DISULFONAMIDES USEFUL IN THE TREATMENT OF INFLAMMATION

Field of the Invention

This invention relates to novel pharmaceutically-useful compounds, which compounds are useful as inhibitors of enzymes belonging to the membrane- associated proteins in the eicosanoid and glutathione metabolism (MAPEG) family. Members of the MAPEG family include the microsomal prostaglandin E synthase-1 (mPGES-1 ), 5-lipoxygenase-activating protein (FLAP), leukotriene C ₄ synthase and microsomal glutathione S-transferases (MGST1 , MGST2 and MGST3). The compounds are of potential utility in the treatment of inflammatory diseases including respiratory diseases. The invention also relates to the use of such compounds as medicaments, to pharmaceutical compositions containing them, and to synthetic routes for their production.

Background of the Invention

There are many diseases/disorders that are inflammatory in their nature. One of the major problems associated with existing treatments of inflammatory conditions is a lack of efficacy and/or the prevalence of side effects (real or perceived).

Inflammatory diseases that affect the population include asthma, inflammatory bowel disease, rheumatoid arthritis, osteoarthritis, rhinitis, conjunctivitis and dermatitis.

Inflammation is also a common cause of pain. Inflammatory pain may arise for numerous reasons, such as infection, surgery or other trauma. Moreover, several diseases including malignancies and cardioavascular diseases are known to have inflammatory components adding to the symptomatology of the patients.

Asthma is a disease of the airways that contains elements of both inflammation and bronchoconstriction. Treatment regimens for asthma are based on the severity of the condition. Mild cases are either untreated or are only treated with inhaled β-agonists which affect the bronchoconstriction element, whereas

patients with more severe asthma typically are treated regularly with inhaled corticosteroids which to a large extent are anti-inflammatory in their nature.

Another common disease of the airways with inflammatory and bronchoconstrictive components is chronic obstructive pulmonary disease (COPD). The disease is potentially lethal, and the morbidity and mortality from the condition is considerable. At present, there is no known pharmacological treatment capable of changing the course of the disease.

The cyclooxygenase (COX) enzyme exists in two forms, one that is constitutively expressed in many cells and tissues (COX-1), and one that in most cells and tissues is induced by pro-inflammatory stimuli, such as cytokines, during an inflammatory response (COX-2).

COXs metabolise arachidonic acid to the unstable intermediate prostaglandin H ₂ (PGH ₂ ). PGH ₂ is further metabolized to other prostaglandins including PGE ₂ , PGF ₂ Q, PGD ₂ , prostacyclin and thromboxane A ₂ . These arachidonic acid metabolites are known to have pronounced physiological and pathophysiological activity including pro-inflammatory effects.

PGE ₂ in particular is known to be a strong pro-inflammatory mediator, and is also known to induce fever and pain. Consequently, numerous drugs have been developed with a view to inhibiting the formation of PGE ₂ , including "NSAIDs" (non-steroidal antiinflammatory drugs) and "coxibs" (selective COX-2 inhibitors). These drugs act predominantly by inhibition of COX-1 and/or COX-2, thereby reducing the formation of PGE ₂ .

However, the inhibition of COXs has the disadvantage that it results in the reduction of the formation of all metabolites downstream of PGH ₂ , some of which are known to have beneficial properties. In view of this, drugs which act by inhibition of COXs are therefore known/suspected to cause adverse biological effects. For example, the non-selective inhibition of COXs by NSAIDs may give rise to gastrointestinal side-effects and affect platelet and renal function. Even the selective inhibition of COX-2 by coxibs, whilst reducing such gastrointestinal side-effects, is believed to give rise to cardiovascular problems.

An alternative treatment of inflammatory diseases that does not give rise to the above-mentioned side effects would thus be of real benefit in the clinic. In particular, a drug that inhibits (preferably selectively) the transformation of PGH ₂ to the pro-inflammatory mediator PGE ₂ might be expected to reduce the inflammatory response in the absence of a corresponding reduction of the formation of other, beneficial arachidonic acid metabolites. Such inhibition would accordingly be expected to alleviate the undesirable side-effects mentioned above.

PGH ₂ may be transformed to PGE ₂ by prostaglandin E synthases (PGES). Two microsomal prostaglandin E synthases (mPGES-1 and mPGES-2), and one cytosolic prostaglandin E synthase (cPGES) have been described.

The leukotrienes (LTs) are formed from arachidonic acid by a set of enzymes distinct from those in the COX / PGES pathway. Leukotriene B ₄ is known to be a strong proinflammatory mediator, while the cysteinyl-containing leukotrienes C ₄ , D ₄ and E ₄ (CysLTs) are mainly very potent bronchoconstrictors and have thus been implicated in the pathobiology of asthma. The biological activities of the CysLTs are mediated through two receptors designated CysLTi and CysLT ₂ . As an alternative to steroids, leukotriene receptor antagonists (LTRas) have been developed in the treatment of asthma. These drugs may be given orally, but do not control inflammation satisfactorily. The presently used LTRas are highly selective for CySLT ₁ . It may be hypothesised that better control of asthma, and possibly also COPD, may be attained if the activity of both of the CysLT receptors could be reduced. This may be achieved by developing unselective LTRas, but also by inhibiting the activity of proteins, e.g. enzymes, involved in the synthesis of the CysLTs. Among these proteins, 5-lipoxygenase, 5-lipoxygenase-activating protein (FLAP), and leukotriene C ₄ synthase may be mentioned. A FLAP inhibitor would also decrease the formation of the proinflammatory LTB ₄ .

mPGES-1 , FLAP and leukotriene C ₄ synthase belong to the membrane- associated proteins in the eicosanoid and glutathione metabolism (MAPEG) family. Other members of this family include the microsomal glutathione S- transferases (MGST1 , MGST2 and MGST3). For a review, c.f. P. -J. Jacobsson

et al in Am. J. Respir. Crit. Care Med. 161 , S20 (2000). It is well known that compounds prepared as antagonists to one of the MAPEGs may also exhibit inhibitory activity towards other family members, c.f. J. H Hutchinson et al in J. Med. Chem. 38, 4538 (1995) and D. Claveau et al in J. Immunol. 170, 4738 (2003). The former paper also describes that such compounds may also display notable cross-reactivity with proteins in the arachidonic acid cascade that do not belong to the MAPEG family, e.g. 5-lipoxygenase.

Thus, agents that are capable of inhibiting the action of mPGES-1 , and thus reducing the formation of the specific arachidonic acid metabolite PGE ₂ , are likely to be of benefit in the treatment of inflammation. Further, agents that are capable of inhibiting the action of the proteins involved in the synthesis of the leukotrienes are also likely to be of benefit in the treatment of asthma and COPD.

The listing or discussion of an apparently prior-published document in this specification should not necessarily be taken as an acknowledgement that the document is part of the state of the art or is common general knowledge.

In Complement and Inflammation (1991), 8, 50-59, Abdel Mawla et al disclose 5,5',5"-(1 ,3,6-naphthalenetriyl-tris[sulfonylimino])-tris(1 ,3-benzenedisulfonic acid)hexasodium salt as a complement inhibitor, and which may therefore be useful in the treatment of inflammation. However, this document does not mention or suggest monocyclic sulfonamides that are only substituted with two aryl sulfonamide groups.

US Patents Nos. 4,369,191 and 4,431 ,638 disclose various compounds that may be useful as complement inhibitors, and thus in the treatment of inflammation. However, the former document does not mention or suggest monocycles that have only two sulfonamide groups attached thereto. The latter does not mention or suggest aromatic sulfonamides in which the aromatic ring is not substituted by a hexose-thio group.

Badawi et al, Oriental Journal of Chemistry (1986), 2(2), 103, Badawi et al,

Pharmazie (1980), 35 (12), 748, Hannout et al, Egyptian Journal of Pharmaceutical Sciences (1986), 26 (1-4), 213 and Shams et al, Journal of

Chemical Society of Pakistan (1986), 8(2), 209 all disclose various benzene disulfonamides as bactericides or antiseptics. International patent application WO 01/016096 discloses various benzene disulfonamides that may be useful in the treatment of hyperlipidemia. National patent application DE 2,459,394 discloses various benzene disulfonamides as anti-hypertensive agents. National patent application GB 909,661, US patent application US 2,947,742 and Liang et al, Yaoxue Xuebao (1963), 10(6), 345-8 all disclose various benzene disulfonamides as inter alia diuretics. International patent application WO 2005/021721 (and Wadkins et al, Molecular Pharmacology (2004), 65(6), 1336) discloses a benzene disulfonamide as a carboxylesterase inhibitor, which compound may therefore be useful in the treatment of cancer. Zhongguo Yaowu Huaxue Zazhi (2004), 14(3), 140 discloses a benzene disulfonamide that may be useful as a platelet aggregator. However, none of the above documents mention that the compounds disclosed therein may be useful as mPGES-1 inhibitors, and therefore useful in the treatment of inflammation.

Journal article Egypt. J. Chem. 28, No. 2, pp. 163-170 (1985) by Maghraby et al discloses the synthesis of various specific disulphonanilide compounds. However, the journal article specifically states that no use has yet been ascribed to such compounds.

US patent applications US 2006/0241296 and US 2006/0183745 both disclose nitrogen-containing monocyclic compounds that may be useful in the treatment of inter alia inflammation. However, there is no disclosure in that document of monocycles that are substituted in a 1 ,3-position with aryl sulfonamide groups.

International patent application WO 93/016036 discloses various compounds that may be useful in the treatment of inflammation. However, this document only relates to compounds in which the requisite benzene ring is substituted with an aromatic ring, which is itself substituted with an amidino moiety.

International patent application WO 99/32433 discloses various benzene monocycles that may be useful in the treatment of inflammation or atherosclerosis. However, this document primarily discloses compounds in which

the benzene rings are substituted with amino, amido, alkyl, urea, thiourea, hydroxy or alkoxy-based substituents.

Finally, international patent application WO 2007/042817 discloses naphthalene 1 ,3-disulfonamides, which compounds may be useful as inhibitors of mPGES-1 and therefore useful in the treatment of inflammation. However, there is no mention in this document of any monocycles substituted with two aromatic sulfonamide groups.

Disclosure of the Invention

According to the invention there is provided a compound of formula I,

wherein

R ¹ and R ² independently represent aryl, heteroaryl (which latter two groups are optionally substituted by one or more substituents selected from Z ¹ and Z ² ), C _1-12 alkyl or heterocycloalkyl (which latter two groups are optionally substituted by one or more substituents selected from Z ¹ , Z ² and =O);

one of T ¹ and T ² represents H, and the other represents H or R ^3a ;

W ¹ and W ² independently represent a direct bond or C _1-6 alkylene optionally substituted by one or more substituents selected from R ^m1 ;

each R ^m1 independently represents fluoro or C _1-4 alkyl (optionally substituted by one or more halo atoms); or

any two R ^m1 groups, for example when attached to adjacent or the same carbon atoms, are linked together to form a 3- to 5-membered carbocyclic ring optionally substituted by one or more substituents selected from halo and C _1-2 alkyl;

in the central ring containing Y ¹ to Y ⁴ : at least one of Y ¹ , Y ² , Y ³ or Y ⁴ represents -C(X ¹ )=; any further two of Y ¹ , Y ² , Y ³ and Y ⁴ represent -N= or -C(X ² )=; and the other represents -C(X ² )=;

X ¹ represents a substituent selected from Z ¹ ;

X ² represents, at each occurrence when used herein, hydrogen, Z ¹ or Z ² ;

Z ¹ represents, at each occurrence when used herein, halo, -R ^3a , -CN, -C(O)OR ^3c , -N(R ^4b )R ^5b , -N(R ^3d )C(O)R ^4c , -N(R ^3e )C(O)N(R ^4d )R ^5d , -N(R ^3f )C(O)OR ^4e , -N ₃ , -NO ₂ , -N(R ³⁹ )S(O) ₂ N(R ^4f )R ^5f , -OR ^3h , -OC(O)N(R ^4g )R ^5g , -OS(O) ₂ R ³ ', -N(R ^3k )S(O) ₂ R ^3m , -OC(O)R ³ⁿ , -OC(O)OR ^3p or -S(O) ₂ N(R ^4h )R ^5h ;

Z ² represents, at each occurrence when used herein, -C(O)R ^3b , -C(O)N(R ^4a )R ^5a or -S(O) _m R ^3j ;

m represents O, 1 or 2;

R ^3b , R ^3d to R ^3h , R ^3k , R ^3Ï€ , R ^4a to R ^4h , R ^5a , R ^5b , R ^5d and R ^5f to R ^5h independently represent H or R ^3a ; or any of the pairs R ^4a and R ^5a , R ^4b and R ^5b , R ^4d and R ^5d , R ^4f and R ^5f , R ^4g and R ^5g or

R ^4h and R ^5h may be linked together to form a 3- to 6-membered ring, which ring optionally contains a further heteroatom (such as nitrogen or oxygen) in addition to the nitrogen atom to which these substituents are necessarily attached, and which ring is optionally substituted by F, Cl, =0 or R ^3a ;

R ^3c , R ³ ', R ^3j , R ^3m and R ^3p independently represent R ^3a ;

R ^3a represents, at each occurrence when used herein, Ci. ₁₂ (e.g. C _1-6 ) alkyl optionally substituted by one or more substituents selected from F, CI, =0, -0R ^6a and -N(R ^6b )R ^7b ;

R ^6a and R ^6b independently represent H or Ci _-6 alkyl optionally substituted by one or more substituents selected from F, Cl, =0, -0R ^8a , -N(R ^9a )R ^10a and -S(O) ₂ -G ¹ ;

R ^7b represents H, -S(O) ₂ CH ₃ , -S(O) ₂ CF ₃ or Ci _-6 alkyl optionally substituted by one or more substituents selected from F, Cl, =0, -0R ^11a , -N(R ^12a )R ^13a and -S(O) ₂ -G ² ; or R ^6b and R ^7b may be linked together to form a 3- to 6-membered ring, which ring optionally contains a further heteroatom (such as nitrogen or oxygen) in addition to the nitrogen atom to which these substituents are necessarily attached, and which ring is optionally substituted by F, Cl, =0 or Ci _-3 alkyl optionally substituted by one or more fluoro atoms;

G ¹ and G ² independently represent -CH ₃ , -CF ₃ or -N(R ^14a )R ^15a ;

R ^8a and R ^11a independently represent H, -CH ₃ , -CH ₂ CH ₃ , -CF ₃ or -CHF ₂ ;

R ^9a , R ^10a , R ^12a , R ^13a , R ^14a and R ^15a independently represent H, -CH ₃ or -CH ₂ CH ₃ ,

or a pharmaceutically acceptable salt thereof,

for use in the treatment of a disease in which inhibition or modulation of the activity of a member of the MAPEG family is desired and/or required,

which compounds may be referred to herein as "compounds of the invention".

Pharmaceutically-acceptable salts include acid addition salts and base addition salts. Such salts may be formed by conventional means, for example by reaction of a free acid or a free base form of a compound of formula I with one or more equivalents of an appropriate acid or base, optionally in a solvent, or in a medium in which the salt is insoluble, followed by removal of said solvent, or said medium, using standard techniques (e.g. in vacuo, by freeze-drying or by filtration). Salts may also be prepared by exchanging a counter-ion of a compound of formula I in the form of a salt with another counter-ion, for example using a suitable ion exchange resin.

Compounds of formula I may contain double bonds and may thus exist as E (entgegen) and Z (zusammen) geometric isomers about each individual double bond. All such isomers and mixtures thereof are included within the scope of the invention.

Compounds of formula I may also exhibit tautomerism. All tautomeric forms and mixtures thereof are included within the scope of the invention. For example, a 2- hydroxypyridine may exist as a pyridinone.

Compounds of formula I may also contain one or more asymmetric carbon atoms and may therefore exhibit optical and/or diastereoisomerism. Diastereoisomers may be separated using conventional techniques, e.g. chromatography or fractional crystallisation. The various stereoisomers may be isolated by separation of a racemic or other mixture of the compounds using conventional, e.g. fractional crystallisation or HPLC, techniques. Alternatively the desired optical isomers may be made by reaction of the appropriate optically active starting materials under conditions which will not cause racemisation or epimerisation (i.e. a 'chiral pool' method), by reaction of the appropriate starting material with a 'chiral auxiliary' which can subsequently be removed at a suitable stage, by derivatisation (i.e. a resolution, including a dynamic resolution), for example with a homochiral acid followed by separation of the diastereomeric derivatives by conventional means such as chromatography, or by reaction with an appropriate chiral reagent or chiral catalyst all under conditions known to the skilled person. All stereoisomers and mixtures thereof are included within the scope of the invention.

Unless otherwise specified, C _1-q alkyl (where q is the upper limit of the range), defined herein may be straight-chain or, when there is a sufficient number (i.e. a minimum of three) of carbon atoms, be branched-chain, and/or cyclic (so forming a C _3-q cycloalkyl group). Further, when there is a sufficient number (i.e. a minimum of four) of carbon atoms, such groups may also be part cyclic. Further, unless otherwise specified, such alkyl groups may also be saturated or, when there is a sufficient number (i.e. a minimum of two) of carbon atoms and unless otherwise specified, be unsaturated (forming, for example, a C _2-q alkenyl or a C _2-q alkynyl group).

In the instance where a 'cycloalkyl' group (e.g. C _3-q cycloalkyl) is specifically mentioned, such groups may be monocyclic or bicyclic non-aromatic alkyl groups, which may be bridged (so forming, for example, fused ring systems). Cycloalkyl groups may also include spiro-cyclic groups. Cycloalkyl groups may be saturated or unsaturated, e.g. containing one or more double bond (forming for example a C _3-q cycloalkenyl). Optional substituents may be attached at any point on the cycloalkyl group. Cycloalkyl groups that may be mentioned include C _3-12 cycloalkyl groups, for instance a 3- to 7-membered monocyclic cycloalkyl group or a C ₈ - _H bicyclic cycloalkyl group. The term 'acyclic' alkyl group when used herein refers to an alkyl group that is not cyclic, but may be part cyclic, branched-chain or, is preferably, straight-chain.

For the avoidance of doubt, the term "bicyclic", when employed in the context of cycloalkyl, refers to such groups in which the second ring is formed between two adjacent atoms of the first ring (i.e. systems of two rings share one bond formed with two adjacent carbon atoms). The term "bridged", when employed in the context of cycloalkyl groups refers to cycloalkyl groups in which two non-adjacent atoms are linked by an alkylene chain. The term "spiro-cyclic group" refers to a cycloalkyl group that is substituted with a further cycloalkyl group via a single carbon atom.

The term "halo", when used herein, includes fluoro, chloro, bromo and iodo.

Aryl groups that may be mentioned include C _6-14 (e.g. C _6-10 ) aryl groups. Such groups may be monocyclic, bicyclic or tricyclic and have between 6 and 14 ring carbon atoms, in which at least one ring is aromatic. C _6-14 aryl groups include phenyl, naphthyl and the like, such as 1 ,2,3,4-tetrahydronaphthyl, indanyl, indenyl and fluorenyl. The point of attachment of aryl groups may be via any atom of the ring system, for instance when aryl groups are bicyclic or tricyclic, they may be linked to the rest of the molecule via an atom of a non-aromatic or an aromatic ring. However, in such instances, the linkage to the rest of the molecule is more preferably via an atom of an aromatic ring.

