Title of Invention

METALLOPROTEINASE INHIBITORS

Abstract

A compound of the formula I or a pharmaceutically acceptable salt thereof wherein X is selected from NR1, O, S; Yl and Y2 are independently selected from O, S; Z is selected from SO, SO2; m is 1 or 2; A is selected from a direct bond, (Cl-6)alkyl, (Cl-6)haloalkyl, or (Cl-6)heteroalkyl containing a hetero group selected from N, O, S, SO, S02 or containing two hetero groups selected from N, O, S, SO, S02 and separated by at least two carbon atoms; Rl is selected from H, (C l-3)alkyl, haloalkyl; Each R2 and R3 is independently selected from H, halogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, alkyl-heteroaryl, heteroalkyl-aryl, heteroalkyl-heteroaryl, aryl-alkyl, aryl- heteroalkyl, heteroaryl-alkyl, heteroaryl-heteroalkyl,aryl-aryl, aryl-heteroaryl, heteroaryl-aryl, heteroaryl-heteroaryl, cycloalkyl-alkyl, heterocycloalkyl-alkyl, alkyl-cycloalkyl, alkyl-heterocycloalkyl; Each R4 is independently selected from H, halogen, (Cl-3)alkyl or haloalkyl; Each of the R2 and R3 radicals may be independently optionally substituted with one or more groups selected from alkyl, heteroalkyl, aryl, heteroaryl, halo, haloalkyl, hydroxy, alkoxy, haloalkoxy, thiol, alkylthiol, arylthiol, alkylsulfon, haloalkylsulfon, arylsulfon, aminosulfon, N-alkylaminosulfon, N,N-dialkylaminosulfon, arylaminosulfon, amino, N-alkylamino, N,N-dialkylamino, amido, N-alkylamido, N,N-dialkylamido, cyano, sulfonamino, alkylsulfonamino, arylsulfonammo, amidino, N-aminosulfon-amidino, guanidino, N-cyano-guanidino, thioguanidino, 2-nitro-ethene-1,1-diamin, c'arboxy, alkyl-carboxy, nitro, carbamate; Optionally R2 and R3 may join to form a ring comprising up to 7 ring atoms, or R2 and R4 may join to form a ring comprising up to 7 ring atoms, or R3 and R4 may join to form a ring comprising up to 7 ring atoms; R5 is a monocyclic, bicyclic or tricyclic group comprising one, two or three ring structures each of up to 7 ring atoms independently selected from cycloalkyl, aryl, heterocycloalkyl or heteroaryl, with each ring structure being independently optionally substituted by one or more substituents independently selected from halogen, hydroxy, alkyl, alkoxy, haloalkoxy, amino, N-alkylamino, N,N-dialkylamino, alkylsulfonamino, alkylcarboxyamino, cyano, nitro, thiol, alkylthiol, alkylsulfonyl, haloalkylsulfonyl, alkylaminosulfonyl, carboxylate, alkylcarboxylate, amino carboxy, N-alkylamino-carboxy, N,N-dialkylamino-carboxy, wherein any alkyl radical within any substituent may itself be optionally substituted with one or more, groups selected from halogen, hydroxy, alkoxy, haloalkoxy, amino, N-alkylamino, N,N-dialkylamino, N-alkylsulfonamino, N-alkylcarboxyamino, cyano, nitro, thiol, alkylthiol, alkylsulfonyl, N- alkylaminosulfonyl, carboxylate, alkyl carboxy, aminocarboxy, N-alkylaminocarboxy, N,N-dialkylaminocarboxy, carbamate; when R5 is a bicyclic or tricyclic group, each ring structure is joined to the next ring structure by a direct bond, by -O-, by (Cl-6)alkyl, by (Cl-6)haloalkyl, by (Cl-6)heteroalkyl, by (Cl-6)alkenyl, by (Cl-6)alkynyl, by sulfone, by CO, by NCO, by CON, by NH, by S, by C(OH) or is fused to the next ring structure

