WO2004073612A2

WO2004073612A2 - Estrogen receptor modulators

Info

Publication number: WO2004073612A2
Application number: PCT/US2004/003723
Authority: WO
Inventors: Wanying Sun; Lovji D. Cama
Original assignee: Merck & Co. Inc.
Priority date: 2003-02-13
Filing date: 2004-02-09
Publication date: 2004-09-02
Also published as: WO2004073612A3

Abstract

The present invention relates to compounds and derivatives thereof, their synthesis, and their use as estrogen receptor modulators. The compounds of the instant invention are ligands for estrogen receptors and as such may be useful for treatment or prevention of a variety of conditions related to estrogen functioning including: bone loss, bone fractures, osteoporosis, metastatic bone disease, Paget s disease, periodontal disease, cartilage degeneration, endometriosis, uterine fibroid disease, hot flashes, increased levels of LDL cholesterol, cardiovascular disease, impairment of cognitive functioning, cerebral degenerative disorders, restenosis, gynecomastia, vascular smooth muscle cell proliferation, obesity, incontinence, and cancer.

Description

TITLE OF THE INVENTION ESTROGEN RECEPTOR MODULATORS

BACKGROUND OF THE INVENTION Naturally occurring and synthetic estrogens have broad therapeutic utility, including: relief of menopausal symptoms, treatment of acne, treatment of dysmenorrhea and dysfunctional uterine bleeding, treatment of osteoporosis, treatment of hirsutism, treatment of prostatic cancer, treatment of hot flashes and prevention of cardiovascular disease. Because estrogen is very therapeutically valuable, there has been great interest in discovering compounds that mimic estrogen-like behavior in estrogen responsive tissues.

For example, estrogen-like compounds would be beneficial in the treatment and prevention of bone loss. Bone loss occurs in a wide range of subjects, including women that are post-menopausal or have had a hysterectomy, patients who were or are currently being treated with corticosteroids, and patient' s having gonadal dysgenesis. The current major bone diseases of public concern are osteoporosis, hypercalcemia of malignancy, osleopenia due to bone metastases, periodontal disease, hyperparathyroidism, periarlicular erosions in rheumatoid arthritis, Paget's disease, immobilization-induced osteopenia, and glucocorticoid-induced osteoporosis. All of these conditions are characterized by bone loss, resulting from an imbalance between bone resorption, i.e. breakdown, and bone formation, which continues throughout life at the rate of about 14% per year on the average. However, the rate of bone turnover differs from site to site, for example, it is higher in the trabecular bone of the vertebrae and the alveolar bone in the jaws than in the cortices of the long bones. The potential for bone loss is directly related to turnover and can amount to over 5% per year in vertebrae immediately following menopause, a condition which leads to increased fracture risk.

In the U.S., there are currently about 20 million people with detectable fractures of the vertebrae due to osteoporosis. In addition, there are about 250,000 hip fractures per year attributed to osteoporosis. This clinical situation is associated with a 12% mortality rate within the first two years, while 30% of the patients require nursing home care after the fracture.

Osteoporosis affects approximately 20 to 25 million post-menopausal women in the U.S. alone. It has been theorized that the rapid loss of bone mass in these women is due to the cessation of estrogen production of the ovaries. Since studies have shown that estrogen slows the reduction of bone mass due to osteoporosis, estrogen replacement therapy is a recognized treatment for post- menopausal osteoporosis.

In addition to bone mass, estrogen appears to have an effect on the biosynthesis of cholesterol and cardiovascular health. Statistically, the rate of occurrence of cardiovascular disease is roughly equal in postmenopausal women and men; however, remenopausal women have a much lower incidence of cardiovascular disease than men. Because postmenopausal women are estrogen deficient, it is believed that estrogen plays a beneficial role in preventing cardiovascular disease. The mechanism is not well understood, but evidence indicates that estrogen can upregulate the low density lipid (LDL) cholesterol receptors in the liver to remove excess cholesterol.

Postmenopausal women given estrogen replacement therapy experience a return of lipid levels to concentrations comparable to levels associated with the premenopausal state. Thus, estrogen replacement therapy could be an effective treatment for such disease. However, the side effects associated with long term estrogen use limit the use of this alternative.

Also, the estrogen receptor ligands of the present invention can have utility as an anti-depressant, especially when the depression results from an estrogen deficiency.

In models, estrogen has been shown to have beneficial effects on cognitive functioning, such as relieveing anxiety and depression and treating and/or preventing Alzheimer's disease. Estrogen affects the central nervous system by increasing cholinergic functioning, neurotrophin and neurotrophin receptor expression. Estrogen also increases glutamergic synaptic transmission, alters amyloid precursor protein processing and provides neuroprotection. Thus, the estrogen receptor modulators of the present invention could be beneficial for improving cognitive functioning.

