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WO2008129288A2 - Disulfonamides useful in the treatment of inflammation - Google Patents

Disulfonamides useful in the treatment of inflammation Download PDF

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Publication number
WO2008129288A2
WO2008129288A2 PCT/GB2008/001397 GB2008001397W WO2008129288A2 WO 2008129288 A2 WO2008129288 A2 WO 2008129288A2 GB 2008001397 W GB2008001397 W GB 2008001397W WO 2008129288 A2 WO2008129288 A2 WO 2008129288A2
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WIPO (PCT)
Prior art keywords
represent
compound
formula
group
methyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
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PCT/GB2008/001397
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French (fr)
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WO2008129288A3 (en
Inventor
Benjamin Pelcman
Kristofer Olofsson
Edgars Suna
Ivars Kalvins
Vita Ozola
Andrejs Krasikovs
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Boehringer Ingelheim International GmbH
Biolipox AB
Original Assignee
Boehringer Ingelheim International GmbH
Biolipox AB
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Publication of WO2008129288A2 publication Critical patent/WO2008129288A2/en
Publication of WO2008129288A3 publication Critical patent/WO2008129288A3/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/18—Sulfonamides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C311/21—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/22—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms
    • C07C311/29—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/30—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/37—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
    • C07C311/38—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring having sulfur atoms of sulfonamide groups and amino groups bound to carbon atoms of six-membered rings of the same carbon skeleton
    • C07C311/44—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring having sulfur atoms of sulfonamide groups and amino groups bound to carbon atoms of six-membered rings of the same carbon skeleton having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/42—Radicals substituted by singly-bound nitrogen atoms having hetero atoms attached to the substituent nitrogen atom
    • C—CHEMISTRY; METALLURGY
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    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/61—Halogen atoms or nitro radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/76—Nitrogen atoms to which a second hetero atom is attached
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/125—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/13—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/135—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/182—Radicals derived from carboxylic acids
    • C07D295/192—Radicals derived from carboxylic acids from aromatic carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • 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.
  • MAPEG membrane-associated proteins in the eicosanoid and glutathione metabolism
  • 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.
  • Inflammatory diseases that affect the population include asthma, inflammatory bowel disease, rheumatoid arthritis, osteoarthritis, rhinitis, conjunctivitis and dermatitis.
  • Inflammation is also a common cause of pain. Inflammatory pain may arise for numerous reasons, such as infection, surgery or other trauma. Moreover, several diseases including malignancies and cardioavascular diseases are known to have inflammatory components adding to the symptomatology of the patients.
  • Asthma is a disease of the airways that contains elements of both inflammation and bronchoconstriction. Treatment regimens for asthma are based on the severity of the condition. Mild cases are either untreated or are only treated with inhaled ⁇ -agonists which affect the bronchoconstriction element, whereas patients with more severe asthma typically are treated regularly with inhaled corticosteroids which to a large extent are anti-inflammatory in their nature.
  • COPD chronic obstructive pulmonary disease
  • COX cyclooxygenase
  • COXs metabolise arachidonic acid to the unstable intermediate prostaglandin H 2 (PGH 2 ).
  • PGH 2 is further metabolized to other prostaglandins including PGE 2 , PGF 2 Q, PGD 2 , prostacyclin and thromboxane A 2 .
  • PGE 2 metabolise arachidonic acid to the unstable intermediate prostaglandin H 2
  • PGD 2 metabolized to other prostaglandins
  • PGE 2 PGF 2 Q
  • PGD 2 prostacyclin
  • thromboxane A 2 oxidation factor 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 .
  • NSAIDs non-steroidal antiinflammatory drugs
  • coxibs selective COX-2 inhibitors
  • 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.
  • drugs which act by inhibition of COXs are therefore known/suspected to cause adverse biological effects.
  • 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.
  • a drug that inhibits (preferably selectively) the transformation of PGH 2 to the pro-inflammatory mediator PGE 2 might be expected to reduce the inflammatory response in the absence of a corresponding reduction of the formation of other, beneficial arachidonic acid metabolites. Such inhibition would accordingly be expected to alleviate the undesirable side-effects mentioned above.
  • PGH 2 may be transformed to PGE 2 by prostaglandin E synthases (PGES).
  • PGES prostaglandin E synthases
  • mPGES-1 and mPGES-2 microsomal prostaglandin E synthases
  • cPGES cytosolic prostaglandin E synthase
  • the leukotrienes are formed from arachidonic acid by a set of enzymes distinct from those in the COX / PGES pathway.
  • Leukotriene B 4 is known to be a strong proinflammatory mediator, while the cysteinyl-containing leukotrienes C 4 , D 4 and E 4 (CysLTs) are mainly very potent bronchoconstrictors and have thus been implicated in the pathobiology of asthma.
  • the biological activities of the CysLTs are mediated through two receptors designated CysLTi and CysLT 2 .
  • leukotriene receptor antagonists LTRas
  • 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).
  • MGST1 , MGST2 and MGST3 microsomal glutathione S- transferases
  • 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.
  • 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.
  • 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.
  • the former document does not mention or suggest monocycles that have only two sulfonamide groups attached thereto.
  • the latter does not mention or suggest aromatic sulfonamides in which the aromatic ring is not substituted by a hexose-thio group.
  • T 1 and T 2 represents H, and the other represents H or R 3a ;
  • W 1 and W 2 independently represent a direct bond or C 1-6 alkylene optionally substituted by one or more substituents selected from R m1 ;
  • each R m1 independently represents fluoro or C 1-4 alkyl (optionally substituted by one or more halo atoms); or any two R m1 groups, for example when attached to adjacent or the same carbon atoms, are linked together to form a 3- to 5-membered carbocyclic ring optionally substituted by one or more substituents selected from halo and C 1-2 alkyl;
  • X 1 represents a substituent selected from Z 1 ;
  • X 2 represents, at each occurrence when used herein, hydrogen, Z 1 or Z 2 ;
  • Z 1 represents, at each occurrence when used herein, halo, -R 3a , -CN, -C(O)OR 3c , -N(R 4b )R 5b , -N(R 3d )C(O)R 4c , -N(R 3e )C(O)N(R 4d )R 5d , -N(R 3f )C(O)OR 4e , -N 3 , -NO 2 , -N(R 39 )S(O) 2 N(R 4f )R 5f , -OR 3h , -OC(O)N(R 4g )R 5g , -OS(O) 2 R 3 ', -N(R 3k )S(O) 2 R 3m , -OC(O)R 3n , -OC(O)OR 3p or -S(O) 2 N(R 4h )R 5h ;
  • Z 2 represents, at each occurrence when used herein, -C(O)R 3b , -C(O)N(R 4a )R 5a or -S(O) m R 3j ;
  • n O, 1 or 2;
  • R 3b , R 3d to R 3h , R 3k , R 3 ⁇ , R 4a to R 4h , R 5a , R 5b , R 5d and R 5f to R 5h independently represent H or R 3a ; or any of the pairs R 4a and R 5a , R 4b and R 5b , R 4d and R 5d , R 4f and R 5f , R 4g and R 5g or
  • R 3c , R 3 ', R 3j , R 3m and R 3p independently represent R 3a ;
  • G 1 and G 2 independently represent -CH 3 , -CF 3 or -N(R 14a )R 15a ;
  • R 8a and R 11a independently represent H, -CH 3 , -CH 2 CH 3 , -CF 3 or -CHF 2 ;
  • R 9a , R 10a , R 12a , R 13a , R 14a and R 15a independently represent H, -CH 3 or -CH 2 CH 3 ,
  • salts include acid addition salts and base addition salts.
  • Such salts may be formed by conventional means, for example by reaction of a free acid or a free base form of a compound of formula I with one or more equivalents of an appropriate acid or base, optionally in a solvent, or in a medium in which the salt is insoluble, followed by removal of said solvent, or said medium, using standard techniques (e.g. in vacuo, by freeze-drying or by filtration). Salts may also be prepared by exchanging a counter-ion of a compound of formula I in the form of a salt with another counter-ion, for example using a suitable ion exchange resin.
  • Compounds of formula I may contain double bonds and may thus exist as E (ent ought) and Z (zusammen) geometric isomers about each individual double bond. All such isomers and mixtures thereof are included within the scope of the invention.
  • Compounds of formula I may also contain one or more asymmetric carbon atoms and may therefore exhibit optical and/or diastereoisomerism.
  • Diastereoisomers may be separated using conventional techniques, e.g. chromatography or fractional crystallisation.
  • the various stereoisomers may be isolated by separation of a racemic or other mixture of the compounds using conventional, e.g. fractional crystallisation or HPLC, techniques.
  • the desired optical isomers may be made by reaction of the appropriate optically active starting materials under conditions which will not cause racemisation or epimerisation (i.e.
  • a 'chiral pool' method by reaction of the appropriate starting material with a 'chiral auxiliary' which can subsequently be removed at a suitable stage, by derivatisation (i.e. a resolution, including a dynamic resolution), for example with a homochiral acid followed by separation of the diastereomeric derivatives by conventional means such as chromatography, or by reaction with an appropriate chiral reagent or chiral catalyst all under conditions known to the skilled person. All stereoisomers and mixtures thereof are included within the scope of the invention.
  • C 1-q alkyl (where q is the upper limit of the range), defined herein may be straight-chain or, when there is a sufficient number (i.e. a minimum of three) of carbon atoms, be branched-chain, and/or cyclic (so forming a C 3-q cycloalkyl group). Further, when there is a sufficient number (i.e. a minimum of four) of carbon atoms, such groups may also be part cyclic. Further, unless otherwise specified, such alkyl groups may also be saturated or, when there is a sufficient number (i.e.
  • Cycloalkyl groups may also include spiro-cyclic groups. Cycloalkyl groups may be saturated or unsaturated, e.g. containing one or more double bond (forming for example a C 3-q cycloalkenyl).
  • 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.
  • 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).
  • 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.
  • spiro-cyclic group refers to a cycloalkyl group that is substituted with a further cycloalkyl group via a single carbon atom.
  • halo when used herein, includes fluoro, chloro, bromo and iodo.
  • Aryl groups that may be mentioned include C 6-14 (e.g. C 6-10 ) aryl groups. Such groups may be monocyclic, bicyclic or tricyclic and have between 6 and 14 ring carbon atoms, in which at least one ring is aromatic.
  • C 6-14 aryl groups include phenyl, naphthyl and the like, such as 1 ,2,3,4-tetrahydronaphthyl, indanyl, indenyl and fluorenyl.
  • the point of attachment of aryl groups may be via any atom of the ring system, for instance when aryl groups are bicyclic or tricyclic, they may be linked to the rest of the molecule via an atom of a non-aromatic or an aromatic ring.
  • the linkage to the rest of the molecule is more preferably via an atom of an aromatic ring.
  • Heteroaryl groups that may be mentioned include those which have between 5 and 14 (e.g. between 5 and 10) members. Such groups may be monocyclic, bicyclic or tricyclic, provided that at least one of the rings is aromatic and wherein at least one (e.g. one to four) of the atoms in the ring system is other than carbon (i.e. a heteroatom).
  • Heteroaryl groups that may be mentioned include oxazolopyridyl (including oxazolo[4,5-b]pyridyl, oxazolo[5,4-b]pyridyl, oxazolo[4,5- c]pyridyl and oxazolo[5,4-c]pyridyl), thiazolopyridyl (including thiazolo[4,5- b]pyridyl, thiazolo[5,4-b]pyridyl, thiazolo[4,5-c]pyridyl and thiazolo[5,4-c]pyridyl) and, preferably, acridinyl, benzimidazolyl, benzodioxanyl, benzodioxepinyl, benzodioxolyl (including 1 ,3-benzodioxolyl), benzofuranyl, benzofurazanyl, benzothiazo
  • 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.
  • heteroaryl groups When heteroaryl groups are bicyclic or tricyclic, they may be linked to the rest of the molecule via an atom of a non-aromatic or an aromatic ring. However, in such instances, the linkage to the rest of the molecule is more preferably via an atom of an aromatic ring.
  • Heteroaryl groups may also be in the N- or S- oxidised form.
  • Heterocycloalkyl groups that may be mentioned include non-aromatic monocyclic and bicyclic heterocycloalkyl groups (which groups may further be bridged) in which at least one (e.g. one to four) of the atoms in the ring system is other than carbon (i.e. a heteroatom), and in which the total number of atoms in the ring system is between three and twelve (e.g. between five and ten). Further, such heterocycloalkyl groups may be saturated or unsaturated containing one or more double and/or triple bonds, forming for example a C 2-q heterocycloalkenyl (where q is the upper limit of the range) or a C 7-q heterocycloalkynyl group.
  • C 2-q heterocycloalkyl groups that may be mentioned include 7-azabicyclo- [2.2.1]heptanyl, 6-azabicyclo[3.1.1]heptanyl, 6-azabicyclo[3.2.1]-octanyl, 8- azabicyclo[3.2.1]octanyl, aziridinyl, azetidinyl, dihydropyranyl, dihydropyridyl, dihydropyrrolyl (including 2,5-dihydropyrrolyl), dioxolanyl (including 1 ,3- dioxolanyl), dioxanyl (including 1 ,3-dioxanyl and 1 ,4-dioxanyl), dithianyl (including 1 ,4-dithianyl), dithiolanyl (including 1 ,3-dithiolanyl), imidazolidinyl, imidazolinyl, morpholinyl, 7-oxabicyclo[2.2.1]
  • Substituents on heterocycloalkyl groups may, where appropriate, be located on any atom in the ring system including a heteroatom. Further, in the case where the substituent is another cyclic compound, then the cyclic compound may be attached through a single atom on the heterocycloalkyl group, forming a so-called "spiro"-compound.
  • the point of attachment of heterocycloalkyl groups may be via any atom in the ring system including (where appropriate) a heteroatom (such as a nitrogen atom), or an atom on any fused carbocyclic ring that may be present as part of the ring system.
  • Heterocycloalkyl groups may also be in the N- or S- oxidised form.
  • Heteroatoms that may be mentioned include include phosphorus, silicon, boron, tellurium, selenium and, preferably, oxygen, nitrogen and sulfur.
  • 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.
  • the respective R 3a groups in question may be the same or different.
  • 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.
  • R 1 represents phenyl substituted by -R 3a and -OR 3h , in which R 3h represents R 3a , and, in each case R 3a represents C 1-6 alkyl, the identities of the two R 3a groups are not to be regarded as being interdependent.
  • R 1 and R 2 independently represent aryl or heteroaryl, both of which are optionally substituted by one or more substituents selected from Z 1 and Z 2 ;
  • W 1 and W 2 independently represent a direct bond or -C(R m )(R n )-; one of T 1 or T 2 represents H, and the other represents H or R 3a ;
  • R m and R n independently represent hydrogen, fluoro or C 1-4 alkyl (optionally substituted by one or more halo atoms); or
  • R m and R n are linked together to form a 3- to 5-membered carbocyclic ring optionally substituted by one or more substituents selected from halo and C 1 ⁇ alkyl;
  • Z 1 represents, at each occurrence when used herein, halo, -R 3a , -CN, -N(R 4b )R 5b ,
  • Z 2 represents, at each occurrence when used herein, -C(O)R 3b , -C(O)OR 3c ,
  • R 4e represents R 3a ;
  • R 8a and R 11a independently represent H, -CH 3 , -CH 2 CH 3 or -CF 3 .
  • X 1 represents halo, -R 3a , -CN, -N(R 4b )R 5b , -N(R 3d )C(O)R 4c , -N(R 3e )C(O)N(R 4d )R 5d , -N(R 3f )C(O)OR 4e , -N 3 , -NO 2 , -N(R 3g )S(O) 2 N(R 4f )R 5f , -0R 3h , -OC(O)N(R 4g )R 59 , -OS(O) 2 R 3 ', -N(R 3k )S(O) 2 R 3m , -OC(O)R 3n or -OC(O)OR 3p .
  • Preferred compounds of formula I include those in which: when any of the pairs R 4a and R 5a , R 4b and R 5b , R 4d and R 5d , R 4f and R 5f , R 49 and R 5s or R 4h and R 5h are linked together, they form a 5- or 6-membered ring, which ring optionally contains a further heteroatom (such as nitrogen or oxygen) and is optionally substituted by one or more (e.g.
  • R 1 and R 2 are each, independently, substituted with less than three (e.g.
  • Z 1 and Z 2 substituent(s) selected from Z 1 and Z 2 ; for example when W 1 and W 2 are direct bonds, then Z 1 and Z 2 substituents on R 1 and R 2 groups are preferably in the positions ⁇ - or ⁇ - relative to the point of attachment of the R 1 and/or R 2 group to the rest of the compound of formula I (e.g. when R 1 and/or R 2 represent phenyl, then the optional substituents are preferably in the ortho- and/or the meta-position);
  • X 1 represents -N(R 4b )R 5b , -N(R 3d )C(O)R 4c , halo (e.g. chloro, fluoro or bromo), -R 3a or -OR 3h ;
  • X 2 represents hydrogen, -C(O)N(R 4a )R 5a , -N(R 4b )R 5b , -N(R 3d )C(O)R 4c , halo (e.g. chloro, fluoro or bromo), -R 3a or -OR 3h ;
  • R 3a represents C 1-6 alkyl (e.g. cyclohexyl, hexyl, ethyl or methyl) optionally substituted by one or more fluoro atoms (so forming, for example, a trifluoromethyl group);
  • R 4a , R 5a , R 4b and R 5b independently represent H, methyl or ethyl;
  • R 3h represents H or R 3a ;
  • R 4c represents R 3a ; when R 3d represents R 3a , then R 3a preferably represents C 1-2 alkyl (e.g. methyl); when R 3h represents R 3a , then R 3a preferably represents C 1-6 alkyl as hereinbefore defined or, more preferably, C 1-3 (e.g. C 1-2 ) aikyl optionally substituted by one or more fluoro atoms (e.g.
  • R 3h may represent cyclopentyl, cyclopropyl, preferably ethyl, difluoromethyl or, more preferably, methyl or trifluoromethyl); when R 4c represents R 3a , then R 3a preferably represents C 1-6 alkyl as hereinbefore defined and, preferably, unsubstituted C 1-6 alkyl such as cyclohexyl, cyclopropyl, tert-butyl, isopropyl, ethyl or, more preferably, methyl); R 6a , R 6b and R 7b independently represent H or C 1-6 alkyl optionally substituted by one or more fluoro atoms.
  • Preferred aryl and heteroaryl groups that R 1 and R 2 may represent include optionally substituted phenyl, naphthyl, pyrrolyl, furanyl, thienyl (e.g. thien-2-yl or thien-3-yl), pyrazolyl, imidazolyl (e.g. 2-imidazolyl or 4-imidazolyl), oxazolyl, isoxazolyl, thiazolyl, pyridyl (e.g.
  • Preferred groups include optionally substituted pyridyl (e.g. 3-pyridyl or, preferably, 2- or 4-pyridyl), pyrazinyl (e.g. 2- pyrazinyl), furanyl, thienyl, oxazolyl, thiazolyl and, more preferably, optionally substituted phenyl.
  • R 1 , R 2 or the Y 1 to Y 4 -containing ring of compounds of formula I include:
  • 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
  • halo e.g. fluoro
  • R 16 to R 18 independently represent, on each occasion when mentioned above, H or R 19 ; and each R 19 independently represents (and
  • R 17 preferably represents) C 1-6 alkyl, such as C 1-4 alkyl (e.g. ethyl, n-propyl, n- butyl, Nbutyl or, preferably, methyl or isopropyl) optionally substituted by one or more halo (e.g. fluoro) groups (so forming e.g. a thfluoromethyl group).
  • C 1-4 alkyl e.g. ethyl, n-propyl, n- butyl, Nbutyl or, preferably, methyl or isopropyl
  • halo e.g. fluoro
  • heteroaryl e.g. pyridyl; which heteroaryl group is optionally substituted by one or more substituents selected from Z 1 and Z 2
  • aryl e.g.
  • R 1 and R 2 independently represent phenyl optionally substituted by one or two substituents selected from Z 1 and Z 2 ; R 1 and R 2 are preferably the same; when R 1 or R 2 represent optionally substituted C 1-12 alkyl, then such a group preferably represents C 3 _ 12 cycloalkyl (such as C 3-8 cycloalkyl, e.g. C 5-6 cycloalkyl, such as cyclohexyl) or C 1-6 (e.g. C 1-4 ) acyclic alkyl (e.g.
  • R 1 or R 2 represent optionally substituted heteroaryl, then they preferably represent a 5- or 6-membered heteroaryl group containing two or, preferably one heteroatom(s), in which the heteroatom is preferably selected from sulfur, oxygen and particularly, nitrogen (so forming for example a pyridyl group); when R 1 or R 2 represent optionally substituted heterocycloalkyl, then they preferably represent a 5- or 6-membered heterocycloalkyi group containing two or, preferably one heteroatom(s), in which the heteroatom is preferably selected from sulfur, particularly, oxygen and more particularly, nitrogen (so forming for example a pyrrolidinyl group); when Z 1 represents a substituent on R 1 or R 2 , then it preferably represents
  • R 3j preferably represents C 1-12 alkyl (which group is preferably acyclic and unsubstituted); m represents 2 or, preferably 0;
  • W 1 and W 2 independently represent a direct bond or C 1-3 (e.g. C 1-2 ) alkylene (e.g.
  • W 1 and W 2 may be different but are preferably the same; both of W 1 and W 2 may represent optionally substituted alkylene (as defined herein), one of W 1 and W 2 may represent a direct bond (particularly when the R 1 or R 2 group that is attached thereto represents optionally substituted heteroaryl or, preferably, optionally substituted aryl) and the other represents optionally substituted alkylene (as defined herein), or, both of W 1 and W 2 may represent direct bonds; one of T 1 and T 2 represents H and the other either represents C 1-3 alkyl (e.g.
  • X 1 represents -R 3a , -CN, -C(O)OR 3c , -NO 2 , -N(R 4b )R 5b , preferably, halo (e.g. chloro, bromo or, preferably, fluoro) or, more preferably, -OR 3h ;
  • X 2 represents -CN, -NO 2 , -N(R 4b )R 5b , preferably, H, halo (e.g. bromo, preferably, chloro or, more preferably, fluoro), -R 3a , -OR 3h or -C(O)N(R 4a )R 5a ;
  • halo e.g. bromo, preferably, chloro or, more preferably, fluoro
  • R 3h represents H or R 3a , in which R 3a preferably represents C 1-2 alkyl (e.g. methyl);
  • R 3c , R 4b and R 5b independently represent C 1-2 alkyl (e.g. methyl) or hydrogen; R 4a and R 5a independently represent R 3a , or, are linked together to form a five- membered ring, preferably containing no further unsaturations and no further heteroatoms (e.g. a pyrrolidine ring); when R 4a and R 5a represent R 3a , then R 3a preferably represents C 1-3 alkyl (e.g. methyl or, preferably, ethyl);
  • R 6a represents hydrogen;
  • R 6b and R 7b independently represent hydrogen or, preferably, C 1-3 (e.g. C 1 _ 2 ) alkyl (e.g. methyl).
  • Particularly preferred compounds of formula I include those of the examples described hereinafter.
  • L 1a and L 1b independently represent a suitable leaving group such as chloro, bromo, fluoro or -0-C 1-3 alkyl optionally substituted by one or more fluoro atoms (so forming for e.g. methoxy or trifluoromethoxy), and Y 1 to Y 4 are as hereinbefore defined, with a compound of formula III, or with two different compounds of formula III,
  • R x represents R 1 and/or R 2 (as appropriate)
  • W x represents W 1 and/or W 2 (as appropriate)
  • T represents T 1 and/or T 2 (as appropriate)
  • R 1 , R 2 , W 1 , W 2 , T 1 and T 2 are as hereinbefore defined, for example at around room temperature or above (e.g. up to 40-180 0 C), optionally in the presence of a suitable base (e.g.
  • Y 1 to Y 4 , T 1 , T 2 , W 1 , W 2 , L 1a and L 1b are as hereinbefore defined, with a compound of formula III as hereinbefore defined, in which R x represents R 1 , W x represents W 1 and T represents T 1 (for reaction with compounds of formula IV) or R x represents R 2 , W x represents W 2 and T represents T 2 (for reaction with compounds of formula V) under standard reaction conditions, such as those described hereinbefore in respect of process step (i);
  • 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.
  • X 1 and/or X 2 represents:
  • a metal may be synthesised under standard conditions by metallation (e.g. lithiation) of a corresponding compound of formula I in which X 1 and/or X 2 (as appropriate) represents H, in the presence of a suitable organometallic reagent (such as an organolithuium base (e.g. n-BuLi, s- BuLi or t-BuLi)) in the presence of a suitable solvent (e.g. a polar aprotic solvent such as THF or diethyl ether), at a suitable temperature (e.g. between -78°C and 0°C).
  • a suitable organometallic reagent such as an organolithuium base (e.g. n-BuLi, s- BuLi or t-BuLi)
  • a suitable solvent e.g. a polar aprotic solvent such as THF or diethyl ether
  • a suitable temperature e.g. between -78°
  • a magnesium-containing group may be synthesised under standard Grignard conditions (e.g. employing magnesium or a suitable reagent such as a mixture of C 1-6 alkyl-Mg-halide and ZnCI 2 or LiCI), followed by reaction with a compound of formula I in which X 1 and/or X 2 represents halo (e.g. bromo), optionally in the presence of a catalyst (e.g. FeCI 3 ).
  • a catalyst e.g. FeCI 3
  • the magnesium of the magnesium- containing reagent e.g. Grignard reagent
  • 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.
  • R 5b , R 5d , R 5f , R 59 and R 5h are as hereinbefore defined, provided that they do not represent hydrogen, and R 3c and R 3p are as hereinbefore defined, may be prepared by reaction of a compound corresponding to a compound of formula I in which R 3c and/or R 3p represents hydrogen or a corresponding compound of formula I in which R 3e , R 3f , R 3g , R 3h , R 4a , R 4b , R 4d , R 4e , R 4f , R 4g , R 4h , R 5a , R 5b , R 5d ,
  • R 5f , R 59 and/or R 5h represent hydrogen (as appropriate), or an appropriate anion thereof, with a compound of formula VII,
  • 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).
  • a suitable base such as one described hereinbefore in respect of process step (i).
  • the relevant group e.g. -N(R 4d )R 5d
  • reaction with an anion of a compound of formula I e.g.
  • a reagent that is a source of another appropriate nucleophile e.g. a source of anions such as cyano, oxy or S " anions
  • a source of anions such as cyano, oxy or S " anions
  • Z y represents -CN, -N(R 4b )R 5b , -N(R 3d )C(O)R 4c , -N(R 3e )C(O)N(R 4d )R 5d , -N(R 3f )C(O)OR 4e , -N(R 3g )S(O) 2 N(R 4f )R 5f , -OR 3h , -SR 3j or -N(R 3k )S(O) 2 R 3m , and R 3d , R 3e , R 3f , R 39 , R 3h , R 3J , R 3k , R 3m , R 4b , R 4c , R 4d , R 4e , R 4f , R 5b , R 5d and R 5f are as hereinbefore defined, or a suitable derivative (e.g.
  • 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.
  • a suitable catalyst for example a metal catalyst containing, preferably, Pd or Cu, and a base and, optionally in the presence of solvent and a ligand.
  • Catalysts that may be mentioned include Pd 2 (dba) 3 (tris(dibenzylideneacetone)dipalladium(O)), bases that may be mentioned include cesium carbonate, ligands that may be mentioned include 2,2'-bis(diphenylphosphino)-1 ,1 '-binaphthyl and solvents that may be employed include toluene.
  • Such reactions may be performed at elevated temperature (e.g. at about 9O 0 C) under an inert (e.g. argon) atmosphere.
  • 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;
  • T x and L 3 are as hereinbefore defined, under standard reaction conditions, for example at around room temperature or above (e.g. up to 40- 18O 0 C), optionally in the presence of a suitable base (e.g. sodium hydride, sodium bicarbonate, potassium carbonate, pyrrolidinopyridine, pyridine, triethylamine, tributylamine, trimethylamine, dimethylaminopyhdine, diisopropylamine, diisopropyl-ethylamine, 1 ,8-diazabicyclo[5.4.0]undec-7-ene, sodium hydroxide, ⁇ /-ethyl-diisopropylamine, ⁇ /-(methylpolystyrene)-4- (methylamino)pyridine, potassium bis(trimethylsilyl)amide, sodium bis(thmethylsilyl)amide, potassium terf-butoxide, lithium diisopropylamide, lithium 2,2,6,6-tetra
  • (ix) compounds of formula I in which X 1 or X 2 is present and represents -OR 3h in which R 3h represents H, may be prepared by deprotection of a corresponding compound of formula I in which the -OH group is protected.
  • protected derivatives may already be compounds of formula I.
  • protected derivatives include corresponding compounds of formula I in which R 3h represents methyl (in this case deprotection may be effected by employing: a suitable reagent such as BBr 3 ; a compound that is a source of anions of an aryl or alkyl sulfide, e.g.
