Title of Invention	"FURAN COMPOUNDS"
Abstract	Compounds of formula (I): wherein: R2 is H or an optionally substituted C1-4 alkyl group; Y is either -(CH2)n-X-, where n is 1 or 2 and X is 0, S, S (=0) , S(=0)2, or NRN1, where RN1 is selected from H or optionally substituted C1-4 alkyl, or Y is -C(=0)NRN2-, where RN2 is selected from H, and optionally substituted C1-7alkyl or C5-20 aryl; R3 is an optionally substituted C6 aryl group linked to a further optionally substituted C6 aryl group, wherein if both C6 aryl groups are benzene rings, there may be an oxygen bridge between the two rings, bound adjacent the link on both rings; A is a single bond or a C1-3 alkylene group; and R5 is either: (i) carboxy; (ii) a group of formula (II); or (iii) a group of formula (III); wherein R is optionally substituted Cl-7 alkyl, C5-20 aryl or NRN3RN4, where RN3 and RN4 are independently selected from optionally substituted C1-4 alkyl; (iv) tetrazol-5-yl.

Title of Invention

"FURAN COMPOUNDS"

Abstract

Compounds of formula (I): wherein: R2 is H or an optionally substituted C1-4 alkyl group; Y is either -(CH2)n-X-, where n is 1 or 2 and X is 0, S, S (=0) , S(=0)2, or NRN1, where RN1 is selected from H or optionally substituted C1-4 alkyl, or Y is -C(=0)NRN2-, where RN2 is selected from H, and optionally substituted C1-7alkyl or C5-20 aryl; R3 is an optionally substituted C6 aryl group linked to a further optionally substituted C6 aryl group, wherein if both C6 aryl groups are benzene rings, there may be an oxygen bridge between the two rings, bound adjacent the link on both rings; A is a single bond or a C1-3 alkylene group; and R5 is either: (i) carboxy; (ii) a group of formula (II); or (iii) a group of formula (III); wherein R is optionally substituted Cl-7 alkyl, C5-20 aryl or NRN3RN4, where RN3 and RN4 are independently selected from optionally substituted C1-4 alkyl; (iv) tetrazol-5-yl.

