WO2005058882A1

WO2005058882A1 - Compounds having morpholinyl and piperidinyl groups for use as glyt1 and glyt2 inhibitors

Info

Publication number: WO2005058882A1
Application number: PCT/EP2004/014469
Authority: WO
Inventors: Clive Leslie Branch; Howard Marshall; David John Nash; Roderick Alan Porter
Original assignee: Glaxo Group Limited
Priority date: 2003-12-18
Filing date: 2004-12-16
Publication date: 2005-06-30
Also published as: GB0329362D0

Abstract

The invention provides a compound of formula (I) or a salt or solvate thereof, wherein R1, R3 and R4, Het, X and Ar are as defined in the specification, and uses of such compounds. The compounds inhibit GlyT1 transporters and are useful in the treatment of certain neurological and neuropsychiatric disorders, including schizophrenia.

Description

COMPOUNDS HAVING MORPHOLINYL AND PIPERIDINYL GROUPS FOR USE AS GLYTl AND GLYT2 INHIBITORS

The present invention relates to glycine transporter inhibiting compounds, their use in the manufacture of medicaments for treating neurological and neuropsychiatric disorders, in particular psychoses, dementia or attention deficit disorder. The invention further comprises processes to make these compounds and pharmaceutical formulations thereof.

Molecular cloning has revealed the existence in mammalian brains of two classes of glycine transporters, termed GlyT1 and GlyT2. GlyT1 is found predominantly in the forebrain and its distribution corresponds to that of glutaminergic pathways and NMDA receptors (Smith, et al., Neuron, 8, 1992: 927-935). Molecular cloning has further revealed the existence of three variants of GlyT1 , termed GlyT-la, GlyT-1b and GlyT-1 c (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 strychnine-sensitive 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 GlyT1. These data are consistent with the view that, by regulating the synaptic levels of glycine, GlyT1 and GlyT2 selectively influence the activity of NMDA receptors and strychnine-sensitive glycine receptors, respectively.

NMDA receptors are critically involved in memory and learning (Rison and Staunton, Neurosci. Biobehav. Rev., 9 533-552 (1995); Danysz et al, Behavioral Pharmacol.. 6 455-474 (1995)); and, furthermore, decreased function of NMDA-mediated neurotransmission appears to underlie, or contribute to, the symptoms of schizophrenia (Olney and Farber, Archives General Psychiatry. 52, 998-1007 (1996). Thus, agents that inhibit GlyT1 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. Conversely, over-activation of NMDA receptors has been implicated in a number of disease states, in particular the neuronal death associated with stroke and possibly neurodegenerative diseases, such as Alzheimer's disease, multi-infarct dementia, AIDS dementia, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis or other conditions in which neuronal cell death occurs, such as stroke or head trauma. Coyle & Puttfarcken, Science, 262. 689-695 (1993); Lipton and Rosenberg, New Enαl. J. of Medicine. 330. 613-622 (1993); Choi, Neuron, 1 , 623-634 (1988). Thus, pharmacological agents that increase the activity of GlyT1 will result in decreased glycine- activation of NMDA receptors, which activity can be used to treat these and related disease states. Similarly, drugs that directly block the glycine site of the NMDA receptors can be used to treat these and related disease states. Glycine transport inhibitors are already known in the art, for example as disclosed in published international patent application WO03/055478 (SmithKline Beecham).

However, there still remains the need to identify further compounds that can inhibit GlyTI transporters, including those that inhibit GlyTI transporters selectively over GlyT2 transporters.

It has now been found that a novel class of compounds inhibit GlyTI transporters and are thus useful in the treatment of certain neurological and neuropsychiatric disorders, including schizophrenia.

Thus, in the first aspect, there is provided a compound of formula (I) or a salt or solvate thereof:

(I)

wherein:

• X is -O- or -NR²- (wherein R² is hydrogen or optionally substituted C_1-8alkyl);

• when X is -O-, R¹ is selected from the group consisting of optionally substituted C_t_ 8alkyl, optionally substituted C_3-8cycloalkyl, optionally substituted C_3-8heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, arylCι_-8alkyl (wherein both aryl and C_1-8alkyl are optionally substituted) and heteroarylC-ι_-8alkyl (wherein both heteroaryl and C_1-8alkyl are optionally substituted);

• when X is -NR²-, R¹ is selected from the group consisting of optionally substituted C_1-8alkyl, optionally substituted C_3-8cycloalkyl, optionally substituted C_3- βheterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, arylC-]. 8alkyl (wherein both aryl and C_1-8alkyl are optionally substituted) and heteroarylC-i..

₈alkyl (wherein both heteroaryl and C_1-8alkyl are optionally substituted) or R¹ and R² together with the nitrogen to which they are attached form a C_4-8heterocyclyl group, which C _-8heterocyclyl group is optionally substituted or optionally fused to an optionally substituted aryl or an optionally substituted heteroaryl group; • Het is an optionally substituted 5- or 6-membered monocyclic heteroaryl group;

• R³ and R⁴ are independently selected from the group consisting of hydrogen, halogen and C_1- alkyl, or R³ and R⁴ together form a C_3-4cycloalkyl; • Ar is an optionally substituted aryl or an optionally substituted heteroaryl; and

• n is O, 1 , 2 or 3.

As used herein, the term "alkyl" refers to a straight or branched alkyl in all isomeric forms. Examples of C_1-4alkyl include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl. Examples of C_1-8alkyl include, in addition to C_1- alkyl, pentyl, neopentyl, sec- pentyl, n-pentyl, isopentyl, tert-pentyl, hexyl, heptyl and octyl.

As used herein, the term "cycloalkyl" refers to a non-aromatic cyclic saturated hydrocarbon ring. Examples of C_3-4cycloalkyl include cyclopropyl and cyclobutyl. Examples of C_3-8cycloalkyl include, in addition, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctanyl.

As used herein, the term "C_3-8heterocyclyl" refers to a C_3-8cycloalkyl group wherein one to three of the carbon atoms are replaced by heteroatom(s) independently selected from N, O and S. Examples include aziridinyl, oxetanyl, oxiranyl, azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, tetrahydrofuranyl, dioxolanyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydrothienyl, tetrahydropyranyl, dioxanyl, dithianyl, azepanyl and octahydroazocinyl. As used herein, the term "C_4-8heterocyclyl" refers to a C_4-8cycloalkyl group wherein one to three of the carbon atoms are replaced by heteroatom(s) independently selected from N, O and S. Examples include azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, tetrahydrofuranyl, dioxolanyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydrothienyl, dioxanyl, dithianyl, azepanyl and octahydroazocinyl.

When X is -NR²-, R¹ and R², together with the nitrogen to which they are attached, may form a C _-8heterocyclyl group, which C_4-8heterocyclyl group is optionally substituted or optionally fused to an aryl or a heteroaryl group. The term "C_4-8heterocyclyl group" as used herein refers to a C_4-8cycloalkyl group wherein one to three of the carbon atoms are replaced by heteroatom(s) independently selected from N, O and S. It should be noted that the C_4-8heterocyclyl group formed by R¹ and R² together with the nitrogen to which they are attached would be N-linked. Examples include azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxaxolidinyl, isothiazolidinyl, thiazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, azepanyl and octahydroazocinyl.

As used herein, the term "aryl" refers to a 5- or 6- membered monocyclic aromatic group or a 8- to 11- membered bicyclic aromatic group. Examples include phenyl, indenyl, azulenyl and naphthyl.

As used herein, the term "heteroaryl" refers to a 5- or 6-membered monocyclic aromatic group wherein one, two, three or four carbon atoms are replaced by a heteroatom independently selected from N, O and S, or a 8- to 11- membered bicyclic aromatic group wherein one to four carbon atoms are replaced by a heteroatom independently selected from N, O and S. Examples of 5- or 6-membered monocyclic heteroaryls include furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, triazolyl, triazinyl, pyridazinyl, pyrimidinyl, isothiazolyl, isoxazolyl, pyrazinyl, pyrazolyl and pyrimidinyl; examples of 8- to 11- membered bicyclic heteroaryls include quinoxalinyl, quinazolinyl, pyridopyrazinyl, benzoxazolyl, benzothiophenyl, benzimidazolyl, naphthyridinyl, quinolinyl, benzofuranyl, indolyl, benzothiazolyl, oxazolyl[4,5-b]pyridiyl, pyridopyrimidinyl and isoquinolinyl.

As used herein, the terms "halogen" and its abbreviation "hal" refer to fluorine, chlorine, bromine, or iodine.

As used herein, the term "salt" refers to any salt of a compound according to the present invention prepared from an inorganic or organic acid or base, quaternary ammonium salts and internally formed salts. Physiologically acceptable salts are particularly suitable for medical applications because of their greater aqueous solubility relative to the parent compounds. Such salts must clearly have a physiologically acceptable anion or cation. Suitably physiologically acceptable salts of the compounds of the present invention include acid addition salts formed with inorganic acids such as hydrochloric, hydrobromic, hydroiodic, phosphoric, metaphosphoric, nitric and sulfuric acids, and with organic acids, such as tartaric, acetic, trifluoroacetic, citric, malic, lactic, fumaric, benzoic, formic, propionic, glycolic, gluconic, maleic, succinic, camphorsulfuric, isothionic, mucic, gentisic, isonicotinic, saccharic, glucuronic, furoic, glutamic, ascorbic, anthranilic, salicylic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, pantothenic, stearic, sulfinilic, alginic, galacturonic and arylsulfonic, for example benzenesulfonic and p-toluenesulfonic, acids; base addition salts formed with alkali metals and alkaline earth metals and organic bases such as N,N-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumaine (N-methylglucamine), lysine and procaine; and internally formed salts. Salts having a non-physiologically acceptable anion or cation are within the scope of the invention as useful intermediates for the preparation of physiologically acceptable salts and/or for use in non-therapeutic, for example, in vitro, situations.