  • sodium salts of thiophenol or dodecanthiol; or a suitable strong acid such as chlorosulfonic acid, HBr (in water or AcOH) and HI), or such protected derivatives may also include compounds in which the -OH group is protected with a benzyl group (in which case deprotection may be effected by hydrogenation under standard conditions, e.g. employing Pd/C);
  • (x) compounds of formula I in which X 1 or X 2 is present and represents -NH 2 may be prepared by reduction of compounds corresponding to compounds of formula I but in which the relevant X 1 or X 2 group represents -NO 2 , for example under hydrogenation conditions in the presence of a catalyst (e.g. palladium on carbon), with a source of hydrogen (e.g. hydrogen gas or nascent hydrogen (e.g. from ammonium formate)), optionally in the presence of a solvent (such as an alcoholic solvent (e.g. methanol)).
  • a catalyst e.g. palladium on carbon
  • a source of hydrogen e.g. hydrogen gas or nascent hydrogen (e.g. from ammonium formate)
  • a solvent such as an alcoholic solvent (e.g. methanol)
  • Y 1 , Y 2 , Y 3 and Y 4 are as hereinbefore defined, with a suitable reagent for the introduction of the sulfonyl halide group (e.g. halosulfonic acid), under conditions known to those skilled in the art (e.g. employing an excess of the halosulfonic acid).
  • a suitable reagent for the introduction of the sulfonyl halide group e.g. halosulfonic acid
  • a salt thereof e.g. a metal salt such as magnesium, sodium or, preferably, lithium, wherein Y 1 , Y 2 , Y 3 , Y 4 , T 1 , T 2 , W 1 , W 2 , R 1 and R 2 are as hereinbefore defined, with a suitable halogenating reagent, such as PCI 5 , PCI 3 or SOCI 2 (as chlorinating reagents) or a reagent such as ⁇ /-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.
  • a suitable halogenating reagent such as PCI 5 , PCI 3 or SOCI 2 (as chlorinating reagents) or a reagent such as ⁇ /-chlorosuccinimde (e.g. in the case where a lithium salt of the
  • compounds of formulae II, IV and V in which L 1a and/or L 1b (as appropriate) represents chloro may be prepared by reaction of a corresponding compound of: (a) formula IXA,
  • J 1 represents -N 2 + (i.e. a diazonium ion) or -S-Si(R zz ) 3 , in which each R zz independently represents C 1 _ 6 alkyl (e.g. isopropyl; so forming for example a -S-Si(isopropyl) 3 group), and Y 1 , Y 2 , Y 3 , Y 4 , T 1 , T 2 , W 1 , W 2 , R 1 and R 2 are as hereinbefore defined, under conditions known to those skilled in the art.
  • J 1 represents a diazonium ion
  • reaction with SO 2 or a compound that is a source of SO 2
  • a suitable reagent containing the appropriate chloride ions e.g. CuCI
  • a suitable solvent such as acetic acid
  • J 1 represents -S-Si(R zz ) 3
  • reaction with Cl 2 in acetic acid preferably in the presence of a suitable solvent such as dichloromethane.
  • Compounds of formula IV and V may alternatively be prepared by reaction of a compound of formula Il with less than 2 equivalents of a compound of formula III in which R x represents R 1 or R 2 (as appropriate), W x represents W 1 or W 2 (as appropriate) and T x represents T 1 or T 2 (as appropriate), under conditions such as those hereinbefore described in respect of preparation of compounds of formula I (process step (i) above).
  • reagents include sulfuric acid at an appropriate concentration (e.g. concentrated, fuming or H 2 SO 4 * H 2 O), SO 3 and/or a halosulfonic acid, under conditions known to those skilled in the art.
  • Y 1 , Y 2 , Y 3 , Y 4 , T 1 , T 2 , W 1 , W 2 , R 1 and R 2 are as hereinbefore defined, under standard oxidation conditions, for example employing HNO 3 (e.g. boiling nitric acid) or m-chloroperbenzoic acid in, where necessary, an appropriate solvent system (e.g. dichloromethane).
  • HNO 3 e.g. boiling nitric acid
  • m-chloroperbenzoic acid e.g. dichloromethane
  • compounds of formulae IX, X and Xl may be prepared by reaction of a compound of: (a) formula XIIA
  • Y 1 , Y 2 , Y 3 , Y 4 , T 1 , T 2 , W 1 , W 2 , R 1 and R 2 are as hereinbefore defined, by conversion of the relevant bromo group(s) of the compounds of formulae XIIA, XIIIA or XIVA to a Grignard reagent (e.g. -Mg-Br) or, preferably, a metal (such as lithium), followed by quench with SO 2 (or a compound that is a source of SO 2 ).
  • a Grignard reagent e.g. -Mg-Br
  • a metal such as lithium
  • the conversion step may be performed under conditions such as those described hereinbefore in respect of preparation of compounds of formula 1 (process step (iii) above), for example conversion of the bromo group(s) to (a) lithium group(s) may be effected under halogen-lithium exchange reaction conditions in the presence of an organolithium base (e.g. t- or n-BuLi) in a polar aprotic solvent (e.g. THF or diethyl ether) at low temperature (e.g. -78 0 C).
  • organolithium base e.g. t- or n-BuLi
  • a polar aprotic solvent e.g. THF or diethyl ether
  • compounds of formulae IX, X and Xl may be prepared by reaction of a compound of: (a) formula XIIB
  • Y 1 , Y 2 , Y 3 , Y 4 , T 1 , T 2 , W 1 , W 2 , R 1 and R 2 are as hereinbefore defined, by conversion of the amino group to a diazonium salt (employing reagents and conditions known to those skilled in the art, e.g. NaNO 2 and HCI at 5°C), followed by quenching by addition of with SO 2 (or a compound that is a source of SO 2 ).
  • a diazonium salt employing reagents and conditions known to those skilled in the art, e.g. NaNO 2 and HCI at 5°C
  • SO 2 or a compound that is a source of SO 2
  • Compounds of formula IXA, XA and XIA in which J 1 represents a diazonium ion may be prepared from compounds corresponding to compounds of formula IXA, XA and XIA but in which the diazonium group is replaced with a nitro group, which reaction sequence comprises two steps, first, reduction to an amino group (for example under reaction condition such as those hereinbefore described in respect of preparation of compounds of formula (process step (x) above), and secondly, by a diazotisation (for example under conditions such as those described herein; e.g. in respect of preparation of compounds of formula IX, X and Xl).
  • reaction sequence comprises two steps, first, reduction to an amino group (for example under reaction condition such as those hereinbefore described in respect of preparation of compounds of formula (process step (x) above), and secondly, by a diazotisation (for example under conditions such as those described herein; e.g. in respect of preparation of compounds of formula IX, X and Xl).
  • R zz is as hereinbefore defined, in the presence of an appropriate catalyst system (e.g. a palladium catalyst, such as PdCI 2 , Pd(OAc) 2 , Pd(Ph 3 P) 2 CI 2 , Pd(Ph 3 P) 4 , Pd 2 (dba) 3 , trans-di( ⁇ -acetato)bis[o-(di-o-tolylphosphino)benzyl]- dipalladium, or the like) optionally in the presence of a suitable additive (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( ⁇ -acetato)bis[o-(di-o-tolylphosphino)benzyl]- dipalladium, or the like
  • a suitable additive e
  • Ph 3 P 2,2'-bis(diphenylphosphino)-1 ,1 '-binaphthyl, xantphos, NaI, an appropriate crown ether or, preferably, tri-tert-butyl-phosphonium tetrafluoroborate), optionally in the presence of a base (such as NaH, Et 3 N, pyridine, ⁇ /. ⁇ / 1 - dimethylethylenediamine, Na 2 CO 3 , K 2 CO 3 , K 3 PO 4 , Cs 2 CO 3 , t-BuONa or t-BuOK) and suitable solvent (e.g.
  • a base such as NaH, Et 3 N, pyridine, ⁇ /. ⁇ / 1 - dimethylethylenediamine, Na 2 CO 3 , K 2 CO 3 , K 3 PO 4 , Cs 2 CO 3 , t-BuONa or t-BuOK
  • suitable solvent e.g.
  • dichloromethane dioxane, toluene, ethanol, isopropanol, dimethylformamide, ethylene glycol, ethylene glycol dimethyl ether, water, dimethylsulfoxide, acetonitrile, dimethylacetamide, ⁇ /-methylpyrrolidinone, tetrahydrofuran or a mixture thereof).
  • a suitable reagent for the conversion of a carbonyl to a thiocarbonyl group e.g. P 2 S 5 or Lawesson's reagent
  • L x represents a suitable leaving group (such as halo (e.g. bromo)) and Y 1 , Y 2 , Y 3 , Y 4 , T 1 , W 1 and R 1 are as hereinbefore defined, with a reagent that is a source of SH anions (e.g. NaSH), under standard conditions, for example such as those described hereinbefore in respect of preparation of compounds of formula I (process step (vii)).
  • a reagent that is a source of SH anions e.g. NaSH
  • compounds of formula XIII may also be prepared in a similar manner from the appropriate starting material.
  • heterocyclic Chemistry by J. A. Joule, K. Mills and G. F. Smith, 3 rd edition, published by Chapman & Hall, "Comprehensive Heterocyclic Chemistry IT by A. R. Katritzky, C. W. Rees and E. F ' . V. Scriven, Pergamon Press, 1996 or “Science of Synthesis", Volumes 9-17 (Hetarenes and Related Ring Systems), Georg Thieme Verlag, 2006) and/or made according to the following general procedures.
  • 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.
  • compounds of formula I, or salts thereof, in which the -N(T 1 )-R 1 and -N(T 2 )-R 2 groups are different may be obtained.
  • a hydroxy substituent e.g.
  • a halo substituent 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).
  • an appropriate reagent e.g. POCI 3 for the introduction of a chloro group.
  • 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 .
  • 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).
  • 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 X
  • the substituents X 1 , X 2 , T 1 , T 2 , W 1 and W 2 and optional substituents on R 1 and R 2 in final compounds of formula I or relevant intermediates may be modified one or more times, after or during the processes described above by way of methods that are well known to those skilled in the art. Examples of such methods include substitutions, reductions, oxidations, alkylations, acylations, hydrolyses, esterifications, etherifications, halogenations and nitrations.
  • the precursor groups can be changed to a different such group, or to the groups defined in formula I, at any time during the reaction sequence. In this respect, the skilled person may also refer to "Comprehensive Organic Functional Group
  • transformations 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).
  • a suitable coupling catalyst e.g. a palladium and/or a copper based catalyst
  • a suitable base e.g.
  • a tri-(C 1-6 alkyl)amine such as triethylamine, tributylamine or ethyldiisopropylamine.
  • amino groups and hydroxy groups may be introduced in accordance with standard conditions using reagents known to those skilled in the art.
  • a suitable reducing agent such as borane and other reagents known to the skilled person.
  • Compounds of formula I may be isolated from their reaction mixtures using conventional techniques.
  • 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 .
  • R 5b both represent H
  • ZZ1 represents unsubstituted phenyl, 4-methylphenyl, 3-methylphenyl, 2- methylphenyl;
  • ZZ2 represents 4-nitrophenyl, 3-nitrophenyl, 2-nitrophenyl;
  • ZZ3 represents 4-chlorophenyl, 3-chlorophenyl, 2-chlorophenyl;
  • W 1 and W 2 both represent -CH 2 - linker groups:
  • (2) X 1 represents -OR 3h , and therefore without all of the above provisos except for (A)(a), (A)(b) and (B)(b);
  • X 1 represents -OR 3h , or a pharmaceutically-acceptable salt thereof;
  • W 1 and W 2 represent direct bonds (in which case proviso (B)(b) is 20. redundant); and/or
  • X 1 represents -N(R 4b )R 5b or, preferably, -0R 3h ;
  • R 4b and R 5b represents hydrogen and the other is as hereinbefore defined;
  • R 3h represents hydrogen;
  • at least one of W 1 and W 2 (e.g. W 2 ) represents a direct bond;
  • T 1 and T 2 independently represent hydrogen
  • R 1 and/or R 2 (preferably R 2 , e.g. when W 2 represents a direct bond) represents phenyl substituted by one or, preferably two substituents selected from Z 1 and Z 2 , and which substituent(s) are preferably located in the ortho and/or mefa-positions (i.e. in the 2- and/or 3-positions); and/or
  • substituents on the R 1 and/or R 2 groups are preferably selected from halo (e.g. chloro; which is preferably located in the 3-position when R 1 and/or R 2 represents phenyl) and R 3a (in which R 3a is as hereinbefore defined and is preferably methyl, e.g. located at the 2-position when R 1 and/or R 2 represents phenyl).
  • halo e.g. chloro; which is preferably located in the 3-position when R 1 and/or R 2 represents phenyl
  • R 3a in which R 3a is as hereinbefore defined and is preferably methyl, e.g. located at the 2-position when R 1 and/or R 2 represents phenyl
  • W 1 and W 2 represent optionally substituted C 1 _ 6 alkylene, then they preferably represent methylene (e.g. -CH 2 -). Particularly in such instances, preferably W 1 and W 2 independently represent -CH 2 - or, more preferably, a direct bond.
  • compounds of formula I and salts thereof may possess pharmacological activity as such, certain pharmaceutically-acceptable (e.g. "protected") derivatives of compounds of formula I may exist or be prepared which may not possess such activity, but may be administered parenterally or orally and thereafter be metabolised in the body to form compounds of formula I.
  • Such compounds (which may possess some pharmacological activity, provided that such activity is appreciably lower than that of the "active" compounds to which they are metabolised) may therefore be described as "prodrugs" of compounds of formula
  • prodrug of a compound of formula I we include compounds that form a compound of formula I, or salt thereof, in an experimentally-detectable amount, within a predetermined time (e.g. about 1 hour), following oral or parenteral administration. All prodrugs of the compounds of formula I are included within the scope of the invention.
  • certain compounds of formula I may possess no or minimal pharmacological activity as such, but may be administered parenterally or orally, and thereafter be metabolised in the body to form compounds of formula I that possess pharmacological activity as such.
  • Such compounds (which also includes compounds that may possess some pharmacological activity, but that activity is appreciably lower than that of the "active" compounds of formula I to which they are metabolised), may also be described as "prodrugs".
  • the compounds of formula I and salts thereof are useful because they possess pharmacological activity, and/or are metabolised in the body following oral or parenteral administration to form compounds which possess pharmacological activity.
  • Compounds of formula I and salts thereof are particularly useful because they may inhibit (for example selectively) the activity of prostaglandin E synthases (and particularly microsomal prostaglandin E synthase-1 (mPGES-1)), i.e. they prevent the action of mPGES-1 or a complex of which the mPGES-1 enzyme forms a part, and/or may elicit a mPGES-1 modulating effect, for example as may be demonstrated in the test described below.
  • Compounds of formula I may thus be useful in the treatment of those conditions in which inhibition of a PGES, and particularly mPGES-1 , is required.
  • Compounds of formula I, and pharmaceutically-acceptable salts thereof are thus expected to be useful in the treatment of inflammation.
  • 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.
  • 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.
  • condition has an inflammatory component associated with it, or a condition characterised by inflammation as a symptom
  • compounds of the invention may be useful in the treatment of the inflammatory symptoms and/or the inflammation associated with the condition.
  • compounds of formula I and salts thereof may be useful in the treatment of asthma, chronic obstructive pulmonary disease, pulmonary fibrosis, inflammatory bowel disease, irritable bowel syndrome, inflammatory pain, fever, migraine, headache, low back pain, fibromyalgia, myofascial disorders, viral infections (e.g. influenza, common cold, herpes zoster, hepatitis C and AIDS), bacterial infections, fungal infections, dysmenorrhea, burns, surgical or dental procedures, malignancies (e.g.
  • 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, ulceris, scleritis, uveitis, wound healing, dermatitis, eczema, psoriasis, stroke, diabetes mellitus, neurodegenerative disorders such as Alzheimer's disease and multiple sclerosis, autoimmune diseases, allergic disorders, rhinitis, ulcers, coronary heart disease, sarcoidosis and any other disease with an inflammatory component.
  • Compounds of formula I, and pharmaceutically-acceptable salts thereof, may also have effects that are not linked to inflammatory mechanisms, such as in the reduction of bone loss in a subject. Conditions that may be mentioned in this regard include osteoporosis, osteoarthritis, Paget's disease and/or periodontal diseases. Compounds of formula I may thus also be useful in increasing bone mineral density, as well as the reduction in incidence and/or healing of fractures, in subjects.
  • a method of treatment of a disease which is associated with, and/or which can be modulated by inhibition of, a member of the MAPEG family such as a PGES (e.g. mPGES-1 ), LTC 4 synthase and/or FLAP and/or a method of treatment of a disease in which inhibition of the activity of a member of the MAPEG family such as PGES (and particularly mPGES-1 ), LTC 4 synthase and/or FLAP is desired and/or required (e.g. inflammation), which method comprises administration of a therapeutically effective amount of a compound of the formula I, or a pharmaceutically-acceptable salt thereof, to a patient suffering from, or susceptible to, such a condition.
  • a member of the MAPEG family such as a PGES (e.g. mPGES-1 ), LTC 4 synthase and/or FLAP
  • 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
  • Patients include mammalian (including human) patients. ,
  • the term "effective amount” refers to an amount of a compound, which confers a therapeutic effect on the treated patient.
  • the effect may be objective (i.e. measurable by some test or marker) or subjective (i.e. the subject gives an indication of or feels an effect).
  • Compounds of formula I and salts thereof will normally be administered orally, intravenously, subcutaneously, buccally, rectally, dermally, nasally, tracheally, bronchially, sublingually, by any other parenteral route or via inhalation, in a pharmaceutically acceptable dosage form.
  • Compounds of formula I and salts thereof may be administered alone, but are preferably administered by way of known pharmaceutical formulations, including tablets, capsules or elixirs for oral administration, suppositories for rectal administration, sterile solutions or suspensions for parenteral or intramuscular administration, and the like.
  • Such formulations may be prepared in accordance with standard and/or accepted pharmaceutical practice.
  • a pharmaceutical formulation including a compound of formula I, as specified herein, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.
  • pharmaceutical formulations that may be mentioned include those in which the active ingredient is present in at least 1 % (or at least 10%, at least 30% or at least 50%) by weight. That is, the ratio of active ingredient to the other components (i.e. the addition of adjuvant, diluent and carrier) of the pharmaceutical composition is at least 1 :99 (or at least 10:90, at least 30:70 or at least 50:50) by weight.
  • the invention further provides a process for the preparation of a pharmaceutical formulation, as hereinbefore defined, which process comprises bringing into association a compound of the formula I, as specified herein, or a pharmaceutically acceptable salt thereof with a pharmaceutically-acceptable adjuvant, diluent or carrier.
  • a pharmaceutical formulation as hereinbefore defined, which process comprises bringing into association a compound of the formula I, as specified herein, or a pharmaceutically acceptable salt thereof with a pharmaceutically-acceptable adjuvant, diluent or carrier.
  • Compounds of the invention may also be combined with other therapeutic agents that are useful in the treatment of inflammation (e.g. NSAIDs, coxibs and glucocorticoids).
  • a combination product comprising:
  • each of components (A) and (B) is formulated in admixture with a pharmaceutically-acceptable adjuvant, diluent or carrier.
  • Such combination products provide for the administration of a compound of formula I, or a salt thereof, in conjunction with the other therapeutic agent, and may thus be presented either as separate formulations, wherein at least one of those formulations comprises a compound of formula I or a pharmaceutically- acceptable salt thereof, and at least one comprises the other therapeutic agent, or may be presented (i.e. formulated) as a combined preparation (i.e. presented as a single formulation including a compound of formula I, or a salt thereof, and the other therapeutic agent).
  • a pharmaceutical formulation including a compound of formula I or a pharmaceutically-acceptable salt thereof, another therapeutic agent that is useful in the treatment of inflammation, and a pharmaceutically-acceptable adjuvant, diluent or carrier;
  • the invention further provides a process for the preparation of a combination product as hereinbefore defined, which process comprises bringing into association a compound of formula I or a pharmaceutically-acceptable salt thereof, with another therapeutic agent that is useful in the treatment of inflammation, and a pharmaceutically-acceptable adjuvant, diluent or carrier.
  • 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
  • Compounds of formula I and salts thereof may be administered at varying doses.
  • Oral, pulmonary and topical dosages may range from between about 0.01 mg/kg of body weight per day (mg/kg/day) to about 100 mg/kg/day, preferably about 0.01 to about 10 mg/kg/day, and more preferably about 0.1 to about 5.0 mg/kg/day.
  • 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.
  • the most preferred doses will range from about 0.001 to about 10 mg/kg/hour during constant rate infusion.
  • 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.
  • physician or the skilled person, will be able to determine the actual dosage which will be most suitable for an individual patient, which is likely to vary with the route of administration, the type and severity of the condition that is to be treated, as well as the species, age, weight, sex, renal function, hepatic function and response of the particular patient to be treated.
  • the above- mentioned dosages are exemplary of the average case; there can, of course, be individual instances where higher or lower dosage ranges are merited, and such are within the scope of this invention.
  • Compounds of formula I and salts thereof may have the advantage that they are effective, and preferably selective, inhibitors of a member of MAPEG family, e.g. inhibitors of prostaglandin E synthases (PGES) and particularly microsomal prostaglandin E synthase-1 (mPGES-1 ).
  • PGES prostaglandin E synthases
  • mPGES-1 microsomal prostaglandin E synthase-1
  • the compounds of formula I may reduce the formation of the specific arachidonic acid metabolite PGE 2 without reducing the formation of other COX generated arachidonic acid metabolites, and thus may not give rise to the associated side-effects mentioned hereinbefore.
  • Compounds of formula I and salts thereof may also have the advantage that they may be more efficacious than, be less toxic than, be longer acting than, be more potent than, produce fewer side effects than, be more easily absorbed than, and/or have a better pharmacokinetic profile (e.g. higher oral bioavailability and/or lower clearance) than, and/or have other useful pharmacological, physical, or chemical properties over, compounds known in the prior art, whether for use in the above-stated indications or otherwise.
  • pharmacokinetic profile e.g. higher oral bioavailability and/or lower clearance
  • 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.
  • 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:
  • a 4 ⁇ l aliquot of this mixture is diluted 1 :750-fold in two steps before detection of PGE 2 with HTRF is performed.
  • Example 3 step (a) The title compound was prepared from 4-hydroxy-6-methoxy-benzene-1 ,3- disulfonyl dichloride (see Example 3 step (a)) and 3-fluoro-2-methylaniline in accordance with Example 3 step (b).
  • n-BuLi 2.5 M in hexanes, 460 ⁇ l_, 1.15 mmol
  • 5-bromo- N 1 , ⁇ / 3 -bis(3-chloro-2-methylbenzyl)-2-hydroxybenzene-1 ,3-disulfon-amide 100 mg, 0.16 mmol; see Example 7, step (b)
  • THF 4.0 mL
  • NH 4 CI aq, sat, 5.0 mL
  • the sub-title compound was prepared in accordance with Example 7, step (b) from 5-bromo-2-hydroxybenzene-1 ,3-disulfonyl dichloride and 3-fluoro-2- methylaniline (47% yield).
  • the title compound was prepared from ⁇ / 7 , ⁇ / 3 -bis(3-fluoro-2-methylphenyl)-4- hydroxy-6-methoxybenzene-1 ,3-disulfonamide (see Example 4) in accordance with Example 12.
  • Example 1 step (a) The title compound was prepared from 4-methoxybenzene-1 ,3-disulfonyl dichloride (see Example 1 step (a)) and 4-chloro-2-methylaniline in accordance with Example 7 step (b), followed by demethylation in accordance with Example 2.
  • Example 3 step (a) The title compound was prepared from 4-hydroxy-6-methoxybenzene-1 ,3- disulfonyl dichloride (see Example 3 step (a)) and 3-chloro-2-methylbenzylarnine in accordance with Example 7 step (b).
  • the title compound was prepared by heating pyridone with chlorosulfonic acid at 150 0 C and then treating the intermediate disulfonyl chloride with 3-chloro-2- methylaniline in accordance with Example 7 step (b). As depicted above, the title compound may exist as tautomers.
  • the title compound was prepared by heating 2-nitroaniline with chlorosulfonic acid and treating the formed disulfonyl chloride with 3-chloro-2-methylaniline in accordance with Example 7 step (b).
  • the title compound was prepared by reducing 4-amino- ⁇ / r , ⁇ / 3 -bis(3-chloro-2- methylphenyl)-5-nitrobenzene-1 ,3-disulfonamide (see Example 21) with Fe / NH 4 CI.
  • the title compound was prepared by heating bromobenzene with chlorosulfonic acid for 15 min at 150 0 C and treating the formed disulfonyl chloride with 3-chloro- 2-methylaniline in accordance with Example 7 step (b).
  • the title compound was prepared by heating 4-bromo- ⁇ /', ⁇ / 3 -bis(3-chloro-2- methylphenyl)benzene-1 ,3-disulfonamide (see Example 23) with CuCN in NMP at 150 °C followed by hydrolysis with 2M aqueous NaOH in dioxane.
  • the title compound was prepared by heating 2-bromoanisole with chlorosulfonic acid and treating the formed disulfonyl chloride with 3-chloro-2-methylaniline in accordance with Example 23, followed by treating the so formed S-bromo- ⁇ /'./V 3 - bis(3-chloro-2-methylphenyl)-4-hydroxybenzene-1 ,3-disulfonamide with Cu / CuCI / MeNH 2 ⁇ CI at 70 0 C for 48h.
  • the title compound was prepared by heating 2-bromoanisole with chlorosulfonic acid at 150 0 C, treating the formed disulfonyl chloride with 3-chloro-2-methyl- aniline followed by heating with CuCN in NMP at 150 0 C.
  • Example 36 The title compounds of Examples 36 to 74 were prepared in accordance with Example 35 using the appropriately substituted aniline or amine.
  • Example 36 The title compounds of Examples 36 to 74 were prepared in accordance with Example 35 using the appropriately substituted aniline or amine.
  • Example 16 410O nM
  • Example 19 360O nM
  • Example 29 160O nM
  • Example 31 100OnM

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Abstract

There is provided compounds of formula (I), wherein Y<SUP>1</SUP>, Y<SUP>2</SUP>, Y<SUP>3</SUP>, Y<SUP>4</SUP>, T<SUP>1</SUP>, T<SUP>2</SUP>, W<SUP>1</SUP>, W<SUP>2</SUP>, R<SUP>1</SUP> and R<SUP>2</SUP> have meanings given in the description, and pharmaceutically-acceptable salts thereof, which compounds are useful in the treatment of diseases in which inhibition of the activity of a member of the MAPEG family is desired and/or required, and particularly in the treatment of inflammation.

Description

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 C4 synthase and microsomal glutathione S-transferases (MGST1 , MGST2 and MGST3). The compounds are of potential utility in the treatment of inflammatory diseases including respiratory diseases. The invention also relates to the use of such compounds as medicaments, to pharmaceutical compositions containing them, and to synthetic routes for their production.
Background of the Invention
There are many diseases/disorders that are inflammatory in their nature. One of the major problems associated with existing treatments of inflammatory conditions is a lack of efficacy and/or the prevalence of side effects (real or perceived).
Inflammatory diseases that affect the population include asthma, inflammatory bowel disease, rheumatoid arthritis, osteoarthritis, rhinitis, conjunctivitis and dermatitis.
Inflammation is also a common cause of pain. Inflammatory pain may arise for numerous reasons, such as infection, surgery or other trauma. Moreover, several diseases including malignancies and cardioavascular diseases are known to have inflammatory components adding to the symptomatology of the patients.
Asthma is a disease of the airways that contains elements of both inflammation and bronchoconstriction. Treatment regimens for asthma are based on the severity of the condition. Mild cases are either untreated or are only treated with inhaled β-agonists which affect the bronchoconstriction element, whereas patients with more severe asthma typically are treated regularly with inhaled corticosteroids which to a large extent are anti-inflammatory in their nature.
Another common disease of the airways with inflammatory and bronchoconstrictive components is chronic obstructive pulmonary disease (COPD). The disease is potentially lethal, and the morbidity and mortality from the condition is considerable. At present, there is no known pharmacological treatment capable of changing the course of the disease.
The cyclooxygenase (COX) enzyme exists in two forms, one that is constitutively expressed in many cells and tissues (COX-1), and one that in most cells and tissues is induced by pro-inflammatory stimuli, such as cytokines, during an inflammatory response (COX-2).
COXs metabolise arachidonic acid to the unstable intermediate prostaglandin H2 (PGH2). PGH2 is further metabolized to other prostaglandins including PGE2, PGF2Q, PGD2, prostacyclin and thromboxane A2. These arachidonic acid metabolites are known to have pronounced physiological and pathophysiological activity including pro-inflammatory effects.
PGE2 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 PGE2, 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 PGE2.
However, the inhibition of COXs has the disadvantage that it results in the reduction of the formation of all metabolites downstream of PGH2, 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 PGH2 to the pro-inflammatory mediator PGE2 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.
