ZA200303118B - Benzoxazinone derivatives, their preparation and use. - Google Patents

Description

Benzoxazinone derivatives, their preparation and use

The present invention relates to novel compounds, processes for their ‘ preparation, pharmaceutical compositions containing the same and their use as . 5 medicaments. More particularly this invention relates to novel benzoxazinone derivatives and their utility in the treatment and/or prophylaxis of CNS and other disorders.

WO 97/45419 discloses a series of benzoxazinone compounds as dopamine Dy receptor antagonists which are claimed to be useful in the treatment of psychosis and schizophrenia. EP 0900 792 Al discloses a series of piperazine and piperidine derivatives as 5-HT] receptor agonists which are claimed to be useful for treating CNS disorders.

Artigas (Trends in Pharmacological Sciences, Vol. 14, 262, 1993) suggests that the co-administration of a 5-HT]a receptor antagonist and a selective serotonin reuptake inhibitor (SSRI) may give rise to an improvement in anti-depressant efficacy.

Patent applications WO 00/40580 and WO 00/40581 both disclose a series of benzoxazine derivatives that are claimed to possess such a combined activity profile.

A novel series of benzoxazinone compounds has now been found that possess high affinity for 5-HT type receptors and / or potent serotonin reuptake inhibition activity. The present invention therefore provides, in a first aspect, a compound of formula (I) or a pharmaceutically acceptable salt thereof:

Rr] =

AT aes Ly | 0

TY

) o; s 25 ®, (0 in which

Ar is phenyl, naphthyl, a monocyclic heteroaromatic group or a bicyclic heteroaromatic croup, said Ar group being optionally substituted by 1 - 4 substituents, which may be the same or different, and which are selected from the group consisting of: halogen. hydroxy, cyano, nitro, trifluoromethyl, trifluoromethoxy, Ci_galkyl, trifluoromethanesulfonyloxy, pentafluoroethyl, Cj_galkoxy, arylCy_galkoxy,

C.galkylthio, C1.ealkoxyCy_galkyl, C3.7cycloalkylCy _galkoxy,

C|.galkanoyl, Cj_galkoxycarbonyl, Cj_galkylsulfonyl, Ci_galkylsulfinyl.

C|.galkylsulfonyloxy, C1_galkylsultonylCq_galkyl, arylsulfonyl, arylsulfonyloxy, arylsulfonylCy _galkyl, C1._galkylsulfonamido, Cy. galkylamido, ~~ Cj_galkylsulfonamidoCy_galkyl, Ci_galkylamidoCy_galkyl, arylsulfonamido, arylcarboxamido, arylsulfonamidoC _galkyl, arylcarboxamidoC_galkyl, aroyl, aroylCj_galkyl, arylCj_galkanoyl, a group

R30CO(CHy)g, R3ICONRA)(CHy)g, RIR4NCO(CHy)g or RIRINSO2(CHy)g where each of R3 and R#4 independently represents a hydrogen atom or

C_galkyl or R3 and R4 form part of a Cj3_gazacyloalkane or C3_g(2- oxo)azacycloalkane ring and s represents zero or an integer from 1 to 4, and a group Arl - 7, wherein Z represents a single bond, O, S or CH; and Arl represents a phenyl or a monocyclic heteroaromatic group, said Ar! group being optionally substituted by 1 - 3 substituents, which may be the same or different, and which are selected from the group consisting of a halogen, hydroxy, cyano, trifluoromethyl, C1_galkyl, C1.galkoxy or C1_galkanoyl; when Ar is a phenyl or a monocyclic heteroaromatic group, substituents positioned ortho to one another may be linked to form a 5- or 6- membered ring;

R! is hydrogen, Cy.galkyl, C3_galkenyl, C3_galkynyl or arylCj_galkyl;

RZ is halogen, C-galkyl, cyano, CF3, Cy_galkanoyl, C-galkoxy or hydroxy;

XisCHorN;

Y is asingle bond, O, or C=0;

pisO, I or 2; ris0, 1,2 or 3; mis 2,3 or 4; ’ n and q are independently 1 or 2. } 5

Alkyl groups which may be employed, whether alone or part of another group, include methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl and any branched isomers thereof such as isopropyl. t-butyl, sec-butyl, and the like. “Cy_galky!l” and “Cj_galkyl” respectively refer to alkyl groups having from one to four and from one to six carbon atoms, in all isomeric forms. Thus, Cy_galkyl would include: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl. Cj_galkyl would include, in addition, pentyl, neopentyl, sec-pentyl, n-pentyl, isopentyl, tert-pentyl and hexyl.

The term "halogen" is used herein to describe, unless otherwise stated, a group selected from fluorine, chlorine, bromine and iodine.

Where used herein the term "aryl", whether alone or as part of another group, is intended, unless otherwise stated, to denote an aromatic carbocyclic or heterocyclic group such as phenyl, pyrimidine, pyrazine or naphthyl, optionally substituted by one or more halogen, Cy-galkyl, CF3, cyano, hydroxy, Cj-galkanoyl, or Cj-galkoxy.

