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WO2008009924A2 - Indoles useful in the treatment of inflammation - Google Patents

Indoles useful in the treatment of inflammation Download PDF

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Publication number
WO2008009924A2
WO2008009924A2 PCT/GB2007/002704 GB2007002704W WO2008009924A2 WO 2008009924 A2 WO2008009924 A2 WO 2008009924A2 GB 2007002704 W GB2007002704 W GB 2007002704W WO 2008009924 A2 WO2008009924 A2 WO 2008009924A2
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WO
WIPO (PCT)
Prior art keywords
formula
compound
compounds
group
single bond
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Application number
PCT/GB2007/002704
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French (fr)
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WO2008009924A3 (en
Inventor
Benjamin Pelcman
Kristofer Olofsson
Martins Katkevics
Vita Ozola
Edgars Suna
Ivars Kalvins
Pavels Arsenjans
Original Assignee
Biolipox Ab
Boehringer Ingelheim International Gmbh
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Application filed by Biolipox Ab, Boehringer Ingelheim International Gmbh filed Critical Biolipox Ab
Publication of WO2008009924A2 publication Critical patent/WO2008009924A2/en
Publication of WO2008009924A3 publication Critical patent/WO2008009924A3/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Definitions

  • This invention relates to novel phamaceutically-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 (MGSTl, 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 5 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 disease0
  • COX cyclooxygenase
  • COXs metabolise arachidonic acid to the unstable intermediate prostaglandin H 2 0 (PGH 2 ).
  • PGH 2 is further metabolized to other prostaglandins including PGE 2 , PGF 2 ⁇ , PGD 2 , prostacyclin and thromboxane A 2 .
  • PGE 2 arachidonic acid metabolites are known to have pronounced physiological and pathophysiological activity including pro-inflammatory effects.
  • 5 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).
  • NSAIDs non-steroidal antiinflammatory drugs
  • coxibs selective COX-2 inhibitors
  • 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 CysLTj. It may be hypothesised that better control of asthma, and possibly also COPD, maybe 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 (MGSTl, MGST2 and MGST3).
  • MGSTl, 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.
  • Indole-based compounds have been disclosed in international patent applications WO 96/03377, WO 01/00197, WO 03/044014 and WO 03/057670, US patents Nos. 5,189,054, 5,294,722, 4,960,786, 5,236,916 and 5,374,615 and European patent applications EP 429 257, EP 483 881, EP 547 556, EP 639 573, EP 1 314 733 and EP 488 532.
  • none of these documents disclose or suggest the use of such compounds in the treatment of inflammation.
  • Indoles have also been disclosed for potential use in the treatment of inflammation in international patent applications WO 99/43672, WO 98/08818, WO 99/43654, WO 99/43651, WO 99/05104 and WO 03/029212, European patent application EP 986 666 and US patents Nos. 6,500,853 and 6,630,496.
  • indole-2-carboxylates in which an aromatic group is directly attached via the indole nitrogen.
  • 2005/005415 discloses such compounds for use as inhibitors of mPGES and thus in the treatment of inflammation.
  • indole-2-carboxylates in which an aromatic group is directly attached via the indole nitrogen.
  • International patent applications WO 2005/123675, WO 2005/123673 and WO 2005/123674 disclose indoles for use as inhibitors of mPGES and thus in the treatment of inflammation.
  • indoles which are substituted at the benzenoid moiety of the indole ring with an aromatic group that is attached via a linking group.
  • unpublished patent application PCT/GB2005/004978 discloses inter alia indole-2-carboxylic acids that are substituted at the benzenoid moiety of the indole with an aromatic group that is attached via a linker group.
  • Unpublished patent application PCT/GB2005/0049828 also discloses similar indoles but in which the indole-2-substituent is inter alia a carboxylic acid isostere.
  • R 1 and E independently represent an aryl group or a heteroaryl group, both of which groups are optionally substituted by one or more substituents selected from
  • R 7 represents C 1-6 alkyl, optionally substituted by one or more substituents selected from W 1 , or R 7a ; or
  • R 7 and R 8 are linked together with the carbon atom to which they are attached to form a 3- to 6-membered ring, which ring contains at least one (e.g. one) unsaturation (e.g. a triple or, preferably, a double bond), optionally contains a heteroatom and is optionally substituted by one or more substituents selected from halo and C 1-3 alkyl, which latter group is optionally substituted by one or more halo substituents;
  • R 7a and R 8 independently represent -OR a , -N(R b )(R°) or -SR d ; .
  • R ⁇ and R 8b independently represent hydrogen, -OR e , -N(R f )(R g ), -SR h or C 1-6 allcyl optionally substituted by one or more substituents selected from W ; or R 713 and R 8b are linked together to form, together with the carbon atom to which they are necessarily attached, a 3- to 6-membered ring optionally containing 1 to 3 heteroatoms and 1 to 3 unsaturations (e.g. double bonds) and which ring is optionally substituted by one or more substituents selected from C 1-6 alkyl (which is optionally substituted by one or more halo atoms) and W ;
  • R a , R b , R G , R d , R e , R f , R ⁇ and R h independently represent H or C 1-6 alkyl optionally substituted by one or more substituents selected from " w ; or any pair of R b and R°, or R f and R ⁇ are linked together with the nitrogen atom to which they are necessarily attached to form a 3- to 6-membered ring optionally containing 1 to 3 heteroatoms and 1 to 3 unsaturations (e.g. double bonds) and which ring is optionally substituted by one or more substituents selected from C 1-6 alkyl (which is optionally substituted by one or more halo atoms) and W ;
  • X 1 represents H, halo, -N(R 9a )-J-R 10a or -Q-X 2 ;
  • J represents a single bond, -C(O)- or -S(O) m -;
  • Q represents a single bond, -O-, -C(O)- or -S(O) m -;
  • X 2 represents: (a) an aryl group or a heteroaryl group, both of which are optionally substituted by one or more substituents selected from A; or (b) C 1-8 alkyl or a heterocycloalkyl group, both of which are optionally substituted by one or more substituents selected from G 1 and/or Z ;
  • T represents: (a) a single bond
  • (iii) may comprise an additional 3- to 8-membered ring formed between any one or more (e.g. one or two) members of the C 1-8 alkylene or C 2-S heteroalkylene chain, which ring optionally contains 1 to 3 heteroatoms and/or 1 to 3 unsaturations (for example double or triple bonds) and which ring is itself optionally substituted by one or more substituents selected from G 1 and/or Z 1 ;
  • T 1 and T 2 represents a C 1-8 alkylene or a C 2-8 heteroalkylene chain, both of which latter two groups:
  • (iii) may comprise an additional 3- to 8-membered ring formed between any one or more (e.g. one or two) members of the C 1-8 alkylene or C 2-S heteroalkylene chain, which ring optionally contains 1 to 3 heteroatoms and/or 1 to 3 unsaturations (for example double or triple bonds) and which ring is itself optionally substituted by one or more substituents selected from G 1 and/or Z 1 ; and the other represents an arylene group or a heteroarylene group chain, both of which groups are optionally substituted by one or more substituents selected from
  • W x represents -O- or -S(O) m -;
  • n represents, on each occasion when mentioned above, 0, 1 or 2;
  • Y represents -C(H)(CF 3 )OH 5 -C(O)CF 3 , -C(OH) 2 CF 3 , -C(O)OR 9b , -S(O) 3 R 9c , -P(O)(OR 9d ) 2 , -P(O)(OR 9e )N(R 10f )R 9f , -P(O)(N(R 10g )R 9g ) 2 , -B(OR 9h ) 2 , -C(CF 3 ) 2 OH, -S(O) 2 N(R 10i )R 9i or any one of the following groups:
  • R 6 , R 9a to R 9x , R 1Oa , R 1Of , R 1O ⁇ , R 1Oi and R 1Oj independently represent, on each occasion when mentioned above:
  • A represents, on each occasion when mentioned above:
  • G 1 represents, on each occasion when mentioned above, halo, cyano, -N 3 , -NO 2 , -ONO 2 or -A ⁇ R 113 ; wherein A 1 represents a single bond or a spacer group selected from -C(O)A 2 -,
  • a 2 represents a single bond, -0-, -N(R 12b )- or -C(O)-;
  • a 3 represents a single bond, -O- or -N(R 12c )-;
  • a 4 and A 5 independently represent a single bond, -C(O)-, -C(0)N(R 12d )-, -C(O)O-,
  • G 2 represents, on each occasion when mentioned above, halo, cyano, -N 3 , -NO 2 , -ONO 2 or -A 6 -R 13a ;
  • a 6 represents a single bond or a spacer group selected from -C(O)A 7 -, -S(O) 2 A 8 -, -N(R 14a )A 9 - or -OA 10 -, in which: A 7 represents a single bond, -0-, -N(R 14b )- or -C(O)-;
  • a 8 represents a single bond, -O- or -N(R 14c )-;
  • a 9 and A 10 independently represent a single bond, -C(O)-, -C(O)N(R 14d )-, -C(O)O-, -S(O) 2 - or -S(O) 2 N(R 146 )-;
  • R 14d , R 14e and R 14f are independently selected from: i) hydrogen; ii) an aryl group or a heteroaryl group, both of which are optionally substituted by one or more substituents selected from G 3 ; iii) C 1-8 alkyl or a heterocycloalkyl group, both of which are optionally substituted by G 3 and/or Z 3 ; or ⁇ any pair of R lla to R llc and R 12a to R 12f , and/or R 13a to R 13c and R 14a to R 14f , may, for example when present on the same or on adjacent atoms, be linked together to form with those, or other relevant, atoms a further 3- to 8-membered ring, optionally containing 1 to 3 hetero atoms and/or 1 to 3 double bonds, which ring is optionally substituted by one or more substituents selected from G 3 and/or Z 3 ; ⁇
  • G 3 represents, on each occasion when mentioned above, halo, cyano, -N 3 , -NO 2 ,
  • A represents a single bond or a spacer group selected from -C(O)A -, -S(O) 2 A 13 -, -N(R 16a )A 14 - or -OA 15 -, in which: A 12 represents a single bond, -0-, -N(R 16b )- or -C(O)-; A 13 represents a single bond, -O- or -N(R 160 )-; T/GB2007/002704
  • a 14 and A 15 independently represent a single bond, -C(O)-, -C(0)N(R 16d )-, -C(O)O-, -S(O) 2 - or -S(O) 2 N(R 166 )-;
  • R 17a , R 17b , R 17c , R 17d , R 17e , R 17f , R 18a , R 18b and R 18 ° are independently selected from hydrogen and C 1-4 alkyl, which latter group is optionally substituted by one or more halo groups;
  • salts include acid addition salts and base addition salts.
  • Such salts may be formed by conventional means, for example by reaction of a free acid or a free base form of a compound of formula I with one or more equivalents of an appropriate acid or base, optionally in a solvent, or in a medium in which the salt is insoluble, followed by removal of said solvent, or said medium, using standard techniques (e.g. in vacuo, by freeze-drying or by filtration). Salts may also be prepared by exchanging a counter-ion of a compound of the invention in the form of a salt with another counter-ion, for example using a suitable ion exchange resin.
  • Compounds of the invention may contain double bonds and may thus exist as E (entgegeri) and Z (zusammen) geometric isomers about each individual double bond. All such isomers and mixtures thereof are included within the scope of the invention.
  • Compounds of the invention may also 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, and C 1-q alkylene, groups (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 two or three, as appropriate) of carbon atoms, be branched-chain, and/or, in the case of alkyl, 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. Such alkyl and alkylene groups may also be saturated or, when there is a sufficient number (i.e.
  • a rmnimum of two) of carbon atoms be unsaturated (forming, for example, in the case of alkyl, a C 2-q alkenyl or a C 2-q alkynyl group or, in the case of alkylene, a C 2-q alkenylene or a C 2-q alkynylene group).
  • Cycloalkyl groups that may be mentioned include non-aromatic C 3-16 , such as C 3-1O , cycloalkyl groups.
  • C 3-q cycloalkyl groups may be monocyclic or bicyclic alkyl groups, which cycloalkyl groups may further be bridged (so forming, for example, fused ring systems such as three fused cycloalkyl groups).
  • Such cycloalkyl groups may be saturated or unsaturated containing one or more double or triple bond (forming for example a C 3-q cycloalkenyl or a C 8-q cycloalkynyl group).
  • Cycloalkyl groups that may be mentioned include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclooctynyl, bicycloheptyl, bicyclooctyl, and bicyclooctenyl, as well as bridged cycloalkyl groups, such as adamantyl, noradamantyl, norbornane, norbornene and norbornadiene groups.
  • Substituents may be attached at any point on the cycloalkyl group. Further in the case where the substituent is another cyclic compound, then the cyclic substituent may be attached through a single atom on the cycloalkyl group, forming a so-called "spiro"-compound.
  • Preferred cycloalkyl groups include optionally substituted C 3- g cycloalkyl groups, which groups optionally contain one unsaturation (e.g. a double bond).
  • Cycloalkyl groups that may be mentioned include optionally substituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl (e.g. cyclopenten-1-yl), cyclohexenyl (e.g. cyclohexen-1-yl) and norbornanyl (e.g. norbornan-2-yl).
  • halo when used herein, includes fluoro, chloro, bromo and iodo.
  • 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 3-q heterocycloalkynyl group.
  • C 2-q heterocycloalkyl groups that may be mentioned include 7- azabicyclo[2.2. ljheptanyl, 6-azabicyclo[3.1. ljheptanyl, 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.
  • ljheptanyl 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-tetrahydro ⁇ yridyl), thietanyl, thiiranyl, thiolanyl, thiomorpholinyl, trithianyl (including 1,3,5-trithianyl), tropanyl and the like.
  • Substituents on heterocycloallcyl groups may, where appropriate, be located on any atom in the ring system including a heteroatom. Further, in the case where the other substituent is another cyclic compound, then the cyclic compound may be attached through a single atom on the heterocycloalkyl group, forming a so- called "s ⁇ iro"-com ⁇ ound.
  • 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 JV- or S- oxidised form.
  • heterocycloalkyl groups include optionally substituted 5 to 6-membered heterocyclic groups containing at least one oxygen or, more preferably, nitrogen atom and, optionally, a further nitrogen and/or oxygen atom.
  • Heterocycloalkyl groups that may be mentioned include optionally substituted pyrrolidinyl (e.g. pyrrolidin-1-yl), morpholinyl (e.g. 4-morpholin-l-yl), piperazinyl (e.g. piperazin-1-yl), piperidinyl (e.g. piperidin-1-yl and piperidin-4-yl) and tetrahydropyridyl (e.g. 1,2,3,6- tetrahydropyridin-2-yl) groups.
  • pyrrolidinyl e.g. pyrrolidin-1-yl
  • morpholinyl e.g. 4-morpholin-l-yl
  • piperazinyl e.g. piperazin
  • R 71 ' and R 8b are as hereinbefore defined and the asterisks (at each point) indicate the point of attachment with the group E or with the benezenoid moiety of the indole ring of formula I (as appropriate).
  • bicyclic when employed in the context of cycloalkyl and heterocycloalkyl groups refers to such groups in which the second ring is formed between two adjacent atoms of the first ring.
  • bridged when employed in the context of cycloalkyl or heterocycloalkyl groups refers to monocyclic or bicyclic groups in which two non-adjacent atoms are linked by either an alkylene or heteroalkylene chain (as appropriate).
  • Aryl groups that may be mentioned include C 6-14 (such as C 6-13 (e.g. C 6-1 o)) aryl groups.
  • Such groups may be monocyclic, bicyclic or tricyclic and have between 6 and 14 ring carbon atoms, in which at least one ring is aromatic.
  • C 6-14 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.
  • aryl groups are bicyclic or tricyclic, they are linked to the rest of the molecule via an aromatic ring.
  • Heteroaryl groups that may be mentioned include those which have between 5 and 14 (e.g. 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).
  • Heterocyclic groups that may be mentioned include benzothiadiazolyl (including 2,1,3-benzothiadiazolyl), isothiochromanyl and, more preferably, acridinyl, benzimidazolyl, benzodioxanyl, benzodioxepinyl, benzodioxolyl (including 1,3- benzodioxolyl), benzofuranyl, benzofurazanyl, benzothiazolyl, benzoxadiazolyl (including 2,1,3-benzoxadiazolyl), benzoxazinyl (including 3 5 4-dihydro-2i?-l,4- benzoxazinyl), benzoxazolyl, benzomorpholinyl, benzoselenadiazolyl (including 2,1,3-benzoselenadiazolyl), benzothienyl, carbazolyl, chromanyl, cinnolinyl, furanyl, imidazolyl,
  • 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 may also be in the 7V- or S- oxidised form.
  • Heteroatoms that may be mentioned include phosphorus, silicon, boron, tellurium, selenium and, preferably, oxygen, nitrogen and sulphur.
  • R 2 to R 5 this will be understood by the skilled person to mean R 2 , R 3 , R 4 and R 5 inclusively.
  • any pair of R lla to R Uc and R 12a to R 12f may be linked as hereinbefore defined.
  • R lla to R llc groups, and R 12a to R 12f groups may be attached to a single nitrogen atom (e.g. R lla and R 12a or R llc and R 12f ), which may form part of the ring.
  • R 9a to R 9x this will be understood by the skilled person to mean R 9a , R 9b , R 9 °, R 9d , R 9e , R 9f , R 9g , R 9h , R 9i , R 9j , R 9k , R 9m , R 9n , R 9p , R 9q , R 9r , R 9s , R 9t , R 9u , R 9v , R 9w and R 9x inclusively.
  • R 9a to R 9x and R 1Oa , R 1Of , R 1Og , R 10i or R 10j may be linked together to form a ring as hereinbefore defined.
  • R 9a to R 9x , R 1Oa , R 10f , R 1Og , R 1Oi and R 1Oj groups may be attached to (a) a single nitrogen atom (e.g. R 9f and R 1Of ), or (b) a nitrogen atom and a J group (i.e. R 9a and R 1Oa ), which also form part of the ring, or two R 9a to R 9x (e.g. two R 9d ) groups may be attached to different oxygen atoms (for example in a 1,3-relationship) all of which may form part of the ring.
  • Still further compounds of the invention include those in which, when one of the groups R 2 , R 3 , R 4 and R 5 represents -D-E and one or more of the other groups represent G 1 then, when G 1 represents -A ⁇ R 1 la , A 1 represents a spacer group selected from -C(O)A 2 -, -S(O) 2 A 3 -, -N(R 12a )A 4 - or -OA 5 -.
  • Ci- 8 alkyl or a heterocycloalkyl group which groups are substituted by G 1 , and, in either case, G 1 is -A ⁇ R 11 * 1 , then A represents a single bond or a spacer group selected from -C(O)-, -S(O) 2 -, -S(O) 2 N(R 12c )-, -N(R 12a )A 4 - or -OA 5 -.
  • Preferred compounds of the invention include those in which: R 6 and, more particularly, R 9a to R 9x , R 1Oa , R 10f , R 1Og , R 1Oi and R 10j independently represent, on each occasion when mentioned above:
  • C 1-8 alkyl or a heterocycloalkyl group both of which are optionally substituted by one or more substituents selected from G 1 and/or Z 1 ; or any pair of R 9a to R 9x and R 1Oa , R 1Of , R 1Og , R 10i or R 1Oj , may be linked together to form, along with the atom(s) and/or group(s) to which they are attached, a 3- to 8- membered ring, optionally containing 1 to 3 heteroatoms and/or 1 to 3 double bonds, which ring is optionally substituted by one or more substituents selected from G 1 and/or Z 1 .
  • R 4 or, more preferably, R 3 represents -D-E;
  • Q represents -O 5 -S- or, more preferably, a single bond
  • A represents G 1 or C 1-6 alkyl optionally substituted by one or more G 1 groups
  • X 2 represents C 1-6 (e.g. C 1-4 ) alkyl or heterocycloalkyl, both of which are optionally substituted by one or more (e.g. one) G 1 and/or Z 1 groups;
  • R 7 represents C 1-6 alkyl optionally substituted as hereinbefore defined
  • R 8 represents -0R a ;
  • R 713 and R 8b independently represent H, -0R e or C 1-4 (e.g. C 1-3 ) alkyl optionally substituted by one or more (e.g. one) W 2 substituent(s); or R 713 and R 8b are linked together to form a 3- to 6-membered ring optionally containing 1 to 3 (e.g. 1 or 2) heteroatoms and which ring is optionally substituted by one or more substitutents selected from C 1-6 alkyl and W ;
  • R a , R b , R c and R d independently represent H or C 1-4 alkyl optionally substituted by one or more substituents selected from w ;
  • R e , R f , R g and R h independently represent H or, preferably, C 1-4 (e-g- C 1-3 ) alkyl optionally substituted by one or more halo (e.g. fluoro) atoms;
  • R 9a to R 9x independently represent H or C 1-6 alkyl (e.g. C 1-2 alkyl);
  • R 1Oa , R lof , R 10g 5 R loi and R 10j independently represent heteroaryl or, preferably, H or C 1-6 (such as C 1-4 (e.g. C 1-3 )) alkyl, which group is optionally substituted by one or more (e.g. one) groups selected from G 1 ; or any pair of R 9a to R 9x and R 1Oa , R 10f , R 1Og , R loi or R 10j are linked to form a 4- to
  • 7-membered (e.g. 5- or 6-membered) ring which ring may contain (in addition to the nitrogen atom to which R 9a to R 9x is attached) a further heteroatom (e.g. nitrogen or oxygen) and which ring is optionally substituted by one or more (e.g. two) Z 1 groups;
  • G 1 represents halo, cyano, -NO 2 or -A ⁇ R 1 la ;
  • a 1 represents a single bond, -C(O)A 2 -, -N(R 12a )A 4 - or -OA 5 -;
  • a 2 represents -O- or -N(R 12b )-;
  • a 4 and A 5 independently represent -C(O)-, -C(O)N(R 12d )-, -C(O)O- or a single bond;
  • R lla , R llb , R Uo , R 13a , R 13b and R 13c independently represent hydrogen, an aryl group, a heteroaryl group, a heterocyclo alkyl group (such as C 4-8 heterocycloalkyl, which group contains one oxygen or, more preferably, nitrogen atom and, optionally, a further nitrogen or oxygen atom) or, preferably, C 1-6 (e.g. C 1-4 ) alkyl, which latter four groups are optionally substituted by one or more G groups and/or (in the case of alkyl and heterocycloalkyl) Z 3 groups;
  • R 12a , R 12b , R 12c , R 12d , R 12e , R 12f , R 14a , R 14b , R 14c , R 14d , R 14e and R 14f independently represent H or C 1-2 alkyl;
  • G 2 represents cyano, -N 3 or, more preferably, halo, -NO 2 or -A 6 -R I3a ;
  • a 6 represents -N(R 14a )A 9 - or -OA 10 -;
  • a 9 represents ⁇ C(O)N(R 14d )- > -C(O)O- or, more preferably, a single bond or
  • a 10 represents a single bond
  • G 3 represents halo, -NO 2 or -A 1 ! -R 15a ;
  • a 11 represents -N(R 16a )- or -0-;
  • R 19a , R 19b and R 19c independently represent H or C 1-4 (e.g. C 1-3 ) alkyl optionally substituted by one or more halo (e.g. fluoro) atoms.
  • Preferred aryl and heteroaryl groups that R , E and (when they represent such aryl or heteroaryl groups) X 2 , R 9a to R 9x , R 1Oa , R 10f , R 1Og , R 1Oi and R 1Oj may represent include optionally substituted phenyl, naphthyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl (e.g 1-imidazolyl, 2-imidazolyl or 4-imidazolyl), oxazolyl, isoxazolyl, thiazolyl, pyridyl (e.g.
  • R 1 examples include optionally substituted pyridyl (e.g. 2-pyridyl or 3- pyridyl), imidazolyl and, especially, phenyl.
  • pyridyl e.g. 2-pyridyl or 3- pyridyl
  • imidazolyl e.g. imidazolyl
  • phenyl e.g. phenyl
  • Preferred values of E include optionally substituted 1,3-benzodioxolyl (e.g. 1,3- benzodioxol-5-yl), preferably, pyridyl (e.g. 2- or 3-pyridyl), imidazolyl, more preferably quinolinyl (e.g. 3-quinolinyl), and particularly phenyl.
  • 1,3-benzodioxolyl e.g. 1,3- benzodioxol-5-yl
  • pyridyl e.g. 2- or 3-pyridyl
  • imidazolyl more preferably quinolinyl (e.g. 3-quinolinyl)
  • quinolinyl e.g. 3-quinolinyl
  • C 1-4 alkyl including ethyl, n-propyl, isopropyl, «-butyl or, preferably, methyl or t-butyl), n-pentyl, isopentyl, n-hexyl or isohexyl), cyclic (e.g. cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), part-cyclic (e.g. cyclopropylmethyl), unsaturated (e.g.
  • halo e.g. fiuoro
  • heterocycloalkyl such as a C 4-5 heterocycloalkyl group, preferably containing a nitrogen atom and, optionally, a further nitrogen or oxygen atom, so forming for example morpholinyl (e.g. 4-morpholinyl), piperazinyl (e.g.
  • 4- ⁇ iperazinyl) or piperidinyl (e.g. 1-piperidinyl and 4- ⁇ iperidinyl) or pyrrolidinyl (e.g. 1- pyrrolidinyl), which heterocycloalkyl group is optionally substituted by one or more (e.g. one or two) substituents selected from C 1-3 alkyl (e.g. methyl) and 0; -OR 20.
  • piperidinyl e.g. 1-piperidinyl and 4- ⁇ iperidinyl
  • pyrrolidinyl e.g. 1- pyrrolidinyl
  • R 20 and R 21 independently represent, on each occasion when mentioned above, H or C 1-6 alkyl, such as ethyl, n-propyl, n-butyl, t-butyl or, preferably, isopropyl or methyl (which allcyl groups are optionally substituted by one or more halo (e.g. fluoro) groups (to form e.g. a trifluoromethyl group)).
  • halo e.g. fluoro
  • R 6 include C 1-4 alkyl and, particularly, H.
  • Particularly preferred compounds of the invention include those in which:
  • T represents a single bond
  • Y represents -C(O)OR 9b ;
  • R 9b represents C 1-4 alkyl and, particularly, H.
  • More preferred compounds of the invention include those in which: one of R 4 and, more preferably, R 3 represents -D-E and the other (more preferably) represents H;
  • X 1 represents -N(R 9a )-J-R 10a or, more preferably, C 1-3 alkyl (e.g. methyl), heterocycloalkyl (which latter two groups are optionally substituted by
  • G 1 and, preferably, -N(R 12a )R lla , -OR lla , -R lla or halo (e.g. fluoro or chloro)), H or halo (e.g. fluoro or chloro);
  • R 2 represents chloro or, preferably H
  • R 5 represents H;
  • A represents G 1 , or C 1-6 (e.g. C 1-4 ) alkyl (e.g. cyclohexyl or, preferably, methyl or t-butyl) optionally substituted by one or more G 1 groups;
  • G 1 represents cyano or, preferably, fluoro, chloro, -NO 2 or -A ⁇ R 118 ;
  • a 4 represents -C(O)- or, preferably, a single bond
  • a 5 represents a single bond
  • R 9a represents H or methyl
  • R 1Oa represents methyl, t-butyl, pyridyl (e.g. 3- ⁇ yridyl) or propyl (e.g. ⁇ -propyl optionally substituted by a G 1 (e.g. -N(R 12 ⁇ R 1 la ) group); or R 9a and R 1Oa are linked to form a 5- or 6-membered (e.g. 5-membered) ring, which is substituted by one Z group;
  • R lla , R llb and R l lc independently represent a phenyl group, a heteroaryl (such as tetrazolyl (e.g. 5-tetrazolyl), imidazolyl (e.g. 4-imidazolyl or 2-imidazolyl) or a pyridyl (e.g. 3-pyridyl, 4-pyridyl or, especially, 2-pyridyl)) group, or, more preferably, C 1-3 alkyl (e.g. methyl or isopropyl) all of which are optionally substituted by one or more G 3 groups;
  • a heteroaryl such as tetrazolyl (e.g. 5-tetrazolyl), imidazolyl (e.g. 4-imidazolyl or 2-imidazolyl) or a pyridyl (e.g. 3-pyridyl, 4-pyridyl or, especially, 2-pyridyl))
  • R 12a , R 12b , R 12c , R 12d , R 12e and R 12f independently represent H or methyl
  • G represents halo (e.g. fluoro); W 1 , W 2 and W 4 independently represent fluoro, -OCH 3 , -OCH 2 CH 3 , -OCHF 2 ,
  • R 19a , R 19b and R 19c independently represent H or C 1-2 alkyl (e.g. methyl), which latter group is optionally substituted by one or more halo (e.g. fluoro) atoms (so forming, for example, a difluoro- or trifluoro-rnethyl group).
