Inosine-5'-monophosphate dehydrogenase (IMPDH ; EC 1.1. 1.205) is an enzyme involved in the de novo synthesis of guanine nucleotides. IMPDH catalyses the ß-nicotinamide adenine dinucleotide (NAD) -dependant oxidation of inosine-5'-monophosphate (IMP) to xanthosine-5'-monophosphate (XMP) (Jackson R. C. et al., Nature, 256, pp. 331-333, (1975) ). Guanine nucleotides are essential to the cell for RNA and DNA synthesis, intermediates in signaling pathways and as energy sources for metabolic pathways.

IMPDH is ubiquitous in eukaryotes, bacteria and protozoa (Y. Natsumeda & S. F. Carr, Ann. N. Y. Acad., 696, pp. 88-93, (1993) ). Two isoforms of human IMPDH, designated type I and type 11, have been identified and sequenced (F. R. Collart and E. Huberman, J. Biol. Chem., 263, pp. 15769-15772, (1988); Y. Natsumeda et al J. Biol. Chem., 265, pp 5292-5295, (1990) ). Each is 514 amino acids and they share 84% sequence identity. Both IMPDH type I and type 11 form active tetramers in solution, with subunit molecular weights of 56 kDa (Y. Yamada et. al., Biochemistry, 27, pp. 2737-2745, (1988)). It is thought that type I is the predominant isoform expressed in normal cells, whilst type 11 is upregulated in neoplastic and replicating cells. Studies have postulated that selective inhibition of type 11 IMPDH could provide a therapeutic advantage by reducing potential toxicity effects caused by inhibiting the type I isoform (Pankiewicz K. W, Expert Opin. Ther. Patents 11 (7) pp 1161-1170, (2001)).

The de novo synthesis of guanine nucleotides, and thus the activity of IMPDH, is particularly important in B and T-lymphocytes. These cells depend on the de novo, rather than the salvage pathway to generate sufficient levels of nucleotides necessary to initiate a proliferative response to mitogen or antigen

(A. C. Allison et. al., Lancet II, 1179, (1975) and A. C. Allison et. al., Ciba Found. Svmp., 48,207, (1977) ). Thus, IMPDH is an attractive target for selectively inhibiting the immune system without also inhibiting the proliferation of other cells.

Mycophenolic acid (MPA) and some of its derivatives have been described in United States patents 5,380, 879 and 5,444, 072 and PCT publications WO 94/01105 and WO 94/12184 as potent, uncompetitive, reversible inhibitors of human IMPDH type) (K, = 33 nM) and type)) (K, = 9 nM). MPA has been demonstrated to block the response of B and T-cells to mitogen or antigen (A. C. Allison et. al., Ann. N. Y. Acad. Sci., 696,63, (1993) ).

Immunosuppressants, such as MPA, are useful drugs in the treatment of transplant rejection and autoimmune diseases. (R. E. Morris, Kidney Intl., 49, Suppl. 53, S-26, (1996) ). However, MPA is characterized by undesirable pharmacological properties, such as gastrointestinal toxicity. (L. M. Shaw, et. al., Therapeutic Drug Monitoring, 17, pp. 690-699, (1995)).

Mycophenolate mofetil, a prodrug which quickly liberates free MPA in vivo, was recently approved to prevent acute allograft rejection following kidney transplantation (i. e. renal allograft failure) and heart transplantation. (L. M.

Shaw, et. al., Therapeutic Drug Monitoring. 17, pp. 690-699, (1995); H. W.

Sollinger, Transplantation, 60, pp. 225-232, (1995); J. Kobashigawa Transplant, 66, pp. 507, (1998)). Mycophenolate mofetil has also been used for the treatment of rheumatoid arthritis. The experimental use of mycophenolate mofetil in the treatment of systemic lupus erythematosus, lupus nephritis, myasthenia gravis, inflammatory eye disease, autoimmune and inflammatory skin disorders (including psoriasis) and glomerular disease has also been described (R. Bentley, Chem. Rev., 100, pp. 3801-3825, (2000) ). Mycophenolate mofetil has also been postulated to be of use for the treatment of atopic dermatitis (Grundmann-Kollman M et al, Archives of Dermatology, 137 (7), pp. 870-873, (2001) ) and has been shown to be effective in predictive animal models of multiple sclerosis (Tran G. T et al, International Immunopharmacology, 1 (9-10) pp. 1709-1723, (2001)).

Several clinical observations, however, limit the therapeutic potential of this drug. (L. M. Shaw, et. al., Therapeutic Drug Monitoring, 17, pp. 690-699, (1995)).

Nucleoside analogues such as tiazofurin, ribavirin and mizoribine also inhibit IMPDH (L. Hedstrom, et. al., Biochemistrv, 29, pp. 849-854, (1990) ). These nucleoside analogues are competitive inhibitors of IMPDH, but also inhibit other NAD dependant enzymes. This lack of specificity limits the therapeutic application of these compounds. New agents with improved selectivity for IMPDH would represent a significant improvement over these nucleoside analogues. Mizorbine (Bredinin0) has been approved in Japan for multiple indications in transplantation and autoimmune diseases including prevention of rejection after renal transplantation, idiopathic glomerulonephritis, lupus nephritis and rheumatoid arthritis.

Vertex has recently disclosed a series of novel IMPDH inhibitors (WO 97/40028), of which VX-497 has been evaluated for the treatment of psoriasis.

It is also known that IMPDH plays a role in other metabolic events. Increased IMPDH activity has been observed in rapidly proliferating human leukemic cell lines and other tumour cell lines, indicating IMPDH as a target for anti-cancer as well as immunosuppressive chemotherapy (M. Nagai et. al., Cancer Res., 51, pp. 3886-3890, (1991), Pankiewicz K. W. , Exp. Opin. Ther. Patents, 11, pp. 1161-1170, (2001)). IMPDH has also been shown to play a role in the proliferation of smooth muscle cells, indicating that inhibitors of IMPDH may be useful in preventing restenosis or other hyperproliferative vascular diseases (C. R. Gregory et. al., Transplantation, 59, pp. 655-61, (1995); PCT publication WO 94/12184; and PCT publication WO 94/01105).

Additionally, IMPDH has been shown to play a role in viral replication in some virus-infected cell lines. (S. F. Carr, J. Biol. Chem., 268, pp. 27286-27290, (1993) ). VX-497 is currently being evaluated for the treatment of hepatitis C in humans.

Thus, there remains a need for potent IMPDH inhibitors with improved pharmacological properties. Such inhibitors would have therapeutic potential as immunosuppressants, anti-cancer agents, anti-inflammatory agents, antipsoriatic and anti-viral agents.

International Patent Application WO 96-38144 discloses a class of isothiazolones.

The present inventors disclose new potent IMPDH inhibitors based on substituted sulfonamide derivatives.

Thus according to one aspect of the invention we provide a compound of formula (1): wherein X is an O or S atom ; Y is an 0 or S atom ; A is a group-S02NR'R2 ; m is zero or the integer 1; n is zero or the integer 1; provided that at least one but not both of m and n are the integer 1; R3 is a hydrogen atom or an alkyl or cycloalkyl group; R'is the group-Alk'-L'-Alk2-R4, in which Alk'is a covalent bond or an optionally substituted aliphatic chain, L1 is a covalent bond or a linking atom or group, Alk2 is a covalent bond or an optionally substituted aliphatic or heteroaliphatic chain and R4 is hydrogen atom or an optionally substituted aromatic, heteroaromatic, cycloaliphatic, heterocycloaliphatic group; provided that R'is other than a hydrogen atom; R2 is a hydrogen atom or an alkyl group; or NR1R2 forms an optionally substituted heterocycloaliphatic ring of formula (1a), which may be optionally fused to an optionally substituted aromatic or heteroaromatic group:

wherein s and t, which may be the same or different, is each zero or the integer 1 or 2; q is zero or the integer 1 or 2; W is a C or N atom or a N-C16 alkyl group; R5, which may be attached to any available C or N atom including W, is the group-Alk'a-L'a-Alk2a-R4a wherein Alk'a is as herein defined for Alk1, Lia is as herein defined for L', Alk2a is as herein defined for Alk2 and R4a is as herein defined for R4 ; when two R5 substituents are attached to the same C atom or to two adjacent C atoms on the group (1a), they may be joined together to form a cycloaliphatic or heterocycloaliphatic group; and the salts, solvates, hydrates, tautomers, isomers, N-oxides thereof.

It will be appreciated that certain compounds of formula (1) may exist as geometric isomers (E or Z isomers) The compounds may also have one or more chiral centres, and exist as enantiomers or diastereomers. The invention is to be understood to extend to all such geometric isomers, enantiomers, diastereomers and mixtures thereof, including racemates. Formula (1) and the formulae hereinafter are intended to represent all individual isomers and mixtures thereof, unless stated or shown otherwise. In addition, compounds of formula (1) may exist as tautomers, for example keto (CH2C=O)-enol (CH=CHOH) tautomers. When R3 in compounds of formula (1) is a hydrogen atom the following tautomers may also exist as illustrated below : Formula (1) and the formulae hereinafter are intended to represent all individual tautomers and mixtures thereof, unless stated otherwise.

It will also be appreciated that where desired the compounds of the invention may be administered in a pharmaceutically acceptable pro-drug form, for example, as a protected carboxylic acid derivative, e. g. as an acceptable ester. It will be further appreciated that the pro-drugs may be converted in vivo to the active compounds of formula (1), and the invention is intended to extend to such pro-drugs. Such pro-drugs are well known in the literature, see for example International Patent Application No. WO 00/23419, Bodor N.

(Alfred Benson Symposium, 1982,17, 156-177), Singh G. et al (J. Sci. Ind.

Res. , 1996,55, 497-510) and Bundgaard H. (Design of Prodrugs, 1985, Elsevier, Amsterdam).

It will be understood that when any of Alk1, L', Alk2, Alk1a, L1a or Alk2a is a covalent bond that the group R'or R5 then consists of one, two or three members.

In the compounds of the invention as represented by formula (1) and the more detailed description hereinafter certain of the general terms used in relation to substituents are to be understood to include the following atoms or groups unless specified otherwise.

The term"aliphatic group"is intended to include optionally substituted straight or branched C1 10alkyl, e. g. C 1-6 alkyl, C2 10alkenyl e. g. C2 6alkenyl or C2 10 alkynyl e. g. C2-6alkynyl groups. Optional substituents when present on those groups include those optional substituents mentioned hereinafter.

Particular examples of aliphatic groups include optionally substituted C1-6 alkyl groups such as-CH3,-CH2CH3,-CH (CH3) 2, -(CH2)2CH3, -(CH2)3CH3, <BR> <BR> <BR> <BR> -CH(CH3) CH2CH3, -CH2CH (CH3) 2,-CH2C (CH3) 3,-C (CH3) 3,-(CH2) 4CH3, - (CH2) 5CH3, or C2 6alkenyl or C2-6alkynyl groups such as-CHCH2, -CHCHCH3, -CH2CHCH2, -CHCHCH2CH3, -CH2CHCHCH3, -(CH2) 2CHCH2, - CCH,-CCCH3,-CH2CCH,-CCCH2CH3,-CH2CCCH3, or- (CH2) 2CCH groups.

The term"aliphatic chain"is intended to include those alkyl, alkenyl or alkynyl groups as just described where a terminal hydrogen atom is replaced by a covalent bond to give a divalent chain.

Examples of aliphatic chains include optionally substituted C1-6 alkylen chains such as-CH2-, -CH2CH2-,-CH (CH3) CH2-,- (CH2) 2CH2-,- (CH2) 3CH2-, -CH(CH3) (CH2) 2CH2-,-CH2CH (CH3) CH2-,-C (CH3) 2-,-C (CH3) 2CH2-, -CH2C(CH3)2CH2-, -(CH2) 2CH (CH3) CH2-,-CH (CH3) CH2CH2-, -CH(CH3) CH2CH (CH3) CH2-, -CH2CH (CH3) CH2CH2-,- (CH2) 2C (CH3) 2CH2-, - (CH2) 4CH2-,- (CH2) 5CH2 or C2-6alkenylene or C2-6alkynylene chains such as -CHCH-, -CHCHCH2 -CH2CHCH-, -CHCHCH2CH2-, -CH2CHCHCH2-, - (CH2) 2CHCH-, -CC-,-CCCH2,-CH2CC-,-CCCH2CH2-,-CH2CCCH2-or - (CH2) 2CCH- chains. More particular examples include optionally substituted C1-3 alkylen chains selected from -CH2-, -CH2CH2-, -CH2CH2CH2-, - CH (CH3) CH2-, -C (CH3) 2- and-CH2CH (CH3)- chains.

