Title of Invention	A SUBSTITUTED BIPHENYL-2-YLOXYACETIC ACID COMPOUNDS
Abstract	The invention relates to substituted phenoxyacetic acids of formula (I), where the variables are as defined in claim 1, as useful pharmaceutical compounds for treating respiratory disorders, pharmaceutical compositions containing them, and processes for their preparation.

Full Text

BIPHENYLOXYACETIC ACID DERIVATIVES FOR THE TREATMENT OF RESPIRATORY DISEASE The present invention relates to substituted phenoxyacetic acids as useful pharmaceutical compounds for treating respiratory disorders, pharmaceutical compositions containing them, and processes for their preparation. EPA 1 170 594 discloses methods for the identification of compounds useful for the treatment of disease states mediated by prostaglandin D2, a ligand for orphan receptor CRTH2. GB 1356834 discloses a series of compounds said to possess anti-inflammatory, analgesic and antipyretic activity. It has been found that certain phenoxyacetic acids active at the CRTH2 receptor, and as a consequence are expected to be potentially useful for the treatment of various respiratory diseases, including asthma and COPD. In a first aspect the invention therefore provides a compound of formula (I) or a phannaceutically acceptable call thereof: X is halogen, or Ci-2 alkyl which is substituted by one or more halogen atoms; A and E are independently selected from halogen, SOiNR3!*4, SOnR5 (n=l or 2), 4, or Ci-3 alkyl which can be optionally substituted by one or more halogen atoms; D is hydrogen or fluorine; Rl and R2 independently represent a hydrogen atom, or a Ci.3alkyl group; R1 and R2 together can form a 3-8 membered ring optionally containing one or more atoms selected from O, S, NR6 and itself optionally substituted by one or more Ci-Cs altyl; R3 and R4 independently represent hydrogen, C1-C7 cycloalkyl or C1-7alkyl, the latter two groups being optionally substituted by one or more substituents independently selected from halogen, C3-C7 cycloalkyl, OR6 and NR7R8; or R3 and R4 together with the nitrogen atom to which they are attached can form a 3-8 membered saturated heterocylic ring optionally containing one or more atoms selected from O, S(O)n (where n = 0,1 or 2), NR8, and itself optionally substituted by halogen or €1-3 alkyl; R5 is Ci-Ce alkyl or Cs-y cycloalkyl, which may be optionally substituted by halo gen atoms; R6 is hydrogen or C1-C9alkyl; R7 and R* independcatiy stymie hydrogen-7 cyclically R7 and R* together wiih tike nitrogen atom to which they are attached can form a 3- membered saturated hetooeyciic ring at defined above far R3 and R4. In the context of (be prefect specification, unfit0. otiietwue indicated, an alkyl group or an alkyl moiety in a substituent group may be linear or branched. Heterocyclic rings as defined for R3 and R4 or R7 and R8 means saturated heterocycles, examples include morpholine, azetidine, pyrrolidine, piperidine and piperazine. Preferably X is trifluoromethyl, chloro or fluoro. Preferably A and E independently represent trifluoromethyl, d-aalkyl, halogen, SOR5, SC^R5, CONR3R4, or SO2NR3R4. More preferably A and E independently represent trifluoromethyl, methyl, fluoro, chloro, Same, SO2Et, Soapier, SO2NR3R4 or CONR3R4. More preferably A is trifluoromethyl, methyl, flour or chloro. More preferably E is SCMe, SOaEt, SO2iPr, SO2NR3R4 where R3 and R4 together form a morpholine ring or E is CONR3R4 where R3 and R4 together form a pyrrolidine, piperidine, azetidine or isoxazoline ring, each optionally substituted by halogen or C1- alkyl, or E is CONR3R4 where R3 and R4 independently represent hydrogen, Ca-C? cycloalkylThe alkyl groups may be linear or branched. Most preferably E is SC^Me, SOzEt, SQzNR4 where R3 and R4 together form a morpholine ring or E is CONR3R4 where R3 and R4 together form a pyrrolidine, piperidine, azetidine or isoxazoline ring, each optionally substituted by fluoro or methyl, or E is CONR3R4 where R3 and R4 independently represent hydrogen, C3-C7 cycloalkyl or 3.6 alkyl. The alkyl groups may be linear or branched. Preferably R1 and R2 are independently hydrogen or Ci-3 alkyl, more preferably R,1 and R2 are both hydrogen or one is hydrogen and the other is methyl. Preferably D is hydogen or fluorine, more preferably hydrogen. Preferred substituents A, D, E, X, R1 and R2 are those exemplified herein. Preferred compounds of the invention include: [[3'-Fluoro-4'-[(l -methylethyI)sulfonyl]-5-(triiluoromethyl)[ 1 , 1 '-biphenyl]-2-yl]oxy]acetic acid; [[5-Chloro-4'-(methylsulfonyl)-3'-(trifluoromethyl)[l , l'-biphenyl]-2-yl]oxy]-acetic acid; [[5-Fluoro-4'-(methylsulfonyl)-3Xtrifluoromethyl)[l,r-biphenyl]-2-yl]oxy]-aceticacid; [[4'-(E%lsulfonyl)-35-bis(trifluoromethyl)[l,l'-biphenyl]-2-yl]oxy]aceticacid; (25)-2-[[4thylsiilfonyl)-3\5-bis(trifluoromemyl)[l,r-biphenyl]-2-yl]oxy]propanoica^ (22-[[5Moro-4l-(4-morpholmylsulfonyl)-3'trifluoromemyl)[l,l'-biphenyl]-2- yl]oxy]propanoic acid; [[5-CMoro^Xl-pyrroUdylcarbonyl)-3Xtrifluoromethyl)[l,r-biphenyl]-2-yl]oxy]-; (2S)-2-[[5 Morol -pyrrolidmylcarpropanoic acid; (25)- 2-[[5-Chloro-3'-fluoro-4l-(niethylsulfonyl)[l , 1 '-biphenyl]-2-yl]oxy]propanoic [[3',5-dichloro-4'-(4-morpholinylcaibonyl)[l,r-biphenyl]-2-yi]oxy]-aceticacid; [[4'-(l-azetidinylcaibonyl)-3l,5-dichloro[l,r-biphenyl]-2-yl]oxy]-aceticacid; [[3\5-dicWoro-[[(2R,6S)-2,6Hlimethyl-l-piperidinyl]carbonyl][14l-biphenyl]-2-yl]oxy]- acetic acid; [[3^5-dicUoro-4'-[(2-methyl-l-pyrrolidinyl)carbonyl][l,l'-biph«iyl]-2-yl]oxy]-aceticacid; [[3',5-dichloro-4'-(2-isoxazolidinylcarbonyl)[l,r-biphenyl]-2-yl]oxy]-aceticacid; [[5-chloro-3'-fluon)-4'-(l-pyrrolidinylcaibonyl)[l,r-biphenyl]-2-yl]oxy]-ace1icacid; (2S)-2-[[5bJoro-3'-fluoro'-(l-pyrrolidiiiylcarbonyl)[l,r-biphenyl]-2-yl]oxy]-propanoic (2S)-2-[[4'-[[bis(l-me%le%l)amino]carbonyl]-5-chloro-3'-fluoro[l,l'-biphenyl]-2-yl]oxy]- propanoic acid; (2S)-2-[[5moro'-[(elhylmethylamino)carbonyl]-3'-fluoro[l,r-biphenyl]-2-yl]oxy]- propanoic acid; (2S)-2-[[5-chloro-3'-fluoro-4'-[[methyl(l-methyiethyl)amino]carbonyl][l,r-biphenyl]-2- yl]oxy]-propanoic acid; (2S)-2-[[5-chloro-4'-[(diethylamino)carbonyl]-3'-fluoro[ 1 ,l'-biphenyl]-2-yl]oxy]- (2S)-2-[[5-chloro-4'-[(3 ,3-difluoro- 1 -pyrrolidinyl)carbonyl]-3'-fluoro[l , 1 '-biphraiyl]- yl]oxy]-propanoic acid; (2S)-2-[[4'-[[(l,liimethylethyl)amiiK)]caibonyl3-3'-fluoio-5^trifluorometh3d)[lJ'- biphenyl]-2-yl]oxy]-propanoic acid; (2S)-2-[[5Morc-3'-fluOTO-[[(l-m propanoic acid; (2S2-[[5-chloro-3'-fluoro-4'-[[(2-methylpiopyl)amino]caibonyl][l,lI-biphenyl]-2-yl]oxy]- propanoic acid; (2S2-[[3'-fluoroXl-pyirolidinylcaibonyl)-5-(trifluoromethyl)[l,r-biphenyl]-2-yl]oxy]- propanoic acid; (2S)-2-[[3^5^cUoroXl-pymlidinylcarbonyl)[l,r-biphenyl]-2-yl]oxy]-propanoicacid; (2S)-2-[[5^Uoro-3'-methyMXl-pynUylcait)onyl)[l,ll-biphenyl]-2-yl]oxy]-propanoic acid; [[5-cUoro-3'-methyl-4'-(l-pyrrolidinylcarbonyl)[l,r-biphenyl]-2-yl]oxy]-aceticacid; [[3'-fluorol-pym)lidinylcarbonyl)-5-(tiifluoromethyl)[l,l'-biphenyl]-2-yl]oxy]-acetic acid; (2S)-2-[[3'-methyMHl-pyn-oUdinylcaibonyl)-5trifluoromethyl)[l,ll-biphenyl]-2-yl]oxy]- propanoic acid; yl]oxy]-propanoic acid; (2S)-2-[[5-cMorc-3'-fluoro-4t-[[(2R)-2-methyl-l-pynroudinyl]carbonyl][l,!'biphenyl]-2- yl]oxy]-propanoic acid; (2S)-2-[[4'-[(cyclopentylamino)carbonyl]-3I-fluoro-5-(trifluoromethyl)[l,r-biphenyl]-2- yl]oxy]-propanoic acid; (2S)-2-[[3'-fluoro-4'-[[(l-methylethyl)amino]carbonyl]-5-(trifluoromethyl)[l,ll-biphenyl]- yl]oxy]-propanoic acid; (2S)-2-[[4l-[(ethylamino)carbonyl]-3l-fluoro-5-(trifluoromethyl)[l,r-biphenyl]-2-yl]oxy]- propanoic acid; (2S)-2-[[5-chloro-4'-[[(l, 1 -dimethylethyl)amino]carbonyl]-3'-fluoro[l, 1 '-biphenyl]-2-yl]oxyjpropanoic acid; (252-[[5-cMoro-4'-[(cyclopentylamino)carbonyl]-3'-fluoro[l,r-biphenyl]-2-yl]oxy]- propanoic acid; (25)-2-[[5-cMoro-4-[(cycloprcylamino)carbonyl]-3'-fluoro[14l-bi (ZS)-2-[[5-chloro-3I-fluoro-4'-[(methylamino)carbonyl] [ 1 , l'-biphenyl]-2-yl]oxy]- (25)-2-[[5K;moro-[[(iaKlime%le%l)ainino]carbonyl]-3'-methyl[l,ll-biphenyl]-2- yljoxy]- propanoic acid; [[5^Uoro^'-[[(l-ethylpropyl)amino]carbonyl]-3l-fluoro[l,l'-biphenyl]-2-yl]oxy]-acetic acid; [ [5-chloro-3 '-fluoro-KmemylammoJcarbonyl] [1,1 -biphenyl] -2-yl]oxy]-acetic acid; (25)-2-[[5-chloro-4'-[( ethylamino)carbonyl]-3'-fluoro[l, l'-biphenyl]-2-yl]oxy]- propano ic acid; (25)-2-[[5-cWoro-[(cyclobutylamiiio)caibonyl]-3l-fluoro[l,r-biphenyl]-2-yl]oxy]- propanoic acid; (25)-25hkOT) 4[(U~dimefli yQaicyJ-propanoic acid; (25V2-[[5hloro-3'-fhMroH[(3-mc&ylbtyl) piopanoic acid; and phannacCTrtically aixxytable Jti thereof. Certain compounds of formula (I) are capable of existing in stereoisomeric forms. It will be understood that the invention encompasses all geometric and optical isomers of the compounds of formula (I) and mixtures thereof including racemates. Tautomers and mixtures thereof also form an aspect of the present invention. The compound of formula (I) above may be converted to a pharmaceutically acceptable salt or solvate thereof, preferably a basic addition salt such as sodium, potassium, calcium, aluminium, lithium, magnesium, zinc, benzathine, chloroprocaine, choline, diethanolamine, ethanolamine, ethyldiamine, meglumine, tromethamine or procaine, or an acid addition salt such as a hydrochloride, hydrobromide, phosphate, acetate, fumarate, maleate, tartrate, citrate, oxalate, methanesulphonate orp-toluenesulphonate. It will be appreciated by those skilled in the art that in the processes of the present invention certain functional groups in the starting reagents or intermediate compound may need to be protected by protecting groups. Thus, the preparation of the compound of formula (I) may involve, at an appropriate stage, the removal of one or more protecting groups. The protection and deprotection of functional groups is fully described in 'Protective Groups in Organic Chemistry', edited by J. W. F. McOmie, Plenum Press (1973), and 'Protective Groups in Organic Synthesis', 3rd edition, T. W. Greene & P. G. M. Wuts, Wiley- Interscience (1999). Compounds of formula (I) can be prepared by reaction of a compound of formula in which X, A, D and E are as defined in fixmula (I) or are protected derivatives Where R1 and R2 are as defined in formula (I) or are protected derivatives thereof, R9 is H or Ci-Cio alkyl group and L is a leaving group, and optionally thereafter in any removing any protecting group • hydrolysing the ester group R9 to the corresponding acid • oxidation of sulphides to sulphoxides or sulphones • forming a pharmaceutically acceptable salt. The reaction can be carried out in a suitable solvent such as acetonitrile or DMF using a base such as potassium carbonate or the like. Suitable groups R9 include Ci-e alkyl groups such as methyl, ethyl or tert-butyl. Suitable L is a leaving group such as tosylate or halo, in particular chlorine or bromine. L may also be hydroxy so that a Mitsunobw reaction may be performed with compound (EC) using for example triphenylphosphine and diethyl azodicarboxylate. Hydrolysis of the ester group R9 can be carried out using routine procedures, for example treatment of methyl and ethyl esters with aqueous sodium hydroxide, and treatment of tert-butyl esters with acids such as trifluoroacetic acid. Compounds of formula (II) can be prepared by reaction of a compound of formula (IV) with a compound of formula (V) via a Suzuki coupling reaction followed by deprotection ofR10: OR10 OR11 in which X, A, D and E are as defined in fonnula (I) or are protected derivatives thereof, R10 Ll is iodide, bromide, chloride or Inflate and R11 and R12 are H or alkyl groups or Rn and R12 together can form a 5 or 6 membered ring optionally substituted by one or more alkyl. The reaction can be carried out in a suitable solvent such as dioxane using a palladium catalyst such as [l,l-bis(diphenylphosphino)ferrocene]dichloropalladium and abase such as cesium fluoride, preferably at elevated temperatures. When R10 is a protecting group such as benzyl it can be removed usin hydrogen with a suitable catalyst for example platinum or palladium on charcoal. If the group R10 is alkyl for eample methyl, then it can be cleaved using borontribromide in a suitable solvent such as dichloromethane. Some compounds of formula (IV) are commercially available. Certain compounds of formula (TV) can be prepared from a compound of formula (VI) by formation of an organometallic (YE) followed by reaction with a borate ester, as outlined in Scheme I. * (IV) Scheme I in which X, is as defined in formula (T) or are protected derivatives thereof, R10 is as defined in formula (IV), W is hydrogen or halogen and M is a metal such as Na or Li. For example when R10 is benzyl and E is bromine, butyl lithium can be used to form the intermediate C VH) where M = Li. The reaction is performed at -78°C hi diethylether, then quenched with a borate ester such as trimetiiyibonte. Compounds of formula (D) may also be prepared by reaction of a compound of formula (XI) with a compound of formula (XII) using Suznlti coupling methodology. in which X, A, D, E, R10, L1, R11 and R12 are as defined above and compounds of formula (XI) and (XII) can be made using the same methodology as above. The sequence of the steps above may be changed, for example a compound of formula (I) may be formed by the reaction of a compound of formula (XVT) with a compound of formula (Xn) using a Suzuki coupling. . Or, compounds of formula (I) can be prepared by reaction of a compound of formula (XVII) with a compound of (Figure Removed) Where the groups A, D, E, L1, X, R1 and R2are as defined above or proteced drivates thereof. R13 is hydrogen or Ci-C6 alkyl for example methyl ethyl or tertiary butyl. If R13 is an ester group it is subsequently hydrolysed using either acidic or basic conditions, such as TFA or NaOH. Compounds of formula (XVD) can be prepared as outlined in WO2004089885 or by reacting a compound of formula (XVII) with bis(pinocolato)diboron Compounds of formula (XB) where the group E is SR can be synthesised by dispalcing the Fluorine with R5SNa in a suitable solvent such as DMF at 50°C. Compounds of formula (XIX) can be converted to the boronic acid using BuLi, then reacting with a borate ester as outlined previously. Alternatively the compounds of formula (XVH) can be prepared by a palladium catalysed coupling of compounds of formula (XIX) with a suitable boronic ester, for example bis(pinocolato)diboron. Compounds of formula (XDQ can also be prepared from compounds of formula (XX) where the chlorosulphonic acid is reduced to the thiol using triphenylphosphine, subsequently alkylated using an alkyl halide such as alkyl iodide or bromide. Compounds of formula (V) where the group E is amide can be prepared by method C: in which a compound of fixmnla. (Va) is coiivcarted to the ackl chloride using reageM such as oxalyl chloride and subsequently reacted with an amire in a suitable solvent soch as dkhkromethane. The group A, D and L1 arc as ddfaed for compounds of fbnmua(V) or ptotDced derivates thereof Compounds of fonrmla (Va) are commercially arailabk or m be readily svnttiesised using literature procedures by those skilled in the art Novel intermediates of the general formulae given above form a further aspect of the invention. In a further aspect, the present invention provides the use of a compound of formula (I), a prodrug, phannaceutically acceptable salt or solvate thereof for use in therapy. The compounds of formula (I) have activity as Pharmaceuticals, in particular as modulators of CRTh2 receptor activity, and may be used in the treatment (therapeutic or prophylactic) of conditions/diseases in human and non-human animals which are exacerbated or caused by excessive or unregulated production of PGD2 and its metabolites. Examples of such conditions/diseases include: 1. respiratory tract: obstructive diseases of the airways including: asthma, including bronchial, allergic, intrinsic, extrinsic, exercise-induced, drug-induced (including aspirin and NS AID-induced) and dust-induced asthma, both intermittent and persistent and of all severities, and other causes of airway hyper-responsiveness; chronic obstructive pulmonary disease (COPD); bronchitis, including infectious and eosinophilic bronchitis; emphysema; bronchiectasis; cystic fibrosis; sarcoidosis; fanner's lung and related diseases; hypersensitivity pneumonitis; lung fibrosis, including cryptogenic fibrosing alveolitis, idiopathic interstitial pneumonias, fibrosis complicating anti-neoplastic therapy and chronic infection, including tuberculosis and aspergillosis and other fungal infections; complications of lung transplantation; vasculitic and thrombotic disorders of the lung vasculature, and puhnonary hypertension; antitussive activity including treatment of chronic cough associated with inflammatory and secretory conditions of the airways, and iatrogenic cough; acute and chronic rhinitis including rhinitis medicamentosa, and vasomotor rhinitis; perennial and seasonal allergic rhinitis including rhinitis nervosa (hay fever); nasal polyposis; acute viral infection including the common cold, and infection due to respiratory syncytial virus, influenza, corona virus (including SARS) and adenovirus; 