SUBSTITUTED ISOXAZOLE AS ESTROGEN RECEPTOR MODULATORS

Abstract: Isoxazole estrogen receptor agonist and antagonist compounds having unexpected and surprising activity in modulating estrogen receptor activity are described. In addition, methods and compositions for treating or preventing estrogen receptor-mediated disorders are disclosed. The compounds, methods, and compositions of the invention have utility in preventing or treating estrogen receptor-mediated disorders such as osteoporosis, breast and endometrial cancers, atherosclerosis, and Alzheimer's disease.

Description: SUBSTITUTED ISOXAZOLE AS ESTROGEN RECEPTOR MODULATORS 1 Background of The Invention 1.1 Field of the Invention The present invention relates to compounds that have biological activity with respect to estrogen receptors and to the use of such compounds to treat diseases and disorders related to estrogen receptor activity. More particularly, the present invention provides selective estrogen receptor modulators ("SERMs"). The present invention therefore relates to the fields of medicine, medicinal chemistry, biochemistry, and endocrinology. 1.2 Background Estrogen is a hormone critical to normal human development and function. Although estrogen is the predominant "sex hormone" in women, in whom estrogen controls the development of female sex characteristics and the development and function of the reproductive system (Berkow, Beers et al. 1997), it is also found in men (Gustafsson 1998). Women produce estrogen primarily in the ovaries; however, estrogen affects a variety of physiological functions in women including body temperature regulation, maintenance of the vaginal lining, and preservation of bone density (Jordan 1998). In addition, estrogen provides additional effects that are related to its ability to modulate production of cholesterol in the liver, as demonstrated by the reduced occurrence of atherocsclerosis in women compared to men due in part to the reduction of low-density lipoprotein ("LDL") (Jordan 1998). Estrogen has also been implicated in delaying and/or reducing the severity of Alzheimer's Disease (Jordan 1998). Failure to produce estrogen has profound physiological consequences in females. Failure to produce estrogen resulting from incomplete or absent ovary development (Turner's Syndrome) causes deficiencies in the skin, bone (e.g., severe osteoporosis), and other organs severely affecting the life of the afflicted individual (Dodge 1995). In normal women, estrogen production falls sharply upon the onset of menopause, usually at about 50 years of age. The effects of the loss of estrogen production include increased atherosclerotic deposits (leading to greatly increase incidence of heart disease), decreased bone density (osteoporosis), and fluctuations in body temperature among others (Jordan 1998). Often, the effects of reduced estrogen production are addressed by hormone replacement therapy (Dodge 1995; Berkow, Beers et al. 1997; Jordan 1998). However, estrogen also has undesirable effects. In menopausal women, supplementation of estrogen is associated with alleviation of the above-described unwanted effects. But, administration of estrogen is also associated with increased risks for breast and endometrial cancer as well as blood clots (Jordan 1998). The increased risk of endometrial cancer can be addressed by the administration of progesterone (or its synthetic analog progestin) to re-initiate menstruation and thereby shed potentially malignant cells, but many older women find this undesirable (Jordan 1998). Breast cancer, however, is by far the greater risk of estrogen replacement therapy, affecting one woman in every 15 between the ages of 60 and 79 (Jordan 1998). Thus for a long time the treatment options for the serious health problems caused by a failure to produce estrogen were limited and entailed severe risks However, the discovery that some agents acted as estrogen agonists m some tissues (e g , bone) and as an antagonists in other tissues (e g , breast) provided hope that more effective treatments for estrogen loss could be found (Gradishar and Jordan 1997, Gustafsson 1998, Jordan 1998, MacGregor and Jordan 1998) The best known of these so-called Selective Estrogen Receptor Modulators ("SERMs"), tamoxifen, has been demonstrated to have therapeutic utility in treating and preventing breast cancer and lowering LDL concentrations, yet, without significant reduction bone density (Jordan 1998, MacGregor and Jordan 1998) However, tamoxifen has been associated with endometrial cancer and venous blood clots (Jordan 1998, MacGregor and Jordan 1998) In addition, tumor resistance to tamoxifen can occur (MacGregor and Jordan 1998) Tamoxifen has been followed recently by newer SERMs, in particular raloxifene, that promise to provide many of tamoxifen's benefits with fewer risks (Howell, Downey et al 1996, Gradishar and Jordan 1997, Gustafsson 1998, Jordan 1998. Purdie 1999, Sato, Grese et al 1999) These newer SERMs. including idoxifene (Nuttall, Bradbeer e/ α/ 1998), CP-336, 156 (Ke, Paralkar ez α/ 1998), GW5638 (Willson, Norris et al 1997), LY353581 (Sato, Turner et al 1998) are part of the second- and third generation of partial estrogen agonists/antagonists In addition, a new generation of pure antiestrogens such as RU 58,688 (Van de Velde, Nique et al 1994) have been reported A large number of additional partial and pure estrogen agonist/antagonist compounds and treatment modalities have reported recently (Bryant and Dodge 1995, Bryant and Dodge 1995, Culhnan 1995, Dodge 1995, Grese 1995, Labπe and Merand 1995, Labπe and Merand 1995, Thompson 1995, Audia and Neubauer 1996, Black, Bryant et al 1996, Thompson 1996, Culhnan 1997, Wilson 1997, Miller, Collini et al 1999, Palkowitz 1999, Wilson 1999) However, no one drug candidate has emerged to fill the needs of women who require the benefits of estrogen replacement to live productive lives and/or treatments for estrogen-dependent cancers The efforts to develop better partial and pure estrogen agonists and antagonists has been aided by several recent developments, including the discovery that human estrogen receptor has at least two isoforms ("ERct" and "ERβ") and the crystal structure of ERα that have permitted high-resolution structure-acitivty relationship studies (Sadler, Cho et al 1998) Recently, a study of the application of combinatorial synthetic methods combined with three-dimensional structure-activity analysis to develop SERMs having optimal therapeutic profiles was reported (Fink, Mortensen et al 1999) That study examined several heterocyclic motifs (lmidazoles, thiazoles, pyrazoles, oxazoles, and isoxazoles) and identified certain pyrazole motifs as being well suited for combinatorial development of SERMs The relative binding effectiveness of the pyrazoles viz the other motifs was based on its ability to carry four substituents in addition to polarity consideration (see p 215) In particular, the study referred the capacity of the pyrazole motif to carry four substituents explained the binding effectiveness pyrazoles compared to the poor binding results found for the oxazole, thiazole, and isoxazole motifs However, despite these recent advances no drug candidate has emerged to fill the needs of women who require the benefits of estrogen replacement to live productive lives and/or treatments for estrogen-dependent cancers The present invention addresses these and other needs 2 Summary of the Invention The present invention provides isoxazole estrogen receptor agonist and antagonist compounds in addition to methods and compositions for treating or preventing estrogen receptor-mediated disorders The compounds described herein have been found to have unexpected and surprising activitv in modulating estrogen receptor activity Thus, the compounds of the present invention have utility m preventing or treating estrogen receptor- mediated disorders such as osteoporosis, breast and endometrial cancers, atherosclerosis, and Alzheimer's disease In a first aspect, the present invention provides compounds having the structure shown below and its pharmaceutically acceptable salts Xi and X 2 are selected independently from the group consisting of nitrogen and oxygen such that if one of ] and X 2 is nitrogen, then the other of X, and X 2 is oxygen to form thereby an isoxazole ring structure R, and R 3 are selected independently from the group consisting of optionally substituted loweralkyl, aryl, heteroaryl, cycloalkyl, cycloheteroalkyl, aralkyl, heteroaralkyl, (cycloalkyl)alkyl, and (cycloheteroalkyl)alkyl R 2 is selected from the group consisting of hydrogen, halo, cyano, nitro, thio, amino, carboxyl, formyl, and optionally substituted loweralkyl, loweralkylcarbonyloxy, arylcarbonyloxy, heteroarylcarbonyloxy, cycloalkylcarbonyloxy, cycloheteroalkylcarbonyloxy, aralkycarbonyloxy, heteroaralkylcarbonyloxy, (cycloalkyl)alkylcarbonyloxy, (cycloheteroalkyl)alkylcarbonyloxy, loweralkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, cycloalkylcarbonyl, cycloheteroalkylcarbonyl, aralkycarbonyl, heteroaralkylcarbonyl, (cycloalkyl)alkylcarbonyl, (cycloheteroalkyl)alkylcarbonyl, loweralkylaminocarbonyl, arylaminocarbonyl, aralkylaminocarbonyl, heteroarylaminocarbonyl, heteroaralkylam ocarbonyl, cycloalkylammocarbonyl, (cycloalkyl)alkylamιnocarbonyl, cycloheteroalkylaminocarbonyl, (cycloheteroalkyl)alkylamιnocarbonyl, loweralkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, cycloalkylcarbonylamino, cycloheteroalkylcarbonylammo, aralkylcarbonylammo, heteroaralkylcarbonylamino (cycloalkyl)alkylcarbonylamιno, (cycloheteroalkyl)alkylcarbonylammo, loweralkylamino, arylamino, aralkylamino, heteroarylamino, heteroaralkylamino, loweralkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, cycloalkylsulfonyi, cycloheteroalkylsulfonyl, aralkylsulfonyl, heteroaralkylsulfonyl, (cycloalkyl)alkylsulfonyl, (cycloheteroalkyl)alkylsulfonyl, loweralkylsulfinyl, arylsulfinyl, heteroarylsulfinyl, cycloalkylsulfinyl, cycloheteroalkylsulfinyl, aralkylsulfinyl, heteroaralkylsulfinyl, (cycloalkyl)alkylsulfinyl, (cycloheteroalkyl)alkylsulfinyl, loweralkyloxy, aryloxy, heteroaryloxy, cycloalkyloxy, cycloheteroalkyloxy, aralkyloxy, heteroaralkyloxy, (cycloalkyl)alkyloxy, and (cycloheteroalkyl)alkyloxy, loweralkylthio, arylthio, heteroarylthio, cycloalkylthio. cycloheteroalkylthio, aralkylthio, heteroaralkylthio, (cycloalkyl)alkylthιo, (cycloheteroaikyl)alkylthιo. loweralkylthiocarbonyl, arylthiocarbonyl, heteroarylthiocarbonyl, cycloalkylthiocarbonyl, cycloheteroalkylthiocarbonyl, aralkythiocarbonyloxythiocarbonyl, heteroaralkylthiocarbonyl, (cycloalkyl)alkylthιocarbonyl, (cycloheteroalkyl)alkylthιocarbonyl, heteroarylcarbonylthio. cycioalkylcarbonylthio, cycloheteroalkylcarbonylthio, aralkycarbonylthiooxycarbonylthio, heteroaralkylcarbonylthio, (cycloalkyl)alkylcarbonylthιo, (cycloheteroalkyl)alkylcarbonylthιo, ioweraikyioxycarbonyl, aryloxycarbonyl, heteroarvloxycarbonyl. cycloal vloxycarbonyl, cycloheteroalkyloxycarbonyl, aralkyoxycarbonyl, heteroaraikvloxycarbonyl, (cycloalkyl)alkyloxycarbonyl, (cycloheteroalkyl)alkyloxycarbonyl, lminoloweralkyl. lmmocycloalkyl, lmmocycloheteroalkyl, lminoaralkyl, lminoheteroaralkyl, (cycloalkyl)ιmmoalkyl, (cycloheteroalkyl)ιmιnoalkyl, (cycloιmιnoalkyl)alkyl. (cycloι ιnoheteroalkyl)alkyl, oximinoloweralkyl, oxi inocycloalkyl. oximinocycloheteroalkyl. oximinoaralkyl, oximinoheteroaralkyl, (cycloalkyl)oxιmmoalkyl, (cyclooxιmιnoalkyl)alkyl, (cyclooxιmιnoheteroalkyl)alkyl, and (cycloheteroalkyl)oxιmιnoaikyl In one more specific embodiment of the invention, R is selected from the group consisting of hydrogen, halo, and optionally substituted loweralkyl, haloloweralkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, aryloxyalkyl, arylthioalkyl, arylcarbonyl, heteroarylcarbonyl, loweralkylcarbonyl, ammocarbonyl, arylammocarbonyl, loweralkylaminocarbonyl, aralkylammocarbonyl, (heterocycloloweralkyl)alkylamιnocarbonyl, heteroarylaminocarbonyl, heteroaralkylaminocarbonyl, (cycloloweralkyl)ammocarbonyl, formyl, amino, loweralkylamino, and alkenyl More particular embodiments are those for which R 2 is selected from the group consisting of optionally substituted phenylcarbonyl, (heterocycloalkyl)loweralkyloxyphenylcarbonyl, hydroxyphenylcarbonyl, halophenylcarbonyl, phenylloweralkylaminocarbonyl, diloweralkylaminocarbonyl phenylloweralkylaminocarbonyl, hydroxyphenyllowerlakylammocarbonyl, cycloalkylaminocarbonyl, loweralkylphenylcarbonyl, haloloweralkylsulfonylloweralkyloxyphenylcarbonyl, and nitrophenylcarbonyl Examples of R 2 substituents within this embodiment having useful properties include, but are not limited to, 4-(2- pipeπdm- 1 -ylethy loxy)phenylcarbonyl, 4-hydroxyphenylcarbony 1, (pheny lmethy l)amιnocarbony 1, 3-(2- oxopyrrolidm- 1 -yl)propylaminocarbonyl, di-w-butylaminocarbony 1, (4-hydroxypheny lmethyl)amιnocarbonyl, (pyπdιn-3-ylmethyl)amιnocarbonyl, (pyπdm-2-ylmethyl)amιnocarbonyl, dimethylammocarbonyl, ethylaminocarbonyl, 4-(2-morphohnoethyloxy)phenylcarbonyl, 4-(3-dιmethylammopropyloxy)phenylcarbonyl, cyclopropylaminocarbonyl, cyclobutylaminocarbonyl, 4-(2-dιmethylamιnoethyloxy)phenylcarbonyl, 4-[2- (benzylmethylamιno)ethyloxy]pheny lcarbony 1, 4-( 1 -methylpιpeπdm-3-y lmethyloxy)pheny lcarbonyl, 4-[2-( 1 - methylpyrrolιdιn-2-yl)ethyloxy]phenylcarbonyl, 4-[2-(4-methylpφerazιn- 1 -yl)ethyloxy]phenylcarbonyl, 4-( 1 - methylpιpeπdιn-4-ylmethyloxy)phenylcarbonyl, 2-chlorophenylcarbonyl, 3-chlorophenylcarbonyl, 4- chloropheny lcarbonyl, 3-nιtrophenylcarbonyl, 4-nιtropheny lcarbonyl, 3,4-dιchlorophenylcarbonyl, A-n- butylphenylcarbonyl, 3-hydroxyphenylcarbonyl, 2-hydroxyphenylcarbonyl, 4-methoxyphenylcarbonyl, 3-(2- pipeπdin- 1 -ylethyloxy)phenylcarbonyl, 3-(2-dιethylamιnoethyloxy)phenylcarbonyl, 3-[2-(pyrrolιdιn- 1 - yl)ethyloxy]phenylcarbonyl, 3-(l-methylpιpeπdιn-3-ylmethyloxy)phenylcarbonyl, and 3-(2- dιmethylamιnoethyloxy)phenylcarbonyl In other embodiments of the invention, R 2 is selected from the group consisting of optionally substituted phenylcarbonyl, (heterocycloalkyl)loweralkyloxyphenylcarbonyl, hydroxyphenylcarbonyl, halophenylcarbonyl, phenylloweralkylaminocarbonyl, diloweralkylaminocarbonyl, phenylloweralkylaminocarbonyl, hydroxyphenyllowerlakylaminocarbonyl, cycloalkylaminocarbonyl, loweralkylphenylcarbonyl, haloloweralkylsulfonylloweralkyloxyphenylcarbonyl, and nitrophenylcarbonyl, R) and R 3 are selected independently from the group consisting of optionally substituted aryl and aralkyl, at least one of R| and R is selected independently from the group consisting of phenyl, pheny loxyloweralkyl, and phenylloweralkyl at least one of R] and R 3 is substituted with at least one hydroxyl or thio group, and at least one of R, and R 3 is substituted optionally with a substituent selected from the group consisting of halogen, loweralkyl halolowerlalkyl, loweralkyloxy, halolowerlakyloxy, carboxy, loweralkyloxycarbonyl, aryloxycarbonyl, (cycloloweralkyl)oxycarbonyl, aralkyloxycarbonyl, heteroaryloxycarbonyl, heteroaralkyloxycarbonyl, (heterocycloloweralkyl)oxycarbonyl, loweralkylsulfinyl, loweralkylsulfonyl, loweralkylthio, arylthio, loweralkylcarbonyloxy, arylcarbonyloxy, aralkylcarbonyloxy, heteroaryicarbonyloxy, heteroaralkylcarbonyloxy, (cycloloweralkyl)carbonyloxy, (heterocycloloweralkyl)carbonyloxy, aminocarbonyl, loweraklyiaminocarbonyl, aryla mocarbonyl, aralkylaminocarbonyl, heteroarylammocarbonyl, and heteroaralkylammocarbonyl Examples of specific useful groups for and R 3 include without limitation 2-methyl-4-hydroxyphenyl, 2-ammocarbonyl-4- hydroxyphenyl, 4-methylsulfonylammophenyl, 3-amιnocarbonyl-4-hydroxyphenyl, 3-amιnocarbonyl-4- methoxyphenyl, 3-chloro-4-hydroxyphenyl, 4-methylcarbonyloxyphenyl, 3-«-hexyl-4-hydroxyphenyl, 4-n- propylcarbonyloxyphenyl, 3-ethyl-4-hydroxyphenyl, 2-methylsulfinyl-4-hydroxyphenyl, 2-ethyl-4-hydroxyphenyl. 2-carboxy-4-hydroxyphenyl, 3-fluoro-4-hydroxyphenyl, 2-ιodo-4-hydroxyphenyl, 2-«-butyl-4-hydroxyphenyl, 2- tπfluoromethoxyphenyl, and 4-fluorophenyl In another aspect, the present invention provides estrogen receptor-modulating compounds having the following structure and their pharmaceutically acceptable salts X 3 and X 4 are selected independently from the group consisting of nitrogen and oxygen such that if one of X 3 and X 4 is nitrogen, then the other of X 3 and X is oxygen to form thereby an isoxazole ring structure X 5 is -(Xιo)«-, wherem n is an integer between 1 and 3 and Xι 0 , for each value of n, is selected independently from the group consisting of oxygen, -SO * - where x is and integer between 0 and 2, nitrogen, nitrogen substituted with optionally substituted loweralkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, arylcarbonyl, alkylcarbonyl, aralkylcarbonyl, heteroaryicarbonyl, heteroaralkylcarbonyl, and methylene or methine, each optionally substituted from the group consisting of halo, cyano, nitro, thio, ammo, carboxyl, formyl, and optionally substituted loweralkyl, loweralkylcarbonyloxy, arylcarbonyloxy, heteroaryicarbonyloxy, cycloalkylcarbonyloxy, cycloheteroalkylcarbonyloxy, aralkycarbonyloxy, heteroaralkylcarbonyloxy, (cycloalkyl)alkylcarbonyloxy, (cycloheteroalkyl)alkylcarbonyloxy, loweralkylcarbonyl, arylcarbonyl, heteroaryicarbonyl, cycloalkylcarbonyl, cycloheteroalkylcarbonyl, aralkycarbonyl, heteroaralkylcarbonyl, (cycloalkyl)alkylcarbonyl, (cycloheteroalkyl)alkylcarbonyl, loweralkylaminocarbonyl, arylammocarbonyl, aralkylaminocarbonyl, heteroarylammocarbonyl, heteroaralkylammocarbonyl, loweralkylcarbonylamino, arylcarbonylammo, heteroarylcarbonylamino, cycloalkylcarbonylamino, cycloheteroalkylcarbonylammo, aralkylcarbonylamino, heteroaralkylcarbonylamino, (cycloalkyl)alkylcarbonylamιno, (cycioheteroalkyl)alkylcarbonylamιno, loweralkylammo, arylamino. aralkylamino, heteroarylamino, heteroaralkylamino, loweralkylsulfonyl, arylsulfonyl. heteroarylsulfonyl, cycloalkylsulfonyi, cycloheteroalkylsulfonyl, aralkylsulfonyl, heteroaralkylsulfonyl, (cycloalkyl)alkylsulfonyl, (cycloheteroalkyl)alkylsulfonyl, loweralkylsulfinyl. arvlsulfinyl, heteroarylsulfinyl, cycloalkyisulfinyl, cycloheteroalkylsulfinyl, aralkylsulfinyl, heteroaralkyisulfinyl, (cycloalkyl)alkylsulfmyl, (cycloheteroalkvl)alkyisulfϊnyl, loweralkyloxy, aryloxv, heteroaryloxy, cycloaikvloxy, cycloheteroalkyloxy, aralkyioxy, heteroaralkyloxy, (cycloalkyl)alkyloxy, and (cycloheteroalkyl)alkyioxy, loweralkylthio, arylthio, heteroarvlthio cycloalkylthio, cycloheteroalkylthio. aralkylthio, heteroaralkylthio, (cycloalkyl)alkylthιo, (cycloheteroalkyl)alkylthιo, loweralkylthiocarbonyl, arylthiocarbonyl, heteroarylthiocarbonyl, cycloalkylthiocarbonyl, cycloheteroalkylthiocarbonyl, aralkythiocarbonyloxlthiocarbonyl, heteroaralkylthiocarbonyl, (cycloalkyl)alkylthιocarbonyl, (cycloheteroalkyi)alkylthιocarbonyi, heteroarylcarbonylthio, cycioalkylcarbonylthio, cycloheteroalkylcarbonylthio, aralkycarbonylthiooxycarbonylthio, heteroaralkylcarbonylthio, (cycloalkyl)alkylcarbonylthιo, (cycloheteroalkyl)alkylcarbonylthιo, loweralkyloxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, cycloalkyloxycarbonyl, cycloheteroalkyloxycarbonyl, aralkyoxycarbonyloxloxycarbonyl, heteroaralkyloxycarbonyl, (cycloalkyl)alkyloxycarbonyl, (cycloheteroalkyl)alkyloxycarbonyl, lmmoloweralkyl, lminocycloalkyl, lmmocycloheteroalkyl, lminoaralkyl, lminoheteroaralkyl, (cycloalkyl)ιmmoalkyl, and (cycloheteroalkyi)ιmmoalkyl X 6 -X 9 are selected independently from the group consisting of oxygen, sulfur, sulfinyl, nitrogen, and optionally substituted methine, and R 4 is selected from the group consisting of optionally substituted loweralkyl, aryl, heteroaryl, cycloalkyl, cycloheteroalkyl, aralkyl, heteroaralkvi, (cycioalkyl)alkyl, and (cycloheteroalkyl)alkyl In some more specific embodiments of this aspect of the invention, n is 1 and X| 0 is selected from the group consisting of nitrogen, optionally substituted nitrogen, and optionally substituted methylene or methine, and R» is selected from the group consisting of optionally substituted aryl, heteroaryl, aralkyl, and heteroaralkyl Still more specific embodiments include those for which n and X, 0 have the values just defined and R 4 is optionally substituted aryl or aralkyl In still more specific embodiments, which n, X :o and R have the values just defined R4 includes at least one hydroxyl, thio, or optionally substituted loweralkyloxy, aryloxy, heteroaryloxy, loweralkylthio, arylthio, heteroarylthio, loweralkylcarbonyl, arylcarbonyl, or heteroaryicarbonyl moiety Yet more specific embodiments are those for which n and Xι 0 have the values just defined wherem R 4 is selected from the group consisting of phenyl, phenyloxyloweralkyl, and phenylloweralkyl, and R 4 includes at least one hydroxyl, thio, or optionally substituted loweralkyloxy, aryloxy, heteroar loxy, loweralkylthio, arylthio. heteroarylthio, loweralkylcarbonyl, arylcarbonyl, or heteroaryicarbonyl moiety Other embodiments are those for which n and X :0 have the values just defined R, is selected from the group consisting of phenyl, phenyloxyloweralkyl, and phenylloweralkyl, R 4 includes at least one hydroxyl, thio, or optionally substituted loweralkyloxy, aryloxy, heteroaryloxy, loweralkylthio, arylthio, heteroarylthio, loweralkylcarbonyl, arylcarbonyl, or heteroaryicarbonyl moiety, and R4 is further substituted optionally with a moiety selected from the group consisting of halogen, loweralkyl, halolowerlalkyl, loweralkyloxy, halolowerlakyloxy, carboxy, loweralkyloxycarbonyl, aryloxycarbonyl, (cycloloweralkyl)oxycarbonyl, aralkyloxycarbonyl, heteroaryloxycarbonyl, heteroaralkyloxycarbonyl, (heterocvcloioweralkyl)oxycarbonyl, loweralkylsulfinyl, loweralkylsulfonyl, loweralkylthio, arylthio, loweralkylcarbonyloxy, arylcarbonyloxy, aralkylcarbonyloxy, heteroaryicarbonyloxy, heteroaralkylcarbonyloxy, (cycloloweralkyl)carbonyloxy, (heterocycloloweralkyl)carbonyloxy, aminocarbonyl, loweraklylaminocarbonyl, arylammocarbonyl, aralkylaminocarbonyl, heteroarylammocarbonyl, cyano. nitro. ammo, loweralkylammo, and heteroaraikyiammocarbonyl Other embodiments of the present invention mclude those structures tor which n is 2 and each Xj 0 is selected independently from the group consisting of nitrogen, optionally substituted nitrogen, optionally substituted methylene, and optionally substituted methine In some embodiments, X )0 and n have the values just described and R, is selected from the group consisting of optionally substituted aryl, heteroaryl, aralkyl. and heteroaralkyl Still more specific embodiments include those for which n and X ]0 have the values just defined and R 4 is optionally substituted aryl or aralkyl In still more specific embodiments, which n and X, 0 have the values just defined, R 4 is optionally substituted aryl or aralkyl, and R, includes at least one hydroxyl, thio, or optionally substituted loweralkyloxy, aryloxy, heteroaryloxy, loweralkylthio, arylthio, heteroarylthio. loweralkylcarbonyl, arylcarbonyl, or heteroaryicarbonyl moiety Yet more specific embodiments are those for which n and X, 0 have the values just defined wherein R4 is selected from the group consisting of phenyl, phenyloxyloweralkyl, and phenylloweralkyl, and R4 includes at least one hydroxyl, thio, or optionally substituted loweralkyloxy, aryloxy, heteroaryloxy, loweralkylthio, arylthio, heteroarylthio, loweralkylcarbonyl, arylcarbonyl, or heteroaryicarbonyl moiety Other embodiments are those for which n and Xι 0 have the values just defined wherein R is selected from the group consisting of phenyl, phenyloxyloweralkyl, and phenylloweralkyl, R, includes at least one hydroxyl, thio, or optionally substituted loweralkyloxy, aryloxy, heteroaryloxy, loweralkylthio, arylthio, heteroarylthio loweralkylcarbonyl, arylcarbonyl, or heteroaryicarbonyl moiety, and R, is further substituted optionally with a moiety selected from the group consisting of halogen, loweralkyl, halolowerlalkyl, loweralkyloxy, halolowerlakyloxy, carboxy, loweralkyloxycarbonyl, aryloxycarbonyl, (cycloloweralkyl)oxycarbonyl, aralkyloxycarbonyl, heteroaryloxycarbonyl, heteroaralkyloxycarbonyl, (heterocycloloweralkyl)oxycarbonyl, loweralkylsulfinyl, loweralkylsulfonyl, loweralkylthio, arylthio, loweralkylcarbonyloxy, arylcarbonyloxy, aralkylcarbonyloxy, heteroaryicarbonyloxy, heteroaralkylcarbonyloxy, (cycloloweralkyl)carbonyloxy, (heterocycloloweralkyl)carbonyloxy, ammocarbonyl, loweraklylaminocarbonyl, arylammocarbonyl, aralkylaminocarbonyl, heteroarylammocarbonyl, cyano, nitro, amino, loweralkylammo, and heteroaralkylammocarbonyl Other embodiments of the present invention include compounds for which X 6 - 9 are selected independently from the group consisting of nitrogen and optionally substituted methine More particular embodiments are those for which X 6 -XQ are selected independently from the group consisting of nitrogen and optionally substituted methine, and at least one of X 6 -X 9 is methine substituted with a moiety selected from the group consisting of loweralkyloxy, aryloxy, heteroaryloxy, loweralkylthio, arylthio, heteroarylthio, loweralkylcarbonyl, arylcarbonyl, and heteroaryicarbonyl Still more particular embodiments having the structural pattern just described include those in which X 7 is methine substituted with hydroxy or loweralkyloxy In yet another aspect, the present invention provides the present invention provides methods for treating or preventing an estrogen receptor-mediated disorder in a human or animal sub j ect in which an amount of an estrogen receptor-modulating compound of the invention that is effective to modulate estrogen receptor activity in the subject Other embodiments provided methods for treating a cell or a estrogen receptor-mediated disorder m a human or animal subject, comprising administering to the cell or to the human or animal subject an amount of a compound or composition of the invention effective to modulate estrogen receptor activity in the cell or subject Representative estrogen receptor-mediated disorders include, for example, osteoporosis, atheroschlerosis, estrogen- mediated cancers (e g , breast and endometrial cancer), and Alzheimer's disease These and other aspects and advantages will become apparent when the Description below is read in conjunction with the accompanying Examples 3 Description of Some Embodiments of the Invention 3 1 Definitions 3 1 1 Estrogen Receptor "Estrogen Receptor ' as defined herein refers to any protein in the nuclear receptor gene family that binds estrogen, including, but not limited to, any isoforms or deletion mutations having the characteristics just described More particularly, the present invention relates to estrogen receptor(s) for human and non-human mammals (e g , animals of veterinary interest such as horses, cows, sheep, and pigs, as well as household pets such as cats and dogs) Human estrogen receptors included in the present invention include the α- and β- isoforms (referred to herein as "ERα" and "ERβ") in addition to any additional isoforms as recognized by those of skill in the biochemistry arts 3 1 2 Estrogen Receptor Modulator "Estrogen Receptor Modulator" refer herein to a compound that can act as an estrogen receptor agonist or antagonist of estrogen receptor having an IC 50 or EC 50 with respect to ERα and/or ERβ of no more than about 10 μM as determined using the ERα and/or ERβ transactivation assay described hereinbelow (Section 4 2 2 3) More typically, estrogen receptor modulators of the invention have IC 50 or EC 50 values (as agonists or antagonists) of not more than about 5 μM Representative compounds of the present invention have been discovered to exhibit agonist or antagonist activity viz estrogen receptor Compounds of the present invention preferably exhibit an antagonist or agonist IC 50 or EC Dθ with respect to ERα and/or ERβ of no more than about 5 μM, more preferably, no more than about 500 nM. even more preferably not more than about 1 nM, and most preferably, not more than about 500 pM, as measured in the ERα and/or ERβ transactivation assays "IC Dθ " is that concentration of inhibitor which reduces the activity of a target (e g , ERα or ERβ) to half-maximal level "EC 50 " is that concentration of modulator that produces half-maximal effect 3 1 3 Selective Estrogen Receptor Modulator A "Selective Estrogen Receptor Modulator" (or "SERM") is a compound that exhibits activity as an agonist or antagonist of an estrogen receptor (e g , ERα or ERβ) in a tissue-dependent manner Thus, as will be apparent to those of skill in the biochemistry and endocrinology arts, compounds of the invention that function as SERMs can act as estrogen receptor agonists in some tissues (e g , bone, brain, and/or heart) and as antagonists in other tissue types, such as the breast and/or uterine lining 3 1 4 Optionally substituted "Optionally substituted" refers to the replacement of hydrogen with a monovalent or divalent radical Suitable substitution groups include, for example, hydroxyl, nitro. amino. imino, cyano, halo, thio, thioamido, amidino, oxo, oxamidino, methoxamidino, lmidino, guanidino. sulfonamido, carboxyl, formyl, loweralkyl, haloloweralkyl, loweralkoxy, haloloweralkoxy, loweralkoxyalkyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, heteroaryicarbonyl heteroaralkylcarbonyl, alkylthio, ammoalkyl, cyanoalkyl, and the like The substitution group can itself be substituted The group substituted onto the substitution group can be, for example, carboxyl, halo, nitro, ammo, cyano, hydroxyl, loweralkyl, loweralkoxy, aminocarbonyl, -SR, thioamido, -S0 3 H, -S0 2 R or cycloalkyl. where R is typically hydrogen, hydroxyl or loweralkyl When the substituted substituent includes a straight chain group, the substitution can occur either within the chain (e g , 2-hydroxypropyl, 2-amιnobutyl, and the like) or at the cham terminus (e g , 2-hydroxyethyl, 3-cyanopropyl, and the like) Substituted substitrutents can be straight chain, branched or cyclic arrangements of covalently bonded carbon or heteroatoms 3 1 5 Loweralkyl and Related Terms "'Loweralkyl" as used herein refers to branched or straight chain alkyl groups comprising one to ten carbon atoms that independently are unsubstituted or substituted, e g , with one or more halogen, hydroxyl or other groups Examples of loweralkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, w-butyl, /-butyl, «-hexyl, neopentyl, trifluoromethyl, pentafluoroethyl, and the like "Alkylenyl" refers to a divalent straight chain or branched chain saturated aliphatic radical having from 1 to 20 carbon atoms Typical alkylenyl groups employed in compounds of the present invention are loweralkylenyl groups that have from 1 to about 6 carbon atoms in their backbone "Alkenyl" refers herein to straight chain, branched, or cyclic radicals havmg one or more double bonds and from 2 to 20 carbon atoms "Alkynyl" refers herein to straight chain, branched, or cyclic radicals having one or more triple bonds and from 2 to 20 carbon atoms The term "haloloweralkyl" refers to a loweralkyl radical substituted with one or more halogen atoms "Loweralkoxy " as used herein refers to RO- wherein R is loweralkyl Representative examples of loweralkoxy groups include methoxy, ethoxy, f-butoxy, tπfluoromethoxy and the like "Loweralkythio" as used herein refers to RS- wherein R is loweralkyl The term "alkoxyalkyl" refers to the group -alk O-alk 2 where alk, is alkylenyl or alkenyl, and alk 2 is alkyl or alkenyl The term "loweralkoxyalkyl" refers to an alkoxyalkyl where alk, is loweralkylenyl or loweralkenyl, and alk 2 is loweralkyl or loweralkenyl The term "aryloxyalkyl" refers to the group -alkylenyl-O-aryl The term "aralkoxyalkyl" refers to the group -alkylenyl-O-aralkyl, where aralkyl is a loweraralkyl "Cycloalkyl" refers to a mono- or polycyclic, loweralkyl substituent Typical cycloalkyl substituents have from 3 to 8 backbone (; e ring) atoms in which each backbone atom is optionally substituted carbon When used in context with cycloaikyi substituents. the term "polycyclic ' refers herein to fused, non-fused cyclic carbon structures and spirocycles Examples of cycloalkyl groups include, but are not limited to, cyciopropyl, cyclobutyl. cyclopentyl, cyclohexyl, adamantyl, bornyl, norbornyi, and the like The term "cycloheteroalkyl" refers herein to cycloalkyl substituents that have from 1 to 5, and more typically from 1 to 4 heteroatoms (; , non-carbon atoms such as nitrogen, sulfur, and oxygen) in the ring structure, with the balance of atoms in the rmg being optionally substituted carbon Representative heterocycloalkyl moieties include, for example, morpholino, piperazmyl, pipeπdinyl, pyrrolidinyl, methylpryolidinyl, pyrro dinone-yl, and the like The terms "(cycloalkyl)alkyF' and "(cycloheteroalkyl)alkyl" refer to alkyl chains substituted with cycloalkyl and cycloheteroalkyl groups respectively The term "haloalkoxy" refers to an alkoxy radical substituted with one or more halogen atoms The term "haloloweralkoxy" refers to a loweralkoxy radical substituted with one or more halogen atoms 3 1 6 Halo "Halo " refers herein to a halogen radical, such as fluorine, chlorine, bromine or iodine 3 1 7 Aryl and Related Terms "Aryl" refers to monocyclic and polycyclic aromatic groups, or fused ring systems having at least one aromatic ring, having from 3 to 14 backbone carbon atoms Examples of aryl groups include without limitation phenyl, naphthyl, dihydronaphtyl, tefrahydronaphthyl, and the like "Aralkyl" refers to an alkyl group substituted with an aryl group Typically, aralkyl groups employed in compounds of the present invention have from 1 to 6 carbon atoms incorporated within the alkyl portion of the aralkyl group Suitable aralkyl groups employed in compounds of the present invention include, for example, benzyl, picolyl, and the like 3 1 8 Heteroaryl and Related Terms The term "heteroaryl" refers herein to aryl groups having from one to four heteroatoms as ring atoms in an aromatic ring with the remainder of the ring atoms being aromatic or non-aromatic carbon atoms When used m connection with aryl substituents, the term "polycyclic" refers herein to fused and non-fused cyclic structures in which at least one cyclic structure is aromatic, such as, for example, benzodioxozolo, naphthyl, and the like Exemplary heteroaryl moieties employed as substituents in compounds of the present invention include pyridyl, pyπmidinyl, thiazolyl, mdolyl, lmidazolyl. oxadiazolyl, tetrazolyl, pyrazinyl, tπazolyl, thiophenyl, furanyl, quinolinyl, puπnyl. benzothiazolyl. benzopyπdyl, and benzimidazolyl, and the like 3 1 9 Ammo and Related Terms "Ammo" refers herein to the group -NH 2 The term "loweralkylamino" refers herein to the group -NRR' where R and R' are each independently selected from hydrogen or loweralkyl The term "arylamino" refers herein to the group -NRR' where R is aryl and R' is hydrogen loweralkyl, aryl, or aralkvl The term aralkylamino ' refers herein to the group -NRR' where R is aralkyl and R' is hydrogen, loweralkyl, aryl, or aralkyl The terms ' heteroarvlamino and heteroaralkvlamino" are defined by analogy to arvlamino and aralkylamino The term "ammocarbonyl" refers herein to the group -C(0)-NH 2 The terms "loweralkylammocarbonyl", arylammocarbonyl", "aralkylaminocarbonyl", "heteroarylammocarbonyl", and "heteroaralkylammocarbonyl" refer to -C(0)NRR' where R and R' independently are hydrogen and optionally substituted loweralkyl, aryl. aralkyl, heteroaryl, and heteroaralkyl respectively by analogy to the corresponding terms above 3 1 10 Thio, Sulfonyl, Sulfinyl and Related Terms The term "thio" refers to -SH The terms "loweralkylthio", "arylthio", "heteroarylthio", "cycloalkylthio", " cycloheteroalkylthio", "aralkylthio", "heteroaralkylthio", "(cycloalkyl)alkylthιo", and "(cycloheteroalkyl)alkylthιo" refer to -SR, where R is optionally substituted loweralkyl, aryl, heteroaryl, cycloalkyl, cycloheteroalkyl, aralkyl. heteroaralkyl, (cycloalkyl)alkyl, and (cycloheteroalkyl)alkyl respectively The term "sulfonyl" refers herein to the group -S0 2 - The terms "loweralkylsulfonyl", "arylsulfonyl", "heteroarylsulfonyl", "cycloalkylsulfonyi", "cycloheteroalkylsulfonyl", "aralkylsulfonyl", "heteroaralkylsulfonyl", "(cycloalkyl)alkylsulfonyl", and "(cycloheteroalkyl)alkylsulfonyl" refer to -S0 2 R where R is optionally substituted loweralkyl, aryl, heteroaryl, cycloalkyl, cycloheteroalkyl, aralkyl, heteroaralkyl, (cycloalkyl)alkyl, and (cycloheteroalkyl)alkyl respectively The term "sulfinyl" refers