Title of Invention "NOVEL COMPOUNDS"
Abstract The invention relates to substituted phenoxyacetic acids (I) as useful pharmaceutical compounds for treating respiratory disorders, pharmaceutical compositions containing them, and processes for their preparation.
Full Text NOVEL COMPOUNDS

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 1170 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 are 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 pharmaceutically acceptable salt or solvate thereof
(Formula Removed)


(I)

in which:

X is halogen, cyano, nitro, S(OXR6 or C1-4alkyl which is substituted by one or more halogen atoms;

Y is selected from hydrogen, halogen, CN, nitro, S02R3, OR4, ~, SOR3, SO2NR4R5, CONR4R5, NR4R5, NR6SO2R3, NR6CO2R6, NR6COR3, C2-C6 alkenyl, C2-C6 alkynyl, C3-C., cycloalkyl or C1-6alkyl, the latter four groups being optionally substituted by one or
more substituents independently selected from halogen, OR and NR6R7, S(O)~R6 where n is 0, 1 or 2;

Z is aryl or a ring A, where A is a six membered heterocyclic aromatic ring containing one or more nitrogen atoms or may be a 6,6 or 6,5 fused bicycle containing one or more 0, N,


S atoms, the aryl or A rings all being optionally substituted by one or more substituents independently selected from from hydrogen, halogen, CN, OH, SH, nitro, COR9, C02R6, S02R9, OR9, SR9, SOR9,S02NR10R11, CONR"0R11, NR10R"1, NIHSO2R9, NR9SO2R9, NR6CO2R6, NHCOR9, NR9COR9, NR6CONR4R5, NR6SO2NR4R5, aryl, heteroaryl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl or Ci.6alkyl, the latter four groups being optionally substituted by one or more substituents independently selected from halogen, C3-C7 cycloalkyl, OR6, NR6R7, S(O)~R6 (where n is 0, 1 or 2), CONR6R7, NR6COR7, SO2NR6R7 and NR6SO2R7.

R1 and R2 independently represent a hydrogen atom, halogen, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloallcyl or a Ci.6alkyl group, the latter four groups being optionally substituted by one or more substituents independently selected from halogen, C3-C7 cycloalkyl, NR6R7, OR6, S(O)~R6 (where n is 0, 1 or 2);

or

R1 and R2 together can form a 3-8 membered ring optionally containing one or more atoms selected from 0, S. NR6 and itself optionally substituted by one or more C1-C3 alkyl or halogen;

R3represents C3-C7 cycloalkyl or C1.6alkyl which may be optionally substituted by one or more substituents independently selected from halogen, C3-C-y cycloalkyl, OR6 and NR6R7, S(O)~R6 (where n = 0,1 or 2), CONR6R7, NR6COR7,SO2NR6R7 and I~6SO2R7"

R4 and R5 independently represent hydrogen, C3-C7 cycloalkyl or C1.6alkyl, the latter two groups being optionally substituted by one or more substituents independently selected from halogen, C3-C7 cycloallcyl, OR6 and NR6R7, S(O)~R6 (where n = 0,1 or 2), CONR6R7, NR6COR7,SO2NR6R7 and NR6SO2R7;

or

R4 and R5 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 0, S(O)~ (where n = 0,1 or 2), NR8, and itself optionally substituted by halogen or C1-
~ alkyl;
R6 and R7 independently represents a hydrogen atom or C1-C6 alkyl
R is hydrogen, C1-4 alkyl, -COC1-C4 alkyl, C02C1-C4alkyl or CONR6C1-C4alkyl;
R9 aryl, heteroaryl, C3-C7 cycloalkyl or Ci..6alkyl, the latter two groups may be optionally substituted by one or more substituents independently selected from halogen, C3-C7 cycloalkyl, aryl, heteroaryl OR6 and NR6R7, S(O)~R6 (where n = 0, 1 or 2), CONR6R7, NR6COR7, SO2NR6R7 and NR6502R7;

R"0 and R" independently represent aryl or heteroaryl, hydrogen, C3-C-, cycloalkyl or C1.6alkyl, the latter two groups being optionally substituted by one or more substituents independently selected from halogen, C3-C7 cycloalkyl, aryl, heteroaryl, OR6 and NR6R7, S(O)~R6 (where n =0, 1 or 2), CONR6R7, NR6COR7, 502NR6R7 and NR6SO2R7;

or

R10 R" 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 0, S(O)~ (where n =0, 1 or 2), NR8, and itself optionally substituted by halogen or C1-C3 alkyl.

Examples of aryl include phenyl and naphthyl.

Heteroaryl is defined as a 5-7 member aromatic ring or can be 6,6- or 6,5-fused bicycic ring optionally containing one or more heteroatoms selected from N, S and 0. The bicycic ring may be linked through carbon or nitrogen and may be attached through the 5 or 6 membered ring and can be fully or partially saturated.
Examples include pyridine, pyrimidine, thiazole, oxazole, pyrazole, imidazole, furan, isoxazole, pyrrole, isothiazole and azulene, naphthyl, indene, quinoline, isoquinoline, indole, indolizine, benzo[b]furan, benzoljb)thiophene, 1H-indazole, benzimidazole, benzthiazole, benzoxazole, purine, 4H-quinolizine, cinnoline, phthalazine, quinazoline, quinoxaline, 1,8-naphthyridine, pteridine, quinolone and 1,2-methylenedioxy benzene.

Aryl or heteroaryl groups can be optionally substituted by one or more substituents
9
independently selected from hydrogen, halogen, CN, OH, SH, nitro, C02R6, 502R9, OR,
SR9, 50R9, 502NR10R"1, CONR10R", NR"~R"1, NHSO2R9, NR9SO2R9, NR6CO2R6, NIHCOR9, NR9COR9, aryl, heteroaryl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl or C1~alkyl, the latter four groups being optionally substituted by one or more substituents independently selected from halogen, C3-C7 cycloalkyl, 6, NR6R7, S(O)~R6 (where n is 0, 1 or 2), CONR6R7, NR6COR7, 502NR6R7 and NR6502R7. Substituents can be present at any suitable position, including appropriate substituents on nitrogen atoms.




The group A is a six membered heterocyclic ring containing one or more nitrogen atoms or may be a 6,6 or 6,5 fused bicycle containing one or more 0, N, S atoms. Examples of suitable rings include pyridine, pyrimidine, pyrazine, pyridazine, indole, quinoline, isoquinoline, benzimidazole, benzthiazole, benzofuran, benzoxazole, benzthiophene, phthalazine and quinazoline.

In the context of the present specification, unless otherwise indicated, an alkyl or alkenyl group or an alkyl or ailcenyl moiety in a substituent group may be linear or branched.

Heterocyclic rings as defined for R4, R5 and R"0 and R1" means saturated heterocycles, examples include morpholine, azetidine, pyrrolidine, piperidine and piperazine. Substitents can be present on carbon and appropriate nitrogen atoms of said rings.

Preferably X is trifluoromethyl, nitro, cyano or halogen. More preferably X is trifluoromethyl, nitro, cyano, chloro or fluoro, even more preferably X is trifluoromethyl, chloro or fluoro. Most preferably X is trifluoromethyl or chioro.

Preferably Y is hydrogen, halogen or Ci.3allcyl. More preferably Y is hydrogen, flouoro or methyl. Most preferably Y is hydrogen.

Preferably Z is phenyl, pyridinyl, pyrimidyl, naphthyl, quinolyl, benzollb]thienyl or benzofuranyl each optionally substituted as defined above, more preferably phenyl optionally substituted as defined above. Preferred substituents for all Z groups include

those substituents exemplified herein, in particular halogen, Ci-3alkyl, cyano, 502R9, OR, SR9. C02R6, NHSO2R9, NR9502R9 and SO2NR"0R11.



More preferably when Z is phenyl it is optionally substituted by one to three, preferably one or two, substituents selected from SEt, SO2Me, SO2Et, chloro, fluoro, cyano, methoxy, propoxy, CO2H, methyl, ethyl, propyl, butyl, amino, hydroxyl, NHCONHEt, NHCONEMe, NIICONHZPr, NHCONH-cyclopropyl, CONH2, SO2NIH2, OCF3, COMe, CO2Me, nitro, phenyl, SCF3, 1-pyrrolidinylsuiphonyl, dimethylaminosulphonyl, ((phenylmethy)lamino)sulphonyl, [(2,2,2-trifluoroethylXlamino]sulphonyl, [(5-methyl-2-thiazolyl)amino]sulphonyl, (phenylamino)sulphonyl,(diethylamino)sulphonyl, (cyclopropylamino)sulphonyl, aminosulphonyl, (methylamino)sulphonyl, (4-methyl-i-piperazinyl)sulphonyl, NHCO2Me, (dimethylamino)sulphonyl, 4-morpholinylsulphonyl, 1-azetidinylsulphonyl, and 1 -pyrrolidinylcarbonyl.

More preferably when Z is pyridyl it is optionally substituted by one or two groups selected from SO2NH2, methyl, amino, chloro and NMeSO2Me,.
More preferably when Z is pyrimidine it is optionally substituted by one or two groups selected from amino, methyl, morpholinyl, dimethylamino, methylamino, benzylamino, piperidine, NMeSO2Me) (methylsulphonul)(benzyl)aniino, (ethylsulphonul)(benzyl)amino, acetyl(phenylmethyl)amino, 5-methyl-i, 1-dioxido- 1 ,2,5-thiadiazolidin-2-yl, 1,1 -dioxido-2-isothiazolidinyl, 3-hydroxy-1 -azetidinyl, 4-methyl-i -piperazinyl, 1 -pyrrolidinyl and
NI{SO2NMe2.

When Z is naphthyl it is preferably substituted with methoxy.

When Z is quinolyl, benzo[b]thienyl or benzofuranyl these groups are preferably unsubstituted.

Preferably R1 and R2 are independently hydrogen or C1-3 alkyl. More preferably both R" and R2 are hydrogen or one is hydrogen and the other is methyl or ethyl or both are methyl. Most preferably both R" and R2 are hydrogen.

Preferred compounds of the invention include those exemplified herein both in free base form as well as pharmaceutically acceptable salts and solvates 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 or p-toluenesulphon ate.

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 (IT):
(Formula Removed)



in which X, Y and Z are as defined in formula (Ii) or are protected derivatives thereof, with a compound of formula (Ill):

L-CR1R2CO2R~2 (LII)

Where R" and R2 are as defined in formula (1) or are protected derivatives thereof, R12 is H or C1-C10 alkyl group and L is a leaving group, and optionally thereafter in any order:
• removing any protecting group
• hydrolysing the ester group R"2 to the corresponding acid
o oxidation of sulphides to sulphoxides or sulphones
o forming a pharmaceutically acceptable salt.

The reaction can be carried out in a suitable solvent such as DMF using a base such as potassium carbonate or the like. Suitable groups R"2 include C1.6 ailkyl groups such as methyl, ethyl or tert-butyl. Suitable L is a leaving group such as halo, in particular chlorine or bromine. L may also be hydroxy so that a Mlitsunobu reaction may be performed with compound (Ill) using for example triphenyiphosphine and diethyl azodicarboxylate.

Hydrolysis of the ester group R"2 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 of group R"3 when R"3 is not equal to H:










in which X, Y and Z are as defined in formula (I) or are protected derivatives thereof, R"3 is H or a suitable protecting group, for example benzyl, L1 is iodide, bromide, chloride or triflate and R"4 and R15 are H or C1-C6 alkyl groups or R"4 and R"5 together can form a 5 or 6 membered ring optionally substituted by one or more C1-C3 allcyl.

The reaction can be carried out in a suitable solvent such as dioxane using a palladium catalyst such as [l,1-bis(diphenylphosphino)ferrocene]dichloropauadium and a base such as cesium fluoride, preferably at elevated temperatures.

Compounds of formula (IV) can be prepared from a compound of formula (VI) by formation of an organometallic (VII) followed by reaction with a borate ester, as outlined in Scheme I.
(Scheme Removed)


in which X, Y are as defined in formula (I) or are protected derivatives thereof, R"3 is as defined in formula (IV), E is hydrogen or halogen and M is a metal such as Na or Li. For example when R13 is benzyl and E is bromine, butyl lithium can be used to form the intermediate (VII) where M = Li. The reaction is performed at —780C in diethylether, then quenched with a borate ester such as trimethylborate.

Compounds of formula (IV) may also be prepared by a palladium catalysed coupling of compounds of formula (VIII) with a suitable boronic ester, for example (LX) or

(Formula Removed)


0~


in which X, Y and R13 are as defined above and G is halogen or triflate

Compounds of formula (II) may also be prepared by reaction of a compound of formula (Xl) with a compound of formula (XII) using Suzuki coupling methodology.
(Formula Removed)




in which X, Y, Z, R"3, L1, R"4 and R15 are as defined above and compounds of formula (XI) and (XII) can be made using the same methodology as above.

Compounds of formula (II), where Z=heteroaryl may also be prepared by ring synthesis, for example a compound of formula (XIII) may be formed by reaction of a compound of formula (XIV) with a compound of formula (XV).
X, Y and R"3 are as defined above and R16 as defined as a substituent on Z as defined in formula (I) or are protected derivatives thereof. The reaction can be carried out in a solvent such as ethanol under reflux, and a base such as sodium ethoxide can be used if compound of formula (XV) is a salt
(Formula Removed)





When R16 is a group 5-alkyl, this may be further elaborated by oxidation to the sulfoxide or sulphone using an oxidizing agent such as mcpba in DCM at RT. This may then be displaced with an appropriate nucleophile as defined for Z in formula 1. Scheme 2;
(Scheme Removed)





The sequence of the steps above may be changed, for example a compound of formula (XVI) may be formed by the reaction of a compound of formula (XVII) with a compound of formula (XII) using a Suzuki coupling.
Compounds of formula (I) may also be prepared by reaction of a compound of formula
(Formula Removed)


(XVIII) in which in which X, Y, R , R , R ,R"4 and R15 are as defined above with a compound of formula (V) using Suzuki coupling method as defined above.


A compound of formula (XVIII) may be prepared by method A or B

Method A
(Formula Removed)














The acid was first converted to the acid chloride, using for example oxalylchloride in DCM at RT, then reacted with 3-methyl-3-oxetanemethanol in the presence of a base such as triethylamine to give the ester. The oxetane ester is the rearranged to the OBO ester using boron trifluoride diethyletherate in DCM at —780C to RT. Deprotonation with a base such as sec —butyl lithium at low temperature followed by quenching with trimethylborate gave the protected diacid which was then deprotected using HCl then sodium hydroxide
Method B
(Formula Removed)


A compound of formula (IV) where R13 = Bn and R"4 and R15= H and pinacol can bestirred at RT ma suitable solvent such as diethylether to give the boronate ester. The benzyl group may be removed by hydrogenation at RT using palladium on carbon as catalyst then alkylated with a compound of formula (III) using a base or mitsunobu conditions. Treatment with acid such as HCl or trifluoroacetic acid then removes the protecting groups.

In a further aspect, the present invention provides the use of a compound of formula (I), a prodrug, pharmaceutically acceptable salt or solvate thereof for use in therapy.

The compounds of formula (1) have activity as phannaceuticals, in particular as modulators of CRT1i2 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) (the respiratory tract) obstructive airways diseases including: asthma (such as bronchial, allergic, intrinsic, extrinsic and dust asthma particularly chronic or inveterate asthma (e.g. late asthma and airways hyper-responsiveness)); chronic obstructive pulmonary disease (COPD)(such as irreversible COPD); bronchitis (including eosinophilic bronchitis); acute, allergic, atrophic rhinitis or chronic rhinitis (such as rhinitis caseosa, hypertrophic rhiitis, rhinitis purulenta, rhinitis sicca), rhinitis medicamentosa, membranous rhinitis (including croupous, fibrinous and pseudomembranous rhinitis), scrofoulous rhinitis, perennial allergic rhinitis, easonal rhinitis (including rhinitis nervosa (hayfever) and vasomotor rhinitis); nasal polyposis; sarcoidosis; farmer"s lung and related diseases; fibroid lung; idiopathic interstitial pneumonia; cystic fibrosis; antitussive activity; treatment of chronic cough associated with inflammation or jatrogenic induced;

(2) (bone and joints) arthrides including rheumatic, infectious, autoimmune, seronegative, spondyloarthropathies (such as ankylosing spondylitis, psoriatic arthritis and Reiter"s disease), Behcet"s disease, Sjogren"s syndrome and systemic sclerosis;

(3) (skin and eyes) psoriasis, atopical dermatitis, contact dermatitis, other eczmatous dermitides, seborrhoetic dermatitis, Lichen planus, Pemphigus, bullous Pemphigus, Epidermolysis bullosa, urticaria, angiodermas,
vasculitides, erythemas, cutaneous eosinophilias, chronic skin ulcers, uVeitis, Alopecia areatacomeal ulcer and vernal conjunctivitis;

(4) (gastrointestinal tract) Coeliac disease, proctitis, eosinopilic gastro-enteritis, mastocytosis, Crohn"s disease, ulcerative colitis, irritable bowel disease; food-related allergies which have effects remote from the gut, (such as migraine, rhinitis and eczema);

(5) (central and peripheral nervous system) Neurodegenerative diseases and dementia disorders (such as Alzheimer"s disease, amyotrophic lateral sclerosis and other motor neuron diseases, Creutzfeldt-Jacob"s disease and other prion diseases, HLV encephalopathy (AIDS dementia complex), Huntington"s disease, frontotemporal dementia, Lewy body dementia and vascular dementia), polyneuropathies (such as Guillain-Barr~ syndrome, chronic inflammatory demyelinating polyradiculoneuropathy, multifocal motor neuropathy), plexopathies, CNS demyelination (such as multiple sclerosis, acute disseminated/haemorrhagic encephalomyelitis, and subacute sclerosing panencephalitis), neuromuscular disorders (such as myasthenia gravis and Lambert-Eaton syndrome), spinal diorders (such as tropical spastic paraparesis, and stiff-man syndrome), paraneoplastic syndromes (such as cerebellar degeneration and encephalomyelitis), CNS trauma, migraine and stroke.

(6) (other tissues and systemic disease) atherosclerosis, acquired Immunodeficiency Syndrome (AIDS), lupus erythematosus; systemic lupus, erythematosus; Hashimoto"s thyroiditis, type I diabetes, nephrotic syndrome, eosinophilia fascitis, hyper IgE syndrome, lepromatous leprosy, idiopathic thrombocytopenia pupura; post-operative adhesions, sepsis and ischemic/reperfusion injury in the heart, brain, peripheral limbs hepatitis (alcoholic, steatohepatitis and chronic viral) , glomerulonephritis, renal impairment, chronic renal failure and other organs

(7) (allograft rejection) acute and chronic following, for example, transplantation of kidney, heart, liver, lung, bone marrow, skin and cornea; and chronic graft versus host disease;

(8) Diseases associated with raised levels of PGD2 or its metabolites.
(1) (respiratory tract) - obstructive diseases of the airways including: asthma, including bronchial, allergic, intrinsic, extrinsic, exercise-induced, drug-induced (including aspirin and NSALD-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; farmer"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 pulmonary 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, coronavirus (including SARS) and adenovirus.

(2) (bone and joints) artliritides associated with or including osteoarthritis/osteoarthrosis, both primary and secondary to e.g. congenital hip dysplasia; cervical and lumbar spondylitis, and low back and neck pain; rheumatoid arthritis and Still"s disease; seronegative spondyloarthropathies including ankylosing spondylitis, psoriatic arthritis, reactive arthritis and undifferentiated spondarthropathy; septic arthritis and other infection-related arthopathies and bone disorders such as tuberculosis,"including Potts" disease and Poncet"s syndrome; acute and chronic crystal-induced synovitis including irate gout, calcium pyrophosphate deposition disease, and calcium apatite related tendon, bursal and synovial inflammation; Behcet"s disease; primary and secondary Sjogren"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 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) (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, pyoderma 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; panniculitis;cutaneous lymphomas, non-melanoma skin cancer and other dysplastic lesions; drug-induced disorders including fixed drug eruptions.

(4) (eyes) blepharitis; conjunctivitis, including perennial and vernal allergic conjunctivitis; iritis; anterior and posterior uveitis; choroiditis; autoimmune; degenerative or inflammatory disorders affecting the retina; ophthalmitis including sympathetic ophthalmitis; sarcoidosis; infections including viral , fungal, and bacterial.

(5) (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).

(6) (abdominal) hepatitis, including autoimmune, alcoholic and viral; fibrosis and cirrhosis of the liver; cholecystitis; pancreatitis, both acute and chronic.

(7) (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).

(8) (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;






(9) (CNS) Alzheimer" s disease and other dementing disorders including CTh and nvCJD; amyloidosis; multiple sclerosis and other demyelinating 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, post-herpetic, and HIV-associated neuropathies; neurosarcoidosis; central and peripheral nervous system complications of malignant, infectious or autoimmune processes.

(10) Other auto-immune and allergic disorders including Hashimoto"s thyroiditis, Graves" disease, Addison"s disease, diabetes mellitus, idiopathic thrombocytopaenic purpura, eosinophilic fasciitis, hyper-IgE syndrome, antiphospholipid syndrome.

(11) Other disorders with an inflammatory or immunological component; including acquired immune deficiency syndrome (ADS), leprosy, Sezary syndrome, and paraneoplastic syndromes.

(12) (Cardiovascular); atherosclerosis, affecting the coronary and peripheral circulation; pericarditis; myocarditis , inflammatory and auto-immune cardiomyopathies including myocardial sarcoid; ischaemic reperfusion injuries; endocarditis, valvulitis, and aortitis including infective (e.g. syphilitic); vasculitides; disorders of the proximal and peripheral veins including phlebitis and thrombosis, including deep vein thrombosis and complications of varicose veins.

(13) (Oncology) treatment of common cancers including prostate, breast, lung, 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.

(14) Diseases associated with raised levels of PGD2 or its metabolites.

Thus, the present invention provides a compound of formula (I), 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
chemokine 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 POD2 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 in therapy in combination with drugs used to treat asthma and rhinitis (such as inhaled and oral steroids, inhaled f32-receptor agonists and oral leukotriene receptor antagonists).

The invention further relates to combination therapies wherein a compound of formula (1) or a pharmaceutically acceptable salt, solvate or in vivo hydrolysable ester thereof, or a pharmaceutical composition or formulation comprising a compound of formula (1) is administered concurrently or sequentially or as a combined preparation with another therapeutic agent or agents, for the treatment of one or more of the conditions listed.

In particular, for the treatment of the inflammatory diseases rheumatoid arthritis, psoriasis, inflammatory bowel disease, COPD, asthma and allergic rhinitis the compounds of the invention may be combined with agents such as tumour necrosis factor alpha (TNF-ct) inhibitors such as anti-TNF monoclonal antibodies (for example Remicade. CDP-870 and adalimumab) and TNF receptor immunoglobulin molecules (such as Enbrel); non-selective cyclo-oxygenase (COX)-1 I COX-2 inhibitors whether applied topically or systemically (such as piroxicam, diclofenac, propionic acids such as naproxen, flubiprofen, fenoprofen, ketoprofen and ibuprofen, fenamates such as mefenamic acid, indomethacin, sulindac, azapropazone, pyrazolones such as phenylbutazone, salicylates such as aspirin). COX-2 inhibitors (such as meloxicain, celecoxib, rofecoxib, valdecoxib, lumarocoxib, parecoxib and etoricoxib); glucocorticosteroids (whether administered by topical,oral, intramuscular, intravenous, or intra-articular routes); methotrexate, lefunomide; hydroxychloroquine, dpenicillamine, auranofin or other parenteral or oral gold preparations.

The present invention still further relates to the combination of a compound of the invention together with a leukotriene biosynthesis inhibitor, 5-lipoxygenase (5-LO)
inhibitor or 5-lipoxygenase activating protein (FLAP) antagonist such as; zileuton; ART-761; fenleuton; tepoxalin; Abbott-79 175; Abbott-8576 1; N-(5-substituted)-thiophene-2-alkylsulfonamides; 2,6-di-tert-butylphenol hydrazones; methoxytetrahydropyrans such as Zeneca ZD-21 38; the compound SB-210661; pyridinyl-substituted 2-cyanonaphthalene compounds such as L-739,010; 2-cyanoquinoline compounds such as L-746,530; indole and quinoline compounds such as MK-591, MiIK-886, and BAY x 1005.

The present invention still further relates to the combination of a compound of the invention together with 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 BflL 284/260; and compounds such as zafirlukast, ablukast, montelukast, pranlukast, verlukast (MK-679), RG-12525, Ro-2459 13, iralukast (CGP 45715A), and BAY x 7195.

The present invention still further relates to the combination of a compound of the invention together with a phosphodiesterase (PDE) inhibitor such as the methylxanthanines including theophylline and aminophylline; and selective PDE isoenzyme inhibitors including PDE4 inhibitors and inhibitors of the isoform PDE4D, and inhibitors of PDE5.

The present invention still further relates to the combination of a compound of the invention together with histamine type 1 receptor antagonists such as cetirizine, loratadine, desloratadine, fexofenadine, acrivastine, terfenadine, astemizole, azelastine, levocabastine, chiorpheniramine, promethazine, cydizine, and mizolastine applied orally, topically or parenterally.

The present invention still further relates to the combination of a compound of the invention together with a gastroprotective histamine type 2 receptor antagonist.

The present invention still further relates to the combination of a compound of the invention with antagonists of the histamine type 4 receptor.

The present invention still further relates to the combination of a compound of the invention together with an alpha-1/alpha-2 adrenoceptor agonist vasoconstrictor sympathomimetic agent, such as propylhexedrine, phenylephrine, phenylpropanolamine, ephedrine, pseudoephedrine, naphazoline hydrochloride, oxymetazoline hydrochloride, tetrahydrozoline hydrochloride, xylometazoline hydrochloride, tramazoline hydrochloride, and ethylnorepinephrine hydrochloride.


The present invention still further relates to the combination of a compound of the invention together with anticholinergic agents including muscarinic receptor (Ml, M2, and M3) antagonists such as atropine, hyoscine, glycpyrrrolate, ipratropium bromide; tiotropium bromide; oxitropium bromide; pirenzepine; and telenzepine.

The present invention still further relates to the combination of a compound of the invention together with a beta-adrenoceptor agonist (including beta receptor subtypes 1-4) such as isoprenaline, salbutamol, formoterol, salmeterol, terbutaline, orciprenaline, bitolterol mesylate, and pirbuterol.

The present invention still further relates to the combination of a compound of the invention together with a chromone, including sodium cromoglycate and nedocromil sodium.

The present invention still further relates to the combination of a compound of the invention together with an insulin-like growth factor type I (IGF-1) mimetic.

The present invention still further relates to the combination of a compound of the invention together with an inhaled glucocorticoid, such as flunisolide, triamcinolone acetonide, beclomethasone dipropionate, budesonide, fluticasone propionate, ciclesonide, and mometasone furo ate.

The present invention still further relates to the combination of a compound of the invention together with an inhibitor of matrix metalloproteases (MMPs), i.e., the stromelysins, the collagenases, and the gelatinases, as well as aggrecanase; especially collagenase-l (MIvIP- 1), collagenase-2 (MIMIP-8), collagenase-3 (MMP-1 3), stromelysin- 1 (MIMIP-3), stromelysin-2 (MMP-l0), and stromelysin-3 (MIVLP-1 1) and MMP-9 and MMP-12.

The present invention still further relates to the combination of a compound of the
invention together with modulators of chemokine receptor function such as antagonists of
CCR1, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9,
CCR1O and CCR1 1 (for the C-C family); CXCR1, CXCR2, CXCR3, CXCR4 and CXCR5
(for the C-X-C family) and CX3CRl for the C-X3-C family.

The present invention still further relates to the combination of a compound of


the invention together with a cytokine or modulator of cytokine function, including alpha-, beta-, and gamma-interferon; interleukins (IL) including ILl to 15, and interleukin antagonists or inhibitors, including agents which act on cytokine signalling pathways.

The present invention still further relates to the combination of a compound of the invention together with an immunoglobulin (Ig) or Ig preparation or an antagonist or antibody modulating Ig function such as anti-IgE (omalizumab).

The present invention still further relates to the combination of a compound of the invention together with other systemic or topically-applied anti-inflammatory agents including thalidomide and derivatives, retinoids, dithranol, and calcipotriol.

The present invention still further relates to the combination of a compound of the invention together with an antibacterial agent including penicillin derivatives, tetracyclines, macrolides, beta-lactams, flouroquinolones, and inhaled aminoglycosides; and antiviral agents including acyclovir, famciclovir, valaciclovir, ganciclovir, cidofovir; amantadine, rimantadine; ribavirin; zanamavir and oseltamavir; protease inhibitors such as indinavir, nelfinavir, ritonavir, and saquinavir; nucleoside reverse transcriptase inhibitors such as didanosine, lamivudine, stavudine, zalcitabine, zidovudine; non-nucleoside reverse transcriptase inhibitors such as nevirapine, efavirenz.

The present invention still further relates to the combination of a compound of the invention together with cardiovascular agents such as calcium channel blockers, betaadrenoceptor blockers, angiotensin-converting enzyme (ACE) inhibitors, angiotensin-2 receptor antagonists; lipid lowering agents such as statins, and fibrates; modulators of blood cell morphology such as pentoxyfylline; thrombolytics, and anticoagulants including platelet aggregation inhibitors.