As used herein, the term "solvate" refers to a complex of variable stoichiometry formed by a solute (in this invention, a compound of formula (I) or a salt thereof) and a solvent. Such solvents for the purpose of the invention may not interfere with the biological activity of the solute. Examples of suitable solvents include, but are not limited to, water, methanol, ethanol and acetic acid. Preferably the solvent used is a pharmaceutically acceptable solvent. Examples of suitable pharmaceutically acceptable solvents include water, ethanol and acetic acid. Most preferably the solvent used is water.

As used herein, the term "optionally substituted" refers to substitution by one or more groups selected from: halogen, hydroxy, oxo, cyano, nitro, C^.Qalkyl, C-|_4alkoxy, haloc -4alkyl, haloC<|_ 4alkoxy,

4alkylsulfonamidoC-ι_4alkyl, C-|_4alkylamidoC<|_4alkyi, arylsulfonamido, arylcarboxamido, arylsulfonamidoC-|.4alkyl, arylcarboxamidoC-|.4alkyl, aroyl, aroylC-ι_4alkyl, arylC-|_4alkanoyl, C-|_4acyl, aryl, arylC-^alkyl, Cι_4alkylaminoC-ι_ 4alkyl, a group R⁹R¹⁰N-, R⁹OCO(CH₂)_m, R⁹CON(R¹⁰)(CH₂)_m, R⁹R¹⁰NCO(CH₂)_m, R⁹R¹⁰NSO₂(CH₂)_m or R⁹SO₂NR¹⁰(CH₂)_m (where each of R⁹ and R¹⁰ is independently selected from hydrogen or C^alkyl , or where appropriate R⁹R¹⁰ forms part of a C3_6azacyloalkane or C3_g(2-oxo)azacycloalkane ring and m is 0, 1 , 2, 3 or 4), a group R⁹R¹⁰N(CH₂)p- or R⁹R¹⁰N(CH₂)pO- (wherein p is 1 , 2, 3 or 4); wherein when the substituent is R⁹R¹⁰N(CH₂)p- or R⁹R¹⁰N(CH₂)pO, R⁹ with at least one CH₂ of the (CH₂)p portion of the group may also form a Cs._βazacycloalkane and R¹⁰ may be hydrogen, C^alkyl or with the nitrogen to which it is attached, form a second C3_gazacycloalkane fused to the first C3_ρazacycloalkane. Furthermore, when R¹ is an optionally substituted C_3-8cycloalkyl or an optionally substituted C₃.₈heterocyclyl, or when R¹ and R² form a C_4-8heterocyclyl, the optionally substituted cycloalkyl or heterocyclyl group may be additionally optionally bridged by a C_1-3alkylene group.

Where there is more than one substituent, the substituents may be different or the same. If substituent(s) is/are present, preferably the number of substituent(s) is 1 , 2, 3 or 4.

In one embodiment, X is -O- and R¹ is optionally substituted C_1-8alkyl, optionally substituted C_3-8cycloalkyl, optionally substituted C_3-8heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, arylC_1-8alkyl (wherein both aryl and C_1-8alkyl are optionally substituted) and heteroarylC_1-8alkyl (wherein both heteroaryl and C_1-8alkyl are optionally substituted). In this embodiment, examples of R¹ include optionally substituted benzyl.

In another embodiment, X is -NR²- wherein R² is hydrogen or optionally substituted C^ ₈alkyl, and R¹ is selected from the group consisting of optionally substituted C_1-8alkyl, optionally substituted C_3-8cycloalkyl, optionally substituted C_3-8heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, arylC_1-8alkyl (wherein both aryl and C-i. ₈alkyl are optionally substituted) and heteroarylC_1-8alkyl (wherein both heteroaryl and C-i. ₈alkyl are optionally substituted)or R¹ and R² together with the nitrogen to which they are attached form a C_4-8heterocyclyl group, which C_4-8heterocyclyl group is optionally substituted or optionally fused to an optionally substituted aryl or an optionally substituted heteroaryl group. In this embodiment, preferably R² is hydrogen and R¹ is C-_M alkyl (such as isopropyl or tert-butyl), C_3-8cycloalkyl (such as cyclopentyl or cyclohexyl), aryl (such as phenyl optionally substituted by one or two groups selected from halogen, C_1-4alkyl and C_1- alkoxy), C_3-8heterocyclyl (such as tetrahydropyranyl or tetrahydrofuryl), arylC_1-8alkyl (such as benzyl and phenethyl, each of which is optionally substituted by one or two groups selected from halogen, C_1- alkyl and C_1-4alkoxy); or R² and R¹ together form a C - aheterocyclyl group such as piperidinyl.

In one embodiment, Ar is an optionally substituted aryl, such as phenyl optionally substituted by one or two groups selected from C_1-4alkyl, CF₃, halogen and C_3-6cycloalkyl.

In another embodiment, Ar is an optionally substituted heteroaryl such as such as pyridinyl or benzimidazolyl, both of which is optionally substituted by one or two C_1-4alkyl or CF₃.

When Het is a 5-membered monocyclic heteroaryl group, it is attached to the morpholinyl group and the nitrogen atom in formula (I) in a 1 ,3 orientation. If Het is a 6-membered monocyclic heteroaryl group, it is attached to the morpholinyl group and the nitrogen atom in formula (I) in a 1 ,4 orientation. In one embodiment, Het is pyridinyl, such as pyridin-3- yi.

Preferably n is 1.

In one embodiment, R³ and R⁴ are both hydrogen.

In one embodiment, the present invention provides a compound of formula (la) or a salt or solvate thereof:

(la)

wherein

• when X is -O-, R¹ is selected from the group consisting of Cι_-8alkyl, C₃,

₈cycloalkyl, C_3-8heterocyclyl, arylC_1-8alkyl and heteroarylC_1-8alkyl, each of which is optionally substituted by one to three groups selected from the group consisting of halogen, oxo, cyano, C^galkyl, C-|_4alkoxy, haloC^alkyl, haloC<ι_4alkoxy, arylC-^alkoxy, C-j^alkylthio, C^alkoxyC^alkyl, C3.. ρcycloalkyl, C3_6cycIoalkylC-j_4alkoxy, C^alkanoyl, C^alkylsulfonyl, C1_

4alkylsulfonylC-|_4alkyl, arylsulfonyl, arylsulfonylC-|_4alkyl, C-i^alkylamido,

C-|_4alkylsulfonamidoCι_4alkyl, aroyl, aroylC-|.4alkyl, , C-^acyl, aryl, arylC-j_

₄alkyl, C-j_₄alkylaminoC-|_4aIkyl, a group R⁹R¹⁰N-, R⁹CON(R¹⁰)(CH₂)_m or R⁹R¹⁰NCO(CH₂)_m (where each of R⁹ and R¹⁰ is independently selected from hydrogen or C^alkyl, or where appropriate R⁹R¹⁰ forms part of a Cβ. ρazacyloalkane ring and m is 0, 1 , 2, 3 or 4);

• when X is -NR²-, R¹ is selected from the group consisting of C_1-8alkyl, C_3- scycloalkyl, C_3-8heterocyclyl, aryl, heteroaryl, arylC_1-8alkyl and heteroarylCi. 8alkyl, each of which is optionally substituted by one to three groups selected from the group consisting of halogen, oxo, cyano, C-j_ρalkyl, C-j _4alkoxy, haloC-_j_4alkyl, haloC-|_4alkoxy, arylC-|_4alkoxy, C^alkylthio, C-j_4alkoxyC-|_

4alkyl, C3_6cycloalkyl, Cs.ρcycloalkylC^alkoxy, C-j^alkanoyl, C-j.

4alkylsulfonyl, C^alkylsulfonylC^alkyl, arylsulfonyl, arylsulfonylC-|.4alkyl, C-|_4alkylamido, C^alkylsulfonamidoC^alkyl, aroyl, aroylC^alkyl, , C-j_

4acyl, aryl, arylC-i^alkyl, C-^alkylaminoC^alkyl, a group R⁹R¹⁰N-,

R⁹CON(R¹⁰)(CH₂)_m or R⁹R¹⁰NCO(CH₂)_m (where each of R⁹ and R¹⁰ is independently selected from hydrogen or C-^alkyl, or where appropriate

R⁹R¹⁰ forms part of a C3_ρazacyloalkane ring and m is 0, 1 , 2, 3 or 4); or R¹ and R² together with the nitrogen to which they are attached form a C_4- sheterocyclyl group, which C_4-8heterocyclyl group is optionally substituted or optionally fused to an aryl or a heteroaryl group , each of which is optionally substituted by one to three groups selected from the group consisting of halogen, oxo, cyano, C-μρalkyl, C-^alkoxy, haloC-]_4alkyl, haloC-^alkoxy, arylC-|_4alkoxy, C<|_4alkylthio, C-|_4alkoxyC-]_4alkyl, Cs.ρcycloalkyl, C3.

6cycloalkylC-|_4alkoxy, C^alkanoyl, C-|.4alkylsulfonyl, C1_4alkylsulfonylC-_|.

4alkyl, arylsulfonyl, arylsulfonylC-j_4alkyl, C-|_4alkylamido, C-_|_

4alkylsulfonamidoC-|_4alkyl, aroyl, aroylC-]_4alkyl, , C^acyl, aryl, arylC^.

₄alkyl, C _₄alkylaminoC₁.₄alkyl, a group R⁹R¹⁰N-, R⁹CON(R¹⁰)(CH₂)_m or R⁹R¹⁰NCO(CH₂)_m (where each of R⁹ and R¹⁰ is independently selected from hydrogen or C-^alkyl, or where appropriate R⁹R¹⁰ forms part of a C3_ gazacyloalkane ring and m is 0, 1 , 2, 3 or 4); and

• Ar is phenyl or heteroaryl, each of which is optionally substituted by one to three groups selected from the group consisting of halogen, oxo, cyano, Chalky!, C-j_ 4alkoxy, haloC-i^alkyl, haloCι_4alkoxy, arylC-^alkoxy, C-|_4alkylthio, C-j_4alkoxyC-_|_

4alkyl, C3_6cycloalkyl, Cs.ρcycloalkylCi^alkoxy, C<j_4alkanoyl, C-j_4alkylsulfonyl, C1.

4alkylsulfonylC-|_4alkyl, arylsulfonyl, arylsulfonylC-^alkyl, C-|.4alkylamido, C-j.