Where used herein the term naphthyl, whether alone or as part of another group, is intended, unless otherwise stated, to denote both 1-naphthyl and 2-naphthy! groups.

The term "monocyclic heteroaromatic group” is used to describe stable 5 or 6 membered heteroaromatic rings containing 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur. Suitable examples of such groups include thienyl, furanyl, pyrrolyl, triazolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, oxadiazolyl, . isothiazolyl, isoxazolyl, thiadiazolyl, pyridyl, pyrimidyl, triazinyl, pyridazy! and pyrazinyl. ) 30

The term "bicyclic heteroaromatic group" is used to describe stable 6.5 and 6,6 heteroaromatic rings containing 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur. Suitable examples of such groups include indolyl, quinolinyl, isoquinolinyl, ) benzofuranyl, benzothienyl, benzimidazolyl, indazolyl, 4-, 5-, 6- or 7-azaindolyl, benzothiazolyl, benzoxazolyl, benzisoxazolyl, benzisothiazolyl. quinazolinyl, quinoxalinyl, cinnolinyl and naphthyridinyl.

The term “C|_galkoxy” refers to a straight chain or branched chain alkoxy (or “alkyloxy”) group having from one to six carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy, neopentoxy, sec-pentoxy, n-pentoxy, isopentoxy, tert-pentoxy and hexoxy.

The term “C1 _galkylthio” refers to a straight chain or branched chain alkylthio group having from one to six carbon atoms, such as methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, sec-butylthio, tert-butylthio, pentylthio, neopentylthio, sec-pentylthio, n-pentylthio, isopentylthio, tert-pentylthio and hexylthio.

The term “arylCj_galkoxy™ refers to an aryl group which is linked by a Cj. galkoxy group. Examples include phenylmethoxy, phenylethoxy, naphthymethoxy, naphthylethoxy, phenylpropoxy, naphthylpropoxy, phenylbutoxy and naphthylpentoxy.

The term *C, ,cycloalkylCj_galkoxy” refers to a cycloalkyl group consisting of from 3 to 7 carbon atoms (for example cyclopropane, cyclobutane, cyclopentane, cyclohexane and cycloheptane) attached to an Cy_galkoxy group.

The term “* Cy_galkanoyl” refers to an alkanoyl group having from 1 to 6 carbon atoms, such as methanoy! (or “formyl”), ethanoyl (or “acetyl”), propanoyl, butanoyl, > pentanoyl and hexanoyl.

The term “aroyl” refers to a group having the formula “aryl-CO” wherein “aryl” is as defined above. ) The term ** C3_gazacyloalkane ring” refers to a cycloalkane ring containing from ) 5 3 to 6 carbon atoms, wherein one or more of the carbon atoms may be replaced by a nitrogen atom. Examples include aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and azepanyl.

The term “C3_g(2-0x0)azacycloalkane ring” refers to a C3_gazacyloalkane ring which also contains a C=O group, e.g. a cyclic amide or a lactam. Examples include aziridin- 2-one, azetidinone, pyrrolidinone, piperidinone and azepanone.

The term “C3_galkenyl” refers to an unsaturated hydrocarbon group containing one or more C=C bonds and having from three to six carbon atoms, in all isomeric forms, such as propenyl, butenyl, pentenyl, and hexenyl.

The term “C3_galkynyl” refers to an unsaturated hydrocarbon group containing one or more triple C-C bonds, having from three to six carbon atoms, in all 1someric forms, such as propynyl, butanediylidyne, butenylidyne, butylidyne, pentenynyl, and pentylidyne.

Preferably Ar is phenyl, naphthyl, indolyl, quinolinyl, quinazolinyl, indazolyl, isoquinolinyl, cinnolinyl or benzofuranyl, said groups being optionally substituted as defined above.

When a substituent on Ar is a further group Arl-Z, Ar! is preferably a monocyclic heteroaromatic group (particularly isoxazolyl), optionally substituted as defined above. Preferably Z is a single bond.

WO $2/34754 PCT/EPO1/12344

When the group Ar is phenyl or a monocyclic heteroaromatic group and optional substituents on the group Ar are positioned ortho to one another are linked to form a 5- or 6- membered ring, preferred examples of the resulting bicyclic system include 2,3-dihydrobenzo(b]furanyl, 3,4-dihydro-2H-benzo[b]pyranyl, 2.2-dimethyl- 2.35-dihydrobenzo[b]furanyl, 2,2-dimethyl-3,4-dihydro-2H-benzo[b]pyranyl, or 5-oxo- 5.6.7 8-tetrahydronaphthyl, the said groups being optionally further substituted as defined above.