The estrogen receptor has been found to have two formsERα and ERβ. Ligands bind differently to these two forms, and each form has a different tissue specificity to binding ligands. Thus, it is possible to have compounds that are selective for ERα or ERβ, and therefore confer a degree of tissue specificity to a particular ligand.

Specifically, estrogen receptor beta (ERβ) selective agonists would be useful in the treatment of anxiety and/or depressive illness, as either a single agent or in combination with other agents. Clinical studies have demonstrated the efficacy of the natural estrogen, 17β-estradiol, for the treatment of various forms of depressive illness, see Schmidt PJ, Nieman L, Danaceau MA, Tobin MB, Roca CA, Murphy JH, Rubinow DR. Estrogen replacement in perimenopause-related depression: a preliminary report. Am J Obstet Gynecol 183:414-20, 2000; and Soares CN, Almeida OP, Joffe H, Cohen LS fficacy of estradiol for the treatment of depressive disorders in perimenopausal women: a double-blind, randomized, placebo-controlled trial. Arch Gen Psychiatry.58:537-8, 2001; which are hereby incorporated by reference. Bethea et al (Lu NZ, Shlaes TA, Gundlah C, Dziennis SE, Lyle RE, Bethea CL. Ovarian steroid action on tryptophan hydroxylase protein and serotonin compared to localization of ovarian steroid receptors in midbrain of guinea pigs. Endocrine 11:257-67, 1999, which is hereby incorporated by reference) have suggested that the anti-depressant activity of estrogen may be mediated via regulation of serotonin synthesis in the serotonin containing cells concentrated in the dorsal raphe nucleus. It is believed by some in the field that the physiological responses to estrogen are generally mediated via a series of biochemical events initiated by a selective, high affinity interaction between estrogen and an estrogen receptor. There are two estrogen receptors, ER and ERβ, and there is co-localization of ERβ (and not ERα) in the serotonin containing cells of the rodent raphe nucleus. Using ERβ selective compounds, estrogen increases transcription of the tryptophan hydroxylase gene (TPH, the key enzyme in serotonin synthesis) via an ERβ mediated event. Potential ERβ selective agonists can be tested in a rodent model of depression by methods familiar to those skilled in the art, for example in a forced swim assay. Likewise, potential ERβ selective agonists can be tested in a rodent model of anxiety by methods familiar to those skilled in the art, for example a guinea pig pup vocalization assay and the resident intruder assay.

Other disease states that affect postmenopausal women include estrogen-dependent breast cancer and uterine cancer. Anti-estrogen compounds, such as tamoxifen, have commonly been used as chemotherapy to treat breast cancer patients. Tamoxifen, a dual antagonist and agonist of estrogen receptors, is beneficial in treating estrogen-dependent breast cancer. However, treatment with tamoxifen is less than ideal because tamoxifen' s agonist behavior enhances its unwanted estrogenic side effects. For example, tamoxifen and other compounds that agonize estrogen receptors tend to increase cancer cell production in the uterus. A better therapy for such cancers would be an anti-estrogen compound that has negligible or nonexistent agonist properties.

Although estrogen can be beneficial for treating pathologies such as bone loss, increased lipid levels, and cancer, long-term estrogen therapy has been implicated in a variety of disorders, including an increase in the risk of uterine and endometrial cancers. These and other side effects of estrogen replacement therapy are not acceptable to many women, thus limiting its use.

Alternative regimens, such as a combined progestogen and estrogen dose, have been suggested in an attempt to lessen the risk of cancer. However, such regimens cause the patient to experience withdrawal bleeding, which is unacceptable to many older women. Furthermore, combining estrogen with progestogen reduces the beneficial cholesterol-lowering effect of estrogen therapy. In addition, the long term effects of progestogen treatment are unknown.

In addition to post-menopausal women, men suffering from prostatic cancer can also benefit from anti-estrogen compounds. Prostatic cancer is often endocrine-sensitive; androgen stimulation fosters tumor growth, while androgen suppression retards tumor growth. The administration of estrogen is helpful in the treatment and control of prostatic cancer because estrogen administration lowers the level of gonadotropin and, consequently, androgen levels. What is needed in the art are compounds that can produce the same positive responses as estrogen replacement therapy without the negative side effects.

Also needed are estrogen-like compounds that exert selective effects on different tissues of the body.