Heteroaryl groups that may be mentioned include those which have between 5 and 14 (e.g. between 5 and 10) members. Such groups may be monocyclic, bicyclic or tricyclic, provided that at least one of the rings is aromatic and wherein at least one (e.g. one to four) of the atoms in the ring system is other than carbon (i.e. a heteroatom). Heteroaryl groups that may be mentioned include oxazolopyridyl (including oxazolo[4,5-b]pyridyl, oxazolo[5,4-b]pyridyl, oxazolo[4,5- c]pyridyl and oxazolo[5,4-c]pyridyl), thiazolopyridyl (including thiazolo[4,5- b]pyridyl, thiazolo[5,4-b]pyridyl, thiazolo[4,5-c]pyridyl and thiazolo[5,4-c]pyridyl) and, preferably, acridinyl, benzimidazolyl, benzodioxanyl, benzodioxepinyl, benzodioxolyl (including 1 ,3-benzodioxolyl), benzofuranyl, benzofurazanyl, benzothiazolyl, benzothiadiazolyl (including 2,1 ,3-benzothiadiazolyl), benzoxadiazolyl (including 2,1 ,3-benzoxadiazolyl), benzoxazinyl (including 3,4- dihydro-2H-1 ,4-benzoxazinyl), benzoxazolyl, benzimidazolyl, benzomorpholinyl, benzothienyl, carbazolyl, chromanyl, cinnolinyl, furanyl, imidazolyl, imidazopyridyl (including imidazo[4,5-b]pyridyl, imidazo[5,4-b]pyridyl, imidazo[4,5-c]pyridyl and, preferably, imidazo[1 ,2-a]pyridyl), indazolyl, indolinyl, indolyl, isobenzofuranyl, isochromanyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiaziolyl, isothiochromanyl, isoxazolyl, naphthyridinyl (including 1 ,5-naphthyridinyl and 1 ,8-naphthyridinyl), oxadiazolyl (including 1 ,2,3-oxadiazolyl, 1 ,2,4-oxadiazolyl and, preferably, 1 ,3,4-oxadiazolyl), oxazolyl, phenazinyl, phenothiazinyl, phthalazinyl, pteridinyl, purinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinolizinyl, quinoxalinyl, tetrahydroisoquinolinyl (including 1 ,2,3,4- tetrahydroisoquinolinyl and 5,6,7,8-tetrahydroisoquinolinyl), tetrahydroquinolinyl (including 1 ,2,3,4-tetrahydroquinolinyl and 5,6,7,8-tetrahydroquinolinyl), tetrazolyl, thiadiazolyl (including 1 ,2,3-thiadiazolyl, 1 ,2,4-thiadiazolyl and, preferably, 1 ,3,4-thiadiazolyl), thiazolyl, thiochromanyl, thienyl, triazolyl (including 1 ,2,3-triazolyl and 1 ,2,4-triazolyl) and the like. Substituents on heteroaryl groups may, where appropriate, be located on any atom in the ring system including a heteroatom. The point of attachment of heteroaryl groups may be via any atom in the ring system including (where appropriate) a heteroatom (such as a nitrogen atom), or an atom on any fused carbocyclic ring that may be present as part of the ring system. When heteroaryl groups are bicyclic or tricyclic, they may be linked to the rest of the molecule via an atom of a non-aromatic or an aromatic ring. However, in such instances, the linkage to the rest of the molecule is more

preferably via an atom of an aromatic ring. Heteroaryl groups may also be in the N- or S- oxidised form.

Heterocycloalkyl groups that may be mentioned include non-aromatic monocyclic and bicyclic heterocycloalkyl groups (which groups may further be bridged) in which at least one (e.g. one to four) of the atoms in the ring system is other than carbon (i.e. a heteroatom), and in which the total number of atoms in the ring system is between three and twelve (e.g. between five and ten). Further, such heterocycloalkyl groups may be saturated or unsaturated containing one or more double and/or triple bonds, forming for example a C _2-q heterocycloalkenyl (where q is the upper limit of the range) or a C _7-q heterocycloalkynyl group. C _2-q heterocycloalkyl groups that may be mentioned include 7-azabicyclo- [2.2.1]heptanyl, 6-azabicyclo[3.1.1]heptanyl, 6-azabicyclo[3.2.1]-octanyl, 8- azabicyclo[3.2.1]octanyl, aziridinyl, azetidinyl, dihydropyranyl, dihydropyridyl, dihydropyrrolyl (including 2,5-dihydropyrrolyl), dioxolanyl (including 1 ,3- dioxolanyl), dioxanyl (including 1 ,3-dioxanyl and 1 ,4-dioxanyl), dithianyl (including 1 ,4-dithianyl), dithiolanyl (including 1 ,3-dithiolanyl), imidazolidinyl, imidazolinyl, morpholinyl, 7-oxabicyclo[2.2.1]heptanyl, 6-oxabicyclo[3.2.1]-octanyl, oxetanyl, oxiranyl, piperazinyl, piperidinyl, pyranyl, pyrazolidinyl, pyrrolidinonyl, pyrrolidinyl, pyrrolinyl, quinuclidinyl, sulfolanyl, 3-sulfolenyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydropyridyl (such as 1 ,2,3,4-tetrahydropyridyl and 1 ,2,3,6-tetrahydropyridyl), thietanyl, thiiranyl, thiolanyl, thiomorpholinyl, trithianyl (including 1 ,3,5-trithianyl), tropanyl and the like. Substituents on heterocycloalkyl groups may, where appropriate, be located on any atom in the ring system including a heteroatom. Further, in the case where the substituent is another cyclic compound, then the cyclic compound may be attached through a single atom on the heterocycloalkyl group, forming a so-called "spiro"-compound. The point of attachment of heterocycloalkyl groups may be via any atom in the ring system including (where appropriate) a heteroatom (such as a nitrogen atom), or an atom on any fused carbocyclic ring that may be present as part of the ring system. Heterocycloalkyl groups may also be in the N- or S- oxidised form.

Heteroatoms that may be mentioned include include phosphorus, silicon, boron, tellurium, selenium and, preferably, oxygen, nitrogen and sulfur.

For the avoidance of doubt, in cases in which the identity of two or more substituents in a compound of formula I may be the same, the actual identities of the respective substituents are not in any way interdependent. For example, in the situation in which any two X ² groups or one X ¹ group and one X ² group represent Z ¹ , and, in both cases Z ¹ represents R ^3a , then the respective R ^3a groups in question may be the same or different. Similarly, when groups are substituted by more than one substituent as defined herein, the identities of those individual substituents are not to be regarded as being interdependent. For example, when R ¹ represents phenyl substituted by -R ^3a and -OR ^3h , in which R ^3h represents R ^3a , and, in each case R ^3a represents C _1-6 alkyl, the identities of the two R ^3a groups are not to be regarded as being interdependent.

For the avoidance of doubt, when a term such as "Y ¹ to Y ⁴ " is employed herein, this will be understood by the skilled person to mean Y ¹ , Y ² , Y ³ and Y ⁴ inclusively.

Compounds of the invention that may be mentioned include those in which:

R ¹ and R ² independently represent aryl or heteroaryl, both of which are optionally substituted by one or more substituents selected from Z ¹ and Z ² ;

W ¹ and W ² independently represent a direct bond or -C(R ^m )(R ⁿ )-; one of T ¹ or T ² represents H, and the other represents H or R ^3a ;

R ^m and R ⁿ independently represent hydrogen, fluoro or C _1-4 alkyl (optionally substituted by one or more halo atoms); or

R ^m and R ⁿ are linked together to form a 3- to 5-membered carbocyclic ring optionally substituted by one or more substituents selected from halo and C ₁ ^ alkyl;

Z ¹ represents, at each occurrence when used herein, halo, -R ^3a , -CN, -N(R ^4b )R ^5b ,

-N(R ^3d )C(O)R ^4c , -N(R ^3e )C(O)N(R ^4d )R ^5d , -N(R ^3f )C(O)OR ^4e , -N ₃ , -NO ₂ .

-N(R ³⁹ )S(O) ₂ N(R ^4f )R ^5f , -OR ^3h , -OC(O)N(R ⁴⁹ )R ^5g , -OS(O) ₂ R ³ ', -N(R ^3k )S(O) ₂ R ^3m ,

-OC(O)R ³ ", -OC(O)OR ^3p or -S(O) ₂ N(R ^4h )R ^5h ; Z ² represents, at each occurrence when used herein, -C(O)R ^3b , -C(O)OR ^3c ,

-C(O)N(R ^4a )R ^5a or -S(O) _m R ^3j ;

R ^4e represents R ^3a ;

R ^8a and R ^11a independently represent H, -CH ₃ , -CH ₂ CH ₃ or -CF ₃ .

Further preferred compounds of the invention that may be mentioned include those in which: when R ¹ or R ² represents C _{1 -12} alkyl (optionally substituted by one or more substituents selected from Z ¹ , Z ² and =O), then it is preferably C _3-12 cycloalkyl (optionally substituted by one or more substituents selected from Z ¹ , Z ² and =0); one of R ¹ and R ² (preferably R ¹ ) represents aryl or heteroaryl (which latter two groups are optionally substituted by one or more substituents selected from Z ¹ and Z ² ), and the other (preferably R ² ) represents aryl, heteroaryl (which latter two groups are optionally substituted by one or more substituents selected from Z ¹ and Z ² ), C _1-12 alkyl or heterocycloalkyl (which latter two groups are optionally substituted by one or more substituents selected from Z ¹ , Z ² and =0); one of R ¹ and R ² (preferably R ¹ ) represents aryl or heteroaryl (which latter two groups are optionally substituted by one or more substituents selected from Z ¹ and Z ² ), and the other (preferably R ² ) represents C _1-12 alkyl (optionally substituted by one or more substituents selected from Z ¹ , Z ² and =O), heterocycloalkyl (optionally substituted by one or more substituents selected from Z ¹ , Z ² and =0), preferably, heteroaryl or, more preferably, aryl (which latter two groups are optionally substituted by one or more substituents selected from Z ¹ and Z ² ); Z ¹ is as defined herein, provided that it does not represent -C(O)OR ^3c ; Z ² may represent a substituent as defined herein or -C(O)OR ^3c .

Compounds of formula I that may be mentioned include those in which X ¹ represents halo, -R ^3a , -CN, -N(R ^4b )R ^5b , -N(R ^3d )C(O)R ^4c , -N(R ^3e )C(O)N(R ^4d )R ^5d , -N(R ^3f )C(O)OR ^4e , -N ₃ , -NO ₂ , -N(R ^3g )S(O) ₂ N(R ^4f )R ^5f , -0R ^3h , -OC(O)N(R ^4g )R ⁵⁹ , -OS(O) ₂ R ³ ', -N(R ^3k )S(O) ₂ R ^3m , -OC(O)R ³ⁿ or -OC(O)OR ^3p .

Further compounds of formula I that may be mentioned include those in which: one of Y ¹ to Y ⁴ represents -C(X ¹ )=. and the others all represent -C(X ² )=; one of Y ¹ to Y ⁴ represents -C(X ¹ )=, a further one represents -N=, and the others represent -C(X ² )=; or one of Y ¹ to Y ⁴ represents -C(X ¹ )=, a further two represent -N=, and the remaining one represents -C(X ² )=.

Preferred compounds of formula I include those in which:

when any of the pairs R ^4a and R ^5a , R ^4b and R ^5b , R ^4d and R ^5d , R ^4f and R ^5f , R ⁴⁹ and R ^5s or R ^4h and R ^5h are linked together, they form a 5- or 6-membered ring, which ring optionally contains a further heteroatom (such as nitrogen or oxygen) and is optionally substituted by one or more (e.g. two or, preferably, one) substituent(s) selected from F, preferably, =0 and, more preferably, R ^3a (so forming, for example, 4,4-difluoropiperidinyl, preferably, 4,4-dimethylpiperidinyl or, more preferably, a pyrrolidinyl, morpholinyl or a piperazinyl (e.g. 4-methylpiperazinyl) ring); R ¹ and R ² are each, independently, substituted with less than three (e.g. one or two) substituent(s) selected from Z ¹ and Z ² ; for example when W ¹ and W ² are direct bonds, then Z ¹ and Z ² substituents on R ¹ and R ² groups are preferably in the positions α- or β- relative to the point of attachment of the R ¹ and/or R ² group to the rest of the compound of formula I (e.g. when R ¹ and/or R ² represent phenyl, then the optional substituents are preferably in the ortho- and/or the meta-position);

X ¹ represents -N(R ^4b )R ^5b , -N(R ^3d )C(O)R ^4c , halo (e.g. chloro, fluoro or bromo), -R ^3a or -OR ^3h ;

X ² represents hydrogen, -C(O)N(R ^4a )R ^5a , -N(R ^4b )R ^5b , -N(R ^3d )C(O)R ^4c , halo (e.g. chloro, fluoro or bromo), -R ^3a or -OR ^3h ; R ^3a represents C _1-6 alkyl (e.g. cyclohexyl, hexyl, ethyl or methyl) optionally substituted by one or more fluoro atoms (so forming, for example, a trifluoromethyl group);

R ^4a , R ^5a , R ^4b and R ^5b independently represent H, methyl or ethyl; R ^3h represents H or R ^3a ; R ^4c represents R ^3a ; when R ^3d represents R ^3a , then R ^3a preferably represents C _1-2 alkyl (e.g. methyl); when R ^3h represents R ^3a , then R ^3a preferably represents C _1-6 alkyl as hereinbefore defined or, more preferably, C _1-3 (e.g. C _1-2 ) aikyl optionally substituted by one or more fluoro atoms (e.g. R ^3h may represent cyclopentyl, cyclopropyl, preferably ethyl, difluoromethyl or, more preferably, methyl or trifluoromethyl); when R ^4c represents R ^3a , then R ^3a preferably represents C _1-6 alkyl as hereinbefore defined and, preferably, unsubstituted C _1-6 alkyl such as cyclohexyl, cyclopropyl, tert-butyl, isopropyl, ethyl or, more preferably, methyl); R ^6a , R ^6b and R ^7b independently represent H or C _1-6 alkyl optionally substituted by one or more fluoro atoms.

Preferred aryl and heteroaryl groups that R ¹ and R ² may represent include optionally substituted phenyl, naphthyl, pyrrolyl, furanyl, thienyl (e.g. thien-2-yl or thien-3-yl), pyrazolyl, imidazolyl (e.g. 2-imidazolyl or 4-imidazolyl), oxazolyl, isoxazolyl, thiazolyl, pyridyl (e.g. 2-pyridyl, 3-pyridyl or 4-pyridyl), indazolyl, indolyl, indolinyl, isoindolinyl, quinolinyl, 1 ,2,3,4-tetrahydroquinolinyl, isoquinolinyl, 1 ,2,3,4-tetrahydroisoquinolinyl, quinolizinyl, benzofuranyl, isobenzofuranyl, chromanyl, benzothienyl, pyridazinyl, pyrimidinyl, pyrazinyl, indazolyl, benzimidazolyl, quinazolinyl, quinoxalinyl, 1 ,3-benzodioxolyl, tetrazolyl, benzothiazolyl, and/or benzodioxanyl, group. Preferred groups include optionally substituted pyridyl (e.g. 3-pyridyl or, preferably, 2- or 4-pyridyl), pyrazinyl (e.g. 2- pyrazinyl), furanyl, thienyl, oxazolyl, thiazolyl and, more preferably, optionally substituted phenyl.

Preferred substituents on R ¹ , R ² or the Y ¹ to Y ⁴ -containing ring of compounds of formula I include:

-N(R ¹⁶ )C(O)R ¹⁷ ;

-C(O)N(R ¹⁶ )R ¹⁸ ; or, preferably halo (e.g. fluoro, chloro or bromo); cyano;

-NO ₂ ;

Ci.6 alkyl, which alkyl group may be cyclic (e.g. C _1-6 alkyl such as cyclohexyl), part-cyclic (e.g. cyclopropylmethyl), unsaturated (e.g. allyl), linear or branched

(e.g. C _1-4 alkyl (such as ethyl, n-propyl, isopropyl, n-butyl, t-butyl or, preferably, methyl)), all of which are optionally substituted with one or more halo (e.g. fluoro) groups (so forming, for example, fluoromethyl, difluoromethyl or, preferably, trifluoromethyl);

-OR ¹⁶ ;

-C(O)OR ¹⁷ ; -C(O)R ¹⁶ ; and

-N(R ¹⁶ )R ¹⁸ ; wherein R ¹⁶ to R ¹⁸ (e.g. R ¹⁶ and R ¹⁸ ) independently represent, on each occasion when mentioned above, H or R ¹⁹ ; and each R ¹⁹ independently represents (and

R ¹⁷ preferably represents) C _1-6 alkyl, such as C _1-4 alkyl (e.g. ethyl, n-propyl, n-

butyl, Nbutyl or, preferably, methyl or isopropyl) optionally substituted by one or more halo (e.g. fluoro) groups (so forming e.g. a thfluoromethyl group).

Preferred compounds of formula I include those in which: R ¹ and R ² independently represent Ci _-12 alkyl (which alkyl group is optionally substituted by one or more substituents selected from Z ¹ , Z ² and =0), heterocycloalkyl (e.g. pyrrolidinyl; which heterocycloalkyl group is optionally substituted by one or more substituents selected from Z ¹ , Z ² and =0), heteroaryl (e.g. pyridyl; which heteroaryl group is optionally substituted by one or more substituents selected from Z ¹ and Z ² ) or, preferably, aryl (e.g. phenyl; which aryl group is optionally substituted by one or two substituents selected from Z ¹ and Z ² ); one of R ¹ and R ² represents heteroaryl (e.g. pyridyl; which heteroaryl group is optionally substituted by one or more substituents selected from Z ¹ and Z ² ) or, preferably, aryl (e.g. phenyl; which aryl group is optionally substituted by one or two substituents selected from Z ¹ and Z ² ) and the other represents C ₁ . ₁₂ alkyl (which alkyl group is optionally substituted by one or more substituents selected from Z ¹ , Z ² and =0), heterocycloalkyl (e.g. pyrrolidinyl; which heterocycloalkyl group is optionally substituted by one or more substituents selected from Z ¹ , Z ² and =0), heteroaryl (e.g. pyridyl; which heteroaryl group is optionally substituted by one or more substituents selected from Z ¹ and Z ² ) or, preferably, aryl (e.g. phenyl; which aryl group is optionally substituted by one or two substituents selected from Z ¹ and Z ² ); R ¹ and R ² independently represent phenyl optionally substituted by one or two substituents selected from Z ¹ and Z ² ; R ¹ and R ² are preferably the same; when R ¹ or R ² represent optionally substituted C _1-12 alkyl, then such a group preferably represents C ₃ _ ₁₂ cycloalkyl (such as C _3-8 cycloalkyl, e.g. C _5-6 cycloalkyl, such as cyclohexyl) or C _1-6 (e.g. C _1-4 ) acyclic alkyl (e.g. butyl, such as n-butyl or 3,3-dimethylbutyl, i.e. -CH ₂ -CH ₂ -C(CH ₃ ) ₃ ); when R ¹ or R ² represent optionally substituted heteroaryl, then they preferably represent a 5- or 6-membered heteroaryl group containing two or, preferably one heteroatom(s), in which the heteroatom is preferably selected from sulfur, oxygen and particularly, nitrogen (so forming for example a pyridyl group);

when R ¹ or R ² represent optionally substituted heterocycloalkyl, then they preferably represent a 5- or 6-membered heterocycloalkyi group containing two or, preferably one heteroatom(s), in which the heteroatom is preferably selected from sulfur, particularly, oxygen and more particularly, nitrogen (so forming for example a pyrrolidinyl group); when Z ¹ represents a substituent on R ¹ or R ² , then it preferably represents

-C(O)OR ^3c , -N(R ^4b )R ^5b or, more preferably, halo (e.g. chloro or fluoro) or R ^3a ; when Z ² represents a substituent on R ¹ or R ² , then it preferably represents

-S(O) _m R ^3j , in which R ^3j preferably represents C _1-12 alkyl (which group is preferably acyclic and unsubstituted); m represents 2 or, preferably 0;

W ¹ and W ² independently represent a direct bond or C _1-3 (e.g. C _1-2 ) alkylene (e.g.

-CH ₂ CH ₂ , -C(CH ₃ )(H)- or, preferably, -CH ₂ -), which alkylene group may be optionally substituted as defined herein; W ¹ and W ² may be different but are preferably the same; both of W ¹ and W ² may represent optionally substituted alkylene (as defined herein), one of W ¹ and W ² may represent a direct bond (particularly when the R ¹ or R ² group that is attached thereto represents optionally substituted heteroaryl or, preferably, optionally substituted aryl) and the other represents optionally substituted alkylene (as defined herein), or, both of W ¹ and W ² may represent direct bonds; one of T ¹ and T ² represents H and the other either represents C _1-3 alkyl (e.g. methyl) or, more preferably, H; one of Y ¹ to Y ⁴ represents -C(X ¹ )=, and the others all represent -C(X ² )=; Y ³ represents -C(X ¹ )=, preferably Y ¹ represents -C(X ¹ )= or, more preferably, Y ² or

Y ⁴ represent -C(X ¹ )=;

X ¹ represents -R ^3a , -CN, -C(O)OR ^3c , -NO ₂ , -N(R ^4b )R ^5b , preferably, halo (e.g. chloro, bromo or, preferably, fluoro) or, more preferably, -OR ^3h ;

X ² represents -CN, -NO ₂ , -N(R ^4b )R ^5b , preferably, H, halo (e.g. bromo, preferably, chloro or, more preferably, fluoro), -R ^3a , -OR ^3h or -C(O)N(R ^4a )R ^5a ;

R ^3h represents H or R ^3a , in which R ^3a preferably represents C _1-2 alkyl (e.g. methyl);

R ^3c , R ^4b and R ^5b independently represent C _1-2 alkyl (e.g. methyl) or hydrogen;

R ^4a and R ^5a independently represent R ^3a , or, are linked together to form a five- membered ring, preferably containing no further unsaturations and no further heteroatoms (e.g. a pyrrolidine ring); when R ^4a and R ^5a represent R ^3a , then R ^3a preferably represents C _1-3 alkyl (e.g. methyl or, preferably, ethyl);

R ^3a represents C _1-12 alkyl or, preferably C _1-4 (e.g. C _1-3 ) alkyl (e.g. butyl, such as tert-butyl, or, preferably, ethyl or methyl) optionally substituted by one or more groups selected from -N(R ^6b )R ^7b , -OR ^6a (so forming, for example a -CH ₂ OR ^6a group), preferably, =0 and, more preferably, halo (e.g. fluoro; so forming for example a difluoromethyl or, preferably, a trifluoromethyl group); when R ^3a represents alkyl substituted by both =0 and -N(R ^6b )R ^7b , then such substituents may both be terminally substituted by both substituents, so forming a -C(O)N(R ^6b )R ^7b group; R ^6a represents hydrogen; R ^6b and R ^7b independently represent hydrogen or, preferably, C _1-3 (e.g. C ₁ _ ₂ ) alkyl (e.g. methyl).

