WO2012136772A1

WO2012136772A1 - Fused pyrrole derivates as estrogen receptor ligands

Info

Publication number: WO2012136772A1
Application number: PCT/EP2012/056293
Authority: WO
Inventors: Lars Hagberg; Daniel NÖTEBERG
Original assignee: Karo Bio Ab
Priority date: 2011-04-07
Filing date: 2012-04-05
Publication date: 2012-10-11
Also published as: GB201105979D0

Abstract

The invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein Z, A, B, D, E, G, M¹, M², M³, M⁴, M⁵, M⁶, p, q, r, R³, R⁴, R⁵ and R⁶ are as defined in the specification. The invention 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

FUSED PYRROLE DERIVATES AS ESTROGEN RECEPTOR LIGANDS

Field of Invention

This invention relates to compounds which are estrogen receptor ligands and are preferably selective for the estrogen receptor β isoform, to methods of preparing such compounds and to methods for using such compounds in treatment of diseases related to the estrogen receptor such as depressive 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 receptor (ER) is a ligand activated mammalian transcription factor involved in the up and down regulation of gene expression. The natural hormone for the estrogen receptor is β- 17-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/DNA 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 cell 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 have neuroprotective effects. Consequently decreased estrogen production in post-menopausal 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, 17P-estradiol, for the treatment of various forms of depressive illness has also been demonstrated and it has been suggested that the anti-depressant activity of estrogen may be mediated via regulation of tryptophan hydroxylase activity and subsequent serotonin synthesis (See, e.g., Lu N Z, Shlaes T A, Cundlah C, Dziennis S E, Lyle 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 11 :257-267, 1999). The pleiotropic nature of natural estrogen precludes its widespread, more chronic use due to the increased risk of proliferative effects on breast, uterine and ovarian tissues. The identification of the estrogen receptor, ERP, 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 ERP-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.

US2003/0220377 (Chesworth) and WO2005/018636 (Wyeth) each disclose certain indole derivatives having estrogen receptor activity. WO2008/006626 (Freie Universitat Berlin) discloses certain 5-membered heterocycles, preferably pyrroles, furans and thiophenes, substituted with three phenyl moieties, and further discloses that the compounds show

antiproliferative effects and inhibitory effects on cyclooxygenases. Drug Metabolism and Disposition, 2008, Vol. 36, No. 5, p.894-903 discloses metabolites of 2- [6-(4-Chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-lH-pyrrolizin-5-yl] acetic acid

(licofelone), including compound (III)

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.

Summary of the Invention

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

(I)

wherein ring Z is a pyrrolyl ring in which A, G and E each represent nitrogen or carbon, and in which B represents CR¹ or NR^{1 A}, and in which D represents CR² or NR^2A; p, q and r are each independently 0 or 1 ; each of M¹, M² and M³, and where present each of M⁴, M⁵ and M⁶, is CR⁷R⁸;

where the bond between one of the pairs M'-M², M²-M³, M³-M⁴, M⁴-M⁵ and M⁵-M⁶ may, instead of being a single bond, be a double bond, in which case R substituents are absent from that pair;

R¹ is selected from the group consisting of optionally substituted 5-10 membered heterocyclyl, optionally substituted phenyl, optionally substituted benzyl, halogen, cyano, nitro, OR^A, N(R^B)₂, -C(0)C|.₄alkyl optionally substituted with from 1 to 3 halogens, -S0₂C|_₄alkyl, Ci-salkyl, C_2- ₈alkenyl, C_2-8alkynyl, haloCi_-8alkyl, dihaloCi_-8alkyl, trihaloCi_-8alkyl, haloC_2-8alkenyl, dihaloC_2-8alkenyl, trihaloC2_-8alkenyl, haloC₂.₈alkynyl, dihaloC_3-8alkynyl, trihaloC_3-8alkynyl, cyanoCi_-8alkyl, Ci_-4alkoxyCi_₈alkyl, C_3-8cycloalkyl, and C_3-8cycloalkylCi_ alkyl, wherein when said heterocyclyl, phenyl or benzyl group is substituted, it is substituted with from 1 to 3 substituents, each substituent being independently selected from the group consisting of OR^A, N(R )₂, halogen, cyano, nitro, -C(0)Ci_-4alkyl, Ci_-6alkyl, C_2-6alkenyl, C_2-6alkynyl, haloC_1-6 alkyl, dihaloC_!-6alkyl and trihaloCi_-6alkyl;

R^1A is selected from the group consisting of optionally substituted 5-10 membered heterocyclyl, optionally substituted phenyl, optionally substituted benzyl, cyano, OR^A, N(R^B)₂, -C(0)C_1-4alkyl optionally substituted with from 1 to 3 halogens, -S0₂Ci_-4alkyl, C_1-8alkyl, C_2- alkenyl, C_2- ₈alkynyl, haloC_1-8alkyl, dihaloCi_-8alkyl, trihaloCi_ alkyl, haloC_2-8alkenyl, dihaloC_2-8alkenyl, trihaloC_2-8alkenyl, haloC_2-8alkynyl, dihaloC_3-8alkynyl, trihaloC_3- alkynyl, cyanoCi_-8alkyl, C_1-4alkoxyCi_-8alkyl, C₃_₈cycloalkyl, and C3_-8cycloalkylCi_-8alkyl, wherein when said heterocyclyl, phenyl or benzyl group is substituted, it is substituted with from 1 to 3 substituents, each substituent being independently selected from the group consisting of OR^A, N(R^B)₂, halogen, cyano, nitro, -C(0)Ci_-4alkyl, Ci_-6alkyl, C_2-6alkenyl, C_2-6alkynyl, haloCi_-6 alkyl, dihaloCi_-6alkyl and trihaloC]_-6alkyl; R² is selected from the group consisting of -C(NH₂)=N-OH, -C(0)N(R^c)₂, cyano, -CHO,

-CH=N-OH, -C(0)C|_-4alkyl optionally substituted with from 1 to 3 halogens, -C(0)NH-OH, -C(NH₂)=N-OH, -C(C0₂H)=N-OH, -C(0-d_-4alkyl)=NH, -C(NH₂)=N-NH₂, -C(0)-C(0)-NH₂, -C(0)C0₂H, -C0₂H, -CH₂-CO₂H, -CH(OH)C0₂H, -CH₂NH-CONH₂, C_l-6alkyl-NH₂, C,_-6alkyl- OH, -CH₂S0₃H, OR^A, -NH-C(NH₂)=NH, -NH-C(0)NH₂, -N=C(-NH-CH₂CH₂-NH-), N(R^B)₂, N(OH)₂, NHS0₂R^D, -S0₂C,_₄alkyl, -S-CN, -S-C(NH₂)=NH, -S-C(NH₂)=N-OH, S0₂N(R^E)₂, SO3H, cyanoC[.₆alkyl, C|-₄alkoxyC|-₆alkyl and optionally substituted 5-10 membered

heterocyclyl, wherein when said heterocyclyl group is substituted, it is substituted with from 1 to 3 substituents, each substituent being independently selected from the group consisting of OR^A, N(R )₂, halogen, cyano, Ci_-6alkyl and trihaloC|-₆alkyl;

R^2A is selected from the group consisting of -C(NH₂)=N-OH, -C(0)N(R^c)₂, cyano, -CHO, -CH=N-OH, -C(0)C alkyl optionally substituted with from 1 to 3 halogens, -C(0)NH-OH, -C(NH₂)=N-OH, -C(C0₂H)=N-OH, -C(0-C,_-4alkyl)=NH, -C(NH₂)=N-NH₂, -C(0)-C(0)-NH₂, -C(0)C0₂H, -C0₂H, -CH₂-CO₂H, -CH(OH)C0₂H, -CH₂NH-CONH₂, C_1-6alkyl-NH₂, C_]-6alkyl- OH, -CH₂S0₃H, hydrogen, OR^A, -NH-C(NH₂)=NH, -NH-C(0)NH₂, -N=C(-NH-CH₂CH₂-NH-), N(R^B)₂, NHS0₂R^D, -S0₂Ci_-4alkyl, -S-CN, -S-C(NH₂)=NH, -S-C(NH₂)=N-OH, S0₂N(R^E)₂, S0₃H, cyanoCi_-6alkyl, Ci_-4alkoxyCi_-6alkyl and optionally substituted 5-10 membered heterocyclyl, wherein when said heterocyclyl group is substituted, it is substituted with from 1 to 3 substituents, each substituent being independently selected from the group consisting of OR^A, N(R )₂, halogen, cyano, Ci_-6alkyl and trihaloCi_-6alkyl; each of R³, R⁴, R⁵ and R⁶ is independently selected from the group consisting of hydrogen, OR^A, N(R^B)₂, halogen, cyano, nitro, -C(0)C_{] -4}alkyl, Ci_-6alkyl, C_2-6alkenyl, C_2-6alkynyl, haloCi_₆ alkyl, dihaloCi_-6alkyl and trihaloCi.₆alkyl; each R⁷ and each R⁸ is independently selected from the group consisting of hydrogen, OR^A, N(R^B)₂, halogen, cyano, -C(0)Ci_-4alkyl, Ci_-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, halo Ci_-6 alkyl, dihalo Ci_-6 alkyl, trihalo Ci_-6 alkyl, haloC_2-6alkenyl, dihaloC_2-6alkenyl, trihaloC_2-6alkenyl, cyanoCi_₆alkyl, Ci_-4alkoxyCi_-6alkyl, C_3-8 cycloalkyl and C_3-8 cycloalkyl Ci_-6 alkyl; and each R^A, each R^B, each R^c, each R^D and each R^E is independently selected from the group consisting of hydrogen, Ci_₆alkyl, C_2-6alkenyl, C_2-6alkynyl, C3_-8cycloalkyl and C_3-8cycloalkylCi_ ₆alkyl; with the proviso that the compound of formula (I) is not:

(HI),

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

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 chiral. 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 ligands. 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 ER selective or display mixed ERoc and ERP activity. For example, the ligand may act both as an agonist or a partial agonist of ERP and as an antagonist or a partial antagonist of ERa. Compounds of the present invention are preferably estrogen receptor ligands that display ER selective agonism.

In the compounds of the invention, ring Z represents a pyrrolyl ring. A pyrrolyl ring is a 5- membered aromatic heterocycle containing four carbon and one nitrogen ring atoms. The invention encompasses compounds of formula (I) in which the pyrrolyl ring nitrogen may be in any position, i.e. having the formula:

(IE)

In one embodiment, ring Z is a pyrrolyl ring in which A represents carbon, B represents CR¹ or NR^{1 A}, D represents CR² or NR^2A, E represents nitrogen or carbon, and G represents nitrogen or carbon. In another, preferred, embodiment, ring Z is a pyrrolyl ring in which A represents nitrogen or carbon, B represents CR¹, D represents CR² or NR^2A, E represents nitrogen or carbon, and G represents carbon. More preferably, ring Z is a pyrrolyl ring in which A represents carbon, B represents CR¹, D represents NR^2A, E represents carbon, and G represents carbon, i.e. the compound h

(IC)

In the compounds of the invention, p, q and r are each independently 0 or 1. In other words, pyrrolyl ring Z is fused to a second ring formed by groups E, G, M¹, M² and M³, and, where present, M⁴, M⁵ and M⁶. The second ring contains 5, 6, 7 or 8 ring atoms. Preferably the second ring contains 5 ring atoms (p, q and r are each 0) or 6 ring atoms (e.g. p is 1, and q and r are both 0).

Each of M¹, M² and M³, and where present, each of M⁴, M⁵ and M⁶, is CR⁷R⁸, where the bond between one of the pairs M'-M², M²-M³, M³-M⁴, M⁴-M⁵ and M⁵-M⁶ may, instead of being a single bond, be a double bond, in which case R⁸ substituents are absent from that pair.

Preferably, each of M¹, M² and M³, and where present, each of M⁴, M⁵ and M⁶, is CR⁷R⁸ (i.e. there is no double bond between one of the pairs M'-M², M²-M³, M³-M⁴, M⁴-M⁵ and M⁵-M⁶). In other words, preferably the compound of formula (I) has the formula:

(IH)

More preferably, the compound of formula (I) has the formula

Still more preferably, the compound of formula (I) has the formula:

Yet more preferably, the compound of formula I has the formula:

When R¹ or R^{I A} represents a C|_-8alkyl, C2_-8alkenyl, C₂-8alkynyl, haloCi_-8alkyl, dihaloC|_-8alkyl, trihaloCi-galkyl, haloC_2-8alkenyl, dihaloC2-₈alkenyl, trihaloC₂_₈alkenyl, haloC₂_₈alkynyl, dihaloC₃_₈alkynyl, trihaloC₃-₈alkynyl, cyanoCi.₈alkyl or C|.₄alkoxyC| .₈alkyl group, this may for example be a C] .₆alkyl, C2-₆alkenyl, C₂.₆alkynyl, haloC|.₆alkyl, dihaloC |_-6alkyl, trihaloC i_₆alkyl, haloC₂_₆alkenyl, dihaloC_2-6alkenyl, trihaloC2_-6alkenyl, haloC₂.₆alkynyl, dihaloC3_₆alkynyl, trihaloC_3-6alkynyl, cyanoCj_₆alkyl or Ci_-4alkoxyCi_-6alkyl group. When R¹ or R^1A represents a C_3-8 cycloalkyl group, this may for example be a C_3-6cycloalkyl group. When R¹ or R^1A represents a C_3-8cycloalkylCi_-8alkyl group, this may for example be a C_3-8cycloalkylCi_₆alkyl, C_3-6cycloalkylCi_-8alkyl, or C_3-6cycloalkylCi_-6alkyl group.

When R¹ or R^1A represents a heterocyclyl group, the heterocyclyl group may be saturated or unsaturated and may contain one or more O, N and/or S atoms. Suitable heterocyclyl groups include furyl, thienyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, imidazolinyl, imidazolidine, pyrazolyl, pyrazolinyl, pyrazolidinyl, pyridyl, morpholinyl, benzofuryl, and piperidyl. In one preferred embodiment, the heterocyclyl group is 6-membered or, especially, 5-membered, and is preferably unsaturated, especially aromatic. Furyl, pyrrolyl, thienyl, isoxazolyl, isothiazolyl and pyrazolyl are preferred heterocyclyl groups, and with furyl, thienyl and especially isoxazolyl being particularly preferred groups. Heterocyclyl group R¹ or R^1A may include 1 to 3, for example 1 or 2, substituents. Preferred substituents are selected from OR^A, N(R^B)₂, halogen, cyano, nitro, -C(0)C_1-4alkyl, Ci_ ₆alkyl, C_2-6alkenyl, C₂-₆alkynyl, haloCi_₆ alkyl, dihaloCi_-6alkyl and trihaloC_1-6alkyl. More preferred substituents are selected from halogen, cyano, C^alkyl (especially methyl or ethyl), -C(0)Ci.₄alkyl, and OR^A in which R^A preferably represents a hydrogen atom or a Ci_₄alkyl group. Especially preferred substituents are selected from halogen, cyano and Ci_-4alkyl

(especially methyl or ethyl). A particularly preferred group R¹ or R^{1 A} is a 5-membered, aromatic heterocyclyl group substituted by two methyl groups. When said group contains only one ring heteroatom, an additional substituent, for example a halogen atom, may also be present.

Preferred substituents for a phenyl or benzyl group R¹ or R^{I A} include those mentioned above for a heterocyclyl group R¹ or R^{I A}.

Preferably, R¹ is selected from the group consisting of optionally substituted 5-10 membered heterocyclyl, optionally substituted phenyl, optionally substituted benzyl, N(R )₂, halogen, cyano, C₂-8alkenyl, C_2-8alkynyl, haloC_2-8alkenyl, dihaloC₂_8alkenyl, trihaloC_2-8alkenyl, haloC_2- galkynyl, dihaloC₃.₈alkynyl and trihaloC₃_₈alkynyl, wherein when said heterocyclyl, phenyl or benzyl group is substituted, it is substituted with from 1 to 3 substituents, each substituent being independently selected from the group consisting of OR A , N(R B )₂, halogen, cyano, nitro, -C(0)C|.₄alkyl, C|.₆alkyl, C₂.₆alkenyl, C₂.₆alkynyl, haloC|.₆ alkyl, dihaloC|_-6alkyl and trihaloCi- ₆alkyl; more preferably R¹ represents N(R^B)₂, halogen, cyano, C_2-6alkenyl or an optionally substituted 5-10 membered heterocyclyl, wherein when said heterocyclyl group is substituted, it is substituted with from 1 to 3 substituents, each substituent being independently selected from the group consisting of OR^A, N(R^B)₂, halogen, cyano, nitro, -C(0)Ci_-4alkyl, Ci_-6alkyl, C_2- ₆alkenyl, C_2-6alkynyl, haloCi_₆ alkyl, dihaloCi_-6alkyl and trihaloC^ealkyl; still more preferably R¹ represents halogen, cyano or a 5-membered aromatic heterocyclyl group substituted by one cyano group, one ethyl group or two methyl groups; yet more preferably R^1A represents cyano or a 5-membered aromatic heterocyclyl group substituted by two methyl groups; still more preferably R¹ represents an isoxazolyl, isothiazolyl, pyrrolyl, thienyl or furyl group substituted by two methyl groups. In one preferred embodiment, R¹ represents an optionally substituted 5- 10 membered heterocyclyl, for example an optionally substituted 5-membered heterocyclyl, such as an isoxazolyl, isothiazolyl, pyrrolyl, thienyl or furyl group.