The compounds of the instant invention are ligands for estrogen receptors and as such may be useful for treatment or prevention of a variety of conditions related to estrogen functioning including: bone loss, bone fractures, osteoporosis, metastatic bone disease, Paget' s disease, periodontal disease, cartilage degeneration, endometriosis, uterine fibroid disease, hot flashes, increased levels of

LDL cholesterol, cardiovascular disease, impairment of cognitive functioning, cerebral degenerative disorders, restenosis, gynecomastia, vascular smooth muscle cell proliferation, obesity, incontinence, anxiety, depression resulting from an estrogen deficiency, and cancer, in particular of the breast, uterus and prostate. SUMMARY OF THE INVENTION

The present invention relates to compounds that are capable of treating and/or preventing a variety of conditions related to estrogen functioning. One embodiment of the present invention is illustrated by a compound of Formula I, and the pharmaceutically acceptable salts and stereoisomers thereof:

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to compounds useful as estrogen receptor modulators. Compounds of the present invention are described by the following chemical formula:

I

wherein R¹ is hydrogen, chloro, bromo, iodo, cyano, OR^a, Cι_ιo alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-7 cycloalkyl, 04.7 heterocycloalkyl, cycloalkylalkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, aryl and heteroaryl groups are optionally substituted with one, two or three groups selected from fluoro, chloro, bromo, iodo, cyano, OR^a, NRaRb, O(C=O)R^a, O(C=O)NRaRb NRa(C=O)Rb (C=O)Ra, CO2R^a; R2 is hydrogen, hydroxy, methyl, fluoro, chloro, bromo or trifluoromethyl;

R4 is hydrogen, Cχ-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, NO2, fluoro, chloro, bromo or iodo;

R⁵ is hydrogen, Ci-io alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-7 cycloalkyl, wherein said alkyl, alkenyl and alkynyl groups are optionally substituted with one, two or three groups selected from fluoro, chloro, bromo, iodo, cyano, OR^a, NR^aRb, O(C=O)R^a, O(C=O)NR^aRb, NR^a(C=O)Rb (C=O)R^a CO2R^a,C(O)H, or C(O)(Ci-4 alkyl);

R⁶ is hydrogen, Ci-io alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-7 cycloalkyl, wherein said alkyl, alkenyl and alkynyl groups are optionally substituted with one, two or three groups selected from fluoro, chloro, bromo, iodo, cyano, OR^a, NR Rb, O(C=O)R^a, O(C=O)NR^aRb NR^a(C=O)Rb (C=O)R^a CO2R C(O)H, or C(O)(Cι_4 alkyl); or R5 and R6 when taken together with the carbon atom to which they are attached, form a carbonyl group;

R7 is hydrogen, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, heteroaryl, OR^a, fluoro, chloro, bromo or iodo;

RS is hydrogen, fluoro, chloro, bromo, iodo, cyano, NRaRb, NO2, NHSO3CH3, OR^a, Cl-10 alkyl, C2-10 alkenyl, C2-IO alkynyl, C3_7 cycloalkyl, C4-7 heterocycloalkyl, cycloalkylalkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, aryl and heteroaryl groups are optionally substituted with one, two or three groups selected from fluoro, chloro, bromo, iodo, cyano, OR^a, NRaRb, O(C=O)R^a O(C=O)NR^aRb NR^a(C=O)Rb (C=O)R , CO2R^a;

R9 is hydrogen, fluoro, chloro, bromo, iodo, cyano, OR^a Ci-io alkyl, C2-10 alkenyl, C2-10 alkynyl, C3.7 cycloalkyl, C4.7 heterocycloalkyl, cycloalkylalkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, aryl and heteroaryl groups are optionally substituted with one, two or three groups selected from fluoro, chloro, bromo, iodo, cyano, OR^a, NR Rb, O(C=O)R^a, O(C=O)NRaRb, NR^a(C=O)Rb (C=O)R^a, CO2R^a; RlO is hydrogen, fluoro, chloro, bromo, iodo, cyano, OR^a, Ci-io alkyl, C2-10 alkenyl, C2-10 alkynyl, C3.7 cycloalkyl, C4-7 heterocycloalkyl, cycloalkylalkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl, wherein said alkyl, alkenyl, alkynyl, ' cycloalkyl, aryl and heteroaryl groups are optionally substituted with one, two or three groups selected from fluoro, chloro, bromo, iodo, cyano, OR^a, NR^aRb, O(C=O)R^a, O(C=O)NRaRb NRa(C=O)Rb (C=O)R^a, CO2 ^a;

Or R8 and R9 can be taken with the two intervening carbon atoms to which they are attached to form a 5-6 membered cycloalkyl or aryl ring which is optionally substituted with one, two or three substituents selected from C1.4 alkyl, OH, O(Ci-4 alkyl), NH2, NH(Ci-4 alkyl), N(Ci-4 alkyltø, halo, cyano, NO2, COOH, CO2(Ci_4 alkyl), C(O)H and C(O)(Ci_4 alkyl);

Or R9 and RlO can be taken with the two intervening carbon atoms to which they are attached to form a 5-6 membered cycloalkyl or aryl ring which is optionally substituted with one, two or three substituents selected from Ci-4 alkyl, OH, O(Ci-4 alkyl), NH2, NH(Ci-4 alkyl), N(Ci_4 alkyl)2, halo, cyano, NO2, COOH, Cθ2(Cχ-4 alkyl), C(O)H and C(O)(Cι_4 alkyl);

