Title of Invention	ARYL-CARBALDEHYDE OXIME DERIVATIVE COMPOUNDS
Abstract	This invention provides estrogen receptor modulators having the structure (I) where R1-R5 are as defined in the specification; or a pharmaceutically acceptable salt thereof.

Full Text

Aryl-Carbaldehyde Oxime Derivativ Compounds FIELD OF THE INVENTION [0001] This invention relates to aryl-carbaldehyde oxime derivatives, and in certain aspects to (hydroxy-phenyl)-aryl-carbaldehyde oxime derivatives, their uses as estrogenic agents, and methods of their preparation. BACKGROUND OF THE INVENTION [0002] The pleiotropic effects of estrogens in mammalian tissues have been well documented, and it is now appreciated that estrogens affect many organ systems [Mendelsohn and Karas, New England Journal of Medicine 340: 1801-1811 (1999), Epperson, et al., Psychosomatic Medicine 61: 676-697 (1999), Crandall, Journal of Womens Health & Gender Based Medicine S: 1155-1166 (1999), Monk and Brodaty, Dementia & Geriatric Cognitive Disorders 11: 1-10 (2000), Hum and Macrae, Journal of Cerebral Blood Flow & Metabolism 20: 631-652 (2000), Calvin, Maturitas 34: 195- 210 (2000), Finking, et al., Zeitschrift fur Kardiologie 89: 442-453 (2000), Brincat, Maturitas 35: 107-117 (2000), Al-Azzawi, Postgraduate Medical Journal 77: 292-304 (2001)]. Estrogens can exert effects on tissues in several ways. Probably, the most well characterized mechanism of action is their interaction with estrogen receptors leading to alterations in gene transcription. Estrogen receptors are ligand-activated transcription factors and belong to the nuclear hormone receptor superfamily. Other members of this family include the progesterone, androgen, glucocorticoid and mineralocorticoid receptors. Upon binding ligand, these receptors dimerize and can activate gene transcription- either by directly binding to specific sequences on DNA (known as response elements) or by interacting with other transcription factors (such as API), which in tum bind directly to specific DNA sequences [Moggs and Orphanides, EMBO Reports 2: 775-781 (2001), Hall, et al., Journal of Biological Chemistry 276: 36869- 36872 (2001), McDonnell, Principles Of Molecular Regulation. p351-361(2000)]. A class of "coregulatory" proteins can also interact with the ligand-bound receptor and further modulate its transcriptional activity [McKenna, et al., Endocrine Reviews 20: 321-344 (1999)]. It has also been shown that estrogen receptors can suppress NFkB- mediated transcription in both a ligand-dependent and independent manner [Quaedackers, et al., Endocrinology 142: 1156-1166 (2001), Boat, et al.. Journal of Steroid Biochemistry & Molecular Biology 61: 233-240 (1998), Pelzer. et al., Biochemical & Biophysical Research Communications 286: 1153-7 (2001)]. [0003] Estrogen receptors can also be activated by phosphorylation. This phosphorylation is mediated by growth factors such as EGF and causes changes in gene transcription in the absence of ligand [Moggs and Orphanides, EMBO Reports 2: 775- 781 (2001), Hall, et al., Journal of Biological Chemistry 276: 36869-36872 (2001)]. [0004] A less well-characterized means by which estrogens can affect cells is through a so-called membrane receptor. The existence of such a receptor is controversial, but it has been well documented that estrogens can elicit very rapid non- genomic responses from cells. The molecular entity responsible for transducing these effects has not been definitively isolated, but there is evidence to suggest it is at least related to the nuclear forms of the estrogen receptors [Levin, Journal of Applied Physiology 91: 1860-1867 (2001), Levin, Trends in Endocrinology & Metabolism 10: 374-377 (1999)]. [0005] Two estrogen receptors have been discovered to date. The first estrogen receptor was cloned about 15 years ago and is now referred to as ERa [Green, et al., Nature 320: 134-9 (1986)]. The second was found comparatively recently and is called ER(3 [Kuiper, et al., Proceedings of the National Academy of Sciences of the United States of America 93: 5925-5930 (1996)]. Early work on ERß focused on defining its affinity for a variety of ligands and, indeed, some differences with ERa were seen. The tissue distribution of ERß has been well mapped in the rodent and it is not coincident with ERcc. Tissues such as the mouse and rat uterus express predominantly ERoc, whereas the mouse and rat lung express predominantly ERß [Couse, et al., Endocrinology 138: 4613-4621 (1997), Kuiper, et al., Endocrinology 138: 863-870 (1997)]. Even within the same organ, the distribution of ERa and ERß can be compartmentalized. For example, in the mouse ovary, ERß is highly expressed in the granulosa cells and ERa is restricted to the thecal and stromal cells [Sar and Welsch, Endocrinology 140: 963-971 (1999), Fitzpatrick, et al., Endocrinology 140: 2581-2591 (1999)]. However, there are examples where the receptors are coexpressed and there is evidence from in vitro studies that ERa and ERp can form heterodimers [Cowley, et al.. Journal of Biological Chemistry 272: 19858-19862 (1997)]. [0006] The most potent endogenous estrogen is 17ß-estradiol. A large number of compounds have been described that either mimic or block the activity of 17(3- estradiol. Compounds having roughly the same biological effects as 17J3-estradio] are referred to as "estrogen receptor agonists". Those which block the effect of 170- estradiol, when given in combination with it, are called "estrogen receptor antagonists". In reality there is a continuum between estrogen receptor agonist and estrogen receptor antagonist activity and indeed some compounds behave as estrogen receptor agonists in some tissues but estrogen receptor antagonists in others. These compounds with mixed activity are called selective estrogen receptor modulators (SERMS) and are therapeutically useful agents (e.g. EVTSTA) [McDonnell, Journal of the Society for Gynecologic Investigation 7: S10-S15 (2000>, Goldstein, et al., Human Reproduction Update 6: 212-224 (2000)]. The precise reason why the same compound can have cell- specific effects has not been elucidated, but the differences in receptor conformation and/or in the milieu of coregulatory proteins have been suggested. [0007] It has been known for some time that estrogen receptors adopt different conformations when binding ligands. However, the consequence and subtlety of these changes only recently has been revealed. The three dimensional structures of ERa and ERß have been solved by co-crystallization with various ligands and clearly show the repositioning of helix 12 in the presence of an estrogen receptor antagonist which sterically hinders the protein sequences required for receptor-coregulatory protein interaction [Pike, et al., Embo 18: 4608-4618 (1999), Shiau, et al., Cell 95: 927-937 (1998)]. In addition, the technique of phage display has been used to identify peptides that interact with estrogen receptors in the presence of different ligands [Paige, et al., Proceedings of the National Academy of Sciences of the United States of America 96: 3999-4004 (1999)]. For example, a peptide was identified that distinguished between ERa bound to the full estrogen receptor agonists 17P-estradiol and diethylstilbesterol. A different peptide was shown to distinguish between clomiphene bound to ERa and ERß. These data indicate that each ligand potentially places the receptor in a unique and unpredictable conformation that is likely to have distinct biological activities. [0008] As mentioned above, estrogens affect a panoply of biological processes. In addition, where gender differences have been described (e.g. disease frequenciences, responses to challenge, etc) it is possible that the explanation involves the difference in estrogen levels between males and females. SUMMARY OF THE INVENTION [0009] The instant invention relates to aryl-carbaldehyde oxime derivatives, particularly those that find use as estrogenic agents. In one aspect, the invention relates to aryl-carbaldehyde derivatives of the formula: wherein: R1 is hydrogen, halogen, lower alkyl, CN, or lower alkoxy; R2 and R3, together, form a fused aryl or heteroaryl ring; R4 is hydrogen, halogen, lower alkyl, CN, or lower alkoxy; R5 is hydrogen, lower alkyl, or -C(O)R6; and R6 is lower alkyl; or a phannaceutically acceptable salt thereof. In some preferred embodiments, R5 is H. [0010] In another aspect, the invention is directed to a pharmaceutical composition comprising at least one of the above compounds as well as a pharmaceutically acceptable carrier. [0011] In yet other aspects, the invention is drawn to the use of the above compounds in the treatment or prevention of diseases including but not limited to inflammatory bowel diseases such as Crohn's disease and colitis. DETAILED DESCRIPTION OF THE INVENTION [0012] This invention provides aryl-carbaldehyde oxime derivatives. These compounds, which preferably act as estrogenic agents, are useful for the treatment and prevention of diseases such as inflammatory bowel diseases (including Crohn's disease and colitis). In one aspect, the invention is directed to compounds of formula I: wherein: R1 is hydrogen, halogen, lower alkyl, CN, or lower alkoxy; R2 and R3, together, form a fused aryl or heteroaryl ring; R4 is hydrogen, halogen, lower alkyl, CN, or lower alkoxy; R5 is hydrogen, lower alkyl, or -C(O)R6; and R6 is lower alkyl; or a pharmaceutically acceptable salt thereof. In some preferred embodiments, R5 is H. [0013] In certain preferred embodiments, R1 is halogen, R2 and R3 together form a 5 or 6 membered fused ring, such as phenyl, furan, thiophene, and R4 is H or halogen. [0014] Phannaceutically acceptable salts can be formed from organic and inorganic acids, for example, acetic, propionic, lactic, citric, tartaric, succinic, fumaric, maleic, malonic, mandelic, malic, phthalic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, methanesulfonic, naphthalenesulfonic, benzenesulfonic, toluenesulfonic, camphorsulfonic, and similarly known acceptable aids when a compound of this invention contains a basic moiety. Salts may also be formed from organic and inorganic bases, such as alkali metal salts (for example, sodium, lithium, or potassium) alkaline earth metal salts, ammonium salts, alkylammonium salts containing 1-6 carbon atoms or dialkylammonium salts containing 1-6 carbon atoms in each alkyl group, and trialkylammonium salts containing 1-6 carbon atoms in each alkyl group, when a compound of this invention contains an acidic moiety. [0015] The term "aryl" means a carbocyclic aromatic ring of 6 to 10 carbon atoms such as phenyl. The term "heteroaryl" means a 5 or 6 membered aromatic ring containing 1 or more heteroatoms, eg 1 to 3, selected from oxygen, nitrogen and sulfur. Aryl and heteroaryl groups may be optionally substituted. [0016] The term "alkyl", as used herein, whether used alone or as part of another group, refers to a substituted or unsubstituted aliphatic hydrocarbon chain and includes, but is not limited to, straight and branched chains containing from 1 to 12 carbon atoms, preferably 1 to 6 carbon atoms, unless explicitly specified otherwise. For example, methyl, ethyl, propyl, isopropyl, butyl, i-butyl and t-butyl are encompassed by the term "alkyl." Specifically included within the definition of "alkyl" are those aliphatic hydrocarbon chains that are optionally substituted. [0017] The carbon number as used in the definitions herein refers to carbon backbone and carbon branching, but does not include carbon atoms of the substituents, such as alkoxy substitutions and the like. [0018] The term "alkenyl", as used herein, whether used alone or as part of another group, refers to a substituted or unsubstituted aliphatic hydrocarbon chain and includes, but is not limited to, straight and branched chains having 2 to 8 carbon atoms and containing at least one double bond. Preferably, the alkenyl moiety has 1 or 2 double bonds. Such alkenyl moieties may exist in the E or Z conformations and the compounds of this invention include both conformations. Specifically included within the definition of "alkenyl" are those aliphatic hydrocarbon chains that are optionally substituted. Heteroatoms, such as O, S or N-R1 attached to an alkenyl should not be attached to a carbon atom that is bonded to a double bond. [0019] The term "phenyl", as used herein, whether used alone or as part of another group, refers to a substituted or unsubstituted phenyl group. [0020] An optionally substituted alkyl, alkenyl, aryl, heteroaryl and phenyl may be substituted with one or more substituents. Suitable optionally substituents may be selected independently from nitro, cyano, -N(Rn)(R12), halo, hydroxy, carboxy, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, alkoxy, aryloxy, heteroaryloxy, alkylalkoxy, alkoxycarbonyl, alkoxyalkoxy, perfluoroalkyl, perfluoroalkoxy, arylalkyl, alkylaryl, hydroxyalkyl, alkoxyalkyl, alkylthio, -S(O)2-N(R11)(R12), -C(=O)- N(R11)(R12), (R10(R12)N-alkyl, (R11)(R12)N-alkoxyalkyl, (R11)(R12)N-alkylaryloxyalkyl, -S(O)5-aryl (where s=0-2) or -S(O)s-heteroaryl (where s=0-2). In certain embodiments of the invention, preferred substituents for alkyl, alkenyl, alkynyl and cycloalkyl include nitro, cyano, -N(R11)(R12), halo, hydroxyl, aryl. heteroaryl, alkoxy, alkoxyalkyl, and alkoxycarbonyl. In