a suitable temperature, for example room temperature.

In step (iv)a, compounds of formula (VII) wherein R⁶ is -CH₂F, -CHF₂ or -CF₃, may be prepared by treating compounds of formula (Vl) with a suitable reducing agent, for example sodium triacetoxyborohydride, in a suitable solvent, for example 1 ,2- dichloroethane, at a suitable temperature, for example room temperature.

In step (v), compounds of formula (I), wherein R⁶ may be -CH₃ or -CH₂, -CHF₂ or -CF₃, may be prepared by reacting compounds of formula (Vl) or formula (VII) with compounds of formula (VIII), in a suitable solvent, for example Λ/,Λ/-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 (VIII) may 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

(IX) (X) (Villa)

wherein R¹ is as defined in the first aspect, and A is hydrogen or

In step (i), compounds of formula (X) can be prepared by treating compounds of formula (IX) with a suitable reducing agent, for example borane or sodium borohydride, in a suitable solvent, for example tetrahydrofuran or methanol. Alternatively they may be commercially available.

In step (ii), compounds of formula (Villa) may be prepared by treating compounds of formula (X) with a suitable brominating agent, for example concentrated hydrobromic acid at a suitable temperature, for example reflux, or phosphorus tribromide or bromo(trimethyl)silane in a suitable solvent, for example chloroform or diethyl ether.

Scheme 3

R¹^ R¹^ ^Br

(Xl) (Villa)

wherein R¹ is as defined in the first aspect.

Compounds of formula (Villa) may be prepared by reacting compounds of formula (Xl) with a suitable brominating agent, such as N-bromosuccinimide, in the presence of suitable radical initiators, such as 2,2'-azobis(2-methylpropionitrile) or dibenzoyl peroxide, in a suitable solvent, such as carbon tetrachloride. Compounds of formula (Xl) are commercially available.

Scheme 4

R¹^OH *^■ R¹^OMs

(X) (VIIIb)

wherein R¹ is as defined in the first aspect.

Compounds of formula (VIIIb) may be prepared by treating compounds of formula (X) with a suitable mesylating agent, for example methanesulfonyl chloride or

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 (X) may be prepared as described in scheme 2 or may be commercially available. Compounds as defined above wherein R⁵ is -C(OH)R⁶ and R⁶ is CF₃ may also be prepared in accordance with the following Scheme 5.

Scheme 5

wherein R¹, R², R³ and R⁴ are as defined in the first aspect, R⁷ is chloro, iodo or bromo, for example bromo, and L is a suitable leaving group such as halogen, for example bromo or chloro, or methanesulfonate.

In step (i), compounds of formula (XII) may be prepared from compounds of formula (V) by treating compounds of formula (V) with an organolithium compound, for example n- butyllithium, and reacting the product with an appropriate electrophile, for example N, N- dimethylformamide, at a suitable temperature, for example -78 ⁰C, in a suitable solvent, for example diethyl ether.

In step (ii), compounds of formula (Vila) may be prepared from compounds of formula (XII) by treating compounds of formula (XII) with a suitable source of trifluoromethyl anion, for example trimethyl(trifluoromethyl)silane in the presence of cesium fluoride, in a suitable solvent, for example tetrahydrofuran, at a suitable temperature, for example room temperature.

In step (iii), compounds of formula (Ia) may be prepared by reacting compounds of formula (Vila) with compounds of formula (VIII), in a suitable solvent, for example N, N- dimethylformamide, in the presence of a suitable base, for example potassium carbonate.

The compounds as defined above inhibit the GIyTI transporter. Such compounds are therefore of potential utility for the treatment or prophylaxis of certain neurological and neuropsychiatric disorders. Furthermore, the compounds as defined above selectively inhibit the GIyTI transporter over the GlyT2 transporter.

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 aspect, the disorder is schizophrenia.

In one aspect, the disorder mediated by GIyTI to be treated is posttraumatic stress disorder.

In one aspect, 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, 4^th Edition, published by the American Psychiatric Association (DSM-IV) and/or the International Classification of Diseases, 10^th Edition (ICD-10). Treatment or prophylaxis of the various subtypes of the disorders mentioned herein using the compounds as defined above 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 of formula (I) as defined above be of use in the treatment 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 of formula (I) as defined above may be also of use in the treatment of mood disorders including Major Depressive Episode, Manic Episode, Mixed Episode and Hypomanic Episode; Depressive Disorders including Major Depressive Disorder, Dysthymic Disorder (300.4), Depressive Disorder Not Otherwise Specified (311 ); Bipolar Disorders including Bipolar I Disorder, Bipolar Il Disorder (Recurrent Major Depressive Episodes with Hypomanic Episodes) (296.89), Cyclothymic Disorder (301.13) and Bipolar Disorder Not Otherwise Specified (296.80); Other Mood Disorders including Mood Disorder Due to a General Medical Condition (293.83) which includes the subtypes With Depressive Features, With Major Depressive-like Episode, With Manic Features and With Mixed Features), Substance-Induced Mood Disorder (including the subtypes With Depressive Features, With Manic Features and With Mixed Features) and Mood Disorder Not Otherwise Specified (296.90). The compounds of formula (I) as defined above may also be of use in the treatment of anxiety disorders including Panic Attack, Agoraphobia, Panic Disorder, Agoraphobia Without History of Panic Disorder (300.22), Specific Phobia (300.29) including the subtypes Animal Type, Natural Environment Type, Blood-lnjection-lnjury Type,

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 of formula (I) as defined above may also be of use in the treatment of substance-related disorders including Substance Use Disorders such as Substance Dependence and Substance Abuse; Substance-Induced Disorders such as Substance Intoxication, Substance Withdrawal, Substance-Induced Delirium, Substance-Induced Persisting Dementia, Substance-Induced Persisting Amnestic Disorder, Substance- Induced Psychotic Disorder, Substance-Induced Mood Disorder, Substance-Induced Anxiety Disorder, Substance-Induced Sexual Dysfunction, Substance-Induced Sleep Disorder and Hallucinogen Persisting Perception Disorder (Flashbacks); Alcohol-Related Disorders such as Alcohol Dependence (303.90), Alcohol Abuse (305.00), Alcohol Intoxication (303.00), Alcohol Withdrawal (291.81 ), Alcohol Intoxication Delirium, Alcohol Withdrawal Delirium, Alcohol-Induced Persisting Dementia, Alcohol-Induced Persisting 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 of formula (I) as defined above may also be of use in the treatment of sleep disorders including primary sleep disorders such as Dyssomnias such as Primary Insomnia (307.42), Primary Hypersomnia (307.44), Narcolepsy (347), Breathing-Related Sleep Disorders (780.59), Circadian Rhythm Sleep Disorder (307.45) and Dyssomnia Not Otherwise Specified (307.47); primary sleep disorders such as Parasomnias such as Nightmare Disorder (307.47), Sleep Terror Disorder (307.46), Sleepwalking Disorder (307.46) and Parasomnia Not Otherwise Specified (307.47); Sleep Disorders Related to Another Mental Disorder such as Insomnia Related to Another Mental Disorder (307.42) and Hypersomnia Related to Another Mental Disorder (307.44); Sleep Disorder Due to a General Medical Condition; and Substance-Induced Sleep Disorder including the subtypes Insomnia Type, Hypersomnia Type, Parasomnia Type and Mixed Type.

The compounds of formula (I) as defined above may also be of use in the treatment of eating disorders such as Anorexia Nervosa (307.1 ) including the subtypes Restricting Type and Binge-Eating/Purging Type; Bulimia Nervosa (307.51 ) including the subtypes Purging Type and Nonpurging Type; Obesity; Compulsive Eating Disorder; and Eating Disorder Not Otherwise Specified (307.50).

The compounds of formula (I) as defined above may also be of use in the treatment of Autistic Disorder (299.00); Attention-Deficit /Hyperactivity Disorder including the subtypes Attention-Deficit /Hyperactivity Disorder Combined Type (314.01 ), Attention-Deficit /Hyperactivity Disorder Predominantly Inattentive Type (314.00), Attention-Deficit /Hyperactivity Disorder Hyperactive-Impulse Type (314.01 ) and Attention-Deficit

/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 of formula (I) as defined above may also be of use in the treatment of Personality Disorders including the subtypes Paranoid Personality Disorder (301.0), Schizoid Personality Disorder (301.20), Schizotypal Personality Disorder (301 ,22), Antisocial Personality Disorder (301.7), Borderline Personality Disorder (301 ,83), Histrionic Personality Disorder (301.50), Narcissistic Personality Disorder (301 ,81 ), Avoidant Personality Disorder (301.82), Dependent Personality Disorder (301.6), Obsessive-Compulsive Personality Disorder (301.4) and Personality Disorder Not Otherwise Specified (301.9). The compounds of formula (I) as defined above may also be of use in the treatment of cognitive impairment. 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 Multiinfarct dementia, alcoholic dementia, hypotiroidism-related dementia, and dementia associated to other degenerative disorders such as cerebellar atrophy and amyotropic lateral sclerosis; other acute or sub-acute conditions that may cause cognitive decline such as delirium or depression

(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 of formula (I) as defined above may also be of use for the treatment of cognition impairment which arises in association or as a result of other diseases such as schizophrenia, bipolar disorder, depression, other psychiatric disorders and psychotic conditions associated with cognitive impairment.

The compounds of formula (I) as defined above may also be of use in the treatment of sexual dysfunctions including Sexual Desire Disorders such as Hypoactive Sexual Desire Disorder (302.71 ), and Sexual Aversion Disorder (302.79); sexual arousal disorders such as Female Sexual Arousal Disorder (302.72) and Male Erectile Disorder (302.72);

orgasmic disorders such as Female Orgasmic Disorder (302.73), Male Orgasmic

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 of formula (I) as defined above may also be of use as anticonvulsants. The compounds of formula (I) as defined above are thus useful in the treatment of convulsions in mammals, and particularly epilepsy in humans. "Epilepsy" is intended to include the following seizures: simple partial seizures, complex partial seizures, secondary generalised seizures, generalised seizures including absence seizures, myoclonic seizures, clonic seizures, tonic seizures, tonic clonic seizures and atonic seizures. The invention also provides a method of treating convulsions, which comprises administering to a mammal in need thereof an effective amount of a compound of the invention as hereinbefore described or a salt thereof. Treatment of epilepsy may be carried out by the administration of a non-toxic anticonvulsant effective amount of a compound of the formula (I) or a salt thereof.

The compounds of formula (I) as defined above may also be useful in the treatment of pain, including acute pain, chronic pain, chronic articular pain, musculoskeletal pain, neuropathic pain, inflammatory pain, visceral pain, pain associated with cancer, pain associated with migraine, tension headache and cluster headaches, pain associated with functional bowel disorders, lower back and neck pain, pain associated with sprains and strains, sympathetically maintained pain; myositis, pain associated with influenza or other viral infections such as the common cold, pain associated with rheumatic fever, pain associated with myocardial ischemia, post operative pain, cancer chemotherapy, headache, toothache and dysmenorrhea.

'Chronic articular pain' conditions include rheumatoid arthritis, osteoarthritis, rheumatoid spondylitis, gouty arthritis and juvenile arthritis.

'Pain associated with functional bowel disorders' includes non-ulcer dyspepsia, non- cardiac chest pain and irritable bowel syndrome.

'Neuropathic pain' syndromes include: diabetic neuropathy, sciatica, non-specific lower back pain, trigeminal neuralgia, multiple sclerosis pain, fibromyalgia, HIV-related neuropathy, post-herpetic neuralgia, trigeminal neuralgia, and pain resulting from physical trauma, amputation, phantom limb syndrome, spinal surgery, cancer, toxins or chronic inflammatory conditions. 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 of formula (I) as defined above 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 of formula (I) as defined above 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 of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, for use in therapy.

In one aspect, there is provided a compound of formula (I) as defined above, 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 of a disorder mediated by GIyTI , which method comprises the administration of a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof. In a further aspect, there is provided the use of a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of a disorder mediated by GIyTI . In one aspect, 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 a further aspect, the disorder is schizophrenia.

In order to use a compound of formula (I) as defined above or a pharmaceutically acceptable salt thereof for the treatment 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 of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, adapted for use in human or veterinary medicine.

In order to use compounds of formula (I) as defined above 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 of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable excipient.

A pharmaceutical composition of the invention is usually adapted for oral, sub-lingual, buccal, parenteral (for example, subcutaneous, intramuscular, or intravenous), rectal, topical and intranasal administration and in forms suitable for administration by inhalation or insufflation (either through the mouth or nose). 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, sublingual, parenteral, buccal, rectal, intranasal or topical administration to a human (of approximately 70 kg bodyweight) for the treatment of neurological and neuropsychiatric disorders mediated by a GIyTI inhibitor, including schizophrenia, may be about 0.1 to about 1000 mg, for example about 0.5 mg to about 1000mg, or about 1 mg to about 1000 mg, or about 5 mg to about 500 mg, or about 10 mg to about 100 mg of the active ingredient per unit dose, which could be administered, for example, 1 to 4 times per day.

The composition may contain from 0.1% to 99% by weight, preferably from 10% to 60% by weight, of the active material, depending on the method of administration. The dose of the compound of formula (I) as defined above or a pharmaceutically acceptable salt thereof used in the treatment or prophylaxis of the aforementioned disorders will vary in the usual way with the seriousness of the disorders, the weight of the sufferer, and other similar factors. 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 third aspect or a pharmaceutically acceptable salt thereof, and 0 to 3 g more suitably 0 to 2g of at least one pharmaceutically acceptable carrier.

In a further aspect, a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, may be suitable for combination with other active ingredients.