  • halo e.g. fluoro
  • X 1 represents halo
  • R 1 and E independently represent a 6-membered aryl (e.g. phenyl) ring optionally substituted, for example at thep ⁇ r ⁇ -position relative to the point of attachment of the R 1 group to the indole ring, or the E group to the D group, respectively, with a (e.g. a single) G 1 group;
  • aryl e.g. phenyl
  • R 2 , R 4 and R 5 independently represent H
  • R 3 represents -D-E
  • D represents -C(R 7 )(R 8 )-;
  • G 1 represents -A ⁇ R 113 ;
  • a 1 represents a single bond or, more preferably, -OA 5 -;
  • R 7 represents Cj -3 alkyl (e.g. methyl or ethyl) optionally substituted by one or more halo (e.g. fluoro) atoms (so forming, for example, a difluoromethyl or trifluoromethyl group);
  • Particularly preferred compounds of the invention include those in which:
  • R represents 4-isopropoxyphenyl
  • R 7 represents -CH 3 , -CH 2 CH 3 , -CHF 2 or -CF 3 ;
  • R 8 represents -OH, -OCH 3 , -OCH 2 CH 3 , -OCHF 2 or -OCF 3 ;
  • R 713 and R 8b independently represent H, -CH 3 , -CH 2 CH 3 , -CHF 2 , -CF 3 , -OCH 3 ,
  • D represents -C(OH)(CF 3 )-
  • E represents 4-trifluoromethoxyphenyl
  • X 1 represents chloro
  • Particularly preferred compounds of the invention include those of the examples described hereinafter.
  • L 1 represents a suitable leaving group such as chloro, bromo, iodo, a sulfonate group (e.g. -OS(O) 2 CF 3 , -OS(O) 2 CH 3 , -OS(O) 2 PhMe or a nonaflate) or -B(OH) 2 and R 1 is as hereinbefore defined, for example optionally in the presence of an appropriate metal catalyst (or a salt or complex thereof) such as Cu, Cu(OAc) 2 , CuI (or Cul/diamine complex), Pd(OAc) 2 , Pd 2 (dba) 3 or NiCl 2 and an optional additive such as Ph 3 P, 2,2'-bis(diphenylphosphino)-l,r-binaphthyl, xantphos, NaI or an appropriate crown ether such as 18-crown-6-benzene, in the presence of an appropriate base such as NaH, Et 3 N, pyridine, i ⁇ yl
  • This reaction may be carried out at room temperature or above (e.g. at a high temperature, such as the reflux temperature of the solvent system that is employed) or using microwave irradiation;
  • L 2 represents a suitable leaving group such as chloro, bromo, iodo, -B(OH) 2 or a protected derivative thereof, for example a 4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl group, 9- borabicyclo[3.3.1]nonane (9-BBN), -Sn(alkyl) 3 (e.g. -SnMe 3 or -SnBu 3 ), or a similar group known to the skilled person, and X 2 is as hereinbefore defined.
  • L 1 and L 2 will be mutually compatible.
  • preferred leaving groups for compounds of formula V in which Q a is -C(O)- include chloro or bromo groups
  • preferred leaving groups for compounds of formula V in which Q a is a single bond include -B(OH) 2 , 4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl, 9-borabicyclo[3.3.1]nonane (9-BBN), or -Sn(alkyl) 3 .
  • This reaction may be performed, for example in the presence of a suitable catalyst system, e.g.
  • a metal such as CuI, Pd/C, PdCl 2 , Pd(OAc) 2 , Pd(Ph 3 P) 2 Cl 2 , Pd(Ph 3 P) 4 , Pd 2 (dba) 3 or NiCl 2 and a ligand such as ⁇ -Bu 3 P, (C 6 Hn) 3 P, Ph 3 P, AsPh 3 , P(O-ToI) 3 , l,2-bis(diphenylphos ⁇ hino)- ethane, 2,2'-bis(di-tert-butylphosphino)-l,l'-biphenyl, 2,2'-bis(diphenyl- phosphino)-l,l'-bi-naphthyl, l,r-bis(diphenyl-phosphinoferrocene), 1,3- bis(diphenylphosphino)propane, xantphos, or
  • reaction may also be carried out for example at room temperature or above (e.g. at a high temperature such as the reflux temperature of the solvent system) or using microwave irradiation.
  • room temperature e.g. at a high temperature such as the reflux temperature of the solvent system
  • microwave irradiation e.g. at a high temperature such as the reflux temperature of the solvent system
  • certain compounds of formula IV in particular those in which L 1 represents chloro, bromo or iodo
  • L 1 represents chloro, bromo or iodo
  • This reaction may be performed under suitable conditions known to those skilled in the art, for example in the presence of a suitable Lewis acid (e.g. AlCl 3 or FeCl 3 ).
  • a suitable Lewis acid e.g. AlCl 3 or FeCl 3
  • Reaction of a compound of formula V in which L represents -N(C 1-6 alkyl) 2 and X 2 represents optionally substituted aryl (e.g. phenyl) or heteroaryl may be performed in the presence of a reagent such as POCl 3 , for example under reaction conditions described in Bioorg. Med. Chem. Lett, 14, Al Al-Al A5 (2004).
  • POCl 3 may convert the compound of formula V into one in which L represents chloro and/or Q a represents a derivative of -C(O)- (e.g. an iminium derivative), which group may be transformed back to a -C(O)- group before or after reaction with the compound of formula I in which X 1 represents H;
  • X lb represents -N(R 9a )-J-R 10a or -Q-X 2 in which Q represents -O- or -S- and R 9a , J, R 1Oa and X 2 are as hereinbefore defined, for example under reaction conditions such as those hereinbefore described in respect of either process (i) or (ii) above;
  • reaction of a compound of formula VI in which X lb represents -Q-X 2 , Q represents -S- and X 2 represents an optionally substituted aryl (phenyl) or heteroaryl (e.g. 2-pyridyl) group may be performed in the presence of PIFA (PhI(OC(O)CF 3 ) 2 ) in a suitable solvent such as (CF 3 ) 2 CHOH.
  • PIFA PhI(OC(O)CF 3
  • a suitable solvent such as (CF 3 ) 2 CHOH.
  • R 1 , R 2 , R 3 , R 4 , R 5 ,T and Y are as hereinbefore defined under reductive amination conditions in the presence of a compound of formula VIII
  • R lla and R 12a are as hereinbefore defined, under conditions well known to those skilled in the art;
  • X 2b represents H, G 1 or Ci -6 alkyl optionally substituted with one or more s ⁇ bstituents selected from G 1 and/or Z 1 and G 1 and Z are as hereinbefore defined, for example, in the case of a reaction of a compound of formula IV with compound of formula IXA, in the presence of an appropriate catalyst (such as PdCl 2 (PPh 3 ) 2 ), a suitable base (e.g. NaOAc and/or triethylamine) and an organic solvent (e.g. DMF) and, in the case of reaction of a compound of formula VII with either a compound of formula EXB, or IXC, under standard Homer- Wadsworth-Emmons, or Wittig, reaction conditions, respectively;
  • an appropriate catalyst such as PdCl 2 (PPh 3 ) 2
  • a suitable base e.g. NaOAc and/or triethylamine
  • organic solvent e.g. DMF
  • L 3 represents L 1 or L 2 as hereinbefore defined, which group is attached to one or more of the carbon atoms of the benzenoid ring of the indole
  • R 2 -R 5 represents whichever of the three other substituents on the benzenoid ring, i.e. R , R 3 , R 4 and R 5 , are already present in that ring
  • X 1 , R 1 , R 2 , R 3 , R 4 , R 5 , T and Y are as hereinbefore defined, with, a compound of formula XI 5
  • L 4 represents L 1 (when L 3 is L 2 ) or L 2 (when L 3 is L 1 )
  • L 1 , L 2 , E 5 R 7 and R 8 are as hereinbefore defined.
  • the reaction may be performed for example under similar conditions to those described hereinbefore in respect of process step (ii) above. Further, the reaction may be performed by first activating the compound of formula X.
  • the skilled person will appreciate that compounds of formula X may first be activated when L 3 represents halo, by:
  • magnesium of the 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
  • L represents a silicon-based group such as 1Ii-C 1-6 alkyl silane (e.g. trimethyl silane; for example in the presence of a suitable solvent such as THF), or an alkali metal-based group such as a magnesium halide or lithium (for example at low temperatures (e.g. below 0 0 C) in the presence of a polar aprotic solvent such as THF) and R 7 is as hereinbefore defined, all under standard reaction conditions, following by, in the case of reaction with a silicon-based group, removal of the silicon-based group, under standard conditions known to those skilled in the art (e.g.
  • tetrabutylammonium fluoride optionally in the presence of an appropriate solvent such as THF
  • a reagent that is a source of protons e.g. water or saturated ammonium chloride solution
  • R aa represents R a or R d (as appropriate) provided that it does not represent H, under standard conditions known to those skilled in the art.
  • R aa represents R a or R d (as appropriate) provided that it does not represent H, under standard conditions known to those skilled in the art.
  • a suitable base and an appropriate solvent and under conditions such as those described hereinafter in respect of preparation of compounds of formula I (process step (xiv));
  • reaction of a corresponding compound of formula I in which R represents -OH which first comprises the step of converting the -OH group to provide a suitable leaving group, such as a sulfonate group (e.g. tosyl chloride, mesyl chloride, triflic anhydride and the like) and then reaction with a compound of formula XIVA,
  • a suitable leaving group such as a sulfonate group (e.g. tosyl chloride, mesyl chloride, triflic anhydride and the like)
  • Z a represents either -N(R b )(R c ) or -SR d , under standard conditions known to those skilled in the art;
  • J, R 1Oa and L 1 are as hereinbefore defined, for example at around room temperature or above (e.g. up to 60-70 0 C) in the presence of a suitable base (e.g. pyrrolidinopyridine, pyridine, triethylamine, tributylamine, trimethylamine, dimethylaminopyridine, diisopropylamine, l,8-diazabicyclo[5.4.0]undec-7-ene, sodium hydroxide, or mixtures thereof), an appropriate solvent (e.g.
  • a suitable base e.g. pyrrolidinopyridine, pyridine, triethylamine, tributylamine, trimethylamine, dimethylaminopyridine, diisopropylamine, l,8-diazabicyclo[5.4.0]undec-7-ene, sodium hydroxide, or mixtures thereof
  • an appropriate solvent e.g.
  • xv for compounds of formula I in which X 1 represents -N(R 9a )-J-R 1Oa , J represents a single bond and R 1Oa represents a C 1-8 alkyl group, reduction of a corresponding compound of formula I, in which J represents -C(O)- and R 1Oa represents H or a C 1-7 alkyl group, in the presence of a suitable reducing agent.
  • a suitable reducing agent may be an appropriate reagent that reduces the amide group to the amine group in the presence of other functional groups (for example an ester or a carboxylic acid).
  • Suitable reducing agents include borane and other reagents known to the skilled person;
  • N-bromosuccinimide, bromine or 1,2-dibromotetrachloroethane may be employed, for iodide atoms, iodine, diiodoethane, diiodotetrachloroethane or a mixture of
  • NaI or KI and iV-chlorosuccinimide may be employed, for chloride atoms, N- chlorosuccinimide may be employed and for fluoride atoms, l-(chloromethyl)-4- fiuoro-l,4-diazoniabicyclo[2.2.2]octane bis(tetrafiuoroborate), 1-fluoropyridinium triflate, xenon difluoride, CF 3 OF or perchloryl fluoride may be employed.
  • This reaction may be carried out in a suitable solvent (e.g. acetone, benzene or dioxane) under conditions known to the skilled person;
  • L 5 represents an appropriate alkali metal group (e.g. sodium, potassium or, especially, lithium), a -Mg-halide, a zinc-based group or a suitable leaving group such as halo or -B(OH) 2 , or a protected derivative thereof (the skilled person will appreciate that the compound of formula XVII in which L 5 represents an alkali metal (e.g. sodium, potassium or, especially, lithium), a -Mg-halide, a zinc-based group or a suitable leaving group such as halo or -B(OH) 2 , or a protected derivative thereof (the skilled person will appreciate that the compound of formula XVII in which L 5 represents an alkali metal (e.g.
  • a Mg-halide or a zinc-based group may be prepared from a corresponding compound of formula XVII in which L 5 represents halo, for example under conditions such as those hereinbefore described in respect of preparation of compounds of formula I (process step (x) above)), and X 1 , R 1 , R 2 , R 3 , R 4 and R 5 are as hereinbefore defined, with a compound of formula XVIII,
  • T a represents T and Y a represents Y, provided that when Y represents -C(O)OR 9b , -S(O) 3 R 90 , -P(O)(OR 9d )2, -P(O)(OR 9e )N(R 10f )R 9f 5 -P(O)(N(R 10g )R 9 ⁇ ) 2 , -B(OR 9h ) 2 or -S(O) 2 N(R 10i )R 9i , R 9b to R 9i , R 1Of , R 1Og and R 10i are other than H, and L 6 represents a suitable leaving group known to those skilled in the art, such as halo (especially chloro or bromo), for example when Y a represents -C(O)OR 9b or -S(O) 3 R 90 , or C 1-3 alkoxy, for example when Y a represents -B(OR 9h ) 2 .
  • the reaction may be performed under
  • R 9j represents hydrogen
  • reaction of a corresponding compound of formula I in which T represents a C 2 alkylene group substituted at the carbon atom that is attached to the indole ring system by Z 1 , in which Z 1 represents 0 and Y represents -C(O)OR 9b , in which R 9b represents C 1-6 alkyl with hydroxylamine or an acid addition salt thereof, for example in the presence of base (e.g. NaOH), e.g. under similar reaction conditions to those described in inter alia J. Med. Chem. 43, 4930 (2000);
  • base e.g. NaOH
  • R 9k and R 9r represent hydrogen, reaction of a corresponding compound of formula I in which T represents a Ci alkylene group substituted with G 1 , in which G 1 represents -A ⁇ R 11 ", A 1 represents -C(O)A 2 -, A 2 represents a single bond and R lla represents H, and Y represents -C(O)OR 9b , in which R 9b represents methyl, or ethyl, respectively, with hydroxylamine or an acid addition salt thereof, for example in the presence of base (e.g. NaOH, or aniline, respectively) and an appropriate solvent (e.g. methanol, or water, respectively), e.g. under similar reaction conditions to those described in J. Med. Chem. 44, 1051 (2001), or inter alia J. Am. Chem. Soc, 58, 1152 (1936), respectively;
  • base e.g. NaOH, or aniline, respectively
  • solvent e.g. methanol, or water, respectively
  • R 9m and R 9 * 1 represent hydrogen
  • L 6 preferably represents e.g. a halo group, such as Br, or I, respectively, or a protected derivative (e.g. at the OH group with, for example, a benzyl group) of either compound, for example under reaction conditions similar to those described hereinbefore in process (ii) above and/or in Heterocycles, 36, 1803 (1993), or in Bioorg. Med. Chem., 11, 1883 (2003), respectively, followed by (if necessary) deprotection under standard conditions;
  • X 1 , R 1 , R 2 , R 3 , R 4 and R 5 are as hereinbefore defined with ethoxycarbonyl isocyanate in the presence of a suitable solvent (e.g. dichloromethane), followed by refiuxing in the presence of Triton B and an alcoholic solvent (e.g. methanol), for example under similar reaction conditions to those described in J. HeL Chem., 19, 971 (1982);
  • a suitable solvent e.g. dichloromethane
  • Triton B and an alcoholic solvent e.g. methanol
  • R 9s represents hydrogen
  • X 1 , R 1 , R 2 , R 3 , R 4 and R 5 are as hereinbefore defined with a base (e.g. NaH) and CS 2 in the presence of a suitable solvent (e.g. tetrahydrofuran), oxidation of the resultant intermediate in the presence of, for example, hydrogen peroxide, and finally heating the resultant intermediate in the presence of a strong acid, such as HCl, for example under similar reaction conditions to those described in inter alia Bioorg. Med. Chem. Lett., 2, 809 (1992);
  • a base e.g. NaH
  • a suitable solvent e.g. tetrahydrofuran
  • R 9u represents hydrogen
  • reaction of a compound of formula XIX as hereinbefore defined with 3,4-dimethoxycyclobutene-l,2-dione for example in the presence of base (e.g. KOH) and an appropriate solvent (e.g. methanol), followed by acid (e.g. aqueous HCl), e.g. under similar reaction conditions to those described in J. Org. Chem. , 68, 9233 (2003);
  • base e.g. KOH
  • an appropriate solvent e.g. methanol
  • acid e.g. aqueous HCl
  • X 1 , R 1 , R 2 , R 3 , R 4 and R 5 are as hereinbefore defined with NaN 3 under standard conditions; (xxix) for compounds of formula I in which T represents optionally substituted C 2-8 alkenylene or C 2-8 heteroalkylene (in which a point of unsaturation is between the carbon atoms that are ⁇ and ⁇ to the indole ring), reaction of a compound of formula XXII,
  • T a represents a single bond or optionally substituted C 1-6 alkylene or C 2-6 heteroalkylene and Y is as hereinbefore defined, for example under standard Wittig reaction conditions, e.g. in the presence of a suitable organic solvent (e.g. DMF);
  • a suitable organic solvent e.g. DMF
  • T represents optionally substituted, saturated C 2-8 alkylene, saturated cyclo alkylene, saturated C 2-8 heteroalkylene, saturated heterocycloalkylene, C 2-8 alkenylene, cycloalkenylene, C 2-8 heteroalkenylene or heterocycloalkenylene, reduction (e.g.
  • R 9b to R 9e and R 9h do not represent H (and does not represent the same value of the corresponding R 9b to R 9e and R 9h group in the compound of formula I to be prepared), under standard conditions in the presence of the appropriate alcohol of formula XXIII,
  • R 9za represents R 9b to R 9e or R 9h provided that it does not represent H
  • R 9bl represents R 9b provided that it does not represent H
  • L 6 is as hereinbefore defined (e.g. L 6 represents chloro or bromo), under conditions known to those skilled in the art;
  • R 9b OH XXIIIC wherein R 9b is as hereinbefore defined, and an appropriate catalyst system (e.g. a palladium catalyst such as one described hereinbefore in respect of process step (ii)) under conditions known to those skilled in the art;
  • an appropriate catalyst system e.g. a palladium catalyst such as one described hereinbefore in respect of process step (ii)
  • L 7 represents a suitable leaving group, such as a halo or sulfonate group
  • X 2 is as hereinbefore defined, for example in the presence of a base or under reaction conditions such as those described hereinbefore in respect of process (ii) or process (xiii) above;
  • G 1 substituent in which G 1 represents -A ⁇ R 1 la , A 1 represents -OA 5 -, A 5 represents a single bond and R lla represents H, reaction of a corresponding compound of formula I in which X 2 represents C 1-7 alkyl substituted (e.g. ⁇ to the indole ring) by a Z 1 group in which Z 1 represents 0, with the corresponding Grignard reagent derivative of a compound of formula V in which L 2 represents chloro, bromo or iodo, Q a is a single bond and X 2 represents C 1-7 alkyl, under conditions known to those skilled in the art;
  • -Q-X and Q represents a single bond or -C(O)-, a compound of formula V as hereinbefore defined;
  • G 1 represents -A'-R 113 , A 1 represents -N(R 12a )A 4 -, A 4 is a single bond and R lla and R 12a are preferably methyl, reaction of a corresponding compound of formula II in which X 1 represents H, with a mixture of formaldehyde (or equivalent reagent) and a compound of formula VIII as hereinbefore defined, for example under reaction conditions similar to those described hereinbefore in respect of preparation of compounds of formula I (process (viia)) above;
  • reaction of a corresponding compound of formula II in which R 8 represents -OH which first comprises the step of converting the -OH group to provide a suitable leaving group, such as a sulfonate group (e.g. tosyl chloride, mesyl chloride, triflic anhydride and the like) and then reaction with a compound of formula XIVA as hereinbefore defined;
  • a suitable leaving group such as a sulfonate group (e.g. tosyl chloride, mesyl chloride, triflic anhydride and the like)
  • PG represents a suitable protecting group, such as
  • R 9j represents hydrogen
  • reaction of a corresponding compound of formula II in which T represents a C 2 alkylene group substituted at the carbon atom that is attached to the indole ring system by Z 1 , in which Z 1 represents 0 and Y represents -C(O)OR 9b , in which R 9b represents C 1-6 atkyl with hydroxylamine or an acid addition salt thereof, for example under reaction conditions similar to those described hereinbefore in respect of preparation of compounds of formula I (process (xx)) above;
  • R 9 and R 9r represent hydrogen
  • reaction of a corresponding compound of formula II in which T represents a C 1 alkylene group substituted with G 1 in which G 1 represents -A ⁇ R 11 * 1 ,
  • a 1 represents -C(O)A 2 -
  • a 2 represents a single bond and R lla represents H
  • Y represents -C(O)OR 9b , in which R 9b represents methyl, or ethyl, respectively, with hydroxylarnine or an acid addition salt thereof, for example under reaction conditions similar to those described hereinbefore in respect of preparation of compounds of formula I (process (xxi)) above;
  • R 9m and R 9p represent hydrogen
  • L 6 preferably represents e.g. a halo group, such as Br, or I, respectively, or a protected derivative (e.g. at the OH group with, for example, a benzyl group) of either compound, for example under reaction conditions similar to those described hereinbefore in respect of preparation of compounds of formula I (process (xxii)) above;
  • R 9s represents hydrogen
  • reaction of the resultant intermediate with N 4 S 4 for example under reaction conditions similar to those described hereinbefore in respect of preparation of compounds of formula I (process (xxiv)) above;
  • X 1 , R 2 , R 3 , R 4 and R 5 are as hereinbefore defined with a base (e.g. NaH) and CS 2 the presence of a suitable solvent (e.g. tetrahydrofuran), oxidation of the resultant intermediate in the presence of, for example, hydrogen peroxide, and finally heating the resultant intermediate in the presence of a strong acid, such as
  • R 9u represents hydrogen
  • T represents optionally substituted, saturated C 2-8 alkylene, saturated cycloalkylene, saturated C 2-8 heteroalkylene, saturated heterocycloalkylene, C 2 - 8 alkenylene, cycloalkenylene, C 2-8 heteroalkenylene or heterocycloalkenylene, reduction (e.g. hydrogenation) of a corresponding compound of formula II in which T represents optionally substituted C 2-8 alkenylene, cycloalkenylene, C 2-8 heteroalkenylene, heterocycloalkenylene, C 2-8 alkynylene, cycloalkynylene, C 2-8 heteroalkynylene or heterocycloalkynylene (as appropriate);
  • R 9b , R 9c , R 9d or R 9h does not represent H, or, for compounds of formula II in which Y represents -P(O)(OR 9d ) 2 or S(O) 3 R 90 , in which R 9 ° and R 9d represent H, a corresponding compound of formula II in which Y represents either -P(O)(OR 9e )N(R 10f )R 9f , -P(O)(N(R 10g )R 9g ) 2 or -S(O) 2 N(R 10i )R 9i (as appropriate);
  • PG represents a suitable protecting group, such as -S(O) 2 Ph, -C(O)O " , -C(O)OtBu or -C(O)N(Et) 2 ) and L 5 , Q, X 2 , R 2 , R 3 , R and R 5 are as hereinbefore defined, with a compound of formula XXIIIB as hereinbefore defined, for example under reaction conditions similar to those described hereinbefore in respect of preparation of compounds of formula I (process (xxxiii)) above), followed by deprotection of the resultant compound under standard conditions;
  • R 1 and L 2 are as hereinbefore defined or a compound of formula III as hereinbefore defined, for example under reaction conditions similar to those described hereinbefore in respect of preparation of compounds of formula I (processes (ii) and (i), respectively) above; or
  • Compounds of formula VII may be prepared by: (a) for compounds of formula VII in which D represents a single bond, -C(O)-, -C(R 7 XR 8 )-, C 2-4 alkylene or -S(O) 2 -, reaction of a compound of formula XXXVIII,
  • Compounds of formula X may be prepared by reaction of a compound of formula XXVIII as hereinbefore defined, with a compound of formula III as hereinbefore defined, for example under reaction conditions similar to those described hereinbefore in respect of preparation of compounds of formula I (process (i)) above.
  • R 9a is as hereinbefore defined, for example under reaction conditions similar to those described hereinbefore in respect of preparation of compounds of formula I (process (ii)) above).
  • R z represents R 1 (in the case of a compound of formula XVII) or PG (in the case of a compound of formula XXXI), and PG, X 1 , R 1 , R 2 , R 3 , R 4 and R 5 are as hereinbefore defined, with an appropriate base, such lithium diisopropylamide or BuLi under standard conditions.
  • Compounds of formulae XVII and XXXI in which L 5 represents -Mg-halide may be prepared from a corresponding compound of formula XVII or XXXI (as appropriate) in which L 5 represents halo, for example under conditions such as those described hereinbefore in respect of process step (x).
  • Compounds of formulae XVII and XXXI in which L 5 represents, for example, a zinc-based group, or a halo or boronic acid group a group (such as a zinc-based group, halo or a boronic acid) may be prepared by reacting a corresponding compound of formula XVII or XXXI in which L 5 represents an alkali metal with an appropriate reagent for introduction of the relevant group, for example by a metal exchange reaction (e.g.
  • a Zn transmetallation by reaction with a suitable reagent for the introduction of a halo group (for example, a reagent described hereinbefore in respect of preparation of compounds of formula I (process (xvi)) or, for the introduction of a boronic acid group, reaction with, for example, boronic acid or a protected derivative thereof (e.g. bis(pinacolato)diboron or triethyl borate) followed by (if necessary) deprotection under standard conditions.
  • a suitable reagent for the introduction of a halo group for example, a reagent described hereinbefore in respect of preparation of compounds of formula I (process (xvi)
  • a boronic acid group reaction with, for example, boronic acid or a protected derivative thereof (e.g. bis(pinacolato)diboron or triethyl borate) followed by (if necessary) deprotection under standard conditions.
  • R 1 , R 2 , R 3 , R 4 and R 5 are as hereinbefore defined, with an appropriate reagent known to be a suitable source of halide atoms (see for example process (xvi) above in respect of preparation of compounds of formula I).
  • Compounds of formulae XX and XXXIII, and XXII and XXXV may be prepared by reduction of a corresponding compound of formula I, or of formula II, respectively, in which T represents a single bond and Y represents -C(O)OR 9b , to the corresponding primary alcohol (using e.g.
  • Compounds of formulae XXI and XXXTV may be prepared by conversion of a corresponding compound of formula I which T represents a single bond and Y represents -C(O)OR 9b to the corresponding primary amide (e.g. when R 9b is H, by reaction with SOCl 2 followed by ammonia or when R 9b is other than H, by reaction with ammonia), followed by dehydration of the resultant intermediate in the presence of a suitable dehydrating agent, such as POCl 3 , in all cases under reaction conditions that will be well known to those skilled in the art.
  • a suitable dehydrating agent such as POCl 3
  • Compounds of formulae XXVII and XXXVIII, in which Q represents a single bond and X 2a represents -CHO, may be prepared from compounds of formulae II, or X, respectively, in which X 1 represents H, by reaction with a mixture of DMF and, for example, oxalyl chloride, phosgene or P(O)Cl 3 (or the like) in an appropriate solvent system (e.g. DMF or dichloromethane) for example as described hereinbefore.
  • an appropriate solvent system e.g. DMF or dichloromethane
  • Indoles of formulae II, IV 5 VII, X, XIII 5 XV 5 XVII, XIX, XX, XXI, XXII, XXIIIA, XXIV, XXVI 5 XXVII, XXVIII, XXIX, XXX, XXXI, XXXIII, XXXTV, XXXV 5 XXXVA, XXVI, XXVIII, XL, XLI and XLII may also be prepared with reference to a standard heterocyclic chemistry textbook (e.g. "Heterocyclic Chemistry" by J. A. Joule, K.
  • SUB represents the substitution pattern that is present in the relevant compound to be formed (in this case, the compound of formula II, XXVIII or XXIX, respectively)
  • X y represents H, -N(R 9a )- J-R 1Oa or -Q-X 2
  • R 9a , R 1Oa , J 5 Q, X 2 , T and Y are as hereinbefore defined, under Fischer indole synthesis conditions known to the person skilled in the art.
  • T is as hereinbefore defined and preferably a single bond or optionally substituted arylene or heteroarylene
  • Y is as hereinbefore defined and, when T represents a single bond, preferably represents -C(O)OR 9b in which R 9b preferably does not represent hydrogen, under conditions known to the person skilled in the art (i.e. conditions to induce a condensation reaction, followed by a thermally induced cyclisation).
  • R x represents a C 1-6 alkyl group
  • R y represents either R (as required for the formation of compounds of formula XXIV), hydrogen (as required for the formation of compounds of formula XXXVI) or a nitrogen-protected derivative thereof
  • R 1 , R 2 , R 3 , R 4 , R 5 , T and Y are as hereinbefore defined for example under cyclisation conditions known to those skilled in the art.
  • SUB, T and Y are as hereinbefore defined, for example under intramolecular cyclisation conditions known to those skilled in the art.