R^a is hydrogen, Ci_io alkyl, benzyl or phenyl, wherein the phenyl is optionally substituted with one, two or three substituents selected from Ci-4 alkyl, OH, O(Ci-4 alkyl), H2, NH(Ci_4 alkyl), N(Ci-4 alkyltø, halo, cyano, NO2, COOH, CO2(Ci-4 alkyl), C(O)H and C(O)(Cι_4 alkyl);

Rb is hydrogen, Ci-io alkyl, benzyl or phenyl, wherein the phenyl is optionally substituted with one, two or three substituents selected from Ci-4 alkyl, OH, O(Cι_4 alkyl), NH2, H(Ci-4 alkyl), N(Cι_4 alkyl)2, halo, cyano, NO2, COOH, CO2(Ci-4 alkyl), C(O)H and C(O)(Cι_4 alkyl); or the pharmaceutically acceptable salts and stereoisomers thereof.

In a class of the invention, R5 is hydrogen or Cχ-io alkyl and R6 is hydrogen or Ci-io alkyl. In another class of the invention, R5 and R6 when taken together with the carbon atom to which they are attached, form a carbonyl group.

In a class of the invention, Rl is hydrogen or C1-3 alkyl. In a class of the invention, R2 is hydrogen or fluoro.

In a class of the invention, R7 is hydrogen, Cχ-6 alkyl, heteroaryl, OR^a, chloro or bromo.

In a class of the invention, R^§ is hydrogen, fluoro, bromo, iodo, NR^aRb, NO2, NHSO3CH3, OR , Ci-5 alkyl, C2-5 ^alkenyl, aryl or arylalkyl wherein said aryl group is optionally substituted with one, two or three groups selected from fluoro, chloro, bromo, iodo, cyano, OR , NR^aRb, O(C=O)R , O(C=O)NR^aRb NR^a(C=O)Rb (C=O)Ra, CO2R^a.

In a class of the invention, R9 is hydrogen, fluoro, chloro, bromo, OR^a, Ci-5 alkyl, C2.5 alkenyl, C2-10 alkynyl or aryl wherein said aryl group is optionally substituted with one, two or three groups selected from fluoro, chloro, bromo, iodo, cyano, OR , NR^aRb 0(C=O)R^a, O(C=O)NR^aRb NR^a(C=O)Rb (C=O)R^a, CO2R .

In an embodiment of the invention, R5 and R are defined such that they can be taken together with the carbon to which they are attached to form a carbonyl group.

In an embodiment of the invention, R8 and R9 are defined such that they can be taken together with the two interventing carbons to which they are attached to form a 5-6 membered cycloalkyl or aryl ring. The cycloalkyl or aryl ring can be substituted with one, two or three substituents selected from Cj_4 alkyl, OH, O(Ci_4 alkyl), NH2, NH(Cι_4 alkyl), N(Ci-4 alkyl)2, halo, cyano, NO2, COOH, CO2(Ci-4 alkyl), C(O)H and C(O)(Cι_4 alkyl).

In an embodiment of the invention, R9 and lO are defined such thai they can be taken together with the two interventing carbons to which they are attached to form a 5-6 membered cycloalkyl or aryl ring. The cycloalkyl or aryl ring can be substituted with one, two or three substituents selected from Cj-4 alkyl, OH, O(Ci_4 alkyl), NH2, NH(Cι_4 alkyl), N(Cι_4 alkyl)2, halo, cyano, NO2, COOH, CO2(Ci-4 alkyl), C(O)H and C(O)(Cι_4 alkyl).