2. bone and joints: authorities associated with or including osteoarthritis/osteoarthrosis, both primary and secondary to, for example congenital hip dysplasia;cemc and hombre Back and nedcpm; ihnm Yilrytnging ymdylitis, psoriatic. Artfirfri marts arthritic Ramp and bone diaofdecf aecia a acute and chronic crystal-induced synovitis including urate gout, calcium pyrophosphate deposition disease, and calcium apatite related tendon, bursal and synovia! inflammation; Behest’s disease; primary and secondary Jorgen’s syndrome; systemic sclerosis and limited scleroderma; systemic lupus erythematosus, mixed connective tissue disease, and undifferentiated connective tissue disease; inflammatory myopathies including dermatomyositits and polymyositis; polymalgia rheumatica; juvenile arthritis including(Figure Removed) idiopathic inflammatory arthritides of whatever joint distribution and associated syndromes, and rheumatic fever and its systemic complications; vasculitides including giant cell arteritis, Takayasu's arteritis, Churg-Strauss syndrome, polyarteritis nodosa, microscopic polyarteritis, and vasculitides associated with viral infection, hypersensitivity reactions, cryoglobulins, and paraproteins; low back pain; Familial Mediterranean fever, Muckle-Wells syndrome, and Familial Hibernian Fever, Kikuchi disease; drug-induced arthalgias, tendonititides, and myopathies; 3. pain and connective tissue remodelling of musculoskeletal disorders due to injury [for example sports injury] or disease: arthttides (for example rheumatoid arthritis, osteoartbritis, gout or crystal arthropathy), other joint disease (such as intervertebral disc Regeneration or temporomandibular joint degeneration), bone remodelling disease (such as osteoporosis, Paget's disease or osteonecrosis), polychondritits, scleroderma, mixed connective tissue disorder, spondyioarthropathies or periodontal disease (such as periodontitis); 4. skin: psoriasis, atopic dermatitis, contact dermatitis or other eczematous dermatoses, and delayed-type hypersensitivity reactions; phyto- and photodermatitis; seborrhoeic dermatitis, dermatitis herpetiformis, lichen planus, lichen sclerosus et atrophica, pyodenna gangrenosum, skin sarcoid, discoid lupus erythematosus, pemphigus, pemphigoid, epidermolysis bullosa, urticaria, angioedema, vasculitides, toxic erythemas, cutaneous eosinophilias, alopecia areata, male-pattern baldness, Sweet's syndrome, Weber-Christian syndrome, erythema multiforme; cellulitis, both infective and non-infective; panniculitisjcutaneous lymphomas, non-melanoma skin cancer and other dysplastic lesions; drug-induced disecden inchiding fixed drag nuptions; 6. gastrointestinal tract glossitis, gingivitis, periodontitis; oesophagitis, including reflux; eosinophilic gastro-enteritis, mastocytosis, Crohn's disease, colitis including ulcerative colitis, proctitis, pruritis ani; coeliac disease, irritable bowel syndrome, and food-related allergies which may have effects remote from the gut (for example migraine, rhinitis or eczema); 7. abdominal: hepatitis, including autoimmune, alcoholic and viral; fibrosis and cirrhosis of the liver, cholecystitis; pancreatitis, both acute and chronic; 8. genitourinary: nephritis including interstitial and glomerulonephritis; nephrotic syndrome; cystitis including acute and chronic (interstitial) cystitis and Hunner's ulcer, acute and chronic urethritis, prostatitis, epididymitis, oophoritis and salpingitis; vulvo-vaginitis; Peyronie's disease; erectile dysfunction (both male and female); 9. allograft rejection: acute and chronic following, for example, transplantation of kidney, heart, liver, lung, bone marrow, skin or cornea or following blood transfusion; or chronic graft versus host disease; 1 0. CMS: Alzheimer's disease and other dementing disorders including CJD and nvCJD; amyloidosis; multiple sclerosis and other demyeUnating syndromes; cerebral atherosclerosis and vasculitis; temporal arteritis; myasthenia gravis; acute and chronic pain (acute, intermittent or persistent, whether of central or peripheral origin) including visceral pain, headache, migraine, trigeminal neuralgia, atypical facial pain, joint and bone pain, pain arising from cancer and tumor invasion, neuropathic pain syndromes including diabetic, postherpetic, and HIV-associated neuropathies; neurosarcoidosis; central and peripheral nervous system complications of malignant, infectious or autoimmune processes; 1 1 . other auto-immune and allergic disorders including Hashimoto's thyroiditis, Graves' disease, Addison's disease, diabetes mellitus, idiopathic thrombocytopaenic purpura, eoshiophilic fasciitis, hyper-IgE syndrome, antiphospholipid syndrome; 12. other disorders with an inflammatory or immunological component; including acquired immune deficiency syndrome (ADDS), leprosy, Sezary syndrome, and paraneoplastic syndromes; 13. cardiovascular: atherosclerosis, affecting the coronary and peripheral circulation; myocardial sarcoid; ischaoxdc reper&sion injuries endc«ttditis, valvulitis, and aortitis including infective (for example syphilitic); vascuKtides; disorders of ifac proximal and peripheral veins including phlebitis and flaoiiibosts,mchidiiig deep van flgomtooaig and complications of varicose veins; 14. oncology: treatment of common cancers including prostate, breast, ?ung, ovarian, pancreatic, bowel and colon, stomach, skin and brain tumors and malignancies affecting the bone marrow (including the leukaemias) and lymphoproliferative systems, such as Hodgkin's and non-Hodgkin's lymphoma; including the prevention and treatment of metastatic disease and tumour recurrences, and paraneoplastic syndromes; and, 15. gastrointestinal tract: Coeliac disease, proctitis, eosinopilic gastro-enteritis, mastocytosis, Crohn's disease, ulcerative colitis, microscopic colitis, ^determinant colitis, irritable bowel disorder, irritable bowel syndrome, non-inflammatory diarrhea, food-related allergies which have effects remote from the gut, e.g., migraine, rhinitis and eczema. 16. Diseases associated with raised levels of PGDa or its metabolites. Thus, the present invention provides a compound of formula (T), or a pharmaceutically-acceptable salt or solvate thereof, as hereinbefore defined for use in therapy. Preferably the compounds of the invention are used to treat diseases in which the chemoldne receptor belongs to the CRTh2 receptor subfamily. Particular conditions which can be treated with the compounds of the invention are asthma, rhinitis and other diseases in which raised levels of PGDa or its metabolites. It is preferred that the compounds of the invention are used to treat asthma. In a further aspect, the present invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined in the manufacture of a medicament for use in therapy. In a further aspect, the present invention provides the use of a compound or formula (I), or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined in the manufacture of a medicament for use hi therapy hi combination with drugs used to treat asthma and rhinitis (such as inhaled and oral steroids, inhaled p2-receptor agonists and oral leukotriene receptor antagonists). The invention further relates to combination therapies wherein a compound of the , nr a pharmaraiirial cnmpngitmn or sequentially or as a combined preparation with ano&erthenqxntic agent or agents, for the treatment of one QJ more of the conditions listed. In particular, foe the treatment of the mflmmmitmy dbeases such as (but not restricted to) rheumatoid arthritis, osteoaithritis, asthma, allergic rhinitis, chronic obstructive pulmonary disease (COPD), psoriasis, and mflammatory bowel disease, the compounds of the invention may be combined with agents listed below. Non-steroidal anti-inflammatory agents (hereinafter NSADDs) including non-selective cyclo-oxygenase COX-1 / COX-2 inhibitors whether applied topically or systemically as piroxicam, diclofenac, propionic acids such as naproxen, flurbiprofen, fenoprofen, ketoprofen and ibuprofen, fenamates such as mefenamic acid, indomethacr:, sulindac, azapropazone, pyrazolones such as phenylbutazone, salicylates such as aspirin); selective COX-2 inhibitors (such as meloxicam, celecoxib, rofecoxib, valdecoxib, lumarocoxib, parecoxib and etoricoxib); cyclo-oxygenase inhibiting nitric oxide donors (CINODs); glucocorticosteroids (whether administered by topical, oral, intramuscular, intravenous, intra-articular routes); methotrexate; leflunomide; hydroxychloroquine; d-penicillamine; auranofin or other parenteral or oral gold preparations; analgesics; diacerein; intra-articular therapies such as hyaluronic acid derivatives; and nutritional supplements such as glucosamine. The present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, together with a cytokine or agonist or antagonist of cytokine function, (including agents which act on cytokine signalling pathways such as modulators of the SOCS system) including alpha-, beta-, and gamma-interferons; insulin-like growth factor type I (IGF-1); interleukins (IL) including IL1 to 17, and interle-ukin antagonists or inhibitors such as anakinra; tumour necrosis factor alpha (TNF-cc) inhibitors such as anti-TNF monoclonal antibodies (for example infliximab; adalimumab, and CDF- 870) and TNF receptor antagonists including immunoglobulin molecules (such as etanercept) and low-molecular-weight agents such as pentoxyfylline. hi addition the invention relates to a combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, with a monoclonal antibody targeting BLymphocytes (such as CD20 (rituximab), MRA-aIL16R and T-Lymphocytes, CTLA4-Ig, HuMaxD-15). The present invention stffl firfberrefatas to die ombmationofacoinpoundofthe invention fir a receptor function such as an antagonist of CCR1, CCR2, CCR2A,CX3R2B,CCR3.CCR4, CCR5, CCR6, CCR7, COW, CCR9, CCR10 and OCR11 (for UK OC finnfly); CXCR1, CXCR2, CXCR3, CXCR4 and CXCR5 (for the C-X-C family) and CX3CR1 for me C-X3-C family. The present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, with an inhibitor of matrix metalloprotease (MMPs), i.e., the stromelysins, the collagenases, and the gelatinases, as well as aggrecanase; especially collagenase-1 (MMP-1), collagenase-2 (MMP-8), collagenase-3 (MMP-13), stromelysin-1 (MMP-3), stromelysin-2 (MMP-10), and stromelysin-3 (MMP-1 1) and MMP-9 and MMP-1 2, including agents such as doxycycline. The present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and a leukotriene biosynthesis inhibitor, 5-lipoxygenase (5-LO) inhibitor or 5-lipoxygenase activating protein (FLAP) antagonist such as; zileuton; ABT-761; fenleuton; tepoxalin; Abbott-79175: Abbott-85761; a N-(5-substituted)-thiophene-2-alkylsulfonamide; 2,6-di-tert-butylphenolhydrazones; a methoxytetrahydropyrans such as Zeneca ZD-2138; the compound SB-210661; a pyridinylsubstituted 2-cyanonaphthalene compound such as L-739,010; a 2-cyanoquinoline compound such as L-746,530; or an indole or quinoline compound such as MK-591, MK-886, and The present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and a receptor antagonist for leukotrienes (LT) B4, LTC4, LTD4, and LTE4. selected from the group consisting of the phenothiazin-3-ls such as L-65 1,392; amidino compounds such as CGS-25019c; benzoxalamines such as ontazolast; benzenecarboximidamides such as BEL 284/260; and compounds such as zafirlukast, ablukast, montelukast, pranlukast, verlukasl (MK-679), 12525, Ro-245913, iralukast (CGP 45715A), and BAY x 7195. The present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and a phosphodiesterase (PDE) The present inv entioa fivtfucr relates to the combination of a compound of the invention, or apiumaceaticalry aoccptaMe cdtlbereoC andalnilaaiiiictypclieoqifcir antagonist such as cetirizine, loratadine, desloratadine, fexofenadine, acrivastine, terfenadine, astemizole, azelastine, levocabastine, chlorpheniramine, promethazine, cyclizine, or mizolastine; applied orally, topically or parenterally. The present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and a proton pump inhibitor (such as omeprazole) or a gastroprotective histamine type 2 receptor antagonist. The present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and an antagonist of the histamine type 4 receptor. The present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and an alpha-l/alpha-2 adrenoceptor agonist vasoconstrictor sympathomimetic agent, such as propylhexedrine, phenylephrine, phenylpropanolamine, ephedrine, pseudoephedrine, naphazoline hydrochloride, oxymetazoline hydrochloride, tetrahydrozoline hydrochloride, xylometazoUne hydrochloride, tramazoline hydrochloride or ethyhiorepinephrine hydrochloride. The present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and an anticholinergic agents including muscarinic receptor (Ml, M2, and M3) antagonist such as atropine, hyoscine, glycopynrolate, ipratropium bromide, tiotropium bromide, oxitropium bromide, pirenzepine or telenzepine. The present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and a beta-adrenoceptor agonist (including beta receptor subtypes 1-4) such as isoprenaline, salbutamol, formoterol, salmeterol, terbutaline, orciprenaline, bitolterol mesylate, or pirbuterol, or a cbiral enantiomer thereof. The present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and a chromone, such as sodium cromog^ycate or nedocromil wxtimn, The present invention still farther icfatef IP the con dbimtion of a. ccmymiiid of the invention, or a pharmaceutically acceptable saft thereof, with a ghicocorticoid, such as flnni$o|i«te propionate, ciclesomde or nxmetnoDe fhroate. The present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, with an agent that modulates a nuclear hormone receptor such as PPARs. The present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, together with an immunoglobulin (Ig) or Ig preparation or an antagonist or antibody modulating Ig function such as anti-IgE (for example omalizumab). The present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and another systemic or topicallyapplied anti-inflammatory agent, such as thalidomide or a derivative thereof, a retinoid, dithranol or calcipotriol. The present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and combinations of aminosalicylates and sulfapyridine such as sulfasalazine, mesalazine, balsalazide, and olsalazine; and imntunomodulatory agents such as the thiopurines, and corticosteroids such as budesonide. The present invention farther relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, together with an antibacterial ags nt such as a penicillin derivative, a tetracycline, a macrolide, a beta-lactam, a fluoroqumoloae, metronidazole, an inhaled aminoglycoside; an antiviral agent including acyclovir, famcidovir, valaciclovir, ganciclovir, cidofovir, amantadine, rimantadine, ribavirin, zanamavir and oseltamavir; a protease inhibitor such as indinavir, nelfinavir, ritonavir, and saquinavir, a nucleoside reverse transcriptase inhibitor such as didanosine, lamivudine, stavudine, zalcitabine or zidovudine; or a non-nucleoside reverse transcriptase inhibitor such as nevirapine or efavirenz. The present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and a cardiovascular agent such as a calcium channel blocker, a beta-adrenoceptor blocker, an angiotensin-converting enzyme (ACE) inhibitor, an angiotcnsin-2 receptor antagonist; a lipid lowering agent such as a statin or a fibn^ a nvdidatar ofblood oca moiplidbg^ anticoagulant such as a platelet aggregation inhibitor. The present invention farther relates to the combination of a confound of the invention, or a pharmaceotkally acceptable salt thereof, and a QSTS agent such as an antidepressant (such as sertraline), an anti-Parkinsonian drug (such as deprenyl, L-dopa, ropinirole, pramipexole, a MAOB inhibitor such as selegine and rasagiline, a comP inhibitor such as tasmar, an A-2 inhibitor, a dopamine reuptake inhibitor, an NMDA antagonist, a nicotine agonist, a dopamine agonist or an inhibitor of neuronal nitric oxide synthase), or an anti-Alzheimer's drug such as donepezil, rivastigmine, tacrine, a COX-2 inhibitor, propentofylline or metrifonate. The present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and an agent for the treatment of acute or chronic pain, such as a centrally or peripherally-acting analgesic (for example an opioid or derivative thereof), carbamazepine, phenytoin, sodium valproate, amitryptiline or other anti-depressant agent-s, paracetamol, or a non-steroidal anti-inflammatory agent. The present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, together with a parenterally or topically-applied (including inhaled) local anesthetic agent such as lignocaine or a derivative thereof A compound of the present invention, or a pharmaceutically acceptable salt thereof, can also be used in combination with an anti-osteoporosis agent including a hormonal agent such as raloxifene, or a biphosphonate such as alendronate. The present invention still further relates to the combination of a compound of Hie invention, or a pharmaceutically acceptable salt thereof, together with a: (i) tryptase inhibi tor, (ii) platelet activating