Preferably, R^{1 A} is selected from the group consisting of optionally substituted 5-10 membered heterocyclyl, optionally substituted phenyl, optionally substituted benzyl, cyano, C_2-8alkenyl, C_2- ₈alkynyl, haloC_2-8alkenyl, dihaloC_2- alkenyl, trihaloC_2-8alkenyl, haloC_2-8alkynyl,

dihaloC_3-8alkynyl and trihaloC_3-8alkynyl, wherein when said heterocyclyl, phenyl or benzyl group is substituted, it is substituted with from 1 to 3 substituents, each substituent being independently selected from the group consisting of OR^A, N(R^B)₂, halogen, cyano, nitro, -C(0)C|_-4alkyl, Ci_-6alkyl, C_2-6alkenyl, C_2-6alkynyl, haloCi-6 alkyl, dihaloC_1-6alkyl and trihaloCi. ₆alkyl; more preferably R^1A represents cyano, C_2-6alkenyl or an optionally substituted 5-10 membered heterocyclyl, wherein when said heterocyclyl group is substituted, it is substituted with from 1 to 3 substituents, each substituent being independently selected from the group consisting of OR^A, N(R^B)₂, halogen, cyano, nitro, -C(0)Ci_-4alkyl, Ci_-6alkyl, C_2-6alkenyl, C_2-6alkynyl, haloC|_₆ alkyl, dihaloC|.₆alkyl and trihaloC|_6alkyl; still more preferably R^{1 A} represents cyano or a 5-membered aromatic heterocyclyl group substituted by one cyano group, one ethyl group or two methyl groups; yet more preferably R^{I A} represents cyano or a 5- membered aromatic heterocyclyl group substituted by two methyl groups; still more preferably R^{1 A} represents an isoxazolyl, isothiazolyl, pyrrolyl, thienyl or furyl group substituted by two methyl groups. In one preferred embodiment, R^{I A} represents an optionally substituted 5-10 membered heterocyclyl, for example an optionally substituted 5-membered heterocyclyl, such as an isoxazolyl, isothiazolyl, pyrrolyl, thienyl or furyl group. Particularly preferred heterocyclyl groups R¹ or R^1A include optionally substituted pyrrolyl, 3,5- dimethylisoxazol-4-yl, 3,5-dimethyl-fur-4-yl, and 3,5-dimethyl-thiophen-4-yl. More particularly preferred heterocyclyl groups R¹ or R^1A include 3,5-dimethylisoxazol-4-yl, 3,5-dimethyl-fur-4- yl, and 3,5-dimethyl-thiophen-4-yl.

Preferably, R² is selected from the group consisting of -C(NH₂)=N-OH, -C(0)N(R^c)₂, cyano, -CHO, -CH=N-OH, -C(0)NH-OH, -C(NH₂)=N-OH, -C(0-C_1-4alkyl)=NH, -C(NH₂)=N-NH₂, an optionally substituted 5-10 membered heterocyclyl group which contains one or more nitrogen atoms and -C(0)-C(0)-NH₂; more preferably, R² represents -C(NH₂)=N-OH, -C(0)NH₂, cyano or -CH=N-OH; still more preferably R² represents -C(NH₂)=N-OH or -CH=N-OH.

Preferably, R ^A is selected from the group consisting of -C(NH₂)=N-OH, -C(0)N(R^c)₂, cyano, -CHO, -CH=N-OH, -C(0)NH-OH, -C(NH₂)=N-OH, -C(0-Ci_-4alkyl)=NH, -C(NH₂)=N-NH₂, hydrogen, an optionally substituted 5-10 membered heterocyclyl group which contains one or more nitrogen atoms, and -C(0)-C(0)-NH₂; more preferably R^2A is selected from the group consisting of -C(NH₂)=N-OH, -C(0)N(R^c)₂, cyano, -CHO, -CH=N-OH, -C(0)NH-OH,

-C(NH₂)=N-OH, -C(0-Ci_₄alkyl)=NH, -C(NH₂)=N-NH₂, hydrogen and -C(0)-C(0)-NH₂; still more preferably, R^2A represents -C(NH₂)=N-OH, -C(0)NH₂, cyano, hydrogen or -CH=N-OH; yet more preferably R^2A represents -C(NH₂)=N-OH or -CH=N-OH.

Preferably each of R³, R⁴, R⁵ and R⁶ is independently selected from the group consisting of hydrogen, OR^A, halogen, cyano, Ci_-4alkyl, for example methyl, haloC|_-4alkyl, for example chloro- or fluoro-methyl, dihaloCi_-4alkyl, for example dichloro- or difluoromethyl, and trihaloCi- ₄alkyl, for example trichloro- or trifluoromethyl. More preferably each of R³, R⁴, R⁵ and R⁶ is independently selected from the group consisting of hydrogen, OH, halogen, cyano, methyl, or trifluoromethyl. Still more preferably each of R³, R⁴, R⁵ and R⁶ independently represents methyl or, especially, hydrogen and/or halogen, especially fluorine. Yet more preferably, each of R³, R⁴, R⁵ and R⁶ is independently selected from the group consisting of hydrogen and halogen. In one embodiment, each of R³, R⁴, R⁵ and R⁶ represents hydrogen. In a further preferred embodiment, one of R³ and R⁴ represents fluorine and the remainder of R³, R⁴, R⁵ and R⁶ represents hydrogen. Preferably, each R and each R is independently selected from the group consisting of hydrogen, Ci_-4 alkyl, C_2-4 alkenyl, C_2-4 alkynyl, halo C_1-4 alkyl, dihalo Ci_-4 alkyl, trihalo C_1-4 alkyl. More preferably, each R and each R is independently selected from the group consisting of hydrogen, halogen, Ci_-4 alkyl and trihalo C_1-4 alkyl.

Each R^A is preferably independently selected from the group consisting of hydrogen, Ci_-4alkyl, C_2-4alkenyl, C_2-4alkynyl and C_3-6cycloalkyl. More preferably, each R^A independently represents hydrogen or Ci_-4alkyl, especially methyl. Each R^B is preferably independently selected from the group consisting of hydrogen and Ci_-4alkyl, especially methyl. Each R is preferably

independently selected from the group consisting of hydrogen and Ci_-4alkyl, especially methyl. Each R^D is preferably independently selected from the group consisting of hydrogen and C_\. ₄alkyl, especially methyl. Each R is preferably independently selected from the group consisting of hydrogen and Ci_-4alkyl, especially methyl. In one preferred embodiment, each R^A, each R^B, each R^c, each R^D and each R^E is independently selected from the group consisting of hydrogen and Ci_-4alkyl.

In one embodiment, each of M¹, M² and M³, and where present each of M⁴, M⁵ and M⁶, is CR⁷R⁸ (i.e. the compound of formula (I) has the formula (IF), (IG), (IH or (II));

R¹ is selected from the group consisting of N(R^B)₂, optionally substituted 5-10 membered heterocyclyl, optionally substituted phenyl, optionally substituted benzyl, halogen, cyano, C₂_ ₈alkenyl, C_2-8alkynyl, haloC_2-8alkenyl, dihaloC_2-8alkenyl, trihaloC_2-8alkenyl, haloC₂_₈alkynyl, dihaloC_3-8alkynyl and trihaloC_3-8alkynyl, wherein when said heterocyclyl, phenyl or benzyl group is substituted, it is substituted with from 1 to 3 substituents, each substituent being

A B

independently selected from the group consisting of OR , N(R )₂, halogen, cyano, nitro,

-C(0)Ci_₄alkyl, C|.₆alkyl, C₂-₆alkenyl, C₂-₆alkynyl, haloCi-6 alkyl, dihaloCi_₆alkyl and trihaloC]. ₆alkyl; or R^{1 A} is selected from the group consisting of optionally substituted 5-10 membered heterocyclyl, optionally substituted phenyl, optionally substituted benzyl, cyano, C₂.₈alkenyl, C₂_ ₈alkynyl, haloC₂. alkenyl, dihaloC_2-8alkenyl, trihaloC_2-8alkenyl, haloC_2-8alkynyl,

dihaloC₃-₈alkynyl and trihaloC₃.₈alkynyl, wherein when said heterocyclyl, phenyl or benzyl group is substituted, it is substituted with from 1 to 3 substituents, each substituent being

A B

independently selected from the group consisting of OR , N(R )₂, halogen, cyano, nitro, -C(0)Ci_-4alkyl, Ci-₆alkyl, C_2-6alkenyl, C_2-6alkynyl, haloC_1-6 alkyl, dihaloCi_-6alkyl and trihaloC]. ₆alkyl;

R² represents -C(NH₂)=N-OH, -C(0)NH₂, cyano, an optionally substituted 5-10 membered heterocyclyl group which contains one or more nitrogen atoms, or -CH=N-OH; or R^2A represents -C(NH₂)=N-OH, -C(0)NH₂, cyano, hydrogen, an optionally substituted 5-10 membered heterocyclyl group which contains one or more nitrogen atoms, or -CH=N-OH;

each of R³, R⁴, R⁵ and R⁶ is independently selected from the group consisting of hydrogen and halogen; each R⁷ and each R⁸ is independently selected from the group consisting of hydrogen, halogen, Ci_₄ alkyl and trihalo C_1-4 alkyl; and

each R^A and each R^B is independently selected from the group consisting of hydrogen and Q. ₄alkyl.

In another embodiment, the compound of formula (I) has the formula (IF) or (IG);

R¹ is selected from the group consisting of optionally substituted 5-10 membered heterocyclyl, optionally substituted phenyl, optionally substituted benzyl, N(R^B)_2, halogen, cyano, C_2-8alkenyl, C_2-8alkynyl, haloC_2-8alkenyl, dihaloC_2-8alkenyl, trihaloC₂_₈alkenyl, haloC₂_₈alkynyl,

dihaloC₃_₈alkynyl and trihaloC _-8alkynyl, wherein when said heterocyclyl, phenyl or benzyl group is substituted, it is substituted with from 1 to 3 substituents, each substituent being independently selected from the group consisting of OR^A, N(R^B)₂, halogen, cyano, nitro, -C(0)Ci-₄alkyl, C]_-6alkyl, C_2-6alkenyl, C_2- alkynyl, haloCi_ alkyl, dihaloCi_₆alkyl and trihaloCi. ₆alkyl; or R^1A is selected from the group consisting of optionally substituted 5-10 membered heterocyclyl, optionally substituted phenyl, optionally substituted benzyl, cyano, C_2-8alkenyl, C_2- ₈alkynyl, haloC_2-8alkenyl, dihaloC_2-8alkenyl, trihaloC₂_₈alkenyl, haloC₂-₈alkynyl,

dihaloC₃_₈alkynyl and trihaloC₃-₈alkynyl, wherein when said heterocyclyl, phenyl or benzyl group is substituted, it is substituted with from 1 to 3 substituents, each substituent being independently selected from the group consisting of OR^A, N(R^B)₂, halogen, cyano, nitro, -C(0)Ci_₄alkyl, C|.₆alkyl, C₂-₆alkenyl, C_2-6alkynyl, haloCi_₆ alkyl, dihaloC|_₆alkyl and trihaloCi. ₆alkyl;

R represents -C(NH₂)=N-OH, -C(0)NH₂, cyano, an optionally substituted 5-10 membered heterocyclyl group which contains one or more nitrogen atoms, or -CH=N-OH; or R^2A represents -C(NH₂)=N-OH, -C(0)NH₂, cyano, hydrogen, an optionally substituted 5-10 membered heterocyclyl group which contains one or more nitrogen atoms, or -CH=N-OH; each of R³, R⁴, R⁵ and R⁶ is independently selected from the group consisting of hydrogen and halogen; each R 7 and each R 8 is independently selected from the group consisting of hydrogen, halogen, Ci_-4 alkyl and trihalo C alkyl; and

each R^A and each R^B is independently selected from the group consisting of hydrogen and C_\. ₄alkyl.

R¹ represents N(R^B)₂, halogen, cyano, C₂-₆alkenyl or a 5-10 membered heterocyclyl optionally substituted with from 1 to 3 substituents, each substituent being independently selected from the group consisting of OR^A, N(R^B)₂, halogen, cyano, nitro, -C(Q)Ci_-4alkyl, Ci_6alkyl, C_2-6alkenyl, C_2-6alkynyl, haloC_1-6 alkyl, dihaloCi_-6alkyl and trihaloCi-₆alkyl; or R^IA is cyano, C_2-6alkenyl or a 5-10 membered heterocyclyl optionally substituted with from 1 to 3 substituents, each substituent being independently selected from the group consisting of OR^A, N(R^B)₂, halogen, cyano, nitro, -C(0)Ci.₄alkyl, Ci_-6alkyl, C₂-₆alkenyl, C_2-6alkynyl, haloCi_-6 alkyl, dihaloCi_₆alkyl and trihaloCi_-6alkyl;

R² represents -C(NH₂)=N-OH, -C(0)NH₂, cyano or -CH=N-OH; or R^2A represents

-C(NH₂)=N-OH, -C(0)NH₂, cyano, hydrogen or -CH=N-OH;

each of R³, R⁴, R⁵ and R⁶ is independently selected from the group consisting of hydrogen and halogen;

each R⁷ and each R⁸ is independently selected from the group consisting of hydrogen, halogen, CM alkyl and trihalo Q_₄ alkyl; and

each R^A and each R^B is independently selected from the group consisting of hydrogen and Ci_ ₄alkyl. In another embodiment the compound of formula (I) has the formula (IF) or (IG);

R¹ is a 5-membered heterocyclyl optionally substituted with from 1 to 3 substituents, each substituent being independently selected from the group consisting of halogen, cyano, -C(0)Ci. ₄alkyl, Ci_-4alkyl, and OR^A; or R^{1 A} is a 5-membered heterocyclyl optionally substituted with from 1 to 3 substituents, each substituent being independently selected from the group consisting of halogen, cyano, -C(0)C_Malkyl, C_Malkyl, and OR^A;

-C(NH₂)=N-OH, -C(0)NH₂, cyano, hydrogen or -CH=N-OH; each of R³, R⁴, R⁵ and R⁶ is independently selected from the group consisting of hydrogen and halogen;

each R and each R is independently selected from the group consisting of hydrogen, halogen, Ci_-4 alkyl and trihalo C1-4 alkyl; and

each R^A and each R^B is independently selected from the group consisting of hydrogen and Ci_ ₄alkyl.

In another embodiment, the compound of formula (I) has the formula (IJ), (IK), (IL), (IM), (IN) or (10);

R is N(R )₂, halogen, cyano, C_2-6alkenyl or a 5-10 membered heterocyclyl optionally substituted with from 1 to 3 substituents, each substituent being independently selected from the group consisting of OR^A, N(R^B)₂, halogen, cyano, nitro, -C(0)Ci_₄alkyl, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, haloC_1-6 alkyl, dihaloCi_-6alkyl and trihaloCi_6alkyl;

-C(NH₂)=N-OH, -C(0)NH₂, cyano, hydrogen or -CH=N-OH;

each R 7 and each R 8 is independently selected from the group consisting of hydrogen, halogen, Ci_-4 alkyl and trihalo C|_-4 alkyl; and

In another embodiment, the compound of formula (I) has the formula ((IJ), (IK), (IL), (IM), (IN) or (10);

R¹ is a 5-membered heterocyclyl optionally substituted with from 1 to 3 substituents, each substituent being independently selected from the group consisting of halogen, cyano, -C(0)C|. ₄alkyl, C alkyl, and OR^A;

-C(NH₂)=N-OH, -C(0)NH₂, cyano, hydrogen or -CH=N-OH;

each R 7 and each R 8 is independently selected from the group consisting of hydrogen, halogen, C I -4 alkyl and trihalo C|_₄ alkyl; and each R and each R is independently selected from the group consisting of hydrogen and C_\. ₄alkyl.

In another embodiment, the compound of formula (I) has the formula (IL) or (IM);

R¹ is halogen, cyano or a 5-10 membered heterocyclyl optionally substituted with from 1 to 3 substituents, each substituent being independently selected from the group consisting of OR^A, N(R )₂, halogen, cyano, nitro, -C(0)C].4alkyl, Ci_-6alkyl, C_2-6alkenyl, C_2-6alkynyl, haloC_1-6 alkyl, dihaloCi_-6alkyl and trihaloCi_-6alkyl;

R^2A represents -C(NH₂)=N-OH, -C(0)NH₂, cyano, hydrogen or -CH=N-OH;

each R and each R is independently selected from the group consisting of hydrogen, halogen, C_1-4 alkyl and trihalo Ci_-4 alkyl; and

each R^A and each R^B is independently selected from the group consisting of hydrogen and Ci. ₄alkyl.

R¹ is a 5-membered heterocyclyl optionally substituted with from 1 to 3 substituents, each substituent being independently selected from the group consisting of halogen, cyano, -C(0)Ci_ ₄alkyl, C_1-4alkyl, and OR^A;

R^2A represents -C(NH₂)=N-OH, -C(0)NH₂, cyano, hydrogen or -CH=N-OH;

each R 7 and each R 8 is independently selected from the group consisting of hydrogen, halogen, C|-₄ alkyl and trihalo Ci_₄ alkyl; and

A B

each R and each R is independently selected from the group consisting of hydrogen and Ci_ ₄alkyl.

Compounds of the formula (I) include, but are not limited to, the compounds specifically mentioned in the Examples herein, including pharmaceutically acceptable esters, amides, carbamates or salts thereof, including salts of such esters, amides or carbamates.