Full Text	This invention relates to Furan compounds, more particularly to EP4 receptor antagonists, pharmaceutical compositions comprising such compounds, and the use of such compounds and compositions to treat various diseases. Background to the invention Postanoids comprise prostaglandins (PGs) and thromboxanes (Txs) and their receptors fall into five different classes (DP, EP,FP, IP and TP) based on their sensitivity to the five naturally occurring prostanoids, PGD2, PGE2, PGF2c(, PGI2 and TxA2, respectively (Coleman, R. A., Prostanoid Receptors. IUPHAR compendium of receptor characterisation and classification, 2nd edition, 338-353, ISBN 0-9533510-3-3, 2000). EP receptors (for which the endogenous ligand is PGE2) have been subdivided into four types termed EP1, EP2, EP3 and EP4. These four types of EP receptors have been cloned and are distinct at both a molecular and pharmacological level (Coleman, R.A., 2000) . EP4 antagonists have been shown to be useful in the treatment of pain, and in particular, in the treatment of primary headache disorders, which include migraines, and secondary headache disorders, such as drug-induced headaches (W) 00/18405 and WO 01/72302). Dilation of the cerebral vasculature and the subsequent stimulation of pain stimulating, perivascular trigeminal sensory afferent nerves is recognized to play an important role in the pathophysiology of migraine. A sterile inflammatory response, associated with activation of cycloxyenase and the generation of PGE2, is also implicated in the pathophysiology of migraine. PGE2 levels have been shown to be raised during migraine attacks and PGE2 contributes to the pain of migraine by directly dilating cerebral arteries and by stimulating the release of vasoactive/pro-inf lammatory peptides from the trigeminal nerves. These effects of PGE2 are mediated in whole or in part by EP4 receptors. Thus, by binding to and preventing the stimulation of EP4 receptors, EP$ antagonists may be used to treat the pain of migraine. antagonists may also be useful in treating a number of other conditions and diseases. For example, they may be used in: the treatment of pain associated with rheumatoid arthritis, osteoarthritis, rheumatoid spondylitis, gouty arthritis and juvenile arthritis; the treatment of musculoskeletal pain, lower back and neck pain, sprains and strains, neuropathic pain, sympathetically mediated pain, myositis, pain associated with cancer and fibromyalgia, pain associated with influenza or other viral infections, such as the common cold, rheumatic fever; pain associated with bowel disorders such as non-ulcer dyspepsia, irritable bowel syndrome; non-cardiac chest pain, pain associated with myocardial ischaemia, post-operative pain, headache, toothache and dysmeriorrhea. Neuropathic pain syndromes include diabetic neuropathy, sciatica, nonspecific lower back pain, multiple sclerosis pain, fibromyalgia, HIV-related neuropathy, post-herpetic neuralgia, trigeminal neuralgia and pain resulting from physical trauma; the treatment of inflammatory diseases including rheumatoid and osteoarthritis, psoriasis, dermatitis, retinitis, conjunctivitis, asthma, bronchitis, chronic obstructive pulmonary disease, inflammatory bowel disease, colitis, nephritis, gingivitis and hepatitis; the treatment of cancers including familial adenomatous polyposis, endometrial carcinoma, colorectal and cervical cancer; the treatment of bone disorders involving altered bone formation or resorption such as osteoporosis; women's health for the treatment of myometrial and endometrial disorders; the treatment of gastrointestinal disease including diarrhoea; the treatment of immunological disorders such as autoimmune disease, immunological deficiency diseases, organ transplantation and increasing the latency of HIV infection; the treatment of diseases of abnormal platelet function. (e.g. occlusive vascular diseases); the preparation of a drug with diuretic properties to treat or prevent various oedema, hypertension, premenstrual tension, urinary calculus, oliguri.a, hyperphosphaturia, mesangial proliferative glomerulonephritis, chronic renal failure or the like; the treatment of impotence or erectile dysfunction, and female sexual dysfunction; the treatment of hair growth disorders; the treatment of sleep disorders such as narcolepsy and insomnia; the treatment of cardiovascular diseases and shock states associated with hypotension (e.g. septic shock); the treatment of neurodegenerative diseases and for preventing neuronal damage following stroke, cardiac arrest, cardiopulmonary bypass, traumatic brain injury or spinal cord injury; the treatment of tinnitus; the treatment of dependence; and the treatment of complications of diabetes. Although EP4 antagonists are known, it is desired to find novel EP4 antagonists, and in particular, EP4 antagonists which are selective against other EP receptors, i.e. EPi, EP2 and EP3. Summary of the invention A first aspect of the present invention provides a compound of formula (I) : (Figure Removed) or a pharmaceutically acceptable salt thereof for use in a method of therapy, wherein: R2 is H or an optionally substituted Ci_4 alkyl group; Y is either -(CH2)n-X-, where n is 1 or 2 and X is 0, S, S(=0), S(=0)2, or NRN1, where RN1 is selected from H or optionally substituted Ci_4 alkyl, or Y is -C(=O)NRN2-, where RN2 is selected from H, and optionally substituted Ci_7 alkyl or Cs-20 aryl; R3 is an optionally substituted Ce aryl group linked to a further optionally substituted C6 aryl group, wherein if both Ce aryl groups are benzene rings, there may be an oxygen bridge between the two rings, bound adjacent the link on both rings; A is a single bond or a Ci-3 alkylene group; and R5 is either: (i) carboxy; (ii) a group of formula (II): (Figure Removed) wherein R is optionally substituted Ci_-7 alkyl, C5-2o aryl or NRN3RN\ where RN3 and RN4 are independently selected from optionally substituted C\-t alkyl; (iv) tetrazol-5-yl . A second aspect of the present invention provides a compound of formula (I) : (Figure Removed) or a salt, solvate and chemically protected form thereof, wherein: R2 is H or an optionally substituted Ci-$ alkyl group; Y is either -(CH2)n-X-, where n is 1 or 2 and X is 0, S, S(=0), S(=0)2 or NRN1, where RN1 is selected from H or optionally substituted C^ alkyl, or Y is-C (=0) NRN2--, where RN2 is selected from H, and optionally substituted Ci-7 alkyl or C5_2o aryl; R3 is an optionally substituted C6 aryl group linked to a further optionally substituted C6 aryl group, wherein if both Ce aryl groups are benzene rings, there may be an oxygen bridge between the two rings, bound adjacent the link on both rings; A is a single bond or a €1-3 alkylene group; and R5 is either: (i) carboxy; (ii) a group of formula (II): (iii) a group of formula (III): (Figure Removed) wherein R is optionally substituted Ci_7 alkyl, C5_2o aryl or NRN3RN4, where RN3 and RN4 are independently selected from optionally substituted Ci_4 alkyl; (iv) tetrazol-5-yl, except that when R2 is methyl, Y is -CHa-O- and R5 is carboxy or Ci_7 alkyl ester thereof, then R3 is not: (Figure Removed) A third aspect of the present invention provides a pharmaceutical composition comprising a compound of formula (I) as defined in the first aspect or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier or diluent. A further aspect of the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of a condition alleviated by antagonism ofan EP4 receptor. Another aspect of the present invention provides a method of treating a condition which can be alleviated by antagonism of an EP4 receptor, which method comprises administering to a patient in need of treatment an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof. Conditions which can be alleviated by antagonism of an EP4 receptor are discussed above, and particularly include primary headache disorders, most particularly migraines. The present invention also provides methods of antagonizing EP4 receptors, in vitro or in vivo, comprising contacting a cell with an effective amount of a. compound of formula (I) . In some embodiments, the compounds described above may be selective as against antagonism of the other three EP receptors, i.e. EPj, EP? and EPj. This selectivity allows for targeting of the effect of the compounds of the invention, with possible benefits in the treatment of certain conditions. Definitions Monodcntate groups (i.e groups with one point of covalent attachment) Alkyl: The term "alkyl" as used 'herein, pertains to a monovalent moiety obtained by removing a hydrogen atom from a carbon atom of a hydrocarbon compound having from 1 to 7 carbon atoms (unless otherwise specified), which may be aliphatic or alicyclic, and which may be saturated or unsaturated. Thus, the term N"alkyl" includes the sub-classes alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cylcoalkynyl, etc., discussed below. In the context of alkyl groups, the prefixes (e.g. Ci_4, Ci_7) denote the number of carbon atoms, or range of number of carbon atoms. For example, the term MCi_4 alkyl" as used herein, pertains to an alkyl group having from 1 to 4 carbon atoms. Examples of groups of alkyl groups include Ci_4 alkyl ("lower alkyl") and Cj-? alkyl. Note that the first prefix may vary according to other limitations; for example, for unsaturated alkyl groups, the first prefix must be at least 2; for cyclic alkyl groups, the first prefix must be at least 3; etc. Examples of saturated alkyl groups include, but are not limited to, methyl (Ci) , ethyl (G2) , propyl (C3) , butyl (C4), pentyl (C5) , hexyl (C6) and heptyl (C7) . Examples of saturated linear alkyl groups include, but are not limited to, methyl (Ci) , ethyl (C2) , n-propyl (Cs) , n-butyl (C4) , n-pentyl (amyl) (C5) , n-hexyl (C6) , and n-heptyl (C7) . Examples of saturated branched alkyl groups include iso-propyl (C3) , iso-butyl (C4) , sec-butyl (C4) , tert-butyl , iso-pentyl (C5) , and neo-pentyl (C5) . Alkenyl: The term "alkenyl" as used herein, pertains to an alkyl group having one or more carbon-carbon double bonds. Examples of groups of alkenyl groups include C2-4 alkenyl and C2_7 alkenyl. Examples of alkenyl groups include, but are not limited to, ethenyl (vinyl, -CH=CH2) , 1-propenyl (-CH=CH-CH3) , 2-propenyl (allyl, -CH-CH=CH2) , isopropenyl (1-methylvinyl, -C (CH3)=CH2) , butenyl (C4) , pentenyl (C5) , and hexenyl Alkynyl: The term "alkynyl" as used herein, pertains to an alkyl group having one or more carbon-carbon triple bonds. Examples of groups of alkynyl groups include C2_4 alkynyl and C2-? alkynyl. Examples of alkynyl groups include, but are not limited to, ethynyl (ethinyl, -C=CH) and 2-propynyl (propargyl, -CH2-CsCH) . Cycloalkyl: The term "cycloalkyl" as used herein, pertains to an alkyl group which is also a cyclyl group; that is, a monovalent moiety obtained by removing a hydrogen atom from an alicyclic ring atom of a carbocyclic ring of a carbocyclic compound, which carbocyclic ring may be saturated or unsaturated, which moiety has from 3 to 7 carbon atoms (unless otherwise specified) , including from 3 to 7 ring atoms. Thus, the term "cycloalkyl" includes the sub-classes cycloalkyenyl and cycloalkynyl. Preferably, each ring has from 3 to 7 ring atoms. Examples of groups of cycloalkyl groups include C3_7 cycloalkyl . Examples of cycloalkyl groups include, but are not limited to, those derived from: saturated monocyclic hydrocarbon compounds: cyclopropane (C3) , cyclobutane (C4) , cyclopentane (C5) , cyclohexane (C6) , cycloheptane (C7) , methylcyclopropane (C,j), dimethylcyclopropane (C5) , methylcyclobutane (C5) , dimethylcyclobutane (Ce) , methylcyclopentane (Ce) , dimethylcyclopentane (C7) , methylcyclohexane (C?) ; unsaturated monocyclic hydrocarbon compounds: cyclopropene (€3) , cyclobutene (04) , cyclopentene cyclohexene (Cg) , methylcyclopropene (04) , dimethylcyclopropene (Cs) , methylcyclobutene dimethylcyclobutene (Cg) , methylcyclopentene dimethylcyclopentene (C7) , methylcyclohexene (C7) ; Heterocyclyl: The term "heterocyclyl" as used herein, pertains to a monovalent moiety obtained by removing a hydrogen atom from a ring atom of a heterocyclic compound, which moiety has from 3. to 20 ring atoms (unless otherwise specified), of which from 1 to 10 are ring heteroatoms. Preferably, each ring has from 3 to 7 ring atoms, of which from 1 to 4 are ring heteroatoms. In this context, the prefixes (e.g. C3.2o/ C3_7, C5-6, etc.) denote the number of ring atoms, or range of number of ring atoms, whether carbon atoms or heteroatoms. For example, the term "Cs-e heterocyclyl" as used herein, pertains to a heterocyclyl group having 5 or 6 ring atoms. Examples of groups of heterocyclyl groups include C3-2o heterocyclyl, Cs_2o heterocyclyl, C3-15 heterocyclyl, C5-15 heterocyclyl, C3_i2 heterocyclyl, C5_i2 heterocyclyl, C3-io heterocyclyl, C5_io heterocyclyl, C3-7 heterocyclyl, C5_7 heterocyclyl, and C$-6 heterocyclyl. Examples of monocyclic heterocyclyl groups include, but are not limited to, those derived from: NI: aziridine (C3) , azetidine (C4) , pyrrolidine (tetrahydropyrrole) (C5) , pyrroline (e.g., 3-pyrroline, 2, 5-dihydropyrrole) (C5) , 2H-pyrrole or 3H-pyrrole (isopyrrole, isoazole) (C5) , piperidine (C6) , dihydropyridine (C6) , tetrahydropyridine (C6), azepine (C7) ; Oi: oxirane (C3), oxetane (C4) , oxolane (tetrahydrofuran) (C5) , oxole (dihydrofuran) (C5) , oxane (tetrahydropyran) (C6) , dihydropyran (C6) , pyran (C6) , oxepin (C7) ; Si: thiirane (C3) , thietane (C4) , thiolane (tetrahydrothiophene) (C5) , thiane (tetrahydrothiopyran) (C6) , thiepane (C7) ; 02: dioxolane (C5) , dioxane (Cs) , and dioxepane (C-,) ; 03: trioxane (C6) ; N2: imidazolidine (C5), pyrazolidine (diazolidine) (C5) , imidazoline (C5) , pyrazoline (dihydropyrazole) (C5) , piperazine (Ce) ; NiOi: tetrahydrooxazole (C5) , dihydrooxazole (C5) , tetrahydroisoxazole (C5) , dihydroisoxazole (C5) , morpholine (C6) , tetrahydrooxazine (Ce) , dihydrooxazine (Ce) , oxazine (C6) ; NiSi: thiazoline (C5) , thiazolidine (Cs) , thiomorpholine (Ce) ; : oxadiazine (C6) ; : oxathiole (Cs) and oxathiane (thioxane) (Ce) ; and, iOiSj: oxathiazine Aryl: The term "aryl" as used herein, pertains to a monovalent moiety obtained by removing a hydrogen atom from an aromatic ring atom of an aromatic compound, which moiety has from 3 to 20 ring atoms (unless otherwise specified) . Preferably, each ring has from 5 to 7 ring atoms. In this context, the prefixes (e.g. 03-20, CS-T, C5_e, etc.) denote the number of ring atoms, or range of number of ring atoms, whether carbon atoms or heteroatoms. For example, the term "Cs-e aryl" as used herein, pertains to an aryl group having 5 or 6 ring atoms. Examples of groups of aryl groups include C3-20 aryl, C5-2o aryl, C5_i5 aryl, C5_i2 aryl, C5_io aryl, CS-T aryl, Cs-g aryl, C5 aryl, and C6 aryl. The ring atoms may be all carbon atoms, as in "carboaryl groups". Examples of carboaryl groups include C3_2o carboaryl, Cs-2o carboaryl, C5_i5 carboaryl, Cs-ia carboaryl, CS-IQ carboaryl, Cs-7 carboaryl, Cs^e carboaryl, 0$ carboaryl, and Ce carboaryl. Examples of carboaryl groups include, but are not limited to, those derived from benzene (i.e. phenyl) (Ce) , naphthalene (Cio) , azulene (Cm), anthracene (Ci4) , phenanthrene (Ci4) , naphthacene (Ci8) , and pyrene (Cj6) . Examples of aryl groups which comprise fused rings, at least one of which is an aromatic ring, include, but are not limited to, groups derived from indane (e.g., 2,3-dihydro-IH-indene) (Cg) , indene (Cg) , isoindene (C9) , tetraline (1, 2, 3, 4-tetrahydronaphthalene (Cio) , acenaphthene (Ci2) , fluorene (C13) , phenalene (C13) , acephenanthrene (C15) , and aceanthrene Alternatively, the ring atoms may include one or more heteroatoms, as in "heteroaryl groups". Examples of heteroaryl groups include €3-20 heteroaryl, Cs_2o heteroaryl, C5_15 heteroaryl, C5_i2 heteroaryl, Cs-io heteroaryl , C5_7 heteroaryl, Cs-e heteroaryl, Cs heteroaryl, and Cg heteroaryl Examples of monocyclic heteroaryl groups include, but are not limited to, those derived from: Nx: pyrrole (azole) (C5) , pyridine (azine) (C6) ; Oi: furan (oxole) (Cs) ; Si: thiophene (thiole) (C5) ; oxazole (Cs) , isoxazole (Cs) , isoxazine (Cg) /' oxadiazole (furazan) (C5) ; N30i: oxatriazole (Cs) ; NiSi: thiazole (C5) , isothiazole (C5) ; N2: imidazole (1, 3-diazole) (C5) , pyrazole (1, 2-diazole) (C5) , pyridazine (1, 2-diazine) (C6) , pyrimidine (1, 3-diazine) (Ce) , pyrazine (1, 4-diazine) N3: triazole (C5) , triazine (C6) ; and, N,j: tetrazole (C5) . Examples of heteroaryl groups which comprise fused rings, include, but are not limited to: C9 (with 2 fused rings) derived from benzofuran (Oi), isobenzofuran (Oi) , indole (Nj), isoindole (Ni) , indolizine (Ni) , indoline (Ni) , isoindoline (Mi) , purine (N4) (e.g., adenine, guanine), benzimidazole (N2), indazole (N2) , benzoxazole (NiOi) , benzisoxazole (NiOi) , benzodioxole (02) , benzofurazan (N20i), benzotriazole (Na) , benzothiofuran (Si), benzothiazole (NiSi) , benzothiadiazole (N2S) ; Cio (with 2 fused rings) derived from chromene (Oa) , isochromene (Oi) , chroman (Oi), isochroman (Oi), benzodioxan (02) , quinoline (Ni) , isoquinoline (Ni) , quinolizine benzoxazine (NiOi), benzodiazine (N2) , pyridopyridine quinoxaline (Nz) , quinazoline (N2) , cinnoline (N2) , phthalazine (N2) , naphthyridine (N2) , pteridine (N4) ; GH (with 2 fused rings) derived from benzodiazepine (N2) ; Cj3 (with 3 fused rings) derived from carbazole (Nj) , dibenzofuran (Oi) , dibenzothiophene (Si) , carboline (N2) , perimidine (N2) , pyridoindole (N2) ; and, Ci4 (with 3 fused rings) derived from acridine (Nj) , xanthene (Ox), thioxanthene (Si), oxanthrene (02) , phenoxathiin (OiSi) , phenazine (N2) , phenoxazine (Nidi) , phenothiazine (NjSi) , thianthrene (S2) , phenanthridine phenanthroline (N2) , phenazine (N2) . If a heteroaryl or heterocyclyl group contains a nitrogen ring atom, this ring atom, where possible, may be in a oxidised state, as an N-oxide. R3 is defined above as an optionally substituted Ce aryl group linked to a further optionally substituted CG aryl group, wherein if both C6 aryl groups are benzene rings , there may be an oxygen bridge between the two rings, bound adjacent the link on both rings. Thus, if both C6 aryl groups are benzene rings, then R3 can be optionally subtitued biphenyl: or optionally substituted dibenzofuran: If one of the Cg aryl groups is a Ce heteroaryl group, then examples of R3 include, but are not limited to (not showing optional substitution): (Figure Removed) The above groups, whether alone or part of another substituent, may themselves optionally be substituted with one or more groups selected from themselves, the additional monodentate substituents listed below and alkoxylene. Halo: -F, -Cl, -Br, and -I. Hydroxy: -OH. Ether: -OR, wherein R is an ether substituent, for example, a Ci-7 alkyl group (also referred to as a C^ alkoxy group, discussed below) , a C3-2o heterocyclyl group (also referred to as a C3_2o heterocyclyloxy group) , or a C5-2o aryl group (also referred to as a C5-2o aryloxy group), preferably a Ci_7 alkyl group. Ci-7 alkoxy: -OR, wherein R is a Ci_7 alkyl group. Examples of Cj-7 alkoxy groups include, but are not limited to, -OMe (methoxy), -OEt (ethoxy), -O(nPr) (n-propoxy), -O(iPr) (isopropoxy), -O(nBu) (n-butoxy), -O(sBu) (sec-butoxy), -O(iBu) (isobutoxy), and -O(tBu) (tert-butoxy). Oxo (keto, -one): =O. Thione (thioketone); =S. Imino (imine): =NR, wherein R is an imino substituent, for example, hydrogen, CI-T alkyl group, a €3-20 heterocyclyl group, or a €5-20 aryl group, preferably hydrogen or a CI-T alkyl group. Examples of imino groups include, but are not limited to, =NH, =NMe, =NEt, and =NPh. Formyl (carbaldehyde, carboxaldehyde): -C(=0)H. Acyl (keto): -C(=0)R, wherein R is an acyl substituent, for example, a €1-7 alkyl group (also referred to as Ci_7 alkylacyl or CI-T alkanoyl) , a C3-2o heterocyclyl group (also referred to as C3_2o heterocyclylacyl) , or a C5_2o aryl group (also referred to as C5-20 arylacyl) , preferably a Ci_7 alkyl group. Examples of acyl groups include, but are not limited to, -C(=O)CH3 (acetyl) , -C(=0)CH2CH3 (propionyl) , -C(=0)C(CH3)3 (t-butyryl) , and -C(=0)Ph (benzoyl, phenone) . Carboxy (carboxylic acid): -C(=0)OH. Thiocarboxy (thiocarboxylic acid): -C(=S)SH. Thiolocarboxy (thiolocarboxylic acid): -C(=0)SH. Thionocarboxy (thionocarboxylic acid): -C(=S)OH. Imidic acid: -C(=NH)OH. Hydroxamic acid: -C(=NOH)OH. Ester (carboxylate, carboxylic acid ester, oxycarbonyl): -C(=O)OR, wherein R is an ester substituent, for example, a Ci-7 alkyl group, a C3_2o heterocyclyl group, or a C5-2o aryl group, preferably a Ci--? alkyl group. Examples of ester groups include, but are not limited to, -C(=0)OCH3, -C(=0)OCH2CH3, -C(=0)OC(CH3)3, and -C(=0)OPh. Acyloxy (reverse ester): -OC(=0)R, wherein R is an acyloxy substituent, for example, a Ci_7 alkyl group, a C3_20 heterocyclyl group, or a C5_2o aryl group, preferably a Ci_-? alkyl group. Examples of acyloxy groups include, but are not limited to, -OC(=0)CH3 (acetoxy) , -OC (=0) CH2CH3, -OC(=0)C(CH3)3, -OC(=0)Ph, and -OC (=0) CH2Ph . Amido (carbamoyl, carbamyl, aminocarbonyl, carboxamide): -C(=0)NR1R2, wherein R1 and R2 are independently amino substituents, as defined for amino groups. Examples of amido groups include, but are not limited to, -C(=0)NH2, -C(=0)NHCH3, -C(=0)N(CH3)2f -C (=0) NHCH2CH3, and -C(=0)N(CH2CH3)2r as well as amido groups in which R1 and R2, together with the nitrogen atom to which they are attached, form a heterocyclic structure as in, for example, piperidinocarbonyl, morpholinocarbonyl, thiomorpholinocarbonyl, and piperazinocarbonyl. Acylamido (acylamino) : -NR1C(=0)R2, wherein R1 is an amide substituent, for example, hydrogen, a Ci_7 alkyl group, a C3-2o heterocyclyl group, or a €5-20 aryl group, preferably hydrogen or a CI_T alkyl group, and R2 is an acyl substituent, for example, a Ci-? alkyl group, a C3_2o heterocyclyl group, or a 05-20 aryl group, preferably hydrogen or a CI_T alkyl group. Examples of acylamide groups include, but are not limited to, -NHC(=0)CH3 , -NHC(=0)CH2CH3, and -NHC(=0)Ph. R1 and R2 may together form a cyclic structure, as in, for example, succinimidyl, maleimidyl, and phthalimidyl: (Figure Removed) Thioamido (thiocarbamyl) : -C(=S)NR1R2, wherein R1 and R2 are independently amino substituents, as defined for amino groups. Examples of thioamido groups include, but are not limited to, -C(=S)NH2, -C(=S)NHCH3, -C (=S)N (CH3)2, and -C(=S)NHCH2CH3. Ureido: -N (R1) CONR2R3 wherein R2 and R3 are independently amino substituents, as defined for amino groups, and R1 is a ureido substituent, for example, hydrogen, a CI-T alkyl group, a C3-2o heterocyclyl group, or a C5_2o aryl group, (Figure Removed) preferably hydrogen or a CI_T alkyl group. Examples of ureido groups include, but are not limited to, -NHCONH2, NHCONHMe, -NHCONHEt, -NHCONMe2, -NHCONEt2, -NMeCONH2, -NMeCONHMe, -NMeCONHEt, -NMeCONMe2, and -NMeCONEt2. Guanidino: -NH-C (=NH) NH2. Tetrazolyl: a five membered aromatic ring having four nitrogen atoms and one carbon atom, Amino: -NR:R2, wherein R1 and R2 are independently amino substituents, for example, hydrogen, a Ci-7 alkyl group (also referred to as CI_T alkylainino or di-Ci_7 alkylamino) , a €3-20 heterocyclyl group, or a Cs-2oaryl group, preferably H or a Ci-7 alkyl group, or, in the case of a "cyclic" amino group, R1 and R2, taken together with the nitrogen atom to which they are attached, form a heterocyclic ring having from 4 to 8 ring atoms. Amino groups may be primary (-NH2) , secondary (-NHR1) , or tertiary (-NHR1R2) , and in cationic form, may be quaternary (-+NR7u2R3) . Examples of amino groups include, but are not limited to, -NH2, -NHCH3, -NHC(CH3)2, -N(CH3)2, -N (CH2CH3) 2f and -NHPh. Examples of cyclic amino groups include, but are not limited to, aziridino, azetidino, pyrrolidino, piperidino, piperazino, morpholino, and thiomorpholino . Amidine (amidino) : -C(=NR)NR2, wherein each R is an amidine substituent, for example, hydrogen, a Ci-? alkyl group, a C3_20 heterocyclyl group, or a C5_20 aryl group, preferably H or a Ci-7 alkyl group. Examples of amidine groups include, but are not limited to, -C(=NH)NH2f -C(=NH)NMe2, and -C(=NMe)NMe2. Nitro: -N02. Nitroso: -NO. Cyano (nitrile, carbonitrrle): -CN. Sulfhydryl (thiol, mercapto): -SH. Thioether (sulfide): -SR, wherein R is a thioether substltuent, for example, a CI-T alkyl group (also referred to as a Ci-7 alkylthio group) , a Cs-ao heterocyclyl group, or a £5-20 aryl group, preferably a Ci-7 alkyl group. Examples of Cj-7 alkylthio groups include, but are not limited to, -SCH3 and -SCH2CH3. Disulfide: -SS-R, wherein R is a disulfide substituent, for example, a Ci-? alkyl group, a 03-20 heterocyclyl group, or a €5-20 aryl group, preferably a Ci-7 alkyl group (also referred to herein as C-^.-j alkyl disulfide) . Examples of Ci--? alkyl disulfide groups include, but are not limited to, -SSCHs and -SSCH2CH3. Sulfine (sulfinyl, sulfoxide): -S(=0)R, wherein R is a sulfine substituent, for example, a Cj-7 alkyl group, a C3_2o heterocyclyl group, or a C5-20 aryl group, preferably a Ci-i alkyl group. Examples of sulfine groups include, but are not limited to, -S(=0)CH3 and -S (=0) CH2CH3. Sulfone (sulfonyl): -S(=0)2R, wherein R is a sulfone substituent, for example, a Cj-? alkyl group, a 03-20 heterocyclyl group, or a C5-20 aryl group, preferably a CI-T alkyl group, including, for example, a fluorinated or perfluorinated Ci_7 alkyl group. Examples of sulfone groups include, but are not limited to, -S(=0)2CH3 (methanesulfonyl, mesyl), -S(=0)2CF3 (triflyl), -S(=0)2CH2CH3 (esyl), -S(=0)2C4F9 (nonaflyl), -S(=0)2CH2CF3 (tresyl), -S(=0)2CH2CH2NH2 (tauryl), -S(=0)2Ph (phenylsulfonyl, besyl) , 4-methylphenylsulfonyl (tosyl), 4-chlorophenylsulfonyl (closyl), 4-bromophenylsulfonyl (brosyl), 4-nitrophenyl (nosyl), 2-naphthalenesulfonate (napsyl), and 5-dimethylamino-naphthalen-l-ylsulfonate (dansyl). Sulfinic acid (sulfino): -S(=0)OH, -S02H. Sulfonic acid (sulfo): -S(=0)2OH, -S03H. Sulfinate (sulfinic acid ester): --S(=0)OR; wherein R is a sulfinate substituent, for example, a Ci_7 alkyl group, a C3_2o heterocyclyl group, or a Cs-20 aryl group, preferably a Ci_7 alkyl group. Examples of sulfinate groups include, but are not limited to, -S(=0)OCH3 (methoxysulfinyl; methyl sulfinate) and -S(=0)OCH2CH3 (ethoxysulfinyl; ethyl sulfinate) . Sulfinyloxy: -OS(=0)R, wherein R is a sulfinyloxy substituent, for example, a Ci-7 alkyl group, a C3_2o heterocyclyl group, or a Cs_2o aryl group, preferably a Ca-7 alkyl group. Examples of sulfinyloxy groups include, but are not limited to, -OS(=0)CH3 and -OS (=0)CH2CH3. Sulfamyl (sulfamoyl; sulfinic acid amide; sulfinamide): -S(=0)NRaR2, wherein R1 and R2 are independently amino substituents, as defined for amino groups. Examples of sulfamyl groups include, but are not limited to, -S(=0)NH2,-S(=0)NH(CH3) , -S(=0)N(CH3)2, -S (=0) NH (CH2CH3) , -S(=0)N(CH2CH3)2, and -S(O)NHPh. Sulfonamido (sulfinamoyl; sulfonic acid amide; sulfonamide): -S (=0)2NR1R2, wherein R1 and R2 are independently amino substituents, as defined for' amino groups. Examples of sulfonamido groups include, but are not limited to, -S(=0)2NH2, -S(=0)2NH(CH3), -S (=0) 2N (CH3) 2, -S (=0) 2NH (CH2CH3) , -S(=0)2N(CH2CH3)2, and -S(=0)2NHPh. Sulfonamino: -NR1S(=O) 2R, wherein R1 is an amino substituent, as defined for amino groups, and R is a Sulfonamino substituent, for example, a Ci-7 alkyl group, a C3_20 heterocyclyl group, or a Cs_20 aryl group, preferably a Ci_7 alkyl group. Examples of Sulfonamino groups include, but are not limited to, -NHS(=0)2CH3 and -N (CH3) S (=O) 2C6H5. Sulfinamino: -NR1S(=0)R, wherein R1 is an amino substituent, as defined for amino groups, and R is a sulfinamino substituent, for example, a d-? alkyl group, a C3-2o heterocyclyl group, or a C5_20 aryl group, preferably a C^ alkyl group. Examples of sulfinamino groups include, but are not limited to, -NHS(=0)CH3 and -N (CH3) S (=O) C6H5. As already mentioned, the above described groups may be substituted, and particular examples include, but are not limited to, C3_20 aryl-Ci--? alkyl groups, which include benzyl (phenylmethyl, PhCH2-) , benzhydryl (Ph2CH-), trityl (triphenylmethyl, Ph3C-), phenethyl (phenylethyl, Ph-CH2CH2-) , styryl (Ph-CH=CH-) andcinnamyl (Ph-CH=CH-CH2-) . Bidentate groups (i.e. groups with two points of covalent attachment; linking groups) Alkylene: The term vCi-3 alkylene", as used herein, pertains to a bidentate moiety obtained by removing two hydrogen atoms from each of two different carbon atoms, of a linear hydrocarbon compound having from 1 to 3 carbon atoms, which may be saturated or unsaturated. Thus, the term "alkylene" includes the sub-classes alkenylene and alkynylene. In this context, the prefix Ci_3 denotes the number of carbon atoms, or range of number of carbon atoms. Examples of saturated Ci_3 alkylene groups include -CH2-(methylene), -CH2CH2- (ethylene) and -CH2CH2CH2- (propylene) . Examples of unsaturated Ci_3 alkylene groups (which may be termed "C2-3 alkenylene" or "C2-3 alkynylene", as appropriate) include -CH=CH- (vinylene) , -CH=CH-CH2-, -CH2-CH=CH-, -OC-, -C=C-CH2- and -CH2-C=C-. The Ci-3 alkylene group may be substituted by any monodentate substituent described above. Alkoxylene: The term "alkoxylene," as used herein, pertains to a bidentate group of formula -O(CH2)nO-, where n is 1 or 2. . Includes Other Forms Unless otherwise specified, included in the above are the well known ionic, salt, solvate, and protected forms of these substituents. For example, a reference to carboxylic acid (-COOH) also includes the anionic (cdrboxylate) form (-COCT) , a salt or solvate thereof, as well as conventional protected forms. Similarly, a reference to an amino group includes the protonated form (-t^HF^R2) , a salt or solvate of the amino group, for example, a hydrochloride salt, as well as conventional protected forms of an amino group. Similarly, a reference to a hydroxyl group also includes the anionic form (-0"), a salt or solvate thereof, as well as conventional protected forms of a hydroxyl group. Isomers, Salts, Solvates and Protected Forms Certain compounds may exist in one or more particular geometric, optical, enantiomeric, diasteriomeric, epimeric, stereoisomeric, tautomeric, conformational, or anomeric forms, including but not limited to, cis- and trans-forms; E- and Z-forms; c-, t-, and r- forms; endo- and exo-forms; R-, S-, and meso-forms; D- and L-forms; d- and 1-forms; (+) and (-) forms; keto-, enol-, and eholate-forms; syn- and anti-forms; synclinal- and anticlinal-forms; a- and (3-forms; axial and equatorial forms; boat-, chair-, twist-, envelope-, and halfchair-forms; and combinations thereof, hereinafter collectively referred to as "isomers" (or "isomeric forms"). Note that, except as discussed below for tautomeric forms, specifically excluded from the term "isomers", as used herein, are structural (or constitutional) isomers (i.e. isomers which differ in the connections between atoms rather than merely by the position of atoms in space). For example, a reference to a methoxy group, -OCHs, is not to be construed as a reference to its structural isomer, a hydroxymethyl group, -CH2OH. Similarly, a reference to ortho-chlorophenyl is not to be construed as a reference to its structural isomer, meta-chlorophenyl. However, a reference to a class of structures may well include structurally isoineric forms falling within that class (e.g. Ci_7alkyl includes n-propyl and iso-propyl; butyl includes n-, iso-, sec-, and tert-butyl; methoxyphenyl includes ortho-, meta-, and para-methoxyphenyl). The above exclusion does not pertain to tautomeric forms, for example, keto-, enol-, and enolate-forms, as in, for example, the following tautomeric pairs: keto/enol (illustrated below), imine/enamine, amide/imino alcohol, amidine/amidine, nitroso/oxime, thioketone/enethiol, N-nitroso/hyroxyazo, and nitro/aci-nitro. (Figure Removed) Note that specifically included in the term "isomer" are compounds with one or more isotopic substitutions. For example, H may be in any isotopic form, including aH, 2H (D), and 3H (T) ; C may be in any isotopic form, including 12C, 13C, and 14C; O may be in any isotopic form, including 160 and 180; and the like. Unless otherwise specified, a reference to a particular compound includes all such isomeric forms, including (wholly or partially) racernic and other mixtures thereof. Methods for the preparation (e.g. asymmetric synthesis) and separation (e.g. fractional crystallisation and chromatographic means) of such isomeric forms are either known in the art or are readily obtained by adapting the methods taught herein, or known methods, in a known manner. Unless otherwise specified, a reference to a particular compound also includes ionic, salt, solvate, and protected forms of thereof, for example, as discussed below. It may be convenient or desirable to prepare, purify, and/or handle a corresponding salt of the active compound, for example, a pharmaceutically-acceptable salt. Examples of pharmaceutically acceptable salts are discussed in Berge, et al., J. Pharm. Sci., 66, 1-19 (1977). For example, if the compound is anionic, or has a functional group which may be anionic (e.g. -COOH may be -COO"), then a salt may be formed with a suitable cation. Examples of suitable inorganic cations include, but are not limited to, alkali metal ions such as Na+ and K+, alkaline earth cations such as Ca2"1" and Mg2, and other cations such as Al+3. Examples of suitable organic cations include, but are not limited to, ammonium ion (i.e. NH/) and substituted ammonium ions (e.g. NHaR"1", NH2R2% NHR3+, NR4+) . Examples of some suitable substituted ammonium ions are those derived from: ethylamine, diethylamine, dicyclohexylamine, triethylamine, butylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, benzylamine, phenylbenzylamine, choline, meglumine, and tromethamine, as well as amino acids, such as lysine and arginine. An example of a common quaternary ammonium ion is N(CH3)4+. If the compound is cationic, or has a functional group which may be cationic (e.g. -NH2 may be -NH3+) , then a salt may be formed with a suitable anion. Examples of suitable inorganic anions include, but are not limited to, those derived from the folio-wing inorganic acids: hydrochloric, hydrobromic, hydroiodic, sulfuric, sulfurous, nitric, nitrous, phosphoric, and phosphorous. Examples of suitable organic anions include, but are not limited to, those derived from the following organic acids: 2-acetyoxybenzoic, acetic, ascorbic, aspartic, benzoic, camphorsulfonic, cinnamic, citric, edetic, ethanedisulfonic, ethanesulfonic, fumaric, glucoheptonic, gluconic, glutamic, glycolic, hydroxymaleic, hydroxynaphthalene carboxylic, isethionic, lactic, lactobionic, lauric, maleic, malic, methanesulfonic, mucic, oleic, oxalic, palmitic, pamoic, pantothenic, phenylacetic, phenylsulfonic, propionic, pyruvic, salicylic, stearic, succinic, sulfanilic, tartaric, toluenesulfonic, and valeric. Examples of suitable polymeric organic anions include, but are not limited to, those derived from the following polymeric acids: tannic acid, carboxymethyl cellulose. It may be convenient or desirable to prepare, purify, and/or handle a corresponding solvate of the active compound. The term "solvate" is used herein in the conventional sense to refer to a complex of solute (e.g., active compound, salt of active compound) and solvent. If the solvent is water, the solvate may be conveniently referred to as a hydrate, for example, a mono-hydrate, a di-hydrate, a tri-hydrate, etc. It may be convenient or desirable to prepare, purify, and/or handle the active compound in a chemically protected form. The term ^chemically protected form" is used herein in the conventional chemical sense and pertains to a compound in which one or more reactive functional groups are protected from undesirable chemical reactions under specified conditions (e.g. pH, temperature, radiation, solvent, and the like). In practice, well known chemical methods are employed to reversibly render unreactive a functional group, which otherwise would be reactive, under specified conditions. In a chemically protected form, one or more reactive functional groups are in the form of a protected or protecting group (also known as a masked or masking group or a blocked or blocking group). By protecting a reactive functional group, reactions involving other unprotected reactive functional groups can be performed, without affecting the protected group; the protecting group may be removed, usually in a subsequent step, without substantially affecting the remainder of the molecule. See, for example, Protective Groups in Organic Synthesis (T. Green and P. Wuts; 3rd Edition; John Wiley and Sons, 1999) . A wide variety of such "protecting", "blocking", or '"masking" methods are widely used and well known in organic synthesis. For example, a compound which has two nonequ'ivalent reactive functional groups, both of which would be reactive under specified conditions, may be derivatized to render one of the functional groups "protected," and therefore unreactive, under the specified conditions; so protected, the compound may be used as a reactant which has effectively only one reactive functional group. After the desired reaction (involving the other functional group) is complete, the protected group may be "deprotected" to return it to its original functionality. For example, a hydroxy group may be protected as an ether (-OR) or an ester (-OC(=0)R), for example, as: a t-butyl ether; a benzyl, benzhydryl (diphenylmethyl), or trityl (triphenylmethyl) ether; a trimethylsilyl or t-butyldimethylsilyl ether; or an acetyl ester (-OC(=O)CH3, -OAc). For example, an aldehyde or ketone group may be protected as an acetal (R-CH(OR)2) or ketal (R2C(OR)2), respectively, in which the carbonyl group (>C=0) is converted to a diether (>C(OR)2), by reaction with, for example, a primary alcohol. The aldehyde or ketone group is readily regenerated by hydrolysis using a large excess of water in the presence of acid. For example, an amine group may be protected, for example, as an amide (-NRCO-R) or a urethane (-NRCO-OR), for example, as: an acetamide (-NHCO-CH3) ; a benzyloxy amide (-NHCO-OCH2C6H5, -NH-Cbz) ; as a t-butoxy amide (-NHCO-OC (CH3) 3, -NH-Boc) ,- a 2-biphenyl-2-propoxy amide (-NHCO-OC^CHsJzCeH/jCeHs, -NH-Bpoc) , as a 9-fluorenylmethoxy amide (-NH-Fmoc) , as a 6-nitroveratryloxy amide (-NH-Nvoc), as a 2-trimethylsilylethyloxy amide (-NH-Teoc), as a 2,2,2-trichloroethyloxy amide (-NH-Troc), as an allyloxy amide (-NH-Alloc) , as a 2(-phenylsulfonyl)ethyloxy amide (-NH-Psec); or, in suitable cases (e.g., cyclic amines), as a nitroxide radical (>N-O) . For example, a carboxylic acid group may be protected as an ester for example, as: an Ci-7 alkyl ester (e.g., a methyl ester; a t-butyl ester); a Ci_7 haloalkyl ester (e.g., a CI-T trihaloalkyl ester) ; a triCi-7 alkylsilyl-Ci-7 alkyl ester; or a C5_2o aryl-Ci-? alkyl ester (e.g. a benzyl ester; a nitrobenzyl ester); or as an amide, for example, as a methyl amide. For example, a thiol group may be protected as a thioether (-SR) , for example, as: a benzyl thioether; an acetamidomethyl ether (-S-CH2NHC(=0)CH3) . The term ""treatment", as used herein in the context of treating a condition, pertains generally to treatment and therapy, whether of a human or an animal (e.g. in veterinary applications), in which some desired therapeutic effect is achieved, for example, the inhibition of the progress of the condition, and includes a reduction in the rate of progress, a halt in the rate of progress, amelioration of the condition, and cure of the condition. Treatment as a prophylactic measure (i.e. prophylaxis) is also included. The term "therapeutically-effective amount", as used herein, pertains to that amount of an active compound, or a material, composition or dosage form comprising an active compound, which is effective for producing some desired therapeutic effect, commensurate with a reasonable benefit/risk ratio, when administered in accordance with a desired treatment regimen. Suitable dose ranges will typically be in the range of from 0.01 to 20 mg/kg/day, preferably from 0.1 to 10 mg/kg/day. Compositions and their administration Compositions may be formulated for any suitable route and means of administration. Pharmaceutically acceptable carriers or diluents include those used in formulations suitable for oral, rectal, nasal, topical (including buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural) administration. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Such methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients. In general the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product. For solid compositions, conventional non-toxic solid carriers include, for example, pharmaceutical grades of mannitol, lactose, cellulose, cellulose derivatives, starch, magnesium stearate, sodium saccharin, talcum, glucose, sucrose, magnesium carbonate, and the like may be used. The active compound as defined above may be formulated as suppositories using, for example, polyalkylene glycols, acetylated triglycerides and the like, as the carrier. Liquid pharmaceutically administrable compositions can, for example, be prepared by dissolving, dispersing, etc, an active compound as defined above and optional pharmaceutical adjuvants in a carrier, such as, for example, water, saline aqueous dextrose, glycerol, ethanol, and the like, to thereby form a solution or suspension. If desired, the pharmaceutical composition to be administered may also contain minor amounts of non-toxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents and the like, for example, sodium acetate, sorbitan monolaurate, triethanolamine sodium acetate, sorbitan monolaurate, triethanolamine oleate, etc. Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example, see Remington's Pharmaceutical Sciences, 20th edition, pub. Lippincott, Williams & Wilkins, 2000. The composition or formulation to be administered will, in any event, contain a quantity of the active compound(s) in an amount effective to alleviate the symptoms of the subject being treated. Dosage forms or compositions containing active ingredient in the range of 0.25 to 95% with the balance made up from non-toxic carrier may be prepared. For oral administration, a pharmaceutically acceptable non-toxic composition is formed by the incorporation of any of the normally employed excipients, such as, for example, pharmaceutical grades of mannitol, lactose, cellulose, cellulose derivatives, sodium crosscarmellose, starch, magnesium stearate, sodium saccharin, talcum, glucose, sucrose, magnesium carbonate, and the like. Such compositions take the form of solutions, suspensions, tablets, pills, capsules, powders, sustained release formulations and the like. Such compositions may contain l%-95% active ingredient, more preferably 2-50%, most preferably 5-8%. Parenteral administration is generally characterized by injection, either subcutaneously,.intramuscularly or intravenously. Injectables can be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for solution or suspension in liquid prior to injection, or as emulsions. Suitable excipients are, for example, water, saline, dextrose, glycerol, ethanol or the like. In addition, if desired, the pharmaceutical compositions to be administered may also contain minor amounts of non-toxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents and the like, such as for example, sodium acetate, sorbitan monolaurate, triethanolamine oleate, triethanolamine sodium acetate, etc. The percentage of active compound contained in such parental compositions is highly dependent on the specific nature thereof, as well as the activity of the compound and the needs of the subject. However, percentages of active ingredient of 0.1% to 10% in solution are employable, and will be higher if the composition is a solid which will be subsequently diluted to the above percentages. Preferably, the composition will comprise 0.2-2% of the active agent in solution. Acronyms For convenience, many chemical moieties are represented using well known abbreviations, including but not limited to, methyl (Me), ethyl (Et), n-propyl (nPr), iso-propyl (iPr), n-butyl (nBu), sec-butyl (sBu), iso-butyl (iBu), tert-butyl (tBu), n-hexyl (nHex), cyclohexyl (cHex), phenyl (Ph), biphenyl (biPh), benzyl (Bn), naphthyl (naph), methoxy (MeO), ethoxy (EtO), benzoyl (Bz), and acetyl (Ac) . For convenience, many chemical compounds are represented using well known abbreviations, including but not limited to, methanol (MeOH), ethanol (EtOH), iso-propanol (i-PrOH), methyl ethyl ketone (MEK), ether or diethyl ether (Et20), acetic acid (AcOH), dichloromethane {methylene chloride, DCM), acetonitrile (ACN), trifluoroacetic acid (TFA), dimethylformamide (DMF), tetrahydrofuran (THF), and dimethylsulfoxide (DMSO) . General Synthesis Methods Compounds of the invention wherein R5 is of formula (II): (Figure Removed) may be synthesised from the analogous compound of the invention wherein R5 is carboxy, by reaction with a compound of formula 1: O in basic conditions, preferably aided by a coupling agent, for example, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride. Compounds of the invention wherein R5 is of formula (III): I Omay be synthesized from a compound of formula 2: by reaction with a compound of formula 3 (Figure Removed) wherein X is either OH or halo, where if X is OH, the use of basic conditions and a coupling agent is preferred. Compounds of formulae (1) and 2, or where the group -A-R5 is present as a precursor or protected form, may be represented as compounds of formula 4: (Figure Removed) where R6 is -A-R5 or its precursor or protected form. The protecting groups used may be conventional, or the group may be resin-bound. If Y is v - (CH2) n-0- or -(CH2)n-S-, then these compounds can be synthesised from compounds of formula 5: (Figure Removed) by one of two possible routes. In the first route, a compound of formula 6: R?—X'H Formula 6 , where X' is S or 0, is coupled to a compound of formula 5 using the Mitsunobu reaction, for example by treatment with triphenyl phosphine (PhaP) and diisopropylazodicarboxylate (DIAD) . The second route is a two stage route, the first stage being the Mitsunobu coupling of a compound of formula 7a: Hal—Ar-X'H Formula 7a wherein Ar1 is the first Ce aryl component of R3 and Hal is I or Br followed by a Suzuki coupling of a compound of formula 8a (or equivalent ester of formula 8c) : (Figure Removed) wherein Ar2 is the second Ce aryl component of R3. The Suzuki coupling may be achieved using, for example, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II) as the palladium catalyst. This route may also be 'reversed' such that the Mitsunobu coupling is of a boronic acid of formula 7b (or preferably equivalent ester of formula 7c): (Figure Removed) wherein Ar1 is the first Ce aryl component of R3, followed by a Suzuki coupling of a compound of formula 8b: Ar2—Hal Formula 8b wherein Ar2 is the second C6 aryl component of R3 and Hal is I or Br. If the compound of formula 7b or 7c is not readily available then a compound of formula 7d: HX1—Ar-Br Formula 7d may be coupled, followed by conversion of the brorno group to the required boronic acid or ester. Compounds of formula 4 where Y is -(CH2)n-NH- can also be synthesized from compounds of formula 5. In one method, the alcohols of formula 5 are oxidized to the corresponding aldehyde, for example using the Dess-Martin reagent, followed by reductive coupling to an amine, which may be of formula 6': R3—NH2 Formulae1 or of formula la', 7b' or 7c': Hal—ArLNH2 Formula 7a' H2N-ArLB(OH)? Formula 7b(Figure Removed) for subsequent Suzuki coupling. The reductive coupling can be carried out using sodium cyanoborohydride. 37 In another method, the alcohol of formula 5 is converted to the corresponding halide, using a halogenating reagent , for example conversion to chlorine using 4-methyl-benzene sulfonyl chloride, followed by coupling to an amine which may be of formula 6', or of formula 7a', 7b' or 7c' for subsequent Suzuki coupling. The amine coupling is carried out in the presence of potassium iodide, or equivalent reagents. This method can also be used to couple alcohols and thiols of formulae 6, 7a, 7b and 7d, where X' is 0 or S. Compounds of formula 4: (Figure Removed) where Y is -C(=0)-NRm- may be synthesised from a compound of formula 9: (Figure Removed) by reaction with a amine of formula 10: (Figure Removed) in basic conditions, preferably with the aid of a coupling agent. (Figure Removed) Compounds of formula (I) where A is a single bond, and R5 is carboxy, and compounds where the group -Y-R3 is present as a precursor or protected form, may be represented as compounds of formula 12: where R7 is -Y-R3 or its precursor or protected form. These compounds may be synthesised from compounds of formula 13: (Figure Removed) by treatment with n-butyllithium, followed by carbon dioxide at low temperatures. In a similar fashion, compounds of formula 2 where A is a single bond, and R5 is carboxy, and compounds where the qroup -Y-R3 is present as a precursor or protected form, may be represented as compounds of formula 14: (Figure Removed) where R7 is -Y-R3 or its precursor or protected form. These compounds may be synthesised from compounds of formula 13: (Figure Removed) by treatment with a strong base and sulphur dioxide at low temperatures, followed by amination. Compounds of formula (I) where A is a -C2H4-, and R5 is carboxy, and compounds where the group -Y-R3 is present as a precursor or protected form, may be represented as compounds of formula 15: (Figure Removed) where R7 is -Y-R3 or its precursor or protected form. These compounds may be synthesised from compounds of formula 16: (Figure Removed) by hydrogenation, using a palladium catalyst. Compounds of formula 16 may be synthesised from compounds of formula 17: (Figure Removed) by the Wittig coupling of an acetic ester, using, for example, triethylphosphonoacetate as the Wittig reagent, followed by hydolysis under alkaline conditions, e.g. lithium hydroxide in a suitable solvent, e.g. aqueous alcohol. Compounds of formula 17 may also be used to synthesise compounds of formula 18: (Figure Removed) where R2 and R7 are as defined above. The reaction proceeds via a cyano intermediate which may be obtained by treating compounds of formula 17 with hydroxylamine to form the oxime derivative, which can be dehydrated to the cyano compound with, for example, 2-chloro-l,3-dimethylimidazolium chloride in the presence of a base. The cyano intermediate can be converted into compounds of formula 18 by treatment with sodium azide, in the presence of a base. Compounds where Y is - (CH2)n-S (=0) - and - (CH2)n-S (=0) 2- may be obtained from the corresponding compound where Y is -(CH2)n~S- by oxidation with a peracid, for example 3-chloro-benzenecarboperoxoic acid. Compounds where Y is - (CH2)n-NRN1- may be obtained from the corresponding compound where Y is -(CH2)n-NH- by direction alkylation by RN11, in the presence of a weak base. The starting materials described above are generally commercially available or synthesisable using known methods. For example, example 22A below describes a method of synthesizing 2-substitued furans. Some of the reaction steps described above may be carried out using resins, as is shown in the examples. Preferences The following preferences may be combined with one another, and may be different for each aspect of the present invention. R2 is preferably selected from H or an optionally substituted Ci_3 alkyl group, more preferably H, methyl, CFj or iso-propyl, and most preferably R2 is a- a methyl group. Y is preferably -(CH2)n-X-, and n is preferably 1. X is preferably 0, S or NH, with NH being the most preferred. In some embodiments the preferred option for Y is -CH2-0-. If Y is -C(=0)NRN2-, then RN2 is preferably selected from H, and optionally substituted Ci_4 alkyl, in particular Me. The C6 aryl groups of R3 are preferably independently selected from those derived from benzene and heteroaryl groups, where the heteroatom or heteroatoms are nitrogen. Most preferred are Cg aryl groups derived from benzene, pyridine and 1,3-pyrimidine. It is further preferred that either both Ce aryl groups are derived from benzene or that one group is derived from benzene and the other from pyridine or 1, 3-pyrimidine, with pyridine being preferred, especially as the aryl group furthest from the furan core. If both Ce aryl groups are derived from benzene, it is preferred that there is not an oxygen bridge between the two rings, bound adjacent the link on both rings, i.e. that Ra is optionally substituted biphenyl rather than optionally substituted dibenzofuranyl. If one or more of the Ce aryl groups is derived frcm pyridine, then it is preferred that the nitrogen ring atom is adjacent the link between the two rings that make up the R3 group. If one or more of the Ce aryl groups is derived from 1,3-pyrimidine, then it is preferred that the link between the two rings that make up the R3 group is between the two nitrogen atoms. It is further preferred that that the single bond joining the two Ce aryl groups is in the 4-position of the ring bound to Y. Thus, 4-phenyl-phenyl is preferred to 3-phenyl-phenyl; dibenzofuran-3-yl is preferred to di-benzofuran-2-yl, 4-pyridin-2-yl-phenyl is preferred to 3-pyridin-2-yl-phenyl and 6-phenyl-pyridin-3-yl is preferred to 6-phenyl-pyridin-2-yl: (Figure Removed) Both C& aryl groups of R3 are optionally substituted, although it is preferred that only the Cg aryl group not bound to Y is substituted. Preferred substituents on the Ce aryls of R3 include, but are not limited to: optionally substituted Ci-? alkyl groups, more preferably methyl and substituted C!_4 alkyl groups, e.g. -CFa, CH2OH; Ci-7 alkoxy groups, more preferably GI--J alkoxy groups, e.g. OMe, -OCF3, -OEt, -OCHF2; Ci--, thioether group, more preferably Cx-4 thioether group, e.g. -SMe; amino groups, optionally substituted by one or two Ci-4 alkyl groups, e.g. -NMe2/ halo groups, more preferably -F or -Cl; cyano; alkoxylene groups, more preferably -0-r'H2-0-; Ci-4 acyl groups, more preferably -C(=O)Me. The preferred location for a substituent on the Ce aryl group not bound to Y is para to the bond between the two aryl groups, with the meta position being less preferred. Therefore, if R3 is 4-phenyl-phenyl, the substituent is preferably at the 4'-position. In some embodiments of the present invention A is.preferably a single bond, whereas in other embodiments A is preferably a Ci-s alkylene group. In particular, when R5 is carboxy, A is more preferably a Ci-3 alkylene group, with vinylene being most preferred. R5 is preferably either: (i) a group of formula (II): (Figure Removed) with a group of formula (II) being more preferred. The above preference for R5 is particularly applicable when R2 is methyl and Y is -CH2-0-. Where R5 is of formula (II) of (III), R is preferably selected from an optionally substituted CS-ZQ aryl group, and an optionally substituted C5_2o aryl-Ci-7 alkyl group, wherein the Ci_7 alkyl group is more preferably methyl. In these groups the C5_2o aryl group is preferably a heteroaryl group, itself preferably having a single aromatic ring. Such groups may preferably be substituted with Ci_4 alkyl groups, such as methyl and hydroxy. Thus, preferred R groups include, but are not limited to: phenyl; benzyl; 3,5, dimethyl-isoxazol-4-yl; thiophen-2-yl; 5-methyl-pyridin-yl; and 4~hydroxy-phenyl. If R in formula (II) or (III) is a Ci_7 alkyl group, it is more preferably a Ci_4 alkyl group, for example methyl or propyl. Particularly preferred compounds of the present invention include: 4- (4'-Methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carboxylic acid (4); N-[4-(4'-Methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carbonyl]-benzenesulfonamide (5); N- [4-(4'-Methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carbonyl]-C-phenyl-methanesulfonamide (6); N- [4-(4'-Methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carbonyl]-methanesulfonamide (7); Propane-1-sulfonic acid [4-(4'-methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carbonyl]—amide (8)/ 3, 5-D_imethyl-isoxazole-4-sulfonic acid [4- (4 ' -methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan~2-carbonyl]-amide (9); Thiophene-2-sulfonic acid [4-(4'-methoxy-biphenyl-4-yloxymethyl) -5-methyl-furan-2--carbonyl] -amide (10) ; 5-Methyl-pyridyl-2-sulfonic acid [4-(4'-methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carbonyl]-amide (11); 4-Aminomethyl-N-[4- (4'-methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carbonyl]-benzenesulfonamide (trifluoroacetate salt) (12); 4-Hydroxy-W-[4-(4'-methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carbonyl]-benzenesulfonamide (13); 4-(Biphenyl-4-yloxymethyl)-5-methyl-furan-2-carboxylic acid (18); N- [4-(Biphenyl-4-yloxymethyl)-5-methyl-furan-2-carbonyl]- benzenesulfonamide (19); 4-(4'-Acetyl-biphenyl-4-yloxymethyl)-5-methyl-furan-2- carboxylic acid (21); N- [4-(4'-Acetyl-biphenyl-4-yloxymethyl)-5-methyl-furan-2- carbonyl]-benzenesulfonamide (22) ; 4- (4'-Methoxy-biphenyl-4-ylcarbamoyl)-5-methyl-furan-2- carboxylic acid (24) ; 5-Benzenesulfonylaminocarbohyl-2-methyl-furan-3-carboxylic acid (4'-roethoxy-biphenyl-4-yl)-amide (25); 4-(4'-Chloro-biphenyl-4-yloxymethyl)-5-methyl-furan-2- carboxylic acid (27); 4-(4-Benzo[1,3]dioxol-5-yl-phenoxymethyl)-5-methyl-iuran-2- carboxylic acid (28); [4-(Biphenyl-4-yloxymethyl)-5-methyl-furan-2-yl]-acetic acid (31) ; 4-(4'-Methoxy-biphenyi-4-yloxymethyl)-5-methyl-furan-2-yl]- acetic acid (32)/ 3- [4- (Biphenyl-4-yloxyrr\ethyl) -5-methyl-furan-2-yl] -propionic acid (37); N-{3-[4-(Biphenyl-4-yloxymethyl) -5-methyl-furan-2-yl]- propionyl)-benzene sulfonamide (38); 3- [4- ( 4 ' -Methoxy-biphenyl-4-yloxymethyl) -5-rnethyl-furan-2- yl]-propionic acid (39); N~ {3-[4-(4'-Methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan- 2-yl]-propionyl)-benzene sulfonamide (40); 3-[4-(Biphenyl-4-yloxymethyl)-5-methyl-furan-2-yl]-acrylic acid (42); 3-[4-(4'-Methoxy-biphenyl-4-yloxymethyl)-5-methyl-furari-2- yl]-acrylic acid (43); 4-(Biphenyl-4-yloxymethyl)-5-methyl-furan-2-sulfonic acid benzoylamide (46) ; 4-(4'-Methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2- sulfonic acid benzoylamide (49); 4-(Dibenzofuran-3-yloxymethyl)-5-methyl-furan-2-carboxylic acid (50); 4-[4-(5-Methoxy-pyridin-2-yl)-phenoxymethyl]-5-methyl-furan- 2-carboxylic acid (53); 4-[6-(4-Methoxy-phenyl)-pyridin-3-yloxymethyl]-5-methyl- furan-2-carboxylic acid (56) ; 4-(4'-Cyano-biphenyl-4-yloxymethyl)-5-methyl-furan-2- carboxylic acid (57); 3-Morpholin-4-yl-propane-l-sulphonic acid [4-(4'-methoxy- biphenyl-4-yloxymethyl)-5-methyl-furan-2-carbonyl]-amide (59); N-[4-(Biphenyl-4-yloxymethyl)-5-methyl-furan-2-carbonyl]-2- methyl-benzenesulphonamide (60); 4-(Biphenyl-4-yloxymethyl)-5-methyl-furan-2-sulfonic acid butyryl-amide (61); 4-(Biphenyl-4-yloxyraethyl)-5-methyl -furan-2-sulfonic acid phenylacetyl-amide (62); 4-(Biphenyl-4-yloxymethyl)-5-methyl-furan-2-sulfonic acid (3,5-dimethyl-isoxazole-4-carbonyl)-amide (63); 4-(Biphenyl-4-yloxymethyl)-5-methyl-furan-2~sulfonic acid (thiophene-2-carbonyl)-amide (64); 4- (Biphenyl-'l-yloxymethyl) -5-methyl-furan-2-sulfonic acid (3-methoxy-propionyl)-amide (65); 4-(Biphenyl-4-yloxymethyl)-5-methyl-furan-2-sulfonic acid (pyridin 3-yl-acetyl)-amide (66)/ 4-(Biphenyl-4-yloxymethyl)-5-methyl-furan-2-sulfonic acid (pyridine-4-carbonyl)-amide (67); 4-(Biphenyl-4-yloxymethyl)-5-methyl-furan-2-sulfonic acid (pyridine-3-carbonyl)-amide (68);4-(4'-Methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2- sulfonic acid (3,5-dimethyl-isoxazole-4-carbonyl)- amide (69); 4-12-(Biphenyl-4-yloxy)-ethyl]-5-methyl-furan-2-carboxylic acid (72); 4-[2-(4'-Methoxy-biphenyl-4-yloxy)-ethyl]-5-methyl-furan-2- carboxylic acid (73); 4-[2-(Dibenzofuran-3-yloxy)-ethyl]-5-methyl-furan-2- carboxylic acid (74); 4-(Biphenyl-4-yloxyrnethyl)-furan-2-carboxylic acid (77); 4-(Dibenzofuran-2-yloxymethyl)-furan-2-carboxylic acid (78); 4-(4'-Cyano-biphenyl-4-yloxymethyl)-furan-2-carboxylic acid (79); 4-(4'-Methoxy-biphenyl-4-yloxymethyl)-furan-2-carboxylic acid (80); 4-(Dibenzofuran-3-yloxyrnethyl)-fur'an-2-carboxylic acid (81); 4-(Biphenyl-4-yloxymethyl)-5-isopropyl~furan-2-carboxylic acid (85); 5-Isopropyl-4-(4'-methoxy-biphenyl-4-yloxymethyl)-furan-2- carboxylic acid (86) ; 4-(Dibenzofuran-3-yloxymethyl)-5-isopropyl-furan-2- carboxylic acid (87); 4-(Biphenyl-4-yloxymethyl)-5-trifluoromethyl-furan-2- carboxylic acid (90); 4- (Biphenyl-3-yloxymethyl) -5-trif luorornethyl-furan-2- carboxylic acid (91); 4-(Dibenzofuran-2-yloxymethyl)-5-trifluoromethyl-furan-2- carboxylic acid (92); 4 - (4 ' -Cyano-biphenyl-4-yloxymethyl) -5-trif luororaethyl-furan-2-carboxylic acid (93); 4-(4'-Methoxy-biphenyl-4-yloxymethyl)-5-trifluoromethyl- furan-2-carboxylic acid (94) ; 4-(Dibenzofuran-3-yloxymethyl)-5-trifluoromethyl-furan-2- carboxylic acid (95); 4-(3, 4'-Dimethoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carboxylic acid (96); 4-(4'-Ethoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carboxylic acid (98); 4-(2'-Chloro-bipbenyl-4-yloxymethyl)-5-methyl-furan-2-carboxylic acid (99); 4-(2',6'-Difluoro-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carboxylic acid (100); 5-Methyl-4-(2'-trifluoromethyl-biphenyl-4-yloxymethyl)-furan-2-carboxylic acid (102); 4- (3' -Fluoro-biphenyl-4-yloxymethyl) -5-inethyl-furan-2-carboxylic acid (104); 5-Methyl-4-(2'-methylsulfanyl-biphenyl-4-yloxymethyl)-furan-2-carboxylic acid (105); 4-(3',4'-Dimethoxy-biphenyl-3-yloxymethyl)-5-methyl-furan-2-carboxylic acid (108); 5-Methyl-4-(3'-trifluoromethyl-biphenyl-3-yloxymethyl)-furan-2-carboxylic acid (109); 4-(4'-Hydroxyraethyl-biphenyl-4-yloxymethyl)-5~methyl-furan-2-carboxylic acid (110); 5-Methyl-4-(4'-methylsulfanyl-biphenyl-4-yloxymethyl)-furan-2-carboxylic acid (111); 4-(3'-Hydroxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carboxylic acid (112); 4-(4'-Dimethylamino-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carboxylic acid (113); 5-Methyl-4-(4'-trifluoromethoxy-biphenyl-4-yloxymethyl)-furan-2-carboxylic acid (114); 5-Methyl-4- (2 ' -trif luorornethoxy-biphenyl-4-yloxymethyl) -furan-2-carboxylic acid (115); 4-(3'-Methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carboxylic acid (116) ;4- (3'-Acetyl-biphenyl-4-yloxymethyl)-5-methyl-furan-2- carboxylic acid (117); 4-(4'-Fluoro-biphenyl-4-yloxymethyl)-5-methyl-furan-2- carboxylic acid (118); N-4-(4'-Methoxy-biphen-4-yloxymethyl)-5-methyl-furan-2- carbonyl]-dimethylaminosulphonamide (122); 4-(2'-Methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2- carboxylic acid (126); N-[4- (2'-Methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2- carbonyl]-benzenesulfonamide (127); 4-(4'-Difluoromethoxy-biphenyl-4-yloxymethyl)-5-methyl- furan-2-carboxylic acid (129); NJ- [4- (4 ' -Dif luoromethoxy-biphenyl-4-yloxyroethyl) -5-methyl- furan-2-carbonyl]-benzenesulfonamide (130); 3,5-Dimethyl-isoxazole-4-sulfonic acid [4-(4'~ difluoromethoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2- carbonyl]-amide (131); N-{4-[4-(5-Methoxy-pyridin-2-yl) -phenoxymethyl]-5-methyl- furan-2-carbonyl}-benzenesulfonamide (132); 3,5-Dimethyl-isoxazole-4-sulfonic acid {4-[4-(5-methoxy- pyridin-2-yl)-phenoxymethyl]-5-methyl-furan-2-carbonyl}- amide (133); N-{4-[4-(5-Methoxy-pyridin-2~yl) - phenoxymethyl]-5-methyl- furan-2-carbonyl}-2-methyl-benzenesulfonamide (134); N-{4- [4- (5-Methoxy-l-oxy-pyridin-2-yl)-phenoxymethyl]-5- methyl-furan-2-carbonyl)-benzenesulfonamide (135); 5-Methyl-4-(4-pyrimidin-2-yl-phenoxymethyl)-furan-2- carboxylic acid (137); N- 15-Methyl-4- (4-pyrimidin-2-yl-phenoxyn\ethyl) -furan-2- carbonyl]-benzenesulfonamide (138); 4- (2 ' ,4'-Dimethoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2- carboxylic acid (140); N-[4- (2',4'-Dimethoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carbonyl]-benzenesulfonamide (141); 3,5-Dimethyl-isoxazole-4-sulfonic acid [4-(2', 4 '-dimethoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carbonyl]-amide (142); 4_ (4 i -Methoxy-2'-methyl-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carboxylic acid (144); N- [4- (4'-Methoxy-2'-methyl-biphenyl-4-yloxyinethyl)-5-methyl-furan-2-carbonyl]-benzenesulfonamide (145); 3,5-Dimethyl-isoxazole-4-sulfonic acid [4-(4'-methoxy-2'-methyl-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carbonyl]-amide (146); 5-[4-(Biphenyl-4-yloxymethyl)-5-methyl-furan-2-yl]-lH-tetrazole (149); 4- (4 ' -Dif luoromethoxy-biphenyl-4-ylsulfanylrnethyl) -5-methyl-furan-2-carboxylic acid (153); N-[4- (4'-Difluoromethoxy-biphenyl-4-ylsulfanylmethyl)-5-methyl-furan-2-carbonyl]-2-methyl-benzenesulfonamide (154); N-[4-(4'-Difluoromethoxy-biphenyl-4-ylsulfanylmethyl)-5-methyl-furan-2-carbonyl]-benzenesulfonamide (155); N-[4-(4'-Difluoromethoxy-biphenyl-4-sulfinylmethyl)-5-methyl-furan-2-carbonyl] -2-methyl-benzenesulfonarnide (156) ; N- [4- (4'-Difluoromethoxy-biphenyl-4-sulfonylmethyl)-5-methyl-furan-2-carbonyl]-2-methyl-benzenesulfonamide (156a); 4-(Biphenyl-4-ylaminomethyl)~5-methyl-furan-2-carboxylic acid (160); N-[4-(Biphenyl-4-ylaminomethyl)-5-methyl-furan-2-carbonyl]-benzenesulfonamide (161); N-[4-(Biphenyl-4-ylaminomethyl)-5-methyl-furan-2-carbonyl]-2-xnethyl-benzenesulfonamide (162) ; N- (4-{[4-(5-Methoxy-pyridin-2-yl)-phenylamino]-methyl)-5-methyl-furan-2-carbonyl)-2-methyl-benzenesulfonamide (167); 4-[(4'-Difluoromethoxy-biphenyl 4-ylamino)-methyl]-5-methyl-furan-2-carboxylic acid (171);N-{4-[(4'-Difluoromethoxy-biphenyl-4-ylamino)-methyl]-5- methyl-furan-2-carbonyl}-benzenesulfonamide (172); N-{4-[(4'-Difluoromethoxy-biphenyl-4-ylamino)-methyl]-5- methyl-furan-2-carbonyl}-2-methyl-benzenesulfonamide (173); 3,5-Dimethyl-isoxazole-4-sulfonic acid {4-[(4'- difluoromethoxy-biphenyl-4-ylamino)-methyl]-5-methyl-furan- 2-carbonyl)-amide (174); 4-{[(A '-Difluoromethoxy-biphenyl-4-yl)-methyl-amino]- methyl}-5-methyl-furan-2-carboxylic acid (176); and N-(4-{[(4'-Difluoromethoxy-biphenyl-4-yl)-methyl-amino]- methyl}-5-methyl-furan-2-carbonyl)-2-methyl- benzenesulfonamide (177). The selectivity of the compound for antagonising EP4 receptors over the other EP receptors (i.e. EPi, EP2, EPa) can be quantified by dividing the -Ki for E?4 (see below) by the Ki for the other EP receptors (see below). The resulting ratio is preferably 10 or more, more preferably 100 or more. Synthesis Examples General Experimental Details All reactions were carried out under an inert atmosphere of nitrogen. Where products were purified by flash chromatography the stationary phase used was silica gel for chromatography, 0.035 to 0.070 mm (220 to 440 mesh) (e.g. Fluka silica gel 60). An applied pressure of nitrogen of ~10 psi was used to accelerate column elution. Thin layer chromatography (TLC) was carried out on aluminium foil plates coated with silica gel containing a fluorescent indicator (254 nm) (e.g. Fluka Petroleum ether refers to that fraction with a boiling point of 40-60°C. Organic solutions were dried over magnesium sulphate unless otherwise specified. PS-TsCl refers to Polystyrene scavenger resin (loading 1.97 mmol/g) - Argonaut Technologies (P/N 800277) Preparative HPLC System Preparative HPLC was carried out on a CIS-reverse-phase column (10 x 2.1 cm i.d Genesis column with 7 urn particle size), eluting with a gradient of acetonitrile (containing 0.1% trifluoroacetic acid) and water (containing 0.1% trifluoroacetic acid) at a flow rate of 5 ml/min. UV detection at 230 nm was used unless otherwise stated. LC/MS Systems The Liquid Chromatography Mass Spectroscopy (LC/MS) systems used are as follows. LC/MS System A: Mass Spectrometer - Platform LC with electrospray source operating in positive and negative Ion mode. HP1100 system running at 2.0 mL/min, 200 uL/min split to the ESI source with inline HP1100 DAD detection .and SEDEX ELS detection. Mobile Phase A) Water 0.1 % Formic Acid B) acetonitrile 0.1% Formic Acid (Table Removed) Column - Luna 3u CIS (2) 30x4.6mm LC/MS System B: Mass Spectrometer - Platform II with electrospray source operating in negative ion mode. HP1100 system running at 2.0 mL/min, 200 uL/min split to the ESI source with inline HP1100 DAD detection and SEDEX ELS detection. Mobile Phase A) Water 0.1 % Diethylamine B) acetonitrile Gradient Table Removed) LCMS System C: Mass Spectrometer - Finnigan TSQ700 with electrospray source operating in negative ion mode. HP1050 system running at 2.0 mL/min, 200 uL/min split to the ESI source with inline HP1050 Single wavelength UV detector at 254 nm. Mobile Phase A) Water 0.1 % Diethylamine Acetonitrile (Table Removed)Column - XTerra MS C18 3.Sum 4.6 x 30mm LC/MS System D: Mass Spectrometer - Finnigan TSQ700 with electrospray source operating in positive or negative ion mode. HP1050 system running at 2.0 mL/min, 200 uL/min split to the ESI source with inline HP1050 Single Wavelength UV detector at 254 nm. Mobile Phase A) Water 0.1 % formic Acid B) acetonitrile 0.1% formic Acid (Table Removed) Column - Higgins Clipius CIS 5pm 100 x 3.0mm J# NMR system The aH NMR spectra were recorded on a Varian Unity Inova 400, which operates at 400 MHz for 1H. It is equipped with a 5nun inverse detection triple resonance probe for detection of H. The magnetic field is provided by a 9.4 Tesla Oxford instruments super-conducting magnet. The host computer is a Sun Microsystems SunBlade 1000 workstation. De-dimethylsulphoxide was used as solvent unless stated otherwise. Tetramethylsilane was used as internal standard. Coupling constants are reported in Hz. Example 1: Synthesis of 4-(4'-Methoxy-biphenyl-4-yloxymethyl)~5-methyl-furan-2-carboxylic acid (4), 4-(Dibenzofuran-3-yloxymethyl)-5-methyl-furan-2-carboxylic acid (50), 4-(Dibenzofuran-2-yloxymethyl)-5-methyl-furan-2-carboxylic acid (56) and 4- (4'-Cyano-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carboxylic acid (57) (a) 3-(tert-Butyl-diphenyl-silanyloxymethyl)-2-methyl-furan (2) (Figure Removed) A stirred solution of (2-methyl-3-furan-3-yl) -raethanol (1)(31.87 g) in N,N-dimethylformamide (250 mL) was treated simultaneously with t-butyldiphenylsilyl chloride (94 g) and imidazole (24 g) and stirring continued for 2 hours at room temperature. The reaction mixture was treated with 1.0 M hydrochloric acid (500 mL), and extracted with diethyl ether (3 x 500 mL). The combined organic extracts were washed successively with 1.0 M hydrochloric acid (500 mL), saturated sodium hydrogen carbonate (500 mL), then dried and concentrated in vacuo. The residue was purified by flash chromatography eluting with mixtures of diethyl ether in hexane (1:9 to 9:1 by volume) to give compound 2 as a clear oil (67.6 g). (b) 4-(tert-Butyl-diphenyl-silanyloxymethyl)- 5-methyl-furan-2-carboxylic acid (3) (Figure Removed) A solution of 3- (tert-Butyl-diphenyl-silanyloxymethyl) -2-methyl-furan (2) (30.0 g) in tetrahydrofuran (75 mL) was cooled to -78°C with stirring and treated drop-wise with a solution of n-butyllithium (2.5 M in hexanes, 71 mL) over 10 mins. The cooling bath was removed for 0.5 hours and then replaced. A large excess of solid carbon dioxide was added and the mixture allowed to warm to ambient temperature. The reaction mixture was acidified, with 1.0 M hydrochloric acid to pH 2 and extracted into diethyl ether (3 x 500 mL). The combined extracts were washed successively with 1.0 M hydrochloric acid (500 mL) , water (500 mL) , dried and concentrated in vacvo. The residue was purified by flash chromatography eluting with mixtures of diethyl ether in pentane (1:5 to 5:1 by volume) to give compound 3 as a yellow oil (10.36 g). LC/MS System A: Rt = 4.33 mins, m/z (ES~) = 393 (M~ for C23H2604Si) . (c) 4-(4' -Methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carboxylic acid (4) (Figure Removed) (i) 2-Chlorotrityl chloride resin (Ig of nominal loading 1.3 mmol/g) was swelled with dichloromethane (20 mL). After draining, a solution of 4-(tert-butyl-diphenyl-silanyloxymethyl)-5-methyl-furan-2~caiboxylic acid (3) (0.512 g) and diisopropylethylamine (0.91 mL) in dichloromethane (10 mL) was added and the mixture was shaken at ambient temperature for 16 hours. The resin was drained, washed sequentially with dichloromethane/triethylamine/methanol (20:1:3 by volume) (3 x 25 mL), dichloromethane (3 x 25 mL), N,N-dimethylformamide (2 x 25 mL), dichloromethane (6 x 25 mL) , and diethyl ether (2 x 25 mL) and then dried at 40°C in vacuo. (ii) The loaded resin from (i) (2.47 g) was swelled in tetrahydrofuran (15 mL), then treated tetrabutylammonium fluoride (12.8 mL of a 1 M solution in tetrahydrofuran) and shaken at room temperature for 16 hours. The resin was drained, washed sequentially with tetrahydrofuran/water (1:1 by volume), tetrahydrofuran, N,N-dimethylformamide, dichloromethane, diethyl ether, and then dried at 40°C in vacua. (iii) The loaded resin (2.83g) from (ii) was swelled in tetrahydrofuran (15 mL), and then treated with a solution of 4-hydroxy-4' -methoxydiphenyl (2.93 g) and triphenylphosphine (3.48 g) in tetrahydrofuran (20 mL), followed by the addition of diisopropylazodicarboxylate (2.96 g). The mixture was shaken at room temperature for 16 hours. The resin was drained, washed sequentially with tetrahydrofuran/water (1:1 by volume), tetrahydrofuran, N,N-dinvethylformamide, dichloromethane, and then dried at 45°C in vacua. The resin was treated with dichloromethane/trifluoroacetic acid (19:1. by volume) (20 mL) for 20 mins and the solution drained from the resin. This procedure was repeated. The combined solutions were concentrated in vacuo and the residue recrystallised from ethanol to afford compound 4 as a white solid (0.42 g). LC/MS System C: Rt = 4.00 mins, m/z (ES~) = 337 (M" for 4-(Dibenzofuran-3~yloxymethyl)-5-methyl-furan-2-carboxylic acid (50) (Figure Removed)Compound (50) was prepared by adapting the procedure of Example l(c). LC/MS System B: Rt = 1.79mins, m/z (ES~) = 321 ((M-H) for C19H1405) . (e) 4-(Dibenzofuran-2-yloxymethyl)-5~methyl-furan-2-carboxylic acid (56) (Figure Removed)Compound (56) was prepared by adapting the procedure of Example l(c). LC/MS System B: Rt = 1.76mins, m/z (ES~) - 321 ((M-H) for Ci9H1405) . (f) 4-(4'-Cyano-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carboxylic acid (57) (Figure Removed) Compound (57) was prepared by adapting the procedure of Example l(c). LC/MS System B: Rt = 1.72mins, m/z (ES~) = 332 ( (M-H) for C20Hi5NO4) . Example 2A: Synthesis of N- [4-(4'-Methoxy-biphenyl-4-yloxymethyl) ~5-methyl~furan-2-carbonyl] -benzenesulfonamide A stirred solution of 4-(4'-methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carboxylic acid (4) (250 mg) in dichloromethane (50 mL) was treated with l-{3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (142 mg) , 4-(N, N-dimethylamino)pyridine (2 mg) and benzenesulfonamide (232 mg). After 16 hours the reaction mixture was concentrated in vacuo, the residue dissolved in ethyl acetate (200 mL) and washed successively with water (20 mL) , 1.0 M hydrochloric acid (20 mL), saturated sodium hydrogen carbonate solution (20 mL) , brine (20 mL), dried and concentrated in vacuo. The crude product was purified by HPLC to afford compound 5 as a white solid (30 mg). LC/MS System D: Rt = 5.45 mins, m/z (ES") = 476 (M~ for By adapting the procedure of Example 2A and using the appropriate sulphonamide there were prepared Examples 2B to 2G: Example 2B: N- [4- (4 ' -Methoxy-biphenyl-4-yloxymethyl) -5-methyl-furan-2-carbonyl]-C-phenyl-methanesulfonamide (6) (Figure Removed) LC/MS System C: Rt = 5.37 mins, m/z (ES") = 490 (M" for C2-7H25N06S) . Example 2C: N- [4- (4 ' -Methoxy-biphenyl-4-yloxymethyl) -5-methyl-furan-2~carbonyl]-methanesulfonamide (7) - (Figure Removed) LC/MS System C: Rt C2iH2iN06S) . =4.50 mins, m/z (ES ) = 414 (M" for Example 2D: Propane-1-sulfonic acid [4-(4' -methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carbonyl]—amide (8) (Figure Removed) LC/MS System C: Rt = 4.78 mins, m/z (ES") = 442 (M~ for C23H25N06S) . Example 2E: 3,5-Dimethyl-isoxazole-4-sulfonic acid [4-(4' methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carbonyl] amide (9) (Figure Removed) LC/MS System C: Rt = 4.91 mins, m/z (ES") = 495 (M~ for Example 2F: Synthesis of Thiophene-2-sulfonic acid [4-(4'~ methoxy-biphenyl-4-yloxymethyl) -5-methyl-furan-2-carbonyl] - amide (10) (Figure Removed) LC/MS System C: Rt = 4.94 mins, m/z (ES~)= 482 (M~ for C24H21N06S2) . Example 2G: 5-Methyl-pyridyl-2-s-ulfonic acid [4-(4'-methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carbonyl]- amide (11) (Figure Removed) LC/MS System D: Rt C26H24N06S) .= 10.09 mins, m/z (ES+) = 493 (MH+ for xample 2H: Synthesis of 4-Aminomethyl-N-[4-(4'-methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carbonyl]-benzenesialfonamide trifluoroacetate (12) 4-(4'-Methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carboxylic acid (4) (50 mg) was reacted with (4-sulphamoyl-benzyl)-carbamic acid tert-butyl ester (85mg) in an analogous manner to that described in Example 2A. The intermediate tert-butyl carbamate was hydrolysed with 1% trifluoroacetic acid/dichloromethane over 24 hours, then concentrated in vacuo to give compound 12 as a white solid (10 mg) . LC/MS System C: Rt = 4.67 mins, m/z (ES~) = 493 (M" I for Example 21: Synthesis of 4-Hydroxy-N- [4-(4' -methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carbonyl]-benzenesulfonamide (13) (Figure Removed) 4-(4'-Methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carboxylic acid (4) (50 mg) was reacted with acetic acid 4-sulphamoyl-phenyl ester (64 mg) in an analogous manner to that described in Example 2A. The acetic ester intermediate was hydrolysed with sodium methoxide (80 mg) in a mixture of methanol (lOmL) and water (ImL) for 1 hour. The solution was concentrated in vacuo then partitioned between dichloromethane (10 mL) and water (10 mL) . The organic layer was washed with brine (10 mL), dried, filtered and concentrated in vacuo. The crude product was purified by preparative HPLC (starting at 30% acetonitrile and increasing at a rate of 1% per minute up to 98% acetonitrile) to give compound 13 as a white solid (15 mg). LC/MS System C: Rt = 3.50 mins, m/z (F,S~) = 492 (M" for Example 3: Synthesis of 4-(Biphenyl-4-yloxymethyl)-5-methyl-furan-2-carboxylic acid (18) (a) Triisopropyl- (2-methyl-furan-3-ylmethoxy) -silane (14) (Figure Removed)Triisopropyl-(2-methyl-furan-3-ylmethoxy)-silane was prepared from (2-methyl-furan-3-yl)-methanol (1)(24.22 g) in an analogous manner to that described in Example 1 to give compound 14 as a clear oil (54.0 g) . (b) 5-Methyl-4-triisopropylsilanyloxymethyl-furan-2-carJboxylic acid methyl ester (15) (Figure Removed) A solution of triisopropyl-(2-methyl-furan-3-ylmethoxy)-silane (14) (10.0 g) in tetrahydrofuran (300 mL) was cooled to -78°C with stirring was treated drop-wise with sec-butyllithium (3.0 M in cyclohexane, 37 mL). After 1 hour the reaction mixture was treated drop-wise with a solution of methyl chloroformate (5.2 g) in tetrahydrofuran (30 mL) over 10 mins and stirring was continued at -78°C for 1 hour. The reaction mixture was then treated with saturated ammonium chloride solution (300 mL) and allowed to warm to ambient temperature. The two layers were separated and the organic phase washed with brine (300 mL) , dried and concentrated in vacvo. The residue was purified by flash chromatography eluting with ethyl acetate/pentane (1:9 by volume) to give compound 15 as a clear oil. (c) 4-Hydroxymethyl-5-methyl-furan-2-carboxylic acid methyl ester (16) (Figure Removed) A stirred solution of 5-methyl-4- triisopropylsilanyloxymethyl-furan-2-carboxylic acid methyl ester (15) (5.2 g) in tetrahydrofuran (200 mL) was treated with tetrabutylammonium fluoride (1.0 M solution in tetrahydrofuran, 3.2 n\L) and stirring continued for 16 hours. The reaction mixture was concentrated in vacuo and the residue taken up in ethyl acetate (350 mL) and washed with water (150 mL) . The aqueous phase was re-extracted with ethyl acetate (2 x 100 mL) . The combined extracts were dried/ concentrated in vacuo and the residue was purified by flash chromatography eluting with ethyl acetate/pentane (1:1 by volume) to give compound 16 as a yellow oil. id) 4~ (Biphenyl-4-yloxymethyl) -5-jnethyI-furan-2-carboxylic acid methyl ester (17) (Figure Removed) A solution of 4-hydroxyinethyl-5-methyl-f uran-2-carboxylic acid methyl ester (16) (Ig) in anhydrous tetrahydrofuran (20mL) was cooled to Q°C under a nitrogen atmosphere. 4-Hydroxybiphenyl (3g) and triphenylphosphine (4.6lg) were added and the mixture was treated with di- isopropylazodicarboxylate (3.46mL) dropwise. The mixture was stirred at 0°C for lOmin then cooling was removed and the mixture stirred for a further 3 hours. The solvent was removed in vacuo and the residue was partitioned between ethyl acetate (50mL) and water (lOOmL). The organic phase was separated, dried and evaporated. The residue was purified by flash chromatography, eluting with pentane /ethyl acetate 9:1 by volume to give a mixture of the title compound and 4-hydroxybiphenyl (1.8g). This material was purified further by flash chromatography eluting with dichloromethane/methanol 99:1 by volume to give compound 17 as a white solid (200mg). LCMS System A: Rt = 4.2 mins. (e) 4~ (Biphenyl-4-yloxymethylJ-5-methyl-furan-2-carJboxylic acid (18) (Figure Removed) 1M Aqueous lithium hydroxide (18mL) was added to solution of 4-(biphenyl-4-yloxymethyl)-5~methyl-furan-2-carboxylic acid methyl ester (17) (Ig) in tetrahydrofuran/methanol (2:1 by volume, lOOmL) and the mixture stirred at room temperature for 5h. The solvent was removed in vacuo, the residue dissolved in water (20mL) and the solution acidified to pH£ with aqueouy dilute hydrochloric acid. The mixture was evaporated to dryness and the residue was purified by HPLC to afford compound 18 as a white solid (210mg). LC/MS System B: Rt = 4.80 mins, m/z = 307 ((M-l) for Ci9H1604) . Example 4: Synthesis of N- [4- (Biphenyl-4-yloxymethyl)-5-methyl-furan-2-carbonyl]-benzenesulfonamide (19) Compound (19) was prepared by adapting the procedure of Example 2A. LC/MS System D: Rt = 9.18mins, m/z (ES") = 446 (M" for C25H2iNO5S) . Example 5: Synthesis of 4-(4'-Acetyl-biphenyl-4-yloxymethyl)-5-methyl~furan~2-carboxylic acid (21) (a) 4- (4-Iodo-phenoxymethyl) -5-methyl-furan-2-carboxylic acid methyl ester (20) (Figure Removed) A solution of 4-hydro; was concentrated in vacuo and taken up in ethyl acetate (100 mL) and washed successively with water (100 mL), 1.0 M aqueous sodium hydroxide solution (100 mL), dried and concentrated in vacuo. The residue was purified by flash chromatography eluting with ethyl acetate/hexane (.1:4 by volume) to give compound 20 as a white solid (1.58 g) . (b) 4- (4 ' -Acetyl-biphenyl-4-yloxymethyl) -5-methyl-furan-2-carboxylic acid (21) (Figure Removed) HO 21 A stirred mixture of 4- (4-iodo-phenoxymethyl)-5-methyl-furan-2-carboxylic acid methyl ester (20) (0.26 g), 4-acetylphenylboronic acid (0.15 g), N,N-dimethylformamide (30 mL) , potassium acetate (0.26 g) and [1,1'-bis(diphenylphosphino) ferrocene] dichloropalladium (II), complex with dichloromethane (1:1) (40 mg) was heated at 90°C over night. The reaction mixture was concentrated in vacuo, dissolved in ethyl acetate (30 mL) and washed successively with water (30 mL), brine (30 'mL) , dried and concentrated in vacuo. The residue was dissolved in a mixture of tetrahydrofuran/methanol (2:1 by volume) (30 mL) and 1.0 M aqueous lithium hydroxide solution (6.78 mL) and stirred for 16 hours. The reaction mixture was acidified to pH 2 using 0.1 M hydrochloric acid and extracted with ethyl acetate (3 x 25 mL) . The extract was dried, concentrated in vacuo and the residue purified by HPLC to give compound 21 as a white solid (50mg) . LC/MS System C: Rt = 4.18 ruins, m/z (ES") = 349 (M~ for C2iHi8O5) . Example 6: Synthesis of N- [4- (4'-Acetyl-biphenyl-4-yloxymethyl) -5-methyl-furan-2-carbonyl] -benzenesulfonamide (22) (Figure Removed) Compound (22) was prepared by adapting the procedure of Example 2A. LC/MS System D: Rt = 9.87 mins, m/z (ES) = 490 (MH4 for C27H23N06S) . Example 7: Synthesis of 4-(4'-Methoxy-biphenyl-4-ylcarbamoyl)-5-methyl-furan-2-carboxylxc acid (24) (a) 5-methyl-furan-2,4-dicarboxylic acid-2-methyl ester (23) Jones' reagent (Prepared according to Fieser and Fieser, Reagents for Organic Synthesis, Volume I, page 142, 1967) was added drop-wise to a stirred solution of 4-hydroxyinethyl-5-methyl-furan-2-carboxylic acid methyl ester (16) (100 mg) in acetone (10 mL) until the orange-colouration just remained. Stirring was continued for a further 5 hours then the reaction mixture was diluted with diethyl ether (20 mL) and filtered. The filtrate was dried and concentrated in vacua to afford compound 23 as a buff coloured solid. (b) 4-(4'-Methoxy-biphenyl-4-ylcarbamoyl)-5-methyl-furan-2- carboxylic acid (24) (Figure Removed) To a solution of 5-methyl-furan-2,4-dicarboxylic acid-2-methyl ester (23) (100 mg) in N,N-dimethylformamide (3.0 mL) was added 0-(7-azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (228 mg), diisopropylethylamine (0.56 mL) and 4'-methoxy-biphenyl-4-ylamine (120 mg). The resulting solution was stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate (20 mL) and washed successively with water (2 x 20 mL), 0.1 M hydrochloric acid (20 mL), water (20 mL), saturated sodium hydrogen carbonate (10 mL) and brine (10 mL). This solution was dried and concentrated in vacuo. The residue (170 mg) wus dissolved in dichloromethane (5 mL), treated with triethylamine (0.3 mL) and a scavenger resin PS-TsCl (0.6 g) and the mixture shaken for 3 hours at room temperature. The reaction mixture was filtered and concentrated iri-vacuo. The residue was dissolved in methanol/tetrahydrofuran (1:3 by volume) (20 mL), treated with 1.0 M aqueous lithium hydroxide solution (2.0 mL) and allowed to stir at room temperature for 4 hours. The pH of the reaction mixture was adjusted to between pH 4 and pH 5 by careful addition of 1.0 M hydrochloric acid (1.0 mL) and partly concentrated in vacuo. The residue was then partitioned between ethyl acetate (2 x 25 mL) and water (25 mL) and the combined organic extracts were washed with brine (35 mL) , dried (Na2S04), and concentrated in vacuo afforded compound 24 as beige solid (58 ing). LC/MS System D: Rt = 7.23 mins, m/z (ES+) = 351 (MH+ for C2oHi7N05) . Example 8: Synthesis of 5-Benzenesulfonylaminocarbonyl-2-methyl-furan-3-carboxylic acid (4'-methoxy-biphenyl-4-yl)- amide (25) (Figure Removed) Compound 25 was synthesised from 4-(4'-Methoxy-biphenyl-4-ylcarbamoyl)-5-methyl-furan-2-carboxylic acid (24) (35 mg) in an analogous manner to that described in Example 2A to give the title compound as a white solid (7 mg). LC/MS System A: Rt = 3.86mins, m/z (ES-) = 489 (M-l for C26H22N206S) . Example 9: Synthesis of 4-(4'-Chloro-biphenyl-4-yloxymethyl)-5-methyl-ft3ran-2-carboxylic acid (27) and 4-(4-Benzo[1,3]dioxol-5-yl-phenoxymethyl)-5-methyl-furan~2-carboxylic acid (28) (a) 4-(4-Iodo-phenoxymethyl)-5~methyl-furan-2-carboxylic acid (26) (Figure Removed) A stirred solution of 4-(4-iodo-phenoxymethyl)-5-methyl-furan-2-carboxylic acid methyl ester (20) (2.7 g) in tetrahydrofuran (25 mL) was treated with a solution of lithium hydroxide (1.5 g) in water (2 mL). After 3 hours the reaction mixture was diluted with water and acidified to pH 2 with 1.0 M hydrochloric acid. The white precipitate was filtered off and dried in vacua. The solid was triturated with ethyl acetate at 0°C then collected by filtration to give compound 26 as a white solid (1.83 g). LC/MS system A: Rt = 1.74 min. (b) 4- (4 '-Chloro-biphenyl-4~yloxymethyl) -5-~methyl-furan-2-carboxylic acid (27) (Figure Removed) (i) 2-Chlorotrityl chloride resin (2.55 g of nominal loading 1.3 mmol/g) was swelled with dichloromethane (20 mL). After draining, a solution of 4-(4-iodo-phenoxymethyl)-5-methyl-furan-2-carboxylic acid (26) (1.18 g) and diisopropylethylamine (2,3 mL) in dichloromethane (30 mL) was added and the mixture was shaken at room temperature for 72 hours. The resin was drained, washed sequentially with dichlororaethane/triethylamine/methanol (20:1:3 by volume) (3 (Figure Removed) 30 mL) , dichloromethane (6 x 30 mL) , N,N-dimethylformamide (2 x 25 mL), dichloromethane (6 x 25 mL), and diethyl ether (2 x 25 mL) and dried at 40°C in vacua. (ii) A stirred mixture of the resin from (i) (0.38g), 4-chlorophenylboronic acid (0.30 g) , [l,l'-bis-(diphenylphosphino)-ferrocene]-dichloropalladium(II) complex with dichloromethane (1:1) (30 mg), potassium acetate (0.20 g) in N,N-dimethylformamide (15 mL) was heated at 40°C for 48 hours. The resin was drained, then washed sequentially with tetrahydrofuran/water (1:1 by volume), tetrahydrofuran, N,N-dimethylformamide, dichloromethane, diethyl ether and then dried at 45°C in vacua. The resin was treated with dichloromethane/trifluoroacetic acid (19:1 by volume) (20 mL) for 20 mins and the solution drained from the resin. This procedure was repeated. The combined solutions were concentrated in vacuo and the residue purified by HPLC to afford compound 27 as a white solid (43 mg). LC/MS System D: Rt = 8.83 mins, m/z (ES~) = 341 (M~ for C19Hi5ClO4) .(c) 4-(4-Benzo[l,3]dioxol-5-yl-phenoxymethyl)-5-methyl-furan-2-carboxylic acid (29) (Figure Removed) Compound 28 was synthesised from the resin from (i) in step (b) above and 3,4-methylenedioxyphenylboronic acid in an analogous manner to that described in step (ii) above. LC/MS System C: Rt = 4.60 mins, iti/z (ES") = 351 (M~ for C2oHi606) . Example 10: Synthesis of [4-(Biphenyl-4-yloxymethyl)-5-methyl-furan-2-yl]-acetic acid (31) and 4-(4' -Methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-yl]-acetic acid (32) (a) (5-Methyl-4-triisopropylsilanyloxymethyl-furan-2-yl)-acetic acid ethyl ester (29) (Figure Removed) A solution of triisopropyl-(2-methyl-furan-3-ylmethoxy)-silane (14) (5.0 g) in tetrahydrofuran (15 mL) was cooled to -~78°C with stirring. This solution was treated drop-wise with n-butyl lithium (2.5 M in hexanes, 8.94 mL). The resulting solution was warmed to 0°C and allowed to stand for 30 minutes after which a solution of dried zinc chloride (3.04 g) in tetrahydrofuran (10 mL) was added and the resulting solution allowed to stand for a further 1 hour at room temperature. Concurrently, a second reaction vessel was charged with tetrahydrofuran (10 mL), nickel(II) acetylacetonate (120 mg) , and triphenylphosphine (122 mg) and cooled (-5°C). Ethyl bromoacetate (1.03 mL) was added to this mixture, followed by the addition of the previously prepared solution of the furyl-zinc chloride. The resulting reaction mixture was allowed to warm to room temperature then stirred for a further 16 hours at room temperature. The reaction was quenched by the addition of saturated ammonium chloride solution (100 mL) and extracted with ethyl acetate (3 x 150 mL). The combined organic extracts were successively washed with water (200 mL) and brine (250 mL), dried, filtered and concentrated in vacuo. The residue was purified by flash chromatography using a gradient elution (diethyl ether /petroleum ether (40-60°) 1:49 to 1:25 by volume) to give compound 29 as a clear oil (1.44 g). LC/MS System A: Rt = 5.16min. (b) (4-Hydroxymethyl-5-methy2-f'uran-2-yl) -acetic acid ethyl ester (30) (Figure Removed) A solution of (5-methyl-4-triiscpropylsilanyloxymethyl-furan-2-yl)-acetic acid ethyl ester (29) (0.5 g) in tetrahydrofuran (3.0 mL) was cooled to 0°C with stirring and treated with tetrabutylammonium fluoride (1.0 M solution in tetrahydrofuran, 2.82 mL) under argon. After 30 minutes, the resulting solution was concentrated in—vacuo and partitioned between water (30 mL) and ethyl acetate (4 x 25 mL). The combined organic extracts were washed with brine (50 mL), dried (Na2S04) , filtered and concentrated in vacuo. The residue was purified by flash chromatography eluting with diethyl ether/petroleum ether (1:1 by volume) to give compound 30 as a clear oil (188 mg). LC/MS System A: Rt = 2.34 mins. (c) {4-(Biphenyl-4-yloxymethyl)-5-methyl-furan-2-yl]-acetic acid (31) Compound (31) was prepared from compound (30) in an analagous manner to the methods described in Examples 3(d) and 3(e). LC/MS System C: Rt = 4.97 mins, m/z (ES~) = 321 (M" for (d) [4- (4' -Methoxy-biphenyl-4-yloxymethyl) -5-jnethyl~furan-2- yl] -acetic acid (32) (Figure Removed) Compound (32) was prepared from compound (30) in an analagous manner to the methods described in Examples 3(d) and 3(e): LC/MS System C: Rt = 4.94 mins, m/z (ES~) = 351 (M" for C21H2o05) . Example 11: Synthesis of 3 (Biphenyl-4-yloxymehhyl)-5-methyl-furan-2-yl]-propionic acid (37) and N-{3-[4-(Biphenyl-4-yloxymethyl)-5-methyl-furan-2-yl]-propionyl)-benzenes salfonamide (38) 79 (a) 5-Methyl-4-triisopropylsilanyloxymethyl-furan-2-carbaldehyde (33) (Figure Removed) A solution of triisopropyl-(2-methyl-furan-3-ylmethoxy)-silane (14) (10 g) in tetrahydrofuran (250 mL) was cooled to -78°C with stirring, and then sec-butyllithium (1.3 M in cyclohexane; 37.25 mL) was added drop-wise over 10 mins. After stirring for 45 mins at -78°C, the cooling bath was removed for a period of 15 mins then re-introduced. A solution of N, N-dimethylformamide (14.4 mL) in tetrahydrofuran (25 mL) was added drop-wise and the resulting reaction mixture was stirred at -78°C for a further 2 hours. The reaction mixture was allowed to warm to-room temperature and then poured into saturated ammonium chloride solution (150 rnL) . This mixture was extracted with diethyl ether (2 x 350 mL), and the combined organic extracts were washed with water (500 mL) and brine (500 mL), dried, and concentrated in vacua to give compound 33 as an amber coloured oil. LC/MG System A: Rt = 4.86 mins. (b) 3- (5-Methyl-4-triisopropylsilanyloxymethyl-furan-2~-yl) -acrylic acid ethyl ester (34) A stirred solution of 5-methyl-4- triisopropylsilanyloxymethyl-furan-2-carbaldehyde (33) (10.6 g) in tetrahydrofuran (25 mL) was treated with triethylphosphonoacatete (7.81 mL) and lithium hydroxide (1.65 g) . The resulting mixture was stirred for 16 hours then concentrated in vacua and the residue partitioned between water (100 mL) and diethyl ether (3 x 100 mL). The combined organic extracts were further washed with water (200 mL) and brine (200 mL), then dried (Na2S04) and concentrated in vacua. The residue was purified by flash chromatography eluting with diethyl ether/petroleum ether (1:40 by volume) to give compound 34 as a clear yellow oil (10.56 g). LC/MS System A: Rt = 4.59 mins. (c) 3- (5-Methyl-4-triisopropylsilanyloxymethyl-furan-2-yl) -propionic acid ethyl ester (35) (Figure Removed) A solution of 3-(5~methyl-4-triisopropylsilanyloxymethyl-furan-2-yl)-acrylic acid ethyl ester (34) (1.0 g) in ethyl acetate (70 mL) was treated with 5% w/w palladium on carbon (350 mg) and hydrogenated at 1 atmosphere for exactly m hours at room temperature. The reaction mixture was filtered through filter-aid and then concentrated in vacuo to afford compound 35 as a clear oil (1.05 g) . LC/MS System A: Rt = 5.52 mins. (d) 3-(4-Hydroxymethyl-5-methyl-furan-2-yl)-propionic acid ethyl ester (36) Compound (36) was prepared in the form of a clear oil from compound (35) by adapting the procedure described in Example 3(c). LC/MS System A: Rt= 2.68 rains.