Non-limiting examples of the present invention include, but are not limited to: 3-hydroxy-8-bromo-4-methyl-6H-benzo[c]chromene-6-one; 3-hydroxy-8-vinyl-4-methyl-6H-benzo[c]chromene-6-one; 3-hydroxy-4,8-dimethyl-10-vinyl-6H-benzo[c]chromen-6-one; 10-allyl-3 -hydroxy-4, 8-dimethyl-6H-benzo [c] chromen-6-one; 3,8-dihydroxy-4,7-dichloro-6Η-benzo[c]chromene-6-one; -Hydroxy-4-methyl- 10-propyl-6H-benzo [c] chromen-6-one; 0-Ethyl-3-hydroxy-8-methoxy-4-methyl-6H-benzo[c]chromen-6-one; ,8-Dihydroxy-4-methyl -6H-benzo[c]chromen-6-one; ,7-Dimethyl-6H-benzo[c]chromene-3,8-diol; ,6- Dimethyl-6H-benzo[c]chromen-3-ol; ,6,6,7 -tetramethyl-6H-benzo[c]chromene-3,8-diol; -Ηydroxy-l,3,7-trimethyl-6H-benzo[c]chromen-6-one; -Ηydroxy-3-methoxy-l,4,7-trimethyl-6H-benzo[c]chromen-6-one; -hydroxy-4,7-dimethyl-6H-benzo[c]chromene-6-one; -hydroxy-4,8-dimethyl-6H-benzo[c]chromene-6-one; -hydroxy-4-methyl-8-methoxy-6H-benzo[c]chromene-6-one; -hydroxy-4-methyl-8-iodo-6H-benzo[c]chromene-6-one; -hydroxy-4-methyl-9-fluoro-6H-benzo[c]chromene-6-one; -hydroxy-4-methyl-9-bromo-6H-benzo[c]chromene-6-one; -hydroxy-4-methyl-10-methyl-6H-benzo[c]chromene-6-one; -hydroxy-4-methyl-10-vinyl-6H-benzo[c]chromene-6-one; -hydroxy-4-methyl-10-(l-propenyl)-6H-benzo[c]chromene-6-one; -hydroxy-4,7-dimethyl-8-methoxy-6H-benzo[c]chromene-6-one -hydroxy-4,7-dimethyl-8-amino-6H-benzo[c]chromene-6-one; -hydroxy-4-methyl-7ethyl-8-methoxy-6H-benzo[c]chromene-6-one; -hydroxy-4-methyl-8,9-difluoro-6H-benzo[c]chromene-6-one; -hydxoxy-4,9-dimethyl-8-bromo-6H-ben∑o[c]chromene-6-one; -hydroxy-4-meth3 -8-methoxy-9-bromo-6H-benzo[c]chromene-6-one; -hydroxy-4-methyl-8-bromo-9-(l-propenyl)-6H-benzo[c]chromene-6-one; -hydroxy-4,7,10-trimethyl-6H-benzo[c]chromene-6-one; -hydroxy-4-methyl-7,9dibromo-6H-benzo[c]chromene-6-one; -hydroxy-4-methyl-6H-naphtho[2, 1 -c]chromen-6-one; -hydroxy-4-methyl-6H-naphtho[2,3-c]chromen-6-one; -hydroxy-4,8,10-trimethyl-6H-benzo[c]chromene-6-one; -hydroxy-4,8-dimethyl- 10-bromo-6H-benzo[c]chromene-6-one; -hydroxy-4-methyl-8-methoxy-10-vinyl-6H-benzo[c]chromene-6-one; -hydroxy-4,8,10-trimethyl-9-bromo-6H-benzo[c]chromene-6-one; -hydroxy-4,8,10-trimethyl-9-methoxy-6H-benzo[c]chromene-6-one; -hydroxy-4,8,10-trimethyl-8-bromo-9-methoxy-6H-benzo[c]chromene-6-one; -hydroxy-4, 10-dimethyl-8-methoxy-6H-benzo[c]chromene-6-one; -hydroxy-4,7-dimethyl-8-methylsulfonamido-6H-benzo[c]chromene-6-one; -hydroxy-4-methyl- 17H-6-oxa- 16, 17-diaza-cyclopenta[a]-phenanthren-7-one; -hydroxy-4,7,10-trimethyl-8-methoxy-6H-benzo[c]chromene-6-one; -hydroxy- 1 ,3 ,6-trimethyl-3H- chromeno[3 ,4-c]pyrazol-4-one; -hydroxy- l,3-diethyl-6-methyl-3H- chromeno[3,4-c]pyrazol-4-one; -hydroxy-l-ethyl-3,6-dimethyl-3H- chromeno[3,4-c]pyrazol-4-one; -hydroxy- 1 ,6-dimethyl-3 -propyl-3H- chromeno [3 ,4-c ]pyrazol-4-one ; ,8-dihydroxy-7,8-dimethoxy-4-methyl-6H-benzo[c]chromen-6-one; ,8-dihydroxy-4-methyl-6H-benzo[c]chromen-6-one; ,8-dihydroxy-4,7-dimethyl-6H-benzo[c]chromene-6-one; ,7,8-trihydroxy-4-methyl-6H-benzo[c]chromene-6-one; ,8-dihydroxy-4-methyl-6H-benzo [c]chromene-6-one; ,8-dihydroxy-7-ethyl-4-methyl-6H-benzo[c]chromene-6-one; ,9-dihydroxy-4,8,10-trimethyl-6H-benzo[c]chromene-6-one; ,8-dihydroxy-4,10-dimethyl-6H-benzo[c]chromene-6-one; ,8-dihydroxy-10-ethyl-4-methyl-6H-benzo[c]chromene-6-one; ,8-dihydroxy-4,7,10-trimethyl-6H-benzo[c]chromene-6-one; ,8-dihydroxy-l-methyl-6H-benxo[c chxom.erie-6-one ,8-dihydroxy-l,7-dimethyl-6H-benzo[c]clιromene-6-one; ,8-dihydroxy- 1 ,4-dimethyl-6H-benzo[c]chromene-6-one; , 8-dihydroxy- 1 -ethyl-6H-benzo[c] chromene-6-one; ,8-dihydroxy-4-fluoro 1 -7-methyl-6H-benzo [c]chromene-6-one; ₈8-dihydroxy-4-fluorol-7-ethyl-6H-benzo[c]chromene-6-one; ,8-dihydroxy-4-brom-7-methyl-6H-benzo[c]chromene-6-one; ,8-dihydroxy-l,4,7-trimethyl-6H-benzo[c]chromene-6-one; ,8-dihydroxy-4,7-dichloro-9-fluoro-6H-benzo[c]chromene-6-one; ,8-dihydroxy-4,7-dimethyl-9-chloro-6H-benzo[c]chromene-6-one; ,8-dihydroxy-4,7-dichloro-10-methyl-6H-benzo[c]chromene-6-one; ,8-dihydroxy-4,7-dimethyl-2-fluoro-9-chloro-6H-benzo[c]clιromene-6-one; ,8-dihydroxy-4,9-dichloro-7,10-dimethyl-6H-benzo[c]chromene-6-one; -amino-3-hydroxy-4,7-dichloro-6H-benzo[c]chromene-6-one; ,8-dihydroxy-4,10-dimethyl -6H-benzo[c]chromene; ,8-dihydroxy-4,7,10-trimethyl -6H-benzo[c]chromene; ,8-dihydroxy-4,6,10-trimethyl -6H-benzo[c]chromene; ,8-dihydroxy-4,6,7-trimethyl -6H-benzo[c]chromene; 3,8-dihydroxy-6-ethyl-4,7-dimethyl -6H-benzo[c]chromene; 3 ,8-dihydroxy-6-n-propyl-4, 10-dimethyl -6H-benzo [cjchromene; 3,8-dihydroxy-6-ethyl-4,10-dimethyl -6H-benzo[c]chromene; 3,8-dihydroxy-6-ethyl-4,7,10-trimethyl -6H-benzo[c]chromene; 3,8-dihydroxy-4,6,7,10-tetramethyl -6H-benzo[c]chromene; 3,8-dihydroxy-6-isobutyl-4,10-dimethyl -6H-benzo[c]chromene; 3,8-dihydroxy-4,6,6, 10-teramethyl -6H-benzo[c]chromene; and the pharmaceutically acceptable salts and stereoisomers thereof.

