WO2005040112A1 - Compounds with pgd2 antagonist activity - Google Patents

Compounds with pgd2 antagonist activity Download PDF

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Publication number
WO2005040112A1
WO2005040112A1 PCT/GB2004/004337 GB2004004337W WO2005040112A1 WO 2005040112 A1 WO2005040112 A1 WO 2005040112A1 GB 2004004337 W GB2004004337 W GB 2004004337W WO 2005040112 A1 WO2005040112 A1 WO 2005040112A1
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WO
WIPO (PCT)
Prior art keywords
methyl
indol
fluoro
acetic acid
benzenesulfonyl
Prior art date
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PCT/GB2004/004337
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French (fr)
Inventor
David Middlemiss
Mark Richard Ashton
Edward Andrew Boyd
Frederick Arthur Brookfield
Richard Edward Armer
Eric Roy Pettipher
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Oxagen Limited
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Filing date
Publication date
Priority claimed from GB0324083A external-priority patent/GB0324083D0/en
Priority claimed from GB0403334A external-priority patent/GB0403334D0/en
Priority claimed from GB0406963A external-priority patent/GB0406963D0/en
Application filed by Oxagen Limited filed Critical Oxagen Limited
Publication of WO2005040112A1 publication Critical patent/WO2005040112A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Definitions

  • the present invention relates to compounds which are useful as pharmaceuticals, to methods for preparing these compounds, compositions containing them and their use in the treatment and prevention of allergic diseases such as asthma, allergic rhinitis and atopic dermatitis and other inflammatory diseases mediated by prostaglandin D 2 (PGD 2 ) acting at the CRTH2 and/or the DP receptor on cells including eosinophils, basophils and Th2 lymphocytes.
  • PPD 2 prostaglandin D 2
  • PGD 2 is an eicosanoid, a class of chemical mediator synthesised by cells in response to local tissue damage, normal stimuli or hormonal stimuli or via cellular activation pathways. Eicosanoids bind to specific cell surface receptors on a wide variety of tissues throughout the body and mediate various effects in these tissues. PGD 2 is known to be produced by mast cells, macrophages and Th2 lymphocytes and has been detected in high concentrations in the airways of asthmatic patients challenged with antigen (Murray et al, (1986), N. Engl. I. Med. 315: 800-804). Instillation of PGD into airways can provoke many features of the asthmatic response including bronchoconstriction (Hardy et al, (1984) N. Engl.
  • the first receptor specific for PGD 2 to be discovered was the DP receptor which is linked to elevation of the intracellular levels of cAMP.
  • PGD 2 is thought to mediate much of its proinflammatory activity through interaction with a G protein- coupled receptor termed CRTH2 (chemoattractant receptor-homologous molecule expressed on Th2 cells) which is expressed by Th2 lymphocytes, eosinophils and basophils (Hirai et al, (2001) /. Exp. Med. 193: 255-261, and EP0851030 and EP-A- 1211513 and Bauer et al, EP-A-1170594).
  • CRTH2 chemoattractant receptor-homologous molecule expressed on Th2 cells
  • the selective DP agonist BW245C does not promote migration of Th2 lymphocytes or eosinophils (Hirai et al, 2001; Gervais et al, (2001) I. Allergy Clin. Immunol. 108: 982-988). Based on this evidence, antagonising PGD 2 at the CRTH2 receptor is an attractive approach to treat the inflammatory component of Th2-dependent allergic diseases such as asthma, allergic rhinitis and atopic dermatitis.
  • EP-A-1170594 suggests that the method to which it relates can be used to identify compounds which are of use in the treatment of allergic asthma, atopic dermatitis, allergic rhinitis, autoimmune disease, reperfusion injury and a number of inflammatory conditions, all of which are mediated by the action of PGD at the CRTH2 receptor.
  • WO-A-03066046 and WO-A-03066047 teach that the compounds to which they relate are modulators of CRTH2 receptor activity and are therefore of use in the treatment or prevention of obstructive airway diseases such as asthma, chronic obstructive pulmonary disease (COPD) and a number of other diseases including various conditions of bones and joints, skin and eyes, GI tract, central and peripheral nervous system and other tissues as well as allograft rejection.
  • COPD chronic obstructive pulmonary disease
  • Indole derivatives are also disclosed in WO-A-9950268. These compounds have a carboxylic acid moiety attached to the indole nitrogen atom. These compounds are said to be of use in the treatment of complications arising from diabetes mellitus.
  • PL 65781 and GB 1172320 also relate to indole derivatives which are similar in structure to indomethacin and, like indomethacin, are said to have anti-inflammatory and antipyretic activity.
  • the compounds they describe are COX inhibitors, an activity which is quite different from that of the compounds of the present invention. Indeed, COX inhibitors are contraindicated in the treatment of many of the diseases and conditions, for example asthma and inflammatory bowel disease for which the compounds of the present invention are useful, although they may sometimes be used to treat arthritic conditions.
  • the present invention relates to compounds similar to those of PL 65781 and GB 1172320 which are antagonists of PGD 2 .
  • R 1 , R 2 , R 3 and R 4 are independently hydrogen, halo, -C ⁇ -C 6 alkyl, -O(C ⁇ -C 6 alkyl), -C C 6 alkyl(C 3 -C 7 cycloalkyl), -CON(R 9 ) 2 , -SOR 9 , -SO 2 R 9 , -SO 2 N(R 9 ) 2 , -N(R 9 ) 2 , -NR 9 COR 9 , -CO 2 R 9 , COR 9 , -SR 9 , -OH, -NO 2 or -CN; each R 9 is independently hydrogen or -C ⁇ alkyl; R 5 and R 6 are each independently hydrogen, or d-C 6 alkyl or together with the carbon atom to which they are attached form a C 3 -C 7 cycloalkyl group;
  • R 7 is hydrogen or C C 6 alkyl
  • R 8 is C ⁇ -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl or an aromatic moiety, any of which may optionally be substituted with one or more substituents selected from halo,
  • R 14 is independently hydrogen, alkyl or aryl, the aryl being optionally substituted by -R 9 , -OR 9 , -CON(R 9 ) 2 , -SOR 9 -SO 2 R 9 , -SO 2 N(R 9 ) 2 , -N(R 9 ) 2 , - NR9COR 9 , -CO 2 R 9 , -COR 9 , -SR 9 , halo, -NO 2 or -CN; wherein R 9 is as defined above; provided that when R 1 , R 3 and R are hydrogen and R 2 is hydrogen, halogen or -O(C !
  • R is not unsubstituted phenyl or phenyl substituted by halo, Ci-C ⁇ alkyl, -O(C 1 -C 6 )alkyl, -S(C ⁇ -C 6 )alkyl or -CO(Ci-C 6 )alkyl; or a pharmaceutically acceptable salt, hydrate, solvate, complex or prodrug thereof.
  • the compounds of general formula (I) are antagonists of PGD 2 . Some of the compounds of general formula (I) act at the CRTH2 receptor, others have dual activity at the CRTH2 and DP receptors and yet others act selectively at the DP receptor. The compounds will be useful in the treatment of conditions which are mediated by PGD 2 binding to the CRTH2 and/or DP receptors.
  • allergic diseases include allergic asthma, perennial allergic rhinitis, seasonal allergic rhinitis, atopic dermatitis, contact hypersensitivity (including contact dermatitis), conjunctivitis, especially allergic conjunctivitis, eosinophilic bronchitis, food allergies, eosinophilic gastroenteritis, inflammatory bowel disease, ulcerative colitis and Crohn's disease, mastocytosis and also other PGD 2 -mediated diseases, for example autoimmune diseases such as hyper IgE syndrome and systemic lupus erythematus, psoriasis, acne, multiple sclerosis, allograft rejection, reperfusion injury and chronic obstructive pulmonary disease; as well as rheumatoid arthritis, psoriatic arthritis and osteoarthritis.
  • autoimmune diseases such as hyper IgE syndrome and systemic lupus erythematus, psoriasis, acne, multiple sclerosis, allograft rejection, reperfusion injury
  • Q-Q alkyl refers to a straight or branched saturated hydrocarbon chain having one to six carbon atoms and optionally substituted with one or more halo substituents or with one or more C 3 -C cycloalkyl groups. Examples include methyl, ethyl, n-propyl, isopropyl, t-butyl, n-hexyl, trifluoromethyl, 2-chloroethyl, mefhylenecyclopropyl, methylenecyclobutyl, methylenecyclobutyl and methylenecyclopentyl.
  • C 1 -C 4 alkyl and “Q-Qs alkyl” have similar meanings except that they contain from one to four and from one to eighteen carbon atoms respectively.
  • C -C 6 alkenyl and “C ⁇ -C 6 alkynyl” refer to straight or branched carbon chains having from one to six carbon atoms and containing respectively a carbon-carbon double bond and a carbon-carbon triple bond.
  • the groups are optionally substituted with one or more halo substituents or with one or more C 3 -C 7 cycloalkyl groups. Examples include ethenyl, ethynyl, 2-propenyl and 2-propynyl.
  • C 3 -C 7 cycloalkyl refers to a saturated 3 to 7 membered carbocyclic ring.
  • Examples of such groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • halo refers to fluoro, chloro, bromo or iodo.
  • aromatic moiety and "aryl” in the context of the present specification refer to an aromatic ring system having from 5 to 14 ring carbon atoms and containing up to three rings, one or more of which may be replaced by a nitrogen, oxygen or sulphur atom.
  • aromatic moieties are benzene, pyridine, naphthalene, biphenyl, quinoline, isoquinoline, quinazoline, benzthiazole, benzoxazole, benzimidazole indole, indazole and imidazole ring systems.
  • Appropriate pharmaceutically and veterinarily acceptable salts of the compounds of general formulae (I) and (II) include basic addition salts such as sodium, potassium, calcium, aluminium, zinc, magnesium and other metal salts as well as choline, diethanolamine, ethanolamine, ethyl diamine and other well known basic addition salts.
  • pharmaceutically or veterinarily acceptable salts may also include salts of organic acids, especially carboxylic acids, including but not limited to acetate, trifluoroacetate, lactate, gluconate, citrate, tartrate, maleate, malate, pantothenate, adipate, alginate, aspartate, benzoate, butyrate, digluconate, cyclopentanate, glucoheptanate, glycerophosphate, oxalate, heptanoate, hexanoate, fumarate, nicotinate, pamoate, pectinate, 3-phenylpropionate, picrate, pivalate, proprionate, tartrate, lactobionate, pivolate, camphorate, undecanoate and succinate, organic sulphonic acids such as methanesulphonate, ethanesulphonate, 2- hydroxyethane sulphonate, camphorsulphonate, 2-naphthalenesul, 2-
  • Salts which are not pharmaceutically or veterinarily acceptable may still be valuable as intermediates.
  • Prodrugs are any covalently bonded compounds which release the active parent drug according to general formula (I) in vivo.
  • Examples of prodrugs include alkyl esters of the compounds of general formula (I), for example the esters of general formula (LI) below.
  • a chiral centre or another form of isomeric centre is present in a compound of the present invention, all forms of such isomer or isomers, including enantiomers and diastereoisomers, are intended to be covered herein.
  • Compounds of the invention containing a chiral centre may be used as a racemic mixture, an enantiomerically enriched mixture, or the racemic mixture may be separated using well-known techniques and an individual enantiomer may be used alone.
  • R 1 is C ⁇ -C 4 alkyl, halo or hydrogen
  • R 2 is C 1 -C 4 alkyl, CN, halo, hydrogen or -CON(R 9 ) 2 , (where R 9 is hydrogen or C ⁇ -C 4 alkyl);
  • R 3 is Q-C 4 alkyl, halo or hydrogen
  • R 4 is C 1 -C 4 alkyl, halo or hydrogen.
  • R 1 , R 3 and R are hydrogen, while R 2 is halo, particularly fluoro.
  • R 5 and R 6 are each independently hydrogen or C 1 -C 4 alkyl. However, in more active compounds, at least one, and preferably both of R 5 and R 6 are hydrogen.
  • Compounds of general formula (I) preferably have an R 7 group chosen from H or Q- C 6 alkyl; most suitably R 7 is methyl.
  • the compounds of general formula (I) have the additional advantage that the selectivity of the compound can be manipulated by making changes to the R 8 substituent.
  • a high selectivity at the CRTH2 receptor is advantageous and the inclusion of certain R 8 substituents give rise to compounds in which binding selectivity at the CRTH2 receptor is more than 200 times greater than DP or TP binding.
  • other compounds of general formula (I) bind selectively to the DP receptor and yet others bind strongly to both CRTH2 and DP receptors and this is preferable for some medical uses such as allergic rhinitis.
  • R is an aromatic moiety having one or two rings and substituted with one or more substituents selected from halo, -C1-C4 alkyl, -O(C C 4 alkyl), -SO 2 (C ⁇ -C 4 alkyl), -R 14 , -N(R 14 ) 2 and -OR 14 ; where R 14 (or one R 14 if two are present) is preferably aryl, optionally substituted as described above.
  • R 8 groups include an aromatic moiety having one or two rings, and especially phenyl or pyridyl, substituted with -SO 2 R 14 , -N(R 14 ) 2 or -OR 14 ; where R 14 (or one of the R 14 groups if two are present) is preferably aryl, optionally substituted as described above.
  • substituents for the R 14 moiety are Q-C 4 alkyl, -0(0 ⁇ 0 4 alkyl), -CN, -SO 2 NH 2 , -SO 2 (C 1 -C 4 alkyl) or halo.
  • R , ⁇ 1 , R ⁇ R ⁇ R 4 , R D , R°, R' and R B are as defined for general formula (I);
  • R 11 is hydrogen or methyl
  • R 12 is Ci-Ci ⁇ alkyl; provided that when R 1 , R 3 and R 4 are hydrogen and R 2 is hydrogen, halogen or - O(C ⁇ -C 6 )alkyl, R 8 is not unsubstituted phenyl or phenyl substituted by halo, Q-C O alkyl, -O(C ⁇ -C 6 )alkyl, -S(C 1 -C 6 )alkyl or -CO(d-C 6 )alkyl.
  • Compounds of general formula (II) are novel and may be used as prodrugs for compounds of general formula (I).
  • the compound of general formula (TT) acts as a prodrug, it is later transformed to the drug by the action of an esterase in the blood or in a tissue of the patient.
  • compounds of formula (II) wherein R 10 is d-C 6 alkyl may be used in a process for the preparation of a compound of general formula (I), the process comprising reacting the compound of general formula (LI) with a base such as sodium hydroxide or lithium hydroxide.
  • a base such as sodium hydroxide or lithium hydroxide.
  • the reaction may take place in an aqueous solvent or an organic solvent or a mixture of the two.
  • a typical solvent used for the reaction is a mixture of tetrahydrofuran and water.
  • R 1 , R 2 , R 3 , R 4 R 5 , R 6 and R 7 are as defined for general formula (I) and R 10 is as defined for general formula (II); by reaction with a compound of general formula (IV): X-SO 2 -R 8 (TV)
  • R 8 is as defined for general formula (I) and X is a leaving group in particular a halo group, for example chloro.
  • the reaction is conducted under strongly basic conditions, for example in the presence of a metal alkoxide, in particular a potassium or sodium alkoxide such as potassium tert-butoxide.
  • a metal alkoxide in particular a potassium or sodium alkoxide such as potassium tert-butoxide.
  • the reaction may be carried out in a polar organic solvent such as tetrahydrofuran and the alkoxide may be solubilised using a polyether, particularly a crown ether. If a potassium alkoxide is used, 18-crown-6 is a particularly suitable solvating agent as it complexes very effectively with potassium ions.
  • R is a trifluoromethanesulfonyl- substituted aryl group (for example trifluoromethylsulfonylbenzene)
  • R is a trifluoromethanesulfonyl- substituted aryl group
  • the reaction may be conducted at elevated temperature, for example 50 to 150°C.
  • the trifluoromethanesulfonyl-substituted aromatic compound may be prepared by oxidising the corresponding sulfide, for example using ruthenium trioxide and sodium periodate. Trifluoromethylsulfonylbenzene may be prepared in this way from phenyltrifluoromethylsulfide.
  • the precursor sulfonyl chloride derivative of general formula (IV) may be prepared by reacting the corresponding pyridyloxyaryl compound with chlorosulfonic acid.
  • the reaction is preferably carried out in a chlorinated organic solvent at a low temperature, for example from -5 to 30°C.
  • Examples of intermediates of general formula (IV) which can be prepared in this way include: 4-(pyridine-2-yloxy) benzene sulf onyl chloride; 4-(pyridine-3-yloxy) benzene sulfonyl chloride; and 4-(pyridine-4-yloxy) benzene sulfonyl chloride.
  • the most suitable method for the preparation of the aryloxy aryl group depends upon the required substitution pattern on the aryloxy group.
  • Some of these compounds can be prepared by the reaction of the corresponding halopyridine with a hydroxyaryl group in the presence of a strong base such as sodium hydride. The reaction is carried out under an inert atmosphere, for example nitrogen in an aprotic organic solvent such as dioxane. This method is appropriate for the preparation of 2- phenyoxypyridine from phenol and 2-fluoropyridine.
  • a hydroxyaryl compound such as a pyridinol
  • a base such as sodium or potassium hydroxide and a halo-substituted aromatic compound in a copper catalysed reaction.
  • This method is suitable for the preparation of compounds such as 3-phenoxypyridine and 4-phenoxypyridine.
  • compounds of general formula (II) in which R 8 is chloro-, bromo- or iodo-substituted aryl may be converted to other compounds of general formula (II) in which R is arylaminoaryl by reaction with an aryl amino compound in a palladium (0) mediated cross-coupling reaction.
  • This reaction may be used to convert o compound in which R is haloaryl (for example bromophenyl or bromopyridyl) to compounds in which R is arylaminoaryl (such as arylaminophenyl or arylaminopyridyl, for example Compounds 109-153).
  • Compounds of general formula (LI) in which R 8 is aryl aminoaryl can be converted into compounds of general formula (LI) in which R 8 is aryl-N-alkylaminoaryl by reaction with an alkyl iodide in the presence of a strong base.
  • R 8 is aryl-sulfinyl-aryl or aryl-sulfonyl- aryl
  • R 8 is aryl- sulfanyl-aryl by oxidation using an appropriate oxidising agent to give either partial or complete oxidation as appropriate.
  • a suitable oxidising agent for the aryl sulfinyl compounds is mCPBA and a suitable oxidising agent for the aryl-sulfonyl compounds is OxoneTM.
  • the precursor sulfonyl chloride derivative of general formula (TV) may be prepared by reacting the corresponding diaryl sulfide compound with chlorosulfonic acid under standard conditions.
  • Compounds of general formula (I) are antagonists of PGD 2 at the CRTH2 and/or DP receptors and compounds of general formula (II) are prodrugs for compounds of general formula (I).
  • Compounds of general formulae (I) and (LI) are therefore useful in a method for the treatment of diseases and conditions mediated by PGD 2 at the CRTH2 and/or DP receptors, the method comprising administering to a patient in need of such treatment a suitable amount of a compound of general formula (I) or
  • a compound of general formula (I) or (II) for use in medicine particularly for use in the treatment or prevention of diseases and conditions mediated by PGD 2 at the CRTH2 and/or DP receptor. Examples of such diseases and conditions are listed above.
  • R 1 , R 2 , R 3 and R 4 are independently hydrogen, halo, -C ⁇ -C 6 alkyl, -O(d-C 6 alkyl), -d-C 6 alkyl(C 3 -C 7 cycloalkyl), -CON(R 9 ) 2 , -SOR 9 , -SO 2 R 9 , -SO 2 N(R 9 ) 2 , -N(R ) 2 , -NR 9 COR 9 , -CO 2 R 9 , COR 9 , -SR 9 , -OH, -NO 2 or -CN; each R 9 is independently hydrogen or d-C 6 alkyl; R 5 and R 6 are each independently hydrogen, or d-C 6 alkyl or together with the carbon atom to which they are attached form a C 3 -C 7 cycloalkyl group; R 7 is hydrogen or d-C 6 alkyl;
  • R 8 is d-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl or an aromatic moiety, any of which may optionally be substituted with one or more substituents selected from halo, -SOR 13 -SO 2 R 13 , -R 14 , -OR 14 , -CON(R 14 ) 2 , -SOR 14 , -SO 2 R 14 , -SO 2 N(R 14 ) 2 , -N(R 14 ) 2 , -NR 14 COR 14 , -CO 2 R 14 , -COR 14 , -SR 14 , -NO 2 or -CN; wherein R 13 is a 5 to 7 membered heterocyclic ring; and each R 14 is independently hydrogen, alkyl or aryl, the aryl being optionally substituted by -R 9 , -OR 9 , -CON(R 9 ) 2 , -SOR 9 -SO 2 R
  • autoimmune diseases such as hyper IgE syndrome and systemic lupus erythematus, psoriasis, acne, multiple sclerosis, allograft rejection, reperfusion injury and chronic obstructive pulmonary disease; as well as rheumatoid arthritis, psoriatic arthritis and osteoarthritis.
  • Preferred compounds are as set out above for the first aspect of the invention.
  • a pharmaceutical composition comprising a compound of general formula (I) or (II) together with a pharmaceutical excipient or carrier.
  • Other active materials may also be present, as may be considered appropriate or advisable for the disease or condition being treated or prevented.
  • each of the carriers must be acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient.
  • the formulations include those suitable for oral, rectal, nasal, bronchial (inhaled), topical (including eye drops, buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration and may be prepared by any methods well known in the art of pharmacy.
  • compositions for oral, nasal, bronchial or topical administration.
  • the composition may be prepared by bringing into association the above defined active agent with the carrier.
  • the formulations are prepared by uniformly and intimately bringing into association the active agent with liquid carriers or finely divided solid carriers or both, and then if necessary shaping the product.
  • the invention extends to methods for preparing a pharmaceutical composition comprising bringing a compound of general formula (I) or (II) in conjunction or association with a pharmaceutically or veterinarily acceptable carrier or vehicle.
  • Formulations for oral administration in the present invention may be presented as: discrete units such as capsules, sachets or tablets each containing a predetermined amount of the active agent; as a powder or granules; as a solution or a suspension of the active agent in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water in oil liquid emulsion; or as a bolus etc.
  • the term "acceptable carrier” includes vehicles such as common excipients e.g. binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, polyvinylpyrrolidone (Povidone), methylcellulose, ethylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, sucrose and starch; fillers and carriers, for example corn starch, gelatin, lactose, sucrose, microcrystalline cellulose, kaolin, mannitol, dicalcium phosphate, sodium chloride and alginic acid; and lubricants such as magnesium stearate, sodium stearate and other metallic stearates, glycerol stearate stearic acid, silicone fluid, talc waxes, oils and colloidal silica.
  • Flavouring agents such as peppermint, oil of wintergreen, cherry flavouring and the like can also be used. It may be desirable to
  • a tablet may be made by compression or moulding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine the active agent in a free flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface-active or dispersing agent.
  • Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active agent.
  • compositions suitable for oral administration include lozenges comprising the active agent in a flavoured base, usually sucrose and acacia or tragacanth; pastilles comprising the active agent in an inert base such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active agent in a suitable liquid carrier.
  • lozenges comprising the active agent in a flavoured base, usually sucrose and acacia or tragacanth
  • pastilles comprising the active agent in an inert base such as gelatin and glycerin, or sucrose and acacia
  • mouthwashes comprising the active agent in a suitable liquid carrier.
  • compounds of general formula (I) or (LT) may be made up into a cream, ointment, jelly, solution or suspension etc.
  • Cream or ointment formulations that may be used for the drug are conventional formulations well known in the art, for example, as described in standard text books of pharmaceutics such as the British
  • Compounds of general formula (I) or (LT) may be used for the treatment of the respiratory tract by nasal, bronchial or buccal administration of, for example, aerosols or sprays which can disperse the pharmacological active ingredient in the form of a powder or in the form of drops of a solution or suspension.
  • Pharmaceutical compositions with powder-dispersing properties usually contain, in addition to the active ingredient, a liquid propellant with a boiling point below room temperature and, if desired, adjuncts, such as liquid or solid non-ionic or anionic surfactants and or diluents.
  • Pharmaceutical compositions in which the pharmacological active ingredient is in solution contain, in addition to this, a suitable propellant, and furthermore, if necessary, an additional solvent and/or a stabiliser.
  • compressed air can also be used, it being possible for this to be produced as required by means of a suitable compression and expansion device.
  • Parenteral formulations will generally be sterile.
  • the dose of the compound will be about 0.01 to 100 mg kg; so as to maintain the concentration of drug in the plasma at a concentration effective to inhibit PGD 2 at the CRTH2 and/or DP receptor.
  • the precise amount of a compound of general formula (I) or (H) which is therapeutically effective, and the route by which such compound is best administered, is readily determined by one of ordinary skill in the art by comparing the blood level of the agent to the concentration required to have a therapeutic effect.
  • Compounds of general formula (I) or (II) may be used in combination with one or more active agents which are useful in the treatment of the diseases and conditions listed above, although these active agents are not necessarily inhibitors of PGD at the CRTH2 and/or DP receptor.
  • the pharmaceutical composition described above may additionally contain one or more of these active agents.
  • additional active agents which may have a completely different mode of action include existing therapies for allergic and other inflammatory diseases including: ⁇ 2 agonists such as salmeterol; corticosteroids such as fluticasone; antihistamines such as loratidine; leukotriene antagonists such as montelukast; anti-IgE antibody therapies such as omalizumab; anti-infectives such as fusidic acid (particularly for the treatment of atopic dermatitis); anti-fungals such as clotrimazole (particularly for the treatment of atopic dermatitis); immunosuppressants such as tacrolimus and particularly pimecrolimus in the case of inflammatory skin disease.
  • ⁇ 2 agonists such as salmeterol
  • corticosteroids such as fluticasone
  • antihistamines such as loratidine
  • leukotriene antagonists such as montelukast
  • anti-IgE antibody therapies such as omalizumab
  • CRTH2 and or DP antagonists may also be combined with therapies that are in development for inflammatory indications including: other antagonists of PGD 2 acting at other receptors such as CRTH2 (for compounds of general formula (I) which are DP antagonsists) or DP (for compounds of general formula (I) which are CRTH2 antagonists); inhibitors of phoshodiesterase type 4 such as cilonilast; drugs that modulate cytokine production such as inhibitors of TNF converting enzyme (TACE); drugs that modulate the activity of Th2 cytokines LL-4 and LL-5 such as blocking monoclonal antibodies and soluble receptors; PPAR- ⁇ agonists such as rosiglitazone; 5-lipoxygenase inhibitors such as zileuton.
  • other antagonists of PGD 2 acting at other receptors such as CRTH2 (for compounds of general formula (I) which are DP antagonsists) or DP (for compounds of general formula (I) which are CRTH
  • a product comprising a compound of general formula (I) or (LT) and one or more of the agents listed above as a combined preparation for simultaneous, separate or sequential use in the treatment of a disease or condition mediated by the action of PGD 2 at the CRTH2 and/or DP receptor.
  • Tr 1.63 min (91%), m/z (ES + ) (M+H) + 362.1.
  • Tr 1.73 min (100%), m/z (ES + ) (M+H) + 426.1.
  • Tr 1.55 min (85%), /z (ES + ) (M+H) + 416.01.
  • Tr 1.66 min (100%), m/z (ES + ) (M+H) + 432.15.
  • Tr 1.60 min (100%), m/z (ES + ) (M+H) + 412.14.
  • Tr 1.28 min (100%), m/z (ES + ) (M+H) + 300.25.
  • Tr 1.50 min (100%), m/z (ES + ) (M+H) + 374.16.
  • Tr 1.60 min (100%), m/z (ES + ) (M+H) + 450.11.
  • Tr 1.45 min (100%), m/z (ES + ) (M+H) + 393.13.
  • Tr 1.46 min (100%), m/z (ES + ) (M+H) + 382.17.
  • Tr 1.40 min (100%), m/z (ES + ) (M+H) + 373.16.
  • Tr 1.41 min (100%), m/z (ES + ) (M+H) + 373.20.
  • Tr 1.30 min (100%), m/z (ES + ) (M+H) + 445.08.
  • Tr 1.49 min (100%), m/z (ES + ) (M+H) + 431.16.
  • Tr 1.66 min (97%), /z (ES + ) (M+H) + 410.22.
  • Tr 1.31 min (100%) m/z (ES + ) 389.12 (M+H) + .
  • sodium hydride 60% dispersion in mineral oil
  • 2-fluoro-pyridine 2.9 g, 29.9 mmol
  • Chlorosulfonic acid (0.77 mL, 11.69 mmol) was added dropwise to a stirred solution of 2-phenoxy-pyridine (500 mg, 2.92 mmol) in chloroform (10 mL) at 0°C. The mixture was left at 0°C for 30 minutes, and then left overnight stirring at room temperature. Three other treatments with chlorosulfonic acid (3 x 0.38 mL, 3 x 5.84 mmol) were required to give complete conversion to the sulfonyl chloride. The resulting mixture was then poured slowly onto a mixture of ice and water (250 mL). The aqueous layer was extracted with dichloromethane (250 mL).
  • Chlorosulfonic acid (0.77 mL, 11.69 mmol) was added dropwise to a stirred solution of 3-phenoxy-pyridine (500 mg, 2.92 mmol) in chloroform (10 mL) at 0°C. The mixture was left at 0°C for 30 minutes, and then left overnight stirring at room temperature. Another treatment with chlorosulfonic acid (0.77 mL, 11.69 mmol) was required to give complete conversion to the sulfonyl chloride. The resulting mixture was then poured slowly onto a mixture of ice and water (250 mL). The aqueous layer was extracted with dichloromethane (250 mL).
  • Chlorosulfonic acid (1.55 mL, 23.38 mmol) was added dropwise to a stirred solution of 4-phenoxy-pyridine (1 g, 5.85 mmol) in chloroform (20 mL) at 0°C. The mixture was left at 0°C for 30 minutes, and then left overnight stirring at room temperature. Four extra treatments with chlorosulfonic acid (4 x 1.55 mL, 4 x 23.38 mmol) were required to give complete conversion to the sulfonyl chloride. The resulting mixture was then poured slowly onto a mixture of ice and water (500 mL). The aqueous layer was extracted with dichloromethane (500 mL).
  • 1,4-Dioxane (5.0 ml) was added to a flask containing [l-(4-bromo-benzenesulfonyl)- 5-fluoro-2-methyl-2H-indol-3-yl]-acetic acid ethyl ester (227 mg, 0.50 mmol), tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (46 mg, 0.044 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (15 mg, 0.025 mmol), cesium carbonate (813 mg, 2.50 mmol) and 3-methylaniline (64 mg, 0.60 mmol) under a nitrogen atmosphere.
  • Examples 155 to 169 were prepared using a similar method to Compound 154 but with appropriately chosen starting materials
  • Chlorosulfonic acid (0.70 mL, 10.74 mmol) was added dropwise to a stirred solution of diphenyl sulfide (2 g, 10 mmol) in chloroform (5 mL) at 0°C. The mixture was left at 0°C for 30 minutes, and then left overnight stirring at room temperature. The resulting mixture was concentrated in vacuo to give a yellow oil which crystallised on standing. The resulting product was dissolved in toluene and treated with phosphorus pentachloride (2.23 g, 10.71 mmol) at 90°C for one hour. The resulting mixture was concentrated in vacuo and then partitioned between dichloromethane and water. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The product was used directly in the next step.
  • Oxone (190 mg, 0.31 mmol) was added to a solution of [5-fluoro-2-methyl-l-(4- phenylsulfanyl-benzenesulfonyl)-2H-indol-3-yl]-acetic acid ethyl ester (100 mg at 50% purity, 0.10 mmol) in 5 mL of dioxane : water (4:1). The resulting mixture was stirred at room temperature overnight and then partitioned between dichloromethane and water. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo.
  • Calcium-3 dye was purchased from Molecular Devices (Wokingham, UK). Monopoly resolving medium was obtained from Dainippon Pharmaceuticals (Osaka, Japan). Macs anti-CD16 microbeads were from Miltenyi biotec (Bisley, Surrey). ChemoTx plates were purchased from Neuroprobe (Gaithesburg, MD). Poly-D- lysine coated 96-well plates were obtained from Greiner (Gloucestershire, UK). [ 3 H]PGD 2 was from Amersham Biosciences (Buckinghamshire, UK). [ 3 H]SQ29548 was purchased from Perkin Elmer Life Sciences (Buckinghamshire, UK). All other reagents were obtained from Sigma-Aldrich (Dorset, UK), unless otherwise stated.
  • Chinese Hamster Ovary cells were transfected with CRTH2 or DP receptors (CHO/CRTH2 and CHO/DP) and were maintained in culture in a humidified atmosphere at 37°C (5% CO 2 ) in Minimum Essential Medium (MEM) supplemented with 10% foetal bovine serum, 2 mM glutamine, and 1 mg ml "1 active G418. The cells were passaged every 2-3 days.
  • MEM Minimum Essential Medium
  • radioligand binding assay cells were prepared in triple-layer flasks or in 175 cm square flasks (for membrane preparation).
  • calcium mobilisation assay cells were grown in a 96 well plate 24h prior to the assay at a density of 80,000 cells per well.
  • Membranes were prepared either from CHO/CRTH2 and CHO/DP cells, or from platelets (as a source of TP receptors). CHO cells grown to confluency were washed with PBS and detached using a Versene solution (15 ml per flask). When the cells were grown in 175 cm 2 square flask, they were collected by scrapping in PBS. The cell suspensions were centrifuged (1,700 rpm, 10 min, 4°C) and resuspended in 15 ml of buffer (lxHBSS, supplemented with 10 mM HEPES, pH 7.3). Cell suspensions were then homogenised using an Ultra Turrax at setting 4-6 for 20 s.
  • the homogenate was centrifuged at 1,700 rpm for 10 min and the supernatant was collected and centrifuged at 20,000 rpm for lh at 4°C. The resulting pellet was resuspended in buffer and stored at -80°C in aliquots of 200-500 ⁇ l.
  • the protein concentration was determined by the method of Bradford (1976), using bovine serum albumin as standard.
  • the platelets were washed by centrifugation at 600xg for 10 min and resuspended in ice-cold assay buffer (10 mM Tris-HCl, pH 7.4, 5 mM Glucose, 120 mM NaCl, 10 ⁇ M indomethacin) and directly centrifuged at 20,000 rpm for 30 min at 4°C. The resulting pellet was treated as described above. Radioligand binding assays
  • [ 3 H]PGD 2 (160 Ci/mmol) binding experiments were performed on membranes prepared as described above. Assays were performed in a final volume of 100 ⁇ l of buffer (1XHBSS/HEPES 10 mM, pH 7.3). Cell membranes (15 ⁇ g). Cell membranes 15mg were preincubated at room temperature with varying concentration of competing ligand for 15 min. [ 3 H]PGD2 (mol, final concentration) was then added and the incubation continued for a further one hour at room temperature.
  • the reaction was terminated by the addition of 200 ⁇ l ice-cold assay buffer to each well, followed by rapid filtration through Whatman GF/B glass fibre filters using a Unifilter Cell harvester (PerkinElmer Life Sciences) and six washes of 300 ⁇ l of ice- cold buffer.
  • the Unifilter plates were dried at room temperature for at least lh and the radioactivity retained on the filters was determined on a Beta Trilux counter (PerkinElmer Life Sciences), following addition of 40 ⁇ l of Optiphase Hi-Safe 3 (Wallac) liquid scintillation. Non specific binding was defined in the presence of 10 ⁇ M unlabelled PGD 2 . Assays were performed in duplicate.
  • TP receptor radioligand binding was done on membranes prepared from platelets. 15-40 ⁇ g of protein were pre-incubated with varying concentrations of competing ligand for 15 min at room temperature in assay buffer (10 mM Tris-HCl, pH 7.4, 5 mM glucose, 120 mM NaCl, 10 ⁇ M indomethacin). [ 3 H]SQ29548 (38 Ci/mmol, 10 nM final concentration) was then added and the incubation continued for a further 30 min at room temperature.
  • the reaction was terminated by the addition of 200 ⁇ l ice-cold assay buffer to each well, followed by rapid filtration through Whatman GF/C glass fibre filters using a Unifilter Cell harvester (PerkinElmer Life Sciences) followed with six washes of 300 ⁇ l of ice-cold buffer.
  • the radioactivity was determined as described above.
  • Cells were seeded onto poly-D-lysine coated 96-well plates at a density of 80,000 cells per well and incubated at 37 °C overnight to allow the cells to adhere. Cells were washed twice with HBSS and incubated for lh at 37°C in lOO ⁇ l HBSS and lOO ⁇ l calcium-3-dye (Molecular Devices), supplemented with 4mM probenecid. Changes in fluorescence were monitored over a 50s time course with agonist addition at 17s using a Flexstation (Molecular Devices).

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Abstract

Compounds of general formula (I); wherein R1, R2, R3 and R4 are independently hydrogen, halo, -C1-C6 alkyl, -O(C1-C6 alkyl), -C1-C6 alkyl(C3-C7 cycloalkyl), -CON(R9)2, -SOR9, -S02R9. -S02N(R9)2, -N(R9)2, -NR9OR9, -C02R9, COR9, -SR9, -OH, -N02 or -CN; each R9 independently hydrogen or C1-C6 alkyl; R5 and R6 are each independently hydrogen, or C1-C6 alkyl or together with the carbon atom to which they are attached form a C3-C7 cycloalkyl. group; R7 is hydrogen or C1-C6 alkyl; R8 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or an aromatic moiety, any of which may optionally be substituted with one or more substituents selected from halo, -SOR13 -S02R13, -R14, -OR14, -CON(R14)2 -SOR14, -S02R14, -S02N(R14) -SO2N(R14)2, -N(R 14)2, NR14COR14, -CO2R14, COR14, -SR14, -N02 or -CN; wherein R13 is a 5 to 7 membered heterocyclic ring; and each R14 is independently hydrogen, alkyl or aryl, the aryl being optionally substituted by -R9, -OR9, -CON(R9)2, -SOR9 -S02R9, -S02N(R9)2, -N(R9)2, NR9COR9, -C02R9, -COR9, -SR9, halo, -N02 or -CN; wherein R9 is as defined above; provided that when R1 , R3 and R4 are hydrogen and R2 is hydrogen, halogen or -O(C1-C6)alkyl, R8 is not unsubstituted phenyl or phenyl substituted by halo, C1-C6 alkyl, -O(C1-C6)alkyl, -S(C1-C6)alkyl or -CO(C1-C6)alkyl; or pharmaceutically acceptable salts, hydrates, solvates, compexes or prodrugs therof are useful in the treatment of allergic diseases such as asthma, allergic rhinitis and atopic dermatitis.

Description

COMPOUNDS WITH PGDZ ANTAGONIST ACTIVITY
The present invention relates to compounds which are useful as pharmaceuticals, to methods for preparing these compounds, compositions containing them and their use in the treatment and prevention of allergic diseases such as asthma, allergic rhinitis and atopic dermatitis and other inflammatory diseases mediated by prostaglandin D2 (PGD2) acting at the CRTH2 and/or the DP receptor on cells including eosinophils, basophils and Th2 lymphocytes.
PGD2 is an eicosanoid, a class of chemical mediator synthesised by cells in response to local tissue damage, normal stimuli or hormonal stimuli or via cellular activation pathways. Eicosanoids bind to specific cell surface receptors on a wide variety of tissues throughout the body and mediate various effects in these tissues. PGD2 is known to be produced by mast cells, macrophages and Th2 lymphocytes and has been detected in high concentrations in the airways of asthmatic patients challenged with antigen (Murray et al, (1986), N. Engl. I. Med. 315: 800-804). Instillation of PGD into airways can provoke many features of the asthmatic response including bronchoconstriction (Hardy et al, (1984) N. Engl. I. Med. 311: 209-213; Sampson et al, (1997) Thorax 52: 513-518) and eosinophil accumulation (Emery et al, (1989) J. Appl Physiol. 67: 959-962).
The potential of exogenously applied PGD2 to induce inflammatory responses has been confirmed by the use of transgenic mice overexpressing human PGD2 synthase which exhibit exaggerated eosinophilic lung inflammation and Th2 cytokine production in response to antigen (Fujitani et al, (2002) /. Immunol. 168: 443-449).
The first receptor specific for PGD2 to be discovered was the DP receptor which is linked to elevation of the intracellular levels of cAMP. However, PGD2 is thought to mediate much of its proinflammatory activity through interaction with a G protein- coupled receptor termed CRTH2 (chemoattractant receptor-homologous molecule expressed on Th2 cells) which is expressed by Th2 lymphocytes, eosinophils and basophils (Hirai et al, (2001) /. Exp. Med. 193: 255-261, and EP0851030 and EP-A- 1211513 and Bauer et al, EP-A-1170594). It seems clear that the effect of PGD2 on the activation of Th2 lymphocytes and eosinophils is mediated through CRTH2 since the selective CRTH2 agonists 13,14 dihydro-15-keto-PGD2 (DK-PGD2) and 15R- methyl-PGD2 can elicit this response and the effects of PGD are blocked by an anti- CRTH2 antibody (Hirai et al, 2001; Monneret et al, (2003) /. Pharmacol. Exp. Ther. 304: 349-355). In contrast, the selective DP agonist BW245C does not promote migration of Th2 lymphocytes or eosinophils (Hirai et al, 2001; Gervais et al, (2001) I. Allergy Clin. Immunol. 108: 982-988). Based on this evidence, antagonising PGD2 at the CRTH2 receptor is an attractive approach to treat the inflammatory component of Th2-dependent allergic diseases such as asthma, allergic rhinitis and atopic dermatitis.
EP-A-1170594 suggests that the method to which it relates can be used to identify compounds which are of use in the treatment of allergic asthma, atopic dermatitis, allergic rhinitis, autoimmune disease, reperfusion injury and a number of inflammatory conditions, all of which are mediated by the action of PGD at the CRTH2 receptor.
Compounds which bind to CRTH2 are taught in WO-A-03066046 and WO-A- 03066047. These compounds are not new but were first disclosed, along with similar compounds, in GB 1356834, GB 1407658 and GB 1460348, where they were said to have anti-inflammatory, analgesic and antipyretic activity. WO-A-03066046 and WO-A-03066047 teach that the compounds to which they relate are modulators of CRTH2 receptor activity and are therefore of use in the treatment or prevention of obstructive airway diseases such as asthma, chronic obstructive pulmonary disease (COPD) and a number of other diseases including various conditions of bones and joints, skin and eyes, GI tract, central and peripheral nervous system and other tissues as well as allograft rejection.
Indole derivatives are also disclosed in WO-A-9950268. These compounds have a carboxylic acid moiety attached to the indole nitrogen atom. These compounds are said to be of use in the treatment of complications arising from diabetes mellitus. PL 65781 and GB 1172320 also relate to indole derivatives which are similar in structure to indomethacin and, like indomethacin, are said to have anti-inflammatory and antipyretic activity. Thus, although this may not have been appreciated at the time when these documents were published, the compounds they describe are COX inhibitors, an activity which is quite different from that of the compounds of the present invention. Indeed, COX inhibitors are contraindicated in the treatment of many of the diseases and conditions, for example asthma and inflammatory bowel disease for which the compounds of the present invention are useful, although they may sometimes be used to treat arthritic conditions.
The present invention relates to compounds similar to those of PL 65781 and GB 1172320 which are antagonists of PGD2.
In a first aspect of the present invention there is provided a compound of general formula (I):
Figure imgf000005_0001
wherein
R1, R2, R3 and R4 are independently hydrogen, halo, -Cι-C6 alkyl, -O(Cι-C6 alkyl), -C C6 alkyl(C3-C7 cycloalkyl), -CON(R9)2, -SOR9, -SO2R9, -SO2N(R9)2, -N(R9)2, -NR9COR9, -CO2R9, COR9, -SR9, -OH, -NO2 or -CN; each R9 is independently hydrogen or -Cβ alkyl; R5 and R6 are each independently hydrogen, or d-C6 alkyl or together with the carbon atom to which they are attached form a C3-C7 cycloalkyl group;
R7 is hydrogen or C C6 alkyl;
R8 is Cι-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or an aromatic moiety, any of which may optionally be substituted with one or more substituents selected from halo,
-SOR13 -SO2R13, -R14, -OR14, -CON(R14)2, -SOR14, -SO2R14, -SO2N(R14)2, -N(R1 )2,
-NR14COR14, -COaR14, -COR14, -SR14, -NO2 or -CN; wherein R13 is a 5 to 7 membered heterocyclic ring; and each R14 is independently hydrogen, alkyl or aryl, the aryl being optionally substituted by -R9, -OR9, -CON(R9)2, -SOR9 -SO2R9, -SO2N(R9)2, -N(R9)2, - NR9COR9, -CO2R9, -COR9, -SR9, halo, -NO2 or -CN; wherein R9 is as defined above; provided that when R1, R3 and R are hydrogen and R2 is hydrogen, halogen or -O(C!-C6)alkyl, R is not unsubstituted phenyl or phenyl substituted by halo, Ci-Cβ alkyl, -O(C1-C6)alkyl, -S(Cι-C6)alkyl or -CO(Ci-C6)alkyl; or a pharmaceutically acceptable salt, hydrate, solvate, complex or prodrug thereof.
