WO2004067524A1 - Ep4 receptor antagonists - Google Patents

Ep4 receptor antagonists Download PDF

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Publication number
WO2004067524A1
WO2004067524A1 PCT/GB2004/000347 GB2004000347W WO2004067524A1 WO 2004067524 A1 WO2004067524 A1 WO 2004067524A1 GB 2004000347 W GB2004000347 W GB 2004000347W WO 2004067524 A1 WO2004067524 A1 WO 2004067524A1
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Prior art keywords
methyl
furan
biphenyl
compound
group
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PCT/GB2004/000347
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French (fr)
Inventor
David Edward Clark
Kenneth Lyle Clark
Robert Alexander Coleman
Richard Jon Davis
Garry Fenton
Neil Victor Harris
George Hynd
Christoper Gregory Newton
Alexander William Oxford
Keith Alfred James Stuttle
Jonathan Mark Sutton
Original Assignee
Pharmagene Laboratories Limited
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Priority claimed from GBGB0302094.8A external-priority patent/GB0302094D0/en
Application filed by Pharmagene Laboratories Limited filed Critical Pharmagene Laboratories Limited
Priority to JP2006502209A priority Critical patent/JP5015586B2/en
Priority to CA2514220A priority patent/CA2514220C/en
Priority to AU2004207675A priority patent/AU2004207675B2/en
Priority to CNB200480007457XA priority patent/CN100408570C/en
Priority to DK04706221T priority patent/DK1603893T3/en
Priority to KR1020057014131A priority patent/KR101094003B1/en
Priority to EP04706221A priority patent/EP1603893B1/en
Priority to DE602004013938T priority patent/DE602004013938D1/en
Publication of WO2004067524A1 publication Critical patent/WO2004067524A1/en
Priority to NO20053971A priority patent/NO332420B1/en

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    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
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    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • This invention relates to EP 4 receptor antagonists, pharmaceutical compositions comprising such compounds, and the use of such compounds and compositions to treat various diseases .
  • Prostanoids 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, PGD 2 , PGE 2 , PGF 2 ⁇ , PGI 2 and TxA 2 , respectively (Coleman, R.A., Prostanoid Receptors. IUPHAR compendium of receptor characterisa tion and classifica tion, 2 nd edition, 338-353, ISBN 0-9533510-3-3, 2000) .
  • EP receptors for which the endogenous ligand is PGE 2 have been subdivided into four types termed EPi, EP 2 , EP 3 and EP 4 . These four types of EP receptors have been cloned and are distinct at both a molecular and pharmacological level (Coleman, R.A. , 2000)
  • EP 4 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 (WO 00/18405 and WO 01/72302) .
  • Dilation of the cerebral vasculature and the subsequent stimulation of pain stimulating, perivascular trigeminal sensory afferent nerves is recognised to play an important role in the pathophysiology of migraine.
  • a sterile inflammatory response associated with activation of cycloxygenase and the generation of PGE 2 , is also implicated in the pathophysiology of migraine.
  • PGE 2 levels have been shown to be raised during migraine attacks and PGE 2 contributes to the pain of migraine by directly dilating cerebral arteries and by stimulating the release of vasoactive/pro- inflammatory peptides from the trigeminal nerves. These effects of PGE 2 are mediated in whole or in part by EP receptors. Thus, by binding to and preventing the stimulation of EP 4 receptors, EP 4 antagonists may be used to treat the pain of migraine.
  • EP 4 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 fibro yalgia, 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 dysmenorrhea.
  • Neuropathic pain syndromes include diabetic neuropathy, sciatica, non- specific 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
  • occlusive vascular diseases e.g. occlusive vascular diseases
  • the treatment of impotence or erectile dysfunction, and female sexual dysfunction the treatment of hair growth disorders
  • sleep disorders such as narcolepsy and insomnia
  • cardiovascular diseases and shock states associated with hypotension e.g. septic shock
  • the treatment of tinnitus the treatment of dependence
  • complications of diabetes e.g. occlusive vascular diseases
  • EP 4 antagonists are known, it is desired to find novel EP 4 antagonists, and in particular, EP 4 antagonists which are selective against other EP receptors, i.e. EPi, EP 2 and EP 3 .
  • a first aspect of the present invention provides a compound of formula (I) :
  • R 2 is H or an optionally substituted C ⁇ - 4 alkyl group
  • Y is either -(CH 2 ) n -X-, where n is 1 or 2 and X is 0, S,
  • R 3 is an optionally substituted Cg aryl group linked to a further optionally substituted C 6 aryl group, wherein if both Cg 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 C ⁇ _ 3 alkyiene group
  • R 5 is either:
  • R is optionally substituted C ⁇ - alkyl, C 5 _ 20 aryl or where R N3 and R N4 are independently selected from optionally substituted C ⁇ - 4 alkyl; (iv) tetrazol-5-yl .
  • a second aspect of the present invention provides a compound of formula (I) :
  • R 2 is H or an optionally substituted C 1 - alkyl group
  • R N2 is selected from H, and optionally substituted C ⁇ - alkyl or C 5 - 20 aryl;
  • R 3 is an optionally substituted C$ aryl group linked to a further optionally substituted C 6 aryl group, wherein if both C 6 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 C ⁇ _ 3 alkyiene group; and R 5 is either: (i) carboxy; (ii) a group of formula (II) :
  • R is optionally substituted C ⁇ _ alkyl, C 5 _ 20 aryl or NR N3 R N4 , where R N3 and R N4 are independently selected from optionally substituted C ⁇ _ alkyl; (iv) tetrazol-5-yl, except that when R 2 is methyl, Y is -CH 2 -0- and R 5 is carboxy or C ⁇ - ⁇ alkyl ester thereof, then R 3 is not:
  • a third aspect of the present invention provides a pharmaceutical composition
  • 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 of an EP 4 receptor.
  • Another aspect of the present invention provides a method of treating a condition which can be alleviated by antagonism of an EP 4 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 EP 4 receptor are discussed above, and particularly include primary headache disorders, most particularly migraines.
  • the present invention also provides methods of antagonizing EP 4 receptors, in vi tro or in vivo, comprising contacting a cell with an effective amount of a compound of formula (I) .
  • the compounds described above may be selective as against antagonism of the other three EP receptors, i.e. EP ⁇ , EP 2 and EP 3 . This selectivity allows for targeting of the effect of the compounds of the invention, with possible benefits in the treatment of certain conditions.
  • Alkyl refers 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.
  • alkyl includes the sub-classes alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cylcoalkynyl, etc., discussed below.
  • the prefixes denote the number of carbon atoms, or range of number of carbon atoms.
  • C1- 4 alkyl as used herein, pertains to an alkyl group having from 1 to 4 carbon atoms.
  • groups of alkyl groups include C ⁇ _ 4 alkyl ("lower alkyl") and Cj--? alkyl.
  • 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.
  • saturated alkyl groups include, but are not limited to, methyl (Ci) , ethyl (C 2 ) , propyl (C 3 ) , butyl (C 4 ) , pentyl (C 5 ) , hexyl (C ⁇ ) and heptyl (C 7 ) .
  • saturated linear alkyl groups include, but are not limited to, methyl (Ci) , ethyl (C 2 ) , n-propyl (C 3 ) , n-butyl (C 4 ) , n-pentyl (amyl) (C 5 ) , n-hexyl (C 6 ) , and n- heptyl (C 7 ) -
  • saturated branched alkyl groups include iso-propyl (C 3 ) , iso-butyl (C ) , sec-butyl (C 4 ) , tert-butyl (C 4 ) , iso-pentyl (C 5 ) , and neo-pentyl (C 5 ) .
  • Alkenyl refers to an alkyl group having one or more carbon-carbon double bonds. Examples of groups of alkenyl groups include C 2 - 4 alkenyl and C2- 7 alkenyl.
  • Alkynyl refers to an alkyl group having one or more carbon-carbon triple bonds.
  • groups of alkynyl groups include C 2 _ alkynyl and C 2 -7 alkynyl.
  • alkynyl groups include, but are not limited to, ethynyl (ethinyl, -C ⁇ CH) and 2-propynyl (propargyl, -CH 2 -C ⁇ CH) .
  • Cycloalkyl refers 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.
  • the term “cycloalkyl” includes the sub-classes cycloalkyenyl and cycloalkynyl .
  • each ring has from 3 to 7 ring atoms.
  • groups of cycloalkyl groups include C 3 _ 7 cycloalkyl .
  • cycloalkyl groups include, but are not limited to, those derived from: saturated monocyclic hydrocarbon compounds: cyclopropane (C 3 ) , cyclobutane (C 4 ) , cyclopentane (C 5 ) , cyclohexane (C 6 ) , cycloheptane (C 7 ) , methylcyclopropane (C 4 ), dimethylcyclopropane (C 5 ) , methylcyclobutane (C 5 ) , dimethylcyclobutane (Ce) , methylcyclopentane (C 6 ) , dimethylcyclopentane (C ) , methylcyclohexane (C 7 ) ; unsaturated monocyclic hydrocarbon compounds: cyclopropene (C 3 ) , cyclobutene (C 4 ) , cyclopentene (C 5 ) , cyclohexene (C 6 ) , cycl
  • Heterocyclyl refers 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.
  • each ring has from 3 to 7 ring atoms, of which from 1 to 4 are ring heteroatoms.
  • the prefixes e.g. C 3 _ 2 o > C 3 - 7 , C5-6, etc.
  • the prefixes denote the number of ring atoms, or range of number of ring atoms, whether carbon atoms or heteroatoms.
  • C5-6 heterocyclyl as used herein, pertains to a heterocyclyl group having 5 or ⁇ ring atoms.
  • groups of heterocyclyl groups include C 3 _ 20 heterocyclyl, Cs- 2 o heterocyclyl, C 3 _ 15 heterocyclyl, C 5 _ ⁇ 5 heterocyclyl, C 3 _ ⁇ 2 heterocyclyl, C 5 - 12 heterocyclyl, C3-10 heterocyclyl, C 5 _ ⁇ 0 heterocyclyl, C3- 7 heterocyclyl, C 5 _ heterocyclyl, and C 5 _ 6 heterocyclyl.
  • monocyclic heterocyclyl groups include, but are not limited to, those derived from:
  • N 2 imidazolidine (C 5 ) , pyrazolidine (diazolidine) (C 5 ) , i idazoline (C5) , pyrazoline (dihydropyrazole) (C 5 ) , piperazine (C 6 ) ;
  • N1O 1 tetrahydrooxazole (C 5 ) , dihydrooxazole (C 5 ) , tetrahydroisoxazole (C 5 ) , dihydroisoxazole (C 5 ) , morpholine (C 6 ) , tetrahydrooxazine (C ⁇ ) , dihydrooxazine (C 6 ) , oxazine (C e ); 1 S 1 : thiazoline (C 5 ) , thiazolidine (C 5 ) , thiomorpholine (C ⁇ ) ; N 2 O ⁇ : oxadiazine (C 6 ) ;
  • O 1 S 1 oxathiole (C5) and oxathiane (thioxane) (C ⁇ ) ; and, N1O1S 1 : oxathiazine (C ⁇ ) •
  • Aryl refers 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) .
  • each ring has from 5 to 7 ring atoms.
  • the prefixes denote the number of ring atoms, or range of number of ring atoms, whether carbon atoms or heteroatoms.
  • C 5 _ 6 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, C5-20 aryl, C 5 _ ⁇ 5 aryl, C5- 1 2 aryl, C 5 _ ⁇ 0 aryl, C 5 -7 aryl, Cs_ 6 aryl, C 5 aryl, and C 6 aryl.
  • the ring atoms may be all carbon atoms, as in "carboaryl groups".
  • carboaryl groups include C 3 _ 2 o carboaryl, C5-20 carboaryl, C 5 _ ⁇ 5 carboaryl, C 5 - 12 carboaryl, C5-.10 carboaryl, C5-7 carboaryl, C5- 6 carboaryl, C s carboaryl, and C ⁇ carboaryl.
  • Examples of carboaryl groups include, but are not limited to, those derived from benzene (i.e.
  • aryl groups which comprise fused rings include, but are not limited to, groups derived from indane (e.g., 2,3-dihydro- IH-indene) (Cg) , indene (C 9 ) , isoindene (C 9 ) , tetraline (1, 2, 3, 4-tetrahydronaphthalene (Cio) , acenaphthene (C i2 ) , fluorene (C 13 ) , phenalene (C ⁇ 3 ) , acephenanthrene (C 15 ) , and aceanthrene •
  • indane e.g., 2,3-dihydro- IH-indene
  • indene C 9
  • isoindene C 9
  • tetraline 1, 2, 3, 4-tetrahydronaphthalene
  • acenaphthene C i2
  • fluorene C 13
  • phenalene C ⁇ 3
  • the ring atoms may include one or more heteroatoms, as in "heteroaryl groups".
  • heteroaryl groups include C 3 - 20 heteroaryl, C 5 _ 2 o heteroaryl, C5-15 heteroaryl, C5-12 heteroaryl, C5-10 heteroaryl, C5-7 heteroaryl, C 5 - 6 heteroaryl, C 5 heteroaryl, and C 6 heteroaryl .
  • monocyclic heteroaryl groups include, but are not limited to, those derived from:
  • N ⁇ S ⁇ thiazole (C 5 ) , isothiazole (C 5 ) ; N 2 : imidazole (1, 3-diazole) (C 5 ) , pyrazole
  • C 9 (with 2 fused rings) derived from benzofuran (Oi) , isobenzofuran (Oi) , indole (Ni) , isoindole (Ni) , indolizine (Ni) , indoline (Ni) , isoindoline (Ni) , purine (N 4 ) (e.g., adenine, guanine) , benzimidazole (N 2 ) , indazole (N 2 ) , benzoxazole ( ⁇ O ⁇ ) , benzisoxazole (NiOi) , benzodioxole (0 2 ) , benzofurazan (N 2 O ⁇ ) , benzotriazole (N 3 ) , benzothiofuran (Si), benzothiazole (NiSi) , benzothiadiazole (N 2 S) ;
  • Cio (with 2 fused rings) derived from chromene (Oi) , isochromene (Oi) , chroman (Oi) , isochroman (Oi) , benzodioxan (0 2 ) , quinoline (Ni) , isoquinoline (Ni) , quinolizine (Ni) , benzoxazine (NiOi) , benzodiazine (N 2 ) , pyridopyridine (N 2 ) , quinoxaline (N 2 ) , quinazoline (N 2 ) , cinnoline (N 2 ) , phthalazine (N 2 ) , naphthyridine (N 2 ) , pteridine (N 4 ) ;
  • C ⁇ 4 (with 3 fused rings) derived from acridine (Ni) , xanthene (Oi) , thioxanthene (Si) , oxanthrene (0 2 ) , phenoxathiin (OiSi) , phenazine (N 2 ) , phenoxazine (NiOi) , phenothiazine (NiSi) , thianthrene (S 2 ) , phenanthridine (Ni) , phenanthroline (N 2 ) , phenazine (N 2 ) .
  • 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.
  • R 3 is defined above as an optionally substituted C ⁇ aryl group linked to a further optionally substituted C ⁇ aryl group, wherein if both C 6 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 C 6 aryl groups are benzene rings, then R 3 can be optionally subtitued biphenyl:
  • examples of R 3 include, but are not limited to (not showing optional substitution) :
  • Ether -OR, wherein R is an ether substituent, for example, a Ci- 7 alkyl group (also referred to as a C ⁇ -7 alkoxy group, discussed below) , a C 3 _ 2 o heterocyclyl group (also referred to as a C 3 -20 heterocyclyloxy group) , or a C 5 -20 aryl group (also referred to as a C 5 - 2 0 aryloxy group) , preferably a C ⁇ _ alkyl group.
  • R is an ether substituent, for example, a Ci- 7 alkyl group (also referred to as a C ⁇ -7 alkoxy group, discussed below) , a C 3 _ 2 o heterocyclyl group (also referred to as a C 3 -20 heterocyclyloxy group) , or a C 5 -20 aryl group (also referred to as a C 5 - 2 0 aryloxy group) , preferably a C ⁇ _ alkyl group.
  • C ⁇ - alkoxy -OR, wherein R is a C ⁇ _ alkyl group.
  • Examples of C ⁇ _ 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) .
  • Imino (i ine) : NR, wherein R is an i ino substituent, for example, hydrogen, C ⁇ _ 7 alkyl group, a C 3 _ 20 heterocyclyl group, or a C 5 - 2 o aryl group, preferably hydrogen or a C ⁇ - 7 alkyl group.
  • R is an acyl substituent, for example, a C 1 - 7 alkyl group (also referred to as C ⁇ _ alkylacyl or C ⁇ _ 7 alkanoyl) , a C 3 _ 2 o heterocyclyl group (also referred to as C3-20 heterocyclylacyl) , or a C5-20 aryl group (also referred to as C 5 _ 2 o arylacyl) , preferably a C ⁇ _ 7 alkyl group.
  • acyl substituent for example, a C 1 - 7 alkyl group (also referred to as C ⁇ _ alkylacyl or C ⁇ _ 7 alkanoyl) , a C 3 _ 2 o heterocyclyl group (also referred to as C3-20 heterocyclylacyl) , or a C5-20 aryl group (also referred to as C 5 _ 2 o arylacyl) , preferably a C ⁇ _ 7 alkyl group.
  • Carboxy (carboxylic acid): -C( 0)OH.
  • R is an acyloxy substituent, for example, a C 1 -7 alkyl group, a C 3 _ 2 o heterocyclyl group, or a C5- 20 aryl group, preferably a C ⁇ _ 7 alkyl group.
  • Amido (carbamoyl, carbamyl, aminocarbonyl, carboxamide) : -C ( 0)NR 1 R 2 , wherein R 1 and R 2 are independently amino substituents, as defined for amino groups.
  • R 1 is an amide substituent, for example, hydrogen, a C ⁇ _ 7 alkyl group, a C3- 2 0 heterocyclyl group, or a C5-20 aryl group, preferably hydrogen or a C 1 -7 alkyl group
  • R 2 is an acyl substituent, for example, a C 1 -7 alkyl group, a C 3 _ 2 o heterocyclyl group, or a C5- 20 aryl group, preferably hydrogen or a C1-7 alkyl group.
  • R 1 and R 2 may together form a cyclic structure, as in, for example, succinimidyl, maleimidyl, and phthalimidyl :
  • R 1 and R 2 are independently amino substituents, as defined for amino groups.