certain embodiments of the invention, preferred substituents for aryl and heteroaryl include -N(Rn)(RI2), alkyl, halo, perfluoroalkyl, perfluoroalkoxy. arylalkyl and alkylaryl. [0021] The term halogen includes bromine, chlorine, fluorine, and iodine. The term "lower alkyl" refers to an alkyl group having 1 to 6 carbon atoms, in some preferred embodiments 1 to 3 carbon atoms. [0022] The term "lower alkoxy," as used herein, refers to the group R-O- where R is an alkyl group of 1 to 6 carbon atoms, in some preferred embodiments 1 to 3 carbon atoms. [0023] As used in accordance with this invention, the term "providing," with respect to providing a compound or substance covered by this invention, means either directly administering such a compound or substance, or administering a prodrug, derivative, or analog which will form the effective amount of the compound or substance within the body. [0024] The compounds of this invention are estrogen receptor modulators useful in the treatment or inhibition of conditions, disorders, or disease states that are at least partially mediated by an estrogen deficiency or excess, or which may be treated or inhibited through the use of an estrogenic agent. The compounds of this invention are particularly useful in treating a peri-menopausal, menopausal, or postmenopausal patient in which the levels of endogenous estrogens produced are greatly diminished. Menopause is generally defined as the last natural menstrual period and is characterized by the cessation of ovarian function, leading to the substantial diminution of circulating estrogen in the bloodstream. As used herein, menopause also includes conditions of decreased estrogen production that may be surgically, chemically, or be caused by a disease state which leads to premature diminution or cessation of ovarian function. [0025] Accordingly, the compounds of this invention are useful in treating or inhibiting osteoporosis and in the inhibition of bone demineralization, which may result from an imbalance in a individual's formation of new bone tissues and the resorption of older tissues, leading to a net loss of bone. Such bone depletion results in a range of individuals, particularly in post-rnenopausal women, women who have undergone bilateral oophorectomy, those receiving or who have received extended corticosteroid therapies, those experiencing gonadal dysgenesis, and those suffering from Cushing's syndrome. Special needs for bone, including teeth and oral bone, replacement can also be addressed using these compounds in individuals with bone fractures, defective bone structures, and those receiving bone-related surgeries and/or the implantation of prosthesis. In addition to those problems described above, these compounds can be used in treatment or inhibition for osteoarthritis, hypocalcemia, hypercalcemia, Paget's disease, osteomalacia, osteohalisteresis, multiple myeloma and other forms of cancer having deleterious effects on bone tissues. [0026] The compounds of this invention are also useful in treating or inhibiting benign or malignant abnormal tissue growth, including prostatic hypertrophy, uterine leiomyomas, breast cancer, endometriosis, endometrial cancer, polycystic ovary syndrome, endometrial polyps, benign breast disease, adenomyosis, ovarian cancer, melanoma, prostrate cancer, cancers of the colon, CNS cancers, such as glioma or astioblastomia. [0027] The compounds of this invention are cardioprotective and they are useful in lowering cholesterol, triglycerides, Lp(a), and LDL levels; inhibiting or treating hypercholesteremia; hyperlipidemia; cardiovascular disease; atherosclerosis; peripheral vascular disease; restenosis, and vasospasm; and inhibiting vascular wall damage from cellular events leading toward immune mediated vascular damage. These cardiovascular protective properties are of great importance when treating postmenopausal patients with estrogens to inhibit osteoporosis and in the male when estrogen therapy is indicated. [0028] The compounds of this invention are also antioxidants, and are therefore useful in treating or inhibiting free radical induced disease states. Specific situations in which antioxidant therapy is indicated to be warranted are with cancers, central nervous system disorders, Alzheimer's disease, bone disease, aging, inflammatory disorders, peripheral vascular disease, rheumatoid arthritis, autoimmune diseases, respiratory distress, emphysema, prevention of reperfusion injury, viral hepatitis, chronic active hepatitis, tuberculosis, psoriasis, systemic lupus erythematosus, adult respiratory distress syndrome, central nervous system trauma and stroke. [0029] The compounds of this invention are also useful in providing cognition enhancement, and in treating or inhibiting senile dementias, Alzheimer's disease, cognitive decline, neurodegenerative disorders, providing neuroprotection or cognition enhancement. [0030] The compounds of this invention are also useful in treating or inhibiting inflammatory bowel disease, ulcerative proctitis, Crohn's disease, and colitis; menopausal related conditions, such as vasomotor symptoms including hot flushes, vaginal or vulvar atrophy, atrophic vaginitis, vaginal dryness, pruritus, dyspareunia, dysuria, frequent urination, urinary incontinence, urinary tract infections, vasomotor symptoms, including hot flushes, myalgia, arthralgia, insomnia, irritability, and the like; male pattern baldness: skin atrophy; acne; type II diabetes; dysfunctional uterine bleeding; and infertility. [0031] The compounds of this invention are useful in disease states where amenorrhea is advantageous, such as leukemia, endometrial ablations, chronic renal or hepatic disease or coagulation diseases or disorders. [0032] The compounds of this invention can be used as a contraceptive agent, particularly when combined with a progestin. [0033] When administered for the treatment or inhibition of a particular disease state or disorder, it is understood that the effective dosage may vary depending upon the particular compound utilized, the mode of administration, the condition, and severity thereof, of the condition being treated, as well as the various physical factors related to the individual being treated. Effective administration of the compounds of this invention may be given at an oral dose of from about 0.1 mg/day to about 1,000 mg/day. Preferably, administration will be from about 10 mg/day to about 600 mg/day, more preferably from about 50 mg/day to about 600 mg/day, in a single dose or in two or more divided doses. The projected daily dosages are expected to vary with route of administration. [0034] Such doses may be administered in any manner useful in directing the active compounds herein to the recipient's bloodstream, including orally, via implants, parenterally (including intravenous, intraperitoneal and subcutaneous injections), rectally, intranasally, vaginally, and transdermally. [0035] Oral formulations containing the active compounds of this invention may comprise any conventionally used oral forms, including tablets, capsules, buccal forms, troches, lozenges and oral liquids, suspensions or solutions. Capsules may contain mixtures of the active compound(s) with inert fillers and/or diluents such as the pharmaceutically acceptable starches (e.g. corn, potato or tapioca starch), sugars, artificial sweetening agents, powdered celluloses, such as crystalline and microcrystalline celluloses, flours, gelatins, gums, etc. Useful tablet formulations may be made by conventional compression, wet granulation or dry granulation methods and utilize pharmaceutically acceptable diluents, binding agentis, lubricants, disintegrants, surface modifying agents (including surfactants), suspending or stabilizing agents, including, but not limited to, magnesium stearate, stearic acid, talc, sodium lauryl sulfate, microcrystalline cellulose, carboxymethylcellulose calcium, polyvinylpyrrolidone, gelatin, alginic acid, acacia gum, xanthan gum, sodium citrate, complex silicates, calcium carbonate, glycine, dextrin, sucrose, sorbitol, dicalcium phosphate, calcium sulfate, lactose, kaolin, mannitol, sodium chloride, talc, dry starches and powdered sugar. Preferred surface modifying agents include nonionic and anionic surface modifying agents. Representative examples of surface modifying agents include, but are not limited to, poloxamer 188, benzalkonium chloride, calcium stearate, cetostearl alcohol, cetomacrogol emulsifying wax, sorbitan esters, colloidol silicon dioxide, phosphates, sodium dodecylsulfate, magnesium aluminum silicate, and triethanolamine. Oral formulations herein may utilize standard delay or time release formulations to alter the absorption of the active compound(s). The oral formulation may also consist of administering the active ingredient in water or a fruit juice, containing appropriate solubilizers or emulsifiers as needed. [0036] In some cases it may be desirable to administer the compounds directly to the airways in the form of an aerosol. [0037] The compounds of this invention may also be administered parenterally or intraperitoneally. Solutions or suspensions of these active compounds as a free base or pharmacologically acceptable salt can be prepared in water suitably mixed with a surfactant such as hydroxy-propylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparation contain a preservative to prevent the growth of microorganisms. [0038] The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils. [0039] For the purposes of this disclosure, transdermal administrations are understood to include all administrations across the surface of the body and the inner linings of bodily passages including epithelial and mucosal tissues. Such administrations may be carried out using the present compounds, or pharmaceutically acceptable salts thereof, in lotions, creams, foams, patches, suspensions, solutions, and suppositories (rectal and vaginal). [0040] Transdermal administration may be accomplished through the use of a transdermal patch containing the active compound and a carrier that is inert to the active compound, is non toxic to the skin, and allows delivery of the agent for systemic absorption into the blood stream via the skin. The carrier may take any number of forms such as creams and ointments, pastes, gels, and occlusive devices. The creams and ointments may be viscous liquid or semisolid emulsions of either the oil-in-water or water-in-oil type. Pastes comprised of absorptive powders dispersed in petroleum or hydrophilic petroleum containing the active ingredient may also be suitable. A variety of occlusive devices may be used to release the active ingredient into the blood stream such as a semi-permeable membrane covering a reservoir containing the active ingredient with or without a carrier, or a matrix containing the active ingredient. Other occlusive devices are known in the literature. [0041] Suppository formulations may be made from traditional materials, including cocoa butter, with or without the addition of waxes to alter the suppository's melting point, and glycerin. Water soluble suppository bases, such as polyethylene glycols of various molecular weights, may also be used. [0042] The reagents used in the preparation of the compounds of this invention can be either commercially obtained or can be prepared by standard procedures described in the literature. [0043] The preparation of several representative compounds are described in the following Schemes 1-7. Example 1 4-Bromonaphthalene-1-carbaldehyde [0044] To a 150 ml flask was added 1,4-dibromonaphthalene ( 2.0 g, 7.0 mmol) and anhydrous ether (50 ml). After cooling to 0 °C n-BuLi (3.1 ml of 2.5 M in hexanes, 7.7 mmol) was added dropwise and stirred for 20 minutes after which anhydrous DMF (1.62 ml, 21 mmol) was added. The reaction was then warmed to ambient temperature and after 1 h the reaction was quenched with water (10 ml), stirred for 10 minutes, and extracted with ether (3x). The ether layer was dried over anhydrous Na2SO4 passed through a silica plug, and concentrated to afford 1.02 g (62%) of product as a pure off- white solid: 1H NMR (300 MHz, DMSO-d6): 5 7.80-7.85 (2H, m), 8.10 (1H, d, J = 7.7 Hz), 8.20 (1H, d, J = 7.7 Hz), 8.32 (1H, m). 9.24 (1H, m), 10.42 (1H, s), Anal, for C11H7BrO: Calc'd: C: 56.20 H: 3.00 Found: C: 56.13 H: 2.98 Example 2 4-[4-(tert-ButyldimethylsiIanyIoxy)-phenyI]-naphthalene-1-carbaldehyde [0045] A mixture of 4-bromonaphthalene-l-carbaldehyde (500 mg, 2.13 mmol), Na2CO3 (3.5 ml 2 N aqueous, 7.0 mmol), Pd(PPh3)4 (0.130 g, 0.11 mmol), 4-(tert- butyldimethylsilanoxy)boronic acid (680 mg, 2.55 mmol), and ethylene glycol dimethyl ether (55 ml) was heated to reflux for 6 h. The reaction was cooled and diluted with EtOAc. The organic layer was dried over anhydrous Na2SO4, passed through a silica plug and concentrated. Column chromatography (20% EtOAc-hexanes) afforded 510 mg (66%) of product as a yellow solid: 1H NMR (300 MHz, DMSO-oV): 5 0.28 (6H, s), 1.01 (9H, s), 7.05 (2H, d, J= 8.2 Hz), 7.43 (2H, d, J= 8.2 Hz), 7.60-7.70 (2H, m), 7.77 (1H, t, J = 8.2 Hz), 7.95 (1H, d, J = 8.5 Hz), 8.23 (1H, d, J = 7.3 Hz), 9.29 (1H, d, J = 8.5 Hz), 10.43 (1H, s). Example 3 4-(4-Hydroxyphenyl)-l-naphthaIdehydeoxime [0046] A mixture of 4-[4-(terr-butyldimethylsilanyloxy)-phenyl]-naphthalene-1- carbaldehyde (510 mg, 1.40 mmol), hydroxylamine hydrochloride (196 mg, 2.82 mmol), and anhydrous pyridine (0.228 ml, 2.82 mmol) in MeOH (3.2 ml) was heated to reflux for 3 h. The mixture was then concentrated under reduced pressure and dissolved in ether (5 ml). Then 1.0 M TBAF in THF (5.1 ml, 4.2 mmol) was added and stirred for 5 minutes. To the reaction was added water (5 ml) and then extracted with EtOAc. The organics were dried over anhydrous Na2SO4 and passed through a silica plug. Evaporation of the solvent and purification by column chromatography (10% MeOH- EtOAc) afforded 150 mg (41%) of product as a white solid: mp 200.0-200.5 °C; ]H NMR (300 MHz, DMSO-de): 6 6.93 (2H, d, J = 8.0 Hz), 7.29 (2H, d, / = 8.0 Hz), 7.42 (1H, d, J = 7.3 Hz), 7.54 (1H, appt, J = 7.6 Hz). 