Further compounds of the formula (I) include, but are not limited to, the following compounds: 2-(3,5-dimethylisoxazol-4-yl)-N'-hydroxy-3-(4-hydroxyphenyl)-2,4,5,6- tetrahydrocyclopenta[c]pyrrole-l -carboximidamide;

2- (3,5-dimethylisoxazol-4-yl)-3-(2-fluoro-4-hydroxyphenyl)-N'-hydroxy-5,6- dihydrocyclopenta[b]pyrrole- 1 (4H)-carboximidamide;

3-(2,6-difluoro-4-hydroxyphenyl)-2-(3,5-dimethylisoxazol-4-yl)-N'-hydroxy-5,6- dihydrocyclopenta[b]pyrrole- 1 (4H)-carboximidamide;

3- (2,5-difluoro-4-hydroxyphenyl)-2-(3,5-dimethylisoxazol-4-yl)-N'-hydroxy-5,6- dihydrocyclopenta[b]pyrrole- 1 (4H)-carboximidamide;

3-(2-chloro-4-hydroxyphenyl)-2-(3,5-dimethylisoxazol-4-yl)-N'-hydroxy-5,6- dihydrocyclopenta[b]pyrrole- 1 (4H)-carboximidamide;

3-(2-chloro-6-fluoro-4-hydroxyphenyl)-2-(3,5-dimethylisoxazol-4-yl)-N'-hydroxy-5,6- dihydrocyclopenta[b]pyrrole- 1 (4H)-carboximidamide;

3-(2,3-difluoro-4-hydroxyphenyl)-2-(3,5-dimethylisoxazol-4-yl)-N'-hydroxy-5,6- dihydrocyclopenta[b]pyrrole- 1 (4H)-carboximidamide;

3-(3,5-difluoro-4-hydroxyphenyl)-2-(3,5-dimethylisoxazol-4-yl)-N'-hydroxy-5,6- dihydrocyclopenta[b]pyrrole- 1 (4H)-carboximidamide;

2-(3,5-dimethylisoxazol-4-yl)-N'-hydroxy-3-(4-hydroxyphenyl)-4,5,6,7-tetrahydro-lH-indole-l- carboximidamide;

2- (3,5-dimethylisoxazol-4-yl)-3-(2-fluoro-4-hydroxyphenyl)-N'-hydroxy-4,5,6,7-tetrahydro-lH- indole- 1 -carboximidamide;

3- (2,6-difluoro-4-hydroxyphenyl)-2-(3,5-dimethylisoxazol-4-yl)-N'-hydroxy-4,5,6,7-tetrahydro- 1 H-indole- 1 -carboximidamide;

3-(2,5-difluoro-4-hydroxyphenyl)-2-(3,5-dimethylisoxazol-4-yl)-N'-hydroxy-4,5,6,7-tetrahydro- 1 H-indole- 1 -carboximidamide;

3-(2-chloro-4-hydroxyphenyl)-2-(3,5-dimethylisoxazol-4-yl)-N'-hydroxy-4,5,6,7-tetrahydro-lH- indole- 1 -carboximidamide;

3-(2,3-difluoro-4-hydroxyphenyl)-2-(3,5-dimethylisoxazol-4-yl)-N'-hydroxy-4,5,6,7-tetrahydro- 1 H-indole- 1 -carboximidamide;

3-(3,5-difluoro-4-hydroxyphenyl)-2-(3,5-dimethylisoxazol-4-yl)-N'-hydroxy-4,5,6,7-tetrahydro- 1 H-indole- 1 -carboximidamide;

or a pharmaceutically acceptable ester, amide, carbamate or salt thereof, including a salt of such an ester, amide or carbamate. In the compounds listed above and in the Examples, the compound names were generated in accordance with IUPAC by the ACD Labs 8.0/name program, version 8.05 and/or with ISIS DRAW Autonom 2000 and/or ChemBioDraw Ultra version 11.0. Depending upon the substituents present in compounds of the formula I, the compounds may form esters, amides, carbamates and/or salts. It will be understood by the skilled person that the invention also encompasses solvates of the compounds of formula (I), as well as solvates of esters, amides, carbamates and/or salts thereof. Salts and solvates of compounds of formula (I) which are suitable for use in medicine are those wherein a counterion or associated solvent is pharmaceutically acceptable. For example, a hydrate is an example of a pharmaceutically acceptable solvate. However, salts and solvates having non-pharmaceutically acceptable counterions or associated solvents are within the scope of the present invention, for example, for use as intermediates in the preparation of the compounds of formula (I) and their

pharmaceutically acceptable salts, solvates 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 (I), 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 alkanecarboxylic 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 hydroxycarboxylic acids, such as amino acids, or with organic sulfonic acids, such as (C,-C₄)-alkyl- or aryl-sulfonic acids which are unsubstituted or substituted, for example by halogen. Pharmaceutically acceptable acid addition salts include those fomied from hydrochloric, hydrobromic, sulphuric, nitric, citric, tartaric, acetic, phosphoric, lactic, pyruvic, acetic, trifluoroacetic, succinic, perchloric, fumaric, maleic, glycolic, lactic, salicylic, oxaloacetic, methanesulfonic, ethanesulfonic, p-toluenesulfonic, formic, benzoic, malonic, naphthalene-2-sulfonic, benzenesulfonic, isethionic, ascorbic, malic, phthalic, aspartic, and glutamic acids, lysine and arginine. 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 dicyclohexylamine, N-methyl-D- glucomine, morpholine, thiomorpholine, piperidine, pyrrolidine, a mono-, di- or tri-lower alkylamine, for example ethyl-, tert-butyl-, diethyl-, diisopropyl-, triethyl-, tributyl- or dimethyl- propylamine, or a mono-, di- or trihydroxy lower alkylamine, 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^F, -CONR^F ₂, -S0₂OR^F, or -S0₂N(R^F)₂, while typical ester and amide and carbamate groups formed from an -OH or -NHR^B group in the compound of the formula (I) include -OC(0)R^F, -NR^FC(0)R^F, -NR^FC0₂R^F -OS0₂R^F, and— NR^FS0₂R^F, where R^F is selected from the group consisting of Ci_-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-8cycloalkyl and C₃_₈cycloalkylCi.₆alkyl, and where R 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".

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, 1985; and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, 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 "alkyl" means both straight and branched chain saturated hydrocarbon groups. Examples of alkyl groups include methyl, ethyl, n-propyl, iso-propyl, n-butyl, t-butyl, i- butyl, sec-butyl, pentyl and hexyl groups. Among unbranched alkyl groups, there are preferred methyl, ethyl, n-propyl, iso-propyl, n-butyl groups. Among branched alkyl groups, there may be mentioned t-butyl, i-butyl, 1 -ethylpropyl and 1-ethylbutyl groups.

As used herein, the term "alkoxy" means the group O-alkyl, where "alkyl" 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 "alkenyl" means both straight and branched chain unsaturated hydrocarbon groups with at least one carbon carbon double bond. Examples of alkenyl groups include ethenyl, propenyl, butenyl, pentenyl and hexenyl. Preferred alkenyl groups include ethenyl, 1 -propenyl, 2-propenyl and but-2-enyl.

As used herein, the term "alkynyl" means both straight and branched chain unsaturated hydrocarbon groups with at least one carbon carbon triple bond. Examples of alkynyl groups include ethynyl, propynyl, butynyl, pentynyl and hexynyl. Preferred alkynyl groups include ethynyl, 1 -propynyl and 2-propynyl.

As used herein, the term "cycloalkyl" means a saturated group in a ring system. A cycloalkyl group can be monocyclic or bicyclic. A bicyclic group may, for example, be fused or bridged. Examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl and cyclopentyl. Other examples of monocyclic cycloalkyl groups are cyclohexyl, cycloheptyl and cyclooctyl. Examples of bicyclic cycloalkyl groups include bicyclo [2. 2.1 ]hept-2-yl. Preferably, the cycloalkyl group is monocyclic.

As used herein, the term "aryl" means a monocyclic or bicyclic aromatic carbocyclic group. Examples of aryl groups include phenyl and naphthyl. A naphthyl group may be attached through the 1 or the 2 position. In a bicyclic aromatic group, one of the rings may, for example, be partially saturated. Examples of such groups include indanyl and tetrahydronaphthyl.

Specifically, the term C5.10 aryl is used herein to mean a group comprising from 5 to 10 carbon atoms in a monocyclic or bicyclic aromatic group. A particularly preferred C_5-io aryl group is phenyl.

As used herein, the term "halogen" means fluorine, chlorine, bromine or iodine. Fluorine, chlorine and bromine are particularly preferred.

As used herein, the term "haloalkyl" means an alkyl group having a halogen substituent, the terms "alkyl" and "halogen" being understood to have the meanings outlined above. Similarly, the term "dihaloalkyl" means an alkyl group having two halogen substituents and the term "trihaloalkyl" means an alkyl group having three halogen substituents. Examples of haloalkyl groups include fluoromethyl, chloromethyl, bromomethyl, fluoromethyl, fluoropropyl and fluorobutyl groups; examples of dihaloalkyl groups include difluoromethyl and difluoroethyl groups; examples of triihaloalkyl groups include trifluoromethyl and trifluoroethyl groups. As used herein, the term "heterocyclyl" 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 heterocyclyl group may, for example, be monocyclic or bicyclic. In a bicyclic heterocyclyl group there may be one or more heteroatoms in each ring, or only in one of the rings. A heteroatom may be S, O or N and is preferably O or N. Heterocyclyl groups containing a suitable nitrogen atom include the corresponding N-oxides.

Examples of monocyclic non-aromatic heterocyclyl groups (also referred to as monocyclic heterocycloalkyl rings) include aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl and azepanyl.

Examples of bicyclic heterocyclyl groups in which one of the rings is non-aromatic include dihydrobenzofuranyl, indanyl, indolinyl, isoindolinyl, tetrahydroisoquinolinyl,

tetrahydroquinolyl and benzoazepanyl.

Examples of monocyclic aromatic heterocyclyl groups (also referred to as monocyclic heteroaryl groups) include furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, pyridyl, triazolyl, triazinyl, pyridazyl, isothiazolyl, isoxazolyl, pyrazinyl, pyrazolyl and pyrimidinyl, with preferred monocyclic aromatic heterocyclyl groups being furanyl, thienyl, pyrrolyl, oxazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, pyridyl, triazolyl, triazinyl, pyridazyl, isothiazolyl, isoxazolyl, pyrazinyl, pyrazolyl and pyrimidinyl.

Examples of bicyclic aromatic heterocyclyl groups (also referred to as bicyclic heteroaryl groups) include quinoxalinyl, quinazolinyl, pyridopyrazinyl, benzoxazolyl, benzothiophenyl, benzimidazolyl, naphthyridinyl, quinolinyl, benzofuranyl, indolyl, benzothiazolyl, oxazolyl[4,5- bjpyridiyl, pyridopyrimidinyl, isoquinolinyl and benzodroxazole.

Examples of preferred heterocyclyl groups include piperidinyl, tetrahydrofuranyl,

tetrahydropyranyl, pyridyl, pyrimidinyl and indolyl. Preferred heterocyclyl groups also include thienyl, thiazolyl, furanyl, pyrazolyl, pyrrolyl, isoxazolyl and imidazolyl. As used herein the term "cycloalkylalkyl" means a group cycloalkyl-alkyl- attached through the alkyl group, "cycloalkyl" and "alkyl" being understood to have the meanings outlined above.

As mentioned above, the compounds of the invention 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 activity as an agonist or a partial agonist of ΕΡνβ. Preferred compounds of this type are selective agonists of the estrogen receptor-beta

The invention also provides a compound of formula (I), or a composition comprising a compound of formula (I), together with a pharmaceutically acceptable carrier, for use as a medicament. The invention also provides a compound of formula (III)

or a pharmaceutically acceptable ester, amide or salt thereof, including a salt of such an ester or amide, for use as a medicament.

A compound of the invention, or a composition comprising a compound 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 are agonists or partial agonists of the estrogen receptor may be used in the treatment of diseases or disorders for which selective agonists or partial 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 levels 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, IBD, IBS, sexual dysfunction, hypertension, retinal degeneration, and lung, colon, breast, uterus, and prostate cancer, lymphoma, and/or disorders related to estrogen functioning.

The compounds of the invention find particular application in the treatment or prophylaxis 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 behavior, attention deficit disorder, attention deficit hyperactivity disorder, sleep disorders, irritability, impulsivity, 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 the bile duct cancer form named cholangiocarcinoma. The compounds of the invention also find particular application in the treatment or prophylaxis of the following: 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 (B-cell lymphoma, T-cell lymphoma), atherosclerosis, left ventricular hypertrophy, congestive heart failure, mesothelia, gallbladder cancer and extra-hepatic chloangiocarcinoma.

In combination with drugs that are known to induce vasomotor symptoms, the compounds of the invention find utility as follows: in combination with SERMs such as tamoxifen, in its use for the treatment of breast cancer, and raloxifene, used for the treatment and/or prevention of osteoporosis, to alleviate SERM-induced vasomotor symptoms; in combination with an aromatase inhibitor, used for the treatment of breast cancer or endometriosis, to alleviate aromatase inhibitor-induced vasomotor symptoms; and in male prostate cancer patients that have undergone androgen deprivation therapy.

In one embodiment of the invention, the present compounds finds particular application in the treatment or prophylaxis of depression, perimenopausal depression, post-partum depression, premenstrual syndrome and manic depression.

The treatment or prophylaxis of hot flashes (or hot flushes) in males, is preferable for patients that have 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 associated with 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 according to the invention, or a composition comprising a compound according to the invention together with a pharmaceutically acceptable character. 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 prophylaxis of a condition associated with a disease or disorder associated with estrogen receptor activity. 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 mg per kg of body weight per day (mg/kg/day) to about 100 mg/kg/day, preferably 0.01 mg per kg of body weight per day (mg/kg/day) 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 mg 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. Furthemiore, preferred compounds for the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdemial 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 than 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 or composition comprising a compound according to the invention, and a pharmaceutically acceptable diluent, excipient or carrier (collectively referred to herein as "carrier" materials). Pharmaceutical compositions of the invention 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 formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. 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 predetermined 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, suspensions or syrups; or as an oil-in-water liquid emulsion or a water-in-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 form suitable for immediate release or extended release. Immediate release or extended release can 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 liposomally.

Exemplary compositions for oral administration include suspensions which can contain, for example, microcrystalline cellulose for imparting bulk, alginic acid or sodium alginate as a suspending agent, methylcellulose 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 excipients, 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, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like. Disintegrators include without limitation starch, methylcellulose, agar, bentonite, xanthan gum and the like. The compounds of formula (I) 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 mannitol, lactose, sucrose and/or cyclodextrins. Also included in such formulations may be high molecular weight excipients 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 cellulose (SCMC), maleic anhydride copolymer (e.g., Gantrez), and agents to control release such as polyacrylic 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 oleate, sodium stearate, magnesium stearate, sodium benzoate, 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 ethanol, glycerol, water, and the like.

The compounds of the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, 1,2- dipalmitoylphosphatidyl choline, phosphatidyl ethanolamine (cephaline) , 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 multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilised) condition requiring only the addition of the sterile liquid carrier, for example saline or water- for-injection, 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, parenterally acceptable diluents or solvents, such as mannitol, 1 ,3- butanediol, 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 solubilizing 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 buccally or sublingually, 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 Plastibase (mineral oil gelled with polyethylene).

Preferred unit dosage formulations are those containing an effective 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 active ingredient in a medicament, it is also possible for the compound to be used in combination with one or more further therapeutic agents. Thus, the invention also provides a compound according to the invention together with a further therapeutic agent, for simultaneous, sequential or separate administration. Such further therapeutic agents may be further compounds according to the invention, or they may be different therapeutic agents, for example 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 material. For example, the compounds of the instant invention may be effectively administered in combination with effective amounts of other agents such as an antidepressant, an anxiolytic, an anti-psychotic, an organic bisphospho- nate 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 noradrenaline reuptake inhibitors (NRI), selective serotonin reuptake inhibitors, monoamine oxidase inhibitors, tricyclic antidepressants (TCA), dopamine reuptake inhibitors (DRI), opioids, selective seretonic reuptake enhancers, tetracyclic antidepressants, reversible inhibitors of monoamine oxidase, melatonin agonists, serotonin and noradrenaline reuptake inhibitors (SNRI), corticotropin releasing factor antagonists, a-adrenoreceptor antagonists, 5ΗΤ1α receptor agonists and antagonists, lithium and atypical anti-psychotics. Examples of antidepressants of the SSRI class include Fluoxetine and Sertraline; examples of antidepressants of the SNRI class Venlafaxine, Citalopram, Paroxetine, Escitalopram, Fluvoxamine; examples of antidepressants of the SNRI class include Duloxetine; examples of antidepressants of the DRI and NRI classes include Bupropion; examples of antidepressants of the TCA class include Amitriptyline 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-benzodiazapines. Examples of benzodiazapines include lorazepam, alprazolam, and diazepam. Examples of non-benzodiazapines include Buspirone (Buspar^®), barbiturates and meprobamate. One or more of those further anti-depressants may be used in combination.

Examples of anti-cancer agents include tamoxifen or an aromatase 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 tamoxifene 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, minodronate, 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 monosodium trihydrate. The precise dosage of the bisphosphonate will vary 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 determined by the caregiver or clinician. An appropriate amount can be determined by routine experimentation from animal models and human clinical studies.

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 μg kg of body weight and preferably about 10 to about 2000 μg/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 this 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, for 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 bisphospho- nate or a cathepsin K inhibitor, the compounds of formula (I) 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 a disease or disorder associated with estrogen receptor activity. 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 identifying ligands for the estrogen receptor (i.e.

discovering other agonists, partial agonists, antagonists or partial antagonists of the estrogen receptor). Thus, the invention provides a method of identifying an estrogen receptor ligand which comprises use of a compound of the invention 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 nitrogen-containing heterocycles, for example: Heterocyclic Chemistry, Joule, J. A.; Mills, K. 2000. A number of possible synthetic routes are shown schematically below. Where appropriate, any initially produced compound according to the invention can be converted 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

1 2

represents nitrogen, B represents CR , D represents CR , E represents carbon, G represents carbon, , q and r are each 0, R² represents cyano or -C(NH₂)=N-OH, each of M¹, M² and M³ is CR⁷R⁸, and each R⁷ and each R⁸ is hydrogen.

(a) CuBr₂, EtOAc; (b) 4-cyclopentenylmorpholine, 4-ethylmorpholine, toluene; (c) AcOH, MeOH;

(d) chlorosulfonyl isocyanate, MeCN/DMF; (e) BF₃ SMe₂, DCM; (f) NH₂OH, MeOH

General Method I as shown in the reaction scheme above was used for the synthesis of the following Examples: 1 and 2. Full experimental details of the individual steps of the general method applicable for the synthesis of the final compounds of those Examples are described in Examples 1 and 2.

General method II

The following general method can be used to prepare compounds of formula (I) wherein wherein A represents nitrogen, B represents CR¹, D represents CR², E represents carbon, G represents carbon, p is 1 , q and r are both 0, and R² is cyano, -C(NH₂)=N-OH or -C(0)NH₂, each of M¹, M², M³ and M⁴ is CR⁷R⁸, and each R⁷ and each R⁸ is hydrogen. General method II

(a) 4-cyclohexenylmorpholine, 4-ethylmorpholine,toluene; (b) AcOH, MeOH;

(c) chlorosulfonyl isocyanate, MeCN/DMF; (d) BF₃ SMe₂, DCM; (e) NH₂OH, MeOH

General Method II as shown in the reaction scheme above was used for the synthesis of the following Examples: 3-5. Full experimental details of the individual steps of the general method applicable for the synthesis of the final compounds of those Examples are described in Examples 3-5.

It should be understood that general methods analogous to General Method II may be used to prepare analogous compounds in which p and q are each 1 and r is 0, and M⁵ is also CR⁷R⁸; and in which p, q and r are each 1 , and M⁵ and M⁶ are also each CR⁷R⁸.

General method III

The following general method can be used to prepare compounds of formula (I) wherein A represents carbon, B represents CR¹, D represents NR^2A, E and G each represent carbon, p, q and r are each 0, R^2A is hydrogen, cyano, -C(NH₂)=N-OH or -C(0)NH₂, each of M¹, M² and M³ is CR⁷R⁸, and each R⁷ and each R⁸ is hydrogen.