The present invention still further relates to the combination of a compound of the invention together with CNS agents such as antidepressants (such as sertraline), antiParkinsonian drugs (such as deprenyl, L-dopa, Requip, Mirapex, MAOB inhibitors such as selegine and rasagiline, comP inhibitors such as Tasmar, A-2 inhibitors, dopamine reuptake inhibitors, NMiDA antagonists, nicotine agonists, dopamine agonists and inhibitors of neuronal nitric oxide synthase), and anti-Alzheimer"s drugs such as donepezil, tacrine, COX-2 inhibitors, propentofylline or metrifonate.

The present invention still further relates to the combination of a compound of the invention together with agents for the treatment of acute and chronic pain, including centrally and peripherally-acting analgesics such as opioid analogues and derivatives,


carbamazepine, phenytoin, sodium valproate, arnitryptiline and other antidepressant agents, and non-steroidal anti-inflammatory agents.

The present invention still further relates to the combination of a compound of the invention together with parenterally or topically-applied local anaesthetic agents such as lignocaine.

The present invention still further relates to the combination of a compound of the invention together with (i) tryptase inhibitors; (ii) platelet activating factor (PAF) antagonists; (iii) interleukin converting enzyme (ICE) inhibitors; (iv) IMPDH inhibitors; (v) adhesion molecule inhibitors including VLA-4 antagonists; (vi) cathepsins; (vii) MAP kinase inhibitors; (viii) glucose-6 phosphate dehydrogenase inhibitors; (ix) kinin-B.subl. -and B.sub2. -receptor antagonists; (x) anti-gout agents, e.g., colchicine; (xi) xanthine oxidase inhibitors, e.g., allopurinol; (xii) uricosuric agents, e.g., probenecid, sulfinpyrazone, and benzbromarone; (xiii) growth hormone secretagogues; (xiv) transforming growth factor (TGF~3); (xv) platelet-derived growth factor (PDGF); (xvi) fibroblast growth factor, e.g., basic fibroblast growth factor (bFGF); (xvii) granulocyte macrophage colony stimulating factor (GM-CSF); (xviii) capsaicin cream; (xix) Tachykinin NK.subl. and NK.sub3. receptor antagonists selected from the group consisting of NKP-608C; SB-233412 (talnetant); and D-4418; (xx) elastase inhibitors selected from the group consisting of UT-77 and ZD-0892; (xxi) TNFD converting enzyme inhibitors (TACE); (xxii) induced nitric oxide synthase inhibitors (iNOS) or (xxiii) chemoattractant receptor-homologous molecule expressed on TH2 cells, (CRTH2 antagonists) (xxiv) inhibitors of P38

The compounds "of the present invention may also be used in combination with anti-osteoporosis agents including hormonal agents such as raloxifene, and biphosphonates such as alendronate.

The compounds of the invention may also be used in combination with existing therapeutic agents for the treatment of osteoarthritis. Suitable agents to be used in combination include standard non-steroidal anti-inflammatory agents (hereinafter NSAIDs) such as piroxicam, diclofenac, propionic acids such as naproxen, flubiprofen, fenoprofen, ketoprofen and ibuprofen, fenamates such as mefenamic acid, indomethacin, sulindac, apazone, pyrazolones such as phenylbutazone, salicylates such as aspirin, COX-2 inhibitors such as celecoxib, valdecoxib, rofecoxib and etoricoxib, analgesics, and intraarticular therapies such as corticosteroids and hyaluronic acid derivatives, and nutritional supplements such as glucosamine.


The compounds of the invention can also be used in combination with existing therapeutic agents for the treatment of cancer. Suitable agents to be used in combination include:
(i) antiproliferative/antineoplastic drugs and combinations thereof, as used in medical oncology, such as alkylating agents (for example cis-platin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chiorambucil, busulphan and nitrosoureas); antimetabolites (for example antifolates such as fluoropyrimi dines like 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytosine arabinoside, hydroxyurea, gemcitabine and paditaxel; antitumour antibiotics (for example anthracycines like adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin and mithramycin); antimitotic agents (for example ymca alkaloids like vincristine, vinblastine, vindesine and vinorelbine and taxoids like taxol and taxotere); and topoisomerase inhibitors (for example epipodophyllotoxins like etoposide and teniposide, amsacrine, topotecan and camptothecins);
(ii) cytostatic agents such as antioestrogens (for example tamoxifen, toremifene, raloxifene, droloxifene and iodoxyfene), Qestrogen receptor down regulators (for example fulvestrant), antiandrogens (for example bicalutamide, flutamide, nilutamide and cyproterone acetate), LHRH antagonists or LHRH agonists (for example goserelin, leuprorelin and buserelin), progestogens (for example megestrol acetate), aromatase inhibitors (for example as anastrozole, letrozole, vora.zole and exemestane) and inhibitors of Scz-reductase such as finasteride;
(iii) Agents which inhibit cancer cell invasion (for example metalloproteinase inhibitors like marimastat and inhibitors of urokinase plasminogen activator receptor function); (iv) inhibitors of growth factor function, for example such inhibitors include growth factor antibodies, growth factor receptor antibodies (for example the anti-erbb2 antibody trastuzumab and the anti-erbbl antibody cetuximab [C225]) , farnesyl transferase inhibitors, tyrosine kinase inhibitors and serine/threonine kinase inhibitors, for example inhibitors of the epidermal growth factor family (for example EGER family tyrosine kinase inhibitors such as ~-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine (gefitinib, AZD 1839), ~-(3-ethynylphenyl)-6 ,7-bis(2-methoxyethoxy)quinazolin4-amine (erlotinib, OSI-774) and 6-acrylamido-N-(3-chloro4-fluorophenyl)-7-(3-morpholinopropoxy)quinazolin-4-amine (CI 1033)), for example inhibitors of the platelet-derived growth factor family and for example inhibitors of the hepatocyte growth factor family;
(v) antiangiogenic agents such as those which inhibit the effects of vascular endothelial growth factor, (for example the anti-vascular endothelial cell growth factor antibody bevacizumab, compounds such as those disclosed in International Patent Applications WO 97122596, WO 97130035, WO 97/32856 and WO 98/13354) and compounds that work by other mechanisms (for example linomide, inhibitors of integrin c~v~3 function and angiostatin);


(vi) vascular damaging agents such as combretastatin A4 and compounds disclosed in International Patent Applications WO 99/02166, WOOO/40529, WO 00/41669, WOO1/92224, W002/04434 and W002/08213;
(vii) antisense therapies, for example those which are directed to the targets listed above, such as ISIS 2503, an anti-ras antisense;
(viii) gene therapy approaches, including for example approaches to replace aberrant genes such as aberrant p53 or aberrant BRCA1 or BRCA2, ODEPT (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; and (ix) immunotherapy approaches, including for example ex-vivo and in-vivo approaches to increase the immunogenicity of patient tumour cells, such as transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor, approaches to decrease T-cell anergy, approaches using transfected immune cells such as cytokine-transfected dendritic cells, approaches using cytokine-transfected tumour cell lines and approaches using anti-idiotypic antibodies.

In a still 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 the treatment of human diseases or conditions in which modulation of CRTh2 receptor activity is beneficial.

In the context of the present specification, the term "therapy" also includes "prophyla~xis" 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), prodrugs and pharmaceutically acceptable salts and solvate~ 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 compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as herein before defined, in association with a pharmaceutically acceptable adjuvant, diluent or carrier.

The pharmaceutical compositions may be administered topically (e.g. to the lung and/or airways or to the skin) in the form of solutions, suspensions, heptafluoroalkane aerosols and dry powder formulations; or systemically, e.g. by oral administration in the form 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, 1H 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 Inc, 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:



EtOAc
DCM
NMP
DMF
THE
mcpba Pd(dppf)Clz


Ethylacetate
Dichioromethane
N-methylpyrrolidine
N,N-dimethylformamide
tetrahydrofuran
3-chloroperoxybenzoic acid (Aldrich 77% max)
[1,1" - Bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichioromethane

room temperature

RT




Example 1 {[5-Chloro-4t-(ethylthio)biphenyl-2-yl]oxy}acetic acid
(Formula Removed)

(i) tert-Butyl (2-bromo-4-chlorophenoxy)acetate tert-Butyl bromoacetate (2.6m1) was added to a stirred mixture. of 4-bromo-2-chlorophenol
(3g) and potassium carbonate (6.2g) in DMF (40m1) at RT. After 16h the reaction was partitioned between diethylether and water, the organics separated, dried and evaporated under reduced pressure. The residue was purified by chromatography on silica eluting with 4% EtOAc/iso-hexane. Yield 4.05g

"H NIvIR CDCl3: 8 7.55 (1H, d) ; 7.21 (1H, dd) ; 6.72 (1H, d) ; 4.57 (2H, s) :1.48 (9H, s)

(ii) tert-Butyl { [5-chloro-4"-(ethylthio)biphenyl-2-yl]oxy } acetate
A mixture of the product from step (i) (2g), 4-(ethylthio)phenylboronic acid (1.5g), cesium fluoride (2g) and Pd(dppf)C12 (0.2g) in dioxane (40m1) was heated under reflux for 3h. After cooling the mixture was partitioned between diethylether and water. The organics were separated, dried and evaporated under reduced pressure. The residue was purified by chromatography on silica eluting with 5% EtOAc/iso-hexane. Yield 0.92g

MS: APCI (+ve): 379/38 1 (M+l)

(iii) { [5-Chloro-4"-(ethylthio)biphenyl-2-yl]oxy } acetic acid
The title compound was prepared by stirring a mixture of the product from step (ii) (0.3g) and trifluoroacetic acid (4m1) in DCM (lOmi) at RT for 5h. The solvent was evaporated under reduced pressure, the residue triturated with diethylether then purified by reverse phase HPLC. Yield 0.106g

"H NN"IR DMSO-d6: δ 13.07 (lH, s) ; 7.54 (2H, d) ; 7.35-7.33 (411, m) ; 7.02 (1H, d) ; 4.74
(211, s) ; 3.02 (2H, q); 1.27 (311, t)
MS: APCI (-ye): 321/3 (M-1)

Example 2
{[5-Chloro-4"-(ethylsulfonyl)biphenyl-2-yl]oxylacetic acid
(Formula Removed)













(i) tert-Butyl { [5-chloro-4"-(ethylsulfonyl)biphenyl-2-yl]oxy} acetate
Mcpba (1.2g) was added to a stirred solution of the product from example 1 step (ii) (0.6g) in DCM (lOmI) at RT. After 4h, the mixture was partitioned between DCM and aqueous sodium metabisulphite solution, the organics separated, washed with aqueous sodium hydrogencarbonate solution, water, dried and evaporated under reduced pressure. Yield 0.65g

(ii) { [5-Chloro-4"-(ethylsulfonyl)biphenyl-2-yl] oxy} acetic acid
The title compound was prepared by the method of example 1 step (iii) using the product from step (i). Yield 0.226g

"HNMRDMSO-d6: δ13.14(111, s) ; 7.92(211, d) ; 7.87(211, d) ; 7.45-7.42(211, m) ; 7.10
(111, d) ; 4.79 (211, s) ; 3.35 (211, q); 1.15 (311, t)
MS: APCI (-ye): 353/5 (M-1)

Example 3
[(4",5-Dichlorobiphenyl-Z-yI)oxy]acetic acid
(Formula Removed)


(i) tert-Butyl [(4",5-dichlorobiphenyl-2-yl)oxy]acetate
The subtitle compound was prepared by the method of example I step (ii) using the product from example 1 step (i) and 4-chiorophenylboronic acid. Yield 0.63g

"H NIMIR CDCl3: 67.54-7.22 (611, m) ; 6.76 (111, dd) ; 4.48 (211, s); 1.47 (911, s)

(ii) [(4",5-Dichlorobiphenyl-2-yl)oxy]acetic acid
The title compound was prepared by the method of example 1 step (iii) using the product from step (i). Yield O.224g






111 NMR DMSO-d6: 6 13.00 (111, s) ; 7.61 (211, d) ; 7.48 (211, d) ; 7.41-7.36 (211, m) ; 7.05

MS: APCI (-ye): 295/7 (M-1)

Example 4
t(5-Chloro-4 "-cyanobiphenyl-2-yI)oxy]acetic acid
(Formula Removed)

(i) tert-Butyl R5-chloro-4"-cyanobiphenyl-2-yl)oxy]acetate
The subtitle compound was prepared by the method of example 1 step (ii) using the product from example 1 step (i) and 4-cyanophenylboronic acid. Yield 0.524g

"HNMR CDCl3: δ 7.70 (411, s) ; 7.32-7.26 (211, m) ; 6.79 (1H, d) ; 4.51 (211, s); 1.48 (911,
s)

(ii) [(5-Chloro-4"-cyanobiphenyl-2-yDoxy]acetic acid
The title compound was prepared by the method of example 1 step (iii) using the product from step (i). Yield 0.109g

"H NMR DMSO-d6: 6 13.14 (111, s) ; 7.90(211, d) ; 7.80 (211, d) ; 7.45-7.41 (211, m) ; 7.10
(111, d) ; 4.78 (211, s)
MS: APCI (-ye): 286/S (M-1)

Example 5
1X5-Chloro-4"-niethoxybiphenyl-2-yl)oxy]acetic acid
(Formula Removed)

(i) tert-Butyl [(5-chloro4"-methoxybiphenyl-2-yI)oxy]acetate
The subtitle compound was prepared by the method of example 1 step (ii) using the product from example 1 step (i) and 4-methoxyphenylboronic acid. Yield 0.6 lOg



"H NMR CDCI3: δ 7.54 (211, d) ; 7.31-7.18 (211, m) ; 6.96 (211, d) ; 6.76 (111, d) ; 4.46 (211, s) ; 3.84 (311, s); 1.46 (9H, s)

(II) [(5-Chloro-4"-methoxybiphenyl-2-yl)oxy] acetic acid
The title compound was prepared by the method of example 1 step (iii) using the product from step (i). Yield 0.119g

"H NMR DMSO-d6: 6 13.08 (111, s) ; 7.53 (211, d) ; 7.32-7.29 (211, m) ; 7.01-6.96 (311, m) 4.72 (211, s) ; 3.79 (311, s)
MS: APCI (-ye): 29 1/3 (M-l)

Example 6
acid, trifluoroacetic acid salt
(Formula Removed)





(i) tert-Butyl (4-chloro-2-quinolin-8-ylphenoxy)acetate
The subtitle compound was prepared by the method of example 1 step (ii) using the product from example 1 step (i) and 8-quinoline boronic acid. Yield O.356g

"H NMJR CDCl3: δ 8.90-8.88 (111, m) ; 8.18 (111, d) ; 7.85 (111, d) ; 7.76 (111, d) ; 7.60 (111, t) ; 7.40-7.30 (311, m) ; 6.87 (111, d) ; 4.37 (211, s); 1.37 (911, s)

(ii) (4-Chloro-2-quinolin-8-ylphenoxy)acetic acid, trifluoroacetic acid salt The title compound was prepared by the method of example 1 step (iii) using the product from step (i). Yield 0.25g

"HNMRDMSO-d6: δ8.91-8.89(111, m) ; 8.62(111, d) ; 8.12(111, d) ; 7.85-7.67(311, in);
7.46 (111, dd) ; 7.38 (1H, d) ; 7.09 (111, d) ; 4.61 (211, s)
MS: APCI (-ye): 312/4 (M-l)

Example 7
[(5-Chloro-3",4"-dimethoxybiphenyl-2-yI)oxy]acetic acid
(Formula Removed)



(i) tert-Butyl [(S-chloro-3",4"-dimethoxybiphenyl~2~yl)oxy]acetate
The subtitle compound was prepared by the method of example 1 step (ii) using the product from example 1 step (i) and 3,4-dimethoxyphenylboronic acid. Yield 0.86g

"H NMR CDCl3: δ7.33-7.12 (411, m) ; 6.93 (111, d) ; 6.79 (111, d) ; 4.46 (211, s) ; 3.93 (311, s) ; 3.92 (311, s); 1.46 (911, s)

(ii) [(S-Chloro-3",4"-dimethoxybiphenyl-2-yl)oxy] acetic acid
The title compound was prepared by the method of example 1 step (iii) using the product from step (i). Yield 0.32g

"H NMR DMSO-d6: 6 13.08 (111, s); 7.36-7.27 (311, m) ; 7.12-6.98 (311, m) ; 4.74 (211, s);
3.78 (611, 2xs)
MS: APCI (-ye): 32 1/3 (M-1)

Example 8
2".(Carboxymethoxy)~5"~chlorobiphenyl-4-carboxylic acid
(Formula Removed)
The title compound was prepared by the method of example 1 step (ii) and step (iii) using the product from example 1 step (i) and 4-carboxyphenylboronic acid. Yield 0.035g

"H NMR DMSO-d6: δ 7.98-7.38 (611, m) ; 7.08-7.05 (111, m) ; 4.75 (211, s)
MS: APCI (-ye): 305 (M-1)

Example 9
{[5-Chloro-4"-(methylsulfonyl)biphenyl-2-yl]oxy}acetic acid
(Formula Removed)

The title compound was prepared by the method of example 1 step (ii) and example
using the product from example 1 step (i) and 4-(methylthio)benzeneboronic acid. Yield
0.1 g

"H NIVIR DMSO-d6: δ7.97-7.08 (711, m) ; 4.78 (211, s) ; 3.31 (311, bs)
MS: APCI (-ye): 339 (M-1)

Example 10
{[5-Chloro-4"-(ethylsuufonyl)-2"-methylbiphenyl-2-yl]oxy}acetic acid
(Formula Removed)








(i) 4-Bromo-3-methylphenyl ethyl sulfide
Bromine (2.2m1) was added to a solution of 1-(ethylthio)-3-methylbenzene (6.6g) in acetic acid (2Onil) at 00C. The mixture was stirred at RT for 2h then the solvent removed under reduced pressure. The residue was purified by chromatography on silica eluting with DCM. Yield 6.6g
MS: APCI (+ve): 247/9 (M+l)

(ii) 2-[4-(Ethylthio)-2-methylphenyl]4,4,5 ,5-tetramethyl-1 ,3 ,2-dioxaborolane A mixture of the product from step (i) (6.6g), 4,45,5-tetramethyl-[1,3,2]-dioxaborolane (1.94m1), triethylamine (2.4m1), palladium acetate (0.06g) and 2-(dicyclohexylphosphino) biphenyl (0.3g) in dioxane (20m1) was heated at 850C for 2h. The mixture was quenched with aqueous ammonium chloride solution, extracted with diethylether, the organics dried and evaporated under reduced pressure. The residue was purified by chromatography on silica eluting with 50% isohexanefDCM. Yield 0.7g

"H NIVIR CDCl3: δ 7.66 (111, d) ; 7.08-7.05 (211, m) ; 2.94-2.92 (211, q) ; 2.5 (311, s); 1.43-1.27 (1511, m)

(iii) { [5-Chloro4"-(ethylsulfonyl)-2"-methylbiphenyl-2-yl]oxy} acetic acid
The title compound was prepared by the method of example 1 step (ii) and example 2 using the product from step (ii) and the product from example 1 step (i). Yield 0.035g

"H NM.R DMSO-d6: δ 7.79-6.99 (611, m) ; 4.67 (211, s) ; 3.35 (211, q) ; 2.23 (311, s); 1.15
(311, t)
MS: APCI (-ye): 367 (M-1)

Example 11
[(5-Cyanobiphenyl-2-yl)oxy]acetic acid
(Formula Removed)


The title compound was prepared by the method of example 1 using 3-bromo-4-hydroxybenzonitrile and phenylboronic acid. Yield 0.175g

"H NMR. DMSO-d6: δ 13.18 (111, s) ; 7.81-7.17 (811, m) ; 4.87 (211, s) MS: APCI (-ye): 252 (M-1)

Example 12
[(5-Nitrobiphenyl-2-yl)oxy]acetic acid
(Formula Removed)





The title compound was prepared by the method of example 1 using 2-bromo-4-nitrophenol and phenylboronic acid. Yield 0.065g

"H NMIR DMSO-d6: 8 13.26 (111, s) ; 8.23 (111, dd); 8.12 (111, d) ; 7.63 (211, d) ; 7.50-
7.38 (311, m) ; 7.25 (111, d) ; 4.94 (211, s)
MS: APCI (-ye): 272 (M-1)

Example 13
{[4"-(Methylthio)-5-(trifluoromethyl)biphenyI~2~yl]oxy}acetic acid
(Formula Removed)


(i) 2-Iodo-4-(trifluoromethyl)phenol
Sodium iodide (3.32g) then chloramine-T (5.91g) were added to a stirred solution of 4-trifluoromethyiphenol (3.Og) in DMF (30m1) at 00C. The mixture was warmed to RT, stirred for lh, diluted with dilute hydrochloric acid then extracted with diethylether. The organic layer was washed with aqueous sodium thiosuiphate solution, dried and the solvent removed under reduced pressure. Yield 5.25g

MS: APCI (-ye): 287 (M-1)

(ii) { [4"-(Methylthio)-5-(trifluoromethyl)biphenyl~2~yl]oxy~acetic acid
The title compound was prepared by the method of example 1 using the product from step (i) and 4-(methylthio)benzeneboronic acid. Yield 0.13g

"HM\4R DMSO-d6: δ 13.16 (111, s) ; 7.68-7.18 (711, m) ; 4.85 (211, s) ; 2.51 (311, s) MS: ARCI (-ye): 341 ~M-1)

Examp1e 14
{[4"-(Methylsulfonyl)-5-(trffluoromethyl)biphenyl-2..yI]oxy}acetic acid, aminonium salt
(Formula Removed)



The title compound was prepared by the methods of example 1 and 2 using the product from example 13 step (i) and 4-(methylthio)benzeneboronic acid. Yield 0.14g

"H NMR DMSO-d6: δ 13.21 (111, s) ; 8.00-7.69 (611, m) ; 7.27 (111, d) ; 4.89 (211, s) ; 3.27
(311, s)
MS: APCI (-ye): 373 (M-1)

Example 15
{[4"-(EthylsulfonyI)-2"-methyl~5~(trifluoromethyl)biphenyl..2..yI]oxy}acetic acid
(Formula Removed)


The title compound was prepared by the methods of example 1 and 2 using the product from example 13 step (i) and the product from example 10 step (ii). Yield 0.055g

"H NMR DMSO-d6: δ 7.80-7.12 (611, m) ; 4.63 (211, s) ; 3.39-3.29 (211, q) ; 2.23 (311, s);

MS: APCI (-ye): 401 (M-l)

Example 16
(4-Chloro-2-pyrimidin-5-ylphenoxy)acetic acid, ammonium salt
(Formula Removed)

(i) Benzyl 2-bromo-4-chlorophenyl ether
Benzyl bromide (13.lml) was added to a stirred mixture of 2-bromo4-chlorophenol (20.7g) and potassium carbonate (27.6g) in DIVIF (200m1). After 72h, 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 on silica eluting with 2% EtOAc/isohexane. Yield 18.lg

"H NMR CDCl3: δ 7.55 (111, s) ; 7.46-7.18 (611, m) ; 6.84 (111, d) ; 5.14 (211, s)

(ii) [2-(Benzyloxy)-5-chlorophenyl]boronic acid
A solution of butyl lithium (1.6M in hexane) (SOmI) was added dropwise to a stirred solution of the product from step (i) (23g) in diethylether (300m1) at —700C. After lh a further iSmi of butyl lithium was added, left for 0.75h, then trimethylborate (lOmi) added and the mixture warmed to RT and left for 16h. 2M Hydrochloric acid (lOOmI) was added, stirred for lh then the organic layer separated and extracted with aqueous sodium hydroxide solution. The basic layer was acidified with 2M hydrochloric acid solution, extracted with diethylether which was dried and evaporated under reduced pressure. The residue was triturated with iso-hexane and filtered. Yield 10.8g




"H NMR CDCl3: δ 7.82 (111, d) ; 7.44-7.34 (611, m) ; 6.90 (111, d) ; 5.99 (211, s) ; 5.12 (211,
s)

(iii) 5-[2-(Benzyloxy)-5-chlorophenyl]pyrimidine
A mixture of the product from step (ii) (0.2g), 5-bromopyrimidine (0.16g), sodium carbonate (0.21g) and tetrakistriphenyiphosphine palladium (0) (0.05g) in dioxane (6m1) was heated under reflux for 48h. The mixture was partitioned between EtOAc and water, the organics separated, dried, and evaporated under reduced pressure. The residue was purified by chromatography on silica eluting with 20% EtOAc/isohexane. Yield 0.283g.

MS: APCI (+ve): 297/9 (M+l)

(iv) 4-Chloro-2-pyrimidin-5-ylphenol
A mixture of the product from step (iii) (0.28g), 10% palladium on carbon (0.04g) in
ethanol (20m1) was hydrogenated at 2Bar for 24h. After filtration the solvent was evaporated under reduced pressure. Yield 0.19g

MS: APCI (+ve): 207/9 (M+1)

(v) tert-Butyl (4-chloro-2-pyrimidin-5-ylphenoxy)acetate
The subtitle compound was prepared by the method of example 1 step (i). Yield 0.2 16g

MS: APCI (+ve): 321/3 (M+1)

(vi) (4-Chloro-2-pyrimidin-5-ylphenoxy)acetic acid, an,monium salt The title compound was prepared by the method of example 1 step (iii). Yield 0.033g

"H NMR DMSO-d6: δ 9.15 (111, s) ; 9.08 (211, s) ; 7.57 (1H, d) ; 7.44 (111, dd) ; 7.10 (111,
d) ; 4.67 (211, s)
MS: APCI (+ve): 265/7(M+1)

Example 17
{2-[5-(Aminosulfonyl)pyridin-2-ylI-4-chlorophenoxylacetic acid
(Formula Removed)











The title compound was prepared by the method of example 16. Yield 0.022g

"H Nl~vfR DMSO-d6: δ 13.19 (111, s) ; 9.05 (111, s); 8.29 (111, d) ; 8.21 (111, d) ; 7.84 (111,
d) ; 7.65 (211, s) ; 7.49 (111, dd) ; 7.16 (111, d) ; 4.86 (211, s)
MS: APCI (+ve): 343/5(M-i-1)



Example 18

[2-(2-Aminopyrhnidin-5-yl)-4-chlorophenoxy]acetic acid, trifluoroacetate salt
(Formula Removed)
The title compound was prepared by the method of example 16. Yield 0.036g

"H NMR DMSO-d6: δ 8.56(211, s) ; 7.45 (111, d) ; 7.33 (111, dd) ; 7.05 (111, d) ; 4.76 (211,
s)
MS: APCI (+ve): 280/2(M+1)

Example 19

[4-Chloro-2-(4-methyl-2-morpholin-4-ylpyrimidin-5-yl)phenoxy]acetic acid HO 0
(Formula Removed)
(i) 2-[2-(Benzyloxy)-5-chiorophenyl]-N-methoxy-N-methylacetamide 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (8.6g) was added to a solution of (2-benzyloxy-5-chlorophenyl)-acetic acid (1 0.6g), N,O-dimethylhydroxylamine hydrochloride (4.4g), l-hydroxybenzotriazole (6.9g) and N,N-diisopropylethylamine (20m1) in DMF (iSOmi) and the mixture stirred at RT for 16h, then partitioned between ethylacetate and water. The organics were washed with 2M hydrochloric acid, water, dried, and evaporated under reduced pressure. Yield 12.2g


MS: APCI (+ve): 320/2(M+l)

(ii) 1-172-(Benzyloxy)-5-chlorophenyl]acetone
A solution of methylmagnesium chloride (3M in TIff) (6m1) was added dropwise to a stirred solution of the product from step (i) (5.2g) in THF (iSOmi) at -700C. After lh the mixture was warmed to RT, stirred for lh then quenched with aqueous ammonium chloride solution. The mixture was partitioned between diethylether and water, the organics separated, dried, and evaporated under reduced pressure. The residue was purified by chromatography on silica eluting with 10% EtOAc/isohexane. Yield 2.22g

"HNMR CDCl3: δ 7.40-7.30(511, m) ; 7.26-7.12(211, m) ; 6.85 (111, d) ; 5.03 (211, s); 3.67 (211, s) ; 2.12 (311, s)

(iii) (3Z)-3-[2-(Benzyloxy)-5-chlorophenyl]-4-(dimethylamino)but-3-en-2-one A mixture of the product from step (ii) (5.72g) and dimethylformamide dimethyl acetal (3.5m1) in toluene (SOmI) were heated at 1000C for 12h. The solvent was evaporated under reduced pressure to give an oil, 6.37g.