  • V represents either -C(O)- or -CH 2 -
  • X z represents H, -N(R 9 ⁇ -J-R 1 Oa or -Q-X 2 in which Q represents a single bond or -C(O)- and SUB, R 9a , R 1Oa , J 5 T and
  • V represents -C(O)-
  • the intramolecular cyclisation may be induced by a reducing agent such as TiCl 3 /C 8 K, TiCL/Zn or
  • R m represents OH, 0-C 1-6 alkyl or C 1-6 alkyl and X y , T and Y are as hereinbefore defined, for example under Japp-Klingemann conditions known to the skilled person.
  • T, Y and V are as hereinbefore defined, under standard coupling conditions.
  • the substituents X 1 , R 1 , R 2 , R 3 , R 4 , R 5 , T and Y in final compounds of the invention or relevant intermediates may be modified one or more times, after or during the processes described above by way of methods that are well known to those skilled in the art. Examples of such methods include substitutions, reductions, oxidations, alkylations, acylations, hydrolyses, esterifications, and etherifications.
  • 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.
  • 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.
  • compounds of the invention may possess pharmacological activity as such, certain pharmaceutically-acceptable (e.g. "protected") derivatives of compounds of the invention may exist or be prepared which may not possess such activity, but may be administered parenterally or orally and thereafter be metabolised in the body to form compounds of the invention.
  • Such compounds (which may possess some pharmacological activity, provided that such activity is appreciably lower than that of the "active" compounds to which they are metabolised) may therefore be described as "prodrugs" of compounds of the invention.
  • prodrug of a compound of the invention we include compounds that form a compound of the invention, in an experimentally-detectable amount, within a predetermined time (e.g. about 1 hour), following oral or parenteral administration. All prodrugs of the compounds of the invention are included within the scope of the invention.
  • certain compounds of the invention may possess no or minimal pharmacological activity as such, but may be administered parenterally or orally, and thereafter be metabolised in the body to form compounds of the invention that possess pharmacological activity as such (including, but not limited to, corresponding compounds of formula I 5 in which R 9b represents hydrogen).
  • Such compounds (which also includes compounds that may possess some pharmacological activity, but that activity is appreciably lower than that of the "active" compounds of the invention to which they are metabolised), may also be described as "prodrugs".
  • the compounds of the invention are useful because they possess pharmacological activity, and/or are metabolised in the body following oral or parenteral administration to form compounds which possess pharmacological activity.
  • Compounds of the invention are particularly useful because they may inhibit the activity of a member of the MAPEG family.
  • Compounds of the invention are particularly useful because they may inhibit (for example selectively) the activity of prostaglandin E synthases (and particularly microsomal prostaglandin E synthase-1 (mPGES-1)), i.e. they prevent the action of mPGES-1 or a complex of which the mPGES-1 enzyme forms a part, and/or may elicit a mPGES-1 modulating effect, for example as may be demonstrated in the test described below.
  • Compounds of the invention may thus be useful in the treatment of those conditions in which inhibition of a PGES, and particularly mPGES-1, is required.
  • Compounds of the invention may inhibit the activity of leukotriene C 4 (LTC 4 ) synthase, for example as may be shown in a test such as that described in Eur. J. Biochem., 208, 725-734 (1992), and may thus be useful in the treatment of those conditions in which inhibition of LTC 4 is required.
  • Compounds of the invention may also inhibit the activity of 5-lipoxygenase-activating protein (FLAP), for example as may be shown in a test such as that described in MoI. Pharmacol., 41, 873-879 (1992).
  • FLAP 5-lipoxygenase-activating protein
  • Compounds of the invention 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.
  • compounds of the invention may be useful in the treatment of asthma, chronic obstructive pulmonary disease, pulmonary fibrosis, inflammatory bowel disease, irritable bowel syndrome, inflammatory pain, fever, migraine, headache, low back pain, fibromyalgia, myofascial disorders, viral infections ⁇ e.g. influenza, common cold, herpes zoster, hepatitis C and AIDS), bacterial infections, fungal infections, dysmenorrhea, burns, surgical or dental procedures, malignancies (e.g.
  • 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 the invention may also have effects that are not linked to inflammatory mechanisms, such as in the reduction of bone loss in a subject. Conditions that may be mentioned in this regard include osteoporosis, osteoarthritis, Paget's disease and/or periodontal diseases. Compounds the invention may thus also be useful in increasing bone mineral density, as well as the reduction in incidence and/or healing of fractures, in subjects.
  • a method of treatment of a disease which is associated with, and/or which can be modulated by inhibition of, a member of the MAPEG family such as a PGES (e.g. mPGES- 1), LTC 4 synthase and/or FLAP and/or a method of treatment of a disease in which inhibition of the activity of a member of the MAPEG family such as PGES (and particularly mPGES-1), LTC 4 synthase and/or FLAP is desired and/or required (e.g. inflammation), which method comprises administration of a therapeutically effective amount of a compound of the invention, as hereinbefore defined, to a patient suffering from, or susceptible to, such a condition.
  • 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 mPGES-1), L
  • Patients include mammalian (including human) patients.
  • the term "effective amount” refers to an amount of a compound, which confers a therapeutic effect on the treated patient.
  • the effect may be objective (i.e. measurable by some test or marker) or subjective (i.e. the subject gives an indication of or feels an effect).
  • Compounds of the invention will normally be administered orally, intravenously, subcutaneously, buccally, rectally, dermally, nasally, tracheally, bronchially, sublingually, by any other parenteral route or via inhalation, in a pharmaceutically acceptable dosage form.
  • Compounds of the invention may be administered alone, but are preferably administered by way of known pharmaceutical formulations, including tablets, capsules or elixirs for oral administration, suppositories for rectal administration, sterile solutions or suspensions for parenteral or intramuscular administration, and the like.
  • Such formulations may be prepared in accordance with standard and/or accepted pharmaceutical practice.
  • a pharmaceutical formulation including a compound of the invention, as hereinbefore defined, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.
  • the invention further provides a process for the preparation of a pharmaceutical formulation, as hereinbefore defined, which process comprises bringing into association a compound of the invention, as hereinbefore defined, or a pharmaceutically acceptable salt thereof with a pharmaceutically-acceptable adjuvant, diluent or carrier.
  • Compounds of the invention may also be combined with other therapeutic agents that are useful in the treatment of inflammation (e.g. NSAIDs and coxibs).
  • 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 the invention in conjunction with the other therapeutic agent, and may thus be presented either as separate formulations, wherein at least one of those formulations comprises a compound of the invention, and at least one comprises the other therapeutic agent, or may be presented (i.e. formulated) as a combined preparation (i.e. presented as a single formulation including a compound of the invention and the other therapeutic agent).
  • a pharmaceutical formulation including a compound of the invention, as hereinbefore defined, another therapeutic agent that is useful in the treatment of inflammation, and a pharmaceutically-acceptable adjuvant, diluent or carrier;
  • kit of parts comprising components: (a) a pharmaceutical formulation including a compound of the invention, as hereinbefore defined, in admixture with a pharmaceutically-acceptable adjuvant, diluent or carrier; and
  • a pharmaceutical formulation including another therapeutic agent that is useful in the treatment of inflammation in admixture with a pharmaceutically-acceptable adjuvant, diluent or carrier, which components (a) and (b) are each provided in a form that is suitable for administration in conjunction with the other.
  • the invention further provides a process for the preparation of a combination product as hereinbefore defined, which process comprises bringing into association a compound of the invention, as hereinbefore defined, with another therapeutic agent that is useful in the treatment of inflammation, and a pharmaceutically-acceptable adjuvant, diluent or carrier.
  • kits 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:
  • Compounds of the invention may be administered at varying doses.
  • Oral, pulmonary and topical dosages may range from between about 0.01 mg/kg of body weight per day (mg/kg/day) to about 100 mg/kg/day, preferably about 0.01 to about 10 mg/kg/day, and more preferably about 0.1 to about 5.0 mg/kg/da ⁇ '.
  • 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.
  • the physician or the skilled person, will be able to determine the actual dosage which will be most suitable for an individual patient, which is likely to vary with the route of administration, the type and severity of the condition that is to be treated, as well as the species, age, weight, sex, renal function, hepatic function and response of the particular patient to be treated.
  • the above-mentioned dosages are exemplary of the average case; there can, of course, be individual instances where higher or lower dosage ranges are merited, and such are within the scope of this invention.
  • Compounds of the invention may have the advantage that they are effective, and preferably selective, inhibitors of a member of MAPEG family, e.g. inhibitors of prostaglandin E synthases (PGES) and particularly microsomal prostaglandin E synthase-1 (mPGES-1).
  • PGES prostaglandin E synthases
  • mPGES-1 microsomal prostaglandin E synthase-1
  • the compounds of the invention may reduce the formation of the specific arachidonic acid metabolite PGE 2 without reducing the formation of other COX generated arachidonic acid metabolites, and thus may not give rise to the associated side-effects mentioned hereinbefore.
  • Compounds of the invention may also have the advantage that they may be more efficacious than, be less toxic than, be longer acting than, be more potent than, produce fewer side effects than, be more easily absorbed than, and/or have a better pharmacokinetic profile (e.g. higher oral bioavailability and/or lower clearance) than, and/or have other useful pharmacological, physical, or chemical properties over, compounds known in the prior art, whether for use in the above-stated indications or otherwise.
  • Biological Test e.g. higher oral bioavailability and/or lower clearance
  • mPGES-1 is expressed in E. coli and the membrane fraction is dissolved in 2OmM NaPi-buffer pH 8.0 and stored at -80°C.
  • mPGES- 1 is dissolved in O,1M KPi-buffer pH 7,35 with 2,5mM glutathione.
  • the stop solution consists Of H 2 O / MeCN (7/3), containing FeCl 2 (25 mM) and HCl (0.15
  • the assay is performed at room temperature in 96-well plates. Analysis of the amount of PGE 2 is performed with reversed phase HPLC (Waters 2795 equipped with a 3.9 x 150 mm C18 column). The mobile phase consists OfH 2 O / MeCN (7/3), containing TFA (0.056%), and absorbance is measured at 195 nm with a Waters 2487 UV-detector.
  • Example 1 The compound of Example 1 was tested in the biological test described above and was found to exhibit 50% inhibition of mPGES-1 at a concentration of 10 ⁇ M or below.

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Abstract

There is provided compounds of formula (I): wherein X1, R1, R2, R3, R4, R5, T and Y 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

ENDOLES USEFUL IN THE TREATMENT OF INFLAMMATION
Field of the Invention
This invention relates to novel phamaceutically-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 (MGSTl, 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 5 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 disease0 (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 constitutively5 expressed in many cells and tissues (COX-I), and one that is induced by proinflammatory stimuli, such as cytokines, during an inflammatory response (COX- 2).
COXs metabolise arachidonic acid to the unstable intermediate prostaglandin H20 (PGH2). PGH2 is further metabolized to other prostaglandins including PGE2, PGF2α, PGD2, prostacyclin and thromboxane A2. These arachidonic acid metabolites are known to have pronounced physiological and pathophysiological activity including pro-inflammatory effects. 5 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-I and/or COX-2, thereby O 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 of arachidonic acid, 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 CysLTj. It may be hypothesised that better control of asthma, and possibly also COPD, maybe 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 (MGSTl, 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.
Prior Art
Indole-based compounds have been disclosed in international patent applications WO 96/03377, WO 01/00197, WO 03/044014 and WO 03/057670, US patents Nos. 5,189,054, 5,294,722, 4,960,786, 5,236,916 and 5,374,615 and European patent applications EP 429 257, EP 483 881, EP 547 556, EP 639 573, EP 1 314 733 and EP 488 532. However, none of these documents disclose or suggest the use of such compounds in the treatment of inflammation. Indoles have also been disclosed for potential use in the treatment of inflammation in international patent applications WO 99/43672, WO 98/08818, WO 99/43654, WO 99/43651, WO 99/05104 and WO 03/029212, European patent application EP 986 666 and US patents Nos. 6,500,853 and 6,630,496. However, there is no specific disclosure in any of these documents of indole-2-carboxylates in which an aromatic group is directly attached via the indole nitrogen.
International patent application WO 01/30343, and European patent application EP 186 367, also mention indoles for potential use as PPAR-γ binding agents, and in the treatment of inflammation, respectively. However, these documents do not mention or suggest compounds in which the benzenoid moiety of the indole is either substituted with an aromatic ring or directly substituted with a cycloalkyl or heterocycloalkyl ring. Further, Dropinski et al, Bioorganic and Medicinal Chemistiγ Letters, 15 (2005) 5035-5038 discloses various indoles for use as
PPAR-γ partial agonists. There is no mention or suggestion of the use of such compounds as inhibitors of mPGES in that document.
Various 1 (N)-benzylmdole-2-carboxylates and derivatives thereof are known from international patent applications WO 99/33800 as Factor Xa inhibitors; WO
99/07678, WO 99/07351, WO 00/46198, WO 00/46197, WO 00/46195 and WO
00/46199 as inhibitors of MCP-I; international patent application WO 96/18393 as inhibitors of IL-8; international patent applications WO 93/25546 and WO
94/13662, European patent application EP 535 924 Al and US patent No. 5,081,138 as inhibitors of leukotriene biosynthesis; international patent application
WO 02/30895 as PPAR-γ binding agents; and European patent application EP 166
591 as prostaglandin antagonists. Further, international patent application WO
2005/005415 discloses such compounds for use as inhibitors of mPGES and thus in the treatment of inflammation. However, there is no specific disclosure in any of these documents of indole-2-carboxylates in which an aromatic group is directly attached via the indole nitrogen. International patent applications WO 2005/123675, WO 2005/123673 and WO 2005/123674 disclose indoles for use as inhibitors of mPGES and thus in the treatment of inflammation. However, there is no suggestion of indoles which are substituted at the benzenoid moiety of the indole ring with an aromatic group that is attached via a linking group.
Further, unpublished patent application PCT/GB2005/004978 discloses inter alia indole-2-carboxylic acids that are substituted at the benzenoid moiety of the indole with an aromatic group that is attached via a linker group. Unpublished patent application PCT/GB2005/0049828 also discloses similar indoles but in which the indole-2-substituent is inter alia a carboxylic acid isostere.
However, there is no disclosure in either of the above-mentioned applications of corresponding indoles in which the relevant linker group (between the benzenoid moiety of the indole ring and the requisite aromatic group) is either a methylene group that is itself further substituted with at least one heteroatom or an unsaturated spirocyclic ring. Nor is there any specific disclosure in either of these documents of corresponding indoles in which the relevant linker group is a methylene group substituted with an exocyclic double bond.
Finally, international patent application WO 94/14434 discloses structurally similar indoles as endothelin receptor antagonists. However, there is no mention or suggestion of indole-2-carboxylates that are substituted by an aromatic group at the benzenoid moiety of the indole ring via a methylene linker group that is either itself further substituted with at least one heteroatom or an exocyclic double bond or via a linker group that is an unsaturated spirocyclic group.
Disclosure of the Invention
According to the invention there is provided a compound of formula I,
Figure imgf000008_0001
wherein
one of the groups R2, R3, R4 and R5 represents -D-E and: a) the other groups are independently selected from hydrogen, G1, C1-8 alkyl and a heterocycloalkyl group (which latter two. groups are optionally substituted by one or more substituents selected from G1 and/or Z1), an aryl group and a heteroaryl group (which latter two groups are optionally substituted by one or more substituents selected from A); and/or b) any two other groups which are adjacent to each other are optionally linked to form, along with two atoms of the essential benzene ring in the compound of formula I, a 3- to 8-membered ring, optionally containing 1 to 3 heteroatoms, which ring is itself optionally substituted by one or more substituents selected from halo, -R6, -OR6 and =0;
D represents -C(R7)(R8)- or -C(=C(R7b)(R8b))-;
R1 and E independently represent an aryl group or a heteroaryl group, both of which groups are optionally substituted by one or more substituents selected from
A;
R7 represents C1-6 alkyl, optionally substituted by one or more substituents selected from W1, or R7a; or
R7 and R8 are linked together with the carbon atom to which they are attached to form a 3- to 6-membered ring, which ring contains at least one (e.g. one) unsaturation (e.g. a triple or, preferably, a double bond), optionally contains a heteroatom and is optionally substituted by one or more substituents selected from halo and C1-3 alkyl, which latter group is optionally substituted by one or more halo substituents;
R7a and R8 independently represent -ORa, -N(Rb)(R°) or -SRd; .
R^ and R8b independently represent hydrogen, -ORe, -N(Rf)(Rg), -SRh or C1-6 allcyl optionally substituted by one or more substituents selected from W ; or R713 and R8b are linked together to form, together with the carbon atom to which they are necessarily attached, a 3- to 6-membered ring optionally containing 1 to 3 heteroatoms and 1 to 3 unsaturations (e.g. double bonds) and which ring is optionally substituted by one or more substituents selected from C1-6 alkyl (which is optionally substituted by one or more halo atoms) and W ;
Ra, Rb, RG, Rd, Re, Rf, Rε and Rh independently represent H or C1-6 alkyl optionally substituted by one or more substituents selected from "w ; or any pair of Rb and R°, or Rf and Rε are linked together with the nitrogen atom to which they are necessarily attached to form a 3- to 6-membered ring optionally containing 1 to 3 heteroatoms and 1 to 3 unsaturations (e.g. double bonds) and which ring is optionally substituted by one or more substituents selected from C1-6 alkyl (which is optionally substituted by one or more halo atoms) and W ;
X1 represents H, halo, -N(R9a)-J-R10a or -Q-X2;
J represents a single bond, -C(O)- or -S(O)m-;
Q represents a single bond, -O-, -C(O)- or -S(O)m-;
X2 represents: (a) an aryl group or a heteroaryl group, both of which are optionally substituted by one or more substituents selected from A; or (b) C1-8 alkyl or a heterocycloalkyl group, both of which are optionally substituted by one or more substituents selected from G1 and/or Z ;
T represents: (a) a single bond;
(b) a C1-S alkylene or a C2-8 heteroalkylene chain, both of which latter two groups:
(i) optionally contain one or more unsaturations (for example double or triple bonds);
(ii) are optionally substituted by one or more substituents selected from G1 and/or Z1; and/or
(iii) may comprise an additional 3- to 8-membered ring formed between any one or more (e.g. one or two) members of the C1-8 alkylene or C2-S heteroalkylene chain, which ring optionally contains 1 to 3 heteroatoms and/or 1 to 3 unsaturations (for example double or triple bonds) and which ring is itself optionally substituted by one or more substituents selected from G1 and/or Z1;
(c) an arylene group or a heteroarylene group, both of which groups are optionally substituted by one or more substituents selected from A; or
(d) -Tl-Wx-T2-;
one of T1 and T2 represents a C1-8 alkylene or a C2-8 heteroalkylene chain, both of which latter two groups:
(i) optionally contain one or more unsaturations (for example double or triple bonds); (ii) are optionally substituted by one or more substituents selected from G and/or Z1; and/or
(iii) may comprise an additional 3- to 8-membered ring formed between any one or more (e.g. one or two) members of the C1-8 alkylene or C2-S heteroalkylene chain, which ring optionally contains 1 to 3 heteroatoms and/or 1 to 3 unsaturations (for example double or triple bonds) and which ring is itself optionally substituted by one or more substituents selected from G1 and/or Z1; and the other represents an arylene group or a heteroarylene group chain, both of which groups are optionally substituted by one or more substituents selected from
A;
Wx represents -O- or -S(O)m-;
m represents, on each occasion when mentioned above, 0, 1 or 2;
Y represents -C(H)(CF3)OH5 -C(O)CF3, -C(OH)2CF3, -C(O)OR9b, -S(O)3R9c, -P(O)(OR9d)2, -P(O)(OR9e)N(R10f)R9f, -P(O)(N(R10g)R9g)2, -B(OR9h)2, -C(CF3)2OH, -S(O)2N(R10i)R9i or any one of the following groups:
Figure imgf000011_0001
Figure imgf000011_0003
Figure imgf000011_0002
Figure imgf000011_0004
R6, R9a to R9x, R1Oa, R1Of, R1Oε, R1Oi and R1Oj independently represent, on each occasion when mentioned above:
I) hydrogen;
II) an aryl group or a heteroaryl group, both of which are optionally substituted by one or more substituents selected from B; or
III) C1-8 alkyl or a heterocycloalkyl group, both of which are optionally substituted by one or more substituents selected from G and/or Z1; or any pair of R9a to R9x and R1Oa, R10f, R1Og, Rloi or R10j 5 may be linked together to form, along with the atom(s) and/or group(s) to which they are attached, a 3- to 8- membered ring, optionally containing 1 to 3 heteroatoms and/or 1 to 3 double bonds, which ring is optionally substituted by one or more substituents selected from G1 and/or Z1;
A represents, on each occasion when mentioned above:
I) an aryl group or a heteroaryl group, both of which are optionally substituted by one or more substituents selected from B; II) C1-8 alkyl or a heterocycloallcyl group, both of which are optionally substituted by one or more substituents selected from G1 and/or Z1; or III) a G1 group;
G1 represents, on each occasion when mentioned above, halo, cyano, -N3, -NO2, -ONO2 or -A^R113; wherein A1 represents a single bond or a spacer group selected from -C(O)A2-,
-S(O)2A3-, -N(R12a)A4- or -OA5-, in which:
A2 represents a single bond, -0-, -N(R12b)- or -C(O)-;
A3 represents a single bond, -O- or -N(R12c)-; A4 and A5 independently represent a single bond, -C(O)-, -C(0)N(R12d)-, -C(O)O-,
-S(0)2- or -S(0)2N(R12e)-;
Z1 represents, on each occasion when mentioned above, =0, =S, =N0R , =NS(O)2N(R12f)Rllc, =NCN or =C(H)N02;
B represents, on each occasion when mentioned above:
I) an aryl group or a heteroaryl group, both of which are optionally substituted by one or more substituents selected from G ;
II) C1-S alkyl or a heterocycloalkyl group, both of which are optionally substituted by one or more substituents selected from G2 and/or Z2; or
III) a G2 group; G2 represents, on each occasion when mentioned above, halo, cyano, -N3, -NO2, -ONO2 or -A6-R13a; wherein A6 represents a single bond or a spacer group selected from -C(O)A7-, -S(O)2A8-, -N(R14a)A9- or -OA10-, in which: A7 represents a single bond, -0-, -N(R14b)- or -C(O)-; A8 represents a single bond, -O- or -N(R14c)-;
A9 and A10 independently represent a single bond, -C(O)-, -C(O)N(R14d)-, -C(O)O-, -S(O)2- or -S(O)2N(R146)-;
Z2 represents, on each occasion when mentioned above, =0, =S, =N0R , =NS(O)2N(R14f)R13c, =NCN Or=C(H)NO2;
U 11a Ti Hb -n llc τ> 12a τ> 12b τ» 12c τ> 12d r> 12e τ» 12f r> 13a τ> 13b D 13c τ> 14a τ> 14b τ> 14c
R14d, R14e and R14f are independently selected from: i) hydrogen; ii) an aryl group or a heteroaryl group, both of which are optionally substituted by one or more substituents selected from G3; iii) C1-8 alkyl or a heterocycloalkyl group, both of which are optionally substituted by G3 and/or Z3; or ■ any pair of Rlla to Rllc and R12a to R12f, and/or R13a to R13c and R14a to R14f, may, for example when present on the same or on adjacent atoms, be linked together to form with those, or other relevant, atoms a further 3- to 8-membered ring, optionally containing 1 to 3 hetero atoms and/or 1 to 3 double bonds, which ring is optionally substituted by one or more substituents selected from G3 and/or Z3; ■
G3 represents, on each occasion when mentioned above, halo, cyano, -N3, -NO2,
-ONO2 or -A1 ^R15'; wherein A represents a single bond or a spacer group selected from -C(O)A -, -S(O)2A13-, -N(R16a)A14- or -OA15-, in which: A12 represents a single bond, -0-, -N(R16b)- or -C(O)-; A13 represents a single bond, -O- or -N(R160)-; T/GB2007/002704
13
A14 and A15 independently represent a single bond, -C(O)-, -C(0)N(R16d)-, -C(O)O-, -S(O)2- or -S(O)2N(R166)-;
Z represents, on each occasion when mentioned above, =0, =S, =N0R , =NS(O)2N(R16f)R15c, =NCN or =C(H)NO2;
R15a, R15b, R150, R16a, R16b, R16c, R16d, R16e and R16f are independently selected from: i) hydrogen; ii) C1-6 alkyl or a heterocycloalkyl group, both of which groups are optionally substituted by one or more substituents selected from halo, C1-4 alkyl, -N(R17a)R18a, -0R17b and =0; and iii) an aryl or heteroaryl group, both of which are optionally substituted by one or more substituents selected from halo, C1-4 alkyl, -N(R17c)R18b and -0R17d; or any pair of R15a to R15c and R16a to R16f may, for example when present on the same or on adjacent atoms, be linked together to form with those, or other relevant, atoms a further 3- to 8-membered ring, optionally containing 1 to 3 heteroatoms and/or 1 to 3 double bonds, which ring is optionally substituted by one or more substituents selected from halo, C1-4 alkyl, -N(R17e)R18c, -OR17f and =0;
R17a, R17b, R17c, R17d, R17e, R17f, R18a, R18b and R18° are independently selected from hydrogen and C1-4 alkyl, which latter group is optionally substituted by one or more halo groups;
W1, W2, W3, W4 and W5 independently represent halo, =0, -OR19a or
Figure imgf000014_0001
R19a, R19b and R19° independently represent H or Ci-6 alkyl optionally substituted by one or more substituents selected from halo and =0,
or a pharmaceutically-acceptable salt thereof, which compounds and salts are referred to hereinafter as "the compounds of the invention".
Pharmaceutically-acceptable salts include acid addition salts and base addition salts. Such salts may be formed by conventional means, for example by reaction of a free acid or a free base form of a compound of formula I with one or more equivalents of an appropriate acid or base, optionally in a solvent, or in a medium in which the salt is insoluble, followed by removal of said solvent, or said medium, using standard techniques (e.g. in vacuo, by freeze-drying or by filtration). Salts may also be prepared by exchanging a counter-ion of a compound of the invention in the form of a salt with another counter-ion, for example using a suitable ion exchange resin.
Compounds of the invention may contain double bonds and may thus exist as E (entgegeri) and Z (zusammen) geometric isomers about each individual double bond. All such isomers and mixtures thereof are included within the scope of the invention.
Compounds of the invention may also exhibit tautomerism. All tautomeric forms and mixtures thereof are included within the scope of the invention.
Compounds of the invention may also contain one or more asymmetric carbon atoms and may therefore exhibit optical and/or diastereoisomerism. Diastereoisomers may be separated using conventional techniques, e.g. chromatography or fractional crystallisation. The various stereoisomers may be isolated by separation of a racemic or other mixture of the compounds using conventional, e.g. fractional crystallisation or 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, and C1-q alkylene, groups (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 two or three, as appropriate) of carbon atoms, be branched-chain, and/or, in the case of alkyl, 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. Such alkyl and alkylene groups may also be saturated or, when there is a sufficient number (i.e. a rmnimum of two) of carbon atoms, be unsaturated (forming, for example, in the case of alkyl, a C2-q alkenyl or a C2-q alkynyl group or, in the case of alkylene, a C2-q alkenylene or a C2-q alkynylene group).
Cycloalkyl groups that may be mentioned include non-aromatic C3-16, such as C3-1O, cycloalkyl groups. C3-q cycloalkyl groups (where q is the appropriate upper limit of the range) may be monocyclic or bicyclic alkyl groups, which cycloalkyl groups may further be bridged (so forming, for example, fused ring systems such as three fused cycloalkyl groups). Such cycloalkyl groups may be saturated or unsaturated containing one or more double or triple bond (forming for example a C3-q cycloalkenyl or a C8-q cycloalkynyl group). Cycloalkyl groups that may be mentioned include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclooctynyl, bicycloheptyl, bicyclooctyl, and bicyclooctenyl, as well as bridged cycloalkyl groups, such as adamantyl, noradamantyl, norbornane, norbornene and norbornadiene groups. Substituents may be attached at any point on the cycloalkyl group. Further in the case where the substituent is another cyclic compound, then the cyclic substituent may be attached through a single atom on the cycloalkyl group, forming a so-called "spiro"-compound. Preferred cycloalkyl groups include optionally substituted C3-g cycloalkyl groups, which groups optionally contain one unsaturation (e.g. a double bond). Cycloalkyl groups that may be mentioned include optionally substituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl (e.g. cyclopenten-1-yl), cyclohexenyl (e.g. cyclohexen-1-yl) and norbornanyl (e.g. norbornan-2-yl).
The term "halo", when used herein, includes fluoro, chloro, bromo and iodo.