4alkylsulfonamidoCι_4alkyl, aroyl, aroylC^alkyl, , C-j^acyl, aryl, arylC-]_4alkyl, C-_j.

₄alkylaminoC-j_₄alkyl, a group R⁹R¹⁰N-, R⁹CON(R¹⁰)(CH₂)_m or R⁹R¹⁰NCO(CH₂)_m (where each of R⁹ and R¹⁰ is independently selected from hydrogen or C-]_4alkyl, or where appropriate R⁹R¹⁰ forms part of a C3_6azacyloalkane ring and m is 0, 1 , 2, 3 or

4). All embodiments and features of compounds of formula (I) apply to compounds of formula (la).

Examples of compounds of the invention include Examples 1 to 7 shown below, as well as salts and solvates thereof.

The compounds of formula (I) may have the ability to crystallise in more than one form. This is a characteristic known as polymorphism, and it is understood that such polymorphic forms ("polymorphs") are within the scope of formula (I). Polymorphism generally can occur as a response to changes in temperature or pressure or both and can also result from variations in the crystallisation process. Polymorphs can be distinguished by various physical characteristics known in the art such as x-ray diffraction patterns, solubility, and melting point.

Certain of the compounds described herein may exist in stereoisomeric forms (i.e. they may contain one or more asymmetric carbon atoms or may exhibit cis-trans isomerism). The individual stereoisomers (enantiomers and diastereoisomers) and mixtures of these are included within the scope of the present invention. Likewise, it is understood that compounds of formula (I) may exist in tautomeric forms other than that shown in the formula and these are also included within the scope of the present invention.

As referred to above, individual enantiomers of compounds of formula (I) may be prepared and an indication of the preferred stereochemistry for such enantiomers has been given. In a preferred embodiment, an optically pure enantiomer is desired. The term "optically pure enantiomer" means that the compound contains greater than about 90 % of the desired isomer by weight, preferably greater than about 95 % of the desired isomer by weight, and most preferably greater than about 99 % of the desired isomer by weight, said weight percent based upon the total weight of the isomer(s) of the compound.

The compounds of this invention may be made by a variety of methods, including standard chemistry. Any previously defined variable will continue to have the previously defined meaning unless otherwise indicated. Illustrative general synthetic methods are set out below and then specific compounds of the invention are prepared in the working Examples.

Compounds of general formula (I) may be prepared by methods disclosed in the documents hereinbefore referred to and by methods known in the art of organic synthesis as set forth in part by the following synthesis schemes. It is also recognised that in all of the schemes described below, it is well understood that protecting groups for sensitive or reactive groups are employed where necessary in accordance with general principles of chemistry. Protecting groups are manipulated according to standard methods of organic synthesis (T. W. Greene and P. G. M. Wuts (1991) Protecting Groups in Organic Synthesis, John Wiley & Sons). These groups are removed at a convenient stage of the compound synthesis using methods that are readily apparent to those skilled in the art. The selection of processes as well as the reaction conditions and order of their execution shall be consistent with the preparation of compounds of formula (I). Those skilled in the art will recognise if a stereocentre exists in compounds of formula (I). Accordingly, the present invention includes both possible stereoisomers and includes not only racemic compounds but the individual enantiomers as well. Where the stereochemistry is indicated as being variable at certain positions, a mixture of stereoisomers may be obtained, this mixture having been separated where indicated. Stereoisomers may be separated by high-performance liquid chromatography or other appropriate means. When a compound is desired as a single enantiomer, it may be obtained by stereospecific synthesis or by resolution of the final product or any convenient intermediate. Resolution of the final product, an intermediate, or a starting material may be effected by any suitable method known in the art. See, for example, Stereochemistry of Organic Compounds by E. L. Eliel, S. H. Wilen, and L. N. Mander (Wiley-lnterscience, 1994).

Typical reaction routes for the preparation of a compound of formula (I) as hereinbefore defined are shown in the following schemes. Starting materials of general structure (2) and (3) and reagents (7), (12) and (13) are known in the literature or can be prepared using methods known in the art.

Scheme 1

(1) where X = NR² 9 (1) where X = 0 wherein R¹, R² , X, Ar and Het are as defined above for formula (I), n = 1 and Y and L are leaving groups.

Examples of leaving group L include halogen, hydroxy, OC(=O)alkyl, OC(=O)O-alkyl and OSO₂Me. Preferably L is halogen and acylation in step (ii) may be carried out in an inert solvent such as dichloromethane, in the presence of a base such as triethylamine. When L represents hydroxy, the reaction takes place in an inert solvent such as dichloromethane in the presence of a diimide reagent such as [O-(7-azabenzotriazol-1-yl)- 1 ,1 ,3,3-teframethyluronium hexafluoro phosphate].

Examples of leaving group Y include halogen and oxy groups such as trifluoromethanesulfonyloxy.

Reduction step (i) can be accomplished using known methods, such as catalytic hydrogenolysis in an inert solvent (e.g. using palladium on charcoal in a lower alcohol or ethyl acetate) and catalytic transfer hydrogenolysis (e.g. using palladium black and formic acid in methanol).

Introduction of morpholine, step (iii), can be achieved by a variety of known methods such as heating of compound (4) with morpholine optionally in the presence of base. Reduction step (iv) uses standard methods such as reduction with lithium aluminium hydride in an inert solvent such as tetrahydrofuran.

Formation of the urea bond, step (v), may be carried out using methods known to those skilled in the art. For example, in an inert solvent such as dichloromethane by use of a suitable isocyanate reagent, either directly or generated in situ from a suitable acid, or acid derivative, and an azide reagent such as diphenyl phosphoryl azide. Step (v) may also be achieved by reaction with a carbamoyl chloride reagent either directly, or generated in situ from suitable amines with reagents such as phosgene or triphosgene. Alternatively this reaction may be carried out with a suitable amine in an inert solvent in the presence of dicarbonyl reagents such as 1 ,1'-dicarbonyldiimidazole. The carbamate formation step, step (vi), can be carried out using known methods e.g. by reaction with a suitable chloroformate in the presence of base, such as triethylamine and in an inert solvent such as dichloromethane. Scheme 2

(1) where X = NR² (1) where X = 0

wherein R¹ - R⁴ , X, Ar, Het, and n are as defined above for (1), and Y and L are leaving groups as defined in scheme 1. Steps (ii) -(vi) are as described for scheme 1. The reductive amination step (vii) can be carried out using known methods, e.g reaction of (3) with an aldehyde (13) in the presence of a reducing agent such as sodium triacetoxyborohydride in an inert solvent such as 1 ,2-dichloroethane or dichloromethane.

Scheme 3

(ix)

wherein R¹ - R⁴ , X, Ar, Het, and n are as defined above for (1), and Y and L are leaving groups as defined in scheme 1. P is a protecting group. Examples of protecting groups P include -butyloxycarbonyl, trifluoroacetyl, benzyloxycarbonyl and optionally substituted benzyl. Deprotection conditions will depend on the particular protecting group; for the groups mentioned above these are respectively, acid (e.g. trifluoroacetic acid in dichloromethane), base (e.g. potassium carbonate in a solvent such as aqueous methanol) and catalytic hydrogenolysis in an inert solvent (e.g. using palladium on charcoal in a lower alcohol or ethyl acetate). Within the scope there is provision for protecting group interchange.

Steps (ii) -(vii) are as described for scheme 1. In addition step (v) can also be achieved through sequential reaction of compound (17) with phosgene or triphosgene in the presence of a suitable base, such as triethylamine, and an appropriate amine R¹R²N. Conversion of amine (19) into compound (1) (ie step ix) can be accomplished by known methods such as reductive amination with an appropriate ketone (R³or R⁴ = H) or aldehyde (R³ = R⁴ = H), or through N-alkylation with an alkylating agent in the presence of base, such as potassium carbonate, and in an inert solvent such as dimethylformamide. Alternatively, alkylation can be achieved with a suitable alcohol under Mitsunobu conditions ie in an inert solvent such as dichloromethane or tetrahydrofuran, in the presence of a phosphine reagent such as triphenylphosphine or tributylphosphine, and an azodicarbonyl reagent such as diethyl azodicarboxylate, diisopropylazodicarboxylate, or 1 ,1'-azodicarbonyldipiperidine.

Accordingly, in a second aspect, the present invention provides a method of preparing a compound of formula (I), comprising the step of:

(a) converting a compound of formula (II):

(II)

wherein Het, R , R , n and Ar are as defined in formula (I), to a compound of formula (I); or

(b) reacting a compound of formula (III)

(III)

wherein R¹, X and Het are as defined in formula (I), with a compound of formula (IV):

R⁴

^Z+i^Ar

R *°³ (IV)

wherein R³, R⁴, n and Ar are as defined in formula (I) and Z is a leaving group such as halogen, hydroxy or trifluoromethanesulfonyloxy; or

(c) for a compound of formula (I) wherein n is 1 , 2 or 3, reacting a compound of formula (III) as defined above with a compound of formula (V):

-.4

Q ^R

_A A -Ar

A _R ,33

(V)

wherein R³, R⁴ and Ar are as defined for formula (I), p is n minus one, and A is R³ or R⁴; and thereafter optionally for step (a), step (b) or step (c):

• removing any protecting groups and/or

• converting a compound of formula (I) into another compound of formula (I) and/or • forming a salt or solvate.

Compounds of formula (I) can be converted into further compounds of formula (I) using standard techniques. For example, and by way of illustration rather than limitation, possible conversion reactions include acylation with an appropriate acylating agent such as acetyl chloride, alkylation using an appropriate alkylating reagent such as methyl iodide, and sulfonylation using a sulfonylating agent such as methanesulfonic anhydride.

Pharmaceutically acceptable salts may be prepared conventionally by reaction with the appropriate acid or acid derivative.

The compounds of the present invention inhibit the GlyTI transporter. The compounds may selectively inhibit the GlyTI transporter over the GlyT2 transporter. Such compounds would be suitable for the treatment of certain neurological and neuropsychiatric disorders. As used herein, the terms "treatment" and "treating" refer to the alleviation and/or cure of established symptoms as well as prophylaxis.