The compounds of general formula (I) are antagonists of PGD2. Some of the compounds of general formula (I) act at the CRTH2 receptor, others have dual activity at the CRTH2 and DP receptors and yet others act selectively at the DP receptor. The compounds will be useful in the treatment of conditions which are mediated by PGD2 binding to the CRTH2 and/or DP receptors. These include allergic diseases, asthmatic conditions and inflammatory diseases, examples of which are allergic asthma, perennial allergic rhinitis, seasonal allergic rhinitis, atopic dermatitis, contact hypersensitivity (including contact dermatitis), conjunctivitis, especially allergic conjunctivitis, eosinophilic bronchitis, food allergies, eosinophilic gastroenteritis, inflammatory bowel disease, ulcerative colitis and Crohn's disease, mastocytosis and also other PGD2-mediated diseases, for example autoimmune diseases such as hyper IgE syndrome and systemic lupus erythematus, psoriasis, acne, multiple sclerosis, allograft rejection, reperfusion injury and chronic obstructive pulmonary disease; as well as rheumatoid arthritis, psoriatic arthritis and osteoarthritis. One particular advantage of the compounds of general formula (I) is that, depending upon the condition to be treated, it is possible to select either a specific CRTH2 or DP antagonist or a dual CRTH2/DP antagonist.
In the present specification "Q-Q alkyl" refers to a straight or branched saturated hydrocarbon chain having one to six carbon atoms and optionally substituted with one or more halo substituents or with one or more C3-C cycloalkyl groups. Examples include methyl, ethyl, n-propyl, isopropyl, t-butyl, n-hexyl, trifluoromethyl, 2-chloroethyl, mefhylenecyclopropyl, methylenecyclobutyl, methylenecyclobutyl and methylenecyclopentyl.
"C1-C4 alkyl" and "Q-Qs alkyl" have similar meanings except that they contain from one to four and from one to eighteen carbon atoms respectively.
"C -C6 alkenyl" and "Cι-C6 alkynyl" refer to straight or branched carbon chains having from one to six carbon atoms and containing respectively a carbon-carbon double bond and a carbon-carbon triple bond. The groups are optionally substituted with one or more halo substituents or with one or more C3-C7 cycloalkyl groups. Examples include ethenyl, ethynyl, 2-propenyl and 2-propynyl.
C3-C7 cycloalkyl refers to a saturated 3 to 7 membered carbocyclic ring. Examples of such groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
In the present specification, "halo" refers to fluoro, chloro, bromo or iodo.
The terms "aromatic moiety" and "aryl" in the context of the present specification refer to an aromatic ring system having from 5 to 14 ring carbon atoms and containing up to three rings, one or more of which may be replaced by a nitrogen, oxygen or sulphur atom. Examples of aromatic moieties are benzene, pyridine, naphthalene, biphenyl, quinoline, isoquinoline, quinazoline, benzthiazole, benzoxazole, benzimidazole indole, indazole and imidazole ring systems. Appropriate pharmaceutically and veterinarily acceptable salts of the compounds of general formulae (I) and (II) include basic addition salts such as sodium, potassium, calcium, aluminium, zinc, magnesium and other metal salts as well as choline, diethanolamine, ethanolamine, ethyl diamine and other well known basic addition salts.
Where appropriate, pharmaceutically or veterinarily acceptable salts may also include salts of organic acids, especially carboxylic acids, including but not limited to acetate, trifluoroacetate, lactate, gluconate, citrate, tartrate, maleate, malate, pantothenate, adipate, alginate, aspartate, benzoate, butyrate, digluconate, cyclopentanate, glucoheptanate, glycerophosphate, oxalate, heptanoate, hexanoate, fumarate, nicotinate, pamoate, pectinate, 3-phenylpropionate, picrate, pivalate, proprionate, tartrate, lactobionate, pivolate, camphorate, undecanoate and succinate, organic sulphonic acids such as methanesulphonate, ethanesulphonate, 2- hydroxyethane sulphonate, camphorsulphonate, 2-naphthalenesulphonate, benzenesulphonate, p-chlorobenzenesulphonate and p-toluenesulphonate; and inorganic acids such as hydrochloride, hydrobromide, hydroiodide, sulphate, bisulphate, hemisulphate, thiocyanate, persulphate, phosphoric and sulphonic acids.
Salts which are not pharmaceutically or veterinarily acceptable may still be valuable as intermediates.
Prodrugs are any covalently bonded compounds which release the active parent drug according to general formula (I) in vivo. Examples of prodrugs include alkyl esters of the compounds of general formula (I), for example the esters of general formula (LI) below.
If a chiral centre or another form of isomeric centre is present in a compound of the present invention, all forms of such isomer or isomers, including enantiomers and diastereoisomers, are intended to be covered herein. Compounds of the invention containing a chiral centre may be used as a racemic mixture, an enantiomerically enriched mixture, or the racemic mixture may be separated using well-known techniques and an individual enantiomer may be used alone.
In the compounds of general formula (I), it is preferred that, independently or in any combination:
R1 is Cι-C4 alkyl, halo or hydrogen;
R2 is C1-C4 alkyl, CN, halo, hydrogen or -CON(R9)2, (where R9 is hydrogen or Cι-C4 alkyl);
R3 is Q-C4 alkyl, halo or hydrogen;
R4 is C1-C4 alkyl, halo or hydrogen.
In more preferred compounds, R1, R3 and R are hydrogen, while R2 is halo, particularly fluoro.
In preferred compounds of general formula (I), R5 and R6 are each independently hydrogen or C1-C4 alkyl. However, in more active compounds, at least one, and preferably both of R5 and R6 are hydrogen.
Compounds of general formula (I) preferably have an R7 group chosen from H or Q- C6 alkyl; most suitably R7 is methyl.
The compounds of general formula (I) have the additional advantage that the selectivity of the compound can be manipulated by making changes to the R8 substituent. For example, for some uses, a high selectivity at the CRTH2 receptor is advantageous and the inclusion of certain R8 substituents give rise to compounds in which binding selectivity at the CRTH2 receptor is more than 200 times greater than DP or TP binding. However, other compounds of general formula (I) bind selectively to the DP receptor and yet others bind strongly to both CRTH2 and DP receptors and this is preferable for some medical uses such as allergic rhinitis.
In more active compounds of the present invention R is an aromatic moiety having one or two rings and substituted with one or more substituents selected from halo, -C1-C4 alkyl, -O(C C4 alkyl), -SO2(Cι-C4 alkyl), -R14, -N(R14)2 and -OR14; where R14 (or one R14 if two are present) is preferably aryl, optionally substituted as described above.
Particularly preferred R8 groups include an aromatic moiety having one or two rings, and especially phenyl or pyridyl, substituted with -SO2 R14, -N(R14)2 or -OR14; where R14 (or one of the R14 groups if two are present) is preferably aryl, optionally substituted as described above.
Particularly preferred substituents for the R14 moiety are Q-C4 alkyl, -0(0^04 alkyl), -CN, -SO2NH2, -SO2(C1-C4 alkyl) or halo.
Among the most preferred compounds are the following: [5-Fluoro-2-methyl-l-(naphthalene-l-sulfonyl)-2H-indol-3-yl]-acetic acid
(Compound 3);
[5-Fluoro-2-methyl-l-(naphthalene-2-sulfonyl)-7H-indol-3-yl]-acetic acid
(Compound 4); [5-Fluoro-2-methyl-l-(4-trifluoromethyl-benzenesulfonyl)-iH-indol-3-yl]-acetic acid (Compound 6);
[l-(4-tert-Butyl-benzenesulfonyl)-5-fluoro-2-methyl-iH-indol-3-yl]-acetic acid
(Compound 7);
[l-(Biphenyl-4-sulfonyl)-5-fluoro-2-methyl-iH-indol-3-yl]-acetic acid (Compound 8);
[l-(l,2-Dimethyl-2H-imidazole-4-sulfonyl)-5-fluoro-2-methyl-iH-indol-3-yl]-acetic acid (Compound 9);
5-(3-Carboxymethyl-5-fluoro-2-methyl-indole-l-sulfonyl)-l-methyl-2H-pyrrole-2- carboxylic acid (Compound 10); [5-Fluoro-2-methyl-l-(4-phenoxy-benzenesulfonyl)-7H-indol-3-yl]-acetic acid
(Compound 13);
[5-Fluoro-2-methyl-l-(4-methanesulfonyl-benzenesulfonyl)-7H-indol-3yl]-acetic acid (Compound 14);
[l-(5-Chloro-naρhthalene-l-sulfonyl)-5-fluoro-2-methyl-2H-indol-3-yl]-acetic acid (Compound 17) [5-Fluoro-2-methyl-l-(4-nitro-benzenesulfonyl)-IH-indol-3-yl]-acetic acid
(Compound 18) [5-Fluoro-2-methyl- 1 -(3-trifluoromethyl-benzenesulfonyl)-2H-indol-3-yl] -acetic acid (Compound 19)
[5-Fluoro-2-methyl-l-(quinoline-8-sulfonyl)-iH-indol-3-yl]-acetic acid (Compound 21) [5-Fluoro-2-methyl-l-(toluene-4-sulfonyl)-7H-indol-3-yl]-acetic acid (Compound 22)
[l-(2-Cyano-benzenesulfonyl)-5-fluoro-2-methyl-7H-indol-3-yl]-acetic acid
(Compound 26) [5-Fluoro-l-(2-fluoro-benzenesulfonyl)-2-methyl-7H-indol-3-yl]-acetic acid
(Compound 27)
[l-(5-Chloro-naphthalene-2-sulfonyl)-5-fluoro-2-methyl-7H-indol-3-yl]-acetic acid (Compound 32)
[5-Fluoro-2-methyl-l-(4-pyrazol-l-yl-benzenesulfonyl)-iH-indol-3-yl]-acetic acid (Compound 34) [ 1 -(2,2-Dimethyl-chroman-6-sulfonyl)-5-fluoro-2-methyl-2H-indol-3-yl] -acetic acid (Compound 35) [5-Fluoro-2-methyl-l-(4-methyl-naphthalene-l-sulfonyl)-iH-indol-3-yl]-acetic acid (Compound 36) [l-(5-Chloro-3-methyl-benzo[b]thiophene-2-sulfonyl)-5-fluoro-2-methyl-iH-indol- 3 -yl] -acetic acid (Compound 37)
{5-Fluoro-2-methyl-l-[4-(morpholine-4-sulfonyl)-benzenesulfonyl]-2H-indol-3-yl}- acetic acid (Compound 38) (l-Ethanesulfonyl-5-fluoro-2-methyl-2H-indol-3-yl)-acetic acid (Compound 39) trans [5-Fluoro-l-(/3-styrenesulfony)-2-methyl-2H-indol-3-yl]-acetic acid
(Compound 40) [l-(Butane-l-sulfonyl)-5-fluoro-2-methyl-2H-indol-3-yl]-acetic acid (Compound 41) [l-(Benzo[l,2,5]thiadiazole-4-sulfonyl)-5-fluoro-2-methyl-2H-indol-3-yl]-acetic acid (Compound 42) [l-(2-Chloro-4-trifluoromethyl-benzenesulfonyl)-5-fluoro-2-methyl-2H-indol-3-yl]- acetic acid (Compound 43)
[5-Fluoro-2-methyl-l-(pyridine-3-sulfonyl)-iH-indol-3-yl]-acetic acid (Compound 44)
[5-Fluoro-2-methyl-l-(3-nitro-benzenesulfonyl)-2H-indol-3-yl]-acetic acid
(Compound 45)
(5-Fluoro-2-methyl-l-phenylmethanesulfonyl-2H-indol-3-yl)-acetic acid (Compound 46)
[l-(3-Cyano-benzenesulfonyl)-5-fluoro-2-methyl-2H-indol-3-yl]-acetic acid
(Compound 48)
[l-(4-Cyano-benzenesulfonyl)-5-fluoro-2-methyl-2H-indol-3-yl]-acetic acid
(Compound 49)
[l-(2-Acetyl-l,2,3,4-tetrahydro-isoquinoline-6-sulfonyl)-5-fluoro-2-methyl-7H- indol-3-yl]-acetic acid (Compound 51)
[5-Ηuoro-2-methyl-l-(5-pyridin-2-yl-thiophene-2-sulfonyl)-2H-indol-3-yl]-acetic acid (Compound 52) [l-(5-Chloro-l,3-dimethyl-7H-pyrazole-4-sulfonyl)-5-fluoro-2-methyl-iH-indol-3- yl]-acetic acid (Compound 53) [5-Fluoro-2-methyl-l-(4-trifluoromethoxy-benzenesulfonyl)-2H-indol-3-yl]-acetic acid (Compound 54) [5-Fluoro-l-(isoquinoline-5-sulfonyl)-2-methyl-iH-indol-3-yl]-acetic acid
(Compound 55)
[5-Fluoro-l-(2-hydroxy-2Η-chromene-6-sulfonyl)-2-methyl-2H-indol-3-yl]-acetic acid (Compound 58)
{5-Fluoro-l-[4-(4-fluoro-phenoxy)-benzenesulfonyl]-2-methyl-2H-indol-3-yl}-acetic acid (Compound 59)
{ l-[4-(4-Chloro-phenoxy)-benzenesulfonyl]-5-fluoro-2-methyl-2H-indol-3-yl}- acetic acid (Compound 60)
({5-Fluoro-2-methyl-l-[4-(4-trifluoromethyl-phenoxy)-benzenesulfonyl]-7H-indol- 3-yl}-acetic acid (Compound 61)
{l-[4-(4-Bromo-phenoxy)-benzenesulfonyl]-5-fluoro-2-methyl-2H-indol-3-yl}- acetic acid (Compound 62) {5-Fluoro-l-[4-(4-methoxy-phenoxy)-benzenesulfonyl]-2-methyl-2H-indol-3-yl}- acetic acid (Compound 63) [l-(3,4-Dihydro-2H-benzo[b][l,4]dioxepine-7-sulfonyl)-5-fluoro-2-methyl-iH- indol-3-yl]-acetic acid (Compound 64) [5 -Fluoro-2-methyl- 1 -(4-oxazol-5-yl-benzenesulfonyl)-i H-indol-3 -yl] -acetic acid (Compound 65) [5-Fluoro-2-methyl-l-(4-p-tolyloxy-benzenesulfonyl)-2H-indol-3-yl]-acetic acid (Compound 66) [5-Fluoro-2-methyl-l-(4-m-tolyloxy-benzenesulfonyl)-iH-indol-3-yl]-acetic acid (Compound 67)
{ l-[4-(3-Chloro-phenoxy)-benzenesulfonyl]-5-fluoro-2-methyl-2H-indol-3-yl}- acetic acid (Compound 68)
{ l-[4-(2,4-Dichloro-phenoxy)-benzenesulfonyl]-5-fluoro-2-methyl-2H-indol-3-yl}- acetic acid (Compound 69)
{ l-[4-(2-Chloro-phenoxy)-benzenesulfonyl]-5-fluoro-2-methyl-2H-indol-3-yl}- acetic acid (Compound 70)
{5-Fluoro-l-[4-(2-methoxy-phenoxy)-benzenesulfonyl]-2-methyl-7H-indol-3-yl}- acetic acid (Compound 71)
{ l-[4-(2,5-Dichloro-phenoxy)-benzenesulfonyl]-5-fluoro-2-methyl-iH-indol-3-yl}- acetic acid (Compound 72) [5-Fluoro-2,4-dimethyl-l-(naphthalene-2-sulfonyl)-2H-indol-3-yl]-acetic acid
(Compound 73) [5-Fluoro-l-(4-methanesulfonyl-benzenesulfonyl)-2,4-dimethyl-7H-indol-3-yl]- acetic acid (Compound 74) [5-Fluoro-2,4-dimethyl-l-(4-phenoxy-benzenesulfonyl)-iH-indol-3-yl]-acetic acid (Compound 75)
{ 5-Fluoro-2-methyl- 1 -[4-(pyrrolidine- 1 -sulf onyl)-benzenesulfonyl] -2H-indol-3-yl } - acetic acid (Compound 76)
[5-Fluoro-l-(4-hydroxy-benzenesulfonyl)-2-methyl-2H-indol-3-yl]-acetic acid
(Compound 77)
[l-(3-Cyano-4-hydroxy-benzenesulfonyl)-5-fluoro-2-methyl-2H-indol-3-yl]-acetic acid (Compound 78) [l-(3-carboxamido-benzenesulfonyl)-5-fluoro-2-methyl-iH-indol-3-yl]-acetic acid (Compound 79)
[l-(4-carboxamido-benzenesulfonyl)-5-fluoro-2-methyl-2H-indol-3-yl]-acetic acid (Compound 80)
[5-Fluoro-2-methyl-l-(3-phenoxy-benzenesulfonyl)-2H-indol-3-yl]-acetic acid
(Compound 81) [5-Fluoro-2-methyl-l-(4-methylsulfanyl-benzenesulfonyl)-2H-indol-3-yl]-acetic acid (Compound 82)
[5-Fluoro-2-methyl-l-(3-methyl-quinoline-8-sulfonyl)-iH-indol-3-yl]-acetic acid (Compound 83)
[5-Fluoro-2-methyl-l-(3-sulfonamido-benzenesulfonyl)-2H-indol-3-yl]-acetic acid (Compound 84)
[5-Cyano-l-(4-methanesulfonyl-benzenesulfonyl)-2-methyl-2H-indol-3-yl]-acetic acid (Compound 85)
[l-(4-Chloro-benzenesulfonyl)-5-cyano-2-methyl-iH-indol-3-yl]-acetic acid
(Compound 86)
[5-Cyano-2-methyl-l-(4-phenoxy-benzenesulfonyl)-iH-indol-3-yl]-acetic acid
(Compound 87)
{5-Fluoro-2-methyl-l-[4-(3-trifluoromethyl-phenoxy)-benzenesulfonyl]-2H-indol-3- yl} -acetic acid (Compound 88)
[5-carboxamido-l-(4-methanesulfonyl-benzenesulfonyl)-2-methyl-2H-indol-3-yl]- acetic acid (Compound 89)
[5-carboxamido-l-(4-chloro-benzenesulfonyl)-2-methyl-iH-indol-3-yl]-acetic acid (Compound 90)
[5-carboxamido-2-methyl-l-(4-phenoxy-benzenesulfonyl)-iH-indol-3-yl]-acetic acid (Compound 91)
[5-Fluoro-2-methyl-l-(3-N-methylsulfonamido-benzenesulfonyl)-iH-indol-3-yl]- acetic acid (Compound 92)
{5-Fluoro-2-methyl-l-[3-(pyrrolidine-l-sulfonyl)-benzenesulfonyl]-iH-indol-3-yl}- acetic acid (Compound 94)
[5-Fluoro-2-methyl-l-(3-N-methylcarboxamido-benzenesulfonyl)-7H-indol-3-yl]- acetic acid (Compound 95) [5-Fluoro-2-methyl-l-(4-N-methylcarboxamido-benzenesulfonyl)-iH-indol-3-yl]- acetic acid (Compound 96)
[5-Fluoro-2-methyl-l-(6-phenoxy-pyridine-3-sulfonyl)-2H-indol-3-yl]-acetic acid (Compound 97)
[l-(3-N,N-Dimethylsulfonamido-benzenesulfonyl)-5-fluoro-2-methyl-lH-indol-3- yl]-acetic acid (Compound 98)
[5-Fluoro-l-(3-methanesulfonyl-benzenesulfonyl)-2-methyl-lH-indol-3-yl]-acetic acid (Compound 99)
[l-(4-N,N-Dimethylcarboxamido-benzenesulfonyl)-5-fluoro-2-methyl-lH-indol-3- yl]-acetic acid (Compound 100)
[l-(3-N,N-dimethylcarboxamido-benzenesulfonyl)-5-fluoro-2-methyl-2H-indol-3- yl] -acetic acid (Compound 101)
[5-Fluoro-2-methyl-l-(4-methyl-3,4-dihydro-2H-benzo[l,4]oxazine-7-sulfonyl)-lH- indol-3-yl]-acetic acid (Compound 102)
[l-(5-Dimethylamino-naphthalene-l-sulfonyl)-5-fluoro-2-methyl-2H-indol-3-yl]- acetic acid (Compound 103)
{5-Fluoro-2-methyl-l-[4-(trifluoromethylsulfanyl-benzenesulfonyl]-lH-indol-3- yl} -acetic acid (Compound 104)
{5-Fluoro-2-methyl-l-[3-(trifluoromethylsulfonyl-benzenesulfonyl]-lH-indol-3- yl} -acetic acid (Compound 105)
{5-Fluoro-2-methyl-l-[4-(pyridin-2-yloxy)-benzenesulfonyl]-lH-indol-3-yl}-acetic acid (Compound 106)
{5-Fluoro-2-methyl-l-[4-(pyridin-3-yloxy)-benzenesulfonyl]-lH-indol-3-yl}-acetic acid (Compound 107)
{5-Fluoro-2-methyl-l-[4-(pyridin-4-yloxy)-benzenesulfonyl]-lH-indol-3-yl}-acetic acid (Compound 108) [5-Fluoro-2-methyl-l-(4-phenylamino-benzenesulfonyl)-7H-indol-3-yl]-acetic acid (Compound 109)
[5-Fluoro-2-methyl-l-(4-m-tolylamino-benzenesulfonyl)-lH-indol-3-yl]-acetic acid (Compound 110)
{5-Fluoro-2-methyl-l-[4-(pyridin-4-ylarnino)-benzenesulfonyl]-lH-indol-3-yl}- acetic acid (Compound 111)
{ 5-Fluoro-2-methyl- 1 - [4-(pyridin-2-ylamino)-benzenesulf onyl] - lH-indol-3 -yl } - acetic acid (Compound 112)
{ 5-Fluoro-2-methyl- 1 - [4-(pyrimidin-4-ylamino)-benzenesulf onyl] - lH-indol-3 -yl } - acetic acid (Compound 113)
{5-Fluoro-2-methyl-l-[4-(5-methyl-isoxazol-3-ylamino)-benzenesulfonyl]-lH-indol-
3-yl}-acetic acid (Compound 114)
{5-Fluoro-2-methyl-l-[4-(pyridin-3-ylamino)-benzenesulfonyl]-lH-indol-3-yl}- acetic acid (Compound 115)
{5-Fluoro-2-methyl-l-[4-(4-methyl-pyridin-2-ylamino)-benzenesulfonyl]-lH-indol-
3 -yl} -acetic acid (Compound 116)
{5-Fluoro-2-methyl-l-[4-(6-methyl-pyridin-2-ylamino)-benzenesulfonyl]-lH-indol-
3-yl}-acetic acid (Compound 117)
{5-Fluoro-2-methyl-l-[4-(4-methyl-pyrimidin-2-ylamino)-benzenesulfonyl]-lH- indol-3-yl}-acetic acid (Compound 118)
{ 5-Fluoro-2-methyl- 1 - [4-(pyrimidin-2-ylamino)-benzenesulf onyl] - lH-indol-3 -yl } - acetic acid (Compound 119)
{ 1 -[4-(3 -Chloro-phenylamino)-benzenesulf onyl] -5-fluoro-2-methyl- 1 H-indol-3 -yl } - acetic acid (Compound 120)
{ l-[4-(2,6-Dimethyl-pyrimidin-4-ylamino)-benzenesulfonyl]-5-fluoro-2-methyl-iH- indol-3-yl}-acetic acid (Compound 121)
{ 5-Fluoro- l-[4-(isoxazol-3-ylamino)-benzenesulfonyl]-2-methyl- lH-indol-3-yl } - acetic acid (Compound 122)
{ l-[4-(4,6-Dimethyl-pyrimidin-2-ylamino)-benzenesulfonyl]-5-fluoro-2-methyl-lH- indol-3-yl} -acetic acid (Compound 123)
{5-Fluoro-2-methyl-l-[4-(5-methyl-pyridin-3-ylamino)-benzenesulfonyl]-iH-indol-
3-yl}-acetic acid (Compound 124)
{5-Fluoro-2-methyl-l-[4-(thiazol-2-ylamino)-benzenesulfonyl]-2H-indol-3-yl}- acetic acid (Compound 125)
{ l-[4-(3,5-Dimethyl-phenylamino)-benzenesulfonyl]-5-fluoro-2-methyl-iH-indol-3- yl} -acetic acid (Compound 126)
{5-Fluoro-2-methyl-l-[4-(4-sulfonamido-phenylamino)-benzenesulfonyl]-iH-indol-
3 -yl} -acetic acid (Compound 127) { l-[4-(3,5-Dichloro-phenylamino)-benzenesulfonyl]-5-fluoro-2-methyl-iH-indol-3- yl}-acetic acid (Compound 128)
{ l-[4-(5-Chloro-pyridin-3-ylamino)-benzenesulfonyl]-5-fluoro-2-methyl-iH-indol- 3-yl} -acetic acid (Compound 129)
{l-[2,5-Difluoro-4-(pyridin-2-ylamino)-benzenesulfonyl]-5-fluoro-2-methyl-7H- indol-3-yl}-acetic acid (Compound 130)
{ l-[2,5-Difluoro-4-(pyridin-2-ylamino)-benzenesulfonyl]-5-fluoro-2-methyl-iH- indol-3-yl} -acetic acid (Compound 131)
{ l-[2,5-Difluoro-4-(5-methyl-isoxazol-3-ylamino)-benzenesulfonyl]-5-fluoro-2- methyl-lH-indol-3-yl}-acetic acid (Compound 132)
{ 5-Fluoro- 1 - [4-(3 -methoxy-phenylamino)-benzenesulf onyl] -2-methyl-iH-indol-3 - yl}-acetic acid (Compound 133)
{ l-[4-(3-Cyano-phenylamino)-benzenesulfonyl]-5-fluoro-2-methyl-2H-indol-3-yl}- acetic acid (Compound 134)
{ l-[4-(3-Ethyl-phenylamino)-benzenesulfonyl]-5-fluoro-2-methyl-2H-indol-3-yl}- acetic acid (Compound 135)
{ 5-Fluoro-2-methyl-l-[6-(pyridin-2-ylamino)-pyridine-3-sulfonyl]- lH-indol-3-yl } - acetic acid (Compound 136)
{5-Fluoro-2-methyl-l-[6-(pyridin-3-ylamino)-pyridine-3-sulfonyl]-lH-indol-3-yl}- acetic acid (Compound 137)
{5-Fluoro-2-methyl-l-[6-(pyrimidin-4-ylamino)-pyridine-3-sulfonyl]-lH-indol-3- yl}-acetic acid (Compound 138) [5-Fluoro-2-methyl-l-(6-phenylamino-pyridine-3-sulfonyl)-lH-indol-3-yl]-acetic acid (Compound 139)
{ l-[6-(3,5-Dimethyl-phenylamino)-pyridine-3-sulfonyl]-5-fluoro-2-methyl-lH- indol-3-yl} -acetic acid (Compound 140)
{5-Fluoro-2-methyl-l-[6-(pyrimidin-2-ylamino)-pyridine-3-sulfonyl]-lH-indol-3- yl} -acetic acid (Compound 141)
{5-Fluoro-2-methyl-l-[6-(6-methyl-pyridin-2-ylamino)-pyridine-3-sulfonyl]-lH- indol-3-yl} -acetic acid (Compound 142)
{5-Fluoro-2-methyl-l-[6-(4-methyl-pyrimidin-2-ylamino)-pyridine-3-sulfonyl]-lH- indol-3-yl} -acetic acid (Compound 143) { l-[6-(4,6-Dimethyl-pyrimidin-2-ylamino)-pyridine-3-sulfonyl]-5-fluoro-2-methyl- lH-indol-3-yl}-acetic acid (Compound 144)
{ l-[6-(3-Chloro-phenylamino)-pyridine-3-sulfonyl]-5-fluoro-2-methyl-lH-indol-3- yl} -acetic acid (Compound 145) [5-Fluoro-2-methyl-l-(6- -tolylamino-pyridine-3-sulfonyl)-lH-mdol-3-yl]-acetic acid (Compound 146)
{l-[6-(2,6-Dimethyl-pyrimidin-4-ylamino)-pyridine-3-sulfonyl]-5-fluoro-2-methyl- lH-indol-3-yl}-acetic acid (Compound 147)
{5-Fluoro-2-methyl-l-[6-(pyridin-4-ylamino)-pyridine-3-sulfonyl]-lH-indol-3-yl}- acetic acid (Compound 148)
{5-Fluoro-2-methyl-l-[6-(5-methyl-isoxazol-3-ylamino)-pyridine-3-sulfonyl]-lH- indol-3-yl}-acetic acid (Compound 149)
{ 5-Fluoro-2-methyl- 1 -[6-(thiazol-2-ylamino)-pyridine-3-sulf onyl] - lH-indol-3-yl } - acetic acid (Compound 150)
{ l-[6-(3,5-Dichloro-phenylamino)-pyridine-3-sulfonyl]-5-fluoro-2-methyl-iH-indol- 3 -yl} -acetic acid (Compound 151)
{5-Fluoro-2-methyl-l-[6-(5-methyl-pyridin-3-ylamino)-pyridine-3-sulfonyl]-2H- indol-3-yl} -acetic acid (Compound 152)
{ l-[6-(5-Chloro-pyridin-3-ylamino)-pyridine-3-sulfonyl]-5-fluoro-2-methyl-iH- indol-3-yl} -acetic acid (Compound 153)
{5-Fluoro-2-methyl-l-[4-(methyl-phenyl-amino)-benzenesulfonyl]-lH-indol-3-yl}- acetic acid (Compound 154)
{5-Fluoro-2-methyl-l-[4-(methyl-m-tolyl-amino)-benzenesulfonyl]-lH-indol-3-yl}- acetic acid (Compound 155) (5-Fluoro-2-methyl-l-{4-[methyl-5-methyl-isoxazol-3-yl)-amino]-benzene- sulfonyl}-lH-indol-3-yl)-acetic acid (Compound 156) (5-Fluoro-2-methyl- 1 - { 4- [methyl-(4-methyl-pyridin-2-yl)-amino] -benzene sulfonyl}-lH-indol-3-yl)-acetic acid (Compound 157) (5-Fluoro-2-methyl-l-{6-[methyl-(6-methyl-pyridin-2-yl)-amino]-pyridine-3- sulfonyl}-lH-indol-3-yl)-acetic acid (Compound 158) {5-Fluoro-2-methyl-l-[4-(methyl-pyrimidin-2-yl-amino)-benzenesulfonyl]-lH-indol- 3-yl}-acetic acid (Compound 159) {5-Fluoro-2-methyl-l-[4-(methyl-pyridin-2-yl-amino)-benzenesulfonyl]-lH-indol-3- yl} -acetic acid (Compound 160)
{5-Fluoro-2-methyl-l-[6-(methyl-pyridin-2-yl-amino)-pyridine-3-sulfonyl]-lH- indol-3-yl}-acetic acid (Compound 161)
{5-Fluoro-2-methyl-l-[6-(methyl-pyridin-4-yl-amino)-pyridine-3-sulfonyl]-iH- indol-3-yl} -acetic acid (Compound 162)
(5-Fluoro-2-methyl- 1- { 4-[methyl-(6-methyl-pyridin-2-yl)-amino] -benzenesulfonyl } - 2H-indol-3-yl)-acetic acid (Compound 163)
(l-{4-[(2,6-Dimethyl-pyrimidin-4-yl)-methyl-amino]-benzenesulfonyl}-5-fluoro-2- methyl-iH-indol-3-yl)-acetic acid (Compound 164)
{5-Fluoro-2-methyl-l-[6-(methyl-phenyl-amino)-pyridine-3-sulfonyl]-2H-indol-3- yl} -acetic acid (Compound 165)
(l-{6-[(3-Chloro-phenyl)-methyl-amino]-pyridine-3-sulfonyl}-5-fluoro-2-methyl- 2H-indol-3-yl)-acetic acid (Compound 166)
(l-{4-[(3-Chloro-phenyl)-methyl-amino]-benzenesulfonyl}-5-fluoro-2-methyl-iH- indol-3-yl)-acetic acid (Compound 167)
{ l-[4-(Ethyl-m-tolyl-amino)-benzenesulfonyl]-5-fluoro-2-methyl-iH-indol-3-yl}- acetic acid (Compound 168)
{5-Fluoro-2-methyl-l-[4-(methyl-pyridin-3-yl-amino)-benzenesulfonyl]-iH-indol-3- yl} -acetic acid (Compound 169)
[5-Fluoro-2-methyl-l-(4-phenylsulfanyl-benzenesulfonyl)-lH-indol-3-yl]-acetic acid (Compound 171) [l-(4-Benzenesulfinyl-benzenesulfonyl)-5-fluoro-2-methyl-2H-indol-3-yl]-acetic acid (Compound 172) [l-(4-Benzenesulfonyl-benzenesulfonyl)-5-fluoro-2-methyl-iH-indol-3-yl]-acetic acid (Compound 173) [5-Chloro-l-(4-chloro-benzenesulfonyl)-2-methyl-2H-indol-3-yl]-acetic acid
(Compound 174) {5-Fluoro-l-[4-(3-isopropyl-phenylamino)-benzenesulfonyl]-2-methyl-iH-indol-3- yl}-acetic acid (Compound 175) {5-Fluoro-2-methyl-l-[4-(methyl-thiazol-2-yl-amino)-benzenesulfonyl]-2H-indol-3- yl} -acetic acid (Compound 176) { l-[2,5-Difluoro-4-(isoxazol-3-ylamino)-benzenesulfonyl]-5-fluoro-2-methyl-iH- indol-3-yl} -acetic acid (Compound 177)
{ l-[4-(5-Chloro-pyridin-3-ylamino)-2,5-difluoro-benzenesulfonyl]-5-fluoro-2- methyl-iH-indol-3-yl} -acetic acid (Compound 178)
{l-[2,5-Difluoro-4-(5-methyl-pyridin-3-ylamino)-benzenesulfonyl]-5-fluoro-2- methyl-2H-indol-3-yl}-acetic acid (Compound 179)
{ l-[6-(3-Ethyl-phenylamino)-pyridine-3-sulfonyl]-5-fluoro-2-methyl-2H-indol-3- yl} -acetic acid (Compound 180)
{5-Fluoro-l-[6-(3-methoxy-phenylamino)-pyridine-3-sulfonyl]-2-methyl-2H-indol-
3-yl}-acetic acid (Compound 181)
{ l-[6-(3-Cyano-phenylamino)-pyridine-3-sulfonyl]-5-fluoro-2-methyl-iH-indol-3- yl} -acetic acid (Compound 182)
{5-Fluoro-l-[6-(3-methanesulfonyl-phenylamino)-pyridine-3-sulfonyl]-2-methyl-
7 H-indol-3 -yl} -acetic acid (Compound 183)
{ 5 -Fluoro- 1 - [4-(isoxazol-3 -yl-methyl-amino)-benzenesulf onyl] -2-methyl-iH-indol-
3-yl}-acetic acid (Compound 184)
(5-Fluoro-2-methyl-l-{4-[methyl-(5-methyl-pyridin-3-yl)-amino]-benzenesulfonyl}- iH-indol-3-yl)-acetic acid (Compound 185)
( 1 - { 4- [(3 ,5-Dimethyl-phenyl)-methyl-amino] -benzenesulfonyl } -5-fluoro-2-methyl- iH-indol-3-yl)- acetic acid (Compound 186)
(5-Fluoro- 1- { 4-[(3-methoxy-phenyl)-methyl-amino]-benzenesulfonyl } -2-methyl-iH- indol-3-yl)-acetic acid (Compound 187)
( 1 - { 4-[(3-Cyano-phenyl)-methyl-amino]-benzenesulf onyl } -5-fluoro-2-methyl-2H- indol-3-yl)-acetic acid (Compound 188)
(l-{4-[(3-Ethyl-phenyl)-methyl-amino]-benzenesulfonyl}-5-fluoro-2-methyl-2H- indol-3-yl)-acetic acid (Compound 189)
(5-Fluoro-l-{4-[(3-isopropyl-phenyl)-methyl-amino]-benzenesulfonyl}-2-methyl- iH-indol-3-yl)-acetic acid (Compound 190)
(l-{6-[(3-Ethyl-phenyl)-methyl-amino]-pyridine-3-sulfonyl}-5-fluoro-2-methyl-2H- indol-3-yl)-acetic acid (Compound 191)
(5-Fluoro- 1 - { 6- [(3 -methanesulf onyl-phenyl)-methyl-amino] -pyridine-3 -sulf onyl } -2- methyl-iH-indol-3-yl)-acetic acid (Compound 192)
( 1 - { 6- [(3-Cyano-phenyl)-methyl- amino] -pyridine-3 -sulf onyl } -5-fluoro-2-methyl- 2H-indol-3-yl)-acetic acid (Compound 193)
(5-Fluoro-2-methyl-l-{6-[methyl-(5-methyl-pyridin-3-yl)-amino]-pyridine-3- sulfonyl}-iH-indol-3-yl)-acetic acid (Compound 194) or the Ci-Cβ alkyl, aryl, (CΗ2)mOC(=O)C1-C6alkyl, (CH2)mN( i l1h1)2,
CH((CH2)mO(C=O)R12)2 esters of any of the above; wherein m is 1 or 2; R11 is hydrogen or methyl; R12 is Ci-Ciβ alkyl.
In a further aspect of the present invention, there is provided a compound of general formula (II)
Figure imgf000021_0001
π
wherein R ,ι1, R\ R\ R4, RD , R°, R' and RB are as defined for general formula (I); and
R ,ιιoυ is Ci-Cβ alkyl, aryl, (CH2)mOC(=O)C1-C6alkyl, (CH2)mN(R 1λ1lN)2, , 12s
CH((CH2)mO(C=O)Rl )2; m is 1 or 2; R11 is hydrogen or methyl; R12 is Ci-Ciβ alkyl; provided that when R1, R3 and R4 are hydrogen and R2 is hydrogen, halogen or - O(Cϊ-C6)alkyl, R8 is not unsubstituted phenyl or phenyl substituted by halo, Q-CO alkyl, -O(Cι-C6)alkyl, -S(C1-C6)alkyl or -CO(d-C6)alkyl.
Compounds of general formula (II) are novel and may be used as prodrugs for compounds of general formula (I). When the compound of general formula (TT) acts as a prodrug, it is later transformed to the drug by the action of an esterase in the blood or in a tissue of the patient.
Examples of particularly suitable R10 groups when the compound of general formula (II) is used as a prodrug include: methyl, ethyl, propyl, phenyl, CH2OC(=O)tBu, CH2CH2N(Me)2 CH2CH2NH2 or CH(CH2O(C=O)R12)2 wherein R12 is as defined above.
Other preferred substituents are as detailed for general formula (I) above.
In addition to their use as prodrugs, compounds of formula (II) wherein R10 is d-C6 alkyl may be used in a process for the preparation of a compound of general formula (I), the process comprising reacting the compound of general formula (LI) with a base such as sodium hydroxide or lithium hydroxide. The reaction may take place in an aqueous solvent or an organic solvent or a mixture of the two. A typical solvent used for the reaction is a mixture of tetrahydrofuran and water.
Compounds of general formula (II) may be prepared from compounds of general formula (HI):
Figure imgf000022_0001
m
wherein R1, R2, R3, R4 R5, R6 and R7 are as defined for general formula (I) and R10 is as defined for general formula (II); by reaction with a compound of general formula (IV): X-SO2-R8 (TV)
wherein R8 is as defined for general formula (I) and X is a leaving group in particular a halo group, for example chloro.
The reaction is conducted under strongly basic conditions, for example in the presence of a metal alkoxide, in particular a potassium or sodium alkoxide such as potassium tert-butoxide. The reaction may be carried out in a polar organic solvent such as tetrahydrofuran and the alkoxide may be solubilised using a polyether, particularly a crown ether. If a potassium alkoxide is used, 18-crown-6 is a particularly suitable solvating agent as it complexes very effectively with potassium ions.
Many compounds of general formulae (III) and (IV) are well known and are readily available or can be prepared by methods known to those skilled in the art.
Compounds of general formula (IV) in which R is a trifluoromethanesulfonyl- substituted aryl group (for example trifluoromethylsulfonylbenzene) may be carried out by the reaction of a trifluoromethanesulfonyl-substituted aromatic compound with chlorosulfonic acid. The reaction may be conducted at elevated temperature, for example 50 to 150°C.
The trifluoromethanesulfonyl-substituted aromatic compound may be prepared by oxidising the corresponding sulfide, for example using ruthenium trioxide and sodium periodate. Trifluoromethylsulfonylbenzene may be prepared in this way from phenyltrifluoromethylsulfide.
For compounds in which R8 is aryl substituted with aryloxy (for example pyridyloxy), the precursor sulfonyl chloride derivative of general formula (IV) may be prepared by reacting the corresponding pyridyloxyaryl compound with chlorosulfonic acid. The reaction is preferably carried out in a chlorinated organic solvent at a low temperature, for example from -5 to 30°C. Examples of intermediates of general formula (IV) which can be prepared in this way include: 4-(pyridine-2-yloxy) benzene sulf onyl chloride; 4-(pyridine-3-yloxy) benzene sulfonyl chloride; and 4-(pyridine-4-yloxy) benzene sulfonyl chloride.
The most suitable method for the preparation of the aryloxy aryl group depends upon the required substitution pattern on the aryloxy group. Some of these compounds can be prepared by the reaction of the corresponding halopyridine with a hydroxyaryl group in the presence of a strong base such as sodium hydride. The reaction is carried out under an inert atmosphere, for example nitrogen in an aprotic organic solvent such as dioxane. This method is appropriate for the preparation of 2- phenyoxypyridine from phenol and 2-fluoropyridine.
Alternatively, a hydroxyaryl compound, such as a pyridinol, can be treated with a base such as sodium or potassium hydroxide and a halo-substituted aromatic compound in a copper catalysed reaction.
This method is suitable for the preparation of compounds such as 3-phenoxypyridine and 4-phenoxypyridine.
Alternatively, compounds of general formula (II) in which R8 is chloro-, bromo- or iodo-substituted aryl may be converted to other compounds of general formula (II) in which R is arylaminoaryl by reaction with an aryl amino compound in a palladium (0) mediated cross-coupling reaction. This reaction may be used to convert o compound in which R is haloaryl (for example bromophenyl or bromopyridyl) to compounds in which R is arylaminoaryl (such as arylaminophenyl or arylaminopyridyl, for example Compounds 109-153).
Compounds of general formula (LI) in which R8 is aryl aminoaryl can be converted into compounds of general formula (LI) in which R8 is aryl-N-alkylaminoaryl by reaction with an alkyl iodide in the presence of a strong base. For example, Compounds 154 to 169 were prepared in this way. Compounds of general formula (LI) in which R8 is aryl-sulfinyl-aryl or aryl-sulfonyl- aryl may be prepared from compounds of general formula (LI) in which R8 is aryl- sulfanyl-aryl by oxidation using an appropriate oxidising agent to give either partial or complete oxidation as appropriate. A suitable oxidising agent for the aryl sulfinyl compounds is mCPBA and a suitable oxidising agent for the aryl-sulfonyl compounds is Oxone™. The precursor sulfonyl chloride derivative of general formula (TV) may be prepared by reacting the corresponding diaryl sulfide compound with chlorosulfonic acid under standard conditions.
Compounds of general formula (I) are antagonists of PGD2 at the CRTH2 and/or DP receptors and compounds of general formula (II) are prodrugs for compounds of general formula (I). Compounds of general formulae (I) and (LI) are therefore useful in a method for the treatment of diseases and conditions mediated by PGD2 at the CRTH2 and/or DP receptors, the method comprising administering to a patient in need of such treatment a suitable amount of a compound of general formula (I) or
(π).
In a third aspect of the invention, there is provided a compound of general formula (I) or (II) for use in medicine, particularly for use in the treatment or prevention of diseases and conditions mediated by PGD2 at the CRTH2 and/or DP receptor. Examples of such diseases and conditions are listed above.
Furthermore, there is also provided the use of a compound of general formula (I) or general formula (IL):
Figure imgf000025_0001
(I) (LI)
wherein
R1, R2, R3 and R4 are independently hydrogen, halo, -Cι-C6 alkyl, -O(d-C6 alkyl), -d-C6 alkyl(C3-C7 cycloalkyl), -CON(R9)2, -SOR9, -SO2R9, -SO2N(R9)2, -N(R )2, -NR9COR9, -CO2R9, COR9, -SR9, -OH, -NO2 or -CN; each R9 is independently hydrogen or d-C6 alkyl; R5 and R6 are each independently hydrogen, or d-C6 alkyl or together with the carbon atom to which they are attached form a C3-C7 cycloalkyl group; R7 is hydrogen or d-C6 alkyl;
R8 is d-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or an aromatic moiety, any of which may optionally be substituted with one or more substituents selected from halo, -SOR13 -SO2R13, -R14, -OR14, -CON(R14)2, -SOR14, -SO2R14, -SO2N(R14)2, -N(R14)2, -NR14COR14, -CO2R14, -COR14, -SR14, -NO2 or -CN; wherein R13 is a 5 to 7 membered heterocyclic ring; and each R14 is independently hydrogen, alkyl or aryl, the aryl being optionally substituted by -R9, -OR9, -CON(R9)2, -SOR9 -SO2R9, -SO2N(R9)2, -N(R9)2, - NR9COR9, -CO2R9, -COR9, -SR9, halo, -NO2 or -CN; wherein R9 is as defined above; R10 is Ci-Cβ alkyl, aryl, -(CH2)raOC(=O)d-C6alkyl, -(CH2)mN(Rπ)2, - CH((CH2)mO(C=O)R12)2; m is 1 or 2; R11 is hydrogen or methyl; R12 is Ci-Ciβ alkyl;
or a pharmaceutically acceptable salt, hydrate, solvate, complex or prodrug thereof in the preparation of an agent for the treatment or prevention of allergic asthma, perennial allergic rhinitis, seasonal allergic rhinitis, atopic dermatitis, contact hypersensitivity (including contact dermatitis), conjunctivitis, especially allergic conjunctivitis, eosinophilic bronchitis, food allergies, eosinophilic gastroenteritis, inflammatory bowel disease, ulcerative colitis and Crohn's disease, mastocytosis and also other PGD2-mediated diseases, for example autoimmune diseases such as hyper IgE syndrome and systemic lupus erythematus, psoriasis, acne, multiple sclerosis, allograft rejection, reperfusion injury and chronic obstructive pulmonary disease; as well as rheumatoid arthritis, psoriatic arthritis and osteoarthritis.