7.61 (1H, appt, J = 7.6 Hz), 7.83 (1H, d, J = 7.3), 7.92 (1H, d, J = 8.4 Hz), 8.73 (1H, d, J = 8.4 Hz), 8.81 (1H, s), 9.66 (lH,s), 11.45 (1H, s): MS (ESI) m/z 262 ([M-H]-). Anal, for C17H13NO2: Calc'd: C, 77.55; H, 4.98; N, 5.32 Found: C, 77.18; H, 4.93; N, 5.14 Example 4 4-(3-Fluoro-4-methoxyphenyl)-naphthaIene-1-carbaIdehyde [0047] A mixture of 4-bromonaphthalene-1-carbaldehyde (550 mg, 2.34 mmol), Na2CO3 (2.34 ml 2 N aqueous, 4.68 mmol), Pd(PPh3)4 (0.135 g, 0.12 mmol), 3-fIuoro-4- methoxyboronic acid (480 mg, 2.83 mmol), and ethylene glycol dimethyl ether (25 ml) was heated to reflux for 12 h. The reaction was cooled, diluted with EtOAc and the layers separated. The organic layer was dried over anhydrous Na2SO4, passed through a silica plug and concentrated to 810 mg crude product which was taken to the next step without further purification. An analytical sample was prepared by reverse phase HPLC (water-CH3CN-0.1% TFA): mp 137-138 °C; 1H NMR (300 MHz, DMSO-d6): 6 3.95 (3H, s), 7.30-7.47 (3H, m), 7.63-7.71 (3H, m), 7.95 (1H, d, /= 8.3 Hz), 8.24 (1H, d, J = 7.4 Hz), 9.28 (1H, d, J = 8.4 Hz), 10.44 (1H, s). Anal, for C18H13FO2 Calc'd: C, 77.13; H, 4.67 Found: C, 76.23; H, 4.74 Example 5 4-(3-Fluoro-4-hydroxyphenyl)-naphthalene-l-carbaldehyde [0048] To a 35 ml flask was added 4-(3-fluoro-4-methoxyphenyl)-naphthalene-l- carbaldehyde (720 mg -80% pure, 2.05 mmol), and pyridine hydrochloride (3 g, 26 mmol). The mixture was wanned to 195 °C for 2 h, cooled slightly, and the remaining pyridine hydrochloride was dissolved in water (50 ml). The aqueous layer was extracted with ethyl acetate (3x), dried over anhydrous Na2SO4, passed through a silica plug and concentrated to afford 570 mg (99%) of product as an off-white foam. The material was carried on to the next step without further purification: lH NMR (300 MHz, DMSO-de) 6 7.16 (2H, m), 7.35 (1H, d, J = 12.00 Hz), 7.60-7.80 (3H, m), 7.98 (2H, d, / = 8.3 Hz) 8.22 (1H, d, J = 7.4 Hz), 9.28 (1H, d, J = 8.4), 10.24 (1H, s), 10.43 (1H, s). Example 6 4-(3-FIuoro-4-hydroxyphenyI)-naphthalene-l-carbaldehydeoximc [0049] A mixture of 4-(3-fluoro-4-hydroxyphenyl)-naphthalene-l-carbaldehyde (570 rag, 2.13 mmol), hydroxylamine hydrochloride (297 mg, 4.27 mmol), and anhydrous pyridine (0.35 ml, 4.27 mmol) in MeOH (13 ml) was heated to reflux for 1.5 h. The mixture was then diluted with ether, washed with water, the organic layer was dried over anhydrous Na2SO4, passed through a silica plug and concentrated. Purification by reverse phase HPLC (water-CH3CN-0.1% TFA) afforded 400 mg (67%) of product as a white solid: mp 187-188 °C; 1H NMR (300 MHz, DMSO-d6): 5 7.12 (2H, m), 7.28 (1H, d, J = 11.4 Hz), 7.45 (1H, d, J = 7.4 Hz), 7.53-7.64 (2H, m). 7.83 (1H, d, J = 7.5 Hz), 7.90 (1H, d, J= 7.6), 8.73 (1H, d,J= 8.1 Hz), 8.81 (1H, s), 10.08 (1H, s), 11.46 (lH,s); MS m/z 282 ([M+H]+). Anal, for CnH12FNO2 Calc'd: C, 72.59; H, 4.30; N, 4.98 Found: C, 72.21; H, 4.34; N, 4.83. Example 7 Trifluoromethanesulfonic acid 4,5-dihydro-l-benzothiophene-4-yl ester [0050] To a 1000 ml round bottom flask was added 6,7-dihydro-5H- benzo[&]thiophen-4-one (7.36 g, 48.35 mmol), anhydrous CH2CI2 (500 ml), 2,6-lutidine (6.76 ml, 58.0 mmol), and the solution was cooled to 0 °C. Trifluoromethanesulfonic anhydride (15 g, 53.2 mmol) was added and the reaction was wanned to room temperature. Over the next 2 h an additional amount of Tf2O (0.6 g, 2.1 mmol) was added and the reaction was quenched with sat. NaHCO3. The aqueous was extracted with CH2Cl2 (3x), passed through a silica plug and concentrated. Column chromatography (10% EtOAc-hexanes) afforded 10.1 g (74%) product as red oil: 1H NMR (300 MHz, DMSO-d6): 5 2.62 (2H, m), 2.92 (2H, t, J == 9.0 Hz), 5.93 (1H, t, J = 4.7 Hz), 6.95 (1H, d, J= 5.2 Hz), 7.45 (1H, d, J= 5.2 Hz). Example 8 4-(4-Methoxyphenyl)-l-benzothiophene 19 [0051] A mixture of trifluoromethanesulfonic acid 4,5-dihydro-l-benzothiophene-4- yl ester (9.0 g, 31.7 nunol), Na2CO3 (39.6 ml 2 N aqueous, 79.2 mmol), Pd(PPh3)4 (1.83 g, 1.6 mmol), 4-methoxyboronic acid (5.78 mg, 38.03 mrnol), and ethylene glycol dimethyl ether (350 ml) was heated to reflux for 6 h. The reaction was cooled, diluted with EtOAc and the layers separated. The organic layer was dried over anhydrous Na2SO4, passed through a silica plug and concentrated to 5.0 g solid (1.44:1 ratio of desired to [6,7,6',7'-tetrahydro-[4,4']bi[benzo[b]thiophenyl]). This material was dissolved in toluene (50 ml) and activated MnO2 (4.5 g) was added. The mixture was refluxed overnight, cooled, filtered, and concentrated to afford a 5 g solid (1.4:1 ratio of [4,4']bi[benzo[b]thiophenyl] to desired). Column chrornatography (3:97 EtOAc/hexanes) managed to isolate 880 mg of pure product: 1H NMR. (300 MHz, DMSO-d6): 5 3.83 (3H, s), 7.09 (2H, d, J = 8.6 Hz), 7.33 (1H, d, J = 7.2 Hz), 7.40-7.45 (2H, m), 7.51 (2H, d, J= 8.7 Hz), 7.79 (1H, d, J= 5.5 Hz), 7.99 (1H, d, J = 8.0 Hz). Example 9 7-Bromo-4-(4-methoxyphenyl)-l-benzothiophene [0052] To a 25 ml round bottom flask was added 4-(4-methoxyphenyl)-l- benzothiophene (500 mg, 2.08 mmol), CH2C12 (10 ml), and the solution was cooled to - 20 °C (acetone-water, CO2). Bromine (8.33 ml of 0.25 M stock in CH2C12, 2.08 mmol) was slowly added dropwise over 0.5 h and the reaction was stirred for a additional 0.5 h. The reaction was then washed with water, dried over anhydrous Na2SO4, passed through a silica plug and concentrated to 460 mg orange oil. Recrystallization from 3:97 EtOAc-hexanes afforded 350 mg (53%) of product as white crystals: 1H NMR (300 MHz, DMSO-d6): 8 3.83 (3H, s), 7.10 (2H, d, J= 8.0 Hz), 7.31 (1H, d, J = 7.9 Hz), 7.51 (2H, d, J = 8.4 Hz), 7.56 (1H, d, J = 5.6 Hz), 7.68 (1H, d, J = 7.9 Hz), 7.92 (1H, d, J = 5.6 Hz). Anal, for C15H11BrOS: Calc'd: C: 56.44 H: 3.47 Found: C: 56.25 H: 3.42 Example 10 4-(4-MethoxyphenyI)-l-benzothiophene-7-carbaldehyde [0053] To a 25 ml round bottom flask was added 7-bromo-4-(4-methoxyphenyl)-l- benzothiophene (300 mg, 0.94 mmol) to anhydrous THF (10 ml) and the solution was cooled to -78 °C. n-BuLi (0.38 ml of 2.5 M in hexanes, 0.94 mmol) was added dropwise and the solution was stirred for 10 min after which anhydrous DMF (0.15 ml, 1.9 mmol) was added all at once at -78 °C. The reaction was stirred for 15 min then quenched with water (10 ml) and extracted with ether. The organic layers were combined, dried over anhydrous Na2SO4, and concentrated to 180 mg (71.4 %) of aldehyde products as a yellow oil. Reverse phase HPLC (CH3CN 0.1% TFA, water 0.1% TFA) produced 160 mg of a 8:3 mixture of desired product and 4-(4- methoxyphenyl)-1-benzothiophene-2-carbaldehyde as a single peak. Another side product (7-bromo-4-(4-methoxyphenyl)-l-benzothiophene-2-carbaldehyde, 20 mg) was collected: 1H NMR (8:3 ratio of desired + 7-bromo-4-(4-methoxyphenyl)-l- benzothiophene-2-carbaldehyde) (300 MHz, DMSO-d6): 5 3.86(3H, s, desired + minor), 7.14 (2H, d, J = 8.9 Hz, minor), 7.14 (2H, d, / = 8.6 Hz, desired), 7.47 (1H, d, J = 7.3 Hz, minor), 7.54-7.67 (4H, m, desired + minor), 7.99 (1H, d, J = 5.6 Hz, desired), 8.09 (1H, d, J = 8.1 Hz, minor), 8.19 (1H, d, J = 7.5 Hz), 8.41 (1H, s, minor), 10.14 (1H, s, minor), 10.27 (1H, s, desired). Anal.for C16H12O2S: Calc'd: C: 71.62 H: 4.51 Found: C: 71.32 H: 4.50 Example 11 4-(4-HydroxyphenyI)-l-benzothiophene-7-carbaldehyde [0054] To a 10 ml round bottom flask a solution of 62.5% pure 4-(4- methoxyphenyl)-1-benzothiophene-7-carbaldehyde ( remainder 37.5% 4-(4- methoxyphenyl)-1-benzothiophene-2-carbaldehyde) (102 mg, 0.38 mmol) and CH2C12 (2 ml) was cooled to -78 °C. Then BBr3 (0.8 ml 1.0 M in CH2C12,0.8 mmol) was added dropwise after which the reaction turned dark red in color. The reaction was allowed to warm to room temperature and after 1 h the reaction was complete by TLC then quenched by pouring into water (15 ml). The mixture was diluted with ether, the layers separated and the aqueous was further extracted with ether. The organic layers were combined, dried over anhydrous Na2SO4, passed through a silica plug and concentrated to a greenish solid. Reverse phase HPLC (CH3CN 0.1% TFA, water 0.1% TFA) afforded 50 mg (52%) desired product as a yellow solid: mp 203-204 °C; 'H NMR (300 MHz, DMSO-d6): 8 6.96 (2H, d, J = 8.5 Hz), 7.50 (2H, d, J = 8.5 Hz), 7.56 (1H, d, J = 5.6 Hz), 7.62 (1H, d, J = 7.5 Hz), 7.97 (1H, d,.J = 5.6 Hz), 8.16 (1H, d, J = 7.5 Hz), 9.84 (1H, s), 10.25 (1H, s); MS (ESI) m/z 253 ([M-H]) Anal, for C15H10O2S: Calc'd: C: 70.84 H: 3.96 Found: C: 70.56 H: 3.88 Example 12 4-(4-Hydroxyphenyl)-l-benzothiophene-7-carbaIdehydeoxime [0055] To a 5 ml round bottom flask was added 4-(4-hydroxyphenyl)-1- benzothiophene-7-carbaldehyde (42.0 mg, 0.165 mmol), hydroxylamine hydrochloride (23 mg, 0.331 mmol), and anhydrous pyridine (0.027 ml, 0.331 mmol) in MeOH (1.0 ml) was brought to reflux for 1.5 h and then allowed to cool. The mixture was then diluted with ether, washed with water (2 ml) and the organic layer was dried over anhydrous Na2SO4 then passed through a silica plug. Concentration under reduced pressure produced 38 mg (85%) of product as white solid. Further purification by column chromatography (30% EtOAc-hexanes) afforded 22 mg of product suitable for analytical analysis: mp 229.5-230.5 °C; 1H NMR (300 MHz, DMSO-d6): d 6.92 (2H, d, J = 8.4 Hz), 7.41 (3H, appt), 7.49 (1H, d, J = 5.7 Hz), 7.59 (1H, d, J = 7.6 Hz), 7.85 (1H, d, J= 5.6 Hz), 8.49 (1H, s), 9.68 (1H, s), 11.62 (1H, s); MS (ESI) in/z 268 ([M-H]). Anal.for C15H11NO2S: Calc'd: C: 66.90 H: 4.12 N: 5.20 Found: C: 66.42 H: 4.25 N: 4.87. Example 13 (2-Bromo-phenylsuIfanyl)-acetaldehydedimethylacetal [0056] To a 200 ml flask was added 2-bromobenzenethiol (10.0 g, 52.9 mmol), potassium carbonate (8.05 g, 58.2 mmol), and acetone (85 ml). The mixture was stirred for 15 min and bromoacetaldehyde dimethylacetal (6.8 ml, 58.2 mmol) was added dropwise. The reaction was allowed to proceed for 3 days then filtered through filtering agent and concentrated. Chromatography (5% EtOAc/hexanes to 15% EtOAc/hexanes) produced 13.25 g (90%) pure product as a yellow oil: ]H NMR (300 MHz, DMSO-d6): 8 3.20 (2H, d, J= 5.8 Hz), 3.30 (6H, s), 4.58 (1H, t, 7 = 5.8 Hz), 7.11 (III, m), 7.40 (2H, m), 7.61 (1H, d, 3 = 8.0 Hz); Anal, for C10H13BrO2S: Calc'd: C: 43.33 H: 4.73 Found: C: 43.40 H: 4.95 Example 14 7-Bromo-1-benzothiophene [0057] To a 500 ml 3-neck flask was weighed out 15 g of polyphosphoric acid (PPA) followed by chlorobenzene (250 ml). After the mixture was heated to reflux (2- bromo-phenylsulfanyl)-acetaldehyde dimethylacetal (8.0g in 60 ml chlorobenzene, 28.9 mmol) was added dropwise over 2.5 h via addition funnel and refluxed for an additional 24 h. After the reaction cooled it was filtered through a silica plug and concentrated to 6.04 g amber colored oil. Further purification by column chromatography (100% hexanes) afforded 5.47 g (89%) product as a clear oil: 1H NMR (300 MHz, DMSO-d6): 5 7.37 (1H, t, J = 7.8 Hz), 7.63 (2H, m), 7.90 (1H, d, J = 5.5 Hz), 7.94 (1H, d, J = 7.9 Hz). Anal, for C8H5BrS: Calc'd: C: 45.09 H: 2.36 Found: C: 45.41 H: 2.37 Example 15 7-(4-Methoxyphenyl)-l-benzothiophene [0058] To a 50 ml round bottom flask was added Pd2(dba)3 (107 mg, 0.117 mmol), KF (2.25 g, 3.9 mmol), 4-methoxyphenylboronic acid (2.14 g, 14.1 mmol), and the flask was purged with nitrogen. Anhydrous THF (25 ml) was then added followed by 7- 23 bromo-1-benzothiophene (2.5 g, 11.73 mmol) in 5 ml THF followed by the addition of P(Cy)3 (100 mg, 0.352 mmol). After 4 h at ambient temperature no product was observed. Heating to 60 °C overnight afforded approx. 