PGH2 may be transformed to PGE2 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 B4 is known to be a strong proinflammatory mediator, while the cysteinyl-containing leukotrienes C4, D4 and E4 (CysLTs) are mainly very potent bronchoconstrictors and have thus been implicated in the pathobiology of asthma. The biological activities of the CysLTs are mediated through two receptors designated CysLTi and CysLT2. 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 CySLT1. 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 C4 synthase may be mentioned. A FLAP inhibitor would also decrease the formation of the proinflammatory LTB4.
mPGES-1 , FLAP and leukotriene C4 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 PGE2, are likely to be of benefit in the treatment of inflammation. Further, agents that are capable of inhibiting the action of the proteins involved in the synthesis of the leukotrienes are also likely to be of benefit in the treatment of asthma and COPD.
The listing or discussion of an apparently prior-published document in this specification should not necessarily be taken as an acknowledgement that the document is part of the state of the art or is common general knowledge.
In Complement and Inflammation (1991), 8, 50-59, Abdel Mawla et al disclose 5,5',5"-(1 ,3,6-naphthalenetriyl-tris[sulfonylimino])-tris(1 ,3-benzenedisulfonic acid)hexasodium salt as a complement inhibitor, and which may therefore be useful in the treatment of inflammation. However, this document does not mention or suggest monocyclic sulfonamides that are only substituted with two aryl sulfonamide groups.
US Patents Nos. 4,369,191 and 4,431 ,638 disclose various compounds that may be useful as complement inhibitors, and thus in the treatment of inflammation. However, the former document does not mention or suggest monocycles that have only two sulfonamide groups attached thereto. The latter does not mention or suggest aromatic sulfonamides in which the aromatic ring is not substituted by a hexose-thio group.
Badawi et al, Oriental Journal of Chemistry (1986), 2(2), 103, Badawi et al,
Pharmazie (1980), 35 (12), 748, Hannout et al, Egyptian Journal of Pharmaceutical Sciences (1986), 26 (1-4), 213 and Shams et al, Journal of Chemical Society of Pakistan (1986), 8(2), 209 all disclose various benzene disulfonamides as bactericides or antiseptics. International patent application WO 01/016096 discloses various benzene disulfonamides that may be useful in the treatment of hyperlipidemia. National patent application DE 2,459,394 discloses various benzene disulfonamides as anti-hypertensive agents. National patent application GB 909,661, US patent application US 2,947,742 and Liang et al, Yaoxue Xuebao (1963), 10(6), 345-8 all disclose various benzene disulfonamides as inter alia diuretics. International patent application WO 2005/021721 (and Wadkins et al, Molecular Pharmacology (2004), 65(6), 1336) discloses a benzene disulfonamide as a carboxylesterase inhibitor, which compound may therefore be useful in the treatment of cancer. Zhongguo Yaowu Huaxue Zazhi (2004), 14(3), 140 discloses a benzene disulfonamide that may be useful as a platelet aggregator. However, none of the above documents mention that the compounds disclosed therein may be useful as mPGES-1 inhibitors, and therefore useful in the treatment of inflammation.
Journal article Egypt. J. Chem. 28, No. 2, pp. 163-170 (1985) by Maghraby et al discloses the synthesis of various specific disulphonanilide compounds. However, the journal article specifically states that no use has yet been ascribed to such compounds.
US patent applications US 2006/0241296 and US 2006/0183745 both disclose nitrogen-containing monocyclic compounds that may be useful in the treatment of inter alia inflammation. However, there is no disclosure in that document of monocycles that are substituted in a 1 ,3-position with aryl sulfonamide groups.
International patent application WO 93/016036 discloses various compounds that may be useful in the treatment of inflammation. However, this document only relates to compounds in which the requisite benzene ring is substituted with an aromatic ring, which is itself substituted with an amidino moiety.
International patent application WO 99/32433 discloses various benzene monocycles that may be useful in the treatment of inflammation or atherosclerosis. However, this document primarily discloses compounds in which the benzene rings are substituted with amino, amido, alkyl, urea, thiourea, hydroxy or alkoxy-based substituents.
Finally, international patent application WO 2007/042817 discloses naphthalene 1 ,3-disulfonamides, which compounds may be useful as inhibitors of mPGES-1 and therefore useful in the treatment of inflammation. However, there is no mention in this document of any monocycles substituted with two aromatic sulfonamide groups.
Disclosure of the Invention
According to the invention there is provided a compound of formula I,
Figure imgf000007_0001
wherein
R1 and R2 independently represent aryl, heteroaryl (which latter two groups are optionally substituted by one or more substituents selected from Z1 and Z2), C1-12 alkyl or heterocycloalkyl (which latter two groups are optionally substituted by one or more substituents selected from Z1, Z2 and =O);
one of T1 and T2 represents H, and the other represents H or R3a;
W1 and W2 independently represent a direct bond or C1-6 alkylene optionally substituted by one or more substituents selected from Rm1;
each Rm1 independently represents fluoro or C1-4 alkyl (optionally substituted by one or more halo atoms); or any two Rm1 groups, for example when attached to adjacent or the same carbon atoms, are linked together to form a 3- to 5-membered carbocyclic ring optionally substituted by one or more substituents selected from halo and C1-2 alkyl;
in the central ring containing Y1 to Y4: at least one of Y1, Y2, Y3 or Y4 represents -C(X1)=; any further two of Y1, Y2, Y3 and Y4 represent -N= or -C(X2)=; and the other represents -C(X2)=;
X1 represents a substituent selected from Z1;
X2 represents, at each occurrence when used herein, hydrogen, Z1 or Z2;
Z1 represents, at each occurrence when used herein, halo, -R3a, -CN, -C(O)OR3c, -N(R4b)R5b, -N(R3d)C(O)R4c, -N(R3e)C(O)N(R4d)R5d, -N(R3f)C(O)OR4e, -N3, -NO2, -N(R39)S(O)2N(R4f)R5f, -OR3h, -OC(O)N(R4g)R5g, -OS(O)2R3', -N(R3k)S(O)2R3m, -OC(O)R3n, -OC(O)OR3p or -S(O)2N(R4h)R5h;
Z2 represents, at each occurrence when used herein, -C(O)R3b, -C(O)N(R4a)R5a or -S(O)mR3j;
m represents O, 1 or 2;
R3b, R3d to R3h, R3k, R3π, R4a to R4h, R5a, R5b, R5d and R5f to R5h independently represent H or R3a; or any of the pairs R4a and R5a, R4b and R5b, R4d and R5d, R4f and R5f, R4g and R5g or
R4h and R5h 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 R3a;
R3c, R3', R3j, R3m and R3p independently represent R3a;
R3a represents, at each occurrence when used herein, Ci.12 (e.g. C1-6) alkyl optionally substituted by one or more substituents selected from F, CI, =0, -0R6a and -N(R6b)R7b; R6a and R6b independently represent H or Ci-6 alkyl optionally substituted by one or more substituents selected from F, Cl, =0, -0R8a, -N(R9a)R10a and -S(O)2-G1;
R7b represents H, -S(O)2CH3, -S(O)2CF3 or Ci-6 alkyl optionally substituted by one or more substituents selected from F, Cl, =0, -0R11a, -N(R12a)R13a and -S(O)2-G2; or R6b and R7b may be linked together to form a 3- to 6-membered ring, which ring optionally contains a further heteroatom (such as nitrogen or oxygen) in addition to the nitrogen atom to which these substituents are necessarily attached, and which ring is optionally substituted by F, Cl, =0 or Ci-3 alkyl optionally substituted by one or more fluoro atoms;
G1 and G2 independently represent -CH3, -CF3 or -N(R14a)R15a;
R8a and R11a independently represent H, -CH3, -CH2CH3, -CF3 or -CHF2;
R9a, R10a, R12a, R13a, R14a and R15a independently represent H, -CH3 or -CH2CH3,
or a pharmaceutically acceptable salt thereof,
for use in the treatment of a disease in which inhibition or modulation of the activity of a member of the MAPEG family is desired and/or required,
which compounds may be referred to herein as "compounds of the invention".
Pharmaceutically-acceptable salts include acid addition salts and base addition salts. Such salts may be formed by conventional means, for example by reaction of a free acid or a free base form of a compound of formula I with one or more equivalents of an appropriate acid or base, optionally in a solvent, or in a medium in which the salt is insoluble, followed by removal of said solvent, or said medium, using standard techniques (e.g. in vacuo, by freeze-drying or by filtration). Salts may also be prepared by exchanging a counter-ion of a compound of formula I in the form of a salt with another counter-ion, for example using a suitable ion exchange resin. Compounds of formula I may contain double bonds and may thus exist as E (entgegen) and Z (zusammen) geometric isomers about each individual double bond. All such isomers and mixtures thereof are included within the scope of the invention.
Compounds of formula I may also exhibit tautomerism. All tautomeric forms and mixtures thereof are included within the scope of the invention. For example, a 2- hydroxypyridine may exist as a pyridinone.
Compounds of formula I may also contain one or more asymmetric carbon atoms and may therefore exhibit optical and/or diastereoisomerism. Diastereoisomers may be separated using conventional techniques, e.g. chromatography or fractional crystallisation. The various stereoisomers may be isolated by separation of a racemic or other mixture of the compounds using conventional, e.g. fractional crystallisation or HPLC, techniques. Alternatively the desired optical isomers may be made by reaction of the appropriate optically active starting materials under conditions which will not cause racemisation or epimerisation (i.e. a 'chiral pool' method), by reaction of the appropriate starting material with a 'chiral auxiliary' which can subsequently be removed at a suitable stage, by derivatisation (i.e. a resolution, including a dynamic resolution), for example with a homochiral acid followed by separation of the diastereomeric derivatives by conventional means such as chromatography, or by reaction with an appropriate chiral reagent or chiral catalyst all under conditions known to the skilled person. All stereoisomers and mixtures thereof are included within the scope of the invention.
Unless otherwise specified, C1-q alkyl (where q is the upper limit of the range), defined herein may be straight-chain or, when there is a sufficient number (i.e. a minimum of three) of carbon atoms, be branched-chain, and/or cyclic (so forming a C3-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 C2-q alkenyl or a C2-q alkynyl group). In the instance where a 'cycloalkyl' group (e.g. C3-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 C3-q cycloalkenyl). Optional substituents may be attached at any point on the cycloalkyl group. Cycloalkyl groups that may be mentioned include C3-12 cycloalkyl groups, for instance a 3- to 7-membered monocyclic cycloalkyl group or a C8-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 C6-14 (e.g. C6-10) aryl groups. Such groups may be monocyclic, bicyclic or tricyclic and have between 6 and 14 ring carbon atoms, in which at least one ring is aromatic. C6-14 aryl groups include phenyl, naphthyl and the like, such as 1 ,2,3,4-tetrahydronaphthyl, indanyl, indenyl and fluorenyl. The point of attachment of aryl groups may be via any atom of the ring system, for instance when aryl groups are bicyclic or tricyclic, they may be linked to the rest of the molecule via an atom of a non-aromatic or an aromatic ring. However, in such instances, the linkage to the rest of the molecule is more preferably via an atom of an aromatic ring. Heteroaryl groups that may be mentioned include those which have between 5 and 14 (e.g. between 5 and 10) members. Such groups may be monocyclic, bicyclic or tricyclic, provided that at least one of the rings is aromatic and wherein at least one (e.g. one to four) of the atoms in the ring system is other than carbon (i.e. a heteroatom). Heteroaryl groups that may be mentioned include oxazolopyridyl (including oxazolo[4,5-b]pyridyl, oxazolo[5,4-b]pyridyl, oxazolo[4,5- c]pyridyl and oxazolo[5,4-c]pyridyl), thiazolopyridyl (including thiazolo[4,5- b]pyridyl, thiazolo[5,4-b]pyridyl, thiazolo[4,5-c]pyridyl and thiazolo[5,4-c]pyridyl) and, preferably, acridinyl, benzimidazolyl, benzodioxanyl, benzodioxepinyl, benzodioxolyl (including 1 ,3-benzodioxolyl), benzofuranyl, benzofurazanyl, benzothiazolyl, benzothiadiazolyl (including 2,1 ,3-benzothiadiazolyl), benzoxadiazolyl (including 2,1 ,3-benzoxadiazolyl), benzoxazinyl (including 3,4- dihydro-2H-1 ,4-benzoxazinyl), benzoxazolyl, benzimidazolyl, benzomorpholinyl, benzothienyl, carbazolyl, chromanyl, cinnolinyl, furanyl, imidazolyl, imidazopyridyl (including imidazo[4,5-b]pyridyl, imidazo[5,4-b]pyridyl, imidazo[4,5-c]pyridyl and, preferably, imidazo[1 ,2-a]pyridyl), indazolyl, indolinyl, indolyl, isobenzofuranyl, isochromanyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiaziolyl, isothiochromanyl, isoxazolyl, naphthyridinyl (including 1 ,5-naphthyridinyl and 1 ,8-naphthyridinyl), oxadiazolyl (including 1 ,2,3-oxadiazolyl, 1 ,2,4-oxadiazolyl and, preferably, 1 ,3,4-oxadiazolyl), oxazolyl, phenazinyl, phenothiazinyl, phthalazinyl, pteridinyl, purinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinolizinyl, quinoxalinyl, tetrahydroisoquinolinyl (including 1 ,2,3,4- tetrahydroisoquinolinyl and 5,6,7,8-tetrahydroisoquinolinyl), tetrahydroquinolinyl (including 1 ,2,3,4-tetrahydroquinolinyl and 5,6,7,8-tetrahydroquinolinyl), tetrazolyl, thiadiazolyl (including 1 ,2,3-thiadiazolyl, 1 ,2,4-thiadiazolyl and, preferably, 1 ,3,4-thiadiazolyl), thiazolyl, thiochromanyl, thienyl, triazolyl (including 1 ,2,3-triazolyl and 1 ,2,4-triazolyl) and the like. Substituents on heteroaryl groups may, where appropriate, be located on any atom in the ring system including a heteroatom. The point of attachment of heteroaryl groups may be via any atom in the ring system including (where appropriate) a heteroatom (such as a nitrogen atom), or an atom on any fused carbocyclic ring that may be present as part of the ring system. When heteroaryl groups are bicyclic or tricyclic, they may be linked to the rest of the molecule via an atom of a non-aromatic or an aromatic ring. However, in such instances, the linkage to the rest of the molecule is more preferably via an atom of an aromatic ring. Heteroaryl groups may also be in the N- or S- oxidised form.
Heterocycloalkyl groups that may be mentioned include non-aromatic monocyclic and bicyclic heterocycloalkyl groups (which groups may further be bridged) in which at least one (e.g. one to four) of the atoms in the ring system is other than carbon (i.e. a heteroatom), and in which the total number of atoms in the ring system is between three and twelve (e.g. between five and ten). Further, such heterocycloalkyl groups may be saturated or unsaturated containing one or more double and/or triple bonds, forming for example a C2-q heterocycloalkenyl (where q is the upper limit of the range) or a C7-q heterocycloalkynyl group. C2-q heterocycloalkyl groups that may be mentioned include 7-azabicyclo- [2.2.1]heptanyl, 6-azabicyclo[3.1.1]heptanyl, 6-azabicyclo[3.2.1]-octanyl, 8- azabicyclo[3.2.1]octanyl, aziridinyl, azetidinyl, dihydropyranyl, dihydropyridyl, dihydropyrrolyl (including 2,5-dihydropyrrolyl), dioxolanyl (including 1 ,3- dioxolanyl), dioxanyl (including 1 ,3-dioxanyl and 1 ,4-dioxanyl), dithianyl (including 1 ,4-dithianyl), dithiolanyl (including 1 ,3-dithiolanyl), imidazolidinyl, imidazolinyl, morpholinyl, 7-oxabicyclo[2.2.1]heptanyl, 6-oxabicyclo[3.2.1]-octanyl, oxetanyl, oxiranyl, piperazinyl, piperidinyl, pyranyl, pyrazolidinyl, pyrrolidinonyl, pyrrolidinyl, pyrrolinyl, quinuclidinyl, sulfolanyl, 3-sulfolenyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydropyridyl (such as 1 ,2,3,4-tetrahydropyridyl and 1 ,2,3,6-tetrahydropyridyl), thietanyl, thiiranyl, thiolanyl, thiomorpholinyl, trithianyl (including 1 ,3,5-trithianyl), tropanyl and the like. Substituents on heterocycloalkyl groups may, where appropriate, be located on any atom in the ring system including a heteroatom. Further, in the case where the substituent is another cyclic compound, then the cyclic compound may be attached through a single atom on the heterocycloalkyl group, forming a so-called "spiro"-compound. The point of attachment of heterocycloalkyl groups may be via any atom in the ring system including (where appropriate) a heteroatom (such as a nitrogen atom), or an atom on any fused carbocyclic ring that may be present as part of the ring system. Heterocycloalkyl groups may also be in the N- or S- oxidised form.
Heteroatoms that may be mentioned include include phosphorus, silicon, boron, tellurium, selenium and, preferably, oxygen, nitrogen and sulfur. For the avoidance of doubt, in cases in which the identity of two or more substituents in a compound of formula I may be the same, the actual identities of the respective substituents are not in any way interdependent. For example, in the situation in which any two X2 groups or one X1 group and one X2 group represent Z1, and, in both cases Z1 represents R3a, then the respective R3a 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 R1 represents phenyl substituted by -R3a and -OR3h, in which R3h represents R3a, and, in each case R3a represents C1-6 alkyl, the identities of the two R3a groups are not to be regarded as being interdependent.
For the avoidance of doubt, when a term such as "Y1 to Y4" is employed herein, this will be understood by the skilled person to mean Y1, Y2, Y3 and Y4 inclusively.
Compounds of the invention that may be mentioned include those in which:
R1 and R2 independently represent aryl or heteroaryl, both of which are optionally substituted by one or more substituents selected from Z1 and Z2;
W1 and W2 independently represent a direct bond or -C(Rm)(Rn)-; one of T1 or T2 represents H, and the other represents H or R3a;
Rm and Rn independently represent hydrogen, fluoro or C1-4 alkyl (optionally substituted by one or more halo atoms); or
Rm and Rn are linked together to form a 3- to 5-membered carbocyclic ring optionally substituted by one or more substituents selected from halo and C1^ alkyl;
Z1 represents, at each occurrence when used herein, halo, -R3a, -CN, -N(R4b)R5b,
-N(R3d)C(O)R4c, -N(R3e)C(O)N(R4d)R5d, -N(R3f)C(O)OR4e, -N3, -NO2.
-N(R39)S(O)2N(R4f)R5f, -OR3h, -OC(O)N(R49)R5g, -OS(O)2R3', -N(R3k)S(O)2R3m,
-OC(O)R3", -OC(O)OR3p or -S(O)2N(R4h)R5h; Z2 represents, at each occurrence when used herein, -C(O)R3b, -C(O)OR3c,
-C(O)N(R4a)R5a or -S(O)mR3j;
R4e represents R3a;
R8a and R11a independently represent H, -CH3, -CH2CH3 or -CF3. Further preferred compounds of the invention that may be mentioned include those in which: when R1 or R2 represents C1 -12 alkyl (optionally substituted by one or more substituents selected from Z1, Z2 and =O), then it is preferably C3-12 cycloalkyl (optionally substituted by one or more substituents selected from Z1, Z2 and =0); one of R1 and R2 (preferably R1) represents aryl or heteroaryl (which latter two groups are optionally substituted by one or more substituents selected from Z1 and Z2), and the other (preferably R2) represents aryl, heteroaryl (which latter two groups are optionally substituted by one or more substituents selected from Z1 and Z2), C1-12 alkyl or heterocycloalkyl (which latter two groups are optionally substituted by one or more substituents selected from Z1, Z2 and =0); one of R1 and R2 (preferably R1) represents aryl or heteroaryl (which latter two groups are optionally substituted by one or more substituents selected from Z1 and Z2), and the other (preferably R2) represents C1-12 alkyl (optionally substituted by one or more substituents selected from Z1, Z2 and =O), heterocycloalkyl (optionally substituted by one or more substituents selected from Z1, Z2 and =0), preferably, heteroaryl or, more preferably, aryl (which latter two groups are optionally substituted by one or more substituents selected from Z1 and Z2); Z1 is as defined herein, provided that it does not represent -C(O)OR3c; Z2 may represent a substituent as defined herein or -C(O)OR3c.
Compounds of formula I that may be mentioned include those in which X1 represents halo, -R3a, -CN, -N(R4b)R5b, -N(R3d)C(O)R4c, -N(R3e)C(O)N(R4d)R5d, -N(R3f)C(O)OR4e, -N3, -NO2, -N(R3g)S(O)2N(R4f)R5f, -0R3h, -OC(O)N(R4g)R59, -OS(O)2R3', -N(R3k)S(O)2R3m, -OC(O)R3n or -OC(O)OR3p.
Further compounds of formula I that may be mentioned include those in which: one of Y1 to Y4 represents -C(X1)=. and the others all represent -C(X2)=; one of Y1 to Y4 represents -C(X1)=, a further one represents -N=, and the others represent -C(X2)=; or one of Y1 to Y4 represents -C(X1)=, a further two represent -N=, and the remaining one represents -C(X2)=.
Preferred compounds of formula I include those in which: when any of the pairs R4a and R5a, R4b and R5b, R4d and R5d, R4f and R5f, R49 and R5s or R4h and R5h 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, R3a (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); R1 and R2 are each, independently, substituted with less than three (e.g. one or two) substituent(s) selected from Z1 and Z2; for example when W1 and W2 are direct bonds, then Z1 and Z2 substituents on R1 and R2 groups are preferably in the positions α- or β- relative to the point of attachment of the R1 and/or R2 group to the rest of the compound of formula I (e.g. when R1 and/or R2 represent phenyl, then the optional substituents are preferably in the ortho- and/or the meta-position);
X1 represents -N(R4b)R5b, -N(R3d)C(O)R4c, halo (e.g. chloro, fluoro or bromo), -R3a or -OR3h;
X2 represents hydrogen, -C(O)N(R4a)R5a, -N(R4b)R5b, -N(R3d)C(O)R4c, halo (e.g. chloro, fluoro or bromo), -R3a or -OR3h; R3a represents C1-6 alkyl (e.g. cyclohexyl, hexyl, ethyl or methyl) optionally substituted by one or more fluoro atoms (so forming, for example, a trifluoromethyl group);
R4a, R5a, R4b and R5b independently represent H, methyl or ethyl; R3h represents H or R3a; R4c represents R3a; when R3d represents R3a, then R3a preferably represents C1-2 alkyl (e.g. methyl); when R3h represents R3a, then R3a preferably represents C1-6 alkyl as hereinbefore defined or, more preferably, C1-3 (e.g. C1-2) aikyl optionally substituted by one or more fluoro atoms (e.g. R3h may represent cyclopentyl, cyclopropyl, preferably ethyl, difluoromethyl or, more preferably, methyl or trifluoromethyl); when R4c represents R3a, then R3a preferably represents C1-6 alkyl as hereinbefore defined and, preferably, unsubstituted C1-6 alkyl such as cyclohexyl, cyclopropyl, tert-butyl, isopropyl, ethyl or, more preferably, methyl); R6a, R6b and R7b independently represent H or C1-6 alkyl optionally substituted by one or more fluoro atoms. Preferred aryl and heteroaryl groups that R1 and R2 may represent include optionally substituted phenyl, naphthyl, pyrrolyl, furanyl, thienyl (e.g. thien-2-yl or thien-3-yl), pyrazolyl, imidazolyl (e.g. 2-imidazolyl or 4-imidazolyl), oxazolyl, isoxazolyl, thiazolyl, pyridyl (e.g. 2-pyridyl, 3-pyridyl or 4-pyridyl), indazolyl, indolyl, indolinyl, isoindolinyl, quinolinyl, 1 ,2,3,4-tetrahydroquinolinyl, isoquinolinyl, 1 ,2,3,4-tetrahydroisoquinolinyl, quinolizinyl, benzofuranyl, isobenzofuranyl, chromanyl, benzothienyl, pyridazinyl, pyrimidinyl, pyrazinyl, indazolyl, benzimidazolyl, quinazolinyl, quinoxalinyl, 1 ,3-benzodioxolyl, tetrazolyl, benzothiazolyl, and/or benzodioxanyl, group. Preferred groups include optionally substituted pyridyl (e.g. 3-pyridyl or, preferably, 2- or 4-pyridyl), pyrazinyl (e.g. 2- pyrazinyl), furanyl, thienyl, oxazolyl, thiazolyl and, more preferably, optionally substituted phenyl.
Preferred substituents on R1, R2 or the Y1 to Y4-containing ring of compounds of formula I include:
-N(R16)C(O)R17;
-C(O)N(R16)R18; or, preferably halo (e.g. fluoro, chloro or bromo); cyano;
-NO2;
Ci.6 alkyl, which alkyl group may be cyclic (e.g. C1-6 alkyl such as cyclohexyl), part-cyclic (e.g. cyclopropylmethyl), unsaturated (e.g. allyl), linear or branched
(e.g. C1-4 alkyl (such as ethyl, n-propyl, isopropyl, n-butyl, t-butyl or, preferably, methyl)), all of which are optionally substituted with one or more halo (e.g. fluoro) groups (so forming, for example, fluoromethyl, difluoromethyl or, preferably, trifluoromethyl);
-OR16;
-C(O)OR17; -C(O)R16; and
-N(R16)R18; wherein R16 to R18 (e.g. R16 and R18) independently represent, on each occasion when mentioned above, H or R19; and each R19 independently represents (and
R17 preferably represents) C1-6 alkyl, such as C1-4 alkyl (e.g. ethyl, n-propyl, n- butyl, Nbutyl or, preferably, methyl or isopropyl) optionally substituted by one or more halo (e.g. fluoro) groups (so forming e.g. a thfluoromethyl group).
Preferred compounds of formula I include those in which: R1 and R2 independently represent Ci-12 alkyl (which alkyl group is optionally substituted by one or more substituents selected from Z1, Z2 and =0), heterocycloalkyl (e.g. pyrrolidinyl; which heterocycloalkyl group is optionally substituted by one or more substituents selected from Z1, Z2 and =0), heteroaryl (e.g. pyridyl; which heteroaryl group is optionally substituted by one or more substituents selected from Z1 and Z2) or, preferably, aryl (e.g. phenyl; which aryl group is optionally substituted by one or two substituents selected from Z1 and Z2); one of R1 and R2 represents heteroaryl (e.g. pyridyl; which heteroaryl group is optionally substituted by one or more substituents selected from Z1 and Z2) or, preferably, aryl (e.g. phenyl; which aryl group is optionally substituted by one or two substituents selected from Z1 and Z2) and the other represents C1.12 alkyl (which alkyl group is optionally substituted by one or more substituents selected from Z1, Z2 and =0), heterocycloalkyl (e.g. pyrrolidinyl; which heterocycloalkyl group is optionally substituted by one or more substituents selected from Z1, Z2 and =0), heteroaryl (e.g. pyridyl; which heteroaryl group is optionally substituted by one or more substituents selected from Z1 and Z2) or, preferably, aryl (e.g. phenyl; which aryl group is optionally substituted by one or two substituents selected from Z1 and Z2); R1 and R2 independently represent phenyl optionally substituted by one or two substituents selected from Z1 and Z2; R1 and R2 are preferably the same; when R1 or R2 represent optionally substituted C1-12 alkyl, then such a group preferably represents C3_12 cycloalkyl (such as C3-8 cycloalkyl, e.g. C5-6 cycloalkyl, such as cyclohexyl) or C1-6 (e.g. C1-4) acyclic alkyl (e.g. butyl, such as n-butyl or 3,3-dimethylbutyl, i.e. -CH2-CH2-C(CH3)3); when R1 or R2 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 R1 or R2 represent optionally substituted heterocycloalkyl, then they preferably represent a 5- or 6-membered heterocycloalkyi group containing two or, preferably one heteroatom(s), in which the heteroatom is preferably selected from sulfur, particularly, oxygen and more particularly, nitrogen (so forming for example a pyrrolidinyl group); when Z1 represents a substituent on R1 or R2, then it preferably represents
-C(O)OR3c, -N(R4b)R5b or, more preferably, halo (e.g. chloro or fluoro) or R3a; when Z2 represents a substituent on R1 or R2, then it preferably represents
-S(O)mR3j, in which R3j preferably represents C1-12 alkyl (which group is preferably acyclic and unsubstituted); m represents 2 or, preferably 0;
W1 and W2 independently represent a direct bond or C1-3 (e.g. C1-2) alkylene (e.g.
