WO2012022776A1 - Substituted thiopenes or furans as estrogen receptor ligands - Google Patents

Abstract

The invention provides: a compound of Formula (I) or a pharmaceutically acceptable ester, amide, or salt thereof, including a salt of such an ester or amide, wherein A, B, R¹, R², R⁴, R⁵, R⁶ and R⁷ are as defined in the specification. The indention also provides the use of such compounds in the treatment or prophylaxis of a condition associated with a disease or disorder associated with estrogen receptor activity.

Description

SUBSTITUTED THIOPENES OR FURANS AS ESTROGEN RECEPTOR LIGANDS

Field of Invention

This invention relates to compounds which are estrogen reeeptor ligands and are preferably selective for the estrogen receptor β isoforrn, to methods of preparing such compounds and to methods for using such compounds in treatment of diseases related to the estrogen reeeptor such as depressi e disorders, anxiety disorders, Alzheimer's disease, cognitive disorders, osteoporosis, elevated blood triglyceride levels, atherosclerosis, endometriosis, urinary incontinence, autoimmune disease, and cancer of the lung, colon, breast, uterus and prostate.

Background of Invention

The estrogen reeeptor (BR) is a iigand activated mammalian transcription factor involved in the up and down regulation of gene expression. The natural hormone for the estrogen receptor is β-l / -estradiol (E2) and closely related metabolites. Binding of estradiol to the estrogen receptor causes a dimerization of the receptor and the dimer in turn binds to estrogen response elements (ERE's) on DNA. The ER/D A complex recruits other transcription factors responsible for the transcription of DNA downstream from the ERE into mRNA which is eventually translated into protein. Alternatively the interaction of ER with DNA may be indirect through the intermediacy of other transcription factors, most notably fos and jun. Since the expression of a large number of genes is regulated by the estrogen receptor and since the estrogen receptor is expressed in many cell types, modulation of the estrogen receptor through binding of either natural hormones or synthetic ER ligands can have profound effects on the physiology and pathophysiology of the organism.

Historically it has been believed there was only one estrogen receptor. However a second subtype (ER-β) has been discovered. While both the "classical" ER-a and the more recently discovered ER-β are widely distributed in different tissues, they nevertheless display markedly different eel! type and tissue distributions. Therefore -synthetic ligands which are either ER-a or ER-β selective may preserve the beneficial effects of estrogen while reducing the risk of .undesirable side effects.

Estrogens are critical for sexual development in females. In addition, estrogens play an important role in maintaining bone density, regulation of blood lipid levels, and appear to ha ve neuroprotective effects. Consequently decreased estrogen production in postmenopausal women is associated with a number of diseases such, as osteoporosis, atherosclerosis, depression and cognitive disorders. Conversely certain types of proliferative diseases such as breast and uterine cancer and endometriosis are stimulated by estrogens and therefore antiestrogens (i.e.. estrogen antagonists) have utility in the prevention and treatment of these types of disorders. The efficacy of the natural estrogen, 17fi¾-estradiol, for the treatment of various forms of depressive illness has also been demonstrated and it has been suggested thai the anti-depressant activity of estrogen may be mediated via regulation of tryptophan hydroxylase activity and subsequent serotonin synthesis (See, e.g., Lu Z, Shiaes T A, Ciindiah C, Dziennis S E, Lyl R E, Bethea C L, "Ovarian steroid action on tryptophan hydroxylase protein and serotonin compared to localization of ovarian steroid receptors in midbrain of guinea pigs." Endocrine 1 1 :257-267, 1999). The pieiotropie nature of natural estrogen precludes its widespread, more chronic use due to the increased risk of proliferative effects on breast, uterine and o varian tissues. The identification of the estrogen receptor, ΕΚβ, has provided a means by which, to identify more selective estrogen agents which have the desired anti-depressant activity in the absence of the proliferative effects which are mediated by ERa. Thus, it has been shown that therapeutic agents having ER -selectivity are potentially effective in the treatment of depression.

What is needed in the. art are compounds that can produce the same positive responses as estrogen replacement therapy without the negative side effects. Also needed are estrogen-like compounds that exert selective effects on different tissues of the body.

WO 2008/006626 discloses certain triphenyl modified 5-rnernbered heterocycles that show

antiproliferative effects and inhibitory effects on cyclooxygenases (COX- 1 and COX-2), and their use as anticancer and anti-inflammatory agents. US 6,835,745 discloses certain phenyl substituted thiophenes that are useful as estrogenic agents. J. Zimmerman and E. von Angerer, "Estrogenic and antiestrogenic activities of 2,4-diphenylfuran-based ligands of estrogen receptors a and β", J. Steroid Biochem. & Mol, Biol, J 04, 2007, 259-268 discloses certain 2,4-diphenylfura.n compounds having estrogen receptor modulator activity. The compounds of the present invention are ligands for estrogen receptors and as such may be useful for treatment or prevention of a variety of conditions related to estrogen functioning including bone loss, bone fractures, osteoporosis, cartilage degeneration, endometriosis, uterine fibroid disease, hot flashes, increased levels of LDL cholesterol, cardiovascular disease, impairment of cognitive functioning, age- related mild cognitive impairment, cerebral degenerative disorders, restenosis, gynecomastia, vascular smooth muscle cell proliferation, obesity, incontinence, anxiety, depression, perimenopansal depression, post-partum depression, premenstrual syndrome, manic depression, dementia, obsessive compulsive- behavior, attention deficit disorder, attention deficit hyperactivity disorder, sleep disorders, irritability, impukivity, anger management, hearing disorders, .multiple sclerosis, Parkinson's disease, Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis, spinal cord injury, stroke, autoimmune disease, inflammation, IBD, IBS, sexual dysfunction, hypertension, retinal degeneration, lung cancer, colon cancer, breast -cancer, uterus cancer, prostate cancer and c-holangiocarc inoma. Summary of the Invention

This invention provides a compound of formula (J) or a pharmaceutically acceptable ester, amide, or salt thereof, including a salt of such an ester or amide,

wherein one of A and B represents sulfur or oxygen, and the other of A and B represents C-R³;

R^l is selected from the group consisting of halogen, N(R^a)₂, C₂,.scycloalkyl, Cj^cycloalkylCi.* alkyl and 5-10 membered heteroeyelyl, wherein heterocyclyl group can be either unsubstituted or substituted with from 1 to 3 substituents, each substituent being independently selected from the group consisting of OR^A, halogen, cyano. nitro, ~C(0)C:.,₍aikyi, C_!-6aiky.l, C^aikenyl, C₂.Aalky.nyl, haloC_;,₆ alkyl, dihaloCV._calkyi and trihaloCi.._salkyl,'

R ^'; is selected from the group consi sting of halogen, cyano, nitro, OR ^A, N(R^b)₂, N(OH}₃, -CHO, -CH^ -OH, -CfO) ;,_;,aiky] optionally substituted with from I to 3 halogens, -S0₂C_Maikyl, -C(0)NH- OH_t -C(N¾)-N"OH, -C(CO_;H)- -OH, -C(0-C;_.aikyi)- li, -C{ H₂)- -NH_?, -NH-CCNlL^ -l, -NH-C(0)NH₂, - <;(-NH-CH₂CH₂-NH-), -S-CN, -S-C(NH₂)=NH, -S-C(NH₂)= -OH, -C0₂H,

-C¾-C0₂H, -CH(OH)CO,H, -C(0)C0₂H, SO_?H, -C¾SO_.,H, -C(0)N<R )₂, S0₂N(R^c)₂, -C(0)-C(0)- NH₂, -CH,NH-CONH₂, C^alkyl haloC,_-6alkyl, dihaloC^alkyl trihaloC_!-6alkyl, eyanoC=.₆alkyl, Ci^alkox Cj^alk l, C₂._f,alkenyl, Gj^alkynyl, C},_scycloalkyl, C_?.*cyeloalkyiCr.6 alkyl, phenyl, benzyl and 5-10 membered heterocyclyl wherein said phenyl, benzyl or heterocyclyl group can be either

unsubstituted -or substituted with from 1 to 3 substituents each substituent being selected from the group consisting of OR^'\ halogen, cyano, nitro. C_halky!, C^. alken l, C₂,₆alkyny!, haloC^_ftaikyL diha!oC<._¾alkyl and trihaloC:. (.alkyl;

11 is selected from the group, consisti g of hydrogen. C_halky!. C₂.Aalkenyl, Q^alkynyi. Qt-scycioalkyl , € ₂,.jiCyeloalk dC _t ^alkyl , halogen, benzyl and .5-10 membered heterocyclyl wherein said benzyl or heterocyclyl group can be either unsubstituted or substituted with from .1 to 3 substituents each substituent being selected from the group consisting of OR :\ halogen, cyano, nitro, C:_₆aikyi, Co-galkenyl,

C - j ilkyny!. haloC's^alkyl. dihaloCj^alkyl and trihaloC}__&alkyl; each of R^'!, R^'\ R" and R' is independently selected from the group consisting of hydrogen, OR^'\ halogen, cyano, nitro, C_halky], C₂._¾alkenyl, Cj^alkynyl, lialoC_t.«alkyl, dihaloCi^alkyl and trihaloCi-ealkyl; each R^A is independently selected from the group consisting of hydrogen, C₍._f>alkyl., C₂.₆alkenyl, C₂. ₆alkynyi, Ci.scyeloalkyi, C sGycloalkylCj^alkyl, phenyl, benzyl and 5-10 rnernbered beterocyclyl, each optionally substituted by from 1 to 3 halogen atoms; each R^b is independently selected^' from the group consisting of hydrogen, C_halky], C^alkeoyl, C ^alkynyi, Cvgcycloalkyl, C^cycloalkylCi-ealkyl, phenyl, benzyl and 5-10 rnernbered beterocyclyl, each optionally substituted by from 1 to 3 halogen atoms; and each R*^" is independently selected from the group consisting of hydrogen and C_halky!; with the proviso th t the compound of formula (J) is not:

3- amin.o-4-(4-hydroxyphenyl)-2-thiophenecai-boxyHc acid., methyl ester; or

4- (4-broTno-2,5-dirnethyl-3-thi.eny}-^'l ,2-benzenedioL

Compounds of the invention, have surprisingly been found to be ligands of the estrogen receptor. The compounds, accordingly have use in the treatment or prophylaxis of conditions associated with estrogen receptor activity. Detailed Description of Invention

The compounds of the invention may contain chiral (asymmetric) centers or the molecule as a whole may be chtral, The individual stereoisomers (enantiomers and diastereoisomers) and mixtures of these are within the scope of the present invention. Certain compounds of the invention contain an oxime group which may be present as the (E) or (Z) oxime isomer. The. individual (E) and (Z) oxime isomers and mixtures of these are -within the scope of the present invention. Throughout the specification, where the oxime structure is shown with a wavy line bond, this indicates either that a single isomer is present but the stereochemistry is unknown, or that a mixture of both isomers is present. The present invention provides compounds that are estrogen receptor iigands. The term "estrogen receptor ligand" as used herein is intended to cover any moiety which binds to an estrogen receptor. The ligand may act as an agonist, a partial agonist, an antagonist or a partial antagonist. The ligand may be ERj3 selective or display mixed ERa and I Rj3 activity. For example, the ligand may act both as an agonist or a partial agonist of BRb' and as an antagonist or a partial antagonist of ERa. Compounds of the present invention are preferably estrogen receptor Iigands that display ΒΚβ selecti ve agonisin.

In one embodiment of the invention, the invention provides a substituted thiophene compound of formula (la) or (lb) or a pharmaceutically acceptable ester, amide, or salt thereof, including a salt of such an ester or amide,

wherein R ¹ , R\ R', R⁴. R", R^b and R" are as defined above.

In another embodiment of the invention, the invention provides a substituted furan compound of formula (lc) or (Id) or a pharmaceutically acceptable ester, amide, or salt thereof, including a salt of such an ester or amide,

wherein R¹, R\ R^"\ R⁴, R\ R⁶ and R^' are as defined above. Preferred compounds of the invention include the group of compounds in which A represents S and B represents C-R'^! (compounds of formula (ifa) above), the group of corapounds in which A represents O and B represents C--R^! (compounds of formula (id) above), and the group of compounds in which B represents S, A represents C- ^"* (compounds of formula (la) above). The group of compounds in which A represents S and B represents C-R^"1 (compounds of formula (Ib) above) are particularly preferred.

Preferably R' is selected from the group consisting of Gt.$cycloalkyl, C^ycloalkylCt-e alkyl and 5-10 rnernbered heterocyclyl wherein said heterocyclyl group can either be unsubstituted or substituted, as above. More preferably, R^! is a 5- 10 rnernbered heterocyclyl that can either be unsubstituted or substituted as above.

When R' represents a heterocyclyl group, this group may be saturated or unsaturated, and may contain one or more O, N and/or S atoms. It is preferably 5- or 6-niembered; more preferably 5-membered. Suitable heterocyclyl groups include furyi thienyl, pyrroiyL pyrrolinyl, pyrrolidinyl, oxazoiy isoxazoivl, thiazolyl, isothi^'azolyl, imidazolyl, imidazolinyi, imidazolidine, pyrazolyl, pyrazoiinyi, pyrazolidiny! , pyridyi, morphoiinyi, and piperidyi, with pyrroly , isoxazoiyl, pyrazolyl and thienyl being a preferred heterocyclyl groups, and isoxazoiyl being a particularly preferred heterocyclyl group. Preferred

.substituents for a heterocyclyl group include 1 to 3, for example 1 or 2, substituents. each substituent being selected from the group consisting of OR'\ halogen, cyano, -C(0)Ci^alkyl, C_halky!, C;..:alkenyl, C;.4alkynyl, haloC:.4alkyi, dihaioCj.₄alkyl and trihaloCj ,ialkyl Especially preferred substituents are selected from halogen, cyano, C^aikyl (especially methyl), trihaloCj.₄alkyl (especially trifluoromethyt), -C(0)C).4alkyl, and GR^A in which R^A preferably represents a hydrogen atom or a C_t .4a.ikyl group. More especially preferred substituents are selected from halogen, cyano and C_halky] (especially methyl or et.hyi). Most especially preferred substituents are selected from cyano and methyl.