factor (PAF) antagonist; (iii) interleukin converting enzyme (ICE) inhibitor, (iv) IMPDH inhibitor; (v) adhesion molecule inhibitors including VLA-4 antagonist; (vi) cathepsin; (vii) kinase inhibitor such as an inhibitor of tyrosine kinase (such as Btk, Itk, Jak3 or MAP, for example Gefitinib or Imatinib mesylate), a serine / threonine kinase (such as an inhibitor of a MAP kinase such as p38, JNK, protein kinase A, B or C, or IKK), or a kinase involved in cell cycle regulation (such as a cylin dependent kinase); (viii) glucose-6 phosphate dehydrogenase inhibitor, (ix) kinin-B.subl, - or B.subT -receptor t, fat cxMOfAc coVfrip"M; (xi) yanflritte oyidasp inhibitor, for n«f ic agent, for COMUMC pmuciicoo, beozbfomaronc; (xiii) growth honnone secretagogne; (xiv) transforming growth factor (TGFfJ); (xv) platelet-derived growth factor (PDGF), (xvi) fibroblast growth factor for example basic fibroblast growth factor (bFGF)i (XM) grannlocytejiiacpophage colony stimulating factor (GM-CSF); (xviii) capsaicin cream; (xix) ta&yIdnm"NK.subl. or NK.sub3. receptor antagonist such as NKP-608C, SB-233412 (tahietant) or D-4418; (xx) elastase inhibitor such as UT-77 or ZD-0892; (xxi) TNF-alpha converting enzyme inhibitor (TACE); (xxii) induced nitric oxide synthase (iNOS) inhibitor, (xxiii) chemoattractant receptorhomologous molecule expressed on TH2 cells, (such as a CRTH2 antagonist); (xxiv) inhibitor of P38; (xxv) agent modulating the function of Toll-like receptors (TLR), (xxvi) agent modulating the activity of purinergic receptors such as P2X7; or (xxvii) inhibitor of transcription factor activation such as NFkB, API, or STATS. A compound of the invention, or a pharmaceutically acceptable salt thereof, can also be used in combination with an existing therapeutic agent for the treatment of cancer, for example suitable agents include: (i) an antiproliferative/antineoplastic drug or a combination thereof, as used in medical oncology, such as an alkylating agent (for example cis-platin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulphan or a nitrosourea); an antimetabolite (for example an antifolate such as a fluoropyrimidine like 5-fluorouracil or tegafur, raltitrexed, methotrexate, cytosine arabinoside, hydroxyurea, gemcitabine or paclitaxel); an antitumour antibiotic (for example an anthracycline such as adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin or mithramycin); an antimitotic agent (for example a vinca alkaloid such as vincristine, vinblastine, vindesine or vinorelbine, or a taxoid such as taxol or taxotere); or a topoisomerase inhibitor (for example an epipodophyllotoxin such as etoposide, teniposide, amsacrine, topotecan or a camptothecin); (ii) a cytostatic agent such as an antioestrogen (for example tamoxifen, toremifene, raloxifene, droloxifene or iodoxyfene), an oestrogen receptor down regulator (for example fulvestrant), an antiandrogen (for example bicalutamide, flutamide, nilutamide or cyproterone acetate), a LHRH antagonist or LHRH agonist (for example goserelin, leuproreUn or buserelin), a progestogen (for example megestrol acetate), an aromatase inhibitor (for example as anastrozole, letrozole, vorazole or exemertane) or an inhibitor of 5oHceductase such as finastendd ••-«»• "u » i«»« "J^ (iii) an agent which inhibits cancer cell invasion (for cxao^fe a metalloproteiiiase inhibitor tilcp martt^a^ta^ nr am mtnhitor nf iimkma»» plagmtnnfyn acthijtor rtrffftrvr fenction); ^v) an mhibitor of powth factor fimctioo, for eauai^ile: a gnmAfi«^or antibody (ror example the anti-erbb2 antibody trastuzumab, or the anti-ert)bl antibody cetuximab [C225]), a famesyl transferase inhibitor, a tyrosine kinase inhibitor or a serine/threonine kinase mhibitor, an mhibitor of the epidermal growth factor family (for example an EGFR family tyrosine kinase inhibitor such as N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3- morpholmopropoxy)qumazoun-4-amine (gefitinib, AZD1839), N-(3-ethynylphenyl)-6,7- bis(2-memoxyemoxy)qiiinazoUn-4-arnine (erlotinib, OSI-774) or 6-acrylamido-N-(3-chloro- 4-fluorophenyl)-7^3-morphoMopropoxy)qumazolin-4-anime (CI1033)), an mhibitor of the platelet-derived growth factor family, or an inhibitor of the hepatocyte growth factor family; (v) an antiangiogenic agent such as one which inhibits the effects of vascular endothelial growth factor (for example the anti-vascular endothelial cell growth factor antibody bevacizumab, a compound disclosed in WO 97/22596, WO 97/30035, WO 97/32856 or WO 98/13354), or a compound that works by another mechanism (for example linomide, an inhibitor of integrin av|33 function or an angiostatin); (vi) a vascular damaging agent such as combretastatin A4, or a compound disclosed in WO 99/02166, WO 00/40529, WO 00/41669, WO 01/92224, WO 02/04434 or WO 02/08213; (vii) an agent used in antisense therapy, for example one directed to one of the targets listed above, such as ISIS 2503, an anti-ras antisense; (viii) an agent used in a gene therapy approach, for example approaches to replace aberrant genes such as aberrant p53 or aberrant BRCA1 or BRCA2, GDEPT (gene-directed enzyme pro-drug therapy) approaches such as those using cytosine deaminase, thymidine kinase or a bacterial nitroreductase enzyme and approaches to increase patient tolerance to chemotherapy or radiotherapy such as multi-drug resistance gene therapy; or (ix) an agent used in an immunotherapeutic approach, for example ex-vivo and in-vivo approaches to increase the immunogenicity of patient tumour cells, such as transfection w ith cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor, approaches to decrease T-cell anergy, approaches using transfected immune cells s uch as cytokine-transfected dendritic cells, approaches using cytokine-transfected tumour cell lines and approaches using ann-idiotypic In n. still fciflm aapcci, tfae piesmt aroraiMiB provides the osc of at cumpuuml of formula (I), or a phanuaceuticalry acceptable sate or sohratefltereoC as hexeinbefbte defined m the manufacture of a medicament for the tr which modulation ofCRTbl receptor activity beneficial. In the context of the present specification, the term "therapy" also includes "prophylaxis" unless there are specific indications to the contrary. The terms "therapeutic" and "therapeutically" should be construed accordingly. The invention still further provides a method of treating diseases mediated by PGD2 or its metabolites wherein the prostanoid binds to its receptor (especially CRTh2) receptor, which comprises administering to a patient a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, solvate or prodrug thereof, as hereinbefore defined. The invention also provides a method of treating an inflammatory disease, especially psoriasis, in a patient suffering from, or at risk of, said disease, which comprises administering to the patient a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined. For the above-mentioned therapeutic uses the dosage administered will, of course, vary with the compound employed, the mode of administration, the treatment desired and the disorder indicated. For the above-mentioned therapeutic uses the dosage administered will, of course, vary with the compound employed, the mode of administration, the treatment desired and the disorder indicated. The compound of formula (I), prodrags and pharmaceutically acceptable salts and solvates thereof may be used on their own but will generally be administered in the form of a pharmaceutical composition in which the formula (I) compound/salt/solvate (active ingredient) is in association with a pharmaceutically acceptable adjuvant, diluent or carrier. Depending on the mode of administration, the pharmaceutical composition will preferably comprise from 0.05 to 99 %w (per cent by weight), more preferably from 0.05 to 80 %w, still more preferably from 0.10 to 70 %w, and even more preferably from 0.10 to 50 %w, of active ingredient, all percentages by weight being based on total composition. The present invention also provides a pharmaceutical composition comprising a annex as herein Before dcfiMd, m association wifltapha Tire pharmaceutical compositor Radford airways or to the skin) in. the fawn ofsohitiDsiiqpemiaa Aerosols and dry powder fbnmdatiom; or qrrtemicrilyyc.g.byoialadnuai!!4udionintfacfb of tablets, capsules, syrups, powders or granules, or by parenteral administration in the form of solutions or suspensions, or by subcutaneous administration or by rectal administration in the form of suppositories or transdermally. Preferably the compound of the invention is administered orally. The invention will now be illustrated by the following non-limiting examples in which, unless stated otherwise: (i) when given, H NMR data is quoted in the form of delta values for major diagnostic protons, given in parts per million (ppm) relative to tetramethylsilane (TMS) as an internal standard; (ii) mass spectra (MS): generally only ions which indicate the parent mass are reported, and unless otherwise stated the mass ion quoted is the positive mass ion - (M+H)+; (iii) the title compounds of the examples and methods were named using the ACD/name and ACD/name batch (version 6.0) from Advanced Chemical Development Ihc, Canada; (iv) unless stated otherwise, reverse phase HPLC was conducted using a Symmetry, NovaPak or Ex-Terra reverse phase silica column; (v) solvents were dried with MgSO4 or Na2SO4 (vi) the following abbreviations are used: A mixture of sodium thiomethoxide (317 mg) and 5-bromo-2-fluorobenzotrifluoride (1 .0 g) in DMF (4 ml) was heated at 50 °C for 1 h then poured into water and extracted with isohexane. The organics were washed with brine, dried and concentrated ir. vacua to give the(Table Removed) n-BuLi (2.7 ml. 2.5M inhexane) was added dropwise to (he product of step a) and tri-isopropyl borate (1 .6ml) in THF at -78 °C. Stirred for 5 mm, then quenched with 2M HC1 (50ml) and extracted with diethyl ether (50 ml). The organic layer was washed with water, brine, dried (Na2SO4) and evaporated in vacua. The resulting solid was triturated with isohexane (100 ml), filtered and dried to give the product (0.83 g). NMR indicated a mixture of product, monomer and trimer of boronic acid, !H NMR CDC13: 5 8.03 (1H, d), 7.51 (1H, dd), 6.7 (1H, d), 4.71 (1H, q), 1.69 (3H, d) and c)4,4-tetramethyl-2-[4-methylthio)-3-(trifluoromethyl)phenyl]-lv3r2-dioxaborolane The product of step b) (0.25 g) was heated in dioxan (2 ml) with pinacol (2 equiv) for 3 h. The solution was treated with diethyl ether and water. The organic layer was separated, washed with brine, dried (Na2SC4) and concentrated in vacua. Yield 85 mg. 'H NMR CDC13: 8 8.03 (1H, d), 7.86 (1H, d), 7.31 (1H, d), 2.53 (3H, s) and 1.35 (12H, s). d) 2-iodo-4-trifluoromethyl)-pheBol 4-(trifluoromethyl)-phenol in anhydrous DMF (80 ml) was cooled to 0 °C. Nal (9.06 g) and chloroamine-T (16.1 g) was added portionwise and stirred at room temperature overnight Then diluted with 2M HC1 and extracted with ethylacetate. The organic phase was washed with sodium thiosulfate solution, dried (MgSO4) and concentatied in vacuo. The residue was purified by chromatography(silica, eluting with isohexanerethyl acetate) to give the sub-title compound as a yellow oil (13 g). MS: APCI (-ve): 287 (M-H) e) 1,1-Dimethylethyl (25)-2-[2-iodo-4-(trifluoromethyl)phenoxy]propanoate DIAD (2.9 ml) was added to the product of step e) (3.5 g), triphenyl phosphine (3 . 87 g) and tert-butyl (R)-(+) lactate (1.96 g) in THF (35 ml) at 0°C and stirred for 1 8 h. The solvent was evaporated in vacua md the residue purified by flash column chromatographv dhrting with petroleum Yield 'HNMRCDCb: 8 8.03 (had),731 (had),d.7 (lH.dX4.71 (lH,qX 1.69 (3H,d) The products of step e) (0.3 g), the product of step c) (230 mg), sodium carbonate (170 mg), Pd(dppf)Cl2 (50 mg), dioxan (10 ml) and methanol (1 ml) were heated at 90 °C for 24 h, then concentrated in vacuo. The residue was purified by flash column chromatography eluting with ethyl acetate:isohexane (2:8) to give the product (0.35 g), which was used directly without further characterisation. g)(25)-2-[[4f-(methylthio)-3'^-bis(trmuoromethyl)[l,l'-biphenyl]-2-yl]oxy]-propanoic acid The product of step f) (0.34 g) in dichloromethane (6 ml) and TFA (3 ml) was stirred for 2 h at room temperature, then concentrated in vacuo. The residue was diluted with dichloromethane, washed with water, dried (MgSCU) then concentrated in vacuo. The residue was then dissolved in acetonitrile (10 ml) and water (10 ml) and treated with oxone (0.6 g). The reaction mixture was stirred for 2 h, further oxone (0.6 g) was added and the reaction stirred for 2 days. The solution was washed with dichloromethane (x 3). The combined extracts were dried (Mugs) then concentrated in vacuum. Further purified by reverse phase HPLC, then trituration with dichloromethane and isoheaxne to give the title compound as a white solid (100 mg). MS: APCI (-ve): 455 (M-H) 1HNMRDMSO-D6:8 8.49 (1H, s), 8.31 (1H, d), 8.12 (1H, d), 7.84-7.76 (2H,m), 7.23 (1H, d), 5.13 (1H, q) and 1.46 (3H, d). Example 2 [[3', 5-Dichloro-4'-(methylsuIfonyO[l,r-biphenyl]-2-yl]oxy]acetic Acid A mixture of 5-cbloro-2-kxkpfaenol (4.75 g), 1,1-diiuediyfcdryl bromoacctate p. OS ml) and potassium carbonate (2.58 g) in acetonitrile (20 ml) was heated under reflux for 2 h. Water was added and the mixture was extracted with ether (three times). The organic extracts were dried (MgSO-O, evaporated and purified by chromatography (silica, petrol - ether as eluent) to give the sub-title compound (6.88 g). 1H NMR CDC13: 8 7.77 (1H, d), 7.45 (1H, dd), 6.61 (1H, d), 4.55 (2H, s), 1.48 (9H, s). b) 4-Bromo-2-chloro-l-(methylthio) benzene A mixture of 4-bromo-2-chloro-l-fluorobenzene (8.04 g) and sodium methylthiolate (3.05 g) in DMF (25 ml) was heated at 50 °C for 2.5 h. Water was added and the mixture was extracted with ether (three times). The organic extracts were washed with water (twice), dried (MgSC>4), and evaporated to give the sub-title compound (8.93 g). JH NMR CDC13:8 7.54 (1H, d), 7.34 (1H, dd), 7.02 (1H, dd), 2.47 (3H, s). c) |3-Chloro-4-(methylthio)pheByI] boronk acid Butyl lithium (1 5 ml, 1 .9M in hexanes) was added over 40 mm to a solution of the product from step b) (6.82 g) and triwropropylborate (8.0 ml) in THF (30 ml) at -78 °C and. stirred for a further 1 h. 2M HC1 (20 ml) was added, the mixture was warmed to 20 °C and. extracted with ether (three times). The organic extracts were dried (MgSO-O, evaporated and purified by chromatography (silica, petrol - ether as eluent) to give the sub-title compound (1.82 g). MS: ESI (-ve): 201 [M-H]' 100% d)l,l-Dimethylethyl[[3',5-dichloro-4l-(methylsulfonyl)[l,l'-biphenyl]-2-yl]oxy]acetate A mixture of the product of step a) (390 mg) and the product of step c) (239 mg), sodium carbonate (220 mg) and Pd(dppf)Cl2 (74 mg) in dioxan (5 ml) and methanol (3 ml) was heated at 100 °C for 24 h, then concentrated in vacua and dissolved in acetone added and stored fin: 2 days. The mixture was extracted with ether (three times) and me oigamc extracts were dried (Mugs), evaporated and purified by dirotnatography !H NMR CDC13: 8 8.18 (1H, d), 7.80 (1H, d), 7.70 (1H, dd), 7.34-7.31 (2H, m), 6.79 (1H, d) , 4.54 (2H, s), 3.30 (3H, s), 1.47 (9H, s). Further elution with ether gave 1,1-dimethylethyl [[3\5-dichloro-4Hmethylsulfinyl)[l,rbiphenyl]- 2-yl]oxy]acetate (35 mg) 'HNMR CDC13: 8 7.99 (1H, d), 7.82 (1H, d), 7.66 (1H, dd), 7.35-7.28 (2H, m), 6.79 (1H, d) , 4.53 (2H, s), 2.87 (2H, s), 1.47 (9H, s). e) [[3'^-Dichloro-4'-(methylsulfonyI)[l,l'-biphenyll-2-ylloxyl acetic acid A solution of the product from step d) (73 mg) in TFA (3 ml) was stirred for 2 h. Th e solvent was removed in vacua, water was added and the mixture was extracted with dichloromethane (three times). The organic extracts were dried (MgSO4), evaporated and triturated with ether to give the title compound (46 mg) as a white solid. M.p. 140-2 °C. MS: ESI (-Hve): 393 [M+NIL,] 100% 'H NMR DMSO-d6: 8 8.06 (1H, d), 8.02 (1H, d), 7.83 (1H, dd), 7.51 (1H, d), 7.46 (1H, dd), 7.13 (1H, d), 4.81 (3H, s), 3.41 (3H, s). Example 3 [[3Dichloro-4-(methylsalfiByI)[loll-biphenyl]-2-yqoxy]aceticacid A solution of the more polar product from Example 2 step d) (35 mg) in TFA (2 ml) was stirred for 24 h. The solvent was removed in vacua, the mixture was azeotroped with toluene and purified by chromatography (silica, CHaCk-MeOH-AcOH as eluent) to give the title compound (22 mg) as a white solid. MS: ESI (+ve): 359 [M+H]+100% JH NMR DMSO-d6: 8 7.86 (3H, s), 7.47 (1H, d), 7.43 (1H, dd), 7.11 (1H, d), 4.80 ( ) 1,1-Dimethylethyl (2S)-2-(4-chloro-2-iodophenoxy)propanoate DIAD (1.64 ml) was added to a solution of 5-chloro-2-iodophenol 1.76 g), triphenyl phosphine (2.17 g) and tert butyl (R) lactate (1.02 g) in THF (8 ml) at 0 °C and stirred °C for 18 h. The solvent was removed in vacua and the residue purified by (silica, ether as eluent) to give the sub-title compound (2.01 g). 