50% completion. After the addition of another 2% Pd2(dba)3 (215 mg), 0.1 equivalent boronic acid (26 mg) and THF, the reaction was complete in 2 h. The reaction was cooled, diluted with ether, filtered through a silica plug and concentrated to 3.33 g amber oil. Purification by column chromatography (load: 5% EtOAc/hexanes to 10% EtOAc/hexanes) afforded 2.75 g (97.5%) product as a light yellow solid: mp 74-75 °C; 1H NMR (300 MHz, DMSO-d6: 5 3.84 (3H, s), 7.11 (2H, d, J= 8.7 Hz), 7.37 (1H, d, 7 = 7.1 Hz), 7.48 (1H, t, J = 7.6 Hz), 7.54 (1H, d, J = 5.5 Hz), 7.67 (2H, d, J = 8.7 Hz), 7.79 (1H, d, J = 5.5 Hz), 7.86 (1H, dd, J = 7.4 Hz, 0.8 Hz); MS (ESI) m/z 239 ([M-H]). Anal, for C15H12OS: Calc'd: C: 74.97 H: 5.03 Found: C: 74.54 H: 4.86 Example 16 4-Bromo-7-(4-methoxyphenyl)-1-benzothiophene [0059] To a -20 °C solution of 7-(4-methoxyphenyl)-1-benzothiophene (500 mg, 2.08 mmol) in CH2Cl2 (15 ml) was added Br2 (8.33 ml of 0.25 M stock in CH2Cl2, 2.08 mmol) over 45 minutes. The reaction was stirred for an additional 0.5 h, washed with water, dried over Na2SO4, passed through a silica plug and concentrated to give 660 mg (100%) of product as a yellow solid. Further purification was done by recrystalization from 3% EtOAc in hexanes: mp 103-104 °C; 1H NMR (300 MHz, DMSO-d6): 5 3.84 (3H, s), 7.12 (2H, d, J = 8.7 Hz), 7.31 (1H, d, J = 7.9 Hz), 7.54 (1H, d,J = 5.6 Hz), 7.65 (2H, d, J= 8.7 Hz), 7.72 (1H, d, J= 7.9 Hz), 7.98 (1H, d, J= 5.6 Hz). Anal. forC15H11BrOS: Calc'd: C: 56.44 H: 3.47 Found: C: 56.83 H: 3.48 Example 17 7_(4-MethoxyphenyI)-1-benzothiophene-4-carbaldehyde [0060] To a 25 ml round bottom flask was added 4-bromo-7-(4- methoxyphenyl)-l-benzothiophene (300 mg, 0.94 mmol) to anhydrous THF (10 ml) and the solution was cooled to -100 °C (N2, ether). Then BuLi (0.38 ml of 2.5 M in hexanes, 0.94 mmol) was added dropwise and the solution was stirred for 10 min after which anhydrous DMF (0.15 ml, 1.9 mmol) was added all at once at -100 °C. The reaction was stirred for 15 min then quenched with water (10 ml) and extracted with ether. The organic layers were combined, dried over anhydrous Na2SO4, and concentrated to 60 mg (24%) product as a yellow solid. Note: This reaction was also run at -80 °C (CO2, ether) to obtain a quantitative yield of aldehyde products of approx. 60% desired: mp 98-99 °C; lH NMR (300 MHz, DMSO-d6): 5 3.86 (3H, s), 7.16 (2H, d, J= 8.8 Hz), 7.64 (1H, d, J = 7.5 Hz), 7.75 (2H, d, J = 8.7 Hz), 8.13 (1H, d, J = 7.7 Hz), 8.15 (1H, d, J = 5.7 Hz), 8.39 (1H, d, J = 5.6 Hz). 10.30 (1H, s); MS (ESI) m/z 269 ([M+H]+) Anal, for C16H12O2S: Calc'd: C: 71.62 H: 4.51 Found: C: 71.29 H: 4.50 Example 18 7-(4-Hydroxyphenyl)-l-benzothiophene-4-carbaldehyde [0061] To a 50 ml round bottom flask was added 7-(4-methoxyphenyl)-l- benzothiophene-4-carbaldehyde (420 mg, 1.57 mmol) to CH2C12 (8.5 ml) and the solution was cooled to -78 °C, To the solution was added BBr3 (3.14 ml of 1.0 M in CH2C12 ,3.13 mmol) dropwise as the reaction turned dark red in color. The reaction was warmed to ambient temperature as it turned dark green and was complete in 1 h by TLC. After the reaction was quenched with water (15 ml) it was extracted with ether and the organic were combined, dried over anhydrous Na2SO4 and concentrated to 460 mg (>95%) product as a slightly impure green solid. Reverse phase HPLC (CH3CN/water with 0.1% TFA) was used to obtain an analytical sample (120 mg) as a slightly yellow solid: mp 202-204 °C; ]H NMR (300 MHz, DMSO-d6): 5 6.97 (2H, d, J = 8.5 Hz), 7.60 (1H, d, J = 7.6), 7.64 (2H, d, J = 8.5 Hz), 8.10 (1H, d, J = 7.6 Hz), 8.14 (1H, d, J = 5.6 Hz), 8.38 (1H, d, J = 5.6 Hz), 9.92 (1H, s), 10.29 (1H, s); MS (ESI) m/z 253 ([M-H]). Anal, for C15H10O2S: Calc'd: C: 70.84 H:3.96 Found: C: 69.34 H:3.97 Example 19 7-(4-Hytlroxyphenyl)-1-benzothiophene-4-carbaldehydeoxime [0062] To a 10 ml round bottom flask was added 7-(4-hydroxyphenyl)-1- benzothiophene-4-carbaldehyde (61.7 mg, 0.24 mmol), hydroxylamine hydrochloride (34 mg, 0.49 mmol), and anhydrous pyridine (0.04 ml, 0.49 mmol) in MeOH (1.5 ml) was heated to reflux for 1 h and then allowed to cool. The mixture was then diluted with ether, washed with water and the organic layer was dried over anhydrous Na2SO4 then passed through a silica plug. Concentration under reduced pressure produced 60 mg of a slightly yellow solid and purification by column chromatography (40% EtOAc- hexanes) afforded 50 mg (92%) product as a slightly yellow solid: mp 230-231 °C; ]H NMR (300 MHz, DMSO-d6): 8 6.93 (2H, d,J= 8.55 Hz), 7.38 (1H, d, J == 7.63), 7.57 (2H, d, J = 8.53 Hz), 7.68 (1H, d, J = 7.71 Hz), 7.91 (1H, d, J = 5.61 Hz), 8.12 (1H, d, J = 5.64 Hz), 8.57 (1H, s), 9.77 (1H, s), 11.41 (1H, s); MS (ESI) m/z 270 ([M+H]+). Anal, for C15H11NO2S Calc'd: C: 66.90 H: 4.12 N: 5.20 Found: C: 65.78 H: 4.16 N: 4.85. Example 20 l-Bromo-2-(2,2-dimethoxy-ethoxy)-4-methyl benzene [0063] To a solution of anhydrous ethanol (40 ml), sodium ethoxide (31.7 ml 21% wt., 86.94 mmol) and 2-bromo-5-methylphenol (Gewali, Mohan B.; Ronald, Bruce P. J. Org. Chan. 1980, 45, 2224-2229) (16.25 g, 86.94 mmol) was added 2-bromo-l,l- dimethoxy ethane (16.17 g, 95.64 mmol). The solution was heated to reflux overnight, reduced under vacuum and partitioned between water and ether. The aqueous layer was extracted with ether and the organics were passed through a silica plug and concentrated to afford 8.71 g (36%) of desired product as a pale yellow oil: 1H NMR (400 MHz, DMSO-d6): 5 2.19 (3H, s), 3.33 (6H, s), 3.96 (2H, d, J = 5.1 Hz), 4.64 (1H, t, J = 5.1 Hz), 6.98 (1H, d, J= 8.5 Hz), 7.08 (1H, dd, J = 8.4 Hz, 1.5 Hz), 7.35 (1H, d, J = 1.7 Hz). Example 21 7-B ro mo-4-methylbenzofuran [0064] To a 500 ml round bottom flask was added 15.6 g polyphosphoric acid (PPA) and anhydrous chlorobenzene (260 ml). The mixture was brought to reflux and 1- bromo-2-(2,2-dimethoxy-ethoxy)-4-methyl benzene (8.11 g, 29.5 mmol) in chlorobenzene (60 ml) was added dropwise over 2 h. The reaction was heated to reflux for 3 h, cooled to room temperature, passed through a silica plug and concentrated. Column chxomatography (100% hexane) afforded 4.67 g (75%) of product as a white waxy solid: mp 32-33 °C; 1H NMR (300 MHz, DMSO-d6): 8 2.46 (3H, s), 7.02 (1H, d, J = 7.9 Hz), 7.16 (1H, d, J = 2.2 Hz), 7.43 (1H, d, J = 7.9 Hz), 8.10 (1H, d, J = 2.2 Hz); MS (EI) m/z 210 ([M+]). Anal .for C9H7BrO: Calc'd: C: 51.22 H: 3.34 Found: C: 50.83 H: 3.08 Example 22 7-(4-Methoxyphenyl)-4-methylbenzofuran [0065] A mixture of 4-methoxyphenylboronic acid (1.51 g, 9.95 mmol), Na2CO3 (10.66 ml 2 N aqueous, 21.32 mmol), Pd(PPh3)4 (0.411 g, 0.355 mmol), 7-bromo-4- methylbenzofuran (1.5 g, 7.11 mmol), and ethylene glycol dimethyl ether (75 ml) was heated to reflux overnight. The reaction was cooled, diluted with EtOAc and the layers separated. The organic layer was dried over anhydrous Na2SO4, passed through a silica plug and concentrated. Column chromatography (10% EtOAc/hexanes) afforded 1.59 g (94%) product as a white waxy solid: mp 39-40 °C; 1H NMR (300 MHz, DMSO-d6): 8 2.51 (3H, s), 7.07 (2H, d, J = 8.8 Hz), 7.08 (1H, d, J = 2.3 Hz), 7.13 (1H, d, 7 = 7.7 Hz), 7.37 (1H, d, J = 7.6 Hz), 7.79 (2H, d, J = 8.8 Hz), 8.04 (1H, d, J = 2.2 Hz); MS (ESI) m/z 239 ([M+H]+). Anal, for C16H14O2. Calc'd: C: 80.65 H: 5.92 Found: C: 80.89 H: 5.85 Example 23 7-(4-MethoxyphenyI)-benzofuran-4-carbaldehyde [0066] To a solution of 7-(4-methoxyphenyl)-4-methylbenzofuran (1.27 g, 5.34 mmol) in carbon tetrachloride (150 ml) was added NBS (1.05 g, 5.87 minol) and AIBN (50 mg). The solution was brought to reflux for 2 h, cooled to room temperature, and the solids were filtered off. The solution was then concentrated and anhydrous CH3CN (50 ml) was added. Then potassium benzeneselenite (Syper, Ludwik; Mlochowski, Jacek Synthesis 1984, 9, 747-752) (1.33 g, 5.87 mmol), and K2HPO4 (0.93 g, 5.34 mmol) were added and the reaction was heated to reflux for 1 h after which it was allowed to cool to room temperature. The solution was then passed through a silica plug and the plug was washed with 30% EtOAc/hexanes after which the CH3CN was stripped off under hi vacuum. Chromatography (100% CH2CI2) removed the Ph2Se2 by-product to afford 1.0 g (75%) of product as a white solid: mp 143-144 °C; 1H NMR (300 MHz, DMSO-d6): 5 3.85 (3H, s), 7.15 (2H, d, J= 8.7 Hz), 7.57 (1H, d, / = 2.1 Hz), 7.75 (1H, d, J = 7.8 Hz), 7.96 (3H, appt), 8.33 (1H, d, / = 2.1 Hz), 8.04 (1H, d, 7 = 2.2 Hz); MS (ESI) m/z 253 QM+H]+). Anal, for C16H12O3: Calc'd: C: 76.18 H: 4.79 Found: C: 75.71 H: 4.96 Example 24 7-(4-HydroxyphenyI)-benzofuran-4-carbaldehyde [0067] To a 25 ml round bottom flask was cooled to -78 °C a solution of 7-(4- methoxyphenyl)-benzofuran-4-carbaldehyde (450 mg, 1.79 mmol) in anhydrous CH2Cl2 (10 ml) after which BBr3 (3.57 ml of 1.0 M in CH2Cl2, 3.57 mmol) was added dropwise. The reaction was allowed to warm to room temperature and stirred for 1 h. The reaction was then quenched with water, diluted with ether, and the organic layer was separated and dried over anhydrous Na2SO4. The solution was passed through a silica plug and concentrated. Chromatography (1:1 EtOAc/hexanes) afforded 390 mg (92%) of product as a light green solid: mp 179-180 °C; 1H NMR (300 MHz, DMSO-d6): d 6.96 (2H, d, J = 6.8 Hz), 7.56 (1H, d, J = 2.1 Hz), 7.71 (1H, d, J = 7.8 Hz), 7.84 (2H, d, J = 6.7 Hz), 7.95 (1H, d,7= 7.9 Hz), 8.31 (lH,d, J = 2.2 Hz), 9.93 (1H, s) 10.22 (1H, s); MS (ESI) m/z 239 ([M+H]+). Anal, for C15H10O3: Calc'd: C: 75.62 H: 4.23 Found: C: 75.48 H: 4.29 Example 25 7-(4-Hydroxyphenyl)-1-benzofuran-4-carbaldehydeoxime [0068] To a 15 ml round bottom flask was added 7-(4-hydroxyphenyl)-benzofuran- 4-carbaldehyde (250 mg, 1.05 mmol), hydroxylamine hydrochloride (146 mg, 2.10 mmol), anhydrous MeOH (6.5 ml), and anhydrous pyridine (0.17 ml, 2.10 mmol). The flask was then sealed and heated to 68 °C for 1 h, cooled to room temperature, dilute with ether, and the layers separated. The ether layer was washed with water, dried over anhydrous Na2SO4, passed through a silica plug, and concentrated to 250 mg (94%) clean product as a yellow solid. Further purification was done by chromatography (1:1 EtOAc/hexanes) for analytical analysis: mp 216-217 °C; 1H NMR (300 MHz, DMSO- d6): 5 6.92 (2H, d, J= 8.7 Hz), 7.36 (1H, d, J = 2.1 Hz), 7.49 (2H, app s), 7.74 (2H, d, J = 8.6 Hz), 8.14 (1H, d, J = 2.1 Hz), 8.42 (1H, s), 9.73 (1H, s) 11.36 (1H, s); MS (ESI) m/z 254 ([M+H]+). Anal, for C15H11NO3: Calc'd: C: 71.14 H: 4.38 N: 5.53 Found: C: 70.53 H: 4.32 N: 5.40. Example 26 4-Methoxy-4-methyl-biphenyl-3-ol [0069] A mixture of 4-methoxyphenylboronic acid (4.55 g, 21.38 mmol), Na2CO3 (32.1 ml 2 N aqueous, 64.2 mmol), Pd(PPh3)4 (1.24 g, 1.07 mmol), 5-iodo-2- methylphenol (Hodgson, Moore J. Client. Soc. 1926, 2038) (5.0 g, 21.38 mmol), and ethylene glycol dimethyl ether (225 ml) was heated to reflux overnight. The reaction was cooled, diluted with EtOAc and the layers separated. The organic layer was dried over anhydrous Na2SO4, passed through a silica plug and concentrated. Chromatography (30% EtOAc/hexanes) afforded 1.64 g (36%) product as a white solid and 2 g 4-methoxy biphenyl as an undesired by-product: mp 146-147 °C; 1H NMR (300 MHz, DMSO-d6): d 2.13 (3H, s), 3.78 (3H, s), 6.94 (1H, dd, J = 8.1 Hz, 2.7 Hz), 7.00 (3H, m), 7.09 (1H, d, J= 8.1 Hz), 7.48 (1H, d, 7= 9.5 Hz), 9.36 (1H, s). Anal, for C14H14O2: Calc'd: C: 78.48 H: 6.59 Found: C: 77.71 H: 6.51 Example 27 3-(2,2-Dimethoxy-ethoxy)-4-methoxy-4-methyl-biphenyI [0070] To NaH (357 mg (600 mg 60% in mineral oil, hexane washed 3X), 14.86 mmol) was added dry THF (100 ml), 4'-methoxy-4-methyl-biphenyl-3-ol (1.59 g, 7.43 mmol), and 2-bromo-l,l-dimethoxy ethane (1.76 g, 10.40 mmol). The reaction was stirred at 60 °C overnight, cooled, passed through a silica plug and concentrated to 1.66 g (74%) of product as a white solid: mp 39-40 °C; 1H NMR (300 MHz, DMSO-d6): 5 2.17 (3H, s), 3.38 (6H, s), 3.79 (3H, s), 4.09 (2H, d, / = 5.2 Hz), 4.73 (1H, t, J = 5.2 Hz), 7.00 (2H, d, J = 8.8 Hz), 7.09 (1H, dd, J = 7.7 Hz, 1.5 Hz), 7.15 (1H, d, J = 1.2 Hz), 7.18 (1H, d, J = 7.8 Hz), 7.62 (2H, d, J = 8.8 Hz); MS (ESI) m/z 303 ([M+Hf). Anal, for C18H22O4: Calc'd: C: 71.50 H: 7.33 Found: C: 71.46 H: 7.04 Example 28 4-(4-Methoxyphenyl)-7-methylbenzofuran [0071] A mixture of polyphosphoric acid (approx. 0.5 g) and chlorobenzene was brought to reflux and 3-(2,2-dimethoxy-ethoxy)-4'-methoxy-4-methyl-biphenyl (1.61 g, 5.33 mmol) in chlorobenzene (12 ml) was added dropwise. After 4 h the reaction was cooled, passed through a silica plug (the plug was washed with ether), and concentrated to 1,26 g (100%) of product as a light tan solid: mp 40-41 °C; 'H NMR (300 MHz, DMSO-d6): 5 2.50 (3H, s), 3.82 (3H, s), 7.03 (1H, d, J = 2.2 Hz), 7.07 (2H, d, J = 9.5 Hz), 7.19 (1H, d, J = 8.1 Hz), 7.23 (1H, d, J = 8.1 Hz). 7.56 (2H, d, J = 9.5 Hz), 8.06 (1H,d,y = 2.2Hz). Anal, for C16H14O2: Calc'd: C: 80.14 H: 5.92 Found: C: 80.14 H: 5.7S Example 29 4-(4-Methoxyphenyl)-benzofuran-7-carbaldehyde [0072] To a 250 ml round bottom flask was added 4-(4-methoxyphenyl)-7- methylbenzofuran (600 mg, 2.52 mmol), CCl4 (70 ml), NBS (490 mg, 2.77 mmol), and a catalytic amount of AIBN (25 mg). The reaction was brought to reflux for 2 h after which the reaction was allowed to cool, the solids were filtered off, and the solution concentrated. CH3CN (30 ml), K2HPO4 (440 mg, 2.53 mmol), and potassium benzeneselenite (630 mg, 2.77 mmol) were added and the reaction was brought to reflux for 2 h after. The reaction was cooled, passed through a silica plug (washed with 30% EtOAc/hex.), and concentrated to 810 mg of an orange solid. Further purification by chromatography (100% CH2Cl2) afforded 500 mg (78%) of product as a tan colored, solid: mp 104-105 °C; 1H NMR (500 MHz, DMSO-d6): 5 3.85 (3H, s), 7.14 (2H, d, J = 8.8 Hz), 7.20 (1H, d, J = 2.2 Hz), 7.56 (1H, d, J = 8.0 Hz), 7.69 (2H, d, J = 8.8 Hz), 7.91 (1H, d, / = 7.7 Hz), 8.26 (1H, d, J = 2.2 Hz), 10.36 (1H, s); HRMS (ESI+) m/z 253.08622 ([M+H]+). Anal, for C16H12O3: Calc'd: C: 76.18 H: 4.79 Found: C: 75.61 H: 4.73 Example 30 4-(4-Hydroxyphenyl)-benzofuran-7-carbaIdehyde [0073] To a 100 ml round bottom flask was added 4-(4-methoxyphenyl)- benzofuran-7-carbaldehyde (480 mg, 1.90 mmol), CH2C12 (12 ml), and the solution was cooled to -78 °C. Then BBr3 (3.8 ml 1.0 M in CH2Cl2, 3.8 mmol) was added dropwise and the reaction was warmed to room temperature. After 1.5 h the reaction was quenched with water (15 ml), extracted with ether (3x), passed through a silica plug and concentrated to 160 mg (35%) of product as a foam. Chromatography (1:1 EtOAchex.) produced an analytical sample: mp 184-185 °C; 1H NMR (500 MHz, DMSO-d6): 5 6.96 (2H, d, J = 8.8 Hz), 7.20 (1H, d, J = 2.5 Hz), 7.52 (1H, d, J = 7.7 Hz), 7.58 (2H, d, J = 8.5 Hz), 7.89 (1H, d, J = 7.7 Hz), 8.24 (1H, d, J = 2.2 Hz), 9.84 (1H, s), 10.35 (1H, s); HRMS (ESI+) m/z 239.07027 ([M+Hf). Anal, for C15H10O3: Calc'd: C: 75.62 H: 4.23 Found: C: 74.52 H: 4.27 Example 31 4-(4-Hydroxyphenyl)-benzofuran-7-carbaldehydeoxime [0074] To a 10 ml round bottom flask was added 4-(4-hydroxyphenyl)-benzofuran- 7-carbaldehyde (100 mg, 0.42 mmol), hydroxylamine hydrochloride (58 mg, 0.84 mmol), and anhydrous pyridine (0.07 ml, 0.84 mmol) in MeOH (3.5 ml) was brought to reflux for 1.5 h and then allowed to cool. The mixture was then diluted with ether, washed with water and the organic layer was dried over anhydrous Na2SO4 then passed through a silica plug. The solution was concentrated under reduced pressure and purified by column chromatography (50% EtOAc-hexanes) afforded 30 mg (28%) of product as a slightly yellow solid. 