The affinities of the compounds of this invention for the GlyTI transporter can be determined by the following assay:

HEK293 cells expressing the Glycine (Type 1 ) transporter were grown in cell medium (DMEM/NUT mix F12) containing 2 mM L-Glutamine, 0.8 mg/mL G418 and 10% heat inactivated fetal calf serum (Gibco BRL) at 37°C in 5% CO2. Cells grown to 70-80% confluency in T175 flasks were harvested and resuspended at 1.6x10^ cells/ml in assay buffer [NaCI (140 mM), KCI (5.4 mM), CaCI₂ (1.8 mM), MgSO₄ (0.8 mM), HEPES (20 mM), glucose (5 mM) and alanine (5 mM), pH 7.4]. An equal volume of Leadseeker™ SPA beads (12.5mg/ml suspended in assay buffer) was added to the cells and 25mL of the cell/bead suspension transferred to each well of a 384-well white solid bottom plate (20,000 cells/well) that contained 14mL of assay buffer. Compounds were prepared as 10mM stocks in DMSO. Two-fold serial dilutions of the compounds were made in DMSO from a top concentration of 5mM. 1 mL of compound at each concentration was added to the assay plate using 384-well parallel dispensing. Substrate (10mL) was added to each well [1 :40 dilution of [^HJ-glycine in assay buffer containing 5mM glycine). Final DMSO concentration = 2%. Data was collected using a PerkinElmer Viewlux as 5 minute exposures. IC50 values were determined using Grafit.

The example compounds below were found to have a PIC50 at the GlyTI transporter of greater than 6.0.

Accordingly, in a further aspect of the invention, there is provided a compound of formula (I) as hereinbefore described or a salt or solvate thereof, for use in therapy.

In another aspect of the invention, there is provided a compound of formula (I) as hereinbefore described or a salt or solvate thereof, for use in the treatment of a disorder mediated by GlyTI .

As used herein, the term "a disorder mediated by GlyTI" refers to a disorder that may be treated by the administration of a medicament that alters the activity of the GlyTI transporter. As hereinbefore described, the action of GlyTI transporters affects the local concentration of glycine around NMDA receptors. As a certain amount of glycine is needed for the efficient functioning of NMDA receptors, any change to that local concentration can affect NMDA-mediated neurotransmission. As hereinbefore described, changes in NMDA-mediated neurotransmission have been implicated in certain neuropsychiatric disorders such as dementia, depression and psychoses, for example schizophrenia, and learning and memory disorders, for example attention deficit disorders and autism. Thus, alterations in the activity of the GlyTI transporter are expected to influence such disorders.

The disorders mediated by GlyTI referred to herein 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 ***e) 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 syndrome), and NMDA receptor-related disorders such as autism, depression, benign forgetfulness, childhood learning disorders and closed head injury.

In another aspect of the invention, there is provided a method of treating a mammal, including a human, suffering from or susceptible to a disorder mediated by GlyTI , which comprises administering an effective amount of a compound of formula (I) as hereinbefore defined or a salt or solvate thereof.

In another aspect of the invention, there is provided use of a compound of formula (I) as hereinbefore defined or a salt or solvate thereof in the preparation of a medicament for the treatment of a disorder mediated by GlyTI .

Preferably, the disorder mediated by GlyTI to be treated by the use or method as hereinbefore described is a psychosis, including schizophrenia, dementia and attention deficit disorders, particularly schizophrenia.

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.

Compounds for use according to the invention may be administered as the raw material but the active ingredients are preferably provided in the form of pharmaceutical compositions.

Accordingly, in a further aspect of the invention, there is provided a pharmaceutical composition comprising a compound of formula (I) as hereinbefore described or a salt or solvate thereof, and at least one pharmaceutically acceptable carrier, diluent or excipient.

These pharmaceutical compositions may be used in the treatment of clinical conditions for which a GlyTI inhibitor is indicated such as, for example, schizophrenia. The carrier must be pharmaceutically acceptable to the recipient and must be compatible with, i.e. not have a deleterious effect upon, the other ingredients in the composition. The carrier may be a solid or a liquid and is preferably formulated with at least one compound of formula (I) or a salt or solvate thereof as a unit dose formulation. If desired, other physiologically active ingredients may also be incorporated in the pharmaceutical compositions of the invention.

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). The various subtypes of the disorders mentioned herein 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) are 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) are 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 II 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) are also 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) are also 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-Like)-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- Induced Psychotic Disorder, Phencyclidine-lnduced Mood Disorder, Phencyclidine- Induced 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- Induced 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) are also 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) are also 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) are also 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) are also 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) are also of use in the enhancement of cognition including the treatment of cognition impairment in other diseases such as schizophrenia, bipolar disorder, depression, other psychiatric disorders and psychotic conditions associated with cognitive impairment. Within the context of the present invention, the term cognitive impairment includes for example the treatment 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 related cognitive disorders; and dyskinetic disorders such as Parkinson's disease, neuroleptic-induced parkinsonism, and tardive dyskinesias.

The compounds of formula (I) are also 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 invention also provides a compound of formula (I) as hereinbefore described or a pharmaceutically acceptable salt or solvate thereof for use in the treatment of schizophrenia, mood disorders, anxiety disorders, substance-related disorders, sleep disorders, eating disorders, autistic disorder, attention-deficit/hyperactivity disorder, disruptive behaviour disorder, tic disorders, personality disorders, cognition impairment in other diseases, sexual dysfunction, Parkinson's disease, dyskinetic disorders, depression, bipolar disorder, cognitive impairment, obesity, emesis, movement disorders, obsessive- compulsive disorders, amnesia, aggression, vertigo, dementia and circadian rhythm disorders.

The invention also provides a compound of formula (I) as hereinbefore described or a pharmaceutically acceptable salt or solvate thereof for use in the treatment of psychotic disorders, schizophrenia, Parkinson's disease, substance abuse, dyskinetic disorders, depression, bipolar disorder, anxiety, cognitive impairment, eating disorders, obesity, sexual dysfunction, sleep disorders, emesis, movement disorders, obsessive-compulsive disorders, amnesia, aggression, autism, vertigo, dementia, circadian rhythm disorders and gastric motility disorders. In another aspect of the invention, there is provided a method of treating a mammal, including a human, suffering from or susceptible to a disorder mediated by GlyTI , which comprises administering an effective amount of a compound of formula (I) as hereinbefore defined or a salt or solvate thereof.

The invention also provides a method of treating schizophrenia, mood disorders, anxiety disorders, substance-related disorders, sleep disorders, eating disorders, autistic disorder, attention-deficit/hyperactivity disorder, disruptive behaviour disorder, tic disorders, personality disorders, cognition impairment in other diseases, sexual dysfunction, Parkinson's disease, dyskinetic disorders, depression, bipolar disorder, cognitive impairment, obesity, emesis, movement disorders, obsessive-compulsive disorders, amnesia, aggression, vertigo, dementia and circadian rhythm disorders which comprises administering to a mammal in need thereof an effective amount of a compound of formula (I) as hereinbefore described or a pharmaceutically acceptable salt or solvate thereof.

The invention also provides a method of treating psychotic disorders, schizophrenia, Parkinson's disease, substance abuse, dyskinetic disorders, depression, bipolar disorder, anxiety, cognitive impairment, eating disorders, obesity, sexual dysfunction, sleep disorders, emesis, movement disorders, obsessive-compulsive disorders, amnesia, aggression, autism, vertigo, dementia, circadian rhythm disorders and gastric motility disorders which comprises administering to a mammal in need thereof an effective amount of a compound of formula (I) as hereinbefore described or a pharmaceutically acceptable salt or solvate thereof.

The invention also provides the use of a compound of formula (I) as hereinbefore described or a pharmaceutically acceptable salt or solvate thereof in the manufacture of a medicament for the treatment of schizophrenia, mood disorders, anxiety disorders, substance-related disorders, sleep disorders, eating disorders, autistic disorder, attention- deficit hyperactivity disorder, disruptive behaviour disorder, tic disorders, personality disorders, cognition impairment in other diseases, sexual dysfunction, Parkinson's disease, dyskinetic disorders, depression, bipolar disorder, cognitive impairment, obesity, emesis, movement disorders, obsessive-compulsive disorders, amnesia, aggression, vertigo, dementia and circadian rhythm disorders. The invention also provides the use of a compound of formula (I) as hereinbefore described or a pharmaceutically acceptable salt or solvate thereof in the manufacture of a medicament for the treatment of psychotic disorders, schizophrenia, Parkinson's disease, substance abuse, dyskinetic disorders, depression, bipolar disorder, anxiety; cognitive impairment, eating disorders, obesity, sexual dysfunction, sleep disorders, emesis, movement disorders, obsessive-compulsive disorders, amnesia, aggression, autism, vertigo, dementia, circadian rhythm disorders and gastric motility disorders.

It will be appreciated by those skilled in the art that the compounds according to the invention may advantageously be used in conjunction with one or more other therapeutic agents, for instance, different antidepressant agents such as 5HT3 antagonists, serotonin agonists, NK-1 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 agonists and/or anticonvulsant agents, as well as atypical antipsychotic drugs and cognitive enhancers.

Suitable 5HT3 antagonists which may be used in combination of the compounds of the inventions include for example ondansetron, granisetron, metoclopramide.

Suitable serotonin agonists which may be used in combination with the compounds of the invention include sumatriptan, rauwolscine, yohimbine, metoclopramide. Suitable SSRIs which may be used in combination with the compounds of the invention include fluoxetine, citalopram, femoxetine, fluvoxamine, paroxetine, indalpine, sertraline, zimeldine.

Suitable SNRIs which may be used in combination with the compounds of the invention include venlafaxine and reboxetine.

Suitable tricyclic antidepressants which may be used in combination with a compound of the invention include imipramine, amitriptiline, chlomipramine and nortriptiline.

Suitable dopaminergic antidepressants which may be used in combination with a compound of the invention include bupropion and amineptine.

Suitable anticonvulsant agents which may be used in combination of the compounds of the invention include for example divalproex, carbamazepine and diazepam.