  • R 1 is a ureido substituent, for example, hydrogen, a C ⁇ _ 7 alkyl group, a C3-20 heterocyclyl group, or a C 5 - 2 o aryl group, preferably hydrogen or a C 1 - 7 alkyl group.
  • ureido groups include, but are not limited to, -NHCONH 2 , NHCONHMe, -NHCONHEt, -NHC0N e 2 , -NHC0NEt 2 , -NMeCONH 2 , - NMeCONHMe, -NMeCONHEt, -N eC0NMe 2 , and -NMeCONEt 2 .
  • Tetrazolyl a five membered aromatic ring having four nitrogen atoms and one carbon atom
  • R 1 and R 2 are independently amino substituents, for example, hydrogen, a C ⁇ _ 7 alkyl group (also referred to as C1-7 alkyla ino or di-C ⁇ _ 7 alkylamino) , a C3- 2 0 heterocyclyl group, or a Cs- 2 oaryl group, preferably H or a C 1 -.7 alkyl group, or, in the case of a "cyclic" amino group, R 1 and R 2 , taken together with the nitrogen atom to which they are attached, form a heterocyclic ring having from 4 to 8 ring atoms.
  • R 1 and R 2 are independently amino substituents, for example, hydrogen, a C ⁇ _ 7 alkyl group (also referred to as C1-7 alkyla ino or di-C ⁇ _ 7 alkylamino) , a C3- 2 0 heterocyclyl group, or a Cs- 2 oaryl group, preferably H or a C 1 -.7 alkyl
  • Amino groups may be primary (-NH 2 ) , secondary (-NHR 1 ) , or tertiary (-NHR-'-R 2 ) , and in cationic form, may be quaternary (- + NR 1 R 2 R 3 ) .
  • amino groups include, but are not limited to, -NH 2 , -NHCH3, -NHC(CH 3 ) 2 , -N(CH 3 ) 2 , -N(CH 2 CH 3 ) 2 / and -NHPh.
  • Examples of cyclic amino groups include, but are not limited to, aziridino, azetidino, pyrrolidino, piperidino, piperazino, morpholino, and thiomorpholino .
  • Thioether (sulfide) -SR, wherein R is a thioether substituent, for example, a - ⁇ alkyl group (also referred to as a C ⁇ _7 alkylthio group) , a C 3 - 2 o heterocyclyl group, or a C 5 - 20 aryl group, preferably a C 1 - 7 alkyl group.
  • R is a thioether substituent, for example, a - ⁇ alkyl group (also referred to as a C ⁇ _7 alkylthio group) , a C 3 - 2 o heterocyclyl group, or a C 5 - 20 aryl group, preferably a C 1 - 7 alkyl group.
  • Examples of C 1 - 7 alkylthio groups include, but are not limited to, -SCH 3 and -SCH 2 CH 3 .
  • Disulfide -SS-R, wherein R is a disulfide substituent, for example, a C ⁇ _ 7 alkyl group, a C3- 20 heterocyclyl group, or a C 5 - 20 aryl group, preferably a C 1 - 7 alkyl group (also referred to herein as C 1 - 7 alkyl disulfide) .
  • R is a disulfide substituent, for example, a C ⁇ _ 7 alkyl group, a C3- 20 heterocyclyl group, or a C 5 - 20 aryl group, preferably a C 1 - 7 alkyl group (also referred to herein as C 1 - 7 alkyl disulfide) .
  • C 1 - alkyl disulfide groups include, but are not limited to, -SSCH 3 and -SSCH 2 CH 3 .
  • Sulfine (sulfinyl, sulfoxide): -S( 0)R, wherein R is a sulfine substituent, for example, a C ⁇ _ 7 alkyl group, a C 3 _ 2 o heterocyclyl group, or a C5- 2 o aryl group, preferably a C ⁇ _ 7 alkyl group.
  • R is a sulfine substituent, for example, a C ⁇ _ 7 alkyl group, a C 3 _ 2 o heterocyclyl group, or a C5- 2 o aryl group, preferably a C ⁇ _ 7 alkyl group.
  • Sulfone (sulfonyl): ⁇ S ( 0) 2 R r
  • R is a sulfone substituent, for example, a C ⁇ alkyl group, a C 3 - 20 heterocyclyl group, or a C 5 - 20 aryl group, preferably a C 1 - 7 alkyl group, including, for example, a fluorinated or perfluorinated C ⁇ _ 7 alkyl group.
  • R is a sulfinyloxy substituent, for example, a C 1 -7 alkyl group, a C 3 _ 20 heterocyclyl group, or a Cs_ 20 aryl group, preferably a C_ 7 alkyl group.
  • R 1 and R 2 are independently amino substituents, as defined for amino groups.
  • R 1 is an amino substituent, as defined for amino groups
  • R is a sulfonamino substituent, for example, a C ⁇ - 7 alkyl group, a C 3 _ 2 o heterocyclyl group, or a Cs_ 20 aryl group, preferably a C ⁇ _ 7 alkyl group.
  • R 1 is an amino substituent, as defined for amino groups
  • R is a sulfinamino substituent, for example, a C ⁇ _ 7 alkyl group, a C 3 _ 20 heterocyclyl group, or a C 5 _ 2 o aryl group, preferably a C ⁇ _ 7 alkyl group.
  • Alkyiene The term "C ⁇ _ 3 alkyiene”, 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.
  • alkyiene includes the sub-classes alkenylene and alkynylene.
  • the prefix C ⁇ _ 3 denotes the number of carbon atoms, or range of number of carbon atoms.
  • saturated C ⁇ _ 3 alkyiene groups include -CH 2 - (methylene) , -CH 2 CH 2 - (ethylene) and -CH 2 CH 2 CH 2 - (propylene) .
  • the Ci-3 alkyiene group may be substituted by any monodentate substituent described above.
  • Alkoxylene refers to a bidentate group of formula -0(CH 2 ) n O-, where n is 1 or 2. .
  • a reference to carboxylic acid (-COOH) also includes the anionic (carboxylate) form (-COO-) , a salt or solvate thereof, as well as conventional protected forms.
  • a reference to an amino group includes the protonated form (-N + HR 1 R 2 ) , a salt or solvate of the amino group, for example, a hydrochloride salt, as well as conventional protected forms of an amino group.
  • 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.
  • 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 enolate-for s; syn- and anti-forms; synclinal- and anticlinal-forms; ⁇ - and ⁇ -forms; axial and equatorial forms; boat-, chair-, twist-, envelope-, and halfchair-forms; and combinations thereof, hereinafter collectively referred to as "isomers" (or "isomeric forms")
  • a reference to a methoxy group, -0CH 3 is not to be construed as a reference to its structural isomer, a hydroxymethyl group, -CH 2 0H.
  • a reference to ortho-chlorophenyl is not to be construed as a reference to its structural isomer, meta-chlorophenyl .
  • a reference to a class of structures may well include structurally isomeric forms falling within that class (e.g.
  • C ⁇ _ 7 alkyl includes n-propyl and iso-propyl; butyl includes n-, iso-, sec-, and tert-butyl; methoxyphenyl includes ortho-, meta-, and para-methoxyphenyl) .
  • keto/enol (illustrated below) , imine/enamine, amide/i ino alcohol, amidine/amidine, nitroso/oxime, thioketone/enethiol, N-nitroso/hyroxyazo, and nitro/aci-nitro.
  • H may be in any isotopic form, including 1 H, 2 H (D) , and 3 H (T) ; C may be in any isotopic form, including 12 C, 13 C, and ⁇ C; 0 may be in any isotopic form, including 16 0 and 18 0; and the like.
  • a reference to a particular compound includes all such isomeric forms, including (wholly or partially) racemic 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.
  • 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).
  • a salt may be formed with a suitable cation.
  • suitable inorganic cations include, but are not limited to, alkali metal ions such as Na + and K + , alkaline earth cations such as Ca 2+ and Mg 2+ , and other cations such as Al +3 .
  • suitable organic cations include, but are not limited to, ammonium ion (i.e. NH 4 + ) and substituted ammonium ions (e.g. NH 3 R + , NH 2 R 2 + , NHR 3 + , NR + ) .
  • 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(CH 3 ) 4 + .
  • a salt may be formed with a suitable anion.
  • suitable inorganic anions include, but are not limited to, those derived from the following inorganic acids: hydrochloric, hydrobro ic, hydroiodic, sulfuric, sulfurous, nitric, nitrous, phosphoric, and phosphorous.
  • Suitable organic anions include, but are not limited to, those derived from the following organic acids: 2-acetyoxybenzoic, acetic, ascorbic, aspartic, benzoic, camphorsulfonic, cinna ic, citric, edetic, ethanedisulfonic, ethanesulfonic, fumaric, glucoheptonic, gluconic, glutamic, glycolic, hydroxymaleic, hydroxynaphthalene carboxylic, isethionic, lactic, lactobionic, lauric, maleic, malic, ethanesulfonic, mucic, oleic, oxalic, palmitic, pamoic, pantothenic, phenylacetic, phenylsulfonic, propionic, pyruvic, salicylic, stearic, succinic, sulfanilic, tartaric, toluenesulfonic, and valeric.
  • 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.
  • 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) .
  • specified conditions e.g. pH, temperature, radiation, solvent, and the like.
  • well known chemical methods are employed to reversibly render unreactive a functional group, which otherwise would be reactive, under specified conditions.
  • 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) .
  • the aldehyde or ketone group is readily regenerated by hydrolysis using a large excess of water in the presence of acid.
  • an amine group may be protected, for example, as an amide (-NRC0-R) or a urethane (-NRCO-OR) , for example, as: an acetamide (-NHCO-CH 3 ) ; a benzyloxy amide (-NHC0- OCH 2 C 6 H 5 , -NH-Cbz); as a t-butoxy amide (-NHC0-0C (CH 3 ) 3 , -NH-Boc) ; a 2-biphenyl-2-propoxy amide (-NHC0- OC (CH 3 ) 2 C 6 H 4 C 6 H 5 , -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- trichlor
  • a carboxylic acid group may be protected as an ester for example, as: an C ⁇ _ alkyl ester (e.g., a methyl ester; a t-butyl ester); a C ⁇ _ 7 haloalkyl ester (e.g., a C 1 - 7 trihaloalkyl ester) ; a triC ⁇ -7 alkylsilyl-C ⁇ - alkyl ester; or a C 5 _ 20 aryl-C ⁇ _ 7 alkyl ester (e.g. a benzyl ester; a nitrobenzyl ester) ; or as an amide, for example, as a methyl amide .
  • an C ⁇ _ alkyl ester e.g., a methyl ester; a t-butyl ester
  • a C ⁇ _ 7 haloalkyl ester e.g., a C 1 - 7 trihaloalkyl ester
  • treatment 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.
  • terapéuticaally-effective amount 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 are provided.
  • 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.
  • 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.
  • a carrier such as, for example, water, saline aqueous dextrose, glycerol, ethanol, and the like
  • 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.
  • wetting or emulsifying agents such as wetting or emulsifying agents, pH buffering agents and the like, for example, sodium acetate, sorbit
  • 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.
  • 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.
  • 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 1% ⁇ 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.
  • 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.
  • the composition will comprise 0.2-2% of the active agent in solution.
  • R X wherein X is either OH or halo, where if X is OH, the use of basic conditions and a coupling agent is preferred.
  • R 6 is -A-R 5 or its precursor or protected form.
  • the protecting groups used may be conventional, or the group may be resin-bound. If Y is -(CH 2 ) n -0- or -(CH 2 ) n ⁇ S-, then these compounds can be synthesised from compounds of formula 5: Formula 5 by one of two possible routes.
  • the second route is a two stage route, the first stage being the Mitsunobu coupling of a compound of formula 7a:
  • 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) : Formula 7c HX'—Ar 1 -B(OH) 2 Formula 7b wherein Ar 1 is the first C aryl component of R 3 , followed by a Suzuki coupling of a compound of formula 8b:
  • Ar—-Hal Formula 8b wherein Ar 2 is the second C 6 aryl component of R 3 and Hal is I or Br .
  • HX'—Ar 1 -Br Formula 7d may be coupled, followed by conversion of the bromo group to the required boronic acid or ester.
  • the reductive coupling can be carried out using sodium cyanoborohydride.
  • 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.
  • OH Formula 9 may be derived from compounds of formula 11
  • R is -Y-R or its precursor or protected form. These compounds may be synthesised from compounds of formula 13:
  • compounds of formula 2 where A is a single bond, and R 5 is carboxy, and compounds where the group -Y-R 3 is present as a precursor or protected form may be represented as compounds of formula 14:
  • R 7 is -Y-R 3 or its precursor or protected form. These compounds may be synthesised from compounds of formula 13:
  • R 7 is -Y-R 3 or its precursor or protected form. These compounds may be synthesised from compounds of formula 16: Formula 16
  • R 2 and R 7 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.
  • example 22A describes a method of synthesizing 2-substitued furans .
  • reaction steps described above may be carried out using resins, as is shown in the examples.
  • the following preferences may be combined with one another, and may be different for each aspect of the present invention .
  • R 2 is preferably selected from H or an optionally substituted C ⁇ _ 3 alkyl group, more preferably H, methyl, CF 3 or iso-propyl, and most preferably R 2 is a- a methyl group.
  • Y is preferably -(CH 2 ) n -X- ⁇ r and n is preferably 1.
  • X is preferably 0, S or NH, with NH being the most preferred.
  • the preferred option for Y is -CH 2 -0-.
  • R N2 is preferably selected from H, and optionally substituted C ⁇ _ 4 alkyl, in particular Me.
  • the C 6 aryl groups of R 3 are preferably independently selected from those derived from benzene and heteroaryl groups, where the heteroatom or heteroatoms are nitrogen. Most preferred are C 6 aryl groups derived from benzene, pyridine and 1, 3-pyrimidine. It is further preferred that either both C 6 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.
  • both C ⁇ 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 R 3 is optionally substituted biphenyl rather than optionally substituted dibenzofuranyl .
  • the nitrogen ring atom is adjacent the link between the two rings that make up the R 3 group.
  • the link between the two rings that make up the R 3 group is between the two nitrogen atoms .
  • the single bond joining the two C aryl groups is in the 4-position of the ring bound to Y.
  • 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 :
  • Both C 6 aryl groups of R 3 are optionally substituted, although it is preferred that only the C 6 aryl group not bound to Y is substituted.
  • Preferred substituents on the C 6 aryls of R 3 include, but are not limited to: optionally substituted C ⁇ _ 7 alkyl groups, more preferably methyl and substituted C ⁇ _ alkyl groups, e.g. -CF 3 , CH 2 0H; C ⁇ _ 7 alkoxy groups, more preferably C ⁇ _ 4 alkoxy groups, e.g. -OMe, -0CF 3 , -OEt, -OCHF 2 ; C ⁇ _ thioether group, more preferably C ⁇ _ 4 thioether group, e.g. -SMe; amino groups, optionally substituted by one or two C ⁇ - 4 alkyl groups, e.g.
  • the preferred location for a substituent on the C 5 aryl group not bound to Y is para to the bond between the two C ⁇ aryl groups, with the eta position being less preferred. Therefore, if R 3 is 4-phenyl-phenyl, the substituent is preferably at the 4' -position.
  • A is preferably a single bond, whereas in other embodiments A is preferably a Ci- 3 alkyiene group.
  • A is more preferably a C ⁇ - 3 alkyiene group, with vinylene being most preferred.
  • R 5 is preferably either: (i) a group of formula (II) :
  • R 5 is particularly applicable when R 2 is methyl and Y is -CH 2 -0-.
  • R 5 is of formula (II) of (III)
  • R is preferably selected from an optionally substituted C 5 - 20 aryl group, and an optionally substituted C5- 2 0 aryl-C ⁇ -7 alkyl group, wherein the C ⁇ _7 alkyl group is more preferably methyl.
  • the C 5 - 20 aryl group is preferably a heteroaryl group, itself preferably having a single aromatic ring.
  • Such groups may preferably be substituted with C ⁇ _ 4 alkyl groups, such as methyl and hydroxy.
  • 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 .
  • R in formula (II) or (III) is a C ⁇ -- alkyl group, it is more preferably a C ⁇ _ 4 alkyl group, for example methyl or propyl .
  • Particularly preferred compounds of the present invention include:
  • the selectivity of the compound for antagonising EP 4 receptors over the other EP receptors can be quantified by dividing the Ki for EP 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.
  • PS-TsCl refers to Polystyrene scavenger resin (loading 1.97 mmol/g) - Argonaut Technologies (P/N 800277)
  • Preparative HPLC was carried out on a C18-reverse-phase column (10 x 2.1 cm i.d Genesis column with 7 ⁇ m 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 Liquid Chromatography Mass Spectroscopy
  • Mass Spectrometer - Platform LC with electrospray source operating in positive and negative Ion mode HP1100 system running at 2.0 mL/min, 200 ⁇ L/min split to the ESI source with inline HP1100 DAD detection .and SEDEX ELS detection.
  • Mass Spectrometer - Platform II with electrospray source operating in negative ion mode HPllOO system running at 2.0 mL/min, 200 ⁇ L/min split to the ESI source with inline HPllOO DAD detection and SEDEX ELS detection.
  • HP1050 system running at 2.0 mL/min, 200 ⁇ L/min split to the ESI source with inline HP1050 Single wavelength UV detector at 254 nm.
  • the 1 H NMR spectra were recorded on a Varian Unity Inova 400, which operates at 400 MHz for 1 H. It is equipped with a 5mm 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. D 6 - 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-f ran-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)
  • 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.
  • the resin was drained, washed sequentially with tetrahydrofuran/water (1:1 by volume), tetrahydrofuran, N,N- dimethylforma ide, dichloromethane, and then dried at 45°C in va cuo.
  • the resin was treated with dichloromethane/trifluoroacetic acid (19:1. by volume) (20 L) 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) .
  • Example 2C N- [4- (4 ' -Methoxy-biphenyl-4-yloxymethyl) -5- methyl-furan-2-carbonyl] -methanesulf onamide (7) —
  • Example 2D Propane- 1- sulfonic acid [4- (4 ' -methoxy-biphenyl - 4 -yloxymethyl) -5-methyl-f uran-2-carbonyl]— amide (8) —
  • Example 2E 3 , 5-Dimethyl-isoxazole-4-sulfonic acid [4- (4'' methoxy-biphenyl-4-yloxymethyl) -5-methyl-furan-2-carbonyl] amide (9)
  • 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) .