When a compound of formula (I) as defined above 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 of formula (I) as defined above may be used in combination with the following agents to treat or prevent psychotic disorders: i) antipsychotics; ii) drugs for extrapyramidal side effects, for example anticholinergics (such as benztropine, biperiden, procyclidine and trihexyphenidyl), antihistamines (such as diphenhydramine) and dopaminergics (such as amantadine); iii) antidepressants; iv) anxiolytics; and v) cognitive enhancers for example cholinesterase inhibitors (such as tacrine, donepezil, rivastigmine and galantamine). The compounds of formula (I) as defined above may be used in combination with antidepressants to treat or prevent depression and mood disorders.

The compounds of formula (I) as defined above may be used in combination with the following agents to treat or prevent bipolar disease: i) mood stabilisers; ii) antipsychotics; and iii) antidepressants.

The compounds of formula (I) as defined above may be used in combination with the following agents to treat or prevent anxiety disorders: i) anxiolytics; and ii) antidepressants.

The compounds of formula (I) as defined above may be used in combination with the following agents to improve nicotine withdrawal and reduce nicotine craving: i) nicotine replacement therapy for example a sublingual formulation of nicotine beta-cyclodextrin and nicotine patches; and ii) bupropion.

The compounds of formula (I) as defined above 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 of formula (I) as defined above may be used in combination with the following agents to improve opiate withdrawal and reduce opiate craving: i) opioid mu receptor agonist/opioid kappa receptor antagonist for example buprenorphine; ii) opioid receptor antagonists for example naltrexone; and iii) vasodilatory antihypertensives for example lofexidine.

The compounds of formula (I) as defined above may be used in combination with the following agents to treat or prevent sleeping disorders: i) benzodiazepines for example temazepam, lormetazepam, estazolam and triazolam; ii) non-benzodiazepine hypnotics for example Zolpidem, zopiclone, zaleplon and indiplon; iii) barbiturates for example aprobarbital, butabarbital, pentobarbital, secobarbita and phenobarbital; iv) antidepressants; v) other sedative-hypnotics for example chloral hydrate and chlormethiazole.

The compounds of formula (I) as defined above may be used in combination with the following agents to treat anorexia: i) appetite stimulants for example cyproheptidine; ii) antidepressants; iii) antipsychotics; iv) zinc; and v) premenstral agents for example pyridoxine and progesterones.

The compounds of formula (I) as defined above may be used in combination with the following agents to treat or prevent bulimia: i) antidepressants; ii) opioid receptor antagonists; iii) antiemetics for example ondansetron; iv) testosterone receptor antagonists for example flutamide; v) mood stabilisers; vi) zinc; and vii) premenstral agents. The compounds of formula (I) as defined above may be used in combination with the following agents to treat or prevent autism: i) antipsychotics; ii) antidepressants; iii) anxiolytics; and iv) stimulants for example methylphenidate, amphetamine formulations and pemoline. The compounds of formula (I) as defined above may be used in combination with the following agents to treat or prevent ADHD: i) stimulants for example methylphenidate, amphetamine formulations and pemoline; and ii) non-stimulants for example norepinephrine reuptake inhibitors (such as atomoxetine), alpha 2 adrenoceptor agonists (such as clonidine), antidepressants, modafinil, and cholinesterase inhibitors (such as galantamine and donezepil).

The compounds of formula (I) as defined above may be used in combination with the following agents to treat personality disorders: i) antipsychotics; ii) antidepressants; iii) mood stabilisers; and iv) anxiolytics.

The compounds of formula (I) as defined above may be used in combination with the following agents to treat or prevent male sexual dysfunction: i) phosphodiesterase V inhibitors, for example vardenafil and sildenafil; ii) dopamine agonists/dopamine transport inhibitors for example apomorphine and buproprion; iii) alpha adrenoceptor antagonists for example phentolamine; iv) prostaglandin agonists for example alprostadil; v) testosterone agonists such as testosterone; vi) serotonin transport inhibitors for example serotonin reuptake inhibitors; v) noradrenaline transport inhibitors for example reboxetine and vii) 5-HT1 A agonists, for example flibanserine. The compounds of formula (I) as defined above 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 third aspect include, but are not limited to: butyrophenones, such as haloperidol, pimozide, and droperidol; phenothiazines, such as chlorpromazine, thioridazine, mesoridazine, trifluoperazine, perphenazine, fluphenazine, thiflupromazine, prochlorperazine, and acetophenazine; thioxanthenes, such as thiothixene and chlorprothixene ; thienobenzodiazepines; dibenzodiazepines; benzisoxazoles; dibenzothiazepines; imidazolidinones ; 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 of formula (I) as defined above may be used in conjunction with one or more other therapeutic agents, for instance, antidepressant agents such as 5HT3 antagonists, serotonin agonists, NK1 antagonists, NK3 antagonists, AMPA modulators, alpha7 positive modulators, 5HT6 antagonists, 5HT2A antagonists, selective serotonin reuptake inhibitors (SSRI), noradrenaline re-uptake inhibitors (SNRI), tricyclic antidepressants, dopaminergic antidepressants, H3 antagonists, 5HT1A antagonists, 5HT1 B antagonists, 5HT1 D antagonists, D1 agonists, M1 and M1/4 muscarinic agonists and/or anticonvulsant agents, as well as cognitive enhancers. When used in the treatment of pain, the compound of formula (I) as defined above or a pharmaceutically acceptable salt thereof may be used in combination with other medicaments indicated to be useful in the treatment of pain of neuropathic origin including neuralgias, neuritis and back pain, and inflammatory pain including osteoarthritis, rheumatoid arthritis, acute inflammatory pain, back pain and migraine. Such therapeutic agents include for Compound COX-2 (cyclooxygenase-2 ) inhibitors, such as celecoxib, deracoxib, rofecoxib, valdecoxib, parecoxib, COX-189 or 2-(4-ethoxy- phenyl)-3-(4-methanesulfonyl-phenyl)-pyrazolo[1 ,5-b]pyridazine (WO99/012930); 5- lipoxygenase inhibitors; NSAIDs (non-steroidal anti-inflammatory drugs) such as diclofenac, indomethacin, nabumetone or ibuprofen; bisphosphonates, leukotriene receptor antagonists; DMARDs (disease modifying anti-rheumatic drugs) such as methotrexate; adenosine A1 receptor agonists; sodium channel blockers, such as lamotrigine; NMDA (N-methyl-D-aspartate) 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, P2X_2/3, P2X₄, P2X₇ or P2X_4/7; 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 of Alzheimer's disease, the compound of formula (I) as defined above or a pharmaceutically acceptable salt thereof may be used in combination with other medicaments indicated to be useful as either disease modifying or

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.

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

Supporting Compounds

The preparation of a number of supporting compounds of formula (I) as defined above 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

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

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

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-3-oxo-3,4-dihydro-2H-1 ,4-benzoxazine-8-carbaldehyde

8-Bromo-2,2-difluoro-2H-1 ,4-benzoxazin-3(4H)-one (3.00 g; may be prepared as described in intermediate 3) was dissolved in Et₂O (56.8 ml) in a 250 ml. 3-necked round-bottomed flask flushed with argon and cooled to -78 ⁰C. BuLi (15.62 ml, 25.00 mmol, 1.6 M in hexanes) was added dropwise and stirring continued for 30 mins at -78 ⁰C. DMF (3.52 ml) was added and stirring at -78 ⁰C continued for 1 hr. The reaction mixture was warmed to room temperature and stood overnight. The reaction mixture was quenched with water (20 ml) then acidified with 1 M hydrochloric acid and extracted with EtOAc (50 ml. X 3). The combined organic solutions were washed with brine (50 ml_), dried over magnesium sulfate, filtered and evaporated to dryness to give the crude product as a pale yellow solid. The crude product was purified on a 40+M Biotage silica cartridge, eluting with a 0 to 20 % mixture of EtOAc in hexane, graduated over 10 CV. This gave two batches of material containing the target compound. The second batch was purified again on a 40+M Biotage silica cartridge, eluting with a 0 to 20 % mixture of EtOAc in hexane, graduated over 20 CV. Each batch was triturated three times with hexane to give the target compound (632 mg) as an off-white solid, m/z [M-H]^": 212.2. Retention time 0.75 min (LC/MS method 3).

Intermediate 5. 2,2-Difluoro-8-(2,2,2-trifluoro-1 -hydroxyethyl)-2H-1 ,4-benzoxazin- 3(4H)-one

Method A

2,2-Difluoro-3-oxo-3,4-dihydro-2H-1 ,4-benzoxazine-8-carbaldehyde (100 mg; may be prepared as described in intermediate 4) and trimethyl(trifluoromethyl)silane (83 μl; Aldrich) were dissolved in THF (2 ml) in a 25 ml. round-bottomed flask flushed with argon, cooled to 0 ⁰C, treated with cesium fluoride (7.13 mg) and stirred at 0 ⁰C for 1 hr. An excess of cesium fluoride was added, the reaction mixture warmed to room temperature and stirring continued overnight. A further portion of

trimethyl(trifluoromethyl)silane (83 μl) was added and stirring at room temperature continued for 3 hr. A further portion of trimethyl(trifluoromethyl)silane (83 μl) was added, giving an exotherm and a colour change from opaque yellow to a clear red/brown solution. Stirring continued for 40 minutes. A further portion of

trimethyl(trifluoromethyl)silane (83 μl) was added dropwise and the reaction mixture stood at room temperature for 3 days. The reaction mixture was treated with 1 M hydrochloric acid (10 ml_), poured into further 1 M hydrochloric acid (20 ml.) and extracted with EtOAc (30 ml X 3). The combined organic layers were washed with brine (30 ml), dried over magnesium sulfate, filtered and evaporated to dryness to give the crude product as a pale yellow oil. The crude product was purified on a 12+M Biotage silica cartridge, eluting with a 0 to 30 % mixture of EtOAc in hexane. This gave the target compound (66 mg) as a colourless oil. No further purification was attempted, m/z [M-H]^": 282.2. Retention time 0.83 min (LC/MS method 3). Method B

2,2-Difluoro-8-(trifluoroacetyl)-2H-1 ,4-benzoxazin-3(4H)-one (1.45 g; may be prepared as described in intermediate 6) was dissolved in 1 ,2-dichloroethane (25.8 ml) in a 10 ml_ round-bottomed flask flushed with argon, treated with sodium triacetoxyborohydride (1.202 g) and stirred at room temperature for 2 days. Sodium triacetoxyborohydride (1.093g) was added to the reaction mixture and stirred at room temperature for 3 hours. Sodium triacetoxyborohydride (1.093g) was added to the reaction mixture and stirred at room temperature for 2 hours. Sodium triacetoxyborohydride (1.093g) was added to the reaction mixture and stirred at room temperature overnight. The reaction mixture was quenched with saturated aqueous sodium bicarbonate solution (100ml) and extracted with DCM (3 x 100 ml). The organic layers were combined, washed with brine (100 ml), dried over magnesium sulfate, filtered and evaporated to dryness to give the crude product (1.43g) as a light brown oil. The crude product was purified on a 40+M Biotage silica cartridge, eluting with a 0 to 50 % mixture of EtOAc in hexane. This gave the target compound (1.13 g) as an off-white solid.

Intermediate 6. 2,2-Difluoro-8-(trifluoroacetyl)-2H-1 ,4-benzoxazin-3(4H)-one

Method A

8-Bromo-2,2-difluoro-2H-1 ,4-benzoxazin-3(4H)-one (264 mg; may be prepared as described in intermediate 3) was dissolved in Et₂O (5.00 ml) in a 50 ml. round-bottomed flask flushed with argon and cooled to -78 ⁰C. BuLi (1.375 ml, 1.6 M) was added dropwise and stirring continued for 30 min at -78 ⁰C. Ethyl trifluoroacetate (0.476 ml) was added and stirring at -78 ⁰C continued for 1 hr. The reaction mixture was warmed to room temperature and stirred for 1.5 hr. The reaction mixture was quenched with MeOH then 2 M hydrochloric acid (2 ml), poured into water (30 ml) and extracted with EtOAc (30 ml X 3). The combined organic solutions were washed with brine (30 ml), dried over magnesium sulfate, filtered and evaporated to dryness to give the crude product (263 mg) as a pale brown solid. The crude product was purified on a 25+M Biotage silica cartridge, eluting with a 0 to 50 % mixture of EtOAc in hexane. This gave the target compound (140 mg) as an off-white solid, m/z [M-H]^": 280.2 / 298.2 (hydrated material). Retention time 0.70 min (LC/MS method 3). Method B

To a solution of 8-bromo-2,2-difluoro-2H-1 ,4-benzoxazin-3(4H)-one (50.0 g; may be prepared as described in intermediate 3) in methyl te/f-butyl ether (1250 ml.) cooled to - 73⁰C was added BuLi (355 ml_, 1.6M in hexanes) dropwise (in 1 hr 10min, maintaining internal temperature below -7O⁰C) at -73⁰C under argon. A brown suspension was formed. The mixture was mechanically stirred for 1 hr at -73⁰C. 2,2,2-Trifluoro-Λ/-methyl- Λ/-(methyloxy)acetamide (68.7 ml_; Aldrich) was added and mechanically stirred at -73⁰C for 2hr. The cooling bath was removed and 1 M hydrochloric acid (600 ml) was added dropwise while the temperature was allowed to rise to 25⁰C. Water (150 ml) was added and the phases were separated. The aqueous phase was back-extracted with EtOAc

(250 ml). The combined organic layers were dried over sodium sulfate and evaporated to give a yellow solid residue (roughly 60 g) that was dissolved in EtOAc (700ml). Silica 230-400 Mesh (120 g) was added and solvent evaporated to give a powder that was chromatographed (ISOLERA LS, silica 750 g snap column), eluting with cyclohexane / EtOAc 9:1 to 1 :1 to give the title compound (37.0 g) as a beige powder.