Suitable atypical antipsychotic drugs which which may be used in combination of the compounds of the invention include for example risperidone, olanzapine, ziprasidone, aripiprazole and clozapine.

It will be appreciated that the compounds of the combination or composition may be administered simultaneously (either in the same or different pharmaceutical formulations), separately or sequentially.

The compounds of formula (I) and their pharmaceutically acceptable salts and solvates thereof are also suitable for combination with other typical and atypical antipsychotics to provide improved treatment of psychotic disorders. Particular advantages associated with the combinations, uses and methods of treatment of compounds of formula (I) and their pharmaceutically acceptable salts and solvates thereof include equivalent or improved efficacy at doses of administration which are lower than those commonly used for the individual components. Improved treatments of positive symptoms and/or negative symptoms and/or cognitive symptoms of the psychotic disorder may also be observed. The combinations, uses and methods of treatment of the invention may also provide advantages in treatment of patients who fail to respond adequately or who are resistant to treatment with certain neuroleptic agents.

The combination therapies of the invention are preferably administered adjunctively. By adjunctive administration is meant the coterminous or overlapping administration of each of the components in the form of separate pharmaceutical compositions or devices. This regime of therapeutic administration of two or more therapeutic agents is referred to generally by those skilled in the art and herein as adjunctive therapeutic administration; it is also known as add-on therapeutic administration. Any and all treatment regimes in which a patient receives separate but coterminous or overlapping therapeutic administration of the compounds of formula (I) or a pharmaceutically acceptable salt or solvate thereof and at least one neuroleptic agent are within the scope of the current invention. In one embodiment of adjunctive therapeutic administration as described herein, a patient is typically stabilised on a therapeutic administration of one or more of the of the components for a period of time and then receives administration of another component. Within the scope of this invention, it is preferred that the compounds of formula (I) or a pharmaceutically acceptable salt or solvate thereof is administered as adjunctive therapeutic treatment to patients who are receiving administration of at least one neuroleptic agent, but the scope of the invention also includes the adjunctive therapeutic administration of at least one neuroleptic agent to patients who are receiving administration of compounds of formula (I) or a pharmaceutically acceptable salt or solvate thereof.

The combination therapies of the invention may also be administered simultaneously. By simultaneous administration is meant a treatment regime wherein the individual components are administered together, either in the form of a single pharmaceutical composition or device comprising or containing both components, or as separate compositions or devices, each comprising one of the components, administered simultaneously. Such combinations of the separate individual components for simultaneous combination may be provided in the form of a kit-of-parts.

In a further aspect therefore, the invention provides a method of treatment of a psychotic disorder by adjunctive therapeutic administration of compounds of formula (I) or a pharmaceutically acceptable salt or solvate thereof to a patient receiving therapeutic administration of at least one neuroleptic agent. In a further aspect, the invention provides the use of compounds of formula (I) or a pharmaceutically acceptable salt or solvate thereof in the manufacture of a medicament for adjunctive therapeutic administration for the treatment of a psychotic disorder in a patient receiving therapeutic administration of at least one neuroleptic agent. The invention further provides compounds of formula (I) or a pharmaceutically acceptable salt or solvate thereof for use for adjunctive therapeutic administration for the treatment of a psychotic disorder in a patient receiving therapeutic administration of at least one neuroleptic agent.

In a further aspect, the invention provides a method of treatment of a psychotic disorder by adjunctive therapeutic administration of at least one neuroleptic agent to a patient receiving therapeutic administration of compounds of formula (I) or a pharmaceutically acceptable salt or solvate thereof. In a further aspect, the invention provides the use of at least one neuroleptic agent in the manufacture of a medicament for adjunctive therapeutic administration for the treatment of a psychotic disorder in a patient receiving therapeutic administration of compounds of formula (I) or a pharmaceutically acceptable salt or solvate thereof. The invention further provides at least one neuroleptic agent for adjunctive therapeutic administration for the treatment of a psychotic disorder in a patient receiving therapeutic administration of compounds of formula (I) or a pharmaceutically acceptable salt or solvate thereof.

In a further aspect, the invention provides a method of treatment of a psychotic disorder by simultaneous therapeutic administration of compounds of formula (I) or a pharmaceutically acceptable salt or solvate thereof in combination with at least one neuroleptic agent. The invention further provides the use of a combination of compounds of formula (I) or a pharmaceutically acceptable salt or solvate thereof and at least one neuroleptic agent in the manufacture of a medicament for simultaneous therapeutic administration in the treatment of a psychotic disorder. The invention further provides the use of compounds of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for simultaneous therapeutic administration with at least one neuroleptic agent in the treatment of a psychotic disorder. The invention further provides compounds of formula (I) or a pharmaceutically acceptable salt thereof for use for simultaneous therapeutic administration with at least one neuroleptic agent in the treatment of a psychotic disorder. The invention further provides the use of at least one neuroleptic agent in the manufacture of a medicament for simultaneous therapeutic administration with compounds of formula (I) or a pharmaceutically acceptable salt thereof in the treatment of a psychotic disorder.

In further aspects, the invention provides a method of treatment of a psychotic disorder by simultaneous therapeutic administration of a pharmaceutical composition comprising compounds of formula (I) or a pharmaceutically acceptable salt or solvate thereof and at least one mood stabilising or antimanic agent, a pharmaceutical composition comprising compounds of formula (I) or a pharmaceutically acceptable salt or solvate thereof and at least one mood stabilising or antimanic agent, the use of a pharmaceutical composition comprising compounds of formula (I) or a pharmaceutically acceptable salt or solvate thereof and at least one mood stabilising or antimanic agent in the manufacture of a medicament for the treatment of a psychotic disorder, and a pharmaceutical composition comprising compounds of formula (I) or a pharmaceutically acceptable salt or solvate thereof and at least one mood stabilising or antimanic agent for use in the treatment of a psychotic disorder.

In a further aspect, the invention provides a kit-of-parts for use in the treatment of a psychotic disorder comprising a first dosage form comprising compounds of formula (I) or a pharmaceutically acceptable salt or solvate thereof and one or more further dosage forms each comprising a neuroleptic agent for simultaneous therapeutic administration.

Within the context of the present invention, the term psychotic disorder includes those disorders mentioned above, such as schizophrenia, mood disorders, anxiety disorders, substance-related disorders, sleep disorders, eating disorders, autistic disorder, attention- deficit hyperactivity disorder, disruptive behaviour disorder, tic disorders, personality disorders, cognition impairment in other diseases, sexual dysfunction, dyskinetic disorders, depression, bipolar disorder, cognitive impairment and obsessive-compulsive disorders and all the various forms of the disorders as mentioned herein, which are contemplated as part of the present invention.

Examples of neuroleptic/antipsychotic drugs that are useful in the present invention 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 neuroleptic drugs that are preferred for use in the present invention are shown in Table 1.

Table 1 Neuroleptic drugs

Examples of tradenames and suppliers of selected neuroleptic drugs are as follows : 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 preferred neuroleptic 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.

Particularly preferred neuroleptic agents for use in the invention are olanzapine, risperidone, quetiapine, aripiprazole, haloperidol, clozapine, ziprasidone and osanetant.

Suitable 5HT3 antagonists which may be used in combination of the compounds of the inventions include for example ondansetron, granisetron, metoclopramide. Suitable serotonin agonists which may be used in combination with the compounds of the invention include sumatriptan, rauwolscine, yohimbine, metoclopramide.

Suitable SSRIs which may be used in combination with the compounds of the invention include fluoxetine, citalopram, femoxetine, fluvoxamine, paroxetine, indalpine, sertraline, zimeldine.

Suitable anticonvulsant agents which may be used in combination of the compounds of the invention include for example divalproex, carbamazepine and diazepam. Suitable atypical antipsychotic drugs which which may be used in combination of the compounds of the invention include for example risperidone, olanzapine, ziprasidone, aripiprazole and clozapine.

Possible formulations include those suitable 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, but, where possible, oral administration is preferred.

Formulations 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.

Formulations 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.

Formulations suitable for parenteral administration typically comprise sterile aqueous solutions containing a predetermined concentration of the active compound; the solution is preferably isotonic with the blood of the intended recipient. Although such solutions are preferably administered intraveneously, they may also be administered by subcutaneous or intramuscular injection.

Formulations suitable for rectal administration are preferably provided as unit-dose suppositories comprising the active ingredient and one or more solid carriers forming the suppository base, for example, cocoa butter.

Formulations suitable for topical or intranasal application include ointments, creams, lotions, pastes, gels, sprays, aerosols and oils. Suitable carriers for such formulations include petroleum jelly, lanolin, polyethylene glycols, alcohols, and combinations thereof.

The formulations of the invention may be prepared by any suitable method, typically by uniformly and intimately admixing the active compound(s) with liquids or finely divided solid carriers, or both, in the required proportions and then, if necessary, shaping the resulting mixture into the desired shape. For example, a tablet may be prepared by compressing an intimate mixture comprising a powder or granules of the active ingredient and one or more optional ingredients, such as a binder, lubricant, inert diluent, or surface active dispersing agent, or by moulding an intimate mixture of powdered active ingredient and inert liquid diluent.

Aqueous solutions for parenteral administration are typically prepared by dissolving the active compound in sufficient water to give the desired concentration and then rendering the resulting solution sterile and isotonic.

It will be appreciated that the precise dose administered will depend on the age and condition of the patient and the frequency and route of administration and will be at the ultimate discretion of the attendant physician. The compound may be administered in single or divided doses and may be administered one or more times, for example 1 to 4 times per day.

A proposed dose of the active ingredient for use according to the invention for oral, sub- lingual, parenteral, buccal, rectal, intranasal or topical administration to a human (of approximately 70 kg bodyweight) for the treatment of neurological and neuropsychiatric disorders mediated by a GlyTI inhibitor, including schizophrenia, may be about 1 to about 1000 mg, preferably about 5 to about 500 mg, more preferably about 10 to about 100 mg of the active ingredient per unit dose which could be administered, for example, 1 to 4 times per day.

The invention is further illustrated by the following non-limiting examples.