MS: APCI (+ve): 330/2(M+1)

(iv) 5-12-(Benzyloxy)-5-chlorophenyl]-4-methyl-2-(methylthio)pyrimidine A solution of the product from step (iii) (4.3g) in ethanol (20m1) was added to a stirred mixture of sodium ethoxide (0.98g) and S-methylisothiouronium sulphate (2g) in ethanol (30m1), and the mixture heated under reflux for 8h. A further 2g of Smethylisothiouronium sulphate and 1.1 Sg of sodium ethoxide were added and heating continued for 16h. The mixture was cooled, partitioned between diethylether and water, the organics washed with water, dried, and evaporated under reduced pressure. The residue was purified by chromatography on silica eluting with 3-5% EtOAc/isohexane. Yield l.84g

MS: APCI (+ve): 357/9(M+1)

(v) 5-[2-(Benzyloxy)-5-chlorophenyl]-4-methyl-2-(methylsulfonyl)pyrimidine The subtitle compound was prepared by the method of example 2 step (i). Yield 0.85g

MS: APCI (+ve): 389/91(M+1)

(vi) 4-Chloro-2-[4-methyl-2-(methylsulfonyl)pyrimidin-5-ylllphenol





The subtitle compound was prepared by the method of example 16 step (iv). Yield 0.5g

MS: APCI (+ve): 299/301(M+1)

(vii) tert-Butyl { 4-chloro-2-[4-methyl-2-(methylsulfonyl)pyri~jdins.. yl]phenoxy} acetate
The subtitle compound was prepared by the method of example 1 step (i). Yield 0.65g

MS: APCI (+ve): 413(M+1)

(viii) tert-Butyl [4-chloro-2-(4-methyl-2-morpholin..4-ylpyrimidins.. yl)phenoxy]acetate
A solution of the product from step (vii) (0.15g) and morpholine (0.15m1) in dioxane (3m1)
was heated at 900C for 24h, cooled and the solvent evaporated under reduced pressure.
Product used crude.
MS: APCI (+ve): 420/422(M+1)

(ix) [4-Chloro-2-(4-methyl-2-morpholin4~ylpyrimidin~s~yl)phenoxy] acetic acid The title compound was prepared by the method of example 1 step (iii). Yield 0.046g

111 NMR DMSO-d6: δ 8.12 (111, s) ; 7.39 (111, dd) ; 7.25 (111, d) ; 7.00 (111, d) ; 4.71 (211,
s) ; 3.73-3.67 (811, m) ; 2.18 (311, s)
MS: APCI (+ve): 364/6(M+1)

Example 20

{4-Chloro-2-[2-(dimethylamino)pyrimidin-5-yl]phenoxy}acetic acid
(Formula Removed)

(i) 5-[2-(Benzyloxy)-5-chlorophenyl]-2-chloropyrimidine
The subtitle compound was prepared by the method of example 1 step (ii) using the
product from example 16 step (ii) (3.2g) and 2-chloro-5-bromopyrimidine (2.59g). Yield
2.43g
MS: APCI (+ve): 331/3(M+l)

(ii) S-[2-(Benzyloxy)-5-chlorophenyl]-2-(propylthio)pyrimidine



Propanethiol (3.lml) was added to a stirred suspension of sodium hydride (1.4g, 60% in oil) in DMF (30m1). After 1 hour a solution of the product from step (i) (2.4g) in DMIF (lOmi) was added. The reaction mixture was stirred at RT for 1 hour then partitioned between EtOAc and water. The organics were washed with water, brine, dried and evaporated under reduced pressure. The residue was purified by chromatography on silica eluting with 5% EtOAc/isohexane. Yield 1. 87g

MS: APCI(+ve) 371 (M+1)

(iii) 5-[2-(Benzyloxy)-5-chlorophenyl]-2-(propylsulfonyl)pyrimidine
The subtitle compound was prepared by the method of example 2 step (i) using the product from step (ii).
MS: APCI(+ve) 403 (M+1)

(iv) tert-Butyl {4-chloro-2-[2-(propylsulfonyl)pyrimidin-5-yl]phenoxy } acetate The subtitle compound was prepared by the method of example 16 step (iv) and example 1 step (i) using the product from step (iii). Yield 1 .04g

MS: APCI(+ve) 427 (M+1)

(v) {4-Chloro-2-112-(dimethylamino)pyrimidin-5-yl]phenoxy} acetic acid Dimethylamine hydrochloride (0.82g) was added to a stirred solution of the product from step (iv) (0.2g) and N,N-diisopropylethylamine (0.9m1) in NMP (5m1). The reaction mixture was heated at 900C for 6h then diluted with EtOAc, washed with water, brine, dried and evaporated under reduced pressure. The residue was dissolved in DCM (lOmi) then trifluoroacetic acid (lOmi) added and stirred for 18h at RT. The reaction mixture was evaporated to dryness and the residue purified by reverse phase HPLC followed by trituration with methanol to give a white solid. Yield 0.035g

111 NMR DMSO-d6: 88.60 (211, s) ; 7.42 (111, d) ; 7.32 (111, dd) ; 7.05 (111, d) ; 4.77 (211, s) ; 3.16 (611, s).
MS: APCI(-ve) 306 (M-1)

Example 21

f4-Chloro-2-(2-morpholin-4-ylpyrimidin-5-yl)phenoxylacetic acid
(Formula Removed)


The title compound was prepared from the product of example 20 step (iv) and morpholine by the method of example 20 step (v).

1H NMR DMSO-d6: δ 13.10 (111, brs); 8.65 (211, s) ; 7.45 (111, d) ; 7.34 (111, dd) ; 7.06
(111, d) ; 4.77 (211, s) ; 3.75 (411, m) ; 3.67 (411, m)
MS: APCI(-ve) 348 (M-1)

Example 22
{4-Chloro-2-[2-(methylan1ino)pyriniAdin~s~yI]phenoxy}acetic acid
(Formula Removed)
The title compound was prepared from the product of example 20 step (iv) and methylamine hydrochloride by the method of example 20 step (v).

111 NMR DMSO-d6: δ 8.54 (211,s) ; 7.42 (111, d) ; 7.32 (111, dd) ; 7.25 (111, brs) ; 7.04 (111,
d) ; 4.76 (211, s) ; 2.84 (311, s)
MS: APCI(-ve) 292 ~M-1)

Example 23

{2-[Z-(Benzylamino)pyrimidin~5-yl].4~chAorophenoxy}acetic acid
(Formula Removed)


The title compound was prepared from the product of example 20 step (iv) and benzylamine by the method of example 20 step (v).

111 NMR DMSO-d6: δ 13.09 (111, brs); 8.54 (211, s) ; 7.90 (111, t) ; 7.42 (111, d) ; 7.35-
7.29 (511, m) ; 7.22 (111, m) ; 7.03 (111, d) ; 4.76 (211, s) ; 4.55 (211, d)
MS: APCI(-ve) 368 (M-1)

Example 24

[4-Chloro-2-(2-piperidin-1-ylpyriniJn..5yl)pheno,~]acetic acid

(Formula Removed)
The title compound was prepared from the product of example 20 step (iv) and piperidine by the method of example 20 step (v).

111 NMIR DMSO-d6: δ 13.10 (111, brs) ; 8.59 (111, d) ; 7.32 (111, dd) ; 7.04 (111, d) ; 4.77

(211, s) ; 3.79 (411, t); 1.65 (211, in); 1.53 (411, m)

MS: APCI(-ve) 346 (M-l)



Example 25

(4-ChIoro~2~{2~[methyl(methyIsulfonyl)amino]pyrin1jdinsyI}phenoxy)acetjc acid
(Formula Removed)
(i) N-(5-Bromopyrimidin-2-yl)-N-methylmethanesulfonamide Sodium hydride (0.22g, 60% in oil) was added to a solution of (5-bromopyrimidin-2-yl)methylamine (O.85g) in DMF (l0mi) at 00C and stirred for 30mm. Methanesulphonyl chloride (O.62g) was added dropwise, the mixture warmed to RT and stirred for a further 2h. The reaction was quenched with water and then extracted with EtOAc. The organics were washed with water, dried, and evaporated under reduced pressure. The residue was purified by chromatography on silica eluting with 1% methanol/DCM. Yield 0.42g

MS: APCI (+ve): 266(M+1)

(ii) N-[S-(S-Chloro-2-hydroxyphenyl)pyrimidin~2~yl]~Nmethylmethanesuj1fon~Ade The subtitle compound was prepared by the method of example 1 step (ii) using the product from step (i) and 2-hydroxy-5-chloroboronic acid (0.27g). Yield 0.2g

MS: APCI (+ve): 314(M-i-l)
(iii) (4-Chloro-2-{ 2-[methyl(methylsulfonyl)amino]pyrimidinsyl }phenoxy)acetic
acid
The title compound was prepared by the method of example 1 step (i) and (iii) using the product from step (ii). Yield 0.017g

"HNMRDMSO-d6: δ 13.16(111, s); 8.94(211, s) ; 7.57(111, d) ; 7.45-7.42(111, m) ; 7.14
(111, d) ; δ.82 (211, s) ; 3.55 (311, s) ; 3.47 (311, s)
MS: APCI (-ye): 370(M-1)

Example 26
[[2",5-Dichloro-4"-(ethylsulfonyl)[1,1 "-biphenyl]-2-yl]oxy]- acetic acid
(Formula Removed)
(i) 2-Chloro4-(ethylthio)- 1-iodo- benzene
A solution of 3-chloro-4-iodo-aniline (5.6g), isoamylnitrite (8.8m1) and ethyldisulphide
(13.4xnI) in acetonitrile (lOOmI) was heated at 600C for 24h. The solvent was removed
under reduced pressure and the residue purified by chromatography on silica eluting with
1% ethylacetate/isohexane. Yield 4.02g

"H NMR CDCl3: δ 7.70 (111, d) ; 7.36 (111, d) ; 6.87 (111, dd) ; 2.94 (211, q); 1.32 (311, t)

(ii) [[[2",5-Dichloro-4"-(ethylthio)[1 , 1 "-biphenyl]-2-yl]oxy]methyl]- benzene The subtitle compound was prepared by the method of example 1 step (ii) using the product from step (i) and the product from example 16 step (ii). Yield 3.64g

"H NMR CDCl3: δ 7.4 (111, s) ; 7.32-7.18 (911, m) ; 6.92 (111, d) ; 5.03 (211, s) ; 2.99 (211, q); 1.36 (311, t)

(iii) [112",5-Dichloro-4"-(ethylsulfonyl)[1 , 1 "-biphenyl]-2-yl]oxy]methyl]- benzene
The subtitle compound was prepared by the method of example 2 step (I) using the product from step (ii). Yield 3.8g

"H NIvIR CDCl3: δ 8.00 (111, s) ; 7.81 (111, d) ; 7.48 (111, d) ; 7.36-7.20 (711, m) ; 6.95 (111, d) ; 5.04 (211, s) ; 3.16 (211, q); 1.32 (311, t)

(FormulaRemoved)

(iv) 2",5-Dichloro-4"-(ethylsulfonyl)- [1,1 "-biphenyl]-2-ol
The subtitle compound was prepared by the method of example 16 step (iv) using the product from step (iii). Yield 2.44g

"HNMR CDCl3: δ 8.03 (111, s) ; 7.85 (111, d) ; 7.55 (111, d) ; 7.30(111, d) ; 7.16 (111, s); 6.92 (111, d) ; 5.20 (211, s) ; 3.17 (211, q) ; 1.36 (311, t)

(v) [[2",5-Dichloro-4"-(ethylsulfonyl)[ 1,1 "-biphenyl]-2-yl]oxy]- acetic acid, ethyl ester The subtitle compound was prepared by the method of example 1 step (i) using the product from step (iv) and ethylbromoacetate. Yield 2.23g

(vi) [[2",5-Dichloro-4"-(ethylsulfonyl)[ 1,1 "-biphenyl]-2-yl]oxy]- acetic acid A mixture of the product from step (v) (2.23g), iM aqueous sodium hydroxide (lOmi) and THF (20m1) was stirred at RT for 3h. The mixture was acidified with 2M hydrochloric acid, extracted with diethylether and the organics washed with water, dried, and evaporated under reduced pressure. The residue was recrystallised from ethylacetate/isohexane, yield 0.45g.

"H NMR CDCl3: δ 13.02 (111, s); 8.02 (111, s) ; 7.89 (111, d) ; 7.69 (111, d) ; 7.48 (111, dd)
7.34 (111, d) ; 7.08 (111, d) ; 4.70 (211, s) ; 3.44 (2H, q); 1.16 (311, t) MS: APCI (-ye): 387/9 (M-1)
Mpt. 163-40C

Example 27

[[2"-Chloro-4"-(ethylsulfonyl)-5-(trifluoromethyl)[1,1 "-biphenyl]-2-yl]oxy]- acetic acid










(i) 2-Bromo-1-(phenylmethoxy)-4-(trifluoromethyl)-benzene
The subtitle compound was prepared by the method of example 16 step (i) using 2-bromo-4-trifluoromethylphenol. Yield 58.7g

"H NMR CDCl3: 87.83 (111, s) ; 7.51-7.32 (611, m) ; 6.98 (111, d) ; 5.21 (211, s)

(ii) [2-(Phenylmethoxy)-5-(trifluoromethyl)phenyl]- boronic acid
The subtitle compound was prepared by the method of example 16 step (ii) using the product from step (i). Yield 30.7g

"HNM~ CDCl3: δ 8.14 (1H, d) ; 7.68 (111, dd) ; 7.44-7.39(511, m) ; 7.05 (111, d) ; 5.79 (211, s) ; 5.20 (211, s)

(iii) [2-Hydroxy-5-(trifluoromethyl)phenyl]... boronic acid
The subtitle compound was prepared by the method of example 16 step (iv) using the product from step (ii). Yield 3 .54g

(iv) 2"-Chloro-4"-(ethylthio)~5~(trifluoromethyl).. [1,1 "-biphenyl]-2-ol A mixture of palladium acetate (O.045g) and tri-p-tolylphosphine (0.213g) in methanol (lOml) was stirred at RT for 30mm. The product from step (iii) (lg), sodium carbonate (1.27g), the product from example (26) step (i) (1.19g) and methanol (20mi) were added and the mixture heated under reflux for 6h. The solvent was removed under reduced pressure and the residue partitioned between diethylether and 2M hydrochloric acid. The organics were separated, dried and evaporated under reduced pressure. The residue was purified by chromatography on silica eluting with 10% ethylacetate/isohexane. Yield 0.503g

MS: ESI (-ye): 33 1/3 (M-1)

(v) 2"-Chloro-4"-(ethylsulfonyl)-5-(trifluoromethyl).. [1,1 "-biphenyl]-2-ol The subtitle compound was prepared by the method of example 2 step (i) using the product from step (iv). Yield 0.277g

MS: ESI (-ye): 363/5 (M-1)

(vi) [112"-chloro-4"-(ethylsulfonyl)-5-(trifluoromethyl)[1, 1 "-biphenyl]-2-yl]oxy]-acetic acid, 1, 1-dimethylethyl ester
The subtitle compound was prepared by the method of example 1 step (i) using the product from step (v). Yield 0.253g

(vii) [112"-Chloro-4"-(ethylsulfonyl)-5-(trifluoromethyl)[1 , 1 "-biphenyl]-2-yl]oxy]- acetic acid
The title compound was prepared by the method of example 1 step (iii) using the product from step (vi). Yield 0.154g
"11 NMR CDCl3: δ 13.12 (111, s) ; 8.04 (111, s) ; 7.91 (111, d) ; 7.81 (111, d) ; 7.72 (111, d);
7.63 (111, s) ; 7.25 (111, d) ; 4.82 (211, s) ; 3.45 (211, q) ; 1.17 (3H, t)
MS: APCI (-ye): 421/3 (M-1)
Mpt. 1670C

Example 28

[[5-Chloro-4"-(ethylsulfonyl)-2" -fluoro[1,1 "-biphenyl]-2-ylJoxy]- acetic acid

(Formula Removed)
C1) l-Bromo-4-(ethylthio)-2-fluoro-benzene
Bromine (0.3mi) was added to a solution of l-ethylsulfanyl-3-fluoro-benzene (ig) in chloroform (20mi) at 00C then warmed to RT. After 2h the mixture was diluted with DCM, washed with aq. sodium thiosulphate solution, dried, and evaporated under reduced pressure. The residue was purified by chromatography on silica eluting with 10% diethylether/iso-hexane. Yield 1.2g

"H NMR CDCl3 δ 7.44—6.93 (311, m) ; 2.99-2.90 (211, q); 1.42-1.30 (311, t).

(ii) 1-Bromo-4-(ethylsulfonyl)-2-fluoro-benzene
The subtitle compound was prepared by the method of example 2 step (i) using the product from step C1). Yield 0.94g

"HNMR CDCl3: δ 7.81—7.07 (311, m) ; 3.17-3.10 (211, q); 1.32-1.19 (311, t).

(iii) [115-Chloro4"-(ethylsulfonyl)-2"-fluoro[1 , 1 "-biphenyl]-2-yl]oxy]methyl]-benzene The subtitle compound was prepared by the method of example 1 step (ii) using the product from step (ii) and the product from example 16 step (ii). Yield 0.55g

"H~ CDCI3: δ 7.73—6.96(1111, in); 5.09(211, s) ; 3.19-3.13 (211, q); 1.331.27(311, t).



(iv) 5-Chloro-4"-(ethylsulfonyl)-2"-fluoro-[1 , 1 "-biphenyl] -2-ol
The subtitle compound was prepared by the method of example 16 step (iv) using the product from step (ii), yield 0.35g


MS: ESI (-ye) 313 (M-1)

(v) [[5-Chloro-4"-(ethylsulfonyl)-2"-fluoro [1,1 "-biphenyl]-2-yl]oxy]- acetic acid
The title compound was prepared by the method of example 1 step (i) and step (iii) using the product from step (iv), yield O.205g

"HNMIRDMSO-d6: δ 7.81—7.08(611, m) ; 4.73(211, s) ; 3.44-3.39(211, q); 1.17-1.14 (311, t).
MS: ESI (-ye) 371 (M-1)

Example 29
[[4"-(EthylsuIfonyl)-2"-fluoro.5~(trrnuoromethyI)[1,1 "-biphenyl]-2-yI]oxy]-acetic acid, sodium salt
(Formula Removed)






The title compound was prepared by the method of example 28, yield 0.26g.

"H NMR DMSO-d6: δ 7.96—7.57(511, m) ; 7.09-7.07 (111, d) ; 4.31 (211, s) ; 3.44-3.35 (211,

MS: ESI (-ye) 405 (M-1)

Example 30
[[S-Chloro-4"~(ethylsuIfonyI)~2"~(trifluoromethyl)[1,1"~biphenyl].2..yl]oxy]. acetic acid
(Formula Removed)



(i) 1-Bromo-4-(ethylthio)-2-(trifluoromethyl)- benzene
lodoethane (0.84m1) was added to a stirred solution of 3-trifluoromethyl-thiophenol (2g) and potassium carbonate (1.42g) in DMF (20m1). After 72h the mixture was partitioned between diethylether and water, the organics separated, dried and evaporated under
reduced pressure. The residue was dissolved in acetic acid (20m1), cooled to 00C, then bromine (0.5 imI) added. The mixture was stirred at RT for 16h, the solvent removed




under reduced pressure and the residue purified by chromatography on silica eluting with 25% DCMIiso-hexane. Yield 2.05g

(ii) 5-Chloro-4"-(ethylthio)-2"-(trifluoromethyl)- [1,1 "-biphenyl]-2-ol
The subtitle compound was prepared by the method of example 1 step (ii) using the product from step (i) and 5-chloro-2-hydroxyphenyl-boronic acid, yield 0.26g

MS: ESI (-ye) 347 (M-1)

(iii) [[5-Chloro-4"-(ethylthio)-2"-(trifluoromethyl)[l , 1 "-biphenyl]-2-yl]oxyjl- acetic acid, 1,1 -dimethylethyl ester
The subtitle compound was prepared by the method of example 1 step (i) using the product from step (ii), yield 0.26g

MS: APCI (-ye) 389/39 1 (M-1) — t-butyl

(iv) [[5-Chloro-4"-(ethylsulfonyl)-2"-(trifluoromethyl)[ 1,1 "-biphenyl] -2-yl]oxy] - acetic acid
The title compound was prepared by the method of example 2 step (i) and example 1 step (iii) using the product from step (iii), yield 0.045g

"H NMR DMSO-d6: δ 7.62—7.01 (611, m) ;4.69-4.66 (211, s) ; 4.20-4.10 (211, q); 1.40-1.35 (311, t).
MS: ESI (-ye) 421 (M-1)

Example 31
Z-[[5-Chloro-4"-(ethylsulfonyl)[1,1"-biphenyl]-2-yl]oxy]-propanoic acid
(Formula Removed)

(i) 2-(2-Bromo-4-chlorophenoxy)-propanoic acid, 1,1-dimethylethyl ester The subtitle compound was prepared by the method of example 1 step (i) using 2-bromo-4-chlorophenol and 2-bromopropionic acid, tert-butyl ester, yield 1.lg

"H NIMIR DMSO-d6: δ 7.54—7.16 (2H, m) ;6.74-6.71 (111, d) ; 3.70 (311, s); 1.78-1.76 (111, d); 1.48 (911, s).


(ii) 2-1115-Chloro-4"-(ethylthio)[1 , 1 "-biphenyl]-2-yl]oxy]- propanoic acid, 1,1 -dimethylethyl ester
The subtitle compound was prepared by the method of example 1 step (ii) using the product from step (i) and 4-(ethylthio)benzeneboronic acid, yield 1.2g.

MS: APCI (-ye) 336 (M-1) — t-butyl

(iii) 2-[[5-Chloro-4"-(ethylsulfonyl)[1 .1 "-biphenyl]-2-yl]oxy]-propanoic acid The title compound was prepared by the method of example 2 step (i) and example 1 step (iii) using the product from step (ii), yield 0.08g

"HNMRDMSO-d6: δ 7.97—6.96(711, m) ; 4.79-4.76 (111, m) ; 3.39-3.31 (211, t); 1.39-1.37 (311, d); 1.16-1.07 (311, t).
MS: ESI (-ye) 367 M-1)

Example 32
2-[[41-(Ethylsulfonyl)-2"-methyl-5-(trifluoromethyl)[1,1 "-biphenyl]-2-yl]oxy]-(2S)-prop anoic acid
(Formula Removed)
(i) l-Bromo4-(ethylsulfonyl)-2-methyl-benzene
The subtitle compound was prepared by the method of example 2 step (i) using the product from example 10 step (i), yield 4.3g.

MS: ESI (+ve) 264 (M+1)

(ii) [2-(Phenylmethoxy)-5-(trifluoromethyl)phenyl]-boronic acid
The subtitle compound was prepared by the method of example 16 step (ii) using the product from example 27 step (i), yield 5.5g.

111 NMR CDCl3: δ 8.14-7.62 (211, m) ; 7.43-7.38 (511, m) ; 7.01 (111, m) ; 5.67 (211, s);

5.19-5.16 (211, s)


(iii) [[[4"-(Ethylsulfonyl)-2"-methyl~5~(trifluoromethyl) [1,1 "-biphenyl]-2-
yl]oxy]methyl]-beazene
The subtitle compound was prepared by the method of example 1 step (ii) using the product from step (i) and (ii), yield 2.72g.

MS: ESI (+ve) 452 (M+1+NH3)

(iv) 4"-(Ethylsulfonyl)-2"-methyl~5-(trifluoromethyl>[ 1,1 "-biphenyl]-2-ol The subtitle compound was prepared by the method of example 16 step (iv) using the product from step (iii), yield 2.1g.

MS: ESI (+ve) 362 (M+1+NH3)

Cv) 2-[1141-(Ethylsulfonyl)-2"-methyl-5-(trifluoromethyl)[1 .1 "-biphenyl]-2-yl]oxy]-(2S)-propanoic acid, methyl ester
Diethyl azodicarboxylate (0. 14m1) was added to a stirred solution of the product from step (iv) (0.3g), methyl-R-lactate (0.083m1) and triphenylphosphine (O.228g) in THE (lOmi) at OaC. After 4h, the mixture was diluted with water and extracted with ethylacetate, the organics separated, dried and evaporated under reduced pressure. The residue was purified by chromatography on silica eluting with 50% diethylether/iso-hexane. Yield 0.4g

MS: ESI (+ve) 448 (M+l+NH3)

(vi) 2-[[4"-(Ethylsulfonyl)-2"-methyl-5-(trifluoromethyl)[ 1,1 "-biphenyl]-2-yl]oxy]-(2S)-
propanoic acid
A mixture of the product from step (v) (0.4g) and lithium hydroxide (2 equiv) in THE (lOmi) and water (lOmi) was stirred at RT overnight. The mixture was partitioned between ethylacetate/water, the aqueous layer was acidified with 2M hydrochloric acid and extracted with ethyl acetate. The organic layer was dried, evaporated under reduced pressure and the residue purified by reverse phase HPLC. Yield 0.035g

"H NMR DMSO-d6: δ 7.78—7.44 (5H, m) ; 7.16-7.14 (111, d) ; 4.91-4.86 (111, q) ; 3.30-3.25 (211, q) ; 2.22 (311, s); 1.33-1.24 (311, d); 1.10-1.07 (311, t).
MS: ESI (+ve) 434 (M+1+NH3)

Example 33 2-[[4"-(Ethylsulfonyl)-2"-methyl-5-(trifluoromethyl)[1,1 "-biphenyl]-2-yl]oxy]-(2R)-propanoic acid, sodium salt
(Formula Removed)









The title compound was prepared by the method of example 32 using methyl-S-lactate, yield 0.2g.

"H NIvIR DMSO-d6: δ 7.77—7.38 (511, m) ; 7.02-7.00 (111, d) ; 4.32 (111, m) ; 3.39-3.25 (211, q) ; 2.32 (311, s); 1.21-1.07 (6H, d+ t).
MS: ESI (+ve) 434 (M+1+NI{3)

Example 34
2-[[2 ",5-Dichloro-4"-(ethylsulfonyl)[1,1 "-biphenyl]-2-yl]oxy]-(2S)- propanoic acid, sodium salt
(Formula Removed)


The title compound was prepared by the method of example 32 step (v) and (vi) using the product from example 26 step (iv), yield 0.18g.

"H NMR DMSO-d6: δ 7.99—7.23 (511, m) ; 6.93-6.91(111, d) ; 4.26424 (111, q) ; 3.46-
3.37 (211, q); 1.20-1.06 (611, d+t).
MS: ESI (-ye) 402/403 (M-1)

Example 35

propanoic acid
(Formula Removed)


The title compound was prepared by the method of example 32 step (v) and (vi) using the product from example 2 step (v), yield 0.05g.
"H NIvlR DMSO-d6: δ 7.98—7.23 (5H, m) ; 6.93-6.91(111, d) ; 4.68 (111, m) ; 3.20-3.15 (211, q); 1.48-1.39 (3H, in); 1.34-1.30 (3H, t)..
MS: ESI (-ye) 436 (M-1)

Example 36 2-[[4"-(Ethylsulfonyl)-2"-methyl-5-(trifluoromethyl)[1,1 "-biphenyl]-2-yl]oxy]-2-methyl- propanoic acid, sodium salt
(Formula Removed)


The title compound was prepared by the method of example 1 step (i) and example 26 step (vi) using the product from example 34 step (iv), yield 0.18g.

"H NMR DMSO-d6: δ 7.72 (111, s) ; 7.71 (111, d) ; 7.56 (111, d) ; 7.44 (111, d) ; 7.35 (111,
s) ; 7.10 (111, d) ; 2.29 (311, s); 1.38 (611, s); 1.13 (311, t)
MS: ESI (-ye) 429 (M-1)

Example 37 2-L[4"-(Ethylsulfonyl)-2"-methyl-5-(trifluoromethyl)[1,1 "-biphenyl]-2-yl]oxy]-butanoic acid, sodium salt
(Formula Removed)
The title compound was prepared by the method of example 1 step (i) and example 26 step (vi) using the product from example 34 step (iv), yield 0.29g.

111 NMR DMSO-d6: δ 7.78 (111, s) ; 7.71 (111, d) ; 7.64 (111, d) ; 7.41 (111, s) ; 7.01 (111,

d) ; 4.27 (111, brs) ; 3.36 (211, q) ; 2.33 (311, brs); 1.64-1.55 (211, in); 1.11 (311, t) ; 0.66
(311, brs)
MS: ESI (-ye) 429 (M-1)

Example 38

E4-Chloro-2-[2-[(methylsuhfonyl)(~phenylmethyl)ainino]~5~pyrimidinyl]phenoxy]~
acetic acid
(Formula Removed)

(i) N-(S-Bromo-2-pyrimidinyl)-N-(phenylmethyl)-methanesulfonamide Sodium hydride (0.lg, 60% disp. in oil) was added to a stirred solution of benzyl-(5-bromo-pyrimidin-2-yl)-amine (0.55g) in DMF (8m1) at 00C. After 30mm methanesulphonyl chloride (0.286g) was added and the mixture stirred at RT for 2h then partitioned between ethyl acetate and water. The organics were separated washed with water, dried and evaporated under reduced pressure. The residue was purified by chromatography on silica eluting with dichioromethane. Yield 0.41g

MS: APCI (+ve) 344 (M+1)

(ii) N-[5-(5-Chloro-2-hydroxyphenyl)-2-pyrimidinyl]-N-(phenylmethyl)-methanesulfonamide
The subtitle compound was prepared by the method of example 1 step (ii) using the product from step (i) and 5-chloro-2-hydroxyphenyl-boronic acid, yield 0.25g.

MS: APCI (+ve) 390 (M+1)

(iii) [4-Chloro-2-[2-Rmethylsulfonyl)(phenylmethyl)amino]-5-pyrimidinyl]phenoxy]-acetic acid

The title compound was prepared by the method of example I step (i) and step (iii) using the product from step (ii), yield 0.07g.

"H NMR DMSO-d6: δ 13.16 (111, s); 8.93 (211, s) ; 7.56 (111, d) ; 7.44-7.41(111, in);
7.37-7.31 (411, in) ; 7.27-7.23 (111, m) ; 7.12 (111, d) ; 5.28 (211, s) ; 4.81 (211, s) ; 3.59
(311, s).
MS: APCI (-ye): 446 (M-1)

Example 39

[4-Chloro-2-[2-[(ethylsulfonyl)(phenylmethyl)axnino]-5-pyriniidinyl]phenoxy]-acetic
acid
(Formula Removed)



(i) N-(5-Bromo-2-pyrimidinyl)-N-(phenylmethyl)-ethanesulfonamide
The subtitle compound was prepared by the method of example 38 step (i) using benzyl-(5-bromo-pyrimidin-2-yl)-amine and ethanesulphonyl chloride , yield 0.3 1g.