-CH2CH2, -C(CH3)(H)- or, preferably, -CH2-), which alkylene group may be optionally substituted as defined herein; W1 and W2 may be different but are preferably the same; both of W1 and W2 may represent optionally substituted alkylene (as defined herein), one of W1 and W2 may represent a direct bond (particularly when the R1 or R2 group that is attached thereto represents optionally substituted heteroaryl or, preferably, optionally substituted aryl) and the other represents optionally substituted alkylene (as defined herein), or, both of W1 and W2 may represent direct bonds; one of T1 and T2 represents H and the other either represents C1-3 alkyl (e.g. methyl) or, more preferably, H; one of Y1 to Y4 represents -C(X1)=, and the others all represent -C(X2)=; Y3 represents -C(X1)=, preferably Y1 represents -C(X1)= or, more preferably, Y2 or
Y4 represent -C(X1)=;
X1 represents -R3a, -CN, -C(O)OR3c, -NO2, -N(R4b)R5b, preferably, halo (e.g. chloro, bromo or, preferably, fluoro) or, more preferably, -OR3h;
X2 represents -CN, -NO2, -N(R4b)R5b, preferably, H, halo (e.g. bromo, preferably, chloro or, more preferably, fluoro), -R3a, -OR3h or -C(O)N(R4a)R5a;
R3h represents H or R3a, in which R3a preferably represents C1-2 alkyl (e.g. methyl);
R3c, R4b and R5b independently represent C1-2 alkyl (e.g. methyl) or hydrogen; R4a and R5a independently represent R3a, or, are linked together to form a five- membered ring, preferably containing no further unsaturations and no further heteroatoms (e.g. a pyrrolidine ring); when R4a and R5a represent R3a, then R3a preferably represents C1-3 alkyl (e.g. methyl or, preferably, ethyl);
R3a represents C1-12 alkyl or, preferably C1-4 (e.g. C1-3) alkyl (e.g. butyl, such as tert-butyl, or, preferably, ethyl or methyl) optionally substituted by one or more groups selected from -N(R6b)R7b, -OR6a (so forming, for example a -CH2OR6a group), preferably, =0 and, more preferably, halo (e.g. fluoro; so forming for example a difluoromethyl or, preferably, a trifluoromethyl group); when R3a represents alkyl substituted by both =0 and -N(R6b)R7b, then such substituents may both be terminally substituted by both substituents, so forming a -C(O)N(R6b)R7b group; R6a represents hydrogen; R6b and R7b independently represent hydrogen or, preferably, C1-3 (e.g. C1_2) alkyl (e.g. methyl).
Particularly preferred compounds of formula I include those of the examples described hereinafter.
Compounds of formula I may be made in accordance with techniques that are well known to those skilled in the art, for example as described hereinafter.
According to a further aspect of the invention there is provided a process for the preparation of a compound of formula I which process comprises:
(i) for compounds of formula I in which R1 and R2 represent the same, or different, optionally substituted aryl or heteroaryl group, W1 and W2 represent the same group and T1 and T2 also represent the same group, reaction of a compound of formula II,
Figure imgf000021_0001
wherein L1a and L1b independently represent a suitable leaving group such as chloro, bromo, fluoro or -0-C1-3 alkyl optionally substituted by one or more fluoro atoms (so forming for e.g. methoxy or trifluoromethoxy), and Y1 to Y4 are as hereinbefore defined, with a compound of formula III, or with two different compounds of formula III,
RX-WX-N(H)TX III
wherein Rx represents R1 and/or R2 (as appropriate), Wx represents W1 and/or W2 (as appropriate) and T represents T1 and/or T2 (as appropriate), and R1, R2, W1, W2, T1 and T2 are as hereinbefore defined, for example at around room temperature or above (e.g. up to 40-1800C), optionally in the presence of a suitable base (e.g. sodium hydride, sodium bicarbonate, potassium carbonate, pyrrolidinopyridine, pyridine, triethylamine, tributylamine, trimethylamine, dimethylaminopyridine, diisopropylamine, 1 ,8-diazabicyclo[5.4.0]undec-7-ene, sodium hydroxide, Λ/-ethyldiisopropylamine, Λ/-(methylpolystyrene)-4- (methylamino)pyridine or mixtures thereof) in an appropriate solvent (e.g. tetrahydrofuran, pyridine, toluene, dichloromethane, chloroform, acetonitrile, dimethylformamide, triethylamine, water or dimethylsulfoxide). Where the compound of formula I to be prepared is one in which R1 and R2, Qx and Qy and T1 and T2 are the same, then the reaction is performed in the presence of a single compound of formula III (in which case Rx would represent both R1 and R2, Wx would represent both W1 and W2 and Tx would represent both T1 and T2). In this instance, the skilled person will appreciate that for optimum yield, at least two equivalents of a compound of formula III is required. Where the compound of formula I to be prepared is one in which R1 and R2, W1 and W2 and/or T1 and T2 are different, then two different compounds of formula III may be employed in which, in each compound, Rx represents either R1 or R2, Wx represents either W1 or W2, and/or T represents either T1 or T2 (as appropriate);
(ii) reaction of a compound of formula IV,
Figure imgf000022_0001
or a compound of formula V,
Figure imgf000022_0002
wherein Y1 to Y4, T1, T2, W1, W2, L1a and L1b are as hereinbefore defined, with a compound of formula III as hereinbefore defined, in which Rx represents R1, Wx represents W1 and T represents T1 (for reaction with compounds of formula IV) or Rx represents R2, Wx represents W2 and T represents T2 (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 Y1, Y2 or Y4 represent -C(X1)= or -C(X2)=, in which X1 and/or X2 represents halo, -R3a, -C(O)R3b, -C(O)OR3c, -C(O)N(R4a)R5a, -S(O)mR3j or -S(O)2N(R4h)R5h, and R3b, R4a, R5a, R4h and R5h are as hereinbefore defined, provided that they do not represent hydrogen, and R3a, R3c, and R3j are as hereinbefore defined, may be synthesised by reaction of a compound corresponding to a compound of formula I but in which X1 and/or X2 (as appropriate) represents a metal (e.g. lithium) or a magnesium-containing group (so forming, for example, a Grignard reagent, e.g. a compound of formula I containing the group -Mg-Br), with a compound of formula Vl,
Zx-L2 Vl
wherein L2 represents a suitable leaving group, such as chloro, bromo or iodo and Zx represents halo, -R3a, -C(O)R3b, -C(O)OR3c, -C(O)N(R4a)R5a, -S(O)mR3j or -S(O)2N(R4h)R5h, and R3b, R4a, R5a, R4h and R5h are as hereinbefore defined, provided that they do not represent hydrogen, and R3a, R3c and R3j are as hereinbefore defined, under standard reaction conditions. For example, the above-mentioned compounds corresponding to a compound of formula I but in which X1 and/or X2 (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 X1 and/or X2 (as appropriate) represents H, in the presence of a suitable organometallic reagent (such as an organolithuium base (e.g. n-BuLi, s- BuLi or t-BuLi)) in the presence of a suitable solvent (e.g. a polar aprotic solvent such as THF or diethyl ether), at a suitable temperature (e.g. between -78°C and 0°C). Alternatively, such compounds may be synthesised by halogen metal exchange under standard conditions from corresponding compounds of formula I in which X1 and/or X2 (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 C1-6 alkyl-Mg-halide and ZnCI2 or LiCI), followed by reaction with a compound of formula I in which X1 and/or X2 represents halo (e.g. bromo), optionally in the presence of a catalyst (e.g. FeCI3). 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 ZnCI2) 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 X1 or X2 is present and represents -N(R4b)R5b in which R5b is H and R4b is as hereinbefore defined, hydrolysis of a corresponding compound of formula I in which the relevant substituent is -N(R4b)C(O)OR4c in which R4b and R4c 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 X1 or X2 is present and represents -C(O)OR3c and R3c is as hereinbefore defined, trans-esterification of a corresponding compound of formula I in which R3c does not represent the same value as the value of R3c 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 X1 or X2 is present and represents -C(O)OR30, -C(O)N(R4a)R5a, -N(R4b)R5b, -N(R3e)C(O)N(R4d)R5d,
-N(R3f)C(O)OR4e, -N(R39)S(O)2N(R4f)R5f, -0R3h, -OC(O)N(R4g)R59, -OC(O)OR3p and/or -S(O)2N(R4h)R5h, and R3e, R3f, R39, R3h, R4a, R4b, R4d, R4e, R4f, R4g, R4h, R5a,
R5b, R5d, R5f, R59 and R5h are as hereinbefore defined, provided that they do not represent hydrogen, and R3c and R3p are as hereinbefore defined, may be prepared by reaction of a compound corresponding to a compound of formula I in which R3c and/or R3p represents hydrogen or a corresponding compound of formula I in which R3e, R3f, R3g, R3h, R4a, R4b, R4d, R4e, R4f, R4g, R4h, R5a, R5b, R5d,
R5f, R59 and/or R5h represent hydrogen (as appropriate), or an appropriate anion thereof, with a compound of formula VII,
R3a-L3 VII
wherein L3 represents a suitable leaving group, such as chloro, bromo, iodo or a triflate (e.g. -OS(O)2CF3) and R3a 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(R4d)R5d) may first need to be protected (and subsequently deprotected). In the case of reaction with an anion of a compound of formula I, e.g. a compound of formula I in which X1 and/or X2 represents -N(R3f)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 X1 and/or X2 (as appropriate) represents -N(R3f)H and -OH, respectively, followed by reaction in the presence of CO2 (or a suitable source of CO2);
(vii) for compounds of formula I in which a substituent X1 or X2 is present and represents halo, -CN, -N(R4b)R5b, -N(R3d)C(O)R4c, -N(R3e)C(O)N(R4d)R5d, -N(R3f)C(O)OR4e, -N(R39)S(O)2N(R4f)R5f, -0R3h, -SR3J and/or -N(R3k)S(O)2R3m, and R3d, R3e, R3f, R39, R3h, R3i, R3k, R3m, R4b, R4c, R4d, R4e, R4f, R5b, R5d and R5f are as hereinbefore defined, reaction of a corresponding compound of formula I in which X1 or X2 (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 X1 and/or X2 substituents mentioned above) with a compound of formula VIII,
Zy-H VIII
wherein Zy represents -CN, -N(R4b)R5b, -N(R3d)C(O)R4c, -N(R3e)C(O)N(R4d)R5d, -N(R3f)C(O)OR4e, -N(R3g)S(O)2N(R4f)R5f, -OR3h, -SR3j or -N(R3k)S(O)2R3m, and R3d, R3e, R3f, R39, R3h, R3J, R3k, R3m, R4b, R4c, R4d, R4e, R4f, R5b, R5d and R5f 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 X1 or X2 (as appropriate) represents a suitable leaving group such as halo (e.g. chloro, bromo and iodo), -OSO2CF3, -B(OH)2 or -Sn(R2)3 (wherein Rz is C1-6 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 Pd2(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 9O0C) 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 T1 or T2 represents R3a, reaction of a corresponding compound of formula I in which T1 or T2 represents H, with a compound of formula VIIIA,
"T-L3 VIIIA
wherein Tx and L3 are as hereinbefore defined, under standard reaction conditions, for example at around room temperature or above (e.g. up to 40- 18O0C), optionally in the presence of a suitable base (e.g. sodium hydride, sodium bicarbonate, potassium carbonate, pyrrolidinopyridine, pyridine, triethylamine, tributylamine, trimethylamine, dimethylaminopyhdine, diisopropylamine, diisopropyl-ethylamine, 1 ,8-diazabicyclo[5.4.0]undec-7-ene, sodium hydroxide, Λ/-ethyl-diisopropylamine, Λ/-(methylpolystyrene)-4- (methylamino)pyridine, potassium bis(trimethylsilyl)amide, sodium bis(thmethylsilyl)amide, potassium terf-butoxide, lithium diisopropylamide, lithium 2,2,6,6-tetramethylpiperidine or mixtures thereof) and an appropriate solvent (e.g. tetrahydrofuran, pyridine, toluene, dichloromethane, chloroform, acetonitrile, dimethylformamide, trifluoromethylbenzene, dioxane or triethylamine);
(ix) compounds of formula I in which X1 or X2 is present and represents -OR3h in which R3h 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 R3h represents methyl (in this case deprotection may be effected by employing: a suitable reagent such as BBr3; a compound that is a source of anions of an aryl or alkyl sulfide, e.g. sodium salts of thiophenol or dodecanthiol; or a suitable strong acid such as chlorosulfonic acid, HBr (in water or AcOH) and HI), or such protected derivatives may also include compounds in which the -OH group is protected with a benzyl group (in which case deprotection may be effected by hydrogenation under standard conditions, e.g. employing Pd/C);
(x) compounds of formula I in which X1 or X2 is present and represents -NH2, may be prepared by reduction of compounds corresponding to compounds of formula I but in which the relevant X1 or X2 group represents -NO2, for example under hydrogenation conditions in the presence of a catalyst (e.g. palladium on carbon), with a source of hydrogen (e.g. hydrogen gas or nascent hydrogen (e.g. from ammonium formate)), optionally in the presence of a solvent (such as an alcoholic solvent (e.g. methanol)).
Compounds of formula Il (e.g. those in which Y1, Y3 or, preferably, Y2 or Y4 represent -C(OR3h)=) in which L1a and L1b each represent halo may be prepared by reaction of a compound of formula VIIIB,
Figure imgf000027_0001
wherein Y1, Y2, Y3 and Y4 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 L1a and/or L1b represents halo, such as chloro, (as appropriate) may be prepared by reaction of a corresponding compound of: (a) formula IX, (b) formula X,
(c) or formula Xl,
Figure imgf000028_0001
respectively, or a salt thereof (e.g. a metal salt such as magnesium, sodium or, preferably, lithium, wherein Y1, Y2, Y3, Y4, T1, T2, W1, W2, R1 and R2 are as hereinbefore defined, with a suitable halogenating reagent, such as PCI5, PCI3 or SOCI2 (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 SO2, 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 L1a and/or L1b (as appropriate) represents chloro may be prepared by reaction of a corresponding compound of: (a) formula IXA,
(b) formula XA,
(C) or formula XIA,
Figure imgf000029_0001
respectively, wherein J1 represents -N2 + (i.e. a diazonium ion) or -S-Si(Rzz)3, in which each Rzz independently represents C1_6 alkyl (e.g. isopropyl; so forming for example a -S-Si(isopropyl)3 group), and Y1, Y2, Y3, Y4, T1, T2, W1, W2, R1 and R2 are as hereinbefore defined, under conditions known to those skilled in the art. For example when J1 represents a diazonium ion, reaction with SO2 (or a compound that is a source of SO2) 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 J1 represents -S-Si(Rzz)3, by reaction with Cl2 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 Rx represents R1 or R2 (as appropriate), Wx represents W1 or W2 (as appropriate) and Tx represents T1 or T2 (as appropriate), under conditions such as those hereinbefore described in respect of preparation of compounds of formula I (process step (i) above). Compounds of formula IX (.g. those in which Y1, Y3 or, preferably, Y2 or Y4 represent -C(OR3h)=), may be prepared by reaction of the corresponding compound of formula VIIIA with a suitable reagent for the introduction of the sulfonic acid group. Such reagents include sulfuric acid at an appropriate concentration (e.g. concentrated, fuming or H2SO4 *H2O), SO3 and/or a halosulfonic acid, under conditions known to those skilled in the art.
Compounds of formulae IX, X and Xl may be prepared by oxidation of a compound of: (a) formula XII
(b) formula XIII1
(c) or formula XIV,
Figure imgf000030_0001
respectively, wherein Y1, Y2, Y3, Y4, T1, T2, W1, W2, R1 and R2 are as hereinbefore defined, under standard oxidation conditions, for example employing HNO3 (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
Figure imgf000031_0001
(b) formula XIIIA,
Figure imgf000031_0002
(c) or formula XIVA,
Figure imgf000031_0003
respectively, wherein Y1, Y2, Y3, Y4, T1, T2, W1, W2, R1 and R2 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 SO2 (or a compound that is a source of SO2). The conversion step may be performed under conditions such as those described hereinbefore in respect of preparation of compounds of formula 1 (process step (iii) above), for example conversion of the bromo group(s) to (a) lithium group(s) may be effected under halogen-lithium exchange reaction conditions in the presence of an organolithium base (e.g. t- or n-BuLi) in a polar aprotic solvent (e.g. THF or diethyl ether) at low temperature (e.g. -780C).
Alternatively still, compounds of formulae IX, X and Xl may be prepared by reaction of a compound of: (a) formula XIIB
Figure imgf000032_0003
(b) formula XIIIB,
Figure imgf000032_0002
(c) or formula XIVB,
Figure imgf000032_0001
respectively, wherein Y1, Y2, Y3, Y4, T1, T2, W1, W2, R1 and R2 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. NaNO2 and HCI at 5°C), followed by quenching by addition of with SO2 (or a compound that is a source of SO2).
Compounds of formula IXA, XA and XIA in which J1 represents a diazonium ion may be prepared from compounds corresponding to compounds of formula IXA, XA and XIA but in which the diazonium group is replaced with a nitro group, which reaction sequence comprises two steps, first, reduction to an amino group (for example under reaction condition such as those hereinbefore described in respect of preparation of compounds of formula (process step (x) above), and secondly, by a diazotisation (for example under conditions such as those described herein; e.g. in respect of preparation of compounds of formula IX, X and Xl). Compounds of formula IXA, XA and XIA in which J1 represents -S-Si(Rzz)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(Rzz)3 XVA
wherein Rzz is as hereinbefore defined, in the presence of an appropriate catalyst system (e.g. a palladium catalyst, such as PdCI2, Pd(OAc)2, Pd(Ph3P)2CI2, Pd(Ph3P)4, Pd2(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. Ph3P, 2,2'-bis(diphenylphosphino)-1 ,1 '-binaphthyl, xantphos, NaI, an appropriate crown ether or, preferably, tri-tert-butyl-phosphonium tetrafluoroborate), optionally in the presence of a base (such as NaH, Et3N, pyridine, Λ/.Λ/1- dimethylethylenediamine, Na2CO3, K2CO3, K3PO4, Cs2CO3, t-BuONa or t-BuOK) and suitable solvent (e.g. dichloromethane, dioxane, toluene, ethanol, isopropanol, dimethylformamide, ethylene glycol, ethylene glycol dimethyl ether, water, dimethylsulfoxide, acetonitrile, dimethylacetamide, Λ/-methylpyrrolidinone, tetrahydrofuran or a mixture thereof).
Compounds of formula XII may be prepared by reaction of a compound of formula XV,
Figure imgf000033_0001
wherein Y2 and Y3 are as hereinbefore defined, and Y1 and Y4 are as hereinbefore defined and, preferably (e.g. when such groups represent -C(X2)=), represent
-C(H)= or -C(R3a)=, with a suitable reagent for the conversion of a carbonyl to a thiocarbonyl group (e.g. P2S5 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,
Figure imgf000034_0001
wherein Lx represents a suitable leaving group (such as halo (e.g. bromo)) and Y1, Y2, Y3, Y4, T1, W1 and R1 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,
Figure imgf000034_0002
(C) or formula XVIII,
Figure imgf000034_0003
respectively, wherein the A ring, X1, X2, R1, R2, T1 and T2 are as hereinbefore defined, for example under hydrogenation conditions such as those hereinbefore described in respect of preparation of compounds of formula I (process step (x) above).
Compounds of formulae III, Vl, VII, VIII, VIIIA, VIIIB, XIIA, XIIB, XIII, XIIIA, XIVA, XVA, XV, XVI, XVII and XVIII are either commercially available, are known in the literature, or may be obtained either by analogy with the processes described herein, or by conventional synthetic procedures, in accordance with standard techniques, from available starting materials using appropriate reagents and reaction conditions. In this respect, the skilled person may refer to inter alia "Comprehensive Organic Synthesis" by B. M. Trost and I. Fleming, Pergamon Press, 1991. Further, when the requisite Y1 to Y4 containing ring of formula I is heterocyclic, it may also be prepared with reference to a standard heterocyclic chemistry textbook (e.g. "Heterocyclic Chemistry" by J. A. Joule, K. Mills and G. F. Smith, 3rd edition, published by Chapman & Hall, "Comprehensive Heterocyclic Chemistry IT by A. R. Katritzky, C. W. Rees and E. F'. V. Scriven, Pergamon Press, 1996 or "Science of Synthesis", Volumes 9-17 (Hetarenes and Related Ring Systems), Georg Thieme Verlag, 2006) and/or made according to the following general procedures. For example, the sulfonamide groups of compounds of formulae XIIIA and XIVA may be prepared from the corresponding sulfonyl chloride or sulfonic acid, and compounds of formulae XVII and XVIII may ultimately be prepared from the corresponding 1-nitro-3-amino compounds using the diazotisation reaction, followed by the SO2 quench, oxidative chlorination and then coupling with an arylamine, all of which reactions are described herein. In these latter cases, compounds of formula I, or salts thereof, in which the -N(T1)-R1 and -N(T2)-R2 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. POCI3 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. H2SO4) and HNO3. 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 X1, X2, T1, T2, W1 and W2 and optional substituents on R1 and R2 in final compounds of formula I or relevant intermediates may be modified one or more times, after or during the processes described above by way of methods that are well known to those skilled in the art. Examples of such methods include substitutions, reductions, oxidations, alkylations, acylations, hydrolyses, esterifications, etherifications, halogenations and nitrations. The precursor groups can be changed to a different such group, or to the groups defined in formula I, at any time during the reaction sequence. In this respect, the skilled person may also refer to "Comprehensive Organic Functional Group
Transformations" by A. R. Katritzky, O. Meth-Cohn and C. W. Rees, Pergamon
Press, 1995 and/or "Comprehensive Organic Transformations" by R. C. Larock, Wiley-VCH, 1999.
Other transformations that may be mentioned include the conversion of a hydroxy group to a halo (e.g. chloro) group (e.g. employing SOCI2), one halo group to another halo group, or of a halo group (preferably iodo or bromo) to a cyano or 1- alkynyl group (e.g. by reaction with a compound which is a source of cyano anions (e.g. sodium, potassium, copper (I) or zinc cyanide) or with a 1-alkyne, as appropriate). The latter reaction may be performed in the presence of a suitable coupling catalyst (e.g. a palladium and/or a copper based catalyst) and a suitable base (e.g. a tri-(C1-6 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(H2)- groups, for example by reduction in the presence of a suitable reducing agent such as borane and other reagents known to the skilled person. Compounds of formula I may be isolated from their reaction mixtures using conventional techniques.
It will be appreciated by those skilled in the art that, in the processes described above and hereinafter, the functional groups of intermediate compounds may need to be protected by protecting groups.
The protection and deprotection of functional groups may take place before or after a reaction in the above-mentioned schemes.
Protecting groups may be removed in accordance with techniques that are well known to those skilled in the art and as described hereinafter. For example, protected compounds/intermediates described herein may be converted chemically to unprotected compounds using standard deprotection techniques. Specific examples of protecting groups that may be employed include a methyl protecting group for a hydroxy group (so forming a methoxy group), which groups may be deprotected under standard conditions, for example employing a suitable reagent such as BBr3.
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", 3rd edition, T.W. Greene & P. G. M. Wutz, Wiley-lnterscience (1999).
Compounds of formula I and salts thereof are useful because they possess pharmacological activity. Such compounds are therefore indicated as pharmaceuticals.
Certain compounds of formula I have not been disclosed before for use as pharmaceuticals. According to a further aspect of the invention, there is provided a compound of formula I as hereinbefore defined, or a pharmaceutically- acceptable salt thereof, for use as a pharmaceutical, provided that, when T1 and T2 both represent H: (A) W1 and W2 both represent direct bonds:
(a) Y3 represents -C(X1)=, in which X1 represents -OR3h and R ,3h represents H, Y1 represents -C(X2)=, in which X2 represents -R3a and R 13a represents methyl, Y2 and Y4 represent -C(X2)=, in which X2 represents H, then R1 and R2 do not both represent a ZZ1 , ZZ2 or ZZ3 group;
(b) Y2 represents -C(X1)=, in which X1 represents -OR3h and R3h represents H, Y1 represents -C(X2)=, in which X2 represents H:
(I) Y4 represents -C(X2)=, in which X2 represents H: (i) when Y3 represents -C(X2)=, in which X2 represents
-OR3h and R3h represents H, then R1 and R2 do not both represent a ZZ1 , 4-bromophenyl or 4-chlorophenyl group; (ii) when Y3 represents -C(X2)=, in which X2 represents -R3a and R3a represents methyl, then R1 and R2 do not both represent a ZZ1 , ZZ2 or ZZ3 group;
(II) Y3 represents -C(X2)=, in which X2 represents H:
(i) when Y4 represents -C(X2)=, in which X2 represents -R3a and R3a represents methyl, then R1 and R2 do not both represent a ZZ1 , ZZ2 or ZZ3 group (e.g. unsubstituted phenyl or 4-methylphenyl);
(ii) when Y4 represents -C(X2)=, in which X2 represents -OR3h and R3h represents H, then R1 and R2 do not both represent a ZZ1 , 4-bromophenyl or 4-chlorophenyl group;
(c) Y1 and Y3 both represent -C(X2)= in which X2 represents H:
(I) Y2 represents -C(X1)=, in which X1 represents -N(R4b)R5b, R4b represents H, R5b represents R3a, in which R3a represents ethyl terminally substituted with -N(R6b)R7b, and R5b and R7b both represent unsubstituted ethyl, Y4 represents -C(X2)= in which X2 is -N(R4b)R5b, then:
(i) when R4b represents H and R5b represents R3a, in which R3a represents ethyl terminally substituted with -N(R6b)R7b, and R6b and R7b both represent unsubstituted methyl; or (ii) when R4fa and R5b are linked together to form a 1- piperazinyl ring substituted at the 4(N)-position with R3a in which R3a is methyl, then R1 and R2 do not both represent unsubstituted phenyl; (II) Y2 represents -C(X1)=, in which X1 represents -N(R4b)R5b, and
R4b and R5b are linked together to form a 1-piperazinyl ring substituted at the 4(N)-position with R3a, in which R3a is methyl, Y4 represents -C(X2)= in which X2 is chloro, then R1 and R2 do not both represent unsubstituted phenyl; (III) Y2 represents -C(X1)=, in which X1 represents R3a in which R3a is methyl, Y4 represents -C(X2)=, in which X2 represents R3a and R3a is methyl, then R1 and R2 do not both represent unsubstituted phenyl;
(d) Y2 represents -C(X1)=, in which X1 represents -N(R4b)R5b, and R4b and
R5b both represent H, Y1 and Y3 both represent -C(X2)=, in which X2 represents H, then:
(i) when Y4 represents -C(X2)=, in which X2 represents chloro; then R1 and R2 do not both represent a ZZ3, unsubstituted phenyl, 2- methylphenyl, 4-methylphenyl, 3-trifluoromethylphenyl, 2- nitrophenyl or (4-S(O)2-NH2)phenyl group;
(ii) when Y4 represents -C(X2)=, in which X2 represents -R3a and R3a represents a trifluoromethyl group, then R1 and R2 do not both represent unsubstituted 2-pyridyl groups;
(e) Y1 represents -C(X1)=, in which X1 represents chloro, Y2 and Y4 represent -C(X2)=, in which X2 represents H and Y3 represents -C(X2)=, in which X2 represents chloro, then R1 and R2 do not both represent A- methoxyphenyl;
(f) Y1, Y3 and Y4 represent -C(X2)=, in which X2 represents H, then when Y2 represents -C(X1)= in which X1 represents either chloro or R3a in which R3a represents methyl, then R1 and R2 do not both represent A- dimethylaminophenyl, (3,4-dimethyl)phenyl, (2,5-dimethyl)phenyl, 2- pyridyl or 2-thiazolyl, in which:
ZZ1 represents unsubstituted phenyl, 4-methylphenyl, 3-methylphenyl, 2- methylphenyl; ZZ2 represents 4-nitrophenyl, 3-nitrophenyl, 2-nitrophenyl;
ZZ3 represents 4-chlorophenyl, 3-chlorophenyl, 2-chlorophenyl;
(B) W1 and W2 both represent -CH2- linker groups:
(a) Y2 represents -C(X1)=, in which X1 represents -N(R4b)R5b, R4b and R5b are linked together to form a 1-piperazinyl ring substituted at the 4(N)- position by R3a in which R3a is methyl, Y1 and Y3 both represent -C(X2)= in which X2 is H, then:
(i) when Y4 represents -C(X2)=, in which X2 represents -N(R4b)R5b and R4b and R5b are linked together to form a 1-piperazinyl ring substituted at the 4(N)-position by R3a in which R3a is methyl, then R1 and R2 do not both represent an unsubstituted phenyl group; (ii) when Y4 represents -C(X2)=, in which X2 represents chloro, then R1 and R2 do not both represent 2-chlorophenyl;
(b) Y2 represents -C(X1)=, in which X1 represents -OR3h, R3h represents R3a in which R3a is methyl, Y1, Y3 and Y4 all represent -C(X2)=, in which X2 represents H, then R1 and R2 do not both represent unsubstituted 3- pyridyl;
(C) Y2 represents -C(X1)=, in which X1 represents -N(R4b)R5b and R4b and R5b both represent hydrogen, Y1 and Y3 both represent -C(X2)=, in which X2 represents H, Y4 represents -C(X2)=, in which X2 represents chloro, then R1 and R2 do not both represent unsubstituted phenyl.