Particularly preferred compounds of formula I include those of the examples described hereinafter.

Compounds of formula I may be made in accordance with techniques that are well known to those skilled in the art, for example as described hereinafter.

According to a further aspect of the invention there is provided a process for the preparation of a compound of formula I which process comprises:

(i) for compounds of formula I in which R ¹ and R ² represent the same, or different, optionally substituted aryl or heteroaryl group, W ¹ and W ² represent the same group and T ¹ and T ² also represent the same group, reaction of a compound of formula II,

wherein L ^1a and L ^1b independently represent a suitable leaving group such as chloro, bromo, fluoro or -0-C _1-3 alkyl optionally substituted by one or more fluoro atoms (so forming for e.g. methoxy or trifluoromethoxy), and Y ¹ to Y ⁴ are as hereinbefore defined, with a compound of formula III, or with two different compounds of formula III,

R ^X -W ^X -N(H)T ^X III

wherein R ^x represents R ¹ and/or R ² (as appropriate), W ^x represents W ¹ and/or W ² (as appropriate) and T represents T ¹ and/or T ² (as appropriate), and R ¹ , R ² , W ¹ , W ² , T ¹ and T ² are as hereinbefore defined, for example at around room temperature or above (e.g. up to 40-180 ⁰ C), optionally in the presence of a suitable base (e.g. sodium hydride, sodium bicarbonate, potassium carbonate, pyrrolidinopyridine, pyridine, triethylamine, tributylamine, trimethylamine, dimethylaminopyridine, diisopropylamine, 1 ,8-diazabicyclo[5.4.0]undec-7-ene, sodium hydroxide, λ/-ethyldiisopropylamine, λ/-(methylpolystyrene)-4- (methylamino)pyridine or mixtures thereof) in an appropriate solvent (e.g. tetrahydrofuran, pyridine, toluene, dichloromethane, chloroform, acetonitrile, dimethylformamide, triethylamine, water or dimethylsulfoxide). Where the compound of formula I to be prepared is one in which R ¹ and R ² , Q ^x and Q ^y and T ¹ and T ² are the same, then the reaction is performed in the presence of a single compound of formula III (in which case R ^x would represent both R ¹ and R ² , W ^x would represent both W ¹ and W ² and T ^x would represent both T ¹ and T ² ). In this instance, the skilled person will appreciate that for optimum yield, at least two equivalents of a compound of formula III is required. Where the compound of formula I to be prepared is one in which R ¹ and R ² , W ¹ and W ² and/or T ¹ and T ² are different, then two different compounds of formula III may be employed in

which, in each compound, R ^x represents either R ¹ or R ² , W ^x represents either W ¹ or W ² , and/or T represents either T ¹ or T ² (as appropriate);

(ii) reaction of a compound of formula IV,

or a compound of formula V,

wherein Y ¹ to Y ⁴ , T ¹ , T ² , W ¹ , W ² , L ^1a and L ^1b are as hereinbefore defined, with a compound of formula III as hereinbefore defined, in which R ^x represents R ¹ , W ^x represents W ¹ and T represents T ¹ (for reaction with compounds of formula IV) or R ^x represents R ² , W ^x represents W ² and T represents T ² (for reaction with compounds of formula V) under standard reaction conditions, such as those described hereinbefore in respect of process step (i);

(iii) for compounds of formula I in which Y ¹ , Y ² or Y ⁴ represent -C(X ¹ )= or -C(X ² )=, in which X ¹ and/or X ² represents halo, -R ^3a , -C(O)R ^3b , -C(O)OR ^3c , -C(O)N(R ^4a )R ^5a , -S(O) _m R ^3j or -S(O) ₂ N(R ^4h )R ^5h , and R ^3b , R ^4a , R ^5a , R ^4h and R ^5h are as hereinbefore defined, provided that they do not represent hydrogen, and R ^3a , R ^3c , and R ^3j are as hereinbefore defined, may be synthesised by reaction of a compound corresponding to a compound of formula I but in which X ¹ and/or X ² (as appropriate) represents a metal (e.g. lithium) or a magnesium-containing

group (so forming, for example, a Grignard reagent, e.g. a compound of formula I containing the group -Mg-Br), with a compound of formula Vl,

Z ^x -L ² Vl

wherein L ² represents a suitable leaving group, such as chloro, bromo or iodo and Z ^x represents halo, -R ^3a , -C(O)R ^3b , -C(O)OR ^3c , -C(O)N(R ^4a )R ^5a , -S(O) _m R ^3j or -S(O) ₂ N(R ^4h )R ^5h , and R ^3b , R ^4a , R ^5a , R ^4h and R ^5h are as hereinbefore defined, provided that they do not represent hydrogen, and R ^3a , R ^3c and R ^3j are as hereinbefore defined, under standard reaction conditions. For example, the above-mentioned compounds corresponding to a compound of formula I but in which X ¹ and/or X ² (as appropriate) represents:

(a) a metal, may be synthesised under standard conditions by metallation (e.g. lithiation) of a corresponding compound of formula I in which X ¹ and/or X ² (as appropriate) represents H, in the presence of a suitable organometallic reagent (such as an organolithuium base (e.g. n-BuLi, s- BuLi or t-BuLi)) in the presence of a suitable solvent (e.g. a polar aprotic solvent such as THF or diethyl ether), at a suitable temperature (e.g. between -78°C and 0°C). Alternatively, such compounds may be synthesised by halogen metal exchange under standard conditions from corresponding compounds of formula I in which X ¹ and/or X ² (as appropriate) represents halo (e.g. under similar conditions to those described above);

(b) a magnesium-containing group, may be synthesised under standard Grignard conditions (e.g. employing magnesium or a suitable reagent such as a mixture of C _1-6 alkyl-Mg-halide and ZnCI ₂ or LiCI), followed by reaction with a compound of formula I in which X ¹ and/or X ² represents halo (e.g. bromo), optionally in the presence of a catalyst (e.g. FeCI ₃ ). The skilled person will also appreciate that the magnesium of the magnesium- containing reagent (e.g. Grignard reagent) or the lithium of the lithiated species may be exchanged to a different metal (i.e. a transmetallation reaction may be performed), for example to zinc (e.g. using ZnCI ₂ ) and the intermediate so formed may then be subjected to reaction with a compound of formula Vl, for example under reaction conditions described above;

(iv) for compounds of formula I in which a substituent X ¹ or X ² is present and represents -N(R ^4b )R ^5b in which R ^5b is H and R ^4b is as hereinbefore defined, hydrolysis of a corresponding compound of formula I in which the relevant substituent is -N(R ^4b )C(O)OR ^4c in which R ^4b and R ^4c are as hereinbefore defined, or a protected derivative thereof, under standard conditions (e.g. employing aqueous acidic conditions);

(v) for compounds of formula I in which a substituent X ¹ or X ² is present and represents -C(O)OR ^3c and R ^3c is as hereinbefore defined, trans-esterification of a corresponding compound of formula I in which R ^3c does not represent the same value as the value of R ^3c in the compound of formula I to be prepared, under standard conditions known to those skilled in the art;

(vi) for compounds of formula I in which a substituent X ¹ or X ² is present and represents -C(O)OR ³⁰ , -C(O)N(R ^4a )R ^5a , -N(R ^4b )R ^5b , -N(R ^3e )C(O)N(R ^4d )R ^5d ,

-N(R ^3f )C(O)OR ^4e , -N(R ³⁹ )S(O) ₂ N(R ^4f )R ^5f , -0R ^3h , -OC(O)N(R ^4g )R ⁵⁹ , -OC(O)OR ^3p and/or -S(O) ₂ N(R ^4h )R ^5h , and R ^3e , R ^3f , R ³⁹ , R ^3h , R ^4a , R ^4b , R ^4d , R ^4e , R ^4f , R ^4g , R ^4h , R ^5a ,

R ^5b , R ^5d , R ^5f , R ⁵⁹ and R ^5h are as hereinbefore defined, provided that they do not represent hydrogen, and R ^3c and R ^3p are as hereinbefore defined, may be prepared by reaction of a compound corresponding to a compound of formula I in which R ^3c and/or R ^3p represents hydrogen or a corresponding compound of formula I in which R ^3e , R ^3f , R ^3g , R ^3h , R ^4a , R ^4b , R ^4d , R ^4e , R ^4f , R ^4g , R ^4h , R ^5a , R ^5b , R ^5d ,

R ^5f , R ⁵⁹ and/or R ^5h represent hydrogen (as appropriate), or an appropriate anion thereof, with a compound of formula VII,

R ^3a -L ³ VII

wherein L ³ represents a suitable leaving group, such as chloro, bromo, iodo or a triflate (e.g. -OS(O) ₂ CF ₃ ) and R ^3a is as hereinbefore defined, under standard conditions known to those skilled in the art, for example in the presence of a suitable base, such as one described hereinbefore in respect of process step (i). The skilled person will appreciate that in certain instances where monoalkylation is desired (or to avoid multiple alkylation generally), then the relevant group (e.g. -N(R ^4d )R ^5d ) may first need to be protected (and subsequently deprotected). In the case of reaction with an anion of a compound of formula I, e.g. a compound of

formula I in which X ¹ and/or X ² represents -N(R ^3f )C(O)O ^" or -OC(O)O ^" , the skilled person will appreciate that these derivatives may be prepared in situ from a corresponding compound of formula I in which the X ¹ and/or X ² (as appropriate) represents -N(R ^3f )H and -OH, respectively, followed by reaction in the presence of CO ₂ (or a suitable source of CO ₂ );

(vii) for compounds of formula I in which a substituent X ¹ or X ² is present and represents halo, -CN, -N(R ^4b )R ^5b , -N(R ^3d )C(O)R ^4c , -N(R ^3e )C(O)N(R ^4d )R ^5d , -N(R ^3f )C(O)OR ^4e , -N(R ³⁹ )S(O) ₂ N(R ^4f )R ^5f , -0R ^3h , -SR ^3J and/or -N(R ^3k )S(O) ₂ R ^3m , and R ^3d , R ^3e , R ^3f , R ³⁹ , R ^3h , R ³ⁱ , R ^3k , R ^3m , R ^4b , R ^4c , R ^4d , R ^4e , R ^4f , R ^5b , R ^5d and R ^5f are as hereinbefore defined, reaction of a corresponding compound of formula I in which X ¹ or X ² (as appropriate) represents a suitable leaving group, such as bromo, iodo or, preferably, fluoro, chloro, nitro or a diazonium salt, with (for the introduction of a halogen group) a halogen, or an appropriate reagent that is a source of a halogen (e.g. a copper halide), a reagent that is a source of another appropriate nucleophile (e.g. a source of anions such as cyano, oxy or S ^" anions), or (for the introduction of the other X ¹ and/or X ² substituents mentioned above) with a compound of formula VIII,

Z ^y -H VIII

wherein Z ^y represents -CN, -N(R ^4b )R ^5b , -N(R ^3d )C(O)R ^4c , -N(R ^3e )C(O)N(R ^4d )R ^5d , -N(R ^3f )C(O)OR ^4e , -N(R ^3g )S(O) ₂ N(R ^4f )R ^5f , -OR ^3h , -SR ^3j or -N(R ^3k )S(O) ₂ R ^3m , and R ^3d , R ^3e , R ^3f , R ³⁹ , R ^3h , R ^3J , R ^3k , R ^3m , R ^4b , R ^4c , R ^4d , R ^4e , R ^4f , R ^5b , R ^5d and R ^5f are as hereinbefore defined, or a suitable derivative (e.g. salt) thereof (e.g. NaCN), under standard aromatic nucleophilic substitution conditions known to those ^" skilled in the art. The skilled person will appreciate that diazonium salts (when employed as leaving groups) may be prepared under standard conditions known to those skilled in the art. The skilled person will also appreciate that (for example for reactions with a corresponding compound of formula I in which X ¹ or X ² (as appropriate) represents a suitable leaving group such as halo (e.g. chloro, bromo and iodo), -OSO ₂ CF ₃ , -B(OH) ₂ or -Sn(R ² ) ₃ (wherein R ^z is C _1-6 alkyl and preferably, methyl or butyl)), the reaction may be performed in the presence of a suitable catalyst, for example a metal catalyst containing, preferably, Pd or Cu, and a base and, optionally in the presence of solvent and a ligand. Catalysts that

may be mentioned include Pd ₂ (dba) ₃ (tris(dibenzylideneacetone)dipalladium(O)), bases that may be mentioned include cesium carbonate, ligands that may be mentioned include 2,2'-bis(diphenylphosphino)-1 ,1 '-binaphthyl and solvents that may be employed include toluene. Such reactions may be performed at elevated temperature (e.g. at about 9O ⁰ C) under an inert (e.g. argon) atmosphere. For example, when a compound of formula I containing a hydroxy group is to be prepared, reaction may be performed in the presence of CsOH (e.g. under reaction conditions known to those skilled in the art, for instance in the presence of a suitable solvent such as water) or in the presence of a protected alcohol such as benzyl alcohol, which may be deprotected after the substitution reaction;

(viii) for compounds of formula I in which T ¹ or T ² represents R ^3a , reaction of a corresponding compound of formula I in which T ¹ or T ² represents H, with a compound of formula VIIIA,

^" T-L ³ VIIIA

wherein T ^x and L ³ are as hereinbefore defined, under standard reaction conditions, for example at around room temperature or above (e.g. up to 40- 18O ⁰ C), optionally in the presence of a suitable base (e.g. sodium hydride, sodium bicarbonate, potassium carbonate, pyrrolidinopyridine, pyridine, triethylamine, tributylamine, trimethylamine, dimethylaminopyhdine, diisopropylamine, diisopropyl-ethylamine, 1 ,8-diazabicyclo[5.4.0]undec-7-ene, sodium hydroxide, λ/-ethyl-diisopropylamine, λ/-(methylpolystyrene)-4- (methylamino)pyridine, potassium bis(trimethylsilyl)amide, sodium bis(thmethylsilyl)amide, potassium terf-butoxide, lithium diisopropylamide, lithium 2,2,6,6-tetramethylpiperidine or mixtures thereof) and an appropriate solvent (e.g. tetrahydrofuran, pyridine, toluene, dichloromethane, chloroform, acetonitrile, dimethylformamide, trifluoromethylbenzene, dioxane or triethylamine);

(ix) compounds of formula I in which X ¹ or X ² is present and represents -OR ^3h in which R ^3h represents H, may be prepared by deprotection of a corresponding compound of formula I in which the -OH group is protected. The skilled person will appreciate that such protected derivatives may already be compounds of formula I. For example, such protected derivatives include corresponding

compounds of formula I in which R ^3h represents methyl (in this case deprotection may be effected by employing: a suitable reagent such as BBr ₃ ; a compound that is a source of anions of an aryl or alkyl sulfide, e.g. sodium salts of thiophenol or dodecanthiol; or a suitable strong acid such as chlorosulfonic acid, HBr (in water or AcOH) and HI), or such protected derivatives may also include compounds in which the -OH group is protected with a benzyl group (in which case deprotection may be effected by hydrogenation under standard conditions, e.g. employing Pd/C);

(x) compounds of formula I in which X ¹ or X ² is present and represents -NH ₂ , may be prepared by reduction of compounds corresponding to compounds of formula I but in which the relevant X ¹ or X ² group represents -NO ₂ , for example under hydrogenation conditions in the presence of a catalyst (e.g. palladium on carbon), with a source of hydrogen (e.g. hydrogen gas or nascent hydrogen (e.g. from ammonium formate)), optionally in the presence of a solvent (such as an alcoholic solvent (e.g. methanol)).

Compounds of formula Il (e.g. those in which Y ¹ , Y ³ or, preferably, Y ² or Y ⁴ represent -C(OR ^3h )=) in which L ^1a and L ^1b each represent halo may be prepared by reaction of a compound of formula VIIIB,

wherein Y ¹ , Y ² , Y ³ and Y ⁴ are as hereinbefore defined, with a suitable reagent for the introduction of the sulfonyl halide group (e.g. halosulfonic acid), under conditions known to those skilled in the art (e.g. employing an excess of the halosulfonic acid).

Compounds of formulae II, IV and V in which L ^1a and/or L ^1b represents halo, such as chloro, (as appropriate) may be prepared by reaction of a corresponding compound of: (a) formula IX,

(b) formula X,

(c) or formula Xl,

respectively, or a salt thereof (e.g. a metal salt such as magnesium, sodium or, preferably, lithium, wherein Y ¹ , Y ² , Y ³ , Y ⁴ , T ¹ , T ² , W ¹ , W ² , R ¹ and R ² are as hereinbefore defined, with a suitable halogenating reagent, such as PCI ₅ , PCI ₃ or SOCI ₂ (as chlorinating reagents) or a reagent such as λ/-chlorosuccinimde (e.g. in the case where a lithium salt of the sulfonic acid of formula Xl is to be converted, for example under oxidative chlorination conditions) or CuCI (e.g. in the case of preparation from a compound of formula XIIB, XIIIB or XIVB, after the steps comprising diazotisation and quench with SO ₂ , again under oxidative chlorination conditions). The skilled person will appreciate that other suitable halo groups may be prepared from the chloro derivative by an appropriate halogen exchange reaction.

Alternatively, compounds of formulae II, IV and V in which L ^1a and/or L ^1b (as appropriate) represents chloro may be prepared by reaction of a corresponding compound of:

(a) formula IXA,

(b) formula XA,

(C) or formula XIA,

respectively, wherein J ¹ represents -N ₂ ⁺ (i.e. a diazonium ion) or -S-Si(R ^zz ) ₃ , in which each R ^zz independently represents C ₁ _ ₆ alkyl (e.g. isopropyl; so forming for example a -S-Si(isopropyl) ₃ group), and Y ¹ , Y ² , Y ³ , Y ⁴ , T ¹ , T ² , W ¹ , W ² , R ¹ and R ² are as hereinbefore defined, under conditions known to those skilled in the art. For example when J ¹ represents a diazonium ion, reaction with SO ₂ (or a compound that is a source of SO ₂ ) in the presence of a suitable reagent containing the appropriate chloride ions (e.g. CuCI), preferably in the presence of a suitable solvent (such as acetic acid), or, when J ¹ represents -S-Si(R ^zz ) ₃ , by reaction with Cl ₂ in acetic acid, preferably in the presence of a suitable solvent such as dichloromethane.

Compounds of formula IV and V may alternatively be prepared by reaction of a compound of formula Il with less than 2 equivalents of a compound of formula III in which R ^x represents R ¹ or R ² (as appropriate), W ^x represents W ¹ or W ² (as appropriate) and T ^x represents T ¹ or T ² (as appropriate), under conditions such as those hereinbefore described in respect of preparation of compounds of formula I (process step (i) above).

Compounds of formula IX (.g. those in which Y ¹ , Y ³ or, preferably, Y ² or Y ⁴ represent -C(OR ^3h )=), may be prepared by reaction of the corresponding compound of formula VIIIA with a suitable reagent for the introduction of the sulfonic acid group. Such reagents include sulfuric acid at an appropriate concentration (e.g. concentrated, fuming or H ₂ SO ₄ ^* H ₂ O), SO ₃ and/or a halosulfonic acid, under conditions known to those skilled in the art.