herein to the group -SO- The terms "loweralkylsulfinyl", "arylsulfinyl", "heteroarylsulfinyl", "cycloalkylsulfinyl", "cycloheteroalkylsulfinyl", "aralkylsulfinyl", "heteroaralkylsulfinyl", "(cycloalkyl)alkylsulfinyl", and "(cycloheteroalkyl)alkylsulfmyl" refer to -SOR where R is optionally substituted loweralkyl, aryl, heteroaryl, cycloalkyl, cycloheteroalkyl, aralkyl, heteroaralkyl, (cycloalkyl)alkyl, and (cycloheteroalkyl)alkyl respectively 3 1 11 Formyl, Carboxyl, Carbonyl, Thiocarbonyl, and Related Terms "Formyl" refers to -C(0)H "Carboxyl" refers to -C(0)OH "Carbonyl" refers to the divalent group -C(O)- The terms "loweralkylcarbonyl", "arylcarbonyl", "heteroaryicarbonyl", "cycloalkylcarbonyl", "cycloheteroalkylcarbonyl", "aralkycarbonyl", "heteroaralkylcarbonyl", "(cycloalkyl)alkylcarbonyl", and "(cycloheteroalkyl)alkylcarbonyl" refer to -C(0)R, where R is optionally substituted loweralkyl, aryl, heteroaryl, cycloalkyl, cycloheteroalkyl, aralkyl, heteroaralkyl, (cycloalkyl)alkyl, and (cycloheteroalkyl)alkyl respectively "Thiocarbonyl" refers to the group -C(S)- The terms "loweralkylthiocarbonyl", "arylthiocarbonyl", 'heteroarylthiocarbonyl", "cycloalkylthiocarbonyl", "cycioheteroalkylthiocarbonyl", araikythiocarbonyloxlthiocarbonyl" "heteroaralkylthiocarbonyl". "(cycloalkyl)alkylthιocarbonyl", and "(cycloheteroalkyl)alkylthιocarbonyl" refer to -C(S)R, where R is optionally substituted loweralkyl, aryl, heteroaryl, cycloalkyl, cycloheteroalkyl, aralkyl, heteroaralkyl, (cycloalkyl)alkyl, and (cycloheteroalkyl)alkyl respectively "Carbonyloxy" refers generally to the group -C(0)-0- The terms "loweralkylcarbonyloxy", "arylcarbonyloxy", "heteroaryicarbonyloxy", "cycloalkylcarbonyloxy". " cycloheteroalkylcarbonyloxy", "aralkycarbonyloxy", "heteroaralkylcarbonyloxy", "(cycloalkyl)alkylcarbonyloxy", "(cycloheteroalkyl)alkylcarbonyloxy" refer to -C(0)OR, where R is optionally substituted loweralkyl, aryl, heteroaryl, cycloalkyl, cycloheteroalkyl, aralkyl, heteroaralkyl, (cycloalkyl)alkyl, and (cycloheteroalkyl)alkyl respectively "Oxycarbonyl" refers to the group -O-C(O)- The terms "loweralkyloxycarbonyl", "aryloxycarbonyl", "heteroaryloxycarbonyl", "cycloalkyloxycarbonyl", "cycloheteroalkyloxycarbonyl", "aralkyoxycarbonyloxloxycarbonyl", "heteroaralkyloxycarbonyl", "(cycloalkyl)alkyloxycarbonyl", "(cycloheteroalkyl)alkyloxycarbonyl" refer to -0-C(0)R, where R is optionally substituted loweralkyl, aryl, heteroaryl, cycloalkyl, cycloheteroalkyl, aralkyl, heteroaralkyl, (cycloalkyl)alkyl, and (cycloheteroalkyl)alkyl respectively "Carbonylamino" refers to the group -NH-C(O)- The terms "loweralkylcarbonylammo", "arylcarbonylammo", "heteroarylcarbonylamino", "cycloalkylcarbonylamino", "cycloheteroalkylcarbonylammo", "aralkylcarbonylammo", "heteroaralkylcarbonylamino", "(cycloalkyl)alkylcarbonylamιno", and "(cycloheteroalkyl)alkylcarbonylammo" refer to -NH-C(0)R, where R is optionally substituted loweralkyl, aryl, heteroaryl, cycloalkyl, cycloheteroalkyl, aralkyl, heteroaralkyl, (cycloalkyl)alkyl, or (cycloheteroalkyl)alkyl respectively In addition, the present invention includes N-substituted carbonylamino (-NR'C(O)R), where R' is optionally substituted loweralkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl and R retains the previous defintion "Carbonylthio " refers to the group -C(0)-S- The terms "loweralkylcarbonylthio", "arylcarbonylthio ', "heteroarylcarbonylthio", "cycioalkylcarbonylthio". "cycloheteroalkylcarbonylthio", "aralkycarbonylthio", "heteroaralkylcarbonylthio", "(cycloalkyl)aikylcarbonylthιo", "(cycloheteroalkyl)alkylcarbonylthιo" refer to - C(0)SR, where R is optionally substituted loweralkyl, aryl, heteroaryl, cycloalkyl, cycloheteroalkyl, aralkyl, heteroaralkyl, (cycioalkyl)alkyl, and (cycloheteroalkyl)alkyl respectively 3 1 12 Guanidino or Guanidyl As used herein, the term "guanidino" or "guanidyl" refers to moieties derived from guanidine, H 2 N-C(=NH)-NH 2 Such moieties include those bonded at the nitrogen atom carrying the formal double bond (the "2 " -posιtιon of the guanidine, e g , diaminomethyleneamino, (H 2 N) 2 C=NH-) and those bonded at either of the nitrogen atoms carrying a formal single bond (the "1 -" and/or "3"-posιtιons of the guanidine, e g , H 2 N-C(=NH)-NH-) The hydrogen atoms at either nitrogen can be replaced with a suitable substituent. such as loweralkyl, aryl, or loweraralkyl 3 1 13 Amidino As used herein, the term 'amidino ' refers to the moieties R-C(=N)-NR'- (the radical being at the "N 1 " nitrogen) and R(NR')C=N- (the radical being at the "N 2 " nitrogen), where R and R' can be hydrogen, loweralkyl, aryl, or Ioweraralkyl 3 1 14 Imino and Oximino The term "imino" refers to the group -C(=NR)-, where R can be hydrogen or optionally substituted loweralkyl, aryl, heteroaryl, or heteroaralkyl respectively The terms lminoloweralkyl", "lminocycloalkyl", "lminocycloheteroalkyi", "lmmoaralkyl", "immoheteroaralkyl", "(cycloalkyl)ιmιnoalkyl", "(cycloιmmoalkyl)alkyl", "(cycloιmιnoheteroalkyl)alkyl", and "(cycloheteroalkyl)ιmιnoalkyl" refer to optionally substituted loweralkyl, cycloalkyl, cycloheteroalkyl, aralkyl, heteroaralkyl, (cycloalkyl)alkyl, and (cycloheteroalkyl)alkyl groups that include an imino group, respectively The term "oximino ' refers to the group -C(=NOR)- where R can be hydrogen ("hydroximmo ') or optionally substituted loweralkyl, aryl, heteroaryl, or heteroaralkyl respectively The terms "oximmoloweralkyl", "oximinocycloalkyl", "oximinocycloheteroalkyl", "oximinoaralkyl", "oximmoheteroaralkyl", "(cycloalkyl)oxιmιnoalkyl", "(cyclooxιmιnoalkyl)alkyl", "(cyclooxιmmoheteroalkyl)alkyl", and (cycloheteroalkyl)oxιmιnoalkyl" refer to optionally substituted loweralkyl, cycloalkyl, cycloheteroalkyl, aralkyl, heteroaralkyl, (cycloalkyl)alkyl, and (cycloheteroalkyl)alkyl groups that include an oximino group, respectively 3 1 15 Methylene and Methine The term "methylene" as used herein refers to an unsubstituted, monosubstituted, or disubstituted carbon atom having a formal sp 3 hybridization (i e , -CRR'-, where R and R' are hydrogen or independent substituents) The term "methine" as used herein refers to an unsubstituted or carbon atom having a formal sp : hybridization (/ e , -CR= or =CR-. where R is hydrogen a substituent) 3 2 Compounds of the Invention The present invention provides compounds that have useful agonist and/or antagonist activity with respect to mammalian estrogen receptors in addition to compounds, compositions, and methods useful for treating estrogen receptor-mediated disorders in mammals More particularly, the compounds of the present invention have been found to possess a suφrising degree of activity with respect to the α- and β-isoforms of human estrogen receptor Thus, the compounds, compositions, and methods described herein have utility in preventing and/or treating a wide variety of estrogen receptor-mediated disorders including, but not limited to osteoporosis, breast cancer, uterine cancer, and congestive heart disease In a first aspect, the present invention provides compounds having the structure (Compound 1) and its pharmaceutically acceptable salts X, and X 2 are selected independently from the group consisting of nitrogen and oxygen such that if one of X, and X 2 is nitrogen, then the other of X| and X 2 is oxygen to form thereby an isoxazole ring structure. Thus, the generic structure shown above encompasses the following regioisomers depending on the identities of X, and X 2 R| and R-, are selected independently from the group consisting of optionally substituted loweralkyl, aryl, heteroaryl. cycloalkyl, cycloheteroalkyl. aralkyl, heteroaralkyl, (cycloalkyl)alkyl, and (cycloheteroalkyl)alkyl R 2 is selected from the group consisting of hydrogen, halo, cyano, nitro, thio, ammo, carboxyl, formyl, and optionally substituted loweralkyl, loweralkylcarbonyloxy, arylcarbonyloxy. heteroaryicarbonyloxy, cycloalkylcarbonyloxy, cycioheteroalkylcarbonyloxy, aralkycarbonyloxy, heteroaralkylcarbonyloxy, (cycloalkyl)alkylcarbonyloxy, (cycloheteroalkyl)alkylcarbonyloxy, loweralkylcarbonyl, arylcarbonyl, heteroaryicarbonyl, cycloalkylcarbonyl, cycloheteroalkylcarbonyl, aralkycarbonyl, heteroaralkylcarbonyl, (eye loalkyl)alky lcarbonyl, (cycloheteroalkyl)alky lcarbonyl, loweralkylaminocarbonyl, arylammocarbonyl, aralkylaminocarbonyl, heteroarylammocarbonyl, heteroaralkylammocarbonyl, cycloalkylaminocarbonyl, (cycloalkyι)alkylamιnocarbonyl, cycloheteroalkylaminocarbonyl, (cycloheteroalkyl)alkylammocarbonyl, loweralkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, cycloalkylcarbonylamino, cycloheteroalkylcarbonylamino, aralkylcarbonylammo, heteroaralkylcarbonylamino, cycloaikyl)alkylcarbonylamιno, (cycloheteroalkyl)alkylcarbonylammo, ioweralkylamino, arylam o, aralkylamino, heteroarylammo, heteroaralkylammo, loweralkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, cycloalkylsulfonyi. cycloheteroalkylsulfonyl, aralkylsulfonyl, heteroaralkylsulfonyl, (cycloalkyl)alkylsulfonyl, (cycloheteroalkyl)alkylsulfonyl, loweralkylsulfinyl, arylsulfinyl, heteroarylsulfinyl, cycloalkylsulfinyl, cycloheteroalkylsulfinyl. aralkylsulfinyl, heteroaralkylsulfinyl, (cycloalkyl)alkylsulfinyl, (cycloheteroalkyl)alkylsulfinyl, loweralkyloxy, aryloxy, heteroaryloxy, cycloalkyloxy, cycloheteroalkyloxy, aralkyloxy, heteroaralkyloxy, (cycloalkyl)alkyloxy, and (cycloheteroalkyl)alkyloxy, loweralkylthio, arylthio, heteroarylthio, cycloalkylthio, cycloheteroalkylthio, aralkylthio, heteroaralkylthio, (cycloalkyl)alkylthιo, (cycloheteroalkyl)aikylthιo, loweralkylthiocarbonyl, arylthiocarbonyl, heteroarylthiocarbonyl, cycloalkylthiocarbonyl, cycloheteroalkylthiocarbonyl, aralkythiocarbonyloxythiocarbonyl, heteroaralkylthiocarbonyl, (cycloalkyl)alkylthιocarbonyl, (cycloheteroalkyi)alkylthιocarbonyl, heteroarylcarbonylthio, cycioalkylcarbonylthio. cycloheteroalkylcarbonylthio, aralkycarbonylthiooxycarbonylthio, heteroaralkylcarbonylthio, (cycloalkyl)alkylcarbonylthιo, (cycloheteroalkyl)alkylcarbonylthιo, loweralkyloxycarbonyl, aryloxycarbonyl. heteroaryloxycarbonyl, cycloalkyloxycarbonyl. cvcloheteroalkvloxycarbonvl, aralkvoxvcarbonvl heteroaralkyloxycarbonyl (cvcloalkvl)alkvloxycarbonvl (cycioheteroalkyl)alkyloxycarbonyl lminoloweralkyl, lminocycloalkyl, lmmocycioheteroalkyl. lmmoaralkvl, lm oheteroaralkyl, (cycloalkyl)ιmιnoalkyl, (cycloheteroalkyl)ιmιnoalkyl, (cycloιmιnoalkyl)alkyl, (cycloιmιnoheteroalkyl)alkyl, oximinoloweraikyl oximinocycloalkyl, oximinocycloheteroalkyl, oximmoaralkyl, oximinoheteroaralkyl, (cycloalkyl)oxιmιnoalkyl, (cyclooxιmmoalkyl)alkyl (cvclooxιmιnoheteroalkyl)alkyl, and (cycloheteroalkyl)oxιmιnoalkyl In one embodiment, Ri and R 3 are selected independently from the group consisting of optionally substituted cycloalkyl, cycloheteroalkyl, (cycloalkyl)alkyl, and (cycloheteroalkyl)alkyl Examples of such groups include without limitation cyclohexyl, pipeπdinyl, adamantyl, and qumuclidyl, each optionally substituted Other examples include cyclohexylmethyl, 2-cyclohexylethyl, and adamantylmethyl, again, each optionally substituted In another embodiment, R, and R 3 are selected independently from the group consisting of optionally substituted aryl, heteroaryl, aralkyl, and heteroaralkyl More particular embodiments of the invention are those for which R, and R 3 are selected independently from the group consisting of optionally substituted heteroaryl and heteroaralkyl, such as pyπdinyl, hydroxypyπdyl, methoxypyπdyl, pyπdylmethyl, and the like Alternatively, R, and R 3 are selected independently from the group consisting of optionally substituted aryl and aralkyl In more specific embodiments, R, and R 3 are selected independently from the group consisting of optionally substituted aryl and aralkyl and at least one of R, and R 3 is substituted with at least one hydroxyl, alkyloxy, aryloxy, thio, alkylthio, or arylthio group Still more specific embodiments are those for which R, and R 3 are selected independently from the group consisting of optionally substituted aryl and aralkyl and at least one of Ri and R 3 is substituted with at least one hydroxyl, alkyloxy, aryloxy, thio, alkylthio, or arylthio group are those wherein at least one of i and R 3 is selected independently from the group consisting of phenyl, phenyloxyloweralkyl, and phenylloweralkyl and include the substitutions just listed Examples of useful groups include without limitation 4-hydoxyphenyl, phenylmethyl, 4-hydroxyphenymethyl, 3-hydroxyphenylmethyl, 2- thιo-4-hydroxyphenylmethyl, 2-(4-hydroxyphenyl)ethyl, phenyloxy)methyl, 4-methoxyphenyl, 2-hydroxyphenyl, 3-(phenylthιo)-4-hydroxyphenyl, and 3-mefhyiphenyl-4-hydroxyphenyl In a still more specific embodiment, the present invention includes compounds of the structure shown for Compound 1 for which R, and R 3 are selected independently from the group consisting of optionally substituted aryl and aralkyl such that at least one of R, and R 3 is substituted with at least one hydroxyl, alkyloxy, aryloxy, thio, alkylthio, or arylthio group and at least one of R, and R 3 is selected independently from the group consisting of phenyl, phenyloxyloweralkyl, and phenylloweralkyl, and further wherein at least one of R, and R 3 is substituted optionally with a substituent selected from the group consisting of halogen, nitro, cyano, loweralkyl, halolowerlalkyl, loweralkyloxy, haloloweralkyloxy, carboxy, loweralkyloxycarbonyl, aryloxycarbonyl, (cycloloweralkyl)oxycarbonyl, aralkyloxycarbonyl, heteroaryloxycarbonyl, heteroaralkyloxycarbonyl, (heterocycloloweralkyl)oxycarbonyl, loweralkylsulfinyl, loweralkylsulfonyl, loweralkylthio, arylthio, loweralkylcarbonyloxy, arylcarbonyloxy, aralkylcarbonyloxy, heteroaryicarbonyloxy, heteroaralkylcarbonyloxy, (cycloloweralkyl)carbonyloxy, alkylsulfonylamino, (heterocycloloweralkyl)carbonyloxy, aminocarbonyl, lowerakylaminocarbonyl, arylammocarbonyl, aralkylaminocarbonyl, heteroarylammocarbonyl and heteroaralkylammocarbonyl Yet more specific embodiments includes those just recited for which at least one of R, and R 3 is further substituted optionally with a substituent selected from the group consisting of halogen nitro, cyano, loweralkyl, halolowerlalkyl, loweralkyloxy, halolowerlakyloxy. carboxy, loweralkylthio, aminocarbonyl, and loweralkylsulfinyl Examples of specific useful groups of this embodiment mclude without limitation 2-methyl-4-hydroxyphenyl, 2-amιnocarbonyl-4- hydroxyphenyl, 4-methylsulfonylamιnophenyl, 3-amιnocarbonyl-4-hydroxyphenyl, 3-amιnocarbonyl-4- methoxyphenyl, 3-chloro-4-hydroxyphenyl, 4-methylcarbonyloxyphenyl, 3-«-hexyl-4-hydroxyphenyl, 4-«- propylcarbonyloxyphenyl, 3-ethyl-4-hydroxyphenyl, 2-methylsulfinyl-4-hydroxyphenyl. 2-ethyl-4-hydroxyphenyl, 2-carboxy-4-hydroxyphenyl, 3-fluoro-4-hydroxyphenvl.2-ιodo-4-hydroxyphenyl, 2-«-butyl-4-hydroxyphenyl, 2- trifluoromethoxyphenyl, and 4-fluorophenyl In other embodiments of the present invention. Compound 1 above includes compounds in R 2 is selected from the group consisting of hydrogen, halo, and optionally substituted loweralkyl, haloloweralkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, aryloxyalkyl, arylthioalkyl, arylcarbonyl, heteroaryicarbonyl, loweralkylcarbonyl, aminocarbonyl, arylammocarbonyl, loweralkylaminocarbonyl, aralkylaminocarbonyl, (heterocycloloweralkyl)alkylamιnocarbonyl, heteroarylammocarbonyl, heteroaralkylammocarbonyl, (cycloloweralkyi)amιnocarbonyl, formyl, amino. loweralkylamino, and alkenyl Particular examples of these embodiments include those for which R 2 is selected from the group consisting of hydrogen and halo Other particular examples of these embodiments are those in which R 2 is selected from the group consisting of optionally substituted phenyl, phenylloweralkyl, hydroxyphenyl, loweralkyloxyphenyl, haloloweralkylsulfonylloweralkyloxyphenyl, diloweralkylaminoloweralkyloxyphenyl, (cycloamιnoloweralkyl)loweralkyloxyphenyl, and (heterocycloalkyl)loweralkyloxyphenyl Specific examples of such groups include pheny lmethyl, 4-hydroxypheny 1, 2-(pιpeπdιn-l-yι)ethyloxyphenyl, 4- hydroxyphenyloxymethyl, and 2-(pιpeπdιn-l-yl)ethyloxypheny lmethyl Still other particular embodiments are those for which R 2 is selected from the group consisting of optionally substituted loweralkyl, haloloweralkyl, hydroxyalkyl. phenyloxyloweralkyl, hydroxyphenyloweralkyl, haloloweralkylsulfonyiloweralkyl, and phenylthioloweralkyl In still other embodiments of Compound 1 above R 2 is selected from the group consisting of optionally substituted phenylcarbonyl, (heterocycloalkyl)loweralkyloxyphenylcarbonyl. hydroxyphenylcarbonyl, halophenylcarbonyl, phenylloweralkylaminocarbonyl, diloweralkylaminocarbonyl, phenylloweralkylaminocarbonyl, hydroxyphenyllowerlakyiaminocarbonyl, cycloalkylaminocarbonyl, loweralkylphenylcarbonyl, haloloweralkylsulfonylloweralkyloxyphenylcarbonyl, and nitrophenylcarbonyl Examples of R 2 substituents within this embodiment having useful properties include, but are not limited to, 4-(2- pιpeπdιn-l-ylefhyloxy)pheny lcarbonyl, 4-hydroxyphenylcarbonyl, (phenylmethyl)amιnocarbonyl, 3-(2- oxopyrrohdin- 1 -yl)propylamιnocarbonyl, dι-«-butylammocarbonyl, (4-hydroxyphenylmethyι)amιnocarbonyl, (pyπdιn-3-ylmethyl)amιnocarbonyl, (pyπdιn-2-ylmethyl)amιnocarbonyl, dimethylaminocarbonyl, ethylaminocarbonyl, 4-(2-moφhohnoefhyloxy)phenylcarbonyl, 4-(3-dιmethylamιnopropyloxy)phenylcarbonyl, cyclopropylammocarbonyl, cyclobutylaminocarbonyi, 4-(2-dιmethylammoethyloxy)phenylcarbonyl, 4-[2- (benzylmethylamιno)efhy loxy]phenylcarbony 1, 4-( 1 -methylpιpeπdιn-3-ylmethyloxy)phenylcarbonyl, 4-[2-( 1 - methylpyrrolιdιn-2-yl)ethyloxy]phenylcarbonyl, 4-[2-(4-methylpιperazιn- 1 -yl)ethyloxy]phenylcarbonyl, 4-( 1 - methylpιpeπdιn-4-ylmethyloxy)pheny lcarbonyl, 2-chlorophenylcarbonyl, 3-chlorophenylcarbonyl, 4- chlorophenylcarbonyl, 3-nιtrophenylcarbonyl, 4-nιtrophenylcarbonyl, 3,4-dιchlorophenylcarbonyl 4-w- butylphenylcarbonyl, 3-hydroxyphenylcarbonyl. 2-hvdroxyphenvlcarbonyl, 4-methoxyphenvlcarbonvl 3-(2- pιpeπdιn-l -ylethyloxy)phenvlcarbonyi, 3-(2-dιethylamιnoethylo\v)phenvlcarbonyl, 3-[2-(pyrrolιdιn-l - yl)ethyloxy]phenyicarbonyl 3-(l-methylpιpeπdιn-3-ylmethvloxy)phenvlcarbonyl, and 3-(2- dιmethylammoethyloxy)phenylcarbonyl In other embodiments, the compounds, compositions, and methods provided by the present invention include those compounds having the structure of Compound 1 above for which R is selected from the group consisting of optionally substituted phenylcarbonyl, (heterocycloalkyl)loweralkyloxyphenylcarbonyl, hydroxyphenylcarbonyl, halophenylcarbonyl, phenylloweralkylaminocarbonyl, diloweralkylaminocarbonyl, phenylloweralkylaminocarbonyl, hydroxyphenyllowerlakylaminocarbonyl, cycloalkylaminocarbonyl, loweralkylphenylcarbonyl, haloloweralkylsulfonylloweralkyloxyphenylcarbonyl, and nitrophenylcarbonyl, and R, and R 3 are selected independently from the group consisting of optionally substituted cycloalkyl, cycloheteroalkyl, (cycloalkyl)alkyl, and (cycloheteroalkyl)alkyl Still other embodiments include those for which R 2 is selected from the group consisting of optionally substituted phenylcarbonyl, (heterocycloalkyl)loweralkyloxyphenylcarbonyl, hydroxyphenylcarbonyl, halophenylcarbonyl. phenylloweralkylaminocarbonyl, diloweralkylaminocarbonyl, phenylloweralkylaminocarbonyl, hydroxyphenyllowerlakylaminocarbonyl, cycloalkylaminocarbonyl. loweralkylphenylcarbonyl, haloloweralkylsulfonylloweralkyloxyphenylcarbonyl, and nitrophenylcarbonyl, and R \ and R 3 are selected independently from the group consisting of optionally substituted aryl, heteroaryl, aralkyl, and heteroaralkyl Of the latter embodiments, more specific embodiments include those for which R ( and R 3 are selected independently from the group consisting of optionally substituted aryl and aralkyl, and, still more particularly, those compounds wherein R is selected from the group consisting of optionally substituted phenylcarbonyl, (heterocycloalkyl)loweralkyloxyphenylcarbonyl, hydroxyphenylcarbonyl, halophenylcarbonyl, phenylloweralkylaminocarbonyl, diloweralkylaminocarbonyl, phenylloweralkylaminocarbonyl, hydroxyphenyllowerlakylaminocarbonyl, cycloalkylaminocarbonyl, loweralkylphenylcarbonyl, haloloweralkylsulfonylloweralkyloxyphenylcarbonyl, and nitrophenylcarbonyl, R, and R 3 are selected independently from the group consisting of optionally substituted aryl and aralkyl, and at least one of Ri and R is selected independently from the group consisting of phenyl, phenyloxyloweralkyl, and phenylloweralkyl, and. more specifically those compounds having the just-described substitution pattern wherein at least one of R| and R 3 is substituted with at least one hydroxyl or thio group Yet more specific embodiments are those for which R 2 is selected from the group consisting of optionally substituted phenylcarbonyl, (heterocycloalkyl)loweralkyloxyphenylcarbonyl, hydroxyphenylcarbonyl, halophenylcarbonyl, phenylloweralkylaminocarbonyl, diloweralkylaminocarbonyl, phenylloweralkylaminocarbonyl, hydroxyphenyllowerlakylaminocarbonyl, cycloalkylaminocarbonyl, loweralkylphenylcarbonyl, haloloweralkylsulfonylloweralkyloxyphenylcarbonyl, and nitrophenylcarbonyl, R, and R 3 are selected independently from the group consisting of optionally substituted aryl and aralkyl, at least one of R, and R 3 is selected independently from the group consisting of phenyl, phenyloxyloweralkyl, and phenylloweralkyl, at least one of R, and R 3 is substituted with at least one hydroxyl or thio group, and at least one of R, and R~ is substituted optionally with a substituent selected from the group consisting of halogen loweralkyl, halolowerlalkyl, loweralkyloxy, halolowerlakyloxy, carboxy, loweralkyloxycarbonyl, aryloxycarbonyl, (cycloloweralkyl)oxycarbonyl. aralkyloxycarbonyl, heteroaryloxycarbonyl, heteroaralkyloxycarbonyl, (heterocycloloweralkvl)oxvcarbonyl, loweralkylsulfinyl, loweralkylsulfonyl, loweralkylthio, arylthio loweralkylcarbonyloxy. arylcarbonyloxy. aralkylcarbonyloxy. heteroaryicarbonyloxy, heteroaralkylcarbonyloxy, (cycloloweralkyl)carbonyloxy, (heterocycloloweralkyl)carbonyloxy, aminocarbonyl, loweraklylaminocarbonyl, arylammocarbonyl, aralkylaminocarbonyl, heteroarylammocarbonyl, and heteroaralkylammocarbonyl Examples of particularly useful substituents are provided above In a second aspect, the present invention provide compounds having the general structure shown below (Compound 2) and their pharmaceutically acceptable salts X 3 and X 4 are selected independently from the group consisting of nitrogen and oxygen such that if one of X 3 and X 4 is nitrogen, then the other of X 3 and X is oxygen to form thereby an isoxazole ring structure, Thus Compound 2 above will be recognized to include the general structures X 5 is -(Xιo)„-, wherein n is an integer between 1 and 3 and X, 0 , for each value of n, is selected independently from the group consisting of oxygen, -SO v - where x is and integer between 0 and 2, nitrogen, nitrogen substituted with optionally substituted loweralkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, arylcarbonyl, alkylcarbonyl, aralkylcarbonyl, heteroaryicarbonyl, heteroaralkylcarbonyl, and methylene or methine, each optionally substituted from the group consisting of halo, cyano, nitro, thio, ammo, carboxyl, formyl, and optionally substituted loweralkyl, loweralkylcarbonyloxy, arylcarbonyloxy, heteroaryicarbonyloxy. cycloalkylcarbonyloxy, cycloheteroalkylcarbonyloxy, aralkycarbonyloxy, heteroaralkylcarbonyloxy, (cycloalkyl)alkylcarbonyloxy, (cycloheteroalkyl)alkylcarbonyloxy, loweralkylcarbonyl, arylcarbonyl, heteroaryicarbonyl, cycloalkylcarbonyl, cycloheteroalkylcarbonyl, aralkycarbonyl, heteroaralkylcarbonyl, (cycloalkyl)alkylcarbonyl, (cycloheteroalkyl)alkylcarbonyl, loweralkylaminocarbonyl, arylammocarbonyl, aralkylaminocarbonyl, heteroarylammocarbonyl. heteroaralkylammocarbonyl, loweralkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, cycloalkylcarbonylamino, cycloheteroalkylcarbonylamino, aralkylcarbonylamino. heteroaralkylcarbonylamino, (cycloalkyl)alkylcarbonylamιno, (cycloheteroalkyl)alkylcarbonylamιno, loweralkyiammo, arylamino, aralkylamino. heteroarylamino, heteroaralkylammo, loweralkylsulfonyl, arylsulfonyl, heteroaryisulfonyl, cycloalkylsulfonyi. cycloheteroalkylsulfonyl, aralkylsulfonyl, heteroaralkylsulfonyl, (cycloalkyl)alkyisulfonyl, (cycloheteroalkyl)alkylsulfonyl, loweralkylsulfinyl, arylsulfinyl, heteroarylsulfinyl, cycioalkylsulfinyl, cycloheteroalkylsulfinyl, aralkylsulfinyl, heteroaralkylsulfinyl, (cycloalkyl)alkylsulfinyl, (cycloheteroalkyl)alkylsulfinyl, loweralkyloxy, aryloxy, heteroaryloxy, cycloalkyloxy, cycloheteroalkyloxy. aralkyloxy. heteroaralkyloxy, (cycloalkyl)alkyloxy, and (cycloheteroalkyl)alkyloxy, loweralkylthio. arylthio. heteroarylthio. cycloalkylthio, cycloheteroalkvlthio. aralkylthio, heteroaralkylthio, (cycloalkyl)alkylthιo, (cvcloheteroalkyl)alkvlthιo. loweralkvlthiocarbonyl. aryithiocarbonyl, heteroarvlthiocarbonvl cycloalkylthiocarbonyl, cycloheteroalkylthiocarbonyl. aralkythiocarbonyloxlthiocarbonyi, heteroaralkylthiocarbonyl, (cycloalkyl)alkylthιocarbonyl, (cycloheteroalkyl)alkvlthιocarbonyl, heteroarylcarbonylthio, cycioalkylcarbonylthio. cycloheteroalkylcarbonylthio. aralkycarbonylthiooxycarbonylthio, heteroaralkylcarbonylthio, (cycloalkyl)alkylcarbonylthιo, (cycloheteroalkyl)alkylcarbonylthιo loweralkyloxycarbonyl, aryloxycarbonvi, heteroaryloxycarbonyl, cycloalkyloxycarbonyl, cycloheteroalkyloxycarbonyl, aralkyoxycarbonyloxloxycarbonyl, heteroaralkyloxycarbonyl, (cycloalkyl)alkyloxycarbonyl, (cycloheteroalkyl)alkyloxycarbonyl, lminoloweralkyl, lminocycloalkyl, lmmocycloheteroalkyl, lminoaralkyl, lmmoheteroaralkyl, (cycloalkyl)ιmιnoalkyl, and (cycloheteroalkyl)ιmιnoalkyl X 6 -X are selected independently from the group consisting of oxygen, sulfur, sulfinyl, nitrogen, and optionally substituted methine, and R, is selected from the group consisting of optionally substituted loweralkyl, aryl, heteroaryl, cycloalkyl, cycloheteroalkyl, aralkyl. heteroaralkyl, (cycloalkyl)alkyl, and (cycloheteroalkyl)alkyl Some embodiments of the present invention mclude those structures having the general form shown m Compound 2 above for which n is 1 and X ]0 is selected from the group consisting of nitrogen, optionally substituted nitrogen, and optionally substituted methylene or methine Such embodiments will be recognized as including ring systems that are completely deloca zed as well as ring systems that are not completely delocalized More specific embodiments include those structures of Compound 2 for which n is 1 and X l0 is selected from the group consisting of nitrogen, optionally substituted nitrogen, and optionally substituted methylene or methine and n is selected from the group consisting of optionally substituted aryl, heteroaryl, aralkyl, and heteroaralkyl Still more specific embodiments are those having the substitution pattern just described and for which R 4 is optionally substituted aryl or aralkyl Yet more specific embodiments of the invention include compounds wherein n is 1 and X,o is selected from the group consisting of nitrogen, optionally substituted nitrogen, and optionally substituted methylene or methine, R, is optionally substituted aryl or aralkyl, and R 4 includes at least one hydroxyl, thio, or optionally substituted loweralkyloxy, aryloxy, heteroaryloxy, loweralkylthio, arylthio, heteroarylthio, loweralkylcarbonyl, arylcarbonyl, or heteroaryicarbonyl moiety In some embodiments having the structure of Compound 2 above, n is 1 and X, 0 is selected from the group consisting of nitrogen, optionally substituted nitrogen, and optionally substituted methylene or methine, R 4 is selected from the group consisting of phenyl, phenyloxyloweralkyl, and phenylloweralkyl wherein R, is optionally substituted aryl or aralkyl, R 4 includes at least one hydroxyl, thio, or optionally substituted loweralkyloxy, aryloxy, heteroaryloxy, loweralkylthio, arylthio, heteroarylthio, loweralkylcarbonyl, arylcarbonyl, or heteroaryicarbonyl moiety and 4 is further substituted optionally with a moiety selected from the group consisting of halogen, loweralkyl, halolowerlalkyl, loweralkyloxy, halolowerlakyloxy, carboxy, loweralkyloxycarbonyl, aryloxycarbonyl, (cycloloweralkyl)oxycarbonyl, aralkyloxycarbonyl, heteroaryloxycarbonyl, heteroaralkyloxycarbonyl, (heterocycloloweralkyl)oxycarbonyl, loweralkylsulfinyl, loweralkylsulfonyl, loweralkylthio, arylthio, loweralkylcarbonyloxy, arylcarbonyloxy, aralkylcarbonyloxy, heteroaryicarbonyloxy, heteroaralkylcarbonyloxy, (cycloioweralkyl)carbonyloxy, (heterocycloloweralkyl)carbonyloxy, aminocarbonyl, loweraklylaminocarbonyl, arylammocarbonyl, aralkylaminocarbonyl, heteroarylammocarbonyl, cyano. nitro, ammo, loweralkyiammo, and heteroaralky lam mocarbony 1 In another embodiment, the present invention provides compounds having the structure of Compound 2 above for which n is 2 and each X 10 is selected independently from the group consisting of nitrogen, optionally substituted nitrogen, optionally substituted methylene. and optionally substituted methine More specific embodiments include those for which n is 2 and each X| 0 is selected independently from the group consisting of nitrogen, optionally substituted nitrogen, optionally substituted methylene. and optionally substituted methine and R 4 is selected from the group consisting of optionally substituted aryl, heteroaryl, aralkyl. and heteroaralkyl Also provided are embodiments in which n is 2 and each X t0 is selected independently from the group consisting of nitrogen, optionally substituted nitrogen, optionally substituted methylene. and optionally substituted methine and R, is optionally substituted aryl or aralkyl Yet more specific embodiments having this latter substitution pattern are those for which R 4 includes at least one hydroxyl, thio. or optionally substituted loweralkyloxy, aryloxy, heteroaryloxy, loweralkylthio, arylthio, heteroarylthio, loweralkylcarbonyl, arylcarbonyl, or heteroaryicarbonyl moiety Still more particular embodiments are those wherein n is 2 and each X, 0 is selected independently from the group consisting of nitrogen, optionally substituted nitrogen, optionally substituted methylene, and optionally substituted methine and R, is optionally substituted aryl or aralkyl, R, is selected from the group consisting of phenyl, phenyloxyloweralkyl, and phenylloweralkyl and R, includes at least one hydroxyl, thio, or optionally substituted loweralkyloxy, aryloxy, heteroaryloxy, loweralkylthio, arylthio, heteroarylthio, loweralkylcarbonyl, arylcarbonyl, or heteroaryicarbonyl moiety Other, more particular embodiments are those in which n is 2 and each X,o is selected independently from the group consisting of nitrogen, optionally substituted nitrogen, optionally substituted methylene, and optionally substituted methine, R 4 is selected from the group consisting of phenyl, phenyloxyloweralkyl, and phenylloweralkyl, R 4 includes at least one hydroxyl, thio, or optionally substituted loweralkyloxy, aryloxy, heteroaryloxy, loweralkylthio, arylthio, heteroarylthio, loweralkylcarbonyl, arylcarbonyl. or heteroaryicarbonyl moiety and R, is further substituted optionally with a moiety selected from the group consisting of halogen, loweralkyl, halolowerlalkyl, loweralkyloxy, halolowerlakyloxy, carboxy, loweralkyloxycarbonyl, aryloxycarbonyl, (cycloloweralkyl)oxycarbonyl. aralkyloxycarbonyl, heteroaryloxycarbonyl, heteroaralkyloxycarbonyl, (heterocycloloweralkyl)oxycarbonyl, loweralkylsulfinyl, loweralkylsulfonyl, loweralkylthio, arylthio, loweralkylcarbonyloxy, arylcarbonyloxy, aralkylcarbonyloxy, heteroaryicarbonyloxy, heteroaralkylcarbonyloxy, (cycloloweralkyl)carbonyloxy, (heterocycloloweralkyl)carbonyloxy, aminocarbonyl, loweraklylaminocarbonyl, arylammocarbonyl, aralkylaminocarbonyl, heteroarylammocarbonyl, cyano, nitro, ammo, loweralkyiammo, and heteroaralkylammocarbonyl Still other embodiments of the present invention include compounds of the general formula of Compound 2 for which X6-X9 are selected independently from the group consisting of nitrogen and optionally substituted methine More particular embodiments are those for which X 6 -X 9 are selected independently from the group consisting of nitrogen and optionally substituted methine and at least one of X 6 -X 9 is methine substituted with a moiety selected from the group consisting of loweralkyloxy, aryloxy, heteroaryloxy, loweralkylthio, arylthio, heteroarylthio. loweralkylcarbonyl, arylcarbonyl. and heteroaryicarbonyl Still more particular embodiments having the structural pattern just described include those in which X 7 is methine substituted with hydroxy or loweralkyloxy In other embodiments of the invention having the general formula of Compound 2, X 6 -X 9 are selected independently from the group consisting of nitrogen and optionally substituted methine, n is 1 and X 10 is selected from the group consisting of nitrogen, optionally substituted nitrogen, and optionally substituted methylene or methine More specific embodiments are those in which X 6 -X 9 are selected independently from the group consisting of nitrogen and optionally substituted methine, n is 1 and X, 0 is selected from the group consisting of nitrogen, optionally substituted nitrogen, and optionally substituted methylene or methine, and R is selected from the group consisting of optionally substituted aryl, heteroaryl, aralkyl, and heteroaralkyl Still more specific embodiments include those for which X6-X9, n, and X 10 have the values just defined and Ri is optionally substituted aryl or aralkyl In yet more specific embodiments, X 6 -X 9 , n and X, 0 have the values just defined. Rt is optionally substituted aryl or aralkyl, and R 4 includes at least one hydroxyl, thio, or optionally substituted loweralkyloxy, aryloxy, heteroaryloxy, loweralkylthio, arylthio, heteroarylthio, loweralkylcarbonyl, arylcarbonyl, or heteroaryicarbonyl moiety Other embodiments are those for which X 6 -X 9 , rt, Xio and R( have the values and substituents just defined, but more specifically R, is selected from the group consisting of phenyl, phenyloxyloweralkyl, and phenylloweralkyl Still more embodiments are those for which X 6 -X 9 , n, X, 0 and Rt have the values and substituents just defined and R 4 is further substituted optionally with a moiety selected from the group consisting of halogen, loweralkyl, halolowerlalkyl, loweralkyloxy, halolowerlakyloxy, carboxy, loweralkyloxycarbonyl, aryloxycarbonyl, (cycloloweralkyl)oxycarbonyl, aralkyloxycarbonyl, heteroaryloxycarbonyl, heteroaralkyloxycarbonyl, (heterocycloloweralkyl)oxycarbonyl, loweralkylsulfinyl, loweralkylsulfonyl, loweralkylthio, arylthio, loweralkylcarbonyloxy, arylcarbonyloxy, aralkylcarbonyloxy, heteroaryicarbonyloxy, heteroaralkylcarbonyloxy, (cycloloweralkyl)carbonyloxy, (heterocycloloweralkyl)carbonyloxy, aminocarbonyl, loweraklylaminocarbonyl, arylammocarbonyl, aralkylaminocarbonyl, heteroarylammocarbonyl, cyano, nitro, amino. loweralkyiammo, and heteroaralky lam inocarbony 1 Yet other embodiments of the invention including the compounds of the general formula of Compound 2 are those in which X 6 -X are selected independently from the group consisting of nitrogen and optionally substituted methine, n is 2 and each X l0 is selected independently from the group consisting of nitrogen, optionally substituted nitrogen, optionally substituted methylene. and optionally substituted methme More specific embodiments are those in which X 6 -X 9 are selected independently from the group consisting of nitrogen and optionally substituted methine, n is 2 and each X 10 is selected independently from the group consisting of nitrogen, optionally substituted nitrogen, optionally substituted methylene, and optionally substituted methine, and R is selected from the group consisting of optionally substituted aryl, heteroaryl, aralkyl, and heteroaralkyl Still more specific embodiments include those for which X 6 -X 9 , t. and X| 0 have the values just defined and 4 is optionally substituted aryl or aralkyl In yet more specific embodiments, X 6 -X 9 , n, Xι 0 and R, have the values just defined and R 4 includes at least one hydroxyl, thio, or optionally substituted loweralkyloxy, aryloxy, heteroaryloxy, loweralkylthio, arylthio, heteroarylthio, loweralkylcarbonyl, arylcarbonyl, or heteroaryicarbonyl moiety Yet more specific embodiments are those for which Xβ-X 9 , n, X, 0 and have the values and substituents just defined, but more particularly in which