Abbreviations

Tetrahydrofuran THF

Dichloromethane DCM

Triethylamine TEA Ethyl acetate EtOAc

Sodium bicarbonate NaHCO₃

Description 1 : 1-[1-(4-Trifluoromethyl-phenyl)-methanoyl]-piperidine-4-carboxylic acid ethyl ester

4-Trifluoromethylbenzoyl chloride (24.93g, 0.12 mol) was added dropwise, with stirring to a solution of ethyl isonipecotate (18.45ml, 0.12 mol) and triethylamine (50.1ml, 0.36 mol) in DCM (200ml) at 0°C and the resultant mixture stirred at room temperature for 20h. The mixture was washed with saturated aqueous NaHCO₃ and the organic layer separated and the aqueous layer extracted with DCM. Combined organics were dried (Na₂SO₄) and evaporated in vacuo to afford the title compound (39.3g, 100%). Mass spectrum (API⁺): Found 330 (MH⁺). C₁₆Hι₈F₃NO₃ requires 329.

Description 2: 1 -[1 -(4-Trifluoromethyl-phenyl)-methanoyI]-piperidine-4-carboxyIic acid

A mixture of 1-[1-(4-trifluoromethyl-phenyl)-methanoyl]-piperidine-4-carboxylic acid ethyl ester D1 (39g, 0.119 mol) and NaOH (4.75g, 0.119 mol) in water (300ml) and MeOH (200ml) was stirred at room temperature for 20h. The reaction mixture was concentrated to approx 200ml, diluted with water (300ml) and washed with EtOAc (300ml). The aqueous layer was acidified with 5N HCI and extracted with DCM (3x200ml). Combined organics were dried (Na₂SO₄) and evaporated in vacuo to afford the title compound as a pale cream solid (34.3g, 96%). Mass spectrum (API⁺): Found 302(MH⁺). C₁₄H₁₄F₃NO₃ requires 301

Description 3: 1-[1-(4-TrifluoromethyI-phenyl)-methanoyI]-piperidine-4-carboxylic acid (6-chloro-pyridin-3-yl)-amide.

Thionyl Chloride (2.54ml, 34.8 mmol) was added dropwise to a stirred supension of 1-[1-

(4-trifluoromethyl-phenyl)-methanoyl]-piperidine-4-carboxylic acid

D2 (8g, 26.6 mmol) in anhydrous toluene (200ml) at 0°C under argon. Cooling was removed and the mixture stirred at room temperature for 20h. Evaporation in vacuo afforded the crude acid chloride as a colourless solid (8.5g, 100%). A solution of the crude acid chloride (6.62g, 20.7 mmol) in DCM (50ml) was added dropwise, with stirring to a solution of 5-amino-2-chloropyridine (2.31 g, 17.3 mmol) and triethylamine (7.22ml, 52 mmol) in DCM (50ml). After 24h the solution was washed with saturated aqueous NaHCO₃ and the organic layer dried (Na₂SO ) and evaporated in vacuo. The residue was chromatographed on silica gel eluting with 0-100% EtOAc in pentane gradient then 0- 5% MeOH in EtOAc gradient to yield the title compound as a colourless solid (5.5g, 77%). Mass spectrum (API⁺): Found 412(MH⁺). C₁₉H₁₇ ³⁵CIF₃N₃O₂ requires 411. Description 4: 1 -[1 -(4-Trif luoromethyl-phenyl)-methanoyl]-piperidine-4-carboxyIic acid (6-morpholin-4-yl-pyridin-3-yl)-amide

A solution of the 1-[1-(4-trifluoromethyl-phenyl)-methanoyl]-piperidine-4-carboxylic acid (6- chloro-pyridin-3-yl)-amide D3 (5.5g, 13.38mmol) in morpholine (30ml) was divided into 8 equal batches and each batch microwaved at a temperature set at 200°C for 2.08h. The combined batches were evaporated in vacuo and the residue partitioned between saturated aqueous NaHCO₃and EtOAc. The aqueous layer was extracted with EtOAc and the combined organics dried (Na₂SO₄) and evaporated in vacuo to give the title product as a pale yellow solid (5.1 g, 83%). Mass spectrum (API⁺): Found 463(MH⁺). C₂₃H₂₅F₃N₄O₃ requires 462.

Description 5: (6-Morpholin-4-yl-pyridin-3-yl)-[1 -(4-trif luoromethyl-benzyl)-piperidin- 4-yImethyl]-amine

1 M Lithium aluminium hydride in THF (30ml) was added in a steady stream to a stirred, ice cooled solution of 1-[1-(4-trifluoromethyl-phenyl)-methanoyl]-piperidine-4-carboxylic acid (6-morpholin-4-yl-pyridin-3-yl)-amide D4 (5g, 10.82mmol) in anhydrous THF (200ml) under argon. On complete addition cooling was removed and the reaction mixture heated at reflux for 2h then cooled in ice and stirred as water (4.9ml), 2N sodium hydroxide (6.1ml) and water (4.9ml) were added sequentially, dropwise. After 0.5h solid Na₂SO was added, stirring continued for 0.25h and the resultant mixture filtered. The filtrate was evaporated in vacuo and the residue chromatographed on silica gel eluting with 0-100% EtOAc in pentane gradient then 0- 10% MeOH in EtOAc gradient to yield the title compound as a pale yellow solid (3.8g, 81%). Mass spectrum (API⁺): Found 435(MH⁺). C₂₃H₂gF₃N₄O requires 434.

Description 6: 4-[1-(6-Morpholin-4-yI-pyridin-3-yl)-3-(tetrahydro-pyran-4-yl)- ureidomethyl]-piperidine-1 -carboxylic acid terf-butyl ester

A solution of 1-(6-morpholin-4-yl-pyridin-3-yl)-3-(tetrahydro-pyran-4-yl)-1-[1-(4- trifluoromethyl-benzyl)-piperidin-4-ylmethyl]-urea E2 (0.5g, 0.89 mmol) in MeOH (15ml) was hydrogenated at room temperature and atmospheric pressure in the presence of 10% palladium on carbon for 5 days. The reaction mixture was filtered through kieselguhr, the filtrate evaporated in vacuo and the residue dissolved in DCM (20ml). Di-fe/if-butyl dicarbonate (0.24g, 1.1 mmol) was added, the mixture stirred at room temperature for 1h and then evaporated in vacuo. Chromatography on silica gel eluting with 0-100% EtOAc in pentane gradient then 0- 15% MeOH in EtOAc gradient yielded the title compound as a colourless amorphous solid (0.31 g, 69%). Mass spectrum (API⁺): Found 526(MNa⁺). C₂₆H₄₁N₅O₅ requires 503.

Description 7: 1 -(6-Morpholin-4-yI-pyridin-3-yI)-1 -piperidin-4-ylmethyl-3-(tetrahydro- pyran-4-yl)-urea

A solution of 4-[1-(6-morpholin-4-yl-pyridin-3-yl)-3-(tetrahydro-pyran-4-yl)-ureidomethyl]- piperidine-1 -carboxylic acid te/ϊ-butyl ester D6 (0.31 g, 0.62 mmol) in DCM (10ml) was stirred at room temperature as trifluoroacetic acid (4ml) was added in one portion. After 2h the reaction mixture was evaporated in vacuo and the residue partitioned between DCM (10ml) and 1 N NaOH (10ml). The aqueous layer was extracted with DCM (2 x 10ml), the organics combined, dried (Na₂SO₄) and evaporated in vacuo to give the title amine (0.23g, 93%). Mass spectrum (API⁺): Found 404(MH⁺). C₂₁H₃₃N₅O₃ requires 403.

Description 8: Ethyl 1-{[4-(1,1-dimethylethyl)phenyl]carbonyl}-4- piperidinecarboxylate

To a stirred solution of 4-fe/τ-butylbenzoic acid (5.2g, 0.029 mol) and ethyl isonipecotate (4.5ml, 0.029mol) in DCM (250ml) at room temperature was added 1-[3- (dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (5.6g, 0.029 mol), followed by 1-hydroxybenzotriazole (0.05g, 0.37 mmol). After 2.5h. the mixture was washed with 1N NaOH (250ml), water (100ml) and 1N HCI (100ml) and dried (Na₂SO₄). Evaporation in vacuo gave the title compound as a colourless oil (9.3g, 100%). Mass spectrum (API⁺): Found 318 (MH⁺). Cι₉H₂₇NO₃ requires 317.

Description 9: 1 -{[4-(1 ,1 -Dimethylethyl)phenyl]carbonyl}-4-piperidinecarboxylic acid

A mixture of ethyl 1-{[4-(1 ,1-dimethylethyl)phenyl]carbonyl}-4-piperidinecarboxylate D8 (9.3g, 0.029 mol) and 2N NaOH (30ml, 0.06 mol) in water (200ml) and methanol (50ml) was stirred at room temperature for 20h. The mixture was concentrated to approx. half volume in vacuo, washed with EtOAc and the aqueous layer acidified with 1N HCI. The mixture was extracted with DCM (3 x 100ml) and the combined halogenated extracts dried (Na₂SO₄) and evaporated in vacuo to afford the title acid as a colourless solid (8.2g, 97%). Mass spectrum (API⁺): Found 290 (MH⁺). C₁₇H₂₃NO₃ requires 289.

Description 10: Λ/-(6-Chloro-3-pyridinyl)-1 -{[4-(1 ,1 -dimethylethyl)phenyl]carbonyl}-4- piperidinecarboxamide

The title compound was prepared as a pale brown amorphous foam from 1-{[4-(1 ,1- dimethylethyl)phenyl]carbonyl}-4-piperidinecarboxylic acid (D9) (4.93g, 0.017 mol) and 5- amino-2-chloropyridine (2.17g, 0.0163 mol) by the method of description D3 (6.6g, 100%). Mass spectrum (APf ): Found 400 (MH⁺). C₂₂H₂₆ ³⁵CIN₃O₂ requires 399. Description 11 : 1 -{[4-(1 ,1 -DimethyIethyl)phenyl]carbonyl}-Λ/-[6-(4-morpholinyl)-3- pyridinyl]-4-piperidinecarboxamide

The title compound was prepared as a brown amorphous solid from /V-(6-chloro-3- pyridinyl)-1-{[4-(1 ,1-dimethylethyl)phenyl]carbonyl}-4-piperidinecarboxamide (D10) (4.48g, 0.0112 mol) and morpholine (30ml) by the method of description D4 (4.35g, 86%). Mass spectrum (API⁺): Found 451 (MH⁺). C₂₆H₃₄N₄O₃ requires 450.

