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 bronchoconsthction. 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 bronchoconsthction 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 ₂₀ , 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 prό-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 ieukotrienes 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 CySLT ₁ 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, which may therefore be useful in the treatment of inflammation. However, this document does not mention or suggest nine- or ten-membered bicycles in which one of the rings are substituted by only two sulfonamide groups that are in a 1 ,3-relationship.

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 bicycles that have only two sulfonamide groups attached thereto, and the latter does not mention or suggest aromatic sulfonamides in which the aromatic ring is not substituted by a hexose-thio group.

International patent application WO 99/20608 discloses various isoquinolines that may be useful in the infiltration of immune cells onto inflammatory cites.

However, there is no disclosure therein of compounds that are not substituted with a guanidine-based substituent.

International patent application WO 2006/075152 discloses various indoles that may be useful in treating inter alia inflammation. However, this document only discloses bicycles that are necessarily substituted with a pyrimidine ring.

International patent application WO 2005/028624 discloses molecular scaffolds for kinase ligand development, and discloses a range of different monocyclic and bicyclic compounds. However, the range of compounds disclosed does not primarily relate to bicyclic structures containing a benzene ring that is substituted by two aryl sulfonamide groups, and nor does it disclose that such compounds may be useful as m-PGES inhibitors and consequently useful in the treatment of inflammation.

US patent application US 2003/0181482 and international patent application WO 2007/010144 both disclose compounds that may be useful in treating inter alia inflammation. International patent application WO 98/50370 discloses compounds that may be useful in treating e.g. fibrotic disorders. US patent application US 2006/0160872 discloses compounds that may be useful in the treatment of inflammation and pain. However, all of these documents disclose compounds in which the requisite bicyclic ring system is substituted, for example via a linker group, with an aromatic or bicyclic group.

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 bicycles, other than naphthalene, that are substituted with two aromatic sulfonamide groups.

Disclosure of the Invention

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

wherein

Q ^x and Q ^y independently represent a direct bond or C _1-6 alkylene optionally substituted by one or more substituents selected from Z ¹ ;

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 ), C _3-I2 cycloalkyl or heterocycloalkyl (which latter two groups are optionally substituted by one or more substituents selected from Z ¹ and =0);

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

the A ring may represent:

Ring Ia Ring Ib

wherein the squiggly lines represent the point of attachment of these A rings to the requisite benzene ring of the compound of formula I (so forming a fused bicycle); and

in ring Ia: the dotted lines denote the presence of an optional double bond; any two of Y ¹ , Y ² , Y ³ and Y ⁴ independently represent -C(X ³ )= or -C(X ⁴ )(X ^a )-, and the other two:

when attached to one single and one double bond in ring Ia, independently represent -N= or -C(X ³ )=; or when attached to two single bonds in ring Ia, independently represent -N(X ^b )-, -C(X ⁴ )(X ^a )- or -C(W ⁹ )-. provided that all of Y ¹ , Y ² , Y ³ and Y ⁴ do not represent -C(X ³ )=;

in ring Ib: the dotted lines denote the presence of an optional double bond, provided that both dotted lines do not represent double bonds; one of Y ⁵ , Y ⁶ or Y ⁷ represents -C(X ⁵ )=, -C(W ¹ )- or -C(X ⁶ )(X ^C )-, and the other two: when attached to one single and one double bond in ring Ib ₁ independently represent -N= or -C(X ⁵ )=; or when attached to two single bonds in ring Ib, independently represent -N(X ^d )-,

-O-, -S-, -C(X ⁶ )(X ^C )- or -C(W ¹ )-;

X ¹ , X ² , X ³ , X ⁴ , X ⁵ and X ⁶ independently represent, at each occurrence when used herein, hydrogen or a substituent selected from Z ² ;

Z ¹ and Z ² independently represent, on each occasion when used herein, halo, -R ^3a , -CN, -C(O)R ^3b , -C(O)OR ^3c , -C(O)N(R ^4a )R ^5a , -N(R ^4b )R ^5b , -N(R^)C(O)R ⁴⁰ , -N(R ^3e )C(O)N(R ^4d )R ^5d , -N(R ³ ^C(O)OR ⁴⁶ , -N ₃ , -NO ₂ , -N(R ^3g )S(O) ₂ N(R ^4f )R ^5f , -OR ^3h , -OC(O)N(R ⁴⁹ )R ^5g , -OS(O) ₂ R ³ ', -S(0) _m R ^3j , -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 ;

m represents O, 1 or 2;

X ^a and X ^c independently represent, at each occurrence when used herein, hydrogen or R ^3a ;

X ^b and X ^d independently represent, at each occurrence when used herein, hydrogen, -R ^3a , -C(0)R ^3b , -C(O)OR ^3c or -C(O)N(R ^4a )R ^5a ;

W ^a and W ¹ independently represent, at each occurrence when used herein, =NH, =NR ^3a , =NOR ^3h , =S or =0;

R ^3b , R ^3d to R ^3h , R ^3k , R ³ⁿ , R ^4a to R ^4h , R ^5a , R ^5b , R ^5d and R ^5f to R ^5h independently represent, at each occurrence when used herein, hydrogen 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 ⁴⁹ and R ⁵⁹ 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 ³¹ , R ^3j , R ^3m and R ^3p independently represent R ^3a ;

R ^3a represents, at each occurrence when used herein, Ci _-6 alkyl optionally substituted by one or more substituents selected from F, Cl, =0, -OR ^6a and -N(R ^6b )R ^7b ; '

R ^6a and R ^6b independently represent H or C _1-6 alkyl optionally substituted by one or more substituents selected from F, Cl ₁ =0, -OR ^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 C _1-6 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 C _1-3 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 ^1Oa , 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,

which compounds and salts are referred to hereinafter as "the 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 the invention in the form of a salt with another counter-ion, for example using a suitable ion exchange resin.

Compounds of the invention 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 the invention may also exhibit tautomerism. All tautomeric forms and mixtures thereof are included within the scope of the invention.

Compounds of the invention 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 chromatographic (e.g. 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 diastereomehc 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^ 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 ^, 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 - _I o) 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 - _M 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- bjpyridyl, thiazoio[5,4-<fc>]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-2/-/-1 ,4-benzoxazinyl), benzoxazolyl, benzimidazolyl, benzomorpholinyl, benzothienyl, carbazolyl, chromanyl, cinnolinyl, furanyl, imidazolyl, imidazopyridyl (including imidazo[4,5-b]pyridyl, imidazo[5,4-ib]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-oxadiazolyI), 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 heterocycloaikynyl group. C _2-q heterocycloalkyl groups that may be mentioned include 7-azabicycio- [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-dihydropyrro!yl), dioxolanyl (including 1 ,3- dioxolanyl), dioxanyl (including 1 ,3-dioxanyl and 1 ,4-dioxanyl), dithianyl (including 1 ,4-dithianyl), dithiolanyi (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), tropanyi 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 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 two of X ¹ , X ² , X ³ , X ⁴ , X ⁵ and X ⁶ (or any two X ³ (or X ⁴ ) groups) represent Z ² , then the respective Z ² 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 Ci _-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 "X ¹ to X ⁶ " is employed herein, this will be understood by the skilled person to mean X ¹ , X ² , X ³ , X ⁴ , X ⁵ and X ⁶ inclusively.

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

Q ^x and Q ^y independently represent a direct bond;

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 ; R ⁴⁶ represents R ^3a ;

R ^8a and R ^11a independently represent H, -CH ₃ , -CH ₂ CH ₃ or -CF ₃ ; when the A ring represents ring Ia, then: the dotted lines denote the presence of an optional double bond; any two of Y ¹ , Y ² , Y ³ and Y ⁴ independently represent -C(X ³ )= or -C(X ⁴ )(X ^a )-, and the other two:

when attached to one single and one double bond in ring Ia, independently represent -N= or -C(X ³ )=; or when attached to two single bonds in ring Ia, independently represent -N(X ^b )- or -C(X ⁴ )(X ^a )-, provided that all of Y ¹ , Y ² , Y ³ and Y ⁴ do not represent -C(X ³ )=.