In one embodiment of the invention, R^' is selected from the group consisting of halogen, cyano, nitro, GR'\ N(R^B)j, N(OH)₂, -CHO, -CH-N-OH, -C(0)C_!-4aikyl optionally substituted with from 1 to 3 halogens, -SO .₄alkyl, -C(0)NH-OH, -C(N¾)-N-OH, -C(C0₂H)-N-OH, -C(0-C_t.,alkyi)-NH, -C( ¾.)-N-NH:_J, - H-C( H₂)- H, -NH-C(0)Ni k -N-C(-NH-CH₃CH NH-), -S-CN, -S-C( H₂)-NH, -S-C(NH₂)-N-OH, -C0₂H, -CH C0₂H, - CH(OH)CO_;H -CfO)C0₂H, SO,H, -CH₂S0₂H, -C(0)N(R^c)₂, S0₂N(R^c ₂, -C(0)-C(0)-NH₂, -CH₂NM-CO M₂, C alkyi, haloC,.₄aIkyJ, dihaloC^alkyi, trihaloC,.₄aikyl, cyanoCj . aikyl, Cmalko Ci^alkyk C_2-4alkenyl, C_2-4alkynyl, ·<¼. _scycloalkyl, CYgcycloalkylC .₄ alkyl , phenyl, benzyl and 5-1.0 rnernbered heterocyclyl wherein said phenyl, benzyl or heterocyclyl group can. be either unsubstituted or substituted with from I to 3 substituents each substituent being selected from the group consisting of OR'\ halogen, cyano, nitro. Ci. alkyi, C₂.₄alkenyl, Cj.₄alkynyl, haloC, ..₄alkyl, dihaloCi^alkyl and trihaloCi.₄alkyl. When IV represents a heterocyclyi group, this group may for example be one of the preferred groups; mentioned above for R^!. Preferred siibsiituents for a heterocyclyi, phenyl or benzyl group R"' include those mentioned above for a heterocyclyi group R^: . In a preferred embodiment of the invention, R* is selected from the group consisting of halogen, eyano, nitro, OR^A, N(R¾, N(OH¾, -CHO, -CH-N-OH, -C(0)C,.₄aikyl optionally substituted with from 1 to 3 halogens, -S0₂C_t..₄alkyl, -C(0)NH-OH, -CCNH₂)-N-OH, -CiC0₂H}===N-OH, -C(0-C alkyl)- H, -C(NH₂)-N- H,, --Nli-G{ Ii₂)- H, -NH-C(0)N¾, - -C{-NH-CHjCH NH-), -S-CN, -S-C(N¾)-NH, -S-C(NH₂)- -OH, -C(¾H, -CH C0₂H, ~CH(OH)C0₂H, -C(0)C0₂H, S0₃H, -CH₂S0₃H. -C(0)N(R°)₂, S0₂N(R^c)₂, -C(0)-C(0)-N¾ -CH₂ H-CONH₂, C_{! 4}alkyl, haloC_Malkyl, dihaloC^alkyl, trihaloC₃. alkyl, cyanoC alky}, C_i4alkoxyCi.₄alkyl. C₂.₄alkenyt, C?.4alkynyl. More preferably, R^''; is selected from the group consisting of halogen, cyano, nitro, OR^A, N(R^B)₂, N(OH)₂, -CHO. -CE N-OH, -C(0)NH-OH, -C(NH₂)-N-OH, -C(C0₂H)-N-OH. -C(0-C,.₄alkyl)-NH, -C(NH₂)-N-NH₂, -NH-C( H₂)-NH,

-NH-C(0)N1¾,••N= (-NH^»CH₂CH₂-NH-)_! -S-CN, -S C(NH₂)-NH, -S-CfNH₂)-N-OH, -Q¾H,

~CH₂-C0₂H, -CH(OH)C0₂R -C(0)C0₂H, SO_.?H, -CH₃SO_?H, -CiO)N(R^c)₂, S0₂N(R^c)₂, -C(O)-CiO)- ΝΗ·₂, ~CH₂NH-CONH₂. Most preferably, R² is selected from the group consisting of cyano, -CH=N-OH, -C(N¾)- -OH and -C(0)N(R^c)₂ (particularly -CON¾).

Preferably, R^J is selected from the group consisting of hydrogen, halogen, Cs._ftalkyl, Cj.₆alkenyl, C₂ alkynyl, C_3-¾cycloalky] and C^eycloaikylCj^alkyL More preferably, R* is selected from the. group consisting of hydrogen, halogen, C_halky!. Cvocycioaikyl and C3 _>cycloalkylCi..*alkyl (especially cyelopropylmethyl). Particularly preferred IV groups include hydrogen, halogen and eyelopropylmethyi.

Preferably each of R^' R\ R ^J and is selected from the group consisting of hydrogen, OR^A, halogen, eyano, C_halky!, for example methyl, haloC_Malkyl, for example chloro- or fiuoro-methyi, dihaloC.. ₄alkyl. for example dichloro- or difluoromethy], and trihaloC,..₄alkyi, for example trichioro- or trifluoromethyl. Preferably each of Κ R⁵, R^TJ and R^' is selected from the group consisting of hydrogen, OH, halogen, cyano, methyl, or triiluoromethyl. Most preferably each of R", R^"', R^" and R independently represents hydrogen -and/or halogen, especially fluorine. In one embodiment, R" and R° are halogen, especially fluorine, and R^" and R^' are hydrogen.

Unless otherwise stated, each R^A is preferably independently selected from the group consisting of hydrogen, C_halky), CS^alkenyl, C₂.₄alky.nyl, C.¾._{,cycloalkyl, phenyl and benzyl. Preferably each R' independently represents hydrogen or C|..₄alkyL especially methyl.

Unless otherwise stated, each R" is preferably independently selected from the group consisting of hydrogen and C;.₄alkyl, especially methyl. Unless^' otherwise- stated, each R* is preferably independentiy selected from the group consisting of hydrogen and Cj^aikyl, especially methyl.

For the avoidance of doubt, an embodiment or preferred aspect of any one feature of the compounds of the invention may be combined with any embodiment or preferred aspect of another feature of the compounds of the in vention to create a further embodiment.

Accordingly, in one preferred group of compounds of the invention, A represents S, B represents C-R^" and V represents hydrogen or halogen, in this embodiment, preferably represents eyano, -CH^~N-OH or -C( -¾)-^:N-01^:i, -C(0)NH_?.. In this embodiment, R¹ preferably represents a 5-10 mernbered heterocyclyl, wherein said heterocyciyl grou can be either unsubstituted or substituted with from 1 to 2 substituents, each substituent being independently selected from eyano or C;._¾alkyl. In this embodiment, each of R.\ R\ R" and R is preferably independently selected from hydrogen and halogen.

In another preferred group of compounds of the invention, A represents O, B represents C-R^" and R-' represents hydrogen or halogen. In this embodiment, R¹ preferably represents "C(NH--)^;:: --OH; R¹ preferably represents a 5-10 mernbered heterocyclyl, wherein said heterocyclyl group can be either unsubstituted or substituted with from 1 to 2 substituents, each substituent being independently selected from eyano or C_halky!; and each of R^J, R\ R^b and R^' is preferably independently selected from hydrogen and halogen.

In a further preferred group of compounds of the i n vention. B represents S, A represents C~R ~ and R^-> represents hydrogen or halogen, hi this embodiment, R^c preferably represents -C(NH₂)= -OF{ or -CH-N-OH; R^! preferably represents a 5-10 membered heterocyclyl, -wherein said heterocyciyl group can be either unsubstituted or substituted with from 1 to 2 substituents, each substituent being independently selected from eyano or C'-_;._f,aikyl; and each of R\ R^'\ R^u and R^' is preferably independently selected from hydrogen and halogen.

In yet -another preferred group of compounds of the invention, B represents S. A represents -C-R^'' and R^'~ represents hydrogen or halogen, in this embodiment, R^" preferably represents -C(NH₂)~ -OH or -CH-N-OI-I; R¹ preferably represents a 5- 10 mernbered heterocyclyl, wherein said heterocyclyl group can be either unsubstituted or substituted with from 1 to 2 substituents, each substituent being independently selected from eyano or C-^alkyl; and each of R", R^'\ R and R is preferably independently selected from hydrogen and halogen. Compounds of the formula (J) include, but are not limited to, the compounds specifically named in the Exampl e-s herein ,

In the Examples, the compound, names were generated in accordance with lU^'FAC by the ACD ^"Labs 8.0/name program, version 8.05^' and/or with ISIS DRAW Autonom 2000 and/or ChemBioDraw Ultra version 1.0.

Depending upo the substituents present in compounds of the formula 1, the compounds nay form esters, amides, carbamates anchor salts. Salts of compounds of formula (1) which are suitable for use in medicine are those wherein a counterfoil is pharmaceutically acceptable. However, salts having rton- pharroaceutically acceptable counterfoils are within the scope of the present invention, for example, for use as intermediates in the preparation of the compounds of formula (1) and their pharmaceutically acceptable salts, and physiologically functional derivatives. By the term "physiologically functional derivative" is meant a chemical derivative of a compound of formula (I) having the same physiological function as the free compound of formula (1), for example, by being convertible in the body thereto. Esters, amides and carbamates are examples of physiologically functional derivatives.

Suitable salts according to the invention include those formed with organic or inorganic acids or bases. In particular, suitable salts formed with acids according to the invention include those formed with mineral acids, strong organic carboxylic acids, such as alkanecarboxylie acids of 1 to 4 carbon atoms which are unsubstituted or substituted, for example, by halogen, such as saturated or unsaturated dicarboxylic acids, such as hydroxycarboxylie acids, such as amino acids, or with organic sulfonic acids, such as (C,- C₄)-al.kyl" or aryl -suifonic acids which are unsubstituted or substituted, for example by halogen.

Pharmaceutically acceptable acid addition salts include those formed from hydrochloric, hydrobromic, sulphuric, nitric, citric, tartaric, acetic, phosphoric, lactic, pyruvic, acetic, triiluoroacetic, succinic, perchloric, fumaric, maieie. glycolic, lactic, salicylic, oxaloacetic, methanesulfonic, ethanesiu ionic, p - loluenesulfonic, formic,, benzoic, malonic, napht.halene-2 -sulfonic, henzetiesuifonic, iset^'hionic, ascorbic, malic, phthalic. aspartic, and glutamic acids, lysine and arginme. Other acids such as oxalic, while not in themselves pharmaceutically acceptable, may be useful as intermediates in obtaining the compounds of the invention and their pharmaceutical acceptable acid addition salts.

Pharmaceutically acceptable base salts include ammonium salts, alkali metal salts, for example those of potassium and sodium, alkaline earth metal salts, for example those of calcium and magnesium, and salts with organic bases, for example dicyclohexyla ine, N-methyl-D-glueomine, rnorpholine, ^'

thiomorpholine, piperidine, pyrrolidine, a mono-, di- or tri-lower alkylarnine, for example ethyl-, ten-butyl-, diethyl-, diisopropyl-, triethyl-, tributyl- or dimethyl -prop lamine, or a mono-, di- or trihydroxy lower alkyla iine, for example mono-, di- or triethanolamine. Corresponding internal salts may furthermore be formed.

Compounds of formula (I) may have an appropriate group converted to an ester, an amide or a carbamate. Thus typical ester and amide groups formed from an acid group in the compound of the formula I include -COOR^B, "CONR 2, -S0₂OR⁸, or -S0₂N(R^B)₂, while typical ester and amide and carbamate groups formed from an -OH or -NHR⁸ group in the compound of the .fonrrola 1 include ~OC(0)R^B, ~NR C(0)R^r\ -NR^BC0₂R^B -OS0₂R^B and - R^BSO R⁸, where R^B has one of the meanings given above. Those skilled in the art of organic chemistry will appreciate that many organic compounds can form complexes with solvents in which they are reacted or from which they are precipitated or crystallized. These complexes are known as "solvates". For example, a complex with water is known as a "hydrate". Solvates, such as hydrates, exist when the drug substance incorporates solvent, such as water, in the crystal lattice in either stoichiometric or non-stoichiornetric amounts. Drug substances are routinely screened for the existence of hydrates since these may be encoun tered at any stage of the drug manufacturing process or upon storage of the drug substance or dosage form. Solvates are described in S. Bym et ah Pharmaceutical Research 12(7), 1 995, 954-954, and Water-insoluble Drug Formulation, 2^nd ed. R. Liu, CRC Press, page 553, which are incorporated herein by reference. Accordingly, it will be understood by the skilled person that the compounds of formula (I), as well as esters, amides, carbamates and/or salts thereof may therefore be present in the form of solvates. Solvates of compounds of formula (1) which are suitable for use in medicine are those wherein the associated solvent is pharmaceutically acceptable. For example, a hydrate is an example of a pharmaceutically acceptable sol vate. However, solvates having non-pharaiaceutically acceptable associated solvents may find use as intermediates in the preparation of the compounds of formula (1) and their pharmaceutically acceptable esters, amides, carbamates and/or salts thereof.