Full Text

FORM 2 THE PATENTS ACT 1970 [39 OF 1970] & THE PATENTS RULES, 2003 COMPLETE SPECIFICATION [See Section 10; rule 13] "METALLOPROTEINASE INHIBITORS" AstraZeneca AB, a Swedish company of S-151 85 Sodertalje, Sweden, The following specification particularly describes the invention and the manner in which it is to be performed: The present invention relates to compounds useful in the inhibition of metalloproteinases and in particular to pharmaceutical compositions comprising these, as well as their use. The compounds of this invention are inhibitors of one or more metalloproteinase enzymes. Metalloproteinases are a superfamily of proteinases (enzymes) whose numbers in recent years have increased dramatically. Based on structural and functional considerations these enzymes have been classified into families and subfamilies as described in N.M. Hooper (1994) FEBS Letters 354:1-6. Examples of metalloproteinases include the matrix metalloproteinases (MMPs) such as the collagenases (MMP1, MMP8, MMP13), the gelatinases (MMP2, MMP9), the stromelysins (MMP3, MMP10, MMP11), matrilysin (MMP7), metalloelastase (MMP12), enamelysin (MMP19), the MT-MMPs (MMP14, MMP15, MMP16, MMP17); the reprolysin or adamalysin or MDC family which includes the secretases and sheddases such as TNT converting enzymes (ADAM 10 and TACE); the astacin family which include enzymes such as procollagen processing proteinase (PCP); and other metalloproteinases such as aggrecanase, the endothelin converting enzyme family and the angiotensin converting enzyme family. Metalloproteinases are believed to be important in a plethora of physiological disease processes mat involve tissue remodelling such as embryonic development, bone formation and uterine remodelling during menstruation. This is based on the ability of the metalloproteinases to cleave a broad range of matrix substrates such as collagen, proteoglycan and fibronectin. Metalloproteinases are also believed to be important in the processing, or secretion, of biological important cell mediators, such as tumour necrosis factor (TNF); and the post translational proteolysis processing, or shedding, of biologically important membrane proteins, such as the low affinity IgE receptor CD23 (for a more complete list see N. M. Hooper et al, (1997) Biochem J. 321:265-279). Metalloproteinases have been associated with many diseases or conditions. Inhibition of the activity of one or more metalloproteinases may well be of benefit in these diseases WO 02/074767 or conditions, for example: various inflammatory and allergic diseases such as, inflammation of the joint (especially rheumatoid arthritis, osteoarthritis and gout), inflammation of the gastro-intestinal tract (especially inflammatory bowel disease, ulcerative colitis and gastritis), inflammation of the skin (especially psoriasis, eczema, dermatitis); in tumour metastasis or invasion; in disease associated with uncontrolled degradation of the extracellular matrix such as osteoarthritis; in bone resorptive disease (such as osteoporosis and Paget's disease); in diseases associated with aberrant angiogenesis; the enhanced collagen remodelling associated with diabetes, periodontal disease (such as gingivitis), corneal ulceration, ulceration of the skin, post-operative conditions (such as colonic anastomosis) and dermal wound healing; demyelinating diseases of the central and peripheral nervous systems (such as multiple sclerosis); Alzheimer's disease; extracellular matrix remodelling observed in cardiovascular diseases such as restenosis and atheroscelerosis; asthma; rhinitis; and chronic obstructive pulmonary diseases (COPD). MMP12, also known as macrophage elastase or metalloelastase, was initially cloned in the mouse by Shapiro et al [1992, Journal of Biological Chemistry 267: 4664] and in man by the same group in 1995. MMP-12 is preferentially expressed in activated macrophages, and has been shown to be secreted from alveolar macrophages from smokers [Shapiro et al, 1993, Journal of Biological Chemistry, 268: 23824] as well as in foam cells in atherosclerotic lesions [Matsumoto et al, 1998, Am J Pathol 153:109]. A mouse model of COPD is based on challenge of mice with cigarette smoke for six months, two cigarettes a day six days a week. Wildtype mice developed pulmonary emphysema after this treatment. When MMP12 knock-out mice were tested in this model they developed no significant emphysema, strongly indicating that MMP-12 is a key enzyme in the COPD pathogenesis. The role of MMPs such as MMP12 in COPD (emphysema and bronchitis) is discussed in Anderson and Shinagawa, 1999, Current Opinion in Anti-inflammatory and Immunomodulatory Investigational Drugs 1(1): 29-38. It was recently discovered that smoking increases macrophage infiltration and macrophage-derived MMP-12 expression WO 02/074767 in human carotid artery plaques Kangavari [Matetzky S, Fishbein MC et al, Circulation 102.-(18). 36-39 Suppl. S, Oct 31, 2000]. MMP13, or collagenase 3, was initially cloned from a cDNA library derived from a breast tumour [J. M. P. Freije etal. (1994) Journal of Biological Chemistry 269(24):1 6766-16773]. PCR-RNA analysis of RNAs from a wide range of tissues indicated that MMP13 expression was limited to breast carcinomas as it was not found in breast fibroadenomas, normal or resting mammary gland, placenta, liver, ovary, uterus, prostate or parotid gland or in breast cancer cell lines (T47-D, MCF-7 and ZR75-1). Subsequent to this observation MMP13 has been detected in transformed epidermal keratinocytes [N. Johansson et al, (1997) Cell Growth Differ. 8(2):243-250], squamous cell carcinomas [N. Johansson et al, (1997) Am. J. Pathol. 151(2):499-5081 and epidermal tumours [K. Airola et al, (1997) J. Invest. Dermatol. 109(2):225-231], These results are suggestive that MMP13 is secreted by transformed epithelial cells and may be involved in the extracellular matrix degradation and cell-matrix interaction associated with metastasis especially as observed in invasive breast cancer lesions and in malignant epithelia growth in skin carcinogenesis. Recent published data implies that MMP13 plays a role in the turnover of other connective tissues. For instance, consistent with MMP13's substrate specificity and preference for degrading type II collagen [P. G. Mitchell et al, (1996) J. Clin. Invest. 97(3):761-768: V. Knauper et al, (1996) The Biochemical Journal 271: 1544-1550], MMP13 has been hypothesised to serve a role during primary ossification and skeletal remodelling [M. Stahle-Backdahl et al, (1997) Lab. Invest. 76(51:717-728: N. Johansson et al, (1997) Dev. Dyn. 208(3):387-397], in destructive joint diseases such as rheumatoid and osteo-arthritis [D. Wernicke et al, (1996) J. Rheumatol. 23:590-595; P. G. Mitchell et al, (1996) J. Clin. Invest. 97(3):761-768: O. Lindy et al, (1997) Arthritis Rheum 40(8):1391-1399]; and during the aseptic loosening of hip replacements [S. Imai et al, (1998) J. Bone Joint Surg. Br. 80(41:701-7101. MMP13 has also been implicated in chronic adult periodontitis as it has been localised to the epithelium of chronically inflamed mucosa human gingival tissue [V. J. Uitto et al, (1998) Am. J. Pathol WO 02/074767 152(6):1489-1499] and in remodelling of the collagenous matrix in chronic wounds [M. Vaalamo et al., (1997) J. Invest. Dermatol. 109(1):96-101]. MMP9 (Gelatinase B; 92kDa TypeIV Collagenase; 92kDa Gelatinase) is a secreted protein which was first purified, then cloned and sequenced, in 1989 [S.M. Wilhelm et al (1989) J. Biol Chem. 264(29): 17213-17221; published erratum in J. Biol Chem. (1990) 265 (36): 22570]. A recent review of MMP9 provides an excellent source for detailed information and references on this protease: T.H. Vu & 2. Werb (1998) (In : Matrix Metalloproteinases. 1998. Edited by W.C. Parks & R.P. Mecham. pp115 -148. Academic Press. ISBN 0-12-545090-7). The following points are drawn from that review 10 by T.H. Vu & Z. Werb (1998). The expression of MMP9 is restricted normally to a few cell types, including trophoblasts, osteoclasts, neutrophils and macrophages. However, it's expression can be induced in these same cells and in other cell types by several mediators, including exposure of the cells to growth factors or cytokines. These are the same mediators often implicated in initiating an inflammatory response. As with other secreted MMPs, MMP9 is released as an inactive Pro-enzyme which is subsequently cleaved to form the enzymatically active enzyme. The proteases required for this activation in vivo are not known. The balance of active MMP9 versus inactive enzyme is further regulated in vivo by interaction with TIMP-1 (Tissue Inhibitor of Metalloproteinases -1), a naturally-occurring 20 protein. TIMP-1 binds to the C-terminal region of MMP9, leading to inhibition of the catalytic domain of MMP9. The balance of induced expression of ProMMP9, cleavage of Pro- to active MMP9 and the presence of TIMP-1 combine to determine die amount of catalytically active MMP9 which is present at a local site. Proteolytically active MMP9 attacks substrates which include gelatin, elastin, and native Type IV and Type V collagens; it has no activity against native Type I collagen, proteoglycans or laminins. There has been a growing body of data implicating roles for MMP9 in various physiological and pathological processes. Physiological roles include the invasion of embryonic trophoblasts through the uterine epithelium in the early stages of embryonic WO 02/074767 implantation; some role in the growth and development of bones; and migration of inflammatory cells from the vasculature into tissues. MMP-9 release, measured using enzyme immunoassay, was significantly enhanced in fluids and in AM supernantants from untreated asthmatics compared with those from other populations [Am. J. Resp. Cell & Mol. Biol., Nov 1997, 17(5):583-591]. Also, increased MMP9 expression has been observed in certain other pathological conditions, thereby implicating MMP9 in disease processes such as COPD, arthritis, tumour metastasis, Alzheimer's, Multiple Sclerosis, and plaque rupture in atherosclerosis leading to acute coronary conditions such as Myocardial Infarction. MMP-8 (collagenase-2, neutrophil collagenase) is a 53 kD enzyme of the matrix metalloproteinase family that is preferentially expressed in neutrophils. Later studies indicate MMP-8 is expressed also in other cells, such as osteoarthritic chondrocytes [Shlopov et al, 1997, Arthritis Rheum, 40:2065]. MMPs produced by neutrophils can cause tissue remodelling, and hence blocking MMP-8 should have a positive effect in fibrotic diseases of for instance the lung, and in degradative diseases like pulmonary emphysema. MMP-8 was also found to be up-regulated in osteoarthritis, indicating that blocking MMP-8 many also be beneficial in this disease. MMP-3 (stromelysin-1) is a 53 kD enzyme of the matrix metalloproteinase enzyme family. MMP-3 activity has been demonstrated in fibroblasts isolated from inflamed gingiva [Uitto V. J. et al, 1981, J. Periodontal Res., 16:417-424]. and enzyme levels have been correlated to the severity of gum disease [Overall C. M. et al, 1987, J. Periodontal Res., 22:81-88]. MMP-3 is also produced by basal keratinocytes in a variety of chronic ulcers [Saarialho-Kere U. K. et al, 1994, J. Clin. Invest., 94:79-88]. MMP-3 mRNA and protein were detected in basal keratinocytes adjacent to but distal from the wound edge in what probably represents the sites of proliferating epidermis. MMP-3 may thus prevent the epidermis from healing. Several investigators have demonstrated consistent elevation of MMP-3 in synovial fluids from rheumatoid and osteoarthritis patients as compared to controls [Walakovits L. A. et al, 1992, Arthritis Rheum., 35:35-42; Zafarullah M. et al, 1993, J. Rheumatol., 20:693-697]. These studies provided the basis for the belief that an WO 02/074767 inhibitor of MMP-3 will treat diseases involving disruption of extracellular matrix resulting in inflammation due to lymphocytic infiltration, or loss of structural integrity necessary for organ function. A number of metalloproteinase inhibitors are known (see for example the review of MMP inhibitors by Beckett R.P. and Whittaker M., 1998, Exp. Opin. Ther. Patents, 8(3):25 9-2821. Different classes of compounds may have different degrees of potency and selectivity for inhibiting various metalloproteinases. Whittaker M. et al (1999, Chemical Reviews 99(9):2735-2776] review a wide range of known MMP inhibitor compounds. They state that an effective MMP inhibitor requires a zinc binding group or ZBG (functional group capable of chelating the active site zinc(II) ion), at least one functional group which provides a hydrogen bond interaction with the enzyme backbone, and one or more side chains which undergo effective van der Waals interactions with the enzyme subsites. Zinc binding groups in known MMP inhibitors include carboxylic acid groups, hydroxamic acid groups, sulfhydryl or mercapto, etc. For 15 example, Whittaker M. et al discuss the following MMP inhibitors: The above compound entered clinical development. It has a mercaptoacyl zinc binding group, a trimethylhydantoinylethyl group at the P1 position and a leucinyl-tert-20 butyllglycinyl backbone. WO 02/074767 The above compound has a mercaptoacyl zinc binding group and an imide group at the P1 position. 5 The above compound was developed for the treatment of arthritis. It has a non-peptidic succinyl hydroxamate zinc binding group and a trimethylhydantoinylethyl group at the P1 position. The above compound is a phthalimido derivative that inhibits collagenases. It has a non-o peptidic succinyl hydroxamate zinc binding group and a cyclic imide group at P1. Whittaker M. et al also discuss other MMP inhibitors having a P1 cyclic imido group and various zinc binding groups (succinyl hydroxamate, carboxylic acid, thiol group, phosphorous-based group). WO 02/074767 The above compounds appear to be good inhibitors of MMP8 and MMP9 (PCT patent applications W09858925, W09858915). They have a pyrimidin-2,3,4-trione zinc binding group. The following compounds are not known as MMP inhibitors:- 10 Lora-Tamayo, M et al (1968, An. Quim 64(6): 591 -606) describe synthesis of the following compounds as a potential anti-cancer agent: WO 02/074767 Czech patent numbers 151744 (19731119) and 152617 (1974022) describe the synthesis and the anticonvulsive activity of the following compounds: US patent number 3529019 (19700915) describes the following compounds used as intermediates: 10 PCT patent application number WO 00/09103 describes compounds useful for treating a vision disorder, including the following (compounds 81 and 83, Table A, page 47): We have now discovered a new class of compounds that are inhibitors of 15 metalloproteinases and are of particular interest in inhibiting MMPs such as MMP-12. The compounds are metalloproteinase inhibitors having a metal binding group that is not found in known metalloproteinase inhibitors. In particular, we have discovered compounds that WO 02/074767 are potent MMP12 inhibitors and have desirable activity profiles. The compounds of this invention have beneficial potency, selectivity and/or pharmacokinetic properties. The metalloproteinase inhibitor compounds of the invention comprise a metal binding group and one or more other functional groups or side chains characterised in that the metal binding group has the formula (k) wherein X is selected from NR1, O, S; Yl and Y2 are independently selected from 0, S; 10 Rl is selected from H, alkyl, haloalkyl; Any alkyl groups outlined above may be straight chain or branched; any alkyl group outlined above is preferably (Cl-7)alkyl and most preferably (Cl-6)alkyl. A metalloproteinase inhibitor compound is a compound that inhibits the activity of a 15 metalloproteinase enzyme (for example, an MMP). By way of non-limiting example the inhibitor compound may show IC50s in vitro in the range of 0.1-10000 nanomolar, preferably 0.1-1000 nanomolar. A metal binding group is a functional group capable of binding the metal ion within the active site of the enzyme. For example, the metal binding group will be a zinc binding 20 group in MMP inhibitors, binding the active site zinc(II) ion. The metal binding group of formula (k) is based on a five-membered ring structure and is preferably a hydantoin group, most preferably a -5 substituted l-H,3-H-imidazolidine-2,4-dione. WO 02/074767 In a first aspect of the invention we now provide compounds of the formula I wherein X is selected from NR1,O,S; Yl and Y2 are independently selected from O, S; Z is selected from SO, SO2; m is 1 or 2; A is selected from a direct bond, (Cl-6)alkyl, (Cl-6)haloalkyl, or (Cl-6)heteroalkyl containing a hetero group selected from N, O, S, SO, SO2 or containing two hetero groups selected from N, O, S, SO, S02 and separated by at least two carbon atoms; Rl is selected from H, (Cl-3)alkyl, haloalkyl; Each R2 and R3 is independently selected from H, halogen (preferably fluorine), alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, alkyl-heteroaryl, heteroalkyl-aryl, heteroalkyl-heteroaryl, aryl-alkyl, aryl-heteroalkyl, heteroaryl-alkyl, heteroaryl-heteroalkyl,aryl-aryl, aryl-heteroaryl, heteroaryl-aryl, heteroaryl-heteroaryl, cycloalkyl-alkyl, heterocycloalkyl-alkyl, alkyl-cycloalkyl, alkyl-heterocycloalkyl; Each R4 is independently selected from H, halogen (preferably fluorine), (Cl-3)alkyl or haloalkyl; Each of the R2 and R3 radicals may be independently optionally substituted with one or more (preferably one) groups selected from alkyl, heteroalkyl, aryl, heteroaryl, halo, haloalkyl, hydroxy, alkoxy, haloalkoxy, thiol, alkylthiol, arylthiol, alkylsulfon, haloalkylsulfon, arylsulfon, aminosulfon, N-alkylaminosulfon, N,N-dialkylaminosulfon, WO 02/074767 arylaminosulfon, amino, N-alkylamino, N,N-dialkylamino, amido, N-alkylamido, N,N-dialkylamido, cyano, sulfonamino, alkylsulfonamino, arylsulfonamino, amidino, N-aminosulfon-amidino, guanidino, N-cyano-guanidino, thioguanidino, 2-nitro-ethene-l,l-diamin, carboxy, alkyl-carboxy, nitro, carbamate; Optionally R2 and R3 may join to form a ring comprising up to 7 ring atoms, or R2 and R4 may join to form a ring comprising up to 7 ring atoms, or R3 and R4 may join to form a ring comprising up to 7 ring atoms; R5 is a monocyclic, bicyclic or tricyclic group comprising one, two or three ring structures each of up to 7 ring atoms independently selected from cycloalkyl, aryl, heterocycloalkyl or heteroaryl, with each ring structure being independently optionally substituted by one or more substituents independently selected from halogen, hydroxy, alkyl, alkoxy, haloalkoxy, amino, N-alkylamino, N,N-diaIkylamino, alkylsulfonamino, alkylcarboxyamino, cyano, nitro, thiol, alkylthiol, alkylsulfonyl, haloalkylsulfonyl, alkylaminosulfonyl, carboxylate, alkylcarboxylate, aminocarboxy, N-alkylamino-carboxy, N,N-dialkylamino-carboxy, wherein any alkyl radical within any substituent may itself be optionally substituted with one or more groups selected from halogen, hydroxy, alkoxy, haloalkoxy, amino, N-alkylamino, N,N-dialkylamino, N-alkylsulfonamino, N-alkylcarboxyamino, cyano, nitro, thiol, alkylthiol, alkylsulfonyl, N-alkylaminosulfonyl, carboxylate, alkylcarboxy, aminocarboxy, N-alkylaminocarboxy, N,N-20 dialkylaminocarboxy, carbamate; when R5 is a bicyclic or tricyclic group, each ring structure is joined to the next ring structure by a direct bond, by -0-, by (Cl-6)alkyl, by (C1 -6)haloalkyl, by (Cl-6)heteroaIkyl, by (C1-6)alkenyl, by (Cl-6)alkynyl, by sulfone, by CO, by NCO, by CON, by NH, by S, by C(OH) or is fused to the next ring structure; Any heteroalkyl group outlined above is a hetero atom-substituted alkyl containing one or more hetero groups independently selected from N, O, S, SO, SO2, (a hetero group being a hetero atom or group of atoms); Any heterocycloalkyl or heteroaryl group outlined above contains one or more hetero groups independently selected from N, O, S, SO, SO2; WO 02/074767 Any alkyl, alkenyl or alkynyl groups outlined above may be straight chain or branched; unless otherwise stated, any alkyl group outlined above is preferably (C1 -7)alkyl and most preferably (Cl-6)alkyl. Preferred compounds of the formula I are those wherein any one or more of the following apply: X is NRl; Z is SO2 or SO; especially Z is SO2; At least one of Yl and Y2 is O; especially both Yl and Y2 are O; 10| mis 1; Rl is H, (C1-3) alkyl, (C1-3) haloalkyl; especially Rl is H, (Cl-3)alkyl; most especially Rl is H; R2 is H, alkyl, hydroxyalkyl, alkoxyalkyl, aryloxy alkyl, aminoalkyl, cycloalkyl-alkyl, alkyl-cycloalkyl, arylalkyl, alkylaryl, alkyl-heteroaryl, heteroalkyl, heterocycloalkyl-alkyl, 15 alkyl-heterocycloalkyl, heteroaryl-alkyl, heteroalkyl-aryl; especially R2 is alkyl, aminoalkyl, alkyl-heteroaryl, alkyl-heterocycloalkyl or heteroaryl-alkyl. R3 and/or R4 is H; R3 and/or R4 is methyl; R5 comprises one, two or three optionally substituted aryl or heteroaryl 5 or 6 20 membered rings; R5 is a bicyclic or tricyclic group comprising two or three optionally substituted ring structures. Particularly preferred compounds of formula I are those wherein R5 is a bicyclic or 25 tricyclic group comprising two or three optionally substituted ring structures. WO 02/074767 The invention further provides compounds of the formula II wherein each of Gl, G2 and G4 is a monocyclic ring structure comprising each of up to 7 ring atoms independently selected from cycloalkyl, aryl, heterocycloalkyl or heteroaryl, with each ring structure being independently optionally substituted by one or two substituents independently selected from halogen, hydroxy, haloalkoxy, amino, N-alkylamino, N,N- dialkylamino, cyano, nitro, alkyl, alkoxy, alkyl sulfone, haloalkyl sulfone, alkylcarbamate, 10 alylamide, wherein any alkyl radical within any substituent may itself be optionally substituted with one or more groups selected from halogen, hydroxy, amino, N- alkylamino, N,N-dialkylamino, cyano, nitro, alkoxy, haloalkoxy, aryloxy, heteroaryloxy, carbamate; Z is SO2; 15 Each of B and F is independently selected from a direct bond, O, (C1-6)alkyl, (C1 - 6)heteroalkyl, alkynyl, CO, NCO, CON, NH, S; R2 is selected from H, alkyl, hydroxyalkyl, alkoxyalkyl, aryloxy alkyl, aminoalkyl, (N-alkylamino)alkyl, (N,N-dialkylamino)alkyl, amidoalkyl, thioalkyl cycloalkyl-alkyl, alkyl-cycloalkyl, arylalkyi, alkylaryl, alkyl-heteroaryl, heteroalkyl, heterocycloalkyl-alkyi, 20 alkyl-heterocycloalkyl, heteroaryl-alkyl, heteroalkyl-aryl; R3 and R4 are independently selected from H or (Cl-3)alkyl; Optionally R2 and R3 may join to form a ring comprising up to 7 ring atoms, or R2 and R4 may join to form a ring comprising up to 7 ring atoms, or R3 and R4 may join to form a ring comprising up to 7 ring atoms; WO 02/074767 Any heteroalkyl group outlined above is a hetero atom-substituted alkyl containing one or more hetero groups independently selected from N, O, S, SO, SO2, (a hetero group being a hetero atom or group of atoms); Any heterocycloalkyl or heteroaryl group outlined above contains one or more hetero groups independently selected from N, O, S, SO, SO2; Any alkyl, alkenyl or alkynyl groups outlined above may be straight chain or branched; unless otherwise stated, any alkyl group outlined above is preferably (Cl-7)alkyl and most preferably (C1 -6)alkyl. Preferred compounds of the formula II include those wherein R2 is alkyl, aminoalkyl, alkyl-heteroaryl, alkyl-heterocycloalkyl or heteroaryl-alkyl. The invention further provides compounds of the formula Ha wherein each of Gl and G2 is a monocyclic ring structure comprising each of up to 7 ring atoms independently selected from cycloalkyl, aryl, heterocycloalkyl or heteroaryl, with each ring structure being independently optionally substituted by one or two substituents independently selected from halogen, hydroxy, haloalkoxy, amino, N-alkylamino, N,N-dialkylamino, cyano, nitro, alkyl, alkoxy, alkyl sulfone, haloalkyl sulfone, alkylcarbamate, alkylamide, wherein any alkyl radical within any substituent may itself be optionally substituted with one or more groups selected from halogen, hydroxy, amino, N- WO 02/074767 alkylamino, N,N-dialkylamino, cyano, nitro, alkoxy, haloalkoxy, aryloxy, heteroaryloxy, carbamate; Z is S02; B is selected from a direct bond, 0, (Cl-6)alkyl, (Cl-6)heteroalkyl, CO, NCO,CON, NH, S, akynyl; R2 is selected from H, (Cl-6)alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, (N-alkylamino)alkyl, (N,N-dialkylamino)alkyl, amidoalkyl, thioalkyi, or R2 is a group of formula III 10 C and D are independently selected from a direct bond, H, (C1 -C6)alkyl, (C1 - C6)haloalkyl, or (Cl-C6)heteroalkyl containing one or two hetero atoms selected from N, O or S such that when two hetero atoms are present they are separated by at least two carbon atoms; G3 is a monocyclic ring structure comprising up to 7 ring atoms independently 15 selected from cycloalkyl, aryl, heterocycloalkyl or heteroaryl, optionally substituted by one or two substituents independently selected from halogen, hydroxy, amino, N-alkylamino, N,N-dialkylamino, cyano, nitro, alkyl, alkoxy, alkyl sulfone, haloalkyl sulfone, or alkyl substituted with one or more groups selected from halogen, hydroxy, amino, N- alkylamino, N,N-dialkylamino, cyano, nitro, alkoxy, haloalkoxy; 20 Optionally R2 is substituted with halo, haloalkyl, hydroxy, alkoxy, haloalkoxy, amino, aminoalkyl, N-alkylamino, N,N-dialkylamino, (N-alkylamino)alkyl, (N,N-dialkylamino)alkyl, alkylsulfone, aminosulfone, N-alkylamino-suIfone, N,N-dialkylamino-sulfone, amido, N-alkylamido, N,N-dialkylamido, cyano, sulfonamino, alkyl-sulfonamino, amidino, N-aminosulfone-amidino, guanidino, N-cyano-guanidino, thioguanidino, 2-25 nitroguanidino, carboxy, alkylcarboxy, carbamate; R3 and R4 are independently selected from H or (Cl-3)alkyl; WO 02/074767 Optionally R2 and R3 may join to form a ring comprising up to 7 ring atoms, or R2 and R4 may join to form a ring comprising up to 7 ring atoms, or R3 and R4 may join to form a ring comprising up to 7 ring atoms; Any heteroalkyl group outlined above is a hetero atom-substituted alkyl containing one or more hetero groups independently selected from N, O, S, SO, SO2, (a hetero group being a hetero atom or group of atoms); Any heterocycloalkyl or heteroaryl group outlined above contains one or more hetero groups independently selected from N, O, S, SO, SO2; Any alkyl, alkenyl or alkynyl groups outlined above may be straight chain or branched; unless otherwise stated, any alkyl group outlined above is preferably (Cl-7)alkyl and most preferably (Cl-6)alkyl. Preferred compounds of the formula IIa are those wherein one or more of the following apply: B is selected from a direct bond, O, CO, S, alkynyl; especially B is a direct bond, O, S, or alkynyl; R2 is selected from H, (Cl-6)alkyl, aryI-(Cl-6)alkyl or heteroaryl-(Cl-6)alkyl optionally substituted with halo, haloalkyl, hydroxy, alkoxy, haloalkoxy, amino, aminoalkyl, N-alkylamino, N,N-dialkylamino, (N-alkylamino)alkyl, (N,N-dialkylamino)alkyl, alkylsulfone, aminosulfone, N-alkylamino-suIfone, N,N-dialkylamino-sulfone, amido, N-alkylamido, N,N-dialkylamido, carbamate, cyano, sulfonamino, alkyl-sulfonamino, amidino, N-aminosulfone-amidino, guanidino, N-cyano-guanidino, thioguanidino, 2-nitroguanidino, 2-nitro-ethene-l,l-diamino, carboxy, alkylcarboxy, carbamate; Each of R3 and R4 is H; G2 is a nitrogen containing six-membered ring; G1 is para substituted. WO 02/074767 Particularly preferred compounds of formula IIa are those wherein each of R3 and R4 is H. For example, particular compounds of the invention include compounds of formula Ila wherein B is a direct bond, O, S or alkynyl; and R2 is selected from H, (Cl-6)alkyl, aryl-(Cl-6)alkyl or heteroaryl-(Cl-6)alkyl optionally substituted with cyckloalkyl, heterocycloalkyl, halo, haloalkyl, hydroxy, alkoxy, aryloxy, haloalkoxy, amino, aminoalkyl, N-alkylamino, N,N-dialkyIamino, (N-alkylamino)alkyl, (N,N-dialkylamino)alkyl, alkylsulfonyl, aminosulfonyl, N-alkylamino-sulfonyl, N,N-dialkylamino-sulfonyl, amido, N-alkylamido, N,N-dialkylamido, cyano, sulfonamino, alkyl-sulfonamino, amidino, N-aminosulfone-amidino, guanidino, N-cyano-guanidino, thioguanidino, 2-nitroguanidino, carbamate, carboxy, alkylcarboxy; and each of R3 and R4 is H. Particularly preferred compounds of the invention are those of Formula lib: wherein G2 is optionally substituted piperidine or piperazine, and G1, B, and R2 are as described for Formula IIa. In a compound of Formula IIb, preferably G2 is unsubstituted and G1 is optionally substituted, preferably G1 is para substituted. WO 02/074767 Suitable values for R2 include the following: WO 02/074767 20 Suitable values for R5 include the following: X' = bond, O, CH2, CHF, CF2. S, SO2, CO X"= bond. CH2; CHF, CF2; SO2, CO R= F, CI, Br, CF3, CF3O, CH3O, OH, CF3CH2 It will be appreciated that the particular substituents and number of substituents in compounds of the invention are selected so as to avoid sterically undesirable combinations. WO 02/074767 21 Each exemplified compound represents a particular and independent aspect of the invention. Where optically active centres exist in the compounds of the invention, we disclose all individual optically active forms and combinations of these as individual specific embodiments of the invention, as well as their corresponding racemates. Racemates may be separated into individual optically active forms using known procedures (cf. Advanced Organic Chemistry: 3rd Edition: author J March, p1O4-107) including for example the formation of diastereomeric derivatives having convenient optically active auxiliary species followed by separation and then cleavage of the auxiliary species. It will be appreciated that the compounds according to the invention may contain one or more asymmetrically substituted carbon atoms. The presence of one or more of these asymmetric centres (chiral centres) in a compound of the invention can give rise to stereoisomers, and in each case the invention is to be understood to extend to all such stereoisomers, including enantiomers and diastereomers, and mixtures including racemic mixtures thereof. Where tautomers exist in the compounds of the invention, we disclose all individual tautomeric forms and combinations of these as individual specific embodiments of the invention. As previously outlined the compounds of the invention are metalloproteinase inhibitors, in particular they are inhibitors of MMP12. Each of the above indications for the compounds of the the invention represents an independent and particular embodiment of the invention. Certain compounds of the invention are of particular use as inhibitors of MMP13 and/or MMP9 and/or MMP8 and/or MMP3. Compounds of the invention show a favourable selectivity profile. Whilst we do not wish to be bound by theoretical considerations, the compounds of the invention are believed to show selective inhibition for any one of the above indications relative to any MMP1 inhibitory activity, by way of non-limiting example they may show 100-1000 fold selectivity over any MMP1 inhibitory activity. The compounds of the invention may be provided as pharmaceutically acceptable salts. These include acid addition salts such as hydrochloride, hydrobromide, citrate and WO 02/074767 maleate salts and salts formed with phosphoric and sulphuric acid. In another aspect suitable salts are base salts such as an alkali metal salt for example sodium or potassium, an alkaline earth metal salt for example calcium or magnesium, or organic amine salt for example triethylamine. They may also be provided as in vivo hydrolysable esters. These are pharmaceutically acceptable esters that hydrolyse in the human body to produce the parent compound. Such esters can be identified by administering, for example intravenously to a test animal, the compound