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  • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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Definitions

• This invention relates to novel pharmaceutically-useful compounds, which compounds are useful as inhibitors of microsomal prostaglandin E synthase- 1 (mPGES-1).
• the compounds are of potential utility in the treatment of inflammatory 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 malignancies are known to have inflammatory components adding to the symptomatology of the patients.
• COX cyclooxygenase
• COXs metabolise arachidonic acid to the unstable intermediate prostaglandin H 2 (PGH 2 ).
• PGH 2 is further metabolized to other prostaglandins including PGE 2 , PGF 2 ⁇ , PGD 2 , prostacyclin and tliromboxane A 2 .
• PGE 2 metabolise arachidonic acid to the unstable intermediate prostaglandin H 2
• PGD 2 metabolized to other prostaglandins
• prostacyclin and tliromboxane A 2 are known to have pronounced physiological and pathophysiological activity including pro- inflammatory effects.
• PGE 2 in particular is known to be a strong pro-inflammatory mediator, and is also known to induce fever and pain. Consequently, numerous drugs have been developed with a view to inhibiting the formation of PGE 2 , including "NSAIDs” (non-steroidal antiinflammatory drugs) and “coxibs 55 (selective COX-2 inhibitors). These drugs act predominantly by inhibition of COX-1 and/or COX-2, thereby reducing the formation of PGE 2 .
• NSAIDs non-steroidal antiinflammatory drugs
• coxibs 55 selective COX-2 inhibitors
• 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.
• drugs which act by inhibition of COXs are therefore known/suspected to cause adverse biological effects.
• the non-selective inhibition of COXs by NSAIDs may give rise to gastrointestinal side-effects and affect platelet and renal function.
• Even the selective inhibition of COX-2 by coxibs, whilst reducing such gastrointestinal side-effects, is believed to give rise to cardiovascular problems.
• 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
• mPGES-1 belongs to the membrane-associated proteins in the eicosanoid and glutathione metabolism (MAPEG) family. Other members of this family include the 5-lipoxygenase-activating protein (FLAP), leukotriene C 4 synthase and microsomal glutathione S-transferases (MGSTl, MGST2 and MGST3).
• FLAP 5-lipoxygenase-activating protein
• MGSTl microsomal glutathione S-transferases
• agents that are capable of inhibiting the action of rnPGESs and, in particular, 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.
• X represents: i) an aryl group or a heteroaryl group, both of which groups are optionally substituted by one or more substituents selected from A; or
• E represents a single bond, -C(O)- or -S(0) n -;
• Y represents -CH 2 OH, -C(0)N(H)R 8 , -C(0)N(H)OR 8 or -C(0)OR 8 ;
• Z represents a C ⁇ personallyg alkylene or a C 2-8 heteroalkylene chain, both of which: (i) optionally contain one or more unsaturations (for example double or triple bonds);
• (iii) may form part of 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
• R 1 represents an aryl or a heteroaryl group, both of which are optionally substituted by one or more substituents selected from A;
• one of the groups R 2 , R 3 , R 4 and R 5 represents an aryl group or a heteroaryl group (both of which are optionally substituted by one or more substituents selected from A) and: a) the other groups are independently selected from hydrogen, G 1 , an aryl group, a heteroaryl group (which latter two groups are optionally substituted by one or more substituents selected from A), C ⁇ -6 alkyl, C 3- ⁇ 0 (e.g. C 3-8 ) cycloalkyl, C 2 . 6 alkenyl, C 2 . 6 alkynyl or C 3 .
• A represents, on each occasion when mentioned above:
• C ⁇ _ 6 alkyl C 3 . ⁇ 0 (e.g. C 3-8 ) cycloalkyl, C 2-6 alkenyl, C 2 . 6 alkynyl or C 3-8 heterocycloalkyl group, all of which are optionally substituted by one or more substituents selected from G 1 and/or Q 1 ; or
• G 1 represents, on each occasion when mentioned above, halo, cyano, -N 3 ,
• a 1 represents a single bond or a spacer group selected from
• a 2 represents A 6 or -S-;
• a 3 represents A 6 ;
• a 4 represents A 7 , -C(Q 2 )N(R ⁇ )C(Q 2 )N(R ⁇ )-, -C(Q 2 )N(R ⁇ )C(Q 2 )0-,
• a 5 represents A 7 or -S(0) n O-;
• a 6 represents a single bond, -N(R ⁇ )- or -0-;
• a 7 represents a single bond, -C(Q 2 )-, -C(Q 2 )N(R ⁇ )-, -C(Q 2 )0-, -S(0) n - or
• R 6 and R 7 independently represent, on each occasion when mentioned above: I) hydrogen
• C ⁇ . 6 alkyl C 3 . 10 (e.g. C 3 . 8 ) cycloalkyl, C 2-6 alkenyl, C 2 . 6 alkynyl or C 3-8 heterocycloalkyl group, all of which groups are optionally substituted by one or more substituents selected from G and/or Q ; or
• R 6 and R 7 may be linked together to form along with the N atom and -E- group to which R and R are respectively attached, a 5- to 8-membered ring, optionally containing 1 to 3 heteroatoms and/or 1 to 3 unsaturations (for example double or triple bonds), which ring is optionally substituted by one or more substituents selected from G and/or Q ;
• G 2 represents, on each occasion when mentioned above, halo, cyano, -N 3 ,
• a 8 represents a single bond or a spacer group selected from
• a 9 represents A 13 or -S-;
• a 10 represents A 13 ;
• a 11 represents A 14 , -C(Q 4 )N(R 13 )C(Q 4 )N(R 13 )-, -C(Q 4 )N(R 13 )C(Q 4 )0- 5
• a 12 represents A 14 or -S(0) n O-;
• a 13 represents a single bond, -N(R 13 )- or -O-;
• a 14 represents a single bond, -C(Q 4 )-, -C(Q 4 )N(R 13 )-, -C(Q 4 )0-, -S(0) n - or
• R , R , R , R and R 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 5- to 8-membered ring, optionally containing 1 to 3 heteroatoms and/or 1 to 3 unsaturations (for example double or triple bonds), which ring is itself optionally substituted by one or more substituents selected from G and/or W ;
• G 3 represents, on each occasion when mentioned above, halo, cyano, -N 3 , -N0 2 , -ON0 2 or-A 15 -R 15 ; wherein A 15 represents a single bond or a spacer group selected from -C(W 2 )A 16 -, -S(0) n A 17 -, -N(R 16 )A 18 -, -OA 19 - and -S-, in which: A 16 represents A 20 or -S-; 11 90
• A represents A ;
• a 18 represents A 21 , -C(W 2 )N(R 16 )C(W 2 )N(R 16 )-, -C(W 2 )N(R 16 )C(W 2 )0-,
• a 19 represents A 21 or -S(0) n O-;
• a 20 represents a single bond, -N(R 16 )- or -0-;
• a 21 represents a single bond, -C(W 2 )-, -C(W 2 )N(R 16 )-, -C(W 2 )0-, -S(0) n - or
• R 1 , R 5 and R are independently selected from: i) hydrogen; ii) an aryl or a heteroaryl group, both of which are optionally substituted by one or more substituents selected from G 4 , methylenedioxy, difluoromefhylenedioxy and/or dimethylmethylenedioxy; or iii) a C 1-6 alkyl, C 3-10 (e.g. C 3-8 ) cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 3 .