A compound which, upon administration to the recipient, is capable of being converted into a compound of formula (I) as described above, or an active metabolite or residue thereof, is known as a "^'prodrug^". A prodrug may, for example, be converted within the body, e. g. by hydrolysis in the blood, into its active form that has medical effects. Pharmaceutical acceptable prodrugs are described in T. Higuchi and V.

Stella, Prodrugs as Novel Delivery Systems, Vol. 14 of the A. C. S. Symposium Series (1976); "Design of Prodrugs" ed. H. Bundgaard, Elsevier, 1 85; and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergarnon Press. 1.98?, which are incorporated herein by reference.

The following definitions apply to the terms as used throughout this specification, unless otherwise limited in specific instances. As used herein, the term "aikyi" means both straight and branched chain saturated hydrocarbon groups. Examples of aikyi groups include methyl, ethyl, n-propyl, iso-propyl, n-butyl, i-butyi. i-butyi. sec-butyl, peatyi and hexyl groups. Among uribranched aikyi groups, there are preferred methyl, ethyl, n-propyl, iso-propyl, n-butyl groups. Among branched aikyi groups, there may be mentioned† -butyl, i-buty , 1 - ethylpropyi and 1 -ethyibutyl groups.

As used herein, the term "alkoxy" means the group O-alkyi, where "aikyi" is used as described above. Examples of alkoxy groups include methoxy and ethoxy groups. Other examples include propoxy and butoxy.

As used herein, the term "alkenyi" means both straight and branched chain unsaturated hydrocarbon groups with at least one carbon carbon double bond. Examples of alkenyi groups include ethenyl.

propenyl, butenyl, pentenyl and hexenyl. Preferred alkenyi groups include ethenyl 1 - propenyl and 2- propenyl .

As used herein, the term "alkynyf means both straight and branched chain unsaturated hydrocarbon groups with at least one carbon carbon triple bond. Examples of aikynyf groups include eihynyl, propynyl. buiynyl, pentynyi and hexynyl. Preferred -alkynyl groups inciude eihynyl 1 - propynyl and 2- propy nyl .

As used herein, the term "cycloalkyi" means a saturated group in a ring system. A cycloalkyl group can be monocyclic or bieyc!ie. A bicyciic group may. for example, be fused or bridged. Examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl and cyelopentyl. Other examples of monocyclic cycloalkyl groups are cyclohexyi, cycioheptyl and cyclooctyl. Examples of bicyciic cycloalkyl groups include bicyclo- [2. 2,l hept-2-yl. Preferably, the cycloalkyi group is monocyclic.

As used herein., the term "aryl" means a monocyclic or bicyciic aromatic carbocyelic group. Examples of aryl groups include phenyl and naphthyl. A naphihyi group may be attached through the 1 or the 2 position, in a bicyciic aromatic group, one of the rings may, for example, be partially saturated.

Examples of such groups include indanyl and ietrahydronaphthyl. Specifically, the term C i aryl is used herein to^' mean a group comprising from 5 to 10 carbon atoms in a monocyclic or bicyciic aromatic group. A particularly preferred <¾.ιο aryl group is phenyl.

A used herein, the term "halogen" means fluorine, chlorine, bromine or iodine. Fluorine, chlorine and bromine are particularly preferred. As used herein, the term "haloaikyl" means an alkyl group having a halogen siibstituent, the terms "alkyl" and "halogen" being understood to have the meanings outlined above. Similarly, the term "dihaloalkyi" means an alkyl group having two halogen substituents and the term "triha!oalkyi" means an alkyl group ha ving three halogen substituents. Examples of haloaikyl groups include ftuoromethyl, chlorornemyi, bromomethyi, fhioromethyl, fiuoropropyl and fiuorobutyl groups; examples of dihaloalkyi groups include di fhioromethyl and difl oroethyl groups; examples of triihaloaikyl groups include trifluoromethyl and triiluoroetbyl groups.

As used herein, the term "heterocyclyi" means an aromatic or a non-aromatic cyclic group of carbon atoms wherein from one to three of the carbon atoms is/are replaced by one or more heteroatoms independently selected from nitrogen, oxygen or sulfur. A heterocyclyi group may. for example, be monocyclic or bicyclie. In a bicyciic heterocyclyi group there may be one or more heteroatoms in each ring, or only in one of the rings. A lieteroatom is preferably O or , Heterocyclyi groups containing a suitable nitrogen atom include the corresponding ^"N-oxides.

Examples of monocyclic non-aromatic heterocyclyi groups ( also referred to as monocyclic

heterocycloalkyl rings) include aziridinyL azetklinyl, pyrrolklinyl, imidazoiidinyl, pyrazolidinyi.

piperidinvl. piperazinyl, teirahydroiiiranyi, tetrahydropyranyl, morpholiny!. thiomorpholinyl and azepanyl.

Examples of bicyciic heterocyclyi groups in which one of the rings is non-aromatic include

dihydrobenzofuranyl, indanyl, indolin l, isoindolinyl, (etnihydroisocjuinolinyl. tetrahydroqninolyi and bcnzoazepanyl . Examples of monocyclic aromatic heterocyclyi groups (also referred to as monocyclic heteroaryi groups) include furanyl, ihienyl. pyrrolyl, oxazolyl, thiazolyl, imidazoiyl, oxadiazolyl, thiadiazolyl, pyridyl, triazolyh triazinyl, pyridazyl, isothiazolyl, isoxazolyl, pyraz.ir.yl, pyrazolyl and pyrimidinyl,

Rxaraples of bicyciic aromatic heterocyclyi groups (also referred to as bicyclie heteroaryi groups) include quinoxalinyl. quinazolinyl, pyridopyrazinyl, benzoxazolyi. be zothiophenyh benzimidazol l, naphthyridinyl, qitinolmyl. henzolYsranyl. indolyl, benzothiazolyl, oxazo!yi[4,5 i]pyridiyl,

pyridopyrsmidinyl, isoquinolmyl and benzodroxazoie.

Examples of preferred heterocycl i groups include piperidinvl , te!rahydrofuranyl , tetrahydropyranyl , pyridyl, pyrimidinyl and indolyl. Preferred heterocyclyi groups also include thienyl, thiazolyl, furanyl. pyrazolyl, pyrrolyl, isoxazolyl and imidazoiyl As used herein the term "cycloalkylaMcyP' means a group eycloalky -alkyl- attached through the alkyi group, "cyeloalkyl"^' and "aikyF being understood to have the meanings outlined above.

As mentioned above, the compounds of the in vention have activity as estrogen receptor ligands. The compounds of the invention have activity as estrogen receptor modulators, and may be agonists, partial agonists, antagonists, or partial antagonists of the estrogen receptor. Particularly preferred compounds of the invention have acti vity as an agonist or a partial agonist of ERj^'3. Preferred compounds of this type are selective agonists of the estrogen receptor-beta (ERJJ). The compounds of the invention may thus be used in the treatment of diseases or disorders associated with estrogen receptor activity. In particular, the compounds of the invention that axe agonists or partiai agonists of the estrogen receptor may be used in the treatment of diseases or disorders for which selective agonists or partiai agonists of the estrogen receptor are indicated. The compounds of the invention that are antagonists or partial antagonists of the estrogen receptor may be used in the treatment of diseases or disorders for which selective antagonists or partial antagonists of the estrogen receptor are indicated.

Clinical conditions for which an agonist or partial agonist is indicated include, but are not limited to, bone loss, bone fractures, osteoporosis, cartilage degeneration, endometriosis, uterine fibroid disease, hot flashes, increased le vels of LDL cholesterol, cardiovascular disease, impairment of cognitive functioning, cerebral degenerative disorders, restenosis, gynecomastia, vascular smooth muscle cell proliferation, obesity, incontinence, anxiety, depression, autoimmune disease, inflammation, 1BD, IBS, .sexual dysfunction, hypertension, retinal degeneration, and lung, colon, breast, uterus, and prostate, cancer, and/or disorders related to estrogen functioning. The compounds of the invention find particular -application in the treatment or prophylaxi of the following: bone loss, bone fractures, osteoporosis, cartilage degeneration, endometriosis, uterine fibroid disease, hot flushes, increased levels of LDL cholesterol, cardiovascular disease, impairment of cognitive functioning, age-related mild cognitive impairment, cerebral degenerative disorders, restenosis, gynecomastia, vascular smooth muscle cell proliferation, obesity, incontinence, anxiety, depression, perimenopausal depression, post-partum depression, premenstrual syndrome, manic depression, dementia, obsessive compulsive beha vior, attention deficit disorder, attention deficit hyperactivity disorder, sleep disorders, irritability, irnpulsivity, anger management, hearing disorders, multiple sclerosis,. Parkinson's disease, Alzheimer^'s disease, Huntington's disease, amyotrophic lateral sclerosis, spinal cord injury, stroke, autoimmune disease, inflammation. TBD. IBS, sexual dysfunction, hypertension, retinal degeneration, lung cancer, colon cancer, breast cancer, uterus cancer, prostate cancer, the bile duct cancer form named cholangiocarcinoma, benign prostatic hyperplasia, lower urinary tract symptoms, overactive bladder, interstitial cystitis, painful bladder symptoms, vaginal atrophy, wound healing, chronic pain, sepsis, inflammatory and neuropathic pain, ovarian cancer, melanoma, lymphoma, atherosclerosis, left ventricular hypertrophy, congestive heart failure, mesothelioma, gallbladder cancer and extra-hepatic cholangiocarcinoma. In one embodiment of the invention, the present compounds finds particular application in the treat ment or prophylaxis of depression, perimenopausai depression, post-partum depression, premenstrual syndrome and manic depression.

The treatment or prophylaxis of hot flashes (or hot (lushes) in males, is preferable for patients that has had an androgen ablation for treatment of prostate cancer.

The phrase "depression" includes but is not limited to, major depressive disorder, dysthymic disorder, bipolar disorder, cyclothymic disorder, mood disorder due to a general medical condition, substance- induced mood misorder, seasonal affective disorder (SAD), postpartum depression and premenstrual dysphoric disorder.

The invention also provides a method for the treatment or prophylaxis of a condition in a mammal mediated by an estrogen receptor, which comprises administering to (he mammal a therapeutically effective amount of a compound according to the invention. Clinical conditions mediated by an estrogen receptor that, may be treated by the method of the invention are preferably those described above.

The invention also provides the use of a compound according to the invention, for the manufacture of a medicament for the treatment or prophylaxi of a condition mediated by an estrogen receptor. Clinical conditions mediated by an estrogen receptor that may be treated, by the- method -of the invention are preferably those described above.

The amount of active ingredient which is required to achieve a therapeutic effect will, of course, vary with the particular compound, the route of administration, the subject under treatment, including the type, species, age, weight., sex, and medical condition of the subject and the renal and hepatic function of the subject, and the particular -disorder or disease being treated, as well as its severity. An ordinarily skilled physician, veterinarian or clinician can readily determine and prescribe the effective amount of the drug required to prevent, counter or arrest the progress of the condition.

Oral dosages of the present invention, when used for the indicated effects, will range between about 0.01 ng per kg of body weight per day (mg/kg/day) to about 1 00 mg/kg/day, preferably 0.01 mg per kg of body weight per day (mg/kg/dayj to 10 mg/kg/day, and most, preferably 0.1 to 5.0 mg/kg/day, for adult humans. For oral administration, the compositions are preferably provided in the form of tablets or other forms of presentation provided in discrete units containing 0.01 , 0.05, 0.1 , 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100. and 500 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. A medicament typically contains from about 0.01 mg to about 500 mg of the active ingredient, preferably from about 1 mg to about 100 rng of active ingredient. Intravenously, the most preferred doses will range from about 0.1 to about 10 mg kg/minute during a constant rate infusion. Advantageously, compounds of the present invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three or four times daily. Furthermore, preferred compounds tor the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using those forms {^^'transdermal skin patches well known to those of ordinary skill in the art. To be administered in the form of a transdermal delivery system, the dosage administration will, of course, be continuous rather titan intermittent throughout the dosage regimen.

While it is possible for the active ingredient to be administered alone, it is preferable for it to be present in a pharmaceutical formulation or composition. Accordingly, the invention provides a pharmaceutical formulation comprising a compound according to the invention, and a pharmaceutically acceptable diluent, excipi^'ent or carrier (collectively referred to herein as "carrier" .materials). Pharmaceutical compositions of the in vention may take the form of a pharmaceutical formulation as described below. The pharmaceutical formulations according to the invention include those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous [bolus or infusion], and intraarticular), inhalation (including fine particle dusts or mists which may be generated by means of various types of metered does pressurized aerosols), nebulizers or insufflators, rectal, intraperitoneal and topical

( including dermal, buccal, sublingual, and intraocular) administration, although the most suitable route may depend upon, for example, the condition and disorder of the recipient.

The formulation may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing the active ingredient into association 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 into the desired formulation.

Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets, pills or tablets each containing a predeteitmned amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid, or a non-aqueous liquid, for example as elixirs, tinctures, sus ensions or syrups; or as an oil-m-water liquid emulsion or a water-m-oil liquid emulsion. The active ingredient may also be presented as a bolus, electuary or paste.