Heteroaliphatic chains represented by Alk2 or Alk2a in the compounds of formula (1) include the aliphatic chains just described but with each additionally containing one, two, three or four heteroatoms or heteroatom-containing groups.

Particular heteroatoms or groups include atoms or groups L3 where L3 is a linker atom or group. Each L3 atom or group may interrupt the aliphatic group, or may be positioned at its terminal carbon atom to connect the group to an adjoining atom or group. Particular examples include optionally substituted-L3CH2-, -CH2L3-, -L3CH(CH3)-, -CH (CH3) L3-,-CH2L3CH2-,-L3CH2CH2-,-L3CH2CH (CH3) -, - CH (CH3) CH2L3-, -CH2CH2L3-, -CH2L3CH2CH2-, -CH2L3CH2CH2L3-, - (CH2)2L3CH2-, -(CH2)3L3CH2-, -L3 (CH2) 2CH2-,-L3CH2CHCH-,-CHCHCH2L3-, -(CH2) 2L3CH2CH2-,-(CH2) 3L3-and-L3CH2L3CH2CH2-chains.

When L3 is present in heteroaliphatic chains as a linker atom or group it may be any divalent linking atom or group. Particular examples include-O-or-S- <BR> <BR> <BR> atoms or-C (O)-,-C (S) -,-S (O)-,-S (O) 2-, -N (R6)- [where R6 is a hydrogen atom<BR> <BR> <BR> <BR> <BR> or a straight or branched C16alkyl group], -N (R6) O-,-N (R6) N-, -C (O) O-, -OC(O) -, -CON(R6)-, -OC(O) N (R6)-, -CSN(R6)-, -N(R6)CO-, -N(R6) C (O) O-, -N (R6) CS-,-S (0) 2N (R6)-,-N (R6) S (0) 2-, -N (R6) CON (R6)-,-N (R6) CSN (R6)-,

-N (R6) SO2N (R6)-,-C (=NOR6)-or-C (R6a) =NO- [where R6a is a straight or branched C16alkyl group] groups. Where L3 contains two R6 groups these may be the same or different.

The term"cycloaliphatic group"includes optionally substituted non-aromatic cyclic or multicyclic, saturated or partially saturated &num 3-10 ring systems, such as, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, adamantyl, norbornyl, norbornenyl, bicyclo [2.2. 1] heptanyl or bicyclo [2.2. 1] heptenyl. Particular examples include optionally substituted C3-6 cycloalkyl ring systems such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl groups. Optional substituents present on those groups include those substituents mentioned hereinafter.

The term"heterocycloaliphatic group"refers to an optionally substituted 3 to 10 membered saturated or partially saturated monocyclic or saturated or partially saturated multicyclic hydrocarbon ring system containing one, two, three or four L2 linker atoms or groups. Particular examples of suitable L2 atoms or groups include any atom or linker group as described hereinbefore in relation to L3. Optional substituents present on the heterocyloaliphatic groups include those substituents mentioned hereinafter.

Particular examples of heterocycloaliphatic groups include optionally substituted cyclobutanonyl, cyclopentanonyl, cyclohexanonyl, azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolinyl, e. g. 2-or 3-pyrrolinyl, pyrrolidinyl, pyrrolidinonyl, oxazolidinyl, oxazolidinonyl, dioxolanyl, e. g. 1,3- dioxolanyl, imidazolinyl, e. g. 2-imidazolinyl, imidazolidinyl, pyrazolinyl, e. g. 2- pyrazolinyl, pyrazolidinyl, thiazolinyl, thiazolidinyl, pyranyl, e. g. 2-or 4-pyranyl, pyranonyl, piperidinyl, piperidinonyl, quinuclidinyl, 1, 4-dioxanyl, morpholinyl, morpholinonyl, 1, 4-dithianyl, thiomorpholinyl, piperazinyl, N-C1-6 alkylpiperazinyl, N-Cl-6 alkylpyrrolidinyl, N-Cl-6 alkylpiperidinyl, N-C1-6 alkylmorpholinyl, homopiperazinyl, dihydrofuran-2-onyl, tetrahydropyran-2- onyl, isothiazolidinyl 1,1-dioxide, [1, 2] thiazinanyl 1,1-dioxide, tetrahydrothiophenyl, tetrahydrothiopyranyl, pyrazolidin-3-onyl,

tetrahydrothiopyranyl 1,1-dioxide, tetrahydrothiophenyl 1,1-dioxide, 1,3, 5- trithianyl, oxazinyl, e. g. 2H-1,3-, 6H-1, 3-, 6H-1,2-, 2H-1, 2- or 4H-1, 4- oxazinyl, 1,2, 5-oxathiazinyl, isoxazinyl, e. g. o-or p-isoxazinyl, oxathiazinyl, e. g. 1,2, 5 or 1,2, 6-oxathiazinyl, or 1,3, 5,-oxadiazinyl groups.

Cycloaliphatic groups may be linked to the remainder of the compound of formula (1) by any available ring carbon atom. Heterocycloaliphatic groups may be linked to the remainder of the compound of formula (1) by any available ring carbon or, where available, ring nitrogen atom.

When R4 or R4a in compounds of formula (1) is an optionally substituted heterocycloaliphatic or cycloaliphatic ring, these may optionally be fused to an optionally substituted monocyclic C6-12aromatic group, such as phenyl or an optionally substituted monocyclic C19heteroaromatic group containing for example one, two, three or four heteroatoms selected from oxygen, sulphur or nitrogen atoms.

The optional substituents which may be present on the aliphatic, cycloaliphatic or heterocycloaliphatic groups or chains, include one, two, three or more substituents, which each may be the same or different, selected from halogen atoms, or alkoxy, haloalkyl, haloalkoxy, hydroxy (-OH), thiol (-SH), alkylthio, amino (-NH2), substituted amino, optionally substituted C6-12arylamino, optionally substituted C1-6 alkyl,-CN,-CO2H,-CO2R7 (where R7 is an optionally substituted C16 alkyl group),-SO3H,-SOR3 (where R8 is a Ci. alkyl group) -SO2R8, -SO3R8, -OCO2R8, -C (O) H, -C (O) R8,-OC (O) R8,-C (S) R8, -C(O) N (R9) (R10) (where R9 and Rio, which may be the same or different is each a hydrogen atom or a Ci-e alkyl group), -OC (O) N (R9) (Rio), - N (R9) C (O) R10, -CSN (R9) (Rio),-N (R9) C (S) (Rio),-S02N (R9) (Rio), - N (R9) SO2R10,-N (R9) C (O) N (R10) (R11) (where R11 is a hydrogen atom or a C1- 6 alkyl group),-N (R9) C (S) N (R10) (R1l),-N (R9) S02N (R10) (R11), or an optionally substituted aromatic, heteroaromatic, cycloaliphatic or heterocycloaliphatic group. Substituted amino groups include-NHR8 and-N (R8) (R9) groups.

When L'or L'a is present in compounds of formula (1) as a linker atom or group it may be any such atom or group as hereinbefore described in relation to L3 linker atoms and groups.

When R6 R6a R7 R8 R9 R10 or R"is present as a C16alkyl group it may be a straight or branched C1-6 alkyl group e. g. a C1-3 alkyl group such as methyl, ethyl or i-propyl. Optional substituents which may be present on R7 include for example one, two or three substituents which may be the same or different selected from fluorine, chlorine, bromine or iodine atoms or hydroxy or C1-6 alkoxy e. g. methoxy or ethoxy groups.

The term"halogen atom"is intended to include fluorine, chlorine, bromine or iodine atoms.

The term"haloalkyl"is intended to include the alkyl groups just mentioned substituted by one, two or three of the halogen atoms just described.

Particular examples of such groups include-CF3,-CCI3,-CHF2,-CHCI2, -CH2F, and -CH2Cl groups.

The term"alkoxy"as used herein is intended to include straight or branched Ci. ioaikoxy for example C16alkoxy such as methoxy, ethoxy, n-propoxy, i-propoxy and t-butoxy."Haloalkoxy"as used herein includes any of those alkoxy groups substituted by one, two or three halogen atoms as described above. Particular examples include-OCF3,-OCC13,-OCHF2,-OCHC12, -OCH2F and -OCH2Cl groups.

As used herein the term"alkylthio"is intended to include straight or branched C1-loalkylthio, e. g. C16alkylthio such as methylthio or ethylthio groups.

The terms"aromatic group"and"aryl group"are intended to include for example optionally substituted monocyclic ring C612 aromatic groups, such as phenyl, or bicyclic fused ring C6-12 aromatic groups, such as, 1-or 2-naphthyl groups.

The terms"heteroaromatic group"and"heteroaryl group"are intended to include for example optionally substituted Cul-9 heteroaromatic groups containing for example one, two, three or four heteroatoms selected from oxygen, sulfur or nitrogen atoms (or oxidised versions thereof). In general, the heteroaromatic groups may be for example monocyclic or bicyclic fused ring heteroaromatic groups. Monocyclic heteroaromatic groups include for example five-or six-membered heteroaromatic groups containing one, two, three or four heteroatoms selected from oxygen, sulfur or nitrogen atoms.

Bicyclic heteroaromatic groups include for example eight-to thirteen- membered fused-ring heteroaromatic groups containing one, two or more heteroatoms selected from oxygen, sulphur or nitrogen atoms.

Each of these aromatic or heteroaromatic groups may be optionally substituted by one, two, three or more R12 atoms or groups as defined below.

Particular examples of monocyclic ring heteroaromatic groups of this type include pyrrolyl, furyl, thienyl, imidazolyl, N-C16alkylimidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, tetrazolyl, triazinyl, pyridyl-N-oxide, dihydropyrazolonyl or imidazolonyl.

Particular examples of bicyclic ring heteroaromatic groups of this type include benzofuryl, benzothienyl, benzotriazolyl, indolyl, indazolinyl, benzimidazolyl, imidazo [1, 2-a] pyridyl, benzothiazolyl, benzoxazolyl, benzisoxazolyl, benzopyranyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pyrido [3,4-b] pyridyl, pyrido [3,2-b] pyridyl, pyrido [4, 3-b]-pyridyl, quinolinyl, isoquinolinyl or phthalazinyl.

The R4 or R4a heteroaromatic groups may be attached to the remainder of the compound of formula (1) by any carbon or hetero e. g. nitrogen atom as appropriate.