• R 14 , R 15 and R 16 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 5- to 7-membered ring, optionally containing 1 to 3 heteroatoms and/or 1 to 3 unsaturations (for example double or triple bonds), which ring is itself optionally substituted by one or more substituents selected from G 4 and J;
• G 4 represents, on each occasion when mentioned above, halo, cyano, -N 3 , -N0 2 , -ON0 2 or-A 22 -R 17 ; 99 wherein A represents a single bond or a spacer group selected from -C(0)A 23 -, -S(0) n A 24 -, -N(R 18 )A 25 -, -OA 26 - and -S-, in which: A 23 represents A 27 or -S-; OA 97
• A represents A ;
• a 25 represents A 28 , -C(0)N(R 18 )C(0)N(R 18 )-, -C(0)N(R 18 )C(O)O-, -C(0)N(R 18 )S(0) n N(R 18 )-, -C(0)S-, -S(0) n N(R 18 )C(0)N(R 18 )-,
• A represents a single bond, -N(R )- or -0-;
• a 28 represents a single bond, -C(O)-, -C(0)N(R 18 )-, -C(0)0-, -S(0) n - or -S(0) n N(R 18 );
• n represents, on each occasion when mentioned above, 1 or 2
• 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 the invention 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 (entgege ⁇ ) 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 HPLC or chromatography over silica, 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 I-q alkyl 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 three) of carbon atoms, be branched-chain.
• C ⁇ _ 6 alkyl groups that may be mentioned include methyl, ethyl, «-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, n- hexyl, and isohexyl.
• C ]-q alkylene chains (where q is the upper limit of the range) defined herein are straight-chain alkyl groups, which groups are attached at each terminal end.
• C v-q heteroalkylene chains (where v is the lower limit and q is the upper limit of the range) defined herein are C v . q alkylene chains, wherein one or more (e.g. 1 to q-1) carbon atoms have been replaced with a heteroatom.
• C 2-q alkenyl 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 three) of carbon atoms, be branched-chain. Such alkenyl groups may contain one or more double bonds.
• C 2 . 6 alkenyl groups that may be mentioned include ethenyl (i.e. vinyl), 1-propenyl, 2-propenyl (i.e. allyl), propadienyl, 1-butenyl, 2-butenyl, 3-butenyl, 1,3-butadienyl, 1-pentenyl, 2-pentenyl, 4-pentenyl, and 5-hexenyl.
• C 2-q alkynyl 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 four) of carbon atoms, be branched-chain. Such alkynyl groups may contain one or more triple bonds.
• C 2-6 alkynyl groups that may be mentioned include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 4-pentynyl, 1-hexynyl, 3-hexynyl, and 5- hexynyl.
• q cycloalkyl groups (where q is the upper limit of the range) that may be mentioned include monocyclic or bicyclic alkyl groups, or 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
• C 3 - q (e.g. C 3- ⁇ o) cycloalkyl groups that may be mentioned include adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclooctynyl, bicycloheptyl, bicyclooctyl, and bicyclooctenyl.
• 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.
• C 3-q heterocycloalkyl groups (where q is the upper limit of the range) that may be mentioned include monocyclic or bicyclic alkyl groups in which at least one (e.g. one to four) of the atoms in the ring system is other than carbon (i.e. a hetereoatom). Further, such heterocycloalkyl groups may be saturated or unsaturated containing one or more double and/or triple bonds, forming for example a C 3 _ q heterocycloalkenyl or a C 3-q heterocycloalkynyl group.
• C 3-q heterocycloalkyl groups that may be mentioned include 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, oxetanyl, oxiranyl, piperazinyl, piperidinyl, pyranyl, pyrazolidinyl, pyrrolidinonyl, pyrrolidinyl, pyrrolinyl, quinuclidinyl, sulfolanyl, 3-sul
• Substituents on the heterocycloalkyl groups may, where appropriate, be located on any atom in the ring system including a heteroatom. Further in the case where the substituent is another cyclic compound, then the cyclic substituent may be attached through a single atom on the heterocycloalkyl group, forming a so- called "spiro"-compound.
• the point of attachment of a heterocycloalkyl group may be via any atom in the ring system including (where appropriate) a heteroatom, or an atom on any fused carbocyclic ring that may be present as part of the ring system.
• Heterocycloalkyl groups may also be in the N- or S- oxidised form.
• halo 55 when used herein, includes fluoro, chloro, bromo and iodo.
• Aryl groups that may be mentioned include C 6- ⁇ 3 aryl (e.g. C 6- ⁇ o) groups. Such groups may be monocyclic, bicyclic or tricylic and have between 6 and 13 ring carbon atoms, in which at least one ring is aromatic.
• C 6 - ⁇ 3 aryl groups include phenyl, naphthyl and the like, such as 1,2,3,4-tetrahydro- naphthyl, indanyl, indenyl and fluorenyl. The point of attachment of aryl groups may be via any atom of the ring system.
• Heteroaryl groups that may be mentioned include those which have between
• Such groups may be monocyclic, bicyclic or tricyclic, in which at least one of the rings is aromatic and wherein at least one (e.g. one to four) of the atoms in the ring system is other than carbon (i.e. a heteroatom).