Further preferred compounds of the invention that may be mentioned include those in which: one of R ¹ and R ² (preferably R ¹ ) represents aryl or heteroaryl (both of which are optionally substituted by one or more substituents selected from Z ¹ ) 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 ), C _3-12 cycloalkyl or heterocycloalkyl (which latter two groups are optionally substituted by one or more substituents selected from Z ¹ and =0); one of R ¹ and R ² (preferably R ¹ ) represents heteroaryl or, preferably, aryl (which latter two groups are optionally substituted by one or more substituents selected from Z ¹ ) and the other (preferably R ² ) represents heteroaryl (optionally substituted by one or more substituents selected from Z ¹ ), preferably, C _3-12 cycloalkyl (optionally substituted by one or more substituents selected from Z ¹ and =0) or, more preferably, aryl (optionally substituted by one or more substituents selected from Z ¹ );

W ^a and W ¹ independently represent =NOR ^3h , preferably, =S or, more preferably, =0.

Compounds of the invention that may be mentioned include those in which: in ring Ia both dotted lines represent double bonds; in ring Ia, at least one of Y ¹ to Y ⁴ represents -N=; in ring Ib, one dotted line represents a double bond; in ring Ib, at least one of Y ⁵ to Y ⁷ represents -N=, -N(X ^d )-, -O- or -S-; in ring Ib, when one of Y ⁵ to Y ⁷ represents -N=, then at least one other represents

-N(X ^d )-, -O- or -S-.

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

all of Y ¹ to Y ⁴ independently represent -C(X ³ )= or -C(X ⁴ )(X ^a )- (provided that all of Y ¹ to Y ⁴ do not represent -C(X ³ )=); - all of Y ⁵ to Y ⁷ independently represent -C(X ⁵ )=, -C(W ¹ )- or -C(X ⁶ )(X ^C )-; and/or the A ring is not aromatic, i.e. when the A ring is ring Ia, then only one of the dotted lines represents a double bond or neither of the dotted lines represents a double bond, or when the A ring is ring Ib, then either: a) neither dotted line (between Y ⁵ and Y ⁶ or between Y ⁶ and Y ⁷ ) represents a double bond; b) when the dotted line between Y ⁵ and Y ⁶ represents a double bond, then Y ⁷ represents -C(W ¹ )- or, more particularly, -C(X ⁶ )(X ^C )-; or c) when the dotted line between Y ⁶ and Y ⁷ represents a double bond, then Y ⁵ represents -C(W ¹ )- or, more particularly, -C(X ⁶ )(X ^C )-.

Compounds of the invention that may be mentioned include those in which: when the A ring represents ring Ib, and one of the dotted lines represents a double bond, and either Y ⁵ represents -C(X ⁵ )= and Y ⁷ represents -C(X ⁶ )(X ^C )- or Y ⁷ represents -C(X ⁵ )= and Y ⁵ represents -C(X ⁶ )(X ^C )-, then Y ⁶ does not represent -N=; when the A ring represents ring Ia, both dotted lines represent double bonds, X ¹ represents Z ² , Y ¹ represents -N= and Y ² , Y ³ and Y ⁴ all independently represent -C(X ³ )=, then Z ² represents halo, -R ^3a , -CN, -C(0)R ^3b , -C(O)OR ³⁰ , -C(O)N(R ^4a )R ^5a , -N(R ³ ^C(O)OR ⁴ *, -N ₃ , -NO ₂ , -0R ^3h , -OC(O)N(R ⁴⁹ JR ⁵⁹ , -OS(O) ₂ R ³ ', -S(0) _m R ^3j , -0C(0)R ³ⁿ , -0C(0)0R ^3p or -S(O) ₂ N(R ^4h )R ^5h .

Preferred compounds of the invention include those in which: when any of the pairs R ⁴³ and R ^5a , R ^4b and R ^5b , R ⁴ " and R ^5d , R ^4f and R ^5f , R ^4g and R ⁵⁹ 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); 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;

either at least one of X ¹ and X ² , preferably X ¹ , represents Z ² and the other represents hydrogen; or both X ¹ and X ² represent H, for example when at least one of Y ¹ or Y ⁴ (when the

A ring is ring Ia) or at least one of Y ⁵ or Y ⁷ (when the A ring is ring Ib) represents -N(H)-;

X ^b and X ^d independently represent -C(0)R ^3b or, more preferably, H or -R ^3a ; when the A ring represents ring Ia in which both dotted lines represent double bonds, then one of Y ¹ to Y ⁴ represents -N=, and the others represent -C(X ³ )= in which at least two X ³ groups represent H; when the A ring represents ring Ia in which both dotted lines represent single bonds, then one of Y ¹ to Y ⁴ represents -N(X ^b )-, and the others represent

-C(X ⁴ )(X ^a )= in which at least two X ⁴ groups and at least two X ^a groups (e.g. when attached to the same carbon atoms) each represent H; when the A ring represents ring Ib and Y ⁵ , Y ⁶ or Y ⁷ are attached to one single and one double bond in ring Ib, then when one of them represents -C(X ⁵ )=, then X ⁵ represents H or Z ² ; when the A ring represents ring Ib and Y ⁵ , Y ⁶ or Y ⁷ represent -C(X ⁶ )(X ^C )- or

-N(X ^d )-, then X ^c and X ^d preferably represent H, and X ⁶ preferably represents H or

Z ² ; when the A ring represents ring Ib and any two of Y ⁵ , Y ⁶ or Y ⁷ represents

-C(W ¹ )-, then the other represents -N(X ^α )-, -O- or -S-;

R ¹ and R ² are each, independently, substituted with less than three (e.g. one or two) substituent(s) selected from Z ¹ ;

Z ¹ 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 mefa-position);

W ¹ represents =0;

Z ¹ and Z ² independently represent -C(O)N(R ^4a )R ^5a or, preferably, -N(R ^4b )R ^5b , -N(R ³ ^C(O)R ⁴⁰ , halo (e.g. chloro, fluoro or bromo), -R ^3a or -OR ^3h ; when R ^3a represents optionally substituted C _1-6 alkyl, then it may represent C _1-6 alkyl optionally substituted by one or more substituents selected from F, Cl, -OR ^6a and -N(R ^6b )R ^7b and/or one =0 substituent;

R ^3a represents C _1-6 alkyl (e.g. butyl or, preferably, 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 ⁴⁰ 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 ) alkyl 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 ⁴⁰ 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, terf-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-tetrahydroquinoiinyl, 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. 2- or 4-pyridyl), pyrazinyl (e.g. 2-pyrazinyl), furanyl, thienyl, oxazolyl, thiazolyl and, more preferably, optionally substituted phenyl.

Preferred essential bicyciic ring systems of the compounds of the invention (i.e. those including the essential benzene ring fused with the A ring of the compound of formula I) include: when the A ring represents ring Ia, optionally substituted quinoxaline (e.g. 3-oxo-

3,4-dihydroquinoxaline) or, more particularly, optionally substituted quinoline or 1 ,2,3,4-tetrahydroquinoline (e.g. in which the requisite nitrogen atom of the

quinoline or tetrahydroquinoline is present at the Y ⁴ or, preferably, Y ¹ position), optionally substituted isoquinoline or 1 ,2,3,4-tetrahydroisoquinoline (e.g. in which the requisite nitrogen atom thereof is present in the Y ³ position) or 5,6,7,8- tetrahydronaphthalene; when the A ring represents ring Ib, optionally substituted indoline, indolinone (in which the requisite nitrogen atoms of these groups are preferably in the Y ⁷ position), preferably, benzothiazole, more preferably, benzimidazole (e.g. 2,3- dihydrobenzimidazole, such as 2-oxo-2,3-dihydrobenzimidazole, or, more particularly, benzimidazole) or, more particularly, benzoxazole (in which the requisite nitrogen atoms of the latter three groups are preferably present in the Y ⁷ or, more particularly, the Y ⁵ position).

Especially preferred essential bicyclic ring systems include those in which (for example when ring A represents ring Ia) one of Y ¹ to Y ⁴ (e.g. Y ¹ ) represents -N=, and the others represent -C(X ³ )= (so forming for example a quinolinyl group, e.g. in which the requisite nitrogen atom is lateral to the X ¹ substituent).

Hence, preferred A rings include optionally substituted pyridine, piperidine, cyclohexyl, oxazole, imidazole, 2,3-dihydroimidazol-2-one and 1 ,3- dihydroimidazol-2-one.

Preferred substituents on R ¹ , R ² or the essential bicycles of compounds of the invention 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. Ci- ₄ alkyl (such as ethyl, n-propyl, isopropyl, n-butyl, f-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) Ci _-6 alkyl, such as C _1-4 alkyl (e.g. ethyl, n-propyl, n- butyl, f-butyl or, preferably, methyl or isopropyl) optionally substituted by one or more halo (e.g. fluoro) groups (so forming e.g. a trifluoromethyl group).