(e) 3-[4-(Biphenyl-4-yloxymethyl)-5-methyl-furan-2-yl]-propionic acid (37) (Figure Removed) To 3 stirred, cooled 0°C solution, in tetrahydrofuran (2.5 mL), a solution of 3-(4-hydroxymethyl-5-methyl-furan-2-yl)-propionic acid ethyl ester (36) (400 mg) in tetrahydrofuran (2.5 mL) was cooled to 0°C and treated successively with triphenylphosphine (542 mg), biphenyl-4-ol (353 mg) and diisopropylasodicarboxylate (0.41 mL). After stirring for 10 mins at 0°C the reaction mixture was allowed to warm to room temperature and then stirred for a further 16 hours. The reaction mixture was concentrated in-vacuo then re-dissolved in dichloromethane (15 mL) and treated with triethylamine (1.50 inL) and a -scavenger resin PS-TsCl (2.5 g) and tl.e mixture was shaken for 6 hours at room temperature. The reaction mixture was purified by flash chromatography, eluting with a mixture of diethyl ether in petroleum ether (40-60°C) (7:93 by volume ). The purified product (320 mg) was dissolved in methanol/tetrahydrof uran (2:1 by volume) (18 mL) , treated with 1.0 M aqueous lithium hydroxide solution (9 mL) and allowed to stir at room temperature for 6 hours. The pH of the reaction mixture was adjusted to between pH4 and pH5 by the addition of 1.0 M hydrochloric acid (~ 5.0 mL) , then treated with saturated ammonium chloride (100 mL) and extracted with ethyl acetate (2 x 100 mL) . The combined organic extracts were further washed with brine (35 mL) , then dried (sodium sulphate) and concentrated in vacua. A sample of the crude product (50 mg) was purified by HPLC to give compound 37 as white solid (25mg) . LC/MS System C: Rt = 5.33 mins, m/z (ES~) = 335 (M" for C2iH2o04) . (f) N-{3-[4- (Biphenyl-4-yloxymethyl) -5-methyl-f uran-2-ylJ -propionyl ) -benzene sulfonamide (38) (Figure Removed) Compound (38) was prepared from compound (37) by the procedure of Example 2A. LC/MS System C: Rt - 5.82 mins, m/z (ES~) = 475 (M" for Example 12: Synthesis of 3-[4-(4'-Methoxy-biphenyl-4-yloxymethyl) -5-methyl-furan-2-yl] -propionic acid (39) and N-{3-[4-(4' -Methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-yl] -propionyl}-benzene sulfonamide (40) (a) 3-[4-(4'-Methoxy-biphenyl-4-yloxymethyl) -5-methyl-furan-2-yl]-propionic acid (39) Compound (39) was prepared from compound (36) in an analogous manner to that described in Example 11 (e) . LC/MS System C: Rt = 5.31 mins, m/z (ES~) = 365 (M~ for C22H2205) - (b) N-{3-[4-(4'-Methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-yl]-propionyl}-benzene sulfonamide (40) (Figure Removed) Compound (40) was prepared from compound (39) by the procedure of Example 2A. LC/MS System C: Rt = 5,78 mins, m/z (ES") - 504 (M~ for C28H27N.06S) . Example 13: Synthesis of 3-[4-(Biphenyl-4-yloxymethyl)-5-methyl-furan-2-yl]-acrylic acid. (42) and 3-[4-(4'-Methoxy-biphenyl-4~yloxymethyl)-5-methyl-furan-2-yl]-acrylic acid (43) Compound (41) was prepared in the form of a yellow oil from compound (34) by adapting the procedure described in Example 3(c). LC/MS System A: Rt= 2.82mins. (b) 3-[4- (Biphenyl-4-yloxymethyl)-5-methyl-furan-2-yl]-acrylic acid (42) (Figure Removed) Compound (42) was prepared from compound (41) by adapting the procedure of Example 11 (e) . LC/MS System C: Rt = 4.91 mins, m/z (ES~) = 333 (M~ for C21Hi8O4) . (c) 3~ [4- (4 ' -Methoxy~biphQnyl-4-yloxymethyl) -5-methyl-furari- 2-ylj-acrylic acid (43) (Figure Removed) Compound (43) was prepared from compound (41) by adapting the procedure of Example ll(e). LC/MS System C: Rt= 4.85 (Figure Removed) mins, m/2 (ES") = 363 (M~ for C22H2o05) - Example 14A: Synthesis of 4-(Biphenyl-4-yloxymethyl)-5-methyl-furan-2-sxilfonic acid benzoylamide (46) (a) 3-(Biphenyl-4-yloxymethyl)-2-methyl-furan (44) 44ethyl-furan-3-yl)-methanol (1)(5.0 g) in diethyl ether (75 mL) was cooled to 0°C with stirring and treated with triphenylphosphine (12.85 g) and biphenyl-4-ol (7.59 g). The resulting solution vas then treated drop-wise with diisopropylazodicarboxylate (9.75 mL). After stirring for 10 minutes at 0°C the reaction mixture was allowed to warm to room temperature and then stirred for a further 3 hours. The reaction mixture was then filtered and concentrated in vacuo. The residue was purified by flash chromatography, eluting with diethyl ether/petroleum ether (1:19 by volume), to give compound 44 as a white solid (7.0 g) . LC/MS System A: Rt= 4.38 mins. (b) 4- (Biphenyl-4-yloxymethyl)-5-methyl-furan-2-sulfonic acid amide (45) (Figure Removed) A solution of 3-(biphenyl-4-yloxymethyl)-2-methyl-furan (44) (5g) in tetrahydrofuran (30 mL) was cooled to -78°C with stirring and was treated with butyllithium (2.5 M in hexanes; 9.84 inL) drop-wise over 10 minutes. After stirring for 45 mins at -78°C, cooling was removed for a period of 15 minutes then re-introduced. A stream of sulphur dioxide gas was then passed over the surface of the reaction mixture until the pH of the reaction was between pH6 and pH7. Stirring was continued for a further 1.5 hours at -78°C and then pentane was added (50 mL). The resulting precipitate was collected by filtration and then re-suspended in water (75 mL). This suspension was cooled to 0°C and treated with sodium acetate (3.88 g) and hydroxylamine-O-sulfonic acid (2.67 g) and stirred at room temperature for 16 hours. The reaction mixture was diluted with water (300 mL) and extracted into ethyl acetate (3 x 250 mL). The combined organic extracts were washed successively with saturated sodium hydrogen carbonate (300 mL) and brine (300 mL), dried, and concentrated in vacua. This material was purified by flash chromatography, eluting with diethyl ether/petroleum ether (2:3 by volume) to give a beige coloured solid (998 mg). A sample of this material (100 mg) was further purified by HPLC to give compound 45 as white solid (55 mg). LC/MS System A: Rt= 3.70 mins. (c) 4- (Biphenyl-4~yloxymethyl)-5-methyl-furan-2-sulfonic acid benzoylamide (46) (Figure Removed) To a stirred solution of benzoic acid (61 mg) in a mixture of tetrahydrofuran (10 mL) and N,N-dimethylformamide (5 mL) was added 4-(N,N-dimethylamino)pyridine (3.0 mg), l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (118 mg) and 4-(biphenyl-4-yloxymethyl)-5-methyl-furan-2-sulfonic acid amide (45) (206 mg). After 16 hours at room temperature the reaction mixture was concentrated in-vacuo, then partitioned between 0.1 M hydrochloric acid (30 mL) and ethyl acetate (3 x 30 mL). The combined organic extracts were washed, with brine (25 mL) , dried (MgSO-j) and concentrated in vacuo. The crude product was purified by HPLC to give compound 46 as light beige solid (17 mg). LC/MS System C: Rt = 5.69 mins, m/z (ES~) = 446 (M~ for C25H2aNO5S) . Example 14B: Synthesis of 4-(Biphenyl-4-yloxymethyl)-5-methyl-furan-2-sulphonic acid butyryl-amide (61) (Figure Removed) To a stirred solution of 4-(biphenyl-4-yloxymethyl)-5- methyl-furan-2-sulphonic acid amide (45) (50mgf 0.146mmoles) in dichloromethane (5.0ml) was added triethylamine (26\|il, 0.189rranoles), dimethyl-pyridin-4-yl-amine (Img) and butyryl chloride (19u.l, 0.184mmoles). After stirring for 16 hours at room temperature the reaction mixture was concentrated in-vacuo, and the residue was purified by HPLC to give compound 61 as as an off-white solid (48mg). LC/MS System C: Rt = 3.82 mins, m/z (ES") = 412 ((M-H) for C22H23N05S) . By adapting the procedure of Example 14B there were prepared Examples 14C to 14E : Example 14C: 4-(Biphenyl-4-yloxymethyl)-5-methyl-furan-2-sulphonic acid phenylacetyl-amide (62) (Figure Removed) LC/MS System C: Rt = 4.20mins, m/z (ES") = 460 ((M-H) for C26H23NOsS) . Example 14D: 4-(Biphenyl-4-yloxymethyl)-5-methyl-fnran-2-sulphonic acid (3,5-dimethyl-isoxazole-4-carbonyl)-amide (63) (Figure Removed) LC/MS System C: Rt = 3.98mins, m/z (ES~) = 465 ( (M-H) for Example 14E: 4- (Biphenyl-4-yloxymethyl) -5-methyl-furan-2-sulphonic acid {thiophene-2-carbonyl) -amide (64) (Figure Removed) LC/i^S System C: Rt = 4.06mins/ ra/z (ES~) = 452 ((M-H) for C23H19N05S2) . Example 14P: Synthesis of 4-(Biphenyl-4-yloxymethyl)-5-methyl-furan-2-sulphonic acid (3-methoxy-propionyl)-amide (65) To a stirred solution of 4-(biphenyl-4-yloxymethyl)-5- raethyl-furan-2-sulphonic acid amide (45) (50mg, 0.146mmoles) in N,N-dimethylformamide (4.0ml) was added diisopropylethylamine (85\|al, 0.480mmoles) then a solution of 3-methoxypropionic acid (14\|al, 0.146mmoles) in N,N-dirnethylformamide (1.0ml). 0- (7-Azabenzotriazol-l-yl) -N,N,N',N'-tetramethyluronium hexafluorophosphate (61mg, O.lGOmmoles) in N,N-dimethylformamide (1.0ml) was added and the solution stirred at room temperature for 16 hours. The reaction mixture was concentrated in-vacuo, and the residue was purified by HPLC to give compound 65 as as a white solid (42rag) . LC/MS System A: Rt=3.80mins, m/z (ES~) = 428 ((M-H) for C22H23NOSS) . By adapting the procedure of Example 14F there were prepared Examples 14G to 141: Example 14G: 4-(Biphenyl-4-yloxymethyl)-5-methyl-furan-2-sulphonic acid (pyridin-3-yl-acetyl)-amide (66) (Figure Removed) LC/MS System D: Rt = 5.64mins, m/z (ES+) = 463 ( (M+H) for C25H22N205S) . Example 14H: 4-(Biphenyl-4-yloxymethyl)-5-methyl-furan-2-sulphonic acid (pyridine-4-carbonyl)-amide (67) C/MS System D: Rt = 5.85mins, m/z (ES+) = 449 ((M+H) for Example 141: 4-{Biphenyl-4-yloxymethyl)-5-methyl-furan-2-siilphonic acid (pyridine-3-carbonyl)-amide (68) (Figure Removed) LC/MS System D: Rt = 5.92mins, m/z (ES+) = 449 ((M+H) for Example 15: Synthesis of 4-(4'-Methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-sulfonic acid benzoylamide (49) and 4-(4 ' -Methoxy-biphenyl-4-yloxymethy 1)-5-methyl-furan-2-sulfonic acid (3,5-dimethyl-isoxazole-4-carbonyl)-amide (69) (a) 3- (4'-Methoxy-Mphenyl-4-yloxymethyi; -2-methyl-furan (47) (Figure Removed) Compound 47 was prepared by adapting the procedure of Example 14A(a). LC/MS System A: Rt = 4.58 mins. (b) 4- (4 ' -Methoxy-biphenyl-4-yloxymethyl) -5-methyl-furan-2-sulfonic acid amide (48) (Figure Removed) Compound (48) was prepared from compound (47) by the procedure of Example 14A(b). LC/MS System A: Rt = 3.63 mins (c) 4- (4f-Methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan~2-svlfonic acid benzoylamide- (49) Compound (49) was prepared from compound (48) by the procedure of Example 14B. LC/MS System C: Rt = 5.37 minsr m/z (ES") = 476 (W for (d) 4- (4' -Met/70xy-biphenyl-4-yloxymethyl) -5-methyl-furan-2-sulphonic acid (3,5-dimethyl~isoxazole-4-carbonyl)-amide (69) (Figure Removed) Compound (69) was prepared from compound (48) by adapting the procedure of example 14B. LC/MS System C: Rt = 4.45 mins, m/z (ES~) = 495 ( (M-H) for Example 16: Synthesis of 4- [4- (5-Methoxy-pyridin-2-yl) -phenoxymethyl] -5~methyl-furan-2-carboxylic acid (53) (a) 5 -Methyl -4- (4- (4,4,5, 5-tetramethyl-f 1,3,2 ]di oxaborolan-2-yl) -phenoxymethyl] -furan-2~carboxylic acid methyl ester (51) (Figure Removed) A mixture of 4-hydroxymethyl-5-methyl-furan-2-carboxylic acid methyl ester (16) (0.5g), 4- (4, 4 , 5, 5-tetramethyl- [1,3,2]dioxaborolan-2-yl)-phenol (1.9g) and triphenylphosphine (2.3g) in dry tetrahydrofuan (20mL) under a nitrogen atmosphere was cooled to 0°C. Di-isopropylazodicarboxylate (1.8mL) was added drop-wise and the mixture was stirred at room temperature for 72 hours. After concentrating in vacuo, the residue was partitioned between ethyl acetate and water. The organic phase was washed with brine, dried (MgS04) and concentrated in vacuo. The residue was extracted with pentane and the pentane phase was decanted and concentrated to give compound 51 as an oil. This was used without further purification. (b) 4-[4-(5-Methoxy-pyridin-2-yl)-phenoxymethyl]-5-methyl-furan-2-carboxylic acid methyl ester (52) (Figure Removed) A mixture of 5-methyl-4-[4-(4, 4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxymethyl]-furan~2-carboxylic acid methyl ester (51) (126mg), 2M aqueous cesium carbonate (0.6mL) and 2-iodo-5-methoxypyridine (95mg) in 1,4-dioxan (lOmL) under an argon atmosphere was sonicated to expel traces of oxygen. [1,1'-Bis-(diphenylphoshino) ferrocene] dichloropalladium (II) (8mg) was added and the mixture heated at 95°C for 18 hours. After cooling, the mixture was acidified to pH6 with 1M aqueous hydrochloric acid and partitioned between ethyl acetate and water. The organic phase was dried (MgSO^) and evaporated to give compound 52 as an oil (70mg), which was used directly in the next step. LC/MS System A: Rt = 3.23 nuns, m/z = 354 ( (M+H) for (c) 4-[4-(5-Methoxy-pyridin-2-yl) -phenoxymethylJ-5-methyl-furan-2-carboxylic acid (53) (Figure Removed) A solution of 4- [4- (5-methoxy-pyridin-2-yl)-phenoxymethyl]- 5-methyl-furan-2-carboxylic acid methyl ester (52) (118mg, 0.33mmoles) in dry tetrahydrofura-n (10ml) was treated with potassium trimethylsilanoate (260mg, 2.0mmoles) and the mixture stirred under an argon atmosphere for 2 hours. After evaporation of the solvent the residue was purified by HPLC (gradient: 18% acetonitrile/82% water containing 0.1% trifluoroacetic acid to 98% acetonitrile/2% water at a rate of 1%/min) to afford compound 53(60mg) as a white solid. Method 2 A mixture of 4-[4- (5-methoxy-pyridin-2-yl)-phenoxymethyl]-5-methyl-furan-2-carboxylic acid methyl ester (52) (70mg) and 1M aqueous lithium hydroxide (ImL) in tetrahydrofuran/methanol (2:1 by volume) (12mL) was stirred at room temperature for 16 hours. The reaction mixture was acidified to between pH6 and pH7, and partitioned between ethyl acetate and water. The organic phase was separated, washed with brine and dried (MgS04) . After removal of the solvent, the residue was purified by HPLC. Compound 53 was obtained as a solid (2.5mg). LC/MS System A: Rt= 2.90 minsr m/z (ES+) = 340 ( (M+H) for C19H17N05) . Example 17: Synthesis of 4~[6-(4-Methoxy-phenyl)-pyridin-3-yloxymethyl]-5-methyl-furan-2-carboxylic acid (56) (a) 4-(6-iodo-pyridin-3-yloxymethyl)-5-methyl-furan-2-carboxylic acid methyl ester (54) (Figure Removed) Compound (54) was prepared from compound (16) and 2-iodo-5-hydroxy-pyridine in a manner analagous to that described in Example 5(a). LC/MS System A: Rt='3.52 mins, m/z = 374 ( (M+H) for Ci3Hi2IN04) (b) 4-[6-(4-Methoxy-phenyl) -pyridin-3-yloxymethyl]-5-methyl-furan-2-carboxylic acid methyl ester (55) (Figure Removed) Compound (55) was prepared from compound (54) by adapting the procedure of Example 5(b). LC/MS System A: Rt= 3.37 mins, m/z ~ 354 ((M+H) for C2oH19N05) . (c) 4-[6- (4-Methoxy-phenyl) -pyridin-3-yloxymethyl] -5-methyl-furan-2-carboxylic acid (56) (Figure Removed) Compound (56) was prepared from compound (55) by adapting the procedure of Example 16(c). LC/MS System A: Rt = 2.79 mins, m/z (ES) = 340 {(M+H) for C19H17N05) Example 18 : Synthesis of 3-Morpholin-4-yl-propane-l-sulphonic acid [4- (4 ' -methoxy-biphenyl-4-yloxymethyl) -5-methyl-furan-2-carbonyl] -amide (59) (a) 3-Morpholin-4-yl-propane-l-sulfonic acid amide (58) (Figure Removed) Dichloromethane (40ml) was saturated with ammonia gas with cooling (dry ice /acetone), and then 3-morpholin-4~yl-propane-1-sulphonyl chloride (279mg, 1.23mmoles) was added. The mixture was stirred at room temperature for 24 hours. The mixture was filtered, the filtrate evaporated and the residue was dried at 40°C in vacuo to afford compound 58 (210mg) as a gum. LC/MS System A; Rt = 0.28 mins, m/z (ES+) = 209. (M+H for C7Hi6N203S) . (b) 3-Morpholin-4~yl-propane-l-sulphonic acid [4-(4'~ methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2~carbonyl] amide (59) (Figure Removed) Compound (59) was prepared from compounds (4) and (58) by adapting the procedure of Example 2A. LC/MS System D; Rt = 4.97mins, m/z (ES) = 529 (M+H for Example 19: Synthesis of N-[4-(Biphenyl-4-yloxymethyl)-5-methyl-furan;-2-carbonyl] -2-methyl-benzenesulphonamide (60) A stirred solution of 4-(biphenyl-4-yloxymethyl)-5-methyl-furan-2-carboxylic acid (18) (SOmg, 0.162mmoles), 2-methyl-benzenesulphonamide (42mg, 0.243mmoles) and 4-(N,N-dimethylamino)-pyridine (2.5mg) in a mixture of tetrahydrofuran (8ml) and acetonitrile (2ml) was treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochlorid.e (38mg, 0.194mmoles) . The mixture was stirred at room temperature for 16 hours under an argon atmosphere, The reaction mixture was concentrated in vacuo and the residue was purified by HPLC to afford compound 60(20mg) as a white solid. LC/MS System D; Rt = 11.09mins, m/z (ES+) = 462 (M+H for Example 20A: Synthesis of 4-[2-(Biphenyl-4-yloxy)-ethyl]-5-methyl-furan-2-carboxylic acid (72) (a) tert-Butyl-[2- (2-methyl-furan-3-yl)-ethoxy]-diphenyl-silane (70) (Figure Removed) (i) A solution of (2-methyl-furan-3-yl)-acetic acid ethyl ester (11.8g, 70.2mmoles) in tetrahydrofuran (50ml) was added to a stirred suspension of lithium aluminium hydride (2.66g,' 70.2mmoles) under a nitrogen atmosphere and with cooling to 0°C. When the addition was complete the mixture was stirred at room temperature for 3 hours, then quenched by the addition of excess acetone. After acidifying with 10% aqueous hydrochloric acid the mixture was extracted three times With diethyl ether. The combined extracts were dried and evaporated to afford crude 2-(2-methyl-furan-3-yl)-ethanol as a yellow oil. (ii) Compound (70) was prepared in the form of a pale yellow oil from crude 2-(2-methyl-furan-3-yl)-ethanol (from (i)) by adapting the procedure of Example l(a). (b) 4-[2-(tert-Butyl-diphenyl-silanyloxy)-ethyl]-5-methyl-furan-2-carboxylic acid (71) Compound (71) was prepared in the form of a pale yellow oil from compound (70) by adapting the procedure of Example Kb) . (c) 4-{2~ (Biphenyl-4-yloxy)-ethyl]-5-methyl-furan-2-carboxylic acid (72) c(Figure Removed) ompound (72) was prepared from compound (71) in an analogous manner to the methods described in Example 1(c). LC/MS System B: Rt = 1.86mins, m/z (ES~) = 321 ((M-H) for Example 20B: Synthesis of 4-[2-(4'-Methoxy-biphenyl-4-yloxy) -ethyl] ~5-methyl~furan-2-carboxylic acid (73) (Figure Removed) Compound (73) was prepared from compound (71) in an analogous manner to the methods described in Example l(c) LC/MS System B: Rt = 1.86mins, m/z (ES~) = 351 ((M-H) for Example 20C: Synthesis of 4-[2-(Dibenzofuran-3-yloxy)-ethyl]-5-methyl-furan-2-carboxylic acid (74) (Figure Removed) Compound (74) was prepared from compound (71) in an analogous manner to the methods described in Example 1 (c) LC/MS System B: Rt = 1.86minsf m/z (ES~) = 335 ( (M-H) for Example 21A: Synthesis of 4- (Biphenyl-4-yloxymethyl) -furan 2-carboxylic acid (77) (a) 4-Hydroxymethyl-furan-2-carboxylic acid (75) (Figure Removed) A solution of furan-3-yl-methanol (1.6g, 16.5mmoles) in dry tetrahydrofuran (25ml) under an argon atmosphere was cooled to -78°C and treated dropwise with n-butyl-lithium (9.2mL, 23mmoles of a 2 . 5M solution in hexanes) . After 1 hour, sec-butyl-lithium (14.0ml, 18.2mmoles of a 1 . 3M solution in hexanes) was added. After stirring for a further 4 hours at -78 °C, the mixture was quenched by the addition of a large excess of solid carbon dioxide. The mixture was allowed to warm to room temperature and was added to a mixture of ethyl acetate and 1M aqueous hydrochloric acid (60ml). The organic phase was separated, washed with brine, dried , and evaporated. The residue was dissolved in dichloromethane and on standing a cream solid precipitated. The precipitate was collected and dried to afford compound 75 as cream solid (0.4g). (b) 4- (tert-Butyl-dimethyl-silanyloxymethyl)-furan-2-carboxylic acid (76) (Figure Removed) A mixture of 4-hydroxymethyl-furan-2-carboxylic acid (75) (1.4g, 9.85mmoles), tert-butyl-chloro-dimethyl-silane (3.2g, 21mmoles) and imidazole (2.14g, 31.5mmoles) in dry DMF (35ml) was stirred at room temperature for 24 hours. Excess methanol (~3ml) was added and the mixture stirred for a further 3 hours. After partitioning between ethyl acetate and water, the aqueous phase was acidified to pH = 1 with 2M aqueous hydrochloric acid and re-extracted with ethyl acetate. The combined ethyl acetate phases were washed with water, dried (MgS04) , and the solvent evaporated to give compound 76 as a white solid (2.4g). 4- (Biphenyl-4-yloxymethyl) -furan-2-carboxylic acid (77) (Figure Removed) Compound (77) was prepared from compound (76) in an analogous manner to the methods described in Example l(c). LC/MS System B; Rt = 1.72mins, m/z (ES") = 293 (M-H for Example 21B: Synthesis of 4-(Dibenzofuran-2-yloxymethyl)-103 furan-2-carboxylic acid (78) (Figure Removed) Compound (78) was prepared from compound (76) in an analogous manner to the methods described in Example 1(c) LC/MS System B; Rt = 1.72mins, m/z (ES") = 307 (M-H for Ci8H1205) . Example 21C: Synthesis of 4-(4'-Cyano-biphenyl-4-yloxymethyl)-furan-2-carboxylic acid (79) Compound (79) was prepared from compound (76) in an analogous manner to the methods described in Example 1(c) LC/MS System B; Rt = 1.65mins, m/z (ES') = 318 (M-H for C19H13N04) . Example 21D: Synthesis of 4-(4'-Methoxy-biphenyl-4-yloxymethyl)-furan-2-carboxylic acid (80) (Figure Removed) compound (80) was prepared from compound (76) in an analogous manner to the methods described in Example 1(c) LC/MS System B; Rt = 1.72mins, m/z (ES") = 323 (M-H. for C19Hi605) • Example 21E: Synthesis of 4- (Dibenzofuran-3-yloxymethyl) furan-2-carboxylic acid (81) Compound (81) was prepared from compound (76) in an analogous manner to the methods described in Example 1(c) LC/MS System B; Rt = 1.75mins, m/z (ES~) = 307 (M-H for xample 22A: Synthesis of 4-(Biphenyl-4-yloxymethyl)-5-isopropyl-f-uran-2-carboxylic acid (85) (a) 2-Isoprcpyl-f~uran-3-carJboxylic acid ethyl ester (82) (Figure Removed) An ice-chilled solution of sodium hydroxide (1.9g) in water (25ml) was added, during 40 minutes, to a stirred solution of 4-methyl-3-oxo-pentanoic acid ethyl ester (3g, 18.96mmoles) and 1,2-dichloro-l-ethoxy-ethane (3.3g, 35.19mmole) in diethyl ether (15ml) with ice bath cooling. When the addition was complete the mixture was stirred rapidly for 1 hour, then the ethereal layer was separated, washed with water and dried. Evaporation of the solvent gave a yellow oil, which was purified by flash chromatography using a gradient elution from neat pentane to pentane/diethyl ether 9:1 v/v as eluent, to afford compound 82 as an oil (2.4g). (b) Tri-isopropyl-(2-isopropyl-furan-3~ylmethoxy)-silane (Figure Removed) (i) A solution of 2-isopropyl-furan-3-carboxylic acid ethyl ester (82) (4.0g, 21.95mmoles) in tetrahydrofuran (70ml) was treated portionwise during 0.5h with lithium aluminium hydride (0.7g, 18.4mmoles) under a nitrogen atmosphere. When the addition was complete the mixture was stirred at room temperature for 18 hours, then quenched by the addition of excess acetone (1ml) and then water (1ml). After diluting with ethyl acetate (150ml) the grey precipitate was removed by filtration. The filtrate was evaporated and the residue dissolved in diethyl ether and dried. Evaporation of the solvent afforded (2-isopropyl-furan-3-yl)-methanol. This material was used immediately in the next step. (ii) A solution of the (2~isopropyl-furan-3-yl)-methanol from (i) in dry dichloromethane (120ml) was treated with chloro-tri-isopropyl-silane (5.2g, 27.0mmoles) and imidazole (3.0g, 44.0mmoles) and the mixture was stirred overnight at room temperature. The reaction mixture was washed sequentially with 2M aqueous hydrochloric acid, water, saturated aqueous sodium bicarbonate, water and brine. After drying, evaporation of the solvents afforded a colourless oil, which heated at 125°C under reduced pressure (lOrnillibars) . The residue was compound 83 obtained as a pale yellow oil. (c) 5-Isopropyl-4-triisopropylsilanyloxymethyl-furan~2-carboxylic acid (84) Compound (84) was prepared in the form of a cream solid from compound (83) by adapting the procedure of Example 1(b). (d) 4- (Biphenyl-4-yloxymethyl) ~5-isopropyl-furan-2-carboxylic acid (85) (Figure Removed) compound (85) was prepared from compound (84) in an analogous manner to the methods described in Example l(c) LC/MS System B; Rt = 1.93mins, m/z (ES") = 335 (M-H for Example 22B: Synthesis of 5-Isopropyl-4- (4 ' -methoxy-biphenyl-4-yloxymethyl) ~furan-2-carboxylic acid (86) Compound (86) was prepared from compound (84) in an analogous manner to the methods described in Example l(c) LC/MS System B; Rt'= 1.93mins, m/z (ES") = 365 (M~H for C22H2205) - Example 22C: Synthesis of 4-(Dibenzofuran-3-yloxymethyl)-5 isopropyl-furan-2-carboxylic acid (87) (Figure Removed) Compound (87) was prepared from compound (84) in an analogous manner to the methods described in Example l(c) LC/MS System B; Rt = 1.93mins, m/z (ES~) = 349 (M-H for Example 23A: Synthesis of 4-(Biphenyl-4-yloxymethyl)-5-trifl-uoromethyl-furan-2-carboxylic acid (90) (a) Tri-isopropyl- (2-trifluoromethyl-fvran-3-ylmethoxy)-silane (88) (Figure Removed) (i) A solution of 2-trifluoroniethyl-furan-3-carboxylic acid ethyl ester (2.2g, lO.Smmoles) in tetrahydrofuran (150ml) was treated portionwise during 0.5h with lithium aluminium hydride (0.55g, 14.5mmoles) under a nitrogen atmosphere. When the addition was complete the mixture was stirred at room temperature for 18h, then quenched by the addition of excess acetone (1ml) and then water (1ml). After diluting with ethyl acetate (200ml) the grey precipitate was removed by filtration. The filtrate was dried and evaporation of the solvent afforded (2-trifluoromethyl-furan-3-yl)-methanol as a colourless oil. This material was used immediately in the next step. (ii) A solution of the (2-trifluoromethyl-furan-3-yl)-inethanol from (i) in dry dichloromethane (180ml) was treated with chloro-tri-isopropyl-silane (2.6g, 13.4mmoles) and imidazole (1.45g, 2l.3mmoles) and the mixture was stirred overnight at room temperature. Further aliquots of chloro-tri-isopropyl-silane (0.9g, 4.64mmoles) and imidazole (0.5g, 7.34mmoles) were added and the mixture was stirred for 3h. The reaction mixture was diluted with water, the organic phase separated and washed sequentially with 0.1M aqueous hydrochloric acid, water, saturated aqueous sodium bicarbonate, water and brine. After drying, evaporation of the solvents afforded a colourless oil. The oil was distilled under reduced pressure (O.OStorr) in a Kugelruhr apparatus collecting the fraction boiling at an oven temperature of 125±20°C to afford compound 88 as a colourless oil. (b) 5-Trifluoromethyl-4-triisopropylsilanyloxymethyl-furan-2-carboxylic acid (89) Astirred solution of tri-isopropyl-(2-trifluoromethyl-furan-3-ylmethoxy)-silane (88) (2.0g, 6.24mmoles) in tetrahydrofuran (70ml) under argon was cooled to -78°C and treated with sec-butyl-lithium (2.2ml, 2.86mmoles of a 1.3M solution in cyclohexane). After In at -78°C, excess solid carbon dioxide, which had been pre-washed with tetrahydrofuran, was added and the mixture was allowed to warm to room temperature. The mixture was acidified to pH= 4 with dilute aqueous hydrochloric acid and extracted several times with ethyl acetate. The combined extracts were dried (MgS04) and solvent removed to afford compound (89) as an off-white solid (1.2g). (c) 4-(Biphenyl-4-yloxymethyl)-5~trifluoromethyl-furan-2-carboxylic acid (90) (Figure Removed) Compound (90) was prepared from compound (89) in an analogous manner to the methods described in Example 1(c). The product was purified by HPLC. LC/MS System B; Rt = 1.97mins, m/z (ES~) = 361 (M-H for CigHi3F304) . Example 23B: Synthesis of 4-(Biphenyl-3-yloxymethyl)-5-trifluoromethyl-furan-2-carboxylic acid (91) Compound (91) was prepared from compound (89) in an analogous manner to the methods described in Example 1 (c). The product was purified by HPLC. LC/MS System B; Rt = 1.97mins, m/z (ES~) = 361 (M-H for C19Hi3F3O4) . Example 23C: Synthesis of 4-(Diben2ofuran-2-yloxymethyl)-5-trifliioroniethyl-furan-2-carboxylic acid (92) (Figure Removed) Compound (92) was prepared from compound (89) in an analogous manner to the methods described in Example 1(c) The product was purified by HPLC. LC/MS System B; Rt = 1.97mins, m/z (ES") = 375 (M-H for Example 23D: 4-(4'-Cyano-biphenyl-4-yloxymethyl)-5 trifl-uoromethyl-f-uran-2-carboxylic acid (93) (Figure Removed)Compound (93) was prepared from compound (89) in an analogous manner to the methods described in Example 1(c). The product was purified by HPLC. LC/MS System B; Rt = 1.89mins, m/z (ES") = 386 (M-H for C20Hi2F3N04) . Example 23E: Synthesis of 4-(4'-Methoxy-biphenyl-4-yloxymethy 1)-5-trifluoromethyl-furan-2-carboxylic acid (94) Compound (94) was prepared from compound (89) in an analogous manner to the methods described in Example l(c). The product was purified by HPLC. LC/MS System B; Rt 1.97mins, m/z (ES") = 391 {M-H for Example 23F: 4- (Dibenzofuran-3-yloxymethyl) -5-trif luoromethyl-furan-2-carboxylic acid (95) (Figure Removed) compound (95) was prepared from compound (89) in an analogous manner to the methods described in Example 1(c) The product was purified by HPLC. LC/MS System B; Rt = 1.97mins, m/z (ES') = 375 (M-H for Ci9HnF3O5) . Example 24A: Synthesis of 4-(31,4'-Dimethoxy-biphenyl-4-yloxy methyl)-5-methyl-furan-2-carboxylic acid (96) (Figure Removed) A stirred mixture of 4-(4-iodo-phenoxymethyl)-5-methyl- furan-2-carboxylic acid methyl ester (20) (0.025g, 0.067mmoles) , (3, 4-dimethoxyphenyl)-boronic acid (0.017g, 0 . 093mmoles) r N^-dimethylf ormamide (3mL) , potassium acetate (0.026g) and [1,1'-bis (diphenylphosphino) ferrocene]dichloropalladium(II), complex with dichloromethane (1:1) (4 mg) was stirred at room temperature under an argon atmosphere for 24h. The reaction mixture was diluted with water and extracted with ethyl 112 acetate. The extracts were washed with water, dried and concentrated in vacuo. The residue was dissolved in a mixture of tetrahydrofuran/methanol (2:1 by volume) (2.5mL) and 1.0 M aqueous lithium hydroxide solution (0.5 mL), and stirred for 16 hours. The reaction mixture was acidified to pH=6 using 1M hydrochloric acid and extracted with ethyl acetate (3 x 25 mL). The extracts were dried, concentrated in vacuo and the residue purified by HPLC (gradient: 30% acetonitrile/70% water containing 0.1% trifluoroacetic acid to 70% acetonitrile/30% water at a rate of 1%/min) to give compound 96 as a solid (15mg). LC/MS System B; Rt = 1.65mins, m/z (ES~) = 367 (M-H for C2aH2o06) . Example 24B: Alternate synthesis of 4-(4-Benzo[1,3]dioxol-5-yl-phenoxymethyl)-5-methyl-furan-2-carboxylic acid (28) (Figure Removed) Compound (28) was prepared from compound 120) and 13,4-methylenedioxyphenyl)-boronic acid by adapting the procedure of Example 24A. LC/MS System B; Rt = 1.76mins, m/z (ES'~) = 351 (M-H for C20H1606) . Example 24C: 4-(4'-Ethoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carboxylic acid (98) (Figure Removed) Compound (98) was prepared from compound (20) and (4-ethoxyphenyl)-boronic acid by an adapting the procedure of Example 24A. LC/MS System B; Rt = 1.8Grains, m/z (ES~) = 351 (M-H for C21H2005) • Example 25A: Synthesis of 4-(2'-Chloro-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carboxylic acid (99) Compound (99) was prepared from compound (20) and (2-chlorophenyl)-boronic acid by adapting the procedure of Example 5 (b) . LC/MS System B; Rt - 1.86mins, m/z (F,S~) - 341 and 343 (M-H for Ci9H15Cl04) . Example 25B: Synthesis of 4- (2 ' , 6 ' -Dif ltioro-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carboxylic acid (100) Compound (100) was prepared from compound (20) and (2,6- difluorophenyl)-boronic acid by adapting the procedure of Example 5(b). LC/MS System B; Rt = 1.83mins, m/z (ES~) = 343 (M~H for C19Hi4F204) . Example 25C: Synthesis of 5-Methyl-4-(2'-trifluoromethyl-biphenyl-4-yloxymethyl)-furan-2-carboxylic acid (102) Compound (102) was prepared from compound (20) and (2-trif luoromethyl-phenyl) -boronic acid by adapting the procedure of Example 5(b). LC/MS System B; Rt = 1.93mins, m/z (ES~) = 375 (M-H for Example 25D: Alternate synthesis of 4- (4 ' -Chloro-biphenyl-4 yloxymethyl) -5-methyl-furan-2-carboxylic acid (27) (Figure Removed) Compound (11) was prepared from compound (20) and (4-chloro-phenyl)-boronic acid by adapting the procedure of Example 5(b). LC/MS System B; Rt - 1. gamins/ m/z (ES~) = 341 and 343 (M-H for C19H15C1O4) - Example 25E: Synthesis of 4-(3'-Fluoro-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carboxylic acid (104) (Figure Removed) Compound (104) was prepared from compound (20) and (3-fluoro-phenyl)-boronic acid by adapting the procedure of Example 5(b). LC/MS System B; Rt = 1.83mins, m/z (ES") = 325 (M-H for C19Hi5F04) . Example 25F: 5-Methyl-4-(2'-methylsulphanyl-biphenyl-4-yloxymethyl)-furan-2-carboxylic acid (105) (Figure Removed) Compound (105) was prepared from compound (20) and (2-methylsulphanyl-phenyl) -boronic acid by adapting the procedure of Example 5 (b) . LC/MS System B; Rt = 1.86mins, m/z (ES") = 353 (M-H for C2oHi804S) . Example 26A: Synthesis of 4- (3 ' , 4 ' -Dimethoxy-biphenyl-3-yloxymethyl) -5-methyl-furan~2-carboxylic acid (108) (a) 4- (3-Iodo-phenoxymethyl) -5~methyl-furan-2-carboxylic acid methyl ester (106)A mixture of 4-hydroxymethyl-5-methyl~furan-2-carboxylic acid methyl ester (16) (1.85g, I0.9mmoles), 3-iodophenol (3.6g, I6.35mmoles), triphenylphosphine (4.3g, 16.35mmoles) in tetrahydrofuran (15mL) was cooled to 0°C. Diisopropylazodicarboxylate (3.3g, 16.35mmoles) was added and the mixture was allowed to warm to room temperature, then stirred for 72h. The tetrahydrofuran was evaporated and the residue purified by flash chromatography using hexane/ethyl acetate 7:3v/v as eluent to give compound 106 (2.8g). This was used directly in step (b). (b) 4- (3-Iodo-phenoxymethyl)-5-methyl-furan-2~carboxylic acid (107) A mixture of 4-(3-iodo-phenoxymethyl)-5-methyl-furan-2-carboxylic acid methyl ester (106) (2.7g, 7.25mmoles) and lithium hydroxide (1.5g, 36.25mmoles) in tetrahydrofuran (25ml) containing .water (2ml) was stirred at room temperature for 3h. The tetrahydrofuran was evaporated, the residue was diluted with water and the mixture acidified to pH=l with 1M aqueous hydrochloric acid. The precipitate was collected washed with water and dried at 70°C in vacuo to give compound 107(1.76g) as a white solid. LC/MS System B; Rt = 3.51mins, m/z (ES~) = 351 (M-H for Ca3HnIO4) . (c) 4 -(3 ' ,4 '-Dimethoxy-biphenyl-3-yloxyjnethyi; -5-methyl-furan-2-carboxylic acid (108) (Figure Removed) (i) 2-Chlorotrityl chloride resin (2.5g of nominal loading 1.3 mmol/g) was swelled with dichloromethane (120 mL). After draining, a solution of 4-(3-iodo-phenoxymethyl)-5-methyl-furan-2-carboxylic acid (107) (1.16g, 3.24 mmoles) and diisopropylethylamine (2.25 mL, 12.96mmoles) in dichloromethane (20mL) was added and the mixture was shaken at ambient temperature for 72 hours. The resin was drained, washed sequentially with dichloromethane/triethylamine/methanol (20:1:3 by volume) (3 x 30 ml), dichloromethane (4 x 30 mL), N,N-dimethylformamide (4 x 30 mL), dichloromethane (6 x 30 mL), and diethyl ether (3 x 30 mL) and then dried at 40°C in vacuo. (ii) The loaded resin (llOmg) from (i) was treated with a mixture of (3,4-dimethoxyphenyl)-boronic acid (119.7mg, 0 . 65mraoles) , [1,1'-bis (diphenylphosphino) ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (10.6mg) and potassium acetate (0.064g, 0.65mmoles) in N,N-din\ethylformamide (5mL) and the mixture was agitated at 100°C for 24 hours. The resin was drained, washed sequentially with tetrahydrofuran/water(1:Iv/v) (2 x 5mL), tetrahydrofuran (2 x 5mL), N,N-dimethylformamide (3 x 5mL), dichloromethane (6 x 5mL) and diethyl ether (2 x 5ml), then dried at 45°C in vacuo. The resin was treated with dichlorornethane/trifluoroacetic acid (19:1 by volume) (3mL) for 30 mins and the solution drained from the resin. This procedure was repeated. The combined solutions were concentrated in vacuo and the residue purified by hplc (gradient: 30% acetonitrile/70% water containing 0.1% trifluoroacetic acid to 90% acetonitrile/10% water at a rate of 1%/min) to afford compound 108(24.9mg) as a solid. LC/MS System B; Rt = 1.69mins, m/z (ES") = 367 (M-H for C21H2o06) . Example 26B: Synthesis of 5-Methyl-4-(3'-trifluoromethyl-biphenyl-3-yloxymethyl)-furan-2-carboxylic acid (109) Compound (109) was prepared from compound (107) and (3-trifluoromethyl-phenyl)-boronic acid by adapting the procedure of Example 26A(c). LC/MS System B; Rt = 1.97mins, m/z (ES") =375 (M-H for C2oHisF304) . Example 27A: Synthesis of 4-(4'-Hydroxymethyl-biphenyl-4-yloxymethyl)-5-methyl~furan-2-carboxylic acid (110) (Figure Removed) (i) 2-Chlorotrityl chloride resin (3.9 g of nominal loading 1.3 mmol/g) was swelled with dichloromethane (40 mL). After draining, a solution of 4-(4-iodo-phenoxymethyl)-5-methyl-furan-2-carboxylic acid (26) (1.78g, 3.3mmoles) and diisopropylethylamine (2.3mL) in dichloromethane (30mL) was added and the mixture was shaken at room temperature for 12 hours. The resin was drained, washed sequentially with dichloromethane/triethylamine/methanol (20:1:3 by volume) (3 x 30 mL), dichloromethane (6 x 30 mL), N,N-dimethylformamide (2 x 25 mL), dichloromethane (6 x 25 mL), and diethyl ether (2 x 25 mL) and dried at 40°C in vacua. (ii) The loaded resin (HOmg) from (i) was treated with a mixture of (4-hydroxymethyl-phenyl)-boronic acid (98.3mg, 0.65mmoles) , [1,1'-bis(diphenylphosphino) ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (lO.Gmg) and cesium carbonate (0.212g, 0.65mmoles) in N,N-dimethylformamide (5mL) and the mixture was agitated at 40°C under a nitrogen atmosphere for 72 hours. The resin was drained, washed sequentially with tetrahydrofuran/water (l:lv/v) (2 x 5mL), tetrahydrofuran (2 x 5mL) , N,N-dimethylformamide (3 x 5mL), dichloromethane (6 x 5mL) and diethyl ether (2 x 5ml), then dried at 45°C in vacuo. The resin was treated with dichloromethane/trifluoroacetic acid (19:1 by volume) (3mL) for 30 mins and the solution drained from the resin. This procedure was repeated. The combined solutions were concentrated in vacuo and the residue purified by hplc (gradient: 30% acetonitrile/70% water containing 0.1% trifInoroacetic acid to 90% acetonitrile/10% water at a rate of 1%/min) to compound 110 (18.3mg) as a solid. LC/MS System B; Rt = 1.4Brains, m/z (ES~ = 337 (M-H for C20H1805) • Example 27B: Synthesis of 5-Methyl-4- (Figure Removed) The loaded resin (HOmg) (from example 27A, (i) ) was treated with a mixture of (4-methylsulphany1-pheny1)-boronic acid (109mg, 0.65mmoles), [1. l'-bis(diphenylphosphino) ferrocene]dichloropalladium(II) complex with dichloromethane { 1:1) (10.6mg) and potassium acetate (0.064g, 0.65mmoles) in N,N-dimethylformamide (5mL) and the mixture was agitated . at 40°C for 60 hours. The resin was drained, washed sequentially with tetrahydrofuran/water (l:lv/v) (2 x 5mL) , tetrahydrofuran (2 x 5mL), N,N-dimethylformamide (3 x 5mL), dichloromethane (6 x 5mL) and diethyl ether (2 x 5ml), then dried at 45°C in vacuo. The resin was treated with dichloromethane/trifluoroacetic acid (19:1 by volume) (3mL) for 30 nuns and the solution drained from the resin. This procedure was repeated. The combined solutions were concentrated in vacuo and the residue purified by hplc (gradient: 30% acetonitrile/70% water containing 0.1% trifluoroacetic acid to 90% acetonitrile/10% water at a rate of 1%/min) to afford compound lll(5.0mg) as a solid. LC/MS System B; Rt = 1.90mins, m/z (ES~) = 353 (M-H for C2oHi804S) . Example 27C: Synthesis of 4-(3'-Hydroxy-biphenyl-4-yloxymethyl) -5-methyl-f-uran~2-carboxylic acid (Figure Removed) Compound (112) was prepared from compound (26) and (3-hydroxy-phenyl)-boronic acid by adapting the procedure of Example 27A. LC/MS System B; Rt = 1.23mins, m/z (ES") = 323 (M-H for Ci9H1605) . Example 27D: 4-(4'-Dimethylamino-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carboxylic acid (113) (Figure Removed) Compound (113) was prepared from compound (26) and (4-dimethylamino-phenyl)-bornnic acid by adapting the procedure of Example 27B. LC/MS System B; Rt = 1.83mins, m/z (ES") = 350 (M-H for C2iH2iN04) . Example 27E: Synthesis of 5-Methyl-4-(4'-trifluoromethoxy-biphenyl-4-yloxymethyl)-furan-2-carboxylic acid (114) (Figure Removed) Compound (114) was prepared from compound (26) and . (4-trif luoromethoxy-phenyl) -boronic acid by adapting the procedure of Example 27B. LC/MS System C; Rt = ll.Olmins, m/z (ES~) = 391 {M-H for C2oHi5F305) . Example 27F: 5-Methyl~4- (2; -trif luoromethoxy-biphenyl-4-yloxymethyl) -furan-2-carboxylic acid (115) (Figure Removed) Compound (115) was prepared from compound (26) and (2-trif luoromethoxy-phenyl) -boronic acid by adapting the procedure of Example 27B. LC/MS System B; Rt = 1.97mins, m/z (ES~) = 391 (.M-H for C2oH15F305) . Example 27G: Synthesis of 4- (3' -Methoxy-biphenyl-4-yloxymethyl) -5-methyl~furan~2-carboxylic acid (116) Compound (116) was prepared from compound (26) and (3- methoxy-phenyD-boronic acid by adapting the procedure of Example 27B. LC/MS System B; Rt = 1.79mins, m/z (ES") = 337 (M-H for C2oH18Ob) . Example 27H: Synthesis of 4-(3'-Acetyl-biphenyl-4-yloxymethyl)-5-methyl-f-uran-2-carboxylic acid (117) Compound (117) was prepared from compound (26) and (3-acetyl-phenyl)-boronic acid by adapting the procedure of Example 27B. LC/MS System B; Rt = 1.69mins, m/z (ES") = 349 (M-H for C21Hi805) . Example 271: Synthesis of 4-(4'-Fluoro-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carboxylic acid (118) ompound (118) was prepared from compound (26) and (4-fluoro-phenyl)-boronic acid by adapting the procedure of Example 27R. LC/MS System B; Rt = 1.79mins, m/z (ES") = 325 (M-H for C19H15FO4) . (Figure Removed)124 example 28: Synthesis of N-[4-(4'-Methoxy-biphenyl-4-yloxymethyl) -5-methyl-f uran-2-carbonyl] -dimethylamino- s-ulphonamide (122)' (Figure Removed) N,N-Dimethylsulphamide (73mg, 0 . 59mmoles) , l-[3-(dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (31mg, 0.162mmoles) and dimethyl-pyridin-4-yl-amine (ling) were added to a stirred solution of 4- (4 ' -methoxy-biphenyl-4-yloxymethyl) -5-methyl-f uran-2-carboxylic acid (4) (50mg, 0.148mmoles) in dichloromethane (20ml). The mixture was stirred under an argon atmosphere for 18 hours. After evaporation of the solvent, the residue was partitioned between dichloromethane and water. The aqueous phase was separated and extracted with dichloromethane. The combined extracts were washed with 1M aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, brine and dried (MgSO4) . Evaporation of the solvent afforded the crude product, which was purified by HPLC (gradient: 30% acetonitrile/70% water containing 0.1% trif luoroacetic acid to 98% acetonitrile/2% water at a rate of 1%/min) to afford compound 122(23. 5mg) as a white solid. LC/MS System C : Rt = 3.67 mins, m/z (ES~) = 443 ( (M-H) for Example 29: Alternative synthesis of 4- (4 ' -Fluoro-biphenyl-4 -yloxymethyl) ~5-methyl-f-uran-2-carboxylic acid (118) (a) 3-(4-Iodo-phenoxymethyl)-2-methyl-furan (123) 3-(4-Iodo-phenoxymethyl)-2-methyl-furan was prepared from (2-methyl-furan-3-yl)-raethanol and 4-iodo-phenol in an analogous manner to that described in Example 14 (a) . (b) 3- (4'-Fluoro-biphenyl-4-yloxymethyl)-2-methyl-furan (124) A mixture of (4-fluoro-phenyl)-boronic acid (300mg, 2.1mmoles), 3-(4-iodophenoxyrnethyl)-2-methyl-furan (123) (SOOmg, 1.6mmoles) and potassium acetate (0.6g) in N,N-dimethylformamide (70mL) was degassed, treated with [1,1'-bis(diphenylphosphino) ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (90mg) and the mixture was agitated at 95°C for 12 hours under an argon atmosphere, The mixture was concentrated in vacuo, partitioned between water (100ml) and diethyl ether (200ml). The aqueous phase was re-extracted with diethyl ether, and the combined etheral phases were dried and evaporated. The residue was purified by flash chromatography, using diethyl ether as eluent, to afford compound 124(200mg) as a solid. This material was used directly. (c) 4-(4'~Fluoro-biphenyl~4~yloxymethyl)-5-methyl-furan~2- carboxylic acid (118) (Figure Removed) A solution of 3-(4'-fluoro-biphenyl-4-yloxymethyl)-2-methyl-furan (124) (200mg, 0.71mmoles) in dry tetrahydrofuran (15ral) was cooled to -70°C and stirred under an argon atmosphere. The mixture was treated dropwise with sec-butyl lithium (0.6ml, of a 1. 3M solution in cyclohexane) and stirred for 1 hour at -70°C. The reaction was quenched by the addition of excess solid carbon dioxide and allowed to warm to room temperature. The mixture was diluted with water, washed with diethyl ether and the aqueous phase acidified to pH = 6 withdilute aqueous hydrochloric acid. The mixture was extracted with ethyl acetate, the extracts dried (MgS04) , and solvent removed in vacua to give a yellow oil. The oil was purified by hplc to afford compound 118(15mg) as a solid. LC/MS System A; Rt = 3.71mins, m/z (ES") = 325 (M-H for Ci3H15FO4) . Example 30: Synthesis of 4-(2'-Methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carboxylic acid (126) and N-[4-(2'-Methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carbonyl]-benzenesnlfonamide (127) (a) 4-(2'-Methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carboxylic acid methyl ester (125) (Figure Removed) A degassed mixture of 5-methyl-4-[4- (4, 4 , 5, 5-tetramethyl-[1, 3, 2]dioxaborolan-2-yl) -phenoxymethyl] -furan-2-carboxylic acid methyl ester (119) (200mg, 0.54mmoles), l-bromo-2-methoxy-benzene (80u.l, 0 . 65mmoles) , 2M aqueous cesium carbonate (1.0ml) and ), [1, 1'-bis (diphenylphosphino) ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (44mg) in 1,4-dioxan (30ml), under an argon atmosphere was heated at 95°C for 18 hours. After cooling, the mixture was concentrated, the residue dissolved in ethyl acetate and washed with brine and dried. After evaporation of the solvent, the residue was purified by flash chromatography using cyclohexane/ethyl acetate 9:lv/v as eluent to afford compound 125(40mg) as an oil. LC/MS System A; Rt = 4.14 mins, m/z (ES+) = 353weak (M+H for C2iH2oO5) . (b) 4- (2' -Methoxy-biphenyl-4-yloxymethyl) -5-methyl-furan-2~ carboxylic acid (126) (Figure Removed) A solution of 4- (2' -inethoxy-biphenyl-4-yloxymethyl) -5- rnethyl-furan-2-carboxylic acid methyl ester (125) (40mg, O.llmmoles) in dry tetrahydrofuran (25ml) was treated with potassium trimethylsilanoate (73mg, 0.56mmoles) and the mixture stirred under an argon atmosphere for 16h. After evaporation of the solvent the residue was acidified to pH 2 with 0.1M aqueous hydrochloric acid and the mixture extracted with ethyl acetate. The dried extracts were evaporated and the residue pumped under high vacuum at 40°C to afford compound 126(29mg) as an off-white solid. LC/MS System D; Rt = 8.30mins, m/z (ES+) = 339 (M+H for C2oHiBO5) . (c) N-[4-(2'-Methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carbonyl]-benzenesulphonamide (127) Compound (127) was prepared from compound (126) by adapting the procedure of Example 2A. LC/MS System D; Rt = i.l7mins, m/z (ES+) - 478 (M+H for C26H23N06S) . Example 31: Synthesis of 4™(4'-Difluoromethoxy-biphenyl-4-yloxymethyl)-5-methyl-furari-2-carboxylic acid (129), N-t4- (4'-Difluoromethoxy-biphenyl-4-yloxymethyl) -5-methyl-furan-2-carbonyl]-benzenesulfonamide (130) and 3,5-Dimethyl-isoxazole-4-sulfonic acid [4-(4'-difluoromethoxy-biphenyl -4-yloxymethyl) -5-methyl-ftiran-2-carbonyl]-amide (131) (a) 4- (4f-difluoromethoxy-biphenyl-4-yloxymethyl) -5-methyl-furan-2-carboxylic acid methyl ester (128) (Figure Removed) A degassed mixture of 5-methyl-4- [4- (4, 4, 5, 5-tetramethyl-[1, 3, 2] dioxaborolan-2-yl) -phenoxymethyl] -furan-2-carboxylic acid methyl ester (119) (200mg, 0.54mmoles), 4-dif luoromethoxy-1-iodo-benzene (175mg, 0.65ramoles), 2M aqueous cesium carbonate (0.81ml) and ), {1,1'-bis (diphenylphosphino) ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (20mg) in 1,4-dioxan (10ml), under an argon atmosphere was heated at 80°C for 20h. Further quantities of 4-dif luoromethoxy-1-iodo-benzene (87.5mg, 0 . 0 . 27mmoles) and [1, 1'-bis (diphenylphosphino) ferrocene] dichloropalladium (II) complex with dichloromethane (1:1) (lOmg) were added and heating at 80°C was continued for 4 hours. After cooling, the mixture was concentrated. The residue was dissolved in dichloromethane and washed with water and brine, and dried. The solvent was evaporated and the residue was purified by flash chromatography using petrol (40-60°) /diethyl ether 9:lv/v as eluent to afford compound 128(120mg) as a wax. LC/MS System A; Rt = 4.14 mins . (b) 4- (4' -Dif luoromethoxy-biphenyl~4-yloxymethyl) -5-methyl-furan-2-carboxylic acid (129) (Figure Removed) Compound (129) was prepared fromcompound (128) by adapting the procedure of Example 30 (b). LC/MS System C; Rt = 8.53mins, m/z (ES") = 373 (M-H for C2oHi6F205) . (c) N-[4-(4'-Difluoromethoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carbonyl]-benzenasulphonamide (130) (Figure Removed) Compound (130) was prepared from compound (129) by adapting the procedure of Example 2A. LC/MS System C; Rt = 9.50mins, m/z (ES") = 512 (M-H for C26H2iF2N06S) . (d) 3,5-Dimethyl-isoxazole-4-sulphonic acid [4~(4f-difluoromethoxy~biphenyl-4~yloxymethyl)-5-methyl-furan-2-carbonyl]-amide (131) (Figure Removed) compound (131) was prepared from compound (129) by adapting the procedure of Example 2A. LC/MS System C; Rt = 9.47mins, m/z (ES') = 531 (M-H for Example 32: Synthesis of N-{4- [4- (5-Methoxy-pyridin-2-yl) -phenoxymethyl] -5-methyl-furan-2-carbonyl) -benzenesulf onamide (132), 3,5-Dimethyl-isoxazole-4-sulfonic acid {4-[4-(5-methoxy-pyridin-2-yl) -phenoxymethyl] -5-methyl-f uran-2-carbonyl) -amide (133), N-{4- [4- (5-Methoxy-pyridin-2-yl) -phenoxymethyl] -5-methyl-f uran-2-carbonyl} -2-methyl-benzenesulfonamide (134) and N-{4- [4- (5-Methoxy-l-oxy-pyridin-2-yl) -phenoxymethyl} -5-methyl-furan-2-carbonyl}-benzenesulf onamide (135) (a) N-{4-[4- (5-Methoxy-pyridin-2-yl) -phenoxymethyl] -5-methyl-furan-2-carbonyl) -benzenesulphonamide (132) (Figure Removed) Compound (132) was prepared from compound (53) by adapting the procedure of Example 2A. LC/MS System D; Rt = 7.10mins, m/z (ES+) = 479 (M+H for (b) 3,5-Dimethyl-isoxazole-4-sulphonic acid {4-[4-(5-methoxy~pyridin~2-yl) -phenoxymethyl] -5 -methyl-f ur an -2 -carbonyl) -amide (133) (Figure Removed) Compound (133) was prepared from compound (53) by adapting the procedure of Example 2A. LC/MS System D; Rt = 7.83mins, m/z (ES+) = 498 (M+H for C24H23N30-,S) . (c) N~{4-[4-(5-Methoxy-pyridin-2-yl)-phenoxymethyl]-5-methyl-furan-2-carbonyl}-2-methyl-benzenesulphonamide (134) (Figure Removed) Compound (134) was prepared from compound (53) by adapting the procedure of Example 2A. LC/MS System D; Rt = 8.43mins, m/z (ESt) ==493 (M+H for (d) N-{4-[4-f5-Methoxy-l-oxy-pyridin-2-ylj -phenoxymethylJ• 5-methyl-£uran-2-carbonyl}-benzenesulphonamide (135) (Figure Removed) solution of N-{4-[4-(5-methoxy-pyridin-2-yl)-phenoxyrnethyl] -5-methyl-f uran-2-carbonyl} - benzenesulphonamide (132) (25mg, 0.042mmoles) in a mixture of methanol (0.5ml) and chloroform (1ml) was treated dropwise with a solution of 3-chloro-benzenecarboperoxoic acid (lO.Gmg of 72% wt.% peracid) in chloroform (1.5ml). After stirring for 21 hours at room temperature, a further quantity of 3-chloro-benzenecarboperoxoic acid (S.Omg of 72% wt.% peracid) in chloroform (1ml) was added and the mixture stirred for 6 hours. Another aliquot of 3-chloro-benzenecarboperoxoic acid (8.0mg of 72% wt .% peracid) in chloroform (1ml) was added and stirring continued for 21 hours. The mixture was evaporated and the residue was purified by HPLC (gradient: 25% acetonitrile/75% water containing 0.1% trifluoroacetic acid to 98% acetonitrile/2% water at a rate of 1%/min) to afford compound 135 (6mg) as a solid. LC/MS System A; Rt = 3.03mins, m/z (ES+) = 495 (M+H for C25H22N207S) . Example 33: Synthesis of 5-Methyl-4-(4-pyrimidin-2-yl-phenoxyroethyl)-furan-2-carboxylic acid (137) and N-[5-Methyl-4-(4-pyrimidin-2-yl-phenoxymethyl)-furan-2-carbonyl]-benzenesulfonamide (138) fa; 5-Methyl-4- (4-pyrimidin-2-yl-phenoxymethyl)-furan-2-carboxylic acid methyl ester (136) (Figure Removed) Compound (136) was prepared from compound (119) and 2-bromo-pyrimidine by adapting the procedure of Example 30 (a). LC/MS System A; Rt = 3.43 mins, m/z (ES+) = 325 (M+H for (b) 5-Methyl-4-(4-pyrimidin-2-yl-phenoxymethylJ-furan-2-carboxylic acid (137) (Figure Removed) Compound (137) was prepared from compound (136) by adapting the procedure of Example 30(b). LC/MS System D; Rt = 6.21mins, m/z (ES4) = 311 (M+H for CnHi4N204) . (c) N-[5-Methyl-4- (4-pyrimidin-2-yl-phenoxymethyl) -furan-2-carbonylJ-Jbenzenesulphonamide • (138) (Figure Removed) Compound (138) was prepared from compound (137) by adapting the procedure of Example 2A. LC/MS System D; Rt = 7.50mins, m/z (ES+) - 450 (M+H for Example 34: Synthesis of 4- (2 ' , 4 ' -Dimethoxy-biphenyl-4-yloxymethyl) -5-methyl-fTiran-2-carboxylic acid (140), N-[4-(2 ' , 4 ' -Dimethoxy-biphenyl-4-yloxymethyl) -5-methyl-furan-2-carbonyl] -benzenesulfonamido (141) and 3 , r>~Dimethyl-isoxazole-4-sulf onic acid [4- (2 ' , 4 ' -dimethoxy-biphenyl-4-yloxymethyl) -5-methyl-fiaran-2 -carbonyl] -amida (142) (a) 4~(2', 4'-Dimethoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2~carboxylic acid methyl ester (139) Compound (139) was prepared from compound (119) and 1-bromo-2,4-dimethoxy-benzene by adapting the procedure of Example 31(a). LC/MS System A; Rt = 4.09 mins. (b) 4-(2',4'-Dimethoxy-biphenyl-4-yloxymethyl)-5-methyl-x"uran-2-cari?oxylic acid (140) (Figure Removed) Compound (140) was prepared from compound (139) by adapting the procedure of Example 31 (b) . LC/MS System D; Rt = 8.20mins, ra/z (ES+) = 369 (M+H for C2iH2oOe) . (c) N-[4-(2r,4 '-Dimethoxy-biphenyl-4-yloxymethyl)-5-methyl• r"uran-2-carJbonyiy --benzenesulphonamide (141) (Figure Removed) stirred solution of 4- (2',4'-dimethoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carboxylic acid (140) (50mg, 0.136mmoles), benzenesulphonamide (32mg, 0.204mmoles) and 4-(N,N-dimethylamino)-pyridine (5mg) in a mixture of tetrahydrofuran (8ml) and acetonitrile (2ml) was treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (32mg, 0.163mmoles) . The mixture was stirred at room temperature for 16 hours under an argon atmosphere. The reaction mixture was concentrated in vacuo and the residue was purified by HPLC to afford compound 141(24mg) as a white solid. LC/MS System C; Rt = 8.99mins, m/z (ES~) = 506 (M-H for C2-7H25N07S) . (d) 3,5-Dimethyl-isoxazole-4-sulphonic acid [4-(2',4'~ dimethoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carbonyl]-amide (142) Compound (142) was prepared from compound (140) and 3,5-dimethyl-isoxazole-sulphonic acid amide by adapting the procedure of Example 34 (c) . LC/MS System C; Rt = 9.13mins, m/z (ES~) = 525 (M-H for Example 35: Synthesis of 4- (41 -Methoxy-2 ' -methyl-biphenyl-4-yloxymethyl) -5-methYl~f"uran-2-carboxylic acid (144), N-[4~ (4 ' -Methoxy-2 ' -methyl-biphenyl-4-yloxymethyl) -5-methyl-furan-2-carbonyl] -benzenesulfonamide (145) and 3 , 5-Dimethyl-isoxazole-4-sulf onic acid [4- (4 ' -methoxy-2 ' -methyl-biphenyl-4-yloxymethyl) -5-methyl-furan-2-carbonyl] -amide (146) (a) 4- (4 '-Methoxy-2f-methyl-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carboxylic acid methyl ester (143) (Figure Removed) Compound (143) was prepared from compound (119) and 1-bromo-4-methoxy-2-methyl-benzene by adapting the procedure of Example 31(a). LC/MS System A; Rt = 4.24 mins. (b) 4- (4 '-Methoxy-2'-methyl-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carboxylic acid (144) (Figure Removed) Compound (144) was prepared from compound (143) by adapting the procedure of Example 31(b). LC/MS System D; Rt = 8.48mins, m/z (ES+) = 353 (M+H for C2iH2o05) . (c) N-[4-(4'-Methoxy-2'-methyl-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carbonyl]-benzenesulphonamide (145) (Figure Removed) Compound (145) was prepared from compound (143) and by adapting the procedure of Example 34(c). LC/MS System C; Rt = 9.40mins, m/z (ES") = 490 (M-H for C27H25N06S) . (d) 3,5-Dimethyl-isoxazole-4-sulphonic acid [4-(4 '-methoxy-2f-methyl'biphenyl-4-yloxymethyl)-5-methyl-furan-2-carbonylj-amide (146) Compound (146) was prepared from compound (143) and 3,5-dimethyl-isoxazole-sulphonic acid amide by adapting the procedure of Example 34 (c) . LC/MS System D; Rt = 11.29mins, m/z (ES~) = 509 (M-H for Example 36: Synthesis of 5- [4- (Biphenyl-4-yloxymethyl) -5-methyl-furan-2-yl] -iH-tetrazole (149) (a) 4-Hydroxymethyl-5-methyl~furan-2-carbonitrile (147) (i) Sec-Butyl lithium (1.3M solution in cyclohexane, 57.1ml, 74.2mmoles) was added, dropwise during lOmin, to a stirred solution of 4-(tert-butyl-diphenyl-silanyloxymethyl)~5-methyl-furan (reference example 2A) (20.Og, 57.1mmoles) under an argon atmosphere and with cooling to -78°C. After stirring for an additional 45 minutes, the cooling bath was removed for 15 minutes, and then the reaction was re-cooled to -78°C. A solution of dimethylformamide (10ml) in tetrahydrofuran (40ml) was added during 5 minutes, the reaction mixture stirred for 2 hours at -78°C then allowed to warm to room temperature. The reaction was quenched by the addition of saturated aqueous ammonium chloride (200ml). Diethyl ether (500ml) was added the organic phase was separated, and the aqueous phase was extracted with diethyl ether (500ml). The combined extracts were washed with water (500ml) and brine (500ml), and dried (MgS04) . Evaporation of the solvent afforded 4-(tert-butyl-diphenyl-silanyloxymethyl)-5-methyl-furan-2-carbaldehyde (20.4g). (ii) Hydroxylamine hydrochloride (l.llg, IS.Ommoles) and triethylamine (2.22ml) were added to a solution of 4-(tert-butyl-diphenyl-silanyloxymethyl)-5-methyl-furan-2-carbaldehyde from (i)(6.3g, IG.Ommoles) in dichloromethane (125ml) and the mixture was stirred at room tempreature for 17 hours. After cooling to 0°C, 2-Chloro-l,3-.dimethylimidazolium chloride (2.81g, 16.6mmoles) and triethylamine (4.6ml) were added and the yellow suspension was stirred at room temperature for 24 hours. The mixture was diluted with water and extracted with dichloromethane. The combined extracts were washed with 5% aqueous hydrochloric acid, saturated aqueous sodium bicarbonate and water, and finally dried (MgS04) . The solvent was evaporated and the residue was purified by flash chromatography (silica, cyclohexane/diethyl ether 99:1 v/v as eluent) to afford 4- (tert-butyl-diphenyl-silanyloxymethyl)-5-methyl-furan~2-carbonitrile as a viscous oil, (3.75g). (iii) .A solution of 4- (tert-butyl-diphenyl-silanyloxymethyl)-5-methyl-furan-2-carbonitrile from (ii) (3.75g) in tetrahydrofuran (100ml) was cooled to 0°C under an argon atmosphere, and was treated with a 1M solution of tetrabutylammonium fluoride in tetrahydrofuran (22ml) . The mixture was allowed to warm to room temperature and stirred for 16 hours. The volatiles were removed and the residue was partitioned between ethyl acetate and water. The organic phase was separarted and the aqueous phase was extracted with more ethyl acetate. The combined ethyl acetate extracts were washed with 1M aqueous hydrochloric acid and brine, and dried. The solvent was evaporated and the crude orange oil was purified by flash chromatography (silica, gradient elution with 0% to 40% ethyl acetate in cyclohexane) to afford compound 147 as a pale yellow oil (1.3g). (b) 4- (Biphenyl-4-yloxymethyl) -5-methyl-furan-2-carbonitrile (148) (c) (Figure Removed) Dlisopropylazodicarboxylate (1.84g, lO.Smmoles) was added to a solution of 4-hydroxymethyl--5-methyl-furan-2-carbonitrile (147) (1.32g, 9.6mmoles), biphenyl-4-ol (1.63g, 9.6mmoles) and triphenylphosphine (4.3g, 16.35mmoles) in tetrahydrofuran (50mL) with stirring and cooling to 0°C under an argon atmosphere. After 5 minutes, the cooling was removed and the mixture stirred at room temperature for 16h. The solvent was evaporated and the residue partitioned between ethyl acetate and water. The ethyl acetate phase was washed with brine and dried. After the solvent was evaporated, the residue was purified by flash chromatography (silica, gradient elution with 5% to 10% ethyl acetate in cyclohexane) to afford compound 148 as a white solid (2.2g).141 -i IR (powder) CN st. 2225cm (c) 5-[4- (Biphenyl-4-yloxymethyl)-5-methyl-furan-2-ylJ-1H-tetrazole (149) (Figure Removed) A mixture of 4-(biphenyl-4-yloxymethyl)-5-methyl-furan-2-carbonitrile (148) (lOOmg, 0.35mmoles), sodium azide (27mg, 0.415mmoles) and potassium carbonate (62ing, 0.45mmoles) in dimethylformamide (5ml) was heated at 90°C for 96 hours then at 120°C for 24 hours. The mixture was evaporated and the residue purified by HPLC to afford compound 149 as a white solid (64mg) . LC/MS System D; Rt = 9.53mins, m/z (ES+) = 333 (M+H for Ci9Hi6N402) . Example 37: Synthesis of 4-(4'-Difluoromethoxy-biphenyl-4-ylsulf any luxe thy 1) -5-methyl-furan-2-carboxylic acid (153) , N-[4-(4'-Difluoromethoxy-biphenyl-4-ylsulfanylmethyl)-5-methyl-furan-2-carbonyl]-2-methyl-benzenes-ulfonamide (154), N- [4- (4 ' -Dif l\ioromethoxy-biphenyl-4 -ylsulfanylmethyl)-5-methyl-furan-2-carbonyl]-benzenesulfonamide (155) and N-[4-(4'-Difluoromethoxy-biphenyl-4-sulfinylmethyl)-5-methyl-furan-2-carbonyl]-2-methyl-benzenesulfonamide (156) (a; 4-(4-Bromo~phenylsulphanylmethyl)-5-methyl-furan-2-carboxylic acid methyl ester (150) (Figure Removed) Diisopropylazodicarboxylate (1.27g, 6.3mmoles) was added to a solution of triphenylphosphine (1.65g, 6.Smnoles) in tetrahydrofuran (15ml) with stirring and cooling in an ice/water bath. A solution of 4-hydroxymethyl-5-methyl-furan-2-carboxylic acid methyl ester (16) (536mg, 3.15mmoles) and 4-bromo-thiophenol (584mg, 3.09mmoles) in tetrahydrofuran (5ml) was added and the mixture stirred for 30 minutes at 0°C then 72 hours at room temperature. The solvent was evaporated and the residue extracted with heptane then diethyl ether. The extracts were combined and evaporated to give a yellow oil which was purified by by flash chromatography using heptane/ethyl acetate 9:lv/v as eluent. This gave compound 150(600mg) as a white solid. LC/MS System A; Rt = 4.12mins. (b) 5~Methyl-4~[4- (4,4,5,5-tetramethyl-[1,3,2]dloxaborolan 2-yl)-phenylsulphanylmethyl]-furan-2-carboxylic acid methyl ester (151) (Figure Removed) [1, l'-Bis (diphenylphosphino) ferrocene] dichloropalladium (II) -omplex with dichloromethane ( 1:1) (30mg) and 4,4,5,5-tetramethyl-[l, 3, 2]dioxaborolane (2.34ml of a 1M solution in tetrahydrofuran) were added to a degassed solution of 4-(4-bromo-phenylsulphanylmethyl)-5-methyl-furan-2-carboxylic acid methyl ester (150) (400mg, 1.17mmoles) in 1,4-dioxan (120ml). The mixture was heated at 100°C, under an argon atmosphere, for 20 hours, cooled and evaporated. The residue was partitioned between ethyl acetate and water, and the organic phase washed -with brine and dried (MgSCu) . After evaporation of the solvent the residue was purified by by flash chromatography, using heptane/ethyl acetate 9:lv/v as eluent, to afford compound 151(212mg) as a colourless oil. (c) 4- (4f-difluoromethoxy-biphenyl-4-ylsulphanylmethyl)-5-methyl-furan-2-carboxylic acid methyl ester (152) (Figure Removed) [1, lf-Bis (diphenylpho.sphino) ferrocene] dichloropalladium (II) complex with dichloromethane (1:1) (12.8mg) was added to a degassed mixture of 5-rnethyl-4- [4- (4 , 4 , 5, 5~tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylsulphanylmethyl]-furan-2-carboxylic acid methyl ester (151) (200mg, 0.516mmoles), 1-difluoromethoxy-4-iodo-benzene (153mg, 0.568mmoles) and 2M aqueous cesium carbonate (4.12ml) in 1,4-dioxan (15ml). The mixture was placed under an argon atmosphere and was heated at 100°C for 20 hours. After cooling, the mixture was concentrated and the residue was partitioned between ethyl acetate and water, and the mixture adjusted to pH= 2 with 1M aqueous hydrochloric acid. The organic phase was washed with brine and dried. After evaporation of the solvent, the residue was purified by flash chromatography, using heptane/ethyl acetate 9:lv/v as eluent, to afford compound 152 (126mg) as a white solid. LC/MS System A; Rt = 4.17mins. (d) 4- (4'~Difluoromethoxy-biphenyl-4-ylsulphanylmethyl)-5-methyl-furan-2-carboxylic acid (153) (Figure Removed) Compound (153) was prepared from compound (152) by adapting the procedure of Example 30(b)(127mg) as a white solid. LC/MS System D; Rt = 10.34mins, m/z (ES~) = 389 (M-H for C2oHi6F204S) . (e) N-[4-(4'-Difluoromethoxy~biphenyl~4~ylsulphanylmethyl) 5-methyl-furan-2-carbonyl]-2-methyl-benzenesulphonamide (154) (Figure Removed) Compound (154) was prepared from compound (153) and 2-methyl-benzenesulphonamide by adapting the procedure of Example 34 (c) . LC/MS System D; Rt = 11.61mins, m/z (ES+) = 544 (M+H for (f) N-[4- (4' -Difluoromethoxy-biphenyl-4-ylsulphanylmethyl) 5-methyl-furan-2-carbonyl]-benzenesulphonamide (155) (Figure Removed) Compound (155) was prepared from compound (153) by adapting the procedure of Example 2A. LC/MS System D; Rt = il.44mins, m/z (ES+) = 530 (M+H for (g) N-[4- (4f -Difluoromethoxy-biphanyl-4-ylsulphinylmethyl) 5-methyl-furan-2-carbonyl]-2-methyl-benzenesulphonamide (156) and N~[4- (4'-DifIuoromethoxy-biphenyl-4-sulfonylmethyl) -5-methyl-fux-an-2-carbonyl]-2-methyl-benzenesulfonamide (156a.) A solution of 3-chloro-benzenecarboperoxoic acid (22mg of 72% wt peracid) in chloroform (3ml) was added to a solution of N-[4-(4'-difluoromethoxy-biphenyl-4-ylsulphanylmethyl)-5- methyl-furan-2-carbonyl]-2-methyl-benzenesulphonamide (154) (50mg, 0.092mmoles) in a mixture of methanol (1ml) and chloroform (2ml). After stirring for 2 hours, the solvent was evaporated and the residue was purified by HPLC (gradient: 45% acetonitrile/55% water containing 0.1% trifluoroacetic acid to 98% acetonitrile/2% water at a rate of 1%/min) to afford compound 156(42mg) as a white solid. LC/MS System D; Rt = 9.61mins, m/z (ES~) = 558 (M-H for Also obtained was N-[4-(4'-difluoromethoxy-biphenyl-4-ylsulphonylmethyl)-5-methyl-furan-2-carbonyl]-2-methyl-benzenesulphonamide (156a)(8mg) as a white solid. LC/MS System D; Rt = 10.24mins, m/z (ES~) = 574 (M-H for C2-7H23F2NO,S2) . Example 38: Synthesis of 4-(Biphenyl-4-ylaminomethyl)-5-methyl-furan-2-carboxylic acid (160), N-[4-(Biphenyl-4-ylaminomethyl) -5-methyl-furan-2-carbonyl]-benzenesulfonamide (161) and N- [4- (Biphenyl-4-ylaminomethyl) -5-nvethyl-furan-2-carbonyl]-2-methyl-benzenesulfonamide (162) (a) 4-Formyl~5-methyl-furan-2-carboxylic acid methyl ester (157) (Figure Removed)Acetic acid 1, l-diacetoxy-3-oxo-lX5-ioda-2-oxa-indan-l-yl ester (Dess-Martin reagent) (549mg, 1.293mmoles) in dry dichloromethane was added to a solution of 4-hydroxymethyl-5-methyl-furan-2-carboxylic acid methyl ester (16) (200mg, 1.176mmoles) in dry dichloromethane (9ml) with cooling to 0°C under an argon atmosphere. After stirring for 20 minutes, the mixture was diluted with diethyl ether (40ml) and was poured into saturated aqueous sodium bicarbonate (30ml) containing sodium thiosulphate pentahydrate (4g) and agitated'vigorously for 5 minutes. The organic phase was washed with saturated aqueous sodium bicarbonate (40ml), water (50ml) and brine (50ml) and dried. After removal of the solvent, the residue was purified by flash chromatography, using petrol/diethyl ether 4:1 v/v as eluent, to afford compound 157 (140mg) as a white solid. (b) 4-(Biphenyl-4-ylaminomethyl)-5-methyl-furan-2-carboxylic acid methyl ester (158) A solution of biphenyl-4-ylamine (150mg, 0.883mmoles) and 4-formyl-5-methyl-furan-2-carboxylic acid methyl ester (157) (135mg, 0.803mmoles) in methanol (2.0ml) was stirred over molecular sieves (type 3A) for Ihour. Sodium cyanoborohydride (55mg, 0.883mmoles) was added and the mixture stirred for 18 hour at room temperature. The mixture was concentrated and partitioned between ethyl acetate (25ml) and saturated aqueous sodium bicarbonate (30ml). The aqueous phase was re-extracted with ethyl acetate (2 x 25ml) and the combined extracts were washed with brine (50ml) and dried (MgS04) . After removal of the solvent, the residue was purified by by flash chromatography, using a gradient elution of petrol/diethyl ether 9:1 v/v to 4:1 v/v, to afford compound 158(75mg). (c) 4-Chloromethyl~5-methyl-furan-2-carboxylic acid methyl ester (159) (Figure Removed) Triethylamine (196u,l, 1.41mmol.es) , followed by 4-methyl-benzenesulphonyl chloride (247mg, 1.293mmoles) were added to a stirred solution of 4-hydroxymethyl-5-methyl-furan-2-carboxylic acid methyl ester (16) (200mg, 1.176mmoles) in dry dichloromethane at 0°C under an argon atmosphere. The reaction mixture was stirred at 0°C for 15 minutes, then allowed to warm to room temperature and was stirred for a further 4 hours. The mixture was washed with saturated aqueous sodium bicarbonate (50ml) and brine (50ml), and dried (MgS04) . After removal of the solvent, the residue was purified by flash chromatography, using petrol/diethyl ether 19:1 v/v as eluent, to afford compound 159(75n\g) as a white solid. LC/MS System D; Rt = 6.34 mins, m/z (ES+) = 189 (M-fH for C8H5C103) - (d) 4- (Biphenyl-4-ylaminomethyl)-5-raethyl-furan-2-carboxylic acid methyl ester (158) (Figure Removed) Potassium iodide (32mg) and a solution of biphenyl-4-ylamine (74mg, 0.438mmoles) in tetrahydrofuran (1ml) was added to a mixture of 4-chloromethyl-5~methyl-furan-2-carboxylic acid methyl ester (159)(75mg, 0.398mmoles) and potassium carbonate (83mg) in tetrahydrofuran (1ml). The mixture was stirred at room temperature under an argon atmosphere for 16 hours, and then refluxed with the exclusion of light for 16 hours. After cooling, the mixture was concentrated and the residue was purified by by flash chromatography, using a gradient elution of petrol/diethyl ether 9:1 v/v to 4:1 v/v, to afford compound 158(91mg). LC/MS System A; Rt = 3.93 mins, m/z (ES+) 4- (Biphenyl-4-ylaminomethyl) -5-methyl-furan-2-carboxylic acid (160) A solution of 4-(biphenyl-4-ylaminomethyl)-5-methyl-furan-2-carboxylic acid methyl ester (158) (91mg, 0.283mmoles) in dry tetrahydrofuran (5ml) was treated with potassium trimethylsilanoate (182mg, 1.42mmoles) and the mixture stirred under an argon atmosphere for 3 hours. After evaporation of the solvent, the residue was purified by HPLC (gradient: 15% acetonitrile/85% water containing 0.1% trifluoroacetic acid to 55% acetonitrile/45% water at a rate of 1%/min) to afford compound 160(35mg) as a white solid. LC/MS System D; Rt = 7.64mins/ m/z (ES) = 300 (M+H for (f) N-[4- (biphenyl- 4-ylaminomethyl)-5-methyl-furan-2-carbonyl]-benzenesulphonamide (161) A stirred solution of 4-(biphenyl-4-ylaminomethyl)-5-methyl-furan-2-carboxylic acid (160) (15mg, 0.036mmoles) , benzenesulphonamide (17mg, 0.107mmoles) and 4-(N,N-dimethylamino)-pyridine (Img) in a mixture of tetrahydrofuran (3ml) and acetonitrile (0.5ml) was treated with triethylamine (5.51, 0.039mmoles) and l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (10.5mg, 0.053mmoles). The mixture was stirred at room temperature for 19 hours under an argon atmosphere. The reaction mixture was concentrated in vacua and the residue was purified by HPLC to afford compound 161 (8mg) as a white solid. LC/MS System D; Rt = 8.84mins, m/z (ES+) = 447 (M+H for C (Figure Removed) (g) N-[4-fbiphenyl- 4-ylaminomethylJ-5-methyl-furan-2-carbonyl]-2-methyl-benzenesvlphonamide (162) compound (162) was prepared from compound (160) and 2-methyl-benzenesulphonamide by adapting the procedure of Example 38(f). LC/MS System D; Rt = 10.39mins, m/z (ES+) = 461 (M+H for Example 39: Synthesis of N- (4-{ [4- (5-Methoxy-pyridin-2-yl) phenylamino] -methyl} -5-methyl-f uran-2-carbonyl) -2-methyl-benzenesulfonamide (167) (a) 4-[ (4-Bromo-phenylamino) -methyl] -5-methyl-furan~2- carboxylic acid methyl ester (163) (Figure Removed) A mixture of 4-chloromethyl-5-methyl-furan-2-carboxylic acid methyl ester (159) (0.5g, 2.65mmoles), 4-bromoaniline (2.28g, 13.25mmoles) and potassium carbonate (0.55g, 3.98mmoles) in terahydrofuran (25ml) was stirred at gentle reflux for 12 hours. The mixture was evaporated to give a yellow residue, which was purified by HPLC to afford compound 163 as a trifluoroacetic acid salt (840mg). LC/MS System A; Rt = 3.82mins/ m/z (ES4) = 324/326 (M+H for Ca4H14BrN03) - (b) 5-Methyl-4-{[4-(4,4,5,5-tetramethyl- [lr 3r2]dioxabozolan~2-yl)-phenylamino]~methyl-furan-2- carboxylic acid methyl ester (164) (Figure Removed) A mixture of 4-[(4-bromo-phenylamino)-methyl]-5-methyl-furan-2-carboxylic acid methyl ester (163) (280mg, 0.864mmoles), [1, l'-Bis (diphenylphosphino) ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (21mg), 4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (240mg, 0.950mmoles) and potassium acetate (250mg, 2.59mmoles) in dimethyl sulphoxide. (6ml) was degassed and placed under an argon atmosphere. The mixture was heated at 80°C for 5 hours, cooled and toluene (100ml) was added. The mixture was washed with water (50ml) and sodium bicarbonate was added until the pH = 9. The aqueous phase was discarded and the tolune layer filtered. After evaporation of the solvent the residue was purified by flash chromatography (silica, heptane/ethyl acetate 4:lv/v as eluent) to give compound 164 as an oil, which was used directly in the next step. (c) 4-{[4-(5-Methoxy-pyridin-2-yl)-phenylamino]-methyl}-5-methyl-furan-2-carboxylic acid methyl ester trifluoroacetic acid salt (165) 5-Methyl-4-{[4-(4,4, 5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylaraino]-methyl-furan-2-carboxylic acid methyl ester (164) (130mg, 0.525mmoles) was added to a degassed mixture of 2-bromo-5-methoxy-pyridine (99mg, 0.350mmoles), bis-(dibenzylidene-acetone)-palladium(0) (6mg) and triphenyl-phosphine (llmg) in toluene/dimethylformamide 1:1 v/v (5ml) under an argon atmosphere. Aqueous potassium carbonate (0.23ml of a 3M solution) was added and the mixture was heated at 100°C for 16 hours. The reaction mixture was concentrated and the residue was purified by HPLC to afford compound 165(38mg). LC/MS System A; Rt = 2.55mins, m/z (ES+) = 353 (M-fH for C2oH2oN204) . 4-{ [4-(5-Methoxy-pyridin-2~yl) -phenylatnino] -methyl)-5-methyl-furan-2-carboxylic acid hydrochloride salt (166) (Figure Removed) A solution of 4-{[4-(5-methoxy-pyridin-2-yl)-phenylamino]- methyl)-5-methyl-furan-2-carboxylic acid methyl ester trifluoroacetic acid salt (165) (38mg, 0.082mmoles) in tetrahydrofuran (4ml) was treated with potassium trimethylsilanoate (63mg, 0.049mmoles) and the mixture stirred at room temperature for 16 hours. The mixture was evaporated to dryness and pumped under high vacuum to remove silanol volatiles. The residue was purified by HPLC to afford a residue, which was dissolved in 1M aqueous hydrochloric acid. The solution was evaporated to give compound 166 as a solid (30mg). LC/MS System A; Rt = 2.22mins, m/z (ES+) = 339 (M+H for CigHie^O,) and m/z (ES~) = 337 (M-H for (e) N- (4-{ [4~ (5-Methoxy-pyridin-2-yl) -phenylamino] -methyl} -5-methyl-furan-2-carbonyl)-2-methyl-benzenesulphonamide (167) (Figure Removed) h suspension of 4-{[4-(5-methoxy-pyridin-2-yl)-phenylamino]- methyl}-5-inethyl-furan-2-carboxylic acid hydrochloride salt (166) (30mg, O.OSmmoles) in tetrahydrofuran (5ml) was treated with toluene-2-sulphonamide (41mg, 0.24mmoles), 1-(3-dimethylaminopropyl)-3-ethylcarbudiimide hydrochlocide (34rng, 0.116mmoles) and 4-(N,N-dimethylamino)-pyridine (lOmg, O.OSmmoles) and the mixture stirred at room temperature for 16 hours. Triethylamine (24.3mg, 0.24mmoles) was added and the mixture was stirred for a further 18 hours. The reaction mixture was concentrated and the residue was purified by HPLC to afford compound 167 as a yellow glass (l.lmg)). LC/MS System A; Rt = 2.72rnins, m/z (ES+) = 492 (M+H for Cze^s^OsS) and m/z (ES") = 490 (M-H for Example 40: Synthesis of 4- [ (4 ' -Dif luoromethoxy-biphenyl-4-ylamino) -methyl] -5-methyl-furan-2-carboxylic acid (171), N- {4- [ (4 ' -Dif luoromethoxy-biphenyl-4-ylamino) -methyl] -5-methyl-furan-2-carbonyl}-benzenesulfonamide (172) , N-{4- [ (4 ' -Dif luororaethoxy-biphenyl-4-ylamino) -methyl] -5-methyl-furan-2-carbonyl) -2-methyl-benzenesulfonamide (173) and 3,5-Dimethyl-isoxazole-4-sulf onic acid {4- [ (4 ' -dif luoromethoxy-biphenyl-4-ylamino) -methyl] -5-methyl-furan-2-carbonyl } -amide (174) (a) 4-Difluoromethoxy-4-nitro-biphenyl (168) [ 1, l'-Bis (diphenylphosphino) ferrocene] dichloropalladium(II) complex with dichloromethane (1:1) (250mg) was added to a degassed mixture of 4 , 4 , 5, 5-tetiamethyl-2- (4-nitro-phenyl) -[1, 3, 2] dioxaborolane (1.67g, 6.70mmoles), 1-dif luoromethoxy-4-iodo-benzene (2.17g, 8.04mmoles) and 2M aqueous cesium carbonate (10.05ml) in 1,4-dioxan (120ml). The mixture was placed under an argon atmosphere and was heated at 80°C for 20 hours. After cooling, the mixture was concentrated and the residue was partitioned between dichloromethane (2 x 200ml) and water (100ml) . The combined extracts were washed with brine (150ml) and dried (MgSO4) . After evaporation of the solvent, the residue was purified by flash chromatography, using petrol (60-80° ) /diethyl ether 19:lv/v as eluent, to afford compound 168(1.15g) as a beige coloured solid. (b) 4' -Difluoromethoxy-biphenyl-4-ylamine (169) A solution of 4-difluoromethoxy-4-nitro-biphenyl (168) (l.lg, 4.ISmmoles) in ethyl acetate (100ml) was hydrogenated over 10% palladium on charcoal catalyst (250mg) using a hydrogen filled balloon. After 20 hours, the mixture was filtered through a pad of diatomaceous earth and the pad rinsed with ethyl acetate. The combined filtrate and washings were evaporated to afford compound 169(855mg) as a solid. LC/MS System A; Rt = 2.87mins, m/z (ES+) = 236(M+H) and 277 (M+H acetonitrile adduct) for Ci3HiiF2NO. (c) 4-(4'-Difluoromethoxy-biphenyl-i-ylaminomethyl)-5-methyl-furan-2-carboxylic acid methyl ester (170) ompound (170) was prepared from compounds (159) and (169) by adapting the procedure of Example 38 (d). (420mg) . LC/MS System A; Rt = 4.00 mins, m/z (ES+) = 388 (M+H) and 429 (M+H acetonitrile adduct) for -4-ylaminomethyl)-5- methyl-furan-2-carboxylic acid (171) Compound (171) was prepared from compound (170) by adapting the procedure of Example 38 (e). LC/MS System D; Rt = 9.07mins, m/z (ES4) = 374 (M+H for ) N-{4-[ (4 ' -Difluoromethoxy-biphenyl- 4-ylamino) -methyl] 5-methyl-fvran-2-carbonyl) -benzenesulphonamide (172) (Figure Removed) Compound (172) was prepared from compound (171) and benzenesulphonamide by adapting the procedure of Example 38(f). LC/MS System D; Rt = 10.38mins, m/z (ES+) = 513 (M+H for (f) N-(4-[(4'-Difluoromethoxy-biphenyl- 4-ylamino)-methyl] 5-methyl-furan-2-carbc,iyl}-2~methyl-benzenesulphonamide (Figure Removed) Compound (173) was prepared from compound (171) and 2-methyl-benzenesulphonamide by adapting the procedure of Example 38 (f). LC/MS System D; Rt = 10.63mins, m/z (ES) 527 (M+H for (d) 3,5-Dimethyl-isoxazole-4-sulphonic acid {4-[(4'~ difluoroniethoxy-biphenyl- 4-ylamino) -methyl]-5-methyl-furan 2-carbonyl)-amide (174) Diisopropylethylamine (60p.l, 0.339mmoles) and a solution of 4- (4' -dif luoromethoxy-biphenyl-4-ylaininomethyl) -5 methyl-furan-2-carboxylic acid (171) (50mg, O.lOSmmoles) in N,N-dimethylformamide (1.0ml) were added to a stirred solution of 3,5-dimethyl-isoxazole-4-sulphonic acid amide (55mg, 0.308mmoles) in N,N-dimethylformamide (5.0ml). A solution of O-(7-azabenzotriazol-l~yl)-N,N,N' , N' -tetramethyluronium hexafluorophosphate (46mg, 0.124mmoles) in N,N-dimethylfornamide (1.0ml) was added and the mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated in vacua and the residue was purified by HPLC to afford compound 174 (2mg) as a solid. LC/MS System D; Rt = 10.35mins, m/z (ES+) = 532 (M-fH for Example 41: Synthesis of 4-{ [ (4 ' -Dif luoromethoxy-biphenyl-4-yl) -methyl-amino] -methyl} -5-methyl-furan-2-carboxylic acid (176) and N- (4- {[ (4 ' -Dif luoromethoxy-biphenyl-4-yl) -methyl-amino] -methyl} -5-methyl-f uran-2-carbonyl) -2-methyl-benzenesulfonamide (177) (a) 4-{ ( (4 ' -Dif luoromethoxy-biphenyl-4-yl) -methyl -amino] -methyl }-5-methyl-furan-2-carboxylic acid methyl ester (175) (Figure Removed) lodomethane (91mg, 0.64mmoles) and potassium carbonate (88mg, 0.64mmoles) were added to a solution of 4-(4'-dif luoromethoxy-biphenyl-4-ylaminomethyl) -5-methyl-furan-2-carboxylic acid methyl ester (170) (62mg, 0.16mmoies) in N,N-dimethylformamide (10ml) and the mixture stirred at room temperature for 36 hours under an argon atmosphere. The mixture was then heated at 35°C for 21 hours. The mixture was partitioned between dichloromethane and water, the organic phase separated and dried (MgSC>4) . After evaporation of the solvent, the residue was purified by flash chromatography, using cyclohexane/ethyl acetate 99:lv/v as eluent, to afford compound 175(41mg) as a brown oil. This was used directly in part (b) . b) 4-{[(4' -Difluoromethoxy-biphenyl-4-yl)-methyl-amino]-methyl)-5-methyl-furan-2-carboxylic acid (176) (Figure Removed) A solution of 4-{[(4'-difluoromethoxy-biphenyl-4-yl)-methyl-amino] -methyl}-5-methyl-furan-2-carboxylic acid methyl ester (175) (30mg, O.OVmmoles) in dry tetrahydrofuran (20ml) was treated with potassium trimethylsilanoate (19mg, O.lSmmoles) and the mixture stirred under an argon atmosphere for 30 hours. Trifluoroacetic acid was added until the pH = 2. After evaporation of the solvent, the residue was purified by HPLC to afford compound 176(4.8mg) as a white solid. LC/MS System D; Rt = 9.42mins, m/z (ES+) = 388 (M+H for (c) N-(4-{ [ (4 '-Difluoromethoxy-biphenyl-4-yl) -methyl-amino]-methyl}-5-methyl-furan-2-carbonyl) -2-methyl-benzenesulfonamide (177) (Figure Removed) A stirred solution of 4-{ [ (4 •'-dif luoromethoxy-biphenyl-4-yl)-methyl-amino]-methyl}-5-methyl-furan-2-carboxylic acid (176) (21mg, 0.054mmoles), 2-methyl-benzenesulphonamide (19mg, O.lOSmmoles) and 4- (N,N-dimethylamino) -pyridine (Img) in a mixture of dichloromethane (8ml) and acetonitrile (2ml) was treated with 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (11.4mg, 0 . 060mmoles) . The mixture was stirred at room temperature for 18 hours under an argon atmosphere. The reaction mixture was concentrated in vacua and the residue was purified by HPLC to afford compound 177(2.9mg) as a solid. LC/MS System D; Rt = 11.21mins, m/z (ES+) = 541 (M+H for Example 42: Biological Results Binding ability to human EP receptors Membranes were prepared from cells stably transfected with human EP receptor cDNA. In brief, cells were cultured to confluency, scraped from culture flasks, and centrifuged (800 g, 8 minutes, 4°C). Cells were twice washed in ice cold homogenisation buffer containing 10 mMTris-HCl, 1 mM EDTA.2Na, 250 mM sucrose, 1 mM PMSF, 0 . 3 mM indomethacin, pH 7.4, homogenised and re-centrifuged as before. The supernatant was stored on ice and pellets re-homogenised and re-spun. Supernatants were pooled and centrifuged at 40000g, 10 minutes, 4°C. Resultant membrane pellets were stored at -80°C until use. For assay, membranes expressing human EP4, EPs, EP2 or receptors were incubated in Millipore (MHVBN45) plates containing assay buffer, radiolabelled [3H]PGE2 and 0 . 1 to 10 000 nM concentrations of compounds. Incubations were performed at suitable temperatures and for suitable times to allow equilibrium to be reached. Non-specific binding was determined in the presence of lOuM PGEa • Bound and free radiolabel was separated by vacuum manifold filtration using appropriate wash buffers, and bound radiolabel was determined by scintillation counting. Constituents of each of the buffers are included in table 1 below. The affinity or pKi of each compound for each receptor was calculated from the concentration causing 50% radioligand displacement (IC50) using the Cheng-Prusoff equation: (radioligand concentration \ radioligand KD } This approach follows that set out in Kenakin, T.P., Pharrnacologic analysis of drug receptor interaction. Raven Press, New York, 2nd edition. (Table Removed) WE CLAIM: 1. A Furan compound of formula (I): (Formula Removed) or a pharmaceutically acceptable salt solvate or chemically protected form thereof, wherein: R2 is H or an optionally substituted C1-4 alkyl group; Y is either -(CH2)n-X-, where n is 1 or 2 and X is 0, S,S(=O)or S(=0)2, or NRN1, where RN1 is selected from H or optionally substituted C1-4 alkyl, or Y is -C(=0)NRN2-, where RN2 is selected from H and optionally substituted C1-7 alkyl or C5-20 aryl; R3 is an optionally substituted C6 aryl group linked to a further optionally substituted C6 aryl group, wherein if both C6 aryl groups are benzene rings, there may be an oxygen bridge between the two rings, bound adjacent the link on both rings; A is a single bond or a C1-3 alkylene group; and R5 is either: (i) carboxy; (ii) a group of formula (II): (Formula Removed) (iii) a group of formula (III): (Formula Removed) wherein R is optionally substituted C1-7 alkyl,C5-20 aryl or NRN3RN4, where RN3 and RN4 are independently selected from optionally substituted C1-4 alkyl; or (iv) tetrazole-5-yl; except that when R2 is methyl, Y is CH2-0- and R5 is carboxy or a C1-7alkyl ester thereof, then R3 is not: (Formula Removed) 2. The compound as claimed in Claim 1, wherein R2 is selected from H, methyl, CF3 and iso-propyl. 3. The compound as claimed in Claim 2, wherein R2 is methyl. 4. The compound as claimed in any one of claims 1 to 3, wherein Y = -(CH2)n-X- 5. The compound as claimed in Claim 4, wherein n is 1. 6. The compound as claimed in Claim 4 or Claim 5, wherein X is selected from 0, S and NH. 7. The compound as claimed in Claim 4 wherein Y = -CH2-0-. 8. The compound as claimed in Claim 6 wherein X is NH. 9. The compound as claimed in any one of claims 1 to 3 wherein Y is -C(=0)NRN2 -. 10. The compound as claimed in Claim 9, wherein RN2 is selected from H and optionally substituted C1-7 alkyl. 11.. The compound as claimed in any one of claims 1 to 10, wherein the C6 aryl groups of R3 are independently selected from those derived from benzene and heteroaryl groups, where the heteroatom or heteroatoms are nitrogen. 12. The compound as claimed in Claim 11, wherein the C6 aryl groups of R3 are independently selected from those derived from benzene, pyridine and 1,3-pyrimidine. 13. The compound as claimed in any of claims 1 to 12, wherein only the aryl group of R3 not bound to Y is substituted. 14. The compound as claimed in any of claims 1 to 13, wherein the optional substituents on the aryl groups of R3 are selected from the group consisting of optionally substituted C1-7 alkyl groups; C1-7 alkoxy groups; C1-7 thioether group; amino groups, optionally substituted by one or two C1-4 alkyl groups; halo groups; cyano; groups of the formula -0(CH2)nO, where n is 1 or 2 and C1-4 acyl groups. 15. The compound as calimed in any one of claims 1 to 13, wherein the optional substituents of the aryl groups of R3 are selected from the group consisting of -CH3, -CF3, -CH2OH, -OMe, -OCF3 -OEt -OCHF2 -SMe, -NMe2, F, CI, -CN, -0-CH2-0- and -C(=0)Me. 16. The compound as claimed in any one of claims 1 to 15, wherein R5 is either: (i) a group of formula (II): (Formula Removed) (ii) a group of the formula (III): (Formula Removed) 17. The compound as claimed in Claim 16, wherein R is selected from an optionally substituted C5-20 aryl group and an optionally substituted C5-20 aryl C1-7alk;yl group. 18. The compound as claimed in any one of claims 1 to 17, wherein the optional substituent of the group R is selected from C1-4 alkyl and -OH. 19. A compound selected from the group consisting of: 4- (4'-Methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carboxylic acid (4); N- [4-(4'-Methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carbonyl]-benzenesulfonamide (5); N- [ 4-(4'-Methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carbonyl]-C-phenyl-methanesulfonamide (6); N- [4- (4'-Methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carbonyl]-methanesulfonamide (7); Propane-1-sulfonic acid [4-(4'-methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carbonyl]—amide (8); 3,5-Dimethyl-isoxazole-4-sulfonic acid [4-(4'-methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carbonyl]-amide (9) ; Thiophene-2-sulfonic acid [4-(4'-methoxy-biphenyl-4- yloxymethyl)-5-methyl-furan-2-carbonyl]-amide (10); 5-Methyl-pyridyl-2-sulfonic acid [4-(4'-methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carbonyl]-amide (11); 4-Aminomethyl-N-[4-(4'-methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carbonyl]-benzenesulfonamide (trifluoroacetate salt) (12); 4-Hydroxy-N-[4-(4'-methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carbonyl]-benzenesulfonamide (13); 4-(Biphenyl-4-yloxymethyl)-5-methyl-furan-2-carboxylic acid (18); N- [4- (Biphenyl-4-yloxymethyl)-5-methyl-furan-2-carbonyl]-benzenesulfonamide (19); 4- (4'-Acetyl-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carboxylic acid (21); N- [4-(4'-Acetyl-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carbonyl]-benzenesulfonamide (22); 4_ (4i-Methoxy-biphenyl-4-ylcarbamoyl)-5-methyl-furan-2-carboxylic acid (24); 5-Benzenesulfonylaminocarbony1-2-methyl-furan-3-carboxylic acid (4'-methoxy-biphenyl-4-yl)-amide (25); 4-(4'-Chloro-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carboxylic acid (27); 4-(4-Benzo[1,3]dioxol-5-yl-phenoxymethyl)-5-methyl-furan-2-carboxylic acid (28); [4-(Biphenyl-4-yloxymethyl)-5-methyl-furan-2-yl]-acetic acid (31); 4- (4'-Methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-yl]-acetic acid (32); 3- [4- (Biphenyl-4-yloxymethyl)-5-methyl-furan-2-yl]-propionic acid (37); N- {3- [4-(Biphenyl-4-yloxymethyl)-5-methyl-furan-2-yl]-propionyl}-benzene sulfonamide (38); 3-[4-(4'-Methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-yl]-propionic acid (39); N- {3- [ 4-(4'-Methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan- 2-yl]-propionyl}-benzene sulfonamide (40); 3-[4-(Biphenyl-4-yloxymethyl)-5-methyl-furan-2-yl]-acrylic acid (42); 3-[4-(4'-Methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-yl]-acrylic acid (43); 4-(Biphenyl-4-yloxymethyl)-5-methyl-furan-2-sulfonic acid benzoylamide (4 6) ; 4-(4'-Methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-sulfonic acid benzoylamide (49); 4-(Dibenzofuran-3-yloxymethyl)-5-methyl-furan-2-carboxylic acid (50); 4-[4- (5-Methoxy-pyridin-2-yl)-phenoxymethyl]-5-methyl-furan-2-carboxylic acid (53); 4-[6- (4-Methoxy-phenyl)-pyridin-3-yloxymethyl]-5-methyl-furan-2-carboxylic acid (56); 4-(4'-Cyano-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carboxylic acid (57); 3-Morpholin-4-yl-propane-l-sulphonic acid [4-(4'-methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carbonyl]-amide (59) ; N-[4-(Biphenyl-4-yloxymethyl)-5-methyl-furan-2-carbonyl]-2-methyl-benzenesulphonamide (60); 4-(Biphenyl-4-yloxymethyl)-5-methyl-furan-2-sulfonic acid butyryl-amide (61); 4-(Biphenyl-4-yloxymethyl)-5-methyl -furan-2-sulfonic acid phenylacetyl-amide (62); 4-(Biphenyl-4-yloxymethyl)-5-methyl-furan-2-sulfonic acid (3,5-dimethyl-isoxazole-4-carbonyl)-amide (63); 4-(Biphenyl-4-yloxymethyl)-5-methyl-furan-2-sulfonic acid (thiophene-2-carbonyl)-amide (64); 4-(Biphenyl-4-yloxymethyl)-5-methyl-furan-2-sulfonic acid (3-methoxy-propionyl)-amide (65); 4-(Biphenyl-4-yloxymethyl)-5-methyl-furan-2-sulfonic acid (pyridin-3-yl-acetyl)-amide (66); 4-(Biphenyl-4-yloxymethyl)-5-methyl-furan-2-sulfonic acid (pyridine-4-carbonyl)-amide (67); 4-(Biphenyl-4-yloxymethyl)-5-methyl-furan-2-sulfonic acid (pyridine-3-carbonyl)-amide (68); 4-(4'-Methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2- sulfonic acid (3,5-dimethyl-isoxazole-4-carbonyl)- amide (69); 4-[2-(Biphenyl-4-yloxy)-ethyl]-5-methyl-furan-2-carboxylic acid (72); 4-[2-(4'-Methoxy-biphenyl-4-yloxy)-ethyl]-5-methyl-furan-2- carboxylic acid (73); 4-[2-(Dibenzofuran-3-yloxy)-ethyl]-5-methyl-furan-2- carboxylic acid (74); 4-(Biphenyl-4-yloxymethyl)-furan-2-carboxylic acid (77); 4-(Dibenzofuran-2-yloxymethyl)-furan-2-carboxylic acid (78); 4-(4'-Cyano-biphenyl-4-yloxymethyl)-furan-2-carboxylic acid (79); 4-(4'-Methoxy-biphenyl-4-yloxymethyl)-furan-2-carboxylic acid (80); 4-(Dibenzofuran-3-yloxymethyl)-furan-2-carboxylic acid (81); 4-(Biphenyl-4-yloxymethyl)-5-isopropyl-furan-2-carboxylic acid (85); 5-Isopropyl-4-(4'-methoxy-biphenyl-4-yloxymethyl)-furan-2- carboxylic acid (86); 4-(Dibenzofuran-3-yloxymethyl)-5-isopropyl-furan-2- carboxylic acid (87); 4-(Biphenyl-4-yloxymethyl)-5-trifluoromethyl-furan-2- carboxylic acid (90); 4-(Biphenyl-3-yloxymethyl)-5-trifluoromethyl-furan-2- carboxylic acid (91); 4-(Dibenzofuran-2-yloxymethyl)-5-trifluoromethyl-furan-2- carboxylic acid (92); 4-(4'-Cyano-biphenyl-4-yloxymethyl)-5-trifluoromethyl-furan- 2-carboxylic acid (93); 4-(4'-Methoxy-biphenyl-4-yloxymethyl)-5-trifluoromethyl- furan-2-carboxylic acid (94); 4-(Dibenzofuran-3-yloxymethyl)-5-trifluoromethyl-furan-2- carboxylic acid (95); 4-(3',4'-Dimethoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2- carboxylic acid (96); 4-(4'-Ethoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2- carboxylic acid (98); 4-(2'-Chloro-biphenyl-4-yloxymethyl)-5-methyl-furan-2- carboxylic acid (99); 4-(2',6'-Difluoro-biphenyl-4-yloxymethyl)-5-methyl-furan-2- carboxylic acid (100); 5-Methy1-4-(2'-trifluoromethyl-biphenyl-4-yloxymethyl)- furan-2-carboxylic acid (102); 4-(3'-Fluoro-biphenyl-4-yloxymethyl)-5-methyl-furan-2- carboxylic acid (104); 5-Methyl-4-(2'-methylsulfany1-bipheny1-4-yloxymethyl)-furan- 2-carboxylic acid (105); 4-(3',4'-Dimethoxy-biphenyl-3-yloxymethyl)-5-methyl-furan-2- carboxylic acid (108); 5-Methyl-4-(3'-trifluoromethyl-biphenyl-3-yloxymethyl)- furan-2-carboxylic acid (109); 4-(4'-Hydroxymethyl-biphenyl-4-yloxymethyl)-5-methyl-furan- 2-carboxylic acid (110); 5-Methyl-4-(4'-methylsulfanyl-biphenyl-4-yloxymethyl)-furan- 2-carboxylic acid (111); 4-(3'-Hydroxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2- carboxylic acid (112); 4-(4'-Dimethylamino-biphenyl-4-yloxymethyl)-5-methyl-furan- 2-carboxylic acid (113); 5-Methyl-4-(4'-trifluoromethoxy-biphenyl-4-yloxymethyl)- furan-2-carboxylic acid (114); 5-Methyl-4-(2'-trifluoromethoxy-biphenyl-4-yloxymethyl)- furan-2-carboxylic acid (115); 4-(3'-Methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2- carboxylic acid (116); 4-(3'-Acetyl-biphenyl-4-yloxymethyl)-5-methyl-furan-2- carboxylic acid (117); 4-(4'-Fluoro-biphenyl-4-yloxymethyl)-5-methyl-furan-2- carboxylic acid (118); N-4-(4'-Methoxy-biphen-4-yloxymethyl)-5-methyl-furan-2- carbonyl]-dimethylaminosulphonamide (122); 4-(2'-Methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2- carboxylic acid (126); N-[4-(2'-Methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2- carbonyl]-benzenesulfonamide (127); 4-(4'-Difluoromethoxy-biphenyl-4-yloxymethyl)-5-methyl- furan-2-carboxylic acid (129); N-[4-(4'-Difluoromethoxy-biphenyl-4-yloxymethyl)-5-methy1- furan-2-carbonyl]-benzenesulfonamide (130) ; 3,5-Dimethyl-isoxazole-4-sulfonic acid [4— (4' — difluoromethoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2- carbonyl]-amide (131); N-{4-[4- (5-Methoxy-pyridin-2-yl)-phenoxymethyl]-5-methyl- furan-2-carbonyl}-benzenesulfonamide (132); 3,5-Dimethyl-isoxazole-4-sulfonic acid {4-[4-(5-methoxy- pyridin-2-yl)-phenoxymethyl]-5-methyl-furan-2-carbonyl}- amide (133); N-(4-[4-(5-Methoxy-pyridin-2-yl)-phenoxymethyl]-5-methyl- furan-2-carbonyl}-2-methyl-benzenesulfonamide (134); N-{4-[4-(5-Methoxy-l-oxy-pyridin-2-yl)-phenoxymethyl]-5- methyl-furan-2-carbonyl}-benzenesulfonamide (135); 5-Methyl-4-(4-pyrimidin-2-yl-phenoxymethyl)-furan-2- carboxylic acid (137); N-[5-Methyl-4-(4-pyrimidin-2-yl-phenoxymethyl)-furan-2- carbonyl]-benzenesulfonamide (138); 4-(2',4'-Dimethoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2- carboxylic acid (140); N-[4- (2',4'-Dimethoxy-biphenyl-4-yloxymethyl)-5-methyl- furan-2-carbonyl]-benzenesulfonamide (141); 3,5-Dimethyl-isoxazole-4-sulfonic acid [4-(2',4'-dimethoxy- biphenyl-4-yloxymethyl)-5-methyl-furan-2-carbonyl]-amide (142); 4-(4'-Methoxy-2'-methyl-biphenyl-4-yloxymethyl)-5-methyl- furan-2-carboxylic acid (144); N-[4-(4'-Methoxy-2'-methyl-biphenyl-4-yloxymethyl)-5-methyl- furan-2-carbonyl]-benzenesulfonamide (145); 3,5-Dimethyl-isoxazole-4-sulfonic acid [4-(4'-methoxy-2'- methyl-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carbonyl]- amide (14 6); 5-[4-(Biphenyl-4-yloxymethyl)-5-methyl-furan-2-yl]-1H- tetrazole (149); 4-(4'-Difluoromethoxy-biphenyl-4-ylsulfanylmethyl)-5-methyl- furan-2-carboxylic acid (153); N-[4-(4'-Difluoromethoxy-biphenyl-4-ylsulfanylmethyl)-5- methyl-furan-2-carbonyl]-2-methyl-benzenesulfonamide (154); N-[4-(4'-Difluoromethoxy-biphenyl-4-ylsulfanylmethyl)-5- methyl-furan-2-carbonyl]-benzenesulfonamide (155); N-[4-(4'-Difluoromethoxy-biphenyl-4-sulfinylmethyl)-5- methyl-furan-2-carbonyl]-2-methyl-benzenesulfonamide (156); N-[4-(4'-Difluoromethoxy-biphenyl-4-sulfonylmethyl)-5- methyl-furan-2-carbonyl]-2-methyl-benzenesulfonamide (156a); 4-(Biphenyl-4-ylaminomethyl)-5-methyl-furan-2-carboxylic acid (160); N-[4-(Biphenyl-4-ylaminomethyl)-5-methyl-furan-2-carbonyl]- benzenesulfonamide (161); N-[4-(Biphenyl-4-ylaminomethyl)-5-methyl-furan-2-carbonyl]- 2-methyl-benzenesulfonamide (162); N- (4-{ [4-(5-Methoxy-pyridin-2-yl)-phenylamino]-methyl}-5- methyl-furan-2-carbonyl)-2-methyl-benzenesulfonamide (167); 4-[(4'-Difluoromethoxy-biphenyl-4-ylamino)-methyl]-5-methy1- furan-2-carboxylic acid (171); N-{4-[(4'-Difluoromethoxy-biphenyl-4-ylamino)-methyl]-5- methyl-furan-2-carbonyl}-benzenesulfonamide (172); N-{4-[(4'-Difluoromethoxy-biphenyl-4-ylamino)-methyl]-5- methyl-furan-2-carbonyl}-2-methyl-benzenesulfonamide (173); 3,5-Dimethyl-isoxazole-4-sulfonic acid {4-[(4'- difluoromethoxy-biphenyl-4-ylamino)-methyl]-5-methyl-furan- 2-carbonyl}-amide (174); 4-{ [ (4'-Difluoromethoxy-biphenyl-4-yl)-methyl-amino]- methyl}-5-methyl-furan-2-carboxylic acid (176); and N- (4-{ [ (4'-Difluoromethoxy-biphenyl-4-yl)-methyl-amino]- methyl}-5-methyl-furan-2 -carbonyl)-2-methyl- benzenesulfonamide (177). or a pharmaceutically acceptable salt thereof. 20. The compound as claimed in claim 1, wherein said compound is N-{4-[4-(5-methoxy-pyridin-2-yl)-phenoxymethyl] 5-methyl-furan-2-carbonyl}-2-methyl-benzenesulfonamide (134 of the formula: (Formula Removed) or a pharmaceutically acceptable salt thereof. 21. The compound as claimed in any of claims 1 to 20 whenever used in the preparation of a medicament for the treatment and/or prevention of migraine.