As hereinbefore stated, certain compounds of formula I have not been disclosed before for use as pharmaceuticals. According to yet a further aspect of the invention, there is provided a compound of formula I, or a pharmaceutically- acceptable salt thereof, for use as a pharmaceutical, as hereinbefore defined but further provided that, when T1 and T2 both represent H, W1 and W2 both represent direct bonds:
(a) Y1 and Y2 both represent -C(H)= and Y3 represents -C(CH3)=, or, when Y1 and Y3 both represent -C(H)= and Y2 represents -C(CH3)=, then when Y4 represents -NH2 or -N(H)C(O)CH3, then R1 and R2 do not both represent unsubstituted phenyl, 2-methylphenyl or4-chlorophenyl;
(b) Y2 and Y4 both represent -C(H)=, Y3 represents -C(CH3)=, then when Y1 represents -NH2 or =N(H)C(O)CH3, then R1 and R2 do not both represent unsubstituted phenyl, 2-methylphenyl, 4-methylphenyl or 4- nitrophenyl.
Alternatively, there is provided a compound of formula I, or a pharmaceutically- acceptable salt thereof, for use as a pharmaceutical, as hereinbefore defined but in which: (1 ) one or two of Y1, Y2, Y3 or Y4 represent(s) -N=, and therefore without the above provisos;
(2) X1 represents -OR3h, and therefore without all of the above provisos except for (A)(a), (A)(b) and (B)(b);
(3) W1 and W2 represent direct bonds, and therefore without the above proviso (B); and/or
(4) when one of Y1 to Y4 represents -C(X1)= and the others represents -C(X2)=, then none, one or, more preferably, all three of those X2 groups represent H, and therefore without all of the above provisos except for (A)(f) and (B)(b).
Hence, when e.g. (2) and (4) above are taken in conjunction, there is provided a compound of formula I as hereinbefore defined, or a pharmaceutically-acceptable salt thereof, for use as a pharmaceutical, but without all of the above provisos except (B)(b). Alternatively, when (2), (3) and (4) above are taken in conjunction, there is provided a compound of formula I as hereinbefore defined, or a pharmaceutically-acceptable salt thereof, for use as a pharmaceutical, but without all of the above provisos.
Certain compounds of formula I, and pharmaceutically-acceptable salts thereof, 5 are novel per se. Thus according to a further aspect of the invention, there is provided:
(1) a compound of formula I as hereinbefore defined, but in which:
(i) one or two of Y1, Y2, Y3 or Y4 represent(s) -N=; and, optionally, 10 (ii) X1 represents -OR3h, or a pharmaceutically-acceptable salt thereof;
(2) a compound of formula I as hereinbefore defined, but in which:
(i) X1 represents -OR3h; and 15 (ii) one of Y1 to Y4 represents -C(X1)= and the others represents
-C(X2)= in which none, one or, more preferably, all three of those X2 groups represent H, provided that the above proviso (B)(b) applies; and, optionally,
(iii) W1 and W2 represent direct bonds (in which case proviso (B)(b) is 20. redundant); and/or
(iv) Y4 or Y2 represent -C(X1)=, or a pharmaceutically-acceptable salt thereof;
(3) a compound of formula I as hereinbefore defined, but in which R1 and R2 25 independently represent C1-12 alkyl (e.g. C3-12 cycloalkyl) or heterocycloalkyl (both of which are optionally substituted as hereinbefore defined), provided that when T1 and T2 represent hydrogen, W1 and W2 represent direct bonds, Y2 and Y4 both represent -C(H)=, then when Y1 and Y3 either both represent -C(CH3)= or both represent -C(CI)=, then R1 and R2 do not both represent cyclohexyl; 30
(4) a compound of formula I as hereinbefore defined, but in which:
(i) one of R1 and R2 (preferably R1) represents aryl or heteroaryl (which latter two groups are optionally substituted by one or more substituents selected from Z1 and Z2), and the other (preferably R2) represents C1 -12 5 alkyl (optionally substituted by one or more substituents selected from Z1, Z2 and =O), heterocycloalkyl (optionally substituted by one or more substituents selected from Z1, Z2 and =0), preferably, heteroaryl or, more preferably, aryl (which latter two groups are optionally substituted by one or more substituents selected from Z1 and Z2); (ii) Y2 represents -C(X1)=;
(iii) X1 represents -N(R4b)R5b or, preferably, -0R3h;
(iv) one of R4b and R5b represents hydrogen and the other is as hereinbefore defined;
(v) R3h represents hydrogen; (vi) at least one of W1 and W2 (e.g. W2) represents a direct bond;
(vii) T1 and T2 independently represent hydrogen;
(viii) R1 and/or R2 (preferably R2, e.g. when W2 represents a direct bond) represents phenyl substituted by one or, preferably two substituents selected from Z1 and Z2, and which substituent(s) are preferably located in the ortho and/or mefa-positions (i.e. in the 2- and/or 3-positions); and/or
(viii) substituents on the R1 and/or R2 groups (e.g. when such groups represent aryl, such as phenyl), are preferably selected from halo (e.g. chloro; which is preferably located in the 3-position when R1 and/or R2 represents phenyl) and R3a (in which R3a is as hereinbefore defined and is preferably methyl, e.g. located at the 2-position when R1 and/or R2 represents phenyl).
As hereinbefore stated, certain compounds of formula I, and pharmaceutically- acceptable salts thereof, are novel per se. Particularly in such instances, it is preferred that when W1 and W2 represent optionally substituted C1_6 alkylene, then they preferably represent methylene (e.g. -CH2-). Particularly in such instances, preferably W1 and W2 independently represent -CH2- or, more preferably, a direct bond.
Although compounds of formula I and salts thereof may possess pharmacological activity as such, certain pharmaceutically-acceptable (e.g. "protected") derivatives of compounds of formula I may exist or be prepared which may not possess such activity, but may be administered parenterally or orally and thereafter be metabolised in the body to form compounds of formula I. Such compounds (which may possess some pharmacological activity, provided that such activity is appreciably lower than that of the "active" compounds to which they are metabolised) may therefore be described as "prodrugs" of compounds of formula
By "prodrug of a compound of formula I", we include compounds that form a compound of formula I, or salt thereof, in an experimentally-detectable amount, within a predetermined time (e.g. about 1 hour), following oral or parenteral administration. All prodrugs of the compounds of formula I are included within the scope of the invention.
Furthermore, certain compounds of formula I may possess no or minimal pharmacological activity as such, but may be administered parenterally or orally, and thereafter be metabolised in the body to form compounds of formula I that possess pharmacological activity as such. Such compounds (which also includes compounds that may possess some pharmacological activity, but that activity is appreciably lower than that of the "active" compounds of formula I to which they are metabolised), may also be described as "prodrugs".
Thus, the compounds of formula I and salts thereof are useful because they possess pharmacological activity, and/or are metabolised in the body following oral or parenteral administration to form compounds which possess pharmacological activity.
Compounds of formula I and salts thereof are particularly useful because they may inhibit the activity of a member of the MAPEG family.
Compounds of formula I and salts thereof are particularly useful because they may inhibit (for example selectively) the activity of prostaglandin E synthases (and particularly microsomal prostaglandin E synthase-1 (mPGES-1)), i.e. they prevent the action of mPGES-1 or a complex of which the mPGES-1 enzyme forms a part, and/or may elicit a mPGES-1 modulating effect, for example as may be demonstrated in the test described below. Compounds of formula I may thus be useful in the treatment of those conditions in which inhibition of a PGES, and particularly mPGES-1 , is required. Compounds of formula I, and pharmaceutically-acceptable salts thereof, are thus expected to be useful in the treatment of inflammation.
The term "inflammation" will be understood by those skilled in the art to include any condition characterised by a localised or a systemic protective response, which may be elicited by physical trauma, infection, chronic diseases, such as those mentioned hereinbefore, and/or chemical and/or physiological reactions to external stimuli (e.g. as part of an allergic response). Any such response, which may serve to destroy, dilute or sequester both the injurious agent and the injured tissue, may be manifest by, for example, heat, swelling, pain, redness, dilation of blood vessels and/or increased blood flow, invasion of the affected area by white blood cells, loss of function and/or any other symptoms known to be associated with inflammatory conditions.
The term "inflammation" will thus also be understood to include any inflammatory disease, disorder or condition per se, any condition that has an inflammatory component associated with it, and/or any condition characterised by inflammation as a symptom, including inter alia acute, chronic, ulcerative, specific, allergic and necrotic inflammation, and other forms of inflammation known to those skilled in the art. The term thus also includes, for the purposes of this invention, inflammatory pain, pain generally and/or fever.
Where a condition has an inflammatory component associated with it, or a condition characterised by inflammation as a symptom, the skilled person will appreciate that compounds of the invention may be useful in the treatment of the inflammatory symptoms and/or the inflammation associated with the condition.
Accordingly, compounds of formula I and salts thereof may be useful in the treatment of asthma, chronic obstructive pulmonary disease, pulmonary fibrosis, inflammatory bowel disease, irritable bowel syndrome, inflammatory pain, fever, migraine, headache, low back pain, fibromyalgia, myofascial disorders, viral infections (e.g. influenza, common cold, herpes zoster, hepatitis C and AIDS), bacterial infections, fungal infections, dysmenorrhea, burns, surgical or dental procedures, malignancies (e.g. breast cancer, colon cancer, and prostate cancer), hyperprostaglandin E syndrome, classic Bartter syndrome, atherosclerosis, gout, arthritis, osteoarthritis, juvenile arthritis, rheumatoid arthritis, rheumatic fever, ankylosing spondylitis, Hodgkin's disease, systemic lupus erythematosus, vasculitis, pancreatitis, nephritis, bursitis, conjunctivitis, iritis, scleritis, uveitis, wound healing, dermatitis, eczema, psoriasis, stroke, diabetes mellitus, neurodegenerative disorders such as Alzheimer's disease and multiple sclerosis, autoimmune diseases, allergic disorders, rhinitis, ulcers, coronary heart disease, sarcoidosis and any other disease with an inflammatory component.
Compounds of formula I, and pharmaceutically-acceptable salts thereof, may also have effects that are not linked to inflammatory mechanisms, such as in the reduction of bone loss in a subject. Conditions that may be mentioned in this regard include osteoporosis, osteoarthritis, Paget's disease and/or periodontal diseases. Compounds of formula I may thus also be useful in increasing bone mineral density, as well as the reduction in incidence and/or healing of fractures, in subjects.
Compounds of formula I and salts thereof are indicated both in the therapeutic and/or prophylactic treatment of the above-mentioned conditions.
According to a further aspect of the present invention, there is provided a method of treatment of a disease which is associated with, and/or which can be modulated by inhibition of, a member of the MAPEG family such as a PGES (e.g. mPGES-1 ), LTC4 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 ), LTC4 synthase and/or FLAP is desired and/or required (e.g. inflammation), which method comprises administration of a therapeutically effective amount of a compound of the formula I, or a pharmaceutically-acceptable salt thereof, to a patient suffering from, or susceptible to, such a condition.
"Patients" include mammalian (including human) patients. ,
The term "effective amount" refers to an amount of a compound, which confers a therapeutic effect on the treated patient. The effect may be objective (i.e. measurable by some test or marker) or subjective (i.e. the subject gives an indication of or feels an effect).
Compounds of formula I and salts thereof will normally be administered orally, intravenously, subcutaneously, buccally, rectally, dermally, nasally, tracheally, bronchially, sublingually, by any other parenteral route or via inhalation, in a pharmaceutically acceptable dosage form.
Compounds of formula I and salts thereof may be administered alone, but are preferably administered by way of known pharmaceutical formulations, including tablets, capsules or elixirs for oral administration, suppositories for rectal administration, sterile solutions or suspensions for parenteral or intramuscular administration, and the like.
Such formulations may be prepared in accordance with standard and/or accepted pharmaceutical practice.
According to a further aspect of the invention there is thus provided a pharmaceutical formulation including a compound of formula I, as specified herein, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.
Depending on e.g. potency and physical characteristics of the compound of the invention (i.e. active ingredient), pharmaceutical formulations that may be mentioned include those in which the active ingredient is present in at least 1 % (or at least 10%, at least 30% or at least 50%) by weight. That is, the ratio of active ingredient to the other components (i.e. the addition of adjuvant, diluent and carrier) of the pharmaceutical composition is at least 1 :99 (or at least 10:90, at least 30:70 or at least 50:50) by weight.
The invention further provides a process for the preparation of a pharmaceutical formulation, as hereinbefore defined, which process comprises bringing into association a compound of the formula I, as specified herein, or a pharmaceutically acceptable salt thereof with a pharmaceutically-acceptable adjuvant, diluent or carrier. Compounds of the invention may also be combined with other therapeutic agents that are useful in the treatment of inflammation (e.g. NSAIDs, coxibs and glucocorticoids).
According to a further aspect of the invention, there is provided a combination product comprising:
(A) a compound of formula I or a pharmaceutically-acceptable salt thereof; and (B) another therapeutic agent that is useful in the treatment of inflammation, wherein each of components (A) and (B) is formulated in admixture with a pharmaceutically-acceptable adjuvant, diluent or carrier.
Such combination products provide for the administration of a compound of formula I, or a salt thereof, in conjunction with the other therapeutic agent, and may thus be presented either as separate formulations, wherein at least one of those formulations comprises a compound of formula I or a pharmaceutically- acceptable salt thereof, and at least one comprises the other therapeutic agent, or may be presented (i.e. formulated) as a combined preparation (i.e. presented as a single formulation including a compound of formula I, or a salt thereof, and the other therapeutic agent).
Thus, there is further provided:
(1 ) a pharmaceutical formulation including a compound of formula I or a pharmaceutically-acceptable salt thereof, another therapeutic agent that is useful in the treatment of inflammation, and a pharmaceutically-acceptable adjuvant, diluent or carrier; and
(2) a kit of parts comprising components:
(a) a pharmaceutical formulation including a compound of formula I or a pharmaceutically-acceptable salt thereof, in admixture with a pharmaceutically-acceptable adjuvant, diluent or carrier; and (b) a pharmaceutical formulation including another therapeutic agent that is useful in the treatment of inflammation in admixture with a pharmaceutically-acceptable adjuvant, diluent or carrier, which components (a) and (b) are each provided in a form that is suitable for administration in conjunction with the other.
The invention further provides a process for the preparation of a combination product as hereinbefore defined, which process comprises bringing into association a compound of formula I or a pharmaceutically-acceptable salt thereof, with another therapeutic agent that is useful in the treatment of inflammation, and a pharmaceutically-acceptable adjuvant, diluent or carrier.
By "bringing into association", we mean that the two components are rendered suitable for administration in conjunction with each other.
Thus, in relation to the process for the preparation of a kit of parts as hereinbefore defined, by bringing the two components "into association with" each other, we include that the two components of the kit of parts may be: (i) provided as separate formulations (i.e. independently of one another), which are subsequently brought together for use in conjunction with each other in combination therapy; or
(ii) packaged and presented together as separate components of a "combination pack" for use in conjunction with each other in combination therapy.
Compounds of formula I and salts thereof may be administered at varying doses. Oral, pulmonary and topical dosages may range from between about 0.01 mg/kg of body weight per day (mg/kg/day) to about 100 mg/kg/day, preferably about 0.01 to about 10 mg/kg/day, and more preferably about 0.1 to about 5.0 mg/kg/day. For e.g. oral administration, the compositions typically contain between about 0.01 mg to about 500 mg, and preferably between about 1 mg to about 100 mg, of the active ingredient. Intravenously, the most preferred doses will range from about 0.001 to about 10 mg/kg/hour during constant rate infusion. Advantageously, compounds may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three or four times daily. In any event, the physician, or the skilled person, will be able to determine the actual dosage which will be most suitable for an individual patient, which is likely to vary with the route of administration, the type and severity of the condition that is to be treated, as well as the species, age, weight, sex, renal function, hepatic function and response of the particular patient to be treated. The above- mentioned dosages are exemplary of the average case; there can, of course, be individual instances where higher or lower dosage ranges are merited, and such are within the scope of this invention.
Compounds of formula I and salts thereof may have the advantage that they are effective, and preferably selective, inhibitors of a member of MAPEG family, e.g. inhibitors of prostaglandin E synthases (PGES) and particularly microsomal prostaglandin E synthase-1 (mPGES-1 ). The compounds of formula I may reduce the formation of the specific arachidonic acid metabolite PGE2 without reducing the formation of other COX generated arachidonic acid metabolites, and thus may not give rise to the associated side-effects mentioned hereinbefore.
Compounds of formula I and salts thereof may also have the advantage that they may be more efficacious than, be less toxic than, be longer acting than, be more potent than, produce fewer side effects than, be more easily absorbed than, and/or have a better pharmacokinetic profile (e.g. higher oral bioavailability and/or lower clearance) than, and/or have other useful pharmacological, physical, or chemical properties over, compounds known in the prior art, whether for use in the above-stated indications or otherwise.
Biological Test
In the assay mPGES-1 catalyses the reaction where the substrate PGH2 is converted to PGE2. mPGES-1 is expressed in E. coli and the membrane fraction is dissolved in 2OmM NaPi-buffer pH 8.0 and stored at -80 0C. 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 H2O, containing FeCI2 (25 mM) and HCI (0.15 M). The assay is performed at room temperature in 384-well plates. Analysis of the amount of PGE2 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 PGH2 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 PGE2 with HTRF is performed.
Examples
The invention is illustrated by way of the following examples, in which the following abbreviations may be employed:
EtOAc ethyl acetate
MeOH methanol
MeOfBu tert-butylmethylether
NMP 1-methyl-2-pyrrolidinone rt room temperature
Example 1 Λ/1,Λ/3-Bis(3-chloro-2-methylphenyl)-4-methoxybenzene-1 ,3-disulfonamide
Figure imgf000051_0001
(a) 4-Methoxybenzene-1 ,3-disulfonyl dichloride
A mixture of 4-methoxybenzenesulfonyl chloride (1.0 g, 4.8 mmol) and chloro- sulfonic acid (5 mL) was heated at 80 0C for 2 h, cooled to rt, poured on ice and extracted with CHCI3. The combined extracts were dried over Na2SO4, concentrated and the residue crystallised from benzene. Yield of the sub-title compound: 450 mg (30%). (b) Λ/^Λ^-BisO-chloro^-methylphenvD^-methoxybenzene-I .S-disulfonamide A mixture of 4-methoxybenzene-1 ,3-disulfonyl dichloride (100 mg, 0.33 mmol; see step (a) above), 3-chloro-2-methylaniline (250 μl_; 2.1 mmol) and CHCI3 (5 mL) was stirred at rt for 4 h. Water was added and the mixture was extracted with EtOAc. The combined extracts were washed with HCI (aq, 4%), dried over Na2SO4 and concentrated. The residue was purified by chromatography to afford 120 mg (70%) of the title compound.
200 MHz 1H-NMR (DMSO-c/6, ppm) δ 9.91 (1 H, s) 9.86 (1 H, s) 7.93 (1 H, d, J = 2.5 Hz) 7.74 (1 H, dd, J = 8.8, 2.5 Hz) 8.38 (1 H, d, J = 8.9 Hz) 7.32 (1 H, dd, J = 8.0, 1.1 Hz) 7.30 (1 H, dd, J = 8.0, 1.1 Hz) 7.11 (1H, dd, J = 8.0, 8.0 Hz) 7.05 (1 H, dd, J = 8.0, 8.0 Hz) 6.93 (1 H, dd, J - 8.0, 1.0 Hz) 6.70 (1 H, dd, J = 8.0, 0.9 Hz) 3.96 (3H, s) 2.18 (3H, s) 1.94 (3H, s).
Example 2 Λ/.Λ^-BisQ-chloro^-methylphenylM-hvdroxybenzene-I .S-disulfonamide
Figure imgf000052_0001
BBr3 (1 M in CH2CI2, 230 μl_, 0.23 mmol) was added to a mixture of Λ/'^-bis- (3-chloro-2-methylphenyl)-4-methoxybenzene-1 ,3-disulfonamide (60 mg, 0.12 mmol; see Example 1 , step (b)) and CH2CI2 (5 mL) and the mixture was stirred at rt for 24 h. MeOH (5 mL) was added and the mixture was stirred for 30 min at rt and concentrated. The residue was dissolved in EtOAc, washed with NaHCO3 (aq, 5%), brine and dried over Na2SO4. The mixture was concentrated to afford 38 mg of the title compound (65% yield).
200 MHz 1H-NMR (DMSO-Cf6, ppm) δ 12.18 (1 H, s) 9.75 (2H, s) 7.85 (1 H, d, J = 2.4 Hz) 7.55 (1 H, dd, J = 8.8, 2.4 Hz) 7.34-7.25 (2H, m) 7.15-7.02 (3H, m) 6.98 (1 H, dd, J = 8.2, 1.2 Hz) 6.70 (1 H, d, J = 7.9 Hz) 2.23 (3H, s) 1.93 (3H, s). Example 3
N1, N3-Bis(3-chloro-2-methylphenvD^-hvdroxy-S-methoxybenzene-I .S- disulfonamide
Figure imgf000053_0001
(a) 4-Hvdroxy-6-methoxybenzene-1 ,3-disulfonyl dichloride 3-Methoxyphenol (2.0 mL, 18.2 mmol) was added in portions over 15 min to chlorosulfonic acid (10 mL) at 0 0C. After stirring at rt for 2 h, the mixture was poured on ice and extracted with CHCI3. The combined extracts were dried over Na2SO4 and concentrated to afford the sub-title compound.
(b) N^/v^-BisO-chloro^-methylphenylM-hvdroxy-e-methoxybenzene-I .S-disul- fonamide
A mixture of 4-hydroxy-6-methoxybenzene-1 ,3-disulfonyl dichloride (300 mg, 0.93 mmol; see step (a) above), 3-chloro-2-methylaniline (680 μ!_; 5.6 mmol) and acetonitrile (3 mL) was stirred at rt for 12 h, diluted with water and extracted with EtOAc. The combined extracts were washed with HCI (aq, 4%), dried over Na2SO4 and concentrated, yielding 250 mg (51%) of the title compound. 200 MHz 1H-NMR (DMSO-d6, ppm) δ 12.1 (1 H, s) 9.56 (1 H, s) 9.52 (1 H, s) 7.69 (1 H, s) 7.27 (1 H, dd, J = 8.0, 1.1 Hz) 7.26 (1 H, dd, J = 8.0, 1.1 Hz) 7.05 (1 H, dd, J = 8.0, 8.0 Hz) 7.03 (1 H, dd, J = 8.0, 8.0 Hz) 6.87 (1 H, dd, J = 8.0, 1.1 Hz) 6.85 (1 H, dd, J = 8.0, 1.1 Hz) 6.67 (1 H, s) 3.84 (3H, s) 2.19 (3H, s) 2.14 (3H, s).
Example 4
Λ/'.Λ^-BisO-fluoro-Σ-methylphenvD^-hydroxy-e-methoxybenzene-I .S- disulfonamide
Figure imgf000053_0002
The title compound was prepared from 4-hydroxy-6-methoxy-benzene-1 ,3- disulfonyl dichloride (see Example 3 step (a)) and 3-fluoro-2-methylaniline in accordance with Example 3 step (b).
200 MHz 1H-NMR (DMSO-Cf6, ppm) δ 12.1 (1 H, s) 9.51 (1 H, s) 9.46 (1 H, s) 7.71 (1 H, s) 7.11-6.90 (4H, m) 6.81-6.70 (2H, m) 6.65 (1 H, s) 3.85 (3H, s) 2.05 (3H, d, J = 2.1 Hz) 2.00 (3H, d, J = 2.1 Hz).
Example 5 4-Hvdroxy-6-methoxy-A/7,Λ/3-di(o-tolyl)benzene-1 ,3-disulfonamide
Figure imgf000054_0001
The title compound was prepared from 4-hydroxy-6-methoxybenzene-1 ,3- disulfonyl dichloride (see Example 3 step (a)) and o-toluidine in accordance with
Example 3 step (b).
200 MHz 1H-NMR (DMSO-Cf6, ppm) δ 12.0-1 1.9 (1 H, br s) 9.23 (1 H, s) 9.16 (1 H, s) 7.70 (1 H, s) 7.17-6.91 (6H, m) 6.91-6.82 (2H, m) 6.66 (1 H, s) 3.85 (3H, s) 2.15
(3H, s) 2.09 (3H, s).
Example 6
4-Chloro-Λ/',Λ/3-bis(3-chloro-2-methylphenyl)-5-hydroxybenzene-1 ,3-disulfon- amide
Figure imgf000054_0002
(a) 4-Chloro-5-hydroxybenzene-1 ,3-disulfonyl dichløride
4,5-Dihydroxybenzene-1 ,3-disu!fonic acid disodium salt (2.0 g, 6.4 mmol) was suspended in thionyl chloride (6 ml_). DMF (1 mL) was added and the mixture was heated at reflux for 7 h. The mixture was concentrated and the residue was partitioned between ice-water and CHCI3. The organic layer was separated, dried over CaCI2 and concentrated to give the sub-title compound as an oil. (b) 4-Chloro-N^N3-bis(3-chloro-2-methylphenyl)-5-hydroxybenzene-1 ,3-disulfon- amide
The title compound was prepared from 4-chloro-5-hydroxybenzene-1 ,3-disulfonyl dichloride and 3-chloro-2-methylaniline in accordance with Example 3 step (b). 200 MHz 1H-NMR (DMSO-Cf6, ppm) δ 11.66 (1 H, s) 10.32 (1 H, s) 10.10 (1 H, s) 7.60 (1 H, d, J = 2.0 Hz) 7.40-7.30 (3H, m) 7.13 (1 H, dd, J = 8.0, 8.0 Hz) 7.10 (1 H, dd, J = 8.0, 8.0 Hz) 6.88 (1 H, d, J = 8.0 Hz) 6.72 (1 H, d, J = 8.0 Hz) 2.22 (3H, s) 1.98 (3H, s).
Example 7
S-Bromo-Λ/'.Λ^-bisO-chloro^-methylbenzvD^-hvdroxybenzene-I.S-disulfon- amide
Figure imgf000055_0001
(a) 5-Bromo-2-hydroxybenzene-1 ,3-disulfonyl dichloride
A mixture of 5-bromo-2-methoxybenzene sulfonyl chloride (285 mg, 1.0 mmol) and chlorosulfonic acid (1.0 mL) was heated in a sealed tube for 12 h and poured on ice. The precipitate was filtered off, washed with water and dried to yield 180 mg (48%) of the sub-title compound.
(b) 5-Bromo-N^/v0-bis(3-chloro-2-methylbenzyl)-2-hvdroxybenzene-1.3-disulfon- amide
A mixture of 3-chloro-2-methylbenzylamine (160 μl_, 1.14 mmol), 5-bromo-2- hydroxybenzene-1 ,3-disulfonyl dichloride (200 mg, 0.54 mmol; see step (a) above) and anhydrous pyridine (3.0 mL) was stirred at rt for 12 h, poured into HCI (aq, 1 M, 20 mL) and extracted with EtOAc. The combined extracts were washed with brine and dried over Na2SO4. Concentration and purification by chromatography gave the title compound (200 mg, 61 %). 200 MHz 1H-NMR (DMSO-Cf6, ppm) δ 7.56 (2H, s) 7.33-7.17 (6H, m) 7.08 (2H, dd, J = 7.6, 7.6 Hz) 3.89 (4H, d, J = 6.0 Hz) 2.25 (6H, s). Example 8 S-Bromo-ΛΛΛ^-bis^-chlorobenzvO^-hvdroxybenzene-I .S-disulfonamide
Figure imgf000056_0001
The title compound was prepared from 5-bromo-2-hydroxybenzene-1 ,3-disulfonyl dichloride (see Example 7, step (b)) and 4-chlorobenzylamine in accordance with Example 7 step (b).
200 MHz 1H-NMR (DMSO- 6, ppm) δ 7.50 (2H, s) 7.35 (2H, t, J = 6.0 Hz) 7.28- 7.27 (8H, m) 3.86 (4H, d, J = 6.0 Hz).
Example 9
/v^/v^-Bis(3-chloro-2-methylbenzyl)-2-hvdroxybenzene-1 ,3-disulfonamide
Figure imgf000056_0002
n-BuLi (2.5 M in hexanes, 460 μl_, 1.15 mmol) was added over 5 min to 5-bromo- N1, Λ/3-bis(3-chloro-2-methylbenzyl)-2-hydroxybenzene-1 ,3-disulfon-amide (100 mg, 0.16 mmol; see Example 7, step (b)) in THF (4.0 mL) at -78 0C. After stirring for 15 min at -78 0C, the mixture was allowed to warm to -40 0C. NH4CI (aq, sat, 5.0 mL) was added and the mixture was allowed to warm to rt. An additional portion of NH4CI (aq, sat, 20 mL) was added and the mixture was extracted with EtOAc. The combined extracts were washed with brine and dried over Na2SO4. Concentration and purification by chromatography gave the title compound (39 mg, 46%).