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 C3-q heterocycloalkynyl group. C2-q heterocycloalkyl groups that may be mentioned include 7- azabicyclo[2.2. ljheptanyl, 6-azabicyclo[3.1. ljheptanyl, 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. ljheptanyl, 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-tetrahydroρyridyl), thietanyl, thiiranyl, thiolanyl, thiomorpholinyl, trithianyl (including 1,3,5-trithianyl), tropanyl and the like. Substituents on heterocycloallcyl groups may, where appropriate, be located on any atom in the ring system including a heteroatom. Further, in the case where the other substituent is another cyclic compound, then the cyclic compound may be attached through a single atom on the heterocycloalkyl group, forming a so- called "sρiro"-comρound. 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 JV- or S- oxidised form. When, for example, one of R2, R3, R4 and R5 represents a cycloalkyl or a heterocycloalkyl group, preferred heterocycloalkyl groups include optionally substituted 5 to 6-membered heterocyclic groups containing at least one oxygen or, more preferably, nitrogen atom and, optionally, a further nitrogen and/or oxygen atom. Heterocycloalkyl groups that may be mentioned include optionally substituted pyrrolidinyl (e.g. pyrrolidin-1-yl), morpholinyl (e.g. 4-morpholin-l-yl), piperazinyl (e.g. piperazin-1-yl), piperidinyl (e.g. piperidin-1-yl and piperidin-4-yl) and tetrahydropyridyl (e.g. 1,2,3,6- tetrahydropyridin-2-yl) groups.
For the avoidance of doubt the term -C(=C(R7b)(R8b))- represents the following substructure:
Figure imgf000018_0001
in which R71' and R8b are as hereinbefore defined and the asterisks (at each point) indicate the point of attachment with the group E or with the benezenoid moiety of the indole ring of formula I (as appropriate).
For the avoidance of doubt, the term "bicyclic", when employed in the context of cycloalkyl and heterocycloalkyl groups refers to such groups in which the second ring is formed between two adjacent atoms of the first ring. The term "bridged", when employed in the context of cycloalkyl or heterocycloalkyl groups refers to monocyclic or bicyclic groups in which two non-adjacent atoms are linked by either an alkylene or heteroalkylene chain (as appropriate). Aryl groups that may be mentioned include C6-14 (such as C6-13 (e.g. C6-1o)) 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. However, when aryl groups are bicyclic or tricyclic, they are linked to the rest of the molecule via an aromatic ring.
Heteroaryl groups that may be mentioned include those which have between 5 and 14 (e.g. 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). Heterocyclic groups that may be mentioned include benzothiadiazolyl (including 2,1,3-benzothiadiazolyl), isothiochromanyl and, more preferably, acridinyl, benzimidazolyl, benzodioxanyl, benzodioxepinyl, benzodioxolyl (including 1,3- benzodioxolyl), benzofuranyl, benzofurazanyl, benzothiazolyl, benzoxadiazolyl (including 2,1,3-benzoxadiazolyl), benzoxazinyl (including 354-dihydro-2i?-l,4- benzoxazinyl), benzoxazolyl, benzomorpholinyl, benzoselenadiazolyl (including 2,1,3-benzoselenadiazolyl), benzothienyl, carbazolyl, chromanyl, cinnolinyl, furanyl, imidazolyl, imidazo[l,2-α]ρyridyl, indazolyl, indolinyl, indolyl, isobenzofuranyl, isochromanyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiaziolyl, isoxazolyl, naphthyridinyl (including 1,6-naphthyridinyl or, preferably, 1,5-naphthyridinyl and 1,8-naphthyridinyl), oxadiazolyl (including 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl and 1,3,4-oxadiazolyl), oxazolyl, phenazinyl, phenothiazinyl, phfhalazinyl, 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 1,3,4-thiadiazolyl), thiazolyl, thiochromanyl, thienyl, triazolyl (including 1,2,3-triazolyl, 1 ,2,4-triazolyl and 1,3,4-triazolyl) and the like. Substitαents 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. Heteroaryl groups may also be in the 7V- or S- oxidised form.
Heteroatoms that may be mentioned include phosphorus, silicon, boron, tellurium, selenium and, preferably, oxygen, nitrogen and sulphur.
For the avoidance of doubt, in cases in which the identity of two or more substituents in a compound of the invention may be the same, the actual identities of the respective substituents are not in any way interdependent. For example, in the situation in which R1 and X2 are both aryl groups substituted by one or more C1-S alkyl groups, the alkyl 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 X2 and/or R1 represents e.g. an aryl group substituted by G1 in addition to, for example, C1-S alkyl, which latter group is substituted by G1, the identities of the two G1 groups are not to be regarded as being interdependent.
For the avoidance of doubt, when a term such as "R2 to R5" is employed herein, this will be understood by the skilled person to mean R2, R3, R4 and R5 inclusively.
As stated hereinbefore, any pair of Rlla to RUc and R12a to R12f, may be linked as hereinbefore defined. For the avoidance of doubt, such Rlla to Rllc groups, and R12a to R12f groups may be attached to a single nitrogen atom (e.g. Rlla and R12a or Rllc and R12f), which may form part of the ring.
For the avoidance of doubt, when a term such as "R9a to R9x" is employed herein, this will be understood by the skilled person to mean R9a, R9b, R9°, R9d, R9e, R9f, R9g, R9h, R9i, R9j, R9k, R9m, R9n, R9p, R9q, R9r, R9s, R9t, R9u, R9v, R9w and R9x inclusively.
Any pair of R9a to R9x and R1Oa, R1Of, R1Og, R10i or R10j, may be linked together to form a ring as hereinbefore defined. Thus R9a to R9x, R1Oa, R10f, R1Og, R1Oi and R1Oj groups may be attached to (a) a single nitrogen atom (e.g. R9f and R1Of), or (b) a nitrogen atom and a J group (i.e. R9a and R1Oa), which also form part of the ring, or two R9a to R9x (e.g. two R9d) groups may be attached to different oxygen atoms (for example in a 1,3-relationship) all of which may form part of the ring.
Compounds of the invention that may be mentioned include those in which: D represents -C(R7)(R8)- in which R7 and R8 are as hereinbefore defined; R and R are not linked together as hereinbefore defined.
Compounds of the invention that may also be mentioned also include those in which D represents -C(=C(R7b)(Rsb))- in which R^ and R8b are as hereinbefore defined.
Compounds of the invention that may be mentioned include those in which, when one of the groups R2, R3, R4 and R5 represents -D-E, then: a) the other groups are independently selected from hydrogen, G1, C1-S alkyl and a heterocycloalkyl group (which latter two groups are optionally substituted by one or more substituents selected from G and/or Z ); and/or b) any two other groups which are adjacent to each other are optionally linked to form, along with two atoms of the essential benzene ring in the compound of formula I5 a 3- to 8-membered ring, optionally containing 1 to 3 heteroatoms (and/or, for example, 1 to 3 double bonds), which ring is itself optionally substituted by one or more substituents selected from halo, -R6, -OR6 and =0.
Further compounds of the invention that may be mentioned include those in which, when one of the groups R2, R3, R4 and R5 represents -D-E and one or more of the other groups represent G1 then, when G1 represents -A^R1 la, A1 represents a single bond, then Rlla represents hydrogen, Ci-8 alkyl or a heterocycloalkyl group (which latter two groups are optionally substituted by one or more substituents selected from G3 and/or Z3).
Yet further compounds of the invention that may be mentioned include those in which, when one of the groups R2, R3, R4 and R5 represents -D-E and one or more of the other groups represent G1 then, when G1 represents -A^R1 la, A1 represents a spacer group selected from -C(O)A2-, -S(O)2A3-, -N(R12a)A4- or -OA5-.
Compounds of the invention that may be mentioned also include those in which when X is -Q-X , Q is a single bond and X is either:
(a) an aryl group or a heteroaryl group, which groups are substituted by A in which A is G1; or
(b) Ci-8 alkyl or a heterocycloalkyl group, which groups are substituted by G1, and, in either case, G1 is -A^R11*1, then A represents a single bond or a spacer group selected from -C(O)-, -S(O)2-, -S(O)2N(R12c)-, -N(R12a)A4- or -OA5-.
Further compounds of the invention that may be mentioned include those in which when X1 represents -Q-X2, Q is a single bond, X2 is C1-8 alkyl substituted by G1, G1 is -A^R113, A1 is a single bond, Rlla represents an aryl group, a heteroaryl group or a heterocycloalkyl group, all of which groups are substituted by G3, and G3 is -An-R15a, then A11 represents a single bond or a spacer group selected from -C(O)-, -S(O)2-, -S(O)2N(R160)-, -N(R16a)A14- or -OA15-.
Yet further compounds of the invention that may be mentioned include those in which when X1 is -Q-X2, X2 represents C1-8 alkyl terminally substituted by both Z1 and G1, in which Z1 represents =0 and G1 represents -A^R1 la, then when A1 represents -N(R12a)A4-, A4 represents -C(O)-, -C(0)N(R12d)-, -C(O)O- or -S(O)2N(R126), and when A1 represents -OA5-, A5 represents -C(O)-, -C(0)N(R12d)-, -C(O)O-, -S(O)2- or -S(O)2N(R126). Still further compounds the invention that may be mentioned include those in which when Y represents either:
Figure imgf000023_0001
and T represents C1-8 alkylene or C2-8 heteroalkylene, both of which are substituted at the carbon atom that is adjacent to Y by Z1, then Z1 represents =S, ^=NOR1 lb, =NS(O)2N(R12f)Rllc, =NCN or =C(H)NO2.
Preferred compounds of the invention include those in which: R6 and, more particularly, R9a to R9x, R1Oa, R10f, R1Og, R1Oi and R10j independently represent, on each occasion when mentioned above:
I) hydrogen; or
II) C1-8 alkyl or a heterocycloalkyl group, both of which are optionally substituted by one or more substituents selected from G1 and/or Z1; or any pair of R9a to R9x and R1Oa, R1Of, R1Og, R10i or R1Oj, may be linked together to form, along with the atom(s) and/or group(s) to which they are attached, a 3- to 8- membered ring, optionally containing 1 to 3 heteroatoms and/or 1 to 3 double bonds, which ring is optionally substituted by one or more substituents selected from G1 and/or Z1.
Further preferred compounds of the invention include those in which:
R4 or, more preferably, R3 represents -D-E;
Q represents -O5 -S- or, more preferably, a single bond;
A represents G1 or C1-6 alkyl optionally substituted by one or more G1 groups;
X2 represents C1-6 (e.g. C1-4) alkyl or heterocycloalkyl, both of which are optionally substituted by one or more (e.g. one) G1 and/or Z1 groups;
R7 represents C1-6 alkyl optionally substituted as hereinbefore defined;
R8 represents -0Ra;
R713 and R8b independently represent H, -0Re or C1-4 (e.g. C1-3) alkyl optionally substituted by one or more (e.g. one) W2 substituent(s); or R713 and R8b are linked together to form a 3- to 6-membered ring optionally containing 1 to 3 (e.g. 1 or 2) heteroatoms and which ring is optionally substituted by one or more substitutents selected from C1-6 alkyl and W ;
Ra, Rb, Rc and Rd independently represent H or C1-4 alkyl optionally substituted by one or more substituents selected from w ;
Re, Rf, Rg and Rh independently represent H or, preferably, C1-4 (e-g- C1-3) alkyl optionally substituted by one or more halo (e.g. fluoro) atoms;
R9a to R9x independently represent H or C1-6 alkyl (e.g. C1-2 alkyl);
R1Oa, Rlof, R10g 5 Rloi and R10j independently represent heteroaryl or, preferably, H or C1-6 (such as C1-4 (e.g. C1-3)) alkyl, which group is optionally substituted by one or more (e.g. one) groups selected from G1; or any pair of R9a to R9x and R1Oa, R10f, R1Og, Rloi or R10j are linked to form a 4- to
7-membered (e.g. 5- or 6-membered) ring, which ring may contain (in addition to the nitrogen atom to which R9a to R9x is attached) a further heteroatom (e.g. nitrogen or oxygen) and which ring is optionally substituted by one or more (e.g. two) Z1 groups;
G1 represents halo, cyano, -NO2 or -A^R1 la;
A1 represents a single bond, -C(O)A2-, -N(R12a)A4- or -OA5-;
A2 represents -O- or -N(R12b)-; A4 and A5 independently represent -C(O)-, -C(O)N(R12d)-, -C(O)O- or a single bond;
Z1 represents =NORllb, =NCN or, preferably, =0;
Rlla, Rllb, RUo, R13a, R13b and R13c independently represent hydrogen, an aryl group, a heteroaryl group, a heterocyclo alkyl group (such as C4-8 heterocycloalkyl, which group contains one oxygen or, more preferably, nitrogen atom and, optionally, a further nitrogen or oxygen atom) or, preferably, C1-6 (e.g. C1-4) alkyl, which latter four groups are optionally substituted by one or more G groups and/or (in the case of alkyl and heterocycloalkyl) Z3 groups;
R12a, R12b, R12c, R12d, R12e, R12f, R14a, R14b, R14c, R14d, R14e and R14f independently represent H or C1-2 alkyl;
G2 represents cyano, -N3 or, more preferably, halo, -NO2 or -A6-RI3a; A6 represents -N(R14a)A9- or -OA10-; A9 represents ~C(O)N(R14d)-> -C(O)O- or, more preferably, a single bond or
-C(O)-;
A10 represents a single bond;
Z2 represents =N0R13b or =NCN or, more preferably, =0; G3 represents halo, -NO2 or -A1 !-R15a;
A11 represents -N(R16a)- or -0-;
Z3 represents =0;
J represents a single bond or, preferably, -C(O)- or -S(O)2-; when any one of R15a, R15b, R15c, R16a, R16b, R16c, R16d, R16e and R16f represents optionally substituted C1-6 alkyl, the optional substituent(s) is/are one or more halo groups; when any one of R17a, R17b, R17c, R17d, R17e, R17f, R18a, R18b and R18c represents optionally substituted C1-4 alkyl, the optional substituent(s) is/are one or more fluoro groups; W1 and W4 independently represent halo (e.g. fluoro), -OR19a or =O;
W2 represents -0R19a, =0 or, more preferably, halo (e.g. fluoro); when any pair of Rb and Rc, R713 and R8b or Rf and Rg are linked together to form an optionally substituted ring, the optional substituents are preferably selected from C1-4 alkyl or W3 or W5 (as appropriate); W3 and W5 independently represent -0R19a or, more preferably, =0;
R19a, R19b and R19c independently represent H or C1-4 (e.g. C1-3) alkyl optionally substituted by one or more halo (e.g. fluoro) atoms.
Preferred aryl and heteroaryl groups that R , E and (when they represent such aryl or heteroaryl groups) X2, R9a to R9x, R1Oa, R10f, R1Og, R1Oi and R1Oj may represent include optionally substituted phenyl, naphthyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl (e.g 1-imidazolyl, 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-tetrahydroisoqumolinyl, quinolizinyl, benzofuranyl, isobenzofuranyl, chromanyl, benzothienyl, pyridazinyl, pyrimidinyl, pyrazinyl, indazolyl, benzimidazolyl, quinazolinyl, quinoxalinyl, 1,3-benzodioxolyl, tetrazolyl, benzothiazolyl, and/or benzodioxanyl, groups.
Preferred values of R1 include optionally substituted pyridyl (e.g. 2-pyridyl or 3- pyridyl), imidazolyl and, especially, phenyl.
Preferred values of E include optionally substituted 1,3-benzodioxolyl (e.g. 1,3- benzodioxol-5-yl), preferably, pyridyl (e.g. 2- or 3-pyridyl), imidazolyl, more preferably quinolinyl (e.g. 3-quinolinyl), and particularly phenyl.
Optional substituents on R1, R2, R3, R4, R5, X2 and E groups are preferably selected from: aryl (e.g. phenyl); in the case of substituents on non-aromatic groups (e.g. cycloalkyl or heterocycloalkyl groups), =0; or, more preferably, halo (e.g. fiuoro, chloro or bromo); cyano; -NO2; C1-6 alkyl, which alkyl group may be linear or branched (e.g. C1-4 alkyl (including ethyl, n-propyl, isopropyl, «-butyl or, preferably, methyl or t-butyl), n-pentyl, isopentyl, n-hexyl or isohexyl), cyclic (e.g. cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), part-cyclic (e.g. cyclopropylmethyl), unsaturated (e.g. 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 4-pentenyl or 5-hexenyl) and/or optionally substituted with one or more halo (e.g. fiuoro) group (so forming, for example, fluoromethyl, difluoromethyl or, preferably, trifluoromethyl); heterocycloalkyl, such as a C4-5 heterocycloalkyl group, preferably containing a nitrogen atom and, optionally, a further nitrogen or oxygen atom, so forming for example morpholinyl (e.g. 4-morpholinyl), piperazinyl (e.g. 4-ρiperazinyl) or piperidinyl (e.g. 1-piperidinyl and 4-ρiperidinyl) or pyrrolidinyl (e.g. 1- pyrrolidinyl), which heterocycloalkyl group is optionally substituted by one or more (e.g. one or two) substituents selected from C1-3 alkyl (e.g. methyl) and =0; -OR 20.
-N(R20)R21; and -C(O)OR20; wherein R20 and R21 independently represent, on each occasion when mentioned above, H or C1-6 alkyl, such as ethyl, n-propyl, n-butyl, t-butyl or, preferably, isopropyl or methyl (which allcyl groups are optionally substituted by one or more halo (e.g. fluoro) groups (to form e.g. a trifluoromethyl group)).
Preferred values of R6 include C1-4 alkyl and, particularly, H.
Particularly preferred compounds of the invention include those in which:
T represents a single bond;
Y represents -C(O)OR9b;
R9b represents C1-4 alkyl and, particularly, H.
More preferred compounds of the invention include those in which: one of R4 and, more preferably, R3 represents -D-E and the other (more preferably) represents H;
X1 represents -N(R9a)-J-R10a or, more preferably, C1-3 alkyl (e.g. methyl), heterocycloalkyl (which latter two groups are optionally substituted by
G1 and, preferably, -N(R12a)Rlla, -ORlla, -Rlla or halo (e.g. fluoro or chloro)), H or halo (e.g. fluoro or chloro);
R2 represents chloro or, preferably H;
R5 represents H; A represents G1, or C1-6 (e.g. C1-4) alkyl (e.g. cyclohexyl or, preferably, methyl or t-butyl) optionally substituted by one or more G1 groups;
G1 represents cyano or, preferably, fluoro, chloro, -NO2 or -A^R118;
A4 represents -C(O)- or, preferably, a single bond;
A5 represents a single bond; R9a represents H or methyl,
R1Oa represents methyl, t-butyl, pyridyl (e.g. 3-ρyridyl) or propyl (e.g. π-propyl optionally substituted by a G1 (e.g. -N(R12^R1 la) group); or R9a and R1Oa are linked to form a 5- or 6-membered (e.g. 5-membered) ring, which is substituted by one Z group;
Rlla, Rllb and Rl lc independently represent a phenyl group, a heteroaryl (such as tetrazolyl (e.g. 5-tetrazolyl), imidazolyl (e.g. 4-imidazolyl or 2-imidazolyl) or a pyridyl (e.g. 3-pyridyl, 4-pyridyl or, especially, 2-pyridyl)) group, or, more preferably, C1-3 alkyl (e.g. methyl or isopropyl) all of which are optionally substituted by one or more G3 groups;
R12a, R12b, R12c, R12d, R12e and R12f independently represent H or methyl;
G represents halo (e.g. fluoro); W1, W2 and W4 independently represent fluoro, -OCH3, -OCH2CH3, -OCHF2,
-OCF3 Or =O; when any pair of Rb and Rc, R715 and R8b or Rf and Rg are linked together to form an optionally substituted ring, the optional sύbstituents are preferably selected from C1-2 alkyl (e.g. methyl) or W3 or W5 (as appropriate); W3 and W5 independently represent -OCH3, -OCH2CH3, -OCHF2, -OCF3 or =0;
R19a, R19b and R19c independently represent H or C1-2 alkyl (e.g. methyl), which latter group is optionally substituted by one or more halo (e.g. fluoro) atoms (so forming, for example, a difluoro- or trifluoro-rnethyl group).
Most preferred compounds of the invention include those in which:
X1 represents halo;
R1 and E independently represent a 6-membered aryl (e.g. phenyl) ring optionally substituted, for example at thepαrα-position relative to the point of attachment of the R1 group to the indole ring, or the E group to the D group, respectively, with a (e.g. a single) G1 group;
R2, R4 and R5 independently represent H;
R3 represents -D-E;
D represents -C(R7)(R8)-;
G1 represents -A^R113; A1 represents a single bond or, more preferably, -OA5-; R7 represents Cj-3 alkyl (e.g. methyl or ethyl) optionally substituted by one or more halo (e.g. fluoro) atoms (so forming, for example, a difluoromethyl or trifluoromethyl group);
Ra to Rd independently represent H or C1-4 (e.g. C1-2) alkyl optionally substituted by -OR19a or, more preferably, =0 or halo (e.g. fluoro).
Particularly preferred compounds of the invention include those in which:
R represents 4-isopropoxyphenyl;
R7 represents -CH3, -CH2CH3, -CHF2 or -CF3; R8 represents -OH, -OCH3, -OCH2CH3, -OCHF2 or -OCF3;
R713 and R8b independently represent H, -CH3, -CH2CH3, -CHF2, -CF3, -OCH3,
-OCH2CH3, -OCHF2 or -OCF3;
D represents -C(OH)(CF3)-;
E represents 4-trifluoromethoxyphenyl; X1 represents chloro.
Particularly preferred compounds of the invention include those of the examples described hereinafter.
Compounds of the invention may be made in accordance with techniques that are well known to those skilled in the art, for example as described hereinafter.
According to a further aspect of the invention there is provided a process for the preparation of a compound of formula I, which process comprises:
(i) reaction of a compound of formula II,
Figure imgf000029_0001
wherein X1, R2, R3, R4, R5, T and Y are as hereinbefore defined, with a compound of formula III,
R1L1 III
wherein L1 represents a suitable leaving group such as chloro, bromo, iodo, a sulfonate group (e.g. -OS(O)2CF3, -OS(O)2CH3, -OS(O)2PhMe or a nonaflate) or -B(OH)2 and R1 is as hereinbefore defined, for example optionally in the presence of an appropriate metal catalyst (or a salt or complex thereof) such as Cu, Cu(OAc)2, CuI (or Cul/diamine complex), Pd(OAc)2, Pd2(dba)3 or NiCl2 and an optional additive such as Ph3P, 2,2'-bis(diphenylphosphino)-l,r-binaphthyl, xantphos, NaI or an appropriate crown ether such as 18-crown-6-benzene, in the presence of an appropriate base such as NaH, Et3N, pyridine, i\yV- dimethylethylenediamine, Na2CO3, K2CO3, K3PO4, Cs2CO3, r-BuONa or t-BuOK (or a mixture thereof), in a suitable solvent (e.g. dichloromethane, dioxane, toluene, ethanol, isopropanol, dimethylfoπnamide, ethylene glycol, ethylene glycol dimethyl ether, water, dimethylsulfoxide, acetonitrile, dimethylacetamide, iV-methylpyrrolidinone, tetrahydrofuran or a mixture thereof) or in the absence of an additional solvent when the reagent may itself act as a solvent (e.g. when R1 represents phenyl and L1 represents bromo, i.e. bromobenzene). This reaction may be carried out at room temperature or above (e.g. at a high temperature, such as the reflux temperature of the solvent system that is employed) or using microwave irradiation;
(ii) for compounds of formula I in which X1 represents -Q-X2, in which Q is a single bond or -C(O)-, reaction of a compound of formula IV,
Figure imgf000030_0001
wherein L1, R1, R2, R3, R4, R5, T and Y are as hereinbefore defined, with a compound of formula V,
X2-Qa-L2 V
wherein Qa represents a single bond or -C(O)-, L2 represents a suitable leaving group such as chloro, bromo, iodo, -B(OH)2 or a protected derivative thereof, for example a 4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl group, 9- borabicyclo[3.3.1]nonane (9-BBN), -Sn(alkyl)3 (e.g. -SnMe3 or -SnBu3), or a similar group known to the skilled person, and X2 is as hereinbefore defined. The skilled person will appreciate that L1 and L2 will be mutually compatible. In this respect, preferred leaving groups for compounds of formula V in which Qa is -C(O)- include chloro or bromo groups, and preferred leaving groups for compounds of formula V in which Qa is a single bond include -B(OH)2, 4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl, 9-borabicyclo[3.3.1]nonane (9-BBN), or -Sn(alkyl)3. This reaction may be performed, for example in the presence of a suitable catalyst system, e.g. a metal (or a salt or complex thereof) such as CuI, Pd/C, PdCl2, Pd(OAc)2, Pd(Ph3P)2Cl2, Pd(Ph3P)4, Pd2(dba)3 or NiCl2 and a ligand such as ^-Bu3P, (C6Hn)3P, Ph3P, AsPh3, P(O-ToI)3, l,2-bis(diphenylphosρhino)- ethane, 2,2'-bis(di-tert-butylphosphino)-l,l'-biphenyl, 2,2'-bis(diphenyl- phosphino)-l,l'-bi-naphthyl, l,r-bis(diphenyl-phosphinoferrocene), 1,3- bis(diphenylphosphino)propane, xantphos, or a mixture thereof, together with a suitable base such as, Na2CO3, K3PO4, Cs2CO3, NaOH, KOH, K2CO3, CsF, Et3N, (Z-Pr)2NEt, t-BuONa or t-BuOK (or mixtures thereof) in a suitable solvent such as dioxane, toluene, ethanol, dimethylformamide, ethylene glycol dimethyl ether, water, dimethylsulfoxide, acetonitrile, dimethylacetamide, TV-methylpyrrolidinone, tetrahydrofuran or mixtures thereof. The reaction may also be carried out for example at room temperature or above (e.g. at a high temperature such as the reflux temperature of the solvent system) or using microwave irradiation. The skilled person will appreciate that certain compounds of formula IV (in particular those in which L1 represents chloro, bromo or iodo) are also compounds of formula I and therefore compounds of the invention. In the case where Qa represents a single bond and X2 represents either C2-8 alkenyl, cycloalkenyl or heterocycloalkenyl in which the double bond is between the carbon atoms that are α and β to L2, the skilled person will appreciate that the double bond may migrate on formation of the compound of formula I to form a double bond that is between the carbon atoms that are β and γ to the indole ring;
(iii) for compounds of formula I in which X represents -Q-X and Q represents -C(O)-, reaction of a compound of formula I in which X1 represents H with a compound of formula V in which Qa represents -C(O)- and L2 represents a suitable leaving group such as chloro or bromo, -N(C1-6 alkyl)2 (e.g. -N(CH3)2) or a carboxylate group such as -O-C(O)-X2y in which X2y represents X2 or H. In the latter case, X2y and X2 are preferably the same, or X2y represents e.g. H, CH3 or CF3. This reaction may be performed under suitable conditions known to those skilled in the art, for example in the presence of a suitable Lewis acid (e.g. AlCl3 or FeCl3). Reaction of a compound of formula V in which L represents -N(C1-6 alkyl)2 and X2 represents optionally substituted aryl (e.g. phenyl) or heteroaryl may be performed in the presence of a reagent such as POCl3, for example under reaction conditions described in Bioorg. Med. Chem. Lett, 14, Al Al-Al A5 (2004). The skilled person will appreciate that in the latter instance, POCl3 may convert the compound of formula V into one in which L represents chloro and/or Qa represents a derivative of -C(O)- (e.g. an iminium derivative), which group may be transformed back to a -C(O)- group before or after reaction with the compound of formula I in which X1 represents H;
(iv) for compounds of formula I in which X1 represents -N(R9a)-J-R10a or -Q-X2 in which Q represents -O- or -S-, reaction of a compound of formula IV as hereinbefore defined with a compound of formula VT,
XlbH VI
in which Xlb represents -N(R9a)-J-R10a or -Q-X2 in which Q represents -O- or -S- and R9a, J, R1Oa and X2 are as hereinbefore defined, for example under reaction conditions such as those hereinbefore described in respect of either process (i) or (ii) above;
(v) for compounds of formula I in which X1 represents -Q-X2 and Q represents -S-, reaction of a compound of formula I in which X1 represents H, with a compound of formula VI in which Xlb represents -Q-X2, Q represents -S- and X2 is as hereinbefore defined, for example in the presence of 7V-chlorosuccinimide and a suitable solvent (e.g. dichloromethane), e.g. as described in inter alia Org. Lett., 819-821 (2004). Alternatively, reaction of a compound of formula VI in which Xlb represents -Q-X2, Q represents -S- and X2 represents an optionally substituted aryl (phenyl) or heteroaryl (e.g. 2-pyridyl) group, may be performed in the presence of PIFA (PhI(OC(O)CF3)2) in a suitable solvent such as (CF3)2CHOH. Introduction of such an -S-X2 group is described in inter alia Bioorg. Med. Chem, Lett, 14, AlAl-Al '45 (2004);
(vi) for compounds of formula I in which X1 represents -Q-X2 and Q represents -S(O)- or -S(O)2-, oxidation of a corresponding compound of formula I in which Q represents -S- under appropriate oxidation conditions, which will be known to those skilled in the art;
(vii) for compounds of formula I in which X represents -Q-X , X represents C1-8 alkyl substituted by G1, G1 represents -A^R113, A1 represents -N(R12a)A4- and A4 is a single bond (provided that Q represents a single bond when X represents substituted C1 alkyl), reaction of a compound of formula VII,
Figure imgf000033_0001
wherein X2a represents a C1-S alkyl group substituted by a -Z1 group in which Z1 represents =O, Q is as hereinbefore defined, provided that it represents a single bond when X2a represents C1 alkyl substituted by =0 (i.e. -CHO), and R1, R2, R3, R4, R5,T and Y are as hereinbefore defined under reductive amination conditions in the presence of a compound of formula VIII,
Rlla(R12a)NH VIII
wherein Rlla and R12a are as hereinbefore defined, under conditions well known to those skilled in the art;
(viia) for compounds of formula I in which X1 represents -Q-X2, Q represents a single bond, X2 represents methyl substituted by G1, G1 represents -A^R118, A1 represents -N(R12a)A4-, A4 is a single bond and Rlla and R12a are preferably methyl, reaction of a corresponding compound of formula I in which X1 represents H, with a mixture of formaldehyde (or equivalent reagent) and a compound of formula VIII as hereinbefore defined (e.g. in which Rlla and R12a represent methyl), for example in the presence of solvent such as a mixture of acetic acid and water, under e.g. standard Mannich reaction conditions known to those skilled in the art;
(viii) for compounds of formula I in which X1 represents -Q-X2, Q represents a single bond and X2 represents optionally substituted C2-S alkenyl (in which a point of unsaturation is between the carbon atoms that are α and β to the indole ring), reaction of a corresponding compound of formula IV in which L1 represents halo (e.g. iodo) with a compound of formula IXA,
H2C=€(H)X2b IXA
or, depending upon the geometry of the double bond, reaction of a compound of formula VII in which Q represents a single bond and X2a represents -CHO with either a compound of formula IXB,
(EtO)2P(O)CH2X213 IXB or the like, or a compound of formula IXC,
(Ph)3P=CHX2b IXC
or the like, wherein, in each case, X2b represents H, G1 or Ci-6 alkyl optionally substituted with one or more sύbstituents selected from G1 and/or Z1 and G1 and Z are as hereinbefore defined, for example, in the case of a reaction of a compound of formula IV with compound of formula IXA, in the presence of an appropriate catalyst (such as PdCl2(PPh3)2), a suitable base (e.g. NaOAc and/or triethylamine) and an organic solvent (e.g. DMF) and, in the case of reaction of a compound of formula VII with either a compound of formula EXB, or IXC, under standard Homer- Wadsworth-Emmons, or Wittig, reaction conditions, respectively;
(ix) for compounds of formula I in which X1 represents -Q-X2 and X2 represents optionally substituted, saturated C2-8 alkyl, saturated cycloalkyl, saturated heterocycloalkyl, C2-S alkenyl, cycloalkenyl or heterocycloalkenyl, reduction (e.g. hydrogenation) of a corresponding compound of formula I in which X2 represents optionally substituted C2-S alkenyl, cycloalkenyl, heterocycloalkenyl, C2.8 alkynyl, cycloalkynyl or heterocycloalkynyl (as appropriate) under conditions that are known to those skilled in the art. For example, in the case where an alkynyl group is converted to a alkenyl group, in the presence of an appropriate poisoned catalyst (e.g. Lindlar's catalyst);
(x) for compounds of formula I in which D is -C(R7)(R8)- or, more preferably, -C(=C(R7b)(R8b))-, reaction of a compound of formula X,
x
Figure imgf000035_0001
wherein L3 represents L1 or L2 as hereinbefore defined, which group is attached to one or more of the carbon atoms of the benzenoid ring of the indole, R2-R5 represents whichever of the three other substituents on the benzenoid ring, i.e. R , R3, R4 and R5, are already present in that ring, and X1, R1, R2, R3, R4, R5, T and Y are as hereinbefore defined, with, a compound of formula XI5
E-Dx-L4 XI
wherein L4 represents L1 (when L3 is L2) or L2 (when L3 is L1), Dx represents -C(R7XR8)- or, more preferably, -C(=C(R7b)(R8b))- and L1, L2, E5 R7 and R8 are as hereinbefore defined. For example, the reaction may be performed for example under similar conditions to those described hereinbefore in respect of process step (ii) above. Further, the reaction may be performed by first activating the compound of formula X. The skilled person will appreciate that compounds of formula X may first be activated when L3 represents halo, by:
(I) forming the corresponding Grignard reagent under standard conditions known to those skilled in the art (e.g. employing magnesium or a suitable reagent such as a mixture of C1-6 alkyl-Mg-halide and ZnCl2 or LiCl), followed by reaction with a compound of formula XI, optionally in the presence of a catalyst (e.g. FeCl3) under conditions known to those skilled in the art; or
(II) forming the corresponding lithiated compound under halogen-lithium exchange reaction conditions known to those skilled in the art (e.g. employing n-BuLi or M3uLi in the presence of a suitable solvent (e.g. a polar aprotic solvent such as THF)), followed by reaction with a compound of formula XI.