Full Text

This invention relates to Furan compounds, more particularly to EP4 receptor antagonists, pharmaceutical compositions comprising such compounds, and the use of such compounds and compositions to treat various diseases.
Background to the invention
Postanoids comprise prostaglandins (PGs) and thromboxanes (Txs) and their receptors fall into five different classes (DP, EP,FP, IP and TP) based on their sensitivity to the five naturally occurring prostanoids, PGD2, PGE2, PGF2c(, PGI2 and TxA2, respectively (Coleman, R. A., Prostanoid Receptors. IUPHAR compendium of receptor characterisation and classification, 2nd edition, 338-353, ISBN 0-9533510-3-3, 2000). EP receptors (for which the endogenous ligand is PGE2) have been subdivided into four types termed EP1, EP2, EP3 and EP4. These four types of EP receptors have been cloned and are distinct at both a molecular and pharmacological level (Coleman, R.A., 2000) .
EP4 antagonists have been shown to be useful in the treatment of pain, and in particular, in the treatment of primary headache disorders, which include migraines, and secondary headache disorders, such as drug-induced headaches (W) 00/18405 and WO 01/72302). Dilation of the cerebral vasculature and the subsequent stimulation of pain stimulating, perivascular trigeminal sensory afferent nerves is recognized to play an important role in the pathophysiology of migraine. A sterile inflammatory response, associated with activation of cycloxyenase and the generation of PGE2, is also implicated in the pathophysiology of migraine. PGE2 levels have been shown to be raised during migraine attacks and PGE2 contributes to

the pain of migraine by directly dilating cerebral arteries and by stimulating the release of vasoactive/pro-inf lammatory peptides from the trigeminal nerves. These effects of PGE2 are mediated in whole or in part by EP4 receptors. Thus, by binding to and preventing the stimulation of EP4 receptors, EP$ antagonists may be used to treat the pain of migraine.
antagonists may also be useful in treating a number of other conditions and diseases. For example, they may be used in:
the treatment of pain associated with rheumatoid arthritis, osteoarthritis, rheumatoid spondylitis, gouty arthritis and juvenile arthritis;
the treatment of musculoskeletal pain, lower back and neck pain, sprains and strains, neuropathic pain, sympathetically mediated pain, myositis, pain associated with cancer and fibromyalgia, pain associated with influenza or other viral infections, such as the common cold, rheumatic fever; pain associated with bowel disorders such as non-ulcer dyspepsia, irritable bowel syndrome; non-cardiac chest pain, pain associated with myocardial ischaemia, post-operative pain, headache, toothache and dysmeriorrhea. Neuropathic pain syndromes include diabetic neuropathy, sciatica, nonspecific lower back pain, multiple sclerosis pain, fibromyalgia, HIV-related neuropathy, post-herpetic neuralgia, trigeminal neuralgia and pain resulting from physical trauma;
the treatment of inflammatory diseases including rheumatoid and osteoarthritis, psoriasis, dermatitis, retinitis, conjunctivitis, asthma, bronchitis, chronic obstructive pulmonary disease, inflammatory bowel disease, colitis, nephritis, gingivitis and hepatitis; the treatment of cancers including familial adenomatous
polyposis, endometrial carcinoma, colorectal and cervical
cancer;
the treatment of bone disorders involving altered bone
formation or resorption such as osteoporosis;
women's health for the treatment of myometrial and
endometrial disorders;
the treatment of gastrointestinal disease including
diarrhoea;
the treatment of immunological disorders such as autoimmune
disease, immunological deficiency diseases, organ
transplantation and increasing the latency of HIV infection;
the treatment of diseases of abnormal platelet function.
(e.g. occlusive vascular diseases);
the preparation of a drug with diuretic properties to treat
or prevent various oedema, hypertension, premenstrual
tension, urinary calculus, oliguri.a, hyperphosphaturia,
mesangial proliferative glomerulonephritis, chronic renal
failure or the like;
the treatment of impotence or erectile dysfunction, and
female sexual dysfunction;
the treatment of hair growth disorders;
the treatment of sleep disorders such as narcolepsy and
insomnia;
the treatment of cardiovascular diseases and shock states
associated with hypotension (e.g. septic shock);
the treatment of neurodegenerative diseases and for
preventing neuronal damage following stroke, cardiac arrest,
cardiopulmonary bypass, traumatic brain injury or spinal
cord injury;
the treatment of tinnitus;
the treatment of dependence; and
the treatment of complications of diabetes.
Although EP4 antagonists are known, it is desired to find
novel EP4 antagonists, and in particular, EP4 antagonists which are selective against other EP receptors, i.e. EPi, EP2 and EP3.
Summary of the invention
A first aspect of the present invention provides a compound
of formula (I) :
(Figure Removed)
or a pharmaceutically acceptable salt thereof for use in a
method of therapy, wherein:
R2 is H or an optionally substituted Ci_4 alkyl group;
Y is either -(CH2)n-X-, where n is 1 or 2 and X is 0, S,
S(=0), S(=0)2, or NRN1, where RN1 is selected from H or
optionally substituted Ci_4 alkyl, or Y is -C(=O)NRN2-,
where RN2 is selected from H, and optionally substituted Ci_7
alkyl or Cs-20 aryl;
R3 is an optionally substituted Ce aryl group linked to a
further optionally substituted C6 aryl group, wherein if
both Ce aryl groups are benzene rings, there may be an
oxygen bridge between the two rings, bound adjacent the link
on both rings;
A is a single bond or a Ci-3 alkylene group; and
R5 is either:
(i) carboxy;
(ii) a group of formula (II): (Figure Removed)
wherein R is optionally substituted Ci_-7 alkyl, C5-2o aryl or NRN3RN\ where RN3 and RN4 are independently selected from optionally substituted C\-t alkyl; (iv) tetrazol-5-yl .
A second aspect of the present invention provides a compound of formula (I) :