A tablet may be made by compression or moulding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free- flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, lubricating, surface active or dispersing agent. Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein. The present compounds can, for example, be administered in a farm suitable for immediate- release or extended release. Immediate release or extended release ca be achieved by the use of suitable pharmaceutical compositions comprising the present compounds, or, particularly in the case of extended release, by the use of devices such as subcutaneous implants or osmotic pumps. The present compounds can also be administered liposomaily.

Exemplary compositions for oral administration include suspensions which can contain, for example, microcrystalline cellulose for imparting bulk, aiginic acid or sodium alginate as -a suspending agent, methylceliulose as a viscosity enhancer, and sweeteners or flavoring agents such as those known in the art; and immediate release tablets which can contain, for example, microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate, calcium sulfate, sorbitol, glucose and/or lactose and/or other exeipients, binders, extenders, disintegrants, diluents and lubricants such as those known in the art.

Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, cor sweeteners, natural and synthetic gums such as acacia, tragacantli or sodium alginate, carboxymethyleeHulose, polyethylene glycol, waxes and the like. Disintegrators include without limitation starch, methylceliulose, agar, bentonite, xanthan gum and the like. The compounds of formula (1) can also be- delivered through the oral cavity by sublingual and/or buccal administration. Molded tablets, compressed tablets Or freeze - dried tablets are exemplary forms which may be used. Exemplary compositions include those formulating the present compound(s) with fast dissolving diluents such as manni tol, lactose, sucrose and/or cyclodextrins. Also included in such formulations may be high molecular weight exeipients such as celluloses (avicel) or polyethylene glycols (PEG). Such formulations can also include -an excipient to aid mucosal adhesion such as hydroxy propyl cellulose (HPC), hydroxy propyl methyl cellulose (HPMC), sodium carboxy methyl cellulos (SCMC), maleic anhydride copolymer (e.g., Gantrez), and agents to control release such as poiyacrylic copolymer (e.g. Carbopol 934). Lubricants, glidants, flavors, coloring agents and stabilizers may also be added for ease of fabrication and use. Lubricants used in these dosage forms include sodium o!eate, -sodium stearate, magnesium stearate, sodium beuzoate, sodium acetate, sodium chloride and the like. For oral administration in liquid form, the oral drug components can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as etbanol, glycerol, water, and the like.

The compounds of the present invention can also be administered in the form of liposome deli ery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles, Liposomes can be formed from a variety of phospholipids, 1 ,2-dipalmitoyl-phosphatidylchoiine, phosphatidyl ethanolamine (eephaiine), or phosphatidylcholine (lecithin).

Formulations for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The formulations may be presented in unit-dose or muiti -dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophiiised) condition requiring only the addition of the sterile liquid carrier, for example saline or water-for-injeetion. immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described. Exemplary compositions for parenteral administration include injectable solutions or suspensions which can contain, for example, suitable non-toxic, parenteral ly acceptable diluents or solvents, such as mannitol, 1 ,3- butanedioi, water. Ringer's solution, an isotonic sodium chloride solution, or other suitable dispersing or wetting and suspending agents, including synthetic mono- or diglycerides, and fatty acids, including oleic acid, or Cremaphor.

Exemplary compositions for nasal, aerosol or inhalation administration include solutions in saline, which can -contain, for example, benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, and/or other soiuhi!izing or dispersing agents such as those known in the art.

Formulations for rectal administration may be presented as a suppository with the usual carriers such as cocoa butter, synthetic glyceride esters or polyethylene glycol. Such carriers are typically solid at ordinary temperatures, but liquefy and/or dissolve in the rectal cavity to release the drug.

Formulations for topical administration in the mouth, for example huccally or sublinguaily, include lozenges comprising the active ingredient in a flavoured basis such as sucrose and acacia or tragacanth, and pastilles comprising the active ingredient in a basis such as gelatin and glycerine or sucrose and acacia. Exemplary .compositions for topical administration include a topical carrier such as Piastibase (mineral oil gelled with polyethylene). Preferred unit dosage formulations are those containing an effect e dose, as hereinbefore recited, or an appropriate fraction thereof, of the active ingredient.

It should be understood that in addition to the ingredients particularly mentioned above, the formulations of this invention may include other agents conventional in the art having regard to the type of formulation in question_., for example those suitable for oral administration may include flavouring agents.

Whilst a compound of the invention may be used as the sole acti ve ingredient in a medicament, it is also possible for the compound to be used in combination with one or more iurther active agents. Such further active agents may be further compounds according to the invention, or they may be different therapeutic agents, for exampl an antidepressant, an anxiolytic, an anti-psychotic, an agent useful in the prevention or treatment of osteoporosis, an agent useful in the prevention or treatment of cancer or other

pharmaceutically active materia]. For example, the compounds of the instant invention may be effectively administered in combination with effecti e amounts of other agents such as an antidepressant, an anxiolytic, a anti-psychotic, an organic bisphosphonate or a cathepsin K inhibitor. In one preferred embodiment, the compounds of the invention may be effectively administered in combination with an effective amount of an antidepressant . Nonlimiting examples of antidepressants include noradrenal ine reuptake inhibitors (MRI), selective serotonin reuptake inhibitors, monoamine oxidase inhibitors, tricyclic antidepressants (TCA), dopamine reuptake inhibitors (DRI), opioids, selective sere-tonic reuptake enhancers, tetracyclic antidepressants, reversible inhibitors of monoamine oxidase, melatonin, agonists, serotonin and noradrenaline reuptake inhibitors (SNRI), corticotropin releasing factor antagonists, a- adrenoreceptor antagonists, 5Ηϊί receptor agonists and antagonists, lithium and atypical antipsychotics. Examples of antidepressants of the SSRI class include Fluoxetine and Sertraline: examples of antidepressants of the S RI class Venlafaxine, Citaloprani, Paroxetine, Escitaioprarn, Fluvoxamine; examples of antidepressants of the SNRI class include Duloxetine; examples of antidepressants of the DRT and NRI -classes- include Bupropion; examples of antidepressants of the TCA class include

Arnitriptyline and Dothiepin (Dosulepin ). Examples of atypical antipsychotics include: Clozapine, Olanzapine, Risperidone, Quetiapine, Ziprasidone and Dopamine partial agonists. Nonlimiting examples of anxiolytics include benzodiazepines and non-heivzodiazapines. Examples of benzodiazepines include iorazepam, alprazolam, and diazepam. Examples of non-benzodiazapines include Buspirone (Buspar ), barbi turates and meprobamate. One or more of those further anti-depressants may be used in ^■combination.

Examples -of anti-cancer agents include iamoxiferie or an arornatase inhibitor, used in treatment of breast cancer. In the event, that hot. flashes are induced by a particular treatment, a compound of the invention may be used in combination therapy with the agent of such treatment. Nonlimiting examples of such combination treatment therapies include: a compound of the invention in combination with ta.mosi.fene treatment of breast cancer, a compound of the invention in combination with aromatase inhibitor treatment of breast cancer or a compound of the invention in combination with raloxifene treatment of osteoporosis.

Nonlimiting examples of above-mentioned organic bisphosphonates include adendronate, clodronate, etidronate, ibandronate, incadronate, roinodronate, neridronate, risedronate, piridronate, pamidronate, tiludronate. zoledronate, pharmaceutically acceptable salts or esters thereof, and mixtures thereof.

Preferred organic biphosphonates include alendronate and pharmaceutically acceptable salts and mixtures thereof. Most preferred, is alendronate monosodiurn trihydrate.

The precise dosage of the bisphosphonate will van/ with the dosing schedule, the oral potency of the particular bisphosphonate chosen, the age, size, sex and condition of the mammal or human, the nature and severity of the disorder to be treated, and other relevant medical and physical factors. Thus, a precise pharmaceutically effective amount cannot be specified in advance and can be readily detennined by the caregiver or clinician. An appropriate amount can be determined by routine experimentation from animal models and human clinical st udies. Generally, an appropriate amount of bisphosphonate is chosen to obtain a bone resorption inhibiting effect, i.e. a bone resorption inhibiting amount of the bisphonsphonate is administered. For humans, an effective oral dose of bisphosphonate is typically from about 1.5 to about 6000 pg kg of body weight and. preferably about 10 to about 2000 pg/kg of body weight.

For human oral compositions comprising alendronate, pharmaceutically acceptable salts thereof, or pharmaceutically acceptable derivatives thereof, a unit dosage typically comprises from about 8.75 mg to about 140 mg of the alendronate compound, on an alendronic acid active weight basis, i.e. on the basis of the corresponding acid.

The compounds of the present invention can be used in combination with other agents useful for treating estrogen-mediated conditions. The individual components -of such combinations can be administered separately at different times during the, course of therapy or concurrently in divided or single combination forms. The present invention is therefore to be understood as embracing all such regimes of simultaneous or alternating treatment and the term "administering" is to be interpreted accordingly. It will be understood that the scope of combinations of the compounds of thi invention with other agents useful for treating estrogen-mediated conditions includes in principle any combination with any pharmaceutical composition useful for treating disorders related to estrogen functioning. The above other therapeutic agents, when employed in combination with the compounds of the present invention, may be used, tor example, in those amounts indicated in the Physicians' Desk Reference (PDR) or as otherwise, determined by one of ordinary skill in the art. Where the compounds of the invention are utilized in combination with one or more other therapeutic agent(s), either concurrently or sequentially, the following combination ratios and dosage ranges are preferred:

When combined with an antidepressant, an anxiolytic, an anti-psychotic, an organic bisphosphonate or a cathepsin K inhibitor, the compounds of formula (1) may be employed in a weight ratio to the additional agent within the range ^' from about. 10: 1 to about 1 : 10.

The compounds of the invention as described above also find use, optionally in labelled form, as a diagnostic agent for the diagnosis of conditions associated with malfunction of the estrogen receptor. For example, such a compound may be radioactively labelled.

The compounds of the invention as described above, optionally in labelled form, also find use as a reference compound in methods of discovering other agonists, partial agonists, antagonists or partial antagonists of the estrogen receptor. Thus, the invention provides a method of discovering a ligand of the estrogen receptor which comprises use of a compound of the in vention or a compound of the invention in labelled form, as a reference compound. For example, such a method may involve a competitive binding experiment in which binding of a compound of the invention to the estrogen receptor is reduced by the presence of a further compound which has estrogen receptor-binding characteristics, for example stronger estrogen receptor-binding characteristics than the compound of the invention in question.

Numerous synthetic routes to the compounds of the present invention can be devised by any person skilled in the art and the possible synthetic routes described below do not limit the invention. Many methods exist in the literature for the synthesis of substituted thiophenes and furans, for example: WO 2008/006626 includes methods of sythesising both substituted thiophenes and furans, US 6,835,745 includes methods of sythesising certain phenyl substituted thiophenes, and J. Zimmerman and E. von Angerer, "Estrogenic and antiestrogenic -activities of 2,4-diphenylfuran -based ligands of estrogen receptors a and β^*\ J. Steroid Biochern, & Mol. Biol,, 104, 2007, 259-268 describes includes methods of sythesising 2,4-diphenylfuran compounds. A number of possible synthetic routes are shown

schematically below. Where appropriate, any initially produced compound according to the invention can be con verted into another compound according to the invention by known methods. General method I

The following general method can be used to prepare compounds of formula (I) wherein A is sulphur or oxygen, B is C-R\ and ll² is cyano, -CHO, -CH-N-OH, -C(NH₂)=N-OH or -C(0)N¾.

fa) IDA, R³Br {THF)_; (b) LDA, DMF (THF); (o) Pd(PPh₃)_4: R B(OH)₂, K₂C0₃ (toluene/BOH/water): (d)

Pd( Ph₃¾,4-hyclroxyphenylborsr)1c add, ₂C0₃ toiuene EtOH/water): (s) NH_£OH*HCI, py (EtOH); f)

Ac₂0: (g) B₂OH {DMSO/ ateri

General Method I as shown in the reaction scheme above was used for the synthesis of the following Examples: 1 , 2, 5-26.. Full experimental details of the individual steps of General Method .1 are described in intermediate 1 (step (a.) of the scheme above). Example 1 (steps (b)-(e) of the scheme above) and Example 2 (steps (f) and (g) of the scheme above).

General method II

The following general method can be used to prepare compounds of formula (I) wherein A is G-R \ B is sulphur or oxygen, and R² is cyano, -CHO, -CH-N-OH, -C(NH₃)- -OH or -C(0)N¾.

(a) DI.BAL-H -78 °C: (DCM); (b) TRAP, NMO (DCM); (c) Pd(PPh₃)_4i 4-hydroxypf»enyiboronic acid,

K₂C0₃, (toluene/EtOH/water); ( ) Pd(PPh₃)₄, R -boronic acid, K₂C0₃ (toiuene EtOH/ ater); (e)

NH_?OH*HCi, py (EtQH); (f) Ac_?0; (g) NH₂OH (DMSO/vvaten

General Method Π as shown in the reaction scheme above was used for the synthesis of Examples 3 and 4, Full experimental details of the individual steps of General Method 11 are described in Example 3 (steps (a)-(e) of the scheme above) and Example 4 (steps (t) and (g) of the scheme above).

General method 111

The following general method can be used to prepare compounds of formula (1) wherein A is sulphur or oxygen, B i C~R \ Rr is cvano or -C(N¾)~ -OH, and R^'' is chloro or bromo.