The skilled person will also appreciate that the magnesium of the 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
ZnCl2) and the intermediate so formed may then be subjected to reaction with a compound of formula XI under conditions known to those skilled in the art, for example such as those described hereinbefore in respect of process (ii) above;
(xi) for compounds of formula I in which D represents -C(R7)(R8)- in which R8 represents -ORa or -SRd and Ra and Rd both represent H, reaction of a compound of formula XII,
Figure imgf000037_0001
wherein -Db-E is attached to one or more of the carbon atoms of the benzenoid ring of the indole, Db represents -C(O)- or -C(S)- and R2-R5, E, X1, R1, T and Y are as hereinbefore defined, with a compound of formula XIII,
R7-L8 XIII
wherein L represents a silicon-based group such as 1Ii-C1-6 alkyl silane (e.g. trimethyl silane; for example in the presence of a suitable solvent such as THF), or an alkali metal-based group such as a magnesium halide or lithium (for example at low temperatures (e.g. below 00C) in the presence of a polar aprotic solvent such as THF) and R7 is as hereinbefore defined, all under standard reaction conditions, following by, in the case of reaction with a silicon-based group, removal of the silicon-based group, under standard conditions known to those skilled in the art (e.g. employing tetrabutylammonium fluoride optionally in the presence of an appropriate solvent such as THF) or, in the case of reaction with an alkali-metal- based group, quenching with a reagent that is a source of protons (e.g. water or saturated ammonium chloride solution);
(xii) for compounds of formula I in which D represents -C(R7)(R8)- in which R8 represents -ORa or -SRd and Ra and Rd do not represent H, reaction of a corresponding compound of formula I in which Ra and Rd represent H, followed by reaction with a compound of formula XIV,
Raa-L9 XIV
wherein Raa represents Ra or Rd (as appropriate) provided that it does not represent H, under standard conditions known to those skilled in the art. For example, in the presence of a suitable base and an appropriate solvent and under conditions such as those described hereinafter in respect of preparation of compounds of formula I (process step (xiv));
1 Si S
(xiii) for compounds of formula I in which D represents -C(R )(R )- and R represents -N(Rb)(Rc) or -SRd, reaction of a corresponding compound of formula I in which R represents -OH, which first comprises the step of converting the -OH group to provide a suitable leaving group, such as a sulfonate group (e.g. tosyl chloride, mesyl chloride, triflic anhydride and the like) and then reaction with a compound of formula XIVA,
H-Za XTVA
wherein Za represents either -N(Rb)(Rc) or -SRd, under standard conditions known to those skilled in the art;
(xiv) for compounds of formula I in which X1 represents -N(R9a)-J-R10a, reaction of a compound of formula XV,
Figure imgf000038_0001
wherein R1, R2, R3, R4, R5, R9a, T and Y are as hereinbefore defined, with a compound of formula XVI,
R103J-L1 XVI
wherein J, R1Oa and L1 are as hereinbefore defined, for example at around room temperature or above (e.g. up to 60-700C) in the presence of a suitable base (e.g. pyrrolidinopyridine, pyridine, triethylamine, tributylamine, trimethylamine, dimethylaminopyridine, diisopropylamine, l,8-diazabicyclo[5.4.0]undec-7-ene, sodium hydroxide, or mixtures thereof), an appropriate solvent (e.g. pyridine, dichloromethane, chloroform, tetrahydrofuran, dimethylformamide, triethylamine, dimethylsulfoxide, water or mixtures thereof) and, in the case of biphasic reaction conditions, optionally in the presence of a phase transfer catalyst;
(xv) for compounds of formula I in which X1 represents -N(R9a)-J-R1Oa, J represents a single bond and R1Oa represents a C1-8 alkyl group, reduction of a corresponding compound of formula I, in which J represents -C(O)- and R1Oa represents H or a C1-7 alkyl group, in the presence of a suitable reducing agent. A suitable reducing agent may be an appropriate reagent that reduces the amide group to the amine group in the presence of other functional groups (for example an ester or a carboxylic acid). Suitable reducing agents include borane and other reagents known to the skilled person;
(xvi) for compounds of formula I in which X1 represents halo, reaction of a compound of formula I wherein X1 represents H, with a reagent or mixture of reagents known to be a source of halide atoms. For example, for bromide atoms,
N-bromosuccinimide, bromine or 1,2-dibromotetrachloroethane may be employed, for iodide atoms, iodine, diiodoethane, diiodotetrachloroethane or a mixture of
NaI or KI and iV-chlorosuccinimide may be employed, for chloride atoms, N- chlorosuccinimide may be employed and for fluoride atoms, l-(chloromethyl)-4- fiuoro-l,4-diazoniabicyclo[2.2.2]octane bis(tetrafiuoroborate), 1-fluoropyridinium triflate, xenon difluoride, CF3OF or perchloryl fluoride may be employed. This reaction may be carried out in a suitable solvent (e.g. acetone, benzene or dioxane) under conditions known to the skilled person;
(xvii) for compounds of formula I in which T and Y are as hereinbefore defined, provided that when Y represents -C(O)OR9b, -S(O)3R90, -P(O)(OR9d)2, -P(O)(OR9e)N(R10f)R9f, -P(O)(N(R10g)R9g)2, -B(OR9h)2 or -S(O)2N(R10i)R9i, R9b to R9i, R10f, R1Og and R1Oi are other than H, reaction of a compound of formula XVII5
Figure imgf000040_0001
wherein L5 represents an appropriate alkali metal group (e.g. sodium, potassium or, especially, lithium), a -Mg-halide, a zinc-based group or a suitable leaving group such as halo or -B(OH)2, or a protected derivative thereof (the skilled person will appreciate that the compound of formula XVII in which L5 represents an alkali metal (e.g. lithium), a Mg-halide or a zinc-based group may be prepared from a corresponding compound of formula XVII in which L5 represents halo, for example under conditions such as those hereinbefore described in respect of preparation of compounds of formula I (process step (x) above)), and X1, R1, R2, R3, R4 and R5 are as hereinbefore defined, with a compound of formula XVIII,
L6Ta-Ya XVIII
wherein Ta represents T and Ya represents Y, provided that when Y represents -C(O)OR9b, -S(O)3R90, -P(O)(OR9d)2, -P(O)(OR9e)N(R10f)R9f 5 -P(O)(N(R10g)R9ε)2, -B(OR9h)2 or -S(O)2N(R10i)R9i, R9b to R9i, R1Of, R1Og and R10i are other than H, and L6 represents a suitable leaving group known to those skilled in the art, such as halo (especially chloro or bromo), for example when Ya represents -C(O)OR9b or -S(O)3R90, or C1-3 alkoxy, for example when Ya represents -B(OR9h)2. The reaction may be performed under similar reaction conditions to those described B2007/002704
40 hereinbefore in respect of process (x) above, followed by (if necessary) deprotection under standard conditions. The skilled person will appreciate that compounds of formula XVII in which L5 represents -B(OH)2 are also compounds of formula I;
(xviii) for compounds of formula I in which T represents a single bond, Y represents -B(OR9h)2 and R9h represents H, reaction of a compound of formula XVII as hereinbefore defined with boronic acid or a protected derivative thereof (e.g. bis(pinacolato)diboron or triethyl borate), followed by (if necessary) deprotection under standard conditions;
(xix) for compounds of formula I in which T represents a single bond and Y represents -S(O)3R90, reaction of a compound of formula XVII as hereinbefore defined with: (A) for such compounds in which R9c represents H, either SO3 (or a suitable source of SO3 such as a SO3*pyridine or SO3*Et3N complex) or with SO2 followed by treatment with N-cMorosuccinimide and then hydrolysis. Alternatively, a compound of formula XVII may be reacted with a protected sulfide, followed by deprotection and oxidation, or a compound of formula XVII may be reacted with chlorosulfonic acid
(ClS(O)2OH) followed by hydrolysis;
(B) for such compounds in which R9c is other than H, chlorosulfonic acid followed by reaction with a compound of formula XXIII as defined hereinafter in which R9za represents R9°, all under standard conditions;
(xx) for compounds of formula I in which T represents a single bond and Y represents
Figure imgf000041_0001
in which R9j represents hydrogen, reaction of a corresponding compound of formula I in which T represents a C2 alkylene group substituted at the carbon atom that is attached to the indole ring system by Z1, in which Z1 represents =0 and Y represents -C(O)OR9b, in which R9b represents C1-6 alkyl with hydroxylamine or an acid addition salt thereof, for example in the presence of base (e.g. NaOH), e.g. under similar reaction conditions to those described in inter alia J. Med. Chem. 43, 4930 (2000);
(xxi) for compounds of formula I in which T represents a single bond and Y represents
Figure imgf000042_0001
in which R9k and R9r represent hydrogen, reaction of a corresponding compound of formula I in which T represents a Ci alkylene group substituted with G1, in which G1 represents -A^R11", A1 represents -C(O)A2-, A2 represents a single bond and Rlla represents H, and Y represents -C(O)OR9b, in which R9b represents methyl, or ethyl, respectively, with hydroxylamine or an acid addition salt thereof, for example in the presence of base (e.g. NaOH, or aniline, respectively) and an appropriate solvent (e.g. methanol, or water, respectively), e.g. under similar reaction conditions to those described in J. Med. Chem. 44, 1051 (2001), or inter alia J. Am. Chem. Soc, 58, 1152 (1936), respectively;
(xxii) for compounds of formula I in which T represents a single bond and Y represents
Figure imgf000043_0001
in which R9m and R9p represent hydrogen, reaction of a corresponding compound of formula I in which T represents a single bond, Y represents -B(OR9h)2 and R9h represents H with a compound of formula XVIII in which Ta represents a single bond, Ya represents
Figure imgf000043_0002
respectively, in which R9m and R9*1 represent hydrogen, and L6 preferably represents e.g. a halo group, such as Br, or I, respectively, or a protected derivative (e.g. at the OH group with, for example, a benzyl group) of either compound, for example under reaction conditions similar to those described hereinbefore in process (ii) above and/or in Heterocycles, 36, 1803 (1993), or in Bioorg. Med. Chem., 11, 1883 (2003), respectively, followed by (if necessary) deprotection under standard conditions;
(xxiii) for compounds of formula I in which T represents a single bond and Y represents
Figure imgf000043_0003
in which R , 9na represents hydrogen, reaction of a compound of formula XIX,
Figure imgf000044_0001
wherein X1, R1, R2, R3, R4 and R5 are as hereinbefore defined with ethoxycarbonyl isocyanate in the presence of a suitable solvent (e.g. dichloromethane), followed by refiuxing in the presence of Triton B and an alcoholic solvent (e.g. methanol), for example under similar reaction conditions to those described in J. HeL Chem., 19, 971 (1982);
(xxiv) for compounds of formula I in which T represents a single bond and Y represents
Figure imgf000044_0002
in which R9s represents hydrogen, reaction of a compound of formula I in which T represents a single bond and Y represents -C(O)OR9b, in which R9b represents H with e.g. trimethylsilyl chloride (or the like), followed by reaction of the resultant intermediate with N4S4, for example under similar reaction conditions to those described in Heterocycles, 20, 2047 (1983);
(xxv) for compounds of formula I in which T represents a single bond and Y represents
Figure imgf000044_0003
in which R9t represents hydrogen, reaction of a compound of formula XX,
Figure imgf000045_0001
wherein X1, R1, R2, R3, R4 and R5 are as hereinbefore defined with a base (e.g. NaH) and CS2 in the presence of a suitable solvent (e.g. tetrahydrofuran), oxidation of the resultant intermediate in the presence of, for example, hydrogen peroxide, and finally heating the resultant intermediate in the presence of a strong acid, such as HCl, for example under similar reaction conditions to those described in inter alia Bioorg. Med. Chem. Lett., 2, 809 (1992);
(xxvi) for compounds of formula I in which T represents a single bond and Y represents
Figure imgf000045_0002
in which R9u represents hydrogen, reaction of a corresponding compound of formula I in which T represents C1 alkylene, Y represents -C(O)OR9b and R9b represents H or, preferably, an activated (e.g. acid halide) derivative thereof with 1,1,2,2-tetraethoxyethene, for example in the presence of base (e.g. triethylamine), followed by acid (e.g. aqueous HCl), e.g. under similar reaction conditions to those described in J. Am. Chem. Soc, 100, 8026 (1978); (xxvii) for compounds of formula I in which T represents a single bond and Y represents
Figure imgf000046_0001
in which R9v and R1Oj represent H, reaction of a compound of formula XIX as hereinbefore defined with 3,4-dimethoxycyclobutene-l,2-dione, for example in the presence of base (e.g. KOH) and an appropriate solvent (e.g. methanol), followed by acid (e.g. aqueous HCl), e.g. under similar reaction conditions to those described in J. Org. Chem. , 68, 9233 (2003);
(xxviii) for compounds of formula I in which T represents a single bond and Y represents
Figure imgf000046_0002
in which R9x represents hydrogen, reaction of a compound of formula XXI,
Figure imgf000046_0003
wherein X1, R1, R2, R3, R4 and R5 are as hereinbefore defined with NaN3 under standard conditions; (xxix) for compounds of formula I in which T represents optionally substituted C2-8 alkenylene or C2-8 heteroalkylene (in which a point of unsaturation is between the carbon atoms that are α and β to the indole ring), reaction of a compound of formula XXII,
Figure imgf000047_0001
wherein X1, R1, R2, R3, R4 and R5 are as hereinbefore defined with a compound of formula XXIIA,
(Ph)3P=CH-Ta-Y XXIIA
or the like (e.g. the corresponding Homer- Wadsworth-Emmons reagent), wherein Ta represents a single bond or optionally substituted C1-6 alkylene or C2-6 heteroalkylene and Y is as hereinbefore defined, for example under standard Wittig reaction conditions, e.g. in the presence of a suitable organic solvent (e.g. DMF);
(xxx) for compounds of formula I in which T represents optionally substituted, saturated C2-8 alkylene, saturated cyclo alkylene, saturated C2-8 heteroalkylene, saturated heterocycloalkylene, C2-8 alkenylene, cycloalkenylene, C2-8 heteroalkenylene or heterocycloalkenylene, reduction (e.g. hydrogenation) of a corresponding compound of formula I in which T represents optionally substituted C2-S alkenylene, cycloalkenylene, C2-8 heteroalkenylene, heterocycloalkenylene, C2-S alkynylene, cycloalkynylene, C2-8 heteroalkynylene or heterocycloalkynylene (as appropriate) under conditions that are known to those skilled in the ail; (xxxi) for compounds of formula I in which Y represents -C(O)OR9b, -S(O)3R90, -P(O)(OR9d)2, or -B(OR9h)2, in which R9b, R9o 5 R9d and R9h represent H, hydrolysis of a corresponding compound of formula I in which R9b, R9c, R9d or R9h (as appropriate) does not represent H, or, for compounds of formula I in which Y represents -P(O)(OR9d)2 or S(O)3R9c, in which R9c and R9d represent H, a corresponding compound of formula I in which Y represents either -P(O)(OR9e)N(R10f)R9f, -P(O)(N(R10g)R9g)2 or -S(O)2N(R10i)R9i (as appropriate), all under standard conditions;
(xxxii) for compounds of formula I in which Y represents -C(O)OR9b, S(O)3R9c, -P(O)(OR9d)2, -P(O)(OR9e)N(R10f)R9f or -B(OR9h)2 and R9b to R9e and R9h (i.e. those R9 groups attached to an oxygen atom) do not represent H:
(A) esterification of a corresponding compound of formula I in which R9b to R9e and R9h represent H; or (B) trans-esterification of a corresponding compound of formula I in which
R9b to R9e and R9h do not represent H (and does not represent the same value of the corresponding R9b to R9e and R9h group in the compound of formula I to be prepared), under standard conditions in the presence of the appropriate alcohol of formula XXIII,
R922OH XXIII
in which R9za represents R9b to R9e or R9h provided that it does not represent H;
(xxxiii) for compounds of formula I in which T represents a single bond, Y represents -C(O)OR9b and R9b is other than H, reaction of a compound of formula XXIIIA, XXIIIA
Figure imgf000049_0001
wherein L5, Q, X2, R1, R2, R3, R4 and R5 are as hereinbefore defined, with a compound of formula XXIIIB,
ly C(O)OR%1 XXIIIB
wherein R9bl represents R9b provided that it does not represent H, and L6 is as hereinbefore defined (e.g. L6 represents chloro or bromo), under conditions known to those skilled in the art;
(xxxiv) for compounds of formula I in which T represents a single bond, Y represents -C(O)OR9b and R9b is H, reaction of a compound of formula XVII in which L5 represents either:
(I) an alkali metal (for example, such as one defined in respect of process step (xvii) above); or
(II) -Mg-halide, with carbon dioxide, followed by acidification under standard conditions known to those skilled in the art, for example, in the presence of aqueous hydrochloric acid;
(xxxv) for compounds of formula I in which T represents a single bond and Y represents -C(O)OR9b, reaction of a corresponding compound of formula XVII in which L5 is a suitable leaving group known to those skilled in the art (such as a sulfonate group (e.g. a trifiate) or, preferably, a halo (e.g. bromo or iodo) group) with CO (or a reagent that is a suitable source of CO (e.g. Mo(CO)6 or Co2(CO)8)), in the presence of a compound of formula XXIIIC,
R9bOH XXIIIC wherein R9b is as hereinbefore defined, and an appropriate catalyst system (e.g. a palladium catalyst such as one described hereinbefore in respect of process step (ii)) under conditions known to those skilled in the art;
(xxxvi) for compounds of formula I in which Y represents -C(O)OR9b and R9b represents H, hydrolysis of a corresponding compound of formula I in which R9b does not represent H under standard conditions;
(xxxvii) for compounds of formula I in which Y represents -C(O)OR9b and R9b does not represent H:
(A) esterification of a corresponding compound of formula I in which R9b represents H; or
(B) trans-esterification of a corresponding compound of formula I in which R9b does not represent H (and does not represent the same value of R9b as the compound of formula I to be prepared), under standard conditions in the presence of the appropriate alcohol of formula XXIIIC as hereinbefore defined but in which R9b represents R9bl as hereinbefore defined;
(xxxviii) for compounds of formula I in which X represents -Q-X and Q represents -O-, reaction of a compound of formula XXTV5
Figure imgf000050_0001
wherein R1, R2, R3, R4, R5, T and Y are as hereinbefore defined, with a compound of formula XXV,
X2L7 XXV wherein L7 represents a suitable leaving group, such as a halo or sulfonate group, and X2 is as hereinbefore defined, for example in the presence of a base or under reaction conditions such as those described hereinbefore in respect of process (ii) or process (xiii) above;
(xxxix) for compounds of formula I in which T represents a C1 alkylene group substituted with G1, in which G1 represents -A^R11*1, A1 represents -C(O)A2-, A2 represents a single bond and Rlla represents H, and Y represents -C(O)OR9b, in which R9b is other than H, reaction of a corresponding compound of formula I in which the Ci alkylene group that T represents is unsubstituted with a Ci-6 alkyl (e.g. ethyl) formate in the presence of a suitable base (e.g. sodium ethoxide), for example under similar conditions to those described in Bioorg. Med. Chem. Lett., 13, 2709 (2003);
(xl) for compounds of formula I in which X represents -Q-X , Q represents a single bond and X2 represents Ci-8 alkyl or heterocycloalkyl substituted α to the indole ring by a G1 substituent in which G1 represents -A^R118, A1 represents -OA5-, A5 represents a single bond and Rlla represents H, reaction of a corresponding compound of formula I in which X represents H with a compound corresponding to a compound of formula VI, but in which X represents -Q-X , Q represents a single bond and X2 represents Ci-8 alkyl or heterocycloalkyl, both of which groups are substituted by a Z1 group in which Z1 represents =0, under conditions known to those skilled in the art, for example optionally in the presence of an acid, such as a protic acid or an appropriate Lewis acid. Such substitutions are described in inter alia Bioorg. Med. Chem. Lett., 14, 4741-4745 (2004) and Tetrahedron Lett. 34, 1529 (1993);
(xli) for compounds of formula I in which X represents -Q-X , Q represents a single bond and X2 represents C2-8 alkyl substituted (e.g. α to the indole ring) by a
G1 substituent in which G1 represents -A^R1 la, A1 represents -OA5-, A5 represents a single bond and Rlla represents H, reaction of a corresponding compound of formula I in which X2 represents C1-7 alkyl substituted (e.g. α to the indole ring) by a Z1 group in which Z1 represents =0, with the corresponding Grignard reagent derivative of a compound of formula V in which L2 represents chloro, bromo or iodo, Qa is a single bond and X2 represents C1-7 alkyl, under conditions known to those skilled in the art;
(xlii) for compounds of formula I in which X represents -Q-X , Q represents a single bond, and X2 represents C1-8 alkyl or heterocycloalkyl, both of which are unsubtituted in the position a to the indole ring, reduction of a corresponding compound of formula I in which X2 represents C1-8 alkyl substituted α to the indole ring by a G1 substiruent in which G1 represents -A^R1 la, A1 represents -OA5-, A5 represents a single bond and Rlla represents H, in the presence of a suitable reducing agent such as a mixture of triethyl silane and a protic acid (e.g. CF3COOH) or a Lewis acid (e.g. (CH3)3SiOS(O)2CF3) for example under conditions described in inter alia Bioorg. Med. Chem. Lett., 14, 4741-4745 (2004);
(xliii) for compounds of formula I in which X1 represents -Q-X2, Q represents a single bond and X2 represents C1-8 alkyl or heterocycloalkyl, neither of which are substituted by Z1 in which Z1 represents =0, reduction of a corresponding compound of formula I in which X2 represents C1-8 alkyl or heterocycloalkyl, which groups are substituted by one or more Z1 groups in which Z1 represents =O under conditions known to those skilled in the art, for example employing NaBH4 in the presence of an acid (e.g. CH3COOH or CF3COOH), Wolff-Kishner reduction conditions (i.e. by conversion of the carbonyl group to a hydrazone, followed by base induced elimination) or by conversion of the carbonyl to the thioacetal analogue (e.g. by reaction with a dithiane) followed by reduction with e.g. Raney nickel, all under reaction conditions known to those skilled, in the art; or
(xliv) for compounds of formula Fin which X1 represents -N(R9a)-J-R10a, reaction of a compound of formula XXIV as hereinbefore defined, with a compound of formula VI in which Xlb represents -N(R9a)-J-R1Oa and R9a, R1Oa and J are as hereinbefore defined, for example under reaction conditions known to those skilled in the art (such as those described in Journal of Medicinal Chemistry 1996, Vol. 39, 4044 (e.g. in the presence OfMgCl2)).