(Figure Removed)
or a salt, solvate and chemically protected form thereof, wherein:
R2 is H or an optionally substituted Ci-$ alkyl group; Y is either -(CH2)n-X-, where n is 1 or 2 and X is 0, S, S(=0), S(=0)2 or NRN1, where RN1 is selected from H or optionally substituted C^ alkyl, or Y is-C (=0) NRN2--, where RN2 is selected from H, and optionally substituted Ci-7 alkyl or C5_2o aryl;
R3 is an optionally substituted C6 aryl group linked to a further optionally substituted C6 aryl group, wherein if both Ce aryl groups are benzene rings, there may be an oxygen bridge between the two rings, bound adjacent the link on both rings;
A is a single bond or a €1-3 alkylene group; and R5 is either: (i) carboxy;
(ii) a group of formula (II):
(iii) a group of formula (III):
(Figure Removed)
wherein R is optionally substituted Ci_7 alkyl, C5_2o aryl or NRN3RN4, where RN3 and RN4 are independently selected from optionally substituted Ci_4 alkyl; (iv) tetrazol-5-yl,
except that when R2 is methyl, Y is -CHa-O- and R5 is carboxy or Ci_7 alkyl ester thereof, then R3 is not:
(Figure Removed)
A third aspect of the present invention provides a
pharmaceutical composition comprising a compound of formula
(I) as defined in the first aspect or a pharmaceutically
acceptable salt thereof together with a pharmaceutically
acceptable carrier or diluent.
A further aspect of the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of a condition alleviated by antagonism ofan EP4 receptor.
Another aspect of the present invention provides a method of treating a condition which can be alleviated by antagonism of an EP4 receptor, which method comprises administering to a patient in need of treatment an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof.
Conditions which can be alleviated by antagonism of an EP4 receptor are discussed above, and particularly include primary headache disorders, most particularly migraines.
The present invention also provides methods of antagonizing EP4 receptors, in vitro or in vivo, comprising contacting a cell with an effective amount of a. compound of formula (I) .
In some embodiments, the compounds described above may be selective as against antagonism of the other three EP receptors, i.e. EPj, EP? and EPj. This selectivity allows for targeting of the effect of the compounds of the invention, with possible benefits in the treatment of certain conditions.
Definitions Monodcntate groups (i.e groups with one point of covalent attachment)
Alkyl: The term "alkyl" as used 'herein, pertains to a monovalent moiety obtained by removing a hydrogen atom from a carbon atom of a hydrocarbon compound having from 1 to 7 carbon atoms (unless otherwise specified), which may be aliphatic or alicyclic, and which may be saturated or unsaturated. Thus, the term N"alkyl" includes the sub-classes
alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cylcoalkynyl, etc., discussed below.
In the context of alkyl groups, the prefixes (e.g. Ci_4, Ci_7) denote the number of carbon atoms, or range of number of carbon atoms. For example, the term MCi_4 alkyl" as used herein, pertains to an alkyl group having from 1 to 4 carbon atoms. Examples of groups of alkyl groups include Ci_4 alkyl ("lower alkyl") and Cj-? alkyl. Note that the first prefix may vary according to other limitations; for example, for unsaturated alkyl groups, the first prefix must be at least 2; for cyclic alkyl groups, the first prefix must be at least 3; etc.
Examples of saturated alkyl groups include, but are not limited to, methyl (Ci) , ethyl (G2) , propyl (C3) , butyl (C4), pentyl (C5) , hexyl (C6) and heptyl (C7) .
Examples of saturated linear alkyl groups include, but are not limited to, methyl (Ci) , ethyl (C2) , n-propyl (Cs) , n-butyl (C4) , n-pentyl (amyl) (C5) , n-hexyl (C6) , and n-heptyl (C7) .
Examples of saturated branched alkyl groups include iso-propyl (C3) , iso-butyl (C4) , sec-butyl (C4) , tert-butyl , iso-pentyl (C5) , and neo-pentyl (C5) .
Alkenyl: The term "alkenyl" as used herein, pertains to an alkyl group having one or more carbon-carbon double bonds. Examples of groups of alkenyl groups include C2-4 alkenyl and C2_7 alkenyl. Examples of alkenyl groups include, but are not limited to, ethenyl (vinyl, -CH=CH2) , 1-propenyl (-CH=CH-CH3) , 2-propenyl (allyl, -CH-CH=CH2) , isopropenyl (1-methylvinyl, -C (CH3)=CH2) , butenyl (C4) , pentenyl (C5) , and
hexenyl
Alkynyl: The term "alkynyl" as used herein, pertains to an alkyl group having one or more carbon-carbon triple bonds. Examples of groups of alkynyl groups include C2_4 alkynyl and C2-? alkynyl. Examples of alkynyl groups include, but are not limited to, ethynyl (ethinyl, -C=CH) and 2-propynyl (propargyl, -CH2-CsCH) .
Cycloalkyl: The term "cycloalkyl" as used herein, pertains to an alkyl group which is also a cyclyl group; that is, a monovalent moiety obtained by removing a hydrogen atom from an alicyclic ring atom of a carbocyclic ring of a carbocyclic compound, which carbocyclic ring may be saturated or unsaturated, which moiety has from 3 to 7 carbon atoms (unless otherwise specified) , including from 3 to 7 ring atoms. Thus, the term "cycloalkyl" includes the sub-classes cycloalkyenyl and cycloalkynyl. Preferably, each ring has from 3 to 7 ring atoms. Examples of groups of cycloalkyl groups include C3_7 cycloalkyl .
Examples of cycloalkyl groups include, but are not limited to, those derived from:
saturated monocyclic hydrocarbon compounds: cyclopropane (C3) , cyclobutane (C4) , cyclopentane (C5) , cyclohexane (C6) , cycloheptane (C7) , methylcyclopropane (C,j), dimethylcyclopropane (C5) , methylcyclobutane (C5) , dimethylcyclobutane (Ce) , methylcyclopentane (Ce) , dimethylcyclopentane (C7) , methylcyclohexane (C?) ;
unsaturated monocyclic hydrocarbon compounds: cyclopropene (€3) , cyclobutene (04) , cyclopentene cyclohexene (Cg) , methylcyclopropene (04) , dimethylcyclopropene (Cs) , methylcyclobutene dimethylcyclobutene (Cg) , methylcyclopentene
dimethylcyclopentene (C7) , methylcyclohexene (C7) ;
Heterocyclyl: The term "heterocyclyl" as used herein, pertains to a monovalent moiety obtained by removing a hydrogen atom from a ring atom of a heterocyclic compound, which moiety has from 3. to 20 ring atoms (unless otherwise specified), of which from 1 to 10 are ring heteroatoms. Preferably, each ring has from 3 to 7 ring atoms, of which from 1 to 4 are ring heteroatoms.
In this context, the prefixes (e.g. C3.2o/ C3_7, C5-6, etc.) denote the number of ring atoms, or range of number of ring atoms, whether carbon atoms or heteroatoms. For example, the term "Cs-e heterocyclyl" as used herein, pertains to a heterocyclyl group having 5 or 6 ring atoms. Examples of groups of heterocyclyl groups include C3-2o heterocyclyl, Cs_2o heterocyclyl, C3-15 heterocyclyl, C5-15 heterocyclyl, C3_i2 heterocyclyl, C5_i2 heterocyclyl, C3-io heterocyclyl, C5_io heterocyclyl, C3-7 heterocyclyl, C5_7 heterocyclyl, and C$-6 heterocyclyl.
Examples of monocyclic heterocyclyl groups include, but are
not limited to, those derived from:
NI: aziridine (C3) , azetidine (C4) , pyrrolidine
(tetrahydropyrrole) (C5) , pyrroline (e.g., 3-pyrroline, 2, 5-dihydropyrrole) (C5) , 2H-pyrrole or 3H-pyrrole
(isopyrrole, isoazole) (C5) , piperidine (C6) , dihydropyridine (C6) , tetrahydropyridine (C6), azepine (C7) ; Oi: oxirane (C3), oxetane (C4) , oxolane (tetrahydrofuran)
(C5) , oxole (dihydrofuran) (C5) , oxane (tetrahydropyran)
(C6) , dihydropyran (C6) , pyran (C6) , oxepin (C7) ; Si: thiirane (C3) , thietane (C4) , thiolane
(tetrahydrothiophene) (C5) , thiane (tetrahydrothiopyran)
(C6) , thiepane (C7) ;
02: dioxolane (C5) , dioxane (Cs) , and dioxepane (C-,) ; 03: trioxane (C6) ;
N2: imidazolidine (C5), pyrazolidine (diazolidine) (C5) , imidazoline (C5) , pyrazoline (dihydropyrazole) (C5) , piperazine (Ce) ;
NiOi: tetrahydrooxazole (C5) , dihydrooxazole (C5) , tetrahydroisoxazole (C5) , dihydroisoxazole (C5) , morpholine (C6) , tetrahydrooxazine (Ce) , dihydrooxazine (Ce) , oxazine (C6) ;
NiSi: thiazoline (C5) , thiazolidine (Cs) , thiomorpholine (Ce) ; : oxadiazine (C6) ;
: oxathiole (Cs) and oxathiane (thioxane) (Ce) ; and, iOiSj: oxathiazine
Aryl: The term "aryl" as used herein, pertains to a monovalent moiety obtained by removing a hydrogen atom from an aromatic ring atom of an aromatic compound, which moiety has from 3 to 20 ring atoms (unless otherwise specified) . Preferably, each ring has from 5 to 7 ring atoms.
In this context, the prefixes (e.g. 03-20, CS-T, C5_e, etc.) denote the number of ring atoms, or range of number of ring atoms, whether carbon atoms or heteroatoms. For example, the term "Cs-e aryl" as used herein, pertains to an aryl group having 5 or 6 ring atoms. Examples of groups of aryl groups include C3-20 aryl, C5-2o aryl, C5_i5 aryl, C5_i2 aryl, C5_io aryl, CS-T aryl, Cs-g aryl, C5 aryl, and C6 aryl.
The ring atoms may be all carbon atoms, as in "carboaryl groups". Examples of carboaryl groups include C3_2o carboaryl, Cs-2o carboaryl, C5_i5 carboaryl, Cs-ia carboaryl, CS-IQ carboaryl, Cs-7 carboaryl, Cs^e carboaryl, 0$ carboaryl, and Ce carboaryl.
Examples of carboaryl groups include, but are not limited to, those derived from benzene (i.e. phenyl) (Ce) , naphthalene (Cio) , azulene (Cm), anthracene (Ci4) , phenanthrene (Ci4) , naphthacene (Ci8) , and pyrene (Cj6) .
Examples of aryl groups which comprise fused rings, at least one of which is an aromatic ring, include, but are not limited to, groups derived from indane (e.g., 2,3-dihydro-IH-indene) (Cg) , indene (Cg) , isoindene (C9) , tetraline (1, 2, 3, 4-tetrahydronaphthalene (Cio) , acenaphthene (Ci2) , fluorene (C13) , phenalene (C13) , acephenanthrene (C15) , and aceanthrene
Alternatively, the ring atoms may include one or more heteroatoms, as in "heteroaryl groups". Examples of heteroaryl groups include €3-20 heteroaryl, Cs_2o heteroaryl, C5_15 heteroaryl, C5_i2 heteroaryl, Cs-io heteroaryl , C5_7 heteroaryl, Cs-e heteroaryl, Cs heteroaryl, and Cg heteroaryl
Examples of monocyclic heteroaryl groups include, but are
not limited to, those derived from:
Nx: pyrrole (azole) (C5) , pyridine (azine) (C6) ;
Oi: furan (oxole) (Cs) ;
Si: thiophene (thiole) (C5) ;
oxazole (Cs) , isoxazole (Cs) , isoxazine (Cg) /'
oxadiazole (furazan) (C5) ; N30i: oxatriazole (Cs) ; NiSi: thiazole (C5) , isothiazole (C5) ; N2: imidazole (1, 3-diazole) (C5) , pyrazole (1, 2-diazole) (C5) , pyridazine (1, 2-diazine) (C6) , pyrimidine (1, 3-diazine) (Ce) , pyrazine (1, 4-diazine) N3: triazole (C5) , triazine (C6) ; and, N,j: tetrazole (C5) .
Examples of heteroaryl groups which comprise fused rings, include, but are not limited to:
C9 (with 2 fused rings) derived from benzofuran (Oi), isobenzofuran (Oi) , indole (Nj), isoindole (Ni) , indolizine (Ni) , indoline (Ni) , isoindoline (Mi) , purine (N4) (e.g., adenine, guanine), benzimidazole (N2), indazole (N2) , benzoxazole (NiOi) , benzisoxazole (NiOi) , benzodioxole (02) , benzofurazan (N20i), benzotriazole (Na) , benzothiofuran (Si), benzothiazole (NiSi) , benzothiadiazole (N2S) ;
Cio (with 2 fused rings) derived from chromene (Oa) , isochromene (Oi) , chroman (Oi), isochroman (Oi), benzodioxan (02) , quinoline (Ni) , isoquinoline (Ni) , quinolizine benzoxazine (NiOi), benzodiazine (N2) , pyridopyridine quinoxaline (Nz) , quinazoline (N2) , cinnoline (N2) , phthalazine (N2) , naphthyridine (N2) , pteridine (N4) ;
GH (with 2 fused rings) derived from benzodiazepine
(N2) ;
Cj3 (with 3 fused rings) derived from carbazole (Nj) , dibenzofuran (Oi) , dibenzothiophene (Si) , carboline (N2) , perimidine (N2) , pyridoindole (N2) ; and,
Ci4 (with 3 fused rings) derived from acridine (Nj) , xanthene (Ox), thioxanthene (Si), oxanthrene (02) , phenoxathiin (OiSi) , phenazine (N2) , phenoxazine (Nidi) , phenothiazine (NjSi) , thianthrene (S2) , phenanthridine phenanthroline (N2) , phenazine (N2) .
If a heteroaryl or heterocyclyl group contains a nitrogen ring atom, this ring atom, where possible, may be in a oxidised state, as an N-oxide.
R3 is defined above as an optionally substituted Ce aryl group linked to a further optionally substituted CG aryl group, wherein if both C6 aryl groups are benzene rings , there may be an oxygen bridge between the two rings, bound adjacent the link on both rings. Thus, if both C6 aryl groups are benzene rings, then R3 can be optionally subtitued biphenyl:
or optionally substituted dibenzofuran: If one of the Cg aryl groups is a Ce heteroaryl group, then examples of R3 include, but are not limited to (not showing optional substitution):
(Figure Removed)
The above groups, whether alone or part of another substituent, may themselves optionally be substituted with one or more groups selected from themselves, the additional monodentate substituents listed below and alkoxylene.
Halo: -F, -Cl, -Br, and -I.
Hydroxy: -OH.
Ether: -OR, wherein R is an ether substituent, for example, a Ci-7 alkyl group (also referred to as a C^ alkoxy group, discussed below) , a C3-2o heterocyclyl group (also referred to as a C3_2o heterocyclyloxy group) , or a C5-2o aryl group (also referred to as a C5-2o aryloxy group), preferably a Ci_7 alkyl group.
Ci-7 alkoxy: -OR, wherein R is a Ci_7 alkyl group. Examples of Cj-7 alkoxy groups include, but are not limited to, -OMe (methoxy), -OEt (ethoxy), -O(nPr) (n-propoxy), -O(iPr) (isopropoxy), -O(nBu) (n-butoxy), -O(sBu) (sec-butoxy), -O(iBu) (isobutoxy), and -O(tBu) (tert-butoxy).
Oxo (keto, -one): =O. Thione (thioketone); =S.
Imino (imine): =NR, wherein R is an imino substituent, for example, hydrogen, CI-T alkyl group, a €3-20 heterocyclyl group, or a €5-20 aryl group, preferably hydrogen or a CI-T alkyl group. Examples of imino groups include, but are not limited to, =NH, =NMe, =NEt, and =NPh.
Formyl (carbaldehyde, carboxaldehyde): -C(=0)H.
Acyl (keto): -C(=0)R, wherein R is an acyl substituent, for example, a €1-7 alkyl group (also referred to as Ci_7 alkylacyl or CI-T alkanoyl) , a C3-2o heterocyclyl group (also referred to as C3_2o heterocyclylacyl) , or a C5_2o aryl group (also referred to as C5-20 arylacyl) , preferably a Ci_7 alkyl group. Examples of acyl groups include, but are not limited
to, -C(=O)CH3 (acetyl) , -C(=0)CH2CH3 (propionyl) , -C(=0)C(CH3)3 (t-butyryl) , and -C(=0)Ph (benzoyl, phenone) .
Carboxy (carboxylic acid): -C(=0)OH. Thiocarboxy (thiocarboxylic acid): -C(=S)SH. Thiolocarboxy (thiolocarboxylic acid): -C(=0)SH. Thionocarboxy (thionocarboxylic acid): -C(=S)OH. Imidic acid: -C(=NH)OH. Hydroxamic acid: -C(=NOH)OH.
Ester (carboxylate, carboxylic acid ester, oxycarbonyl): -C(=O)OR, wherein R is an ester substituent, for example, a Ci-7 alkyl group, a C3_2o heterocyclyl group, or a C5-2o aryl group, preferably a Ci--? alkyl group. Examples of ester groups include, but are not limited to, -C(=0)OCH3, -C(=0)OCH2CH3, -C(=0)OC(CH3)3, and -C(=0)OPh.
Acyloxy (reverse ester): -OC(=0)R, wherein R is an acyloxy substituent, for example, a Ci_7 alkyl group, a C3_20 heterocyclyl group, or a C5_2o aryl group, preferably a Ci_-? alkyl group. Examples of acyloxy groups include, but are not limited to, -OC(=0)CH3 (acetoxy) , -OC (=0) CH2CH3, -OC(=0)C(CH3)3, -OC(=0)Ph, and -OC (=0) CH2Ph .
Amido (carbamoyl, carbamyl, aminocarbonyl, carboxamide): -C(=0)NR1R2, wherein R1 and R2 are independently amino substituents, as defined for amino groups. Examples of amido groups include, but are not limited to, -C(=0)NH2, -C(=0)NHCH3, -C(=0)N(CH3)2f -C (=0) NHCH2CH3, and
-C(=0)N(CH2CH3)2r as well as amido groups in which R1 and R2, together with the nitrogen atom to which they are attached, form a heterocyclic structure as in, for example, piperidinocarbonyl, morpholinocarbonyl, thiomorpholinocarbonyl, and piperazinocarbonyl.
Acylamido (acylamino) : -NR1C(=0)R2, wherein R1 is an amide substituent, for example, hydrogen, a Ci_7 alkyl group, a C3-2o heterocyclyl group, or a €5-20 aryl group, preferably hydrogen or a CI_T alkyl group, and R2 is an acyl substituent, for example, a Ci-? alkyl group, a C3_2o heterocyclyl group, or a 05-20 aryl group, preferably hydrogen or a CI_T alkyl group. Examples of acylamide groups include, but are not limited to, -NHC(=0)CH3 , -NHC(=0)CH2CH3, and -NHC(=0)Ph. R1 and R2 may together form a cyclic structure, as in, for example, succinimidyl, maleimidyl, and phthalimidyl:
(Figure Removed)
Thioamido (thiocarbamyl) : -C(=S)NR1R2, wherein R1 and R2 are independently amino substituents, as defined for amino groups. Examples of thioamido groups include, but are not limited to, -C(=S)NH2, -C(=S)NHCH3, -C (=S)N (CH3)2, and -C(=S)NHCH2CH3.
Ureido: -N (R1) CONR2R3 wherein R2 and R3 are independently amino substituents, as defined for amino groups, and R1 is a ureido substituent, for example, hydrogen, a CI-T alkyl group, a C3-2o heterocyclyl group, or a C5_2o aryl group,
(Figure Removed)
preferably hydrogen or a CI_T alkyl group. Examples of ureido groups include, but are not limited to, -NHCONH2, NHCONHMe, -NHCONHEt, -NHCONMe2, -NHCONEt2, -NMeCONH2, -NMeCONHMe, -NMeCONHEt, -NMeCONMe2, and -NMeCONEt2.
Guanidino: -NH-C (=NH) NH2.
Tetrazolyl: a five membered aromatic ring having four nitrogen atoms and one carbon atom, Amino: -NR:R2, wherein R1 and R2 are independently amino substituents, for example, hydrogen, a Ci-7 alkyl group (also referred to as CI_T alkylainino or di-Ci_7 alkylamino) , a €3-20 heterocyclyl group, or a Cs-2oaryl group, preferably H or a Ci-7 alkyl group, or, in the case of a "cyclic" amino group, R1 and R2, taken together with the nitrogen atom to which they are attached, form a heterocyclic ring having from 4 to 8 ring atoms. Amino groups may be primary (-NH2) , secondary (-NHR1) , or tertiary (-NHR1R2) , and in cationic form, may be quaternary (-+NR7u2R3) . Examples of amino groups include, but are not limited to, -NH2, -NHCH3, -NHC(CH3)2, -N(CH3)2, -N (CH2CH3) 2f and -NHPh. Examples of cyclic amino groups include, but are not limited to, aziridino, azetidino, pyrrolidino, piperidino, piperazino, morpholino, and thiomorpholino .
Amidine (amidino) : -C(=NR)NR2, wherein each R is an amidine substituent, for example, hydrogen, a Ci-? alkyl group, a C3_20 heterocyclyl group, or a C5_20 aryl group, preferably H or a Ci-7 alkyl group. Examples of amidine groups include,
but are not limited to, -C(=NH)NH2f -C(=NH)NMe2, and -C(=NMe)NMe2.
Nitro: -N02.
Nitroso: -NO.
Cyano (nitrile, carbonitrrle): -CN.
Sulfhydryl (thiol, mercapto): -SH.
Thioether (sulfide): -SR, wherein R is a thioether substltuent, for example, a CI-T alkyl group (also referred to as a Ci-7 alkylthio group) , a Cs-ao heterocyclyl group, or a £5-20 aryl group, preferably a Ci-7 alkyl group. Examples of Cj-7 alkylthio groups include, but are not limited to, -SCH3 and -SCH2CH3.
Disulfide: -SS-R, wherein R is a disulfide substituent, for example, a Ci-? alkyl group, a 03-20 heterocyclyl group, or a €5-20 aryl group, preferably a Ci-7 alkyl group (also referred to herein as C-^.-j alkyl disulfide) . Examples of Ci--? alkyl disulfide groups include, but are not limited to, -SSCHs and -SSCH2CH3.
Sulfine (sulfinyl, sulfoxide): -S(=0)R, wherein R is a sulfine substituent, for example, a Cj-7 alkyl group, a C3_2o heterocyclyl group, or a C5-20 aryl group, preferably a Ci-i alkyl group. Examples of sulfine groups include, but are not limited to, -S(=0)CH3 and -S (=0) CH2CH3.
Sulfone (sulfonyl): -S(=0)2R, wherein R is a sulfone substituent, for example, a Cj-? alkyl group, a 03-20 heterocyclyl group, or a C5-20 aryl group, preferably a CI-T
alkyl group, including, for example, a fluorinated or perfluorinated Ci_7 alkyl group. Examples of sulfone groups include, but are not limited to, -S(=0)2CH3
(methanesulfonyl, mesyl), -S(=0)2CF3 (triflyl), -S(=0)2CH2CH3 (esyl), -S(=0)2C4F9 (nonaflyl), -S(=0)2CH2CF3 (tresyl), -S(=0)2CH2CH2NH2 (tauryl), -S(=0)2Ph (phenylsulfonyl, besyl) , 4-methylphenylsulfonyl (tosyl), 4-chlorophenylsulfonyl (closyl), 4-bromophenylsulfonyl (brosyl), 4-nitrophenyl (nosyl), 2-naphthalenesulfonate (napsyl), and 5-dimethylamino-naphthalen-l-ylsulfonate (dansyl).
Sulfinic acid (sulfino): -S(=0)OH, -S02H. Sulfonic acid (sulfo): -S(=0)2OH, -S03H.
Sulfinate (sulfinic acid ester): --S(=0)OR; wherein R is a sulfinate substituent, for example, a Ci_7 alkyl group, a C3_2o heterocyclyl group, or a Cs-20 aryl group, preferably a Ci_7 alkyl group. Examples of sulfinate groups include, but are not limited to, -S(=0)OCH3 (methoxysulfinyl; methyl sulfinate) and -S(=0)OCH2CH3 (ethoxysulfinyl; ethyl sulfinate) .
Sulfinyloxy: -OS(=0)R, wherein R is a sulfinyloxy substituent, for example, a Ci-7 alkyl group, a C3_2o heterocyclyl group, or a Cs_2o aryl group, preferably a Ca-7 alkyl group. Examples of sulfinyloxy groups include, but are not limited to, -OS(=0)CH3 and -OS (=0)CH2CH3.
Sulfamyl (sulfamoyl; sulfinic acid amide; sulfinamide): -S(=0)NRaR2, wherein R1 and R2 are independently amino substituents, as defined for amino groups. Examples of sulfamyl groups include, but are not limited to, -S(=0)NH2,-S(=0)NH(CH3) , -S(=0)N(CH3)2, -S (=0) NH (CH2CH3) , -S(=0)N(CH2CH3)2, and -S(O)NHPh.
Sulfonamido (sulfinamoyl; sulfonic acid amide; sulfonamide): -S (=0)2NR1R2, wherein R1 and R2 are independently amino substituents, as defined for' amino groups. Examples of sulfonamido groups include, but are not limited to, -S(=0)2NH2, -S(=0)2NH(CH3), -S (=0) 2N (CH3) 2, -S (=0) 2NH (CH2CH3) , -S(=0)2N(CH2CH3)2, and -S(=0)2NHPh.
Sulfonamino: -NR1S(=O) 2R, wherein R1 is an amino substituent, as defined for amino groups, and R is a Sulfonamino substituent, for example, a Ci-7 alkyl group, a C3_20 heterocyclyl group, or a Cs_20 aryl group, preferably a Ci_7 alkyl group. Examples of Sulfonamino groups include, but are not limited to, -NHS(=0)2CH3 and -N (CH3) S (=O) 2C6H5.
Sulfinamino: -NR1S(=0)R, wherein R1 is an amino substituent, as defined for amino groups, and R is a sulfinamino substituent, for example, a d-? alkyl group, a C3-2o heterocyclyl group, or a C5_20 aryl group, preferably a C^ alkyl group. Examples of sulfinamino groups include, but are not limited to, -NHS(=0)CH3 and -N (CH3) S (=O) C6H5.
As already mentioned, the above described groups may be substituted, and particular examples include, but are not limited to, C3_20 aryl-Ci--? alkyl groups, which include benzyl (phenylmethyl, PhCH2-) , benzhydryl (Ph2CH-), trityl (triphenylmethyl, Ph3C-), phenethyl (phenylethyl, Ph-CH2CH2-) , styryl (Ph-CH=CH-) andcinnamyl (Ph-CH=CH-CH2-) .
Bidentate groups
(i.e. groups with two points of covalent attachment; linking groups)
Alkylene: The term vCi-3 alkylene", as used herein, pertains to a bidentate moiety obtained by removing two hydrogen atoms from each of two different carbon atoms, of a linear hydrocarbon compound having from 1 to 3 carbon atoms, which may be saturated or unsaturated. Thus, the term "alkylene" includes the sub-classes alkenylene and alkynylene.
In this context, the prefix Ci_3 denotes the number of carbon atoms, or range of number of carbon atoms.
Examples of saturated Ci_3 alkylene groups include -CH2-(methylene), -CH2CH2- (ethylene) and -CH2CH2CH2- (propylene) .
Examples of unsaturated Ci_3 alkylene groups (which may be termed "C2-3 alkenylene" or "C2-3 alkynylene", as appropriate) include -CH=CH- (vinylene) , -CH=CH-CH2-, -CH2-CH=CH-, -OC-, -C=C-CH2- and -CH2-C=C-.
The Ci-3 alkylene group may be substituted by any monodentate substituent described above.
Alkoxylene: The term "alkoxylene," as used herein, pertains to a bidentate group of formula -O(CH2)nO-, where n is 1 or 2. .
Includes Other Forms
Unless otherwise specified, included in the above are the well known ionic, salt, solvate, and protected forms of these substituents. For example, a reference to carboxylic acid (-COOH) also includes the anionic (cdrboxylate) form (-COCT) , a salt or solvate thereof, as well as conventional
protected forms. Similarly, a reference to an amino group includes the protonated form (-t^HF^R2) , a salt or solvate of the amino group, for example, a hydrochloride salt, as well as conventional protected forms of an amino group. Similarly, a reference to a hydroxyl group also includes the anionic form (-0"), a salt or solvate thereof, as well as conventional protected forms of a hydroxyl group.
Isomers, Salts, Solvates and Protected Forms Certain compounds may exist in one or more particular geometric, optical, enantiomeric, diasteriomeric, epimeric, stereoisomeric, tautomeric, conformational, or anomeric forms, including but not limited to, cis- and trans-forms; E- and Z-forms; c-, t-, and r- forms; endo- and exo-forms; R-, S-, and meso-forms; D- and L-forms; d- and 1-forms; (+) and (-) forms; keto-, enol-, and eholate-forms; syn- and anti-forms; synclinal- and anticlinal-forms; a- and (3-forms; axial and equatorial forms; boat-, chair-, twist-, envelope-, and halfchair-forms; and combinations thereof, hereinafter collectively referred to as "isomers" (or "isomeric forms").
Note that, except as discussed below for tautomeric forms, specifically excluded from the term "isomers", as used herein, are structural (or constitutional) isomers (i.e. isomers which differ in the connections between atoms rather than merely by the position of atoms in space). For example, a reference to a methoxy group, -OCHs, is not to be construed as a reference to its structural isomer, a hydroxymethyl group, -CH2OH. Similarly, a reference to ortho-chlorophenyl is not to be construed as a reference to its structural isomer, meta-chlorophenyl. However, a reference to a class of structures may well include structurally isoineric forms falling within that class
(e.g. Ci_7alkyl includes n-propyl and iso-propyl; butyl includes n-, iso-, sec-, and tert-butyl; methoxyphenyl includes ortho-, meta-, and para-methoxyphenyl).
The above exclusion does not pertain to tautomeric forms, for example, keto-, enol-, and enolate-forms, as in, for example, the following tautomeric pairs: keto/enol (illustrated below), imine/enamine, amide/imino alcohol, amidine/amidine, nitroso/oxime, thioketone/enethiol, N-nitroso/hyroxyazo, and nitro/aci-nitro.
(Figure Removed)
Note that specifically included in the term "isomer" are compounds with one or more isotopic substitutions. For example, H may be in any isotopic form, including aH, 2H (D), and 3H (T) ; C may be in any isotopic form, including 12C, 13C, and 14C; O may be in any isotopic form, including 160 and 180; and the like.
Unless otherwise specified, a reference to a particular compound includes all such isomeric forms, including (wholly or partially) racernic and other mixtures thereof. Methods for the preparation (e.g. asymmetric synthesis) and separation (e.g. fractional crystallisation and chromatographic means) of such isomeric forms are either known in the art or are readily obtained by adapting the methods taught herein, or known methods, in a known manner.
Unless otherwise specified, a reference to a particular compound also includes ionic, salt, solvate, and protected forms of thereof, for example, as discussed below.
It may be convenient or desirable to prepare, purify, and/or handle a corresponding salt of the active compound, for example, a pharmaceutically-acceptable salt. Examples of pharmaceutically acceptable salts are discussed in Berge, et al., J. Pharm. Sci., 66, 1-19 (1977).
For example, if the compound is anionic, or has a functional group which may be anionic (e.g. -COOH may be -COO"), then a salt may be formed with a suitable cation. Examples of suitable inorganic cations include, but are not limited to, alkali metal ions such as Na+ and K+, alkaline earth cations such as Ca2"1" and Mg2*, and other cations such as Al+3. Examples of suitable organic cations include, but are not limited to, ammonium ion (i.e. NH/) and substituted ammonium ions (e.g. NHaR"1", NH2R2% NHR3+, NR4+) . Examples of some suitable substituted ammonium ions are those derived from: ethylamine, diethylamine, dicyclohexylamine, triethylamine, butylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, benzylamine, phenylbenzylamine, choline, meglumine, and tromethamine, as well as amino acids, such as lysine and arginine. An example of a common quaternary ammonium ion is N(CH3)4+.
If the compound is cationic, or has a functional group which may be cationic (e.g. -NH2 may be -NH3+) , then a salt may be formed with a suitable anion. Examples of suitable inorganic anions include, but are not limited to, those derived from the folio-wing inorganic acids: hydrochloric, hydrobromic, hydroiodic, sulfuric, sulfurous, nitric, nitrous, phosphoric, and phosphorous.
Examples of suitable organic anions include, but are not limited to, those derived from the following organic acids: 2-acetyoxybenzoic, acetic, ascorbic, aspartic, benzoic,
camphorsulfonic, cinnamic, citric, edetic, ethanedisulfonic, ethanesulfonic, fumaric, glucoheptonic, gluconic, glutamic, glycolic, hydroxymaleic, hydroxynaphthalene carboxylic, isethionic, lactic, lactobionic, lauric, maleic, malic, methanesulfonic, mucic, oleic, oxalic, palmitic, pamoic, pantothenic, phenylacetic, phenylsulfonic, propionic, pyruvic, salicylic, stearic, succinic, sulfanilic, tartaric, toluenesulfonic, and valeric. Examples of suitable polymeric organic anions include, but are not limited to, those derived from the following polymeric acids: tannic acid, carboxymethyl cellulose.
It may be convenient or desirable to prepare, purify, and/or handle a corresponding solvate of the active compound. The term "solvate" is used herein in the conventional sense to refer to a complex of solute (e.g., active compound, salt of active compound) and solvent. If the solvent is water, the solvate may be conveniently referred to as a hydrate, for example, a mono-hydrate, a di-hydrate, a tri-hydrate, etc.
It may be convenient or desirable to prepare, purify, and/or handle the active compound in a chemically protected form. The term ^chemically protected form" is used herein in the conventional chemical sense and pertains to a compound in which one or more reactive functional groups are protected from undesirable chemical reactions under specified conditions (e.g. pH, temperature, radiation, solvent, and the like). In practice, well known chemical methods are employed to reversibly render unreactive a functional group, which otherwise would be reactive, under specified conditions. In a chemically protected form, one or more reactive functional groups are in the form of a protected or protecting group (also known as a masked or masking group or a blocked or blocking group). By protecting a reactive
functional group, reactions involving other unprotected reactive functional groups can be performed, without affecting the protected group; the protecting group may be removed, usually in a subsequent step, without substantially affecting the remainder of the molecule. See, for example, Protective Groups in Organic Synthesis (T. Green and P. Wuts; 3rd Edition; John Wiley and Sons, 1999) .
A wide variety of such "protecting", "blocking", or '"masking" methods are widely used and well known in organic synthesis. For example, a compound which has two nonequ'ivalent reactive functional groups, both of which would be reactive under specified conditions, may be derivatized to render one of the functional groups "protected," and therefore unreactive, under the specified conditions; so protected, the compound may be used as a reactant which has effectively only one reactive functional group. After the desired reaction (involving the other functional group) is complete, the protected group may be "deprotected" to return it to its original functionality.
For example, a hydroxy group may be protected as an ether (-OR) or an ester (-OC(=0)R), for example, as: a t-butyl
ether; a benzyl, benzhydryl (diphenylmethyl), or trityl (triphenylmethyl) ether; a trimethylsilyl or
t-butyldimethylsilyl ether; or an acetyl ester (-OC(=O)CH3,
-OAc).
For example, an aldehyde or ketone group may be protected as an acetal (R-CH(OR)2) or ketal (R2C(OR)2), respectively, in which the carbonyl group (>C=0) is converted to a diether (>C(OR)2), by reaction with, for example, a primary alcohol. The aldehyde or ketone group is readily regenerated by
hydrolysis using a large excess of water in the presence of acid.
For example, an amine group may be protected, for example, as an amide (-NRCO-R) or a urethane (-NRCO-OR), for example, as: an acetamide (-NHCO-CH3) ; a benzyloxy amide (-NHCO-OCH2C6H5, -NH-Cbz) ; as a t-butoxy amide (-NHCO-OC (CH3) 3, -NH-Boc) ,- a 2-biphenyl-2-propoxy amide (-NHCO-OC^CHsJzCeH/jCeHs, -NH-Bpoc) , as a 9-fluorenylmethoxy amide (-NH-Fmoc) , as a 6-nitroveratryloxy amide (-NH-Nvoc), as a 2-trimethylsilylethyloxy amide (-NH-Teoc), as a 2,2,2-trichloroethyloxy amide (-NH-Troc), as an allyloxy amide (-NH-Alloc) , as a 2(-phenylsulfonyl)ethyloxy amide (-NH-Psec); or, in suitable cases (e.g., cyclic amines), as a nitroxide radical (>N-O) .
For example, a carboxylic acid group may be protected as an ester for example, as: an Ci-7 alkyl ester (e.g., a methyl ester; a t-butyl ester); a Ci_7 haloalkyl ester (e.g., a CI-T trihaloalkyl ester) ; a triCi-7 alkylsilyl-Ci-7 alkyl ester; or a C5_2o aryl-Ci-? alkyl ester (e.g. a benzyl ester; a nitrobenzyl ester); or as an amide, for example, as a methyl amide.
For example, a thiol group may be protected as a thioether (-SR) , for example, as: a benzyl thioether; an acetamidomethyl ether (-S-CH2NHC(=0)CH3) .
The term ""treatment", as used herein in the context of treating a condition, pertains generally to treatment and therapy, whether of a human or an animal (e.g. in veterinary applications), in which some desired therapeutic effect is achieved, for example, the inhibition of the progress of the condition, and includes a reduction in the rate of progress,
a halt in the rate of progress, amelioration of the condition, and cure of the condition. Treatment as a prophylactic measure (i.e. prophylaxis) is also included.
The term "therapeutically-effective amount", as used herein, pertains to that amount of an active compound, or a material, composition or dosage form comprising an active compound, which is effective for producing some desired therapeutic effect, commensurate with a reasonable benefit/risk ratio, when administered in accordance with a desired treatment regimen. Suitable dose ranges will typically be in the range of from 0.01 to 20 mg/kg/day, preferably from 0.1 to 10 mg/kg/day.
Compositions and their administration
Compositions may be formulated for any suitable route and means of administration. Pharmaceutically acceptable carriers or diluents include those used in formulations suitable for oral, rectal, nasal, topical (including buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural) administration. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Such methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients. In general the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.
For solid compositions, conventional non-toxic solid carriers include, for example, pharmaceutical grades of
mannitol, lactose, cellulose, cellulose derivatives, starch, magnesium stearate, sodium saccharin, talcum, glucose, sucrose, magnesium carbonate, and the like may be used. The active compound as defined above may be formulated as suppositories using, for example, polyalkylene glycols, acetylated triglycerides and the like, as the carrier. Liquid pharmaceutically administrable compositions can, for example, be prepared by dissolving, dispersing, etc, an active compound as defined above and optional pharmaceutical adjuvants in a carrier, such as, for example, water, saline aqueous dextrose, glycerol, ethanol, and the like, to thereby form a solution or suspension. If desired, the pharmaceutical composition to be administered may also contain minor amounts of non-toxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents and the like, for example, sodium acetate, sorbitan monolaurate, triethanolamine sodium acetate, sorbitan monolaurate, triethanolamine oleate, etc. Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example, see Remington's Pharmaceutical Sciences, 20th edition, pub. Lippincott, Williams & Wilkins, 2000. The composition or formulation to be administered will, in any event, contain a quantity of the active compound(s) in an amount effective to alleviate the symptoms of the subject being treated.
Dosage forms or compositions containing active ingredient in the range of 0.25 to 95% with the balance made up from non-toxic carrier may be prepared.
For oral administration, a pharmaceutically acceptable non-toxic composition is formed by the incorporation of any of the normally employed excipients, such as, for example, pharmaceutical grades of mannitol, lactose, cellulose,
cellulose derivatives, sodium crosscarmellose, starch, magnesium stearate, sodium saccharin, talcum, glucose, sucrose, magnesium carbonate, and the like. Such compositions take the form of solutions, suspensions, tablets, pills, capsules, powders, sustained release formulations and the like. Such compositions may contain l%-95% active ingredient, more preferably 2-50%, most preferably 5-8%.
Parenteral administration is generally characterized by injection, either subcutaneously,.intramuscularly or intravenously. Injectables can be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for solution or suspension in liquid prior to injection, or as emulsions. Suitable excipients are, for example, water, saline, dextrose, glycerol, ethanol or the like. In addition, if desired, the pharmaceutical compositions to be administered may also contain minor amounts of non-toxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents and the like, such as for example, sodium acetate, sorbitan monolaurate, triethanolamine oleate, triethanolamine sodium acetate, etc.
The percentage of active compound contained in such parental compositions is highly dependent on the specific nature thereof, as well as the activity of the compound and the needs of the subject. However, percentages of active ingredient of 0.1% to 10% in solution are employable, and will be higher if the composition is a solid which will be subsequently diluted to the above percentages. Preferably, the composition will comprise 0.2-2% of the active agent in solution.
Acronyms
For convenience, many chemical moieties are represented using well known abbreviations, including but not limited to, methyl (Me), ethyl (Et), n-propyl (nPr), iso-propyl (iPr), n-butyl (nBu), sec-butyl (sBu), iso-butyl (iBu), tert-butyl (tBu), n-hexyl (nHex), cyclohexyl (cHex), phenyl (Ph), biphenyl (biPh), benzyl (Bn), naphthyl (naph), methoxy (MeO), ethoxy (EtO), benzoyl (Bz), and acetyl (Ac) .
For convenience, many chemical compounds are represented using well known abbreviations, including but not limited to, methanol (MeOH), ethanol (EtOH), iso-propanol (i-PrOH), methyl ethyl ketone (MEK), ether or diethyl ether (Et20), acetic acid (AcOH), dichloromethane {methylene chloride, DCM), acetonitrile (ACN), trifluoroacetic acid (TFA), dimethylformamide (DMF), tetrahydrofuran (THF), and dimethylsulfoxide (DMSO) .
General Synthesis Methods
Compounds of the invention wherein R5 is of formula (II):
(Figure Removed)
may be synthesised from the analogous compound of the invention wherein R5 is carboxy, by reaction with a compound of formula 1: O
in basic conditions, preferably aided by a coupling agent, for example, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride.

Compounds of the invention wherein R5 is of formula (III):
I Omay be synthesized from a compound of formula 2:

by reaction with a compound of formula 3
(Figure Removed)
wherein X is either OH or halo, where if X is OH, the use of basic conditions and a coupling agent is preferred.
Compounds of formulae (1) and 2, or where the group -A-R5 is present as a precursor or protected form, may be represented as compounds of formula 4:

(Figure Removed)
where R6 is -A-R5 or its precursor or protected form. The protecting groups used may be conventional, or the group may be resin-bound. If Y is v - (CH2) n-0- or -(CH2)n-S-, then these compounds can be synthesised from compounds of formula 5:

(Figure Removed)
by one of two possible routes.
In the first route, a compound of formula 6:
R?—X'H Formula 6
, where X' is S or 0, is coupled to a compound of formula 5
using the Mitsunobu reaction, for example by treatment with
triphenyl phosphine (PhaP) and diisopropylazodicarboxylate
(DIAD) .
The second route is a two stage route, the first stage being the Mitsunobu coupling of a compound of formula 7a:
Hal—Ar-X'H Formula 7a
wherein Ar1 is the first Ce aryl component of R3 and Hal is I or Br followed by a Suzuki coupling of a compound of formula 8a (or equivalent ester of formula 8c) :
(Figure Removed)

wherein Ar2 is the second Ce aryl component of R3. The Suzuki coupling may be achieved using, for example, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II) as the palladium catalyst.
This route may also be 'reversed' such that the Mitsunobu coupling is of a boronic acid of formula 7b (or preferably equivalent ester of formula 7c):
(Figure Removed)
wherein Ar1 is the first Ce aryl component of R3, followed by a Suzuki coupling of a compound of formula 8b:
Ar2—Hal Formula 8b
wherein Ar2 is the second C6 aryl component of R3 and Hal is
I or Br.
If the compound of formula 7b or 7c is not readily available then a compound of formula 7d:
HX1—Ar-Br Formula 7d
may be coupled, followed by conversion of the brorno group to the required boronic acid or ester.
Compounds of formula 4 where Y is -(CH2)n-NH- can also be synthesized from compounds of formula 5. In one method, the alcohols of formula 5 are oxidized to the corresponding aldehyde, for example using the Dess-Martin reagent, followed by reductive coupling to an amine, which may be of formula 6':
R3—NH2 Formulae1
or of formula la', 7b' or 7c': Hal—ArLNH2 Formula 7a'
H2N-ArLB(OH)? Formula 7b(Figure Removed)
for subsequent Suzuki coupling. The reductive coupling can be carried out using sodium cyanoborohydride.
37
In another method, the alcohol of formula 5 is converted to the corresponding halide, using a halogenating reagent , for example conversion to chlorine using 4-methyl-benzene sulfonyl chloride, followed by coupling to an amine which may be of formula 6', or of formula 7a', 7b' or 7c' for subsequent Suzuki coupling. The amine coupling is carried out in the presence of potassium iodide, or equivalent reagents. This method can also be used to couple alcohols and thiols of formulae 6, 7a, 7b and 7d, where X' is 0 or S.
Compounds of formula 4:
(Figure Removed)
where Y is -C(=0)-NRm- may be synthesised from a compound of formula 9:
(Figure Removed)
by reaction with a amine of formula 10:
(Figure Removed)
in basic conditions, preferably with the aid of a coupling agent.
(Figure Removed)
Compounds of formula (I) where A is a single bond, and R5 is carboxy, and compounds where the group -Y-R3 is present as a precursor or protected form, may be represented as compounds of formula 12:
where R7 is -Y-R3 or its precursor or protected form. These compounds may be synthesised from compounds of formula 13:
(Figure Removed)
by treatment with n-butyllithium, followed by carbon dioxide at low temperatures.
In a similar fashion, compounds of formula 2 where A is a single bond, and R5 is carboxy, and compounds where the
qroup -Y-R3 is present as a precursor or protected form, may be represented as compounds of formula 14:

(Figure Removed)
where R7 is -Y-R3 or its precursor or protected form. These compounds may be synthesised from compounds of formula 13:
(Figure Removed)
by treatment with a strong base and sulphur dioxide at low temperatures, followed by amination.
Compounds of formula (I) where A is a -C2H4-, and R5 is carboxy, and compounds where the group -Y-R3 is present as a precursor or protected form, may be represented as compounds of formula 15:
(Figure Removed)
where R7 is -Y-R3 or its precursor or protected form. These compounds may be synthesised from compounds of formula 16:

(Figure Removed)
by hydrogenation, using a palladium catalyst.
Compounds of formula 16 may be synthesised from compounds of formula 17:
(Figure Removed)
by the Wittig coupling of an acetic ester, using, for example, triethylphosphonoacetate as the Wittig reagent, followed by hydolysis under alkaline conditions, e.g. lithium hydroxide in a suitable solvent, e.g. aqueous alcohol.
Compounds of formula 17 may also be used to synthesise compounds of formula 18:
(Figure Removed)
where R2 and R7 are as defined above. The reaction proceeds via a cyano intermediate which may be obtained by treating
compounds of formula 17 with hydroxylamine to form the oxime derivative, which can be dehydrated to the cyano compound with, for example, 2-chloro-l,3-dimethylimidazolium chloride in the presence of a base. The cyano intermediate can be converted into compounds of formula 18 by treatment with sodium azide, in the presence of a base.
Compounds where Y is - (CH2)n-S (=0) - and - (CH2)n-S (=0) 2- may be obtained from the corresponding compound where Y is -(CH2)n~S- by oxidation with a peracid, for example 3-chloro-benzenecarboperoxoic acid.
Compounds where Y is - (CH2)n-NRN1- may be obtained from the corresponding compound where Y is -(CH2)n-NH- by direction alkylation by RN11, in the presence of a weak base.
The starting materials described above are generally commercially available or synthesisable using known methods. For example, example 22A below describes a method of synthesizing 2-substitued furans.
Some of the reaction steps described above may be carried out using resins, as is shown in the examples.
Preferences
The following preferences may be combined with one another,
and may be different for each aspect of the present
invention.
R2 is preferably selected from H or an optionally substituted Ci_3 alkyl group, more preferably H, methyl, CFj or iso-propyl, and most preferably R2 is a- a methyl group.
Y is preferably -(CH2)n-X-, and n is preferably 1. X is
preferably 0, S or NH, with NH being the most preferred. In some embodiments the preferred option for Y is -CH2-0-.
If Y is -C(=0)NRN2-, then RN2 is preferably selected from H, and optionally substituted Ci_4 alkyl, in particular Me.
The C6 aryl groups of R3 are preferably independently selected from those derived from benzene and heteroaryl groups, where the heteroatom or heteroatoms are nitrogen. Most preferred are Cg aryl groups derived from benzene, pyridine and 1,3-pyrimidine. It is further preferred that either both Ce aryl groups are derived from benzene or that one group is derived from benzene and the other from pyridine or 1, 3-pyrimidine, with pyridine being preferred, especially as the aryl group furthest from the furan core.
If both Ce aryl groups are derived from benzene, it is preferred that there is not an oxygen bridge between the two rings, bound adjacent the link on both rings, i.e. that Ra is optionally substituted biphenyl rather than optionally substituted dibenzofuranyl.
If one or more of the Ce aryl groups is derived frcm pyridine, then it is preferred that the nitrogen ring atom is adjacent the link between the two rings that make up the R3 group.
If one or more of the Ce aryl groups is derived from 1,3-pyrimidine, then it is preferred that the link between the two rings that make up the R3 group is between the two nitrogen atoms.
It is further preferred that that the single bond joining the two Ce aryl groups is in the 4-position of the ring
bound to Y. Thus, 4-phenyl-phenyl is preferred to 3-phenyl-phenyl; dibenzofuran-3-yl is preferred to di-benzofuran-2-yl, 4-pyridin-2-yl-phenyl is preferred to 3-pyridin-2-yl-phenyl and 6-phenyl-pyridin-3-yl is preferred to 6-phenyl-pyridin-2-yl:
(Figure Removed)
Both C& aryl groups of R3 are optionally substituted, although it is preferred that only the Cg aryl group not bound to Y is substituted.
Preferred substituents on the Ce aryls of R3 include, but are not limited to: optionally substituted Ci-? alkyl groups, more preferably methyl and substituted C!_4 alkyl groups, e.g. -CFa, CH2OH; Ci-7 alkoxy groups, more preferably GI--J alkoxy groups, e.g. OMe, -OCF3, -OEt, -OCHF2; Ci--, thioether group, more preferably Cx-4 thioether group, e.g. -SMe; amino groups, optionally substituted by one or two Ci-4 alkyl groups, e.g. -NMe2/ halo groups, more preferably -F or -Cl; cyano; alkoxylene groups, more preferably -0-r'H2-0-; Ci-4 acyl groups, more preferably -C(=O)Me.
The preferred location for a substituent on the Ce aryl group not bound to Y is para to the bond between the two

aryl groups, with the meta position being less preferred. Therefore, if R3 is 4-phenyl-phenyl, the substituent is preferably at the 4'-position.
In some embodiments of the present invention A is.preferably a single bond, whereas in other embodiments A is preferably a Ci-s alkylene group. In particular, when R5 is carboxy, A is more preferably a Ci-3 alkylene group, with vinylene being most preferred.
R5 is preferably either:
(i) a group of formula (II): (Figure Removed)
with a group of formula (II) being more preferred.
The above preference for R5 is particularly applicable when R2 is methyl and Y is -CH2-0-.
Where R5 is of formula (II) of (III), R is preferably selected from an optionally substituted CS-ZQ aryl group, and an optionally substituted C5_2o aryl-Ci-7 alkyl group, wherein the Ci_7 alkyl group is more preferably methyl. In these groups the C5_2o aryl group is preferably a heteroaryl group, itself preferably having a single aromatic ring. Such groups may preferably be substituted with Ci_4 alkyl groups, such as methyl and hydroxy. Thus, preferred R groups

include, but are not limited to: phenyl; benzyl; 3,5, dimethyl-isoxazol-4-yl; thiophen-2-yl; 5-methyl-pyridin-yl; and 4~hydroxy-phenyl.
If R in formula (II) or (III) is a Ci_7 alkyl group, it is more preferably a Ci_4 alkyl group, for example methyl or propyl.
Particularly preferred compounds of the present invention include:
4- (4'-Methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carboxylic acid (4);
N-[4-(4'-Methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carbonyl]-benzenesulfonamide (5);
N- [4-(4'-Methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carbonyl]-C-phenyl-methanesulfonamide (6);
N- [4-(4'-Methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carbonyl]-methanesulfonamide (7);
Propane-1-sulfonic acid [4-(4'-methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carbonyl]—amide (8)/ 3, 5-D_imethyl-isoxazole-4-sulfonic acid [4- (4 ' -methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan~2-carbonyl]-amide (9);
Thiophene-2-sulfonic acid [4-(4'-methoxy-biphenyl-4-yloxymethyl) -5-methyl-furan-2--carbonyl] -amide (10) ; 5-Methyl-pyridyl-2-sulfonic acid [4-(4'-methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carbonyl]-amide (11); 4-Aminomethyl-N-[4- (4'-methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carbonyl]-benzenesulfonamide (trifluoroacetate salt) (12);
4-Hydroxy-W-[4-(4'-methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carbonyl]-benzenesulfonamide (13); 4-(Biphenyl-4-yloxymethyl)-5-methyl-furan-2-carboxylic acid