Preferred compounds are as set out above for the first aspect of the invention.
Compounds which are particularly preferred in this aspect of the invention are: [5-Fluoro-l-(4-fluoro-benzenesulfonyl)-2-methyl-iH-indol-3-yl]-acetic acid (l) [l-(4-Chloro-benzenesulfonyl)-5-fluoro-2-methyl-lH-indol-3-yl]-acetic acid (2) [5-Fluoro-2-methyl-l-(naphthalene-l-sulfonyl)-iH-indol-3-yl]-acetic acid (3) [5-Fluoro-2-methyl- l-(naphthalene-2-sulfonyl)-7H-indol-3-yl]-acetic acid (4) [5-Fluoro-l-(4-methoxy-benzenesulfonyl)-2-methyl-2H-indol-3-yl]-acetic acid (5) [5-Fluoro-2-methyl-l-(4-trifluoromethyl-benzenesulfonyl)-iH-indol-3-yl]-acetic acid
(6)
[l-(4-tert-Butyl-benzenesulfonyl)-5-fluoro-2-methyl-2H-indol-3-yl]-acetic acid (7) [ l-(Biphenyl-4-sulfonyl)-5-fluoro-2-methyl-2H-indol-3-yl]-acetic acid (8) [l-(l,2-Dimethyl-iH-imidazole-4-sulfonyl)-5-fluoro-2-methyl-iH-indol-3-yl]-acetic acid (9)
5-(3-Carboxymethyl-5-fluoro-2-methyl-indole-l-sulfonyl)-l-methyl-iH-pyrrole-2- carboxylic acid (10)
[l-(3,5-Dichloro-benzenesulfonyl)-5-fluoro-2-methyl-2H-indol-3-yl]-acetic acid (11) [l-(3,4-Dichloro-benzenesulfonyl)-5-fluoro-2-methyl-iH-indol-3-yl]-acetic acid (12) [5-Fluoro-2-methyl-l-(4-phenoxy-benzenesulfonyl)-iH-indol-3-yl]-acetic acid (13) [5-Fluoro-2-methyl-l-(4-methanesulfonyl-benzenesulfonyl)-2H-indol-3yl]-acetic acid (14) [5-Fluoro-2-methyl-l-(toluene-3-sulfonyl)-iH-indol-3-yl]-acetic acid (15) [l-(4-Bromo-benzenesulfonyl)-5-fluoro-2-methyl-iH-indol-3-yl]-acetic acid (16) [l-(5-Chloro-naphthalene-l-sulfonyl)-5-fluoro-2-methyl-iH-indol-3-yl]-acetic acid (17) [5-Fluoro-2-methyl-l-(4-nitro-benzenesulfonyl)-iH-indol-3-yl]-acetic acid (18) [5-Fluoro-2-methyl-l-(3-trifluoromethyl-benzenesulfonyl)-iH-indol-3-yl]-acetic acid (19)
( 1 -Benzenesulfonyl-5-fluoro-2-methyl-iH-indol-3-yl)-acetic acid (20) [5-Fluoro-2-methyl-l-(quinoline-8-sulfonyl)-iH-indol-3-yl]-acetic acid (21) [5-Fluoro-2-methyl-l-(toluene-4-sulfonyl)-iH-indol-3-yl]-acetic acid (22) [l-(3-Chloro-benzenesulfonyl)-5-fluoro-2-methyl-iH-indol-3-yl]-acetic acid (23) [l-(2,5-Dichloro-benzenesulfonyl)-5-fluoro-2-methyl-2H-indol-3-yl]-acetic acid
(24) [5-Fluoro-l-(3-fluoro-benzenesulfonyl)-2-methyl-iH-indol-3-yl]-acetic acid (25) [l-(2-Cyano-benzenesulfonyl)-5-fluoro-2-methyl-2H-indol-3-yl]-acetic acid (26) [5-Fluoro-l-(2-fluoro-benzenesulfonyl)-2-methyl-iH-indol-3-yl]-acetic acid (27) [l-(2,3-Dichloro-benzenesulfonyl)-5-fluoro-2-methyl-iH-indol-3-yl]-acetic acid
(28) [l-(2,4-Dichloro-benzenesulfonyl)-5-fluoro-2-methyl-iH-indol-3-yl]-acetic acid
(29) [5-Fluoro-2-methyl-l-(3-trifluoromethoxy-benzenesulfonyl)-2H-indol-3-yl]-acetic acid (30) [5-Fluoro-2-methyl- l-(toluene-2-sulfonyl)-iH-indol-3-yl]-acetic acid (31) [l-(5-Chloro-naphthalene-2-sulfonyl)-5-fluoro-2-methyl-iH-indol-3-yl]-acetic acid
(32) [5-Fluoro-l-(3-methoxy-benzenesulfonyl)-2-methyl-iH-indol-3-yl]-acetic acid (33) [5-Fluoro-2-methyl-l-(4-pyrazol-l-yl-benzenesulfonyl)-iH-indol-3-yl]-acetic acid
(34) [l-(2,2-Dimethyl-chroman-6-sulfonyl)-5-fluoro-2-methyl-2H-indol-3-yl]-acetic acid
(35) [5-Fluoro-2-methyl-l-(4-methyl-naphthalene-l-sulfonyl)-2H-indol-3-yl]-acetic acid
(36) [l-(5-Chloro-3-methyl-benzo[b]thiophene-2-sulfonyl)-5-fluoro-2-methyl-2H-indol-
3-yl]-acetic acid (37)
{5-Fluoro-2-methyl-l-[4-(morpholine-4-sulfonyl)-benzenesulfonyl]-iH-indol-3-yl}- acetic acid (38) (l-Ethanesulfonyl-5-fluoro-2-methyl-2H-indol-3-yl)-acetic acid (39) trans [5-Fluoro-l-(/ -styrenesulfony)-2-methyl-2H-indol-3-yl]-acetic acid (40) [l-(Butane-l-sulfonyl)-5-fluoro-2-methyl-iH-indol-3-yl]-acetic acid (41) [l-(Benzo[l,2,5]thiadiazole-4-sulfonyl)-5-fluoro-2-methyl-2H-indol-3-yl]-acetic acid (42) [l-(2-Chloro-4-trifluoromethyl-benzenesulfonyl)-5-fluoro-2-methyl-7H-indol-3-yl]- acetic acid (43) [5-Fluoro-2-methyl-l-(pyridine-3-sulfonyl)-iH-indol-3-yl]-acetic acid (44) [5-Fluoro-2-methyl- l-(3-nitro-benzenesulfonyl)-iH-indol-3-yl]-acetic acid (45) (5-Fluoro-2-methyl-l-phenylmethanesulfonyl-iH-indol-3-yl)-acetic acid (46) [l-(2-Chloro-benzenesulfonyl)-5-fluoro-2-methyl-iH-indol-3-yl]-acetic acid (47) [l-(3-Cyano-benzenesulfonyl)-5-fluoro-2-methyl-7H-indol-3-yl]-acetic acid (48) [ 1 -(4-Cyano-benzenesulf onyl)-5 -fluoro-2-methyl-7H-indol-3 -yl] -acetic acid (49) [5-Fluoro-l-(4-isopropyl-benzenesulfonyl)-2-methyl-iH-indol-3-yl]-acetic acid (50) [l-(2-Acetyl-l,2,3,4-tetrahydro-isoquinoline-6-sulfonyl)-5-fluoro-2-methyi-iH- indol-3-yl] -acetic acid (51) [5-Fluoro-2-methyl-l-(5-pyridin-2-yl-thiophene-2-sulfonyl)-2H-indol-3-yl]-acetic acid (52) [l-(5-Chloro-l,3-dimethyl-iH-pyrazole-4-sulfonyl)-5-fluoro-2-methyl-2H-indol-3- yl]-acetic acid (53) [5-Fluoro-2-methyl-l-(4-trifluoromethoxy-benzenesulfonyl)-iH-indol-3-yl]-acetic acid (54) [5-Fluoro-l-(isoquinoline-5-sulfonyl)-2-methyl-iH-indol-3-yl]-acetic acid (55) [l-(5-Chloro-2-methoxy-benzenesulfonyl)-5-fluoro-2-methyl-2H-indol-3-yl]-acetic acid (56) [l-(4-Chloro-2,5-dimethyl-benzenesulfonyl)-5-fluoro-2-methyl-iH-indol-3-yl]- acetic acid (57) [5-Fluoro-l-(2-hydroxy-2Η-chromene-6-sulfonyl)-2-methyl-iH-indol-3-yl]-acetic acid (58)
{ 5 -Fluoro- 1 - [4-(4-fluoro-phenoxy)-benzenesulf onyl] -2-methyl-2H-indol-3 -yl } -acetic acid (59)
{l-[4-(4-Chloro-phenoxy)-benzenesulfonyl]-5-fluoro-2-methyl-iH-indol-3-yl}- acetic acid (60) ({5-Fluoro-2-methyl-l-[4-(4-trifluoromethyl-phenoxy)- benzenesulfonyl]-iH-indol-3-yl}-acetic acid (61) {l-[4-(4-Bromo-phenoxy)-benzenesulfonyl]-5-fluoro-2-methyl-iH-indol-3-yl}- acetic acid (62)
{5-Fluoro-l-[4-(4-methoxy-phenoxy)-benzenesulfonyl]-2-methyl-iH-indol-3-yl}- acetic acid (63) [l-(3,4-Dihydro-2Η-benzo[b][l,4]dioxepine-7-sulfonyl)-5-fluoro-2-methyl-iH- indol-3-yl]-acetic acid (64) [5-Fluoro-2-methyl-l-(4-oxazol-5-yl-benzenesulfonyl)-iH-indol-3-yl]-acetic acid (65) [5-Fluoro-2-methyl-l-(4-/?-tolyloxy-benzenesulfonyl)-2H-indol-3-yl]-acetic acid (66) [5-Fluoro-2-methyl-l-(4-/n-tolyloxy-benzenesulfonyl)-7H-indol-3-yl]-acetic acid (67)
{ l-[4-(3-Chloro-phenoxy)-benzenesulfonyl]-5-fluoro-2-methyl-iH-indol-3-yl}- acetic acid (68)
{ l-[4-(2,4-Dichloro-phenoxy)-benzenesulfonyl]-5-fluoro-2-methyl-2H-indol-3-yl}- acetic acid (69)
{ l-[4-(2-Chloro-phenoxy)-benzenesulfonyl]-5-fluoro-2-methyl-7H-indol-3-yl}- acetic acid (70)
{5-Fluoro-l-[4-(2-methoxy-phenoxy)-benzenesulfonyl]-2-methyl-iH-indol-3-yl}- acetic acid (71)
{ l-[4-(2,5-Dichloro-ρhenoxy)-benzenesulfonyl]-5-fluoro-2-methyl-2H-indol-3-yl}- acetic acid (72) [5-Fluoro-2,4-dimethyl- l-(naphthalene-2-sulfonyl)-7H-indol-3-yl]-acetic acid (73) [5-Fluoro- 1 -(4-methanesulf onyl-benzenesulfonyl)-2,4-dimethyl-iH-indol-3-yl] - acetic acid (74) [5-Fluoro-2,4-dimethyl-l-(4-phenoxy-benzenesulfonyl)-iH-indol-3-yl]-acetic acid (75)
{ 5-Fluoro-2-methyl- 1 - [4-(pyrrolidine- 1 -sulf onyl)-benzenesulf onyl]-iH-indol-3-yl } - acetic acid (76) [5-Fluoro-l-(4-hydroxy-benzenesulfonyl)-2-methyl-iH-indol-3-yl]-acetic acid (77) [l-(3-Cyano-4-hydroxy-benzenesulfonyl)-5-fluoro-2-methyl-iH-indol-3-yl]-acetic acid (78) [l-(3-carboxamido-benzenesulfonyl)-5-fluoro-2-methyl-2H-indol-3-yl]-acetic acid (79) [l-(4-carboxamido-benzenesulfonyl)-5-fluoro-2-methyl-2H-indol-3-yl]-acetic acid (80)
[5-Fluoro-2-methyl-l-(3-phenoxy-benzenesulfonyl)-2H-indol-3-yl]-acetic acid (81) [5-Fluoro-2-methyl-l-(4-methylsulfanyl-benzenesulfonyl)-iH-indol-3-yl]-acetic acid (82)
[5-Fluoro-2-methyl-l-(3-methyl-quinoline-8-sulfonyl)-2H-indol-3-yl]-acetic acid (83)
[5-Fluoro-2-methyl-l-(3-sulfonamido-benzenesulfonyl)-iH-indol-3-yl]-acetic acid (84)
[5-Cyano-l-(4-methanesulfonyl-benzenesulfonyl)-2-methyl-2H-indol-3-yl]-acetic acid (85)
[l-(4-Chloro-benzenesulfonyl)-5-cyano-2-methyl-2H-indol-3-yl]-acetic acid (86) [5-Cyano-2-methyl- 1 -(4-phenoxy-benzenesulfonyl)-2H-indol-3-yl]-acetic acid (87) {5-Fluoro-2-methyl-l-[4-(3-trifluoromethyl-phenoxy)-benzenesulfonyl]-2H-indol-3- yl} -acetic acid (88)
[5-carboxamido-l-(4-methanesulfonyl-benzenesulfonyl)-2-methyl-2H-indol-3-yl]- acetic acid (89)
[5-carboxamido-l-(4-chloro-benzenesulfonyl)-2-methyl-iH-indol-3-yl]-acetic acid (90)
[5-carboxamido-2-methyl-l-(4-phenoxy-benzenesulfonyl)-iH-indol-3-yl]-acetic acid (91)
[5-Fluoro-2-methyl-l-(3-N-methylsulfonamido-benzenesulfonyl)-2H-indol-3-yl]- acetic acid (92)
{5-Fluoro-2-methyl-l-[3-(pyrrolidine-l-sulfonyl)-benzenesulfonyl]-iH-indol-3-yl}- acetic acid (94)
[5-Fluoro-2-methyl-l-(3-N-methylamido-benzenesulfonyl)-2H-indol-3-yl]-acetic acid (95) [5-Fluoro-2-methyl-l-(4-N-methylcarboxamido-benzenesulfonyl)-iH-indol-3-yl]- acetic acid (96) [5-Fluoro-2-methyl-l-(6-phenoxy-pyridine-3-sulfonyl)-7H-indol-3-yl]-acetic acid (97)
[l-(3-N,N-Dimethylsulfonamido-benzenesulfonyl)-5-fluoro-2-methyl-lH-indol-3- yl]-acetic acid (98)
[5-Fluoro-l-(3-methanesulfonyl-benzenesulfonyl)-2-methyl-lH-indol-3-yl]-acetic acid (99)
[l-(4-N,N-Dimethylcarboxamido-benzenesulfonyl)-5-fluoro-2-methyl-lH-indol-3- yl]-acetic acid (100)
[l-(3-N,N-Dimethylcarboxamido-benzenesulfonyl)-5-fluoro-2-methyl-7H-indol-3- yl]-acetic acid (101)
[5-Fluoro-2-methyl- 1 -(4-methyl-3 ,4-dihydro-2H-benzo [ 1 ,4] oxazine-7-sulf onyl)- 1 H- indol-3-yl]-acetic acid (102)
[l-(5-Dimethylamino-naphthalene-l-sulfonyl)-5-fluoro-2-methyl-2H-indol-3-yl]- acetic acid (103)
{5-Fluoro-2-methyl-l-[4-(trifluoromethylsulfanyl-benzenesulfonyl]-lH-indol-3- yl} -acetic acid (104)
{5-Fluoro-2-methyl-l-[3-(trifluoromethylsulfonyl-benzenesulfonyl]-lH-indol-3- yl}-acetic acid (105)
{5-Fluoro-2-methyl-l-[4-(pyridin-2-yloxy)-benzenesulfonyl]-lH-indol-3-yl}-acetic acid (106)
{ 5 -Fluoro-2-methyl- 1 - [4-(pyridin-3 -yloxy)-benzenesulf onyl] - lH-indol-3-yl } -acetic acid (107)
{5-Fluoro-2-methyl-l-[4-(pyridin-4-yloxy)-benzenesulfonyl]-lH-indol-3-yl}-acetic acid (108) [5-Fluoro-2-methyl-l-(4-phenylamino-benzenesulfonyl)-iH-indol-3-yl]-acetic acid (109)
[5-Fluoro-2-methyl-l-(4- -tolylamino-benzenesulfonyl)-lH-indol-3-yl]-acetic acid (110) { 5-Fluoro-2-methyl- 1 - [4-(pyridin-4-ylamino)-benzenesulf onyl] - lH-indol-3 -yl } - acetic acid (111)
{5-Fluoro-2-methyl-l-[4-(pyridin-2-ylamino)-benzenesulfonyl]-lH-indol-3-yl}- acetic acid (112) {5-Fluoro-2-methyl-l-[4-(pyrimidin-4-ylamino)-benzenesulfonyl]-lH-indol-3-yl}- acetic acid (113)
{5-Fluoro-2-methyl-l-[4-(5-methyl-isoxazol-3-ylamino)-benzenesulfonyl]-lH-indol-
3-yl}-acetic acid (114)
{ 5-Fluoro-2-methyl- 1 -[4-(pyridin-3-ylamino)-benzenesulf onyl]- lH-indol-3 -yl } - acetic acid (115)
{5-Fluoro-2-methyl-l-[4-(4-methyl-pyridin-2-ylamino)-benzenesulfonyl]-lH-indol-
3-yl} -acetic acid (116)
{5-Fluoro-2-methyl-l-[4-(6-methyl-pyridin-2-ylamino)-benzenesulfonyl]-lH-indol-
3-yl} -acetic acid (117)
{ 5-Fluoro-2-methyl- 1 - [4-(4-methyl-pyrimidin-2-ylamino)-benzenesulf onyl] - 1H- indol-3-yl} -acetic acid (118)
{5-Ηuoro-2-methyl-l-[4-(pyrimidin-2-ylamino)-benzenesulfonyl]-lH-indol-3-yl}- acetic acid (119)
{ l-[4-(3-Chloro-phenylamino)-benzenesulfonyl]-5-fluoro-2-methyl-lH-indol-3-yl}- acetic acid (120)
{ l-[4-(2,6-Dimethyl-pyrimidin-4-ylamino)-benzenesulfonyl]-5-fluoro-2-methyl-iH- indol-3-yl} -acetic acid (121)
{5-Fluoro-l-[4-(isoxazol-3-ylamino)-benzenesulfonyl]-2-methyl-lH-indol-3-yl}- acetic acid (122)
{ l-[4-(4,6-Dimethyl-pyrimidin-2-ylamino)-benzenesulfonyl]-5-fluoro-2-methyl-lH- indol-3-yl}-acetic acid (123)
{5-Fluoro-2-methyl-l-[4-(5-methyl-pyridin-3-ylamino)-benzenesulfonyl]-iH-indol-
3-yl}-acetic acid (124)
{5-Fluoro-2-methyl-l-[4-(thiazol-2-ylamino)-benzenesulfonyl]-iH-indol-3-yl}- acetic acid (125)
{ l-[4-(3,5-Dimethyl-phenylamino)-benzenesulfonyl]-5-fluoro-2-methyl-2H-indol-3- yl} -acetic acid (126)
{ 5-Fluoro-2-methyl- 1 -[4-(4-sulfonamido-phenylamino)-benzenesulf onyl]-lH-indol-
3-yl}-acetic acid (127) { l-[4-(3,5-Dichloro-phenylamino)-benzenesulfonyl]-5-fluoro-2-methyl-iH-indol-3- yl} -acetic acid (128) { l-[4-(5-Chloro-pyridm-3-ylamino)-benzenesulfonyl]-5-fluoro-2-methyl-iH-indol- 3-yl}-acetic acid (129)
{ l-[2,5-Difluoro-4-(pyridin-2-ylamino)-benzenesulfonyl]-5-fluoro-2-methyl-iH- indol-3-yl} -acetic acid (130)
{ l-[2,5-Difluoro-4-(pyridin-2-ylamino)-benzenesulfonyl]-5-fluoro-2-methyl-iH- indol-3-yl} -acetic acid (131)
{ l-[2,5-Difluoro-4-(5-methyl-isoxazol-3-ylamino)-benzenesulfonyl]-5-fluoro-2- methyl-iH-indol-3-yl} -acetic acid (132)
{5-Fluoro-l-[4-(3-methoxy-phenylamino)-benzenesulfonyl]-2-methyl-7H-indol-3- yl}-acetic acid (133)
{ l-[4-(3-Cyano-phenylamino)-benzenesulfonyl]-5-fluoro-2-methyl-iH-indol-3-yl}- acetic acid (134)
{ l-[4-(3-Ethyl-phenylamino)-benzenesulfonyl]-5-fluoro-2-methyl-2H-indol-3-yl}- acetic acid (135)
{5-Fluoro-2-methyl-l-[6-(pyridin-2-ylamino)-pyridine-3-sulfonyl]-lH-indol-3-yl}- acetic acid (136)
{5-Fluoro-2-methyl-l-[6-(pyridin-3-ylamino)-pyridine-3-sulfonyl]-lH-indol-3-yl}- acetic acid (137)
{5-Fluoro-2-methyl-l-[6-(pyrimidin-4-ylamino)-pyridine-3-sulfonyl]-lH-indol-3- yl}-acetic acid (138) [5-Fluoro-2-methyl-l-(6-phenylamino-pyridine-3-sulfonyl)-lH-indol-3-yl]-acetic acid (139)
{ l-[6-(3,5-Dimethyl-phenylamino)-pyridine-3-sulfonyl]-5-fluoro-2-methyl-lH- indol-3-yl}-acetic acid (140)
{5-Fluoro-2-methyl-l-[6-(pyrimidin-2-ylamino)-pyridine-3-sulfonyl]-lH-indol-3- yl}-acetic acid (141)
{5-Fluoro-2-methyl-l-[6-(6-methyl-pyridin-2-ylamino)-pyridine-3-sulfonyl]-lH- indol-3-yl} -acetic acid (142) {5-Fluoro-2-methyl-l-[6-(4-methyl-pyrimidin-2-ylamino)-pyridine-3-sulfonyl]-lH- indol-3-yl} -acetic acid (143) {l-[6-(4,6-Dimethyl-pyrimidin-2-ylamino)-pyridine-3-sulfonyl]-5-fluoro-2-methyl- lH-indol-3-yl} -acetic acid (144) { l-[6-(3-Chloro-phenylamino)-pyridine-3-sulfonyl]-5-fluoro-2-methyl-lH-indol-3- yl}-acetic acid (145) [5-Fluoro-2-methyl-l-(6-m-tolylamino-pyridine-3-sulfonyl)-lH-indol-3-yl]-acetic acid (146)
{ l-[6-(2,6-Dimethyl-pyrimidin-4-ylamino)-pyridine-3-sulfonyl]-5-fluoro-2-methyl- lH-indol-3-yl}-acetic acid (147)
{ 5-Fluoro-2-methyl- 1 -[6-(pyridin-4-ylamino)-pyridine-3-sulf onyl] - lH-indol-3-yl } - acetic acid (148)
{5-Fluoro-2-methyl-l-[6-(5-methyl-isoxazol-3-ylamino)-pyridine-3-sulfonyl]-lH- indol-3-yl}-acetic acid (149)
{5-Fluoro-2-methyl-l-[6-(thiazol-2-ylamino)-pyridine-3-sulfonyl]-lH-indol-3-yl}- acetic acid (150)
{ l-[6-(3,5-Dichloro-phenylarnino)-pyridine-3-sulfonyl]-5-fluoro-2-methyl-2H-indol- 3-yl}-acetic acid (151)
{5-Fluoro-2-methyl-l-[6-(5-methyl-pyridin-3-ylamino)-pyridine-3-sulfonyl]-iH- indol-3-yl} -acetic acid (152)
{ l-[6-(5-Chloro-pyridin-3-ylamino)-pyridine-3-sulfonyl]-5-fluoro-2-methyl-j'H- indol-3-yl} -acetic acid (153)
{5-Fluoro-2-methyl-l-[4-(methyl-phenyl-amino)-benzenesulfonyl]-lH-indol-3-yl}- acetic acid (154)
{5-Fluoro-2-methyl-l-[4-(methyl-m-tolyl-amino)-benzenesulfonyl]-lH-indol-3-yl}- acetic acid (155) (5-Fluoro-2-methyl-l-{4-[methyl-(5-methyl-isoxazol-3-yl)-amino]-benzene- sulfonyl}-lH-indol-3-yl)-acetic acid (156)
(5-Fluoro-2-methyl- 1 - { 4- [methyl-(4-methyl-pyridin-2-yl)-amino] -benzene sulfonyl }-lH-indol-3-yl)-acetic acid (157)
(5-Fluoro-2-methyl-l-{6-[methyl-(6-methyl-pyridin-2-yl)-amino]-pyridine-3- sulfonyl}-lH-indol-3-yl)-acetic acid (158) {5-Fluoro-2-methyl-l-[4-(methyl-pyrimidin-2-yl-amino)-benzenesulfonyl]-lH-indol- 3-yl}-acetic acid (159) {5-Fluoro-2-methyl-l-[4-(methyl-pyridin-2-yl-amino)-benzenesulfonyl]-lH-indol-3- yl} -acetic acid (160) {5-Fluoro-2-methyl-l-[6-(methyl-pyridin-2-yl-amino)-pyridine-3-sulfonyl]-lH- indol-3-yl} -acetic acid (161)
{5-Fluoro-2-methyl-l-[6-(methyl-pyridin-4-yl-amino)-pyridine-3-sulfonyl]-iH- indol-3-yl}-acetic acid (162)
(5-Fluoro-2-methyl- 1 - { 4- [methyl-(6-methyl-pyridin-2-yl)-amino] -benzenesulfonyl } -
7H-indol-3-yl)-acetic acid (163)
(l-{4-[(2,6-Dimethyl-pyrimidin-4-yl)-methyl-amino]-benzenesulfonyl}-5-fluoro-2- methyl-iH-indol-3-yl)-acetic acid (164)
{5-Fluoro-2-methyl-l-[6-(methyl-phenyl-amino)-pyridine-3-sulfonyl]-iH-indol-3- yl} -acetic acid (165)
(l-{6-[(3-Chloro-phenyl)-methyl-amino]-pyridine-3-sulfonyl}-5-fluoro-2-methyl-
7H-indol-3-yl)-acetic acid (166)
( 1 - { 4- [(3-Chloro-phenyl)-methyl-amino]-benzenesulfonyl } -5-fluoro-2-methyl-2H- indol-3-yl)-acetic acid (167)
{ l-[4-(Ethyl-m-tolyl-amino)-benzenesulfonyl]-5-fluoro-2-methyl-iH-indol-3-yl}- acetic acid (168)
{5-Fluoro-2-methyl-l-[4-(methyl-pyridin-3-yl-amino)-benzenesulfonyl]-iH-indol-3- yl} -acetic acid (169)
[5-Fluoro-2-methyl-l-(4-phenylsulfanyl-benzenesulfonyl)-lH-indol-3-yl]-acetic acid
(171) [l-(4-Benzenesulfinyl-benzenesulfonyl)-5-fluoro-2-methyl-7H-indol-3-yl]-acetic acid (172) [ 1 -(4-B enzenesulf onyl-benzenesulf onyl)-5 -fluoro-2-methyl-iH-indol-3 -yl] -acetic acid (173) [5-Chloro- 1 -(4-chloro-benzenesulf onyl)-2-methyl-iH-indol-3 -yl] -acetic acid ( 174) {5-Fluoro-l-[4-(3-isopropyl-phenylamino)-benzenesulfonyl]-2-methyl-2H-indol-3- yl}-acetic acid (175)
{5-Fluoro-2-methyl-l-[4-(methyl-thiazol-2-yl-amino)-benzenesulfonyl]-iH-indol-3- yl}-acetic acid (176)
{l-[2,5-Difluoro-4-(isoxazol-3-ylamino)-benzenesulfonyl]-5-fluoro-2-methyl-2H- indol-3-yl} -acetic acid (177) {l-[4-(5-Chloro-pyridin-3-ylamino)-2,5-difluoro-benzenesulfonyl]-5-fluoro-2- methyl-2H-indol-3-yl} -acetic acid (178) {l-[2,5-Difluoro-4-(5-methyl-pyridin-3-ylamino)-benzenesulfonyl]-5-fluoro-2- methyl-iH-indol-3-yl} -acetic acid (179)
{l-[6-(3-Ethyl-phenylamino)-pyridine-3-sulfonyl]-5-fluoro-2-methyl-2H-indol-3- yl} -acetic acid (180)
{5-Fluoro-l-[6-(3-methoxy-phenylamino)-pyridine-3-sulfonyl]-2-methyl-2H-indol-
3-yl}-acetic acid (181)
{l-[6-(3-Cyano-ρhenylamino)-pyridine-3-sulfonyl]-5-fluoro-2-methyl-2H-indol-3- yl}-acetic acid (182)
{5-Fluoro-l-[6-(3-methanesulfonyl-phenylamino)-pyridine-3-sulfonyl]-2-methyl-
7H-indol-3-yl}-acetic acid (183)
{5-Fluoro-l-[4-(isoxazol-3-yl-methyl-amino)-benzenesulfonyl]-2-methyl-iH-indol-
3-yl}-acetic acid (184)
(5-Fluoro-2-methyl-l-{4-[methyl-(5-methyl-pyridin-3-yl)-amino]-benzenesulfonyl}- iH-indol-3-yl)-acetic acid (185)
(l-{4-[(3,5-Dimethyl-phenyl)-methyl-amino]-benzenesulfonyl}-5-fluoro-2-methyl-
7H-indol-3-yl)-acetic acid (186)
(5-Fluoro- 1 - { 4- [(3-methoxy-phenyl)-methyl-amino] -benzenesulfonyl } -2-methyl-iH- indol-3-yl)-acetic acid (187)
( 1 - { 4- [(3 -Cyano-phenyl)-methyl- amino] -benzenesulfonyl } -5 -fluoro-2-methyl-iH- indol-3-yl)-acetic acid (188)
(l-{4-[(3-Ethyl-phenyl)-methyl-amino]-benzenesulfonyl}-5-fluoro-2-methyl-IH- indol-3-yl)-acetic acid (189)
(5-Fluoro- 1 - { 4-[(3-isopropyl-phenyl)-methyl-amino]-benzenesulfonyl } -2-methyl- iH-indol-3-yl)-acetic acid (190)
(l-{6-[(3-Ethyl-phenyl)-methyl-amino]-pyridine-3-sulfonyl}-5-fluoro-2-methyl-iH- indol-3-yl)-acetic acid (191)
(5-Fluoro- 1 - { 6- [(3-methanesulf onyl-phenyl)-methyl-amino] -pyridine-3 -sulfonyl } -2- methyl-iH-indol-3-yl)-acetic acid (192) (l-{ 6- [(3 -Cyano-phenyl)-methyl-amino] -pyridine-3 -sulfonyl } -5-fluoro-2-methyl- iH-indol-3-yl)-acetic acid (193) (5-Fluoro-2-methyl-l-{6-[methyl-(5-methyl-pyridin-3-yl)-amino]-pyridine-3- sulfonyl}-iH-indol-3-yl)-acetic acid (194). The compounds of general formula (I) or (II) must be formulated in an appropriate manner depending upon the diseases or conditions they are required to treat.
Therefore, in a further aspect of the invention there is provided a pharmaceutical composition comprising a compound of general formula (I) or (II) together with a pharmaceutical excipient or carrier. Other active materials may also be present, as may be considered appropriate or advisable for the disease or condition being treated or prevented.
The carrier, or, if more than one be present, each of the carriers, must be acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient.
The formulations include those suitable for oral, rectal, nasal, bronchial (inhaled), topical (including eye drops, buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration and may be prepared by any methods well known in the art of pharmacy.
The route of administration will depend upon the condition to be treated but preferred compositions are formulated for oral, nasal, bronchial or topical administration.
The composition may be prepared by bringing into association the above defined active agent with the carrier. In general, the formulations are prepared by uniformly and intimately bringing into association the active agent with liquid carriers or finely divided solid carriers or both, and then if necessary shaping the product. The invention extends to methods for preparing a pharmaceutical composition comprising bringing a compound of general formula (I) or (II) in conjunction or association with a pharmaceutically or veterinarily acceptable carrier or vehicle.
Formulations for oral administration in the present invention may be presented as: discrete units such as capsules, sachets or tablets each containing a predetermined amount of the active agent; as a powder or granules; as a solution or a suspension of the active agent in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water in oil liquid emulsion; or as a bolus etc.
For compositions for oral administration (e.g. tablets and capsules), the term "acceptable carrier" includes vehicles such as common excipients e.g. binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, polyvinylpyrrolidone (Povidone), methylcellulose, ethylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, sucrose and starch; fillers and carriers, for example corn starch, gelatin, lactose, sucrose, microcrystalline cellulose, kaolin, mannitol, dicalcium phosphate, sodium chloride and alginic acid; and lubricants such as magnesium stearate, sodium stearate and other metallic stearates, glycerol stearate stearic acid, silicone fluid, talc waxes, oils and colloidal silica. Flavouring agents such as peppermint, oil of wintergreen, cherry flavouring and the like can also be used. It may be desirable to add a colouring agent to make the dosage form readily identifiable. Tablets may also be coated by methods well known in the art.
A tablet may be made by compression or moulding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active agent in a free flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface-active or dispersing agent. Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active agent.
Other formulations suitable for oral administration include lozenges comprising the active agent in a flavoured base, usually sucrose and acacia or tragacanth; pastilles comprising the active agent in an inert base such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active agent in a suitable liquid carrier. For topical application to the skin, compounds of general formula (I) or (LT) may be made up into a cream, ointment, jelly, solution or suspension etc. Cream or ointment formulations that may be used for the drug are conventional formulations well known in the art, for example, as described in standard text books of pharmaceutics such as the British Pharmacopoeia.
Compounds of general formula (I) or (LT) may be used for the treatment of the respiratory tract by nasal, bronchial or buccal administration of, for example, aerosols or sprays which can disperse the pharmacological active ingredient in the form of a powder or in the form of drops of a solution or suspension. Pharmaceutical compositions with powder-dispersing properties usually contain, in addition to the active ingredient, a liquid propellant with a boiling point below room temperature and, if desired, adjuncts, such as liquid or solid non-ionic or anionic surfactants and or diluents. Pharmaceutical compositions in which the pharmacological active ingredient is in solution contain, in addition to this, a suitable propellant, and furthermore, if necessary, an additional solvent and/or a stabiliser. Instead of the propellant, compressed air can also be used, it being possible for this to be produced as required by means of a suitable compression and expansion device.
Parenteral formulations will generally be sterile.
Typically, the dose of the compound will be about 0.01 to 100 mg kg; so as to maintain the concentration of drug in the plasma at a concentration effective to inhibit PGD2 at the CRTH2 and/or DP receptor. The precise amount of a compound of general formula (I) or (H) which is therapeutically effective, and the route by which such compound is best administered, is readily determined by one of ordinary skill in the art by comparing the blood level of the agent to the concentration required to have a therapeutic effect.
Compounds of general formula (I) or (II) may be used in combination with one or more active agents which are useful in the treatment of the diseases and conditions listed above, although these active agents are not necessarily inhibitors of PGD at the CRTH2 and/or DP receptor.
Therefore, the pharmaceutical composition described above may additionally contain one or more of these active agents.
There is also provided the use of a compound of general formula (I) or (LI) in the preparation of an agent for the treatment of diseases and conditions mediated by PGD2 at the CRTH2 and/or DP receptor, wherein the agent also comprises an additional active agent useful for the treatment of the same diseases and conditions.
These additional active agents which may have a completely different mode of action include existing therapies for allergic and other inflammatory diseases including: β2 agonists such as salmeterol; corticosteroids such as fluticasone; antihistamines such as loratidine; leukotriene antagonists such as montelukast; anti-IgE antibody therapies such as omalizumab; anti-infectives such as fusidic acid (particularly for the treatment of atopic dermatitis); anti-fungals such as clotrimazole (particularly for the treatment of atopic dermatitis); immunosuppressants such as tacrolimus and particularly pimecrolimus in the case of inflammatory skin disease.
CRTH2 and or DP antagonists may also be combined with therapies that are in development for inflammatory indications including: other antagonists of PGD2 acting at other receptors such as CRTH2 (for compounds of general formula (I) which are DP antagonsists) or DP (for compounds of general formula (I) which are CRTH2 antagonists); inhibitors of phoshodiesterase type 4 such as cilonilast; drugs that modulate cytokine production such as inhibitors of TNF converting enzyme (TACE); drugs that modulate the activity of Th2 cytokines LL-4 and LL-5 such as blocking monoclonal antibodies and soluble receptors; PPAR-γ agonists such as rosiglitazone; 5-lipoxygenase inhibitors such as zileuton.
In yet a further aspect of the invention, there is provided a product comprising a compound of general formula (I) or (LT) and one or more of the agents listed above as a combined preparation for simultaneous, separate or sequential use in the treatment of a disease or condition mediated by the action of PGD2 at the CRTH2 and/or DP receptor.
The invention will now be described in greater detail with reference to the following non limiting examples.
Example 1 - Synthesis of Compounds of general formula (I)
[5-Fluoro-l-(4-fluoro-benzenesulfonyI)-2-methyl-2H-indol-3-yl]-acetic acid ethyl ester
(5-Fluoro-7H-indol-3-yl)-acetic acid ethyl ester (50 mg, 0.21 mmol) in tetrahydrofuran (0.5 ml) was added dropwise over 1 min to a stirred solution of potassium tert-butoxide (33 mg, 0.29 mmol) and 18-crown-6 (56 mg, 0.021 mmol) in tetrahydrofuran (0.5 ml) at 0 °C. After stirring at 0 °C for 15 min, 4-fluorobenzene sulfonyl chloride (41 mg, 0.21 mmol) in tetrahydrofuran (0.5 ml) was added dropwise and the resulting mixture stirred at room temperature for 4 h. The mixture was then partitioned between ethyl acetate (5 ml) and water (5 ml) and the organic layer separated. The aqueous layer was extracted with ethyl acetate (3 x 5 ml) and the combined organic extracts were washed with brine, dried and concentrated in vacuo to leave a brown residue. Purification by flash column chromatography on silica gel eluting with 15 % ethyl acetate : hexane gave the sulphonamide (31 mg, 40 %) as an off-white solid, Tr = 1.69 min (100%), m/z (ES+) (M+Η)+ 394.28
[5-Fluoro-l-(4-fluoro-benzenesuIfonyl)-2-methyl--{iϊ-indol-3-yl]-acetic acid (Compound 1) Lithium hydroxide monohydrate (16 mg, 0.38 mmol) was added in one portion to a stirred solution of [5-fluoro-l-(4-fluoro-benzenesulfonyl)-iH-indol-3-yl]-acetic acid ethyl ester (30 mg, 0.08 mmol) in tetrahydrofuran : water (2 ml; 1:1) at room temperature. The reaction mixture was stirred for 1 h and then adjusted to pΗ 4 with concentrated hydrochloric acid. The product was extracted with ethyl acetate (3 5 ml) and the combined organic extracts were then dried and concentrated in vacuo to give the carboxylic acid (4.5 mg, 16 %) as an off-white solid, Tr = 1.45 min (91%), m/z (ES)+ (M+Η)+ 366.20.
Compounds 2 to 104 were prepared using a similar method to Compound 1 but with appropriately chosen starting materials.
[l-(4-Chloro-benzenesulfonyl)-5-fluoro-2-methyl-2H-indol-3-yl]-acetic acid
(Compound 2) δH 8.04 (IH, dd / 9.1, 4.4 Hz, Ar), 7.62 (2H, d / 8.8 Hz, Ar), 7.36 (2H, d J 8.8 Hz, Ar), 7.10 (IH, dd / 8.7, 2.5 Hz, Ar), 6.95 (IH, dt J 9.04, 2.6 Hz, Ar), 3.50 (2H, s, CH2CO2H), 2.52 (3H, s, CH3); Tr = 1.69 min (100%), m/z (ES+) (M+Η)+ 382.25
[5-Fluoro-2-methyl-l-(naphthalene-l-sulfonyl)-2H-indol-3-yl]-acetic acid (Compound 3)
Tr = 1.58 min (100%), m/z (ES+) (M+H)+ 398.18
[5-Fluoro-2-methyl-l-(naphthalene-2-sulfonyl)-Iflr-indol-3-yl]-acetic acid
(Compound 4)
Tr = 1.63 min (100%), m/z (ES+) (M+H)+ 398.02
[5-Fluoro-l-(4-methoxy-benzenesulfonyl)-2-methyl-IH-indol-3-yl]-acetic acid (Compound 5)
Tr = 1.45 min (100%), m/z (ES+) (M+H)+ 378.20
[5-Fluoro-2-methyl-l-(4-trifluoromethyl-benzenesulfonyl)-2H-indol-3-yl]-acetic acid (Compound 6)
Tr = 1.60 min (100%), m/z (ES+) (M+H)+ 416.21
[l-(4-tert-Butyl-benzenesulfonyl)-5-fluoro-2-methyl-2H-indol-3-yl]-acetic acid
(Compound 7)
Tr = 1.66 min (100%), m/z (ES+) (M+H)+ 404.26
[l-(Biphenyl-4-sulfonyl)-5-fluoro-2-methyl-2H-indol-3-yl]-acetic acid
(Compound 8)
Tr = 1.67 min (83%), m/z (ES+) (M+H)+ 424.24
[l-(l,2-Dimethyl-2Hr-imidazole-4-suIfonyl)-5-fluoro-2-methyl-/H-indol-3-yl]- acetic acid (Compound 9)
Tr = 1.18 min (100%), m/z (ES+) (M+H)+ 366.19
5-(3-Carboxymethyl-5-fluoro-2-methyl-indole-l-sulfonyl)-l-methyl-2H-pyrroIe- 2-carboxylic acid (Compound 10) δH (400 MHz, CDC13) 7.86 (IH, dd, I 9.0, 4.4 Hz, Ar), 7.06 (IH, d, J 2.0 Hz, Ar), 6.94 (IH, dd, / 8.8, 2.5 Hz, Ar), 6.83 (IH, d, J 2.0 Hz, Ar), 6.78 (IH, td, I 9.1, 2.5 Hz, Ar), 3.68 (3H, s, CH3), 3.35 (2Η, s, CH2), 1.06 (3Η, s, CH3); Tr = 1.38 min (96%), m/z (ES+) (M+Η)+ 395.27.
[l-(3,5-Dichloro-benzenesulfonyl)-5-fluoro-2-methyl-lH-indol-3-yl]-acetic acid (Compound 11) δH (400 MHz, MeOD) 8.07 (IH, dd / 9.1, 4.4 Hz, Ar), 8.04 (IH, br t J 1.8 Hz, Ar), 7.83 (2H d / 1.8 Hz, Ar), 7.36 (IH, dd / 9.0, 2.6 Hz, Ar), 7.18 (IH, td / 9.2, 2.6 Hz, Ar), 3.69 (2H, s, CH2), 2.55 (3Η, s, CH3); Tr = 1.77 min (98 %), m/z (ES+) (M+Η)+ 416.13.
[l-(3,4-Dichloro-benzenesulfonyl)-5-fluoro-2-methyl-J/ -indol-3-yl]-acetic acid (Compound 12) δH (400 MHz, MeOD) 8.09 (IH, d 2.2 Hz, Ar) 8.07 (IH, dd / 8.9, 4.3 Hz, Ar), 7.85 (IH, d 8.6 Hz, Ar), 7.78 (IH, dd / 8.6, 2.2 Hz, Ar), 7.35 (IH, dd J 9.0, 2.6 Hz, Ar), 7.18 (IH, td 9.1, 2.7 Hz, Ar), 3.68 (2H, s, CH2), 2.54 (3Η, s, CH3); Tr = 1.75 min (98 %), m/z (ES+) (M+Η)+ 415.99.
[5-Fluoro-2-methyl-l-(4-phenoxy-benzenesulfonyl)-.fiϊ-indol-3-yl]-acetic acid (Compound 13)
LCMS (M+H)+ (92%) 440.12 @ 1.63 min.
[5-FIuoro-2-methyl-l-(4-methanesulfonyl-benzenesulfonyl)-2H-indol-3yl]-acetic acid (Compound 14)
LCMS (M+H)+ (92%) 426.15 @ 1.82 min.
[5-Fluoro-2-methyl-l-(toluene-3-sulfonyI)-/H-indol-3-yl]-acetic acid (Compound
15)
Tr = 1.63 min (91%), m/z (ES+) (M+H)+ 362.1.
[l-(4-Bromo-benzenesulfonyl)-5-fluoro-2-methyl-2H-indol-3-yl]-acetic acid
(Compound 16)
Tr = 1.73 min (100%), m/z (ES+) (M+H)+ 426.1.