(a) HMDS, HOAc; EtOH; (b) NBS, DCM; (c) Boc₂0, Et₃N, DMAP, MeCN; (d) Pd(PPh₃)₄, K₂C0₃, DME/H₂0; (e) MeONa, THF; (f) BF₃ SMe₂, DCM; (g) 4,4'-(propane-2,2-diyl)bis(cyanatobenzene), NaH, THF, (h) BF₃ SMe₂, DCM; (i) NH₂OH, MeOH

General Method III as shown in the reaction scheme above was used for the synthesis of the following Examples: 6-9, 13 and 14. Full experimental details of the individual steps of the general method applicable for the synthesis of the final compounds of those Examples are described in Examples 6-9.

It should be understood that general methods analogous to General Method III may be used to

4 7 8 prepare analogous compounds in which p is 1 and q and r are each 0, and M is CR R ; in which p and q are each 1 and r is 0, and M⁴ and M⁵ are each CR⁷R⁸; and in which p, q and r are each 1, and M⁴, M⁵ and M⁶ are each CR⁷R⁸.

General method IV The following general method can be used to prepare compounds of formula (I) wherein A represents carbon, B represents CR¹, D represents NR^2A, E and G each represent carbon, p is 1 , q and r are each 0, R^2A is hydrogen, each of M¹, M², M³ and M⁴ is CR⁷R⁸, and each R⁷ and each R^! is hydrogen.

General method IV

(a) HMDS, HOAc; EtOH; (b) NBS, DCM; (c) Boc₂0, Et₃N, DMAP, MeCN;

(d) Pd(PPh₃)₄, K₂C0₃, DME/H₂0; (e) MeONa, THF; (f) BF₃ SMe₂, DCM;

General Method IV as shown in the reaction scheme above was used for the synthesis of Example 10. Full experimental details of the individual steps of the general method applicable for the synthesis of the final compound of that Example are described in Example 10.

General method V

The following general method can be used to prepare compounds of formula (I) wherein A represents carbon, B represents NR^{I A}, D represents CR², E and G each represent carbon, p is 1 , q and r are each 0, R² is cyano or -C(NH₂)=N-OH, each of M¹, M², M³ and M⁴ is CR⁷R⁸, and each R⁷ and each R⁸ is hydrogen. General method V

(a) Ethyl isocyanoacetate, DBU, THF; (b) Aryliodide, Cul, Cs₂C0₃, DMF; (c) NBS,

DCM; (d) Pd(PPh₃)₄, NaHC0₃,DME/H₂0; (e) 1.Bu₄NOH, MeOH 2.HCI;

(f) chlorosulfonyl isocyanate, MeCN/DMF; (g) BBr₃, DCM; (h) NH₂OH, MeOH

General Method V as shown in the reaction scheme above was used for the synthesis of Example 1 1. Full experimental details of the individual steps of the general method applicable for the synthesis of the final compound of that Example are described in Example 1 1.

It should be understood that general methods analogous to General Method V may be used to prepare analogous compounds in which p, q and r are each 0; in which p and q are each 1 and r is 0, and M⁴ and M⁵ are each CR⁷R⁸; and in which p, q and r are each 1 , and M⁴, M⁵ and M⁶ are each CR⁷R⁸.

General method VI

The following general method can be used to prepare compounds of formula (I) wherein A represents carbon, B represents CR , D represents CR , E represents carbon, G represents nitrogen, , q and r are each 0, R is cyano or -C( H₂)=N-OH, each of M¹, M² and M³ is CR⁷R⁸,

7 R

and each R and each R is hydrogen. general method VI

(a) Methyl 2-cyanoacetate; (b) NaOH, H₂0; (c) LDA, THF; (d) THF; (e) Silica gel, DCM; (f) NBS, DCM;

(g) BBr₃, DCM; (h) R¹-boronic acid or ester, Pd(PPh₃)₄, NaHC0₃, DME/H₂0; (i) NH₂OH, MeOH

General Method VI as shown in the reaction scheme above was used for the synthesis of Example 12. Full experimental details of the individual steps of the general method applicable for the synthesis of the final compound of that Example are described in Example 12. It should be understood that general methods analogous to General Method VI may be used to prepare analogous compounds in which p is 1 and q and r are each 0, and M⁴ is CR⁷R⁸; in which p and q are each 1 and r is 0, and M⁴ and M⁵ are each CR⁷R⁸; and in which p, q and r are each 1 , and M⁴, M⁵ and M⁶ are each CR⁷R⁸. General method VII

The following general method can be used to prepare compounds of formula (I) wherein A represents carbon, B represents CR , D represents CR , E represents nitrogen, G represents carbon, , q and r are each 0, R² is cyano or -C(NH₂)=N-OH, each of M¹, M² and M³ is CR⁷R⁸, and each R and each R is hydrogen.

General method VII

(a) Br₂, HOAc; (b) 3-bromopropene, K₂C0₃, MeCN; (c) Potassium vinyltrifluoroborate, Pd(PPh₃)₄, K₂C0₃,

DME/H₂0; (d) Pd(PPh₃)₄, K₂C0₃, DME/H₂0; (e) Hoveyda-Grubbs cat., DCM; (f) Rh/C, H₂, EtOAc;

(g) NBS, DMF; (h) BBr₃, DCM; (i) R¹-boronic acid or ester, Pd(PPh₃)₄, K₂C0₃, DME/H₂0; (j) NH₂OH, EtOH

General Method VII as shown in the reaction scheme above was used for the synthesis of Example 15. Full experimental details of the individual steps of the general method applicable for the synthesis of the final compound of that Example are described in Example 15. The following Examples illustrate the invention.

Examples 1 and 2

2- (3,5-dimethylisoxazol-4-yI)-l-(4-hydroxyphenyl)-l,4,5,6-tetrahydrocyclopenta[b]pyrrole-

3- carbonitrile (El)

2-(3,5-dimethylisoxazol-4-yl)-N'-hydroxy-l-(4-hydroxyphenyl)-l,4,5,6- tetrahydrocycIopenta[b]pyrrole-3-carboximidamide (E2)

(a) CuBr₂, EtOAc; (b) 4-cyclopentenylmorp oline, 4-ethylmorpholine, toluene; (c) 4-methoxyaniline, AcOH, MeOH; (d) chlorosulfonyl isocyanate, MeCN/DMF; (e) BF₃ SMe₂, DCM; (f) NH₂OH, MeOH

Scheme 1 Step (a): l-(3,5-dimethylisoxazol-4-yl)ethanone (139 mg, 3.0 mmol) was dissolved in EtOAc (15 mL) and CuBr₂ (1364 mg, 6.1 mmol) was added. The mixture was stirred for 2 h at 75 °C. CuBr₂ (150 mg, 0.67 mmol) was added and the mixture was stirred at 75 °C for another hour. The mixture was cooled to room temperature, filtered through a plug of celite and concentrated. The crude product was purified on silica using a gradient of EtOAc/rc-heptane (1 :9 to 2:8) as mobile phase. 320 mg 2-bromo-l-(3,5-dimethylisoxazol-4-yl)ethanone was obtained as a clear oil.

Step (b): 4-cyclopentenylmorpholine (230 mg, 1.51 mmol) and 4-ethylmorpholine (173 mg, 1.51 mmol) were dissolved in dry toluene (2 mL). The vial was sealed and heated at 1 10 °C and 2-bromo-l -(3,5-dimethylisoxazol-4-yl)ethanone (328 mg, 1.51 mmol) dissolved in dry toluene (1.5 mL) was added dropwise over 15 min. The resulting orange mixture was heated at 1 10 °C for 16 h and then cooled to room temperature. HC1 (1.5 mL, 1 M) was added and the mixture was stirred for 2 h. The phases were partitioned, the organic phase was washed with water and brine, dried over Na₂S0₄ and concentrated. The crude product was purified on silica using a gradient of EtOAc/rc-heptane (20:80 to 25:75) as mobile phase. 221 mg 2-(2-(3,5- dimethylisoxazol-4-yl)-2-oxoethyl)cyclopentanone was obtained as a yellowish oil. Step (c): 2-(2-(3,5-dimethylisoxazol-4-yl)-2-oxoethyl)cyclopentanone (50 mg, 0.23 mmol), 4- methoxyaniline (139 mg, 1.13 mmol) and molecular sieves (230 mg, 4A) were mixed in MeOH (4.6 mL) and AcOH (0.065 mL, 1.13 mmol) was added. The vial was flushed with nitrogen, sealed and heated at 60 °C for 21 h. The mixture was cooled to room temperature, filtered through celite and concentrated. The crude product was purified on silica using EtOAc/«-heptane (1 :9) as mobile phase. 47.6 mg 4-(l-(4-methoxyphenyl)-l,4,5,6-tetrahydrocyclopenta[b]pyrrol-2- yl)-3,5-dimethylisoxazole was obtained as a yellowish solid.

Step (d): Chlorosulfonyl isocyanate (43.8 mg, 0.31 mmol) was added to a solution of 4-(l-(4- methoxyphenyl)-l,4,5,6-tetrahydrocyclopenta[b]pyrrol-2-yl)-3,5-dimethylisoxazole (47.8 mg, 0.16 mmol) in dry MeCN/DMF (1 :1, 1.5 mL) at 0 °C under nitrogen. The mixture was stirred at 0 °C for 0.5 h.

Chlorosulfonyl isocyanate (56.9 mg, 0.40 mmol) was added and the mixture was stirred for another 0.5 h. HC1 (1M) and DCM were added. The phases were partitioned, the aqueous phase was extracted with DCM. The combined organic layers were dried over Na₂S0_4j filtered and concentrated. The crude product was purified on silica using a gradient of EtOAc/n-heptane (15:85 to 20:80) as mobile phase. 44.5 mg 2-(3,5-dimethylisoxazol-4-yl)-l-(4-methoxyphenyl)- l,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carbonitrile was obtained as a white solid. Step (e): 2-(3,5-dimethylisoxazol-4-yl)-l -(4-methoxyphenyl)-l, 4,5,6- tetrahydrocyclopenta[b]pyrrole-3-carbonitrile (45mg, 0.13) was dissolved in DCM (1.5 mL) and the mixture was cooled to 0 °C. BF₃ SMe₂ (173 mg, 1.33 mmol) was added, the cooling bath was removed and the reaction mixture was stirred at room temperature for 0.5 h. The mixture was cooled to 0 °C and MeOH (320 μΐ) was added followed by NaHC0₃ (sat., 50 %) The aqueous phase was extracted with DCM and the combined organic phases were concentrated. The crude product was purified on silica using DCM/MeOH as mobile phase. 33 mg 2-(3,5- dimethylisoxazol-4-yl)-l -(4-hydroxyphenyl)- 1 ,4,5, 6-tetrahydrocyclopenta[b]pyrrole-3- carbonitrile (El) was obtained as a white solid. ES/MS m/z: 320.3 (M+H), 317.8 (M-H); Ή NMR (CDC1₃, 500MHz): 6.89 (m, 2H), 6.78 (m, 2H), 2.82 (m, 2H), 2.76 (m, 1H), 2.66 (m, 1H), 2.47 (m, 2H), 2.28 (s, 3H) and 1.89 (s, 3H).

Step (f): 2-(3,5-dimethylisoxazol-4-yl)-l -(4-hydroxyphenyl)-l , 4,5,6- tetrahydrocyclopenta[b]pyrrole-3-carbonitrile (20 mg, 0.06 mmol) was dissolved in MeOH (0.51 mL) and hydroxylamine (1.53 mL, 21.0 mmol, 16.3 M) was added under nitrogen. The mixture was heated in microwave at 150 °C for 10 min. The solvent was evaporated, the remaining aqueous mixture was extracted with DCM and the combined organic phases were concentrated. The crude product was purified on reversed phase chromatography using MeCN/H₂0 (2:8 - 35:65) as mobile phase. 14.7 mg 2-(3,5-dimethylisoxazol-4-yl)-N'-hydroxy-l-(4- hydroxyphenyl)-l,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carboximidamide (E2) was obtained as a white solid. ES/MS m/z: 353.3 (M+H), 351.4 (M-H); Ή NMR (MeOD, 500MHz): 6.86 (m, 2H), 6.73 (m, 2H), 2.81 (m, 2H), 2.67 (m, 2H), 2.42 (m, 2H), 2.04 (s, 3H) and 1.92 (s, 3H). For Example 2, the title compound was identified by ¹ 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 3,4 and 5

2-(3,5-dimethylisoxazol-4-yl)-l-(4-hydroxyphenyl)-4,5,6,7-tetrahydro-lH-indoIe-3- carbonitrile (E3)

2-(3,5-dimethylisoxazol-4-yl)-N'-hydroxy-l-(4-hydroxyphenyl)-4,5,6,7-tetrahydro-lH- indole-3-carboximidamide (E4)

2-(3,5-dimethylisoxazol-4-yl)-l-(4-hydroxyphenyl)-4,5,6,7-tetrahydro-lH-indole-3- carboxamide (E5)

(a) 4-cyclohexenylmorpholine, 4-ethylmorpholine, toluene; (b) 4-methoxyaniline, AcOH, MeOH; (c) chlorosulfonyl isocyanate, MeCN/DMF; (d) BF₃ SMe₂, DCM; (e) NH₂OH, MeOH

Scheme 2 Step (a): 4-cyclohexenylmorpholine (249 mg, 1.49 mmol) and 4-ethylmorpholine (172 mg, 1.49 mmol) were dissolved in dry toluene (2 mL). The vial was sealed and heated at 110 °C. 2-bromo-

1- (3,5-dimethylisoxazol-4-yl)ethanone (325 mg, 1.49 mmol) dissolved in dry toluene (1.5 mL) was added dropwise over 15 min. The resulting orange mixture was heated at 110 °C for 16 h and then cooled to room temperature. HCl (2 mL, 1M) was added and the mixture was stirred for 2 h. The phases were partitioned, the organic phase was washed with water and brine, dried over Na₂S0₄ and concentrated. The crude product was purified on silica using a gradient of EtOAc/rc- heptane (1 :9 to 3:7) as mobile phase. 129 mg 2-(2-(3,5-dimethylisoxazol-4-yl)-2- oxoethyl)cyclohexanone was obtained.

Step (b): 22-(2-(3,5-dimethylisoxazol-4-yl)-2-oxoethyl)cyclohexanone (58 mg, 0.25 mmol), 4- methoxyaniline (152 mg, 1.23 mmol) and molecular sieves (250 mg, 4A) were mixed in MeOH (5 mL). AcOH (0.070 mL, 1.23 mmol) was added. The vial was flushed with nitrogen, sealed and heated at 60 °C for 16 h. The mixture was cooled to room temperature, filtered through celite and concentrated. The crude product was purified on silica using EtOAc/ra-heptane (2:8) as mobile phase. 64 mg 4-(l-(4-methoxyphenyl)-4,5,6,7-tetrahydro-lH-indol-2-yl)-3,5- dimethylisoxazole was obtained. Step (c): Chlorosulfonyl isocyanate (56 mg, 0.40 mmol) was added to a solution of 4-(l-(4- methoxyphenyl)-4,5,6,7-tetrahydro-lH-indol-2-yl)-3,5-dimethylisoxazole (64 mg, 0.20 mmol) in dry MeCN/DMF (1 :1 , 2 mL) at 0 °C under nitrogen. The mixture was stirred at 0 °C for 2 h. HCl (1M) and DCM was added. The phases were partitioned and the aqueous phase was extracted with DCM. The combined organic phases were washed with brine and concentrated. The crude product was purified on silica using a gradient of EtOAc/n-heptane (2:8) as mobile phase. 54 mg

2- (3,5-dimethylisoxazol-4-yl)-l-(4-methoxyphenyl)-4,5,6,7-tetrahydro-lH-indole-3-carbonitrile was obtained as a white solid.

Step (d): 2-(3,5-dimethylisoxazol-4-yl)-l -(4-methoxyphenyl)-4,5,6,7-tetrahydro-lH-indole-3- carbonitrile (54, 0.16) was dissolved in DCM (2 mL) and the mixture was cooled to 0 °C.

BF₃ ^'SMe₂ (304 mg, 2.34 mmol) was added, the cooling bath was removed and the reaction was stirred at room temperature for 48 h. The mixture was cooled to 5 °C and MeOH was added followed by NaHC0₃ (aq) and DCM. The phases were partitioned, the aqueous phase was extracted with DCM and the combined organic phases were concentrated. The crude product was purified on silica using EtOAc/rc-heptane (1 :9) as mobile phase. 34 mg 2-(3,5-dimethylisoxazol- 4-yl)-l-(4-hydroxyphenyl)-4,5,6,7-tetrahydro-lH-indole-3-carbonitrile (E3) was obtained as a white solid. ES/MS m/z: 334.4 (M+H), 332.5 (M-H); 1H NMR (CDC1₃, 500MHz): 6.88 (m, 2H), 6.79 (m, 2H), 2.66 (m, 2H), 2.43 (m, 1H), 2.33 (m, 1H), 2.25 (s, 3H), 1.93 (s, 3H) and 1.86-1.73 (m, 4H).