• Heteroaryl groups that may be mentioned include acridinyl, benzimidazolyl, benzodioxanyl, benzodioxepinyl, benzodioxolyl (including 1,3-benzodioxolyl), benzofuranyl, benzofurazanyl, benzothiazolyl (including 2, 1,3 -benzothiazolyl), benzoxadiazolyl (including 2,1,3- benzoxadiazolyl), benzoxazinyl (including 3,4-dihydro-2H-l,4- benzoxazinyl), benzoxazolyl, benzimidazolyl, benzomorpholinyl, benzoselenadiazolyl (including 2,1,3-benzoselenadiazolyl), benzothienyl, carbazolyl, chromanyl, cinnolinyl, furanyl, imidazolyl, imidazo[l,2- ⁇ ]pyridyl
• 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.
• Heteroaiyl groups may also be in the N- or S- oxidised form.
• Heteroatoms that may be mentioned include oxygen, nitrogen, sulphur and selenium.
• optionally substituted methylenedioxy groups when attached to a ring system, are formed between any two adjacent atoms of the ring system.
• the alkyl groups in question may be the same or different.
• groups are substituted by more than one substituent as defined herein, the identities of those individual substituents are not to be regarded as being interdependent.
• X and/or R 1 represents e.g. an aryl group substituted by G 1 in addition to, for example, C ⁇ _ 6 alkyl, which latter group is substituted by G 1 , the identities of the two G 1 groups are not to be regarded as being interdependent.
• Compounds that may be mentioned include those in which: E represents -C(O)-; when any two adjacent R 2 , R 3 , R 4 or R 5 groups, adjacent A substituents, adjacent B substituents, and/or, when B represents aryl or heteroaryl, adjacent atoms of those aryl or heteroaryl groups are linked to form a 5- to 6-membered ring, then that ring is fully saturated.
• Preferred compounds of the invention include those in which:
• Y represents -CH 2 OH or, more preferably, -C(0)N(H)R 8 , -C(0)N(H)OR 8 or -C(0)OR 8 ;
• a 8 represents a single bond, -C(Q 4 )A 9 -, -S(0) n A 10 -, -N(R 13 )A ⁇ - or -OA 12 -;
• a 9 represents A 13 ;
• a 11 represents A 14 ;
• a 15 represents a single bond, -C(W 2 )A 16 -, -S(0) n A 17 -, -N(R 16 )A 18 - or -OA 19 -:
• a 16 represents A 20 ;
• A represents A ;
• a 22 represents a single bond, -C(0)A 23 -, -S(0) n A 24 -, -N(R 18 )A 25 - or -OA 26 -; 9 97
• A represents A ; 9 ⁇ 9R
• A" represents A ;
• More preferred compounds of the invention include those in which:
• Y represents -CH 2 OH or, more preferably, -C(0)N(H)R 8 or -C(0)OR 8 ; when any two members of the C ⁇ -8 alkylene or C 2-8 heteroalkylene chain that Z may represent form part of an additional optionally substituted 3- to 8-membered ring, then that ring optionally contains 1 to 2 heteroatoms and/or 1 unsaturation;
• a 1 represents ⁇ S- or, more preferably, a single bond, -C(Q 2 )A 2 -, -S(0) n A 3 -,
• a 4 represents A 7 ;
• More preferred compounds include those in which: Y represents -CH 2 OH, -C(0)NHR 8 or, more preferably, -C(0)OR 8 ; when any one or more members of the C ⁇ -8 alkylene or C 2-8 heteroalkylene chain that Z may represent form part of an additional ring, then that ring is a cyclopropyl group formed together with the same or adjacent carbon atoms of that Cj_ 8 alkylene or C 2 .
• Preferred compounds of the invention include those in which R 1 , and (when they represent an aryl or a heteroaryl group) X, R 2 , R 3 , R 4 and/or R 5 represent an optionally substituted fluorenyl, phenyl, naphthyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridyl (e.g.
• R 1 examples include optionally substituted fluorenyl (e.g. 2- fluorenyl) or pyridyl and, especially, optionally substituted phenyl.
• Preferred values of X, when X represents an optionally substituted aryl or heteroaryl group include optionally substituted phenyl, thienyl (e.g. 2- thienyl), pyridyl (e.g. 3 -pyridyl and 4-pyridyl), pyrazolyl, pyrazinyl or quinolinyl.
• R 2 , R 3 , R 4 and R 5 when they represent an optionally substituted aryl or heteroaryl group, include optionally substituted phenyl, pyridyl (e.g. 3-pyridyl) or naphthyl (e.g. 1 -naphthyl).
• Z represents C ⁇ -6 alkylene, such as methylene, propylene or hexylene, in which one of the carbon atoms in the chain may be replaced with a heteroatom (e.g. oxygen) so forming, for example, an oxypentylene group
• 9 1 R represents hydrogen or G ;
• R 3 represents hydrogen, phenyl or pyridyl (e.g. 3-pyridyl), which latter two groups are optionally substituted by one or more substituents selected from
• R 4 represents hydrogen, phenyl or naphthyl, which latter two groups are optionally substituted by one or more substituents selected from A;
• R 5 represents hydrogen or phenyl, which latter group is optionally substituted by one or more substituents selected from A or is preferably unsubstituted; when R 2 , R 3 , R 4 or R 5 represents an optionally substituted phenyl, pyridyl or naphthyl group, then the other substituents on the essential benzene ring of the indole of formula I, (i.e. R 2 , R 3 , R 4 or R 4 (as appropriate)) represent hydrogen or G 1 ;
• A represents G 3 or any two adjacent A substituents may be linked to form a further ring, wherein the linking divalent substituent that forms part of that ring is preferably methylenedioxy, which group is preferably unsubstituted;
• G 1 represents halo (such as chloro or fluoro), cyano, -N0 2 or -A ⁇ R 10 ;
• A represents a single bond
• a 4 represents A 7 ;
• A represents A and, preferably, a single bond; 7 9
• A represents a single bond, -C(Q )- or -S(0) 2 -;
• R represents hydrogen or C ⁇ -3 alkyl group (such as methyl or ethyl), which latter group is optionally substituted by G ;
• R 7 represents an aryl group (such as phenyl) or a heteroaryl group (such as pyridyl), which latter two groups are optionally substituted by one or more substituents selected from B, or
• R 7 represents C ⁇ -4 alkyl (such as methyl, ethyl, propyl, butyl (e.g. n-butyl or t-butyl)), C 2 . 4 alkenyl (such as ethenyl) or C 5- ⁇ o cycloalkyl (such as cyclohexyl or adamantyl), which latter three groups are optionally substituted by one or more substituents selected from
• B represents G 2 ;
• G represents halo (such as chloro or fluoro), cyano, -N0 2 or -A -R ;
• a 8 represents a single bond, -N(R 13 )A ⁇ - or -OA 12 -;
• a 11 and A 12 independently represent A 14 ;
• a 14 represents a single bond;
• R 8 represents C ⁇ . 3 alkyl (such as ethyl) or, preferably, hydrogen;
• R 10 represents hydrogen, aryl (such as phenyl), heteroaryl (such as tetrazolyl), C ⁇ -4 alkyl (such as methyl, ethyl, isopropyl or butyl (e.g.