[l-(5-Chloro-naphthalene-l-sulfonyl)-5-fluoro-2-methyl-Ijfi -indol-3-yl]-acetic acid (Compound 17) δH (400 MHz, 6-DMSO) 8.83 (IH, d / 1.92 Hz, Ar), 8.30 (IH, d J 9.1 Hz, Ar), 8.28 (IH, d / 9.1 Hz, Ar), 8.15 (IH, dd J 9.2, 4.4 Hz, Ar), 7.94 (IH, dd 7.5, 1.0 Hz, Ar), 7.87 (IH, dd / 9.1, 2.0 Hz, Ar), 7.71 (IH, t / 8.1 Hz, Ar), 7.32 (IH, dd 9.2, 2.6 Hz, Ar), 7.16 (IH, td / 9.2, 2.6 Hz, Ar), 3.66 (2H, s, CH2CO2H), 2.60 (3H, s, CH3); Tr = 2.13 min (100%), m/z (ES+) (M+Η)+ 432.3.
[5-Fluoro-2-methyl-l-(4-nitro-benzenesulfonyl)-/H-indol-3-yl]-acetic acid
(Compound 18) δH (400 MHz, dβ-DMSO) 8.35 (2H, d 79.0 Hz, Ar), 8.12 (2H, d 79.0 Hz, Ar), 8.08 (IH, dd / 9.0, 4.4 Hz, Ar), 7.35 (IH, dd J 9.0, 2.7 Hz, Ar), 7.19 (IH, td / 9.3, 2.7 Hz, Ar), 3.68 (2H, s, CH2CO2H), 2.55 (3H, s, CH3); Tr = 1.95 min (90%), m/z (ES+) (M+Η)+ 393.22.
[S-Fluoro^-methyl-l-tS-trifluoromethyl-benzenesulfony^-liϊ-indol-S-yU-acetic acid (Compound 19) δH (400 MHz, 6-DMSO) 8.13-8.06 (4H, m, Ar), 7.84 (IH, t J 7.9 Hz, Ar), 7.34 (IH, dd 9.1, 7.65 Hz, Ar), 7.18 (IH, td 9.2, 2.7 Hz, Ar), 3.67 (2H, s, CH2CO2H), 2.55 (3H, s, CH3); Tr = 2.02 min (97%), m/z (ES+) (M+Η)+ 416.18.
(l-Benzenesulfonyl-5-fluoro-2-methyl-lH-indol-3-yl)-acetic acid (Compound 20) δH (400 MHz, -DMSO) 8.07 (IH, dd J 9.1, 4.4 Hz, Ar), 7.85 (2H, m, Ar), 7.72 (IH, t / 7.3 Hz, Ar), 7.60 (2H, m, Ar), 7.32 (IH, dd 9.1, 2.7 Hz, Ar), 7.16 (IH, td J 9.04, 2.7 Hz, Ar), 3.66 (2H, s, CH2CO2H), 2.54 (3H, s, CH3); Tr = 1.92 min (93%), m/z (ES+) (M+Η)+ 348.22.
[5-Fluoro-2-methyl-l-(quinoline-8-sulfonyl)-2H-indol-3-yl]-acetic acid
(Compound 21) δH (400 MHz, MeOD) 8.79 (IH, dd / 4.2, 1.7 Hz, Ar), 8.45 (IH, dd / 7.3, 1.2 Hz, Ar), 8.35 (IH, dd / 8.3, 1.7 Hz, Ar), 8.23 (IH, dd / 8.3, 1.5 Hz, Ar), 7.95 (IH, dd I 9.1, 4.4 Hz, Ar), 7.75 (IH, t / 7.6 Hz, Ar), 7.54 (IH, dd J 8.3, 4.4 Hz, Ar), 7.18 (IH, dd / 9.1, 2.5 Hz, Ar), 6.90 (IH, td 9.1, 2.4 Hz, Ar), 3.55 (2H, s, CH2CO2H), 2.76 (3H, s, CH3); Tr = 1.39 min (100%), m/z (ES+) (M+Η)+ 399.08.
[5-Fluoro-2-methyl-l-(toluene-4-sulfonyl)-2H-indol-3-yl]-acetic acid (Compound
22)
6H (400 MHz, -DMSO) 8.06 (IH, dd / 9.1, 4.5, Hz, Ar), 7.74 (2H, d / 8.1 Hz, Ar), 7.39 (2H, / 8.1 Hz, Ar), 7.30 (IH, dd / 9.1, 2.5 Hz, Ar), 7.15 (IH, td / 9.1, 2.5 Hz, Ar), 3.64 (2H, s, CH2CO2H), 2.50 (3H, s, CH3), 2.34 (3Η, s, ArCH3); Tr = 1.48 min (84%), m/z (ES+) (M+Η)+ 362.22. [l-(3-Chloro-benzenesulfonyl)-5-fluoro-2-methyl-2Hr-indol-3-yl]-acetic acid
(Compound 23) δH (400 MHz, dβ-D SO) 8.06 (IH, dd / 9.6, 4.5 Hz, Ar), 7.86 (IH, 1 2.0 Hz, Ar), 7.80 (2H, m,Ar), 7.62 (IH, t / 8.1 Hz, Ar), 7.33 (IH, dd 79.1, 2.5 Hz, Ar), 7.17 (IH, td / 9.6, 3.0 Hz, Ar), 3.66 (2H, s, CH2CO2H), 2.53 (3H, s, CH3); Tr = 1.51 min (93%), m/z (ES+) (M+Η)+ 382.19.
[l-(2,5-DichIoro-benzenesulfonyl)-5-fluoro-2-methyl-/H-indol-3-yl]-acetic acid (Compound 24)
Tr = 1.55 min (96%), m/z (ES+) (M+H)+ 416.14.
[5-Fluoro-l-(3-fluoro-benzenesulfonyl)-2-methyl-J,H-indol-3-yl]-acetic acid
(Compound 25)
Tr = 1.45 min (95%), m/z (ES+) (M+H)+ 366.15.
[l-(2-Cyano-benzenesulfonyl)-5-fluoro-2-methyl-/H-indol-3-yl]-acetic acid
(Compound 26)
Tr = 1.36 min (89%), m/z (ES+) (M+H)+ 373.13.
[5-Fluoro-l-(2-fluoro-benzenesulfonyl)-2-methyl-2H-indol-3-yl]-acetic acid
(Compound 27)
Tr = 1.42 min (85%), m/z (ES+) (M+H)+ 366.09.
[l-(2,3-Dichloro-benzenesulfonyl)-5-fluoro-2-methyl-2H-indol-3-yl]-acetic acid (Compound 28)
Tr = 1.55 min (85%), /z (ES+) (M+H)+ 416.01.
[l-(2,4-Dichloro-benzenesulfonyl)-5-fluoro-2-methyl-2H-indol-3-yl]-acetic acid (Compound 29)
Tr = 1.57 min (86%), m/z (ES+) (M+H)+ 416.08. [5-Fluoro-2-methyl-l-(3-trifluoromethoxy-benzenesulfonyl)-/H-indol-3-yl]- acetic acid (Compound 30)
Tr = 1.56 min (97%), m/z (ES+) (M+H)+ 432.12.
[5-Fluoro-2-methyl-l-(toluene-2-sulfonyI)-2H-indol-3-yl]-acetic acid (Compound 31) δH (400 MHz, 6-DMSO) 7.87 (IH, dd / 9.1, 4.5, Ar), 7.63 (IH, t J 7.5 Hz, Ar), 7.48 (2H, m, Ar), 7.43-7.40 (2H, m, Ar), 7.12 (IH, td, 9.1, 2.5 Hz, Ar), 3.71 (2H, s, CH2CO2H), 2.35 (3H, s, CH3), 2.34 (3Η, s, CH3); Tr = 1.48 min (92%), m/z (ES+) (M+Η)+ 362.18.
[l-(5-Chloro-naphthalene-2-sulfonyl)-5-fIuoro-2-methyl-/H-indol-3-yl]-acetic acid (Compound 32)
Tr = 1.66 min (100%), m/z (ES+) (M+H)+ 432.15.
[5-Fluoro-l-(3-methoxy-benzenesulfonyl)-2-methyl-7H-indol-3-yl]-acetic acid (Compound 33) δH (400 MHz, -DMSO) 8.06 (IH, dd / 9.1, 4.5 Hz, Ar), 7.51 (IH, t / 7.5 Hz, Ar), 7.38 (IH, d 8.6 Hz, Ar), 7.33 (IH, dd / 9.1, 3.0 Hz, Ar), 7.28 (IH, dd, / 8.5, 2.3 Hz, Ar), 7.22 (IH, t / 2.0 Hz, Ar), l.ll (IH, td I 9.1, 2.5 Hz, Ar), 3.76 (3H, s, OCH3), 3.66 (2Η, s, CH2CO2H), 2.54 (3H, s, CH3); Tr = 1.45 min (89%), m/z (ES+) (M+Η)+ 378.17.
[5-Fluoro-2-methyl-l-(4-pyrazol-l-yl-benzenesulfonyl)-/H-indol-3-yl]-acetic acid (Compound 34) δH (400 MHz, 6-DMSO) 8.60 (IH, d 4.0 Hz, Ar), 8.10 (IH, dd J 9.1, 4.6 Hz, Ar), 8.03 (2H, d / 9.1 Hz, Ar), 7.96 (2H, d / 9.1 Hz, Ar), 7.83 (IH, d / 3.0 Hz, Ar), 7.32 (IH, dd / 9.1, 2.5 Hz, Ar), 111 (IH, td J 9.3, 2.5 Hz, Ar), 6.61(1H, t / 2.5 Hz, Ar), 3.64 (2H, s, CH2CO2H), 2.56 (3H, s, CH3); Tr = 1.43 min (100%), m/z (ES+) (M+Η)+ 414.16. [l-(2,2-Dimethyl-chroman-6-sulfonyl)-5-fluoro-2-methyl- H-indol-3-yl]-acetic acid (Compound 35)
Tr = 1.60 min (100%), m/z (ES+) (M+H)+ 432.19.
[5-Fluoro-2-methyl-l-(4-methyl-naphthalene-l-sulfonyl)-lH-indol-3-yl]-acetic acid (Compound 36)
Tr = 1.60 min (100%), m/z (ES+) (M+H)+ 412.14.
[l-(5-Chloro-3-methyl-benζo[b]thiophene-2-sulfonyl)-5-fluoro-2-methyl-2H- indol-3-yl] -acetic acid (Compound 37) δH (400 MHz, -DMSO) 8.11 (2H, m, Ar), 8.03 (IH, dd 9.1, 4.5 Hz, Ar), 7.63 (IH, dd / 8.8, 2.2 Hz, Ar), 7.39 (IH, dd / 9.1, 2.5 Hz, Ar), 7.20 (IH, td 9.1, 2.5 Hz) 3.69 (2H, s, CH2CO2H), 2.57 (3H, s, CH3), 2.52 (3Η, s, CH3); Tr = 1.71 min (98%), m/z (ES+) (M+Η)+ 452.09.
{5-Fluoro-2-methyl-l-[4-(morpholine-4-suIfonyl)-benzenesulfonyl]-2H-indol-3- yl}-acetic acid (Compound 38) δH (400 MHz, J6-DMSO) 8.06 (2H, d J 8.6 Hz, Ar), 7.99 (IH, dd / 9.08, 4.04 Hz, Ar), 7.91 (2H, d / 8.6 Hz, Ar), 7.30 (IH, dd / 9.1, 2.5 Hz, Ar), 7.11 (IH, td J 9.1, 2.5 Hz, Ar), 3.59 (4H, t J 4.6 Hz, CH2CH2), 3.27 (2Η, s, CH2CO2H), 2.89 (4H, t, / 4.6 Hz, CH2CH2), 2.51 (3H, s, CH3); Tr = 1.40 min (96%), m/z (ES+) (M+Η)+ 497.11.
(l-Ethanesulfonyl-5-fluoro-2-methyl-2H-indol-3-yl)-acetic acid (Compound 39)
Tr = 1.28 min (100%), m/z (ES+) (M+H)+ 300.25.
trans [5-Fluoro-l-(^-styrenesulfony)-2-methyi-iH-indol-3-yI]-acetic acid (Compound 40)
Tr = 1.50 min (100%), m/z (ES+) (M+H)+ 374.16.
[l-(Butane-l-sulfonyl)-5-fluoro-2-methyl-2H-indol-3-yl]-acetic acid (Compound 41) δH (400 MHz, -DMSO) 7.89 (IH, dd J 9.4, 4.2 Hz, Ar), 1.31 (IH, dd 9.3, 2.7 Hz, Ar), 7.14 (IH, td J 9.08, 2.5 Hz, Ar), 3.71 (2H, s, CH CO2H), 3.52 (2H, t J 7.6 Hz, CH2), 2.50 (3Η, s, CH3), 1.48 (2Η, m, CH2), 1.27 (2Η, q /7.6 Hz, CH2), 0.77 (3Η, t J 7.6 Hz, CH2CH3); Tr = 1.43 min (97%), m/z (ES+) (M+Η)+ 328.22.
[l-(Benzo[l,2,5]thiadiazole-4-sulfonyl)-5-fluoro-2-methyl-2H-indol-3-yl]-acetic acid (Compound 42) δH (400 MHz, 6-DMSO) 8.55 (IH, d / 6.6 Hz, Ar), 8.47 (IH, d I 2.5 Hz, Ar), 7.96- 7.90 (2H, m, Ar), 7.27 (IH, dd / 9.1, 2.5 Hz, Ar), 7.08 (IH, td, 9.1, 2.5 Hz, Ar), 3.65 (2H, s, CH2CO2H), 2.72 (3H, s, CH3); Tr = 1.40 min (100%), m/z (ES+) (M+Η)+ 406.14.
[l-(2-Chloro-4-trifluoromethyl-benζenesulfonyl)-5-fluoro-2-methyl-2H-indol-3- yl]-acetic acid (Compound 43)
Tr = 1.60 min (100%), m/z (ES+) (M+H)+ 450.11.
[5-Fluoro-2-methyl-l-(pyridine-3-sulfonyl)-2H-indol-3-yl]-acetic acid
(Compound 44)
Tr = 1.27 min (98%), m/z (ES+) (M+H)+ 349.16.
[5-Fluoro-2-methyl-l-(3-nitro-benzenesulfonyl)-2H-indol-3-yl]-acetic acid
(Compound 45)
Tr = 1.45 min (100%), m/z (ES+) (M+H)+ 393.13.
(5-Fluoro-2-methyl-l-phenylmethanesulfonyl-2H-indol-3-yl)-acetic acid
(Compound 46)
Tr = 1.43 min (95%), m/z (ES+) (M+H)+ 362.19.
[l-(2-ChIoro-benzenesulfonyl)-5-fluoro-2-methyl-2H-indol-3-yl]-acetic acid (Compound 47)
Tr = 1.46 min (100%), m/z (ES+) (M+H)+ 382.17.
[l-(3-Cyano-benzenesulfonyl)-5-fluoro-2-methyl-2/ -indol-3-yl]-acetic acid
(Compound 48)
Tr = 1.40 min (100%), m/z (ES+) (M+H)+ 373.16.
[l-(4-Cyano-benzenesulfonyl)-5-fluoro-2-methyl-2H-indol-3-yl]-acetic acid
(Compound 49)
Tr = 1.41 min (100%), m/z (ES+) (M+H)+ 373.20.
[5-Fluoro-l-(4-isopropyl-benzenesulfonyl)-2-methyl-2H-indol-3-yl]-acetic acid (Compound 50) δH (400 MHz, 6-DMSO) 8.08 (IH, dd / 9.1, 4.6 Hz, Ar), 7.79 (2H, d / 8.6 Hz, Ar), 7.48 (2H, d / 8.1 Hz, Ar), 7.32 (IH, dd / 9.1, 2.5 Hz, Ar), 7.16 (IH, td / 9.1, 2.5 Hz, Ar), 3.66 (2H, s, CH2CO2H), 2.94 (IH, m, CH2(CH3)2), 2.54 (3H, s, CH3), 1.16 (6Η, d, CH2(CH3)2); Tr = 1.60 min (100%), m/z (ES+) (M+Η)+ 390.33.
[l-(2-Acetyl-l,2,3,4-tetrahydro-isoquinoline-6-sulfonyl)-5-fluoro-2-methyl-2H- indol-3-yl]-acetic acid (Compound 51)
Tr = 1.30 min (100%), m/z (ES+) (M+H)+ 445.08.
[5-Fluoro-2-methyl-l-(5-pyridin-2-yl-thiophene-2-suIfonyl)-2H-indoI-3-yl]-acetic acid (Compound 52)
Tr = 1.49 min (100%), m/z (ES+) (M+H)+ 431.16.
[l-(5-Chloro-l,3-dimethyl-2H-pyraζole-4-sulfonyl)-5-fluoro-2-methyl-2iϊ-indol- 3-yl]-acetic acid (Compound 53) δH (400 MHz, -DMSO) 7.89 (IH, dd / 9.3, 4.4 Hz, Ar), 7.36 (IH, dd, / 9.0, 2.7 Hz, Ar), 7.15 (IH, dd / 9.2, 2.5 Hz, Ar), 3.74 (3H, s, NCH3), 3.68 (2Η, s, CH2CO2H), 3.46 (3H, s, CH3), 3.21 (3Η, s, CH3); Tr = 1.37 min (95%), m/z (ES+) (M+Η)+ 400.5. [5-Fluoro-2-methyl-l-(4-trifluoromethoxy-benzenesulfonyl)-2H-indol-3-yl]- acetic acid (Compound 54) δH (400 MHz, d6-DMSO) 8.07 (IH, dd / 9.3, 4.4 Hz, Ar), 8.01 (2H, d / 9.0 Hz, Ar), 7.58 (2H, d / 8.1 Hz, Ar), 7.34 (IH, dd / 9.0, 2.7 Hz, Ar), 7.18 (IH, td / 9.2, 2.5 Hz, Ar), 3.67 (2H, s, CH2CO2H), 2.54 (3H, s, CH3); Tr = 1.56 min (100%), m/z (ES+) (M+Η)+ 432.04.
[5-Fluoro-l-(isoquinoline-5-suIfonyl)-2-methyl-2fiT-indol-3-yl]-acetic acid
(Compound 55)
Tr = 1.18 min (93%), m/z (ES+) (M+H)+ 399.21.
[l-(5-Chloro-2-methoxy-benzenesulfonyl)-5-fluoro-2-methyl-2/2r-indol-3-yl]- acetic acid (Compound 56)
Tr = 1.51 min (100%), m/z (ES+) (M+H)+ 412.02.
[l-(4-Chloro-2,5-dimethyl-benzenesulfonyl)-5-fluoro-2-methyl-2H-indol-3-yl]- acetic acid (Compound 57)
Tr = 1.66 min (97%), /z (ES+) (M+H)+ 410.22.
[5-Fluoro-l-(2-hydroxy-2H-chromene-6-sulfonyl)-2-methyl-22 -indol-3-yI]- acetic acid (Compound 58)
Tr = 1.36 min (100%), m/z (ES+) (M+H)+ 416.23.
{5-Fluoro-l-[4-(4-fluoro-phenoxy)-benzenesulfonyl]-2-methyl-2H-indol-3-yl}- acetic acid (Compound 59) δH (250 MHz, d6-DMSO) 8.00 (IH, dd / 9.1, 4.5 Hz, Ar), 7.84 (2H, d / 8.9 Hz, Ar), 7.33-7.20 (5H, m, Ar), 7.09 (IH, dd /9.3, 2.8 Hz, Ar), 7.03 (2H, d/ 8.9 Hz, Ar), 3.14 (2H, s, CH2CO2H), 2.49 (3H, s, CH3); Tr = 1.63 min (95%), m/z (ES+) (M+Η)+ 458.08. {l-[4-(4-Chloro-phenoxy)-benzenesulfonyl]-5-fluoro-2-methyl-22jT-indol-3-yl}- acetic acid (Compound 60) δH (250 MHz, J6-DMSO) 8.00 (IH, dd /9.1, 4.6 Hz), 7.84 (2H, d / 8.8 Hz, Ar), 7.50 (2H, d / 9.0 Hz, Ar), 7.29 (IH, dd / 9.1, 2.7 Hz, Ar), 7.20 (2H, d / 8.9Hz, Ar), 7.07 (3H, m, Ar), 3.12 (2H, s, CH2CO2H), 2.49 (3H, s, CH3); Tr = 1.71 min (98%), /z (ES+) (M+Η)+ 473.98.
{5-Fluoro-2-methyl-l-[4-(4-trifluoromethyl-phenoxy)-benzenesulfonyl]-2H- indoI-3-yl}-acetic acid (Compound 61) δH (250 MHz, d6-DMSO) 8.00 (IH, dd / 9.0, 4.6 Hz, Ar), 7.88 (2H, d / 8.9 Hz, Ar), 7.81 (2H, d / 7.3 Hz, Ar), 7.35-7.27 (3H, m, Ar), 7.18 (2H, d / 9.0 Hz, Ar), 7.08 (IH, td / 9.0, 2.8 Hz, Ar), 3.14 (2H, s, CH2CO2H), 2.50 (3H, s, CH3); Tr = 1.71 min (100%), m/z (ES+) 508.06 (M+Η)+.
{l-[4-(4-Bromo-phenoxy)-benzenesuIfonyl]-5-fluoro-2-methyl-2H-indol-3-yl}- acetic acid (Compound 62) δH (250 MHz, MeOD) 8.14 (IH, dd / 9.1, 4.5 Hz, Ar), 7.80 (2H, d / 8.9 Hz, Ar), 7.57 (2H, d / 9.0 Hz, Ar), 7.19 (IH, dd / 8.9, 2.6 Hz, Ar), 7.09-6.99 (5H, m, Ar), 3.66 (2H, s, CH2CO2H), 2.61 (3H, s, CH3); Tr = 1.73 min (100%), m/z (ES+) (M+Η)+ 517.99.
{5-Fluoro-l-[4-(4-methoxy-phenoxy)-benzenesulfonyl]-2-methyl-2H-indol-3-yl}- acetic acid (Compound 63) δH (400 MHz, d6-DMSO) 7.99 (IH, dd / 8.99, 4.6 Hz, Ar), 7.81 (2H, d / 9.1 Hz, Ar), 7.28 (IH, dd / 9.3, 2.5 Hz, Ar), 7.12-7.05 (3H, m, Ar), 7.02-6.95 (4H, m, Ar), 3.77 (3H, s, OCH3), 3.14 (2Η, s, CH2CO2H), 2.49 (3H, s, CH3); Tr = 1.61 min (100%), m/z (ES+) (M+Η)+ 470.20.
[l-(3,4-Dihydro-2H-benzo[b][l,4]dioxepine-7-suIfonyl)-5-fluoro-2-methyI-2H- indol-3-yl]-acetic acid (Compound 64) δH (400 MHz, 6-DMSO) 8.06 (IH, dd / 9.1, 4.5 Hz, Ar), 7.44 (IH, dd / 8.6, 2.5 Hz, Ar), 7.35-7.32 (2H, m, Ar), 7.17 (IH, td / 9.1, 2.5 Hz, Ar), 7.11 (IH, d / 8.6 Hz, Ar), 4.25 (2H, t / 5.6 Hz, OCH2), 4.20 (2Η, t / 6.0 Hz, OCH2), 3.67 (2Η, s, CH2CO2H), 2.51 (3H, s, CH3), 2.12 (2Η, m, CH2CH2CH2); Tr = 1.67 min (100%), m/z (ES+) (M+H)+ 420.25.
[5-Fluoro-2-methyl-l-(4-oxazol-5-yl-benzenesulfonyl)-2H-indol-3-yl]-acetic acid (Compound 65) δH (400 MHz, -DMSO) 8.56 (IH, s, Ar), 8.09 (IH, dd / 9.1, 4.6 Hz, Ar), 7.96-7.89 (5H, m, Ar), 7.33 (IH, dd / 9.1, 2.5 Hz, Ar), 1.11 (IH, td, / 9.4, 2.5 Hz, Ar), 3.66 (2H, s, CH2CO2H), 2.56 (3H, s, CH3); Tr = 1.62 min (92%), m/z (ES+) (2M+Η)+ 829.54.
[5-Fluoro-2-methyl-l-(4-p-tolyloxy-benζenesulfonyl)-2H-indol-3-yl]-acetic acid (Compound 66) δH (250 MHz, MeOD) 8.09 (IH, dd / 9.0, 4.5 Hz, Ar), 1.11 (2H, d / 9.0 Hz, Ar), 7.30-7.23 (3H, m, Ar), 7.03-6.94 (5H, m, Ar), 3.47 (2H, s, CH2CO2H), 2.61 (3H, s, CH3), 2.37 (3Η, s, CH3); Tr = 1.71 min (100%), m/z (ES+) (M+Η)+ 454.15.
[5-Fluoro-2-methyl-l-(4- -tolyloxy-benzenesulfonyl)-2H-indol-3-yl]-acetic acid (Compound 67) δH (250 MHz, MeOD) 8.09 (IH, dd / 9.2, 4.3 Hz, Ar), 7.78 (2H, d / 8.9 Hz, Ar), 7.34-7.25 (2H, m, Ar), 7.08 (IH, d / 7.6 Hz, Ar), 6.98 (2H, d / 9.0 Hz, Ar), 6.91-6.84 (3H, m, Ar), 3.47 (2H, s, CH2CO2H), 2.61 (3H, s, CH3), 2.36 (3Η, s, CH3); Tr = 1.70 min (100%), m/z (ES+) (M+Η)+ 454.17.
{l-[4-(3-Chloro-phenoxy)-benzenesulfonyl]-5-fluoro-2-methyl-2H-indol-3-yl}- acetic acid (Compound 68) δH (250 MHz, MeOD) 8.09 (IH, dd / 9.1, 4.5 Hz, Ar), 7.82 (2H, d / 9.0 Hz, Ar), 7.42 (IH, t / 8.1 Hz, Ar), 7.30-7.25 (2H, m, Ar), 7.14 (IH, t / 2.2 Hz, Ar), 7.07-6.96 (4H, m, Ar), 3.47 (2H, s, CH2CO2H), 2.62 (3H, s, CH3); Tr = 1.71 min (100%), m/z (ES+) (M+Η)+ 474.10. {l-[4-(2,4-DichIoro-phenoxy)-benzenesulfonyl]-5-fluoro-2-methyl-2H-indol-3- yl}-acetic acid (Compound 69) δH (250 MHz, MeOD) 8.09 (IH, dd / 8.9, 4.5 Hz, Ar), 7.82 (2H, d / 8.9 Hz, Ar), 7.64 (IH, d / 2.5 Hz, Ar), 7.41 (IH, dd / 9.6, 2.5 Hz, Ar), 7.28 (IH, dd / 9.2, 2.5 Hz, Ar),
7.19 (IH, d / 8.6 Hz, Ar), 7.04-6.96 (3H, m, Ar), 3.47 (2H, s, CH2CO2H), 2.61 (3H, s, CH3); Tr = 1.76 min (97%), m/z (ES+) (M+Η)+ 508.08.
{l-[4-(2-Chloro-phenoxy)-benζenesulfonyl]-5-fluoro-2-methyl-2H-indol-3-yl}- acetic acid (Compound 70) δH (250 MHz, MeOD) 8.09 (IH, dd / 9.0, 4.4 Hz, Ar), 7.80 (2H, d / 9.1 Hz, Ar), 7.57 (IH, dd / 7.8, 2.9 Hz, Ar), 7.38 (IH, dd / 7.6, 1.9 Hz, Ar), 7.33-7.26 (2H, m, Ar),
7.20 (IH, dd / 7.8, 1.6 Hz, Ar), 7.01 (IH, dd / 9.0, 2.5 Hz, Ar), 6.95 (2H, d / 9.1 Hz, Ar), 3.47 (2H, s, CH2CO2H), 2.61 (3H, s, CH3); Tr = 1.66 min (100%) m/z (ES+) (M+Η)+ 474.11.
{5-FIuoro-l-[4-(2-methoxy-phenoxy)-benzenesulfonyl]-2-methyl-2H-indol-3-yl}- acetic acid (Compound 71) δH (250 MHz, MeOD) 8.09 (IH, dd / 9.0, 4.4 Hz, Ar), 7.74 (2H, d / 8.9 Hz, Ar), 7.32-7.25 (2H, m, Ar), 7.14 (IH, d / 8.7 Hz, Ar), 7.09 (IH, dd / 7.9, 2.0 Hz, Ar), 7.04-6.95 (2H, m, Ar), 6.87 (2H, d / 8.9 Hz, Ar), 3.72 (3H, s, OCH3), 3.47 (2Η, s, CH2CO2H), 2.61 (3H, s, CH3); Tr = 1.60 min (100%) m/z (ES+) (M+Η)+ 470.16.
{l-[4-(2,5-DichIoro-phenoxy)-benζenesulfonyl]-5-fluoro-2-methyl-2H-indol-3- yl}-acetic acid (Compound 72) δH (250 MHz, MeOD) 8.09 (IH, dd / 9.1, 4.4 Hz, Ar), 7.82 (2H, d / 9.0 Hz, Ar), 7.56 (2H, d 8.5 Hz, Ar), 7.35-7.25 (3H, m, Ar), 7.04-6.95 (3H, m, Ar), 3.47 (2H, s, CH2CO2H), 2.62 (3H, s, CH3); Tr = 1.74 min (97%) m/z (ES+) (M+Η)+ 508.08.
[5-Fluoro-2,4-dimethyl-l-(naphthalene-2-sulfonyl)-2H-indol-3-yl]-acetic acid (Compound 73) δH (400 MHz, ((CD3)2CO) 8.62 (IH, s, Ar), 8.20 (IH, d / 9.3 Hz, Ar), 8.15 (IH, dd / 9.3, 4.3 Hz, Ar), 8.07 (IH. d / 8.8 Hz, Ar), 8.03 (IH, d / 7.9 Hz, Ar), 7.78-7.70 (3H, m, Ar), 7.06 (IH, t / 9.7 Hz, Ar), 3.90 (2H, s, CH2CO2H), 2.71 (3H, s, CH3), 2.50 (3Η, s, CH3); Tr = 1.79 min (98%) m/z (ES+) (M+Η)+ 412.17.
[5-Fluoro-l-(4-methanesulfonyl-benzenesulfonyl)-2,4-dimethyl-22ιf-indol-3-yl]- acetic acid (Compound 74) δH (400 MHz, ((CD3)2CO) 8.16 (2H, d / 8.8 Hz, Ar), 8.12 (2H, d / 8.8 Hz, Ar), 8.07 (IH, dd / 9.0, 4.2 Hz, Ar), 7.10 (IH, t / 9.6 Hz, Ar), 3.92 (2H, s, CH2CO2H), 3.22 (3H, s, SO2CH3), 2.67 (3Η, s, CH3), 2.51 (3Η, s, CH3); Tr = 1.36 min (87%) m/z (ES+) (M+Η)+ 440.13.
[5-Fluoro-2,4-dimethyl-l-(4-phenoxy-benzenesulfonyl)-2H-indol-3-yl]-acetic acid (Compound 75) δH (400 MHz, ((CD3)2CO) 8.07 (IH, dd / 9.1, 4.4 Hz, Ar), 7.88 (2H, d / 9.0 Hz, Ar), 7.52-7.48 (2H, m, Ar), 7.31 (IH, t / 7.5 Hz, Ar), 7.14 (2H, m, Ar), 7.08-7.03 (3H, m, Ar), 3.91 (2H, s, CH2CO2H), 2.66 (3H, s, CH3), 2.52 (3Η, s, CH3); Tr = 1.89 min (100%) m/z (ES+) (M+Η)+ 454.19.
{5-Fluoro-2-methyl-l-[4-(pyrrolidine-l-sulfonyl)-benzenesulfonyl]-2/ -indol-3- yl}-acetic acid (Compound 76) δH (400 MHz, -DMSO) 8.06-8.03 (3H, m, Ar), 7.97 (2H, d / 8.6 Hz, Ar), 7.35 (IH, dd / 9.0, 2.7 Hz, Ar), 7.19 (IH, td / 9.3, 2.7 Hz, Ar), 3.67 (2H, s, CH2CO2H), 3.12 (4H, m, 2 x CH2), 2.51 (3Η, s, CH3), 1.60 (4Η, m, 2 x CH2); Tr = 1.47 min (100%) m/z (ES+) (M+Η)+ 481.10.
[5-Fluoro-l-(4-hydroxy-benζenesuIfonyI)-2-methyl-2H-indol-3-yl]-acetic acid (Compound 77) δH (400 MHz, 6-DMSO) 8.05 (IH, dd / 9.0, 4.5 Hz, Ar), 7.71 (2H, d / 8.8 Hz, Ar), 7.31 (IH, dd / 9.2, 2.6 Hz, Ar), 7.16 (IH, / 9.2, 2.6 Hz, Ar), 6.88 (2H, d / 8.9 Hz, Ar), 3.64 (2H, s, CH2CO2H), 2.53 (3H, m, CH3); Tr = 1.29 min (97%) m/z (ES+) (M+Η)+ 364.12.
[l-(3-Cyano-4-hydroxy-benζenesulfonyl)-5-fluoro-2-methyl-2H-indol-3-yl]- acetic acid (Compound 78)
Tr = 1.31 min (100%) m/z (ES+) 389.12 (M+H)+.
[l-(3-carboxamido-benzenesulfonyl)-5-fluoro-2-methyl-22 -indol-3-yl]-acetic acid (Compound 79) δH (400 MHz, -DMSQ) 8.35 (IH, s, NH), 8.31 (1Η, s, NH), 8.18 (1Η, d / 7.8 Ηz, Ar), 8.09 (1Η, dd / 9.1, 4.3 Ηz, Ar), 7.95 (1Η, d / 8.0 Ηz, Ar), 7.70-7.66 (2Η, m, Ar), 7.33 (IH, dd / 9.0, 2.6 Hz, Ar), 7.17 (IH, td / 9.1, 2.6 Hz, Ar), 3.66 (2H, s, CH2CO2H), 2.54 (3H, m, CH3); Tr = 1.19 min (100%) m/z (ES+) (M+Η)+ 391.12.
[l-(4-carboxamido-benzenesulfonyl)-5-fluoro-2-methyl-2H-indol-3-yl]-acetic acid (Compound 80) δH (400 MHz, -DMSO) 8.16 (IH, s, NH), 8.08 (1Η, dd / 9.1, 4.4 Ηz, Ar), 7.97 (2Η, d / 8.8 Hz, Ar), 7.93 (2H, d / 8.8 Hz, Ar), 1.66 (IH, s, NH), 7.33 (1Η, dd / 9.2, 2.5 Ηz, Ar), 7.16 (1Η, td / 9.2, 2.6 Ηz, Ar), 3.66 (2Η, s, CH2CO2H), 2.55 (3H, m, CH3); Tr = 1.20 min (100%) m/z (ES+) (M+Η)+ 391.14.
[5-Fluoro-2-methyl-l-(3-phenoxy-benzenesulfonyl)-2H-indol-3-yl]-acetic acid (Compound 81) δH (250 MHz, CDC13) 7.92 (IH, dd / 9.1, 4.4 Hz, Ar), 7.35-7.20 (4H, m, Ar), 7.14- 7.05 (3H, m, Ar), 6.97 (IH, dd / 8.6, 2.3 Hz, Ar), 6.87 (IH, dd / 9.1, 2.5 Hz, Ar), 6.81 (2H, d / 6.8 Hz, Ar), 3.46 (2H, s, CH2CO2H), 2.42 (3H, m, CH3); Tr = 1.63 min (100%) m/z (ES+) (M+Η)+ 440.11.
[5-Fluoro-2-methyl-l-(4-methylsulfanyl-benzenesulfonyl)-2H-indol-3-yl]-acetic acid (Compound 82) δH (400 MHz, MeOD) 8.14 (IH, dd / 9.1, 4.6 Hz, Ar), 7.68 (2H, d / 8.6 Hz, Ar), 7.32 (2H, d / 8.6 Hz, Ar), 7.19 (IH, dd / 8.6, 2.5 Hz, Ar), 7.06 (IH, td / 9.1, 2.5 Hz, Ar), 3.65 (2H, s, CH2CO2H), 2.61 (3H, m, CH3), 2.50 (3Η, m, CH3); Tr = 1.50 min (100%) m/z (ES+) (M+Η)+ 394.12.
[5-Fluoro-2-methyl-l-(3-methyl-quinoline-8-sulfonyl)-2H-indol-3-yI]-acetic acid (Compound 83) δH (400 MHz, -DMSO) 8.67 (IH, d / 2.2 Hz, Ar), 8.50 (IH, dd / 7.4, 1.2 Hz, Ar), 8.26 (IH, dd / 8.3, 1.1 Hz, Ar), 8.23 (IH, s, Ar), 7.83-7.77 (2H, m, Ar), 6.99 (IH, td / 9.2, 2.7 Hz, Ar), 3.61 (2H, s, CH2CO2H), 2.71 (3H, m, CH3), 2.44 (3Η, m, CH3); Tr = 1.46 min (100%) /z (ES+) (M+Η)+ 413.14.
[5-FIuoro-2-methyl-l-(3-sulfonamido-benzenesulfonyl)-2iϊ-indol-3-yl]-acetic acid (Compound 84) δH (400 MHz, 6-DMSO) 8.30 (IH, s, Ar), 8.13-8.01 (3H, m, Ar), 7.81 (IH, t / 7.8 Hz, Ar), 7.70 (2H, s, NH2), 7.35 (1Η, dd / 8.8, 2.2 Ηz, Ar), 7.18 (1Η, td / 10.0, 2.2 Ηz, Ar), 3.61 (2Η, s, CH2CO2H), 2.55 (3H, m, CH3); Tr = 1.27 min (100%) m/z (ES+) (M+Η)+ 427.06.
[5-Cyano-l-(4-methanesulfonyl-benzenesulfonyl)-2-methyl-2H-indol-3-yl]-acetic acid (Compound 85) δH (400 MHz, i6-DMSO) 8.27 (IH, d / 9.1 Hz, Ar), 8.23 (2H, d / 8.6 Hz, Ar), 8.15 (2H, d / 8.6 Hz, Ar), 8.13 (IH, d / 1.0 Hz, Ar), 1.11 (IH, dd / 8.6, 1.5 Hz), 3.76 (2H, s, CH2CO2H), 3.30 (3H, m, CH3), 2.58 (3Η, m, CH3); Tr = 1.28 min (100%) m/z (ES+) (M+Η)+ 433.06.
[l-(4-Chloro-benzenesulfonyl)-5-cyano-2-methyl-2H-indol-3-yl]-acetic acid
(Compound 86) δH (400 MHz, 6-DMSO) 8.24 (IH, d / 8.6 Hz, Ar), 8.11 (IH, d / 1.5 Hz, Ar), 7.94 (2H, d / 8.6 Hz, Ar), 7.74 (IH, dd / 8.6, 1.5, Ar), 7.70 (2H, d /9.1 Hz, Ar), 3.75 (2H, s, CH2CO2H), 2.55 (3H, m, CH3); Tr = 1.46 min (100%) m/z (ES+) (M+Η)+ 389.08.
[5-Cyano-2-methyl-l-(4-phenoxy-benζenesulfonyl)-22 -indol-3-yl]-acetic acid (Compound 87) δH (400 MHz, 6-DMSO) 8.24 (IH, d / 8.6 Hz, Ar), 8.10 (IH, d / 1.0 Hz, Ar), 7.95 (2H, d / 9.1 Hz, Ar), 7.73 (IH, dd / 8.8, 1.8 Hz, Ar), 7.48 (2H, m, Ar), 7.30 (IH, t / 7.6 Hz, Ar), 7.16 (2H, m, Ar), 7.07 (2H, d / 9.1 Hz, Ar), 3.75 (2H, s, CH2CO2H), 2.56 (3H, m, CH3); Tr = 1.58 min (98%) m/z (ES+) (M+Η)+ 447.10.
{5-Fluoro-2-methyl-l-[4-(3-trifluoromethyl-phenoxy)-benzenesulfonyl]-2H- indol-3-yl}-acetic acid (Compound 88) δH (250 MHz, CDC13) 8.11 (IH, dd / 9.0, 4.4 Hz, Ar), 7.72 (2H, d / 8.8 Hz, Ar) 7.49 (2H, m, Ar), 7.28 (IH, s, Ar), 7.18 (IH, d / 6.7 Hz, Ar), 7.09 (IH, dd / 8.6, 2.5 Hz, Ar), 7.02 (IH, dd / 9.0, 2.5 Hz, Ar), 6.95 (2H, d / 8.8 Hz, Ar) 3.60 (2H, s, CH2CO2H), 2.57 (3H, m, CH3); Tr = 1.68 min (94%) m/z (ES+) (M+Η)+ 508.07.
[5-carboxamido-l-(4-methanesulfonyl-benzenesulfonyl)-2-methyl-2H-indol-3- yl] -acetic acid (Compound 89) δH (400 MHz, ti6-DMSO) 8.18 (2H, d, / 8.6 Hz, Ar), 8.14-8.10 (3H, m, Ar), 8.08 (IH, d / 1.5 Hz, Ar), 8.02 (IH, s, NH), 7.87 (1Η, dd / 8.6, 1.5 Ηz, Ar), 7.38 (1Η, s, NH), 3.71 (2Η, s, CH2CO2H), 3.29 (3H, m, CH3), 2.58 (3Η, m, CH3); Tr = 1.08 min (96%) m/z (ES+) (M+Η)+ 451.06.
[5-carboxamido-l-(4-chloro-benzenesulfonyl)-2-methyl-2H-indol-3-yl]-acetic acid (Compound 90) δH (400 MHz, 6-DMSO) 8.13 (2H, m, Ar), 8.05 (IH, bs, NH), 7.95 (2Η, d / 9.1 Hz, Ar), 7.90 (IH, dd / 8.9, 2.0 Hz, Ar), 7.71 (2H, d / 8.6 Hz, Ar), 7.42 (IH, s, NH), 3.74 (2Η, s, CH2CO2H), 2.59 (3H, m, CH3); Tr = 1.24 min (100%) m/z (ES+) (M+Η)+ 407.08.
[5-carboxamido-2-methyI-l-(4-phenoxy-benzenesulfonyl)-2H-indol-3-yl]-acetic acid (Compound 91) δH (400 MHz, c 6-DMSO) 8.07 (IH, d / 2.5 Hz, Ar), 8.06 (IH, s, Ar), 8.00 (IH, bs, NH), 7.91 (2Η, d / 9.1 Hz, Ar), 7.84 (IH, dd / 9.1, 1.5 Hz, Ar), 7.48 (2H, m, Ar), 7.36 (IH, bs, NH), 7.30 (1Η, t / 7.1 Ηz, Ar), 7.15 (2Η, m, Ar), 7.06 (2H, d / 9.1 Hz, Ar), 3.69 (2H, s, CH2CO2H), 2.52 (3H, m, CH3); Tr = 1.37 min (100%) m/z (ES+) (M+Η)+ 465.11.
[5-Fluoro-2-methyl-l-(3-N-methylsulfonamido-benzenesulfonyl)-2H-indol-3-yl]- acetic acid (Compound 92) δH (400 MHz, ^6-DMSO) 8.15 (IH, t / 1.6 Hz, Ar), 8.09-8.06 (3H, m, Ar, NHCH3), 7.85-7.81 (2H, m, Ar), 7.33 (IH, dd / 9.0, 2.6 Hz, Ar), 7.18 (IH, td / 9.2, 2.6 Hz, Ar), 3.66 (2H, s, CH2CO2H), 2.55 (3H, s, CH3), 2.28 (3Η, d /4.7 Hz, NHCH3); Tr = 1.34 min (93%) m/z (ES+) (M+Η)+ 441.14.
{5-Fluoro-2-methyI-l-[3-(pyrrolidine-l-sulfonyl)-benzenesulfonyl]-2H-indol-3- yl}-acetic acid (Compound 94) δH (400 MHz, J6-DMSO) 8.19 (IH, d / 8.0 Hz, Ar), 8.11-8.08 (2H, m, Ar), 7.91 (IH, t / 1.7 Hz, Ar), 7.86 (IH, t / 7.8, Ar), 7.34 (IH, dd / 9.0, 2.6 Hz, Ar), 7.22 (IH, td /
9.2, 2.6 Hz, Ar), 3.65 (2H, s, CH2CO2H), 2.88 (4H, m, 2 x NCH2), 2.54 (3Η, m,
CH3), 1.45 (4Η, m, 2 x NCH2); Tr = 1.45 min (100%) m/z (ES+) (M+Η)+ 481.17.
[5-Fluoro-2-methyl-l-(3-N-methylcarboxamido-benzenesulfonyl)-2H-indol-3- yl]-acetic acid (Compound 95)
Tr = 1.24 min (97%) m/z (ES+) (M+H)+ 405.18.
[5-Fluoro-2-methyl-l-(4-N-methylcarboxamido-benzenesulfonyl)-2H-indol-3- yl]-acetic acid (Compound 96)
Tr = 1.24 min (97%) m/z (ES+) (M+H)+ 405.16.