Description 12: Λf-[(1 -{[4-(1 ,1 -Dimethylethyl)phenyl]methyl}-4-piperidinyl)methyl]-6- (4-morpholinyl)-3-pyridinamine

The title compound was prepared as a brown amorphous solid from 1-{[4-(1 ,1- dimethylethyl)phenyl]carbonyl}-Λ/-[6-(4-morpholinyl)-3-pyridinyl]-4-piperidinecarboxamide (D11) (4.35g, 0.0097 mol) by the method of description D5 (4.1g, 100%). Mass spectrum (API⁺): Found 423 (MH⁺). C_2BH₃₈N₄O requires 422.

Example 1 : 3-Cyclopentyl-1 -(6-morpholin-4-yl-pyridin-3-yl)-1 -[1 -(4-trifluoromethyl- benzyl)-piperidin-4-ylmethyl]-urea

A solution of (6-morpholin-4-yl-pyridin-3-yl)-[1-(4-trifluoromethyl-benzyl)-piperidin-4- ylmethylj-amine D5 (0.1 g, 0.23 mmol) and cyclopentyl isocyanate (0.038g, 0.34mmol) in 1 ,2-dichlorobenzene (5ml) was heated at 100°C for 20h. The cooled mixture was passed through a 2g Varian Mega Bond Elute SCX cartridge. The cartridge was washed with DCM, then MeOH(10ml of each) prior to elution with 1N NH₃ in methanol (10ml). Evaporation in vacuo afforded the title compound as a colourless amorphous solid (0.12g, 96%). ¹H NMR (CDCIa) δ: 1.05 - 1.30 (5H, m), 1.35 - 1.70 (5H, m), 1.80 - 2.00 (4H, m), 2.80 (2H, d, J = 12Hz), 3.48 - 3.52 (5H, m), 3.52 - 3.60 (4H, m), 3.82 -3.85 (4H, m), 4.00 - 4.08 (2H, m), 6.65 (1 H, d, J = 9Hz), 7.32 (1 H, dd, J = 2.4, 9Hz), 7.41 (2H, d, J = 8Hz), 7.53 (2H, d, J = 8Hz), 8.04 (1 H, d, J = 2.4Hz). Mass spectrum (API⁺): Found 546(MH⁺). C₂₉H₃₈F₃N₅O₂ requires 545.

Example 2: 1-(6-Morpholin-4-yl-pyridin-3-yl)-3-(tetrahydro-pyran-4-yl)-1-[1-(4- trifluoromethyl-benzyl)-piperidin-4-ylmethyl]-urea

To a stirred solution of tetrahydro-pyran-4-carboxylic acid (0.26g, 2 mmol) and triethylamine (0.28ml, 2 mmol) in toluene (3ml) at 0°C was added diphenylphosphoryl azide (0.43ml, 2 mmol). Cooling was removed and the mixture stirred at room temperature for 2.5h and then heated at 100°C for 2h. The reaction mixture was cooled to room temperature and a 0.55ml aliquot added to a solution of (6-morpholin-4-yl-pyridin-3- yl)-[1-(4-trifluoromethyl-benzyl)-piperidin-4-ylmethyl]-amine D5 (0.1g, 0.23 mmol) in 1 ,2- dichlorobenzene (5ml). The reaction mixture was heated at 100°C for 20h, cooled to room temperature and passed through a 2g Varian Mega Bond Elute SCX cartridge. The cartridge was washed with DCM, then MeOH (10ml of each) prior to elution with 1N NH₃ in MeOH (10ml). Evaporation in vacuo afforded the title compound as a colourless amorphous solid (0.08g, 62%). Mass spectrum (API⁺): Found 562(MH⁺). C₂gH₃₈F₃N₅θ₃ requires 561.

Example 3: 1 -[1 -(4-Cyclopropyl-benzyI)-piperidin-4-ylmethyl]-1 -(6-morpholin-4-yl- pyridin-3-yl)-3-(tetrahydro-pyran-4-yl)-urea

A solution of 1-(6-morpholin-4-yl-pyridin-3-yl)-1-piperidin-4-ylmethyl-3-(tetrahydro-pyran-4- yl)-urea D7 (0.11g, 0.273 mmol) and 4-cyclopropylbenzaldehyde (0.048g, 0.33 mmol) in DCM (4ml) was shaken for 1 h prior to addition of MP-triacetoxyborohydride solid supported reagent (ex Argonaut, loading 2.07 mmol/g) (0.3g, 0.621 mmol). The mixture was shaken for 20h, filtered and the filtrate applied directly to a 10g pre-packed silica gel column. Chromatography eluting with 10 -100% EtOAc in pentane gradient then 0 -15% MeOH in EtOAc gradient yielded the title compound as a colourless amorphous solid (0.13g, 89%). Mass spectrum (API⁺): Found 534(MH⁺). C₃ιH₄₃N₅O₃ requires 533.

Example 4: 1 -[1 -(4-ferM3utyl-benzyl)-piperidin-4-ylmethyl]-1 -(6-morpholin-4-yl- pyridin-3-yl)-3-(tetrahydro-pyran-4-yl)-urea

The title compound was prepared from 1-(6-morpholin-4-yl-pyridin-3-yl)-1-piperidin-4- ylmethyl-3-(tetrahydro-pyran-4-yl)-urea D7 (0.11g, 0.273 mmol) and 4-tert- butylbenzaldehyde (0.054g, 0.33 mmol) using the method of E3 as a colourless amorphous solid (0.13g, 87%) Mass spectrum (API⁺): Found 550(MH⁺). C₃₂H₄₇N₅O₃ requires 549.

Example 4 (alternative method): 1-[1-(4-terf-Butyl-benzyl)-piperidin-4-ylmethyl]-1-(6- morpholin-4-yl-pyridin-3-yl)-3-(tetrahydro-pyran-4-yl)-urea

To a stirred solution of tetrahydro-pyran-4-carboxylic acid (1g, 0.0077 mol) and triethylamine (1.07ml, 0.0077 mol) in toluene (15ml) at 0°C was added diphenylphosphoryl azide (1.66ml, 0.0077 mol). After 0.16h cooling was removed and stirring continued for 2h at room temperature. The mixture was heated at 100°C for 1.5h, cooled to room temperature and added to a stirred solution of Λ/-[(1-{[4-(1 ,1-dimethylethyl)phenyl]methyl}- 4-piperidinyl)methyl]-6-(4-morpholinyl)-3-pyridinamine (D12) (1.5g, 0.0036 mol) in chlorobenzene (20ml). The mixture was heated at 100°C for 18h, cooled to room temperature and evaporated in vacuo. The residue was dissolved in EtOAc, washed with aqueous NaHCO₃ then brine, dried (Na₂SO₄) and the solvent evaporated in vacuo. Chromatography on silica gel eluting with 50-100% EtOAc in pentane gradient then 1- 10% MeOH in EtOAc gradient and evaporation of combined fractions gave a gum that was dissolved in DCM and applied to a 10g SCX cartridge. After washing with DCM (50ml), and MeOH (50ml) the product was eluted with IN ammonia in MeOH. Evaporation in vacuo afforded the title compound as a pale brown solid (1.2g, 51%). Mass spectrum (API⁺): Found 550 (MH⁺). C₃₂H₄₇N₅O₃ requires 549.

The compounds of the Examples below were prepared using similar procedures to those described in the Descriptions and Examples above.

Claims

1. A compound of formula (I) or a salt or solvate thereof:

(I) wherein:

• when X is -O-, R¹ is selected from the group consisting of optionally substituted C^ 8alkyl, optionally substituted C_3-8cycloalkyl, optionally substituted C_3-8heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, arylC_1-8alkyl (wherein both aryl and C_1-8alkyl are optionally substituted) and heteroarylC_1-8alkyl (wherein both heteroaryl and C_1-8al yl are optionally substituted);

• when X is -NR²-, R¹ is selected from the group consisting of optionally substituted C-ι_-8alkyl, optionally substituted C_3-8cycloalkyl, optionally substituted C_3- sheterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, arylC^ 8alkyl (wherein both aryl and C_1-8alkyl are optionally substituted) and heteroarylC-i.

₈alkyl (wherein both heteroaryl and C_1-8alkyl are optionally substituted) or R¹ and R² together with the nitrogen to which they are attached form a C_4-8heterocyclyl group, which C_4-8heterocyclyl group is optionally substituted or optionally fused to an optionally substituted aryl or an optionally substituted heteroaryl group; • Het is an optionally substituted 5- or 6-membered monocyclic heteroaryl group;

• R³ and R⁴ are independently selected from the group consisting of hydrogen, halogen and C^alkyl, or R⁷ and R⁸ together form a C_3-4cycloalkyl;

• Ar is an optionally substituted aryl or an optionally substituted heteroaryl; and

• n is 0, 1 , 2 or 3.

2. A compound as claimed in claim 1 , wherein X is -O- and R¹ is optionally substituted C_1-8alkyl, optionally substituted C_3-8cycloalkyl, optionally substituted C_3- sheterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, arylC_1-8alkyl (wherein both aryl and C_1-8alkyl are optionally substituted) and heteroarylC_1-8alkyl (wherein both heteroaryl and Cι.₈alkyl are optionally substituted).

3. A compound as claimed in claim 1 , wherein X is -NR²-, R² is hydrogen or optionally substituted C_1-8alkyl, and R is selected from the group consisting of optionally substituted C_1-8alkyl, optionally substituted C_3-8cycloalkyl, optionally substituted C_3- aheterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, arylC_1-8alkyl (wherein both aryl and C_1-8alkyl are optionally substituted) and heteroarylC_1-8alkyl (wherein both heteroaryl and C_1-8alkyl are optionally substituted) or R¹ and R² together with the nitrogen to which they are attached form a C₄.₈heterocyclyl group, which C_4- aheterocyclyl group is optionally substituted or optionally fused to an optionally substituted aryl or an optionally substituted heteroaryl group.