1HNMRCDC13: 6 7.76 (1H, d), 7.21 (1H, dd), 6.61 (1H, d), 4.61 (1H, q), 1.65 (3H, b) 1,1-Dimethylethyl (25)-2-[[3'^-dichloro-4'-(methyIsulfonyO[l,l'-biphenyl]-2- yl]oxy]propanoate A mixture of the product of step a) (412 mg) and the product of Example 2 step c) (246 mg), palladium acetate (22 mg), trisort/totoluenephosphine (49 mg) and sodium carbonate (220 mg) in dioxane (5 ml) and methanol (3 ml) was heated at 100 °C for 12 h, then concentrated in vacua and dissolved in acetone (10 ml). A solution of oxone (2.0 g) in water and aq KzCOs (to keep the mixture at ca. pH 8) were added and stirred for 2 days. The mixture was extracted with ether (three times) and the organic extracts were dried (MgSO0, evaporated and purified by chromatography (silica, petrol - ether as eluent) to give the sub - title compound (319 mg). 'H NMR CDC13: 5 8.17 (IH, d), 7.86 (IH, d), 7.71 (IH, dd), 7.32-7.27 (2H, m), 6.78 (IH, d), 4.67 (IH, q), 3.31 (3H, s), 1.52 (3H, d), 1.44 (9H, s). c)(25>2-l[3',5-DichIoro-4'-(methylsulfonyl)[l,l'-biphenyl]-2-yl]oxy]propanoicacid The title compound was prepared by the method of Example 2 step e) using the product of step b). MS: ESI (+ve): 407 [M+NH4]+ 100% TH NMR DMSO-d6: 8 13.23 (IH, s), 8.07 (IH, d), 8.06 (IH, s), 7.87 (IH, dd), 7.52 (IH, d), 7.45 (IH, dd), 7,06 (IH, d), 5.03 (IH, q), 3.41 (3H, s\ 1.46 (3H, d). a)4-[(4-bromo-2,5-difluorophenyl)sulfonyl]-morpholine Morpholine (0.16 ml) was added to a stirred solution of 4-bromo-2,5-difluorobenzenesulfonyl chloride(0.18 g) in dichloromethane (6 ml) under nitrogen. The reaction mixture was stirred overnight and then quenched with water. The organic phase was dried (MgSO4) and concentrated in vacua to give the sub-title compound as a wb'te solid (200 mg). 1H NMR CDC13: 6 7.62 (IH, dd), 7.52 (IH, dd), 3.77-3.7 (4H, m) and 3.23-3.2 (4H, m). b) Benzyl 2-bromo-4-chlorophenyl ether Benzyl bromide (13.1 ml) was added to a stirred mixture of 2-bromo-4-chlorophenol (20.7 g) and potassium carbonate (27.6 g) in DMF (200 ml). After 72 h, the mixture was partitioned between diethylether and water, the organic layer washed with water, dried and the solvent evaporated under reduced pressure. The residue was purified by chromatography (silica, EtOAc/isohexane as eluent). to give the sub-title compound (18.1 g). 1H NMR CDC13: 5 7.55 (1H, s); 7.46-7.18 (6H, m) ; 6.84 (1H, d) ; 5.14 (2H, s) c) [2-(Benzyloxy)-5-chIorophenyl]boronic acid A solution of butyl lithium (1.6 M in hexane) (50 ml) was added dropwise to a stirred solution of the product from step a) (23 g) in diethylether (300 ml) at -70 °C. After 1 h a further 18 ml of butyl lithium was added, left for 0.75 h, then trimethylborate (10 ml) added and the mixture warmed to RT and left for 16 h. 2 M Hydrochloric acid (100 ml) was added, stirred for Ih then the organic layer separated and extracted with aqueous sodium hydroxide solution. The basic layer was acidified with 2 M hydrochloric acid solution, extracted with diethylether which was dried and evaporated under reduced pressure. The residue was triturated witii iso-hexane and filtered to give tbesub-tiik compound (10.8 g) 'H NMR CDCh: 6 7.82 (IH, d); 7.44-734 (6H, m); 6.90 (IH, d); 5.99 (2H, s); 5.12 (2H, s) d) H5Uor&plttBrlH4h)prim The sub-tide compound was prepared from fee productofscpb)(5gXpin»cool(2.7g) in anhydrous diethyl ether (200 ml). The reagents were stirred under nitrogen overnight. A further 1.2 g of pinacol and molecular seives were added and stirred overnight. The reacion mixture was washed with water, dried (MgSCU) and concentrated in vacua to give the subtitle compound (5.6 g). XH NMR DMSO-d6: S 7.27-7.64 (m, 7H), 6.85 (d, IH), 5.09 (s, 2H), 1.36 (s, 12H) e)4-Chloro-2-(4,4^,5-tetramethyl-l,3-dioxaboroIan-2-yl)phenol The product from step d) was dissolved in ethanol (100 ml) and treated with palladium on activated carbon (5%), the suspension was stirred for 30 min under hydrogen (1 bar). The mixture was then filtered, and the filtrate was concentrated in vacua to give the subtitle compound (4.2 g). : 8 7.76-7.79 (s, IH), 6.79-7.62 (m, 3H), 1.36 (s, 12H) f) U-Dimethylethyl 2-[4-Chloro-2-(4,4-tetramethyl-l-dioxaborolan-2- y!)phenoxy)-(ZS)-propanoate The subtitle compound was prepared by the method of Example 2 step a) using the product from step e) and tert-butyl (RM+) lactate. g) 2-(2-Borono-4-chloropheiioxyH2iS)-propanoic acid The subtitle compound was prepared by the method of Example 4 step a) using the product from step (f). Yield 2.5g. The crude material was carried forward to step h). h)(lS)-2-[4-chloro-2-[2,5-difluoro-4-(4-norpholiiiylsulfonyl)phenoxy]phenoxy]- propanoic acid The product of step g) (0.1 g), the product of step a) (0.15 g), tetrakis palladiumtriphenylphosphme (0), sodium carbonate (2M solution, 4 ml), ethanol (4 ml) and toluene (8 ml) were healed at 90 *Cftr 18 h. The reaction mixture was cooled to room temperature, men concentrated in vacuo and further purified by reverse phase HPLC to give the title compound (0.1 g). 'HNMRDMSOi6:88.17-15(lH,mX7.630H,tX7.4(2H,sX7.0(lH,sX436(had), 3.6 (4H, m), 3.11 (4H, s) and 1.3 (3H, d). Example 6 rf3t-Fluoro-4'-f(l-methvlethvnsulfonyl1-5-(trifluoromethvlMl.l>-biphenvll-2- vllorvlacetic acid a) 4-Bromo-2-fluorobenzenethiol Triphenylphosphine was added portionwise to a solution of 4-bromo-2- fluorobenzenesulfonyl chloride (8.44 g) in THF (30 ml) at 0 °C. After 15 min water was added and the colourless solution was stirred at 20 °C for 18 h. The solvent was removed in vacuo, the residues dissolved in DCM and extracted with 2M sodium hydroxide (twice). The aqueous layers were washed with DCM, combined, acidified (4M HC1) and extracted witii ethyl acetate (thrice). These organic extracts were dried (MgSCU) and evaporated to give the sub-title compound (5.89 g). MS: ESI (-ve): 206 [M-H]' 94% b)4-Bromo-2-fluoro-[(l-methylethyl)thio]benzene A mixture of the product from step a) (2.77 g), isopropyliodide (1.7 ml) and H^CO^ (2.0 g) in acetone (10 ml) was stirred for 3 h. Water was added and the mixture was extracted with ether (three times). The organic extracts were dried (MgSO4) and, evaporated and to give the sub-title compound (3.22 g). 'H NMR CDC13: 8 7.44-7.21 (3H, m), 3.41 (1H, heptet), 1.27 (6H, d). c) [3-ITBoro-4-iO-«etkyk*kyI)AioJpfce»yqboro«k acid The subtitle conyoand was iHcyaredtyte product of step b). MS: ESI (-ve): 213 [M-Hf 100% d) Methyl [2-bromo-4-(trifIuoromethyl)phenoiy]acetate The sub-title compound was prepared by the method of Example 2 step a) using methyl bromoacetate and 2-bromo-4-(trifluoromethyl)phenol. 1H NMR CDC13:8 7.82 (1H, d), 7.48 (1H, dd), 6.81 (1H, d), 3.77 (3H, s). e) Methyl [p'-fluoro^'-Kl-methylethyl^ulfonyll-S^trifluoromethyOl^l'-biphenyl]-!- yljoxy] acetate The sub-title compound was prepared by the method of Example 2 step d) using the products of step c) and step d). MS: ESI (4ve): 452 [M+NHJ 100% f)l[3'-Fluoro-4'-[(l-inethylethyl)sulfonyl]-5-(trinuoromethyl)[l,r-biphetiyl]-2- yl]oxy]acetic acid A sohition of me product from step e) (140 mg) in NaOH (0.35 ml, 1 M), THF (2 ml) and MeOH (1 ml) was stirred for 2 h. The solvent was removed in vacuo and the residue was washed with ether, acidified (2M HCI) and extracted with DCM (thrice). The organic extracts were dried (MgSC4), evaporated and crystallized from tsohexane - DCM to give the title compound (105 mg). Mr. 170-1 °C. MS: ESI (+vet): 438 [Manhood 100% (2H, s), 3.54 (1H, heptet), 1.25 (6H, d). Example 7 frS-Chloro-4>-fmethvlsulfonvlV3t-(trifluoromethvlMl.lt-biphenvn-2-vnoxvl-aceticacid ») Methyl (4-ehloro-2-todopferoxy)ac4te A mixture of 5-chloro-2-iodo|AcBol (4.95 §X methyl biomoacetate (1.85 ml) and potassium carbonate (2.79 g) in aceftonitrile (20 id) was heated aider icfikn for 2 LAq HCI was added and the mixture was extracted with ether (three times). The organic extracts were dried (MgSOO, evaporated and purified by chromatography (silica, petrol - ether as eluent) to give the sub-title compound (5.75 g). !H NMR CDC13: 5 7.77 (1H, d), 7.25 (1H, dd), 6.64 (1H, d), 4.68 (2H, s), 3.81 (3H, s). acetate The sub-title compound was prepared by the method of Example 2 step d) using the products from step a) and Example 1 step b). 1H NMR DMSO-d6: 6 11.69 (1H, s), 8.30-8.27 (2H, m), 8.15 (1H, d), 7.58 (1H, d), 7.50 (1H, dd), 7.19 (1H, d), 4.82 (3H, s). c)[[5-Chloro-4Mmethylsnlfonyl-3'-(trifliioromethyl)ll,lt-biphenyl]-2-yl]oxy]-acetic acid The sub-title compound was prepared by the method of Example 6 step f) using the product from step b). MS: EPCI (+ve): 407 [M+NRrf 100% 1H NMRDMSO-d6: 5 11.69 (IH, s), 8.33 (IH, d), 8.26 (IH, d), 8.15 (IH, dd), 7.57 (IH, 7.48 (IH, dd), 7.17 (IH, d), 4.82 (2H, s), 3.33 (3H, s). Example 8 If5-Fluoro-4'-fmethvlsulfonvlVa'-ftrifluoromethvlin .1 '-hiphenvll-2-vllnYvl-acetir. acid a) Ethyl (2-bromo-4-fluorophenoxy)acetate The sub-title compound was prepared by the method of Example 2 step a) using ttanao-4-flaorophenDl and ethyl bromoacetate. MS: ESI (4ve): 277 muff 100% acetate The sub-title compound was prepared by the method of Example 2 step d) (but in dioxane-ethanol) using the products from step a) and Example 1 step b). 'H NMR CDC13: 5 8.35 (IH, d), 8.17 (IH, d), 8.01 (IH, dd), 7.14-7.06 (2H, m), 6.90- (IH, d), 4.63 (2H, s),4.25 (2H, q), 3.23 (2H, s), 1.28 (3H, t). c) [[5-Fluoro-4'-(inethylsulfonyl)-3'-(trifluoromethyl)[l,r-biphenyl]-2-yl]oxy]aceticacid The title compound was prepared by the method of Example 6 step f) using the product from step b). MS: EPCI (+vet): 407 [M-Honshu 100% NMRDMSO-de: 5 8.35 (IH, d), 8.27 (IH, d), 8.17 (IH, dd), 7.40 (lH,dd), 7.28 (IH, d), 7.16 (IH, dd), 4.79 (2H, s), 3.32 (3H, s). Example 9 H4'-(EthvlsulfoavlV3'.5-bi8(trinuoromethvnH.r-biDheDvll-2-vl1 oxvlacetic acid a)4-Bromo-l-(ethylthio)-2-(trifluoromethyl)beiizeiie The sub-title compound was prepared by the method of Example 2 step b) using sodium ethylthiolate and 4-bromo-l-fluoro-2-(trifluoromethyl)benzene. 'H NMR CDC13: 8 7.76 (IH, d), 7.58 (IH, dd), 7.32 (IH, d), 2.96 (2H, q), 1.31 (3H, t). b) l-(Ethyhkio)-2-{t The sub-title compound was prepared by the method of Example 2 step c) using the product from step a) MS: ESI (-ve): 213 (M-Hp 100% c) Methyl [2-bromo-4-(trifluoromethyl)phenoxy] acetate The sub-title compound was prepared by the method of Example 2 step a) using methyl bromoacetate and 2-bromo-4-(trifhioromethyl)phenol. *H NMR CDCU: 8 7.82 (IH, d), 7.48 (IH, dd), 6.81 (IH, d), 3.77 (3H, s). d) Methyl [[4'-(ethylsulfonyl3'-bis(triflnoromethyI)loll '-biphenyl]-2-ylloxy]acetate The sub-title compound was prepared by the method of Example 2 step d) using the products from steps b) and c). MS: APCI (-ve): 469 [M-H]' 100% e)[[4*-(Etfaylsulfonyl)-3'^.bis(triiluoromethyl)[l,l1-biplaenyl]-2-yl]oxy]aceticacid The title compound was prepared by the method of Example 5 step f) using the product from step d). M.p. 174-5 °C. MS: ESI (-ve): 455 [M-H]' 100% 'H NMRDMSO-d6: 8 8.38 (1H, d), 8.24 (1H, d), 8.18 (1H, dd), 7.84-7.80 (2H, m), 7.33 (1H, d), 4.91 (2H, s), 3.41 (2H, q), 1.21 (3H, t). Example 10 (2^)-2-fr4'-nEthvIsulfonvlV3',5-bisarifluoromethvnria'-biDheDvll-2-vnoxvlDroDanoic acid a) 1,1-Dimethylethyl (25)- 2-[[4Xethylsulfonyl)-3'^-bis(trifluoroinethyl)[l,l'-biphenyl]- 2-yl]oxyJpropaiioale The sub-title compound was prepared by Ac method of Example 2 step d) using the products from step b) and Example 1 step b). MS: APd (-ve): 525 [M-HT100% b) (25 2-[[4'-{Ethylsulfonyl)-3-bis(trifluoromethyI)[l,ll-biphenyl]-2- yl]oxy]propanoic acid The sub-title compound was prepared by the method of Example 2 step e) using the product from step a). M.p. 124-6 °C. MS: ESI (-ve): 469 [M-H]' 100% ^NMRDMSO-de: 8 8.47 (1H, d), 8.26-8.19 (2H, m), 8.18 (1H, dd), 7.82 (1H, dd), 7.25 (1H, d), 5.20 (1H, q), 3.41 (2H, q),1.48 (3H, d), 1.21 (3H, t). Example 11 |[5-Chloro-4'-r4-morpholinvlsulfoDvlV3'-ftrinuoromethvn[l.r-biDhenvn-2-vlloivlicetic acid a) 4-[[4-Bromo-2-(trifIuoromethyI)phenyl]sulfonyl]morpholine Morpholine (1.1 ml) was added to a solution of [4-bromo-2- (trifluoromethyl)phenyl]sulfonyl chloride ( 2.03 g) in DCM (7 ml) at 0 °C and stirred at 20 °C for 16 h. Water was added and the mixture was extracted with DCM. The organic extracts were dried (MgSCU), evaporated and purified by chromatography (silica, petrol - ether as ducat) to give the sob-tide compound 2.10 jj. *H NMR CDC13: & 8.04 (1H, d), 7.97 (1H, d), 7.85 (1H, dd), 3.73 (4H, t), 3 23 (4H, t). morpholine A mixture of the product of step a) (450 mg) and [5-chloro-2- (phenylmemoxy)phenyl]boronic acid (351 mg), sodium carbonate (277 mg) and Pd(dppf)Cl2 (93 mg) in dioxan (3 ml) and methanol (0.5 ml) was heated at 85 °C for 16 h. Water was added and the mixture was extracted with ether (three times), the organic extracts were dried (MgSCU), evaporated and purified by chromatography (silica, petrol - ether as eluent) to give the sub-title compound (538 mg). M.p. 118-9°C. JH NMR CDC13: 8 8.13-8.04 (2H, m), 7.83 (1H, dd), 7.37-7.26 (7H, m), 7.04 (1H, d), 5.09 (2H, s), 3.74 (4H, t), 3.25 (4H, t). c) 4-[[5'-Chloro-2'-hydroxy-3-(trifluoromethyl)[l ,1 '-biphenyl]-4-yl]sulfonyI] morphoiine Boron tribromide (2.5 ml, 1 .0 M in DCM) was added to a solution of the product from step b) (1.16 g) in DCM (15 ml) at 0 °C. The solution was stirred for 15 min then quenched with water. The mixture was extracted with DCM (three times), the organic extracts were dried (MgSO4), evaporated and purified by chromatography (silica, petrol - ether as elueat) to give the sub-title compound (851 mg). MS: ESI (-ve): 420 [M-H]' 100% d) Ethyl [[5-chloro-4'-(4-morpholinylsulfonyl)-3'-(trifluoromethyl)[l,l '-biphenyl]-2- yl]oxy]acetate The sub-title compound was prepared by the method of Example 2 step a) using the product from steps c) and ethyl bromoacetate. MS: ESI (+ve): 508 [M+H]+ 100% yl]oxy]acetic acid The sub-tide compound was prepared by the mediod of Example 5 step f) using the product fiom step d),NLp. 208-9 °C. MS: ESI (-ve): 478 [M-fif 100% 'H NMR DMSOd6: 5 831 (1H, d), 8.11 (2H, d), 7.56 (IB, d), 7.41 (1H. ddX 7.16 (1H, 4.80 (2H, s), 3.66 (4H, t\ 3, 19 (4H, t). Example 12 (25V2-rr5-Chioro-4>-(4-morDholinvIsuIfonviV3>-(trifluoromethvnri,l'-biDhenvll-2- vlloxvlpropanoic acid a) 1,1-Dimethylethyl (lS)-2-[[5-chloro-4'-(4-morpholinylsulfonyl)-3'- (trifluoromethyl)[l,l'-biphenyl]-2-yl]oxy]propanoate The sub-title compound was prepared by the method of Example 4 step a) using the product from Example 11 step c). 'H NMR CDC13: 8 8.27 (1H, d), 8.14 (1H, d), 7.93 (1H, dd), 7.35 (1H, d), 7.30 (1H, dd), (1H, d), 4.70 (1H, q), 3.76 (4H, t), 3.28 (4H, t), 1.52 (3H, d), 1.42 (9H, s). yl]oxy]propanoic acid The sub-titie compound was prepared by the method of Example 2 step e) using trie product from step a). M.p. 148-9 °C. MS: ESI (-ve): 492 [M-H]' 100% !HNMRDMSO-d6: 8 13.26 (1H, s), 8.44 (1H, d), 8.12 (2H, s), 7.58 (1H, d), 7.47 (lH,dd), 7.08 (1H, d), 5.07 (1H, q), 3.66 (4H, t), 3.20 (4H, t), 1.45 (3H, d). Example 13 ffS-Chloro-fl-pvrroIidinvIcarbonvn-S'-ftrifluoromethvnfl.l'-biDhenvII-Z-vnoxvlacetic acid a) 4-Bnm»o-2-{trilhioroinethyI)- beanie add A mixture of l-bromo-4-fluoro-3-(trifluoromethyl)benzene (5.02 g) and potassium cyanide (1.38 g) in DMSO (20 ml) was heated at 80 °C for 14 h. Water was added and the mixture was extracted ether, the organic extracts were dried (MgSO/O and evaporated to give a brown oil. This was dissolved in DMSO (10 ml) and 4 M NaOH (10 ml) and heated at 100 °C for 16 h. 2 M Hcl (20 ml) was added and the mixture was extracted with DCM (three times), the organic extracts were dried (Mugs,), evaporated and punned by chromatography (silica, CHaCk-MeOH-AcOH as eluent) to give the sub-title compound (1.99 g). MS: ESI (-ve): 268 [M-H]' 100%. b) l-[4-Bromo-2-(trifluoromethyI)benzoyl pyrrolidine EDCI (1.70 g) was added to a solution of the product from step a) (1.97 g), pyrrolidine (1.2 ml) and DMAP (1.43 g) in DCM (10 ml) and THF (2 ml) and the resultant solution was stirred for 16 h. Aq HC1 was added and the mixture was extracted with DCM (three times), the organic extracts were dried (MgSO4), evaporated and purified by chromatography (silica, petrol - ether as eluent) to give the sub-title compound (616 mg). 'H NMR CDa3: 8 8.27 (1H, d), 7.93 (1H, d), 7.74 (1H, dd), 7.25 (1H, d), 3.64 (2H, t), 3.11 (2H, t), 1.98 (2H, hex), 1.88 (2H, hex). c)l-[[5'-CUoro-2'Kphenylmethoxy)-3-(triflaoromethyl)[l,l'-bipheiiyl]-4-yl]carbonyl]- pyrrolidine The sub-title compound was prepared by the method of Example 1 1 step b) using the product of step b) and [5-cMoro-2-(phenylmethoxy)phenyl]boronic acid. M.p. 143-4 °C. MS: ESI (+ve): 460 [M+Hf 100% d) l-[[5'-Chloro-2'-hydrory-3-(trifluoroinethyl)[l,l'-biphenyl]-4-yllcarbonyI]pyrrolidine The sub-title compound was prepared by the method of Example 1 1 step c) using the product of step c). M4. 220-1 °C. MS: ESI (-ve): 368 [M-H] 100%. e) Ethyl nS-cMMQ-jij 1 1 ifclfajkjt MjfraHteilfcm alkyl)U4t-bipheyq-2- yl]oxy]-acetate The sub-title compound was prepared by the method of Example 2 step a) using the product from steps d) and ethyl bromoacetate. 