• R 11 represents hydrogen or C 2- alkenyl (such as propenyl (e.g. propen-2-yl, i.e. allyl)); 19
• R represents hydrogen, an aryl group (such as a phenyl group), a heteroaryl group (such as a pyrrolyl group), . 4 alkyl (such as methyl, isopropyl or butyl (e.g. n-butyl or t-butyl)) or C 5 .] 0 cycloalkyl (such as cyclohexyl or adamantyl) which latter four groups are optionally substituted by one or more substituents selected from G ; 1
• R represents hydrogen or C ⁇ 3 alkyl (such as methyl); G 3 represents halo (such as fluoro) or -A 15 -R 15 ; A 15 represents a single bond or -OA 1 -; A 19 represents a single bond;
• R 15 represents hydrogen, C 1-3 alkyl (such as C 1-2 alkyl (e.g. methyl)) or aryl (such as phenyl).
• R , R , R and (when they represent an aryl or heteroaryl group) X, R 2 , R 3 , R 4 and R 5 groups are selected from: halo (e.g. chloro, fluoro or bromo); -N0 2 ; cyano; methylenedioxy;
• C I-6 alkyl which alkyl group may be linear or branched (e.g. C ⁇ -4 alkyl (including methyl, ethyl, z-z-propyl, isopropyl, 77-butyl, s-butyl, isobutyl or t- butyl), 7 -pentyl, isopentyl, «-hexyl or isohexyl), and which alkyl groups are optionally substituted by one or more substituents selected from a halo (e.g.
• fluoro) group (so forming, for example, -CH 2 F, -CHF 2 or -CF 3 ), an aryl group (such as phenyl) and OR 19 ;
• C 2 _ 6 alkenyl e.g. ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3- butenyl, 1-pentenyl, 2-pentenyl, 4-pentenyl or 5-hexenyl);
• C 3- J O e.g. C 3 . 8
• cycloalkyl e.g.
• R 19 and R 20 independently represent, on each occasion when used above, hydrogen, phenyl, C 1-4 alkenyl (such as propenyl (e.g. propen-2-yl, i.e. allyl) or butenyl (e.g. but-3-enyl)), C I-6 alkyl (such as methyl, ethyl, n- propyl, isopropyl, w-butyl or t-butyl) which alkyl group is optionally substituted by one or more fluoro atoms or a phenyl group;
• C 1-4 alkenyl such as propenyl (e.g. propen-2-yl, i.e. allyl) or butenyl (e.g. but-3-enyl)
• C I-6 alkyl such as methyl, ethyl, n- propyl, isopropyl, w-butyl or t-butyl
• alkyl group is
• R 21 represents phenyl or C ⁇ -6 alkyl (such as methyl, ethyl, z-z-propyl, isopropyl, 77-butyl or r-butyl), which alkyl group is optionally substituted by one or more fluoro atoms.
• X represents an aryl or a heteroaryl group
• the substituents on such groups are preferably selected from carboxy, acetyl, methoxy, -N0 2 , fluoro, methyl, chloro, hydroxymethyl, ethyl, isopropoxy, trifluoromethoxy and methylthio.
• Preferred optional substituents on R 1 groups include phenoxy, trifluoromethyl, nitro, fluoro, chloro, cyano, carbamoyl, trifluoromethoxy, tetrazolyl (e.g. 2 -tetrazol-5-yl) and methyl.
• R 2 , R 3 , R 4 or R 5 groups include t-butyl, methylenedioxy, benzyloxy, nitro, methoxy, acetyl, chloro, fluoro, N-allyl-N- methanesulfonyl, cyano, trifluoromethyl, 2,2-dimethylpropionylamino, methanesulfonylamino, amino, but-3-enylamino, isopropoxy, methylthio, methylsulfonyl, ethenyl (i.e. vinyl), trifluoromethoxy, cyclohexyl, w-butyl, carboxy and hydroxymethyl.
• preferred optional substituents on R 2 , R 3 , R 4 or R 5 groups include t-butyl, methylenedioxy, benzyloxy, nitro, methoxy, acetyl, chloro, fluoro, N-allyl-N- methanesulfony
• Preferred optional substituents on R include an optionally substituted phenyl group.
• Optional substituents on such phenyl groups include halo (especially fluoro) and C ⁇ 3 alkoxy (such as methoxy), which substituents are preferably in the 4-position of the phenyl ring.
• Preferred optionally substituents on R include chloro, methoxy, amino, methyl, dimethylamino, phenyl, 4-methoxyphenyl, adamantyl, cyclohexyl, 3,3,5,5-tetramethylcyclohexyl, isopropoxy, trifluoromethyl, z'-butyl, n-butyl, isopropyl, trifluoromethoxy, cyano, pyrrole (e.g. 2,5-dimethylpyrrole) and nitro.
• Particularly preferred compounds of the invention include those of the examples described hereinafter.
• L 1 represents a suitable leaving group, such as halo (e.g. chloro, bromo or iodo), a carboxylate group, a sulfonylate group (e.g. -OS(0) 2 CF 3 , -OS(0) 2 CH 3 , -OS(0) 2 PhMe or nonaflates), or an V-imidazolyl group and R 1 and Z are as hereinbefore defined, for example at around 0°C to room temperature, or at above room temperature (e.g. up to 40-180°C) in the presence of a suitable base (e.g.
• halo e.g. chloro, bromo or iodo
• a carboxylate group e.g. -OS(0) 2 CF 3 , -OS(0) 2 CH 3 , -OS(0) 2 PhMe or nonaflates
• R 1 and Z are as hereinbefore defined, for example at around 0°C to room temperature, or at above room temperature (e.