4-(7-Dimethoxymethylbenzofuran-4-yl)-phenol as an undesired by-product was isolated (60 mg). The by-product (60 mg, 0.212 mmol) was converted to the desired product by heating to 65 °C with hydroxylamine hydrochloride (15 mg, 0.212 mmol) in MeOH (2 ml) overnight in a sealed flask. The reaction was then diluted with ether/water, the organic layer was passed through a silica plug and concentrated to 40 mg (75%) of product as a pure white solid: mp 219-220 °C; 'H NMR (300 MHz, DMSO-ds): 5 6.92 (2H, d, J = 8.6 Hz), 7.11 (1H, d, J = 2.2 Hz), 7.34 (1H, d, 7 = 7.8 Hz), 7.50 (2H, d, J = 8.6 Hz), 7.61 (1H, d, / = 7.9 Hz), 8.12 (1H, d, J = 2.2 Hz), 8.44 (1H, s), 9.72 (1H, s), 11.53 (1H, s); MS (ESI) m/z 254 ([M+H]+). Anal, for C15H11NO3: Calc'd: C: 71.14 H: 4.38 N: 5.53 Found: C: 71.07 H: 4.41 N: 5.51. Example 32 l-(2,2-Dimethyoxy-ethoxy)-4-iodo-2-methyl benzene [0075] To a 1 L round bottom flask was cooled to 0 ° C a solution of 4-iodo-2- methylphenol (10.0 g, 42.7 mmol) in anhydrous DMF (300 ml). Then NaH (3.42 g 60% in mineral oil, 85.5 mmol) was slowly added in small portions and the reaction was wanned to room temperature (approx. 0.5 h) after which 2-bromo-l,l-dimethoxy ethane (10.1 ml, 85.5 mmol) was added then stirred overnight. The reaction was cooled to 0 ° C, 5% NaOH (300 ml) was slowly added, and the mixture was diluted with ether (1.5 L). The layers were separated and the aqueous was washed with ether (3 x 500 ml). The organic layers were dried over anhydrous Na2SO4, passed through a silica plug and concentrated under reduced pressure. Chiomatography (30% EtOAc/hex.) afforded 12.49 (91%) product as a clear oil: !H NMR (300 MHz, DMSO-d6): 5 2.11 (3H, s), 3.35 (6H, s), 3.95 (2H, d, J = 5.2 Hz), 4.68 (1H, t, J = 5.2 Hz), 6.80 (1H, d, J = 8.5 Hz), 7.43- 7.48 (2H, m). Anal.for C11H15IO3: Calc'd: C: 41.01 H: 4.69 Found: C: 40.73 H: 4.62 Example 33 5-Iodo-7-methyl-benzofuran [0076] To a 1 L 3-neck flask was added PPA (2.0 g), anhydrous chlorobenzene (300 ml) and the mixture was brought to reflux. Then l-(2,2-dimethyoxy-ethoxy)-4-iodo-2- methyl benzene (11.16 g, 34.66 mmol) in chlorobenzene (80 ml) was slowly added by addition funnel over a 2 h period. The reaction was then cooled and passed through a silica plug (washed with chlorobenzene) and concentrated to a mixture of product plus 4-iodo-2-methylphenol. Column chromatography (100% hexane) afforded 4.49 g (53%) product as a clear oil: 'H NMR (300 MHz, DMSO-d6): 6 2.44 (3H, s), 6.91 (1H, d, J = 2.2 Hz), 7.46 (1H, brs), 7.86 (1H, d, J - 1.2 Hz), 8.00 (1H, d, J = 2.2 Hz); MS (El) in/z 258 ([M]+). Anal.for C9H7IO: Calc'd: C: 41.89 H: 2.73 Found: C: 41.46 H: 2.63 Example 34 5-(4-Methoxyphenyl)-7-methyl-benzofuran [0077] A mixture of 4-methoxyphenylboronic acid (4.64 g, 30.54 ramol), Na2CO3 (31 ml 2 N aqueous, 61.09 mmol), Pd(PPh3)4 (0.88 g, 0.76 mmol), 5-iodo-7-methyl- benzofuran (3.94 g, 15.27 mmol), and ethylene glycol dimethyl ether (160 ml) was refluxed for 1.5 h. The reaction was cooled, ether/water (1 L/50 ml) was added and the layers separated. The aqueous was further extracted with ether (2 x 500 ml). The organic layers were dried over anhydrous Na2SO4, passed through a silica plug and concentrated to 6.54 g brown solid. Analysis by 1H NMR showed desired product plus 4-methoxy-biphenyl in about a 1:1 ratio (6.54 g approx. 3.69 g product, 99% yield) which could not be separated by column chromatography and was carried on to the next step. Reverse phase HPLC (CH3CN/water/0.1% TFA) afforded an analytical sample as a white solid: mp 82-83 °C; 1H NMR (300 MHz, DMSO-d6): d 2.52 (3H, s), 3.80 (3H, s>, 6.97 (1H, d, J = 2.1 Hz), 7.12 (2H, d, J = 8.7 Hz), 7.38 (1H, s), 7.60 (2H, d, J = 8.7 Hz), 7.66 (1H, d, J= 1.4 Hz), 8.01 (1H, d, J = 2.1 Hz); MS (EI) m/z 238 ([M]+). Anal.for C16H14O2: Calc'd: C: 80.65 H: 5.92 Found: C: 80.52 H: 5.55 Example 35 5-(4-Methoxy-phenyl)-benzofuran-7-carbaIdehyde [0078] To a solution of 5-(4-methoxyphenyl)-7-methyl-benzofuran (1.60 g, 2.83 g 1:1 ratio with 4-methoxy-biphenyl 6.72 mmol) in carbon tetrachloride (190 ml) was added NBS (1.32 g, 7.40 mmol) and AIBN (50 mg). The solution was brought to reflux for 2 h, cooled to room temperature, and the solids were filtered off. The solution was then concentrated and anhydrous CH3CN (80 ml) was added. Then potassium benzeneselenite (2.14 g, 9.41 mmol), and K2HPO4 (1.17 g, 6.72 mmol) were added and then reaction was heated to reflux for 1 h after which it was allowed to cool to room temperature. The solution was then passed through a silica plug and concentrated under high vacuum. Chromatography (100% CH2Cl2) afforded 850 mg (50%) product as a white solid: mp 94-95 °C; 1H NMR (300 MHz, DMSO-d6): 5 3.82 (3H, s), 7.08 (2H, d, J = 8.8 Hz), 7.14 (1H, d, J = 2.2 Hz), 7.71 (2H, d, J = 8.8 Hz), 8.10 (1H, d, J = 1.9 Hz), 8.21 (1H, d, J = 2.2 Hz), 8.25 (1H, d, J = 1.9 Hz), 10.37 (1H, s); MS (ESI) m/z 253 ([M+H]+). Anal, for C16H12O3: Calc'd: C: 76.18 H: 4.79 Found: C: 74.96 H: 4.32 Example 36 5-(4-OH-Phenyl)-benzofuran-7-carbaldehyde [0079] To a 10 ml round bottom flask was added 5-(4-methoxy-phenyl)-benzofuran- 7-carbaldehyde (100 mg, 0.395 mmol), and pyridine hydrochloride (600 mg, 5.2 mmol). The mixture was heated to 195 °C for 1 h, cooled slightly, then water was added to dissolve the remaining pyridine hydrochloride. The aqueous was extracted with EtOAc, passed through a silica plug, and concentrated. Further purification by column chromatography afforded 76 mg (81%) of product as a yellow solid: mp 148-149 °C; 1H NMR (400 MHz, DMSO-d6): 5 6.86 (2H, d, J - 8.7 Hz), 7.09 (1H, d, J = 2.2 Hz), 7.55 (2H, d, J= 8.6 Hz), 8.02 (1H, d, J = 1.8 Hz), 8.16 (2H, appd), 9.56 (1H, s), 10.32 (1H, s); MS (ESI) m/z 237 ([M-H]"). Anal, for C15H10O3: Calc'd: C: 75.62 H: 4.23 Found: C: 74.88 H: 4.08 Example 37 5-(4-Hydroxyphenyl)-l-benzofuran-7-carbaldehydeoxime [0080] To a 10 ml round bottom flask was added 5-(4-hydroxyphenyl)-benzofuran- 7-carbaldehyde (76 mg, 0.32 mmol), hydroxylamine hydrochlorode (44.4 mg, 0.64 mmol), anhydrous MeOH (2 ml), and anhydrous pyridine (0.06 ml, 0.67 mmol). The reaetion was then heated to 68 °C and the reaction was done in 5 minutes. The reaction was then cooled to room temperature, dilute with ether, arid the layers separated. The ether layer was washed with water, dried over anhydrous Na2SO4, passed through a silica plug, and concentrated to 20 mg (25%) of product as a yellow solid: 1H NMR (300 MHz, DMSO-d6): 5 6.86 (2H, d, J = 8.5 Hz), 7.03 (1H, d, J = 2.1 Hz), 7.51 (2H, d, J = 8.5 Hz), 7.73 (1H, d, J= 1.4 Hz), 7.84 (1H, d, J = 1.6 Hz), 8.08 (1H, d, / = 2.1 Hz), 8.45 (1H, s) 9.56 (1H, s), 11.57 (1H, s); MS (ESI) m/z 254 ([M+H]+). Anal, for C15H11NO3: Calc'd: C: 71.14 H: 4.38 N: 5.53 Found: C: 69.67 H: 4.23 N: 5.15. Example 38 2-Bromo-l-(2,2-dimethyoxy-ethoxy)-4-methyI benzene [0081] To a 2 L round bottom flask was cooled to 0 ° C a solution of 2-bromo-4- methylphenol (25 g, 133.66 mmol) in anhydrous DMF (940 ml). Then NaH (10.7 g 60% in mineral oil, 267.3 mmol) was slowly added in small portions and the reaction was wanned to room temperature (approx. 0.5 h) after which 2-brorno-l,l-dimethoxy ethane (31.6 ml, 267.4 mmol) was added. The reaction was warmed to room temperature for 3 h and then to 100 °C for 4 h. The reaction was cooled, pass through a silica plug, and concentrated. The brown mixture was diluted with EtOAc, passed through a silica plug again to remove brown solids and concentrated to 24.0 g (65%) amber colored oil: 1H NMR (300 MHz, DMSO-d6): 8 2.23 (3H, s), 3.37 (6H, s), 4.00 (2H, d, J = 5.2 Hz), 4.68 (1H, t, J = 5.2 Hz), 7.03 (1H, d, /= 8.4 Hz), 7.12 (1H, dd, J = 8.4 Hz, 1.7 Hz), 7.40 (1H, d, J= 1.7 Hz). Example 39 7-Bromo-5-methylbenzofuran. [0082] To a 2 L round bottom flask was added PPA (3 g), anhydrous chlorobenzene (1.0 L) and the mixture was brought to reflux followed by the slow addition of 2-bromo- 1-(2,2-dimethyoxy-ethoxy)-4-methyl benzene (22.9 g, 83.3 mmol) in chlorobenzene (200 ml) by addition funnel over a 2 h period. The reaction was then cooled and passed 36 through a silica plug (washed with chlorobenzene) and concentrated to a mixture of product plus 4-iodo-2-methylphenol. Column chromatogfaphy (10% EtOAc/hexane) afforded 11.54 g (66%) of product as a clear oil: 1H NMR (300 MHz, DMSO-d6): 8 2.40 (3H, s), 7.02 (1H, d, J = 2.2 Hz), 7.39 (1H, s), 7.45 (1H, s), 8.07 (1H, d, J = 2.2 Hz). Anal for C9H7BrO: Calc'd: C: 51.22 H: 3.34 Found: C: 52.54 H: 3.58 Example 40 7-(4-Methoxyphenyl)-5-methyl-benzofuran [0083] A mixture of 4-methoxyphenylboronic acid (4.76 g, 31.3 mmol), Na2CO3 (32.6 2 N aqueous, 65.2 mmol), Pd(PPh3)4 (1.5 g, 1.3 mmol), 7~bromo-5- methylbenzofuran (5.5 g, 26.1 mmol), and ethylene glycol dimethyl ether (275 ml) was heated to reflux for 12 h. The reaction was cooled, ether (500 ml) was added and the layers separated. The aqueous was further extracted with ether and the organic layers were dried over anhydrous Na2SO4, passed through a silica plug and concentrated to 7.16 g brown oil. Further purification by column chromatography (10% EtOAc/hexanes) afforded 5.62 g (91%) product as a clear oil: 1H NMR (300 MHz, DMSO-d6): 6 3.44 (3H, s), 3.82 (3H, s), 6.94 (1H, d, J = 2.2 Hz), 7.108 (2H, d, J = 8.8 Hz), 7.30 (1H, s), 7.38 (1H, s), 7.81 (2H, d, J = 8.8 Hz), 8.00 (1H, d, / = 2.2 Hz). Example 41 7-(4-Methoxyphenyl)-benzofuran-5-carbaldehyde [0084] To a solution of 7-(4-methoxyphenyl)-5-methyl-benzofuran (4.66 g, 19.58 mmol) in carbon tetrachloride (560 ml) was added NBS (3.83 g, 21.54 mmol) and AIBN (75 mg). The solution was brought to reflux for 4 h, cooled to room temperature, reduced by half, and the solids were filtered off. The solution was then concentrated to a yellow solid and anhydrous CH3CN (230 ml) was added. Then potassium benzeneselenite (5.34 g, 23.5 mmol), and K2HPO4 (4.09 g, 23.48 mmol) were added and then reaction was refluxed for 1.5 h after which it was allowed to cool to room temperature. The solution was then passed through a silica plug and concentrated under high vacuum. Chromatography (100% CH2CI2) afforded 3.3 g (67%) product as a light orange solid: mp 79-SO °C; 'H NMR (300 MHz, DMSO-d*): 5 3.85 (3H, s), 7.13 (2H, d, 7= 8.8 Hz), 7.23 (1H, d, J= 2.2 Hz), 7.88 (2H, d, 7= 8.8 Hz), 8.02 (1H, d, J = 1.4 Hz), 8.23 (2H, m), 10.13 (1H, s); MS (ESI) m/z 253 ([M+H]+). Anal.forC16H12O3: Calc'd: C: 76.18 H: 4.79 Found: C: 75.44 H: 4.85 Example 42 7-(4-HydroKyphenyl)-benzofuran-5-carbaIdehyde [0085] To a 10 ml round bottom flask was added 7-(4-methoxyphenyl)-benzofuran- 5-carbaIdehyde (0.50 g, 1.98 rnmol), and pyridine hydrochloride (1.2 g. 5.2 mmol). The mixture was heated to 190 °C for 2 h, cooled slightly, then water (10 ml) was added to dissolve the remaining pyridine hydrochloride. The aqueous was extracted with EtOAc (3X), passed through a silica plug, and concentrated to 450 mg (96%) of crude product as a light yellow foam. The crude from this reaction was combined with a second batch (1 g scale reaction) and purified by column chromatography (1:1 EtOAc/Hexanes) to afford 760 mg of product as a yellow solid: mp 154-155 °C; 1H NMR (300 MHz, DMSO-d6): 5 6.95 (2H, d, J = 8.6 Hz), 7.21 (1H, d, J = 2.2 Hz), 7.76 (2H, d, J = 8.6 Hz), 7.98 (1H, d, J= 1.5 Hz), 8.19 (1H, d, J = 1.5 Hz), 8.22 (1H, d, J = 2.2 Hz), 9.81 (1H, s), 10.12 (1H, s); MS (ESI) m/z 237 ([M-H]-). Anal, for C15H10O3: Calc'd: C: 75.62 H: 4.23 Found: C: 75.19 H: 4.01 Example 43 7-(4-Hydroxyphenyl)-benzofuran-5-carbaldehydeoxime [0086] To a 25 ml round, bottom flask was added 7-(4-hydroxyphenyl)-benzofuran- 5-carbaldehyde (400 mg, 1.68 mmol), hydroxylamine hydrochlorode (234 rag, 3.36 mmol), anhydrous MeOH (10.4 ml), and anhydrous pyridine (0.272 ml, 3.36 mmol). The reaction was then heated to 68 °C and the reaction was brought to reflux for 1 h. The reaction was then cooled to room temperature, dilute with ether, and the layers separated. The ether layer was washed with water, dried over anhydrous Na2SO4). passed through a silica plug, and concentrated to 410 mg (96%) product as a yellow solid. The crude material was pure by 1H NMR (~ 4% cis isomer