'H NMR CDC13: 8 7.92 (1H, s), 7.81 (1H, dd), 7.41 (1H, d), 7.33-7.28 (2H, m), 6.82 (1H, d), 4.61 (2H, s) 4.24 (2H, q), 3.68 (2H, t), 3.20 (2H, t), 1.98 (2H, hex), 1.90 (2H, hex), 1.26 (3H, t)- f)[l5-Chloro-4'-(l-pyrrolidinyIcarbonyl)-3f-(trifluoromethyl)[l,l'-biphenyl]-2-yl]oxy]- acetic acid The title compound was prepared by the method of Example 5 step f) using the product from step e). M.p. 197-8 °C. MS: ESI (-ve): 426 [M-H]' 100% JH NMR DMSO-D6: 8 8.09 (1H, s), 8.01 (1H, d), 7.51 (1H, d), 7.41 (1H, d), 7.32 (lH,d d), 6.97 (1H, d), 4.42 (2H, s), 3.47 (2H, t), 3.10 (2H, t\ 1.93-1.78 (4H, m). Example 14 (ISVZ-HS-Chloro-d-PvrrolidinvlcarfaonvlVaWtrinuoromethvnn.l'-biDhenvn-Zvlloxy] propanoic acid a)l,l-Dimethylethyl(lS2-[[5-Chloro-41-(l-pyiTolidinylcarbonyl)-3'-(trinuoromethyl- [l,l'-biphenyl]-2-yl]oxy] propanoate The sub-title compound was prepared by the method of Example 4 step a) using the product from Example 13 step d). 1H NMR CDC13:S 8.03 (IH, sX 7.80 (IH, do 7.40 (IH, did), 7.31 (IH, dX 726-7.24 (IH, m), 6.77 (IH, d), 4.64 (IH, ax 3.68 (2H, tX 3J20 (2H, tX 1.99 (2H, faocX 1-90 (2H, hexX 1.49 (3H, d),L41(9H,s). yljoxy] propanoic add The sub-title compound was prepared by the method of Example 2 step e) using the product from step a). M.p. 164-5 °C. MS: ESI (-ve): 440 [M-H]' 100% 'H NMR DMSO-d6: 8 13.26 (IH, s), 8.44 (IH, d), 8.12 (2H, s), 7.58 (IH, d), 7.47 (lH,dd), 7.08 (IH, d), 5.07 (IH, q), 3.66 (4H, t), 3.20 (4H, t), 1.45 (3H, d). Example 15 [[S-Chloro-rethvlsulfopvIVS'-arifluoromethvnua'-bipheavn-l-viloxvlaceticacid a) Methyl [[5-chkra-(ethylsuIfonyl)-3'-trinuororaethyI) [l, r-bipheiiyl]-2- yl]oxy]acetate The sub-title compound was prepared by the method of Example 2 step d) using the products from Example 7 step a) and Example 9 step b). MS: APCI (-ve): 435 [M-H]' 100% b)[[5-Chloro-4t-(ethylsulfonyl3'-(triflttoromethyI)[l,l'-biphenyl]-2--yellowy]aceticacid The title was prepared by the method of Example 6 step f) using the product from step MS: ESI (-ve): 421 [M-H]' 100% 'HNMRDMSO-De: 6 8.35 (1H, d), 8.21 (1H, d), 8.15 (1H, dd), 7.58 (1H, d), 7.48 (1H, dd), 7.17 (1H, d), 4.82 (2H, s) 3.42 (2H, q), 121 (3H, t). Example 16 vIloTvlnronanoic acid Methyl (IS)-2-[[5-chloro4'-(methylsulfonylH3'-trifluoromethyl)-[l,l'-biphenyl]-2- yl]oxy]propanoate The sub-title compound was prepared by the method of Example 2 step d) using the products from Example 4 step b) and Example 1 step b). Extensive saponification occurred during this reaction and the product was re-esterified using trimethylsilyldiazomethane in methanol. MS: APCI (-ve): 435 [M-H]' 100% (2S)-2-l[5-Cailoro4HmethyIsulfoiiy!H3'-trifluoroiiiethyl)-[l,lt-biphenyl]-2- yi]oxy]propanoic acid The sub-title compound was prepared by the method of Example 6 step f) using the product from step a). M.p. 77-9 °C MS: ESI (-ve): 421 [M-H]' 100% lHNMRDMSO-d6) 8 8.48 (s, IH), 8.28 (d, IH), 8.18 (d, IH), 7.58 (s, IH), 7.47 (d, IH), 7.09 (d, IH), 5.06 (q, IH), 3.40 (s, 3H), 1.45 (d, 3H) Example 17 (2V2-fr5-Chloro-3'-fluoro-4t-(methvlsuifonvRri.l'-biDhenvll-2-ylloxv]propanoicacid a) l3-Ftaonv4-(meAyltW)pkaiylHorokdd The sub-tide compound was prepared by fee method of Example I step c) using the product of step b). MS: ESI (-ve): 185 [M-H]' 100% b) 1,1-Dimethylethyl (25)- 2-[[5-Chloro-3'-nuoro-4'-(methyIsulfonyl)[l,l'-biphenjl]-2- yl]oxy]propanoate The sub-title compound was prepared by the method of Example 2 step d) using the products from step a) and Example 4 step a). 'H NMRDMSO-d6: 8 7.91 (IH, t), 7.82 (IH, dd), 7.73 (IH, dd), 7.52 (IH, d), 7.47 (IH, dd), 7.03 (IH, d), 4.99 (IH, q), 3.38 (3H, s), 1.44 (3H, d), 1.38 (9H, s). c)(252-[[5-Chloro-3'-fluoro-4'-(methylsulfonyI)[l,lt-biphenyI]-2-yl]oxy]propaiioic acid The sub-title compound was prepared by the method of Example 2 step e) using the product from step a). M.p. 190-2 °C. MS: ESI (-ve): 371 [M-H]" 100% 'H NMR DMSO-d6: 5 7.92-7.82 (2H, m), 7.74 (lH,dd), 7.50 (1H, d), 7.46 (1H, dd), 7.05 (1H, d), 5.02 (1H, q), 3.38 (3H, s), 1.46 (3H, d). Example 18 [f3',5-dichloro-4Wl-DvrrolidiDvlcarbonvnHJ'-biDhenvl1-2-vlloxv1-aceticacid a) l-(4-bromo-2-chlorobenzoyl)-pyrrolidine Oxalyl chloride (0.56 ml) was added to a stirred suspension of 4-bromo-2-chlorobenzoic acid (0.5 g) in dichloromethane (10 ml). DMF (1 drop was added) and stirred for 1 h, then evaporated in vacua. The product was dissolved in DCM (10 ml), triethylarnine (0.21 ml) was added, followed by pyrroli£ne(07mQidstin7Bdoveciii0it WaSor was added and the organic layer separated, then washed with 1MHQ, dried (Mugs) and evaporated in vacua. Yield 0.6 g MS: ESI (-vc): 249 (M-H) b)l-[(3,5'-dichloro-2'-methoxy[l,l'-biphenyl]-4-yl)carbonyl]-pyrroIidine The product of step a) (0.6 g), 4-chloro-2-methoxy boronic acid (0.69 g), toluene (10 ml), ethanol (4 ml) and 2M NaaCOa (2 ml) were charged to a flask and stirred. Tetrakistriphenylphospine palladium (0) (0.09 g) was added and the mixture stirred at reflux forl6h. The mixture was concentrated in vacua. The residue was purified by flash column chromatography eluting with isohexane:ethyl acetate (6:4) to give the sub-title c) l-[(3j5f-dichloro-2'-hydroxy [1, 1 '-biphenyl]-4-yl) carbonyl]-pyramiding The product from step b) (0.6 g) was dissolved in DCM (20 ml) and treated with boron tribromide (7 ml) and stirred for 1 h. Ice was added and a solid formed, which was d) [[3'-dichIoro-4'-(l-PyrroUd'nylcarbonyl) [l, l’-biphenyI]-2-yl]oxy]-aceticacid The product from step c) (180 mg), tert-butyl bromoacetate (0.07 ml), potassium carbonate (0.1 g) and DMF (10 ml) were charged to a flask and stirred for 16 h. Water was added and then washed with ethyl acetate. The organic extracts were dried (MgSO4) and evaporated in vacua. The residue was purified by flash column chromatognphy eluting with isohexane:ethyl acetate (8:2). The sub-title compound was dissolved in DCM (8 ml) and TFA (2 ml) was added, stirred for 1 h, then concentrated in vacua. Trituration with a mixture of ether and isohexane gave a solid, which was further purified by reverse phase HPLC to give the title compound Yield (48 mg) 'HNMRDMSO-De: 8 7.81 (1H, s), 7.64 (1H, d), 7.42-7.35 (3H, m), 7.02 (1H, d), 4.6 (2H, s), 3.58-3.01 (6H, m) and 1.86 (2H, d). MS: APCI (-vet): 392 (M-B) Enunplel9 add a) 4-(4-bromo-2-chIorobenzoyl)-morph line The sub-title compound was prepared by the method of example 18 part a) using morpholine MS: ESI (-vet): 306 (M-H) b) 4-[(3,5l-dichloro-2l-hydroxy[loll '-biphenyl]-4-yl)carboiiyl]-morph line The sub-title compound was prepared by the methods of example 18 step b) and c) using the product from step a) and 4-chloro-2-methoxy moronic acid. MS: ESI (-ve): 351 (M-H) c) l[3'-dicliloro-4'-(4-inorpholinylcarboiiyl)[14'-bipheiiyll-2-yIloxy]-acetk acid The title compound was prepared by the method of example 18 step d) using the product of step b). 1HNMRDMSO-D6: 8 7.81 (1H, s), 7.67 (1H, d), 7.73-7.30 (3H, m), 7.04 (1H, d), 4.64 (2H, s), 3.72-3.50 (6H, m) and 3.22 (2H, t). MS: APCI (-vet): 408 (M-H) Example 20 [[4'-a-azetidinvlcarboDvlV3t.5-dichorori.r-biphenvll-2-vlloxv1-aceticacid a) !- 4-broino-2-cWorobeiizoyI)- The sub-tide compound was prepared by the method of example 18 pant a) using azetidme bydrockloride MS: ESI (-ve): 273 (M-H) b)l-[(dichloro-2'-methoxy[loll-biphenyl]-4-yl)carbonyl]-astatine The sub-title compound was prepared by the method of example 18 steps b) and c) using the product from step a) and 4-chloro-2-methoxy moronic acid. MS: ESI (+ve): 322 (M+H) c) [-(l-azetidmylcarbonylS'-dichloroll'-biphenyll-Z-ylloxyl-aceilcacid The title compound was prepared by the method of example 18 step d) using the product of step b). 'HNMRDMSO-De: 6 7.82 (1H, s), 7.7 (1H, d), 7.43 (1H, d), 7.38-7.29 (2H, m), 6.93 (1H, d), 4.36 (2H, s), 4.16 (2H, t), 3.96 (2H, t) and 2.3 (2H, q). MS: APCI (-ve): 378 (M-H) Example 21 [[3'5-dichloro-4'-[f(lR.6tSV2.6-dimethvl-l-Dip€ridinvllcarbonvll 11,1 '-biPhenvll-2- ylloxvl-acetic acid a) 3,5'-dichloro-2'-methoxy-[l,l'-biphenyl]-4-carborylic acid 4-bromo-2-chlorobenzoic acid (0.4 g), 5-chloro-2-methoxybenzoic acid (0.4 g), Pd(dppf)Cli (0.12 g), sodium carbonate (0.9 g), dioxan (15 ml) and methanol (5 ml) were charged to a flask and heated at reflux for 16 h. Cooled to room temp and filtered (hyflo). The filtrate was concentrated in vacua, then dissolved in ethyl actetate. The suspension was made basic by addition of dilute NaOKL The aqueous layer was separated and acidified using 2M HC1, extracted with EtOAc, dried (MgSO,) and cn^xMteddi wawtoghre thesaiKtitJe compound Yield 0.4 g !H NMR DMSOD6: 5 1337 (1H, s). 7.86 (1H. m\ 744 (1H, s), 7.41-7.38 (3H, m), 72 b)(2J?,65l-[(3'-dichIoro-2t-methoxy[l,lt-biphenyl]-4-yl)carbonyI]-2,6- dimethylpiperidine The sub-title compound was prepared by the method of example 1 8 step a) using the product of step a) and 2,6-dimethyl cis-piperazine. MS:ESI(+ve):393(M+H) c)(2JR,65)-l-[(3'-dichloro-2'-hydroxy[loll'-biphenyl]-4-yl)carbonyl]-2,6-dimethyI piperidine The sub-title compound was prepared by the method of example 18 step c) using the product of step b). MS: ESI (+ve): 378 (M+H) yl]oxy]-acetic acid The title compound was prepared by the method of example 18 step d) using the product of step c). *H NMR DMSO-D6: 8 7.78 (1H, dd), 7.64-7.57 (1H, m), 7.43-7.3 (3H, m), 7.1-7.02 (1H, m), 4.97 (2H, s), and 1.96-1.04 (14H, m). MS: APCI (-ve): 436 (M-H) Example 22 f[3'.5-dichloro-4'-rf2-methvI-l-DvrrolidinvncarbonvnHJ'-biphenvll-2-vnoxv1-acetic acid a) l-tQlkhloro-r-mrthorytU'-biphcjiyq 4 yOcarbonZHDetfayi-pyrroBdhie Thesub-tittecoinpopndwasjptqMedbytfaeincdiodofc!xan 18 step a) using the product of step couple 21 step a) and 2-mdfapynotidine. MS: ESI (+ve): 364 (MHz) b) l-[(3,5'-dichloro-2'-hydroxy[l,l'-biphenyl]-4-yOcarbonyl]-2-methyl-pyrroIidme The sub-title compound was prepared by the method of example 18 step c) using the product of step a). MS: ESI (+ve): 350 (M+H) c) [[3',5-dichIoro-4'-[(2-methyl-l-pyrrolidinyI)carbonyl][l,l'-biphenyl]-2-yl]oxy]- The title compound was prepared by the method of example 18 step d) using the product of step b). JH NMR DMSO-D6: 8 7.73 (1H, s), 7.6 (1H, d), 7.42-7.35 (3H, m), 7.06 (1H, d), 4.68 s), 4.2-4.13 (1H, m), 3.24-2.82 (2H, m, + DMSO), 2.17-1.51 (4H, m) 1.23 (3H, d) and [[3'.5-dichloro-4'42-isoxazoUdinvlcarbonvmi.l '-bipheavll-l-vlloxvl-acetic acid a)2-[(3'-dichIoro-2'-methoiy[l,r-biphenyl]-4-yI)carbonyl]-isoxazolidine The sub-title compound was prepared by the method of example 21 step b) using the product of example 21 step a) and isoxazolidine. MS: ESI (+ve): 352 (M+H) The sub-tide compound was prepared by me method of example 18 port c) using the product of step a). MS: ESI (+ve): 338 (M+H) c) rfS'S-dichloro'-ll-isoxaTOlidinvlcarbonvrtn.l'-biphenvll-l-vnoxvl-acetic acid The title compound was prepared by the method of example 18 step d) using the product of step b). !H NMR DMSO-D6: 8 7.84 (IH, s), 7.62 (IH, dd), 7.42 (IH, d), 7.38-7.29 (2H, m), 6.93 (IH, d), 4.32 (2H, s), 3.93 (2H, t), 3.7 (2H, t, broad) and 2.39-2.22 (2H, m). MS: APCI (4-ve): 396 (M+H) Example 24 [fS-chloro-S'-fluoro'-d-DvrrolidinvlcarbonvDfl.l'-biphenyll-vnoxvl-aceticacid a) l-(4-bromo-2-fluorobenzoyl)-pyrroIidine The sub-title compound was prepared by the method of example 18 step a) using 4- bromo-2-fluoro-benzoic acid andpyrrolidine. b) l-[(5'-chloro-3-fluoro-2 '-metonym [1, 1 '-biphenyl]-4-yI) carbonyl]-pyrrolidine The sub-title compound was prepared by the method of example 18 step b) using the product from step a) and 4-chloro-2-methoxy moronic acid. MS:ESI(-ve):333(M+H) c)l-[(5'-chIoro-3-fluoro-2'-hydroiy[l,r-biphenyl]-4-yI)carbonyl]-pvrrolidine The sub-title compound was prepared by the method of example 1 8 step c) using the product of step b). MS: ESI (+ve): 320 (M+H) ethyl ester The product of step c) (0.11 g) was dissolved in DMF (5 ml), eftyferamoacetate (0.04 ml) and potassium cariwnate (0.1 g) woe added. TJie reaction mixture was stincd for 16 hat RT. Water and ethyl acetate were added. The organic layer was removed, dried (MgSO-O and evaporated in vacua. The residue was purified by flash column chromatography eluting with isohexane:ethyl acetate (1 :1) to give the sub-tiltie compound. Yield 0.12g. MS: ESI (+ve): 406 (M+H) eHf5-chloro-3'-fluoro-4f-('l-PvrrolidktvlcarbonvRfl.l>-biDhenvn-2-vi]oryl-aceticacid The title compound was prepared by the method of example 6 step f) using the product of step d). ^NMRDMSO-De: 8 13.12 (1H, s), 7.6-7.4 (5H, m), 7.08 (1H, d), 4.8 (2H, s), 3.48-3.46 (2H, m), 3.38-3.13 (2H, m), 1.91-1.84 (4H, m). MS: APCI (-ve): 376 (M-H) Example 25 (25V2-f[5-chloro-3'-fluoro-4'-(l-DvrroUdiDvlcarbonvnH.r-biDhepvll-2-vnorvlpropanoic acid dimethylethyl ester, propanoic acid The sub-title compound was prepared by the method of example 1 step e) using the product of example 24 step c) MS: ESI (+ve): 448 (M+H) propanoic add The product of step a) (033 g) was dissohnedindlciikxamediane (6 ml) andTFA (1.5 ml) was added, the solution was stirred for 2 hours, then concentrated in vacua, diluted with 1M NaOH and ethyl acetate. The aqueous layer was separated and acidified using 2M HC1, then extracted with ethyl acetate (x 2). The organic layers were dried (Mugs/ and evaporated in vacua to give the title compound. Yield 0.18 g. 'HNMRDMSO-De: 6 7.67-7.44 (5H, m), 7.07 (1H, d), 5.03 (1H, q), 3.58 (2H, t), 3.25 (2H, t), 2.02-1.83 (4H, m), 1.5 (3H, d). MS: APCI (-ve): 390 (M-H) f[3'-methvl-4'-(1-piperidinvlcarbonvlV5-(trifluorometfavr)ri.l'-biphenvn-2- a) [2-borono-4-(triflaoromethyl)peony]-acetic acid, 1,1-dimethylethyl ester To a flask, purged with nitrogen, was charged 6ty(dibenylideneacetone)palladium(0) (1.4 g), tricyclohexylphosphine (0.57 g), potassium acetate (4.14 g), [2-bromo-4- (trifluoromethyl)phenoxy]-acetk acid. 1,1-dimethylethyl ester [WO2004089885] (10 Boxanc(TOmOandbis(PtMO)fato)diboron(76g). The unlove was heated to 100 "C for 3 hours, cooled and then filtered before water (50 ml) wac added to me filtrates which were stirred overnight at room temperature. The mixture was poured into water (300 ml), extracted witti ethyiacetate, washed wife brine, dried (MgSO«) and ccoccotrated in vocw to grve crude material. Purification using flash column chromatography (eraent 10% etfaylacetate/hexane mcreasing to 20% ethylacetate/hexane) gave the sub-title compound as a solid (4.1 g). 1H NMR DMSO-d6: 6 8.03 (2H, s), 7.91 (1H, d), 7.76 (1H, t), 7.13 (1H, d), 4.83 (2H, s), 1.47 (9H, s). b) l-(4-bromo-2-methyIbenzoyl)-piper dine The sub-title compound was prepared by the method of example 18 step a) using 4- bromo-2-methyl benzoic acid and piper dine. MS: ESI (+vet): 282 (M+H) c) [[3'-methyl-4'-(l-piperidinylcarbonyl)-5-trinuoromethyO [l, l’-biphenyI]-2-yl]oxy]- acetic acid The title compound was prepared by the method of example 21 step a) using the products of step a) and step b). 1H NMR DMSO-D6: b 7.67-(lH, d), 7.6 (IH, s), 7.45-7.41 (2H, m), 7.19-7.13 (2H, m), 4.72 (2H, s), 3.65-3.6 (2H, m), 3.17 (2H, t), 2.25 (3H, s), 1.62-1.39 (6H, m). MS: APCI (-ve): 420 (M-H) Example 27 [fa'-tnethvM'-ri-DvrrolidinvlcarbonvllVS-ftrifluoromethvnfl.l'-biDhenvIl-Z-vlloxvlacetic acid a) M4-bromc-2-mediyIb«mzoyI) pyrrolidiae The sub-title compound was prepared by the method of example 18 step a) using 4- bromo-2-methyi bcuzoic acid and pyaohdmc. MS: ESI (+ve): 268 (M+H) b) [[3'-methyl-4'-(l- pyrroiidinylcarbonyl I)-5-(trifhioromediyIH14'-bipli«yl]-2-yl]orylacetic acid The titie compound was prepared by the method of example 21 step a) using the product of step a) and the product of example 26 step a). 