  • reaction mixture was concentrated in va cuo, dissolved in ethyl acetate (30 mL) and washed successively with water (30 L) , brine (30 L) , dried and concentrated in vacuo.
  • the residue was dissolved in a mixture of tetrahydrofuran/methanol (2:1 by volume) (30 L) and 1.0 M aqueous lithium hydroxide solution (6.78 L) 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 L) .
  • the extract was dried, concentrated in vacuo and the residue purified by HPLC to give compound 21 as a white solid (50mg) .
  • the reaction mixture was diluted with ethyl acetate (20 L) and washed successively with water (2 x 20 mL) , 0.1 M hydrochloric acid (20 mL) , water (20 L) , saturated sodium hydrogen carbonate (10 mL) and brine (10 mL) . This solution was dried and concentrated in vacuo .
  • the residue (170 mg) was dissolved in dichloromethane (5 L) , 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 in-vacuo .
  • the resin was drained, washed sequentially with dichloromethane/triethylamine/methanol (20:1:3 by volume) (3 x 30 L) , 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 vacuo .
  • 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 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 L) 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 L) , dried, filtered and concentrated in vacuo .
  • the residue was purified by flash chromatography using a gradient elution
  • Example 11 Synthesis of 3- (Biphenyl-4-yloxymethyl) -5- methyl-furan-2-yl] -propionic acid (37) and N- ⁇ 3-[4- (Biphenyl-4-yloxymethyl) -5-methyl-furan-2-yl] -propionyl ⁇ ' benzene sulfonamide (38) - 7!
  • reaction mixture was concentrated in-vacuo then re-dissolved in dichloromethane (15 mL) and treated with triethylamine (1.50 mL) and a scavenger resin PS-TsCl (2.5 g) and the mixture was shaken for 6 hours at room temperature.
  • the reaction mixture was purified by flash chromatography, 11 -
  • 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- -yl] -propionic acid (39)
  • 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) (a) 3- (4-Hydroxymethyl-5-methyl-furan-2-yl) -acrylic acid ethyl ester (41)
  • Example 14A Synthesis of 4- (Bipheny 1-4 -yloxymethyl) -5- methyl-furan-2-sulfonic acid benzoylamide (46)
  • Example 14C 4- (Biphenyl-4-yloxymethyl) -5-methyl-furan-2- sulphoni ⁇ acid phenylacetyl-amide (62)
  • Example 14D 4- (Bxphenyl-4-yloxymethyl) -5-meth ⁇ l-furan-2- sulphonic acid (3 , 5-dimethyl-isoxazole-4-carbonyl) -amide ( 63)
  • Example 14E 4- (Biphenyl- 4-yloxymethyl) -5-methyl-f uran-2 - sulphonic acid (thiophene-2 -carbonyl) -amide (64)
  • Example 14F Synthesis of 4- (Biphenyl- 4 -yloxymethyl) -5- methyl-furan-2-sulphonic acid (3-methoxy-propionyl) -amide (65)
  • Example 14G 4- (Biphenyl-4-yloxymethyl) -5-methyl-furan-2- sulphonic acid (pyridin-3-yl-acetyl) -amide (66)
  • Example 14H 4- (Bxphenyl-4- ⁇ loxymethyl) -5-methyl-f ran-2 - sulphonic acid (pyridine- 4 -carbonyl) -amide ( 67) ) 0 -
  • Example 141 4- (Bi ⁇ henyl-4-yloxymethyl) -5 -me hyl -f uran-2 ⁇ sulphonic acid (pyridine-3-carbonyl) -amide (68)
  • Example 15 Synthesis of 4- (4' - ethoxy-biphenyl-4- yloxymethyl) -5-methyl-furan-2-sulfonic acid benzoylamide (49) and 4- (4 ' - ethoxy-biphen ⁇ l-4-yloxymethy
  • the mixture was stirred at room temperature for 24 hours.
  • Example 20A Synthesis of 4- [2- (Biphenyl-4-yloxy) -ethyl] -5- methyl-furan-2-carboxylic acid (72)
  • Compound (71) was prepared in the form of a pale yellow oil from compound (70) by adapting the procedure of Example Kb) .
  • Example 20B Synthesis of 4- [2- (4 ' -Methoxy-biphenyl-4- yloxy) -ethyl] -5-methyl- uran-2-carboxylic acid (73)
  • Example 22A Synthesis of 4- (Biphenyl-4-yloxymethyl) -5- isopropyl-furan-2-carboxylic acid (85)
  • Compound (84) was prepared in the form of a cream solid from compound (83) by adapting the procedure of Example 1(b).
  • Example 23D 4- (4 ' -Cyano-biphenyl-4-yloxymethyl) -5- tri luoromethyl-f ran-2-carboxylic acid (93)
  • Example 24A Synthesis of 4- (3 1 , 4 ' -Dimethoxy-biphenyl-4- yloxy methyl) -5-methyl-furan-2-carboxylic acid (96)
  • Example 24C 4- (4' -Ethoxy-biphenyl-4-yloxymethyl) -5-methyl- furan-2- ⁇ arb ⁇ xylic acid (98) 20 98
  • Example 25B Synthesis of 4- (2 ' , 6 ' -Difluoro-biphenyl-4- yloxymethyl) -5-methyl-furan-2-carboxylic acid (100)
  • Example 25D Alternate synthesis of 4- (4 ' -Chloro-biphenyl-4- yloxymethyl) -5-methyl-furan-2-carboxylic acid (27)
  • Example 25E Synthesis of 4- (3 ' -Fluoro-biphenyl-4- yloxymethyl) -5-methyl-furan-2-carboxylic acid (104)
  • Example 25F 5-Methyl-4- (2 ' -methylsulphanyl-biphenyl-4- yloxymethyl) -furan-2-carboxylic acid (105)
  • Example 26A Synthesis of 4- (3 ' , 4 ' -Dimethoxy-biphenyl-3- yloxymethyl) -5-methyl-furan-2-carboxylic acid (108)
  • step (b) 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) .
  • 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
  • Example 27A Synthesis of 4- (4 ' -Hydroxymethyl-biphenyl-4- yloxymethyl) -5-methyl-furan-2-carboxylic acid (110)
  • 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 loaded resin (llOmg) (from example 27A, (i) ) was treated with a mixture of (4-methylsulphanyl-phenyl) -boronic acid (109mg, 0.65mmoles), [1, l'-bis (diphenylphosphino) ferrocene] dichloropalladium (II) complex with dichloromethane ( 1:1) (lO. ⁇ mg) and potassium acetate (0.064g, 0.65mmoles) in N, -dimethylformamide (5mL) and the mixture was agitated at 40°C for 60 hours.
  • a mixture of (4-methylsulphanyl-phenyl) -boronic acid 109mg, 0.65mmoles
  • 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 .
  • Example 27D 4- (4 ' -Dxmethylamino-biphenyl-4-yloxymethyl) -5- methyl-furan-2-carboxylic acid (113)
  • Example 29 Alternative synthesis of 4- (4 ' -Fluoro-biphenyl- 4-yloxymethyl) -5-methyl-furan-2 ⁇ carboxyli ⁇ acid (118) (a) 3- (4-Iodo-phenoxymethyl) -2-methyl-furan (123)
  • Example 30 Synthesis of 4- (2 ' -Methoxy-biphenyl-4- yloxymethyl) -5-methyl-furan-2-carboxylic acid (126) and N- [4- (2 ' -Methox ⁇ -biphenyl-4-yloxymethyl) -5-methyl-furan-2- carbonyl] -benzenesulfonamide (127) (a) 4- (2 ' -Methoxy-biphenyl- 4-yloxymethyl) -5-methyl - furan-2- carboxylic acid methyl ester (125)
  • Example 31 Synthesis of 4- (4 ' -Difluoromethoxy-biphenyl-4- yloxymethyl) -5-methyl-furan-2-carboxylic acid (129), N-[4- (4 ' -Difluoromethoxy-biphen ⁇ l-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-furan-2-carbonyl] -amide (131) (a) 4- (4 ' -difluoromethoxy-biphenyl-4-yloxymethyl) -5-methyl- furan-2-carboxylic acid methyl ester (128)
  • Compound (129) was prepared fromcompound (128) by adapting the procedure of Example 30(b) .
  • Example 32 Synthesis of 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) and N- ⁇ 4- [4- (5-Methoxy-1-oxy- pyridin-2-yl) -phenoxymethyl] -5-methyl- uran-2-carbonyl ⁇ - benzenesulfonamide (135)
  • Compound ( 132 ) was prepared from compound ( 53) by adapting the procedure of Example 2A .
  • Example 34 Synthesis of 4- (2 ' , 4 ' -Dimethoxy-biphenyl-4- yloxymethyl) -5-methyl-f ran-2-carboxylic acid (140), N-[4- (2 ' , 4 ' -Dimethoxy-bxphenyl-4-yloxym thyl) -5-methyl-furan-2- carbonyl] -benzenesulfonamide (141) and 3,5-Dimethyl- isoxazole-4-sulfonic acid [4- (2 ' , 4 ' -dimethoxy-biphenyl-4- yloxymethyl) -5-methyl-furan-2-carbonyl] -amide (142) (a) 4- (2 1 , 4 ' -Dimethoxy-biphenyl -4-yloxymethyl) -5-methyl furan -2-carboxylic a cid methyl ester (139)
  • Example 35 Synthesis of 4- (4 ' -Methoxy-2 ' -methyl-bxphenyl-4- yloxymethyl) -5-methyl-furan-2-carboxylic acid (144), N-[4- (4 ' -Methoxy-2 ' -methyl-biphenyl-4-yloxymeth ⁇ l) -5-methyl- furan-2-carbonyl] -benzenesulfonamide (145) and 3 ,5-Dimethyl- isoxazole-4-sulfonic acid [4- (4 ' -methoxy-2 ' -methyl-biphenyl- 4-yloxymethyl) -5-methyl-furan-2-carbonyl] -amide (146) (a) 4- (4 ' ' -Methoxy-2 ' -methyl -biphenyl- 4-yloxymethyl) -5- methyl-furan-2-carboxylic acid methyl ester (143)
  • Compound ( 146 ) was prepared from compound ( 143) and 3 , 5- dimethyl-isoxazole-sulphonic acid amide by adapting the procedure of Example 34 ( c) .
  • Diisopropylazodicarboxylate (1.84g, lO. ⁇ mmoles) 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.
  • Example 37 Synthesis of 4- (4 ' -Difluoromethoxy-biphen ⁇ l-4- ylsulfanylmethyl) -5-methyl-furan-2-carbox ⁇ lic acid (153) , N- [4- (4 ' -Difluoromethoxy-biphenyl-4-ylsulfanylmeth ⁇ l) -5- methyl-furan-2-carbonyl] -2-methyl-benzenesulfonamide (154) , N- [4- (4 ' -Difluoromethoxy-biphenyl-4 -ylsuIf nylmethyl) -5-methyl-furan-2-carbonyl] - benzenesulfonamide (155) and N- [4- (4 ' -Difluoromethoxy- biphenyl-4-sulfinylmethyl) -5-methyl-furan-2-carbon ⁇ l] -2- methyl-benzenesulfonamide (156) (a) 4- ( 4-B
  • Diisopropylazodicarboxylate (1.27g, 6.3mmoles) was added to a solution of triphenylphosphine (1.65g, 6.3mmoles) 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.
  • Compound (154) was prepared from compound (153) and 2- methyl-benzenesulphonamide by adapting the procedure of Example 34 ( c) .
  • Example 38 Synthesis of 4- (Biphen ⁇ l-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-methyl-furan-2- carbonyl] -2-methyl-benzenesulfonamide (162)

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 O, S, S(=O), S(=O)2, or NRN1, where RN1 is selected from H or optionally substituted C1-4 alkyl, or Y is -C(=O)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); or(iii) a group of formula (III):, 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;(iv) tetrazol-5-yl.

Description

EP4 RECEPTOR ANTAGONISTS
This invention relates 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
Prostanoids 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, PGF2α, PGI2 and TxA2, respectively (Coleman, R.A., Prostanoid Receptors. IUPHAR compendium of receptor characterisa tion and classifica tion, 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 EPi, 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 (WO 00/18405 and WO 01/72302) . Dilation of the cerebral vasculature and the subsequent stimulation of pain stimulating, perivascular trigeminal sensory afferent nerves is recognised to play an important role in the pathophysiology of migraine. A sterile inflammatory response, associated with activation of cycloxygenase 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- inflammatory peptides from the trigeminal nerves. These effects of PGE2 are mediated in whole or in part by EP receptors. Thus, by binding to and preventing the stimulation of EP4 receptors, EP4 antagonists may be used to treat the pain of migraine.
EP4 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 fibro yalgia, 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 dysmenorrhea. Neuropathic pain syndromes include diabetic neuropathy, sciatica, non- specific 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, oliguria, 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 imgf000006_0001
or a pharmaceutically acceptable salt thereof for use in a method of therapy, wherein:
R2 is H or an optionally substituted Cχ-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 Cι_4 alkyl, or Y is -C (=0) NRN2-, where RN2 is selected from H, and optionally substituted Cι_7 alkyl or C5_20 aryl;
R3 is an optionally substituted Cg aryl group linked to a further optionally substituted C6 aryl group, wherein if both Cg 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 Cι_3 alkyiene group; and
R5 is either:
(i) carboxy; (ii) a group of formula (II) :
Figure imgf000006_0002
(iii) a group of formula (III)
Figure imgf000007_0001
wherein R is optionally substituted Cι- alkyl, C5_20 aryl or where RN3 and RN4 are independently selected from optionally substituted Cχ-4 alkyl; (iv) tetrazol-5-yl .
A second aspect of the present invention provides a compound of formula (I) :
Figure imgf000007_0002
or a salt, solvate and chemically protected form thereof, wherein:
R2 is H or an optionally substituted C1- 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 Cχ- alkyl or C5-20 aryl;
R3 is an optionally substituted C$ 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 Cχ_3 alkyiene group; and R5 is either: (i) carboxy; (ii) a group of formula (II) :
Figure imgf000008_0001
(iii) a group of formula (III)
Figure imgf000008_0002
wherein R is optionally substituted Cι_ alkyl, C5_20 aryl or NRN3RN4, where RN3 and RN4 are independently selected from optionally substituted Cι_ alkyl; (iv) tetrazol-5-yl, except that when R2 is methyl, Y is -CH2-0- and R5 is carboxy or C\-η alkyl ester thereof, then R3 is not:
Figure imgf000008_0003
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 of an 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 vi tro 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. EPα, EP2 and EP3. This selectivity allows for targeting of the effect of the compounds of the invention, with possible benefits in the treatment of certain conditions.
Definitions onodentate 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 alkyl" includes the sub-classes alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cylcoalkynyl, etc., discussed below.
In the context of alkyl groups, the prefixes (e.g. Cι_4, Cι_ ) denote the number of carbon atoms, or range of number of carbon atoms. For example, the term "C1-4 alkyl" as used herein, pertains to an alkyl group having from 1 to 4 carbon atoms. Examples of groups of alkyl groups include Cι_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 (C2) , propyl (C3) , butyl (C4) , pentyl (C5) , hexyl (Cζ) and heptyl (C7) .
Examples of saturated linear alkyl groups include, but are not limited to, methyl (Ci) , ethyl (C2) , n-propyl (C3) , 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 (C ) , sec-butyl (C4) , tert-butyl (C4) , 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 (Ce) .
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_ alkynyl and C2-7 alkynyl. Examples of alkynyl groups include, but are not limited to, ethynyl (ethinyl, -C≡CH) and 2-propynyl (propargyl, -CH2-C≡CH) .
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 (C4), dimethylcyclopropane (C5) , methylcyclobutane (C5) , dimethylcyclobutane (Ce) , methylcyclopentane (C6) , dimethylcyclopentane (C ) , methylcyclohexane (C7) ; unsaturated monocyclic hydrocarbon compounds: cyclopropene (C3) , cyclobutene (C4) , cyclopentene (C5) , cyclohexene (C6) , methylcyclopropene (C4) , dimethylcyclopropene (C5) , methylcyclobutene (C5) , dimethylcyclobutene (C6) , methylcyclopentene (C6) , 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 "C5-6 heterocyclyl" as used herein, pertains to a heterocyclyl group having 5 or β ring atoms. Examples of groups of heterocyclyl groups include C3_20 heterocyclyl, Cs-2o heterocyclyl, C3_15 heterocyclyl, C5_ι5 heterocyclyl, C3_ι2 heterocyclyl, C5-12 heterocyclyl, C3-10 heterocyclyl, C5_ι0 heterocyclyl, C3-7 heterocyclyl, C5_ heterocyclyl, and C5_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 (Cβ) , dihydropyridine (C6) , tetrahydropyridine (Cβ) , azepine (C7) ; Oi: oxirane (C3) , oxetane (C4) , oxolane (tetrahydrofuran) (C5) , oxole (dihydrofuran) (C5) , oxane (tetrahydropyran) (C6) , dihydropyran (C6) , pyran (C6) , oxepin (C7) ; Si: t iirane (C3) , thietane (C4), thiolane (tetrahydrothiophene) (C5) , thiane (tetrahydrothiopyran) (C6) , thiepane (C7) ; 02: dioxolane (C5) , dioxane (Ce) , and dioxepane (C7) ; 03 : trioxane (C6) ;
N2: imidazolidine (C5) , pyrazolidine (diazolidine) (C5) , i idazoline (C5) , pyrazoline (dihydropyrazole) (C5) , piperazine (C6) ;
N1O1: tetrahydrooxazole (C5) , dihydrooxazole (C5) , tetrahydroisoxazole (C5) , dihydroisoxazole (C5) , morpholine (C6) , tetrahydrooxazine (Cβ) , dihydrooxazine (C6) , oxazine (Ce); 1S1: thiazoline (C5) , thiazolidine (C5) , thiomorpholine (Cς) ; N2Oι: oxadiazine (C6) ;
O1S1: oxathiole (C5) and oxathiane (thioxane) (Cβ) ; and, N1O1S1: oxathiazine (Cβ) •
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. C3-2o, C5--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 "C5_6 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, C5-20 aryl, C5_α5 aryl, C5-12 aryl, C5_ι0 aryl, C5-7 aryl, Cs_6 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, C5-20 carboaryl, C5_ι5 carboaryl, C5-12 carboaryl, C5-.10 carboaryl, C5-7 carboaryl, C5-6 carboaryl, Cs carboaryl, and Cδ carboaryl. Examples of carboaryl groups include, but are not limited to, those derived from benzene (i.e. phenyl) [Cβ) , naphthalene (Cio) , azulene (Cι0) , anthracene (C14) , phenanthrene (Cι ) , naphthacene (Cι8) , and pyrene (Cι6) .