Also included within the scope of the present invention is a pharmaceutical composition which is comprised of a compound of Formula I as described above and a pharmaceutically acceptable carrier. The invention is also contemplated to encompass a pharmaceutical composition which is comprised of a pharmaceutically acceptable carrier and any of the compounds specifically disclosed in the present application. The present invention also relates to methods for making the pharmaceutical compositions of the present invention. The present invention is also related to processes and intermediates useful for making the compounds and pharmaceutical compositions of the present invention. These and other aspects of the invention will be apparent from the teachings contained herein.

Utilities

The compounds of the present invention are selective modulators of estrogen receptors and are therefore useful to treat or prevent a variety of diseases and conditions related to estrogen receptor functioning in mammals, preferably humans. A variety of diseases and conditions related to estrogen receptor functioning includes, but is not limited to, bone loss, bone fractures, osteoporosis, metastatic bone disease, Paget' s disease, periodontal disease, cartilage degeneration, endometriosis, uterine fibroid disease, hot flashes, increased levels of LDL cholesterol, cardiovascular disease, impairment of cognitive functioning, cerebral degenerative disorders, restenosis, gynecomastia, vascular smooth muscle cell proliferation, obesity, incontinence, anxiety, depression resulting from an estrogen deficiency, and cancer, in particular of the breast, uterus and prostate. In treating such conditions with the instantly claimed compounds, the required therapeutic amount will vary according to the specific disease and is readily ascertainable by those skilled in the art. Although both treatment and prevention are contemplated by the scope of the invention, the treatment of these conditions is the preferred use. The present invention also relates to methods for eliciting an estrogen receptor modulating effect in a mammal in need thereof by administering the compounds and pharmaceutical compositions of the present invention.

The present invention also relates to methods for eliciting an estrogen receptor antagonizing effect in a mammal in need thereof by administering the compounds and pharmaceutical compositions of the present invention. The estrogen receptor antagonizing effect can be either an ERα antagonizing effect, an ERβ antagonizing effect or a mixed ERα and ERβ antagonizing effect.