under test and subsequently examining the test animal's body fluids. Suitable in vivo hydrolysable esters for carboxy include methoxymethyl and for hydroxy include formyl and acetyl, especially acetyl. In order to use a metalloproteinase inhibitor compound of the invention (a compound of the formula I or II, IIa or IIb) or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof for the therapeutic treatment (including prophylactic treatment) of mammals including humans, it is normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition. Therefore in another aspect the present invention provides a pharmaceutical composition which comprises a compound of the invention (a compound of the formula I or II, IIa or IIb) or a pharmaceutically acceptable salt or an in vivo hydrolysable ester and pharmaceutically acceptable carrier. The pharmaceutical compositions of this invention may be administered in standard manner for the disease or condition that it is desired to treat, for example by oral, topical, parenteral, buccal, nasal, vaginal or rectal adminstration or by inhalation. For these purposes the compounds of this invention may be formulated by means known in the art into the form of, for example, tablets, capsules, aqueous or oily solutions, suspensions, emulsions, creams, ointments, gels, nasal sprays, suppositories, finely divided powders or aerosols for inhalation, and for parenteral use (including intravenous, intramuscular or infusion) sterile aqueous or oily solutions or suspensions or sterile emulsions. In addition to the compounds of the present invention the pharmaceutical composition of this invention may also contain, or be co-administered (simultaneously or sequentially) with, one or more pharmacological agents of value in treating one or more diseases or conditions referred to hereinabove. WO 02/074767 The pharmaceutical compositions of this invention will normally be administered to humans so that, for example, a daily dose of 0.5 to 75 mg/kg body weight (and preferably of 0.5 to 30 mg/kg body weight) is received. This daily dose may be given in divided doses as necessary, the precise amount of the compound received and the route of administration depending on the weight, age and sex of the patient being treated and on the particular disease or condition being treated according to principles known in the art. Typically unit dosage forms will contain about 1 mg to 500 mg of a compound of this invention. Therefore in a further aspect, we provide a compound of the formula I or a . pharmaceutically acceptable salt or in vivo hydrolysable ester thereof for use in a method of therapeutic treatment of the human or animal body or for use as a therapeutic agent. We disclose use in the treatment of a disease or condition mediated by one or more metalloproteinase enzymes. In particular we disclose use in the treatment of a disease or condition mediated by MMP12 and/or MMP13 and/or MMP9 and/or MMP8 and/or MMP3; especially use in the treatment of a disease or condition mediated by MMP12 or MMP9; most especially use in the treatment of a disease or condition mediated by MMP12. In particular we provide a compound of the formula II, IIa or IIb or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof for use in a method of therapeutic treatment of the human or animal body or for use as a therapeutic agent (such as use in the treatment of a disease or condition mediated by MMP 12 and/or MMP 13 and/or MMP9 and/or MMP8 and/or MMP3; especially MMP12 or MMP9; most especially MMP12). In yet a further aspect we provide a method of treating a metalloproteinase mediated disease or condition which comprises administering to a warm-blooded animal a therapeutically effective amount of a compound of the formula I or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof. We also disclose the use of a compound of the formula I or a pharmaceutically acceptable salt or in vivo hydrolysable precursor thereof in the preparation of a medicament for use in the treatment of a disease or condition mediated by one or more metalloproteinase enzymes. WO 02/074767 For example we provide a method of treating a metalloproteinase mediated disease or condition which comprises administering to a warm-blooded animal a therapeutically effective amount of a compound of the formula II, IIa or IIb (or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof). We also provide the use of a compound of the formula II, IIa or IIb (or a pharmaceutically acceptable salt or in vivo hydrolysable precursor thereof) in the preparation of a medicament for use in the treatment of a disease or condition mediated by one or more metalloproteinase enzymes. Metalloproteinase mediated diseases or conditions include asthma, rhinitis, chronic obstructive pulmonary diseases (COPD), arthritis (such as rheumatoid arthritis and osteoarthritis), atherosclerosis and restenosis, cancer, invasion and metastasis, diseases involving tissue destruction, loosening of hip joint replacements, periodontal disease, fibrotic disease, infarction and heart disease, liver and renal fibrosis, endometriosis, diseases related to the weakening of the extracellular matrix, heart failure, aortic aneurysms, CNS related diseases such as Alzheimer's disease and Multiple Sclerosis (MS), hematological disorders. Preparation of the compounds of the invention In another aspect the present invention provides a process for preparing a compound of the formula I or II, IIa, IIb or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, as described in (a) to (d) below. It will be appreciated that many of the relevant starting materials are commercially or otherwise available or may be synthesised by known methods or may be found in the scientific literature. (a) Compounds of formula I in which Y1 and Y 2 are each 0, Z is SO2, R2 is as defined in formula I, A is a direct bond and R5 comprises a nitrogen directly attached to Z, or A is (C1-6) N-alkyl, may be prepared by reacting a compound of the formula IV in which R5 is defined as in formula I with the known compounds of the formula V in which X and m are as defined in formula I: WO 02/075767 The reaction is preferably performed in suitable solvent optionally in the presence of base for 1 to 24h at ambient to reflux temperature. Preferably, solvents such as pyridine, dimethylformamide, tetrahydrofurane, acetonitrile or dichlorometane are used with bases like triethylamine, N-methylmorpholine, pyridine or alkali metal carbonates at ambient temperature for 2-16 h reaction time, or until end of reaction is achieved as detected by chromatographic or spectroscopic methods. Reactions of sulfonyl chlorides of formula V with various primary and secondary amines are previously described in the literature, and the variations of the conditions will be evident for those skilled in the art. Synthesis of compounds of formula V is described in the literature and can be prepared from e.g. cystein or homocystein (Mosher,J.:J.Org.Chem.23,1257 (1958). Sulfonylchlorides of formula V, in which m=l, X=NR1(R1=H) and R2 is as described in formula I, are conveniently prepared by oxidative chlorination of compounds of formula Va, in which R2 is as described in formula I (Griffith, 0.: J. Biol. Chem., 1983,258, 3, 1591). WO 020767 (b) Compounds of formula I in which Yl and Y2 are each 0, 2 is S, and X and R5 are as described in formula I may be prepared by reacting a compound of formula VI in which K is a leaving group (e.g chloride, or sulfonate ester) and R5 as described in formula I, with a compound of formula VII, in which G is a sulfhydryl (SH), X and m as described in formula I. The reaction is preferably performed in the presence of base such as diethyl isopropyl amine or cesium carbonate and in the presence of a suitable solvent e.g DMF. Alternatively, the compounds under process (b) may be prepared in the same manner as in process (b), by reacting the compounds of formula VI and VII, but in which K in compound VI is the sulfhydryl (SH) or a hydroxyl group and G in formula VII represents a leaving group. (c) Compounds of the formula I in which Yl and Y2 are each O, Z is SO2 or S(O), and X, A , and R5 are as described in formula I, may be prepared by oxidizing the final products described under process (b) and in which Z is S, with oxidizing agents like peroxide reagents, preferably m-chloroperbenzoic acid or oxone. (d) Compounds of the formula I in which Yl and Y2 are each 0, X is NR1 (R1=H), m is I, and R2, R3, R4, R5 are as described in formula I may be prepared by reacting a compound of formula XI in which R2, R3, R4, R5 and A are as described in formula I, WO 02/074767 XI with ammonium and cyanide salts in protic solvents, preferably in the presence of excess ammonium carbonat and potassium cyanide in ethanol in a sealed vessel at 40-80 C for 4-24 hours. The ketones of formula XI are conveniently prepared by treating sulfonamides of formula XII in which R3 is H and R5 is as described in formula I, with excess strong base and then treatment with esters of formula XIII, in which R is an alkyl or aryl residue and R2 are as described for formula I, in non-protic solvents. Preferrable conditions are 2-3 equivalents of lithium bases like lithium diisopropylamide or lithium hexamethyldisilazane or butyl lithium in dried etheral solvents like tetrahydrofurane. The ketones of formula XI, in which R3 and R4 are each alkyl or form a ring, R5 is aryl or heteroaryl and R2 is alkyl or aryl, can also be prepared by treating sulfinates of formula XIV in which R5 is aryl or heteroaryl as described in formula I, with a base such as tetrabutylammonium bromide and a ketone of formula XV in which R2 is alkyl or aryl (Crandall et al J. Org. Chem. 1985, (8) 50, 1327-1329). R3 and R4 are then introduced by reaction with alkyl halides or alkyl dihalides. The reaction is preferably performed in the presence of base such as potassium carbonate or caesium carbonate and in the presence of a suitable solvent e.g. DMF or DMSO at 50-100°C. WO/02/074767 PCTVSE02/00472 The compounds of the invention may be evaluated for example in the following assays: Isolated Enzyme Assays Matrix Metalloproteinase family including for example MMP12, MMP13. Recombinant human MMP12 catalytic domain may be expressed and purified as described by Parkar A.A. et al, (2000), Protein Expression and Purification, 20:152. The purified enzyme can be used to monitor inhibitors of activity as follows: MMP12 (50 ng/ml final concentration) is incubated for 30 minutes at RT in assay buffer (0. 1M Tris-HC1, pH 7.3 containing 0.1M NaCl, 20mM CaCl2, 0.040 mM ZnCl and 0.05% (w/v) Brij 35) using the synthetic substrate Mac-Pro-Cha-Gly-Nva-His-Ala-Dpa-NH2 in the presence or absence of inhibitors. Activity is determined by measuring the fluorescence at λex 328nm and Xem 393nm. Percent inhibition is calculated as follows: % Inhibition is equal to 10 the [Fluorescenceplus inhibitor - FluorescencebaCkground] divided by the [Fluorescenceminus inhibitor - Fluorescencebackground]. Recombinant human proMMP13 may be expressed and purified as described by Knauper et ,at. [V. Knauper et al, (1996) The Biochemical Journal 271.1544-1550 (1996)]. The purified enzyme can be used to monitor inhibitors of activity as follows: purified proMMP13 is activated using 1mM amino phenyl mercuric acid (APMA), 20 hours at 21°C; the activated MMP13 (11.25ngper assay) is incubated for 4-5 hours at 35°C in assay buffer (0.1M Tris-HCl, pH 7.5 containing O.lMNaCl, 20mM CaC12, 0.02 mM ZnCl and 0.05% (w/v) Brij 35) using the synthetic substrate 7-methoxycoumarin-4-yl)acetyl.Pro.Leu.Gly.Leu,N-3-(2,4-dinitrophenyI)-L-2,3-diaminopropionyl.Ala.Arg.NH2 in the presence or absence of inhibitors. Activity is determined by measuring the fluorescence at λex 328nm and λem 393nm. Percent inhibition is calculated as follows: % Inhibition is equal to the [FIuorescenceplus inhibitor - FluorescencebaCkground] divided by the [Fluorescenceminus inhibitor- Fluorescencebackground] A similar protocol can be used for other expressed and purified pro MMPs using substrates and buffers conditions optimal for the particular MMP, for instance as described in C. Graham Knight et al., (1992) FEBS Lett. 296(3):263-266. Adamalvsin family including for example TNF convertase The ability of the compounds to inhibit proTNFa convertase enzyme may be assessed using a partially purified, isolated enzyme assay, the enzyme being obtained from the membranes of THP-1 as described by K. M. Mohler et al, (1994) Nature 370:218-220. The purified enzyme activity and inhibition thereof is determined by incubating the partially purified enzyme in the presence or absence of test compounds using the substrate 4',5'-Dimethoxy-fluoresceinyl Ser.ProXeu.Ala.GIn.Ala.Val.Arg.Ser.Ser.Ser.Arg.Cys(4-(3-succinimid-l-yl)-fluorescein)-NH2 in assay buffer (50mM Tris HC1, pH 7.4 containing 0.1 % (w/v) Triton X-100 and 2mM CaCl2), at 26°C for 18 hours. The amount of inhibition is determined as for MMP 13 except λex 490nm and λem 530nm were used. The substrate was synthesised as follows. The peptidic part of the substrate was assembled on Fmoc-NH-Rink-MBHA-polysryrene resin either manually or on an automated peptide synthesiser by standard methods involving the use of Fmoc-amino acids and O-benzotriazol-1-yl- N,N,N',N'-tetramethyiuronium hexafluorophosphate (HBTU) as coupling agent with at least a 4- or 5-fold excess of Fmoc-amino acid and HBTU. Ser1 and Pro1 were double-coupled. The following side chain protection strategy was employed; Ser1 (But), Gln5(Trityl), Arg8.l2(Pmc or Pbf), Ser9,10'11(Trityl), Cys13(Trityl). Following assembly, the N-terminal Fmoc-protecting group was removed by treating the Fmoc-peptidyl-resin with 30 in DMF. The amino-peptidyl-resin so obtained was acylated by treatment for 1.5-2hr at 70°C with 1.5-2 equivalents of 4',5,-dimethoxy-fluorescein-4(5)-carboxylic acid [Khanna WO 02074767 & Ullman, (1980) Anal Biochem. K)8:156-161) which had been preactivated with diisopropylcarbodiimide and 1-hydroxybenzotriazole in DMF]. The dimethoxyfluoresceinyl-peptide was then simultaneously deprotected and cleaved from the resin by treatment with trifluoroacetic acid containing 5% each of water and triethylsilane. The dimethoxyfluoresceinyl-peptide was isolated by evaporation, trituration with diethyl ether and filtration. The isolated peptide was reacted with 4-{N-maleimido)-fluorescein in DMF containing diisopropylethylamine, the product purified by RP-HPLC and finally isolated by freeze-drying from aqueous acetic acid. The product was characterised by MALDI-TOF MS and amino acid analysis. Natural Substrates The activity of the compounds of the invention as inhibitors of aggrecan degradation may be assayed using methods for example based on the disclosures of E. C. Amer et al., (1998) Osteoarthritis and Cartilage 6:214-228; (1999) Journal of Biological Chemistry, 274 C10), 6594-6601 and the antibodies described therein. The potency of compounds to act as inhibitors against collagenases can be determined as described by T. Cawston and A. Barrett (1979) Anal. Biochem. 99:340-345. Inhibition of metalloproteinase activity in cell/tissue based activity Test as an agent to inhibit membrane sheddases such as TNF convertase The ability of the compounds of this invention to inhibit the cellular processing of TNFa production may be assessed in THP-1 cells using an ELISA to detect released TNF essentially as described K. M. Mohler et al, (1994) Nature 370:218-220. In a similar 25 fashion the processing or shedding of other membrane molecules such as those described in N. M. Hooper et al., (1997) Biochem. J. 321:265-279.may be tested using appropriate cell lines and with suitable antibodies to detect the shed protein. WO 02/07-1767 Test as an agent to inhibit cell based invasion The ability of the compound of this invention to inhibit the migration of cells in an invasion assay may be detennined as described in A. Albini et al., (1987) Cancer Research 47:3239-3245. Test as an agent to inhibit whole blood TNF sheddase activity The ability of the compounds of this invention to inhibit TNFa production is assessed in a human whole blood assay where LPS is used to stimulate the release of TNFa. Heparinized (l0Units/ml) human blood obtained from volunteers is. diluted 1:5 with medium (RPMI1640 + bicarbonate, penicillin, streptomycin and glutamine) and incubated (160μl) with 20μl of test compound (triplicates), in DMSO or appropriate vehicle, for 30 min at 37°C in a humidified (5%CO2/95%air) incubator, prior to addition of 20ul LPS (E. coli. 0111:B4; final concentration l0μg/ml). Each assay includes controls of diluted blood incubated with medium alone (6 wells/plate) or a known TNFa inhibitor as standard. The plates are then incubated for 6 hours at 37°C (humidified incubator), centrifuged (2000rpm for 10 min; 4°C ), plasma harvested (50-100μl) and stored in 96 well plates at -70°C before subsequent analysis for TNFa concentration by ELISA. Test as an agent to inhibit in vitro cartilage degradation The ability of the compounds of this invention to inhibit the degradation of the aggrecan or collagen components of cartilage can be assessed essentially as described by K. M. Bottomley et al, (1997) Biochem J. 323:483-488. Pharmacodynamic test To evaluate the clearance properties and bioavailability of the compounds of this invention an ex vivo pharmacodynamic test is employed which utilises the synthetic substrate assays above or alternatively HPLC or Mass spectrometric analysis. This is a generic test which can be used to estimate the clearance rate of compounds across a range of species. Animals (e,g. rats, marmosets) are dosed iv or po with a soluble formulation of compound (such as 20% w/v DMSO, 60% w/v PEG400) and at subsequent time points (e.g. 5, 15, 30, 60, 120, 240, 480, 720, 1220 mins) the blood samples are taken from an WO 02/074767 appropriate vessel into 10U heparin. Plasma fractions are obtained following centrifiigation and the plasma proteins precipitated with acetonitrile (80% w/v final concentration). After 30 mins at -20°C the plasma proteins are sedimented by centrifiigation and the supernatant fraction is evaporated to dryness using a Savant speed vac. The sediment is reconstituted in assay buffer and subsequently analysed for compound content using the synthetic substrate assay. Briefly, a compound concentration-response curve is constructed for the compound undergoing evaluation. Serial dilutions of the reconstituted plasma extracts are assessed for activity and the amount of compound present in the original plasma sample is calculated using the concentration-response curve taking into account the total plasma dilution factor. In vivo assessment Test as an anti-TNF agent The ability of the compounds of this invention as ex vivo TNFa inhibitors is assessed in the rat. Briefly, groups of male Wistar Alderley Park (AP) rats (180-210g) are dosed with compound (6 rats) or drug vehicle (10 rats) by the appropriate route e.g. peroral (p.o.), intraperitoneal (i.p.), subcutaneous (s.c). Ninety minutes later rats are sacrificed using a rising concentration of CO2 and bled out via the posterior vena cavae into 5 Units, of sodium heparin/ml blood. Blood samples are immediately placed on ice and centrifuged at 2000 rpm for 10 min at 4°C and the harvested plasmas frozen at -20°C for subsequent assay of their effect on TNFa production by LPS-stimulated human blood. The rat plasma samples are thawed and 175μl of each sample are added to a set format pattern in a 96U well plate. Fifty μl of heparinized human blood is then added to each well, mixed and the plate is incubated for 30 min at 37°C (humidified incubator). LPS (25μl; final concentration 10μg/ml) is added to the wells and incubation continued for a further 5.5 hours. Control wells are incubated with 25μl of medium alone. Plates are then centrifuged for 10 min at 2000 rpm and 200μl of the supernatants are transferred to a 96 well plate and frozen at -20° C for subsequent analysis of TNF concentration by ELISA. Data analysis by dedicated software calculates for each compound/dose: WO 02/07*767 Percent inhibition of TNFa= Mean TNFa(Controls) - Mean TNFa (Treated) X 100 Mean TNFa (Controls) Test as an anti-arthritic agent Activity of a compound as an anti-arthritic is tested in the collagen-induced arthritis (CIA) as defined by D. E. Trentham et al, (1977) J. Exp. Med. 146,:857. In this model acid soluble native type II collagen causes polyarthritis in rats when administered in Freunds incomplete adjuvant. Similar conditions can be used to induce arthritis in mice and primates. Test as an anti-cancer agent Activity of a compound as an anti-cancer agent may be assessed essentially as described in I. J. Fidler (1978) Methods in Cancer Research 15:399-439, using for example 15 the B16 cell line (described in B. Hibner et al., Abstract 283 p75 10th NCI-EORTC Symposium, Amsterdam June 16-19 1998). Test as an anti-emphysema agent Activity of a compound as an anti-emphysema agent may be assessed essentially as 20 described in Hautamaki et al (1997) Science, 277: 2002. The invention will now be illustrated but not limited by the following Examples: 26 General analytical methods; 1H-NMR spectra were recorded on either a Varian unityInova 400MHz or Varian Mercury-VX 300MHz instrument. The central solvent peak of chloroform-d(ΔH 7.27 ppm), dimethylsulfoxide-d6 (5H 2.50 ppm) or methanol-d4 (SH 3.31 ppm) were used as internal references. Low resolution mass spectra were obtained on a Agilent 1100 LC-MS system equipped with an APCI ionization chamber. 30 WO 0^074767 EXAMPLE 1 5-(2-{[4-(4'-fluoo(l,1'-biphenyl)-4-yl)-l-piperazinvllsulfonyl}ethyl)-2,4- imidazolidinedione To the solution of l-(4-fluorophenyl)-phenylpiperazin (0.125 mg ,0.48 mmol) in 5 ml of dichloromethane was added triethylamin (0.06 ml, 0.5 mmol) and 2-(2,5-dioxo-4-imidazolidinyl)-l-ethanesulfonyl chloride (0.113 ml 0.48 mol). The mixture was stirred for 18 hrs,diluted with DCM to 25 ml,extracted with IN HC1 (5 ml) sat.NaHC03 (5 ml) and dried,evap6rated,crystallised. (EtOH-dioxan) LC-MS (APCI) m/z 446.9 (MH+). 1H NMRδ 1.95m (1H); 2.1m (1.15H),3.2 m(13.3H),4.1m (lH),7.05d (2H),7.25d(2.1H),7.65d (2.2H),7.80d(1.8H),8.0 bs (NH). The starting materials were prepared as follows: 2-(2,5-dioxo-4-imidazoIidinyl)-l-ethanesulfonyI chloride To the suspension of 5-(2-{[2-(2,5-dioxo-4-imidazolidinyl)ethyl]disulfanyl}ethyl)-2,4-imidazolidinedione (6.9 mol) in the mixture of 25 ml AcOH and 2 ml water stirred violently in three necked flask with gas-inlet tube,thermometer and short reflux condenser placed in the ice bath, was bubbled chlorine gas for 15 min (until all precipitate dissolved) at max.temp.+5oC.Then,it was stirred 15 min more,evaporated to a small volume in vacuo (max.temp 30°C),dissolved in 50 ml of dichloromethane,shaken carefully WO 02/074767 with sat.NaHCO3 (ca 25 ml),then with 10% sodium thiosulfate, dried, evaporated, crystallised from THF-hexane (Lora-Tamayo, M. et al, 1968, An. Quim., 64(6):59I-606); 1HNMR : 5 2.55m (1,1H),2.65m (1.8H),2.70m (lH),4.55m (1H). 5-(2-{[2-(2,5-dioxo-4-imidazolidinyl)ethyI]disulfanyl)ethyl)-2,4-imidazolidinedione Commercially available RS homocystine (0.18 mol) was suspended in 25 ml water and of potassium cyanate 1.5 g (0.2 mol) was added and the mixture was stirred at 100°C for 45 min.Then it was allowed to cool partially and 10 ml of 10% HC1 were added at once and the mixture was stirred at 100°C again for 50 min.It was placed in the fridge overnight,crystals were filtered and washed successively with water and dried in vacuo. LC-MS (APCI) m/z 319.1 (MH+). The overall generalised reaction scheme is shown below: WO 02/074767 EXAMPLE 2 (5R)-5-{[(4-phenyl-l-piperazinyl)sulfonyl}methyl)-2,4-imidazolidinedione The title compound was prepared according to the scheme shown in Example 1. To the solution of R-(2,5-dioxo-4-imidazoIidinyl)methanesulfonyl chloride (100 mg,0.47 mmol) in 2.5 ml THF was added the solution of 1-phenylpiperazine (85 mg,0.52 mmol) and 65 ul of triethylamine (0.52 mmol) in 2.5 ml THF via syringe at once. The mixture was stirred for 3 hrs, precipitated triethylammonium chloride was filtered, washed with two small portions of THF, evaporated and recrystallised from EtOH and a small amount of AcOH. LC-MS (APCI) m/z 339.1 (MH+). 1HNMR δ 2.5 m (2H),3.1bs(6.5H),3.3m(2.5H),4.55m (1H),6.8 t(lH),6.9d(1.88H),7.2 t(2.05H),9.1bs(1.7H). The starting materials were prepared as follows: R-(2,5-dioxo-4-imidazoIidinyl)methanesulfonyl chloride To the suspension of R-5-({[(2,5-dioxo-4-imidazolidinyl)methyl]disulfanyl}methyl)-2,4-imidazolidinedione ( 6.9 mol) in the mixture of 25 ml AcOH and 2 ml water stirred violently in three necked flask with gas-inlet tube thermometer and short reflux condenser,placed in the ice bath,was bubbled chlorine gas for 15 min (until all precipitate dissolved) at max.temp.+5oC.Then,it was stirred 15 min more,evaporated to a small volume in vacuo (max.temp 30°C),dissolved in 50 ml of dichloromethane,shaken carefully with sat.NaHC03 (ca 25 ml),then with 10% sodium thiosulfate, dried, evaporated, crystallised from THF-hexane (Lora-Tamayo, M. et at, 1968, An. Quim., 64(6):591-606); 1HNMR(DMSO-d6):δ 3.21m(l.lH),3.3m(0.7H).4,65m(lH). R-5-({[(2,5-dioxo-4-imidazolitJinyl)methyl]disulfanyl}methyl)-2,4-imidazolidinedione Commercially available R cystine (0.18 mol) was suspended in 25 ml water and of potassium cyanate 1.5 g (0.2 mol) was added and the mixture was stirred at 100°C for 45 WOJH7&74767 PGT75E02/00472 min.Then it was allowed to cool partially and 10 ml of 10% HC1 were added at once and the mixture was stirred at 100°C again for 50 min.lt was placed in the fridge ovemight,crystals were filtered and washed successively with water and dried in vacuo. LC-MS (APCI) m/z 291 (MH+). / EXAMPLE 3 (5S)-5-{[4-phenyl-l-piperazinyl)sulfonyl]methyl)-2,4-imidazolidinedione The title compound was prepared according to the scheme shown in Example 1. To the solution of S-(2,5-dioxo-4-imidazolidinyl)methanesulfonyl chloride (100 mg,0.47 mmol) in 2.5 ml THF was added the solution of 1-phenylpiperazine (85 mg,0.52 mmol) and 65 ul of triethylamine (0.52 mmol) in 2.5 ml THF via syringe at once.The mixture was stirred for 3 hrs, precipitated triethylammonium chloride was filtered, washed with two small portions of THF, evaporated and recrystallised from EtOH and a small amount of AcOH. LC-MS (APCI) m/z 339.1 (MH+). 1HNMR; δ 2.5 m (2H),3.1bs(6.5H),3.3m(2.5H),4.55m (1H),6.8 t(lH),6.9d(1.88H),7.2 t(2.05H),9.1bs(1.7H) . The starting materials were prepared as follows: S-(2,5-dioxo-4-imidazolidinyI)methanesuIfonyl chloride To the suspension of S-5-({[(2,5-dioxo-4-imidazolidinyl)methyl]disulfanyl}methyl)-2,4-imidazolidinedione ( 6.9 mol) in the mixture of 25 ml AcOH and 2 ml water stirred violently in three necked flask with gas-inlet tube,thermometer and short reflux condenser,placed in the ice bath,was bubbled chlorine gas for 15 min (until all precipitate dissolved) at max.temp.+5°C.Then,it was stirred 15 min more,evaporated to a small volume in vacuo (max.temp 30°C),dissolved in 50 ml of dichloromethane,shaken carefully with sat.NaHC03 (ca 25 ml),then with 10% sodium thiosulfate, dried, evaporated, crystallised from THF-hexane (Lora-Tamayo, M. et al, 1968, An. Quim., 64(6):591-606); 1H NMR (DMSO-d6): δ 3.2m (0.9H,3.35m (0.9H),4.50m (1H). S-5-({[(2,5-dioxo-4-imidazolidinyI)methyl]disulfanyl}methyl)-2,4-imidazolidinedione Commercially available S cystine (0.18 mol) was suspended in 25 ml water and of potassium cyanate 1.5 g (0.2 mol) was added and the mixture was stirred at 100°C for 45 min.Then it was allowed to cool partially and 10 ml of 10% HC1 were added at once and the mixture was stirred at 100°C again for 50 min.lt was placed in the fridge ovemight,crystals were filtered and washed successively with water and dried in vacuo. LC-MS (APCI) m/z 291.1 (MH+). EXAMPLE 4 (R)-5-([4-(4'-fluoro[l,1-biphenyl]-4-yl)-l-piperazinyl]sulfonyl)methyl)-2,4-imidazolidinedione [R)-2,5-DioxoimidazolidinylJmethanesulfonyl chloride(0.0127 g, 0.060 mmol), l-(4'-fluoro[l,l'-biphenyl]-4-yl)piperazine (0.0154 g, 0.060 mmol), triethylamine (0.0084 mL, 0.060 mmol) and dry tetrahydrofuran (0.70 mL) were stirred at room temperature over WO 02/0 night. Polystyrene methylisocyanate (0.025 g, 0.030 mmol) was added and the mixture was shaken over night. The white suspension was carefully transferred to a round-bottomed flask, the resin was rinsed with tetrahydrofuran (2x1 mL) and washings were transferred to the bulk of suspension. The solvent was evaporated, the white solid was suspended in water (5 mL), collected on a filter, washed with water (2x1 mL), sucked free of water and dried in vacuo at 45°C over night to afford approx. 0.010 g of the title compound. LC-MS (APCI) m/z 434 (MH+). 1H NMR (DMSO-d6) δ 10.8 (IH, bs), 7.98 (1H, d, J=2Hz), 7.63 (2H, dd, J,=5Hz, J2=9Hz), 7.53 (2H, d, J=9Hz), 7.23 (2H, t, J=9Hz), 7.05 (2H, d, J=9Ez), 4.45 (1H, ddd, J1=2Hz, J2=4Hz, J3=6Hz), 3.51 (1H, dd, J,=15Hz, J2=7Hz), 3.44 (1H, dd,J1=I5Hz, J2=4Hz), 3.35- 3.25 (8H, m's; obscured by water signal) ppm. 13C NMR (DMSO-d6) δ 173.7,161.3 (d,J=243Hz), 157.3, 149.8,136.4 (d,J=3Hz), 130.1, 127.7 (d, J=8Hz), 127.2, 116.2, 115.5 (d, J=21Hz), 53.4, 49.4, 48.0, 44.9. / The starting materials were prepared as follows: [(R)-2,5-Dioxoimidazolidinyl]merhanesulfonyl chloride was prepared according to Mosher et al, 1958, J. Org. Chem 23:1257. l-(4'-Fluoro[l,l'-biphenyl]-4-yI)piperazine 4-Bromo-4'-fluorobiphenyl (4.46 g, 17.8 mmol), N-tert-butoxycarbonyl piperazine (3.97 g, 21.3 mmol), sodium tert-butoxide (2.39 g, 24.9mmol), racemic 2,2'-bis(diphenylphosphino)-l,l'-binaphthyl (rac-BINAP) (0.082 g, 0.131 mmol), bis-(dibenzylideneacetone)palladium (0) (0.041 g, 0.045 mmol) and dry toluene (45 mL) were stirred at 80°C under nitrogen atmosphere for six hours. The warm mixture was filtered, the solids were washed twice with warm toluene and the filtrate was concentrated in vacuo giving an orange-red crude, which was stirred with ether (50mL) for two hours. The solid was filtered off, washed with small volumes of ether and dried in vacuo at 45°C over night WO-027074767 to give 5.57 g (88% yield) of tert-butyl 4-(4'-fiuoro[l,l'-biphenyl]-4-yI)-l-piperazinecarboxylate. This product (5.52 g, 15.5 mmol) was dissolved in dioxane (150 mL) and stirred with 4M hydrochloric acid (8.1 mL) at RT over night. Concentrated hydrochloric acid (3.0 mL) was added and stirring was continued at 45°C for 1.5 hours and at 60°C for 1 hour. The solution was concentrated to dryness and the solid was triturated with ether (100 mL), filtered, washed with small volumes of ether and dried in vacuo at 45°C for two hours to give 5.26 g (103% yield) of l-(4'-fluoro[l,l '-biphenyl]-4-yl)piperazine dihydrochloride as a light-yellow salt LC-MS (APCI) m/z 257 (MH+). 'H NMR (DMSO-d6) δ 9.40 (2H, bs), 7.64 (2H, dd,J1=6Hz, J2=9Hz), 7.55 (2H, d, J=9Hz), 7.24 (2H, t, J=9Hz), 7.07 (2H, d,J=9Hz), 3.46-3.41 (4H, m), 3.25-3.17 (4H, m). The salt was treated with aqueous sodium hydroxide solution and the base was taken up in dichloro-methane. Drying with Na2SO4, filtering and concentrating the organic phase gave the title compound as an offwhite solid. 