Preferred compounds of the invention include those in which:

R ¹ and R ² independently represent phenyl optionally substituted by one or two substituents selected from Z ¹ ; when R ¹ or R ² represent optionally substituted C _3-12 cycloalkyl, then such a group preferably represents C _3-8 cycloalkyl (e.g. C _5-6 cycloalkyl, such as cyclohexyl); 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 heterocycloalkyl 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);

R ¹ and R ² are the same; Z ¹ represents halo (e.g. chloro or fluoro) or R ^3a ;

X ¹ represents H or, more preferably, Z ² ; when the A ring represents ring Ia, then when Y ¹ or Y ⁴ represents -N(H)-, then X ¹ represents Z ² or, more preferably, H; when the A ring represents ring Ib, then when Y ⁵ or Y ⁷ represents -N(H)-, then X ¹ represents Z ² or, more preferably, H; when X ¹ represents Z ² , then Z ² is preferably -OR ^3h , -N(R ^4b )R ^5b or

-N(R^)C(O)R ⁴⁰ ;

R ^4c represents R ^3a ;

X ² represents Z ² or, more preferably, H;

when X ² represents Z ² , then Z ² is preferably halo (e.g. fluoro or chloro), R ^3a (e.g.

C _1-2 alkyl such as methyl) or, more preferably, -OR ^3h (e.g. -OH); when the A ring represents ring Ia, then the dotted lines between Y ¹ and Y ² may represent a double bond, whilst the dotted lines between Y ³ and Y ⁴ represent a single bond, or, more preferably, the dotted lines either both represent double bonds or both represent single bonds;

Y ¹ and Y ³ independently represent -C(W ³ )- or, preferably, -N=, -N(X ^b )-, -C(X ³ )= or

-C(X ⁴ )(X ^a )- (and most preferably Y ¹ represents -N= and/or Y ³ represents -C(X ³ )=);

Y ² and Y ⁴ independently represent -N= or, preferably, -C(X ³ )= or -C(X ⁴ )(X ^a )-; X ³ represents H or Z ² (and most preferably Y ² and Y ⁴ independently represent

-C(X ³ )=); when Y ¹ , Y ³ and Y ⁴ represent -C(X ³ )=, then X ³ represents Z ² or more preferably represents hydrogen; when Y ² represents -C(X ³ )=, then X ³ may represent hydrogen or Z ² ; only one X ³ group is present that represents a substituent selected from Z ² ; when X ³ represents Z ² , then Z ² represents halo (e.g. chloro), -N(R ^4b )R ^5b ,

-OR ^3h or, more preferably, R ^3a ;

X ⁴ represents Z ² or, preferably, H;

X ^a represents Z ² or, preferably, H; one of X ⁴ and X ^a represents H and the other represents Z ² or, preferably, H; when X ⁴ or X ^a represent Z ² , then Z ² represents halo (e.g. chloro), -N(R ^4b )R ^5b ,

-OR ^3h or, more preferably, R ^3a (in which R ^3a preferably represents d- ₃ (e.g. Ci _-2 ) alkyl (e.g. methyl)); only one of X ⁴ or X ^a is present that represents a substituent selected from Z ² ; X ^b represents H;

R ^3h represents H;

R ^3d , R ^4b and R ^5b independently represent C _1-3 (e.g. Ci _-2 ) alkyl (e.g. methyl) or, preferably, H; when the A ring represents ring Ib, then neither of the dotted lines represent double bonds or, more preferably, one of the dotted lines (e.g. the one between

Y ⁵ and Y ⁶ ) represents a double bond; one of Y ⁵ or Y ⁷ (e.g. Y ⁵ ) represents -C(X ⁶ )(X ^C )- (e.g. -CH ₂ -) or, preferably, -N=, and the other (e.g. Y ⁷ ) represents -N(X ^d )- (e.g. -N(H)-, -N(CH ₃ )-), -S- or, more preferably, -O-; Y ⁶ represents -C(W ¹ )- (e.g. -C(=O)-) or, preferably, -C(X ⁵ )=;

X ⁵ represents H or, more preferably, Z ² ; only one X ⁵ is present that represents a substituent selected from Z ² ; when X ⁵ represents Z ² , then Z ² represents -OR ^3h (e.g. -OH) or, more preferably,

R ^3a ; R ^3a represents C _1-6 (e.g. C _1-4 or, preferably, C _1-2 ) alkyl (e.g. butyl, such as tert- butyl, or, preferably, cyclohexyl or methyl) optionally substituted by one or more halo (e.g. fluoro) atoms (so forming, for example, a trifiuoromethyl group);

X ^c and X ⁶ independently represent H;

X ^d represents H or C _1-4 (e.g. C _1-2 ) alkyl (e.g. methyl).

Further preferred compounds of the invention include those in which: when the A ring represents ring Ia, and both dotted lines represent single bonds, then preferably: all of Y ¹ to Y ⁴ independently represent -C(X ⁴ )(X ^a )-, or any one of Y ¹ to Y ⁴ (e.g. Y ¹ or Y ³ ) represents -N(X ^b )- and the others independently represent -C(X ⁴ )(X ^a )-; when the A ring represents ring Ia, and both dotted lines represent double bonds, then preferably: one of Y ¹ and Y ⁴ (e.g. Y ¹ ) represents -N=, the other represents -N(X ^b )-, and Y ² and Y ³ independently represent -C(W ⁸ )- or -C(X ³ )= (as appropriate; for example, Y ³ represents -C(W ^a )- and Y ² represents -C(X ³ )=); preferably, two of Y ¹ to Y ⁴ (e.g. Y ¹ and Y ⁴ ) represent -N=, and the others independently represent -C(X ³ )=; or, more preferably, one of Y ¹ to Y ⁴ (e.g. Y ¹ , Y ³ or Y ⁴ ) represents -N= and the others independently represent -C(X ³ )=; when the A ring represents ring Ib, and neither of the dotted lines represent double bonds, then preferably: any two of Y ⁵ , Y ⁶ and Y ⁷ (preferably Y ⁵ and Y ⁷ ) independently represent -C(W ¹ )-,

-C(X ⁶ )(X ^C ) or, preferably -N(X ^d )-, and the other (preferably Y ⁶ ) represents -C(W ¹ )-.

Preferred R ¹ and R ² groups include 4,4-dimethylcyclohexyl and, preferably, 2- methyl-3-chlorophenyl and 2-methyl-3-fluorophenyl. Preferred substituents on R ¹ and R ² groups include C _1-3 (e.g. Ci _-2 ) alkyl (e.g. methyl) and halo (e.g. chloro and fluoro). Preferred substituents that X ¹ and X ² may represent include -OH, -NH ₂ and -N(H)C(O)CH ₃ . Preferred substituents on the A ring include C _1-6 alkyl (e.g.

cyclohexyl, butyl (such as tert-butyl) or methyl), halo (e.g. chloro), =0, -OH and -N(CHs) ₂ .

Particularly preferred compounds of the invention include those of the examples described hereinafter.

Compounds of the invention 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, 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 the A ring, X ¹ and X ² are as hereinbefore defined, with a compound of formula III or, with two different compounds of formula III,