[5-Fluoro-2-methyl-l-(6-phenoxy-pyridine-3-sulfonyl)-2H-indol-3-yl]-acetic acid (Compound 97) δH (400 MHz, J6-DMSO) 8.71 (IH, d / 2.2 Hz, Ar), 8.24 (IH, dd / 8.9, 2.54 Hz, Ar), 8.07 (IH, dd / 9.1, 4.4 Hz, Ar), 7.44 (2H, m, Ar), 7.34 (IH, dd / 9.0, 2.2 Hz, Ar), 7.28 (IH, t / 7.6 Hz, Ar), 7.20-7.13 (4H, m, Ar), 3.67 (2H, s, CH2CO2H), 2.56 (3H, s, CH3); Tr = 1.55 min (97%) m/z (ES+) (M+Η)+ 441.17.
[l-(3-N,N-Dimethylsulfonamido-benζenesulfonyl)-5-fluoro-2-methyl-lH-indol-3- yl]-acetic acid (Compound 98) δH (400 MHz, -i6-DMSO) 8.20-8.18 (IH, m, Ar), 8.10 (IH, dd / 9.1, 4.4 Hz, Ar), 8.07-8.05 (IH, m, Ar), 7.90-7.86 (2H, m, Ar), 7.33 (IH, dd / 9.0, 2.6 Hz, Ar), 7.21 (IH, td / 9.1, 2.7 Hz, Ar), 3.65 (2H, s, CH2CO2H), 2.52 (3H, masked s, CH3), 2.43 (6Η, s, N(CH3)2); Tr = 1.45 min (93%), m/z (ES+) (M+Η)+ 455.09.
[5-Fluoro-l-(3-methanesuIfonyl-benzenesulfonyl)-2-methyl-lH-indol-3-yl]-acetic acid (Compound 99) δH (400 MHz, DMSO) 12.44 (IH, br s, CO2H), 8.29-8.25 (2Η, m, Ar), 8.13-8.08 (2H, m, Ar), 7.87 (IH, t / 7.9 Hz, Ar), 7.35 (IH, dd / 9.0, 2.6 Hz, Ar), 7.19 (IH, td / 9.1, 2.7 Hz, Ar), 3.67 (2H, s, CH2CO2H), 3.31 (3H, s, SO2CH3), 2.55 (3Η, s, CH3); Tr = 1.35 min (100%), m z (ES+) (M+Η)+ 426.10.
[l-(4-N,N-Dimethylcarboxamido-benζenesulfonyl)-5-fluoro-2-methyl-lH-indol- 3-yl] -acetic acid (Compound 100) δH (400 MHz, rf6-DMSO) 12.45 (IH, br s, CO2H), 8.08 (1Η, dd / 9.1, 4.6 Ηz, Ar), 7.89 (2Η, d / 8.6 Hz, Ar), 7.60 (2H, d Jt 8.6 Hz, Ar), 7.34 (IH, dd / 9.1, 2.5 Hz, Ar), 7.17 (IH, td / 9.1, 2.5 Hz, Ar), 3.66 (2H, s, CH2CO2H), 2.97 (3H, s, N(CH3)2), 2.79 (3Η, s, N (CH3)2), 2.54 (3Η, s, CH3); Tr = 1.28 min (96%), m/z (ES+) (M+Η)+ 419.23.
[l-(3-N,N-Dimethylcarboxamido-benzenesulfonyl)-5-fluoro-2-methyl-2H-indol- 3-yl]-acetic acid (Compound 101)
Tr = 1.74 min (100%), m/z (ES+) (M+H)+ 419.09. [5-Fluoro-2-methyl-l-(4-methyl-3,4-dihydro-2H-benzo[l,4]oxazine-7-sulfonyl)- 12ϊ-indol-3-yl]-acetic acid (Compound 102) δH (400 MHz, -DMSO) 8.08 (IH, dd / 9.1, 4.5 Hz, Ar), 7.31 (IH, dd / 9.1, 2.5 Hz, Ar), 7.14 ( IH, td / 9.1, 2.5 Hz, Ar), 7.06 (IH, app dd 8.3, 2.3 Hz, Ar), 6.88 (IH, app s, Ar), 6.79 (IH, d / 8.6 Hz, Ar), 4.25 (2H, obs t /4.0 Hz, NCH2CH2O), 3.65 (2Η, s, CH2CO2H), 3.26 (2H, obs t / 4.5 Hz, NCH2CH2O), 2.79 (3H, s, NCH3), 2.53 (3Η, s, CH3); Tr = 1.88 min (100%), m/z (ES+) (M+Η)+ 419.10.
[l-(5-Dimethylamino-naphthalene-l-sulfonyl)-5-fluoro-2-methyl-2H-indol-3-yl]- acetic acid (Compound 103) δH (400 MHz, solvent, ci6-DMSO) 8.38-8.34 (IH, m, Ar), 7.86-7.83 (2H, m, Ar), 7.44-7.39 (3H, m, Ar), 7.26 (IH, dd / 9.0, 2.4 Hz, Ar), 7.10 (IH, d / 7.6 Hz, Ar), 7.00 (IH, td / 9.1, 2.6 Hz, Ar), 3.55 (2H, s, CH2CO2H), 2.66 (6H, s, N(CH3)2), 2.52 (3Η, s, CH3); Tr = 1.48 min (93%), /z (ES+) (M+Η)+ 441.26.
{5-Fluoro-2-methyl-l-[4-(trifluoromethylsulfanyl-benzenesulfonyI]-lH-indol-3- yl}-acetic acid (104) δH (400 MHz, CDC13) 8.11 (IH, dd / 9.1, 4.4 Hz, Ar), 7.75 (2H, app d / 8.7 Hz, Ar), 7.68 (2H, d / 8.6 Hz, Ar), 7.10 (IH, dd / 8.5, 2.6 Hz, Ar), 7.03 (IH, td / 9.0, 2.6 Hz, Ar), 3.60 (2H, s, CH2CO2H), 2.56 (3H, s, CH3); Tr = 1.62 min (80%), m/z (ES+) (M+Η)+ 198.21.
Example 2 trifluoromethyl sulfone
Trifluoromethanesulfonyl-benzene
Ruthenium trioxide (13.9 mg, 0.07 mmol) was added in one portion to a stirred solution of phenyltrifluoromethylsulfide (1.4 ml, 9.8 mmol) in water : dichloromethane : acetonitrile (2:1:1; 80 ml) at room temperature. Sodium periodate (6.42 g, 0.03 mol) was then added over 5 min and the resulting mixture stirred at room temperature for 90 minutes. The mixture was then diluted with 'butyl methyl ether (250 ml) and water (250 ml) and the organic layer separated and washed sequentially with a saturated solution of sodium bicarbonate (2 x 100 ml) and then brine (100 ml). The organic extract was dried over sodium sulfate, filtered through a plug of silica and then concentrated in vacuo to give the trifluoromethyl sulfone (2.06 g, 100%). The product was used directly in the next step.
3-Trifluoromethanesulfonyl-benzenesulfonyl chloride
A solution of trifluoromethylsulfonyl-benzene (596 mg, 2.84 mmol) and chlorosulfonic acid (1.2 ml, 18.1 mmol) was heated at 120 °C for 8 hours. The mixture was then cooled to room temperature and poured into ice water (50 ml) and extracted into dichloromethane (3 x 50 ml). The organic extracts were dried and concentrated in vacuo to give the sulfonyl chloride (111 mg, 81 %). The product was used directly in the next step.
{5-Fluoro-2-methyl-l-[3-(trifluoromethylsulfonyl-benzenesulfonyl]-lH-indol-3- yl}-acetic acid (Compound 105)
The sulfonamide formation and hydrolysis were performed as described for compound 1. δH (400 MHz, i6-DMSO) 8.07 (IH, dd / 9.1, 4.5 Hz, Ar), 8.03 (IH, app s, Ar), 7.89 (IH, app d 7.7 Hz, Ar), 7.79 (IH, app d / 8.8 Hz, Ar), 7.58 (IH, t / 7.6 Hz, Ar), 7.33 (IH, dd / 9.1, 2.6 Hz, Ar), 7.19 (IH, td / 9.2, 2.7 Hz, Ar), 3.67 (2H, s, CH2CO2H), 2.52 (3H, masked s, CH3); Tr = 1.04 min (100%), m/z (ES+) (M+Η)+ 443.25.
Example 3 phenoxy pyridines
A(i). 2-Phenoxy-pyridine
Phenol (3.37 g, 35.88 mmol) in dioxane (15 mL) was added dropwise to sodium hydride (60% dispersion in mineral oil) (1.67 g, 41.75 mmol) under a nitrogen atmosphere. After stirring at room temperature for lhour, 2-fluoro-pyridine (2.9 g, 29.9 mmol) in dioxane (15 mL) was added and the resulting mixture stirred at 80 °C for 48 hours. The mixture was concentrated in vacuo, and then partitioned between DCM and saturated potassium carbonate solution. The organic layer was washed twice with saturated potassium carbonate solution, dried over sodium sulfate and concentrated in vacuo to give an oil. This oil was partitioned between acetonitrile (20 mL) and hexane (20 mL). The acetonitrile layer was collected, dried and concentrated in vacuo to give 2-phenoxy-pyridine (950 mg, 18%). δπ (400 MHz, CDCh) 8.20 (IH, dd / 4.7, 1.7 Hz, Ar), 7.71-7.65 (IH, m, Ar), 7.40 (2H, t / 7.9 Hz, Ar), 7.20 (IH, t / 7.4 Hz, Ar), 7.14 (2H, dd / 8.5, 1.0 Hz, Ar), 6.99 (IH, dd / 7.1, 5.0 Hz, Ar), 6.90 (IH, d / 8.3 Hz, Ar); Tr = 1.20 min (97%), m/z (ES+) (M+H)+ 172.02
(ii) 4-(Pyridin-2-yloxy)-benzenesulfonyl chloride
Chlorosulfonic acid (0.77 mL, 11.69 mmol) was added dropwise to a stirred solution of 2-phenoxy-pyridine (500 mg, 2.92 mmol) in chloroform (10 mL) at 0°C. The mixture was left at 0°C for 30 minutes, and then left overnight stirring at room temperature. Three other treatments with chlorosulfonic acid (3 x 0.38 mL, 3 x 5.84 mmol) were required to give complete conversion to the sulfonyl chloride. The resulting mixture was then poured slowly onto a mixture of ice and water (250 mL). The aqueous layer was extracted with dichloromethane (250 mL). The resulting organic layer was washed with water (20 mL), dried over sodium sulfate, filtered and concentrated in vacuo to give 4-(pyridin-2-yloxy)-benzenesulfonyl chloride (440 mg, 56%). δH (250 MHz, CDCl3) 8.26 (IH, dd / 4.8, 1.7 Hz, Ar), 8.06 (2H, d / 9.0 Hz, Ar), 7.88-7.78 (IH, m, Ar), 7.35 (2H, d / 9.0 Hz, Ar), 7.21-7.13 (IH, m, Ar), 7.07 (IH, d / 8.2 Hz, Ar); Tr = 1.54 min (95%), m/z (ES+) (M+H)+ 270.17
(iii) {5-FIuoro-2-methyl-l-[4-(pyridin-2-yloxy)-benzenesulfonyl]-lH-indol-3- yl}-acetic acid (Compound 106)
The sulfonamide formation and hydrolysis were performed as described for compound 1. δH (250 MHz, -DMSO) 8.18 (IH, br d / 5.1 Hz, Ar), 8.06 (IH, dd / 9.0, 4.2 Hz, Ar), 7.96-7.88 (3H, m, Ar), 7.36-7.07 (6H, m, Ar), 3.49 (2H, s, CH2CO2H), 2.52 (3H, masked s, CH3); Tr = 1.91 min (100%), m/z (ES+) (M+Η)+ 441.07.
B(i) 3-Phenoxy-pyridine Pyridin-3-ol (9.5 g, 100 mmol) and potassium hydroxide (5.6 g, 100 mmol) were heated at 150°C for 30 minutes. An excess of pyridin-3-ol (6 g, 63 mmol) was then added together with bromo-benzene (15.7 g, 100 mmol) and copper powder (0.2 g, 3 mmol). The resulting mixture was then heated at 200°C overnight. The copper powder was filtered off, and the resulting mixture was partitioned between ethyl acetate and water. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo to give a solid. This solid was washed with diethyl ether and the filtrate collected and concentrated in vacuo. The resulting product was purified by column chromatography using a lOg silica gel column, eluting with 20% ethyl acetate : heptane and gave 3-phenoxy-pyridine (1.15g, 7%). δπ (250 MHz, CDCI3) 8.41 (IH, dd / 2.4, 1.0 Hz, Ar), 8.36 (IH, dd / 4.2 1.9 Hz, Ar), 7.40-7.34 (2H, m, Ar), 7.29-7.26 (2H, m, Ar), 7.20-7.13 (IH, m, Ar), 7.05-7.04 (IH, m, Ar), 7.02-7.01 (IH, m, Ar); Tr = 0.87 min (100%), m/z (ES+) (M+H)+ 171.98
(ii) 4-(Pyridin-3-yloxy)-benzenesuIfonyl chloride
Chlorosulfonic acid (0.77 mL, 11.69 mmol) was added dropwise to a stirred solution of 3-phenoxy-pyridine (500 mg, 2.92 mmol) in chloroform (10 mL) at 0°C. The mixture was left at 0°C for 30 minutes, and then left overnight stirring at room temperature. Another treatment with chlorosulfonic acid (0.77 mL, 11.69 mmol) was required to give complete conversion to the sulfonyl chloride. The resulting mixture was then poured slowly onto a mixture of ice and water (250 mL). The aqueous layer was extracted with dichloromethane (250 mL). The resulting organic layer was washed with water (20 mL), dried over sodium sulfate, filtered and concentrated in vacuo to give 4-(pyridin-3-yloxy)-benzenesulfonyl chloride (327 mg, 41%). δπ (250 MHz, CDCk) 8.55 (2H, dd / 14.0, 3.2 Hz, Ar), 8.05 (2H, d / 9.2 Hz, Ar), 7.56-7.43 (2H, m, Ar), 7.16 (2H, d / 9.2 Hz, Ar); Tr = 1.16 min (85%), m/z (ES+) (M+H)+ 270.17
(iii) {5-Fluoro-2-methyl-l-[4-(pyridin-3-yloxy)-benzenesulfonyl]-lH-indol-3- yl}-acetic acid (Compound 107)
The sulfonamide formation and hydrolysis were performed as described for compound 1. δH (250 MHz, dβ-DMSO) 8.52-8.48 (2H, m, Ar), 8.07 (IH, dd /9.1, 4.5 Hz, Ar), 7.89 (2H, app d / 9.0 Hz, Ar), 7.69-7.64 (IH, m, Ar), 7.51 (IH, dd / 8.4, 4.6 Hz, Ar), 7.33 (IH, dd / 9.1, 2.6 Hz, Ar), 7.20-7.10 (3H, m, Ar), 3.67 (2H, s, CH2CO2H), 2.54 (3H, s, CH3); Tr = 1.72 min (100%), m/z (ES+) (M+Η)+ 441.07.
C(i) 4-(Pyridin-4-yloxy)-benzenesulfonyl chloride
Chlorosulfonic acid (1.55 mL, 23.38 mmol) was added dropwise to a stirred solution of 4-phenoxy-pyridine (1 g, 5.85 mmol) in chloroform (20 mL) at 0°C. The mixture was left at 0°C for 30 minutes, and then left overnight stirring at room temperature. Four extra treatments with chlorosulfonic acid (4 x 1.55 mL, 4 x 23.38 mmol) were required to give complete conversion to the sulfonyl chloride. The resulting mixture was then poured slowly onto a mixture of ice and water (500 mL). The aqueous layer was extracted with dichloromethane (500 mL). The resulting organic layer was washed with water (40 mL), dried over sodium sulfate, filtered and concentrated in vacuo and triturated with diethyl ether to give 4-(pyridin-4-yloxy)-benzenesulfonyl chloride (334 mg, 21%). Tr = 1.04 min (94%), m/z (ES+) (M+H)+ 270.17
(ii) {5-Fluoro-2-methyl-l-[4-(pyridin-4-yloxy)-benζenesulfonyl]-lH-indol-3- yl}-acetic acid (Compound 108)
The sulfonamide formation and hydrolysis were performed as described for compound 1. δH (400 MHz, -DMSO) 8.56-S.55 (2H, m, Ar), 8.08 (IH, dd / 9.1, 4.5 Hz, r), 7.94 (2H, app d / 9.0 Hz, Ar), 7.34 (IH, dd / 9.1, 2.6 Hz, Ar), 7.30 (2H, app d / 9.0 Hz, Ar), 7.17 (IH, td / 9.2, 2.7 Hz, Ar), 7.09 (2H, app d / 6.2 Hz, Ar), 3.68 (2H, s, CH2CO2H), 2.54 (3H, s, CH3); Tr = 1.22 min (95%), m/z (ES+) (M+Η)+ 441.17.
Example 4 phenyl proximal Compounds - Method 1
[5-Fluoro-2-methyl-l-(4-phenylamino-benζenesulfonyl)-2H-indol-3-yl]-acetic acid ethyl ester
Anhydrous toluene (3 mL) was added to a flask containing [l-(4-bromo- benzenesulfonyl)-5-fluoro-2-methyl-iH-indol-3-yl]-acetic acid ethyl ester (100 mg, 0.22 mmol), bis(dibenzylideneacetone)palladium (6.3 mg, 0.01 mmol), 2-(di-t- butylphosphino)biphenyl (6.6 mg, 0.02 mmol), sodium oxide (29.6 mg, 0.31 mmol) and aniline (24.7 mg, 0.26 mmol) under a nitrogen atmosphere. The resulting mixture was stirred at 40°C overnight. The mixture was partitioned between water and ethyl acetate. The organic layer was separated, dried over sodium sulphate and concentrated in vacuo. The residue was purified by column chromatography, using a 5g silica gel cartridge, eluting with 50% ethyl acetate:heptane to give the ester (69 mg, 63%); Tr =1.83 min (80%), m/z (ES+) (M+Η)+ 456.07.
[5-Fluoro-2-methyl-l-(4-phenylamino-benzenesulfonyl)-2H-indol-3-yl]-acetic acid (Compound 109)
Hydrolysis of the ester intermediate was performed as described for compound 1. δH (250 MHz, MeOD) 8.16 (IH, dd / 8.9, 4.5 Hz, Ar), 7.60 (2H, d / 9.0 Hz, Ar), 7.33 (2H, m, Ar), 7.22-7.15 (3H, m, Ar), 7.09-7.03 (2H, m, Ar), 6.99 (2H, d / 9.1 Hz, Ar), 3.65 (2H, s, CH2CO2H), 2.61 (3H, s, CH3); Tr = 1.55 min (100%), m/z (ES+) (M+Η)+ 439.17. Example 5 Phenyl Proximal Compounds - Method 2
[5-Fluoro-2-methyl-l-(4-»ζ-tolylamino-benζenesulfonyl)-lH-indol-3-yl]-acetic acid ethyl ester
1,4-Dioxane (5.0 ml) was added to a flask containing [l-(4-bromo-benzenesulfonyl)- 5-fluoro-2-methyl-2H-indol-3-yl]-acetic acid ethyl ester (227 mg, 0.50 mmol), tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (46 mg, 0.044 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (15 mg, 0.025 mmol), cesium carbonate (813 mg, 2.50 mmol) and 3-methylaniline (64 mg, 0.60 mmol) under a nitrogen atmosphere. The reaction was heated to 60 °C for 16 hours. The reaction mixture was allowed to cool and filtered through a pad of celite and the filtrate concentrated in vacuo. Purification of the crude mixture by flash column chromatography using a silica gel column eluting with a gradient of 0 to 10% ethyl acetate in n-heptane gave the ester (70 mg, 29%). Tr = 1.92 (95%), m/z (ES+) (M+Η)+481.63. [5-Fluoro-2-methyl-l-(4-w-tolylamino-benzenesulfonyl)-lH-indol-3-yl]-acetic acid (Compound 110)
Hydrolysis of the ester was performed as described for compound 1. δH (400 MHz, CDC13) 8.14 (IH, dd / 9.3, 4.4 Hz, Ar), 7.57 (2H, d / 8.8 Hz, Ar), 7.21
(IH, t / 7.3 Hz, Ar), 7.10 (IH, d / 8.5 Hz, Ar), 6.99 (IH, t / 8.8 Hz, Ar), 6.93 (3H, obs s, Ar), 6.85 (2H, d / 8.8 Hz, Ar), 6.04 (IH, br s, NH), 3.59 (2Η, s, CH2CO2H),
2.58 (3H, s, CH3), 2.33 (3Η, s, CH3); Tr = 1.61 min (83%), m/z (ES+) (M+Η)+
453.14.
Compounds 111 to 135 were prepared using a similar method to Compound 110 but with appropriately chosen starting materials.
{5-Fluoro-2-methyl-l-[4-(pyridin-4-yIamino)-benzenesulfonyl]-ljHr-indol-3-yl}- acetic acid (Compound 111) δH (250 MHz, -DMSO) 9.73 (IH, s, NH), 8.30 (2Η, d / 5.5 Hz, Ar), 8.02 (IH, dd / 8.9, 4.6 Hz, Ar), 7.73 (2H, d / 9.0 Hz, Ar), 7.29 (3H, m, Ar), 7.09 (3H, m, Ar), 3.22 (2H, s, CH2CO2H), 2.52 (3H, masked s, CH3); Tr = 1.20 min (100%), m/z (ES+) (M+Η)+ 440.16.
{5-Fluoro-2-methyl-l-[4-(pyridin-2-ylamino)-benzenesulfonyl]-lH-indol-3-yl}- acetic acid (Compound 112) δH (400 MHz, 6-DMSO) 9.73 (IH, s, NH), 8.22 (1Η, app br d / 4.9 Ηz, Ar), 8.08 (1Η, dd / 9.0, 4.4 Ηz, Ar), 7.85 (2Η, d / 9.0 Hz, Ar), 7.75 (2H, d / 9.0 Hz, Ar), 7.68- 7.64 (IH, m, Ar), 7.29 (IH, dd / 9.0, 2.4 Hz, Ar), 7.14 (IH, td / 9.3, 2.7 Hz, Ar), 6.92-6.88 (2H, m, Ar), 3.64 (2H, s, CH2CO2H), 2.52 (3H, s, CH3); Tr = 1.27 min (81%), m/z (ES+) (M+Η)+ 440.22.
{5-Fluoro-2-methyl-l-[4-(pyrimidin-4-ylamino)-benzenesulfonyl]-lH-indol-3- yl}-acetic acid (Compound 113) δH (400 MHz, rf6-DMSO) 10.16 (IH, s, NH), 8.71 (1Η, s, Ar), 8.40 (1Η, d / 5.9 Ηz, Ar), 8.08 (IH, dd / 9.0, 4.4 Hz, Ar), 7.91 (2H, d / 9.0 Hz, Ar), 7.83 (2H, d / 9.0 Hz, Ar), 7.30 (IH, dd / 9.2, 2.6 Hz, Ar), 7.15 (IH, td / 9.1, 2.7 Hz, Ar), 6.89 (IH, d / 5.8 Hz, Ar), 3.63 (2H, s, CH2CO2H), 2.52 (3H, s, CH3); Tr = 1.20 min (100%), m/z (ES+) (M+Η)+ 441.20.
{5-Fluoro-2-methyl-l-[4-(5-methyl-isoxazol-3-ylamino)-benzenesulfonyl]-lH- indol-3-yl}-acetic acid (Compound 114) δH (400 MHz, -DMSO) 9.82 (IH, s, NH), 8.07 (1Η, dd / 9.2, 4.5 Ηz, Ar), 7.80 (2Η, d / 8.9 Hz, Ar), 7.51 (2H, d / 8.9 Hz, Ar), 7.30 (IH, dd / 9.0, 2.4 Hz, Ar), 7.14 (IH, td / 9.3, 2.7 Hz, Ar), 5.97 (IH, s, Isoxazole-H), 3.64 (2Η, s, CH2CO2H), 2.52 (3H, s, CH3) 2.35 (3Η, s, Isoxazole-CH3); Tr = 1.46 min (94%), m/z (ES+) (M+Η)+ 444.20.
{5-Fluoro-2-methyl-l-[4-(pyridin-3-ylamino)-benzenesulfonyl]-lH-indol-3-yl}- acetic acid (Compound 115) δH (400 MHz, rf6-DMSO) 9.15 (IH, s, NH), 8.41 (1Η, app s, Ar), 8.23 (1Η, br d / 4.3 Ηz, Ar), 8.05 (1Η, dd / 9.1, 4.6 Ηz, Ar), 1.69 (2Η, d / 9.0 Hz, Ar), 7.61 (IH, d / 9.1 Hz, Ar), 7.35-7.28 (2H, m, Ar), 7.12 (IH, td / 9.1, 2.5 Hz, Ar), 7.06 (2H, d / 9.0 Hz, Ar), 3.55 (2H, s, CH2CO2H), 2.52 (3H, s, CH3); Tr = 1.20 min (100%), m/z (ES+) (M+Η)+ 440.23.
{5-Fluoro-2-methyl-l-[4-(4-methyl-pyridin-2-ylamino)-benzenesulfonyI]-lH- indol-3-yl}-acetic acid (Compound 116) δH (400 MHz, -DMSO) 8.08-8.01 (2H, m, Ar), 7.80 (2H, d / 9.2 Hz, Ar), 7.70 (2H, d / 9.2 Hz, Ar), 7.26 (IH, dd / 9.3, 2.7 Hz, Ar), 7.09 (IH, td / 9.3, 2.7 Hz, Ar), 6.74 (IH, d / 5.4 Hz, Ar), 6.70 (IH, s, Ar), 3.69 (2H, s, CH2CO2H), 2.53 (3H, s, CH3), 2.23 (3Η, s, ArCH3); Tr = 1.33 min (100%), m/z (ES+) (M+Η)+ 454.23.
{5-Fluoro-2-methyl-l-[4-(6-methyl-pyridin-2-ylamino)-benzenesulfonyl]-lH- indol-3-yl}-acetic acid (Compound 117) δH (400 MHz, -DMSO) 9.71 (IH, s, NH), 8.03 (1Η, dd / 9.1, 4.5 Ηz, Ar), 7.87 (2H, d / 9.0 Hz, Ar), 7.69 (2H, d / 9.0 Hz, Ar), 7.54 (IH, t / 7.8 Hz, Ar), 7.28 (IH, dd / 9.2, 2.5 Hz, Ar), 7.08 (IH, td / 9.2, 2.6 Hz, Ar), 6.75-6.71 (2H, m, Ar), 3.26 (2H, s, CH2CO2H), 2.52 (3H, masked s, CH3), 2.40 (3Η, s, ArCH3); Tr = 1.28 min (96%), m/z (ES+) (M+Η)+ 454.27.
{5-Fluoro-2-methyl-l-[4-(4-methyl-pyrimidin-2-ylamino)-benzenesulfonyl]-l/ϊ- indol-3-yl}-acetic acid (Compound 118) δH (400 MHz, -DMSO) 10.17 (IH, s, NH), 8.39 (1Η, d / 5.0 Ηz, Ar), 8.01 (1Η, dd /9.0, 4.5 Ηz, Ar), 7.95 (2Η, d/9.1 Hz, Ar), 7.70 (2H, d/9.1 Hz, Ar), 7.26 (IH, dd / 9.3, 2.7 Hz, Ar), 7.05 (IH, td / 9.3, 2.7 Hz, Ar), 6.87 (IH, d / 5.0 Hz, Ar), 3.15 (2H, s, CH2CO2H), 2.52 (3H, masked s, CH3), 2.39 (3Η, s, ArCH3); Tr = 1.46 min (100%), m/z (ES+) (M+Η)+ 455.24.
{5-Fluoro-2-methyl-l-[4-(pyrimidin-2-ylamino)-benzenesulfonyl]-lH-indol-3- yl}-acetic acid (Compound 119) δH (400 MHz, -DMSO) 10.28 (IH, s, NH), 8.56 (2Η, d / 5.1 Hz, Ar), 8.08 (IH, dd / 9.1, 4.5 Hz, Ar), 7.94 (2H, d / 9.1 Hz, Ar), 7.79 (2H, d / 9.1 Hz, Ar), 7.35-7.24 (IH, m, Ar), 7.16-7.11 (IH, m, Ar), 7.00 (IH, t / 5.0 Hz, Ar), 3.61 (2H, s, CH2CO2H), 2.55 (3H, s, CH3); Tr = 1.64 min (100%), m/z (ES+) (M+Η)+ 473.15.
{l-[4-(3-Chloro-phenylamino)-benzenesulfonyl]-5-fluoro-2-methyl-lH-indol-3- yl}-acetic acid (Compound 120) δH (400 MHz, ti6-DMSO) 9.16 (IH, s, NH), 8.07 (1Η, dd / 9.1, 4.5 Ηz, Ar), 7.72 (2Η, d / 8.9 Hz, Ar), 7.40-7.25 (2H, m, Ar), 7.18-7.02 (5H, m, Ar), 6.57 (IH, s, Ar), 3.65 (2H, s, CH2CO2H), 2.54 (3H, s, CH3); Tr = 1.64 min (100%), m/z (ES+) (M+Η)+ 473.15.
{l-[4-(2,6-Dimethyl-pyrimidin-4-ylamino)-benzenesulfonyl]-5-fluoro-2-methyl- 222-indol-3-yl}-acetic acid (Compound 121) δH (400 MHz, -DMSO) 10.81 (IH, s, NH), 8.08 (1Η, dd / 9.2, 4.5 Ηz, Ar), 7.93- 7.87 (4Η, m, Ar), 7.32 (IH, dd / 9.1, 2.6 Hz, Ar), 7.17 (IH, td / 9.2, 2.7 Hz, Ar), 6.73 (lH,bs, Ar), 3.66 (2H, s, CH2CO2H), 2.55 (6H, s, 2 x CH3), 2.41 (3Η, s, CH3); Tr = 1.25 min (100%), m/z (ES+) (M+Η)+ 469.22.
{5-Fluoro-l-[4-(isoxaζol-3-ylamino)-benζenesulfonyl]-2-methyl-lH-indol-3-yl}- acetic acid (Compound 122) δH (400 MHz, -DMSO) 9.56 (IH, s, NH), 8.70 (1Η, app d / 1.7 Ηz, Ar), 8.07 (1Η, dd / 9.1, 4.5 Ηz, Ar), 7.81 (2Η, d / 9.1 Hz, Ar), 7.55 (2H, d / 9.1 Hz, Ar), 7.30 (IH, dd / 9.2, 2.5 Hz., Ar), 7.14 (IH, dt / 9.2, 2.6 Hz, Ar), 6.28 (IH, app d, 1.7 Hz, Ar), 3.62 (2H, s, CH2CO2H), 2.54 (3H, s, CH3); Tr = 1.41 min (96%), m/z (ES+) (M+Η)+ 430.29.
{l-[4-(4,6-Dimethyl-pyrimidin-2-ylamino)-benzenesulfonyl]-5-fluoro-2-methyl- lH-indol-3-yl}-acetic acid (Compound 123) δH (400 MHz, J6-DMSO) 10.14 (IH, s, NH), 8.08 (1Η, dd / 9.1, 4.5 Ηz, Ar), 7.99 (2Η, d / 9.0 Hz, Ar), 1.11 (2H, d / 9.0 Hz, Ar), 7.31-7.28 (IH, m, Ar), 7.16-7.11 (IH, m, Ar), 6.11 (IH, s, Ar), 3.61 (2H, s, CH2CO2H), 2.55 (3H, s, CH3) 2.34 (6Η, s,2 x CH3); Tr = 1.46 min (91%), m/z (ES+) (M+Η)+ 469.35.
{5-Fluoro-2-methyl-l-[4-(5-methyl-pyridin-3-ylamino)-benzenesulfonyI]-2H- indol-3-yl}-acetic acid (Compound 124) δH (400 MHz, -DMSO) 9.10 (IH, s, NH), 8.21 (1Η, d / 2.3 Ηz, Ar), 8.08-8.05 (2Η, m, Ar), 7.70 (2H, d / 8.9 Hz, Ar), 7.45 (IH, s, Ar), 7.31 (IH, dd / 9.0, 2.1 Hz, Ar), 7.14 (IH, td / 9.2, 2.3 Hz, Ar), 7.06 (2H, d / 8.9 Hz, Ar), 3.62 (2H, s, CH2CO2H), 2.54 (3H, s, CH3), 2.27 (3Η, s, CH3); Tr = 1.24 min (97%) m/z (ES+) (M+Η)+ 454.34.
{5-Fluoro-2-methyl-l-[4-(thiazol-2-ylamino)-benzenesulfonyl]-2H-indol-3-yl}- acetic acid (Compound 125)_ δH (400 MHz, -DMSO) 10.82 (IH, s, NH), 8.06 (1Η, dd / 9.1, 4.5 Ηz, Ar), 7.80 (2Η, d / 9.3 Hz, Ar), 7.77 (2H, d / 9.3 Hz, Ar), 7.33 (IH, d / 3.7 Hz, Ar), 7.29 (IH, dd / 9.2, 2.4 Hz, Ar), 7.13 (IH, td / 9.2, 2.5 Hz, Ar), 7.08 (IH, d / 3.7 Hz, Ar), 3.58 (2H, s, CH2CO2H), 2.54 (3H, s, CH3); Tr = 1.41 min (93%) m/z (ES+) (M+Η)+ 446.21.
{l-[4-(3,5-Dimethyl-phenylamino)-benzenesulfonyl]-5-fluoro-2-methyl-2H- indol-3-yl}-acetic acid (Compound 126) δH (400 MHz, d6-DMSO) 8.88 (IH, s, NH), 8.06 (1Η, dd / 9.1, 4.5 Ηz, Ar), 7.66 (2Η, d / 8.9 Hz, Ar), 7.30 (IH, dd / 9.2, 2.6 Hz, Ar), 7.14 (IH, td / 9.2, 2.7 Hz, Ar), 7.00 (2H, d / 8.9 Hz, Ar), 6.77 (2H, s, Ar), 6.69 (IH, s, Ar), 3.63 (2H, s, CH2CO2H), 2.53 (3H, s, CH3), 2.23 (6Η, s, 2 x CH3); Tr = 1.68 min (94%) m/z (ES+) (M+Η)+ 467.30.
{5-Fluoro-2-methyl-l-[4-(4-sulfonamido-phenylamino)-benζenesulfonyl]-2H- indol-3-yl}-acetic acid (Compound 127) δH (400 MHz, -DMSO) 9.39 (IH, s, NH), 8.08 (1Η, dd / 9.1, 4.5 Ηz, Ar), 7.75 (2Η, d / 7.8 Hz, Ar), 7.72 (2H, d, / 7.6 Hz, Ar), 7.32 (IH, dd / 9.1, 2.6 Hz, Ar), 7.27 (2H, d / 8.8 Hz, Ar), 7.24 (2H, s, NH2), 7.19 (2Η, d / 8.9 Hz, Ar), 7.14 (IH, dd / 9.2, 2.7 Hz, Ar), 3.66 (2H, s, CH2CO2H), 2.54 (3H, s, CH3); Tr = 1.35 min (100%) m/z (ES+) (M+Η)+ 518.26.
{l-[4-(3,5-Dichloro-phenylamino)-benζenesulfonyl]-5-fluoro-2-methyl-2H-indol-
3-yl}-acetic acid (Compound 128) δH (400 MHz, -DMSO) 9.31 (IH, s, NH), 8.08 (1Η, dd / 9.2, 4.5 Ηz, Ar), 7.76
(2Η, d / 9.0 Hz, Ar), 7.31 (IH, dd / 9.1, 2.6 Hz, Ar), 7.14-7.13 (6H, m, Ar), 3.65
(2H, s, CH2CO2H), 2.54 (3H, s, CH3); Tr = 1.73 min (100%) /z (ES+) (M+Η)+
507.18.
{l-[4-(5-Chloro-pyridin-3-ylamino)-benzenesulfonyl]-5-fluoro-2-methyl-22r- indol-3-yl}-acetic acid (Compound 129) δH (400 MHz, 6-DMSO) 9.34 (IH, s, NH), 8.37 (1Η, d / 2.2 Ηz, Ar), 8.24 (1Η, d / 2.2 Ηz, Ar), 8.08 (1Η, dd / 9.0, 4.5 Ηz, Ar), 7.75 (2Η, d / 8.9 Hz, Ar), 7.71 (IH, t / 2.2 Hz, Ar), 7.32 (IH, dd / 9.1, 2.6 Hz, Ar), 7.18-7.12 (3H, m, Ar), 3.66 (2H, s, CH2CO2H), 2.54 (3H, s, CH3); Tr = 1.40 min (100%) m/z (ES+) (M+Η)+ 474.24.
{l-[2,5-Difluoro-4-(pyridin-2-ylamino)-benζenesulfonyl]-5-fluoro-2-methyl-2H- indol-3-yl}-acetic acid (Compound 130) δH (400 MHz, -DMSO) 9.66 (IH, bs, NH), 8.65 (1Η, dd / 14.0, 6.5 Ηz, Ar), 8.25 (1Η, dd / 5.0, 1.6 Ηz, Ar), 7.95 (2Η, m, Ar), 7.73 (IH, t / 8.7 Hz, Ar), 7.34 (IH, dd / 9.0, 2.6 Hz, Ar), 7.27 (IH, d / 8.4 Hz, Ar), 7.14 (IH, td / 9.1, 2.6 Hz, Ar), 6.99 (IH, d / 5.0 Hz, Ar), 3.68 (2H, s, CH2CO2H), 2.48 (3H, m, CH3); Tr = 1.48 min (100%) m/z (ES+) (M+Η)+ 476.26.
{l-[2,5-Difluoro-4-(pyridin-2-ylamino)-benζenesulfonyl]-5-fluoro-2-methyl-2H- indol-3-yI}-acetic acid (Compound 131) δH (400 MHz, rf6-DMSO) 9.21 (IH, bs, NH), 8.49 (1Η, d / 2.5, Ar), 8.33 (1Η, dd / 4.6 Ηz, Ar), 7.95-7.89 (2Η, m, Ar), 7.71 (IH, d / 9.5 Hz, Ar), 7.39-7.33 (2H, m, Ar), 7.14 (IH, dd / 9.1, 2.6 Hz, Ar), 6.95 (IH, dd / 12.4, 6.7 Hz), 3.67 (2H, s, CH2CO2H), 2.47 (3H, m, CH3); Tr = 1.21 min (100%) m/z (ES+) (M+Η)+ 476.26. {l-[2,5-Difluoro-4-(5-methyl-isoxazol-3-ylamino)-benzenesulfonyl]-5-fluoro-2- methyl-2H-indol-3-yl}-acetic acid (Compound 132) δH (400 MHz, t DMSO) 10.10 (IH, br s, NH), 7.96-7.82 (3Η, m, Ar), 7.30 (IH, dd / 9.2, 2.6 Hz, Ar), 7.05 (IH, td / 9.2, 2.8 Hz, Ar), 6.13 (IH, app s , Oxazole-H), 3.22 (2Η, s, CH2CO2H), 2.43 (3H, s, CCH3), 2.34 (3Η, s, Oxazole-CH3); Tr = 1.51 min (100%), m/z (ES+) (M+Η)+ 480.28.
{5-Fluoro-l-[4-(3-methoxy-phenylamino)-benzenesulfonyl]-2-methyl-2H-indol- 3-yl}-acetic acid (Compound 133) δH (400 MHz, -DMSO) 9.01 (IH, s, NH), 8.06 (1Η, dd / 9.1, 4.5 Ηz, Ar), 7.68 (2Η, d / 8.9 Hz, Ar), 7.30 (IH, dd / 8.2, 2.6 Hz, Ar), 7.23 (IH, t / 8.0 Hz, Ar), 7.13 (IH, td / 9.2, 2.7 Hz, Ar), 7.05 (2H, d / 9.0 Hz, Ar), 6.14 (IH, dd / 8.0, 1.4 Hz, Ar), 6.68 (IH, t / 2.2 Hz, Ar), 6.62 (IH, dd / 8.2, 1.8 Hz, Ar), 3.73 (3H, m, OCH3), 3.63 (2Η, s, CH2CO2H), 2.53 (3H, m, CH3); Tr = 1.56 min (90%) m/z (ES+) (M+Η)+ 469.32. {l-[4-(3-Cyano-phenylamino)-benzenesulfonyl]-5-fluoro-2-methyl-2H-indol-3- yl}-acetic acid (Compound 134) δH (400 MHz, rf6-DMSO) 9.29 (IH, s, NH), 8.07 (1Η, dd / 9.0, 4.5 Ηz, Ar), 7.72 (2Η, d / 8.9 Hz, Ar), 7.55 (IH, s, Ar), 7.52-7.43 (3H, m, Ar), 7.31 (IH, dd / 9.0, 1.9 Hz, Ar), 7.16-7.12 (3H, m, Ar), 3.62 (2H, s, CH2CO2H), 2.54 (3H, m, CH3); Tr = 1.51 min (100%) m/z (ES+) (M+Η)+ 464.29.
{l-[4-(3-Ethyl-phenylamino)-benzenesulfonyl]-5-fluoro-2-methyl-2H-indol-3- yl}-acetic acid (Compound 135) δH (400 MHz, cie-DMSO) 8.97 (IH, bs, NH), 8.06 (1Η, dd / 9.1, 4.5 Ηz, Ar), 1.66 (2Η, d / 8.9 Hz, Ar), 7.30 (IH, dd / 9.1, 2.6 Hz, Ar), 7.23 (IH, t / 7.7 Hz, Ar), 7.13 (IH, td / 9.2, 2.6 Hz, Ar), 7.02-6.96 (4H, m, Ar), 6.90 (IH, d / 7.44, Ar,) 3.62 (2H, s, CH2CO2H), 2.57 (2H, q / 7.6 Hz, CH2CH3), 2.53 (3H, m, CH3) 1.16 (3Η, t, CH2CH3); Tr = 1.68 min (87%) m/z (ES+) (M+Η)+ 467.31.
Example 6 Pyridyl Proximal Compounds
[l-(6-ChIoro-pyridine-3-sulfonyl)-5-fluoro-2-methyI-2H-indol-3-yl]-acetic acid ethyl ester
A solution of (5-fluoro-2-methyl-2H-indol-3-yl)-acetic acid ethyl ester (1.85 g, 7.86 mmol) and benzyltriethylammonium chloride (179 mg, 0.78 mmol) in dichloromethane (75 mL) was stirred at room temperature for 5 minutes. Potassium hydroxide (2.64 g, 47.2 mmol) was added to the solution, followed immediately by the addition of a solution of 6-chloro-pyridine-3 -sulfonyl chloride (2 g, 9.43 mmol) in dichloromethane (75 mL). The reaction was stirred at room temperature for one hour. The resulting solution was neutralised with 1M ΗC1 and the aqueous layer was extracted with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. Purification by column chromatography using a 50 g silica gel column, eluting with 10 % ethyl acetate : hexane, followed by trituration in diethyl ether gave the sulfonamide (1.19 g, 37 %). δΗ (250 MHz, CDCh) 8.73 (IH, d / 2.2 Hz, Ar), 8.07 (IH, dd / 9.1, 4.4 Hz, Ar), 7.86 (IH, dd / 8.5, 2.6 Hz, Ar), 7.36 (IH, dd / 8.4, 0.4 Hz, Ar), 7.14-6.98 (2H, m, Ar), 4.11 (2H, q / 7 Hz, OCH2CH3), 3.55 (2H, s, CH2), 2.58 (3H, s, CH3), 1.20 (3H, t / 7.1 Hz, OCH2CH3); Tr =1.69 min (96%), m/z (ES+) (M+Η)+411.29.
{5-Fluoro-2-methyl-l-[6-(pyridin-2-ylamino)-pyridine-3-sulfonyl]-LH-indol-3- yl}-acetic acid (Compound 136)
Palladium mediated coupling and hydrolysis were performed using a similar method to Compound 110. δH (400 MHz, d6-DMSO) 10.48 (IH, s, NH), 8.69 (1Η, d / 2.6 Ηz, Ar), 8.28 (1Η, br d /4.5 Ηz, Ar), 8.09 (1Η, dd / 9.1, 4.5 Ηz, Ar), 8.03 (1Η, dd / 9.1, 2.7 Ηz, Ar), 7.80 (1Η, d / 9.2 Ηz, Ar), 1.11-1.10 (2Η, m, Ar), 7.32 (IH, dd / 9.1, 2.6 Hz, Ar), 7.16 (IH, td / 9.1, 2.6 Hz, Ar), 7.03-7.00 (IH, m, Ar), 3.66 (2H, s, CH2CO2H), 2.57 (3H, s, CH3); Tr = 1.19 min (100%), m/z (ES+) (M+Η)+ 441.17.
Compounds 137 to 153 were prepared using a similar method to Compound 136 but with appropriately chosen starting materials.
{5-Fluoro-2-methyI-l-[6-(pyridin-3-ylamino)-pyridine-3-sulfonyl]-lH-indoI-3- yl}-acetic acid (Compound 137) δH (400 MHz, -DMSO) 10.07 (IH, s, NH), 8.77 (1Η, d / 2.6 Ηz, Ar), 8.66 (1Η, d / 2.6 Ηz, Ar), 8.23 (1Η, app dd / 4.6, 1.4 Ηz, Ar), 8.15-8.12 (1Η, m, Ar), 8.08 (1Η, dd / 9.0, 4.5 Ηz, Ar), 7.91 (1Η, dd / 9.0, 2.6 Ηz, Ar), 7.36-7.31 (2Η, m, Ar), 7.16 (IH, td / 9.2, 2.6 Hz, Ar), 6.88 (IH, d / 9.0 Hz, Ar), 3.66 (2H, s, CH2CO2H), 2.56 (3H, s, CH3); Tr = 1.18 min (98%), m/z (ES+) (M+Η)+ 441.17.