Compounds of formulae IX, X and Xl may be prepared by oxidation of a compound of: (a) formula XII

(b) formula XIII ₁

(c) or formula XIV,

respectively, wherein Y ¹ , Y ² , Y ³ , Y ⁴ , T ¹ , T ² , W ¹ , W ² , R ¹ and R ² are as hereinbefore defined, under standard oxidation conditions, for example employing HNO ₃ (e.g. boiling nitric acid) or m-chloroperbenzoic acid in, where necessary, an appropriate solvent system (e.g. dichloromethane).

Alternatively, compounds of formulae IX, X and Xl may be prepared by reaction of a compound of:

(a) formula XIIA

(b) formula XIIIA,

(c) or formula XIVA,

respectively, wherein Y ¹ , Y ² , Y ³ , Y ⁴ , T ¹ , T ² , W ¹ , W ² , R ¹ and R ² are as hereinbefore defined, by conversion of the relevant bromo group(s) of the compounds of formulae XIIA, XIIIA or XIVA to a Grignard reagent (e.g. -Mg-Br) or, preferably, a metal (such as lithium), followed by quench with SO ₂ (or a compound that is a source of SO ₂ ). The conversion step may be performed under conditions such as those described hereinbefore in respect of preparation of compounds of formula 1 (process step (iii) above), for example conversion of the bromo group(s) to (a) lithium group(s) may be effected under halogen-lithium exchange reaction conditions in the presence of an organolithium base (e.g. t- or n-BuLi) in a polar aprotic solvent (e.g. THF or diethyl ether) at low temperature (e.g. -78 ⁰ C).

Alternatively still, compounds of formulae IX, X and Xl may be prepared by reaction of a compound of: (a) formula XIIB

(b) formula XIIIB,

(c) or formula XIVB,

respectively, wherein Y ¹ , Y ² , Y ³ , Y ⁴ , T ¹ , T ² , W ¹ , W ² , R ¹ and R ² are as hereinbefore defined, by conversion of the amino group to a diazonium salt (employing reagents and conditions known to those skilled in the art, e.g. NaNO ₂ and HCI at 5°C), followed by quenching by addition of with SO ₂ (or a compound that is a source of SO ₂ ).

Compounds of formula IXA, XA and XIA in which J ¹ represents a diazonium ion may be prepared from compounds corresponding to compounds of formula IXA, XA and XIA but in which the diazonium group is replaced with a nitro group, which reaction sequence comprises two steps, first, reduction to an amino group (for example under reaction condition such as those hereinbefore described in respect of preparation of compounds of formula (process step (x) above), and secondly, by a diazotisation (for example under conditions such as those described herein; e.g. in respect of preparation of compounds of formula IX, X and Xl).

Compounds of formula IXA, XA and XIA in which J ¹ represents -S-Si(R ^zz ) ₃ may be prepared from corresponding compounds of formula XIIA, XIIIA and XIVA, respectively, in the presence of a compound of formula XVA,

HS-Si(R ^zz ) ₃ XVA

wherein R ^zz is as hereinbefore defined, in the presence of an appropriate catalyst system (e.g. a palladium catalyst, such as PdCI ₂ , Pd(OAc) ₂ , Pd(Ph ₃ P) ₂ CI ₂ , Pd(Ph ₃ P) ₄ , Pd ₂ (dba) ₃ , trans-di(μ-acetato)bis[o-(di-o-tolylphosphino)benzyl]- dipalladium, or the like) optionally in the presence of a suitable additive (e.g. Ph ₃ P, 2,2'-bis(diphenylphosphino)-1 ,1 '-binaphthyl, xantphos, NaI, an appropriate crown ether or, preferably, tri-tert-butyl-phosphonium tetrafluoroborate), optionally in the presence of a base (such as NaH, Et ₃ N, pyridine, λ/.λ/ ¹ - dimethylethylenediamine, Na ₂ CO ₃ , K ₂ CO ₃ , K ₃ PO ₄ , Cs ₂ CO ₃ , t-BuONa or t-BuOK) and suitable solvent (e.g. dichloromethane, dioxane, toluene, ethanol, isopropanol, dimethylformamide, ethylene glycol, ethylene glycol dimethyl ether, water, dimethylsulfoxide, acetonitrile, dimethylacetamide, λ/-methylpyrrolidinone, tetrahydrofuran or a mixture thereof).

Compounds of formula XII may be prepared by reaction of a compound of formula XV,

wherein Y ² and Y ³ are as hereinbefore defined, and Y ¹ and Y ⁴ are as hereinbefore defined and, preferably (e.g. when such groups represent -C(X ² )=), represent

-C(H)= or -C(R ^3a )=, with a suitable reagent for the conversion of a carbonyl to a thiocarbonyl group (e.g. P ₂ S ₅ or Lawesson's reagent), under conditions known to those skilled in the art.

Compounds of formula XIV may be prepared by reaction of a compound of formula XVI,

wherein L ^x represents a suitable leaving group (such as halo (e.g. bromo)) and Y ¹ , Y ² , Y ³ , Y ⁴ , T ¹ , W ¹ and R ¹ are as hereinbefore defined, with a reagent that is a source of SH anions (e.g. NaSH), under standard conditions, for example such as those described hereinbefore in respect of preparation of compounds of formula I (process step (vii)). The skilled person will also appreciate that compounds of formula XIII may also be prepared in a similar manner from the appropriate starting material.

Compounds of formulae XIIIB and XIVB may be prepared by reduction of a corresponding compound of:

(a) formula XVII,

(C) or formula XVIII,

respectively, wherein the A ring, X ¹ , X ² , R ¹ , R ² , T ¹ and T ² are as hereinbefore defined, for example under hydrogenation conditions such as those hereinbefore

described in respect of preparation of compounds of formula I (process step (x) above).

Compounds of formulae III, Vl, VII, VIII, VIIIA, VIIIB, XIIA, XIIB, XIII, XIIIA, XIVA, XVA, XV, XVI, XVII and XVIII are either commercially available, are known in the literature, or may be obtained either by analogy with the processes described herein, or by conventional synthetic procedures, in accordance with standard techniques, from available starting materials using appropriate reagents and reaction conditions. In this respect, the skilled person may refer to inter alia "Comprehensive Organic Synthesis" by B. M. Trost and I. Fleming, Pergamon Press, 1991. Further, when the requisite Y ¹ to Y ⁴ containing ring of formula I is heterocyclic, it may also be prepared with reference to a standard heterocyclic chemistry textbook (e.g. "Heterocyclic Chemistry" by J. A. Joule, K. Mills and G. F. Smith, 3 ^rd edition, published by Chapman & Hall, "Comprehensive Heterocyclic Chemistry IT by A. R. Katritzky, C. W. Rees and E. F ^' . V. Scriven, Pergamon Press, 1996 or "Science of Synthesis", Volumes 9-17 (Hetarenes and Related Ring Systems), Georg Thieme Verlag, 2006) and/or made according to the following general procedures. For example, the sulfonamide groups of compounds of formulae XIIIA and XIVA may be prepared from the corresponding sulfonyl chloride or sulfonic acid, and compounds of formulae XVII and XVIII may ultimately be prepared from the corresponding 1-nitro-3-amino compounds using the diazotisation reaction, followed by the SO ₂ quench, oxidative chlorination and then coupling with an arylamine, all of which reactions are described herein. In these latter cases, compounds of formula I, or salts thereof, in which the -N(T ¹ )-R ¹ and -N(T ² )-R ² groups are different may be obtained. Further, a hydroxy substituent (e.g. on an aromatic ring) may be replaced with a halo substituent by reaction in the presence of an appropriate reagent (e.g. POCI ₃ for the introduction of a chloro group). Furthermore, a nitro substituent may be introduced onto an aromatic ring under standard aromatic nitration reaction conditions, for example, in the presence of a strong acid (e.g. H ₂ SO ₄ ) and HNO ₃ . Further still, an amino group (such a phenyl amino group), for example when attached to an aromatic ring (especially an aromatic ring containing electron withdrawing groups such as nitro and sulfonamido in the ortho and/or para-position), may be replaced with a hydroxy group or another suitable nucleophile (such as one mentioned hereinbefore in respect of process step (vii) above), for example, in the case of

the introduction of a hydroxy group, by reaction in the presence of a suitable reagent (e.g. dioxane in aqueous NaOH). Other transformations that may be mentioned include the conversion of a nitro group to an amino group (for example under reaction conditions described herein; e.g. for preparation of compounds of formula I) and the conversion of an amino group to a diazonium ion (for example under conditions described herein; e.g. for preparation of compounds of formula IX, X or Xl).

The substituents X ¹ , X ² , T ¹ , T ² , W ¹ and W ² and optional substituents on R ¹ and R ² in final compounds of formula I or relevant intermediates may be modified one or more times, after or during the processes described above by way of methods that are well known to those skilled in the art. Examples of such methods include substitutions, reductions, oxidations, alkylations, acylations, hydrolyses, esterifications, etherifications, halogenations and nitrations. The precursor groups can be changed to a different such group, or to the groups defined in formula I, at any time during the reaction sequence. In this respect, the skilled person may also refer to "Comprehensive Organic Functional Group

Transformations" by A. R. Katritzky, O. Meth-Cohn and C. W. Rees, Pergamon

Press, 1995 and/or "Comprehensive Organic Transformations" by R. C. Larock, Wiley-VCH, 1999.

Other transformations that may be mentioned include the conversion of a hydroxy group to a halo (e.g. chloro) group (e.g. employing SOCI ₂ ), one halo group to another halo group, or of a halo group (preferably iodo or bromo) to a cyano or 1- alkynyl group (e.g. by reaction with a compound which is a source of cyano anions (e.g. sodium, potassium, copper (I) or zinc cyanide) or with a 1-alkyne, as appropriate). The latter reaction may be performed in the presence of a suitable coupling catalyst (e.g. a palladium and/or a copper based catalyst) and a suitable base (e.g. a tri-(C _1-6 alkyl)amine such as triethylamine, tributylamine or ethyldiisopropylamine). Further, amino groups and hydroxy groups may be introduced in accordance with standard conditions using reagents known to those skilled in the art. Further still, -C(=O)- groups may be converted to the corresponding -C(H ₂ )- groups, for example by reduction in the presence of a suitable reducing agent such as borane and other reagents known to the skilled person.

Compounds of formula I may be isolated from their reaction mixtures using conventional techniques.

It will be appreciated by those skilled in the art that, in the processes described above and hereinafter, the functional groups of intermediate compounds may need to be protected by protecting groups.

The protection and deprotection of functional groups may take place before or after a reaction in the above-mentioned schemes.

Protecting groups may be removed in accordance with techniques that are well known to those skilled in the art and as described hereinafter. For example, protected compounds/intermediates described herein may be converted chemically to unprotected compounds using standard deprotection techniques. Specific examples of protecting groups that may be employed include a methyl protecting group for a hydroxy group (so forming a methoxy group), which groups may be deprotected under standard conditions, for example employing a suitable reagent such as BBr ₃ .

The type of chemistry involved will dictate the need, and type, of protecting groups as well as the sequence for accomplishing the synthesis.

The use of protecting groups is fully described in "Protective Groups in Organic Synthesis", 3 ^rd edition, T.W. Greene & P. G. M. Wutz, Wiley-lnterscience (1999).

Compounds of formula I and salts thereof are useful because they possess pharmacological activity. Such compounds are therefore indicated as pharmaceuticals.

Certain compounds of formula I have not been disclosed before for use as pharmaceuticals. According to a further aspect of the invention, there is provided a compound of formula I as hereinbefore defined, or a pharmaceutically- acceptable salt thereof, for use as a pharmaceutical, provided that, when T ¹ and T ² both represent H:

(A) W ¹ and W ² both represent direct bonds:

(a) Y ³ represents -C(X ¹ )=, in which X ¹ represents -OR ^3h and R ,3h represents H, Y ¹ represents -C(X ² )=, in which X ² represents -R ^3a and R ₁ 3a represents methyl, Y ² and Y ⁴ represent -C(X ² )=, in which X ² represents H, then R ¹ and R ² do not both represent a ZZ1 , ZZ2 or ZZ3 group;

(b) Y ² represents -C(X ¹ )=, in which X ¹ represents -OR ^3h and R ^3h represents H, Y ¹ represents -C(X ² )=, in which X ² represents H:

(I) Y ⁴ represents -C(X ² )=, in which X ² represents H: (i) when Y ³ represents -C(X ² )=, in which X ² represents

-OR ^3h and R ^3h represents H, then R ¹ and R ² do not both represent a ZZ1 , 4-bromophenyl or 4-chlorophenyl group; (ii) when Y ³ represents -C(X ² )=, in which X ² represents -R ^3a and R ^3a represents methyl, then R ¹ and R ² do not both represent a ZZ1 , ZZ2 or ZZ3 group;

(II) Y ³ represents -C(X ² )=, in which X ² represents H:

(i) when Y ⁴ represents -C(X ² )=, in which X ² represents -R ^3a and R ^3a represents methyl, then R ¹ and R ² do not both represent a ZZ1 , ZZ2 or ZZ3 group (e.g. unsubstituted phenyl or 4-methylphenyl);

(ii) when Y ⁴ represents -C(X ² )=, in which X ² represents -OR ^3h and R ^3h represents H, then R ¹ and R ² do not both represent a ZZ1 , 4-bromophenyl or 4-chlorophenyl group;

(c) Y ¹ and Y ³ both represent -C(X ² )= in which X ² represents H:

(I) Y ² represents -C(X ¹ )=, in which X ¹ represents -N(R ^4b )R ^5b , R ^4b represents H, R ^5b represents R ^3a , in which R ^3a represents ethyl terminally substituted with -N(R ^6b )R ^7b , and R ^5b and R ^7b both represent unsubstituted ethyl, Y ⁴ represents -C(X ² )= in which X ² is -N(R ^4b )R ^5b , then:

(i) when R ^4b represents H and R ^5b represents R ^3a , in which R ^3a represents ethyl terminally substituted with -N(R ^6b )R ^7b , and R ^6b and R ^7b both represent unsubstituted methyl; or

(ii) when R ^4fa and R ^5b are linked together to form a 1- piperazinyl ring substituted at the 4(N)-position with R ^3a in which R ^3a is methyl, then R ¹ and R ² do not both represent unsubstituted phenyl; (II) Y ² represents -C(X ¹ )=, in which X ¹ represents -N(R ^4b )R ^5b , and

R ^4b and R ^5b are linked together to form a 1-piperazinyl ring substituted at the 4(N)-position with R ^3a , in which R ^3a is methyl, Y ⁴ represents -C(X ² )= in which X ² is chloro, then R ¹ and R ² do not both represent unsubstituted phenyl; (III) Y ² represents -C(X ¹ )=, in which X ¹ represents R ^3a in which R ^3a is methyl, Y ⁴ represents -C(X ² )=, in which X ² represents R ^3a and R ^3a is methyl, then R ¹ and R ² do not both represent unsubstituted phenyl;

(d) Y ² represents -C(X ¹ )=, in which X ¹ represents -N(R ^4b )R ^5b , and R ^4b and

R ^5b both represent H, Y ¹ and Y ³ both represent -C(X ² )=, in which X ² represents H, then:

(i) when Y ⁴ represents -C(X ² )=, in which X ² represents chloro; then R ¹ and R ² do not both represent a ZZ3, unsubstituted phenyl, 2- methylphenyl, 4-methylphenyl, 3-trifluoromethylphenyl, 2- nitrophenyl or (4-S(O) ₂ -NH ₂ )phenyl group;

(ii) when Y ⁴ represents -C(X ² )=, in which X ² represents -R ^3a and R ^3a represents a trifluoromethyl group, then R ¹ and R ² do not both represent unsubstituted 2-pyridyl groups;

(e) Y ¹ represents -C(X ¹ )=, in which X ¹ represents chloro, Y ² and Y ⁴ represent -C(X ² )=, in which X ² represents H and Y ³ represents -C(X ² )=, in which X ² represents chloro, then R ¹ and R ² do not both represent A- methoxyphenyl;

(f) Y ¹ , Y ³ and Y ⁴ represent -C(X ² )=, in which X ² represents H, then when Y ² represents -C(X ¹ )= in which X ¹ represents either chloro or R ^3a in which R ^3a represents methyl, then R ¹ and R ² do not both represent A- dimethylaminophenyl, (3,4-dimethyl)phenyl, (2,5-dimethyl)phenyl, 2- pyridyl or 2-thiazolyl,

in which:

ZZ1 represents unsubstituted phenyl, 4-methylphenyl, 3-methylphenyl, 2- methylphenyl; ZZ2 represents 4-nitrophenyl, 3-nitrophenyl, 2-nitrophenyl;

ZZ3 represents 4-chlorophenyl, 3-chlorophenyl, 2-chlorophenyl;

(B) W ¹ and W ² both represent -CH ₂ - linker groups:

(a) Y ² represents -C(X ¹ )=, in which X ¹ represents -N(R ^4b )R ^5b , R ^4b and R ^5b are linked together to form a 1-piperazinyl ring substituted at the 4(N)- position by R ^3a in which R ^3a is methyl, Y ¹ and Y ³ both represent -C(X ² )= in which X ² is H, then:

(i) when Y ⁴ represents -C(X ² )=, in which X ² represents -N(R ^4b )R ^5b and R ^4b and R ^5b are linked together to form a 1-piperazinyl ring substituted at the 4(N)-position by R ^3a in which R ^3a is methyl, then R ¹ and R ² do not both represent an unsubstituted phenyl group; (ii) when Y ⁴ represents -C(X ² )=, in which X ² represents chloro, then R ¹ and R ² do not both represent 2-chlorophenyl;

(b) Y ² represents -C(X ¹ )=, in which X ¹ represents -OR ^3h , R ^3h represents R ^3a in which R ^3a is methyl, Y ¹ , Y ³ and Y ⁴ all represent -C(X ² )=, in which X ² represents H, then R ¹ and R ² do not both represent unsubstituted 3- pyridyl;

(C) Y ² represents -C(X ¹ )=, in which X ¹ represents -N(R ^4b )R ^5b and R ^4b and R ^5b both represent hydrogen, Y ¹ and Y ³ both represent -C(X ² )=, in which X ² represents H, Y ⁴ represents -C(X ² )=, in which X ² represents chloro, then R ¹ and R ² do not both represent unsubstituted phenyl.

As hereinbefore stated, certain compounds of formula I have not been disclosed before for use as pharmaceuticals. According to yet a further aspect of the invention, there is provided a compound of formula I, or a pharmaceutically- acceptable salt thereof, for use as a pharmaceutical, as hereinbefore defined but

further provided that, when T ¹ and T ² both represent H, W ¹ and W ² both represent direct bonds:

(a) Y ¹ and Y ² both represent -C(H)= and Y ³ represents -C(CH ₃ )=, or, when Y ¹ and Y ³ both represent -C(H)= and Y ² represents -C(CH ₃ )=, then when Y ⁴ represents -NH ₂ or -N(H)C(O)CH ₃ , then R ¹ and R ² do not both represent unsubstituted phenyl, 2-methylphenyl or4-chlorophenyl;

(b) Y ² and Y ⁴ both represent -C(H)=, Y ³ represents -C(CH ₃ )=, then when Y ¹ represents -NH ₂ or =N(H)C(O)CH ₃ , then R ¹ and R ² do not both represent unsubstituted phenyl, 2-methylphenyl, 4-methylphenyl or 4- nitrophenyl.

Alternatively, there is provided a compound of formula I, or a pharmaceutically- acceptable salt thereof, for use as a pharmaceutical, as hereinbefore defined but in which: (1 ) one or two of Y ¹ , Y ² , Y ³ or Y ⁴ represent(s) -N=, and therefore without the above provisos;

(2) X ¹ represents -OR ^3h , and therefore without all of the above provisos except for (A)(a), (A)(b) and (B)(b);

(3) W ¹ and W ² represent direct bonds, and therefore without the above proviso (B); and/or

(4) when one of Y ¹ to Y ⁴ represents -C(X ¹ )= and the others represents -C(X ² )=, then none, one or, more preferably, all three of those X ² groups represent H, and therefore without all of the above provisos except for (A)(f) and (B)(b).

Hence, when e.g. (2) and (4) above are taken in conjunction, there is provided a compound of formula I as hereinbefore defined, or a pharmaceutically-acceptable salt thereof, for use as a pharmaceutical, but without all of the above provisos except (B)(b). Alternatively, when (2), (3) and (4) above are taken in conjunction, there is provided a compound of formula I as hereinbefore defined, or a

pharmaceutically-acceptable salt thereof, for use as a pharmaceutical, but without all of the above provisos.