MS: APCI (+ve) 358 (M+1)

(ii) N-[5-(5-Chloro-2-hydroxyphenyl)-2-pyrimidinyl]-N-(phenylmethyl)-ethanesulfonamide
The subtitle compound was prepared by the method of example 1 step (ii) using the product from step (i) and 5-chloro-2-hydroxyphenyl-boronic acid, yield 0.25g.

MS: APCI (+ve) 404 (M+1)

(iii) [4-Chloro-2-[2-[(ethylsulfonyl)(phenylmethyl)amino]-5-pyrimidinyHphenoxy]-acetic acid

The title compound was prepared by the method of example 1 step (i) and step (iii) using the product from step (ii), yield 0.13g.

"HNMRDMSO-d6: δ 13.14(111, s) ; 8.92(211, s) ; 7.56(111, d) ; 7.44-7.31(511, in);
7.27-7.23 (111, m) ; 7.12 (1H, d) ; 5.27 (211, s) ; 4.81 (2H, s) ; 3.87 (2H, q); 1.25 (311, t).
MS: APCI (-ye): 460 (M-1)

Example 40
(2-[2-[Acetyl(phenylmethyl)aniino]-5-pyrimidinyl]-4-chlorophenoxy]-acetic acid
(Formula Removed)





(i) N-(S-Bromo-2-pyrimidinyl)~N~(phenylmethyl>acetamide
The subtitle compound was prepared by the method of example 38 step (i) using benzyl-(5-bromo-pyrirnidin-2-yl)-amine and acetylchloride , yield 0.2 1g.

MS: APCI (+ve) 306 (M+1)



(ii) N-[S-(S-Chloro-2-hydroxyphenyl)~2~pyrimidinyl]N..(phenylmethyl)..acet~de
The subtitle compound was prepared by the method of example 1 step (ii) using the product from step (i) and 5-chloro-2-hydroxyphenyl-boronic acid, yield 0.16g.

MS: APCI (+ve) 354 (M+1)

(iii) [2-[2-[Acetyl(phenylmethyl)amino]~5~pyrimidinyly4~chlorophenoxyyacetic acid The title compound was prepared by the method of example 1 step (i) and step (iii) using the product from step (ii), yield 0.08g.

"HNMRDMSO-d6: δ 9.01(211, s) ; 7.59(111, d) ; 7.44(111, q) ; 7.30-7.18(511, in); 7.13

(111, d) ; 5.26 (211, s) ; 4.81 (211, s) ; 2.45 (311, s).

MS: APCI (+ve): 412 (M+1)



Example 41

114"-(Ethylsulfonyl)-5-fluoro-2t-methyl[1,1"-biphenyl]-2-yl]oxy]-acetic acid HO
(Formula Removed)



(i) [4-(Ethylthio)-2-methylphenyl]-boronic acid
A lOOmI portion of a solution of the product from example 10 step (i) (120.7g) in THF (SQOml) was added to a stirred mixture of magnesium turnings (13.4g) in THE (lOOmI). Dibromoethane (0.2m1) was added, and the mixture gently refluxed on initiation. The remaining bromide solution was added dropwise maintaining the reaction at reflux. After addition the mixture was allowed to cool to RT then transferred via cannula into a stirred
solution of trimethylborate (1 12mi) in TIHF (200m1) at 00C. The mixture was warmed to RT, stirred for 2h then quenched with 2M hydrochloric acid (300m1). After stirring at RT for 1 8h the THF was removed under reduced pressure and the mixture extracted with diethylether. The organics were separated, washed with water, dried and evaporated under reduced pressure. The residue was triturated with "diethylether/isohexane and filtered. Yield 53.02g

111 NMR CDCl3 δ 8.08 (111, d) ; 7.18 (111, d) ; 7.15 (1H,s) ; 3.04 (211, q) ; 2.76 (311, s);

1.38 (311,t)



(ii) (2-Bromo-4-fluorophenoxy)-acetic acid, 1,1-dimethylethyl ester The subtitle compound was prepared by the method of example 1 step (i).

(iii) [14"-(Ethylsulfonyl)-5-fluoro-2"-methyl[1 .1 "-biphenyl] -2-yl]oxy]-acetic acid The title compound was prepared by the method of example 27 step (iv), example 2 step (i) and example 1 step (iii) using the products from step (i) and (ii), yield 0.045g.

"H NMR DMSO-d6: δ 7.8-7.64 (211, m) ; 7.42 (211, d) ; 7.8-6.0 (311, rn) ; 4.10 (211, s);

3.20 (211, q); 1.18 (311, t)

MS: APCI (-ye): 351 (M-1)



Example 42

[[4"-(Ethylsulfonyl)-4,5-difluoro-2"-methyl[1,1"-biphenyfl-2-yl]oxy]-acetic acid HO 0

(Formula Removed)
The title compound was prepared by the method of example 41, yield 0.08 1g.



111 NMR DMSO-d6: δ 7.76 (111, s) ; 7.71 (111, dd) ; 7.44 (111, d) ; 7.23 (111, t) ; 7.01-6.94

(111, m) ; 4.32 (211, s) ; 3.39 (211, m) ; 2.25 (311, s) ; 1.18 (311, t)

MS: APCI (-ye): 369 (M-1)



Example 43
[[4"-(Ethylsulfonyl)-3,5-difluoro-2"-methyl[1,1 "-biphenylj-2-yl]oxy]-acetic acid
(Formula Removed)








The title compound was prepared by the method of example 41, yield 0.15g.

111 NMR DMSO-d6: δ 7.82-7.70 (211, m) ; 7.49-7.38 (211, m) ; 7.02-6.90 (111, m) ; 4.40 (211, d) ; 3.34 (211, q); 1.11 (311, t)

Example 44
[2-(2-Amino-5-methyl-3-pyridinyl)-4-(trifluoromethyl)phenoxy]- acetic acid
(Formula Removed)


(i) [4-(Trifluoromethyl)phenoxy]- acetic acid
Sodium hydride (2.96g, 60% disp. in oil) was added to a stirred solution of 4-hydroxybenzo-trifluoride (lOg) in tetrahydrofuran (iSOmI) at —780C. The cooling bath was removed, the mixture stirred for lh then methyl bromoacetate (7m1) added. After lh, water was added, the tetrahydrofuran evaporated off under reduced pressure and the residue partitioned between ethyl acetate/2M hydrochloric acid. The organic layer was evaporated under reduced pressure and the residue dissolved in tetrahydrofuran (120m1). Methanol (30m1), water (30m1) and conc. sodium hydroxide solution (6m1) was added and the mixture stirred at RT overnight. The organics were removed under reduced pressure and the residue partitioned between ethylacetate and 2M hydrochloric acid. The organics were separated, dried and evaporated under reduced pressure, yield 12.42g
"HNMRDMSO-d6: δ 13.13 (1H, s); 7.65 (211, d); 7.10 (2H, d); 4.80 (2H, s). MS: APCI (-ye) 219 (M-1)

(ii) [4-(Trifluoromethyl)phenoxy]- acetic acid, (3-methyl-3-oxetanyl)methyl ester
Oxalyl chloride (14m1) was added to a solution of the product from step (i) (12.42g) and
N,N-dimethylformamide (2 drops) in dichloromethane (lOOml), and stirred at RT for 72h.
The mixture was evaporated under reduced pressure, the residue dissolved in
dichioromethane (lOOmI) then triethylamine (20m1) and 3-methyl-3-oxetanemethanol
(17m1) added. After 2h the mixture was washed with water, evaporated under reduced
pressure and the residue purified by chromatography on silica eluting with dichloromethane, yield 14.2g.

"HNrvIRDMSo-d6: δ 7.66 (2H, d); 7.14 (2H, d); 4.98 (2H, s), 4.34(211, d); 4.24 (2H, s); 4.19 (2H, d), 1.21 (311, s).

(iii) 4-Methyl-i -[[4-(trifluoromethyl)phenoxy]methyl]- 2,6,7-trioxabicyclo [2.2.2]octane
Boron trifluoride diethyl etherate (1.48mi) was added to a solution of the product from step (ii) (14.2g) in dichloromethane at —780C. The cooling bath was removed, the mixture stirred for 3h then triethylamine (6.2m1) added. The mixture was reduced to half the volume under reduced pressure then filtered. The filtrate was evaporated under reduced pressure then the residue purified by chromatography on silica (pre-eluted with one column volume of neat triethylamine) eluting with dichioromethane, yield 11.1g.

"H NMR DMSO-d6: δ 7.62 (211, d); 7.14 (211, d); 4.04 (211, s); 3.91 (611, s); 0.77 (311, s). MS: APCI (-i-ye) 305 (M+1)
(Formula Removed)

(iv) [2-B orono-4-(trifluoroinethyl)phenoxy]- acetic acid
A solution of sec-butyllithium (66m1, 1.4M in cyclohexane) was added dropwise over 10mm to a stirred solution of the product from step (iii) (9.44g) in THE (lOOmi) at —780C. After 3h the mixture was warmed to —400C for 5mm, then cooled to —780C. Trimethylborate (14. lml) was added, then after 10mm the reaction quenched with 2M hydrochloric acid. The mixture was warmed to RT and the organic phase separated. The aqueous layer was extracted with ethylacetate, the organics combined and evaporated under reduced pressure. The residue was dissolved in methanol (500m1) then bondelutNH2 resin(1 80g) added and the mixture swirled for 0.Sh then filtered. The resin was washed with 10% acetic acid/methanol, the washings then evaporated under reduced pressure and dried under high vacuum. The residue was dissolved in methanol(50m1), tetrahydrofuran (50m1) and saturated aqueous sodium hydroxide solution (2m1), left for 30mm then 2M hydrochloric acid (SOmi) added and the organics evaporated under reduced pressure. The residual aqueous layer was extracted with ethylacetate, the organics separated, dried and evaporated under reduced pressure, yield 5.05g.

1H NIMIR DMSO-d6: δ 8.07 (111, s); 7.89 (111, d); 7.75 (111, dd); 7.14 (111, d); 4.85 (211,
s).
MS: APCI (-ye) 263 (M-1)

(v) [2-(2-Amino-5-methyl-3-pyridinyl)-4-(trifluoromethyl)phenoxy].. acetic acid

A mixture of the product from step (iv) (O.lg), 2-amino-3-bromo-5-methylpyridine (0.071 g), tetrakis(triphenylphosphine)palladium(0) (0.046g), sodium carbonate (0.1 2g) in methanol (2m1) was heated in a CEM microwave (variable wattage up to 150W) at 100~C for 10mm. The mixture was loaded onto SOX resin (sulphonic acid resin), flushed with methanol then the product eluted with methanol/ammonia. The methanol/ammonia filtrate was evaporated under reduced pressure then loaded onto bondelut-NH2 resin. The resin was flushed with methanol then the product eluted with methanol/acetic acid. The methanol/acetic acid filtrate was evaporated and the residue purified by RPHPLC. Yield 0.089g

1HNMRDMSO-d6: 87.87 (111, s); 7.79 (1H, d); 7.69 (111, 5); 7.63 (111, s); 7.26 (1H, d); 4.9 (211,s); 2.2 (311, s).
MS: APCI (-ye) 325 ~M-1)

Example 45-123
The following compounds were synthesised in an analogous method to example 44

Example 45
[[4"-Amino-2"-methyl-5-(trifluoromethyl)[1,1 t-biphenyl]-2-yl]o~y]- acetic acid
(Formula Removed)


1H NMR DMSO-d6: δ 7.62 (111, d); 7.32 (111, s); 7.05 (111, d); 6.81 (111, d); 6.47 (111, s); 6.44 (111, d); 4.74 (2H, s); 1.98 (311, s).
MS: APCI (-ye) 324 (M-1)
EXAMPLE : 46 δ 7.65(111, d); 7.4(111, s), 7.15( 111, d); 7.04(111, d); 6.7 (lh, s); 6.56 (111, d); 4.76 (211, s).
MS: APCI (-ye) 344/6 (M-1)

Example 47
[[2"-Chloro-4"-hydroxy-5-(trifluoromethyl)[1,1 "-biphenyl]-2-yl]oxy]- acetic acid
(Formula Removed)
"H NMR DMSO-d6: δ 9.98 (111, s); 7.69 (111, d); 7.44 (111, s); 7.21 (111, d); 7.14 (111, d); 6.91 (lh, s); 6.80 (111, d); 4.76 (211, s).
MS: APCI (-ye) 345/7 (M-1)

Example 48
[2-(2,4-Dimethoxy-5-pyriniidinyl)-4-(trifluoromethyl)phenoxy]- acetic acid
(Formula Removed)
"H NMR DMSO-d6: δ 8.32 (111, s); 7.71 (111, d); 7.63 (111, s); 7.20 (111, d); 4.8 (2H, s); 3.95 (311, 5); 3.87 (311, s).
MS: APCI (-ye) 357 (M-1)

Example 49
[[2"-Chloro-5- (trifluoromethyl)[1,1 "-biphenyl]-2-yl]oxy]- acetic acid
(Formula Removed)
1H NMR DMSO-d6: δ 7.75 (111, d); 7.55 (111, in), 7.50 (111, s); 7.42 (111, in); 7.41( 111, d);
7.40 (111, d); 7.19 (111, d); 4.78 (211, s).
MS: APCI (-ye) 329/3 1 (M-1)



Example 50
[2,5,-Bis(trifuoromethyl)[1,1-biphenyl]-2-yl]oxy]-acetic acid
(Formula Removed)



1H NMR DMSO-d6: δ 7.83 (1H, d); 7.75 (1H, d); 7.71 (111, d); 7.63 (111, t); 7.44 (lH, 5);
7.43 (1H, d); 4.74 (211, in).
MS: APCI (-ye) 363 (M-1)

Example 51
[[5t-Fluoro-2"-methoxy-5-(trifluoromethyl)[1,1 "-biphenyl]-2-yl]oxy]- acetic acid
(Formula Removed)


"HNMRDMSO-d6: δ 8 7.68 (111, d); 7.51 (111, s); 7.20 (111, d); 7.17 (111, in); 7.15 (111, in); 7.10 (111, d); 4.78 (2H, s); 3.7 (311, s).
MS: APCI (-ye) 343 (M-1)

Example 52
II[5"-Cyano-2" -methoxy-S-(trifluoromethyl)[1,1"-biphenyl]-2-yl]oxy]- acetic acid
(Formula Removed)

"H NMR DMSO-d6: δ 7.87 (111, d); 7.74 (111, s); 7.71 (1H, d); 7.56 (1H,s); 7.29 (111, d); 7.19 (111, d); 4.77 (211, s); 3.81 (311, s).
MS: APCI (-ye) 350 (M-1)

Example 53
[[4"-Chloro-2"-methyl-5-(trifluoromethyl)[1,1" -biphenyl]-2-yl]oxy] - acetic acid
(Formula Removed)




"H NMR DMSO-d6: δ 7.71 (111, d), 7.47 (111, s), 7.34 (111, d), 7.30 (lH, d), 7.24 (111, s),
7.13 (111, d), 4.73 (211, s), 2.11 (311, s)
MS: APCI (-ye) 343 / 345 (M-1)

Example 54

2,5,Dimethyl-5-(trifuoromenthyl)[1,1-biphenyl]-2yl]oxy]-acetic acid
(Formula Removed)


"HNN"JR DMSO-d6: δ 7.64(111, d), 7.35 (111, s), 7.13 (111, d), 7.07 (111, d), 7.02 (111, d),
6.94 (111, s), 4.50 (211, s), 2.30 (311, s), 2.08 (311, s)
MS: APCI (-ye) 323 (M-1)

Example 55
,5,chloro-2-methyl-1-5-(trifluoromethyl)biphenyl]-2yl]oxy]-acetic acid
(Formula Removed)

1HNMZRDMSO-d6: δ 7.70(111, d), 7.43 (111, s), 7.38 (111, s), 7.29(111, d), 7.19(111, d),
7.14 (111, s), 4.70 (211, s), 2.14 (311, s)
MS: ARCI (-ye) 343/345 (M-1)

Example 56
[[2"-Fluoro-6"-methyl-5-(trifluoromethyl)[1,1 "-biphenyl]-2-yl]oxy]- acetic acid
(Formula Removed)



1HNN4iRDMSO-d6: δ 7.71 (1H, d), 7.44(111, s), 7.27(111, q), 7.18 (1H, t), 7.11 (1H, d),
7.04 (111, d), 4.67 (211, s), 2.06 (311, s)
MS: APCI (-ye) 327 (M-1)

Example 57
[[4"-Fluoro-2"-methyl-5-(trifluoromethyl)[1,1 "-biphenyl]-2-yl]oxy]- acetic acid
(Formula Removed)

"HNMRDMSO-d6: δ 7.70(111, d), 7.42(111, s), 7.30(111, t), 7.12(111, d), 7.10(111, d),
7.04 (111, d), 4.69 (211, s), 2.11 (311, s)
MS: APCI (-ye) 327 (M-1)



E%ample 58
[[4"4[(Ethylainino)carbonyl]amino]-2"-methyl-5-(trifluoromethyl)[1,1 "-biphenyl]-2-yl]oxy]- acetic acid
(Formula Removed)
"HNMRDMSO-d6: δ 8.49(111, s), 7.62(111, d), 7.31 (111, s), 7.29(111, s), 7.24(111, d),
7.04 (111, d), 7.00 (111, d), 6.25 (111, t), 4.60 (211, s), 3.10 (211, in), 1.06 (311, t)
MS: APCI (-ye) 395 (M-1)

Example 59 [[2"-Methyl-4"-[[(methylamino)carbonyl]amino]-5-(trifluoromethyl)[1,1 " -biphenyl]-2-yl]oxy]- acetic acid
(Formula Removed)





"H NMR DMSO-d6: δ 8.52 (111, s), 7.65 (111, d), 7.39 (111, s), 7.26 (111, s), 7.26 (111, d),
7.07 (1H, d), 7.00 (111, d), 6.05 (1H, d), 4.72 (211, s), 2.09 (311, s)
MS: APCI (+ve) 383 (M+l)


Example 60
[[4" -[[(Cyclopropylamino)carbonyl]amino]-2"-methyl-5-(trifluoromethyl)[1,1 t..
biphenyl]-2-yl]oxy]- acetic acid
(Formula Removed)

"H NMIR DMSO-d6: δ 8.33 (111, s), 7.66 (111, d), 7.37 (111, s), 7.31 (111, s), 7.26 (111, d),
7.08 (111, d), 7.00 (111, d), 6.46 (111, s), 4.75 (211, s), 2.54 (1H,m), 0.63 (211, in), 0.42 (211,
m)
MS: APCI (+ve) 409 (M+1)

Example 61 [[2"-Methyl-4"-[[(propylamino)carbonyl]amino]-5-(trffluoromethyl)[1,1 "-biphenyl] -2-yl]oxy]- acetic acid,
(Formula Removed)
"H NIMR DMSO-d6: δ 8.48 (111, s), 7.64 (111, d), 7.36 (1H, s), 7.30 (111, s), 7.24 (111, d), 7.07 (111, d), 7.00 (111, d), 6.23 (111, t), 4.68 (211, s), 3.05 (211, q), 2.10 (311, s), 1.44 (211, in), 0.88 (311, d)
MS: APCI (+ve) 411 (M+1)

Example 62
[[2",4"-Dimethyl-5-(trifluoromethyl)[1,1 "-biphenyl]-2-yl]oxy]- acetic acid




(Formula Removed)





111 NlvIiR DMSO-d6: δ 7.63 (111, d), 7.34 (1H, s), 7.03 (411, in), 4.50 (211, s), 2.32 (311, s),
2.11 (311, s)
MS: APCI (-ye) 323 (M-1)

Example 63
[[5 "-Fluoro-2"-methyl-5-(trifluoromethyl)[1,1 "-biphenyl]-2-yl]oxy]- acetic acid
(Formula Removed)
"HNj\4~ DMSO-d6: δ 7.65 (111, d), 7.38 (111, s), 7.29 (111, d), 7.27 (1H, d), 7.11 (111, d),
7.06 (111, in), 4.40 (211, s), 2.13 (311, s)
MS: APCI (-ye) 327 (M-1)

Example 64
[[4 "-(Aminocarbonyl)-2"-methyl-5-(trifluoromethyl)[1,1 "-biphenyl]-2-yl]oxy]- acetic acid
(Formula Removed)



"H NMR DMSO-d6: δ (111, s), 7.77 (111, s), 7.70 (111, d), 7.63 (111, d), 7.34 (111, s), 7.30
(111, s), 7.25 (111, d), 6.98 (1H, d), 4.22 (211, s), 2.21 (311, s)
MS: APCI (+ve) 354 (M-i-1)

Example 65
[[3 "-Fluoro-2"-methyl-5-(trifluoromethyl)[1,1 "-biphenyl]-2-yl]oxy]- acetic acid
(Formula Removed)



EXAMPLE -d6: ~ δ.66 (111, d), 7.40 (111, s), 7.27 (111, d), 7.24 (111, d), 7.16 (111, t),
7.05 (111, d), 4.45 (211, s), 2.07 (311, s)
MS: APCI (lye) 327 (M-l)


Example 66
[[2",5"-Difluoro-5-(trifluoromethyl)[1,1 "-biphenyl]-2-yl]oxy]- acetic acid
(Formula Removed)


"H NMR DMSO-d6: δ 7.68 (111, d), 7.58 (111, s), 7.53 (111, in), 7.30 (111, in), 7.28 (111, in), 7.09 (111, d), 4.44 (211, s)

Example 67 [[5"-~Aminosuli"onyl)-2"-chloro-5-(trifluoromethyl)[1,1"-biphenyl]-2-yl]oxy]- acetic acid
(Formula Removed)

"H NIvIIR DMSO-d6: δ 7.93 (111, d), 7.82 (111, d), 7.76 (111, s), 7.73 (111, d), 7.53 (111, s),
7.10 (111, d), 4.38 (211, s)
MS: APCI (+ve) 408/4 10 (M+1)

Example 68
[[4"-Cyano-2"-methyl-5-(trifluoromethyl)[1,1 "-biphenyl]-2-yl]oxy]- acetic acid
(Formula Removed)



"H NIMR DMSO-d6: δ 7.78 (111, s), 7.71 (111, t), 7.71 (111, in), 7.46 (1H, s), 7.40 (111, d),
7.11 (lH, d), 4.61 (2H, s), 2.18 (3H, s)
MS: APCI (-ye) 334 (M-1)


Example 69

[[4 "-Chloro-2"-fluoro-5-(trifluoromethyl)[1,1 "-hiphenyl]-2-yl]oxy]- acetic acid
(Formula Removed)



"H NMIR DMSO-d6: δ 7.73 (111, d), 7.60 (1H, s), 7.56 (1H, s), 7.52 (1H, d), 7.36 (111, d), 7.17 (111, d), 4.70 (2H, s)


Example 70

[[2 ",5"-Difluoro-4"-methoxy-5-(trifluoromethyl)[1,1 "-biphenyl]-Z-yl]o~~y]- acetic acid
(Formula Removed)



"H NMIR DMSO-d6: δ 7.63 (111, d), 7.60 (111, in), 7.52(111, s), 7.19 (111, in), 7.06 (111, d), 4.39 (211, s), 3.91 (311, s)


Example 71

[[2"-fluoro-5 "-methyl-5-(trifluoromethyl)[1,1 "-biphenyl]-2-yl]oxy]- acetic acid
(Formula Removed)

"H NlvliR DMSO-d6: δ 7.74 (111, d), 7.57 (111, s), 7.25 (111, d), 7.26 (111, s), 7.19 (111, d), 7.14 (lH, d), 4.85 (211, s), 2.35 (311, s)

Example 72
[[2"-Fluoro-4"-methyl-5-(trifluoromethyl)[1,1 "-biphenyl]-2-yl]oxy]- acetic acid
(Formula Removed)

"H NMR DMSO-d6: δ7.67 (111, d), 7A6 (111, s), 7.40 (111, t), 7.10 (111, d), 7.07 (111, d), 7.07 (1H, s), 4.49 (2H, s), 2.34 (311, s)

Example 73

[[4"-Methoxy-2"-methyl-5-(trifluoromethyl)[1,1 "-biphenyl]-2-yl]oxy]- acetic acid
(Formula Removed)


111 NMR DMSO-d6: δ7.62 (1H, d), 7.33 (111, s), 7.08 (111, d), 7.00 (111, d), 6.82 (111, s),

6.78 (lI-I, d), 4.45 (211, s), 3.80 (311, s), 2.13 (311, s)

Example 74

[[4 "-(Aminosulfonyl)-2",5"-difluoro-5-(trifluoromethyl)[1,1 "-biphenyl]-2-yl]oxy]-acetic acid
(Formula Removed)


"H NMR DMSO-d6: δ 7.83 (111, in), 7.75 (111, d), 7.69 (111, s), 7.63 (1H, in), 7.18 (111, d),
4.53 (2H, s)
MS: APCI (-ye) 410 (M-1)

Example 75

[2-B enzo [b]thien-3-yl-4-(trifluoromethyl)phenoxy].. acetic acid
(Formula Removed)



"H NMR DMSO-d6: δ 8.04 (111, d), 7.87 (111, s), 7.78 (111, d), 7.69 (1H, d), 7.67 (111, s),
7.38 (211, in), 7.24 (111, d), 4.81 (2H, s)
MS. APCI (-ye) 351 (M-l)

E~arnple 76
[[5-(Trifluoromethyl)[1,1 "-biphenyl]-2-yl]oxy]- acetic acid
(Formula Removed)

"H NMIR DMSO-d6: δ 7.69 (111, d), 7.60 (311, in), 7.41 (311, in), 7.20 (111, d), 4.88 (211, s)

MS: APCI (-ye) 295 (M-1)

Example 77

[2-(2-Benzofuranyl)~4~(trifluoromethyl)phenoxyJ. acetic acid
(Formula Removed)


"H NMR DMSO-d6: δ 8.24 (111, s), 7.85 (111, s), 7.75 (111, d), 7.70 (211, d), 7.33 (311, in),
5.07 (211, s)
MS: APCI (-ye) 335 ~M-1)


Example 78

[[4" -Chloro-5-(trifluoromethyl)[1,1"-biphenyl]-2-yl]oxy]- acetic acid
(Formula Removed)


111 NMIR DMSO-d6: δ 7.70 (111, d), 7.64 (111, d), 7.62(111, s), 7.62(111, d), 7.50 (111, d),

7.50 (111, d), 7.21 (111, d), 4.81 (211, s)
MS: APCI (-ye) 329/33 1 (M-1)


Example 79
[[3"-(1-Methylethyl)-5-(tril"luoromethyl)[1,1"-biphenylj-2-yl]oxy]- acetic acid
(Formula Removed)
"H NMIR DMSO-d6: δ 7.67 (111, d), 7.57 (111, s), 7.48 (111, s), 7.38 (111, t), 7.36 (111, d),
7.25 (111, d), 7.20 (111, d), 4.85 (211, s)
MS: APCI (-ye) 337 (M-1)

Example 80

[[3" ,4"-Difluoro-5-(trifluoromethyl)[1,1"-biphenyl]-2-yl]oxy]- acetic acid
(Formula Removed)






111 NMR DMSO-d6: δ 7.76 (111, d), 7.71 (111, d), 7.65 (1H, s), 7.51 (111, d), 7.48 (111, s),
7.25 (1H, d), 4.89 (2H, s)
MS: APCI (-ye) 331 (M-1)

Example 81

[2-(l,3-Benzodioxol-5-yl)-4-(trifluoromethyl)phenoxy]. acetic acid
(Formula Removed)



1H NMIR DMSO-d6: δ 7.63 (111, d), 7.57 (1H, s), 7.22 (1H, s), 7.16 (1H, d), 7.05 (111, d),
6.98 (111, d), 6.04 (211, s), 4.83 (2H, s)
MS: APCI (-ye) 339 (M-1)

Example 82
[[41-Ethyl-5-(trifluoromethyl)[1,1"..biphenyl]2yljoxy}. acetic acid
(Formula Removed)

"H NMR DMSO-d6: δ 7.66 (111, d), 7.58 (111, s), 7.51 (211, d), 7.27 (211, d), 7.18 (111, d),

4.86 (211, s), 2.65 (211, q), 1.22 (311, t)
MS: APCI (-ye) 323 (M-1)

Example 83

[[3 "-Fluoro-5-(trifluoromethyl)[1,1" :4,1 "-terphenyl]-2-yl]oxy]- acetic acid

(Formula Removed)

111 NMR DMSO-d6: δ 7.74 (111, d), 7.65 (211, in), 7.60 (111, in), 7.59 (211, in), 7.58 (111,

in), 7.52 (211, in), 7.43 (111, in), 7.12 (111, in), 4.51 (211, s)
MS: APCI (-ye) 389 (M-1)

Example 84

[[4" -(Trifluoromethoxy)-5-(trifluoromethyl)[1,1"-biphenyl]-2-yl]oxy]- acetic acid
(Formula Removed)


"H l\TMiR DMSO-d6 δ 7.82 (211, d), 7.62 (111, d), 7.58 (111, s), 7.41 (211, d), 7.05 (111, d),
4.39 (211, s)
MS: APCI (-ye) 379 (M-1)