is selected from the group consisting of phenyl, phenyloxyloweralkyl, and phenylloweralkyl Other embodiments having the general structure of Compound 2 are those for which X 6 -X are selected independently from the group consisting of nitrogen and optionally substituted methine, n is 2 and each X ]0 is selected independently from the group consisting of nitrogen, optionally substituted nitrogen, optionally substituted methylene, and optionally substituted methine, R, is selected from the group consisting of phenyl phenyloxyloweralkvl, and phenylloweralkyl, R includes at least one hydroxvl thio, or optionally substituted loweralkyloxy. aryloxy, heteroaryloxy, loweralkylthio. arylthio. heteroarylthio, loweralkylcarbonyl, arylcarbonyl, or heteroaryicarbonyl moiety, and R( is further substituted optionally with a moiety selected from the group consisting of halogen, loweralkyl, halolowerlalkyl, loweralkyloxy, halolowerlakyloxy, carboxy, loweralkyloxycarbonyl, aryloxycarbonyl, (cycloloweralkyl)oxycarbonyl, aralkyloxycarbonyl, heteroaryloxycarbonyl, heteroaralkyloxycarbonyl, (heterocycloloweralkyl)oxycarbonyl, loweralkylsulfinyl, loweralkylsulfonyl. loweralkylthio, arylthio, loweralkylcarbonyloxy, arylcarbonyloxy, aralkylcarbonyloxy, heteroaryicarbonyloxy, heteroaralkylcarbonyloxy, (cycloloweralkyl)carbonyloxy, (heterocycloloweralkyl)carbonyloxy, aminocarbonyl, loweraklylaminocarbonyl. arylammocarbonyl, aralkylaminocarbonyl, heteroarylammocarbonyl, cyano. nitro, ammo, loweralkyiammo, and heteroaralkylammocarbonyl 3 3 Synthesis of tha Compounds of the Invention The compounds of the present invention can be synthesized using techniques and materials known to those of skill in the art (Carey and Sundberg 1983, Carey and Sundberg 1983, Greene and Wuts 1991 , March 1992) Starting materials for the compounds of the invention may be obtained using standard techniques and commercially available precursor materials, such as those available from Aldrich Chemical Co (Milwaukee, Wis ), Sigma Chemical Co (St Louis, Mo ), Lancaster Synthesis (Windham, N H ), Apm Chemicals, Ltd (New Brunswick, N J ), Ryan Scientific (Columbia, S C ), Maybridge (Cornwall, England), Arcos (Pittsburgh, Pa ), and Trans World Chemicals (Rockville, Md ) The procedures described herein for synthesizing the compounds of the invention may include one or more steps of protection and deprotection (eg, the formation and removal of acetal groups) (Greene and Wuts 1991) In addition, the synthetic procedures disclosed below can mclude various purifications, such as column chromatography. flash chromatography, thin-layer chromatography ("TLC"), recrystal zation, distillation, high- pressure liquid chromatography ("HPLC") and the like Also, various techniques well known in the chemical arts for the identification and quantification of chemical reaction products, such as proton and carbon- 13 nuclear magnetic resonance (Η and lj C NMR), infrared and ultraviolet spectroscopy ("IR" and "UV"), X-ray crystallography, elemental analysis ("EA") HPLC and mass spectroscopy ("MS") can be used for identification, quantitation and purification as well Scheme 1 is a general scheme for synthesis of isoxazoles Id 4-OH-phenyl R. = 3-OH-phenyl 2-OH-phenyl Scheme 1 Step A is a Claisen-type condensation, in which X is a leaving group such as -OR (R = alkyl, aryl, arlkyl, heteroaryl, or heteroaralkyl), or halogen When X is -OR and R is alkyl (e g , X is methoxy or ethoxy) the reaction of la and lb to produce lc can be done using procedures known to those of skill in the organic chemistry arts (Tietze and Eicher 1989) When X is halogen, e g , Cl, a typical procedure involves deprotonation of ketone la with a base such as lithium bιs(trιmethylsιlyl)amιde (LiHMDS) followed by addition of lb Suitable solvents for performing such reactions will be familiar to those of skill in the organic chemistry arts Examples of suitable solvents include ether-type solvents such as tetrahydrofuran ("THF"), diethyl ether (H 3 CH 2 COCH 2 CH 3 ), or aliphatic and aromatic hydrocarbon solvents such as cyclohexane (C 6 H 12 ) and toluene (C 7 H 8 ) Typical reaction temperatures range from -78 °C to +25 °C and the reaction times from 6 hours ("h") to 20 h Step B is a cycloaddition reaction to form the desired isoxazole In a typical procedure, a mixture of lc, two equivalents of hydroxyamme hydrochloπde, and three equivalents of pyπdine m ethanol are heated to reflux overnight Removal of the solvent followed by extraction yields a crude material that can be purified to afford substantially pure compound Id If R, and R 2 are not identical, then a mixture of regioisomers is formed In some cases, protecting groups have to be removed to obtain targeted compound le, as illustrated by Step C Protection and deprotection will depend greatly on the chemical properties of the molecule and its functional groups, appropriate methods for protection and deprotection are well known in the organic chemistry arts (Greene and Wuts 1991) For example, when Ri is methoxyphenyl, three methods can be used for demethylation 1) reaction of aqueous hydrogen bromide (HBr) and glacial acetic acid with Id with heating to 100-120 °C for 6 to 16 h, 2) reaction of ethane thiol, aluminum trichloride, and Id in dichloroethane with stirring at room temperature ("rt") for 16 to 72 h, or 3) stirring boron tπbromide with Id in dichloromefhane at room temperature overnight Scheme 2 describes an alternative method to synthesize compound lc of Scheme 1 2a lc Scheme 2 Step A above can be performed using various methods familiar to those of skill in the organic chemistry arts For example, at least three well known methods can be used to convert 2a to lc 1 ) deprotonation of 2a with a base such as sodium hvdride (NaH) in an aprotic solvent such as dimethylformamide ("DMF") or THF, followed by reaction of the resulting anion with an electrophile R 3 X, wherein X is a leaving group such as halogen or MsO; or 2) compound 2a is reacted with R 3 X, potassium carbonate and tetrabutylammonium bromide in DMF while stirring at rt -100 °C for 6 to 24 h. If R 3 is paraalkyloxyphenyl, then a plumbate method can be applied (Craig, Holder et al 1979. Pinhey, Holder et al 1979) Regiospecific synthesis of the isoxazoles of the invention can be performed using known methods One example of such a method is shown in Scheme 3 below (Perkins. Beam et al ) 3a 3b 3c Scheme 3 Scheme 4 describes an alternative method to synthesize compound Id in Scheme 1 C Scheme 4 Formation of isoxazoles 4a from 1 ,3-dιketone 2a (Step A) can be performed using Step B of Scheme 1 Bromination of isoxazole 4a (Step B) can be accomplished by addition of bromine in chloroform solution to a solution of 4a under temperatures from rt— 55 °C for a period between 0 5 to 2 h to form 4-bromoιsoxazole 4b A variety of substituents at the R 3 can be introduced to 4-bromoιsoxazole 4b to form the desired product Id (Step C) as will be apparent to those of skill in the organic chemistry arts For example, metal-halogen exchange followed by trapping the resulting isoxazole anion with an electrophile can be used to attach R ^ This can be done, for example, by reaction of bromoisoxazole 4b in THF solution at -78 °C with n-BuLi The mixture is stirred at -78 °C for 1 h The desired electrophile corresponding to R 3 is then added, and the reaction is warmed to 0 °C-rt over a period between 2 to 16 h Suitable electrophiles include, but are not limited to, the following alkyl hahdes, disulfides, iodine, N-chlorosuccinimide, tosyl nitrile, ethyl chloroformate. acid chlorides, carbon dioxide, dimethylformamide, aldehydes, Weinreb amides and sulfonyl chlorides Alternatively, a 4-carboxyιsoxazole (; e , R 3 = -C0 2 " ) can be obtained if carbon dioxide is used as the electrophile The carboxyhc acid can be further transformed to various esters, amides, and ketones To form an amide at R 3 , typical amide bond formation condition can be applied For example, the corresponding carboxyhc acid can be activated with l-(3-dιmethylamιnopropyl)-3-ethylcarbodnmιde ("EDC") HCl salt, 1- hydroxybenzotriazole ("HOBt"), and Hunig's base and mixed with a primary or secondary am e in THF or DMF The reaction is complete in 6 to 16 hours at rt Suzuki coupling can also be used to introduce aryl and alkenyl moieties at R 3 (Miyaura, Author et al 1979, Miyaura and Suzuki 1979) The Ullmann reaction can be used to introduce aryloxy groups at R 3 (Knight , Semmelhack, Author et al ) Moieties having C-N and C-0 bonds at 4- position of isoxazole 4b can be achieved by applying palladium catalyzed coupling reactions (Palucki, Wolfe et al 1996, Wolfe and Buchwald 1996, Wolfe, Wagaw et al 1996) Scheme 5 illustrates more specific modifications at 4-posιtιon of the isoxazole + regioisomer + regioisomer + regioisomer 5a 5b 5c Scheme 5 Starting material 5a can be synthesized by methods described above The linker Z can be -CH 2 -, -0-, -S-, -S0 2 -, -NR'R"-, -(C=0)-, -(C=NOR)-, or the aryl group can be attached to the isoxazole core directly In the Scheme above. R 3 is a phenol protecting group that can be removed selectively (Greene and Wuts 1991) as shown in Step A The free hydroxyl group can be derivatized using known methods and materials (Step B) However, other suitable groups such as, but not limited to, thiols, protected thiols, amines, and the like can be synthesized using analogous methodologies One specific methodology is described with respect to Scheme 6 below where Z is -SOτ or -(C=0)- and Y is O, S, or N The index can be 1 , 2, or 3, and R, is -NR'R" or -N(R')(C=0)R" In one example, sodium hydride was mixed with HY(CH 2 ) n R , to generate the nucleophile and added to 6a in THF or DMF solution at a temperature between rt and 60 °C and completed within 2 to 8 h regioisomer + regioisomer 6a 6b Scheme 6 Specific modifications at 5-posιtιon of the isoxazole can be performed using the methodologies described with Scheme 7 below regioisomer Scheme 7 where E is alkyl, aryl, aralkyl, halo, cyano, amido, carboxy, sulfide, and sulfoxide Starting material 7a can be synthesized according to methods described above The functional group E is introduced using the methods described in Step C of Scheme 4 above Modifications at the 4-posιtιon of the isoxazole can be made, for example, using the methods described with respect to Scheme 8 Scheme 8 Starting material 8a was synthesized according to methods described in Scheme 1 Bromination at the methyl position was performed using N-bromosuccinimide in carbon tetrachloπde Alkylation to form derivatives of 8c where R, is -OR, -SR or -NRR' can be conducted with appropriate nucleophile in a suitable solvent (e g, DMF or THF) at temperatures ranging between rt and 100 °C The procedures described above can be applied to solid phase methodologies as well The actual implementation depends, of course, on the details of the desired products and starting materials One example of a suitable methodology where R, is hydroxyphenyl, is shown in Scheme 9 Scheme 9 In step A, commercially available hvdroxylated Rink resin (Calbiochem, La Jolla, CA) is reacted with mesvl chloride and Hunig ' s base in methylene chloride (CH C1 2 ) at 0 °C with warming to room temperature over a two- hour period Next, 4-hydroxyacetophenone and Hunig's base are reacted with the resin product in methylene chloride at room temperature overnight provides resin-bound ketone 9a Reaction of the bound ketone with an ester bearing the R 3 substituent (R 3 C0 2 R) and base (e g , potassium tert-butoxide, /-BuOK and dibenzo- 18-crown- 6) in a suitable solvent (e g , THF) at 70 °C for six hours (Step B) provides diketone 9b Deprotonation of 9b, using, e g , /erf-butyl ammonium iodide ("TBAI") under mild conditions (70 °C overnight) and the R 2 substituent bearing a suitable leaving group (e g , halogen, tosylate, mesylate) provides 9c Cyclization of 9c to form the desired isoxazole (resin-bound regioisomers 9d and 9e) can be performed by reaction of the bound diketone with H 2 NOH HCl and Hunig's base in a suitable solvent (e , dimethylsulfoxide, ("DMSO")) at 70 °C for fifteen hours Cleavage from the resin can be performed under mild conditions (e g , reaction with 5% tπfluoroacetic acid ("TFA") in methylene chloride) provides the final products 9d and 9e 3 4 Biological Activity The activities of the compounds of the invention to function as estrogen receptor agonists or antagonists can be determined using a wide variety of assays known to those having skill in the biochemistry, medicinal chemistry, and endochπnology arts Several useful assays are described generally in this Section 3 4 Specific examples are described in Section 4 2 below 34 1 Assays for Estrogen Receptor Modulating Activity In Vivo and Ex Vivo 34 1 1 Allen-Doisy Test for Estrogenicity This test (described in greater detail in Section 4 2 1 1 below) is used to evaluate a test compound for estrogenic activity, and, more specifically, the ability of a test compound to induce an estrogenic comification of vaginal epithelium (Allen and Doisy 1923, Muhlbock 1940. Terenius 1971) Test compounds are formulated and administered subcutaneouslv to mature, ovaπectomized female rats in test groups In the third week after bilateral ovaπectomy the rats are primed with a single subcutaneous dose of estradiol to ensure maintenance of sensitivirv and greater uniformity of response In the fourth week, 7 days after priming, the test compounds are administered The compounds are given in three equal doses over two days (evening of the first day and morning and evening of the second day) Vagmal smears are then prepared twice daily for the following three days The extent of comified and nucleated epithelial cells, as well as of leucocytes are evaluated for each of the smears 34 1 2 Anti-Allen-Doisy Test for Anti-Estrogenicity This test (described in greater detail in Section 4 2 1 2 below) is used to evaluate a test compound for anti- estrogenic activity by observation of cornification of the vaginal epithelium of in ovaπectornized rats after administration of a test compound (Allen and Doisy 1923, Muhlbock 1940, Terenius 1971) Evaluation of anti- estrogenic activity is performed using mature female rats which, two weeks after bilateral ovaπectomy, are treated with estradiol to induce a cornification of the vaginal epithelial This was followed by administration of the test compound m a suitable formulation daily for 10 days Vaginal smears are prepared daily, starting on the first day of test compound administration and proceeding until one day following the last administration of test compound The extent of comified and nucleated epithelial cells and leucocytes is evaluated for each of the smears as above 34 1 3 Immature Rat Uterotrophic Bioassay for Estrogenicity and Anti-Estrogenicity Changes in uterine weight in response to estrogenic stimulation can be used to evaluate the estrogenic characteristics of test compounds on uterine tissues (Reel, Lamb et al 1996, Ashby, Odum et al 1997) In one example, described in Section 4 2 1 3 below, immature female rats having low endogenous levels of estrogen are dosed with test compound (subcutaneously) daily for 3 days Compounds are formulated as appropriate for subcutaneous injection As a control, 17-beta-estradιol is admmistered alone to one dose group Vehicle control dose groups are also included in the study Twenty-four hours after the last treatment, the animals are necropsied. and their uteri excised, nicked, blotted and weighed to Any statistically significant increases in uterine weight in a particular dose group as compared to the vehicle control group demonstrate evidence of estrogenicity 34 1 4 Estrogen Receptor Antagonist Efficacy In MCF-7 Xenograft Model This test (described in detail in Section 4 2 1 4 below) is used to evaluate the ability of a compound to antagonize the growth of an estrogen-dependent breast MCF-7 tumor in vivo Female Ncr-nu mice are implanted subcutaneously with an MCF-7 mammary tumor from an existing in vivo passage A 17-β-estradιol pellet is implanted on the side opposite the tumor implant on the same day Treatment with test compound begins when tumors have reached a certain mmimum size (e g 75-200 mg) The test compound is administered subcutaneously on a daily basis and the animals are subjected to daily mortality checks Body weights and tumor volume are determined twice a week starting the first day of treatment Dosing continues until the tumors reach 1 ,000 ram' Mice with tumors larger than 4,000 mg, or with ulcerated tumors, are sacrificed prior to the day of the study determination The tumor weights of animals in the treatment group are compared to those in the untreated control group as well as those given the estradiol pellet alone 34 1 5 OVX Rat Model This model evaluates the ability of a compound to reverse the decrease in bone density and increase in cholesterol levels resulting from ovaπectomy One example of such a model is described in Section 4 2 1 5 Three- month old female rats are ovanectomized, and test compounds are administered daily by subcutaneous route beginning one day post-surgery Sham operated animals and ovanectomized animals with vehicle control administered are used as control groups After 28 days of treatment, the rats are weighed, the overall bodv weight gains obtained, and the animals euthanized Characteristics indicative of estrogenic activity, such as blood bone markers (e g osteocalcin, bone-specific alkaline phosphatase), total cholesterol, and urine markers (e g deoxypyπdinoline, creatinine) are measured in addition to uterine weight Both tibiae and femurs are removed from the test animals for analysis, such as the measurement of bone mineral density A comparison of the ovanectomized and test vehicle animals to the sham and ovanectomized control animals allows a determination of the tissue specific estrogenic/anti-estrogenic effects of the test compounds 342 Assays for Estrogen Receptor Modulating Activity In Vitro 342 1 ERα/ERβ Binding Assays For evaluation of ERα/ERβ receptor binding affinity, a homogeneous scintillation proximity assay is used (described in Sections 4 2 2 1 and 4 2 2 2 below) 96-well plates are coated with a solution of either ERα or ERβ After coating, the plates are washed with PBS The receptor solution is added to the coated plates, and the plates are incubated For library screenmg, [ΗJestradiol is combined with the test compounds in the wells of the 96-well plate Non-specific binding of the radio-ligand is determined by adding estradiol to one of the wells as a competitor The plates are gently shaken to mix the reagents and a sample from each of the wells is then transferred to the pre-coated ERα or ERβ plates The plates are sealed and incubated, and the receptor-bound estradiol read directly after incubation using a scintillation counter to determine test compound activity If estimates of both bound and free ligand are desired, supernatant can be removed and counted separately in a liquid scintillation counter 34 22 ERα/ERβ Transactivation Assays The estrogenicity of the compounds of the invention can be evaluated in an in vitro bioassay using Chinese hamster ovary ("CHO") cells that have been stably co-transfected with the human estrogen receptor ("hER"), the rat oxytocin promoter ("RO") and the luciferase reporter gene ( 'LUC") as described in Section 4 22 3 below The estrogen transactivation activity (potency ratio) of a test compound to inhibit transactivation of the enzyme luciferase as mediated by the estrogen receptor is compared with a standard and the pure estrogen antagonist 3 4 2 3 MCF-7 Cell Proliferation Assays MCF-7 cells are a common line of breast cancer cells used to determine in vitro estrogen receptor agonist/antagonist activity (MacGregor and Jordan 1998) The effect of a test compound on the proliferation of MCF-7 cells, as measured by the incoφoration of 5-bromo-2'-deoxvuπdιne ("BrdU") in a chemiluminescent assay format, can be used to determine the relative agonist antagonist activity of the test compound MCF-7 cells (ATCC HTB-22) are mainatined in log-phase culture The cells are plated and incubated in phenol-free medium to avoid external sources of estrogenic stimulus (MacGregor and Jordan 1998) The test compound is added at varying concentrations to determine an IC 5θ for the compound To determine agonist activity, the assay system is kept free of estrogen or estrogen-acting sources To determine antagonist activity, controlled amounts of estrogen are added 3 5 Pharmaceutical Compositions The compounds of the present invention can be used in the form of salts derived from inorganic or organic acids These salts include, but are not limited to, the following acetate, adipate, algmate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, cyclopentanepro- pionate, dodecylsulfate, ethanesulfonate, glucoheptanoate, glycerophosphate, hemi-sulfate, heptanoate. hexanoate, fumarate, hydrochloπde. hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate. nicotinate. 2-napth-alenesulfonate, oxalate, pamoate. pectinate, sulfate, 3-phenyIpropιonate, picrate, pivalate, propionate, succ ate, tartrate, thiocyanate, p-toluenesulfonate and undecanoate Also, any basic nitrogen-containing groups can be quaternized with agents such as loweralkyl hahdes, such as methyl, ethyl, propyl, and butyl chloride, bromides, and iodides, dialkyl sulfates like dimethyl, diethyl, dibutyl, and diamyl sulfates, long chain hahdes such as decyl, lauryl, mynstyl and stearyl chlorides, bromides and iodides, aralkyl hahdes like benzyl and phenethyl bromides, and others Water or oil-soluble or dispersible products are thereby obtained. Examples of acids which may be employed to form pharmaceutically acceptable acid addition salts include such inorganic acids as hydrochloric acid, sulfuπc acid, and phosphoric acid, and organic acids such as oxalic acid, maleic acid, succmic acid and citric acid. Basic addition salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or separately by reacting carboxyhc acid moieties with a suitable base such as the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation or with ammonia, or an organic primary, secondary or tertiary amine Pharmaceutically acceptable salts include, but are not limited to, cations based on the alkali and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium, alummum salts and the like, as well as nontoxic ammonium, quaternary ammonium, and amine cations, including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamme, tπmethylamine, tnethylamine, ethylamine, and the like Other representative organic amines useful for the formation of base addition salts include diethylamine, efhylenediamine. ethanolamme, diethanolamine, piperazine and the like Compounds of the present invention can be administered in a variety of ways including enteral, parenteral and topical routes of administration For example, suitable modes of administration include oral, subcutaneous, transdermal. transmucosal. iontophoretic. intravenous, intramuscular, intraperitoneal, intranasal. subdural, rectal, vaginal, and the like In accordance with other embodiments of the present invention, there is provided a composition comprising an estrogen receptor-modulating compound of the present invention, together with a pharmaceuticalK acceptable carrier or excipient Suitable pharmaceutically acceptable excipients include processing agents and drug delivery modifiers and enhancers, such as, for example, calcium phosphate, magnesium stearate. talc, monosaccharides. disacchaπdes, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, dextrose, hydroxypropvl-β- cyclodextπn, polyvinylpyrrohdinone, low melting waxes, ion exchange resins, and the like, as well as combinations of any two or more thereof Other suitable pharmaceutically acceptable excipients are described in Remington 's Pharmaceutical Sciences, Mack Pub Co , New Jersey (1991), which is mcoφorated herein by reference Pharmaceutical compositions containing estrogen receptor modulating compounds of the present invention may be in any form suitable for the intended method of administration, including, for example, a solution, a suspension, or an emulsion Liquid carriers are typically used in preparing solutions, suspensions, and emulsions Liquid carriers contemplated for use in the practice of the present invention include, for example, water saline. pharmaceutically acceptable organic solvent(s), pharmaceutically acceptable oils or fats, and the like, as well as mixtures of two or more thereof The liquid carrier may contain other suitable pharmaceutically acceptable additives such as solubi zers, emulsifiers, nutrients, buffers, preservatives, suspending agents, thickening agents, viscosity regulators, stabilizers, and the like Suitable organic solvents include, for example, monohydπc alcohols, such as ethanol, and polyhydnc alcohols, such as glycols Suitable oils include, for example, soybean oil, coconut oil, olive oil, safflower oil, cottonseed oil, and the like For parenteral administration, the carrier can also be an oily ester such as ethyl oleate, isopropyl myπstate, and the like Compositions of the present invention may also be in the form of microparticles, microcapsules. liposomal encapsulates, and the like, as well as combinations of any two or more thereof The compounds of the present invention may be administered orally, parenterally, sublmgually by inhalation spray, rectally, vagmally, or topically in dosage unit formulations containing conventional nontoxic pharmaceutically acceptable carriers, adjuvants, and vehicles as desired Topical administration may also involve the use of transdermal administration such as transdermal patches or lonophoresis devices The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection, or infusion techniques Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents The sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1.3-propanedιol Among the acceptable vehicles and solvents that may be employed are water. Ringer s solution, and lsotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium For this puφose, any bland fixed oil may be employed including synthetic mono- or diglyceπdes In addition, fatty acids such as oleic acid can be useful in the preparation of mjectables Suppositories for rectal or vaginal administration of the drug can be prepared by mixing the drug with a suitable nonimtatmg excipient such as cocoa butter and polyethylene glycols that are solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum and release the drug Solid dosage forms for oral administration may include capsules, tablets pills, powders and granules In such solid dosage forms, the active compound may be admixed with at least one inert diluent such as sucrose lactose or starch Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents e g , lubricating agents such as magnesium stearate In the case of capsules, tablets, and pills, the dosage forms may also comprise buffering agents Tablets and pills can additionally be prepared with enteric coatings Liquid dosage forms for oral administration may mclude pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art, such as water Such compositions may also comprise adjuvants, such as wetting agents, emulsifying and suspending agents, cvclodextnns, and sweetening, flavoring, and perfuming agents The compounds of the present invention can also be administered in the form of liposomes As is known in the art liposomes are generally derived from phosphohpids or other lipid substances Liposomes are formed by mono- or multilamellar hydrated liquid crystals that are dispersed in an aqueous medium Any non-toxic, physiologically acceptable and metabohzable lipid capable of forming liposomes can be used The present compositions in hposome form can contain, in addition to a compound of the present invention, stabilizers, preservatives, excipients, and the like The preferred lipids are the phosphohpids and phosphatidyl cholines (lecithins), both natural and synthetic Methods to form liposomes are known in the art (Prescott 1976) While the compounds of the invention can be administered as the sole active pharmaceutical agent, they can also be used in combination with one or more other compound as described herein, and/or in combination with other agents used m the treatment and/or prevention of estrogen receptor-mediated disorders Alternatively, the compounds of the present invention can be admmistered sequentially with one or more such agents to provide sustained therapeutic and prophylactic effects Suitable agents include, but are not limited to, other SERMs as well as traditional estrogen agonists and antagonists Representative agents useful m combination with the compounds of the invention for the treatment of estrogen receptor-mediated disorders include, for example, tamoxifen, 4- hydroxytamoxifen, raloxifene, toremifene, droloxifene, TAT-59, idoxifene, RU 58,688, EM 139, ICI 164,384, ICI 182,780, clomiphene, MER-25, DES, nafoxidene CP-336,156, GW5638, LY139481, LY353581, zuclomiphene, enclomiphene, ethamoxytπphetol, delmadinone acetate, bisphosphonate, and the like Other agents that can be combined with one or more of the compounds of the invention include aromatase inhibitors such as, but not limited to 4-hydroxyandrostenedιone, plomestane exemestane, aminogluethimide, rogletimide, fadrozole, vorozole, letrozole, and anastrozole Still other agents useful for combination with the compounds of the invention include, but are not limited to antineoplastic agents such as alkylatmg agents Other classes of relevant antineoplastic agents include antibiotics hormonal antineoplastics and antimetabolites Examples of useful alkvlating agents include alkyl sulfonates such as busulfan, improsulfan and piposulfan. aziπdines such as a benzodizepa, carboquone, meturedepa and uredepa ethylenimmes and methyimelamines such as aitretam e. tπethvlenemelamine. triethylenephosphoramide tnethylenethiophosphoramide and tπmethylolmeiamine nitrogen mustards such as chlorambucil. chlornaphazme cyciophosphamide. estramustme, φhosphamide, mechlorethamine, mechlorethamine oxide hydrochloride. melphalan, novembichine, phenesteπne, prednimustine, trofosfamide, and uracil mustard, mtroso ureas, such as carmustine, chlorozotocm, fotemustine, lomustine. nimustine ranimustine, dacarbazine, mannomustme mitobronitol. mitolactol and pipobroman More such agents will be known to those having skill in the medicinal chemistry and oncology arts Additional agents suitable for combination with the compounds of the present invention include protein synthesis inhibitors such as abrm, aurintπcarboxylic acid, chloramphenicol, cohcin E3, cycloheximide, diphtheria toxin, edeme A, emetine, erythromycm, ethionme, fluoride, 5-fluorotryptophan, fusidic acid, guanylyl methylene diphosphonate and guanylyl lmidodiphosphate, kanamycin, kasugamycm, kirromycm, and O-methyl threonine, modeccin, neomycin, norvaline, pactamycin, paromomycine, puromycin, πcin, α-sarcin, shiga toxin, showdomycm, sparsomyαn, spectinomycm, streptomycin, tetracycline, thiostrepton and tπmethopπm Inhibitors of DNA synthesis, including alkylating agents such as dimethyl sulfate, mitomycin C, nitrogen and sulfur mustards, MNNG and NMS, intercalating agents such as acndine dyes, actmomycins, adriamycin, anthracenes, benzopyrene, ethidium bromide, propidium diiodide-intertwining, and agents such as distamycin and netropsin, can also be combined with compounds of the present invention in pharmaceutical compositions DNA base analogs such as acyclovir, adenine, β-1-D-arabmosιde, amethopterm, aminopteπn, 2-amιnopuπne, aphidicolin, 8- azaguanme, azasenne, 6-azauracιl, 2'-azιdo-2'-deoxynucleosιdes, 5-bromodeoxycytιdme, cytosine, β-l-D- arabinoside, diazooxynorleucme, dideoxynucleosides, 5-fluorodeoxycytιdιne, 5-fluorodeoxyuπdιne. 5-fluorouracιl, hydroxyurea and 6-mercaptopuπne also can be used in combination therapies with the compounds of the invention Topoisomerase inhibitors, such as coumermycin, na dixic acid, novobiocin and oxohnic acid, inhibitors of cell division, including colcemide, colchicme, vmblastine and vmcristine, and RNA synthesis inhibitors including actinomycm D, α-amanitine and other fungal amatoxins, cordycepm (3'-deoxyadenosιne), dichloroπbofuranosyl benzimidazole, rifampic e, streptovaricm and streptolydigin also can be combined with the compounds of the invention to provide pharmaceutical compositions Still more such agents will be known to those having skill in the medicinal chemistry and oncology arts In addition, the compounds of the present invention can be used, either smgly or in combination as described above, in combination with other modalities for preventing or treating estrogen receptor-mediated diseases or disorders Such other treatment modalities include without limitation, surgery, radiation, hormone supplementation, and diet regulation These can be performed sequentially (e g treatment with a compound of the invention following surgery or radiation) or in combination (e g , in addition to a diet regimen) In another embodiment, the present invention includes compounds and compositions in which a compound of the invention is either combined with, or covalently bound to a cytotoxic agent bound to a targeting agent, such as a monoclonal antibody (e g a murine or humanized monoclonal antibody) It will be appreciated that the latter combination may allow the introduction of cytotoxic agents into cancer cells with greater specificity Thus, the active form of the cytotoxic agent (; e the free form) will be present only in cells targeted by the antibody Of course, the compounds ot the invention may also be combined with monoclonal antibodies that have therapeutic activity against cancer The additional active agents may generally be employed in therapeutic amounts as indicated in the PHYSICIANS' DESK REFERENCE (PDR) 53rd Edition ( 1999), which is incoφorated herein by reference, or such therapeutically useful amounts as would be known to one of ordinary skill in the art The compounds of the invention and the other therapeutically active agents can be administered at the recommended maximum clinical dosage or at lower doses Dosage levels of the active compounds in the compositions of the invention may be varied to obtain a desired therapeutic response depending on the route of administration, severity of the disease and the response of the patient The combination can be administered as separate compositions or as a single dosage form containing both agents When administered as a combination, the therapeutic agents can be formulated as separate compositions that are given at the same time or different times, or the therapeutic agents can be given as a single composition 3 6 Treatment of Estrogen Receptor-Mediated Disorders In accordance with yet other embodiments, the present invention provides methods for treating or preventing an estrogen receptor-mediated disorder in a human or animal subject in which an amount of an estrogen receptor- modulating compound of the invention that is effective to modulate estrogen receptor activity in the subject Other embodiments provided methods for treating a cell or a estrogen receptor-mediated disorder in a human or animal subject, comprising administering to the cell or to the human or animal subject an amount of a compound or composition of the invention effective to modulate estrogen receptor activity in the cell or subject Preferably, the subject will be a human or non-human animal subject Modulation of estrogen receptor activity detectable suppression or up-regulation of estrogen receptor activity either as compared to a control or as compared to expected estrogen receptor activity Effective amounts of the compounds of the invention generally include any amount sufficient to detectably modulate estrogen receptor activity by any of the assays described herein, by other activity assays known to those having ordinary skill in the art, or by detecting prevention or alleviation of symptoms in a subject afflicted with a estrogen receptor-mediated disorder Estrogen receptor-mediated disorders that may be treated in accordance with the invention include any biological or medical disorder in which estrogen receptor activity is implicated or in which the inhibition of estrogen receptor potentiates or retards signaling through a pathway that is characteristically defective m the disease to be treated The condition or disorder may either be caused or characterized by abnormal estrogen receptor activity Representative estrogen receptor-mediated disorders include, for example, osteoporosis, atheroschlerosis, estrogen-mediated cancers (e g breast and endometrial cancer), Turner's svndrome, benign prostate hypeφlasia (/ e prostate enlargement), prostate cancer, elevated cholesterol, restenosis, endometπosis, uterine fπbroid disease, skin and/or vagina atrophy, and Alzheimer's disease Successful treatment of a subject in accordance with the invention may result the prevention inducement of a reduction in, or alleviation of symptoms in a subject afflicted with an estrogen receptor-mediated medical or biological disorder Thus, for example treatment can result in a reduction in breast or endometrial tumors and/or various clinical markers associated with such cancers Likewise treatment of Alzheimer's disease can result in a reduction in the rate of disease progression detected for example, by measuring a reduction in the rate of increase of dementia The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration It will be understood however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, bodv weight, general health, sex, diet, time of administration route of administration, rate of excretion, drug combination, and the severity of the particular disease undergoing therapy The prophvlactically or therapeutically effective amount for a given situation can be readily determined by routine experimentation and is within the skill and judgment of the ordinary clinician For exemplary puφoses of the present invention, a prophylactically or therapeutically effective dose will generally be from about 0 1 mg/kg/day to about 100 mg/kg/day, preferably from about 1 mg/kg/day to about 20 mg/kg/day, and most preferably from about 2 mg/kg/day to about 10 mg/kg/day of a estrogen receptor-modulating compound of the present invention which av be administered in one or multiple doses 4 Examples The following Examples are provided to illustrate certain aspects of the present invention and to aid those of skill in the art in the art in practicing the invention These Examples are in no way to be considered to limit the scope of the invention in any manner 4 1 Preparation of Compounds of the Invention 4 1 1 General Procedures All reactions were carried out under nitrogen or argon atmosphere All reagents obtained from commercial sources were used without further purification Anhydrous solvents were obtained from commercial sources and used without further drying Separation and purification of the products were carried out using any or combination of the following methods Flash column chromatography was performed with silica gel, 200-400 mesh, 60 A (Aldrich Chemical Company, Inc , Milwaukee, WI) or a Flash 40 chromatography system and KP-Sil, 60 A (Biotage, Charlottesville, Virginia) Typical solvents employed were dichloromethane (DCM), methanol (MeOH), ethyl acetate (EtOAc), and hexane (Hex) Preparative TLC was conducted using 20 x 20 cm plates coated with Merch-EM Type-60, GF-254 silica gel Preparative HPLC was performed with Dynamax System using a C-18 reversed phase column (Ranin) Compounds of the present invention were characterized by LC MS using either Waters Micromass Platform LCZ system (ionization mode electron spray positive column HP-Eclipse XDB-C18, 2 x 50 mm, buffer A H 2 0 with 0 1 % trifluoroacetic acid (TFA), buffer B acetonitnle (MeCN) with 0 1% TFA, elution gradient 5-95% buffer over 5 minute period, flow rate 0 8 mL/min) or HP 1 100 Series LC MSD system (ionization mode electron spray positive, column HP-Eclipse XDB-C18. 