4. A compound as claimed in claim 3, wherein R² is hydrogen and R¹ is C_1-4 alkyl (such as isopropyl or tert-butyl), C_3-8cycloalkyl (such as cyclopentyl or cyclohexyl), aryl (such as phenyl optionally substituted by one or two groups selected from halogen, C^ ₄alkyl and C_1-4alkoxy), C_3-8heterocyclyl (such as tetrahydropyranyl), arylC_1-8alkyl (such as benzyl and phenethyl, each of which is optionally substituted by one or two groups selected from halogen, C_1-4alkyl and C_1-4alkoxy); or R² and R¹ together form a C_4- aheterocyclyl group such as piperidinyl.

5. A compound as claimed in any of claims 1-4 wherein Ar is an optionally substituted aryl, such as phenyl optionally substituted by one or two groups selected from

C_1-4alkyl, CF₃, halogen and C₃.₆cycloalkyl.

6. A compound as claimed in any of claims 1-4 wherein Ar is an optionally substituted heteroaryl such as such as pyridinyl or benzimidazolyl, both of which is optionally substituted by one or two C_1-4alkyl or CF₃.

7. A compound as claimed in any of claims 1-6, wherein Het is a 6-membered monocyclic heteroaryl group, which is attached to the morpholinyl group and the nitrogen atom in formula (I) in a 1 ,4 orientation.

8. A compound as claimed in claim 7 wherein Het is pyridin-3-yl.

9. A compound as claimed in any of claims 1 -8, wherein n is 1.

10. A compound as claimed in any of claims 1-9, wherein R³ and R⁴ are both hydrogen.

11. A compoud of formula (la) or a salt or solvate thereof:

(la) wherein

• ^"X is -O- or -NR²- (wherein R² is hydrogen or optionally substituted C_1-8alkyl);

• when X is -O-, R¹ is selected from the group consisting of C_1-8alky(, C_3- scycloalkyl, C_3-8heterocyclyl, arylC_1-8alkyl and heteroarylC_1-8alkyl, each of which is optionally substituted by one to three groups selected from the group consisting of halogen, oxo, cyano, C-j.galkyl, C-_|_4alkoxy, haloC^alkyl, haloC-_j_4alkoxy, arylC^alkoxy, C-|_4alkylthio, Cι_4alkoxyC-_j_4alkyl, C3_ βcycloalkyl, C3_gcycloalkylC-_|.4alkoxy, C-_|.4alkanoyl, C-|_4alkylsulfonyl, C1_ 4alkylsulfonylC-j_4alkyl, arylsulfonyl, arylsulfonylC-|_4alkyl, C^alkylamido,

Cι.4alkylsulfonamidoCι_4alkyl, aroyl, aryl, arylC-j. 4alkyl, C-j^alkylaminoC-j^alkyl, a

¹⁰)(CH₂)m or R⁹R¹⁰NCO(CH₂)_m (where each of R⁹ and R¹⁰ is independently selected from hydrogen or C^alkyl, or where appropriate R⁹R¹⁰ forms part of a C3.

ring and m is 0, 1 , 2, 3 or 4);

• when X is -NR²-, R¹ is selected from the group consisting of C_1-8alkyl, C_3- scycloalkyl, C_3-8heterocyclyl, aryl, heteroaryl, arylC_1-8alkyl and heteroarylCi. 8alkyl, each of which is optionally substituted by one to three groups selected from the group consisting of halogen, oxo, cyano, C-j_galkyl, C-_j^alkoxy, haloC-j_4alkyl, haloC-j^alkoxy, arylC^alkoxy, C-j.4alkylthio, Cι_4alkoxyC-j_

4alkyl, Cs.gcycloalkyl, C3_6cycloalkylC-j_4alkoxy, C-|.4alkanoyl, C^_ 4alkylsulfonyl, C1.4alkylsulfonylC-ι.4alkyl, arylsulfonyl, arylsulfonylC-|.4alkyl, C^alkylamido, C^alkylsulfonamidoC^alkyl, aroyl, aroylC-)_4alkyl, , C-_j_ 4acyl, aryl, arylC-]_4alkyl, C-j_4alkylaminoC-j_4alkyl, a group R⁹R¹⁰N-, R⁹CON(R¹⁰)(CH₂)_m or R⁹R¹⁰NCO(CH₂)_m (where each of R⁹ and R¹⁰ is independently selected from hydrogen or C^alkyl, or where appropriate R⁹R¹⁰ forms part of a C3_6azacyloalkane ring and m is 0, 1, 2, 3 or 4); or R¹ and R² together with the nitrogen to which they are attached form a C - ₈heterocyclyl group, which C_4-8heterocyclyl group is optionally substituted or optionally fused to an aryl or a heteroaryl group , each of which is optionally substituted by one to three groups selected from the group consisting of halogen, oxo, cyano, C-j.galkyl, C^alkoxy, haloC-]_4alkyl, haloC-].4alkoxy, arylC-j_4alkoxy, C^alkylthio, C-j_4alkoxyC-j_4alkyl, C^gcycloalkyl, C3.. 6cycloalkylC-j_4alkoxy, C^alkanoyl, C-j.4alkylsulfonyl, C1_4alkylsulfonylC-]_ 4alkyl, arylsulfonyl, arylsulfonylC-_j^alkyl, C-_|_4alkylamido, C-]_

4alkylsulfonamidoCι_4alkyl, aroyl, aroylC-]_4alkyl, , C-|_4acyl, aryl, arylC-j.

4alkyl,

a group R⁹R¹⁰N-, R⁹CON(R¹⁰)(CH₂)_m or

R⁹R¹⁰NCO(CH₂)_m (where each of R⁹ and R¹⁰ is independently selected from hydrogen or C-_|_4alkyl, or where appropriate R⁹R¹⁰ forms part of a C3. gazacyloalkane ring and m is 0, 1 , 2, 3 or 4); and

• Ar is phenyl or heteroaryl, each of which is optionally substituted by one to three groups selected from the group consisting of halogen, oxo, cyano, C-|_galkyl, C^_

4alkoxy, haloC^alkyl, haloC^alkoxy, arylC-|_4alkoxy, C-|_4alkylthio, C-_j^alkoxyC-_j. 4alkyl, Cs.gcycloalkyl, C3_gcycloalkylC-]_4alkoxy, C-j_4alkanoyl, C-|.4alkylsulfonyl, C1_

4alkylsulfonylC-j_4alkyl, arylsulfonyl, arylsulfonylC-j_4alkyl, C-j.4alkylamido, C-]_

4alkylsulfonamidoC-|_4alkyl, aroyl, aroylC^alkyl, , C-j.4acyl, aryl, arylC-_|_4alkyl, C-j.

4alkylaminoC-j.₄alkyl, a group R⁹R¹⁰N-, R⁹CON(R¹⁰)(CH₂)_m or R⁹R¹⁰NCO(CH₂)_m

(where each of R⁹ and R¹⁰ is independently selected from hydrogen or C-|_4alkyl, or where appropriate R⁹R¹⁰ forms part of a C3_gazacyloalkane ring and m is 0, 1 , 2, 3 or

4).

12. A compound as claimed in claim 11 , wherein X is -NR²-, R² is hydrogen and R¹ is Cι_-4 alkyl (such as isopropyl or tert-butyl), C_3-8cycloalkyl (such as cyclopentyl or cyclohexyl), aryl (such as phenyl optionally substituted by one or two groups selected from halogen, C_1-4alkyl and C_1-4alkoxy), C_3-8heterocyclyl (such as tetrahydropyranyl), arylC_1-8alkyl (such as benzyl and phenethyl, each of which is optionally substituted by one or two groups selected from halogen, C_1-4alkyl and C_1-4alkoxy); or R² and R¹ together form a C_4-8heterocyclyl group such as piperidinyl.

13. A compound as claimed in claim 11 or 12, wherein Ar is an optionally substituted aryl, such as phenyl optionally substituted by one or two groups selected from C_1-4alkyl, CF₃, halogen and C₃.₆cycloalkyl.

14. A compound as claimed in claim 11 or 12, wherein Ar is an optionally substituted heteroaryl such as pyridinyl or benzimidazolyl, both of which is optionally substituted by one or two C_1-4alkyl or CF₃.

15. A compound as claimed in claim 1 which is any of Examples 1 to 7 or a salt or solvate thereof.

16. A compound as claimed in any of claims 1 -15 for use in therapy.

17. A compound as claimed in any of claims 1-15 for use in the treatment of a disorder mediated by GlyTI .

18. A compound as claimed in claim 17, wherein the disorder is psychosis, including schizophrenia, dementia or attention deficit disorder.

19. A method of treating a mammal, including a human, suffering from or susceptible to a disorder mediated by GlyTI , which comprises administering an effective amount of a compound as claimed in any of claims 1-15.

20. A method as claimed in claim 19, wherein the disorder is psychosis, including schizophrenia, dementia or attention deficit disorder.

21. Use of a compound as claimed in any of claims 1-15 in the preparation of a medicament for the treatment of a disorder mediated by GlyTI .

22. Use as claimed in claim 21 , wherein the disorder is psychosis, including schizophrenia, dementia or attention deficit disorder.

23. A pharmaceutical composition comprising a compound as claimed in any of claims 1-15, and at least one pharmaceutically acceptable carrier, diluent or excipient.

24. A method of preparing a compound as defined in claim 1 , comprising the step of:

(a) converting a compound of formula (II):

(II)

wherein Het, R , R , n and Ar are as defined in claim 1 , to a compound of formula (I); or

(b) reacting a compound of formula (III)

(III)

wherein R¹, X and Het are as defined in claim 1 , with a compound of formula (IV):

(IV)

wherein R , R , n and Ar are as defined in claim 1 and L is a leaving group; or

(V)

• removing any protecting groups and/or

• converting a compound of formula (I) into another compound of formula (I) and/or forming a salt or solvate.