'H NMR (DMSO-d6) δ 7.61 (2H, dd, J,=6Hz, J2=9Hz), 7.49 (2H, d, J=9Hz), 7.22 (2H, t, J=9Hz), 6.98 (2H, d, 7=9Hz), 3.10-3.06 (4H, m), 2.86-2.81 (4H, m). WO 02/04767 EXAMPLE 5 Using an analogous procedure to that described in Example 4, [(4R)-2,5-dioxoimidazolidinyl]methanesulfonyl chloride was reacted with the appropriate primary or secondary amine to give the Compounds listed below. All the amines employed are commercially available. The Table below gives the Amine group for each compound of the above structure. WO 02074761 EXAMPLE 6 (S)-5-(( [4-( 4'-fluoro[l.1 r-biphenyl]-4-yl)-l-piperazinyl]sulfonyl)methyl)-2.4- imidazolidinedione [(S)-2,5-Dioxoimidazolidinyl]methanesulfonyl chloride (0.0127 g, 0.060 mmol), l-(4'-fluoro[1,1 '-biphenyl]-4-yl)piperazine (0.0154 g, 0.060 mmol), triethylamine (0.0084 mL, 0.060 mmol) and dry tetrahydrofuran (0.70 mL) were stirred at room temperature over night. Polystyrene methylisocyanate (0.025 g, 0.030 mmol) was added and the mixture was shaken over night. The white suspension was carefully transferred to a round-bottomed flask, the resin was rinsed with tetrahydrofuran (2x1 mL) and washings were transferred to the bulk of suspension. The solvent was evaporated, the white solid was suspended in water (5 mL), collected on a filter, washed with water (2x1 mL), sucked free of water and dried in vacuo at 45°C over night to afford approx. 0.010 g of the title compound. LC-MS (APCI) m/z 433 (MH+). 1H NMR (DMSO-d6) δ 10.8 (1H, br s), 7.98 (1H, d, J=2Hz), 7.63i2H, dd, J,=5Hz, J2=9Hz), 7.53 (2H, d, J=9Hz), 7.23 (2H, t, J=9Hz), 7.05 (2H, d, y=9Hz), 4.45 (1H, ddd, J,=2Hz, J2=4Hz, J3=6Hz), 3.51 (1H, dd, J1=15Hz,J2=7Hz), 3.44 (1H, dd, J,=15Hz, J2=4Hz), 3.35-3.25 (8H, m's; obscured by water signal). 13C NMR (DMSO-d6) δ 173.7, 161.3 (d, 7=243 Hz), 157.3, 149.8, 136.4 (d,J=3Hz), 130.1, 127.7 (d, J=8Hz), 127.2, 116.2, 115.5 (d, J=21 Hz), 53.4, 49.4, 48.0, 44.9. The starting materials were prepared as follows: {(5)-2,5-Dioxoimidazolidinyl]methanesulfonyl chloride was prepared according to Mosher et al, 1958, J. Org. Chem 23:1257. l-(4'-Fluoro[l,l '-biphenyl]-4-yl)piperazine was prepared according to Example 4. WO 02/874767 PCT/SEol/00472 EXAMPLE 7 Using an analogous procedure to that described in Example 6, [(4S)-2,5-dioxoimidazolidinyl]methanesulfonyI chloride was reacted with the appropriate primary or secondary amine to give the compounds listed below. All the amines employed are commercially available. The Table below gives the Amine group for each compound of the above structure. WO 02/07467 EXAMPLE 8 Hydantoins with the following general structure were synthesised (where E is carbon or a heteroatom): / Representative synthetic route: (5R,S)-5-[4-(4-Fluoro-phenyl)-piperidine-l-sulfonylmethyl]-5-methyl-imidazolidine-2,4-dione. / Reagents: a) McSO2CI, DCM, 0°C, 2.5h. b) i. LHMDS, THF, 45min. ii. MeOAc, THF, 40min. c) KCN, (NHO4)2CO3, 50%EtOH/H2O, 70°C, I7h. SULFONYL-AMIDE INTERMEDIATES (1): For NMR-data see experimental part. 4-(4-Fluoro-phenyl)-I-methanesuIfonyl-piperidine 4-(4-Fluoro-phenyl)piperidine hydrochloride (2.l6g; l0mmol) and diisopropylethylamine (4.35ml; 25mmol) was dissolved in DCM (60ml) and cooled under nitrogen on a ice/water bath. Methanesulfonyl chloride (1.56ml; l0.lmmol) was dissolved in DCM (5ml) and added droppwise during 2 min. The reaction mixture was stirred for 2.5 h on the ice/water bath. The reaction mixture was washed with dilute HCi (aq), pH=2, H2O, and 1M Na2CO3-The organic phase was dried (Na2SO4), filtered and evaporated to give a crude product mat was recrystallised from THF/n-Heptane. The colourless crystalls was removed by filtration and dried under vaccurn at 45° C. Obtained 1.96g (76% yield) of the title compound. LC-MS (APCI) ra/z 258 (MH+). 1H NMR(DMSO-d6): δ 7.31 (m, 2H), 7.12 (m, 2H), 3.67 (m, 2H), 2.80 (dt, 2H), 2.64 (m, 1H), 1.85 (m, 2H), 1.65 (m, 2H). 5-ChIoro-2-{l-methanesulfonyl-piperidine-4-yIoxy)-pyridine The title compound was prepared as described in the synthesis of 4-(4-Fluoro-phenyl)-l- methanesulfonyl-piperidine. 5-Chloro-2-(piperidine-4-yloxy)-pyridine (2.13g; l0mmol) (preparation of this compound was made as described in WO 99-GB2801), diisopropylethylamine (2.20ml; 12.5mmol) and Methanesulfonyl chloride (1.56ml; l0.lmmol) gave 2.14g (74%) of the title compound. LC-MS (APCI)m/z 291 (MH+). 1H NMR (DMSO-d6): δ 8.20 (d, 1H), 7.81 (dd, 1H), 6.87 (d, 1H), 5.09 (m, 1H), 3.41-3.30 (m, 2H), 3.15-3.06 (m, 2H), 2.90 (s, 3H), 2.04 (m, 2H)} 1.75 (m, 2H). l-(methylsulfonyl)-4-[5-(trifluoromethyI)pyridin-2-yl]piperazine 20 1 -[5-(Trifluoromethyl)-Pyridin-2-yl]-piperazine (l.0g; 4.3mmol) and Diisopropylethylamine (0.9ml; 5.4mmoI) was dissolved in DCM (10ml). Molecular sieves (4A) was added and the solution was cooled on a ice/water bath. Methanesulfonylchloride (0.9ml; 12mmol) was added and a slurry formed that was stirred for 15 min, the reaction mixture was allowed to reach room temperature and after 1 h. the reaction was quenched by adding 5% KHCO3. Evaporation of solvents and the residue was dissolved between DCM and 5% KHCO3. Separation and extraction of the waterphase with DCM (1x). The combined organic phases was dried (MgSO4), filtered and evaporated to give a crude product as a slightly yellow solid. RecrystaJlised (3x) from EtOAc/Heptan gave the title compound as colourless crystalls. Obtained 1.06g (79% yield) of the title compound. Purity >95% (HPLC, 254nm) LC-MS (APCI) m/z 310 (MH+). 1H-NMRpMSO-d6): δ 8.44 (1H, bs), 7.85 (1H, dd), 7.02 (1H, d), 3.77 (4H, bt), 3.20 (4H, bt), 2.90 (3H, s). The following compounds were prepared as described in the synthesis of 1-(methylsulfonyl)-4-[5-(trifluoromethyl)pyridin-2-yl]piperazine 6-[4-(methylsulfonyl)piperazine-l-yl]pyridine-3-carbonitrile 6-(l-Piperazmo)-pyridine-3-carbonitrile (2.07g; 1 lmmol), Diisopropylethylamine (2.4ml; 13.8mmol) and Methanesulfonylchloride (0.86ml; 1 lmmol) in DCM (20ml) gave 2.53g (86%) of the title compound. Purity >95% (NMR). LC-MS (APCI) m/z 267 (MH+). 1H-NMR(DMSO-d6): 5 8.52 (lH,dd), 7.90 (1H, dd), 7.00 (1H, d), 3.79 (4H, brt), 3.19 (4H, bt), 2.90 (3H, s). l-(4-fluorophenyl)-4-(raethylsulfonyI)piperazine l-(4-Fluorophenyl)-piperazine (1.98g; 1 lmmol), Diisopropylethylamine (2.4ml; 13.8mrnol) and Methanesulfonylchloride (0.86ml; 1 lmmol) in DCM (20ml) gave 2.46g (86%) of the title compound. Purity >95% (NMR). LC-MS (APCI) m/z 259 (MH+). 1H-NMR(DMSO-d6): δ 7.11-6.96 (4H, m), 3.28-3.20 (4H, m), 3.20-3.14 (4H, m), 2.92 (3H,s). l-[(4-fluorophenyl)methyl]-4-(methylsulfonyI)piperazine l-(4-Fluor-benzyI)-piperazine (2.14g; 11mmol), Diisopropylethylamine (2.4ml; 13.8mmol) and Methanesulfonylchloride (0.86ml; 11mmol) in DCM (20ml) gave 1.97g (65%) of the title compound. Purity>95%(NMR) LC-MS (APCI) m/z 273 (MH+). 1H-NMR(DMSO-d6): δ 7.40-7.28 (2H, m), 7.21-7.10 (2H, m), 3.50 (2H, bs), 3.10 (4H, m), 2.87(3H,bs), 2.44(4H, m). 2-[4-(methylsulfonyl)piperazin-l-yI)pyrimidine l-(2-Pyrimidyl)-piperazine dihydrochloride (2.61g;11mmol) and Diisopropylethylamine (7.2ml; 41.3mmol) was stirred in DCM (20ml) for 30 min. The precipitated salts was removed by filtration and solvents evaporated, residue was redissolved in DCM (20ml). Diisopropylethylamine (2.4ml; 1 lmmol) and 4A mol. sieves was added, the yellow solution was cooled on ice/water bath and Methanesulfonylchloride (0,86ml; 1 lmmol) was added. The resulting red solution was stirred for 15 min, the reaction mixture was allowed to reach room temperature and after 1 h. the reaction was quenched by adding 5% KHCO3. Evaporation of solvents and the residue was dissolved between DCM and 5%KHCC>3. Separation difficult due to foam formation. Waterphase was saturated with NaCl and pH adjusted to 10-11. Extraction with EtOAc (3x). The combined organic phases was dried (K2CO3), filtered and evaporated to give a crude product as a red solid. Recrystallised (3x) from EtOAc/Heptan gave the title compound as a red powder. Obtained 0.6g (22%) of the title compound. Purity >95% (NMR). LC-MS (APCI) m/z 243 (MH+). 1H-NMR(DMSO-d6): δ 8.39 (2H, d), 6.68 (1H, t), 3.85 (4H, bt), 3.17 (4H, bt), 2.88 (3H, s). 4-(4-chlorophenyl)-l-(methyIsulfonyl)piperidine The title compound was prepared as described in the synthesis of 4-(4-Fluoro-phenyl)-l-methanesulfonyl-piperidine. 4-(4-Chlorophenyi)piperidine hydrochloride (0.9g, 3.9 mmol), diisopropylethylamine (1.7 ml, 9.7 mmol) and methanesulfonylchloride (0.33ml, 4.3 mmol) in DCM (30ml) and gave 0.82g (78%) of the title compound after recrystallisation from EtOAc/ Heptane. Purity > 95%. LC-MS(APCI) m/z 274 (MH+). 1H NMR CDC13: δ 1.83 (2H, dd); 1.92-2.01 (2H, m); 2.55-2.68 (1H, m); 2.79 (2H, dt); 2.85(3H,s);3.97(2H,d);7.16(2H,d);7.32(2H,d). ESTER INTERMEDIATES All other esters used are commercially available or earlier described. 4-Pyrimidin-2-yl-butyric acid ethyl ester 2-Bromopyrimidine (l.0g, 6.3mmol) was slurried in dry THF (8mL). N2 (g) was bubbled through the slurry for 5 min. Pd(CH3CN)2Cl2 (8mg, 0.03mmol) and PPh3 (23.6mg, 0.09mmol) was added. Under N2-atmosphere 4-Ethoxy-4-oxo-butylzincbromide (0.5M/THF) (15mL, 7.5mL) was added in one portion. The resulting brown solution was stirred at room temperature for 2h. H2O (5mL) was added and the mixture stirred for 60 min. before evaporation of solvents. The residue was redissolved in DCM (150mL) and washed with 0.5M trisodiumcitrate (l00mL), H2O (l00mL) and brine (l00mL), dried (MgSO4), filtered and evaporated to give 1.3 g of an orange oil The crude product was purified on 70g of Si-60 gel using a gradient of 100%Heptane to 100% EtOAc as eluent. The fractions containing the product was collected and solvent evaporated to give a yellow oil. Purity by NMR>95% was considered enough for our need. Obtained 1.12g (92% yield) of the title compound. LC-MS (APCI) m/z 195 (MH+). 1H-NMR(CDC13): δ 8.67 (d, 2H), 7.14 (t, 1H), 4.12 (q, 2H), 3.02 (t, 2H), 2.41 (t, 2H), 2.18 (q,2H), 1.25 (t,3H). 3-Pyrimidin-2-yl-propionic acid ethyl ester 2-Bromopyrimidine (l.0g, 6.3mmol) was dissolved in THF (8 mL) and bubbled through with nitrogen. Pd(MeCN)2Cl2 (8mg, 0.03mmol) and PPh3 (23.6mg, 0.09mmoi) was added followed by addition of 3-ethoxy-3-oxopropylzinkbromid (15mL, 7.5mmol). The reaction was stirred at rt for several days. The crude product was purified on silica with Heptane -EtOAc 3 :1 as eluent giving 0.60g (52%) of the title compound. LC-MS (APCI) m/z 181 (MH+)- tert-butyl 4-(2-methoxy-2-oxoethyl)piperidine-l-carboxylate tert-Butyl 4-(2-methoxy-2-oxoethylidene)piperidine-l-carboxylate (3.6 g, 14 mmol) and 10% Pd/C moistered with water (0.8 g) was mixed in MeOH (75 mL) and stirred under H2 (1 atm) for 4 h. The mixture was filtered through Celite and concentrated to give the title compound (3.6 g, 99%). LC-MS (APCI) m/z 158 (MH+-boc). 1H NMR (CDCl3): δ 4.07 (2 H, bs); 3.68 (3 H, s); 2.72 (2 H, t); 2.25 (2 H, d,J=7.1 Hz); 2.01-1.86 (1 H, m); 1.68 (2 H, d); 1.46 (9 H, s); 1.23-1.08 (2 H, m). WQ'02/074767 PCTC/8E02/00472 : crude products, no NMR available, mtrl. used directly in next synthetic step. l-[4-4(Fluoro-phenyl)-piperidine-l-sulfonyl]-propan-2-one. 4-(4-Fluoro-phenyl)-l-methanesulfonyl-piperidine (l00mg; 0.39mmol) was dissolved in dry THF (3mL) under a protective nitrogen atmosphere. Lithium bis(trimethylsilyl)amide as a 1.0 M solution in THF (l.0mL; l.Ommol) was added in one portion at room temperature, the resulting yellow solution was stirred for 45 min. Methylacetate (50mg; 0.68mmol) dissolved in dry THF (0.5mL) was added, the mixture was stirred at room temperature for 40 min. The reaction was quenched by adding NH4Cl (sat.) (2mL)..The 10 mixture was evaporated and the resulting solid was dissolved in a mixture of DCM and H2O. The organic phase was separated and washed with brine, dried (MgSO4), filtrated and evaporated. The crude product was purified on 20g of Si-60 gel using a gradient of 100%Heptane to 50%EtOAc, a flow of 20mL/min was used and UV=254nm was used for detection, The fractions containing the product was evaporated and this gave the title compound as a colourless solid. Obtained 70mg (59% yield). TLC(Si-60; EtOAc:Heptane (2:1)): Rt=0.65 LC-MS (APCI) m/z 300.1 (MH+). 1H-NMR(CDC13): δ 7.17 (m, 2H), 7.01 (m, 2H), 4.02 (s, 2H), 3.93 (m, 2H), 2.94 (dt, 2H), 2.63 (m, 1H), 2.46 (s, 3H), 1.91 (m, 2H), 1.77 (m, 2H). WO 02/074767 PCT/E02/00472 The following compounds were prepared as described in the synthesis of 1-[4-4 (Fluoro-phenyl)-piperidine-l-sulfonyl]'propan-2-one. l-[4-4(FIuoro-phenyl)-piperidine-l-sulfonyl]-4-phenyl-butan-2-one 4-(4-Fluoro-phenyl)-l-methanesuIfonyl-piperidine (l00mg; 0.39mmol), Methyl-3-phenylpropionate (112mg; 0.68mmol) and Lithium bis(trimethylsilyl)amide 1.0 M/THF (l.0mL; l.Ommol) gave 93 mg (61%) of the title compound. TLC(Si-60; EtOAcrHeptane (2:1)): RpO.68 1H-NMR(CDC13): δ 7.30-7.10 (m, 7H), 6.99 (m, 2H), 3.97 (s, 2H), 3.79 (m, 2H), 3.11 (t, 2H), 2.94 (t,.2H), 2.83 (dt, 2H) 2.57 (m, 1H), 1.83 (m, 2H), 1.70 (m, 2H). l-[4-4(FIuoro-phenyl)-piperidine-l-sulfonyl]-5-imidazol-pentan-2-one 4-(4-Fluoro-phenyI)-l-methanesuIfonyl-piperidine (l00mg; 0.39mmol), 4-imidazol-lyl-butyric acid ethyl ester (127mg; 0.70mmol) and Lithium bis(trimethylsilyl)amide 1.0 M/THF (1 .0mL; 1 .0mmol) gave 75 mg (48%) of the title compound. LC-MS (APCI) m/z 394 (MH+). 1H-NMR(CDCl3): δ 7.48 (s, 1H), 7.16 (m, 2H), 7.08 (s, 1H), 7.02 (m, 2H), 6.93 (s, 2H), 4.00 (t, 2H), 3.97 (s, 2H), 3.90 (m, 2H), 2.92 (dt, 2H), 2.77 (t, 2H), 2.63 (m, 1H), 2.12 (q, 2H), 1.92 (m, 2H), 1.77 (m, 2H). l-[4-(4-Fluoro-phenyl)-piperidine-l-sulfonyl]-5-pyrimidin-2-yI-pentan-2-one 4-(4-Fluoro-phenyl)-l-methanesulfonyl-piperidine (150mg; 0.39mmol) was dissolved in dry THF (3mL) and cooled on an ice/brine mixture. Lithium bis(trimethylsilyl)amide as a 1.0 M solution in THF (1.5mL; 1.5mmol) was added and the mixture was stirred for 40 min. 4-Pyrimidin-2-yl-butyric acid ethyl ester (169mg; 0.87mmol) in THF (0.5mL) was added, the reaction was stirred for 30 min and then allowed to reach room temperature. After 2 h. LC/MS analysis of the reaction mixture showed >98% conversion of the starting material and the reaction was quenched by adding saturated NH4Cl (aq) (2mL). The mixture was evaporated and the resulting solid was dissolved in a mixture of DCM and PCT/SK02/00472 5%KHC03. The organic phase was separated and the water phase was extracted once with DCM. The combined organic phases was washed with brine, dried (MgSO4), filtered, and evaporated to give a yellow oil. The oil was dissolved in EtOAc and isoHexane was added until a solid formed. Evaporation of solvent gave a yellow solid crude product. This material was analysed using LC/MS only and used without further purification in the next step. Obtained 234 mg of the crude title compound. LC-MS (APCI) m/z 406.1.(MH+). The following compounds were prepared as described in the synthesis of]-[4-(4-Fluoro-phenyl)-piperidine-l-sulfonyl]-5-pyrimidin-2-yl-pentan-2-one. They were obtained as . crude products and used without further purification. l-[4-{5-Chloro-pyridin-2-yloxy)-piperidine-l-sulfonyl]-propan-2-one Starting from 5-Chloro-2-(l-methanesulfonyl-piperidine-4-yloxy)-pyridine (150mg; 0.51mmol), Methylacetate (6lmg; 0.82mmol) and Lithium bis(trimethylsilyl)amide 1.0M/THF (1.3ml; 1.3mmol). Obtained 161mg of the crude title compound. Used without further purification. LC-MS (APCI) m/z 333.1 (MH+). l-[4-(5-Chloro-pyridin-2-yloxy)-piperidine-l-suIfonyl]-4-phenyl-butan-2-one Starting from 5-Chloro-2-(l-methanesulfonyl-piperidine-4-yloxy)-pyridine (150mg; 0.5lmmol), Methyl-3-phenylpropionate (126mg; 0.77mmol) and Lithium bis(trimethylsilyl)amide 1.0M/THF (1.3ml; 1.3mmol). Obtained 258mg of the crude title compound. Used without further purification. LC-MS (APCI) m/z 423.2 (MH+). WO 02/074767 PCT/SE02/00472 l-[4-(5-Chloro-pyridin-2-yloxy)-piperidine-l-sulfonyl]-5-imidazol-l-yl-pentan-2-one Starting from 5-Chloro-2-( I-methanesulfonyl-piperidine-4-yloxy)-pyridine (150mg; 0.51mmol), 4-imidazol-lyl-butyric acid ethyl ester (140mg; 0.77mmol) and Lithium bis(trimethylsilyl)amide 1.0 M/THF (1.3mi; 1.3mmol). Obtained 268mg of the crude title compound. Used without further purification. LC-MS (APCI) m/z 427,2 (MH+). l-[4-(5-Chloro-pyridin-2-yloxy)-piperidine-l-sulfonyI]-5-pyrimidin-2-yl-pentan-2-one Starting from 5-Chloro-2-(l-methanesulfonyl-piperidine-4-yloxy)-pyridine (150mg; 0.51mmol), 4-Pyrimidin-2-yl-butyric acid ethyl ester (147mg; 0.76mmol) and Lithium bis(trimethylsilyl)amide 1.0 M/THF (1.3ml; 1.3mmol). Obtained 244mg of the crude title compound. Used without further purification. LC-MS (APCI) m/z 439.2 (MH+). l-[4-(5-Chloro-pyridin-2-yIoxy)-piperidine-l-sulfonyl]-butan-2-one LC-MS (APCI) m/z 347 (MH+) l-[4-(5-ChIoro-pyridin-2-yloxy)-piperidine-l-sulfonyl]-pentan-2-one LC-MS (APCI) m/z 361 (MH+) l-[4-(5-Chloro-pyridin-2-yIoxy)-piperidine-l-sulfonyl]-4-methyl-pentan-2-one LC-MS (APCI) m/z 375 (MH+) l-[4-(5-Chloro-pyridin-2-yIoxy)-piperidine-l-sulfonyl]-4-pyrimidin-2-yl-butan-2-one LC-MS (APCI) m/z 425 (MH+) l-({4-[(5-Chloropyridin-2-yl)oxy]piperidin-l-yI}sulfonyl)-3-(3-methylphenyl)propan-2-one LC-MS (APCI) m/z 423 (MH+) l-({4-[(5-Chloropyridin-2-yl)oxy]piperidin-l-yl}sulfonyI)-3-tetrahydro-2H-pyran-4-ylpropan-2-one LC-MS (APCI) m/z 417 (MH+) l-({4-[(5-chloropyridin-2-yl)oxy]piperidin-l-yI}sulfonyI)-5-morpholin-4-ylpentan-2-one LC-MS (APCI) m/z 446 (MH+) 5-({4-[(5-chIoropyridin-2-yl)oxy]piperidin-l-yl}sulfonyl)-4-oxopentanenitriIe LC-MS (APCI) m/z 372 (MH+) l,l-dimethylethyl 5-({4-[(5-chloropyridin-2-yl)oxy]piperidin-l-yl}sulfonyl)-4-oxopentylcarbamate LC-MS (APCI) m/z 476 (MH+.) l-({4-[(5-chloropyridin-2-yl)oxy]piperidin-1-yl}sulfonyl)-4-morpholin-4-ylbutan-2-one LC-MS (APCI) m/z 432 (MH+) 2-({4-[(5-chloropyridin-2-yl)oxy]piperidin-l-yl}sulfonyl)-l-phenylethanone LC-MS (APCI) m/z 395 (MH+) 2-({4-{(5-chIoropyridin-2-yl)oxy]piperidin-l-yl}sulfonyl)-l-(4-fluorophenyl)ethanone LC-MS (APCI) m/z 413 (MH+) 2-({4-[(5-chloropyridin-2-yI)oxy]piperidin-l-yl}sulfonyl)-l-(lH-imidazol-4-yl)ethanone LC-MS (APCI) m/z 385 (MH+) WO 02/074767 PC17SE02/00472 4-{({4-[(5-chloropyridin-2-yl)oxy]piperidin-l-yl}sulfonyl)acetyl]benzamide n.d. ({4-[(5-chloropyridin-2-yl)oxyIpiperidin-l-yl}sulfonyl)-4-(lH-l,2,4-triazoI-l-yI)butan-2-one LC-MS (APCI) m/z 414 (MH+) l-{[4-(4-fluorophenyl)piperidin-l-yl]sulfonyl}-4-pyrimidin-2-yIbutan-2-one LC-MS (APCI) m/z 392 (MH+) l-{{4-(4-fluorophenyl)piperidin-l-yl]sulfonyl}-3-tetrahydro-2H-pyran-4-ylpropan-2-one LC-MS (APCI) m/z 3 84 (MH+) 4-({[4-(4-fluorophenyI)piperidin-l-yl]sulfonyl}acetyI)benzamide LC-MS (APCI) m/z 405 (MH+) 2-{[4-(4-fluorophenyl)piperidin-l-yl]sulfonyl}-l-(lH-imidazol-4-yI)ethanone LC-MS (APCI) m/z 352 (MH+) l-{[4-(4-chlorophenyl)piperidin-l-yl]sulfonyl}-3-tetrahydro-2H-pyran-4-ylpropan-2-one LC-MS (APCI) m/z 400 (MH+) l-{[4-(4-chlorophenyl)piperidin-l-yl]sulfonyl}-5-morpholin-4-ylpentan-2-one LC-MS (APCI) m/z 429 (MH+) l-({4-[5-(trifluoromethyl)pyridin-2-yl]piperazine-l-yl}sulfonyl)propan-2-one LC-MS (APCI) m/z 352.1 (MH+) 6-{4-[(2-oxopropyl)sulfonyl]piperazin-l-yl}pyridine-3-carbonitrile LC-MS (APCI) m/z 309.1 (MH+) l-{[4-(4-fluorophenyl)piperazine-l-yl]sulfonyl}propan-2-one LC-MS (APCI) m/z 301.1 (MH+) l-({4-((4-fluorophenyl)methyl]piperazine-l-yI}suIfonyl)propan-2-one LC-MS (APCI) m/z 315.1 (MH+) l-[(4-pyrimidin-2-ylpiperazine-l-yI)sulfonyl]propan-2-one LC-MS (APCI) m/z 285.1 (MH+) 1,1-dimethylethyl4-[3-({4-[(5-chloropyridin-2-yl)oxy]piperidin-l-yI}sulfonyl)-2-oxopropyl]piperidine-l-carboxylate LC-MS (APCI) m/z 517 (MH+). HYPANTOINS OF FORMULA I WO 027074767 PCPSE02/00472 WOQ27074767 PCT7SE02/00472 WO O2i074767 PCT/SE02/00472 (1): NMR available, see experimental part. (2): Not purified. (5R,S)-5-f4-(4-FIuoro-phenyl)-piperidine-l-suIfonylmethyl]-5-methyl-imidazolidine- 2,4-dione The ketone l-[4-4(Fluorophenyl)-piperidine-l-sulfonyl]-propan-2-one (68mg; 0.23mmol), KCN (30mg; 0.46mmol) and (NH4)2CO3 (11 lmg; 1.16mmol) was suspended in 50% EtOH/H2O (8mL) in a 22 mL sealed tube and heated to 70° C, a solution was formed. The mixture was stirred at 70° C for 17 h. a solid formed in the tube, the mixture was cooled to room temperature and solvent evaporated, the residue was suspended in water and pH adjusted to pH=6 using 1.0M HC1 and preciptated product removed by filtration and washed with water. The water phase was saturated with NaCl and extracted with MeCN. The solid material and MeCN solutions was combined and evaporated. The crude product was purified using a semipreparative HPLC system and a C-18 column with MeCN/H2O+0.1%TFA as eluent. Fractions containing the product was combined and solvent removed by evaporation to give the title compound as a colourless solid. Obtained 53 mg (62% yield). Purity by NMR >98% LC-MS (APCI) m/z 370.0 (MH+). WO 02/474767 PCT/SE02/00472 1H-NMR (DMSO-d6): δ 10.74 (s, 1H), 8.02 (s, 1H), 7.31 (m, 2H), 7.12 (m, 2H), 3.61 (m, 2H), 3.51 (d, 1H), 3.34 (d, lH), 2.86 (m, 2H), 2.63 (m, 1H), 1.82 (m, 2H), 1.63 (m, 2H), 1.34 (s,3H). (SR,S)-5-[4-(4-Fluoro-phenyl)-piperidine-l-sulfonylmethyl]-5-phenethyl-imidazolidine-2,4-dione The title compound was prepared as described in the synthesis of (5R,S)-5-[4-(4-Fluoro-phenyl)-piperidine-1 -sulfonylmethyI]-5-methyl-imidazolidine-2,4-dione. I-[4-4(Fluorophenyl)-piperidine-l-sulfonyl]-phenyl-butan-2-one (93mg; 0.24mmol), KCN (40mg; 0.61mmol) and (NH4)CO3 (117mg; 1.22mmoI) gave 37mg (33%) of the title compound. LC-MS (APCI) m/z 460.1 (MH+). 1H-NMR (DMSO-d6): δ 10.87 (s, 1H), 8.13 (s, 1H), 7.30 (m, 4H), 7.15 (m, 5H), 3.63 (m, 2H)5 3.56 (d, 1H), 3.41 (d, 1H), 2.87 (m, 2H), 2.61 (m, 2H), 2.39 (m, 1H), 1.92 (bt, 2H), 1.83 (m, 2H), 1.63 (m, 2H). (5R.S)-5-[4-(4-Fluoro-phenyl)-piperidine-l-sulfonylmethyl]-5-(3-imidazol-l-yl-propyl)-imidazolidine-2,4-dione 1 -[4-4(Fluorophenyl)-piperidine-1 -sulfonyl]-5-imidazol-butan-2-one (75mg; 0.19mmol), KCN (30mg; 0.46mmol) and (NH4)O2CO3 (91mg; 0.95mmol) was dissolved in EtOH/H2O (1/1) (l0mL) in a sealed 22 mL tube and stirred for 17.5 h at 70 °C. Another portion of KCN (40mg; 0.61mmol) and (NH4)CO3 (250mg; 2.60 mmol) was added and the mixture was stirred at 70 °C for another 16 h. Evaporation of solvent and the residual material was suspended in H2O, precipitating crude product was removed by filtration and purified using a semipreparative HPLC system and a C-18 column with MeCN/H2O+0.1%TFA as eluent. Fractions containing the product was combined and MeCN was removed by evaporation, the acidic waterphase was made basic, pH=8-9, using 5% KHCO3 and the precipitating product was extracted using EtOAc. Organic phase dried (Na2SO4), filtered and evaporated to give the title compound as a colourless solid. WO 02/074767 Obtained 60mg (68% yield) LC-MS (APCI) m/z 464.2 (MH+). 1H-NMR (DMSO-d6): δ 10.75 (bs, IH), 8.06 (s, 1H), 7.59 (s,1H), 7.30 (m, 2H), 7.16-7.08 (ra, 3H), 6.88 (s, 1H), 3.95 (m, 2H), 3.60 (m, 2H), 3.47 (d, 1H), 3.35 (d, 1H), 2.86 (m, 2H), 2.62(m,lH), 1.86-1.50 (m,8H). (5R,S)-5-[4-[4-Fluoro-phenyl)-piperidine-l-sulfonylmethyl]-5-(3-Pyrimidin-2-yl-propyl-imidazolidine-2.4-dione Crude 1 -[4-(4-Fluoro-phenyl)-piperidine-1 -sulfonyl]-5-pyrimidin-2-yl-pentan-2-one (234mg; max 0.58mmol), KCN (151mg; 2.3mmoI) and (NH4)2CO3 (557mg; 5.8mmol) was suspended in EtOH/H2O (1/1) (26mL) in a 40mL sealed tube. The mixture was heated 70° C and the resulting yellow solution was stirred for 16h. LC/MS analysis showed that 15% unreacted ketone remained and another portion of KCN (65mg; lmmol) and (NH4)CO3 (245mg; 2.55mmol) was added and the mixture was heated to 70° C for another l6h. Solvent was removed by evaporation and the residue was treated with H2O (25mL). The precipitating crude product was removed by filtration and purified using semipreparative HPLC system and a C-18 column with MeCN/H2O+0.1%TFA as eluent. Fractions containing the product was combined and MeCN was removed by evaporation, the acidic waterphase was made basic, pH=8-9, using 5% KHCO3 and the precipitating product was filtered off, washed with water and dried in a desiccator under reduced pressure at 40° C over night. This gave the title compound as a colourless solid. Purity >98% by NMR. Obtained 120mg (43% yield, 2 steps). LC-MS (APCI) m/z 476.2 (MH+). 1H-NMR (DMSO-d6): δ 10.77 (s, 1H), 8.72 (d, 2H), 8.03 (s, 1H), 7.36-7.27 (m, 3H), 7.15- 7.09 (m, 2H), 3.60 (m, 2H), 3.50 (d, 1H), 3.34 (d, 1H), 2.92-2.80 (m, 4H), 2.62 (m, 1H), 1.86-1.54(m,8H). WO02/O74767 PC?75E02/00472 The following compounds were prepared as described in the synthesis of(5R,S)-5-[4-(4-Fluoro-phenyl)-piperidine-l-sulfonylmethyl]-5-(3-pyrimidin-2-yl-propyl)Imidazolidine-2,4-dione. (5R.S)-5-[4-(5-Chloro-pyridin-2-yloxy)-piperidine-l-sulfonylmethyl]-5-methyl-imidazolidine-2,4-dione Purification not needed, after evaporation of reaction mixture and addition of water the precipitating product was pure enough >98% by HPLC (220nm, 254nm) and NMR. Obtained 147mg (71% yield, 2steps) of the title compound as a colorless solid, LC-MS (APCI) m/z 403.1 (MH+). 1H-NMR (DMSO-d6): δ 10.73 (bs, 1H), 8.20 (d, 1H), 8.01 (s, 1H), 7.81 (dd, 1H), 6.87 (d, 1H), 5.09 (m,1H), 3.52 (d, 1H), 3.35 (d, 1H), 3.42-3.26 (m, 2H + H2O), 3.18-3.06 (m, 2H), 2.08-1.96 (m, 2H), 1,79-1.65 (m, 2H), 1.33 (s, 3H). (5S)-5-[4-(5-Chloro-pyridin-2-yloxy)-piperidine-l-sulfonylmethyl]-5-methyl-imidazolidine-2,4-dione and (SR)-5-[4-(5-Chloro-pyridin-2-yloxy)-piperidine-l-sulfonylmethyl]-5-methyl-imidazolidine-2,4-dione The coresponding racemic material (74mg), was dissolved in 36mL of isoHexane/EtOH (25/75) and separated into the pure enantiomers by using the following Gilson HPLC system: Column: CHIRALCEL OD, 2.0x25 cm, flow = 6.0 mL/min, eluent = isoHexane/EtOH (25/75), temp = ambient, detector UV = 220nm. The enantiomers were collected and analysed on a CHIRALCEL OD-H, 0.46x25 cm, 0.5 mL/min, isoHexane/EtOH (25/75), ambient temperature, 220nm. Rt - 9.88 min. ee>99% for the faster eluting enantiomer, 29mg (39%). Rt = 11.45 min. ee=98.7% for the slower eluting enatiomer, 27mg (36%). LC-MS (APCI) m/z 403.1 (MH+). WO 02/074767 (5R,S)-5-[4-(S-Chloro-pyridin-2-yloxy)-piperidine-l-sulfonylmethyl]-5-phenethyl-imidazolidine-2,4-dione. Starting from crude l-[4-(5-Chloro-pyridin-2-yloxy)-piperidine-l-sulfonyl]-4-phenyl- butan-2-one (258mg; max 0.51mmol). Purification of crude product was made on 70g Si-60 gel using DCM+5%MeOH as eluent. Purity >96% by NMR and HPLC (220nm, 254nm). Obtained 201mg (80% yield, 2 steps) of the title compound as a colourless solid. LC-MS (APCI) m/z 493.0 (MH+). 1H-NMR (DMSO-d6): δ 10.86 (bs, 1H), 8.21 (bd, 1H), 8.13 (s, 1H), 7.81 (dd, 1H), 7.33- 7.24 (m, 2H), 7.22-7.14 (m, 3H), 6.87 (d, 1H), 5.10 (m, 1H), 3.56 (d, 1H), 3.42 (d, 1H), 3.43-3.28 (m, 2H + H20), 3.20-3.08 (m, 2H), 2.66-2.52 (m,1H), 2.45-2.31 (m, 1H), 2.08- 1.96 (m,2H), 1.96-1.83 (m, 2H), 1.81-1.65 (m,2H. (5R,S)-5-[4-(5-Chloro-pyridin-2-yIoxy)-piperidine-l-sulfonylmethyl]-S-(3-imidazol- lvl-propyl)-imidazolidine-2,4-dione Starting from crude l-[4-(5-ChIoro-pyridin-2-yloxy)-piperidine-l-sulfonyl]-5-imidazol-l-yl-pentan-2-one (268mg; max 0.51mmol). Obtained 151mg (59% yield, 2 steps) of the title compound as a colourless solid. Purity >98% by NMR. LC-MS (APCI) m/z 497.2 (MH+). lH-NMR (DMSO-d6): δ 10.81 (bs, 1H), 8.20 (d, 1H), 8.05 (s, 1H), 7.81 (dd, 1H), 7.59 (bs, 1H), 7.13 (bs, 1H), 6.88 (bs, 1H), 6.87 (d, 1H), 5.08 (m, 1H), 3.47 (d, 1H), 3.40-3.28 (m, 3H + H20), 3.17-3.06 (m, 2H), 2.07-1.95 (m, 2H), 1.79-1.64 (m, 3H), 1.61-1.48 (m, 3H). 25/ (5R,S)5-[4-(5-Chloro-pyridin-2-yloxy)-piperidine-l-sulfonylmethyl]-5-(3-pyrimidin-2-yI-propyn-imidazolidine-2.4-dione Starting from crude l-[4-(5-Chloro-pyridin-2-yloxy)-piperidine-l-sulfonyl]-5-pyrimidin-2- yl-pentan-2-one (244mg; max 0.51mmol). Obtained 105mg (49% yield, 2 steps) of the title compound as a colourless solid. WO 020/74767 Purity >98% by NMR. 1H-NMR (DMSO-d6): δ 10.77 (bs, 1H), 8.72 (d, 2H), 8.20 (d, 1H), 8.03 (s, 1H), 7.81 (dd, 1H), 7.34 (t, 1H), 6.87 (d, 1H), 5.08 (m, 1H), 3.50 (d, IH); 3.41-3.29 (m, 3H + H20), 3.16-3.07 (m, 2H), 2.83 (t, 2H), 2.06-1.96 (m, 2H), 1.81-1.66 (m, 5H), 1.63-1.51 (m, 1H). (5S)-5-[4-(5-Chloro-pyridin-2-yloxy)-piperidine-l-sulfonylmethyl]-5-(3-pyrimidin-2- ylI-propyl)-imidazolidine-2,4-dione and(5R)-5-[4-(5-Chloro-pyridin-2-yloxy)- piperidine-l-sulfonylmethyl]-5-(3-pyrimidin-2-yl-propyl)-imidazolidine-2,4-dione The coresponding racemic material (40mg), was dissolved in 26mL of isoHexane/EtOH (25/75) and separated into the pure enantiomers by using the same conditions as described for separation of (5R,S)-5-[4-(5-Chloro-pyridin-2-yloxy)-piperidine-l -sulfonylmethyl]-5- methyl-imidazolidine-2,4-dione. Rt = 17.6 min. ee>99% for the faster eluting enantiomer, 17mg (42%). Rt - 21.0 min. ee=98.9% for the slower eluting enatiomer, 15mg (37%). LC-MS (APCI) m/z 509 (MH+). 5-[(4-[(5-chloropyridin-2-yl)oxylpiperidin-l-yl)sulfoyl)methyl]-5-ethvlimidazoIidine-2,4-dione LC-MS (APCI) m/z 417 (MH+). 1H NMR (DMSO-d6): δ 0.76 (3H, t); 1.63 (2H, q); 1.66-1.76 (2H, m); 1.96-2.06 (2H, m); 3.12 (2H, bt); 3.48, 3.35 (1H each, ABq, J=\4.9); 3.32-3.41 (2H, m); 5.04-5.12 (1H, m); 6.86 (1H, d); 7.80 (1H, dd); 7.96 (1H, s); 8.19 (1H, d); 10.73 (IH, s). LC-MS (APCI) m/z 417 (MH+). 5-[(4-[(5-chloropyridin-2-yl)oxylpiperidin-l-yl}sulfonyl)methyl]-5-propylimidazolidine-2,4-dione LC-MS (APCI) m/z 431 (MH+). lH NMR (DMSO-d6): δ 0.84 (3H, t); 1.03-1.16 (1H, m); 1.20-1.35 (1H, m); 1.58 (2H, t); 1.65-1.77 (2H, m); 1.96-2.06 (2H, m); 3.11 (2H, t); 3.21-3.42 (3H, D2O); 3.48 (1H, half WO 02/O74767 PCTV5E02/00472 ABq J=14.9); 5.04-5.12 (1H, m); 6.86 (1H, d); 7.80 (1H, dd); 7.99 (1H, s); 8.19 (1H, d); 10.74 (1H, s). 5-[({4-[(5-chloropyridin-2-yl)oxyl]piperidin-l-yl}sulfonyl)methyl]-5-(2-methylpropyl)imidazolidine-2,4-dione LC-MS (APCI) m/z 445 (MH+). 1HNMR (DMSO-d6): δ 0.81 (3H, d); 0.88 (3H, d); 1.50-1.59 (3H, m); L64-1.78 (2H, m); 1.95-2.05 (2H, m); 3.06-3.16 (2H, m); 3.22-3.41 (3H, D2O); 3.46 (1H half Abq, J=15.1); 5.03-5.12 (1H, m); 6.86 (1H, d); 7.80 (1H, dd); 7.99 (1H, bs); 8.19 (1H, d); 10.71 (1H, bs). 5-[({4-[(5-chloropyridin-l-yl)oxy]piperidin-l-yl}sulfonyl)methyl]-5-(2-pyrimidin-2 ylethyl)imidazolidine-2,4-dione LC-MS (APCI) m/z 495 (MH+). 1HNMR(DMSOd6):δ 1.66-1.78 (2H,m); 1.96.-2.16(4H,m);2.64-2.76 (1H,m);2.84-2.95 (1H, m); 3.08-3.18 (2H, m); 3.33-3.41 (2H, m); 3.43, 3.57 (1H each, ABq, J=14.9); 5.04-5.12 (1H, m); 6.86 (1H, d); 7.34 (1 H, t); 7.80 (1H, dd); 8.12 (1H, d); 8.19 (1H, d); 8.70 (lH,d); 10.84 (lH,s). 5-[({4-{(5-Chloropyridin-2-yl)oxy]piperidin-l-yl]sulfonyl)methyl]-5-[(3- methylphenyl)methyl]imidazolidine-2,4-dione LC-MS (APCI) m/z 493 (MH+). 1H NMR (DMSO-d6): δ 1.66-1.78 (2H, m); 1.96-2.07 (2H, m); 2.23 (3H, s); 2.84 (2H, s); 3.09-3.20 (2H, m); 3.34-3.43 (2H, m); 3.45, 3.69 (1H each, ABq, J=14.7 Hz); 5.06-5.13 (1H, m); 6.87 (1H, d); 6.93-6.98 (2H, m); 7.01-7,06 (1H, m); 7.10-7.17 (1H, m); 7.81 (1H, 2/ dd); 8.08 (1H, s); 8.20 (1H, d); 10.35 (1H, s). 5-[({4-[(5-chloropyridin-2-yl)oxy]piperidin-l-yl}sulfonyl)methyl]-5-(tetrahydro-2H-pvran-4-ylmethyl)imidazolidine-2,4-dione LC-MS (APCI) m/z 487 (MH+). 1H NMR (DMSO-d6): δ 1.06-1.26 (2H, m); 1.39-1.77 (7H, m); 1.95-2.05 (2H, m); 3.06- 3.27 (4H, m); 3.27-3.41 (3H, D20); 3.48 (1H half A Bq, J=15.0 Hz); 3.69-3.79 (2H, m); 5.03-5.12 (IH, m); 6.85 (1H, d); 7.80 (1H, dd);8.03 (1H, bs); 8.19 (1H, d); 10.79 (1H, s). 5-[((4-[(5-chioropvridin-2-yl)oxy]piperidin-l-yl]}sulfonyl)methyl]-5-(3-morpholin-4-vIpropvl)imidazolidine-2,4-dione trifluoroacetic acid LC-MS (APCI) m/z 517 (MH+). 1H NMR (DMSO-d6): δ 1.40-1.78 (6H, m); 1.96-2.06 (2H, m); 2.94-3.18 (6H, m); 3.31-3.44 (5H, m); 3.54 (1H half Abq,J=14.9 Hz); 3.60 (2H, t); 3.90-4.01 (2H, m); 4.25-6.27 (1H);6.85 (1H, d); 7.80 (1H, dd); 8.05 (1H, bs); 8.19 (1H, d); 9.52 (1H, bs); 10.88 (1H, s). 3-(4-[({4-[(5-chloropyridin-2-yl)oxy]piperidin-l-yl}sulfonyl)methyl]-2,5-dioxoimidazolidin-4-yl)propanenitrUe LC-MS (APCI) m/z 442 (MH+). lH NMR (DMSO-d6): δ 1.66-1.78 (2H, m); 1.95-2.05 (4H, m); 2.37-2.57 (2H, DMSO-d6); 3.07-3.17 (2H, m); 3.25-3.40 (2H, D20); 3.42, 3.52 (1H each, Abq, J=14.7); 5.04-5.12 (1H, m); 6.86 (1H, d); 7.80 (lH,'dd); 7.99 (1H, bs); 8.20 (1H, d); 10.91 (1H, s). 1,1-dimethylethyl 3-!4-ff(4-lY5-chloropyridin-2-vI)oxv]piperidin-l-yl}sulfonyl)methyl)-23-dioxoimidazolidin-4-yl}propylcarbamate LC-MS (APCI) m/z 547,490 (MH+); (MH+)-tBu. 1HNMR (DMSO-d6): δ 1.10-1.27 (1H, m); 1.27-1.43 (9H, s); 1.52-1.77 (4H, m); 1.94-2.06 ■(2H, m); 2.80-2.90 (2H, m); 3.06-3.16 (2H, m); 3.22-3.40 (4H, D20); 3.47 (1H halfABq, J=15.1 Hz); 5.03-5.12 (1H, m); 6.76-6.88 (2H, m); 7.80 (1H, dd); 7.95 (1H, bs); 8.19 (1H, d); 10.73 (1H,bs). WO 0274767 5-[((4-(5-chloroyridin-2-yl)oxy]piperidin-l-yl]sulfonyl)methyl]-5-(2-morpholin-4-ylethyl)imidazolidine-2,4-dione . Not purified. LC-MS (APCI) m/z 502 (MH+). 