Optional substituents which may be present on the aromatic or heteroaromatic groups include one, two, three or more substituents, each selected from an atom or group R12 in which R12 is -R12a or-Alk3 (Rl2a) f, where R12a is a halogen atom, or an amino (-NH2), -NHR13 [where R13 is an optionally substituted heterocycloaliphatic, cycloaliphatic, aryl, heteroaryl group or-Alk3 (R13a) f where R13a is the same as R13], -N(R13) 2, nitro, cyano, amidino, formyl, hydroxy (OH), carboxyl (-CO2H), -CO2R13, thiol (-SH), -SR13, -OR13, -COR13 - R13, S02N (R13) 2, -CONH2, -CSNH2, -CONHR13, -CSNHR13, -CON(R13)2, <BR> <BR> <BR> -CSN(R13) 2, -N (R14) SO2R13, [where R14 is a hydrogen atom or a C1-6alkyl group] -N (SO2R13) 2, -N (R14) SO2NH2, -N (R14) SO2NHR13,-N (R13) SO2N (R14) 2, <BR> <BR> <BR> <BR> -N(R14)COR13, -N(R14) CONH2, -N (R14) CONHR13,-N (R14) CON (R13) 2,<BR> <BR> <BR> <BR> <BR> -N(R14) CSNH2, -N (R14) CSNHR13,-N (R14) CSN (R13)2, -N(R14)CSR13, - N (Ri4) C (O) OR13,-S02NHet1 [where -NHet1 is an optionally substituted C 3-7 heterocycloaliphatic group optionally containing one or more other -O- or -S- atoms or-N (R14)-, -C (O)- or -C(S)- groups], -CONHet1, -CSNHet1, -N(R14)SO2NHet1, -N(R14)CONHet1, -N(R14)CSNHet1, -SO2N(R14)Het2 [where Het2 is an optionally substituted monocyclic C3-7 cycloaliphatic group optionally containing one or more -O- or -S- atoms or-N (R14)-, -C (O)- or -C(S)- groups], <BR> <BR> <BR> -CON(R14)Het2, -CSN(R14) Het2, -N (R14) CON (R14) Het2, -N (R14) CSN (R14) Het2, optionally substituted aryl, heteroaryl, cycloaliphatic or heterocycloaliphatic group; Alk3 is a straight or branched C1-6alkylene, C2-6alkenylene or C26 alkynylene chain, optionally interrupted by one, two or three -O- or -S- atoms or-S (O) g- [where g is an integer 1 or 2] or-N (R14)- groups ; and f is zero or an integer 1,2 or 3. It will be appreciated that when two R13 or R14 groups are present in one of the above substituents, the R13 or R14 groups may be the same or different.

When in the group-Alk3 (R12a) f or-Alk3 (Rl3a) f f is an integer 1,2 or 3, it is to be understood that the substituent or substituents R12a or R13a may be present on any suitable carbon atom in-Alk3. Where more than one R12a or R13a substituent is present these may be the same or different and may be present on the same or different atom in-Alk3. Clearly, when f is zero and no

substituent R12a or R13a is present the alkylene, alkenylene or alkynylene chain represented by Alk3 becomes an alkyl, alkenyl or alkynyl group.

When-NHet1 or-Het2 forms part of a substituent R12 each may be for example an optionally substituted 2-or 3-pyrrolinyl, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, piperazinyl, imidazolinyl, imidazolidinyl, morpholinyl, thiomorpholinyl, piperidinyl, oxazolidinyl or thiazolidinyl group. Additionally Het2 may represent for example, an optionally substituted cyclopentyl or cyclohexyl group. Optional substituents which may be present on-NHet1 or -Het2 include those substituents described above in relation to aromatic groups.

Particularly useful atoms or groups represented by R12 include fluorine, chlorine, bromine or iodine, C1-6 alkyl, haloC1-6alkyl, e. g.-CF3, halo16 alkoxy, e. g.-OCF3,-OCF2H,-NH2,-NHR,-N (R) 2,-CN,-C02H,-C02R,-SR -OH, -OR13, -COR13, -CSR13, -SO2R13, -SO2NH2, -SO2NHR13, SO2N(R13)2, <BR> <BR> <BR> <BR> <BR> .-CONH2,-CSNH2,-CONHR13,-CSNHR13,-CON (Rl3) 2,-CSN (R'3) 2,<BR> <BR> <BR> <BR> <BR> <BR> <BR> -N(R14)SO2R13, -N(R14)COR13, -N(R14) CONH2, -N (R14) CONHR13, -N(R14)CSR13, - N(R14) C (O) OR13,-S02NHet',-CONHetI,-CSNHetI,-Alk3NH2, -Alk3NHR13, -Alk3N(R13)2, -Alk3CN, -Alk3CO2H, -Alk3CO2R13, - Alk3SR13, <BR> <BR> <BR> <BR> Alk3OR13-Aik3COR13,-Alk3CSR13,-Alk3SO2R13,-Alk3S02NH2,<BR > <BR> <BR> <BR> <BR> <BR> <BR> <BR> - Alk3SO2NHR'3,-Alk3S02N (R3) 2,-Alk3CONH2,-Alk3CSNH2,<BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> - Alk3CONHR13,-Alk3CSNHR13,-Alk3CON (R13) 2,-Alk3CSN (R13) 2, -Alk3N(R14)SO2R13, -Alk3N(R14)COR13, -Alk3N(R14) CONH2, -Alk3N(R14)CONHR13, -Alk3N(R14)CSR13, -Alk3N(R14) C (O) OR13, -Alk3SO2NHet1, -Alk3CONHet1, -Alk3CSNHet1, optionally substituted phenyl, monocyclic heteroaryl, monocyclic heterocycloaliphatic, cycloaliphatic, -Alk3phenyl, -Alk3monocyclic heteroaryl, -Alk3monocyclic heterocycloaliphatic or-Alk3cycloaliphatic.

Particularly useful R13 groups include-Alk3 (where f is zero), optionally substituted phenyl, monocyclic heteroaryl, monocyclic heterocycloaliphatic, <BR> <BR> <BR> cycloaliphatic,-Alk3phenyl,-Alk3monocyclic heteroaryl,-Alk3monocyclic

heterocycloaliphatic or-Alk3cycloaliphatic. R14 is particularly hydrogen or methyl.

When Alk3 is present it may be for example a methylene, ethylene, n- propylene, i-propylene, n-butylene, i-butylene, s-butylene, t-butylene, ethenylene, 2-propenylene, 2-butenylene, 3-butenylene, ethynylene, 2- propynylene, 2-butynylene or 3-butynylene chain, optionally interrupted by one, two, or three-O-or-S-, atoms or-S (O)-,-S (O) 2-or-N (R14)-groups.

Particular examples of Alk3 include C16 alkylene chains especially C13 alkylene chains e. g. methylene, ethylene or propylene or when f is zero C16 alkyl groups especially C14 alkyl groups e. g methyl, ethyl, n-propyl, i-propyl, n-butyl or t-butyl.

Particular examples of aryl, heteroaryl, heterocycloaliphatic or cycloaliphatic groups which may represent-R12a, R13 or-R13a include optionally substituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, <BR> <BR> <BR> <BR> pyrrolidinonyl, piperidinyl, imidazolidinyl, thiazolidinyl, piperazinyl, N-C16<BR> <BR> <BR> <BR> <BR> <BR> <BR> alkylpiperazinyl, especially N-methylpiperazinyl, N-C16 alkylpyrrolidinyl, especially N-methylpyrrolidinyl, N-C16 alkylpiperidinyl, especially N- methylpiperidinyl, homopiperazinyl, morpholinyl, thiomorpholinyl, oxazolidinyl, <BR> <BR> <BR> <BR> tetrahydrofuranyl, tetrahydropyranyl, phenyl, pyrrolyl, furyl, thienyl, imidazolyl,<BR> <BR> <BR> <BR> <BR> <BR> N-C16alkylimidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, tetrazolyl, triazinyl, pyridyl-N-oxide, dihydropyrazolonyl or imidazolonyl.

Optional substituents which may in particular be present on the aryl or heteroaryl groups represented by -R12a, R13 or -R13a include one, two, three or more atoms or groups selected from fluorine, chlorine, methyl, OCH3, OCF3, OCF2H, CF3, CN, NHCH3, N (CH3) 2, CONH2, CONHCH3, CON (CH3) 2, C02CH3, C02CH2CH3,-C02C (CH3) 3,-COCH3,-NHCOCH3, - N (CH3) COCH3,-SCH3,-SO2CH3 or C02H.

Optional substituents which may in particular be present on the heterocycloaliphatic or cycloaliphatic groups represented by-R12a, R13 or - R13a include one, two, three or more atoms or groups selected from-OCH3, OCF3, OCF2H, CF3, d-saikyithio, straight or branched C13alkyl,-CN, NHCH3, N (CH3) 2, CONH2, CONHCH3, CON (CH3) 2, CO2CH3, C02CH2CH3, - C02C (CH3) 3, or-COCH3,-NHCOCH3,-N (CH3) COCH3 or C02H.

Where desired, two adjacent R12 substituents may be linked together to form a cyclic group such as a cyclic ether, e. g. a d-eaikyienedioxy group such as methylenedioxy or ethylenedioxy or a C3-6 cycloalkyl or 3-10 membered monocylic heterocycloaliphatic group as defined herein.

It will be appreciated that where two or more R12 substituents are present, these need not necessarily be the same atoms and/or groups. In general, the substituent (s) may be present at any available ring position in the aromatic or heteroaromatic group.

Examples of aliphatic chains, which may represent Alk1, Alk'a, Alk2 or Alk2a include C16 alkylene chains (wherein the terminal hydrogen atom of a C1-6 alkyl group is replaced by a covalent bond), as herein described. More particular examples include C1-3 alkylen chains, such as-CH2-,-CH2CH2-, -CH2CH2CH2-,-CH (CH3) CH2-or-CH2CH (CH3) -.

Examples of alkyl groups, which may represent R3 include C1-6 alkyl groups as herein described. More particular examples include C1-3 alkyl groups, such as -CH3,-CH2CH3,-CH2CH2CH3 or-CH (CH3) CH3. Examples of cycloalkyl groups which may represent R3 include C3-6 cycloalkyl groups, such as those described previously.

In a similar manner alkyl groups which may represent R2 are as defined herein for R3 alkyl groups.

Particular examples of R13 groups present in esterified carboxyl groups of formula-Co2R13 include C16 alkyl groups optionally substituted with R, 3a as herein defined.

The presence of certain substituents in the compounds of formula (1) may enable salts of the compounds to be formed. Suitable salts include pharmaceutical acceptable salts, for example acid addition salts derived from inorganic or organic acids, and salts derived from inorganic and organic bases.

Acid addition salts include hydrochlorides, hydrobromides, hydroiodides, alkylsulphonates, e. g. methanesulphonates, ethanesulphonates, or isothionates, arylsulphonates, e. g. p-toluenesulphonates, besylates or napsylates, phosphates, sulphates, hydrogen sulphates, acetates, trifluoroacetates, propionates, citrates, maleates, fumarates, malonates, succinates, lactates, oxalates, tartrates and benzoates.

Salts derived from inorganic or organic bases include alkali metal salts such as sodium or potassium salts, alkaline earth metal salts such as magnesium or calcium salts, and organic amine salts such as morpholine, piperidine, dimethylamine or diethylamine salts.

Particularly useful salts of compounds according to the invention include pharmaceutically acceptable salts, especially acid addition pharmaceutically acceptable salts.

One particular group of compounds of the invention has the formula (1) wherein X is a S atom.

One particular group of compounds has the formula (1) wherein Y is an O atom. Another group of compounds of the invention has the formula (1) wherein Y is a S atom. A particular group of compounds of the invention has the formula (1) wherein n is zero and m is the integer 1.

A particularly useful group of compounds of the invention has the formula (2):

wherein R', R2 and R3 are as described for formula (1); and the salts, solvates, hydrates, tautomers, isomers, N-oxides thereof.

One particular group of compounds of the invention has the formulae (1) or (2) wherein R'is the group-Alk'-L'-Alk2-R4 and R2 is a hydrogen atom or a C13 alkyl group, especially a methyl group.

R1 is most especially the group-Alk'-R4.

Another particularly preferred group of compounds of formulae (1) or (2) has the formula (3): wherein q, s, t, W, R3 and R5 are as herein defined for formula (1); and the salts, solvates, hydrates, tautomers, isomers, N-oxides thereof.

In one particular group of compounds of formulae (1), (2) or (3) R3 is a hydrogen atom or a C16 alkyl group. Especially preferred is when R3 is a C1-3 alkyl group, particularly methyl or isopropyl.

One particular group of compounds of the invention has the formulae (1), (2) or (3) in which the sum of s + t is zero, 1,2 or 3.

Alk1 or Alk1a is each particularly a covalent bond or an optionally substituted C 1-6 alkylen chain. Especially preferred is when Alk'or Alk'a is a covalent bond

or an optionally substitued C13 alkylene chain, particularly,-CH2-,-CH2CH2-or -CH2CH2CH2-. Optional substituents which may in particular be present on Alk1 or Alk1a include C1-3 alkoxy e. g. methoxy, OCF3, OCF2H, CF3, C1-3 alkylthio,-CN, NHCH3, N (CH3) 2, CONH2, CONHCH3, CON (CH3) 2, C02CH3, C02CH2CH3,-C02C (CH3) 3,-COCH3,-NHCOCH3,-N (CH3) COCH3 or COsH.