(a) Trm-!ethoxymethane, trifluoroacetic acid, MeOH: (b) 1. NBS or NCS, MeCN 2. HCI ; (c) NH₂OH\HCI, Pyridine, DCM: (d) Ac₂0; (e) BBr₃. DCM: (f) NH₂OH, DMSO.

General Method ill as shown in the reaction scheme above was used for the synthesis of Examples 2 to 30.

Genera! Method IV

The following general method can be used to prepare compounds of formula (1) wherein Λ is sulphur, B is C-R- , R² is cyano or ~C(NH_;i)-N-OH, R- is H or chloro, and R* is chloro.

(a) R '-tributyisiannyl, PdCI_?.(PP ₃}₂, dioxane; (b) Pd(PPh₃)₄. K₂C0_3! d^'ioxane/H₂0;

(c) NGS, DMF; (ci) 1.. BBr₃, DGM; 2 NH₂OH (aq) MeOH.

General Method IV as shown in the reaction scheme -above was used for the synthesis of Examples 31 to 34.

Intermediate 1

3,4 -Dihromo-2-(ey lopropylmethyl)t!»ophe«e

Di- -propy{avnine (637 itL, 4.55 mmol) was dissolved in THE ( i 5 ml) and cooled to °C. 1 eq. « -BuLi (4.55 mmol) was added and the mixture was stirred for 15 min. T his solution was added to 2,3- dibromoihiophene ( 1.0 g, 4.13 mmol) in TMF (8 ml) that was cooled to -78C. After 15 rain (b.romomethyi)cyelopropane (2.79 g, 20.7 mino!) was added and the mixture was allowed to warm io room temperature.. DCM and iM HCl were added and the phases were separated. After flash

chromatographic separation 3_s4-dibronx>-2-(cyc]opropylmethyl}thiophene 640 nig, (2, 16 mmol) was obtained.

Intermediate- 1 was used in the synthesis of Examples 10 and 11.

The following Examples illustrate the invention.

Example 1

3-(3,5-dimethylisoxazoI-4- I)-4~(4-h droxyphenyl)thiophene-2-carba.UIehyde o ime (El)

(a) IDA, DMF (THF); (b) Pd(PP ₃}. _: 3,:>-dimethyiisoxazoi-4-ylboron!C acid,

rCCO¾ (toluene/EtQH/water); (c) d(PPh¾ ₄.4- ydroxvphenylboronic acid,

K2CO3 toluene/EtOH/water); {d)^' NH₂QH*HCi, py (EtOH)

Scheme 2

Step (a): DW-propylamine ( 159 L., 1.14 mmol) was dissolved in THF (4 ml) and cooled to O^'-^'C. .1 eq, «.- Buli ( 1 .14 mmol) was added and the mixture was stirred for 1 5 mm. This solution was added to 2,3- dibromolhiopbene (250 mg, 1.03 mmol) in THF (6 ml) thai was cooled to -78C. After 15 mm DMF ( 1 60LIL, 2.0? mmol) was added and the mixture was allowed to warm to room temperature. DCM and 1 M HCl were added and the phases were separated.. After flash chromatographic separation

3.4-dibromothiophene-2-carbakkhyd.e ( 130 mg, 0.47 mmol) was obtained. Step (b): 3,4 )ibromothiophene-2-earhaldehy<le (25 mg, 0.09 mmol), 3,5-dimdhylisoxazoi-4-yihoroni.c .acid .ft 4.4 rng, 0.1 mmol), potassiw.ncarbonate (25.6 mg, 0.18 nimol) and Pd(PPhj.)₄ (10.7 mg, 0.009 mmol) were dissolved in toluene (0.8 mL) and ethanol (0.2 mL, 95%). The mixture was heated to 140°C in the microwave reactor for 20 minutes. The crude mixture was filtered through a pad of silica with ethyl acetate. After flash chromatographic separation 4~bromo-3-{3,5-dii-n.ethylisoxazol-4-yi)tluophene-2- carbaldehyde (9.0 mg, 0.033 mmol) was obtained.

Step (c): 3-(3,5-Diraeftylisoxazol-4-yl)-4-(4-h> oxyphenyl)tliiophene-2-carbaklehyde (9.0 mg, 0.0 1 mmol), 4--hydroxyphenylboromc acid (6.5 mg, 0.047 mmol), potass iumcarbonate (8.7 mg, 0.062 mmol) and Pd(PPh._?.)₄ (3.6 mg, 0.003 mmol) were dissolved in toluene (0.8 mL) and ethanol (0.2 mL, 95%). The mixture was heated to 140°C in the microwave reactor for 20 minutes. The crude product was filtered through a pad of silica with ethyl .acetate. After flash chromatographic separation 3-(3,5- dimethyHsoxazol-4-yl)-4-(4-hydroxyphenyr)tbiophene-2-carbaldehyde (4.0 mg, 0.013 mmol) was obtained.

Step (d): 3-{3,5-Djmethy.lisoxaml-4-yl)-4-(4-hydro^ (4 mg, 0.013 mmol) was mixed with hydroxylamirie hydrochloride (1 8.6 mg, 0.27 mmol) and pyridine (32 μΐ,, 0.40 mmol) in dry ethanol (0.5 nil.) and heated at 150*0 for 10 minutes in the microwave reactor. 1M HC1 and DCM were added and the phases were separated. After flash chromatographic separation (E) or (Z)-3- (3,5 limethyl isQxazol-4--y^ oxime (1.24 mg, 0.004 mmol) wa obtained. The \H-NMR. showed that the oxime product wa a single isomer, but did not confirm whether the product was the (E) or (Z) oxime isomer. ES/MS m/z; 15.2 (M+HL 313 (M-H); Ή ^'NMR (aceto.ne-d6, 500MHz): 7.93 (s, 1 H), 7.49 (s. 1H), 7.04 (m, 2H). 6.78 (m, 2H), 2.16 (s, 3H) and 1.78 (s, 3Hj.

Example 2

3-(3,5-dimethyiis0xazol-4-yl)-4-(3^

carboximidamkle (E2)

Step (a): 3-(3,5-Dimethylisoxa2ol-4~yl ) oxime (Example 1 , 45 mg, 0.14 mmol) was dissolved in acetic anhydride (2.0 ml., 20.3 nimol) and heated to \5Q°C for 20 rain in the microwave reactor. The remaining solvent was removed and the crude mixture was filtered through a pad of silica with EtOAc, The crude product was used in the next step.

Step (b)5 2M hydroxylamine hydrochloride solution in water (1.34 rnL, 2.71 nimol) and the crude product i om step (a) were added to DMSO (2 mL) and heated to 65°C over night. After HPI.C purificatio!i 3-(3,5-dinieth_v.lisoxazol-4-y )--4-f3~flu

carboximidamide. ^'(^'7.6 ing, 0.022 mrao^'l) was obtained. The 'H-NMR was unclear as to whether^' the product was a single oxime isomer, or whether it was a mixture of the (E) and (Z) oxime isomers. ES/M.S nvz: 348.13 (M÷H), 346.17 fM-H) ^!H NMR (MeOD, 500MHz): 7.48 (s, 1 H), 6.85-6.80 ⁽m, 2H), 6.74 (rn, ill), 2.04 (s, 3H) and 1.88 (s, 3H).

Example 3

4-(3,5-<Hmethylis0xazol"4--yl)-5-(4-hyd™^ oxime (E3)

(a) DIBAL-H -78 °C (DCM); (b) TRAP. NMQ (DCM); (c) Pd(PPh₃),,, 4-hydrox phenylboronic

acid. ₂CQ₃, (tofuene/EtOH/water); (d i PdfPPh-j)*. 3.5-dimethylisoxazol-4-y!boronic acid,

K₂C0₃ (toluene/EtOH/water); (e) NH₂ ^'OH^*HCi.. py (EtOH)

Scheme 4

Step (a): Methyl 4,5-dibromothiophene~3-carboxylate (3.34 mmol, 3 .00 g) was dissolved in DCM (25 ml.) and cooled to -78 °C. DIBAL-H (4.18 rnL of IM solution in toluene, 4.18 mmol,) was slowly added over 1 rnin and the mixture was then stirred at -78 °C for 60 min. The cooling bath was removed and the reaction was stirred at room temp for 90 min. 3 ml, MeOH were added, followed by 30 nil, of Roeheiie- salt solution (5% w/w in j¾0). The mixture was stirred until a clear solution, was obtained. The phases were separated and the organic phase was dried with Mg₂SQ₄ and the solvent was evaporated. The crude product (4.5-dibroniothiophen-3-yi)methanol (883 mg) was used without further purification in the next step.

Step (fa): (4,.5-Dibromothiop3ien-3-yl)met.hanol (883 nig. 3.25 mmol) was dissolved in DCM (30 nth.) and MO (761 .mg, 6.49 mmol) and TPAP ( 1 14 mg, 0.32 mmol) were added. The mixture was stirred at room temperature and the progress of the reaction followed by LLC. After 90 min the starting material was consumed and the mixture was then filtered through a silica-plug with EtOAc. No thither purification was done and 4,5-dibromothiopliene-3-earbaldehyde ( 689 mg. 2.55 mmol) was used in the next step.

Step (c): 4,5-Dibromothiophene-3-carbaldeliyde ( 500 mg, 0.37 mmol), 4-hyctroxyphenyiboronie acid (61 mg, 0.44 mmol), ) Pd(PPh_?)4 (43 mg, 0.04 mmol) and potassium carbonate ( 102 rug, 0.74 mmol) were dissolved i toluene/EtOH/water (4 mL/3 mL/0.5 mL) and then stirred at 60 °C over night. ΓΜ HCl_(aai and DCM were added and the phases were separated. The organic phase was evaporated in vacuo and the crude product was purified on an Argonaut. Flashmasler with 25 g siiica-cohiran (Biotage) with 0 - 30 % EtOAc in n-heptane as a gradient o ver 15 min at 20 niL/min as mobile phase. 4-Bromo-5-{4- hydroxyphe«yi)thiophene-3-cai-baidehyde (25 mg, 0.09 mmol) was isolated as a white -powder.

Step (d): 4-Bromo-5~(4-bydroxyphenyl)thiophene-3-carhaldehyde (40 mg, 0.1.4 .mmol), 3,5- .dimethylisoxazoi-4-ylboronic acid (80 mg, 0.57 mmol), ) Pd(PPh?)4 (33 rag, 0.03 mmol) and potassium carbonate (78 mg, 0.57 mmol) were dissolved in DME/water (.1 .5 mL/1.5 mL) and stirred at 120 °C for 20 min in a Biotage Initiator-microwa ve oven, 1M HCl_;aq, and EtOAc were added and the phases were separated. The organic phase was e vaporated in vacuo and the crude product was purified on a preparative HPLC. 4-(3,5~d»nethylisoxazo) --yl)-5-(4 iydroxyphenyl)thiophene-3-cafbaldehyde (4 mg, 0.01 mmoi) was obtained.

Step (e): 4-(3,5~Djmethylisoxazol-4-yl)-5-(4-hydroxyi5henyI)thiophene-3-carbaldehyde (7 mg, 0.03 mmol) was mixed with hydroxylamine hydrochloride (16 mg, 0.53 mmol) and pyridine (28 iiL, 0.53 mmol) in dry ethanol (2 mL) under N_? and heated to 1 10 °C for 10 minutes in a Biotage Initiator- microwave oven. The crude mixture was diluted with 2 mL DCM and then washed with 3 4 mL brine and 2 x 4 mL NH₄Cl_i;iCj). The organic phase was collected and evaporated in vacuo. The crude product was purified on preparative HPLC and 4-{3,5-dimethylisoxazol-4-yl)"5-(4-hydroxyphen.yl)rhioph.ene-3- carbaldehyde oxitne (3 mg, 0.01 mmol) was obtained, identification by Tl-NM.R showed that the product was an approximately 1 : 1 mixture of the (E) and (Z) oxtrae isomers. ES/MS m z: 315.1 (M+H), 313.1 (M-H); ^;H NMR (aeetone-d6, 500MHz): 8.69 (s, I E), 7.32 (m, 2H). 6.92 (s, 1H), 6. S3 (m, 2H), 2.12 (s, 3H) and 1 ,88 is. 3H).

Example 4

4-(3,S~dimdhyiisoxazoI~4^^ (E4)

obtained according

to scheme 4

(a) Ac,0; (b) NH₂OH (DMSO/water)

Scheme 5 Step (a): 4-(3_;5--din&ihyii$oxa2q (10 mg,

0.03 mmol) was dissolved in dry NMP (0.5 ml.) and acetic anhydride (30 uL. 0.32 mmol) was added. The mixture was heated to 50 °C for 15 mm in a Biotage tiator-microwave oven. The crude mixture was diluted with 1 nil. I M HCl_(;¾3y and 1 m^'L EtOAc and the phases were separated. The organic phase was washed with 3 x 2 ml. brine and then collected, dried and evaporated in vacuo. The crude product was purified on an Argonaut Flashrnaster, on a 10 g silica-column (Biotage) with 0^■■ 50 % EtOAc in n- heptane over 25 mm as mobile phase at 15 mL/min. 4-(3,5-Diinethylisoxazol-4-yl.)-5-(4- hydroxyphenyl}thiophene-3-carbonitrile (3 n g. 0.01 mmol) was obtained.