2 x 50 mm, buffer A H 2 0 with 0 1 % TFA, buffer B MeCN with 0 1% TFA, elution gradient 5-95% buffer over 3 5 to 6 minute period, flow rate 0 8 to 04 mL/min) Purity of the compounds was also evaluated by HPLC using a Waters Millennium chromatography system with a 2690 Separation Module (Milford, Massachusetts) The analytical columns were Alltima C-18 reversed phase. 4 6 x 250 mm from Alltech (Deerfield, Illinois) A gradient elution was used, typically starting with 5% MeCN/ 95% water and progressing to 100% MeCN over a period of 40 minuets All solvents contained 0 1% TFA Compounds were detected by ultraviolet light (UV) absoφtion at 214 nm Some of the mass spectrometnc analysis was performed on a Fisons Electrospray Mass Spectrometer All masses are reported as those of the protonated parent ions unless otherwise noted Nuclear magnetic resonance (NMR) analysis was performed with a Vanan 300 MHz NMR (Palo Alto, California) The spectral reference was either TMS or the known chemical shift of the solvent Proton NMR (Η NMR) data are reported as follows chemical shift (δ) in ppm, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, p = pentet, m = multiplet, dd = doublet of doublet, br = broad), coupling constant (Hz), mtegration and assignment Melting points were determined on a Laboratory Devices MEL-TEMP apparatus (Holhston, Massachusetts) and are reported uncorrected Compound names were generated using NOMENCLATOR (Chemlnnovation Software, Inc , San Diego, CA) 4 1 2 Synthesis of Estrogen Receptor-Modulating Isoxazoles 4 1 2 1 Synthesis of 4-{5-[2-(4-hydroxyphenyl)ethyl]-4-benzylιsoxazol-3-yl}phenol This compound was synthesized by following Scheme 1 and Scheme 3 using 4'-mefhoxyacetophenone and methyl 3-(4-methoxyphenyl)propanoate for the Claisen condensation and benzyl bromide for the alkylation Demethylation was performed using Method 3 described m Step C of Scheme 1 ESMS m/z 372 (MH + ), C 24 H 2 ,N0 3 = 371 g/mol, HPLC purity = 70% 4 1 2 2 Synthesis of 4-[4-ethyl-5-(phenoxymethyl)ιsoxazol-3-yl]phenol This compound was synthesized by following the methods described above for Scheme 1 using l-(4- methoxyphenyl)butan-l-one and 2-phenoxyacetyl chloride as starting materials Demethylation was performed using Method 3 described for Step C of Scheme 1 ESMS m/z 296 (MH + ), C| 8 H, 7 N0 3 = 295 g/mol, HPLC purity = 60% 4 1 2 3 Synthesis of 4-[5-(4-hydroxyphenyl)-4-phenylιsoxazol-3-yl]phenol This compound was synthesized by following methods described above for Scheme 1 using l-(4-methoxyphenyl)- 2-phenylethan-l-one and 4-methoxybenzoyl chloride as starting materials Demethylation was performed using Method 1 described for Step C in Scheme 1 Η NMR (d 6 -DMSO) δ 7 60-7 36 (m, 9H), 7 00-6 90 (m, 4H), MS m/z 330 (MH+), C 2 ,H, 5 N0 3 = 329 g/mo, HPLC purity = 80% 4 1 2 4 Synthesis of 4-[4-ethyl-5-(4-hydroxyphenyl)ιsoxazol-3-yl]ρhenol This compound was synthesized by following methods described above for Scheme 1 using 1 -(4-methoxyphenyl)- butane-1-one and 4-methoxybenzoyl chloride as starting materials. Demethylation was performed using Method 1 described for Step C in Scheme 1 Η NMR (d 6 -DMSO) δ 7.70 (d, J = 8.24 Hz, 2H), 7.50 (d, J = 8 24 Hz, 2H), 7.00 (dd, J = 8.24, 2.2 Hz, 4H), 2.80 (q, = 6 75 Hz, 2H), 1.20 (t, J= 6.75 Hz, 3H); GCMS m/z 281 (M+), C l7 H, 5 N0 3 = 281 g/mol; HPLC purity = 90%. 4 1.2 5 Synthesis of 4-{5-[2-(4-hydroxyphenyl)ethyl]-4-phenylιsoxazol-3-yl}phenol This compound was synthesized by following methods described above for Scheme 1 using 1 -(4-methoxyphenyl)- 2-phenylethan- 1 -one and 4-nιtrophenyl 3-(4-methoxyphenyl)propanoate as starting materials. Demethylation was performed using Method 3 described for Step C Scheme 1 ESMS m/z 358 (MH T ). C 23 H, 9 N0 3 = 357 g/mol, HPLC purity = 70% 4.1.26 Synthesis of 4-[5-(4-hydroxyphenyl)-4-benzylιsoxazol-3-yl]phenol This compound was synthesized by following methods described above for Scheme 1 using l-(4-methoxyphenyl)- 3-phenylpropan-l-one and p-anisoyl chloride as starting materials. Demethylation was performed using Method 1 described for Step C in Scheme 1. Η NMR (d 4 -MeOH) δ 7.60-7.20 (m, 9H), 7.01-6.80 (m, 4H), 4 20 (s, 2H), MS m/z 344 (MH+), C 22 H :7 N0 3 = 343 g/mol; HPLC purity = 80%. 4 1.27 Synthesis of 4-[3,5-bιs(4-hydroxyphenyi)ιsoxazol-4-yl]phenol This compound was synthesized by following Scheme 1 and Scheme 3 Step 1. To a solution of 4'-methoxyacetophenone in THF at -78 °C was added dropwise 1.5 eq. of [(CH 3 ) 2 Sι] 2 NLι The solution was stirred for 1 h at -78 °C, followed by addition of 1.2 eq. of j-anisoyl chloride. The reaction mixture was stirred for 10 min at -78 °C and then for 22 h at rt, acidified with 10% citric acid, and extracted with EtOAc. The combined organic layers were washed with water and dried over Na 2 S0 . Removal of solvent in vacuo provided a crude solid which was purified by flash chromatography (CH C1 2 ) to give 1,3-diketone as a white solid Step 2: Synthesis of -methoxyphenyllead triacetate To a solution of lead tetraacetate (0 73 equiv) in chloroform and dichloroacetic acid was added anisole (1 0 equiv ) The reaction mixture was allowed to stir at room temperature for 90mιn. After this period the solution was washed with water and the organic layer was treated with hexane. The product precipitated out and was collected by filtration. The solid was taken up in chloroform and acetic acid. The resultant solution was stirred for 1 h and then washed with water The later 2 steps were repeated and the chloroform layer was treated with hexane This mixture was cooled to 2 °C for 24 h The material that precipitated was collected by filtration and dried under vacuum to afford ^-methoxyphenyllead triacetate Step 3 A mixture of the 1,3-diketone (1 0 equiv , obtained from step 1 ), -methoxyphenyllead triacetate (1 1 equiv obtained from step 2) and pyndine (3 3 equiv ) in chloroform was stirred at room temperature for 48 h After this time had elapsed the reaction was diluted with chloroform, washed with water and 4M sulfuric acid The aqueous washes were back extracted with chloroform The combined organic extracts were washed with water, dried over magnesium sulfate, filtered and concentrated in vacuo The crude product was purified by flash column chromatography (ethyl acetate/ hexane, 1 3) to afford an off white solid as l,2,3-tπs(4-methoxyphenyI)propane- 1,3-dιone Step 4 A mixture of the 1,3-diketone obtained in step 3 (1 0 equiv ), hydroxylamine hydrochlonde (1 5 equiv ), pyndine (2 0 equiv ) and ethanol was heated to reflux overnight Cooled to rt and removed solvent in vacuo Water and ethyl acetate were added The organic layer was separated, washed with dil HCl, brine, dried, filtered and the solvent was concentrated in vacuo The product l-[4,5-bιs(4-methoxvphenyl)ιsoxazol-3-yl]-4-methoxybenzene was obtained as an off white solid Step 5 Demethylation was performed using Method 1 described for Step C in Scheme 1 to afford the product 4- [3,5-bιs(4-hydroxyphenyl)ιsoxazol-4-yl]phenol Η NMR (d 6 -DMSO) δ 7 30 (d, J= 90 Hz, 2H), 7 20 (d, J = 9 0 Hz, 2H), 7 10 (d, J= 9 0 Hz, 2H), 6 80 (d, J= 9 0 Hz, 2H), 6 76 (d, J = 9 0 Hz, 2H), 6 74 (d, J = 9 0 Hz, 2H), MS m/z 346 (MH+), C 2 ,H, 5 N0 4 = 345 g/mol, HPLC purity = 97% 4 1 28 Synthesis of 4-[5-(4-hydroxyphenyl)ιsoxazol-3-yl]phenol This compound was synthesized by following the methods described above for Scheme 1 using 4'-acetophenone and p-amsovl chloride as starting materials Demethylation was performed using Method I described for Step C in Scheme 1 Η NMR (d 6 -DMSO) δ 7 80-7 75 (m,4H), 7 5 (s, 1 H), 6 99-690 (m, 4H), MS m/z 254 (MH+), C , 5 H, ,N0 3 = 253 g/mol, HPLC purity = 96% 4 1 2 9 Synthesis of 4-{5-(4- ydroxyphenyl)-4-[4-(2-pιpeπdylethoxy)phenyl]ιsoxazol-3-yl}phenol This compound was synthesized by following Scheme 1 , Scheme 3, and Scheme 5 Step 1 Synthesis of 1 ,3-diketone is the same as Step 1 of the Example tn Section 4 1 2 7 Step 2 Synthesis of p-allyloxyphenyllead triacetate Similar as Step 2 in Section 4 1 2 7 except allylphenyl ether was used as the starting material instead of/?-amsole Step 3 Similar as Step 3 in Section 4 1 2 7. using p-allyloxypheny Head triacetate instead of p-methoxvphenvllead triacetate Step 4 Formation of isoxazole skeleton is the same as Step 4 of Section 4 1 2 7 The product obtained from this step is l-[3,5-bιs(4-methoxyphenyl)ιsoxazol-4-yl]-4-prop-2-enyloxybenzene Step 5 Selective removal of the allyl protecting group A mixture of the above isoxazole (1 0 equiv ), pyrrohdine (20 equiv ), tnphenylphosphine (0 05 equiv ) and tetrakιs(tιphenylphosphιne) palladιum(O) (0 05 equiv ) in THF was heated to reflux overnight The solution was concentrated m vacuo and the crude material was purified by flash column chromatography (ethyl acetate/hexane 1 3) The product 4-[3,5-bιs(4-methoxyphenyl)ιsoxazol-4- yl]phenol was obtained as a white solid Step 6 A mixture of the phenol (1 0 equiv , obtained from step 5), l-(2-chloroethyl)pιpeπdιne monohydrochlonde (1 2 equiv ) cesium carbonate (2 5 equiv ) in DMF (30ml) was heated at 100°C overnight The solids were removed by filtration, the filtrate was concentrated in vacuo and the residue was taken up into ethyl acetate The solution was washed with water, brine, dried over sodium sulfate, filtered and concentrated in vacuo to give l-[3,5-bιs(4- methoxyphenyl)ιsoxazol-4-yl]-4-(2-pιpeπdylethoxy)benzene Step 7 Demethylation was performed using Method 2 described for Step C in Scheme I To a solution of the isoxazole obtained from step 6 (1 0 equiv ) in dichloroethane was added aluminum chloride (5 0 equiv ) and ethane thiol (5 0 equiv ) The resultant mixture was stirred for 40mm at room temperature and quenched with THF, 20% HCl and water A precipitate was formed and this was collected by filtration After drying the product the material was taken up in methanol, treated with activated charcoal, filtered through sodium sulfate and concentrated in vacuo Purification with flash chromatography followed by addition of HCl aq and lyophilization, then afforded the product 4-{5-(4-hydroxyphenyl)-4-[4-(2-pιpendylethoxy)phenyl]ιsoxazol-3-yl}phenol as hydrochlonde salt Η NMR (d 4 -MeOH) δ 743 (d, J=9 0Hz, 2H), 7 25 (d, =8 0Hz, 2H), 7 20 (d, =90Hz, 2H), 7 03 (d, J=90Hz, 2H), 6 77 (d, _/=8 0Hz, 2H), 6 75 (d, =8 0Hz, 2H), 4 20 (t. J=5 5Hz. 2H), 2 90 (t J=5 5Hz, 2H) 2 60 - 2 70 (m 4H), 1 63 - 1 75 (m, 4H), 1 50 - 1 60 (m, 2H), MS m/z 457 (MH + , 100%), C 2S H 28 N 2 0 4 = 456 g/mol, HPLC purity = 98% 4 1 2 10 Synthesis of 4-{4-(4-hydroxyphenyl)-3-[4-(2-pιpeπdylethoxy)phenyl]ιsoxazol-5-yl}phenol This compound was synthesized by following the procedures described above in Scheme 1, Scheme 3, and Scheme 7 Stepl Synthesis of 1,3-diketone is similar to that described in Step 1 of Section 4 1 2 7 To a solution of desoxyanisoin (1 0 equiv) in THF at -78°C was added lithium bιs(tπmefhylsιlyl)amιde (1 2 equiv ) dropwise The resultant solution was allowed to stir for 40mιn at -78°C and a solution of/?-allyloxybenzoyl chloride (1 1 equiv ) in THF was added dropwise The reaction mixture was allowed to warm to room temperature slowly overnight to produce an orange colored solution The mixture was diluted with 0 5N HCl, extracted with ethyl acetate, washed with 0 5N HCl, water, brine, dried over sodium sulfate, filtered and concentrated in vacuo The crude product was purified bv recrystalhzation This afforded some of the desired compound and the remaining residue was purified by flash column chromatography (ethyl acetate hexanes 1 3) to afford the 1,3-diketone Step 2 Formation of isoxazole is the same as Step 4 of Section 4 1 2 7 The product afforded from this step is 4- methoxy-l-[4-(4-methoxyphenyl)-5-(4-prop-2-enyloxyphenyl)ιsoxazol-3-yl]benzene Step 3 Selective removal of the allyl protecting group Same as Step 5 of Section 4 1 2 9 The product afforded from this step is 4-[3,4-bιs(4-methoxyphenyl)ιsoxazol-5-yl]phenol Step 4 Alkylation Same as Step 6 Section 4 1 2 9 The product afforded from this step is 4-methoxy-l-{4-(4- methoxyphenyl)-5-[4-(2-pιpeπdylethoxy)phenyl]ιsoxazol-3-yl}benzene Step 5 Demethylation was performed using Method 2 described for Step C in Scheme 1 (see Step 7 of Section 4 1 2 9) The product was 4-{4-(4-hydroxyphenyl)-3-[4-(2-pιperιdylethoxy)phenyl]ιsoxazol-5-yl}phenol Η NMR (d 6 -DMSO) δ 6 70-7 50 (m, 2H), 4 35 - 4 42 (m, 2H), 3 30 - 3 50 (m, 2H), 2 90 - 3 25 (m, 4H). 1 60 - 1 80 (m. 4H) 1 30 - 1 45 (m, 2H), MS m/z 457 (MH 100%,), C 28 H 28 N 2 0 4 = 456 g/mol, HPLC purity = 98% 4 1 2 11 Synthesis of 3-[4,5-bιs(4-hydroxyphenyl)ιsoxazol-3-yl]phenol This compound was synthesized by following Scheme 1 Desoxyanisoin and w-anisoyl chloride were used as starting materials Demethylation was performed using Method 1 described for Step C in Scheme 1 The product obtained was an off-white solid MS m/z 346 (MH+), C 2 ,H, 5 N0 4 = 345 g/mol, HPLC purity = 95% 4 1 2 12 Synthesis of 2-[4,5-bιs(4-hydroxyphenyl)ιsoxazol-3-yl]phenol This compound was synthesized by following Scheme 1 Desoxyanisoin and o-amsoyl chloride were used as starting materials Demethylation was performed using Method 1 described for Step C in Scheme 1 The product obtained was an off-white solid MS m/z 346 (MH+), C 21 H l5 N0 4 = 345 g/mol, HPLC purity = 96% 4 1 2 13 Synthesis of 4-[3-(4-hydroxyphenyl)-4-methylιsoxazol-5-yl]phenol This compound was synthesized by following Scheme 1 1 -(4-methoxyphenyl)propan- 1 -one and -anisoyl chloride were used as starting materials Demethylation was performed using Method 1 described for Step C in Scheme 1 ESMS m/z 268 (MH + ), C, 6 H, 3 N0 3 = 267 g/mol, HPLC purity = 85% 4 1 2 14 Synthesis of 4-[3-(4-hydroxyphenyl)-5-phenylιsoxazol-4-yl]phenol This compound was synthesized by following Scheme 1 Desoxyanisoin and benzoyl chloride were used as starting materials Demethylation was performed using Method 1 described for Step C in Scheme 1 ESMS m/z 330 (MH * ), C„H, 5 NO- = 329 g/mol, HPLC purity = 90% 4 1 2 15 Synthesis of 4-[5-(4-fluorophenyl)-3-(4-hydroxyphenyl)ιsoxazol-4-yl]phenol This compound was synthesized by following Scheme 1 Desoxyanisoin and /?-fluorobenzoyl chloride were used as starting materials Demethylation was performed using Method 1 described for Step C in Scheme 1 ESMS m/z 348 (MH + ), C 2 ,H, 4 FN0 3 = 347 g/mol, HPLC purity = 85% 4 1 2 16 Synthesis of 4-{4-(4-hydroxyphenyl)-5-[3-(trιfluoromethoxy)phenyl]ιsoxazol-3-yl}phenol This compound was synthesized by following Scheme 1 Desoxyanisoin and w-tπfluoromethylbenzoyl chloride were used as starting materials Demethylation was performed using Method 1 described for Step C in Scheme 1 ESMS m/z 414 (MH + ), C 22 H, 4 F 3 N0 4 = 413 g mol, HPLC purity = 90% 41 2 17 Synthesis of 4-{4-(4-hydroxyphenyl)-5-[4-(tπfluoromethoxy)phenyl]ιsoxazol-3-yl}phenol This compound was synthesized by following Scheme 1 Desoxyanisoin and /rj-trifluoromethylbenzoyl chloride were used as startmg materials Demethylation was performed using Method 1 described for Step C in Scheme 1 ESMS m/z 414 (MH + ), C 22 H, 4 F 3 N0 4 = 413 g/mol, HPLC purity = 90% 4 1 2 18 Synthesis of 4-[5-(4-hydroxyphenyl)-4-(phenoxymethyl)ιsoxazol-3-yl]phenol This compound was synthesized by following the procedures described for Scheme 1 and Scheme 8 Step 1 Formation of 1,3-diketone Same as Step 1 of Section 4 1 2 7, except l-(4-methoxyphenyl)propan-l-one was used as a startmg material Step 2 Formation of the isoxazole skeleton Same as Step 4 of Section 4 1 2 7 The product obtained from this step was 4-methoxy- 1 -[5-(4-methoxyphenyl)-4-methylιsoxazol-3-yl]benzene Step 3 Bromination of 4-methylιsoxazole A suspension of the above 4-methylιsoxazole (1 0 eq ), N- bromosuccinimide (NBS) (1 1 eq ), and PhC0 3 H (catalytic amount) in CC1 was heated to reflux under argon for 2 h, cooled to rt and filtered The filtrate was diluted with DCM washed with 10% Na 2 S 2 0 3 and 10% NaHCO , dried and concentrated in vacuo The resulting crude material was purified with flash column chromatography to give product l-[4-(bromomethyl)-5-(4-methoxyphenyl)ιsoxazol-3-yl]-4-methoxybenzene Step 4 Alkylation To a solution of phenol ( 1 1 eq ) in dry THF at 0 °C was added powder NaH (1 1 eq ) under argon When the solution stopped bubbling, the above bromide was added to the solution and the mixture was stirred overnight at rt The resulting solution was acidified with saturated NH 4 C1 and extracted with ethyl ether The combined organic layers were dried over Na-,S0 4 and rotary evaporated to give a white solid Step 5 Demethylation The above white solid was converted to product 4-[5-(4-hydroxyphenyl)-4- (phenoxymethyl)ιsoxazol-3-yl]phenol using Method 1 described for Step C of Scheme 1 ESMS mle 360 (MH + ), C, 2 Hι 7 N0 4 = 359 g mol, HPLC purity = 90% 4 1 2 19 Synthesis of 4-[5-(4-hydroxyphenyl)-4-(phenyithιomethyl)ιsoxazol-3-yl]phenol This compound was synthesized by following the procedures described for Scheme 1 and Scheme 8 Step 1-3 are the same as described for Steps 1-3 of Section 4 1 2 18, respectively Step 4 Alkylation Same as Step 4 of Section 4 1 2 18, except thiophenol was used instead of phenol Step 5 Demethylation Same as Step 5 of Section 4 1 2 18 The product obtained was 4-[5-(4-hydroxyphenyl)-4- (phenylthιomethyl)ιsoxazol-3-yl]phenol ESMS m/e 376 (MH + ), C 22 Hι 7 N0 3 S = 375 g/mol, HPLC purity = 90% 4 1 220 Synthesis of 3 5-bιs(4-hydroxyphenyl)ιsoxazol-4-yl 4-(2-pιperιdylethoxy)phenyl ketone This compound was synthesized by following the procedures described above for Scheme 5 Step 1 Same as Step 1 described in Section 4 1 2 7 Step 2 Formation of isoxazole heterocycle Same as Step 4 in Section 4 1 2 7 The product obtained from this step was 4-methoxy- 1 -[5-(4-methoxyphenyl)ιsoxazol-3-y ljbenzene Step 3 Brommation To a solution of the above isoxazole (1 0 eq ) in anhydrous CHC1 3 at reflux (70 °C) under argon was added dropwise bromine (1 01 eq ) in anhydrous CHC1 3 solution The mixture was stirred for 50 mm at reflux, followed by addition of 10% Na 2 S 2 0 3 in saturated NaHCO ^ aqueous solution The aqueous-organic solution was separated and the aqueous layer was extracted with CH 2 C1 2 The combined organic phases were dried over Na->S0 4 and rotary evaporated to give a yellow solid that was washed with ethyl acetate ("EtOAc") to afford pale yellow solid as l-[4-bromo-5-(4-methoxyphenyl)ιsoxazol-3-yl]-4-methoxybenzene in 92 5% yield Step 4 Acylation To a solution of the above 4-bromoιsoxazole (1 0 eq ) in anhydrous THF at -98 °C under argon was added n-BuLi (1 2 eq , 1 6 M in hexane) The resultant solution was stirred for 1 h at -98 °C and then transferred dropwise to a solution of 4-allyoxybenzoyl chloride (1 2 eq ) in THF at -78 °C through a double-tipped needle The reaction mixture was stirred overnight at -78 °C, diluted with water, and then acidified with 10% aqueous citric acid The organic layer was dried over Na 2 S0 and purified with flash chromatography (CH 2 C1 2 ) to give acvlated product 3 5-bιs(4-methoxyphenyl)ιsoxazol-4-yl 4-prop-2-envloxyphenyl ketone as a pale yellow solid in 64% yield Step 5 Selective removal of the allyl protecting group Same as Step 5 of Section 4 1 2 9 Step 6 Alkylation Same as Step 6 of Section 4 1 2 9 Step 7 Demethylation was following Method 2 described for Step C of Scheme 1 To a solution of the compound obtained from the above step 6 in dry CH 2 C1 2 was added 5 0 equivalents of A1C1 3 and 5 0 equivalents of ethane thiol ("EtSH") The reaction mixture was stirred at rt for 1 2 h and the resultant slurry was then poured to ice- water The organic layer was separated The aqueous layer was extracted with EtOAc three times The combined organic layers were dried over Na 2 S0 4 and rotary evaporated in vacuo The obtained reaction mixture which contained desired product and side product as mono-demethylated compound The mixture was separated by HPLC to give product 3,5-bιs(4-hydroxyphenyl)ιsoxazol-4-yl 4-(2-pιpendylethoxy)phenyl ketone in 22% yield after HPLC purification The product obtained from HPLC purification was dissolved in EtOAc/ sat NaHC0 3 (1 1) solution The bilayer solution was shaken vigorously and separated The aqueous layer was extracted with EtOAc several times The combined organic layer was dried over MgS0 4 and rotary evaporated to give a yellow solid The solid was then dissolved in cold acetone/ cone HCl (2 1) and the solution was rotary evaporated in vacuo to produce the HCl salt of 3,5-bιs(4-hydroxyphenyl)ιsoxazol-4-yl 4-(2-pιpeπdylethoxy)phenyl ketone as an off white powder Recrystalization with methanol/water gave the salt as fine flaky crystals Η NMR (d 6 -DMSO) δ 10 2 (s, 1H, OH), 9 93 (s, 1H, OH), 7 8-6 72 (m, 12H, 3Ph), 44 (br t, 2H, OCH 2 -), 3 49 (m, 4H N(CH 2 )_), 2 98 (br t, 2H, -CH 2 -N), 1 79-1 39 (m, 6H -(CH 2 ) 3 ) ESMS m/e 485 (MH + ), C 29 H 28 N 2 0 5 = 484 g/mol, HPLC purity = 99% mp 255 "C decomposed 4 1 221 Synthesis of 5-(4-hydroxyphenyl)-3-(4-methoxyphenyl)ιsoxazol-4-yi 4-(2-pιpeπdylethoxy)phenyl ketone This compound was synthesized by following Scheme 5 Steps 1-6 are exactly the same as the corresponding Steps of Section 4 1 220 Step 7 Same as Step 7 of Section 4 1 2 20 Partial demethylation gave the title compound 5-(4-hydroxyphenyl)-3- (4-methoxyphenyl)ιsoxazol-4-yl 4-(2-pιpendylethoxy)phenyl ketone which was isolated by HPLC ESMS m/e 499 (MH + ), C 30 H 30 N 2 O 5 = 498 g/mol, HPLC purity = 97% 53236 4 1 222 Synthesis of 35-bιs(4-hydroxyphenyl)ιsoxazol-4-yl 4-[2-(hydroxypιpeπdyl)ethoxy]phenyl ketone This compound was obtained as a side product of the reactions described in Section 4 1 2 20 The crude material obtained from Step 7 of Section 4 1 2 20 was dissolved in DMSO and left at rt overnight HPLC analysis of this mixture showed formation of new compound that was 16 mass units higher than any of the products found in the reaction of Step 7 of Section 4 1 2 20 HPLC isolation thus afforded N-oxide 3,5-bιs(4-hydroxyphenyl)ιsoxazol-4- yl 4-[2-(hydroxypιpendyl)ethoxy]phenyl ketone Η NMR (d 6 -DMSO) δ 1022 (s, 1H), 9 94 (s, 1H), 7 82-7 79 (d, J= 8 76 Hz, 2H), 746-743 (d, J = 8 76 Hz. 2H), 7 34-7 32 (d, J= 8 30 Hz, 2H), 7 04-7 01 (d, J = 8 76 Hz, 2H), 6 83-6 80 (d, J= 8 76 Hz, 2H), 6 78-6 75 (d, J = 8 30 Hz, 2H), 4 55 (br, 2H), 4 05 (br, 2H), 3 67 (br, 4H), 2 00-1 35 (m, 6H), LC/MS m/z 501 (MH + ), C 29 H 28 N 2 0 6 = 500 g/mol, HPLC purity = 99% 4 1 2 23 Synthesis of 3-(4-hydroxyphenyl)-5-(4-methoxyphenyl)ιsoxazol-4-yl 4-[2-(hydroxypιperιdyl)ethoxy]phenyl ketone This compound was obtained as a side product of the synthesis described in Section 4 1 2 21 The crude material obtained from Step 7 was dissolved in DMSO and left at rt overnight HPLC analysis of this mixture showed formation of new compound which was 16 mass units higher than any of the products characterized previously HPLC isolation afforded 3-(4-hydroxyphenyl)-5-(4-methoxyphenyl)ιsoxazol-4-yl 4-[2- (hydroxypιpeπdyl)ethoxy]phenyl ketone ESMS m/e 515 (MH + ), C 30 H 30 N 2 O 6 = 514 g mol) , HPLC purity = 88% 4 1 224 Synthesis of 3,5-bιs(4-hydroxyphenyl)ιsoxazol-4-yl 4-hydroxyphenyl ketone This compound was synthesized by following the procedures described for Scheme 5 Steps 1-4 were performed exactly the same as corresponding Steps in Section 4 1 2 20 Step 5 Deprotection was performed by following Method 3 described for Step C in Scheme 1 This step gave the desired product 3,5-bιs(4-hydroxyphenyl)ιsoxazol-4-yl 4-hydroxyphenyl ketone ESMS m/e 374 (MH"), C 22 H, 5 N0 5 = 373 g/mol, HPLC purity = 90% 4 1 225 Synthesis of 4-[4-bromo-5-(4-hydroxyphenyl)ιsoxazol-3-yl]phenol This compound was synthesized by following the procedures described for Scheme 4 Step 1-3 are exactly the same as the corresponding steps in Section 4 1 2 20 Step 4 Demethylation was performed using Method 1 described for Step C in Scheme 1 ESMS m/e 332/334 (MH T ), C l3 H 10 BrNO 3 = 331/333 g/mol (I Br) , HPLC purity = 90% 4.1.2.26 Synthesis of 4-[4-(bromomethyl)-5-(4-hydroxyphenyl)isoxazol-3-yl]phenol This compound was synthesized by following the procedures described above for Scheme 1 and Scheme 8. Steps 1-3 are same as corresponding steps in Section 4.1.2.20. Step 4: Demethylation was following Method 3 described for Step C in Scheme 1. To a solution of above isoxazole in DCM at -78 C was added dropwise 5 eq. boron tribromide (IM in DCM solution). The mixture was slowly warmed to rt and stirred under argon for 1.5 h. The reaction was quenched by adding water and neutralized to pH 5. Extracted with EtOAc, dried with Na 2 S0 4 and concentrated in vacuo to give a crude material. Purification by HPLC afforded 10% of desired product. ESMS m/e 346/348 (MH + , 100%), C l6 H 12 BrN0 3 = 345/347 g/mol (IBr); HPLC purity = 80%. 4.1.2.27 Synthesis of 4-{5-(4-hydroxyphenyl)-4-[(4-hydroxyphenoxy)methyl]isoxazol-3-yl}phenol This compound was synthesized by following the procedures described above for Scheme 1 and Scheme 8. Steps 1, 2 and 3 are same as corresponding steps in Section 4.1.2.18. Step 4: Alkylation. Same as step 4 of Section 4.1.2.18 except 4-(benzyloxy)phenol was used in the procedure. The product obtained form this step is l-{[3,5-bis(4-methoxyphenyl)isoxazol-4-yl]methoxy}-4- (phenylmethoxy)benzene. Step 5: Demethylation was following Method 3 described for Step C in Scheme 1. The product obtained was 4-{5- (4-hydroxyphenyl)-4-[(4-hydroxyphenoxy)methyl]isoxazol-3-yl}phenol. ESMS m/e 376 (MH + ), C 22 H 17 N0 5 = 375 g/mol; HPLC purity = 80%. 4.1.2.28 Synthesis of 4-[4-(hydroxymethyl)-5-(4-hydroxyphenyl)isoxazol-3-yl]phenol This compound was obtained as a side product in the synthesis of product in Section 4.1.2.27; isolation was achieved with HPLC. ESMS m/z 284 (MH + ), C, 6 H, 3 N0 4 = 283 g/mol, HPLC purity = 99%. 4.1.2.29 Synthesis of 3-(4-hydroxyphenyl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-ol This compound was synthesized by following the methods described in Scheme 1, using 6-methoxy-l-tetralone and p-anisoyl chloride as the starting materials. Demethylation was performed following Method 1 of Step C in Scheme 1. ESMS m/e 280 (MH + ), C 17 H, 3 N0 3 = 279 g/mol; HPLC purity = 90%. 4 1 230 Synthesis of 4-(7-methoxy-4 5-dιhydronaphtho[1 2-c]ιsoxazol-3-yl)phenol This compound was synthesized in the same manner as described in Section 4 1 2 29 Partial demethylation afforded mono-methylated product 4-(7-methoxy-4,5-dιhydronaphtho[l,2-c]ιsoxazol-3-yl)phenol, which was isolated by HPLC to provide the desired product ESMS m/e 294 (MH + ), C, 8 H, 5 N0 3 = 293 g/mol, HPLC purity = 89% 4 1 231 Synthesis of 3-[3-(4-hydroxyphenyl)ιsoxazol-5-yl]phenol This compound was synthesized in the same manner as described in Section 4 1 2 8 except 4'- methoxyacetophenone and /w-anisoyl chloride were used as the starting materials ESMS m/e 254 (MH + ), C| 5 H„N0 3 = 253 g/mol, HPLC purity = 90% 4 1 232 Synthesis of 3-(4-hydroxyphenyl)naphtho[1 2-c]ιsoxazol-7-ol This compound was synthesized by following the methods described in Scheme 1 Step 1 Formation of 1,3-diketone Same as Step 1 of Section 4 1 2 7 except 6-methoxy-l-tetralone and/n-amsoyl chloride were used as the starting materials Step 2 Formation of isoxazole heterocycle Same as Step 4 of Section 4 1 2 7 The product obtained from this step was 7-methoxy-3-(4-methoxyphenyl)-4,5-dιhydronaphtho[l,2-c]ιsoxazole Step 3 Oxidation with 2,3-dιchloro-5,6-dιcyano-l,4-benzoquιnone ("DDQ") To the product of Step 2 in dry toluene was added DDQ (1 1 eq ) The solution was refluxed overnight, quenched with sat NaHCO J5 K 2 C0 3 and extracted with CH 2 C1 2 The combined organic layers were dried over Mg 2 S0 and evaporated in vacuo to give a solid residue Purification with flash column chromatography yield product 7-methoxy-3-(4- methoxyphenyl)naphfho[ 1 ,2-c]ιsoxazole Step 4 Demethylation was following Method 1 described for Step C in Scheme 1 ESMS m/e 278 (MH + ), C, 7 H,,N0 3 = 277 g/mol, HPLC purity = 95% 4 1 233 Synthesis of 3-(3-hydroxyphenyl)-4,5-dιhydronaphtho[1 ,2-c]ιsoxazol-7-ol This compound was synthesized in the same manner as described in Section 4 1 2 29 except w-anisoyl chloride was used as one of the starting materials ESMS m/e 280 (MH"), C, 7 H 13 N0 3 = 279 g/mol, HPLC purity = 90% 4 1 2 34 Synthesis of 3-(2-hydroxyphenyl)-4 5-dιhydronaphtho[1 2-c]ιsoxazol-7-ol This compound was synthesized in the same manner as described in Section 4 1 2 29, except ø-anisovl chloride was used as one of the starting materials ESMS m/e 280 (MH"), C 17 H 13 N0 3 = 279 g/mol, HPLC purity = 90% 4 1 235 Synthesis of 3-[5-(3-hydroxyphenyl)ιsoxazol-3-yl]phenol This compound was synthesized in the same manner as described in Section 4 1 2 8, except 3'- methoxyacetophenone and /w-anisoyl chloride were used as starting materials ESMS m/e 254 (MH + ), C 15 H,,N0 3 = 253 g/mol, HPLC purity = 97% 4 1 236 Synthesis of 2-[3-(3-hydroxyphenyl)ιsoxazol-5-yl]phenol This compound was synthesized in the same manner as described in Section 4 1 2 8, except 3'- methoxyacetophenone and o-anisoyl chloride were used as starting materials ESMS m/e 254 (MH + ), C 15 Hι,N0 3 = 253 g/mol, HPLC purity = 96% 4 1 237 Synthesis of 2-[5-(2-hydroxyphenyl)ιsoxazol-3-yl]phenol This compound was synthesized m the same manner as described in Section 4 1 2 8 except 2'- methoxyacetophenone and o-anisoyl chloride were used as starting materials ESMS m/e 254 (MH + ), C, 5 H„N0 3 = 253 g/mol, HPLC purity = 90% 4 1 238 Synthesis of 3-[3-(3-hydroxyphenyl)-4-methylιsoxazol-5-yl]phenol This compound was synthesized by following the procedures described for Scheme 1 and Scheme 3 Step 1 Formation of 1,3-diketone is the same as Step 1 as described in Section 4 1 2 7 using 3'- methoxyacetophenone and m-anisoyl chlonde as the starting materials Step 2 Alkylation A THF solution of the above 1,3-diketone (1 0 eq ) was added dropwise to a suspension of sodium hydride (1 1 eq) in THF at 0 °C The mixture was stirred at rt for 30 min followed by addition of lodomethane ( 1 1 eq ) The reaction mixture was stirred at rt overnight, poured into saturated NH C1 aq and extracted with ether and DCM The organic extracts were washed with brine, dried with MgS0 and concentrated in vacuo to give the product l,3-bιs(3-methoxyphenyl)-2-methylpropane-l,3-dιone Step 3 Formation of isoxazole heterocycle Same as Step 4 as described in Section 4 1 2 7 The product obtained from this step is 3-methoxy-l-[5-(3-methoxyphenyl)-4-methyhsoxazol-3-yl]benzene Step 4 Demethylation was performed following Method 1 of Step C of Scheme 1 to give the desired product ESMS m/e 268 (MH T ), C 16 H, 3 N0 3 = 267 g/mol, HPLC purity = 94% 4 1 2 39 Synthesis of 2-[3-(3-hydroxyphenyl)-4-methylιsoxazol-5-yl]phenol This compound was synthesized in the same manner as described in Section 4 1 2 38, except 3'- methoxyacetophenone and o-anisoyl chloride were used as starting materials ESMS m/e 268 (MH"), C^H^NO, = 267 g/mol, HPLC purity = 90% 4 1 240 Synthesis of 2-[3-(2-hydroxyphenyl)-4-methylιsoxazol-5-yl]phenol This compound was synthesized in the same manner as described in Section 4 1 2 38, except 2'- methoxyacetophenone and o-anisoyl chloride were used as starting materials ESMS m/e 268 (MH ), C, 6 H l3 N0 3 = 267 g/mol, HPLC purity = 90% 4 1 241 Synthesis of 3-[4-ethyl-3-(3-hydroxyphenyl)ιsoxazol-5-yl]phenol This compound was synthesized by following the procedures described for Scheme 1 and Scheme 3 Steps 1 was performed as the corresponding Step described in Section 4 1 2 38 Step 2 alkylation procedure was performed as Step 2 of Section 4 1 2 38, using lodoethane as the alkylaing agent Steps 3 and 4 are exactly the same as the correspondmg Steps described in Section 4 1 2 38 The product obtained was 3-[4-ethyl-3-(3-hydroxyphenyl)ιsoxazol-5-yl]phenol ESMS m/e 282 (MH + ), C l7 H, 5 N0 3 = 281 g/mol, HPLC purity - 90% 4 1 242 Synthesis of 2-[4-ethyl-3-(3-hydroxyphenyl)ιsoxazol-5-yl]phenol This compound was synthesized in the same manner described m Section 4 1 2 41, except 3'- methoxyacetophenone and o-anisoyl chloride were used as starting materials ESMS m/e 282 (MH + ), C 17 H 15 N0 3 = 281 g/mol, HPLC purity = 90% 4 1 243 Synthesis of 2-[4-ethyl-3-(2-hydroxyphenyl)ιsoxazol-5-yl]phenol This compound was synthesized in the same manner described in Section 4 1 2 41 , except 2'- methoxyacetophenone and o-anisoyl chloride were used as starting materials ESMS m/e 282 (MH"), C, 7 H, 5 N0 3 = 281 g/mol. HPLC purity = 90% 4 1 244 Synthesis of 3-[4-(4-hydroxyphenyl)-5-(3-hydroxyphenyl)ιsoxazol-3-yl]phenol This compound was synthesized in the same manner described in Section 4 1 2 7, except 3 '-methoxyacetophenone and /w-anisoyl chloride were used as starting materials ESMS m/z 346 (MH+), C 2 ,H 15 N0 4 = 345 g/mol, HPLC purity = 94% 4 1 245 Synthesis of 2-[3-(3-hydroxyphenyl)-4-(4-hydroxyphenyl)ιsoxazol-5-yl]phenol This compound was synthesized in the same manner described in Section 4 1 2 7, except 3 '-methoxyacetophenone and o-anisoyl chloride were used as starting materials ESMS m/z 346 (MH+), C 21 H 15 N0 4 = 345 g/mol, HPLC purity = 90% 4 1 246 Synthesis of 2-[4-(4-hydroxyphenyl)-5-(2-hydroxyphenyl)ιsoxazol-3-yl]phenol This compound was synthesized in the same manner described in Section 4 1 2 2, except 2'-methoxyacetophenone and o-anisoyl chloride were used as starting materials ESMS m/z 346 (MH+), C 21 H 15 N0 4 = 345 g/mol, HPLC purity = 94% 4 1 247 Synthesis of 3-(2-hydroxyphenyl)-4,5-dιhydronaphtho[2, 1 -d]ιsoxazol-7-ol This compound was synthesized in the same manner as described in Section 4 1 2.29, except 6-methoxy-l- tetralone and o-anisoyl chloride were used as starting materials Demethylation was performed following Method 1 described Step C of Scheme 1 to provide the desired product ESMS m/e 280 (MH + ), C, 7 H 13 N0 3 = 279 g/mol, HPLC purity = 90% 4 1 248 Synthesis of 2-(7-methoxy-4,5-dιhydronaphtho[1 ,2-c]ιsoxazol-3-yl)phenol This compound was synthesized in the same manner as described in Section 4 1 2 47 Partial demethylation afforded mono-methylated product 2-(7-methoxy-4,5-dιhydronaphtho[l,2-c]ιsoxazol-3-yl)phenol ESMS m/e 294 (MH + ), C 18 H 15 N0 3 = 293 g/mol, HPLC purity = 95% 4 1 249 Synthesis of 2-[5-(3-hydroxyphenyl)-4-methylιsoxazol-3-yl]phenol This compound is the regioisomer of the compound described in Section 4 1 2 39 Both regioisomers were obtained using the methods described in that Section, and the two regioisomers were separated by HPLC using a C, 8 column (Relιasιl-BDXC18. 