was detected) and LC- MS (one peak): mp 192-194 °C ]H NMR (300 MHz, DMSO-d6): 5 6.92 (2H, d, J = 8.6 Hz), 7.05 (1H, d, J = 2.2 Hz), 7.69-7.72 (3H, m), 7.79 (1H, d, J = 1.4 Hz), 8.09 (1H, d, J = 1.1 Hz), 8.27 (1H, s), 9.74 (1H, s), 11.14 (1H, s); MS (ESI) m/z 254 (|M+H]+). Anal, for C15H11NO3: Calc'd: C: 71.14 H: 4.38 N: 5.53 Found: C: 70.82 H: 4.22 N: 5.45. Example 44 [0087] Representative examples of the invention were evaluated for their ability to compete with 17ß-estradiol for both ERa and ERß. This test procedure provides the methodology for one to determine whether a particular compound binds to the estrogen receptor (and is therefore "estrogenic") and whether there is selectivity for ERa or ER|3. The values are shown in the Table infra and are reported as IC50S. 17ß- estradiol is included as a standard reference for comparison. The procedure used is briefly described below. A crude lysate of E. coli expressing the estrogen receptor ligand binding domains (D, E, & F) of human ERa or ERp was prepared. Both receptors and compounds were diluted in 1X Dulbecco's PBS (DPBS) supplemented with 1 mM EDTA. Using a high binding masked microtiter plate, 100 uL of receptor (1 uG/well) was combined with 2 nM [3H]-17P-estradiol and various concentrations of compound. After between 5 and 15 hours at room temperature, the plates were washed with DPBS/1 mM EDTA and bound radioactivity determined by liquid scintillation counting. The IC50 is defined as the concentration of compound that decreases total 17P-estradiol binding by 50%. The results obtained are described in the table below. Table. l-(4'-Hydroxy-Phenyl)-Aryl-Carbaldehyde Oxime Derivatives [0088] The results obtained in the standard pharmacological test procedure demonstrate that the compounds of this invention are estrogenic compounds, some with strong preferential affinity for the ERp receptor. The compounds of this invention range from having high preferential affinity for ERp over ERa to almost equal affinity for both receptors. Thus, compounds of this invention will span a range of activity based, at least partially, on their receptor affinity selectivity profiles. Additionally, since each novel receptor ligand complex is unique and thus its interaction with various coregulatory proteins is unique, compounds of this invention will display different modulatory behavior depending on the cellular context they are in. For example, in some cell-types, it is possible for a compound to behave as an estrogen agonist while in other tissues, an antagonist. Compounds with such activity have sometimes been referred to as SERMs (Selective Estrogen Receptor Modulators). Unlike many estrogens, however, many of the SERMs do not cause increases in uterine wet weight. These compounds are antiestrogenic in the uterus and can completely antagonize the trophic effects of estrogen agonists in uterine tissue. These compounds, however, act as estrogen agonists in the bone, cardiovascular, and central nervous systems. Due to this tissue selective nature of these compounds, they are useful in treating or preventing in a mammal disease states or syndromes which are caused or associated with an estrogen deficiency (in certain tissues such as bone or cardiovascular) or an excess of estrogen (in the uterus or mammary glands). [0089] Even beyond such cell-specific modulation, compounds of this invention also have the potential to behave as agonists on one receptor type while behaving as antagonists on the other. For example, it has been demonstrated that compounds can be an antagonist on ERp while being an agonist on ERa (Meyers, Marvin I; Sun, Jun; Carlson, Kathryn E.; Katzenellenbogen, Benita S.; Katfcenellenbogen, John A.. J. Med. Chem. (1999), 42(13), 2456-2468). Such ERSAA (Estrogen Receptor Selective Agonist Antagonist) activity provides for pharmacologically distinct estrogenic activity within this series of compounds. [0090] Standard pharmacological test procedures are readily available to determine the activity profile of a given test compound. The following briefly summarizes several representative test procedures procedures. Standard pharmacological test procedures for SERMs are also provided in US Patents 4,418,068 and 5,998,402. Example 45 Rat Uterotrophic/Antiuterotrophic Test Procedure [0091] The estrogenic and antiestrogenic properties of the compounds can be determined in an immature rat uterotrophic assay (4 day) that (as described previously by L.J.Black and R.L.Goode, Life Sciences, 26, 1453 (1980). Immature Sprague- Dawley rats (female, 18 days old) were tested in groups of six. The animals are treated by daily ip injection with 10 uG compound, 100 uG compound, (100 uG compound + 1 uG 173-estradiol) to check antiestrogenicity, and 1 uG 17P-estradioI, with 50% DMSO/50% saline as the injection vehicle. On day 4 the animals are sacrificed by CO2 asphyxiation and their uteri removed and stripped of excess lipid, any fluid removed and the wet weight determined. A small section of one horn is submitted for histology and the remainder used to isolate total RNA in order to evaluate complement component 3 gene expression. Example 46 6-Week Ovariectomized Rat Test Procedure - Bone and Cardioprotection [0092] Female Sprague Dawley CD rats, ovx or sham ovx, are obtained 1 day after surgery from Taconic Farm (weight range 240 - 275 g). They are housed 3 or 4 rats/cage in a room on a 12/12 (light/dark) schedule and provided with food (Purina 5K96C rat chow) and water ad libitum. Treatment for all studies begin 1 day after the animals arrival and dosed 7 days per week as indicated for 6 weeks. A group of age matched sham operated rats not receiving any treatment serve as an intact, estrogen replete control group for each study. [0093] All treatments are prepared in 1% tween 80 in normal saline at defined concentrations so that the treatment volume is 0.1mL/100g body weight. 17ß-estradiol is dissolved in corn oil (20 µg/mL) and delivered subcutaneously, 0.1 mL/rat. All dosages are adjusted at three week intervals according to group mean body weight measurements. [0094] Five weeks after the initiation of treatment and one week prior to the termination of the study, each rat is evaluated for bone mineral density (BMD). The total and trabecular density of the proximal tibia are evaluated in anesthetized rats using an XCT-960M (pQCT; Stratec Medizintechnik, Pforzheim, Germany). The measurements are performed as follows: Fifteen minutes prior to scanning, each rat is anesthetized with an intraperitoneal injection of 45 mg/kg ketamine, 8.5 mg/kg xylazine, and 1.5 mg/kg acepromazine. [0095] The right hind limb is passed through a polycarbonate tube with a diameter of 25 mm and taped to an acrylic frame with the ankle joint at a 90° angle and the knee joint at 180°. The polycarbonate tube is affixed to a sliding platform that maintains it perpendicular to the aperture of the pQCT. The platform is adjusted so that the distal end of the femur and the proximal end of the tibia would be in the scanning field. A two dimensional scout view is run for a length of 10 mm and a line resolution of 0.2 mm. After the scout view is displayed on the monitor, the proximal end of the tibia is located. The pQCT scan is initiated 3.4 mm distal from this point. The pQCT scan is 1 mm thick, has a voxel (three dimensional pixel) size of 0.140 mm, and consists of 145 projections through the slice. [0096] After the pQCT scan is completed, the image is displayed on the monitor. A region of interest including the tibia but excluding the fibula is outlined. The soft tissue is automatically removed using an iterative algorithm. The density of the remaining bone (total density) is reported in mg/cm3. The outer 55% of the bone is peeled away in a concentric spiral. The density of the remaining bone (Trabecular density) is reported in mg/cm3. One week after BMD evaluation the rats are euthanized by carbon dioxide suffocation and blood collected for cholesterol determination. The uteri are removed and the weights taken. Total cholesterol is determined using a Boehringer-Mannheim Hitachi 911 clinical analyzer using the Cholesterol/HP kit. Statistics were compared using one-way analysis of variance with Dunnet's test. Example 47 MCF-7/ERE Antiproliferative Test Procedure [0097] Stock solutions of test compounds (usually 0.1 M) are prepared in DMSO and then diluted 10 to 100-fold with DMSO to make working solutions of 1 or 10 mM. The DMSO stocks are stored at either 4°C (0.1 M) or -20°C ( cells are passaged twice a week with growth medium [D-MEM/F-12 medium containing 10% (v/v) heat-inactivated fetal bovine serum, 1% (v/v) Penicillin-Streptomycin, and 2 mM glutaMax-1]. The cells are maintained in vented flasks at 37°C inside a 5% CO2/95% humidified air incubator. One day prior to treatment, the cells are plated with growth medium at 25,000/well into 96 well plates and incubated at 37°C overnight. [0098J The cells are infected for 2 hr at 37°C with 50 µl/well of a 1:10 dilution of adenovirus 5-ERE-tk-luciferase in experimental medium [phenol red-free D-MEM/F- 12 medium containing 10% (v/v) heat-inactived charcoal-stripped fetal bovine serum, 1% (v/v) Penicillin-Streptomycin, 2 mM glutaMax-1, 1 mM sodium pyruvate]. The wells axe then washed once with 150 µ?. of experimental medium. Finally, the cells are treated for 24 hr at 37°C in replicates of 8 wells/treatment with 150 µ?/well of vehicle ( 1000-fold into experimental medium. [0099] Initial screening of test compounds is done at a single dose of 1 u,M that is tested alone (agonist mode) or in combination with 0.1 nM 17|3~estradiol (EC80; antagonist mode). Each 96 well plate also includes a vehicle control group (0.1% v/v DMSO) and an agonist control group (either 0.1 or 1 nM 17(3-estradiol). Dose-response experiments are performed in either the agonist and/or antagonist modes on active compounds in log increases from 10"14 to 10"5 M. From these dose-response curves, EC50 and IC50 values, respectively, are generated. The final well in each treatment group contains 5 µl of 3 x 10-5 M ICI-182,780 (10-6 M final concentration) as an ER antagonist control. [0100] After treatment, the cells are lysed on a shaker for 15 rnin with 25 µl/well of 1X cell culture lysis reagent (Promega Corporation). The cell lysates (20µl) are transferred to a 96 well luminometer plate, and luciferase activity is measured in a MicroLumat LB 96 P luminometer (EG & G Berthold) using 100 µl/well of luciferase substrate (Promega Corporation). Prior to the injection of substrate, a 1 second background measurement is made for each well. Following the injection of substrate, luciferase activity is measured for 10 seconds after a 1 second delay. The data are transferred from the luminometer to a Macintosh personal computer and analyzed using the JMP software (SAS Institute); this program subtracts the background reading from the luciferase measurement for each well and then determines the mean and standard deviation of each treatment. [0101] The luciferase data are transformed by logarithms, and the Huber M- estimator is used to down-weight the outlying transformed observations. The JMP software is used to analyze the transformed and weighted data for one-way ANOVA (Dunnett's test). The compound treatments are compared to the vehicle control results in the agonist mode, or the positive agonist control results (0.1 nM 17|3-estradiol) in the antagonist mode. For the initial single dose experiment, if the compound treatment results are significantly different from the appropriate control (p are reported as the percent relative to the 17fi-estradiol control [i.e., ((compound - vehicle control)/(17p-estradiol control - vehicle control)) x 100]. The IMP software is also used to determine the EC50 and/or IC50 values from the non-linear dose-response curves. Example 48 Inhibition of LDL Oxidation - Antioxidant Activity [0102] Porcine aortas are obtained from an abattoir, washed, transported in chilled PBS, and aortic endothelial cells are harvested. To harvest the cells, the intercostal vessels of the aorta are tied off and one end of the aorta clamped. Fresh, sterile filtered, 0.2% collagenase (Sigma Type I) is placed in the vessel and the other end of the vessel then clamped to form a closed system. The aorta is incubated at 37°C for 15-20 minutes, after which the collagenase solution is collected and centrifuged for 5 minutes at 2000 x g. Each pellet is suspended in 7 ml. of endothelial cell culture medium consisting of phenol red free DMEM/Ham's F12 media supplemented with charcoal stripped FBS (5%), NuSerum (5%), L-glutamine (4mM), penicillin- streptomycin (1000U/ml, 1000µg/ml) and gentimicin (75µg/ml), seeded in 100mm petri dish and incubated at 37°C in 5%CO2. After 20 minutes, the cells are rinsed with PBS and fresh medium added, this was repeated again at 24 hours. The cells are confluent after approximately 1 week. The endothelial cells are routinely fed twice a week and, when confluent, trypsinized and seeded at a 1:7 ratio. Cell mediated oxidation of 12.5 µg/mL LDL is allowed to proceed in the presence of the compound to be evaluated (5 uM) for 4 hours at 37 °C. Results are expressed as the percent inhibition of the oxidative process as measured by the TBARS (thiobarbituric acid reactive substances) method for analysis of free