Compounds of formula II may be prepared by:
(a) reaction of a compound of formula XXVI,
Figure imgf000053_0001
wherein L1, R2, R3, R , R5, T and Y are as hereinbefore defined, with, for compounds of formula II in which X1 represents:
(1) -Q-X and Q represents a single bond or -C(O)-, a compound of formula V as hereinbefore defined; or
(2) -N(R9a)-J-R1Oa or -Q-X2, in which Q represents -O- or -S-, a compound of formula VI as hereinbefore defined, for example under reaction conditions similar to those described hereinbefore in respect of preparation of compounds of formula I (processes (ii) and (iv), respectively) above;
(b) for compounds of formula II in which X1 represents -Q-X2 and Q represents -C(O)-, reaction of a corresponding compound of formula II in which X1 represents H, with a compound of formula V in which Qa represents -C(O)- and L2 represents a suitable leaving group, for example under conditions such as those described in respect of preparation of compounds of formula I (process (iii)) above; (c) for compounds of formula II in which X represents -Q-X" and Q represents -S-, reaction of a corresponding compound of formula II in which X1 represents H with a compound of formula VI in which Xlb represents -Q-X2 and Q represents -S-, for example under conditions such as those described hereinbefore in respect of preparation of compounds of formula I (process (v)) above;
(d) for compounds of formula II in which Q represents -S(O)- or -S(O)2-, oxidation a corresponding compound of formula II in which Q represent -S-;
(e) for compounds of formula II in which X1 represents -Q-X2, X2 represents C1-8 alkyl substituted by G1, G1 represents -A^R11*1, A1 represents -N(R12a)A4- and A4 is a single bond (provided that Q represents a single bond when X2 represents substituted C1 alkyl), reaction of a compound of formula XXVII5
R2 Q-X2a
XXVII
Figure imgf000054_0001
wherein Q, X2a, R2, R3, R4, R5, T and Y are as hereinbefore defined by reductive amination in the presence of a compound of formula VIII as hereinbefore defined;
(ea) for compounds of formula II in which X1 represents -Q-X2, Q represents a single bond, X2 represents methyl substituted by G1,
G1 represents -A'-R113, A1 represents -N(R12a)A4-, A4 is a single bond and Rlla and R12a are preferably methyl, reaction of a corresponding compound of formula II in which X1 represents H, with a mixture of formaldehyde (or equivalent reagent) and a compound of formula VIII as hereinbefore defined, for example under reaction conditions similar to those described hereinbefore in respect of preparation of compounds of formula I (process (viia)) above;
(f) for compounds of formula II in which X represents -Q-X , Q represents a single bond and X2 represents optionally substituted C2-8 alkenyl (in which a point of unsaturation is between the carbon atoms that are α and β to the indole ring), reaction of a compound of formula XXVI in which L1 represents halo (e.g. iodo) with a compound of formula XXVII as hereinbefore defined, or reaction of compound of formula XXTV in which Q represents a single bond and X2a represents -CHO with a compound of formula IXB or a compound of formula IXC as hereinbefore defined, for example under reaction conditions similar to those described hereinbefore in respect of preparation of compounds of formula I (process (viii)) above;
(g) for compounds of formula II in which X1 represents -Q-X2 and X2 represents optionally substituted, saturated C2-8 alkyl, saturated cycloalkyl, saturated heterocycloalkyl, C2-8 alkenyl, cycloalkenyl or heterocycloalkenyl, reduction (e.g. hydrogenation) of a corresponding compound of formula II in which X2 represents optionally substituted C2-8 alkenyl, cycloalkenyl, heterocycloalkenyl, C2-8 alkynyl, cycloalkynyl or heterocycloalkynyl (as appropriate);
(h) reaction of a compound of formula XXVIII, XXVIII
Figure imgf000056_0001
wherein L3, R2-R5, X1, T and Y are as hereinbefore defined, with, a compound of formula XI as hereinbefore defined, for exmple under reaction conditions similar to those described hereinbefore in respect of preparation of compounds of formula I (process (x)) above;
for compounds of formula II in which D represents -C(R )(R )- in which R8 represents -ORa or -SRd and Ra and Rd both represent H may be prepared by reaction of a compound of formula XXIX,
Figure imgf000056_0002
wherein -Db-E, Db, R2-R5, E5 X1, R1, T and Y are as hereinbefore defined, with a compound of formula XIII as hereinbefore defined under reaction conditions similar to those described hereinbefore in respect of preparation of compounds of formula I (process (xi)) above;
for compounds of formula II in which D represents -C(R )(R )- in which R8 represents -ORa or -SRd and Ra and Rd do not represent H may be prepared by reaction of a corresponding compound of formula II in which Ra and Rd represent H, followed by reaction with a compound of formula XIV as hereinbefore defined, for example under reaction conditions similar to those described hereinbefore in respect of preparation of compounds of formula I (process (xii)) above;
(k) for compounds of formula II in which D represents -C(R )(R )- and R8 represents -N(Rb)(Rc) or -SRd, reaction of a corresponding compound of formula II in which R8 represents -OH, which first comprises the step of converting the -OH group to provide a suitable leaving group, such as a sulfonate group (e.g. tosyl chloride, mesyl chloride, triflic anhydride and the like) and then reaction with a compound of formula XIVA as hereinbefore defined;
(1) for compounds of formula II in which X1 represents
-N(R9a)-J-R1Oa, reaction of a compound of formula XXX,
Figure imgf000057_0001
wherein R2, R3, R4, R5, R9a, T and Y are as hereinbefore defined with a compound of formula XVI as hereinbefore defined, for example under reaction conditions similar to those described hereinbefore in respect of preparation of compounds of formula I (process (xiv)) above;
(m) for compounds of formula II in which X1 represents -N(R9a)-J-R10a, J represents a single bond and R1Oa represents a C1-8 alkyl group, reduction of a corresponding compound of formula II, in which J represents -C(O)- and R1Oa represents H or a C1-7 alkyl group, for example under reaction conditions similar to those described hereinbefore in respect of preparation of compounds of formula I (process (xv)) above;
(n) for compounds of formula II in which X1 represents halo, reaction of a compound of formula II wherein X1 represents H, with a reagent or mixture of reagents known to be a source of halide atoms, for example under reaction conditions similar to those described hereinbefore in respect of preparation of compounds of formula I (process (xvi)) above;
(o) for compounds of formula II in which T and Y are as hereinbefore defined, provided that when Y represents -C(O)OR9b, -S(O)3R90, -P(O)(OR9d)2, -P(O)(OR9e)N(R10f)R9f, -P(O)(N(R10g)R9g)2, -B(OR9h)2 or -S(O)2N(R10i)R9i, R9b to R9i, R1Of, R1Og and R101 are other than H, reaction of a compound of formula
XXXI,
Figure imgf000058_0001
wherein PG represents a suitable protecting group, such as
-S(O)2Ph, -C(O)O", -C(O)CHBu or -C(O)N(Et)2) and L5, X1, R2, R3, R4 and R5 are as hereinbefore defined, with a compound of formula XVIII as hereinbefore defined, or a protected derivative thereof, for example under similar coupling conditions to those described hereinbefore in respect of process (xvii) above, followed by deprotection of the resultant compound under standard conditions;
(p) for compounds of formula II in which T represents a single bond, Y represents -B(OR9h)2 and R9h represents H, reaction of a compound of formula XXXI as hereinbefore defined with boronic acid or a protected derivative thereof (e.g. bis(pinacolato)diboron or triethyl borate), followed by deprotection of the resultant compound under standard conditions;
(q) for compounds of formula II in which T represents a single bond and Y represents -S(O)3R90, reaction of a compound of formula XXXI as hereinbefore defined with:
(A) for such compounds in which R9c represents H, either SO3 or with SO2 followed by treatment with N-cMorosuccinirnide and then hydrolysis;
(B) for such compounds in which R9c is other than H, chlorosulfonic acid followed by reaction with a compound of formula XXIII as defined hereinbefore in which R9za represents R9c, all under standard conditions such as those described hereinbefore in respect of preparation of compounds of formula I (process (xix)) above;
(r) for compounds of formula II in which T represents a single bond and Y represents
Figure imgf000059_0001
in which R9j represents hydrogen, reaction of a corresponding compound of formula II in which T represents a C2 alkylene group substituted at the carbon atom that is attached to the indole ring system by Z1, in which Z1 represents =0 and Y represents -C(O)OR9b, in which R9b represents C1-6 atkyl with hydroxylamine or an acid addition salt thereof, for example under reaction conditions similar to those described hereinbefore in respect of preparation of compounds of formula I (process (xx)) above;
(s) for compounds of formula II in which T represents a single bond and Y represents
Figure imgf000060_0001
in which R9 and R9r represent hydrogen, reaction of a corresponding compound of formula II in which T represents a C1 alkylene group substituted with G1, in which G1 represents -A^R11*1,
A1 represents -C(O)A2-, A2 represents a single bond and Rlla represents H, and Y represents -C(O)OR9b, in which R9b represents methyl, or ethyl, respectively, with hydroxylarnine or an acid addition salt thereof, for example under reaction conditions similar to those described hereinbefore in respect of preparation of compounds of formula I (process (xxi)) above;
(t) for compounds of formula II in which T represents a single bond and Y represents
Figure imgf000060_0002
in which R9m and R9p represent hydrogen, reaction of a corresponding compound of formula II in which T represents a single bond, Y represents -B(OR9h)2 and R9h represents H with a compound of formula XVIII in which Ta represents a single bond, Ya represents
Figure imgf000061_0001
respectively, in which R9m and R9p represent hydrogen, and L6 preferably represents e.g. a halo group, such as Br, or I, respectively, or a protected derivative (e.g. at the OH group with, for example, a benzyl group) of either compound, for example under reaction conditions similar to those described hereinbefore in respect of preparation of compounds of formula I (process (xxii)) above;
(u) for compounds of formula II in which T represents a single bond and Y represents
Figure imgf000061_0002
in which R9n represents hydrogen, reaction of a compound of formula XXXII,
XXXII
Figure imgf000061_0003
wherein X1, R1, R2, R3, R4 and R5 are as hereinbefore defined with ethoxycarbonyl isocyanate, for example under reaction conditions similar to those described hereinbefore in respect of preparation of compounds of formula I (process (xxiii)) above;
(v) for compounds of formula II in which T represents a single bond and Y represents
Figure imgf000062_0001
in which R9s represents hydrogen, reaction of a compound of formula II in which T represents a single bond and Y represents -C(O)OR9b, in which R9b represents H with e.g. trimethylsilyl chloride (or the like), followed by reaction of the resultant intermediate with N4S4, for example under reaction conditions similar to those described hereinbefore in respect of preparation of compounds of formula I (process (xxiv)) above;
(w) for compounds of formula II in which T represents a single bond and Y represents
Figure imgf000062_0002
in which R9t represents hydrogen, reaction of a compound of formula XXXIII, XXXIII
Figure imgf000063_0001
wherein X1, R2, R3, R4 and R5 are as hereinbefore defined with a base (e.g. NaH) and CS2 the presence of a suitable solvent (e.g. tetrahydrofuran), oxidation of the resultant intermediate in the presence of, for example, hydrogen peroxide, and finally heating the resultant intermediate in the presence of a strong acid, such as
HCl, for example under reaction conditions similar to those described hereinbefore in respect of preparation of compounds of formula I (process (xxv)) above;
(x) for compounds of formula I in which T represents a single bond and Y represents
Figure imgf000063_0002
in which R9u represents hydrogen, reaction of a corresponding compound of formula II in which T represents C1 alkylene, Y represents -C(O)OR9b and R9b represents H or, preferably, an activated (e.g. acid halide) derivative thereof with 1,1,2,2- tetraethoxyethene, for example under reaction conditions similar to those described hereinbefore in respect of preparation of compounds of formula I (process (xxvi)) above; (y) for compounds of formula II in which T represents a single bond and Y represents
Figure imgf000064_0001
in which R v and R1Oj independently represent hydrogen, reaction of a compound of formula XXXII as hereinbefore defined with 3,4- dimethoxycyclobutene-l,2-dione, for example under reaction conditions similar to those described hereinbefore in respect of preparation of compounds of formula I (process (xxvii)) above;
(z) for compounds of formula II in which T represents a single bond and Y represents
Figure imgf000064_0002
in which R9x represents hydrogen, reaction of a compound of formula XXXIV,
XXXIV
Figure imgf000064_0003
R5 wherein X1, R2, R3, R4 and R5 are as hereinbefore defined with NaN3 under standard conditions;
(aa) for compounds of formula II in which T represents optionally substituted C2-s alkenylene or C2-8 heteroalkylene (in which a point of unsaturation is between the carbon atoms that are α and β to the indole ring), may be prepared by reaction of a corresponding compound of formula XXXV,
Figure imgf000065_0001
wherein X1, R2, R3, R4 and R5 are as hereinbefore defined with a compound of formula XXIIA as hereinbefore defined, under standard Wittig reaction conditions;
(ab) for compounds of formula II in which T represents optionally substituted, saturated C2-8 alkylene, saturated cycloalkylene, saturated C2-8 heteroalkylene, saturated heterocycloalkylene, C2-8 alkenylene, cycloalkenylene, C2-8 heteroalkenylene or heterocycloalkenylene, reduction (e.g. hydrogenation) of a corresponding compound of formula II in which T represents optionally substituted C2-8 alkenylene, cycloalkenylene, C2-8 heteroalkenylene, heterocycloalkenylene, C2-8 alkynylene, cycloalkynylene, C2-8 heteroalkynylene or heterocycloalkynylene (as appropriate);
(ac) for compounds of formula II in which Y represents -C(O)OR9b, -S(O)3R90, -P(O)(OR9d)2, or -B(OR9h)2, in which R9b, R9c, R9d and R9h represent H, hydrolysis of a corresponding compound of 02704
65 formula II in which R9b, R9c, R9d or R9h (as appropriate) does not represent H, or, for compounds of formula II in which Y represents -P(O)(OR9d)2 or S(O)3R90, in which R9° and R9d represent H, a corresponding compound of formula II in which Y represents either -P(O)(OR9e)N(R10f)R9f, -P(O)(N(R10g)R9g)2 or -S(O)2N(R10i)R9i (as appropriate);
(ad) for compounds of formula II in which Y represents -C(O)OR9b, -S(O)3R90, -P(O)(OR9d)2, -P(O)(OR9e)N(R10f)R9f or -B(OR9h)2 and R9b to R9e and R9h (i.e. those R9 groups attached to an oxygen atom), do not represent H:
(A) esterification of a corresponding compound of formula II in which R9b to R9e and R9h represents H; or
(B) trans-esterification of a corresponding compound of formula II in which R9b to R9e and R9h do not represent H (and does not represent the same value of the corresponding R9b to R9e and R9h group in the compound of formula II to be prepared), under standard conditions in the presence of the appropriate alcohol of formula XXIII as hereinbefore defined;
(ae) for compounds of formula II in which T represents a single bond, Y represents -C(O)OR9b and R9b is other than H, reaction of a compound of formula XXXVA,
XXXVA
Figure imgf000066_0001
wherein PG represents a suitable protecting group, such as -S(O)2Ph, -C(O)O", -C(O)OtBu or -C(O)N(Et)2) and L5, Q, X2, R2, R3, R and R5 are as hereinbefore defined, with a compound of formula XXIIIB as hereinbefore defined, for example under reaction conditions similar to those described hereinbefore in respect of preparation of compounds of formula I (process (xxxiii)) above), followed by deprotection of the resultant compound under standard conditions;
(af) for compounds of formula II in which T represents a single bond, Y represents -C(O)OR9b and R9b is H, reaction of a compound of formula XXXVA in which L5 represents an alkali metal, or -Mg-halide, with carbon dioxide, followed by acidification;
(ag) for compounds of formula II in which T represents a single bond, Y represents -C(O)OR9b, reaction of a corresponding compound of formula XXXVA in which L5 represents a suitable leaving group known to those skilled in the art (such as a halo (e.g. bromo or iodo) group) with CO (or a suitable reagent that is a source of CO), in the presence of a compound of formula XXIIIC as hereinbefore defined;
(ah) for compounds of formula II in which Y represents
-C(O)OR9b and R9b represents H, hydrolysis of a corresponding compound of formula II in which R9b does not represent H;
(ai) for compounds of formula II in which Y represents -C(O)OR9b and R9b does not represent H:
(A) esterification of a corresponding compound of formula II in which R9b represents H; or
(B) trans-esterification of a corresponding compound of formula II in which R9b does not represent H (and does not represent the same value of R9b as the compound of formula II to be prepared); (aj) for compounds of formula II in which X represents -Q-X and Q represents -O-, reaction of a compound of formula XXXVI3
XXXVI
Figure imgf000068_0001
wherein R2, R3, R4, R5, T and Y are as hereinbefore defined, with a compound of formula XXV as hereinbefore defined;
(ak) for compounds of formula II in which T represents a C1 alkylene group substituted with G1, in which G1 represents -A1^-R118, A1 represents -C(O)A2-, A2 represents a single bond and Rlla represents H, and Y represents -C(O)OR9b, in which R9b is other than H, reaction of a corresponding compound of formula II in which the C1 alkylene group that T represents is unsubstituted with a Ci-6 alkyl formate in the presence of a suitable base;
(al) for compounds of formula II in which X represents -Q-X , Q represents a single bond and X2 represents C1-S alkyl or heterocycloalkyl substituted α to the indole ring by a G1 sύbstituent in which G1 represents -A1^-R113, A1 represents -OA5-, A5 represents a single bond and Rlla represents H, reaction of a corresponding compound of formula II in which X1 represents H with a compound corresponding to a compound of formula VI5 but in which Xlb represents -Q-X2, Q represents a single bond and X2 represents C1-8 alkyl or heterocycloalkyl, both of which groups are substituted by a
Z group in which Z1 represents =0, for example under reaction conditions similar to those described hereinbefore in respect of preparation of compounds of formula I (process (xl)) above; (am) for compounds of formula II in which X1 represents -Q-X2, Q represents a single bond and X2 represents C2-8 alkyl substituted (e.g. α to the indole ring) by a G1 substituent in which G1 represents -A^R113, A1 represents -OA5-, A5 represents a single bond and Rlla represents H, reaction of a corresponding compound of formula II in which X2 represents C1-7 alkyl substituted (e.g. α to the indole ring) by a Z1 group in which Z1 represents =0, with the corresponding Grignard reagent derivative of a compound of formula V in which L2 represents chloro, bromo or iodo, Qa is a single bond and X2 represents C1-7 alkyl, under conditions known to those skilled in the art;
(an) for compounds of formula II in which X represents -Q-X , Q represents a single bond, and X2 represents C1-8 alkyl or heterocycloalkyl, both of which are unsubtituted in the position α to the indole ring, reduction of a corresponding compound of formula
II in which X2 represents Ci-8 alkyl substituted α to the indole ring by a G1 substituent in which G1 represents -A^R11*1, A1 represents -OA5-, A5 represents a single bond and Rlla represents H, for example under reaction conditions similar to those described hereinbefore in respect of preparation of compounds of formula I
(process (xlii)) above;
(ao) for compounds of formula II in which X1 represents -Q-X2, Q represents a single bond and X2 represents C1-8 alkyl or heterocycloalkyl, neither of which are substituted by Z1 in which Z1 represents =0, reduction of a corresponding compound of formula II in which X2 represents C1-8 alkyl or heterocycloalkyl, which groups are substituted by one or more Z1 groups in which Z1 represents =0, for example under reaction conditions similar to those described hereinbefore in respect of preparation of compounds of formula I (process (xliii)) above; or
(ap) for compounds of formula II in which X1 represents -N(R9a)-J-R1Oa, reaction of a compound of formula XXXVI as hereinbefore defined, with a compound of formula VI in which Xlb represents
-N(R9a)-J-R10a and R9a, R1Oa and J are as hereinbefore defined, for example under conditions similar to those described hereinbefore in respect of preparation of compounds of formula I (process (xliv)) above.
Compounds of formula IV may be prepared as follows:
(a) Reaction of a compound of formula XXVI as hereinbefore defined with a compound of formula XXXVII,
R1L2 XXXVII
wherein R1 and L2 are as hereinbefore defined or a compound of formula III as hereinbefore defined, for example under reaction conditions similar to those described hereinbefore in respect of preparation of compounds of formula I (processes (ii) and (i), respectively) above; or
(b) for compounds of formula IV in which L1 represents a sulfonate group, reaction of a compound of formula XXIV as hereinbefore defined, with an appropriate reagent for the conversion of the hydroxyl group to the sulfonate group (e.g. tosyl chloride, mesyl chloride, trifiic anhydride and the like) under conditions known to those skilled in the art.
Compounds of formula VII may be prepared by: (a) for compounds of formula VII in which D represents a single bond, -C(O)-, -C(R7XR8)-, C2-4 alkylene or -S(O)2-, reaction of a compound of formula XXXVIII,
XXXVIII
Figure imgf000071_0001
wherein Q, X2a, L3, R1, R2-R5, T and Y are as hereinbefore defined (L3 in particular may represent halo, such as bromo) with a compound of formula XI as hereinbefore defined (in which L4 may in particular represent
-B(OH2)), for example under reaction conditions similar to those described hereinbefore in respect of preparation of compounds of formula I (process (x)) above;
(b) reaction of a compound of formula XXVII as hereinbefore defined with a compound of formula III as hereinbefore defined, for example under reaction conditions similar to those described hereinbefore in respect of preparation of compounds of formula I (process (i)) above); or
(c) for compounds of formula VII in which Q represents a single bond and X2a represents -CHO, reaction of a corresponding compound of formula I in which X1 represents H with a mixture of DMF and, for example, oxalyl chloride, phosgene or P(O)Cl3 (or the like) in an appropriate solvent system (e.g. DMF or dichloromethane).
Compounds of formula X may be prepared by reaction of a compound of formula XXVIII as hereinbefore defined, with a compound of formula III as hereinbefore defined, for example under reaction conditions similar to those described hereinbefore in respect of preparation of compounds of formula I (process (i)) above.
Compounds of formula X in which L represents L may be prepared by reaction of a compound of formula X in which L3 represents L1, with an appropriate reagent for the conversion of the L1 group to the L2 group. This conversion may be performed by methods known to those skilled in the art, for example, compounds of formula X, in which L3 is 4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl may be prepared by reaction of the reagent bis(pinacolato)diboron with a compound of formula X in which L3 represents L1, for example under reaction conditions similar to those described hereinbefore in respect of preparation of compounds of formula I (process (ii)) above).
Compounds of formulae XV and XXX may be prepared by reaction of a corresponding compound of formula IV, or XXVI, respectively, with a compound of formula XXXIX,
R9aNH2 XXXIX
wherein R9a is as hereinbefore defined, for example under reaction conditions similar to those described hereinbefore in respect of preparation of compounds of formula I (process (ii)) above).
Compounds of formulae XVII and XXXI in which L5 represents an appropriate alkali metal, such as lithium may be prepared by reaction of a compound of formula XL,
Figure imgf000072_0001
wherein Rz represents R1 (in the case of a compound of formula XVII) or PG (in the case of a compound of formula XXXI), and PG, X1, R1, R2, R3, R4 and R5 are as hereinbefore defined, with an appropriate base, such lithium diisopropylamide or BuLi under standard conditions. Compounds of formulae XVII and XXXI in which L5 represents -Mg-halide may be prepared from a corresponding compound of formula XVII or XXXI (as appropriate) in which L5 represents halo, for example under conditions such as those described hereinbefore in respect of process step (x). Compounds of formulae XVII and XXXI in which L5 represents, for example, a zinc-based group, or a halo or boronic acid group a group (such as a zinc-based group, halo or a boronic acid) may be prepared by reacting a corresponding compound of formula XVII or XXXI in which L5 represents an alkali metal with an appropriate reagent for introduction of the relevant group, for example by a metal exchange reaction (e.g. a Zn transmetallation), by reaction with a suitable reagent for the introduction of a halo group (for example, a reagent described hereinbefore in respect of preparation of compounds of formula I (process (xvi)) or, for the introduction of a boronic acid group, reaction with, for example, boronic acid or a protected derivative thereof (e.g. bis(pinacolato)diboron or triethyl borate) followed by (if necessary) deprotection under standard conditions.
Compounds of formula XVII in which L5 represents halo may alternatively by prepared by reaction of a compound of formula XLI,
Figure imgf000073_0001
wherein R1, R2, R3, R4 and R5 are as hereinbefore defined, with an appropriate reagent known to be a suitable source of halide atoms (see for example process (xvi) above in respect of preparation of compounds of formula I). Compounds of formulae XX and XXXIII, and XXII and XXXV, may be prepared by reduction of a corresponding compound of formula I, or of formula II, respectively, in which T represents a single bond and Y represents -C(O)OR9b, to the corresponding primary alcohol (using e.g. LiAlH4), followed by reaction of the relevant resultant intermediate with, in the case of preparation of a compound of formula XX or XXXIII, SOCl2, MeSO2Cl or bromine followed by a suitable source of cyanide ions (e.g. NaCN or KCN) or, in the case of preparation of a compound of formula XXII or XXXV, oxidation to the aldehyde in the presence of a suitable oxidising agent, such as MnO2, in all cases under reaction conditions that will be well known to those skilled in the art. In the case of the latter, the skilled person will appreciate that an appropriate reagent for the reduction of the ester group directly to the aldehyde may be employed (e.g. DIBAL).
Compounds of formulae XXI and XXXTV may be prepared by conversion of a corresponding compound of formula I which T represents a single bond and Y represents -C(O)OR9b to the corresponding primary amide (e.g. when R9b is H, by reaction with SOCl2 followed by ammonia or when R9b is other than H, by reaction with ammonia), followed by dehydration of the resultant intermediate in the presence of a suitable dehydrating agent, such as POCl3, in all cases under reaction conditions that will be well known to those skilled in the art.
Compounds of formula XXVI may be prepared by standard techniques. For example compounds of formula XXVI in which D represents a single bond, -C(O)-, -C(R7)(R8)-, C2-4 alkylene or -S(O)2-, may be prepared by reaction of a compound of formula XLII,
XLII
Figure imgf000074_0001
wherein L1, L3, R2 -R5 T and Y are as hereinbefore defined with a compound of formula XI as hereinbefore defined, for example under reaction conditions similar to those described hereinbefore in respect of preparation of compounds of formula I (process (x)) above.
Compounds of formulae XXVII and XXXVIII, in which Q represents a single bond and X2a represents -CHO, may be prepared from compounds of formulae II, or X, respectively, in which X1 represents H, by reaction with a mixture of DMF and, for example, oxalyl chloride, phosgene or P(O)Cl3 (or the like) in an appropriate solvent system (e.g. DMF or dichloromethane) for example as described hereinbefore.
Compounds of formulae III, V, VI, VIII, IXA, IXB, IXC, XI, XII5 XIII, XTV, XIVA, XVI, XVIII, XIX, XXIIA, XXIII, XXIIIA, XXIIIB, XXIIIC, XXIV, XXV, XXVIII, XXIX, XXXII, XXXVA, XXXVI, XXXVII, XXXIX, XL, XLI and XLII 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.
Indoles of formulae II, IV5 VII, X, XIII5 XV5 XVII, XIX, XX, XXI, XXII, XXIIIA, XXIV, XXVI5 XXVII, XXVIII, XXIX, XXX, XXXI, XXXII, XXXIII, XXXTV, XXXV5 XXXVA, XXXVI, XXXVIII, XL, XLI and XLII 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 or "Comprehensive Heterocyclic Chemistry IF by A. R. Katritzky, C. W. Rees and E. F. V. Scriven, Pergamon Press, 1996) and/or made according to the following general procedures. For example, compounds of formulae II, XXVIII and XXIX in which X1 represents H, -N(R9a)- J-R1Oa or -Q-X2, may be prepared by reaction of a compound of formula XLIII,
Xv
Figure imgf000076_0001
wherein SUB represents the substitution pattern that is present in the relevant compound to be formed (in this case, the compound of formula II, XXVIII or XXIX, respectively), Xy represents H, -N(R9a)- J-R1Oa or -Q-X2, and R9a, R1Oa, J5 Q, X2, T and Y are as hereinbefore defined, under Fischer indole synthesis conditions known to the person skilled in the art.
Compounds of formulae II, XXVIII and XXIX in which X1 represents H may be prepared by reaction of a compound of formula XLIV,
Figure imgf000076_0002
wherein SUB is as hereinbefore defined with a compound of formula XLV,
N3CH2-T-Y XLV
wherein T is as hereinbefore defined and preferably a single bond or optionally substituted arylene or heteroarylene, and Y is as hereinbefore defined and, when T represents a single bond, preferably represents -C(O)OR9b in which R9b preferably does not represent hydrogen, under conditions known to the person skilled in the art (i.e. conditions to induce a condensation reaction, followed by a thermally induced cyclisation).
Compounds of formulae XXTV and XXXVI may be prepared by reaction of a compound of formula XLVI,
Figure imgf000077_0001
wherein Rx represents a C1-6 alkyl group, Ry represents either R (as required for the formation of compounds of formula XXIV), hydrogen (as required for the formation of compounds of formula XXXVI) or a nitrogen-protected derivative thereof, and R1, R2, R3, R4, R5, T and Y are as hereinbefore defined for example under cyclisation conditions known to those skilled in the art.
Compounds of formulae II and XXIX wherein X1 represents -NH2, may be prepared by reaction of a compound of formula XLVII,
SUB XLVII
Figure imgf000077_0002
wherein SUB, T and Y are as hereinbefore defined, for example under intramolecular cyclisation conditions known to those skilled in the art.
Compounds of formulae II and XXIX in which X1 represents H, -N(R9a)-J-R10a or -Q-X2 in which Q represents a single bond or -C(O)-, may alternatively be prepared by reaction of a compound of formula XLVIII5 SUB XLVIII
Figure imgf000078_0001
wherein V represents either -C(O)- or -CH2-, Xz represents H, -N(R9^-J-R1 Oa or -Q-X2 in which Q represents a single bond or -C(O)- and SUB, R9a, R1Oa, J5 T and
Y are as hereinbefore defined. When V represents -C(O)-, the intramolecular cyclisation may be induced by a reducing agent such as TiCl3/C8K, TiCL/Zn or
SmI2 under conditions known to the skilled person, for example, at room temperature in the presence of a polar aprotic solvent (such as THF). When V represents -CH2-, the reaction may be performed in the presence of base under intramolecular condensation reaction conditions known to the skilled person.