Intermediate 7: 8-(difluoroacetyl)-2,2-difluoro-2H-1 ,4-benzoxazin-3(4H)-one

The title compound (484 mg) was prepared by a similar method to 2,2-difluoro-8- (trifluoroacetyl)-2H-1 ,4-benzoxazin-3(4H)-one (may be prepared as described in intermediate 6), replacing ethyl trifluoroacetate with ethyl difluoroacetate. ¹H NMR (DMSO-de) 5: 6.84 - 7.11 (1 H, t), 7.41 - 7.47 (2H, m), 7.62 - 7.69 (1 H, m), 12.26 (1 H, s).

Intermediate 8: 8-(2,2-difluoro-1 -hydroxyethyl)-2,2-difluoro-2H-1 ,4-benzoxazin- 3(4H)-one

The title compound (427 mg) was prepared by a similar method to 2,2-difluoro-8-(2,2,2- trifluoro-1-hydroxyethyl)-2H-1 ,4-benzoxazin-3(4H)-one (may be prepared as described in intermediate 5, method B), replacing 2,2-difluoro-8-(trifluoroacetyl)-2H-1 ,4-benzoxazin- 3(4H)-one with 8-(difluoroacetyl)-2,2-difluoro-2H-1 ,4-benzoxazin-3(4H)-one (may be prepared as described in intermediate 7). m/z [M-H]^": 264.3. Retention time 0.79 min (LC/MS method 3).

Intermediate 9: 2,2-difluoro-8-(fluoroacetyl)-2H-1 ,4-benzoxazin-3(4H)-one

The title compound (60 mg) was prepared by a similar method to 2,2-difluoro-8- (trifluoroacetyl)-2H-1 ,4-benzoxazin-3(4H)-one (may be prepared as described in intermediate 6), replacing ethyl trifluoroacetate with ethyl fluoroacetate. m/z [M-H]^": 244.2. Retention time 0.79 min (LC/MS method 3). Intermediate 10: 2,2-difluoro-8-(2-fluoro-1 -hydroxyethyl)-2H-1 ,4-benzoxazin-3(4H)- one

The title compound (30 mg) was prepared by a similar method to 2,2-difluoro-8-(2,2,2- trifluoro-1-hydroxyethyl)-2H-1 ,4-benzoxazin-3(4H)-one (may be prepared as described in intermediate 5, method B), replacing 2,2-difluoro-8-(trifluoroacetyl)-2H-1 ,4-benzoxazin- 3(4H)-one with 2,2-difluoro-8-(fluoroacetyl)-2H-1 ,4-benzoxazin-3(4H)-one (may be prepared as described in intermediate 9). m/z [M-H]^": 246.3. Retention time 0.74 min (LC/MS method 3). Intermediate 11 : 4-(bromomethyl)-2-pyridinecarbonitrile

4-Methyl-2-pyridinecarbonitrile (1 g; Apollo) was dissolved in carbon tetrachloride (17 ml) in a 100 ml round-bottomed flask. This solution was treated with N-bromosuccinimide (1.507 g) followed by AIBN (0.139 g) then flushed with Argon, heated to 80 ⁰C and stirred overnight. The reaction mixture was allowed to cool to room temperature, filtered through Kieselguhr, washed with DCM and evaporated to give the crude product (2.01 g) as a brown solid. The crude product was purified on a 40+M Biotage silica cartridge, eluting with a 0 to 50 % mixture of diethyl ether in hexane. This gave the target compound (345 mg) as a white solid, m/z [M+H]⁺: 197.1 / 199.1. Retention time 0.76 min (LC/MS method 3).

Intermediate 12: (2-fluoro-4-pyridinyl)methyl methanesulfonate

(2-Fluoro-4-pyridinyl)methanol (500 mg, 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 13: 8-[(1 /?)-2,2-difluoro-1 -hydroxyethyl]-2,2-difluoro-2H-1 ,4- benzoxazin-3(4H)-one and intermediate 14: 8-[(1 S)-2,2-difluoro-1-hydroxyethyl]-2,2- difluoro-2H-1 ,4-benzoxazin-3(4H)-one

R-stereoisomer S-stereoisomer

Racemic 2_!2-difluoro-8-(2,2-difluoro-1-hydroxyethyl)-2H-1 ,4-benzoxazin-3(4H)-one (275 mg; may be prepared as described in intermediate 8) was resolved using a Chiralcel OJ column eluting with heptane: ethanol (90:10) v/v pump-mixed. Using these conditions the faster-running enantiomer (118 mg, intermediate 13 or 14) and the slower-running enantiomer (1 18 mg, intermediate 13 or 14) were obtained in >99.8% enantiomeric excess, m/z [M-H]^": 264.2. Retention time 0.70 min (LC/MS method 3).

Intermediate 15: 2,2-difluoro-8-[(1 /?)-2-fluoro-1 -hydroxyethyl]-2H-1 ,4-benzoxazin- 3(4H)-one and intermediate 16: 2,2-difluoro-8-[(1 S)-2-fluoro-1 -hydroxyethyl]-2H-1 ,4- benzoxazin-3(4H)-one

R-stereoisomer S-stereoisomer

Racemic 8-(2,2-difluoro-1-hydroxyethyl)-2-fluoro-2H-1 ,4-benzoxazin-3(4H)-one (470 mg; may be prepared as described in intermediate 10) was resolved using a Chiralcel OJ column eluting with heptane: ethanol (90:10) v/v pump-mixed. Using these conditions the faster-running enantiomer (175 mg, intermediate 15 or 16) and the slower-running enantiomer (145 mg, intermediate 15 or 16) were obtained in >99.8% enantiomeric excess, m/z [M-H]^": 246.0. Retention time 0.66 min (LC/MS method 3).

Intermediate 17: 6-(bromomethyl)quinoxaline

A mixture of 6-methylquinoxaline (300 mg), NBS (370 mg) and benzoyl peroxide (5.04 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, 40+M column, 20-100% EtOAc / isohexane. The fractions containing product were combined and concentrated under reduced pressure to give the title compound (243 mg) as a white solid, m/z [M+H]⁺: 223.1 / 225.0. Retention time 0.80 min (LC/MS method 3). Intermediate 18: 2-bromo-2,2-difluoro-Λ/-(4-fluoro-2-hydroxyphenyl)acetamide

Bromo(difluoro)acetyl chloride (2.28 g; Fluorochem) and triethylamine (2.2 ml.) were added to a solution of 2-amino-5-fluorophenol (1.00 g; 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 combine 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 19: 2,2,7-trifluoro-2H-1 ,4-benzoxazin-3(4H)-one

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-Λ/-(3-bromo-2-hydroxyphenyl)-2,2- difluoroacetamide with 2-bromo-2,2-difluoro-Λ/-(4-fluoro-2-hydroxyphenyl)acetamide (may be prepared as described in intermediate 18). m/z [M-H]^": 201.8. Retention time 0.85 min (LC/MS method 3).

Intermediate 20: 2,2,7-trifluoro-8-(2,2,2-trifluoro-1 -hydroxyethyl)-2H-1 ,4-benzoxazin- 3(4H) -one

2,2,7-Trifluoro-2H-1 ,4-benzoxazin-3(4/-/)-one (1.026 g; may be prepared as described in intermediate 19) was dissolved in THF (16 ml.) in a 150 ml. round bottomed flask flushed with argon, and cooled to -78⁰C. BuLi (6.95 ml_, 1.6 M in hexanes) was added dropwise and stirring continued at -78 ⁰C for 30 min. Ethyl trifluoroacetate (2.404 ml.) was added and stirring at -78⁰C continued for 3 hr. The reaction mixture was warmed to RT and stirred for 1.5 hr. The reaction mixture was quenched with MeOH, poured into 2M hydrochloric acid (25 ml_), treated with water (50 ml.) and extracted with EtOAc (3 x 50 ml_). The organic layers were combined, washed with brine (100 ml_), dried over magnesium sulfate, filtered and evaporated to dryness to give a yellow oil (2.276 g). The crude product was purified on a 10Og Biotage silica cartridge, eluting with a 0 to 50 % mixture of EtOAc in hexane, to give a yellow oil (1.1 g). This was dissolved in 1 ,2- dichloroethane (20 ml.) in a 50 ml. round-bottomed flask flushed with argon, treated with sodium triacetoxyborohydride (0.779 g) and stirred at RT overnight. The reaction mixture was quenched with saturated aqueous sodium bicarbonate solution (70 ml.) and extracted with DCM (3 x 70 ml_). The organic layers were combined, washed with brine (70 ml_), dried using a phase separation cartridge and evaporated to dryness to give the crude product (867 mg) as an orange oil. The crude product was purified on a SNAP 5Og Biotage silica cartridge, eluting with a 0 to 50 % mixture of EtOAc in hexane, to give a yellow oil (727 mg). This was purified again on a Biotage 25+M amine-doped silica cartridge, eluting with a 0 to 100 % mixture of EtOAc in hexane, then a 10 to 20 % mixture of MeOH in DCM, to give the title compound (608 mg) as a pale yellow solid, m/z [M-H]^": 300.1. Retention time 0.86 min (LC/MS method 3). Intermediate 21 : 2,2,7-trifluoro-8-(fluoroacetyl)-2H-1 ,4-benzoxazin-3(4H)-one

The title compound (505 mg) was made in a similar fashion to the preparation of 2,2- difluoro-8-(trifluoroacetyl)-2H-1 ,4-benzoxazin-3(4H)-one (may be prepared as described in intermediate 6), replacing 8-bromo-2,2-difluoro-2H-1 ,4-benzoxazin-3(4/-/)-one with 2,2,7-trifluoro-2H-1 ,4-benzoxazin-3(4H)-one (may be prepared as described in intermediate 19), and replacing ethyl trifluoroacetate with ethyl fluoroacetate. m/z [M-H]^": 262.1. Retention time 0.81 min (LC/MS method 3).

Intermediate 22: 2,2,7-trifluoro-8-(2-fluoro-1 -hydroxyethyl)-2H-1 ,4-benzoxazin- 3(4H) -one

The title compound (180 mg) was made in a similar fashion to the preparation of 2,2- difluoro-8-(2,2,2-trifluoro-1-hydroxyethyl)-2H-1 ,4-benzoxazin-3(4H)-one (may be prepared as described in intermediate 5, method B), replacing 2,2-difluoro-8- (trifluoroacetyl)-2H-1 ,4-benzoxazin-3(4H)-one with 2,2,7-trifluoro-8-(fluoroacetyl)-2H-1 ,4- benzoxazin-3(4H)-one (may be prepared as described in intermediate 21 ). m/z [M-H]^": 264.0. Retention time 0.77 min (LC/MS method 3).

Intermediate 23: 2,2-difluoro-8-[(1 /?)-2,2,2-trifluoro-1 -hydroxyethyl]-2H-1 ,4- benzoxazin-3(4H)-one and intermediate 24: 2,2-difluoro-8-[(1 S)-2,2,2-trifluoro-1- hydroxyethyl]-2H-1,4-benzoxazin-3(4H)-one

Method A Racemic 2,2-difluoro-8-(2,2,2-trifluoro-1-hydroxyethyl)-2/-/-1 ,4-benzoxazin-3(4/-/)-one (2.49 g; may be prepared as described in intermediate 5) was resolved using a Chiralcel OJ column eluting with heptane (+ 0.1% trifluoroacetic acid) / ethanol (+ 0.1 %

trifluoroacetic acid) 80:20 (v/v) pump mixed. Under these conditions the faster-running enantiomer (974 mg; intermediate 23 or 24) and the slower-running enantiomer (807 mg; intermediate 23 or 24) were isolated in > 97.6% enantiomeric excess, m/z [M-H]^": 282.1. Retention time 0.83 min (LC/MS method 3).

Method B

(3aS)-1-Methyl-3,3-diphenyltetrahydro-3H-pyrrolo[1 ,2-c][1 ,3,2]oxazaborole (65.8 mL, 1 M in toluene) was dissolved in dry THF (370 ml) and borane-THF complex (52.6 mL, 1 M in THF) was added. The mixture was stirred at 25⁰C for 15 min. A solution of 2,2-difluoro-8- (trifluoroacetyl)-2H-1 ,4-benzoxazin-3(4/-/)-one (37.0 g; may be prepared as described in intermediate 6) in dry THF (370 ml) was added dropwise (in 1 hr). The mixture was stirred for 1 hr at 25⁰C. Further borane-THF complex (35 ml) was added in 30min and the mixture was stirred for a further 30 min at 25⁰C. Saturated aqueous ammonium chloride solution (740 ml) was added dropwise to the reaction mixture. Then EtOAc (740 ml) and water (370 ml) were added. The phases were separated and the aqueous phase was back-extracted with EtOAc (740 ml). The combined organic layers were evaporated and the residue (88 g) was dissolved in EtOAc (740 ml) and MeOH (370 ml). Silica (230-400 Mesh, 160 g) was added and solvent was evaporated to give a beige powder that was chromatographed (ISOLERA LS, 750 g silica snap cartridge) eluting with cyclohexane / EtOAc 8:2 to 7:3 to give a beige solid (33.1 g).

This was resolved using a Chiralcel OJ-H column eluting with hexane / ethanol 85:15 (v/v). Under these conditions the faster-running enantiomer (6.9 g; intermediate 23 or 24) and the slower-running enantiomer (20.3 g; intermediate 23 or 24) were isolated in 100% enantiomeric excess.