5-[(4-[(5-chloropyridin-2-yl)oxy]piperidin-l-yl}sulfonyl)methyl]-5-phenylimidazolidine-2,4-dione Not purified. LC-MS (APCI) m/z 465 (MH+). 5-[({4-[(5-chloropyridin-2-yl)oxy]piperidin-l-yl}sulfony])methyl]-5-(4-fluorophenyl)imidazolidine-2,4-dione Not purified; LC-MS (APCI) m/z 483 (MH+). 5-[({4-[(5-chloropyridin-2-yl)oxy]piperidin-l-yl}sulfonyl)methyl]-5(1H-imidazol-4-yl)imidazoIidine-2,4-dione Not purified. LC-MS (APCI) m/z 455 (MH+). 4-{4-[((4-[(5-chloropyridin-2-yl)oxy]piperidin-l-yl}sulfonyl)methyl]-2,5-dioxoimidazolidin-4-yl}benzamide Not purified. LC-MS (APCI) m/z 508 (MH+). 5-[({4-[(5-chloropvridin-2-yl)oxy]piperidin-l-yl}sulfonyl)methyl]-5-[2-(lH-l,2,4-triazol-l-yl)ethyl]imidazolidine-2,4-dione Not purified. LC-MS (APCI) m/z 484 (MH+). WO 020767 PCT/SE02700472 5-({[4-(4-fluorophenyl)piperidin-l-yl]sulfonyl}methyl)-5-(2-pyrimidin-2-ylethyl)imidazolidine-2,4-dione LC-MS (APCI) m/z 462 (MH+). lH NMR (DMSO-d6): δ 1.62 (2H, dq); 1.77-1.86 (2H, m); 2.07-2.19 (2H, m); 2.57-2.76 (2H, m); 2.81-2.96 (3H, m); 3.42, 3.56 (1H each, ABq, J=14.6 Hz); 3.59-3.68 (2H, m); 7.11 (2H, t); 7.27-7.36 (3H, m); 8.08 (1H, bs); 8.71 (1H, d); 10.84 (1H, bs). 5-({[4-(4-fluorophenyl)piperidin-l-yl]sulfonyl}methyl)-5-(tetrahydro-2H-pyran-4-ylmethyl)imidazolidine-2,4-dione LC-MS (APCI) m/z 454 (MH+). 1H NMR (DMSO-d6): δ 1.07-1.28 (2H, m); 1.40-1.68 (7H, m); 1.77-1.85 (2H, m); 2.56-2.67 (1H, m); 2.85 (2H, dq); 3.22 (2H, dq); 3.39-3.45 (1H, m); 3.48 (1H half ABq,J=14.5 Hz); 3.53-3.66 (2H, m); 3.75 (2H, dt); 7.11 (2H, t); 7.26-7.33 (2H, m); 8.00 (1H, bs); 10.68 (lH,bs). 4-[4-({[4-r4-fluorophenyl)piperidin-l-yl]sulfoyl]methyl-2.5-dioxoimidazolidin-4-yllbenzamide LC-MS (APCI) m/z 475 (MH+). lH NMR (DMSO-d6): δ 1.61 (2H, dq); 1.77-1.88 (2H, m); 2.58-2.69 (1H, m); 2.85-3.01 (2H, m); 3.60 (1H half ABq, J=14.6 Hz); 3.60-3.69 (2H, m); 7.12 (2H, t); 7.26-7.34 (2H, m); 7.42 (1H, bs); 7.65 (2H, d); 7.91 (2H, d); 8.01 (1H, bs); 8.85 (1H, s); 10.95 (1H, bs). 5-({[4-(4-fluorophenyl)piperidin-l-yl]sulfonyl}methyl)-5-(lH-imidazol-4-vl)imidazolidine-2,4-dione Not purified. LC-MS (APCI) m/z 422 (MH+). T/SE02/00 WO 02/074767 PCT/5E02/00472 5-({f4-(4-chlorophenyl)piperidin-l-yl]sulfonyl}methyl)-5-(tetrahvdro-2H-pyran-4-vImethvl)imidazoIidine-2,4-dione LC-MS (APCI) m/z 470 (MH+). 1H NMR (DMSO-d6): δ 1.07-1.28 (2H, m); 1.40-1.68 (7H, m); 1.76-1.85 (2H, m); 2.56- 2.68 (1H, m); 2.85 (2H, q); 3.22 (2H, q); 3.48 (1H half ABq, .J=14.5 Hz); 3.53-3.67 (2H, m); 3.75 (2H, t); 7.26-7.37 (4H, m); 8.02 (1H, bs); 10.79 (1H, bs). 5-({[4-(4-chlorophenyl)piperidin-l-yl]sulfonyl}methyl)-5-(3-morpholin-4-ylpropyl)imidazolidine-2,4-dione trifluoroacetic acid LC-MS (APCI) m/z 499 (MH+). 1H NMR (DMSO-d6): δ 1.41-1.87 (8H, m); 2.56-2.69 (1H, m); 2.86 (2H, q); 2.95-3.14 (4H, m); 3.33-3.44 (3H, m); 3.52 (1H half ABq, J=14.6 Hz); 3.55-3.69 (4H, m); 3.90-4.00 (2H, m); 7.25-7.37 (4H, m); 8.07 (1H, s); 9.89 (1H, bs); 10.87 (1H, s). (5R,S)-5-Methyl-5-[{4-[5-(trifluoromethyl)pyridin-2-yl]piperazine-l-yl)sulfonyl)methyl]imidazolidine-2.4-dione LC-MS (APCI) m/z 422.1 (MH+). Purity >95% by NMR. lH-NMR (DMSO-d6): δ 10.75 (1H, s); 8.44 (1H, d); 8.02 (1H, s); 7.85 (1H, dd); 7.03 (1H, d); 3.75 (4H, m); 3.55 (1H, d); 3.35 (1H, d); 3.21 (4H, m); 1.31 (3H, s). 6-(4-[({4R,S}-4-methyl-2,5-dioxoimidazolidin-4-yl)methvnsulfonyl)piperazin-l-yl)pyridine-3-carbonitril LC-MS (APCI) m/z 379.1 (MH+). Purity >99% by NMR. 1H-NMR (DMSO-d6): δ 10.74 (1H, s); 8.52 (1H, d); 8.00 (1H, s); 7.90 (1H, dd); 7.00 (1H, d); 3.78 (4H, m); 3.55 (1H, d); 3.36 (1H, d); 3.20 (4H, m); 1.31 (3H, s). WO 02/074767 PCT/SE&2700472 (5R,S)-5-({[4-(4-fluorophenyl)piperazine-l-yl]sulfonyl)methyl)-5-methylimidazolidine-2,4-dione LC-MS (APCI) m/z 371.1 (MH+). Purity >98% by NMR. 1H-NMR (DMSO-d6): δ 10.75 (1H, s); 8.03 (IH, s); 7.11-6.95 (4H, m); 3.56 (1H, d); 3.36 (1H, d); 3.25 (4H, m); 3.15 (4H, m); 1.33 (3H, s). (5R,S)-5-[((4-[(4-fluorophenyl)methyl]piperazine-l-yl]sulfonyl)methyl]-5-methylimidazolidine-2,4-dione LC-MS (APCI) m/z 385.1(MH+). Purity >95% by NMR. 1H-NMR (DMSO-d6): δ10.72 (1H, s); 7.99 (1H, s); 7.33 (2H, m); 7.15 (2H, m); 3.50 (2H, s); 3.49 (1H, d); 3.30 (1H, d); 3.12 (4H, m); 2.42 (4H, m); 1.32 (3H, s). (5R,S)-5-methyl-5-{[(4-pvrimidin-2-ylpiperazine-l-yl)sulfonyl]methyl}imidazolidine-2,4-dione. LC-MS (APCI) m/z 355.1 (MH+). Purity >99% by NMR. 1H-NMR (DMSO-d6): δ10.74 (1H, s); 8.40 (2H, d); 8.01 (1H, s); 6.68 (1H, t); 3.83 (4H, m);3.5(lH,d);3.33(lH,d);3.18(4H,m);1.31(3H,s). 5-(3-aminopropyl)5-[({4-[(5-chloropyridin-2-yl)oxy]piperidin-l-yl}sulfonyl)methyl]imidazolidine-2,4-dione trifluoroacetic acid 1,1-dimethylethyl 3-{4-[({4-[(5-chloropyridin-2-yl)oxy]piperidin-l-yl}sulfonyl)methyl]- 2,5-dioxoimidazolidin-4-yl}propylcarbamate (426mg, 0.78mmol) was dissolved in 10 mL CH2Cl2 and 4 mL of TFA was added. The reaction was stirred at rt for 1 hour. The solvent was removed to give 408mg (93%) of the title compound as a white solid. LC-MS (APCI) m/z 446 (MH+). 1HNMR (CD3OD): δ 1.48-1.63 (1H, m); 1.69-1.96 (5H, m); 2.01-2.12 (2H, m); 2.93 (2H, WO02/074767 P t); 3.20-3.29 (2H, m); 3.40, 3.60 (1H each ABq,J=14.6 Hz); 3.44-3.54 (2H, m); 4.85 (4H, D20); 5.14-5.22 (1H, m); 6.78 (1H, d); 7.67 (1H, dd); 8.08 (1H, d). 5-[4-(5-Chloro-pyridin-2-yloxy)-piperidine-l-sulfonylmethyl]-5-piperidin-4-yl- imidazolidine-2,4-dion hydro chloride 4-{4-[4-(5-Chloro-pyridin-2-yloxy)-piperidine-l-sulfonylmethyl]-2,5-dioxo-imidazolidin-4-yl}-piperidine-l-carboxylic acid tert-butyl ester (100 mg, 0.16 mmol) was solved in 2 M hydrogen chloride (ethyl acetate, 30 ml) and methanol (5 ml). The solution was stirred at 50 °C for 1 hour. Evaporation afforded 90.5 mg (0.16 mmol) of the title compound 5-[4- (5-Chloro-pyridin-2-y Ioxy)-piperidine-1 -sulfonylmethyl]-5-piperidin-4-yl-imidazolidine-2,4-dion hydro chloride in quantitative yield. LC-MS (APCI) m/z 472.3 (MH+). 1H NMR (DMSO-d6): δ10.88 (1H, s); 9.05 (1H, d); 8.48 (lH,m); 8.21 (1H, d); 7.82 (1H, dd); 6.87 1H, d); 5.10 1H, m); 3.47 (2H, s); 3.43-3.13 (7H, m); 2.78 (2H, m); 2.02-1.39 (9H,m). 4-{4-[4-(5-Chloro-pyridin-2-yloxy)-piperidine-l-sulfonylmethyI]-2,5-dioxo-imidazolidin-4-yl}-piperidine-l-carboxylic acid tert-butyl ester For preparation of the reacting ester, piperidine-1,4-dicarboxylic acid 1 -tert-butyl ester 4-methyl ester, se for example Albert A Carr et ai, Journal of Organic Chemistry (1990), 55(4), 1399-401. LC-MS (APCI) m/z 472.3 (MH+-Boc). 5-[4-(5-Chloro-pyridin-2-yloxy)-piperidine-l-sulfonylmethyl]-5-(tetrahydo-pyran-4-yl)-2,4-dion LC-MS (APCI) m/z 403.2 (MH+). 1H NMR (DMSO-d6): δ 10.77 (lH,s); 8.20 (1H, d); 8.19 (lH,s); 7.81 (1H, dd); 6.87 (1H, d); 5.09 (1H, m); 3.88 (2H, t); 3.45 (2H, s); 3.38 (2H, m); 3.21 (2H, t); 3.13 (2H, m); 2.02 (2H, m); 1.84 (1H, t); 1.72 (2H, m); 1.60 (1H, d); 1.32 (4H, m). WO 02/074767 PCT/SE02/00472 5-f4-(5-Chloro-pyridin-2-yloxy)piperidine-l-sulfonylmethyl]-5-pyridin-4-yl-imidazolidine-2,4-dion trifluoroacetic acid LC-MS (APCI) m/z 466.2 (MH+). 1H NMR (DMSO-d6): δ 11.15 (1H, s); 8.97 (1H, s); 8.76 (2H, d); 8.20 (1H, d); 7.82 (2H, dd); 7.80 (1H, d); 6.86 (1H, d); 5.10 (1H, m); 4.17 (1H, m); 3.73 (1H, d); 3.41 (2H, m); 3.17 (2H, m); 2.08 (2H, m); 1.72 (2H, m). 1,1-dimethylethyl 4-({4-[({|4-[(5-chloropvridin-2-yl)oxy1piperidin-l-yl)sulfonyl)methyl]-2,5-dioxoimidazolidin-4-yl}methyl)piperidine-l-carboxylate The title compound was prepared essentially as described in the synthesis of (5R,S)-5-[4-(4-Fluoro-phenyl)-piperidine-1 -sulfonylmethyl]-5-methyl-imidazolidine- 2,4-dione LC-MS (APCI) m/z 530 (MH+ -boc). 1H NMR (DMSO-d6): δ 0.88-1.10 (2H, m); 1.30-1.77 (16H, m); 1.94-2.06 (2H, m); 2.53-2.77 (2H, m); 3.05-3.17 (2H, m); 3.21-3.41 (4H, D20); 3.48 (1H half ABq, J=14.7 Hz); 3.73-3.88 (2H, m); 5.03-5.12 (1H, m); 6.86 (1H, d); 7.80 (1H, dd); 8.04 (1H, bs); 8.19 (1H, d); 10.55 (lH,bs). 5-[({4-[(5-chloropyridin-2-yl)oxyl]piperidin-l--yl}sulfonyl)methyl]-5-(piperidin-4-ylmethyl)imidazolidine-2,4-dione trifluoroacetate The title compound was prepared as described in the synthesis of 5-(3-aminopropyl)-5-[({4-[(5-chloropyridin-2-yl)oxy]piperidin-l - yl} sulfonyl)methyl]imidazolidine-2,4-dione trifluoroacetic acid. LC-MS (APCI) m/z 486 (MH+). 'H NMR (DMSO-d6): δ 1.17-1.40 (2H, m); 1.47-1.81 (7H, m); 1.94-2.07 (2H, m); 2.75- 2.93 (2H, m); 3.06-3.42 (7H, m); 3.50 (IH half ABq, J=15.6 Hz); 5.04-5.12 (1H, m); 6.85 (1H, d); 7.80 (1H, dd); 8.D6 (1H, s); 8.08-8.22 (2H, m); 8.45 (1H, bd);}0.85 (1H, s). N-(3-{4-[({(4-[(5-chloropvridin-2-yyl)oxy]piperidin-l-yl)sulfonyl)methyl]-2,5-dioxoimidazolidin-4-yl}propyl)methanesulfonarnide 5-(3-AminopropyI)-5-[( {4-[(5-chloropyridin-2-yI)oxy}piperidin-1 -yl}sulfonyl)memyl]imidazolidine-2,4-dione trifluoroacetic acid (l00mg, 0.18mmol) was slurried in 2 mL DCM. DIPEA (62JJ.L, 0.36mmol) was added and the slurry was stirred for some minutes. Sulfonylchloride (16μL, 0.18mmol) was added and the reaction was stirred at it over night. The crude product was purified by preparative HPLC. LC-MS (APCI) m/z 524 (MH+). 1H NMR (DMSO-d6): δ 1.19-1.52 (2H, m); 1.58-1.77 (4H, m); 1.95-2.06 (2H, m); 2.85 (3H, s); 2.83-2.93 (2H, m); 3.12 (2H, t); 3.19-3.46 (3H, D20); 3.50 (1H half ABq,J=l 5.7 Hz); 5.04-5.12 (1H, m); 6.86 (1H, d); 6.97 (1H, t); 7.80 (1H, dd); 8.01 (1H, s); 8.19 (1H, d); 10.79 (lH,s). ^f EXAMPLE 9 (5R,S)-5-r4-(5-ChIoro-pvridin-2-vn-piperazine-l-sulfonvlmethvH-5-(,3-pvrimidin-2-vl-propvl)-»imidazolidine-2,4-dione 1 -([4-(5-Chloro-2-pyridinyl)-1 -piperazinyl]sulfonyl)-5-(2-pyrimidinyl)-2-pentanone (0.397 g, 0.936 mmol), potassium cyanide (0.122 g, 1.87 mmol), ammonium carbonate (0.500 g, 4.68 mmol) and 50% ethanol (4 mL) were stirred in a sealed vial at 75°C (oil temp) for 17 hours. The ethanol was removed by rotary evaporation, pH was adjusted to 6 25 with 1M HC1, the suspension was filtered, the solid was washed with a little water, collected and dried, in vacuo at 45°C. Some more product was recovered from the aqueous filtrate by adding solid sodium chloride to saturation and extracting the mixture with acetonitrile (2x10 mL). Drying with.Na2SO4, filtering and concentrating the organic phase gave a second crop. The combined crops were dissolved in tetrahydrofuran (5-10 mL), adsorbed on silica-(3 g) and applied on a short silica column. Elution with EtOAc followed by EtOAc-MeCN (1:1) gave 0.30 g (65% yield) of the title compound as a white crystalline solid. LC-MS (APCI) m/z 494 (MH+). 1H NMR (DMSO-d6) δ 10.78 (1H, bs); 8.70 (2H, d, J= 5Hz); 8.13 (1H, d, J= 3Hz); 8.02 (1H, s); 7.63 (1H, dd, J1= 3Hz, J2= 9Hz); 7.33 (1H, t,J= 5Hz); 6.93 (1H, d, J= 10Hz); 3.63-3.56 (4H, m); 3.52 (1H, d,J= MHz); 3.34 (1H, d,J= 14Hz; obscured by water signal), 3.24-3.14 (4H, m); 2.82 (2H, t,J= 7Hz) and 1.79-1.50 (4H,m's). 13C NMR (DMSO-d6)5 175.6, 169.5, 157.2, 157.0, 156.5, 1.45.6, 137.3, 119.2, 119.1,108.8,62.4, 52.7,44.5, 38.2, 36.4 and 21.2. The starting materials were prepared as follows: l-([4-(5-Chloro-2-pyridinyl)-l-piperazinyl]sulfonyl)-5-(2-pyrimidinyl)-2-pentanone WO 02/07/767 PCT/S A stirred solution of l-(5-Chloro-2-pyridinyl)-l-methylsulfonyl piperazine (0.64g, 2.32mmol) in dry THF (25 mL, 40 rel vol), under nitrogen, was cooled to -10°C causing the sulfonamide to precipitate out of solution. LHMDS 1M in THF (4.64mL, 4.64mmoI) was added dropwise, over 4 min, to the suspension of sulfonamide, the mixture was then stirred for 40 min. 4-(2-Pyrimidinyl)-butyric acid ethyl ester (0.68g, 3.48mmol) (example 8) in dry THF (6.4 mL, 10 rel vol) was added dropwise, over 4 min, and the mixture stirred for 30 min. The mixture was quenched with saturated NH4Cl (0.64 mL, I rel vol) and evaporated to a semi-solid residue. The residue was taken up in DCM (20 rel vol) and the organic layer was washed with water (15 mL, 24 rel vol), brine (15mL, 24 rel vol), and dried with MgSCU- Removal of the solvent by rotary evaporation gave the crude product as an off white solid (0.84g, 85%). The crude product was purified by Biotage FLASH chromatography, using ethyl acetate/isohexane (90:10) as eluant, to give pure ketone as a white amorphous solid. l-(5-Chloro-2-pyridinyl)-l-methylsulfonyl piperazine To a solution containing l-(5-Chloro-2-pyridinyl)-piperazine (1 eq.) in toluene (25 volumes) is added triethylamine (1 .leq), and the mixture is cooled down to 5°C in an ice bath. Methanesulfonyl chloride diluted with toluene (0.5vols) is slowly added to the cooled solution, keeping the temperature below 10°C. Once the addition is finished, the reaction is allowed to warm-up to room temperature. Water (6.6vols) is added and the mixture is filtered and cake slurried in Toluene (2 vols). The cake is then washed with Toluene (2 vols) and dried in a vacuum oven at 40°C overnight. WO 02/075767 PCT/SE02/0O472 Piperazine (4 eq) is charged in the reaction vessel as a solid. At room temperature pyridine (1.43 vols) is added to the vessel followed by toluene (2.14 vols). The final slurry is stirred and heated to reflux at 120°C to obtain a complete solution. To a separate vessel charge 2,5-dichloropyridine (DCP) followed by Toluene (1.43 vols) to dissolve the solid. The dissolution is endothermic, and it is necessary to warm up the solution to ~ 30°C to get complete solution. The solution containing DCP is then slowly discharged into the reaction vessel over 5hours. At this point the remaining amount of DCP should be about 20%. The reaction is left refluxing overnight to reach completion. The reaction mixture is allowed to cool to room temperature, then water is added (6 vols). The two layers are separated, and the aqueous phase is re-extracted with Toluene (5 vols). The two organic layers are combined and re-washed with H2O (6 vols). Finally, the organic layer is washed with brine (6 vols). WO 02/07- PCT/8E02/00472 (5S)-5-[4-(5-Chloro-pvridin-2-yl)-piperazine-l-sulfonylmethyl]-5-(3-pyrimidin-2-yl-propvlVimidazolidine-2.4-dione and (5R)-5-[4-(5-Chloro-pyridin-2-yI)-piperazine-l-sulfonvlmethyn-5-(3-pyrimidin-2-vl-propyI)-imidazolidine-2,4-dione The coresponding racemic material (23mg) was dissolved in 8 mL of isoHexane/EtOH (25/75) and separated into the pure enantiomers by using the following Gilson HPLC system: Column: CHIRALCEL OD, 2.0x25 cm, flow = 6.0 mL/min, eluent = isoHexane/EtOH (25/75), temp = ambient, detector UV = 230nm. The enantiomers were collected and analysed on a CHIRALCEL OD-H, 0.46x25 cm, 0.5 mL/min, isoHexane/EtOH (25/75), ambient temperature, 220nm. Rt = 11.5 min. ee>99% for the faster during enantiomer, 8.7mg (37%). LC-MS (APCI) m/z 494.1 (MH+). [α]D = -26.4° (c=0.0022 g/mL, EtOH, t=20°C) Rt = 14.5 min. ee=98 % for the slower eluting enatiomer, 9mg (39%). LC-MS (APCI) m/z 494.1 (MH+). [α]D = +24.5° (c=0.0026 g/mL, EtOH, t=20°C) PCT/SE02/00472 EXAMPLE 10 The following compounds were prepared using a method analogous to that described in Example 8 or 9. WO 02/0767 PCTZE02/00472 EXAMPLE 11 were synthesised according to the method described in Example 8 KETONE INTERMEDIATES Compounds with the general formula (1): For NMR-data see experimental part. l-(l,1-bipheny-4-ylthio)propan-2-one l-[(4-bromophenyl)thio]propan-2-one (357 mg, 1.46 mmol) was treated with phenyl boronic acid (231 mg, 1.89 mmol), [l,l'-bis(diphenylphosphino)ferrocene]dichloro palladium (II) complex with dichloromethane (1:1) (36 mg), toluene (20 ml), methanol PCT/SE03/90472 (7.5 ml), saturated sodium carbonate solution (3.5 ml) and were stirred together at 80 °C for 18 hours. After cooling the reaction mixture was treated with dilute hydrochloric acid and extracted into ethyl acetate. The product was purified by flash chromatography on silica, eluting with 25 % ethyl acetate : iso-hexane to give 277 mg product, GC/MS m/z: 242 [M+]. 'H NMR (CDC13): 5 2.33 (3H, s); 3.73 (2H, s); 7.37 (1H, s); 7.42-7.48 (4H, m); 7.54-7.59 (4H,m). The following compounds were prepared as described in the synthesis of l-(l,l'-biphenyl-4-ylthio)propan -2-one 4'-{(2-oxopropyI)thio]-l,l'-biphenyl-4-carbonitrile GC/MS m/z: 267 [M +j. 1H NMR (CDCl3): δ 2.34 (3H, s); 3.75 (2H, s); 7.44, 7.54 (4H, abq,J=8.5 Hz); 7.67, 7.74 (4H, abq, .J=8.5 Hz). l-({4'-[(trifluoromethyl)oxy]-l,1'-biphenyl-4-yl}thio)propan-2-one GC/MS m/z: 326 [M+]. 1H NMR (CDCl3): δ 2.34 (3H, s); 3.73 (2H, s); 7.30 (2H, d); 7.43 (2H, d); 7.51 (2H, d); 7.58 (2H, d). l-(l,l'-biphenyl-4-ylsulfonyI)propan-2-one l-( 1,1 '-biphenyl-4-ylthio)propan-2-one (69 mg, 0.28mmol) was stirred at room temperature with sodium bicarbonate (72 mg, 0.85 mmol), oxone ((525 mg, 0.85 mmol), water (5 ml) and methanol (10ml) for 3 hours. Water (50 ml) was added and the product extracted into ethyl, acetate (3 x 25 ml). The extracts were brine washed, sodium sulphate dried and evaporated to give 78 mg (99%) product that was of sufficient purity to use with out further purification. PCT/SEB2/00472 WO 02/874767 LC-MS (APCI) m/z 275 (MH+). lH NMR (CDCl3): δ 2.47 (3H, s); 4.22 (2H, s); 7.44-7.54 (3H, m); 7.64 (2H, d); 7.80, 7.97 (4H,abq, .J=8.6 Hz). 4,-[(2-oxopropyl)suIfonyll-l,l'-biphenyl-4-carbonitrile The title compound was prepared as described in the synthesis of 1 -(1 ,1-biphenyl-4-ylsulfonyI)propan-2-one. 1H NMR (DMSO-d6): δ 2.48 (3H, s); 4.23 (2H, s); 7.74 (2H, d); 7.81 (4H, t); 8.02 (2H, d). HYDANTOINS OF FORMULA I The following compounds were prepared as described in the synthesis of(5R,S)-5-[4-(4-Fluoro-phenyl)-piperidine-l-Sulfonylmethyl]-5-methyl-imidazolidine-2,4-dione (Example 8). (I): For NMR-data see experimental part. (5R,S)-[4-(5-Chloro-pyridin-2-yloxy)-ben2enesulfonylmethyl]-5-methyl-imidazolidine-2.4-dione LC-MS (APCI) m/z 396 (MH+). 1HNMR (DMSO-d6): δ 1.27 (3H, s); 3.71, 3.78 (1H each, ABq, J=15.0); 7.23 (1H, d); 7.36-7.41 (2H, m); 7.82-7.87 (3H, m); 8.04 (1H, dd); 8.27 (1H, d); 10.79 (1H, s). WOJM/074767 Rgt/SE02/00472 5-chloro-2-{[4-(methyIsuIfonyI)phenyl]oxy}pyridine 2,5-dichloropyridine (1.48g; l0mmol), 4-methylsuIfonylphenol (1.89g; 1 lmmol) and CS2CO3 (4.24g; 13mmol) was slurried in 75mL of NMP. The slurry was heated to approx 170°C over night. After cooling the CS2CO3 was filtered off and the solvent was extracted between H2O and EtOAc. The organic phase was dried over Na2SO4 and evaporated. Heptane:EtOAc 2:1 was added to the residue and the crystalls was filtered off.L42 g (50%). LC-MS(APCI) m/z 284 (MH+). 1H NMR CDCl3: δ 3.09 (3H, s); 7.02 (1H, d); 7.33 (2H, d); 7.76 (1H, dd); 8.00 (2H, d); 8.17(lH,s). 5-methvl-5-[({4'-[(trifluoromethyl)oxy]-l,l,-biphenyl-4-yl}sulfinyl)methyl]imidazolidine-2,4-dione 5-methyl-5-[({4'-[(trifluoromethyl)oxy]-1,1 '-biphenyl-4-yl}thio)methyl]imidazoIidine-2,4-dione (48 mg, 0.112 mmol) was stirred at room temperature with oxone (50 mg), sodium bicarbonate (50 mg), water (5 ml)'and Methanol (10 ml) for 18 hours. The solid was filtered off and crystalissed from ethanol to give 20 mg of the title compound. LC-MS(APCI) m/z very weak 413 (MH+). 1H NMR (DMSO-d6): δ 1.41 (3H, s); 3.04-3.27 (2H, m); 7.47 (2H, d); 7.67-7.73 (2H, m); 7.78-7.90 (5H, m); 8.21 and 8.37 (1H, 2 s); 10.79 and 10.91 (1H, 2 s) 5-methyI-5-[({4'-[(trifluoromethyl)oxy]-l,1-biphenyl-4-yI}thio)methyl]imidazolidine-2,4-dione LC-MS(APCI) m/z very weak 397 (MH+). 1H NMR (DMSO-d6); δ 1.33 (3H5 s); 3.29 (2H, s); 7.42-7.45 (4H, m); 7.61 (2H, d); 7.77 (2H, d); 7.99 (1H, s); 10.75 (1H, s). T/SE02/00472 5-[(l,l'-biphenvl-4-ylsulfonyl)methyl]-5-methylimidazolidine-2.4-dione LC-MS(APCI) m/z 345 (MH+). 1HNMR (DMSO-d6): δ 1.27 (3H, s); 3.72, 3.81 (2H, abq,J=15.3 Hz); 7.45 (1H, t); 7.52 (2H, t); 7.76 (2H, d); 7.82 (1H, s); 7.88, 7.94 (4H, abq, 7=8.9 Hz); 10.80 (1H, bs). 4'{[(4-methyl-2,5-dioxoimidazolidin-4-vl)methvnsulfonyl)-l,l'-biphenyl-4-carbonitrile LC-MS(APCI) m/z very weak 370 (MH+). 1HNMR(DMSO-d6): δ 1.26 (3H, s); 3.74, 3.84 (2H, abq,J=16.0 Hz); 7.81 (1H, s); 7.91- 8.03 (8H,m); 10.81 (lH,s). EXAMPLE 12 Representative synthetic route is shown overleaf. Synthesis of enantiomeric pure hydantoins WO 02/074767 PCT7E027OO472 Reagents and conditions: a) KCN, NH4CO:, EtOH/H20, +90°C, 3h. b) Chiral separation, CHIRALPAK AD, Methanol as clucnt. c) Cl2 (g), AcOH/H20, Experimental procedures (551-5-({[4-f4-fluorophenyl)piperidin-l-yl]sulfonyl}methyl)-5-methylimidazoIidine- 2,4-dione 4-(4-FIuorophenyl)piperidine hydrochloride (63 mg, 0.29 mmol) was taken up in 3 mL of dry THF , neutralized with diisopropylethylamine (50 oX, 0.29 mmol) and cooled on an ice-water bath. [(4.S)-4-metyl-2,5-dioxo-imidazolodin-4-yl]methanesulfonyl chloride (80 mg, 0.35 mmol) was added and after stirring for 10 min, diisopropylethylamine (50 μL, 0.29 mmol) was added and the reaction mixture was stirred at ambient temperature until LC-MS (APCI) indicated consumption of the amine. The reaction mixture was evaporated WO 02/03*767 PCT/SE027OO472 and the residue taken up in EtOH and heated to 50 °C and allowed to cool before water was added. The precipitated product was collected and washed with EtOH/water and dried in vacuum to yield 87 mg. LC-MS (APCI) m/z 370 (MH+). 1H NMR (DMSO-d6): δ 10.73 (1 H, s); 8.01 (1 H, s); 7.29 (2 H, dd); 7.11 (2 H, dd); 3.61 (2 H, dd); 3.50, 3.33 (1 H each, ABq, J=14.7 Hz); 2.91-2.80 (2 H, m); 2.67-2.57 (1 H, m); 1.82 (2 H, d); 1.62 (2 H, ddd); 1.33 (3 H, s). The starting materials were prepared as follows: 5-methyI-5-{[(phenylmethyI)thio]methyI}imidazoIidine-2,4-dione A steel vessel was charged with ethanol and water (315mL/135mL). 31.7g (0.175 mol) of benzylthioacetone, 22.9g (0.351 mol) of potassium cyanide and 84.5g (0.879 mol) of ammonium carbonate was added. The closed reaction vessel was kept in an oil bath (bath temperature 90 °C) under vigorous stirring for 3h. The reaction vessel was cooled with ice-water (0.5 h), the yellowish slurry was evaporated to dryness and the solid residue partitioned between 400 mL water and 700 mL ethylacetate and separated. The water-phase was extracted with ethylacetate (300 mL). The combined organic phases were washed with saturated brine (150 mL), dried (Na2SO4), filtered and evaporated to dryness. If the product did not crystallize, 300 mL of dichloromethane was added to the oil. Evaporation gave the product as a slightly yellowish powder,43.8 g (90%). LC-MS (APCI) m/z 251.1 (MH+). 1H NMR (DMSO-d6) δ: 10.74 (lH,s); 8.00 (1H, s); 7.35-7.20 (5H, m); 3.76 (2H, s); 2.72, 2.62 (1H each, ABq, 7=14.0 Hz);.1.29 (3H, s). 13CNMR(DMSO-d6)δ: 177.30, 156.38, 138.11, 128.74, 128.24, 126.77, 62.93, 37.96, 36.39,23.15. (5iS)-5-methyl-5-{[(phenyImethyl)thio]methyI}imidazoIidine-2,4-dione The title compound was prepared by chiral separation of the racemic material using a 250mm x 50mm column on a Dynamic Axial Compression Preparative HPLC system. The stationary phase used was CHIRALPAK AD, eIuent=Methanol, flow=89mL/min, temp=ambient, UV=220nm, sample conc=150mg/mL, injection volume=20mL. Retention time for title compound = 6 min. Analysis of chiral purity was made using a 250mm x 4.6mm CHIRALPAK-AD column from Daicel, flow=0.5mL/min, e!uent=Ethanol, UV=220nm, temp=ambient. Retention time for title compound = 9.27min. Purity estimated to >99% ee. LC-MS (APCI) m/z 251.1 (MH+). [a]D=-30.3° (c=0.01g/mL, MeOH, T=20°C). 'H NMR (DMSO-d6) 5: 10.74 (lH,s); 8.00 (1H, s); 7.35-7.20 (5H, m); 3.76 (2H, s); 2.72, 2.62 (1H each, ABq, .7=14.0 Hz); 1.29 (3H, s). 13CNMR(DMSO-d6)δ: 177.30, 156.28,138.11,128.74, 128.24,126.77, 62.93, 37.96, 36.39,23.15. (5R)-5-methyl-5-{((phenyImethyI)thio]methyl}imidazolidine-2,4-dione The title compound was prepared by chiral separation of the racemic material using a 250mm x 50mm column on a Dynamic Axial Compression Preparative HPLC system. The stationary phase used was CHIRALPAK AD, eluent=Methanol, flow=89mL/min, temp=ambient, UV=220nm, sample conc=150mg/mL, injection volume=20mL. Retention time for title compound =10 min. Analysis of chiral purity was made using a 250mm x 4.6mm CHIRALPAK-AD column from Daicel, flow=0.5mL/min, eluent=Ethanol, UV=220nm, temp=ambient. Retention time for title compound = 17.81 min. Chiral purity estimated to >99% ee. LC-MS (APCI) m/z 251.0 (MH+). [α]D=+30.3° (c=0.0lg/mL, MeOH, T=20°C). lH NMR (DMSO-d6) 5: 10.74 (lH,s); 8.00 (1H, s); 7.35-7.20 (5H, m); 3.76 (2H, s); 2.72, 2.62 (1H each, ABq, /=14.0 Hz); 1.29 (3H, s). 13C NMR (DMSO-d6) α: 177.31, 156.30, 138.11, 128.74, 128.25, 126.77,62.94, 37.97, 36.40,23.16. [(4S) -4-methyl-2,5-dioxoimidazolidin-4-yl]methanesulfonyl chloride (5S)-5-methyl-5-{[(phenylmethyI)thio]methyl}imidazolidine-2,4-dione (42.6g; 0.17mol) was dissolved in a mixture of AcOH (450 mL) and H2O (50 mL). The mixture was immersed in an ice/water bath, Cl2 (g) was bubbled through the solution, the flow of gas was adjusted so that the temperature was kept below +15 °C. After 25 min the solution became yellow-green in colour and a sample was withdrawn for LC/MS and HPLC analysis. It showed that starting material was consumed. The yellow clear solution was stirred for 30 min and an opaque solution /slurry was formed. The solvent was removed on a rotary evaporator using waterbath with temperature held at +37°C. The yellowish solid was suspended in Toluene (400mL) and solvent removed on the same rotary evaporator. This was repeated once more. The crude product was then suspended in iso-Hexane (400mL) and warmed to +40° C while stirring, the slurry was allowed to cool to room temperature before the insoluble product was removed by filtration, washed with iso-Hexane (6xl00mL), and dried under reduced preassure at +50" C over night. This gave the product as a slightly yellow powder. Obtained 36.9 g (95%) of the title compound. Purity by HPLC = 99%, NMR supported that purity. [α]D=-l2.4° (c=0.01g/mL, THF, T=20°C). 1H NMR (THF-dg): δ 9.91 (1H, bs); 7.57 (1H, s); 4.53,4.44 (1H each, ABq,J=14.6Hz); 1.52(s,3H,CH3). 13C NMR (THF-d8): δ 174.96; 155.86; 70.96; 61.04; 23.66. PCT/SE027OO472 [(4R) -4-methyl-2,5-dioxoimidazolidin-yl]methanesulfonyl chloride Following the procedure described for [(4S)-4-methyl-2,5-dioxoimidazolidin-4- yl]methanesulfonyl chloride. Starting from (5R)-5-methyl-5-{ [(phenylmethyl)thio]methyl}imidazolidine-2,4-dione (10.0g, 40mmol). Obtained 8.78g (96% yield) of the title compound. Purity by NMR > 98%. [α]D=+12.8°(c=0.01g/mL,THF,T=20°C). - 1H NMR (THF-d6): δ 9.91 (1H, brs); 7.57 (1H, s); 4.53, 4.44 (1H each, ABq, J=l4.6Ez); 1.52(s,3H,CH3). 13C NMR (THF-dg): 5 174.96; 155.84; 70.97; 61.04; 23.66. EXAMPLE 13 Compounds with the general formula / were synthesised according to the method described in Example 12. AMINE INTERMEDIATES WO 02/074767 WO 02/074?67 PCT/S PCT/SE02/00472 WO 02/074767 All other amines used are commercially available or earlier described. 4-{4-[(trifluoromethyI)oxy]phenyl}piperidine trifluoroacetic acid Pd(PPh3)4 (87 mg, 0.0075mmol), LiCl (190 mg, 4.5 mmol), tert-butyl 4- {[(trifluoromethyl)sulfonyl]oxy}-3,6-dihydropyridine-1 (2//)-carboxylate (0.50 g 1.5 mmol), 4-(trifluoromethoxy)phenylboronic acid (0.43 g, 2.1 mmol) and aq Na2CO3 (2 mL, 2N solution) were mixed in 5.2 mL DME and heated at 85 °C for 3h followed by cooling to room temperature and concentrated under reduced pressure. The residure was partitioned between DCM (10 mL), aq Na2CO3 (10 mL, 2N solution) and cone NH4OH (0.6 mL). The layers were separated and the aqueous layer extracted with DCM (3x10 mL). The combined organic layers were dried (Na2SO4) and concentrated. Purification by column chromatography (Si O2, Heptane/Ethylacetate/DCM 5:1:1) gave tert-butyl 4-[4-(trifluoromethoxy)phenyl]-3,6-dihydropyridine- l(2H)-carboxylate (0.27g, 52%). The product and 5% Pd/C (30 mg) was mixed in MeOH (3 mL) and stirred under H2 (1 atm) for 24 h. The mixture was filtered through Celite and concentrated to give tert-buly\ 4-[4- (trifluoromethoxy)phenyl]piperidine-l-carboxylate (0.23g, 86%). The crude product was dissolved in a mixture of TFA (2 mL) and DCM (4 mL) and stirred at RT for 2 h. The reaction mixture was concentrated and purified by preparative HPLC to give the title compound (0.14 g, 58%, three steps 26%). LC-MS (APCI) m/z 246 (MH+). 1H NMR (CDCl3): δ 9.38 (1 H, bs); 8.97 (1 H, bs); 7.26 (2 H, d); 7.20 (2 H, d); 3.60 (2 H, bd); 3.07 (2 H, q); 2.88-2.72 (1 H, m); 2.18-2.01 (4 H, m). 19F NMR (CDCI3): 5 -58.35 (3F),-76.19 (3F). WO 02/074767 PCT/SE02/00472 4-{(4-chlorophenyl)ethynyl]-l,2,3,6-tetrahydropyridine hydrochloride PdCl2(PPh3)2 (47 mg, 0.07 mrnol) and Cul (13 mg, 0.07 mmol) were dissolved in Et3N (2.7 mL) and THF (8.4 mL) under a stream of argon and stirred for 10 min. A solution of tert-butyl 4- {[(trifluoromethyl)sulfonyl]oxy} -3,6-dihydropyridine-1 (2H)-carboxylate (0.46 g 1.4 mmol) and 2-ethynylpyridine (152 μL, 1.5 mmol) in 3.5 mL THF was added. The reaction mixture was stirred at RT for 2h, diethyl ether was added and the precipitate was filtered off. The clear solution was washed with saturated aqueous NH4CI, water, Brine and dried (Na2SO4). Concentration and purification by column chromatography (SiO2 Heptane/Diethyl ether 1:2) gave tert-butyl 4-[(4-chlorophenyl)ethynyl]-3,6- dihydropyridine-l(2H)-carboxylate (0.26 g, 58%). The product was dissolved in THF (3 mL) and cone HC1 (3 mL) and stirred at RT for 30 min. Concentration several times with toluene and EtOH gave the title compound (0.20 g, 98%, two steps 57%), LC-MS (APCI) m/z 218/220 3; 1 (MH+). 1H NMR (DMSO-d6: δ 9.25 (2 H, bs); 7.49-7.44 (4 H, m); 6.24-6.11 (1 H, m); 3.75-3.63 (2 H, m); 3.25-3.15 (2 H, m); 2.48-2.42 (2 H, m). The following amines were prepared in a similar way as descibed for 4-[(4-chlorophenyl)ethynyl]-l,2,3,6-tetrahydropyridine hydrochloride. 2-(l,2,3,6-tetrahydropyridine-4-ylethynyl)pyridine LC-MS (APCI) m/z 185 (MH+). 1H NMR (CDCl3): δ 8.59-8.55 (1 H, m); 7.64 (1 H, dt); 7.43-7.39 (1 H, m); 7.20 (1 H, ddd); 6.30 (1 H, bs); 3.51 (2 H, q); 3.04 (2 H, t); 2.37-2.31 (2 H, m). 4-[(4-methylphenyl)ethynyl]- 1,2,3,6-tetxahydropyridine LC-MS (APCI) m/z 198 (MH+). 1H NMR (CDCl3): δ 8.91 (1 H, bs); 7.33 (2 H, d); 7.15 (2 H, d); 6.06 (1 H, bs); 3.93-3.80 (2 H, m); 3.49-3.335 (2 H, m); 2.73-2.60 (2 H, m); 2.37 (3 H, s). 2-{Piperidin-4-yloxy)-5-trifluorornethyl-pyridine Sodium hydride (0.52g, 12 mmol, 55% in oil) was washed twice in hexane, and suspended in dry dimethoxyethane (30 ml). 4-hydroxypiperidine (1.21g, 12 mmol) and 2-chIoro-5-trifluoromethylpyridine was dissolved in dry dimethoxyethane (30 ml). The solution was added dropwise to the sodium hydride-suspension. The reaction was stirred at 80 °C under nitrogen over night. After cooling. Water was carefully added to the mixture and the solvents were removed by rotary evaporation. The residue was dissolved in water and extracted with ethyl acetate. The organic phase was dried over Na2SO4 and evaporated. The residue was chromatographed on silica gel eluting with 80:20:2 EtOAc/MeOH/Et3N affording 1.7g (63%) of the title compound as a yellow oil, which crystallised after a few hours. LC-MS (APCI) m/z 247.1 (MH+). 1H NMR (CDC13): δ 8.40 (1 H, s); 7.74 (1 H, dd, .J=2.52, 8.70 Hz); 6.78 (1 H, d, .J=8.74 Hz); 5.25-5.17 (1 H, m); 3.19-3.08 (2 H, m); 2.83-2.73 (2 H, m); 2.10-2.00 (2 H, m); 1.83 (lH,s); 1.73-1.62 (2 H,m). The following amines were prepared in a similar way as descibed described in the synthesis of 2-(Piperidin-4-yloxy)-5-trifluoromethyl-pyridine. 6-(Piperidin-4-yloxy)-nicotinonitrile LC-MS (APCI) m/z 204.2 (MH+). 1H NMR (CDCl3): δ 8.45 (1 H, s); 7.76 (1 H, dd, ,7=2.40, 8.77 Hz); 6.78 (1 H, d, J=8.77 Hz); 5.28-5.17 (1 H, m); 3.19-3.09 (2 H, m); 2.83-2.74 (2 H,.m); 2.10-2.01 (2H,m); 1.74-1.63 (2 H,m). 5-Methyl-2-(piperidin-4-yloxy)-pyridine 1 NMR (Methanol-d4): δ 7.90 (1 H, s); 7.46 (1 H, dd, J=2.47, 8.46 Hz); 6.68 (1 H, d, J=8.50 Hz); 5.07-4.98 (1 H, m); 3.15-3.07 (2 H, m); 2.82-2.73 (2 H, m); 2.23 (3 H, s); 2.07-1.97 (2 H, m); 1.84-1.74 (2 H, m). 2-Methoxy-6-(piperidin-4-yIoxy)-pyridine 1H NMR (CDCl3): 5 7.44 (1 H, t, J=7.90 Hz); 7.25 (2 H, dd, J=1.83, 7.90 Hz); 5.19-5.11 (1 H, m); 3.82 (3 H, s); 3.23-3.16 (2 H, m); 2.96-2.88 (2 H, m); 2.13-2.05 (2 H, m); 1.89-1.79 (2 H, m). . : 2-chloro-6-{piperidine-4-yloxy)-pyridine 1H NMR (Methanol-d4): δ 7.64 (1 H, dd, 7=7.60, 8.22 Hz); 6.96 (1 H, dd, 7=0.66, 7.60 Hz); 6.73 (1 H, dd, 7=0.60, 8.19 Hz); 5.25-5.14 (1 H, m); 3.28-3.18 (2 H, m); 3.05-2.94 (2 H,m);2.19-2.07(2H,m);1.93-1.80(2H,m). 