• Preferred base/solvent systems include sodium hydride/dimethylformarnide, dimethylaminopyridine/pyridine, sodium hydroxide/dichloromethane (optionally in the presence of a phase transfer catalyst (e.g. tetrabutylammonium hydrogensulfate)), lithiumdiisopropylamide/tetrahydrofuran, potassium hydroxide/dimethyl- sulfoxide.
• phase transfer catalyst e.g. tetrabutylammonium hydrogensulfate
• lithiumdiisopropylamide/tetrahydrofuran potassium hydroxide/dimethyl- sulfoxide.
• Other systems that may be mentioned include sodium/ammonia.
• L represents L or L , in which L represents a leaving group such as halo (e.g. chloro, bromo or iodo), a sulfonylate group (e.g. -OS(0) 2 CF 3 , -OS(0) 2 CH 3 , -OS(0) 2 PhMe or nonaflates) or -B(OH) 2 , L 3 represents a leaving group such as -B(OH) 2 ,
• L 4 is attached to one or more of the carbon atoms of the benzenoid ring of the indole, and the remaining positions of the benzenoid ring are substituted with 1 to 3 (depending on the number of L 4 substituents) substituents R 2 to R 5 as appropriate, and Z, X, Y, R 1 , R 2 , R 3 , R 4 and R 5 are as hereinbefore defined, with a compound of formula V, R 22 L 5 V
• R 22 represents R 2 , R 3 , R 4 or R 5 (as appropriate), and L 5 represents L 2 (when L 4 is L 3 ) or L 3 (when L 4 is L 2 ) as hereinbefore defined.
• L and L must be mutually compatible. This reaction may be performed, for example in the presence of a suitable catalyst system, e.g.
• a metal such as Cul, Pd/C, 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 t-Bu 3 P, (C 6 Hn) 3 P, Ph 3 P, P(o-ToI) 3 , l,2-bis(diphenylphosphino)- ethane, 2,2'-bis(di-tert-butylphosphino)- 1 , 1 '-biphenyl, 2,2'-bis(diphenyl- phosphino)- 1 , 1 '-binaphthyl, 1,1 ' -bis(diphenylphosphinoferrocene), 1,3- bis(diphenylphosphino)propane or xantphos, together with a suitable base, such as Na 2 C0 3
• X a represents an aryl or heteroaryl group, optionally substituted as hereinbefore defined, and L is as hereinbefore defined, for example under reaction conditions such as those hereinbefore described hereinbefore in respect of process step (ii);
• E, R and R are 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 , Cul (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 or xantphos, in the presence of an appropriate base such as Et 3 N, pyridine, N,N-dimethylethylenediamine, ⁇ a 2 C0 3 , K 3 P0 , Cs 2 C0 3 or t-BuOK (or mixtures thereof), in a suitable solvent (e.g.
• an appropriate metal catalyst or a salt or complex thereof
• an appropriate metal catalyst such as Cu, Cu(OAc) 2 , Cul (or Cul/diamine complex), Pd(OAc) 2 , Pd 2 (dba
• Compounds of formula IV may be prepared by reaction of a compound of formula XI as hereinbefore defined, with a compound of formula III as hereinbefore defined for example under conditions such as those described hereinbefore in respect of process step (i).
• Compounds of formula IV in which L represents L 3 may be prepared by A 9 reaction of a compound of formula IV in which L represents L , with an 9 3 appropriate reagent for the conversion of the L group to the L group. This conversion may be performed by methods known to those skilled in the art, for example, compounds of formula IV, in which L 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 IV in which L 4 represents L 2 , for example under reaction conditions such as those described hereinbefore in respect of process route (ii) above.
• Compounds of formula VI may be prepared by:
• Y, Z, R 1 , R 2 , R 3 , R 4 and R 5 are as hereinbefore defined, with an appropriate reagent for the conversion of the hydroxyl group to the sulfonylate group (e.g. tosyl chloride, mesyl chloride, triflic anhydride and the like) under conditions known to those skilled in the art.
• an appropriate reagent for the conversion of the hydroxyl group to the sulfonylate group e.g. tosyl chloride, mesyl chloride, triflic anhydride and the like
• Compounds of formula XII may be prepared by standard techniques. For example: (a) Compounds of formula XII, wherein L represents halo may be prepared by reaction of a compound of formula XV,
• R 2 , R 3 , R 4 , R 5 and Y are as hereinbefore defined, with a reagent, or mixture of reagents known to be a source of halide ions.
• a reagent or mixture of reagents known to be a source of halide ions.
• N-bromosuccinimide may be employed, for iodide ions, iodine or a mixture of ⁇ al and N- chlorosuccinimide may be employed, for chloride ions, N- chlorosuccinimide may be employed and for fluoride ions, 1- (chloromethyl)-4-fluoro-l,4-diazoniabicyclo[2.2.2]octane bis(tetra- fluoroborate) may be employed.
• This reaction may be carried out in a suitable solvent (e.g. acetone or benzene) under conditions known to the skilled person.
• Compounds of fo ⁇ nula XIII may be prepared by reaction of a compound of fo ⁇ nula XII as hereinbefore defined with a compound of formula XVIII,
• R is as hereinbefore defined, for example under reaction conditions such as those described in respect of process step (iv).
• Compounds of fonnula XIII wherein R 6 represents hydrogen may be prepared by an aromatic nitration reaction carried out on a compound of formula XV, as hereinbefore defined, followed by reduction of the nitro group of the resultant intermediate to an amino group. Both reactions may be performed under conditions known to the skilled person.
• Compounds of formulae III, V, VII, VIII, X, XVIII are either commercially available, are known in the literature, or may be obtained either by analogy with the processes described herein, or by conventional synthetic procedures, in accordance with standard techniques, from available starting materials using appropriate reagents and reaction conditions.
• Indoles of formulae II, IV, VI, IX, XI, XII, XIII, XIV, XV, XVI and XVII may also be prepared with reference to a standard heterocyclic chemistry textbook (e.g. "Heterocyclic Chemistry” by J. A. Joule, K. Mills and G. F. Smith, 3 rd edition, published by Chapman & Hall) and/or made according to the following general procedures.