Intermediate 25: (5-cyano-3-pyridinyl)methyl methanesulfonate

The title compound (730 mg) was made in a similar fashion to the preparation of (2- fluoro-4-pyridinyl)methyl methanesulfonate (may be prepared as described in intermediate 12), replacing (2-fluoro-4-pyridinyl)methanol with 5-(hydroxymethyl)-3- pyridinecarbonitrile (Sunshine Chemlab). m/z [M+H]⁺: 212.9. Retention time 0.57 min (LC/MS method 3). Intermediate 26: (2-cyano-4-pyridinyl)methyl methanesulfonate

4-(Hydroxymethyl)-2-pyridinecarbonitrile (0.5 g; 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 27. 8-Acetyl-2,2-difluoro-2H-1 ,4-benzoxazin-3(4H)-one

To a solution of 8-bromo-2,2-difluoro-2H-1 ,4-benzoxazin-3(4H)-one (4.00 g, 15 mmol; may be prepared as described in intermediate 3) in Et₂O (100 ml) was added BuLi (13.3 ml, 33 mmol, 2.5 M) dropwise at -78⁰C under nitrogen. The mixture was stirred for 30 min. Λ/-methyl-Λ/-(methoxy)acetamide (3.15 g, 30 mmol; Aldrich) was added and the mixture was stirred for 1 hr at -78⁰C. 1 N hydrochloric acid was added until pH 7. It was extracted with EtOAc (3 x 100 ml) and the combined organic extracts were washed with water and brine, and then dried and concentrated. The crude product was purified via column chromatography on silica gel, eluting with petroleum ether / EtOAc 10:1 to obtain the target compound as a white solid (1.96 g). m/z [M-H]^": 226.0. Retention time 0.84 min (LC/MS method 3).

Intermediate 28: 8-Acetyl-2,2-difluoro-4-{[3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan- 2-yl)phenyl]methyl}-2H-1 ,4-benzoxazin-3(4H)-one

To a mixture of 8-acetyl-4-[(3-bromophenyl)methyl]-2,2-difluoro-2H-1 ,4-benzoxazin- 3(4H)-one (200 mg, 0.54 mmol, may be prepared as described in compound 42), 4_!4_!4'_!4\5_!5_!5\5'-octamethyl-2_!2'-bi-1 _!3_!2-dioxaborolane (413 mg, 1.63 mmol, Aldrich) and potassium acetate (288 mg, 3.24 mmol) in dioxane (10 ml.) under nitrogen was added [1 ,1-bis(diphenylphosphino)ferrocene]palladium (II) chloride (56 mg, 0.077 mmol, Aldrich). The mixture was stirred at 80 ⁰C for 20 hr then diluted with EtOAc (20 ml_). The mixture was washed with water and brine, then dried and concentrated to give a black solid (638 mg). This was purified by column chromatography on silica gel (eluting with petroleum ether / ethyl acetate 5:1 ) to give 8-acetyl-2,2-difluoro-4-{[3-(4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]methyl}-2H-1 ,4-benzoxazin-3(4H)-one (157 mg) as a white solid.

Intermediate 29. {3-[(8-Acetyl-2,2-difluoro-3-oxo-2,3-dihydro-4H-1 ,4-benzoxazin-4- yl)methyl]phenyl}boronic acid

A suspension of 8-acetyl-2,2-difluoro-4-{[3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl]methyl}-2H-1 ,4-benzoxazin-3(4H)-one (100 mg, 0.23 mmol, may be prepared as described in intermediate 28) and phenylboronic acid (56 mg, 0.46 mmol) in 3 N hydrochloric acid (5 ml.) was stirred for 16 hr at 80 ⁰C then diluted with EtOAc (15 ml_). It was washed with water (10 ml. x 3) and brine, then dried and concentrated to give {3-[(8- acetyl-2,2-difluoro-3-oxo-2,3-dihydro-4H-1 ,4-benzoxazin-4-yl)methyl]phenyl}boronic acid (150 mg), which was used in the next step without purification. Intermediate 30. 1 -(4-fluoro-2-hydroxy-3-nitrophenyl)ethanone

A mixture of 1-(4-fluoro-2-hydroxyphenyl)ethanone (1000 mg, 6.49 mmol, Aldrich) and 82% sulfuric acid (9 ml.) was stirred vigorously and cooled to 0 ⁰C. 70% Nitric acid (0.5 ml_, 7.83 mmol) was added dropwise. The mixture was stirred for 30 min. It was poured in to ice / water (100 ml.) and extracted with EtOAc (2 x 50 ml_). The combined organic layers were dried over sodium sulfate, filtered and evaporated to give an off-white solid. Mass: 1.16 g. This was purified by Biotage (4OM silica cartridge; eluent A / B 0 to 20%; A = 1% acetic acid in isohexane; B = 1 % acetic acid in EtOAc; collection by UV trigger). Impure fractions from this column were combined and re-purified using the same protocol. The output from both of the columns was combined to give the target compound (0.49 g) as a yellow solid, m/z [M-H]^": 197.9. Retention time 0.93 min (LC/MS method 3). Intermediate 31. 1 -(3-amino-4-fluoro-2-hydroxyphenyl)ethanone

The title compound (0.27 g) was made in a similar manner to the preparation of 2-amino- 6-bromophenol (may be prepared as described in intermediate 1 ), replacing 2-bromo-6- nitrophenol with 1-(4-fluoro-2-hydroxy-3-nitrophenyl)ethanone (may be prepared as described in intermediate 7). m/z [M+H]⁺: 169.9. Retention time 0.75 min (LC/MS method 3).

Intermediate 32. Λ/-(3-Acetyl-6-fluoro-2-hydroxyphenyl)-2-bromo-2,2- difluoroacetamide

Batch A

Bromo(difluoro)acetyl chloride (114 mg, 0.591 mmol, Apollo) and triethylamine (82 μl_, 0.592 mmol) were added to a solution of 1-(3-amino-4-fluoro-2-hydroxyphenyl)ethanone (50 mg, 0.296 mmol, may be prepared as described in intermediate 31 ) in dry THF (2 ml_). The mixture was heated to 100 ⁰C for 10 min in a microwave. It was diluted with water (10 ml.) and EtOAc (10 ml_). The layers were separated and the aqueous was extracted with EtOAc (1 x 10 ml_). The combined organic layers were washed with aqueous citric acid solution (1 x 10 ml_, 10% w/v) and brine (1 x 10 ml_), dried (sodium sulfate), filtered and evaporated to give a brown solid. Mass: 0.181 g. This was combined with Batch B for purification.

Batch B

Bromo(difluoro)acetyl chloride (510 mg, 2.64 mmol, Apollo) and triethylamine (0.37 ml_, 2.67 mmol) were added to a solution of 1-(3-amino-4-fluoro-2-hydroxyphenyl)ethanone (223 mg, 1.318 mmol, may be prepared as described in intermediate 31 ) in dry THF (15 ml_). The mixture was heated to 100 ⁰C for 10 min in a microwave (high absorbance). It was diluted with water (50 ml.) and EtOAc (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 brown solid. Mass: 0.456 g. This was combined with Batch A for purification. The mixture was purified by Biotage (100 g silica column; eluent isohexane / EtOAc 0 to 30%; collection by UV trigger). Fractions corresponding to the main peak were combined and evaporated to give the target compound (391 mg) as a white solid, m/z [M+H]⁺: 325.7 / 327.7. Retention time LC/MS method 3).

Intermediate 33: 8-Acetyl-2,2,5-trifluoro-2H-1 ,4-benzoxazin-3(4H)-one

The target compound (264 mg) was made in a similar manner to the preparation of 8- bromo-2,2-difluoro-2H-1 ,4-benzoxazin-3(4/-/)-one (may be prepared as described in intermediate 3), replacing 2-bromo-Λ/-(3-bromo-2-hydroxyphenyl)-2,2-difluoroacetamide with Λ/-(3-acetyl-6-fluoro-2-hydroxyphenyl)-2-bromo-2,2-difluoroacetamide (may be prepared as described in intermediate 9). m/z [M-H]^": 243.9. Retention time 0.78 min (LC/MS method 3).

Compound 1 : 4-[(5-Chloro-3-pyridinyl)methyl]-2,2-difluoro-8-(2,2,2-trifluoro-1^■ hydroxyethyl)-2H-1 ,4-benzoxazin-3(4H)-one (racemate)

2_!2-Difluoro-8-(2_!2_!2-trifluoro-1-hydroxyethyl)-2H-1 _!4-benzoxazin-3(4/-/)-one (66 mg; may be prepared as described in intermediate 5), 3-(bromomethyl)-5-chloropyridine hydrobromide (80 mg, 0.280 mmol; Sunshine Chemicals) and potassium carbonate (64.4 mg, 0.466 mmol) were dissolved in DMF (2 ml.) in a 25 ml. round-bottomed flask open to the atmosphere and stirred at room temperature for 2 hr. The reaction mixture was evaporated to dryness under reduced pressure and the residue redissolved in EtOAc (30 ml) then washed with a saturated aqueous sodium bicarbonate solution (30 ml). This aqueous solution was extracted with further portions of EtOAc (30 ml X 2) and the combined organic solutions washed with brine (30 ml), dried over magnesium sulfate, filtered and evaporated to dryness to give the crude product (79 mg) as a colourless oil. The crude product was purified on a 12+M Biotage silica cartridge, eluting with a 0 to 50 % mixture of EtOAc in hexane, and then by MDAP (formic acid method) to give the target compound (50 mg) as a white solid, m/z [M+H]⁺: 409.1. Retention time 1.04 min (LC/MS method 3). Compound 2: 6-{[2,2-Difluoro-3-oxo-8-(2,2,2-trifluoro-1 -hydroxyethyl)-2,3-dihydro- 4H-1,4-benzoxazin-4-yl]methyl}-2-pyridinecarbonitrile (racemate)

The title compound was prepared (41 mg) by a similar method to 4-[(5-chloro-3- pyridinyl)methyl]-2_!2-difluoro-8-(2_!2_!2-trifluoro-1-hydroxyethyl)-2H-1 _!4-benzoxazin-3(4/-/)- one (may be prepared as described in compound 1 ), replacing 3-(bromomethyl)-5- chloropyridine hydrobromide with 6-(bromomethyl)-2-pyridinecarbonitrile (Astatech). m/z [M-H]^": 398.2. Retention time 1.03 min (LC/MS method 3).

Compound 3: 4-[(5-Chloro-3-pyridinyl)methyl]-2,2-difluoro-8-[(1 S)-2,2,2-trifluoro-1^■ hydroxyethyl]-2H-1,4-benzoxazin-3(4H)-one and Compound 4: 4-[(5-chloro-3- pyridinyl)methyl]-2,2-difluoro-8-[(1 /?)-2,2,2-trifluoro-1 -hydroxyethyl]-2H-1 ,4- benzoxazin-3(4H)-one

R-stereoisomer S-stereoisomer

Racemic 4-[(5-chloro-3-pyridinyl)methyl]-2_!2-difluoro-8-(2,2,2-trifluoro-1-hydroxyethyl)- 2H-1 ,4-benzoxazin-3(4H)-one (35 mg; may be prepared as described in compound 1 ) was resolved using a Chiralpak IA column eluting with heptane: ethanol (90:10) v/v pump-mixed. Using these conditions the faster-running enantiomer (15 mg, compound 3 or 4) and the slower-running enantiomer (19 mg, compound 3 or 4) were obtained in >99.8% enantiomeric excess. Compound 5: 6-({2,2-Difluoro-3-oxo-8-[(1 S)-2,2,2-trifluoro-1 -hydroxyethyl]-2,3- dihydro-4H-1 ,4-benzoxazin-4-yl}methyl)-2-pyridinecarbonitrile and Compound 6: 6- ({2,2-difluoro-3-oxo-8-[(1/?)-2,2,2-trifluoro-1-hydroxyethyl]-2,3-dihydro-4H-1 ,4- benzoxazin-4-yl}methyl)-2-pyridinecarbonitrile

R-stereoisomer S-stereoisomer

Racemic 6-{[2_!2-difluoro-3-oxo-8-(2_!2_!2-trifluoro-1-hydroxyethyl)-2_!3-dihydro-4H-1 _!4- benzoxazin-4-yl]methyl}-2-pyridinecarbonitrile (98 mg; may be prepared as describ ed in compound 2) was resolved using a Chiralpak AD column eluting with heptane: ethanol (90:10) v/v pump-mixed. Using these conditions the faster-running enantiomer (87 mg, compound 5 or 6) and the slower-running enantiomer (54 mg, compound 5 or 6) were obtained in >98.8% enantiomeric excess.

The following compound were prepared by a similar procedure to that used for compound 1 , from the appropriate racemic benzoxazinone and the appropriate alkylating agent.