Step (e): 2-(3,5-dimethylisoxazol-4-yl)-l-(4-hydroxyphenyl)-4,5,6,7-tetrahydro-lH-indole-3- carbonitrile (32 mg, 0.10 mmol) was dissolved in MeOH (1.5 mL) and hydroxylamine (1.53 mL, 32.2 mmol, 16.3 M) was added under nitrogen. The mixture was heated in microwave at 150 °C for 10 min. EtOAc and brine were added and the phases were partitioned. The aqueous phase was extracted with EtOAc and Et₂0 and the combined organic phases were concentrated. The crude product was purified on HPLC using MeCN/acidic H₂0 (20-100% MeCN, 40 min gradient) as mobile phase. 12.5 mg 2-(3,5-dimethylisoxazol-4-yl)-N'-hydroxy-l-(4- hydroxyphenyl)-4,5,6,7-tetrahydro-lH-indole-3-carboximidamide (E4) ES/MS m/z: 367.14

(M+H); Ή NMR (Acetone-d6, 500MHz): 6.97 (br s, 2H), 6.84 (m, 2H), 2.80 (m, 2H), 2.35 (m, 2H), 2.08 (s, 3H), 1.97 (s, 3H) and 1.76 (m, 4H) and 6.0 mg 2-(3,5-dimethylisoxazol-4-yl)-l-(4- hydroxyphenyl)-4,5,6,7-tetrahydro-lH-indole-3-carboxamide (E5) ES/MS m/z: 352.1 (M+H); Ή NMR (Acetone-d6, 500MHz): 6.94 (m, 2H), 6.82 (m, 2H), 2.66 (m, 2H), 2.37 (m, 2H), 2.06 (s, 3H), 1.91 (s, 3H) and 1.74 (m, 4H) were obtained. For Example 4, 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 6,7,8 and 9

4-(2-(3,5-dimethylisoxazol-4-yl)-l,4,5,6-tetrahydrocyclopenta[b]pyrrol-3-yl)phenol (E6) 2-(3,5-dimethylisoxazol-4-yl)-3-(4-hydroxyphenyl)-5,6-dihydrocyclopenta[b]pyrroIe-l(4H)- carbonitrile (E7)

2-(3,5-dimethylisoxazol-4-yl)-N'-hydroxy-3-(4-hydroxyphenyl)-5,6- dihydrocyclopenta[b]pyrrole-l(4H)-carboximidamide (E8)

2-(3,5-dimethylisoxazol-4-yI)-3-(4-hydroxyphenyl)-5,6-dihydrocyclopenta[b]pyrrole-l(4H)- carboxamide (E9)

(a) HMDS, HOAc; EtOH; (b) NBS, DCM; (c) Boc₂0, Et₃N, DMAP, MeCN; (d) 4-methoxyphenylboronic acid, Pd(PPh₃)₄, K₂C0₃, DME/H₂0; (e) MeONa, THF; (f) BF₃- SMe₂, DCM;

(g) 4,4'-(propane-2,2-diyl)bis(cyanatobenzene), NaH, THF, (h) BF₃ SMe₂, DCM; (i) NH₂OH, MeOH

Scheme 3

Step (a): 2-(2-(3,5-dimethylisoxazol-4-yl)-2-oxoethyl)cyclopentanone (174 mg, 0.79 mmol), HMDS (2344 mg, 14 mmol) and AcOH (0.20 mL) were mixed in MeOH (10 mL). The vial was flushed with nitrogen, sealed and heated at 130 °C for 15 min. The mixture was cooled to room temperature and the solvent was evaporated. The crude product was purified on silica using EtOAc/n-heptane (2:8) as mobile phase. 142 mg 3,5-dimethyl-4-(l ,4,5,6- tetrahydrocyclopenta[b]pyrrol-2-yl)isoxazole was obtained as a white solid.

Step (b): 3,5-dimethyl-4-(l,4,5,6-tetrahydrocyclopenta[b]pyrrol-2-yl)isoxazole (15 mg, 0.07 mmol) was dissolved in DCM (3 mL) and NBS (14 mg, 0.08 mmol) was added at 0 °C under nitrogen. The cooling bath was removed and the mixture was stirred for 1 h. The solvent was evaporated without heating and the crude product was purified on aluminium oxide using EtOAc/n-heptane (3:7) as mobile phase. 18.7 mg 4-(3-bromo-l ,4,5,6- tetrahydrocyclopenta[b]pyrrol-2-yl)-3,5-dimethylisoxazole was obtained as a reddish solid. Step (c): 4-(3-bromo-l,4,5,6-tetrahydrocyclopenta[b]pyrrol-2-yl)-3,5-dimethylisoxazole (18.7 mg, 0.07 mmol), Boc-anhydride (49 mg, 0.22 mmol), DMAP (0.91 mg, 0.01 mmol) and Et₃N (41 mg, 0.41 mmol) were mixed in MeCN (2 mL) under nitrogen. The mixture was stirred for 1.5 h and the solvent was evaporated. The crude product was purified on silica using a gradient of EtOAc/n-heptane (3:7 to 4:6) as mobile phase, t-butyl 3-bromo-2-(3,5-dimethylisoxazol-4-yl)- 5,6-dihydrocyclopenta[b]pyrrole-l(4H)-carboxylate was obtained as a yellowish oil.

Step (d): i-butyl 3-bromo-2-(3,5-dimethylisoxazol-4-yl)-5,6-dihydrocyclopenta[b]pyrrole- 1 (4H)-carboxylate (25 mg, 0.07 mmol), tetrakis(triphenylphosphine)palladium (12.9, 0.01 mmol), 4-methoxyphenylboronic acid (33.8 mg, 0.22 mmol), K₂C0₃ (51.2 mg, 0.37 mmol) and Nal (22.2 mg, 0.14 mmol) were mixed in degassed DME/water (1 :1, 1.7 mL) under nitrogen. The resulting mixture was stirred at 90 °C for 1.5 h and then cooled to room temperature. The solvent was evaporated under nitrogen flow and water and DCM were added to the residue. The phases were partitioned, the aqueous phase was extracted with DCM and the combined organic phases were concentrated. The crude product was purified on silica usinf EtOAc/n-Heptane (8:2) as mobile phase. 6.7 mg i-butyl 2-(3,5-dimethylisoxazol-4-yl)-3-(4-methoxyphenyl)-5,6- dihydrocyclopenta[b]pyrrole-l(4H)-carboxylate was obtained as a yellow solid. Step (e): tert-butyl 2-(3,5-dimethylisoxazol-4-yl)-3-(4-methoxyphenyl)-5,6- dihydrocyclopenta[b]pyrrole-l(4H)-carboxylate (6.7 mg, 0.02 mmol) and NaOMe (8.9 mg, 0.16 mmol) were mixed in THF (1 mL) and MeOH (0.2 mL) under nitrogen. The mixture was stirred for 16 h at 45 °C. The solvent was concentrated and the crude product was purified on silica using a EtOAc/n-heptane gradient (2:8 - 3:7) as mobile phase. 4.5 mg 4-(3-(4-methoxyphenyl)- l ,4,5,6-tetrahydrocyclopenta[b]pyrrol-2-yl)-3,5-dimethylisoxazole was obtained as a green solid.

Step (f): 4-(3-(4-methoxyphenyl)-l,4,5,6-tetrahydrocyclopenta[b]pyrrol-2-yl)-3,5- dimethylisoxazole (6.1 mg, 0.02 mmol) was dissolved in DCM (0.5 mL) . BF₃ ^'SMe₂ (51.4 mg, 0.40 mmol) was added and the reaction mixture was stirred at room temperature for 48 h. MeOH (96 μΐ) was added followed by NaHC0₃ (sat., 50 %) The aqueous phase was extracted with DCM and the combined organic phases were concentrated. The crude product was purified on silica using a EtOAc/«-heptane gradient (2:8 - 3:7) as mobile phase. 2.6 mg 4-(2-(3,5- dimethylisoxazol-4-yl)-l ,4,5,6-tetrahydrocyclopenta[b]pyiTol-3-yl)phenol (E6) was obtained as a white solid. ES/MS m/z: 295.4 (M+H), 292.9 (M-H); Ή NMR (MeOD, 500MHz): 6.98 (m, 2H), 6.65 (m, 2H), 2.76 - 2.70 (m, 4H), 2.45 (m, 2H), 2.12 (s, 3H) and 1.95 (s, 3H).

Step (g): 4-(3-(4-methoxyphenyl)-l ,4,5,6-tetrahydrocyclopenta[b]pyrrol-2-yl)-3,5- dimethylisoxazole (35 mg, 0.11 mmol) was dissolved in THF (3 mL) under nitrogen. NaH (10.9 mg, 0.45 mmol) was added followed by 4,4'-(propane-2,2-diyl)bis(cyanatobenzene) (63.2 mg, 0.23 mmol). The mixture was stirred at room temperature for 16 h and was then cooled to 0 °C. Water and EtOAc were added. The phases were partitioned and the aqueous phase was extracted with EtOAc. The combined organic phases were washed with brine, dried over Na₂S0₄ and concentrated. The crude product was purified on silica using an EtOAc/«-heptane gradient (1 :9 - 2:8) as mobile phase. 2.6 mg 2-(3,5-dimethylisoxazol-4-yl)-3-(4-methoxyphenyl)-5,6- dihydrocyclopenta[b]pyrrole-l(4H)-carbonitrile was obtained as a white solid.

Step (h): 2-(3,5-dimethylisoxazol-4-yl)-3-(4-methoxyphenyl)-5,6-dihydrocyclopenta[b]pyrrole- 1 (4H)-carbonitrile (39.9 mg, 0.12 mmol) was dissolved in DCM (3 mL) under nitrogen.

BF₃ ^'SMe₂ (31 1 mg, 2.39 mmol) was added at room temperature and the reaction mixture was stirred at 2 °C for 64 h. The mixture was cooled to 0 °C and MeOH (580 μΐ) was added followed by NaHC0₃ (sat, 50 %) The aqueous phase was extracted with DCM and the combined organic phases were concentrated. The crude product was purified on silica using an EtOAc/n-heptane gradient (2:8 - 3:7). 23.2 mg 2-(3,5-dimethylisoxazol-4-yl)-3-(4-hydroxyphenyl)-5,6- dihydrocyclopenta[b]pyrrole-l(4H)-carbonitrile (E7) was obtained as a white solid. ES/MS m/z: 320.3 (M+H), 318.1 (M-H); Ή NMR (MeOD, 500MHz): 7.04 (m, 2H), 6.72 (m, 2H), 2.89 (m, 2H), 2.81 (m, 2H), 2.56 (m, 2H), 2.25 (s, 3H) and 1.97 (s, 3H). Step (i): 2-(3,5-dimethylisoxazol-4-yl)-3-(4-hydroxyphenyl)-5,6-dihydrocyclopenta[b]pyrrole- 1 (4H)-carbonitrile (13.2 mg, 0.04 mmol) was dissolved in MeOH (2 mL) and hydroxylamine (0.26 mL, 4.13 mmol, 16 M) was added under nitrogen at 0 °C . The mixture was stirred at 1 °C for 23 h. The solvent was evaporated and the crude product was purified on reversed phase chromatography using MeCN/acidic H₂0 (8 - 50% MeCN, 20 min gradient) as mobile phase. 15.9 mg 2-(3,5-dimethylisoxazol-4-yl)-N'-hydroxy-3-(4-hydroxyphenyl)-5,6- dihydrocyclopenta[b]pyrrole-l (4H)-carboximidamide (E8) ES/MS m/z: 353.3 (M+H), 351.4 (M- H); Ή NMR (MeOD, 500MHz): 6.95 (m, 2H), 6.65 (m, 2H), 2.83 (m, 2H), 2.76 (m, 2H), 2.45 (m, 2H), 2.1 1 (s, 3H) and 1.96 (s, 3H) and 4.5 mg 2-(3,5-dimethylisoxazol-4-yl)-3-(4- hydroxyphenyl)-5,6-dihydrocyclopenta[b]pyrrole-l(4H)-carboxamide (E9) ES/MS m/z: 338.6 (M+H), 336.7 (M-H); Ή NMR (MeOD, 500MHz): 6.92 (m, 2H), 6.66 (m, 2H), 2.99 (m, 2H), 2.78 (m, 1H), 2.68 (m, 1H), 2.47 (m, 2H), 2.04 (s, 3H) and 2.00 (s, 3H) were obtained as white solids. For Example 8, 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.

Example 10

4-(2-(3,5-dimethylisoxazoI-4-yl)-4,5,6,7-tetrahydro-lH-indol-3-yl)phenol (E10)

(a) HMDS, HOAc, EtOH, (b) NBS, DCM; (c) Boc₂0, Et₃N, DMAP, eCN; (d) 4-methoxyphenylboronic acid, Pd(PPh₃)₄, NaHC0₃,DME/H₂0; (e) NaOMe, THF; (f) BF₃ SMe₂, DCM

Scheme 4 Step (a): 2-(2-(3,5-dimethylisoxazol-4-yl)-2-oxoethyl)cyclohexanone (150 mg, 0.64 mmol),

HMDS (1904 mg, 12 mmol) and AcOH (0.20 mL) were mixed in MeOH (10 mL). The vial was flushed with nitrogen, sealed and heated at 130 °C for 15 min. The reaction mixture was cooled to room temperature and the solvent was evaporated. The crude product was purified on silica using EtOAc/n-heptane (2:8) as mobile phase. 94 mg 3,5-dimethyl-4-(4,5,6,7-tetrahydro-lH- indol-2-yl)isoxazole was obtained as a white solid.

Step (b): 3,5-dimethyl-4-(4,5,6,7-tetrahydro-l H-indol-2-yl)isoxazole (94 mg, 0.43 mmol) was dissolved in dry DCM (20 mL) and NBS (81 mg, 0.46 mmol) was added at 0 °C under nitrogen. The reaction mixture was stirred at 0 °C for 15 min and then the solvent was evaporated without heating. The crude product was purified on aluminium oxide using EtOAc/n-heptane (3:7) as mobile phase. 4-(3-bromo-4,5,6,7-tetrahydro-lH-indol-2-yl)-3,5-dimethylisoxazole was obtained.

Step (c): 4-(3-bromo-4,5,6,7-tetrahydro-lH-indol-2-yl)-3,5-dimethylisoxazole (127 mg, 0.43 mmol), Boc-anhydride (142 mg, 0.65 mmol), DMAP (5.3 mg, 0.04 mmol) and Et₃N (132 mg, 1.3 mmol) were mixed in dry MeCN under nitrogen. The mixture was stirred for 30 min and then the solvent was evaporated. The crude product was purified on silica using EtOAc/rc-heptane (2:8) as mobile phase. 131 mg t-butyl 3-bromo-2-(3,5-dimethylisoxazol-4-yl)-4,5,6,7-tetrahydro- lH-indole-l-carboxylate was obtained.

Step (d): t-butyl 3-bromo-2-(3,5-dimethylisoxazol-4-yl)-4,5,6,7-tetrahydro-lH-indole-l- carboxylate (90 mg, 0.23 mmol), tetrakis(triphenylphosphine)palladium (26.3 mg, 0.02 mmol) and 4-methoxyphenylboronic acid (51.9 mg, 0.34 mmol) were mixed in degassed DME (6 mL). The mixture was stirred at 50 °C for 5 min and then NaHC0₃ (0.91 mL, 1 M) was added dropwise over 2 min. The resulting slurry was stirred at 50 °C for 18 h.

Tetrakis(triphenylphosphine)palladium (13.0 mg, 0.01 mmol) and 4-methoxyphenylboronic acid (42 mg, 0.27 mmol) were added and the stirring was continued at 50 °C for 1 h. The reaction mixture was cooled to room temperature, EtOAc and brine were added and the phases were partitioned. The organic phase was concentrated and the crude product was purified on silica using EtOAc/rc -Heptane (1 :9) as mobile phase. 42 mg i-butyl 2-(3,5-dimethylisoxazol-4-yl)-3-(4- methoxyphenyl)-4,5,6,7-tetrahydro- 1 H-indole- 1 -carboxylate was obtained. Step (e): i-butyl 2-(3,5-dimethylisoxazol-4-yl)-3-(4-methoxyphenyl)-4,5,6,7-tetrahydro-lH- indole-1 -carboxylate (42 mg, 0.10 mmol) and NaOMe (54 mg, 0.99 mmol) were mixed in THF (3 mL) and MeOH (0.6 mL) under nitrogen. The reaction mixture was stirred for 5 h at 50 °C. NaOMe (75 mg, 1.4 mmol) and MeOH (0.6 mL) were added and the stirring continued at 50 °C for 16 h. THF (5 mL) was added and the temperature was raised to reflux for 2 h. The solvent was evaporated and the crude product was purified on silica using EtOAc/n-heptane (1 :9) as mobile phase. 15 mg 4-(3-(4-methoxyphenyl)-4,5,6,7-tetrahydro-lH-indol-2-yl)-3,5- dimethylisoxazole was obtained. Step (f): 4-(3-(4-methoxyphenyl)-4,5,6,7-tetrahydro-lH-indol-2-yl)-3,5-dimethylisoxazole (7.5 mg, 0.02 mmol) was dissolved in DCM under nitrogen. BF₃ ^'SMe₂ (60.4 mg, 0.47 mmol) was added and the reaction mixture was stirred at 4 °C for 16 h and at room temperature for 8 h. BF₃ SMe₂ (12.4 mg, 0.0095 mmol) was added and the mixture was stirred at 4 °C for 64 h. Water, DCM and NaHC0₃ (sat) were added. The aqueous phase was extracted with DCM and the combined organic phases were dried and concentrated. The crude product was purified on preparative HPLC using MeCN/acidic H₂0 (20 - 80 % MeCN, 40 min gradient). 6.0 mg 4-(2- (3,5-dimethylisoxazol-4-yl)-4,5,6,7-tetrahydro-lH-indol-3-yl)phenol (E10) was obtained.

ES/MS m/z: 309.14 (M+H), 307.19 (M-H); Ή NMR (CDC13, 500MHz): 7.01 (m, 2H), 6.70 (m, 2H), 2.65 (m, 2H), 2.56 (m, 2H), 2.10 (s, 3H), 1.99 (s, 3H), 1.88 (m, 2H) and 1.77 (m, 2H).

Example 11

2-(3,5-dimethylisoxazoI-4-yl)-N'-hydroxy-3-(4-hydroxyphenyl)-4,5,6,7-tetrahyd] isoindole-l-carboximidamide (Ell)

(a) Ethyl isocyanoacetate, DBU, THF; (b) 4-iodo-3,5-dimethylisoxazole, Cul, Cs₂C0₃, DMF; (c) NBS, DCM; (d) 4-methoxyphenylboronic acid,Pd(PPh₃)₄, NaHC0₃,DME/H₂0; (e) 1. Bu₄NOH, MeOH 2.HCI; (f) chlorosulfonyl isocyanate, MeCN/DMF; (g) BBr₃, DCM; (h) NH₂OH, MeOH

Scheme 5 Step (a): A solution of 1 -nitrocyclohexene (2.00 g, 15.73 mmol) and methyl isocyanoacetate (1779 mg, 15.73) mmol in anhydrous THF (24 mL) was cooled to 0 °C with stirring and was treated dropwise with DBU (2395 mg, 15.73 mmol) over 5 min. After the addition was complete, the reaction mixture was allowed to warm to room temperature and stirring was continued for 60 h. The mixture was then poured over 100 g of crushed ice containing HC1 (IN, 25 mL). After melting, the aqueous solution was extracted with EtOAc (3 x 20 mL). The combined organic extracts were dried over anhydrous Na₂S0₄, filtered and concentrated under reduced pressure. The crude product was purified on silica using EtOAc/n-heptane gradient (5:95 - 2:8) as mobile phase. 2381 mg ethyl 4,5,6,7-tetrahydro-2H-isoindole-l-carboxylate was isolated as a yellow solid.