• SUB represents the substitution pattern that is present in the compound of formula II, XI, XIII or XV to be formed
• G represents either X (as required for formation of compounds of fo ⁇ nulae II and XI), a
• R >2 , ⁇ R.3 , R ⁇ ,4 a plausiblensuingd, R ⁇ 5 are as hereinbefore defined with a compound of formula XXI,
• Y is as hereinbefore defined, and preferably does not represent -COOH, 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 -Z-R 1 as hereinbefore defined (as required for formation of compounds of formula
• Q represents either -C(0)- or -CH 2 -
• X represents aryl or heteroaryl
• SUB and Y are as hereinbefore defined.
• Q represents -C(O)-
• the intramolecular cyclisation may be induced by a reducing agent such as TiCl 3 /C 8 K, TiCl 4 /Zn or Sml 2 under conditions known to the skilled person, for example, at room temperature in the presence of a polar aprotic solvent (such as THF).
• Q represents -CH -
• the reaction may be performed in the presence of base under intramolecular condensation reaction conditions known to the skilled person.
• the substituents X, Y, Z, R 1 , R 2 , R 3 , R 4 and R 5 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, 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 represent a carboxylic acid ester functional group, the skilled person will appreciate that at any stage during the synthesis (e.g.
• the relevant substituent may be hydrolysed so forming for example a carboxylic acid functional group.
• the relevant substituent may be reduced, under suitable conditions known to the skilled person (for example in the presence of other potentially reducible functional groups), at any stage during the synthesis (e.g. the final step), so forming for example a hydroxymethyl substituent.
• Compounds of the invention may be isolated from their reaction mixtures using conventional techniques.
• the protection and deprotection of functional groups may take place before or after a reaction in the above-mentioned schemes.
• Protecting groups may be removed in accordance with techniques that are well known to those skilled in the art and as described hereinafter. For example, protected compounds/intermediates described herein may be converted chemically to unprotected compounds using standard deprotection techniques.
• 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 pha ⁇ nacological 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 55 of compounds of the invention.
• prodrug of a compound of the invention 55 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, corcesponding compounds of formula I in which Y represents -COOH).
• Such compounds which also includes compounds that may possess some pha ⁇ nacological activity, but that activity is appreciably lower than that of the "active 5 ' 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 (for example selectively) the activity of prostaglandin E synthases (mPGESs) and particularly the activity of microsomal prostaglandin E synthase-1 (mPGES-1), i.e. they prevent the action of mPGES-1 or a complex of which the mPGES-1 enzyme forms a part, and/or may elicit a mPGES-1 modulating effect, for example as may be demonstrated in the test described below.
• Compounds of the invention may thus be useful in the treatment of those conditions in which inhibition of a PGES, and particularly mPGES-1, is required.
• Compounds of the invention are thus expected to be useful in the treatment of inflammation.
• 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 mflammation 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 inflammatory bowel disease, irritable bowel syndrome, migraine, headache, low back pain, fibromyalgia, myofascial disorders, viral infections (e.g. influenza, common cold, herpes zoster, and AIDS), bacterial infections, fungal infections, dysmeno ⁇ hea, burns, surgical or dental procedures, malignancies (e.g.
• Atherosclerosis gout, arthritis, osteoarthritis, juvenile arthritis, rheumatoid arthritis, rheumatic fever, ankylosing spondylitis, systemic lupus erythematosus, vasculitis, pancreatitis, nephritis, bursitis, conjunctivitis, ulceris, scleritis, uveitis, wound healing, dermatitis, eczema, psoriasis, stroke, diabetes (e.g.
• diabetes mellitus neurodegenerative disorders such as Alzheimer's disease and multiple sclerosis, autoimmune diseases, osteoporosis, asthma, chronic obstructive pulmonary disease, pulmonary fibrosis, allergic disorders, rhinitis, ulcers, coronary heart disease, sarcoidosis and any other disease with an inflammatory component.
• Compounds of the invention are indicated both in the therapeutic and/or prophylactic treatment of the above-mentioned conditions.
• a method of treatment of a disease which is associated with, and/or which can be modulated by inhibition of, a PGES (such as a mPGES, e.g. mPGES-1), and/or a method of treatment of a disease in which inhibition of the activity of a PGES, and particularly mPGES-1, 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 PGES such as a mPGES, e.g. mPGES-1
• a method of treatment of a disease in which inhibition of the activity of a PGES, and particularly mPGES-1, is desired and/or required e.g. inflammation
• 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, intraperitoneally, topically (e.g. ocularly), intramuscularly, intraspinally, epidurally, trans dermally, 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 pha ⁇ naceutical fo ⁇ nulations, including tablets, capsules or elixirs for oral, administration, suppositories for rectal administration, sterile solutions or suspensions for parenteral or intramuscular administration, and the like.
• pha ⁇ naceutical fo ⁇ nulations 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.
• 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).
• 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 fo ⁇ nulations 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 (b) a pharmaceutical fo ⁇ nulation 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.
• Oral dosages may range from between about 0.01 mg/kg of body weight per day (mg/kg/day) to about 100 mg/kg/day, preferably about 0.01 to about 10 mg/kg/day, and more preferably about 0.1 to about 5.0 mg/kg/day.
• the compositions typically contain between about 0.01 mg to about 500 mg, and preferably between about 1 mg to about 100 mg, of the active ingredient.
• the most preferred doses will range from about 0.001 to about 10 mg/kg/hour during constant rate infusion.
• compounds may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three or four times daily.
• 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 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 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.
• pharmacokinetic profile e.g. higher oral bioavailability and/or lower clearance
• mPGES-1 catalyses the reaction where the substrate PGH 2 is converted to PGE 2 .
• mPGES-1 is expressed in E. coli and the membrane fraction is dissolved in 20mM NaPi-buffer pH 8.0 and stored at -80 °C.
• mPGES-1 is dissolved in 0.1M KPi-buffer pH 7.35 with 2.5mM glutathione.
• the stop solution consists of H 2 0 / MeCN (7/3), containing FeCl 2 (25 mM) and HCI (0.15 M). The assay is performed at room temperature in 96-well plates.
• Example 1(a) from 5-chloro-3-phenyl-l-(3-phenylpropyl)indole-2- carboxylic acid ethyl ester (see step (c)) and 3,4- methylenedioxyphenylboronic acid, followed by hydrolysis in accordance with the procedure described in Example 2(b).
• a 0.01 M stock solution of a Pd/(C 6 Hn) 3 P was prepared from Pd 2 (dba) 3 , (0.457 g, 0.5 mmol), tricyclohexylphosphine (0.841 g, 3 mmol) and dioxane (100 mL).