Compounds of formula XLIII maybe prepared by:
(a) reaction of a compound of formula XLIX,
Figure imgf000078_0002
wherein SUB is as hereinbefore defined with a compound of formula L,
Figure imgf000078_0003
wherein Xy, T and Y are as hereinbefore defined under condensation conditions known to the skilled person;
(b) reaction of a compound of formula LI,
Figure imgf000079_0001
wherein SUB is as hereinbefore defined with a compound of formula LII,
Figure imgf000079_0002
wherein Rm represents OH, 0-C1-6 alkyl or C1-6 alkyl and Xy, T and Y are as hereinbefore defined, for example under Japp-Klingemann conditions known to the skilled person.
Compounds of formula XLVHI may be prepared by reaction of a compound of LIII,
Figure imgf000079_0003
wherein SUB and Xz are as hereinbefore defined with a compound of formula LIV, Y-T-V-Cl LIV
wherein T, Y and V are as hereinbefore defined, under standard coupling conditions.
Compounds of formulae XLIV, XLV, XLVI, XLVII, XLIX, L5 LI, LII, LIII and LIV 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. Li this respect, the skilled person may refer to inter alia "Comprehensive Organic Synthesis'" by B. M. Trost and I. Fleming, Pergamon Press, 1991.
The substituents X1, R1, R2, R3, R4, R5, T and Y in final compounds of the invention or relevant intermediates may be modified one or more times, after or during the processes described above by way of methods that are well known to those skilled in the art. Examples of such methods include substitutions, reductions, oxidations, alkylations, acylations, hydrolyses, esterifications, and etherifications. 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. For example, in cases where Y is -C(O)OR9b and R9b does not initially represent hydrogen (so providing an ester functional group), the skilled person will appreciate that at any stage during the synthesis (e.g. the final step), the relevant substituent may be hydrolysed to form a carboxylic acid functional group (in which case R9b will be hydrogen). 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.
Compounds of the invention may be isolated from their reaction mixtures using conventional techniques . It will be appreciated by those skilled in the art that, in the processes described above and hereinafter, the functional groups of intermediate compounds may need to be protected by protecting groups.
The protection and deprotection of functional groups may take place before or after a reaction in the above-mentioned schemes.
Protecting groups may be removed in accordance with techniques that are well known to those skilled in the art and as described hereinafter. For example, protected compounds/intermediates described herein may be converted chemically to unprotected compounds using standard deprotection techniques.
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
Chemistry", edited by J W F McOmie, Plenum Press (1973), and "Protective
Groups in Organic Synthesis", 3rd edition, T. W. Greene & P.G.M. Wutz, Wiley-
Interscience (1999).
Medical and Pharmaceutical Uses
Compounds of the invention are indicated as pharmaceuticals. According to a further aspect of the invention there is provided a compound of the invention, as hereinbefore defined, for use as a pharmaceutical.
Although compounds of the invention may possess pharmacological activity as such, certain pharmaceutically-acceptable (e.g. "protected") derivatives of compounds of the invention may exist or be prepared which may not possess such activity, but may be administered parenterally or orally and thereafter be metabolised in the body to form compounds of the invention. Such compounds (which may possess some pharmacological activity, provided that such activity is appreciably lower than that of the "active" compounds to which they are metabolised) may therefore be described as "prodrugs" of compounds of the invention.
By "prodrug of a compound of the invention", we include compounds that form a compound of the invention, in an experimentally-detectable amount, within a predetermined time (e.g. about 1 hour), following oral or parenteral administration. All prodrugs of the compounds of the invention are included within the scope of the invention.
Furthermore, certain compounds of the invention (including, but not limited to, compounds of formula I in which Y represents -C(O)OR9b and R9b is other than hydrogen) may possess no or minimal pharmacological activity as such, but may be administered parenterally or orally, and thereafter be metabolised in the body to form compounds of the invention that possess pharmacological activity as such (including, but not limited to, corresponding compounds of formula I5 in which R9b represents hydrogen). Such compounds (which also includes compounds that may possess some pharmacological activity, but that activity is appreciably lower than that of the "active" compounds of the invention to which they are metabolised), may also be described as "prodrugs".
Thus, the compounds of the invention are useful because they possess pharmacological activity, and/or are metabolised in the body following oral or parenteral administration to form compounds which possess pharmacological activity.
Compounds of the invention are particularly useful because they may inhibit the activity of a member of the MAPEG family.
Compounds of the invention are particularly useful because they may inhibit (for example selectively) the activity of prostaglandin E synthases (and particularly microsomal prostaglandin E synthase-1 (mPGES-1)), i.e. they prevent the action of mPGES-1 or a complex of which the mPGES-1 enzyme forms a part, and/or may elicit a mPGES-1 modulating effect, for example as may be demonstrated in the test described below. Compounds of the invention may thus be useful in the treatment of those conditions in which inhibition of a PGES, and particularly mPGES-1, is required.
Compounds of the invention may inhibit the activity of leukotriene C4 (LTC4) synthase, for example as may be shown in a test such as that described in Eur. J. Biochem., 208, 725-734 (1992), and may thus be useful in the treatment of those conditions in which inhibition of LTC4 is required. Compounds of the invention may also inhibit the activity of 5-lipoxygenase-activating protein (FLAP), for example as may be shown in a test such as that described in MoI. Pharmacol., 41, 873-879 (1992).
Compounds of the invention are thus expected to be useful in the treatment of inflammation.
The term "inflammation" will be understood by those skilled in the art to include any condition characterised by a localised or a systemic protective response, which may be elicited by physical trauma, infection, chronic diseases, such as those mentioned hereinbefore, and/or chemical and/or physiological reactions to external stimuli (e.g. as part of an allergic response). Any such response, which may serve to destroy, dilute or sequester both the injurious agent and the injured tissue, may be manifest by, for example, heat, swelling, pain, redness, dilation of blood vessels and/or increased blood flow, invasion of the affected area by white blood cells, loss of function and/or any other symptoms known to be associated with inflammatory conditions.
The term "inflammation" will thus also be understood to include any inflammatory disease, disorder or condition per se, any condition that has an inflammatory component associated with it, and/or any condition characterised by inflammation as a symptom, including inter alia acute, chronic, ulcerative, specific, allergic and necrotic inflammation, and other forms of inflammation known to those skilled in the art. The term thus also includes, for the purposes of this invention, inflammatory pain, pain generally and/or fever.
Accordingly, compounds of the invention may be useful in the treatment of asthma, chronic obstructive pulmonary disease, pulmonary fibrosis, inflammatory bowel disease, irritable bowel syndrome, inflammatory pain, fever, migraine, headache, low back pain, fibromyalgia, myofascial disorders, viral infections {e.g. influenza, common cold, herpes zoster, hepatitis C and AIDS), bacterial infections, fungal infections, dysmenorrhea, burns, surgical or dental procedures, malignancies (e.g. breast cancer, colon cancer, and prostate cancer), hyperprostaglandin E syndrome, classic Bartter syndrome, atherosclerosis, gout, arthritis, osteoarthritis, juvenile arthritis, rheumatoid arthritis, rheumatic fever, ankylosing spondylitis, Hodgkin's disease, systemic lupus erythematosus, vasculitis, pancreatitis, nephritis, bursitis, conjunctivitis, iritis, scleritis, uveitis, wound healing, dermatitis, eczema, psoriasis, stroke, diabetes mellitus, neurodegenerative disorders such as Alzheimer's disease and multiple sclerosis, autoimmune diseases, allergic disorders, rhinitis, ulcers, coronary heart disease, sarcoidosis and any other disease with an inflammatory component.
Compounds of the invention may also have effects that are not linked to inflammatory mechanisms, such as in the reduction of bone loss in a subject. Conditions that may be mentioned in this regard include osteoporosis, osteoarthritis, Paget's disease and/or periodontal diseases. Compounds the invention may thus also be useful in increasing bone mineral density, as well as the reduction in incidence and/or healing of fractures, in subjects.
Compounds of the invention are indicated both in the therapeutic and/or prophylactic treatment of the above-mentioned conditions.
According to a further aspect of the present invention, there is provided a method of treatment of a disease which is associated with, and/or which can be modulated by inhibition of, a member of the MAPEG family such as a PGES (e.g. mPGES- 1), 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 invention, as hereinbefore defined, to a patient suffering from, or susceptible to, such a condition.
"Patients" include mammalian (including human) patients.
The term "effective amount" refers to an amount of a compound, which confers a therapeutic effect on the treated patient. The effect may be objective (i.e. measurable by some test or marker) or subjective (i.e. the subject gives an indication of or feels an effect).
Compounds of the invention will normally be administered orally, intravenously, subcutaneously, buccally, rectally, dermally, nasally, tracheally, bronchially, sublingually, by any other parenteral route or via inhalation, in a pharmaceutically acceptable dosage form.
Compounds of the invention may be administered alone, but are preferably administered by way of known pharmaceutical formulations, including tablets, capsules or elixirs for oral administration, suppositories for rectal administration, sterile solutions or suspensions for parenteral or intramuscular administration, and the like.
Such formulations may be prepared in accordance with standard and/or accepted pharmaceutical practice.
According to a further aspect of the invention there is thus provided a pharmaceutical formulation including a compound of the invention, as hereinbefore defined, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier. The invention further provides a process for the preparation of a pharmaceutical formulation, as hereinbefore defined, which process comprises bringing into association a compound of the invention, as hereinbefore defined, or a pharmaceutically acceptable salt thereof with a pharmaceutically-acceptable adjuvant, diluent or carrier.
Compounds of the invention may also be combined with other therapeutic agents that are useful in the treatment of inflammation (e.g. NSAIDs and coxibs).
According to a further aspect of the invention, there is provided a combination product comprising:
(A) a compound of the invention, as hereinbefore defined; and
(B) another therapeutic agent that is useful in the treatment of inflammation, wherein each of components (A) and (B) is formulated in admixture with a pharmaceutically-acceptable adjuvant, diluent or carrier.
Such combination products provide for the administration of a compound of the invention in conjunction with the other therapeutic agent, and may thus be presented either as separate formulations, wherein at least one of those formulations comprises a compound of the invention, and at least one comprises the other therapeutic agent, or may be presented (i.e. formulated) as a combined preparation (i.e. presented as a single formulation including a compound of the invention and the other therapeutic agent).
Thus, there is further provided:
(1) a pharmaceutical formulation including a compound of the invention, as hereinbefore defined, another therapeutic agent that is useful in the treatment of inflammation, and a pharmaceutically-acceptable adjuvant, diluent or carrier; and
(2) a kit of parts comprising components: (a) a pharmaceutical formulation including a compound of the invention, as hereinbefore defined, in admixture with a pharmaceutically-acceptable adjuvant, diluent or carrier; and
(b) a pharmaceutical formulation including another therapeutic agent that is useful in the treatment of inflammation in admixture with a pharmaceutically-acceptable adjuvant, diluent or carrier, which components (a) and (b) are each provided in a form that is suitable for administration in conjunction with the other.
The invention further provides a process for the preparation of a combination product as hereinbefore defined, which process comprises bringing into association a compound of the invention, as hereinbefore defined, with another therapeutic agent that is useful in the treatment of inflammation, and a pharmaceutically-acceptable adjuvant, diluent or carrier.
By "bringing into association", we mean that the two components are rendered suitable for administration in conjunction with each other.
Thus, in relation to the process for the preparation of a kit of parts as hereinbefore defined, by bringing the two components "into association with" each other, we include that the two components of the kit of parts may be:
(i) provided as separate formulations (i.e. independently of one another), which are subsequently brought together for use in conjunction with each other in combination therapy; or (ii) packaged and presented together as separate components of a "combination pack" for use in conjunction with each other in combination therapy.
Compounds of the invention may be administered at varying doses. Oral, pulmonary and topical dosages may range from between about 0.01 mg/kg of body weight per day (mg/kg/day) to about 100 mg/kg/day, preferably about 0.01 to about 10 mg/kg/day, and more preferably about 0.1 to about 5.0 mg/kg/da}'. For e.g. oral administration, the compositions typically contain between about 0.01 mg to about 500 mg, and preferably between about 1 mg to about 100 mg, of the active ingredient. Intravenously, the most preferred doses will range from about 0.001 to about 10 mg/kg/hour during constant rate infusion. Advantageously, compounds may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three or four times daily.
In any event, the physician, or the skilled person, will be able to determine the actual dosage which will be most suitable for an individual patient, which is likely to vary with the route of administration, the type and severity of the condition that is to be treated, as well as the species, age, weight, sex, renal function, hepatic function and response of the particular patient to be treated. The above-mentioned dosages are exemplary of the average case; there can, of course, be individual instances where higher or lower dosage ranges are merited, and such are within the scope of this invention.
Compounds of the invention may have the advantage that they are effective, and preferably selective, inhibitors of a member of MAPEG family, e.g. inhibitors of prostaglandin E synthases (PGES) and particularly microsomal prostaglandin E synthase-1 (mPGES-1). The compounds of the invention may reduce the formation of the specific arachidonic acid metabolite 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 the invention may also have the advantage that they may be more efficacious than, be less toxic than, be longer acting than, be more potent than, produce fewer side effects than, be more easily absorbed than, and/or have a better pharmacokinetic profile (e.g. higher oral bioavailability and/or lower clearance) than, and/or have other useful pharmacological, physical, or chemical properties over, compounds known in the prior art, whether for use in the above-stated indications or otherwise. Biological Test
In the assay mPGES-1 catalyses the reaction where the substrate 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°C. In the assay mPGES- 1 is dissolved in O,1M KPi-buffer pH 7,35 with 2,5mM glutathione. The stop solution consists Of H2O / MeCN (7/3), containing FeCl2 (25 mM) and HCl (0.15
M). The assay is performed at room temperature in 96-well plates. Analysis of the amount of PGE2 is performed with reversed phase HPLC (Waters 2795 equipped with a 3.9 x 150 mm C18 column). The mobile phase consists OfH2O / MeCN (7/3), containing TFA (0.056%), and absorbance is measured at 195 nm with a Waters 2487 UV-detector.
The following is added chronologically to each well:
1. 100 μL mPGES-1 in KPi-buffer with glutathione. Total protein concentration: 0.02 mg/mL. 2. 1 μL inhibitor in DMSO. Incubation of the plate at room temperature for 25 minutes.
3. 4 μL of a 0,25 mM PGH2 solution. Incubation of the plate at room temperature for 60 seconds.
4. 100 μL stop solution. 180 μL per sample is analyzed with HPLC.
Examples
The invention is illustrated by way of the following examples, in which the following abbreviations may be employed:
EtOAc ethyl acetate
NMR nuclear magnetic resonance
THF tetrahydrofuran
TLC thin layer chromatography
Starting materials and chemical reagents specified in the syntheses described below are commercially available from, e.g. Sigma- Aldrich Fine Chemicals. Example 1
3 -Chloro- 1 -( 4-isopropoxyphenviy 5-[2,2,2-trifluoro- 1 -hydroxy- 1 -( 4-trifluoro methoxyphenyl)ethyl]indole-2-carboxylic acid
(a) 5-Bromo-3-chloroindole-2-carboxylic acid ethyl ester
A solution of 5-bromoindole-2-carboxylic acid ethyl ester (10.0 g, 37.3 rnmol) in benzene (250 mL) was mixed with sulfuryl chloride (4.5 mL, 55.5 mmol) and heated at reflux for 2 h. Approximately half the volume of solvent was removed under reduced pressure. The remaining solution was then cooled to room temperature resulting in the formation of a precipitate. Filtration of the formed precipitate afforded the sub-title compound (6.33 g, 56% yield).
(b) 5-Bromo-3 -chloro- l-f4-isopropoxyphenyl')indole-2-carboxylic acid ethyl ester Anhydrous CH2Cl2 (80 mL), followed by triethylamine (3.36 mL, 23.9 mmol) and pyridine (1.95 mL, 23.9 mmol) were added to a mixture of 5-bromo-3- chloroindole-2-carboxylic acid ethyl ester (3.60 g, 11.9 mmol; see step (a) above), Cu(OAc)2 (4.34 g, 23.9 mmol), 3 A molecular sieves (ca. 7 g) and 4- cyclopentyloxyphenylboronic acid (4.30 g, 23.9 mmol). The mixture was stirred vigorously at ambient temperature for 48 h, then additional triethylamine (1.6 mL, 11.0 mmol), pyridine (0.90 mL, 11.0 mmol), Cu(OAc)2 (2.00 g, 11.0 mmol) and 4-cyclopentyloxyphenylboronic acid (2.27 g, 11.0 mmol) was added and the mixture was stirred at ambient temperature for another 48 h. After the reaction was complete, the mixture was filtered through Celite®. The filter cake was washed with EtOAc. The combined filtrates were washed with aqueous NH4OH, 0.1 M HCl solution, brine, dried over Na2SO4, concentrated under reduced ' pressure and purified by chromatography to afford the sub-title compound (4.40 g,
(c) 3 -Chloro- l-f4-isopropoxyphenyl)-5-iodoindole-2-carboxylic acid ethyl ester A mixture of 5-bromo-3-chloro-l-(4-isopropoxyphenyl)indole-2-carboxylic acid ethyl ester (2.70 g, 6.2 mmol; see step (b)), CuI (0.12 g, 0.62 mmol), ΛζiV- dimethyl-l,2-diamino ethane (130 μL, 1.24 mmol) and sodium iodide (1.85 g, 12.4 mmol) in dioxane (10 mL) was heated at HO0C for 48 h, then cooled to room temperature, diluted with aq. sat. NH4Cl, poured into water (150 mL) and extracted with EtOAc. The combined organic extracts were washed with water, brine and dried over Na2SO4. Concentration under reduced pressure and filtration through a silica gel pad afforded the sub-title compound (2.29g, 76%).
(d) 3 -Chloro- 1 -(4-isopropoxyphenyl)-5-(4-trifluoromethoxybenzoyl)indole-2- carboxylic acid ethyl ester
A solution of 3-chloro-l-(4-isopropoxyphenyl)-5-iodoindole-2-carboxylic acid ethyl ester (1.93 g, 4.0 mmol; see step (c) above) in THF (5 mL) was rapidly added (all at once) to a 1 M solution of z-PrMgCl-LiCl in THF (8.4 mL, 8.4 mmol) at -4O0C under argon. After stirring for 2 hours, a solution of 4- trifluoromethoxybenzoyl chloride (1.9 mL, 12.0 mmol) in THF (5 mL) was added and the reaction was allowed to warm to room temperature, quenched with aq. sat. NH4Cl (20 mL) and extracted with EtOAc. The combined organic extracts were washed with water, brine and dried over Na2SO4. Concentration under reduced pressure and purification by chromatography afforded the sub-title compound (1.41 g, 65%).
(e) 3 -Chloro- 1 -(4-isopropoxyphenyl)-5-[2,2,2-Mfluoro- 1 -hydroxy- 1 -f 4-trifluoro- methoxyphenyl)ethyl"lindole-2-carboxyric acid ethyl ester
To a mixture of 3 -chloro- l-(4-isopropoxyphenyl)-5-(4-trifluoromethoxy- benzoyl)indole-2-carboxylic acid ethyl ester (180 mg, 0.33 mmol; see step (d) above) and a 0.5 M solution of trifluoromethyltrimethyl silane in THF (1.2 mmol, 2.4 mL) in dry THF was added a 1 M solution of tetrabutylammonium fluoride in THF (0.1 mL) at O0C. After stirring for 48 hours at room temperature an additional 2 mL of 1 M tetrabutylammonium fluoride was added. The reaction mixture was stirred for 12 hours, poured into aq. sat. NH4Cl (20 mL) and extracted with diethylether. The combined organic extracts were washed with water, brine and dried over Na2SO4. Concentration under reduced pressure and purification by chromatography afforded the sub-title compound (57 mg, 28%). (f) 3-Chloro-l-(4-isopropoxyphenyl)-5-r2.,2.2-trifluoro-l-hvdroxy-l-f4-trifluoro- memoxyphenyl)ethyl1indole-2-carboxylic acid
A mixture of 3-chloro-l-(4-isopropoxyphenyl)-5-[2,2,2-trifluoro-l-hydroxy-l-(4- trifluoromethoxyphenyl)efhyl]indole-2-carboxylic acid ethyl ester (55 mg, 0.089 mmol; see step (e) above) in dioxane (1 mL) was mixed with 2 M NaOH aq solution (0.5 mL, 1.0 mmol) and heated under reflux for 4h. The reaction progress was monitored by TLC. After the ester spot disappeared, the solution was poured into 10 ml of water, acidified to pH 5.0 by an 1 M HCl solution in water and extracted with EtOAc (3 x 20 mL). The combined organic extracts were washed with water, brine and dried over Na2SO4. Concentration under reduced pressure and purification by chromatography afforded the title compound (36 mg, 53%). 1H-NMR (200 MHz OMSO-d6, ppm) δ 7.74 (IH, s) 7.59-7.53 (3H, m) 7.41-7.37 (2H, m) 7.30-7.23 (2H, m) 7.07 (IH, d, J = 9.0 Hz) 7.03-6.95 (2H3 m) 4.66 (IH, septet, J= 6.1 Hz) 1.31 (6H, d, J= 6.1 Hz).
Example 2
The compound of Example 1 was tested in the biological test described above and was found to exhibit 50% inhibition of mPGES-1 at a concentration of 10 μM or below.

Claims

Claims
1. A compound of formula I,
Figure imgf000093_0001
wherein
one of the groups R2, R3, R4 and R5 represents -D-E and: a) the other groups are independently selected from hydrogen, G1, Cμg alkyl and a heterocycloalkyl group (which latter two groups are optionally substituted by one or more substituents selected from G1 and/or Z1), an aryl group and a heteroaryl group (which latter two groups are optionally substituted by one or more substituents selected from A); and/or b) any two other groups which are adjacent to each other are optionally linked to form, along with two atoms of the essential benzene ring in the compound of formula I, a 3- to 8-membered ring, optionally containing 1 to 3 heteroatoms, which ring is itself optionally substituted by one or more substituents selected from halo, -R6, -OR6 and =0;
D represents -C(R7)(R8)- or -C(=C(R7b)(R8b))-;
R1 and E independently represent an aryl group or a heteroaryl group, both of which groups are optionally substituted by one or more substituents selected from A;
R7 represents C1-6 alkyl, optionally substituted by one or more substituents selected from W , or R7a; or R7 and R8 are linked together with the carbon atom to which they are attached to form a 3- to 6-menϊbered ring, which ring contains at least one unsaturation, optionally contains a heteroatom and is optionally substituted by one or more substituents selected from halo and Ci-3 alkyl, which latter group is optionally substituted by one or more halo substituents;
R7a and R8 independently represent -ORa, -N(Rb)(Rc) or -SRd;
R^ and R8b independently represent hydrogen, -ORe, -N(Rf)(Rg), -SRh or C1-6 alkyl optionally substituted by one or more substituents selected from W2; or R713 and R8b are linked together to form, together with the carbon atom to which they are necessarily attached, a 3- to 6-membered ring optionally containing 1 to 3 heteroatoms and 1 to 3 unsaturations and which ring is optionally substituted by one or more substituents selected from C1-6 alkyl (which is optionally substituted by one or more halo atoms) and W ;
Ra, Rb, Rc, Rd, Re, Rf, Rg and Rh independently represent H or C1-6 alkyl optionally substituted by one or more substituents selected from W4; or any pair of Rb and Rc, or Rf and Rε are linked together with the nitrogen atom to which they are necessarily attached to form a 3- to 6-membered ring optionally containing 1 to 3 heteroatoms and 1 to 3 unsaturations and which ring is optionally substituted by one or more substituents selected from C1-6 alkyl (which is optionally substituted by one or more halo atoms) and W5;
X1 represents H, halo, -N(R9a)-J-R10a or -Q-X2;
J represents a single bond, -C(O)- or -S(O)m-;
Q represents a single bond, -O-, -C(O)- or -S(O)m-;
X2 represents: (a) an aryl group or a heteroaryl group, both of which are optionally substituted by one or more substituents selected from A; or
(b) C1-8 alkyl or a heterocycloalkyl group, both of which are optionally substituted by one or more substituents selected from G1 and/or Z1;
T represents:
(a) a single bond;
(b) a Ci-S alkylene or a C2-8 heteroalkylene chain, both of which latter two groups: (i) optionally contain one or more unsaturations; (ii) are optionally substituted by one or more substituents selected from G1 and/or Z1; and/or (iii) may comprise an additional 3- to 8-membered ring formed between any one or more members of the C1-8 alkylene or C2-8 heteroalkylene chain, which ring optionally contains 1 to 3 hetero atoms and/or 1 to 3 unsaturations and which ring is itself optionally substituted by one or more substituents selected from G1 and/or Z1;
(c) an arylene group or a heteroarylene group, both of which groups are optionally substituted by one or more substituents selected from A; or
(d) -T^-W-T2-;
one of T1 and T2 represents a C1-8 alkylene or a C2-8 heteroalkylene chain, both of which latter two groups:
(i) optionally contain one or more unsaturations;
(ii) are optionally substituted by one or more substituents selected from G1 and/or Z1; and/or
(iii) may comprise an additional 3- to 8-membered ring formed between any one or more members of the C1-8 alkylene or C2-8 heteroalkylene chain, which ring optionally contains 1 to 3 heteroatoms and/or 1 to 3 unsaturations and which ring is itself optionally substituted by one or more substituents selected from G1 and/or Z1; and the other represents an arylene group or a heteroarylene group chain, both of which groups are optionally substituted by one or more substituents selected from A;
Wx represents -O- or -S(O)m-;
m represents 0, 1 or 2;
Y represents -C(H)(CF3)OH, -C(O)CF3, -C(OH)2CF3, -C(O)OR9b, -S(O)3R9c, -P(O)(OR9d)2, -P(O)(OR9e)N(R10f)R9f, -P(O)(N(R10g)R9g)2, -B(OR9h)2, -C(CF3)2OH, -S(O)2N(R10i)R9i or any one of the following groups:
Figure imgf000096_0001
R6, R9a to R9x, R1Oa, R1Of, R1Og, R1Oi and R1Oj independently represent:
I) hydrogen;
II) an aryl group or a heteroaryl group, both of which are optionally substituted by one or more substituents selected from B; or III) C1-S alkyl' or a heterocycloalkyl group, both of which are optionally substituted by one or more substituents selected from G1 and/or Z1; or any pair of R9a to R9x and R1Oa, R10f 5 R1Og, R1Oi or R10j, may be linked together to form, along with the atom(s) and/or group(s) to which they are attached, a 3- to 8- membered ring, optionally containing 1 to 3 heteroatoms and/or 1 to 3 double bonds, which ring is optionally substituted by one or more substituents selected
Figure imgf000097_0001
A represents:
I) an aryl group or a heteroaryl group, both of which are optionally substituted by one or more substituents selected from B; II) C1-S alkyl or a heterocycloalkyl group, both of which are optionally substituted by one or more substituents selected from G and/or Z ; or III) a G1 group;
G1 represents halo, cyano, -N3, -NO2, -ONO2 or -A^R11*; wherein A1 represents a single bond or a spacer group selected from -C(O)A2-,
-S(O)2A3-, -N(R12a)A4- or -OA5-, in which:
A2 represents a single bond, -0-, -N(R12b)- or -C(O)-;
A3 represents a single bond, -O- or -N(R12c)-;
A4 and A5 independently represent a single bond, -C(O)-, -C(O)N(R12d)-5 -C(O)O-, -S(O)2- or -S(O)2N(R126)-;
Z1 represents =0, =S, =N0Rllb, -NS(O)2N(R12^R1 lo, =NCN Or=C(H)NO2;
B represents: I) an aryl group or a heteroaryl group, both of which are optionally substituted by one or more substituents selected from G2;
II) C1-S alkyl or a heterocycloalkyl group, both of which are optionally substituted by one or more substituents selected from G2 and/or Z2; or
III) a G2 group;
G2 represents halo, cyano, -N3, -NO2, -ONO2 or -A6-R13a; wherein A6 represents a single bond or a spacer group selected from -C(O)A7-, -S(O)2A8-, -N(R14a)A9- or -OA10-, in which: A7 represents a single bond, -0-, -N(R14b)- or -C(O)-; A represents a single bond, -O- or -N(R14c)-; A9 and A10 independently represent a single bond, -C(O)-, -C(O)N(R14d)-5 -C(O)O-, -S(O)2- or -S(0)2N(R14e)-;
Z2 represents =0, =S, =NOR13b, =NS(O)2N(R14f)R13c, =NCN or =C(H)N02;
Rlla, Rllb, Rllc, R12a, R12b, R12c, R12d 3 R12e, R12f, R13a, R13b, R13c, R14a, R14b, R14c,
R14d, R14e and R14f are independently selected from: i) hydrogen; ii) an aryl group or a heteroaryl group, both of which are optionally substituted by one or more substituents selected from G ; iii) C1-8 alkyl or a heterocycloalkyl group, both of which are optionally substituted by G3 and/or Z3; or any pair of Rlla to Rllc and R12a to R12f, and/or R13a to R13c and R14a to R14f, may be linked together to form with those, or other relevant, atoms a further 3- to 8- membered ring, optionally containing 1 to 3 heteroatoms and/or 1 to 3 double bonds, which ring is optionally substituted by one or more substituents selected from G3 and/or Z3;
G3 represents halo, cyano, -N3, -NO2, -ONO2 or -Au-R15a; wherein A11 represents a single bond or a spacer group selected from -C(O)A12-, -S(O)2A13-, -N(R16a)A14- or -OA15-, in which:
A12 represents a single bond, -0-, -N(Rlδb)- or -C(O)-;
A13 represents a single bond, -O- or -N(R16c)-;
A14 and A15 independently represent a single bond, -C(O)-, -C(O)N(R16d)-,
-C(O)O-, -S(O)2- or -S(O)2N(R16e)-;
Z3 represents =0, =S, =N0R15b, ^=NS(O)2N(R16^)R15o, =NCN or =C(H)N02; R15a, R15b, R15c, R16a, R16b, R16c, R16d, R16e and R16f are independently selected from: i) hydrogen; ii) C1-6 alkyl or a heterocycloallcyl group, both of which groups are optionally substituted by one or more substituents selected from halo, C1-4 alkyl, -N(R17a)R18a, -OR17b and =0; and iii) an aryl or heteroaryl group, both of which are optionally substituted by one or more substituents selected from halo, C1-4 alkyl, -N(R17c)R18b and -OR17d; or any pair of RI5a to R15c and R16a to R16f may be linked together to form with those, or other relevant, atoms a further 3- to 8-membered ring, optionally containing 1 to 3 heteroatoms and/or 1 to 3 double bonds, which ring is optionally substituted by one or more substituents selected from halo, C1-4 alkyl, -N(R17e)R18c, -OR17f and =O;
R17a, R17b, R17c, R17d, R17e, R17f, R18a, R18b and R18° are independently selected from hydrogen and C1-4 alkyl, which latter group is optionally substituted by one or more halo groups;
W1, W2, W3, W4 and W5 independently represent halo, =0, -OR19a or -N(R19b)R19c;
R19a, R19b and R19c independently represent H or C1-6 alkyl optionally substituted by one or more substituents selected from halo and =0,
or a pharmaceutically-acceptable salt thereof.