Example 85
[[2" ,3"-Dichloro-5-(trifluoromethyl)[1,1 "-biphenyll-2-yl]oxy]- acetic acid
(Formula Removed)

"H NMR DMSO-d6: δ 7.68 (111, d), 7.66 (111, d), 7.47 (111, d), 7.48 (111, s), 7.41 (111, t),
7.05 (111, d), 4.26 (211,d)

MS: APCI (-ye) 363 (M-l)

Example 86

[[4"-(1,1-Dimethylethyl)-5-(trifluoromethyl)[1,1 "-biphenyl]-2-yl]oxy]- acetic acid
(Formula Removed)





"H NIN"IR DMSO-d6: δ 7.59 (111, d), 7.57 (2H, d), 7.51 (111, s), 7.44 (211, d), 7.04 (111, d),
4.47 (211, s)
MS: APCI (-ye) 351 (M-1)

Example 87

[2-(6-Methoxy-2-naphthalenyl)-4-(trifluoromethyl)phenoxy]- acetic acid HO 0
(Formula Removed)
"H MVIR DMSO-d6: δ 8.07 (111, s), 7.87 (111, d), 7.85 (211, s), 7.62 (211, d), 7.34 (111, s),
7.17 (111, d), 7.08 (111, d), 4.41 (211, s)
MS: APCI (-ye) 375 (M-1)

Example 88

[[4"-(Ethylthio)-5-(trifluoromethyl)[1,1 "-biphenyl]-2-yl]oxy]- acetic acid
(Formula Removed)
111 NMR DMSO-d6: δ 7.61 (211, d), 7.59 (111, d), 7.52 (111, s), 7.35 (211, d), 7.07 (111, d),
4.50 (211, s), 3.02 (211, q), 1.27 (311, t)
MS: APCI (-ye) 355 (M-1)

Example 89

[[4"-Acetyl-5-(trifluoroniethyl)[1,1 "-biphenyl]-2-yI]oxy]- acetic acid
(Formula Removed)

"H NlvIiR DMSO-d6: δ 8.02 (211, d), 7.77 (211, d), 7.64 (111, s), 7.72 (111, d), 7.23 (111, d),
4.83 (211, s), 2.63 (311, s)
MS: APCI (-ye) 337 (M-1)

Example 90
[2-(2-Chloro-5-methyl-4-pyridinyl)-4-(trifluoromethyl)phenoxy}. acetic acid, ammonium salt
(Formula Removed)




"H NMIR DMSO-d6: δ 8.30 (111, d), 7.75 - 7.66 (111, in), 7.49 (111, d), 7.04 (211, d), 4.28
(211, s), 2.15 (311, s)
MS:APCI (-ye) 449 (M-1)

Example 91
[[S"-(Aminosnlfonyl)-2"~methyl~5-(trifluoromethyl)[1,1 "-biphenyl]-2-yl]oxy]- acetic acid, ammonium salt
(Formula Removed)




"H NrvIR DMSO-d6: δ 7.73 - 7.65 (311, in), 7.63 (111, d), 7.44 (111, d), 7.37 (111, d), 7.01
(111, d), 4.23 (211, s), 2.24 (311, s)
MS:APCI (-ye) 388 (M-1)

Example 92
[2-(S-Quinolinyl)-4-(trifluoromethyl)phenoxy].. acetic acid, ammonium salt

(Formula Removed)











"HNMR CDCl3: δ 8.85 - 8.82 (111, in), 8.33 - 8.29 (1H, in), 7.95 - 7.91 (111, in), 7.82 -
7.78 (1H, in), 7.68 - 7.58 (311, in), 7.50 - 7.46 (111, in), 7.14 - 7.10 (1H, in), 4.54 (211, s)
MS:APCI (-ye) 346 (M-1)

Example 93

[[3 "-Cyano-5-(trifluoromethyl)[1,1"-biphenyl]-2-yl]oxy]- acetic acid, ammonium
(Formula Removed)


"H NMR. CDCl3: δ 8.00 (111, d), 7.87 - 7.83 (111, in), 7.66 - 7.52 (411, in), 6.99 (111, d),
4.68 (2H, s)
MS:AP~I (-ye) 320 ~M-1)

Er~ample 94
[2-[4-Methyl-6-[methyl(methylsulfonyl)aniino]-3-pyridinyl]-4-(trifluoromethyl)

phenoxyl- acetic acid, ammonium salt
(Formula Rrmoved)






"H NIvIIR DMSO-d6: δ 8.20 (111, s), 7.71 (111, in), 7.51 - 7.47 (1H, in), 7.33 (111, s), 7.09 (111, d), 4.52 (211, s), 3.32 (3H, s), 3.18 (311, d), 2.21 (311, s)
MS:APCI (-ye) 419 (M-1)

Example 95

[[2"-Methyl-5 "-(methylsulfonyl)-5-(trifluoroinethyl)[1,1 "-biphenyl]-2-yl]oxy]- acetic acid, ammonium salt
(Formula Removed)



111 NMR DMSO-d6: δ 7.83 - 7.80 (111, in), 7.74 - 7.69 (211, in), 7.55 (111, d), 7.49 (111, d),
7.09 (111, d), 4.46 (2H, s), 3.23 (311, s), 2.26 (311, s) MS:APCI (+ve) 406 (M+1)

Example 96

2"-(Carboxymethoxy)~5"~(trifluoromethyl).. [1,1 "-biphenyl]-3-carboxylic acid,

methyl ester
(Formula Removed)










"H NMR DMSO-d6: δ 8.15 - 8.13 (111, in), 7.99 - 7.93 (211, in), 7.68 - 7.55 (311, in), 7.10
(111, d), 4.46 (211, s), 3.87 (311, s)
MS:APCI (-ye) 353 (M-1)

Example 97
2"-(Carboxymethoxy)-5 "-(trifluoromethyl)- (1,1 t-biphenyl]-2-carboxyllc acid, 2-

methyl ester










111 NN4R DMSO-d6: δ 7.77 (111, M), 7.66 - 7.59 (211, in), 7.51 - 7.42 (311, in), 4.23 (211, s),
3.59 (411, s)
MS:APCI (-ye) 353 (M-1)

Example 98

[[5-(Trifluoromethyl)[1,1 ":4",1 "-terphenyl]-2-yl]oxy]- acetic acid
(Formula Removed)




"H NMR DMSO-d6: δ7.75 - 7.62 (711, in), 7.53 - 7.46 (311, in), 7.42 - 7.35 (111, in), 7.21 -
7.15 (1H, in), 4.76 (211, s)
MS:APCI (-ye) 371 (M-1)

Example 99

[[3" -Fluoro-2",4" -dimethyl-5-(trifluoromethyl)[1,1 "-biphenyl]-2-yl]oxy]- acetic acid
(Formula Removed)


"H N1YIIR DMSO-d6: δ 7.66 - 7.62 (111, in), 7.55 (111, d), 7.34 (211. d), 7.16 (111, d), 4.78
(211, s), 2.25 (611, d)
MS:APCI (-ye) 341 ~M-1)

Example 100
[[2"-Nitro-5-(trifluoromethyl)[1,1"acetic acid, ammonium salt
(Formula Removed)






111 NMR DMSO-d6 δ 8.00 (111, in), 7.83 - 7.76 (111, in), 7.70 - 7.55 (411, in), 6.94(111, d),
4.08 (211, s)
MS:APCI (-ye) 340 (M-1)

Example 101
[[2 "-Methyl-5-(trifluoromethyl)[1,1 "-biphenyl]-2-yl]oxy]- acetic acid
(Formula Removed)


"H NMR DMSO-d6: δ 7.65 - 7.61 (111, in), 7.34 - 7.32 (111, in), 7.28 - 7.14 (411, in), 7.02 -
6.98 (1H, in), 4.36 (211, s), 2.13 (311, s)
MS:APCI (-ye) 340 (M-1)

Example 102

[113 "-Chloro-2"-methyl-5-(trifluoromethyl)[1,1 -biphenyl]-2-yl]oxy]- acetic acid
(Formula Removed)



"H NMR DMSO-d6: δ 7.72-7.66 (111, in), 7.47 - 7.40 (211, in), 7.30 - 7.22 (111, in), 7.18 -
7.14 (111, in), 7.10 - 7.06 (111, in), 4.56 (211, s), 2.14 (311, s)
MS:APCI (-ye) 343 ~M-1)

E%ample 103
[[5-(Trifluoromethyl)[1,1" :3 ",1" "-terphenyl]-2-yl]oxy]- acetic acid
(Formula Removed)


"H NMIR DMSO-d6: δ 7.92 (111, t), 7.76 -7.72(211, in), 7.68 - 7.59 (411, in), 7.56 - 7.34
(411, in), 7.19 - 7.15 (111, in), 4.69 (211, s)
MS:APCI (-ye) 371 (M-1)

Example 104

2"-(Carboxymethoxy)-5 "-(trifluoromethyl)- [1,1 "-biphenyl]-4-carboxylic acid, 4-

methyl ester
(Formula Removed)

















"H NMR DMSO-d6: δ 8.03 - 7.99 (211, in), 7.82 - 7.79 (211, in), 7.70 - 7.66 (111, in), 7.63 -
7.61 (111, in), 7.17 - 7.14 (111, in), 4.62 (211, s), 3.88 (311, s)
MS:APCI (-ye) 353 (N/I-i)

Example 105

[[4 "-Nitro-5-(trifluoromethyl)[1,1"-biphenyl]-2-yl]oxy]- acetic acid

"H NMIR DMSO-d6: δ 8.30 - 8.26 (211, in), 7.99 - 7.94 (211, in), 7.75 - 7.67 (211, in), 7.20
(111, d), 4.65 (211, s)
MS:APCI (-ye) 340 (M-1)

Example 106
[[5- (Trifluoromethyl)-3"-[(trifluoromethyl)thio)[1,1-biphenyl]-2,yl]-acetic acid
(Formula Removed)



"H NMR DMSO-d6: δ 8.05 (111, s), 7.91 - 7.87 (111, in), 7.74 - 7.58 (411, in), 7.17 (111, d), 4.64 (211, s)
MS:APCI (-ye) 395 (M-1)

Example 107

[[5-(Trifluoromethyl)-4 "-[(trifluoromethyl)thio] [1,1 "-biphenyl]-2-yl]oxy]- acetic acid

(Formula Removed)

"H NIMIR DMSO-d6: δ 7.79 (411, s), 7.76 - 7.72 (111, in), 7.69 - 7.67 (111, in), 7.25 (111, d),
4.89 (211, s)

MS:APCI (-ye) 395 (M-1)

Example 108

[[4"-Methyl-5-(trifluoromethyI)[1,1 "-biphenyl]-2-yl]oxy]- acetic acid
(Formula Removed)




"H NMR DMSO-d6: δ 7.67 - 7.63 (111, in), 7.57 -7.54(111, in), 7.51 - 7.47 (211, in), 7.25
(211, d), 7.17 (111, d), 4.82 (2H, s), 2.35 (3H, s)
MS:APCI (-ye) 309 (M-l)

Example 109
[[4 "-Fluoro-5- (trifluoromethyl)[1,1 "-biphenyl]-2-yl]oxy]- acetic acid
(Formula Removed)




111 NMR DMSO-d6: δ 7.71 - 7.58 (411, in), 7.31 - 7.18 (311, in), 4.86 (211, s) MS:APCI (-ye) 314 (M-1)

Example 110
[[3 "-Fluoro-5-(trifluoromethyl)[1,1 "-biphenyl]-2-yl]oxy]- acetic acid
(Formula Removed)
1H NMR DMSO-d6: δ 7.74 - 7.69 (111, in), 7.66 - 7.64 (111, in), 7.53 - 7.42 (311, in), 7.26 -
7.18 (211, in), 4.88 (2H, s)
MS:APCI (-ye) 314 (M-1)


Example 111

[[3" -Methyl-5-(trifluoromethyl)[1,1 "-biphenyl]-2-yI]oxy]- acetic acid
(Formula Removed)
~H NTVIIR DMSO-d6: δ 7.70-7.63 (111, in), 7.56 (111, d), 7.42 - 7.28 (311, in), 7.21 - 7.15

(211, in), 4.82 (211, s), 2.34 (311, s)
MS:APCI (-ye) 309 (M-l)

Example 112
[2- (3-Pyridinyl)-4-(trifluoromethyl)phenoxy].. acetic acid
(Formula Removed)

1H NMR DMSO-d6: δ 8.88 (111, s), 8.56 - 8.53 (111, in), 8.15 - 8.09 (111, in), 7.68 - 7.60
(211, in), 7.48 - 7.42 (111, in), 7.10 (111, d), 4.43 (211, s)
MS:APCI (+ve) 298 (M+1)


Example 113

[[2" -Fluoro-5-(trifluoromethyl)[1,1 "-biphenyl]-2-yl]oxy]- acetic acid

(Formula Removed)




1HNMRDMSO-d6: δ 8.02(111, d), 7.92-7.90(111, in), 7.79-7.54(411, in), 7.28 (111, d),

4.90(211, s)
MS:APCI (-ye) 313 (N/I-i)


Example 114

[[2"-Methoxy-5-(trifluoromethyl)[1,1"-biphenyl]-2-yl]oxy]- acetic acid
(Formula Removed)
"HNIVIRDMSO-d6: δ 7.59(111, d), 7.42(111, s), 7.37 -7.30(211, in), 7.11 -6.95 (311, in),
4.42(211, s), 3.72 (311, s)
MS:APCI (-ye) 325 (M-1)


Example 115

[[3"-Methoxy-5-(trifluoromethyl)[1,1"-biphenyl]-2-yl]oxy]- acetic acid
(Formula Removed)
111 NMR DMSO-d6: δ 7.62 (111, d), 7.56 - 7.54 (111, in), 7.34 (111, t), 7.27 - 7.25 (111, in),

7.16 (111, d), 7.11 (111, d), 6.95 - 6.90 (111, in), 4.56 (211, s), 3.79 (311, s)
MS:APCI (-ye) 325 (M-1)



Example 116

[[4"-Methoxy-5-(trifluoromethyl)[1,1"-biphenyl]-2-yl]oxy]- acetic acid
(Formula Removed)






"H NIVIR DMS O-d6: δ 7.62 - 7.54 (411, in), 7.04 (111, d), 6.98 (2H, d), 4.45 (211, s), 3.79
(3H, s)
MS:APCI (-ye) 325 (M-1)


Example 117

[[3 "-(Ethylsulfonyl)-5-(trifluoromethyl)[1,1 t-biphenyl]-2-ylloxy]- acetic acid
(Formula Removed)














1HNMRDMSO-d6: 3 8.19- 8.17 (111, in), 8.11 - 8.07 (111, in), 7.87-7.83 (111, in), 7.73-
7.64 (3H, in), 7.11 (111, d), 4.39 (211, s), 3.38 (211, q), 1.14 (311, t)
MS:APCI (-ye) 387 ~M-1)



Example 118

[[3"-Propoxy-5-(trifluoromethyl)[1,1"-biphenyl]-2-yl]oxy]- acetic acid


(Formula Removed)

"H NMIR DMSO-d6: 37.70- 7.65 (111, in), 7.59 (111, d), 7.33 (1H, t), 7.22 - 7.10

6.95 - 6.91 (111, in), 4.86 (2H, s), 3.97 (2H, t), 1.79 - 1.68 (211, in), 0.98 (311, t)
MS:APCI (-ye) 353 (M-1)



Example 119

[[4"-Propoxy-5-(trffluoromethyl)[1,1 "-biphenyl]-2-yl]oxyl- acetic acid
(Formula Removed)

"H NMIR DMSO-d6: 8 7.65 - 7.61 (111, in), 7.56 - 7.50 (311, in), 7.16 (111, d), 7.01 - 6.96
(211, in), 4.85 (211, s), 3.97 (211, t), 1.80 - 1.70 (211, in), 0.99 (311, t)
MS:APCI (-ye) 353 (M-1)


Example 120

[2- (2-Amino-4-methyl-5-pyrimidinyl)-4- (trifluoromethyl)phenoxylj- acetic acid
(Formula Removed)
111 NMR DMSO-d6: 37.99 (s, 111), 7.62 (dd, 111), 7.43 (d, 111), 7.01 (d, 1111), 6.56 (s,


211), 4.41 (s, 211), 2.15 (s, 311).
MS:APCI (+ve) 328

Example 121
[[4?..cyano..5..(trifluoromethyl)[1,1 "-biphenyl]-2-yl]oxy]- acetic acid
(Formula Removed)
111 NMR CD3OD: 87.86 - 7.73 (in, 411), 7.65 (dd, 111), 7.60 (d, 111), 7.14 (d, 111), 4.66 (s,

211)
MS:APCI (-I-ye) 320


Example 122

[[4",5-Bis(trifluoromethyl)[1,1 "-biphenyl]-2-yl]oxy]- acetic acid
(Formula Removed)







"11 NMR DMSO-d6: 87.90(211, d), 7.78 (211, d), 7.67 (111, d), 7.62(111, s), 7.10(111, d),
4.47 (211, s)
MS: APCI (-ye) 363 (M-1)

Example 123

[2-(2-Naphthalenyl)-4-(trifluoromethyl)phenoxy]. acetic acid
(Formula Removed)

1HNMRDMSO-d6: 6 8.15 (111, s), 7.93 (411, in), 7.67 (111, s), 7.64 (111, d), 7.53 (211, in),
7.09 (111, d), 4.44 (211, s)
MS: APCI (-ye) 345 (M-1)

Example 124

[[4"-(1-Pyrrolidinylaulfonyl)-5-(trifluoromethyl)[1,1 "-biphenyl]-2-yl]oxy]- acetic acid
(Formula Removed)




(i) 1-[(4-Bromophenyl)sulfonyl]- pyrrolidine
A solution of 4-bromobenzenesulphonyl chloride (0.Sg) and pyrrolidine (0.284g) in acetonitrile (Smi) were stirred at RT for 48h then partitioned between ethylacetate and water. The organics were separated, washed with water, dried and evaporated under reduced pressure. The residue was triturated with isohexane and filtered, yield 0.5g.

"HNMR CDCl3: 87.72-7.65 (411, in) ; 3.28-3.21 (411, in); 1.84-1.76 (411, m)

(ii) [[4"-( 1 -Pyrrolidinylsulfonyl)-5-(trifluoroinethyl)[ 1,1 "-biphenyl]-2-yl]oxy]- acetic acid
The title compound was prepared by the method of example 44, yield 0.13g.



111 NMIR CD3OD: 87.83 - 7.75 (in, 4H), 7.56 - 7.52 (in, 1H), 7.50 (d, 111), 7.01 (d, 111),

4.46 (s, 211), 3.20 - 3.14 (in, 411), 1.72 - 1.65 (in, 4H).
MS:APCI (-ye) 428.

Example 125-134
The following compounds were synthesised in an analogous method to example 124

Example 125
[[4"-[(Dimethylamino)sulfonyl]~5~(trifluoromethyl)[1,1 "-biphenyl]-2-yl]oxy]- acetic acid






111 NMR CD3OD: 37.92-7.81 (in, 4117), 7.67 - 7.61 (in, 211), 7.14 (d, 1H), 4.64 (s, 211),

2.73 (s, 611).
MS:APCI (+ve) 402

Example 126
L[4-[[(Phenylmethyl)amino]suMonyl]~s~(trirIuoromethyl)[11 "-biphenyl]-2-yl]o;~iy]-acetic acid
(Formula Removed)


111 NMR CD3OD: 37.92 - 7.77 (in, 411), 7.68 (d, 111), 7.62 (s, 111), 7.29 - 7.14 (in, 611),
4.73 (s, 211), 4.13 (s, 211).
MS:APCI (-ye) 464.

Example 127
[[4 "-[[(2,2,2-Trifluoroethyl)anlino]sulfonyl]..s..(trinuoromethyl)[1l t-biphenyl]-2-yl]oxy]- acetic acid
(Formula Removed)







1HNN/m CD3OD: 37.93-7.79 (in, 411), 7.64 (d, 111), 7.59 (d, 111), 7.12 (d, 111), 4.64 (s,
211), 3.63 (t, 211).
MS:APCI (-ye) 456



Example 128 [[4"-[[(5-Methyl-2-thiazolyl)amino]sulfonyl]-5-(trifluoromethyl)[1,1 "-biphenyl]-2-yl]oxy]- acetic acid
(Formula Removed)


NMIR CD3OD: 87.97 - 7.92 (in, 211), 7.82 - 7.78 (in, 211), 7.67 - 7.61 (in, 111), 7.61 -7.58 (in, 111), 7.12 (d, 211), 6.82 (d, 111), 4.61 (s, 211), 2.27 (d, 311).
MS:APCI (-ye) 471

Example 129
[[4"-RPhenylamino)sulfonyl]-5-(trifluoromethyl)[1,1 "-biphenyl]-2-yl]oxy]- acetic acid
(Formula Removed)

111NMR CD3OD: 37.81 -7.73 (in, 411), 7.60 (dd, 111), 7.54 (d, 111), 7.25 -7.02 (in, 611),

4.55 (s, 211).
MS:APCI (-ye) 45Q~



Example 130

[[4"-[(Diethylamino)sulfonyl]-5-(trifluoromethyl)[1,1 "-biphenyl]-2-yl]oxy]- acetic acid
(Formula Removed)

111 NMR CD3OD: 8 7.85 (s, 411), 7.63 (dd, 1H), 7.59 (d, 111), 7.11 (d, 111), 4.58 (s, 211),
3.27 (q, 411), 1.16 (t, 611).
MS:APCI (-ye) 450.

Example 131
[[4".[(Cyclopropy1amino)sulfonyl]~5~(trifluoromethyI)[1,1"~biphe11y1]-2-yl]OXy]- acetic acid
(Formula Removed)

111 NI\4R CD3OD: 87.95 - 7.84 (in, 411), 7.64 (dd, 111), 7.61 (d, 111), 7.12 (d, 111), 4.61 (s, 211), 2.23 - 2.16 (in, 111), 0.58 - 0.53 (in, 411).
MS:APCI (-ye) 414.

Example 132
[[4"-(Aminosulfonyl)-5-(trifluoromethyl)[1,lt-biphenylj-2-yl]oxyI- acetic acid
(Formula Removed)

NMR CD3OD: 8 7.94 (d, 211), 7.81 (d, 211), 7.63 (dd, 111), 7.58 (d, 1117), 7.12 (d, 111), 4.60 (s, 211).
MS:APCI (-ye) 374.



Example 133

[[4"-[(Methylamino)sulfonyl]-5-(trifluoromethyl)[1,1 "-biphenyl]-2-yl]oxy]- acetic acid
(Formula Removed)
NMR CD3OD: 3 7.80 - 7.74 (in, 411), 7.53 (dd, 111), 7.50 (d, 111), 4.48 (s, 211), 2.47 (s, 311).
MS:APCI (-ye) 388

Example 134 [[4"-[(4-Methyl-1-piperazinyl)sulfonyl]-5-(trifluoromethyl)[1,1 "..biphenyl]..2..yJloxyl.. acetic acid
(Formula Removed)


111 NMR CD3OD: 3 7.85 - 7.70 (in, 411), 7.55 - 7.51 (in, 111), 7.49 (d, 111), 7.00 (d, 111),

4.41 (s, 211), 3.03 - 2.95 (in, 411), 2.48 (t, 411), 2.21 (s, 3117). MS:APCI (-ye) 457

E%ample 135 [2-[4-Methyl-2-(5-methyl-1,1-dioxido.1,2,5-thiadiazolidin-2-yl)-5-pyrimidinyl]-4-(trifluoromethyl)phenoxy]- acetic acid
(Formula Removed)
(i) 2,5-Dibromo-4-inethyl-pyrimidine Isoamylnitrite (21m1) was added to a stirred suspension of 5-bromo-inethyl-2-
pyrimidinamine (1.75g) in broinoform (30m1) and the mixture heated at 850C for 4h. After cooling, isohexane (300niI) was added and the solution passed through a pad of silica-gel. The silica was washed with petrol (lOOOinl), dichloroinethane (200m1) then the product eluted with ethylacetate. The ethylacetate layer was evaporated under reduced pressure and the residue purified by chromatography on silica eluting with 5% diethylether/ isohexane, yield 0.9g
NMR CDCl3: 8 8.52 (s, 111), 2.64 (s, 311)
MS :APCI (-ye) 249/51/53

(ii) 5-Bromo-4-methyl-2-(5-methyl-1, 1-dioxido-1 ,2,5-thiadiazolidin-2-yl)- pyrimidine Sodium hydride (0. 128g, 60% disp. in oil) was added to a stirred solution of 2-methyl-1,2,5-thiadiazolidine 1,1-dioxide (0.433g) in THE (lOmi). DMF (lOmI) was added and the mixture heated at 800C for 5mm then a solution of the product from step (i) (0.Sg) in DMIF (SmI) was added. The mixture was heated at 600C for 10mm, poured into water (lOOmi), acidified with citric acid and extracted with ethylacetate. The organics were evaporated under reduced pressure and the residue purified by chromatography on silica eluting with diethylether, yield 0.5 8g.

1H~ff~ CDCl3: 3 8.50 (s, 111), 4.05 (t, 211), 3.45 (t, 211), 2.87 (s, 311), 2.58 (s, 311).
MS:APCI (+ve) 307/9

(iii) [2-[4-Methyl-2-(5-methyl-1 , 1-dioxido-1 ,2,5-thiadiazolidin-2-yl)-5-pyrimidinyl]-4-(trifluoromethyl)phenoxy]- acetic acid
The title compound was prepared by the method of example 44, yield 0.05g.

111 NIvIR CDCl3: 3 8.34 (s, 111), 7.47 (dd, 111), 7.32 (d, 111), 6.90 (d, 111), 4.36 (s, 211),
4.05 (t, 211), 3.40 (t, 411), 2.77 (s, 311), 2.27 (s, 311). MS:APCI (+ve) 447

Example 136-137
The following compounds were synthesised in an analogous method to example 135

Example 136
[2-[4-Methyl-2-[methyl(methylsulfonyl)amino]-5-pyrimidinyl]-4.
(trifluoromethyl)phenoxy]- acetic acid
(Formula Removed)
~11 NMR CDCl3: 8 8.37 (s, 111), 7.63 (dd, 111), 7.40 (d, 111), 6.96 (d, 111), 4.60 (s, 211),
3.57 (s, 311), 3.53 (s, 311), 2.40 (s, 311).
MS:APCI (-ye) 418
Example 137

(trifluoromethyl)phenoXy]- acetic acid, ammonium salt
(Formula Removed)
111 NMIR CDCl3: 3 8.37 (s, 111), 7.60 (dd 111), 7.36 (d, 111), 7.02 (d, 111), 4.53 (s, 211),
4.09 (t, 211), 3.49 (t, 211), 2.51 (quintet, 211), 2.39 (s, 311). MS:APCI (+ve) 432.

Example 138
[2-[2-[3-Hydroxy-1-azetidinyl)-4-methyl-5-pyramidinyl]-4-(trifluoromethyl)phenoxy)-acetic acid
(Formula Removed)

(Formula Removed)
(i) 1~(5~Bromo~4~methyl-2-pyrimidinyl)- 3-azetidinol
A mixture of the product from example 135 step (i) (0.75g), azetidin-3-ol hydrochloride (0.66g) and triethylamine (0.9m1) in ethanol (lOmI) was stirred at RT for 2h. The solvent was removed under reduced pressure and the residue purified by chromatography on silica eluting with 60% diethylether/isohexane as eluant, yield 0.7g.

111 NMR CDCI3: 3 8.22 (s, 111), 4.78 - 4.72 (in, 111), 4.40 - 4.33 (in, 211), 3.99 - 3.93 (in,
211), 2.45 (s, 311)

(ii) ~ phenoxyl - acetic acid
The title compound was prepared in an analogous method to example 44, yield 0.04g.

111 NMR CD3OD: 8 8.09 (s, 111), 7.64 (in, 111), 7.43 (d, 111), 7.08 (d, 111), 4.71 - 4.64 (in,
111), 4.61 (s, 211), 4.41 - 4.34 (in, 211), 3.96 - 3.91 (in, 211), 2.25 (s, 311). MS:APCI (+ve) 384



Example 139-141
The following compounds were synthesised in an analogous method to example 138

Example 139 [2-[4-Methyl-2- (4-methyl-1-piperazinyl)-5-pyrimidinyl]-4-(trifluoromethyl)phenoxy]-acetic acid
(Formula Removed)



1HNMIR CDCl3: 8 8.19 (s, 111), 7.57 (d, 111), 7.38 (d, 111), 6.99 (d, 111), 4.51 (s, 211),
4.3-3.8 (br s, 411). 3-2.8 (br s, 411), 2.63 (s, 311), 2.29 (s, 311). MS:APCI (+ve) 411

Example 140 [2-[4-Methyl-2-(1-pyrrolidinyl)-5-pyriniidinyll-4-(trifluoromethyl)phenoxy]- acetic acid
(Formula Removed)

111 NMR CD3OD: 3 7.95 (s, 111), 7.36 (d, 111), 7.59 - 7.54 (in, lii), 7.01 (d, 111), 4.65 (s,
211), 3.50 (t, 411), 2.15 (s, 311), 1.96 - 1.91 (in, 411).
MS:APCl (+ve) 382

Example 141 [2-[2-(Dimethylamino)-4-methyl-5-pyrimidinyl]-4-(trifluoromethyl)phenoxy]- acetic acid
(Formula Removed)


111 NMZR CD3OD: 3 8.05 (s, 111), 7.67 - 7.63 (in, 111), 7.44 (d, 111), 7.10 (d, 111), 4.75 (s, 211), 3.20 (s, 611).
MS:APCI (+ve) 356

Example 142
[2- [5-Methyl-2-[methyl(methylsulfonyl)amino]-4-pyrimidinyl]-4-
(trifluoromethyl)phenoxy]- acetic acid
(Formula Removed)

(i) N-(4-Chloro-5-methyl-2-pyrimidinyl)-N-methyl-methanesulfonamide
A mixture of N-methylsulphonamide (3.35g), 2,4-dichloro-5-methyl pyrimidine (5g) and potassium carbonate (4.3g) in DMF (SOmI) was heated at 800C for 4h. The reaction was quenched with water (200m1) and extracted with ethylacetate. The organic s were dried, evaporated under reduced pressure and the residue triturated with ether. The solid was
filtered off (4-isomer) and the filtrate evaporated under reduced pressure and subjected to RPI{PLC to obtain the 2-isomer, yield 0.37g.