Preferred optional substituents for Ar are halogen (particularly fluoro or chloro),

Cj-galkyl (particularly methyl, ethyl and propyl), cyano, CF3, C-galkoxy (particularly methoxy, ethoxy or isopropoxy), C-galkanoyl or a group Arl-Z as defined above.

Particularly preferred Ar groups, including optional substituents, are 4-indolyl, 4-indolyl(2-CN), 5-quinolinyl, 5-quinolinyl(2-Me), 8-quinolinyl, 1-isoquinolinyl, naphthyl, phenyl(2-CN), phenyl(2,3-dichloro), phenyl(3-Br), phenyl(3-Me), phenyl(3-

CF3), phenyl(2-propyl), phenyl(2-CN, 4-F), phenyl(2-(5-isoxazolyl), phenyl(3-ethyl-4-

Ch, 2,2-dimethyl-2,3-dihydrobenzo[b}furan-7-yl, (5-F)-2,2-dimethyl-2,3- dihydrobenzo[b]furan-7-yl, (6-F)-3,4-dihydro-2H-benzo{blpyranyl, (2,2-dimethyl)3,4- dihydro-2 H-benzo[b]pyranyl, 5-0x0-3,6,7,8-tetrahydronaphth-1-yl, 7-(2,3- dihydrobenzofuranyl), 7-(2-methyl)benzo[b}furanyl, 7-benzo[b}furanyl, 5-quinolinyl(2-

Me, 8-Cl), 5-quinolinyl(2-Me, 8-F), 5-quinolinyl(2-Me, 7-Cl), 5-quinolinyl(2-Me, 7-F) and 5-quinazolinyl(2-Me).

Most particularly preferred Ar groups, including optional substituents, are 5- quinolinyl(2-Me), 5-quinolinyl(2-Me, 7-Cl), 5-quinolinyl(2-Me, 7-F) and S- quinazolinyl(2-Me). ‘ When RI is C1-galkyl a preferred group is methyl. Preferably Rl is hydrogen or methyl. ) 30

When r is other than 0, preferred substituents include halogen (particularly fluoro or chloro), C|-galky! (particularly methyl or ethyl), cyano, C1-galkanoyl or CF3.

Preferably mis 2.

When n is 2, preferably q is 1.

Preferably, ris 0, 1 or 2.

Preferably R2 is halogen, particularly fluoro.

Preferably Y is oxygen or is a single bond. When Y is oxygen, preferably pis 0 or 1. When Y is a single bond, it is preferred that p is 1, so that X and the benzoxazinone group are linked by a CH, group.

Preferred compounds of this invention are examples E1 - E167 (as described below) and pharmaceutically acceptable salts thereof. Particularly preferred compounds according to this invention are: 6-(4-(1-(2-(4-1 F-Indolyloxy)ethyDpiperidinyloxy)-4H-benzo[1 4 Joxazin-3-one, 6-(4-(1-(2-(4-(2-Cyano)-1 H-indolyloxy)ethylpiperidinyoxy)-4f1-benzo[1 ,4]Joxazin-3- one, 6-(4-(1 _(3-(2-(5-Isoxazolyl)phenoxy)propyDpiperidiny oxy)-4H-benzo{ 1 ,4]oxazin-3- one, 6-(4-(1-(2-(5-Quinolinyloxy)ethy)piperidinyhmethyl)-4F-benzo{ 1 4Joxazin-3-one, 6-(4-(1 _(3-(2-Cyanophenoxy)propylpiperidinyl)oxy)-4/i-benzo(l .4Joxazin-3-one, 6-(4-(1 -(3-(7-(2,2-Dimethyl-2,3-dihydro)benzo [b]furanyloxy)propy!)piperidinyl)-oxy)- . 4H-benzo[ 1,4]oxazin-3-one, 6-(4-(1 (2-(7-(2.2-Dimethyl-2,3-dihydro)benzo[b]furanyloxy)ethyDpiperidinyloxy)-4- methyl-4H-benzo{1,4]oxazin-3-one,

6-(4-(1-(2-(1-naphthyloxy)ethyl)piperidinyl)oxy)-4-methyl-4 /{-benzo[ 1 ,4]oxazin-3- one, (H)-6-(3-(1-(3-(2-Cyanophenoxy)propyl)piperidinyl)methoxy)-4/-benzo|1,4]Joxazin-3-

one, (H)-6-(3-(1-(3-(2-Cyanophenoxy)propyl)pyrrolidinyl) methoxy)-4 H-benzo[ 1 4 Joxazin- 3-one, 6-(4-(1-(3-(2-(5-Isoxazolyl)phenoxy)propyl)piperazinylymethyl)-4 //-benzo[1,4Joxazin- 3-one, 6-(4-(1-(2-(5-(2-Methyl)quinolinyloxy)ethyl)piperidinyl)methyl)-4 f{-benzo[1,4]oxazin-