Step (b): 4,5,6,7-tetrahydro-2H-isoindole-l-carboxylate (200 mg, 1.03 mmol), 4-iodo-3,5- dimethylisoxazole (692 mg, 3.10 mmol), Cul (99 mg, 0.52 mmol) and Cs₂C0₃ (674 mg, 2.07 mmol) were mixed in dry DMF (10 mL). The mixture was degassed by freeze-pump-thaw (-78 °C, 3x) and was then heated at 180 °C for 20 min. 4-iodo-3,5-dimethylisoxazole (350 mg, 1.6 mmol) was added and the mixture was heated at 180 °C for 15 min. Cul (99 mg, 0.52 mmol) was added and the heating continued for 15 min at 190 °C. Water (50 mL) and DCM (50 mL) were added and the mixture was filtered through celite. The phases were separated and the organic phase was concentrated. The crude product was purified on silica using EtOAc/rc-heptane (3:7) as mobile phase. 46.7 mg ethyl 2-(3,5-dimethylisoxazol-4-yl)-4,5,6,7-tetrahydro-2H-isoindole-l - carboxylate was obtained as a yellow oil.

Step (c): 2-(3,5-dimethylisoxazol-4-yl)-4,5,6,7-tetrahydro-2H-isoindole-l -carboxylate (46.7 mg, 0.16 mmol) was dissolved in DCM (2 mL) and NBS (31.7 mg, 0.18 mmol) was added at 0 °C under nitrogen. The mixture was stirred at 0 °C for 50 min. NBS (5.8 mg, 0.03 mmol) was added and the stirring continued for 10 min. Water and DCM were added and the phases were partitioned. The organic phase was concentrated and the crude product was purified on silica using an EtOAc/n-heptane gradient (2:8 - 3:7) as mobile phase. 54.7 mg ethyl 3-bromo-2-(3,5- dimethylisoxazol-4-yl)-4,5,6,7-tetrahydro-2H-isoindole-l -carboxylate was obtained.

Step (d): Ethyl 3-bromo-2-(3,5-dimethylisoxazol-4-yl)-4,5,6,7-tetrahydro-2H-isoindole-l - carboxylate (54.7 mg, 0.15 mmol), tetrakis(triphenylphosphine)palladium (34.4 mg, 0.03 mmol) and 4-methoxyphenylboronic acid (45.3 mg, 0.30 mmol) were mixed in degassed DME (2.5 mL) under nitrogen. The mixture was heated to 90 °C and then NaHC0₃ (0.52 mL, 1 M) was added dropwise. The reaction mixture was stirred at 90 °C for 3.5 h. The mixture was cooled to room temperature, the solvent was evaporated and the residue was filtered through a plug of silica. The crude product was treated with MP-TMT (100 mg) and was then purified on silica using an EtOAc/n-Heptane gradient (25:75 - 3:7) as mobile phase. 48.4 mg ethyl 2-(3,5-dimethylisoxazol- 4-yl)-3-(4-methoxyphenyl)-4,5,6,7-tetrahydro-2H-isoindole-l -carboxylate was obtained.

Step (e): Tetrabutylammonium hydroxid (7.6 mL, 1M) in MeOH was added to ethyl 2-(3,5- dimethylisoxazol-4-yl)-3-(4-methoxyphenyl)-4,5,6,7-tetrahydro-2H-isoindole-l-carboxylate (45.4 mg, 0.12 mmol) under nitrogen and the vial was sealed. The mixture was heated at 55 °C for 3 h and then at 70 °C for 21 h. All MeOH except ~2 ml was evaporated. The solution was acidified with HC1 (1M) and extracted with DCM. The crude product was purified on silica using EtOAc/rc-heptane (6:4) as mobile phase affording 2-(3,5-dimethylisoxazol-4-yl)-3-(4- methoxyphenyl)-4,5,6,7-tetrahydro-2H-isoindole-l -carboxylic acid with Bu₄ ⁺ as counter ion. A 5 g SCX-3 ion exchange column was activated with MeOH (50 mL) followed by HC1 (150 mL, 0.05 M). The sample was loaded onto the column with MeOH and product 1 was eluted with MeOH. Addition of 3 drops HC1 (1M) to the methanolic solution of 2-(3,5-dimethylisoxazol-4- yl)-3-(4-methoxyphenyl)-4,5,6,7-tetrahydro-2H-isoindole-l-carboxylic acid followed by evaporation at 45 °C led to full conversion to 4-(l-(4-methoxyphenyl)-4,5,6,7-tetrahydro-2H- isoindol-2-yl)-3,5-dimethylisoxazole. The crude product was purified on silica using EtOAc - heptane (3:7) as mobile phase. 40.8 mg 4-(l-(4-methoxyphenyl)-4,5,6,7-tetrahydro-2H-isoindol- 2-yl)-3,5-dimethylisoxazole was obtained.

Step (f): Chlorosulfonyl isocyanate (35.8 mg, 0.13 mmol) was added to a solution of 4-(l-(4- methoxyphenyl)-4,5,6,7-tetrahydro-2H-isoindol-2-yl)-3,5-dimethylisoxazole (40.8 mg, 0.13 mmol) in dry MeCN/DMF (1 : 1 , 2 mL) at 0 °C under nitrogen. The mixture was stirred at 0 °C for 1 h. HC1 (1M) and DCM was added. The phases were partitioned and the aqueous phase was extracted with DCM and EtOAc. The combined organic phases were dried over Na₂S0₄ and concentrated. The crude product was purified on silica using EtOAc/n-heptane (2:8) as mobile phase. 17.5 mg 2-(3,5-dimethylisoxazol-4-yl)-3-(4-methoxyphenyl)-4,5,6,7-tetrahydro-2H- isoindole-1 -carbonitrile was obtained.

Step (g): 2-(3,5-dimethylisoxazol-4-yl)-3-(4-methoxyphenyl)-4,5,6,7-tetrahydro-2H-isoindole-l - carbonitrile (17.5 mg, 0.05 mmol) was dissolved in dry DCM (2.5 mL). BBr₃ (0.5 mL, 1 M) was added and the reaction was stirred at room temperature for 3.5 h. The mixture was cooled to 0 °C and MeOH (120 μΐ) was added followed by NaHC0₃ (sat, 50 %) The aqueous mixture was extracted with DCM and the combined organic phases were concentrated. The crude product was purified on silica using EtOAc/n-heptane (1 : 1) as mobile phase. 15.9 mg 2-(3,5- dimethylisoxazol-4-yl)-3-(4-hydroxyphenyl)-4,5,6,7-tetrahydro-2H-isoindole-l-carbonitrile was obtained as a white crystals.

Step (h): 2-(3,5-dimethylisoxazol-4-yl)-3-(4-hydroxyphenyl)-4,5,6,7-tetrahydro-2H-isoindole-l- carbonitrile (15.9 mg, 0.05 mmol) was dissolved in MeOH (0.63 mL) and hydroxylamine (0.40 mL, 14.1 mmol, 16 M) was added under nitrogen. The mixture was heated in microwave at 100 °C for 30 min. The solvent was evaporated and the crude product was purified on preparative HPLC using MeCN/ acidic H20 (8 - 50% MeCN, 20 min gradient) as mobile phase. 1 1.9 mg 2- (3,5-dimethylisoxazol-4-yl)-N'-hydroxy-3-(4-hydroxyphenyl)-4,5,6,7-tetrahydro-2H-isoindole-l- carboximidamide (Ell) was obtained as a white solid. ES/MS m/z: 367.1 (M+H); Ή NMR (MeOD, 500MHz): 6.96 (m, 2H), 6.68 (m, 2H), 2.70 (m, 2H), 2.53 (m, 2H), 2.35 (s, 3H), 1.83 (s, 3H) and 1.79- 1.69 (m, 4H). For Example 11 , 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.

Example 12

6-(2,4-dimethylthiophen-3-yl)-N'-hydroxy-5-(4-hydroxyphenyl)-2,3-dihydro-lH- pyrrolizine-7-carboximidamide (E12)

(a) Methyl 2-cyanoacetate; (b) NaOH, H₂0; (c) LDA, THF; (d) (4-methoxyphenyl)lithium, THF; (e) Silica gel, DCM; (f) NBS, DCM; (g) BBr₃, DCM; (h) Pd(PPh₃)₄, NaHC0₃, DME/H₂0; (i) NH₂OH, MeOH

Scheme 6 Step (a): 5-methoxy-3,4-dihydro-2H-pyrrole (3.00 g, 30.26 mmol) and methyl 2-cyanoacetate (10.50 g, 106 mmol) were mixed and kept at room temperature for 16 h. White crystals were formed which were washed with n-heptane and dried. 5.20 g (Z)-methyl 2-cyano-2-(pyrrolidin- 2-ylidene)acetate was obtained. Step (b): (Z)-methyl 2-cyano-2-(pyrrolidin-2-ylidene)acetate (5200 mg, 31.29 mmol) was suspended in NaOH (50 ml, 1M). The mixture was stirred at 100 °C until decarboxylation was completed and was then cooled to 0 °C. HCl (1M) was slowly added and the clear solution was neutralized by addition of K₂C0₃. The mixture was extracted with DCM (5x200 mL) and the combined organic extracts were dried over MgS0₄. The solvent was concentrated under reduced pressure. 1.50 g (E)-2-(pyrrolidin-2-ylidene)acetonitrile was obtained.

Step (c): To a solution of (E)-2-(pyrrolidin-2-ylidene)acetonitrile ( 1 148 mg, 10.62 mmol) in dry THF at -78 °C was added LDA (7.96 mL, 15.92 mmol, 2M) dropwise over 40 min followed by stirring for 30 min. Then 2-bromo-N-methoxy-N-methylacetamide (3285 mg, 18.05 mmol, synthesized following literature procedure JOC, 2009, 74(10), 3689-3697) in dry THF was added slowly and stirring was continued for 4h at -78 °C. The reaction was hydrolysed with HCl (aq, 5%) and neutralized with solid NaHC0₃. The solvent was evaporated under reduced pressure and the residue was extracted with DCM (3x). The combined organic phases were dried over MgS0₄ and concentrated. The crude product was purified on silica using an EtOAc/«- heptane gradient (0:1 - 2:8) as mobile phase. 761 mg 2-(3,5-dimethylisoxazol-4-yl)-4,5,6,7- tetrahydro-2H-isoindole-l-carboxylate was obtained.

Step (d): To a stirred solution of (E)-3-cyano-N-methoxy-N-methyl-3-(pyrrolidin-2- ylidene)propanamide (748 mg, 3.57 mmol) in dry THF (10 mL) at -40 °C was added (4- methoxyphenyl)lithium (1019 mg, 8.94 mmol) made by litiation of bromo-4-methoxybenzene. Bromo-4-methoxybenzene (1.80 g) was dissolved in ether. n-BuLi (5.71 mL, 1M) was added at - 78 °C. The mixture was stirred at -78 °C for 20 min before it was added to the above mixture. After 3 h at -40 °C the reaction was completed and the product was hydrolyzed by addition of water. The organic phase was separated, washed with brine and dried over MgS0₄. The solvent was evaporated and 140 mg (E)-4-(4-methoxyphenyl)-4-oxo-2-(pyrrolidin-2- ylidene)butanenitrile was obtained.

Step (e): (E)-4-(4-methoxyphenyl)-4-oxo-2-(pyrrolidin-2-ylidene)butanenitrile (1600 mg, 6,2 mmol) was dissolved in chloroform (30 mL) and silica gel (5 w/w). The mixture was heated at reflux for 2 h. The silica gel was filtered off and washed with hot acetone. The solvent was evaporated and the crude product was purified on silica using an EtOAc/«-heptane gradient (0:1 - 3:7) as mobile phase. 400 mg 5-(4-methoxyphenyl)-2,3-dihydro-lH-pyrrolizine-7-carbonitrile was obtained.

Step (f): 5-(4-methoxyphenyl)-2,3-dihydro-lH-pyrrolizine-7-carbonitrile (100 mg, 0.42 mmol) was dissolved in dry DCM (30 mL) and NBS (101 mg, 0.57 mmol) was added under nitrogen. The mixture was stirred for 40 min and then the mixture was poured into HC1 (100 mL, 1 M). The phases were separated and the organic phase was concentrated. The crude product was purified on silica using EtOAc/rc-heptane (4:6) as mobile phase. 129 mg 6-bromo-5-(4- methoxyphenyl)-2,3-dihydro-lH-pyrrolizine-7-carbonitrile was obtained as a straw coloured solid. Step (g): 6-bromo-5-(4-methoxyphenyl)-2,3-dihydro-l H-pyrrolizine-7-carbonitrile (129 mg,

0.41 mmol) was dissolved in dry DCM (20 mL) under nitrogen. BBr₃ (4.07 mL, 1M) was added dropwise at 0 °C and the reaction mixture was stirred at 2 °C for 16 h. The mixture was cooled to 0 °C and MeOH (0.97 mL) was added followed by NaHC0₃ (100 mL, sat, 50 %). The aqueous phase was extracted with DCM and the combined organic phases were dried over Na₂S0₄ and concentrated. The crude product was purified on silica using EtOAc/«-heptane (6:4) as mobile phase. I l l mg 6-bromo-5-(4-methoxyphenyl)-2,3-dihydro-lH-pyrrolizine-7-carbonitrile was obtained as yellow crystals.

Step (h): 6-bromo-5-(4-methoxyphenyl)-2,3-dihydro-lH-pyrrolizine-7-carbonitrile (50.0 mg, 0.16 mmol), tetrakis(triphenylphosphine)palladium (19.06 mg, 0.02 mmol), 2-(2,4- dimethylthiophen-3-yl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (78.6 mg, 0.33 mmol) and K₂C0₃ (91.2, 0.66 mmol) were mixed in degassed DME /water (3 mL, 1 :1) under nitrogen. The reaction mixture was heated at 70 °C for 5.5 h. The mixture was cooled to room temperature, the solvent was evaporated and water and DCM were added. The aqueous phase was extracted with DCM and the combined organic phases were concentrated. The crude product was purified on reversed phase flash chromatography using a MeCN/H₂0 gradient (45 - 60% MeCN) as mobile phase. 21.6 mg 6-(2,4-dimethylthiophen-3-yl)-5-(4-hydroxyphenyl)-2,3-dihydro-lH-pyrrolizine- 7-carbonitrile was obtained.

Step (i): 6-(2,4-dimethylthiophen-3-yl)-5-(4-hydroxyphenyl)-2,3-dihydro-lH-pyrrolizine-7- carbonitrile (21.6 mg, 0.06 mmol) was dissolved in MeOH (1 mL) and hydroxylamine (0.54 mL, 8.59 mmol, 16 M) was added under nitrogen. The mixture was heated in microwave at 120 °C for 30 min. The solvent was evaporated and the crude product was purified on preparative HPLC using MeCN/acidic H₂0 (5 - 50% MeCN, 20 min gradient) as mobile phase. 1 1.9 mg 6-(2,4- dimethylthiophen-3-yl)-N'-hydroxy-5-(4-hydroxyphenyl)-2,3-dihydro-lH-pyrrolizine-7- carboximidamide (E12) was obtained as a yellow solid. ES/MS m/z: 368 (M+H), 366.4 (M-H); Ή NMR (MeOD, 500MHz): 6.90 (m, 2H), 6.77 (q, 1H, J=1.0Hz), 6.65 (m, 2H), 4.12 (m, 1H), 4.04 (m, 1H), 3.09 (m, 2H), 2.54 (m, 2H), 2.03 (s, 3H) and 1.89 (d, 3H, J=1.0Hz). For Example 12, 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 13 and 14

Example 13 and 14 were prepared using a method analogous to that used to synthesise Examples 6 - 9 above. Full experimental details of the individual steps of the general methods are described in Examples 1 - 9 above. Identification of the title compounds by Ή-NMR showed that the oxime product was a single isomer, but did not confirm whether the (E) or (Z) oxime isomer had been obtained.

Example 15

6-(2,4-dimethylfuran-3-yl)-N'-hydroxy-7-(4-hydroxyphenyl)-2,3-dihydro-lH-pyrrolizine-5- carboximidamide (E15)

DME/H₂0; (d) 4-met oxyphenylboronic acid, Pd(PP ₃)₄, K₂C0₃, DME/H₂0; (e) Hoveyda-Grubbs cat, DCM; (f) Rh/C, H₂, EtOAc; (g) NBS, DMF; (h) BBr₃, DCM; (i) Pd(PPh₃)₄, K₂C0₃, DME/H₂0; (j) LiOH,

THF/MeOH/H₂0; (k) Phenanthroline, Cu₂0, Quinoline, NMP; (I) NH₂OH, EtOH

Scheme 7

Step (a): lH-pyrrole-2-carbonitrile (200 mg, 2.17 mmol) was dissolved in AcOH (1 1 mL) and Br₂ (347 mg, 2.17 mmol) was added dropwise. The mixture was stirred for 2 h and Br₂ (1 eq) was added. The mixture was stirred for 5.5 h, Br₂ (0.5 eq) was added and the stirring continued for 16 h. The solvent was evaporated and the crude product was filtered through a plug of silica using DCM as mobile phase. 473 mg 4,5-dibromo-lH-pyrrole-2-carbonitrile was obtained as a white solid.

Step (b): 4,5-dibromo-l H-pyrrole-2-carbonitrile (91.3 mg, 0.37 mmol) and K₂C0₃ (202 mg, 1.46 mmol) were mixed in dry MeCN (4 mL) under nitrogen and 3-bromopropene (176.8 mg, 1.46 mg) was added. The reaction mixture was stirred at 80 °C for 30 min and was then filtered through celite. The solvent was evaporated and the crude product was filtered through a plug of silica using DCM as mobile phase. 77.9 mg l-allyl-4,5-dibromo-lH-pyrrole-2-carbonitrile was obtained as a yellow liquid.

Step (c) and (d): l-allyl-4,5-dibromo-lH-pyrrole-2-carbonitrile (267.5 mg, 0.92 mmol), tetrakis(triphenylphosphine)palladium (106.6 mg, 0.09 mmol), potassium vinyltrifluoroborate (123.6 mg, 0.92 mmol) and K₂C0₃ (510.0 mg, 3.69 mmol) were mixed in DME/water (10 mL, 1 :1) under nitrogen and the mixture was degassed. The reaction mixture was heated in microwave at 120 °C for 30 min. 4-methoxyphenylboronic acid (280.4 mg, 1.85 mmol) was added and the mixture was again heated in microvawe at 120 °C for 30 min. The mixture was cooled to room temperature, the solvent was evaporated and water and DCM were added. The phases were partitioned and the aqueous phase was extracted with DCM. The combined organic phases were concentrated and the crude product was purified on silica using an EtOAc/«-heptane gradient (5:95 - 15:95) as mobile phase. 97 mg l-allyl-4-(4-methoxyphenyl)-5-vinyl-lH-pyrrole- 2-carbonitrile was obtained.