R ^x -Q ^xy -N(H)T ^X III

wherein R ^x represents R ¹ and/or R ² (as appropriate), Q ^xy represents Q ^x and/or Q ^y (as appropriate), T ^x represents T ¹ and/or T ² (as appropriate) and R ¹ , R 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, N- 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 , Q ^xy would represent both Q ^x and Q ^y 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 ill is required. Where the compound of formula I to be prepared is one in which R ¹ and R ² , Q ^x and Q ^y 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 , Q ^xy represents either Q ^x or Q ^y , 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 the A ring, X ¹ , X ² , R ¹ , R ² , T ¹ , T ² , Q ^x , Q ^y , 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 , Q ^xy represents Q ^x and T represents T ¹ (for reaction with compounds of formula IV) or R ^x represents R ² , Q ^xy represents Q ^y 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 the A ring represents ring Ia in which both dotted lines represent double bonds and Y ⁴ represents -C(X ³ )=, or for compounds of formula I in which the A ring represents ring Ib in which the dotted line between Y ⁶ and Y ⁷ represents a double bond and Y ⁷ represents -C(X ⁴ )=, and, in both cases X ³ and/or X ⁴ represent Z ² , in which Z ² represents halo, -R ^3a , -C(O)R ^3b , -C(O)OR ^3c , -C(O)N(R ^4a )R ^5a , -S(O) _m R ³⁾ 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 ³ and/or X ⁴ (as applicable) 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 ³ and/or X ⁴ (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 ³ and/or X ⁴ (as appropriate) represents H, in the presence of a suitable organometallic reagent (such as an organolithuium base (e.g. n-BuLi, s- BuLi or NBuLi)) 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 ³ and/or X ⁴ (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 ³ and/or X ⁴ 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 Z ¹ or Z 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 ⁴⁰ 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 Z ¹ or Z ² is present and represents -C(O)OR ³⁰ 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 Z ¹ or Z ² is present and represents -C(O)OR ^3c , -C(O)N(R ^4a )R ^5a , -N(R ^4b )R ^5b , -N(R ^3S )C(O)N(R^)R ⁵ ', -N(R ³ ^C(O)OR ⁴⁸ , -N(R ³⁹ )S(O) ₂ N(R ^4f )R ^5f , -0R ^3h , -OC(O)N(R ⁴⁹ )R ^5g , -0C(0)0R ^3p and/or -S(O) ₂ N(R ^4h )R ^5h , and R ^3e , R ^3f , R ^3g , R ^3h , R ^4a , R ^4b , R ⁴⁰ , R ⁴⁶ , 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 ⁴⁸ , R ^4f , R ⁴⁹ , 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 ₁ e.g. a compound of formula I in which Z ¹ and/or Z 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 Z ¹ and/or Z 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 Z ¹ or Z ² (e.g. Z ² ) is present and represents halo, -CN, -N(R ^4b )R ^5b , -N(R^)C(O)R ⁴⁰ , -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 , -0R ^3h , -SR ³⁾ and/or -N(R ^3k )S(O) ₂ R ^3m , and R ^3d , R ^3e , R ^3f , R ^3g , R ^3h , R ³⁾ , 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 Z ¹ or Z 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 Z ¹ and/or Z 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 ³ ^C(O)OR ⁴⁶ , -N(R ³⁹ )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 ^M , R ⁴⁶ , 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 Z ¹ or Z 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 ^z ) ₃ (wherein R ² is Ci _-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 90 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 the A ring represents ring Ia and the dotted lines both represent single bonds, hydrogenation of a corresponding compound of formula I in which the A ring represents ring Ia and both dotted lines represent double bonds, under standard conditions known to those skilled in the art, for example in the presence of hydrogen gas (or a source thereof) under catalytic hydrogenation conditions employing a suitable (e.g. Pd on carbon (10%)) and a suitable solvent, such as an alcoholic solvent (e.g. methanol);

(ix) compounds of formula I in which T ¹ or T ² represents R ^3a may be prepared by reaction of a corresponding compound of formula I in which T ¹ or T ² represents H, with a compound of formula VIIIA,

^" P-L ³ VIIIA

wherein T 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, dimethylaminopyridine, 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(trimethylsilyl)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);

(x) compounds of formula I in which Z ¹ or Z 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);

(xi) compounds of formula I in which Z ¹ or Z 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 Z ¹ or Z 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));

(xii) compounds of formula I in which the A ring represents ring Ib, Y ⁶ represents -C(X ⁵ )=, either one of Y ⁵ and Y ⁷ represents -N=, and the other represents -N(X ^d )-, -O- or -S-, cyclisation of a compound of formula VIIIB ₁

VIIIB

wherein either one of Q ¹ or Q ² represents -NH ₂ and the other represents -N(X ^d )H,

-OH or -SH, and X ¹ , X ² , X ^d , T ¹ , T ² , Q ^x , Q ^y , R ¹ and R ² are as hereinbefore defined, with (for compounds of formula I in which X ⁵ represents hydrogen), paraformaldehyde or, preferably, CH(OEt) ₃ , or the like, for example in the presence of a suitable Lewis acid, such as BF ₃ ^* OEt ₂ , or with (for compounds of formula I in which X ⁵ represents a Z ² substituent, such as R ^3a ), a compound of formula VIIIC,

X ⁵ -C(O)L ⁴ VIIIC

wherein L ⁴ represents a suitable leaving group, such bromo, chloro or -OH (or an ester thereof, e.g. a C _1-6 alkyl ester, which alkyl moiety is optionally substituted with one or more halo groups, or an activated derivative of -OH, which group may be activated using a suitable coupling agent such as 1 ,1 '-carbonyldiimidazole, λ/./V-dicyclohexylcarbodiimide, 1-(3-dimethylamino-propyl)-3-ethylcarbodiimide (or hydrochloride thereof), or the like) and X ⁵ is as hereinbefore defined, for example a R ^3a substituent, which reaction may be performed under standard conditions;

(xiii) compounds of formula I in which the A ring represents ring Ib, Y ⁶ represents -C(X ⁵ )= (and X ⁵ preferably represents a R ^3a substituent), either one of Y ⁵ and Y ⁷ represents -N=, and the other represents -N(X ^d )-, -O- or -S-, intramolecular condensation of a compound of formula VIIID ₁

VIIID

wherein one of Q ^a and Q ^b represents -N(X ^d )H, and the other represents -N(H)-C(O)X ⁵ (when X ^d represents hydrogen or a substituent as hereinbefore defined, e.g. R ^3a ), or -0-C(O)X ⁵ or -S-C(O)X ⁵ (when X ^d represents hydrogen only), and X ⁵ , X ¹ , X ² , X ^d , T ¹ , T ² , Q ^x , Q ^y , R ¹ and R ² are as hereinbefore defined, under standard conditions known to those skilled in the art, for example in the presence of a suitable acid (e.g. a strong acid such as HCI) and a suitable solvent (e.g. acetic acid); or

(xiv) for compounds of formula I in which the A ring represents ring Ia, one of Y ¹ and Y ⁴ represents -N= and the other represents -N(H)-, -O- or -S-, when Y ¹ represents -N=, Y ² represents -C(H)= and Y ³ represents -C(O)- (or vice versa, when Y ⁴ represents -N=), reaction of a compound of formula VIIIB as

hereinbefore defined, but in which X ^d represents hydrogen, with glyoxylic acid, or the like, under standard conditions.

Compounds of formula Il (e.g. those in which X ¹ or, more preferably, X ² represent -OH) in which L ^1a and L ^1b each represent halo may be prepared by reaction of a compound of formula VIIIE,

wherein the A ring, X ¹ and X ² 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,

X

(c) or formula Xl,

respectively, or a salt thereof (e.g. a metal salt such as magnesium, sodium or, preferably, lithium), wherein the A ring, X ¹ , X ² , R ¹ , R ² , Q ^x , Q ^y , T ¹ and T 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 as chloro may be prepared by reaction of a corresponding compound of: (a) formula IXA,

IXA

(b) formula XA,

(c) or formula XIA,

respectively, wherein J ¹ represents -N ₂ ⁺ (i.e. a diazonium ion) or -S-Si(R^) ₃ , in which each R ²² independently represents C _1-6 alkyl (e.g. isopropyl; so forming for example a -S-Si(isopropyl) ₃ group), and the A ring, X ¹ , X ² , R ¹ , R ² , Q ^x , Q ^y , T ¹ and T 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^) 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) and T 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 VIIIE in which the A ring is ring Ib in which Y ⁶ represents -C(X ⁵ )=, either one of Y ⁵ or Y ⁷ represents -N=, and the other represents -N(X ^d )-, -O- or -S-, may be prepared by cyclisation of a compound of formula XIB,

wherein either one of Q ¹ or Q ² represents -NH ₂ and the other represents -N(X ^d )H, -OH or -SH, and X ¹ , X ² and X ^d are as hereinbefore defined, under standard reaction conditions, for example in the presence of a reagent (e.g. an acid) that effects the cyclisation (for example in the presence of reagents and under conditions such as those hereinbefore described in respect of preparation of compounds of formula I (process step (xii)), e.g. under standard cyclisation, followed by standard condensation/dehydration conditions. Such conditions include reaction in the presence of a reagent such as P ₂ O ₅ or an acid (such as concentrated acetic acid or a sulfonic acid such as para-toluenesulfonic acid monohydrate) at room or, preferably, elevated temperature (e.g. at reflux).