Step (b): 4-(3,5T)imethylisoxa^ (3 mg, 0.01 mmol) was dissolved in dry DMSO (2 ml) and a hydroxylamine NaOH-stock solution (2 M in water, 0.51 ml.., 1.01 mmol) was added. The reaction was stirred at 65 °C over night. After cooling to room temperature, the reaction mixture was diluted with 4 rnL brine and washed with 4 5 ml. EtOAc. The organic phase was collected, dried and evaporated in vacuo. The crude product was purified on a preparative HPLC and 4-(3,5-dimethylisoxazol-4-yl)-N'-hy rag, 0.002 mmol). was obtained. The 'H--NMR was unclear as to whether the product was a single oxime isomer, or whether it was a mixture of the (E) and (Z) oxime isomers. ES/MS ra/z: 330.1 (M+H), 328.2 (M-H); '.H NMR fMeOD, 500MHz): 7.65 (s. Hi), 7.03 (m, 2H), 6.73 (m, 2H), 2,00 (s, 3H) and 1.92 (s, 3H).

Examples 5-24

The following compounds were prepared according to General Method 1 above. Full experimental detail: of the individual steps of that general method are described in Examples 1 and 2 above.

For Example 5, the title compound was identified by ^!H- MR which showed that the -oxime product was a single isomer, but did not confirm whether the (E) or (Z) oxime isomer had been obtained. For each of Examples 10- 18, the title compound was identified by T1--NMR which showed that the product was an approximately 1 :1 mixture of the- (E) and (Z) oxime isomers. For each of Examples 6, 9 and 19-24, the Ή- MR was unclear as to whether the product was a single oxime isomer, or whether it wa a mixture o the (E) and (Z) oxime isomers.

Examples 25 and 26

The following compounds were prepared according to General Method I above. Full experimental details of the individual steps of that general method are described in Example 1 and 2 above.

For Example 25. the title compound was identified by ⁵H-NMR which showed that the oxime product was a single isomer, but did not confirm whether the (E) or (Z) oxime isomer had been obtained. For Example 26, the 'H-NMR was unclear as to whether the product was a single oxime isomer, or whether it was a mixture of the (E) arid fZ) oxime isomers.

Example 27

Example 27 was prepared according to General Method HI above, and as shown in Scheme 6 below.

(a) Trimet oxymethane, trifluoroacetic acid, MeOH; (b) 1 . NBS, MeCN 2. HCI; (c) MH₂OH HCl,Pyridine. DCM; (d) Ac₂0; (e) BBr₅, DCM; (f) NH₂OH,D SO.

Scheme 6

Step (a): 4~(2,5~ciifiuoro~4-methox^ (58 mg, 0.17 mM) was dissolved in MeOH (3 m^'L), trimethoxym.eth.ane (176.2 mg, 0.33 mmol) and trifluoroacetic acid (37.9 mg, 0.33 mmol) were added. The reaction mixture was stirred at room temperature for 55 in. The sol ent was evaporated under reduced pressure. The residue was dissolved in MeCN and then concentrated to dryness. 4-(4-(2,5-difluoro-4-methoxyphenyl)-2- (dimethoxymethy thiophen-S-ylj-S^-diraethylisoxa/XMe was obtained in quantitative yield.

Step (b): 4-(4--(2,5 lifruon 4-methoxypheny^

dimethylisoxazole (67.2 mg. 0.17 mM) was dissolved in MeCN and NBS (29.6, 0.17 mmol) was added. The reaction mixture was stirred at room temperature for 16 h. HCI (0.2 mL, 2M) was added, the mixture was stirred for 30 min and then concentrated under reduced pressure. The crude mixture was purified on preparative HPLC using MeCN/aeidic ίΤΟ (20 - 80% MeCN) as mobile phase. 5-bromo-4-(2,5-dtfluoro- 4-methoxyphenyl)-3-(3,5-ditnethylisoxa?x)l- -yl)thiophene-2-carbaldehyde was obtained in quantitative yield.

Step (c): 54m⁾]no-4-(^'2,5Hlii1iK>ro-4miethoxYphenyi)-3-(3,5-d

earbaldehvde ( 17.1 mg, 0,04 mmol) was mixed with hydroxylamine hydrochloride (27.8 mg, 0.40 mmol) and pyridine (36 ,uL, 0.44 nunol) in dry eihanol (imL). The reaction mixture was heated at 100°C for 5 minutes in the microwave reactor. DCM was added, the mixture way filtered through a phase separator and the solvent was concentrated. 5-bromo-4-(2,5-(Mf1uoiO-4-nierthoxyphenyl)"3-(3,5^imethylisoxazol-4yl)thiophene-2-earbaldehyde oxime was obtained.

Step (d): 5"bromo-4-(2,5-difluoro-4-methox}9^

carbaldehyde oxime was dissolved in acetic anhydride (1 mL) and the reaction mixture was heated at 150 °C for 0.5 h. The solvent was concentrated and the crude product was purified on silica using EtOAc/n-heptane (20-50 % EtOAc) as mobile phase. 17 mg 5-bro:mo^l-(2,5-difltioro- -ffiethoxyphenyl)3 -(3 ,5- dimeth> isoxazol-4"yl)tlhopherie-2-carbonitrile was obtained.

Step (e): 5-bromo-4~(2,5-diflnoro-4-methoxy^^

carbonitrile (17 mg, 0,04 mrool) was dissolved in DCM (1.5 ml.) and BBr₃ (0.5 ml., 1 M) was added. The reaction mixture was stirred at room temperature for 16 h. MeOH was added and the solvet was removed under reduced pressure. The crude product was purified on preparative 1TPLC using MeCN/acidic 1LO (20 - 100% MeCN) as mobile phase. 1 .2 mg 5-bromo-4-(2,5-difluoro-4-hydrox.yplienyl)-3-(3,5dimethylisoxazol-4-y])t^'hiophene-2 -carbonitrile was obtained.

Step (f): 5-bromo-4-(2,5-diiluoro-4-hydroxyph^

carbonitrile (13.2 m , 0.03 mmol) was dissolved in DMSO (0.4mLj and H₂OH (0.2 mL, aq, 16 M) was added. The reaction mixture was heated at 150 °C for 1 5 rain in a microwave reactor, 1¾0 (3 mL) and brine (2 ml,) were added. The aqueous mixture was extracted with EtOAc and the organic extracts were concentrated under reduced pressure. The crude product was purified on preparative HPLC using MeCN/acidic TLO (10-80 % MeCN) as mobile phase, 12.04 mg 5-broroo-4~(2,5-difluoro-4lyydroxyphenyl)~3-f3,5-dimetby!^^ (E27) was obtained. For Example 27, the title compound was identified by ^!H-NMR which showed that the oxime product was a single isomer, but did not confirm whether the (E) or (Z) oxime isomer had been obtained.

Examples 28-30

Example 30 was prepared according to General Method III above, and as shown in Scheme 7 below. Examples 28 and. 29 were produced as byproducts.

d)

(a) 1. NCS, eCN 2. HCi; (b) NH₂OH HCl, Pyridine, DCM; (c) Ac_zO; (d) BBr₃, DCM: (e) NH₂OH, DMSO

Scheme 7

Step (a): 4-(4-(2,5-difluoro .-methoxv henyl)-2-(dimettoxyme(liyl)t¾jophen-3-yl)-3,5-- dimediylisoxazole (79 mg, 0.23· mM) was dissolved in MeCN and NCS (60.4, 0.46 ramoJ) was added. The reaction mixture was stirred at 50 °C for 16 h. HCI (0.2 ml., 2M) was added, the mixture was stirred for 30 min and then concentrated under reduced pressure. The crude mixture was purified on preparative HPLC -using MeCN/acidic j¾0 (20 - 100% MeCN) as mobile phase. 53.3 mg 5-chk>ro-4-(2,5-difluoro- 4-metboxyphenyi)-3-(3,5-d«netliylisoxazol-4-yl)thiophene-2-carbaldehyde and 14.35 mg 4~(2,5-dichioro- 4~{2,5-difluoro-4-memoxyphenyl)A^ were obtained. Step (b): 5-c]:d:oro~4-(2.5-diflvioro-4-!rietlToxyphenylj-3-(3

earbaldeiiyde (53.2 mg. 0.14 mmol) was mixed with hydroxylamine hydrochloride (48.16 mg, 0.69 mrrsol) and pyridine (67 μΐ,, 0.83 mmol) in dry ethano! (I mL). The reaction mixture was heated at 100°C for 5 minutes in the microwave reactor. DClV'i was added, the mixture was filtered through a phase separator and the solvent was concentrated. 5 -alik)ro^ -(2,5-difl ioro-4-niethoxYphenyl)-3~(3,5- dimethyiisoxazol~4-yl}tlitophene-2~carbaklehyde oxime was obtained.

Step (e)r 5-chloro-4-(2,5-difluoro-4-metto

earbaldeiiyde oxime was dissolved in acetic anhydride (1 mL) and the reaction mixture was heated at 150 °C for 0.5 The solvent was concentrated and the crude product was purified on silica using EtOAc n- heptane (10-20 % EtOAc) as mobile phase. 42.8 mg 5-chloro-4-(2,5-difluoiO-4-methoxyplienyl)-3-{3,5- dimethylisoxazol~4-yl)t!iiophene-2~carboiiitri!e was obtained.

Ste (d): 5-cn{oro-4-{2₄5-difluoro-4-methoxyp

carbonitrile (42.8 mg, 0.1 1 mmol) and 4-(2,5-didiloro-4-(2,5-di:fluoro-4-m^

3.5-dimethylisoxazole (14.35 mg, 0.04 mmol) were separately treated, with BBr_? (20 e , 1 M) in DCM (2.5 mL resp 1.5 ml. ). The reaction mixtures were stirred at room temperature for 16 h. M.eOH was added and the solvent was removed Under reduced pressure. The crude products were purified on preparative HPLC using MeCN/acidic H₂0 (20 - 300% MeCN) as mobile phase. 34 mg 5-chioro-4-(2,5-difluoro-4- hydroxyphenyl)-3-(3,5-dirnethyHsoxazol-4-yl)thiophene-2-carbonitrile, 3.45 mg 5-chloro-4-(2,5-dsfTuoro- 4-hydrox^henyl)"3-(3,5 3imethyiisoxazol-4-yl)thiophene-2-carbaxaraide (E28) and 1 1.27 mg 4-(2,5- dichloro-4-(3.,5-dimethyl isoxazol - -yl)thiop.hen-3 -yi)-2.5 -d ifluorophenol (E29) were obtained.

Step (e): 5"Cld o '-(2,5 u¾ o-44iYd.ro^^

carbonitrile (34 mg. 0.09 mmol) was dissolved in DM SO (0.4 mL) and N¾OH (0.35 ml... aq, 16 M) was added. The reaction mixture was heated at 150 °C for 15 min in a microwave reactor. H₂0 ( 1 mL) and brine (2 mL) were added. The aqueous mixture was extracted with EtOAc and the organic extracts were concentrated under reduced pressure. The crude product was purified on preparative HPLC using MeCN/acidic ILO ( 10-80 % MeCN) as mobile phase. 39.4 mg .5-chloro-4-(2,5-diiluoro-4- hydroxyphenyl)-3"(3.,5-dimethylis0x (E30) was obtained. For Example 30, the title compound was identified by Ή-NM which showed that the oxime product wa a single isomer, but. did not confirm whether the (E) or (Z) oxime isomer had been obtained.

Examples 31 and 32

4-(3-chloro-4-hydroxyplK^

carboximidamide (E 1 )

5~chloro-4~(3~chior0-4-hydroxyph^

carboximidanude (E32)

(a) 3,5-dime y -{tributyis{annyl)!.soxazote. PdCI₂(PP _¾)₂, dioxane; (b) 4-methoxyphenylboronic acid, Pd(PPh₃)_4! K₂C0₃, dtoxane/H₂0; (c) NCS, D F; (d) 1. BBr₃. DCfvl; 2. NH₂OH (aq) eOH.

Scheme 8

Step (a): 3,4 ljbroinotlnophene-2-carbor:ilrile (50 mg, 0.19 mmol), 3,5-dimethyl-4- (tributylstannyl)isoxazole (75.9 mg, 0.20 mmol), PdCl^PP *)_? ( 13.2 mg. 0.02 mmol) were mixed in dioxane (1.4 niL) under nitrogen. The reaction mixture was heated in microwave at 140 °C for 30 min. The crude mixture- was purified on preparative HPLC using MeC /acidic- ¾0 (20 - 100% -eCN) as mobile phase. 15 mg 4-btOmo-3-(3,5-dime^{hylisoxazol-4-yl)thiophene-2-earbonitrile was obtained.

Step (b): 4^romo-3-(3.5-dimeihylisoxazol -> lhiophe«e-2-carbonitrik (15 mg, O.OSmmol), 4- metboxyphenylboronie acid ( 12.1 mg. 0.08 mmol), ) Pd(PPh.₅>4 (6.12 mg, 0.01 mmol) and potassium carbonate (29.3 mg, 0.21 mmol) were dissolved in dioxane/I¾0 (0.53 mL, 1 : 1 ). The reaction mixture was stirred in microwave at 1 SO "^JC for 20 rain. HC1 ( IM, aq), EtOAc and DCM were added and the phases were separated. The organic phase was filtered, through a phase separator and evaporated under reduced pressure. The crude product was purified on preparative HPLC using MeCN/acidic ¾0 (20 -- 100% MeCN) as mobile phase. 7.0 rag 3-0,5-dimethylisoxazol-4-yl)-4-(4~m.ethoxypte

earbonitrile was obtained.