200 MHz 1H-NMR (DMSO-Cf6, ppm) δ 8.1-7.9 (2H, br s) 7.80 (2H, d, J = 7.4 Hz) 7.40-7.04 (6H, m) 6.86 (1 H, t, J = 7.4 Hz) 4.07 (4H, s) 2.27 (6H, s). Example 10
N^/v^-Bis(3-fluoro-2-methylphenyl)-2-hvdroxybenzene-1 ,3-disulfonamide
Figure imgf000057_0002
(a) δ-Bromo-Λ/^.Λ^-bisO-fluoro^-methylphenvD^-hydroxybenzene-I .S-disulfon- amide
The sub-title compound was prepared in accordance with Example 7, step (b) from 5-bromo-2-hydroxybenzene-1 ,3-disulfonyl dichloride and 3-fluoro-2- methylaniline (47% yield).
10 (b) N^Λ/%is(3-Fluoro-2-methylphenyl)-2-hvdroxybenzene-1 ,3-disulfonamide The title compound was prepared from 5-bromo-Λ/f,Λ/3-bis(3-fluoro-2- methylphenyl)-2-hydroxybenzene-1 ,3-disulfonamide (see step (a) above) in accordance with Example 9.
200 MHz 1H-NMR (DMSO-Cf6, ppm) δ 7.59 (2H, d, J = 7.7 Hz) 7.08-6.88 (4H, m)
15 6.81-6.76 (2H, m) 6.48 (1 H, t, J = 7.7 Hz) 2.14 (6H, d, JH.F=1.8 Hz).
Example 11
Λ^-O-Chloro^-methylphenvD-Λ/^-chlorobenzvπ^-hydroxy-Λ^-methylbenz-ene-
1 ,3-disulfonamide
20.
Figure imgf000057_0001
(a) Λ/-(3-Chloro-2-methylphenyl)formamide
Formic acid (1.2 ml_, 31.8 mmol) was added dropwise at 0 0C to a mixture of 3-chloro-2-methylaniline (2.6 ml_, 21.2 mmol), 1-(3-dimethylaminopropyl)-3-ethyl- carbodiimide hydrochloride (6.1 g, 31.8 mmol) and CH2CI2 (45 ml_). After stirring
25 at rt for 12 h the mixture was washed with HCI (aq, 0.1 M), brine and dried over Na2SO4. Concentration and recrystallisation from EtOAc-petroleum ether afforded 3.43 g (95%) of the sub-title compound. (b) (3-Chloro-2-methylphenyl)methanamine
Borane-tetrahydrofuran (1 M in THF, 61 mL, 61 mmol) was added dropwise to Λ/-(3-chloro-2-methylphenyl)formamide (3.43 g, 20.2 mmol; see step (a) above) in THF (25 mL) at -40 0C. The mixture was allowed to warm to rt and HCI (aq, 0.1 M) was added. The mixture was extracted with MeOfBu and the combined extracts were washed with water and brine, dried over Na2SO4 and concentrated. The residue was dissolved in Et2O (30 mL) and HCI (4 M in dioxane, 5.5 mL) was added. The precipitate was collected and dissolved in acetonitrile (5 mL). NaOH (aq, 2 M, 15 mL) was added and the mixture was extracted with MeOfBu. The combined extracts were washed with water, brine and dried over Na2SO4. Concentration and vacuum distillation afforded the sub-title compound (2.5 g, 79% yield) as a colourless oil.
(c) 5-Bromo-Λ/-(3-chloro-2-methylphenyl)-2-methoxy-Λ/-methylbenzenesulfon- amide
A mixture of 5-bromo-2-methoxybenzenesulfonyl chloride (1.0 g, 3.5 mmol) and (3-chloro-2-methylphenyl)methanamine (1.4g, 8.8 mmol; see step (b) above) in acetonitrile (10 mL) was heated at 90 0C for 18 h. The mixture was partitioned between HCI (aq, 1 M) and EtOAc. The layers were separated and the aqueous layer extracted with EtOAc. The combined organic phases were washed with HCI (aq, 1 M), brine and dried over Na2SO4. Concentration and purification by chromatography afforded the sub-title compound (700 mg, 50%).
(d) /v^-O-Chloro^-methylphenvD-A/^-chlorobenzvn^-methoxy-A^-methyl- benzene-1 ,3-disulfonamide n-BuLi (2.5 M in hexanes, 400 μL, 1.0 mmol) was added over 5 min to 5-bromo- Λ/-(3-chloro-2-methylphenyl)-2-methoxy-Λ/-methylbenzenesulfonamide (360 mg, 0.89 mmol; see step (c) above) in THF (6 mL) at -78 0C. After stirring at -78 0C for 1 h, a stream of SO2 (g) was passed through the mixture for 20 min while keeping the temperature at -78 0C. The mixture was allowed to warm to rt, after which sulfuryl chloride (80 μL, 1.0 mmol) was added and the mixture was left to stir at rt for an additional 12 h. 4-Chlorobenzylamine (440 μL, 3.6 mmol) in THF (2 mL) was added and the mixture was heated at reflux for 6 h. After cooling, the mixture was partitioned between HCI (aq, 1 M) and EtOAc. The aqueous layer was extracted with EtOAc and the combined extracts were washed with brine and dried over Na2SO4. Concentration and purification by chromatography afforded the sub-title compound (70 mg, 15%).
(e) Λ/3-(3-Chloro-2-methylpheny[)-Λ/r-(4-chlorobenzyl)-4-hvdroxy-Λ/3-methyl- benzene-1 ,3-disulfonamide
The title compound was prepared from Λ/3-(3-chloro-2-methylphenyl)-Λ/'-(4- chlorobenzylH-methoxy-Λ^-methylbenzene-i ,3-disulfonamide (see step (d) above) in accordance with Example 2.
400 MHz 1H-NMR (DMSO-d6, ppm) δ 8.10 (1 H, t, J = 6.2 Hz) 7.82-7.78 (2H, m)
7.39 (1 H1 dd J = 8.1 , 0.7 Hz) 7.33-7.29 (2H, m), 7.21-7.16 (2H, m) 7.15-7.08 (2H, m) 6.84 (1 H, d, J = 8.1 Hz) 3.81 (2H, d, J = 5.9 Hz) 3.25 (3H, s) 2.28 (3H, s).
Example 12 Λ/7,Λ/3-Bis(3-chloro-2-methylphenyl)-4,6-dihvdroxybenzene-1 ,3-disulfonamide
Figure imgf000059_0001
BBr3 (1 M in CH2CI2, 5.0 ml_, 5.0 mmol) was added dropwise at rt to a mixture of Λ/t,Λ/3-bis(3-chloro-2-methylphenyl)-4-hydroxy-6-methoxybenzene-1 ,3-disulfon- amide (180 mg, 0.34 mmol; see Example 3) and CH2CI2 (4.0 ml_). The mixture was left at rt for 72 h. MeOH (10 ml_) was added and the mixture was concentrated. The residue was treated with petroleum ether and the resulting solid was collected to afford the title compound (125 mg, 71 % yield). 200 MHz 1H-NMR (DMSO-d6, ppm) δ 11.9-11.2 (2H, br s) 9.8-9.0 (2H1 br s) 7.61 (1 H, s) 7.29-7.21 (2H, m) 7.03 (2H, dd, J = 8.0, 8.0 Hz) 6.92-6.84 (2H, m) 6.62 (1 H1 s) 2.18 (6H1 s). Example 13 ^/v^-Bis(3-fluoro-2-methylphenyl)-4,6-dihvdroxybenzene-1 ,3-disulfonamide
Figure imgf000060_0001
The title compound was prepared from Λ/7,Λ/3-bis(3-fluoro-2-methylphenyl)-4- hydroxy-6-methoxybenzene-1 ,3-disulfonamide (see Example 4) in accordance with Example 12.
20O MHz 1H-NMR (DIvISO-Cf6, ppm) δ 12.0-11.0 (2H1 br s) 10.0-8.7 (2H, br s) 7.63 (1 H, s) 7.09-6.89 (4H, m) 6.77 (2H, dd, J = 7.4, 1.3 Hz) 6.60 (1 H, s) 2.04 (6H, d, J = 6.0 Hz).
Example 14 4,6-Dihvdroxy-Λ/f,Λ/3-di(o-tolyl)benzene-1 ,3-disulfonamide
Figure imgf000060_0002
The title compound was prepared from 4-hydroxy-6-methoxy-Λ/', Λ^-di(o-tolyl)- benzene-1 ,3-disulfonamide (see Example 5) in accordance with Example 12. 200 MHz 1H-NMR (DMSOd6, ppm) δ 11.8-1 1.1 (2H, br s) 9.4-8.7 (2H, br s) 7.61 (1 H, s) 7.15-6.85 (8H, m) 6.59 (1 H, s) 2.15 (6H, s). ESI-MS (m/z): 447 [M-H]".
Example 15
Λ/'.Λ/^BisO-chloro^-methylphenylM-hvdroxy-S-fpyrrolidine-i-carbonvDbenz- ene-1 ,3-disulfonamide
Figure imgf000061_0001
(a) 4-Hydroxy-5-(pyrrolidine-1-carbonyl)benzene-1 ,3-disulfonyl dichloride
A mixture of 1-(2-hydroxybenzoyl)-pyrrolidine (1.5 g, 7.8 mmol) and chlorosulfonic acid (8.0 ml.) was heated to 150 0C, heated at 150 0C for 20 min, cooled and poured on crushed ice. Filtration and drying of the precipitate in vacuo over P2O5 afforded the sub-title compound (480 mg, 16% yield).
(b) Λ/^./v^-BisO-chloro^-methylphenylM-hvdroxy-δ-fpyrrolidine-i-carbonyl)- benzene-1 ,3-disulfonamide
The title compound was prepared from 4-hydroxy-5-(pyrrolidine-1- carbonyl)benzene-1 ,3-disulfonyl dichloride (see step (a) above) and 3-chloro-2- methylaniline in accordance with Example 7, step (b).
200 MHz 1H-NMR (DMSOd6, ppm) δ 9.47-9.34 (1 H, br s) 7.73 (1 H, s) 7.29-6.97 (6H, m) 6.82 (1 H, d, J = 8.0 Hz) 3.45-3.34 (2H, m, overlapped with water) 3.08- 2.96 (2H, m) 2.30 (3H, s) 1.91 (3H, s)1.83-1.72 (4H, m). ESI-MS (m/z): 596 [M-H]".
Example 16 3,5-Bis(Λ/-(3-chloro-2-methylphenyl)sulfamoyl)-Λ/.A/-diethyl-2-hvdroxybenzamide
Figure imgf000061_0002
The title compound was prepared from Λ/,Λ/-diethylsalicylamide and chlorosulfonic acid in accordance with Example 15, step (a), followed by reaction with 3-chloro- 2-methylaniline in accordance with Example 7, step (b).- 200 MHz 1H-NMR (DMSO-Cf6, ppm) δ 9.19 (1 H, s) 7.56 (1H, d, J = 2.6 Hz) 7.24- 7.16 (2H, m) 7.06-6.95 (4H, m) 6.84-6.79 (1 H, m) 3.30-3.18 (2H, m) 3.09-2.97 (2H, m) 2.31 (3H, s) 1.95 (3H, s) 1.10-0.95 (3H, m) 0.92-0.78 (3H, m). ESI-MS (m/z): 598 [M-H]".
Example 17
N^Λ^-Bis(3Λ-difluorophenyl)-4-hydroxybenzene-1.3-disulfonamide
Figure imgf000062_0001
The title compound was prepared from 4-methoxybenzene-1 ,3-disulfonyl dichloride (see Example 1 step (a)) and 3,4-difluoroaniline in accordance with Example 7 step (b), followed by demethylation in accordance with Example 2. 200 MHz 1H-NMR (DMSO-Cf6, ppm) δ 12.4-11.8 (1 H, br s) 10.41 (1 H1 S) 8.07 (1 H, d, J=2.4 Hz) 7.69 (1 H, dd, J=8.6, 2.4 Hz) 7.36-7.14 (2H, m) 7.09-6.75 (5H, m)
Example 18 Λ/7,Λ/3-Bis(4-Chloro-2-methylphenyl)-4-hvdroxybenzene-1 ,3-disulfonamide
Figure imgf000062_0002
The title compound was prepared from 4-methoxybenzene-1 ,3-disulfonyl dichloride (see Example 1 step (a)) and 4-chloro-2-methylaniline in accordance with Example 7 step (b), followed by demethylation in accordance with Example 2.
200 MHz 1H-NMR (DMSO-d6, ppm) δ 9.8-9.7 (1 H, br s) 7.82 (1 H, d, J=2.4 Hz) 7.58 (1 H, dd, J=8.6, 2.4 Hz) 7.17-6.94 (7H, m) 2.10 (3H, s) 1.72 (3H, s) Example 19
Λ/^Λ^-BisO-Chloro^-methylbenzylM-hydroxy-θ-methoxybenzene-I .S- disulfonamide
Figure imgf000063_0001
The title compound was prepared from 4-hydroxy-6-methoxybenzene-1 ,3- disulfonyl dichloride (see Example 3 step (a)) and 3-chloro-2-methylbenzylarnine in accordance with Example 7 step (b).
200 MHz 1H-NMR (DMSO-d6, ppm) δ 11.69 (1 H, s) 7.95 (1 H, s) 7.71-7.64 (1 H, m) 7.35-7.01 (6H, m) 6.51 (1 H, s) 3.98-4.08 (4H, m) 3.80 (3H, s) 2.25 (6H, s)
Example 20
Λ^.Λ^-BisQ-Chloro^-methylphenvD^-hvdroxypyridine-S.δ-disulfonamide; or ΛΛΛ^-Bis (3-chloro-2-methylphenyl)pyhdone-3,5-disulfonamide
Figure imgf000063_0002
The title compound was prepared by heating pyridone with chlorosulfonic acid at 150 0C and then treating the intermediate disulfonyl chloride with 3-chloro-2- methylaniline in accordance with Example 7 step (b). As depicted above, the title compound may exist as tautomers.
200 MHz 1H-NMR (DMSO-d6, ppm) δ 13.3-12.9 (1 H, br s) 9.93 (1 H, s) 9.87 (1 H, s) 8.06 (1 H, d, J=2.8 Hz) 7.87 (1 H, d, J=2.8 Hz) 7.35 (2H, d, J=8.0 Hz) 7.17 (1 H, dd, J=8.0, 8.0 Hz) 7.10 (1 H, dd, J=8.0 Hz) 7.07 (1 H, d, J=8.0 Hz) 6.71 (1 H, d, J=8.0 Hz) 2.27 (3H, s) 2.06 (3H, s) Example 21 ^Amino-Λ/'.Λ^-bisQ-chloro^-rriethylphenvD-S-nitrobenzene-I .S-disulfonamide
Figure imgf000064_0001
The title compound was prepared by heating 2-nitroaniline with chlorosulfonic acid and treating the formed disulfonyl chloride with 3-chloro-2-methylaniline in accordance with Example 7 step (b).
200 MHz 1H-NMR (DMSO-Cf6, ppm) δ 10.56 (1H, s) 9.95 (1H, s) 8.37 (1H, d, J=2.4 Hz) 8.13-7.87 (2H, br s) 7.96 (1 H, d, J=2.4 Hz) 7.36 (1 H, dd, J=8tt, 1.0 Hz) 7.33 (1 H, dd, J=8.0, 1.0 Hz) 7.11 (1 H, dd, J=8.0, 8.0 Hz) 7.07 (1 H, dd, J=8.0, 8.0 Hz) 6.95 (1 H, dd, J=8.0, 1.1 Hz) 6.70 (1 H, dd, J=8.0, 1.0 Hz) 2.22 (3H, s) 2.09 (3H, s).
Example 22 Λ/^Λ^-bisO-Chloro^-methylphenylM.S-diaminobenzene-I .S-disulfonamide
Figure imgf000064_0002
The title compound was prepared by reducing 4-amino-Λ/r,Λ/3-bis(3-chloro-2- methylphenyl)-5-nitrobenzene-1 ,3-disulfonamide (see Example 21) with Fe / NH4CI.
200 MHz 1H-NMR (DMSO-c/6, ppm) δ 9.85 (1 H, s) 9.49 (1 H, s) 7.27 (2H, d, J=7.8 Hz) 7.17 (1 H, s) 7.14-6.92 (3H, m) 6.76 (1 H, s) 6.75 (1 H, d. J=7.8 Hz) 6.07 (2H, s) 5.35 (2H, s) 2.16 (3H, s) 2.03 (3H, s) Example 23 4-Bromo-N^Λ/3-bis(3-chloro-2-methylphenyl)benzene-1 ,3-disulfonamide
Figure imgf000065_0001
The title compound was prepared by heating bromobenzene with chlorosulfonic acid for 15 min at 150 0C and treating the formed disulfonyl chloride with 3-chloro- 2-methylaniline in accordance with Example 7 step (b).
200 MHz 1H-NMR (DMSO-d6, ppm) δ 10.4-10.3 (1 H, br s) 10.2-10.0 (1 H, br s) 8.12 (1 H, d, J=2.2 Hz) 8.08 (1 H, d, J=8.3 Hz) 7.65 (1 H, dd, J=8.3, 2.2 Hz) 7.39- 7.27 (2H, m) 7.16-7.00 (2H, m) 6.84 (1 H, d, J=7.9 Hz) 6.68 (1 H, d, J=7.7 Hz) 2.18 (3H, s) 1.98 (3H, s).
Example 24 2,4-BisfΛ/-(3-chloro-2-methylphenyl)sulfamovnbenzoic acid
Figure imgf000065_0002
The title compound was prepared by heating 4-bromo-Λ/',Λ/3-bis(3-chloro-2- methylphenyl)benzene-1 ,3-disulfonamide (see Example 23) with CuCN in NMP at 150 °C followed by hydrolysis with 2M aqueous NaOH in dioxane. 200 MHz 1H-NMR (DMSOd6, ppm) δ 12.5-11.5 (1 H, br s) 10.0-9.9 (1 H, br s) 7.87-7.77 (2H, m) 7.74-7.67 (1 H, m) 7.35-7.21 (2H, m) 7.09-6.95 (2H, m) 6.81- 6.72 (1 H, m) 6.68-6.61 (1 H, m) 2.25 (3H, s) 1.98 (3H, s). Example 25 Λ/'.Λ^-BisO-chloro-Z-methylphenvD^-fhydroxymethvDbenzene-I .S-disulfonamide
Figure imgf000066_0001
The title compound was prepared by reducing 2,4-bis(Λ/-(3-chloro-2-methyl- phenyl)sulfamoyl)benzoic acid (See Example 24) with BH3 XTHF. 200 MHz 1H-NMR (DMSO-Cf6, ppm) δ 10.2-9.9 (1H, br s) 8.02-7.92 (2H, m) 7.83 (1 H, dd, J=8.2, 2.1 Hz) 7.34-7.26 (2H, m) 7.06 (2H, dd, J=8.1 , 8.1 Hz) 6.79-6.67 (2H, m) 6.1-5.5 (1 H, br s) 4.86 (2H, s) 2.07 (3H, s) 2.00 (3H, s).
Example 26(a) δ-Bromo-Λ/^.Λ^-bisO-chloro^-methylphenylM-hydroxybenzene-I .S-disulfon- amide; and
Example 26(b)
Λ/^Λ^-BisO-chloro^-methylphenvπ^-hvdroxy-δ^methylamino^enzene-I .S- disulfonamide
Figure imgf000066_0002
The title compound was prepared by heating 2-bromoanisole with chlorosulfonic acid and treating the formed disulfonyl chloride with 3-chloro-2-methylaniline in accordance with Example 23, followed by treating the so formed S-bromo-Λ/'./V3- bis(3-chloro-2-methylphenyl)-4-hydroxybenzene-1 ,3-disulfonamide with Cu / CuCI / MeNH2 ΗCI at 70 0C for 48h.
200 MHz 1H-NMR (DMSO-Cy6, ppm) δ 9.1-9.0 (1 H, br s) 7.21 (1 H, dd, J=7.9, 1.1 Hz) 7.12 (1 H, dd, J=7.6, 1.5 Hz) 7.05-6.98 (2H, m) 6.97-6.95 (1 H, m) 6.93-6.84 (2H, m) 6.14 (1 H, d, J=2.4 Hz) 5.6-4.9 (1 H, br s) 2.54 (3H, s) 2.29 (3H, s) 1.97 (3H, s). Example 27 Λ^-O-Chloro-Σ-methylphenvD^-hvdroxy-Λ/'-phenylbenzene-lS-disulfonamide
Figure imgf000067_0002
The title compound was prepared according to the following scheme:
Figure imgf000067_0003
200 MHz 1H-NMR (DMSO-c/6, ppm) δ 12.2-11.9 (1 H, br s) 10.13 (1 H, s) 9.9-9.5 (1 H, br s) 7.90 (1 H, d, J=2.4 Hz) 7.70 (1 H, dd, J=8.6, 2.4 Hz) 7.29 (1 H, dd, J=8.0, 1.2 Hz) 7.23-6.86 (8H, m) 2.17 (3H, s).
The title compounds of Examples 28 to 32 were prepared in accordance with Example 27 using the appropriately substituted aniline.
Example 28
Λ^-O-Chloro^-methylphenvD-Λ/Vs.δ-dichlorophenylM-hvdroxybenzene-I .S- disulfonamide
Figure imgf000067_0001
200 MHz 1H-NMR (DMSOd6, ppm) δ 12.4-12.1 (1 H, br s) 10.74 (1 H, s) 9.9-9.5 (1 H, br s) 7.91 (1 H, d, J=2.5 Hz) 7.82 (1 H, dd, J=8.6, 2.5 Hz) 7.28-7.22 (2H, m) 7.16 (1 H, d, J=8.6 Hz) 7.04-6.95 (3H, m) 6.86 (1 H, dd, J=8.0, 1.2 Hz) 2.17 (3H, s).
Example 29
Λ/'.Λ^-BisO-chloro^-methylphenvD^-hvdroxy-Λ/^-methylbenzene-I .S- disulfonamide
Figure imgf000068_0001
200 MHz 1H-NMR (DMSO-Cf6, ppm) δ 12.4-12.2 (1H, br s) 10.0-9.7 (1 H, br s) 7.70 (1 H, dd, J=8.6, 2.4 Hz) 7.63 (1 H, d, J=2.4 Hz) 7.42 (1 H, dd, J=8.0, 0.8 Hz) 7.30 (1 H, dd, J=8.0, 1.2 Hz) 7.21 (1 H, d, J=8.6 Hz) 7.14 (1 H, dd, J=8.0, 8.0 Hz) 7.05- 6.94 (2H, m) 6.37-6.31 (1 H, m) 2.90 (3H, s) 2.24 (6H, s).
Example 30 Methyl 3-(3-fΛ/-(3-chloro-2-methylphenyl)sulfamoyl]-4-hvdroxyphenylsulfon- amido)-2-methylbenzoate
Figure imgf000068_0002
200 MHz 1H-NMR (DMSO-C6, ppm) δ 12.2-12.0 (1 H, br s) 9.8-9.5 (2H, m) ) 7.84 (1 H, d, J=2.4 Hz) 7.58-7.48 (2H, m) 7.26 (1 H, dd, J=7.8, 1.1 Hz) 7.15-7.00 (3H, m) 6.97-6.83 (2H, m) 3.78 (3H, s) 2.20 (3H, s) 2.05 (3H, s). Example 31 N1-(3-Chloro-2-methylphenyl)-4-hvdroxy-N3-(4-trifluoromethylphenyl)benzene-1,3- disulfonamide
Figure imgf000069_0001
200 MHz 1H-NMR (DMSO-d6, ppm) δ 12.3-11.8 (1H, br s) 10.74 (1H, s) 10.0-9.3 (1H, br s) 7.94-7.90 (1H, m) 7.84-7.75 (1H, m) 7.59-7.50 (2H, m) 7.24-7.05 (4H, m) 6.97 (1H, dd, J=8.0, 8.0 Hz) 6.86 (1H, dd, J=1.2, 7.9 Hz) 2.13 (3H, s).
Example 32 N1-(3-Chloro-2-methylphenyl)-Λ/1-(3,4-difluorophenvl)-4-hvdroxybenzene-1,3- disulfonamide
Figure imgf000069_0002
200 MHz 1H-NMR (DMSO-d6, ppm) δ 12.8-11.4 (1H, br s) 10.5-9.31 (1H, br s) 10.3 (1H, s) 7.85 (1H, d, J=2.2 Hz) 7.71 (1H, dd, J=8.6, 2.6 Hz) 7.31-7.17 (2H, m) 7.11-6.84(4H, m) 6.76-6.67 (1 H, m) 2.15 (3H, s).
Example 33
N7.Λ/3-Bis(3-chloro-2-methylphenyl)-5-cvano-4-hvdroxybenzene-1 ,3-disulfon- amide
Figure imgf000070_0001
The title compound was prepared by heating 2-bromoanisole with chlorosulfonic acid at 150 0C, treating the formed disulfonyl chloride with 3-chloro-2-methyl- aniline followed by heating with CuCN in NMP at 150 0C.
200 MHz 1H-NMR (DMSO-Cf6, ppm) δ 9.3-9.2 (1 H, br s) 7.61-7.57 (1 H, m) 7.39- 7.35 (1 H, m) 7.29-7.18 (2H, m) 7.12-6.91 (3H, m) 6.75-6.67 (1 H, m) 2.29 (3H, s) 1.99 (3H1 m).
Example 34 Λ/*-(3-Chloro-2-methylphenyl)- /^-(SΛ-dichloro^-methylphenylM-hvdroxyben- zene-1 ,3-disulfonamide
Figure imgf000070_0002
The title compound was prepared according to the following scheme:
Figure imgf000070_0003
200 MHz 1H-NMR (DMSOd6, ppm) δ 9.76 (1 H, br s) 7.85 (1 H, d, J=2.4 Hz) 7.56 (1 H, dd, J=8.6, 2.4 Hz) 7.45-7.37 (1 H, m) 7.34-7.26 (1 H, m) 7.14-6.99 (3H, m) 6.77-6.68 (1 H, m) 2.28 (3H, s) 1.90 (3H, s).
Example 35
Λ/7-(3-Chloro-2-methylphenyl)-4-hvdroxy-N3-phenylbenzene-1 ,3-disulfonamide
Figure imgf000071_0001
The title compound was prepared according to the following scheme:
Figure imgf000071_0002
200 MHz 1H-NMR (DMSO-c/6, ppm) δ 12.2-11.9 (1 H, br s) 10.4-10.0 (1 H, br s) 9.78 (1 H, s) 8.08 (1 H, d, J=2.4 Hz) 7.47 (I H1 dd, J=8.6, 2.4 Hz) 7.34-7.26 (1 H, m) 7.24-6.93 (7H, m) 6.74-6.66 (1 H, m) 1.96 (3H, s).
The title compounds of Examples 36 to 74 were prepared in accordance with Example 35 using the appropriately substituted aniline or amine. Example 36
ΛΛΛ^-Bis O-chloro^-methylphenvD-^-hvdroxy-Λ^-methylbenzene-I .S-disulfon- amide
Figure imgf000072_0001
200 MHz 1H-NMR (DMSO-Cf6, ppm) δ 9.8-9.7 (1H, br s) 7.77 (1 H, d, J=2.4 Hz) 7.63 (1 H, dd, J=8.6, 2.4 Hz) 7.49-7.41 (1 H, m) 7.35-7.28 (1 H, m) 7.20-7.05 (3H, m) 6.89-6.82 (1 H, m) 6.79-6.72 (1 H, m) 3.25 (3H, s) 2.29 (3H, s) 2.03 (3H, s).
Example 37
Λ/?-(3-Chloro-2-methylphenyl)-Λ/3-(2-chloro-4-pyridinyl)-4-hvdroxybenzene-1 ,3- disulfonamide
Figure imgf000072_0002
200 MHz 1H-NMR (DMSO-Cf6, ppm) δ 12.4-12.3 (1 H, br s) 11.4-11.3 (1 H, br s) 9.88 (1 H, s) 8.22 (1 H, d, J=2.4 Hz) 8.13 (1 H, d, J=5.6 Hz) 7.57 (1 H, dd, J=8.6, 2.4 Hz) 7.36-7.28 (1 H, m) 7.11-6.98 (4H, m) 6.82-6.74 (1 H, m) 2.01 (3H, s).
Example 38 Λ/7-(3-Chloro-2-methylphenyl)- A^-O^-difluorophenvD^-hvdroxybenzene-I .S- disulfonamide
Figure imgf000072_0003
200 MHz 1H-NMR (DMSO-d6, ppm) δ 9.6-9.1 (1H, br s) 7.83-7.75 (1 H, m) 7.32- 7.14 (3H, m) 7.12-6.92 (2H, m) 6.92-6.73 (2H, m) 6.54 (1 H, d, J=8.8 Hz) 1.88 (3H, s).