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 (C9) , isoindene (C9) , tetraline (1, 2, 3, 4-tetrahydronaphthalene (Cio) , acenaphthene (Ci2) , fluorene (C13) , phenalene (Cι3) , acephenanthrene (C15) , and aceanthrene
Figure imgf000014_0001
•
Alternatively, the ring atoms may include one or more heteroatoms, as in "heteroaryl groups". Examples of heteroaryl groups include C3-20 heteroaryl, C5_2o heteroaryl, C5-15 heteroaryl, C5-12 heteroaryl, C5-10 heteroaryl, C5-7 heteroaryl, C5-6 heteroaryl, C5 heteroaryl, and C6 heteroaryl .
Examples of monocyclic heteroaryl groups include, but are not limited to, those derived from:
Ni: pyrrole (azole) (C5) , pyridine (azine) (C6) ;
Oi: furan (oxole) (C5) ; Si: thiophene (thiole) (C5) ;
NιOχ: oxazole (C5) , isoxazole (C5) , isoxazine (Ce) ; 2Oι : oxadiazole (furazan) (C5) ;
N3Oχ: oxatriazole (C5) ;
NχSι: thiazole (C5) , isothiazole (C5) ; N2: imidazole (1, 3-diazole) (C5) , pyrazole
(1, 2-diazole) (C5) , pyridazine (1, 2-diazine) (Cβ) , pyrimidine (1, 3-diazine) (Cβ) , pyrazine (1, -diazine) (C6) ; N3: triazole (C5) , triazine (Cβ) ; and, : 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 (Ni) , isoindole (Ni) , indolizine (Ni) , indoline (Ni) , isoindoline (Ni) , purine (N4) (e.g., adenine, guanine) , benzimidazole (N2) , indazole (N2) , benzoxazole ( ιOχ) , benzisoxazole (NiOi) , benzodioxole (02) , benzofurazan (N2Oι) , benzotriazole (N3) , benzothiofuran (Si), benzothiazole (NiSi) , benzothiadiazole (N2S) ;
Cio (with 2 fused rings) derived from chromene (Oi) , isochromene (Oi) , chroman (Oi) , isochroman (Oi) , benzodioxan (02) , quinoline (Ni) , isoquinoline (Ni) , quinolizine (Ni) , benzoxazine (NiOi) , benzodiazine (N2) , pyridopyridine (N2) , quinoxaline (N2) , quinazoline (N2) , cinnoline (N2) , phthalazine (N2) , naphthyridine (N2) , pteridine (N4) ;
Cu (with 2 fused rings) derived from benzodiazepine
(N2) ;
Ci3 (with 3 fused rings) derived from carbazole (Ni) , dibenzofuran (Oi) , dibenzothiophene (Si) , carboline (N2) , perimidine (N2) , pyridoindole (N2) ; and,
Cχ4 (with 3 fused rings) derived from acridine (Ni) , xanthene (Oi) , thioxanthene (Si) , oxanthrene (02) , phenoxathiin (OiSi) , phenazine (N2) , phenoxazine (NiOi) , phenothiazine (NiSi) , thianthrene (S2) , phenanthridine (Ni) , 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 Cβ aryl group linked to a further optionally substituted Cβ 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:
Figure imgf000016_0001
or optionally substituted dibenzofuran:
Figure imgf000016_0002
If one of the C6 aryl groups is a C6 heteroaryl group, then examples of R3 include, but are not limited to (not showing optional substitution) :
Figure imgf000016_0003
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 Cχ-7 alkoxy group, discussed below) , a C3_2o heterocyclyl group (also referred to as a C3-20 heterocyclyloxy group) , or a C5-20 aryl group (also referred to as a C5-20 aryloxy group) , preferably a Cι_ alkyl group.
Cι- alkoxy: -OR, wherein R is a Cι_ alkyl group. Examples of Cι_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) : =0.
Thione (thioketone) : =S .
Imino (i ine) : =NR, wherein R is an i ino substituent, for example, hydrogen, Cι_7 alkyl group, a C3_20 heterocyclyl group, or a C5-2o aryl group, preferably hydrogen or a Cι-7 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 C1-7 alkyl group (also referred to as Cι_ alkylacyl or Cι_7 alkanoyl) , a C3_2o heterocyclyl group (also referred to as C3-20 heterocyclylacyl) , or a C5-20 aryl group (also referred to as C5_2o arylacyl) , preferably a Cι_7 alkyl group. Examples of acyl groups include, but are not limited to, -C(=0)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(=0)OR, wherein R is an ester substituent, for example, a Cι_7 alkyl group, a C3_2o heterocyclyl group, or a C5_2o aryl group, preferably a C1-7 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 C1-7 alkyl group, a C3_2o heterocyclyl group, or a C5-20 aryl group, preferably a Cι_7 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)2, -C (=0) NHCHCH3, and -C (=0)N (CH2CH3) , 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) : -NRXC (=0) R2, wherein R1 is an amide substituent, for example, hydrogen, a Cι_7 alkyl group, a C3-20 heterocyclyl group, or a C5-20 aryl group, preferably hydrogen or a C1-7 alkyl group, and R2 is an acyl substituent, for example, a C1-7 alkyl group, a C3_2o heterocyclyl group, or a C5-20 aryl group, preferably hydrogen or a C1-7 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 imgf000019_0001
succinimidyl maleimidyl phthalimidyl
Thioamido (thiocarbamyl) : -C(=S)NRXR2, 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 Cχ_7 alkyl group, a C3-20 heterocyclyl group, or a C5-2o aryl group, preferably hydrogen or a C1-7 alkyl group. Examples of ureido groups include, but are not limited to, -NHCONH2, NHCONHMe, -NHCONHEt, -NHC0N e2, -NHC0NEt2, -NMeCONH2, - NMeCONHMe, -NMeCONHEt, -N eC0NMe2, and -NMeCONEt2.
Guanidino: -NH-C (=NH) NH2.
Tetrazolyl: a five membered aromatic ring having four nitrogen atoms and one carbon atom,
Amino: -NRαR2, wherein R1 and R2 are independently amino substituents, for example, hydrogen, a Cι_7 alkyl group (also referred to as C1-7 alkyla ino or di-Cι_7 alkylamino) , a C3-20 heterocyclyl group, or a Cs-2oaryl group, preferably H or a C1-.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 (-NHR-'-R2) , and in cationic form, may be quaternary (-+NR1R2R3) . Examples of amino groups include, but are not limited to, -NH2, -NHCH3, -NHC(CH3)2, -N(CH3)2, -N(CH2CH3)2/ 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 Cι_7 alkyl group, a C3_20 heterocyclyl group, or a C5_2o aryl group, preferably H or a C1-7 alkyl group. Examples of amidine groups include, but are not limited to, -C(=NH)NH2, -C(=NH)NMe2, and -C(=NMe)NMe2.
Nitro: -N02.
Nitroso: -NO.
Cyano (nitrile, carbonitrile) : -CN.
Sulfhydryl (thiol, mercapto) : -SH.
Thioether (sulfide) : -SR, wherein R is a thioether substituent, for example, a -η alkyl group (also referred to as a Cι_7 alkylthio group) , a C3-2o heterocyclyl group, or a C5-20 aryl group, preferably a C1-7 alkyl group. Examples of C1-7 alkylthio groups include, but are not limited to, -SCH3 and -SCH2CH3.
Disulfide: -SS-R, wherein R is a disulfide substituent, for example, a Cι_7 alkyl group, a C3-20 heterocyclyl group, or a C5-20 aryl group, preferably a C1-7 alkyl group (also referred to herein as C1-7 alkyl disulfide) . Examples of C1- alkyl disulfide groups include, but are not limited to, -SSCH3 and -SSCH2CH3.
Sulfine (sulfinyl, sulfoxide): -S(=0)R, wherein R is a sulfine substituent, for example, a Cι_7 alkyl group, a C3_2o heterocyclyl group, or a C5-2o aryl group, preferably a Cι_7 alkyl group. Examples of sulfine groups include, but are not limited to, -S(=0)CH3 and -S (=0) CH2CH3.
Sulfone (sulfonyl): ~S (=0) 2Rr wherein R is a sulfone substituent, for example, a C^ alkyl group, a C3-20 heterocyclyl group, or a C5-20 aryl group, preferably a C1-7 alkyl group, including, for example, a fluorinated or perfluorinated Cι_7 alkyl group. Examples of sulfone groups include, but are not limited to, -S(=0)2CH3
( ethanesulfonyl, mesyl) , -S(=0)2CF3 (triflyl) , -S (=0) CH2CH3 (esyl), -S(=0)2C4F9 (nonaflyl) , -S (-0) 2CH2CF3 (tresyl) ,
-S(=0)2CH2CH2NH2 (tauryl), -S(=0)2Ph (phenylsul onyl, 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)0H, -S02H.
Sulfonic acid (sulfo) : -S(=0)20H, -S03H.
Sulfinate (sulfinic acid ester): -S(=0)0R; wherein R is a sulfinate substituent, for example, a Cχ-ι alkyl group, a C3-20 heterocyclyl group, or a C5-.20 aryl group, preferably a C1-7 alkyl group. Examples of sulfinate groups include, but are not limited to, -S(=0)0CH3 (methoxysulfinyl; methyl sulfinate) and -S (=0) OCH2CH3 (ethoxysulfinyl; ethyl sulfinate) .
Sulfinyloxy: -0S(=0)R, wherein R is a sulfinyloxy substituent, for example, a C1-7 alkyl group, a C3_20 heterocyclyl group, or a Cs_20 aryl group, preferably a C_7 alkyl group. Examples of sulfinyloxy groups include, but are not limited to, -0S(=0)CH3 and -OS (=0) CH2CH3.
Sulfamyl (sulfamoyl; sulfinic acid amide; sulfinamide) : -S (=0)NRαR2, 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 (=0) 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 (=0) 2R, wherein R1 is an amino substituent, as defined for amino groups, and R is a sulfonamino substituent, for example, a Cι-7 alkyl group, a C3_2o heterocyclyl group, or a Cs_20 aryl group, preferably a Cι_7 alkyl group. Examples of sulfonamino groups include, but are not limited to, -NHS(=0)2CH3 and -N (CH3) S (=0) 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 Cι_7 alkyl group, a C3_20 heterocyclyl group, or a C5_2o aryl group, preferably a Cι_7 alkyl group. Examples of sulfinamino groups include, but are not limited to, -NHS(=0)CH3 and -N (CH3) S (=0) C6H5.
As already mentioned, the above described groups may be substituted, and particular examples include, but are not limited to, C3_2o aryl-Cι- alkyl groups, which include benzyl (phenylmethyl, PhCH2-) , benzhydryl (Ph2CH-) , trityl (triphenylmethyl, Ph3C-) , phenethyl (phenylethyl, Ph-CH2CH2-), styryl (Ph-CH=CH-) and cinnamyl (Ph-CH=CH-CH2-) . Bidentate groups
(i.e. groups with two points of covalent attachment; linking groups)
Alkyiene: The term "Cι_3 alkyiene", 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 "alkyiene" includes the sub-classes alkenylene and alkynylene.
In this context, the prefix Cι_3 denotes the number of carbon atoms, or range of number of carbon atoms.
Examples of saturated Cι_3 alkyiene groups include -CH2- (methylene) , -CH2CH2- (ethylene) and -CH2CH2CH2- (propylene) .
Examples of unsaturated Cι-3 alkyiene groups (which may be termed "C2-3 alkenylene" or "C2_3 alkynylene", as appropriate) include -CH=CH- (vinylene) , -CH=CH-CH2-, -CH2-CH=CH-, -C≡C-, -C≡C-CH2- and -CH2-C≡C-.
The Ci-3 alkyiene group may be substituted by any monodentate substituent described above.
Alkoxylene: The term "alkoxylene, " as used herein, pertains to a bidentate group of formula -0(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 (carboxylate) form (-COO-) , a salt or solvate thereof, as well as conventional protected forms. Similarly, a reference to an amino group includes the protonated form (-N+HR1R2) , 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 enolate-for s; syn- and anti-forms; synclinal- and anticlinal-forms; α- and β-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, -0CH3, is not to be construed as a reference to its structural isomer, a hydroxymethyl group, -CH20H. 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 isomeric forms falling within that class (e.g. Cι_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/i ino alcohol, amidine/amidine, nitroso/oxime, thioketone/enethiol, N-nitroso/hyroxyazo, and nitro/aci-nitro.
Figure imgf000026_0001
keto enol enolate
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 1H, 2H (D) , and 3H (T) ; C may be in any isotopic form, including 12C, 13C, and αC; 0 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) racemic 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+ and Mg2+, and other cations such as Al+3. Examples of suitable organic cations include, but are not limited to, ammonium ion (i.e. NH4 +) and substituted ammonium ions (e.g. NH3R+, NH2R2 +, NHR3 +, NR+) . 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 following inorganic acids: hydrochloric, hydrobro ic, 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, cinna ic, citric, edetic, ethanedisulfonic, ethanesulfonic, fumaric, glucoheptonic, gluconic, glutamic, glycolic, hydroxymaleic, hydroxynaphthalene carboxylic, isethionic, lactic, lactobionic, lauric, maleic, malic, ethanesulfonic, 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 nonequivalent 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 (-0C(=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(=0)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 (-NRC0-R) or a urethane (-NRCO-OR) , for example, as: an acetamide (-NHCO-CH3) ; a benzyloxy amide (-NHC0- OCH2C6H5, -NH-Cbz); as a t-butoxy amide (-NHC0-0C (CH3) 3, -NH-Boc) ; a 2-biphenyl-2-propoxy amide (-NHC0- OC (CH3) 2C6H4C6H5, -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-0-) .
For example, a carboxylic acid group may be protected as an ester for example, as: an Cι_ alkyl ester (e.g., a methyl ester; a t-butyl ester); a Cι_7 haloalkyl ester (e.g., a C1-7 trihaloalkyl ester) ; a triCι-7 alkylsilyl-Cα- alkyl ester; or a C5_20 aryl-Cι_7 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 1%~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 imgf000034_0001
may be synthesised from the analogous compound of the invention wherein R5 is carboxy, by reaction with a compound of formula 1:
O
H,N-S-R Formula 1
2 II 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!
Figure imgf000035_0001
may be synthesized from a compound of formula 2:
Formula 2
Figure imgf000035_0002
by reaction with a compound of formula 3 :
O
II Formula 3
R X 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 (I) and 2, or where the group -A-R5 is present as a precursor or protected form, may be represented as compounds of formula 4 :
Formula 4
Figure imgf000035_0003
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 -(CH2)n-0- or -(CH2)n~S-, then these compounds can be synthesised from compounds of formula 5: Formula 5
Figure imgf000036_0001
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 (Ph3P) 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—Ar1-X'H Formula 7a wherein Ar1 is the first Cβ 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) :
Formula 8c
Ar2—B(OH) '22 Formula 8a
Figure imgf000036_0002
wherein Ar2 is the second Cβ 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) : Formula 7c HX'—Ar1-B(OH)2 Formula 7b
Figure imgf000037_0001
wherein Ar1 is the first C aryl component of R3, followed by a Suzuki coupling of a compound of formula 8b:
Ar—-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:
HX'—Ar1-Br Formula 7d may be coupled, followed by conversion of the bromo 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' :
R—NH. Formula 6' or of formula 7a' , 7b' or 7c'
Hal—Ar-N Formula 7a'
H2N-ArLB(OH)? Formula 7b"
H^-A -B Formula 7c'
for subsequent Suzuki coupling. The reductive coupling can be carried out using sodium cyanoborohydride. 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
Formula 4
Figure imgf000038_0001
where Y is -C(=0)-NRN1- may be synthesised from a compound of formula 9:
Formula 9
Figure imgf000038_0002
by reaction with a amine of formula 10:
RN1
R— N Formula 10
H in basic conditions, preferably with the aid of a coupling agent. Compounds of formula 9:
OH Formula 9
Figure imgf000039_0001
may be derived from compounds of formula 11
Formula 11
Figure imgf000039_0002
by oxidation, for example, using Jones' reagent.
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:
Formula 12
Figure imgf000039_0003
where R is -Y-R or its precursor or protected form. These compounds may be synthesised from compounds of formula 13:
Formula 13
Figure imgf000039_0004
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 group -Y-R3 is present as a precursor or protected form, may be represented as compounds of formula 14:
Formula 14
Figure imgf000040_0001
where R7 is -Y-R3 or its precursor or protected form. These compounds may be synthesised from compounds of formula 13:
Formula 13
Figure imgf000040_0002
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:
Formula 15
Figure imgf000040_0003
where R7 is -Y-R3 or its precursor or protected form. These compounds may be synthesised from compounds of formula 16: Formula 16
Figure imgf000041_0001
by hydrogenation, using a palladium catalyst
Compounds of formula 16 may be synthesised from compounds of formula 17:
Formula 17
Figure imgf000041_0002
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:
Formula 18
Figure imgf000041_0003
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 RN1I, 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 Cι_3 alkyl group, more preferably H, methyl, CF3 or iso-propyl, and most preferably R2 is a- a methyl group.
Y is preferably -(CH2)n-X-~r 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 Cι_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 C6 aryl groups derived from benzene, pyridine and 1, 3-pyrimidine. It is further preferred that either both C6 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 Cβ 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 R3 is optionally substituted biphenyl rather than optionally substituted dibenzofuranyl .
If one or more of the C aryl groups is derived from 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 C5 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 C 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 imgf000044_0001
4-phenyl-phenyl 3-phenyl-phenyl Dibenzofuran-3-yl Dibenzofuran-2-yl
Figure imgf000044_0002
4-pyridin-2-yl-pheny! 3-pyridin-2-yl-phenyl 6-phenyl-pyridin-3-yl 6-phenyl-pyridin-2-yl
Both C6 aryl groups of R3 are optionally substituted, although it is preferred that only the C6 aryl group not bound to Y is substituted.