(18);
N- [4-(Biphenyl-4-yloxymethyl)-5-methyl-furan-2-carbonyl]-
benzenesulfonamide (19);
4-(4'-Acetyl-biphenyl-4-yloxymethyl)-5-methyl-furan-2-
carboxylic acid (21);
N- [4-(4'-Acetyl-biphenyl-4-yloxymethyl)-5-methyl-furan-2-
carbonyl]-benzenesulfonamide (22) ;
4- (4'-Methoxy-biphenyl-4-ylcarbamoyl)-5-methyl-furan-2-
carboxylic acid (24) ;
5-Benzenesulfonylaminocarbohyl-2-methyl-furan-3-carboxylic
acid (4'-roethoxy-biphenyl-4-yl)-amide (25);
4-(4'-Chloro-biphenyl-4-yloxymethyl)-5-methyl-furan-2-
carboxylic acid (27);
4-(4-Benzo[1,3]dioxol-5-yl-phenoxymethyl)-5-methyl-iuran-2-
carboxylic acid (28);
[4-(Biphenyl-4-yloxymethyl)-5-methyl-furan-2-yl]-acetic acid
(31) ;
4-(4'-Methoxy-biphenyi-4-yloxymethyl)-5-methyl-furan-2-yl]-
acetic acid (32)/
3- [4- (Biphenyl-4-yloxyrr\ethyl) -5-methyl-furan-2-yl] -propionic
acid (37);
N-{3-[4-(Biphenyl-4-yloxymethyl) -5-methyl-furan-2-yl]-
propionyl)-benzene sulfonamide (38);
3- [4- ( 4 ' -Methoxy-biphenyl-4-yloxymethyl) -5-rnethyl-furan-2-
yl]-propionic acid (39);
N~ {3-[4-(4'-Methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-
2-yl]-propionyl)-benzene sulfonamide (40);
3-[4-(Biphenyl-4-yloxymethyl)-5-methyl-furan-2-yl]-acrylic
acid (42);
3-[4-(4'-Methoxy-biphenyl-4-yloxymethyl)-5-methyl-furari-2-
yl]-acrylic acid (43);
4-(Biphenyl-4-yloxymethyl)-5-methyl-furan-2-sulfonic acid
benzoylamide (46) ;
4-(4'-Methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-
sulfonic acid benzoylamide (49);
4-(Dibenzofuran-3-yloxymethyl)-5-methyl-furan-2-carboxylic
acid (50);
4-[4-(5-Methoxy-pyridin-2-yl)-phenoxymethyl]-5-methyl-furan-
2-carboxylic acid (53);
4-[6-(4-Methoxy-phenyl)-pyridin-3-yloxymethyl]-5-methyl-
furan-2-carboxylic acid (56) ;
4-(4'-Cyano-biphenyl-4-yloxymethyl)-5-methyl-furan-2-
carboxylic acid (57);
3-Morpholin-4-yl-propane-l-sulphonic acid [4-(4'-methoxy-
biphenyl-4-yloxymethyl)-5-methyl-furan-2-carbonyl]-amide
(59);
N-[4-(Biphenyl-4-yloxymethyl)-5-methyl-furan-2-carbonyl]-2-
methyl-benzenesulphonamide (60);
4-(Biphenyl-4-yloxymethyl)-5-methyl-furan-2-sulfonic acid
butyryl-amide (61);
4-(Biphenyl-4-yloxyraethyl)-5-methyl
-furan-2-sulfonic acid phenylacetyl-amide (62);
4-(Biphenyl-4-yloxymethyl)-5-methyl-furan-2-sulfonic acid
(3,5-dimethyl-isoxazole-4-carbonyl)-amide (63);
4-(Biphenyl-4-yloxymethyl)-5-methyl-furan-2~sulfonic acid
(thiophene-2-carbonyl)-amide (64);
4- (Biphenyl-'l-yloxymethyl) -5-methyl-furan-2-sulfonic acid
(3-methoxy-propionyl)-amide (65);
4-(Biphenyl-4-yloxymethyl)-5-methyl-furan-2-sulfonic acid
(pyridin 3-yl-acetyl)-amide (66)/
4-(Biphenyl-4-yloxymethyl)-5-methyl-furan-2-sulfonic acid
(pyridine-4-carbonyl)-amide (67);
4-(Biphenyl-4-yloxymethyl)-5-methyl-furan-2-sulfonic acid
(pyridine-3-carbonyl)-amide (68);4-(4'-Methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-
sulfonic acid (3,5-dimethyl-isoxazole-4-carbonyl)-
amide (69);
4-12-(Biphenyl-4-yloxy)-ethyl]-5-methyl-furan-2-carboxylic
acid (72);
4-[2-(4'-Methoxy-biphenyl-4-yloxy)-ethyl]-5-methyl-furan-2-
carboxylic acid (73);
4-[2-(Dibenzofuran-3-yloxy)-ethyl]-5-methyl-furan-2-
carboxylic acid (74);
4-(Biphenyl-4-yloxyrnethyl)-furan-2-carboxylic acid (77);
4-(Dibenzofuran-2-yloxymethyl)-furan-2-carboxylic acid (78);
4-(4'-Cyano-biphenyl-4-yloxymethyl)-furan-2-carboxylic acid
(79);
4-(4'-Methoxy-biphenyl-4-yloxymethyl)-furan-2-carboxylic
acid (80);
4-(Dibenzofuran-3-yloxyrnethyl)-fur'an-2-carboxylic acid (81);
4-(Biphenyl-4-yloxymethyl)-5-isopropyl~furan-2-carboxylic
acid (85);
5-Isopropyl-4-(4'-methoxy-biphenyl-4-yloxymethyl)-furan-2-
carboxylic acid (86) ;
4-(Dibenzofuran-3-yloxymethyl)-5-isopropyl-furan-2-
carboxylic acid (87);
4-(Biphenyl-4-yloxymethyl)-5-trifluoromethyl-furan-2-
carboxylic acid (90);
4- (Biphenyl-3-yloxymethyl) -5-trif luorornethyl-furan-2-
carboxylic acid (91);
4-(Dibenzofuran-2-yloxymethyl)-5-trifluoromethyl-furan-2-
carboxylic acid (92);
4 - (4 ' -Cyano-biphenyl-4-yloxymethyl) -5-trif luororaethyl-furan-2-carboxylic acid (93);
4-(4'-Methoxy-biphenyl-4-yloxymethyl)-5-trifluoromethyl-
furan-2-carboxylic acid (94) ;
4-(Dibenzofuran-3-yloxymethyl)-5-trifluoromethyl-furan-2-
carboxylic acid (95);
4-(3*, 4'-Dimethoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carboxylic acid (96);
4-(4'-Ethoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carboxylic acid (98);
4-(2'-Chloro-bipbenyl-4-yloxymethyl)-5-methyl-furan-2-carboxylic acid (99);
4-(2',6'-Difluoro-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carboxylic acid (100);
5-Methyl-4-(2'-trifluoromethyl-biphenyl-4-yloxymethyl)-furan-2-carboxylic acid (102);
4- (3' -Fluoro-biphenyl-4-yloxymethyl) -5-inethyl-furan-2-carboxylic acid (104);
5-Methyl-4-(2'-methylsulfanyl-biphenyl-4-yloxymethyl)-furan-2-carboxylic acid (105);
4-(3',4'-Dimethoxy-biphenyl-3-yloxymethyl)-5-methyl-furan-2-carboxylic acid (108);
5-Methyl-4-(3'-trifluoromethyl-biphenyl-3-yloxymethyl)-furan-2-carboxylic acid (109);
4-(4'-Hydroxyraethyl-biphenyl-4-yloxymethyl)-5~methyl-furan-2-carboxylic acid (110);
5-Methyl-4-(4'-methylsulfanyl-biphenyl-4-yloxymethyl)-furan-2-carboxylic acid (111);
4-(3'-Hydroxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carboxylic acid (112);
4-(4'-Dimethylamino-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carboxylic acid (113);
5-Methyl-4-(4'-trifluoromethoxy-biphenyl-4-yloxymethyl)-furan-2-carboxylic acid (114);
5-Methyl-4- (2 ' -trif luorornethoxy-biphenyl-4-yloxymethyl) -furan-2-carboxylic acid (115);
4-(3'-Methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carboxylic acid (116) ;4- (3'-Acetyl-biphenyl-4-yloxymethyl)-5-methyl-furan-2-
carboxylic acid (117);
4-(4'-Fluoro-biphenyl-4-yloxymethyl)-5-methyl-furan-2-
carboxylic acid (118);
N-4-(4'-Methoxy-biphen-4-yloxymethyl)-5-methyl-furan-2-
carbonyl]-dimethylaminosulphonamide (122);
4-(2'-Methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-
carboxylic acid (126);
N-[4- (2'-Methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-
carbonyl]-benzenesulfonamide (127);
4-(4'-Difluoromethoxy-biphenyl-4-yloxymethyl)-5-methyl-
furan-2-carboxylic acid (129);
NJ- [4- (4 ' -Dif luoromethoxy-biphenyl-4-yloxyroethyl) -5-methyl-
furan-2-carbonyl]-benzenesulfonamide (130);
3,5-Dimethyl-isoxazole-4-sulfonic acid [4-(4'~
difluoromethoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-
carbonyl]-amide (131);
N-{4-[4-(5-Methoxy-pyridin-2-yl) -phenoxymethyl]-5-methyl-
furan-2-carbonyl}-benzenesulfonamide (132);
3,5-Dimethyl-isoxazole-4-sulfonic acid {4-[4-(5-methoxy-
pyridin-2-yl)-phenoxymethyl]-5-methyl-furan-2-carbonyl}-
amide (133);
N-{4-[4-(5-Methoxy-pyridin-2~yl) - phenoxymethyl]-5-methyl-
furan-2-carbonyl}-2-methyl-benzenesulfonamide (134);
N-{4- [4- (5-Methoxy-l-oxy-pyridin-2-yl)-phenoxymethyl]-5-
methyl-furan-2-carbonyl)-benzenesulfonamide (135);
5-Methyl-4-(4-pyrimidin-2-yl-phenoxymethyl)-furan-2-
carboxylic acid (137);
N- 15-Methyl-4- (4-pyrimidin-2-yl-phenoxyn\ethyl) -furan-2-
carbonyl]-benzenesulfonamide (138);
4- (2 ' ,4'-Dimethoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-
carboxylic acid (140);
N-[4- (2',4'-Dimethoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carbonyl]-benzenesulfonamide (141);
3,5-Dimethyl-isoxazole-4-sulfonic acid [4-(2', 4 '-dimethoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carbonyl]-amide (142);
4_ (4 i -Methoxy-2'-methyl-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carboxylic acid (144);
N- [4- (4'-Methoxy-2'-methyl-biphenyl-4-yloxyinethyl)-5-methyl-furan-2-carbonyl]-benzenesulfonamide (145); 3,5-Dimethyl-isoxazole-4-sulfonic acid [4-(4'-methoxy-2'-methyl-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carbonyl]-amide (146);
5-[4-(Biphenyl-4-yloxymethyl)-5-methyl-furan-2-yl]-lH-tetrazole (149);
4- (4 ' -Dif luoromethoxy-biphenyl-4-ylsulfanylrnethyl) -5-methyl-furan-2-carboxylic acid (153);
N-[4- (4'-Difluoromethoxy-biphenyl-4-ylsulfanylmethyl)-5-methyl-furan-2-carbonyl]-2-methyl-benzenesulfonamide (154); N-[4-(4'-Difluoromethoxy-biphenyl-4-ylsulfanylmethyl)-5-methyl-furan-2-carbonyl]-benzenesulfonamide (155); N-[4-(4'-Difluoromethoxy-biphenyl-4-sulfinylmethyl)-5-methyl-furan-2-carbonyl] -2-methyl-benzenesulfonarnide (156) ; N- [4- (4'-Difluoromethoxy-biphenyl-4-sulfonylmethyl)-5-methyl-furan-2-carbonyl]-2-methyl-benzenesulfonamide (156a); 4-(Biphenyl-4-ylaminomethyl)~5-methyl-furan-2-carboxylic acid (160);
N-[4-(Biphenyl-4-ylaminomethyl)-5-methyl-furan-2-carbonyl]-benzenesulfonamide (161);
N-[4-(Biphenyl-4-ylaminomethyl)-5-methyl-furan-2-carbonyl]-2-xnethyl-benzenesulfonamide (162) ;
N- (4-{[4-(5-Methoxy-pyridin-2-yl)-phenylamino]-methyl)-5-methyl-furan-2-carbonyl)-2-methyl-benzenesulfonamide (167); 4-[(4'-Difluoromethoxy-biphenyl 4-ylamino)-methyl]-5-methyl-furan-2-carboxylic acid (171);N-{4-[(4'-Difluoromethoxy-biphenyl-4-ylamino)-methyl]-5-
methyl-furan-2-carbonyl}-benzenesulfonamide (172);
N-{4-[(4'-Difluoromethoxy-biphenyl-4-ylamino)-methyl]-5-
methyl-furan-2-carbonyl}-2-methyl-benzenesulfonamide (173);
3,5-Dimethyl-isoxazole-4-sulfonic acid {4-[(4'-
difluoromethoxy-biphenyl-4-ylamino)-methyl]-5-methyl-furan-
2-carbonyl)-amide (174);
4-{[(A '-Difluoromethoxy-biphenyl-4-yl)-methyl-amino]-
methyl}-5-methyl-furan-2-carboxylic acid (176); and
N-(4-{[(4'-Difluoromethoxy-biphenyl-4-yl)-methyl-amino]-
methyl}-5-methyl-furan-2-carbonyl)-2-methyl-
benzenesulfonamide (177).
The selectivity of the compound for antagonising EP4 receptors over the other EP receptors (i.e. EPi, EP2, EPa) can be quantified by dividing the -Ki for E?4 (see below) by the Ki for the other EP receptors (see below). The resulting ratio is preferably 10 or more, more preferably 100 or more.
Synthesis Examples
General Experimental Details
All reactions were carried out under an inert atmosphere of nitrogen.
Where products were purified by flash chromatography the stationary phase used was silica gel for chromatography, 0.035 to 0.070 mm (220 to 440 mesh) (e.g. Fluka silica gel 60). An applied pressure of nitrogen of ~10 psi was used to accelerate column elution. Thin layer chromatography (TLC) was carried out on aluminium foil plates coated with silica gel containing a fluorescent indicator (254 nm) (e.g. Fluka
Petroleum ether refers to that fraction with a boiling point of 40-60°C.
Organic solutions were dried over magnesium sulphate unless otherwise specified.
PS-TsCl refers to Polystyrene scavenger resin (loading 1.97 mmol/g) - Argonaut Technologies (P/N 800277)
Preparative HPLC System
Preparative HPLC was carried out on a CIS-reverse-phase column (10 x 2.1 cm i.d Genesis column with 7 urn particle size), eluting with a gradient of acetonitrile (containing 0.1% trifluoroacetic acid) and water (containing 0.1% trifluoroacetic acid) at a flow rate of 5 ml/min. UV detection at 230 nm was used unless otherwise stated.
LC/MS Systems
The Liquid Chromatography Mass Spectroscopy (LC/MS) systems
used are as follows. LC/MS System A:
Mass Spectrometer - Platform LC with electrospray source operating in positive and negative Ion mode. HP1100 system running at 2.0 mL/min, 200 uL/min split to the ESI source with inline HP1100 DAD detection .and SEDEX ELS detection.
Mobile Phase
A) Water 0.1 % Formic Acid
B) acetonitrile 0.1% Formic Acid
(Table Removed)
Column - Luna 3u CIS (2) 30x4.6mm
LC/MS System B:
Mass Spectrometer - Platform II with electrospray source operating in negative ion mode. HP1100 system running at 2.0 mL/min, 200 uL/min split to the ESI source with inline HP1100 DAD detection and SEDEX ELS detection.
Mobile Phase
A) Water 0.1 % Diethylamine
B) acetonitrile
Gradient
Table Removed)
LCMS System C:
Mass Spectrometer - Finnigan TSQ700 with electrospray source operating in negative ion mode.
HP1050 system running at 2.0 mL/min, 200 uL/min split to the ESI source with inline HP1050 Single wavelength UV detector at 254 nm.
Mobile Phase
A) Water 0.1 % Diethylamine
Acetonitrile
(Table Removed)Column - XTerra MS C18 3.Sum 4.6 x 30mm
LC/MS System D:
Mass Spectrometer - Finnigan TSQ700 with electrospray source operating in positive or negative ion mode. HP1050 system running at 2.0 mL/min, 200 uL/min split to the ESI source with inline HP1050 Single Wavelength UV detector at 254 nm.
Mobile Phase
A) Water 0.1 % formic Acid
B) acetonitrile 0.1% formic Acid
(Table Removed)
Column - Higgins Clipius CIS 5pm 100 x 3.0mm
J# NMR system
The aH NMR spectra were recorded on a Varian Unity Inova 400, which operates at 400 MHz for 1H. It is equipped with a 5nun inverse detection triple resonance probe for detection of *H. The magnetic field is provided by a 9.4 Tesla Oxford instruments super-conducting magnet. The host computer is a Sun Microsystems SunBlade 1000 workstation. De-dimethylsulphoxide was used as solvent unless stated otherwise. Tetramethylsilane was used as internal standard. Coupling constants are reported in Hz.
Example 1: Synthesis of 4-(4'-Methoxy-biphenyl-4-yloxymethyl)~5-methyl-furan-2-carboxylic acid (4), 4-(Dibenzofuran-3-yloxymethyl)-5-methyl-furan-2-carboxylic acid (50), 4-(Dibenzofuran-2-yloxymethyl)-5-methyl-furan-2-carboxylic acid (56) and 4- (4'-Cyano-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carboxylic acid (57)
(a) 3-(tert-Butyl-diphenyl-silanyloxymethyl)-2-methyl-furan (2)

(Figure Removed)
A stirred solution of (2-methyl-3-furan-3-yl) -raethanol (1)(31.87 g) in N,N-dimethylformamide (250 mL) was treated simultaneously with t-butyldiphenylsilyl chloride (94 g) and imidazole (24 g) and stirring continued for 2 hours at room temperature. The reaction mixture was treated with 1.0 M hydrochloric acid (500 mL), and extracted with diethyl ether (3 x 500 mL). The combined organic extracts were washed successively with 1.0 M hydrochloric acid (500 mL), saturated sodium hydrogen carbonate (500 mL), then dried and concentrated in vacuo. The residue was purified by flash chromatography eluting with mixtures of diethyl ether in hexane (1:9 to 9:1 by volume) to give compound 2 as a clear oil (67.6 g).
(b) 4-(tert-Butyl-diphenyl-silanyloxymethyl)- 5-methyl-furan-2-carboxylic acid (3)
(Figure Removed)
A solution of 3- (tert-Butyl-diphenyl-silanyloxymethyl) -2-methyl-furan (2) (30.0 g) in tetrahydrofuran (75 mL) was cooled to -78°C with stirring and treated drop-wise with a solution of n-butyllithium (2.5 M in hexanes, 71 mL) over 10

mins. The cooling bath was removed for 0.5 hours and then replaced. A large excess of solid carbon dioxide was added and the mixture allowed to warm to ambient temperature. The reaction mixture was acidified, with 1.0 M hydrochloric acid to pH 2 and extracted into diethyl ether (3 x 500 mL). The combined extracts were washed successively with 1.0 M hydrochloric acid (500 mL) , water (500 mL) , dried and concentrated in vacvo. The residue was purified by flash chromatography eluting with mixtures of diethyl ether in pentane (1:5 to 5:1 by volume) to give compound 3 as a yellow oil (10.36 g). LC/MS System A: Rt = 4.33 mins, m/z (ES~) = 393 (M~ for C23H2604Si) .
(c) 4-(4' -Methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carboxylic acid (4)
(Figure Removed) (i) 2-Chlorotrityl chloride resin (Ig of nominal loading 1.3 mmol/g) was swelled with dichloromethane (20 mL). After draining, a solution of 4-(tert-butyl-diphenyl-silanyloxymethyl)-5-methyl-furan-2~caiboxylic acid (3)
(0.512 g) and diisopropylethylamine (0.91 mL) in dichloromethane (10 mL) was added and the mixture was shaken at ambient temperature for 16 hours. The resin was drained, washed sequentially with
dichloromethane/triethylamine/methanol (20:1:3 by volume) (3 x 25 mL), dichloromethane (3 x 25 mL), N,N-dimethylformamide
(2 x 25 mL), dichloromethane (6 x 25 mL) , and diethyl ether
(2 x 25 mL) and then dried at 40°C in vacuo. (ii) The loaded resin from (i) (2.47 g) was swelled in tetrahydrofuran (15 mL), then treated tetrabutylammonium fluoride (12.8 mL of a 1 M solution in tetrahydrofuran) and shaken at room temperature for 16 hours. The resin was drained, washed sequentially with tetrahydrofuran/water (1:1 by volume), tetrahydrofuran, N,N-dimethylformamide, dichloromethane, diethyl ether, and then dried at 40°C in vacua.
(iii) The loaded resin (2.83g) from (ii) was swelled in tetrahydrofuran (15 mL), and then treated with a solution of 4-hydroxy-4' -methoxydiphenyl (2.93 g) and triphenylphosphine (3.48 g) in tetrahydrofuran (20 mL), followed by the addition of diisopropylazodicarboxylate (2.96 g). The mixture was shaken at room temperature for 16 hours. The resin was drained, washed sequentially with
tetrahydrofuran/water (1:1 by volume), tetrahydrofuran, N,N-dinvethylformamide, dichloromethane, and then dried at 45°C in vacua. The resin was treated with
dichloromethane/trifluoroacetic acid (19:1. by volume) (20 mL) for 20 mins and the solution drained from the resin. This procedure was repeated. The combined solutions were concentrated in vacuo and the residue recrystallised from ethanol to afford compound 4 as a white solid (0.42 g). LC/MS System C: Rt = 4.00 mins, m/z (ES~) = 337 (M" for
4-(Dibenzofuran-3~yloxymethyl)-5-methyl-furan-2-carboxylic acid (50)
(Figure Removed)Compound (50) was prepared by adapting the procedure of Example l(c). LC/MS System B: Rt = 1.79mins, m/z (ES~) = 321 ((M-H) for C19H1405) .
(e) 4-(Dibenzofuran-2-yloxymethyl)-5~methyl-furan-2-carboxylic acid (56)
(Figure Removed)Compound (56) was prepared by adapting the procedure of Example l(c). LC/MS System B: Rt = 1.76mins, m/z (ES~) - 321 ((M-H) for Ci9H1405) .
(f) 4-(4'-Cyano-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carboxylic acid (57)
(Figure Removed)
Compound (57) was prepared by adapting the procedure of Example l(c). LC/MS System B: Rt = 1.72mins, m/z (ES~) = 332 ( (M-H) for C20Hi5NO4) .
Example 2A: Synthesis of N- [4-(4'-Methoxy-biphenyl-4-yloxymethyl) ~5-methyl~furan-2-carbonyl] -benzenesulfonamide

A stirred solution of 4-(4'-methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carboxylic acid (4) (250 mg) in dichloromethane (50 mL) was treated with l-{3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (142 mg) , 4-(N, N-dimethylamino)pyridine (2 mg) and benzenesulfonamide (232 mg). After 16 hours the reaction mixture was concentrated in vacuo, the residue dissolved in ethyl acetate (200 mL) and washed successively with water (20 mL) , 1.0 M hydrochloric acid (20 mL), saturated sodium hydrogen carbonate solution (20 mL) , brine (20 mL), dried and concentrated in vacuo. The crude product was purified by HPLC to afford compound 5 as a white solid (30 mg). LC/MS System D: Rt = 5.45 mins, m/z (ES") = 476 (M~ for
By adapting the procedure of Example 2A and using the appropriate sulphonamide there were prepared Examples 2B to 2G:

Example 2B: N- [4- (4 ' -Methoxy-biphenyl-4-yloxymethyl) -5-methyl-furan-2-carbonyl]-C-phenyl-methanesulfonamide (6)
(Figure Removed)
LC/MS System C: Rt = 5.37 mins, m/z (ES") = 490 (M" for C2-7H25N06S) .
Example 2C: N- [4- (4 ' -Methoxy-biphenyl-4-yloxymethyl) -5-methyl-furan-2~carbonyl]-methanesulfonamide (7) -

(Figure Removed)
LC/MS System C: Rt C2iH2iN06S) .

=4.50 mins, m/z (ES ) = 414 (M" for

Example 2D: Propane-1-sulfonic acid [4-(4' -methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carbonyl]—amide (8)
(Figure Removed)
LC/MS System C: Rt = 4.78 mins, m/z (ES") = 442 (M~ for C23H25N06S) .
Example 2E: 3,5-Dimethyl-isoxazole-4-sulfonic acid [4-(4' methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carbonyl] amide (9)
(Figure Removed)
LC/MS System C: Rt = 4.91 mins, m/z (ES") = 495 (M~ for
Example 2F: Synthesis of Thiophene-2-sulfonic acid [4-(4'~ methoxy-biphenyl-4-yloxymethyl) -5-methyl-furan-2-carbonyl] -
amide (10)

(Figure Removed)
LC/MS System C: Rt = 4.94 mins, m/z (ES~)= 482 (M~ for C24H21N06S2) .

Example 2G: 5-Methyl-pyridyl-2-s-ulfonic acid [4-(4'-methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carbonyl]-
amide (11)
(Figure Removed)
LC/MS System D: Rt C26H24N06S) .= 10.09 mins, m/z (ES+) = 493 (MH+ for
xample 2H: Synthesis of 4-Aminomethyl-N-[4-(4'-methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carbonyl]-benzenesialfonamide trifluoroacetate (12)
4-(4'-Methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carboxylic acid (4) (50 mg) was reacted with (4-sulphamoyl-benzyl)-carbamic acid tert-butyl ester (85mg) in an analogous manner to that described in Example 2A. The intermediate tert-butyl carbamate was hydrolysed with 1% trifluoroacetic acid/dichloromethane over 24 hours, then concentrated in vacuo to give compound 12 as a white solid (10 mg) . LC/MS System C: Rt = 4.67 mins, m/z (ES~) = 493 (M" I for
Example 21: Synthesis of 4-Hydroxy-N- [4-(4' -methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carbonyl]-benzenesulfonamide (13)
(Figure Removed)
4-(4'-Methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carboxylic acid (4) (50 mg) was reacted with acetic acid 4-sulphamoyl-phenyl ester (64 mg) in an analogous manner to that described in Example 2A. The acetic ester intermediate was hydrolysed with sodium methoxide (80 mg) in a mixture of methanol (lOmL) and water (ImL) for 1 hour. The solution was concentrated in vacuo then partitioned between dichloromethane (10 mL) and water (10 mL) . The organic layer was washed with brine (10 mL), dried, filtered and concentrated in vacuo. The crude product was purified by preparative HPLC (starting at 30% acetonitrile and increasing at a rate of 1% per minute up to 98% acetonitrile) to give compound 13 as a white solid (15 mg). LC/MS System C: Rt = 3.50 mins, m/z (F,S~) = 492 (M" for
Example 3: Synthesis of 4-(Biphenyl-4-yloxymethyl)-5-methyl-furan-2-carboxylic acid (18)
(a) Triisopropyl- (2-methyl-furan-3-ylmethoxy) -silane (14)
(Figure Removed)Triisopropyl-(2-methyl-furan-3-ylmethoxy)-silane was prepared from (2-methyl-furan-3-yl)-methanol (1)(24.22 g) in an analogous manner to that described in Example 1 to give compound 14 as a clear oil (54.0 g) .
(b) 5-Methyl-4-triisopropylsilanyloxymethyl-furan-2-carJboxylic acid methyl ester (15)
(Figure Removed)
A solution of triisopropyl-(2-methyl-furan-3-ylmethoxy)-silane (14) (10.0 g) in tetrahydrofuran (300 mL) was cooled to -78°C with stirring was treated drop-wise with sec-butyllithium (3.0 M in cyclohexane, 37 mL). After 1 hour the reaction mixture was treated drop-wise with a solution of methyl chloroformate (5.2 g) in tetrahydrofuran (30 mL) over 10 mins and stirring was continued at -78°C for 1 hour. The reaction mixture was then treated with saturated ammonium chloride solution (300 mL) and allowed to warm to ambient temperature. The two layers were separated and the organic phase washed with brine (300 mL) , dried and concentrated in vacvo. The residue was purified by flash chromatography eluting with ethyl acetate/pentane (1:9 by volume) to give
compound 15 as a clear oil.
(c) 4-Hydroxymethyl-5-methyl-furan-2-carboxylic acid methyl ester (16) (Figure Removed)
A stirred solution of 5-methyl-4-
triisopropylsilanyloxymethyl-furan-2-carboxylic acid methyl ester (15) (5.2 g) in tetrahydrofuran (200 mL) was treated with tetrabutylammonium fluoride (1.0 M solution in tetrahydrofuran, 3.2 n\L) and stirring continued for 16 hours. The reaction mixture was concentrated in vacuo and the residue taken up in ethyl acetate (350 mL) and washed with water (150 mL) . The aqueous phase was re-extracted with ethyl acetate (2 x 100 mL) . The combined extracts were dried/ concentrated in vacuo and the residue was purified by flash chromatography eluting with ethyl acetate/pentane (1:1 by volume) to give compound 16 as a yellow oil.
id) 4~ (Biphenyl-4-yloxymethyl) -5-jnethyI-furan-2-carboxylic acid methyl ester (17)
(Figure Removed)
A solution of 4-hydroxyinethyl-5-methyl-f uran-2-carboxylic acid methyl ester (16) (Ig) in anhydrous tetrahydrofuran
(20mL) was cooled to Q°C under a nitrogen atmosphere. 4-Hydroxybiphenyl (3g) and triphenylphosphine (4.6lg) were added and the mixture was treated with di-
isopropylazodicarboxylate (3.46mL) dropwise. The mixture was stirred at 0°C for lOmin then cooling was removed and the mixture stirred for a further 3 hours. The solvent was removed in vacuo and the residue was partitioned between ethyl acetate (50mL) and water (lOOmL). The organic phase was separated, dried and evaporated. The residue was purified by flash chromatography, eluting with pentane /ethyl acetate 9:1 by volume to give a mixture of the title compound and 4-hydroxybiphenyl (1.8g). This material was purified further by flash chromatography eluting with dichloromethane/methanol 99:1 by volume to give compound 17 as a white solid (200mg). LCMS System A: Rt = 4.2 mins.
(e) 4~ (Biphenyl-4-yloxymethylJ-5-methyl-furan-2-carJboxylic acid (18)
(Figure Removed)
1M Aqueous lithium hydroxide (18mL) was added to solution of 4-(biphenyl-4-yloxymethyl)-5~methyl-furan-2-carboxylic acid methyl ester (17) (Ig) in tetrahydrofuran/methanol (2:1 by volume, lOOmL) and the mixture stirred at room temperature for 5h. The solvent was removed in vacuo, the residue dissolved in water (20mL) and the solution acidified to pH£ with aqueouy dilute hydrochloric acid. The mixture was evaporated to dryness and the residue was purified by HPLC
to afford compound 18 as a white solid (210mg). LC/MS System B: Rt = 4.80 mins, m/z = 307 ((M-l) for Ci9H1604) .
Example 4: Synthesis of N- [4- (Biphenyl-4-yloxymethyl)-5-methyl-furan-2-carbonyl]-benzenesulfonamide (19)

Compound (19) was prepared by adapting the procedure of Example 2A. LC/MS System D: Rt = 9.18mins, m/z (ES") = 446 (M" for C25H2iNO5S) .
Example 5: Synthesis of 4-(4'-Acetyl-biphenyl-4-yloxymethyl)-5-methyl~furan~2-carboxylic acid (21)

(a) 4- (4-Iodo-phenoxymethyl) -5-methyl-furan-2-carboxylic
acid methyl ester (20)
(Figure Removed)
A solution of 4-hydro;
was concentrated in vacuo and taken up in ethyl acetate (100 mL) and washed successively with water (100 mL), 1.0 M aqueous sodium hydroxide solution (100 mL), dried and concentrated in vacuo. The residue was purified by flash chromatography eluting with ethyl acetate/hexane (.1:4 by volume) to give compound 20 as a white solid (1.58 g) .

(b) 4- (4 ' -Acetyl-biphenyl-4-yloxymethyl) -5-methyl-furan-2-carboxylic acid (21)
(Figure Removed)
HO 21
A stirred mixture of 4- (4-iodo-phenoxymethyl)-5-methyl-furan-2-carboxylic acid methyl ester (20) (0.26 g), 4-acetylphenylboronic acid (0.15 g), N,N-dimethylformamide (30 mL) , potassium acetate (0.26 g) and [1,1'-bis(diphenylphosphino) ferrocene] dichloropalladium (II), complex with dichloromethane (1:1) (40 mg) was heated at 90°C over night. The reaction mixture was concentrated in vacuo, dissolved in ethyl acetate (30 mL) and washed successively with water (30 mL), brine (30 'mL) , dried and concentrated in vacuo. The residue was dissolved in a mixture of tetrahydrofuran/methanol (2:1 by volume) (30 mL) and 1.0 M aqueous lithium hydroxide solution (6.78 mL) and stirred for 16 hours. The reaction mixture was acidified to pH 2 using 0.1 M hydrochloric acid and extracted with ethyl acetate (3 x 25 mL) . The extract was dried, concentrated in vacuo and the residue purified by HPLC to give compound 21 as a white solid (50mg) . LC/MS System C: Rt = 4.18 ruins, m/z (ES") = 349 (M~ for C2iHi8O5) .

Example 6: Synthesis of N- [4- (4'-Acetyl-biphenyl-4-yloxymethyl) -5-methyl-furan-2-carbonyl] -benzenesulfonamide
(22)
(Figure Removed)
Compound (22) was prepared by adapting the procedure of Example 2A. LC/MS System D: Rt = 9.87 mins, m/z (ES*) = 490 (MH4 for C27H23N06S) .
Example 7: Synthesis of 4-(4'-Methoxy-biphenyl-4-ylcarbamoyl)-5-methyl-furan-2-carboxylxc acid (24)
(a) 5-methyl-furan-2,4-dicarboxylic acid-2-methyl ester (23)
Jones' reagent (Prepared according to Fieser and Fieser, Reagents for Organic Synthesis, Volume I, page 142, 1967) was added drop-wise to a stirred solution of 4-hydroxyinethyl-5-methyl-furan-2-carboxylic acid methyl ester (16) (100 mg) in acetone (10 mL) until the orange-colouration just remained. Stirring was continued for a further 5 hours then the reaction mixture was diluted with diethyl ether (20 mL) and filtered. The filtrate was dried

and concentrated in vacua to afford compound 23 as a buff coloured solid.
(b) 4-(4'-Methoxy-biphenyl-4-ylcarbamoyl)-5-methyl-furan-2-
carboxylic acid (24)
(Figure Removed)
To a solution of 5-methyl-furan-2,4-dicarboxylic acid-2-methyl ester (23) (100 mg) in N,N-dimethylformamide (3.0 mL) was added 0-(7-azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (228 mg), diisopropylethylamine (0.56 mL) and 4'-methoxy-biphenyl-4-ylamine (120 mg). The resulting solution was stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate (20 mL) and washed successively with water (2 x 20 mL), 0.1 M hydrochloric acid (20 mL), water (20 mL), saturated sodium hydrogen carbonate (10 mL) and brine (10 mL). This solution was dried and concentrated in vacuo. The residue (170 mg) wus dissolved in dichloromethane (5 mL), treated with triethylamine (0.3 mL) and a scavenger resin PS-TsCl (0.6 g) and the mixture shaken for 3 hours at room temperature. The reaction mixture was filtered and concentrated iri-vacuo. The residue was dissolved in methanol/tetrahydrofuran (1:3 by volume) (20 mL), treated with 1.0 M aqueous lithium hydroxide solution (2.0 mL) and allowed to stir at room temperature for 4 hours. The pH of the reaction mixture was adjusted to between pH 4 and pH 5 by careful addition of 1.0 M hydrochloric acid (1.0 mL) and partly concentrated in vacuo.
The residue was then partitioned between ethyl acetate (2 x 25 mL) and water (25 mL) and the combined organic extracts were washed with brine (35 mL) , dried (Na2S04), and concentrated in vacuo afforded compound 24 as beige solid (58 ing). LC/MS System D: Rt = 7.23 mins, m/z (ES+) = 351 (MH+ for C2oHi7N05) .
Example 8: Synthesis of 5-Benzenesulfonylaminocarbonyl-2-methyl-furan-3-carboxylic acid (4'-methoxy-biphenyl-4-yl)-
amide (25)
(Figure Removed)
Compound 25 was synthesised from 4-(4'-Methoxy-biphenyl-4-ylcarbamoyl)-5-methyl-furan-2-carboxylic acid (24) (35 mg) in an analogous manner to that described in Example 2A to give the title compound as a white solid (7 mg). LC/MS System A: Rt = 3.86mins, m/z (ES-) = 489 (M-l for C26H22N206S) .
Example 9: Synthesis of 4-(4'-Chloro-biphenyl-4-yloxymethyl)-5-methyl-ft3ran-2-carboxylic acid (27) and 4-(4-Benzo[1,3]dioxol-5-yl-phenoxymethyl)-5-methyl-furan~2-carboxylic acid (28)
(a) 4-(4-Iodo-phenoxymethyl)-5~methyl-furan-2-carboxylic acid (26)
(Figure Removed)
A stirred solution of 4-(4-iodo-phenoxymethyl)-5-methyl-furan-2-carboxylic acid methyl ester (20) (2.7 g) in tetrahydrofuran (25 mL) was treated with a solution of lithium hydroxide (1.5 g) in water (2 mL). After 3 hours the reaction mixture was diluted with water and acidified to pH 2 with 1.0 M hydrochloric acid. The white precipitate was filtered off and dried in vacua. The solid was triturated with ethyl acetate at 0°C then collected by filtration to give compound 26 as a white solid (1.83 g). LC/MS system A: Rt = 1.74 min.
(b) 4- (4 '-Chloro-biphenyl-4~yloxymethyl) -5-~methyl-furan-2-carboxylic acid (27)
(Figure Removed)
(i) 2-Chlorotrityl chloride resin (2.55 g of nominal loading 1.3 mmol/g) was swelled with dichloromethane (20 mL). After draining, a solution of 4-(4-iodo-phenoxymethyl)-5-methyl-furan-2-carboxylic acid (26) (1.18 g) and diisopropylethylamine (2,3 mL) in dichloromethane (30 mL) was added and the mixture was shaken at room temperature for 72 hours. The resin was drained, washed sequentially with dichlororaethane/triethylamine/methanol (20:1:3 by volume) (3
(Figure Removed)
30 mL) , dichloromethane (6 x 30 mL) , N,N-dimethylformamide (2 x 25 mL), dichloromethane (6 x 25 mL), and diethyl ether (2 x 25 mL) and dried at 40°C in vacua.
(ii) A stirred mixture of the resin from (i) (0.38g), 4-chlorophenylboronic acid (0.30 g) , [l,l'-bis-(diphenylphosphino)-ferrocene]-dichloropalladium(II) complex with dichloromethane (1:1) (30 mg), potassium acetate (0.20 g) in N,N-dimethylformamide (15 mL) was heated at 40°C for 48 hours. The resin was drained, then washed sequentially with tetrahydrofuran/water (1:1 by volume), tetrahydrofuran, N,N-dimethylformamide, dichloromethane, diethyl ether and then dried at 45°C in vacua. The resin was treated with dichloromethane/trifluoroacetic acid (19:1 by volume) (20 mL) for 20 mins and the solution drained from the resin. This procedure was repeated. The combined solutions were concentrated in vacuo and the residue purified by HPLC to afford compound 27 as a white solid (43 mg). LC/MS System D: Rt = 8.83 mins, m/z (ES~) = 341 (M~ for C19Hi5ClO4) .(c) 4-(4-Benzo[l,3]dioxol-5-yl-phenoxymethyl)-5-methyl-furan-2-carboxylic acid (29) (Figure Removed)
Compound 28 was synthesised from the resin from (i) in step (b) above and 3,4-methylenedioxyphenylboronic acid in an analogous manner to that described in step (ii) above. LC/MS System C: Rt = 4.60 mins, iti/z (ES") = 351 (M~ for C2oHi606) .
Example 10: Synthesis of [4-(Biphenyl-4-yloxymethyl)-5-methyl-furan-2-yl]-acetic acid (31) and 4-(4' -Methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-yl]-acetic acid (32)
(a) (5-Methyl-4-triisopropylsilanyloxymethyl-furan-2-yl)-acetic acid ethyl ester (29)

(Figure Removed)
A solution of triisopropyl-(2-methyl-furan-3-ylmethoxy)-silane (14) (5.0 g) in tetrahydrofuran (15 mL) was cooled to -~78°C with stirring. This solution was treated drop-wise with n-butyl lithium (2.5 M in hexanes, 8.94 mL). The resulting solution was warmed to 0°C and allowed to stand for 30 minutes after which a solution of dried zinc chloride (3.04 g) in tetrahydrofuran (10 mL) was added and the resulting solution allowed to stand for a further 1 hour at room temperature. Concurrently, a second reaction vessel was charged with tetrahydrofuran (10 mL), nickel(II) acetylacetonate (120 mg) , and triphenylphosphine (122 mg) and cooled (-5°C). Ethyl bromoacetate (1.03 mL) was added to this mixture, followed by the addition of the previously prepared solution of the furyl-zinc chloride. The resulting reaction mixture was allowed to warm to room temperature then stirred for a further 16 hours at room temperature. The
reaction was quenched by the addition of saturated ammonium chloride solution (100 mL) and extracted with ethyl acetate (3 x 150 mL). The combined organic extracts were successively washed with water (200 mL) and brine (250 mL), dried, filtered and concentrated in vacuo. The residue was purified by flash chromatography using a gradient elution (diethyl ether /petroleum ether (40-60°) 1:49 to 1:25 by volume) to give compound 29 as a clear oil (1.44 g). LC/MS System A: Rt = 5.16min.
(b) (4-Hydroxymethyl-5-methy2-f'uran-2-yl) -acetic acid ethyl ester (30)
(Figure Removed)
A solution of (5-methyl-4-triiscpropylsilanyloxymethyl-furan-2-yl)-acetic acid ethyl ester (29) (0.5 g) in tetrahydrofuran (3.0 mL) was cooled to 0°C with stirring and treated with tetrabutylammonium fluoride (1.0 M solution in tetrahydrofuran, 2.82 mL) under argon. After 30 minutes, the resulting solution was concentrated in—vacuo and partitioned between water (30 mL) and ethyl acetate (4 x 25 mL). The combined organic extracts were washed with brine (50 mL), dried (Na2S04) , filtered and concentrated in vacuo. The residue was purified by flash chromatography eluting with diethyl ether/petroleum ether (1:1 by volume) to give compound 30 as a clear oil (188 mg). LC/MS System A: Rt = 2.34 mins.
(c) {4-(Biphenyl-4-yloxymethyl)-5-methyl-furan-2-yl]-acetic acid (31)
Compound (31) was prepared from compound (30) in an analagous manner to the methods described in Examples 3(d) and 3(e). LC/MS System C: Rt = 4.97 mins, m/z (ES~) = 321 (M" for
(d) [4- (4' -Methoxy-biphenyl-4-yloxymethyl) -5-jnethyl~furan-2-
yl] -acetic acid (32)

(Figure Removed)

Compound (32) was prepared from compound (30) in an analagous manner to the methods described in Examples 3(d) and 3(e): LC/MS System C: Rt = 4.94 mins, m/z (ES~) = 351 (M" for C21H2o05) .
Example 11: Synthesis of 3 (Biphenyl-4-yloxymehhyl)-5-methyl-furan-2-yl]-propionic acid (37) and N-{3-[4-(Biphenyl-4-yloxymethyl)-5-methyl-furan-2-yl]-propionyl)-benzenes salfonamide (38)
79
(a) 5-Methyl-4-triisopropylsilanyloxymethyl-furan-2-carbaldehyde (33)

(Figure Removed)
A solution of triisopropyl-(2-methyl-furan-3-ylmethoxy)-silane (14) (10 g) in tetrahydrofuran (250 mL) was cooled to -78°C with stirring, and then sec-butyllithium (1.3 M in cyclohexane; 37.25 mL) was added drop-wise over 10 mins. After stirring for 45 mins at -78°C, the cooling bath was removed for a period of 15 mins then re-introduced. A solution of N, N-dimethylformamide (14.4 mL) in tetrahydrofuran (25 mL) was added drop-wise and the

resulting reaction mixture was stirred at -78°C for a further 2 hours. The reaction mixture was allowed to warm to-room temperature and then poured into saturated ammonium chloride solution (150 rnL) . This mixture was extracted with diethyl ether (2 x 350 mL), and the combined organic extracts were washed with water (500 mL) and brine (500 mL), dried, and concentrated in vacua to give compound 33 as an amber coloured oil. LC/MG System A: Rt = 4.86 mins.

(b) 3- (5-Methyl-4-triisopropylsilanyloxymethyl-furan-2~-yl) -acrylic acid ethyl ester (34)
A stirred solution of 5-methyl-4-
triisopropylsilanyloxymethyl-furan-2-carbaldehyde (33) (10.6 g) in tetrahydrofuran (25 mL) was treated with triethylphosphonoacatete (7.81 mL) and lithium hydroxide
(1.65 g) . The resulting mixture was stirred for 16 hours then concentrated in vacua and the residue partitioned between water (100 mL) and diethyl ether (3 x 100 mL). The combined organic extracts were further washed with water
(200 mL) and brine (200 mL), then dried (Na2S04) and concentrated in vacua. The residue was purified by flash chromatography eluting with diethyl ether/petroleum ether
(1:40 by volume) to give compound 34 as a clear yellow oil
(10.56 g). LC/MS System A: Rt = 4.59 mins.
(c) 3- (5-Methyl-4-triisopropylsilanyloxymethyl-furan-2-yl) -propionic acid ethyl ester (35)

(Figure Removed)
A solution of 3-(5~methyl-4-triisopropylsilanyloxymethyl-furan-2-yl)-acrylic acid ethyl ester (34) (1.0 g) in ethyl acetate (70 mL) was treated with 5% w/w palladium on carbon (350 mg) and hydrogenated at 1 atmosphere for exactly m hours at room temperature. The reaction mixture was filtered through filter-aid and then concentrated in vacuo to afford compound 35 as a clear oil (1.05 g) . LC/MS System A: Rt = 5.52 mins. (d) 3-(4-Hydroxymethyl-5-methyl-furan-2-yl)-propionic acid ethyl ester (36)
Compound (36) was prepared in the form of a clear oil from compound (35) by adapting the procedure described in Example 3(c). LC/MS System A: Rt= 2.68 rains.(e) 3-[4-(Biphenyl-4-yloxymethyl)-5-methyl-furan-2-yl]-propionic acid (37) (Figure Removed)
To 3 stirred, cooled 0°C solution, in tetrahydrofuran (2.5 mL), a solution of 3-(4-hydroxymethyl-5-methyl-furan-2-yl)-propionic acid ethyl ester (36) (400 mg) in tetrahydrofuran (2.5 mL) was cooled to 0°C and treated successively with triphenylphosphine (542 mg), biphenyl-4-ol (353 mg) and diisopropylasodicarboxylate (0.41 mL). After stirring for 10 mins at 0°C the reaction mixture was allowed to warm to room temperature and then stirred for a further 16 hours. The reaction mixture was concentrated in-vacuo then re-dissolved in dichloromethane (15 mL) and treated with triethylamine (1.50 inL) and a -scavenger resin PS-TsCl (2.5 g) and tl.e mixture was shaken for 6 hours at room temperature. The reaction mixture was purified by flash chromatography,
eluting with a mixture of diethyl ether in petroleum ether (40-60°C) (7:93 by volume ). The purified product (320 mg) was dissolved in methanol/tetrahydrof uran (2:1 by volume) (18 mL) , treated with 1.0 M aqueous lithium hydroxide solution (9 mL) and allowed to stir at room temperature for 6 hours. The pH of the reaction mixture was adjusted to between pH4 and pH5 by the addition of 1.0 M hydrochloric acid (~ 5.0 mL) , then treated with saturated ammonium chloride (100 mL) and extracted with ethyl acetate (2 x 100 mL) . The combined organic extracts were further washed with brine (35 mL) , then dried (sodium sulphate) and concentrated in vacua. A sample of the crude product (50 mg) was purified by HPLC to give compound 37 as white solid (25mg) . LC/MS System C: Rt = 5.33 mins, m/z (ES~) = 335 (M" for C2iH2o04) .
(f) N-{3-[4- (Biphenyl-4-yloxymethyl) -5-methyl-f uran-2-ylJ -propionyl ) -benzene sulfonamide (38)
(Figure Removed)
Compound (38) was prepared from compound (37) by the procedure of Example 2A. LC/MS System C: Rt - 5.82 mins, m/z (ES~) = 475 (M" for
Example 12: Synthesis of 3-[4-(4'-Methoxy-biphenyl-4-yloxymethyl) -5-methyl-furan-2-yl] -propionic acid (39) and N-{3-[4-(4' -Methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-yl] -propionyl}-benzene sulfonamide (40) (a) 3-[4-(4'-Methoxy-biphenyl-4-yloxymethyl) -5-methyl-furan-2-yl]-propionic acid (39)

Compound (39) was prepared from compound (36) in an analogous manner to that described in Example 11 (e) . LC/MS System C: Rt = 5.31 mins, m/z (ES~) = 365 (M~ for C22H2205) -
(b) N-{3-[4-(4'-Methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-yl]-propionyl}-benzene sulfonamide (40)
(Figure Removed)
Compound (40) was prepared from compound (39) by the procedure of Example 2A. LC/MS System C: Rt = 5,78 mins, m/z (ES") - 504 (M~ for C28H27N.06S) .
Example 13: Synthesis of 3-[4-(Biphenyl-4-yloxymethyl)-5-methyl-furan-2-yl]-acrylic acid. (42) and 3-[4-(4'-Methoxy-biphenyl-4~yloxymethyl)-5-methyl-furan-2-yl]-acrylic acid (43)
Compound (41) was prepared in the form of a yellow oil from compound (34) by adapting the procedure described in Example 3(c). LC/MS System A: Rt= 2.82mins.
(b) 3-[4- (Biphenyl-4-yloxymethyl)-5-methyl-furan-2-yl]-acrylic acid (42)
(Figure Removed)
Compound (42) was prepared from compound (41) by adapting the procedure of Example 11 (e) . LC/MS System C: Rt = 4.91 mins, m/z (ES~) = 333 (M~ for C21Hi8O4) .
(c) 3~ [4- (4 ' -Methoxy~biphQnyl-4-yloxymethyl) -5-methyl-furari-
2-ylj-acrylic acid (43)
(Figure Removed)
Compound (43) was prepared from compound (41) by adapting the procedure of Example ll(e). LC/MS System C: Rt= 4.85
(Figure Removed)
mins, m/2 (ES") = 363 (M~ for C22H2o05) -
Example 14A: Synthesis of 4-(Biphenyl-4-yloxymethyl)-5-methyl-furan-2-sxilfonic acid benzoylamide (46)
(a) 3-(Biphenyl-4-yloxymethyl)-2-methyl-furan (44)
44ethyl-furan-3-yl)-methanol (1)(5.0 g) in diethyl ether (75 mL) was cooled to 0°C with stirring and treated with triphenylphosphine (12.85 g) and biphenyl-4-ol (7.59 g). The resulting solution vas then treated drop-wise with diisopropylazodicarboxylate (9.75 mL). After stirring for 10 minutes at 0°C the reaction mixture was allowed to warm to room temperature and then stirred for a further 3 hours. The reaction mixture was then filtered and concentrated in vacuo. The residue was purified by flash chromatography, eluting with diethyl ether/petroleum ether (1:19 by volume), to give compound 44 as a white solid (7.0 g) . LC/MS System A: Rt= 4.38 mins.
(b) 4- (Biphenyl-4-yloxymethyl)-5-methyl-furan-2-sulfonic acid amide (45)

(Figure Removed)
A solution of 3-(biphenyl-4-yloxymethyl)-2-methyl-furan (44) (5g) in tetrahydrofuran (30 mL) was cooled to -78°C with stirring and was treated with butyllithium (2.5 M in hexanes; 9.84 inL) drop-wise over 10 minutes. After stirring for 45 mins at -78°C, cooling was removed for a period of 15 minutes then re-introduced. A stream of sulphur dioxide gas was then passed over the surface of the reaction mixture until the pH of the reaction was between pH6 and pH7. Stirring was continued for a further 1.5 hours at -78°C and then pentane was added (50 mL). The resulting precipitate was collected by filtration and then re-suspended in water
(75 mL). This suspension was cooled to 0°C and treated with sodium acetate (3.88 g) and hydroxylamine-O-sulfonic acid (2.67 g) and stirred at room temperature for 16 hours. The reaction mixture was diluted with water (300 mL) and extracted into ethyl acetate (3 x 250 mL). The combined organic extracts were washed successively with saturated sodium hydrogen carbonate (300 mL) and brine (300 mL), dried, and concentrated in vacua. This material was purified by flash chromatography, eluting with diethyl ether/petroleum ether (2:3 by volume) to give a beige coloured solid (998 mg). A sample of this material (100 mg) was further purified by HPLC to give compound 45 as white solid (55 mg). LC/MS System A: Rt= 3.70 mins.
(c) 4- (Biphenyl-4~yloxymethyl)-5-methyl-furan-2-sulfonic acid benzoylamide (46)
(Figure Removed)
To a stirred solution of benzoic acid (61 mg) in a mixture of tetrahydrofuran (10 mL) and N,N-dimethylformamide (5 mL) was added 4-(N,N-dimethylamino)pyridine (3.0 mg), l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (118 mg) and 4-(biphenyl-4-yloxymethyl)-5-methyl-furan-2-sulfonic acid amide (45) (206 mg). After 16 hours at room temperature the reaction mixture was concentrated in-vacuo, then partitioned between 0.1 M hydrochloric acid (30 mL) and ethyl acetate (3 x 30 mL). The combined organic extracts were washed, with brine (25 mL) , dried (MgSO-j) and concentrated in vacuo. The crude product was purified by HPLC to give compound 46 as light beige solid (17 mg). LC/MS System C: Rt = 5.69 mins, m/z (ES~) = 446 (M~ for C25H2aNO5S) .
Example 14B: Synthesis of 4-(Biphenyl-4-yloxymethyl)-5-methyl-furan-2-sulphonic acid butyryl-amide (61)
(Figure Removed)

To a stirred solution of 4-(biphenyl-4-yloxymethyl)-5-
methyl-furan-2-sulphonic acid amide (45) (50mgf 0.146mmoles) in dichloromethane (5.0ml) was added triethylamine (26|il, 0.189rranoles), dimethyl-pyridin-4-yl-amine (Img) and butyryl chloride (19u.l, 0.184mmoles). After stirring for 16 hours at room temperature the reaction mixture was concentrated in-vacuo, and the residue was purified by HPLC to give compound 61 as as an off-white solid (48mg). LC/MS System C: Rt = 3.82 mins, m/z (ES") = 412 ((M-H) for C22H23N05S) .
By adapting the procedure of Example 14B there were prepared Examples 14C to 14E :
Example 14C: 4-(Biphenyl-4-yloxymethyl)-5-methyl-furan-2-sulphonic acid phenylacetyl-amide (62)
(Figure Removed)
LC/MS System C: Rt = 4.20mins, m/z (ES") = 460 ((M-H) for C26H23NOsS) .
Example 14D: 4-(Biphenyl-4-yloxymethyl)-5-methyl-fnran-2-sulphonic acid (3,5-dimethyl-isoxazole-4-carbonyl)-amide (63)

(Figure Removed)
LC/MS System C: Rt = 3.98mins, m/z (ES~) = 465 ( (M-H) for
Example 14E: 4- (Biphenyl-4-yloxymethyl) -5-methyl-furan-2-sulphonic acid {thiophene-2-carbonyl) -amide (64)
(Figure Removed)
LC/i^S System C: Rt = 4.06mins/ ra/z (ES~) = 452 ((M-H) for C23H19N05S2) .
Example 14P: Synthesis of 4-(Biphenyl-4-yloxymethyl)-5-methyl-furan-2-sulphonic acid (3-methoxy-propionyl)-amide (65)
To a stirred solution of 4-(biphenyl-4-yloxymethyl)-5-
raethyl-furan-2-sulphonic acid amide (45) (50mg, 0.146mmoles) in N,N-dimethylformamide (4.0ml) was added
diisopropylethylamine (85|al, 0.480mmoles) then a solution of 3-methoxypropionic acid (14|al, 0.146mmoles) in N,N-dirnethylformamide (1.0ml). 0- (7-Azabenzotriazol-l-yl) -N,N,N',N'-tetramethyluronium hexafluorophosphate (61mg, O.lGOmmoles) in N,N-dimethylformamide (1.0ml) was added and the solution stirred at room temperature for 16 hours. The reaction mixture was concentrated in-vacuo, and the residue was purified by HPLC to give compound 65 as as a white solid (42rag) . LC/MS System A: Rt=3.80mins, m/z (ES~) = 428 ((M-H) for C22H23NOSS) .
By adapting the procedure of Example 14F there were prepared Examples 14G to 141:
Example 14G: 4-(Biphenyl-4-yloxymethyl)-5-methyl-furan-2-sulphonic acid (pyridin-3-yl-acetyl)-amide (66)