Certain compounds of formula I, and pharmaceutically-acceptable salts thereof, 5 are novel per se. Thus according to a further aspect of the invention, there is provided:

(1) a compound of formula I as hereinbefore defined, but in which:

(i) one or two of Y ¹ , Y ² , Y ³ or Y ⁴ represent(s) -N=; and, optionally, 10 (ii) X ¹ represents -OR ^3h , or a pharmaceutically-acceptable salt thereof;

(2) a compound of formula I as hereinbefore defined, but in which:

(i) X ¹ represents -OR ^3h ; and 15 (ii) one of Y ¹ to Y ⁴ represents -C(X ¹ )= and the others represents

-C(X ² )= in which none, one or, more preferably, all three of those X ² groups represent H, provided that the above proviso (B)(b) applies; and, optionally,

(iii) W ¹ and W ² represent direct bonds (in which case proviso (B)(b) is 20. redundant); and/or

(iv) Y ⁴ or Y ² represent -C(X ¹ )=, or a pharmaceutically-acceptable salt thereof;

(3) a compound of formula I as hereinbefore defined, but in which R ¹ and R ² 25 independently represent C _1-12 alkyl (e.g. C _3-12 cycloalkyl) or heterocycloalkyl (both of which are optionally substituted as hereinbefore defined), provided that when T ¹ and T ² represent hydrogen, W ¹ and W ² represent direct bonds, Y ² and Y ⁴ both represent -C(H)=, then when Y ¹ and Y ³ either both represent -C(CH ₃ )= or both represent -C(CI)=, then R ¹ and R ² do not both represent cyclohexyl; 30

(4) a compound of formula I as hereinbefore defined, but in which:

(i) one of R ¹ and R ² (preferably R ¹ ) represents aryl or heteroaryl (which latter two groups are optionally substituted by one or more substituents selected from Z ¹ and Z ² ), and the other (preferably R ² ) represents C _{1 -12} 5 alkyl (optionally substituted by one or more substituents selected from Z ¹ ,

Z ² and =O), heterocycloalkyl (optionally substituted by one or more substituents selected from Z ¹ , Z ² and =0), preferably, heteroaryl or, more preferably, aryl (which latter two groups are optionally substituted by one or more substituents selected from Z ¹ and Z ² ); (ii) Y ² represents -C(X ¹ )=;

(iii) X ¹ represents -N(R ^4b )R ^5b or, preferably, -0R ^3h ;

(iv) one of R ^4b and R ^5b represents hydrogen and the other is as hereinbefore defined;

(v) R ^3h represents hydrogen; (vi) at least one of W ¹ and W ² (e.g. W ² ) represents a direct bond;

(vii) T ¹ and T ² independently represent hydrogen;

(viii) R ¹ and/or R ² (preferably R ² , e.g. when W ² represents a direct bond) represents phenyl substituted by one or, preferably two substituents selected from Z ¹ and Z ² , and which substituent(s) are preferably located in the ortho and/or mefa-positions (i.e. in the 2- and/or 3-positions); and/or

(viii) substituents on the R ¹ and/or R ² groups (e.g. when such groups represent aryl, such as phenyl), are preferably selected from halo (e.g. chloro; which is preferably located in the 3-position when R ¹ and/or R ² represents phenyl) and R ^3a (in which R ^3a is as hereinbefore defined and is preferably methyl, e.g. located at the 2-position when R ¹ and/or R ² represents phenyl).

As hereinbefore stated, certain compounds of formula I, and pharmaceutically- acceptable salts thereof, are novel per se. Particularly in such instances, it is preferred that when W ¹ and W ² represent optionally substituted C ₁ _ ₆ alkylene, then they preferably represent methylene (e.g. -CH ₂ -). Particularly in such instances, preferably W ¹ and W ² independently represent -CH ₂ - or, more preferably, a direct bond.

Although compounds of formula I and salts thereof may possess pharmacological activity as such, certain pharmaceutically-acceptable (e.g. "protected") derivatives of compounds of formula I may exist or be prepared which may not possess such activity, but may be administered parenterally or orally and thereafter be metabolised in the body to form compounds of formula I. Such compounds (which may possess some pharmacological activity, provided that such activity is

appreciably lower than that of the "active" compounds to which they are metabolised) may therefore be described as "prodrugs" of compounds of formula

By "prodrug of a compound of formula I", we include compounds that form a compound of formula I, or salt thereof, in an experimentally-detectable amount, within a predetermined time (e.g. about 1 hour), following oral or parenteral administration. All prodrugs of the compounds of formula I are included within the scope of the invention.

Furthermore, certain compounds of formula I may possess no or minimal pharmacological activity as such, but may be administered parenterally or orally, and thereafter be metabolised in the body to form compounds of formula I that possess pharmacological activity as such. Such compounds (which also includes compounds that may possess some pharmacological activity, but that activity is appreciably lower than that of the "active" compounds of formula I to which they are metabolised), may also be described as "prodrugs".

Thus, the compounds of formula I and salts thereof are useful because they possess pharmacological activity, and/or are metabolised in the body following oral or parenteral administration to form compounds which possess pharmacological activity.

Compounds of formula I and salts thereof are particularly useful because they may inhibit the activity of a member of the MAPEG family.

Compounds of formula I and salts thereof are particularly useful because they may inhibit (for example selectively) the activity of prostaglandin E synthases (and particularly microsomal prostaglandin E synthase-1 (mPGES-1)), i.e. they prevent the action of mPGES-1 or a complex of which the mPGES-1 enzyme forms a part, and/or may elicit a mPGES-1 modulating effect, for example as may be demonstrated in the test described below. Compounds of formula I may thus be useful in the treatment of those conditions in which inhibition of a PGES, and particularly mPGES-1 , is required.

Compounds of formula I, and pharmaceutically-acceptable salts thereof, are thus expected to be useful in the treatment of inflammation.

The term "inflammation" will be understood by those skilled in the art to include any condition characterised by a localised or a systemic protective response, which may be elicited by physical trauma, infection, chronic diseases, such as those mentioned hereinbefore, and/or chemical and/or physiological reactions to external stimuli (e.g. as part of an allergic response). Any such response, which may serve to destroy, dilute or sequester both the injurious agent and the injured tissue, may be manifest by, for example, heat, swelling, pain, redness, dilation of blood vessels and/or increased blood flow, invasion of the affected area by white blood cells, loss of function and/or any other symptoms known to be associated with inflammatory conditions.

The term "inflammation" will thus also be understood to include any inflammatory disease, disorder or condition per se, any condition that has an inflammatory component associated with it, and/or any condition characterised by inflammation as a symptom, including inter alia acute, chronic, ulcerative, specific, allergic and necrotic inflammation, and other forms of inflammation known to those skilled in the art. The term thus also includes, for the purposes of this invention, inflammatory pain, pain generally and/or fever.

Where a condition has an inflammatory component associated with it, or a condition characterised by inflammation as a symptom, the skilled person will appreciate that compounds of the invention may be useful in the treatment of the inflammatory symptoms and/or the inflammation associated with the condition.

Accordingly, compounds of formula I and salts thereof may be useful in the treatment of asthma, chronic obstructive pulmonary disease, pulmonary fibrosis, inflammatory bowel disease, irritable bowel syndrome, inflammatory pain, fever, migraine, headache, low back pain, fibromyalgia, myofascial disorders, viral infections (e.g. influenza, common cold, herpes zoster, hepatitis C and AIDS), bacterial infections, fungal infections, dysmenorrhea, burns, surgical or dental procedures, malignancies (e.g. breast cancer, colon cancer, and prostate cancer), hyperprostaglandin E syndrome, classic Bartter syndrome,

atherosclerosis, gout, arthritis, osteoarthritis, juvenile arthritis, rheumatoid arthritis, rheumatic fever, ankylosing spondylitis, Hodgkin's disease, systemic lupus erythematosus, vasculitis, pancreatitis, nephritis, bursitis, conjunctivitis, iritis, scleritis, uveitis, wound healing, dermatitis, eczema, psoriasis, stroke, diabetes mellitus, neurodegenerative disorders such as Alzheimer's disease and multiple sclerosis, autoimmune diseases, allergic disorders, rhinitis, ulcers, coronary heart disease, sarcoidosis and any other disease with an inflammatory component.

Compounds of formula I, and pharmaceutically-acceptable salts thereof, may also have effects that are not linked to inflammatory mechanisms, such as in the reduction of bone loss in a subject. Conditions that may be mentioned in this regard include osteoporosis, osteoarthritis, Paget's disease and/or periodontal diseases. Compounds of formula I may thus also be useful in increasing bone mineral density, as well as the reduction in incidence and/or healing of fractures, in subjects.

Compounds of formula I and salts thereof are indicated both in the therapeutic and/or prophylactic treatment of the above-mentioned conditions.

According to a further aspect of the present invention, there is provided a method of treatment of a disease which is associated with, and/or which can be modulated by inhibition of, a member of the MAPEG family such as a PGES (e.g. mPGES-1 ), LTC ₄ synthase and/or FLAP and/or a method of treatment of a disease in which inhibition of the activity of a member of the MAPEG family such as PGES (and particularly mPGES-1 ), LTC ₄ synthase and/or FLAP is desired and/or required (e.g. inflammation), which method comprises administration of a therapeutically effective amount of a compound of the formula I, or a pharmaceutically-acceptable salt thereof, to a patient suffering from, or susceptible to, such a condition.

"Patients" include mammalian (including human) patients. ,

The term "effective amount" refers to an amount of a compound, which confers a therapeutic effect on the treated patient. The effect may be objective (i.e.

measurable by some test or marker) or subjective (i.e. the subject gives an indication of or feels an effect).

Compounds of formula I and salts thereof will normally be administered orally, intravenously, subcutaneously, buccally, rectally, dermally, nasally, tracheally, bronchially, sublingually, by any other parenteral route or via inhalation, in a pharmaceutically acceptable dosage form.

Compounds of formula I and salts thereof may be administered alone, but are preferably administered by way of known pharmaceutical formulations, including tablets, capsules or elixirs for oral administration, suppositories for rectal administration, sterile solutions or suspensions for parenteral or intramuscular administration, and the like.

Such formulations may be prepared in accordance with standard and/or accepted pharmaceutical practice.

According to a further aspect of the invention there is thus provided a pharmaceutical formulation including a compound of formula I, as specified herein, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.

Depending on e.g. potency and physical characteristics of the compound of the invention (i.e. active ingredient), pharmaceutical formulations that may be mentioned include those in which the active ingredient is present in at least 1 % (or at least 10%, at least 30% or at least 50%) by weight. That is, the ratio of active ingredient to the other components (i.e. the addition of adjuvant, diluent and carrier) of the pharmaceutical composition is at least 1 :99 (or at least 10:90, at least 30:70 or at least 50:50) by weight.

The invention further provides a process for the preparation of a pharmaceutical formulation, as hereinbefore defined, which process comprises bringing into association a compound of the formula I, as specified herein, or a pharmaceutically acceptable salt thereof with a pharmaceutically-acceptable adjuvant, diluent or carrier.

Compounds of the invention may also be combined with other therapeutic agents that are useful in the treatment of inflammation (e.g. NSAIDs, coxibs and glucocorticoids).

According to a further aspect of the invention, there is provided a combination product comprising:

(A) a compound of formula I or a pharmaceutically-acceptable salt thereof; and (B) another therapeutic agent that is useful in the treatment of inflammation, wherein each of components (A) and (B) is formulated in admixture with a pharmaceutically-acceptable adjuvant, diluent or carrier.

Such combination products provide for the administration of a compound of formula I, or a salt thereof, in conjunction with the other therapeutic agent, and may thus be presented either as separate formulations, wherein at least one of those formulations comprises a compound of formula I or a pharmaceutically- acceptable salt thereof, and at least one comprises the other therapeutic agent, or may be presented (i.e. formulated) as a combined preparation (i.e. presented as a single formulation including a compound of formula I, or a salt thereof, and the other therapeutic agent).

Thus, there is further provided:

(1 ) a pharmaceutical formulation including a compound of formula I or a pharmaceutically-acceptable salt thereof, another therapeutic agent that is useful in the treatment of inflammation, and a pharmaceutically-acceptable adjuvant, diluent or carrier; and

(2) a kit of parts comprising components:

(a) a pharmaceutical formulation including a compound of formula I or a pharmaceutically-acceptable salt thereof, in admixture with a pharmaceutically-acceptable adjuvant, diluent or carrier; and

(b) a pharmaceutical formulation including another therapeutic agent that is useful in the treatment of inflammation in admixture with a pharmaceutically-acceptable adjuvant, diluent or carrier, which components (a) and (b) are each provided in a form that is suitable for administration in conjunction with the other.

The invention further provides a process for the preparation of a combination product as hereinbefore defined, which process comprises bringing into association a compound of formula I or a pharmaceutically-acceptable salt thereof, with another therapeutic agent that is useful in the treatment of inflammation, and a pharmaceutically-acceptable adjuvant, diluent or carrier.

By "bringing into association", we mean that the two components are rendered suitable for administration in conjunction with each other.

Thus, in relation to the process for the preparation of a kit of parts as hereinbefore defined, by bringing the two components "into association with" each other, we include that the two components of the kit of parts may be: (i) provided as separate formulations (i.e. independently of one another), which are subsequently brought together for use in conjunction with each other in combination therapy; or

(ii) packaged and presented together as separate components of a "combination pack" for use in conjunction with each other in combination therapy.

Compounds of formula I and salts thereof may be administered at varying doses. Oral, pulmonary and topical dosages may range from between about 0.01 mg/kg of body weight per day (mg/kg/day) to about 100 mg/kg/day, preferably about 0.01 to about 10 mg/kg/day, and more preferably about 0.1 to about 5.0 mg/kg/day. For e.g. oral administration, the compositions typically contain between about 0.01 mg to about 500 mg, and preferably between about 1 mg to about 100 mg, of the active ingredient. Intravenously, the most preferred doses will range from about 0.001 to about 10 mg/kg/hour during constant rate infusion. Advantageously, compounds may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three or four times daily.

In any event, the physician, or the skilled person, will be able to determine the actual dosage which will be most suitable for an individual patient, which is likely to vary with the route of administration, the type and severity of the condition that is to be treated, as well as the species, age, weight, sex, renal function, hepatic function and response of the particular patient to be treated. The above- mentioned dosages are exemplary of the average case; there can, of course, be individual instances where higher or lower dosage ranges are merited, and such are within the scope of this invention.

Compounds of formula I and salts thereof may have the advantage that they are effective, and preferably selective, inhibitors of a member of MAPEG family, e.g. inhibitors of prostaglandin E synthases (PGES) and particularly microsomal prostaglandin E synthase-1 (mPGES-1 ). The compounds of formula I may reduce the formation of the specific arachidonic acid metabolite PGE ₂ without reducing the formation of other COX generated arachidonic acid metabolites, and thus may not give rise to the associated side-effects mentioned hereinbefore.

Compounds of formula I and salts thereof may also have the advantage that they may be more efficacious than, be less toxic than, be longer acting than, be more potent than, produce fewer side effects than, be more easily absorbed than, and/or have a better pharmacokinetic profile (e.g. higher oral bioavailability and/or lower clearance) than, and/or have other useful pharmacological, physical, or chemical properties over, compounds known in the prior art, whether for use in the above-stated indications or otherwise.

Biological Test

In the assay mPGES-1 catalyses the reaction where the substrate PGH ₂ is converted to PGE ₂ . mPGES-1 is expressed in E. coli and the membrane fraction is dissolved in 2OmM NaPi-buffer pH 8.0 and stored at -80 ⁰ C. In the assay mPGES-1 is dissolved in 0,1 M KPi-buffer pH 7,35 with 2,5mM glutathione. The stop solution consists of H ₂ O, containing FeCI ₂ (25 mM) and HCI (0.15 M). The assay is performed at room temperature in 384-well plates. Analysis of the amount of PGE ₂ is performed with a commercially available PGE2 HTRF kit from CisBio or by reversed phase HPLC.

The following is added chronologically to each well:

1. 50 μL mPGES-1 in KPi-buffer with glutathione. Total protein concentration: 0.02 mg/mL.

2. 0,5 μL inhibitor in DMSO. Incubation of the plate at room temperature for 25 minutes.

3. 2 μL of a 0,25 mM PGH ₂ solution. Incubation of the plate at room temperature for 60 seconds.

4. 30 μL stop solution.

A 4 μl aliquot of this mixture is diluted 1 :750-fold in two steps before detection of PGE ₂ with HTRF is performed.

Examples

The invention is illustrated by way of the following examples, in which the following abbreviations may be employed:

EtOAc ethyl acetate

MeOH methanol

MeOfBu tert-butylmethylether

NMP 1-methyl-2-pyrrolidinone rt room temperature

Example 1 λ/ ¹ ,λ/ ³ -Bis(3-chloro-2-methylphenyl)-4-methoxybenzene-1 ,3-disulfonamide

(a) 4-Methoxybenzene-1 ,3-disulfonyl dichloride

A mixture of 4-methoxybenzenesulfonyl chloride (1.0 g, 4.8 mmol) and chloro- sulfonic acid (5 mL) was heated at 80 ⁰ C for 2 h, cooled to rt, poured on ice and extracted with CHCI ₃ . The combined extracts were dried over Na ₂ SO ₄ , concentrated and the residue crystallised from benzene. Yield of the sub-title compound: 450 mg (30%).

(b) λ/^λ^-BisO-chloro^-methylphenvD^-methoxybenzene-I .S-disulfonamide A mixture of 4-methoxybenzene-1 ,3-disulfonyl dichloride (100 mg, 0.33 mmol; see step (a) above), 3-chloro-2-methylaniline (250 μl_; 2.1 mmol) and CHCI ₃ (5 mL) was stirred at rt for 4 h. Water was added and the mixture was extracted with EtOAc. The combined extracts were washed with HCI (aq, 4%), dried over Na ₂ SO ₄ and concentrated. The residue was purified by chromatography to afford 120 mg (70%) of the title compound.

200 MHz ¹ H-NMR (DMSO-c/ ₆ , ppm) δ 9.91 (1 H, s) 9.86 (1 H, s) 7.93 (1 H, d, J = 2.5 Hz) 7.74 (1 H, dd, J = 8.8, 2.5 Hz) 8.38 (1 H, d, J = 8.9 Hz) 7.32 (1 H, dd, J = 8.0, 1.1 Hz) 7.30 (1 H, dd, J = 8.0, 1.1 Hz) 7.11 (1H, dd, J = 8.0, 8.0 Hz) 7.05 (1 H, dd, J = 8.0, 8.0 Hz) 6.93 (1 H, dd, J - 8.0, 1.0 Hz) 6.70 (1 H, dd, J = 8.0, 0.9 Hz) 3.96 (3H, s) 2.18 (3H, s) 1.94 (3H, s).

Example 2 λ/.λ^-BisQ-chloro^-methylphenylM-hvdroxybenzene-I .S-disulfonamide

BBr ₃ (1 M in CH ₂ CI ₂ , 230 μl_, 0.23 mmol) was added to a mixture of λ/'^-bis- (3-chloro-2-methylphenyl)-4-methoxybenzene-1 ,3-disulfonamide (60 mg, 0.12 mmol; see Example 1 , step (b)) and CH ₂ CI ₂ (5 mL) and the mixture was stirred at rt for 24 h. MeOH (5 mL) was added and the mixture was stirred for 30 min at rt and concentrated. The residue was dissolved in EtOAc, washed with NaHCO ₃ (aq, 5%), brine and dried over Na ₂ SO ₄ . The mixture was concentrated to afford 38 mg of the title compound (65% yield).

200 MHz ¹ H-NMR (DMSO-Cf ₆ , ppm) δ 12.18 (1 H, s) 9.75 (2H, s) 7.85 (1 H, d, J = 2.4 Hz) 7.55 (1 H, dd, J = 8.8, 2.4 Hz) 7.34-7.25 (2H, m) 7.15-7.02 (3H, m) 6.98 (1 H, dd, J = 8.2, 1.2 Hz) 6.70 (1 H, d, J = 7.9 Hz) 2.23 (3H, s) 1.93 (3H, s).