Preferred substituents on the C6 aryls of R3 include, but are not limited to: optionally substituted Cι_7 alkyl groups, more preferably methyl and substituted Cι_ alkyl groups, e.g. -CF3, CH20H; Cι_7 alkoxy groups, more preferably Cι_4 alkoxy groups, e.g. -OMe, -0CF3, -OEt, -OCHF2; Cι_ thioether group, more preferably Cι_4 thioether group, e.g. -SMe; amino groups, optionally substituted by one or two Cι-4 alkyl groups, e.g. -NMe2; halo groups, more preferably -F or -Cl; cyano; alkoxylene groups, more preferably -0-CH2-0-; Cι-4 acyl groups, more preferably -C(=0)Me.
The preferred location for a substituent on the C5 aryl group not bound to Y is para to the bond between the two Cβ aryl groups, with the eta 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-3 alkyiene group. In particular, when R5 is carboxy, A is more preferably a Cι-3 alkyiene group, with vinylene being most preferred.
R5 is preferably either: (i) a group of formula (II) :
Figure imgf000045_0001
(ii) a group of formula (III) :
Figure imgf000045_0002
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 C5-20 aryl group, and an optionally substituted C5-20 aryl-Cι-7 alkyl group, wherein the Cι_7 alkyl group is more preferably methyl. In these groups the C5-20 aryl group is preferably a heteroaryl group, itself preferably having a single aromatic ring. Such groups may preferably be substituted with Cι_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 Cχ-- alkyl group, it is more preferably a Cι_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- ( ' -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- -yloxymethyl) -5- methyl-furan-2-carbonyl] -benzenesulfonamide (trifluoroacetate salt) (12) ;
4-Hydroxy-AJ- [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- ( ' -Methoxy-biphenyl-4-ylcarbamoyl) -5-methyl-furan-2- carboxylic acid (24) ; 5-Benzenesulfonylaminocarbonyl-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-f uran-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- -yloxymethyl) -5-methyl-furan-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-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- ( ' -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 ' , ' -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-Methyl-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 ' -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- ( ' -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- ( ' -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] -di ethylaminosulphonamide (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-methyl- furan-2-carbonyl] -benzenesulfonamide (130) ; 3, 5-Dimethyl-isoxazole-4-sulfonic acid [4-(4'~ difluoromethoxy-bipheny1-4-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- (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-ρhenoxymethyl) -furan-2- carboxylic acid (137) ;
N- [5-Methyl-4- (4-pyrimidin-2-yl-phenoxymethyl) -furan-2- carbonyl] -benzenesulfonamide (138);
4- (2 ' , ' -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 ' , ' -dimethoxy- biphenyl-4-yloxymethyl) -5-methyl-furan-2-carbonyl] -amide
(142); 4- ( ' -Methoxy-2 ' -methyl-biphenyl-4-yloxymethyl) -5-methyl- furan-2-carboxylic acid (144) ;
N- [4- ( ' -Methoxy-2 ' -methyl-biphenyl-4-yloxymethyl) -5-methyl- furan-2-carbonyl] -benzenesulfonamide (145) ;
3, 5-Dimethyl-isoxazole-4-sulfonic acid [4- ( ' -methoxy-2 ' - methyl-biphenyl-4-yloxymethyl) -5-methyl-furan-2-carbonyl]- amide (146) ;
5- [4- (Biphenyl-4-yloxymethyl) -5-methyl-furan-2-yl] -1H- tetrazole (149) ;
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- [ ( '-Difluoromethoxy-biphenyl-4-ylamino) -methyl] -5-methyl- furan-2-carboxylic acid (171) ; N-{ - [ (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-{ [ ( ' -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, EP3) can be quantified by dividing the Ki for EP4 (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 60778) . 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)
Prepara tive HPLC System
Preparative HPLC was carried out on a C18-reverse-phase column (10 x 2.1 cm i.d Genesis column with 7 μm 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 μL/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 Gradient
Time Flow %A %B
(min) (mL/min)
0.00 2.0 95 5
0.50 2.0 95 5
4.50 2.0 5 95
5.00 2.0 5 95
5.50 2.0 95 5
Column - Luna 3u C18(2) 30x .6mm
LC/MS System B:
Mass Spectrometer - Platform II with electrospray source operating in negative ion mode. HPllOO system running at 2.0 mL/min, 200 μL/min split to the ESI source with inline HPllOO DAD detection and SEDEX ELS detection.
Mobile Phase
A) Water 0.1 % Diethylamine
B) acetonitrile
Gradient
Time Flow %A %B
(min) (mL/min)
0.00 2.0 95 5
0.50 2.0 95 5
4.00 2.0 5 95
4.50 2.0 5 95
5.00 2.0 95 5
20.00 2.0 95 5
Column - XTerra MS C18 3.5μm 4.6 x 30mm LCMS System C:
Mass Spectrometer - Finnigan TSQ700 with electrospray source operating in negative ion mode.
HP1050 system running at 2.0 mL/min, 200 μL/min split to the ESI source with inline HP1050 Single wavelength UV detector at 254 nm.
Mobile Phase
A) Water 0.1 % Diethylamine
B) acetonitrile
Gradient
Time Flow %A %B
(min) (mL/min)
0.00 2.0 95 5
1.00 2.0 95 5
15.00 2.0 5 95
17.00 2.0 5 95
18.00 2.0 95 5
20.00 2.0 95 5
Column - XTerra MS C18 3.5μm 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 μL/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 Gradient
Time Flow %A %B
(min) (mL/min)
0.00 2.0 95 5
1.00 2.0 95 5
15.00 2.0 5 95
17.00 2.0 5 95
18.00 2.0 95 5
20.00 2.0 95 5
Column - Higgins Clipius C18 5μm 100 x 3.0mm
H NMR system
The 1H NMR spectra were recorded on a Varian Unity Inova 400, which operates at 400 MHz for 1H. It is equipped with a 5mm inverse detection triple resonance probe for detection of αH. 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. D6- 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-f ran-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 imgf000058_0001
1 2
A stirred solution of (2-methyl-3-furan-3-yl) -methanol
(1) (31.87 g) in N,N-dimethylformamide (250 L) 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 L) . The combined organic extracts were washed successively with 1.0 M hydrochloric acid (500 L) , 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-carjoxylic acid (3)
Figure imgf000058_0002
A solution of 3- (tert-Butyl-diphenyl-silanyloxy ethyl) -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 L) over 10 ins . 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 vacuo. 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-f uran-2- carboxylic acid (4)
Figure imgf000059_0001
(i) 2-Chlorotrityl chloride resin (lg 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-carboxylic acid (3) (0.512 g) and diisopropylethylamine (0.91 L) 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 vacuo .
(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- dimethylforma ide, dichloromethane, and then dried at 45°C in va cuo. The resin was treated with dichloromethane/trifluoroacetic acid (19:1. by volume) (20 L) 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 C20H18O5) . (d) 4- (Dibenzofuran-3-yloxymethyl) -5-methyl-f uran-2- carboxylic acid (50)
Figure imgf000061_0001
Compound (50) was prepared by adapting the procedure of Example 1(c) . LC/MS System B: Rt = 1.79mins, m/z (ES-) = 321 ( (M-H) for Cι9Hι405) .
(e) 4- (Dibenzofuran-2-yloxymethyl) -5-methyl-furan-2- carboxylic acid (56)
Figure imgf000061_0002
56
Compound (56) was prepared by adapting the procedure of Example 1(c). LC/MS System B: Rt = 1.76mins, m/z (ES") - 321 ((M-H) for C19H1405) .
(f) 4- (4 ' -Cyano-biphenyl-4-yloxymethyl) -5-methyl-furan-2- carboxylic acid (57)
Figure imgf000061_0003
HO 57 Compound (57) was prepared by adapting the procedure of Example 1(c). LC/MS System B: Rt = 1.72mins, m/z (ES") = 332 ( (M-H) for C20H15NO4) .
Example 2A: Synthesis of N- [4- (4 ' -Methoxy-biphenyl-4- yloxymethyl) -5-methyl-furan-2-carbonyl] -benzenesulfonamide (5)
Figure imgf000062_0001
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- dimethyla inopropyl) -3-ethylcarbodiimide hydrochloride (142 mg) , 4- (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 L) , 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 C26H23N06S) .
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 imgf000063_0001
LC/MS System C: Rt = 5.37 mins, m/z (ES ) = 490 (M~ for C27H25N06S) .
Example 2C: N- [4- (4 ' -Methoxy-biphenyl-4-yloxymethyl) -5- methyl-furan-2-carbonyl] -methanesulf onamide (7) —
Figure imgf000063_0002
LC/MS System C: Rt = 4.50 mins, m/z (ES") - 414 (M" for C2ιH2ιN06S) .
Example 2D: Propane- 1- sulfonic acid [4- (4 ' -methoxy-biphenyl - 4 -yloxymethyl) -5-methyl-f uran-2-carbonyl]— amide (8) —
Figure imgf000063_0003
LC/MS System C: Rt = 4.78 mins, m/z (ES") = 442 (M" for C23H25 O6S) .
Example 2E: 3 , 5-Dimethyl-isoxazole-4-sulfonic acid [4- (4'' methoxy-biphenyl-4-yloxymethyl) -5-methyl-furan-2-carbonyl] amide (9)
Figure imgf000064_0001
LC/MS System C: Rt - 4.91 mins, m/z (ES") = 495 (M~ for
C25H24N2θ7S) .
Example 2F: Synthesis of Thiophene-2 -sulfonic acid [4- (4'- methoxy-biphenyl-4 -yloxymethyl) -5-methyl-f uran-2 -carbonyl] amide (10)
Figure imgf000064_0002
LC/MS System C: Rt = 4.94 mins, m/z (ES~)= 482 (M" for C24H2ιN06S2) . Example 2G: 5-Methyl-pyridyl-2-sulfonic acid [4- (4' - methoxy-biphenyl-4-yloxymethyl) -5-methyl-furan-2-carbonyl] amide (11)
Figure imgf000065_0001
LC/MS System D : Rt = 10 . 09 mins , m/z (ES+) = 493 (MH+ for C26H24N0eS ) .
Example 2H : Synthesis of 4-Aminomethyl-N- [4- (4 ' -methoxy- biphenyl -4 -yloxymethyl) -5-methyl-furan-2-carbonyl] - benzenesulfonamide trif luoroacetate (12)
Figure imgf000065_0002
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 carba ate 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~ 1 for C27H26N206S) . Example 21: Synthesis of 4-Hydroxy-N- [4- (4' -methoxy- biphenyl-4-yloxymethyl) -5-methyl-furan-2-carbonyl] - benzenesulfonamide (13)
Figure imgf000066_0001
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 (lOrL) 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 (ES") = 492 (M" for C26H23N207S) .
Example 3 : Synthesis of 4- (Biρhenyl-4-yloxymethyl) -5- methyl-furan-2-carboxylic acid (18)
(a) Triisopropyl- (2-methyl-furan-3-ylmethoxy) -silane (14)
Figure imgf000067_0001
1 14
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 -Me thyl -4-tri isopropyl si lanyl oxyme thyl -furan-2- carboxylic acid methyl ester (15)
Figure imgf000067_0002
14 15
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 va cuo . 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-Hydroxymethy -5 -methyl- furan-2-carboxylic acid methyl ester (16)
Figure imgf000068_0001
16 15
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 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.
(d) 4- (Biphenyl - 4 -yloxymethyl ) -5-methyl -furan-2-carboxylic acid methyl ester (17)
Figure imgf000068_0002
17
A solution of 4-hydroxymethyl-5-methyl-furan-2-carboxylic acid methyl ester (16) (lg) in anhydrous tetrahydrofuran (20mL) was cooled to 0°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 dichloro ethane/methanol 99:1 by volume to give compound 17 as a white solid (200mg) . LCMS System A: Rt = 4.2 mins.
(ej 4- (Biphenyl- 4-yloxymethyl) -5~methyl-furan-2-carboxylic acid (18)
Figure imgf000069_0001
17 IM 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 pH6 with aqueous 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 Cι9Hι604) .
Example 4: Synthesis of N- [4- (Biphenyl-4-yloxymethyl) -5- methyl-f ran-2-carbonyl] -benzenesulfonamide (19)
Figure imgf000070_0001
18 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 C25H2ιN05S) .
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 imgf000070_0002
16 20
A solution of 4-hydroxymethyl-5-methyl-furan-2-carboxylic acid methyl ester (16) (1.14 g) in tetrahydrofuran (15 mL) was cooled to 0°C with stirring and treated with 4- iodophenol (4.6 g) , triphenylphosphine (5.5 g) and diisopropylazodicarboxylate (4.2 g) . After 10 minutes the cooling bath was removed. After 3 hours the reaction mixture 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-f uran-2- carboxylic acid (21)
Figure imgf000071_0001
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 va cuo, dissolved in ethyl acetate (30 mL) and washed successively with water (30 L) , brine (30 L) , dried and concentrated in vacuo. The residue was dissolved in a mixture of tetrahydrofuran/methanol (2:1 by volume) (30 L) and 1.0 M aqueous lithium hydroxide solution (6.78 L) 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 L) . 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: R = 4.18 mins, m/z (ES") = 349 (M" for C2ιHι805) . Example 6: Synthesis of N- [4- (4 ' -Acetyl-biphenyl-4- yloxymethyl) -5-methyl-furan-2-carbonyl] -benzenesulfonamide (22)
Figure imgf000072_0001
21 22
Compound (22) was prepared by adapting the procedure of Example 2A. LC/MS System D: Rt = 9.87 mins, m/z (ES+) = 490 (MH+ for C27H23N06S) .
Example 7: Synthesis of 4- (4' -Methoxy-biphenyl-4- ylcarbamoyl) -5-methyl-furan-2-carboxylic acid (24)
(a) 5 -methyl- f uran-2, 4-dicarboxylic acid-2-methyl ester (23)
Figure imgf000072_0002
16 23 Jones' reagent (Prepared according to Fieser and Fieser, Reagents for Organic Synthesis, Volume 1, page 142, 1967) was added drop-wise to a stirred solution of 4- hydroxymethyl-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 vacuo to afford compound 23 as a buff coloured solid.
(b) 4- (4 -Methoxy-biphenyl-4-ylcarbamoyl) -5-methyl-f uran-2- carboxylic acid (24)
Figure imgf000073_0001
To a solution of 5-methyl-furan-2, -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 L) and washed successively with water (2 x 20 mL) , 0.1 M hydrochloric acid (20 mL) , water (20 L) , saturated sodium hydrogen carbonate (10 mL) and brine (10 mL) . This solution was dried and concentrated in vacuo . The residue (170 mg) was dissolved in dichloromethane (5 L) , 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 in-vacuo . The residue was dissolved in methanol/tetrahydrofuran (1:3 by volume) (20 L) , 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 mg) . LC/MS System D: Rt = 7.23 mins, m/z (ES+) = 351 (MH+ for C20H17NO5) .
Example 8 : Synthesis of 5-Benzenesul onylaminocarbonyl-2- methyl-furan-3-carboxylic acid (4' -methoxy-biphenyl-4-yl) - amide (25)
Figure imgf000074_0001
Compound 25 was synthesised from 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 C26H22N2O6S) .
Example 9: Synthesis of 4- (4 ' -Chloro-biphenyl-4- yloxymethyl) -5-methyl-furan-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 imgf000075_0001
20 26
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 vacuo . 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 imgf000075_0002
(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 diisopropylethylamme (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 dichloromethane/triethylamine/methanol (20:1:3 by volume) (3 x 30 L) , 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 vacuo .
(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, -dimethylformamide, dichloromethane, diethyl ether and then dried at 45°C in vacuo . 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 d9Hι5C10) .
(c) 4- (4-Benzo [1 , 3] dioxol-5-yl-phenoxymethyl) -5-methyl- furan-2-carboxylic acid (28)
Figure imgf000076_0001
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 , m/z (ES") = 351 (M" for C20Hι6O6) .
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 imgf000077_0001
14
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 L) . 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 L) 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 L) , 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: R = 5.16min.
(b) (4-Hydroxymethyl -5-methyl -furan-2-yl) -acetic acid ethyl ester (30)
Figure imgf000078_0001
A solution of (5-methyl-4-triisopropylsilanyloxymethyl- 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-f uran-2-yl ] -acetic acid (31)
Figure imgf000079_0001
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 C20Hι8O4) .
(d) [4- (4 ' -Methoxy~biphenyl-4-yloxymethyl) -5-methyl ~furan-2- yl] -acetic acid (32)
Figure imgf000079_0002
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 C21H20O5) .
Example 11: Synthesis of 3- (Biphenyl-4-yloxymethyl) -5- methyl-furan-2-yl] -propionic acid (37) and N-{3-[4- (Biphenyl-4-yloxymethyl) -5-methyl-furan-2-yl] -propionyl}' benzene sulfonamide (38) - 7!
(a) 5 -Methyl- 4 -triisopropyl silanyloxymethyl- f uran-2 - carbaldehyde (33)
Figure imgf000080_0001
14 33
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 L) 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, -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 mL) . This mixture was extracted with diethyl ether (2 x 350 L) , and the combined organic extracts were washed with water (500 mL) and brine (500 mL) , dried, and concentrated in vacuo to give compound 33 as an amber coloured oil. LC/MS System A: Rt = 4.86 mins.
(b) 3- (5-Methyl-4-triisopropylsilanyloxymethyl-furan-2-yl) - acrylic acid ethyl ester (34)
Figure imgf000080_0002
33 34
A stirred solution of 5-methyl-4- triisopropylsilanyloxymethyl-furan-2-carbaldehyde (33) (10.6 g) in tetrahydrofuran (25 L) was treated with triethylphosphonoacatete (7.81 mL) and lithium hydroxide
(1.65 g) . The resulting mixture was stirred for 16 hours then concentrated in vacuo 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 vacuo . 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 imgf000081_0001
34 35
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)
Figure imgf000082_0001
35 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 mins.
( e) 3- [ 4 - (Biphenyl-4 -yloxymethyl ) -5-methyl-furan-2-yl ] - propionic acid ( 37 )
Figure imgf000082_0002
To a 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 diisopropylazodicarboxylate (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 mL) and a scavenger resin PS-TsCl (2.5 g) and the mixture was shaken for 6 hours at room temperature. The reaction mixture was purified by flash chromatography, 11 -
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/tetrahydrofuran (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 L) . The combined organic extracts were further washed with brine (35 L) , then dried (sodium sulphate) and concentrated in vacuo . 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 C2ιH20O4) .