111 NIvIiR CDCI3: 3 8.35 (s, 111), 3.51 (s, 311), 3.48 (s, 311), 2.29 (d, 311).


(ii) [2-[5-Methyl-2-[methyl(methylsulfonyl)amino]-4-pyrimidinyllj-4-(trifluoromethyl)phenoxy]- acetic acid
The title compound was prepared in an analogous method to example 44, yield 0.04g.

NMR CD3OD: 3 8.50 (s, 111), 7.16 (d, 111), 7.74 (dd, 111), 7.62 (d, 111"), 4.68 (s, 211), 3.50 (s, 311), 3.45 (s, 311"), 2.19 (s, 311").
MS:APCI (+ve) 420

Example 143
[2-[2-[[(Dimethylaniino)sulfonyl]amino]-4-methyl-5-pyrimidinyl]-4-
(trifluoromethyl)phenoxy]- acetic acid
(Formula Removed)


(i) N"-(5-Bromo-4-methyl-2-pyrimidinyl)-N,N-dimethyl- sulfamide
A mixture of 5-bromo-4-methyl-2-pyrimidinamine (0.75g") and dimethylsulphonyl chloride (0.43m1) in pyridine (20m1) was heated at 800C for 17h. The solvent was





removed under reduced pressure and the residue purified by chromatography on silica eluting with diethylether then ethylacetate. The residue was then purified by RPIIPLC, yield 0.12g.

MS:APCI (-ye) 295/6

(ii) [2-[2-[[(Dimethylamino)sulfonyl]amino]-4-methyl-5-pyrimidinyl]4-(trifluoromethyl)phenoxy] - acetic acid
The title compound was prepared in an analogous method to example 44, yield 0.01g.

111 NIVIIR CD3OD: 3 8.27 (s, 111), 7.68 (d, 111), 7.49 (s, 111), 7.11 (d, 111), 4.70 (s, 211),
2.98 (s, 611), 2.32 (s, 311). MS:APCI (+ve) 435.

Example 144
[[2"-Chloro-4"-[(methoxycarbonyl)amino]-5-(trifluoromethyl)[1,1 "-biphenyl]-2-ylloxy]acetic acid
(Formula Removed)

i) 2-Chloro-2"-(phenylmethoxy)-5 "-(trifluoromethyl)-[1 ,1 "-biphenyl] -4-amine The product from example 32 step (ii) (0.Sg) and 4-bromo-3-chloroaniline (0.38g) were dissolved in toluene (4m1). Ethanol (lml), 2M aqueous sodium carbonate (lml) and Pd(PPh3)4 (0.1 15g) were added sequentially and the mixture heated at reflux for 4h. The reaction was cooled, evaporated, dissolved in EtOAc, washed with water and brine, dried (MgS 04) and evaporated. The residue was purified by chromatography on silica eluting with 10% EtOAc/isohexane. Yield 0.23g.
111 NMIR DMSO-d6: 87.67 (ddd, 111), 7.4 (d, 111), 7.27-7.34 (in, 611), 7.01 (d, 111), 6.7 (d, 111), 6.55 (dd, 111), 5.47 (s, 211) 5.18 (s, 211)

ii) 4~ -Amino-2"-chloro-5-(trifluoromethyI)-[1,1 "-biphenyl]-2-ol
5% Pt/C (O.088g) was added to a solution of the product from step (i) in ethanol (20m1)
and hydrogenated at RT and 1 bar for iSh. Extra Pt/C (0.lg) was added and hydrogenated
for a further 3h at 2 bar. The catalyst was removed by filtration and the filtrate evaporated
to leave a solid residue. The residue was purified by chromatography on silica eluting with
50% EtOAc/isohexane. Yield 0.083g.




111 NMR DMSO-d6: 8 10.2 (s, 111), 7.49 (d, 111), 7.3 (d, 111), 7.03 (d, 111), 6.96 (d, 111),

6.68 (d, 1H), 6.54 (dd, 111), 5.44 (s, 2H)

iii) [[4" -Amino-2" -chloro-5-(trifluoromethyl)-[1 , 1 "-biphenyl]-2-yl]oxy]acetic acid, 1,1 -dimethylethyl ester

The subtitle compound was prepared by the method of example 1 step (i) using the product from step (ii). Yield 0.07g. Used in step (iv) without characterisation.

iv) [[2" -Chloro-4" -[(methoxycarbonyl)amino]~5~(trifluoromethyl")[1 , 1, -biphenyl]2-yl]oxy]acetic acid, 1,1-dimethylethyl ester
The product from step (iii) (0.07g) was dissolved in DCM (5m1), triethylamine (0.024m1) added, followed by methyl chloroformate (0.013m1) and stirred for 20h. Further
triethylamine (0.024m1) and methyl chloroformate (0.013m1) were added three times over to achieve complete reaction. The solvent was removed by evaporation to give the crude product which was carried forward to step (v) without characterisation.

v) [[2" -Chloro-4" -[(methoxycarbonyl)amino]~5~(trifluoromethyl")[1 , 1 "-biphenyl]-2-yl]oxy]acetic acid
The title compound was prepared by the method of example 1 step (iii) using the product
from step (iv).
111 NMR DMSO-d6: 89.94 (s, 111), 7.69 (dd, 211), 7.4 1-7.47 (in, 211), 7.35 (d, 111), 7.13
(d, 111), 4.65 (s, 211), 3.7 (s, 311)
MS:APCI (-ye) 402

Example 145
2-[[2"-Chloro-4"~(methylsulfonyl)~5~(trifJuoromethyl)[1,1"biphenyl]2y1]oxy]..(2s).
propanoic acid
(Formula Removed)







i) 2-Chloro- 1 -iodo4-(methylthio)benzene
Sodium methanethiolate (Sg) was added to a solution of 4-fluoro-2-chloro-iodobenzene (18.3g) and stirred for 20h. The mixture was poured into water, extracted with ether,
washed with brine, dried (MgSO4) and evaporated. Yield 18.5g.
111 NMIR DMSO-d6: 8 7.81 (d, 111), 7.43 (dd, 111), 6.98 (dd, 111), 3.32 (s, 311)


ii) 2-Chloro-l-iodo-4-(methylsulfonyl)benzene.
Mcpba (8.6g) was added portionwise to a stirred solution of the product from step (i) (Sg) in DCM (lOOml). After lh, the reaction was diluted with DCM (200m1), washed with saturated aqueous sodium bicarbonate, dried (MgS 04) and evaporated under reduced pressure. Yield 3.2g
NMR DMSO-d6: 8 8.26 (d, 111), 8.06 (d, lii), 7.59 (dd, 111), 3.32 (s, 311)

iii) 2"-Chloro-4" -(methylsulfonyl)-5 -(trifluoromethyl)-[ 1,1, -biphenyl] -2-yl]oxy]methyl]benzene
The subtitle compound was prepared by the method of example 144 step (i) using the
product from step (ii) and the product from example 32 step (ii). Yield 2.2g
111 NMR DMSO-d6: 8 8.11 (s, 111), 7.95 (dd, 111), 7.82 (d, 111), 7.72 (d, 111), 7.61 (d, 111),
7.41 (d, 111), 7.27-7.36 (in, 511), 5.25 (s, 211), 3.35 (s, 311)

iv) 2" -Chloro-4"-(methylsulfonyl)-5-(trifluoromethyl)-[1 , 1 "-biphenyl]-2-ol
The subtitle compound was prepared by the method of example 144 step (ii) using the
product from step (iii). Yield 0.95g
111 NMR DMSO-d6: 8 10.72 (s, 111), 8.08 (d, 111), 7.93 (dd, 111), 7.63-7.68 (in, 211), 7.49
(d, 111), 7.14 (d, 111), 3.35 (s, 311)
MS:APCI (-ye) 349

v) 2-[[2"-Chloro-4"-(methylsulfonyl)-5-(trifluoromethyl)[1 ,1 "-biphenyl]-2-yl]oxy]-(2S)- propanoic acid, 1, 1-dimethylethyl ester
The subtitle compound was prepared by the method of example 32 step (v) using the product from step (iv) and tert-butyl R-lactate. Yield 0.25g.
111 NMR.DMSO-d6: 8 8.11 (d, 111), 7.97 (d, 111), 7.82 (dd; 111), 7.73 (d, 111), 7.62 (d, 111), 7.15 (d, 111), 5.0 (brs, 111), 3.36 (s, 311), 1.36-1.39 (in, 1211)

vi) 2-[[2"-Chloro-4"-(methylsulfonyl)-5-(trifluoroinethyl)[1 , 1 "-biphenyl]-2-ylljoxy]-(2S)- propanoic acid
The title compound was prepared by the method of example 1 step (iii) using the product
from step (v). Yield 0.12g.
111 NMR DMSO-d6: 8 8.09 (d, 111), 7.95 (dd, 111), 7.82 (s, 111), 7.76 (dd, 111), 7.58 (d,
111), 7.14 (d, 111), 4.87 (q, 111), 3.36 (s, 311), 1.35 (d, 311)
MS:APCI (-ye) 421


Example 146
2-[[3 "-Cyano-5-(trifluoromethyl)[1,1 "-biphenyl]-2-yl]oxy]-(2S)-propanoic acid
(Formula Removed)


i) 4,4~5 ,5-Tetramethyl-2-[2-(phenylmethoxy)-5-(trifluoromethyl)phenyl]-1 ,3 ,2-
dioxaborolane
Pinacol (1.82g) was added to a solution of the product from example 32 step (ii) (4.54g) in
ether (40m1) and stirred at RT for 20h. The reaction was diluted with ether (lOOmi),
washed with brine, dried (MgSO4) and evaporated. Yield 5.7g.
111 NMR DMSO-d6: 87.82 (d, 111), 7.79 (d, 111), 7.6 (d, 211), 7.4 (t, 211), 7.32 (d, 111),
7.27 (d, iB), 5.24 (s, 211), 1.32 (s, 1211)

ii) 2-(4,4,5,5-Tetramethyl- 1 ,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)phenol 10% Pd/C (0.Sg) was added to a solution of the product from step (i) in EtOAc (SOmI) and hydrogenated at RT and 1 bar for lh, and for a further 3h at 3 bar. The catalyst was removed by filtration and the filtrate evaporated to leave a solid product. Yield 4.2g.
NMR DMSO-d6: 89.99 (d, 111), 7.72 (s, 111), 7.63 (d, 111"), 6.99 (d, 111), 1.3 (d, 1211)

iii) 2-[2-(4,4,5,5-Tetramethyl- 1 ,3,2-dioxaborolan-2-yl)-4-
(trifluoromethyl)phenoxyl-(2S)-propanoic acid, 1, 1-dimethylethyl ester The subtitle compound was prepared by the method of example 32 step (v) using the product from step (ii) and tert-butyl R-lactate. Yield 4.0g. The crude material was carried forward to step (iv).

iv) 2-[2-Borono-4-(trifluoromethyl)phenoxy]-(25)-propanoic acid
TFA (lOml) was added to a solution of the product from step (iii) (4.Og) in DCM (lOOml) and stirred for 30mm. The TFA was evaporated and the residue dissolved in a mixture of iM hydrochloric acid (30m1) and acetonitrile (30m1) After lh the mixture was evaporated to dryness, dissolved in iM sodium hydroxide, washed with ether and adjusted to p112 with concentrated hydrochloric acid. The aqueous was then extracted with ether, washed with brine, dried (MgSO4) and evaporated. Yield 2.0g. The crude material was carried forward to step (v).

v) 2-[[3 "-Cyano-5-(trifluoromethyl)[1 .1 "-biphenyl]-2-yl]oxy]-(2S)-propanoic acid The title compound was prepared by the method of example 144 step (i) using the product from step (iv) and 3-bromobenzonitrile.

NMR DMSO-d6: 8 8.13 (t, 111), 8.01 (tdt, 111), 7.85 (dt, 111), 7.71-7.76 (in, 211), 7.65
(dt, 111), 7.17-7.2 (in, 111), 5.11 (q, 111), 1.47 (d, 311)
MS:APCI (-ye) 334

Example 147
2-[[4 "-[(Dimethylamino)sulfonyl]-5-(trifluoromethyl)[1,1 "-biphenyl]-2-yl]oxy]-(2S)-propanoic acid
(Formula Removed)


The title compound was prepared by the method of example 144 step (i) using the product from example 146 step (iv) and 4-bromo-N,N-diinethyl-benzenesulfonamide.
NMR DMSO-d6: 87.95 (d, 211), 7.83 (d, 211), 7.77 (d, 111), 7.73 (s, 111), 7.21 (d, 111), 5.14 (q, 111), 2.69 (s, 611), 1.51 (d, 311)
MS:APCI (-ye) 416

Example 14g 2-[[2"-Chloro-4"-[(dimethylaxnino)sulFonyl]-5-(trifluoromethyl)(1,1 "-biphenyl]-2-yl]oxy]-(2S)-propanoic acid
(Formula Removed)

i) 3-Chloro-4-iodobenzenesulfonamide
A solution of sodium nitrite (3.27g) in water was added dropwise over lh to a stirred solution of 3-chloro-4-iodoaniline (10.Og) in a mixture of TRIP (120m1) and concentrated hydrochloric acid (50m1) at -5 to -10C. Magnesium chloride (6.39g) was then added and the resulting mixture poured into a stirred solution of acetic acid (SOmI) saturated with sulfur dioxide and containing cuprous chloride (2.14g). After heating at 340C for 30mm, the mixture was poured into brine, extracted with EtOAc, washed with aqueous sodium bicarbonate and brine, dried (MgSO4) and evaporated. The residue was dissolved in TRIP (lOOmi), 0.880 ammonia (lOOmi) added and stirred for 2h. The mixture was diluted with brine, extracted with EtOAc, washed with brine, dried (MgSO4) and evaporated. The


residue was treated with isohexane/ether (4:1) and filtered to give the subtitle compound. Yield 5.67g.
1HI~4N/fl~ DMSO-d6: 8 8.18 (d, 111), 7.92 (d, 111), 7.56 (s, 1H), 7.47 (dd, 111)

ii) 3-Chloro-iodo-N,N-dimethylbenzenesulfonamide
Sodium hydride (0.33g) was added to a solution of the product from step (i) (1 .2g) in DMF (25m1) and stirred for 20mm. Methyl iodide (0.5mi) was added dropwise and then stirred
for a further lh. The reaction mixture was quenched with water, extracted with EtOAc, dried (MgSO4) and evaporated. The residue was treated with ether to give to give the
subtitle compound as a white solid. Yield 0.45g.
111 NMIR DMSO-d6: 8 8.05 (d, 111), 7.82 (d, 111), 7.31 (dd, 111), 2.75 (s, 611)

iii) 2-[[2"-Chloro-4"-[(dimethylamino)sulfonyl]-5-(trifluoromethyl) [1,1 "-biphenyl]2-yl]oxy]-(2S)-propanoic acid
The title compound was prepared by the method of example 144 step (i) using the product
from step (ii) and the product from example 146 step (iv).
111 NIMIR DMSO-d6: 8 7.86 (t, 111), 7.75-7.79 (in, 311), 7.61 (d, 111), 7.14 (d, 111), 4.88 (q,
111), 2.7 (s, 611), 1.35 (d, 311)
MS:APCI (-~"e) 450

Example 149
2-[[2"-Fluoro-4"-(methylsulfonyl)-5-(trifluoromethyl)[1,1"-biphenyl]-2-yl]oxy]-(2S)-propanoic acid
(Formula Removed)


i) Trifluoromethanesulfonic acid, 2-fluoro-4-(methylsulfonyl)phenyl ester
2-Fluoro-4-(methylsulfonyl)phenol (1.44g) was dissolved in DCM (20m1), triethylamine (1.17m1) added, followed by trifluoromethanesulfonic anhydride (1.57m1) and stirred for
lh. The solution was washed with brine, dried (MgSO4) and evaporated to give the subtitle compound.
NMIR CDCl3: 8 7.83-7.92 (in, 211), 7.55-7.61 (in, 1117), 3.11 (s, 311)

ii) 2-[[2"-Fluoro-4"-(methylsulfonyl)-5-(trifluoromethyl)[ 1,1 "-biphenyl]-2-yl]oxy]-(2S)- propanoic acid


The title compound was prepared by the method of example 144 step (i) using the product
from step (i) and the product from example 146 step (iv).
111 NMR DMSO-d6: 87.79-7.9 (in, 3H), 7.74 (dd, 111), 7.64 (s, 111), 7.12 (d,1H), 4.87 (q,
111), 3.31 (s, 311), 1.35 (d, 311)
MS:APCI (-ye) 405

Example 150
[[2 ",5-Dichloro-4"-(methylsulfonyl)[1,1 "-biphenyl]-2-yl]oxy]-(2S)-propanoic acid
(Formula Removed)


i) [[[2",5-Dichloro4"-(methylsulfonyl)[1 , 1 "-biphenyl]-2-yl] oxy]methyl]benzene The subtitle compound was prepared by the method of example 144 step (i) using the product from example 16 step (ii) and the product from example 145 step (ii). Yield 1.08g.
NIMIR DMSO-d6: 8 8.09 (d, 111), 7.94 (dd, 111), 7.67 (d, 111), 7.49 (dd, 111), 7.22-7.34 (in, 711), 5.14 (s, 211), 3.35 (s, 311)

ii) [fl12",5-Dichloro-4"-(inethylsulfonyl)[1 , 1 "-biphenyl]-2-ol
The subtitle compound was prepared by the method of example 144 step (ii) using the product from step (i). Yield 0.45g.
NMR DMSO-d6: 8 10.04 (s, 111), 8.06 (d, 111), 7.91 (dd, III), 7.63 (d, 111), 7.32 (dd, 111), 7.2 (d, 111), 6.97 (d, 1117), 3.34 (s, 311)

iii) [[2",5-Dichloro-4"-(methylsulfonyl)[ 1,1 "-biphenyl]-2-yl]oxy]-(2S)-propanoic acid, 1,1 -diinethylethyl ester
The subtitle compound was prepared by the method of example 32 step (v) using the product from step (ii) and tert-butyl R-lactate. Yield 0.24g.
NMR DMSO-d6: 8 8.09 (d, 111), 7.95 (d, 111), 7.7 (d, 111), 7.48 (dd, 111), 7.33 (d, 111), 6.98 (d, 111), 4.85 (brs, 111), 3.35 (s, 311), 1.37 (s, 911), 1.32 (d, 311)

iv) [[2",5-Dichloro-4"-(methylsulfonyl)[1 , 1 "-biphenyl]-2-yl]oxy]-(25")-propanoic acid
The title compound was prepared by the method of example 1 step (iii) using the product from step (iii). Yield 0.11g.
NIVIIR DMSO-d6: 8 8.07 (d, 111), 7.92 (dd, 111), 7.81 (s, 111), 7.42 (dd, 111"), 7.28 (d, 1I{), 6.97 (d, 111), 4.65 (q, 111), 3.35 (s, 311), 1.29 (d, 311)




MS:APCI (-ye) 387

Example 151

[[5-Chloro-4"-[(dimethylamino)sulfonyl][1,1 "-biphenyl]-2-yl]oxy]~(2S)~propanoic acid
(Formula Removed)

i) 2-[5-Chloro-2-(phenylmethoxy)phenyl]-4,4,5 ,5-tetramethyl-1 ,3 ,2-dioxaboralane The subtitle compound was prepared by the method of example 146 step (i) using the product from example 16 step (ii). Yield 3.3g.
NMR DMSO-d6: 87.27-7.64 (in, 711), 6.85 (d, 111), 5.09 (s, 211), 1.36 (s, 1211)

ii) 4-Chloro-2-(4,4,5 ,5-tetramethyl- 1,3 ,2-dioxaborolan-2-yl)phenol The subtitle compound was prepared by the method of example 146 step (ii) using the product from step (i). Purified by chromatography on silica eluting with 50% EtOAc/isohexane. Yield 1.89g.
NJVIIR DMSO-d6: 87.76-7.79 (s, 111), 6.79-7.62 (in, 311), 1.36 (s, 1211)

iii) 2-[4-Chloro-2-(4,4,5 ,5-tetramethyl- 1,3 ,2-dioxaborolan-2-yl)phenoxy]-(2S)-
propanoic acid, 1,1 -dimethylethyl ester
The subtitle compound was prepared by the method of example 32 step (v) using the product from step (ii) and tert-butyl R-lactate. Yield 3.5g. The crude material was carried forward to step (iv).

iv) 2-(2-Borono4-chlorophenoxy)-(25)-propanoic acid
The subtitle compound was prepared by the method of example 146 step (iv) using the product from step (iii). Yield 2.5g. The crude material was carried forward to step (v).

v) [[5-Chloro4-[(dimethylamino)sulfonyl] [1,1 "-biphenyl]-2-yl]oxy]-(2S)-propanoic acid
The title compound was prepared by the method of example 144 step (i) using the product from step (iv) and 4-bromo-N,N-dimethylbenzenesulfonan~jde and TRIP as solvent. Yield (0.068g).
NMR DMSO-d6: 8 8.01 (d, 211), 7.75 (d, 211), 7.3-7.41 (in, 211), 6.93 (d, 111), 4.56 (bin, 111), 2.65 (s, 611), 1.33 (d, 311)
MS:APCI (-ye) 382





Example 152
[[2" ,5-Dichloro-4"-[(dimethylamino)suIfOflyl][1,1 "-biphenyl]-2-yl]oxy]-(2S)-propanoic acid
(Formula Removed)


The title compound was prepared by the method of example 144 step (i) using the product from example 151 step (iv), the product from example 148 step (ii) and methanol as solvent. Yield (0.08g).
111 NMR DMSO-d6: 87.9 (bin, 111), 7.82 (s, 111), 7.74 (dd, 111), 7.4 (dd, 111), 7.26 (d~
111), 6.92 (d, 111), 4.34 (bin, 111), 2.7 (s, 611), 1.2 (d, 311) MS:APCI (-ye) 416

Example 153
[(5- Chloro-3"-cyano[1,1 "-biphenyl]-2-yl~oxy]-(2S)-propanOic acid
(Formula Removed)

The title compound was prepared by the method of example 144 step (i) using the product
from example 151 step (iv), 3-bromobenzenenitrile and TIff as solvent.
111 NMR DMSO-d6: 8 8.25 (s, 111), 8.06 (d, 111), 7.79 (d, 111), 7.63 (t, 111), 7.4 (d, 111),
7.33 (dd, 111), 6.95 (d, 111), 4.64 (q, 111), 1.32 "(d, 311)
MS:APCI (-ye) 300

Example 154

ff5-Chloro-4 "-[(dimethylaxnino)sulfonyl]-2"-flUOrO[l,l "-biphenyl]-2-yl]oxy]-(2S)-propanoic acid
(Formula Removed)

i) 4.Bromo-N,N~dimethyl-3-fluorobenzene5ulfOnaTflide





The subtitle compound was prepared by the method of example 148 step (ii) using 4-bromo-3-fluorobenzenesulfonamide 1.14g.

ii) [[5-Chloro-4"-[(dimethylamino)sulfonyl]-2"-fluoro[1 , 1 "-biphenyl]-2-yl]oxy]-(25)-propanoic acid
The title compound was prepared by the method of example 144 step (i) using the product
from step (i), the product from example 151 step (iv) and TRIP as solvent.
111 NMIR DMSO-d6: 87.94 (t, 111), 7.58-7.62 (in, 211), 7.35-7.4 (in, 211), 6.93 (d, 111),
448 (q, 1H), 2.7 (s, 611), 1.26 (d, 311)
MS:ESI (-i-ye) 402

Example 155
[[5-Chloro-4"-(4-morpholinylsulfonyl)[1,1"-biphenyl]-2-yl]oxy]-(2S)-propanoic acid
(Formula Removed)




A mixture of the product from example 151 step (iv) (0.126g), sodium carbonate (0.22g),
4-[(4-bromophenyl)sulfonylllmorpholine (0.16g) and Pd(dppf)C12 (0.03g) in dioxane
(lOml) was heated under reflux for 4h. The mixture was evaporated and purified by
RVIHPLC (MeCN/aqNH4Cl). Yield 0.09g.
NMR DMSO-d6: 8 8.03 (d, 211), 7.74 (d, 211), 7.3 1-7.39 (in, 211), 6.93 (d, 111), 4.55 (in, 1H), 3.65 (in, 211), 2.92 (in, 211), 1.34 (d, 311)
MS:APCI (-ye) 426

Example 156

[[5~Chloro~2"~fluoro-4"-(methylsulfonym1,1"-hiphenylJ-2-yl1oxy)-(2S)-propanoic acid
(Formula Removed)

The title compound was prepared by the method of example 155 using the product from
example 151 step (iv) and the product from example 149 step (i).
111 NMR DMSO-d6: 37.81-7.88 (in, 311), 7.41-7.49 (in, 211), 7.0 (d, 111), 4.9 (q, 111), 3.3
(s, 311), 1.37 (d, 311)
MS:ESI (-ye) 371






Example 157
2-fl14"-(1-Azetidinylsulfonyl)-5-chloro[1,1 "-biphenyl]-2-yljoxy]-(2S)-propanoic acid
(Formula Removed)

The title compound was prepared by the method of example 144 step (i) using the product
from example 151 step (iv), 1-[(4-bromophenyl)sulfonyl]azetidine and THE as solvent.
Yield 0.028g.
111 NMR DMSO-d6: 87.97 (d, 211), 7.82 (d, 211), 7.39-7.43 (in, 211), 7.01 (d, 111), 4.85
(in, 111), 3.72 (t, 411), 2.04 (q, 211), 1.42 (d, 311)
MS:ESI (-ye) 394


Example 158
2-[[5-Chloro-2"-methyl-4"-(1-pyrrolidinylcarbonyl)[1,1 "-biphenyl]-2-yl]oxy]-(2S)-propanoic acid, sodium salt
(Formula Removed)



The title compound was prepared by the method of example 155 using the product from example 151 step (iv) and l-(4-bromo-3-methylbenzoyl)pyrrolidine. Yield 0.152g. 111 NMR DMSO-d6: 87.2-7.41 (in, 411), 7.25 (s, 111), 6.85 (d, 111), 4.22 (in, 111), 3.56 (in,

411), 2.2 (s, 311), 1.85 (in, 411), 1.17 (d, 311)
MS:APCI (-ye) 388
acid
i) 2-(2-Brorno-4-cyanophenoxy)-(25)-propanoic acid


Diethyl azodicarboxylate (2.12g) was added to a stirred solution of 2-bromo-4-
cyanophenol (2.Og), methyl-R-lactate (1.47g) and triphenylphosphine (2.65g) in TRIP (80m1). After 20h, the mixture was filtered through silica using isohexane/EtOAc as
solvent and the filtrate evaporated to dryness. The residue was dissolved in DOM (SOmi), treated with TFA (lOml) and stirred for 2h. The solution was evaporated and the residue partitioned between EtOAc and aqueous sodium bicarbonate. The aqueous was acidified with 2M hydrochloric acid, extracted with EtOAc, dried (MgSO4) and evaporated to give the subtitle compound.
111 NMiR DMSO-d6: 8 7.87 (s, 1H), 7.56 (d, 111), 6.83 (d, 111), 4.91 (q, 1H), 1.7 (d, 311) MS:APCI (-ye) 270

ii) 2-[(2",4"-Dichloro-5-cyano[1 ,I "-biphenyl]-2-yl)oxy)-(2S)-propanoic acid
The title compound was prepared by the method of example 16 step (iii) using the product from step (i) and 2,6-dichlorophenylboronic acid.
NMR DMSO-d6: 87.58-7.78 (in, 411), 7.46 (d, 111), 7.02 (d, 111), 4.51 (q, 111), 1.26 (d, 3H)
MS:APCI (-ye) 334

Example 160
2-[[5-Cyano-2"-fluoro-4 "-(trifluoromethyl)[1,1"-biphenyl]-2-yl]oxy]-(2S)-propanoic acid
(Formula Removed)

The title compound was prepared by the method of example 16 step (iii) using the product
from example 159 step (i) and 3-cyanophenylboronic acid.
111 NMIR DMSO-d6: 8 7.81-8.04 (in, 411), 7.56 (t, 111), 7.18 (d, 111), 5.1 (q, 111), 1.4 (d,
311)
MS:APCI (-ye) 352

Example 161
2-[(3"-Cyano-5-fluoro[1,1 "-biphenyU-2-yI)oxy]-(2S)-propanoic acid, sodium salt
(Formula Removed)




i) 2-(2-Bromo-4-fluorophenoxy)-(25)-propanoic acid, 1, 1-dimethylethyl ester The subtitle compound was prepared by the method of example 159 step (i) using 2-bromo-4-fluorophenol (2.Sg). Yield 3.0g.
1H NMR DMSO-d6: 87.28-7.32 (in, 111), 6.89-6.98 (in, 111), 6.78-6.83 (in, 111), 4.56 (q, 111), 1.62 (d, 311), 1.4 (s, 911)

ii) 2-(2-Bromo-4-fluorophenoxy)-(25)-propanoic acid
The subtitle compound was prepared by the method of example 146 step (iv) using the product from step (i). Yield 1.2g. Carried forward to step (iii) without characterisation.

iii) 2-[(3 "-Cyano-5-fluoro[1 , 1 "-biphenyl]-2-yl)oxy]-(2S)-propanoic acid, sodium sa The title compound was prepared by the method of example 155 using the product from step (ii) and 3-cyanophenylboronic acid. The product was dissolved in acetonitrile, treate with iM sodium hydroxide and evaporated to give the title compound.
NMR DMSO-d6: 8 8.4 (s, 111), 8.13 (d, 111), 7.75 (d, 111), 7.6 (t, 111), 6.9-7.2 (in, 311)
4.4 (q, 111), 1.28 (d, 3H) MS:APCI (-ye) 284

Example 162

2-[(2",4"-Dichloro-5-tluoro[1,1 "-biphenyl]-2-yl)oxyl-(2S)-propanoic acid, sodium salt
(Formula Removed)

The title compound was prepared by the method of example 155 using the product from example 161 step (ii) and 2,4-dichiorophenylboronic acid. The product was dissolved in acetonitrile, treated with iM sodium hydroxide and evaporated to give the title compound.
1HNMRDMSO-d6: 87.66-7.72 (in, 211), 7.43 (d, 111), 6.86-7.11 (in, 311), 4.18 (q, 111),
1.2 (d, 311)
MS:APCI (-ye) 327

Example 163


2-[[2"-Chloro-5-fluoro-4"-(methylsulfonyl)[1,1 "-biphenyl]-2-yl]oxy]-(2S)-propanoic
acid
(Formula Removed)


i) Benzyl 2-bromo-4-fluorophenyl ether
The subtitle compound was prepared by the method of example 16 step (i) using 2-bromo-
4-fluorophenol and acetone as solvent. Yield 27.5g.
111 NMIR DMSO-d6: 87.27-7.49 (in, 611), 6.82-6.99 (in, 211), 5.12

ii) [2-(Benzyloxy)-5-fluorophenyl]boronic acid
The subtitle compound was prepared by the method of example 16 step (ii) using the product from step (i). Yield 18.77g.
NMR DMSO-d6: 87.9 (s, 2H), 7.0-7.5 (in, 811), 5.14 (s, 211)

iii) 2-[5-Fluoro-2-(phenylmethoxy)phenyl]-4,4,s,5-tetramethyl-1 ,3 ,2-dioxaborolane The subtitle compound was prepared by the method of example 146 step (i) using the product from step (ii). Yield 4.1g.
NMIR DMSO-d6: 87.58 (d, 111), 7.29-7.4 (in, 311), 7.26 (s, 111), 7.04 (dt, 111), 6.84 (ci, 211), 5.07 (s, 211), 1.36 (s, 1211)

iv) 4-Fluoro-2-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)phenol The subtitle compound was prepared by the method of example 146 step (ii) using the product from step (iii) and ethanol as solvent.
111 NMR DMSO-d6: 87.63 (s, 111), 7.2-7.27 (in, 111), 7.01-7.08 (in, 111), 6.8-6.83 (in, 111), 1.37 (s, 1211)

v) 4-Fluoro-2-[2-(4,4,5 ,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenoxy]-(25)-propanoic acid, 1,1-dimethylethyl ester
The subtitle compound was prepared by the method of example 32 step (v) using the product from step (iv) and tert-butyl R-lactate. Yield 2.6g. The crude material was carried forward to step (vi).

vi) 2-[2-Borono-4-(trifluoroinethyl)phenoxy]-(2S)-propanoic acid
The subtitle compound was prepared by the method of example 146 step (iv) using the product from step (v). Yield 1.65g.