The present invention also relates to methods for eliciting an estrogen receptor agonizing effect in a mammal in need thereof by administering the compounds and pharmaceutical compositions of the present invention. The estrogen receptor agonizing effect can be either an ERα agonizing effect, an ERβ agonizing effect or a mixed ERα and ERβ agonizing effect. In a class of the invention, the method of the present invention is eliciting an ERβ agonizing effect. The present invention also relates to methods for treating or preventing disorders related to estrogen functioning, bone loss, bone fractures, osteoporosis, metastatic bone disease, Paget' s disease, periodontal disease, cartilage degeneration, endometriosis, uterine fibroid disease, hot flashes, increased levels of LDL cholesterol, cardiovascular disease, impairment of cognitive functioning, cerebral degenerative disorders, restenosis, gynecomastia, vascular smooth muscle cell proliferation, obesity, incontinence, anxiety, depression resulting from an estrogen deficiency, and cancer, in particular of the breast, uterus and prostate in a mammal in need thereof by administering the compounds and pharmaceutical compositions of the present invention. Exemplifying the invention is a method of treating or preventing depression. Exemplifying the invention is a method of treating or preventing anxiety. Exemplifying the invention is a method of treating or preventing hot flashes. Exemplifying the invention is a method of treating or preventing cancer. Exemplifying the invention is a method of treating or preventing cardiovascular disease. An embodiment of the invention is a method for treating or preventing cancer, especially of the breast, uterus or prostate, in a mammal in need thereof by administering the compounds and pharmaceutical compositions of the present invention. The utility of SERMs for the treatment of breast, uterine or prostate cancer is known in the literature, see T. J. Powles, "Breast cancer prevention," Oncologist 2002; 7(l):60-4; Park, W.C. and Jordan, V.C., "Selective estrogen receptor modulators (SERMS) and their roles in breast cancer prevention." Trends Mol Med. 2002 Feb;8(2):82-8; Wolff, A.C. et al, "Use of SERMs for the adjuvant therapy of early-stage breast cancer," Ann N Y Acad Sci. 2001 Dec;949:80-8; Steiner, M.S. et al. , "Selective estrogen receptor modulators for the chemoprevention of prostate cancer," Urology 2001 Apr; 57(4 Suppl l):68-72.

Another embodiment of the invention is a method of treating or preventing metastatic bone disease in a mammal in need thereof by administering to the mammal a therapeutically effective amount of any of the compounds or pharmaceutical compositions described above. The utility of SERMS in the treatment of metastatic bone disease is known in the literature, see, Campisi, C. et al, "Complete resoultion of breast cancer bone metastasis through the use of beta- interferon and tamoxifen," Eur J Gynaecol Oncol 1993;14(6):479-83.

Another embodiment of the invention is a method of treating or preventing gynecomastia in a mammal in need thereof by administering to the mammal a therapeutically effective amount of any of the compounds or pharmaceutical compositions described above. The utility of SERMS in the treatment of gynecomastia is known in the literature, see, Ribeiro, G. and Swindell R., "Adjuvant tamoxifen for male breast cancer." Br J Cancer 1992;65:252-254; Donegan, W., "Cancer of the Male Breast," JGSM Vol. 3, Issue 4, 2000. Another embodiment of the invention is a method of treating or preventing post-menopausal osteoporosis, glucocorticoid osteoporosis, hypercalcemia of malignancy, bone loss and bone fractures in a mammal in need thereof by administering to the mammal a therapeutically effective amount of any of the compounds or pharmaceutical compositions described above. The utility of SERMs to treat or prevent osteoporosis, hypercalcemia of malignancy, bone loss or bone fractures is known in the literature, see Jordan, V.C. et al, "Selective estrogen receptor modulation and reduction in risk of breast cancer, osteoporosis and coronary heart disease," Natl Cancer Inst 2001 Oct; 93(19): 1449-57; Bjarnason, NH et al, "Six and twelve month changes in bone turnover are realted to reduction in vertebral fracture risk during 3 years of raloxifene treatment in postemenopausal osteoporosis," Osteoporosis Int 2001; 12(ll):922-3; Fentiman I.S., "Tamoxifen protects against steroid-induced bone loss," Eur J Cancer 28:684-685 (1992); Rodan, G.A. et al, "Therapeutic Approaches to Bone Diseases," Science Vol 289, 1 Sept. 2000. Another embodiment of the invention is a method of treating of preventing periodontal disease or tooth loss in a mammal in need thereof by administering to the mammal a therapeutically effective amount of any of the compounds or pharmaceutical compositions described above. The use of SERMs to treat periodontal disease or tooth loss in a mammal is known in the literature, see Rodan, G.A. et al, "Therapeutic Approaches to Bone Diseases," Science Vol 289, 1 Sept. 2000 pp. 1508-14.