Compounds of formula IX (e.g. those in which X ¹ or X ² represent -OH), may be prepared by reaction of the corresponding compound of formula VIIIB 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 ¹ 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 the A ring, X ¹ , X ² , R ¹ , R ² , T ¹ and T 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,

XIIIA

(c) or formula XIVA,

respectively, wherein the A ring, X ¹ , X ² , R ¹ , R ² , T ¹ and T 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 π-BuLi) in a polar aprotic solvent (e.g. THF or diethyl ether) at low temperature (e.g. -78°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,

XIIIB

(c) or formula XIVB,

respectively, wherein the A ring, X ¹ , X ² , R ¹ , R ² , T ¹ and T 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 ⁰ 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 (xi) 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(FH ₃ XVA

wherein R ²² 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-terf-butyl-phosphonium tetrafluoroborate), optionally in the presence of a base (such as NaH, Et ₃ N ₁ pyridine, λ/.λ/ ¹ - dimethylethylenediamine, Na ₂ CO ₃ , K ₂ CO ₃ , K ₃ PO ₄ , Cs ₂ CO ₃ , f-BuONa or NBuOK) and suitable solvent (e.g. dichloromethane, dioxane, toluene, ethanol, isopropanol, dimethylformamide, ethylene glycol, ethylene glycol dimethyl ether, water, dimethylsuifoxide, 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 the A ring is as hereinbefore defined, and X ¹ and X ² are as hereinbefore defined and, more preferably, H or 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 the A ring, X ¹ , X ² , R ¹ and T 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,

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 (xi) above).

Compounds of formulae III, Vl, VII, VIII, VIIIA, VIIIB, VIIIC, VIIID, XIB, 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 bicyclic 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 If 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 the invention 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 and optional substituents on R ¹ and R ² and, if present, X ³ , X ⁴ , X ⁵ , X ⁶ , X ^a , X ^b , X ^c and X ^d in final compounds of the invention 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 W-(Ci _-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 the invention 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).

Medical and Pharmaceutical Uses

Compounds of the invention are indicated as pharmaceuticals. According to a further aspect of the invention there is provided a compound of the invention, as hereinbefore defined, for use as a pharmaceutical.

Although compounds of the invention may possess pharmacological activity as such, certain pharmaceutically-acceptable (e.g. "protected") derivatives of compounds of the invention 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 the invention. 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 the invention.

By "prodrug of a compound of the invention", we include compounds that form a compound of the invention, 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 the invention are included within the scope of the invention.

Furthermore, certain compounds of the invention 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 the invention 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 the invention to which they are metabolised), may also be described as "prodrugs".

Thus, the compounds of the invention 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 the invention are particularly useful because they may inhibit the activity of a member of the MAPEG family.

Compounds of the invention 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 the invention may thus be useful in the treatment of those conditions in which inhibition of a PGES, and particularly mPGES-1, is required.

Compounds of the invention 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 the invention 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 the invention 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 the invention 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 the invention 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 invention, as hereinbefore defined, 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 the invention 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 the invention 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 the invention, as hereinbefore defined, 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 invention, as hereinbefore defined, 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 the invention, as hereinbefore defined; 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 the invention 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 the invention, 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 the invention and the other therapeutic agent).

Thus, there is further provided:

(1 ) a pharmaceutical formulation including a compound of the invention, as hereinbefore defined, 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 the invention, as hereinbefore defined, 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 the invention, as hereinbefore defined, 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 the invention 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 the invention 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 the invention 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 the invention 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: rt room temperature

Example 1 λ/ ⁵ ,λ/ ⁷ -bis(3-Chloro-2-methylphenyl)-8-hvdroxyquinoline-5,7-disulfo namide

(a) 8-Hydroxyquinoline-5,7-disulfonyl dichloride

A mixture of 8-hydroxyquinoline (2 g, 13.8 mmol) and chlorosulfonic acid (15.0 mL, 225 mmol) was heated at 150 °C for 20 min, cooled to 5 ⁰ C and poured onto crushed ice. The precipitate was collected by filtration and washed with water and dried to yield 2.6 g (55%) of the sub-title compound.

(b) λ^.λ/^BisO-chloro^-methylphenvD-δ-hvdroxyquinoline-δ.y-d isulfonamide A solution of 8-hydroxyquinoline-5,7-disulfonyl dichloride (300 mg, 0.88 mmol) and 3-chloro-2-methylaniline (600 μl_, 5.0 mmol) in acetonitrile (3.0 ml.) was heated at reflux for 8 hours, cooled, poured in water and extracted with EtOAc. The combined organic extracts were washed with HCI (aq, 5%), water and dried over Na ₂ SO ₄ . The solvents were removed in vacuo and the residue was crystallised from diethyl ether. Filtration and recrystallisation from acetonitrile afforded the title compound (180 mg, 37%). 200 MHz ¹ H-NMR (DMSO-d ₆ , ppm) δ 10.0 (1 H, s) 9.75 (1 H, s) 9.02 (1 H, dd, J = 4.4, 1.4 Hz) 8.85 (1 H, dd, J = 8.8, 1.4 Hz) 8.14 (1 H, s) 7.87 (1 H, dd, J = 8.8, 4.4 Hz) 7.31-7.19 (2H, m) 7.08-6.90 (3H, m) 6.74 (1 H, dd, J = 8.0, 1.0 Hz) 2.22 (3H, s) 1.86 (3H, s).

Example 2

/V ⁵ ,λ/ ⁷ -Bis(3-fluoro-2-methylphenyl)-8-hydroxyquinoline-5,7-disulfo namide

The title compound was prepared from 8-hydroxyquinoline-5,7-disulfonyl dichloride in accordance with Example 1 , step (b). 200 MHz ¹ H-NMR (DMSO-d ₆ , ppm) δ 10.02 (1 H, s) 9.69 (1 H, s) 7.87 (1 H, dd, J = 4.4, 1.3 Hz) 8.89 (1 H , dd, J = 8.8, 1.4 Hz) 8.17 (1 H, s) 7.87 (1 H ₁ dd, J = 8.8, 4.4 Hz) 7.08-6.87 (4H, m) 6.84 (1 H, dd, J = 7.6, 1.7 Hz) 6.70-6.62 (1 H, m) 2.07 (3H, d, J = 2.2 Hz, overlapped with MeCN) 1.72 (3H, d, J = 2.2 Hz).

Example 3

8-Hvdroxy- λ/ ⁵ ,/V ⁷ -di(o/t/7θ-tolyl)quinoline-5,7-disulfonamide

The title compound was prepared from 8-hydroxyquinoline-5,7-disulfonyl dichloride in accordance with Example 1 , step (b).

200 MHz ¹ H-NMR (DMSO-Cf ₆ , ppm) δ 9.80 (1 H, s) 9.43 (1 H, s) 9.01 (1 H, dd, J = 4.4, 1.4 Hz) 8.88 (1H, dd, J = 8.8, 1.4 Hz) 8.17 (1H, s) 7.83 (1H, dd, J = 8.8, 4.4 Hz) 7.14-6.90 (7H, m) 6.79-6.75 (1 H, m) 2.17 (3H, s) 1.80 (3H, s).

Example 4

λ/^/V ⁷ -bis(3-Fluoro-2-methylphenyl)-8-hvdroxy-1 ,2λ4-tetrahydroquinoline-5J- disulfonamide

A mixture of /^//-bis^-fluoro^-methylphenylJ-β-hydroxyquinoline-S^-disul fon- amide (150 mg, 0.29 mmol; see Example 2) and 10% palladium on carbon (30 mg, 0.028 mmol) in MeOH (10 mL) was stirred under hydrogen atmosphere (4 bar) for 14 h at rt. Filtration and concentration afforded the title compound (135 mg, 89% yield).

200 MHz ¹ H-NMR (DMSO-Cf ₆ , ppm) δ 9.69 (1 H, s) 7.20 (1 H, s) 7.14-6.93 (4H, m) 6.79-6.70 (2H, m) 3.30-3.17 (2H, m, overlapped with H ₂ O) 2.95 (2H, t, J = 5.9 Hz)

2.02 (3H, d, J = 2.1 Hz) 1.96 (3H, d, J = 2.1 Hz) 1.80-1.62 (2H, m).

Example 5

λλ/V ⁷ -Bis(3-chloro-2-methylphenyl)-8-hvdroxy-2-methylquinoline-5. 7- disulfonamide

The title compound was prepared from 2-methylquinolin-8-ol and chlorosulfonic acid in accordance with Example 1 , step (a), followed by reaction with 3-chloro-2- methylaniline in accordance with Example 1 , step (b).