Step (c): 3-(3,5 limetlr isoxa2ol-4-yl)-4-(4-rnethoxypl^'ienyl)thi (7.0 mg, 0.02 mM ) was dissolved in DMF (0.5 mL) and NCS (8.0 mg, 0.06 mmol) was added. The reactionmixture was stirred at 60 °C for 16 h. 3.0 mg -(3-chloro-4-methoxyplienyl)-3-(3₅5-djmethylisoxazol~4-yl)tb.iophene- 2-carbonitrile and 9.0 mg 5-chkiro-4-(3--cWoro-4-inethox> henyl)-3-(3_t5-diraethyKsoxazol-4- yi)thiophene-2-ciirbonitri!e were obtained.

Step (d): 4~(3-ehloro~4-methoxypheny^^ (2.0 mg, 0.01 mmol) and 5-chloro-4-(3 hloro-4-methoxyphenyl)^

earbonitrile (7.0 mg, 0.02 mmol) were separately treated with BBrj (I S eq resp. 6 eq, 1 M) in DCM (1.2 ml. resp. 0.4 mL). The reaction mixtures were stirred at room temperature over night. H20 and DCM. were added and the layers were separated. The organic layers were filtered through a phase separator and concentrated under reduced pressure. The crude mixture were dissolved in MeOH {0.6 mL resp 0.4 mL) and NI-LOH (280 eq resp 90 eq, aq, 16 M) was added. The reaction mixtures were heated in mierovawe at 120 °C for 20 rain. T he crude mixtures were purified on preparative HPLC using MeCN/acidic 1LO ( 5 - 50% MeCN) as mobile phase. 0.3 mg 4-(3-chloro-4-hydroxyphenyl)-3-(3,5-dimethylisoxazolr-4-yl)^»N'- hydroxythiophene-2 -earboximidamide (E31 ) ES/MS m/z: 364.1 1 , (M- H), 362.2 (M-H); ^lH NMR (aeetone-d6. 500MHz): 9.08 (b . 1H), 7.53 (s, LH). 7.17 (d, J = 2.2 Hz, lH). 6.94 (d, J - S.5 Hz, IH), 6.90 (dd. J - 8.5, 2.2 Hz, 1H), 5.16 (br s, 2H), 2.03 (s, 3H), 1 .88 (s. 3H) and 5-chloro-4-(3-chioro-4- hydroxyphenyO-S-iJ ^limelhylisoxazol^-y -N'-hydrox^hiophene-^-carboximidamide (E32) ES/MS m/z: 39S.06 (M÷H), 396.13 (M-H),; ^!H NMR ((aeetone-d6, 500MHz): 9.25 (br s. IH), 7.16 (d, .? - 2.2 Hz, 1H), 7.00 (d, J - S.4 Hz. IH), 6.90 (dd, J - 8.4, 2.2 Hz, IH), 5.14 (br s, 2H), 2.06 (s, 3H), 1.91 (s, 3H) were obtained as solids. For Example 31 and 32, the title compound was identified by Ή-NMR which showed that the oxime product was a single isomer, but did not confirm whether the (E) or (Z) oxime isomer had been obtained.

Examples 33 and 34

The following compounds were prepared according to General Method IV above. Full experimental details of the individual steps of that general method are described in Examples 31 and 32 above. For Examples 33 and 34, the title compound was identified by Ή-NMR which showed that the oxime product was a single isomer, but did not confirm whether the (E) or (Z) oxiine isomer had been obtained.

Binding Assay 1 : Estrogen Receptor Binding Assay

The estrogen receptor iigand binding assays are designed as scintillation proximity assays (SPA), employing the use of initiated estradiol (TI-E2) and recombinant expressed biotinylated estrogen receptor binding domains. The binding domains of human BRot (ERu-L D, pET-N-AT #1 , aa 301 -595) and ER(3 (ERfi -LBD. pET-N-AT # 1 , aa 255030) proteins are produced in E.coli ((BL21 , (DE3), pBirA)) at 22 C in 2xLB medium supplemented with 50 uM biotin. After 3 h of fPTG induction (0.55 mM), cells are harvested by centrifiigat n at 7300xg for 15 min and cell pellets stored frozen in -20C. Extraction of ERa and ERB are performed using 5 g of cells suspended in 50 inL of extraction buffer (50 mM Tris, pH 8.0, 100 mM KC3, 4 mM EDTA, 4 mM DDT and 0.1 -mM PMSF). The cell suspension is run twice through a Microti uidtzer -1 l^'OL (Microfiuidics) arid centrifuged at 15,000xg for 60 rain. The supernatant is aliquoted and stared in - 70C.

Dilute ERa-LBD or ERp-LBD extracts in assay buffer (18 mM ₂H?0₄₍ 2 mM KH₂P0 , 20 mM

Na_sM.o0₄, I raM EDTA. lmM TC'EP) 1 :676 and 1 :517 for alpha and beta respectively. The diluted receptor concentrations should be: 900 fmol/L. Preincubate the extracts with streptavidin coated polyvifiyltoluene SPA heads (RPNQ0007, ⁽IE Healthcare) at a concentration of 0.43 mg/rnL for 1 hr at room temperature'. Test compounds are evaluated over a range of concentrations from 157 μΜ to 37.5 pM. lire test compound stock solutions should be made in 100% DMSO at 5x of the final concentration desired for testing in the assay. The amount of DMSO in the test wells of the 384 well plate will be 20%. Add 18μ1 aliquots of test compounds to the assay plates followed by 35ul of the preincubated receptor/SPA bead mix and finally add 35μ! of 3nM ^"Ή-Ε2. Cover the plates with a plastic sealer, centrifuge for 1 minute at 1000 rpm and equilibrate over night on a shaker at room temperature. The following morning, centrifuge the plates 5 minutes at 2000 rpm. and measure on a plate scintillation counter e.g. a PerkinElmer

Microbeta 1450 Trilux.

For compounds able to displace 3fH]-E2 from the receptor an IC=o- value (the concentration required to inhibit 50% of the binding of 3[H]-E2) is determined by a non-linear four parameter logistic model; b ^~ ((bmax-bniin) n +(.i/lC5 jS))-^}-bttiin 1 is added concentration of binding inhibitor. IC₅o is the concentration of inhibitor at half maximal binding and S is a slope factor. The. Microbeta-instrument generates the mean cpm (counts per minute) value / minute and corrects for individual variations between the detectors thus generating corrected cpm values.

Transact! vatiou Assay 1 : Transactivation assay in human embryonic kidney 293 cells stably transfeeted with pERE- ALP and human estrogen receptor alpha

The expression vector pMThERa contains an insert of wild type human estrogen receptor alpha with deleted leader. The pERE-ALP reporter construct contains the gene for the secreted form of placental alkaline phosphatase (ALP) and the vitellogenin estrogen response element (ERE). The human embryonic kidney 293 cells are transfeeted in two steps. Firstly, a stable clone mix transfeeted with the pERE-ALP reporter gene construct and pSV2-Neo for selection is developed. Secondly, the stable clone mix is transfeeted with pMThERa and a pKSV-liyg resistance vector for selection. All transfections are performed using I.ipofectarnine (Invitrogen) according to supplier's recommendations. A selected clone with both pERE-ALP and pMThERa is used for the transactivation assay. The cells are seeded in 384-welI plates .at 12500 cells per well in Ham ^'s Pi 2 Coon's modification ( without phenol red) with 10 % dextran-coated charcoal treated (DCC) fetal bovine serum (PBS), 2 mM L-g^'lutamine and 50 pg/m! gentanhcin. After 24 h incubation (37°C, 5 % CQ₂) the seeding medium is discarded and replaced with 20 μ.1 Ham's F12 Coon^'s modification (without phenol red) with 1.5 % DCC- FC8, 2 mM L-glutamine and supplemented with 100 U/ml penicillin and 100 pg/ml streptomycin. The selected compounds are added to the wells in 12 concentrations ranging from 3.3 pM to 33 uM. T^'he compounds are dissolved in 100 % dimethylsuiphoxide (DMSO) and the final concentration of DM SO in the assay is 0.1 %. After 72 h incubation (3?^aC, 5 % C0₂) the medium is assayed for ALP activity by a chemihiminescenee assay; a 10 ul aliquot of the cell culture medium is mixed with .100 μΐ assay buffer (0.1 M diethanolamine, 1 mM MgCi₂) and 0.5 mM disodium 3-(4-methoxyspiro l,2 -dioxetane-3,2'-(5'- chloro)-tricyclo[3.3. i . i 3,7]decan-4-yi)phenyl phosphate (CSPD) (Tropix, Applied Biosystems) and incubated for 20 min at 37^CC and 15 min at room temperature before measurement ehemihtniineseem light signal (one second per well) in a Waliac Microbeta Triiux 1450-028 (PerkinElmer). ^'T^'he half maximal effective concentrations EC.$o) are calculated from the curves fitted to the concentration- response data with a four parameter logistic model in XI.fi t software version 2.0 (IDBS) or later.

Transactivatiba Assay 2: Transact! vation assay in human embryonic kidney 293 cells stably transfected with pE^'RE2-AL.P and human estrogen receptor beta

Generation of stable HEK293 cell lines (CRL- 1573; American Type Culture Collection) expressing the reporter vector pBRE2- ALP and human estrogen receptor beta (h^'ERB 530) have been described (Mol Pharmacol 1998, 54,105-1 12; Endocrinology 2002. 143, 1558-1561 ).

The ceils were seeded in 84-well plates at 12 500 cells per well in Ham^'s IT2 Coon's modification (without phenol red) with 10 % dextran-coated charcoal treated (DCC) fetal bovine serum (FBS), 2 mM L-gli!tamine and 50 g. ^'in 1 gentamicin. After 24 h incubation (37°G, 5 % C02) the seeding medium was discarded and replaced with 20 ul Ham^'s F1.2 Coon's modification (without phenol red) with 1 .5 % DCC- FCS, 2 mM L-glutamine and supplemented with 100 U/ml penicillin and 1 0 fi ,- nil streptomycin. The selected compounds were added to the wells in 12 concentrations ranging from 3.3 pM to 33 iiM. The compounds were dissolved in 1 00 % dimethylsulfox ide (DMSO) and the final concentration of DMSO in the assay was 0.1 %, After 72 h. incubation (37^CC, 5 % C02) the medium was assayed for ALP activity by a chemiiuminescence assay; a 10 ,u1 aliquot of the conditioned medium was mixed with 100 μΐ assay- buffer (0.1 M diethanolamine, .1 mM MgC12) and 0.5 mM disodium 3-(4-methoxysptro 1,2-dioxetane- 3,2H^'5'-chloro^')-tricyc!o[3.3.L13,7)decan-4-yl)phenyl phosphate (CSPD) (Tropix, Applied Biosystems) and incubated for 20 min at 37°C and 15 min at room temperature before measurement of the chemilummescent signal (one second per well) in a Waliac Microbeta Triiux 1450-028 (PerkinElmer). The ALP activity expressed in LCPS is directly proportional to the level of ALP expressed by the cells. The half maximal effective concentrations of the test compounds (EC50) were calculated from the curves fitted to the concentration-response data with a four parameter logistic model in X^'Lfit software version 2.0 f i BS) or later.

The compounds of Examples 1-34 were tested in the transactivation assays I and 2 above, and the compounds of Examples 1 -26 were additionally tested in the binding assay above.

The compounds of Examples 1 -34 exhibit one or more of the following:

(i) a binding affinity to the estrogen receptor a-subtype in the range οΠ(\,·_; 1 to 10,000 nM in the binding assay

(ii) a binding affinity to the estrogen receptor β-subtype in the range of IC¾. 1 to 10,000 nM in the binding assay;

(hi) a potency in the range ofECjo 1 to 10,000 nM at the estrogen receptor a-subtype in transactivation assay 1 :

(iv) a potency in the range of BC5₀ 1 to 10,000 nM at the estrogen receptor β-subtype in transactivation assay 2.

Preferred Example compounds of the invention are those which exhibit, a bindi ng af fi n ity to the estrogen receptor β-siibtype at lower concentrations within the ICj,,. range shown above. For example, the compounds of Examples 1 , 3, 5, 6, 9-15, .17 and 21 exhibit a binding affinity to the estrogen receptor {3-subtype in the range of ¾ 1 to 50 nM in the binding assay.

Preferred Example compounds of the invention are those which are selective for the estrogen receptor β-subtype over the estrogen receptor a-subtype in the binding assay. .For example, the compounds of Examples 1 , 3, 5, 6, 10, 1 , 15, 1 ? and 1 -21 display selectivity for the estrogen receptor β-subtype of 50 or greater in the binding assay.

Preferred Example compounds of the invention are those which display a potency at the estrogen receptor β-subtype at lower concentrations within the EC_¾) range shown above. For example, the compounds of Examples 1-6, 9-21 , 27, 30 and 32 exhibit a potency in the range of EC5₀ 0.1 to 10 nM at the estrogen receptor β-sub^'type in transactivation assay 2.

Preferred Example compounds of the invention are those which are selective for the estrogen receptor β-subtype over the estrogen receptor a-subtype in the transacti vation assays 1 and 2. For example, the compounds of Examples 1 -6, 9- 1 1 , 13-22, 27, 30 and 32 display selectivity for the estrogen receptor p-subtype of 10 or greater in the transactivation assays.