Step (e): l-allyl-4-(4-methoxyphenyl)-5-vinyl-lH-pyrrole-2-carbonitrile (97 mg, 0.37 mmol) was dissolved in DCM (15 mL) and Hoveyda-Grubbs catalyst (35.3 mg, 0.056 mmol) was added. The reaction mixture was stirred at room temperature for 48 h. The mixture was filtered through silica and concentrated. The crude product was purified on silicausing DCM/n-heptane (1 : 1) as mobile phase. 65.9 mg 7-(4-methoxyphenyl)-3H-pyrrolizine-5-carbonitrile was obtained as a yellowish solid.

Step (f): 7-(4-methoxyphenyl)-3H-pyrrolizine-5-carbonitrile (66 mg, 0.28 mmol) and rhodium (5% on carbon) were mixed in EtOAc (15 mL). The mixture was degassed by using a water aspirator and hydrogen gas and was then stirred under 2.5 bars of hydrogen pressure for 5 h. The mixture was filtered through silica and concentrated. The crude product was purified on silica using DCM//i-heptane (1 :1) as mobile phase. 66 mg 7-(4-methoxyphenyl)-2,3-dihydro-lH- pyrrolizine-5-carbonitrile was obtained.

Step (g): 7-(4-methoxyphenyl)-2,3-dihydro-lH-pyrrolizine-5-carbonitrile (56.0 mg, 0.24 mmol) was dissolved in dry DMF (5 mL) and NBS (46.0 mg, 0.26 mmol) was added under nitrogen. The reaction mixture was stirred for 3.5 h and was then filtered through silica. The solvent was evaporated and the crude product was purified on silica using an EtOAc/«-heptane gradient (5:95 - 2:8) as mobile phase. 65.3^'mg 6-bromo-7-(4-methoxyphenyl)-2,3-dihydro-lH-pyrrolizine-5- carbonitrile was obtained as a yellowish solid.

Step (h): 6-bromo-7-(4-methoxyphenyl)-2,3-dihydro-lH-pyrrolizine-5-carbonitrile (65.3 mg, 0.21 mmol) was dissolved in dry DCM (3 mL) under nitrogen. BBr₃ (1.03 mL, 1 M) was added dropwise at 0 °C and the reaction mixture was stirred at room temperature for 4 h. MeOH (250 □ L) was added followed by NaHC0₃ (sat, 50 %). The aqueous phase was extracted with EtOAc, the combined organic phases were washed with brine, dried over Na₂S0₄ and concentrated. The crude product was purified on silica using an EtOAc/ra-heptane gradient (4:6 - 6:4) as mobile phase. 58.3 mg 6-bromo-7-(4-hydroxyphenyl)-2,3-dihydro-lH-pyrrolizine-5-carbonitrile was obtained as yellow crystals.

Step (i): 6-bromo-7-(4-hydroxyphenyl)-2,3-dihydro-lH-pyrrolizine-5-carbonitrile (58.3 mg, 0.19 mmol), tetrakis(triphenylphosphine)palladium (22.22 mg, 0.02 mmol), methyl 3,5- dimethyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)furan-2-carboxylate (107.7 mg, 0.38 mmol) and K₂C0₃ (79.7, 0.58 mmol) were mixed in degassed DME/water (6 mL, 1 : 1) under nitrogen. The reaction mixture was heated at 100 °C for 2 h. Methyl 3,5-dimethyl-4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)furan-2-carboxylate (1 eq) and K₂C0₃ (2 eq) were added and the heating continued for 2 h. The mixture was cooled to room temperature, the solvent was evaporated and EtOAc was added. The organic phase was washed with brine and dried over Na₂S0₄. The solvent was evaporated and the crude product was purified on silica using

EtOAc/Vz-heptane as mobile phase. 30.4 mg methyl 4-(5-cyano-7-(4-hydroxyphenyl)-2,3- dihydro-l H-pyrrolizin-6-yl)-3,5-dimethylfuran-2-carboxylate was obtained as a yellowish solid. Step (j): Methyl 4-(5-cyano-7-(4-hydroxyphenyl)-2,3-dihydro-lH-pyrrolizin-6-yl)-3,5- dimethylfuran-2-carboxylate (30.4 mg, 0.08 mmol) and LiOH (19.3 mg, 0.81 mmol) were mixed in THF/MeOH/water (3: 1.5: 1.5 mL) and the reaction mixture was stirred for 24 h at room temperature. The mixture was acidified with HC1 (2M). The aqueous phase was extracted with EtOAc, the combined organic extracts were washed with brine, dried over Na₂S0₄ and concentrated. The crude product was filtered through a plug of silica. 27.2 mg 4-(5-cyano-7-(4- hydroxyphenyl)-2,3-dihydro-lH-pynOlizin-6-yl)-3,5-dimethylfuran-2-carboxylic acid was obtained as a yellow glassy solid. Step (k): 4-(5-cyano-7-(4-hydroxyphenyl)-2,3-dihydro-lH-pyrrolizin-6-yl)-3,5-dimethylfuran-2- carboxylic acid (27 mg, 0.07 mmol), phenanthroline (5.37 mg, 0.03 mmol), Cu₂0 (2.13 mg, 0.01 mmol) and freshly distilled quinoline (0.35 niL) were mixed in NMP (1 mL) under nitrogen. The vial was sealed and the mixture was heated at 190 °C for 15 min. HC1 (2M) and DCM were added, the phases were partitioned and the aqueous phase was extracted with DCM. The combined organic phases were concentrated, the residue was dissolved in EtOAc, the solution was washed with water and brine and dried over Na₂S0₄. The solvent was evaporated and the crude product was purified on silica using an EtOAc/n-heptane gradient (0: 100 - 1 :1) as mobile phase. 20.3 mg 6-(2,4-dimethylfuran-3-yl)-7-(4-hydroxyphenyl)-2,3-dihydro-lH-pyrrolizine-5- carbonitrile was obtained as an orange solid.

Step (1): 6-(2,4-dimethylfuran-3-yl)-7-(4-hydroxyphenyl)-2,3-dihydro-lH-pyrrolizine-5- carbonitrile (20 mg, 0.06 mmol) was dissolved in MeOH (3.2 mL) and hydroxylamine (1.18 mL, 18.9 mmol, 16 M) was added under nitrogen. The mixture was heated in microwave at 150 °C for 15 min. The solvent was evaporated and the crude product was purified on preparative HPLC using MeCN/acidic H₂0 (5 - 50% MeCN, 20 min gradient) as mobile phase. 17.8 mg 6-(2,4- dimethylfuran-3-yl)-N'-hydroxy-7-(4-hydroxyphenyl)-2,3-dihydro-lH-pyrrolizine-5- carboximidamide (E15) was obtained as a yellow solid. ES/MS m/z: 352.7 (M+H), 350.5 (M-H); Ή NMR (MeOD, 500MHz): 7.15 (q, 1H, J=1.2Hz), 6.90 (m, 2H), 6.62 (m, 2H), 4.18 (m, 2H), 2.98 (m, 2H), 2.51 (m, 2H), 1.91 (s, 3H) and 1.66 (d, 3H, J=1.2Hz). For Example 15, the title compound was identified by ¹ H-NMR which showed that the oxime product was a single isomer, but did not r the (E) or (Z) oxime isomer had been obtained.

Binding Assay 1: Estrogen Receptor Binding Assay

The estrogen receptor ligand binding assays are designed as scintillation proximity assays (SPA), employing the use of tritiated estradiol (³H-E2) and recombinant expressed biotinylated estrogen receptor binding domains. The binding domains of human ERa (ERa-LBD, pET-N-AT #1, aa 301-595) and ERp (ERp-LBD, pET-N-AT #1 , aa 255-530) proteins are produced in E.coli ((BL21 , (DE3), pBirA)) at 22 C in 2xLB medium supplemented with 50 uM biotin. After 3 h of IPTG induction (0.55 mM), cells are harvested by centrifugation at 7300xg for 15 min and cell pellets stored frozen in -20C. Extraction of ERa and ER are performed using 5 g of cells suspended in 50 mL of extraction buffer (50 mM Tris, pH 8.0, 100 mM KC1, 4 mM EDTA, 4 mM DDT and 0.1 mM PMSF). The cell suspension is run twice through a Micro fluidizer M- 1 10L (Microfluidics) and centrifuged at 15,000xg for 60 min. The supernatant is aliquoted and stored in -70C.

Dilute ERa-LBD or ERP-LBD extracts in assay buffer (18 mM K₂HP0₄, 2 mM KH₂P0₄, 20 mM Na_sMo0₄, 1 mM EDTA, ImM TCEP) 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 polyvinyltoluene SPA beads (RPNQ0007, GE Healthcare) at a concentration of 0.43 mg/mL for lhr at room temperature. Test compounds are evaluated over a range of concentrations from 157 μΜ to 37.5 pM. The 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 35μ1 of the preincubated receptor/SPA bead mix and finally add 35μ1 of 3nM ³H-E2. 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 3[H]-E2 from the receptor an IC₅₀-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-bmin)/(l+(I/IC₅₀)S))+bmin I is added concentration of binding inhibitor, IC₅₀ 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.

Transactivation Assay 1 : Transactivation assay in human embryonic kidney 293 cells stably transfected 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 transfected in two steps. Firstly, a stable clone mix transfected with the pERE-ALP reporter gene construct and pSV2-Neo for selection is developed. Secondly, the stable clone mix is transfected with pMThERa and a pKSV-Hyg resistance vector for selection. All transfections are performed using Lipofectamine (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-well plates at 12 500 cells per well in Ham's F12 Coon's

modification (without phenol red) with 10 % dextran-coated charcoal treated (DCC) fetal bovine serum (FBS), 2 mM L-glutamine and 50 μg/ml gentamicin. After 24 h incubation (37°C, 5 % C0₂) the seeding medium is discarded and replaced with 20 μΐ Ham's F12 Coon's modification (without phenol red) with 1.5 % DCC-FCS, 2 mM L-glutamine and supplemented with 100 U/ml penicillin and 100 μ^ιηΐ streptomycin. The selected compounds are added to the wells in 12 concentrations ranging from 3.3 pM to 33 μΜ. The compounds are dissolved in 100 % dimethylsulphoxide (DMSO) and the final concentration of DMSO in the assay is 0.1 %. After 72 h incubation (37°C, 5 % C0₂) the medium is assayed for ALP activity by a

chemiluminescence assay; a 10 μΐ aliquot of the cell culture medium is mixed with 100 μΐ assay buffer (0.1 M diethanolamine, 1 mM MgCl₂) and 0.5 mM disodium 3-(4-methoxyspiro 1,2- dioxetane-3,2'-(5'-chloro)-tricyclo[3.3.1.13,7]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 chemiluminescent light signal (one second per well) in a Wallac Microbeta Trilux 1450-028 (PerkinElmer). The half maximal effective concentrations (EC₅₀) are calculated from the curves fitted to the concentration-response data with a four parameter logistic model in XLfit software version 2.0 (IDBS) or later.

Transactivation Assay 2: Transactivation assay in human embryonic kidney 293 cells stably transfected with pERE2-ALP and human estrogen receptor beta

Generation of stable HEK293 cell lines (CRL-1573; American Type Culture Collection) expressing the reporter vector pERE2-ALP and human estrogen receptor beta (hERB 530) have been described (Mol Pharmacol 1998, 54,105-1 12; Endocrinology 2002, 143, 1558-1561).

The cells were seeded in 384-well plates at 12 500 cells per well in Ham's F12 Coon's modification (without phenol red) with 10 % dextran-coated charcoal treated (DCC) fetal bovine serum (FBS), 2 mM L-glutamine and 50 μg/ml gentamicin. After 24 h incubation (37°C, 5 % C02) the seeding medium was discarded and replaced with 20 μΐ Ham's F12 Coon's

modification (without phenol red) with 1.5 % DCC-FCS, 2 mM L-glutamine and supplemented with 100 U/ml penicillin and 100 μ^ηιΐ streptomycin. The selected compounds were added to the wells in 12 concentrations ranging from 3.3 pM to 33 μΜ. The compounds were dissolved in 100 % dimethylsulfoxide (DMSO) and the final concentration of DMSO in the assay was 0.1 %. After 72 h incubation (37°C, 5 % C02) the medium was assayed for ALP activity by a chemiluminescence assay; a 10 μΐ 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-methoxyspiro l,2-dioxetane-3,2'-(5'-chloro)-tricyclo[3.3.1.13,7]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 chemiluminescent signal (one second per well) in a Wallac Microbeta Trilux 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 XLfit software version 2.0 (IDBS) or later. The Example compounds were tested in binding assay 1 and in transactivation assays 1 and 2.

The compounds of Examples 1-15 exhibit one or more of the following:

(i) a binding affinity to the estrogen receptor a-subtype in the range of IC₅₀ 1 to 10,000 nM in binding assay 1 ;

(ii) a binding affinity to the estrogen receptor β-subtype in the range of IC₅₀ 1 to 10,000 nM in binding assay 1 ;

(iii) a potency in the range of EC₅₀ 1 to 10,000 nM at the estrogen receptor a-subtype in transactivation assay 1 ;

(iv) a potency in the range of EC₅o 0.1 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 binding affinity to the estrogen receptor β-subtype at lower concentrations within the IC50 range shown above. For example, the compounds of Examples 8, 13 and 14 exhibit a binding affinity to the estrogen receptor β-subtype in the range of IC50 1 to 100 nM in binding assay 1.

Preferred Example compounds of the invention are those which are selective for the estrogen receptor β-subtype over the estrogen receptor α-subtype in binding assay 1. For example, the compounds of Examples 6, 13 and 14 display selectivity for the estrogen receptor β-subtype of 10 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 EC₅₀ range shown above. For example, the compounds of Examples 6, 8, 10, 13, 14 and 15 exhibit a potency in the range of EC₅₀ 0.1 to 100 nM at the estrogen receptor β-subtype 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 transactivation assays 1 and 2. For example, the compounds of Examples 8 and 13 display selectivity for the estrogen receptor β-subtype of 50 or greater in the transactivation assays.

Claims

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

(I)

wherein ring Z is a pyrrolyl ring in which A, G and E each represent nitrogen or carbon, and in which B represents CR¹ or NR^1A, and in which D represents CR² or NR^2A; p, q and r are each independently 0 or 1 ; each of M¹, M² and M³, and where present each of M⁴, M⁵ and M⁶, is CR⁷R⁸;

where the bond between one of the pairs M' -M², M²-M³, M³-M⁴, M⁴-M⁵ and M⁵-M⁶ may, instead of being a single bond, be a double bond, in which case R⁸ substituents are absent from that pair;

R¹ is selected from the group consisting of optionally substituted 5-10 membered heterocyclyl, optionally substituted phenyl, optionally substituted benzyl, halogen, cyano, nitro, OR^A, N(R^B)₂, -C(0)Ci_₄alkyl optionally substituted with from 1 to 3 halogens, -S0₂C|.₄alkyl, Ci_₈alkyl, C_2- _galkenyl, C₂.₈alkynyl, haloC|_₈alkyl, dihaloCi_-8alkyl, trihaloC|_-8alkyl, haloC_2-8alkenyl, dihaloC₂.₈alkenyl, trihaloC_2-8alkenyl, haloC_2-8alkynyl, dihaloC .₈alkynyl, trihaloC₃.₈alkynyl, cyanoC|.₈alkyl, C|_₄alkoxyC|-₈alkyl, C₃_₈cycloalkyl, and C₃.₈cycloalkylC|.₈alkyl, wherein when said heterocyclyl, phenyl or benzyl group is substituted, it is substituted with from 1 to 3 substituents, each substituent being independently selected from the group consisting of OR^A, N(R^B)₂, halogen, cyano, nitro, -C(0)C|.₄alkyl, C|_-6alkyl, C_2-6alkenyl, C₂_₆alkynyl, haloC|_-6 alkyl, dihaloCi.₆alkyl and trihaloCi_₆alkyl;

R^{I A} is selected from the group consisting of optionally substituted 5-10 membered heterocyclyl, optionally substituted phenyl, optionally substituted benzyl, cyano, OR^A, N(R^B)₂, -C(0)C|.₄alkyl optionally substituted with from 1 to 3 halogens, -S0₂Ci_-4alkyl, Ci_₈alkyl, C_2-8alkenyl, C_2- ₈alkynyl, haloC]_₈alkyl, dihaloCi_-8alkyl, trihaloCi_-8alkyl, haloC_2-8alkenyl, dihaloC_2-8alkenyl, trihaloC_2-8alkenyl, haloC_2-8alkynyl, dihaloC_3-8alkynyl, trihaloC_3-8alkynyl, cyanoCi_-8alkyl, Ci_₄alkoxyCi_-8alkyl, C_3-8cycloalkyl, and C_3-8cycloalkylC]_-8alkyl, wherein when said heterocyclyl, phenyl or benzyl group is substituted, it is substituted with from 1 to 3 substituents, each substituent being independently selected from the group consisting of OR^A, N(R^B)₂, halogen, cyano, nitro, -C(0)C_1-4alkyl, Ci_-6alkyl, C₂_₆alkenyl, C_2-6alkynyl, haloCi_₆ alkyl, dihaloC_{] -6}alkyl and trihaloCi_-6alkyl; R² is selected from the group consisting of -C(NH₂)=N-OH, -C(0)N(R^c)₂, cyano, -CHO, -CH=N-OH, -C(0)Ci_-4alkyl optionally substituted with from 1 to 3 halogens, -C(0)NH-OH, -C(NH₂)=N-OH, -C(C0₂H)=N-OH, -C(0-C_1-4alkyl)=NH, -C(NH₂)=N-NH₂, -C(0)-C(0)-NH₂, -C(0)C0₂H, -C0₂H, -CH₂-C0₂H, -CH(OH)C0₂H, -CH₂NH-CONH₂, Ci_-6alkyl-NH₂, Ci_₆alkyl- OH, -CH₂S0₃H, OR^A, -NH-C(NH₂)=NH, -NH-C(0)NH₂, -N=C(-NH-CH₂CH₂-NH-), N(R^B)₂, N(OH)₂, NHS0₂R^D, -S0₂Ci_-4alkyl, -S-CN, -S-C(NH₂)=NH, -S-C(NH₂)=N-OH, S0₂N(R^E)₂, S0₃H, cyanoC_)-6alkyl, Ci_-4alkoxyCi.₆alkyl and optionally substituted 5-10 membered

heterocyclyl, wherein when said heterocyclyl group is substituted, it is substituted with from 1 to 3 substituents, each substituent being independently selected from the group consisting of OR^A, N(R^B)₂, halogen, cyano, Ci_-6alkyl and trihaloC|_₆alkyl;