3-one, 6-(4-(1-(2-(5-(3-Methyl)quinolinyloxy)ethyl)piperidinylymethyl)-4H-benzo[ 1 ,4 Joxazin-3-one, 6-(4-(1-(2-(5-Cinnolinyloxy)ethyDpiperidinyl)methyl)-4 H-benzo[ 1 ,4}oxazin-3-one, 6-(4-(1-(2-(4-(1,2-Dihydro)benzo[b]furanyloxy)ethyl)piperidinyl)methyl)-4/7- benzo(!,4]Joxazin-3-one,

6-(4-(1-(2-(4-(1 A)-Indazolyloxy)ethyl)piperidiny )methyl)-4H-benzo[1,4]oxazin-3-one, 6-(4-(1-(2-(5-(2-Methyl)quinolinyloxy)ethylpiperidinyl)oxy)-4 H-benzo[ 1 ,4]Joxazin-3- one, 4-Methyl-6-(4-(1-(2-(5-(2-methyl)quinohinyloxy)ethyl)piperidinyl)oxy)-4 /- benzo[l,3]oxazin-3-one,

6-(4-(1-(2-(5-(2-Methyl)quinolinyloxy)ethyl)piperazinyl)methyl)-4 /1- benzo[1,4]oxazin-3-one, 6-(4-(1-(3-(5-(2-Methyl)quinolinyloxy)propyl)piperidinyl)methyl)-4 H- benzo|l,4]oxazin-3-one, 6-(4-(1-(3-(5-(2-Methyl)quinolinyloxy)propyl)piperazinyl)methyl)-4 H-

benzo(l,4]Joxazin-3-one, 6-(4-(1-(3-(5-(2-Methyl)quinolinyloxy)propyl)piperidinyl)oxy)-4 H-benzo[1,4]Joxazin- 3-one,

: 4-Methyl-6-(4-(1-(3-(5-(2-methyl)quinolinyloxy)propy)piperidinyl)oxy)-4 H- benzo[1,4}oxazin-3-one,

4-Methyl-6-(4-(1 _(2-(5-(2-methyl)quinolinyloxy)ethyl)piperidinyl)methyl)-4/- benzo[[,4]Joxazin-3-one, 6-(4-(1-(2-(5-(8-Chloro-2-methyl)quinolinyloxy)ethyl)piperidinyl)methyl)-4/1-

benzo|[l,4]oxazin-3-one,

4-Methyl-6-(4-(1-(3-(5-(2-methyl)quinolinyloxy)propyl)piperidinyl)-methyl)-4H/- benzofl,4]Joxazin-3-one, 6-(4-( 1-(2-(5-(8-Chloro-2-methyl)quinolinyloxy)ethyl)piperidiny)methyl)-4-methyi- 4 H-benzo[1,4]oxazin-3-one, 6-(4-(1 -(2-(5-(8-Fluoro-2-methyl)quinolinyloxy)ethylpiperidinyl)methyl)-4 4-

benzoll,4]oxazin-3-one, 6-(4-(1-(2-(5-(8-Fluoro-2-methyl)quinolinyloxy)ethylpiperidinyl)methyl)-4-methyl- 4 H-benzo[1,4]oxazin-3-one, 6-(4-(1-(2-(5-(8-Fluoro-2-methyl)quinolinyloxy)ethyl)piperidiny)oxy)-4/1- benzo[1,4]oxazin-3-one,

6-(4-(1-(2-(5-(8-Fluoro-2-methyl)quinolinyloxy)ethyDpiperidinyl)oxy)-4-methyl-4 /4- benzo[1.4]oxazin-3-one, 6-(4-(1-(2-(5-(7-Chloro-2-methyl)quinolinyloxy)ethylpiperidinyl)methyl)-4£- benzo[1,4]oxazin-3-one,

6-(4-(1 ~(2-(5-(7-Chloro-2-methyl)quinolinyloxy)ethyDpiperidinyl)methyl)-4-methyl-

4H-benzo[l,4]oxazin-3-one, 6-(4-(1-(2-(5-(7-Chloro-2-methyhquinolinyloxy)ethyl)piperidinyloxy)-4£- benzo[1,4]Joxazin-3-one,

6-(4-(1 -(2-(5-(7-Chloro-2-methyl)quinolinyloxy)ethyl)piperidinyl)oxy)-4-methyl-4 H- benzo[1,4]oxazin-3-one,

6-(4-(1 -(2-(5-(7-Chloro-2-methyl)quinolinyloxy)ethyl)piperazinyl)methyl)-4 H- benzo[1,4]oxazin-3-one, 6-(4-(1-(3-(5-(7-Chloro-2-methyl)quinolinyloxy)propyl)piperidinyHoxy)-4 - benzo{1,4]oxazin-3-one,

6-(4-(1 -(3-(5-(7-Chloro-2-methyl)quinolinyloxy)propyl)piperidinyl)oxy)-4-methyl-4 H- benzo[l.4]Joxazine-3-one,