L1 in compounds of formulae (1) or (2) is especially a covalent bond or a linking atom or group selected from-O-,-C (O)-,-NH-or-NCH3-.

In compounds of formulae (1), (2) or (3) L la is preferably a covalent bond or a <BR> <BR> <BR> linking atom or group selected from-O-,-C (O)-,-C (S) -,-S (O) 2-, -N (R6)-, -C (O) O-,-CON (R6)-,-CSN (R6)-,-N (R6) CO-,-N (R6) CS-,-S (0) 2N (R6)-, -N(R6) S (O) 2-, -C (=NOR6)- or -C(R6a) =NO-, where R6 and R6a are as previously defined herein. Especially preferred is when L la is a -O-, -C (O)-,-S (O) 2-, -C(O)O- or -CON(R6)- group. R6 and R6a are especially a hydrogen atom or a methyl group.

Alk2 in the group R'is especially a covalent bond or a C1-3 alkylen chain, particularly-CH2-,-CH2CH2-or- (CH2) 2CH2-.

Ale 2a in the group R5 is particularly a covalent bond or a straight or branched C1-6 alkylen chain. Particular examples include-CH2-,-CH2CH2-,- CH (CH3) CH2-,- (CH2) 2CH2-, -CH2CH (CH3) CH2-, -C (CH3) 2-, -C (CH3) 2CH2- or -CH2C (CH3) 2CH2-.

R4 in one particular group of compounds of the invention is a hydrogen atom.

R4 in one class of compounds of formulae (1) or (2) is in particular an optionally substituted aromatic, heteroaromatic or heterocycloaliphatic group.

R4 in compounds of this type is especially an optionally substituted 3-10 membered saturated monocyclic heterocycloaliphatic, phenyl or heteroaromatic group. Particular R4 examples include optionally substituted azetidinyl, pyrrolidinyl, pyrrolidinonyl, piperidinyl, imidazolidinyl, thiazolidinyl,

piperazinyl, N-Cl-6 alkylpiperazinyl, especially N-methylpiperazinyl, N-Ci-6 alkylpyrrolidinyl, especially N-methylpyrrolidinyl, N-C16 alkylpiperidinyl, especially N-methylpiperidinyl, homopiperazinyl, morpholinyl, thiomorpholinyl, oxazolidinyl, tetrahydrofuranyl, tetrahydropyranyl, phenyl, pyrrolyl, furyl, thienyl, imidazolyl, N-C16alkylimidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, tetrazolyl, triazinyl, pyridyl-N-oxide, benzofuryl, benzothienyl, indolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, benzisoxazolyl, quinolinyl or isoquinolinyl. In one particular group of compounds R4 is an optionally substituted morpholinyl, pyrrolidinyl, piperidinyl, piperazinyl, N-methylpiperazinyl, phenyl, pyrrolyl, furyl, thienyl, imidazolyl, N- <BR> <BR> <BR> <BR> C16alkylimidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl or pyridyl-N-oxide group.

R4a in one particular group of compounds of the invention is a hydrogen atom.

Another particular group of compounds of the invention has the formulae (1), (2) or (3) wherein R4a is an optionally substituted aromatic or heteroaromatic group. Particular R4a examples include optionally substituted phenyl, pyrrolyl, <BR> <BR> <BR> <BR> furyl, thienyl, imidazolyl, N-C16alkylimidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrimidinyl, <BR> <BR> <BR> <BR> pyridazinyl, pyrazinyl, tetrazolyl, triazinyl, pyridyl-N-oxide, benzofuryl, benzothienyl, indolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, benzisoxazolyl, quinolinyl or isoquinolinyl. In one particular group of compounds of this type R4a is an optionally substituted phenyl, furyl, pyridyl, pyrimidinyl, benzoxazolyl or benzisoxazolyl group.

In one group of compounds of formulae (1), (2) or (3) the heterocycloaliphatic ring of formula (1 a) is fused to an optionally substituted phenyl ring.

In another group of compounds of formulae (1), (2) or (3) the heterocycloaliphatic ring of formula (1a) contains two R5 substituents attached

to the same C atom which link to form a heterocycloaliphatic ring, especially 1, 3-dioxolanyl.

Particular aryl or heteroaryl substituents which may be present on compounds of formulae (1), (2) or (3), in particular on the groups R4 or R4a, include one, two, three or more atoms or groups selected from fluorine, chlorine, bromine, iodine, optionally substituted straight or branched Cri_6 alkyl, methoxy, OCF3, OCF2H, CF3, CN, NH2, NHCH3, N (CH3) 2, CONH2, CONHCH3, CON (CH3) 2, C02CH3, C02CH2CH3,-C02C (CH3) 3,-COCH3,-NHCOCH3,-N (CH3) COCH3, - SCH3,-S02CH3, C02H ; optionally substituted morpholinyl, thiomorpholinyl, piperazinyl, pyrrolidinyl, piperidinyl, aryl or monocyclic heteroaryl group; or two adjacent substituents link together to form a heterocycloaliphatic group, especially methylenedioxy, ethylenedioxy or dihydrofuranonyl. Particular examples of optionally substituted straight or branched C16 alkyl groups in substituents of this type include C13 alkyl groups especially methyl, ethyl or propyl optionally substituted with CN, NH2, NHCH3, N (CH3) 2, CONH2, CONHCHs, CON (CH3) 2, C02CH3, C02CH2CH3,-C02C (CH3) 3,-COCH3, -NHCOCH3,-N (CH3) COCH3,-N (CH3) C (O) OC (CH3) 3, -NHC (O) OC (CH3) 3, - SCHs,-S02CH3 or C02H. Particular examples of optionally substituted aryl or monocyclic heteroaryl groups in substituents of this type include phenyl, pyrrolyl, furyl, thienyl, imidazolyl, N-C16alkylimidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, tetrazolyl, triazinyl or pyridyl-N-oxide, where the optional substituent includes one, two, three or more atoms or groups selected from fluorine, chlorine, straight or branched C16 alkyl e. g methyl, methoxy, OCF3, OCF2H, CF3, CN, NHCH3, N (CH3) 2, CONH2, CONHCH3, CON (CH3) 2, C02CH3, C02CH2CH3,-C02C (CH3) 3,-COCH3,-NHCOCH3, - N (CH3) COCH3,-SCH3,-S02CH3 or C02H.

One group of compounds of the invention has the formulae (1), (2) or (3) wherein R4 or R4a is optionally substituted with one, two, three or more atoms or groups selected from fluorine, chlorine, bromine, iodine, methyl, ethyl,

methoxy, OCF3, OCF2H, CF3, CN, C02CH3, oxazolyi, phenyl, or two adjacent substituents link to form a methylenedioxy or dihydrofuranonyl group.

One particular group of aliphatic, especially alkyl, cycloaliphatic or heterocycloaliphatic substituents, which may be present on the compounds of formulae (1), (2) or (3) are one, two, three or more groups selected from C13 alkoxy, OCF3, OCF2H, CF3, C13 alkylthio, optionally substituted straight or branched C1-3 alkyl (wherein the optional alkyl substituent is in particular an optionally substituted phenyl or monocyclic heteroaromatic group),-CN, NH2, NHCH3, N (CH3) 2, CONH2, CONHCH3, CON (CH3) 2, C02CH3, C02CH2CH3, - C02C (CH3) 3, or-COCH3,-NHCOCH3,-N (CH3) COCH3 or CO2H. The optional phenyl or heteroaromatic substituents which may be present in compounds of this type include one, two, three or more atoms or groups selected from fluorine, chlorine, methyl, methoxy, phenyl, OCF3, OCF2H, CF3, CN, NHCH3, N (CH3) 2, CONH2, CONHCH3, CON (CH3) 2, C02CH3, C02CH2CH3,-C02C (CH3) 3,-COCH3,-NHCOCH3,-N (CH3) COCH3, -SCH3, -SO2CH3 or COsH.

Particular compounds of the invention include: 2-methyl-3-oxo-2, 3-dihydrobenzo [cisothiazole-5-sulfonic acid (2-ethyl- phenyl) amide; 4- (2-methyl-3-oxo-2, 3-dihydrobenzo [] isothiazole-5-sulfonyl) piperazine-1- carboxylic acid ethylamide ; (S)-1- (2-methyl-3-oxo-2, 3-dihydrobenzo [agisothiazole-5-sulfonyl)-pyrrolidine-2- carboxylic acid amide; 5-(4-acetylpiperazine-1-sulfonyl)-2-methylbenzo[d]isothiazol -3-one ; 5- (1, 4-dioxa-8-azaspiro [4.5] decane-8-sulfonyl)-2-methyl benzo [d] isothiazol-3- one; 5- [4- (1-furan-2-ylmethanoyl) piperazine-1-sulfonyl]-2-methyl- benzo [d]isothiazol-3-one ; and the salts, solvates, hydrates, tautomers, isomers, N-oxides thereof.

Compounds of formulae (1), (2) or (3) are potent inhibitors of IMPDH. The ability of the compounds to act in this way may be simply determined by employing tests such as those described in the Examples hereinafter.

Thus the compounds of the invention may be used in the treatment of IMPDH- associated disorders. The invention extends to such a use and in general to the use of the compounds of formulae (1), (2) or (3) for the manufacture of a medicament for treating such diseases and disorders.

"IMPDH-associated disorders"refers to any disorder or disease state in which inhibition of the enzyme IMPDH (inosine monphosphate dehydrogenase, EC1.1. 1.205, of which there are presently two known isozymes referred to as IMPDH type 1 and IMPDH type 2) would modulate the activity of cells (such as lymphocytes or other cells) and thereby ameliorate or reduce the symptoms or modify the underlying cause (s) of that disorder or disease.

There may or may not be present in the disorder or disease an abnormality associated directly with the IMPDH enzyme. Examples of IMPDH-associated disorders include transplant rejection and autoimmune disorders, such as rheumatoid arthritis, lupus, multiple sclerosis, juvenile diabetes, asthma, and inflammatory bowel disease, as well as inflammatory disorders, cancer and tumors, T-cell mediated hypersensitivity diseases, ischemic or reperfusion injury, viral replication diseases, proliferative disorders and vascular diseases.

Use of the compounds of the present invention is exemplified by, but is not limited to, treating a range of disorders such as: treatment of transplant rejection (e. g. kidney, liver, heart, lung, pancreas (e. g., islet cells), bone marrow, cornea, small bowel, skin allografts, skin homografts (such as employed in burn treatment), heart valve xenografts, serum sickness, and graft vs. host disease, in the treatment of autoimmune diseases, such as rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, juvenile diabetes, asthma, inflammatory bowel disease (such as Crohn's disease and ulcerative colitus), pyoderma gangrenum, lupus (systemic lupus erythematosis), myasthenia gravis, psoriasis, eczema, dermatitis, dermatomyosis, atopic dermatitis; multiple sclerosis, seborrhoea, pulmonary inflammation, eye

uveitis, hepatitis, Grave's disease, Hashimoto's thyroiditis, autoimmune thyroiditis, Behcet's syndrome, Sjorgen's syndrome (dry eyes/mouth), pernicious or immunohaemolytic anaemia, Addison's disease (autoimmune disease of the adrenal glands), idiopathic adrenal insufficiency, autoimmune polyglandular disease (also known as autoimmune polyglandular syndrome) glomerulonephritis, scleroderma, morphea, lichen planus, viteligo (depigmentation of the skin), alopecia areata, autoimmune alopecia, autoimmune hypopituatarism, cicatricial pemphigoid, Gullivan-Barre syndrome, and alveolitis ; in the treatment of T-cell mediated hypersensitivity diseases, including contact hypersensitivity, delayed-type hypersensitivity, contact dermatitis (including that due to poison ivy), urticaria, skin allergies, respiratory allergies (hayfever, allergic rhinitis) and gluten-sensitive enteropathy (Celiac disease); in the treatment of inflammatory diseases such as osteoarthritis, acute pancreatitis, chronic pancreatitis, asthma, acute respiratory distress syndrome, Sezary's syndrome and vascular diseases which have an inflammatory and or a proliferatory component such as restenosis, stenosis and artherosclerosis ; in the treatment of cancer and tumor disorders, such as solid tumors, lymphomas and leukemia ; in the treatment of fungal infections such as mycosis fungoides; in protection from ischemic or reperfusion injury such as ischemic or reperfusion injury that may have been incurred during organ transplantation, myocardial infarction, stroke or other causes; in the treatment of DNA or RNA viral replication diseases, such as herpes simplex type 1 (HSV-1), herpes simplex type 2 (HSV-2), hepatitis (including hepatitis B and hepatitis C) cytomegalovirus, Epstein-Barr, human immundeficiency virus (HIV) and influenza.