aldehydes (Yagi K., Biochem Med 15:212-216 (1976)). Example 49 D12 Hypothalmic Cell Test Procedure [0103] D12 rat hypothalamic cells are subcloned from the RCF17 parental cell line and stored frozen. They are routinely grown in DMEM:F12 (1:1), glutaMAX-1 (2 mM); penicillin (100 U/ml)-streptomycin (100 rag/ml), plus 10% fetal bovine serum (FBS). The cells are plated in phenol red-free medium (DMEM:F12, glutaMAX, penicillin-streptomycin) containing 2-10% charcoal stripped FBS at a subconfluent density (1-4 x 10 6 cells/ 150 mm dish). The cells are refed 24 h later with medium containing 2% stripped serum. To test for agonist activity, cells are treated with 10 nM 17b-estradiol or various doses of test compound (1 mM or a range from 1 pM to 1 mM). To test for antagonist activity the cells are treated with 0.1 nM 17(3-estradiol in the absence or presence of varying doses (100 pM to 1 mM) of test compound. Control dishes are also treated with DMSO as a negative control. Forty-eight hours after hormone addition, the cells are lysed and binding test procedure performed. [0104] For each binding test procedure 100-150 mg protein is incubated with 10 nM 3H-R5020 + 100-fold excess R5020 in a 150 ml volume. Triplicate reactions (three with R5020, three without R5020) are prepared in a 96 well plate. The protein extract is added first followed by 3H-R5020 or 3H-R5020 + lOOx unlabeled R5020. The reaction is performed for 1-2 hr at room temperature . The reaction is stopped by the addition of 100 ml cold 5% charcoal (Norit SX-4), 0.5% dextran 69K (Pharmacia) in TE pH 7.4 . After 5 min at room temperature, the bound and unbound ligand are separated by centrifugation (5 min, 1000 RCF, 4°C). The supernatant solution (-150 ml) is removed and transferred to a scintillation vial. Following the addition of scintillation fluid (Beckman Ready Protein+), the samples are counted for 1 min in a scintillation counter. Example 50 Progesterone Receptor in the CNS Preoptic Area [0105] Sixty (60) day old female Sprague-Dawley rats are ovariectomized. The animals are housed in an animal care facility with a 12-h light, 12-h dark photoperiod and free access to tap water and rodent chow. [0106] Ovariectomized animals are randomly divided into groups that are injected with vehicle (50% DMSO, 40% PBS, 10% ethanol vehicle), 17|3-estradiol (200ng/kg) or the compound to be tested. Additional animals are injected with the test compound lhr prior to injection of 17P-estradiol to evaluate the antagonistic properties of this compound. Six hrs after s.c. injection, animals are euthanized with a lethal dose of CO2 and their brains collected and frozen. [0107] Tissue collected from animals is cut on a cryostat at -16°C and collected on Silane-coated microscope slides. The section-mounted slides are then dried on a slide warmer maintained at 42°C and stored in desiccated slide boxes at -S0°C. Prior to processing, the desiccated slide boxes are slowly warmed to room temperature (-20°C for 12-16 hrs; 4oC for 2 hrs; room temperature for 1 hr) to eliminate condensation formation on slides and thus minimize tissue and RNA degradation. The dry slides are loaded into metal racks, postfixed in 4% paraformaldehyde (pH 9.0) for 5 min and processed as previously described. [0108] A plasmid containing a 815bp fragment of the rat PR cDNA 9 (ligand binding domain) is linearized and used to generate a S 35 -UTP labeled probe that is complimentary to a portion of the rat PR mRNA. Processed section-mounted slides are hybridized with 200ml of hybridization mix containing the riboprobe (4-6x10 6 DPM/ slide) and 50% formamide and incubated overnight in a 55 °C humidified chamber. In the morning, the slides are placed in metal racks that are immersed in 2xSSC (0.15M NaCl, 0.015M sodium citrate; pH 7.0) / 10mM DTT. The racks are all transferred to a large container and washed in 2xSSC/ lOmM DTT for 15 min at RT with gentle agitation. Slides are then washed in RNase buffer at 37°C for 30 min, treated with RNase A (20mg/ml) for 30 min at 37°C, and washed for 15 min in room temperature 1X SSC. Subsequently, the slides are washed (2 X 30 min) in 65°C in 0.1X SSC to remove nonspecific label, rinsed in room temperature 0.1X SSC for 15 min and dehydrated with a graded series of alcohol: ammonium acetate (70%, 95%, and 100%). Air dried slides are opposed to x-ray film for 3 days and then photographically processed. The slides from all animals are hybridized, washed, exposed and photographically processed together to eliminate differences due to interassay variation in conditions. Example 51 Rat Hot Flush - CNS Effects [0109] Ovariectomized-female, 60 day-old Sprague-Dawley rats are obtained following surgery. The surgeries are done a minimum of 8 days prior to the first treatment. The animals are housed individually under 12 h light/dark cycle and given standard rat chow and water ad libitum. [0110] Two control groups are included in every study. Doses are prepared based on mg/kg mean group body weight in either 10% DMSO in sesame oil (sc studies) or in 1.0% tween 80 in saline (po studies). Animals are administered test compounds at doses ranging from 0.01 to 10 mg/kg mean group body weight. Vehicle and ethinyl estradiol (EE) controls (0.1 mg/kg, sc or 0.3 mg/kg, po) control groups are included in each test. When the compounds are tested for their antagonist activity, EE is coadministered at 0.1 or 0.3 mg/kg for sc or po studies, respectively. The test compounds are administered up to the day tail skin temperature is measured. [0111] After the acclimation period of four days, the animals are treated once daily with the compound(s) of interest. There are 10 animals/treatment group. Administration of the compound is either by sc injection of 0.1 ml in the nape of the neck or po in a volume of 0.5 ml. On the 3rd day of treatment, a morphine pellet (75 mg morphine sulfate) is implanted subcutaneously. On the 5th day of treatment, one or two additional morphine pellets are implanted. On the eighth day, approximately half of the animals are injected with Ketamine (80 mg/kg, intramuscularly) and a thermocouple, connected with to a MacLab Data Acquisition System (API Insturments, Milford, MA) is taped on the tail approximately one inch from the root of the tail. This system allowed the continuous measurement of tail skin temperature. Baseline temperature is measured for 15 min, then naloxone (1.0 mg/kg) is given sc (0.2 ml) to block the effect of morphine and tail skin temperature is measured for one hour thereafter. On the ninth day, the remaining of the animals are set up and analyzed similarly. Example 52 Vasomotor Function in Isolated Rat Aortic Rings [0112] Sprage-Dawley rats (240-260 grams) are divided into 4 groups: 1. Normal non-ovariectomized (intact) 2. Ovariectomized (ovex) vehicle treated 3. Ovariectomized 17-ß-estradiol treated (1mg/kg/day) 4. Ovariectomized animals treated with test compound (i.e., lmg/kg/day) [0113] Animals are ovariectomized approximately 3 weeks prior to treatment. Each animal receives 1mg/kg/day of either 17ß-estradiol sulfate or test compound suspended in distilled, deionized water with 1% tween-80 by gastric gavage. Vehicle treated animals received an appropriate volume of the vehicle used in the drug treated groups. [0114] Animals are euthanized by CO2 inhalation and exsanguination. Their thoracic aortas are rapidly removed and placed in 37°C physiological solution with the following composition (mM): NaCl (54.7), KC1 (5.0), NaHCO3 (25.0), MgCl2 2H2O (2.5), D-glucose (11.8) and CaCl2 (0.2) gassed with CO2-O2, 95%/5% for a final pH of 7.4. The advantitia is removed from the outer surface and the vessel is cut into 2-3 mm wide rings. Rings are suspended in at 10 mL tissue bath with one end attached to the bottom of the bath and the other to a force transducer. A resting tension of 1 gram is placed on the rings. Rings are equilibrated for 1 hour, signals are acquired and analyzed. [0115] After equilibration, the rings are exposed to increasing concentrations of phenylephrine (10-8 to 10-4 M) and the tension recorded. Baths are then rinsed 3 times with fresh buffer. After washout, 200 mM L-NAME is added to the tissue bath and equilibrated for 30 minutes. The phenylephrine concentration response curve is then repeated. Example 53 Eight Arm Radial Arm Maze - Cognition Enhancement [0116] Male Sprague-Dawley, CD rats (Charles River, Kingston, NY) weighing 200-250 g on arrival are used. For one week, the rats are housed, six per cage, with standard laboratory chow and water available ad libitum. Housing is in a colony room maintained at 22°C and had a 12 hour light/dark cycle with lights on at 6:00 AM. Following habituation to the facility, animals are individually housed and maintained at 85% of free-feeding weight Once stable weights are attained, the rats are acclimated to the 8-arm radial maze. [0117] The structure of the maze is an adaptation from that of Peele and Baron (Pharmacology, Biochemistry, and Behavior, 29:143-150, 1988). The maze is elevated to a height of 75.5 cm and composed of a circular area surrounded by 8 arms radiating away from the center, equidistant from one another. Each arm is 58 cm long x 13 cm high. A clear plexiglass cylinder is lowered to enclose the animal in the center portion of the maze prior to the start of each session. Each arm of the maze is equipped with 3 sets of photocells interfaced to a data acquisition unit, which in turn is interfaced to a computer. The photocells are used to track the movement of the rat in the maze. Pellet feeders located above food cups at the end of each arm, dispensed two 45 mg chocolate pellets when the outer photocell ol the arm is activated for the first time in a given session. The maze is located in a testing room with black and white geometric posters on each wall to serve as visual cues. During all training and testing procedures, white noise is audible (~ 70 db). [0118] The training procedure consists of five phases, each with daily sessions lasting 5 or 10 minutes. A 10 second delay is imposed between the time the rat is placed in the center portion of the maze and when the cylinder is raised to begin the session. During Phase 1, food-restricted pairs of rats are placed on the maze for 10 minutes with 45 mg chocolate food pellets scattered throughout the 8 arms of the maze. During Phase II, each rat is placed individually on the maze for a 10 minute period, with pellets scattered from the middle photocell to the food cup of each arm. During Phase III, each rat is placed on the maze for a 10 minute period, with food pellets located only in and around the food cups in each arm. In Phase IV, each rat is allowed 10 minutes to collect two pellets from each arm. Re-entry into an arm is considered an error. Flats are trained daily in this manner until they achieved criterion performance with less than or equal to 2 total errors on three consecutive days of training. Total habituation and training time is approximately 3 weeks. [0119] Test compound is prepared in phosphate buffered saline and administered in a volume of 1 ml/kg. Scopolamine HBr (0.3 mg/kg s.c.) served as the impairing agent, producing an increase in error rate (loss of memory). Test compound is given intraperitoneally simultaneously with scopolamine, 30 minutes prior to the first maze exposure on any given test day. [0120] To assess the test compound, an 8 x 8 balanced latin square for repeated measures is designed, in order to achieve a high experimental efficiency with the least amount of animals. Eight experimental sessions, two per week, are conducted with the 8 treatments (vehicle, scopolamine, 3 doses of test compound in combination with scopolamine) randomized within each session. Each treatment followed every other treatment the same number of times. Therefore, the residual effect of every treatment could be estimated and removed from the direct treatment effect. Following ANOVA, multiple comparisons are performed using Dunnett's two-sided test on adjusted means. [0121] Animals that did not make 4 correct choices within 5 minutes during the first exposure, or that had not made a total of S choices by the end of the 2nd exposure, are considered to have "timed-out" for that session. Any animal that "timed- out" following administration of more than one dose of the test compound is excluded from the analysis. Example 54 Neuroprotection Inhibition of Time-Dependent Death of Cells in Primary Cortical Neuron Cultures [0122] Primary cortical neurons were produced from rat brains that were 0-1 day old using a variation of methods described by Monyer et al. 1989, Brain Research 483:347-354. Dispersed brain tissue was grown in DMEM/10% PDHS (pregnant donor horse serum) for three days and then treated with cytosine arabinoside (ARC) for two days to remove contaminating glial cells. On day 5, the ARC media was removed and replaced with DMEM/10% PDHS. The neuronal cells were cultured for a further 4-7 days before use. [0123] Control primary neuronal cultures show progressive cell death between days 12 and 18 in culture. Twelve cultures were evaluated on days 12 and 16 for levels of the enzyme lactate dehydrogenase (LD) after adding test compound to 6 cultures maintained in DMEM and 10% PDHS on day 9 and maintaining the remaining cultures as controls. LD