'HNMRDMSO-De: 8 13.08 (IH, s), 7.7-7.42 (4H, m), 7.31-7.18 (2H, m), 4.86 (2H, s), 3.49 (2H, t), 3.13(2H, t), 2.26 (3H, s), 1.91-1.8 (4H, m). MS: APCI (-ve): 407 (M-H) Example 28 (25V-2-f[4t-frbis(l-methvlethvnamino]carbonvll-5-chioro-3'-fluorori,l-biphenvn-2- viloxvl-propanoic acid a)2-[5-chloro-2-(phenylmethoxy)phenyl]-4,4^,5-tetramethyl-Mr2-dioxaborolane Pinacol (3.24 g) was added to a solution of [5-cMoro-2-(phenylmethoxy)phenyl]- boronic acid (6 g) in diethyl ether, and stirred for 24 h. 4A molecular sieves and pinacol (1.5 g) were added, stirred for a further 24 h. The sieves were filtered and the filtrate was washed with water and brine, then dried (MgSO4) and concentrated in vacua. Yield 6.8 g. 1E NMR DMSO-D6: 8 7.6-7.25 (7H, m), 7.08 (1H, d), 5.13 (2H, s), 1.32 (12H, s) b)4-chloro-2-(4,4,5,5-tetramethyHr3^-dioxaborolan-2-yl)-phenol 10% Palladium on activated carbon was added to a solution of the product from step a) (4 g) in ethanol (100 ml), and stirred under 1 bar hydrogen for 30 min. The mixture was filtered and the filtrate was concentrated in vacua to give the sub-title compound. Yield 3.51 g. Used without characterisation. DIAD (3 ml) was addedtoanmrturcof the product ftom step b)(3.51 g),triphenyl mixture was concentrated in vacua. The residue was purified by flash column chromatography eluting with isohexane:ethyl acetate (7:3) to give the sub-tiltle compound (4 g). The intermediate obtained was dissolved in acetone and 1M HC1 (15 ml) was added, stirred for 20 min, then concentrated in vacua. Redissolved in dichloromethane (10 ml) and added TFA (5 ml). Stirred for 2 h, then added water (1 ml), stirred for 1 h. The reaction mixture was then diluted (water) and made alkaline by adding dilute NaOH. The organic layer was separated and discarded. The aquous phase was acidified with concentrated HC1 to pHl, then washed with dichloromethane (x 2). These organic extracts were dried (MgSCU) then concentrated in vacua to give the sub-title compound. Yield 1.4 g MS: ESI (-ve): 244 (M-H) d) 4-bromo-2-fluoro-AyV-bis(l-metiiylethyl)-benzamide The sub-title compound was prepared by the method of example 18 step a) using 4- bromo-2-fluorobenzoic acid and diisopropylamine. MS: ESI (-Hre): 304 (M+H) 2-[[4'-[[bis(l-methyIethyl)amino]carboiiyll-5-chloro-3t-fluoro[l,r-biphenyl]-2- yl]oxy]-propanoic acid The product of step c) (200 mg), the product of step d) (200 mg), Pd(dppf)Cl2 (60 mg), sodium carbonate (350 mg) and dioxan (5 ml) were charged to a flask and heated at reflux for 24 h, then cooled to room temp and filtered (hyflo). The filtrate was concentrated in vaci4o, then purified by reverse phase HPLC to give the title compound Yield 22 mg 'H NMRDMSO-D6: 8 13.19 (1H, s), 7.62-7.21 (5H, m), 6.92 (1H, m), 4.97 (1H, q), 3.8-3.46 (2H, m) 1.47(12H, s), and 1.18 (3H, d). Example 29 a)4-bromo-JV-ethyl-2-fluoro-7V-iiiethyl-benzamide The sub-title compound was prepared by the method of example 18 step a) using 4- bromo-2-fluorobenzoic acid and methyl-ethanamine. b) (lS)-2-[[5-chloro-4'-[(ethylniethylamino)carbonyl]-3'-fluoro[l ,1 '-biphenyl]-2-yl]oxy]- propanoic acid The title compound was prepared by the method of example 28 step e) using the product of step a) and the product of example 28 step c) 'H NMR DMSO-D6: 8 7.7 (1H, d), 7.55 (1H, d), 7.4-7.19 (3H, m), 7.02-6.9 (1H, m), 4.62 (1H, q), 3.5-3.2 (2H, q), 2.3 (3H, d), 1.4 (3H, d) and 1.04-1.18 (3H, m). MS:ESI(-ve):378(M-H)(Figure Removed) Example 30 a)4-bromo-2-fluoro-A'-methyl-JV-(l-methylethyI)-benzamide The sub-title compound was prepared by the method of example 1 8 step a) using 4- bromo-2-fluorobenzoic acid and JV-methyl-2-propanamine. product of step a) and flic product of example 28 step c) *H NMR DMSO-D6: 8 7.57-731 (5H, mX 7.02(1H, dX 43 (IH. qX 3 (IH, s, broadX 3.19(2H, s, broad + waterX 2^2 (3H, s) and 1.4X1H, dX 12-1.16(01, m) MS: APQ (-ve): 392 (M-H) Example 31 a5r)-2-ff5-chloro-4'-trdiethvlamino)carbonvl1-3'-fluoron.r-biDhenvl1-2-vI1oxvlpropanoic acid a) 4-bromo-AyV-diethyl-2-fluoro-benzamide The sub-title compound was prepared by the method of example 18 step a) using 4- bromo-2-fluorobenzoic acid and 7V-ethyl-ethanamine. b)(2^}-2-[[5-chlora-4'-[(diethylamiiio)cartH)nyl]-31-fluoro[l,l'-biphenyl]-2-yI]oxy]- acid The title compound was prepared by the method of example 28 step e) using the product of step a) and the product of example 28 step c) H NMR DMSO-D6: 8 7.76-7.21 (5H, m), 6.96(1H, s), 4.71 (1H, q, broad), 3.47 (2H, broad), 3.19(2H, s, broad), 1.4 (3H, d), 1.16 (3H, t) and 1.04(3H, t). MS:ESI(-ve):392(M-H) Example 32 (25V2-rr5-chloro-4'-rf3.3-difluoro-l-pvrrolidinvncarbonvIl-3>-nuoro[l.lbiDhenvll-2- vlloxvl-propanoic acid (Figure Removed)a) H44remo-2 The sub-tide compound was prepared by Ifae method of example 18 step a) using bromo-2-fluarobenzoic arid «ad 33-dJflm salt and tricfoyJarnrne (2 molar equivaleiit). muoro-l-pyrrolidinyl)carbonyl]-3'-fluoro[l,ll-biphenyI]-2- yl]oxy]-propanoic acid Tetrakispalladiumtriphenylphosphine (0) (0.14 g) was added to a mixture of the product of example 28 step c) (0.3 g), toluene (10 ml), 2M sodium carbonate solution (4 ml), ethanol (4 ml) and the product of step a). The reaction mixture was heated at 90°C overnight, then concentrated in vacuo. The residue was filtered (hyflo) and the filtrate was purified by reverse phase HPLC to give the title compound. Yield 0.12g. JH NMR DMSO-D6: 6 7.7-7.36 (5H, m), 6.9(1H, d), 4.8 (1H, d), 3.9 (1H, t), 3.83-3.66 (1H, m), 3.6-3.45 (2H, m) 2.5 (1H, m), 2.07 (1H, s) and 1.44 (3H, d).. MS: ESI (-ve): 426 (M-H)Example 33 biphenvll-2-vlloxvl-propanoicacid a)4-bromo-Ar-(l,l-dimethylethyr)-2-fliioro-benzaiiiide The sub-title compound was prepared by the method of example 1 8 step a) and tertiary-butyl amine. 'H NMR DMSO-D6: 8 7.6 (IH, t), 7.4 (IH, dd), 7.3 (IH, dd), 6.57-6.44 (IH, m) and (25)-2-[2-boroi)-4trifluoromeAvI)phenoxy]-piop«ioic acid [WO2004089885] by the method of example 32 step b). NMRDMSO-De: 8 7.9 (IH, s), 7.9-7.53 (5H, m), 7.16 (IH, d), 5.05 (IH, d), 1.47-1.16 (12H, m). MS: APCI (-ve): 374 (M-H) Example 34 2-rr5-chloro-3t-fluoro-4f-[ra-methvlethvnainuio1carbonvl1fl.l>-biphenvIl-2-vl1oxylpropanoic acid a)4-bromo-2-fluoro-JV-(l-methylethyI}-be»zamide The sub-title compound was prepared by the method of example 18 step a) using 4- bromo-2-fluorobenzoic acid and 2-propanamine. !H NMR CDC13:8 7.97 (IH, t), 7.41 (IH, dd), 7.37 (IH, dd), 6.45 (IH, s), 4.33-4.25 b)(2J2-[[5-chIoro-3'-fluoro-4-[[(l-methylethyI)ailing]carbonyl][l,l-biphenyl]-2- yl]oxy]-propanoic acid The title compound was prepared by the method of example 32 step b) using the product of step a) and the product of example 28 step c). 'H NMR DMSO-D6:8 8.21 (IH, d), 7.71-7.26 (4H, m), 6.97 (IH, d), 4.92 (IH, d), 4.07 (IH, d), 2.52 (broad peak, contains DMSO and IH), 1.4 (3H, d) and 1.16 (6H, d), MS:APCI(4ve):380(M+H) a)4-bromo-2-fluoro-A'-(2-methylpropyl)-benzamide The sub-title compound was prepared by the method of example 18 step a) using 4- bromo-2-fluorobenzoic acid and 2-methyl-l-propanamine. MS: ESI (+ve): 274 (M+H) b)(252-[[5-chloro-3'-nuoro-4'-[[(2-methylpropyl)amino]carbonyl](l,r-biphenyl]- yl]oxy]-propanoic acid The title compound was prepared by the method of example 32 step b) using the product of step a) and the product of example 28 step c). 1H NMR DMSO-D6: 8 8.36 (IH, s), 7.7-7.42 (3H, m), 7.42-7.31 (2H, m), 6.96 (IH, d), 4.82 (IH, q), 3.08 (2H, t), 1.94-1.73 (IH, m), 1.4 (3H, d) and 0.9 (6H, m). MS: APCI (+ve): 394 (M+H) Example 36 (25V2-[r3'-fluoro-4'-a-DvrrolidiDvlcarboDvn-5-(trifluorotnethvnH.l'-biphcnvn- ylloxvl-propanoic acid The title compound was prepared using the product of euunple 24 part a) and acid [WO2004089885] by the method of example 32 step b). 'H NMR DMSO-D6:5 7.88 (IH. dX 7.7-731 (3H, nfc 7.43 (IH, tX 7.05 (IH, dX 4.54 (IH, qX 3.58-3.06 (4H, mX 1-84 (4H, c) and 138 (3H, d). MS: APCI (-ve): 424 (M-H) Example 37 (25V-2-rr3t.5-dichloro-4'-(l-DvrrolidinvlcarbonvlMl.lt-biDhenvIl-2-vlloyv1- a)(25)-2-[[3dichloro-4f-(l-pyrrolidiiiylcarbonyOll,l'-biphenyl]-2-yl]oxyl-l,ldimethylethyl ester propanoic acid The sub-title compound was prepared by the method of example 1 step e) using the product of example 18 step c). acid The title compound was prepared by the method of example 25 step b) using the product of step a). JH NMR DMSO-D6: 8 7.82 (1H, s), 7.63 (1H, d), 7.45-7.39 (3H, m), 7.01 (1H, d), 4.9611H, q), 3.5 (2H, t), 1.97-1.81 (4H, m) and 1.42 (3H, d). MS: APCI (-ve): 406 (M-H) Example 38 (25V2-rrS-chloro-3>-methvl-4t-(l-pvrroMdinvicarbonvnfl.lt-biphenvIl-2-vl1oxvlpropanoic acid HO. ,0 The sub-title compound was prepared by the method of example 18 step b) using the product of example 27 step a) MS: ESI (-ve): 315 (M-H) b)(25)-2-[[S-chloro-3l-methyl-4l-(l-pyrrolidinylcarbonyl)[l,ll-biphenyl]-2-yl]oxyl-l,ldimethylethyl ester propanoic acid The sub-title compound was prepared by the method of example 1 step e) using the product of step a) MS: ESI (-ve): 442 (M-H) c)(2S)-2-[[5-chloro-3l-methyl-4t-(l-pyr0lidinylcarbonyl)[l,ll-biphenyl]-2-ylloxyJpropanoic acid The product of step b) (0.2 g) was dissolved in dicloromethane (3 ml) and TFA (3 ml) was added and stirred for 2 hours, then concentrated in vacua. Purified by reverse phase HPLC to give the title compound. 1H NMRDMSO-D6: 8 7.54 (2H, s), 7.37-7.21 (3H, m), 6.92 (IH, d), 4.76 (IH, d), 3.5 s), 3.1 1 (2H, s), 2.23 (3H, s), 1.98-1.77 (4H, m) and 1.4 (3H, d). MS: APCI (+ve): 388 (M+H) Example 39 IIS-chloro-S'-methvM'-d-pyrroIidinylcarbonyRflJ'-biphenyll-l-ylloryl-aceticacM HO. ,0 The title compound was prepared by the method of example 18 step d) using the product of example 38 step a). 'H NMR DMSO-D6:5 7.57-7.18 (5H, m), 7.0 (IH, s), 4.63 (2H, s), 3.48 (2H, s), 3.12 (2H, s), 2.24 (3H, s) and 2.0-1.72 (4H, m). MS: APCI (-Ke): 374 (M+H) Example 40 rrS'-fluonM'-fl-pvrrolidinvlcarbonvlVS-ftrifluoromethvRfl.l'-biphenvn-l-vnorylacetic acid a)H3'-fluoro-4'-(l-pyrrolidiiiylcarbo0yI)-5-(trifluoromethyl)[l,ll-biphenyl]-2-yI]oryIacetic acid-l,l-dimethylethyl ester The sub-title compound was prepared by the method of example 32 step b) using the product of example 26 step a) and the product of example 24 step a). b) [[3t-nuoro-4'-(l-pyrrolidinylcarbonyl)-5-(trinuoromethyO[l,r-biphenyl]-2-yl]or']- acetic acid The title compound was prepared by the method of example 38 step c) using the product of step a). 'H NMR DMSO-D6: 8 7.73 (IH, dd), 7.70 (IH, d), 7.59 (IH, dd), 7.54-7.46 (2H, m), 7.26 (IH, d), 4.6 (2H, s), 3.49 (2H, t), 3.27 (2H, t), and 1.94-1.8 (4H, m). MS: APCI (+ve): 412 (M+H) Example 41 (Z^Vl-fra'-methvM'-d-pvrrolidinvlcarbonvIVS-ftrifluoromethvnria'-biphenvll-Zylloxvl- proDanoic acid (Figure Removed)The tide compound was prepared using the product of example 27 step a) and (25)-2-[2-borono-4-(trifluoromethyl)phenoxy]-propanoic acid [WO2004089885] by the method of example 32 step b). !H NMR DMSO-D6: 8 7.78-7.43 (4H, m), 7.23 (IH, d), 7.06 (IH, d), 5.04 (IH, d), 3.37 (2H, d), 3.08 (2H, m), 2.28 (3H, s), 1.96-1.72 (4H, m) and 1.45 (3H, d). MS: APCI (+ve): 422 (M+H) Example 42 ff3'.S-difluoro-4'-fl-Dvrrolidinvlcarbonvnfl.lt-biphenvn-2-vno3cvl-aceticacid a) 3^'-difluoro-2'-methoxy-[l,l'-biphenyl]-4-carboxyIic acid 5-fluoro-2-methoxyboronic acid (1 g), 4-bromo-2-fluorobenzoic aciu (1.29 g), tetrakis palladiumtriphenyphosphine (0) (0.6 g), toluene (40 ml), ethanol (16 ml) and 2M sodium carbonate (10 ml) were charged to a flask and heated at reflux overnight The mixture was concentrated in vacua then diluted with water and ethyl acetate. The aqueous layed was separated and acidified with IN HC1, then extracted with ethyl acetate. The latter ethyl acetate layers were dried (MgSO4) and concentrated in vacua to give the sub-title compound as a beige solid. Yield 1 .45 g. JH NMR CDC13: 8 8.08 (1H, t), 7.4 (2H, d), 7.11-7.04 (2H, m), 6.96-6.9 (1H, m), 3.81 (3H, s). MS: ESI (-ve): 306 (M-H) The sub-title compound was prepared by Ac method of example 18 step a) using the product of step a) andpyrrobdme. MS: ESI (+ve): 318 (NUB) c) l-[(3,5'-difluoro-2f-hydroxy[l,l'-biphenyl]-4-yl)carbonyl]-pyrrolidine The sub-title compound was prepared by the method of example 1 8 step c) using the product of step b). MS: ESI (-ve): 304 (M-H) d) [[3f,5-difluoro-4'-(l-pyrrolidinylcarbonyl)[l,l'-biphenyl]-2-yl]oxy]-aceticacid The title compound was prepared by the method of example 18 step d) using the product of step c). MS: ESI (-ve): 362 (M-H) JH NMR DMSO-D6: 8 7.8-6.6 (6H, m), 4.49 (2H, s), 3.6-3.04 (4H, m) and 2-1.67 (4H, m). Example 43 (ZS)-2-[[3',5-difluoro-4'-(l-pyrroKdinylcarbonyl)[l,ll-biphenyl]-2-yl]oxy]-propanoic acid HOV ,0 The title compound was prepared by the methods of example 1 step e) and exampl e 38 step c) using the product of example 42 step c). 'HNMRDMSCM: 8 7.76 (IH, d),7.573 (IH, d), 7.39 (IH, t), 7.24 (IH, d), 7.17-7.01 (IH, m), 6.95-6.84 (IH, m), 4.67 (IH, m), 3.47 (2H, t), 3.4-3.1 (4H, m), 1.89-1.84 (2H, m) and 138(3H,d). MS: APCI (-ve): 374 (KH) Example 44 vHoxyl-propanoic acid The title compound was prepared by the methods of example 32 step a) and example 32 step b) using the products of example 28 step c) and 2-methylpyrrolidine. 'HNMRDMSO-De: 8 7.74-7.65 (IH, m), 7.59-7.5 (IH, m), 7.42-7.31 (3H, m), 6.92 (IH, 4.7 (IH, q), 4.21-4.08 (IH, m), 3.6-3.5 (IH, m), 3.4-3.2 (IH, m), 2.1-1.7 (4H, m), 1.4 (3H, (Figure Removed) The compound was further purified by chiral HPLC to give:- Examok 45 (2y-2-H5-chloro-3'-fluoro-4'-ff(25V2-methvl-l-pvrrolidinvl1carbonvllHa'- Example 46 (ZS'V-2-F[S-chloro-3>-flaoro-4>-rK21gV2-methvH-pvrrolidmvl]carbonviiri.l'- a)4-bromo-A-cyclopentyl-2-fluoro-benzamide The sub-title compound was prepared by the method of example 18 step a) using 4- bromo-2-fluorobenzoic acid and cyclopentanamine. 'H NMR CDC13: 8 7.98 (IH, t), 7.4 (IH, d), 7.36-7.12 (IH, m), 6.65-6.43 (IH, m), 4.4 (IH, qd), 2.19-2 (2H, m), 1.8-1.43 (6H, m). b) (252-[[4'-[(cycIopentylamino)carbonyl]-3'-fluoro-5-(trifluorometby1)[l,l'-biphenyl]- 2-yl]oxy]-propanoic acid The title compound was prepared using the product of step a) and (25)-2-[2-borono-4-(trifluoromethyl)phenoxy]-propanoic acid [WO2004089885] by the method of example 32 step b). 'HNMRDMSO-rte 6 8.31(1H, d), 7.78-7.43 (5H, m), 7.17 (IH, d), 5.03 (IH, q), 4.21 (1H, q), 1.9-1.8 (2H, m), 1.78-L63 (2H, m) and 1.78-1.4 (7H, m). MS: APCI (-ve): 438 (M-H) Example 48 (2SV2-rf3'-nuoro-4'-ff(l-methvlethvnaminolcarfaonvl1-5-rtrifluoromethvnriJ'- biphenvll-2-vnoxvl-Dropanoic acid HO. ,O The tatlecoayoid was prepared ttsnlfaepiuuMcl of faainpie 34 step a) and (25)-2-[2-boronotrifliK)romethyi)phenoxy]-propanoic acid [WO2004089885] by the method of example 32 step b). 1HNMRDMSOD6:5 8.19 (IH,d), 7.73-734 (5H. m), 7.11 (IH, d), 4^3 (IH, q), 4.06(IH, sept), 1.4 (3H, d), and 1.16 (6H, d). MS: APCI (-ve): 412 (M-H) Example 49 (2SV2-r[4l-r(ethvlammokarbonvll-3'-fluoro-5-(trinuQromethvnri.l'-biphenvl1-2-vnoxv1- propanoic acid a) 4-bromo-7V-ethyl-2-fluoro-benzamide The sub-title compound was prepared by the method of example 18 step a) using 4- bromo-2-fluorobenzoic acid, ethylamine hydrochloride and triethylamine. 1H NMR CDC13: 5 8.01 (1H, t), 7.41 (1H, d), 7.31 (1H, d), 6.62 (1H, s), 3.51 (2H, q) and 1.26 3H, t). b)(2SV2-rf4'-rfethvlamiDo)carboDvl1-3'-nuoro-5-ftrifluoromethvnna'-biDheavl1-2- Ylloxvl-propanoic acid The title compound was prepared using the product of step a) and (25)-2-[2-borono-4-(trifluoromethyl)phenoxy]-propanoic acid [WO20Q4089885] by the method of example 32 step h). 'H NMR DMSO-D6: 8 8.35 (1H, t), 7.73-7.5 (5H, m), 7.14 (1H, d), 5.03 (1H, m), 3.3 (2H, q), 1.43(3H,d),andl.l(3H,t). MS: APCI (+ve): 400 (M+H) The title compound was prepared using the product of example 33 step a) and the product of example 28 step c) by the method of example 32 step b). *H NMR DMSO-D6: 8 7.89 (1H, s), 7.57-7.38 (5H, m), 6.99 (1H, d), 4.98 (1H, q), 1.43 (3H, d)andl.39(9H,s) MS: APCI (-ve): 392 (M-H) Example 51 (25V2-rf5-chIorot-f(cyclopentvlaniino)carbonvll-3t-fluorofl,l-biphenyll-2-vl1ory propanoic acid The title compound was prepared by the method of example 32 step b) using the products of example 28 step c) and example 47 step a). 1HNMRDMSO-D6: 8 13.18 (1H, s), 8.32 (1H, d), 7.6-7.39(5H, m), 7.01 (1H, d), 4.98 (1H, q), 4.24-4.19 (1H, m), 1.98-1.82 (2H, m), 1.81-1.59 (2H, m) and 1.78-1.41 (7H, m). MS: APCI (-ve): 404 (M-H) Examples! a)4-bromo-Ar-cyclopropyl-2-fluoro-beiizamide The sub-title compound was prepared by the method of example 1 8 step a) using ) 4- bromo-2-fluorobenzoic acid, and cyclopropylamine. 'HNMR CDC13: s 8.02 (m, t), 7.42 (in, d), 7.29 (IH, dd), 6.73-6.71 (m, m), 2.96-2.94 (1H, m), 1.63-1.6 (2H, m) and 0.87-0.82 (2H, m). propanoic acid The title compound was prepared by the method of example 32 step b) using the products of example 28 step c) and step a). *K NMR DMSO-D6: 5 8.40 (IH, d), 7.60 - 7.55 (2H, m), 7.50 (IH, dd), 7.42 - 7.38 (2E, m), 7.01 (IH, d), 4.98 (IH, q), 2.86 (IH, dsextet), 1.44 (3H, d), 0.73 - 0.68 (2H, m), 0.58 - 0.53 (2H,m). MS: APCI (-ve): 376 (M-H) Example 53 (25V-2-f[5-chloro-4'-rrfl-ethvlpropvl)aminolcarbonvll-3'-fluoro[l.lt--biphenvl1-2-vI]oxvlpropanoic acid HO The sab-tide compound was prepared by the method of example 18 step a) using 4- bromo-2-fluorobcnzoic acid and 3-pentanamine. 'H NMR CDCfe: 5 7.97 (IH, tX 7.42 (IH. dd), 731 (IH, ddX 6.4-633 (IH, mX 4.06-40) (IH, m), 1.7-1.62 (2H, m), 1.51-1.42 (2H, m) and 0.97 (6H, t). b) 5'-chloro-AL(l-ethylpropyI)-3-fluoro-2'-methoxy-[l,l'-bipb.enyl]-4-carboxamide The sub-title compound was prepared by the method of example 18 step b) using the product of step a) and 4-chloro-2-methoxy boronic acid. MS: ESI (+ve): 350 (M+H) c)5'-chloro-^V-(l-ethylpropyl)-3-fluoro-2'-hydroxy-[l,lf-biphenyl]-4-carboxaiiiide The sub-title compound was prepared by the method of example 18 step c) using the product of step b). MS: ESI (-ve): 334 (M-H) d) (2R)- 2-(4-methylphenoxy)-propanoic acid, methyl ester A solution of methyl (/?)-(+)-lactate (6.66 g) in acetonitrile (33 ml) rvas cooled to 5 °C and triethylamine (9.8 ml) added followed by trimemylamine hydrochloride (0.62 g). A separate solution of^-toluenesulfonyl chloride (11.6 g) in acetonitrile (33 ml) was added dropwise over 20 mins maintaining the temperature below 5°C. The reaction mixture was filtered and concentrated. Diethyl ether and water were added and the organic fraction dried (MgSO4) and concentrated in vacua to give the sub-title compound as a yellow oil (13.71 g). H NMR CDC13: 8 7.82 (2H, d), 7.35 (2H, d), 4.95 (1H, q), 3.67 (3H, s), 2.45 (3H, s), 1.51 (3H,d). 2-ff5-chioro-4t-rf(l-ethvlpropvnanunolcarbonvn-3-fluorori.lt-biphenvU-2- ylloxvl-DroDanoic add The product of step c) (300 nag), the product of step d) (219 nag) and potassium carbonate (135 mg) in acetonitrile (10 ml) were durgcd to flask and stirred at 50°C for 16 h. The reaction mixture was cooled, diluted with water (20 ml) and extracted with diethyl 3 x 10 inl). The organic fractkins were was concentrated in VOCMO, The mntinig ycDtrw oil was dissolved in a, 1:1 imnlnie of THF/methanol (10 ml) and 1M NaOH added (1.1 ml). The mixture was stirred at room temperature for 4 h and then concentrated in vacua. The residue was purified by RPHPLC to give the title compound as a white solid (175 mg). ^NMRDMSO-De: 8 8.02 (1H, d), 7.75 (1H, d), 7.59-7.48 (2H, m), 7.31 (2H, td), 6.93 (1H, d), 4.59 (1H, q), 3.75 (1H, quintet), 1.59-1.37 (4H, m), 1.34 (3H, d), 0.89 (6H, t). MS: APCI (-ve): 406 (M-H) Example 54 (25V2Moro-3t-fluoro-4f-r(mcttiviaminokarbonvlUl.l-biDhenvl1-2-vl1ory1- a) 4-bromo-2-fluoro-JV-methyl-beiizamide The sub-title compound was prepared by the method of example 18 step a) using 4- bromo-2-fluorobenzoic acid and methylamine hydrochloride. 