• the title compound was prepared in accordance with Example 1 from 4-benzyloxyphenylboronic acid, 3-nitrobenzylbromide and 3-carboxyphenyl- boronic acid.
• Example 6 3 -(3 -Carboxyphenyl -4-phenyl- 1 - [ " 3 -(trifluoromethyl)benzyll indole-2- carboxylic acid
• the title compound was prepared in accordance with Example 1 from ⁇ 4-bromoindole-2-carboxylic acid ethyl ester, phenylboronic acid, 3-(trifluoromethyl)benzylbromide and 3-carboxyphenylboronic acid.
• Example 7 6-(4-B enzyloxyphenyl)- 1 -(3 -nitrobenzyl)-3 -(2-oxopy ⁇ olidin- 1 -yl indole-2- carboxylic acid
• a stock suspension of a CuI/MeNHCH 2 CH 2 NHMe complex was prepared by heating Cul (95.2 mg, 0.5 mmol), MeNHCH 2 CH 2 NHMe (213 ⁇ L, 2.0 mmol), and dioxane (5 mL) at 100°C for 5 min using microwave frradiation.
• the title compound was prepared according in accordance with Example 7 from 6-bromoindole-2-carboxylic acid ethyl ester, 3,4-methylenedioxy- phenylboronic acid, 3,5-bis(trifluoromethyl)benzylchloride and 4-chloro- benzamide.
• the title compound was prepared from 5-(4-nitrophenyl)indole-2-carboxylic acid ethyl ester (prepared from 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)indole-2-carboxylic acid ethyl ester (prepared from 5-bromoindole-2- carboxylic acid ethyl ester) and 4-nitrobromobenzene), 3-phenoxy- benzylchloride and 3,5-dimethoxybenzamide in accordance with Example 7.
• the title compound was prepared in accordance with Example 7 from 5-bromoindole-2-carboxylic acid ethyl ester, 4-tert-butylphenylboronic acid, 3-chlorobenzylchloride and nicotinamide.
• the title compound was prepared in accordance with Example 7 from 6-bromoindole-2-carboxylic acid ethyl ester, 3,4-methylenedioxy- phenylboronic acid, 3 -phenoxybenzyl chloride and 4-(dimethylamino)- butyrylamide.
• the title compound was prepared in accordance with Example 7 from 6- bromoindole-2-carboxylic acid ethyl ester, 3,4-methylenedioxy- phenylboronic acid, 3-cyanobenzylchloride and cinnamamide.
• the title compound was prepared in accordance with Example 7 from 5-bromoindole-2-carboxylic acid ethyl ester, 3,4-methylenedioxy- phenylboronic acid, (5-bromopentyloxy)benzene, and acetamide.
• the title compound was prepared in accordance with Example 7 from 5- bromoindole-2-carboxylic acid ethyl ester, 3,4-methylenedioxy- phenylboronic acid, (5-bromopentyloxy)benzene, and 2-piperidone.
• the title compound was prepared in accordance with Example 19 using pyridin-3 -ylboronic acid and 5 mol% Pd(PPh 3 ) 2 Cl .
• Example 24 3-(4-Fluoro-3-methylphenyl)-5-(4-methoxyphenyl)-l-r3-(trifluoromethyl)- benzyl]indole-2-carboxylic acid
• the title compound was prepared in accordance with Example 19 using 4-fluoro-3-methyl ⁇ henylboronic acid and 5 mol% Pd(PPh 3 ) Cl 2 .
• H NMR 200 MHz, DMSO-d 6 ): ⁇ 7.69-7.50 (m, 8H), 7.42 (m, IH), 7.37-
• the sub-title compound was prepared in accordance with Example 26(a) using 3-acetylphenylboronic acid and 2.5 mol% Pd(PPh 3 ) 2 Cl 2 and heating at 160°C for 10 min.
• the title compound was prepared in accordance with Example 29 using phenylboronic acid and 2.5 mol% Pd(PPh 3 ) 2 Cl 2 .
• the title compound was prepared in accordance with Example 29 using chlorophenylboronic acid and 2.5 mol% Pd(PPh 3 ) 2 Cl 2 .
• Example 37 The title compound was prepared in accordance with Example 34 using 4-fluoro-3-methylphenylboronic acid and 5 mol% Pd(PPh 3 ) 2 Cl .
• Example 37 The title compound was prepared in accordance with Example 34 using 4-fluoro-3-methylphenylboronic acid and 5 mol% Pd(PPh 3 ) 2 Cl .
• the title compound was prepared in accordance with Example 34 using 4-ethylphenylboronic acid and 5 mol% Pd(PPh 3 ) 2 Cl .
• 6-(3-Nitrophenyl)-3-phenyl-l-[(3-(trifluoiOmethoxy)benzyl]-indole-2- carboxylic acid ethyl ester prepared in accordance with the procedure in Example l(a)-(d) from 6-bromoindole-2-carboxylic acid ethyl ester, 3-nitro- phenylboronic acid and 3-(trifluoromethoxy)benzyl chloride (1.55 g, 2.76 mmol), in EtOAc (35 mL) was hydrogenated at ambient temperature and pressure over Pd-C (10%, 440 mg) until all starting material was consumed as judged by TLC. The mixture was filtered through Celite ® and the filtrate concentrated. The residue was purified by chromatography, dissolved in anhydrous Et 2 0, whereafter the sub-title compound was precipitated by the addition of an excess of HCI (4M) in dioxane. Yield: 955 mg (73%).
• the title compound was prepared by hydrolysis of 6-(3-aminophenyl)-3- phenyl-l-[(3-(trifluoromethoxy)benzyl]-indole-2-carboxylic acid ethyl ester in accordance with the procedure described in Example 2(b) (2M KOH (aq.), dioxane, 100°C, 1 h), followed by precipitation from an ethereal solution by addition of HCI (4M) in dioxane as described above.
• the title compound was prepared by hydrolysis of 6-[3-(2,2-dimethyl- ⁇ ropionylamino)phenyl]-3-phenyl-l-[3-(trifluoromethoxy)benzyl]indole-2- carboxylic acid ethyl ester in accordance with the procedure described in Example 1(e) (2M KOH (aq.), dioxane, 120 °C, 2 h).