(f) N~ {3- [4- (Biphenyl-4-yloxymethyl) -5-methyl-f uran-2-yl] - propionyl } -benzene sulfonamide (38)
Figure imgf000083_0001
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 C27H25θ5S) .
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- -yl] -propionic acid (39)
Figure imgf000084_0001
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 imgf000084_0002
Compound (40) was prepared from compound (39) by the procedure of Example 2A. LC/MS System C: = 5.78 mins, m/z (ES") = 504 (M" for C28H27N06S) .
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) (a) 3- (4-Hydroxymethyl-5-methyl-furan-2-yl) -acrylic acid ethyl ester (41)
Figure imgf000085_0001
34 41
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 imgf000085_0002
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 C2ιHι804) .
(c) 3- [4- (4 ' -Methoxy-biphenyl-4-yloxymethyl) -5-methyl-furan- 2-yl] -acrylic acid (43)
Figure imgf000085_0003
Compound (43) was prepared from compound (41) by adapting the procedure of Example 11(e). LC/MS System C: Rt = 4.85 mins , m/z (ES") = 363 (M" for C22H2o05 ) .
Example 14A: Synthesis of 4- (Bipheny 1-4 -yloxymethyl) -5- methyl-furan-2-sulfonic acid benzoylamide (46)
(a) 3- (Biphenyl-4-yloxymethyl) -2-methyl-furan (44)
Figure imgf000086_0001
1 44
A solution of (2-methyl-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 was 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- -yloxymethyl) -5-methyl-furan-2-sulfonic acid amide (45)
Figure imgf000086_0002
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 L) 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 L) and brine (300 mL) , dried, and concentrated in vacuo . 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.
16 -
(c) 4- (Biphenyl-4-yloxymethyl) -5-methyl-furan-2-sulfonic acid benzoylamide (46)
Figure imgf000088_0001
45 46
To a stirred solution of benzoic acid (61 mg) in a mixture of tetrahydrofuran (10 L) and 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-va cuo, 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 (MgS04) 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 C25H21NO5S) .
Example 14B: Synthesis of 4- (Biphenyl-4-yloxymethyl) -5- methyl-furan-2-sulphonic acid butyryl-amide (61)
Figure imgf000088_0002
To a stirred solution of 4- (biphenyl-4-yloxymethyl) -5- methyl-furan-2-sulphonic acid amide (45) (50mg, 0.146mmoles) in dichloromethane (5.0ml) was added triethylamine (26μl, 0.189mmoles) , dimethyl-pyridin-4-yl-amine (lmg) and butyryl chloride (19μl, 0.184mmoles) . After stirring for 16 hours at room temperature the reaction mixture was concentrated in- va cuo, 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- sulphoniσ acid phenylacetyl-amide (62)
Figure imgf000089_0001
LC/MS System C : Rt = 4 . 20mins , m/z ( ES" ) = 460 ( (M-H) for C26H23N05S ) .
Example 14D : 4- (Bxphenyl-4-yloxymethyl) -5-methγl-furan-2- sulphonic acid (3 , 5-dimethyl-isoxazole-4-carbonyl) -amide ( 63)
Figure imgf000090_0001
LC/MS System C: Rt = 3.98mins, m/z (ES~) = 465 ( (M-H) for C24H22N206S) .
Example 14E: 4- (Biphenyl- 4-yloxymethyl) -5-methyl-f uran-2 - sulphonic acid (thiophene-2 -carbonyl) -amide (64)
Figure imgf000090_0002
LC/MS System C: Rt = 4.06mins, m/z (ES" 452 ((M-H) for C23Hι9 05S2) .
Example 14F: Synthesis of 4- (Biphenyl- 4 -yloxymethyl) -5- methyl-furan-2-sulphonic acid (3-methoxy-propionyl) -amide (65)
Figure imgf000090_0003
To a stirred solution of 4- (biphenyl-4-yloxymethyl) -5- methyl-furan-2-sulphonic acid amide (45) (50mg, 0.146mmoles) in N, -dimethylformamide (4.0ml) was added diisopropylethylamine (85μl, 0.480mmoles) then a solution of 3-methoxypropionic acid (14μl, 0.146mmoles) in N,N- dimethylformamide (1.0ml). 0- (7-Azabenzotriazol-l-yl) - N,N,N' ,N' -tetramethyluronium hexafluorophosphate (61mg, 0.160mmoles) 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 (42mg) . LC/MS System A: Rt=3.80mins, m/z (ES") = 428 ((M-H) for C22H23N06S) .
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 imgf000091_0001
LC/MS System D : Rt = 5 . 64mins , m/z (ES+) = 463 ( (M+H) for C25H22 2O5S ) .
Example 14H : 4- (Bxphenyl-4-γloxymethyl) -5-methyl-f ran-2 - sulphonic acid (pyridine- 4 -carbonyl) -amide ( 67) )0 -
Figure imgf000092_0001
LC/MS System D: Rt = 5.85mins, m/z (ES+) = 449 ( (M+H) for C24H20N2O5S) .
Example 141: 4- (Biρhenyl-4-yloxymethyl) -5 -me hyl -f uran-2 ■ sulphonic acid (pyridine-3-carbonyl) -amide (68)
Figure imgf000092_0002
LC/MS System D: Rt = 5.92mins, m/z (ES+) = 449 ((M+H) for C24H2oN205S) .
Example 15: Synthesis of 4- (4' - ethoxy-biphenyl-4- yloxymethyl) -5-methyl-furan-2-sulfonic acid benzoylamide (49) and 4- (4 ' - ethoxy-biphenγl-4-yloxymethy
1) -5-methyl-furan-2-sulfonic acid (3 , 5-dimethyl-isoxazole-4- carbonyl) -amide (69) (a) 3- ( 4 ' -Methoxy-biphenyl- 4-yloxymethyl) -2-methyl- furan (47)
Figure imgf000093_0001
1 47
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- uran-2- sulfonic acid amide (48)
Figure imgf000093_0002
Compound (48) was prepared from compound (47) by the procedure of Example 14A(b). LC/MS System A: Rt = 3.63 mins
(c) 4- (4 ' -Methoxy-biphenyl- -yloxymethyl) -5-methyl-furan-2- sulfonic acid benzoylamide (49)
Figure imgf000093_0003
48 49
Compound (49) was prepared from compound (48) by the procedure of Example 14B. LC/MS System C: Rt = 5.37 mins, m/z (ES") = 476 (M" for C26H23NOeS) .
(d) 4- (4 r -Methoxy-biphenyl- 4-yloxymethyl) -5-methyl-f uran-2- sulphonic acid (3 ,5-dimethyl-isoxazole~4-carbonyl) -amide (69)
Figure imgf000094_0001
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 C25H24N207S) .
Example 16: Synthesis of 4- [4- (5-Methoxγ-pyridin-2-yl) - phenoxymethyl] -5-methyl-furan-2-carboxylic acid (53)
(a) 5-Methyl-4- [4- (4,4,5, 5-tetramethyl- [ 1,3,2 ] dioxaborolan- 2-yl) -phenoxymethyl] -furan-2-carboxylic acid methyl ester (51)
Figure imgf000094_0002
16 51
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 imgf000095_0001
51 52
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 (O.βmL) 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 IM aqueous hydrochloric acid and partitioned between ethyl acetate and water. The organic phase was dried (MgS04) 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 mins , m/z = 354 ( (M+H) for C20Hι9NO5) •
(c) 4- [4- (5-Methoxy-pyridin-2-yl) -phenoxymethyl] -5 -me hyl - furan-2-carboxylic acid (53)
Figure imgf000096_0001
Method 1
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 tetrahydrofuran (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 IM 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 mins, m/ z (ES+) = 340 ( (M+H) for Cι9H17N05) •
Example 17 : Synthesis of 4- [6- (4-Methoxy-phenyl) -pyridin-3- yloxymethyl] -5-methyl-furan-2-carboxγlic acid (56)
(a) 4- (6-iodo-pyridin-3-yloxymethyl) -5-methyl- furan-2- carboxylic acid methyl ester (54)
Figure imgf000097_0001
16 54
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 C13Hι2IN04)
(b) 4- [6- (4-Methoxy-phenyl) -pyridin-3-yloxymethyl] -5-methyl- furan-2-carJoxylic acid methyl ester (55)
Figure imgf000097_0002
54 55
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 C20Hι9NO5 ) . (c) 4- [ 6- (4-Methoxy-phenyl) -pyridin-3-yloxymethyl ] -5-methyl- furan-2-carboxylic acid (56)
Figure imgf000098_0001
55 56
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 C19Hι7N05)
Example 18: Synthesis of 3-Morpholin-4-yl-propane-l- sulphonic acid [4- (4 ' -methoxy-biphenyl-4-yloxγmethyl) -5- methyl-furan-2-carbonyl] -amide (59)
(a) 3-Morpholin-4-yl-propane-l -sulfonic acid amide (58)
Figure imgf000098_0002
58
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 C7H16N203S) .
(b) 3-Morpholin-4-yl-propane-l-sulphonic acid [4- (4 ' - methoxy-biphenyl-4-yloxymethyl) -5-methyl-furan-2~carbonyl] amide (59)
Figure imgf000099_0001
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 C27H32N207S) .
Example 19: Synthesis of N- [4- (Biphenyl-4-yloxymethyl) -5- methyl-f ran-2-carbonyl] -2-methyl-benzenesulphonamide (60)
Figure imgf000099_0002
18 60
A stirred solution of 4- (biphenyl-4-yloxymethyl) -5-methyl- furan-2-carboxylic acid (18) (50mg, 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 hydrochloride (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 C26H23N05S) .
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 imgf000100_0001
70 (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 1(a).
(b) 4- [2- (tert-Butyl-diphenyl-silanyloxy) -ethyl] -5-methyl- furan-2-carboxylic acid (71)
Figure imgf000101_0001
70
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-f uran-2- carboxylic acid (72)
Figure imgf000101_0002
Compound (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
Figure imgf000101_0003
Example 20B: Synthesis of 4- [2- (4 ' -Methoxy-biphenyl-4- yloxy) -ethyl] -5-methyl- uran-2-carboxylic acid (73)
Figure imgf000101_0004
Compound (73) 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") = 351 ((M-H) for C2ιH20θ5) . Example 20C: Synthesis of 4- [2- (Dibenzofuran-3-yloxy) ethyl] -5-methyl-furan-2-carboxylic acid (74)
Figure imgf000102_0001
Compound (74) was prepared from compound (71) in an analogous manner to the methods described in Example 1(c). LC/MS System B: Rt = 1.86mins, m/z (ES") = 335 ((M-H) for
C2oHi6θ5 ) .
Example 21A: Synthesis of 4- (Biphenyl-4-yloxymethyl) -furan- 2-carboxylic acid (77)
(a) 4-Hydroxymethyl -furan-2-carboxylic acid (75)
Figure imgf000102_0002
75
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 IM 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 imgf000103_0001
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).
(c) 4- (Biphenyl-4-yloxymethyl) -furan-2-carboxylic acid (77)
Figure imgf000103_0002
Compound (77) 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") = 293 (M-H for Ci8Hι404) .
Example 21B: Synthesis of 4- (Dibenzofuran-2-yloxymethyl) - uran-2 -carboxylic acid (78)
Figure imgf000104_0001
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 CιeHι205) .
Example 21C: Synthesis of 4- (4 ' -Cyano-biphenyl-4- yloxymethyl) -furan-2-carboxylic acid (79)
Figure imgf000104_0002
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 Cι9Hι3N04) .
Example 21D: Synthesis of 4- (4 ' -Methoxy-biphenyl-4- yloxymethyl) - uran-2-carboxylic acid (80)
Figure imgf000104_0003
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 Ci9H1605 )
Example 21E : Synthesis of 4- (Dibenzofuran- 3 -yloxymethyl ) - f ran-2 -carboxylic acid (81)
Figure imgf000105_0001
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 Cι8Hι205) .
Example 22A: Synthesis of 4- (Biphenyl-4-yloxymethyl) -5- isopropyl-furan-2-carboxylic acid (85)
(a) 2-Isopropyl-furan-3-carboxylic acid ethyl ester (82)
Figure imgf000105_0002
82
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 (83)
Figure imgf000106_0001
(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-isoρropyl-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
(lOmillibars) . The residue was compound 83 obtained as a pale yellow oil.
(c) 5 -Isopropyl- 4- triisopropylsilanyloxymethyl -furan-2- carboxylic acid (84)
Figure imgf000107_0001
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 imgf000107_0002
Compound (85) was prepared from compound (84) in an analogous manner to the methods described in Example 1(c) LC/MS System B; Rt = 1.93mins, m/z (ES") = 335 (M-H for C2ιH2o04) .
Example 22B: Synthesis of 5-Isopropyl-4- (4 ' -methoxy- biphenyl- -yloxyme hyl) ~ uran-2-carboxylic acid (86)
Figure imgf000107_0003
84 86
Compound (86) was prepared from compound (84) in an analogous manner to the methods described in Example 1(c) LC/MS System B; Rt = 1.93mins, m/z (ES") = 365 (M-H for
C22H22θ5) . Example 22C: Synthesis of 4- (Dibenzofuran-3-yloxymethyl) -5- isopropyl-furan-2-carboxylic acid (87)
Figure imgf000108_0001
84 87
Compound (87) was prepared from compound (84) in an analogous manner to the methods described in Example 1(c) LC/MS System B; Rt = 1.93mins, m/z (ES") = 349 (M-H for C2Hι805) .
Example 23A: Synthesis of 4- (Biphenyl-4-yloxymethyl) -5- trifluoromethyl-furan-2-carboxylic acid (90)
(a) Tri-isopropyl - (2-trif luoromethyl-f uran-3-ylmethoxy) - silane (88)
Figure imgf000108_0002
(i) A solution of 2-trifluoromethyl-furan-3-carboxylic acid ethyl ester (2.2g, 10.5mmoles) 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) - methanol from (i) in dry dichloromethane (180ml) was treated with chloro-tri-isopropyl-silane (2.6g, 13.4mmoles) and imidazole (1.45g, 21.3mmoles) 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. IM 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 (0.05torr) 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)
Figure imgf000109_0001
88 89
A stirred 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 lh 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-trif luoromethyl-f uran-2- carboxylic acid (90)
Figure imgf000110_0001
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 C19Hι3F304) .
Example 23B: Synthesis of 4- (Biphenyl-3-yloxymethyl) -5- trifluoromethyl-furan-2-carboxylic acid (91)
Figure imgf000110_0002
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 Cι9Hι3F304) .
Example 23C: Synthesis of 4- (Dibenzofuran-2-γloxymethyl) -5- trifluoromethyl-furan-2-carboxylic acid (92)
Figure imgf000111_0001
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 Cι9HιιF305) .
Example 23D: 4- (4 ' -Cyano-biphenyl-4-yloxymethyl) -5- tri luoromethyl-f ran-2-carboxylic acid (93)
Figure imgf000111_0002
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 C20Hι2F3Nθ4) .
Example 23E: Synthesis of 4- (4' -Methoxy-biphenyl-4- yloxymethy 1) -5-trifluoromethyl-furan-2-carboxylic acid (94)
Figure imgf000111_0003
89 94
Compound (94) 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") = 391 (M-H for C20H15F3O5) .
Example 23F: 4- (Dibenzofuran-3-yloxymethyl) -5-trifluσromethyl- furan-2-carboxylic acid (95)
Figure imgf000112_0001
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 C19HuF305) .
Example 24A: Synthesis of 4- (31 , 4 ' -Dimethoxy-biphenyl-4- yloxy methyl) -5-methyl-furan-2-carboxylic acid (96)
Figure imgf000112_0002
96
20 A stirred mixture of 4- (4-iodo-phenoxymethyl) -5-me hyl- furan-2-carboxylic acid methyl ester (20) (0.025g, 0.067mmoles) , (3, 4-dimethoxyphenyl) -boronic acid (0.017g, 0.093mmoles) , N,N-dimethylformamide (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 - Ill
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 IM hydrochloric acid and extracted with ethyl acetate (3 x 25 L) . 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 C2ιH20O6) .
Example 24B: Alternate synthesis of 4- (4-Benzo [1, 3] dioxol-5- yl-phenoxymethyl) -5-methyl-furan-2-carboxylic acid (28)
Figure imgf000113_0001
Compound (28) was prepared from compound (20) and (3,4- methylenedioxyphenyl) -boronic acid by adapting the procedure of Example 24A. LC/MS System B; Rt = 1.76mins, m/z (ES") = 351 (M-H for C2oHιeOe) .
Example 24C: 4- (4' -Ethoxy-biphenyl-4-yloxymethyl) -5-methyl- furan-2-σarbσxylic acid (98)
Figure imgf000114_0001
20 98
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 = 1.86mins, m/z (ES") = 351 (M-H for C2ιH20O5) .
Example 25A: Synthesis of 4- (2 ' -Chloro-biphenyl-4- yloxymethyl) -5-methyl-furan-2-carboxylic acid (99)
Figure imgf000114_0002
20 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 (ES") = 341 and 343 (M-H for Cι9H15C104) .
Example 25B: Synthesis of 4- (2 ' , 6 ' -Difluoro-biphenyl-4- yloxymethyl) -5-methyl-furan-2-carboxylic acid (100)
Figure imgf000114_0003
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 C19H14F204).
Example 25C: Synthesis of 5-Methγl-4- (2 ' -trifluoromethyl- biphenyl-4-yloxymethyl) -furan-2-carboxylic acid (102)
Figure imgf000115_0001
Compound (102) was prepared from compound (20) and (2- trifluoro ethyl-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 C20Hι5F3O4) .
Example 25D: Alternate synthesis of 4- (4 ' -Chloro-biphenyl-4- yloxymethyl) -5-methyl-furan-2-carboxylic acid (27)
Figure imgf000115_0002
Compound (77) was prepared from compound (20) and (4-chloro- phenyl) -boronic acid by adapting the procedure of Example
5(b). LC/MS System B; Rt = 1.93mins, m/z (ES") = 341 and 343
(M-H for Cι9Hι5C104) .
Example 25E: Synthesis of 4- (3 ' -Fluoro-biphenyl-4- yloxymethyl) -5-methyl-furan-2-carboxylic acid (104)
Figure imgf000116_0001
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 C19Hι5F04) .
Example 25F: 5-Methyl-4- (2 ' -methylsulphanyl-biphenyl-4- yloxymethyl) -furan-2-carboxylic acid (105)
Figure imgf000116_0002
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 C20H18OS) .