Additionally, IMPDH is also known to be present in bacteria and thus may regulate bacterial growth. As such, the IMPDH-inhibitor compounds of the present invention may be useful in treatment or prevention of bacterial infection, alone or in combination with other antibiotic agents.

In a particular embodiment, the compounds of the present invention are useful for the treatment of the afore mentioned exemplary disorders irrespective of their etiology, for example, for the treatment of lupus, psoriasis, inflammatory

bowl disease, multiple sclerosis, atopic dermatitis, transplant rejection or rheumatoid arthritis.

In another particular embodiment the compounds of the present invention are of particular use for the treatment of DNA or RNA viral replication diseases, such as hepatitis (including hepatitis B and hepatitis C) cytomegalovirus, human immundeficiency virus (HIV) and influenza.

In an additional particular embodiment the compounds of the present invention are of particular use for the treatment of cancer and tumour disorders, such as solid tumors, lymphom, leukemia and other forms of cancer.

The compounds of formulae (1), (2) or (3) can be used alone or in combination with other therapeutic or prophylactic agents, such as anti-virals, anti-inflammatory agents, antibiotics, anticancer agents and immunosuppressants.

For the prophylaxis or treatment of disease the compounds according to the invention may be administered as pharmaceutical compositions, and according to a further aspect of the invention we provide a pharmaceutical composition which comprises a compound of formulae (1), (2) or (3) together with one or more pharmaceutical acceptable carriers, excipients or diluents.

Alternate compositions of this invention comprise a compound of formulae (1), (2) or (3) or a salt thereof; an additional agent selected from an immunosuppressant, an anti-cancer agent, an anti-viral agent, anti- inflammatory agent, anti-fungal agent, anti-vascular hyperproliferation agent or an antibiotic agent; and any pharmaceutical acceptable carrier, adjuvant or vehicle.

Thus, for example, additional immunosuppression agents include, but are not limited to, cyclosporin A, FK506, rapamycin, leflunomide, deoxyspergualin, prednisone, azathioprine, OKT3, ATAG, interferon and mizoribine. Additional

anti-vascular hyperproliferative agents include, but are not limited to, HMG Co-A reductase inhibitors such as lovastatin, thromboxane A2 synthetase inhibitors, ciprostene, trapidil, eicosapentanoic acid, ACE inhibitors, low molecular weight heparin, and rapamycin. Additional anti-cancer agents include, but are not limited to, cis-platin, actinomycin D, amsacrine, mitoxantrone, doxorubicin, vincristine, vinblastine, etoposide, tenipaside, taxol, colchicine, cyclosporin A, phenothiazines, interferon and thioxantheres.

Additional anti-viral agents include, but are not limited to, Cytovene, Ganiclovir, trisodium phosphonoformate, Ribavirin, d4T, ddl, AZT and acyclovir.

The above other therapeutic agents, when employed in combination with the compounds of the present invention, may be used, for example, in amounts generally indicated for use in standard formularies (e. g. in the Physician's Desk Reference (PDR) ) or as determined using routine pharmaceutical dosing methods.

Pharmaceutical compositions according to the invention may take a form suitable for oral, buccal, parenteral, nasal, topical, vaginal or rectal administration, or a form suitable for administration by inhalation or insufflation.

For oral administration, the pharmaceutical compositions may take the form of, for example, tablets, lozenges or capsules prepared by conventional means with pharmaceutical acceptable excipients such as binding agents (e. g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose) ; fillers (e. g. lactose, microcrystalline cellulose or calcium hydrogen phosphate); lubricants (e. g. magnesium stearate, talc or silica) ; disintegrants (e. g. potato starch or sodium glycollate) ; or wetting agents (e. g. sodium lauryl sulphate). The tablets may be coated by methods well known in the art. Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may be prepared by conventional means with

pharmaceutical acceptable additives such as suspending agents, emulsifying agents, non-aqueous vehicles and preservatives. The preparations may also contain buffer salts, flavouring, colouring and sweetening agents as appropriate.

Preparations for oral administration may be suitably formulated to give controlled release of the active compound For buccal administration the compositions may take the form of tablets or lozenges formulated in conventional manner.

The compounds for formulae (1), (2) or (3) may be formulated for parenteral administration by injection e. g. by bolus injection or infusion. Formulations for injection may be presented in unit dosage form, e. g. in glass ampoule or multi dose containers, e. g. glass vials. The compositions for injection may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilising, preserving and/or dispersing agents. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e. g. sterile pyrogen- free water, before use. For particle mediated administration the compounds of formulae (1), (2) or (3) may be coated on particles such as microscopic gold particles.

In addition to the formulations described above, the compounds of formulae (1), (2) or (3) may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation or by intramuscular injection.

For nasal administration or administration by inhalation, the compounds for use according to the present invention are conveniently delivered in the form of an aerosol spray presentation for pressurised packs or a nebuliser, with the use of suitable propellant, e. g. dichlorodifluoromethane, trichlor- fluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas or mixture of gases.

For vaginal or rectal administration the compounds of formulae (1), (2) or (3) may be formulated as a suppository. These formulations may be prepared by mixing the active ingredient with a suitable non-irritating excipient which is a solid at room temperature but liquid at the body temperature. Such materials include for example cocoa butter and polyethylene glycols.

The compositions may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient. The pack or dispensing device may be accompanied by instructions for administration.

The quantity of a compound of the invention required for the prophylaxis or treatment of a particular condition will vary depending on the compound chosen, and the condition of the patient to be treated. In general, however, daily dosages may range from around 100ng/kg to 100mg/kg e. g. around 0. 01mg/kg to 40mg/kg body weight for oral or buccal administration, from around 10ng/kg to 50mg/kg body weight for parenteral administration and around 0.05mg to around 1000mg e. g. around 0.5mg to around 1000mg for nasal administration or administration by inhalation or insufflation.

The compounds of the invention may be prepared by a number of processes as generally described below and more specifically in the Examples hereinafter. Many of the reactions described are well-know standard synthetic methods which may be applied to a variety of compounds and as such can be used not only to generate compounds of the invention, but also where necessary the intermediates thereto.

In the following process description, the symbols R1, R2, R3 etc when used in the formulae depicted are to be understood to represent those groups described above in relation to formulae (1), (2) or (3) unless otherwise indicated. In the reactions described below, it may be necessary to protect reactive functional groups, for example hydroxy, amino, thio or carboxy groups, where these are desired in the final product, to avoid their unwanted

participation in the reactions. Conventional protecting groups may be used in accordance with standard practice [see, for example, Green, T. W. in "Protective Groups in Organic Synthesis", John Wiley and Sons, (1999) and the examples herein]. In some instances, deprotection may be the final step in the synthesis of a compound of formulae (1), (2) or (3) and the processes according to the invention described hereinafter are to be understood to extend to such removal of protecting groups.

For example, a compound of formulae (1), (2) or (3) where Y is an O atom may be prepared by following the general route as shown in Scheme A: (i) Scheme A (1) Thus an amine of formula (ii) may be reacted with a sulfonyl chloride of formula (i) using appropriate conditions to give a compound of formula (1).

For example, when R2 in the amine of formula (ii) is a hydrogen atom a base such as pyridine in a halogenated hydrocarbon e. g. dichloromethane may be used. When R2 in amines of formula (ii) is an alkyl group a base such as sodium hydride in a solvent such as N, N-dimethylformamide (DMF) may be employed. It will be appreciated that a compound of formula (1) where R2 is a hydrogen atom may be further manipulated by alkylation of the sulfonamide using standard conditions to give a compound of formula (1) where R2 is an alkyl group. The amines of formula (ii) may be available commercially or prepared using methods known to those skilled in the art.

A compound of formula (i) may be prepared using a variety of conditions. For example when X is a S atom and Y is an O atom the general Scheme B may be used:

0 0 0 OH R3NH2 V)- NHR3 -1-32 t eS 2 S (vi) (iii) (v) Scheme B O 0 CI02S S N-R3 H2N/S N-R3 (i) (vii) A compound of formula (iii) (which may be commercially available or made using methods known to those skilled in the art) may be reacted with an activating agent such as thionyl chloride, to give an intermediate acid choride.

The resulting acid chloride may then be reacted with an amine of formula (iv) (which may be commercially available or made using methods known to those skilled in the art), using standard methodology or methods as described herein for sulfonamide formation to give an amide of formula (v). The compound of formula (v) may be cyclise using appropriate conditions such as treatment with bromine in carbon tetrachloride followed by reflux in acetic acid to yield a compound of formula (vi). See also US 6,191, 275. The nitro group in compounds of formula (vi) may be reduced to an amine, for example using hydrogen in the presence of palladium on carbon, to give an amine of formula (vii). These amines may converted to compounds of formula (i) for example, by initial diazotization using sodium nitrite in the presence of concentrated hydrochloric acid, acetic acid and water at a suitable temperature e. g.-5-0°C followed by addition of acetic acid saturated with sulfur dioxide, copper (I) chloride and warming to room temperature.

The analogues of the compounds of formula (vi) where Y is an O atom may be prepared using literature methodology. See, for example, Wrübel et al Z.

Chem. 1980,20 (1), 18 or Chem. Ber. 1967,100 (3), 954-960.

Alternatively the-SO2CI group in compounds of formula (i) may be introduced directly as shown in the general Scheme C:

(viii) SchemeC (i)<BR> Scheme C Thus, for example, a compound of formula (viii) may be reacted with excess chlorosulfonic acid to give a sulfonyl chloride of formula (i) as shown.

Compounds of formula (viii) may be commercially available or made using methods known to those skilled in the art. For example, when X is a S atom, similar methodology may be used to that as shown in Scheme B using the appropriate starting material of formula (ix): (ix) Appropriate conditions may include treatment of the compound of formula (ix) with oxalyl chloride in dioxane in the presence of catalytic DMF followed by addition of excess methylamine in DMF to afford the corresponding analogue of the compound of formula (vi).

Intermediates of formulae (i)- (ix) and any other intermediates required to obtain compounds of formulae (1), (2) or (3), if not available commercially, may be prepared by methods known to those skilled in the art following procedures set forth in references such as Rodd's Chemistry of Carbon Compounds, Volumes 1-15 and Supplementals (Elsevier Science Publishers, 1989), Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-19 (John Wiley and Sons, 1999), Comprehensive Heterocyclic Chemistry, Ed.

Katritzky et al, Volumes 1-8,1984 and Volumes 1-11,1994 (Pergamon), Comprehensive Organic Functional Group Transformations, Ed. Katritzky et al, Volumes 1-7,1995 Pergamon), Comprehensive Organic Synthesis, Ed. Trost and Flemming, Volumes 1-9, (Pergamon, 1991), Encyclopedia of Reagents for Organic Synthesis Ed. Paquette, Volumes 1-8 (John Wiley and Sons, 1995), Larock's Comprehensive Organic Transformations (VCH

Publishers Inc., 1989) and March's Advanced Organic Chemistry (John Wiley and Sons, 1992). See also the following literature methods which may be used to synthesize the compounds of formulae (vi), (viii) and similar analogues, Fischer R et al Arzneimittel-Forsch 1964 14 (12) 1301-1306, International Patent Application No. WO 98-28283 and Synlett 2000,10, 1427-1428. The analogues of (viii) where both X and Y are an O atom may be prepared using literature methodology, such as Ueda et al, Bull. Chem.