200 MHz ¹ H-NMR (DMSOd ₆ , ppm) δ 9.98 (1 H ₁ s) 9.60 (1 H, s) 8.75 (1 H ₁ d, J = 9.0 Hz) 8.05 (1 H, s) 7.76 (1H, d, J = 9.0 Hz) 7.26-7.19 (2H, m) 7.04-6.91 (3H ₁ m) 6.74-6.70 (1 H ₁ m) 2.80 (3H ₁ s) 2.21 (3H, s) 1.87 (3H ₁ s).

Example 6

λ^.λ/^BisO-fluoro^-methylphenvD-δ-hvdroxy^-methylquino line-δJ- disulfonamide

The title compound was prepared from 2-methylquinolin-8-ol and chlorosulfonic acid in accordance with Example 1 , step (a), followed by reaction with 3-fluoro-2- methylaniline in accordance with Example 1 , step (b). 200 MHz ¹ H-NMR (DMSO- Cf ₆ , ppm) δ 9.96 (1 H, s) 9.55 (1 H ₁ s) 8.81 (1 H ₁ d, J = 9.0 Hz) 8.09 (1 H, s) 7.79 (1 H, d, J = 9.0 Hz) 7.07-6.90 (4H ₁ m) 6.84 (1 H, dd, J = 7.6, 1.8 Hz) 6.70-6.61 (1 H, m) 2.81 (3H, s) 2.09 (3H ₁ d, J = 2.2 Hz) 1.75 (3H, d, J = 2.2 Hz).

Example 7

8-Hvdroxy-2-methyl- λ/ ⁵ ,λ/ ⁷ -di(o/t^o-tolyl)quinoline-5,7-disulfonamide

The title compound was prepared from 2-methylquinolin-8-ol and chlorosulfonic acid in accordance with Example 1 , step (a), followed by reaction with 2-methyl- aniline in accordance with Example 1, step (b).

200 MHz ¹ H-NMR (DMSOd ₆ , ppm) δ 9.75 (1 H ₁ s) 9.32 (1 H, s) 8.78 (1 H, d, J = 9.0 Hz) 8.09 (1 H, s) 7.74 (1 H, d, J = 9.0 Hz) 7.15-6.90 (7H ₁ m) 6.79 (1 H, d, J = 7.4 Hz) 2.80 (3H, s) 2.18 (3H, s) 1.81 (3H, s).

Example 8

5-Hvdroxyisoquinoline-6,8-disulfonic acid bis-[(3-chloro-2-methylphenyl)amide1

The title compound was prepared from isoquinolin-5-ol and chlorosulfonic acid in accordance with Example 1 , step (a), followed by reaction with 3-chloro-2-methyl- aniline in accordance with Example 1 , step (b).

200 MHz ¹ H-NMR (DMSOd ₆ , ppm) δ 9.81 (1 H, s) 9.41 (1 H, s) 9.36-8.90 (1 H, br s) 8.61-8.53 (1 H, m) 8.08 (1 H ₁ s) 7. 28-7. 16 (2H, m) 7.05-6.91 (3H, m) 6.75 (1 H, d, J = 8.0 Hz) 2.27 (3H, s) 1.90 (3H, s)

Example 9 λ^.λ^-BisO-fluoro^-methylphenvD-δ-hvdroxyisoquinoline-θ. δ-disulfonamicle

The title compound was prepared from isoquinolin-5-ol and chlorosulfonic acid in accordance with Example 1 , step (a), followed by reaction with 3-fluoro-2-methyl- aniline in accordance with Example 1 , step (b).

200 MHz ¹ H-NMR (DMSOd ₆ , ppm) δ 9.77 (1H, s) 9.46 (1 H, s) 9.27-8.83 (1H, br s) 8.56 (2H ₁ s) 8.10 (1 H, s) 7.06-6.81 (4H, m) 6.71-6.61 (4H, m) 2.12 (3H ₁ d, J = 2.2 Hz) 1.77 (3H ₁ d, J = 2.2 Hz).

Example 10 δ-Hvdroxy-λ^.A^-difOAt^o-tolvDisoquinoline-δ.δ-disulfona mide

The title compound was prepared from isoquinolin-5-ol and chlorosulfonic acid in accordance with Example 1 , step (a), followed by reaction with 2-methylaniline in accordance with Example 1 , step (b).

200 MHz ¹ H-NMR (DMSO-d ₆ , ppm) δ 9.60 (1 H, s) 9.46 (1 H, s) 9.20-8.58 (1 H, br s) 8.55 (2H ₁ s) 8.13 (1 H, s) 7.15-6.90 (7H, m) 6.83 (1 H, d, J = 7.2 Hz) 2.22 (3H ₁ s) 1.81 (3H, s).

Example 11

λ^.λ^-BisO-fluoro^-methylphenvD-δ-hvdroxy-I ^.Sλ-tetrahydroisoquinoline-θ.δ- disulfonamide

The title compound was prepared from λ/ ⁶ ,λ/ ^e -bis(3-fluoro-2-methylphenyl)-5- hydroxyisoquinoline-6,8-disulfonamide (see Example 9) in accordance with Example 4.

200 MHz ¹ H-NMR (DMSO-d ₆ , ppm) δ 9.35 (1 H, s) 8.94-8.79 (2H, br s) 7.63 (1 H, s) 7.11-6.79 (5H ₁ m) 6.71 (1 H, dd, J = 6.5, 2.6 Hz) 4.27 (2H, s) 3.32-3.24 (2H, m, overlapped with water) 2.68 (2H, t, J = 5.4 Hz) 2.15 (3H, d, J = 2.0 Hz) 2.04 (3H, d, J = 2.0 Hz).

Example 12

4-Amino-λ/ ⁷ .λ/ ³ -bis(3-chloro-2-methylphenyl)-5,6,7,8-tetrahvdronaphthalene- 1 ,3- disulfonamide

(a) λ/-(5,6,7,8-Tetrahvdronaphthalen-1-yl)acetamide

A mixture of acetic acid anhydride (3.2 ml_, 34 mmol) and EtOH (10 ml_) was added dropwise at 0 ⁰ C to 5,6,7,8-tetrahydronaphthalen-1-ylamine (2.5 g, 17 mmol) in EtOH (15 ml_). After stirring for 1 h, the precipitate was collected and dried to yield 1.9 g (59%) of the sub-title compound.

(b) 4-Amino-5,6,7,8-tetrahydronaphthalene-1 ,3-disulfonyl dichloride

The sub-title compound was prepared in 56% yield from λ/-(5,6,7,8-tetrahydro- naphthalen-1-yl)acetamide (see step (a) above) and chlorosulfonic acid in accordance with Example 1 , step (a).

(c) 4-Amino-^λ/ ³ -bis(3-chloro-2-methylphenyl)-5.6J,8-tetrahvdronaphthalene- 1.3-disulfonamide

A mixture of 4-amino-5,6,7,8-tetrahydronaphthalene-1 ,3-disulfonyl dichloride (520 mg, 1.5 mmol), 3-chloro-2-methylaniline (730 μl_, 6.04 mmol) and pyridine (4.0 ml_) was stirred at rt for 24 h. The bulk of the pyridine was removed in vacuo and the residue was partitioned between EtOAc and HCI (aq, 1 M). The aqeous layer was extracted with EtOAc, the combined organic extracts were washed with HCI (aq, 1 M) and brine and finally dried over Na ₂ SO ₄ . Concentration and purification by chromatography afforded the title compound (390 mg, 47%). 200 MHz ¹ H-NMR (DMSO-Cf ₆ , ppm) δ 9.9-9.8 (1 H ₁ br s) 9.6-9.5 (1 H, br s) 7.72 (1 H, s) 7.29-7.21 (2H, m) 7.08-6.95 (2H, m) 6.89-6.82 (1 H, m) 6.80-6.72 (1 H, m) 6.34 (2H, s) 3.00-2.86 (2H, m) 2.43-2.31 (2H, m) 2.11 (3H, s) 2.08 (3H ₁ s) 1.80- 1.52 (4H, m). ESI-MS (m/z): 552 [M-H] ^" ; 576 [M+Na] ⁺ .

Example 13

λ/-(2,4-Bis(λ/-(3-chloro-2-methylphenyl)sulfamoyl)-5.6, 7.8-tetrahvdronaphthalen-

1-yl)acetamide

A mixture of 4-amino-λ/',λ/ ³ -bis(3-chloro-2-methylphenyl)-5,6,7,8-tetrahydro- naphthalene-1 ,3-disulfonamide (300 mg, 0.54 mmol; see Example 12, step (c)), acetyl chloride (46 μl_, 0.65 mmol) and toluene (3.0 ml_) was heated in a sealed vessel at 110 ⁰ C for 6 h. After cooling to rt, the mixture was diluted with EtOAc, washed with NaHCO ₃ (aq., sat.), brine and dried over Na ₂ SO ₄ . Concentration and purification by preparative TLC afforded 130 mg (40%) of the title compound.