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)
Figure imgf000116_0003
16 106 A mixture of 4-hydroxymethyl-5-methyl-furan-2-carboxylic acid methyl ester (16) (1.85g, 10.9mmoles), 3-iodophenol (3.6g, 16.35mmoles) , 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)
Figure imgf000117_0001
106 107 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 IM 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~) = 357 (M-H for C13HnI04) .
(c) 4- (3 ' , 4 ' -Dimethoxy-biphenyl-3-yloxymethyl) -5-methyl- furan-2-carboxylic acid (108)
Figure imgf000118_0001
107 108
(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) (l.lβg, 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,
0.65mmoles) , [1, l'-bis (diphenylphosphino) ferrocene] dichloropalladium(II) complex with dichloromethane
(1:1) (10.6mg) and potassium acetate (0.064g, 0.65mmoles) in N, -dimethylformamide (5mL) and the mixture was agitated at 100°C for 24 hours. The resin was drained, washed sequentially with tetrahydrofuran/water (1 : lv/v) (2 x 5mL) , tetrahydrofuran (2 x 5mL) , 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% 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 C2ιH20O6) .
Example 26B: Synthesis of 5-Methyl-4- (3 ' -trifluoromethyl- biphenyl-3-yloxymethyl) -furan-2-carboxylic acid (109)
Figure imgf000119_0001
107 109 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 C2oHι5F304) .
Example 27A: Synthesis of 4- (4 ' -Hydroxymethyl-biphenyl-4- yloxymethyl) -5-methyl-furan-2-carboxylic acid (110)
Figure imgf000119_0002
26 110
(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 72 hours. The resin was drained, washed sequentially with - I I S
dichloromethane/triethylamine/methanol (20:1:3 by volume) (3 x 30 mL) , dichloromethane (6 x 30 L) , N, -dimethylformamide
(2 x 25 mL) , dichloromethane (6 x 25 L) , and diethyl ether
(2 x 25 mL) and dried at 40°C in vacuo .
(ii) The loaded resin (llOmg) from (i) was treated with a mixture of (4-hydroxymethyl-phenyl) -boronic acid (98.3mg,
0.65mmoles) , [1, l'-bis (diphenylphosphino) ferrocene] dichloropalladium (II) complex with dichloromethane (1:1) (lO.βmg) 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% trifluoroacetic 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 = 1.48mins, m/z (ES" = 337 (M-H for C20Hι8O5) .
Example 27B: Synthesis of 5-Methyl-4- (4' -methylsulphanyl- biphenγl-4-yloxymethyl) -furan-2-carboxylic acid (111)
Figure imgf000121_0001
26 111
The loaded resin (llOmg) (from example 27A, (i) ) was treated with a mixture of (4-methylsulphanyl-phenyl) -boronic acid (109mg, 0.65mmoles), [1, l'-bis (diphenylphosphino) ferrocene] dichloropalladium (II) complex with dichloromethane ( 1:1) (lO.βmg) and potassium acetate (0.064g, 0.65mmoles) in 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 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 lll(5.0mg) as a solid. LC/MS System B; Rt = 1.90mins, m/z (ES") = 353 (M-H for C20Hι8O4S) .
Example 27C: Synthesis of 4- (3' -Hydroxy-bxρhenyl-4- yloxymethyl) -5-methyl-furan-2-carboxylic acid (112)
Figure imgf000122_0001
26 112
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 Cι9Hιe05) .
Example 27D: 4- (4 ' -Dxmethylamino-biphenyl-4-yloxymethyl) -5- methyl-furan-2-carboxylic acid (113)
Figure imgf000122_0002
Compound (113) was prepared from compound (26) and (4- dimethyla ino-phenyl) -boronic acid by adapting the procedure of Example 27B. LC/MS System B; Rt = 1.83mins, m/z (ES") = 350 (M-H for C2ιH2ιN0 ) .
Example 27E: Synthesis of 5-Methyl-4- (4' -trifluoromethoxy- biphenyl-4-yloxymethyl) -furan-2-carboxylic acid (114)
Figure imgf000123_0001
26 114
Compound (114) was prepared from compound (26) and (4- tri 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 CsoHisFaOs) .
Example 27F: 5-Methyl-4- (2' -trifluoromethoxy-biphenyl-4- yloxymethyl) -furan-2-carboxylic acid (115)
Figure imgf000123_0002
26 115 Compound (115) was prepared from compound (26) and (2- trifluoromethoxy-phenyl) -boronic acid by adapting the procedure of Example 27B. LC/MS System B; Rt = 1.97mins, m/z (ES") = 391 (M-H for C2oHi5F305) .
Example 27G: Synthesis of 4- (3' -Methoxy-biphenyl-4- yloxymethyl) -5-methyl-furan-2-carboxyliσ acid (116)
Figure imgf000123_0003
26 116
Compound (116) was prepared from compound (26) and (3- methoxy-phenyl) -boronic acid by adapting the procedure of Example 27B. LC/MS System B; Rt = 1.79minsf m/z (ES") = 337 (M-H for C20H18O5) .
Example 27H: Synthesis of 4- (3' -Acetγl-bxphenyl-4- yloxymethyl) -5-methyl-furan-2-carboxylic acid (117)
Figure imgf000124_0001
26 117
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 C2ιH1805) .
Example 271: Synthesis of 4- (4' -Fluoro-biphenyl-4- yloxymethyl) -5-methγl-furan-2-carboxγlic acid (118)
Figure imgf000124_0002
Compound (118) was prepared from compound (26) and (4- fluoro-phenyl) -boronic acid by adapting the procedure of Example 27B. LC/MS System B; Rt = 1.79mins, m/z (ES") = 325 (M-H for C19Hι5F04) . Example 28 : Synthesis of N- [4- (4 ' -Methoxy-biphenyl-4- yloxymethyl) -5-methyl-furan-2-carbonyl] -dimethylamino- sulphonamide (122) "
Figure imgf000125_0001
122 N,N-Dimethylsulphamide (73mg, 0.59mmoles), l-[3-
(dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (31mg, 0.162mmoles) and dimethyl-pyridin-4-yl-amine (lmg) were added to a stirred solution of 4- (4 ' -methoxy-biphenyl- 4-yloxymethyl) -5-methyl-furan-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 IM aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, brine and dried (MgS0) . Evaporation of the solvent afforded the crude product, which was purified by HPLC (gradient: 30% acetonitrile/70% water containing 0.1% trifluoroacetic 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 C22H24N206S) .
Example 29: Alternative synthesis of 4- (4 ' -Fluoro-biphenyl- 4-yloxymethyl) -5-methyl-furan-2~carboxyliσ acid (118) (a) 3- (4-Iodo-phenoxymethyl) -2-methyl-furan (123)
Figure imgf000126_0001
3- (4-Iodo-phenoxymethyl) -2-methyl-furan was prepared from (2-methyl-furan-3-yl) -methanol 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)
Figure imgf000126_0002
A mixture of (4-fluoro-phenyl) -boronic acid (300mg,
2.1mmoles), 3- (4-iodophenoxymethyl) -2-methyl-furan (123) (500mg, l.βmmoles) 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 imgf000127_0001
A solution of 3- ( 4' -fluoro-biphenyl-4-yloxymethyl) -2-methyl- furan (124) (200mg, 0.71mmoles) in dry tetrahydrofuran (15ml) 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 vacuo 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 Cι9H15F04) .
Example 30: Synthesis of 4- (2 ' -Methoxy-biphenyl-4- yloxymethyl) -5-methyl-furan-2-carboxylic acid (126) and N- [4- (2 ' -Methoxγ-biphenyl-4-yloxymethyl) -5-methyl-furan-2- carbonyl] -benzenesulfonamide (127) (a) 4- (2 ' -Methoxy-biphenyl- 4-yloxymethyl) -5-methyl - furan-2- carboxylic acid methyl ester (125)
Figure imgf000128_0001
119 125
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- ethoxy-benzene (80μl, 0.65mmoles), 2M aqueous cesium carbonate (1.0ml) and ), [1, l'-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 C21H20O5) .
(b) 4- (2 ' -Methoxy-biphenyl- 4-yloxymethyl) - 5 -methyl- fur an- 2- carboxylic acid (126)
Figure imgf000128_0002
125 126
A solution of 4- (2 ' -methoxy-biphenyl-4-yloxymethyl ) -5- methyl-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 C20Hι8O5) .
(c) N- [4- (2 ' -Methoxy-biphenyl-4-yloxymethyl ) -5-methyl- furan-2-carbonyl] -benzenesulphonamide (127)
Figure imgf000129_0001
Compound (127) was prepared from compound (126) by adapting the procedure of Example 2A. LC/MS System D; Rt = 9.17mins, m/z (ES+) = 478 (M+H for C2eH23N06S) .
Example 31: Synthesis of 4- (4 ' -Difluoromethoxy-biphenyl-4- yloxymethyl) -5-methyl-furan-2-carboxylic acid (129), N-[4- (4 ' -Difluoromethoxy-biphenγl-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-furan-2-carbonyl] -amide (131) (a) 4- (4 ' -difluoromethoxy-biphenyl-4-yloxymethyl) -5-methyl- furan-2-carboxylic acid methyl ester (128)
Figure imgf000130_0001
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- difluoromethoxy-1-iodo-benzene (175mg, 0.65mmoles), 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-difluoromethoxy-l-iodo-benzene (87.5mg, 0.0.27mmoles) and [1, l'-bis (diphenylphosphino) ferrocene] dichloropalladium (II) complex with dichloromethane (1:1) (lO g) 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 ' -Difluoromethoxy-biphenyl -4~yloxymethyl) -5-methyl- furan-2-carboxylic acid (129)
Figure imgf000131_0001
128 129
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 C2oHι6F205) .
(c) N- [4- (4' -Difluoromethoxy-biphenyl-4-yloxymethyl) -5- methyl-furan-2-carbonyl] -benzenesulphonamide (130)
Figure imgf000131_0002
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- (4'- difluoromethoxy-biphenyl- 4-yloxymethyl) -5-methyl- furan-2- carbonyl] -amide (131)
Figure imgf000131_0003
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 C25H22F2N207S) .
Example 32: Synthesis of 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) and N-{4- [4- (5-Methoxy-1-oxy- pyridin-2-yl) -phenoxymethyl] -5-methyl- uran-2-carbonyl }- benzenesulfonamide (135)
(a) N- { 4- [4- (5-Methoxy-pyridin-2-yl) -phenoxymethyl] -5- methyl-furan-2-carbonyl } -benzenesulphonamide (132)
Figure imgf000132_0001
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 C25H22N206S ) .
(b) 3, 5-Dimethyl-isoxazole-4-sulphonic acid { 4- [4- (5- methoxy-pyridin-2-yl) -phenoxymethyl] -5-methyl-f uran-2- carbonyl ) -amide (133)
Figure imgf000133_0001
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 C24H23N307S) .
(c) N-(4-[4- (5-Methoxy-pyridin-2-yl) -phenoxymethyl] -5 - methyl- f uran-2-carbonyl } -2-methyl-benzenesulphonamide (134)
Figure imgf000133_0002
Compound (134) was prepared from compound (53) by adapting the procedure of Example 2A. LC/MS System D; Rt = 8.43mins, m/z (ES+) = 493 (M+H for C26H2 N206S) .
(d) N~{4-[4- (5-Methoxy-l-oxy-pyridin-2-yl) -phenoxymethyl ] ■ 5-methyl- f uran-2-carbonyl } -benzenesulphonamide (135)
Figure imgf000133_0003
A solution of N-{ 4- [4- (5-methoxy-pyridin-2-yl) - phenoxymethyl] -5-methyl-furan-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 (10.6mg of 72% wt . % peracid) in chloroform (1.5ml). After stirring for 21 hours at room temperature, a further quantity of 3-chloro-benzenecarboperoxoic acid (8.0mg 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 C25H22N2θ7S) .
Example 33: Synthesis of 5-Methyl-4- (4-pyrimidin-2-yl- phenoxymethyl) -furan-2-carboxylic acid (137) and N-[5- Methyl-4- (4-pyrimidin-2-yl-phenoxymethyl) -furan-2-carbonyl] - benzenesulfonamide (138)
(a) 5-Methyl-4- (4-pyrimidin-2-yl-phenoxymethyl) -furan-2- carboxylic acid methyl ester (136)
Figure imgf000134_0001
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 Cι8Hι6N204 ) .
(b) 5 -Methyl- 4- (4-pyrimidin-2-yl-phenoxymethyl) -furan-2- carboxylic acid (137)
Figure imgf000135_0001
136 37
Compound (137) was prepared from compound (136) by adapting the procedure of Example 30(b). LC/MS System D; Rt = 6.21mins, m/z (ES+) = 311 (M+H for Cι7Hι4N204) .
(c) N- [5-Methyl-4- (4-pyrimidin-2-yl-phenoxymethyl) -furan-2- carbonyl] -benzenesulphonamide - (138)
Figure imgf000135_0002
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 C23H19N3O5S) .
Example 34: Synthesis of 4- (2 ' , 4 ' -Dimethoxy-biphenyl-4- yloxymethyl) -5-methyl-f ran-2-carboxylic acid (140), N-[4- (2 ' , 4 ' -Dimethoxy-bxphenyl-4-yloxym thyl) -5-methyl-furan-2- carbonyl] -benzenesulfonamide (141) and 3,5-Dimethyl- isoxazole-4-sulfonic acid [4- (2 ' , 4 ' -dimethoxy-biphenyl-4- yloxymethyl) -5-methyl-furan-2-carbonyl] -amide (142) (a) 4- (2 1 , 4 ' -Dimethoxy-biphenyl -4-yloxymethyl) -5-methyl furan -2-carboxylic a cid methyl ester (139)
Figure imgf000136_0001
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 ' -Dime thoxy -bipheny 1-4 -yloxymethyl) -5-methyl - furan-2-carboxyli c acid (140)
Figure imgf000136_0002
139 140
Compound (140) was prepared from compound (139) by adapting the procedure of Example 31(b). LC/MS System D; Rt = 8.20mins, m/z (ES+) = 369 (M+H for C2ιH2o06) .
(c) N- [4- (2 f , 4 ' -Dimethoxy-biphenyl-4 -yloxymethyl) -5-methyl- furan-2-carbonyl] -benzenesulphonamide (141)
Figure imgf000136_0003
A 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 C27H25N07S) .
(d) 3 , 5-Dimethyl-isoxazole-4-sulphonic acid [4- (2 ' , 4 '- dimethoxy-biphenyl-4-yloxymethyl) -5 -methyl- furan-2- carbonyl] -amide (142)
Figure imgf000137_0001
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 C26H26N208S) .
Example 35: Synthesis of 4- (4 ' -Methoxy-2 ' -methyl-bxphenyl-4- yloxymethyl) -5-methyl-furan-2-carboxylic acid (144), N-[4- (4 ' -Methoxy-2 ' -methyl-biphenyl-4-yloxymethγl) -5-methyl- furan-2-carbonyl] -benzenesulfonamide (145) and 3 ,5-Dimethyl- isoxazole-4-sulfonic acid [4- (4 ' -methoxy-2 ' -methyl-biphenyl- 4-yloxymethyl) -5-methyl-furan-2-carbonyl] -amide (146) (a) 4- (4 ' ' -Methoxy-2 ' -methyl -biphenyl- 4-yloxymethyl) -5- methyl-furan-2-carboxylic acid methyl ester (143)
Figure imgf000138_0001
X _-o
119 143
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 imgf000138_0002
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 C2ιH2o05) .
(c) N- [4- (4 ' ' -Methoxy-2 '' -methyl-biphenyl- 4-yloxymethyl) -5- methyl-furan-2-carbonyl] -benzenesulphonamide (145)
Figure imgf000138_0003
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 C27H25NO6S) .
(d) 3, 5-Dimethyl-isoxazole-4-sulphonic acid [4- (4 ' ' -methoxy - 2 ' ' -methyl-biphenyl- 4-yloxymethyl) - 5 -methyl- fur an- 2 - carbonyl] -amide (146)
Figure imgf000139_0001
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 C2eH26N207S ) .
Example 36: Synthesis of 5- [4- (Biphenyl-4-yloxymethyl) -5- methyl-furan-2-γl] -lH-tetrazole (149)
(a) 4-Hydroxymethyl-5-methyl-furan-2-carbonitrile (147)
Figure imgf000139_0002
(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, Iδ.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, Iδ.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 (MgS0) . 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 IM 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 IM 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- carboni trile (148)
Figure imgf000141_0001
47 148
Diisopropylazodicarboxylate (1.84g, lO.δmmoles) 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). IR (powder) CN st . 2225cm' -1
(c) 5- 14- (Biphenyl-4-yloxymethyl) -5-methyl- furan-2-yl] -1H- tetrazole (149)
Figure imgf000142_0001
A mixture of 4- (biphenyl-4-yloxymethyl) -5-methyl-furan-2- carbonitrile (148) (lOO g, 0.35mmoles), sodium azide (27mg, 0.415mmoles) and potassium carbonate (62mg, 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 Cι9Hι6N402) .
Example 37: Synthesis of 4- (4 ' -Difluoromethoxy-biphenγl-4- ylsulfanylmethyl) -5-methyl-furan-2-carboxγlic acid (153) , N- [4- (4 ' -Difluoromethoxy-biphenyl-4-ylsulfanylmethγl) -5- methyl-furan-2-carbonyl] -2-methyl-benzenesulfonamide (154) , N- [4- (4 ' -Difluoromethoxy-biphenyl-4 -ylsuIf nylmethyl) -5-methyl-furan-2-carbonyl] - benzenesulfonamide (155) and N- [4- (4 ' -Difluoromethoxy- biphenyl-4-sulfinylmethyl) -5-methyl-furan-2-carbonγl] -2- methyl-benzenesulfonamide (156) (a) 4- ( 4-Bromo-phenylsulphanylmethyl) -5-methyl-f uran-2- carboxylic acid methyl ester (150)
Figure imgf000143_0001
Diisopropylazodicarboxylate (1.27g, 6.3mmoles) was added to a solution of triphenylphosphine (1.65g, 6.3mmoles) 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 ] dioxaborolan- 2-yl) -phenylsulphanylmethyl] -furan-2-carboxylic acid methyl ester (151)
Figure imgf000143_0002
150 151
[1, l'-Bis (diphenylphosphino) ferrocene] dichloropalladium (II) complex with dichloromethane ( 1:1) (30mg) and 4,4,5,5- tetramethyl- [1, 3, 2] dioxaborolane (2.34ml of a IM 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 (MgS04) . 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- (4 ' -difluoromethoxy-biphenyl~4-ylsulphanylmethyl) -5- methyl-furan-2-carboxylic acid methyl ester (152)
Figure imgf000144_0001
[1, l'-Bis (diphenylphosphino) ferrocene] dichloropalladium (II) complex with dichloromethane (1:1) (12.8mg) was added to a degassed mixture of 5-methyl-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 IM 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 imgf000145_0001
152 153 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 C2oHι6F204S) .