10 x 50 mm, Ra n Dynamax) running a first buffer of H,O/0 1% TFA and a second buffer of HCN/0 1% TFA through a gradient from 5-95% of the second buffer over a nine-minute period at a flow rate often ml/mm ESMS m/e 268 (MH T ), C 16 H, 3 NO = 267 g mol, HPLC purity = 90% 4 1 250 Synthesis of 2-[4-ethyl-5-(3-hydroxyphenyl)ιsoxazol-3-yl]phenol This compound is the regioisomer of compound described in Section 4 1 2 42 Both regioisomers were obtained using the methods described in that Section, and the two regioisomers were separated by HPLC using a C !8 column (Rehasil-BDXC 18, 10 x 50 mm. Ranin Dynamax) running a first buffer of H 2 O/0 1 % TFA and a second buffer of HCN/0 1% TFA through a gradient from 5-95% of the second buffer over a nine-minute period at a flow rate of ten ml/mm ESMS m/e 282 (MH + ), C, 7 H 15 N0 3 = 281 g/mol, HPLC purity = 90% 4 1 251 Synthesis of 2-[4-(4-hydroxyphenyl)-5-(3-hydroxyphenyl)ιsoxazol-3-yl]phenol This compound is the regioisomer of the compound described in Section 4 1 2 45 Both regioisomers were obtained using the methods described in that Section, and the two regioisomers were separated bv HPLC using a C !8 column (Rehasιl-BDXC18, 10 x 50 mm, Ranin Dynamax) running a first buffer of H->O/0 1% TFA and a second buffer of HCN/0 1% TFA through a gradient from 5-95%) of the second buffer over a nme-mmute period at a flow rate often ml/min ESMS m/z 346 (MH+), C 21 H 15 N0 4 = 345 g/mol, HPLC purity = 90% 4 1 252 Synthesis of 3-(5-(3-hydroxyphenyl)-4-{[4-(2-pιperιdylethoxy)phenyl]methyl}ιsoxazol-3-yl)phenol This compound is synthesized as described m Section 4 1 2 20 The starting materials used were 3'- methoxyacetophenone, /w-anisoyl chloride, and 4-allyloxybenzyl bromide ESMS m/z 471 (MH+), C 29 H 30 N 2 O 4 = 470 g/mol, HPLC purity = 88 3% 4 1 253 Synthesis of 3-(3-hydroxyphenyl)-5-(4-hydroxyphenyl)ιsoxazol-4-yl 4-(2-pιperιdylethoxy)phenyl ketone This compound was synthesized as described in Section 4 1 2 20 except /n-anisoyl chloride as one of the starting materials The product was obtained as hydrochloric acid salt in a form of an off-white powder Η NMR (d 6 -DMSO) δ 7 84 (d, J = 8 76 Hz, 2H, ArH, regioisomer 1), 7 82 (d, J = 8 76 Hz, 2H, ArH, regioisomer 2), 7 44 (d, J = 8 76 Hz, 2H, ArH, regioisomer 2), 7 36 (d, J = 8 76 Hz, 2H, ArH, regioisomer 1), 7 30-7 09 (m, 2H, ArH), 7 04-7 02 (m, 2H, ArH), 6 94-6 79 (m, 4H, ArH), 4 41 (br t, 2H, OCH2), 3 46 (br m, 4H, NCH2), 2 79 (br m, 2H, NCH2), 1 80-1 32 (m, 6H, CH2), ESMS m/e 485 (MH + ), C 29 H 28 N,0 5 = 484 g/mol HPLC purity = 100% 4 1 2 54 Synthesis of 2-[3-(4-hydroxyphenyl)-4-phenylιsoxazol-5-yl]phenol This compound was synthesized as described in Section 4 1 2 3, except o-anisoyl chloride was used as one of the starting materials MS m/z 330 (MH+) CιH, 5 NO* = 329 g/mol, HPLC puntv = 90% 4 1 2 55 Synthesis of 3-[3-(4-hydroxyphenyl)4-phenylιsoxazol-5-yl]phenol This compound was synthesized as described in Section 4 1 2 54 except w-anisoyl chloride was used as one of the starting materials MS m/z 330 (MH+), C 2 ,H 15 N0 3 = 329 g/mol, HPLC purity = 90% 4 1 2 56 Synthesis of 2-[4-ethyl-3-(4-hydroxyphenyl)ιsoxazol-5-yl]phenol This compound was synthesized as described in Section 4 1 2 54, except o-anisoyl chloride was used as one of the starting materials ESMS m/z 282 (MH+), C 17 Hι 5 N0 3 = 281 g/mol, HPLC purity = 90% 4 1 257 Synthesis of 3-[4-ethyl-3-(4-hydroxyphenyl)ιsoxazol-5-yl]phenol This compound was synthesized as described in Section 4 1 2 54, except w-anisoyl chloride was used as one of the starting materials ESMS m/z 282 (MH+), C, 7 H 15 N0 3 = 281 g/mol, HPLC purity = 90% 4 1 258 Synthesis of 2-[3-(4-hydroxyphenyl)-4-methylιsoxazol-5-yl]phenol This compound was synthesized as described in Section 4 1 2 13, except using o-anisoyl chloride as one of the startmg materials ESMS m/z 268 (MH+), C, 6 H 13 N0 3 = 267 g/mol, HPLC purity = 90% 4 1 259 Synthesis of 3-[3-(4-hydroxyphenyl)-4-methylιsoxazol-5-yl]phenol This compound was synthesized as described in Section 4 1 2 13, except w-anisoyl chloride was used as one of the starting materials ESMS m/z 268 (MH+), C 16 H 13 N0 3 = 267 g/mol, HPLC purity = 90% 4 1 260 Synthesis of 2-[3-(4-hydroxyphenyl)ιsoxazol-5-yl]phenol This compound was synthesized as described in Section 4 1 2 8, except o-anisoyl chloride was used as one of the starting mateπals ESMS m/z 254 (MH+), C 15 H„N0 3 = 253 g/mol, HPLC purity = 90% 4 1 261 Synthesis of 4-(5-(4-hydroxyphenyl)-4-{[4-(2-pιperιdylethoxy)phenyl]methyl}ιsoxazol-3-yl)phenol This compound was synthesized as described in Section 4 1 2 20 The starting materials used are 4'- methoxyacetophenone, -anisoyl chloride, and 4-allyloxybenzyl bromide Η NMR (d 6 -DMSO & CDC1 3 ) δ 1 8-2 05 (2H, m), 2 62-2 75 (4H, m), 2 78-2 85 (2H, m), 3 32-3 38 (2H. m), 3 51 (2H, d, J=\ 1 9Hz), 3 88 (2H, s), 4 35 (2H, t, J=Λ 5Hz), 6 71 (2H, d, 8 6Hz), 6 74 (2H, d, J=8 6Hz), 6 76 (2H, d, =8 8Hz), 6 96 (2H, d, =8 6Hz), 7 22 (2H, d, =8 6Hz), 7 35 (2H, d, =8 8Hz), ESMS m/z 471 (MH+), C 29 H 30 N 2 O 4 = 470 g/mol, HPLC purity = 85 4% 4 1 262 Synthesis of 2-[5-(4-hydroxyphenyl)-4-methylιsoxazol-3-yl]phenol This compound is the regioisomer of the compound synthesized as described in Section 4 1 2 58 Both regioisomers were obtained using the methods described in that Section and the two regioisomers were separated by HPLC using a C l8 column (Relιasιl-BDXC18, 10 x 50 mm, Ranin Dynamax) running a first buffer of H 2 O/0 1% TFA and a second buffer of HCN/0 1% TFA through a gradient from 5-95% of the second buffer over a nine-minute period at a flow rate often ml/mm ESMS m/z 268 (MH+), C 16 H 13 N0 3 = 267 g/mol, HPLC purity = 99% 4 1 263 Synthesis of 1 -(4-hydroxyphenyl)-4,5-dιhydronaphtho[1 ,2-d]ιsoxazol-8-ol This compound was synthesized by following the procedures described in Scheme 1 using 7-methoxy-2-tetralone and phenyl 4'-allyloxybenzoate as starting materials Demethylation was performed following Method 1 of Step C ESMS m/e 280 (MH + ), C, 7 H, 3 N0 3 = 279 g/mol, HPLC purity = 92% 4 1 264 Synthesis of 3-(4-hydroxyphenyl)-4 5-dιhydronaphtho[1 ,2-c]ιsoxazol-8-ol This compound was synthesized as described in Section 4 1 2 29, except 7-methoxy- 1 -tetralone and p-anisoyl chloride were used as starting materials ESMS m/e 280 (MH + ), C 17 H l3 N0 3 = 279 g/mol, HPLC purity = 90% 4 1 265 Synthesis of 3-(4-hydroxyphenyl)-4,5-dιhydronaphtho[1 ,2-c]ιsoxazol-6-ol This compound was synthesized as described in Section 4 1 229, except using 5-methoxy-l -tetralone and/?- anisoyl chloride as starting materials ESMS m/e 280 (MH + ), C, 7 H, 3 N0 3 = 279 g/mol, HPLC purity = 90% 4 1 2 66 Synthesis of 4-[5-(4-hydroxyphenyl)-4-ιodoιsoxazol-3-yl]phenol This compound was synthesized by following Scheme 4 Steps 1-3 were performed as described for the corresponding steps described in Section 4 1 2 20 to afford l-[4- bromo-5-(4-methoxyphenyl)ιsoxazol-3-yl]-4-methoxybenzene Step 4 To the above 4-bromoιsoxazole m THF at -78 °C was added dropwise 1 1 eq of n-BuLi solution (1 6 M m hexane) Maintained the reaction at -78 °C for 1 h followed by addition of 1 1 eq of I 2 in THF solution The reaction was warmed to rt and stirred overnight, poured into saturated NH 4 C1 aq and extracted with DCM The organic extracts were washed with Na 2 S 2 0 3 aq , brine, dried with MgS0 4 and concentrated in vacuo to give l-[4- ιodo-5-(3-methoxyphenyl)ιsoxazol-3-yl]-3-methoxybenzene Step 5 Demethylation was following Method 1 described for Step C in Scheme 1 Η NMR [(CD 3 ) 2 CO] δ 7 08 (m, 4H), 7 72 (d, 7=8 4 Hz, 2H), 8 01 (d, 7=8 6Hz, 2H), 8 86 (s, 1H), 9 10 (s, 1H), ESMS m/z 380 (MH+), C 15 H l0 INO 3 = 379 g/mol, HPLC purity = 85 8% 4 1 2 67 Synthesis of 4-[4-chloro-5-(4-hydroxyphenyl)ιsoxazol-3-yl]phenol This compound was synthesized as described m Section 4 1 2 66 except, in step 4, N-chlorosuccinimide (NCS) was used as the electrophile to trap the isoxazole anion Η NMR [(CD 3 ) 2 CO] δ 7 09 (m, 4H), 7 82 (d, 7=8 4Hz, 2H), 7 98 (d, 7=9 0Hz, 2H), 9 70 (br s, 2H), ESMS m/z 288 (MH+), C 15 H, 0 ClNO 3 = 287 g/mol, HPLC purity = 960% 4 1 268 Synthesis of 3-(4-hydroxyphenyl)naphtho[1 ,2-c]ιsoxazol-8-ol This compound was synthesized as described in Section 4 1 2 32, except 7-methoxy- 1 -tetralone and /?-anιsoyl chloride were used as starting materials ESMS m/e 278 (MH + ), Cι 7 H„N0 3 = 277 g/mol, HPLC purity = 80% 4 1 2 69 Synthesis of [3,5-bιs(4-hydroxyphenyl)ιsoxazol-4-yl]-N-benzylcarboxamιde This compound was synthesized by following the procedure described m Scheme 4 Steps 1-3 were performed as the corresponding Steps in Section 4 1 220 to afford 1 -[4-bromo-5-(4- methoxyphenyl)ιsoxazol-3-yl]-4-methoxybenzene Step 4 To the above 4-bromoιsoxazole in THF at -78 °C was added dropwise 1 1 eq of w-BuLi solution (1 6 M in hexane) Maintained the reaction at -78 °C for 1 h followed by blowing carbon dioxide gas from a gauge controlled cvl der for ca 20 mm The reaction was warmed to rt carefully, poured into saturated NH 4 C1 aq and extracted with DCM The organic extracts were washed with brine, dried with MgS0 4 and concentrated in vacuo to give 3,5- bιs(3-methoxyphenyl)ιsoxazole-4-carboxylιc acid Step 5 Amide bond formation 4-carboxyιsoxazole (obtained from step 4) was dissolved in THF and activated with EDC HCl salt/HOBt DIEA ( 1 5 1 5 1 5) and allowed to stand at rt for 5mιn Benzylamme (1 5 equiv ) was then added The reaction was allowed to stand at rt overnight, after which it was diluted with EtOAc and washed with 10% citric acid, 10% NaHCO j; brine and solvent was removed Residue was lyophilized in 90% MeCN/HiO and sampled Products were purified by flash chromatography (EtOAc / petroleum ether) to give pure [3,5-bιs(4- methoxyphenyl)isoxazol4-yl]-N-benzamide Step 6 Demethylation procedure was described in Method 3 for Step C in Scheme 1 Η NMR (d 6 -DMSO) δ 4 39 (2H, d, 7=5 86Hz), 6 79 (2H, d, 7=8 79Hz), 6 83 (2H, d, 7=8 79Hz), 7 22-7 24 (IH, m), 7 26-7 32 (2H, m), 7 50 (2H, d, 7=8 61 Hz), 7 56 (2H, d, 7=8 79Hz), 9 20 (IH, t, 7=5 95Hz), 9 87 (IH, s), 10 10 (IH, s), ESMS m/z 387 (MH+), C 23 H, 8 N 2 0 4 = 386 g/mol, HPLC purity = 96 4% 4 1 270 Synthesis of [3,5-bιs(4-hydroxyphenyl)ιsoxazol-4-yl]-N,N-dιbutylcarboxamιde This compound was synthesized as described in Section 4 1 2 69 except, in step 5, N.N-di-n-butyl amine was used for amide bond formation Η NMR (d 6 -DMSO) δ 0 48 (3H, t, 7=7 33Hz), 0 85 (2H, q, 7=7 33Hz), 0 90 (3H, t, 7=7 33Hz), 1 00 (2H, t, 7=7 42 Hz), 1 23-1 31 (3H, m), 1 51 (2H, t, 7=7 24Hz), 2 86-2 91 (2H, m), 3 43-3 50 (IH, m), 6 86 (2H, d, 7=8 61 Hz), 6 90 (2H, d, 7=8 79Hz), 7 51 (2H, d, 7=8 79Hz), 7 58 (2H, d, 7=8 61 Hz), 9 93 (IH, s), 10 13 (IH, s), ESMS m/z 409 (M+H), C 24 H 28 N 2 0 4 = 408 g mol, HPLC purity = 96 7% 4 1 271 Synthesis of [3,5-bιs(4-hydroxyphenyl)ιsoxazol-4-yl]-N-[3-(2-oxopyrrolιdιnyl)propyl]carboxamιde This compound was synthesized as described in Section 4 1 2 69 except, in step 5, l-(3-amιnopropyl)pyrrolιdιn-2- one was used for amide bond formation Η NMR (d 6 -DMSO) δ 1 60 (2H, t, 7=7 05Hz). 1 90 (2H. d, 7=7 60Hz), 2 19 (2H, d, 7=8 06Hz). 3 10 (2H, t, 7=7 14Hz), 3 16 (2H, q, 7=6 59Hz), 3 25 (2H, t, 7=6 96Hz), 3 87 (2H, d, 7=8 79Hz), 7 62 (2H, d, 7=8 79Hz), 7 54 (2H, d, 7=8 79Hz), 8 64 (IH, t, 7=5 58Hz), 9 88 (IH, s), 10 1 1 (IH, s), ESMS m/z 422 (M+H), C 23 H 23 N 3 0 5 = 421 g/mol, HPLC purity = 92 8% 4 1 272 Synthesis of '[3,5-bιs(4-hydroxyphenyl)ιsoxazol4-yl]-N-(2-phenylethyl)carboxamιde This compound was synthesized as described in Section 4 1 2 69 except, in step 5, benzethyl amine was used for amide bond formation Η NMR (d 6 -DMSO) δ 2 75 (2H, d, 7=7 23Hz), 7 46 (2H, d, 7=6 72Hz), 6 84 (2H, d, 7=8 61 Hz) 6 88 (2H, d, 7=8 61 Hz), 7 12-7 20 (3H, m), 7 23-7 26 (2H, m), 7 49 (2H, d.7=8 61 Hz), 7 56 (2H. d, 7=8 79Hz), 8 76 (IH, t, 7=5 49Hz), 9 86 (I H, s), 10 10 (I H. s), ESMS m/z 401 (M+H). C, 4 H 20 N 2 O 4 = 400 g/mol, HPLC purity = 82 0% 4 1 273 Synthesis of [3 5-bιs(4-hydroxyphenyl)ιsoxazol-4-yl]-N-[(4-hydroxyphenyl)methyl] carboxamide This compound was synthesized as described in Section 4 1 2 69 except, in step 5, -methoxybenzyl amine was used for amide bond formation Η NMR (d 6 -DMSO) δ 4 28 (2h, d, 7=5 86Hz), 6 68 (2H, d, 7=8 43Hz), 6 79 (2H, d, 7=8 79Hz), 6 82 (2H, d, 7=8 79Hz), 7 03 (2H, d, 7=8 24Hz), 7 49 (2H, d, 7=8 97Hz), 7 55 (2H, d,7=8 79Hz), 9 08 (IH, t, 7=5 86Hz), 9 87 (IH, s), 10 10 (IH, s), ESMS m/z 403 (M+H), C 23 H 18 N 2 0 5 = 402 g mol, HPLC purity = 93 0% 4 1 274 Synthesis of [3,5-bιs(4-hydroxyphenyl)ιsoxazol-4-yl]-N-(3-pyπdylmethyl)carboxamιde This compound was synthesized as described in Section 4 1 2 69 except, in step 5, 3-pyndylmethylamιne was used for amide bond formation Η NMR (d 6 -DMSO) δ 4 42 (2H d, 7=5 86Hz), 6 79 (2H, d, 7=8 79Hz), 6 84 (2H, d, 7=8 61 Hz), 7 34 (2H, dd, 7=7 69Hz, 4 76Hz), 7 46 (2H, d, 7=8 61Hz), 7 53 (2H, d, 7=8 79Hz), 7 62 (2H, d, 7=7 69Hz), 928 (IH, t, 7=5 86Hz), 9 95 (IH, s), 10 20 (IH, s), ESMS m/z 388 (M+H), C 22 H 17 N 3 0 4 = 387 g/mol, HPLC purity = 92 7% 4 1 2 75 Synthesis of [3,5-bιs(4-hydroxyphenyl)ιsoxazol-4-yl]-N-(2-pyrιdylmethyl)carboxamιde This compound was synthesized as described in Section 4 1 2 69 except, in step 5, 2-pyndylmethylamme was used for amide bond formation Η NMR (d 6 -DMSO) δ 4 49 (2H, d, 7=6 04Hz), 6 82 (2H, d, 7=8 61Hz), 6 86 (2H, d, 7=8 61Hz), 7 21 (IH, d, 7=7 88Hz), 7 29 (IH, dd, 7=6 8Hz, 5 OHz), 7 55 (2H, d, 7=8 79Hz), 7 63 (2H, d, 7=8 79Hz), 7 71 (IH, td, 7=7 5Hz, 1 65Hz), 8 51 (IH, d, 7=4 03Hz), 9 29 (IH, t, 7=5 86Hz), 9 86 (IH, s), 10 10 (IH, s), ESMS m/z 388 (M+H), C 22 H, 7 N 3 0 4 = 387 g/mol, HPLC purity = 91 9% 4 1 276 Synthesis of [3,5-bιs(4-hydroxyphenyl)ιsoxazol-4-yl]-N,N-dιmethylcarboxamιde This compound was synthesized as described in Section 4 1 2 69 except, in step 5, N,N-dιmethylamιne was used for amide bond formation Η NMR (d 6 -DMSO) δ 2 72 (3H, s), 6 90 (2H, d, 7=8 79Hz), 6 94 (2H, d, 7=8 79Hz), 746 (2H, d, 7=861Hz), 7 54 (2H, d, 7=8 79Hz), 10 04 (IH, s), 10 28 (IH, s), ESMS m/z 325 (M+H), C, 8 H, 6 N,0 4 = 324 g/mol, HPLC purity = 95 6% 4 1 277 Synthesis of [3,5-bιs(4-hydroxyphenyl)ιsoxazol-4-yl]-N-ethylcarboxamιde This compound was synthesized as described in Section 4 1 2 69 except, in step 5, ethylamine was used for amide bond formation Η NMR (dβ-DMSO) δ 2 49 (3H, t.7=l 83Hz). 3 18-3 25 (2H, m), 6 86 (2H, d.7=8 61 Hz), 6 91 (2H, d, 7=8 79Hz), 7 55 (2H, d, 7=8 79Hz), 7 62 (2H, d.7=8 79Hz), 8 64 (I H. t, 7=5 49Hz), 9 87 (I H, s) 10 10 (IH, s), ESMS m/z 325 (M+H), C 18 H, 6 N 2 0 4 = 324 g mol, HPLC purity = 95 1% 4 1 278 Synthesis of 3,5-bιs(4-hydroxyphenyl)ιsoxazol-4-yl 4-(2-pyrrolιdιnylethoxy)phenyl ketone This compound was synthesized as described Section 4 1 2 20 except, in step 6, (2-chloroethyi)pyrrolιdιne was used for alkylation LC/MS m/z 471 (MH+), C 28 H 26 N 2 0 5 = 470 g/mol, purity = 90% 4 1 279 Synthesis of 3,5-bιs(4-hydroxyphenyl)ιsoxazol-4-yl 4-(2-morpholιn-4-ylethoxy)phenyl ketone This compound was synthesized as described in Section 4 1 2 20 except, m step 6, 4-(2-chloroethyl)moφhohne was used for alkylation LC/MS m/z 487 (MH+), C 28 H 26 N 2 0 6 = 486 g/mol, purity = 90% 4 1 280 Synthesis of 3,5-bιs(4-hydroxyphenyl)ιsoxazol4-yl 4-[3-(dιmethylamιno)propoxy]phenyl ketone This compound was synthesized as described in Section 4 1 2 20 except, in step 6, (3-chloropropyl)dιmethylamιne was used for alkylation LC/MS m/z 459 (MH+), C 27 H 26 N 2 O s = 458 g/mol, purity = 90% 4 1 2 81 Synthesis of 4-[3-(dιethylamιno)propoxy]phenyl 3,5-bιs(4-hydroxyphenyl)ιsoxazol-4-yl ketone This compound was synthesized as described in Section 4 1 220 except, in step 6, (3-chloropropyl)dιefhylamιne was used for alkylation LC/MS m/z 487 (MH+), C 29 H 30 N 2 O 5 = 486 g/mol, purity = 90% 4 1 282 Synthesis of [3,5-bιs(4-hydroxyphenyl)ιsoxazol-4-yl]-N-cyclopropylcarboxamιde This compound was synthesized as described in Section 4 1 2 69except, in step 5, cyclopropylamme was used for amide bond formation Η NMR (d 6 -DMSO) δ 0 04-0 08 (2H. m), 0 34-0 37 (2H, m), 2 48-2 51 (IH m), 6 57 (2H, d, 7=8 61 Hz), 6 62 (2H, d, 7=8 79Hz), 7 23 (2H, d, 7=8 61 Hz), 7 30 (2H, d, 7=8 79Hz), 8 40-8 41 (IH, m), 9 64 (I H, s), 9 87 (IH, s), ESMS m/z 337 (M+H, C l9 H 16 N 2 0 4 = 336 g/mol, HPLC purity = 81 1% 4 1 283 Synthesis of [3,5-bιs(4-hydroxyphenyl)ιsoxazol4-yl]-N-cyclobutylcarboxamιde This compound was synthesized as described in Section 4 1 2 69 except, in step 5, cyclobutylamine was used for amide bond formation Η NMR (d 6 -DMSO) δ 1 59-1 67 (2H, m), 1 7«-l 88 (2H, m), 2 15-2 22 (2H, m), 4 31-4 37 (IH, m), 6 85 (2H. d. 7=8 59Hz), 6 90 (2H, d, 7=8 77Hz), 7 54 (2H, d, 7=8 59Hz), 7 60 (2H, d, 7=8 77Hz), 8 88 (IH, d, 7=7 59Hz), 9 87 (IH, s), 10 1 1 (IH, s), ESMS m/z 351 (M+H), C 20 H, 8 N 2 O 4 = 350 g/mol, HPLC purity = 98 0% 4 1 2 84 Synthesis of 4-[2-(dιethylamιno)ethoxy]phenyl 3,5-bιs(4-hydroxyphenyl)ιsoxazol-4-yl ketone This compound was synthesized as described in Section 4 1 2 20 except, in step 6, (2-chloroethyl)dιethylamιne was used for alkylation LC/MS m/z 473 (MH+), C 28 H 28 N 2 O s = 472 g/mol, purity = 90% 4 1 2 85 Synthesis of 3,5-bιs(4-hydroxyphenyl)ιsoxazol-4-yl 4-[2-(dιmethylamιno)ethoxy]phenyl ketone This compound was synthesized as described in Section 4 1 2 20 except, in step 6, (2- chloroethyl)dιmethylamιne was used for alkylation LC/MS m/z 445 (MH+), C 26 H 24 N 2 0 5 = 444 g/mol, purity = 90% 4 1 286 Synthesis of 3,5-bιs(4-hydroxyphenyl)ιsoxazol-4-yl 4-{2-[methylbenzylamιno]ethoxy}phenyl ketone This compound was synthesized as described in Section 4 1 220 except, m step 6, (2- chloroethyl)methylbenzylamιne was used for alkylation LC/MS m/z 521 (MH+), C 32 H 28 N 2 0 5 = 520 g/mol, purity = 90% 4 1 2 87 Synthesis of 2-(4-{[3,5-bιs(4-hydroxyphenyl)ιsoxazol-4-yl]carbonyl}phenoxy)-N,N-dιmethylacetamιde This compound was synthesized as described in Section 4 1 2 20 except, in step 6, 2-chloro-N,N- dimethylacetamide was used for alkylation LC MS m/z 459 (MH+), C 26 H 22 N 2 0 6 = 458 g/mol, purity = 90% 4 1 2 88 Synthesis of 3,5-bιs(4-hydroxyphenyl)ιsoxazol-4-yl 4-[2-(1 -methylpyrrolιdιn-2-yl)ethoxy]phenyl ketone This compound was synthesized as described in Section 4 1 2 20 except, in step 6, 2-(2-chloroethyl)-l- methylpyrrolidine was used for alkylation LC/MS m/z 485 (MH+), C 29 H 28 N 2 0 5 = 484 g/mol, purity = 90% 4 1 289 Synthesis of 3 5-bιs(4-hydroxyphenyl)ιsoxazol-4-yl 4-[(1-methyl(3-pιperιdyl))methoxy]phenyl ketone This compound was synthesized as described in Section 4 1 2 20 except, in step 6, 2-(chloromethyl)-l- methylpipeπdine was used for alkylation LC/MS m/z 485 (MH+), C 29 H 28 N 2 0 5 = 484 g/mol, purity = 90% 4 1 290 Synthesis of 3,5-bιs(4-hydroxyphenyl)ιsoxazol-4-yl 4-[3-(4-methylpιperazιnyl)propoxy]phenyl ketone This compound was synthesized as described in Section 4 1 2 20 except, in step 6, 1 -(2-chloroethyl)-4- methylpiperazine was used for alkylation LC/MS m/z 514 (MH+), C 30 H 31 N 3 O 5 = 513 g/mol, purity = 90% 4 1 291 Synthesis of 3,5-bιs(4-hydroxyphenyl)ιsoxazol4-yl 4-(1-methyl(4-pιperιdyloxy))phenyl ketone This compound was synthesized as described in Section 4 1 2 20 except, in step 6, 4-chloro- 1 -methylpipendme was used for alkylation LC/MS m/z 471 (MH+), C 28 H 26 N 2 0 5 = 470 g/mol, purity = 90% 4 1 292 Synthesis of 3-ethyl-4-[4-ethyl-3-(4-hydroxyphenyl)ιsoxazol-5-yl]phenol Synthesis of this compound was performed using the methods described in Scheme 7 Step 1 Synthesis of 1,3-diketone was following the same procedure as for Step 1 m Section 4 1 2 7 usmg /?-anιsyol chloride and l-(2-bromo-4-methoxyphenyl)butan-l-one as starting materials Step 2 Isoxazole formation was following the same procedure as for Step 4 m Section 4 1 2 7 to afford l-[5-(2- brorno-4-methoxyphenyl)-4-ethylιsoxazol-3-yl]-4-methoxybenzene Step 3 To a solution of phenylbromoisoxazole (1 eq , obtained from above step) in THF at -78 °C was added nBuLi (1 1 eq , 1 6 M in hexane) After the solution was stirred at -78°C for 1 5 h, it was added dropwise into a solution of the bromoethane (1 2 eq ) in THF at -78°C After 15 mm , the solution was allowed to warm to room temperature and stirred overnight After quenching reaction with 1 M HCl, the layers were separated and the aqueous layer extracted with EtOAc (χ3) The combined organic layers were washed with saturated NaHC0 3 ( l) and brine, dried over Na 2 S0 4 , filtered and concentrated to afford a crude product mixture Flash chromatography yielded the alkylated product Step 4 Demethylation was using Method 1 described for Step C of Scheme 1 Η NMR (αVacetone) δ 7 61 (dd, 7= 1 8. 8 8 Hz. 2H), 7 21 (d, 7 = 8 3 Hz, IH), 7 00 (dd, 7= 1 8, 8 8 Hz, 2H), 6 90 (d, 7= 2 3 Hz, IH), 6 83 (dd, 7= 2 3, 8 3 Hz, IH), 2 55 (q, 7= 7 4, 2H), 2 54 (q, 7= 74 Hz, 2H), 1 13 (t, 7 = 7 4 Hz, 3H), 0 96 (t, 7= 7 4 Hz, 3H), LC MS m/z 310 (MH+), C 19 H, 9 N0 3 = 309 g/mol, purity = 99% 4 1 2 93 Synthesis of 4-[4-ethyl-3-(4-hydroxyphenyl)ιsoxazol-5-yl]-3-methylphenol The compound was synthesized as described in Section 4 1 2 92 In Step 3, lodomethane was used as the electrophile Η NMR (d 6 -acetone) δ 7 60 (d, 7= 8 8 Hz, 2H), 7 22 (d, 7= 8 8 Hz, IH), 7 00 (d, 7 = 8 8 Hz, 2H), 6 87 (d, 7 = 2 3 Hz, IH), 6 82 (dd, 7= 8 3,2 3 Hz, IH), 2 55 (q, 7= 7 4 Hz, 2H), 2 22 (s, 3H), 0 95 (t, 7= 7 4 Hz, 3H), LC/MS m/z 296 (MH+), C 18 H l7 N0 3 = 295 g/mol, purity = 99% 4 1 2 94 Synthesis of 3-bromo-4-[4-ethyl-3-(4-hydroxyphenyl)ιsoxazol-5-yl]phenol This compound was synthesized by following the procedures described for Scheme 1 usmg /n-anisyol chloride and l-(2-bromo-4-methoxyphenyl)butan-l-one as starting materials Demethylation was using Method 1 described for Step C m Scheme 1 Η NMR (d 6 -acetone) δ 7 60 (d, 7 = 8 8 Hz, 2H), 7 37 (d, 7 = 8 8 Hz, IH), 7 28 (d, 7= 2 3 Hz), 7 02-6 99 (m, 3H), 2 56 (q, 7 = 7 4 Hz, 2H), 0 96 (t, 7 = 7 4 Hz, 3H), LC/MS m/z 360 (MH+), C, 7 H, 4 BrN0 3 = 359 g/mol, purity = 99% 4 1 295 Synthesis of 3-butyl-4-[4-ethyl-3-(4-hydroxyphenyl)ιsoxazol-5-yl]phenol The compound was synthesized as described Section 4 1 2 92 In step 3, 1 -bromobutane was used as the electrophile Η NMR (d 6 -acetone) δ 7 60 (d, 7= 8 8 Hz, 2H), 7 21 (d, 7= 8 3 Hz, IH), 7 00 (d, 7= 8 8 Hz, 2H), 6 89 (d, 7 = 2 3 Hz, IH), 6 83 (dd, 7= 8 3, 2 3 Hz, IH), 2 56 (2q, 7= 74 Hz, 4H), 1 53-1 45 (m, 2H), 1 30-1 22 (m, 2H), 0 96 (t, 7= 7 4 Hz, 3H), 0 84 (t, 7= 7 4 Hz, 3H), LC MS m/z 338 (MH+), C 21 H 23 N0 3 = 337 g/mol, purity = 99% 4 1 296 Synthesis of 4-[4-ethyl-3-(4-hydroxyphenyl)ιsoxazol-5-yl]-3-hexylphenol The compound was synthesized as described in Section 4 1 2 92 In Step 3, 1 -bromohexane was used as the electrophile Η NMR (d 6 -acetone) δ 7 60 (d, 7 = 8 8 Hz, 2H), 721 (d, 7 = 8 3 Hz, 1 H), 6 99 (d, 7 = 8 8 Hz, 2H), 6 90 (d, 7 = 2 3 Hz, IH), 6 82 (dd, 7= 8 3,2 3 Hz, IH), 2 56 (2q, 7 = 7 4 Hz, 4H), 1 52-1 46 (m, 2H), 1 29-1 22 (m, 6H), 0 96 (t, 7= 74 Hz, 3H), 0 83 (t, 7= 6 4 Hz, 3H), LC/MS m/z 366 (MH+), C 23 H 27 N0 3 = 365 g/mol, purity = 99% 4 1 2 97 Synthesis of 3-(2-bromopropyl)-4-[4-ethyl-3-(4-hydroxyphenyl)ιsoxazol-5-yl]phenol The compound was synthesized as described m Section 4 1 2 92 In Step 3 3-bromo-l-propene was used as the electrophile 1 H NMR (d 6 -acetone) δ 7 61 (d, 7 = 8 8 Hz, 2H), 7 28 (d, 7 = 8 3, 1 H), 7 02-6 99 (m, 3H), 6 92 (dd.7= 8 3, 2 7 Hz, lH), 4 31-4 27 (m, 1H), 3 14 (d, 7 = 6 9. 2H), 2 58 (q, 7 = 7 8 Hz, 2H), 1 62 (d, 7 = 6 5 Hz, 3H), 0 98 (t, 7 = 7 8 Hz, 3H), LC MS m/z 402 (MH+), C 20 H 20 BrNO 3 = 401 g/mol, purity = 96% 4 1 298 Synthesis of 3,5-bιs(4-hydroxyphenyl)ιgoxazole-4-carbaldehyde This compound was synthesized based upon Scheme 7 Step 1^1 Same as correspondmg steps in Section 4 1 2 20 Step 5 Weinreb amide formation 4-carboxy isoxazole (obtained from Steps 1-4 above) was dissolved in THF and activated with EDC HOBt DIEA (1 5 1 5 1 5) and allowed to stand at rt for 5mm N-methoxymethylamine (1 5 equiv ) was then added The reaction mixture was allowed to stand at rt overnight, after which it was diluted with EtOAc and washed with 10% citric acid, 10% NaHC0 3 , and brine The solvent was removed, and the residue was purified by flash chromatography (EtOAc / petrol) and lyophihzed m 90% MeCN/H 2 0 to give the desired product as a white powder Step 6 Reduction of the amide to aldehyde The Wemreb amide (obtained from step 5) was dissolved in THF and added to a suspension of LiAlK, (4equιv ) in THF at -78 °C The reaction was allowed to stir at -78 °C for 2 5 h and was quenched by dropwise addition of IM HCl The reaction mixture was then diluted with EtOAc and washed with 10% NaHC0 3 and brine After drying over Na 2 S0 4 , the solvent was removed and the residue was lyophihzed in 90% MeCN/H,0 Step 7 Demethylation was performed based upon Method 3 described for step C in Scheme 1 The above aldehyde was dissolved in DCM and cooled in an ice-bath BBr 3 (10 equiv ) was added and the reaction was allowed to stir at rt for 5 h The reaction was then cooled in an ice-bath and quenched with water EtOAc was added and the reaction was washed with water and brine After drying over Na 2 S0 4 , the solvent was removed and the residue was purified by flash chromatography (EtOAc/petrol) to yield pure product Η NMR (d 6 -DMSO) δ 6 85 (2h, d, 7=8 42Hz), 6 93 (2H, d, 7=8 61 Hz), 7 54 (2H, d, 7=8 42Hz), 7 88 (2H, d, 7=8 61 Hz), 9 81 (IH, s), ESMS m/z 282 (M+H), C 16 H„N0 4 = 281 g/mol, HPLC purity = 97 1% 4 1 299 Synthesis of 4-[4-ethyl-3-(4-hydroxyphenyl)ιsoxazol-5-yl]-3-ιodophenol The compound was synthesized as described in Section 4 1 2 92 In Step 3, iodine was used as the electrophile 'H NMR (d 6 -acetone) 5 7 61 (d, 7= 8 8 Hz, 2H), 7 54 (d, 7 = 2 3 Hz, IH), 7 31 (d, 7= 8 3 Hz, IH), 7 05 (dd, 7 = 8 3. 2 3 Hz, IH), 7 00 (d, 7= 8 8 Hz, 2H), 2 54 (q, 7 = 7 4 Hz, 2H), 0 98 (t, 7 = 7 4 Hz, 3H), LC/MS m/z 408 (MH+), C I7 H, 4 IN0 3 = 407 g/mol, purity = 99% 4 1 2 100 Synthesis of 3-chloro-4-[4-ethyl-3-(4-hydroxyphenyl)ιsoxazol-5-yl]phenol The compound was synthesized as described in Section 4 1 2 92 In Step 3, NCS was used as the electrophile Η NMR (d 6 -acetone) δ 7 60 (d 7= 8 8 Hz 2H). 7 39 (d, 7= 8 8 Hz IH) 7 10 (d, 7= 2 8 Hz, IH) 705-6 98 (m, 3H), 2 57 (q, 7= 7 8 Hz, 2H), 0 96 (t, 7 = 7 4 Hz, 3H), LC/MS m/z 316 (MH+), C 17 H 14 C1N0 3 = 315 g/mol, purity = 99% 4 1 2 101 Synthesis of 4-[4-ethyl-3-(4-hydroxyphenyl)ιsoxazol-5-yl]-2-fluorophenol This compound was synthesized by following Scheme 1 using /?-amsyol chloride and l-(3-fluoro-4- methoxyphenyl)butan-l-one as starting materials Demethylation was using Method 1 described for Step C Scheme 1 Η NMR (d 6 -acetone) δ, LC/MS m/z 300 (MH+), C, 7 H 14 FN0 3 = 299 g/mol, purity = 95% 4 1 2 102 Synthesis of 2-[4-ethyl-3-(4-hydroxyphenyl)ιsoxazol-5-yl]-5-hydroxybenzoιc acid The compound was synthesized as described in Section 4 1 2 92 In Step 3, ethyl chloroformate was used as the electrophile Η NMR (d 6 -acetone) δ 7 60-7 54 (m, 3H), 7 38 (s, IH), 7 20 (d, 7= 8 3 Hz, IH), 6 99 (d, 7= 8 8 Hz, 2H), 2 56 (q, 7= 7 8 Hz, 2H), 097 (t, 7= 74 Hz, 3H), LC/MS m/z 326 (MH+), C 18 H, 5 N0 5 = 325 g/mol, purity = 99% 4 1 2 103 Synthesis of ethyl 2-[4-ethyl-3-(4-hydroxyphenyl)ιsoxazol-5-yl]-5-hydroxybenzoate The compound was synthesized as described m Section 4 1 2 92 In Step 3, ethyl chloroformate was used as the electrophile Demethylation was following Method 3 described for Step C in Scheme 1 Η NMR (d 6 -acetone) δ 7 64 (d, 7= 8 8 Hz, 2H), 749 (d, 7= 2 8 Hz, IH), 7 34 (d, 7= 8 3 Hz, IH), 7 19 (dd, 7 = 8 3, 2 3 Hz, IH), 7 01 (d, 7= 8 8 Hz, 2H), 4 12 (q, 7= 7 4 Hz, 2H), 2 54 (q, 7= 7 4 Hz, 2H), 1 08 (t, 7= 7 4 Hz, 3H). 0 98 (t, 7= 7 4 Hz, 3H), LC/MS m/z 354 (MH+), C 20 H 19 NO 5 = 353 g/mol. purity = 99% 4 1 2 104 Synthesis of 4-[4-ethyl-3-(4-hydroxyphenyl)ιsoxazol-5-yl]-3-(methylsulfinyl)phenol The compound was synthesized as described m Section 4 1 2 92 In Step 3, methyl disulfide was used as the electrophile Η NMR (d 6 -acetone) δ 7 66 (d, 7 = 2 3 Hz, 1 H), 7 60 (d, 7 = 8 8 Hz, 2H), 7 50 (d, 7 = 8 3 Hz, 1 H), 7 15 (dd, 7 = 8 3, 2 3 Hz, IH), 701 (d, 7= 8 8 Hz, 2H), 2 83 (s, 3H), 2 64 (q, 7 = 7 4 Hz, 2H), 1 00 (t, 7= 74 Hz, 3H), LC/MS m/z 344 (MH+), C, 8 H 17 N0 4 S = 343 g/mol, purity = 99%) 4 1 2 105 Synthesis of 4-[4-ethyl-3-(4-hydroxyphenyl)ιsoxazol-5-yl]-3-sulfanylphenol The compound was synthesized as described in Section 4 1 2 92 In Step 3, methyl disulfide was used as the electrophile Demethylation was following Method 3 described for Step C in Scheme 1 Η NMR (αVacetone): δ 7.68 (d, 7= 2.3 Hz, IH), 7.60 (d, 7 = 8.8 Hz, 2H), 7.50 (d. 7= 8.3 Hz, IH). 7.15 (dd, 7 = 8.3, 2.3 Hz, IH), 7.01 (d, 7= 8.8 Hz, 2H), 2.65 (q, 7 = 7.4 Hz, 2H), 1.00 (t, 7 = 7.4 Hz, 3H); LC/MS m/z 314 (MH+), C 17 H 15 N0 3 S = 313 g/mol; purity = 87%. 4.1.2.106 Synthesis of 4-[4-ethyl-3-(4-hydroxyphenyl)isoxazol-5-yl]-2-methylphenol The compound was synthesized as described in Section 4.1.2.92. In Step 1 , /D-anisyol chloride and l-(3-bromo-4- methoxyphenyl)butan-l-one as starting materials. In Step 3, iodomethane was used as the electrophile. Η NMR (d6-acetone): δ 7.63 (d, 7= 8.8 Hz, 2H), 7.54 (d, 7= 8 Hz, IH), 7.42 (s, IH), 7.04-6.96 (m, 3H), 2.74 (q, 7= 7.4 Hz, 2H), 2.29, 2.28 (2s, 3H), 1.11 (t, 7= 7.4 Hz, 3H); LC/MS m/z 296 (MH+), C 18 H, 7 N0 3 = 295 g/mol; purity = 98%. 4.1.2.107 Synthesis of 2-butyl-4-[4-ethyl-3-(4-hydroxyphenyl)isoxazol-5-yl]phenol The compound was synthesized as described in Section 4.1.2.106. In Step 3, 1-bromobutane was used as the electrophile. Η NMR (dβ-acetone): δ 7.64 (d, 7= 8.8 Hz, IH), 7.54 (d, 7 = 8.8 Hz, 2H), 7.43 (s, IH), 7.04-6.98 (m, 3H), 2.74 (q, 7= 7.4 Hz, 2H), 2.72 (t, 7 = 7.4 Hz, 2H), 1.69-1.61 (m, 2H), 145-1.38 (m, 2H), 1.12 (t, 7= 7.4 Hz, 3H), 0.95 (t, 7 = 7.4 Hz, 3H); LC/MS m/z 338 (MH+), C 21 H 23 N0 3 = 337 g/mol; purity = 99%. 4.1.2.108 Synthesis of 2-ethyl-4-[4-ethyl-3-(4-hydroxyphenyl)isoxazol-5-yl]phenol The compound was synthesized as described in Section 4.1.2.106. In Step 3, bromoethane was used as the electrophile. Η NMR (d 6 -acetone): δ 7.64 (d, 7= 8.8 Hz, 2H), 7.54 (d, 7= 8.8 Hz, IH), 7.44 (d, 7= 2.3 Hz, IH), 7.01-6.97 (m, 3H), 2.75 (q, 7= 7.4 Hz, 2H), 2.73 (q, 7= 7.4 Hz, 2H), 1.24 (t, 7= 7.4 Hz, 3H), 1.13 (t, 7= 7.4 Hz, 3H); LC/MS m/z 310 (MH+), C !9 H, 9 N0 3 = 309 g/mol; purity = 99%. 4.1.2.109 Synthesis of 2-bromo-4-[4-ethyl-3-(4-hydroxyphenyl)isoxazol-5-yi]phenol This compound was synthesized by following Scheme 1 using p-anisyol chloride and l-(3-bromo-4- methoxyphenyl)butan-l-one as starting materials. Demethylation was performed using Method 1 described for Step C in Scheme 1. Η NMR (dβ-acetone): δ 7.89 (d, 7= 2.3 Hz, IH), 7.64 (d, 7 = 9.2 Hz, IH), 7.54 (d, 7= 8.8 Hz, 2H), 7.20 (dd, 7 = 14, 8.3 Hz, 1 H), 7.02 (dd, 7 = 0.9, 8.8 Hz, 2H), 2.75 (q, 7 = 7.5Hz, 2H), 1.12 (t, 7 = 7.9, 3H); LC/MS m/z 360 (MH+), C l7 H 14 BrN0 3 = 359 g/mol; purity = 99%. 4 1 2 110 Synthesis of 4-[3-(4-butanoyloxyphenyl)-4-ethylιsoxazol-5-yl]phenyl butanoate This compound was made as a derivative of the compound prepared according to Section 4 1 2 4 To a THF solution of 4-[4-ethyl-5-(4-hydroxyphenyl)ιsoxazol-3-yl]phenol was added butyryl chloride (3 0 eq ) and pyndine (3 0 eq ) The mixture was stirred at rt for 24 h, poured into cold NaHCO ^ , extracted with EtOAc The organic extracts were washed with brine, dried with Na 2 S0 4 and concentrated in vacuo to give the product as a white powder LC/MS m/z 422 (MH+), C 25 H 27 N0 5 = 421 g/mol, purity = 98% 4 1 2 111 Synthesis of 4-[3-(4-acetyloxyphenyl)-4-ethylιsoxazol-5-yl]phenyl acetate This compound was made as a derivative of the compound prepared according to Section 4 1 2 4 To a THF solution of 4-[4-ethyl-5-(4-hydroxyphenyl)ιsoxazol-3-yl]phenol was added acetyl chloride (3 0 eq ) and pyndine (3 0 eq ) The mixture was stirred at rt for 24 h, poured into cold NaHC0 3 , extracted with EtOAc The organic extracts were washed with brme, dried with Na 2 S0 and concentrated in vacuo to give the product as a white powder LC/MS m/z 366 (MH+), C 2 ,H l9 N0 5 = 365 g/mol, purity = 98% 4 1 2 112 Synthesis of 3-(4-butanoyloxyphenyl)naphtho[1 ,2-c]ιsoxazol-7-yl butanoate This compound was made as a derivative of the compound prepared as described in Section 4 1 2 32 To a THF solution of 3-(4-hydroxyphenyl)naphtho[l,2-c]ιsoxazol-7-ol was added butyryl chloride (3 0 eq ) and pyridme (3 0 eq ) The mixture was stirred at rt for 24 h, poured into cold NaHC0 3 , extracted with EtOAc The organic extracts were washed with brine, dried with Na S0 4 and concentrated in vacuo to give the product as a white powder LC/MS m/z 418 (MH+), C 25 H 23 N0 5 = 417 g/mol, purity = 98% 4 1 2 113 Synthesis of 3-(4-acetyloxyphenyl)naphtho[1 ,2-c]ιsoxazol-7-yl acetate This compound was made as a derivative of the compound prepared as described m Section 4 1 2 32 To a THF solution of 3-(4-hydroxyphenyl)naphtho[l,2-c]ιsoxazol-7-ol was added acetyl chloride (3 0 eq ) and pyndine (3 0 eq ) The mixture was stirred at rt for 24 h, poured into cold NaHC0 3 , extracted with EtOAc The organic extracts were washed with brine, dried with Na 2 S0 and concentrated in vacuo to give the product as a white powder LC/MS m/z 362 (MH+), C 2l H 15 N0 5 = 361 g/mol. purity = 98% 4 1 2 114 Synthesis of 3,5-bιs(4-methoxyphenyl)ιsoxazol-4-yl 4-(2-pιperιdylethoxy)phenyl ketone, chloride This compound was synthesized by following the methods outlined in Scheme 5 Steps 1-6 were performed as described in Section 4 1 2 20 Step 7 Formation of HCl salt The pure product obtained from Step 6 was dissolved in acetone To this solution was added at least 5 eq of cone HCl aq and an acetonιtπle/H20 (1 1) solution The mixture was then lyophihzed overnight to give the product as an off-white powder LC/MS m/z 360 (MH+), C, 7 H l4 BrN0 3 = 359 g/mol, purity = 99% 4 1 2 115 Synthesis of 4-[4-ethyl-3-(4-hydroxyphenyl)ιsoxazol-5-yl]-2-hexylphenol The compound was synthesized as described in Section 4 1 2 106 In Step 3 1 -bromohexane was used as the electrophile Η NMR (d 6 -acetone) δ 7 63 (d, 7= 8 8 Hz, 2H), 7 53 (d, 7= 8 8 Hz, IH), 743 (d, 7 = 23 Hz, IH), 704-7 97 (m, 3H), 2 76-2 68 (m, 4H), 1 74-1 62 (m, 2H), 1 36-1 33 (m, 6H), 1 12 (t, 7 = 7 8 Hz, 3H), 0 91 (t, 7= 7 4 Hz, 3H), LC/MS m/z 366 (MH+), C 23 H 27 N0 3 = 365 g/mol, purity = 99% 4 1 2 116 Synthesis of 2-chloro-4-[4-ethyl-3-(4-hydroxyphenyl)ιsoxazol-5-yl]phenol The compound was synthesized as described in Section 4 1 2 106 In step 3, NCS was used as the electrophile ! H NMR (d 6 -acetone) δ 7 67-7 50 (m, 4H), 7 20 (d, 7= 8 3 Hz, IH), 7 03 (d, 7= 8 8 Hz, 2H), 2 76 (q, 7= 74 Hz, 2H), 1 13 (t, 7= 7 4 Hz, 3H), LC/MS m/z 315 (MH+), C, 7 H 14 C1N0 3 = 314 g/mol, purity = 95% 4 1 2 117 Synthesis of 5-[4-ethyl-5-(4-hydroxyphenyl)ιsoxazol-3-yl]pyrιdιn-2-ol This compound was synthesized by following Scheme 1 , using p-anisyol chloride and methyl 6-mefhoxypyπdιne- 3 -carboxy late as starting materials Demethylation was using Method 1 described for Step C in Scheme 1 Η NMR (d 6 -DMSO) δ 10 04 (one isomer s, IH), 9 87 (other isomer s, IH) 7 78-6 47 (m, 7H), 2 64 (q, 7 = 7 50 Hz, 2H), 1 08 (one isomer t, 7 = 7 50 Hz, 3H), i 02(other isomer t 7= 7 50 Hz, 3H), LCMS m'z 283 (MH + ), CieHπNsO, = 282 g/mol, purity = 99% 4 1 2 118 Synthesis of ethyl 5-[4-ethyl-3-(4-hydroxyphenyl)ιsoxazol-5-yl]-2-hydroxybenzoate The compound was synthesized as described in Section 4 1 2 106 In Step 3, chloro ethylformate was used as the electrophile Demethylation was following Method 3 described for Step C m Scheme 1 Η NMR (d 6 -acetone) δ 7 89 (d, 7= 8 8 Hz IH), 7 65 (d, 7 = 8 8 Hz, 2H), 7 55 (d, 7= 8 8 Hz, IH), 7 17 (d, 7 = 8 8 Hz, IH), 7 04 (d, 7= 8 8 Hz, 2H), 448 (q, 7= 7 1 Hz, 2H), 2 76 (q, 7 = 7 4 Hz, 2H), 1 44 (t, 7 = 7 6 Hz, 3H), 1 16 (t, 7 = 7 6 Hz. 3H), LC/MS m/z 354 (MH+), C, 0 H ]8 NO 5 = 353 g/mol purity = 91% 4 1 2 119 Synthesis of 35-bιs(4-hydroxyphenyl)ιsoxazol-4-yl 4-methylphenyl ketone This compound was synthesized by following the procedure described in Scheme 7 Steps, 1-3 were performed as described in Section 4 1 2 20 Step 4 Again, this step was performed as described in Step 4 of Section 4 1 2 20 except p-toluoyl chloride was used for acylation Step 5 Demethylation was following Method 3 described for Step C in Scheme 1 Η NMR (d 6 -DMSO) δ 2 26 (3H, s), 6 70 (2H, d, 7=8 8Hz), 6 76 (2H, d, 7=9 OHz), 7 19 (2H, d, 7=8 OHz), 726 (2H, d, 7=8 8Hz), 7 39 (2H, d, 7=9 OHz), 7 63 (2H, d, 7=8 2Hz), 9 92 (IH, s,br), ESMS m/z 372 (M+H), C 2j H, 7 N0 = 371 g/mol, HPLC purity = 98% 4 1 2 120 Synthesis of 3,5-bιs(4-hydroxyphenyl)ιsoxazol-4-yl 2-chlorophenyl ketone This compound was synthesized as described in Section 4 1 2 119 In Step 4, o-chlorobenzoyl chloride was used for acylation Η NMR (d 6 -DMSO) δ 6 67 (2H, d. 7=8 8Hz) 6 75 (2H, d, 7=8 8Hz), 7 18 (IH, ddd, 7=7 8, 7 2, 1 3Hz), 7 24-7 27 (lH, m), 7 24 (2H, d, 7=8 8Hz), 7 31 (IH, ddd, 7=7 8, 7 2, 1 8Hz), 7 46 (IH, dd, 7=7 8, 1 3Hz), 7 51 (2H, d, 7=9 OHz), 9 77 (IH, s,br), ESMS m/z 392 (M+H), C 22 H, 4 C1N0 4 = 391 g mol, HPLC purity = 97% 4 1 2 121 Synthesis of 3,5-bιs(4-hydroxyphenyl)ιsoxazol-4-yl 3-chlorophenyl ketone This compound was synthesized as described in Section 4 1 2 119 In Step 4, m-chlorobenzoyl chloride was used for acylation Η NMR (d 6 -DMSO) 5 6 71 (2H, d, 7=8 8Hz), 6 77 (2H, d, 7=8 6Hz), 725 (2H, d, 7=8 8Hz), 735 (IH, t, 7=7 8Hz), 743 (2H, d, 7=8 8Hz), 7 57 (IH, ddd, 7=8 0, 22, 1 OHz), 7 61 (IH, dt, 7=7 8, 1 2Hz), 7 70 (IH, t, 7=1 8Hz), 9 81 (IH, s), 10 14 (IH, s), ESMS m/z 392 (M+H), C 22 H I4 C1N0 4 = 391 g/mol, HPLC purity = 86% 4 1 2 122 Synthesis of 3,5-bιs(4-hydroxyphenyl)ιsoxazol-4-yl 4-chlorophenyl ketone This compound was synthesized as described in Section 4 1 2 119 In Sep 4, /?