400 MHz ¹ H-NMR (DMSO-d ₆ , ppm) 10.2-10.0 (1H, br s) 9.8-9.7 (1 H, br s) 9.42 (1 H, s) 7.89 (1 H, s) 7.34-7.24 (2H, m) 7.09-7.02 (1 H, m) 7.01-6.93 (1 H, m) 6.77- 6.68 (2H, m) 3.14-3.01 (2H, m) 2.67-2.55 (2H, m) 2.16 (3H, s) 2.08 (3H, s) 2.01 (3H ₁ s) 1.72-1.57 (4H, m). ESI-MS (m/z): 618 [M+Na] ⁺ .

Example 14

λ/ ⁵ ,λ/ ⁷ -Bis(3-chloro-2-methylphenyl)-2-cvclohexyl-4-hydroxybenzoxaz ole-5,7- disulfonamide

(a) 2-Aminoresorcinol

A mixture of 2-nitroresorcinol (3.0 g, 19.3 mmol), 10% palladium on carbon (1.03 g, 0.97 mmol) and MeOH (50 mL) was stirred under a hydrogen atmosphere at ambient pressure and temperature for 1 h. Filtration and concentration afforded the sub-title compound (2.20 g, 91%).

(b) 2-Cvclohexyl-4-hvdroxybenzoxazole

2-Aminoresorcinol (500 mg, 4.0 mmol; see step (a) above), cyclohexanecarbonyl chloride (590 μl_, 4.4 mmol) and dry dioxane (2.5 mL) were mixed in a sealed vessel and heated by microwave irradiation at 210 ⁰ C for 15 min. After cooling, the mixture was poured into water and extracted with EtOAc. The combined organic extracts were filtered through a silica gel plug which was washed with EtOAc. The combined filtrates where concentrated and dried to afford 860 mg (99%) of the sub-title compound.

(c) 2-Cvclohexyl-4-hvdroxybenzoxazole-5,7-disulfonyl dichloride

A mixture of 2-cyclohexyl-4-hydroxybenzoxazole (434 mg, 2.0 mmol) and chloro- sulfonic acid (5.0 mL) was heated to 150 ⁰ C, heated at that temperature for 20 min, cooled and poured onto crushed ice. The precipitate was collected and dried to afford the sub-title compound (710 mg, 86% yield).

(d) /v^.λ/^BisO-chloro-σ-methylphenyD^-cyclohexyl^-hvdroxybenz oxazole-δy- disulfonamide

The title compound was prepared from 2-cyclohexyl-4-hydroxybenzoxazole-5,7- disulfonyl dichloride (see step (c) above) and 3-chloro-2-methylaniline in accordance with Example 12, step (c).

400 MHz ¹ H-NMR (DMSO-Cf ₆ , ppm) δ 9.33 (1 H ₁ s) 7.54 (1 H, s) 7.20-7.18 (1 H, m) 7.13 (1 H, dd, J = 7.0, 2.4 Hz) 7.01-6.95 (3H, m) 6.89 (1 H ₁ dd, J = 8.0, 1.2 Hz) 2.68-2.61 (1 H, m) 2.32 (3H, s) 1.92 (3H, s) 1.89-1.84 (2H, m) 1.72-1.59 (3H, m) 1.43-1.18 (5H ₁ m).

Example 15

2-Cvclohexyl-λ/ ⁵ ,λ/ ⁷ -bis(3-fluoro-2-methylphenyl)-4-hvdroxybenzoxazole-5,7- disulfonamide

The title compound was prepared from 2-cyclohexyl-4-hydroxybenzoxazole-5,7- disulfonyl dichloride (see Example 14, step (c)) and 3-fluoro-2-methylaniline in accordance with Example 12, step (c).

200 MHz ¹ H-NMR (DMSO-de, ppm) δ 9.33 (1 H ₁ s) 7.56 (1 H, s) 7.03-6.95 (2H, m) 6.92-6.81 (4H, m) 2.72-2.64 (1H, m) 2.16 (3H, d, J = 2.0 Hz) 1.92-1.87 (2H, m) 1.79 (3H, d, J = 2.0 Hz) 1.74-1.69 (2H, m) 1.65-1.60 (1 H ₁ m) 1.47-1.19 (5H, m). ESI-MS (m/z): 590 [M-H] ^" .

Example 16

/V ⁵ ,A/ ⁷ -Bis(3-chloro-2-methylphenyl)-4-hydroxy-2-methylbenzoxazole- 5,7- disulfonamide

(a) 4-Hydroxy-2-methylbenzoxazole

The sub-title compound was prepared in accordance with Example 14, step (b) from 2-aminobenzene-1 ,3-diol (see Example 14, step (a)) and acetyl chloride.

(b) 4-Hydroxγ-2-methylbenzoxazole-5,7-disulfonyl dichloride

The sub-title compound was prepared in accordance with Example 14, step (c) from 4-hydroxy-2-methylbenzoxazole (see step (a) above) and chlorosulfonic acid.

(c) λ/ ⁵ ,λ/ ⁷ -Bis(3-chloro-2-methylphenyl)-4-hvdroxy-2-methylbenzoxazole- 5,7- disulfonamide

The title compound was prepared from 4-hydroxy-2-methylbenzoxazole-5,7- disulfonyl dichloride (see step (b) above) and 3-chloro-2-methylaniline in accordance with Example 12, step (c).

200 MHz ¹ H-NMR (DMSO-Cf ₆ , ppm) δ 9.38 (1 H, s) 7.48 (1 H, s) 7.24-7.13 (2H, m)

7.01-6.89 (3H, m) 6.85-6.80 (1 H, m) 2.32 (6H ₁ s) 1.92 (3H, s).

ESI-MS (m/z): 555 [M-H] ^" ; 595 [M+K] ⁺ .

Example 17

λ^./V^BisO-fluoro^-methylphenyD-δ-hvdroxy^-methyl-I ^.S^-tetrahydro- quinoline-5,7-disulfonamide

The title compound was prepared from λ/ ⁵ ,/V ⁷ -bis(3-fluoro-2-methylphenyl)-8- hydroxy-2-methylquinoline-5,7-disulfonamide (see Example 6) in accordance with Example 4.

200 MHz ¹ H-NMR (DMSO-Cf ₆ , ppm) δ 9.63 (1 H, s) 7.24 (1 H, s) 7.14-6.89 (4H, m) 6.83-6.69 (2H, m) 3.24-2.69 (3H, m) 1.94-1.76 (1 H, m) 1.45-1.21 (1 H, m) 2.05 (3H, d, J=2.2 Hz) 1.95 (3H, d, J=2.2 Hz) 1.17 (3H, d, J=6.4 Hz).

Example 18

2-Chloro-λ/ ⁵ ,λ/ ⁷ -bis(3-chloro-2-methylphenyl)-8-hvdroxyquinoline-5,7-disulfo n- amide

The title compound was prepared from 2-chloro-8-hydroxyquinoline and chlorosulfonic acid in accordance with Example 1 , step (a), followed by reaction with 3-chloro-2-methylaniline in accordance with Example 1 , step (b). 200 MHz ¹ H-NMR {DMSO-d ₆ , ppm) δ 9.47 (1 H, s) 8.52 (1 H, d, J=9.0 Hz) 7.89 (1 H, s) 7.49 (1 H, d, J=9.0 Hz) 7.24-7.10 (2H, m) 7.04-6.89 (3H, m) 6.78 (1 H ₁ d, J=8.0 Hz) 2.32 (3H, s) 1.94 (3H, s).

Example 19

2-Chloro-λ/ ⁵ ,λ/ ⁷ -bis(3-fluoro-2-methylphenyl)-8-hydroxyquinoline-5,7-disulfo n- amide

The title compound was prepared from 2-chloro-8-hydroxyquinoline and chlorosulfonic acid in accordance with Example 1 , step (a), followed by reaction with 3-fluoro-2-methylaniline in accordance with Example 1 , step (b). 200 MHz ¹ H-NMR (DMSO-Cy ₆ , ppm) δ 9.44 (1 H, s) 8.74 (1 H, d, J=9.0 Hz) 7.94 (1 H, s) 7.50 (1 H ₁ d, J=9.0 Hz) 7.05-6.78 (5H, m) 6.71 (1 H ₁ dd, J=7.4, 1.8 Hz) 2.17 (3H, d, J=2.2 Hz) 1.80 (3H, d, J=2.2 Hz).