(e) N- [4- (4 ' -Difluoromethoxy-biphenyl-4-ylsulphanylmethyl) 5-methyl-f uran-2 -carbonyl] -2-methyl-benzenesulphonamide (154)
Figure imgf000145_0002
Compound (154) was prepared from compound (153) and 2- methyl-benzenesulphonamide by adapting the procedure of Example 34 ( c) . LC/MS System D; Rt ll.δlmins, m/z (ES+) 544 (M+H for C27H23F2N05S2 ) .
(f) N- [4- (4 ' -Difluoromethoxy-biphenyl-4-ylsulphanylmethyl)
5-methyl-f 'uran-2- carbonyl] -benzene sulphonamide (155)
Figure imgf000146_0001
Compound (155) was prepared from compound (153) by adapting the procedure of Example 2A. LC/MS System D; Rt = 11.44mins, m/z (ES+) = 530 (M+H for C26H21F2N05S2) .
(g) N- [4- (4 f -Difluoromethoxy-biphenyl-4-ylsulphinylmethyl) - 5-methyl- furan-2-carbonyl ] -2-methyl-benzenesulphonamide (156) and N- [4- (4 ' -Difluoromethoxy-biphenyl-4- sulfonylmethyl) -5-methyl -f uran-2-carbonyl] -2-methyl - benzenesulfonamide (156a)
Figure imgf000146_0002
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 C27H23F2Nθ6S2) . 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 C27H23F2Nθ7S2) .
Example 38: Synthesis of 4- (Biphenγl-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-methyl-furan-2- carbonyl] -2-methyl-benzenesulfonamide (162)
(a) 4-Formyl-5-methyl-furan-2-carboxylic acid methyl ester (157)
Figure imgf000147_0001
Acetic acid 1, l-diacetoxy-3-oxo-l 5-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- fur an- 2- carboxylic acid methyl ester (158)
Figure imgf000148_0001
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 imgf000149_0001
Triethylamine (196μl, 1.41mmoles), 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(75mg) as a white solid. LC/MS System D; Rt = 6.34 mins, m/z (ES+) = 189 (M+H for C8H9C103) •
(d) 4- (Biphenyl- 4-ylaminomethyl) -5-methyl-furan-2- carboxylic acid methyl ester (158)
Figure imgf000149_0002
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+) = 322 (M+H for C20H19NO3) .
(e) 4- (Biphenyl~4-ylaminomethyl) -5-methyl-furan-2- carboxylic acid (160)
Figure imgf000150_0001
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+) = 308 (M+H for Cι9H17N03) .
(f) N- [ 4- (biphenyl- 4-ylaminomethyl) -5-methyl-furan-2- carbonyl] -benzenesulphonamide (161)
Figure imgf000151_0001
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 (lmg) in a mixture of tetrahydrofuran (3ml) and acetonitrile (0.5ml) was treated with triethylamine (5.5μl, 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 vacuo 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 C25H22N204S) .
(g) N- [ 4- (biphenyl- 4-ylaminomethyl) -5-methyl-furan-2- carbonyl] -2-methyl-benzenesulphonamide (162)
Figure imgf000151_0002
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 C26H24N204S) .
Example 39: Synthesis of N- (4-{ [4- (5-Methoxy-pyridin-2-yl) - phenylamino] -methyl}-5-methγl-furan-2-carbonyl) -2-methyl- benzenesulfonamide (167)
(a) 4- [ (4-Bromo-phenylamino) -methyl] -5-methyl- fur an-2- carboxylic acid methyl ester (163)
Figure imgf000152_0001
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 72 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 (ES+) = 324/326 (M+H for Cι4Hι4BrN03) .
(b) 5 -Methyl- 4- { [ 4- (4 , 4 , 5 , 5-tetramethyl- [ 1 , 3 , 2 ] dioxaborolan-2-yl) -phenylamino] -methyl- f uran-2 - carboxylic a cid methyl ester (164)
Figure imgf000153_0001
163 164
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)
Figure imgf000154_0001
164 165
5-Methyl-4-{ [4- (4 , 4, 5, 5-tetramethyl- [1, 3, 2] dioxaborolan-2- yl) -phenylamino] -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(O) (6mg) and triphenylphosphine (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+H for C20H20N2O4) .
(d) 4- { [4- (5-Methoxy-pyridin-2-yl) -phenylamino] -methyl ] -5- methyl-furan-2-carboxylic acid hydrochloride salt (166)
Figure imgf000154_0002
165 166
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 IM 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 Cι9H18N204) and m/z (ES") = 337 (M-H for C26H25 3θ5S) .
(e) TV- (4- { [4- (5-Methoxy-pyridin-2-yl) -phenylamino] -methyl ] - 5-methyl-f uran-2 -carbonyl) -2-methyl -benzenesulphonamide (167)
Figure imgf000155_0001
A suspension of 4- { [4- (5-methoxy-pyridin-2-yl) -phenylamino] - methyl} -5-methyl-furan-2-carboxylic acid hydrochloride salt (166) (30mg, 0.08mmoles) in tetrahydrofuran (5ml) was treated with toluene-2-sulphonamide (41mg, 0.24mmoles), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (34mg, 0.176mmoles) and 4- (N,N-dimethylamino) -pyridine (lOmg, O.Oδmmoles) 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 = 2.72mins, m/z (ES+) = 492 (M+H for C26H25N3θ5S) and m/z (ES") = 490 (M-H for C26H25N3O5S) .
Example 40: Synthesis of 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) and 3,5- Dimethyl-isoxazole-4-sulfonic acid {4- [ (4 ' -difluoromethoxy- biphenyl-4-ylamino) -methyl] -5-methyl-furan-2-carbonyl}-amide (174) (a) 4-Difluoromethoxy-4-ni tro-biphenyl (168)
Figure imgf000156_0001
[1, 1'-Bis (diphenylphosphino) ferrocene] dichloropalladium (II) complex with dichloromethane (1:1) (250mg) was added to a degassed mixture of 4, 4, 5, 5-tetramethyl-2- (4-nitro-phenyl) - [1, 3, 2] dioxaborolane (1.67g, 6.70mmoles), 1-difluoromethoxy- 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 (MgS04) . 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)
Figure imgf000157_0001
A solution of 4-difluoromethoxy-4-nitro-biphenyl (168) (l.lg, 4.15mmoles) 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 Cι3HιιF2N0.
(c) 4- (4 r -Difluoromethoxy-biphenyl-4-ylaminomethyl) -5- methyl-furan-2-carboxylic acid methyl ester (170)
Figure imgf000157_0002
Compound (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 C2ιHι9F2N03. (d) 4- (4' -Difluoromethoxy-biphenyl-4-ylaminomethyl) -5- methyl-furan-2-carboxylic acid (171)
Figure imgf000158_0001
Compound (171) was prepared from compound (170) by adapting the procedure of Example 38 (e) . LC/MS System D; Rt = 9.07mins, m/z (ES+) = 374 (M+H for C2oHι7F2N04) .
(e) N-{4-[(4'-Difluoromethoxy-biphenyl- 4-ylamino) -methyl] 5-methyl-f uran-2-carbonyl ) -benzenesulphonamide (172)
Figure imgf000158_0002
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 C26H22F2N2O5S) .
(f) N-{4- [ (4'-Difluoromethoxy-biphenyl- 4-ylamino) -methyl] ■ 5-methyl- f uran-2 -carbonyl } -2-methyl-benzenesulphonamide (173)
Figure imgf000159_0001
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 C27H24F2N205S) .
(d) 3 , 5 -Oimethyl-isoxazole- 4- sulphonic acid { 4- [ (4 ' ~ difluoromethoxy-biphenyl- 4-ylamino) -methyl] -5-methyl-f uran- 2- carbonyl ) -amide (174)
Figure imgf000159_0002
Diisopropylethylamine (60μl, 0.339mmoles) and a solution of 4- (4' -difluoromethoxy-biphenyl-4-ylaminomethyl) -5-methyl- furan-2-carboxylic acid (171) (50mg, 0.103mmoles) 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 0- (7-azabenzotriazol-l-yl) -N,N,N' ,N' -tetramethyluronium hexafluorophosphate (46mg, 0.124mmoles) in N,N- dimethylformamide (1.0ml) was added and the mixture was - 15Ϊ
stirred at room temperature for 16 hours. The reaction mixture was concentrated in vacuo 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+H for C25H23F2 3O6S) .
Example 41: Synthesis of 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)
(a) 4- { [ (4 r -Difluoromethoxy-biphenyl-4-yl) -methyl-amino] - methyl] -5-methyl- furan-2-carboxylic acid methyl ester (175)
Figure imgf000160_0001
Iodomethane (91mg, 0.64mmoles) and potassium carbonate (88mg, 0.64mmoles) were added to a solution of 4-(4'- difluoromethoxy-biphenyl-4-ylaminomethyl) -5-methyl-furan-2- carboxylic acid methyl ester (170) (62mg, 0.16mmoles) 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 (MgS04) . 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 r -Difluoromethoxy-biphenyl-4-yl) -methyl-amino] methyl } -5-methyl-f uran-2-carboxylic acid (176)
Figure imgf000161_0001
A solution of 4- {[( 4 ' -difluoromethoxy-biphenyl-4-yl) -methyl- amino] -methyl } -5-methyl-furan-2-carboxylic acid methyl ester (175) (30mg, 0.07mmoles) in dry tetrahydrofuran (20ml) was treated with potassium trimethylsilanoate (19mg, 0.15mmoles) 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 C2ιHι9F2N04) .
(c) TV- (4- { [ (4 ' -Difluoromethoxy-biphenyl-4-yl) -methyl- amino] -methyl ] -5-methyl-f uran-2-carbonyl) -2-methyl - benzenesulfonamide (177)
Figure imgf000161_0002
A stirred solution of 4-{ [ (4' -difluoromethoxy-biphenyl-4- yl) -methyl-amino] -methyl} -5-methyl-f ran-2-carboxylic acid (176) (21mg, 0.054 moles) , 2-methyl-benzenesulphonamide (19mg, 0.108mmoles) and 4- (N, N-dimethylamino) -pyridine (lmg) in a mixture of dichloromethane (8ml) and acetonitrile (2ml) was treated with 1- (3-dimethylaminopropyl) -3- ethylcarbodiimide hydrochloride (11.4mg, 0. OδOmmoles) . The mixture was stirred at room temperature for 18 hours under an argon atmosphere. The reaction mixture was concentrated in vacuo 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 C28H26F2N2θ5S) .
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. Supematants 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, EP3, EP2 or EPX 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 PGE2- 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: /C,
Ki ' 50 radioligand concentration
1 + radioligand KD
This approach follows that set out in Kenakin, T.P., Pharmacologic analysis of drug receptor interaction. Raven Press, New York, 2nd edition.
Table 1
Figure imgf000163_0001
The results are presented as pKi values in table 2 below. Table 2
Figure imgf000164_0001
Figure imgf000165_0001
Figure imgf000166_0001
Figure imgf000167_0001

Claims

C AIMS
1. A compound of formula (I):
Figure imgf000168_0001
or a pharmaceutically acceptable salt thereof for use in a method of therapy, wherein:
R2 is H or an optionally substituted Cι- 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 Cι_4 alkyl, or Y is -C(=0)NRN2-, where RN2 is selected from H, and optionally substituted Cι-7 alkyl or C5_2o aryl;
R3 is an optionally substituted C6 aryl group linked to a further optionally substituted Cβ 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 Cι-3 alkyiene group; and
R5 is either: (i) carboxy;
(ii) a group of formula (II) :
Figure imgf000168_0002
(iii) a group of formula (III) :
Figure imgf000169_0001
wherein R is optionally substituted Cι_7 alkyl, C5_o aryl or NRN3RN4, where RN3 and RN4 are independently selected from optionally substituted Cι-4 alkyl; (iv) tetrazol-5-yl .
2. The compound according to claim 1, wherein R2 is selected from H, methyl, CF3 or iso-propyl.
3. The compound according to claim 2, wherein R2 is methyl .
4. The compound according to any one of claims 1 to 3, wherein Y is -(CH2)n-X-.
5. The compound according to claim 4, wherein n is 1.
6. The compound according to either claim 4 or claim 5, wherein X is selected from 0, S and NH.
7. The compound according to claim 6, wherein X is NH.
8. The compounds according to any one of claims 1 to 3, wherein Y is -C(=0)NRN2-.
9. The compound according to claim 8, wherein RN2 is selected from H, and optionally substituted Cι_ alkyl.
10. The compound according to any one of the preceding claims, wherein the Cβ aryl groups of R3 are independently selected from those derived from benzene and heteroaryl groups, where the heteroatom or heteroatoms are nitrogen.
11. The compound according to claim 10, wherein the Ce aryl ggrroouuppss ooff RR33 aarree iinnddeeppeennddeennttllyy sseelleecctteedd ffrrom those derived from benzene, pyridine and 1, 3-pyrimidine ,
12. The compound according to any one of claims 1 to 11, wherein A is a single bond.
13. The compound according to any one of claims 1 to 11, wherein A is a Cι_3 alkyiene group.
14. The compound according to any one of the preceding claims, wherein R5 is either:
(i) a group of formula (II) :
Figure imgf000170_0001
; or
(ii) a group of formula (III) :
Figure imgf000170_0002
15. The compound according to claim 14, wherein R is selected from an optionally substituted C5-2o aryl group, and an optionally substituted C5-2o aryl-Cι_7 alkyl group.
16. A pharmaceutical composition comprising a compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier or diluent.
17. The use of according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of a condition alleviated by antagonism of an EP4 receptor.
18. The use according to claim 17, wherein the condition alleviated by antagonism of an EP4 receptor is a primary headache disorder.
19. The use according to claim 17, wherein the condition alleviated by antagonism of an EP4 receptor is migraines.
20. A compound of formula (I):
Figure imgf000171_0001
or a salt, solvate and chemically protected form thereof, wherein:
R2 is H or an optionally substituted Cι-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 Cι_ alkyl, or Y is -C(=0)NRN2-, where RN2 is selected from H, and optionally substituted Cχ_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 d_3 alkyiene group; and R5 is either:
(i) carboxy;
(ii) a group of formula (II) :
Figure imgf000172_0001
; or
(iii) a group of formula (III)
Figure imgf000172_0002
wherein R is optionally substituted Cι_7 alkyl, C5-20 aryl or NRN3RN4, where RN3 and RN4 are independently selected from optionally substituted Cι_4 alkyl; (iv) tetrazol-5-yl, except that when R2 is methyl, Y is -CH2-0- and R5 is carboxy or Cι_7 alkyl ester thereof, then R3 is not:
Figure imgf000172_0003
21. The compound according to claim 20, wherein R2 is selected from H, methyl, CF3 or iso-propyl.
22. The compound according to claim 21, wherein R2 is methyl .
23. The compound according to any one of claims 20 to 22, wherein Y is -(CH2)n-X-.
24. The compound according to claim 23, wherein n is 1.
25. The compound according to either claim 23 or claim 24, wherein X is selected from 0, S and NH.
26. The compound according to claim 25, wherein X is NH.
27. The compounds according to any one of claims 20 to 22, wherein Y is -C(=0)NRN2-.
28. The compound according to claim 27, wherein RN2 is selected from H, and optionally substituted Cι_4 alkyl.
29. The compound according to any one of claims 20 to 28, wherein the β aryl groups of R3 are independently selected from those derived from benzene and heteroaryl groups, where the heteroatom or heteroatoms are nitrogen.
30. The compound according to claim 29, wherein the Ce aryl groups of R3 are independently selected from those derived from benzene, pyridine and 1, 3-pyrimidine.
31. The compound according to any one of claims 20 to 30, wherein A is a single bond.
32. The compound according to any one of claims 20 to 30, wherein A is a Cι_3 alkyiene group.
33. The compound according to any one of claims 20 to 32, wherein R5 is either:
(i) a group of formula (II) :
Figure imgf000174_0001
( ii ) a group of formula ( III ) :
Figure imgf000174_0002
34. The compound according to claim 33, wherein R is selected from an optionally substituted C5_2o aryl group, and an optionally substituted C5_2o aryl-Cι_7 alkyl group.
PCT/GB2004/000347 2003-01-29 2004-01-29 Ep4 receptor antagonists WO2004067524A1 (en)

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US8513268B2 (en) 2005-04-11 2013-08-20 Novartis Ag 1H-quinazoline-2,4-diones processes for their production, pharmaceutical compositions, and treatment for epilepsy
US8012988B2 (en) 2005-04-11 2011-09-06 Novartis Ag N-(2,4-dioxo-6-(tetrahydrofuran-2-yl)-7-(trifluoromethyl)-1,4-dihydro-2H-quinazolin-3-yl)methanesulfonamide
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WO2008071736A1 (en) 2006-12-15 2008-06-19 Glaxo Group Limited Benzamide derivatives as ep4 receptor agonists
WO2009056582A1 (en) 2007-11-02 2009-05-07 Glaxo Group Limited Novel compounds
US8455668B2 (en) 2008-10-10 2013-06-04 University Of Science And Technology Of China Method for preparing hydroxymethylfurfural
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WO2011003300A1 (en) 2009-07-09 2011-01-13 中国科学技术大学 Method for preparing hydroxymethylfurfural
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WO2018162562A1 (en) 2017-03-10 2018-09-13 Bayer Pharma Aktiengesellschaft Use of an ep4 antagonist for the treatment of inflammatory pain
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US11325899B2 (en) 2017-05-18 2022-05-10 Idorsia Pharmaceuticals Ltd Benzofurane and benzothiophene derivatives as PGE2 receptor modulators
US11446298B2 (en) 2017-05-18 2022-09-20 Idorsia Pharmaceuticals Ltd Pyrimidine derivatives
US11712438B2 (en) 2017-05-18 2023-08-01 Idorsia Pharmaceuticals Ltd Phenyl derivatives as PGE2 receptor modulators
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