Compound 12: 2,2-difluoro-4-[(5-fluoro-3-pyridinyl)methyl]-8-[(1/?)-2,2,2-trifluoro-1 - hydroxyethyl]-2H-1 ,4-benzoxazin-3(4H)-one and compound 13: 2,2-difluoro-4-[(5- fluoro-3-pyridinyl)methyl]-8-[(1 S)-2,2,2-trifluoro-1-hydroxyethyl]-2H-1,4-benzoxazin- 3(4H) -one

R-stereoisomer S-stereoisomer

2_!2-Difluoro-8-(2_!2,2-trifluoro-1-hydroxyethyl)-2H-1 ,4-benzoxazin-3(4H)-one (105 mg, 0.369 mmol; may be prepared as described in intermediate 5), 3-(bromomethyl)-5- fluoropyridine (100 mg; Sunshine Chemicals) and potassium carbonate (102 mg) were dissolved in DMF (5000 μl) in a 10 ml. round-bottomed flask open to the atmosphere and stirred at RT overnight. The reaction mixture was evaporated to dryness, redissolved in EtOAc (30 ml) and treated with saturated aqueous sodium bicarbonate solution (30 ml). The aqueous layer was extracted with EtOAc (2 x 30 ml) and the organic layers were combined, washed with brine (30 ml), dried over magnesium sulfate, filtered and evaporated to dryness to give the crude product (160 mg) as a colourless oil. The crude product was purified on a 25+S Biotage silica cartridge, eluting with a 0 to 75 % mixture of EtOAc in hexane. This gave the target compound (racemate) (94 mg) as a white solid. 83 mg of this racemic mixture was separated into its constituent enantiomers by chiral preparative HPLC (Chiralpak AD column eluting with heptane: ethanol (70:30) v/v pump- mixed) to give the faster-running enantiomer as a white solid and the slower-running enantiomer as a white solid. These compounds were purified on 12+M Biotage silica cartridges, eluting with 0 to 75 % mixtures of EtOAc in hexane. This gave the faster- running enantiomer as a white solid and the slower-running enantiomer (22 mg, compound 12 or 13) as a white solid. The faster-running enantiomer was purified again by MDAP to give the faster-running enantiomer (12 mg, compound 12 or 13) as a white solid. ¹H NMR (CD₃OD) δ: 4.52 (2H, q), 4.62 (1 H, q), 6.40 - 6.45 (2H, m), 6.63 (1 H, q), 6.70 (1 H, dt), 7.51 - 7.55 (2H, m). m/z [M+H]⁺: 393.2. Retention time 0.98 min (LC/MS method 3).

Compound 14: 4-({2,2-difluoro-3-oxo-8-[(1/?)-2,2,2-trifluoro-1-hydroxyethyl]-2,3- dihydro-4H-1,4-benzoxazin-4-yl}methyl)-2-pyridinecarbonitrile and compound 15: 4-({2,2-difluoro-3-oxo-8-[(1 S)-2,2,2-trifluoro-1 -hydroxyethyl]-2,3-dihydro-4H-1 ,4- benzoxazin-4-yl}methyl)-2-pyridinecarbonitrile

R-stereoisomer S-stereoisomer

Method A

2_!2-difluoro-8-(2_!2_!2-trifluoro-1-hydroxyethyl)-2H-1 ,4-benzoxazin-3(4H)-one (95 mg; may be prepared as described in intermediate 5), 4-(bromomethyl)-2-pyridinecarbonitrile (66.1 mg; may be prepared as described in intermediate 11 ) and potassium carbonate (93 mg) were dissolved in DMF (2 ml.) in a 25 ml. round-bottomed flask open to the atmosphere and stirred at RT for 1 hr. The reaction mixture was evaporated to dryness under reduced pressure and the residue redissolved in EtOAc (20 ml.) then washed with a saturated aqueous solution of ammonium chloride (20 ml_). This aqueous solution was extracted with further portions of EtOAc (20 ml. X 2) and the combined organic solutions dried over magnesium sulfate, filtered and evaporated to dryness to give the crude product (155 mg) as a colourless oil. The crude product was purified on a 12+M Biotage silica cartridge, eluting with a 0 to 50 % mixture of ethyl acetate in hexane to give the racemic target compound (95 mg) as a white solid. 86 mg of this racemic mixture was separated into its constituent enantiomers by chiral preparative HPLC (Chiralpak IA column eluting with heptane: isopropanol 90:10 (v/v) pump-mixed. Using these conditions the faster-running enantiomer 4-({2,2-difluoro-3-oxo-8-[(1 R)-2,2,2-trifluoro-1- hydroxyethyl]-2,3-dihydro-4H-1 ,4-benzoxazin-4-yl}methyl)-2-pyridinecarbonitrile (27 mg, compound 14) and the slower-running enantiomer 4-({2,2-difluoro-3-oxo-8-[(1 S)-2, 2, 2- trifluoro-1-hydroxyethyl]-2,3-dihydro-4H-1 ,4-benzoxazin-4-yl}methyl)-2- pyridinecarbonitrile (1 1 mg, compound 15) were isolated as white solids in > 95% enantiomeric excess. ¹H NMR (DMSO-c/₆) δ: 5.40 (2H, q), 5.43 - 5.51 (1 H, m), 7.18 (1 H, s), 7.24 - 7.34 (2H, m), 7.45 (1 H, d), 7.62 (1 H, dd), 8.09 (1 H, d), 8.71 (1 H, d). m/z

[M+H]⁺: 400.1. Retention time 0.98 min (LC/MS method 3). The absolute configurations were determined by ab initio vibrational circular dichroism.

Method B 2_!2-Difluoro-8-[(1 R or S)-2_!2_!2-trifluoro-1-hydroxyethyl]-2/-/-1 _!4-benzoxazin-3(4H)-one (20.3 g; may be prepared as described in intermediate 23 and 24 method B - slower- running enantiomer) was dissolved in dry (DMF) (487 ml.) and (2-cyano-4- pyridinyl)methyl methanesulfonate (15.22 g; may be prepared as described in

intermediate 26) and potassium carbonate (19.82 g) were added at 25⁰C. The mixture (suspension, which turned to orange) was stirred at 25⁰C overnight. Saturated aqueous sodium bicarbonate solution (970 ml) and Et₂O (970 ml) were added and phases were separated. The aqueous phase was back-extracted with EtOAc (970 ml). The combined organic layers were washed with water (3 x 480 ml), dried over sodium sulfate and evaporated. The residue (roughly 40 g) was dissolved in EtOAc (200 ml) and MeOH (50 ml), and silica (230-400 Mesh, 120 g) was added. The solvent was evaporated to leave a white powder that was chromatographed (ISOLERA LS, 1500 g silica snap cartridge), eluting with cyclohexane / EtOAc 9:1 to 6:4 to give a white powder which was dried at 4O⁰C under vacuum overnight to give the title compound (22.5 g). ¹H NMR (DMSO-c/β) δ: 5.40 (2H, q), 5.44 - 5.52 (1 H, m), 7.18 (1 H, d), 7.25 - 7.35 (2H, m), 7.46 (1 H, d), 7.63 (1 H, dd), 8.10 (1 H, s), 8.72 (1 H, d). m/z [M+H]⁺: 400.1. Retention time 0.97 min (LC/MS method 3). Comparison of the product with a sample of 4-({2,2-difluoro-3-oxo-8-[(1 R)- 2,2,2-trifluoro-1-hydroxyethyl]-2,3-dihydro-4H-1 ,4-benzoxazin-4-yl}methyl)-2- pyridinecarbonitrile (compound 14, prepared according to method A) by chiral HPLC (column - Chiralpak IA; eluent - heptane / isopropanol 70:30 v/v) showed that the product was the R-isomer in 100% enantiomeric excess.

Compound 16: 2,2-difluoro-4-[(2-fluoro-4-pyridinyl)methyl]-8-[(1/?)-2,2,2-trifluoro-1 - hydroxyethyl]-2H-1,4-benzoxazin-3(4H)-one and compound 17: 2,2-difluoro-4-[(2- fluoro-4-pyridinyl)methyl]-8-[(1 S)-2,2,2-trifluoro-1-hydroxyethyl]-2H-1,4-benzoxazin- 3(4H) -one

R-stereoisomer S-stereoisomer

2,2-difluoro-8-(2,2,2-trifluoro-1-hydroxyethyl)-2H-1 ,4-benzoxazin-3(4H)-one (150 mg; may be prepared as described in intermediate 5), (2-fluoro-4-pyridinyl)methyl methanesulfonate (130 mg; may be prepared as described in intermediate 12) and potassium carbonate (146 mg, 1.060 mmol) were dissolved in DMF (2.649 ml) in a 25 ml_ round-bottomed flask open to the atmosphere and stirred at RT overnight. The reaction mixture was evaporated to dryness under reduced pressure and the residue redissolved in EtOAc (30 ml) then washed with a saturated aqueous solution of ammonium chloride (30 ml). This aqueous solution was extracted with further portions of EtOAc (30 ml X 2) and the combined organic solutions dried over magnesium sulfate, filtered and evaporated to dryness to give the crude product (216 mg) as a colourless oil. The crude product was purified on a 25+S Biotage silica cartridge, eluting with a 0 to 50 % mixture of ethyl acetate in hexane to give the racemic target compound (169 mg) as a white solid. 146 mg of this racemic mixture was separated into its constituent enantiomers by chiral preparative HPLC (Chiralpak IA column eluting with heptane: isopropanol (95:5) v/v pump-mixed). This gave the faster-running enantiomer (50 mg, compound 16 or 17) as a white solid and the slower-running enantiomer (45 mg, compound 16 or 17) as a white solid. ¹H NMR (CD₃OD) δ: 5.40 (2H, q), 5.52 (1 H, q), 6.98 (1 H, s), 7.15 - 7.21 (2H, m), 7.29 (1 H, t), 7.52 (1 H, d), 8.18 (1 H, d). m/z [M+H]⁺: 393.1. Retention time 1.00 min (LC/MS method 3).

Compound 18: 4-[(5-chloro-3-pyridinyl)methyl]-8-[(1/?)-2,2-difluoro-1-hydroxyethyl]- 2,2-difluoro-2H-1,4-benzoxazin-3(4H)-one and compound 19: 4-[(5-chloro-3- pyridinyl)methyl]-8-[(1S)-2,2-difluoro-1-hydroxyethyl]-2,2-difluoro-2H-1 ,4- benzoxazin-3(4H)-one

R-stereoisomer S-stereoisomer

8-(2,2-Difluoro-1-hydroxyethyl)-2,2-difluoro-2H-1 ,4-benzoxazin-3(4H)-one (100 mg; may be prepared as described in intermediate 8), 3-(bromomethyl)-5-chloropyridine (130 mg; Sunshine Chemicals) and potassium carbonate (156 mg) were dissolved in DMF (2 ml.) in a 10 ml. round-bottomed flask open to the atmosphere and stirred at RT overnight. The reaction mixture was evaporated to dryness under reduced pressure and the residue redissolved in EtOAc (20 ml.) then washed with a saturated aqueous solution of sodium bicarbonate (20 ml_). This aqueous solution was extracted with further portions of EtOAc (20 mL X 2) and the combined organic solutions washed with brine (20 ml_), dried over magnesium sulfate, filtered and evaporated to dryness to give the crude product (187 mg) as a pale yellow oil. The crude product was purified on a 25+S Biotage silica cartridge, eluting with a 0 to 50 % mixture of EtOAc in hexane. This gave the racemic target compound (104 mg) as a white solid. 86 mg of this racemic mixture was separated into its constituent enantiomers by chiral preparative HPLC (Chiralpak AD column eluting with heptane: ethanol (70:30) v/v pump-mixed) to give the faster running enantiomer (32 mg, compound 18 or 19) as a white solid and the slower running enantiomer (26 mg, compound 18 or 19) as a white solid. ¹H NMR (CDCI₃) δ: 2.85 (1 H, d), 5.25 (2H, q), 5.33 - 5.42 (1 H, m), 5.76 - 6.08 (1 H, td), 7.00 (1 H, dd), 7.20 - 7.30 (1 H, m), 7.44 (1 H, d), 7.58 (1 H, t), 8.48 (1 H, d), 8.54 (1 H, d). m/z [M+H]⁺: 391.1 / 393.1. Retention time 0.96 min (LC/MS method 3).

Compound 20: 4-({8-[(1/?)-2,2-difluoro-1-hydroxyethyl]-2,2-difluoro-3-oxo-2,3- dihydro-4H-1,4-benzoxazin-4-yl}methyl)-2-pyridinecarbonitrile and compound 21 : 4-({8-[(1 S)-2,2-difluoro-1-hydroxyethyl]-2,2-difluoro-3-oxo-2,3-dihydro-4H-1 ,4- benzoxazin-4-yl}methyl)-2-pyridinecarbonitrile