Claims

Claims

1 . A compound of formula (I) or pharmaceutically acceptable ester, amide, or salt thereof, including a salt of such an ester or amide.

wherein one of A and B represents sulfur or oxygen, and the other of A and B represents C~R^J;

R^l is selected from the group consisting of halogen, N(R^!,)₂, C₃.vCycloalkyl, Q scyeki lkylC . lky! and S-10 metnbered heterocyclyl, wherein said heterocyclyl .group can be either unsubstiaited or substituted with from 1 to 3 siibstituents, each substituent being independently selected from the group consisting of OR^A, halogen, cyano, nitro, -C(0)C_Malkyl, C_;.._;,alkyL C₂.₀alkenyl, C^aikynyl. haloC.^ alky], dihaloC,. ;,aikyl and trihatoC^alkyl;

R^' is selected from the group consisting of halogen, cyano, nitro, OR^"\ N(R^l>)₂, N{OH)₂, -CHO, -CH-N-OH, -C(0)C_walkyl optionally substituted with from 1 to 3 halogens, -SO_;C alkyl -C(0)NH- OH, ~C(NH₂)=N-OH, -C(CO,Hj=N-OH. -C(0-C₃.₄alkyl)=NH_: -C(NH₂)-N-NB₂, ~NH-C(NH₃)-NH, -NH-C(0)N¾, -N-C(-NH-CH₂CH₂-NH-), -S-CN. -S-C(N¾ H. -S-C(N¾)= -OH₍ -C0₂H,

-CH C0₂H, -CH(OH)C0₂H, -C(0)C0₂H, SChH, -CH₂S0₃H, ~C(0)N(R^c)₂, S0₂N(R^c)₂, -C(0)-C(0)- N¾, -CH₂NH-CQ M,, C^aikyl, haloC,._!3aikyi, dihaloC^alkyi, trihaioC_:.₆alkyl , cyanoC,_-6alkyl, Ci..₄alk.o.xyC| .i,alky], C₂.<_>alkenyi, C₂^alkyny], Q.scyeloaikyi, C¾._scycloa.lkylC j ._f, alkyl, phenyl, benzyl and 5-10 meinbered heterocyclyl wherein said phenyl, benzyl or heterocyclyl group can be eithe

unsubstiti!ted or substituted with from i to 3 subsiituents each substituent being selected from the group consisting of OR^A, halogen, cyano, nitro. C_halk ! C₂._f.alkenyl, ^'C^alkynyl, haloC^alkyl, dihaloC;.₆alkyl and trihaloC j ,_ftalkyl ;

R" is selected from the group consist ing of hydrogen, Cj.₆alkyl, C^alkenyl, C_2-6alkynyi, C_.vxcycloaikyl , C^cycloalkylC , .§alkyl, halogen, benzyl and 5-10 membered heterocyclyl wherein said benzyl or heterocyclyl group can be either unsubstituted or substituted with from 1 to 3 subsiituents each substituent being .selected from the group consisting of O.R^'\ halogen, cya.no, nilro, C^alkyi, C^alkenyl,

C^alkynyl, haloC^alkyi, dihaloCj,_;)aikyl and trihaloC .aikyl; each of R^'\ R\ R^y and ' is independently selected from the group consisting of hydrogen, OR'\ halogen.. cyano, nitro, Q.^aikyl, C^alkenyl, C₂._¾alkynyl, haloCi^alkyl, dthaloCj^alkyl and trihaloC_1-6alkyl; each R^A is independently selected from the group consisting of hydrogen, C_halky!. C^alkenyl, C¾. «alkynyl, C3.xcycl0al.kyi, C^^eycioalkylCj^alkyl, phenyl, benzyl and 5-10 membered heteroeyclyl, each optionally substituted by from. 1 to 3 alogen atoms; each R⁸ is independently selected from the group consisting of hydrogen, C_halky! Cs^alkeoyl, ⁽ . ^alkynyl, C _sCycloalkyl, Ca-gc cloalkylCi^alky], phenyl, benzyl and 5-10 membered heteroeyclyl, each optionally substituted by from 1 to 3 halogen atoms; and each R¹ is independently selected .from the group consisting of hydrogen and C_halky!; with the proviso that the compound of formula (1) is not:

3- anxino- -(4-hydrox>' henyl)-2-thiop^'henecarboxyl}c acid, inethyl ester; or

4- (4-bromo-2,5-dimeihyi-3-thieayl-l ,2-benzenedjol.

2. A compound as claimed in claim 1 , in which R¹ is selected from the group consisting of

Cj.xcycioaikyl, Cj-scycloalkylC alkyl and 5 - 10 membered heteroeyclyl, wherein heteroeyclyl group can be either imsubstituied or substituted with from 1 to 3 substituents, each substituent being independently selected from the group consisting of OR'\ halogen, cyano, nitro, ~C(0)C:^alkyl,. C_halky!, Cj .alkenyl, CS^alkynyi, haioCj__t5 alkyL dihaloCj.₆alkyi and irihaioC^alkyl.

3. A compound as claimed in claim 1 or claim 2. wherein R^* is selected from the group consisting of hydrogen, halogen, C_:._ealkyl, C^alkenyl, C;._(!alkynyi, C\.*eycloalkyi. and CvsCycloalkylCj-_ftalkyL 4. A compound as claimed in any one of the preceding claims, in which A represents S, B represents C-R^! and R^J represents hydrogen or halogen.

5. A compound as claimed in any one of the preceding claims . in which R^" represents cy ano,

-CfcNN-OH or -C(NH₂)-N-OH, -C(G)N¾.

6. A compound as claimed in any one of the preceding claims, in which R^'! represents a 5- 10 mernbered heterocyclyl, wherein said heterocyclyl group can be either unsuhstituted or substituted with from 1 to 2 substituents, each substituent being independently selected from cyano or Cj.₆alkyl.

5 7. A compound as claimed in any one of the preceding claims, in wh ich in which each of R\ R^s, R^f' and R' is independently selected from hydrogen and halogen.

8. A compound as claimed in any of claims 1-3, i which A represent s O, B represents C-R⁵ and R^" represents hydrogen or halogen.

10

9. A compound as claimed in claim 8, in which R^'' represents --C{ l ₂)- -OH; R¹ represents a 5- 10 mernbered heterocyclyl, wherein said heterocyclyl group can be either unsub.stit.uted or substituted with from 1 to 2 substituents, each substitttent being independently selected from cyano or C_halky!.; each of R⁴, R^', R° and R' is independently selected from hydrogen and halogen.

15

10. A compound as claimed in any of claims 1 -3, in which B represents S, A represents C-R^J and R^J represents hydrogen or halogen.

1.1. A compound as claimed in claim 10, in which R"^: represents -CXNH_?.)^~N-QH or -CH^::: -OH R¹ 20. represents a 5-10 mernbered heterocyclyl, wherein said heterocyclyl group can be either unsubstifuted or substituted with from 1 to 2 substiiuents, each substituent being ndependently selected from cyano or Q. ¾aikyi; each of R^' E.\ K" and R^' is independently selected from hydrogen and halogen.

12. A compound as claimed in claim 1 , which is any one of the following compounds:

25 3-(3,5-dimeth>¾soxazQl-4-yl)-4 4-hydroxyphenyl)thiophene-2-carbaldehyde oxime;

3~(3,5-dimetlrylisoxazol~4-yl)~4-(3 ^^

4-(3,5<limetltylisoxa¾ol-4-yi)-5-(4-hydrox> benyi)thiophene-3-carbaldehyde oxime;

4-i3,5-dimet.hyiisoxazol- -yl)- ^!d]ydroxy--5 -(4 -hydrox

3-(3,5-dimethylisoxazoi-4-yl}-4-(4-h^^

30 4-(4-auunophenyl)-3-(3,5--dimet! vlisoxazol-4-yl)

3-(3,5~diinethylisoxazol-4-yl)-4-i4-hydroxyphenyl thiopherie-2-carboxamide;

3-(3,5- imetlrylisoxazol-4^

3-(3,5- iin^'iethylisoxa201 -4--yl) -4--{3- iluarc>--4 -hydr oxime;

S~(cydopropylmediyi ^-f 3,5 iimethy

35 oxime;

5 ~(cyek>pr opy !me

carbaldehyde oxime; 4-(4~hydroxyphenyl)-3~( 1 -mie†l3yl-lH-pvm⁾l-2~yi)thiopheae-2-carbaldehyde oxime;

4-{4-hydiOxyplienyl)-:3-(1 -Tnethyl-lH-pyrazo 5-yi)thiopbene-2-carbaldehyde oxime;

4- 2,5- {ti!iK>iO- -4}ydroxyp oxime; 3"{3_>5-dwnethylisoxazol-4-yl)-4-(2-fli^^ oxime;

4-(3,5-diftuoro~4-hydroxyphenyl)-3-(3,5"

4~(2.3-djfluoro-4- ydroxyplienyl)-3-(3,5-dimethylisoxazol-4~yl)thiophe

2^(hydt\v<yimino)niethyi)^^

4-(2,3-difluoro-4 tydrox>phenyi)-3~(3.^

carboximidamide;

4-(2,5-difluora-4-hydroxypheiiyl)-3-{3.5-dimem^

carboximidamide;

3- (3_¾5-dimediylis«xazol-4-yl)-4-(2~Buo^

4- (3.5-difluoro-4- ydK⁾xyphenyl)-3-{3,5-dimethylisoxazol-4"yl)-N^,-hyd

carboximidamide;

N'~hydroxy-4-(4-hydroxypheiry!)-3-^^

'"hydroxy-4-(44iydroxyphe yi)-^'3-{ Ί -.metbyl-4H^yraz.ol.- -yl}diiopheiie--2--carboximidamide;

3- {3,5-dimetbylisoxazol-4-yl)^-(4-hydroxvphenyi)fumi-2^arbaklehyde oxime;

3"(3,5- Siinethylisc:'Xazoi -4--yl)-- '-liydroxy-4- ^'4-hy

54:>romo~4-(2 -difiuoro-4 iydroxyphenyl^^

carboxi midamide;

5 ¾oro-4-{2,5rdifluoro-4-hydroxyph^

4- (2,5-dicbk.«x>4~(3,5-dimethylisoxazo] -yl)i i

5"Chloro--4 -(2,S iifluoro - iydroxyphen )-3

carboximidamide;

4~(3-cldoro~4 iy irox\phenyi)-3-(3 ^

5 ;hloro-4-i3-cldoro-4-lvydroxypjtenylj^

carboximidamide;

4-(S~cMoro-2 -difiuoro-4-hydroxy^

carboximidamide;

4 -{ 5 ^>ldoro-2 1uoro 4vvdroxyph

carbox hnid am ide ;

or a pharmaceutically acceptable ester, amide, or salt thereof, including salt of such an ester or amide.

13. A compound as claimed in any one of claims 1 to 12 together with a further therapeutic agent, for simultaneous, sequential or separate administration.

14. A pharmaceutical composition which comprises a compound as churned in any one of claims 1 to 12, together with a pharmaceutically acceptable carrier.

.15. A compound s claimed in any one of claims 1 to 1 . or a pharmaceutical composition as claimed in claim 14, for use as a medicament.

16. A compound as claimed in any one of claims 1 to 13, or a pharmaceutical composition as claimed in claim 14,for use in the treatment or prophylaxis of a condition associated with a disease or disorder associated with estrogen receptor activity.

27. Use of a compound as claimed in any one of claims 1 to 13. for the manufacture of a . medicament for the treatment or prophylaxis of a condition associated with a disease or disorder associated with estrogen receptor activity.

18. A method, for the treatment or prophylaxis of a disease or disorder associated with estrogen receptor activity in a mammal, which comprises administering to the mammal a therapeutically effective amount of a compound as claimed in a ny one of claims 1 to 13 or a pharmaceutical composition as claimed i n claim 14.

19. Use of a compound as claimed in any one of claims i to 1 2 in labelled form as a diagnostic agen for the diagnosis of conditions associated with a disease or disorder associated with estrogen receptor activity, or use of a compound as claimed in any one of claims 1 to 12 or labelled form of such a compound as a reference compound in a method of identifying ligands for the estrogen receptor.

20. A compound or a pharmaceutical composition as claimed in. claim 1 6, a method as claimed in claim 18, or a use as claimed in either claim 17 or claim 19, wherein the condition associated with a disease or disorder associated with estrogen receptor activity is selected from bone loss, bone fractures, osteoporosis, cartilage degeneration, endometriosis, uterine fibroid disease, hot flushes, increased levels of LDL cholesterol, cardiovascular disease, impairment of cognitive functioning, age-related mild cognitive impairment, cerebral degenerative disorders, restenosis, gynecomastia, vascular smooth muscle cell proliferation, obesity, incontinence, anxiety, depression, perimenopausal depression, post-partum depression, premenstrual syndrome, manic depression, dementia, obsessive compulsive behavior, attention deficit disorder, attention deficit hyperactivity disorder, sleep disorders, irritability, impuisivity, anger management, hearing disorders, ^'multiple sclerosis, Parkinson 's disease, Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis, spinal cord i jury, stroke, autoimmune disease, inflammation, IBD, IBS, sexual dysfunction, hypertension, retinal degeneration, lung cancer, colon cancer, breast cancer, uterus cancer, prostate cancer, the bile duct cancer form named choiaiigjocarciiioma, benign prostat ic hyperplasia, lower urinary tract symptoms, overactive bladder, interstitial cystitis, painful bladder symptoms, vaginal atrophy, wound healing, chrome pain, sepsis, inflammatory and neuropathic pain, ovarian cancer, melanoma, lymphoma, atherosclerosis, left ventricular hypertrophy, congestive heart failure, mesothelioma, gallbladder cancer and extra-hepatic cholanaiocarcinoma.