5-FIuoro-2-(piperidin-4-yloxy)-pyrimidine 1H NMR (CDCl3): δ 8.36 (2 H, s); 5.16-5.06 (1 H, m); 3.29-3.18 (2 H, m); 2.98-2.87 (2 H, m); 2.21-2.08 (2 H, m); 1.97-1.81 (2 H, m). 2-(Piperidin-4-yIoxy)-4-trifluoromethyl-pyrimidine 1H NMR (CDCl3): δ 8.75 (1 H, d, 7=4.93 Hz); 7.27 (1 H, d, 7=5.07 Hz); 5.39-5.30 (1 H, m); 3.44-3.33 (2 H, m); 3.28-3.17 (2 H, m); 2.35-2.10 (4 H, m). 5-Ethyl-2-(piperidin-4-yloxy)-pyrimidine 1H NMR (Methanol-d4): δ 8.40 (2 H, s); 5.16-5.08 (1 H, m); 3.16-3.06 (2 H, m); 2.77-2.70 (2 H, m); 2.60 (2 H, q, 7=7.66, 15.28 Hz); 2.10-2.00 (2 H, m); 1.76-1.66 (2 H, m); 1.23 (3 H,t,J=7.63 Hz). .5 5-Methoxy-2-(piperidin-4-yIoxy)-pyridine; hydrochloride 4-(5-Methoxy-pyridin-2-yloxy)-piperidine-l-carboxylic acid tert-butyl ester (45 mg, 0.14 mmol) was dissolved in THF (3 ml) and cone. HC1 (2 ml) was added. The reaction was stirred at room temprature for 2 hrs after which the solvents were removed in vacuo and the remaining water was removed by azeotropic evaporation using EtOH/TouIene affording 35 mg (97%) of the title compound as oily crystals. LC-MS (APCI) m/z 225.1 (MH+). The starting material was prepared as follows: 2-Chloro-5-methoxy-pvridine 1 -oxide 2-chloro-5-methoxy-pyridine (200 mg, 1.39 mmol) and mCPBA (360 mg, 2.09 mmol) was dissolved in CH2Cl2 (10 ml). The mixture was stirred at room temperature for 2 days. The mixture was then diluted with CH2Cl2 and washed with 10% aqueous K2CO3 and brine and dried over Na2SO4. The solvent were removed in vacuo affording 140 mg (63%) of the title compound as white crystals. 1H NMR (DMSO-d6):δ 8.30 (1 H, d, J=2.72 Hz); 7.68 (1 H, d, J=9.23 Hz); 7.08 (1 H,dd, J=2.70,9.23 Hz); 3.31 (3 H,s). 4-('5-Methoxy-l-oxv-pyridin-2-vloxv')-piperidine-l-carboxvlic acid terr-butyl ester Potassium tert-butoxide (128 mg, 1.14 mmol) was dissolved in dry THF (10 ml) and 4-Hydroxy-piperidine-1-carboxylic acid /erf-butyl ester (177 mg, 0.88 mmol) dissolved in dry THF (5 ml) was added under nitrogen. The mixture was stirred at room temperature for 10 minutes after which 2-Chloro-5-methoxy-pyridine 1-oxide (140 mg, 0.88 mmol) dissolved in dry THF (5 ml) was added. The reaction was stirred for 3 days at room temperature. The solvent were removed and the residue was partitioned between H2O and CHCl3. The organic phase was washed with brine and dried over Na2SO4. The solvent were removed in vacuo affording 245 mg (86%) of the title compound as a brown oil. lH NMR (CDCl3):δ 7.95-7.93 (1 H, m); 6.86-6.84 (2 H, m); 4.95-4.85 (1 H, m); 3.79 (3 H, s); 3.25-3.14 (2 H, m); 3.07-2.96 (2 H, m); 1.98-1.79 (4 H, m); 1.46 (9 H, s). WO 02/0X?67 PCTiS£1T2700472 4-(5-Methoxv-pyridin-2-yloxy)-piperidine-l-carboxylic acid tert-butyl ester 4-(5-Methoxy-l-oxy-pyridin-2-yloxy)-piperidine-l-carboxylic acid tert-butyl ester (200 mg, 0.62 mmol) was dissolved in EtOH (5 ml). Indium (498 mg, 4.34 mmol) and saturated aqueous NH4Cl (4ml) was added to the solution and the reaction was refluxed for 4 days. The mixture was filtered through celite after cooling and the solvents were removed in vacuo. The residue was chromatographed on silica gel eluting with 5:1 Heptane/EtOAc affording 50 mg (26%) of the title compound as a yellowish oil. 1H NMR (CDCl3): δ 7.77 (1 H, d, J=3.06 Hz); 7.20 (1 H, dd, J=3.07, 8.89 Hz); 6.66 (1 H, d, J=8.99 Hz); 5.14-5.07 (1 H, m); 3.80 (3 H, s); 3.79-3.72 (2 H, m); 3.31-3.23 (2 H, m); 2.00-1.91 (2 H, m); 1.75-1.64 (2 H, m); 1.47 (9 H, s). 4-(4-Pyridin-3-yl-phenyI)piperazine; hydrochloride 4-(4-Pyridin-3-yl-phenyl)piperazine-l-carboxyIic acid tert-butyl ester (60 mg, 0.18 mmol) in THP (3 ml) and cone. HC1 (3 ml) was stirred for 1 hr. The solvents were removed in vacuo and the remaining water was removed by azeotropic evaporation using EtOH/Toulene, affording 50 mg (100%) of the title compound as a yellow powder. LC-MS (APCI) m/z 240.2 (MH+). The starting material was prepared as follows: 4-(4-Iodophenyl)piperazine-l-carboxylic acid tert-butyl ester was prepared according to La Clair in Angew. Chem. Int. Ed.1998, 37(3), 325-329 in 55% overall yield starting from N-phenylpiperazine (19 mmol). 25 4-(4-Pyridin-3-vl-phenyl)piperazine-l-carboxylic acid tert-butyl ester (Ref. Wellmar et ah J. Heterocycl. Chem. 32(4), 1995, 1159-1164.) 4-(4-IodophenyI)piperazine-l-carboxylic acid tert-butyl ester (0.272 g, 0.70 mmoles), 3-pyridylboronic acid (0.078 g, 0.64 mmoles), tetrakis(triphenylphosphine)palladium (0.024 g, 0.02 mmoles), 1 M sodium hydrogencarbonate (1.0 mL) and 1,2-dimethoxyethane (1.5 T/SP»2705472 WO 02/Q74767 PCT/S mL) were stirred under nitrogen at 84° C for 3 hours, taken up in ethyl acetate and washed with water and brine. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated with silica (1 g) by rotary evaporation to give a solid which was applied on a / short silica column. Elution with dichloromethane, dichloromethane/ethyl acetate (4:1) and neat ethyl acetate gave 0.060 g (32% yield) of the title compound as a white solid and 0.060 g of starting material (the iodide), respectively. Yield was calculated from amount of converted iodide. LC-MS (APCI) m/z 340.3 (MH+). 1H NMR (Methanol-d4):δ 8.75 (1H, d, .J=2.0 Hz); 8.43 (1H, m); 8.04 (1H, m); 7.58 (2H, d, J =8.0 Hz); 7.47 (1H, m); 7.10 (2H, d, J=8.0 Hz); 3.59 (4H, m); 3.22 (4H, m); 1.50 (9H, s). N-[3-(Piperidin-4-yloxy)-phenyl]-acetamide; hydrochloride 4-Hydroxy-piperidine-l-carboxylic acid /erf-butyl ester (300 mg, 1.5 mmol) was dissolved in dry CH2CI2 and cooled to -10°C. Polymer bound triphenylphosphine (750 mg, 2.25 mmol) was added and allowed to swell. N-(3-Hydroxy-phenyl)-acetamide (340 mg, 2.25 mmol) dissolved in dry THF was added and the reaction was stirred at -10°C for 10 minutes after which DEAD (0.35 ml, 2.25 mmol) was added dropwise to the mixture. The reaction was stirred over night allowing the temperature rise to room temperature. The polymer was filtered off, using a short plug of silica with Toluene/EtOAc (5:1) as eluent. The volume of the combined fractions was reduced by rotary evaporation and the solution was washed with 5% aqueous KOH and water, dried over Na2SO4 and the solvent removed in vacuo. The resulting white powder was dissolved in THF (10 ml) and cone. HC1 (10 ml) and stirred at ambient temperature for 1 hr. The solvents were removed in vacuo and the remaining water was removed by azeotropic evaporation using EtOH/Toulene, affording 230 mg (57%) of the title compound as a white powder. LC-MS (APCI) m/z 235.1 (MH+). The following amines were prepared in a similar way as descibed described in the synthesis N-[3-(Piperidin-4~yloxy)-phenyl] -acetamide. 3-(Piperidin-4-yIoxy)-benzonitrile LC-MS (APCI) m/z 203.2 (MH+). 4-(3-Methoxy-phenoxy)-piperidine LC-MS (APCI) m/z 208.2 (MH+). 4-(3-Trifluoromethoxy-phenoxy)-piperidine LC-MS (APCI) m/z 262.1 (MH+). 4-(2,4-Difluoro-phenoxy)-piperidine LC-MS (APCI) m/z 214.2 (MH+). 4-(4-Chloro-phenoxy)-piperidine LC-MS (APCI) m/z 212.2 (MH+). 4-(Piperidin-4-yloxy)-benzonitrile LC-MS (APCI) m/z 203.2 (MH+). 4-(4-Methoxy-phenoxy)-piperidine LC-MS (APCI) m/z 208.2 (MH+). . 4-(3,4-Dichloro-phenoxy)-piperidine LC-MS (APCI) m/z 246.1 (MH+). 4-(3,4-Difluoro-phenoxy)-piperidine LC-MS (APCI) m/z 214.2 (MH+). N-{4-(Piperidin-4-yloxy)-phenyl]-acetamide LC-MS (APCI) m/z 235.1 (MH+). Wp1J2/074767 PCJZSE02700472 4-{[(3,4-dimethylphenyl)methylloxy}piperidine hydrochloride LC-MS (APCI) m/z 220 (MH+). 4-{[(2,5-dimethylphenyl)methyl]oxy}piperidine hydrochloride LC-MS (APCI) m/z 220 (MH+). 5-chloro-2-piperidin-4-yIpyridine hydrochloride Zn dust (225 mg, 3.5 mmol) was stirred in THF (1 mL) under Ar and 1,2-dibromoethane (50 μL) was added at room temperature. The mixture was heated to 65 °C for 3 min and allowed to cool to room temperature before trimethylsilyi chloride (70 μX) was added and the mixture was stirred at room temperature for 30 min. A solution of 4-iodo-N-Boc-piperideine (840 mg, 2.7 mmol) in THF (1.5 mL) was slowly added and the reaction mixture was stirred at 40 °C for 2h. Pd2(dba)3 (22 mg, 0.024 mmol) and P(2-furyl)3 (23 mg, 0.10 mmol) were mixed in THF (0.5 mL), the mixture stirred at room temperature for 10 min and then added to the organozink reagent solution, followed by 2-bromo-5-chloro-pyridine (624 mg, 3.24 mmol) in THF (1 mL) and DMA (4 mL).The reaction mixture was heated at 80 °C for 3 h, allowed to cool to room temperature and then filtered through Celite and diluted with EtOAc. The filtrate was washed with saturated aqueous NaHCO3 and brine, dried Na2SO4 and concentrated. Purification on SiO2 eluting with heptane/EtOAc 95:5 to 2:1 gave tert-butyl 4-(5-chIoropyridin-2-yl)piperidine-l-carboxylate as an yellow oil (128 mg, 16%). The oil was dissolved in THF (1.5 mL) and cone HC1 (1.5 mL) and stirred at RT for 30 min. Concentration several times with toluene and EtOH gave the title compound (89 mg, 89%) LC-MS (APCI) m/z 197 (MH+). 1H NMR (MeOD-d4): δ 8.54 (1 H, d); 7.86 (1 H, dd); 7.38 (1 H, d); 3.55-3-45 (2 H, m); 3.22-3.06 (3 H, m); 2.19-2.09 (2 H, m); 2.08-1.98 (2 H, m). 5-Benzyloxy-2-(piperidin-4-yloxy)-pyridine; hydrochloride The amine was prepared in the same way as described in the synthesis of 5-Methoxy-2- (piperidin-4-yloxy)-pyridine. LC-MS (APCI) m/z 285 (MH+). The starting material was prepared as follows: 2-Chloro-5-benzyloxypyridine Sodium hydride (55% in oil, 236 mg, 5.40 mmol) washed in Hexane and 2-Chioro-5- hydroxypyridine (350 mg3 2.70 mmol) was suspended in dry DMF (20 ml). After 10 minutes at room temperature Benzylbromide (0.32 ml, 2.70 mmol) was added and the mixture was stirred for an additional 2 hrs. The reaction was diluted with water and extracted with EtOAc (3*50 ml). The combined organic layers were washed with water and brine, and dried over Na2SO4. The solvent was removed by rotary evaporation, affording 520 mg (88%) of the title compound as a yellow oil. LC-MS (APCI) m/z 220 (MH+). 1H NMR (CDC13): δ 8.19 (lH,d, 7=3.00 Hz); 7.55 (1H, dd,.J=3.15, 8.81 Hz); 7.48-7.31 (6H,m);5.19(2H,s). 2-Chloro5-benzyloxy-pyridine 1 -oxide The amine was prepared in the same way as described in the synthesis of 2-Chloro-5- methoxy-pyridine 1-oxide. LC-MS (APCI) m/z 236 (MH+). lH NMR (DMSO-d6): δ 8.38 (1H, d, J=2.61 Hz); 7.69 (1H, d, 7=9.28 Hz); 7.47-7.33 (5H, m); 7.15 (1H, dd, J=2.69, 9.15 Hz); 5.19 (2H, s). 4-(5-Benzvloxy-l-oxy-pyridin-2-yloxy)-piperidine-l-carboxylic acid tert-butyl ester The compound was prepared as described in the synthesis of 4-(5-Methoxy-l-oxy-pyridin- 2-yloxy)-piperidine-1 -carboxylic acid tert-butyl ester. LC-MS (APCI) m/z 401 (MH+). 1H NMR (DMSO-d6): δ 8.12 (1H, d, 7=2.79 Hz); 7.48-7.32 (5H, m); 7.19 (1H, d, 7=9.16 Hz); 7.07 (1H, dd, 7=2.88, 9.18 Hz); 5.13 (2H, s); 4.84-4.76 (1H, m); 3.20-3.11 (2H, m); 3.00-2.87 (2H, m); 1.86-1.78 (2H, m); 1.59-1.49 (2H, m)rl.40 (9H, s). 4-(5-Benzyloxy-pyridin-2-yloxy)-piperidine-l-carboxvlic acid tert-butyl ester The compound was prepared as described in the synthesis of 4-(5-Methoxy-pyridin-2-yloxy)-piperidine-l-carboxy{ic acid tert-butyl ester. LC-MS (APCI) m/z 385 (MH+). lH NMR (CDC13): δ 7.86 (1H, d, 7=3.10 Hz); 7.46-7.32 (5H, m); 7.28 (1H, dd, 7=3.16, 9.04 Hz); 6.67 (1H, d, 7-9.04 Hz); 5.16-5.08 (1H, m); 5.05 (2H, s); 3.84-3.72 (2H, m); 3.33-3.25 (2H, m); 2.02-1.93 (2H, m); 1.76-1.66 (2H, m); 1.49 (9H, s). 5-Hydroxy-2-(piperidin-4-yloxy)-pyridine trifluoroacetic acid 4-(5-Benzyloxy-1 -oxy-pyridin-2-yloxy)-piperidine-1 -carboxylic acid tert-butyl ester (476 mg, 1.19 mmol) was dissolved in Methanol (20 ml) and Pd(OH)2 (30 mg) was added. The mixture was hydrogenated at 1 atm and room temperature for 24 hrs. The catalyst was filtered off, and the mixture was purified using preparative HPLC affording, after freeze drying, 110 mg (30%) of the title compound as a TFA-salt and 34 mg (10%) of the neutral Boc-protected intermediate. LC-MS (APCI) m/z 195 (MH+). 1H NMR (DMSO-d6): δ 7.66 (1H, d, 7=2.94 Hz); 7.20 (1H, dd, 7=3.07, 8.82 Hz); 6.68 (1H, d, 7=8.93 Hz); 5.12-5.00 (1H, m); 3.29-3.00 (4H, m); 2.16-2.02 (2H, m); 1.93-1.75 (2H, m). 5-Bromo-2-(piperidin-4-yloxy)-pyridine hydrochloride The amine was prepared in the same way as described in the synthesis of 5-Methoxy-2- (piperidin-4-yloxy)-pyridine. LC-MS (APCI) m/z 257 + 259 (MH+) The starting material was prepared as described in the synthesis of 4-(5-Methoxy-pyridin-2-yloxy)-piperidine-l-carboxylic acid tert-butyl ester: 4-(5-Bromo-pvridin-2-yloxy)-piperidine-l-carboxylic acid tert-butyl ester LC-MS (APCI) m/z 357 + 359 (MH+). 1H NMR (DMSO-d6): δ 8.26 (1H, dd, J=0.53, 2.67 Hz); 7.88 (1H, dd, J=2.66, 8.81 Hz); 6.80 (1H, dd, 7=0.53, 8.79 Hz); 5.15-5.07 (1H, m); 3.72-3.64 (2H, m); 3.20-3.09 (2H, m); 1.97-1.88 (2H, m); 1.58-1.48 (2H, m); 1.40 (9H, s). 4-(5-(4-FIuoro-phenyl)-pyridine-2-yl)-piperazine hydrochloride 4-(5-(4-Fluoro-phenyl)-pyridine-2-yl)-piperazine-l-carbaldehyde (98 mg, 0.34 mmol) was dissolved in MeOH (5 ml) and cone. HC1 (12M, 5 ml) was added. The mixture was stirred at room temperature over night. The solvents were removed in vacuo and the remaining water was removed by azeotropic evaporation using EtOH/Toulene affording 102 mg (100%) of the title compound as a yellow powder. LC-MS (APCI) m/z 258 (MH+). The starting material was prepared as follows: 4-(5-(4-Fluoro-phenyl)-pyridine-2-yl)-piperazine-l-carbaJdehvde 4-(5-Bromo-pyridine-2-yl)-piperazine-l-carbaldehyde (100 mg, 0.37 mmol), 4-Fluorobenzeneboronic acid (55 mg, 0.39 mmol), (l,l'-bis(diphenyIphosphino)ferrocene)-dichloropalladium(II) (10 mg, 0.01 mmol), Toluene (2 ml), EtOH (0.5 ml) and 2M Na2CO3 solution (0.5 ml, I mmol) were heated at 80°C under N2 overnight. After cooling the mixture was diluted with toluene and separated. The organic phase was washed with water and brine, filtered through a pad of celite and dried overNa2SO4 The solvent were removed in vacuo affording 100 mg (94%) of the title product as a beige powder. LC-MS (APCI) m/z 286 (MH+). 1H NMR (DMSO-d6): δ 8.44 (1H, d, J=2.66 Hz); 8.10 (1H, s); 7.97 (1H, dd, 7=2.52, 8.82 Hz); 7.70-7.31 (2H, m); 7.31-7.21 (2H, m); 6.97 (1H, d, J=8.97 Hz); 3.65-3.43 (8H, m). The following compounds were synthesised as described in the synthesis of4-(5-(4-Fluoro- phenyl)-pyridine-2-yl)-piperazine hydrochloride: 4-(5-(4-Methoxy-phenyI)-pyridine-2-yI)-piperazine hydrochloride LC-MS (APCI) m/z 270 (MH+). 4-(5-(4-Ch]oro-phenyI)-pyridine-2-yl)-piperazine hydrochloride LC-MS (APCI) m/z 274,276 (MH+). 4-(5-(4-Trifluoromethoxy-phenyl)-pyridine-2-yI)-piperazine hydrochloride LC-MS (APCI) m/z 324 (MH+). 4-(5-Furan-2-yl-pyridine-2-yI)-piperazine hydrochloride LC-MS (APCI) m/z 230 (MH+). 4-(5-(lH-PyrroI-2-yI)-pyridine-2-yl)-piperazine dihydrochloride The title compound was prepared from 2-(6-(4-FormyI-piperazine-l-yl)-pyridine-3-yl)-pyrrole-1-carboxylic acid tert-butyl ester. LC-MS (APCI) m/z 229 (MH+). 4-[3,3']-Bipyridinyl-6-yl-piperazine hydrochloride LC-MS (APCI) m/z 241 (MH+). 4-{6-Piperazine-l-yl-pyridine-3-yl)-benzonitrile hydrochloride LC-MS (APCI) m/z 265 (MH+). WO 02/074767 HYDANTOINS OF FORMULA I WO 02/07/767 PCT/S PCT/SE02/00472 (1). For NMR-data see experimental part. The following compounds were prepared in the same way as (5S)-5-({[4-(4- fluorophenyl)piperidin-l-yl]sulfonyl} methyl)-5-methylimidazolidine-2,4-dione (Example 12) and purified either by precipitation and washing with EtOH/water or by preparative HPLC. yl]sulfonyl]methyl)imidazolidine-2,4-dione LC-MS (APCI) m/z 380 (MH+). 1H NMR (Methanol-d4,): δ 7.35 (2 H, d, J=8.9 Hz); 6.87 (2 H, d', 7=8.9 Hz); 6.01 (1 H, dd); 3.92 (2 H, dd); 3.78 (3 H, s);.3.56, 3.41 (1 H each, ABq, 7=14.6 Hz); 3.51-3.46 (2 H, m); 2.62-2.57 (2 H, m); 1.47 (3 H,s). WO O2/0W67 PCT7SE02/00472 (5S)-5-methyl-5-([{4-[4-(methyloxy)phenyl]piperidin-l-yl}sulfonyl)methyl]imidazolidine-2.4-dione LC-MS (APCI) m/z 3 82 (MH+). 1HNMR (DMSO-d6): δ 10.73 (1 H, s); 8.01 (1 H, s); 7.17 (2 H, d); 6.85 (2 H, d); 3.71 (3 H, s); 3.60 (2 H, dd); 3.50 (1 H,-part of ABq, J=14.8 Hz); 2.85 (2 H, q); 2.54 (1 H, t); 1.79 (2 H, d); 1.64-1.53 (2 H, m); 1.33 (3 H, s). (5S)-5-({([4-(4-chlorophenyl)-4-hydroxypiperidin-l-yl]sulfonyl}methyl)-5-methylimidazolidine-2,4-dione LC-MS (APCI) m/z 402/404 3:1 (MH+). 1H NMR (DMSO-d6): δ 10.72 (1 H, s); 8.01 (1 H, s); 7.51 (2 H, d); 7.37 (2 H, d); 5.22 (1 H, s); 3.49, 3.34 (1 H each, ABq,J14.9 Hz); 3.47-3.35 (2 H, m); 3.15 (2 H, q); 1.93 (2 H, t);1.64(2H,d);1.33(3H,s). (5S)5-methyl-5-[({4-[2-(methyloxy)phenyl1piperidin-l-yl}sulfonyl)methyl)imidazolidine-2,4-dione LC-MS (APCI)' m/z 3 82 (MH+), 1H NMR (DMSO-d6): δ 10.72 (1 H, s); 8.01 (1 H, s); 7.24-7.14 (2 H, m); 6.96 (1 H, d); 6.90 (1 H, t); 3.78 (3 H, s); 3.60 (2 H, dd); 3.51, 3.33 (1 H each, ABq, J=14.7 Hz); 3.02- 2.94 (1 H, m); 2.88 (2 H, q); 1.77 (2 H, d); 1.66-1.56 (2 H, m); 1.33 (3 H, s). (5S)-5-methyl-5-[({4-[4-(trifluoromethyl)phenvnpiperidin-l-yl}sulfonyl)methylimidazolidine-2,4-dione LC-MS (APCI) m/z 420 (MH+). 1H NMR (DMSO-d6): δ 10.73 (1 H, s); 8.01 (1 H, s); 7.66 (2 H, d); 7.50 (2 H, d); 3.63 (2 H, dd); 3.52, 3.34 (1 H each, ABq, .J=14.9 Hz); 2.88 (2 H, ddd); 2.79-2.68 (1 H, m); 1.86 (2 H, d); 1.67 (2 H, ddd); 1.33 (3 H, s). (5S)-5-methyl-5-[(C{4-{3-(trifluoromethyl)phenyl|piperidin-l-yl)sulfonyl)methylimidazolidine-2,4-dione LC-MS (APCI) m/z 420 (MH+). 1H NMR (DMSO-d6): δ 10.74 (1 H, s); 8.02 (1 H, s); 7.63-7.52 (4 H, m); 3.63 (2 H, dd); 3.52 (1 H, part of ABq, J=14.9 Hz); 2.87 (2 H, ddd); 2.79-2.70 (1 H, m); 1.87 (2 H, d); 1.75-1.63(2H,m);1.33(3H,s). (5S)-5-[({4-[3T5-bis(trifluoromethyl)phenyl]piperidin-l-yl}sulfonyl)methyl]-5-methylimidazolidine-2,4-dione LC-MS (APCI) m/z 488 (MH+). 1H NMR (DMSO-d6): δ 10.74 (1 H, s); 8.02 (1 H, s); 8.00 (2 H, s); 7.93 (1 H, s); 3.64 (2 H, dd); 3.52 (1 H, part of ABq, .J=14.9 Hz); 2.95-2.81 (3 H, m); 1.89 (2 H, d); 1.83-1.69 (2 H, m); 1.34 (3 H,s). (5S)-5-({[4-(4-(4-chlorophenyn-3,6-dihvdropyridin-l(2H)-yl]sulfonyl)methyl)-5-methyIimidazolidine-2,4-dione LC-MS (APCI) m/z 384/386 3:1 (MH+). 1HNMR (DMSO-d6): δ 10.74 (1 H, s); 8.03 (1 H, s); 7.47 (2 H, d); 7.40 (2 H, d); 6.23 (1 H, app s); 3.85 (2 H, app s); 3.52, 3.39 (1 H each, ABq, .J=14.7 Hz); 3.39-3.32 (2 H, m); 2.55 (2 H, br s); 1.32 (3 H, s). (5S)-5-({f4-f3-fluorophenyl)piperidin-l-yl]sulfonyl)methyl)-5-methylimidazolidine-2.4-dione LC-MS (APCI) m/z 370 (MH+). 1H NMR (DMSO-d6): δ 10.73 (1 H, s); 8.01 (I H, s); 7.38-7.31 (1 H,m); 7.15-7.08 (2 H, m); 7.05-6.98 (1 H, m); 3.62 (2 H, dd); 3.51, 3.33 (1 H each, ABq, J=14.7 Hz); 2.95-2.80 (2 H, m); 2.68-2.60 (1 H, m); 1.82 (2 H, br d); 1.69-1.58 (2 H, m); 1.33 (3 H, s). (5S)-S-({[4-(2-fluorophenyl)piperidin-l-yl]lsulfonyl}methyl)-5-methylimidazolidine-2.4-dione LC-MS (APCI) m/z 370 (MH+). 1HNMR (DMSO-d6): δ 10.73 (1 H, s); 8.01 (1 H, s); 7.36"(1 H, t); 7.30-7.20 (1 H, m); 7.18-7.12 (2 H, m); 3.63 (2 H, dd); 3.52, 3.33 (1 H each, ABq); 2.96-2.85 (3 H, m); 1.80 (2 H, brd); 1.69 (2 H, ddd); 1.33 (3 H, s). (5S)-5-methyl-5-({f4-(4-methylphenyl)piperidin-l-yl|sulfonyl}methyl)imidazolidine-2,4-dione Y LC-MS (APCI) m/z 366 (MH+). 1H NMR (DMSO-d6): δ 10.73 (1 H, s); 8.01 (1 H, s); 7.15-7.07 (4 H, m); 3.60 (2 H, dd); 3.50,3.32 (1 H each, ABq); 2.85 (2 H, q); 2.59-2.51 (1 H, m); 2.25 (3 H, s); 1.79 (2 H, br d); 1.60 (2 H, ddd). (5S)-5-methyl-5-({[4-(phenylmethyl)piperidin-l-yl]sulfonyl)methyl])imidazolidine-2,4-dione LC-MS (APCI) m/z 3 66 (MH+). 1H NMR (DMSO-d6): δ 10.70 (1 H, s); 7.96 (1 H, s); 7.29-7.15 (5 H, m); 3.46 (2 H, t); 3.41, 3.24 (1 H each, ABq, J=14,9 Hz); 2.68 (2 H, dt); 2.52 (2 H, d); 1.54-1.51 (3 H, m); 1.30 (3 H,s). (5S)-5-[(l,4'-bipiperidin-1-ylsulfonyl)methyl]-5-methylimidazolidine-2,4-dione trifluoroacetic acid LC-MS (APCI) m/z 359 (MH+). 1HNMR (DMSO-d6): δ 10.74 (1 H, s); 9.25 (1 H, br s); 8.02 (1 H, s); 3.63 (2 H, t); 3.51, 3.34 (1 H each, ABq, J=14.8 Hz); 3.39 (2 H, d);.3.24 (1 H, t); 2.92 (2 H, q); 2.81 (2 H, t); 2.07 (2 H, d); 1.82 (2 H, d); 1.74-1.58 (5 H, m); 1.45-1.34 (1 H, m); 1.31 (3 H, s). 19F NMR (DMSO-d6): 5 -74.48. WO 02074767 PCT/SEO2/0t42 (5S)-5-({[4-[3-furan-2-yl-lH-pyrazol-5-vl)piperidin-l-vl]sulfonyl}methyl)-5-methylimidazolidine-2,4-dione LC-MS (APCI) m/z 408 (MH+). 1HNMR (DMSO-d6): δ 10.73 (1 H, s); 8.01 (1 H, s); 7.66 (1 H, s); 6.64 (1 H, s); 6.53 (1 H, s); 6.34 (1 H, s); 3.61-3.49 (2 H, m); 3.49 (1 H, half ABq,J=14.9 Hz); 2.94-2.84 (2 H, m); 2.81-2.72 (1 H, m); 1.98 (2H, br d); 1.70-1.58 (2 H, m); 1.32 (3 H, s). (5S)-5-methyl-5-([(4-{4-[(trifluoromethyl)oxy]phenyl}piperidin-l-yl)sulfonyl]methyl}imidazolidine-2,4-dione LC-MS (APCI) m/z 436 (MH+). 1H NMR (DMSO-d6): δ 10.73 (1 H, s); 8.01 (1 H, s); 7.40 (2 H, d); 7.28 (2 H, d); 3.70-3.55 (2 H, m); 3.51, 3.33 (1 H each, ABq, 7=14.7 Hz); 2.94-2.80 (2 H, m); 2.73-2.61 (2 H, m); 1.86 (2 H, d); 1.71-1.57 (2 H, m); 1.33 (3 H, s). (5S)-5-({[4-(4-chlorophenyl)piperidin-l-yl]-sulfonyl)methyl)-5-methylimidazolidine-2,4-dione LC-MS (APCI) m/z 386/388 3:1 (MH+). 1H NMR (DMSO-d6): δ 10.73 (1 H, s); 8.01 (1 H, s); 7.36-7.28 (4 H, m); 3.66-3.54 (2 H, m); 3.51, 3.33 (I H each, ABq, 7=14.9 Hz); 2.92-2.80 (2 H, m); 2.67-2.58 (1 H, m); 1.81 (2 H, br d); 1.68-1.56 (2 H,m); 1.33 (3 H,s); (5S)-5-methyl-5-{[(4-pyrolidin-l-ylpiperidin-l-yl)sulfonyl]methyl)imidazolidine-2,4-dione trifluoroacetic acid LC-MS (APCI) m/z 345 (MH+). 1H NMR (DMSO-d6): δ 10.74 (1 H, s); 9.61 (1 H, br s); 8.01 (I H, s); 3.60 (2 H, t); 3.51, 3.36 (1 H each, ABq, 7=14.8 Hz); 3.55-3.47 (2 H, m); 3.27-3,15 (1 H, m); 3.13-3.02 (2 H, m); 2.80 (2 H, t); 2.12 (2 H, br d); 2.07-1.94 (2 H, m); 1.86-1.77 (2 H, m); 1.62-1.49 (2 H, m); 1.32 (3 H,s). !9F NMR (DMSO-d6): δ -74.02 (5S)-5-methyl-5-(([4-(tetrahydrofuran-2-ylcarbaonyl)piperazin-l-vnsuifonvl)methvl)imidazoIidine-2.4-dione LC-MS (APCI) m/z 375 (MH+). 1H NMR (DMSO-d6); δ 10.73 (1 H, s); 8.01 (1 H, s); 4.65 (1 H, dd); 3.80-3.68 (2 H, m); 3.60-3.42 (3 H and water, m); 3.33 (1 H, half ABq, 7=14.9 Hz); 3.19-3.00 (4 H, m); 2.09-1.92 (2 H, m); 1.87-1.75 (2 H, m); 1.30 (3 H, s). N-[l-({[(4iy)-4-methyl-2,5-dioxominidazolidin-4-yl]methyl}sulfonyl)piperidin-4- yl]benzamide LC-MS (APCI) m/z 395 (MH+). 1HNMR (DMSO-d6): δ 10.72 (1 H, s); 8.30 (1 H, d); 8.01 (1 H, s); 7.82 (2 H, d); 7.51 (1 H, t); 7.45 (2 H, t); 3.96-3.85 (1 H, m); 3.52 (2 H, t); 3.50, 3.32 (1 H each, ABq, .J=14.7 Hz); 2.92 (2 H, t); 1.88 (2 H, d); 1.55 (2 H, q); 1.33 (3 H, s). (5S)-5-([(4-{[2-q,l-dimethylethyl)-lH-indol-5-yl]amino}piperidin-l-yl)sulfonyl]methyl}-5-methyl]imidazolidine-2,4-dione LC-MS (APCI) m/z 462 (MH+). 1H NMR (DMSO-d6): δ 10.72 (1 H, s); 10.37 (1 H, s); 8.00 (1 H, s); 7.02 (1 H, d, J=8.4 Hz); 6.5S (1 H, s); 6.45 (1 H, d, J=8.4 Hz); 5.86 (i H, s); 4.65 (1 H, Br s); 3.48, 3.29 (1 H each, ABq, 7=14.7 Hz); 3.46 (2 H, t); 2.93 (2 H, t); 1.95 (2 H, t); 1.45-1.35 (2 H, m); 1.33 (3H,s);1.29(9H,s). (551-5-methvl-5-[(piperidin-l-yl]sulfonyl)methyl]-imidazolidine-2,4-dione LC-MS (APCI) m/z 276 (MH+). 1H NMR (DMSO-dg): δ 10.70 (1 H, s); 7.97 (1 H, s); 3.44, 3.23 (1 H each, ABq, 7=14.8 Hz); 3.13-3.01 (4 H, m); 1.58-1.42 (6 H, m); 1.30 (3 H, s). (5S)-5-[(3.6-dihydropyridin-l(2H)-ylsulfonyl)methyl]-5-methylimidazolidine-2.4-dione LC-MS (APCI) m/z 274 (MH+). 1H NMR (DMSO-d6): δ 10.72 (1 H, s); 8.00 (1 H, s); 5.85-5.78 (1 H, m); 5.74-5.68 (1 H, m); 3.67-3.62 (2 H, m); 3.47, 3.33 (1 H each, ABq, J=14.7 Hz); 3.22 (2 H, dd); 2.14-2.10 (2H,m);1.31(3H,s). (5S)-S-methyl-5-({[4-(2-oxo-2,3-dihvdro-lH-benzimidazoM-yl)piperidin-l-yl]-sulfonyllmethyl)imidazolidine-2,4-dione LC-MS (APCI) m/z 408 (MH+). 1HNMR (DMSO-d6): δ 10.86 (1 H, s); 10.75 (1 H, s); 8.02 (1 H, s); 7.27-7.17 (1 H, m); 7.05-6.91 (3 H, m); 4.38-4.20 (1 H, m); 3.65 (2 H, t); 3.56, 3.38 (1 H each, ABq, J=14.8 Hz); 3.03-2.90 (2 H, m); 2.41-2.24 (2 H, m); 1.76 (2 H, d); 1.34 (3 H, s). (5S)-5-({[4-(rlH-l,2.3-benzotriazol-l-yl)piperidin-l-yl]sulfonyl]-methyl)-5-methylimidazolidine-2.4-dione LC-MS (APCI) m/z 393 (MH+). 1H NMR (DMSO-d6): δ 10.77 (1 H, s); 8.05 (1 H, s); 8.05 (1 H, d); 7.93 (1 H, d); 7.56 (1 H, t); 7.41 (1 H, t); 5.12-4.97 (1 H, m); 3.71 (2 H, t); 3.58, 3.43 (1 H each, ABq, 7-14.7 Hz);3.19-3.03(2H,m);2.29-2.16(4H,m);1.35(3H,s). (5S)-5-methyl-5-({[4-(pyridin-2-ylethynyl)-3,6-dihydropyridin-l(,2H)-yl]-sulfonylmethylimidazolidine-2.4-dione trifluoroacetic acid LC-MS (APCI) m/z 375 (MH+). 2/ 1H NMR (DMSO-d6): δ 10.57 (1 H, s); 8.56 (1 H, d); 8.03 (1 H, s); 7.82 (1 H, t); 7.53 (1 H, d); 7.38 (1 H, dd); 6.31 (1 H, br s); 3.83 (2 H, d); 3.54, 3.41 (1 H each, ABq, J=14.8 Hz); 3.36-3.25 (2 H, m); 2.42-2.34 (2 H, m); 1.32 (3 H, s). 19F NMR (DMSO-d6): δ -75.10 WO 02/0>4767 (5S)-5-methyl-5-[([4-[(4-methylphaenyl)ethynyl]-3,6-dihydropyridin-1(2H)-vPsuIfonvI)methvOimidazoIidme-2,4-dione LC-MS (APCI) m/z 388 (MH+). 1HNMR (DMSO-d6): δ 10.74 (1 H, s); 8.02 (1 H, s); 7.32 (2 H, d); 7.19 (2 H, d); 6.17(1 H, br s); 3.80 (2 H, d); 3.52, 3.39 (1 H each, ABq, J=14.8 Hz); 3.29 (2 H, t); 2.39-2.32 (2 H,m);2.30(3H,s); 1.32(3H,s). (5S)-5-({[4-[(4-chlorophenyl)ethynyl]-3,6-dihydropyridin-1/2H-yl]sulfonyl}methyl)-5-methyIimidazoIidine-2,4-dione LC-MS (APCI) m/z 408 (MH+). 'H NMR (DMSO-d6): 5 10.74 (1 H, s); 8.02 (1 H, s); 7.54-7.38 (4 H, m); 6.23 (1 H, br s); 3.87-3.76 (2 H, m); 3.53, 3.41, (1 H each, ABq, 7=14.9 Hz); 3.34-2.25 (2 H, m); 2.42-2.29 (2Hm);1.32(3H,s). (5S)-5-[4-(3,4-Dichioro-phenox)-piperidine-l-sulfonylmethyl]-5-methyl-imidazolidine-2,4-dione LC-MS (APCI) m/z (APCI) m/z 436.1 (MH+). 1H NMR (DMSO- d6): δ 10.74 (1 H, s); 8.01 (1 H, s); 7.53 (1 H, d, J=9.2 Hz); 7.31 (1 H, d, 7=2.9 Hz); 7.02 (l H, dd, 7=9.2, 2.9 Hz); 4.65-4.57 (1 H, m); 3.51, 3.34 (1 H each, ABq, J=15.2 Hz); 3.39-3.27 (2 H, m); 3.17-3.08 (2 H, m); 2.00-1.90 (2 H, m); 1.75-1.65 (2 H, m);1.33(3H, s). (5S)-5-[4-(5-Chloro-pyridin-2-yloxy)-piperidine-l-sulfonvlmethyl]-S-methyl-imidazolidine-2.4-dione LC-MS (APCI) m/z 403.3 (MH+). 1H NMR (DMSO-d6): δ 10.74(1 H, s); 8.20(1 H, d, J=2.7 Hz); 7.81 (1 H, dd, J=8.7, 2.7 Hz); 6.87 (1 H, d, J=2.7 Hz); 5.16-5.03 (1 H, m); 3.52, 3.35 (1 H each, ABq, 7=15.0 Hz); 3.43-3.28 (2 H, m); 3.19-3.07 (2 H, m); 2.08-1.95 (2 H, m); 1.80-1.65 (2 H, m); 1.33 (3 H, s). WO82/074767 PCT7SC02/00472 (5S)-5-Methyl-5-[4-(5-trifluoromethyl-pyridin-2-yloxy)-piperidine-l-sulfonylmethyl]-imidazoIidine-2.4-dione LC-MS (APCI) m/z 437 (MH+). 1HNMR (CDCl3): δ 8.95 (1 H, s); 8.42-8.38 (1 H, m); 7.79 (1 H, dd, J=8.8, 2.5 Hz); 6.81 (1 H, d, J=8.8 Hz); 6.71 (I H, s); 5.40-5.28 (1 H, m); 3.52-3.39 (2.H, m); 3.40-3.28 (2 H, m); 3.32 (2 H, ABq, 7=24.6, 14.0 Hz); 2.16-2.02 (2 H, m); 2.02-1.84 (2 H, m); 1.67 (3 H, s). 6-[l-((4S)-4-Methyl-2,5-dioxo-imidazolidin-4-ylmethanesulfonyl)-piperidin-4-yloxy]-nicotinonitrile LC-MS (APCI) m/z 394.3 (MH+). 1H NMR (DMSO- d6): δ 10.72 (1 H, s); 8.68 (1 H, d, J=2.3 Hz); 8.14 (1 H, dd, J=8.7,2.3 Hz); 8.00 (1 H, s); 6.98 (1 H, d, J=8.7 Hz); 5.27-5.14 (1 H, m); 3.56-3.28 (4H, m); 3.18- 3.06 (2 H, m); 2.08-1.96 (2 H, m); 1.81-1.66 (2 H, m); 1.31 (3 H, s). (5S)-5-Methyl-5-(4-p-tolyloxy-piperidine-l-sulfonylmethyl)-imidazolidine-2,4-dione LC-MS (APCI) m/z 382.5 (MH+). 1H NMR (DMSO- d6): δ 10.73 (1 H, s); 8.01 (1 H, s); 7.09 (2 H, d, J=8.4 Hz); 6.87 (2 H, d, J=8.4 Hz); 4.50-4.42 (1 H, m); 3.50, 3.34 (1 H each, ABq, J=14.8 Hz); 3.38-3.29 (2 H, m); 3.17-3.09 (2 H, m); 2.23 (3 H, s); 1.99-1.89 (2 H, m); 1.73-1.63 (2 H, m); 1.33 (3 H, s). (5S)-5-Methyl-5-[4-(4-trifluoromethyl-phenoxy)-piperidine-l-sulfonylmethyl]-imidazolidine-2,4-dione LC-MS (APCI) m/z 436.3 (MH+). 1HNMR (DMSO- d6): δ 10.71 (1 H, brs); 8.02 (1 H, s); 7.65 (2 H, d, J=8.8 Hz); 7.17 (2 H, d, J=8.8 Hz); 4.72-4.64 (1 H, rn); 3.52, 3.35 (1 H each, ABq, J=14.7 Hz); 3.40-3.28 (2 H, m); 3.19-3.10 (2 H, m); 2.05-1.95 (2 H, m); 1.78-1.68 (2 H, m); 1.33 (3 H, s). PCTSE02/00472 WO 02/074767 4-[l-(4S)-4-Methyl-2.5-dioxo-imidazolidin-4-ylmethanesulfonyl)-piperidin-4-yloxy]-benzonitrile LC-MS (APCI) M/Z 393.2 (MH+). 1H NMR (DMSO- d6): δ 10.73 (1 H, s); 8.00 (1 H, s); 7.76 (2 H, d, J=8.8 Hz); 7.15 (2 H, d, J=8.8 Hz); 4.74-4.65 (1 H, m); 3.51, 3.34 (1 H each, ABq, 7=14.9 Hz); 3.40-3.27 (2 H, m); 3.17-3.07 (2 H, m); 2.03-1.94 (2 H, m); 1.77-1.66 (2 H, m); 1.32 (3 H, s). f5if)-5~f4-r4-Methoxv-phenoxy)-piperidine-l-sulfonvlniethvll-5-methvl-imidazolidine-2.4-dione LC-MS (APCI) m/z 398.2 (MH+). 1H NMR (DMSO- d6): δ 10.73 (1 H,.s); 8.01 (1 H, s); 6.89 (4 H, ABq, J=29.1, 9.1 Hz); 4.43-4.34 (1 H, m); 3.70 (3 H, m); 3.51, 3.33 (1 H, ABq, J=15.0 Hz); 3.38-3.28 (2 H, m); 3.16-3.05 (2 H,m); 1.97-1.87 (2 H, m); 1.73-1.62 (2 H, m); 1.33 (3 H, s). (5S-5-[4-(3.4-Difluoro-phenoxy)-piperidine-l-sulfonylmethyl]-5-methyl-imidazoIidine-2,4-dione LC-MS (APCI) m/z 404.2 (MH+). 1HNMR (DMSO- d6): δ 10.74 (1 H, s); 8.01 (1 H, s); 7.35 (1 H, q, J=19.6, 9.2 Hz); 7.19-7.11 (1 H, m); 6.86-6.80 (1 H, m); 4.57-4.48 (1 H, m); 3.51, 3.34 (1 H each, ABq, J=14.9 Hz); 3.38-3.28 (2 H, m); 2.16-2.06 (2 H, m); 2.00-1.90 (2 H, m); 1.74-1.64 (2 H, m); 1.33 (3H,s). (5S)-5-[4-(4-Chloro-phenoxy)-piperidine-l-sulfonylmethyl]-5-methyl-imidazoIidine-2.4-dione LC-MS (APCI) m/z 402 (MH+). 1HNMR (DMSO- d6): δ 10.73 (1 H, s); 8.00 (1 H, s); 7.32 (2 H, d, 7=8.8 Hz); 7.00 (2 H, d, 7=8.8 Hz); 4.56-4.48 (1 H, m); 3.50, 3.33 (1 H each, ABq, 7=14.8 Hz); 3.37-3.28 (2 H, m); 3.16-3.06 (2 H, m); 2.00-1.90 (2 H, m); 1.73-1.63 (2 H, m); 1.32 (3 H, s). WO 027074767 PCT/SE02/00472 (55)-5-[4-(5-Ethyl-Pyrimidin-2-yloxy)-piperidine-l-sulfonylnmethyl]-5-methyl-imidazolidine-2.4-dione LC-MS (APCI) m/z 398 (MH+). 1HNMR (DMSO- d6); δ 10.74 (1 H, s); 8.47 (2 H, s); 8.02 (1 H, s); 5.11-5.03 (1 H, m); 3.52, 3.35 (1 H each, ABq, 7=14.8 Hz); 3.42-3.28 (2 H, m); 3.19-3.10 (2 H, m); 2.54 (2 H, q, 7=15.2, 7.6 Hz); 2.06-1.98 (2 H, m); 1.81-1.71 (2 H, m); 1.33 (3 H, s); 1.17 (3 H, t, 7=7.2 Hz). (5S)-5-Methyl-5-[4-(4-trifluoromethyl-pyrimidin-2-yloxy)-piperidine-l- sulfonylmethyl]-imidazolidine-2,4-dione LC-MS (APCI) m/z 438 (MH+). 1H NMR (CDC13): δ 8.84-8.76 (1 H, m); 8.02 (1 H, s); 7.31 (1 H, d, 7=4.8 Hz); 6.33 (1 H, s); 5.41-5.34 (1 H, m); 4.54-4.42 (4 H, m); 3.35, 3.24 (1 H each, ABq, J=12.9 Hz); 2.17- 2.07(4H,m);2.02(3H,s). (5S)-5-Methyl-5-[4-(5-methyl-pyridin-2-yloxy)-piperidine-l-sulfonylmethvn-imidazoIidine-2,4-dione LC-MS (APCI) m/z 383 (MH+). lH NMR (CDCl3): δ 8.14 (1 H, s); 8.06-7.99 (2 H, m); 7.19 (1 H,_s); 7.09 (1 H, d, J=11.6 Hz); 5.28-5.21 (1 H, m); 3.70-3.41 (6 H, m); 2.44 (3 H, s); 2.13-1.96 (4 H, m); 1.62 (3 H, s)- (5S)-5-[4-(4-Fluoro-benzoyl)piperidine-l-sulfonylmethyl]-5-methyl-imidazolidine-2,4-dione LC-MS (APCI) m/z 398 (MH+). 1H NMR (DMSO- d6): δ 8.06 (2 H, q, 7=9.2, 6.0 Hz); 7.40 (2 H, t, 7=8.8 Hz); 3.61-3.41 (4 H, m); 3.00-2.91 (2 H, m); 1.90-1.81 (2 H, m); 1.62-1.50 (2 H, m); 1.33 (3 H, s). W902/074767 PQF/SED2/00472 (5S)-5-[4-(5-Fluoro-pyrimidin-2-yloxy)-piperidine-l-sulfonylmethyl]-5-methyl-imidazolidine-2,4-dione LC-MS (APCI) m/z 388 (MH+). 1H NMR (CDCl3): δ 8.42 (2 H, s); 8.30 (1 H, s); 6.40 (1 H, s); 5.30-5.23 (1 H, m); 3.53- 3.35 (4 H, m); 3.36, 3.21 (1 H each, ABq, J=14.4 Hz); 2.10-2.02 (4 H, m); 1.70 (3 H, s). (5S)-5-[4-(6-Methoxy-pyridin-2-yloxy)-piperidine-l-sulfonylmethyl]-5-methyl-imidazoIidine-2,4-dione LC-MS (APCI) m/z 399 (MH+). 1H NMR (MeOD): δ 7.54 (1 H, t, 7=8.4 Hz); 6.33-6.28 (2 H, m); 5.24-5.14 (1 H, m); 3.86 (3 H, s); 3.53-3.42 (2 H, m); 3.58, 3.39 (1 H each, ABq, 7=14.4 Hz); 3.30-3.22 (2 H, m); 2.13-2.02 (2 H, m); 1.96-1.82 (2 H, m); 1.47 (3 H, s). (5S)-5-[4-(6-Chloro-pyridin-2-yloxy)-piperidine-l-sulfonylmethyl]-5-methyl-imidazolidine-2,4-dione LC-MS (APCI) m/z 403 (MH+). 1H NMR (MeOD): δ 7.65 (1 H, t, .J=7.8 Hz); 6.97 (1 H, d, 7=7.2 Hz); 6.73 (1 H, d, J=7.2 Hz); 5.25-5.14 (1 H, m); 3.55-3.44 (2 H, m); 3.58, 3.39 (1 H each, ABq, 7=14.4 Hz); 3.28-3.19 (2 H, m); 2.14-2.02 (2 H, m); 1.92-1.79 (2 H, m); 1.47 (3 H, s). 3-[l-((4S)-4-Methyl-2,5-dioxo-imidazolidin-4-ylmethanesulfonyl)-piperidin-4-yloxy]-benzonitrile LC-MS (APCI) m/z 3 93 (MH+). 1HNMR (DMSO- d6): δ 10.74 (1 H, s);.8.02 (1 H, s); 7.52-7.47 (2 H, m); 7.42-7.38 (1 H, m); 7.36-7.31 (1 H, m); 4.69-4.61 (1 H, m); 3.52, 3.35 (1 H each, ABq, J=17.2 Hz); 3.18-3.07 (2 H, m); 2.02-1.95 (2 H, m); 1.79-1.65 (2 H, m); 1.33 (3 H, s). WO0W74767 PCT/SE02/0047: (5S)_5-[4-(3-Methoxy-phenoxy)-piperidine-l-sulfonylmethyl]-5-methyl-imidazolidine-2.4-dione LC-MS (APCI) m/z 398 (MH+). 