1H NMR CDC13: 5 8.00 (IH, t), 7.42 (IH, dd), 7.32 (IH, dd), 6.66 (IH, s), 3.03 (3H, b) S-chloro-3-floro-2' The sob-tide compound was prepared by the method of example 18 step b) using the product of step a) and 4-chloro-2-niethoxy boronic acid. MS: ESI (+ve): 294 (M+H) c) S'-chloro-3-fluoro-2'-hydroxy-JV-methyl-[l,l '-biphenyl]-4-carboxamide The sub-title compound was prepared by the method of example 1 8 step c) using the product of step b). MS: ESI (-vet): 278 (M-H) dH25V2-ff5-chloro-3'-fluoro-4'-[(methvlanunokarbonvlUl.l'-biphenvl1-2-vnoxv1- propanoic acid The title compound was prepared by the method of example 53 step e) using the product of step c). Purification by RPHPLC gave a white solid (170 mg). 'H NMR DMSO-D6: d 8.27 (IH, s), 7.85 (IH, d), 7.70-7.51 (2H, m), 7.34 (IH, d), 7.28 (IH, dd), 6.91 (IH, d), 4.50 (IH, q), 2.78 (3H, d), 1.33 (3H, d). MS: APCI (-ve): 350 (M-H) Example 55 (lSV2-[[5-chloro-4'-rKia-dimethvlethvnamiuolcarbonvll-3'-methvIH.L'-biphenvll-2- ylloxvl- propane acid a)4-bromo-7V-(l,l-dimethylethyl)-2-methyl-beiizainide The sub-title compound was prepared by the method of example 18 step a) using 4- bromo-2-methylbenzoic acid and tertiarybutylamine. 'H NMR CDC13: 6 7.36 (1H, d), 7.32 (1H, did), 7.18 (1H, d), 5.50 (1H, s), 1.40 (3H, s), 1 The sub-title compound was prepared by the medicos of example 13 step b) using the product of step a) and4-cfalon-2H9ndhaxy borzoi tad. MS: ESI (+ve): 332.0 (M+H) c) S'-chloro-V-(l,l-dimethylethyI)-2'-hydroxy-3-methyl-[l,l '-biphenyl] -4-carboxamide The sub-title compound was prepared by the method of example 1 8 step c) using the product of step b). MS:ESI(-ve):316.0(M-H) dU25V2-rr5-chloro-4>-rr(l.l-dimethviethvnaminolcarbonvn-3f-methvHl.l>-biDhenvn-2- vlloxvl- propanoic acid The title compound was prepared by the method of example 53 step e) using the product of step c). Purification by RPHPLC gave a white solid (230 mg). 'HNMRDMSO-De: 5 7.86 (1H, s), 7.56 (1H, d), 7.54 (1H, s), 7.25-7.19 (3H, m), 6.93-6.88 (1H, m), 4.39 (1H, m), 2.33 (3H, s), 1.36 (9H, s), 1.30 (3H, d). MS: APCI (-ve): 388 (M-H) Example 56 ff5-€hloro-4'-ffri-ethvlDropvnaminolcarbonvl1-3'-fluoroH.l'-biDhenvH-2-vl1oxvl-aceticacid HO. .0 The title compound was prepared by the method of example 18 step d) using the product of example 53 step c). Purification by RPHPLC gave a white solid (81 mg). !H NMRDMSO-D6:5 8.06 (1H, d), 7.66-7.48 (3H, m), 7.42-7.35 (2H, m), 7.04 (1H, d), 4.60 (2H, s), 3.85-3.69 (1H, m), 1.64-1.38 (4H, m), 0.91 (6H, t). MS: APCI (-ve): 392 (M-H) The title compound was prepared by the method of example 18 step d) using the product of example 54 step c). Purification by trituration from diethyl ether/ isohexane gave a white solid (320 mg). 'HNMRDMSO-De: 5 13.11 (1H, s), 8.27 (1H, s), 7.65 (1H, t), 7.56 (1H, dd), 7.48 (1H, dd), 7.44-7.38 (2H, m), 7.09 (1H, d), 4.78 (2H, s), 3.79 (3H, d). MS: APCI (-ve): 336 (M-H) Example 58 r25V2-fr5-chIoro-4'-Kethvlaminocarbonvll-3'-nuoroH.l'-biphcnvl1-2-vlloxvlpropanoic acid a) 5'-chloro-7V-ethyl-3-fluoro-2'-methoxy-[l,l '-biphenyl]-4-carboxamide The sub-title compound was prepared by the method of example 18 step a) using the product of example 21 step a) and ethylamine hydrochloride. MS: ESI (+ve): 310 (M+H) The sub-title compound was prepared by the method of example 18 step c) using the product of step a). MS: ESI (-ve): 294 (M-H) cU25V2-rrS-chloro-4'-ff ethvlamino)carbonvn-3t-fluorofl.lt-biphenvll-2-vlloxv]- propanoic acid The title compound was prepared by the methods of example 1 step e) and example 38 step c) using the product of step b). Purification by RPHPLC gave a white solid (28 mg). 1H NMR CDC13:8 7.93 (IH, t), 7.37 (IH, dd), 7.3 (IH, d), 7.23 (IH, d), 7.14 (IH, d), 6.79 (2H, m), 4.55 (IH, q), 3.48 (2H, m), 1.41 (3H, d) and 1.26 (3H, t). MS: APCI (-ve): 364 (M-H) Example 59 (25-2-ff5-chloro-4'-K(rvclobatvlammocarfaoavn-3'-fliioroH.l'-biDhenvll-2-vnoxvl propanoic acid a) 5'-chloro-Ar-cyclobutyl-3-fluoro-2'-methoxy-Il,l '-biphenyl]-4-carboxamide The sub-title compound was prepared by the method of example 1 8 step a) using the product of example 21 step a) and cyclobutanamine. MS: ESI (+ve): 336 (M+H) The sub-title componod was prepared by (he method of example 18 step c) using the product of step a). MS: ESI (-ve): 320 (M-H) cHlJVl-ffS-chloro-KrthvIaminocarbonvll-a'-fluorofl.l'-biphenvn-Z-vnoxvlpropanoic acid The title compound was prepared by the methods of example 1 step e) and example 38 step c) using the product of step b). Purification by RPHPLC gave a white solid (27 mg). 'H NMR CDC13: 8 7.92 (1H, t), 7.35 (2H, m), 7.12 (1H, d), 6.99 (2H, m), 6.74 (1H, d), 4.95 (1H, m), 4.56 (1H, m), 2.4 (2H, s (broad)), 1.97 (2H, t), 1.77 (2H, s (broad) and 1.41 (3H, d). MS: APCI (+ve): 392 (M+H) Example 60 ylloxvl-Dropanoic acid a a)5'-chloro-A'-(l,l-dimethylpropyI3-fluoro-2'-methoxy-[l,r-biphenyl]-4-carboxaiaide The sub-title compound was prepared by the method of example 18 step a) using the product of example 21 step a) and tert-amylamine. MS: ESI (+ve): 352 (M+H) The sub-tide compound was prepared by the method of example 18 step c) using the product of step a). MS: ESI (-vc): 334 (M-H) cH25V2-f[5-chloro-4t-f(ethvlaminokarbonvil-3'-fluorofl.lt-biDhenvn-2-vl1oxvlpropanoic acid The title compound was prepared by the method of example 53 step e) using the product of step b). Purification by RPHPLC gave a white solid (220 mg). 1H NMR CDC13: 8 7.86 (IH, t), 7.35 (IH, d), 7.26 (IH, t), 7.18 (IH, d), 7.00 (IH, d), 6.66 (IH, d), 6.53 (IH, d), 4.41 (IH, d), 1.78 (2H, q), 1.38 (6H, s), 1.30 (3H, d), 0.89 (3H, t). MS: APCI (-ve): 406 (M-H) Example 61 2-f[5-chIoro-3'-fluoro4'-[|(3-methvlbutvnamiDolcarboDvlUl.l'-biphenyl-2- vnoxvl-propanoic acid a) 5'-chloro-3-fluoro-2'-methoxy-JV-(3-methylbntyl)- [1,1 '-biphenyl]-4-carboxamide The sub-title compound was prepared by the method of example 1 8 step a) using the product of example 21 step a) and isoamylamine. MS: ESI (+ve): 352 (M+H) The sub-tide confound was prepared by Ac medwd of example 18 step c) using the product of step a). MS: ESI (-ve): 334 (M-H) c) fl.SVl-rrS-chloro-a'-nuoro'-rfO-methvlbutvnaminolcarbonvll fl.1 '-biphenvll- ylloxvl-propanoic acid The title compound was prepared by the method of example 53 step e) using the product of step b). 'H NMR CDC13: 8 7.75 (1H, t), 7.32 (1H, d), 7.23 (1H, d), 7.10 (1H, s), 6.90 (1H, d), 6.83 (1H, t), 6.61 (1H, d), 4.28 (1H, d), 3.37 (2H, d), 1.62 (1H, t), 1.44 (2H, d), 1.17 (3H, d), 0.90 [3H]PGD2 was purchased from Perkin Elmer Life Sciences with a specific activity of 100-210Ci/mmol. All other chemicals were of analytical grade. HEK cells expressing rhCRTh2 / Gal 6 were routinely maintained in DMEM containing 10% Foetal Bovine Serum (HyClone), Img/ml geneticin, 2mM L-glutamine aad 1% non-essential amino acids. For the preparation of membranes, the adherent transfected HBKcells were grown to confluence in two layer tissue culture factories (Fisher, catalogue number TKT-170-070E). Maximal levels of receptor expression were induced by addition of SOOmM sodium butyrate for the last 18 hours of culture. The adherent cells were washed once with phosphate buffered saline (PBS, 50ml per cell factory) and detached by the addition of bacitracin]. Cefls were pdktedbycentnmgatkMi at 220kg fcr 10 minutes at 4°C, resuspended disrupted wing a Poiytron horaogeaicar far 2 x 20 second taste keeping me tube in ice at afl. times. Unbroken cells were removed by centrifugation at 220xg for 10 minutes at 4°C and the membrane fraction pelleted by centrifugation at 90000xg for 30 minutes at 4°C. The final pellet was re-suspended in 4 ml of membrane homogenisation buffer per cell factory used and the protein content determined. Membranes were stored at -80°C hi suitable aliquots. All assays were performed in Corning clear bottomed, white 96-well NBS plates (Fisher). Prior to assay, the HEK cells membranes containing CRTh2 were coated onto SPA PVT WGA beads (Amersham). For coating membranes were incubated with beads at typically 25 fig membrane protein per mg beads at 4°C with constant agitation overnight. (The optimum coating concentrations were determined for each batch of membranes) The beads were polluted by centrifugation (Sox for Minutes at 4°C), washed once with assay buffer (50mM HEPES pH 7.4 containing 5mM magnesium chloride) and finally re-suspended in assay buffer at a bead concentration of long/ml. Each assay contained 20yl of 6.25nM (HfJPGDz, 20} d membrane saturated SPA beads bom in assay buffer and loftily of compound solution or 13,14-dihydro-l 5-keto prostaglandin I2 (DK-PGE2, for determination of non-specific binding, Cayman chemical company). Compounds and DK-Pig were dissolved in DMSO and diluted in me same solvent to lox the required final concentration. Assay buffer was added to give a final concentration of 10% DMSO (compounds were now at lox the required final concentration) and miss was the solution added to the assay plate. The assay plate was incubated at room temperature For 2 hours and counted on a Wallace Micro beta liquid scintillation counter (1 minute per well). Compounds of formula (I) have an Ices value of less than 10|iM. Specifically example 5 has a picot value of 8.75; example 11 has a picot value of and example 13 has apices of 8.15. Shape Change Assay DK-PGD2 [13,14-dihydro-15-keto Prostaglandin Eh] was obtained from Cayman Chemical (Michigan,USA). OptilyseB was from Immunities (Marseille, France). All other chemical reagents were of analytical grade from Fisher Scientific (Southborough, UK) or Sigma (Poole, UK). followed by incubation at room temperature for 10 min. Next, red blood cells were lysed by the addition of 1 mL of water and further incubation at room temperature for 45 min. The plate was centrifuged for 5 min at 375 x g, the supernatant was discarded and cells were resuspended in 400 ^L of assay buffer (Dulbecco's PBS without Ca2"1" and Mg2"1" supplemented with 10 mM HEPES, 10 mM glucose and 0.1% BSA; pH 7.4). The fixed cells were transferred to tubes suitable for use with the flow cytometer. Shape change was determined using a Coulter FC500 flow cytometer, by measuring the ability of these cells to scatter light when illuminated. By gating the granulocyte region on the basis of their FS/SS profile, FL-2 was plotted against FL-1 identifying two populations of cells: neutrophils with low auto-fluorescence and eosinophils that showed higher natural autofluorescence. The eosinophil population is gated and changes in the median value in FS are recorded. Compounds were tested at final concentrations of 1 and 10 pM. These were dissolved in DMSO to give a 10 mM solution. Further dilutions were performed in 96-well polypropylene plates in assay buffer to give a 100 uM solution containing !%DMSO. An additional 1 in 10 dilution was made in assay buffer containing 1% DMSO. Both these solutions were diluted 1 in 10 into the assay mixture to give a final DMSO concentration of 0.1% (v/v). Concentration response curves for DK-PGDa were constructed as a control ir each experiment. The efficacy of tested compounds was expressed as a fraction of the maximum response to PGDj. These compounds were considered antagonists when their efficacy ratio was lower than 0.25. Claims A compound of formula (I) or a pharmaceutically acceptable salt thereof: (Figure Removed) X is halogen, or C1-2alkyl which is substituted by one or more halogen atoms; A and E are independently selected from halogen, SQJR5 (no or 2), CONR'R4, or CM alkyl whkii can be optionally sdb«titated by one or mace halogen atoins; D is hydrogen or fluorine; R1 and R2 independently represent a hydrogen atom, or a Cualkyl group; or R1 and R2 together can form a 3-8 membered ring optionally containing one or more atoms selected from O, S, NR6 and itself optionally substituted by one or more C1-C1alkyl; R3 and R4 independently represent hydrogen, cyclically or Chalky!, the latter two groups being optionally substituted by one or more substituents independently selected from halogen, C3-C7 cycloalkyl, OR6 and NR7R8; or R3 and R1 together with the nitrogen atom to which they are attached can form a 3-8 membered saturated heterocylic ring optionally containing one or more atoms selected from O, S(O)n (where n = 0,1 or 2), NR8, and itself optionally substituted by halogen or C1-3 alkyl; R5 is C1-10alkyl or C3-7 cycloalkyl, which may be optionally substituted by halogen atoms; R6 is hydrogen or C1-C6 aficyl; R7 and R8 independently represent hydrogen, C1-6 alkyl or C3-7 cycloalkyi or R7 and R8 together with the nitrogen atom to which they are attached can form a 3-8 membered saturated heterocyclic ring as defined above for R3 and R4. 2. A compound according to claim 1 in which X is chlorine, fluorine or trifluoromethyl. 3 . A compound according to claims 1 to 2 above hi which A and E independently represent trifluoromethyl, C1-3alkyl, halogen, SOR5, SO2R5, CONR3R4 or SO2NR3R4. 4. A compound according to any one of claims 1 to 3 in which D is hydrogen or fluorine; 5. A compound accenting to oaf drains to 4m wider 6. A concord according to ouch of damns ItoAmwhk hydrogen and the other is methyl 7. A compound according to any one of claims 1 to 6 selected from: (22-[[4'Kme%lsulfonyl)-35-bis(trifluoromemyl)[l, -biphenyl]-2-yl]oxy]- acid; [[35-DichloroHmethylsulfonyl)[ 1 ,lMnphehyl]-2-yl]oxy]acetic acid; [[3's5-Dichloro-4'-(methylsulfmyl)[l,l'-biphenyl]-2-yl]oxy]aceticacid; (25)-2-[[3t,5-Dichloro-4'-(methylsulfonyl)[ 1 ,1 '-biphenyl3-2-yi]oxy]propanoic acid; (25)-2-[4K:Moro-2-[2,5-d!ifluoro-4-(4-morphouiiylsulfonyl)phenoxy]phenoxy]--propanoic acid; [[3l-Fluoro-[(l-methylethyl)sulfonyl]-5trifluoromethyl)[l,r-biphenyl]-2-yl]o acid; (25)- 2-[[4'thysulfonyl)-35-bs(trmu acid; X acid; (252-[[5MoroXniorpholinylsulfc yl]oxy]propanoic acid; [[5-CMorol-pyrroUdmylcarbonyl)-3Xt acid; (2,S)-2-[[5HoroHl-pyn:oUdinylcarbony propane acid; [[5-Chloro-4'-(ethylsulfonyl)-3'-(trifluoromethyl)[ 1 ,l'-biphenyl]-2-yl]oxy]acetic acid; (2iS)-2-[[5-(^oro44methykulfonyl (3'-Mfluoromethyl)-[l,r-biphenyl]-2-yl]oxy]propa3ioic acid; (2-2-[[5-CWorc3'-fluoroXme%lsulfonyl)[l,l'-biphaiyl]-2-yl]oxy]propanoicacid; acid; HnGqpl acid; [[4Xl-azctidinykarixmy!)- acid; crkiinyI [[3',5-dichloro-4'-(2-isoxazolidinylcarbonyl)[l , 1 '-biphenyl]-2-yl]oxy]-acetic acid; [[S-cMoro-S'-l-pyrrolidinylcarbonytljl'-biphenylJ^-ylloxyj-aceticacid; (2S)-2-[[5^Moro-3'-fluoro-4l-(l-pyrrolidinylcarbonyl) [lord-biphenyl]-2-yl]oxy]-propanoic acid; [[3'-methyl-4'-(l-piperidinylcarbonyl)-5-(trifluoromethyl)[lord-biphenyl]-2-yl]oxy]-acetic acid; [[3'-methyl-4'-(l-pyrrolidinylcarbonyll)-5-(trifluoromethyl)[l,r-biphenyl]-2-yl]oxy]-acetic acid; (2S)-2-[[4l-[ is(l-methylethyl)amino]rarbonyl]-5-chloro-3'-nuoro[l,ll-biphenyl]-2-yl]oxy]- propanoic acid; (2S)-2-[[5-chloro-4l-[(ethylmethylamino)caibonyl]-3'-fluoro[ 1 , l'-biphenyl]-2-yl]oxy]- propane acid; (2S)-2 [5WoK)-3l-fluoro -[[methyl(l-methyl ethyl)amino eel] oxy]-prcpanoic acid; (2S2-[[5n;Uoro-4'-[(diethylaniino)caibonyl]-3l-fluoro[l,r-biphenyl]-2-yl]oxy]-pn)paiii)ic acid; yl]oxy]-propanoic acid; biphenyl]-2-yl]oxy]-propanoic acid; (2S)-2-[[5-chloro-3I-fluoro-4'-[[(l-methylethyl)amino]carbonyl][l,l'-biphenyl]-2-yl]oxy]- propanoic acid; (2S)-2-[[5^hloro-3l-fluoro-4'-[[(2-methylpropyl)amino]carbonyl][lJl'-biphenyl]-2-yl]oxy']- propanoic acid; (2S2-[[3I-fluoro1-(l-pyrroUdinylcarbonyl)-5-(trifluoromethyl)[l,r-biphenyl]-2-yl]oxy]- (Figure Removed) (2S)-2-[[3'-methyl-4'-(l -pyrrolidinylcarbonyl)-5-(trifluoromethyl)[l , 1 '-biphenyl]-2-yl]oxy]- propanoic acid; [[35-fluoro-4'-(l-pyrrolidinylcarbonyl)[l,r-biphenyl]-2-yl]oxy]-aceticacid; (2S)-2-[[35-difluoro-(l-pyiroUdinylcarbonyl)[l,ll-biphenyl]-2-yl]oxy]-propanoicacid; (2S)-2-[[5-chloro-3'-fluoro-4'-[(2-methyl-l -pyrrolidinyl)carbonyl] [1,1 '-biphenyl]-2-yl]oxy]- propanoic acid; (2S)-2-[[5-chloro-3I-fluoro-41-[[(2S2-methyl-l-pyrrolidinyl]carbonyl][l,l'-biphenyl]-2- yl]oxy]-propanoic acid; (2S)-2-[[5hloro-3t-fluorol-[[(2R2-methyl4-pyrrolidinyl]carbonyl][l,l'-biphenyl]-2- yljoxyj-propanoic acid; (2S)-2-[[3'-fluoro-[[(l-methyle%l)amino]caibonyl]-5trifluoromethyi)[14yl]oxy]-propanoic acid; propanoic acid; (2S25MonM4[(l,l-dime%lethyl) propanoic acid; (22-[[5Morc4(cyclcpentylamirtf propane acid; (25)-2-[[5bloro-[(cyclopropylaniino) carbonyl]-3l-fluoro [l ,1 r-biphenyl]-2-yl]oxy]- Propanoic acid; propanoic acid; (2^2-[[5Uoro-3'-fluoro-[(methyl acid; acid; 2-[[5H3Moro'-[(cyclobutylamino)caAonyl]-31-flucTO propanoic acid; (2^2-[[5Kjmoro^'-[[(l,l-dimethylpiopyl)amino]CTrbciiyl]-3'-fluoro yl]oxy]-propanoic acid; (22-[[5Moro-3'-fluoro1-[[(3-methylbutyl)amino]carbonyl][loll-b propanoic acid; (Figure Removed) in which X, A, D and £ are as defined in formula (I) in claim 1. 9. A compound of formula (I) or pharmaceutically acceptable salt substantially as herein described with reference to the given examples.