MS:APCI (-ye) 227

vii) 2-[[2"-Chloro-5-fluoro-4"-(methylsulfonyl)[1, 1 "-biphenyl]-2-yl]oxy]-(2S)-propanoic acid
The title compound was prepared by the method of example 155 using the product from step (vi) and the product from example 145 step (ii).
N~v1iR DMSO-d6: 8 8.06 (s, 11-1), 7.86-7.93 (in, 211), 7.03-7.23 (in, 211), 6.9-6.97 (in, 1W), 4.43 (q, 111), 1.24 (ci, 311)
MSAPCI (-ye) 371

Example 164
2-[[2"-Chloro-5-fluoro-5"-(trifluoromethyl)[1,1 "-biphenyl]-2-yl]oxy]-(2S)-propanoic acid, sodium salt

(Formula Removed)


The title compound was prepared by the method of example 155 using the product from
example 161 step (ii) and 2-broino-1-chloro-(trifluoroinethyl)benzene. The product was dissolved in acetonitnile, treated with iM sodium hydroxide and evaporated" to give the title compound. Yield 0.07g.
111 NMR DMSO-d6: 8 8.31 (bs, 111), 7.68-7.77 (in, 211), 7.09-7.15 (in, 211), 6.9-6.93 (in, 111). 4.25 (q, 1H), 1.21 (ci, 311)
MS:APCI (-ye) 361

Example 165
[[4"-(Ethylsulfonyl)..6..methylsnitro[1,1 "-biphenyl]-2-yI]oxy]acetic acid
(Formula Removed)



i) (2-Broino-3-methyl-4-nitophenoxy)acetic acid, methyl ester
Bromine (5.27g) in acetic acid (3m1) was added dropwise to a solution of 3-methyl-4-nitrophenol (5.04g) in acetic acid (43mi) over 45mins, and then stirred for a further lh. The solvent was evaporated, water added, extracted with ether, dried (Na2SO4) and
evaporated. The crude material was dissolved in DMF (lOml), potassium carbonate (3.79g) added, followed by methyl bromoacetate (3.37m1) and the mixture stirred at RT for 30mins and 600C for 2h. The mixture was cooled and poured into a mixture of EtOAc and water. The organic phase was separated, washed with water, aqueous potassium carbonate and brine, dried (Na2SO4) and evaporated. The residue was recrystallised from toluene/isohexane. Yield 1.8g.
1HNIVIR CDCl3: 3 7.86 (ci, 111), 6.69 (ci, 111), 4.81 (s, 211), 3.83 (s, 311), 2.19 (s, 3117).

(ii) [[4" -(Ethylsulfonyl)-6-methyl-5-nitro[1 , 1 "-biphenyl]-2-yl]oxy] acetic acid, methyl ester
The subtitle compound was prepared by the method of example 1 step (ii) using the ~roduct from step (i) (1.78g) and 4-(ethylthio)phenylboronic acid (1.6g). Yield 2.59g. H NIvIIR CDCl3: 3 8.02 (d, 111), 8.0 (ci, 211), 7.45 (d, 211), 6.75 (ci, 111), 4.65 (s, 211), 3.76 (s, 311), 3.2 (q, 211), 2.25 (s, 311)1.36 (t, 311)

(iii) [[4" -(Ethylsulfonyl)-6-methyl-5-nitro[1 , 1 "-biphenyl]-2-yl] oxylacetic acid
The title compound was prepared by the method of example 26 step (vi) using the product
from step (ii). Yield 0.22g.
111 NIMR DMSO-d6: 8 13.16 (bs, 111), 8.06 (ci, 111), 7.97 (d, 211), 7.57 (ci, 211), 7.12 (ci,
111), 4.8 (s, 211), 3.38 (q, 211), 2.14 (s, 311)1.16 (t, 311)
MS: APCI (+ve): 412 (M+MeOH+114)

Example 166
[[5-Chloro-4"-(ethylsulfonyl)-6-methyl[1,1 "-biphenyl]-2-yl]oxy]acetic acid
(Formula Removed)

i) [[5-Amino-4" -(ethylsulfonyl)-6-methyl[1 , 1 "-biphenyl]-2-yl]oxy]acetic acid, methyl ester
10% Pd/C (0.15g) was added to a solution of the product from example 165 step (ii) in
EtOAc (20m1) was hydrogenated at RT and 3 bar for 2h. The mixture was filtered through
celite and the filtrate evaporated to give the sub-title compound. Yield 1.4g.
111 NIVIR CDCI3: 3 7.95 (ci, 211), 7.48 (ci, 211), 6.7 (ci, 111), 6.65 (ci, 111), 4.4 (s, 211), 3.71
(s, 311), 3.51 (bs, 211), 3.18 (q, 211), 1.88 (s, 311)1.34 (t, 311)


ii) [[5-Chloro-4" -(ethylsulfonyl)-6-methyl [1,1" -biphenyl]-2-yl]oxy]acetic acid, methyl ester
Cuprous chloride (0.18g) was dissolved in acetonitrile (6m1), isopentylamine (0.24mi) added, followed by the dropwise addition of a solution of the product from step (i) in acetonitrile (6mi). The mixture was stirred for 12h, evaporated and purified by chromatography on silica eluting with 30-50% ether/isohexane. Yield 2.59g. 111 NMR CDCl3: 3 7.97 (d, 211), 7.46 (d, 211), 7.34 (d, 111), 6.65 (ci, 111), 4.32 (s, 211), 3.73 (s, 311), 3.19 (q, 211), 2.09 (s, 311)1.35 (t, 311)

iii) [[5-Chloro-4" -(ethylsulfonyl)-6-methyl[1, 1, -biphenyl]-2-yl]oxy]acetic acid
The title compound was prepared by the method of example 26 step (vi) using the product
from step (ii). Purified by RPHPLC (MeCN/aqN7H4Cl). Yield 0.07g.
111 NMR DMSO-d6: 87.94 (ci, 211), 7.53 (ci, 211), 7.44 (ci, 111), 6.91 (ci, 111), 4.64 (s, 211),
3.36 (q, 211), 2.03 (s, 311) 1.15 (t, 311)
MS:APCI (+ve) 367 (M+MeOH+114)

Example 167
[[4t-(Methylsulfonyl)-2",5~bis(trifIuoromethyl)[11"~biphenyl]2yl]oxy]ace1jc acid
(Formula Removed)

i) 4-Bromo- l-(methylthio)-2-(trifluoromethyl)benzene Isopentyl nitrite (0.67m1) was added dropwise to a solution of 4-bromo-2-
(trifluoromethyl)aniline (1.2g) and dimethyl sulfide (0.45ni1) in acetonitrile (12m1). The reaction was slowly heated to reflux and then refluxed until gas evolution ceased. The volatiles were evaporated, the residue absorbed onto silica and the product eluted off with isohexane. Yield 0.8g.
111 NMR DMSO-d6: 87.59 (dci, 211), 7.23 (ci, 111), 2.51 (s, 311)

ii) 4,4,S,S-Tetramethyl-2-[4-(methylthio)-3~(trifluoromethyl")phenyl]...1 ,3,2-dioxaborolane
Pd2dba3 (O.135g) and tricyclohexylphosphine (0.199g) were dissolved in dioxane (20mi) and stirred for 30mm. Potassium acetate (0.867g), bis(pinacolato)diboron (1.65g) and the product from step (i) were sequentially added and the mixture heated at 900C for 3h. The reaction was cooled, evaporated, partitioned between ether and brine, separated, dried




(Na2SO4) and evaporated. The residue was purified by chromatography on silica eluting with 10% ether/isohexane. Yield 0.695g.
111 NMR DMSO-d6: 3 7.31 (ci, 211), 2.53 (s, 311), 1.3 (s, 1211)

iii) 2-Bromo-4-(trifluoromethyl)phenoxyacetic acid, 1 ,1-dimethylethyl ester
The title compound was prepared by the method of example 1 step (i) using 2-bromo-4-
(trifluoromethyl)phenol.
111 NMR DMSO-d6: 8 6.8-7.83 (in, 311), 4.65 (s, 211), 1.48 (s, 911)

iv) [[4"-(Methylthio)-2",5-bis(trifluoromethyl) [1,1 "-biphenyl]-2-yl]oxy] acetic acid, 1,1 -dimethylethyl ester
The title compound was prepared by the method of example 1 step (ii) using the products from steps (ii) and (iii). Yield 0.564g. Carried forward to step (v) without characterisation.

v) [[4"-(Methylsulfonyl)-2",5-bis(trifluoromethyl)[1 , 1 "-biphenyl]-2-yl]oxy] acetic acid, 1,1-dimethylethyl ester
The product from step (iv) (0.564g) was dissolved in 50% aqueous acetone (lOmi), sodium bicarbonate (0.94g) added, followed by a solution of oxone (1.5g) in water (ml) and stirred for 3h. The reaction was quenched with aqueous sodium metabisulfite, extracted with EtOAc, washed with aqueous potassium carbonate, dried (Na2SO4) and evaporated to give the subtitle compound. Yield 0.32g.
111 NIVIR DMSO-d6: 8 8.31 (ci, 111), 8.29 (s, 111), 8.18 (dci, 111), 7.83 (s, 111), 7.81 (ci, 111),
7.32 (ci, 111), 4.9 (s, 211), 3.36 (s, 211), 1.41 (s, 911)

vi) [[4"-(Methylsulfonyl)-2",5-bis(trifluoromethyl)[ 1, 1"-biphenyl)-2-yl]oxylacetic acid
The title compound was prepared by the method of example 26 step (vi) using the product from step (v). Yield 0.2g.
NMR DMSO-d6: 8 8.33 (s, 111), 8.3 (ci, 111), 8.19 (ci, 111), 7.83 (s, 111), 7.81 (d, 111), 7.34 (ci, 111), 4.92 (s, 211), 3.36 (s, 211)
MS:APCI (-ye) 441

Example 168 2-[4-Chloro-2-[4-methyl-6-[methyl(methylsulfonyl)amino]-3-pyridinyl]phenoxy]-(2S)-propanoic acid

(Formula Removed)
i) N-(5-Bromo-4-methyl-2-pyridinyl)methanesulfonamide 5-Bromo-4-methylpyridin-2-amine (1.56g) was dissolved in DCM (40m1), trimethylamine (1.4m1) added, followed by methanesulfonyl chloride (1.9g) and the mixture stirred for 20mm. The solution was washed with water, dried (MgSO4) and evaporated. The residue was dissolved in TRIP, treated with TBAF, stirred for 16h and evaporated. The residue was purified by chromatography on silica eluting with 27% EtOAc/isohexane. Yield 1.3g. Carried forward to step (ii) without characterisation.

ii) N-(5-Bromo-4-methyl-2-pyridinyl)-N-methylmethanesulfonamide The product from step (i) (2.23g), potassium carbonate (2.33g) and methyl iodide (0.7mi) were stirred in DMIP (20m1) for 20h. The reaction was quenched with water, extracted with EtOAc, dried (MgSO4) and evaporated. The residue was purified by chromatography on silica eluting with 30% EtOAc/isohexane. Yield 1.5g. Carried forward to step (ii) without characterisation.

iii) 2-[4-Chloro-2-[4-methyl-6-[methyl(methylsulfonyl)amino]-3-
pyridinyl]phenoxy]-(2S)- propanoic acid
The title compound was prepared by the method of example 155 using the product from
step (ii) and the product from example 151 step (iv). Yield 0.125g.
111 NtVIR DMSO-d6: 8 8.18 (s, 1W), 7.26-7.44 (in, 3W), 6.94 (ci, 111), 4.8 (in, 1W), 3.32 (s,
311), 3.2 (s, 311), 2.2 (s, 311), 1.32 (d, 311)
MS:APCI (-ye) 397

Example 169
2-[2-[4-Methyl-2-[(methylsulfonyl)amino]-S-pyrimidinyl]-4-
(trifluoromethyl)phenoxy]-(2S)-propanoic acid
(Formula Removed)





i) Potassium N-(5-bromo-4-methyl-2-pyrimidinyl)methanesulfonamide




Methanesulfonyl chloride (0.7Srnl) was added to a solution of 5-bromo-4-methyl-2-pyrimidinamine (1.8g) in TIlE (60m1), followed by the rapid dropwise addition of iM potasssiurn tert-butoxidejTHF (20m1). After 30mm the resulting precipitate was filtered off and dried. Yield 3.2g.
1H1~{RK~ DMSO-d6: 88.13 (s, 1W), 2.81 (s, 311), 2.26 (s, 311)

ii) N-(5-Bromo-4-methyl-2-pyrimidinyl)-N-[[2-(trimethylsilyl)ethoxy]methyl] methanesulfonamide
[2-(Chloromethoxy)ethyl]trimethylsilane (0.4m1) was added to a solution of the product from step (i) in DMF (lOmI) and stirred for 20mm. The mixture was poured into water, extracted with ether, washed with brine, dried (MgSO4) and evaporated. The residue was purified by chromatography on silica eluting with 20% EtOAc/isohexane. Yield 0.53g. 111 NMR DMSO-d6: 8 8.88 (s, 1W), 5.49 (s, 2W), 3.59-3.64 (in, 511), 2.63 (s, 311), 0.9 (t, 211), 0.0 (t, 9W)

iii) 2-[2-[4-Methyl-2-[(methylsulfonyl)[[2-(trimethylsilyl)ethoxy]methyl]amino]-5-pyrimidinyl]-4-(trifluoromethyl)phenoxy]-(2S)-propanoic acid
The title compound was prepared by the method of example 144 step (i) using the product from step (ii) and the product from example 146 step (iv). Carried forward to step (iv) without characterisation.

iv) 2-[2-[4-Methyl-2-[(methylsulfonyl)aminoll-5-pyrimidinyl]-4-(trifluoromethyl)phenoxy]-(2S)-propanoic acid
The product from step (iii) was treated with WA (20m1) and stirred for 20mm. The TFA
was evaporated and the residue purified by RVHPLC (CH3CN/aqTFA).
111 NMR DMSO-d6: 8 8.84 (s, 111), 7.77 (dd,"2W), 7.65 (ci, 111), 7.14 (ci, 5W), 5.04 (q,1W),
3.4 (s, 3W), 2.3 (s, 3W), 1.41 (d, 3W)
MS:APCI (-ye) 418

Example 170
[(5-Chloro-3"-cyano[1,1 "-biphenyl]-2-yI)oxy]- acetic acid
(Formula Removed)

(i) S"-Chloro-2"-methoxy-[1 , 1 "-biphenyl]-3-carbonitrile



The subtitle compound was prepared by the method of example 1 step (ii) using 3-iodobenzonitrile and 5-chloro-2-methoxyphenyl boronic acid. Yield 0.465g "Hl~4MJ~ CDCI3: 3 7.82 (111, t), 7.71 (111, cit), 7.62 (111, cit), 7.51 (111, t), 7.32 (211, dd), 7.26 (1H, in), 6.93 (111, ci), 3.81 (311, s)

(ii) 5"-Chloro-2"-hydroxy-[1, 1 "-biphenyl]-3-carbonitrile
A solution of boron tribromide (iM in dichloromethane, 6m1) was added to a stirred solution of the product from step (i) in dichloromethane (lOmi) at 00C. After 15mm the mixture was warmed to room temperature, stirred for 16h then poured onto ice. The mixture was extracted with dichioromethane then ethylacetate, the organics combined, dried and evaporated under reduced pressure. The residue was purified by chromatography on silica eluting with 30-70% diethylether/isohexane. Yield 0.415g "H NMR CDCl3: 3 7.83 (1H, s), 7.75 (111, d), 7.68 (111, ci), 7.58 (1H, t), 7.25 (211, in), 6.89 (111, d), 5.00 (111, s)

(iii) [(5-chloro-3"-cyano[ 1,1 "-biphenyl]-2-yl)oxy]- acetic acid, 1,1 -dimethylethyl ester
The subtitle compound was prepared by the method of example 1 step (i) using the product from step (ii). Yield 0.60g
"H N1VJIR CDCI3: 3 7.90 (111, s), 7.82 (111, ci), 7.63 (111, ci), 7.53 (111, td), 7.28 (211, in), 6.78 (111, ci), 4.52 (211, s), 1.47 (1011, s)

(iv) [(5-Chloro-3 "-cyano[1 , 1 "-biphenyl]-2-yl)oxy]- acetic acid
The title compound was prepared by the method of example 1 step (iii) using the product from step (iii). Yield 0.265g
"H NMIR DMSO-d6: 8 13.12 (1H, s), 8.08 (111, s), 7.94 (111, ci), 7.82 (111, ci), 7.64 (1H, t), 7.43 (211, in), 7.10 (111, ci), 4.78 (211, s).
MS: APCI (-ye): 286

Pharmacological Data

Liaand Bindina Assay

[311]PGD2 was purchased from Perkin Elmer Life Sciences with a specific activity of 100-2lOCi/mmol. All other chemicals were of analytical grade.

HEK cells expressing rhCRTh2 / Gcd6 were routinely maintained in DMEM containing 10% Foetal Bovine Serum (HyClone), 1mg/mi geneticin, 2mM L-glutamine and 1% nonessential amino acids. For the preparation of membranes, the adherent transfected HEKcells 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 500mJA sodium butyrate for the last 18 hours of culture. The adherent cells were washed once with phosphate buffered saline (PBS, 50m1 per cell factory) and detached by the addition of 50mi per cell factory of ice-cold membrane homogenisation buffer [20mM HEPES (pH 7.4), 0.1mM dithiothreitol, 1mM EDTA, 0.1mM phenyl methyl sulphonyl fluoride and 100µg/ml bacitracin]. Cells were pelleted by centrifugation at 220xg for 10 minutes at 40C, re-suspended in half the original volume of fresh membrane homogenisation buffer and disrupted using a Polytron homogeniser for 2 x 20 second bursts keeping the tube in ice at all times. Unbroken cells were removed by centrifugation at 220xg for 10 minutes at 40C and the membrane fraction pelleted by centrifugation at 90000xg for 30 minutes at 40C. 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 -800C in 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 25µg membrane protein per mg beads at 40C with constant agitation overnight. (The optimum coating concentrations were determined for each batch of membranes) The beads were pelleted by centrifugation (800xg for 7minutes at 40C), washed once with assay buffer (50mM HEPES pH 7.4 containing 5mM magnesium chloride) and finally resuspended in assay buffer at a bead concentration of 10mg/mi.

Each assay contained 2OµL of 6.25nM [3H]PGD2, 20µL membrane saturated SPA beads both in assay buffer and lOµL of compound solution or 13,14-dihydro-15-keto prostaglandin D2 (DK-PGD2, for determination, of non-specific binding, Cayman chemical company). Compounds and DK-PGD2 were dissolved in DMSO and diluted in the same solvent to lOOx 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 this was the solution added to the assay plate. The assay plate was incubated at room temperature for 2 hours and counted on a Wallac Microbeta liquid scintillation counter (1 minute per well).

Compounds of formula (I) have an IC50 value of less than (







CLAIMS

1. A compound of formula (D or a pharmaceutically acceptable salt thereof:
(Formula Removed)




(I)

in which:

X is halogen, cyano, nitro, S(O)~R or C1-4aIIkyl which is substituted by one or more
halogen atoms;

Y is selected from hydrogen, halogen, CN, nitro, S02R3, OR4, SR4, SOR3, S02NR4R5, CONR4R5, NR4R5, NR6SO2R3, NR6C02R6, NR6COR3, C2-C6 alkenyl, C2-C6 alkynyl, C3-C-, cycloalkyl or C1-6 alkyl, the latter four groups being optionally substituted by one or more substituents independently selected from halogen, OR6 and NR6R"7, S(O)~R6 where n isO, 1 or2;

Z is aryl or a ring A, where A is a six membered heterocydic aromatic ring containing one or more nitrogen atoms or may be a 6,6 or 6,5 fused bicycle containing one or more 0, N, S atoms, the aryl or A rings all being optionally substituted by one or more substituents independently selected from from hydrogen, halogen, CN, OH, SH, nitro, COR9, C02R6, S02R9, OR9, SR9, SOR9, SO2NR"0R", C0NR10R11, NRrnRII, NHSO2R9, NR9SO2R9, NR6CO2R6, NHCOR9, NR9COR9, NR6CONR4R5, NR6SO2NR4R5, aryl, heteroaryl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl or C1~alkyl, the latter four groups being optionally substituted by one or more substituents independently selected from halogen, C3-C7 cycloalkyl, OR6, NR6R7, S(O)~R6 (where n is 0, 1 or 2), CONR6R7, NR6COR7, SO2NR6R7 and NR6SO2R7.

R" and R2 independently represent a hydrogen atom, halogen, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl or a C1-6 alkyl group, the latter four groups being optionally substituted by one or more substituents independently selected from halogen,



C3-C7 cycloalkyl, NR6R7, OR6, S(O)~R6 (where n is 0, 1 or 2); or


R" and R2 together can form a 3-8 membered ring optionally containing one or more atoms selected from 0, S, NR6 and itself optionally substituted by one or more C1-C3 alkyl or halogen;
3

R represents C3-C7 cycloalkyl or C1-6alkyl which may be optionally substituted by one or more substituents independently selected from halogen, C3-C7 cycloalkyl, OR6 and NR6R7, S(O)~R6 (where n = 0,1 or 2), CONIR6R7, NR6COR7,SO2NR6R7 and NR6SO2R7;

R4 and R5 independently represent hydrogen, C3-C7 cycloalkyl or Ci6alkyl, the latter two groups being optionally substituted by one or more substituents independently selected from halogen, C3-C-, cycloalkyl, OR6 and NR6R7, S(O)~R6 (where n = 0,1 or 2), CONR6R7, NR6COR7,SO2NR6R7 and NR6SO2R7;

or

R4 and R5 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 0, S(O)~ (where n = 0,1 or 2), NR8, and itself optionally substituted by halogen or C1-
~ alkyl;
6 7
R and R independently represents a hydrogen atom or C1-C6 alkyl;

R8 hydrogen, C1-4 alkyl, -CO C1-C4 alkyl, CO2 C1-C4 alkyl or CONR6C1-C4aIkyl;

R9 represents aryl, heteroaryl, C3-C7 cycloalkyl or C1-6aIkyl, the latter two groups may be optionally substituted by one or more substituents independently selected from halogen, C3-C-, cycloalkyl, aryl, heteroaryl OR6 and NR6R7, S(O)~R6 (where n = 0, 1 or 2), CONR6R7, NR6COR7, SO2NR6R7 and NR6SO2R7;

R10 and R" independently represent aryl or heteroaryl, hydrogen, C3-C7 cycloalkyl or C1..6alkyl, the latter two groups being optionally substituted by one or more substituents independently selected from halogen, C3-C7 cycloalkyl, aryl, heteroaryl, OR6 and NR6RZ, S(O)~R6 (where n =0, 1 or 2), CONR6R7, NR6COR7, SO2NR6R7 and NR6SO2R7;

or



R10 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 0, S(O)~ (where n =0, 1 or 2), IPR8 and itself optionally substituted by halogen or C1-C3 alkyl.

2. A compound according to claim 1 in which X is halogen, cyano, nitro, S(O)~R6 or C1-C4 alkyl which is substituted by one or more halogen atoms;

3. A compound according to claim 1 in which X is trifluoromethyl, nitro, cyano or halogen.

4. A compound according to any one of claims 1 to 3 in which Y is hydrogen, halogen or Ci.3alkyl.

5. A compound according to any one of claims 1 to 4 in which Z is phenyl, pyridinyl, pyrimidyl, naphthyl, quinolyl, benzo[b]thienyl or benzofuranyl each optionally substituted with substituents as defined in claim 1.

6. A compound according to any one of claims 1 to 4 in which Z is phenyl optionally substituted with substituents as defined in claim 1.

7. A compound according to any one of claims 1 to 6 in which both R" and R2 are hydrogen or one is hydrogen and the other is methyl or ethyl or both are methyl.