{5-Fluoro-2-methyl-l-[6-(pyrimidin-4-ylamino)-pyridine-3-sulfonyl]-lH-indol-3- yl}-acetic acid (Compound 138) δH (400 MHz, dg-DMSO) 10.89 (IH, s, NH), 8.81 (1Η, app s, Ar), 8.78 (1Η, d / 2.6 Ηz, Ar), 8.54 (1Η, d / 5.9 Ηz, Ar), 8.16 (1Η, dd / 9.1, 2.7 Ηz, Ar), 8.09 (1Η, dd / 9.1, 4.5 Ηz, Ar), 7.83 (1Η, d / 9.0 Ηz, Ar), 7.78 (1Η, app dd / 5.9, 1.2 Ηz, Ar), 7.33 (1Η, dd / 9.0, 2.6 Ηz, Ar), 7.17 (1Η, td / 9.2, 2.7 Ηz, Ar), 3.67 (2Η, s, CH2CO2H), 2.57 (3H, s, CH3); Tr = 1.18 min (83%), m/z (ES+) (M+Η)+ 442.13.
[5-Fluoro-2-methyl-l-(6-phenylamino-pyridine-3-sulfonyl)-lH-indol-3-yl]-acetic acid (Compound 139) δH (400 MHZ, 5-DMSO) 9.89 (IH, s, NH), 8.62 (1Η, d / 2.7 Ηz, Ar), 8.07 (1Η, dd / 9.2, 4.5 Ηz, Ar), 7.86 (1Η, dd / 9.1, 2.7 Ηz, Ar), 7.63-7.61 (2Η, m, Ar), 7.35-7.30 (3H, m, Ar), 7.15 (IH, td / 9.1, 2.7 Hz, Ar), 7.04 (IH, app t /7.3 Hz, Ar), 6.82 (IH, d / 9.2 Hz, Ar), 3.66 (2H, s, CH2CO2H), 2.56 (3H, s, CH3); Tr = 1.53 min (100%), m/z (ES+) (M+Η)+ 440.17.
{l-[6-(3,5-Dimethyl-phenylamino)-pyridine-3-sulfonyl]-5-fluoro-2-methyl-lflr- indol-3-yl}-acetic acid (Compound 140) δH (400 MHz, -DMSO) 9.74 (IH, s, NH), 8.62 (1Η, app s, Ar), 8.08 (1Η, dd / 9.1, 4.5 Ηz, Ar), 7.84 (1Η, dd / 9.1, 2.5 Ηz, Ar), 7.32 (1Η, dd / 9.1, 2.5 Ηz, Ar), 7.23 (2Η, s, Ar), 7.16 (IH, td / 9.1, 2.5 Hz, Ar), 6.80 (IH, d / 9.0 Hz, Ar), 6.69 (IH, s, Ar), 3.66 (2H, s, CH2CO2H), 2.56 (3H, s, CH3), 2.24 (6Η, 2 x CH3); Tr = 1.64 min (89%), m/z (ES+) (M+Η)+ 468.19.
{5-FIuoro-2-methyl-l-[6-(pyrimidin-2-ylamino)-pyridine-3-sulfonyl]-lH-indol-3- yl}-acetic acid (Compound 141) δH (250 MHz, -DMSO) 10.75 (IH, br s, NH), 8.71 (1Η, d / 2.7 Ηz, Ar), 8.62 (2Η, d /4.8 Hz, Ar), 8.38 (IH, d / 8.6 Hz, Ar), 8.16-8.06 (2H, m, Ar), 7.31 (IH, dd / 9.1, 2.5 Hz, Ar), 7.20-7.08 (2H, m, Ar), 3.63 (2H, s, CH2CO2H), 2.57 (3H, s, CH3); Tr = 1.28 min (100%), m/z (ES+) (M+Η)+ 442.18.
{5-Fluoro-2-methyl-l-[6-(6-methyl-pyridin-2-ylamino)-pyridine-3-sulfonyl]-12 - indol-3-yl}-acetic acid (Compound 142) δH (250 MHz, i6-DMSO) 10.41 (IH, s, NH), 8.68 (1Η, d / 2.6 Ηz, Ar), 8.09 (1Η, dd / 9.1, 4.6 Ηz, Ar), 7.99 (1Η, dd / 9.1, 2.7 Ηz, Ar), 7.75 (1Η, d / 9.2 Ηz, Ar), 7.63- 7.59 (2Η, m, Ar), 7.36-7.29 (IH, m, Ar), 7.16 (IH, td / 9.1, 2.4 Hz, Ar), 6.88 (IH, app dd / 6.2, 2.1 Hz, Ar), 3.66 (2H, s, CH2CO2H), 2.57 (3H, s, CH3), 2.41 (3Η, s, ArCH3); Tr = 1.23 min (100%), m/z (ES+) (M+Η)+ 445.22.
{5-Fluoro-2-methyl-l-[6-(4-methyl-pyrimidin-2-ylamino)-pyridine-3-sulfonyl]- lH-indol-3-yl}-acetic acid (Compound 143) δH (400 MHZ, 6-DMSO) 10.65 (IH, s, NH), 8.71 (1Η, d / 2.3 Ηz, Ar), 8.47-8.43 (2Η, m, Ar), 8.15-8.08 (2H, m, Ar), 7.32 (IH, dd / 9.1, 2.6 Hz, Ar), 7.16 (IH, td / 9.2, 2.6 Hz, Ar), 6.99 (IH, d / 5.1 Hz, Ar), 3.66 (2H, s, CH2CO2H), 2.57 (3H, s, CH3), 2.42 (3Η, s, ArCH3); Tr = 1.33 min (100%), m/z (ES+) (M+Η)+ 456.23.
{l-[6-(4,6-Dimethyl-pyrimidin-2-ylamino)-pyridine-3-sulfonyl]-5-fluoro-2- methyl-lH-indol-3-yl}-acetic acid (Compound 144) δH (400 MHZ, 6-DMSO) 10.53 (IH, s, NH), 8.70 (1Η, d / 2.6 Ηz, Ar), 8.52 (1Η, d / 9.2 Ηz, Ar), 8.12-8.07 (2Η, m, Ar), 7.32 (IH, dd / 9.1, 2.7 Hz, Ar), 7.16 (IH, td / 9.1, 2.7 Hz, Ar), 6.87 (IH, s, Ar), 3.66 (2H, s, CH2CO2H), 2.57 (3H, s, CH3), 2.36 (6Η, s,2 x CH3); Tr = 1.35 min (95%), m/z (ES+) (M+Η)+ 470.27. {l-[6-(3-Chloro-phenylamino)-pyridine-3-sulfonyl]-5-fluoro-2-methyl-lH-indol- 3-yl}-acetic acid (Compound 145) δH (400 MHz, c?6-DMSO) 10.06 (IH, s, NH), 8.71 (1Η, d / 2.6 Ηz, Ar), 8.08 (1Η, dd / 9.1, 4.5 Ηz, Ar), 7.93-7.90 (2Η, m, Ar), 7.51-7.48 (IH, m, Ar), 7.36-7.31 (2H, m, Ar), 7.16 (IH, td / 9.2, 2.6 Hz, Ar), 7.07 (IH, app d / 8.0 Hz, Ar), 6.86 (IH, d / 9.0 Hz, Ar), 3.67 (2H, s, CH2CO2H), 2.57 (3H, s, CH3); Tr = 1.67 min (100%), m/z (ES+) (M+Η)+ 474.23.
[5-Fluoro-2-methyl-l-(6- -tolylamino-pyridine-3-sulfonyl)-lH-indol-3-yl]-acetic acid (Compound 146) δH (400 MHz, 5-DMSO) 9.82 (IH, s, NH), 8.62 (1Η, d / 2.6 Ηz, Ar), 8.08 (1Η, dd / 9.1, 4.5 Ηz, Ar), 7.85 (1Η, dd / 9.1, 2.7 Ηz, Ar), 7.45-7.41 (2Η, m, Ar), 7.28 (IH, dd / 9.0, 2.6 Hz, Ar), 7.22-7.12 (2H, m, Ar), 6.86 (IH, d / 7.5 Hz, Ar), 6.81 (IH, d / 9.2 Hz, Ar), 3.66 (2H, s, CH2CO2H), 2.56 (3H, s, CH3), 2.29 (3Η, s, PhCH3); Tr = 1.63 min (86%), m/z (ES+) (M+Η)+ 454.27. {l-[6-(2,6-Dimethyl-pyrimidin-4-ylamino)-pyridine-3-sulfonyl]-5-fluoro-2- methyl-lH-indol-3-yl}-acetic acid (Compound 147) δH (400 MHz, .ie-DMSO) 12.42 (IH, br s, CO2H), 10.84 (1Η, br s, NH), 8.78 (1Η, d / 2.6 Ηz , Ar), 8.13-8.07 (2Η, m, Ar), 7.78 (IH, app d / 9.1 Hz, Ar), 7.56 (IH, br s, Ar), 7.34 (IH, dd / 9.0, 2.6 Hz, Ar), 7.17 (IH, td / 9.2, 2.6 Hz, Ar), 3.67 (2H, s, CH2CO2H), 2.57 (3H, s, CH3), 2.49 (3Η, s, ArCH3) 2.37 (3Η, s, ArCH3); Tr = 1.21 min (96%), m/z (ES+) (M+Η)+ 470.21.
{5-Fluoro-2-methyl-l-[6-(pyridin-4-ylamino)-pyridine-3-suIfonyl]-lH-indol-3- yl}-acetic acid (Compound 148) δH (400 MHz, -DMSO) 10.30 (IH, br s, NH), 8.74 (1Η, br s, Ar), 8.39 (2Η, br s, Ar), 8.08-8.06 (IH, br m, Ar), 7.98 (IH, br s, Ar), 7.68 (2H, br s, Ar), 7.32 (IH, br s, Ar), 7.15 (IH, br t / 8.5 Hz, Ar), 6.97 (IH, br s, Ar), 3.59 (2H, s, CH2CO2H), 2.56 (3H, s, CH3); Tr = 1.17 min (100%), m/z (ES+) (M+Η)+ 441.22.
{5-Fluoro-2-methyl-l-[6-(5-methyI-isoxazol-3-yIamino)-pyridine-3-sulfonyl]-12jT- indol-3-yl}-acetic acid (Compound 149) δH (400 MHz, e-DMSO) 10.66 (IH, s, NH), 8.67 (1Η, d, Ar), 8.09-8.06 (2Η, m, Ar), 7.36-7.31 (2H, m, Ar), 7.16 (IH, td / 9.2, 2.6 Hz, Ar), 6.47 (IH, s, Ar), 3.65 (2H, s, CH2CO2H), 2.56 (3H, s, CH3), 2.37 (3Η, s, Isoxazole-CH3); Tr = 1.42 min (96%), m/z (ES+) (M+Η)+ 455.20.
{5-FIuoro-2-methyl-l-[6-(thiazol-2-ylamino)-pyridine-3-sulfonyl]-lH-indol-3- yl}-acetic acid (Compound 150) δH (400 MHz, -DMSO) 12.18 (IH, br s, CO2H), 8.78 (1Η, app d /2.1 Ηz, Ar), 8.10 (1Η, dd / 9.2, 4.5 Ηz, Ar), 8.06 (1Η, dd / 9.0, 2.6 Ηz, Ar), 7.47 (1Η, d / 3.6 Ηz, Ar), 7.33 (1Η, dd / 9.0, 2.6 Ηz, Ar), 7.19-7.11 (3Η, m, Ar), 3.67 (2H, s, CH2CO2H), 2.57 (3H, s, CH3); Tr = 1.33 min (100%), m/z (ES+) (M+Η)+ 447.16.
{l-[6-(3,5-Dichloro-phenylamino)-pyridine-3-suIfonyI]-5-fluoro-2-methyI-22f- indol-3-yl}-acetic acid (Compound 151) δH (400 MHz, ci6-DMSO) 10.20 (IH, bs, NH), 8.77 (1Η, d / 2.6 Ηz, Ar), 8.09 (1Η, dd / 9.1, 4.4 Ηz, Ar), 7.96 (1Η, dd / 9.1, 2.6 Ηz, Ar), 7.78 (2Η, m, Ar), 7.33 (IH, d / 9.1, 2.6 Hz, Ar), 7.21 (IH, t / 1.8 Hz, Ar), 7.16 (IH, td / 9.1, 2.6 Hz, Ar), 6.88 (IH, d / 9.0 Hz, Ar), 3.67 (2H, s, CH2CO2H), 2.57 (3H, s, CH3); Tr = 1.77 min (85%) m/z (ES+) (M+Η)+ 508.22.
{5-Fluoro-2-methyl-l-[6-(5-methyl-pyridin-3-ylamino)-pyridine-3-sulfonyl]-2H- indol-3-yl}-acetic acid (Compound 152) δH (400 MHz, -DMSO) 10.34 (IH, bs, NH), 8.88 (1Η, s , Ar), 8.72 (1Η, d, Ar), 8.25 (1Η, s, Ar), 8.15 (1Η, s, Ar), 8.10 (1Η, dd, / 9.2, 4.5 Ηz, Ar), 7.98 (1Η, dd, / 9.1, 2.6 Ηz, Ar), 7.33 (1Η, dd / 9.1, 2.6 Ηz, Ar), 111 (1Η, td / 9.2, 2.6 Ηz, Ar), 6.96 (1Η, d / 9.0 Ηz, Ar), 3.67 (2Η, s, CH2CO2H), 2.57 (3H, s, CH3), 2.38 (3Η, s, CH3); Tr = 1.20 min (100%) m/z (ES+) (M+Η)+ 455.30.
{l-[6-(5-Chloro-pyridin-3-ylamino)-pyridine-3-sulfonyl]-5-fluoro-2-methyl-2H- indol-3-yl}-acetic acid (Compound 153) δH (400 MHz, -DMSO) 10.42 (IH, s, NH), 8.72 (1Η, d / 2.6 Ηz, Ar), 8.64 (1Η, d / 2.5 Ηz, Ar), 8.45 (1Η, t / 2.2 Ηz, Ar), 8.24 (1Η, d / 2.1 Ηz, Ar), 8.07 (1Η, dd / 9.0, 4.5 Ηz, Ar), 7.88 (1Η, dd / 9.0, 2.5 Ηz, Ar), 7.30 (1Η, dd / 9.1, 2.4 Ηz, Ar), 7.13 (1Η, td / 9.2, 2.4 Ηz, Ar), 6.88 (1Η, d / 9.0 Ηz, Ar), 3.46 (2Η, s, CH2CO2H), 2.55 (3H, s, CH3); Tr = 1.42 min (100%) m/z (ES+) (M+Η)+ 475.29.
Example 7 N-methyl; Phenyl and Pyridyl Proximal Compounds
{5-Fluoro-2-methyl-l-[4-(methyl-phenyl-amino)-benzenesulfonyl]-lH-indol-3- yl}-acetic acid ethyl ester
Anhydrous tetrahydrofuran (2.0 ml) was added to [5-fluoro-2-methyl-l-(4- phenylamino-benzenesulfonyl)-2H-indol-3-yl]-acetic acid ethyl ester (36 mg, 0.08 mmol) and sodium hydride (60% dispersion in mineral oil) (10 mg, 0.24 mmol). After stirring for 30 minutes at room temperature methyl iodide (15 μl, 0.24 mmol) was added and the reaction mixture stirred for 16 h. The reaction was concentrated in vacuo and the residue partitioned between ethyl acetate (2 ml) and water (2 ml). The pH of the aqueous layer was adjusted with 1.0 N HC1 until the suspended solids dissolved (~pH 6). The organic layer was separated and the aqueous layer extracted with a further portion of ethyl acetate (2.0 ml). The combined organic layers were dried over sodium sulfate and concentrated. The residue was purified by preparative HPLC (C-18) eluting with a water/acetonitrile (1%TFA) gradient to give the acid (26 mg, 68%). Tr = 1.78 (100%), m/z (ES+) (M+H)+ 481.42.
{5-Fluoro-2-methyl-l-[4-(methyl-phenyl-amino)-benzenesulfonyl]-lH-indol-3- yl}-acetic acid (Compound 154)
Hydrolysis of the ester intermediate was performed as described for compound 1. δH (400 MHz, CDC13) 8.08 (IH, dd / 9.1, 4.4 Hz, Ar), 7.49 (2H, d / 9.1 Hz, Ar), 7.37-7.34 (2H, m, Ar), 7.24-7.19 (2H, m, Ar), 7.11-7.08 (IH, m, Ar), 7.03 (IH, dd / 8.7, 2.6 Hz, Ar), 6.93 (IH, td / 9.1, 2.6 Hz, Ar), 6.57 (2H, d / 9.1 Hz, Ar), 3.54 (2H, s, CH2CO2H), 3.24 (3H, s, NCH3), 2.52 (3Η, s, CH3); Tr = 1.63 min (98%), m/z (ES+) (M+Η)+ 453.14.
Examples 155 to 169 were prepared using a similar method to Compound 154 but with appropriately chosen starting materials
{5-Fluoro-2-methyl-l-[4-(methyl- -tolyl-amino)-benzenesulfonyl]-lH-indol-3- yl}-acetic acid (Compound 155) δH (400 MHz, CDC13) 8.13 (IH, dd / 9.1, 4.4 Hz, Ar), 7.53 (2H, d / 9.1 Hz, Ar), 7.30-7.26 (IH, m, Ar), 7.09-7.06 (2H, m, Ar), 7.00-6.89 (3H, m, Ar), 6.60 (2H, d / 9.1 Hz, Ar), 3.59 (2H, s, CH2CO2H), 3.26 (3H, s, NCH3), 2.57 (3Η, s, CH3), 2.34 (3Η, s, ArCH3); Tr = 1.72 min (96%), m/z (ES+) (M+Η)+ 467.17.
(5-Fluoro-2-methyl-l-{4-[methyl-(5-methyl-isoxaζol-3-yl)-amino]-benζene- sulfonyl}-lH-indol-3-yl)-acetic acid (Compound 156) δH (400 MHz, 6-DMSO) 8.08 (IH, dd / 9.2, 4.5 Hz, Ar), 7.79 (2H, d / 9.2 Hz, Ar), 7.40 (2H, d / 9.2 Hz, Ar), 7.31 (IH, dd / 9.3, 2.7 Hz, Ar), 7.15 (IH, td / 9.3, 2.7 Hz, Ar), 6.27 (IH, app s, Ar), 3.63 (2H, s, CH2CO2H), 3.34 (3H, s, NCH3), 2.52 (3Η, masked s, CH3), 2.34 (3Η, s, CH3); Tr = 1.55 min (100%), m/z (ES+) (M+Η)+ 458.24.
(5-Fluoro-2-methyl-l-{4-[methyl-(4-methyl-pyridin-2-yl)-amino]-benzene sulfonyl}- lH-indol-3-yl)-acetic acid (Compound 157) δH (400 MHz, da-OMSO) 8.17 (IH, d / 5.2 Hz, Ar), 8.09 (IH, dd / 9.2, 4.5 Hz, Ar), 7.74 (2H, d / 9.1 Hz, Ar), 7.32 (IH, dd / 9.1, 2.7 Hz, Ar), 7.22 (2H, d / 9.1 Hz, Ar), 7.15 (IH, td / 9.3, 2.7 Hz, Ar), 6.99 (IH, s, Ar), 6.89 (IH, d / 5.1 Hz, Ar), 3.66 (2H, s, CH2CO2H), 3.32 (3H, s, NCH3), 2.55 (3Η, s, CH3), 2.27 (3Η, s, ArCH3); Tr = 1.34 min (81%), m/z (ES+) (M+Η)+ 468.25.
(5-Fluoro-2-methyl-l-{6-[methyl-(6-methyl-pyridin-2-yl)-amino]-pyridine-3- sulfonyl}-lH-indoI-3-yl)-acetic acid (Compound 158) δH (400 MHz, 6-DMSO) 8.68 (IH, d / 2.6 Hz, Ar), 8.07 (IH, dd / 9.2, 4.5 Hz, Ar), 7.83 (IH, dd / 9.2, 2.7 Hz, Ar), 7.76 (IH, t / 7.8 Hz, Ar), 7.32 (IH, dd / 9.1, 2.7 Hz, Ar), 7.21-7.12 (3H, m, Ar), 6.94 (IH, d / 9.4 Hz, Ar), 3.67 (2H, s, CH2CO2H), 3.47 (3H, s, NCH3), 2.55 (3Η, s, CH3), 2.43 (3Η, s, ArCH3); Tr = 1.35 min (100%), m/z (ES+) (M+Η)+ 469.26.
{5-Fluoro-2-methyl-l-[4-(methyl-pyrimidin-2-yl-amino)-benzenesulfonyl]-lH- indol-3-yl}-acetic acid (Compound 159) δH (400 MHz, -DMSO) 8.46 (2H, d / 4.9 Hz, Ar), 8.11 (IH, dd / 9.1, 4.5 Hz, Ar), 7.85 (2H, d / 9.0 Hz, Ar), 7.62 (2H, d / 9.0 Hz, Ar), 7.34 (IH, dd / 9.1, 2.7 Hz, Ar), 7.17 (IH, td / 9.1, 2.7 Hz, Ar), 6.91 (IH, t / 4.8 Hz, Ar), 3.68 (2H, s, CH2CO2H), 3.51 (3H, s, NCH3), 2.58 (3Η, s, CH3); Tr = 1.44 min (100%), m/z (ES+) (M+Η)+ 455.21. {5-Fluoro-2-methyI-l-[4-(methyl-pyridin-2-yl-amino)-benzenesulfonyl]-lH- indol-3-yl}-acetic acid (Compound 160) δH (400 MHz, dβ-DMSO) 8.31-8.29 (IH, m, Ar), 8.08 (IH, dd / 9.1, 4.6 Hz, Ar), 7.75 (2H, d / 9.1 Hz, Ar), 7.73-7.68 (IH, m, Ar), 7.33-7.30 (IH, m, Ar), 7.27 (2H, d / 9.1 Hz, Ar), 7.18-7.11 (2H, m, Ar), 7.04-7.01 (IH, m, Ar), 3.63 (2H, s, CH2CO2H), 3.41 (3H, s, NCH3), 2.55 (3Η, s, CH3); Tr = 1.25 min (93%), m/z (ES+) (M+Η)+ 454.21.
{5-Fluoro-2-methyI-l-[6-(methyl-pyridin-2-yl-amino)-pyridine-3-sulfonyl]-lH- indol-3-yl}-acetic acid (Compound 161) δH (400 MHZ, 6-DMSO) 8.69 (IH, app d / 2.6 Hz, Ar), 8.45-8.43 (IH, m, Ar), 8.08 (IH, dd / 9.1, 4.5 Hz, Ar), 7.89-7.84 (2H, m, Ar), 7.43 (IH, d / 8.2 Hz, Ar), 7.32 (IH, dd / 9.1, 2.6 Hz, Ar), 7.28-7.24 (IH, m, Ar), 7.15 (IH, td / 9.1, 2.7 Hz, Ar), 6.99 (IH, d / 9.2 Hz, Ar), 3.67 (2H, s, CH2CO2H), 3.49 (3H, s, NCH3), 2.55 (3Η, s, CH3); Tr = 1.29 min (100%), m/z (ES+) (M+Η)+ 455.22.
{5-Fluoro-2-methyl-l-[6-(methyl-pyridin-4-yl-amino)-pyridine-3-sulfonyl]-2H- indol-3-yl}-acetic acid (Compound 162) δH (400 MHZ, d6-DMSO) 8.68 (IH, d / 2.6 Hz, Ar), 8.56 (2H, d / 6.1 Hz, Ar), 8.06 (IH, dd / 9.1, 4.5 Hz, Ar), 7.89 (IH, dd / 9.2, 2.7 Hz, Ar), 7.38 (2H, d / 6.2 Hz, Ar), 7.32 (IH, dd / 9.1, 2.6 Hz, Ar), 7.15 (IH ,td / 9.1, 2.6 Hz, Ar), 6.90 (IH, d / 9.1 Hz, Ar), 3.58 (2H, s, CH2CO2H), 3.45 (3H, s, NCH3), 2.54 (3Η, s, CH3); Tr = 1.18 min (98%) m/z (ES+) (M+Η)+ 455.34.
(5-Fluoro-2-methyl-l-{4-[methyl-(6-methyl-pyridin-2-yl)-amino]- benzenesulfonyl}-222-indol-3-yl)-acetic acid (Compound 163) δH (250 MHz, -DMSO) 8.03 (IH, bs, Ar), 7.69 (2H, m, Ar), 7.59 (IH, t / 4.8 Hz, Ar), 7.23 (IH, d / 4.5 Hz, Ar), 7.13-7.11 (3H, m, Ar), 6.91 (2H, m, Ar), 3.54 (2H, s, CH2CO2H), 3.33 (3H, s, NCH3), 2.52 (3Η, s, CH3), 2.34 (3Η, s, CH3); Tr = 1.25 min (93%) m/z (ES+) (M+Η)+ 468.29.
(l-{4-[(2,6-Dimethyl-pyrimidin-4-yl)-methyl-amino]-benzenesulfonyl}-5-fluoro- 2-methyl-2H-indol-3-yl)-acetic acid (Compound 164) δH (400 MHz, J6-DMSO) 8.11 (IH, dd / 9.1, 4.4 Hz, Ar), 8.05 (2H, d / 8.8 Hz, Ar), 7.65 (2H, d / 8.7 Hz, Ar), 7.36 (IH, dd / 9.0, 2.7 Hz, Ar), 7.19 (IH, td / 9.2, 2.7 Hz, Ar), 6.67 (IH, bs, Ar), 3.69 (2H, s, CH2CO2H), 3.49 (3H, s, NCH3), 2.57 (3Η, s, CH3), 2.52 (3Η, s, CH3), 2.37 (3Η, s, CH3); Tr = 1.24 min (100%) m/z (ES+) (M+Η)+ 483.32.
{5-Fluoro-2-methyl-l-[6-(methyl-phenyl-amino)-pyridine-3-sulfonyl]-2H-indol- 3-yl}-acetic acid (Compound 165) δH (250 MHz, 6-DMSO) 8.64 (IH, d / 2.6 Hz, Ar), 8.05 (IH, dd / 9.1, 4.5 Hz, Ar), 7.75 (IH, dd / 9.3, 2.7 Hz, Ar), 7.49 (IH, t / 7.7 Hz, Ar), 7.39-7.29 (4H, m, Ar), 7.13 (IH, td / 9.2, 2.7 Hz, Ar), 6.36 (2H, d, Ar), 3.66 (2H, s, CH2CO2H), 3.40 (3H, s, NCH3), 2.56 (3Η, s, CH3); Tr = 1.60 min (100%) m/z (ES+) (M+Η)+ 454.27.
(l-{6-[(3-Chloro-phenyl)-methyl-amino]-pyridine-3-sulfonyl}-5-fluoro-2-methyl- 22 -indol-3-yl)-acetic acid (Compound 166) δH (400 MHz, -DMSO) 8.64 (IH, d / 2.6 Hz, Ar), 8.06 (IH, dd / 9.1, 4.2 Hz, Ar), 7.80 (IH, dd / 9.3, 2.6 Hz, Ar), 7.51-7.48 (2H, m, Ar), 7.42 (IH, d / 8.0 Hz, Ar), 7.32 (2H, m, Ar), 7.14 (IH, td / 9.2, 2.6 Hz, Ar), 6.48 (IH, d / 9.2 Hz, Ar), 3.66 (2H, s, CH2CO2H), 3.31 (3H, s, NCH3), 2.54 (3Η, s, CH3); Tr = 1.67 min (84%) m/z (ES+) (M+Η)+ 488.22.
(l-{4-[(3-Chloro-phenyl)-methyl-amino]-benzenesulfonyl}-5-fIuoro-2-methyl- 1H -indol-3-yl)-acetic acid (Compound 167) δH (400 MHz, 6-DMSO) 8.06 (IH, dd / 9.2, 4.5 Hz, Ar), 7.67 (2H, d / 9.2 Hz, Ar), 7.45 (IH, t / 7.5 Hz, Ar), 7.36 (IH, t / 2.1 Hz, Ar), 7.34 (IH, d / 7.9 Hz, Ar), 7.29 (IH, dd / 9.1, 2.6 Hz, Ar), 7.19 (IH, d / 7.9 Hz, Ar), 7.12 (IH, td / 9.2, 2.7 Hz, Ar), 6.78 (2H, d / 9.3 Hz, Ar), 3.64 (2H, s, CH2CO2H), 3.27 (3H, s, NCH3), 2.53 (3Η, s, CH3); Tr = 1.72 min (100%) m/z (ES+) (M+Η)+ 487.27. {l-[4-(Ethyl- -tolyl-amino)-benzenesulfonyl]-5-fluoro-2-methyl-2H-indol-3-yl}- acetic acid (Compound 168) δH (400 MHz, dβ-DMSO) 8.01 (IH, dd / 9.0, 4.2 Hz, Ar),7.59 (2H, d / 8.8 Hz, Ar), 7.32 (IH, t / 7.7 Hz, Ar), 7.25 (IH, dd / 9.2, 2.6 Hz, Ar), 7.12 (2H, m, Ar), 6.99 (IH, s, Ar), 6.92 (IH, d / 8.8 Hz, Ar), 6.69 (2H, d / 7.2 Hz, Ar), 3.67 (2H, q / 7.6 Hz, CH2CH3), 3.62 (2H, s, CH2CO2H), 2.55 (3H, s, CH3), 2.30 (3Η, s, CH3), 1.05 (3Η, q / 7.6 Hz, CH2CH3); Tr = 1.76 min (91%) m/z (ES+) (M+Η)+ 481.35.
{5-Fluoro-2-methyl-l-[4-(methyl-pyridin-3-yl-amino)-benζenesulfonyl]-2H- indol-3-yl}-acetic acid (Compound 169) δH (400 MHz, -DMSO) 8.50 (IH, d / 2.4 Hz, Ar), 8.48 (IH, dd / 4.7, 1.4 Hz, Ar), 8.06 (IH, dd / 9.2, 4.5 Hz, Ar), 1.16-1.11 (IH, m, Ar), 7.67 (2H, d / 9.2 Hz, Ar), 7.48 (IH, dd / 8.1, 7.7 Hz, Ar), 7.30 (IH, dd / 9.0, 2.6 Hz, Ar), 7.13 (IH, td / 9.2, 2.6 Hz, Ar), 6.78 (2H, d / 9.2 Hz, Ar), 3.62 (2H, s, CH2CO2H), 3.31 (3H, s, NCH3), 2.52 (3Η, masked s, CH3); Tr = 1.22 min (97%), m/z (ES+) (M+Η)+ 454.31.
Example 8 sulfur linked Compounds
4-Phenylsulfanyl-benzenesulfonyl chloride
Chlorosulfonic acid (0.70 mL, 10.74 mmol) was added dropwise to a stirred solution of diphenyl sulfide (2 g, 10 mmol) in chloroform (5 mL) at 0°C. The mixture was left at 0°C for 30 minutes, and then left overnight stirring at room temperature. The resulting mixture was concentrated in vacuo to give a yellow oil which crystallised on standing. The resulting product was dissolved in toluene and treated with phosphorus pentachloride (2.23 g, 10.71 mmol) at 90°C for one hour. The resulting mixture was concentrated in vacuo and then partitioned between dichloromethane and water. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The product was used directly in the next step.
[5-Fluoro-2-methyl-l-(4-phenyIsulfanyl-benzenesulfonyl)-2H-indoI-3-yl]-acetic acid ethyl ester
A solution of (5-fluoro-2-methyl-iH-indol-3-yl)-acetic acid ethyl ester (500 mg, 2.12 mmol) and benzyltriethylammonium chloride (48 mg, 0.21 mmol) in dichloromethane (25 mL) was stirred at room temperature for 5 minutes. Potassium hydroxide (715 mg, 12.76 mmol) was added to the solution, followed immediately by the addition of a solution of 4-phenylsulfanyl-benzenesulfonyl chloride (1.45 g at -50% purity, 2.55 mmol) in dichloromethane (25 mL). The reaction was stirred at room temperature for two hours. The resulting solution was neutralised with 1M HC1 and the aqueous layer extracted with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. Purification by column chromatography using a 25 g silica gel column, eluting with 20 % ethyl acetate : heptane, gave the sulfonamide (360 mg) with a purity of 50%. Tr =1.93 min (50%), m/z (ES+) (M+H)+ 484.33
[5-Fluoro-2-methyl-l-(4-phenylsulfanyl-benzenesulfonyl)-lH-indol-3-yl]-acetic acid (Compound 171)
Hydrolysis of the ester intermediate was performed as described for compound 1. δH (400 MHz, dβ-DMSO) 8.02 (IH, dd / 9.2, 4.4 Hz, Ar), 1.16 (2H, d / 8.7 Hz, Ar), 7.57-7.51 (5H, m, Ar), 7.32 (IH, dd / 9.1, 2.6 Hz, Ar), 7.20 (2H, app d / 8.8 Hz, Ar), 7.13 (IH, td / 9.1, 2.8 Hz, Ar), 3.64 (2H, s, CH2CO2H), 2.52 (3H, masked s, CH3); Tr = 1.69 min (100%), m/z (ES+) (M+Η)+ 456.10.
Example 9 Sulfoxide
[l-(4-Benzenesulfinyl-benzenesulfonyl)-5-fluoro-2-methyl-2H-indoI-3-yl]-acetic acid ethyl ester mCPBA (26 mg, 0.10 mmol) was added to a solution of [5-fluoro-2-methyl-l-(4- phenylsulfanyl-benzenesulfonyl)-7H-indol-3-yl]-acetic acid ethyl ester (100 mg at 50% purity, 0.10 mmol) in dichloromethane (5 mL). The resulting mixture was stirred at room temperature overnight and then partitioned between dichloromethane and water. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. Purification by column chromatography using a 10 g silica gel column, eluting with 20% ethyl acetate : heptane gave the ester (50 mg at 50% purity). Tr = 1.64 min, m/z (ES+) (M+H)+ 500.27
[l-(4-Benzenesulfinyl-benzenesulfonyl)-5-fluoro-2-methyl-2H-indol-3-yl]-acetic acid (Compound 172)
Hydrolysis of the ester intermediate was performed as described for compound 1. δH (400 MHz, -DMSO) 8.03 (IH, dd / 9.3, 4.5 Hz, Ar), 8.00 (2H, d / 8.5 Hz, Ar), 7.91 (2H, d / 8.5 Hz, Ar), 7.75-7.71 (2H, m, Ar), 7.56 (3H, m , Ar), 7.32 (IH, dd / 9.0, 2.6 Hz, Ar), 7.15 (IH, td / 9.1, 2.7 Hz, Ar), 3.65 (2H, s, CH2CO2H), 2.52 (3H, masked s, CH3); Tr = 1.41 min (88%), m/z (ES+) (M+Η)+ 472.08.
Example 10 sulfones
[l-(4-Benzenesulfonyl-benzenesulfonyl)-5-fluoro-2-methyl-2H-indol-3-yl]-acetic acid ethyl ester
Oxone (190 mg, 0.31 mmol) was added to a solution of [5-fluoro-2-methyl-l-(4- phenylsulfanyl-benzenesulfonyl)-2H-indol-3-yl]-acetic acid ethyl ester (100 mg at 50% purity, 0.10 mmol) in 5 mL of dioxane : water (4:1). The resulting mixture was stirred at room temperature overnight and then partitioned between dichloromethane and water. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. Purification by column chromatography using a 10 g silica gel column, eluting with 20% ethyl acetate : heptane gave the ester (50 mg at 60% purity). Tr = 1.72 min (61%), m/z (ES+) (M+Η)+516.25
[l-(4-Benzenesulfonyl-benzenesulfonyl)-5-fluoro-2-methyl-2H-indol-3-yl]-acetic acid (Compound 173)
Hydrolysis of the ester intermediate was performed as described for compound 1. δH (400 MHz, CDC13) 8.07 (IH, dd / 9.0, 4.4 Hz, Ar), 7.97 (2H, d / 8.6 Hz, Ar), 7.91 (2H, app d / 7.5 Hz, Ar), 7.80 (2H, d / 8.6 Hz, Ar), 7.64-7.61 (IH, m Ar), 7.55-7.51 (2H, m, Ar), 7.11 (IH, dd / 8.4, 2.4 Hz, Ar), 7.02 (IH, td /9.1, 2.5 Hz, Ar), 3.60 (2H, s, CH2CO2H), 2.54 (3H, s, CH3); Tr = 1.52 min (100%), m/z (ES+) (M+Η)+ 488.11.
Compound 174 was prepared from appropriate starting materials using the method set out in Example 1.
[5-Chloro-l-(4-chloro-benzenesulfonyl)-2-methyl-2H-indol-3-yl]-acetic acid
(Compound 174) δH (400 MHz, CD3OD) 8.13 (IH, d / 8.6 Hz, Ar), 7.79 (2H, d / 9.1 Hz, Ar), 7.55
(2H, d / 9.1 Hz, Ar), 7.50 (IH, d / 2.0 Hz, Ar), 7.31 (IH, dd / 7.3, 2.0 Hz, Ar), 3.67
(2H, s, CH2CO2H), 2.60 (3H, s, CH3); Tr = 2.08 min (100%) m/z (ES+) (M+Η)+
398.06.
Compounds 175 to 179 were prepared from appropriate starting materials using either the method of Example 4 or the method of Example 5
{5-Fluoro-l-[4-(3-isopropyI-phenylamino)-benzenesulfonyl]-2-methyl-2H-indol- 3-yl}-acetic acid (Compound 175) δH (400 MHz, -DMSO) 8.98 (IH, s, NH), 8.06 (1Η, dd / 8.9, 4.2 Ηz, Ar), 7.67 (2Η, d / 9.0 Hz, Ar), 7.30 (IH, dd /9.1, 2.7 Hz, Ar), 7.24 (IH, t / 7.3 Hz, Ar), 7.13 (IH, td / 9.2, 2.7 Hz, Ar), 7.01-6.97 (4H, m, Ar), 6.94 (IH, d, Ar), 3.62 (2H, s, CH2CO2H), 2.86 (IH, m, CH(CH3)2), 2.53 (3H, s, CH3), 1.19 (6Η, d/ 7.00Hz, CH(CH3)2); Tr = 1.73 min (94%) m/z (ES+) (M+Η)+ 481.07.
{5-Fluoro-2-methyl-l-[4-(methyl-thiazol-2-yl-amino)-benzenesulfonyl]-2H- indol-3-yl}-acetic acid (Compound 176) δH (400 MHz, dβ-DMSO) 8.07 (IH, dd / 10.2, 4.5 Hz, Ar), 7.78 (2H, d / 8.8 Hz, Ar), 7.32 (IH, dd /9.1, 2.7 Hz, Ar), 7.21 (IH, d /4.8 Hz, Ar), 7.18-7.13 (3H, m, Ar), 6.49 (IH, d /4.8 Hz, Ar), 3.66 (2H, s, CH2CO2H), 3.42 (3H, s, NCH3), 2.54 (3Η, s, CH3); Tr = 1.21 min (98%) m/z (ES+) (M+Η)+ 459.98.
{l-[2,5-Difluoro-4-(isoxaζol-3-ylamino)-benζenesuIfonyl]-5-fluoro-2-methyl-2H- indol-3-yl}-acetic acid (Compound 177) δH (400 MHz, -DMSO) 10.10 (IH, s, NH), 8.75 (IH, d / 1.7 Hz, Ar), 8.02-7.92 (3H, m, Ar), 7.34 (IH, dd / 9.0, 2.6 Hz, Ar), 7.13 (IH, td / 9.2, 2.7 Hz, Ar), 6.47 (IH, d / 1.8 Hz, Ar), 3.65 (2H, s, CH2CO2H), 2.47 (3H, s, CH3); Tr = 1.46 min (100%) /z (ES+) (M+Η)+ 466.25.
{l-[4-(5-Chloro-pyridin-3-ylamino)-2,5-difluoro-benzenesulfonyl]-5-fluoro-2- methyl-2H-indol-3-yl}-acetic acid (Compound 178) δH (400 MHz, 6-DMSO) 9.32 (IH, s, NH), 8.45 (IH, d / 2.2 Hz, Ar), 8.33 (IH, d / 2.2 Hz, Ar), 7.96-7.92 (2H, m, Ar), 7.83 (IH, t / 2.2 Hz, Ar), 7.36 (IH, dd / 9.0, 2.6 Hz, Ar), 7.18-7.11 (2H, m, Ar), 3.66 (2H, s, CH2CO2H), 2.48 (3H, s, CH3); Tr = 1.47 min (94%) m/z (ES+) (M+Η)+ 510.24.
{l-[2,5-DifIuoro-4-(5-methyl-pyridin-3-yIamino)-benzenesuIfonyl]-5-fluoro-2- methyl-2H-indol-3-yl}-acetic acid (Compound 179) δH (400 MHz, -DMSO) 9.15 (IH, s, NH), 8.28 (IH, d / 2.3 Hz, Ar), 8.17 (IH, s,
Ar), 7.94-7.88 (2H, m, Ar), 7.53 (IH, s, Ar), 7.34 (IH, dd / 9.1, 2.5 Hz, Ar), 7.12
(IH, td / 9.2, 2.6 Hz, Ar), 6.95 (IH, dd / 12.5, 6.7 Hz, Ar), 3.64 (2H, s, CH2CO2H),
2.47 (3H, s, CH3), 2.27 (3Η, s, CH3); Tr = 1.26 min (100%) m/z (ES+) (M+Η)+
490.30.
Compounds 180 to 183 were prepared from appropriate starting materials using the method set out in Example 6.
{l-[6-(3-Ethyl-phenylamino)-pyridine-3-sulfonyl]-5-fluoro-2-methyl-2i -indol-3- yl}-acetic acid (Compound 180) δH (400 MHZ, 6-DMSO) 9.84 (IH, bs, NH), 8.62 (IH, d / 2.7 Hz, Ar), 8.07 (IH, dd / 9.0, 4.5 Hz, Ar), 7.84 (IH, dd / 9.1, 2.7 Hz, Ar), 7.49 (IH, d, / 8.0 Hz, Ar), 7.40 (IH, s, Ar), 7.32 (IH, dd / 9.0, 2.6 Hz, Ar), 7.22 (IH, t / 7.9 Hz, Ar), 7.14 (IH, td / 9.1, 2.6 Hz, Ar), 6.89 (IH, d / 7.8 Hz, Ar), 6.81 (IH, d / 9.2 Hz, Ar), 3.63 (2H, s, CH2CO2H), 2.58 (2H, q / 7.6 Hz, CH2CH3), 2.55 (3H, s, CH3), 1.18 (3Η, t / 7.6 Hz, CH2CH3); Tr = 1.65 min (95%) m/z (ES+) (M+Η)+ 468.06. {5-Fluoro-l-[6-(3-methoxy-phenylamino)-pyridine-3-sulfonyl]-2-methyl-2H- indol-3-yl}-acetic acid (Compound 181) δH (400 MHz, -DMSO) 9.88 (IH, bs, NH), 8.65 (1Η, d / 2.6 Ηz, Ar), 8.07 (1Η, dd / 9.2, 4.5 Ηz, Ar), 7.85 (1Η, dd / 9.1, 2.6 Ηz, Ar), 7.32 (2Η, m, Ar), 7.24-7.12 (3H, m, Ar), 6.83 (IH, d / 9.0 Hz, Ar), 6.62 (IH, m, Ar), 3.74 (3H, s, OCH3), 3.64 (2Η, s, CH2CO2H), 2.56 (3H, s, CH3); Tr = 1.53 min (100%) m/z (ES+) (M+Η)+ 470.05.
{l-[6-(3-Cyano-phenylamino)-pyridine-3-sulfonyl]-5-fluoro-2-methyl-2ijr-indol- 3-yl}-acetic acid (Compound 182) δH (400 MHz, -DMSO) 10.20 (IH, s, Ar), 8.74 (IH, d/2.6 Hz, Ar), 8.28 (IH, t / 1.9 Hz, Ar), 8.08 (IH, dd /9.0, 4.5 Hz, Ar), 7.94 (IH, dd /9.1, 2.6 Hz, Ar), 7.82 (IH, dt / 8.2, 1.5 Hz, Ar), 7.53 (IH, t /7.8Hz, Ar), 7.47 (IH, dt /7.8, 1.4 Hz, Ar), 7.32 (IH, dd / 9.1, 2.6 Hz, Ar), 7.16 (IH, td / 9.1, 2.6 Hz, Ar), 6.90 (IH, d / 9.0 Hz, Ar), 3.66 (2H, s, CH2CO2H), 2.57 (3H, s, CH3); Tr = 1.50 min (100%) m/z (ES+) (M+Η)+ 465.04.
{5-Fluoro-l-[6-(3-methanesulfonyl-phenylamino)-pyridine-3-sulfonyl]-2-methyl- 2H-indol-3-yl}-acetic acid (Compound 183) δH (400 MHz, dβ-D SO) 10.27 (IH, s, Ar), 8.69 (IH, d / 2.6 Hz, Ar), 8.23 (IH, t / 1.9 Hz, Ar), 8.09 (IH, dd /9.0, 4.5 Hz, Ar), 8.03 (IH, dt / 8.2, 1.5 Hz, Ar), 7.94 (IH, dd / 9.1, 2.6 Hz, Ar), 7.60 (IH, t / 7.8Hz, Ar), 7.56 (IH, dt / 7.8, 1.4 Hz, Ar), 7.33 (IH, dd / 9.1, 2.6 Hz, Ar), 7.16 (IH, td / 9.1, 2.6 Hz, Ar), 6.90 (IH, d / 9.0 Hz, Ar), 3.66 (2H, s, CH2CO2H), 3.21 (3H, s, SO2CH3), 2.57 (3Η, s, CH3); Tr = 1.40 min (100%) m/z (ES+) (M+Η)+ 518.02.