• 6- f3 -(Allylmethanesulfonylamino)phenyl] -3 -phenyl- 1 -(3 -trifluoromethoxy- benzyl)indole-2-carboxylic acid AUyl iodide 54 ⁇ L, 0.59 mmol was added to a mixture of 6-[3-(mefhane- sulfonylamino)phenyl]-3 -phenyl- 1 -(3 -trifluoromethoxy-benzyl)indole-2- carboxylic acid ethyl ester (178 mg, 0.29 mmol; see Example 40), Cs 2 C0 3 (333 mg, 1.02 mmol), and dry DMF (2.5 mL).
• the title compound was prepared by hydrolysis of l-(3-chlorobenzyl)-6- (3 , 5 -difluorophenyl)-3 - [3 -(4-methoxyphenyl)-propiony lamino] indole-2- carboxylic acid ethyl ester (108 mg, 0.18 mmol) according to the procedure described in Example 2(b) (KOH (aq., 2M), dioxane, 60 °C 50 min then 100 °C 30 min). Yield 75 mg (73 %).
• Example 85 l-(3-Chlorobenzyl)-5-(4-chlorophenyD-3-phenylindole-2-carboxylic acid 1H NMR (200 MHz, DMSO-d 6 ): ⁇ 13.2-13.0 (IH, br s), 7.77-7.57 (5H, m), 7.54-7.29 (9H, m), 7.22 (IH, s), 7.05-6.97 (IH, m), 5.87 (2H, s).
• Example 86 l-(3-Chlorobenzyl)-5-(4-chlorophenyD-3-phenylindole-2-carboxylic acid 1H NMR (200 MHz, DMSO-d 6 ): ⁇ 13.2-13.0 (IH, br s), 7.77-7.57 (5H, m), 7.54-7.29 (9H, m), 7.22 (IH, s), 7.05-6.97 (IH, m), 5.87 (2H, s).
• Example 94
• LiAlH (6.4 mg, 0.17 mmol) was added to a solution of l-(3-chlorobenzyl)- 6-(4-isopropoxyphenyl)-3-(4-methoxybenzoylamino)indole-2-carboxylic acid ethyl ester, prepared in accordance with the procedure described in Example 7(a), (100 mg, 0.17 mmol) in THF (5 mL) at 0°C. After stirring for 1 h another portion of LiAlH (6.4 mg, 0.17 mmol) was added and the sti ⁇ ing was continued at room temperature for 1 h. The mixture was acidified to pH 2 with HCI (aq., 4M), diluted with water and extracted with EtOAc. The combined extracts were washed with water, brine, and dried over ⁇ a 2 S0 and concentrated. Purification of the residue by chromatography gave the title compound (59 mg, 64%).
• Example 111 The following Examples 111 to 130 were prepared by analogous techniques to those described herein.
• Example 111 The following Examples 111 to 130 were prepared by analogous techniques to those described herein.
• Example 111
• the title compound (45 mg, 32%) was prepared by hydrolysis of 6-(4- butylphenyl)- 1 -(3 -chlorobenzyl)-3 -(4-isopropoxybenzoylamino)indole-2- carboxylic acid ethyl ester (see Example 131(a)) under conditions as hereinbefore described, for example at 90°C for 10 min in 1,4-dioxane.
• IM BH 3 xTHF (IM, 200 ⁇ L, 0.20 mmol) was added to a stirred solution of 6-(4-carboxy ⁇ henyl)-3-(4-chlorobenzoylamino)-l-(3-chlorobenzyl)indole- 2-carboxylic acid ethyl ester, prepared by analogous techniques to those described hereinbefore, (120 mg, 0.20 mmol) in THF (5 mL) at -5 °C. The temperature of the mixture was allowed to reach room temperature and sti ⁇ ing was continued for 12 h whereafter another portion of IM BH 3 xTHF (IM, 200 ⁇ L, 0.20 mmol) was added.
• the title compound was prepared by hydrolysis of 3-(4-chlorobenzoyl- amino)- 1 -(3 -chlorobenzyl)-6-(4-hy droxymethylphenyl)indole-2 -carboxylic acid ethyl ester in accordance with the procedure in Example 2(b) (NaOH (IM), MeCN, 80 °C, 20 min).
• the sub-title compound was prepared in accordance with Example 131(a) using 3-nitrobenzoyl chloride (room temperature overnight, and then 90°C for 10 min, 110°C for 10 min and finally 130°C for 20 min).
• the title compound was prepared by hydrolysis of 6-(4-butylphenyl)-l-(3- chlorobenzyl)-3-[3-(2,5-dimethylpy ⁇ ol- 1 -yl)benzoylamino]indole-2- carboxylic acid ethyl ester (see Example 136(c)) in accordance with the procedure described in Example 2(b) (2M KOH, dioxane, 70 °C, 10 min, then 80 °C 20 min and finally 90 °C 10 min).
• the sub-title compound was prepared in accordance with Example 1(c) from 3-bromo-5-(4-isopropoxyphenyl)indole-2-carboxylic acid ethyl ester (1.0 g, 2.5 mmol, see step (a) above) and 3-chlorobenzylchloride (0.604 g, 3.75 mmol). Yield 0.784 g (60 %).
• the title compound was prepared by hydrolysis of 3-[acetyl-(4- methoxybenzyl)amino]-l-(3-chlorobenzyl)-5-(4-isopro ⁇ oxy ⁇ henyl)indole- 2-carboxylic acid ethyl ester (136 mg, 0.217 mmol; see step (d) above), in accordance with the procedure in Example 1(e) (NaOH (aq.), dioxane, 80°C, 1 h). Yield: 93 mg (72 %).
• Example 141 l-(3-Chlorobenzyl)-3- ⁇ (6-chloropyridine-3-carbonyl)-[2-(4-fluorophenyl)- ethyl]aminoX5-(4-isopropoxyphenyl)indole-2-carboxylic acid
• the title compound was prepared in accordance with the procedure in Example 139(c)-(e) from l-(3-chlorobenzyl)-5-(4-isopropoxyphenyl)indole- 2-carboxylic acid ethyl ester, 2-(4-fluor ⁇ phenyl)ethylamine and 6-chloro- nicotinoyl chloride.
• Example 142 Title compounds of the invention were tested in the biological test described above and were found to exhibit 50% inhibition of mPGES-1 at a concentration of 10M or below.
• the inhibition of mPGES-1 is exemplified by the following compounds of the examples, as listed in the following table:
• Example 1 96% inhibition at 10M
• Example 5 93% inhibition at 10M
• Example 6 100% inhibition at 10M

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