R-stereoisomer S-stereoisomer

8-[(1 R)-2,2-Difluoro-1-hydroxyethyl]-2,2-difluoro-2H-1 ,4-benzoxazin-3(4H)-one or 8-[(1 S)- 2,2-difluoro-1-hydroxyethyl]-2,2-difluoro-2H-1 ,4-benzoxazin-3(4H)-one (1 18 mg; may be prepared as described in intermediate 13 and 14; slower-running enantiomer by chiral HPLC), 4-(bromomethyl)-2-pyridinecarbonitrile (96 mg; may be prepared as described in intermediate 11 ) and potassium carbonate (123 mg, 0.890 mmol) were dissolved in DMF (2.225 ml) in a 10 mL round-bottomed flask open to the atmosphere and stirred at RT overnight. The reaction mixture was treated with a further portion of 4-(bromomethyl)-2- pyridinecarbonitrile (22 mg) and stirred for 30 minutes. The reaction mixture was diluted with EtOAc (30 ml), washed with a saturated aqueous solution of ammonium chloride (30 ml) followed by water (30 ml x 2), dried over magnesium sulfate, filtered and evaporated to dryness to give the crude product (178 mg) as an off-white solid. The crude product was purified on a 12+M Biotage silica cartridge, eluting with a 0 to 50 % mixture of EtOAc in hexane. This gave the target compound (126 mg, compound 20 or 21 ) as an off-white solid. ¹H NMR (DMSO-d₆) δ: 5.11 - 5.21 (1 H, m), 5.40 (2H, q), 5.94 - 6.26 (1 H, td), 6.48 (1 H, d), 7.18 - 7.31 (2H, m), 7.40 (1 H, dd), 7.60 (1 H, dd), 8.08 (1 H, s), 8.72 (1 H, d). m/z [M+H]⁺: 382.0. Retention time 0.91 min (LC/MS method 3). 8-[(1 R)-2,2-Difluoro-1-hydroxyethyl]-2,2-difluoro-2H-1 ,4-benzoxazin-3(4H)-one or 8-[(1 S)- 2,2-difluoro-1-hydroxyethyl]-2,2-difluoro-2H-1 ,4-benzoxazin-3(4H)-one (1 18 mg; may be prepared as described in intermediate 13 and 14; faster-running enantiomer by chiral HPLC), potassium carbonate (123 mg, 0.890 mmol) and potassium iodide (0.074 mg, 0.445 μmol) were added to a solution of 4-(bromomethyl)-2-pyridinecarbonitrile (88 mg, 0.445 mmol ; prepared as described in intermediate 11 ) in DMF (1 ml_). The reaction mixture was left for 5 hr. It was diluted with EtOAc (50 ml.) and water (50 ml_), vigorously shaken, the two phases were separated and the organic phase was washed with water (3x). Organics were dried over sodium sulfate, filtered and the solvent was evaporated to afford the crude product that was triturated with MeOH and purified by silica chromatography (EtOAc - hexane) and by MDAP to afford the target compound (30 mg, compound 20 or 21 ). ¹H NMR (DMSO-d₆) δ: 5.1 1 - 5.21 (1 H, m), 5.40 (2H, q), 5.94 - 6.26 (1 H, td), 6.48 (1 H, d), 7.18 - 7.31 (2H, m), 7.40 (1 H, dd), 7.60 (1 H, dd), 8.08 (1 H, s), 8.72 (1 H, d). m/z [M+H]⁺: 382.2. Retention time 0.90 min (LC/MS method 3). Compound 22: 4-[(5-chloro-3-pyridinyl)methyl]-2,2-difluoro-8-[(1/?)-2-fluoro-1- hydroxyethyl]-2H-1,4-benzoxazin-3(4H)-one and compound 23: 4-[(5-chloro-3- pyridinyl)methyl]-2,2-difluoro-8-[(1 S)-2-fluoro-1 -hydroxyethyl]-2H-1 ,4-benzoxazin- 3(4H) -one

R-stereoisomer S-stereoisomer 2,2-difluoro-8-(2-fluoro-1-hydroxyethyl)-2H-1 ,4-benzoxazin-3(4H)-one (1 10 mg; may be prepared as described in intermediate 10), 3-(bromomethyl)-5-chloropyridine (153 mg; Sunshine Chemicals) and potassium carbonate (185 mg, 1.335 mmol) were dissolved in DMF (2 ml.) in a 10 mL round-bottomed flask open to the atmosphere and stirred at RT overnight. The reaction mixture was evaporated to dryness under reduced pressure and the residue redissolved in EtOAc (20 mL) then washed with a saturated aqueous solution of sodium bicarbonate (20 mL). This aqueous solution was extracted with further portions of EtOAc (20 mL X 2) and the combined organic solutions washed with brine (20 mL), dried over magnesium sulfate, filtered and evaporated to dryness to give the crude product (186 mg) as a pale yellow oil. The crude product was purified on a 25+S Biotage silica cartridge, eluting with a 0 to 50 % mixture of EtOAc in hexane. This gave the racemic target compound (158 mg) as a white solid. 140 mg of this racemic mixture was separated into its constituent enantiomers by chiral preparative HPLC (Chiralpak AD column eluting with heptane: ethanol (80:20) v/v pump-mixed) to give the faster running enantiomer (74 mg, compound 22 or 23) as a white solid and the slower running enantiomer (63 mg, compound 22 or 23) as a white solid. ¹H NMR (CDCI₃) δ: 2.66 (1 H, d), 4.30 - 4.75 (2H, m), 5.24 (2H, s), 5.41 - 5.51 (1 H, m), 6.96 (1 H, d), 7.23 (1 H, t), 7.46 (1 H, d), 7.57 (1 H, s), 8.48 (1 H, d), 8.54 (1 H, d). m/z [M+H]⁺: 373.2 / 375.2. Retention time 0.93 min (LC/MS method 3).

Compound 24: 4-({2,2-difluoro-8-[(1 /?)-2-fluoro-1 -hydroxyethyl]-3-oxo-2,3-dihydro- 4H-1,4-benzoxazin-4-yl}methyl)-2-pyridinecarbonitrile and compound 25: 4-({2,2- difluoro-8-[(1 S)-2-fluoro-1 -hydroxyethyl]-3-oxo-2,3-dihydro-4H-1 ,4-benzoxazin-4- yl}methyl)-2-pyridinecarbonitrile

R-stereoisomer S-stereoisomer

To a solution of 2,2-difluoro-8-[(1 R)-2-fluoro-1-hydroxyethyl]-2H-1 ,4-benzoxazin-3(4H)- one or 2,2-difluoro-8-[(1 S)-2-fluoro-1-hydroxyethyl]-2H-1 ,4-benzoxazin-3(4H)-one (175mg; may be prepared as described in intermediate 15 and 16; faster-running enantiomer by chiral HPLC) in DMF (4ml) was added potassium carbonate (196mg) followed by the addition of 4-(bromomethyl)-2-pyridinecarbonitrile (160mg; may be prepared as described in intermediate 11 ) in DMF (2ml) and the reaction mixture was stirred for 1 hr at room temperature. The reaction mixture was diluted with EtOAc (50ml) and washed with water (3x25ml) then dried (magnesium sulfate), filtered and evaporated. The residue was dissolved in DCM and purified on the Biotage SP4 using a 25+M column and eluting with 0 to 50% EtOAc / isohexane over 15CV to afford the title compound (180mg, compound 24 or 25) as a white solid. ¹H NMR (DMSO-c/₆) δ: 4.31 - 4.58 (2H, m), 5.14 - 5.25 (1 H, m), 5.40 (2H, t), 6.00 (1 H, d), 7.16 (1 H, dd), 7.25 (1 H, t), 7.39 (1 H, d), 7.61 (1 H, dd), 8.07 (1 H, d), 8.71 (1 H, d). m/z [M+H]⁺: 364.0. Retention time 0.87 min (LC/MS method 3).

To a solution of 2,2-difluoro-8-[(1 R)-2-fluoro-1-hydroxyethyl]-2H-1 ,4-benzoxazin-3(4H)- one or 2,2-difluoro-8-[(1 S)-2-fluoro-1-hydroxyethyl]-2H-1 ,4-benzoxazin-3(4H)-one (145mg; may be prepared as described in intermediate 15 and 16; slower-running enantiomer by chiral HPLC) in DMF (4ml) was added potassium carbonate (162mg) followed by the addition of 4-(bromomethyl)-2-pyridinecarbonitrile (127mg; may be prepared as described in intermediate 11 ) in DMF (2ml) and the reaction mixture stirred for 1 hr at room temperature. The reaction mixture was diluted with EtOAc (50ml) and washed with water (3x25ml) then dried (magnesium sulfate), filtered and evaporated. The residue was dissolved in DCM and purified on the Biotage SP4 using a 25+M column and eluting with 0 to 50% EtOAc / isohexane over 15CV to afford the title compound (127mg, compound 24 or 25) as a white solid. ¹H NMR (DMSO-c/₆) δ: 4.31 - 4.58 (2H, m), 5.14 - 5.25 (1 H, m), 5.40 (2H, t), 6.00 (1 H, d), 7.16 (1 H, dd), 7.25 (1 H, t), 7.39 (1 H, d), 7.61 (1 H, dd), 8.07 (1 H, d), 8.71 (1 H, d). m/z [M+H]⁺: 364.0. Retention time 0.87 min (LC/MS method 3).

Compound 26: 2,2-difluoro-4-(6-quinoxalinylmethyl)-8-[(1 /?)-2,2,2-trifluoro-1 - hydroxyethyl]-2H-1,4-benzoxazin-3(4H)-one and compound 27: 2,2-difluoro-4-(6- quinoxalinylmethyl)-8-[(1 S)-2,2,2-trifluoro-1 -hydroxyethyl]-2H-1 ,4-benzoxazin- 3(4H)-one

R-stereoisomer S-stereoisomer

6-(Bromomethyl)quinoxaline (50 mg; may be prepared as described in intermediate 17) was added to a solution of 2,2-difluoro-8-(2,2,2-trifluoro-1-hydroxyethyl)-2H-1 ,4- benzoxazin-3(4H)-one (63.5 mg; may be prepared as described in intermediate 5) in DMF (3 ml_). Potassium carbonate (75 mg) and potassium iodide (1.860 mg) were added. The reaction was stirred overnight at RT, under argon. Then water (20 ml.) was added to the reaction mixture, and the new mixture was extracted 3 times with 20 ml. of EtOAc. The combined organic phases were washed 3 times with 20 ml. of water, and finally with 25 ml. of brine. Then this phase was dried over anhydrous magnesium sulfate, and the solvent was evaporated to give a colorless oil and crystals. The crude product was purified by MDAP to give 26.2 mg of white crystals. The enantiomers were resolved using a Chiracel OJ column eluting with heptane / ethanol 50:50 (v/v) pump mixed. Under these conditions the faster-running enantiomer (1 1.6 mg; compound 26 or 27) and the faster-running enantiomer (12.4 mg; compound 26 or 27) were obtained in > 99.8% enantiomeric excess, m/z [M+H]⁺: 426.1. Retention time 1.00 min (LC/MS method 3).

Compound 28: 4-({2,2,7-trifluoro-3-oxo-8-[(1 S)-2,2,2-trifluoro-1 -hydroxyethyl]-2,3- dihydro-4H-1 ,4-benzoxazin-4-yl}methyl)-2-pyridinecarbonitrile and compound 29: 4-({2,2,7-trifluoro-3-oxo-8-[(1/?)-2,2,2-trifluoro-1-hydroxyethyl]-2,3-dihydro-4H-1,4- benzoxazin-4-yl}methyl)-2-pyridinecarbonitrile

R-stereoisomer S-stereoisomer

The title compounds (faster-running enantiomer: 27 mg and slower-running enantiomer: 27 mg) were made in a similar fashion to the preparation of 2,2-difluoro-4-(6- quinoxalinylmethyl)-8-[(1R)-2_!2_!2-trifluoro-1-hydroxyethyl]-2H-1 _!4-benzoxazin-3(4/-/)-one and 2,2-difluoro-4-(6-quinoxalinylmethyl)-8-[(1 S)-2,2,2-trifluoro-1-hydroxyethyl]-2H-1 ,4- benzoxazin-3(4H)-one (may be prepared as described in compounds 26 and 27), replacing 2,2-difluoro-8-(2_!2_!2-trifluoro-1-hydroxyethyl)-2H-1 _!4-benzoxazin-3(4/-/)-one with 2_!2_!7-trifluoro-8-(2_!2_!2-trifluoro-1-hydroxyethyl)-2H-1 ,4-benzoxazin-3(4H)-one (may be prepared as described in intermediate 20), and replacing 6-(bromomethyl)quinoxaline with 4-(bromomethyl)-2-pyridinecarbonitrile (may be prepared as described in intermediate 11 ). m/z [M+H]⁺: 417.9. Retention time 0.98 min (LC/MS method 3).

Compound 30: 2,2,7-trifluoro-4-[(5-fluoro-3-pyridinyl)methyl]-8-[(1 /?)-2,2,2-trifluoro- 1-hydroxyethyl]-2H-1,4-benzoxazin-3(4H)-one and compound 31 : 2,2,7-trifluoro-4- [(5-fluoro-3-pyridinyl)methyl]-8-[(1 S)-2,2,2-trifluoro-1 -hydroxyethyl]-2H-1 ,4- benzoxazin-3(4H)-one

R-stereoisomer S-stereoisomer

The title compounds (faster-running enantiomer: 20 mg and slower-running enantiomer: 20 mg) were made in a similar fashion to the preparation of 2,2-difluoro-4-(6- quinoxalinylmethyl)-8-[(1R)-2_!2_!2-trifluoro-1-hydroxyethyl]-2H-1 _!4-benzoxazin-3(4/-/)-one and 2,2-difluoro-4-(6-quinoxalinylmethyl)-8-[(1 S)-2,2,2-trifluoro-1-hydroxyethyl]-2H-1 ,4- benzoxazin-3(4H)-one (may be prepared as described in compounds 26 and 27), replacing 2,2-difluoro-8-(2,2,2-trifluoro-1-hydroxyethyl)-2/-/-1 ,4-benzoxazin-3(4/-/)-one with 2_!2_!7-trifluoro-8-(2_!2_!2-trifluoro-1-hydroxyethyl)-2H-1 ,4-benzoxazin-3(4H)-one (may be prepared as described in intermediate 20), and replacing 6-(bromomethyl)quinoxaline with 3-(bromomethyl)-5-fluoropyridine hydrobromide (Sunshine Chemicals), m/z [M+H]⁺: 411.0. Retention time 0.98 min (LC/MS method 3). Compound 32: 2,2,7-trifluoro-8-[(1 /?)-2-fluoro-1 -hydroxyethyl]-4-[(5-fluoro-3- pyridinyl)methyl]-2H-1,4-benzoxazin-3(4H)-one and compound 33: 2,2,7-trifluoro-8- [(1 S)-2-fluoro-1 -hydroxyethyl]-4-[(5-fluoro-3-pyridinyl)methyl]-2H-1 ,4-benzoxazin- 3(4H)-one

R-stereoisomer S-stereoisomer

The title compounds (faster-running enantiomer: 27 mg and slower-running enantiomer:

27 mg) were made in a similar fashion to the preparation of 2,2-difluoro-4-(6- quinoxalinylmethyl)-8-[(1R)-2,2,2-trifluoro-1-hydroxyethyl]-2H-1 ,4-benzoxazin-3(4H)-one and 2,2-difluoro-4-(6-quinoxalinylmethyl)-8-[(1 S)-2_!2_!2-trifluoro-1-hydroxyethyl]-2H-1 _!4- benzoxazin-3(4H)-one (may be prepared as described in compounds 26 and 27), replacing 2,2-difluoro-8-(2_!2_!2-trifluoro-1-hydroxyethyl)-2H-1 _!4-benzoxazin-3(4/-/)-one with 2,2,7-trifluoro-8-(2-fluoro-1-hydroxyethyl)-2H-1 ,4-benzoxazin-3(4H)-one (may be prepared as described in intermediate 22), and replacing 6-(bromomethyl)quinoxaline with 3-(bromomethyl)-5-fluoropyridine hydrobromide (Sunshine Chemicals), m/z [M+H]⁺: 375.0. Retention time 0.88 min (LC/MS method 3).