6-(4-(1-(2-(5-(2-Methyl)quinolinyloxy)ethy)piperidinylymethyl)-4-(2-propyl)-4 4- benzol1,4]Joxazin-3-one, 6-(4-(1 -(2-(5-(2-Methyl)quinazolinyloxy)ethyl)piperidiny))methyl)-4 H-benzol 1 A41- oXazin-3-one, h) 6-(4-(1-(2-(5-(7-Fluoro-2-methyhquinolinyloxy)ethyDpiperidinyhmethyl)-4- benzo[1,4]oxazin-3-one, 7_Fluoro-6-(4-(1-(2-(5-(2-methyl)quinolinyloxy)ethyDpiperidinymethyl)-4- benzo[1.4]Joxazin-3-one, 8-Fluoro-d-methyl-6-(4-(1-(2-(5-(2-methyl)quinolinyloxy)ethylpiperidinyl) methyl)- 4H-benzo[l,4]oxazin-3-one, 8-Fluoro-6-(4-(1 _(2-(5-(2-methylyquinolinyloxy)ethylpiperidinymethyl)-4- benzo[1,4]oxazin-3-one, 7 8-Difluoro-6-(4-(1-(2-(5-(2-methylquinolinyloxy)ethyl)piperazinyhmethyl)-4H- benzo[1,4]Joxazin-3-one, 4-Ethyl-6-{1 _[2-(2-methyl-quinolin-5-yloxy)-ethyl]-piperidin-4-ylmethyl}-4H- benzo[1,4]oxazin-3-one and pharmaceutically acceptable salts thereof.

The compounds of formula (I) can form acid addition salts thereof. It will be appreciated that for use in medicine the salts of the compounds of formula (I) should be pharmaceutically acceptable. Suitable pharmaceutically acceptable salts will be apparent to those skilled in the art and include those described in J. Pharm. Sci., 1977, 66. 1-19, such as acid addition salts formed with inorganic acids e.g. hydrochloric, hydrobromic, sulfuric, nitric or phosphoric acid; and organic acids e.g. succinic, maleic, acetic, fumaric, citric, tartaric, benzoic, p-toluenesulfonic, methanesulfonic or naphthalenesulfonic acid. Certain of the compounds of formula (I) may form acid : addition salts with one or more equivalents of the acid. The present invention includes within its scope all possible stoichiometric and non-stoichiometric forms.

The compounds of formula (I) may be prepared in crystalline or non-crystalline form, and, if crystalline, may optionally be hydrated or solvated. This invention includes within its scope stoichiometric hydrates or solvates as well as compounds containing variable amounts of water and/or solvent.

Certain compounds of formula (I) arc capable of existing in stereoisomeric forms (e.g. geometric or (*“cis-trans’”) isomers, 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. For compounds of formula (I) where RI is a Cy_galkenyl group, the compounds may also exist as geometric isomers around the double bond. The present invention includes within its scope all such isomers, including mixtures.

In a further aspect, this invention provides a process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof, which process

Comprises: (a) the coupling of a compound of formula (II): r! a

HN X Y N 0 aves 0 (R%), (ID) in which Rl, R2,Y, n, p, q and r are defined in formula (I),

S11 -

Claims (1)

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof: Rr] Ar oo Y ! 0) AEave; 0 (R%), (0) in which Ar is phenyl. naphthyl, a monocyclic heteroaromatic group or a bicyclic heteroaromatic group. said Ar group being optionally substituted by I - 4 substituents, which may be the same or different, and which are selected from the group consisting of: halogen, hydroxy, cvano, nitro, trifluoromethyl, trifluoromethoxy, Ci_galkyl, trifluoromethanesulfonyloxy, pentafluoroethyl, Cy_galkoxy, arylCj_galkoxy, 13 C1 alkylthio, C1.galkoxyCj_galkyl, Cs_7cycloalkylCy_galkoxy,