Compounds 184 to 194 were prepared from appropriate starting materials using the method set out in Example 7
{5-Fluoro-l-[4-(isoxazol-3-yl-methyl-amino)-benzenesulfonyl]-2-methyl-2H- indol-3-yl}-acetic acid (Compound 184) δH (400 MHz, -DMSO) 8.79 (IH, d / 1.8 Hz, Ar), 8.09 (IH, dd / 9.0, 4.5 Hz, Ar), 7.81 (2H, d, Ar), 7.45 (2H, d/9.0 Hz, Ar), 7.32 (IH, dd / 9.1, 2.6 Hz, Ar), 7.16 (IH, td / 9.2, 2.7 Hz, Ar), 6.62 (IH, d / 1.8 Hz, Ar), 3.66 (2H, s, CH2CO2H), 3.39 (3H, s, NCH3), 2.55 (3Η, s, CH3); Tr = 1.45 min (93%) m/z (ES+) (M+Η)+ 444.00.
(5-Fluoro-2-methyl-l-{4-[methyl-(5-methyl-pyridin-3-yl)-amino]- benzenesulfonyl}-2H-indol-3-yl)-acetic acid (Compound 185) δH (400 MHz, J6-DMSO) 8.47 (IH, bs, Ar), 8.42 (IH, bs, Ar), 8.08 (IH, dd / 9.1, 4.4 Hz, Ar), 7.90 (IH, bs, Ar), 7.73 (2H, d/ 9.0 Hz, Ar), 7.31 (IH, dd /9.1, 2.6 Hz, Ar), 7.15 (IH, dt / 9.2, 2.7 Hz, Ar), 6.99 (2H, d / 9.0 Hz, Ar), 3.66 (2H, s, CH2CO2H), 3.34 (3H, s, NCH3), 2.54 (3Η, s, CH3), 2.37 (3Η, s, CH3); Tr = 1.24 min (100%) m/z (ES+) (M+Η)+ 468.03.
(l-{4-[(3,5-Dimethyl-phenyl)-methyl-amino]-benζenesulfonyl}-5-fluoro-2- methyl-2/2-indol-3-yl)-acetic acid (Compound 186) δH (400 MHz, -DMSO) 8.06 (IH, dd / 9.1, 4.5 Hz, Ar), 7.63 (2H, d / 9.2 Hz, Ar), 7.29 (IH, dd / 9.2, 2.6 Hz, Ar), 7.12 (IH, td / 9.2, 2.7 Hz, Ar), 6.93 (IH, s, Ar), 6.84 (6H, s, Ar), 6.67 (2H, d / 9.2 Hz, Ar), 3.64 (2H, s, CH2CO2H), 3.22 (3H, s, NCH3), 2.53 (3Η, s, CH3), 2.26 (6Η, s, 2 x CH3); Tr = 1.78 min (100%) m/z (ES+) (M+Η)+ 481.05.
(5-Fluoro-l-{4-[(3-methoxy-phenyl)-methyl-amino]-benzenesulfonyl}-2-methyl- 2£T-indol-3-yl)-acetic acid (Compound 187) δH (400 MHz, -DMSO) 8.06 (IH, dd / 9.2, 4.5 Hz, Ar), 1.64 (2H, d / 9.2 Hz, Ar), 7.34 (IH, t / 8.0 Hz, Ar), 7.29 (IH, dd / 9.2, 2.7 Hz, Ar), 7.11 (IH, td / 9.2, 2.6 Hz, Ar), 6.87 (IH, bd / 8.1 Hz, Ar), 6.81-6.78 (2H, m, Ar), 6.72 (2H, d /9.2 Hz, Ar), 3.73 (3H, s, OCH3), 3.64 (2Η, s, CH2CO2H), 3.25 (3H, s, NCH3), 2.55 (3Η, s, CH3); Tr = 1.64 min (100%) m/z (ES+) (M+Η)+ 482.13.
(l-{4-[(3-Cyano-phenyl)-methyl-amino]-benζenesulfonyl}-5-fluoro-2-methyl-2H- indol-3-yl)-acetic acid (Compound 188) δH (400 MHz, dβ-DMSO) 8.06 (IH, dd / 9.2, 4.5 Hz, Ar), 7.78 (IH, s, Ar), 7.71-7.66 (3H, m, Ar), 7.61-7.59 (2H, m, Ar), 7.29 (IH, dd / 9.1, 2.6 Hz, Ar), 7.12 (IH, td / 9.2, 2.7 Hz, Ar), 6.83 (2H, d / 9.2 Hz, Ar), 3.64 (2H, s, CH2CO2H), 3.29 (3H, s, NCH3), 2.55 (3Η, s, CH3); Tr = 1.56 min (97%) m/z (ES+) (M+Η)+ 478.29.
(l-{4-[(3-Ethyl-phenyl)-methyl-amino]-benzenesulfonyl}-5-fluoro-2-methyl-2H- indoI-3-yl)-acetic acid (Compound 189) δH (400 MHz, dβ-DMSO) 8.06 (IH, dd / 9.1, 4.5 Hz, Ar), 7.62 (2H, d / 9.2 Hz, Ar), 7.34 (IH, t / 7.7 Hz, Ar), 7.28 (IH, dd / 9.2, 2.6 Hz, Ar), 7.14 (IH, bd / 6.6 Hz, Ar), 7.11-7.08 (2H, m, Ar), 7.02 (IH, bd / 6.6 Hz, Ar), 6.68 (2H, d / 9.2 Hz, Ar), 3.63 (2H, s, CH2CO2H), 3.25 (3H, s, NCH3), 2.59 (2Η, q / 7.6 Hz, CH2CH3), 2.55 (3H, s, CH3), 1.16 (3Η, 177.6 Hz, CH2CH3); Tr = 1.73 min (96%) m/z (ES+) (M+Η)+ 481.32.
(5-Fluoro-l-{4-[(3-isopropyl-phenyI)-methyl-amino]-benzenesulfonyl}-2-methyl- 2H-indol-3-yl)-acetic acid (Compound 190) δH (400 MHz, -DMSO) 8.05 (IH, dd/9.0, 4.5 Hz, Ar), 7.64 (2H, d, / 8.7 Hz, Ar), 7.33 (IH, t /7.7 Hz, Ar), 7.29 (IH, dd /9.1, 2.3 Hz, Ar), 7.14-7.09 (2H, m, Ar), 7.03 (IH, bd / 7.8 Hz, Ar), 6.69 (2H, d / 8.8 Hz, Ar), 3.64 (2H, s, CH2CO2H), 3.26 (3H, s, NCH3), 2.89 (1Η, m, CH(CΗ3)2), 2.55 (3H, s, CH3), 1.19 (6Η, d /6.8 Hz, CH(CH3)2); Tr = 1.82 min (90%) m/z (ES+) (M+Η)+ 495.35. (l-{6-[(3-Ethyl-phenyl)-methyl-amino]-pyridine-3-sulfonyl}-5-fluoro-2-methyl- 222-indol-3-yl)-acetic acid (Compound 191) δH (400 MHz, 6-DMSO) 8.64 (IH, d / 2.6 Hz, Ar), 8.05 (IH, dd / 9.0, 4.4 Hz, Ar), 7.74 (IH, dd / 9.3, 2.6 Hz, Ar), 7.39 (IH, t / 7.7 Hz, Ar), 7.31 (IH, dd / 9.0, 2.6 Hz, Ar), 7.26 (IH, d /7.4 Hz, Ar), 7.17-7.11 (3H, m, Ar), 6.34 (IH, d / 9.3 Hz, Ar), 3.63 (2H, s, CH2CO2H), 3.39 (3H, s, NCH3), 2.61 (2Η, q / 7.6 Hz, CH2CH3), 2.54 (3H, s, CH3), 1.18 (3Η, t / 7.6 Hz, CH2CH3); Tr = 1.73 min (96%) m/z (ES+) (M+Η)+ 482.30.
(5-Fluoro-l-{6-[(3-methanesulfonyl-phenyl)-methyl-amino]-pyridine-3- sulfonyl}-2-methyl-2H-indol-3-yI)-acetic acid (Compound 192) δH (400 MHz, d6-DMSO) 8.65 (IH, d / 2.3 Hz, Ar), 8.06 (IH, dd / 9.0, 4.5 Hz, Ar), 7.89 (IH, bs, Ar), 7.87 (IH, dt / 6.6, 1.8 Hz, Ar), 7.83 (IH, dd / 9.3, 2.6 Hz, Ar), 7.75-7.68 (2H, m, Ar), 7.31 (IH, dd / 9.0, 2.6 Hz, Ar), 7.14 (IH, td / 9,2, 2.6 Hz, Ar), 6.58 (IH, d / 9.4 Hz, Ar), 3.62 (2H, s, CH2CO2H), 3.44 (3H, s, NCH3), 3.26 (3Η, s, SO2CH3), 2.54 (3Η, s, CH3); Tr = 1.42 min (98%) m/z (ES+) (M+Η)+ 532.31.
(l-{6-[(3-Cyano-phenyl)-methyl-amino]-pyridine-3-sulfonyl}-5-fluoro-2-methyl- 2H-indol-3-yl)-acetic acid (Compound 193) δH (400 MHz, J6-DMSO) 8.64 (IH, d / 2.4 Hz, Ar), 8.06 (IH, dd / 9.1, 4.5 Hz, Ar), 7.91 (IH, t / 1.7 Hz, Ar), 7.83-7.78 (2H, m, Ar), 7.72-7.63 (2H, m, Ar), 7.32 (IH, dd / 9.1, 2.6 Hz, Ar), 7.13 (IH, td / 9.2, 2.6 Hz, Ar), 6.56 (IH, d / 9.3 Hz, Ar), 3.64 (2H, s, CH2CO2H), 3.41 (3H, s, NCH3), 2.54 (3Η, s, CH3); Tr = 1.52 min (96%) m/z (ES+) (M+Η)+ 479.29.
(5-Fluoro-2-methyl-l-{6-[methyl-(5-methyl-pyridin-3-yl)-amino]-pyridine-3- sulfonyI}-22 -indol-3-yl)-acetic acid (Compound 194) δH (400 MHz, dβ-DMSO) 8.69 (IH, d / 2.6 Hz, Ar), 8.29 (IH, d / 5.0 Hz, Ar), 8.07 (IH, dd / 9.0, 4.5 Hz, Ar), 7.82 (IH, dd / 9.3, 2.6 Hz, Ar), 7.32 (IH, dd /9.1, 2.7 Hz, Ar), 7.26 (IH, s, Ar), 7.16 (IH, dd / 9.1, 2.7 Hz, Ar), 7.11 (IH, d / 6.5 Hz, Ar), 6.94 (IH, d / 9.2 Hz, Ar), 3.63 (2H, s, CH2CO2H), 3.47 (3H, s, NCH3), 2.56 (3Η, s, CH3), 2.33 (3Η, s, CH3); Tr = 1.26 min (92%) m/z (ES+) (M+Η)+ 469.33.
Example 11 - Measurement of CRTH2 Antagonist Activity
Materials and Methods
Materials
Calcium-3 dye was purchased from Molecular Devices (Wokingham, UK). Monopoly resolving medium was obtained from Dainippon Pharmaceuticals (Osaka, Japan). Macs anti-CD16 microbeads were from Miltenyi biotec (Bisley, Surrey). ChemoTx plates were purchased from Neuroprobe (Gaithesburg, MD). Poly-D- lysine coated 96-well plates were obtained from Greiner (Gloucestershire, UK). [3H]PGD2 was from Amersham Biosciences (Buckinghamshire, UK). [3H]SQ29548 was purchased from Perkin Elmer Life Sciences (Buckinghamshire, UK). All other reagents were obtained from Sigma-Aldrich (Dorset, UK), unless otherwise stated.
Methods Cell culture
Chinese Hamster Ovary cells were transfected with CRTH2 or DP receptors (CHO/CRTH2 and CHO/DP) and were maintained in culture in a humidified atmosphere at 37°C (5% CO2) in Minimum Essential Medium (MEM) supplemented with 10% foetal bovine serum, 2 mM glutamine, and 1 mg ml"1 active G418. The cells were passaged every 2-3 days. For radioligand binding assay, cells were prepared in triple-layer flasks or in 175 cm square flasks (for membrane preparation). For calcium mobilisation assay, cells were grown in a 96 well plate 24h prior to the assay at a density of 80,000 cells per well.
Preparation of cell membranes
Membranes were prepared either from CHO/CRTH2 and CHO/DP cells, or from platelets (as a source of TP receptors). CHO cells grown to confluency were washed with PBS and detached using a Versene solution (15 ml per flask). When the cells were grown in 175 cm2 square flask, they were collected by scrapping in PBS. The cell suspensions were centrifuged (1,700 rpm, 10 min, 4°C) and resuspended in 15 ml of buffer (lxHBSS, supplemented with 10 mM HEPES, pH 7.3). Cell suspensions were then homogenised using an Ultra Turrax at setting 4-6 for 20 s. The homogenate was centrifuged at 1,700 rpm for 10 min and the supernatant was collected and centrifuged at 20,000 rpm for lh at 4°C. The resulting pellet was resuspended in buffer and stored at -80°C in aliquots of 200-500 μl. The protein concentration was determined by the method of Bradford (1976), using bovine serum albumin as standard. The platelets were washed by centrifugation at 600xg for 10 min and resuspended in ice-cold assay buffer (10 mM Tris-HCl, pH 7.4, 5 mM Glucose, 120 mM NaCl, 10 μM indomethacin) and directly centrifuged at 20,000 rpm for 30 min at 4°C. The resulting pellet was treated as described above. Radioligand binding assays
[3H]PGD2 (160 Ci/mmol) binding experiments were performed on membranes prepared as described above. Assays were performed in a final volume of 100 μl of buffer (1XHBSS/HEPES 10 mM, pH 7.3). Cell membranes (15μg). Cell membranes 15mg were preincubated at room temperature with varying concentration of competing ligand for 15 min. [3H]PGD2 (mol, final concentration) was then added and the incubation continued for a further one hour at room temperature. The reaction was terminated by the addition of 200 μl ice-cold assay buffer to each well, followed by rapid filtration through Whatman GF/B glass fibre filters using a Unifilter Cell harvester (PerkinElmer Life Sciences) and six washes of 300 μl of ice- cold buffer. The Unifilter plates were dried at room temperature for at least lh and the radioactivity retained on the filters was determined on a Beta Trilux counter (PerkinElmer Life Sciences), following addition of 40 μl of Optiphase Hi-Safe 3 (Wallac) liquid scintillation. Non specific binding was defined in the presence of 10 μM unlabelled PGD2. Assays were performed in duplicate.
The results of the radioligand binding experiments to the CRTH2 and DP receptors are shown in Tables 1 and 2.
Table 1 - Radioligand binding data (Ki on CRTH2 Receptor).
Figure imgf000094_0001
Table 2 - Radioligand binding data (Ki on DP Receptor).
Figure imgf000095_0001
The results of the experiments demonstrate that for compounds of general formula (I) the affinity for the CRTH2 receptor is higher than for DP receptor.
The TP receptor radioligand binding was done on membranes prepared from platelets. 15-40 μg of protein were pre-incubated with varying concentrations of competing ligand for 15 min at room temperature in assay buffer (10 mM Tris-HCl, pH 7.4, 5 mM glucose, 120 mM NaCl, 10 μM indomethacin). [3H]SQ29548 (38 Ci/mmol, 10 nM final concentration) was then added and the incubation continued for a further 30 min at room temperature. The reaction was terminated by the addition of 200 μl ice-cold assay buffer to each well, followed by rapid filtration through Whatman GF/C glass fibre filters using a Unifilter Cell harvester (PerkinElmer Life Sciences) followed with six washes of 300 μl of ice-cold buffer. The radioactivity was determined as described above.
All of the compounds studied in this assay bound to the TP receptor with low affinity (Ki>lμM).
Compounds of general formula (I) bound to CRTH2 receptor expressed in CHO cells with a range of affinity varying from very high to moderate. In fact the Ki values determined in competition versus [3H]PGD2 varied from 500 pM to 1 μM. The inventors have found that by varying the R8 substitutent of the compounds of general formula (I), it is possible to vary the degree of selectivity for the CRTH2 receptor or DP receptor. Calcium mobilisation Assay
Cells were seeded onto poly-D-lysine coated 96-well plates at a density of 80,000 cells per well and incubated at 37 °C overnight to allow the cells to adhere. Cells were washed twice with HBSS and incubated for lh at 37°C in lOOμl HBSS and lOOμl calcium-3-dye (Molecular Devices), supplemented with 4mM probenecid. Changes in fluorescence were monitored over a 50s time course with agonist addition at 17s using a Flexstation (Molecular Devices).
Effect ofCRTH2 agonists on calcium mobilisation in CHO-CRTH2 cells PPGGDD22 ccaauusseedd aa ddoossee--ddeeppeennddeenntt iinnccrreeaassee iinn iinnttrraaccellular Ca2+ mobilisation in CHO/CRTH2 cells, with an EC50 = 2.4 ± 0.5nM (n=3).
Effect of compounds of general formula (I) on the calcium mobilisation induced by PGD2
PGD2-stimulated Ca2+ flux was fully inhibited by the compounds of general formula (I) and the IC50 value for each compound in the calcium assay was comparable to its Ki value in Radioligand binding. IC50 values of compounds of general formula (I) varied from 5 nM to 1 μM. The results for several compounds of general formula (I) are shown in Table 3. Increasing doses of the compounds of general formula (I) caused a dose-dependent and parallel shift of the PGD2 dose response curve in CHO/CRTH2 cells, thereby indicating that the compounds are competitive CRTH2 antagonists.
The antagonistic effect of the compounds of general formula (I) appears to be
CRTH2 selective, since no inhibitory effect was seen with ATP-stimulated Ca 2+ . flux
Table 3 - Inhibition of PGD2-induced calcium flux
Figure imgf000096_0001
Figure imgf000097_0001

Claims

1. A compound of general formula (I):
Figure imgf000098_0001
I
wherein
R1, R2, R3 and R4 are independently hydrogen, halo, -Ci-C6 alkyl, -O(Ci-C6 alkyl), -C C6 alkyl(C3-C7 cycloalkyl), -CON(R9)2, -SOR9, -SO2R9, -SO2N(R9)2, -N(R9)2, -NR9COR9, -CO2R9, COR9, -SR9, -OH, -NO2 or -CN; each R9 is independently hydrogen or -Cβ alkyl; R5 and R6 are each independently hydrogen, or -Cβ alkyl or together with the carbon atom to which they are attached form a C3-C7 cycloalkyl group; R7 is hydrogen or C^Q alkyl;
R8 is Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or an aromatic moiety, any of which may optionally be substituted with one or more substituents selected from halo, -SOR13 -SO2R13, -R14, -OR14, -CON(R14)2, -SOR14, -SO2R14, -SO2N(R14)2, -N(R14)2, -NR14COR14, -CO2R14, -COR14, -SR14, -NO2 or -CN; wherein R13 is a 5 to 7 membered heterocyclic ring; and each R14 is independently hydrogen, alkyl or aryl, the aryl being optionally substituted by -R9, -OR9, -CON(R9)2, -SOR9 -SO2R9, -SO2N(R9)2, -N(R9)2, - NR9COR9, -CO2R9, -COR9, -SR9, halo, -NO2 or -CN; wherein R9 is as defined above; provided that when R1, R3 and R4 are hydrogen and R2 is hydrogen, halogen or -O(C!-C6)alkyl, R8 is not unsubstituted phenyl or phenyl substituted by halo, d-C6 alkyl, -O(C1-C6)alkyl, -S(d-C6)alkyl or
Figure imgf000098_0002
or a pharmaceutically acceptable salt, hydrate, solvate, complex or prodrug thereof.
2. A compound of general formula (LI)
Figure imgf000099_0001
π
wherein R1, R2, R3, R4, R5 , R6, R7 and R8 are as defined for general formula (I); and R10 is Ci-Qs alkyl, aryl, -(CH2)raOC(=O)C1-C6alkyl, -(CH2)mN(Rπ)2, - CH((CH2)mO(C=O)R12)2; m is 1 or 2; R11 is hydrogen or methyl; R12 is Ci-Ciβ alkyl; provided that when R1, R3 and R4 are hydrogen, R2 is not hydrogen or -O( - C6)alkyl.
3. A compound as claimed in claim 1 or claim 2 wherein, independently or in any combination:
R1 is C1-C alkyl, halo or hydrogen;
R2 is d-C4 alkyl, CN, halo, hydrogen or -CON(R9)2, (where R9 is hydrogen or Q-Q alkyl);
R3 is Q-C4 alkyl, halo or hydrogen;
R4 is Q-Q alkyl, halo or hydrogen.
4. A compound as claimed in claim 3 wherein R1, R3 and R4 are hydrogen, and R2 is halo.
5. A compound as claimed in claim 4 wherein R is fluoro.
6. A compound as claimed in any one of claims 1 to 5 wherein R5 and R6 are each independently hydrogen or C1-C alkyl.
7. A compound as claimed in claim 6 wherein at least one of R5 and R6 is hydrogen.
8. A compound as claimed in claim 7 wherein both R5 and R6 are hydrogen.
9. A compound as claimed in any one of claims 1 to 8 wherein R7 is H or d-C6 alkyl.
10. A compound as claimed in claim 9 wherein R7 is methyl.
11. A compound as claimed in any one of claims 1 to 10 wherein R8 is an aromatic moiety having one or two rings and substituted with one or more substituents selected from halo, -C1-C4 alkyl, -O(C!-C alkyl), -SO2(C!-C4 alkyl), -R14 -NR14 and -OR14; where R14 is as defined in claim 1.
12. A compound as claimed in claim 11, wherein R is an aromatic moiety having one or two rings, substituted with -SO2 R14, -NR14 or -OR14, where R14 is defined in claim 1.
13. A compound as claimed in claim 11 or claim 12, wherein R8 is phenyl or pyridyl substituted with -SO2 R14, -NR14 or -OR14, where R14 is defined in claim 1.
14 A compound as claimed in any one of claims 11 to 13 wherein R14 is an optionally substituted aryl group.
15. A compound as claimed in any one of claims 11 to 14 wherein R14 is unsubstituted or substituted with d-C4 alkyl, -O(d-C4 alkyl), -CN, -SO2NH2, - SO2(d-C4 alkyl) or halo.
16. [5-Fluoro-2-methyl-l-(naphthalene-l-sulfonyl)-iH-indol-3-yl]-acetic acid (Compound 3);
[5-Fluoro-2-methyl- 1 -(naphthalene-2-sulfonyl)-2H-indol-3-yl] -acetic acid
(Compound 4); [5-Fluoro-2-methyl-l-(4-trifluoromethyl-benzenesulfonyl)-2H-indol-3-yl]-acetic acid (Compound 6);
[l-(4-tert-Butyl-benzenesulfonyl)-5-fluoro-2-methyl-iH-indol-3-yl]-acetic acid
(Compound 7); [l-(Biphenyl-4-sulfonyl)-5-fluoro-2-methyl-2H-indol-3-yl]-acetic acid (Compound
8);
[l-(l,2-Dimethyl-2H-imidazole-4-sulfonyl)-5-fluoro-2-methyl-7H-indol-3-yl]-acetic acid (Compound 9);
5-(3-Carboxymethyl-5-fluoro-2-methyl-indole- 1 -sulfonyl)- 1 -methyl-2H-pyrrole-2- carboxylic acid (Compound 10); [5-Fluoro-2-methyl-l-(4-phenoxy-benzenesulfonyl)-iH-indol-3-yl]-acetic acid
(Compound 13);
[5-Fluoro-2-methyl-l-(4-methanesulfonyl-benzenesulfonyl)-2H-indol-3yl]-acetic acid (Compound 14);
[l-(5-Chloro-naphthalene-l-sulfonyl)-5-fluoro-2-methyl-7H-indol-3-yl]-acetic acid (17) [5-Fluoro-2-methyl-l-(4-nitro-benzenesulfonyl)-2H-indol-3-yl]-acetic acid (18) [5-Fluoro-2-methyl-l-(3-trifluoromethyl-benzenesulfonyl)-2H-indol-3-yl]-acetic acid (19) [5-Fluoro-2-methyl-l-(quinoline-8-sulfonyl)-iH-indol-3-yl]-acetic acid (21) [5-Fluoro-2-methyl-l-(toluene-4-sulfonyl)-iH-indol-3-yl]-acetic acid (22) [l-(2-Cyano-benzenesulfonyl)-5-fluoro-2-methyl-iH-indol-3-yl]-acetic acid (26) [5-Fluoro-l-(2-fluoro-benzenesulfonyl)-2-methyl-2H-indol-3-yl]-acetic acid (27) [l-(5-Chloro-naphthalene-2-sulfonyl)-5-fluoro-2-methyl-2H-indol-3-yl]-acetic acid (32) [5-Fluoro-2-methyl-l-(4-pyrazol-l-yl-benzenesulfonyl)-iH-indol-3-yl]-acetic acid (34)
[l-(2,2-Dimethyl-chroman-6-sulfonyl)-5-fluoro-2-methyl-iH-indol-3-yl]-acetic acid (35) [5-Fluoro-2-methyl-l-(4-methyl-naphthalene-l-sulfonyl)-2H-indol-3-yl]-acetic acid (36) [l-(5-Chloro-3-methyl-benzo[b]thiophene-2-sulfonyl)-5-fluoro-2-methyl-2H-indol- 3-yl]-acetic acid (37)
{5-Fluoro-2-methyl-l-[4-(morpholine-4-sulfonyl)-benzenesulfonyl]-2H-indol-3-yl}- acetic acid (38)
(l-Ethanesulfonyl-5-fluoro-2-methyl-2H-indol-3-yl)-acetic acid (39) trans [5-Fluoro-l-(/?-styrenesulfony)-2-methyl-2H-indol-3-yl]-acetic acid (40) [ 1 -(Butane- 1 -sulf onyl)-5 -fluoro-2-methyl-.Z H-indol-3 -yl] -acetic acid (41) [l-(Benzo[l,2,5]thiadiazole-4-sulfonyl)-5-fluoro-2-methyl-2H-indol-3-yl]-acetic acid (42)
[l-(2-Chloro-4-trifluoromethyl-benzenesulfonyl)-5-fluoro-2-methyl-2H-indol-3-yl]- acetic acid (43)
[5-Fluoro-2-methyl-l-(pyridine-3-sulfonyl)-7H-indol-3-yl]-acetic acid (44) [5-Fluoro-2-methyl-l-(3-nitro-benzenesulfonyl)-7H-indol-3-yl]-acetic acid (45) (5-Fluoro-2-methyl- 1 -phenylmethanesulf onyl-7H-indol-3-yl)-acetic acid (46) [l-(3-Cyano-benzenesulfonyl)-5-fluoro-2-methyl-iH-indol-3-yl]-acetic acid (48) [l-(4-Cyano-benzenesulfonyl)-5-fluoro-2-methyl-2H-indol-3-yl]-acetic acid (49) [l-(2-Acetyl-l,2,3,4-tetrahydro-isoquinoline-6-sulfonyl)-5-fluoro-2-methyl-2H- indol-3-yl]-acetic acid (51)
[5-Fluoro-2-methyl-l-(5-pyridin-2-yl-thiophene-2-sulfonyl)-7H-indol-3-yl]-acetic acid (52) [l-(5-Chloro-l,3-dimethyl-iH-pyrazole-4-sulfonyl)-5-fluoro-2-methyl-2H-indol-3- yl]-acetic acid (53) [5-Fluoro-2-methyl-l-(4-trifluoromethoxy-benzenesulfonyl)-iH-indol-3-yl]-acetic acid (54) [5-Fluoro-l-(isoquinoline-5-sulfonyl)-2-mefhyl-2H-indol-3-yl]-acetic acid (55) [5-Fluoro-l-(2-hydroxy-2Η-chromene-6-sulfonyl)-2-methyl-2H-indol-3-yl]-acetic acid (58) {5-Fluoro-l-[4-(4-fluoro-phenoxy)-benzenesulfonyl]-2-methyl-2H-indol-3-yl}-acetic acid (59)
{ l-[4-(4-Chloro-phenoxy)-benzenesulfonyl]-5-fluoro-2-methyl-2H-indol-3-yl}- acetic acid (60) ({5-Fluoro-2-methyl-l-[4-(4-trifluoromethyl-phenoxy)- benzenesulfonyl]-7H-indol-3-yl}-acetic acid (61)
{l-[4-(4-Bromo-phenoxy)-benzenesulfonyl]-5-fluoro-2-methyl-2H-indol-3-yl}- acetic acid (62)
{5-Fluoro-l-[4-(4-methoxy-phenoxy)-benzenesulfonyl]-2-methyl-2H-indol-3-yl}- acetic acid (63) [l-(3,4-Dihydro-2Η-benzo[b][l,4]dioxepine-7-sulfonyl)-5-fluoro-2-methyl-7H- indol-3-yl] -acetic acid (64) [5-Fluoro-2-methyl-l-(4-oxazol-5-yl-benzenesulfonyl)- H-indol-3-yl]-acetic acid (65) [5-Fluoro-2-methyl-l-(4-p-tolyloxy-benzenesulfonyl)-2H-indol-3-yl]-acetic acid (66) [5 -Fluoro-2-methyl- 1 -(4-m-tolyloxy-benzenesulf onyl)-2 H-indol-3 -yl] -acetic acid (67)
{ l-[4-(3-Chloro-phenoxy)-benzenesulfonyl]-5-fluoro-2-methyl-iH-indol-3-yl}- acetic acid (68)
{ l-[4-(2,4-Dichloro-phenoxy)-benzenesulfonyl]-5-fluoro-2-methyl-7H-indol-3-yl}- acetic acid (69)
{ l-[4-(2-Chloro-phenoxy)-benzenesulfonyl]-5-fluoro-2-methyl-iH-indol-3-yl } - acetic acid (70)
{5-Fluoro-l-[4-(2-methoxy-phenoxy)-benzenesulfonyl]-2-methyl-2H-indol-3-yl}- acetic acid (71)
{ l-[4-(2,5-Dichloro-phenoxy)-benzenesulfonyl]-5-fluoro-2-methyl-iH-indol-3-yl}- acetic acid (72) [5-Fluoro-2,4-dimethyl-l-(naphthalene-2-sulfonyl)-2H-indol-3-yl]-acetic acid (73) [5-Fluoro-l-(4-methanesulfonyl-benzenesulfonyl)-2,4-dimethyl-2H-indol-3-yl]- acetic acid (74) [5-Fluoro-2,4-dimethyl-l-(4-phenoxy-benzenesulfonyl)-iH-indol-3-yl]-acetic acid (75) {5-Fluoro-2-methyl-l-[4-(pyrrolidine-l-sulfonyl)-benzenesulfonyl]-2H-indol-3-yl}- acetic acid (76)
[5-Fluoro- l-(4-hydroxy-benzenesulfonyl)-2-methyl-7H-indol-3-yl]-acetic acid (77) [l-(3-Cyano-4-hydroxy-benzenesulfonyl)-5-fluoro-2-methyl-iH-indol-3-yl]-acetic acid (78)
[l-(3-carboxamido-benzenesulfonyl)-5-fluoro-2-methyl-2H-indol-3-yl]-acetic acid (79)
[l-(4-carboxamido-benzenesulfonyl)-5-fluoro-2-methyl-2H-indol-3-yl]-acetic acid (80)
[5-Fluoro-2-methyl-l-(3-phenoxy-benzenesulfonyl)-iH-indol-3-yl]-acetic acid (81) [5-Fluoro-2-methyl- 1 -(4-methylsulf anyl-benzenesulfonyl)-7H-indol-3-yl] -acetic acid (82)
[5-Fluoro-2-methyl-l-(3-methyl-quinoline-8-sulfonyl)-2H-indol-3-yl]-acetic acid (83)
[5-Fluoro-2-methyl-l-(3-sulfonamido-benzenesulfonyl)-2H-indol-3-yl]-acetic acid (84)
[5-Cyano-l-(4-methanesulfonyl-benzenesulfonyl)-2-methyl-iH-indol-3-yl]-acetic acid (85)
[l-(4-Chloro-benzenesulfonyl)-5-cyano-2-methyl-2H-indol-3-yl]-acetic acid (86) [5-Cyano-2-methyl-l-(4-phenoxy-benzenesulfonyl)-iH-indol-3-yl]-acetic acid (87) {5-Fluoro-2-methyl-l-[4-(3-trifluoromethyl-phenoxy)-benzenesulfonyl]-iH-indol-3- yl} -acetic acid (88)
[5-carboxamido-l-(4-methanesulfonyl-benzenesulfonyl)-2-methyl-2H-indol-3-yl]- acetic acid (89)
[5-carboxamido-l-(4-chloro-benzenesulfonyl)-2-methyl-iH-indol-3-yl]-acetic acid (90)
[5-carboxamido-2-methyl-l-(4-phenoxy-benzenesulfonyl)-7H-indol-3-yl]-acetic acid (91)
[5-Fluoro-2-methyl-l-(3-N-methylsulfonamido-benzenesulfonyl)-2H-indol-3-yl]- acetic acid (92)
{5-Fluoro-2-methyl-l-[3-(pyrrolidine-l-sulfonyl)-benzenesulfonyl]-iH-indol-3-yl}- acetic acid (94) [5-Fluoro-2-methyl-l-(3-N-methylcarboxamido-benzenesulfonyl)-2H-indol-3-yl]- acetic acid (95)
[5-Fluoro-2-methyl-l-(4-N-methylcarboxamido-benzenesulfonyl)-2H-indol-3-yl]- acetic acid (96)
[5-Fluoro-2-methyl-l-(6-phenoxy-pyridine-3-sulfonyl)-7H-indol-3-yl]-acetic acid (97)
[l-(3-N,N-Dimethylsulfonamido-benzenesulfonyl)-5-fluoro-2-methyl-lH-indol-3- yl] -acetic acid (98)
[5-Fluoro-l-(3-methanesulfonyl-benzenesulfonyl)-2-methyl-lH-indol-3-yl]-acetic acid (99)
[l-(4-N,N-Dimethylcarboxamido-benzenesulfonyl)-5-fluoro-2-methyl-lH-indol-3- yl] -acetic acid (100)
[l-(3-N,N-Dimethylcarboxamido-benzenesulfonyl)-5-fluoro-2-methyl-2H-indol-3- yl] -acetic acid (101)
[5-Fluoro-2-methyl-l-(4-methyl-3,4-dihydro-2H-benzo[l,4]oxazine-7-sulfonyl)-lH- indol-3-yl]-acetic acid (102)
[l-(5-Dimethylamino-naphthalene-l-sulfonyl)-5-fluoro-2-methyl-2H-indol-3-yl]- acetic acid (103)
{5-Fluoro-2-methyl-l-[4-(trifluoromethylsulfanyl-benzenesulfonyl]-lH-indol-3- yl}-acetic acid (104)
{5-Fluoro-2-methyl-l-[3-(trifluoromethylsulfonyl-benzenesulfonyl]-lH-indol-3- yl}-acetic acid (105)
{ 5 -Fluoro-2-methyl- 1 - [4-(pyridin-2-yloxy)-benzenesulf onyl] - lH-indol-3 -yl } -acetic acid (106)
{5-Fluoro-2-methyl-l-[4-(pyridin-3-yloxy)-benzenesulfonyl]-lH-indol-3-yl}-acetic acid (107)
{ 5 -Fluoro-2-methyl- 1 - [4-(pyridin-4-yloxy)-benzenesulf onyl] - lH-indol-3 -yl } -acetic acid (108) [5-Fluoro-2-methyl-l-(4-phenylamino-benzenesulfonyl)-2H-indol-3-yl]-acetic acid (109)
[5-Fluoro-2-methyl-l-(4-m-tolylamino-benzenesulfonyl)-lH-indol-3-yl]-acetic acid (110) { 5-Fluoro-2-methyl- l-[4-(pyridin-4-ylamino)-benzenesulfonyl]- lH-indol-3-yl }- acetic acid (111)
{ 5-Fluoro-2-methyl- l-[4-(pyridin-2-ylamino)-benzenesulfonyl]- lH-indol-3-yl }- acetic acid (112)
{5-Fluoro-2-methyl-l-[4-(pyrimidin-4-ylamino)-benzenesulfonyl]-lH-indol-3-yl}- acetic acid (113)
{5-Fluoro-2-methyl-l-[4-(5-methyl-isoxazol-3-ylamino)-benzenesulfonyl]-lH-indol-
3-yl}-acetic acid (114)
{ 5 -Fluoro-2-methyl- 1 - [4-(pyridin-3 -ylamino)-benzenesulf onyl] - lH-indol-3 -yl } - acetic acid (115)
{ 5 -Fluoro-2-methyl- 1 - [4-(4-methyl-pyridin-2-ylamino)-benzenesulf onyl] - lH-indol-
3-yl}-acetic acid (116)
{5-Fluoro-2-methyl-l-[4-(6-methyl-pyridin-2-ylamino)-benzenesulfonyl]-lH-indol-
3-yl}-acetic acid (117)
{5-Fluoro-2-methyl-l-[4-(4-methyl-pyrimidin-2-ylamino)-benzenesulfonyl]-lH- indol-3-yl} -acetic acid (118)
{5-Fluoro-2-methyl-l-[4-(pyrimidin-2-ylamino)-benzenesulfonyl]-lH-indol-3-yl}- acetic acid (119)
{ l-[4-(3-Chloro-phenylamino)-benzenesulfonyl]-5-fluoro-2-methyl-lH-indol-3-yl}- acetic acid (120)
{ l-[4-(2,6-Dimethyl-pyrimidin-4-ylamino)-benzenesulfonyl]-5-fluoro-2-methyl-2H- indol-3-yl} -acetic acid (121)
{5-Fluoro-l-[4-(isoxazol-3-ylamino)-benzenesulfonyl]-2-methyl-lH-indol-3-yl}- acetic acid (122)
{ l-[4-(4,6-Dimethyl-pyrimidin-2-ylamino)-benzenesulfonyl]-5-fluoro-2-methyl-lH- indol-3-yl} -acetic acid (123)
{5-Fluoro-2-methyl-l-[4-(5-methyl-pyridin-3-ylamino)-benzenesulfonyl]-iH-indol-
3-yl}-acetic acid (124)
{5-Fluoro-2-methyl-l-[4-(thiazol-2-ylamino)-benzenesulfonyl]-7H-indol-3-yl}- acetic acid (125)
{l-[4-(3,5-Dimethyl-ρhenylamino)-benzenesulfonyl]-5-fluoro-2-methyl-2H-indol-3- yl} -acetic acid (126) {5-Huoro-2-methyl-l-[4-(4-sulfonamido-phenylamino)-benzenesulfonyl]-2H-indol- 3-yl}-acetic acid (127)
{ l-[4-(3,5-Dichloro-phenylamino)-benzenesulfonyl]-5-fluoro-2-methyl-2H-indol-3- yl} -acetic acid (128)
{ l-[4-(5-Chloro-pyridin-3-ylamino)-benzenesulfonyl]-5-fluoro-2-methyl-iH-indol- 3-yl}-acetic acid (129)
{l-[2,5-Difluoro-4-(pyridm-2-ylamino)-benzenesulfonyl]-5-fluoro-2-methyl-2H- indol-3-yl} -acetic acid (130)
{ l-[2,5-Difluoro-4-(pyridm-2-ylamino)-benzenesulfonyl]-5-fluoro-2-methyl-2H- indol-3-yl} -acetic acid (131)
{ l-[2,5-Difluoro-4-(5-methyl-isoxazol-3-ylamino)-benzenesulfonyl]-5-fluoro-2- methyl-7H-indol-3-yl}-acetic acid (132)
{5-Fluoro-l-[4-(3-methoxy-phenylamino)-benzenesulfonyl]-2-methyl-7H-indol-3- yl} -acetic acid (133)
{ l-[4-(3-Cyano-phenylamino)-benzenesulfonyl]-5-fluoro-2-methyl-7H-indol-3-yl}- acetic acid (134)
{ 1 -[4-(3 -Ethyl -phenylamino)-benzenesulf onyl] -5-fluoro-2-methyl-iH-indol-3 -yl } - acetic acid (135)
{ 5 -Fluoro-2-methyl- 1 - [6-(ρyridin-2-ylamino)-pyridine-3-sulf onyl] - lH-indol-3 -yl } - acetic acid (136)
{5-Fluoro-2-methyl-l-[6-(pyridin-3-ylamino)-pyridine-3-sulfonyl]-lH-indol-3-yl}- acetic acid (137)
{5-Fluoro-2-methyl-l-[6-(pyrirrιidin-4-ylamino)-pyridine-3-sulfonyl]-lH-indol-3- yl}-acetic acid (138) [5-Fluoro-2-methyl-l-(6-phenylamino-pyridine-3-sulfonyl)-lH-indol-3-yl]-acetic acid (139)
{ 1 - [6-(3 ,5-Dimethyl-ρhenylamino)-pyridine-3-sulf onyl]-5-fluoro-2-methyl- 1H- indol-3-yl} -acetic acid (140)
{5-Fluoro-2-methyl-l-[6-(pyrimidin-2-ylamino)-pyridine-3-sulfonyl]-lH-indol-3- yl} -acetic acid (141)
{5-Fluoro-2-methyl-l-[6-(6-methyl-pyridin-2-ylamino)-pyridine-3-sulfonyl]-lH- indol-3-yl} -acetic acid (142) {5-Fluoro-2-methyl-l-[6-(4-methyl-pyrimidin-2-ylamino)-pyridine-3-sulfonyl]-lH- indol-3-yl}-acetic acid (143)
{ l-[6-(4,6-Dimethyl-pyrimidin-2-ylamino)-pyridine-3-sulfonyl]-5-fluoro-2-methyl- lH-indol-3-yl}-acetic acid (144)
{ l-[6-(3-Chloro-phenylamino)-pyridine-3-sulfonyl]-5-fluoro-2-methyl-lH-indol-3- yl} -acetic acid (145) [5-Fluoro-2-methyl-l-(6-m-tolylamino-pyridine-3-sulfonyl)-lH-indol-3-yl]-acetic acid (146)
{ l-[6-(2,6-Dimethyl-pyrimidin-4-ylamino)-pyridine-3-sulfonyl]-5-fluoro-2-methyl- lH-indol-3-yl}-acetic acid (147)
{ 5-Fluoro-2-methyl- 1 - [6-(pyridin-4-ylamino)-pyridine-3-sulfonyl] - lH-indol-3-yl } - acetic acid (148)
{5-Fluoro-2-methyl-l-[6-(5-methyl-isoxazol-3-ylamino)-pyridine-3-sulfonyl]-lH- indol-3-yl}-acetic acid (149)
{5-Fluoro-2-methyl-l-[6-(thiazol-2-ylamino)-pyridine-3-sulfonyl]-lH-indol-3-yl}- acetic acid (150)
{ l-[6-(3,5-Dichloro-phenylamino)-pyridine-3-sulfonyl]-5-fluoro-2-methyl-7H-indol- 3-yl} -acetic acid (151)
{5-Fluoro-2-methyl-l-[6-(5-methyl-pyridin-3-ylamino)-pyridine-3-sulfonyl]-7H- indol-3-yl} -acetic acid (152)
{ l-[6-(5-Chloro-pyridin-3-ylamino)-pyridine-3-sulfonyl]-5-fluoro-2-methyl-iH- indol-3-yl}-acetic acid (153)
{ 5 -Fluoro-2-methyl- 1 - [4-(methyl-phenyl-amino)-benzenesulf onyl] - lH-indol-3 -yl } - acetic acid (154)
{5-Fluoro-2-methyl-l-[4-(methyl-m-tolyl-amino)-benzenesulfonyl]-lH-indol-3-yl}- acetic acid (155) (5-Fluoro-2-methyl- 1 - { 4- [methyl-(5-methyl-isoxazol-3-yl)-amino] -benzene- sulfonyl}-lH-indol-3-yl)-acetic acid (156)
(5-Fluoro-2-methyl-l-{4-[methyl-(4-methyl-pyridin-2-yl)-amino]-benzene sulfonyl }-lH-indol-3-yl)-acetic acid (157)
(5-Fluoro-2-methyl- 1 - { 6- [methyl-(6-methyl-pyridin-2-yl)-amino] -pyridine-3- sulfonyl}-lH-indol-3-yl)-acetic acid (158) {5-Fluoro-2-methyl-l-[4-(methyl-pyrimidin-2-yl-amino)-benzenesulfonyl]-lH-indol-
3-yl}-acetic acid (159)
{5-Fluoro-2-methyl-l-[4-(methyl-pyridin-2-yl-amino)-benzenesulfonyl]-lH-indol-3- yl} -acetic acid (160)
{ 5 -Fluoro-2-methyl- 1 - [6-(methyl-pyridin-2-yl-amino)-pyridine-3 -sulfonyl] - 1H- indol-3-yl} -acetic acid (161)
{5-Fluoro-2-methyl-l-[6-(methyl-pyridin-4-yl-amino)-pyridine-3-sulfonyl]-iH- indol-3-yl} -acetic acid (162)
(5-Fluoro-2-methyl- 1 - { 4- [methyl-(6-methyl-pyridin-2-yl)-amino] -benzenesulfonyl } -
7H-indol-3-yι)-acetic acid (163)
(l-{4-[(2,6-Dimethyl-pyrimidin-4-yl)-methyl-amino]-benzenesulfonyl}-5-fluoro-2- methyl-2H-indol-3-yl)-acetic acid (164)
{5-Fluoro-2-methyl-l-[6-(methyl-phenyl-amino)-pyridine-3-sulfonyl]-iH-mdol-3- yl}-acetic acid (165)
( 1- { 6-[(3-Chloro-phenyl)-methyl- amino] -pyridine-3-sulfonyl } -5-fluoro-2-methyl-
7H-indol-3-yl)-acetic acid (166)
( 1 - { 4- [(3 -Chloro-phenyl)-methyl-amino] -benzenesulfonyl } -5-fluoro-2-methyl-2H- indol-3-yl)-acetic acid (167)
{ l-[4-(Εthyl-m-tolyl-amino)-benzenesulfonyl]-5-fluoro-2-methyl-2H-indol-3-yl}- acetic acid (168)
{5-Fluoro-2-methyl-l-[4-(methyl-pyridin-3-yl-amino)-benzenesulfonyl]-2H-indol-3- yl} -acetic acid (169)
[5-Fluoro-2-methyl-l-(4-phenylsulfanyl-benzenesulfonyl)-lH-indol-3-yl]-acetic acid
(171) [l-(4-Benzenesulfinyl-benzenesulfonyl)-5-fluoro-2-methyl-7H-indol-3-yl]-acetic acid (172) [l-(4-Benzenesulfonyl-benzenesulfonyl)-5-fluoro-2-methyl-2H-indol-3-yl]-acetic acid (173) [5-Chloro-l-(4-chloro-benzenesulfonyl)-2-methyl-2H-indol-3-yl]-acetic acid (174) {5-Fluoro-l-[4-(3-isopropyl-phenylamino)-benzenesulfonyl]-2-methyl-iH-indol-3- yl}-acetic acid (175) (5-Fluoro-2-methyl-l-[4-(methyl-thiazol-2-yl-amino)-benzenesulfonyl]-2H-indol-3- yl} -acetic acid (176)
{ l-[2,5-Difluoro-4-(isoxazol-3-ylamino)-benzenesulfonyl]-5-fluoro-2-methyl-2H- indol-3-yl}-acetic acid (177)
{ l-[4-(5-Chloro-pyridin-3-ylamino)-2,5-difluoro-benzenesulfonyl]-5-fluoro-2- methyl-2H-indol-3-yl} -acetic acid (178)
{ l-[2,5-Difluoro-4-(5-methyl-pyridm-3-ylarnino)-benzenesulfonyl]-5-fluoro-2- methyl-2H-indol-3-yl} -acetic acid (179)
{ l-[6-(3-Ethyl-phenylamino)-pyridine-3-sulfonyl]-5-fluoro-2-methyl-2H-indol-3- yl}-acetic acid (180)
{5-Fluoro-l-[6-(3-methoxy-phenylamino)-pyridine-3-sulfonyl]-2-methyl-2H-indol-
3-yl}-acetic acid (181)
{ l-[6-(3-Cyano-phenylamino)-pyridine-3-sulfonyl]-5-fluoro-2-methyl-7H-indol-3- yl} -acetic acid (182)
{5-Fluoro-l-[6-(3-methanesulfonyl-phenylamino)-pyridine-3-sulfonyl]-2-methyl- iH-indol-3-yl} -acetic acid (183)
{5-Fluoro-l-[4-(isoxazol-3-yl-methyl-amino)-benzenesulfonyl]-2-methyl-iH-indol-
3-yl}-acetic acid (184)
(5-Fluoro-2-methyl-l-{4-[methyl-(5-methyl-pyridin-3-yl)-amino]-benzenesulfonyl}-
7H-indol-3-yl)-acetic acid (185)
( 1 - { 4- [(3 ,5-Dimethyl-phenyl)-methyl- amino] -benzenesulfonyl } -5 -fluoro-2-methyl-
2H-indol-3-yl)-acetic acid (186)
(5-Fluoro- 1 - { 4-[(3-methoxy-phenyl)-methyl-amino]-benzenesulf onyl } -2-methyl-7H- indol-3-yl)-acetic acid (187)
(l-{4-[(3-Cyano-phenyl)-methyl-amino]-benzenesulfonyl}-5-fluoro-2-methyl-2H- indol-3-yl)-acetic acid (188)
( 1 - { 4- [(3-Ethyl-phenyl)-methyl-amino] -benzenesulfonyl } -5 -fluoro-2-methyl-2H- indol-3-yl)-acetic acid (189)
(5-Fluoro-l-{4-[(3-isopropyl-phenyl)-methyl-amino]-benzenesulfonyl}-2-methyl-
2H-indol-3-yl)-acetic acid (190)
(l-{6-[(3-Ethyl-phenyl)-methyl-amino]-pyridine-3-sulfonyl}-5-fluoro-2-methyl-2H- indol-3-yl)-acetic acid (191)
(5-Fluoro-l-{6-[(3-methanesulfonyl-phenyl)-methyl-amino]-pyridine-3-sulfonyl}-2- methyl-7H-indol-3-yl)-acetic acid (192)
(l-{6-[(3-Cyano-phenyl)-methyl-amino]-ρyridine-3-sulfonyl}-5-fluoro-2-methyl- 2H-indol-3-yl)-acetic acid (193)
(5-Fluoro-2-methyl-l-{6-[methyl-(5-methyl-pyridin-3-yl)-amino]-pyridine-3- sulfonyl}-2H-indol-3-yl)-acetic acid (194)
or the Ci-Qs alkyl, aryl, (CΗ2)mOC(=O)d-C6alkyl, (CH2)mN(Rπ)2, CH((CH2)mO(C=O)R12)2 esters of any of the above; wherein m is 1 or 2; R11 is hydrogen or methyl; R12 is Ci-Cig alkyl.