Example 20 λ^.λ^-BisQ-chloro^-methylphenvD-δ-hvdroxyquinoline-θ.δ- disulfonamicle

The title compound was prepared from 5-hydroxyquinoline and chlorosulfonic acid in accordance with Example 1 , step (a), followed by reaction with 3-chloro-2- methylaniline in accordance with Example 1 , step (b).

200 MHz ¹ H-NMR (DMSO-Cf ₆ , ppm) δ 8.86 (1 H, dd, J=4.4, 1.8 Hz) 8.67 (1H, s) 8.61 (1 H, dd, J=8.0, 1.8 Hz) 7.93 (1 H, s) 7.38 (1 H ₁ dd, J=8.0, 4.4 Hz) 7.18-7.06 (2H, m) 7.01-6.85 (3H, m) 6.76 (1 H, d, J=8.0 Hz) 2.30 (3H ₁ s) 2.16 (3H, s).

Example 21 λ^.λ^-BisO-fluoro^-methylphenvD-δ-hvdroxyquinoline-e.δ-d isulfonamide

The title compound was prepared from 5-hydroxyquinoline and chlorosulfonic acid in accordance with Example 1 , step (a), followed by reaction with 3-fluoro-2- methylaniline in accordance with Example 1 , step (b).

200 MHz ¹ H-NMR (DMSO-Cf ₆ , ppm) δ 8.85 (1 H, dd, J=4.2, 1.4 Hz) 8.73-8.44 (1 H, br s) 8.58 (1 H, dd, J=8.0, 1.2 Hz) 8.01 (1 H, s) 7.36 (1 H, dd, J=8.0, 4.4 Hz) 7.40- 6.60 (6H, m) 2.13-2.12 (3H, m) 1.99-1.97 (3H ₁ m).

Example 22

λ^.λ^-BisO-chloro^-methylphenvπ^-oxo^.S-clihydrobeπzi midazole^.θ- disulfonamide

The title compound was prepared according to the following scheme:

3-chloro-2-methylaniline

200 MHz ¹ H-NMR (DMSO-Cf ₆ , ppm) 511.51 (1 H, s) 11.06 (1 H, s) 9.86 (1 H ₁ s) 9.77 (1 H I,, s O )^ H1 I,, d U,, H I izi-)J 7 I..3^1 I d \λ,, J \J= —8 W..0 \J 7 I..2£-7 I Hl I,, d \J,, J \J= —1 I ..5*-* H I lzit)

7 7. π0R6 / (2OUH ₁ A dAd, 8 Q. n0 U Hz-λ) C 6.778O M (1UH, ^ dI, J I-=8Q. n0 U Hz-λ) R 6.774/I / (11UH, A d, J I—=8 O. n0 2 O.I18Q (3H ₁ s) 2.00 (3H ₁ S).

Example 23

λr ^> ,λ/ ⁶ -Bis(3-chloro-2-methylphenyl)benzimidazole-4,6-disulfonamide The title compound was prepared according to the following scheme:

200 MHZ ¹ H-NMR(DMSO-CZ ₆ , ppm) δ(ca.1:1 mixture of benzimidazole tautomers)d 12.70 (0.3H, s) 13.33 (0.37H ₁ s) 10.11 (1H, s) 9.98 (1H, s) 8.71

(0.4H, s) 8.46 (0.6H, s) 8.14 (0.6H, s) 7.94 (0.4H, s) 7.91 (1 H, s) 7.36-7.18 (2H, m) 7.15-6.92 (2H, m) 6.92-6.58 (2H, m) 2.06 (3H ₁ s) 2.09-1.88 (3H, m).

Example 24

λ/ ⁵ .λ/ ⁷ -Bis(3-chloro-2-methylphenyl)-2-(dimethylamino)-8-hvdroxyqui noline-5,7- disulfonamide

The title compound was prepared by treating 2-chloro-λ/ ⁵ ,λ/ ⁷ -bis(3-fiuoro-2- methylphenyl)-8-hydroxyquinoline-5,7-disulfonamide (see Example 19) with dimethylamine in EtOH.

200 MHz ¹ H-NMR (DMSO-d _6l ppm) δ 8.41 (1 H, d, J=9.3 Hz) 7.64 (1 H ₁ s) 7.22- 7.07 (2H, m) 7.07-6.85 (5H, m) 6.80 (1 H, d, J=8.0 Hz) 3.14 (6H, s) 2.32 (3H, s) 2.04 (3H ₁ s)

Example 25

2-te/t-Butyl-λ/ ⁵ .λ/ ⁷ -bis(3-chloro-2-methylphenyl)-4-hydroxy-1-methylbenz- imidazole-5,7-disulfonamide

The title compound was prepared according to the following scheme:

200 MHz ¹ H-NMR (DMSO-Cf ₆ , ppm) 510.15 (1H, s) 9.6-9.5 (2H, br s) 7.94 (1H, s) 7.31-7.28 (1H, m) 7.23 (1H, dd, J=8.0, 0.9 Hz) 7.02 (1H, dd, J=8.0, 8.0 Hz) 7.00 (1H, dd, J=8.0, 8.0 Hz) 6.93 (1H ₁ dd, J=8.0, 0.8 Hz) 6.77-6.73 (1H, m) 4.17 (3H, s) 2.23 (3H ₁ s) 2.14 (3H ₁ s) 1.54 (9H, s).

Example 26

λ/^/V ⁷ -Bis(3-chloro-2-methylphenyl)-3-oxo-3λ-dihvdroquinoxaline-5 J- disulfonamide

The title compound was prepared according to the following scheme:

200MHz ¹ H-NMR(DMSO-Cf ₆ , ppm) 511.2-10.7 (1H ₁ brs) 10.7-10.3 (1H ₁ brs)

10.16 (1H, s) 8.44 (1H, s) 8.13 (1H, d, J=1.9 Hz) 8.01 (1H, d, J=1.9 Hz) 7.34 (2H ₁ d, J=7.8 Hz) 7.06 (2H, dd, J=8.0, 8.0 Hz) 6.88 (1H, d, J=8.0 Hz) 6.72 (1H, d, J=7.8 Hz) 2.14 (3H, s) 2.06 (3H, s).

Example 27

A^.A/^BisO-chloro^-methylphenvD-S-hvdroxy^-oxo-i ^-clihvdroquinoline-S.y- disulfonamide

The title compound was prepared by treating 2-chloro-λ/ ⁵ ,W ⁷ -bis(3-fluoro-2- methylphenyl)-8-hydroxyquinoline-5,7-disulfonamide (see Example 19) with CsOH in H ₂ O.

200 MHz ¹ H-NMR (DMSO-d ₆ , ppm) 511.4-10.9 (1 H, br s) 9.45 (1 H, s) 8.18-8.05 (1 H, m) 7.56 (1 H ₁ s) 7.39-6.70 (6H, m) 6.49-6.42 (1 H, m) 2.34 (3H ₁ s) 1.95 (3H ₁ s)

Example 28

8-Amino-λ/ ⁵ (3-chloro-2-methylphenyl)-/V ⁷ -(4,4-dimethylcvclohexyl)quinoline-5,7- disulfonamide

The title compound was prepared according to the following scheme:

200 MHz ¹ H-NMR (DMSO-Cf ₆ , ppm) δ 9.98 (1 H, s) 8.90 (1 H, dd, J=4.2, 1.4 Hz) 8.84-8.75 (1 H, m) 8.13 (1 H, s) 7.90 (1 H ₁ d, J=7.6 Hz) 7.73 (1 H, dd, J=8.6, 4.2 Hz) 7.20-7.11 (1 H, m) 7.01 (1 H, dd, J=8.0, 8.0 Hz) 6.90 (1 H, dd, J=8.0, 1.2 Hz) 2.79- 2.65 (1 H, m) 1.90 (3H, s) 1.4-0.8 (8H, m) 0.78 (6H, s).

Example 29

λ/ ⁵ (3-chloro-2-methylphenyl)-λ/ ⁷ -(4,4-dimethylcyclohexyl)quinoline-8-hydroxy-5,7- disulfonamide

Example 30

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 3: 200 nM

Example 9: 330 nM

Example 12: 87 nM

Example 14: 510 nM

Example 20: 390 nM

Example 26: 270 nM

Example 27: 67 nM

Example 28: 690 nM