R^2A is selected from the group consisting of -C(NH₂)=N-OH, -C(0)N(R^c)₂, cyano, -CHO, -CH=N-OH, -C(0)C alkyl optionally substituted with from 1 to 3 halogens, -C(0)NH-OH, -C(NH₂)=N-OH, -C(C0₂H)=N-OH, -C(0-C alkyl)=NH, -C(NH₂)=N-NH₂, -C(0)-C(0)-NH₂, -C(0)C0₂H, -C0₂H, -CH₂-C0₂H, -CH(OH)C0₂H, -CH₂NH-CONH₂, C,_-6alkyl-NH₂, C,_₆alkyl- OH, -CH₂S0₃H, hydrogen, OR^A, -NH-C(NH₂)=NH, -NH-C(0)NH₂, -N=C(-NH-CH₂CH₂-NH-), N(R^B)₂, NHS0₂R^D, -S0₂C,.₄alkyl, -S-CN, -S-C(NH₂)=NH, -S-C(NH₂)=N-OH, S0₂N(R^E)₂, S0₃H, cyanoC|_₆alkyl, C[_₄alkoxyCi_-6alkyl and optionally substituted 5-10 membered

heterocyclyl, wherein when said heterocyclyl group is substituted, it is substituted with from 1 to 3 substituents, each substituent being independently selected from the group consisting of OR^A, N(R )₂, halogen, cyano, Ci_-6alkyl and trihaloC|_6alkyl; each of R³, R⁴, R⁵ and R⁶ is independently selected from the group consisting of hydrogen, OR^A, N(R )₂, halogen, cyano, nitro, -C(0)Ci_-4alkyl, Ci_-6alkyl, C_2-6alkenyl, C_2-6alkynyl, haloCi_-6 alkyl, dihaloCi_-6alkyl and trihaloCi_-6alkyl; each R⁷ and each R⁸ is independently selected from the group consisting of hydrogen, OR^A, N(R^B)₂, halogen, cyano, -C(0)Ci_-4alkyl, Ci_₆ alkyl, C_2-6 alkenyl, C_2-6 alkynyl, halo C_1-6 alkyl, dihalo C_1-6 alkyl, trihalo Ci_₆ alkyl, haloC_2-6alkenyl, dihaloC_2-6alkenyl, trihaloC_2-6alkenyl, cyanoCi_-6alkyl, C_1-4alkoxyCi_-6alkyl, C_3-8 cycloalkyl and C_3-8 cycloalkyl C_1-6 alkyl; and each R^A, each R^B, each R^c, each R^D and each R^E is independently selected from the group consisting of hydrogen, Ci_-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-8cycloalkyl and C_3-8cycloalkylCi. 6alkyl; with the proviso that the compound of formula (I) is not:

2. The compound as claimed in claim 1 , wherein each of M¹, M² and M³, and where present each of M⁴, M⁵ and M⁶, is CR⁷R⁸.

3. The compound as claimed in claim 2, wherein the compound has the formula (IF) or (IG)

4. The compound as claimed in any one of claims 1 to 3, wherein ring Z is a pyrrolyl ring in which A represents nitrogen or carbon, B represents CR¹, D represents CR² or NR^2A, E represents nitrogen or carbon, and G represents carbon.

5. The compound as claimed in claim 4, wherein A represents carbon, B represents CR¹, D represents NR^2A, E represents carbon, and G represents carbon.

6. The compound as claimed in any one of claims 1 to 5, wherein R¹ is selected from the group consisting of optionally substituted 5-10 membered heterocyclyl, optionally substituted phenyl, optionally substituted benzyl, N(R^B)₂, halogen, cyano, C_2-8alkenyl, C_2-8alkynyl, haloC_2-8alkenyl, dihaloC_2-8alkenyl, trihaloC_2-8alkenyl, haloC₂_₈alkynyl, dihaloC_3-8alkynyl and trihaloC_3-8alkynyl, wherein when said heterocyclyl, phenyl or benzyl group is substituted, it is substituted with from 1 to 3 substituents, each substituent being independently selected from the group consisting of OR^A, N(R^B)₂, halogen, cyano, nitro, -C(0)d_-4alkyl, Ci_-6alkyl, C₂_₆alkenyl, C_2-6alkynyl, haloQ.e alkyl, dihaloCi_-6alkyl and trihaloCi_₆alkyl; or

R^1A is selected from the group consisting of optionally substituted 5-10 membered heterocyclyl, optionally substituted phenyl, optionally substituted benzyl, cyano, C₂_₈alkenyl, C_2-8alkynyl, haloC_2-8alkenyl, dihaloC₂_₈alkenyl, trihaloC_2-8alkenyl, haloC_2-8alkynyl, dihaloC₃.₈alkynyl and trihaloC₃.₈alkynyl, wherein when said heterocyclyl, phenyl or benzyl group is substituted, it is substituted with from 1 to 3 substituents, each substituent being independently selected from the group consisting of OR^A, N(R^B)₂, halogen, cyano, nitro, -C(0)C,_-4alkyl, Ci_-6alkyl, C₂_₆alkenyl, C_2-6alkynyl, haloC]_-6 alkyl, dihaloC]_₆alkyl and trihaloCi_-6alkyl.

7. The compound as claimed in claim 6, wherein R¹ represents R¹ represents N(R^B)₂, halogen, cyano, C₂-₆alkenyl or an optionally substituted 5-10 membered heterocyclyl, wherein when said heterocyclyl group is substituted, it is substituted with from 1 to 3 substituents, each substituent being independently selected from the group consisting of OR^A, N(R^B)₂, halogen, cyano, nitro, -C(0)C|.₄alkyl, Ci_-6alkyl, C₂-₆alkenyl, C₂_₆alkynyl, haloC].₆ alkyl, dihaloC|_₆alkyl and trihaloC|. ₆alkyl; or R^{I A} represents cyano, C₂.₆alkenyl or an optionally substituted 5-10 membered heterocyclyl, wherein when said heterocyclyl group is substituted, it is substituted with from 1 to 3 substituents, each substituent being independently selected from the group consisting of OR^A, N(R )₂, halogen, cyano, nitro, -C(0)Ci_-4alkyl, Ci_₆alkyl, C_2-6alkenyl, C_2-6alkynyl, haloCj_₆ alkyl, dihaloCi- alkyl and trihaloCi_-6alkyl.

8. The compound as claimed in claim 7, wherein R¹ represents halogen, cyano or a 5-membered aromatic heterocyclyl group substituted by two methyl groups; or R^1A represents cyano or a 5- membered aromatic heterocyclyl group substituted by two methyl groups.

9. The compound as claimed in claim 8, wherein R¹ represents an isoxazolyl, isothiazolyl, pyrrolyl, thienyl or furyl group substituted by two methyl groups; or R^1A represents an isoxazolyl, isothiazolyl, pyrrolyl, thienyl or furyl group substituted by two methyl groups.

10. The compound as claimed in any one of claims 1 to 9, wherein R² represents

-C(NH₂)=N-OH, -C(0)NH₂, cyano or -CH=N-GH; or R^2A represents -C(NH₂)=N-OH,

-C(0)NH₂, cyano, hydrogen or -CH=N-OH.

11. The compound as claimed in claim 10, wherein R² represents -C(NH₂)=N-OH or

-CH=N-OH; or R^2A represents -C(NH₂)=N-OH or -CH=N-OH.

12. The compound as claimed in any one of claims 1 to 1 1, wherein each of R³, R⁴, R⁵ and R⁶ is independently selected from the group consisting of hydrogen and halogen.

13. The compound as claimed in any one of claims 1 to 12, wherein each R⁷ and each R⁸ is independently selected from the group consisting of hydrogen, halogen, C i_-4 alkyl and trihalo Ci_ 4 alkyl.

14. The compound as claimed in any one of claims 1 to 13, wherein each R^A, each R^B, each R^c, each R^D and each R^E is independently selected from the group consisting of hydrogen and C|. ₄alkyl.

15. The compound as claimed in claim 1 or claim 2, wherein

R¹ is selected from the group consisting of N(R^B)₂, optionally substituted 5-10 membered heterocyclyl, optionally substituted phenyl, optionally substituted benzyl, halogen, cyano, C₂. ₈alkenyl, C₂_₈alkynyl, haloC₂.₈alkenyl, dihaloC₂.₈alkenyl, trihaloC₂.₈alkenyl, haloC₂-₈alkynyl, dihaloC_3-8alkynyl and trihaloC_3-8alkynyl, wherein when said heterocyclyl, phenyl or benzyl group is substituted, it is substituted with from 1 to 3 substituents, each substituent being independently selected from the group consisting of OR^A, N(R^B)₂, halogen, cyano, nitro, -C(0)Ci_-4alkyl, Ci_-6alkyl, C_2-6alkenyl, C₂_₆alkynyl, haloCi-₆ alkyl, dihaloCi-₆alkyl and trihaloCi. ₆alkyl; or R^1A is selected from the group consisting of optionally substituted 5-10 membered heterocyclyl, optionally substituted phenyl, optionally substituted benzyl, cyano, C_2-8alkenyl, C₂. ₈alkynyl, haloC₂_₈alkenyl, dihaloC_2-8alkenyl, trihaloC_2-8alkenyl, haloC_2-8alkynyl,

dihaloC_3-8alkynyl and trihaloC_3-8alkynyl, wherein when said heterocyclyl, phenyl or benzyl group is substituted, it is substituted with from 1 to 3 substituents, each substituent being independently selected from the group consisting of OR^A, N(R^B)₂, halogen, cyano, nitro,

-C(0)C_1-4alkyl, Ci-₆alkyl, C_2-6alkenyl, C₂_₆alkynyl, haloCi_-6 alkyl, dihaloCi_-6alkyl and trihaloCi. ₆alkyl;

-C(NH₂)=N-OH, -C(0)NH₂, cyano, hydrogen or -CH=N-OH;

each of R³, R⁴, R⁵ and R⁶ is independently selected from the group consisting of hydrogen and halogen; each R⁷ and each R⁸ is independently selected from the group consisting of hydrogen, halogen, Ci_₄ alkyl and trihalo C alkyl; and

each R^A and each R^B is independently selected from the group consisting of hydrogen and C|_ ₄alkyl.

16. The compound as claimed in claim 15, wherein the compound has the formula (IF) or (IG)

R¹ is selected from the group consisting of optionally substituted 5-10 membered heterocyclyl, optionally substituted phenyl, optionally substituted benzyl, halogen, cyano, C₂.₈alkenyl, C₂- galkynyl, haloC₂-₈alkenyl, dihaloC₂-₈alkenyl, trihaloC₂.₈alkenyl, haloC₂-₈alkynyl,

dihaloC₃_₈alkynyl and trihaloC₃-₈alkynyl, wherein when said heterocyclyl, phenyl or benzyl group is substituted, it is substituted with from 1 to 3 substituents, each substituent being independently selected from the group consisting of OR^A, N(R^B)₂, halogen, cyano, nitro, -C(0)C_1-4alkyl, Ci-6alkyl, C_2-6alkenyl, C_2-6alkynyl, haloC_1-6 alkyl, dihaloC].₆alkyl and trihaloCi. ₆alkyl; or R^1A is selected from the group consisting of optionally substituted 5-10 membered heterocyclyl, optionally substituted phenyl, optionally substituted benzyl, cyano, C_2-8alkenyl, C_2- galkynyl, haloC₂.galkenyl, dihaloC_2-8alkenyl, trihaloC_2-galkenyl, haloC_2-8alkynyl,

dihaloC_3-8alkynyl and trihaloC_3-8alkynyl, wherein when said heterocyclyl, phenyl or benzyl group is substituted, it is substituted with from 1 to 3 substituents, each substituent being independently selected from the group consisting of OR^A, N(R^B)₂, halogen, cyano, nitro, -C(0)C]_-4alkyl, C_2-6alkenyl, C_2-6alkynyl, haloC].₆ alkyl, dihaloCi_-6alkyl and trihaloCi. ₆alkyl; and

R² represents -C(NH₂)=N-OH, -C(0)NH₂, cyano or -CH=N-OH, or R^2A represents

-C(NH₂)=N-OH, -C(0)NH₂, cyano, hydrogen or -CH=N-OH.

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

2-(3,5-dimethylisoxazol-4-yl)- 1 -(4-hydroxyphenyl)- 1 ,4,5,6-tetrahydrocyclopenta[b]pyrrole-3- carbonitrile;

2-(3,5-dimethylisoxazol-4-yl)-N'-hydroxy-l-(4-hydroxyphenyl)-l, 4,5,6- tetrahydrocyclopenta[b]pyrrole-3-carboximidamide;

2-(3,5-dimethylisoxazol-4-yl)-l-(4-hydroxyphenyl)-4,5,6,7-tetrahydro-lH-indole-3-carbonitrile; 2-(3,5-dimethylisoxazol-4-yl)-N'-hydroxy-l-(4-hydroxyphenyl)-4,5,6,7-tetrahydro-lH-indole-3- carboximidamide;

2-(3,5-dimethylisoxazol-4-yl)-l-(4-hydroxyphenyl)-4,5,6,7-tetrahydro-lH-indole-3- carboxamide;

4-(2-(3,5-dimethylisoxazol-4-yl)-l ,4,5,6-tetrahydrocyclopenta[b]pyrrol-3-yl)phenol;

2-(3,5-dimethylisoxazol-4-yl)-3-(4-hydroxyphenyl)-5,6-dihydrocyclopenta[b]pyrrole-l(4H)- carbonitrile;

2-(3,5-dimethylisoxazol-4-yl)-N'-hydroxy-3-(4-hydroxyphenyl)-5,6- dihydrocyclopenta[b]pyrrole- 1 (4H)-carboximidamide;

2-(3,5-dimethylisoxazol-4-yl)-3-(4-hydroxyphenyl)-5,6-dihydrocyclopenta[b]pyrrole-l (4H)- carboxamide;

4-(2-(3,5-dimethylisoxazol-4-yl)-4,5,6,7-tetrahydro-l H-indol-3-yl)phenol;

2-(3,5-dimethylisoxazol-4-yl)-N'-hydroxy-3-(4-hydroxyphenyl)-4,5,6,7-tetrahydro-2H-isoindole- 1 -carboximidamide; 6-(2,4-dimethylthiophen-3-yl)-N'-hydroxy-5-(4-hydroxyphenyl)-2,3-dihydro-lH-pyrroli carboximidamide;

2-(2,4-dimethylthiophen-3-yl)-N'-liydroxy-3-(4-hydroxyphenyl)-5,6- dihydrocyclopenta[b]pyrrole- 1 (4H)-carboximidamide;

2-(2,4-dimethylthiophen-3-yl)-3-(2-fluoro-4-hydroxyphenyl)-N'-hydroxy-5,6- dihydrocyclopenta[b]pyrrole- 1 (4H)-carboximidamide;

6-(2,4-dimethylfuran-3-yl)-N'-hydroxy-7-(4-hydroxyphenyl)-2,3-dihydro-lH-pyrrolizm^ carboximidamide;

2-(3,5-dimethylisoxazol-4-yl)-N'-hydroxy-3-(4-hydroxyphenyl)-2,4,5,6- tetrahydrocyclopenta[c]pyrrole- 1 -carboximidamide;

3- (2,6-difluoro-4-hydroxyphenyl)-2-(3,5-dimethylisoxazol-4-yl)-N'-hydroxy-5,6- dihydrocyclopenta[b]pyrrole- 1 (4H)-carboximidamide;

3-(2,5-difluoro-4-hydroxyphenyl)-2-(3,5-dimethylisoxazol-4-yl)-N'-hydroxy-5,6- dihydrocyclopenta[b]pyrrole- 1 (4H)-carboximidamide;

3-(2-chloro-6-fluoro-4-hydroxyphenyl)-2-(3,5-dimethylisoxazol-4-yl)-N'-hydroxy-5,6- dihydrocyclopenta[b]pyrrole-l (4H)-carboximidamide;

3-(3,5-difluoro-4-hydroxyphenyl)-2-(3,5-dimethylisoxazol-4-yl)-N'-hydroxy-5,6- dihydrocyclopenta[b]pyrrole-l (4H)-carboximidamide;

3-(2,5-difluoro-4-hydroxyphenyl)-2-(3,5-dimethylisoxazol-4-yl)-N'-hydroxy-4,5,6,7-tetrahydro- 1 H-indole- 1 -carboximidamide; 3-(2-chloro-4-hydroxyphenyl)-2-(3,5-dimethylisoxazol-4-yl)-N'-hydroxy-4,5,6,7-tetrahydro-lH- indole- 1 -carboximidamide;

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

18. The compound as claimed in any one of claims 1 to 17 together with a further therapeutic agent, for simultaneous, sequential or separate administration.

19. A pharmaceutical composition which comprises a compound as claimed in any one of claims 1 to 18, together with a pharmaceutically acceptable carrier.

20. A compound as claimed in any one of claims 1 to 18, or a composition as claimed in claim 19, for use as a medicament.

21. A compound of formula (III)

22. A compound as claimed in claim 20 or claim 21 , or a composition as claimed in claim 20, for use in the treatment or prophylaxis of a condition associated with a disease or disorder associated with estrogen receptor activity.

23. Use of a compound as defined in any one of claims 1 to 18, or a compound as defined in claim 21, 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.

24. 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 defined in any one of claims 1 to 18, a compound as defined in claim 21 , or a composition as defined in claim 19.

25. Use of a compound as defined in any one of claims 1 to 17, or a compound as defined in claim 21, in labelled form as a diagnostic agent for the diagnosis of conditions associated with a disease or disorder associated with estrogen receptor activity.

26. Use of a compound as defined in any one of claims 1 to 17, a compound as defined in claim 21 , or a labelled form of such a compound as a reference compound in a method of identifying ligands for the estrogen receptor.

27. A compound or composition as claimed in claim 22, a use as claimed in claim 23 or 25, or a method as claimed in claim 24, 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, impulsivity, 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, 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, mesothelia, gallbladder cancer and extra-hepatic chloangiocarcinoma.