2. A compound as claimed in Claim 1, wherein A represents G1 or C1-6 alkyl optionally substituted by one or more G1 groups.
3. A compound as claimed in Claim 1 or Claim 2, wherein G1 represents halo, cyano, -NO2 or -A^R1 la.
4. A compound as claimed in Claim 3, wherein G Λ ~ re,presents -A 1 - uR Ha .
5. A compound as claimed in any one of the preceding claims, wherein A1 represents a single bond, -C(O)A2-, -N(R12a)A4- or -OA5-.
6. A compound as claimed in Claim 5, wherein A1 represents a single bond or -OA5-.
7. A compound as claimed in any one of the preceding claims, wherein A represents -O- or -N(R12a)-.
8. A compound as claimed in any one of the preceding claims, wherein A and A5 independently represent a single bond.
9. A compound as claimed in any one of the preceding claims, wherein R1 la, Rllb and Rllc independently represent a phenyl group, a tetrazolyl group, an imidazolyl group, a pyridyl group, or a C1-3 alkyl group, all of which are optionally substituted by one or more G groups.
10. A compound as claimed in Claim 9, wherein Rlla, Rllb and Rllc independently represent Ci-3 alkyl group optionally substituted by one or more G3 groups.
11. A compound as claimed in any one of the preceding claims, wherein G3 represents halo.
12. A compound as claimed in any one of the preceding claims, wherein R7 represents Ci-6 alkyl optionally substituted by one or more W1 groups.
13. A compound as claimed in any one of the preceding claims, wherein R8 represents -ORa.
14. A compound as claimed in any one of the preceding claims, wherein W1, W2 and W4 independently represent halo, -OR19a or =0.
15. A compound as claimed in any one of the preceding claims, wherein W3 and W5 independently represent -OR19a or =0.
16. A compound as claimed in any one of the preceding claims, wherein R19a, R19b and R19c independently represent H or Ci-4 alkyl optionally substituted by one or more halo atoms.
17. A compound as claimed in any one of the preceding claims, wherein Ra, Rb, Rc and Rd independently represent H or Ci-4 alkyl optionally substituted by one or more substituents selected from W4.
18. A compound as claimed in any one of the preceding claims, wherein Re, Rf, Rg and Rh independently represent H or Ci-4 alkyl optionally substituted by one or more halo atoms.
19. A compound as claimed in any one of the preceding claims, wherein R9a to R9x independently represent H or Ci-6 alkyl.
20. A compound as claimed in any one of the preceding claims, wherein R1Oa, R iof R iog 5 R ioi and R ioj independently represent H or C1-6 alkyl optionally substituted by one or more groups selected from G1.
21. A compound as claimed in any one of Claims 1 to 18, wherein any pair of R9a to R9x and R1Oa, R1Of, R1Og, R10i or R10j are linked to form a 4- to 7-membered ring, which ring may contain a further heteroatom and which ring is optionally substituted by one or more Z1 groups.
22. A compound as claimed in any one of the preceding claims, wherein R1, E and (when they represent such aryl or heteroaryl groups) X2, R9a to R9x and R1Oa, R iof R iogj R ioi mά R ioj represent 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, groups.
23. A compound as claimed in Claim 22, wherein the optional substituents are selected from phenyl, =0 (in the case of substituents on non-aromatic rings), halo, cyano, -NO2, Cμ6 alkyl (which alkyl group may be linear or branched, cyclic, part- cyclic, unsaturated and/or optionally substituted with one or more halo group), heterocycloalkyl (which heterocycloalkyl group is optionally substituted by one or more substituents selected from C1-3 alkyl and =0), -OR20, -N(R20)R21 and -C(O)OR20, wherein R20 and R21 independently represent H or C1-6 alkyl (which alkyl group is optionally substituted by one or more halo groups).
24. A compound as claimed in any one of the preceding claims, wherein X1 represents -N(R9)-J-R10, C1-3 alkyl, heterocycloalkyl (which latter two groups are optionally substituted by -N(R12a)Rlla-, -ORlla, -Rlla or halo), H or halo.
25. A compound as claimed in Claim 24, wherein X1 represents halo.
26. A compound as claimed in any one of the preceding claims, wherein J represents -C(O)- or -S(O)2-.-
27. A compound as claimed in any one of the preceding claims, wherein one of R4 and R3 represents -D-E and the other represents H.
28. A compound as claimed in Claim 27, wherein R3 represents -D-E.
29. A compound as claimed in any one of the preceding claims, wherein R2 and/or R5 independently represent H.
30. A compound as claimed in any one of the preceding claims, wherein T represents a single bond.
31. A compound as claimed in any one of the preceding claims, wherein Y represents -C(O)OR9b.
32. A compound as defined in any one of Claims 1 to 31, or a pharmaceutically-acceptable salt thereof, for use as a pharmaceutical.
33. A pharmaceutical formulation including a compound as defined in any one of Claims 1 to 31, or a pharmaceutically-acceptable salt thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.
34. A compound, as defined in any one of Claims 1 to 31, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease in which inhibition of the activity of a member of the MAPEG family is desired and/or required.
35. The use of a compound as defined in any one of Claims 1 to 31, or a pharmaceutically-acceptable salt thereof, for the manufacture of a medicament for the treatment of a disease in which inhibition of the activity of a member of the MAPEG family is desired and/or required.
36. A compound as claimed in Claim 34, or a use as claimed in Claim 35, wherein the member of the MAPEG family is microsomal prostaglandin E synthase- 1, leukotriene C4 synthase and/or 5-lipoxygenase-activating protein.
37. A compound or use as claimed in Claim 36, wherein the member of the MAPEG family is microsomal prostaglandin E synthase- 1.
38. A compound or use as claimed in any one of Claims 34 to 37, wherein the disease is inflammation.
39. A compound or use as claimed in any one of Claims 34 to 38 wherein the disease is asthma, chronic obstructive pulmonary disease, pulmonary fibrosis, inflammatory bowel disease, irritable bowel syndrome, 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.
40. 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 31, or a pharmaceutically-acceptable salt thereof, to a patient suffering from, or susceptible to, such a condition.
41. A method as claimed in Claim 40, wherein the member of the MAPEG family is microsomal prostaglandin E synthase- 1, leukotriene C4 synthase and/or 5-lipoxygenase-activating protein.
42. A method as claimed in Claim 41, wherein the member of the MAPEG family is microsomal prostaglandin E synthase-1.
43. A combination product comprising:
(A) a compound as defined in any one of Claims 1 to 31, 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.
44. A combination product as claimed in Claim 43 which comprises a pharmaceutical formulation including a compound as defined in any one of Claims 1 to 31, 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.
45. A combination product as claimed in Claim 43 which comprises a kit of parts comprising components:
(a) a pharmaceutical formulation including a compound as defined in any one of Claims 1 to 31, 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.
46. A process for the preparation of a compound as defined in Claim 1, which comprises:
(i) reaction of a compound of formula II,
Figure imgf000105_0001
wherein X1, R2, R3, R4, R5, T and Y are as defined in Claim 1, with a compound of formula III,
R1L1 III wherein L1 represents a suitable leaving group and R1 is as defined in Claim 1 ; (ii) for compounds of formula I in which X1 represents -Q-X2, in which Q is a single bond or -C(O)-, reaction of a compound of formula IV,
Figure imgf000106_0001
wherein R1, R2, R3, R4, R5, T and Y are as defined in Claim 1 and L1 is as defined above, with a compound of formula V, X2-Qa-L2 V wherein Qa represents a single bond or -C(O)-, L2 represents a suitable leaving group and X is as defined in Claim 1 ;
(iii) for compounds of formula I in which X represents -Q-X and Q represents
-C(O)-, reaction of a compound of formula I in which X1 represents H, with a compound of formula V in which Qa represents -C(O)- and L2 represents a suitable leaving group;
(iv) for compounds of formula I in which X1 represents -N(R9a)-J-R10a or
-Q-X2 in which Q represents -O- or -S-, reaction of a compound of formula IV as defined above with a compound of formula VI, XlbH VI in which Xlb represents -N(R9^-J-R1 Oa or -Q-X2 in which Q represents -O- or -S- and R9a, J, R1Oa and X2 are as defined in Claim 1 ;
(v) for compounds of formula I in which X represents -Q-X and Q represents
-S-, reaction of a compound of formula I in which X1 represents H, with a compound of formula VI in which Xlb represents -Q-X2, Q represents -S- and X2 is as defined in Claim 1 ;
(vi) for compounds of formula I in which X1 represents -Q-X2 and Q represents
-S(O)- or -S(O)2-, oxidation of a corresponding compound of formula I in which Q represents -S-; (vii) for compounds of formula I in which X represents -Q-X , X represents C1-8 alkyl substituted by G1, G1 represents -A^R113, A1 represents -N(R12a)A4- and A is a single bond (provided that Q represents a single bond when X2 represents substituted C1 alkyl), reaction of a compound of formula VII,
Figure imgf000107_0001
wherein X2a represents a C1-S alkyl group substituted by a -Z1 group in which Z1 represents =0, Q is as defined in Claim 1, provided that it represents a single bond when X2a represents C1 alkyl substituted by =0, and R1, R2, R3, R4, R5, T and Y are as defined in Claim 1, under reductive amination conditions in the presence of a compound of formula VIII,
Rlla(R12a)NH VIII wherein Rlla and R12a are as defined in Claim 1;
(viia) for compounds of formula I in which X represents -Q-X , Q represents a single bond, X2 represents methyl substituted by G1, G1 represents -A^R118, A1 represents -N(R12a)A - and A is a single bond, reaction of a corresponding compound of formula I in which X1 represents H, with a mixture of formaldehyde (or equivalent reagent) and a compound of formula VIII as defined above; (viii) for compounds of formula I in which X represents -Q-X , Q represents a single bond and X2 represents optionally substituted C2-S alkenyl (in which a point of unsaturation is between the carbon atoms that are α and β to the indole ring), reaction of a corresponding compound of formula IV in which L1 represents halo with a compound of formula IXA,
H2C=C(H)X2b IXA or reaction of a compound of formula VII in which Q represents a single bond and X2a represents -CHO with either a compound of formula IXB,
(EtO)2P(O)CH2X2b IXB or the like, or a compound of formula IXC,
(Ph)3P=CHX2b IXC or the like, wherein, in each case, X2b represents H, G1 or C1-6 alkyl optionally substituted with one or more substituents selected from G1 and/or Z1 and G1 and Z1 are as defined in Claim 1;
(ix) for compounds of formula I in which X1 represents -Q-X2 and X2 represents optionally substituted, saturated C2-8 alkyl, saturated cycloalkyl, saturated heterocycloalkyl, C2-8 alkenyl, cycloalkenyl or heterocycloalkenyl, reduction of a corresponding compound of formula I in which X2 represents optionally substituted C2-8 alkenyl, cycloalkenyl, heterocycloalkenyl, C2-8 alkynyl, cycloalkynyl or heterocycloalkynyl (as appropriate); (x) reaction of a compound of formula X,
Figure imgf000108_0001
wherein L3 represents L1 or L2 as defined above, which group is attached to one or more of the carbon atoms of the benzenoid ring of the indole, R -R represents whichever of the three other substituents on the benzenoid ring, i.e. R2, R3, R4 and
R5, are already present in that ring, and X1, R1, R2, R3, R4, R5, T and Y are as defined in Claim 1 , with a compound of formula XI,
E-Dx-L4 XI wherein L4 represents L1 (when L3 is L2) or L2 (when L3 is L1), Dx represents D, and D, E, R7 and R8 are as defined in Claim 1 and L1 and L2 are as defined above;
(xi) for compounds of formula I in which D represents -C(R7)(R8)- in which R8 represents -ORa or -SRd and Ra and Rd both represent H, reaction of a compound of formula XII,
Figure imgf000108_0002
wherein -Db-E is attached to one or more of the carbon atoms of the benzenoid ring of the indole, Db represents -C(O)- or -C(S)- and E, X1, R1, T and Y are as defined in Claim 1 and R2-R5 is as defined above, with a compound of formula XIII, R7-L8 XIII wherein L8 represents a silicon-based group, or an alkali metal-based group;
(xii) for compounds of formula I in which D represents -C(R )(R )- in which R represents -ORa or -SRd and Ra and Rd do not represent H, reaction of a corresponding compound of formula I in which Ra and Rd represent H, followed by reaction with a compound of formula XIV,
R∞-L9 XTV wherein R^ represents Ra or Rd (as appropriate) provided that it does not represent
H;
(xiii) for compounds of formula I in which D represents -C(R7)(R8)- and R8 represents -N(Rb)(Rc) or -SRd, reaction of a corresponding compound of formula I in which R8 represents -OH, which first comprises the step of converting the -OH group to provide a suitable leaving group, and then reaction with a compound of formula XTVA,
H-Za XIVA wherein Za represents either -N(Rb)(Rc) or -SRd;
(xiv) for compounds of formula I in which X1 represents -N(R9a)-J-R10a, reaction of a compound of formula XV,
Figure imgf000109_0001
wherein R1, R2, R3, R4, R5, T5 Y and R9a are as defined in Claim 1, with a compound of formula XVI,
R10^J-L1 XVT wherein J and R1Oa are as defined in Claim 1 and L1 is as defined above; (xv) for compounds of formula I in which X1 represents -N(R5^)-J-R1 Oa, J represents a single bond and R1Oa represents a C1-8 alkyl group, reduction of a corresponding compound of formula I, in which J represents -C(O)- and R1Oa represents H or a C1-7 alkyl group; (xvi) for compounds of formula I in which X1 represents halo, reaction of a compound of formula I wherein X1 represents H, with a reagent or mixture of reagents known to be a source of halide atoms;
(xvii) for compounds of formula I in which T and Y are as defined in Claim 1, provided that when Y represents -C(O)OR9b, -S(O)3R9c, -P(O)(OR9d)2, -P(O)(OR9e)N(R10f)R9f, -P(O)(N(R10g)R9g)2, -B(OR9h)2 or -S(O)2N(R10i)R9i, R9b to R9i, R1Of, R1Og and R1Oi are other than H, reaction of a compound of formula XVII,
Figure imgf000110_0001
wherein L5 represents an appropriate alkali metal group, a -Mg-halide, a zinc- based group or a suitable leaving group, and X1, R1, R2, R3, R4 and R5 are as defined in Claim 1 , with a compound of formula XVIII,
L6-Ta_γa Xy1n wherein Ta represents T and Ya represents Y, provided that when Y represents -C(O)OR9b, -S(O)3R9c, -P(O)(OR9d)2, -P(O)(OR9e)N(R10f)R9f, -P(O)(N(R10g)R9g)2, -B(OR9h)2 or -S(O)2N(R10i)R9i, R9b to R9i, R10f, R1Og and R1Oi are other than H, and L represents a suitable leaving group;
(xviii) for compounds of formula I in which T represents a single bond, Y represents -B(OR9h)2 and R9h represents H, reaction of a compound of formula XVII as defined above with boronic acid or a protected derivative thereof, followed by (if necessary) deprotection; (xix) for compounds of formula I in which T represents a single bond and Y represents -S(O)3R90, reaction of a compound of formula XVII as defined above with:
(A) for such compounds in which R9c represents H, either SO3 or with SO2 followed by treatment with iV-chlorosuccinimide and then hydrolysis; (B) for such compounds in which R9c is other than H, chlorosulfonic acid followed by reaction with a compound of formula XXIII as defined below in which R9za represents R9c;
(xx) for compounds of formula I in which T represents a single bond and Y represents
Figure imgf000111_0001
in which R9j represents hydrogen, reaction of a corresponding compound of formula I in which T represents a C2 alkylene group substituted at the carbon atom that is attached to the indole ring system by Z1, in which Z1 represents =0 and Y represents -C(O)OR9b, in which R9b represents C1-6 alkyl with hydroxylamine or an acid addition salt thereof;
(xxi) for compounds of formula I in which T represents a single bond and Y represents
Figure imgf000111_0002
in which R9k and R9r represent hydrogen, reaction of a corresponding compound of formula I in which T represents a C1 alkylene group substituted with G1, in which G1 represents -A^R118, A1 represents -C(O)A2-, A2 represents a single bond and Rl la represents H, and Y represents -C(O)OR9b, in which R9b represents methyl, or ethyl, respectively, with hydroxylamine or an acid addition salt thereof; (xxϋ) for compounds of formula I in which T represents a single bond and Y represents
Figure imgf000111_0003
in which R9m and R9p represent hydrogen, reaction of a corresponding compound of formula I in which T represents a single bond, Y represents -B(OR91l)2 and R9h represents H with a compound of formula XVIII in which Ta represents a single bond, Ya represents
Figure imgf000112_0001
respectively, in which R9m and R9p represent hydrogen, and L6 represents a halo group, or a protected derivative of either compound;
(xxiii) for compounds of formula I in which T represents a single bond and Y represents
Figure imgf000112_0002
in which R9n represents hydrogen, reaction of a compound of formula XIX,
Figure imgf000112_0003
wherein X1, R1, R2, R3, R4 and R5 are as defined in Claim 1 with ethoxycarbonyl isocyanate;
(xxiv) for compounds of formula I in which T represents a single bond and Y represents
Figure imgf000112_0004
in which R9s represents hydrogen, reaction of a compound of formula I in which T represents a single bond and Y represents -C(O)OR9b, in which R9b represents H with trimethylsilyl chloride, followed by reaction of the resultant intermediate with N4S4; (xxv) for compounds of formula I in which T represents a single bond and Y represents
Figure imgf000113_0001
in which R represents hydrogen, reaction of a compound of formula XX,
Figure imgf000113_0002
wherein X , R , R , R , R and R are as defined in Claim 1 with a base and CS2, oxidation of the resultant intermediate, and heating the resultant intermediate in the presence of a strong acid;
(xxvi) for compounds of formula I in which T represents a single bond and Y represents
Figure imgf000113_0003
in which R9u represents hydrogen, reaction of a corresponding compound of formula I in which T represents C1 alkylene, Y represents -C(O)OR9b and R9b represents H or an activated derivative thereof with 1,1,2,2-tetraethoxyethene, followed by acid;
(xxvii) for compounds of formula I in which T represents a single bond and Y represents
Figure imgf000113_0004
in which R9v and R1Oj independently represent H, reaction of a compound of formula XIX as defined above with 3,4-dimethoxycyclobutene-l,2-dione; (xxviii) for compounds of formula I in which T represents a single bond and Y represents
Figure imgf000114_0001
in which R9x represents hydrogen, reaction of a compound of formula XXI,
Figure imgf000114_0002
wherein X1, R1, R2, R3, R4 and R5 are as defined in Claim 1 with NaN3; (xxix) for compounds of formula I in which T represents optionally substituted C2-8 alkenylene or C2-8 heteroalkylene (in which a point of unsaturation is between the carbon atoms that are α and β to the indole ring), reaction of a compound of formula XXII,
Figure imgf000114_0003
wherein X , R1, R2, R3, R4 and R5 are as defined in Claim 1 with a compound of formula XXIIA,
(Ph)3P=CH-Ta-Y XXIIA or the like, wherein Ta represents a single bond or optionally substituted C1-6 alkylene or C2-6 heteroalkylene and Y is as defined in Claim 1; (xxx) for compounds of formula I in which T represents optionally substituted, saturated C2-8 alkylene, saturated cyclo alkylene, saturated C2-8 heteroalkylene, saturated hetero cyclo alkylene, C2-8 alkenylene, cycloalkenylene, C2-8 heteroalkenylene or heterocycloalkenylene, reduction of a corresponding compound of formula I in which T represents optionally substituted C2-8 alkenylene, cycloalkenylene, C2_s heteroalkenylene, heterocycloalkenylene, C2-8 alkynylene, cycloalkynylene, C2_s heteroalkynylene or heterocycloalkynylene (as appropriate); (xxxi) for compounds of formula I in which Y represents -C(O)OR9b, -S(O)3R9c, -P(O)(OR9d)2, or -B(OR9h)2, in which R9b, R9c, R9d and R9h represent H, hydrolysis of a corresponding compound of formula I in which R9b, R9c, R9d or R9h (as appropriate) does not represent H, or, for compounds of formula I in which Y represents -P(O)(OR9d)2 or S(O)3R90, in which R9c and R9d represent H, a corresponding compound of formula I in which Y represents either -P(O)(OR9e)N(R10f)R9f, -P(O)(N(R10g)R9g)2 or -S(O)2N(R10l)R91 (as appropriate); (xxxii) for compounds of formula I in which Y represents -C(O)OR9b, S(O)3R90, -P(O)(OR9d)2, -P(O)(OR9e)N(R10f)R9f or -B(OR9h)2 and R9b to R9e and R9h do not represent H: (A) esterification of a corresponding compound of formula I in which R to R9e and R9 represent H; or
(B) trans-esterification of a corresponding compound of formula I in which R9 to R9e and R9h do not represent H (and does not represent the same value of the corresponding R9b to R9e and R9h group in the compound of formula I to be prepared), in the presence of the appropriate alcohol of formula XXIII,
R9zaOH XXIII in which R9za represents R9b to R9e or R9h provided that it does not represent H; (xxxiii) for compounds of formula I in which T represents a single bond, Y represents -C(O)OR9b and R9b is other than H, reaction of a compound of formula XXIIIA5
R2 Q-X2 XXIIIA
Figure imgf000115_0001
wherein Q, X2, R1, R2, R3, R4 and R5 are as defined in Claim 1 and L5 is as defined above, with a compound of formula XXIIIB,
L6C(O)OR9" XXIIIB wherein R9bl represents R9b provided that it does not represent H5 and L6 is as defined above;
(xxxiv) for compounds of formula I in which T represents a single bond, Y represents -C(O)OR9b and R9b is H, reaction of a compound of formula XXIIIA in which L5 represents either:
(I) an alkali metal; or (II) -Mg-halide, with carbon dioxide, followed by acidification;
(xxxv) for compounds of formula I in which T represents a single bond and Y represents -C(O)OR9b, reaction of a corresponding compound of formula XXIIIA in which L5 is a suitable leaving group with CO (or a reagent that is a suitable source of CO), in the presence of a compound of formula XXIIIC,
R9bOH XXIIIC wherein R9b is as defined in Claim 1, and an appropriate catalyst system; (xxxvi) for compounds of formula I in which Y represents -C(O)OR9b and R9b represents H, hydrolysis of a corresponding compound of formula I in which R9b does not represent H;
(xxxvii) for compounds of formula I in which Y represents -C(O)OR9b and R9b does not represent H:
(A) esterification of a corresponding compound of formula I in which R9b represents H; or (B) trans-esterification of a corresponding compound of formula I in which R9b does not represent H (and does not represent the same value of R9b as the compound of formula I to be prepared), in the presence of the appropriate alcohol of formula XXIIIC as defined above but in which R9 represents R bl as defined above; (xxxviii) for compounds of formula I in which X1 represents -Q-X2 and Q represents -O-, reaction of a compound of formula XXIV,
Figure imgf000117_0001
wherein R1, R2, R3, R4, R5, T and Y are as defined in Claim 1, with a compound of formula XXV,
X2L7 XXV wherein L7 represents a suitable leaving group, and X2 is as defined in Claim 1 ; (xxxix) for compounds of formula I in which T represents a C1 alkylene group substituted with G1, in which G1 represents -A^R113, A1 represents -C(O)A2-, A2 represents a single bond and Rlla represents H, and Y represents -C(O)OR9b, in which R9b is other than H, reaction of a corresponding compound of formula I in which the C1 alkylene group that T represents is unsubstituted with a C1-6 alkyl formate in the presence of a suitable base;
(xl) for compounds of formula I in which X1 represents -Q-X2, Q represents a single bond and X2 represents C1-8 alkyl or heterocycloalkyl substituted α to the indole ring by a G1 substituent in which G1 represents -A^R1 la, A1 represents -OA5-, A5 represents a single bond and Rlla represents H, reaction of a corresponding compound of formula I in which X1 represents H with a compound corresponding to a compound of formula VI, but in which X represents -Q-X2, Q represents a single bond and X2 represents C1-8 alkyl or heterocycloalkyl, both of which groups are substituted by a Z1 group in which Z1 represents =0; (xli) for compounds of formula I in which X1 represents -Q-X2, Q represents a single bond and X2 represents C2-8 alkyl substituted by a G1 substituent in which G1 represents -A^R118, A1 represents -OA5-, A5 represents a single bond and Rlla represents H, reaction of a corresponding compound of formula I in which X2 represents C1-7 alkyl substituted by a Z1 group in which Z1 represents =O, with the corresponding Grignard reagent derivative of a compound of formula V in which L2 represents chloro, bromo or iodo, Qa is a single bond and X2 represents Ci-7 alkyl;
(xlii) for compounds of formula I in which X represents -Q-X , Q represents a single bond, and X2 represents Ci-8 alkyl or heterocycloalkyl, both of which are unsubtiτuted in the position α to the indole ring, reduction of a corresponding compound of formula I in which X represents C1-8 alkyl substituted α to the indole ring by a G1 substituent in which G1 represents -A^R1 la, A1 represents -OA5-, A5 represents a single bond and Rlla represents H, in the presence of a suitable reducing agent;
(xliii) for compounds of formula I in which X1 represents -Q-X2, Q represents a single bond and X2 represents C1-8 atkyl or heterocycloalkyl, neither of which are substituted by Z1 in which Z1 represents =0, reduction of a corresponding compound of formula I in which X2 represents Cμg alkyl or heterocycloalkyl, which groups are substituted by one or more Z1 groups in which Z1 represents =0; or
(xliv) for compounds of formula I in which X1 represents -N(R9a)-J-R10a, reaction of a compound of formula XXTV as defined above, with a compound of formula VI in which Xlb represents -N(R9a)-J-R10a and R9a, R1Oa and J are as defined in Claim 1.
47. A process for the preparation of a pharmaceutical formulation as defined in Claim 33, which process comprises bringing into association a compound, as defined in any one of Claims 1 to 31, or a pharmaceutically acceptable salt thereof with a pharmaceutically-acceptable adjuvant, diluent or carrier.
48. A process for the preparation of a combination product as defined in any one of Claims 43 to 45, which process comprises bringing into association a compound, as defined in any one of Claims 1 to 31, or a pharmaceutically acceptable salt thereof with the other therapeutic agent that is useful in the treatment of inflammation, and at least one pharmaceutically-acceptable adjuvant, diluent or carrier.
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