Example 3

N ¹ , N ³ -Bis(3-chloro-2-methylphenvD^-hvdroxy-S-methoxybenzene-I .S- disulfonamide

(a) 4-Hvdroxy-6-methoxybenzene-1 ,3-disulfonyl dichloride 3-Methoxyphenol (2.0 mL, 18.2 mmol) was added in portions over 15 min to chlorosulfonic acid (10 mL) at 0 ⁰ C. After stirring at rt for 2 h, the mixture was poured on ice and extracted with CHCI ₃ . The combined extracts were dried over Na ₂ SO ₄ and concentrated to afford the sub-title compound.

(b) N^/v^-BisO-chloro^-methylphenylM-hvdroxy-e-methoxybenzene-I .S-disul- fonamide

A mixture of 4-hydroxy-6-methoxybenzene-1 ,3-disulfonyl dichloride (300 mg, 0.93 mmol; see step (a) above), 3-chloro-2-methylaniline (680 μ!_; 5.6 mmol) and acetonitrile (3 mL) was stirred at rt for 12 h, diluted with water and extracted with EtOAc. The combined extracts were washed with HCI (aq, 4%), dried over Na ₂ SO ₄ and concentrated, yielding 250 mg (51%) of the title compound. 200 MHz ¹ H-NMR (DMSO-d ₆ , ppm) δ 12.1 (1 H, s) 9.56 (1 H, s) 9.52 (1 H, s) 7.69 (1 H, s) 7.27 (1 H, dd, J = 8.0, 1.1 Hz) 7.26 (1 H, dd, J = 8.0, 1.1 Hz) 7.05 (1 H, dd, J = 8.0, 8.0 Hz) 7.03 (1 H, dd, J = 8.0, 8.0 Hz) 6.87 (1 H, dd, J = 8.0, 1.1 Hz) 6.85 (1 H, dd, J = 8.0, 1.1 Hz) 6.67 (1 H, s) 3.84 (3H, s) 2.19 (3H, s) 2.14 (3H, s).

Example 4

λ/'.λ^-BisO-fluoro-σ-methylphenvD^-hydroxy-e-methoxybe nzene-I .S- disulfonamide

The title compound was prepared from 4-hydroxy-6-methoxy-benzene-1 ,3- disulfonyl dichloride (see Example 3 step (a)) and 3-fluoro-2-methylaniline in accordance with Example 3 step (b).

200 MHz ¹ H-NMR (DMSO-Cf ₆ , ppm) δ 12.1 (1 H, s) 9.51 (1 H, s) 9.46 (1 H, s) 7.71 (1 H, s) 7.11-6.90 (4H, m) 6.81-6.70 (2H, m) 6.65 (1 H, s) 3.85 (3H, s) 2.05 (3H, d, J = 2.1 Hz) 2.00 (3H, d, J = 2.1 Hz).

Example 5 4-Hvdroxy-6-methoxy-A/ ⁷ ,λ/ ³ -di(o-tolyl)benzene-1 ,3-disulfonamide

The title compound was prepared from 4-hydroxy-6-methoxybenzene-1 ,3- disulfonyl dichloride (see Example 3 step (a)) and o-toluidine in accordance with

Example 3 step (b).

200 MHz ¹ H-NMR (DMSO-Cf ₆ , ppm) δ 12.0-1 1.9 (1 H, br s) 9.23 (1 H, s) 9.16 (1 H, s) 7.70 (1 H, s) 7.17-6.91 (6H, m) 6.91-6.82 (2H, m) 6.66 (1 H, s) 3.85 (3H, s) 2.15

(3H, s) 2.09 (3H, s).

Example 6

4-Chloro-λ/',λ/ ³ -bis(3-chloro-2-methylphenyl)-5-hydroxybenzene-1 ,3-disulfon- amide

(a) 4-Chloro-5-hydroxybenzene-1 ,3-disulfonyl dichløride

4,5-Dihydroxybenzene-1 ,3-disu!fonic acid disodium salt (2.0 g, 6.4 mmol) was suspended in thionyl chloride (6 ml_). DMF (1 mL) was added and the mixture was heated at reflux for 7 h. The mixture was concentrated and the residue was partitioned between ice-water and CHCI ₃ . The organic layer was separated, dried over CaCI ₂ and concentrated to give the sub-title compound as an oil.

(b) 4-Chloro-N^N ³ -bis(3-chloro-2-methylphenyl)-5-hydroxybenzene-1 ,3-disulfon- amide

The title compound was prepared from 4-chloro-5-hydroxybenzene-1 ,3-disulfonyl dichloride and 3-chloro-2-methylaniline in accordance with Example 3 step (b). 200 MHz ¹ H-NMR (DMSO-Cf ₆ , ppm) δ 11.66 (1 H, s) 10.32 (1 H, s) 10.10 (1 H, s) 7.60 (1 H, d, J = 2.0 Hz) 7.40-7.30 (3H, m) 7.13 (1 H, dd, J = 8.0, 8.0 Hz) 7.10 (1 H, dd, J = 8.0, 8.0 Hz) 6.88 (1 H, d, J = 8.0 Hz) 6.72 (1 H, d, J = 8.0 Hz) 2.22 (3H, s) 1.98 (3H, s).

Example 7

S-Bromo-λ/'.λ^-bisO-chloro^-methylbenzvD^-hvdroxybenzen e-I.S-disulfon- amide

(a) 5-Bromo-2-hydroxybenzene-1 ,3-disulfonyl dichloride

A mixture of 5-bromo-2-methoxybenzene sulfonyl chloride (285 mg, 1.0 mmol) and chlorosulfonic acid (1.0 mL) was heated in a sealed tube for 12 h and poured on ice. The precipitate was filtered off, washed with water and dried to yield 180 mg (48%) of the sub-title compound.

(b) 5-Bromo-N^/v ⁰ -bis(3-chloro-2-methylbenzyl)-2-hvdroxybenzene-1.3-disulfon- amide

A mixture of 3-chloro-2-methylbenzylamine (160 μl_, 1.14 mmol), 5-bromo-2- hydroxybenzene-1 ,3-disulfonyl dichloride (200 mg, 0.54 mmol; see step (a) above) and anhydrous pyridine (3.0 mL) was stirred at rt for 12 h, poured into HCI (aq, 1 M, 20 mL) and extracted with EtOAc. The combined extracts were washed with brine and dried over Na ₂ SO ₄ . Concentration and purification by chromatography gave the title compound (200 mg, 61 %). 200 MHz ¹ H-NMR (DMSO-Cf ₆ , ppm) δ 7.56 (2H, s) 7.33-7.17 (6H, m) 7.08 (2H, dd, J = 7.6, 7.6 Hz) 3.89 (4H, d, J = 6.0 Hz) 2.25 (6H, s).

Example 8 S-Bromo-λλλ^-bis^-chlorobenzvO^-hvdroxybenzene-I .S-disulfonamide

The title compound was prepared from 5-bromo-2-hydroxybenzene-1 ,3-disulfonyl dichloride (see Example 7, step (b)) and 4-chlorobenzylamine in accordance with Example 7 step (b).

200 MHz ¹ H-NMR (DMSO- ₆ , ppm) δ 7.50 (2H, s) 7.35 (2H, t, J = 6.0 Hz) 7.28- 7.27 (8H, m) 3.86 (4H, d, J = 6.0 Hz).

Example 9

/v^/v^-Bis(3-chloro-2-methylbenzyl)-2-hvdroxybenzene-1 ,3-disulfonamide

n-BuLi (2.5 M in hexanes, 460 μl_, 1.15 mmol) was added over 5 min to 5-bromo- N ¹ , λ/ ³ -bis(3-chloro-2-methylbenzyl)-2-hydroxybenzene-1 ,3-disulfon-amide (100 mg, 0.16 mmol; see Example 7, step (b)) in THF (4.0 mL) at -78 ⁰ C. After stirring for 15 min at -78 ⁰ C, the mixture was allowed to warm to -40 ⁰ C. NH ₄ CI (aq, sat, 5.0 mL) was added and the mixture was allowed to warm to rt. An additional portion of NH ₄ CI (aq, sat, 20 mL) was added and the mixture was extracted with EtOAc. The combined extracts were washed with brine and dried over Na ₂ SO ₄ . Concentration and purification by chromatography gave the title compound (39 mg, 46%).

200 MHz ¹ H-NMR (DMSO-Cf ₆ , ppm) δ 8.1-7.9 (2H, br s) 7.80 (2H, d, J = 7.4 Hz) 7.40-7.04 (6H, m) 6.86 (1 H, t, J = 7.4 Hz) 4.07 (4H, s) 2.27 (6H, s).

Example 10

N^/v^-Bis(3-fluoro-2-methylphenyl)-2-hvdroxybenzene-1 ,3-disulfonamide

(a) δ-Bromo-λ/^.λ^-bisO-fluoro^-methylphenvD^-hydroxybenzene- I .S-disulfon- amide

The sub-title compound was prepared in accordance with Example 7, step (b) from 5-bromo-2-hydroxybenzene-1 ,3-disulfonyl dichloride and 3-fluoro-2- methylaniline (47% yield).

10 (b) N^λ/%is(3-Fluoro-2-methylphenyl)-2-hvdroxybenzene-1 ,3-disulfonamide The title compound was prepared from 5-bromo-λ/ ^f ,λ/ ³ -bis(3-fluoro-2- methylphenyl)-2-hydroxybenzene-1 ,3-disulfonamide (see step (a) above) in accordance with Example 9.

200 MHz ¹ H-NMR (DMSO-Cf ₆ , ppm) δ 7.59 (2H, d, J = 7.7 Hz) 7.08-6.88 (4H, m)

15 6.81-6.76 (2H, m) 6.48 (1 H, t, J = 7.7 Hz) 2.14 (6H, d, J _H . _F =1.8 Hz).

Example 11

λ^-O-Chloro^-methylphenvD-λ/^-chlorobenzvπ^-hydroxy-λ ^-methylbenz-ene-

1 ,3-disulfonamide

20.

(a) λ/-(3-Chloro-2-methylphenyl)formamide

Formic acid (1.2 ml_, 31.8 mmol) was added dropwise at 0 ⁰ C to a mixture of 3-chloro-2-methylaniline (2.6 ml_, 21.2 mmol), 1-(3-dimethylaminopropyl)-3-ethyl- carbodiimide hydrochloride (6.1 g, 31.8 mmol) and CH ₂ CI ₂ (45 ml_). After stirring

25 at rt for 12 h the mixture was washed with HCI (aq, 0.1 M), brine and dried over Na ₂ SO ₄ . Concentration and recrystallisation from EtOAc-petroleum ether afforded 3.43 g (95%) of the sub-title compound.

(b) (3-Chloro-2-methylphenyl)methanamine

Borane-tetrahydrofuran (1 M in THF, 61 mL, 61 mmol) was added dropwise to λ/-(3-chloro-2-methylphenyl)formamide (3.43 g, 20.2 mmol; see step (a) above) in THF (25 mL) at -40 ⁰ C. The mixture was allowed to warm to rt and HCI (aq, 0.1 M) was added. The mixture was extracted with MeOfBu and the combined extracts were washed with water and brine, dried over Na ₂ SO ₄ and concentrated. The residue was dissolved in Et ₂ O (30 mL) and HCI (4 M in dioxane, 5.5 mL) was added. The precipitate was collected and dissolved in acetonitrile (5 mL). NaOH (aq, 2 M, 15 mL) was added and the mixture was extracted with MeOfBu. The combined extracts were washed with water, brine and dried over Na ₂ SO ₄ . Concentration and vacuum distillation afforded the sub-title compound (2.5 g, 79% yield) as a colourless oil.

(c) 5-Bromo-λ/-(3-chloro-2-methylphenyl)-2-methoxy-λ/-methylbe nzenesulfon- amide

A mixture of 5-bromo-2-methoxybenzenesulfonyl chloride (1.0 g, 3.5 mmol) and (3-chloro-2-methylphenyl)methanamine (1.4g, 8.8 mmol; see step (b) above) in acetonitrile (10 mL) was heated at 90 ⁰ C for 18 h. The mixture was partitioned between HCI (aq, 1 M) and EtOAc. The layers were separated and the aqueous layer extracted with EtOAc. The combined organic phases were washed with HCI (aq, 1 M), brine and dried over Na ₂ SO ₄ . Concentration and purification by chromatography afforded the sub-title compound (700 mg, 50%).

(d) /v^-O-Chloro^-methylphenvD-A/^-chlorobenzvn^-methoxy-A^-meth yl- benzene-1 ,3-disulfonamide n-BuLi (2.5 M in hexanes, 400 μL, 1.0 mmol) was added over 5 min to 5-bromo- λ/-(3-chloro-2-methylphenyl)-2-methoxy-λ/-methylbenzenesul fonamide (360 mg, 0.89 mmol; see step (c) above) in THF (6 mL) at -78 ⁰ C. After stirring at -78 ⁰ C for 1 h, a stream of SO ₂ (g) was passed through the mixture for 20 min while keeping the temperature at -78 ⁰ C. The mixture was allowed to warm to rt, after which sulfuryl chloride (80 μL, 1.0 mmol) was added and the mixture was left to stir at rt for an additional 12 h. 4-Chlorobenzylamine (440 μL, 3.6 mmol) in THF (2 mL) was added and the mixture was heated at reflux for 6 h. After cooling, the mixture was partitioned between HCI (aq, 1 M) and EtOAc. The aqueous layer was extracted with EtOAc and the combined extracts were washed with brine and

dried over Na ₂ SO ₄ . Concentration and purification by chromatography afforded the sub-title compound (70 mg, 15%).

(e) λ/ ³ -(3-Chloro-2-methylpheny[)-λ/ ^r -(4-chlorobenzyl)-4-hvdroxy-λ/ ³ -methyl- benzene-1 ,3-disulfonamide

The title compound was prepared from λ/ ³ -(3-chloro-2-methylphenyl)-λ/'-(4- chlorobenzylH-methoxy-λ^-methylbenzene-i ,3-disulfonamide (see step (d) above) in accordance with Example 2.

400 MHz ¹ H-NMR (DMSO-d ₆ , ppm) δ 8.10 (1 H, t, J = 6.2 Hz) 7.82-7.78 (2H, m)

7.39 (1 H ₁ dd J = 8.1 , 0.7 Hz) 7.33-7.29 (2H, m), 7.21-7.16 (2H, m) 7.15-7.08 (2H, m) 6.84 (1 H, d, J = 8.1 Hz) 3.81 (2H, d, J = 5.9 Hz) 3.25 (3H, s) 2.28 (3H, s).

Example 12 λ/ ⁷ ,λ/ ³ -Bis(3-chloro-2-methylphenyl)-4,6-dihvdroxybenzene-1 ,3-disulfonamide

BBr ₃ (1 M in CH ₂ CI ₂ , 5.0 ml_, 5.0 mmol) was added dropwise at rt to a mixture of λ/ ^t ,λ/ ³ -bis(3-chloro-2-methylphenyl)-4-hydroxy-6-methoxybenzene-1 ,3-disulfon- amide (180 mg, 0.34 mmol; see Example 3) and CH ₂ CI ₂ (4.0 ml_). The mixture was left at rt for 72 h. MeOH (10 ml_) was added and the mixture was concentrated. The residue was treated with petroleum ether and the resulting solid was collected to afford the title compound (125 mg, 71 % yield). 200 MHz ¹ H-NMR (DMSO-d ₆ , ppm) δ 11.9-11.2 (2H, br s) 9.8-9.0 (2H ₁ br s) 7.61 (1 H, s) 7.29-7.21 (2H, m) 7.03 (2H, dd, J = 8.0, 8.0 Hz) 6.92-6.84 (2H, m) 6.62 (1 H ₁ s) 2.18 (6H ₁ s).

Example 13 ^/v^-Bis(3-fluoro-2-methylphenyl)-4,6-dihvdroxybenzene-1 ,3-disulfonamide

The title compound was prepared from λ/ ⁷ ,λ/ ³ -bis(3-fluoro-2-methylphenyl)-4- hydroxy-6-methoxybenzene-1 ,3-disulfonamide (see Example 4) in accordance with Example 12.

20O MHz ¹ H-NMR (DIvISO-Cf ₆ , ppm) δ 12.0-11.0 (2H ₁ br s) 10.0-8.7 (2H, br s) 7.63 (1 H, s) 7.09-6.89 (4H, m) 6.77 (2H, dd, J = 7.4, 1.3 Hz) 6.60 (1 H, s) 2.04 (6H, d, J = 6.0 Hz).

Example 14 4,6-Dihvdroxy-λ/ ^f ,λ/ ³ -di(o-tolyl)benzene-1 ,3-disulfonamide

The title compound was prepared from 4-hydroxy-6-methoxy-λ/', λ^-di(o-tolyl)- benzene-1 ,3-disulfonamide (see Example 5) in accordance with Example 12. 200 MHz ¹ H-NMR (DMSOd ₆ , ppm) δ 11.8-1 1.1 (2H, br s) 9.4-8.7 (2H, br s) 7.61 (1 H, s) 7.15-6.85 (8H, m) 6.59 (1 H, s) 2.15 (6H, s). ESI-MS (m/z): 447 [M-H] ^" .

Example 15

λ/'.λ/^BisO-chloro^-methylphenylM-hvdroxy-S-fpyrrolidin e-i-carbonvDbenz- ene-1 ,3-disulfonamide

(a) 4-Hydroxy-5-(pyrrolidine-1-carbonyl)benzene-1 ,3-disulfonyl dichloride

A mixture of 1-(2-hydroxybenzoyl)-pyrrolidine (1.5 g, 7.8 mmol) and chlorosulfonic acid (8.0 ml.) was heated to 150 ⁰ C, heated at 150 ⁰ C for 20 min, cooled and poured on crushed ice. Filtration and drying of the precipitate in vacuo over P ₂ O ₅ afforded the sub-title compound (480 mg, 16% yield).

(b) λ/^./v^-BisO-chloro^-methylphenylM-hvdroxy-δ-fpyrrolidine- i-carbonyl)- benzene-1 ,3-disulfonamide

The title compound was prepared from 4-hydroxy-5-(pyrrolidine-1- carbonyl)benzene-1 ,3-disulfonyl dichloride (see step (a) above) and 3-chloro-2- methylaniline in accordance with Example 7, step (b).

200 MHz ¹ H-NMR (DMSOd ₆ , ppm) δ 9.47-9.34 (1 H, br s) 7.73 (1 H, s) 7.29-6.97 (6H, m) 6.82 (1 H, d, J = 8.0 Hz) 3.45-3.34 (2H, m, overlapped with water) 3.08- 2.96 (2H, m) 2.30 (3H, s) 1.91 (3H, s)1.83-1.72 (4H, m). ESI-MS (m/z): 596 [M-H] ^" .

Example 16 3,5-Bis(λ/-(3-chloro-2-methylphenyl)sulfamoyl)-λ/.A/-dieth yl-2-hvdroxybenzamide

The title compound was prepared from λ/,λ/-diethylsalicylamide and chlorosulfonic acid in accordance with Example 15, step (a), followed by reaction with 3-chloro- 2-methylaniline in accordance with Example 7, step (b).-

200 MHz ¹ H-NMR (DMSO-Cf ₆ , ppm) δ 9.19 (1 H, s) 7.56 (1H, d, J = 2.6 Hz) 7.24- 7.16 (2H, m) 7.06-6.95 (4H, m) 6.84-6.79 (1 H, m) 3.30-3.18 (2H, m) 3.09-2.97 (2H, m) 2.31 (3H, s) 1.95 (3H, s) 1.10-0.95 (3H, m) 0.92-0.78 (3H, m). ESI-MS (m/z): 598 [M-H] ^" .

Example 17

N^λ^-Bis(3λ-difluorophenyl)-4-hydroxybenzene-1.3-disulf onamide

The title compound was prepared from 4-methoxybenzene-1 ,3-disulfonyl dichloride (see Example 1 step (a)) and 3,4-difluoroaniline in accordance with Example 7 step (b), followed by demethylation in accordance with Example 2. 200 MHz ¹ H-NMR (DMSO-Cf ₆ , ppm) δ 12.4-11.8 (1 H, br s) 10.41 (1 H ₁ S) 8.07 (1 H, d, J=2.4 Hz) 7.69 (1 H, dd, J=8.6, 2.4 Hz) 7.36-7.14 (2H, m) 7.09-6.75 (5H, m)

Example 18 λ/ ⁷ ,λ/ ³ -Bis(4-Chloro-2-methylphenyl)-4-hvdroxybenzene-1 ,3-disulfonamide

The title compound was prepared from 4-methoxybenzene-1 ,3-disulfonyl dichloride (see Example 1 step (a)) and 4-chloro-2-methylaniline in accordance with Example 7 step (b), followed by demethylation in accordance with Example 2.