Ci.galkanoyl, Cj.galkoxycarbonyl, Cq.galkylsulfonyl, Cj_galkylsulfinyl,

Ci.gatkylsulfonyloxy, C-galkylsulfonylCy_galkyl, arylsulfonyl, arylsulfonyloxy, arylsulfonylC_galkyl, C1.galkylsulfonamido, Ci. galkylamido, Cj_galkylsulfonamidoCj_galkyl, Cj.galkylamidoCy_galkyl, arylsulfonamido, arylcarboxamido, arylsulfonamidoC1 _galkyl, arylcarboxamidoC|_galkyl, aroyl, aroylC|_galkyl, arylC|_galkanoyl, a group R30CO(CHy)s, RRICON(RH (CH), RIRNCO(CHo)s or RIRNSO2(CHa)g where each of R3 and R# independently represents a hydrogen atom or Cy_galkyl or R3 and R4 form part of a C3_gazacyloalkane or C3_g(2- oxo)azacycloalkane ring and s represents zero or an integer from 1 to 4, and a group Ar! - Z, wherein Z represents a single bond, QO, S or CH» and Arl represents a phenyl or a monocyclic heteroaromatic group. said Ar! group being optionally substituted by 1 - 3 substituents. which may be the same or different, and which are selected from the group consisting of: a halogen. hydroxy. cyano, trifluoromethyl. Cy_galkyl. Cy _galkoxy or Cj _galkanoyl: when Ar is a phenyl or a monocyclic heteroaromatic group. substituents positioned ortho to one another may be linked to form a 3- or 6- membered ring, RY is hydrogen. Cj _galkyl. Cy_galkenyl. Cy_galkynyl or arylCj_galkyl: R= is halogen. C-galkyl. cyano, CF3. Cj _galkanovl. C-galkoxy or hydroxy; XisCHorN: Y 1s a single bond. O, or C=0; pisO, 1 or2: ris0. 1.2 or 3: mis 2. ord: nand q are independently | or 2.

2. A compound according to claim | in which Ar is phenyl, naphthyl, indolyl, quinolinyl, quinazolinyl. indazolyl, isoquinolinyl, cinnolinyl or benzofuranyl, said groups being optionally substituted as defined in claim 1.

3. A compound according to claim | or 2, in which Ar is substituted by halogen (particularly fluoro or chloro), Ci-galkyl (particularly methyl, ethyl and propyl), cvano. CFj3. Cj-galkoxy (particularly methoxy, ethoxy or isopropoxy), C1-galkanoyl or a group Ar! - Z as defined in claim 1.

4. A compound according to claim 3. in which Arl is a monocyclic heteroaromatic group (particularly isoxazolyl). optionally substituted as defined in : claim 1. and Z is a single bond.

S. A compound according to claim 1 in which Ar is 4-indolyl. 4-indolyl(Z-

CN). 3-quinolinvl. 35-quinolinvl(2-Me). $-guinolinyl. I-isoquinolinyl. naphthyl. phenyl(2-CN). phenvl{2.3-dichloro). phenyl(3-Br). phenyl(3-Me), phenyl(3-CF3). phenvl(2-propvl). phenvi{2-CN. 4-F). phenyl(2-(5-isoxazolyvl). phenyl(3-ethyl-4-Cl). ; 3 2.2-dimethyl-2.3-dihydrobenzo{bjturan-7-vl. (3-F)-2.2-dimethyl-2.3- dihvdrobenzo[b]furan-7-vl. (6-F)-3.4-dihvdro-2H-benzo[b]pyranyl, (2.2-dimethyl)3.4- dihvdro-2H-benzo[b]pyranyl. 5-0x0-5.6,7,8-tetrahydronaphth-1-vl, 7-(2.3- dihvdrobenzofuranvl). 7-(2-methybenzo[b]furanyl. 7-benzo{b}furanyl. 5-quinolinyl(2-

Me. 8-C1). 3-quinolinvl(2-Me. 8-F). 3-quinolinyl(2-Me, 7-C1), 3-quinolinyl(2-Me, 7-F) or 3-quinazolinvI(2-Me).

6. A compound according to any of claims | to 5, whereinris 0, 1 or 2.

7. A compound according to any of claims 1 to 6, wherein R2 is halogen. 153 particularly fluoro.

8. A compound according to any of claims 1 to 7, in which R1 is hydrogen or methyl.

9. A compound according to any of claims 1 to 8, in which m is 2.

10. A compound according to claim 1 which is a compound selected from Example El - E167 or a pharmaceutically acceptable salt thereof.

11. A compound according to claim 1 which is: 6-(4-(1-(2-(4-1 A-Indolvloxy)ethyl)piperidinyl)oxy)-4H-benzo[1.4]oxazin-3-one; 6-(4-( 1-(2-(4-(2-Cyano)- | H-indolyloxy)ethy)piperidinyhoxy)-4 H-benzo[ 1 .4]oxazin-3- one: 6-(4-(1-(3-(2-(5-Isoxazolyl)phenoxy)propylpiperidinyl)oxy)-4 f-benzo[ | 4Joxazin-3- one:

6-(4-(1-(2-(3-Quinolinyloxy)ethylpiperidiny)methyl)-4H-benzo[ 1 4 ]oxazin-3-one; 0-(4-(1-(3-(2-Cyvanophenoxy)propylpiperidinyoxy)-4 H-benzo[ 1 .4]oxazin-3-one: O-(4-(1-(3-(7-(2.2-Dimethyl-2.3-dihydro)benzo[b]turanyloxy)propypiperidiny )-oxy)- 4/H-benzo[!.4]oxazin-3-one:

. 50 0-(4-(1-(2-(7-(22-Dimethyl-2_3-dihvdrojbenzo[blturanvioxy)ethyDpiperidinyljoxy)-4- methyl-4/-benzo[1.4]oxazin-3-one, 0-(4-(1-(2-(1-naphthvloxy)ethyDpiperidinyl)oxy)-#-methyl-4 H-benzo{1.4]Joxazin-3- one: (+)-6-(3-(1-(3-(2-Cyanophenoxy)propyl)piperidinyl)methoxy)-4 /1-benzo[ 1 4Joxazin-3- one: {+)-6-(3-(1-(3-(2-Cvanophenoxy)propylpvrrolidinyl)methoxy)-4H-benzo[ 1.4]oxazin- 3-one: O-(4-(1-(3-(2-(5-Isoxazolvl)phenoxy)propyl)piperazinyl)methyl)-44-benzo[1.4]oxazin- 3-one; 13 6-(4-(1-(2-(5-(2-MethyDquinolinyloxy)ethyl)piperidinyl)methyl)-4/H-benzo[ 1.4 ]oxazin- 3-0ne; O-(4-(1-(2-(5-(3-Methyl)quinolinyloxy)ethyl)piperidinyl)methyl)-4 H-benzo[ 1,4 Joxazin- 3-one; 6-(4-(1-(2-(5-Cinnolinyloxy)ethyl)piperidinyl)methyl)-4 H-benzo[ 1 ,4]oxazin-3-one; 6-(4-(1-(2-(#-(1,2-Dihydro)benzo[b}turanyloxy)ethyl)piperidinyl)methyl)-4 H- benzo[1.4]oxazin-3-one; 6-(4-(1-(2-(4-(1 F)-Indazolyloxy)ethyl)piperidinyl)methyl)-4 H-benzo[1,4]oxazin-3-one; 6-(4-(1-(2-(5-(2-Methyl)quinolinyloxy)ethyl)piperidinyl)oxy)-4 H-benzo[1,4]oxazin-3- one; 4-Methyl-6-(4-(1-(2-(5-(2-methyl)quinolinyloxy)ethyl)piperidinyl)oxy)-4 H- benzo[1,3]oxazin-3-one; 6-(4-(1-(2-(3-(2-Methyl)quinolinyloxy)ethyl)piperazinyl)methyl)-4 H- ‘ benzo[l,4]oxazin-3-one; 6-(4-(1-(3-(5-(2-Methyl)quinolinyloxy)propy!)piperidinyl)methyl)-4 A- benzo[l.4]oxazin-3-one;

6-(4-(1-(3-(5-(2-Methyhquinolinvioxyv)propvlpiperazinymethy|)-4 H- benzo[1.4Joxazin-3-one; O-(4-(1-(3-(5-(2-Methy)quinofinyloxy)propyl)piperidinyoxy)-4/-benzo[ 1 .4]oxazin- 3-one;

. 3 A-Methyl-6-(4-(1-{3-(5-(2 methyDquinolinyloxy)propvDpiperidinyloxy)-4 H- benzo[l.4loxazin-3-one: 4-Methyl-6-(4-(1-(2-(5-(2-methyDquinolinvloxy)ethypiperidinyl)methv1)-4 /- benzo[1,4]Joxazin-3-one; 6-(4-(1-(2-(3-(8-Chloro-2-methylquinolinyloxy)ethylpiperidiny)methy1)-4 /H- benzo[l.4}oxazin-3-one; d4-Methyl-6-(4-(1-(3-(5-(2-methyl)quinolinyloxy)propyl)piperidinyl)-methyl)-4 H- benzo[l.4]Joxazin-3-one; O-(#4-(1-(2-(5-(8-Chloro-2-methy!)quinolinvloxy)ethyl)piperidinyl)methyl)-4-methyvl- 4 H-benzo[1,4]Joxazin-3-one; 6-(4-(1-(2-(5-(8-Fluoro-2-methylquinolinvioxy)ethylpiperidinyDmethyl)-4 H- benzo l.4]oxazin-3-one; 6-(4-(1-(2-(5-(8-Fluoro-2-methyl)quinolinyloxy)ethyDpiperidinyl)methyl)-4-methyl- 4 H-benzo[1,4]oxazin-3-one; 6-(4-(1-(2-(5-(8-Fluoro-2-methylquinolinyloxy)ethyl)piperidinyoxy)-4 H- benzo[l,4]oxazin-3-one; 6-(4-(1-(2-(5-(8-Fluoro-2-methyl)quinolinyloxy)ethy)piperidinyl)oxy)-4-methyl-4 /- benzo(1,4]Joxazin-3-one; 6-(4-(1-(2-(5-(7-Chloro-2-methyl)quinolinyloxy)ethylpiperidinyl)methyl)-4 H- benzo[1.4}oxazin-3-one; 6-(4-(1-(2-(5-(7-Chloro-2-methyl)quinolinyloxy)ethyl)piperidinyl)methy1)-4-methyl- 4 H-benzo[|.4]Joxazin-3-one; 6-(4-(1-(2-(3-(7-Chloro-2-methyl)quinolinyloxy)ethyl)piperidinyl)oxy)-= H- benzo[l,4]Joxazin-3-one: 6-(4-(1-(2-(3-(7-Chloro-2-methyi)quinolinyloxy)ethy!)piperidinyl)oxy)-#+-methyl-4 H- benzo[l.4]oxazin-3-one;

S00.