was assayed using a variation of the method by Wroblewski et al. 1955, Proc. Soc. Exp. Biol. Med. 90:210-213. LD is a cytosolic enzyme which is commonly used in both clinical and basic research to determine tissue viability. An increase in media LD is directly related to cell death. Neuroprotection Against Cvtotoxicity Induced by Hypoglycemia [0124] C6 glioma cells obtained from ATCC were plated in RPMI media with FBS at a concentration of 1 x 10 cells/ml in FALCON 25 cm2 tissue culture flasks. Four hours prior to the onset of hypoglycemia, the maintenance media was discarded, monolayers were washed twice in the appropriate media and then incubated for four hours at 37°C in either serum free or serum free plus test compound. Kreb's Ringer Phosphate buffer was used to wash the monolayers twice before the addition of pptopriate glucose treatment. RPMI medium contains 2 mg glucose/ml; flasks were divided into groups of 6 each receiving 100% glucose (2 mg/ml), 80% glucose (1.6 mg/ml), 60% glucose (1.2 mg/ml) or 0% glucose (buffer) or supplemented with test compound. AH flasks were incubated for 20 hours and then evaluated for total, live, and dead cell number utilizing trypan blue. Neuroprotection Apainst Excitotoxic Amino Acids [0125] Five culture dishes containing SK-N-SH neuroblastoma cells were treated with test compound and 5 culture dishes were treated with RPMI media. Four hours later, all cell were treated with NMDA (500 mu M) for 5 minutes. Total live cells and dead cells were then determined. Neuroprotection Against Oxygen-Glucose Deprivation [0126] Analysis of pyknotic nuclei to measure apoptosis: Cortical neurons are prepared from E18 rat fetus and plated in 8-well chamber slides precoated with poly-D- lysine (10 ng/ml) and serum at a density of 100,000 cells/well. Cells are plated in high glucose DMEM containing 10% FCS and kept in the incubator at 37 °C with 10% CO2/90% air. On the next day, serum is removed by replacing culture media with high glucose DMEM containing B27 supplement and cells are kept in the incubator without further media change until the day of experiment. On day 6, slides are divided into two groups; control group and OGD group. Cells in control group receive DMEM with glucose and custom B27 (without antioxidants). Cells in OGD group receive no- glucose DMEM with custom B27, which has been degassed under vacuum for 15 min. Cells are flushed with 90% N2/10% CO2 for 10 min in an airtight chamber and incubated at 37 °C for 6 hrs. After 6 hrs, both control and OGD cells are subject to replacement of media containing either vehicle (DMSO) or test compound in glucose- containing DMEM with custom B27. Cells are returned to normoxic incubator at 37 °C. After 24 hrs, cells are fixed in 4 % PFA for 10 min at 4 oC and stained with Topro (Fluorescent nuclear binding dye). Apoptosis is assessed using Laser Scanning Cytometer by measuring pyknotic nuclei. [0127] Measurement of LDH release as an indication of cell death: Cortical neurons are prepared from El 8 rat fetus and plated in 48-well culture plates precoated with poly-D-lysine (10 ng/ml) and serum at a density of 150,000 cells/well. Cells are plated in high glucose DMEM containing 10% FCS and kept in the incubator at 37 °C with 10% CO2/90% air. On the next day, serum is removed by replacing culture media with high glucose DMEM containing B27 supplement. On day 6, cells are divided into two groups; control group and OGD group. Cells in control group receive DMEM with glucose, and custom B27 (without antioxidants). Cells in OGD group receive no- glucose DMEM with custom B27, which has been degassed under vacuum for 15 min. Cells are flushed with 90% N2/10% CO2 for 10 min in an airtight chamber and incubated at 37 °C for 6 hrs. After 6 hrs, both control and OGD cells are subject to replacement of media containing either vehicle (DMSO) or test compound in glucose- containing DMEM with custom B27. Cells are returned to normoxic incubator at 37 °C. After 24 hrs, cell death is assessed by measuring cellular release of LDH (lactate dehydrogenase) into the culture medium. For LDH assay, an aliquot of 50 µl culture medium is transferred into the 96 well plate. After the addition of 140 ul 0.1M potassium phosphate buffer (pH 7.5) and 100 |il 0.2 mg/rnl NADH, the plate is let sit in the dark at room temperature for 20 min. The reaction is initiated by the addition of 10 µl of sodium pyruvate. The plate is read immediately at 340 nM in a Thermomax plate reader (Molecular Devices). The absorbance, an index of NADH concentration, is recorded every 6 seconds for 5 minutes and the slope indicating the rate of NADH disappearance is used to calculate LDH activity. LDH Activity(U/ml) = (AA/min) (TCF)(20) (0.0S33)/(.78) where: 0.0833 = proportionality constant 0.78 = instrument light path length (cm) Example 55 HLA Rat Test Procedure - Crohn's Disease and Inflammatory Bowel Disorders [0128] Male HLA-B27 rats are obtained from Taconic and provided unrestricted access to a food (PMI Lab diet 5001) and water. At the start of the study, rats are 22-26 weeks old. [0129] Rats are dosed subcutaneously once per day for seven days with one of the formulations listed below. There are five rats in each group and the last dose is administered two hours before euthanasia. • vehicle (50% DMSO/50% Dulbecco' s PBS) • 17a-ethinyl-17ß-estradiol (10ag/kg) • test compound [0130] Stool quality is observed daily and graded according to the following scale: Diarrhea = 3; soft stoo] = 2; normal stool = 1. At the end of the test procedure, serum is collected and stored at -70 °C. A section of colon is prepared for histological analysis and an additional segment is analyzed for myeloperoxidase activity. [0131] The following method is used to measure myeloperoxidase activity. Colon tissue is harvested and flash frozen in liquid nitrogen. A representative sample of the entire colon is used to ensure consistency between samples. The tissue is stored at -80 °C until use. Next, the tissue is weighed (approximately 500mg) and homogenized in 1:15 w/v of 5mM H2KPO4 (pH6) washing buffer. The tissue is spun down at 20,000 x g in a Sorvall RC 5B centrifuge for 45 minutes at 2-8 °C. Supernatant is then discarded. Tissue is resuspended and homogenized in 2.5ml (1:5 w/v) of 50mM H2KPO4 with 10mM EDTA and 0.5% Hex Ammonium Bromide to help solubilize the intracellular MPO. Tissue is frozen in liquid Nitrogen, thawed in a 37 °C-water bath and sonicated for 15 seconds to ensure membrane lysis. This procedure is repeated 3 times. Samples are then kept on ice for 20 minutes and centrifuged at 12,000 x g for 15 minutes at 2-8 °C. The supernatant is analyzed following these steps. [0132] The test mixture is prepared by adding 2.9ml of 50mM H2KPO4 with 0.167 O-Dianisidine/ml with 0.0005% H2O2 into a reaction tube. When hydrogen peroxide is degraded, O-Dianisidine is oxidized and absorbs at 460nm in a concentration dependent manner. The mixture is heated to 25 °C. One hundred (100) µL of the tissue supernatant is added to the reaction tube, incubated for one minute at 25 °C, then 1ml is transferred to a disposable plastic cuvette. OD is measured every 2 minutes reaction time at 460nm against a blank containing 2.9 ml of the reaction mixture and 100µl of the 0.5% ammonium bromide solution. [0133] Enzyme activity units are quantified by comparison of absorbence @ 460 to a standard curve prepared with purified human MPO 31.1 Units/Vial. The MPO is reconstituted and serially diluted using 50mM H2KPO4 with lOmM EDTA and 0.5% Hex Ammonium Bromide to four known concentrations. Sample absorbencies are compared against this curve to determine activity. [0134] Histological analysis is performed as follows. Colonic tissue is immersed in 10% neutral buffered formalin. Each specimen of colon is separated into four samples for evaluation. The formalin-fixed tissues are processed in a vacuum infiltration processor for paraffin embedding. The samples are sectioned at 5 p.m and then stained with hematoxylin and eosin (H&E) for blinded histologic evaluations using a scale modified after Boughton-Smith. After the scores are completed the samples are unblinded, and data are tabulated and analyzed by ANOVA linear modeling with multiple mean comparisons. [0135] All patents, publications, and other documents cited herein are hereby incorporated by reference in their entirety. WE CLAIM; 1. Aryl-carbaldehyde oxime derivative compounds of the formula (I): wherein: R1 is hydrogen, halogen, C1-6 alkyl, CN, or C1-6 alkoxy; R2 and R3, together, form a fused aryl or heteroaryl ring; R4 is hydrogen, halogen, C1-6 alkyl, CN, or C1-6 alkoxy; each R5 is the same or different selected from hydrogen, C1-6 alkyl, and-C(O)R6; and R6 is C1-6 alkyl; or a pharmaceutically acceptable salt thereof. 2. A compound as claimed in claim 1 where R4 is hydrogen or halogen 3. A compound as claimed in claim 1 or claim 2 wherein R1 is halogen. 4. A compound as claimed in any one of claims 1 to 3 wherein R2 and R3, together, form a 5- or 6-membered ring. 5. A compound as claimed in any one of claims 1 to 4 wherein: R2 and R3, together, form a phenyl, furan, or thiophene ring 6. A compound as claimed in any one of claims 1 to 5 wherein R1 is F and R4 is hydrogen or F. 7. A compound as claimed in any one of claims 1 to 6 wherein each R5 is H. 8. A compound as claimed in claim 1 which is one of the following: (a) 4-(4-Hydroxyphenyl)-l-naphthaidehyde oxime; (b) 4-(3-Fluoro-4-bydroxyphenyl)-naphthalene-l-carbaldehyde oxime; (c) 4-(4-Hydroxyphenyl)-l-benzothiophene-7-carbaldehyde oxime;: (d) 7-(4-Hydroxyphenyl)-l-benzothiophene-4-carbaldehyde oxime; (e) 7-(4-Hydroxyphenyl)-1 -benzofuran-4-carbaldehyde oxime; (f) 4-(4-Hydroxyphenyl)-benzofuran-7-carbaldehyde oxime; (g) 5-(4-Hydroxypnenyl) -1-benzofuran-7-carbaldehyde oxime; or (h) 7-(4-Hydroxyphenyl)-benzofuran-5-carbaldehyde oxime. 9. A pharmaceutical composition comprising a compound of the formula (I) as claimed in any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier. 10. A compound of the formula (I) as claimed in any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for inhibiting osteoporosis in a mammal. 11. A compound of the formula (I) as claimed in any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for inhibiting osteoarthritis, hypocalcemia, hypercalcemia, Paget's disease, osteomalacia, osteohalisteresis, multiple myeloma or other forms of cancer having deleterious effects on bone tissues in a mammal. 12. A compound of the formula (I) as claimed in any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for inhibiting benign or malignant abnormal tissue growth in a mammal. 13. A compound as claimed in claim 12 wherein the abnormal tissue growth is prostatic hypertrophy, uterine leiomyomas, breast cancer, endometriosis, endometrial cancer, polycystic ovary syndrome, endometrial polyps, benign breast disease, adenomyosis, ovarian cancer, melanoma, prostrate cancer, cancers of the colon, or CNS cancers. 14. A compound of the formula (I) as claimed in any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for lowering cholesterol, triglycerides, Lp(a), or LDL levels; or inhibiting hypercholesteremia; hyperlipidemia; cardiovascular disease: atherosclerosis; peripheral vascular disease; restenosis, or vasospasm; or inhibiting vascular wall damage from cellular events leading toward immune mediated vascular damage in a mammal. 15. A compound of the formula (I) as claimed in any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for inhibiting free radical induced disease states in a mammal 16. A compound of the formula (I) as claimed in any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for providing cognition enhancement or neuroprotection; or treating or inhibiting senile dementias, Alzheimer's disease, cognitive decline, or neurodegenerative disorders in a mammal. 17. A compound of the formula (I) as claimed in any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for inhibiting inflammatory bowel disease, ulcerative proctitis, Crohn's disease, colitis, hot flashes, vaginal or vulvar atrophy, atrophic vaginitis, vaginal dryness, pruritus., dyspareunia, dysuria, frequent urination, urinary incontinence, urinary tract infections, vasomotor symptoms; male pattern baldness; skin atrophy; acne; type II diabetes; dysfunctional uterine bleeding; or infertility in a mammal. 18. A compound of the formula (I) as claimed in any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for inhibiting leukemia, endometrial ablations, chronic renal or hepatic disease or coagulation diseases or disorders in a mammal. This invention provides estrogen receptor modulators having the structure (I) where R1-R5 are as defined in the specification; or a pharmaceutically acceptable salt thereof.

Documents:

2070-kolnp-2005-granted-abstract.pdf

2070-kolnp-2005-granted-assignment.pdf

2070-kolnp-2005-granted-claims.pdf

2070-kolnp-2005-granted-correspondence.pdf

2070-kolnp-2005-granted-description (complete).pdf

2070-kolnp-2005-granted-examination report.pdf

2070-kolnp-2005-granted-form 1.pdf

2070-kolnp-2005-granted-form 18.pdf

2070-kolnp-2005-granted-form 3.pdf

2070-kolnp-2005-granted-form 5.pdf

2070-kolnp-2005-granted-gpa.pdf

2070-kolnp-2005-granted-reply to examination report.pdf

2070-kolnp-2005-granted-specification.pdf