200 MHz ¹ H-NMR (DMSO-d ₆ , ppm) δ 9.8-9.7 (1 H, br s) 7.82 (1 H, d, J=2.4 Hz) 7.58 (1 H, dd, J=8.6, 2.4 Hz) 7.17-6.94 (7H, m) 2.10 (3H, s) 1.72 (3H, s)

Example 19

λ/^λ^-BisO-Chloro^-methylbenzylM-hydroxy-θ-methoxybenz ene-I .S- disulfonamide

The title compound was prepared from 4-hydroxy-6-methoxybenzene-1 ,3- disulfonyl dichloride (see Example 3 step (a)) and 3-chloro-2-methylbenzylarnine in accordance with Example 7 step (b).

200 MHz ¹ H-NMR (DMSO-d ₆ , ppm) δ 11.69 (1 H, s) 7.95 (1 H, s) 7.71-7.64 (1 H, m) 7.35-7.01 (6H, m) 6.51 (1 H, s) 3.98-4.08 (4H, m) 3.80 (3H, s) 2.25 (6H, s)

Example 20

λ^.λ^-BisQ-Chloro^-methylphenvD^-hvdroxypyridine-S.δ-d isulfonamide; or λλλ^-Bis (3-chloro-2-methylphenyl)pyhdone-3,5-disulfonamide

The title compound was prepared by heating pyridone with chlorosulfonic acid at 150 ⁰ C and then treating the intermediate disulfonyl chloride with 3-chloro-2- methylaniline in accordance with Example 7 step (b). As depicted above, the title compound may exist as tautomers.

200 MHz ¹ H-NMR (DMSO-d ₆ , ppm) δ 13.3-12.9 (1 H, br s) 9.93 (1 H, s) 9.87 (1 H, s) 8.06 (1 H, d, J=2.8 Hz) 7.87 (1 H, d, J=2.8 Hz) 7.35 (2H, d, J=8.0 Hz) 7.17 (1 H, dd, J=8.0, 8.0 Hz) 7.10 (1 H, dd, J=8.0 Hz) 7.07 (1 H, d, J=8.0 Hz) 6.71 (1 H, d, J=8.0 Hz) 2.27 (3H, s) 2.06 (3H, s)

Example 21 ^Amino-λ/'.λ^-bisQ-chloro^-rriethylphenvD-S-nitrobenzene-I .S-disulfonamide

The title compound was prepared by heating 2-nitroaniline with chlorosulfonic acid and treating the formed disulfonyl chloride with 3-chloro-2-methylaniline in accordance with Example 7 step (b).

200 MHz ¹ H-NMR (DMSO-Cf ₆ , ppm) δ 10.56 (1H, s) 9.95 (1H, s) 8.37 (1H, d, J=2.4 Hz) 8.13-7.87 (2H, br s) 7.96 (1 H, d, J=2.4 Hz) 7.36 (1 H, dd, J=8tt, 1.0 Hz) 7.33 (1 H, dd, J=8.0, 1.0 Hz) 7.11 (1 H, dd, J=8.0, 8.0 Hz) 7.07 (1 H, dd, J=8.0, 8.0 Hz) 6.95 (1 H, dd, J=8.0, 1.1 Hz) 6.70 (1 H, dd, J=8.0, 1.0 Hz) 2.22 (3H, s) 2.09 (3H, s).

Example 22 λ/^λ^-bisO-Chloro^-methylphenylM.S-diaminobenzene-I .S-disulfonamide

The title compound was prepared by reducing 4-amino-λ/ ^r ,λ/ ³ -bis(3-chloro-2- methylphenyl)-5-nitrobenzene-1 ,3-disulfonamide (see Example 21) with Fe / NH ₄ CI.

200 MHz ¹ H-NMR (DMSO-c/ ₆ , ppm) δ 9.85 (1 H, s) 9.49 (1 H, s) 7.27 (2H, d, J=7.8 Hz) 7.17 (1 H, s) 7.14-6.92 (3H, m) 6.76 (1 H, s) 6.75 (1 H, d. J=7.8 Hz) 6.07 (2H, s) 5.35 (2H, s) 2.16 (3H, s) 2.03 (3H, s)

Example 23 4-Bromo-N^λ/ ³ -bis(3-chloro-2-methylphenyl)benzene-1 ,3-disulfonamide

The title compound was prepared by heating bromobenzene with chlorosulfonic acid for 15 min at 150 ⁰ C and treating the formed disulfonyl chloride with 3-chloro- 2-methylaniline in accordance with Example 7 step (b).

200 MHz ¹ H-NMR (DMSO-d ₆ , ppm) δ 10.4-10.3 (1 H, br s) 10.2-10.0 (1 H, br s) 8.12 (1 H, d, J=2.2 Hz) 8.08 (1 H, d, J=8.3 Hz) 7.65 (1 H, dd, J=8.3, 2.2 Hz) 7.39- 7.27 (2H, m) 7.16-7.00 (2H, m) 6.84 (1 H, d, J=7.9 Hz) 6.68 (1 H, d, J=7.7 Hz) 2.18 (3H, s) 1.98 (3H, s).

Example 24 2,4-Bisfλ/-(3-chloro-2-methylphenyl)sulfamovnbenzoic acid

The title compound was prepared by heating 4-bromo-λ/',λ/ ³ -bis(3-chloro-2- methylphenyl)benzene-1 ,3-disulfonamide (see Example 23) with CuCN in NMP at 150 °C followed by hydrolysis with 2M aqueous NaOH in dioxane. 200 MHz ¹ H-NMR (DMSOd ₆ , ppm) δ 12.5-11.5 (1 H, br s) 10.0-9.9 (1 H, br s) 7.87-7.77 (2H, m) 7.74-7.67 (1 H, m) 7.35-7.21 (2H, m) 7.09-6.95 (2H, m) 6.81- 6.72 (1 H, m) 6.68-6.61 (1 H, m) 2.25 (3H, s) 1.98 (3H, s).

Example 25 λ/'.λ^-BisO-chloro-Z-methylphenvD^-fhydroxymethvDbenzene-I .S-disulfonamide

The title compound was prepared by reducing 2,4-bis(λ/-(3-chloro-2-methyl- phenyl)sulfamoyl)benzoic acid (See Example 24) with BH ₃ ^X THF. 200 MHz ¹ H-NMR (DMSO-Cf ₆ , ppm) δ 10.2-9.9 (1H, br s) 8.02-7.92 (2H, m) 7.83 (1 H, dd, J=8.2, 2.1 Hz) 7.34-7.26 (2H, m) 7.06 (2H, dd, J=8.1 , 8.1 Hz) 6.79-6.67 (2H, m) 6.1-5.5 (1 H, br s) 4.86 (2H, s) 2.07 (3H, s) 2.00 (3H, s).

Example 26(a) δ-Bromo-λ/^.λ^-bisO-chloro^-methylphenylM-hydroxybenzene- I .S-disulfon- amide; and

Example 26(b)

λ/^λ^-BisO-chloro^-methylphenvπ^-hvdroxy-δ^methylamin o^enzene-I .S- disulfonamide

The title compound was prepared by heating 2-bromoanisole with chlorosulfonic acid and treating the formed disulfonyl chloride with 3-chloro-2-methylaniline in accordance with Example 23, followed by treating the so formed S-bromo-λ/'./V ³ - bis(3-chloro-2-methylphenyl)-4-hydroxybenzene-1 ,3-disulfonamide with Cu / CuCI / MeNH ₂ ηCI at 70 ⁰ C for 48h.

200 MHz ¹ H-NMR (DMSO-Cy ₆ , ppm) δ 9.1-9.0 (1 H, br s) 7.21 (1 H, dd, J=7.9, 1.1 Hz) 7.12 (1 H, dd, J=7.6, 1.5 Hz) 7.05-6.98 (2H, m) 6.97-6.95 (1 H, m) 6.93-6.84 (2H, m) 6.14 (1 H, d, J=2.4 Hz) 5.6-4.9 (1 H, br s) 2.54 (3H, s) 2.29 (3H, s) 1.97 (3H, s).

Example 27 λ^-O-Chloro-σ-methylphenvD^-hvdroxy-λ/'-phenylbenzene-lS- disulfonamide

The title compound was prepared according to the following scheme:

200 MHz ¹ H-NMR (DMSO-c/ ₆ , ppm) δ 12.2-11.9 (1 H, br s) 10.13 (1 H, s) 9.9-9.5 (1 H, br s) 7.90 (1 H, d, J=2.4 Hz) 7.70 (1 H, dd, J=8.6, 2.4 Hz) 7.29 (1 H, dd, J=8.0, 1.2 Hz) 7.23-6.86 (8H, m) 2.17 (3H, s).

The title compounds of Examples 28 to 32 were prepared in accordance with Example 27 using the appropriately substituted aniline.

Example 28

λ^-O-Chloro^-methylphenvD-λ/Vs.δ-dichlorophenylM-hvdro xybenzene-I .S- disulfonamide

200 MHz ¹ H-NMR (DMSOd ₆ , ppm) δ 12.4-12.1 (1 H, br s) 10.74 (1 H, s) 9.9-9.5 (1 H, br s) 7.91 (1 H, d, J=2.5 Hz) 7.82 (1 H, dd, J=8.6, 2.5 Hz) 7.28-7.22 (2H, m)

7.16 (1 H, d, J=8.6 Hz) 7.04-6.95 (3H, m) 6.86 (1 H, dd, J=8.0, 1.2 Hz) 2.17 (3H, s).

Example 29

λ/'.λ^-BisO-chloro^-methylphenvD^-hvdroxy-λ/^-methylbe nzene-I .S- disulfonamide

200 MHz ¹ H-NMR (DMSO-Cf ₆ , ppm) δ 12.4-12.2 (1H, br s) 10.0-9.7 (1 H, br s) 7.70 (1 H, dd, J=8.6, 2.4 Hz) 7.63 (1 H, d, J=2.4 Hz) 7.42 (1 H, dd, J=8.0, 0.8 Hz) 7.30 (1 H, dd, J=8.0, 1.2 Hz) 7.21 (1 H, d, J=8.6 Hz) 7.14 (1 H, dd, J=8.0, 8.0 Hz) 7.05- 6.94 (2H, m) 6.37-6.31 (1 H, m) 2.90 (3H, s) 2.24 (6H, s).

Example 30 Methyl 3-(3-fλ/-(3-chloro-2-methylphenyl)sulfamoyl]-4-hvdroxypheny lsulfon- amido)-2-methylbenzoate

200 MHz ¹ H-NMR (DMSO-C ₆ , ppm) δ 12.2-12.0 (1 H, br s) 9.8-9.5 (2H, m) ) 7.84 (1 H, d, J=2.4 Hz) 7.58-7.48 (2H, m) 7.26 (1 H, dd, J=7.8, 1.1 Hz) 7.15-7.00 (3H, m) 6.97-6.83 (2H, m) 3.78 (3H, s) 2.20 (3H, s) 2.05 (3H, s).

Example 31 N ¹ -(3-Chloro-2-methylphenyl)-4-hvdroxy-N ³ -(4-trifluoromethylphenyl)benzene-1,3- disulfonamide

200 MHz ¹ H-NMR (DMSO-d ₆ , ppm) δ 12.3-11.8 (1H, br s) 10.74 (1H, s) 10.0-9.3 (1H, br s) 7.94-7.90 (1H, m) 7.84-7.75 (1H, m) 7.59-7.50 (2H, m) 7.24-7.05 (4H, m) 6.97 (1H, dd, J=8.0, 8.0 Hz) 6.86 (1H, dd, J=1.2, 7.9 Hz) 2.13 (3H, s).

Example 32 N ¹ -(3-Chloro-2-methylphenyl)-λ/ ¹ -(3,4-difluorophenvl)-4-hvdroxybenzene-1,3- disulfonamide

200 MHz ¹ H-NMR (DMSO-d ₆ , ppm) δ 12.8-11.4 (1H, br s) 10.5-9.31 (1H, br s) 10.3 (1H, s) 7.85 (1H, d, J=2.2 Hz) 7.71 (1H, dd, J=8.6, 2.6 Hz) 7.31-7.17 (2H, m) 7.11-6.84(4H, m) 6.76-6.67 (1 H, m) 2.15 (3H, s).

Example 33

N ⁷ .λ/ ³ -Bis(3-chloro-2-methylphenyl)-5-cvano-4-hvdroxybenzene-1 ,3-disulfon- amide

The title compound was prepared by heating 2-bromoanisole with chlorosulfonic acid at 150 ⁰ C, treating the formed disulfonyl chloride with 3-chloro-2-methyl- aniline followed by heating with CuCN in NMP at 150 ⁰ C.

200 MHz ¹ H-NMR (DMSO-Cf ₆ , ppm) δ 9.3-9.2 (1 H, br s) 7.61-7.57 (1 H, m) 7.39- 7.35 (1 H, m) 7.29-7.18 (2H, m) 7.12-6.91 (3H, m) 6.75-6.67 (1 H, m) 2.29 (3H, s) 1.99 (3H ₁ m).

Example 34 λ/*-(3-Chloro-2-methylphenyl)- /^-(Sλ-dichloro^-methylphenylM-hvdroxyben- zene-1 ,3-disulfonamide

The title compound was prepared according to the following scheme:

200 MHz ¹ H-NMR (DMSOd ₆ , ppm) δ 9.76 (1 H, br s) 7.85 (1 H, d, J=2.4 Hz) 7.56 (1 H, dd, J=8.6, 2.4 Hz) 7.45-7.37 (1 H, m) 7.34-7.26 (1 H, m) 7.14-6.99 (3H, m) 6.77-6.68 (1 H, m) 2.28 (3H, s) 1.90 (3H, s).

Example 35

λ/ ⁷ -(3-Chloro-2-methylphenyl)-4-hvdroxy-N ³ -phenylbenzene-1 ,3-disulfonamide

The title compound was prepared according to the following scheme:

200 MHz ¹ H-NMR (DMSO-c/ ₆ , ppm) δ 12.2-11.9 (1 H, br s) 10.4-10.0 (1 H, br s) 9.78 (1 H, s) 8.08 (1 H, d, J=2.4 Hz) 7.47 (I H ₁ dd, J=8.6, 2.4 Hz) 7.34-7.26 (1 H, m) 7.24-6.93 (7H, m) 6.74-6.66 (1 H, m) 1.96 (3H, s).

The title compounds of Examples 36 to 74 were prepared in accordance with Example 35 using the appropriately substituted aniline or amine.

Example 36

λλλ^-Bis O-chloro^-methylphenvD-^-hvdroxy-λ^-methylbenzene-I .S-disulfon- amide

200 MHz ¹ H-NMR (DMSO-Cf ₆ , ppm) δ 9.8-9.7 (1H, br s) 7.77 (1 H, d, J=2.4 Hz) 7.63 (1 H, dd, J=8.6, 2.4 Hz) 7.49-7.41 (1 H, m) 7.35-7.28 (1 H, m) 7.20-7.05 (3H, m) 6.89-6.82 (1 H, m) 6.79-6.72 (1 H, m) 3.25 (3H, s) 2.29 (3H, s) 2.03 (3H, s).

Example 37

λ/ ^? -(3-Chloro-2-methylphenyl)-λ/ ³ -(2-chloro-4-pyridinyl)-4-hvdroxybenzene-1 ,3- disulfonamide

200 MHz ¹ H-NMR (DMSO-Cf ₆ , ppm) δ 12.4-12.3 (1 H, br s) 11.4-11.3 (1 H, br s) 9.88 (1 H, s) 8.22 (1 H, d, J=2.4 Hz) 8.13 (1 H, d, J=5.6 Hz) 7.57 (1 H, dd, J=8.6, 2.4 Hz) 7.36-7.28 (1 H, m) 7.11-6.98 (4H, m) 6.82-6.74 (1 H, m) 2.01 (3H, s).

Example 38 λ/ ⁷ -(3-Chloro-2-methylphenyl)- A^-O^-difluorophenvD^-hvdroxybenzene-I .S- disulfonamide

200 MHz ¹ H-NMR (DMSO-d ₆ , ppm) δ 9.6-9.1 (1H, br s) 7.83-7.75 (1 H, m) 7.32- 7.14 (3H, m) 7.12-6.92 (2H, m) 6.92-6.73 (2H, m) 6.54 (1 H, d, J=8.8 Hz) 1.88 (3H, s).

Example 39

Methyl 3-(5-(λ/-(3-chloro-2-methylphenyl)sulfamoyl)-2-hvdroxypheny lsulfonami- do)-2-methylbenzoate

200 MHz ¹ H-NMR (DMSOd ₆ , ppm) δ 9.7-9.5 (1 H, br s) 7.79 (1 H, d, J=2.4 Hz) 7.58-7.50 (1 H, m) 7.46 (1 H, dd, J=8.6, 2.4 Hz) 7.32-7.24 (1 H, m) 7.23-7.14 (2H, m) 7.09-6.90 (2H, m) 6.77-6.70 (1 H, m) 3.80 (3H, s) 2.35 (3H, s) 1.94 (3H, s).

Example 40

A/^O-Chloro-σ-methylphenvD-λ^^-triifluorophenyD^-hydrox ybenzene-I .S- disulfonamide

200 MHz ¹ H-NMR (DMSO-Cf ₆ , ppm) δ 12.3-11.9 (1 H, br s) 11.1-10.6 (1 H, br s) 9.81 (1 H, s) 8.19 (1 H, d, J=2.4 Hz) 7.62-7.52 (1 H, m) 7.47 (1 H, dd, J=8.6, 2.4 Hz) 7.33-7.22 (3H, m) 7.05-6.93 (2H, m) 6.79-6.71 (2H, m) 1.91 (3H, s).

Example 41 λ/VS-Chloro^-methylphenvD-λ^-cvclohexyM-hvdroxybenzene-I .S-disulfonamide

200 MHz ¹ H-NMR (DMSO- ₆ , ppm) δ 11.9-11.8 (1 H, br s) 9.80 (1 H, s) 8.00 (1 H, d, J=2.4 Hz) 7.56 (1 H, dd, J=8.6, 2.4 Hz) 7.45-7.28 (2H, m) 7.17-7.02 (2H, m) 6.90-6.83 (1 H, m) 2.97-2.79 (1 H, m) 2.06 (3H, s) 1.7-1.4 (5H, m) 1.3-0.9 (5H, m).

Example 42 λ/VS-Chloro^-methylphenvD-λ^^-methylcvclohexylM-hvdroxybeÏ €zene-I .S- disulfonamide

200 MHz ¹ H-NMR (DMSO-cfe, ppm) δ 1 1.8 (1 H, s) 9.79 (1 H, s) 7.99 (0.6H, d, J=2.4 Hz, major diastereomer) 7.93 (0.4H, d, J=2.4 Hz, minor diastereomer) 7.59 (0.4H, dd, J-8.6, 2.4 Hz, minor diastereomer) 7.55 (0.6H, dd, J=8.6, 2.4 Hz, major diastereomer) 7.44-7.02 (4H, m) 6.90-6.85 (1 H, m) 3.08-2.98 (1 H, m) 2.07 (2H, s, major diastereomer) 2.06 (1 H, s, minor diastereomer) 1.68-0.83 (9H, m) 0.73 (2H, d, J=6.4 Hz, major diastereomer) 0.71 (1 H, d, J=6.4 Hz, minor diastereomer).

Example 43

λ/^-O-Chloro^-methylphenvD-λ^-fS-chloro^-methylphenylH- hydroxybenzene-

1,3-disulfonamide

200 MHz ¹ H-NMR (DMSO-c/ ₆ , ppm) δ 12.19 (1H, s) 9.78 (1H, s) 9.70 (1H, s) 7.89 (1H, d, J=2.4 Hz) 7.56 (1H, dd, J=8.8, 2.4 Hz) 7.29 (1H, d, J=8.0 Hz) 7.21-7.07 (4H, m) 7.02 (1H, dd, J=8.0, 8.0 Hz) 6.71 (1H, d, J=8.0 Hz) 2.14 (3H, s) 1.94 (3H, s)

Example 44

λ/^-O-Chloro^-methylphenvD-λ^-O-pyridylM-hvdroxybenzene -I.S-disulfonamide

200 MHz ¹ H-NMR (DMSO-Cf ₆ , ppm) δ 9.6-9.4 (1H, br s) 8.26 (1H, d, J=2.4 Hz) 8.16 (1H, dd, J=4.6, 1.4 Hz) 7.87 (1H, d, J=2.2 Hz) 7.45-7.37 (1H, m) 7.33-7.13 (3H, m) 7.06-6.95 (1H, m) 6.76-6.60 (2H, m) 1.96 (3H, s)

Example 45 λ^-Benzyl-λ/'-O-chloro^-methylphenvD^-hvdroxybenzene-I.S-d isulfonamide

200 MHz ¹ H-NMR (DMSO-d ₆ , ppm) δ 11.9-11.8 (1H, br s) 9.75 (1H, s) 8.03-7.92 (1H, br s) 7.90 (1H, d, J=2.4 Hz) 7.56 (1H, dd, J=8.6, 2.4 Hz) 7.32-7.15 (6H, m)

7.15-7.04 (1 H, m) 7.04-6.96 (1 H, d, J=8.8 Hz) 6.88-6.79 (1 H, m) 4.00-3.90 (2H, m) 2.05 (3H, s).