O-(4-(1-(2-(3-(7-Chloro-2-methy)quinolinyloxy)ethylpiperazinyl)methyl)-4 /- benzo[1.4]oxazin-3-one: O-(4-(1-(3-(3-(7-Chloro-2-methvhquinolinvloxy)propyDpiperidinyoxy)-4 H- henzoll.4Joxazin-3-one: 0-{4-(1-(3-(3-({7-Chloro-2-methvhquinolinvioxyipropylipiperidinyDoxy )-4-methvl-4 H- benzo[l.4]Joxazine-3-one: O-{-(1-(2-(5-(2-MethyDquinolinvloxy)ethvl)piperidinylimethyl)-4-(2-propyl)-4 H- benzo[t.4]oxazin-3-one; 6-{4-(1-(2-(3-(2-MethyhguinazolinyloxyethyDpiperidiny l)methyl)-4 H-benzo[ 1.4]- [0 oxazin-3-one:; 6-(-(1-(2-(3-(7-Fluoro-2-methyvhquinolinyloxy)ethyl)piperidinyl)methyl)-4 H- benzo[1.4]oxazin-3-one; 7-Fluoro-6-(2-( 1-(2-(3-(2-methyl)quinolinyloxy)ethyl)piperidinyl)methy)-4 H- benzo[l.4]oxazin-3-one; 13 8-Fluoro-4-methyl-6-(4-(1-(2-(5-(2-methyl)quinolinyloxy)ethylpiperidinyl) methyl)- 4H-benzo[1,4]Joxazin-3-one; 8-Fluoro-6-(4-(1-(2-(5-(2-methvquinolinyloxy)ethyl)piperidinyl)methyl)-4 A- benzo[1.4]oxazin-3-one;

7.8-Difluoro-6-(4-(1-(2-(5-(2-methyl)quinolinyloxy)ethyl)piperazinyl)methyl)-4 H- benzo[l.4]oxazin-3-one; 4-Ethyl-6-{1-[2-(2-methyl-quinolin-5-yloxy)-ethyl]-piperidin-4-ylmethyl}-4 H- benzo[1,4]oxazin-3-one or a pharmaceutically acceptable salt thereof.

12. A process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof, which process comprises: (a) the coupling of a compound of formula (I):

gr] [Hs HN X Y N 0 (iver

O . ®%) (11) in which RT, RZ. Y. n. p. q and r are defined in formula (I). with a compound of formula (111): Ar —O L hy (1h in which Ar and m are as defined for formula (I) and L is a leaving group: or (b) reacting a compound of formula (II) as defined above with a compound of formula (IV) Ar —O CHO (IV) in which Ar and m are defined in formula (I), in the presence of a reducing agent; or (c) for a compound of formula (I) wherein X is N, reacting a compound of formula (VX Rr! YY 0 TT 0] O (R%), , Vv) in which p, R°, rand R' are as defined in formula (I), with a compound of formula (V1):

Ar —0O / J Rv , NH vA 4 m n I (VI) in which Ar. m. q and n are as defined in formula (I), in the presence of a reducing agent; > and optionally thereafter for each of process (a). (b) or (c): e removing any protecting groups. and/or e converting a compound of formula (1) into another compound of formula (I), and/or e forming a pharmaceutically acceptable salt.

13. A pharmaceutical composition which comprises a compound according to any one of claims 1 to 11 and a pharmaceutically acceptable carrier or excipient.

14. A process for preparing a pharmaceutical composition according to claim 13, the process comprising mixing a compound according to any one of claims 1 to 11 and a pharmaceutically acceptable carrier or excipient.

15. A compound according to any one of claims 1 to 1! or a composition according to claim 13 for use in therapy.

16. A compound according to any one of claims 1 to 11 or a composition according to claim 13 for use in the treatment or prophylaxis of CNS and other disorders. , 17. A compound according to any one of claims 1 to 11 or a composition according to claim [3 for use in the treatment or prophylaxis of depression and/or - anxiety.

18. The use of a compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof, or a composition according to claim 13, in the manufacture of a medicament for the treatment or prophylaxis of CNS and other disorders.

19. The use as claimed in claim 18, wherein the medicament is for the treatment or prophylaxis of depression and/or anxiety.

20. A compound according to anyone of claims 1, 15, 16 & 17 substantially as herein described and exemplified.

21. A process according to either one of claims 12 and 14, substantially as herein described and exemplified.

22. A pharmaceutical composition according to claim 13, substantially as herein described and exemplified.

23. Use according to claim 18, substantially as herein described and exemplified. -96- AMENDED SHEET