Example 39
Methyl 3-(5-(Λ/-(3-chloro-2-methylphenyl)sulfamoyl)-2-hvdroxyphenylsulfonami- do)-2-methylbenzoate
Figure imgf000073_0001
200 MHz 1H-NMR (DMSOd6, ppm) δ 9.7-9.5 (1 H, br s) 7.79 (1 H, d, J=2.4 Hz) 7.58-7.50 (1 H, m) 7.46 (1 H, dd, J=8.6, 2.4 Hz) 7.32-7.24 (1 H, m) 7.23-7.14 (2H, m) 7.09-6.90 (2H, m) 6.77-6.70 (1 H, m) 3.80 (3H, s) 2.35 (3H, s) 1.94 (3H, s).
Example 40
A/^O-Chloro-Σ-methylphenvD-Λ^^-triifluorophenyD^-hydroxybenzene-I .S- disulfonamide
Figure imgf000073_0002
200 MHz 1H-NMR (DMSO-Cf6, ppm) δ 12.3-11.9 (1 H, br s) 11.1-10.6 (1 H, br s) 9.81 (1 H, s) 8.19 (1 H, d, J=2.4 Hz) 7.62-7.52 (1 H, m) 7.47 (1 H, dd, J=8.6, 2.4 Hz) 7.33-7.22 (3H, m) 7.05-6.93 (2H, m) 6.79-6.71 (2H, m) 1.91 (3H, s). Example 41 Λ/VS-Chloro^-methylphenvD-Λ^-cvclohexyM-hvdroxybenzene-I .S-disulfonamide
Figure imgf000074_0001
200 MHz 1H-NMR (DMSO- 6, ppm) δ 11.9-11.8 (1 H, br s) 9.80 (1 H, s) 8.00 (1 H, d, J=2.4 Hz) 7.56 (1 H, dd, J=8.6, 2.4 Hz) 7.45-7.28 (2H, m) 7.17-7.02 (2H, m) 6.90-6.83 (1 H, m) 2.97-2.79 (1 H, m) 2.06 (3H, s) 1.7-1.4 (5H, m) 1.3-0.9 (5H, m).
Example 42 Λ/VS-Chloro^-methylphenvD-Λ^^-methylcvclohexylM-hvdroxybeπzene-I .S- disulfonamide
Figure imgf000074_0002
200 MHz 1H-NMR (DMSO-cfe, ppm) δ 1 1.8 (1 H, s) 9.79 (1 H, s) 7.99 (0.6H, d, J=2.4 Hz, major diastereomer) 7.93 (0.4H, d, J=2.4 Hz, minor diastereomer) 7.59 (0.4H, dd, J-8.6, 2.4 Hz, minor diastereomer) 7.55 (0.6H, dd, J=8.6, 2.4 Hz, major diastereomer) 7.44-7.02 (4H, m) 6.90-6.85 (1 H, m) 3.08-2.98 (1 H, m) 2.07 (2H, s, major diastereomer) 2.06 (1 H, s, minor diastereomer) 1.68-0.83 (9H, m) 0.73 (2H, d, J=6.4 Hz, major diastereomer) 0.71 (1 H, d, J=6.4 Hz, minor diastereomer). Example 43
Λ/^-O-Chloro^-methylphenvD-Λ^-fS-chloro^-methylphenylH-hydroxybenzene-
1,3-disulfonamide
Figure imgf000075_0001
200 MHz 1H-NMR (DMSO-c/6, ppm) δ 12.19 (1H, s) 9.78 (1H, s) 9.70 (1H, s) 7.89 (1H, d, J=2.4 Hz) 7.56 (1H, dd, J=8.8, 2.4 Hz) 7.29 (1H, d, J=8.0 Hz) 7.21-7.07 (4H, m) 7.02 (1H, dd, J=8.0, 8.0 Hz) 6.71 (1H, d, J=8.0 Hz) 2.14 (3H, s) 1.94 (3H, s)
Example 44
Λ/^-O-Chloro^-methylphenvD-Λ^-O-pyridylM-hvdroxybenzene-I.S-disulfonamide
Figure imgf000075_0002
200 MHz 1H-NMR (DMSO-Cf6, ppm) δ 9.6-9.4 (1H, br s) 8.26 (1H, d, J=2.4 Hz) 8.16 (1H, dd, J=4.6, 1.4 Hz) 7.87 (1H, d, J=2.2 Hz) 7.45-7.37 (1H, m) 7.33-7.13 (3H, m) 7.06-6.95 (1H, m) 6.76-6.60 (2H, m) 1.96 (3H, s)
Example 45 Λ^-Benzyl-Λ/'-O-chloro^-methylphenvD^-hvdroxybenzene-I.S-disulfonamide
Figure imgf000075_0003
200 MHz 1H-NMR (DMSO-d6, ppm) δ 11.9-11.8 (1H, br s) 9.75 (1H, s) 8.03-7.92 (1H, br s) 7.90 (1H, d, J=2.4 Hz) 7.56 (1H, dd, J=8.6, 2.4 Hz) 7.32-7.15 (6H, m) 7.15-7.04 (1 H, m) 7.04-6.96 (1 H, d, J=8.8 Hz) 6.88-6.79 (1 H, m) 4.00-3.90 (2H, m) 2.05 (3H, s).
Example 46
Λ/VS-Chloro^-methylphenvD-Λ^^^-dimethylcvclohexylM-hvdroxybenzene-I.S- disulfonamide
Figure imgf000076_0001
200 MHz 1H-NMR (DMSO-Cf6, ppm) δ 11.9-11.8 (1 H, br s) 9.78 (1 H, s) 7.97 (1 H, d, J=2.4 Hz) 7.55 (1 H, dd, J=8.6, 2.4 Hz) 7.40-7.26 (2H, m) 7.14-7.00 (2H, m) 6.89-6.82 (1 H, m) 2.91-2.73 (1 H, m) 2.03 (3H, s) 1.5-0.9 (8H, m) 0.80 (6H, s).
Example 47
Λ/^O-Chloro^-methylphenvD-Λ^-O-hvdroxy^-methylphenylM-hydroxybenzene-
1 ,3-disulfonamide
Figure imgf000076_0002
200 MHz 1H-NMR (DMSO-CZ6, ppm) δ 12.06 (1 H, s) 9.72 (1 H, s) 9.40 (1 H, s) 9.26 (1 H, s) 7.83 (1 H, d, J=2.4 Hz) 7.51 (1 H, dd, J=8.6, 2.4 Hz) 7.31-7.24 (1 H, m) 7.11-6.96 (2H, m) 6.85-6.74 (1 H, m) 6.68-6.57 (2H, m) 6.44-6.36 (1 H, m) 1.98 (3H, s) 1.97 (3H, s). Example 48
Λ/^O-Chloro^-methylphenvD-Λ^-fcvclohexylmethylM-hydroxybenzene-I .S- disulfonamide
Figure imgf000077_0001
200 MHz 1H-NMR (DMSO-Cf6, ppm) δ 11.9-11.8 (1 H1 br s) 9.78 (1 H, s) 7.91 (1 H, d, J=2.4 Hz) 7.59 (1 H, dd, J=8.6, 2.4 Hz) 7.40-7.33 (1 H, m) 7.29 (1 H, dd, J=8.0, 1.0 Hz) 7.10 (1 H, dd, J=8.0, 8.0 Hz) 7.06 (1 H, d, J=8.6 Hz) 6.86 (1 H, dd, J=8.0, 1.0 Hz) 2.55-2.45 (2H, m overlapped with DMSO) 2.04 (3H, s) 1.7-1.5 (5H, m) 1.4-1.2 (1 H, m) 1.2-1.0 (3H, m) 0.9-0.6 (2H, m).
Example 49 /^-(ButvD-A/^-O-chloro^-methylpheπylM-hvdroxybenzene-I .S-disulfonamide
Figure imgf000077_0002
200 MHz 1H-NMR (DMSO-Cf6, ppm) δ 11.84 (1 H, s) 9.78 (1 H, s) 7.89 (1 H, d, J=2.4 Hz) 7.61 (1 H, dd, J=8.6, 2.4 Hz) 7.35 (1 H, t, J=6.0 Hz) 7.29 (1 H, dd, J=8.0, 1.0 Hz) 7.10 (1 H, dd, J=8.0, 8.0 Hz) 7.07 (1 H, d, J=8.8 Hz) 6.91-6.83 (1 H, m) 2.72-2.59 (2H, m) 2.02 (3H, s) 1.37-1.10 (4H, m) 0.80-0.69 (3H, m).
Example 50 /vVs-Chloro-Σ-methylphenvD-Λ^-O-dimethylamino-Σ-methylphenylM- hydroxybenzene-1 ,3-disulfonamide
Figure imgf000077_0003
200 MHz 1H-NMR (DMSO-d6, ppm) δ 12.12 (1H, s) 9.76 (1H, s) 9.58 (1H, s) 7.83 (1H, d, J=2.4 Hz) 7.57 (1H, dd, J=8.6, 2.4 Hz) 7.36-6.97 (4H, m) 7.03 (1H, dd, J=8.0, 8.0 Hz) 6.89-6.76 (1H, m) 6.75-6.66 (1H, m) 2.83 (6H, s) 2.24 (3H, s) 1.97 (3H, s).
Example 51
Λ^-O-ChlorobenzvD-Λ/VS-chloro^-methylphenylM-hydroxybenzene-I.S- disulfonamide
Figure imgf000078_0001
200 MHz 1H-NMR (DMSO-Cf6, ppm) δ 11.93 (1H, s) 9.75 (1H, s) 8.17-8.00 (1H, m) 7.89 (1H, d, J=2.4 Hz) 7.58 (1H, dd, J=8.6, 2.4 Hz) 7.32-7.20 (4H, m) 7.17-6.99 (3H, m) 6.86-6.78 (1 H, m) 4.04-3.93 (2H, m) 2.04 (3H, s)
Example 52
Λ/^-ChlorobenzvD-Λ/VS-chloro^-methylphenvD^-hvdroxybenzene-I.S- disulfonamide
Figure imgf000078_0002
200 MHz 1H-NMR (DMSO-Cf6, ppm) δ 11.95 (1H, s) 9.77 (1H1 s) 8.09-7.97 (1H, m) 7.96 (1H, d, J=2.4 Hz) 7.56 (1H, dd, J=8.6, 2.4 Hz) 7.47-7.40 (1H, m) 7.37-7.20 (4H, m) 7.09 (1H, dd, J=8.0, 8.0 Hz) 7.02 (1H, d, J=8.6 Hz) 6.87-6.80 (1H, m) 4.15-4.06(2H, m) 2.04 (3H, s). Example 53
Λ^^-ChlorobenzvD-A/'-O-chloro-Σ-methylphenvO^-hydroxybenzene-I .S- disulfonamide
Figure imgf000079_0001
200 MHz 1H-NMR (DMSO-Cf6, ppm) δ 11.88 (1 H, s) 9.76 (1 H, s) 8.03 (1 H, t, J=6.2 Hz) 7.90 (1 H, d, J=2.4 Hz) 7.58 (1 H, dd, J=8.6, 2.4 Hz) 7.32-7.16 (5H, m) 7.10 (1 H, dd, J=8.0, 8.0 Hz) 7.01 (1 H, d, J=8.8 Hz) 6.89-6.81 (1 H, m) 3.95 (2H, d, J=6.2 Hz) 2.04 (3H, s).
Example 54
/^-(δ-Bromo-S-methyl^-pyridvD-Λ/^-O-chloro^-methylphenvD^-hvdroxy- benzene-1 ,3-disulfonamide
Figure imgf000079_0002
200 MHz 1H-NMR (DMSO-Cf6, ppm) δ 9.75 (1 H, br s) 8.08 (1 H, d, J=2.4 Hz) 7.83- 7.82 (1 H, m) 7.72-7.71 (1 H, m) 7.46 (1 H, dd, J=8.8, 2.4 Hz) 7.31-7.26 (1 H, m) 7.07 (1 H, dd, J=8.0 Hz) 6.94-6.82 (2H, m) 6.71-6.61 (1 H, m) 2.15 (3H, s) 2.04 (3H, s).
Example 55 Λ/3-(4-Bromo-2-methylphenyl)-Λ/7-(3-chloro-2-methylplienyl)-4-hvdroxybenzene- 1 ,3-disulfonamide
Figure imgf000079_0003
200 MHz 1H-NMR (DMSO-d6, ppm) δ 12.13 (1H, s) 9.74 (1H, s) 9.55 (1H, s) 7.84 (1H, d, J=2.4 Hz) 7.54 (1H, dd, J=8.6, 2.4 Hz) 7.40-7.34 (1H, m) 7.31-7.20 (2H, m) 7.10-7.00 (2H, m) 6.99-6.91 (1H, m) 6.70-6.63 (1H, m) 2.14 (3H, s) 1.93 (3H, s).
Example 56
/^-(fraπs^-te/t-ButylcvclohexyD-Λ/'-O-chloro^-methylphenvD^-hvdroxybenzene-
1,3-disulfonamide
Figure imgf000080_0001
200 MHz 1H-NMR (DMSOd6, ppm) δ 11.84 (1H, s) 9.76 (1H, s) 7.89 (1H, d, J=2.4 Hz) 7.61 (1H, dd, J=8.6, 2.4 Hz) 7.29 (1H, d, J=7.6 Hz) 7.24 (1H, d, J=6.6 Hz) 7.12-7.06 (2H, m) 6.87 (1H, d, J=8.0 Hz) 3.19-3.13 (1H, m) 2.02 (3H, s) 1.6- 1.5 (2H, m) 1.4-1.2 (6H, m) 0.9-0.8 (1 H, m) 0.79 (9H, s).
Example 57
Λ/3-(c/s-4-te/t-Butylcvclohexyl)-Λ/?-(3-chloro-2-methylphenyl)-4-hvdroxybenzene-
1,3-disulfonamide
Figure imgf000080_0002
200 MHz 1H-NMR (DMSO-d6, ppm) δ 11.82 (1H, s) 9.77 (1H, s) 7.98 (1H, d, J=2.4 Hz) 7.54 (1H, dd, J=8.6, 2.4 Hz) 7.40-7.32 (1H, br s) 7.29 (1H, d, J=8.0 Hz) 7.10 (1H, dd, J=8.0, 8.0 Hz) 7.03 (1H, d, J=8.6 Hz) 6.87 (1H, d, J=8.0 Hz) 2.84- 2.73 (1H, m) 2.04 (3H, s) 1.66-1.56 (4H, m) 1.23-1.09 (2H, m) 0.86-0.73 (12H, m). Example 58 N1-(3-Chloro-2-methylphenyl)-N3-[2-(1-piperidinyl)ethyl]-4-hvdroxybenzene-1,3- disulfonamide
Figure imgf000081_0001
200 MHz 1H-NMR (DMSO-c/6, ppm) δ 9.7-9.5 (1H, br s) 7.87 (1H, d, J=2.4 Hz) 7.52 (1H, dd, J=8.6, 2.4 Hz) 7.29 (1H, dd, J=8.2, 1.2 Hz) 7.11 (1H, dd, J=8.0, 8.0 Hz) 6.94-6.82 (2H, m) 3.2-2.9 (8H, m, overlapped with H20) 2.07 (3H, s) 1.8-1.6 (4H, m) 1.6-1.4(2H, m).
Example 59 N1-(3-Chloro-2-methylphenyl)-4-hvdroxy-N3-(trans-4-methylcvclohexyl)benzene- 1,3-disulfonamide
Figure imgf000081_0002
200 MHz 1H-NMR (DMSOd6, ppm) δ 9.77 (1H, s) 7.98 (1H, d, J=2.4 Hz) 7.53 (1H, dd, J=8.6, 2.4 Hz) 7.30 (1H, dd, J=8.0, 1.0 Hz) 7.09 (1H, dd, J=8.0, 8.0 Hz) 7.01 (1H, d, J=8.6 Hz) 6.86 (1H, dd, J=8.0, 1.0 Hz) 2.85-2.71 (1H} m) 2.04 (3H, s) 1.62-1.45 (4H, m) 1.3-1.0 (4H, m) 0.88-0.70 (1 H, m) 0.77 (3H1 d, J=6.4 Hz). Example 60
A/?-(3-chloro-2-methylphenyl)-4-hvdroxy-^-(c/s-4-trifluoromethylcvclohexyl)- benzene-1 ,3-disulfonamide
Figure imgf000082_0001
200 MHz 1H-NMR (DMSO-c/6, ppm) δ 11.91 (1H, s) 9.77 (1H, s) 7.90 (1H, d, J=2.4 Hz) 7.61 (1H, dd, J=8.6, 2.4 Hz) 7.60-7.53 (1H, m) 7.30 (1H, d, J=8.0 Hz) 7.10 (1H, dd, J=8.0, 8.0 Hz) 7.06 (1H, d, J=8.6 Hz) 6.85 (1H, d, J=8.0 Hz) 3.23- 3.12 (1H, m) 2.2-2.1 (1H, m) 2.03 (3H, s) 1.7-1.3 (8H, m).
Example 61
Λ/^-O-Chloro^-methylphenvD^-hvdroxy-Λ^-ffraπs^-trifluoromethylcvclohexyl)- benzene-1 ,3-disulfonamide
Figure imgf000082_0002
200 MHz 1H-NMR (DMSO-J6, ppm) δ 11.86 (1H, s) 9.78 (1H, s) 7.99 (1H, d, J=2.4 Hz) 7.55 (1H, dd, J=8.6, 2.4 Hz) 7.29 (1H, d, J=8.0 Hz) 7.60-7.51 (1H, m) 7.10 (1H, dd, J=8.0, 8.0 Hz) 7.05 (1H, d, J=8.6 Hz) 6.86 (1H, d, J=8.0 Hz) 2.98- 2.80(1 H, m) 2.18-2.07 (1H1 m) 2.03 (3H, s) 1.83-1.60 (4H, m) 1.38-1.02 (4H, m).
Example 62
3-(4-(5-rN-(3-Chloro-2-methylphenv[)sulfamovn-2-hvdroxyphenylsulfonamidoV2- fluoro-3-methylphenyl)-Λ/,N-dimethylpropanamide
Figure imgf000083_0001
200 MHz 1H-NMR (DMSO-d6, ppm) δ 11.86 (1 H, s) 9.78 (1 H, s) 7.99 (1 H, d, 9.7-9.5 (1 H, br s) 7.78 (1 H, d, J=2.4 Hz) 7.45 (1H, dd, J=8.6, 2.4 Hz) 7.27 (1 H, dd, J=8.0, 1.0 Hz) 7.08-6.91 (3H, m) 6.73 (1 H, d, J=8.0 Hz) 6.71 (1 H, d, J=7.6 Hz) 2.84 (3H, s) 2.75 (3H, s) 2.72-2.64 (2H, m) 2.54-2.40 (2H, m, overlapped with DMSO) 2.08 (3H, d, J=2.0 Hz) 1.93 (3H, s).
Example 63
N^-fS-Chloro^-methylphenvD-Λ^-fO-chloro-δ-trifluoromethyl^-pyridvDmethvn^- hvdroxybenzene-1 ,3-disulfonamide
Figure imgf000083_0002
200 MHz 1H-NMR (DMSO-c/6, ppm) δ 11.84 (1 H, s) 9.77 (1 H, s) 8.66 (1 H, d, J=1.4 Hz) 8.34 (1 H, d, J=1.4 Hz) 7.92 (1 H, d, J=2.4 Hz) 7.95-7.84 (1 H, m) 7.54 (1 H, dd, J=8.6, 2.4 Hz) 7.28 (1 H, dd, J=8.0, 1.0) 7.09 (1 H, dd, J=8.0, 8.0 Hz) 6.95 (1 H, d, J=8.8 Hz) 6.84 (1 H, dd, J=8.0, 1.0 Hz) 4.37 (2H, d, J=5.8 Hz) 2.04 (3H, s). Example 64 N1-(3-Chloro-2-methylphenyl)-Λ/3-(2-pyridylmethyl)-4-hvdroxybenzene-1 ,3- disulfonamide
Figure imgf000084_0001
200 MHz 1H-NMR (DMSO-d6, ppm) δ 9.78 (1 H, s) 8.67-8.60 (1 H, m) 8.30-8.11 (2H, m) 7.92 (1 H, d, J=2.4 Hz) 7.74-7.58 (1 H, m) 7.69 (1 H, d, J=8.2 Hz) 7.61 (1 H, dd, J=8.6, 2.4 Hz) 7.30 (1 H, dd, J=8.0, 1.0 Hz) 7.11 (1 H, dd, J=8.0, 8.0 Hz) 7.08 (1 H, d, J=8.8 Hz) 6.82 (1 H, dd, J=8.0, 1.0 Hz) 4.31 (2H, d, J=5.6 Hz) 2.06 (3H, s).
Example 65 N1-(3-Chloro-2-methylphenyl)-4-hydroxy-N3-(1-phenylethyl)benzene-1,3-
Figure imgf000084_0002
200 MHz 1H-NMR (DMSO-d6, ppm) δ 11.81 (1 H, s) 9.75 (1 H, s) 8.01 (1 H, d, J=8.6 Hz) 7.89 (1 H, d, J=2.4 Hz) 7.52 (1 H, dd, J=8.6, 2.4 Hz) 7.30 (1 H, dd, J=8.0, 1.2 Hz) 7.22-7.06 (6H, m) 6.94 (1 H, d, J=8.8 Hz) 6.84 (1 H, dd, J=8.0, 1.2 Hz) 4.18 (1 H, dd, J=8.0, 8.0 Hz) 2.05 (3H, s) 1.23 (3H, d=7.0 Hz).
Example 66 N1-(3-Chloro-2-methylphenyl)-Λ/3-(4,4-difluorocvclohexyl)-4-hydroxybenzene-1 ,3- disulfonamide
Figure imgf000084_0003
200 MHz 1H-NMR (DMSO-d6, ppm) 612.1-11.7 (1 H, br s) 9.77 (1 H, s) 7.96 (1 H, d, J=2.4 Hz) 7.58 (1 H, dd, J=8.6, 2.4 Hz) 7.7-7.5 (1 H, m) 7.30 (1 H, d, J=8.0 Hz) 7.11 (1 H, dd, J=8.0, 8.0 Hz) 7.05 (1 H, d, J=8.6 Hz) 6.84 (1 H, d, J=8.0 Hz) 3.22- 3.06 (1 H, m) 2.04 (3H, s) 2.0-1.4 (8H, m).
Example 67 N1-(3-Chloro-2-methylphenyl)-Λ/3-(3,3-dimethylbutyl)-4-hvdroxybenzene-1 ,3- disulfonamide
Figure imgf000085_0001
MS [M+H]+ m/z = 461/463
Example 68 N1-(3-Chloro-2-methylphenyl) -4-hvdroxy-N3-(1-methylcvclohexyl)benzene-1 ,3- disulfonamide
Figure imgf000085_0002
MS [M+H]+ m/z = 473/475
Example 69 N1-(3-Chloro-2-methylphenyl)-4-hvdroxy-N3-(3-trifluoromethylcvclohexyl)benzene- 1 ,3-disulfonamide
Figure imgf000085_0003
MS [M+H]+ m/z = 527/529 Example 70 N1-(3-Chloro-2-methylphenyl) -4-hvdroxy-N3-(3,3,5-trimethylcyclohexyl)benzene- 1 ,3-disulfonamide
Figure imgf000086_0001
MS [M+-H]+ m/z = 501/503
Example 71 N1-(3-Chloro-2-methylphenyl) -N3-(2-chlorophenethyl)-4-hvdroxybenzene-1,3- disulfonamide
Figure imgf000086_0002
MS [M+H]+ m/z = 515/517
Example 72 N1-(3-Chloro-2-methylphenyl) -N3-(2-chlorophenethyl)-4-hvdroxybenzene-1,3- disulfonamide
Figure imgf000086_0003
MS [M+H]+ m/z = 499/501 Example 73
Λ/7-(3-Chloro-2-methylphenyl)-4-hydroxy-Λ/3-f2-(1-pyrrolidinyl)benzyllbenzene-1 ,3- disulfonamide
Figure imgf000087_0001
MS [M+H]+ m/z = 536/538
Example 74
Λ/?-(3-Chloro-2-methylphenyl)-Λ/3-f(6-dodecylthio-3-pyridyl)methylM- hvdroxybenzene-1 ,3-disulfonamide
Figure imgf000087_0002
The title compound was prepared in accordance with Example 35 using
5-aminomethyl-2-chloropyridine and sodium dodecanthiolate as the demethylating reagent.
MS [M+H]+ m/z = 668/669/670
Example 75
Title compounds of the Examples were tested in the biological test described above and were found to exhibit 50% inhibition of mPGES-1 at a concentration of
10 μM or below. For example, the following representative compounds of the examples exhibited the following IC50 values:
Example 1 : 200O nM
Example 8: 150O nM
Example 13: 110O nM
Example 16: 410O nM Example 19: 360O nM
Example 24: 160O nM
Example 29: 160O nM Example 31: 100OnM
Example 37: 2400 nM
Example 43: 2400 nM
Example 49: 100OnM
Example 63: 680 nM
Example 70: 130OnM

Claims

Claims
1. A compound of formula I,
Figure imgf000089_0001
wherein
R1 and R2 independently represent aryl, heteroaryl (which latter two groups are optionally substituted by one or more substituents selected from Z1 and Z2), CM2 alkyl or heterocycloalkyl (which latter two groups are optionally substituted by one or more substituents selected from Z1, Z2 and =0);
one of T1 and T2 represents H, and the other represents H or R3a;
W1 and W2 independently represent a direct bond or Ci-6 alkylene optionally substituted by one or more substituents selected from Rm1;
each Rm1 independently represents fluoro or Ci-4 alkyl (optionally substituted by one or more halo atoms); or any two Rm1 groups, when attached to adjacent or the same carbon atoms, are linked together to form a 3- to 5-membered carbocyclic ring optionally substituted by one or more substituents selected from halo and Ci-2 alkyl;
in the central ring containing Y1 to Y4: at least one of Y1, Y2, Y3 or Y4 represents -C(X1)=; any further two of Y1, Y2, Y3 and Y4 represent -N= or -C(X2)=; and the other represents -C(X2)=;
X1 represents a substituent selected from Z1; X2 represents, at each occurrence when used herein, hydrogen, Z1 or Z2;
Z1 represents, at each occurrence when used herein, halo, -R3a, -CN, -C(O)OR3c, -N(R4b)R5b, -N(R3d)C(O)R4c, -N(R3e)C(O)N(R4d)R5d, -N(R3f)C(O)OR4e, -N3, -NO2, -N(R3g)S(O)2N(R4f)R5f, -0R3h, -OC(O)N(R4g)R59, -OS(O)2R3', -N(R3k)S(O)2R3m, -OC(O)R3", -OC(O)OR3p or -S(O)2N(R4h)R5h;
Z2 represents, at each occurrence when used herein, -C(0)R3b, -C(O)N(R4a)R5a or -S(O)mR3);
m represents O, 1 or 2;
R3b, R3d to R3h, R3k, R3n, R4a to R4h, R5a, R5b, RM and R5f to R5h independently represent H or R3a; or any of the pairs R4a and R5a, R4b and R5b, R4d and R5d, R4f and R5f, R49 and R59 or R4h and R5h may be linked together to form a 3- to 6-membered ring, which ring optionally contains a further heteroatom in addition to the nitrogen atom to which these substituents are necessarily attached, and which ring is optionally substituted by one or more substituents selected from F, Cl, =0 and R3a;
R3c, R31, R3j, R3m and R3p independently represent R3a;
R3a represents, at each occurrence when used herein, Ci-6 alkyl optionally substituted by one or more substituents selected from F, Cl, =0, -0R6a and -N(R6b)R7b;
R6a and R6b independently represent H or Ci-6 alkyl optionally substituted by one or more substituents selected from F, Cl, =0, -0R8a, -N(R9a)R10a and -S(O)2-G1;
R7b represents H, -S(O)2CH3, -S(O)2CF3 or Ci-6 alkyl optionally substituted by one or more substituents selected from F, Cl, =0, -0R11a, -N(R12a)R13a and -S(O)2-G2; or R6b and R7b may be linked together to form a 3- to 6-membered ring, which ring optionally contains a further heteroatom in addition to the nitrogen atom to which these substituents are necessarily attached, and which ring is optionally substituted by one or more substituents selected from F, Cl, =0 and C1-3 alkyl optionally substituted by one or more fluoro atoms;
G1 and G2 independently represent -CH3, -CF3 or -N(R14a)R15a;
R8a and R11a independently represent H, -CH3, -CH2CH3, -CF3 or -CHF2;
R9a, R1Oa, R12a, R13a, R14a and R15a independently represent H, -CH3 Or -CH2CH3,
or a pharmaceutically acceptable salt thereof,
for use in the treatment of a disease in which inhibition or modulation of the activity of a member of the MAPEG family is desired and/or required.