-chlorobenzoyl chloride was used for acylation Η NMR (d 6 -DMSO) δ 6 71 (2H, d, 7=8 8Hz), 6 77 (2H, d, 7=8 8Hz), 725 (2H, d, 7=8 8Hz), 741 (2H, d, 7=8 8Hz), 7 42 (2H, d, 7=8 8Hz), 7 72 (2H, d, 7=8 8Hz), 9 82 (IH, s), 10 14 (IH, s), ESMS m/z 392 (M+H), C 22 H 14 C1N0 4 = 391 g/mol. HPLC purity = 90% 4 1 2 123 Synthesis of 3 5-bιs(4-hydroxyphenyl)ιsoxazol-4-yl 2-fluorophenyl ketone This compound was synthesized as described in Section 4 1 2 1 19 In Step 4, o-fluorobenzoyl chloride was used for acylation 'H NMR (d 6 -DMSO) δ 6 68 (2H, d, 7=8 8Hz), 6 77 (2H, d, 7=9 OHz) 7 01 ( I H, dd, 7=1 1 1 , 8 2Hz), 7 13 ( I H. td 7=7 8. 1 OHz), 7 25 (2H, d, 7=8 8Hz), 7 42-7 48 (IH, m), 7 51 (2H, d, 7=8 8Hz), 7 59 (IH, td, 7=6 8, 1 8Hz), 9 89 (IH, s,br), ESMS m/z 376 (M+H), C 22 H 14 FN0 4 =375 g/mol, HPLC purity = 98% 4 1 2 124 Synthesis of 3,5-bιs(4-hydroxyphenyl)ιsoxazol-4-yl 3-nιtrophenyl ketone This compound was synthesized as described in Section 4 1 2 1 19 In Step 4, /w-mtrobenzoyl chloride was used for acylation Η NMR (d 6 -DMSO) δ 6 68 (2H, d, 7=8 4Hz), 6 75 (2H, d, 7=8 8Hz), 7 26 (2H, d, 7=8 4Hz), 7 47 (2H, d, 7=8 6Hz), 7 59 (IH, t, 7=8 OHz), 8 06 (IH, dd, 7=7 8, 1 2Hz), 8 29 (IH, dd.7=8 2, 2 3Hz), 8 36 (IH, t, 7=2 OHz), 9 89 (IH, s,br), ESMS m/z 403 (M+H), C 22 H, 4 N 2 0 6 = 402 g/mol, HPLC purity = 95% 4 1 2 125 Synthesis of 3,5-bιs(4-hydroxyphenyl)ιsoxazol-4-yl 4-nιtrophenyl ketone This compound was synthesized as described in Section 4 1 2 119 In Step 4, p-nitrobenzoyl chloride was used for acylation Η NMR (d 6 -DMSO) δ 6 70 (2H, d, 7=8 8Hz), 6 76 (2H, d, 7=8 8Hz), 7 25 (2H, d, 7=8 8Hz), 7 44 (2H, d, 7=8 8Hz), 7 93 (2H, d, 7=9 OHz), 8 1 1 (2H, d, 7=8 8Hz), 9 90 (IH, s,br), ESMS m/z 403 (M+H), C 22 H, 4 N 2 0 6 = 402 g/mol, HPLC purity = 93% 4 1 2 126 Synthesis of 3,4-dιchlorophenyl 3,5-bιs(4-hydroxyphenyl)ιsoxazol-4-yl ketone This compound was synthesized as described in Section 4 1 2 119 In Step 4, 3,4-dιchloro-benzoyl chloride was used for acylation Η NMR (d 6 -DMSO) δ 6 71 (2H, d, 7=8 8Hz), 6 78 (2H, d, 7=9 OHz), 7 25 (2H, d, 7=8 8Hz), 7 44 (2H, d, 7=8 8Hz), 7 58 (IH, d, 7=8 4Hz), 7 62 (IH, dd, 7=8 4, 2 OHz), 7 88 (IH, d. 7=2 OHz), 9 82 (IH, s), 10 16 (IH, s), ESMS m/z 426 (M+H), C 22 H ]3 C1 2 N0 4 = 425 g/mol, HPLC purity = 96% 4 1 2 127 Synthesis of 3,5-bιs(4-hydroxyphenyl)ιsoxazol-4-yl 4-butylphenyl ketone This compound was synthesized as described in Section 4 1 2 1 19 In Step 4, p-n-butylbenzoyl chloride was used for acylation Η NMR (d 6 -DMSO) δ 0 80 (3H, t, 7=7 4Hz), 1 16-1 24 (2H, m), 1 40-1 50 (2H, m), 2 53 (2H, t, 7=7 6Hz), 6 70 (2H, d, 7=8 8Hz), 6 75 (2H, d, 7=9 OHz), 7 19 (2H, d, 7=8 6Hz), 7 26 (2H, d, 7=8 8Hz), 7 39 (2H, d, 7=8 8Hz), 7 63 (2H, d, 7=8 4Hz), ESMS m/z 4 \4 (M+H), C 26 H 23 N0 4 = 413 g/mol, HPLC purity = 92% 4 1 2 128 Synthesis of 3 5-bιs(4-hydroxyphenyl)ιsoxazol-4-yl 4-(tert-butyl)phenyl ketone This compound was synthesized as described in Section 4 1 2 1 19 In Step 4, -t-butylbenzoyl chloride was used for acylation Η NMR (d 6 -DMSO) δ 1 18 (9H, s), 6 71 (2H, d, 7=8 8Hz), 6 76 (2H. d 7=8 8Hz), 7 28 (2H, d, 7=8 8Hz), 7 39 (2H, d, 7=9 OHz), 740 (2H, d.7=8 8Hz), 7 66 (2H, d, 7=8 6Hz), 9 81 (IH. s), 10 10 (IH, s), ESMS m/z 414 (M+H), C 26 H 23 N0 4 = 413 g/mol, HPLC purity = 98% 4 1 2 129 Synthesis of 3,5-bιs(4-hydroxyphenyl)ιsoxazol-4-yl 3-hydroxyphenyl ketone This compound was synthesized as described in Section 4 1 2 119 In Step 4, /«-anιsoyl chloride was used for acylation Η NMR (d 6 -DMSO) δ 6 68-6 72 (IH, m), 6 71 (IH, d, 7=8 8Hz), 6 77 (2H, d, 7=8 8Hz), 6 83 (IH, dd, 7=8 2, 0 6Hz), 7 27 (2H, d, 7=8 8Hz), 7 34-7 40 (2H, m), 7 43 (2H, d.7=8 8Hz), 9 80 (IH, s), 10 1 1 (IH, s), 11 00 (IH, s), ESMS m/z 374 (M+H), C 22 H 15 NO, = 373 g/mol, HPLC purity = 95% 4 1 2 130 Synthesis of 3,5-bιs(4-hydroxyphenyl)ιsoxazol-4-yl 2-hydroxyphenyl ketone This compound was synthesized as described in Section 4 1 2 1 19 In Step 4, o-anisoyl chloride was used for acylation Η NMR (d 6 -DMSO) δ 6 71 (2H, d, 7=8 8Hz), 6 77 (2H, d, 7=8 8Hz), 6 93 (IH, ddd, 7=7 6, 2 6, 1 6Hz), 7 11-7 19 (3H, m), 7 27 (2H, d, 7=8 8Hz), 7 39 (2H, d, 7=8 8Hz), 9 75 (IH, s), 9 83 (IH, s), 10 13 (IH, s), ESMS m/z 374 (M+H), C 22 Hi 5 NO s = 373 g/mol, HPLC purity = 96% 4 1 2 131 Synthesis of 3,5-bιs(4-hydroxyphenyl)ιsoxazol-4-yl phenyl ketone This compound was synthesized as described in Section 4 1 2 1 19 In Step 4, benzoyl chloride was used for acylation Η NMR (d 6 -DMSO) δ 6 69 (2H, d, 7=8 8Hz), 6 75 (2H, d, 7=8 8Hz), 7 26 (2H, d, 7=8 8Hz), 740 (2H, d, 7=8 8Hz), 7 53 (IH, t, 7=7 5Hz), 7 72 (2H, dd, 7=8 3. 1 2Hz), 9 80 (IH, s), 10 1 1 (I H, s), ESMS m/z 358 (M+H), C 22 H 15 N0 4 = 357 g/mol, HPLC purity = 93% 4 1 2 132 Synthesis of 3,5-bιs(4-hydroxyphenyl)ιsoxazol-4-yl 4-methoxyphenyl ketone This compound was synthesized as described in Section 4 1 2 1 19 In Step 4, -anisoyl chloride was used for acylation Η NMR (d 6 -DMSO) δ 3 77 (3H, s) 6 71 (2H, d 7=9 OHz) 6 77 (2H. d 7=9 OHz), 6 91 (2H d 7=8 8Hz). 7 28 (2H, d, 7=9 OHz) 7 39 (2H, d, 7=9 OHz), 7 72 (2H, d 7=9 OHz), 9 80 (IH, s), 10 12 (IH s), ESMS m/z 388 (M+H), C 23 H 17 NO, = 387 g/mol. HPLC purity = 97% 4 1 2 133 Synthesis of 4-[4-ethyl-3-(4-hydroxyphenyl)ιsoxazol-5-yl]-3-phenylthιophenol The compound was synthesized as described in Section 4 1 2 92 In Step 3, phenyl disulfide was used as the electrophile Η NMR (d 6 -acetone) δ 7 58 (d, 7 = 8 8 Hz, 2H), 7 42-7 38 (m, 5H), 7 32 (d, 7= 8 3 Hz, IH), 6 99 (d, 7= 8 8 Hz, 2H), 6 87 (dd, 7= 2 8, 8 5 Hz, IH), 6 68 (d, 7 = 2 3 Hz, IH), 2 56 (q, 7= 7 4 Hz, 2H), 0 97 (t, 7= 7 4 Hz, 3H) LC/MS m/z 390 (MH+), C 23 H, 9 N0 3 S = 389 g/mol, purity = 95% 4 1 2 134 Synthesis of 5-[4-ethyl-3-(4-hydroxyphenyl)ιsoxazol-5-yl]-2-hydroxybenzamιde The compound was synthesized as described in Section 4 1 2 106 In Step 3, tosyl nitrile was used as the electrophile Η NMR (d 6 -acetone) 5 7 71 (dd, 7= 2 3, 8 3 Hz, IH), 7 64 (d, 7= 8 8 Hz, 2H), 7 54 (d, 7= 2 3 Hz, IH), 7 07- 6 99 (m, 3H), 2 76 (q, 7 = 7 4 Hz, 2H), 1 09 (t, 7= 7 4 Hz, 3H), LC/MS m/z 325 (MH+), C 18 H 16 N 2 0 4 = 324 g/mol, purity = 99% 4 1 2 135 Synthesis of 4-[4-ethyl-3-(4-hydroxyphenyl)ιsoxazol-5-yl]-2-phenylthιophenol The compound was synthesized as described in Section 4 1 2 106 In Step 3, phenyl disulfide was used as the electrophile 'H NMR (d 6 -acetone) δ 7 59-7 36 (m, 9H) 7 14 (d 7=8 3 Hz, IH), 7 01 (d, 7= 8 8 Hz, 2H), 2 63 (q, 7=7 4 Hz 2H), 1 02 (t, 7= 7 4 Hz, 3H) LC/MS m/z 390 (MH+), C 23 H 19 NO-S = 389 g/mol, purity = 99% 4 1 2 136 Synthesis of 4-[4-ethyl-3-(4-hydroxyphenyl)ιsoxazol-5-yl]-2-methylthιophenol The compound was synthesized as described in Section 4 1 2 106 In Step 3, methyl disulfide was used as the electrophile Η NMR (d 6 -acetone) δ 7 64 (d, 7= 8 8 Hz, 1), 7 54 (d, 7= 8 8 Hz, 2H), 7 37 (d, 7= 2 3 Hz, IH), 7 07-6 99 (m, 3H), 2 76 (q, 7= 7 4 Hz, 2H), 2 50, 2 47 (2s, 3H), 1 14 (t, 7 = 7 4 Hz, 3H), LC/MS m/z 328 (MH+) C, 8 H 17 N0 3 S = 327 g/mol, purity = 99% 4 1 2 137 Synthesis of 4-[4-ethyl-3-(4-hydroxyphenyl)ιsoxazol-5-yl]-3-phenylphenol The compound was synthesized as described in Section 4 1 2 92 Steps 1 and 2 were performed as described in Section 4 1 2 92 Step 3 Suzuki coupling was used to introduce the phenyl ring The isoxazole obtained from Step 2 was dissolved in toluene and degassed with argon for 10 mim To this solution was added Pd(PPh 3 ) 4 (4 0 mol %) After an additional 10 mim, Na 2 C0 3 (5 eq ) was added followed by a solution of phenyl boronic acid (1 1 rq ) in ethanol The reaction was heated to reflux and stirred for 16 h The reaction mixture was then poured into a separatory funnel and the aqueous layer extracted twice with ethyl acetate The organic layers were combmed, washed with a brine solution and dried over Na 2 S0 Purification by flash chromatography (40% ethyl acetate/hexanes) yielded the product Step 4 Demethylation of the product of Step 3 was performed as described in Method 3 of Step C in Scheme 1 Η NMR (d 6 -acetone) 5 7 45-7 40 (m, 3H), 7 32-7 25 (m, 5H), 7 03-7 01 (m, 2H), 6 93 (d, 7= 7 8 Hz, 2H), 2 15 (q, 7= 7 4 Hz, 2H), 0 63 (t, 7= 7 4 Hz, 3H), LC/MS m/z 358 (MH+), C 23 H, 9 N0 3 = 357 g/mol, purity = 99% 4 1 2 138 Synthesis of {4-[4-ethyl-3-(4-hydroxyphenyl)ιsoxazol-5-yl]phenyl}(methylsulfonyl)amιne This compound was synthesized by following the procedures described here Step 1 Synthesis of 1,3-diketone This was performed as described in Step 1 of Section 4 1 2 7 except 4'- methoxybutyrylphenone and methyl 4-nιtrobenzoyl chloride were used as the starting materials Step 2 Isoxazole formation using the above diketone was performed as described as Step 4 of Section 4 1 2 7 Step 3 Reduction of nitro group to aniline was achieved by Pd-catalyzed hydrogenation To a solution of product obtained from Step 2 in ethanol was added catalytic amount 10% Pd on charcoal This mixture was stirred under hydrogen (balloon) overnight, filtered through cehte and washed with ethyl acetate The filtrate was concentrated in vacuo The residue was purified by flash column chromatography to afford product 4-[4-ethyl-3-(4- methoxyphenyl)ιsoxazol-5-yl]phenviamιne Step 4 To a DCM solution of the above aniline was added methanesulfonyl chloride (2 0 eq ) and pyndine (3 0 eq ) The mixture was stirred at rt for 4 h, poured into water and extracted with ethyl acetate The organic layers were combined, washed with brme and dried over Na 2 S0 4 Purification by flash chromatography yielded the product {4-[4-ethyl-3-(4-methoxyphenyl)ιsoxazol-5-yl]phenyl}(methylsulfonyl)amιne Step 5 Demethylation was following Method 2 described for Step C in Scheme 1 Η NMR (CDC1 3 ) δ 7 74-7 50 (m, 4H), 7 32-7 15 (m, 2H), 6 95-6 88 (m, 2H), 3 06 (m, 3H), 2 68 (m, 2H), 1 14 (m, 3H), LC/MS m/z 359 (MH+), C 18 H, 8 N 2 0 4 S = 358 g/mol, purity = 99% 4 1 2 139 Synthesis of 5-[4-ethyl-3-(4-hydroxyphenyl)ιsoxazol-5-yl]-2-methoxybenzamιde This compound was synthesized as described in Section 4 1 2 134 Partial demethylation of the product afforded 5- [4-ethyl-3-(4-hydroxyphenyl)ιsoxazol-5-yl]-2-methoxybenzamιde by following the progress of the reaction using thin-layer chromatography Η NMR (d 6 -acetone) δ 8 42 (d, 7 = 2 3 Hz, IH), 7 84 (dd, 7 = 8 8, 2 9 Hz. IH), 7 65 (d.7= 8 8 Hz, 2H), 7 36 (d, 7 = 8 8 Hz, IH), 7 04 (d, 7= 8 8 Hz, 2H), 4 12, 4 11 (2s, 3H), 2 77 (q, 7= 7 4 Hz, 3H), 1 15 (t, 7= 74 Hz, 3H), LC/MS m/z 339 (MH+), Cι 9 H 18 N 2 0 4 = 338 g/mol, purity = 99% 4 1 2 140 Synthesis of 5-[4-ethyl-3-(4-methoxyphenyl)ιsoxazol-5-yl]-2-hydroxybenzamιde This compound is the regioisomer of the compound prepared as described in Section 4 1 2 139 Both regioisomers were obtained using the methods described in that Section and the two regioisomers were separated by HPLC using a C 18 column (Relιasιl-BDXC18, 10 x 50 mm, Ranin Dynamax) running a first buffer of H 2 O/0 1% TFA and a second buffer of HCN/0 1% TFA through a gradient from 5-95% of the second buffer over a nine-minute period at a flow rate often ml/mm Η NMR (d 6 -acetone) δ 8 06 (s, IH), 7 65 (d, 7= 8 8 Hz, IH), 7 55 (d, 7= 8 8 Hz, 2H), 7 45 (d, 7= 8 8 Hz, IH), 7 01 (d, 7 = 8 8 Hz, 2H), 4 08, 4 07 (2s, 3H), 2 78 (q, 7 = 7 4 Hz, 2H), 1 12 (t, 7= 7 4 Hz, 3H), LC/MS m/z 339 (MH+), C l9 H 18 N 2 0 4 = 338 g/mol, purity = 99% 4 1 2 141 Synthesis of 3,5-bιs(4-hydroxyphenyl)ιsoxazol-4-yl 3-(2-pιperιdylethoxy)phenyl ketone, chloride This compound was synthesized as described in Section 4 1 2 20 In Step 4, 3-allyloxybenzoyl chloride for acylation Η NMR (d 6 -DMSO) δ 10 28 (s, IH), 9 96 (s, IH), 7 46 (d, 7 = 8 76 Hz, 2H), 7 36-7 30 (m, 5H), 7 24-7 20 (m, 1 H), 6 84 (d, 7 = 8 76 Hz, 2H), 6 78 (d, 7 = 8 76 Hz. 2H), 4 40-4 30 (br, 2H), 3 50-3 40 (m 4H), 3 00-2 90 (m 2H), 1 85-1 65 (m, 6H), LC/MS m/z 485 (MH+), C 29 H 28 N 2 0 5 = 484 g/mol, purity = 95% 4 1 2 142 Synthesis of 5-(4-hydroxyphenyl)-3-(4-methoxyphenyl)ιsoxazol-4-yl 3-(2-pιperιdylethoxy)phenyl ketone, chloride This compound was synthesized as described in Section 4 1 2 142 Partial demethylation afforded the mono- demethylated product by monitoring reaction progress by thin-layer chromatography Η NMR (d 6 -DMSO) δ 7 58 (one isomer d, 7 = 8 76 Hz, 2H), 7 48-7 42 (other isomer m, 2H), 740-728 (m, 5H), 7 28-7 18 (m, IH), 7 03 (one isomer d, 7 = 8 76 Hz, 2H), 6 97 (other isomer d, 7= 8 76 Hz, 2H), 6 83 (one isomer d, 7 = 8 76 Hz, 2H), 6 78 (other isomer d, 7 = 8 76 Hz, 2H), 4 40-4 30 (br, 2H), 3 78 (one isomer s, 2H), 3 75 (other isomer s, IH), 3 50-3 40 (br, 4H), 3 00-2 90 (m, 2H), 1 85-1 65 (m, 6H), LC/MS m/z 499 (MH+), C j0 H 30 N 2 O 5 = 498 g/mol, purity = 95% 4 1 2 143 Synthesis of 35-bιs(4-hydroxyphenyl)ιsoxazol-4-yl 3-(2-pyrrolιdιnylethoxy)phenyl ketone chloride This compound was synthesized as described in Section 4 1 2 141 In Step 6, N-(2-chloroethyl)pyrrolιdιne was used for alkylation Η NMR (d 6 -DMSO) δ 10 29 (s, IH), 9 97 (s. IH), 7 46 (d, 7 = 8 76 Hz, 2H), 7 36-7 30 (m, 5H), 7 25-7 20 (m, 1 H), 6 84 (d, 7 = 8 76 Hz, 2H), 6 78 (d, 7 = 8 76 Hz, 2H), 4 31 (br, 2H), 3 60-3 45 (m 4H). 3 15-3 00 (m, 2H), 2 10-1 80 (m, 4H), LC/MS m/z 471 (MH+), C 28 H 26 N 2 0 5 = 470 g/mol, purity = 99% 4 1 2 144 Synthesis of 3-[2-(dιethylamιno)ethoxy]phenyl 3,5-bιs(4-hydroxyphenyl)ιsoxazol-4-yl ketone, chloπde This compound was synthesized as described m Section 4 1 2 141 In Step 6, N-(2-chloroefhyl)dιefhylamιne was used for alkylation Η NMR (d 6 -DMSO) δ 10 31 (s, IH), 9 98 (s, IH), 7 46 (d, 7= 8 76 Hz, 2H), 7 36-7 30 (m, 5H). 7 24-7 20 (m, 1 H), 6 84 (d, 7 = 8 76 Hz, 2H), 6 78 (d, 7 = 8 76 Hz, 2H), 4 33 (br t, 2H,), 3 4 (m 2H), 3 19-3 14 (m, 4H), 1 25- 1 20 (t, 7= 7 14 Hz, 6H), LC/MS m/z 473 (MH+), C 28 H 28 N 2 0 5 = 472 g/mol, purity = 99% 4 1 2 145 Synthesis of 3,5-bιs(4-hydroxyphenyl)ιsoxazol4-yl 3-[(1-methyl(3-pιperιdyl))methoxy]phenyl ketone, chloride This compound was synthesized as described in Section 4 1 2 141 In Step 6, 2-(chloromefhyl)-l-methyl-pιperιdιne was used for alkylation Η NMR (d 6 -DMSO) δ 10 31 (s, IH), 998 (s, IH), 745 (d, 7= 8 76 Hz, 2H), 733-729 (m, 5H), 720-7 12 (m, IH), 6 84 (d, 7= 8 76 Hz, 2H), 6 78 (d, 7= 8 76 Hz, 2H), 3 93-3 74 (m, 2H), 3 50-3 40 (br d, 2H), 2 90-2 70 (m, 5H), 2 40-2 25(m, IH), 1 90-1 7 (m, 4H), LC MS m/z 485 (MH+), C 29 H 28 N 2 0 5 = 484 g/mol, purity = 99% 4 1 2 146 Synthesis of 3,5-bιs(4-hydroxyphenyl)ιsoxazol-4-yl 3-[2-(dιmethylamιno)ethoxy]phenyl ketone, chloride This compound was synthesized as described in Section 4 1 2 141 In Step 6, N-(2-chloroethyl)-dιmethylamme was used for alkylation Η NMR (d 6 -DMSO) δ 10 35 (s, IH), 10 02 (s, IH), 745 (d, 7= 8 76 Hz, 2H), 7 37-7 29 (m, 5H), 726-720 (m, IH), 6 86-6 83 (d, 7= 8 76 Hz, 2H), 6 85 (d, 7= 8 76 Hz 2H), 6 79 (d, 7= 8 76 Hz, 2H), 4 33 (t, 7= 4 61 Hz, 2H), 3 47 (t, 7= 4 61 Hz, 2H), 2 80 (s, 6H), LC/MS m/z 445 (MH+), C 26 H 24 N 2 O s = 444 g/mol, purity = 99% 4 1 2 147 Synthesis of 3-(4-hydroxyphenyl)-5-(4-methoxyphenyl)ιsoxazol4-yl 3-[(1-methyl(3-pιperιdyl))methoxy]phenyl ketone, chloride This compound was synthesized as described in Section 4 1 2 145 Partial demethylation afforded the mono- demethylated product by monitoring reaction progress by thin-layer chromatography Η NMR (d 6 -DMSO) δ 10 32 (one isomer s. I H), 9 98 (other isomer s, IH), 7 57 (one isomer d, 7 = 8 76 Hz, 2H), 7 44 (other isomer d. / = 8 76 Hz. 2H) 7 34-7 29 (m. 2H), 7 19-7 17 (m, IH) 7 03 (one isomer d, 7= 8 76 Hz. 2H), 6 97 (other isomer d, 7 = 8 76 Hz, 2H), 6 84 (one isomer d. 7 = 8 76 Hz. 2H), 6 80-6 76 (other isomer d 7= 8 76 Hz, 2H), 3 94-3 75 (m, 5H), 3 48-3 43 (br d, 2H) 2 90-2 70 (m 5H), 2 40-2 25 (m, I H), 1 84 (m, 4H), LC/MS m/z 499 (MH+), C j0 H 30 N 2 O, = 498 g/mol, purity = 93% 4 1 2 148 Synthesis of 3-[2-(dιmethylamιno)ethoxy]phenyl 3-(4-hydroxyphenyl)-5-(4-methoxyphenyl)ιsoxazol-4-yl ketone chloπde This compound was synthesized as described in Section 4 1 2 146 Partial demethylation afforded the mono- demethylated product by monitoring reaction progress by thin-layer chromatography Η NMR (d 6 -DMSO) δ 7 59-6 75 (m, 12H), 744 (other isomer d, 2H, 78 76), 4 31 (br, 2H), 3 78(one isomer s, 3H), 3 75 (other isomer s, 3H), 3 47 (br, 2H), 2 82 (s, 6H), LC/MS m/z 459 (MH+), C 27 H 26 N 2 0 5 = 458 g/mol, purity = 98% 4 1 2 149 Synthesis of 4-[4-ethyl-3-(4-hydroxy-2-methylphenyl)ιsoxazol-5-yl]-3-methylphenol This compound was synthesized by following the procedures described in Scheme 1 using 2'-methyl-4'- methoxyacetophenone and 2-methyl-4-methoxybenzoyl chloride as starting materials Η NMR (d 6 -Acetone) δ 7 24 (d, J = 8 29 Hz, IH, ArH), 7 19 (d, J = 8 29 Hz, IH, ArH), 6 87-6 79 (m, 4H, ArH), 2 31(q, J = 7 38 Hz, 2H, CH2), 2 24 (s, 3H, CH3), 2 22 (s, 3H, CH3), 0 82 (t, J = 7 38 Hz, 3H, CH2CH3), LC/MS m/z 310 (MH+), C, 9 H 19 N0 3 = 309 g/mol, purity = 95% 4 1 2 150 Synthesis of 4-[3-(4-hydroxyphenyl)-4-propylιsoxazol-5-yl]phenol This compound was synthesized based upon Scheme 4 Step 1-3 Same as the corresponding steps in Section 4 1 2 20 Step 4 Alkylation To a solution of 4-bromoιsoxazole (1 eq , obtained from step 3) in THF at -78 °C was added nBuLi (1 1 eq , 1 6 M in hexane) After the solution was stirred at -78°C for 1 5 h, it was added dropwise into a solution of the bromopropane(l 2 eq ) in THF at -78 °C After 15 mm , the solution was allowed to warm to room temperature and stirred overnight After quenching reaction with 1 M HCl, the layers were separated and the aqueous layer extracted with EtOAc (x3) The combined organic layers were washed with saturated NaHC0 3 (x 1 ) and brme, dried over Na 2 S0 4 , filtered and concentrated to afford a crude product mixture Flash chromatography yielded the alkylated product Step 5 Demethylation was performed using Method 3 for Step C in Scheme 1 Η NMR (CDCl 3 /DMSO, 6 1) δ 729 (d, J=8 60Hz, 2H), 7 18 (d, J=8 60Hz, 2H), 6 70 (d, J=8 40Hz, 2H). 6 68 (d, J=8 40Hz, 2H), 2 34-2 39 (m, 2H), 1 21-1 24 (m, 2H), 0 58 (t, J=7 23Hz, 3H), ESMS m/z 296 (MH+), C, 8 H, 7 N0 3 =295 g/mol. HPLC purity = 87 3% 4 1 2 151 Synthesis of 4-[3-(4-hydroxyphenyl)-4-prop-2-enylιsoxazol-5-yl]phenol This compound was synthesized in the same manner as Section 4 1 2 150, except, in step 4, allylbromide was used as the alkylatmg agent Η NMR (CDCl 3 /DMSO, 6 1) 5 9 10 (s, IH), 8 93 (s, IH), 7 23 (d, J=8 79Hz. 2H), 7 14 (d, J=8 79Hz, 2H), 6 59 (d, J=8 79Hz, 2H), 6 57 (d. J=8 79Hz, 2H), 5 69-5 78 (m, 1 H), 4 87 (d, J= 10 36Hz, 1 H), 4 71 (d, J= 17 19 Hz, 1 H), 3 01-3 02 (m, 2H), ESMS m/z 294 (MH+), C, 8 H I5 N0 3 =293 g mol HPLC purity = 80 8% 4 1 2 152 Synthesis of 4-[2-(dιethylamιno)ethylthιo]phenyl 35-bιs(4-hydroxyphenyl)ιsoxazol-4-yl ketone This compound was synthesized by following the procedures described in Scheme 6 Steps 1-3 were performed as described in Section 4 1 2.20 Step 4 Performed as described m Step 4 in Section 4 1 2 20 except 4-fluorobenzoyl chloride was used for acylation Step 5 In a THF suspension of sodium hydride (1 1 eq ) was added 2-dιethylamιno-ethane thiol The mixture was stirred at rt for 30 min , followed by addition of the compound obtained from Step 4 The reaction mixture was stirred at rt for 2 h, poured mto water, extracted with ethyl acetate The organic extracts were combined, washed with brine, dried with Na 2 S0 4 , and concentrated in vacuo Purification by flash column chromatography yielded product 4-[2-(dιethylamιno)ethylthιo]phenyl 3,5-bιs(4-methoxyphenyl)ιsoxazol-4-yl ketone Step 6 Demethylation was performed using Method 2 for Step C m Scheme 1 Η NMR (d 6 -Acetone) δ 7 75 (d, 7= 8 76 Hz, 2H), 7 57 (d, 7= 8 76 Hz, 2H), 7 45 (d, 7= 8 76 Hz, 2H), 7 29 (d, 7 = 7 84 Hz. 2H), 6 90 (d, 7= 8 76 Hz, 2H), 6 83 (d, 7= 8 30 Hz, 2H), 3 10 (t, 7= 7 83 Hz, 2H), 2 52 (t 7 = 7 07 Hz, 2H), 0 96 (t, 7= 7 14 Hz. 2H) LC MS m/z 489 (MH+), C 28 H 28 N 2 0 4 S = 488 g/moi, purity = 99% 4 1 2 153 Synthesis of 3,5-bιs(4-hydroxyphenyl)ιsoxazol-4-yl 4-[2-(dιmethylamιno)ethylthιo]phenyl ketone This compound was synthesized as described m Section 4 1 2 152 In Step 5, 2-dιmethylamιno-ethane thiol was used Η NMR (d 6 -Acetone) δ 7 74 (d, 7 = 8 76 Hz. 2H), 7 57 (d, 7 = 9 22 Hz, 2H), 7 45 (d, 7 = 8 76 Hz, 2H) 7 27 (d, 7 = 8 76 Hz, 2H), 6 89 (d, 7= 922 Hz, 2H), 6 82 (d, 7= 8 76 Hz, 2H). 3 00 (t, 7= 7 14 Hz, 2H), 2 54 (t 7= 7 14 Hz, 2H), 2 14(s, 6H), LC/MS m/z 461 (MH+), C 26 H, 4 N,0 4 S = 460 g/mol, purity = 95% 4 1 2 154 Synthesis of 4-(2-azaperhydroepιnylethoxy)phenyl 35-bιs(4-hydroxyphenyl)ιsoxazol-4-yl ketone This compound was synthesized as described Section 4 1 2 152 In step 5 2-azaperhydroepιnylethan- l -ol was used Η NMR (d 6 -Acetone) δ 7 82 (d. 7 = 8 76 Hz, 2H). 7 57 (d.7 = 8 76 Hz 2H), 7 47 (d. 7 = 8 76 Hz 2H), 6 93 - 6 88 (m, 4H), 6 84 (d, 7 = 8 76Hz, 2H), 4 10 (t, 7 = 5 99 Hz. 2H) 2 89 (t, 7 = 5 99 Hz, 2H), 2 72 (t 7 = 5 53 Hz 2H), 1 65-1 52 (m, 6H), LC MS m/z 499 (MH+), C, 0 H 30 N 2 O 5 = 498 g/mol, purity = 95% 4 1 2 155 Synthesis of 3 5-bιs(4-hydroxyphenyl)ιsoxazol-4-yl 4-(2-pιperιdylethoxy)-2-(tnfluoromethyl)phenyl ketone This compound was synthesized as described Section 4 1 2 152 In step 4 2-tπfluoromethyl-4-methoxybenzoyl chloride was used In step 5, N-(2-hydroxyethyl)-pιpeπdιne was used Η NMR (d 6 -DMSO) δ 7 56 (d, 7 = 8 76 Hz, 1 H), 7 54 (d, 7 = 8 76 Hz, 2H), 7 27 (d, 7 = 8 76 Hz, 2H), 7 27 (d. 7 = 8 30 Hz, lH), 6 86 (dd.7= 8 76 Hz and 2 31Hz, 1H), 6 81 (d, 7= 8 76 Hz, 2H), 6 73 (d, 7= 8 76 Hz, 2H), 4 12 (t, 7= 5 76 Hz, 2H), 3 31 (br s, 2H), 2 59 (br s, 2H), 2 38 (br m, 4H), 1 46 (br m, 4H), 1 37 (br m, 2H), LC MS m/z 553 (MH+), C 30 H 27 F 3 N 2 O 5 = 552 g/mol, purity = 99% 4 1 2 156 Synthesis of 3 5-bιs(4-hydroxyphenyl)ιsoxazol-4-yl 4-{2-[(2-ethylthιoethyl)amιno]ethoxy}phenyl ketone This compound was synthesized as described Section 4 1 2 152 In step 5, N-(2-hydroxyethyl)-azιrιdιne was used Η NMR (d 6 - Acetone) δ 7 83 (d, 7 = 8 76 Hz, 2H), 7 57 (d, 7 = 922 Hz, 2H), 7 46 (d, 7 = 922 Hz, 2H), 6 94 (d, 7 = 8 76 Hz, 2H), 6 89 (d, 7= 8 76 Hz, 2H), 6 83 (d, 7= 8 76 Hz, 2H), 4 1 1 (t, 7= 5 53 Hz, 2H), 2 98 (t, 7= 5 53 Hz, 2H), 2 82 (t, 7= 6 50 Hz, 2H), 2 63 (t, 7 = 6 50 Hz, 2H), 2 51 (q, 7= 7 38 Hz, 2H), 1 17 (t, 7= 7 38 Hz, 2H), LC/MS m/z 505 (MH T ), C 28 H 28 N 2 0 5 S = 504 g/mol, purity = 95% 4 1 2 157 Synthesis of 3-(4-hydroxy-2-methylphenyl)-4,5-dιhydronaphtho[1 ,2-c]ιsoxazol-7-ol This compound was synthesized as described in Section 4 1 2 29 using 6-methoxy-l-tetralone and 2-methyl-4- methoxybenzoyl chloride as starting materials Η NMR (d 6 -acetone) δ 7 75 (d, 7= 8 8 Hz. I H), 7 30 (d, 7 = 8 3 Hz, I H), 6 86-6 80 (m, 4H), 2 91-2 72 (m, 4H), 2 34 (s, 3H), LC/MS m/z 294 (MH+), C, 8 H, 5 N0 3 = 293 g/mol, purity = 90% 4 1 2 158 Synthesis of 3,5-bιs(4-hydroxyphenyl)ιsoxazole-4-carbonιtrιle This compound was synthesized based upon the methodology described in Scheme 4 Steps 1-3 were performed as described in Section 4 1 2 20 Step 4 was also performed as described in Section 4 1 2 20 except tosyl nitrile was used as the electrophile Step 5 Demethylation was based upon Method 3 for Step C in Scheme 1 Η NMR (d 6 -acetone) δ 8 04 (d, 7 = 8 8 Hz. I H), 7 87 (d, 7 = 8 8 Hz IH), 7 13 (d, 7= 8 8 Hz, I H) 7 06 (d, 7 = 8 8 Hz. IH), LC/MS m/z 279 (MH+), C l6 H 10 N,O 3 = 278 g/mol. puπtv = 99% 4 1 2 159 Synthesis of 4-[4-ethyl-5-(4-hydroxyphenyl)ιsoxazol-3-yl]-3-methylphenol This compound was synthesized regiospecifically by following procedures described in Scheme 3 Step 1 Oxime synthesis To a suspension of 2'-methyl-4'-methoxy-acetophenone ( 1 0 eq ) in ethanol was added NH->OH HCl (1 2 eq ) and pyndine (1 2 eq ) The mixture was heated to reflux and stirred overnight The solvent was removed under reduced pressure and the residue was dissolved in EtOAc. washed with water and brine, dried over Na 2 S0 4 , filtered and concentrated to afford a crude product mixture Flash chromatography yielded the oxime as two regioisomers in 85%> yield Step 2 isoxazole synthesis To a solution of oxime obtained from step 1 (2 eq ) in THF at 0 °C was added «-BuLι (4 2 eq ) After 30 min, methyl 4-methoxybenzoate (1 0 eq ) was added as a solution in THF After stirring for 30 mm at 0 °C, the mixture was warmed to room temperature HCl (10 mL, 5 N) was added and the biphasic reaction mixture was heated to reflux and stirred overnight Upon cooling to 0°C, isoxazole precipitated and was collected via filtration The filtrate was washed with water and the aqueous layer extracted with EtOAc (x3) The organic layers were combined washed with saturated NaHCO- and brme, dried over NaιS0 , filtered and concentrated to afford a crude reaction mixture Flash chromatography (THF/Hexanes) and recrvstalhzation (THF/EtOH) yielded the isoxazole Step 3 Demethylation was performed as described in Method 3 of Step C of Scheme 1 Η NMR (d 6 -acetone) δ = 7 67 (d, 7 = 8 8 Hz, 2H), 7 15 (d, 7 = 8 4 Hz, 1 H), 7 03 (d, 7 = 8 8 Hz, 2H), 6 85 (d, 7 = 2 5 Hz, IH), 6 80 (dd, 7= 8 2, 2 5 Hz, IH), 2 52 (q, 7= 7 6 Hz, 2H), 2 18 (s, 3H), 0 98 (t, 7= 7 6 Hz, 3H), LC MS m/z 296 (MH= + ), C 18 H, 7 N0 3 = 295 g/mol, purity = 99% 4 1 2 160 Synthesis of 3-(4-hydroxy-2-methylphenyl)naphtho[1 ,2-c]ιsoxazol-7-ol This compound was synthesized as described in Section 4 1 2 32 using 6-methoxy- l-tetralone and 2-methyl-4- methoxybenzovl chloride as starting materials Η NMR (d 6 -acetone) 5 8 31 (d, 7= 8 3 Hz, IH), 7 64 (d, 7 = 8 8 Hz, IH), 7 52 (d, 7 = 8 8 Hz, lH), 7 47 - 7 38 (m, 3H), 6 94 - 6 88 (m, 2H), 242, 2 38 (2s, 3H), LC/MS m/z 292 (MH + ), C, 8 H, 3 N0 3 = 291 g/mol, purity = 85% 4 1 2 161 Synthesis of 3-(4-hydroxyphenyl)-4,5,6-trιhydrobenzo[a]ιsoxazolo[3,4-c][7]annulen-8-ol This compound was synthesized in the same manner as Section 4 1 2 29, except in Step 1 , 7-methoxy- 1- benzosuberone was used to form the 1 ,3-dιketone ESMS m/z 294 (MH+), C, 8 Hι 5 N0 3 = 293 g mol, HPLC purity = 80 6% 4 1 2 162 Synthesis of 4-[3-(4-hydroxyphenyl)-4-(2-methoxyphenyl)ιsoxazol-5-yl]phenol This compound was synthesis based upon Scheme 4 Step 1-3 Same as corresponding steps in Section 4 1 2 20 Step 4 Suzuki coupling of 4-bromoιsoxazole with arylboronic acid Reaction was carried out under an atmosphere of nitrogen and solvents were degassed by bubbling nitrogen for 2 h prior to the reaction Pd(PPh 3 ) 4 (0 04eq) in DMF was added to the 4-bromoιsoxazole (obtained from step 3) and 2-methoxyphenylboronιc acid (or vinyltnbutyltin) (1 leq) Sodium carbonate (0 4mL, 2M) was then added The reaction was sealed and allowed to stand overnight at 90°C Ethyl acetate (20mL) was then added and the reaction was washed with water and brine The organic fractions were filtered and concentrated under reduced pressure Residues were lyophilised in 90%MeCN/H 2 O Purification of the compound was achieved by teturation with 60%) MeCN/H 2 0 and HPLC purification Step 5 Demethylation was following Method 3 described for Step C in Scheme 1 Η NMR (CDCL, & DMSO-d 6 ) δ 3 04 (3H, s), 6 16 (2H, d, J=8 5Hz), 6 20 (2H, d, J=8 7Hz),6 44 (IH, t, J=7 5Hz), 6 47 (IH, d, J=8 4Hz), 6 58 (IH, dd, J=7 1Hz, 1 6Hz), 6 67 (2H, d, J=8 5Hz), 6 78 (2H, d, J=8 6Hz), 6 87 (3H, t, J=8 3Hz), 8 69 (IH, s), 8 91 (IH s), ESMS m/z 360 (MH+), C 22 H, 7 N0 4 = 359 g/mol HPLC puritv = 98 2% 4 1 2 163 Synthesis of 4-{4-[3,5-bιs(trιfluoromethyl)phenyl]-5-(4-hydroxyphenyl)ιsoxazol-3-yl}phenol This compound was synthesized in the same manner as product in Section 4 1 2 162, except in Step 4, 3,5-dι- tπfluoromethylphenylboronic acid was used for coupling Η NMR (CDC1 3 ) δ 6 71 (IH, d, J=8 7Hz), 6 73 (IH, d, J=10 8Hz), 7 04 (IH, d, J=84Hz), 720 (IH, d, J=84Hz), 7 60 (2H, s), 7 76 (IH, s), 9 25 (IH, s), 9 50 (IH, s), ESMS m/z 466 (MH+), C 23 H, 3 F 6 N0 3 = 465 g/mol, HPLC purity = 864 % 4 1 2 164 Synthesis of 3-[3,5-bιs(4-hydroxyphenyl)ιsoxazol-4-yl]phenol This compound was synthesized in the same manner as product in Section 4 1 2 162, except in Step 4, 3- methoxyphenylboronic acid was used for coupling Η NMR (CDC1 3 ) δ 6 30 (4H, d, J=64Hz), 6 33 (IH, s), 6 35 (IH, d, J=7 7Hz), 6 44 (IH, d, J=8 1Hz), 6 80 (IH, t, J=7 8Hz), 6 85 (2H, d, 1=1 6Hz), 6 95 (2H, d, J=7 8Hz), 8 64 (IH s), 8 81 (IH, s), 8 98 (IH, s), ESMS m/z 346 (MH+), C 2 ιH, 5 N0 4 = 345 g/mol, HPLC purity = 91 % 4 1 2 165 Synthesis of 4-{3-(4-hydroxyphenyl)-4-[3-(trιfluoromethyl)phenyl]ιsoxazol-5-yl}phenol This compound was synthesized m the same manner as product in Section 4 1 2 162, except in Step 4, 3- tπfluoromethylphenylboronic acid was used for coupling Η NMR (CDC1 3 ) δ 6 13 (2H, d, J=8 5Hz), 6 17 (2H, d, J=8 7Hz), 6 67 (2H, d, J=8 7Hz), 6 87 (IH, s), 6 88 (IH d, J=6 9Hz), 6 97 (IH, t, J=7 9Hz), 7 06 (IH d, J=8 5Hz), 8 79 ( IH, s), 9 02 (I H, s), ESMS m/z 398 (MH+), C, 2 H, 4 F 3 NO,= 397 g/mol HPLC puritv =99 3 % 4 1 2 166 Synthesis of 4 {3-(4-hydroxyphenyl)-4-[4-(tπfluoromethyl)phenyl]ιsoxazol-5-yl}phenol This compound was synthesized in the same manner as product in Section 4 1 2 162 except in step 4 4- tπfiuoromethylphenylboronic acid was used for coupling Η NMR (CDC1 3 & DMSO-d 6 ) δ 6 34 (2H, d, J=8 4Hz), 6 38 (2H, d, J=8 4Hz), 6 75 (2H, d, J=8 4Hz), 6 88 (2H, d, J=8 2Hz), 6 98 (2H, d, J=8 1Hz), 7 22 (2H, d, J=8 4Hz), 8 87 (I H, s), 9 09 (IH, s) ESMS m/z 398 (MH+), C 22 H, 4 F 3 N0 3 = 397 g/mol, HPLC purity =98 8% 4 1 2 167 Synthesis of 4-[3-(4-hydroxyphenyl)-4-(2-thιenyl)ιsoxazol-5-yl]phenol This compound was synthesized in the same manner as product in Section 4 1 2 162, except in Step 4, 2- thiophenylboronic acid was used for coupling Η NMR (CDC1 3 & DMSO-d 6 ) 5 6 45 (2H, d, J=8 8Hz), 6 48 (2H, d, J=8 8Hz), 6 69 (IH, dt, J=3 8, 1 2Hz), 6 79 (lH. dd J=3 8 1 2Hz), 7 00 (2H, d, J=8 2Hz), 7 11 (2H d, J=8 2Hz), 7 12-7 15 (IH m), 8 90 (IH, s), 946 (IH, s), ESMS m/z 336 (MH+), C 19 H, 3 N0 3 S= 335 g/mol, HPLC purity =87 9% 4 1 2 168 Synthesis of 4-[3-(4-hydroxyphenyl)-4-(3-thιenyl)ιsoxazol-5-yl]phenol This compound was synthesized in the same manner as product in Section 4 1 2 162, except m Step 4, 3- thiophenylboro c acid was used for coupling Η NMR (CDC1 3 & DMSO-d 6 ) 5 6 32 (2H, d, J=8 8Hz), 6 36 (2H, d, J=8 6Hz), 6 54 (IH, d, J=4 8Hz), 6 76 (IH, s), 6 82 (2H, d J=8 5Hz), 6 94 (2H, d, J=8 5Hz), 7 01-7 03 (IH, m), 8 83 (IH, s), 9 03 (IH, s), ESMS m/z 336 (MH+), C 19 H I3 N0 3 S= 335 g mol, HPLC purity =94 0% 4 1 2 169 Synthesis of 4-[3-(4-hydroxyphenyl)4-vιnylιsoxazol-5-yl]phenol This compound was synthesized in the same manner as product in Section 4 1 2 162 except in Step 4, vinylboronic acid was used for coupling Η NMR (CDCL & DMSO-d 6 ) δ 5 03 (IH, dd, J=l 1 4 1 6Hz), 5 06 (IH, dd, J=17 8, 1 6Hz), 6 32 (IH, dd, J=17 8 1 1 4Hz) 6 65 (2H, d, J=9 OHz), 6 67 (2H, d, J=9 2Hz), 7 19 (2H, d, J=8 8Hz), 7 19 (2H, d, J=8 8Hz), 8 95 (IH s), 9 17 (IH, s), ESMS m/z 280 (MH+), C, 7 H 13 NO,= 279 g/mol, HPLC purity =93 2% 4 1 2 170 Synthesis of 3-(4-hydroxy-2-methylphenyl)-5-(4-hydroxyphenyl)ιsoxazol-4-yl 4-(2-pιperιdylethoxy)phenyl ketone This compound is synthesized as described in Section 4 1 2 20 except, in Stepl, 4'-methoxy-2'- methylacetophenone and /?