(Figure Removed)
LC/MS System D: Rt = 5.64mins, m/z (ES+) = 463 ( (M+H) for C25H22N205S) .
Example 14H: 4-(Biphenyl-4-yloxymethyl)-5-methyl-furan-2-sulphonic acid (pyridine-4-carbonyl)-amide (67)
C/MS System D: Rt = 5.85mins, m/z (ES+) = 449 ((M+H) for
Example 141: 4-{Biphenyl-4-yloxymethyl)-5-methyl-furan-2-siilphonic acid (pyridine-3-carbonyl)-amide (68)

(Figure Removed)
LC/MS System D: Rt = 5.92mins, m/z (ES+) = 449 ((M+H) for
Example 15: Synthesis of 4-(4'-Methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-sulfonic acid benzoylamide (49) and 4-(4 ' -Methoxy-biphenyl-4-yloxymethy
1)-5-methyl-furan-2-sulfonic acid (3,5-dimethyl-isoxazole-4-carbonyl)-amide (69) (a) 3- (4'-Methoxy-Mphenyl-4-yloxymethyi; -2-methyl-furan (47)

(Figure Removed)
Compound 47 was prepared by adapting the procedure of Example 14A(a). LC/MS System A: Rt = 4.58 mins.
(b) 4- (4 ' -Methoxy-biphenyl-4-yloxymethyl) -5-methyl-furan-2-sulfonic acid amide (48)
(Figure Removed)
Compound (48) was prepared from compound (47) by the procedure of Example 14A(b). LC/MS System A: Rt = 3.63 mins
(c) 4- (4f-Methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan~2-svlfonic acid benzoylamide- (49)
Compound (49) was prepared from compound (48) by the
procedure of Example 14B. LC/MS System C: Rt = 5.37 minsr m/z (ES") = 476 (W for
(d) 4- (4' -Met/70xy-biphenyl-4-yloxymethyl) -5-methyl-furan-2-sulphonic acid (3,5-dimethyl~isoxazole-4-carbonyl)-amide
(69)
(Figure Removed)
Compound (69) was prepared from compound (48) by adapting the procedure of example 14B. LC/MS System C: Rt = 4.45 mins, m/z (ES~) = 495 ( (M-H) for
Example 16: Synthesis of 4- [4- (5-Methoxy-pyridin-2-yl) -phenoxymethyl] -5~methyl-furan-2-carboxylic acid (53)
(a) 5 -Methyl -4- (4- (4,4,5, 5-tetramethyl-f 1,3,2 ]di oxaborolan-2-yl) -phenoxymethyl] -furan-2~carboxylic acid methyl ester (51)
(Figure Removed)
A mixture of 4-hydroxymethyl-5-methyl-furan-2-carboxylic acid methyl ester (16) (0.5g), 4- (4, 4 , 5, 5-tetramethyl-
[1,3,2]dioxaborolan-2-yl)-phenol (1.9g) and
triphenylphosphine (2.3g) in dry tetrahydrofuan (20mL) under a nitrogen atmosphere was cooled to 0°C. Di-isopropylazodicarboxylate (1.8mL) was added drop-wise and the mixture was stirred at room temperature for 72 hours. After concentrating in vacuo, the residue was partitioned between ethyl acetate and water. The organic phase was washed with brine, dried (MgS04) and concentrated in vacuo. The residue was extracted with pentane and the pentane phase was decanted and concentrated to give compound 51 as an oil. This was used without further purification.
(b) 4-[4-(5-Methoxy-pyridin-2-yl)-phenoxymethyl]-5-methyl-furan-2-carboxylic acid methyl ester (52)
(Figure Removed)
A mixture of 5-methyl-4-[4-(4, 4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxymethyl]-furan~2-carboxylic acid methyl ester (51) (126mg), 2M aqueous cesium carbonate (0.6mL) and 2-iodo-5-methoxypyridine (95mg) in 1,4-dioxan (lOmL) under an argon atmosphere was sonicated to expel traces of oxygen. [1,1'-Bis-(diphenylphoshino) ferrocene] dichloropalladium (II) (8mg) was added and the mixture heated at 95°C for 18 hours. After cooling, the mixture was acidified to pH6 with 1M aqueous hydrochloric acid and partitioned between ethyl acetate and water. The organic phase was dried (MgSO^) and evaporated to give compound 52 as an oil (70mg), which was used directly in the next step.
LC/MS System A: Rt = 3.23 nuns, m/z = 354 ( (M+H) for
(c) 4-[4-(5-Methoxy-pyridin-2-yl) -phenoxymethylJ-5-methyl-furan-2-carboxylic acid (53) (Figure Removed)
A solution of 4- [4- (5-methoxy-pyridin-2-yl)-phenoxymethyl]-
5-methyl-furan-2-carboxylic acid methyl ester (52) (118mg,
0.33mmoles) in dry tetrahydrofura-n (10ml) was treated with
potassium trimethylsilanoate (260mg, 2.0mmoles) and the
mixture stirred under an argon atmosphere for 2 hours. After
evaporation of the solvent the residue was purified by HPLC
(gradient: 18% acetonitrile/82% water containing 0.1%
trifluoroacetic acid to 98% acetonitrile/2% water at a rate
of 1%/min) to afford compound 53(60mg) as a white solid.
Method 2
A mixture of 4-[4- (5-methoxy-pyridin-2-yl)-phenoxymethyl]-5-methyl-furan-2-carboxylic acid methyl ester (52) (70mg) and 1M aqueous lithium hydroxide (ImL) in
tetrahydrofuran/methanol (2:1 by volume) (12mL) was stirred at room temperature for 16 hours. The reaction mixture was acidified to between pH6 and pH7, and partitioned between ethyl acetate and water. The organic phase was separated, washed with brine and dried (MgS04) . After removal of the solvent, the residue was purified by HPLC. Compound 53 was obtained as a solid (2.5mg). LC/MS System A: Rt= 2.90 minsr
m/z (ES+) = 340 ( (M+H) for C19H17N05) .
Example 17: Synthesis of 4~[6-(4-Methoxy-phenyl)-pyridin-3-yloxymethyl]-5-methyl-furan-2-carboxylic acid (56)
(a) 4-(6-iodo-pyridin-3-yloxymethyl)-5-methyl-furan-2-carboxylic acid methyl ester (54)
(Figure Removed)
Compound (54) was prepared from compound (16) and 2-iodo-5-hydroxy-pyridine in a manner analagous to that described in Example 5(a). LC/MS System A: Rt='3.52 mins, m/z = 374 ( (M+H) for Ci3Hi2IN04)
(b) 4-[6-(4-Methoxy-phenyl) -pyridin-3-yloxymethyl]-5-methyl-furan-2-carboxylic acid methyl ester (55)
(Figure Removed)
Compound (55) was prepared from compound (54) by adapting the procedure of Example 5(b). LC/MS System A: Rt= 3.37 mins, m/z ~ 354 ((M+H) for C2oH19N05) .
(c) 4-[6- (4-Methoxy-phenyl) -pyridin-3-yloxymethyl] -5-methyl-furan-2-carboxylic acid (56)
(Figure Removed)
Compound (56) was prepared from compound (55) by adapting the procedure of Example 16(c). LC/MS System A: Rt = 2.79 mins, m/z (ES*) = 340 {(M+H) for C19H17N05)
Example 18 : Synthesis of 3-Morpholin-4-yl-propane-l-sulphonic acid [4- (4 ' -methoxy-biphenyl-4-yloxymethyl) -5-methyl-furan-2-carbonyl] -amide (59)
(a) 3-Morpholin-4-yl-propane-l-sulfonic acid amide (58)
(Figure Removed)
Dichloromethane (40ml) was saturated with ammonia gas with cooling (dry ice /acetone), and then 3-morpholin-4~yl-propane-1-sulphonyl chloride (279mg, 1.23mmoles) was added. The mixture was stirred at room temperature for 24 hours. The mixture was filtered, the filtrate evaporated and the residue was dried at 40°C in vacuo to afford compound 58 (210mg) as a gum. LC/MS System A; Rt = 0.28 mins, m/z (ES+) = 209. (M+H for C7Hi6N203S) .
(b) 3-Morpholin-4~yl-propane-l-sulphonic acid [4-(4'~

methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2~carbonyl]
amide (59)
(Figure Removed)
Compound (59) was prepared from compounds (4) and (58) by adapting the procedure of Example 2A. LC/MS System D; Rt = 4.97mins, m/z (ES*) = 529 (M+H for
Example 19: Synthesis of N-[4-(Biphenyl-4-yloxymethyl)-5-methyl-furan;-2-carbonyl] -2-methyl-benzenesulphonamide (60)
A stirred solution of 4-(biphenyl-4-yloxymethyl)-5-methyl-furan-2-carboxylic acid (18) (SOmg, 0.162mmoles), 2-methyl-benzenesulphonamide (42mg, 0.243mmoles) and 4-(N,N-dimethylamino)-pyridine (2.5mg) in a mixture of tetrahydrofuran (8ml) and acetonitrile (2ml) was treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochlorid.e (38mg, 0.194mmoles) . The mixture was stirred at room temperature for 16 hours under an argon atmosphere, The reaction mixture was concentrated in vacuo and the
residue was purified by HPLC to afford compound 60(20mg) as a white solid. LC/MS System D; Rt = 11.09mins, m/z (ES+) = 462 (M+H for
Example 20A: Synthesis of 4-[2-(Biphenyl-4-yloxy)-ethyl]-5-methyl-furan-2-carboxylic acid (72)
(a) tert-Butyl-[2- (2-methyl-furan-3-yl)-ethoxy]-diphenyl-silane (70)
(Figure Removed)
(i) A solution of (2-methyl-furan-3-yl)-acetic acid ethyl ester (11.8g, 70.2mmoles) in tetrahydrofuran (50ml) was added to a stirred suspension of lithium aluminium hydride (2.66g,' 70.2mmoles) under a nitrogen atmosphere and with cooling to 0°C. When the addition was complete the mixture was stirred at room temperature for 3 hours, then quenched by the addition of excess acetone. After acidifying with 10% aqueous hydrochloric acid the mixture was extracted three times With diethyl ether. The combined extracts were dried and evaporated to afford crude 2-(2-methyl-furan-3-yl)-ethanol as a yellow oil.
(ii) Compound (70) was prepared in the form of a pale yellow oil from crude 2-(2-methyl-furan-3-yl)-ethanol (from (i)) by adapting the procedure of Example l(a).
(b) 4-[2-(tert-Butyl-diphenyl-silanyloxy)-ethyl]-5-methyl-furan-2-carboxylic acid (71)

Compound (71) was prepared in the form of a pale yellow oil from compound (70) by adapting the procedure of Example Kb) .
(c) 4-{2~ (Biphenyl-4-yloxy)-ethyl]-5-methyl-furan-2-carboxylic acid (72)

c(Figure Removed)
ompound (72) was prepared from compound (71) in an analogous manner to the methods described in Example 1(c). LC/MS System B: Rt = 1.86mins, m/z (ES~) = 321 ((M-H) for

Example 20B: Synthesis of 4-[2-(4'-Methoxy-biphenyl-4-yloxy) -ethyl] ~5-methyl~furan-2-carboxylic acid (73)
(Figure Removed)
Compound (73) was prepared from compound (71) in an analogous manner to the methods described in Example l(c) LC/MS System B: Rt = 1.86mins, m/z (ES~) = 351 ((M-H) for
Example 20C: Synthesis of 4-[2-(Dibenzofuran-3-yloxy)-ethyl]-5-methyl-furan-2-carboxylic acid (74)
(Figure Removed)
Compound (74) was prepared from compound (71) in an analogous manner to the methods described in Example 1 (c) LC/MS System B: Rt = 1.86minsf m/z (ES~) = 335 ( (M-H) for
Example 21A: Synthesis of 4- (Biphenyl-4-yloxymethyl) -furan 2-carboxylic acid (77) (a) 4-Hydroxymethyl-furan-2-carboxylic acid (75)
(Figure Removed)
A solution of furan-3-yl-methanol (1.6g, 16.5mmoles) in dry tetrahydrofuran (25ml) under an argon atmosphere was cooled to -78°C and treated dropwise with n-butyl-lithium (9.2mL, 23mmoles of a 2 . 5M solution in hexanes) . After 1 hour, sec-butyl-lithium (14.0ml, 18.2mmoles of a 1 . 3M solution in hexanes) was added. After stirring for a further 4 hours at -78 °C, the mixture was quenched by the addition of a large excess of solid carbon dioxide. The mixture was allowed to warm to room temperature and was added to a mixture of ethyl acetate and 1M aqueous hydrochloric acid (60ml). The organic phase was separated, washed with brine, dried , and evaporated. The residue was dissolved in dichloromethane and on standing a cream solid precipitated. The precipitate was collected and dried to afford compound 75 as cream solid (0.4g).
(b) 4- (tert-Butyl-dimethyl-silanyloxymethyl)-furan-2-carboxylic acid (76)

(Figure Removed)
A mixture of 4-hydroxymethyl-furan-2-carboxylic acid (75) (1.4g, 9.85mmoles), tert-butyl-chloro-dimethyl-silane (3.2g, 21mmoles) and imidazole (2.14g, 31.5mmoles) in dry DMF (35ml) was stirred at room temperature for 24 hours. Excess methanol (~3ml) was added and the mixture stirred for a further 3 hours. After partitioning between ethyl acetate and water, the aqueous phase was acidified to pH = 1 with 2M aqueous hydrochloric acid and re-extracted with ethyl acetate. The combined ethyl acetate phases were washed with water, dried (MgS04) , and the solvent evaporated to give compound 76 as a white solid (2.4g). 4- (Biphenyl-4-yloxymethyl) -furan-2-carboxylic acid (77)
(Figure Removed)
Compound (77) was prepared from compound (76) in an analogous manner to the methods described in Example l(c). LC/MS System B; Rt = 1.72mins, m/z (ES") = 293 (M-H for
Example 21B: Synthesis of 4-(Dibenzofuran-2-yloxymethyl)-103
furan-2-carboxylic acid (78)

(Figure Removed)
Compound (78) was prepared from compound (76) in an analogous manner to the methods described in Example 1(c) LC/MS System B; Rt = 1.72mins, m/z (ES") = 307 (M-H for Ci8H1205) .
Example 21C: Synthesis of 4-(4'-Cyano-biphenyl-4-yloxymethyl)-furan-2-carboxylic acid (79)

Compound (79) was prepared from compound (76) in an analogous manner to the methods described in Example 1(c) LC/MS System B; Rt = 1.65mins, m/z (ES') = 318 (M-H for C19H13N04) .
Example 21D: Synthesis of 4-(4'-Methoxy-biphenyl-4-yloxymethyl)-furan-2-carboxylic acid (80)
(Figure Removed) compound (80) was prepared from compound (76) in an analogous manner to the methods described in Example 1(c) LC/MS System B; Rt = 1.72mins, m/z (ES") = 323 (M-H. for
C19Hi605) •
Example 21E: Synthesis of 4- (Dibenzofuran-3-yloxymethyl) furan-2-carboxylic acid (81)
Compound (81) was prepared from compound (76) in an analogous manner to the methods described in Example 1(c) LC/MS System B; Rt = 1.75mins, m/z (ES~) = 307 (M-H for
xample 22A: Synthesis of 4-(Biphenyl-4-yloxymethyl)-5-isopropyl-f-uran-2-carboxylic acid (85)
(a) 2-Isoprcpyl-f~uran-3-carJboxylic acid ethyl ester (82)
(Figure Removed)
An ice-chilled solution of sodium hydroxide (1.9g) in water (25ml) was added, during 40 minutes, to a stirred solution of 4-methyl-3-oxo-pentanoic acid ethyl ester (3g, 18.96mmoles) and 1,2-dichloro-l-ethoxy-ethane (3.3g, 35.19mmole) in diethyl ether (15ml) with ice bath cooling. When the addition was complete the mixture was stirred rapidly for 1 hour, then the ethereal layer was separated, washed with water and dried. Evaporation of the solvent gave a yellow oil, which was purified by flash chromatography using a gradient elution from neat pentane to pentane/diethyl ether 9:1 v/v as eluent, to afford compound 82 as an oil (2.4g).
(b) Tri-isopropyl-(2-isopropyl-furan-3~ylmethoxy)-silane

(Figure Removed)

(i) A solution of 2-isopropyl-furan-3-carboxylic acid ethyl ester (82) (4.0g, 21.95mmoles) in tetrahydrofuran (70ml) was treated portionwise during 0.5h with lithium aluminium hydride (0.7g, 18.4mmoles) under a nitrogen atmosphere. When the addition was complete the mixture was stirred at room temperature for 18 hours, then quenched by the addition of excess acetone (1ml) and then water (1ml). After diluting with ethyl acetate (150ml) the grey precipitate was removed by filtration. The filtrate was evaporated and the residue dissolved in diethyl ether and dried. Evaporation of the solvent afforded (2-isopropyl-furan-3-yl)-methanol. This material was used immediately in the next step.
(ii) A solution of the (2~isopropyl-furan-3-yl)-methanol from (i) in dry dichloromethane (120ml) was treated with chloro-tri-isopropyl-silane (5.2g, 27.0mmoles) and imidazole (3.0g, 44.0mmoles) and the mixture was stirred overnight at room temperature. The reaction mixture was washed sequentially with 2M aqueous hydrochloric acid, water, saturated aqueous sodium bicarbonate, water and brine. After drying, evaporation of the solvents afforded a colourless oil, which heated at 125°C under reduced pressure (lOrnillibars) . The residue was compound 83 obtained as a pale yellow oil.
(c) 5-Isopropyl-4-triisopropylsilanyloxymethyl-furan~2-carboxylic acid (84)
Compound (84) was prepared in the form of a cream solid from compound (83) by adapting the procedure of Example 1(b).
(d) 4- (Biphenyl-4-yloxymethyl) ~5-isopropyl-furan-2-carboxylic acid (85)
(Figure Removed) compound (85) was prepared from compound (84) in an analogous manner to the methods described in Example l(c) LC/MS System B; Rt = 1.93mins, m/z (ES") = 335 (M-H for
Example 22B: Synthesis of 5-Isopropyl-4- (4 ' -methoxy-biphenyl-4-yloxymethyl) ~furan-2-carboxylic acid (86)
Compound (86) was prepared from compound (84) in an analogous manner to the methods described in Example l(c) LC/MS System B; Rt'= 1.93mins, m/z (ES") = 365 (M~H for C22H2205) -
Example 22C: Synthesis of 4-(Dibenzofuran-3-yloxymethyl)-5 isopropyl-furan-2-carboxylic acid (87)

(Figure Removed)

Compound (87) was prepared from compound (84) in an analogous manner to the methods described in Example l(c) LC/MS System B; Rt = 1.93mins, m/z (ES~) = 349 (M-H for
Example 23A: Synthesis of 4-(Biphenyl-4-yloxymethyl)-5-trifl-uoromethyl-furan-2-carboxylic acid (90)
(a) Tri-isopropyl- (2-trifluoromethyl-fvran-3-ylmethoxy)-silane (88)
(Figure Removed)

(i) A solution of 2-trifluoroniethyl-furan-3-carboxylic acid ethyl ester (2.2g, lO.Smmoles) in tetrahydrofuran (150ml) was treated portionwise during 0.5h with lithium aluminium hydride (0.55g, 14.5mmoles) under a nitrogen atmosphere. When the addition was complete the mixture was stirred at room temperature for 18h, then quenched by the addition of excess acetone (1ml) and then water (1ml). After diluting with ethyl acetate (200ml) the grey precipitate was removed by filtration. The filtrate was dried and evaporation of the solvent afforded (2-trifluoromethyl-furan-3-yl)-methanol as a colourless oil. This material was used immediately in the
next step.
(ii) A solution of the (2-trifluoromethyl-furan-3-yl)-inethanol from (i) in dry dichloromethane (180ml) was treated with chloro-tri-isopropyl-silane (2.6g, 13.4mmoles) and imidazole (1.45g, 2l.3mmoles) and the mixture was stirred overnight at room temperature. Further aliquots of chloro-tri-isopropyl-silane (0.9g, 4.64mmoles) and imidazole (0.5g, 7.34mmoles) were added and the mixture was stirred for 3h. The reaction mixture was diluted with water, the organic phase separated and washed sequentially with 0.1M aqueous hydrochloric acid, water, saturated aqueous sodium bicarbonate, water and brine. After drying, evaporation of the solvents afforded a colourless oil. The oil was distilled under reduced pressure (O.OStorr) in a Kugelruhr apparatus collecting the fraction boiling at an oven temperature of 125±20°C to afford compound 88 as a colourless oil.
(b) 5-Trifluoromethyl-4-triisopropylsilanyloxymethyl-furan-2-carboxylic acid (89)
Astirred solution of tri-isopropyl-(2-trifluoromethyl-furan-3-ylmethoxy)-silane (88) (2.0g, 6.24mmoles) in tetrahydrofuran (70ml) under argon was cooled to -78°C and treated with sec-butyl-lithium (2.2ml, 2.86mmoles of a 1.3M solution in cyclohexane). After In at -78°C, excess solid carbon dioxide, which had been pre-washed with tetrahydrofuran, was added and the mixture was allowed to warm to room temperature. The mixture was acidified to pH= 4
with dilute aqueous hydrochloric acid and extracted several times with ethyl acetate. The combined extracts were dried (MgS04) and solvent removed to afford compound (89) as an off-white solid (1.2g).
(c) 4-(Biphenyl-4-yloxymethyl)-5~trifluoromethyl-furan-2-carboxylic acid (90)
(Figure Removed)
Compound (90) was prepared from compound (89) in an analogous manner to the methods described in Example 1(c). The product was purified by HPLC. LC/MS System B; Rt = 1.97mins, m/z (ES~) = 361 (M-H for CigHi3F304) .
Example 23B: Synthesis of 4-(Biphenyl-3-yloxymethyl)-5-trifluoromethyl-furan-2-carboxylic acid (91)
Compound (91) was prepared from compound (89) in an analogous manner to the methods described in Example 1 (c). The product was purified by HPLC. LC/MS System B; Rt = 1.97mins, m/z (ES~) = 361 (M-H for C19Hi3F3O4) .

Example 23C: Synthesis of 4-(Diben2ofuran-2-yloxymethyl)-5-trifliioroniethyl-furan-2-carboxylic acid (92)

(Figure Removed)
Compound (92) was prepared from compound (89) in an analogous manner to the methods described in Example 1(c) The product was purified by HPLC. LC/MS System B; Rt = 1.97mins, m/z (ES") = 375 (M-H for
Example 23D: 4-(4'-Cyano-biphenyl-4-yloxymethyl)-5 trifl-uoromethyl-f-uran-2-carboxylic acid (93)
(Figure Removed)Compound (93) was prepared from compound (89) in an analogous manner to the methods described in Example 1(c). The product was purified by HPLC. LC/MS System B; Rt = 1.89mins, m/z (ES") = 386 (M-H for C20Hi2F3N04) .
Example 23E: Synthesis of 4-(4'-Methoxy-biphenyl-4-yloxymethy 1)-5-trifluoromethyl-furan-2-carboxylic acid (94)

Compound (94) was prepared from compound (89) in an analogous manner to the methods described in Example l(c).
The product was purified by HPLC. LC/MS System B; Rt 1.97mins, m/z (ES") = 391 {M-H for
Example 23F: 4- (Dibenzofuran-3-yloxymethyl) -5-trif luoromethyl-furan-2-carboxylic acid (95)
(Figure Removed) compound (95) was prepared from compound (89) in an analogous manner to the methods described in Example 1(c) The product was purified by HPLC. LC/MS System B; Rt = 1.97mins, m/z (ES') = 375 (M-H for Ci9HnF3O5) .
Example 24A: Synthesis of 4-(31,4'-Dimethoxy-biphenyl-4-yloxy methyl)-5-methyl-furan-2-carboxylic acid (96) (Figure Removed)

A stirred mixture of 4-(4-iodo-phenoxymethyl)-5-methyl-
furan-2-carboxylic acid methyl ester (20) (0.025g,
0.067mmoles) , (3, 4-dimethoxyphenyl)-boronic acid (0.017g,
0 . 093mmoles) r N^-dimethylf ormamide (3mL) , potassium acetate
(0.026g) and [1,1'-bis (diphenylphosphino)
ferrocene]dichloropalladium(II), complex with
dichloromethane (1:1) (4 mg) was stirred at room
temperature under an argon atmosphere for 24h. The reaction
mixture was diluted with water and extracted with ethyl
112

acetate. The extracts were washed with water, dried and concentrated in vacuo. The residue was dissolved in a mixture of tetrahydrofuran/methanol (2:1 by volume) (2.5mL) and 1.0 M aqueous lithium hydroxide solution (0.5 mL), and stirred for 16 hours. The reaction mixture was acidified to pH=6 using 1M hydrochloric acid and extracted with ethyl acetate (3 x 25 mL). The extracts were dried, concentrated in vacuo and the residue purified by HPLC (gradient: 30% acetonitrile/70% water containing 0.1% trifluoroacetic acid to 70% acetonitrile/30% water at a rate of 1%/min) to give compound 96 as a solid (15mg). LC/MS System B; Rt = 1.65mins, m/z (ES~) = 367 (M-H for C2aH2o06) .
Example 24B: Alternate synthesis of 4-(4-Benzo[1,3]dioxol-5-yl-phenoxymethyl)-5-methyl-furan-2-carboxylic acid (28)

(Figure Removed)
Compound (28) was prepared from compound 120) and 13,4-methylenedioxyphenyl)-boronic acid by adapting the procedure of Example 24A. LC/MS System B; Rt = 1.76mins, m/z (ES'~) = 351 (M-H for C20H1606) .
Example 24C: 4-(4'-Ethoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carboxylic acid (98)
(Figure Removed)
Compound (98) was prepared from compound (20) and (4-ethoxyphenyl)-boronic acid by an adapting the procedure of Example 24A. LC/MS System B; Rt = 1.8Grains, m/z (ES~) = 351 (M-H for C21H2005) •
Example 25A: Synthesis of 4-(2'-Chloro-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carboxylic acid (99)
Compound (99) was prepared from compound (20) and (2-chlorophenyl)-boronic acid by adapting the procedure of Example 5 (b) . LC/MS System B; Rt - 1.86mins, m/z (F,S~) - 341 and 343 (M-H for Ci9H15Cl04) .
Example 25B: Synthesis of 4- (2 ' , 6 ' -Dif ltioro-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carboxylic acid (100)
Compound (100) was prepared from compound (20) and (2,6-
difluorophenyl)-boronic acid by adapting the procedure of Example 5(b). LC/MS System B; Rt = 1.83mins, m/z (ES~) = 343 (M~H for C19Hi4F204) .
Example 25C: Synthesis of 5-Methyl-4-(2'-trifluoromethyl-biphenyl-4-yloxymethyl)-furan-2-carboxylic acid (102)

Compound (102) was prepared from compound (20) and (2-trif luoromethyl-phenyl) -boronic acid by adapting the procedure of Example 5(b). LC/MS System B; Rt = 1.93mins, m/z (ES~) = 375 (M-H for
Example 25D: Alternate synthesis of 4- (4 ' -Chloro-biphenyl-4 yloxymethyl) -5-methyl-furan-2-carboxylic acid (27)
(Figure Removed)
Compound (11) was prepared from compound (20) and (4-chloro-phenyl)-boronic acid by adapting the procedure of Example 5(b). LC/MS System B; Rt - 1. gamins/ m/z (ES~) = 341 and 343 (M-H for C19H15C1O4) -
Example 25E: Synthesis of 4-(3'-Fluoro-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carboxylic acid (104)

(Figure Removed)

Compound (104) was prepared from compound (20) and (3-fluoro-phenyl)-boronic acid by adapting the procedure of Example 5(b). LC/MS System B; Rt = 1.83mins, m/z (ES") = 325 (M-H for C19Hi5F04) .
Example 25F: 5-Methyl-4-(2'-methylsulphanyl-biphenyl-4-yloxymethyl)-furan-2-carboxylic acid (105)
(Figure Removed)
Compound (105) was prepared from compound (20) and (2-methylsulphanyl-phenyl) -boronic acid by adapting the procedure of Example 5 (b) . LC/MS System B; Rt = 1.86mins, m/z (ES") = 353 (M-H for C2oHi804S) .
Example 26A: Synthesis of 4- (3 ' , 4 ' -Dimethoxy-biphenyl-3-yloxymethyl) -5-methyl-furan~2-carboxylic acid (108)
(a) 4- (3-Iodo-phenoxymethyl) -5~methyl-furan-2-carboxylic acid methyl ester (106)A mixture of 4-hydroxymethyl-5-methyl~furan-2-carboxylic acid methyl ester (16) (1.85g, I0.9mmoles), 3-iodophenol (3.6g, I6.35mmoles), triphenylphosphine (4.3g, 16.35mmoles) in tetrahydrofuran (15mL) was cooled to 0°C. Diisopropylazodicarboxylate (3.3g, 16.35mmoles) was added and the mixture was allowed to warm to room temperature, then stirred for 72h. The tetrahydrofuran was evaporated and the residue purified by flash chromatography using hexane/ethyl acetate 7:3v/v as eluent to give compound 106 (2.8g). This was used directly in step (b).
(b) 4- (3-Iodo-phenoxymethyl)-5-methyl-furan-2~carboxylic acid (107)

A mixture of 4-(3-iodo-phenoxymethyl)-5-methyl-furan-2-carboxylic acid methyl ester (106) (2.7g, 7.25mmoles) and lithium hydroxide (1.5g, 36.25mmoles) in tetrahydrofuran (25ml) containing .water (2ml) was stirred at room temperature for 3h. The tetrahydrofuran was evaporated, the residue was diluted with water and the mixture acidified to pH=l with 1M aqueous hydrochloric acid. The precipitate was collected washed with water and dried at 70°C in vacuo to give compound 107(1.76g) as a white solid. LC/MS System B; Rt = 3.51mins, m/z (ES~) = 351 (M-H for Ca3HnIO4) .
(c) 4 -(3 ' ,4 '-Dimethoxy-biphenyl-3-yloxyjnethyi; -5-methyl-furan-2-carboxylic acid (108)
(Figure Removed)
(i) 2-Chlorotrityl chloride resin (2.5g of nominal loading 1.3 mmol/g) was swelled with dichloromethane (120 mL). After draining, a solution of 4-(3-iodo-phenoxymethyl)-5-methyl-furan-2-carboxylic acid (107) (1.16g, 3.24 mmoles) and diisopropylethylamine (2.25 mL, 12.96mmoles) in dichloromethane (20mL) was added and the mixture was shaken at ambient temperature for 72 hours. The resin was drained, washed sequentially with
dichloromethane/triethylamine/methanol (20:1:3 by volume) (3 x 30 ml), dichloromethane (4 x 30 mL), N,N-dimethylformamide
(4 x 30 mL), dichloromethane (6 x 30 mL), and diethyl ether
(3 x 30 mL) and then dried at 40°C in vacuo.
(ii) The loaded resin (llOmg) from (i) was treated with a mixture of (3,4-dimethoxyphenyl)-boronic acid (119.7mg, 0 . 65mraoles) , [1,1'-bis (diphenylphosphino)
ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (10.6mg) and potassium acetate (0.064g, 0.65mmoles) in N,N-din\ethylformamide (5mL) and the mixture was agitated at 100°C for 24 hours. The resin was drained, washed sequentially with tetrahydrofuran/water(1:Iv/v) (2 x 5mL), tetrahydrofuran (2 x 5mL), N,N-dimethylformamide (3 x 5mL), dichloromethane (6 x 5mL) and diethyl ether (2 x 5ml), then dried at 45°C in vacuo.
The resin was treated with dichlorornethane/trifluoroacetic acid (19:1 by volume) (3mL) for 30 mins and the solution drained from the resin. This procedure was repeated. The combined solutions were concentrated in vacuo and the
residue purified by hplc (gradient: 30% acetonitrile/70% water containing 0.1% trifluoroacetic acid to 90% acetonitrile/10% water at a rate of 1%/min) to afford compound 108(24.9mg) as a solid. LC/MS System B; Rt = 1.69mins, m/z (ES") = 367 (M-H for C21H2o06) .
Example 26B: Synthesis of 5-Methyl-4-(3'-trifluoromethyl-biphenyl-3-yloxymethyl)-furan-2-carboxylic acid (109)

Compound (109) was prepared from compound (107) and (3-trifluoromethyl-phenyl)-boronic acid by adapting the procedure of Example 26A(c). LC/MS System B; Rt = 1.97mins, m/z (ES") =375 (M-H for C2oHisF304) .
Example 27A: Synthesis of 4-(4'-Hydroxymethyl-biphenyl-4-yloxymethyl)-5-methyl~furan-2-carboxylic acid (110)

(Figure Removed)
(i) 2-Chlorotrityl chloride resin (3.9 g of nominal loading 1.3 mmol/g) was swelled with dichloromethane (40 mL). After draining, a solution of 4-(4-iodo-phenoxymethyl)-5-methyl-furan-2-carboxylic acid (26) (1.78g, 3.3mmoles) and diisopropylethylamine (2.3mL) in dichloromethane (30mL) was added and the mixture was shaken at room temperature for 12 hours. The resin was drained, washed sequentially with

dichloromethane/triethylamine/methanol (20:1:3 by volume) (3 x 30 mL), dichloromethane (6 x 30 mL), N,N-dimethylformamide
(2 x 25 mL), dichloromethane (6 x 25 mL), and diethyl ether
(2 x 25 mL) and dried at 40°C in vacua.
(ii) The loaded resin (HOmg) from (i) was treated with a mixture of (4-hydroxymethyl-phenyl)-boronic acid (98.3mg, 0.65mmoles) , [1,1'-bis(diphenylphosphino)
ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (lO.Gmg) and cesium carbonate (0.212g, 0.65mmoles) in N,N-dimethylformamide (5mL) and the mixture was agitated at 40°C under a nitrogen atmosphere for 72 hours. The resin was drained, washed sequentially with tetrahydrofuran/water (l:lv/v) (2 x 5mL), tetrahydrofuran (2 x 5mL) , N,N-dimethylformamide (3 x 5mL), dichloromethane (6 x 5mL) and diethyl ether (2 x 5ml), then dried at 45°C in vacuo.
The resin was treated with dichloromethane/trifluoroacetic acid (19:1 by volume) (3mL) for 30 mins and the solution drained from the resin. This procedure was repeated. The combined solutions were concentrated in vacuo and the residue purified by hplc (gradient: 30% acetonitrile/70% water containing 0.1% trifInoroacetic acid to 90% acetonitrile/10% water at a rate of 1%/min) to compound 110 (18.3mg) as a solid. LC/MS System B; Rt = 1.4Brains, m/z (ES~ = 337 (M-H for C20H1805) •
Example 27B: Synthesis of 5-Methyl-4-

(Figure Removed)
The loaded resin (HOmg) (from example 27A, (i) ) was treated with a mixture of (4-methylsulphany1-pheny1)-boronic acid (109mg, 0.65mmoles), [1. l'-bis(diphenylphosphino) ferrocene]dichloropalladium(II) complex with dichloromethane { 1:1) (10.6mg) and potassium acetate (0.064g, 0.65mmoles) in N,N-dimethylformamide (5mL) and the mixture was agitated . at 40°C for 60 hours. The resin was drained, washed sequentially with tetrahydrofuran/water (l:lv/v) (2 x 5mL) , tetrahydrofuran (2 x 5mL), N,N-dimethylformamide (3 x 5mL), dichloromethane (6 x 5mL) and diethyl ether (2 x 5ml), then dried at 45°C in vacuo.
The resin was treated with dichloromethane/trifluoroacetic acid (19:1 by volume) (3mL) for 30 nuns and the solution drained from the resin. This procedure was repeated. The combined solutions were concentrated in vacuo and the residue purified by hplc (gradient: 30% acetonitrile/70% water containing 0.1% trifluoroacetic acid to 90% acetonitrile/10% water at a rate of 1%/min) to afford compound lll(5.0mg) as a solid. LC/MS System B; Rt = 1.90mins, m/z (ES~) = 353 (M-H for C2oHi804S) .
Example 27C: Synthesis of 4-(3'-Hydroxy-biphenyl-4-yloxymethyl) -5-methyl-f-uran~2-carboxylic acid
(Figure Removed)
Compound (112) was prepared from compound (26) and (3-hydroxy-phenyl)-boronic acid by adapting the procedure of Example 27A. LC/MS System B; Rt = 1.23mins, m/z (ES") = 323 (M-H for Ci9H1605) .
Example 27D: 4-(4'-Dimethylamino-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carboxylic acid (113)
(Figure Removed)

Compound (113) was prepared from compound (26) and (4-dimethylamino-phenyl)-bornnic acid by adapting the procedure of Example 27B. LC/MS System B; Rt = 1.83mins, m/z (ES") = 350 (M-H for C2iH2iN04) .
Example 27E: Synthesis of 5-Methyl-4-(4'-trifluoromethoxy-biphenyl-4-yloxymethyl)-furan-2-carboxylic acid (114)
(Figure Removed)
Compound (114) was prepared from compound (26) and . (4-trif luoromethoxy-phenyl) -boronic acid by adapting the procedure of Example 27B. LC/MS System C; Rt = ll.Olmins, m/z (ES~) = 391 {M-H for C2oHi5F305) .
Example 27F: 5-Methyl~4- (2; -trif luoromethoxy-biphenyl-4-yloxymethyl) -furan-2-carboxylic acid (115)
(Figure Removed)
Compound (115) was prepared from compound (26) and (2-trif luoromethoxy-phenyl) -boronic acid by adapting the procedure of Example 27B. LC/MS System B; Rt = 1.97mins, m/z (ES~) = 391 (.M-H for C2oH15F305) .
Example 27G: Synthesis of 4- (3' -Methoxy-biphenyl-4-yloxymethyl) -5-methyl~furan~2-carboxylic acid (116)
Compound (116) was prepared from compound (26) and (3-
methoxy-phenyD-boronic acid by adapting the procedure of Example 27B. LC/MS System B; Rt = 1.79mins, m/z (ES") = 337 (M-H for C2oH18Ob) .
Example 27H: Synthesis of 4-(3'-Acetyl-biphenyl-4-yloxymethyl)-5-methyl-f-uran-2-carboxylic acid (117)
Compound (117) was prepared from compound (26) and (3-acetyl-phenyl)-boronic acid by adapting the procedure of Example 27B. LC/MS System B; Rt = 1.69mins, m/z (ES") = 349 (M-H for C21Hi805) .
Example 271: Synthesis of 4-(4'-Fluoro-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carboxylic acid (118)
ompound (118) was prepared from compound (26) and (4-fluoro-phenyl)-boronic acid by adapting the procedure of Example 27R. LC/MS System B; Rt = 1.79mins, m/z (ES") = 325 (M-H for C19H15FO4) .
(Figure Removed)124
example 28: Synthesis of N-[4-(4'-Methoxy-biphenyl-4-yloxymethyl) -5-methyl-f uran-2-carbonyl] -dimethylamino-
s-ulphonamide (122)'
(Figure Removed)
N,N-Dimethylsulphamide (73mg, 0 . 59mmoles) , l-[3-(dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (31mg, 0.162mmoles) and dimethyl-pyridin-4-yl-amine (ling) were added to a stirred solution of 4- (4 ' -methoxy-biphenyl-4-yloxymethyl) -5-methyl-f uran-2-carboxylic acid (4) (50mg, 0.148mmoles) in dichloromethane (20ml). The mixture was stirred under an argon atmosphere for 18 hours. After evaporation of the solvent, the residue was partitioned between dichloromethane and water. The aqueous phase was separated and extracted with dichloromethane. The combined extracts were washed with 1M aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, brine and dried (MgSO4) . Evaporation of the solvent afforded the crude product, which was purified by HPLC (gradient: 30% acetonitrile/70% water containing 0.1% trif luoroacetic acid to 98% acetonitrile/2% water at a rate of 1%/min) to afford compound 122(23. 5mg) as a white solid. LC/MS System C : Rt = 3.67 mins, m/z (ES~) = 443 ( (M-H) for
Example 29: Alternative synthesis of 4- (4 ' -Fluoro-biphenyl-4 -yloxymethyl) ~5-methyl-f-uran-2-carboxylic acid (118)
(a) 3-(4-Iodo-phenoxymethyl)-2-methyl-furan (123)
3-(4-Iodo-phenoxymethyl)-2-methyl-furan was prepared from (2-methyl-furan-3-yl)-raethanol and 4-iodo-phenol in an analogous manner to that described in Example 14 (a) .
(b) 3- (4'-Fluoro-biphenyl-4-yloxymethyl)-2-methyl-furan (124)
A mixture of (4-fluoro-phenyl)-boronic acid (300mg, 2.1mmoles), 3-(4-iodophenoxyrnethyl)-2-methyl-furan (123) (SOOmg, 1.6mmoles) and potassium acetate (0.6g) in N,N-dimethylformamide (70mL) was degassed, treated with [1,1'-bis(diphenylphosphino) ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (90mg) and the mixture was agitated at 95°C for 12 hours under an argon atmosphere, The mixture was concentrated in vacuo, partitioned between water (100ml) and diethyl ether (200ml). The aqueous phase was re-extracted with diethyl ether, and the combined etheral phases were dried and evaporated. The residue was purified by flash chromatography, using diethyl ether as eluent, to afford compound 124(200mg) as a solid. This material was used directly.

(c) 4-(4'~Fluoro-biphenyl~4~yloxymethyl)-5-methyl-furan~2-
carboxylic acid (118) (Figure Removed)
A solution of 3-(4'-fluoro-biphenyl-4-yloxymethyl)-2-methyl-furan (124) (200mg, 0.71mmoles) in dry tetrahydrofuran (15ral) was cooled to -70°C and stirred under an argon atmosphere. The mixture was treated dropwise with sec-butyl lithium (0.6ml, of a 1. 3M solution in cyclohexane) and stirred for 1 hour at -70°C. The reaction was quenched by the addition of excess solid carbon dioxide and allowed to warm to room temperature. The mixture was diluted with water, washed with diethyl ether and the aqueous phase acidified to pH = 6 withdilute aqueous hydrochloric acid. The mixture was extracted with ethyl acetate, the extracts dried (MgS04) , and solvent removed in vacua to give a yellow oil. The oil was purified by hplc to afford compound 118(15mg) as a solid. LC/MS System A; Rt = 3.71mins, m/z (ES") = 325 (M-H for Ci3H15FO4) .
Example 30: Synthesis of 4-(2'-Methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carboxylic acid (126) and N-[4-(2'-Methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carbonyl]-benzenesnlfonamide (127)
(a) 4-(2'-Methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carboxylic acid methyl ester (125)
(Figure Removed)
A degassed mixture of 5-methyl-4-[4- (4, 4 , 5, 5-tetramethyl-[1, 3, 2]dioxaborolan-2-yl) -phenoxymethyl] -furan-2-carboxylic acid methyl ester (119) (200mg, 0.54mmoles), l-bromo-2-methoxy-benzene (80u.l, 0 . 65mmoles) , 2M aqueous cesium
carbonate (1.0ml) and ), [1, 1'-bis (diphenylphosphino) ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (44mg) in 1,4-dioxan (30ml), under an argon atmosphere was heated at 95°C for 18 hours. After cooling, the mixture was concentrated, the residue dissolved in ethyl acetate and washed with brine and dried. After evaporation of the solvent, the residue was purified by flash chromatography using cyclohexane/ethyl acetate 9:lv/v as eluent to afford compound 125(40mg) as an oil. LC/MS System A; Rt = 4.14 mins, m/z (ES+) = 353weak (M+H for C2iH2oO5) .
(b) 4- (2' -Methoxy-biphenyl-4-yloxymethyl) -5-methyl-furan-2~ carboxylic acid (126)
(Figure Removed)
A solution of 4- (2' -inethoxy-biphenyl-4-yloxymethyl) -5-
rnethyl-furan-2-carboxylic acid methyl ester (125) (40mg, O.llmmoles) in dry tetrahydrofuran (25ml) was treated with potassium trimethylsilanoate (73mg, 0.56mmoles) and the mixture stirred under an argon atmosphere for 16h. After evaporation of the solvent the residue was acidified to pH 2 with 0.1M aqueous hydrochloric acid and the mixture extracted with ethyl acetate. The dried extracts were evaporated and the residue pumped under high vacuum at 40°C to afford compound 126(29mg) as an off-white solid. LC/MS System D; Rt = 8.30mins, m/z (ES+) = 339 (M+H for C2oHiBO5) .
(c) N-[4-(2'-Methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carbonyl]-benzenesulphonamide (127)

Compound (127) was prepared from compound (126) by adapting the procedure of Example 2A. LC/MS System D; Rt = i.l7mins, m/z (ES+) - 478 (M+H for C26H23N06S) .
Example 31: Synthesis of 4™(4'-Difluoromethoxy-biphenyl-4-yloxymethyl)-5-methyl-furari-2-carboxylic acid (129), N-t4-
(4'-Difluoromethoxy-biphenyl-4-yloxymethyl) -5-methyl-furan-2-carbonyl]-benzenesulfonamide (130) and 3,5-Dimethyl-isoxazole-4-sulfonic acid [4-(4'-difluoromethoxy-biphenyl -4-yloxymethyl) -5-methyl-ftiran-2-carbonyl]-amide (131)
(a) 4- (4f-difluoromethoxy-biphenyl-4-yloxymethyl) -5-methyl-furan-2-carboxylic acid methyl ester (128)
(Figure Removed)
A degassed mixture of 5-methyl-4- [4- (4, 4, 5, 5-tetramethyl-[1, 3, 2] dioxaborolan-2-yl) -phenoxymethyl] -furan-2-carboxylic acid methyl ester (119) (200mg, 0.54mmoles), 4-dif luoromethoxy-1-iodo-benzene (175mg, 0.65ramoles), 2M aqueous cesium carbonate (0.81ml) and ), {1,1'-bis (diphenylphosphino) ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (20mg) in 1,4-dioxan (10ml), under an argon atmosphere was heated at 80°C for 20h. Further quantities of 4-dif luoromethoxy-1-iodo-benzene (87.5mg, 0 . 0 . 27mmoles) and [1, 1'-bis (diphenylphosphino) ferrocene] dichloropalladium (II) complex with dichloromethane (1:1) (lOmg) were added and heating at 80°C was continued for 4 hours. After cooling, the mixture was concentrated. The residue was dissolved in dichloromethane and washed with water and brine, and dried. The solvent was evaporated and the residue was purified by flash chromatography using petrol (40-60°) /diethyl ether 9:lv/v as eluent to afford compound 128(120mg) as a wax. LC/MS System A; Rt = 4.14 mins .
(b) 4- (4' -Dif luoromethoxy-biphenyl~4-yloxymethyl) -5-methyl-furan-2-carboxylic acid (129)

(Figure Removed)
Compound (129) was prepared fromcompound (128) by adapting the procedure of Example 30 (b). LC/MS System C; Rt = 8.53mins, m/z (ES") = 373 (M-H for C2oHi6F205) .
(c) N-[4-(4'-Difluoromethoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carbonyl]-benzenasulphonamide (130)
(Figure Removed)
Compound (130) was prepared from compound (129) by adapting the procedure of Example 2A. LC/MS System C; Rt = 9.50mins, m/z (ES") = 512 (M-H for C26H2iF2N06S) .
(d) 3,5-Dimethyl-isoxazole-4-sulphonic acid [4~(4f-difluoromethoxy~biphenyl-4~yloxymethyl)-5-methyl-furan-2-carbonyl]-amide (131) (Figure Removed)
compound (131) was prepared from compound (129) by adapting the procedure of Example 2A. LC/MS System C; Rt = 9.47mins, m/z (ES') = 531 (M-H for
Example 32: Synthesis of N-{4- [4- (5-Methoxy-pyridin-2-yl) -phenoxymethyl] -5-methyl-furan-2-carbonyl) -benzenesulf onamide (132), 3,5-Dimethyl-isoxazole-4-sulfonic acid {4-[4-(5-methoxy-pyridin-2-yl) -phenoxymethyl] -5-methyl-f uran-2-carbonyl) -amide (133), N-{4- [4- (5-Methoxy-pyridin-2-yl) -phenoxymethyl] -5-methyl-f uran-2-carbonyl} -2-methyl-benzenesulfonamide (134) and N-{4- [4- (5-Methoxy-l-oxy-pyridin-2-yl) -phenoxymethyl} -5-methyl-furan-2-carbonyl}-benzenesulf onamide (135)
(a) N-{4-[4- (5-Methoxy-pyridin-2-yl) -phenoxymethyl] -5-methyl-furan-2-carbonyl) -benzenesulphonamide (132)
(Figure Removed)
Compound (132) was prepared from compound (53) by adapting the procedure of Example 2A. LC/MS System D; Rt = 7.10mins, m/z (ES+) = 479 (M+H for
(b) 3,5-Dimethyl-isoxazole-4-sulphonic acid {4-[4-(5-methoxy~pyridin~2-yl) -phenoxymethyl] -5 -methyl-f ur an -2 -carbonyl) -amide (133)
(Figure Removed)
Compound (133) was prepared from compound (53) by adapting the procedure of Example 2A. LC/MS System D; Rt = 7.83mins, m/z (ES+) = 498 (M+H for C24H23N30-,S) .
(c) N~{4-[4-(5-Methoxy-pyridin-2-yl)-phenoxymethyl]-5-methyl-furan-2-carbonyl}-2-methyl-benzenesulphonamide (134)
(Figure Removed)
Compound (134) was prepared from compound (53) by adapting the procedure of Example 2A. LC/MS System D; Rt = 8.43mins, m/z (ESt) ==493 (M+H for
(d) N-{4-[4-f5-Methoxy-l-oxy-pyridin-2-ylj -phenoxymethylJ• 5-methyl-£uran-2-carbonyl}-benzenesulphonamide (135)
(Figure Removed) solution of N-{4-[4-(5-methoxy-pyridin-2-yl)-phenoxyrnethyl] -5-methyl-f uran-2-carbonyl} -
benzenesulphonamide (132) (25mg, 0.042mmoles) in a mixture of methanol (0.5ml) and chloroform (1ml) was treated dropwise with a solution of 3-chloro-benzenecarboperoxoic acid (lO.Gmg of 72% wt.% peracid) in chloroform (1.5ml). After stirring for 21 hours at room temperature, a further quantity of 3-chloro-benzenecarboperoxoic acid (S.Omg of 72% wt.% peracid) in chloroform (1ml) was added and the mixture stirred for 6 hours. Another aliquot of 3-chloro-benzenecarboperoxoic acid (8.0mg of 72% wt .% peracid) in chloroform (1ml) was added and stirring continued for 21 hours. The mixture was evaporated and the residue was purified by HPLC (gradient: 25% acetonitrile/75% water containing 0.1% trifluoroacetic acid to 98% acetonitrile/2% water at a rate of 1%/min) to afford compound 135 (6mg) as a solid. LC/MS System A; Rt = 3.03mins, m/z (ES+) = 495 (M+H for C25H22N207S) .
Example 33: Synthesis of 5-Methyl-4-(4-pyrimidin-2-yl-phenoxyroethyl)-furan-2-carboxylic acid (137) and N-[5-Methyl-4-(4-pyrimidin-2-yl-phenoxymethyl)-furan-2-carbonyl]-benzenesulfonamide (138)
fa; 5-Methyl-4- (4-pyrimidin-2-yl-phenoxymethyl)-furan-2-carboxylic acid methyl ester (136)

(Figure Removed)
Compound (136) was prepared from compound (119) and 2-bromo-pyrimidine by adapting the procedure of Example 30 (a). LC/MS System A; Rt = 3.43 mins, m/z (ES+) = 325 (M+H for
(b) 5-Methyl-4-(4-pyrimidin-2-yl-phenoxymethylJ-furan-2-carboxylic acid (137)
(Figure Removed)
Compound (137) was prepared from compound (136) by adapting the procedure of Example 30(b). LC/MS System D; Rt = 6.21mins, m/z (ES4) = 311 (M+H for CnHi4N204) .
(c) N-[5-Methyl-4- (4-pyrimidin-2-yl-phenoxymethyl) -furan-2-carbonylJ-Jbenzenesulphonamide • (138)
(Figure Removed)
Compound (138) was prepared from compound (137) by adapting the procedure of Example 2A. LC/MS System D; Rt = 7.50mins, m/z (ES+) - 450 (M+H for
Example 34: Synthesis of 4- (2 ' , 4 ' -Dimethoxy-biphenyl-4-yloxymethyl) -5-methyl-fTiran-2-carboxylic acid (140), N-[4-(2 ' , 4 ' -Dimethoxy-biphenyl-4-yloxymethyl) -5-methyl-furan-2-carbonyl] -benzenesulfonamido (141) and 3 , r>~Dimethyl-isoxazole-4-sulf onic acid [4- (2 ' , 4 ' -dimethoxy-biphenyl-4-yloxymethyl) -5-methyl-fiaran-2 -carbonyl] -amida (142)
(a) 4~(2', 4'-Dimethoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2~carboxylic acid methyl ester (139)

Compound (139) was prepared from compound (119) and 1-bromo-2,4-dimethoxy-benzene by adapting the procedure of Example 31(a). LC/MS System A; Rt = 4.09 mins.
(b) 4-(2',4'-Dimethoxy-biphenyl-4-yloxymethyl)-5-methyl-x"uran-2-cari?oxylic acid (140)
(Figure Removed)
Compound (140) was prepared from compound (139) by adapting the procedure of Example 31 (b) . LC/MS System D; Rt = 8.20mins, ra/z (ES+) = 369 (M+H for C2iH2oOe) .
(c) N-[4-(2r,4 '-Dimethoxy-biphenyl-4-yloxymethyl)-5-methyl• r"uran-2-carJbonyiy --benzenesulphonamide (141)
(Figure Removed) stirred solution of 4- (2',4'-dimethoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carboxylic acid (140) (50mg, 0.136mmoles), benzenesulphonamide (32mg, 0.204mmoles) and 4-(N,N-dimethylamino)-pyridine (5mg) in a mixture of tetrahydrofuran (8ml) and acetonitrile (2ml) was treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (32mg, 0.163mmoles) . The mixture was stirred at room temperature for 16 hours under an argon atmosphere. The reaction mixture was concentrated in vacuo and the residue was purified by HPLC to afford compound 141(24mg) as a white solid. LC/MS System C; Rt = 8.99mins, m/z (ES~) = 506 (M-H for C2-7H25N07S) .
(d) 3,5-Dimethyl-isoxazole-4-sulphonic acid [4-(2',4'~ dimethoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carbonyl]-amide (142)

Compound (142) was prepared from compound (140) and 3,5-dimethyl-isoxazole-sulphonic acid amide by adapting the procedure of Example 34 (c) . LC/MS System C; Rt = 9.13mins, m/z (ES~) = 525 (M-H for
Example 35: Synthesis of 4- (41 -Methoxy-2 ' -methyl-biphenyl-4-yloxymethyl) -5-methYl~f"uran-2-carboxylic acid (144), N-[4~ (4 ' -Methoxy-2 ' -methyl-biphenyl-4-yloxymethyl) -5-methyl-furan-2-carbonyl] -benzenesulfonamide (145) and 3 , 5-Dimethyl-isoxazole-4-sulf onic acid [4- (4 ' -methoxy-2 ' -methyl-biphenyl-4-yloxymethyl) -5-methyl-furan-2-carbonyl] -amide (146)
(a) 4- (4 '-Methoxy-2f-methyl-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carboxylic acid methyl ester (143)
(Figure Removed)
Compound (143) was prepared from compound (119) and 1-bromo-4-methoxy-2-methyl-benzene by adapting the procedure of Example 31(a). LC/MS System A; Rt = 4.24 mins.
(b) 4- (4 '-Methoxy-2'-methyl-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carboxylic acid (144)
(Figure Removed)
Compound (144) was prepared from compound (143) by adapting the procedure of Example 31(b). LC/MS System D; Rt = 8.48mins, m/z (ES+) = 353 (M+H for C2iH2o05) .
(c) N-[4-(4'-Methoxy-2'-methyl-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carbonyl]-benzenesulphonamide (145)
(Figure Removed)
Compound (145) was prepared from compound (143) and by
adapting the procedure of Example 34(c). LC/MS System C; Rt = 9.40mins, m/z (ES") = 490 (M-H for C27H25N06S) .
(d) 3,5-Dimethyl-isoxazole-4-sulphonic acid [4-(4 '-methoxy-2f-methyl'biphenyl-4-yloxymethyl)-5-methyl-furan-2-carbonylj-amide (146)
Compound (146) was prepared from compound (143) and 3,5-dimethyl-isoxazole-sulphonic acid amide by adapting the procedure of Example 34 (c) . LC/MS System D; Rt = 11.29mins, m/z (ES~) = 509 (M-H for
Example 36: Synthesis of 5- [4- (Biphenyl-4-yloxymethyl) -5-methyl-furan-2-yl] -iH-tetrazole (149)
(a) 4-Hydroxymethyl-5-methyl~furan-2-carbonitrile (147)