Soc. Jpn. 1983,56 (8), 2485-2489.

It will be appreciated that the compounds of formula (vi), (vii) etc. where R3 is a hydrogen atom may be alkylated using standard conditions to give the corresponding intermediate where R3 is an alkyl group. See, for example, Jpn Kokai Tokkyo Koho 08277278 and J. Med. Chem. 1985, 28 (12), 1772-1779.

It will be appreciated that compounds of formulae (1), (2) or (3) or any preceding intermediates may be further derivatised by one or more standard synthetic methods employing substitution, oxidation, reduction or cleavage reactions. Particular substitution approaches include conventional alkylation, <BR> <BR> <BR> arylation, heteroarylation, acylation, thioacylation, halogenation, sulphonylation, nitration, formylation and coupling procedures. It will be appreciated that these methods may also be used to obtain or modify other compounds of any of formulae (1), (2) or (3) or any preceding intermediates where appropriate functional groups exist in these compounds.

Thus, for example, the compounds where Y is an O atom may be converted to compounds where Y is a S atom, for example, by reaction with Lawesson's reagent in a suitable solvent, such as tetrahydrofuran.

For example, ester groups when present may be converted to the corresponding acid [-C02H] by acid-or base-catalysed hydrolysis depending on the nature of the ester. Acid-or base-catalysed hydrolysis may be achieved for example by treatment with an organic or inorganic acid, e. g. trifluoroacetic acid in an aqueous solvent or a mineral acid such as hydrochloric acid in a solvent such as dioxan or an alkali metal hydroxide, e. g.

lithium hydroxide in an aqueous alcohol, e. g. aqueous methanol. Similarly an acid [-C02H] may be prepared by hydrolysis of the corresponding nitrile [-CN], using for example a base such as sodium hydroxide in a refluxing alcoholic solvent, such as ethanol.

In another example,-OH groups may be generated from the corresponding ester or aldehyde [-CHO] by reduction, using for example a complex metal hydride such as lithium aluminium hydride or sodium borohydride in a solvent such as methanol. Alternatively an alcohol may be prepared by reduction of the corresponding acid [-C02H], using for example lithium aluminium hydride in a solvent such as tetrahydrofuran.

Alcohol groups may be converted into leaving groups, such as an halogen atoms or sulfonyloxy groups such as an alkylsulfonyloxy, e. g. trifluoromethylsulfonyloxy or arylsulfonyloxy, e. g. p-toluenesulfonyloxy group using conditions known to the skilled artisan. For example, an alcohol may be reacted with thionyl chloride in a halogenated hydrocarbon e. g., dichloromethane to yield the corresponding chloride. A base e. g., triethylamine may also be used in the reaction.

In another example, alcohol or phenol groups may be converted to ether groups groups by coupling a phenol with an alcohol in a solvent such as tetrahydrofuran in the presence of a phosphine, e. g. triphenylphosphine and an activator such as diethyl-, diisopropyl-, or dimethylazodicarboxylate. Alternatively ether groups may be prepared by deprotonation of an alcohol, using a suitable base e. g. sodium hydride followed by subsequent addition of an alkylating agent, such as an alkylhalide.

Aldehyde [-CHO] groups may be obtained by oxidation of a corresponding alcohol using well-know conditions. For example using an oxidising agent such as a period inane e. g Dess Martin, in a solvent such as a halogenated hydrocarbon, e. g. dichloromethane. An alternative oxidation may be suitably activating dimethyl sulfoxide using for example, oxalyl chloride, followed by addition of an alcohol, and subsequent quenching of the reaction by the

addition of an amine base, such as triethylamine. Suitable conditions for this reaction may be using an appropriate solvent, for example, a halogenated hydrocarbon, e. g. dichloromethane at-78°C followed by subsequent warming to room temperature.

In a further example primary amine (-NH2) or secondary amine (-NH-) groups may be alkylated using a reductive alkylation process employing an aldehyde and a borohydride, for example sodium triacetoxyborohyride or sodium cyanoborohydride, in a solvent such as a halogenated hydrocarbon, e. g. dichloromethane, a ketone such as acetone, or an alcohol, e. g. ethanol, where necessary in the presence of an acid such as acetic acid at around ambient temperature.

In a further example, amine [-NH2] groups may be obtained by hydrolysis from a corresponding imide by reaction with hydrazine in a solvent such as an alcohol, e. g. ethanol at ambient temperature.

In another example, a nitro [-NO2] group may be reduced to an amine [-NH2], for example by catalytic hydrogenation using for example hydrogen in the presence of a metal catalyst, for example palladium on a support such as carbon in a solvent such as an ether, e. g. tetrahydrofuran or an alcohol e. g. methanol, or by chemical reduction using for example a metal, e. g. tin or iron, in the presence of an acid such as hydrochloric acid.

In a further example amine (-CH2NH2) groups may be obtained by reduction of nitriles (-CN), for example by catalytic hydrogenation using for example hydrogen in the presence of a metal catalyst, for example palladium on a support such as carbon, or Raney nickel, in a solvent such as an ether e. g. a cyclic an ether, e. g. a cyclic ether such as tetrahydrofuran, at a temperature from-78°C to the reflux temperature.

Aromatic halogen substituents in the compounds may be subjected to halogen-metal exchange by treatment with a base, for example a lithium base such as n-butyl or t-butyl lithium, optionally at a low temperature, e. g. around

- 78°C, in a solvent such as tetrahydrofuran and then quenched with an electrophile to introduce a desired substituent. Thus, for example, a formyl group may be introduced by using dimethylformamide as the electrophile ; a thiomethyl group may be introduced by using dimethyidisulphide as the electrophile. Aromatic halogen substituents may also be subjected to palladium catalysed reactions, to introduce, for example, acid, ester, cyano or amino substituents.

In another example, sulphur atoms in the compounds, for example when present in a linker group may be oxidised to the corresponding sulphoxide or sulphone using an oxidising agent such as a peroxy acid, e. g. 3- chloroperoxybenzoic acid, in an inert solvent such as a halogenated hydrocarbon, e. g. dichloromethane, at around ambient temperature.

N-oxides of compounds of formulae (1), (2) or (3) may be prepared for example by oxidation of the corresponding nitrogen base using an oxidising agent such as hydrogen peroxide in the presence of an acid such as acetic acid, at an elevated temperature, for example around 70°C to 80°C, or alternatively by reaction with a peracid such as peracetic acid in a solvent, e. g. dichloromethane, at ambient temperature.

Salts of compounds of formulae (1), (2) or (3) may be prepared by reaction of a compound of formulae (1), (2) or (3) with an appropriate base or acid in a suitable solvent or mixture of solvents e. g. an organic solvent such as an ether e. g. diethylether, or an alcohol, e. g. ethanol or an aqueous solvent using conventional procedures. Salts of compounds of formulae (1), (2) or (3) may be exchanged for other salts by use of conventional ion-exchange chromatography procedures.

Where it is desired to obtain a particular enantiomer of a compound of formulae (1), (2) or (3) this may be produced from a corresponding mixture of enantiomers using any suitable conventional procedure for resolving enantiomers.

Thus for example diastereomeric derivatives, e. g. salts, may be produced by reaction of a mixture of enantiomers of formulae (1), (2) or (3) e. g. a racemate, and an appropriate chiral compound, e. g. a chiral base. The diastereomers may then be separated by any convenient means, for example by crystallisation and the desired enantiomer recovered, e. g. by treatment with an acid in the instance where the diastereomer is a salt.

In another resolution process a racemate of formulae (1), (2) or (3) may be separated using chiral High Performance Liquid Chromatography.

Alternatively, if desired a particular enantiomer may be obtained by using an appropriate chiral intermediate in one of the processes described above.

Chromatography, recrystallisation and other conventional separation procedures may also be used with intermediates or final products where it is desired to obtain a particular geometric isomer of the invention.

The following Examples illustrate the invention. All temperatures are in °C.

Where experimental detail is not given for the preparation of a reagent it is either commercially available, known in the literature (for which the CAS number is quoted) or may be prepared using standard methodology known to those skilled in the art. The compounds are named with the aid of Beilstein Autonom.

1H NMR spectra were obtained at 300MHz unless otherwise indicated.

Abbreviations used: CDC13-deuterated chloroform CD30D-deuterated methanol d6-DMSO-deuterated dimethylsulfoxide BOC-tert-butoxy carbonyl R. T. -retention time LCMS conditions: Method A HP1050 (Diode Array) linked to a Finnigan LC-Q Mass Spectrometer, ESI mode with Pos/Neg ionization Column : Luna C18 (2) 100x4. 6mm, 5 m particle size Analytical column Column Temp : 30° C Mobile Phase: A: Water + 0.08% formic acid B: Acetonitrile + 0.08% formic acid Flow rate: 2ml/min Gradient: Time (mins): % Composition B:

0.0 5 6.50 95 8.00 95 8.05 5 10.00 5 Run time : 10. 0 mins Typical Injection Vol : 5, u1 Detector Wavelength: DAD 210nu LCMS conditions : Method B HP1050 (Diode Array) linked to a Finnigan LC-Q Mass Spectrometer, ESI mode with Pos/Neg ionization Column : Luna C18 (2) 100x4. 6mm, 5µm particle size Analytical column Column Temp: 35° C Mobile Phase: A: Water + 0.08% formic acid B: Acetonitrile + 0.08% formic acid Flow rate: 3ml/min Gradient: Time (mins): % Composition B: 0.0 5 4.40 95 5.30 95 5.32 5 6.50 5 Run time: 6.50 mins Typical Injection Vol : 5, u1 Detector Wavelength : DAD 210nu INTERMEDIATE 1 2-Methvl-3-oxo-2, 3-dihvdrobenzofdlisothiazole-5-sulfonvl chloride Ice cold chlorosulfonic acid (10mi) was added dropwise to 2-methyl- benzo [d]isothiazol-3-one (0.42g) at 0°C and the mixture was allowed to slowly warm to room temperature and was stirred under nitrogen for 54h.

The reaction mixture was taken up in ethyl acetate (150 ml) and washed with water (150 ml), dried (magnesium sulfate) and concentrated in vacuo to give a brown solid. The product was purified by flash chromatography on silica eluting with 7: 3 to 6: 4 heptane: ethyl acetate to yield the title compound (0.17g) as a white solid. TLC Rf 0.2 (1: 1 heptane: ethyl acetate).'HNMR (CDCl3, 300MHz) 8 8.71 (1 H, d), 8,21 (1 H, dd), 7.8 (1 H, d), 3.48 (3H, s)

Intermediates 2 and 3 were similarly prepared: INTERMEDIATE 2 2-Isopropvl-3-oxo-2, 3-dihvdrobenzofdlisothiazole-5-sulfonvl chloride Using 2-isopropylbenzo [d]isothiazol-3one (CAS 6479119) to give a mixture of isomers that was used without further purification.

INTERMEDIATE 3 3-Oxo-2, 3-dihvdrobenzofdlisothiazole-5-sulfonvl chloride Using benzo [agisothiazol-3-one (CAS 119510) ) to give a mixture of isomers that was used without further purification.