17. A compound as claimed in any one of claims 1 to 16 for use in medicine.
18. A compound as claimed in any one of claims 1 to 16 for use in the treatment of allergic asthma, perennial allergic rhinitis, seasonal allergic rhinitis, atopic dermatitis, contact hypersensitivity (including contact dermatitis), conjunctivitis, especially allergic conjunctivitis, eosinophilic bronchitis, food allergies, eosinophilic gastroenteritis, inflammatory bowel disease, ulcerative colitis and Crohn's disease, mastocytosis and also other PGD2-mediated diseases, for example autoimmune diseases such as hyper IgE syndrome and systemic lupus erythematus, psoriasis, acne, multiple sclerosis, allograft rejection, reperfusion injury and chronic obstructive pulmonary disease; as well as rheumatoid arthritis, psoriatic arthritis and osteoarthritis.
19. The use of a compound of general formula (I) or general formula (II):
Figure imgf000112_0001
(I) (TT)
wherein
R1, R2, R3 and R4 are independently hydrogen, halo, -d-C6 alkyl, -O(d-C6 alkyl), -d-C6 alkyl(C3-C7 cycloalkyl), -CON(R9)2, -SOR9, -SO2R9, -SO2N(R9)2, -N(R9)2, -NR9COR9, -CO2R9, COR9, -SR9, -OH, -NO2 or -CN; each R9 is independently hydrogen or d-C6 alkyl; R5 and R6 are each independently hydrogen, or Cι-C6 alkyl or together with the carbon atom to which they are attached form a C3-C cycloalkyl group; R7 is hydrogen or d-C6 alkyl;
R is d-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or an aromatic moiety, any of which may optionally be substituted with one or more substituents selected from halo, -SOR13 -SO2R13, -R14, -OR14, -CON(R14)2, -SOR14, -SO2R14, -SO2N(R14)2, -N(R14)2, -NR14COR14, -CO2R14, -COR14, -SR14, -NO2 or -CN; wherein R13 is a 5 to 7 membered heterocyclic ring; and each R14 is independently hydrogen, alkyl or aryl, the aryl being optionally substituted by -R9, -OR9, -CON(R )2, -SOR9 -SO2R9, -SO2N(R9)2, -N(R9)2, - NR9COR9, -CO2R9, -COR9, -SR9, halo, -NO2 or -CN; wherein R9 is as defined above; R10 is Ci-Cs alkyl, aryl, -(CH2)mOC(=O)d-C6alkyl, -(CH2)mN(Rπ)2, - CH((CH2)mO(C=O)R12)2; m is 1 or 2; R11 is hydrogen or methyl; R12 is d-C18 alkyl; or a pharmaceutically acceptable salt, hydrate, solvate, complex or prodrug thereof in the preparation of an agent for the treatment or prevention of allergic asthma, perennial allergic rhinitis, seasonal allergic rhinitis, atopic dermatitis, contact hypersensitivity (including contact dermatitis), conjunctivitis, especially allergic conjunctivitis, eosinophilic bronchitis, food allergies, eosinophilic gastroenteritis, inflammatory bowel disease, ulcerative colitis and Crohn's disease, mastocytosis and also other PGD2-mediated diseases, for example autoimmune diseases such as hyper IgE syndrome and systemic lupus erythematus, psoriasis, acne, multiple sclerosis, allograft rejection, reperfusion injury and chronic obstructive pulmonary disease; as well as rheumatoid arthritis, psoriatic arthritis and osteoarthritis.
20. The use as claimed in claim 20 wherein, in the compound of general formula (I) or (II), independently or in any combination:
R1 is Cι-C alkyl, halo or hydrogen;
R2 is C1-C4 alkyl, CN, halo, hydrogen or -CON(R9)2, (where R9 is hydrogen or C C4 alkyl);
R3 is d-C4 alkyl, halo or hydrogen;
R4 is d-C4 alkyl, halo or hydrogen.
21. The use as claimed in claim 20 wherein, in the compound of general formula (I) or (TT), R1, R3 and R4 are hydrogen, and R2 is halo.
22. The use as claimed in claim 21 wherein, in the compound of general formula (I) or (LI), R2 is fluoro.
23. The use as claimed in any one of claims 19 to 22 wherein, in the compound of general formula (I) or (II), R5 and R6 are each independently hydrogen or C1-C4 alkyl.
24. The use as claimed in claim 23 wherein at least one of Rs and R6 is hydrogen.
25. The use as claimed in claim 24 wherein both R5 and R6 are hydrogen.
26. The use as claimed in any one of claims 19 to 25 wherein, in the compound of general formula (I) or (II), R7 is H or d-C6 alkyl.
•η
27. The use as claimed in claim 26 wherein R is methyl.
28. The use as claimed in any one of claims 19 to 27 wherein, in the compound of general formula (I) or (LI), R is an aromatic moiety having one or two rings and substituted with one or more substituents selected from halo, -C1-C4 alkyl, -O(d-C4 alkyl), -SO2(d-C4 alkyl), -R14 -NR14 and -OR14; where R14 is as defined in claim 1.
29. The use as claimed in claim 28, wherein R8 is an aromatic moiety having one or two rings, substituted with -SO2 R14, -NR14 or -OR14, where R14 is defined in claim 1.
30. The use as claimed in claim 28 or 29, wherein R8 is phenyl or pyridyl substituted with -SO2 R14, -NR14 or -OR14, where R14 is defined in claim 1.
31 The use as claimed in any one of claims 28 to 30 wherein R14 is an optionally substituted aryl group.
32. The use as claimed in any one of claims 28 to 31 wherein R14 is unsubstituted or substituted with d-C4 alkyl, -O(d-C4 alkyl), -CN, -SO2NH2, -SO2(d-C4 alkyl) or halo.
33. The use as claimed in any one of claims 19 to 32, wherein the compound of general formula (I) or (II) is: [5-Fluoro-l-(4-fluoro-benzenesulfonyl)-2-methyl-iH-indol-3-yl]-acetic acid (l) [l-(4-Chloro-benzenesulfonyl)-5-fluoro-2-methyl-2H-indol-3-yl]-acetic acid (2) [5-Fluoro-2-methyl-l-(naphthalene-l-sulfonyl)-7H-indol-3-yl]-acetic acid (3) [5-Fluoro-2-methyl-l-(naphthalene-2-sulfonyl)-2H-indol-3-yl]-acetic acid (4) [5-Fluoro-l-(4-methoxy-benzenesulfonyl)-2-methyl-2H-indol-3-yl]-acetic acid (5) [5-Fluoro-2-methyl-l-(4-trifluoromethyl-benzenesulfonyl)-2H-indol-3-yl]-acetic acid (6)
[ 1 -(4-tert-Butyl-benzenesulf onyl)-5-fluoro-2-methyl- 7H-indol-3 -yl] -acetic acid (7) [l-(Biphenyl-4-sulfonyl)-5-fluoro-2-methyl-2H-indol-3-yl]-acetic acid (8) [l-(l,2-Dimethyl-2H-imidazole-4-sulfonyl)-5-fluoro-2-methyl-2H-indol-3-yl]-acetic acid (9)
5-(3-Carboxymethyl-5-fluoro-2-methyl-indole-l-sulfonyl)-l-methyl-7H-pyrrole-2- carboxylic acid (10)
[l-(3,5-Dichloro-benzenesulfonyl)-5-fluoro-2-methyl-2H-indol-3-yl]-acetic acid (11) [l-(3,4-Dichloro-benzenesulfonyl)-5-fluoro-2-methyl-iH-indol-3-yl]-acetic acid (12) [5-Fluoro-2-methyl-l-(4-phenoxy-benzenesulfonyl)-iH-indol-3-yl]-acetic acid (13) [5-Fluoro-2-methyl-l-(4-methanesulfonyl-benzenesulfonyl)-iH-indol-3yl]-acetic acid (14) [5-Fluoro-2-methyl-l-(toluene-3-sulfonyl)-2H-indol-3-yl]-acetic acid (15) [l-(4-Bromo-benzenesulfonyl)-5-fluoro-2-methyl-2H-indpl-3-yl]-acetic acid (16) [l-(5-Chloro-naphthalene-l-sulfonyl)-5-fluoro-2-methyl-iH-indol-3-yl]-acetic acid (17) [5-Fluoro-2-methyl-l-(4-nitro-benzenesulfonyl)-2H-indol-3-yl]-acetic acid (18) [5-Fluoro-2-methyl-l-(3-trifluoromethyl-benzenesulfonyl)-2H-indol-3-yl]-acetic acid (19) (l-Benzenesulfonyl-5-fluoro-2-methyl-7H-indol-3-yl)-acetic acid (20) [5-Fluoro-2-methyl-l-(quinoline-8-sulfonyl)-7H-indol-3-yl]-acetic acid (21) [5-Fluoro-2-methyl-l-(toluene-4-sulfonyl)-2H-indol-3-yl]-acetic acid (22) [l-(3-Chloro-benzenesulfonyl)-5-fluoro-2-methyl-2H-indol-3-yl]-acetic acid (23) [l-(2,5-Dichloro-benzenesulfonyl)-5-fluoro-2-methyl-2H-indol-3-yl]-acetic acid (24) [5-Fluoro-l-(3-fluoro-benzenesulfonyl)-2-methyl-7H-indol-3-yl]-acetic acid (25) [l-(2-Cyano-benzenesulfonyl)-5-fluoro-2-methyl-2H-indol-3-yl]-acetic acid (26) [5-Fluoro-l-(2-fluoro-benzenesulfonyl)-2-methyl-2H-indol-3-yl]-acetic acid (27) [l-(2,3-Dichloro-benzenesulfonyl)-5-fluoro-2-methyl-7H-indol-3-yl]-acetic acid (28) [l-(2,4-Dichloro-benzenesulfonyl)-5-fluoro-2-methyl-2H-indol-3-yl]-acetic acid (29) [5-Fluoro-2-methyl-l-(3-trifluoromethoxy-benzenesulfonyl)-7H-indol-3-yl]-acetic acid (30) [5-Fluoro-2-methyl-l-(toluene-2-sulfonyl)-2H-indol-3-yl]-acetic acid (31) [l-(5-Chloro-naphthalene-2-sulfonyl)-5-fluoro-2-methyl-2H-indol-3-yl]-acetic acid (32) [5-Fluoro-l-(3-methoxy-benzenesulfonyl)-2-methyl-7H-indol-3-yl]-acetic acid (33) [5-Fluoro-2-methyl-l-(4-pyrazol-l-yl-benzenesulfonyl)-iH-indol-3-yl]-acetic acid (34) [l-(2,2-Dimethyl-chroman-6-sulfonyl)-5-fluoro-2-methyl-7H-indol-3-yl]-acetic acid (35) [5-Fluoro-2-methyl-l-(4-methyl-naphthalene-l-sulfonyl)-iH-indol-3-yl]-acetic acid (36) [l-(5-Chloro-3-methyl-benzo[b]thiophene-2-sulfonyl)-5-fluoro-2-methyl-7H-indol- 3-yl]-acetic acid (37)
{5-Fluoro-2-methyl-l-[4-(morpholine-4-sulfonyl)-benzenesulfonyl]-2H-indol-3-yl}- acetic acid (38) (l-Ethanesulfonyl-5-fluoro-2-methyl-2H-indol-3-yl)-acetic acid (39) trans [5-Fluoro-l-( ?-styrenesulfony)-2-methyl-2H-indol-3-yl]-acetic acid (40) [1 -(Butane- 1 -sulfonyl)-5-fluoro-2-methyl-2H-indol-3-yl]-acetic acid (41 ) [l-(Benzo[l,2,5]thiadiazole-4-sulfonyl)-5-fluoro-2-methyl-2H-indol-3-yl]-acetic acid (42) [l-(2-Chloro-4-trifluoromethyl-benzenesulfonyl)-5-fluoro-2-methyl-7H-indol-3-yl]- acetic acid (43) [5-Fluoro-2-methyl-l-(pyridine-3-sulfonyl)-2H-indol-3-yl]-acetic acid (44) [5-Fluoro-2-methyl-l-(3-nitro-benzenesulfonyl)-iH-indol-3-yl]-acetic acid (45) (5-Fluoro-2-methyl- 1 -phenylmethanesulfonyl-7H-indol-3-yl)-acetic acid (46) [l-(2-Chloro-benzenesulfonyl)-5-fluoro-2-methyl-2H-indol-3-yl]-acetic acid (47) [l-(3-Cyano-benzenesulfonyl)-5-fluoro-2-methyl-iH-indol-3-yl]-acetic acid (48) [l-(4-Cyano-benzenesulfonyl)-5-fluoro-2-methyl-2H-indol-3-yl]-acetic acid (49) [5-Fluoro-l-(4-isopropyl-benzenesulfonyl)-2-methyl-iH-indol-3-yl]-acetic acid (50) [l-(2-Acetyl-l,2,3,4-tetrahydro-isoquinoline-6-sulfonyl)-5-fluoro-2-methyl-2H- indol-3-yl]-acetic acid (51) [5-Fluoro-2-methyl-l-(5-pyridin-2-yl-thiophene-2-sulfonyl)-2H-indol-3-yl]-acetic acid (52) [l-(5-Chloro-l,3-dimethyl-7H-pyrazole-4-sulfonyl)-5-fluoro-2-methyl-7H-indol-3- yl] -acetic acid (53) [5-Fluoro-2-methyl-l-(4-trifluoromethoxy-benzenesulfonyl)-iH-indol-3-yl]-acetic acid (54) [5-Fluoro-l-(isoquinoline-5-sulfonyl)-2-methyl-2H-indol-3-yl]-acetic acid (55) [l-(5-Chloro-2-methoxy-benzenesulfonyl)-5-fluoro-2-methyl-2H-indol-3-yl]-acetic acid (56) [l-(4-Chloro-2,5-dimethyl-benzenesulfonyl)-5-fluoro-2-methyl-7H-indol-3-yl]- acetic acid (57) [5-Fluoro-l-(2-hydroxy-2Η-chromene-6-sulfonyl)-2-methyl-2H-indol-3-yl]-acetic acid (58)
{5-Fluoro-l-[4-(4-fluoro-phenoxy)-benzenesulfonyl]-2-methyl-2H-indol-3-yl}-acetic acid (59)
{ l-[4-(4-Chloro-phenoxy)-benzenesulfonyl]-5-fluoro-2-methyl-7H-indol-3-yl}- acetic acid (60) ({5-Fluoro-2-methyl-l-[4-(4-trifluoromethyl-phenoxy)- benzenesulfonyl]-7H-indol-3-yl}-acetic acid (61)
{ l-[4-(4-Bromo-phenoxy)-benzenesulfonyl]-5-fluoro-2-methyl-2H-indol-3-yl}- acetic acid (62)
{ 5 -Fluoro- 1 - [4-(4-methoxy-phenoxy)-benzenesulf onyl] -2-methyl-iH-indol-3-yl } - acetic acid (63) [l-(3,4-Dihydro-2Η-benzo[b][l,4]dioxeρine-7-sulfonyl)-5-fluoro-2-methyl-2H- indol-3-yl]-acetic acid (64) [5-Fluoro-2-methyl-l-(4-oxazol-5-yl-benzenesulfonyl)-iH-indol-3-yl]-acetic acid (65) [5-Fluoro-2-methyl-l-(4-p-tolyloxy-benzenesulfonyl)-7H-indol-3-yl]-acetic acid (66) [5-FluoiO-2-methyl-l-(4-m-tolyloxy-benzenesulfonyl)-7H-indol-3-yl]-acetic acid (67)
{l-[4-(3-Chloro-phenoxy)-benzenesulfonyl]-5-fluoro-2-methyl-2H-indol-3-yl}- acetic acid (68)
{ l-[4-(2,4-Dichloro-phenoxy)-benzenesulfonyl]-5-fluoro-2-methyl-7H-indol-3-yl}- acetic acid (69)
{ l-[4-(2-Chloro-phenoxy)-benzenesulfonyl]-5-fluoro-2-methyl-7H-indol-3-yl}- acetic acid (70)
{5-Fluoro-l-[4-(2-methoxy-phenoxy)-benzenesulfonyl]-2-methyl-2H-indol-3-yl}- acetic acid (71)
{ l-[4-(2,5-Dichloro-phenoxy)-benzenesulfonyl]-5-fluoro-2-methyl-7H-indol-3-yl}- acetic acid (72) [5-Fluoro-2,4-dimethyl-l-(naphthalene-2-sulfonyl)-2H-indol-3-yl]-acetic acid (73) [5-Fluoro-l-(4-methanesulfonyl-benzenesulfonyl)-2,4-dimethyl-iH-indol-3-yl]- acetic acid (74) [5-Fluoro-2,4-dimethyl-l-(4-phenoxy-benzenesulfonyl)-2H-indol-3-yl]-acetic acid (75)
{5-Fluoro-2-methyl-l-[4-(pyrrolidine-l-sulfonyl)-benzenesulfonyl]-2H-indol-3-yl}- acetic acid (76) [5-Fluoro-l-(4-hydroxy-benzenesulfonyl)-2-methyl-iH-indol-3-yl]-acetic acid (77) [ 1 -(3-Cyano-4-hydroxy-benzenesulfonyl)-5-fluoro-2-methyl-2H-indol-3-yl] -acetic acid (78) [l-(3-carboxamido-benzenesulfonyl)-5-fluoro-2-methyl-7H-indol-3-yl]-acetic acid (79) [l-(4-carboxamido-benzenesulfonyl)-5-fluoro-2-methyl-2H-indol-3-yl]-acetic acid (80)
[5-Fluoro-2-methyl-l-(3-phenoxy-benzenesulfonyl)-iH-indol-3-yl]-acetic acid (81) [5-Fluoro-2-methyl-l-(4-methylsulfanyl-benzenesulfonyl)-7H-indol-3-yl]-acetic acid (82)
[5-Fluoro-2-methyl- 1 -(3-methyl-quinoline-8-sulfonyl)-2H-indol-3-yl] -acetic acid (83)
[5-Fluoro-2-methyl- 1 -(3-sulfonamido-benzenesulfonyl)-7H-indol-3-yl]-acetic acid (84) [5-Cyano-l-(4-methanesulfonyl-benzenesulfonyl)-2-methyl-2H-indol-3-yl]-acetic acid (85)
[l-(4-Chloro-benzenesulfonyl)-5-cyano-2-methyl-7H-indol-3-yl]-acetic acid (86)
[5-Cyano-2-methyl-l-(4-phenoxy-benzenesulfonyl)-2H-indol-3-yl]-acetic acid (87)
{5-Fluoro-2-methyl-l-[4-(3-trifluoromethyl-phenoxy)-benzenesulfonyl]-2H-indol-3- yl} -acetic acid (88)
[5-carboxamido-l-(4-methanesulfonyl-benzenesulfonyl)-2-methyl-2H-indol-3-yl]- acetic acid (89)
[5-carboxamido-l-(4-chloro-benzenesulfonyl)-2-methyl-iH-indol-3-yl]-acetic acid
(90)
[5-carboxamido-2-methyl-l-(4-phenoxy-benzenesulfonyl)-7H-indol-3-yl]-acetic acid
(91)
[5-Fluoro-2-methyl-l-(3-N-methylsulfonamido-benzenesulfonyl)-7H-indol-3-yl]- acetic acid (92)
{5-Fluoro-2-methyl-l-[3-(pyrrolidine-l-sulfonyl)-benzenesulfonyl]-iH-indol-3-yl}- acetic acid (94)
[5-Fluoro-2-methyl-l-(3-N-methylcarboxamido-benzenesulfonyl)-2H-indol-3-yl]- acetic acid (95)
[5-Fluoro-2-methyl-l-(4-N-methylcarboxamido-benzenesulfonyl)-7H-indol-3-yl]- acetic acid (96)
[5-Fluoro-2-methyl-l-(6-phenoxy-pyridine-3-sulfonyl)-2H-indol-3-yl]-acetic acid
(97)
[l-(3-N,N-Dimethylsulfonamido-benzenesulfonyl)-5-fluoro-2-methyl-lH-indol-3- yl]-acetic acid (98)
[5-Fluoro-l-(3-methanesulfonyl-benzenesulfonyl)-2-methyl-lH-indol-3-yl]-acetic acid (99)
[ 1 -(4-N,N-Dimethylcarboxamido-benzenesulfonyl)-5-fluoro-2-methyl- lH-indol-3- yl] -acetic acid (100)
[l-(3-N,N-Dimethylcarboxamido-benzenesulfonyl)-5-fluoro-2-methyl-7H-indol-3- yl]-acetic acid (101)
[5 -Fluoro-2-mefhyl- 1 -(4-methyl-3 ,4-dihydro-2H-benzo [ 1 ,4] oxazine-7-sulf onyl)- 1H- indol-3-yl]-acetic acid (102) [l-(5-Dimethylamino-naphthalene-l-sulfonyl)-5-fluoro-2-methyl-2H-indol-3-yl]- acetic acid (103)
{5-Fluoro-2-methyl-l-[4-(trifluoromethylsulfanyl-benzenesulfonyl]-lH-indol-3- yl}-acetic acid (104)
{5-Fluoro-2-methyl-l-[3-(trifluoromethylsulfonyl-benzenesulfonyl]-lH-indol-3- yl} -acetic acid (105)
{5-Fluoro-2-methyl-l-[4-(pyridin-2-yloxy)-benzenesulfonyl]-lH-indol-3-yl}-acetic acid (106)
{5-Fluoro-2-methyl-l-[4-(pyridin-3-yloxy)-benzenesulfonyl]-lH-indol-3-yl}-acetic acid (107)
{5-Fluoro-2-methyl-l-[4-(pyridin-4-yloxy)-benzenesulfonyl]-lH-indol-3-yl}-acetic acid (108) [5-Fluoro-2-methyl-l-(4-phenylamino-benzenesulfonyl)-2H-indol-3-yl]-acetic acid (109)
[5-Fluoro-2-methyl-l-(4-m-tolylamino-benzenesulfonyl)-lH-indol-3-yl]-acetic acid (110)
{5-Fluoro-2-methyl-l-[4-(pyridin-4-ylamino)-benzenesulfonyl]-lH-indol-3-yl}- acetic acid (111)
{ 5 -Fluoro-2-methyl- 1 - [4-(pyridin-2-ylamino)-benzenesulf onyl] - lH-indol-3 -yl } - acetic acid (112)
{5-Fluoro-2-methyl-l-[4-(pyrimidin-4-ylamino)-benzenesulfonyl]-lH-indol-3-yl}- acetic acid (113)
{5-Fluoro-2-methyl-l-[4-(5-methyl-isoxazol-3-ylamino)-benzenesulfonyl]-lH-indol- 3-yl}-acetic acid (114)
{5-Fluoro-2-methyl-l-[4-(pyridin-3-ylamino)-benzenesulfonyl]-lH-indol-3-yl}- acetic acid (115)
{ 5-Fluoro-2-methyl- 1 - [4-(4-methyl-pyridin-2-ylamino)-benzenesulf onyl] - lH-indol- 3-yl}-acetic acid (116)
{5-Fluoro-2-methyl-l-[4-(6-methyl-pyridin-2-ylamino)-benzenesulfonyl]-lH-indol- 3-yl}-acetic acid (117)
{5-Fluoro-2-methyl-l-[4-(4-methyl-pyrimidin-2-ylamino)-benzenesulfonyl]-lH- indol-3-yl} -acetic acid (118) {5-Fluoro-2-methyl-l-[4-(pyrirnidin-2-ylamino)-benzenesulfonyl]-lH-indol-3-yl}- acetic acid (119)
{l-[4-(3-Chloro-phenylamino)-benzenesulfonyl]-5-fluoro-2-methyl-lH-indol-3-yl}- acetic acid (120)
{ l-[4-(2,6-Dimethyl-pyrimidin-4-ylamino)-benzenesulfonyl]-5-fluoro-2-methyl-7H- indol-3-yl} -acetic acid (121)
{5-Fluoro-l-[4-(isoxazol-3-ylamino)-benzenesulfonyl]-2-methyl-lH-indol-3-yl}- acetic acid (122)
{l-[4-(4,6-Dimemyl-pyrimidin-2-ylamino)-benzenesulfonyl]-5-fluoro-2-methyl-lH- indol-3-yl} -acetic acid (123)
{5-Fluoro-2-methyl-l-[4-(5-methyl-pyridin-3-ylamino)-benzenesulfonyl]-7H-indol- 3-yl}-acetic acid (124)
{5-Fluoro-2-methyl-l-[4-(thiazol-2-ylamino)-benzenesulfonyl]-7H-indol-3-yl}- acetic acid (125)
{ l-[4-(3,5-Dimethyl-phenylamino)-benzenesulfonyl]-5-fluoro-2-methyl-2H-indol-3- yl}-acetic acid (126)
{ 5 -Fluoro-2-methyl- 1 - [4-(4-sulf onamido-phenylamino)-benzenesulf onyl] -2H-indol- 3-yl}-acetic acid (127)
{l-[4-(3,5-Dichloro-phenylamino)-benzenesulfonyl]-5-fluoro-2-methyl-iH-indol-3- yl}-acetic acid (128)
{l-[4-(5-Chloro-pyridin-3-ylamino)-benzenesulfonyl]-5-fluoro-2-methyl-2H-indol- 3-yl}-acetic acid (129)
{ l-[2,5-Difluoro-4-(pyridin-2-ylamino)-benzenesulfonyl]-5-fluoro-2-methyl-2H- indol-3-yl}-acetic acid (130)
{l-[2,5-Difluoro-4-(pyridin-2-ylamino)-benzenesulfonyl]-5-fluoro-2-methyl-2H- indol-3-yl} -acetic acid (131)
{l-[2,5-Difluoro-4-(5-methyl-isoxazol-3-ylamino)-benzenesulfonyl]-5-fluoro-2- methyl-2H-indol-3-yl}-acetic acid (132)
{5-Fluoro-l-[4-(3-methoxy-phenylamino)-benzenesulfonyl]-2-methyl-7H-indol-3- yl}-acetic acid (133)
{ l-[4-(3-Cyano-phenylamino)-benzenesulfonyl]-5-fluoro-2-methyl-7H-indol-3-yl}- acetic acid (134) { l-[4-(3-Ethyl-phenylamino)-benzenesulfonyl]-5-fluoro-2-methyl-iH-indol-3-yl}- acetic acid (135)
{5-Fluoro-2-methyl-l-[6-(pyridin-2-ylamino)-pyridine-3-sulfonyl]-lH-indol-3-yl}- acetic acid (136)
{5-Fluoro-2-methyl-l-[6-(pyridin-3-ylamino)-pyridine-3-sulfonyl]-lH-indol-3-yl}- acetic acid (137)
{5-Fluoro-2-methyl-l-[6-(pyrimidin-4-ylamino)-pyridine-3-sulfonyl]-lH-indol-3- yl}-acetic acid (138) [5-Fluoro-2-methyl-l-(6-phenylamino-pyridine-3-sulfonyl)-lH-indol-3-yl]-acetic acid (139)
{ l-[6-(3,5-Dimethyl-phenylamino)-pyridine-3-sulfonyl]-5-fluoro-2-methyl-lH- indol-3-yl} -acetic acid (140)
{5-Fluoro-2-methyl-l-[6-(pyrimidin-2-ylamino)-pyridine-3-sulfonyl]-lH-indol-3- yl}-acetic acid (141)
{5-Fluoro-2-methyl-l-[6-(6-methyl-pyridin-2-ylamino)-pyridine-3-sulfonyl]-lH- indol-3-yl} -acetic acid (142)
{5-Fluoro-2-methyl-l-[6-(4-methyl-pyrimidin-2-ylamino)-pyridine-3-sulfonyl]-lH- indol-3-yl} -acetic acid (143)
{ l-[6-(4,6-Dimethyl-pyrimidin-2-ylamino)-pyridine-3-sulfonyl]-5-fluoro-2-methyl- lH-indol-3-yl}-acetic acid (144)
{ l-[6-(3-Chloro-phenylamino)-pyridine-3-sulfonyl]-5-fluoro-2-methyl-lH-indol-3- yl}-acetic acid (145) [5-Fluoro-2-methyl-l-(6-m-tolylamino-pyridine-3-sulfonyl)-lH-indol-3-yl]-acetic acid (146)
{l-[6-(2,6-Dimethyl-pyrirrιidin-4-ylamino)-pyridine-3-sulfonyl]-5-fluoro-2-methyl- lH-indol-3-yl}-acetic acid (147)
{5-Fluoro-2-methyl-l-[6-(pyridin-4-ylamino)-pyridine-3-sulfonyl]-lH-indol-3-yl}- acetic acid (148)
{5-Fluoro-2-methyl-l-[6-(5-methyl-isoxazol-3-ylamino)-pyridine-3-sulfonyl]-lH- indol-3-yl} -acetic acid (149)
{5-Fluoro-2-methyl-l-[6-(thiazol-2-ylamino)-pyridine-3-sulfonyl]-lH-indol-3-yl}- acetic acid (150) { l-[6-(3,5-Dichloro-phenylamino)-pyridine-3-sulfonyl]-5-fluoro-2-methyl-2H-indol- 3-yl}-acetic acid (151)
{5-Fluoro-2-methyl-l-[6-(5-methyl-pyridin-3-ylamino)-pyridine-3-sulfonyl]-iH- indol-3-yl} -acetic acid (152)
{ l-[6-(5-Chloro-pyridin-3-ylamino)-pyridine-3-sulfonyl]-5-fluoro-2-methyl-iH- indol-3-yl}-acetic acid (153)
{5-Fluoro-2-methyl-l-[4-(methyl-phenyl-amino)-benzenesulfonyl]-lH-indol-3-yl}- acetic acid (154)
{5-Fluoro-2-methyl-l-[4-(methyl-m-tolyl-amino)-benzenesulfonyl]-lH-indol-3-yl}- acetic acid (155) (5-Fluoro-2-methyl-l-{4-[methyl-(5-methyl-isoxazol-3-yl)-amino]-benzene- sulfonyl}-lH-indol-3-yl)-acetic acid (156)
(5-Fluoro-2-methyl-l-{4-[methyl-(4-methyl-pyridin-2-yl)-amino]-benzene sulfonyl }-lH-indol-3-yl)-acetic acid (157)
(5-Fluoro-2-methyl- 1- { 6-[methyl-(6-methyl-pyridin-2-yl)-amino]-pyridine-3- sulfonyl}-lH-indol-3-yl)-acetic acid (158)
{5-Fluoro-2-methyl-l-[4-(methyl-pyrimidin-2-yl-amino)-benzenesulfonyl]-lH-indol- 3-yl}-acetic acid (159)
{5-Fluoro-2-methyl-l-[4-(methyl-pyridin-2-yl-amino)-benzenesulfonyl]-lH-indol-3- yl} -acetic acid (160)
{5-Fluoro-2-methyl-l-[6-(methyl-pyridin-2-yl-amino)-pyridine-3-sulfonyl]-lH- indol-3-yl}-acetic acid (161)
{5-Fluoro-2-methyl-l-[6-(methyl-pyridin-4-yl-amino)-pyridine-3-sulfonyl]-7H- indol-3-yl} -acetic acid (162)
(5-Fluoro-2-methyl-l-{4-[methyl-(6-methyl-pyridin-2-yl)-amino]-benzenesulfonyl}- 2H-indol-3-yl)-acetic acid (163)
(l-{4-[(2,6-Dimethyl-pyrimidin-4-yl)-methyl-amino]-benzenesulfonyl}-5-fluoro-2- methyl-2H-indol-3-yl)-acetic acid (164)
{5-Fluoro-2-methyl-l-[6-(methyl-phenyl-amino)-pyridine-3-sulfonyl]-2H-indol-3- yl}-acetic acid (165)
(l-{6-[(3-Chloro-phenyl)-methyl-amino]-pyridine-3-sulfonyl}-5-fluoro-2-methyl- 2H-indol-3-yl)-acetic acid (166) (l-{4-[(3-Chloro-phenyl)-methyl-amino]-benzenesulfonyl}-5-fluoro-2-methyl-7H- indol-3-yl)-acetic acid (167)
{ l-[4-(Ethyl- -tolyl-amino)-benzenesulfonyl]-5-fluoro-2-methyl-iH-indol-3-yl}- acetic acid (168)
{5-Fluoro-2-methyl-l-[4-(methyl-pyridin-3-yl-amino)-benzenesulfonyl]-7H-indol-3- yl} -acetic acid (169) [5-Fluoro-2-methyl-l-(4-phenylsulfanyl-benzenesulfonyl)-lH-indol-3-yl]-acetic acid (171) [l-(4-Benzenesulfinyl-benzenesulfonyl)-5-fluoro-2-methyl-iH-indol-3-yl]-acetic acid (172) [l-(4-Benzenesulfonyl-benzenesulfonyl)-5-fluoro-2-methyl-2H-indol-3-yl]-acetic acid (173) [5-Chloro-l-(4-chloro-benzenesulfonyl)-2-methyl-2H-indol-3-yl]-acetic acid (174) {5-Fluoro-l-[4-(3-isopropyl-phenylamino)-benzenesulfonyl]-2-methyl-2H-indol-3- yl}-acetic acid (175)
{5-Fluoro-2-methyl-l-[4-(methyl-thiazol-2-yl-amino)-benzenesulfonyl]-7H-indol-3- yl} -acetic acid (176)
{ l-[2,5-Difluoro-4-(isoxazol-3-ylamino)-benzenesulfonyl]-5-fluoro-2-methyl-2H- indol-3-yl}-acetic acid (177)
{ l-[4-(5-Chloro-pyridin-3-ylamino)-2,5-difluoro-benzenesulfonyl]-5-fluoro-2- methyl-2H-indol-3-yl} -acetic acid (178)
{ 1 - [2,5-Difluoro-4-(5 -methyl-pyridin-3 -ylamino)-benzenesulfonyl] -5-fluoro-2- methyl-7H-indol-3-yl} -acetic acid (179)
{ l-[6-(3-Ethyl-phenylamino)-pyridine-3-sulfonyl]-5-fluoro-2-methyl-7H-indol-3- yl}-acetic acid (180)
{5-Fluoro-l-[6-(3-methoxy-phenylamino)-pyridine-3-sulfonyl]-2-methyl-7H-indol- 3-yl} -acetic acid (181) { l-[6-(3-Cyano-phenylamino)-pyridine-3-sulfonyl]-5-fluoro-2-methyl-7H-indol-3- yl} -acetic acid (182) {5-Fluoro-l-[6-(3-methanesulfonyl-phenylamino)-pyridine-3-sulfonyl]-2-methyl- 7H-indol-3-yl} -acetic acid (183) {5-Fluoro-l-[4-(isoxazol-3-yl-methyl-amino)-benzenesulfonyl]-2-methyl-2H-indol- 3-yl}-acetic acid (184)
(5-Fluoro-2-methyl-l - { 4- [methyl-(5-methyl-pyridin-3 -yl)-amino] -benzenesulfonyl } -
2H-indol-3-yl)-acetic acid (185)
(l-{4-[(3,5-Dimethyl-phenyl)-methyl-amino]-benzenesulfonyl}-5-fluoro-2-methyl-
2H-indol-3-yl)-acetic acid (186)
(5-Fluoro-l-{4-[(3-methoxy-phenyl)-methyl-amino]-benzenesulfonyl}-2-methyl-7H- indol-3-yl)-acetic acid (187)
(l-{4-[(3-Cyano-phenyl)-methyl-amino]-benzenesulfonyl}-5-fluoro-2-methyl-7H- indol-3-yl)-acetic acid (188)
(l-{4-[(3-Ethyl-phenyl)-methyl-amino]-benzenesulfonyl}-5-fluoro-2-methyl-7H- indol-3-yl)-acetic acid (189)
(5-Fluoro-l-{4-[(3-isopropyl-phenyl)-methyl-amino]-benzenesulfonyl}-2-methyl-
7H-indol-3-yl)-acetic acid (190)
(l-{6-[(3-Ethyl-phenyl)-methyl-amino]-pyridine-3-sulfonyl}-5-fluoro-2-methyl-7H- indol-3-yl)-acetic acid (191)
(5-Fluoro- 1 - { 6- [(3-methanesulfonyl-phenyl)-methyl-amino]-pyridine-3-sulfonyl } -2- methyl-7H-indol-3-yl)-acetic acid (192)
(l-{6-[(3-Cyano-phenyl)-methyl-amino]-pyridine-3-sulfonyl}-5-fluoro-2-methyl-
7H-indol-3-yl)-acetic acid (193)
(5-Fluoro-2-methyl- 1 - { 6-[methyl-(5-methyl-pyridin-3-yl)-amino] -pyridine-3- sulfonyl}-7H-indol-3-yl)-acetic acid (194).
34. A process for the preparation of a compound as claimed in claim 1, the process comprising treating a compound of general formula (IL) as defined in claim 2 and wherein R10 is d-C6 alkyl with a base.
35. A pharmaceutical composition comprising a compound as claimed in any one of claims 1 to 16 together with a pharmaceutical excipient or carrier.
36. A pharmaceutical composition as claimed in claim 35 formulated for oral, rectal, nasal, bronchial (inhaled), topical (including eye drops, buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration.
37. A composition as claimed in claim 36 formulated for oral, nasal, bronchial or topical administration.
38. A composition as claimed in any one of claims 35 to 37 containing one or more additional active agents useful in the treatment of diseases and conditions mediated by PGD2 at the CRTH2 and/or DP receptor.
39. A composition as claimed in claim 38, wherein the additional active agents are selected from: β2 agonists such as salmeterol; corticosteroids such as fluticasone; antihistamines such as loratidine; leukotriene antagonists such as montelukast; anti-IgE antibody therapies such as omalizumab; anti-infectives such as fusidic acid (particularly for the treatment of atopic dermatitis); anti-fungals such as clotrimazole (particularly for the treatment of atopic dermatitis); immunosuppressants such as tacrolimus and particularly pimecrolimus in the case of inflammatory skin disease; other antagonists of PGD2; inhibitors of phoshodiesterase type 4 such as cilonilast; drugs that modulate cytokine production such as inhibitors of TNFα converting enzyme (TACE); drugs that modulate the activity of Th2 cytokines LL-4 and LL-5 such as blocking monoclonal antibodies and soluble receptors;
PPAR-γ agonists such as rosiglitazone;
5-lipoxygenase inhibitors such as zileuton.
40. A process for the preparation of a pharmaceutical composition as claimed in any one of claims 35 to 39 comprising bringing a compound as claimed in any one of claims 1 to 16 into conjunction or association with a pharmaceutically or veterinarily acceptable carrier or vehicle.
41. A product comprising a compound as claimed in any one of claims 1 to 16 and one or more of the agents listed in claim 39 as a combined preparation for simultaneous, separate or sequential use in the treatment of a disease or condition mediated by the action of PGD2 at the CRTH2 and/or DP receptor.
42. The use as claimed in any one of claims 19 to 33, wherein the agent also comprises an additional active agent useful for the treatment of diseases and conditions mediated by PGD2 at the CRTH2 and/or DP receptor.
43. The use as claimed in claim 42, wherein the additional active agent is one of the agents listed in claim 39.
PCT/GB2004/004337 2003-10-14 2004-10-13 Compounds with pgd2 antagonist activity WO2005040112A1 (en)

Applications Claiming Priority (6)

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GB0324083.5 2003-10-14
GB0324083A GB0324083D0 (en) 2003-10-14 2003-10-14 Compounds
GB0403334.6 2004-02-14
GB0403334A GB0403334D0 (en) 2004-02-14 2004-02-14 Compounds
GB0406963A GB0406963D0 (en) 2004-03-27 2004-03-27 Compounds
GB0406963.9 2004-03-27

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