Example 46

λ/VS-Chloro^-methylphenvD-λ^^^-dimethylcvclohexylM-hvdr oxybenzene-I.S- disulfonamide

200 MHz ¹ H-NMR (DMSO-Cf ₆ , ppm) δ 11.9-11.8 (1 H, br s) 9.78 (1 H, s) 7.97 (1 H, d, J=2.4 Hz) 7.55 (1 H, dd, J=8.6, 2.4 Hz) 7.40-7.26 (2H, m) 7.14-7.00 (2H, m) 6.89-6.82 (1 H, m) 2.91-2.73 (1 H, m) 2.03 (3H, s) 1.5-0.9 (8H, m) 0.80 (6H, s).

Example 47

λ/^O-Chloro^-methylphenvD-λ^-O-hvdroxy^-methylphenylM-h ydroxybenzene-

1 ,3-disulfonamide

200 MHz ¹ H-NMR (DMSO-CZ ₆ , ppm) δ 12.06 (1 H, s) 9.72 (1 H, s) 9.40 (1 H, s) 9.26 (1 H, s) 7.83 (1 H, d, J=2.4 Hz) 7.51 (1 H, dd, J=8.6, 2.4 Hz) 7.31-7.24 (1 H, m) 7.11-6.96 (2H, m) 6.85-6.74 (1 H, m) 6.68-6.57 (2H, m) 6.44-6.36 (1 H, m) 1.98 (3H, s) 1.97 (3H, s).

Example 48

λ/^O-Chloro^-methylphenvD-λ^-fcvclohexylmethylM-hydroxy benzene-I .S- disulfonamide

200 MHz ¹ H-NMR (DMSO-Cf ₆ , ppm) δ 11.9-11.8 (1 H ₁ br s) 9.78 (1 H, s) 7.91 (1 H, d, J=2.4 Hz) 7.59 (1 H, dd, J=8.6, 2.4 Hz) 7.40-7.33 (1 H, m) 7.29 (1 H, dd, J=8.0, 1.0 Hz) 7.10 (1 H, dd, J=8.0, 8.0 Hz) 7.06 (1 H, d, J=8.6 Hz) 6.86 (1 H, dd, J=8.0, 1.0 Hz) 2.55-2.45 (2H, m overlapped with DMSO) 2.04 (3H, s) 1.7-1.5 (5H, m) 1.4-1.2 (1 H, m) 1.2-1.0 (3H, m) 0.9-0.6 (2H, m).

Example 49 /^-(ButvD-A/^-O-chloro^-methylpheπylM-hvdroxybenzene-I .S-disulfonamide

200 MHz ¹ H-NMR (DMSO-Cf ₆ , ppm) δ 11.84 (1 H, s) 9.78 (1 H, s) 7.89 (1 H, d, J=2.4 Hz) 7.61 (1 H, dd, J=8.6, 2.4 Hz) 7.35 (1 H, t, J=6.0 Hz) 7.29 (1 H, dd, J=8.0, 1.0 Hz) 7.10 (1 H, dd, J=8.0, 8.0 Hz) 7.07 (1 H, d, J=8.8 Hz) 6.91-6.83 (1 H, m) 2.72-2.59 (2H, m) 2.02 (3H, s) 1.37-1.10 (4H, m) 0.80-0.69 (3H, m).

Example 50 /vVs-Chloro-σ-methylphenvD-λ^-O-dimethylamino-σ-methylphe nylM- hydroxybenzene-1 ,3-disulfonamide

200 MHz ¹ H-NMR (DMSO-d ₆ , ppm) δ 12.12 (1H, s) 9.76 (1H, s) 9.58 (1H, s) 7.83 (1H, d, J=2.4 Hz) 7.57 (1H, dd, J=8.6, 2.4 Hz) 7.36-6.97 (4H, m) 7.03 (1H, dd, J=8.0, 8.0 Hz) 6.89-6.76 (1H, m) 6.75-6.66 (1H, m) 2.83 (6H, s) 2.24 (3H, s) 1.97 (3H, s).

Example 51

λ^-O-ChlorobenzvD-λ/VS-chloro^-methylphenylM-hydroxyben zene-I.S- disulfonamide

200 MHz ¹ H-NMR (DMSO-Cf ₆ , ppm) δ 11.93 (1H, s) 9.75 (1H, s) 8.17-8.00 (1H, m) 7.89 (1H, d, J=2.4 Hz) 7.58 (1H, dd, J=8.6, 2.4 Hz) 7.32-7.20 (4H, m) 7.17-6.99 (3H, m) 6.86-6.78 (1 H, m) 4.04-3.93 (2H, m) 2.04 (3H, s)

Example 52

λ/^-ChlorobenzvD-λ/VS-chloro^-methylphenvD^-hvdroxybenz ene-I.S- disulfonamide

200 MHz ¹ H-NMR (DMSO-Cf ₆ , ppm) δ 11.95 (1H, s) 9.77 (1H ₁ s) 8.09-7.97 (1H, m) 7.96 (1H, d, J=2.4 Hz) 7.56 (1H, dd, J=8.6, 2.4 Hz) 7.47-7.40 (1H, m) 7.37-7.20 (4H, m) 7.09 (1H, dd, J=8.0, 8.0 Hz) 7.02 (1H, d, J=8.6 Hz) 6.87-6.80 (1H, m) 4.15-4.06(2H, m) 2.04 (3H, s).

Example 53

λ^^-ChlorobenzvD-A/'-O-chloro-σ-methylphenvO^-hydroxybe nzene-I .S- disulfonamide

200 MHz ¹ H-NMR (DMSO-Cf ₆ , ppm) δ 11.88 (1 H, s) 9.76 (1 H, s) 8.03 (1 H, t, J=6.2 Hz) 7.90 (1 H, d, J=2.4 Hz) 7.58 (1 H, dd, J=8.6, 2.4 Hz) 7.32-7.16 (5H, m) 7.10 (1 H, dd, J=8.0, 8.0 Hz) 7.01 (1 H, d, J=8.8 Hz) 6.89-6.81 (1 H, m) 3.95 (2H, d, J=6.2 Hz) 2.04 (3H, s).

Example 54

/^-(δ-Bromo-S-methyl^-pyridvD-λ/^-O-chloro^-methylphenv D^-hvdroxy- benzene-1 ,3-disulfonamide

200 MHz ¹ H-NMR (DMSO-Cf ₆ , ppm) δ 9.75 (1 H, br s) 8.08 (1 H, d, J=2.4 Hz) 7.83- 7.82 (1 H, m) 7.72-7.71 (1 H, m) 7.46 (1 H, dd, J=8.8, 2.4 Hz) 7.31-7.26 (1 H, m) 7.07 (1 H, dd, J=8.0 Hz) 6.94-6.82 (2H, m) 6.71-6.61 (1 H, m) 2.15 (3H, s) 2.04 (3H, s).

Example 55 λ/ ³ -(4-Bromo-2-methylphenyl)-λ/ ⁷ -(3-chloro-2-methylplienyl)-4-hvdroxybenzene- 1 ,3-disulfonamide

200 MHz ¹ H-NMR (DMSO-d ₆ , ppm) δ 12.13 (1H, s) 9.74 (1H, s) 9.55 (1H, s) 7.84 (1H, d, J=2.4 Hz) 7.54 (1H, dd, J=8.6, 2.4 Hz) 7.40-7.34 (1H, m) 7.31-7.20 (2H, m) 7.10-7.00 (2H, m) 6.99-6.91 (1H, m) 6.70-6.63 (1H, m) 2.14 (3H, s) 1.93 (3H, s).

Example 56

/^-(fraπs^-te/t-ButylcvclohexyD-λ/'-O-chloro^-methylphe nvD^-hvdroxybenzene-

1,3-disulfonamide

200 MHz ¹ H-NMR (DMSOd ₆ , ppm) δ 11.84 (1H, s) 9.76 (1H, s) 7.89 (1H, d, J=2.4 Hz) 7.61 (1H, dd, J=8.6, 2.4 Hz) 7.29 (1H, d, J=7.6 Hz) 7.24 (1H, d, J=6.6 Hz) 7.12-7.06 (2H, m) 6.87 (1H, d, J=8.0 Hz) 3.19-3.13 (1H, m) 2.02 (3H, s) 1.6- 1.5 (2H, m) 1.4-1.2 (6H, m) 0.9-0.8 (1 H, m) 0.79 (9H, s).

Example 57

λ/ ³ -(c/s-4-te/t-Butylcvclohexyl)-λ/ ^? -(3-chloro-2-methylphenyl)-4-hvdroxybenzene-

1,3-disulfonamide

200 MHz ¹ H-NMR (DMSO-d ₆ , ppm) δ 11.82 (1H, s) 9.77 (1H, s) 7.98 (1H, d, J=2.4 Hz) 7.54 (1H, dd, J=8.6, 2.4 Hz) 7.40-7.32 (1H, br s) 7.29 (1H, d, J=8.0 Hz) 7.10 (1H, dd, J=8.0, 8.0 Hz) 7.03 (1H, d, J=8.6 Hz) 6.87 (1H, d, J=8.0 Hz) 2.84- 2.73 (1H, m) 2.04 (3H, s) 1.66-1.56 (4H, m) 1.23-1.09 (2H, m) 0.86-0.73 (12H, m).

Example 58 N ¹ -(3-Chloro-2-methylphenyl)-N ³ -[2-(1-piperidinyl)ethyl]-4-hvdroxybenzene-1,3- disulfonamide

200 MHz ¹ H-NMR (DMSO-c/ ₆ , ppm) δ 9.7-9.5 (1H, br s) 7.87 (1H, d, J=2.4 Hz) 7.52 (1H, dd, J=8.6, 2.4 Hz) 7.29 (1H, dd, J=8.2, 1.2 Hz) 7.11 (1H, dd, J=8.0, 8.0 Hz) 6.94-6.82 (2H, m) 3.2-2.9 (8H, m, overlapped with H20) 2.07 (3H, s) 1.8-1.6 (4H, m) 1.6-1.4(2H, m).

Example 59 N ¹ -(3-Chloro-2-methylphenyl)-4-hvdroxy-N ³ -(trans-4-methylcvclohexyl)benzene- 1,3-disulfonamide

200 MHz ¹ H-NMR (DMSOd ₆ , ppm) δ 9.77 (1H, s) 7.98 (1H, d, J=2.4 Hz) 7.53 (1H, dd, J=8.6, 2.4 Hz) 7.30 (1H, dd, J=8.0, 1.0 Hz) 7.09 (1H, dd, J=8.0, 8.0 Hz) 7.01 (1H, d, J=8.6 Hz) 6.86 (1H, dd, J=8.0, 1.0 Hz) 2.85-2.71 (1H _} m) 2.04 (3H, s) 1.62-1.45 (4H, m) 1.3-1.0 (4H, m) 0.88-0.70 (1 H, m) 0.77 (3H ₁ d, J=6.4 Hz).

Example 60

A/ ^? -(3-chloro-2-methylphenyl)-4-hvdroxy-^-(c/s-4-trifluoromethy lcvclohexyl)- benzene-1 ,3-disulfonamide

200 MHz ¹ H-NMR (DMSO-c/ ₆ , ppm) δ 11.91 (1H, s) 9.77 (1H, s) 7.90 (1H, d, J=2.4 Hz) 7.61 (1H, dd, J=8.6, 2.4 Hz) 7.60-7.53 (1H, m) 7.30 (1H, d, J=8.0 Hz) 7.10 (1H, dd, J=8.0, 8.0 Hz) 7.06 (1H, d, J=8.6 Hz) 6.85 (1H, d, J=8.0 Hz) 3.23- 3.12 (1H, m) 2.2-2.1 (1H, m) 2.03 (3H, s) 1.7-1.3 (8H, m).

Example 61

λ/^-O-Chloro^-methylphenvD^-hvdroxy-λ^-ffraπs^-trifluo romethylcvclohexyl)- benzene-1 ,3-disulfonamide

200 MHz ¹ H-NMR (DMSO-J ₆ , ppm) δ 11.86 (1H, s) 9.78 (1H, s) 7.99 (1H, d, J=2.4 Hz) 7.55 (1H, dd, J=8.6, 2.4 Hz) 7.29 (1H, d, J=8.0 Hz) 7.60-7.51 (1H, m) 7.10 (1H, dd, J=8.0, 8.0 Hz) 7.05 (1H, d, J=8.6 Hz) 6.86 (1H, d, J=8.0 Hz) 2.98- 2.80(1 H, m) 2.18-2.07 (1H ₁ m) 2.03 (3H, s) 1.83-1.60 (4H, m) 1.38-1.02 (4H, m).

Example 62

3-(4-(5-rN-(3-Chloro-2-methylphenv[)sulfamovn-2-hvdroxyph enylsulfonamidoV2- fluoro-3-methylphenyl)-λ/,N-dimethylpropanamide

200 MHz ¹ H-NMR (DMSO-d ₆ , ppm) δ 11.86 (1 H, s) 9.78 (1 H, s) 7.99 (1 H, d, 9.7-9.5 (1 H, br s) 7.78 (1 H, d, J=2.4 Hz) 7.45 (1H, dd, J=8.6, 2.4 Hz) 7.27 (1 H, dd, J=8.0, 1.0 Hz) 7.08-6.91 (3H, m) 6.73 (1 H, d, J=8.0 Hz) 6.71 (1 H, d, J=7.6 Hz) 2.84 (3H, s) 2.75 (3H, s) 2.72-2.64 (2H, m) 2.54-2.40 (2H, m, overlapped with DMSO) 2.08 (3H, d, J=2.0 Hz) 1.93 (3H, s).

Example 63

N^-fS-Chloro^-methylphenvD-λ^-fO-chloro-δ-trifluorometh yl^-pyridvDmethvn^- hvdroxybenzene-1 ,3-disulfonamide

200 MHz ¹ H-NMR (DMSO-c/ ₆ , ppm) δ 11.84 (1 H, s) 9.77 (1 H, s) 8.66 (1 H, d, J=1.4 Hz) 8.34 (1 H, d, J=1.4 Hz) 7.92 (1 H, d, J=2.4 Hz) 7.95-7.84 (1 H, m) 7.54 (1 H, dd, J=8.6, 2.4 Hz) 7.28 (1 H, dd, J=8.0, 1.0) 7.09 (1 H, dd, J=8.0, 8.0 Hz) 6.95 (1 H, d, J=8.8 Hz) 6.84 (1 H, dd, J=8.0, 1.0 Hz) 4.37 (2H, d, J=5.8 Hz) 2.04 (3H, s).

Example 64 N ¹ -(3-Chloro-2-methylphenyl)-λ/ ³ -(2-pyridylmethyl)-4-hvdroxybenzene-1 ,3- disulfonamide

200 MHz ¹ H-NMR (DMSO-d ₆ , ppm) δ 9.78 (1 H, s) 8.67-8.60 (1 H, m) 8.30-8.11 (2H, m) 7.92 (1 H, d, J=2.4 Hz) 7.74-7.58 (1 H, m) 7.69 (1 H, d, J=8.2 Hz) 7.61 (1 H, dd, J=8.6, 2.4 Hz) 7.30 (1 H, dd, J=8.0, 1.0 Hz) 7.11 (1 H, dd, J=8.0, 8.0 Hz) 7.08 (1 H, d, J=8.8 Hz) 6.82 (1 H, dd, J=8.0, 1.0 Hz) 4.31 (2H, d, J=5.6 Hz) 2.06 (3H, s).

Example 65 N ¹ -(3-Chloro-2-methylphenyl)-4-hydroxy-N ³ -(1-phenylethyl)benzene-1,3-

200 MHz ¹ H-NMR (DMSO-d ₆ , ppm) δ 11.81 (1 H, s) 9.75 (1 H, s) 8.01 (1 H, d, J=8.6 Hz) 7.89 (1 H, d, J=2.4 Hz) 7.52 (1 H, dd, J=8.6, 2.4 Hz) 7.30 (1 H, dd, J=8.0, 1.2 Hz) 7.22-7.06 (6H, m) 6.94 (1 H, d, J=8.8 Hz) 6.84 (1 H, dd, J=8.0, 1.2 Hz) 4.18 (1 H, dd, J=8.0, 8.0 Hz) 2.05 (3H, s) 1.23 (3H, d=7.0 Hz).

Example 66 N ¹ -(3-Chloro-2-methylphenyl)-λ/ ³ -(4,4-difluorocvclohexyl)-4-hydroxybenzene-1 ,3- disulfonamide

200 MHz ¹ H-NMR (DMSO-d ₆ , ppm) 612.1-11.7 (1 H, br s) 9.77 (1 H, s) 7.96 (1 H, d, J=2.4 Hz) 7.58 (1 H, dd, J=8.6, 2.4 Hz) 7.7-7.5 (1 H, m) 7.30 (1 H, d, J=8.0 Hz) 7.11 (1 H, dd, J=8.0, 8.0 Hz) 7.05 (1 H, d, J=8.6 Hz) 6.84 (1 H, d, J=8.0 Hz) 3.22- 3.06 (1 H, m) 2.04 (3H, s) 2.0-1.4 (8H, m).

Example 67 N ¹ -(3-Chloro-2-methylphenyl)-λ/ ³ -(3,3-dimethylbutyl)-4-hvdroxybenzene-1 ,3- disulfonamide

MS [M+H] ⁺ m/z = 461/463

Example 68 N ¹ -(3-Chloro-2-methylphenyl) -4-hvdroxy-N ³ -(1-methylcvclohexyl)benzene-1 ,3- disulfonamide

MS [M+H] ⁺ m/z = 473/475

Example 69 N ¹ -(3-Chloro-2-methylphenyl)-4-hvdroxy-N ³ -(3-trifluoromethylcvclohexyl)benzene- 1 ,3-disulfonamide

MS [M+H] ⁺ m/z = 527/529

Example 70 N ¹ -(3-Chloro-2-methylphenyl) -4-hvdroxy-N ³ -(3,3,5-trimethylcyclohexyl)benzene- 1 ,3-disulfonamide

MS [M+-H] ⁺ m/z = 501/503

Example 71 N ¹ -(3-Chloro-2-methylphenyl) -N ³ -(2-chlorophenethyl)-4-hvdroxybenzene-1,3- disulfonamide

MS [M+H] ⁺ m/z = 515/517

Example 72 N ¹ -(3-Chloro-2-methylphenyl) -N ³ -(2-chlorophenethyl)-4-hvdroxybenzene-1,3- disulfonamide

MS [M+H] ⁺ m/z = 499/501

Example 73

λ/ ⁷ -(3-Chloro-2-methylphenyl)-4-hydroxy-λ/ ³ -f2-(1-pyrrolidinyl)benzyllbenzene-1 ,3- disulfonamide

MS [M+H] ⁺ m/z = 536/538

Example 74

λ/ ^? -(3-Chloro-2-methylphenyl)-λ/ ³ -f(6-dodecylthio-3-pyridyl)methylM- hvdroxybenzene-1 ,3-disulfonamide

The title compound was prepared in accordance with Example 35 using

5-aminomethyl-2-chloropyridine and sodium dodecanthiolate as the demethylating reagent.

MS [M+H] ⁺ m/z = 668/669/670

Example 75

Title compounds of the Examples were tested in the biological test described above and were found to exhibit 50% inhibition of mPGES-1 at a concentration of

10 μM or below. For example, the following representative compounds of the examples exhibited the following IC ₅₀ values:

Example 1 : 200O nM

Example 8: 150O nM

Example 13: 110O nM

Example 16: 410O nM Example 19: 360O nM

Example 24: 160O nM

Example 29: 160O nM

Example 31: 100OnM

Example 37: 2400 nM

Example 43: 2400 nM

Example 49: 100OnM

Example 63: 680 nM

Example 70: 130OnM