Compound 34: 2,2-difluoro-4-(2-pyridinylmethyl)-8-[(7/? or S)-2,2,2-trifluoro-1 - hydroxyethyl]-2H-1,4-benzoxazin-3(4H)-one

The title compound (99 mg) was made in a similar fashion to the preparation of 4-[(5- chloro-3-pyridinyl)methyl]-2_!2-difluoro-8-(2_!2_!2-trifluoro-1-hydroxyethyl)-2H-1 _!4- benzoxazin-3(4H)-one (may be prepared as described in compound 1 ), replacing 2,2- difluoro-8-(2,2,2-trifluoro-1-hydroxyethyl)-2H-1 ,4-benzoxazin-3(4H)-one with 2,2-difluoro- 8-[(1 R or S)-2_!2_!2-trifluoro-1-hydroxyethyl]-2H-1 _!4-benzoxazin-3(4/-/)-one (may be prepared as describe in intermediates 23 and 24; slower-running enantiomer), and replacing 3-(bromomethyl)-5-chloropyridine hydrobromide with 2-(bromomethyl)pyridine hydrobromide (Aldrich). m/z [M+H]⁺: 374.9. Retention time 0.99 min (LC/MS method 3).

Compound 35: 5-({2,2-difluoro-3-oxo-8-[(1/? or S)-2,2,2-trifluoro-1-hydroxyethyl]- 2,3-dihydro-4H-1 ,4-benzoxazin-4-yl}methyl)-3-pyridinecarbonitrile

The title compound (248 mg) was made in a similar fashion to the preparation of 4-[(5- chloro-3-pyridinyl)methyl]-2_!2-difluoro-8-(2_!2_!2-trifluoro-1-hydroxyethyl)-2H-1 _!4- benzoxazin-3(4H)-one (may be prepared as described in compound 1 ), replacing 2,2- difluoro-8-(2,2,2-trifluoro-1-hydroxyethyl)-2/-/-1 ,4-benzoxazin-3(4H)-one with 2,2-difluoro- 8-[(1R or S)-2_!2_!2-trifluoro-1-hydroxyethyl]-2H-1 _!4-benzoxazin-3(4/-/)-one (may be prepared as described in intermediates 23 and 24; slower-running enantiomer), and replacing 3-(bromomethyl)-5-chloropyridine hydrobromide with (5-cyano-3- pyridinyl)methyl methanesulfonate (may be prepared as described in intermediate 25). m/z [M+H]⁺: 399.9. Retention time 0.96 min (LC/MS method 3). Compound 36: 8-Acetyl-2,2-difluoro-4-(3-pyridinylmethyl)-2H-1,4-benzoxazin-3(4H)-

A stirred solution of 8-acetyl-2,2-difluoro-2H-1 ,4-benzoxazin-3(4H)-one (50 mg, 0.220 mmol, may be prepared as described in intermediate 27) in DMF (3ml) at room temperature under argon was treated with potassium carbonate (60.8 mg, 0.440 mmol) followed by the addition of a solution of 3-(chloromethyl)pyridine hydrochloride (72.2 mg, 0.440 mmol, Aldrich) in DMF (3ml) and the resulting mixture was stirred at room temperature for 42 hours. The reaction mixture was concentrated under vacuum and the residue treated with 10% aqueous sodium carbonate solution (20ml) and extracted with DCM (2 x 20ml). The 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).

Compound 37: 8-Acetyl-2,2-difluoro-4-[(5-fluoro-3-pyridinyl)methyl]-2H-1 ,4- benzoxazin-3(4H)-one

The title compound was (31 mg) made in a similar fashion to the preparation of 8-acetyl- 2,2-difluoro-4-(3-pyridinylmethyl)-2H-1 ,4-benzoxazin-3(4/-/)-one (may be prepared as described in example 36), replacing 3-(chloromethyl)pyridine hydrochloride with 3- (bromomethyl)-5-fluoropyridine hydrochloride (Sunshine Chemlab). Purification was by MDAP (formic acid method), m/z [M+H]⁺: 336.9. Retention time 0.99 min (LC/MS method 3).

The following compounds are commercially available:

Compound 38: 8-Acetyl-2,2-difluoro-4-[(2-methyl-1 ,3-thiazol-4-yl)methyl]-2H-1 ,4- benzoxazin-3(4H)-one (Biofocus)

Compound 39: 8-Acetyl-2,2-difluoro-4-{[6-(trifluoromethyl)-3-pyridinyl]methyl}-2H- 1 ,4-benzoxazin-3(4H)-one (Biofocus)

Compound 40: Methyl 5-[(8-acetyl-2,2-difluoro-3-oxo-2,3-dihydro-4H-1,4- benzoxazin-4-yl)methyl]-2-furancarboxylate (Biofocus)

Compound 41 : 8-acetyl-2,2-difluoro-4-(2-pyridinylmethyl)-2H-1,4-benzoxazin-3(4H)- one (Biofocus)

Compound 42. 8-Acetyl-4-[(3-bromophenyl)methyl]-2,2-difluoro-2H-1,4-benzoxazin- 3(4H) -one

To a solution of 8-acetyl-2,2-difluoro-2H-1 ,4-benzoxazin-3(4/-/)-one (51 mg, may be prepared as described in intermediate 27) in acetonitrile (3 ml) was added 1-bromo-3- (bromomethyl)benzene (56 mg, Aldrich) and potassium carbonate (91 mg). The mixture was stirred for 5 hr at room temperature, diluted with ethyl acetate (10 ml), washed with water and brine, then dried and concentrated. The crude product was purified by preparative thin-layer chromatography (eluting with petroleum ether / EtOAc 2:1 ) to give the target compound (54 mg) as a white solid, m/z [M+H]⁺: 395.7 / 397.7. Retention time 1.21 min (LC/MS method 3). The following compounds were prepared in a similar manner to that described for compound 42, from 8-acetyl-2,2-difluoro-2H-1 ,4-benzoxazin-3(4H)-one (may be prepared as described in intermediate 27) and the appropriate alkylating agent.

Compound 48. 8-Acetyl-2,2-difluoro-4-{[3-(1H-imidazol-1-yl)phenyl]methyl}-2H-1,4- benzoxazin-3(4H)-one

Copper (I) oxide (61 mg, 0.42 mmol) was added to a mixture of {3-[(8-acetyl-2,2-difluoro- 3-0X0-2, 3-dihydro-4H-1 ,4-benzoxazin-4-yl)methyl]phenyl}boronic acid (150 mg, 0.42 mmol, may be prepared as described in intermediate 29) and imidazole (141 mg, 2.08 mmol) in methanol (10 ml_). The mixture was stirred at 80 ⁰C for 18 hr. It was diluted with EtOAc (20 ml_), filtered and the filtrate was concentrated under reduced pressure. EtOAc (20 ml.) was added and it was washed with water and brine then dried and concentrated. The residue was purified by preparative thin-layer chromatography (eluting with petroleum ether / EtOAc 1 :2) to give the target compound as a grey solid, m/z [M+H]⁺: 383.8. Retention time 0.76 min (LC/MS method 3). Compound 49. 8-Acetyl-2,2,5-trifluoro-4-[(3-fluorophenyl)methyl]-2H-1 ,4- benzoxazin-3(4H)-one

Potassium carbonate (70 mg, 0.506 mmol) and 3-fluorobenzyl bromide (50 μl_, 0.408 mmol, Aldrich) were added to a solution of 8-acetyl-2,2,5-trifluoro-2H-1 ,4-benzoxazin- 3(4H)-one (50 mg, 0.204 mmol, may be prepared as described in intermediate 33) in dry DMF (2 ml_). The mixture was stirred overnight at room temperature. The solvent was evaporated and the residue was dissolved in DCM (2 ml.) and aqueous citric acid solution (1 ml_, 10% w/v). The layers were separated and the aqueous was extracted with DCM (1x 2 ml_). The combined organic layers were dried (hydrophobic frit) and evaporated to give a yellow oil. Mass: 80 mg. This was purified by Biotage (10 g silica cartridge; eluent isohexane / ethyl acetate 0 to 20%; collection by UV trigger). One peak was collected and the fractions were combined and evaporated to give the target compound (53 mg) as a white solid, m/z [M+H]⁺: 353.8. Retention time 1.16 min (LC/MS method 3). Compound 50: Methyl 3-[(8-acetyl-2,2-difluoro-3-oxo-2,3-dihydro-4H-1,4- benzoxazi n -4-yl ) methyl ] benzoate

The target compound (342 mg) was made in a similar fashion to the preparation of 8- acetyl-4-[(3-bromophenyl)methyl]-2,2-difluoro-2H-1 ,4-benzoxazin-3(4H)-one (may be prepared as described in compound 42), replacing 1-bromo-3-(bromomethyl)benzene with methyl 3-(bromomethyl)benzoate (Aldrich).

Compound 51 : 3-[(8-acetyl-2,2-difluoro-3-oxo-2,3-dihydro-4H-1 ,4-benzoxazin-4- yl)methyl]benzoic acid

To a solution of methyl 3-[(8-acetyl-2,2-difluoro-3-oxo-2,3-dihydro-4H-1 ,4-benzoxazin-4- yl)methyl]benzoate (1 10 mg, may be prepared as described in Compound 50) in THF was added aqueous lithium hydroxide solution (0.2 ml, 8 M). The mixture was stirred at room temperature for 18 hr. 1 N hydrochloric acid was added until the pH was less than 5. It was diluted with EtOAc (10 ml) then washed with water and brine, then dried and concentrated to give the target compound as a grey solid.

Compound 52: 3-[(8-acetyl-2,2-difluoro-3-oxo-2,3-dihydro-4H-1 ,4-benzoxazin-4- yl)methyl]-Λ/,Λ/-dimethylbenzamide

To a solution of 3-[(8-acetyl-2,2-difluoro-3-oxo-2,3-dihydro-4H-1 ,4-benzoxazin-4- yl)methyl]benzoic acid (66 mg, may be prepared as described in Compound 51 ) in DCM was added dimethylamine hydrochloride (29 mg), HOBt (27 mg), EDC (38 mg) and triethylamine (72 mg). The mixture was stirred for 3 hr at room temperature. The solvent was evaporated under reduced pressure. Then the mixture was diluted with EtOAc (10 ml), and washed with 1 N hydrochloric acid, saturated aqueous sodium bicarbonate solution, water and brine. It was dried and concentrated, then purified by preparative thin- layer chromatography eluting with petroleum ether / EtOAc 2:1 , to give the target compound (40 mg) as a brown solid, m/z [M+H]⁺: 388.8. Retention time 0.96 min (LC/MS method 3).