1H NMR (DMSO- d6): δ 10.74 (1 H, s); 8.01 (1 H, s); 7.21-7.15 (1 H, m); 6.58-6.50 (3 H, m); 4.57-4.49 (1 H, m); 3.73 (3 H, s); 3.51,3.34 (1 H each, ABq, 7=14.4 Hz); 3.17-3.08 (2 H, m); 2.01-1.91 (2 H, m); 1.74-1.64 (2 H, m); 1.33 (3 H, s). N-{4-[(4S)-Methyl-2,5-dioxo-imidazolidin-4-yl]methanesulfonyl)-piperidin-4-yloxyl-phenyl]-acetamide LC-MS (APCI) m/z 425 (MH+). 1H NMR (DMSO- d6): δ 10.69 (1 H, brs); 9.78 (1 H, s); 8.00 (1 H, s); 7.47 (2 H, d, 7=9.2 Hz); 6.91 (2 H, d/J=9.2 Hz); 4.48-4.41 (1 H, m); 3.51 (1 H from ABq, J=14.4 Hz); 3.16-3.06 (2 H, m); 2.00 (3 H, s); 1.98-1.90 (2 H, m); 1.73-1.63 (2 H, m); 1.33 (3 H, s). (5S)-5-[4-(3-Chloro-phenoxy)-piperidine-l-sulfonylmethyl]-5-methyl-imidazolidine-2,4-dione LC-MS (APCI) m/z 402 (MH+). 1H NMR (DMSO- d6): δ 10.76 (1 H, brs); 7.99 (1 H, s); 7.31 (1 H, t, J=8.4 Hz); 7.08 (1 H, t, J=2.2 Hz); 7.02-6.95 (2 H, m); 4.64-4.56 (1 H, m); 3.51 (1 H from ABq, 7=14.4 Hz); 3.17-3.09 (2 H, m); 2.00-1.91 (2 H, m); 1.75-1.65 (2 H, m); 1.33 (3 H, s). (5S)-5-Methyl-5-[4-(4-trifluoroniethoxv-phenoxy)-piperidine-l-suIfonvlmethyl]-imidazolidine-2,4-dione LC-MS (APCI) m/z 452 (MH+). 1H NMR (DMSO- d6): δ 10.74 (I H, s); 8.01 (1 H, s); 7.29 (2 H, d, 7=8.8 Hz); 7.08 (2 H, d, 7=9.2 Hz); 4.60-4.52 (1 H, m); 3.51 (1 H from ABq, 7=14.8 Hz); 3.17-3.08 (2 H, m); 2.02-1.93 (2 H, m); 1.75-1.65 (2 H, m); 1.33 (3 H, s). (5S)-5-Methyl-5-[4-(3-trifluoromethoxy-phenoxy)-piperidine-l-sulfonylmethyl]-imidazoIidine-2.4-dione LC-MS (APCI) m/z 452 (MH+). 1H NMR (DMSO- d6): δ 10.74 (1 H, s); 8.01 (1 H, s); 7.41 (1 H, t,J=8.4 Hz); 7.06-6.91 (3 H, m); 4.65-4.58 (1 H, m); 3.51 (1 H from ABq,.J=14.8 Hz); 3.18-3.08 (2 H, m); 2.02-1.93 (2 H, m); 1.76-1,65 (2 H, m); 1.33 (3 H, s). (5S)-5-[4-(2,4-Difluoro-phenoxv)-piperidine-l-sulfonylmethyl]-5-methyl-imidazolidine-2,4-dione LC-MS (APCI) m/z 404 (MH+). 1H NMR (DMSO-d6): δ 10.74 (1 H, s); 8.02 (1 H, s); 7.34-7.23 (2 H, m); 7.06-6.97 (1 H, m); 4.50-4.41 (1 H, m); 3.50 (1 H from ABq); 3.17-3.06 (2 H, m); 2.02-1.90 (2 H, m); 1.78-1.65 (2 H,m); 1.33 (3 H, s). (5S)-5-[4-(4-Fluoro-phenoxypiperidine-l-sulfonylmethyl]-5-methyl]-imidazolidine-2,4-dione LC-MS (APCI) m/z 386 (MH+). 1H NMR (DMSO- d6): δ 10.75 (1 H, s); 8.02 (1 H, s); 7.17-6.97 (2 H, m); 4.52-4.43 (1 H, m); 3.17-3.06 (2 H, m); 2.00-1.89 (2 H, m); 1.75-1.62 (2 H, m); 1.33 (3 H, s). (5S)-5-[4-(3-Fluoro-phenoxy)piperidine-l-sulfonylmethyl]-5-methyl]-imidazolidine-2.4-dione LC-MS (APCI) m/z 386 (MH+). 1H NMR (DMSO- d6): δ 10.72 (1 H, s); 8.02 (1 H, s); 7.36-7.26 (1 H, m); 6.91-6.71 (3 H, m); 4.62-4.52 (1 H, m); 3.18-3.06 (2 H, m); 2.02-1.91 (2 H, m); 1.78-1.63 (2 H, m); 1.33 (3 H, s). WO 02/07^26?- PCT££02/WUZ2 (5S)-5-[4-(2-Fluoro-phenoxy)-piperidine-l-sulfonylmethyl]-5-methyl-imidazolidine-2.4-dione LC-MS (APCI) m/z 386 (MH+). 1HNMR (DMSO- d6): δ 10.74 (1 H, s); 8.01 (1 H, s); 7.28-7.17 (2 H, m); 7.17-7.08 (1 H, m); 7.02-6.97 (1 H, m); 4.59-4.47 (1 H, m); 2.04-1.92 (2 H, m); 1.80-1.67 (2 H, m); 1.33 (3 H, s). (5S)-5-[4-(5-Methoxy-pvridin-2-yloxy)-piperidine-l-sulfonylmethyl]-5-methyl-imidazolidine-2,4-dione LC-MS (APCI) m/z 399 (MH+). lH NMR (DMSO- d6): δ 10.74 (1 H, s); 8.01 (1 H, s); 7.89 (1 H, d, 7=3.16 Hz); 7.39 (1 H, dd, 7=3.18, 9.07 Hz); 6.77 (1 H, d, 7=8,95 Hz); 5.08-4.96 (1 H, m); 3.76 (3 H, s); 3.51, 3.34 (1 H each, ABq, 7=14.7 Hz); 3.43-3.29 (2 H, m); 3.18-3.05 (2 H, m); 2.05-1.94 (2 H, m); 1.77-1.61 (2 H, m); 1.33 (3 H, s). (5S)-5-Methyl-5-[4-(4-pyridin-3-yl-phenyl)-piperazin6-l-sulfonylmethyl]-imidazoIidine-2.4-dione LC-MS (APCI) m/z 430 (MH+). 1H NMR (DMSO- d6): δ 10.76 (1 H, s); 8.99 (1 H, s); 8.60 (1 H, d, J=4.91 Hz); 8.35 (1 H, d, J=7.81 Hz); 8.04 (1 H, s); 7.70 (2 H, d, J=8.87 Hz); 7.32 (2 H, d, J=8.91 Hz); 3.57 (1 H from ABq); 3.35 (4 H, m); 3.27 (4 H, m); 1.33 (3 H, s). (5S)-5-methyl-5-({[4-(pyridin-2-yloxy)piperidin-l-yl]sulfonyl}methyl]imidazolidine-2.4-dione LC-MS (APCI) m/z 369 (MH+). 1H NMR (CDCl3): δ 1.73 (3H, s); 1.96-2.04 (2H, m); 2.04-2.13 (2H, m); 3.21 (1H, d); 3.36-3.42 (3H, m); 3.45-3.50 (2H, m); 5.29-5.33 (1H, m); 6.30 (1H, bs); 6.78 (1H, d); 6.93 (1H, t); 7.65 (1H, t); 7.70 (1H, bs); 8.16 (1H, d). 02/074767 9eT7SEOl700472 (5S)-5-[({4-[(3,4-dimethyl]benzyl)oxy]piperidin-l-yl}sulfonyl)methyl]-5-methylimidazolidine-2,4-dione (NB. contains 30% of the 2,3-dimethyl isomer which was in the starting material) LC-MS(APCI)m/z410(MH+). 1H NMR (DMSO-d6): δ 1.3 (3H, s); 1.53- 1.64 (2H, m); 1.83-1.89 (2H, m); 2.18 (3H, s); 2.20 (3H, s); 2.95-3.33 (2H, m); 3.25-3.31 (3H, m); 3.45 (1H, d); 3.45-3.53 (1H, m); 4.42 (2H, s); 7.01-7.15 (3H, m); 7.97 (1H, s); 10.70 (1H, s). (5S)-5-methyl-5-{[(4-phenoxypiperidin-l-yl)sulfonynmethyl}imidazolidine-2,4-dione LC-MS (APCI) m/z 368 (MH+). lHNMR(DMSO-d6): δ 1.30 (3H, s); 1.64-1.73 (2H, m); 1.92-2.00 (2H, m); 3.08-3.15 (2H, m); 3.28-3.44 (4H, m); 4.49-4.54 (1H, m); 6.92 (1H, t); 6.96 (2H, d); 7.28 (2H, t); 7.69 (1H, bs);l0.7(1 H,bs). 4-Fluoro-N-[I-((4S)-4-methyl-2.5-dioxo-imidazolidin-4-ylmethanesulfonyl)-piperidin-4-yl]-ben2amide LC-MS (APCI) m/z 413 (MH+). 1H NMR (DMSO- d6): δ 10.73 (1 H, s); 8.34 (1 H, d, 7=7.50 Hz); 8.02 (1 H, s); 7.94-7.88 (2 H, m); 7.33-7.26 (2 H, m); 3.96-3.86 (1 H, m); 3.58-3.47 (2 H, m); 3.51, 3.32 (l.H each, ABq, 7=14.81 Hz); 2.97-2.88 (2 H, m); 1.92-1.84 (2 H, m); 1.62-1.48 (2 H, m); 1.33 (3 H, s). (5S)-5-[({4-[(2.5-dimethylbenzyl)oxy]piperidin-l-yl)sulfonyll)methyl-5- methylimidazolidine-2,4-dione LC-MS (APCI) m/z 410 (MH+). 1H NMR (DMSO-d6): δ 1.30 (3H, s); 1.54-1.62 (2H, m); 1.85-1.91 (2H, m); 2.21 (3H, s); 2.24 (3H, s); 2.97-3.03 (2H, m); 3.27-3.34 (3H, m); 3.45 (1H, d); 3.49-3.55 (1H, m); 6.97-7.04 (2H, m); 7.11 (1H, s); 7.98 (1H, s); 10.70 (1H, s). WO 02/074767 PCT7SE02/00472 (5S)-5-{[4-5-chloropyridin-2-yl)piperidin-l-yl]sulfonyl}-5-methylimidazolidine-2,4-dione LC-MS (APCI) m/z 3 87 (MH+). 1H NMR (DMSO-d6): δ 10.72 (1 H, s); 8.54 (1 H, d); 8.01 (1 H, s); 7.86 (1 H, dd); 7.38 (1 H, d); 3.61 (2 H, bt); 3.50, 3.32 (1 H each, ABq, 7=14.9 Hz); 2.96-2.76 (3 H, m); 1.92 (2 H, brd); 1.77-1.62 (2 H, m); 1.33 (3 H, s). (5S)-5-[4-(5-Benzyloxy-pyridin-2-yloxy)-piperidine-l-sulfonylmethyl]-5-methyl-imidazolidine-2.4-dione LC-MS (APCI) m/z 475 (MH+). 1H NMR (DMSO-d6): δ 10.73 (1H, s); 8.01 (1H, s); 7.90 (1H, d, J=3.13 Hz); 7-48-7.30 (6H, m); 6.76 (1H, d,J=8.97Hz); 5.10 (2H, s); 5.054.98 (1H, m); 3.51 (1H (from ABq), J=14.84 Hz); 3.40-3.30 (3H, m); 3.15-3.07 (2H, m); 2.07-1.95 (2H, m); 1.74-1.64 (2H, m); 1.33 (3H,s). (5S)-5-[4-(6-Chloro-pyridine-3-yloxl)-piperidine-l-sulfonylmethyl] -5-methyl-imidazolidine-2,4-dione LC-MS (APCI) m/z 403 (MH+). 1H NMR (DMSO-d6): δ 10.74 (1H, s); 8.17 (1H, d, 7=3.10 Hz); 8.01 (1H, s); 7.56 (1H, dd, J=3.18, 8.80 Hz); 7.44 (1H, d, 7=8.77 Hz); 4.67-4.59 (1H, m); 3.52, 3.35 (2H, ABq, J=15.22 Hz); 3.39-3.28 (2H, m); 3.17-3.08 (2H, m); 2.03-1.93 (2H, m); 1.77-1.67 (2H, m); 1.33 (3H,s). (5S)-5-[4-(5-Hydroxy-pyridin-2-yloxy)-piperidine-l-sulfonylmethyl]-5-methyl-imidazoIidine-2.4-dione LC-MS (.APCI) m/z 385 (MH+). 1H NMR (Methanol-d4): δ 7.73 (1H, d, 7=3.01 Hz); 7.53 (1H, dd, J=3.11, 9.03 Hz); 7.04 WO 02/074767 PCT/SE02/00472 130 (1H, d, J=9.04 Hz); 3.80-3.67 (1H, m); 3.58," 3.41 (2H, ABq, J=15.04 Hz); 3.53-3.42 (2H, m); 3.36-3.18 (2H, m); 2.17-2.02.(2H, m); 1.96-1.81 (2H, m); 1.48 (3H, s). (5S)-5-[4-(4-Chloro-phenylsulfanyl)-piperidine-l-sulfonylmethyl]-5-methyl-imidazolidine-2,4-dione LC-MS (APCI) m/z 418 (MH+). . 1H NMR (DMSO-d6): δ 10.74 (1H, s); 8.00 (1H, s); 7.45-7.39 (4H, m); 2.97-2.89 (2H, m); 2.00-1.91 (2H, m); 1.56-1.45 (2H, m); 1.31 (3H, s). (5S)-5-[4-(4-Chloro-benzenesu]fonyl)-piperidine-l-sulfonylmethyl]-5-methyl-imidazolidine-2,4-dione LC-MS (APCI) m/z 450 (MH+). 1H NMR (DMSO-d6): δ 10.73 (1H, s); 7.99 (1H, s); 7.86 (2H, d, J=8.77 Hz); 7.77 (2H, d, J-8.75 Hz); 3.66-3.54 (2H, m); 3.50-3.41 (1H, in); 3.44, 3.32 (1H each, ABq, 7=14.63 Hz); 2.82-2.73 (2H, m); 1.97-1.88 (2H, m); 1.57-1.42 (2H, m); 1.30 (3H, s). (5SV5-[4-f4-Fluoro-phenylamino)-piperidine-l-sulfonylmethyl)-5-methyl-imidazolidine-2,4-dione LC-MS (APCI) m/z 385 (MH+). 1H NMR (Methanol-d4): δ 7.20-7.11 (4H, m); 3.84-3.71 (2H, m); 3.60-3.48 (1H, m); 3.56, 3.39 (1H each, ABq, 7=14.96 Hz); 2.97-2.84 (2H, m); 2.10-2.00 (2H, m); 1.69-1.53 (2H, m); 1.46 (3H,s). N-(3-[l-((4S)-4-Methyl-2.5-dioxo-imidazoIidin-4-ylmethanesulfonyl)-piperidin-4-vloxvI-phenyl}-acetamide LC-MS (APCI) m/z 425 (MH+). lH NMR (DMSO-d6): δ 10.74 (1H, s); 9.89 (1H, s); 8-01 (1H, s); 7.37-7.33 (1H, m); 7.21- 7.14 (1H, m); 7.08-7.03 (1H, m); 6.65 (1H, dd,J=1.89, 8.04 Hz); 4.49-4.42 (1H, m); 3.51, 3.34 (1H each, ABq, 7=14.73 Hz); 3.39-3.28 (2H, in); 3.18-3.08 (2H, m); 2.02 (3H, s); 2.00-1.92 (2H, m); 1.76-1.65 (2H, m); 1.33 (3H, s). (5S)5-[4-(4-Chloro-benzoyl)-piperazine-l-sulfonylmethyl]-5-methyl-imidazolidine 2,4-dione LC-MS (APCI) m/z 415 (MH+). 1H NMR (DMSO-d6): δ 10.75 (1H, s); 8.04 (1H, s); 7.54 (2H, d,.J=8.38 Hz); 7.45 (2H, d, J=8.38 Hz); 3.79-3.55 (2H, bs); 3.56, 3.35 (1H each, ABq, J=14.84 Hz); 3.51-3.31 (2H, 3.27-3.06 (4H,bs); 1.33 (3H,s). l-(4S)-4-methyl-2,5-dioxo-imidazoIidine-4-ylmethanesulfonyl)-Piperidine-4-carboxylic acid (4-fluoro-phenyl-amide LC-MS (APCI) m/z 413 (MH+). 1H NMR (DMSO-d6): δ 10.74 (1H, s); 9.97 (1H, s);. 8.02 (1H, s); 7.65-7.58 (2H, m); 7.16-7.09 (2H, m); 3.62-3.52 (2H, m); 3.49, 3.33 (1H each, ABq, J=14.94 Hz); 2.87-2.77 (2H, m); 2.48-2.39 (1H, m); 1.91-1.84 (2H, m); 1.70-1.57 (2H, m); 1.33 (3H, s). (5S)-5-[4-(5-Bromo-pyridin-2-yloxy)-piperidine-l-sulfonylmethyl]-5-methyl-itnidazolidine-2,4-dione LC-MS (APCI) m/z 447, 449 (MH+). 1H NMR (DMSO-d6): δ 10.73 (1H, s); 8.28 (1H, d, J=2.64 Hz); 8.01 (1H, s); 7.91 (1H, dd, J=2.60, 8.84 Hz); 6.83 (1H, d, 7=8.79 Hz); 5.12-5.05 (1H, m); 3.52,3.35 (1H each,-ABq, WO 02/074767 PCT/SE02/00472 132 7=14.85 Hz); 3.41-3.34 (2H m); 3.17-3.08 (2H, m); 2.06-1.97 (2H, m); 1.78-1.67 (2H, m); 1.33 (3H,s). (5S)5-[4-5-(4-FIuoro-phenyl)-pyridin-2-yl)-piperazine-l-sulfonylmethyl]-5-methyl-imidazolidine-2,4-dione LC-MS (APCI) m/z 448 (MH+). 1HNMR (DMSO-d6): δ 10.75 (1H, s); 8.45 (1H, d, J=2.51 Hz); 8.02 (1H, s); 7.88 (1H, dd, 7=2.57, 8.86 Hz); 7.70-7.62 (2H, m); 7.30-7.22 (2H, m); 6.98 (1H, d, J=8.94 Hz); 3.70-3.62 (4H, m); 3.55, 3.36 (1 H each, ABq, 7=14.73 Hz); 3.26-3-19 (4H, m); 1.32 (3H, s) (5S)-5-[4-(5-(4-Methoxy-phenyl)-pyridin-2-yl)-piperazine-l-sulfonylmethyl]-5-methyl- imidazoIidine-2,4-dione LC-MS (APCI) m/z 460 (MH+). (5S)-5-[4-(5-(4-Chlorophenyl)pyridin-2-vn-piperazine-l-sulfonylmethyl]-5-methyl-imidazolidine-2.4-dione LC-MS (APCI) m/z 464, 466 (MH+). (5S)-5-14-(5-(4-Trifluoromethoxy-pheny1)-pyridin-2-yl)-piperazine-l-sulfonylmethyl]- 5-methyl-imidazolidine-2,4-dione LC-MS (APCI) m/z 514 (MH+). (5S)-5-[4-(5-Furan-2-yl-pvridin-2-yl)-piperazine-l-sulfonylmethyl]-5-methyl- imidazolidine-2.4-dione 25 LC-MS (APCI) m/z 420 (MH+). (5S)-5-Methyl-5-(4-[5-(1H-pyrrol-2-yl)-pyridine-2-yl]-piperazine-l-sulfonylmethyl)-imidazolidine-2,4-dione LC-MS (APCI) m/z 419 (MH+). WO 02/074767 PCT/SE02/00472 133 (5S)-5-(4-[33']-Bipvridiinyl]-6-yll-piperazine-l-sulfonylmethyl)-5-methyl-imidazolidine-2,4-dione LC-MS (APCI) m/z 431 (MH+). (4S)-4-(6-[4-(4-Methyl-2.5-dioxo-imidazolidin-4-ylmethanesulfonyl)-piperazine-l-yl]- pyridine-3-yl)-benzonitrile LC-MS (APCI) m/z 455 (MH+). EXAMPLE 14 Compounds with the general formula 15 were synthesised according to the method described in Example 12. WO 027074767 PCT02/00472 (1): NMR available, see experimental part. 5-[({4-([5-chloropyridin-2-yl)oxy]piperidin-l-vl}sulfonyl)methyl]-5-[(3,4,4-trimethyl-2.5-dioxoimidazolidm-l-yl)methyl]imidazolidine-2,4-dione The title compound was prepared as described in Example 12 from racemic {2,5-dioxo-4-[(3 ,4,4-trimethyl-2,5-dioxoimidazoIidin-1 -yl)methyI]imidazolidin-4-yl} methanesulfonyl chloride and 5-chloro-2-(piperidin-4-yloxy)-pyridine. LC-MS (APCI) m/z 543 (MH+). 1HNMR (DMSO-d6): δ 1.28 (6H, s); 1.63-1.74 (2H, m); 1.95-2.05 (2H, m); 2.77 (3H, s); 3.14 (4H, d); 3.53-3.73 (3H, m); 4.14 (1H, q); 5.04-5.11 (1H, m); 6.85 (1H, d); 7.80 (1H, dd); 7.94 (1H, s); 8.19 (1H, d); 10.83 (1H, s). The startingmaterial was prepared as follows: S-[3-(benzylthio)-2-oxopropyl]-1,5,5-trimethylimidazolidine-2,4dione Benzyl mercaptan (256 μl, 2.2 mmol) was stirred with cesium carbonate (712 mg, 2.2 mmol) in dimethyl formamide (5 ml) at room temperature for 1 hour. 3-(3-bromo-2- oxopropyI)-l,5,5-trimethyIimidazolidine-2,4-dione (552 mg, 1.99 mmol) prepared as in W099/06361 was added and the mixture stirred 18 hours at room temperature. The reaction mixture was treated with water, extracted into ethyl acetate (3 x 25 ml), the organic phases combined, brine washed and dried. The product was purified by silica chromatography, eluting with 50% ethyl acetate / iso-hexane to give 300 mg product. LC-MS (APCI) m/z 321 (MH+). 1H NMR (CDC13): μ 1.45 (6H, s); 2.91 (3H, s); 3.16 (2H, s); 3.70 (2H, s); 4.53 (2H, s); 7.22-7.33 (5H, m). WO 02/074767 PCT/SE02/00472 135 S-[(benzylthio)methyl]-5-[(3.4,4-trimethvl-2,5-dioxoirnidazolidin-l-yl)methyl]imidazolidine-2.4-dione The title compound was prepared as described in the synthesis of 5-methyl-5- {[(phenylmethyl)thio]methyl} imidazolidine-2,4-dione in Example 12. LC-MS (APCI) m/z 391 (MH+). 1H NMR (DMSO-d6): δ 1.28 (6H, s); 2.64 and 2.76 (2H, abq, J=14.2 Hz); 2.78 (3H, s); 3.54 & 3.64 (2H, abq, .J=14.2 Hz); 3.73 (2H, s); 7.20-7.32 (5H, m); 7.98 (1H, s); 10.83 (1H, s). (2.5-dioxo-4-[(3,4.4-trimethyl-2,5-dioxoimidazolidin-l-yl)methyl]imidazolidin-4-yl}methanesulfonyl chloride The title compound was prepared as described in the synthesis of [{AS) and (4R)-4-methyl-2,5-dioxoiirndazolidin-4-yl]methanesulfonyl chloride in Example 12. 1H NMR (CD3OD): δ 1.38 (6H, s); 2.89 (3H, s); 3.81 and 3.92 (2H, abq, . J=14.3 Hz); 4.61 (2H, s). The following compounds were prepared as described in the synthesis of5-[({4-[(5-chloropyridin-2-yl)oxy]piperidin-l-yl}sulfonyl)methyl]-5-[(3,4,4-trimethyl-2,5-20/ dioxoimidazolidin-1-yl) methyl]imidazolidine-2,4-dione. m/ 5-[((4-[5-(trifluoromethyl)pyridin-2-yl]piperazin-l-yl}sulfonyl)methyl]-5-[(3,4,4-trimethvi--2,5-dioxoimidazo[idin-l-vnmethvnimidazolidine-2,4-dione LC-MS (APCI) m/z 562 (MH+). 1H NMR (DMSO-d6): δ 1.26 (6H, s); 2.76 (3H, s); 3.16-3r22 (4H, m); 3.48-3.76 (8H, m); 7.02 (1H, d); 7.81-7.76 (2H, m); 8.43 (1H, s); 10.83 (1H, s). WO 02/074767 PCT/SE02/00472 136 5-[4-(4-Fluoro-phenyl-piperazine-l-sulfonylmethyl-5-[(3.4.4-trimethyl-2.5-dioxoimidazolidin-l-yl)methyl]imidazolidine-2,4-dione LC-MS (APCI) m/z 511 (MH+). 1HNMR (DMSO-d6): δ 1.28 (6H, s); 2.77 (3H, s); 3.10-3.16 (4H, m); 3.21-3.26 (4H, m); 3.48-3.71 (4H, m); 6.95-7.09 (4H, m); 7.88 (1H, s); 10.84 (1H, bs). 5-[({4-[(5-chloropvridin-2-vl)oxv|piperidin-l-yl}sulfonyl)methyl]-5-(2-[(phenylmethyl)oxylethyl)imidazolidine-2,4-dione The title compound was prepared as described in the synthesis of 5-[({4-[(5-chloropyridin- 2-yl)oxy]piperidin-1 -yl} sulfonyl)methyl]-5-[(3,4,4-trimethyl-2,5-dioxoimidazolidin-1 -yl)methyl]imidazolidine-2,4-dione starting from 5-Chloro-2-(piperidine-4-yloxy)-pyridine hydrochloride and (2,5-dioxo-4-{2-[(phenylmethyl)oxyJethyl}imidazolidin-4-yl)methanesulfonyl chloride. LC-MS (APCI) m/z 523 (MH+). 1H NMR (DMSO-d6): δ 1.37-1.79 (3H, m); 1.83-2.08 (4H, m); 3.00-3.56 (7H, m partially obscured by D20); 4.33-4.44 (2H, m); 5.01-5.12 (1H, m); 6.85 (1H, d); 7.21-7.36 (5H, m); 7.80 (1H, dd); 8.02 (1H, s);8.19(1H,d); 10.70(1H,bs). 6-({4-[(5-chloropyridin-2-yl)oxy]piperidin-l-yl)sulfonyl)-l,3-diazaspiro[4.51decane- 2.4-dione LC-MS (APCI) m/z 443 (MH+). The startingmaterial was prepared as follows: 6-[(phenylmethyl)thio]-1.3-diazaspiror4.5]decane-2,4-dione Benzylmercaptan (937mg3 7.5mmol) was dissolved in 70 mL of THF. NaH (362mg 60%, 9.0mmol) was added and the slurry was stirred for some minutes. 2-chlorocyclohexanone (l.0g, 7.5mmof) was added and the reaction was stirred at it over night. The solid was filtered of and the solvent was removed by rotary evaporation. Potassium cyanid (4 eq), WO 02/074767 PCT/SE02/00472 (NH4)2O3 (8eq) and 25mL of ethanol was added. The reaction was stirred in a sealed vial at 80°C over night. The suspension was filtered and the solid was recrystallised from DMSO and water to give the title compound as a white solid LC-MS (APCI) m/z 291 (MH+). 1H NMR (DMSO-d6): δ 1.21-1.81 (8H, m); 2.79 (1H, dd); 3.67-3.76 (2H, m); 7.18-7.32 (5H, m); 8.43 (1H, s); 10.68 (1H, s). EXAMPLE 15 5-Methyl-5-(l-(toluene-4-sulfonyl)-cyclopentyl)-imidazolidine-2,4-dione l-(l-(Toluene-4-sulfonyl)-cyclopentyl))-ethanone (0.10 g, 0.38 mmol), potassium cyanide (0.049 g, 0.75 mmol), ammonium carbonate (0.18 g, 1.9 mmol), 50% ethanol in water (1.6 mL) were stirred in a sealed tube (2 mL volume) at 90°C for 70 hours. The solution was acidified with 10% acetic acid to pH 6 and concentrated by rotary evaporation to half of its original volume upon which part of the product fell out. The solution and its solid contents were taken up in ethyl acetate, the aqueous phase was separated and washed twice with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated by rotary evaporation to give 0.74 g of a white solid. The crude product was dissolved in methanol (5 mL), concentrated with silica (1 g) by rotary evaporation and applied on a short silica column. Elution with ethyl acetate/ n-heptane (1:2 and 2:2) gave 0.060 g (48%) of the title product as colourless needles. LC-MS (APCI) m/z 337 (MH+). 1H NMR (DMSO-d6): δ 0.96-1.10 (lH,m); 1.324.44 (1H, m); 1.36 (3H, s); 1.47-1.58 (2H, m); 2.10-2.30 (4H, m); 2.40 (3H, s); 7.41 (2H, d,J= 8 Hz); 7.72 (2H, d, J= 8 Hz); 7.80 (1H, bs) and 10.7 (1H, bs). WO 02/074767 PCT/SE02/00472 13C NMR(DMSO-d6): δ 21.0, 22.60,22.64,26.1, 26.3, 30.8,31.5, 64.1, 78.9, 129.2, 130.3, 135.3, 144.2, 156.0 and 176.2. The starting material was prepared as follows: l-(Toluene-4-sulfonyl)-propan-2-one was prepared according to Crandall et al. J. Org. Chem. 1985, (8) 50, 1327-1329 from sodium p-toluensulfinate dihydrate (4.2 g, 18 mmol), chloroacetone (1.0 mL, 12 mmol), n-tetrabutylammonium bromide (0.30 g) and water-benzene-acetone 4:3:3 (10 mL). Work-up and chromatography on silica of the crude using ethyl acetate/ n-heptane (1:3 through 1:2) as eluent gave 2.4 g (95%) of the title product as an oil which crystallised on standing in the fridge. LC-MS (APCI) m/z 213 (MH+). 1H NMR (CDC13): δ 2.38 (3H, s); 2.42 (3H, s); 4.10 (2H, s); 7.35 (d2H, d, J= 8 Hz); 7.74 (d, 2 H, d, J= 8 Hz). 13C NMR (CDCI3): 5 21.7, 31.4, 67.7, 128.0,129.8, 135.5, 145.3 and 195.9. 1 -(1 -(Toluene-4-sulfonyl)-cvclopentyl)-ethanone l-(Toluene-4-sulfonyl)-propan-2-one (0.10 g, 0.47 mmol), 1,4-diiodobutane (0.068 mL, 0.52 mmol), finely ground potassium carbonate (0.14 g, 1.0 mmol) and dry dimethylsulfoxide (0.80 mL) were stirred at 50° C (oil bath temperature) for 22 hours. The heating was shut off and stirring was continued at 22° C for 22 hours. The crude product was taken up in ethyl acetate, washed with water (5x 50 mL) and brine (1x 50 mL), dried over anhydrous sodium sulfate, filtered and concentrated by rotary evaporation. The oily residue was chromatographed on silica using ethyl acetate/ n-heptane (1:4 through 1:3) to give 0.10 g (80%) of the title product as a colourless oil. LC-MS (APCI) m/z 267 (MH+). 1H NMR (CDCl3): δ 1.52 (2H, m); 1.77 (2H, m); 2.26 (2H, m); 2.37 (2H, m); 2.42 (3H, s); 2.48 (3H, s); 7.30 (2H, d, J= 8 Hz) and 7.60 (2H, d, 7= 8 Hz). 13C NMR (CDCI3): 5 21.7, 25.4, 28.0, 31.3, 83.9, 129.4, 129.5,133.2, 145.0 and 202.5." WE CLAIM: 1. A compound of the formula I or a pharmaceutically acceptable salt thereof wherein X is selected from NR1, O, S; Yl and Y2 are independently selected from O, S; Z is selected from SO, SO2; m is 1 or 2; A is selected from a direct bond, (Cl-6)alkyl, (Cl-6)haloalkyl, or (Cl-6)heteroalkyl containing a hetero group selected from N, O, S, SO, S02 or containing two hetero groups selected from N, O, S, SO, S02 and separated by at least two carbon atoms; Rl is selected from H, (C l-3)alkyl, haloalkyl; Each R2 and R3 is independently selected from H, halogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, alkyl-heteroaryl, heteroalkyl-aryl, heteroalkyl-heteroaryl, aryl-alkyl, aryl- heteroalkyl, heteroaryl-alkyl, heteroaryl-heteroalkyl,aryl-aryl, aryl-heteroaryl, heteroaryl-aryl, heteroaryl-heteroaryl, cycloalkyl-alkyl, heterocycloalkyl-alkyl, alkyl-cycloalkyl, alkyl-heterocycloalkyl; Each R4 is independently selected from H, halogen, (Cl-3)alkyl or haloalkyl; Each of the R2 and R3 radicals may be independently optionally substituted with one or more groups selected from alkyl, heteroalkyl, aryl, heteroaryl, halo, haloalkyl, hydroxy, alkoxy, haloalkoxy, thiol, alkylthiol, arylthiol, alkylsulfon, haloalkylsulfon, arylsulfon, aminosulfon, N-alkylaminosulfon, N,N-dialkylaminosulfon, arylaminosulfon, amino, N-alkylamino, N,N-dialkylamino, amido, N-alkylamido, N,N-dialkylamido, cyano, sulfonamino, alkylsulfonamino, arylsulfonammo, amidino, N-aminosulfon-amidino, guanidino, N-cyano-guanidino, thioguanidino, 2-nitro-ethene-1,1-diamin, c'arboxy, alkyl-carboxy, nitro, carbamate; Optionally R2 and R3 may join to form a ring comprising up to 7 ring atoms, or R2 and R4 may join to form a ring comprising up to 7 ring atoms, or R3 and R4 may join to form a ring comprising up to 7 ring atoms; R5 is a monocyclic, bicyclic or tricyclic group comprising one, two or three ring structures each of up to 7 ring atoms independently selected from cycloalkyl, aryl, heterocycloalkyl or heteroaryl, with each ring structure being independently optionally substituted by one or more substituents independently selected from halogen, hydroxy, alkyl, alkoxy, haloalkoxy, amino, N-alkylamino, N,N-dialkylamino, alkylsulfonamino, alkylcarboxyamino, cyano, nitro, thiol, alkylthiol, alkylsulfonyl, haloalkylsulfonyl, alkylaminosulfonyl, carboxylate, alkylcarboxylate, amino carboxy, N-alkylamino-carboxy, N,N-dialkylamino-carboxy, wherein any alkyl radical within any substituent may itself be optionally substituted with one or more, groups selected from halogen, hydroxy, alkoxy, haloalkoxy, amino, N-alkylamino, N,N-dialkylamino, N-alkylsulfonamino, N-alkylcarboxyamino, cyano, nitro, thiol, alkylthiol, alkylsulfonyl, N- alkylaminosulfonyl, carboxylate, alkyl carboxy, aminocarboxy, N-alkylaminocarboxy, N,N-dialkylaminocarboxy, carbamate; when R5 is a bicyclic or tricyclic group, each ring structure is joined to the next ring structure by a direct bond, by -O-, by (Cl-6)alkyl, by (Cl-6)haloalkyl, by (Cl-6)heteroalkyl, by (Cl-6)alkenyl, by (Cl-6)alkynyl, by sulfone, by CO, by NCO, by CON, by NH, by S, by C(OH) or is fused to the next ring structure. 2. A compound of the formula I as claimed in claim 1 or a pharmaceutically acceptable salt thereof, wherein X is NRI, Z is SO2 or SO, at least one of Yl and Y2 is 0, m is 1, and Rl is H, (C1-3) alkyl, or (C1-3) haloalkyl. 3. A compound of the formula I as claimed in either claim 1 or claim 2 or a pharmaceutically acceptable salt thereof, wherein R2 is H, alkyl, hydroxyalkyl, alkoxyalkyl, aryloxy alkyl, aminoalkyl, cycloalkyl-alkyl, alkyl-cycloalkyl, arylalkyl, alkylaryl, alkyl-heteroaryl, heteroalkyl, heterocycloalkyl-alkyl, alkyl-heterocycloalkyl, heteroaryl-alkyl, heteroalkyl-aryl. 4. A compound of the formula I as claimed in any of the preceding claims or a pharmaceutically acceptable salt thereof, wherein each of R3 and R4 is independently selected from H, methyl. 5. A compound of the formula I as claimed in any of the preceding claims or a pharmaceutically acceptable salt or thereof, wherein R5 comprises one, two or three optionally substituted aryl or heteroaryl 5 or 6 membered rings, 6. A compound of the formula I as claimed in any-of the preceding claims or a pharmaceutically acceptable salt thereof, wherein R5 is a bicyclic or tricyclic group comprising two or three optionally substituted ring structures. 7. A compound of the formula II or a pharmaceutically acceptable salt thereof wherein each of G1, G2 and G4 is a monocyclic ring structure comprising each of up to 7 ring atoms independently selected from cycloalkyl, aryl, heterocycloalkyl or heteroaryl, with each ring structure being independently optionally substituted by one or two substituents independently selected from halogen, hydroxy, haloalkoxy, amino, N-alkylamino, N,N-dialkylamino, cyano, nitro, alkyl, alkoxy, alkyl sulfone, haloalkyl sulfone, alkylcarbamate, alkylamide, wherein any alkyl radical within any substituent may itself be optionally substituted with one or more groups selected from halogen, hydroxy, amino, N-alkylamino, N,N-dialkylamino, cyano, nitro, alkoxy, haloalkoxy, aryloxy, heteroaryloxy, . carbamate; Z is S02; each of B and F is independently selected from a direct bond, O, (Cl-6)alkyl, (Cl-6)heteroalkyl, alkynyl, CO, NCO, CON, NH, S; R2 is selected from H, alkyl, hydroxyalkyl, alkoxyalkyl, aryloxy alkyl, aminoalkyl, (N-alkylamino) alkyl, (N,N-dialkylamino )alkyl, amidoalkyl, thioalkyl cycloalkyl-alkyl, alkyl-cycloalkyl, arylalkyl, alkylaryl, alkyl-heteroaryl, heteroalkyl, heterocycloalkyl-alkyl, alkyl-heterocycloalkyl, heteroaryl-alkyl, heteroalkyl-aryl; R3 and R4 are independently selected from H or (Cl-3)alkyl; Optionally R2 and R3 may join to form a ring comprising up to 7 ring atoms, or R2 and R4 may join to form a ring comprising up to 7 ring atoms, or R3 and R4 may join to form a ring comprising up to 7 ring atoms. 8. A compound of the formula II as claimed in claim 7 or a pharmaceutically acceptable salt thereof, wherein R2 is alkyl, aminoalkyl, alkyl-heteroaryl, alkyl-heterocycloalkyl or heteroaryl-alkyl. 9. A compound of the formula IIa or a pharmaceutically acceptable salt thereof. wherein each of G1 and G2 is a monocyclic ring structure comprising each of up to 7 ring atoms independently selected from cycloalkyl, aryl, heterocycloalkyl or heteroaryl, with each ring structure being independently optionally substituted by one or two substituents independently selected from halogen, hydroxy, haloalkoxy, amino, N-alkylamino, N,N-dialkylamino, cyano, nitro, alkyl; alkoxy, alkyl sulfone, halo alkyl sulfone, alkylcarbamate, alkylamide, wherein any alkyl radical within any substituent may itself be optionally substituted with one or more groups selected from halogen, hydroxy, amino, N-alkyl amino, N,N-dialkyamino, cyano, nitro, alkoxy, haloalkoxy, aryloxy, heteroaryloxy, carbamate; Z is S02; B is selected from a direct bond, O, (Cl-6)alkyl, (Cl-6)heteroalkyl, CO, NCO,CON, NH, S, akynyl; R2 is selected from H, (Cl-6)alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, (N-alkylamino)alkyl, (N,N-dialkylamino)alkyl, amidoalkyl, thioalkyl, or R2 is a group of formula III C and D are independently selected from a direct bond, H, (CI-C6)alkyl, (Cl-C6)haloalkyl, or (Cl-C6)heteroalkyl containing one or two hetero atoms selected from N, O or S such that when two hetero atoms are present they are separated by at least two carbon atoms; G3 is a monocyclic ring structure comprising up to 7 ring atoms independently selected from cycloalkyl, aryl, heterocycloalkyl or heteroaryl, optionally substituted by one or two substituents independently selected from halogen, hydroxy, amino, N-alkylamino,N,N-dialkylamino, cyano, nitro, alkyl, alkoxy, alkyl sulfone, haloalkyl sulfone, or alkyl substituted with one or more groups selected from halogen, hydroxy, amino, N-alkylamino, N,N-dialkylamino, cyano, nitro, alkoxy, haloalkoxy; Optionally R2 is substituted with halo, haloalkyl, hydroxy, alkoxy, haloalkoxy, amino, aminoalkyl, N-alkylamino, N,N-dialkylamino, (N-alkylamino)alkyl, (N,N-dialkylamino)alkyl, alkylsulfone, aminosulfone, N-alkylamino-sulfone, N ,N-dialkylamino-sulfone, amido, N-alkylamido, N,N-dialkylamido, cyano, sulfonamino, alkyl-sulfonamino, amidino, N-aminosulfone-amidino, guanidino, N-cyano-guanidino, thioguanidino, 2-nitroguanidino, carboxy, alkylcarboxy, carbamate; R3 and R4 are independently selected from H or (Cl-3)alkyl; Optionally R2 and R3 may join to form a ring comprising up to 7 ring atoms, or R2 and R4 may join to form a ring comprising up to 7 ring atoms, or R3 and R4 may join to form a ring comprising up to 7 ring atoms. wherein 10. A compound of the formula IIa as claimed in claim 9 or a pharmaceutically acceptable salt thereof, wherein B is selected from a direct bond, O, CO, S, alkynyl. 11. A compound of the formula Ha as claimed in either claim 9 or claim 10 or a pharmaceutically acceptable salt thereof, wherein R2 is selected from H, (CI-6)alkyl, aryl-(CI-6)alkyl or heteroaryl-(Cl-6)alkyl optionally substituted with halo, haloalkyl, hydroxy, alkoxy, haloalkoxy, amino, aminoalkyl, N-alkylamino, N,N-dialkylamino, (N-alkylamino)alkyl, (N,N-dialkylamino)alkyl, alkylsulfone, aminosulfone, N-alkylamino-sulfone, N,N-dialkylamino-sulfone, amido, N-alkylamido, N,N-dialkylamido, carbamate, cyano, sulfonamino, alkyl-sulfonamino, amidino, N-aminosulfone-amidino, guanidino, N-cyano-guanidino, thioguahidino, 2-nitro-amidino, 2-nitro-ethene- I, I -diamino, carboxy, alkyl carboxy, carbamate. 12. A compound of the formula IIa as claimed in any of claims 9 to 11 or a pharmaceutically acceptable salt thereof, wherein each of R3 and R4 is H. 13. A compound of the formula IIb or a pharmaceutically acceptable salt thereof Gl is a monocyclic ring structure comprising each of up to 7 ring atoms independently selected from cycloalkyl, aryl, heterocycloalkyl or heteroaryl, with each ring structure being independently optionally substituted by one or two substituents independently selected from halogen, hydroxy, haloalkoxy, amino, N-alkylamino, N,N-dialkylamino, cyano, nitro, alkyl, alkoxy, alkyl sulfone, haloalkyl sulfone, alkyl carbamate, alkylamide, wherein any alkyl radical within any substituent may itself be optionally substituted with one or more groups selected from halogen, hydroxy, amino, N-alkylamino, N,N-dialkylamino, cyano, nitro, alkoxy, haloalkoxy, aryloxy, heteroaryloxy, carbamate; G2 is optionally substituted piperidine or piperazine; B is selected from a direct bond, O, (Cl-6)alkyl, (Cl-6)heteroalkyl, CO, NCO, CON, NH, S, akynyl; R2 is selected from H, (Cl-6)alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, (N-alkylamino)alkyl, (N,N-dialkylamino)alkyl, amidoalkyl, thioalkyl, or R2 is a group of formula III C and D are independently selected from a direct bond, H, (CI-C6)alkyl, (Cl-C6)haloalkyl, or (Cl-C6)heteroalkyl containing one or two hetero atoms selected from N, O or S such that when two hetero atoms are present they are separated by at least two carbon atoms; G3 is a monocyclic ring structure comprising up to 7 ring atoms independently selected from cycloalkyl, aryl, heterocycloalkyl or heteroaryl, optionally substituted by one or two substituents independently selected from halogen, hydroxy, amino, N-alkylamino, N,N-dialkylamino, cyano, nitro, alkyl, alkoxy, alkyl sulfone, haloalkyl sulfone, or alkyl substituted with one or more groups selected from halogen, hydroxy, amino, N-alkylamino, N,N-dialkylamino, cyano, nitro, alkoxy, haloalkoxy; Optionally R2 is substituted with halo, haloalkyl, hydroxy, alkoxy, haloalkoxy, amino, aminoalkyl, N-alkylamino, N,N-dialkylamino, (N-alkylaminojalkyl, (N,N-dialkylamino)alkyl, alkylsulfone, aminosulfone, N-alkylamino-sulfone, N,N-dialkylamino-sulfone, amido, N-alkylamido, N,N-dialkylamido, cyano, sulfonamino, alkyl-sulfonamino, amidino, N-aminosulfone-amidino, guanidino, N-cyano-guanidino, thioguanidino, 2-nitroguanidino, carboxy, alkylcarboxy, carbamate; R3 and R4 are independently selected from H or (Cl-3)alkyl; Optionally R2 and R3 may join to form a ring comprising up to 7 ring atoms, or R2 and R4 may join to form a ring comprising up to 7 ring atoms, or R3 and R4 may join to form a ring comprising up to 7 ring atoms. 14. A pharmaceutical composition which comprises a compound of the formula I as claimed in claim 1 or a compound of the formula II as claimed in claim 7 or a compound of the formula IIa as claimed in claim 9 or a compound of the formula IIb as claimed in claim 13 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. Dated this August 27, 2003. (RANJAN MEHTA DUTT) OF REMFRY AND SAGAR ATTORNEY FOR THE APPLICANTS