-anιsoylchloπde are used as starting materials A mixture of regioisomers is obtained ESMS m/e 499 (MH T ), C j0 H 30 N 2 O 5 = 498 g/mol HPLC purity = 90% 4 1 2 171 Synthesis of 3-(2-ethyl-4-hydroxyphenyl)-5-(4-hydroxyphenyl)ιsoxazol-4-yl 4-(2-pιpeπdylethoxy)phenyl ketone This compound is synthesized as described in Section 4 1 2 20 except, in Step 1 4'-methoxy-2'-ethvlacetophenone and p-anisoylchloπde are used as starting materials A mixture of regioisomers is obtained ESMS m/e 513 (MH T ), C 31 H 32 N 2 0 5 = 512 g/mσl, HPLC purity = 90% 4 1 2 172 Synthesis of 3,5-bιs(4-hydroxy-2-methylphenyl)ιsoxazol-4-yl 4-(2-pιperιdylethoxy)phenyl ketone This compound is synthesized as described in Section 4 1 2 20 except, in Step 1 , 4'-methoxy-2'- methylacetophenone and 4-mefhoxy-2-methylbenzoyl chloride are used as starting materials ESMS m/e 513 (MH + ), C 31 H 32 N 2 0 5 = 512 g/mol, HPLC purity = 90% 4 1 2 173 Synthesis of 4-(4-{(hydroxyιmιno)[4-(2-pιperιdylethoxy)phenyl]methyl}-5-(4-hydroxyphenyl)ιsoxazol-3-yl)phenol This compound is synthesized based upon Scheme 7 Steps 1-7 Same as corresponding steps in Section 4 1 2 20 Step 8 Oxime synthesis To a suspension of the ketone obtained from Step 7 (1 0 eq ) in ethanol is added NH 2 OH HCl (1 2 eq ) and pyndine (1 2 eq ) The mixture is heated to reflux and stirred overnight The solvent is removed under reduced pressure and the residue is dissolved in EtOAc, washed with water and brine, dried over Na 2 S0 , filtered and concentrated to afford a crude product mixture Flash chromatography yielded the oxime as a mixture of two regioisomers ESMS m/e 500 (MH + ), C 29 H 29 N 3 O s = 499 g/mol, HPLC purity = 90% 4 1 2 174 Synthesis of 4-(4-{(1 E)-2-aza-2-methoxy-1-[4-(2-pιpeπdvlethoxy)phenyl]vιnyl}-5-(4-hydroxyphenyl)ιsoxazol-3- yl)phenol This compound is synthesized in the same manner as the above compound except m Step 8, methoxyamine was used to form the oxime ESMS m/e 514 (MH"), C 30 H 3 ,N 3 O, = 513 g/mol, HPLC purity = 90% 4 1 2 175 Synthesis of 3,5-bιs(4-hydroxyphenyl)ιsoxazol-4-yl 4-[2-(tert-butoxy)ethoxy]phenyl ketone This compound is synthesized in the same manner as Section 4 1 2 152 In step 5, 2-(tert-butoxy)ethan-l-ol is used as the nucleophile ESMS m/e 474 (MH ), C 28 H, 7 N0 6 = 473 g/mol. HPLC purity = 90% 4 1 2 176 Synthesis of 3-(4-hydroxyphenyl)-5-(4-methoxyphenyl)ιsoxazol-4-yl 4-(2-pιpeπdylethoxy)phenyl ketone This compound is synthesized based upon Scheme 3 and Scheme 6 Step 1 and 2 Same as corresponding steps in Section 4 1 2 152 except 4'-benzyloxyacetophenone is used to form oxime in Step 1 Step 3-5 Same as correspondmg steps in Section 4 1 2 152 except 2-pιperιdylethan-l-ol is used in Step 5 as the nucleophile Step 6 Selective removal of benzyl protecting group To the above obtained compound in MeOH solution was added 10% Pd/C (catalytic amount) The mixture is stirred under hydrogen atmosphere (balloon) at rt overnight, and filtered through celite pad Ethyl acetate is used to wash the residue The filtrate is concentrated and subjected to purification to yield the title compound ESMS m/e 499 (MH + ), C 30 H 30 N 2 O 5 = 498 g/mol, HPLC purity = 90% 4 1 2 177 Synthesis of 3 5-bιs(4-hydroxyphenyl)-4-{[4-(2-pιperιdylethoxy)phenyl]sulfonyl}ιsoxazole This compound is synthesized based on Scheme 6 Steps 1-3 Same as corresponding steps in Scheme 4 1 2 20 Step 4 Same as Step 4 in Scheme 4 1 2 20 except, 4-fluorophenylsulfonyl chloride is used as the electrophile to quench the isoxazole anion Step 5 Same as Step 5 in the above example Step 6 Demethylation was performed using Method 3 described for Step C in Scheme 1 ESMS m/e 521 (MH"), C 28 H 28 N 2 0 6 S = 520 g mol HPLC purity = 90% 4 1 2 178 Synthesis of 3-(4-hydroxyphenyl)ιsoxazolo[4,3-c]quιnolιn-7-ol Step 1 Formation of 1,3-diketone Same as Step 1 in Section 4 1 2 7 except, 2-fluoro-4-mefhoxyacetophenone and -anisoyl chloride were used as starting materials Step 2 To a THF solution of the above 1 ,3-diketone was added dimethylformamidedimethylacetal (4 eq ) The mixture was heated to reflux for 16 h and concentrated in vacuo to give a dark residue Purification with column chromatography afforded 2-[(dιmethvlamιno)methylene]-3-(2-fluoro-4-methoxyphenyl)-l-(4- methoxypheny propane- 1 ,3-dιone Step 3 The above intermediate is mixed with ammonia under pressure (a bomb equipment) and heated to 60 "C overnight The reaction is cooled to -78 °C and allowed ammonia to evaporate To the residue is added water and EtOAc Routine extraction followed bv concentration then gives the crude product, which is purified to give qu olone product Step 4 Formation of isoxazole heterocycle Same as step 4 in Section 4 1 2 7 except, using compound obtained above as starting material This step gives 7-methoxy-3-(4-methoxyphenyl)ιsoxazolo[4,3-c]quιnolιne as product Step 5 Demethylation is performed using Method 3 described for Step C in Scheme 1 ESMS m/e 279 (MH + ), C 16 H 10 N 2 O 3 = 278 g mol, HPLC purity = 90% 4 1 2 179 Synthesis of (2E)-3-(4-{[3,5-bιs(4-hydroxyphenyl)ιsoxazol-4-yl]carbonyl}phenyl)prop-2-enoιc acid Step 1-3 Same as correspondmg steps in Section 4 1 2 20 Step 4 Suzuki coupling was used to introduce the phenyl ring The isoxazole obtained from step 3 is dissolved m toluene and degassed with argon for 10 min To this solution is added Pd(PPh 3 ) 4 (4 0 mol %) After an additional 10 mm, Na 2 COj (5 eq ) is added followed by a solution of 4-formylphenvl boronic acid ( 1 1 rq ) in ethanol The reaction is heated to reflux and stirred for 16 h The reaction mixture is then poured into a separatory funnel and the aqueous layer extracted twice with ethyl acetate The organic layers are combined, washed with a brine solution and dried over Na 2 S0 Purification by flash chromatography (40% ethyl acetate/hexanes) then give the product Step 5 Honor-Emmons reaction to form α,β-unsaturated ester The above product is subjected to Honor-Emmons reaction condition using tπmethyl phosphonoacetate to afford methyl (2E)-3-{4-[3,5-bιs(4- methoxyphenyl)ιsoxazol-4-yl]ρhenyl}prop-2-enoate Step 6 Saponification (NaOH in water/THF) of the above compound then gives (2E)-3-{4-[3,5-bιs(4- methoxyphenyl)ιsoxazol-4-yl]phenyl}prop-2-enoιc acid Step 7 Demethylation is performed using Method 3 described for Step C in Scheme 1 ESMS m/e 400 (MH + ), C 24 H, 7 N0 5 = 399 g/mol, HPLC purity = 90% 4 1 2 180 Synthesis of 7-hydroxy-3-(4-hydroxyphenyl)(4,5-dιhydroιsoxazolo[4 3-c]quιnolιn-5-yl) 4-(2-pιperιdylethoxy)phenyl ketone Steps 1-3 Same as Section 4 1 2.178 Step 4 Reduction To a methanol solution of the compound obtained from step 3 is added 10% Pd/C The mixture is stirred under hydrogen atmosphere (balloon) at rt overnight, and filtered through celite pad Ethyl acetate is used to wash the residue The filtrate is concentrated and subjected to purification to yield product as 7-methoxy-3-[(4- methoxyphenyl)carbonyl]- 1 ,2,3-tπhydroquιnolιn-4-one Step 5 Formation of isoxazole heterocycle Same as step 4 in Section 4 1 2 7 except, using compound obtained above as starting material This step gives 7-methoxy-3-(4-methoxyphenyl)-4,5-dιhydroιsoxazolo[4,3-c]quιnoiιne as the product Step 6 Acylation To a suspension of sodium hydride (1 1 eq) in THF is added the above compound (1 0 eq ) at 0 "C The mixture is stirred at rt for 1 h or until the bubbling stops To this is added 4-(2-pιpeπdylethoxy)benzoyl chloride in THF solution This mixture is stirred at rt overnight, poured into water followed by routine extraction procedure to give a crude product which is purified to yield 7-methoxy-3-(4-methoxyphenyl)(4,5- dιhydroιsoxazolo[4,3-c]quιnolιn-5-yl) 4-(2-pιperιdylethoxy)phenyl ketone Step 7 Demethylation is performed using Method 3 described for Step C in Scheme 1 ESMS m/e 512 (MH + ), C 30 H 29 N 3 O 5 = 511 g/mol, HPLC purity = 90% 4 1 2 181 Synthesis of 2-[4-ethyl-5-(4-hydroxyphenyl)ιsoxazol-3-yl]-5-hydroxybenzenecarbonιtrιle Same procedure as Section 4 1 2 92 except, in step 3, tosyl nitrile was used as the electrophile and in step 4, demethylation was using Method 3 for Step C in Scheme 1 ESMS m/z 307 (MH+), C l8 H 14 N 2 0 3 = 306 g/mol, HPLC purity = 99% 4 1 2 182 Synthesis of 2-[4-ethyl-5-(4-methoxyphenyl)ιsoxazol-3-yl]-5-hydroxybenzenecarbonιtrιle Partial demethylation yielded of the compound synthesized as described in Section 4 1 2 181 provided the title compound ESMS m/z 321 (MH+), C 19 H, 6 N 2 0 3 = 320 g/mol, HPLC purity = 99% 4 2 Biological Activity of Compounds of the Invention 4 2 1 In vivo Assays 4 2 1 1 Allen-Doisy Test for Estrogenicity This test is used to evaluate a test compound for estrogenic activity by observation of cornification of the vaginal epithelium of in ovanectomized rats after administration of a test compound (Allen and Doisy 1923, Muhlbock 1940, Terenms 1971) Mature female Hsd/Cpb rats, having initial weights between about 150-200 g, were obtained from a commercial supplier (Harlan-CPB, Horst, The Netherlands) The rats were housed in housed in aluminium cages in a light- and temperature-controlled room ( 14 hours light/10 hours dark at 19 °C-23 °C) Four rats were housed per cage The rats were provided free access to standard pelleted food and to tap water After a period of acclimatization (a few days) the rats were ovanectomized bilaterally under ether anaesthesia Vaginal smears were taken over a period of 4-5 days Rats showing positive smears were discarded The rats of each treatment group were housed in two juxtaposed cages Each experiment consisted of 2 + n groups of eight rats per group Two reference groups received the reference compound (estradiol 1 3, 5 (10)- estratπene-3 17-β-dιol for subcutaneous ("sc ') administration, ethmvlestradiol for oral administration), n groups received the test compound For subcutaneous administration, between 0 1 μg and 0 2 μg total dose/rat (approx 0 4-0 8 μg/kg total dose) was used For oral administration, 0 008-0 016 mg total dose/rat (approx 0 032-0 064 mg kg total dose) was used Vehicles used for sc administration were (in preferential order) arachis oil, arachis oil with 100 ml 1 benzyl alcohol, gelatin (5 0 g/1) and manmtol (50 g/1) in water, methylcellulose (2 0 g/1) and NaCI, (9 0 g/1) in water, or any other suitable vehicle For oral administration, the vehicles used were (in preferential order) gelatin (5 0 g/1) and manmtol (50 g/1) in water, methylcellulose (2 0 g/1) and NaCI, (9 0 g/1) m water, mulgofen (50 g/1) (sold under the tradename ELF 719, GAF) and NaCI (90 g/1) in water, or any other suitable vehicle Three weeks after ovaπectomy, the rats were primed with a single sc dose of 1 μg estradiol (in 0 1 ml arachis oil) to ensure maintenance of sensitivity and greater uniformity of response In the fourth week. 7 days after priming, (preferably on a Monday), the reference or test compound was administered m 3 equal doses, one in the afternoon of the first day of treatment, and two (one in the morning and one in the afternoon) of the second day of treatment Compound doses were chosen based on extrapolations of in vitro data obtained in the CHO-transactivation (Section ) and/or binding assays for estrogen receptor using known estrogen agonists and antagonists For sc administration, the reference compound (estradiol) was administered in total doses of 0 1-02 μg/rat Test compounds were usually admmistered in total doses of 0 01-1 0 mg/rat Each total sc dose was divided equally over three administrations, each m a dose volume of 025 ml For oral administration, the reference compound (ethinylestradiol) was administered in total doses of 0 008-0 016 mg/rat Test compounds are usually administered in total doses of 0 01-1 0 mg/rat Each total oral dose was divided equally over 3 administrations each in a dose volume of 0 25 ml For expression of doses per kg, an average body weight of 250 g was assumed Vaginal smears were taken in the afternoon of the third day, in the morning and afternoon of the fourth day, and in the morning of the fifth day of the treatment week Additional vaginal smears were taken on succeeding days (in the morning) until the estrogenic response was complete The vaginal smears were made on microscope slides The slides were dried and fixed with 96% ethanol, and stained for about twenty minutes with Giemsa solution (Merck, Darmstadt, Germany), that had been diluted 1 10 with tap water, washed thoroughly under tap water, then dried The percentage of comified and nucleated epithelial cells was estimated for each smear was evaluated under microscope observation (60χ) The rats were allowed to rest for one week (week five of the experiment) The experiment was then repeated, with priming on the sixth week and administration and observation during the seventh week, as described The rats were then euthanized under deep anesthesia or with C0 2 /0 2 gas The developmental phase of the vagmal epithelium for each rat was evaluated using a scale from a"-"g" determined as follows (Table 1) The vaginal sequence of normal non-ovanectomized rats with a 4-dav estrous cycle is: diestrus - diestrus — proestrus → estrus. The usual phases observed in the mornings of the 4-day estrous cycle using the scale in Table 1 are therefore a. a, e, and g, respectively. The phases b, c, d and fare intermediates. Table 1 Percentage Of Percentage of Nucleated Percentage of Comified Developmental Leucocytes Epithelial Cells Epithelial Cells Phase > 67%> — — a. diestrus 5-50% > 50% — b. late diestrus < 5% > 50% — e. proestrus < 5% — > 50% f. estrus < 5% < 5% > 90% g. estrus 5-33% — > 50% d. metestrus 33-67% — < 50% c. late metestrus The number of rats with a positive response is a measure for the estrogenic activity of the test compound. The interpretation of the results was made as shown in Table 2. Table 2 Percentage of Rats Showing Conclusion a Positive Response 0% inactive l%-50% weakly active > 50% active 4.2.1.2 Anti— Allen-Doisy Test for Anti-Estrogenicity This test is used to evaluate a test compound for anti-estrogenic activity when administered in the presence of estrogen (Allen and Doisy 1923; Jongh and Laqueur 1938; Miihlbock 1940; Emmens, Cox et al. 1959). More specifically, the ability of the test compound to counteract the estrogenic cornification of vaginal epithelium is determined. Mature female Cpb rats, having initial weights between about 150-200 g, were obtained from a commercial supplier (CPB-TNO, Zeist, The Netherlands). The rats were housed in housed in aluminium cages in a light- and temperature-controlled room (14 hours light/10 hours dark at 21 °C-23 °C). Four rats were housed per cage. The rats were provided free access to standard pelleted food and to tap water. After a period of acclimatization (a few days) the rats were ovariectomized bilaterally under ether anaesthesia. Vaginal smears were taken over a period of 4-5 days. Rats showing positive smears were discarded. The rats of each treatment group were housed in two juxtaposed cages. Each experiment consisted of 1 + n groups of eight rats per group. One reference group received the reference compound (nafoxidine HCl); n groups received the test compound. For oral administration, 0.25 mg/rat/day (approx. 144 mg/kg/day) was used. Vehicles used for subcutaneous ("sc") administration were (in preferential order): arachis oil, arachis oil with 10% benzyl alcohol; gelatin (0.5%) and mannitol (5%) in water; and methylcellulose (0.2%) and NaCI (9.0 %) in water. For oral administration, the vehicles used were (in preferential order): gelatin (0.5%) and mannitol (5%) in water; methylcellulose (0.2%) and NaCI (9.0 %) in water; and mulgofen (5%) (sold under the tradename ELF 719, GAF) and NaCI (0.9%) in water. Two weeks after ovanectomy, the rats were primed with a single sc dose of 0 2 μg estradiol (in 0 1 ml arachis oil) administered daily for ten days to ensure maintenance of sensitivity and greater uniformity of response Administration of estradiol was followed immediately by administration of test compound or vehicle Test compounds were administered at 1 0 mg/rat For sc administration, the dose volume was 0 1 ml, for oral administration, the dose volume was 025 ml Vaginal smears were taken dailv throughout the administration period The vaginal smears were made on microscope slides The slides were dried and fixed with 96% ethanol and stained for about twenty minutes with Giemsa solution (Merck, Darmstadt. Germany), that had been diluted 1 10 with tap water, washed thoroughly under tap water, then dried The percentage of comified and nucleated epithelial cells was estimated for each smear was evaluated under microscope observation (60χ) Following the experiment, rats were euthanized under deep anesthesia or with C0 2 /0 2 gas The developmental phase of the vagmal epithelium for each rat was evaluated using a scale from "a"-"g" determined as follows (Table 3) The vaginal sequence of normal non-ovaπectomized rats with a 4-day estrous cycle is diestms -> diestms — > proestrus — estms The usual phases observed in the mornings of the 4-day estrous cycle using the scale in Table 3 are therefore a, a, e, and g, respectively The phases b, c, d and fare intermediates Table 3 ercentage Of Percentage of Nucleated Percentage of Comified Developmental Leucocytes Epithelial Cells Epithelial Cells Phase > 67% — — a diestms 5-50%) > 50% — b late diestms < 5% > 50% — e proestrus < 5% — > 50% f estms < 5% < 5% > 90% g estms 5-33% — > 50% d metestms 33-67% — < 50% c late metestms Smears showing any of phases e, f, or g were considered to be estrogenic (/ e the vaginal epithelium showed cornification) The final result was expressed as a ratio of the number of smears showing estrogenic response to the total number of smears collected from the third day through the final day of the study The number of rats with a positive response is a measure for the anti-estrogenic activity of the test compound The interpretation of the results was made as shown in Table 4 Table 4 Percentage of Rats Showing Conclusion a Positive Response > 70%) inactive 35%-70% weakly active < 35% active 4 2 1 3 Immature Rat Uterotrophic Bioassay for Estrogenicity and Anti-Estrogenicity Antiestrogenic activity is determined by the ability of a test compound (3,5-bιs(4-hydroxyphenyl)ιsoxazol-4-vl 4-(2-pιpeπdylethoxy)phenvl ketone) to suppress the increase in uterine wet weight resulting from the administration of 0 2 μg 17-β-estradιol ("E 2 ") per day Anv statistically significant decreases in uterine weight in a particular dose group as compared with the E 2 control group are indicative of anti-estrogenicity One hundred sixty (160) female pups (10 per foster dam) were received at 12 days of age One hundred forty (140) female pups (19 days old) in the 35-50 g body weight range were selected for the study On day 19 of age, when the pups weighed approximately 35-50 g, they were body weight-order randomized into treatment groups Observations for mortality, morbidity, availability of food and water, general appearance and signs of toxicity were made twice daily Pups not used in the study were euthanized along with the foster dams Initial body weights were taken just prior to the start of treatment at day 19 of age The final body weights were taken at necropsy on day 22 of age Treatment commenced on day 19 of age and continued until day 20 and 21 of age Each animal was given three subcutaneous ("sc") injections daily for 3 consecutive days Three rats in each of the control and mid- to high-level dose test groups were anesthetized with a ketamme/xylazme mixture Their blood was collected by exsanguination using a 22 gauge needle and 5 ml syringe flushed with 10 USP units sodium hepaπn/ml through the descending vena cava, and then transferred into a 5 ml green top plasma tube (sodium hepaπn (freeze-dπed), 72 USP units) Plasma samples were collected by centrifugation, frozen at -70°C, and analyzed using mass spectrographic to determine the presence and amount of test compound in the semm Blood chemistry was also analyzed to determine other blood parameters The uteri from the rats were excised and weighed The remaining rats were sacrificed by asphyxiation under C0 2 The uteri from these rats were excised, nicked, blotted to remove fluid, and weighed to the nearest 0 lmg In order to determine whether the test compound significantly affected final body weight, a parametric one-way analysis of variance (ANOVA) was performed (SIGMASTAT version 2 0, available commercially from Jandel Scientific, San Rafael, CA) Estrogen agonist and antagonist activity was assessed by comparing uterine wet weights across treatment groups using a parametric ANOVA on loglo transformed data The data were transformed to meet assumptions of normality and homogeneity of variance of the parametric ANOVA The F value was determined to be significant (p < 0 05) and a Student-Newman-Kuels multiple range test was performed to determine the presence of significant differences among the treatment groups Since the final body weights were not significantly different across treatment groups (p = 0 999), uterine weight body weight ratios were not compared The test compound was determined to act as a mixed estrogen agonist/antagonist The uterotrophic response was submaximal compared to that seen with the reference estrogen, 17β-estradιol Submaximal uterotrophic response even at elevated dose levels, is characteristic of partial estrogen agonists When the test compound was tested in combination with 17β-estradιol, partial inhibition of the uterotrophic response was observed at all three dose levels, hence, the test compound possessed estrogen antagonist activity However, the test compound did not completely inhibit the 17β-estradιoi-stιmuiated uterotrophic response, implying that it is a mixed estrogen agonist/antagonist in this bioassay 4 2 1 4 Estrogen Receptor Antagonist Efficacy In MCF-7 Xenograft Model MCF-7 human mammary tumors from existing in vivo passages are implanted subcutaneously into 95 female Ncr-nu mice A 17-β-estradιol pellet (Innovative Research of America) is implanted on the side opposite the tumor Both implants are performed on the same day Treatment is started when the tumor sizes are between 75 mg and 200 mg Tumor weight is calculated according to the formula for the volume of an ellipsoid lx w 2 where / and w are the larger- and smaller dimensions of the tumor and unit tumor density is assumed The test compounds are administered BID q7h x 2, with one dmg preparation per week The test compounds are stored at + 4 °C between injections The dose of test compound is determined according to the individual animal's body weight on each day of treatment Gross body weights are determined twice weekly, starting the first day of treatment Mortality checks are performed daily Mice having tumors larger than 4,000 mg, mice having ulcerated tumors, as and moribund mice are sacrificed prior to the day of study termination The study duration is limited to 60 days from the day of tumor implantation but termination could occur earlier as determined to be necessary Terminal bleeding of all surviving mice is performed on the last day of the experiment Statistical analysis is performed on the data gathered, including mortality, gross individual and group average body weights at each weighing, individual tumor weights and median group tumor weight at each measurement, the incidence of partial and complete regressions and tumor-free survivors, and the calculated delay in the growth of the median tumor for each group 42 1 5 OVX Rat Model This model evaluates the ability of a compound to reverse the decrease in bone density and increase in cholesterol levels resulting from ovanectomy (Black. Author et al 1994, Willson, Author et al 1997) Three- month old female rats are ovanectomized ("ovx"), and test compounds are administered daily by subcutaneous route beginning one day post-surgery Sham operated animals and ovx animals with vehicle control administered are used as control groups After 28 days of treatment, the rats are weighed, the overall body weight gains obtained and the animals euthanized Blood bone markers (e g , osteocalcm and bone-specific alkaline phosphatase), total cholesterol, and urine markers (e g deoxypyndinoline and creatinine) are measured Uterine wet weights are also obtained Both tibiae and femurs are removed from the test animals for peripheral quantitative computed tomography scanning or other measurement of bone mineral density Data from the ovx and test vehicle animals are compared to the sham and ovx control animals to determme tissue specific estrogenic/antiestrogenic effects of the test compounds 422 In vitro Assays 422 1 ERα Binding Assays ERα receptor (~0 2 mg/ml, Affinity Bioreagents) was diluted to about 2 x 10 3 mg/ml in phosphate-buffered saline ("PBS") at a pH of 7 4 Fifty microliters 1 of the ERα-PBS solution was then added to each the wells of a flashplate (Wallac SCI TISCTRIPS) The plates were sealed and stored in the dark at 4 °C for 16-18 hours The buffered receptor solution is removed just prior to use, and the plates were washed 3 times with 200 microliters per well of PBS The washing was typically performed using a slow dispense of reagent into the wells to avoid stripping the receptor from the well surface For library screening, 150 microliters of 1 nM 3 H-estradιol (New England Nuclear, Boston, MA) in 20 mM Tris-HCl, 1 mM EDTA, 10% glycerol, 6 mM monothioglycerol, 5mM KCl, pH 7 8 was mixed with 50 microliters of the test compound (in same buffer) in a 96 well mictrotiter plate (Costar 3794), resulting in a final estradiol concentration of 0 6 nM In addition, several dilutions of estradiol, centered on the IC 3θ of 1-2 nM were also added to individual wells to generate a standard curve The plates were gently shaken to mix the reagents A total of 150 microliters from each of the wells is added to the corresponding wells of the pre-coated ERα plates The plates were sealed (Packard #6005185) and the components in the wells were incubated either at room temperature for 4 hours or at 4 °C overnight The receptor bound ligand was read directly after incubation using a scintillation counter (TRILUX, Wallac) The amount of receptor bound ligand was determined directly, / e without separation of bound from free ligand If estimates of both bound and free ligand were required, the supernatant was removed from the wells, liquid scintillant added, and the wells counted separately in a liquid scintillation counter 4222 ERβ Binding Assays ERβ receptor (~0 2 mg/ml, Affinity Bioreagents) was diluted to about 2 x 10 3 mg/ml in phosphate-buffered saline ("PBS") at a pH of 7 4 Fifty microliters of the ERβ-PBS solution was then added to each the wells of a flashplate (Wallac SCINTISCTRIPS) The plates were sealed and stored in the dark at 4 °C for 16-18 hours The buffered receptor solution is removed just prior to use, and the plates were washed 3 times with 200 microliters per well of PBS The washing was typically performed using a slow dispense of reagent into the wells to avoid stripping the receptor from the well surface For library screening, 150 microliters of 1 nM Η-estradiol (New England Nuclear, Boston, MA) in 20 M Tris-HCl, 1 mM EDTA, 10% glycerol, 6 mM monothioglycerol, 5mM KCl, pH 7 8 was mixed with 50 microliters of the test compound (in same buffer) in a 96 well mictrotiter plate (Costar 3794), resulting in a final estradiol concentration of 0 6 nM In addition, several dilutions of estradiol, centered on the IC,o of 1-2 nM were also added to individual wells to generate a standard curve The plates were gently shaken to mix the reagents A total of 150 microliters from each of the wells is added to the corresponding wells of the pre-coated ERβ plates The plates were sealed (Packard #6005185) and the components in the wells were incubated at room temperature either for 4 hours or at 4 °C overnight The receptor bound ligand was read directly after incubation using a scintillation counter (TRILUX Wallac) The amount of receptor bound ligand was determined directly, / e without separation of bound from free ligand If estimates of both bound and free ligand were required the supernatant was removed from the wells, liquid scmtillant added, and the wells counted separately in a liquid scintillation counter 422 3 ERα/ERβ Transactivation Assays 4223 1 Construction of Transfected CHO Cells The above-mentioned transfected CHO cells were derived from CHO KI cells obtained from the American Type Culture Collection ("ATCC", Rockville, MD) The transfected cells were modified to contain the following four plasmid vectors (1) pKCRE with DNA for the human estrogen receptor (2) pAG-60-weo with DNA for the protein leading to neomycin resistance, (3) pRO-LUC with DNA for the rat oxytocin promoter and for firefly luciferase protem, and (4) pDR2 with DNA for the protein leading to hygromvcine resistance All transformations with these genetically modified CHO cells were performed under rec-VMT contamment according to the guidelines of the COGEM (Commissie Genetische Modificatie) Screening was performed either in the absence of estradiol (estrogenicity) or in the presence of estradiol (anti-estrogenicity) Reagents The following reagents were prepared using ultra pure water (milli-Q quality) 1 Culture Medium Dulbecco ' s MEM/HAM F12 powder (12 5 g/1, Gibco, Paisley, UK) was dissolved in water Sodium bicarbonate (2 5 grams/liter ("g/1")), L-glutamine (0 36 g/1) and sodium pyruvate (5 5 x 10 2 g/1) were added This medium was supplemented with an aqueous mixture (0 50 ml/1 medium) of ethanoiamine (2 44 ml/1), sodium selenite (0 9 mg/1), and 2-mercaptoethanol (42 ml/1) The pH of the medium was adjusted to 7 0 ± 0 1 with NaOH or HCl (1 mol/1), and the medium was sterilized by membrane filtration using a filter having 0 2 μm pores The resulting semm-free culture medium was stored at 4 °C 2 Antibiotics Solution Streptomycin sulfate (25 g, Mycofarm, Delft, The Netherlands) and sodium penicillin G (25 g, Mycofarm) were dissolved in 1 1 water and sterilized by membrane filtration using a filter having 0 2 μm pores 3 Defined Bovine Calf Semm Supplemented ("DBCSS") DBCSS (Hyclone, Utah), sterilized by the manufacturer, was inactivated by heating for 30 mm at 56 °C with mixing every 5 min Aliquots of 50 ml and 100 ml were stored at -20 °C 4 Charcoal-Treated DBCSS ("cDBCSS") Charcoal (0 5 g, Noπt A) was washed with 20 ml water (3 times) and then suspended in 200 ml Tns buffer For coating 0 05 g dextran (T70, Pharmacia, Sweden) is dissolved in a suspension that was stirred continuously for 3 hours at room-temperature The resulting dextran-coated charcoal suspension was centrifuged for 10 mm at 8,000 N kg The supernatant was removed and 100 ml DBCSS was added to the residue The suspension was stirred for 30 mm at 45 °C under aseptic conditions Following stirring, the charcoal was removed by centrifugation for 10 mm at 8000 N/kg The supernatant was sterilized by membrane filtration using a first filter having a pore size of 0 8 μm followed by filtration with a second filter having a pore size of 0 2 μm The sterilized, heat-inactivated cDBCSS was stored at -20 °C 5 Tπs Buffer Tromethamine ("Tns", 1 21 g, 10 mmol) was dissolved in approximately 950 ml water The solution pH was adjusted to 74 using HCl (0 2 mol/1) and the volume raised to 1 1 with additional water This buffer was prepared fresh prior to use 6 Luclite Substrate Solution Luclite luminescense kit, developed for firefly luciferase activity measurements in microtiter plates was obtained from a commercial source (Packard, Menden, CT) Ten milliliters of the above-described buffer solution was added to each flask of substrate Preparation of Transfected Cells Under aseptic conditions, the above-described culture medium was supplemented with antibiotics solution (2 5 ml/1) and heat-inactivated cDBCSS (50 ml/1) to give complete medium One vial of the above-described recombinant CHO cells was taken from the seed stock m liquid nitrogen and allowed to thaw in water at approximately 37 °C A Roux flask (80 cc) was inoculated with about 5 x 10 5 viable cells/ml in complete medium The flask was flushed with 5 % C0 2 in air until a pH of 7 2-7 4 resulted The cells were subsequently incubated at 37 °C During this period, the complete medium was refreshed twice Following incubation the cell culture was trypsinized and inoculated at 1 10 dilution in a new flask (180 cc cell culturing) and at 5 x 10 ' ' cells with 100 μl complete medium per well in a 96-well white culture plate for transactivation assavs The 96 well plates were incubated over two days The cells were grown as a monolayer at the bottoms of the wells and reached confluence after two days After a cell culture period of 20 passages, new cells were taken from the seed stock in liquid nitrogen 23 2 Assay of Compounds Assay for Estrogenicity Experiments were performed in groups of three blocks, each block in a separate microtiter plate Each block included the following four groups Group Contents 1 One transactivation group of four wells, each containing ethanol and transfected cells This group was used to estimate total transactivation One total transactivation group of four wells containing beta-estradiol ( 1 x 10 7 M) and transfected cells This group was used to estimate total transactivation of cells Three standard groups of five wells each, containing five different concentrations of non-transfected and transfected cells Test or reference compound groups (n groups, n ≤ 21 ) of three wells each, containing three different concentrations of test or reference compound and transfected cells Aliquots often μl of control, standard, test, and reference compounds were added by pipette into wells of the relevant groups as defined above Each of the wells included 190 μl of complete medium Group Contents 1 Ethanol 2 Standard solution in ethanol (10 "9 M, to be raised to 10 6 M final concentration) 3 Standard solutions in ethanol (047 x 10 " " M, 0 95 x 10 " " M, 1 95 x 10 " " M, 3 9 x 10 " " M, and 7 8 x 10 " " M, to be raised to 047 x 10 "8 M, 0.95 x 10 '8 M, 1 95 x 10 "8 M. 3 9 x 10 "8 M. and 7 8 x 10 "8 M respectively) 4 Test or reference compound in six different concentrations 1 x 10 "5 M, 3 16 x lO^M, 1 x 10 "6 M,3 16 x 10 "7 M, 1 x 10 "7 M, 3 16 x 10 "8 M, respectively Assay for Anti-Estrogenicity Experiments were performed in groups of three blocks, each block in a separate microtiter plate. Each block included the following four groups, each group containmg estradiol, 1, 3, 5 (10)-estratnene-3, 17-β-dιol (10 " M) in the final reaction mixture Group Contents 1 One transactivation group of four wells, each containing ethanol and transfected cells This group was used to estimate total transactivation 2 One group of completely inhibited transactivation group of four wells containing ICI 164,384 (10 "6 M) and transfected cells This group was used to estimate complete inhibition of transactivation 3 Three standard groups of five wells each, containing five different concentrations of non-transfected and transfected cells Test or reference compound groups (n groups, n ≤ 21 ) of three wells each, containing three different concentrations of test or reference compound and transfected cells Aliquots often μl of control, standard, test, and reference compounds were added by pipette into wells of the relevant groups as defined above Each of the wells included 190 μl of complete medium Group Contents 1 Ethanol 9 Standard solution in ethanol (10 9 M. to be raised to 10 ° M final concentration) Standard solutions in ethanol (0 47 x 10 " M, 0 95 x 10 " " M, 1 95 x 10 " M, 3 9 x 10 " " M, and 7 8 x 10 " M, to be raised to 0 47 x 10 "8 M, 0 95 x 10 "8 M. 1 95 x 10 "8 M, 3 9 x 10 "8 M, and 7 8 x 10 "8 M respectively) Test or reference compound in six different concentrations 1 x 10 "3 M, 3 16 x 10 "6 M, 1 x 10 6 M,3 16 x 10 "7 M, 1 x 10 "7 M, 3 16 x 10 "8 M, respectively The microtiter plates were shaken for at least 15 minutes to ensure dissolution of all compounds Simultaneously, 100 μl estradiol, 1 , 3. 5 (10)-estratnene-3, 17-β-dιol (10 "7 M) was added to 40 ml of complete medium, shaken, and equilibrated to 37 °C About 100 μl of this solution was added to microtiter white culture plates seeded the previous day with 10 4 transfected cells in 100 μl of complete medium The microtiter white culture plates were gently shaken for at least 15 minutes and incubated for 16 h at 37 C C in the dark under a humidified atmosphere flushed with 5 % C0 in air Finally, 200 μl of complete medium was removed from the microtiter culture plates, while 50 μl of LUCLITE substrate solution was added to the remaining 50 μl of medium and cells After ten mmutes cell, cell lysis was substantially complete. After sealing the top of the plate, luciferase activity was measured with a luminescence counter Each sample was counted once for 2 5 s using a scintillation (luminescence) counter. All luminescence measurements were recorded on a teleprinter 23 3 Evaluation of Responses The counting figures are corrected to a standardized plate and converted into numbers of light flashes per second ("cps") For each block (microtiter plate), the mean cps values for the total and non-specific transactivation groups were calculated For each concentration of standard (separate for each well), test and reference compound, the percentage of transactivation activity relative to the maximum specific estradiol, 1, 3, 5 (10)-estratnene-3, 17-β-dιol transactivation activity was calculated using the formula cps (standard/test compound) - mean cps (non-specific transactivation) cps (total transactivation) - mean cps (non-specific transactivation) The percentage in the three blocks was evaluated statistically using the analysis of a 3-poιnt parallel line assay in blocks In order to meet better the requirements for this analysis, the percentages were replaced by their logit values The log concentration-response curves for the standard, test, and reference compounds were tested for linearity, and the latter curves also for parallelism with the curve for the standard compound If no significant curvature and no significant deviation from parallelism at the 0 01 levels were found, then the relative transactivation activity of the test compound with respect to estradiol, 1, 3, 5 (10)-estratnene-3, 17-β- diol (potency ratio), together with the 95% confidence interval, was calculated For antagonist assays, the relative inhibitory potency of transactivation activity of the test compound with respect to the standard antagonist. ICI 164,384 was calculated For compounds showing significant agonist or antagonist activity in these initial screens, more accurate EC 50 values were determined by generating twelve-point curves with 3-fold dilutions of the compounds In this case, the range of concentrations was selected based on the compound activity in the initial screens The following compounds of the invention were determined to be active (; e , have agonist or antagonist values of EC 50 < 4 x 10 6 M (ERα) and or EC 50 < 4 x 10 "6 M (ERβ)) against either or both ERα and ERβ 4-{5- [2-(4-hydroxyphenyl)ethyl]-4-benzylιsoxazol-3-yl} phenol, 4-[4-ethyl-5-(phenoxymethyl)ιsoxazol-3-yl]phenol, 4-[5-(4-hydroxyphenyl)-4-phenyhsoxazol-3-yl]phenol. 