INTERMEDIATE 4 <BR> <BR> <BR> <BR> 4- (2-Methyl-3-oxo-2, 3-dihvdrobenzoldlisothiazole-5-sulfonvl) piperazine- 1-carboxvlic acid tert-butyl ester To a solution of 2-methyl-3-oxo-2, 3-dihydrobenzo [d] isothiazole-5-sulfonyl chloride (261 mg, 0. 9mmol)) in anhydrous dichloromethane (20ml) was added tert-butyl piperazine carboxylate (184mg, 0. 99mmol) followed by triethylamine (0. 207moi, 1. 48ml) and the mixture stirred overnight at room temperature. The organic solvent was removed in vacuo and the resulting residue dissolved in ethyl acetate (75ml). The organics were washed with sodium carbonate solution (2x1 Oml), water (1 Oml), 1 % citric acid solution (2x20ml), water (10ml), sodium carbonate solution (10ml), saturated sodium chloride solution (20ml), dried over sodium sulfate, filtered and concentrated down to yield the title compound as a cream solid (222mg, 54%). TLC Rf 0.53 (5% methanol : dichloromethane) INTERMEDIATE 5 2-Methvl-5- (piperazine-1-sulfonvll-benzordlisothiazole-3-one To a solution of 4- (2-methyl-3-oxo-2, 3-dihydrobenzo [dJisothiazole-5-sulfonyl)- piperazine-1-carboxylic acid tert-butyl ester (504mg, 1. 22mmol) in dichloromethane (18ml) was added trifluoroacetic acid (2ml) and the mixture stirred overnight at room temperature. The organic solvent was removed in vacuo and the resulting residue dissolved in water (20mut) and washed with diethyl ether (20ml). The organic layer was extracted with water (5ml) and the aqueous layer basified with concentrated sodium hydroxide solution to pH 13, saturated with solid sodium chloride and extracted with ethyl acetate (3x15m1).

The basic aqueous layer was further extracted with dichloromethane

(5x10ml). The ethyl acetate and dichloromethane extracts were independantly washed with saturated sodium chloride solution (15mi) then combined and dried over sodium sulfate, filtered and concentrated down to yield the title compound as a white solid (356mg, 93%). TLC Rf 0.24 (5% methanol : dichloromethane plus 1 % ammonia solution). MS 314 (M+H); HPLC method B: R. T = 1.27 mins.

EXAMPLE 1 2-Methvl-3-oxo-2, 3-dihvdrobenzordlisothiazole-5-sulfonic acid (2-ethyl- phenvl) amide To a solution of 2-methyl-3-oxo-2, 3-dihydrobenzo [agisothiazole-5-sulfonyl chloride (50mg) in dichloromethane (20mi) under nitrogen at room temperature was added pyridine (0.1 ml) followed by 2-ethylaniline (0.1ml) and the mixture was stirred for 24h. The reaction mixture was taken up in ethyl acetate (150 ml) and washed with 1 N hydrochloric acid (200ml), sodium hydrogen carbonate solution (150ml), dried (magnesium sulfate) and concentrated in vacuo to give an off white solid. The solid was washed with diethyl ether (15ml) and dried in vacuo to yield the title compound as a white solid (40mg). TLC Rf 0.18 (1: 1 heptane: ethyl acetate); MS 347 (M+H) 'H NMR (CDC13, 300MHz) 5 8.48 (1H, d), 7.88 (1H, dd), 7.59 (1H, d), 7.12- 7.16 (3H, m), 6.44 (1 H, s), 3.47 (3H, s), 2.40 (2H, q), 1.06 (3H, t).

The following examples 2-9 were similarly prepared as for example 1 using 2- methyl-3-oxo-2, 3-dihydro-benzo [d]isothiazole-5-sulfonyl chloride and the appropriate amine: EXAMPLE 2 <BR> <BR> <BR> <BR> 2-Methvl-3-oxo-2, 3-dihvdrobenzordlisothiazole-5-sulfonic acid (pvridin-2- ylmethyl)amide Purification was carried out by flash chromatography on silica eluting with ethyl acetate to yield the title compound (18mg) as a white solid. TLC Rf 0.17 (ethyl acetate); MS 336 (M+H)'H NMR (CD30D, 300MHz) 88. 25 (1H, d), 8.20 (1H, d), 7.92 (1H, dd), 7.82 (1H, d), 7.6 (1H, td), 7.3 (1H, d), 7.1 (1H, td), 4.14 (2H, s), 3.35 (3H, s).

EXAMPLE 3 Methvl-3-(2-methvl-3-oxo-2X3-dihvdrobenzordlisothiazole-5- sulfonylamino)benzoic acid methyl ester.

Purification was carried out by flash chromatography on silica eluting with 50% ethyl acetate in hexane to yield the title compound (8mg) as a white solid. TLC Rf 0.21 (1: 1 heptane: ethyl acetate); MS 393 (M+H) 1H NMR (d6- DMSO, 300MHz) 8 8.05 (1H, d), 7.89 (1H, d), 7.73 (1H, dd), 7.55 (1H, dd), 7.43 (1H, d), 7.18 (1H, d), 3.65 (3H, s), 3.24 (3H, s), 1.90 (3H, s).

EXAMPLE 4 2-Methvl-3-oxo-23-dihvdrobenzordlisothiazole-5-sulfonic acid (3-oxo- 1, 3-dihvdroisobenzofuran-5-vl) amide Purification was carried out by flash chromatography on silica eluting with 5% methanol in dichloromethane to yield the title compound (17mg) as a white solid. TLC Rf 0.45 (5 % methanol in dichloromethane) ; MS 376 (M+H) 1HNMR (d6-DMSO, 300MHz) 610. 78 (1H, bs), 8.16 (1H, d), 8.14 (1H, d), 7.95 (1 H, dd), 7.55 (1 H, d), 7.47 (1 H, d), 7.45 (1 H, d), 5.27 (2H, s), 3.30 (3H, s).

EXAMPLE 5 2-Methvl-3-oxo-2, 3-dihvdrobenzofdlisothiazole-5-sulfonic acid (3- methoxv-4-oxazol-5-vl-phenvl) amide Purification was carried out by flash chromatography on silica eluting with 5% methanol in dichloromethane to yield the title compound (36mg) as a white solid. TLC Rf 0.34 (5 % methanol in dichloromethane) ; MS 418 (M+H)'H NMR (d6-DMSO, 300MHz) 8 10.74 (1H, bs), 8.45 (1H, s), 8.29 (1H, d), 8.28 (1H, d), 8.10 (1H, dd), 7.65 (1H, d), 7.50 (1H, s), 7.02 (1H, d), 6.90 (1H, dd), 3.95 (3H, s), 3.42 (3H, s).

EXAMPLE 6 <BR> <BR> <BR> <BR> 2-Methvl-3-oxo-2, 3-dihvdrobenzordlisothiazole-5-sulfonic acid (5-iodo- Pvridin-2-vl) amide Using 2-amino-5-iodopyridine to yield 71.0 mg (42%). Purification was carried out by recrystallisation in ethyl acetate. TLC Rf 0.19 (1: 1 heptane: ethyl acetate). MS 448.0 (M+H); HPLC method A: R. T. =4.08 EXAMPLE 7 5- (2, 3-Dihvdroindole-1-sulfonVi)-2-methylbenzof dlisothiazol-3-one

Using indoline to yield 8.0 mg (31%). Purification was carried out by flash chromatography on silica eluting with a gradient of 30 to 80 % ethyl acetate in heptane. TLC Rf 0.69 (ethyl acetate). MS 447.1 (M+H); HPLC method A: R. T. =4.66 EXAMPLE 8 2-Isopropvl-3-oxo-2, 3-dihvdrobenzordlisothiazole-5-sulfonic acid (2- ethvlphenvl) amide Using 2-isopropyl-3-oxo-2, 3-dihydrobenzo [agisothiazole-5-sulfonyl chloride and 2-ethylaniline to yield 43 mg (10%). Purification was carried out by flash chromatography on silica eluting with a gradient of 20 to 30 % ethyl acetate in heptane. TLC Rf 0.32 (1: 1 heptane: ethyl acetate). MS 377.1 (M+H); HPLC method A: R. T. =5.17 EXAMPLE 9 3-Oxo-2, 3-dihvdrobenzordlisothiazole-5-sulfonic acid (2-ethvlphenvl) amide Using 3-oxo-2,3-dihydrobenzo [agisothiazole-5-sulfonyl chloride and 2- ethylaniline to yield 10.9 mg (4 %). Purification was carried out by flash chromatography on silica eluting with a gradient of 30 to 50 % ethyl acetate in heptane. TLC Rf 0.20 (1: 1 heptane: ethyl acetate). MS 335.2 (M+H); HPLC method A: R. T. =4.33 EXAMPLE 10 <BR> <BR> <BR> <BR> 4- (2-Methvl-3-oxo-2, 3-dihvdrobenzof dlisothiazole-5-sulfonvl) piperazine- 1-carboxvlic acid ethylamide To a solution of 2-methyl-5-(piperazine-1-sulfonyl) benzo [d] isothiazole-3-one (50mg, 0. 16mmol) in dichloromethane (5ml) was added ploymer supported diisopropylethylamine (110mg, 0. 38mmol) followed by ethyl isocyanate 23mg, 0. 32mmol) and the reaction stirred at room temperature for 3.5h. To the reaction mixture was added polymer supported isocyanate (277mg, 0. 40mmol) and polymer supported trisamine (236mg, 0. 80mi) and the mixture stirred overnight at room temperature. The reaction was filtered and concentrated using a Genevac to yield the title compound (64mg, quantative).

MS 385 (M+H); HPLC method B: R. T = 2. 13.

The following examples 11-12 were similarly prepared as for example 10 using 2-methyl-5-(piperazine-1-sulfonyl) benzo [d]isothiazole-3-one and the appropriate sulfonyl chloride or isocyante.

EXAMPLE 11 <BR> <BR> <BR> <BR> 5-(4-Methanesulfonvlpiperazine-1-sulfonvl)-2-methvibenzordli sothiazole- 3-one Using methane sulfonyl chloride to yield 46mg (73%).

MS 392 (M+H); HPLC method B: R. T = 2.33 mins.

EXAMPLE 12 <BR> <BR> <BR> <BR> 5-(4-Benzenesulfonvlpiperazine-1-sulfonvl)-2-methvibenzordli sothiazole- 3-one Using benzene sulfonyl chloride to yield 78mg (54%).

MS 454 (M+H); HPLC method B: R. T = 3.02 mins.

EXAMPLE 13 2-Methvl-3-oxo-2, 3-dihvdrobenzofdlisothiazole-5-sulfonic acid [3- (4- methvlpiperazin-1 vl) Propvllamide To a mixture of polymer supported diisopropylethylamine (31 mg) in dichloromethane (1.5 ml), which had been stirred for 5 minutes under nitrogen, was added 1- (3-aminopropyl)-4-methylpiperazine (11 mg) in dichloromethane (1.5 mi) followed by 2-methyl-3-oxo-2, 3-dihydro- benzo [dJisothiazole-5-sulfonyl chloride (20 mg) and the mixture was stirred for 16 hours at room temperature under nitrogen. To the reaction mixture was added polymer supported isocyanate (145 mg) and polymer supported trisamine (47 mg) and the mixture was stirred for a further 5 hours. The reaction was filtered and concentrated using a Genevac to yield the title compound (15 mg, 51%). MS 385.3 (M+H); HPLC method A: R. T = 1.48 mins The following examples 14-37 were similarly prepared as for example 13 using 2-methyl-3-oxo-2, 3-dihydrobenzo [d] isothiazole-5-sulfonyl chloride and the appropriate amine.