(i) Sec-Butyl lithium (1.3M solution in cyclohexane, 57.1ml, 74.2mmoles) was added, dropwise during lOmin, to a stirred solution of 4-(tert-butyl-diphenyl-silanyloxymethyl)~5-methyl-furan (reference example 2A) (20.Og, 57.1mmoles) under an argon atmosphere and with cooling to -78°C. After stirring for an additional 45 minutes, the cooling bath was removed for 15 minutes, and then the reaction was re-cooled to -78°C. A solution of
dimethylformamide (10ml) in tetrahydrofuran (40ml) was added during 5 minutes, the reaction mixture stirred for 2 hours at -78°C then allowed to warm to room temperature. The reaction was quenched by the addition of saturated aqueous ammonium chloride (200ml). Diethyl ether (500ml) was added the organic phase was separated, and the aqueous phase was extracted with diethyl ether (500ml). The combined extracts were washed with water (500ml) and brine (500ml), and dried
(MgS04) . Evaporation of the solvent afforded 4-(tert-butyl-diphenyl-silanyloxymethyl)-5-methyl-furan-2-carbaldehyde
(20.4g).
(ii) Hydroxylamine hydrochloride (l.llg, IS.Ommoles) and triethylamine (2.22ml) were added to a solution of 4-(tert-butyl-diphenyl-silanyloxymethyl)-5-methyl-furan-2-carbaldehyde from (i)(6.3g, IG.Ommoles) in dichloromethane (125ml) and the mixture was stirred at room tempreature for 17 hours. After cooling to 0°C, 2-Chloro-l,3-.dimethylimidazolium chloride (2.81g, 16.6mmoles) and triethylamine (4.6ml) were added and the yellow suspension was stirred at room temperature for 24 hours. The mixture was diluted with water and extracted with dichloromethane. The combined extracts were washed with 5% aqueous hydrochloric acid, saturated aqueous sodium bicarbonate and water, and finally dried (MgS04) . The solvent was evaporated and the residue was purified by flash chromatography (silica, cyclohexane/diethyl ether 99:1 v/v as eluent) to afford 4- (tert-butyl-diphenyl-silanyloxymethyl)-5-methyl-furan~2-carbonitrile as a viscous oil, (3.75g).
(iii) .A solution of 4- (tert-butyl-diphenyl-silanyloxymethyl)-5-methyl-furan-2-carbonitrile from (ii) (3.75g) in tetrahydrofuran (100ml) was cooled to 0°C under
an argon atmosphere, and was treated with a 1M solution of tetrabutylammonium fluoride in tetrahydrofuran (22ml) . The mixture was allowed to warm to room temperature and stirred for 16 hours. The volatiles were removed and the residue was partitioned between ethyl acetate and water. The organic phase was separarted and the aqueous phase was extracted with more ethyl acetate. The combined ethyl acetate extracts were washed with 1M aqueous hydrochloric acid and brine, and dried. The solvent was evaporated and the crude orange oil was purified by flash chromatography (silica, gradient elution with 0% to 40% ethyl acetate in cyclohexane) to afford compound 147 as a pale yellow oil (1.3g).
(b) 4- (Biphenyl-4-yloxymethyl) -5-methyl-furan-2-carbonitrile (148)
(c) (Figure Removed)
Dlisopropylazodicarboxylate (1.84g, lO.Smmoles) was added to a solution of 4-hydroxymethyl--5-methyl-furan-2-carbonitrile
(147) (1.32g, 9.6mmoles), biphenyl-4-ol (1.63g, 9.6mmoles) and triphenylphosphine (4.3g, 16.35mmoles) in tetrahydrofuran (50mL) with stirring and cooling to 0°C under an argon atmosphere. After 5 minutes, the cooling was removed and the mixture stirred at room temperature for 16h. The solvent was evaporated and the residue partitioned between ethyl acetate and water. The ethyl acetate phase was washed with brine and dried. After the solvent was evaporated, the residue was purified by flash chromatography
(silica, gradient elution with 5% to 10% ethyl acetate in cyclohexane) to afford compound 148 as a white solid (2.2g).141
-i
IR (powder) CN st. 2225cm
(c) 5-[4- (Biphenyl-4-yloxymethyl)-5-methyl-furan-2-ylJ-1H-tetrazole (149)
(Figure Removed)
A mixture of 4-(biphenyl-4-yloxymethyl)-5-methyl-furan-2-carbonitrile (148) (lOOmg, 0.35mmoles), sodium azide (27mg, 0.415mmoles) and potassium carbonate (62ing, 0.45mmoles) in dimethylformamide (5ml) was heated at 90°C for 96 hours then at 120°C for 24 hours. The mixture was evaporated and the residue purified by HPLC to afford compound 149 as a white solid (64mg) . LC/MS System D; Rt = 9.53mins, m/z (ES+) = 333 (M+H for Ci9Hi6N402) .
Example 37: Synthesis of 4-(4'-Difluoromethoxy-biphenyl-4-ylsulf any luxe thy 1) -5-methyl-furan-2-carboxylic acid (153) , N-[4-(4'-Difluoromethoxy-biphenyl-4-ylsulfanylmethyl)-5-methyl-furan-2-carbonyl]-2-methyl-benzenes-ulfonamide (154), N- [4- (4 ' -Dif l\ioromethoxy-biphenyl-4 -ylsulfanylmethyl)-5-methyl-furan-2-carbonyl]-benzenesulfonamide (155) and N-[4-(4'-Difluoromethoxy-biphenyl-4-sulfinylmethyl)-5-methyl-furan-2-carbonyl]-2-methyl-benzenesulfonamide (156)
(a; 4-(4-Bromo~phenylsulphanylmethyl)-5-methyl-furan-2-carboxylic acid methyl ester (150)

(Figure Removed)
Diisopropylazodicarboxylate (1.27g, 6.3mmoles) was added to a solution of triphenylphosphine (1.65g, 6.Smnoles) in tetrahydrofuran (15ml) with stirring and cooling in an ice/water bath. A solution of 4-hydroxymethyl-5-methyl-furan-2-carboxylic acid methyl ester (16) (536mg, 3.15mmoles) and 4-bromo-thiophenol (584mg, 3.09mmoles) in tetrahydrofuran (5ml) was added and the mixture stirred for 30 minutes at 0°C then 72 hours at room temperature. The solvent was evaporated and the residue extracted with heptane then diethyl ether. The extracts were combined and evaporated to give a yellow oil which was purified by by flash chromatography using heptane/ethyl acetate 9:lv/v as eluent. This gave compound 150(600mg) as a white solid. LC/MS System A; Rt = 4.12mins.
(b) 5~Methyl-4~[4- (4,4,5,5-tetramethyl-[1,3,2]dloxaborolan 2-yl)-phenylsulphanylmethyl]-furan-2-carboxylic acid methyl ester (151)
(Figure Removed)
[1, l'-Bis (diphenylphosphino) ferrocene] dichloropalladium (II)
-omplex with dichloromethane ( 1:1) (30mg) and 4,4,5,5-tetramethyl-[l, 3, 2]dioxaborolane (2.34ml of a 1M solution in tetrahydrofuran) were added to a degassed solution of 4-(4-bromo-phenylsulphanylmethyl)-5-methyl-furan-2-carboxylic acid methyl ester (150) (400mg, 1.17mmoles) in 1,4-dioxan (120ml). The mixture was heated at 100°C, under an argon atmosphere, for 20 hours, cooled and evaporated. The residue was partitioned between ethyl acetate and water, and the organic phase washed -with brine and dried (MgSCu) . After evaporation of the solvent the residue was purified by by flash chromatography, using heptane/ethyl acetate 9:lv/v as eluent, to afford compound 151(212mg) as a colourless oil.
(c) 4- (4f-difluoromethoxy-biphenyl-4-ylsulphanylmethyl)-5-methyl-furan-2-carboxylic acid methyl ester (152)
(Figure Removed)
[1, lf-Bis (diphenylpho.sphino) ferrocene] dichloropalladium (II) complex with dichloromethane (1:1) (12.8mg) was added to a degassed mixture of 5-rnethyl-4- [4- (4 , 4 , 5, 5~tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylsulphanylmethyl]-furan-2-carboxylic acid methyl ester (151) (200mg, 0.516mmoles), 1-difluoromethoxy-4-iodo-benzene (153mg, 0.568mmoles) and 2M aqueous cesium carbonate (4.12ml) in 1,4-dioxan (15ml). The mixture was placed under an argon atmosphere and was heated at 100°C for 20 hours. After cooling, the mixture was concentrated and the residue was partitioned between ethyl acetate and water, and the mixture adjusted to pH= 2 with 1M

aqueous hydrochloric acid. The organic phase was washed with brine and dried. After evaporation of the solvent, the residue was purified by flash chromatography, using heptane/ethyl acetate 9:lv/v as eluent, to afford compound 152 (126mg) as a white solid. LC/MS System A; Rt = 4.17mins.
(d) 4- (4'~Difluoromethoxy-biphenyl-4-ylsulphanylmethyl)-5-methyl-furan-2-carboxylic acid (153)
(Figure Removed)
Compound (153) was prepared from compound (152) by adapting the procedure of Example 30(b)(127mg) as a white solid. LC/MS System D; Rt = 10.34mins, m/z (ES~) = 389 (M-H for C2oHi6F204S) .
(e) N-[4-(4'-Difluoromethoxy~biphenyl~4~ylsulphanylmethyl)
5-methyl-furan-2-carbonyl]-2-methyl-benzenesulphonamide
(154)
(Figure Removed)
Compound (154) was prepared from compound (153) and 2-methyl-benzenesulphonamide by adapting the procedure of
Example 34 (c) . LC/MS System D; Rt = 11.61mins, m/z (ES+) = 544 (M+H for
(f) N-[4- (4' -Difluoromethoxy-biphenyl-4-ylsulphanylmethyl) 5-methyl-furan-2-carbonyl]-benzenesulphonamide (155)
(Figure Removed)
Compound (155) was prepared from compound (153) by adapting the procedure of Example 2A. LC/MS System D; Rt = il.44mins, m/z (ES+) = 530 (M+H for
(g) N-[4- (4f -Difluoromethoxy-biphanyl-4-ylsulphinylmethyl) 5-methyl-furan-2-carbonyl]-2-methyl-benzenesulphonamide (156) and N~[4- (4'-DifIuoromethoxy-biphenyl-4-sulfonylmethyl) -5-methyl-fux-an-2-carbonyl]-2-methyl-benzenesulfonamide (156a.)
A solution of 3-chloro-benzenecarboperoxoic acid (22mg of 72% wt peracid) in chloroform (3ml) was added to a solution of N-[4-(4'-difluoromethoxy-biphenyl-4-ylsulphanylmethyl)-5-
methyl-furan-2-carbonyl]-2-methyl-benzenesulphonamide (154) (50mg, 0.092mmoles) in a mixture of methanol (1ml) and chloroform (2ml). After stirring for 2 hours, the solvent was evaporated and the residue was purified by HPLC (gradient: 45% acetonitrile/55% water containing 0.1% trifluoroacetic acid to 98% acetonitrile/2% water at a rate of 1%/min) to afford compound 156(42mg) as a white solid. LC/MS System D; Rt = 9.61mins, m/z (ES~) = 558 (M-H for

Also obtained was N-[4-(4'-difluoromethoxy-biphenyl-4-ylsulphonylmethyl)-5-methyl-furan-2-carbonyl]-2-methyl-benzenesulphonamide (156a)(8mg) as a white solid. LC/MS System D; Rt = 10.24mins, m/z (ES~) = 574 (M-H for C2-7H23F2NO,S2) .
Example 38: Synthesis of 4-(Biphenyl-4-ylaminomethyl)-5-methyl-furan-2-carboxylic acid (160), N-[4-(Biphenyl-4-ylaminomethyl) -5-methyl-furan-2-carbonyl]-benzenesulfonamide
(161) and N- [4- (Biphenyl-4-ylaminomethyl) -5-nvethyl-furan-2-carbonyl]-2-methyl-benzenesulfonamide (162)
(a) 4-Formyl~5-methyl-furan-2-carboxylic acid methyl ester
(157)
(Figure Removed)Acetic acid 1, l-diacetoxy-3-oxo-lX5-ioda-2-oxa-indan-l-yl ester (Dess-Martin reagent) (549mg, 1.293mmoles) in dry dichloromethane was added to a solution of 4-hydroxymethyl-5-methyl-furan-2-carboxylic acid methyl ester (16) (200mg, 1.176mmoles) in dry dichloromethane (9ml) with cooling to 0°C under an argon atmosphere. After stirring for 20 minutes, the mixture was diluted with diethyl ether (40ml) and was poured into saturated aqueous sodium bicarbonate
(30ml) containing sodium thiosulphate pentahydrate (4g) and agitated'vigorously for 5 minutes. The organic phase was washed with saturated aqueous sodium bicarbonate (40ml), water (50ml) and brine (50ml) and dried. After removal of the solvent, the residue was purified by flash chromatography, using petrol/diethyl ether 4:1 v/v as eluent, to afford compound 157 (140mg) as a white solid.
(b) 4-(Biphenyl-4-ylaminomethyl)-5-methyl-furan-2-carboxylic acid methyl ester (158)

A solution of biphenyl-4-ylamine (150mg, 0.883mmoles) and 4-formyl-5-methyl-furan-2-carboxylic acid methyl ester (157) (135mg, 0.803mmoles) in methanol (2.0ml) was stirred over molecular sieves (type 3A) for Ihour. Sodium cyanoborohydride (55mg, 0.883mmoles) was added and the mixture stirred for 18 hour at room temperature. The mixture was concentrated and partitioned between ethyl acetate (25ml) and saturated aqueous sodium bicarbonate (30ml). The aqueous phase was re-extracted with ethyl acetate (2 x 25ml) and the combined extracts were washed with brine (50ml) and dried (MgS04) . After removal of the solvent, the residue was purified by by flash chromatography, using a gradient elution of petrol/diethyl ether 9:1 v/v to 4:1 v/v, to afford compound 158(75mg).
(c) 4-Chloromethyl~5-methyl-furan-2-carboxylic acid methyl ester (159)
(Figure Removed)
Triethylamine (196u,l, 1.41mmol.es) , followed by 4-methyl-benzenesulphonyl chloride (247mg, 1.293mmoles) were added to a stirred solution of 4-hydroxymethyl-5-methyl-furan-2-carboxylic acid methyl ester (16) (200mg, 1.176mmoles) in dry dichloromethane at 0°C under an argon atmosphere. The reaction mixture was stirred at 0°C for 15 minutes, then allowed to warm to room temperature and was stirred for a further 4 hours. The mixture was washed with saturated aqueous sodium bicarbonate (50ml) and brine (50ml), and dried (MgS04) . After removal of the solvent, the residue was purified by flash chromatography, using petrol/diethyl ether 19:1 v/v as eluent, to afford compound 159(75n\g) as a white solid. LC/MS System D; Rt = 6.34 mins, m/z (ES+) = 189 (M-fH for C8H5C103) -
(d) 4- (Biphenyl-4-ylaminomethyl)-5-raethyl-furan-2-carboxylic acid methyl ester (158)
(Figure Removed)
Potassium iodide (32mg) and a solution of biphenyl-4-ylamine (74mg, 0.438mmoles) in tetrahydrofuran (1ml) was added to a mixture of 4-chloromethyl-5~methyl-furan-2-carboxylic acid methyl ester (159)(75mg, 0.398mmoles) and potassium carbonate (83mg) in tetrahydrofuran (1ml). The mixture was stirred at room temperature under an argon atmosphere for 16
hours, and then refluxed with the exclusion of light for 16 hours. After cooling, the mixture was concentrated and the residue was purified by by flash chromatography, using a gradient elution of petrol/diethyl ether 9:1 v/v to 4:1 v/v, to afford compound 158(91mg). LC/MS System A; Rt = 3.93 mins, m/z (ES+) 4- (Biphenyl-4-ylaminomethyl) -5-methyl-furan-2-carboxylic acid (160)

A solution of 4-(biphenyl-4-ylaminomethyl)-5-methyl-furan-2-carboxylic acid methyl ester (158) (91mg, 0.283mmoles) in dry tetrahydrofuran (5ml) was treated with potassium trimethylsilanoate (182mg, 1.42mmoles) and the mixture stirred under an argon atmosphere for 3 hours. After evaporation of the solvent, the residue was purified by HPLC (gradient: 15% acetonitrile/85% water containing 0.1% trifluoroacetic acid to 55% acetonitrile/45% water at a rate of 1%/min) to afford compound 160(35mg) as a white solid. LC/MS System D; Rt = 7.64mins/ m/z (ES*) = 300 (M+H for
(f) N-[4- (biphenyl- 4-ylaminomethyl)-5-methyl-furan-2-carbonyl]-benzenesulphonamide (161)

A stirred solution of 4-(biphenyl-4-ylaminomethyl)-5-methyl-furan-2-carboxylic acid (160) (15mg, 0.036mmoles) , benzenesulphonamide (17mg, 0.107mmoles) and 4-(N,N-dimethylamino)-pyridine (Img) in a mixture of tetrahydrofuran (3ml) and acetonitrile (0.5ml) was treated with triethylamine (5.51, 0.039mmoles) and l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (10.5mg, 0.053mmoles). The mixture was stirred at room temperature for 19 hours under an argon atmosphere. The reaction mixture was concentrated in vacua and the residue was purified by HPLC to afford compound 161 (8mg) as a white solid. LC/MS System D; Rt = 8.84mins, m/z (ES+) = 447 (M+H for C (Figure Removed)
(g) N-[4-fbiphenyl- 4-ylaminomethylJ-5-methyl-furan-2-carbonyl]-2-methyl-benzenesvlphonamide (162) compound (162) was prepared from compound (160) and 2-methyl-benzenesulphonamide by adapting the procedure of Example 38(f). LC/MS System D; Rt = 10.39mins, m/z (ES+) = 461 (M+H for

Example 39: Synthesis of N- (4-{ [4- (5-Methoxy-pyridin-2-yl) phenylamino] -methyl} -5-methyl-f uran-2-carbonyl) -2-methyl-benzenesulfonamide (167)
(a) 4-[ (4-Bromo-phenylamino) -methyl] -5-methyl-furan~2-
carboxylic acid methyl ester (163)
(Figure Removed)
A mixture of 4-chloromethyl-5-methyl-furan-2-carboxylic acid methyl ester (159) (0.5g, 2.65mmoles), 4-bromoaniline (2.28g, 13.25mmoles) and potassium carbonate (0.55g, 3.98mmoles) in terahydrofuran (25ml) was stirred at gentle reflux for 12 hours. The mixture was evaporated to give a yellow residue, which was purified by HPLC to afford compound 163 as a trifluoroacetic acid salt (840mg). LC/MS System A; Rt = 3.82mins/ m/z (ES4) = 324/326 (M+H for Ca4H14BrN03) -
(b) 5-Methyl-4-{[4-(4,4,5,5-tetramethyl-
[lr 3r2]dioxabozolan~2-yl)-phenylamino]~methyl-furan-2-
carboxylic acid methyl ester (164)
(Figure Removed)
A mixture of 4-[(4-bromo-phenylamino)-methyl]-5-methyl-furan-2-carboxylic acid methyl ester (163) (280mg, 0.864mmoles), [1, l'-Bis (diphenylphosphino)
ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (21mg), 4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (240mg, 0.950mmoles) and potassium acetate (250mg, 2.59mmoles) in dimethyl sulphoxide. (6ml) was degassed and placed under an argon atmosphere. The mixture was heated at 80°C for 5 hours, cooled and toluene (100ml) was added. The mixture was washed with water (50ml) and sodium bicarbonate was added until the pH = 9. The aqueous phase was discarded and the tolune layer filtered. After evaporation of the solvent the residue was purified by flash chromatography (silica, heptane/ethyl acetate 4:lv/v as eluent) to give compound 164 as an oil, which was used directly in the next step.
(c) 4-{[4-(5-Methoxy-pyridin-2-yl)-phenylamino]-methyl}-5-methyl-furan-2-carboxylic acid methyl ester trifluoroacetic acid salt (165)
5-Methyl-4-{[4-(4,4, 5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylaraino]-methyl-furan-2-carboxylic acid methyl ester (164) (130mg, 0.525mmoles) was added to a degassed mixture of 2-bromo-5-methoxy-pyridine (99mg, 0.350mmoles), bis-(dibenzylidene-acetone)-palladium(0) (6mg) and triphenyl-phosphine (llmg) in toluene/dimethylformamide 1:1 v/v (5ml) under an argon atmosphere. Aqueous potassium carbonate (0.23ml of a 3M solution) was added and the mixture was heated at 100°C for 16 hours. The reaction mixture was concentrated and the residue was purified by HPLC to afford compound 165(38mg). LC/MS System A; Rt = 2.55mins, m/z (ES+) = 353 (M-fH for C2oH2oN204) . 4-{ [4-(5-Methoxy-pyridin-2~yl) -phenylatnino] -methyl)-5-methyl-furan-2-carboxylic acid hydrochloride salt (166)
(Figure Removed)
A solution of 4-{[4-(5-methoxy-pyridin-2-yl)-phenylamino]-
methyl)-5-methyl-furan-2-carboxylic acid methyl ester trifluoroacetic acid salt (165) (38mg, 0.082mmoles) in tetrahydrofuran (4ml) was treated with potassium trimethylsilanoate (63mg, 0.049mmoles) and the mixture stirred at room temperature for 16 hours. The mixture was evaporated to dryness and pumped under high vacuum to remove silanol volatiles. The residue was purified by HPLC to afford a residue, which was dissolved in 1M aqueous hydrochloric acid. The solution was evaporated to give compound 166 as a solid (30mg). LC/MS System A; Rt = 2.22mins, m/z (ES+) = 339 (M+H for CigHie^O,) and m/z (ES~) = 337 (M-H for
(e) N- (4-{ [4~ (5-Methoxy-pyridin-2-yl) -phenylamino] -methyl} -5-methyl-furan-2-carbonyl)-2-methyl-benzenesulphonamide (167)
(Figure Removed)
h suspension of 4-{[4-(5-methoxy-pyridin-2-yl)-phenylamino]-
methyl}-5-inethyl-furan-2-carboxylic acid hydrochloride salt (166) (30mg, O.OSmmoles) in tetrahydrofuran (5ml) was
treated with toluene-2-sulphonamide (41mg, 0.24mmoles), 1-(3-dimethylaminopropyl)-3-ethylcarbudiimide hydrochlocide (34rng, 0.116mmoles) and 4-(N,N-dimethylamino)-pyridine (lOmg, O.OSmmoles) and the mixture stirred at room
temperature for 16 hours. Triethylamine (24.3mg, 0.24mmoles)
was added and the mixture was stirred for a further 18 hours. The reaction mixture was concentrated and the residue was purified by HPLC to afford compound 167 as a yellow glass (l.lmg)). LC/MS System A; Rt = 2.72rnins, m/z (ES+) = 492 (M+H for Cze^s^OsS) and m/z (ES") = 490 (M-H for

Example 40: Synthesis of 4- [ (4 ' -Dif luoromethoxy-biphenyl-4-ylamino) -methyl] -5-methyl-furan-2-carboxylic acid (171), N-
{4- [ (4 ' -Dif luoromethoxy-biphenyl-4-ylamino) -methyl] -5-methyl-furan-2-carbonyl}-benzenesulfonamide (172) , N-{4-
[ (4 ' -Dif luororaethoxy-biphenyl-4-ylamino) -methyl] -5-methyl-furan-2-carbonyl) -2-methyl-benzenesulfonamide (173) and 3,5-Dimethyl-isoxazole-4-sulf onic acid {4- [ (4 ' -dif luoromethoxy-biphenyl-4-ylamino) -methyl] -5-methyl-furan-2-carbonyl } -amide
(174)
(a) 4-Difluoromethoxy-4-nitro-biphenyl (168)
[ 1, l'-Bis (diphenylphosphino) ferrocene] dichloropalladium(II) complex with dichloromethane (1:1) (250mg) was added to a degassed mixture of 4 , 4 , 5, 5-tetiamethyl-2- (4-nitro-phenyl) -[1, 3, 2] dioxaborolane (1.67g, 6.70mmoles), 1-dif luoromethoxy-4-iodo-benzene (2.17g, 8.04mmoles) and 2M aqueous cesium carbonate (10.05ml) in 1,4-dioxan (120ml). The mixture was placed under an argon atmosphere and was heated at 80°C for 20 hours. After cooling, the mixture was concentrated and the residue was partitioned between dichloromethane (2 x 200ml) and water (100ml) . The combined extracts were washed with brine (150ml) and dried (MgSO4) . After evaporation of
the solvent, the residue was purified by flash chromatography, using petrol (60-80° ) /diethyl ether 19:lv/v as eluent, to afford compound 168(1.15g) as a beige coloured solid.
(b) 4' -Difluoromethoxy-biphenyl-4-ylamine (169)

A solution of 4-difluoromethoxy-4-nitro-biphenyl (168) (l.lg, 4.ISmmoles) in ethyl acetate (100ml) was hydrogenated over 10% palladium on charcoal catalyst (250mg) using a hydrogen filled balloon. After 20 hours, the mixture was filtered through a pad of diatomaceous earth and the pad rinsed with ethyl acetate. The combined filtrate and washings were evaporated to afford compound 169(855mg) as a solid. LC/MS System A; Rt = 2.87mins, m/z (ES+) = 236(M+H) and 277 (M+H acetonitrile adduct) for Ci3HiiF2NO.
(c) 4-(4'-Difluoromethoxy-biphenyl-i-ylaminomethyl)-5-methyl-furan-2-carboxylic acid methyl ester (170)
ompound (170) was prepared from compounds (159) and (169) by adapting the procedure of Example 38 (d). (420mg) . LC/MS System A; Rt = 4.00 mins, m/z (ES+) = 388 (M+H) and 429 (M+H acetonitrile adduct) for
-4-ylaminomethyl)-5-
methyl-furan-2-carboxylic acid (171)

Compound (171) was prepared from compound (170) by adapting the procedure of Example 38 (e). LC/MS System D; Rt = 9.07mins, m/z (ES4) = 374 (M+H for
) N-{4-[ (4 ' -Difluoromethoxy-biphenyl- 4-ylamino) -methyl] 5-methyl-fvran-2-carbonyl) -benzenesulphonamide (172)
(Figure Removed)
Compound (172) was prepared from compound (171) and benzenesulphonamide by adapting the procedure of Example 38(f). LC/MS System D; Rt = 10.38mins, m/z (ES+) = 513 (M+H for
(f) N-(4-[(4'-Difluoromethoxy-biphenyl- 4-ylamino)-methyl] 5-methyl-furan-2-carbc,iyl}-2~methyl-benzenesulphonamide (Figure Removed)
Compound (173) was prepared from compound (171) and 2-methyl-benzenesulphonamide by adapting the procedure of Example 38 (f). LC/MS System D; Rt = 10.63mins, m/z (ES*) 527 (M+H for
(d) 3,5-Dimethyl-isoxazole-4-sulphonic acid {4-[(4'~ difluoroniethoxy-biphenyl- 4-ylamino) -methyl]-5-methyl-furan 2-carbonyl)-amide (174) Diisopropylethylamine (60p.l, 0.339mmoles) and a solution of 4- (4' -dif luoromethoxy-biphenyl-4-ylaininomethyl) -5 methyl-furan-2-carboxylic acid (171) (50mg, O.lOSmmoles) in N,N-dimethylformamide (1.0ml) were added to a stirred solution of 3,5-dimethyl-isoxazole-4-sulphonic acid amide (55mg, 0.308mmoles) in N,N-dimethylformamide (5.0ml). A solution of O-(7-azabenzotriazol-l~yl)-N,N,N' , N' -tetramethyluronium hexafluorophosphate (46mg, 0.124mmoles) in N,N-dimethylfornamide (1.0ml) was added and the mixture was
stirred at room temperature for 16 hours. The reaction mixture was concentrated in vacua and the residue was purified by HPLC to afford compound 174 (2mg) as a solid. LC/MS System D; Rt = 10.35mins, m/z (ES+) = 532 (M-fH for
Example 41: Synthesis of 4-{ [ (4 ' -Dif luoromethoxy-biphenyl-4-yl) -methyl-amino] -methyl} -5-methyl-furan-2-carboxylic acid
(176) and N- (4- {[ (4 ' -Dif luoromethoxy-biphenyl-4-yl) -methyl-amino] -methyl} -5-methyl-f uran-2-carbonyl) -2-methyl-benzenesulfonamide (177)
(a) 4-{ ( (4 ' -Dif luoromethoxy-biphenyl-4-yl) -methyl -amino] -methyl }-5-methyl-furan-2-carboxylic acid methyl ester (175)

(Figure Removed)

lodomethane (91mg, 0.64mmoles) and potassium carbonate (88mg, 0.64mmoles) were added to a solution of 4-(4'-dif luoromethoxy-biphenyl-4-ylaminomethyl) -5-methyl-furan-2-carboxylic acid methyl ester (170) (62mg, 0.16mmoies) in N,N-dimethylformamide (10ml) and the mixture stirred at room temperature for 36 hours under an argon atmosphere. The mixture was then heated at 35°C for 21 hours. The mixture was partitioned between dichloromethane and water, the organic phase separated and dried (MgSC>4) . After evaporation of the solvent, the residue was purified by flash chromatography, using cyclohexane/ethyl acetate 99:lv/v as eluent, to afford compound 175(41mg) as a brown oil. This was used directly in part (b) .
b) 4-{[(4' -Difluoromethoxy-biphenyl-4-yl)-methyl-amino]-methyl)-5-methyl-furan-2-carboxylic acid (176)
(Figure Removed)
A solution of 4-{[(4'-difluoromethoxy-biphenyl-4-yl)-methyl-amino] -methyl}-5-methyl-furan-2-carboxylic acid methyl ester (175) (30mg, O.OVmmoles) in dry tetrahydrofuran (20ml) was treated with potassium trimethylsilanoate (19mg, O.lSmmoles) and the mixture stirred under an argon atmosphere for 30 hours. Trifluoroacetic acid was added until the pH = 2. After evaporation of the solvent, the residue was purified by HPLC to afford compound 176(4.8mg) as a white solid. LC/MS System D; Rt = 9.42mins, m/z (ES+) = 388 (M+H for
(c) N-(4-{ [ (4 '-Difluoromethoxy-biphenyl-4-yl) -methyl-amino]-methyl}-5-methyl-furan-2-carbonyl) -2-methyl-benzenesulfonamide (177)
(Figure Removed)
A stirred solution of 4-{ [ (4 •'-dif luoromethoxy-biphenyl-4-yl)-methyl-amino]-methyl}-5-methyl-furan-2-carboxylic acid (176) (21mg, 0.054mmoles), 2-methyl-benzenesulphonamide
(19mg, O.lOSmmoles) and 4- (N,N-dimethylamino) -pyridine (Img) in a mixture of dichloromethane (8ml) and acetonitrile (2ml) was treated with 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (11.4mg, 0 . 060mmoles) . The mixture was stirred at room temperature for 18 hours under an argon atmosphere. The reaction mixture was concentrated in vacua and the residue was purified by HPLC to afford compound 177(2.9mg) as a solid. LC/MS System D; Rt = 11.21mins, m/z (ES+) = 541 (M+H for
Example 42: Biological Results
Binding ability to human EP receptors
Membranes were prepared from cells stably transfected with human EP receptor cDNA. In brief, cells were cultured to confluency, scraped from culture flasks, and centrifuged (800 g, 8 minutes, 4°C). Cells were twice washed in ice cold homogenisation buffer containing 10 mMTris-HCl, 1 mM EDTA.2Na, 250 mM sucrose, 1 mM PMSF, 0 . 3 mM indomethacin, pH 7.4, homogenised and re-centrifuged as before. The supernatant was stored on ice and pellets re-homogenised and re-spun. Supernatants were pooled and centrifuged at 40000g,
10 minutes, 4°C. Resultant membrane pellets were stored at -80°C until use.
For assay, membranes expressing human EP4, EPs, EP2 or receptors were incubated in Millipore (MHVBN45) plates containing assay buffer, radiolabelled [3H]PGE2 and 0 . 1 to 10 000 nM concentrations of compounds. Incubations were performed at suitable temperatures and for suitable times to allow equilibrium to be reached. Non-specific binding was determined in the presence of lOuM PGEa • Bound and free radiolabel was separated by vacuum manifold filtration using appropriate wash buffers, and bound radiolabel was
determined by scintillation counting. Constituents of each of the buffers are included in table 1 below.

The affinity or pKi of each compound for each receptor was calculated from the concentration causing 50% radioligand displacement (IC50) using the Cheng-Prusoff equation:

(radioligand concentration \ radioligand KD }

This approach follows that set out in Kenakin, T.P., Pharrnacologic analysis of drug receptor interaction. Raven Press, New York, 2nd edition. (Table Removed)

WE CLAIM:
1. A Furan compound of formula (I):
(Formula Removed)
or a pharmaceutically acceptable salt solvate or chemically
protected form thereof, wherein:
R2 is H or an optionally substituted C1-4 alkyl group;
Y is either -(CH2)n-X-, where n is 1 or 2 and X is 0,
S,S(=O)or S(=0)2, or NRN1, where RN1 is selected from H or
optionally substituted C1-4 alkyl, or Y is -C(=0)NRN2-, where
RN2 is selected from H and optionally substituted C1-7 alkyl
or C5-20 aryl;
R3 is an optionally substituted C6 aryl group linked to a
further optionally substituted C6 aryl group,
wherein if both C6 aryl groups are benzene rings, there may
be an oxygen bridge between the two rings, bound adjacent
the link on both rings;
A is a single bond or a C1-3 alkylene group; and
R5 is either:
(i) carboxy;
(ii) a group of formula (II):
(Formula Removed)
(iii) a group of formula (III):
(Formula Removed)

wherein R is optionally substituted C1-7 alkyl,C5-20 aryl or NRN3RN4, where RN3 and RN4 are independently selected from optionally substituted C1-4 alkyl; or (iv) tetrazole-5-yl;
except that when R2 is methyl, Y is CH2-0- and R5 is carboxy or a C1-7alkyl ester thereof, then R3 is not:

(Formula Removed)
2. The compound as claimed in Claim 1, wherein R2 is selected from H, methyl, CF3 and iso-propyl.
3. The compound as claimed in Claim 2, wherein R2 is methyl.
4. The compound as claimed in any one of claims 1 to 3, wherein Y = -(CH2)n-X-
5. The compound as claimed in Claim 4, wherein n is 1.
6. The compound as claimed in Claim 4 or Claim 5, wherein X is selected from 0, S and NH.
7. The compound as claimed in Claim 4 wherein Y = -CH2-0-.
8. The compound as claimed in Claim 6 wherein X is NH.
9. The compound as claimed in any one of claims 1 to 3

wherein Y is -C(=0)NRN2 -.
10. The compound as claimed in Claim 9, wherein RN2 is selected from H and optionally substituted C1-7 alkyl.
11.. The compound as claimed in any one of claims 1 to 10, wherein the C6 aryl groups of R3 are independently selected from those derived from benzene and heteroaryl groups, where the heteroatom or heteroatoms are nitrogen.
12. The compound as claimed in Claim 11, wherein the C6 aryl groups of R3 are independently selected from those derived from benzene, pyridine and 1,3-pyrimidine.
13. The compound as claimed in any of claims 1 to 12, wherein only the aryl group of R3 not bound to Y is substituted.
14. The compound as claimed in any of claims 1 to 13, wherein the optional substituents on the aryl groups of R3 are selected from the group consisting of optionally substituted C1-7 alkyl groups; C1-7 alkoxy groups; C1-7 thioether group; amino groups, optionally substituted by one or two C1-4 alkyl groups; halo groups; cyano; groups of the formula -0(CH2)nO, where n is 1 or 2 and C1-4 acyl groups.
15. The compound as calimed in any one of claims 1 to 13, wherein the optional substituents of the aryl groups of R3 are selected from the group consisting of -CH3, -CF3, -CH2OH, -OMe, -OCF3 -OEt -OCHF2 -SMe, -NMe2, F, CI, -CN, -0-CH2-0- and -C(=0)Me.
16. The compound as claimed in any one of claims 1 to 15, wherein R5 is either:

(i) a group of formula (II):
(Formula Removed)
(ii) a group of the formula (III):
(Formula Removed)
17. The compound as claimed in Claim 16, wherein R is selected from an optionally substituted C5-20 aryl group and an optionally substituted C5-20 aryl C1-7alk;yl group.
18. The compound as claimed in any one of claims 1 to 17, wherein the optional substituent of the group R is selected from C1-4 alkyl and -OH.
19. A compound selected from the group consisting of: 4- (4'-Methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carboxylic acid (4);
N- [4-(4'-Methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carbonyl]-benzenesulfonamide (5);
N- [ 4-(4'-Methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carbonyl]-C-phenyl-methanesulfonamide (6);
N- [4- (4'-Methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carbonyl]-methanesulfonamide (7);
Propane-1-sulfonic acid [4-(4'-methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carbonyl]—amide (8); 3,5-Dimethyl-isoxazole-4-sulfonic acid [4-(4'-methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carbonyl]-amide (9) ; Thiophene-2-sulfonic acid [4-(4'-methoxy-biphenyl-4-

yloxymethyl)-5-methyl-furan-2-carbonyl]-amide (10); 5-Methyl-pyridyl-2-sulfonic acid [4-(4'-methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carbonyl]-amide (11); 4-Aminomethyl-N-[4-(4'-methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carbonyl]-benzenesulfonamide (trifluoroacetate salt) (12);
4-Hydroxy-N-[4-(4'-methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carbonyl]-benzenesulfonamide (13);
4-(Biphenyl-4-yloxymethyl)-5-methyl-furan-2-carboxylic acid (18);
N- [4- (Biphenyl-4-yloxymethyl)-5-methyl-furan-2-carbonyl]-benzenesulfonamide (19);
4- (4'-Acetyl-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carboxylic acid (21);
N- [4-(4'-Acetyl-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carbonyl]-benzenesulfonamide (22);
4_ (4i-Methoxy-biphenyl-4-ylcarbamoyl)-5-methyl-furan-2-carboxylic acid (24);
5-Benzenesulfonylaminocarbony1-2-methyl-furan-3-carboxylic acid (4'-methoxy-biphenyl-4-yl)-amide (25); 4-(4'-Chloro-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carboxylic acid (27);
4-(4-Benzo[1,3]dioxol-5-yl-phenoxymethyl)-5-methyl-furan-2-carboxylic acid (28);
[4-(Biphenyl-4-yloxymethyl)-5-methyl-furan-2-yl]-acetic acid (31);
4- (4'-Methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-yl]-acetic acid (32);
3- [4- (Biphenyl-4-yloxymethyl)-5-methyl-furan-2-yl]-propionic acid (37);
N- {3- [4-(Biphenyl-4-yloxymethyl)-5-methyl-furan-2-yl]-propionyl}-benzene sulfonamide (38);
3-[4-(4'-Methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-yl]-propionic acid (39); N- {3- [ 4-(4'-Methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-

2-yl]-propionyl}-benzene sulfonamide (40);
3-[4-(Biphenyl-4-yloxymethyl)-5-methyl-furan-2-yl]-acrylic acid (42);
3-[4-(4'-Methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-yl]-acrylic acid (43);
4-(Biphenyl-4-yloxymethyl)-5-methyl-furan-2-sulfonic acid benzoylamide (4 6) ;
4-(4'-Methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-sulfonic acid benzoylamide (49);
4-(Dibenzofuran-3-yloxymethyl)-5-methyl-furan-2-carboxylic acid (50);
4-[4- (5-Methoxy-pyridin-2-yl)-phenoxymethyl]-5-methyl-furan-2-carboxylic acid (53);
4-[6- (4-Methoxy-phenyl)-pyridin-3-yloxymethyl]-5-methyl-furan-2-carboxylic acid (56);
4-(4'-Cyano-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carboxylic acid (57);
3-Morpholin-4-yl-propane-l-sulphonic acid [4-(4'-methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carbonyl]-amide (59) ;
N-[4-(Biphenyl-4-yloxymethyl)-5-methyl-furan-2-carbonyl]-2-methyl-benzenesulphonamide (60);
4-(Biphenyl-4-yloxymethyl)-5-methyl-furan-2-sulfonic acid butyryl-amide (61);
4-(Biphenyl-4-yloxymethyl)-5-methyl -furan-2-sulfonic acid phenylacetyl-amide (62); 4-(Biphenyl-4-yloxymethyl)-5-methyl-furan-2-sulfonic acid (3,5-dimethyl-isoxazole-4-carbonyl)-amide (63); 4-(Biphenyl-4-yloxymethyl)-5-methyl-furan-2-sulfonic acid (thiophene-2-carbonyl)-amide (64);
4-(Biphenyl-4-yloxymethyl)-5-methyl-furan-2-sulfonic acid (3-methoxy-propionyl)-amide (65);
4-(Biphenyl-4-yloxymethyl)-5-methyl-furan-2-sulfonic acid (pyridin-3-yl-acetyl)-amide (66); 4-(Biphenyl-4-yloxymethyl)-5-methyl-furan-2-sulfonic acid

(pyridine-4-carbonyl)-amide (67);
4-(Biphenyl-4-yloxymethyl)-5-methyl-furan-2-sulfonic acid
(pyridine-3-carbonyl)-amide (68);
4-(4'-Methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-
sulfonic acid (3,5-dimethyl-isoxazole-4-carbonyl)-
amide (69);
4-[2-(Biphenyl-4-yloxy)-ethyl]-5-methyl-furan-2-carboxylic
acid (72);
4-[2-(4'-Methoxy-biphenyl-4-yloxy)-ethyl]-5-methyl-furan-2-
carboxylic acid (73);
4-[2-(Dibenzofuran-3-yloxy)-ethyl]-5-methyl-furan-2-
carboxylic acid (74);
4-(Biphenyl-4-yloxymethyl)-furan-2-carboxylic acid (77);
4-(Dibenzofuran-2-yloxymethyl)-furan-2-carboxylic acid (78);
4-(4'-Cyano-biphenyl-4-yloxymethyl)-furan-2-carboxylic acid
(79);
4-(4'-Methoxy-biphenyl-4-yloxymethyl)-furan-2-carboxylic
acid (80);
4-(Dibenzofuran-3-yloxymethyl)-furan-2-carboxylic acid (81);
4-(Biphenyl-4-yloxymethyl)-5-isopropyl-furan-2-carboxylic
acid (85);
5-Isopropyl-4-(4'-methoxy-biphenyl-4-yloxymethyl)-furan-2-
carboxylic acid (86);
4-(Dibenzofuran-3-yloxymethyl)-5-isopropyl-furan-2-
carboxylic acid (87);
4-(Biphenyl-4-yloxymethyl)-5-trifluoromethyl-furan-2-
carboxylic acid (90);
4-(Biphenyl-3-yloxymethyl)-5-trifluoromethyl-furan-2-
carboxylic acid (91);
4-(Dibenzofuran-2-yloxymethyl)-5-trifluoromethyl-furan-2-
carboxylic acid (92);
4-(4'-Cyano-biphenyl-4-yloxymethyl)-5-trifluoromethyl-furan-
2-carboxylic acid (93);
4-(4'-Methoxy-biphenyl-4-yloxymethyl)-5-trifluoromethyl-
furan-2-carboxylic acid (94);

4-(Dibenzofuran-3-yloxymethyl)-5-trifluoromethyl-furan-2-
carboxylic acid (95);
4-(3',4'-Dimethoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-
carboxylic acid (96);
4-(4'-Ethoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-
carboxylic acid (98);
4-(2'-Chloro-biphenyl-4-yloxymethyl)-5-methyl-furan-2-
carboxylic acid (99);
4-(2',6'-Difluoro-biphenyl-4-yloxymethyl)-5-methyl-furan-2-
carboxylic acid (100);
5-Methy1-4-(2'-trifluoromethyl-biphenyl-4-yloxymethyl)-
furan-2-carboxylic acid (102);
4-(3'-Fluoro-biphenyl-4-yloxymethyl)-5-methyl-furan-2-
carboxylic acid (104);
5-Methyl-4-(2'-methylsulfany1-bipheny1-4-yloxymethyl)-furan-
2-carboxylic acid (105);
4-(3',4'-Dimethoxy-biphenyl-3-yloxymethyl)-5-methyl-furan-2-
carboxylic acid (108);
5-Methyl-4-(3'-trifluoromethyl-biphenyl-3-yloxymethyl)-
furan-2-carboxylic acid (109);
4-(4'-Hydroxymethyl-biphenyl-4-yloxymethyl)-5-methyl-furan-
2-carboxylic acid (110);
5-Methyl-4-(4'-methylsulfanyl-biphenyl-4-yloxymethyl)-furan-
2-carboxylic acid (111);
4-(3'-Hydroxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-
carboxylic acid (112);
4-(4'-Dimethylamino-biphenyl-4-yloxymethyl)-5-methyl-furan-
2-carboxylic acid (113);
5-Methyl-4-(4'-trifluoromethoxy-biphenyl-4-yloxymethyl)-
furan-2-carboxylic acid (114);
5-Methyl-4-(2'-trifluoromethoxy-biphenyl-4-yloxymethyl)-
furan-2-carboxylic acid (115);
4-(3'-Methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-
carboxylic acid (116);
4-(3'-Acetyl-biphenyl-4-yloxymethyl)-5-methyl-furan-2-

carboxylic acid (117);
4-(4'-Fluoro-biphenyl-4-yloxymethyl)-5-methyl-furan-2-
carboxylic acid (118);
N-4-(4'-Methoxy-biphen-4-yloxymethyl)-5-methyl-furan-2-
carbonyl]-dimethylaminosulphonamide (122);
4-(2'-Methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-
carboxylic acid (126);
N-[4-(2'-Methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-
carbonyl]-benzenesulfonamide (127);
4-(4'-Difluoromethoxy-biphenyl-4-yloxymethyl)-5-methyl-
furan-2-carboxylic acid (129);
N-[4-(4'-Difluoromethoxy-biphenyl-4-yloxymethyl)-5-methy1-
furan-2-carbonyl]-benzenesulfonamide (130) ;
3,5-Dimethyl-isoxazole-4-sulfonic acid [4— (4' —
difluoromethoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-
carbonyl]-amide (131);
N-{4-[4- (5-Methoxy-pyridin-2-yl)-phenoxymethyl]-5-methyl-
furan-2-carbonyl}-benzenesulfonamide (132);
3,5-Dimethyl-isoxazole-4-sulfonic acid {4-[4-(5-methoxy-
pyridin-2-yl)-phenoxymethyl]-5-methyl-furan-2-carbonyl}-
amide (133);
N-(4-[4-(5-Methoxy-pyridin-2-yl)-phenoxymethyl]-5-methyl-
furan-2-carbonyl}-2-methyl-benzenesulfonamide (134);
N-{4-[4-(5-Methoxy-l-oxy-pyridin-2-yl)-phenoxymethyl]-5-
methyl-furan-2-carbonyl}-benzenesulfonamide (135);
5-Methyl-4-(4-pyrimidin-2-yl-phenoxymethyl)-furan-2-
carboxylic acid (137);
N-[5-Methyl-4-(4-pyrimidin-2-yl-phenoxymethyl)-furan-2-
carbonyl]-benzenesulfonamide (138);
4-(2',4'-Dimethoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-
carboxylic acid (140);
N-[4- (2',4'-Dimethoxy-biphenyl-4-yloxymethyl)-5-methyl-
furan-2-carbonyl]-benzenesulfonamide (141);
3,5-Dimethyl-isoxazole-4-sulfonic acid [4-(2',4'-dimethoxy-
biphenyl-4-yloxymethyl)-5-methyl-furan-2-carbonyl]-amide

(142);
4-(4'-Methoxy-2'-methyl-biphenyl-4-yloxymethyl)-5-methyl-
furan-2-carboxylic acid (144);
N-[4-(4'-Methoxy-2'-methyl-biphenyl-4-yloxymethyl)-5-methyl-
furan-2-carbonyl]-benzenesulfonamide (145);
3,5-Dimethyl-isoxazole-4-sulfonic acid [4-(4'-methoxy-2'-
methyl-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carbonyl]-
amide (14 6);
5-[4-(Biphenyl-4-yloxymethyl)-5-methyl-furan-2-yl]-1H-
tetrazole (149);
4-(4'-Difluoromethoxy-biphenyl-4-ylsulfanylmethyl)-5-methyl-
furan-2-carboxylic acid (153);
N-[4-(4'-Difluoromethoxy-biphenyl-4-ylsulfanylmethyl)-5-
methyl-furan-2-carbonyl]-2-methyl-benzenesulfonamide (154);
N-[4-(4'-Difluoromethoxy-biphenyl-4-ylsulfanylmethyl)-5-
methyl-furan-2-carbonyl]-benzenesulfonamide (155);
N-[4-(4'-Difluoromethoxy-biphenyl-4-sulfinylmethyl)-5-
methyl-furan-2-carbonyl]-2-methyl-benzenesulfonamide (156);
N-[4-(4'-Difluoromethoxy-biphenyl-4-sulfonylmethyl)-5-
methyl-furan-2-carbonyl]-2-methyl-benzenesulfonamide (156a);
4-(Biphenyl-4-ylaminomethyl)-5-methyl-furan-2-carboxylic
acid (160);
N-[4-(Biphenyl-4-ylaminomethyl)-5-methyl-furan-2-carbonyl]-
benzenesulfonamide (161);
N-[4-(Biphenyl-4-ylaminomethyl)-5-methyl-furan-2-carbonyl]-
2-methyl-benzenesulfonamide (162);
N- (4-{ [4-(5-Methoxy-pyridin-2-yl)-phenylamino]-methyl}-5-
methyl-furan-2-carbonyl)-2-methyl-benzenesulfonamide (167);
4-[(4'-Difluoromethoxy-biphenyl-4-ylamino)-methyl]-5-methy1-
furan-2-carboxylic acid (171);
N-{4-[(4'-Difluoromethoxy-biphenyl-4-ylamino)-methyl]-5-
methyl-furan-2-carbonyl}-benzenesulfonamide (172);
N-{4-[(4'-Difluoromethoxy-biphenyl-4-ylamino)-methyl]-5-
methyl-furan-2-carbonyl}-2-methyl-benzenesulfonamide (173);

3,5-Dimethyl-isoxazole-4-sulfonic acid {4-[(4'-
difluoromethoxy-biphenyl-4-ylamino)-methyl]-5-methyl-furan-
2-carbonyl}-amide (174);
4-{ [ (4'-Difluoromethoxy-biphenyl-4-yl)-methyl-amino]-
methyl}-5-methyl-furan-2-carboxylic acid (176); and
N- (4-{ [ (4'-Difluoromethoxy-biphenyl-4-yl)-methyl-amino]-
methyl}-5-methyl-furan-2 -carbonyl)-2-methyl-
benzenesulfonamide (177).
or a pharmaceutically acceptable salt thereof.
20. The compound as claimed in claim 1, wherein said compound is N-{4-[4-(5-methoxy-pyridin-2-yl)-phenoxymethyl] 5-methyl-furan-2-carbonyl}-2-methyl-benzenesulfonamide (134 of the formula:
(Formula Removed)
or a pharmaceutically acceptable salt thereof.
21. The compound as claimed in any of claims 1 to 20 whenever used in the preparation of a medicament for the treatment and/or prevention of migraine.

Documents:

3257-DELNP-2005-Correspondence-Others-(01-09-2008).pdf

3257-DELNP-2005-GPA-(01-09-2008).pdf

3357-DELNP-2005-Abstract-(11-08-2008).pdf

3357-delnp-2005-abstract.pdf

3357-DELNP-2005-Claims-(11-08-2008).pdf

3357-DELNP-2005-Claims-11-08-2008.pdf

3357-delnp-2005-claims.pdf

3357-DELNP-2005-Correspondence-Others-(11-08-2008).pdf

3357-DELNP-2005-Correspondence-Others-(18-08-2008).pdf

3357-delnp-2005-correspondence-others.pdf

3357-delnp-2005-description (complete)-11-08-2008.pdf

3357-delnp-2005-description (complete).pdf

3357-DELNP-2005-Form-1-(11-08-2008).pdf

3357-delnp-2005-form-1.pdf

3357-delnp-2005-form-13.pdf

3357-delnp-2005-form-18.pdf

3357-DELNP-2005-Form-2-(11-08-2008).pdf

3357-delnp-2005-form-2.pdf

3357-DELNP-2005-Form-3-(11-08-2008).pdf

3357-delnp-2005-form-3.pdf

3357-delnp-2005-form-5.pdf

3357-DELNP-2005-Others-Document-(18-08-2008).pdf

3357-delnp-2005-pct-210.pdf

3357-DELNP-2005-Petition-137-(18-08-2008).pdf

« Previous Patent

Next Patent »

Patent Number

222958

Indian Patent Application Number

3357/DELNP/2005

PG Journal Number

37/2008

Publication Date

12-Sep-2008

Grant Date

28-Aug-2008

Date of Filing

28-Jul-2005

Name of Patentee

ASTERAND UK LIMITED formely known as PHARMAGENE LABORATORIES LIMITED.

Applicant Address

2 ORCHARD ROAD, ROYSTON, HERTFORDSHIRE SG8 5HD, U.K.

Inventors:

#	Inventor's Name	Inventor's Address
1	CLARK, KENNETH LYLE	15 PARSONAGE WAY, LINTON, CAMBRIDGE, CAMBRIDGESHIRE CB1 6YL, U.K
2	COLEMAN, ROBERT ALEXANDER	54 LONDON ROAD, ROYTON, HERTFORDSHIRE SG8 9EL, U.K
3	DAVIS, RICHARD JON	16 STOREHOUSE LANE, HITICHIN, HERTFORDSHIRE SG9 4AB, U.K
4	FENTON, GARRY	C/O ARGENTA DISCOVERY LIMITED 8/9 SPIRE GREEN CENTRE, FLEX MEADOW, HARLOW, ESSEX CM19 5TR, U.K
5	HARRIS, NEIL VICTOR	C/O ARGENTA DISCOVERY LIMITED, 8/9 SPIRE GREEN CENTRE, FLEX MEADOW, HARLOW, ESSEX CM19 5TR. U.K
6	STUTTLE KEITH ALFRED JAMES	C/O ARGENTA DISCOVERY LIMITED 8/9 SPIRE GREEN CENTRE FLEX MEADOW, HARLOW ESSEX CM19 5TR U.K
7	CLARK, DAVID EDWARD	C/O ARGENTA DISCOVERY LIMITED, 8/9 SPIRE GREEN CENTRE, FLEX MEADOW, HARLOW, ESSEX CM19 5TR U.K
8	HYND, GEORGE	C/O ARGENTA DISCOVERY LIMITED, 8/9 SPIRE GREEN CENTRE, FLEX MEADOW, HARLOW ESSEX CM19 5TR U.K
9	NEWTON, CHRISTOPER GREGORY	C/O ARGENTA DISCOVERY LIMITED 8/9 SPIRE GREEN CENTRE, FLEX MEADOW, HARLOW, ESSEX CM19 5TR U.K
10	OXFORD, ALEXANDER WILLIAM	60 GREEN DRIFT, ROYSTON, HERTFORDSHIRE SG8 5BX, U.K
11	SUTTON, JONATHAN MARK	C/O ARGENTA DISCOVERY LIMITED 8/9 SPIRE GREEN CENTRE, FLEX MEADOW, HARLOW, ESSEX CM19 5TR U.K

PCT International Classification Number

C07D 307/52

PCT International Application Number

PCT/GB2004/000347

PCT International Filing date

2004-01-29

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	0302094.8	2003-01-29	U.S.A.
2	60/443,872	2003-01-31	U.S.A.
3	60/509,521	2003-10-09	U.S.A.