2. A compound as claimed in Claim 1 , wherein one of R1 and R2 represents aryl or heteroaryl (which latter two groups are optionally substituted by one or more substituents selected from Z1 and Z2), and the other represents C1-12 alkyl (optionally substituted by one or more substituents selected from Z1, Z2 and =0), heterocycloalkyl (optionally substituted by one or more substituents selected from Z1, Z2 and =0), heteroaryl or aryl (which latter two groups are optionally substituted by one or more substituents selected from Z1 and Z2).
3. A compound as claimed in Claim 2, wherein R1 and R2 independently represent aryl or heteroaryl, both of which are optionally substituted by one or more substituents selected from Z1 and Z2.
4. A compound as claimed in any one of the preceding claims, wherein W1 and W2 independently represent a direct bond or Ci-3 alkylene.
5. A compound as claimed in any one of the preceding claims, wherein one of T1 and T2 represents H and the other represents C1-3 alkyl or H.
6. A compound as claimed in any one of the preceding claims, wherein one of Y1 to Y4 represents -C(X1)=, and the others all represent -C(X2)=.
7. A compound as claimed in any one of the preceding claims, wherein Y2 or Y4 represent -C(X1)=.
8. A compound as claimed in any one of the preceding claims, wherein X1 represents X1 represents -R3a, -CN, -C(O)OR3c, -NO2, -N(R4b)R5b, halo or -OR3h.
9. A compound as claimed in any one of the preceding claims, wherein X2 represents -CN, -NO2, -N(R4b)R5b, H, halo, -R3a, -0R3h or -C(O)N(R4a)R5a.
10. A compound as claimed in any one of the preceding claims, wherein R3h represents H or R3a, in which R3a represents C1-2 alkyl.
11. A compound as claimed in any one of the preceding claims, wherein R4a and R5a independently represent R3a, or, are linked together to form a five- membered ring.
12. A compound as claimed in any one of the preceding claims, wherein R3a represents CM2 alkyl optionally substituted by one or more substituents selected from -N(Rδb)R7b, -OR6a, =0 and halo.
13. A compound as claimed in any one of the preceding claims, wherein R1 and R2 independently represent an optionally substituted phenyl, naphthyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridyl, indazolyl, indolyl, indolinyl, isoindolinyl, quinolinyl, 1 ,2,3,4- tetrahydroquinolinyl, isoquinolinyl, 1 ,2,3,4-tetrahydroisoquinolinyl, quinolizinyl, benzofuranyl, isobenzofuranyl, chromanyl, benzothienyl, pyridazinyl, pyrimidinyl, pyrazinyl, indazolyl, benzimidazolyl, quinazolinyl, quinoxalinyl, 1 ,3-benzodioxolyl, tetrazolyl, benzothiazolyl, and/or benzodioxanyl, group.
14. A compound as claimed in Claim 13, wherein R1 and R2 independently represent phenyl optionally substituted by one or two substituents selected from Z1 and Z2.
15. A compound as claimed in Claim 13 or Claim 14, wherein the optional substituents are selected from -N(R16)C(O)R17; -C(O)N(R16)R18; halo; cyano; -NO2; C1-6 alkyl, which alkyl group may be cyclic, part-cyclic, unsaturated, linear or branched, all of which are optionally substituted with one or more halo groups; -OR16; -C(O)OR17; -C(O)R16; and -N(R16)R18; wherein R16 to R18 independently represent H or R19; and each R19 independently represents C1-6 alkyl optionally substituted by one or more halo groups.
16. A compound of formula I as defined in any one of Claims 1 to 15, or a pharmaceutically-acceptable salt thereof, for use as a pharmaceutical, provided that, when T1 and T2 both represent H: (A) W1 and W2 both represent direct bonds:
(a) Y3 represents -C(X1)=, in which X1 represents -0R3h and R3h represents H, Y1 represents -C(X2)=, in which X2 represents -R3a and R3a represents methyl, Y2 and Y4 represent -C(X2)=, in which X2 represents H, then R1 and R2 do not both represent a ZZ1 , ZZ2 or ZZ3 group; (b) Y2 represents -C(X1)=, in which X1 represents -0R3h and R3h represents H, Y1 represents -C(X2)=, in which X2 represents H:
(I) Y4 represents -C(X2)=, in which X2 represents H:
(i) when Y3 represents -C(X2)=, in which X2 represents -0R3h and R3h represents H, then R1 and R2 do not both represent a ZZ1 , 4-bromophenyl or 4-chlorophenyl group;
(ii) when Y3 represents -C(X2)=, in which X2 represents -R3a and R3a represents methyl, then R1 and R2 do not both represent a ZZ1 , ZZ2 or ZZ3 group;
(II) Y3 represents -C(X2)=, in which X2 represents H: (i) when Y4 represents -C(X2)=, in which X2 represents -R3a and R3a represents methyl, then R1 and R2 do not both represent a ZZ1 , ZZ2 or ZZ3 group; (ii) when Y4 represents -C(X2)=, in which X2 represents -OR3h and R3h represents H, then R1 and R2 do not both represent a ZZ1 , 4-bromophenyl or 4-chlorophenyl group;
(c) Y1 and Y3 both represent -C(X2)= in which X2 represents H:
(I) Y2 represents -C(X1)=, in which X1 represents -N(R4b)R5b, R4b represents H, R5b represents R3a, in which R3a represents ethyl terminally substituted with -N(R6b)R7b, and R6b and R7b both represent unsubstituted ethyl, Y4 represents -C(X2)= in which X2 is -N(R4b)R5b, then:
(i) when R4b represents H and R5b represents R3a, in which R3a represents ethyl terminally substituted with -N(R6b)R7b, and R6b and R7b both represent unsubstituted methyl; or
(ii) when R4b and R5b are linked together to form a 1- piperazinyl ring substituted at the 4(N)-position with R3a in which R3a is methyl, then R1 and R2 do not both represent unsubstituted phenyl; (II) Y2 represents -C(X1)=, in which X1 represents -N(R4b)R5b, and
R4b and R5b are linked together to form a 1-piperazinyl ring substituted at the 4(N)-position with R3a, in which R3a is methyl, Y4 represents -C(X2)= in which X2 is chloro, then R1 and R2 do not both represent unsubstituted phenyl; (III) Y2 represents -C(X1)=, in which X1 represents R3a in which R3a is methyl, Y4 represents -C(X2)=, in which X2 represents R3a and R3a is methyl, then R1 and R2 do not both represent unsubstituted phenyl;
(d) Y2 represents -C(X1)=, in which X1 represents -N(R4b)R5b, and R4b and R5b both represent H, Y1 and Y3 both represent -C(X2)=, in which X2 represents H, then:
(i) when Y4 represents -C(X2)=, in which X2 represents chloro; then R1 and R2 do not both represent a ZZ3, unsubstituted phenyl, 2- methylphenyl, 4-methylphenyl, 3-trifluoromethylphenyl, 2- nitrophenyl or (4-S(O)2-NH2)phenyl group;
(ii) when Y4 represents -C(X2)=, in which X2 represents -R3a and R3a represents a trifluoromethyl group, then R1 and R2 do not both represent unsubstituted 2-pyridyl groups;
(e) Y1 represents -C(X1)=, in which X1 represents chloro, Y2 and Y4 represent -C(X2)=, in which X2 represents H and Y3 represents -C(X2)=, in which X2 represents chloro, then R1 and R2 do not both represent A- methoxyphenyl;
(f) Y1, Y3 and Y4 represent -C(X2)=, in which X2 represents H, then when Y2 represents -C(X1)= in which X1 represents either chloro or R3a in which R3a represents methyl, then R1 and R2 do not both represent 4- dimethylaminophenyl, (3,4-dimethyl)phenyl, (2,5-dimethyl)phenyl, 2- pyridyl or 2-thiazolyl, in which:
ZZ1 represents unsubstituted phenyl, 4-methylphenyl, 3-methylphenyl, 2- methylphenyl;
ZZ2 represents 4-nitrophenyl, 3-nitrophenyl, 2-nitrophenyl; ZZ3 represents 4-chlorophenyl, 3-chlorophenyl, 2-chlorophenyl;
(B) W1 and W2 both represent -CH2- linker groups: (a) Y2 represents -C(X1)=, in which X1 represents -N(R4b)R5b, R4b and R5b are linked together to form a 1-piperazinyl ring substituted at the 4(N)- position by R3a in which R3a is methyl, Y1 and Y3 both represent -C(X2)= in which X2 is H, then:
(i) when Y4 represents -C(X2)=, in which X2 represents -N(R4b)R5b and R4b and R5b are linked together to form a 1-piperazinyl ring substituted at the 4(N)-position by R3a in which R3a is methyl, then R1 and R2 do not both represent an unsubstituted phenyl group; (ii) when Y4 represents -C(X2)=, in which X2 represents chloro, then R1 and R2 do not both represent 2-chlorophenyl; (b) Y2 represents -C(X1)=, in which X1 represents -OR3h, R3h represents
R3a in which R3a is methyl, Y1, Y3 and Y4 all represent -C(X2)=, in which X2 represents H, then R1 and R2 do not both represent unsubstituted 3- pyridyl;
(C) Y2 represents -C(X1)=, in which X1 represents -N(R4b)R5b and R4b and R5b both represent hydrogen, Y1 and Y3 both represent -C(X2)=, in which
X2 represents H, Y4 represents -C(X2)=, in which X2 represents chloro, then R1 and R2 do not both represent unsubstituted phenyl.
17. A compound of formula I as defined in any one of Claims 1 to 15, or a pharmaceutically-acceptable salt thereof, for use as a pharmaceutical, but in which one or two of Y1, Y2, Y3 or Y4 represent(s) -N=.
18. A compound of formula I as defined in any one of Claims 1 to 15, or a pharmaceutically-acceptable salt thereof, for use as a pharmaceutical, but in which X1 represents -OR3h, provided that, when T1 and T2 both represent H: (A) W1 and W2 both represent direct bonds:
(a) Y3 represents -C(X1)=, in which X1 represents -OR3h and R3h represents H, Y1 represents -C(X2)=, in which X2 represents -R3a and R3a represents methyl, Y2 and Y4 represent -C(X2)=, in which X2 represents H, then R1 and R2 do not both represent a ZZ1 , ZZ2 or ZZ3 group;
(b) Y2 represents -C(X1)=, in which X1 represents -OR3h and R3h represents H, Y1 represents -C(X2)=, in which X2 represents H:
(I) Y4 represents -C(X2)=, in which X2 represents H:
(i) when Y3 represents -C(X2)=, in which X2 represents -OR3h and R3h represents H, then R1 and R2 do not both represent a ZZ1 , 4-bromophenyl or 4-chlorophenyl group; (ii) when Y3 represents -C(X2)=, in which X2 represents -R3a and R3a represents methyl, then R1 and R2 do not both represent a ZZ1 , ZZ2 or ZZ3 group; (II) Y3 represents -C(X2)=, in which X2 represents H:
(i) when Y4 represents -C(X2)=, in which X2 represents -R3a and R3a represents methyl, then R1 and R2 do not both represent a ZZ1 , ZZ2 or ZZ3 group; (ii) when Y4 represents -C(X2)=, in which X2 represents -OR3h and R3h represents H, then R1 and R2 do not both represent a ZZ1 , 4-bromophenyl or 4-chlorophenyl group; in which:
ZZ1 represents unsubstituted phenyl, 4-methylphenyl, 3-methylphenyl, 2- methylphenyl; ZZ2 represents 4-nitrophenyl, 3-nitrophenyl, 2-nitrophenyl;
ZZ3 represents 4-chlorophenyl, 3-chlorophenyl, 2-chlorophenyl;
(B) W1 and W2 both represent -CH2- linker groups:
(b) Y2 represents -C(X1)=, in which X1 represents -OR3h, R3h represents R3a in which R3a is methyl, Y1, Y3 and Y4 all represent -C(X2)=, in which X2 represents H, then R1 and R2 do not both represent unsubstituted 3- pyridyl.
19. A compound of formula I as defined in any one of Claims 1 to 15, or a pharmaceutically-acceptable salt thereof, for use as a pharmaceutical, but in which W1 and W2 represent direct bonds, provided that, when T1 and T2 both represent H:
(A) W1 and W2 both represent direct bonds:
(a) Y3 represents -C(X1)=, in which X1 represents -OR3h and R3h represents H, Y1 represents -C(X2)=, in which X2 represents -R3a and R3a represents methyl, Y2 and Y4 represent -C(X2)=, in which X2 represents H, then R1 and R2 do not both represent a ZZ1 , ZZ2 or ZZ3 group;
(b) Y2 represents -C(X1)=, in which X1 represents -OR3h and R3h represents H, Y1 represents -C(X2)=, in which X2 represents H: (I) Y4 represents -C(X2)=, in which X2 represents H:
(i) when Y3 represents -C(X2)=, in which X2 represents -OR3h and R3h represents H, then R1 and R2 do not both represent a ZZ1 , 4-bromophenyl or 4-chlorophenyl group; (ii) when Y3 represents -C(X2)=, in which X2 represents -R3a and R3a represents methyl, then R1 and R2 do not both represent a ZZ1 , ZZ2 or ZZ3 group; (II) Y3 represents -C(X2)=, in which X2 represents H:
(i) when Y4 represents -C(X2)=, in which X2 represents -R3a and R3a represents methyl, then R1 and R2 do not both represent a ZZ1 , ZZ2 or ZZ3 group;
(ii) when Y4 represents -C(X2)=, in which X2 represents -OR3h and R3h represents H, then R1 and R2 do not both represent a ZZ1 , 4-bromophenyl or 4-chlorophenyl group;
(c) Y1 and Y3 both represent -C(X2)= in which X2 represents H: (I) Y2 represents -C(X1)=, in which X1 represents -N(R4b)R5b, R4b represents H, R5b represents R3a, in which R3a represents ethyl terminally substituted with -N(R6b)R7b, and R6b and R7b both represent unsubstituted ethyl, Y4 represents -C(X2)= in which X2 is -N(R4b)R5b, then: (i) when R4b represents H and R5b represents R3a, in which
R3a represents ethyl terminally substituted with -N(R6b)R7b, and R6b and R7b both represent unsubstituted methyl; or (ii) when R4b and R5b are linked together to form a 1- piperazinyl ring substituted at the 4(N)-position with R3a in which R3a is methyl, then R1 and R2 do not both represent unsubstituted phenyl;
(II) Y2 represents -C(X1)=, in which X1 represents -N(R4b)R5b, and R4b and R5b are linked together to form a 1-piperazinyl ring substituted at the 4(N)-position with R3a, in which R3a is methyl, Y4 represents -C(X2)= in which X2 is chloro, then R1 and R2 do not both represent unsubstituted phenyl;
(III) Y2 represents -C(X1)=, in which X1 represents R3a in which R3a is methyl, Y4 represents -C(X2)=, in which X2 represents R3a and R3a is methyl, then R1 and R2 do not both represent unsubstituted phenyl;
(d) Y2 represents -C(X1)=, in which X1 represents -N(R4b)R5b, and R4b and R5b both represent H, Y1 and Y3 both represent -C(X2)=, in which X2 represents H, then:
(i) when Y4 represents -C(X2)=, in which X2 represents chloro; then R1 and R2 do not both represent a ZZ3, unsubstituted phenyl, 2- methylphenyl, 4-methylphenyl, 3-trifluoromethylphenyl, 2- nitrophenyl or (4-S(O)2-NH2)phenyl group;
(ii) when Y4 represents -C(X2)=, in which X2 represents -R3a and
R3a represents a trifluoromethyl group, then R1 and R2 do not both represent unsubstituted 2-pyridyl groups;
(e) Y1 represents -C(X1)=, in which X1 represents chloro, Y2 and Y4 represent -C(X2)=, in which X2 represents H and Y3 represents -C(X2)=, in which X2 represents chloro, then R1 and R2 do not both represent (4- methoxy)phenyl; (f) Y1, Y3 and Y4 represent -C(X2)=, in which X2 represents H, then when
Y2 represents -C(X1)= in which X1 represents either chloro or R3a in which R3a represents methyl, then R1 and R2 do not both represent A- dimethylaminophenyl, (3,4-dimethyl)phenyl, (2,5-dimethyl)phenyl, 2- pyridyl or 2-thiazolyl, in which:
ZZ1 represents unsubstituted phenyl, 4-methylphenyl, 3-methylphenyl, 2- methylphenyl;
ZZ2 represents 4-nitrophenyl, 3-nitrophenyl, 2-nitrophenyl; ZZ3 represents 4-chlorophenyl, 3-chlorophenyl, 2-chlorophenyl.
20. A compound of formula I as defined in any one of Claims 1 to 15, or a pharmaceutically-acceptable salt thereof, for use as a pharmaceutical, but in which, when one of Y1 to Y4 represents -C(X1)= and the others represents -C(X2)=, then none, one or all three of those X2 groups represent H, provided that, when T1 and T2 both represent H:
(A) W1 and W2 both represent direct bonds:
(f) Y1, Y3 and Y4 represent -C(X2)=, in which X2 represents H, then when Y2 represents -C(X1)= in which X1 represents either chloro or R3a in which R3a represents methyl, then R1 and R2 do not both represent 4- dimethylaminophenyl, (3,4-dimethyl)phenyl, (2,5-dimethyl)phenyl, 2- pyridyl or 2-thiazolyl;
(B) W1 and W2 both represent -CH2- linker groups:
(b) Y2 represents -C(X1)=, in which X1 represents -OR3h, R3tl represents R3a in which R3a is methyl, Y1, Y3 and Y4 all represent -C(X2)=, in which X2 represents H, then R1 and R2 do not both represent unsubstituted 3- pyridyl.
21. A compound of formula I as defined in any one of Ciaims 1 to 15, or a pharmaceutically-acceptable salt thereof, for use as a pharmaceutical, but in which:
(i) X1 represents -OR3h;
(ii) W1 and W2 represent direct bonds;
(iii) when one of Y1 to Y4 represents -C(X1)= and the others represents
-C(X2)=, then none, one or all three of those X2 groups represent H.
22. A pharmaceutical formulation including a compound as defined in any one of Claims 16 to 21 , or a pharmaceutically-acceptable salt thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.
23. A compound of formula I, as defined in Claim 1 , or a pharmaceutically- acceptable salt thereof, but in which:
(i) one or two of Y1, Y2, Y3 or Y4 represent(s) -N=; and, optionally, (ii) X1 represents -OR3h.
24. A compound of formula I, as defined in any one of Claims 1 to 15, or a pharmaceutically-acceptable salt thereof, but in which:
(i) X1 represents -OR3h; and
(ii) one of Y1 to Y4 represents -C(X1)= and the others represents -C(X2)= in which none, one or all three of those X2 groups represent H, provided that, when T1 and T2 both represent H:
(B) W1 and W2 both represent -CH2- linker groups:
(b) Y2 represents -C(X1)=, in which X1 represents -OR3h, R3h represents R3a in which R3a is methyl, Y1, Y3 and Y4 all represent -C(X2)=, in which X represents H, then R1 and R2 do not both represent unsubstituted 3- pyridyl.
25. A compound of formula I, as defined in Claim 24, or a pharmaceutically- acceptable salt thereof, but without the proviso, but also in which: (iii) W1 and W2 represent direct bonds; and/or (iv) Y4 or Y2 represent -C(X1)=.
26. A use of a compound as defined in any one of Claims 1 to 15, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a disease in which inhibition or modulation of the activity of a member of the MAPEG family is desired and/or required.
27. A compound as claimed in any one of Claims 1 to 15, or a use as claimed in Claim 26, wherein the member of the MAPEG family is microsomal prostaglandin E synthase-1 , leukotriene C4 synthase and/or 5-lipoxygenase- activating protein.
28. A compound or use as claimed in Claim 27 (as appropriate), wherein the member of the MAPEG family is microsomal prostaglandin E synthase-1.
29. A compound or use as claimed in any one of Claims 26 to 28 (as appropriate), wherein the disease is inflammation.
30. A compound as defined in any one of Claims 1 to 15, or a pharmaceutically-acceptable salt thereof, for use in the treatment of asthma, chronic obstructive pulmonary disease, pulmonary fibrosis, inflammatory bowel disease, irritable bowel syndrome, pain, inflammatory pain, fever, migraine, headache, low back pain, fibromyalgia, a myofascial disorder, a viral infection, a bacterial infection, a fungal infection, dysmenorrhea, a burn, a surgical or dental procedure, a malignancy, 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, a neurodegenerative disorder, an autoimmune disease, an allergic disorder, rhinitis, an ulcer, coronary heart disease, sarcoidosis, any other disease with an inflammatory component, osteoporosis, osteoarthritis, Paget's disease or a periodontal disease.
31. The use of a compound as defined in any one of Claims 1 to 15, or a pharmaceutically-acceptable salt thereof, for the manufacture of a medicament for the treatment of a disease as defined in Claim 30.
32. A method of treatment of a disease in which inhibition of the activity of a member of the MAPEG family is desired and/or required, which method comprises administration of a therapeutically effective amount of a compound as defined in any one of Claims 1 to 15, or a pharmaceutically-acceptable salt thereof, to a patient suffering from, or susceptible to, such a condition.
33. A method as claimed in Claim 32, wherein the member of the MAPEG family is microsomal prostaglandin E synthase-1 , leukotriene C4 synthase and/or 5-lipoxygenase-activating protein.
34. A method as claimed in Claim 33, wherein the member of the MAPEG family is microsomal prostaglandin E synthase-1.
35. A combination product comprising:
(A) a compound as defined in any one of Claims 1 to 21 or 23 to 25, or a pharmaceutically-acceptable salt thereof; and (B) another therapeutic agent that is useful in the treatment of inflammation, wherein each of components (A) and (B) is formulated in admixture with a pharmaceutically-acceptable adjuvant, diluent or carrier.
36. A combination product as claimed in Claim 35 which comprises a pharmaceutical formulation including a compound as defined in any one of Claims 1 to 21 or 23 to 25, or a pharmaceutically-acceptable salt thereof, another therapeutic agent that is useful in the treatment of inflammation, and a pharmaceutically-acceptable adjuvant, diluent or carrier.
37. A combination product as claimed in Claim 35 which comprises a kit of parts comprising components:
(a) a pharmaceutical formulation including a compound as defined in any one of Claims 1 to 21 or 23 to 25, or a pharmaceutically-acceptable salt thereof, in admixture with a pharmaceutically-acceptable adjuvant, diluent or carrier; and
(b) a pharmaceutical formulation including another therapeutic agent that is useful in the treatment of inflammation in admixture with a pharmaceutically-acceptable adjuvant, diluent or carrier, which components (a) and (b) are each provided in a form that is suitable for administration in conjunction with the other.
38. A process for the preparation of a compound as defined any one of Claim 16 to 21 or 23 to 25, which comprises:
(i) for compounds of formula I in which R1 and R2 represent the same optionally substituted aryl or heteroaryl group, W1 and W2 represent the same group and T1 and T2 also represent the same group, reaction of a compound of formula II,
Figure imgf000102_0001
wherein L1a and L1b independently represent a suitable leaving group, with a compound of formula III, RX-WX-N(H)TX III wherein Rx represents both R1 and/or R2 (as appropriate), Wx represents W1 and/or W2 (as appropriate) and T represents T1 and/or T2 (as appropriate), and R1, R2, W1, W2, T1 and T2 are as defined in Claim 1 ; (ii) reaction of a compound of formula IV,
Figure imgf000103_0002
or a compound of formula V,
Figure imgf000103_0001
wherein Y1 to Y4, T1, T2, W1 and W2 are as defined in Claim 1 and L1a and L1b are as defined above, with a compound of formula III as defined above, in which Rx represents R1, Wx represents W1 and Tx represents T1 (for reaction with compounds of formula IV) or Rx represents R2, Wx represents W2 and Tx represents T2 (for reaction with compounds of formula V); (iii) for compounds of formula I in which Y1, Y2 or Y4 represent -C(X1)= or -C(X2)=, in which X1 and/or X2 represents halo, -R3a, -C(O)R3b, -C(O)OR3c, -C(O)N(R4a)R5a, -S(O)mR3j or -S(O)2N(R4h)R5h, and R3b, R4a, R5a, R4h and R5h are as defined in Claim 1 , provided that they do not represent hydrogen, and R3a, R3c, and R3j are as defined in Claim 1 , reaction of a compound corresponding to a compound of formula I but in which X1 and/or X2 (as appropriate) represents a metal) or a magnesium-containing group, with a compound of formula Vl, Zx-L2 Vl wherein L2 represents a suitable leaving group and Zx represents halo, -R3a, -C(O)R3b, -C(O)OR30, -C(O)N(R4a)R5a, -S(O)mR3j or -S(O)2N(R4h)R5h, and R3b, R4a, R5a, R4h and R5h are as defined in Claim 1 , provided that they do not represent hydrogen, and R3a, R3c and R3j are as defined in Claim 1 ; (iv) for compounds of formula I in which a substituent X1 or X2 is present and represents -N(R4b)R5b in which R5b is H and R4b is as defined in Claim 1 , hydrolysis of a corresponding compound of formula I in which the relevant substituent is -N(R4b)C(O)OR4c in which R4b and R4c are as defined in Claim 1 , or- a protected derivative thereof;
(v) for compounds of formula I in which a substituent X1 or X2 is present and represents -C(O)OR30 and is as defined in Claim 1 , trans-esterification of a corresponding compound of formula I in which R3c does not represent the same value as the value of R3c in the compound of formula I to be prepared; (vi) for compounds of formula I in which a substituent X1 or X2 is present and represents -C(O)OR3c, -C(O)N(R4a)R5a, -N(R4b)R5b, -N(R3e)C(O)N(R4d)R5d, -N(R3f)C(O)OR4e, -N(R39)S(O)2N(R4f)R5f, -OR3h, -OC(O)N(R49)R5g, -OC(O)OR3p and/or -S(O)2N(R4h)R5h, and R3e, R3f, R39, R3h, R4a, R4b, R4d, R4e, R4f, R49, R4h, R5a, R5b, R5d, R5f, R59 and R5h are as defined in Claim 1 , provided that they do not represent hydrogen, and R3c and R3p are as defined in Claim 1 , reaction of a compound corresponding to a compound of formula I in which R3c and/or R3p represents hydrogen or a corresponding compound of formula I in which R3e, R3f, R39, R3h, R4a, R4b, R4d, R4e, R4f, R4g, R4h, R5a, R5b, R5d, R5f, R5g and/or R5h represent hydrogen (as appropriate), or an appropriate anion thereof, with a compound of formula VII,
R3a-L3 VII wherein L3 represents a suitable leaving group and R3a is as defined in Claim 1 ; (vii) for compounds of formula I in which a substituent X1 or X2 is present and represents halo, -CN, -N(R4b)R5b, -N(R3d)C(O)R4c, -N(R3e)C(O)N(R4d)R5d, -N(R3f)C(O)OR4e, -N(R39)S(O)2N(R4f)R5f, -OR3h, -SR3J and/or -N(R3k)S(O)2R3m, and R3d, R3e, R3f, R39, R3h, R3J, R3k, R3m, R4b, R4c, R4d, R4e, R4f, R5b, R5d and R5f are as defined in Claim 1 , reaction of a corresponding compound of formula I in which X1 or X2 (as appropriate) represents a suitable leaving group, with (for the introduction of a halogen group) a halogen, or an appropriate reagent that is a source of a halogen, a reagent that is a source of another appropriate nucleophile, or (for the introduction of the other X1 and/or X2 substituents mentioned above) with a compound of formula VIII,
Zy-H VIII wherein Zy represents -CN, -N(R4b)R5b, -N(R3d)C(O)R4c, -N(R3e)C(O)N(R4d)R5d, -N(R3f)C(O)OR4e, -N(R39)S(O)2N(R4f)R5f, -OR3h, -SR3j or -N(R3k)S(O)2R3m, and R3d, R3e, R3f, R39, R3h, R3), R3k, R3m, R4b, R4c, R4d, R4e, R4f, R5b, R5d and R5f are as defined in Claim 1 , or a suitable derivative thereof;
(viii) for compounds of formula I in which T1 or T2 represents R3a, reaction of a corresponding compound of formula I in which T1 or T2 represents H, with a compound of formula VIIIA,
"P-L3 VIIIA wherein T* and L3 are as defined above;
(ix) for compounds of formula I in which X1 or X2 is present and represents -OR3h in which R3h represents H, by deprotection of a corresponding compound of formula I in which the -OH group is protected;
(x) for compounds of formula I in which X1 or X2 is present and represents -NH2, reduction of compounds corresponding to compounds of formula I but in which the relevant X1 or X2 group represents -NO2.
39. A process for the preparation of a pharmaceutical formulation as defined in Claim 22, which process comprises bringing into association a compound of formula I, as defined in any one of Claims 16 to 21 , or a pharmaceutically acceptable salt thereof with a pharmaceutically-acceptable adjuvant, diluent or carrier.
40. A process for the preparation of a combination product as defined in any one of Claims 35 to 37, which process comprises bringing into association a compound of formula I, as defined in any one of Claims 1 to 21 or 23 to 25, or a pharmaceutically acceptable salt thereof with another therapeutic agent that is useful in the treatment of inflammation, and a pharmaceutically-acceptable adjuvant, diluent or carrier.
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