Documents:

805-mumnp-2003-cancelled page(10-11-2005).pdf

805-mumnp-2003-claim(granted)-(10-11-2005).pdf

805-mumnp-2003-claims(granted)-(10-11-2005).doc

805-mumnp-2003-correspondence(02-11-2005).pdf

805-mumnp-2003-correspondence(ipo)-(25-04-2006).pdf

805-mumnp-2003-form 19(27-08-2003).pdf

805-mumnp-2003-form 1a(10-11-2005).pdf

805-mumnp-2003-form 1a(21-08-2003).pdf

805-mumnp-2003-form 2(granted)-(10-11-2005).doc

805-mumnp-2003-form 2(granted)-(10-11-2005).pdf

805-mumnp-2003-form 3(10-11-2005).pdf

805-mumnp-2003-form 3(27-08-2003).pdf

805-mumnp-2003-form 5(27-08-2003).pdf

805-mumnp-2003-form-pct-ipea-409(10-11-2005).pdf

805-mumnp-2003-form-pct-isa-210(10-11-2005).pdf

805-mumnp-2003-petition under rule 137(10-11-2005).pdf

805-mumnp-2003-petition under rule 138(10-11-2005).pdf

805-mumnp-2003-power of authority(10-11-2005).pdf

805-mumnp-2003-power of authority(18-08-2003).pdf