EXAMPLE 14 <BR> <BR> <BR> 2-Methvt-3-oxo-2, 3-dihydrobenzordlisothiazole-5-sulfonic acid (3-<BR> <BR> <BR> <BR> <BR> imidazol-1-vlpropvl) amide

Using 1- (3-aminopropyl) imidazole to yield 10 mg (37%). MS 353.2 (M+H); HPLC method A: R. T. =1.23 EXAMPLE 15 2-Methvl-3-oxo-2, 3-dihvdrobenzofdlisothiazole-5-sulfonic acid (2- morpholin-4-yl-ethyl)amide Using 4- (2-aminomethyl) morpholine to yield 15 mg (55%). MS 358.2 (M+H); HPLC method A: R. T. =1.73 EXAMPLE 16 5-r4- (6-Fluorobenzordlisoxazol-3-vl) piperidine-1-sulfonvil-2-methvl- benzo[d]isothiazol-3-one Using 6-fluoro-3-piperidin-4-yl-benzo [agisoxazole (CAS 5543727) to yield 85 mg (83%). MS 448.1 (M+H); HPLC method A: R. T. =3.47 EXAMPLE 17 5-94-(4-Chlorophenoxv) piperidine-1-sulfonvll-2-methvl- benzo[d]isothiazol-3-one Using 4- (4-chloro-phenoxy)-piperidine to yield 83 mg (100%). MS 439.1 (M+H); HPLC method B: R. T. =3.77 EXAMPLE 18 <BR> <BR> <BR> <BR> 2-Methvl-5-f4- (pvrazin-2-vloxv) piperidine-1-sulfonvllbenzordlisothiazol-3- one Using 2-(piperidin-4-yl-oxy)-pyrazine to yield 77.1 mg (59%). MS 407.0 (M+H); HPLC method B: R. T. =2.75 EXAMPLE 19 2-Methvl-5- (morpholine-4-sulfonvllbenzordlisothiazol-3-one Using morpholine to yield 59.7 mg (100%). MS 315.1 (M+H); HPLC method B: R. T. =2.24 EXAMPLE 20 5-((S)-2-Methoxvmethvlpvrrolidine-1-sulfonvl)-2-methvl- benzo[d]isothiazol-3-one Using (S)-2-methoxymethylpyrrolidine to yield 65.0 mg (100%). MS 343.1 (M+H); HPLC method B: R. T. =2.61 EXAMPLE 21 2-Methvl-3-oxo-2, 3-dihydrobenzo[d]isothiazole-5-sulfonic acid (2- dimethvlamino-ethvl) amide

Using 2-dimethylaminoethylamine to yield 60.0 mg (100%). MS 316.1 (M+H); HPLC method B: R. T. =1.16 EXAMPLE 22 <BR> <BR> <BR> <BR> 2-Methvl-3-oxo-2, 3-dihvdrobenzordlisothiazole-5-sulfonic acid<BR> <BR> <BR> <BR> dimethvlamide Using dimethylamine to yield 51.7 mg (100%). MS 273.2 (M+H); HPLC method B: R. T. =2.27 EXAMPLE 23 5-94-(5-Methoxvbenzooxazol-2-vl) piperidine-1-sulfonvil-2-methvl- benzo[d]isothiazol-3-one Using 5-methoxy-2-piperidin-4-yl-benzooxazole to yield 34.9 mg (40%).

The title compound was then purified by trituration with ethyl acetate.

MS 460.2 (M+H); HPLC method B: R. T. =3.21 EXAMPLE 24 5-[3-(3,4-Dichlorobenzyloxy)-azetidine-1-sulfonyl]-2-methyl- benzordlisothiazol-3-one Using 3- (3, 4-dichloro-benzyloxy)-azetidine to yield 25.7 mg (29%). The title compound was then purified by column chromatography eluting with 5 % methanol in dichloromethane. MS 459.1 (M+H); HPLC method B: R. T. =3.66 EXAMPLE 25 4-(2-Methvl-3-oXo-2q3-dihvdrobenzordlisothiazole-5-sulfonvl) - [1,4]diazepane-1-carboxylic acid tert-butyl ester Using 1-Boc-homopiperazine to yield 15mg (50%). MS 428 (M+H); HPLC method A: R. T = 4.59 mins EXAMPLE 26 (S)-1- (2-Methvl-3-oxo-2, 3-dihvdrobenzordlisothiazole-5-sulfonvl)- pvrrolidine-2-carboxvlic acid amide Using L-prolinamide to yield 15mg (63%). MS 342 (M+H); HPLC method B: R. T= 1.81 mins EXAMPLE 27 5- (4-Acetvlpiperazine-1-sulfonvl)-2-methvlbenzofdlisothiazol-3 -one Using 1-acetylpiperazine to yield 15mg (60%).

MS 356 (M+H); HPLC method A: R. T = 2.98 mins.

EXAMPLE 28 5-(1,4-Dioxa-8-azaspiro[4.5]decane-8-sulfonyl)-2-methyl benzofdlisothiazol-3-one Using 1,4-dioxa-8-azaspiro (4,5) decane to yield 15mg (58%).

MS 371 (M+H); HPLC method A: R. T = 3.73 mins.

EXAMPLE 29 5- (4-Benzvlpiperidine-1-sulfonvl)-2-methvlbenzordlisothiazol-3 -one Using 4-benzylpiperidine to yield 15mg (55%).

MS 403 (M+H); HPLC method A: R. T = 5.55 mins.

EXAMPLE 30 2-Methvl-5- benzordlisothiazol- 3-one Using 1- (4-pyridylmethyl) piperazine to yield 15mg (55%).

MS 405 (M+H); HPLC method B: R. T = 1.46 mins.

EXAMPLE 31 <BR> <BR> <BR> <BR> <BR> N-Methvl-2-r4-(2-methvl-3-oxo-23-dihvdrobenzordlisothiazole- 5-<BR> <BR> <BR> <BR> <BR> <BR> <BR> sulfonvl) iperazin-1-yll-N-phenvlacetamide Using piperazinoacetic acid-N-methylanilide to yield 15mg (48%).

MS 461 (M+H); HPLC method B: R. T = 1.75 mins.

EXAMPLE 32 2-Methvl-3-oxo-2, 3-dihvdrobenzordlisothiazole-5-sulfonic acid (2- methoxvethvl) amide Using 2-methoayethylamine to yield 45mg (88%).

MS 303 (M+H); HPLC method B: R. T = 2.03 mins.

EXAMPLE 33 <BR> <BR> <BR> <BR> 5-f4- (1-Furan-2-vimethanovl) piperazine-1-sulfonvll-2-methvl-<BR> <BR> <BR> <BR> <BR> <BR> <BR> benzofdlisothiazol-3-one Using 1- (2-furoyl) piperazine to yield 71 mg (quantative).

MS 408 (M+H); HPLC method B: R. T = 2.45 mins.

EXAMPLE 34 <BR> <BR> <BR> <BR> <BR> N-Isopropvl-2-r4- (2-methvl-3-oxo-2, 3-dihvdrobenzof dlisothiazole-5-<BR> <BR> <BR> <BR> <BR> <BR> sulfonvl) piperazin-1-vllacetamide Using N-isopropyl-1-piperazineacetamide to yield 72mg (quantative).

MS 431 (M+H); HPLC method B: R. T = 1.58mins.

EXAMPLE 35 <BR> <BR> <BR> <BR> 5-(4-Benzof1 31dioxol-5-vlmethvlPiperazine-1-sulfonvl)-2-methvl-<BR> ; <BR> <BR> <BR> <BR> benzordlisothiazol-3-one Using 1-piperonylpiperazine to yield 102mg (quantative).

MS 448 (M+H); HPLC method B: R. T = 1.67mins.

EXAMPLE 36 <BR> <BR> <BR> <BR> 6-r4- (2-methvl-3-oxo-2, 3-dihvdrobenzofdlisothiazole-5-sulfonvl)-<BR> <BR> <BR> <BR> <BR> piperaain-1-vllnicotinonitrile Using 6-piperazinonicotinonitrile to yield 74mg (quantative).

MS 416 (M+H); HPLC method B: R. T = 2.93 mins.

EXAMPLE 37 <BR> <BR> <BR> <BR> 2-Methvl-3-oxo-2, 3-dihvdrobenzordlisothiazole-5-sulfonic acidfl- (2-<BR> <BR> <BR> <BR> <BR> phenvloxazol-4-vimethvl) pvrrolidin-3-vllamide Using 1-(2-phenyl-oxazol-4-ylmethyl) pyrrolidin-3-yl-amide to yield 77mg (96%). MS 471 (M+H); HPLC method B: R. T = 1. 84 mins.

EXAMPLE 38 <BR> <BR> <BR> <BR> 2-Methvl-3-oxo-23-dihvdrobenzordlisothiazole-5-sulfonic acid (2-<BR> <BR> <BR> <BR> <BR> ethvlphenvl) methvlamide To a stirred suspension of sodium hydride in dry dimethylformamide under nitrogen at room temperature was added 2-methyl-3-oxo-2, 3-dihydro- benzo [agisothiazole-5-sulfonic acid (2-ethyl-phenyl)-amide (60 mg) in dimethyl formamide dropwise and the mixture was stirred for 10 minutes before the addition of iodomethane (0.011 ml). The reaction mixture was stirred for 16 hours and then taken up in ethyl acetate (150 ml) and washed with water, dried (magnesium sulfate) and concentrated in vacuo to give an off white solid. The solid was washed with diethyl ether (15ml) and dried in vacuo to yield the title compound as a white solid (19.4 mg, 31%). TLC Rf 0.19 (1: 1 heptane: ethyl acetate). MS 363.1 (M+H); HPLC method A: R. T. =5.05 The ability of the compounds of the invention to inhibit the IMPDH enzymes may be determined using the following assays: Abbreviatons used: IMPDH Inosine 5'monophosphate dehydrogenase IMP Inosine 5'monophosphate

XMP Xanthosine 5'-monophosphate NAD Nicotinamide adenine dinucleotide NADH Nicotinamide adenine dinucleotide, reduced form MTT 3- (4, 5-Dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide Assay Protocol 1 IMPDH catalyses the NAD dependent oxidation of IMP to XMP with the concomitant production of NADH. IMPDH activity was determined in a coupled assay, where the NADH produced by IMPDH is utilised by the enzyme Diaphorase to reduce it's substrate, MTT, to give a purple product.

The appearance of this product is monitored as an increase in absorbance at 580nm. Assays were performed in a final volume of 100, u1 containing IMPDH (25µg), NAD (1. 1mM), IMP (2.6mM), Diaphorase (40, ug), MTT (0.12mM), 2% DMSO, 30mM KCI and 100mM Tris/HCI, pH7.5. The change in absorbance at 540 nm is read after incubation at 37°C for 60 minutes. To determine the IC50 values, test compounds were prepared at an initial concentration of 1.5 mM in 100% DMSO, then diluted in assay buffer to 0.3mM. Further dilutions were made in assay buffer containing 20% DMSO, prior to diluting 10-fold into the assay, to allow testing across the range 1 nM to 30, uM.

Diaphorase assay To exclude the possibility of identifying compounds that inhibit the Diaphorase component of the coupled assay, all compounds showing inhibition in the IMPDH assay were screened again in a Diaphorase only assay. Assays were performed in a final volume of 100/il containing Diaphorase (0. 6µg), NADH (159, uM), MTT (0.12mM), 2% DMSO, 30mM KCI and 100mM Tris/HCI, pH7.5.

The change in absorbance at 540 nm is read after incubation at 37°C for 60 minutes. Compounds were included at the concentrations used in the coupled assay.

Assay Protocol 2 IMPDH catalyses the NAD dependent oxidation of IMP to XMP with concomitant reduction of the coenzyme. IMPDH activity was determined by monitoring the production of the fluorescent product, NADH. Assays were performed in a final volume of 200µl containing IMPDH (2, ug), NAD (1001-iM),

IMP (100, uM), 1 % DMSO, 30mM KCI and 10OOmM Tris/HCI, pH7.5.

Fluorescence (excitation 340nm/emission 465nm) was read continuously at 25°C for 30 minutes. From this data, initial rates (i. e. change in fluorescence intensity per minute) were calculated. To determine the IC50 values, test compounds were prepared at an initial concentration of 1. 0mM in 100% DMSO, then diluted in assay buffer to 0.2mM. Further dilutions were made in assay buffer containing 20% DMSO, prior to diluting 20-fold into the assay, to allow testing across the range 0.3nM to 10µM.

The functional effect of the compounds of the invention may be demonstrated using the following assay: PBMC Proliferation Assav Peripheral blood mononuclear cells were isolated from freshly taken human blood using standard procedures. Cells were plated out in RPMI medium containing 5% human serum in the presence and absence of inhibitor. PHA (25F1 of 30Fg/ml solution to each well) was added and the plates were incubated at 37°C in an atmosphere of 95% air/5% C02 for 48 hours. 0. 5, uCi of tritiated thymidine was added to each well and the plates were incubated for a further 18 hours. The contents of the plate were transferred to a filter plate and the cells washed with saline. The plates were dried, microscintillation fluid was added to each well and the plate was counted on a scintillation counter. IC50 values were calculated by plotting inhibitor concentration versus % inhibition.

The assay described above can be carried out using anti-CD3 (401l1 of 3750ng/ml concentration to each well) stimulation instead of PHA.