4-[4-ethyl-5-(4-hydroxyphenyl)ιsoxazol-3-yl]phenol, 4- {5-[2-(4-hydroxyphenyl)ethyl]-4-phenyhsoxazol-3-yl}phenol, 4-[5-(4-hydroxyphenyl)-4-benzyhsoxazol-3- yljphenol, 4-[3,5-bιs(4-hydroxyphenyl)ιsoxazol-4-yl]phenol, 4-[5-(4-hydroxyphenyl)ιsoxazol-3-yl]phenol, 4- {5-(4-hydroxyphenyl)-4-[4-(2-pιpendylethoxy)phenyl]ιsoxazol-3-yI}phenol, 4-{4-(4-hydroxyphenyl)-3-[4-(2- pιpeπdylethoxy)phenyl]ιsoxazol-5-yl}phenol, 3-[4,5-bιs(4-hydroxyphenyl)ιsoxazol-3-yl]phenol, 2-[4,5-bιs(4- hydroxyphenyl)ιsoxazol-3-yl]phenol, 4-[3-(4-hydroxyphenyl)-4-methylιsoxazol-5-yl]phenoI, 4-[3-(4- hydroxyphenyl)-5-phenylιsoxazol-4-yl]phenol, 4-[5-(4-fluorophenyi)-3-(4-hydroxyphenyl)ιsoxazol-4- yl]phenol, 4- {4-(4-hydroxypheny l)-5-[3-(tnfluoromethoxy)pheny 1] ιsoxazol-3-y 1 } phenol, 4- {4-(4- hydroxyphenyl)-5-[4-(trιfluoromethoxy)phenyl]ιsoxazol-3-yl}phenol, 4-[5-(4-hydroxyphenyl)-4- (phenoxymethyl)ιsoxazol-3-yl]phenol, 4-[5-(4-hydroxyphenyl)-4-(phenylthιomethyl)ιsoxazol-3-yl]phenol, 3,5- bιs(4-hydroxyphenyl)ιsoxazol-4-yl 4-(2-pιpeπdylethoxy)phenyl ketone, 5-(4-hydroxyphenyl)-3-(4- methoxyphenyl)ιsoxazol-4-yl 4-(2-pιpeπdylethoxy)phenyl ketone, 3,5-bιs(4-hydroxyphenyl)ιsoxazol-4-yl 4-[2- (hydroxypιperιdyl)ethoxy]phenyl ketone, 3-(4-hydroxyphenyl)-5-(4-methoxyphenyl)ιsoxazol-4-yl 4-[2- (hydroxypιpeπdyl)ethoxy]phenyl ketone, 3,5-bιs(4-hydroxyphenyl)ιsoxazol-4-yl 4-hydroxyphenyl ketone, 4- hydroxyphenyl 3-(4-hydroxyphenyl)-5-(4-methoxyphenyl)ιsoxazol-4-yl ketone, 4-[4-bromo-5-(4- hydroxyphenyl)ιsoxazol-3-y l]phenol, 4-[4-(bromomethyl)-5-(4-hydroxypheny l)ιsoxazol-3-y ljphenol, 4- { 5-(4- hydroxyphenyl)-4-[(4-hydroxyphenoxy)methyl]ιsoxazol-3-yl}ρhenol. 4-[4-(hydroxymethyl)-5-(4- hydroxyphenyl)ιsoxazol-3-yl]phenol, 4-(7-methoxy-4,5-dιhydronaphtho[l ,2-c]ιsoxazol-3-yl)phenol. 3-(4- hydroxyphenyl)-4,5-dιhydronaphtho[l,2-c]ιsoxazol-7-ol, 3-[3-(4-hydroxyphenyl)ιsoxazol-5-yl]phenol, 3-(4- hydroxyphenyl)naphtho[l,2-c]ιsoxazol-7-ol, 3-(3-hydroxyphenyl)-4,5-dιhydronaphtho[l,2-c]ιsoxazol-7-ol, 3- (2-hydroxyphenyl)-4,5-dιhydronaphtho[l,2-c]ιsoxazol-7-ol, 3-[5-(3-hydroxyphenyl)ιsoxazol-3-yl]phenol, 2-[3- (3-hydroxyphenyl)ιsoxazol-5-yl]phenol, 2-[5-(2-hydroxyphenyl)ιsoxazol-3-yl]phenol, 3-[3-(3-hydroxyphenyl)- 4-methylιsoxazol-5-yl]phenol, 2-[3-(3-hydroxyphenyl)-4-methyhsoxazol-5-yl]phenol, 2-[3-(2-hydroxyphenyl)- 4-methylιsoxazol-5-yl]phenol, 3-[4-ethyl-3-(3-hydroxyphenyI)ιsoxazol-5-yl]phenol, 2-[4-ethyl-3-(3- hydroxyphenyl)ιsoxazol-5-yl]phenol. 2-[4-ethyl-3-(2-hydroxyphenyl)ιsoxazol-5-yl]phenol, 3-[4-(4- hydroxyphenyl)-5-(3-hydroxyphenyl)ιsoxazol-3-yl]phenol, 2-[3-(3-hydroxyphenyl)-4-(4- hydroxyphenyl)ιsoxazol-5-yl]phenol, 2-[4-(4-hydroxyphenyl)-5-(2-hydroxyphenyl)ιsoxazol-3-yl]phenol. 3-(2- hydroxyphenyl)-4,5-dιhydronaphtho[2, l-d]ιsoxazol-7-ol, 2-(7-methoxy-4,5-dιhydronaphtho[l,2-c]ιsoxazol-3- yl)phenol, 2-[5-(3-hydroxyphenyl)-4-methyhsoxazol-3-yl]phenoI, 2-[4-ethyl-5-(3-hydroxyphenyl)ιsoxazol-3- yljphenol, 2-[4-(4-hydroxyphenyl)-5-(3-hydroxyphenyl)ιsoxazol-3-yl]phenol, 3-(5-(3-hydroxyphenyl)-4-{[4- (2-pιperιdylethoxy)phenyl]methyl} ιsoxazol-3-yl)phenol, , 2-[3-(4-hydroxyphenyl)-4-phenvhsoxazol-5- yljphenol. 3-[3-(4-hydroxyphenyl)-4-phenylisoxazol-5-yl]phenoI, 2-[4-ethyl-3-(4-hydroxyphenyl)isoxazol-5- yljphenol, 3-[4-ethyI-3-(4-hydroxyphenyl)isoxazol-5-yl]phenol, 2-[3-(4-hydroxyphenyl)-4-methyiisoxazol-5- yl]phenol, 3-[3-(4-hydroxyphenyl)-4-methylisoxazol-5-yl]ρhenol, 2-[3-(4-hydroxyphenyl)isoxazol-5- yl]phenol, 4-(5-(4-hydroxypheny l)-4- { [4-(2-piperidylethoxy)pheny lj ethy 1 } isoxazol-3-y l)phenol, 2-[5-(4- hydroxyphenyl)-4-mefhylisoxazol-3-yl]phenol, 1 -(4-hydroxyphenyl)-4.5-dihydronaphtho[ 1 ,2-d]isoxazol-8-ol, 3-(4-hydroxyphenyl)-4,5-dihydronaphtho[ 1 ,2-c]isoxazol-8-ol, 3-(4-hydroxyphenyl)-4,5-dihydronaphtho[ 1 ,2- c]isoxazol-6-ol, 4-[5-(4-hydroxyphenyl)-4-iodoisoxazol-3-yl]phenol. 4-[4-chloro-5-(4- hydroxyphenyl)isoxazol-3-yl]phenol, 3-(4-hydroxyphenyl)naphtho[l,2-c]isoxazol-8-ol, [3,5-bis(4- hydroxyphenyl)isoxazol-4-yl]-N-benzylcarboxamide, [3,5-bis(4-hydroxyphenyl)isoxazol-4-yl]-N,N- dibutylcarboxamide, [3,5-bis(4-hydroxyphenyl)isoxazol-4-yl]-N-[3-(2-oxopyrrolidinyl)propyl]carboxamide, [3,5-bis(4-hydroxyphenyI)isoxazol-4-yl]-N-(2-phenylethyl)carboxamide, [3,5-bis(4-hydroxyphenyl)isoxazol-4- yl]-N-[(4-hydroxyphenyl)methyl]carboxamide, [3,5-bis(4-hydroxyphenyl)isoxazol-4-yl]-N-(3- pyridylmethyl)carboxamide, [3,5-bis(4-hydroxyphenyl)isoxazol-4-yl]-N-(2-pyridylmethyl)carboxamide, [3,5- bis(4-hydroxyphenyl)isoxazol-4-yl]-N,N-dimethylcarboxamide, [3,5-bis(4-hydroxyphenyl)isoxazol-4-yl]-N- e hylcarboxamide, 3,5-bis(4-hydroxyphenyl)isoxazol-4-yl 4-(2-pyrrolidinylethoxy)phenyl ketone, 3,5-bis(4- hydroxyphenyl)isoxazol-4-y 14-(2-moφholin-4-y lethoxy)pheny 1 ketone, 3 ,5-bis(4-hydroxypheny l)isoxazol-4- yl 4-[3-(dimethylamino)propoxy]phenyl ketone, 4-[3-(diethylamino)propoxy]phenyl 3,5-bis(4- hydroxyphenyl)isoxazol-4-yl ketone, [3,5-bis(4-hydroxyphenyl)isoxazol-4-yl]-N-cyclopropylcarboxamide, [3,5-bis(4-hydroxyphenyl)isoxazol-4-yl]-N-cyclobutylcarboxamide, 4-[2-(diethylamino)ethoxy]phenyl 3,5- bis(4-hydroxyphenyl)isoxazol-4-yl ketone, 3,5-bis(4-hydroxyphenyl)isoxazol-4-yl 4-[2- (dimethylamino)ethoxy]phenyl ketone, 3,5-bis(4-hydroxyphenyI)isoxazol-4-yl 4-{2- [methylbenzylamino]ethoxy}phenyl ketone, 2-(4-{[3,5-bis(4-hydroxyρhenyl)isoxazol-4-yl]carbonyl}phenoxy)- N,N-dimethylacetamide, 3,5-bis(4-hydroxyphenyl)isoxazol-4-yl 4-[2-( 1 -methylpyrrolidin-2-yl)ethoxy]phenyl ketone, 3,5-bis(4-hydroxyphenyl)isoxazol-4-yl 4-[(l-methyl(3-piperidyl))methoxy]phenyl ketone, 3,5-bis(4- hydroxyphenyl)isoxazol-4-yl 4-[3-(4-methylpiperazinyl)propoxy]phenyl ketone, 3,5-bis(4- hydroxyphenyl)isoxazol-4-yl 4-( 1 -methyl(4-piperidyloxy))phenyl ketone, 3-ethyl-4-[4-ethyl-3-(4- hydroxyphenyl)isoxazol-5-yl]phenol. 4-[4-ethyl-3-(4-hydroxyphenyl)isoxazoI-5-yl]-3-methylphenol. 3-bromo- 4-[4-ethyl-3-(4-hydroxyphenyl)isoxazol-5-yl]phenol. 3-butyl-4-[4-ethyl-3-(4-hydroxyphenyl)isoxazol-5- yljphenol, 4-[4-ethyl-3-(4-hydroxyphenyl)isoxazol-5-yl]-3-hexylphenol, 3-(2-bromopropyl)-4-[4-ethyl-3-(4- hydroxyphenyl)isoxazoI-5-yl]phenol, 3,5-bis(4-hydroxyphenyl)isoxazole-4-carbaldehyde, 4-[4-ethyl-3-(4- hydroxyphenyl)isoxazol-5-yl]-3-iodophenol, 3-chloro-4-[4-ethyl-3-(4-hydroxyphenyl)isoxazol-5-yl]phenol, 4- [4-ethyl-3-(4-hydroxyphenyl)isoxazol-5-yl]-2-fluorophenol, 2-[4-ethyl-3-(4-hydroxyphenyi)isoxazol-5-yl]-5- hydroxybenzoic acid, ethyl 2-[4-ethyl-3-(4-hydroxyphenyl)isoxazol-5-yl]-5-hydroxybenzoate, 4-[4-ethyl-3-(4- hydroxyphenyl)isoxazol-5-yl]-3-(methylsulfinyl)phenol, 4-[4-ethyl-3-(4-hydroxyphenyl)isoxazol-5-yl]-3- sulfanylphenol, 4-[4-ethyI-3-(4-hydroxyphenyl)isoxazol-5-yl]-2-methylphenol, 2-butyl-4-[4-ethyl-3-(4- hydroxyphenyl)isoxazol-5-yl]phenol. 2-ethyl-4-[4-ethyl-3-(4-hydroxyphenyi)isoxazol-5-yl]phenol, 2-bromo-4- [4-ethyl-3-(4-hydroxyphenyl)isoxazol-5-yl]phenol, 4-[3-(4-butanoyloxyphenyI)-4-ethylisoxazol-5-yl]phenyl butanoate, 4-[3-(4-acetyloxyphenyl)-4-ethy lisoxazol-5-yl]phenyl acetate, 3-(4-butanoyloxyphenyl)naphtho[ 1 ,2- c]isoxazol-7-yI butanoate, 3-(4-acetyloxyphenyl)naphtho[l,2-c]isoxazol-7-yl acetate, 3,5-bis(4- methoxyphenyl)isoxazol-4-yI 4-(2-piperidylethoxy)phenyl ketone, chloride, 4-[4-ethyl-3-(4- hydroxyphenvi)ιsoxazol-5-yl]-2-hexylphenol. 2-chloro-4-[4-ethvl-3-(4-hydroxyphenyl)ιsoxazol-5-yl]phenol ethyl 5-[4-efhyl-3-(4-hydroxyphenyl)ιsoxazol-5-yl]-2-hydroxybenzoate. 3,5-bιs(4-hydroxyphenyl)ιsoxazol-4-yi 4-methylphenyl ketone, 3,5-bιs(4-hydroxyphenyl)ιsoxazol-4-yl 2-chlorophenyl ketone, 3,5-bιs(4- hydroxyphenyl)ιsoxazol-4-yl 3-chlorophenyl ketone, 3.5-bιs(4-hydroxyphenyl)ιsoxazol-4-yl 4-chlorophenyl ketone, 3,5-bιs(4-hydroxyphenyl)ιsoxazol-4-yl 2-fluorophenyl ketone, 3,5-bιs(4-hydroxyphenyl)ιsoxazol-4-yl 3-nιtrophenyl ketone, 3,5-bιs(4-hydroxyphenyl)ιsoxazol-4-yl 4-nιtrophenyl ketone, 3,4-dιchlorophenyl 3,5- bιs(4-hydroxyphenyl)ιsoxazol-4-yl ketone, 3,5-bιs(4-hydroxyphenyl)ιsoxazol-4-yl 4-butylphenyl ketone, 3,5- bιs(4-hydroxyphenyl)ιsoxazol-4-yl 4-(tert-butyl)phenyl ketone, 3,5-bιs(4-hydroxyphenyl)ιsoxazol-4-yl 3- hydroxyphenyl ketone, 3,5-bιs(4-hydroxyphenyl)ιsoxazol-4-yl 2-hydroxyphenyl ketone, 3,5-bιs(4- hydroxyphenyl)ιsoxazol-4-yl phenyl ketone, 3,5-bιs(4-hydroxyphenyl)ιsoxazol-4-yl 4-methoxyphenyl ketone, 4-[4-ethyl-3-(4-hydroxyphenyl)ιsoxazol-5-yl]-3-phenylthιophenol, 5-[4-ethyl-3-(4-hydroxyphenyl)ιsoxazol-5- yl]-2-hydroxybenzamιde, 4-[4-ethyl-3-(4-hydroxyphenyl)ιsoxazol-5-yl]-2-phenylthιophenol, 4-[4-ethyl-3-(4- hydroxyphenyl)ιsoxazol-5-yl]-2-methylthιophenol, 4-[4-ethyl-3-(4-hydroxyphenyl)ιsoxazol-5-yl]-3- phenylphenol, {4-[4-ethyl-3-(4-hydroxyphenyl)ιsoxazol-5-yl]phenyl}(methylsulfonyl)amιne, 5-[4-ethyl-3-(4- hydroxyphenyl)ιsoxazol-5-yl]-2-methoxybenzamιde, 5-[4-ethyl-3-(4-methoxyphenyl)ιsoxazol-5-yl]-2- hydroxybenzamide, 2-[4-ethyl-3-(4-methoxyphenyl)ιsoxazol-5-yl]-5-hydroxybenzamιde, 3,5-bιs(4- hydroxyphenyl)ιsoxazol-4-yl 3-(2-pιpendylethoxy)phenyl ketone, chloride, 5-(4-hydroxyphenyI)-3-(4- methoxyphenyl)ιsoxazol-4-yl 3-(2-pιpendylethoxy)phenyl ketone, chloride, 3,5-bιs(4-hydroxyphenyl)ιsoxazol- 4-yl 3-(2-pyrrolιdmylethoxy)phenyl ketone, chloride, 3-[2-(dιethylammo)ethoxy]phenyl 3,5-bιs(4- hydroxyphenyI)ιsoxazol-4-yl ketone, chloride, 3,5-bιs(4-hydroxyphenyl)ιsoxazol-4-yl 3-[(l-methyl(3- pιpendyl))methoxy]phenyl ketone, chloride, 3,5-bιs(4-hydroxyphenyl)ιsoxazol-4-yl 3-[2- (dιmethylamιno)ethoxy]phenyl ketone, chloride, 3-(4-hydroxyphenyl)-5-(4-methoxyphenyl)ιsoxazol-4-yl 3- [(l-methyl(3-pιpendyl))methoxy]phenyl ketone, chloride, 3-[2-(dιmethylamιno)ethoxy]phenyl 3-(4- hydroxyphenyl)-5-(4-methoxyphenyl)ιsoxazol-4-yl ketone, chloride, 4-[4-ethyl-3-(4-hydroxy-2- methylphenyl)ιsoxazol-5-yl]-3-methylphenol, 4-[3-(4-hydroxyphenyl)-4-propylιsoxazol-5-yl]phenol, and 4-[3- (4-hydroxyphenyl)-4-prop-2-enyhsoxazol-5-yl]phenol 4224 MCF-7 Cell Proliferation Assays This assay determines the estrogen agonist/antagonist activity of a test compound by the effect of the test compound on the proliferation of MCF-7 cells as measured by the incorporation of 5-bromo-2'-deoxyundme ("BrdU") in a chemiluminescent assay format MCF-7 cells (ATCC HTB-22) were maintained in log-phase culture using DMEM/HamF12 medium (v/v 1/1) that had been supplemented with 10% fetal bovine serum ("FBS"), at 37 °C, and under at 5% C0 2 atmosphere The cells were plated in a 96-well plate at a density of 7,000 cells per well After 24 hours, the cells were further incubated in phenol red-free DMEM/HamF12 medium supplemented with 10% FBS that had been filtered with dextran-coated charcoal to deplete endogenous estrogen (DCC-FBS) The cells were incubated in this medium for an additional 24 hours, at which time either test compound at varying concentrations to determine the 1C 50 for the compound Each test compound was incubated with the cells either in the absence of estradiol (detection of estrogen agonist activity) or in the presence of 1 nM estradiol (detection of estrogen antagonist activity) The cells were cultured m the presence of test compounds for 24 hours at 37 °C and under a 5% COτ atmosphere Cell proliferation was detected bv measuring the level of BrdU incorporation into DNA This was accomplished using a commercially available reagent kit (Boeπnger Mannheim/Roche) The assay was mn according to the manufacturers direction Ten microliters of BrDU labeling reagent, diluted according to the manufacturers directions, was added directly into each well, and incubation was continued for four hours The culture media was then aspirated from the wells, and 100 μl of the fixing/denaturing agent from the kit was added The cells were fixed for 30 minutes at room temperature The plates were aspirated again, and 100 μl of peroxidase-labeled anti-BrdU antibody from the kit was added to each well After one hour, the plates were washed six times with phosphate buffered saline ("PBS"), and 100 μl of SUPERSIGNAL (a chemilumiscent peroxidase substrate, Pierce Chemical) was added The plates were shaken for ten minutes at room temperature, and the resulting chemiluminescent signals were counted using a TRILUX scintillation counter Two compounds of the invention, 4-{5-(4-hydroxyphenyl)-4-[4-(2-pιpendylethoxy)phenyl]ιsoxazol-3-yl}phenol and 3,5-bιs(4- hydroxyphenyi)ιsoxazol-4-yl 4-(2-pιpeπdylethoxy)phenyl ketone, were tested using the above-described protocol, were determined to have IC 3θ values of less than 600 nM m the presence of 1 nM estradiol Thus, the present invention will be seen to provide new compounds that have strong estrogen receptor- modulating action These compounds can be employed in compositions and methods for treating estrogen receptor- mediated disorders, such as osteoporosis, breast and endometrial cancer, Alzheimer's disease, and atherosclerosis The disclosure above is for the purposes of illustration and not limitation Those having skill the arts relevant to the present invention (e g , the organic chemistry, medicinal chemistry, endocrinology, and medical arts) will appreciate from the foregoing the present mvention encompasses many additional embodiments of the invention that are not described explicitly, but which nevertheless are provided by the teach gs of the present invention Such additional embodiments include, but are not limited to, estrogen receptor-mediated diseases other than osteoporosis, breast and endometrial cancer, Alzheimer's disease, and atherosclerosis, that are preventable or treatable using the compounds, compositions, and methods of the invention Still other aspects include compounds that can be designed, synthesized, and tested for therapeutic or prophylactic effect using the teachmgs of the foregoing disclosure 5 Bibliography Allen, F and E A Doisy 1923 "An Ovarian Hormone Preliminary Report on its Localization Extraction and Partial Purification and Action in Test Animals " J Am Med Assn 81 (10) 819-821 Ashby J J Odum, et al 1997 Reg Toxocol Pharm 25 226-231 Audia, J E and B L Neubauer 1996 Methods for Inhbiting Bone Loss US Patent No 5,550,134 August 27, 1996 Berkow, R , M H Beers, et al 1997 The Merck Manual of Medical Information Whitehouse Station Merck 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Claims: WHAT IS CLAIMED: 1. A compound having the formula: and its pharmaceutically acceptable salts, wherein: Xι and X 2 are selected independently from the group consisting of nitrogen and oxygen such that if one of X, and X 2 is nitrogen, then the other of X, and X 2 is oxygen to form thereby an isoxazole ring structure; Ri and R 3 are selected independently from the group consisting of optionally substituted loweralkyl, aryl, heteroaryl, cycloalkyl, cycloheteroalkyl, aralkyl, heteroaralkyl, (cycloalkyl)alkyl, and (cycloheteroalkyl)alkyl; and R 2 is selected from the group consisting of hydrogen, halo, cyano, nitro, thio, amino, carboxyl, formyl, and optionally substituted loweralkyl, loweralkylcarbonyloxy, arylcarbonyloxy, heteroaryicarbonyloxy, cycloalkylcarbonyloxy, cycloheteroalkylcarbonyloxy, aralkycarbonyloxy, heteroaralkylcarbonyloxy, (cycloalkyl)alkylcarbonyloxy, (cycloheteroalkyl)alkylcarbonyloxy, loweralkylcarbonyl, arylcarbonyl, heteroaryicarbonyl, cycloalkylcarbonyl, cycloheteroalkylcarbonyl, aralkycarbonyl, heteroaralkylcarbonyl, (cycloalkyl)alkylcarbonyl, (cycloheteroalkyl)alkylcarbonyl, loweralkylaminocarbonyl, arylammocarbonyl, aralkylaminocarbonyl, heteroarylammocarbonyl, heteroaralkylammocarbonyl, cycloalkylaminocarbonyl, (cycloalkyl)alkylaminocarbonyl, cycloheteroaikylaminocarbonyl, (cycloheteroalkyl)alkylaminocarbonyl, loweralkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, cycloalkylcarbonylamino, cycloheteroalkylcarbonylamino, aralkylcarbonylamino, heteroaralkylcarbonylamino, (cycloalkyl)alkylcarbonylamino, (cycloheteroalkyl)alkylcarbonylamino, loweralkylamino, arylamino, aralkylamino, heteroarylamino, heteroaralkylammo, loweralkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, cycloalkylsulfonyi, cycloheteroalkylsulfonyl, aralkylsulfonyl, heteroaralkylsulfonyl, (cycloalkyl)alkylsulfonyl, (cycloheteroalkyl)alkylsulfonyl, loweralkylsulfinyl, arylsulfinyl, heteroarylsulfinyl, cycloalkylsulfinyl, cycloheteroalkylsulfinyl, aralkylsulfinyl, heteroaralkylsulfinyl, (cycloaikyl)alkylsulfinyl, (cycloheteroalkyl)alkylsulfinyl, loweralkyloxy, aryloxy, heteroaryloxy, cycloalkyloxy, cycloheteroalkyloxy, aralkyloxy, heteroaralkyloxy, (cycloalkyl)alkyloxy, and (cycloheteroalkyl)alkyloxy, loweralkylthio, arylthio, heteroarylthio, cycloalkylthio, cycloheteroalkylthio, aralkylthio, heteroaralkylthio, (cycloalkyl)alkylthio, (cycloheteroalkyl)alkylthio, loweralkylthiocarbonyl, arylthiocarbonyl, heteroarylthiocarbonyl, cycloalkylthiocarbonyl, cycloheteroalkylthiocarbonyl, aralkythiocarbonyloxythiocarbonyl, heteroaralkylthiocarbonyl, (cycloalkyl)alkylthiocarbonyl, (cycloheteroalkyl)alkylthiocarbonyl, heteroarylcarbonylthio, cycioalkylcarbonylthio, cycloheteroalkylcarbonylthio, aralkycarbonylthiooxycarbonylthio, heteroaralkylcarbonylthio. (cycloalkyl)alkylcarbonylthio, (cycloheteroalkyl)alkylcarbonylthio, loweralkyloxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, cycloalkyloxycarbonyl, cycloheteroalkyloxycarbonyl, aralkyoxycarbonyl, heteroaralkyloxycarbonyl, (cycloalkyl)alkyloxycarbonyl, (cycloheteroalkyl)alkyloxycarbonyl, iminoloweralkyl. iminocycloalkyl, iminocycloheteroalkyl, iminoaralkyl, iminoheteroaralkyl, (cycloalkyl)iminoalkyl, (cycloheteroalkyl)iminoalkyl, (cycloiminoalkyl)alkyl, (cycloiminoheteroalkyl)alkyl, oximinoloweralkyl, oximinocycloalkyl, oximinocycloheteroalkyl, oximinoaralkyl, oximinoheteroaralkyl, (cycloalkyl)oximinoalkyl, (cyclooximinoalkyl)alkyl, (cyclooximinoheteroalkyl)alkyl, and (cycloheteroalkyl)oximinoalkyl. 2. The compound of claim 1, wherein R| and R 3 are selected independently from the group consisting of optionally substituted cycloalkyl, cycloheteroalkyl, (cycloalkyl)alkyl. and (cycloheteroalkyl)alkyl. 3. The compound of claim 1, wherein R, and R 3 are selected independently from the group consisting of optionally substituted aryl, heteroaryl, aralkyl, and heteroaralkyl. 4. The compound of claim 3, wherein Ri and R 3 are selected independently from the group consisting of optionally substituted heteroaryl and heteroaralkyl. D. The compound of claim 3, wherein R| and R 3 are selected independently from the group consisting of optionally substituted aryl and aralkyl. 6. The compound of claim 5, wherein at least one of Ri and R 3 is substituted with at least one hydroxyl, alkyloxy, aryloxy, thio, alkylthio, or arylthio group. 7. The compound of claim 6, wherein at least one of R, and R 3 is selected independently from the group consisting of phenyl, phenyloxyloweralkyl, and phenylloweralkyl. 8. The compound of claim 7, wherein at least one of Ri and R 3 is substituted optionally with a substituent selected from the group consisting of halogen, nitro, cyano, loweralkyl, halolowerlalkyl, loweralkyloxy, haloloweralkyloxy, carboxy, loweralkyloxycarbonyl, aryloxycarbonyl, (cycloloweralkyl)oxycarbonyl, aralkyloxycarbonyl, heteroaryloxycarbonyl, heteroaralkyloxycarbonyl, (heterocycioloweralkyl)oxycarbonyl, loweralkylsulfinyl, loweralkylsulfonyl, loweralkylthio, arylthio, loweralkylcarbonyloxy, arylcarbonyloxy, aralkylcarbonyloxy, heteroaryicarbonyloxy, heteroaralkylcarbonyloxy, (cycloloweralkyl)carbonyloxy, alkylsulfonylamino, (heterocycloloweralkyl)carbonyloxy, aminocarbonyl, lowerakylaminocarbonyl, arylaminocarbonyi, aralkylaminocarbonyl, heteroarylammocarbonyl, and heteroaralkylammocarbonyl. 9. The compound of claim 8, wherein at least one of R| and R 3 is further substituted optionally with a substituent selected from the group consisting of halogen, nitro, cyano, loweralkyl, halolowerlalkyl, loweralkyloxy, halolowerlakyloxy, carboxy, loweralkylthio, aminocarbonyl, and loweralkylsulfinyl. 10. The compound of claim 1, wherein R 2 is selected from the group consisting of hydrogen, halo, and optionally substituted loweralkyl, haloloweralkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, aryloxyalkyl, arylthioalkyl, arylcarbonyl, heteroaryicarbonyl, loweralkylcarbonyl, aminocarbonyl, arylaminocarbonyi, loweralkylaminocarbonyl, aralkylaminocarbonyl, (heterocycloloweralkyl)alkylaminocarbonyl. heteroarylammocarbonyl, heteroaralkviaminocarbonyl, (cycloloweralkyl)ammocarbonyl, formyl, ammo loweralkyiammo, and alkenyl The compound of claim 10, wherein R 2 is selected from the group consisting of hydrogen and halo The compound of claim 10, wherein R 2 is selected from the group consisting of optionally substituted phenyl, phenylloweralkyl, hydroxyphenyl, loweralkyloxyphenyl, haloloweralkylsulfonylloweralkyloxyphenyl, diloweralkylaminoloweralkyloxyphenyl, (cycloamιnoloweralkyl)loweralkyloxyphenyl, and (heterocycloalkyl)loweralkyloxyphenyl The compound of claim 10, wherein R 2 is selected from the group consisting of optionally substituted loweralkyl, haloloweralkyl, hydroxyalkyl, phenyloxyloweralkyl, hydroxyphenyloweralkyl, haloloweralkylsulfonylloweralkyl, and phenylthioloweralkyl The compound of claim 10, wherein R 2 is selected from the group consisting of optionally substituted phenylcarbonyl, (heterocycloalkyl)loweralkyloxypheny lcarbonyl, hydroxyphenylcarbonyl, halophenylcarbonyl, phenylloweralkylaminocarbonyl, diloweralkylaminocarbonyl, phenylloweralkylaminocarbonyl, hydroxyphenyllowerlakylammocarbonyl, cycloalkylaminocarbonyl, loweralkylphenylcarbonyl, haloloweralkylsulfonylloweralkyloxyphenylcarbonyl, and nitrophenylcarbonyl The compound of claim 14, wherein R, and R 3 are selected independently from the group consisting of optionally substituted cycloalkyl, cycloheteroalkyl, (cycloalkyl)alkyl, and (cycloheteroalkyl)alkyl The compound of claim 14, wherem R, and R 3 are selected independently from the group consisting of optionally substituted aryl, heteroaryl, aralkyl, and heteroaralkyl The compound of claim 16, wherein R, and R 3 are selected independently from the group consisting of optionally substituted aryl and aralkyl The compound of claim 17, wherein at least one of Rj and R 3 is substituted with at least one hydroxyl or thio group The compound of claim 18, wherein at least one of R| and R 3 is selected independently from the group consisting of phenyl, phenyloxyloweralkyl, and phenylloweralkyl The compound of claim 19, wherein at least one of R, and R 3 is substituted optionally with a substituent selected from the group consisting of halogen, loweralkyl, halolowerlalkyl, loweralkyloxy, halolowerlakyloxy, carboxy, loweralkyloxycarbonyl, aryloxycarbonyl, (cycloloweralkyl)oxycarbonyl, aralkyloxycarbonyl, heteroaryloxycarbonyl, heteroaralkyloxycarbonyl, (heterocycloloweralkyl)oxycarbonyl, loweralkylsulfinyl, loweralkylsulfonyl. loweralkylthio, arylthio, loweralkylcarbonyloxy, arylcarbonyloxy, aralkylcarbonyloxy, heteroaryicarbonyloxy, heteroaralkylcarbonyloxy, (cycloloweralkyl)carbonyloxy, (heterocycloloweralkyl)carbonyloxy. ammocarbonyl, loweraklylaminocarbonyl, arylammocarbonyl, aralkylaminocarbonyl, heteroarylammocarbonyl, and heteroaralkylammocarbonyl 1. A compound having the formula: and its pharmaceutically acceptable salts, wherein: X 3 and X 4 are selected independently from the group consisting of nitrogen and oxygen such that if one of X 3 and X is nitrogen, then the other of X 3 and X 4 is oxygen to form thereby an isoxazole ring structure; X 5 is -{Xιo) n -, wherein n is an integer between 1 and 3 and X 10 , for each value of n, is selected independently from the group consisting of oxygen, -SO * - where x is and integer between 0 and 2, nitrogen, nitrogen substituted with optionally substituted loweralkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, arylcarbonyl, alkylcarbonyl, aralkylcarbonyl, heteroaryicarbonyl, heteroaralkylcarbonyl, and methylene or methine. each optionally substituted from the group consisting of halo, cyano, nitro, thio, amino, carboxyl, formyl, and optionally substituted loweralkyl, loweralkylcarbonyloxy, arylcarbonyloxy, heteroaryicarbonyloxy, cycloalkylcarbonyloxy, cycloheteroalkylcarbonyloxy, aralkycarbonyloxy, heteroaralkylcarbonyloxy, (cycloalkyl)alkylcarbonyloxy, (cycloheteroalkyl)alkylcarbonyloxy, loweralkylcarbonyl, arylcarbonyl, heteroaryicarbonyl, cycloalkylcarbonyl, cycloheteroalkylcarbonyl, aralkycarbonyl, heteroaralkylcarbonyl, (cycloalkyl)alkylcarbonyl, (cycloheteroalkyl)alkylcarbonyl, loweralkylaminocarbonyl, arylaminocarbonyi, aralkylaminocarbonyl, heteroarylammocarbonyl, heteroaralkylammocarbonyl, loweralkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, cycloalkylcarbonylamino, cycloheteroalkylcarbonylamino, aralkylcarbonylamino, heteroaralkylcarbonylamino, (cycloalkyl)alkylcarbonylamino, (cycloheteroalkyl)alkylcarbonylamino, loweralkyiammo, arylamino, aralkylamino, heteroarylamino, heteroaralkylammo, loweralkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, cycloalkylsulfonyi, cycloheteroalkylsulfonyl, aralkylsulfonyl, heteroaralkylsulfonyl, (cycloalkyl)alkylsulfonyl, (cycloheteroalkyl)alkylsulfonyl, loweralkylsulfinyl, arylsulfmyl, heteroarylsulfinyl, cycloalkylsulfinyl, cycloheteroalkylsulfinyl, aralkylsulfinyl, heteroaralkylsulfinyl, (cycloalkyl)alkylsulfinyl, (cycloheteroalkyl)alkylsulfmyl, loweralkyloxy, aryloxy, heteroaryloxy, cycloalkyloxy, cycloheteroalkyloxy, aralkyloxy, heteroaralkyloxy, (cycloalkyl)alkyloxy, and (cycloheteroalkyl)alkyloxy, loweralkylthio, arylthio, heteroarylthio, cycloalkylthio, cycloheteroalkylthio, aralkylthio, heteroaralkylthio, (cycloalkyl)alkylthio, (cycloheteroalkyl)alkylthio, loweralkylthiocarbonyl, arylthiocarbonyl, heteroarylthiocarbonyl, cycloalkylthiocarbonyl, cycloheteroalkylthiocarbonyl, aralkythiocarbonyloxlthiocarbonyl, heteroaralkylthiocarbonyl, (cycloalkyl)alkylthiocarbonyl, (cycloheteroalkyl)alkylthiocarbonyl, heteroarylcarbonylthio, cycioalkylcarbonylthio, cycloheteroalkylcarbonylthio, aralkycarbonylthiooxycarbonylthio, heteroaralkylcarbonylthio, (cycloalkyl)alkylcarbonylthio. (cycloheteroalkyl)alkylcarbonylthio, loweralkyloxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, cycloalkyloxycarbonyl, cycloheteroalkyloxycarbonyl, aralkyoxycarbonyloxloxycarbonyl, heteroaralkyloxycarbonyl, (cycloalkyl)alkyloxycarbonyl, (cycloheteroalkyl)alkyloxycarbonyl, iminoloweralkyl, iminocycloalkyl, lm ocycloheteroalkyl, lminoaralkyl, lmmoheteroaraikyl, (cycloalkvl)ιmιnoalkyl. and (cycloheteroalkyl)ιmιnoalkyl, X 6 -X 9 are selected independently from the group consisting of oxygen, sulfur, sulfinyl. nitrogen, and optionally substituted methine, and R, is selected from the group consisting of optionally substituted loweralkyl, aryl, heteroaryl, cycloalkyl, cycloheteroalkyl, aralkyl, heteroaralkyl, (cycloalkyl)alkyl, and (cycloheteroalkyl)alkyl 22 The compound of claim 21, wherem n is 1 and X 10 is selected from the group consisting of nitrogen, optionally substituted nitrogen, and optionally substituted methylene or methine 23 The compound of claim 22, wherein R 4 is selected from the group consisting of optionally substituted aryl, heteroaryl, aralkyl, and heteroaralkyl 24 The compound of claim 23, wherein R 4 is optionally substituted aryl or aralkyl 25 The compound of claim 24, wherein R 4 includes at least one hydroxyl, thio, or optionally substimted loweralkyloxy, aryloxy, heteroaryloxy, loweralkylthio, arylthio, heteroarylthio, loweralkylcarbonyl, arylcarbonyl, or heteroaryicarbonyl moiety 26. The compound of claim 25, wherein R 4 is selected from the group consisting of phenyl, phenyloxyloweralkyl, and phenylloweralkyl 27 The compound of claim 26, wherein R is further substituted optionally with a moiety selected from the group consisting of halogen, loweralkyl, halolowerlalkyl, loweralkyloxy, halolowerlakyloxy, carboxy, loweralkyloxycarbonyl, aryloxycarbonyl, (cycloloweralkyl)oxycarbonyl, aralkyloxycarbonyl, heteroaryloxycarbonyl, heteroaralkyloxycarbonyl, (heterocycloloweralkyl)oxycarbonyl. loweralkylsulfinyl, loweralkylsulfonyl, loweralkylthio, arylthio, loweralkylcarbonyloxy, arylcarbonyloxy, aralkylcarbonyloxy, heteroaryicarbonyloxy, heteroaralkylcarbonyloxy, (cycloloweralkyl)carbonyloxy, (heterocycloloweralkyl)carbonyloxy, aminocarbonyl, loweraklylaminocarbonyl, arylammocarbonyl, aralkylaminocarbonyl, heteroarylammocarbonyl, cyano, nitro, amino, loweralkyiammo, and heteroaralkylammocarbonyl 28 The compound of claim 21 wherein n is 2 and each X] 0 is selected independently from the group consisting of nitrogen, optionally substituted nitrogen, optionally substituted methylene, and optionally substimted methine 29 The compound of claim 28, wherein R, is selected from the group consisting of optionally substimted aryl, heteroaryl, aralkyl, and heteroaralkyl 30 The compound of claim 29. wherein R 4 is optionally substituted aryl or aralkyl The compound of claim 30. wherein j includes at least one hydroxyl, thio. or optionally substimted loweralkyloxy, aryloxy, heteroaryloxy, loweralkylthio, arylthio, heteroarylthio, loweralkylcarbonyl, arylcarbonyl, or heteroaryicarbonyl moiety The compound of claim 31 , wherem R, is selected from the group consisting of phenyl, phenyloxyloweralkyl, and phenylloweralkyl The compound of claim 32, wherein R is further substituted optionally with a moiety selected from the group consisting of halogen, loweralkyl, halolowerlalkyl, loweralkyloxy, halolowerlakyloxy, carboxy, loweralkyloxycarbonyl, aryloxycarbonyl, (cycloloweralkyl)oxycarbonyl, aralkyloxycarbonyl, heteroaryloxycarbonyl, heteroaralkyloxycarbonyl, (heterocycloloweralkyl)oxycarbonyl, loweralkylsulfinyl, loweralkylsulfonyl, loweralkylthio, arylthio, loweralkylcarbonyloxy, arylcarbonyloxy, aralkylcarbonyloxy, heteroaryicarbonyloxy, heteroaralkylcarbonyloxy, (cycloloweralkyl)carbonyloxy, (heterocycloloweralkyl)carbonyloxy, aminocarbonyl, loweraklylaminocarbonyl, arylaminocarbonyi, aralkylaminocarbonyl, heteroarylammocarbonyl, cyano, nitro, ammo, loweralkyiammo, and heteroaralkylammocarbonyl The compound of claim 21 , wherein X 6 -X 9 are selected independently from the group consisting of nitrogen and optionally substimted methme The compound of claim 34. wherein at least one of X 6 -X 9 is methme substimted with a moiety selected from the group consisting of loweralkyloxy, aryloxy, heteroaryloxy, loweralkylthio, arylthio, heteroarylthio, loweralkylcarbonyl, arylcarbonyl, and heteroaryicarbonyl The compound of claim 35, wherein X 7 is methine substituted with hydroxy or loweralkyloxy The compound of claim 34, wherein n is 1 and X, 0 is selected from the group consisting of nitrogen, optionally substimted nitrogen, and optionally substimted methylene or methine The compound of claim 37, wherein R, is selected from the group consisting of optionally substituted aryl, heteroaryl, aralkyl, and heteroaralkyl The compound of claim 38, wherein R 4 is optionally substituted aryl or aralkyl The compound of claim 39, wherein R, includes at least one hydroxyl, thio, or optionally substituted loweralkyloxy, aryloxy, heteroaryloxy, loweralkylthio, arylthio, heteroarylthio, loweralkylcarbonyl, arylcarbonyl, or heteroaryicarbonyl moiety The compound of claim 40. wherein R 4 is selected from the group consisting of phenyl, phenyloxyloweralkyl, and phenylloweralkyl The compound of claim 41. wherein R4 is further substituted optionally with a moiety selected from the group consisting of halogen, loweralkyl, halolowerlalkyl, loweralkyloxy, halolowerlakyloxy. carboxy, loweralkyloxycarbonyl, aryloxycarbonyl, (cycloioweralkyl)owcarbonyl. aralkvloxycarbonyl, heteroaryloxycarbonyl, heteroaralkyloxycarbonyl, (heterocycloloweralkyl)oxycarbonyl, loweralkylsulfinyl, loweralkylsulfonyl, loweralkylthio, arylthio, loweralkylcarbonyloxy, arylcarbonyloxy, aralkylcarbonyloxy, heteroaryicarbonyloxy, heteroaralkylcarbonyloxy. (cycloloweralkyl)carbonyloxy, (heterocycloloweralkyl)carbonyloxy, aminocarbonyl, loweraklylaminocarbonyl, arylaminocarbonyi, aralkylaminocarbonyl, heteroarylammocarbonyl, cyano, nitro, am o, loweralkyiammo, and heteroaralkylammocarbonyl The compound of claim 34, wherein n is 2 and each X ]0 is selected independently from the group consisting of nitrogen, optionally substituted nitrogen, optionally substimted methylene, and optionally substituted methine The compound of claim 43, wherein R 4 is selected from the group consisting of optionally substituted aryl, heteroaryl, aralkyl, and heteroaralkyl The compound of claim 44, wherein R, is optionally substituted aryl or aralkyl The compound of claim 45, wherein R 4 includes at least one hydroxyl, thio, or optionally substimted loweralkyloxy, aryloxy, heteroaryloxy, loweralkylthio, arylthio, heteroarylthio, loweralkylcarbonyl, arylcarbonyl, or heteroaryicarbonyl moiety The compound of claim 46, wherein R4 is selected from the group consisting of phenyl, phenyloxyloweralkyl, and phenylloweralkyl The compound of claim 47, wherein R, is further substimted optionally with a moiety selected from the group consisting of halogen, loweralkyl, halolowerlalkyl, loweralkyloxy, halolowerlakyloxy, carboxy, loweralkyloxycarbonyl, aryloxycarbonyl, (cycloloweralkyl)oxycarbonyl, aralkyloxycarbonyl, heteroaryloxycarbonyl, heteroaralkyloxycarbonyl, (heterocycloloweralkyl)oxycarbonyl, loweralkylsulfinyl, loweralkylsulfonyl, loweralkylthio, arylthio, loweralkylcarbonyloxy, arylcarbonyloxy, aralkylcarbonyloxy, heteroaryicarbonyloxy, heteroaralkylcarbonyloxy, (cycloloweralkyl)carbonyloxy, (heterocycloloweralkyl)carbonyloxy, aminocarbonyl, loweraklylaminocarbonyl, arylammocarbonyl, aralkylaminocarbonyl, heteroarylammocarbonyl, cyano, nitro, am o, loweralkyiammo, and heteroaralkylammocarbonyl A composition for use in treating an estrogen receptor-mediated disorder m a mammal, comprising a therapeutically effective amount of a compound of claim 1 in a pharmaceutically effective carrier A composition for use in treating an estrogen receptor-mediated disorder in a mammal, comprising a therapeutically effective amount of a compound of claim 21 in a pharmaceutically effective carrier A method for treating an estrogen receptor-mediated disorder in a mammal, comprising administering to such mammal a therapeutically effective amount of a compound of claim 1 in a pharmaceutically effective carrier The method of claim 51, wherein said disease is chosen from the group consisting of osteoporosis estrogen-dependent cancer, Alzheimer's disease, and estrogen-dependent illness A method for treating an estrogen receptor-mediated disorder in a mammal, comprising administering to such mammal a therapeutically effective amount of a compound of claim 21 in a pharmaceutically effective carrier The method of claim 53, wherein said disease is chosen from the group consisting of osteoporosis, estrogen-dependent cancer, and estrogen-dependent illness A method for preventing an estrogen receptor-mediated disorder in a mammal, comprising administering to such mammal a prophylactically effective amount of a compound of claim 1 in a pharmaceutically effective carrier The method of claim 55, wherein said disease is chosen from the group consisting of osteoporosis, estrogen-dependent cancer, Alzheimer's disease and estrogen-dependent illness A method for preventing an estrogen receptor-mediated disorder in a mammal, comprising administering to such mammal a prophylactically effective amount of a compound of claim 21 in a pharmaceutically effective carrier The method of claim 57, wherein said disease is chosen from the group consisting of osteoporosis, estrogen-dependent cancer, and estrogen-dependent illness A method for modulating the biological activity of an estrogen receptor, comprising exposing said estrogen receptor to a compound of claim 1 to modulate thereby the binding of said estrogen receptor to an associated estrogen receptor element The method of claim 5°, wherein said estrogen receptor is the α isoform The method of claim 59, wherein said estrogen receptor is the β isoform A method for modulating the biological activity of an estrogen receptor, comprising exposing said estrogen receptor to a compound of claim 21 to modulate thereby the bindmg of said estrogen receptor to an associated estrogen receptor element The method of claim 62, wherein said estrogen receptor is the α isoform The method of claim 62, wherein said estrogen receptor is the β isoform

Inventors: CHEN LIYA, DESAI MANOJ, HUEBNER VERENA D, JAMES IAN, KRYWULT BEATA, LIN XIAODONG, MOORE JENNIFER C, NAVARATNAM THAYALAN, SINGH RAJINDER, TRAINOR ROB, WANG LIANG, CHEN, LIYA, DESAI, MANOJ, HUEBNER, VERENA, D., JAMES, IAN, KRYWULT, BEATA, LIN, XIAODONG, MOORE, JENNIFER, C., NAVARATNAM, THAYALAN, SINGH, RAJINDER, TRAINOR, ROB, WANG, LIANG
Applicants: CHEN LIYA, CHIRON CORP, DESAI MANOJ, HUEBNER VERENA D, JAMES IAN, KRYWULT BEATA, LIN XIAODONG, MOORE JENNIFER C, NAVARATNAM THAYALAN, SINGH RAJINDER, TRAINOR ROB, WANG LIANG, CHEN, LIYA, CHIRON CORPORATION, DESAI, MANOJ, HUEBNER, VERENA, D., JAMES, IAN, KRYWULT, BEATA, LIN, XIAODONG, MOORE, JENNIFER, C., NAVARATNAM, THAYALAN, SINGH, RAJINDER, TRAINOR, ROB, WANG, LIANG
Application year: 1999
Main classification: C07D261
IPC codes: A61K31, A61P5, A61P19, A61P25, A61P43, C07D261, C07D409, C07D413, C07D498