Documents:

1441-delnp-2007-Abstract-(18-04-2013).pdf

1441-delnp-2007-abstract.pdf

1441-delnp-2007-Claims-(18-04-2013).pdf

1441-delnp-2007-claims.pdf

1441-delnp-2007-Correspondence Others-(18-04-2013).pdf

1441-delnp-2007-Correspondence Others-(29-08-2012).pdf

1441-DELNP-2007-Correspondence-Others-(21-08-2008).pdf

1441-delnp-2007-Correspondence-Others-(24-01-2013).pdf

1441-delnp-2007-Correspondence-Others-(31-05-2013).pdf

1441-delnp-2007-correspondence-others.pdf

1441-DELNP-2007-Description (Complete)-(21-08-2008).pdf

1441-delnp-2007-description (complete).pdf

1441-delnp-2007-Form-1-(18-04-2013).pdf

1441-delnp-2007-Form-1-(29-08-2012).pdf

1441-delnp-2007-form-1.pdf

1441-delnp-2007-form-13-(21-08-2008).pdf

1441-delnp-2007-Form-2-(18-04-2013).pdf

1441-delnp-2007-form-2.pdf

1441-delnp-2007-Form-3-(18-04-2013).pdf

1441-delnp-2007-Form-3-(24-01-2013).pdf

1441-delnp-2007-form-3.pdf

1441-delnp-2007-form-5.pdf

1441-delnp-2007-GPA-(18-04-2013).pdf

1441-delnp-2007-pct-210.pdf

1441-delnp-2007-pct-304.pdf