The following compounds are commercially available: Compound 53: 3-[(8-acetyl-2,2-difluoro-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4- yl)methyl]benzonitrile (Biofocus)

Compound 54: 2-[(8-acetyl-2,2-difluoro-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4- yl)methyl]benzonitrile (Biofocus)

Compound 55: 8-acetyl-4-{[5-acetyl-2-(methyloxy)phenyl]methyl}-2,2-difluoro-2H- 1,4-benzoxazin-3(4H)-one (Biofocus)

Compound 56: 8-acetyl-4-[(4-chlorophenyl)methyl]-2,2-difluoro-2H-1 ,4-benzoxazin- 3(4H)-one (Biofocus)

Compound 57:8-acetyl-2,2-difluoro-4-[(4-methylphenyl)methyl]-2H-1,4-benzoxazin- 3(4H)-one (Biofocus)

Compound 58: 8-acetyl-2,2-difluoro-4-[(2-fluorophenyl)methyl]-2H-1 ,4-benzoxazin-

3(4H)-one (Biofocus)

Compound 59: 8-acetyl-2,2-difluoro-4-[(4-fluorophenyl)methyl]-2H-1 ,4-benzoxazin- 3(4H)-one (Biofocus)

Compound 60: 8-acetyl-2,2-difluoro-4-[(3-fluorophenyl)methyl]-2H-1,4-benzoxazin-

3(4H)-one (Biofocus)

Compound 61 : δ-acetyl^^-difluoro^-^-chlorophenylJmethylJ^H-i^-benzoxazin-

3(4H)-one (Biofocus)

Compound 62: 8-acetyl-4-[(4-ethenylphenyl)methyl]-2,2-difluoro-2H-1,4- benzoxazin-3(4H)-one (Biofocus)

Compound 63: 8-acetyl-2,2-difluoro-4-{[4-(methylthio)phenyl]methyl}-2H-1,4- benzoxazin-3(4H)-one (Biofocus)

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 5_H 0, δ_c 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:

Time (min) Flow rate (mL/min) % A % B

I) 3 97 3

0.1 3 97 3 4.2 3 0 100

4.8 3 0 100

4.9 3 97 3

5.0 3 97 3

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:

Time (min) Flow rate (mL/min) % A % B

~0 3 99 1

0.1 3 99 1

4.0 3 3 97

5.0 3 3 97

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:

Time (min) Flow rate (mL/min) % A % B

~0 1 97 3

1.5 1 0 100

1.9 1 0 100

2.0 1 97 3

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:

Time (min) Flow rate (mL/min) % A % B

I) 1 99 1

1.5 1 3 97

1.9 1 3 97

2 1 0 100

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:

Time (min) (normal / extended run) Flow rate (mL/min) %A % B

0/0 40 95 5

1/1 40 95 5

10/20 40 70 30

10.5/20.5 40 1 99

15/25 40 1 99

Method B:

Time (min) (normal / extended run) Flow rate (mL/min) %A %B

0/0 40 85 15

1/1 40 85 15

10/20 40 45 55

10.5/20.5 40 1 99

15/25 40 1 99

Method C:

Time (min) (normal / extended run) Flow rate (mL/min) %A % B

0/0 40 70 30

1 /1 40 70 30

10/20 40 15 85

10.5/20.5 40 1 99

15/25 40 1 99

Method D:

Time (min) (normal / extended run) Flow rate (mL/min) %A %B

0/0 40 50 50

1/1 40 50 50

10/20 40 1 99

10.5/20.5 40 1 99

15/25 40 1 99

Method E:

Time (min) (normal / extended run) Flow rate (mL/min) %A %B 0/0 40 20 80 1 /1 40 20 80 10/20 40 1 99 10.5/20.5 40 1 99 15/25 40 1 99

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:

Time (min) (normal / extended run) Flow rate (mL/min) %A %B

0/0 40 99 1

1 /1 40 99 1

10/20 40 70 30

10.5/20.5 40 1 99

15/25 40 1 99 Method B: Time (min) (normal / extended run) Flow rate (mL/min) %A %B

0/0 40 85 15

1/1 40 85 15

10/20 40 45 55

10.5/20.5 40 1 99

15/25 40 1 99

Method C:

Time (min) (normal / extended run) Flow rate (mL/min) %A % B

0/0 40 70 30

1/1 40 70 30

10/20 40 15 85

10.5/20.5 40 1 99

15/25 40 1 99

Method D:

Time (min) (normal / extended run) Flow rate (mL/min) %A %B

0/0 40 50 50 1 /1 40 50 50 10/20 40 1 99 10.5/20.5 40 1 99 15/25 40 1 99

Method E:

Time (min) (normal / extended run) Flow rate (mL/min) %A %B

0/0 40 20 80

1/1 40 20 80

10/20 40 1 99

10.5/20.5 40 1 99

15/25 40 1 99

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 of formula (I) as defined above for the GIyTI transporter were determined by the following assay. The compounds of formula (I) as defined above were used in the form as described herein. The compounds of formula (I) as defined above 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, plC₅o (negative Iog10 of the molar IC50) values were calculated using the ActivityBase™ software.

Supporting compounds 1 to 49 and 52 to 63 have been tested in the above assay. Compounds 1 to 40, 42 to 49, 53 and 55 to 63 have a plC₅o of 5.0 or above. Compounds 1 , 2, 3/4 (faster running enantiomer), 5/6 (slower running enantiomer), 7 to 1 1 , 12 or 13 (slower running enantiomer), 14 or 15 (faster running enantiomer), 16 or 17 (faster running enantiomer), 18 or 19 (slower running enantiomer), 20 or 21 (compound prepared from slower running enantiomer of intermediate 13/14), 22, 23, 24 or 25 (compound prepared from slower running enantiomer of intermediate 15/16), 27 to 35, 37, 40, 42 to 47, 49, 53, 56 and 60 have a plC₅₀ of 6.0 or above. Compound 3/4 (faster running enantiomer) has a plC₅₀ of 7.9. Compound 40 has a plC₅₀ of 6.6. Compound 44 has a pi C₅₀ of 7.1. 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 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 4, 5/6 (slower running enantiomer), 7, 8, 9, 10, 1 1 , 12/13 (slower running enantiomer), 14/15 (faster running enantiomer), 16, 17, 18, 19, 20/21 (compound prepared from slower running enantiomer of intermediate 13/14), 22, 23, 24, 25, 27 to 35, 37 to 40, 42 to 47, 49, 53, 56 to 60 and 62 have a plC₅₀ for the GIyTI transporter that is greater than the plC₅₀ for the GlyT2 transporter by 1.0 or more. Compounds 1 , 2 and 3/4 (faster running enantiomer), 5/6 (slower running enantiomer), 7, 8, 9, 10, 11 , 12/13 (slower running enantiomer), 14/15 (faster running enantiomer), 16/17 (faster running enantiomer), 18/19 (slower running enantiomer), 20/21 (compound prepared from slower running enantiomer of intermediate 13/14), 22/23 (slower running enantiomer) and 24/25 (compound prepared from slower running enantiomer of intermediate 15/16), 27 to 30, 34, 35 and 40 have a plC₅₀ for the GIyTI transporter that is greater than the plC₅₀ for the GlyT2 transporter by 2.0 or more. Compounds 42 to 49, 53, 55 to 63 have a plC₅₀ for the GIyTI transporter that is greater than the plC50 for the GlyT2 transporter by 0.5 or more. Compound 3/4 (faster running enantiomer) has a plC₅o for the GIyTI transporter that is greater than the plC₅o for the GlyT2 transporter by 3.1. Compound 44 has a plC₅₀ for the GIyTI transporter that is greater than the plC₅o for the GlyT2 transporter by 2.3.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein

(I)

R¹ is selected from

c) R¹ is phenyl which is unsubstituted or substituted with 1 to 3 substituents

S;

n is 1 , 2, 3 or 4;

R² is selected from hydrogen, halo, cyano, C_1-4alkyl, haloC_1-4alkyl, C_1-4alkoxy and FIaIoC_1- ₄alkoxy;

R³ is selected from hydrogen, halo, cyano and haloC_1-4alkyl;

₄alkoxy;

R⁵ is selected from -C(OH)R⁶ and -C(O)Me; and

R⁶ is selected from -CF₃, -CHF₂ and -CH₂F,

for use in therapy.

2. The compound according to claim 1 wherein R², R³ and R⁴ are independently selected from hydrogen, halo, cyano and haloC_1-4alkyl.

3. The compound according to claim 2 wherein R², R³ and R⁴ are hydrogen.

4. The compound according to any one of claims 1 to 3 wherein R⁵ is -C(O)R⁶.

5. The compound according to any one of claims 1 to 4 wherein R⁶ is -CF₃.

6. The compound according to any one of claims 1 to 5 wherein R¹ is

(a) 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_1-4alkoxy, cyano, hydroxyl, hydroxy C_1-4alkyl, -(CH₂)_n-(NR^1aR^1b), -(C0)NR^1aR^1b, -(CO)O- C_1-4alkyl, -(CHO), haloC_1-4alkyl and haloC_1-4alkoxy;

(b) 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_1-4alkyl, C_1-4alkoxy, cyano, hydroxyl, hydroxy C_1-4alkyl, -(CH₂)_n-(NR^1aR^1b), -(C0)NR^1aR^1b, -(CO)O-C_1-4alkyl, - (CHO), haloC_1-4alkyl and haloC_1-4alkoxy; or

(c) phenyl which is unsubstituted or substituted with 1 to 2 substituents independently selected from halo, C_1-4alkyl, C_1-4alkoxy, cyano, hydroxy, hydroxyC_1-4alkyl, -(CH₂)_n- (NR^1aR^1b), -(C0)NR^1aR^1b, -(CO)O-C_1-4alkyl, -(CO)OH, -(CHO), -S0₂(NR^1aR^1b), halod. ₄alkyl, haloCi_-4alkoxy, -(CO)Ci_-4alkyl, C_2-4alkenyl, -SCi_-4alkyl and 5 to 6 membered heteroaryl ring which contains 1 to 4 heteroatoms independently selected from O, N and S.

7. The compound, or a salt thereof, according to claim 1 selected from

1 ,4-benzoxazin-3(4H)-one;

4-[(5-chloro-3-pyridinyl)methyl]-2,2-difluoro-8-[(1 R)-2,2,2-trifluoro-1-hydroxyethyl]-2H-1 ,4- benzoxazin-3(4H)-one; 6-({2,2-Difluoro-3-oxo-8-[(1 S)-2,2,2-trifluoro-1-hydroxyethyl]-2,3-dihydro-4H-1 ,4- benzoxazin-4-yl}methyl)-2-pyridinecarbonitrile;

6-({2_!2-difluoro-3-oxo-8-[(1 R)-2_!2_!2-trifluoro-1-hydroxyethyl]-2_!3-dihydro-4H-1 ,4- benzoxazin-4-yl}methyl)-2-pyridinecarbonitrile;

2,2-difluoro-4-[(5-fluoro-3-pyridinyl)methyl]-8-[(1 f?)-2,2,2-trifluoro-1 -hydroxyethyl]-2H-1 ,4- benzoxazin-3(4H)-one;

2_!2-difluoro-4-[(5-fluoro-3-pyridinyl)methyl]-8-[(1 S)-2_!2_!2-trifluoro-1-hydroxyethyl]-2H-1 _!4- benzoxazin-3(4H)-one;

4-[(5-chloro-3-pyridinyl)methyl]-2_!2-difluoro-8-[(1 R)-2-fluoro-1-hydroxyethyl]-2H-1 ,4- benzoxazin-3(4H)-one; 4-[(5-chloro-3-pyridinyl)methyl]-2_!2-difluoro-8-[(1 S)-2-fluoro-1-hydroxyethyl]-2H-1 _!4- benzoxazin-3(4H)-one;

4-({2,2-difluoro-8-[(1 S)-2-fluoro-1-hydroxyethyl]-3-oxo-2,3-dihydro-4H-1 ,4-benzoxazin-4- yl}methyl)-2-pyridinecarbonitrile;

8-Acetyl-2,2-difluoro-4-(3-pyridinylmethyl)-2/-/-1 ,4-benzoxazin-3(4/-/)-one; and

8-Acetyl-2_!2-difluoro-4-[(5-fluoro-3-pyridinyl)methyl]-2H-1 _!4-benzoxazin-3(4/-/)-one. 8. The compound, or a pharmaceutically acceptable salt thereof, according to any of claims 1 to 7, for use in the treatment of a disorder mediated by GIyTI .

9. The compound, or a pharmaceutically acceptable salt thereof, according to claim 8, wherein the disorder is psychosis, including schizophrenia, dementia or attention deficit disorder.

10. Use of a compound, or a pharmaceutically acceptable salt thereof, according to any of claims 1 to 7, in the manufacture of a medicament for the treatment of a disorder mediated by GIyTL

1 1. Use according to claim 10, wherein the disorder is psychosis, including schizophrenia, dementia or attention deficit disorder.

12. 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 of claims 1 to 7.

13. The method according to claim 12 wherein the disorder is psychosis, including schizophrenia, dementia or attention deficit disorder.

14. A pharmaceutical composition comprising (a) a compound, or a pharmaceutically acceptable salt thereof, according to any of claims 1 to 7 and (b) a pharmaceutically acceptable excipient.

15. A compound of formula (I), or a salt thereof, as defined in any of claims 1 to 7 with the proviso that the compound of formula (I) is other than:- 8-acetyl-2_!2-difluoro-4-[(2-methyl-1 _!3-thiazol-4-yl)methyl]-2H-1 ,4-benzoxazin-3(4H)-one;

8-acetyl-2_!2-difluoro-4-{[6-(trifluoromethyl)-3-pyridinyl]methyl}-2/-/-1 _!4-benzoxazin-3(4/-/)- one;

methyl 5-[(8-acetyl-2_!2-difluoro-3-oxo-2_!3-dihydro-4H-1 _!4-benzoxazin-4-yl)methyl]-2- furancarboxylate;

8-acetyl-2_!2-difluoro-4-(2-pyridinylmethyl)-2H-1 _!4-benzoxazin-3(4/-/)-one;

3-[(8-acetyl-2,2-difluoro-3-oxo-2,3-dihydro-4/-/-1 ,4-benzoxazin-4-yl)methyl]benzonitrile;

2-[(8-acetyl-2,2-difluoro-3-oxo-2,3-dihydro-4/-/-1 ,4-benzoxazin-4-yl)methyl]benzonitrile;

8-acetyl-4-{[5-acetyl-2-(methyloxy)phenyl]methyl}-2_!2-difluoro-2H-1 _!4-benzoxazin-3(4/-/)- one;

8-acetyl-4-[(4-chlorophenyl)methyl]-2,2-difluoro-2H-1 ,4-benzoxazin-3(4/-/)-one;

8-acetyl-2,2-difluoro-4-[(4-methylphenyl)methyl]-2/-/-1 ,4-benzoxazin-3(4/-/)-one;

8-acetyl-2,2-difluoro-4-[(4-fluorophenyl)methyl]-2H-1 ,4-benzoxazin-3(4/-/)-one;

8-acetyl-2,2-difluoro-4-[(3-fluorophenyl)methyl]-2H-1 ,4-benzoxazin-3(4H)-one;

8-acetyl-4-[(4-ethenylphenyl)methyl]-2,2-difluoro-2H-1 ,4-benzoxazin-3(4/-/)-one; and

8-acetyl-2,2-difluoro-4-{[4-(methylthio)phenyl]methyl}-2/-/-1 ,4-benzoxazin-3(4/-/)-one.