8. A compound according to any one of claims 1 to 7 selected from:
{ [5-Chloro-4"-(ethylthio)biphenyl-2..ylboxy} acetic acid
{ [S-Chloro-4"-(ethylsulfonyl)biphenyl-2-yl]oxy} acetic acid
[(4",S-Dichlorobiphenyl~2...yl)oxy]ace1jc acid
[(S-Chloro-4"-cyanobiphenyl-2-yl)oxy]acetic acid
[(S-Chloro-4"-methoxybiphenyl-2-yl)oxy]acetic acid
(4-Chloro-2-quinolin-8-ylphenoxy)acetic acid,
[(S-Chloro-3",4"-dimethoxybiphenyl~2-yl)oxy]acetic acid
[SCarboxymethoxy)-5"~chlorobiphenylAcarboxylic acid
{ [S-Chloro-4"-(methylsulfonyl)biphenyp2yl]oxy} acetic acid
{ [S-Chloro-4"-(ethy1sulfonyl)~2"methylbiphenyl...2yl] oxy } acetic acid
[(S-Cyanobiphenyl-2-yl)oxy]acetic acid
[(5-Nitrobiphenyl-2-yl)oxy]acetic acid
{ [41-(Methylthio)-5-(trifluoromethyl)biphenyl2yl]oxy} acetic acid





{ [4"-(Methylsulfonyl)-5 ..(trifluoromethyl)biphenyl-2-yl)oxy I acetic acid, { [4"-(Ethylsulfonyl)-2"-methyl-5~(trifluoromethyl)biphenyl~2~yl]oxy } acetic acid (4-Chloro-2-pyrimidin-5-ylphenoxy)acetic acid, (2- [5-(Aminosulfonyl)pyridin-2-yl] -4-chiorophenoxy } acetic acid [2-(2-Aniinopyrimidin-5-yl)-4-chlorophenoxy]acetic acid, trifluoroacetate salt [4-Chloro-2-(4-methyl-2-morpholin-4~ylpyrimidin-5~yl)phenoxy]acetic acid { 4-Chloro-2-[2-(dimethylamino)pyrimidin-5-yl]phenoxy I acetic acid [4-Chloro-2-(2-morpholin-4-ylpyrimidin-5-yl)phenoxy] acetic acid {4-Chloro-2-[2-(methylamino)pyrimidin-5-yl]phenoxy} acetic acid { 2-[2-(Benzylamino)pyrimidin-5-yl]4chlorophenoxy} acetic acid [4-Chloro-2-(2-piperidin-1-ylpyrimidin-5-yl)phenoxy]acetic acid (4-Chloro-2- { 2- [methyl (methylsulfonyl)aminollpyrimidin-5-yl }phenoxy)acetic acid [112",5-Dichloro-4"-(ethylsulfonyl)[1 ,1 "-biphenyl] -2-yl]oxy]- acetic acid [[2"-Chloro-4"-(ethylsulfonyl)-5-(trifluoromethyl)[ 1,1 "-biphenyl]-2-yl]oxy]- acetic acid [[5-Chloro-4"-(ethylsulfonyl)-2"-fluoro[1 , 1 "-biphenyl]-2-yl]oxy]- acetic acid [[4"-(Ethylsulfonyl)-2"-fluoro-5-(trifluoromethyl) [1,1 "-biphenylll-2-yl]oxy]-acetic acid, [[5-Chloro-4"-(ethylsulfonyl)-2"-(trifluoromethyl)[ 1, 1"-biphenyl]-2-yl]oxy]- acetic acid 2- U15-Chloro-4"-(ethylsulfonyl)[ 1,1 "-biphenyl]-2-yl]oxy]-propanoic acid
2-II[4"-cEthylsulfonyl)-2"-methyl-5-(trifluoromethyl)[ 1,1 "-biphenyl]-2-yl] oxy]-(2S)-propanoic acid
2-[[4"-(Ethylsulfonyl)-2"-methyl-5-(trifluoromethyl)[ 1,1 "-biphenyl]-2-yl]oxy]-(2R)-propanoic acid, 2.{(2",5-Dichloro-4"-(ethylsulfonyl)[ 1, 1"-biphenyl]-2-yl] oxy]-(2S)- propanoic acid, 2-[[2"-Chloro-4"-(ethylsulfonyl)-5-(trifluoromethyl)[1 .1 "-biphenyl]-2-yl]oxy]-(25)-propanoic acid
2-[[4"-(Ethylsulfonyl)-2"-methyl-5-(trifluoromethyl)[ 1,1 "-biphenyl]-2-yl]oxy]-2-methyl-propanoic acid, 2-[[4"-(Ethylsulfonyl)-2"-methyl-5-(trifluoromethyl)[ 1,1 "-biphenyl)-2-yl]oxy] -butanoic acid, [4-Chloro-2-[2-[(methylsulfony1)(phenylmethyl)aniino]~5~pyriniJdinyl]phenoxy]..acetic acid [4-Chloro-2~[2-[(ethylsulfonyI)(pheny1methy1)an.xino]~5~pyrimidinyl]phenoxy]acetic acid [2-[2- [Acetyl(phenylmethyl)amino]-5-pyrimidinyly4-.chlorophenoxy]..acetic acid [[4"-(Ethylsulfonyl)-5-fluoro-2"-methyl[ 1,1 "-biphenyl]-2-yl]oxy]-acetic acid [114"-(Ethylsulfonyl)-4,5-difluoro-2"-methyl [1,1 "-biphenylll-2-yl]oxy]-acetic acid [[4"-(Bthylsulfonyl)-3,5-difluoro-2"-methyl[1 , 1 "-biphenyl]-2-yl]oxy]-acetic acid [2-(2-Aniino-5-methyl-3-pyridinyl)-4~(trifluoromethyl)phenoxy].. acetic acid [[4"-Amino-2"-methyl-5-(trifluoromethyl)[1 , 1 "-biphenyl]-2-yl]oxy]- acetic acid [[4"-Amino-2"-chloro-5-(trifluoromethyl)[ 1,1 "-biphenylj-2-yl]oxy]- acetic acid


[[2"-Chloro-4"-hydroxy-5-(trifluoromethyl)[ 1,1 "-biphenyl] -2-yl] oxy]- acetic acid [2~(2,4~Dimethoxy~5~pyrirnidinyl)-4-(trifluoromethyl)phenOXy]- acetic acid [[2"-Chloro-5-(trifluoromethyl) [1,1 "-biphenyl]-2-ylIIoxyI- acetic acid [[2",5-Bis(trifluoromethyl)[1 , 1"-biphenyl] -2-yllloxy]- acetic acid [[5"-Fluoro-2"-methoxy-5-(trifluoromethyl)[1 , 1 "-biphenyl] -2-yl] oxy] - acetic acid [[5"-Cyano-2"-methoxy-5-(trifluoromethyl) [1,1 "-biphenyl]-2-yllloxy]- acetic acid [[4"-Chloro-2"-methyl-5-(trifluoromethyl)[1, 1 "-biphenyl]-2-yl]oxy]- acetic acid [[2",5"-Dimethyl-5-(trifluoromethyl)[1 , 1 "-biphenyl]-2-yl]oxy] - acetic acid [115"-Chloro-2"-methyl-5-(trifluoromethyl) [1,1 "-biphenyl]-2-yl]oxy]- acetic acid [[2"-Fluoro-6"-methyl-5-(trifluoromethyl)[ 1,1 "-biphenyl]-2-yl]oxy]- acetic acid [[4"-Fluoro-2"-methyl-5 -(trifluoromethyl)[1 , 1 "-biphenyfl-2-yl]oxy]- acetic acid [[4"- [ [(Ethylamino)carbonyl]aniino]~2"-methyl-5-(trifluoromethyl) [1,1 "-biphenyl]-2-yllloxy]- acetic acid [[2"~Methyl~4"~[[(methylamino)carbonyl]amino]-5-(trifluoromethyl)[ 1,1 "-biphenyl]-2-yl]oxy]- acetic acid [[4"~[[(Cyclopropylamino)carbonyl]aInino1-2"-methyl-5-(trifluOrOrnethyl) [1, 1"-biphenyl]-2-yl]oxy]- acetic acid [[2"-Methyl-4"-[[(propylamino)carbonyl] amino] -5-(trifluoromethyl)II1 , 1 "-biphenyl]-2-yl]oxy]- acetic acid, [[2",4"-Dimethyl-5 -(trifluoromethyl)[1 , 1 "-biphenyl]-2-yl]oxy]- acetic acid [~I5"-Fluoro-2"-methyl-5-(trifluoromethyl)[1 , 1 "-biphenyl]-2-yl]oxy]- acetic acid [[4"-(Aminocarbonyl)-2"-methyl-5-(trifluoromethyl)[ 1,1 "-biphenyl]-2-yl]oxy]- acetic acid [[3"-Fluoro-2"-methyl-5-(trifluoromethyl)[ 1,1 "-biphenyl]-2-yl]oxy]- acetic acid [[2", 5"-Difluoro-5-(trifluoromethyl)[ 1,1 "-biphenyl]-2-yl]oxy]- acetic acid [[5"-(Aminosulfonyl)-2"-chloro-5-(trifluoromethyl) [1,1 "-biphenyl]-2-yl]oxy]- acetic acid [[4"~Cyano-2"-methyl-5-(trifluoromethylM 1,1 "-biphenyl] -2-yl]oxy]- acetic acid [[4"-Chloro-2"-fluoro-5-(trifluoromethyD[ 1,1 "-biphenyl]-2-yl]oxy]- acetic acid [[2" ,5"-Difluoro-4"-methoxy-5-(trifluoromethyl)[ 1,1 "-biphenyl]-2-yl] oxy]- acetic acid [[2"-fluoro-5 "-methyl-5-(trifluoromethyl)[1 , 1 "-biphenyl]-2-yl]oxy]- acetic acid [[2"-Fluoro-4"-methyl-5-(trifluoromethyl) [1,1 "-biphenyl]-2-yl]oxy]- acetic acid [[4"-Methoxy-2"-methyl-5-(trifluoromethyl)[ 1, 1"-biphenyl]-2-yl]oxy]- acetic acid [[4"-(Aminosulfonyl)-2",5 "-difluoro-5-(trifluoromethyl)[1 , 1 "-biphenyl]-2-yl]oxy]- acetic acid
[2-Benzo[b]thien-3-yl-4-(trifluoromethyl)phenOxy]- acetic acid [2-(2-Benzofuranyl)-4-(trifluoromethyl)phenoXy]- acetic acid [[4"-Chloro-5-(trifluoromethyl)[ 1,1 "-biphenyl]-2-yl]oxy]- acetic acid [[3"-(l -Methylethyl)-5-(trifluoromethyl)[1 , 1 "-biphenyl]-2-yl]oxy]- acetic acid [[3 ",4"-Difluoro-5-(trifluoromethyl)[1 , 1 "-biphenyl]-2-yl]oxy]- acetic acid [2-(1 ,3-Benzodioxol-5-yl)-4-(trifluoromethyl)phenoxy]- acetic acid





[[4"-Ethyl-5-(trifluoromethyl)[ 1,1 "-biphenyl]-2-yl] oxy]- acetic acid [[3"-Fluoro-5-(trifluoromethyl)[1 , 1 ":4", 1 "-terphenyl]-2-yl]oxy]- acetic acid [[4"-(Trifluoromethoxy)-5-(trifluoromethyl)[ 1,1 "-biphenyl]-2-yl]oxy]- acetic acid [[2",3 "-Dichloro-5-(trifluoromethyl)[1 , 1 "-biphenyl]-2-yl]oxy]- acetic acid [[4"-( 1, 1-Dimethylethyl)-5-(trifluoromethyl)[ 1,1 "-biphenyl]-2-yl] oxy]- acetic acid [2-(6-Methoxy-2-naphthalenyl)-4-(trifluoromethyl)phenoxy]- acetic acid [[4"-(Ethylthio)-5-(trifluoromethyl)[1 , 1 "Lbiphenyl]~2~yl] oxy]- acetic acid [[4"-Acetyl-5-(trifluoromethyl)[1 , 1 "-biphenyl]-2-yl]oxy]- acetic acid [2-(2-Chloro-5-methyl-4-pyridinyl)-4-(trifiuoromethyl)phenoxy]- acetic acid, [[5"-(Aminosulfonyl)-2"-methyl-5-(trifluoromethyl)[1 .1 "-biphenyl]-2-yl] oxy]- acetic acid, [2-(8-Quinolinyl)-4-(trifluoromethyl)phenoxy]- acetic acid, [[3 "-Cyano-5-(trifluoromethyl) [1,1 "-biphenyl]-2-yl]oxy]- acetic acid, [2-[4-Methyl-6-[methyl(methylsulfonyl)amino]-3-pyridinyl]4.(trifluoromethyl) phenoxy]acetic acid, [[2"-Methyl-5 "-(methylsulfonyl)-5-(trifluoromethyl)[1 .1 "-biphenyl]-2-yl]oxy]- acetic acid, 2"-(Carboxymethoxy)-5 "-(trifluoromethyl)- [1,1 "-biphenyl] -3-carboxylic acid, 3-methyl ester
2"-(Carboxymethoxy)-5 "-(trifluoromethyl)- [1,1 "-biphenyl]-2-carboxylic acid, 2-methyl ester
[[5-(Trifluoromethyl)[1 , 1 ":4", 1 "-terphenyl]-2-yl]oxy]- acetic acid
[[3 "-Fluoro-2",4"-dimethyl-5-(trifluoromethyl)[1 , 1 "-biphenyll-2-yl]oxy]- acetic acid [[2"-Nitro-5-(trifluoromethyl) [1,1 "-biphenyl]-2-yl]oxy]- acetic acid, [[2"-Methyl-5-(trifluoromethyl)[1 , 1 "-biphenyl]-2-yl]oxy]- acetic acid [[3"-Chloro-2"-methyl-5-(trifluoromethyl)[ 1,1 "-biphenyl]-2-yl]oxy]- acetic acid [[5-(Trifluoromethyl)[ 1,1 ":3", 1 "-terphenyl]-2-yl]oxy]- acetic acid 2"-(Carboxymethoxy)-5 "-(trifluoromethyl)- [1, 1"-biphenyl]-4-carboxylic acid, 4-methyl ester
[[4"-Nitro-5-(trifluoromethyl)[1 , 1 "-biphenyl]-2-yl]oxy]- acetic acid [[5-(Trifluoromethyl)-3 "- [(trifluoromethyl)thio] [1,1 "-biphenyl]-2-yl]oxy]- acetic acid [[5-(Trifluoromethyl)-4"-[(trifluoromethyl)thio] [1,1 "-biphenyl]-2-yl]oxy]- acetic acid [[4"-Methyl-5-(trifluoromethyl) [1,1 "-biphenyl]-2-yl]oxy]- acetic acid [[4"-Fluoro-5-(trifluoromethyl)[1 , 1 "-biphenyl]-2-yl]oxy]- acetic acid [[3"-Fluoro-5-(trifluoromethyl)[ 1,1 "-biphenyl]-2-yl]oxy]- acetic acid [[3 "-Methyl-5-(trifluoromethyl)[ 1,1 "-biphenyl]-2-yl]oxy]- acetic acid [2-(3-Pyridinyl)-4-(trifluoromethyl)phenoxy]- acetic acid [[2"-Fluoro-5-(trifluoromethyl)[ 1,1 "-biphenyl]-2-yl]oxy]- acetic acid [[2"-Methoxy-5-(trifluoromethyl)[ 1, 1"-biphenyl]-2-yl]oxy]- acetic acid 11113"-Methoxy-5-(trifluoromethyl)[l , 1 "-biphenyl]-2-yl]oxy]- acetic acid [[4"-Methoxy-5-(trifluoromethyl) [1,1 "-biphenyl]-2-yl]oxy]- acetic acid



[[3"-(Ethylsulfonyl)-5-(trifluoromethyl) [1,1 "-biphenyl] -2-yl] oxy]- acetic acid [[3"-Propoxy-5-(trifluoromethyl)[ 1,1 "-biphenyl]-2-yl]oxy]- acetic acid [[4"-Propoxy-5-(trifluoromethyl)[1 , 1 "-biphenyl]-2-yl]oxy]- acetic acid [2-(2-Amino-4-methyl-5-pyrirnidinyl)-4-(trifluoromethyl)phenoxy]- acetic acid [[4"-Cyano-5-(trifluoromethyl) [1,1 "-biphenyl]-2-yl]oxy]- acetic acid [[4",5-Bis(trifluoromethyl)[1 , 1 "-biphenyl]-2-yl]oxy]- acetic acid [2-(2-Naphthalenyl)-4-(trifluoromethyl)phenoxy]- acetic acid [[4"-(1-Pyrrolidinylsulfonyl)-5-(trifluoromethyl)[1 , 1 "-biphenyl]-2-yl]oxy]- acetic acid [[4"- [(Dimethylamino)sulfonyl]-5-(trifluoromethyl)[1 ,1 "-biphenyl]-2-yl]oxy]- acetic acid [[4"-[[(Phenylmethyl)arnino]suifonyl]-5-(trifluoromethyl)[ 1,1 "-biphenyl]-2-yl]oxy]- acetic acid
[[4"-[[(2,2,2-Trifluoroethyl)amino]sulfonyl]-5-(trifluoromethyl)[l , 1 "-biphenyl]-2-yl]oxy]-acetic acid
[[4"-[[(5-Methyl-2-thiazolyl)a~nino]sulfonyl]-5-(trifluoromethyl)[1 , 1 "-biphenyl]-2-yl]oxyj-acetic acid
[[4"-[(Phenylamino)sulfonyl]-5-(trifluoromethyl)[1 , 1 "-biphenyl]-2-yl]oxy]- acetic acid [[4"-IXDiethylamino)sulfonyl]-5-(trifluoromethyL)[ 1,1 "-biphenyl]-2-yl]oxy]- acetic acid [[4"-[(Cyclopropylamino)sulfonyl]-5-(trifluoromethyl)[1 , 1 "-biphenyl]-2-yl]oxy]- acetic acid [[4"-(Aminosulfonyl)-5-(trifluoromethyl)[1 , 1 "-biphenyl]-2-yl]oxy]- acetic acid [[4"-[(Methylamino)sulfonyl]-5-(trifluoromethyl)[ 1,1 "-biphenyl]-2-yl]oxyi. acetic acid [[4"-[(4-Methyl- 1 -piperazinyl)sulfonyl]-5-(trifluoromethyl) [1,1 "-biphenyl]-2-yl]oxy]- acetic acid
[2-[4-Methyl-2-(5-methyl-1 ,1-dioxido-1 ,2,5-thiadiazolidin-2-yl)-5-pyrimidinyl]-4-(trifluoromethyl)phenoxy]- acetic acid [2-[4-Methyl-2-[methyl(methylsulfonyl)amino]-5-pyrimidinyl]-4-
(trifluoromethyl)phenoxy]- acetic acid [2- [2-(l , 1-Dioxido-2-isothiazolidinyl)4-methyl-5-pyrimidinyl]4-
(trifluoromethyl)phenoxy]- acetic acid, ammonium salt [2-[2-(3-Hydroxy- 1 -azetidinyl)-4-methyl-5-pyrimidinyl]-4-(trifluoromethyl)phenoxy]-acetic acid [2-[4-Methy1-2-(4-methyl-1-piperazinyl)-5-pyrin~idinyl]4-(trifluoromethyl)phenoxy]~ acetic acid [2- [4-Methyl-2-( 1 -pyrrolidinyl)-5-pyrimidinylI-4~(trifluoromethyl)phenoxy]~ acetic acid [2-[2-(Dimethylamino)-4-methyl-5-pyrimidinyl]-4-(trifluoromethyl)phenoxy]- acetic acid [2-[S-Methyl-2-[methyl(methylsulfonyl)aminoj-4-pyrimidinyl]-4-
(trifluoromethyl)phenoxy]- acetic acid [2-[2-[[(Dimethylanino)sulfonyl]amino]4methyb5pyrimicjinyl]..4 (trifi uoromethyl)phenoxy]- acetic acid




[[2"-Chloro-4"- [(methoxycarbonyl)amino] -5-(trifluoromethyl)[1, 1 "-biphenylll-2-yl]oxy]acetic acid 2-[[2"-Chloro-4"-(methylsulfonyl)-5-(trifluoromethyl) [1,1 "-biphenyl]-2-yl]oxy]-(2S)-propanoic acid
2-[[3t-Cyano-5-(trifluoromethyl)[ 1, 1"-biphenyl]-2-yl]oxy]-(2S)-propanoic acid
2- [[4"-[(Dimethylaniino)sulfonyl]-5-(trifluoromethyl)[ 1,1 "-biphenyl]-2-yl]oxy]-(2S")-propanoic acid 2-[[2"-Chloro-4"-[(dimethylamino)sulfonyl]-5-(trifluoromethyl)[1, 1 "-biphenyl]-2-yl]oxy]-(2S)-propanoic acid 2-[[2"-Fluoro-4"-(methylsulfonyl)-5-(trifluoromethyl)[ 1,1 "-biphenyl]-2-yl]oxy]-(2S)-propanoic acid [[2" ,5-Dichloro-4"-(methylsulfonyl)J 1,1 "-biphenyl]-2-yl]oxy]-(2S)-propanoic acid [[5-Chloro-4"-[(dimethylaniino)sulfonyl] [1,1 "-biphenyl]-2-yl]oxy]-(28)-propanoic acid [[2~,5-Dich1oro-4"- [(dimethylamino)sulfonyl] [1, 1"-biphenyl]-2-yl]oxy]-(2S)-propanoic acid [(5-Chloro-3 "-cyano[ 1,1 "-biphenyll-2-yl)oxy]-(2S)-propanoic acid [[5-Chloro-4"-[(dimethylaniino)sulfonyl]-2"-fluoro[1, 1"-biphenyl]-2-yl]oxy]-(2S)-propanoic acid
[[5-Chloro-4"-(4-morpholinylsulfonyl)[ 1,1 "-biphenyl]-2-yl]oxyi-(2S)-propanoic acid [[5-Chloro-2"-fluoro-4"-(methylsulfonyl)[ 1,1 "-biphenyl]-2-yl]oxy]-(2S)-propanoic acid 2-[[4"-(1-Azetidinylsulfonyl)-5-chloro[ 1,1 "-biphenyl]-2-yl] oxy]-(2S)-propanoic acid
2-[115-Chloro-2"-inethyl-4"-(1 -pyrrolidinylcarbonyl)[1 , 1"-biphenyl]-2-yl]oxy]-(2S)-propanoic acid,
2- [(2"A"-Dichloro-5-cyano[1 , 1 "-biphenyl]-2-yl)oxy]-(2S)-propanoic acid
2-[[5-Cyano-2"-fluoro-4"-(trifluoromethyl)[ 1,1 "-biphenyl]-2-yljoxy]-(2S)-propanoic acid
2-[(3 "-Cyano-5-fluoro[ 1,1 "-biphenyl]-2-yl)oxy]-(25)-propanoic acid, sodium salt
2-[(2",4"-Dichloro-5-fluoro[ 1,1 "-biphenyl]-2-yl)oxy]-(2S)-propanoic acid, sodium salt
2- [[2"-Chloro-5-fluoroA"-(methylsulfonyl)fl , 1 "-biphenyl]-2-yl] oxy]-(2S)-propanoic acid
2-[[2"-Chloro-5-fluoro-5"-(trifluoromethyl)[1,1 "-biphenyl]-2-yl]oxy]-(2S)-propanoic acid, [[4" -(Ethylsulfonyl)-6-methyl-5-nitro[ 1,1" -biphenyl] -2-yl] oxy] acetic acid [[5-Chloro-4" -(ethylsulfonyl)-6-methyl[ 1,1 "-biphenyl]-2-yl]oxy]acetic acid [[4"-(Methylsulfonyl)-2",5-bis(trifluoromethyl)[1, 1 "-biphenyll-2-yl]oxy]acetic acid 2- [4-Chloro-2-[4-methyl-6-[methyl(methylsulfonyl)amino]-3-pyridinyl]phenoxy]-(2S)-propanoic acid 2-[2-[4-Methyl-2-[(methylsulfonyl)aniino]-5-pyriniidinyl]-4-(trifluoromethyl)phenoxy]-(2S)-propanoic acid
[(5-Chloro-3"-cyano[ 1,1 "-biphenyl]-2-yl)oxy] - acetic acid
and pharmaceutically acceptable salts thereof.







9. A compound of formula (I) according to any one of claims 1 to 8 for use in therapy.

10. A method of treating a disease mediated by prostaglandin D2, which comprises administering to a patient a therapeutically effective amount of a compound of formula (1), or a pharmaceutically acceptable salt as defined in claims 1 to 8.

11. A method of treating a respiratory disease, such as asthma and rhinitis, 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 defined in claims 1 to 8.

12. A compound •of formula (I) or a pharmaceutically acceptable salt thereof, a method of treating a disease and a method of treating a respiratory disease substantially as herein described with reference to the foregoing examples.

Documents:

http://ipindiaservices.gov.in/documents/4421-DELNP-2005/4421-DELNP-2005-Abstract-(01-07-2009).pdf

http://ipindiaservices.gov.in/documents/4421-DELNP-2005/4421-delnp-2005-abstract.pdf

http://ipindiaservices.gov.in/documents/4421-DELNP-2005/4421-DELNP-2005-Claims-(01-07-2009).pdf

http://ipindiaservices.gov.in/documents/4421-DELNP-2005/4421-delnp-2005-claims.pdf

http://ipindiaservices.gov.in/documents/4421-DELNP-2005/4421-delnp-2005-correspondence-others.pdf

http://ipindiaservices.gov.in/documents/4421-DELNP-2005/4421-delnp-2005-correspondence-po.pdf

http://ipindiaservices.gov.in/documents/4421-DELNP-2005/4421-DELNP-2005-Corresponence-Others-(01-07-2009).pdf

http://ipindiaservices.gov.in/documents/4421-DELNP-2005/4421-DELNP-2005-Description%20(Complete)-(01-07-2009).pdf

http://ipindiaservices.gov.in/documents/4421-DELNP-2005/4421-delnp-2005-description%20(complete).pdf

http://ipindiaservices.gov.in/documents/4421-DELNP-2005/4421-DELNP-2005-Form-1-(01-07-2009).pdf

http://ipindiaservices.gov.in/documents/4421-DELNP-2005/4421-delnp-2005-form-1.pdf

http://ipindiaservices.gov.in/documents/4421-DELNP-2005/4421-delnp-2005-form-13-(01-07-2009).pdf

http://ipindiaservices.gov.in/documents/4421-DELNP-2005/4421-delnp-2005-form-18.pdf

http://ipindiaservices.gov.in/documents/4421-DELNP-2005/4421-DELNP-2005-Form-2-(01-07-2009).pdf

http://ipindiaservices.gov.in/documents/4421-DELNP-2005/4421-delnp-2005-form-2.pdf

http://ipindiaservices.gov.in/documents/4421-DELNP-2005/4421-delnp-2005-form-26.pdf

http://ipindiaservices.gov.in/documents/4421-DELNP-2005/4421-DELNP-2005-Form-3-(01-07-2009).pdf

http://ipindiaservices.gov.in/documents/4421-DELNP-2005/4421-delnp-2005-form-3.pdf

http://ipindiaservices.gov.in/documents/4421-DELNP-2005/4421-delnp-2005-form-5.pdf

http://ipindiaservices.gov.in/documents/4421-DELNP-2005/4421-DELNP-2005-GPA-(01-07-2009).pdf

http://ipindiaservices.gov.in/documents/4421-DELNP-2005/4421-delnp-2005-pct-210.pdf

http://ipindiaservices.gov.in/documents/4421-DELNP-2005/4421-delnp-2005-pct-304.pdf

http://ipindiaservices.gov.in/documents/4421-DELNP-2005/4421-delnp-2005-pct-409.pdf

http://ipindiaservices.gov.in/documents/4421-DELNP-2005/4421-delnp-2005-pct-416.pdf

http://ipindiaservices.gov.in/documents/4421-DELNP-2005/4421-DELNP-2005-Petition-137-(01-07-2009).pdf

http://ipindiaservices.gov.in/documents/4421-DELNP-2005/abstract.jpg


Patent Number 240516
Indian Patent Application Number 4421/DELNP/2005
PG Journal Number 21/2010
Publication Date 21-May-2010
Grant Date 14-May-2010
Date of Filing 29-Sep-2005
Name of Patentee ASTRAZENECA AB
Applicant Address S-151 85 SODERTELJE, SWEDEN
Inventors:
# Inventor's Name Inventor's Address
1 BROUGH , STEPHEN ASTRAZENECA R & D CHARNWOOD, BAKEWELL ROAD, LOUGHBOROUGH, LEICESTERSHIRE LE11 5RH, GREAT BRITAIN.
2 DAVIES, ANDREW ASTRAZENECA R & D CHARNWOOD, BAKEWELL ROAD, LOUGHBOROUGH, LEICESTERSHIRE LE11 5RH, GREAT BRITAIN.
3 LUKER, TIMOTHY ASTRAZENECA R & D CHARNWOOD, BAKEWELL ROAD, LOUGHBOROUGH, LEICESTERSHIRE LE11 5RH, GREAT BRITAIN.
4 BONNERT, ROGER ASTRAZENECA R & D CHARNWOOD, BAKEWELL ROAD, LOUGHBOROUGH, LEICESTERSHIRE LE11 5RH, GREAT BRITAIN.
5 MCINALLY, THOMAS ASTRAZENECA R & D CHARNWOOD, BAKEWELL ROAD, LOUGHBOROUGH, LEICESTERSHIRE LE11 5RH, GREAT BRITAIN.
6 MILLICHIP, LAN ASTRAZENECA R & D CHARNWOOD, BAKEWELL ROAD, LOUGHBOROUGH, LEICESTERSHIRE LE11 5RH, GREAT BRITAIN.
7 PAIRAUDEAU , GARRY ASTRAZENECA R & D CHARNWOOD, BAKEWELL ROAD, LOUGHBOROUGH, LEICESTERSHIRE LE11 5RH, GREAT BRITAIN.
8 PATEL, ANIL ASTRAZENECA R & D CHARNWOOD, BAKEWELL ROAD, LOUGHBOROUGH, LEICESTERSHIRE LE11 5RH, GREAT BRITAIN.
9 RASUL , RUKHSANA ASTRAZENECA R & D CHARNWOOD, BAKEWELL ROAD, LOUGHBOROUGH, LEICESTERSHIRE LE11 5RH, GREAT BRITAIN.
10 THOM, STEPHEN ASTRAZENECA R & D CHARNWOOD, BAKEWELL ROAD, LOUGHBOROUGH, LEICESTERSHIRE LE11 5RH, GREAT BRITAIN.
PCT International Classification Number C07C 317/22
PCT International Application Number PCT/SE2004/000535
PCT International Filing date 2004-04-06
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 0301010-5 2003-04-07 Sweden