Another embodiment of the invention is a method of treating of preventing Paget' s disease in a mammal in need thereof by administering to the mammal a therapeutically effective amount of any of the compounds or pharmaceutical compositions described above. The use of SERMs to treat Paget' s disease in a mammal is known in the literature, see Rodan, G.A. et al, "Therapeutic Approaches to Bone Diseases," Science Vol 289, 1 Sept. 2000 pp. 1508-14.

Another embodiment of the invention is a method of treating or preventing uterine fibroid disease in a mammal in need thereof by administering to the mammal a therapeutically effective amount of any of the compounds or pharmaceutical compositions described above. The use of SERMS to treat uterine fibroids, or uterine leiomyomas, is known in the literature, see Palomba, S., et al, "Effects of raloxifene treatment on uterine leiomyomas in postmenopausal women," Fertil Steril. 2001 Jul;76(l):38-43.

Another embodiment of the invention is a method of treating or preventing obesity in a mammal in need thereof by administering to the mammal a therapeutically effective amount of any of the compounds or pharmaceutical compositions described above. The use of SERMs to treat obesity is known in the literature, see Picard, F. el al, "Effects of the estrogen antagonist EM-652.HC1 on energy balance and lipid metabolism in ovariectomized rats," hit J Obes Relat Metab Disord. 2000 Jul;24(7):830-40.

Another embodiment of the invention is a method of treating or preventing cartilage degeneration, rheumatoid arthritis or osteoarthritis in a mammal in need thereof by administering to the mammal a therapeutically effective amount of any of the compounds or pharmaceutical compositions described above. The use of SERMs to treat cartilage degeneration, rheumatoid arthritis or osteoarthritis is known in the literature, see Badger, A.M. et al, "Idoxifene, a novel selective estrogen receptor modulator, is effective in a rat model of adjuvant-induced arthritis." J Pharmacol Exp Ther. 1999 Dec;291(3):1380-6.

Another embodiment of the invention is a method of treating or preventing endometriosis in a mammal in need thereof by administering to the mammal a therapeutically effective amount of any of the compounds or pharmaceutical compositions described above. The use of SERMs to treat endometriosis is known in the art, see Steven R. Goldstein, "The Effect of SERMs on the Endometrium," Annals of the New York Academy of Sciences 949:237-242 (2001).

Another embodiment of the invention is a method of treating or preventing urinary incontinence in a mammal in need thereof by administering to the mammal a therapeutically effective amount of any of the compounds or pharmaceutical compositions described above. The use of SERMs to treat urinary incontinence is known in the art, see, Goldstein, S.R., "Raloxifene effect on frequency of surgery for pelvic floor relaxation," Obstet Gynecol. 2001 Jul;98(l):91-6.

Another embodiment of the invention is a method of treating or preventing cardiovascular disease, restenosis, lowering levels of LDL cholesterol and inhibiting vascular smooth muscle cell proliferation in a mammal in need thereof by administering to the mammal a therapeutically effective amount of any of the compounds or pharmaceutical compositions described above. The utility of SERMs in treating or preventing cardiovascular disease, restenosis, lowering levels of LDL cholesterol and inhibiting vascular smooth muscle cell proliferation is known in the art, see Nuttall, ME et al., "Idoxifene: a novel selective estrogen receptor modulator prevents bone loss and lowers cholesterol levels in ovariectomized rats and decreases uterine weight in intact rats," Endocrinology 1998 Dec; 139(12):5224-34; Jordan, V.C. et al., "Selective estrogen receptor modulation and reduction in risk of breast cancer, osteoporosis and coronary heart disease," Natl Cancer Inst 2001 Oct; 93(19): 1449-57; Guzzo JA., "Selective estrogen receptor modulators—a new age of estrogens in cardiovascular disease?," Clin Cardiol 2000 Jan;23(l):15-7; Simoncini T, Genazzani AR., "Direct vascular effects of estrogens and selective estrogen receptor modulators," Curr Opin Obstet Gynecol 2000 Jun;12(3):181-7.

Another embodiment of the invention is a method of treating or preventing the impairment of cognitive functioning or cerebral degenerative disorders in a mammal in need thereof by administering to the mammal a therapeutically effective amount of any of the compounds or pharmaceutical compositions described above. The utility of SERMs to prevent the impairment of cognitive functioning is known in the art, see Yaffe, K., K. Krueger, S. Sarkar, et al. 2001. Cognitive function in postmenopausal women treated with raloxifene. N. Eng. J. Med. 344: 1207-1213. Another embodiment of the invention is a method of treating or preventing depression in a mammal in need thereof by administering to the mammal a therapeutically effective amount of any of the compounds or pharmaceutical compositions described above. The utility of estrogens to prevent depression has been described in the art, see Carranza-Liram S., Valentino-Figueroa ML, "Estrogen therapy for depression in postmenopausal women." Int J Gynnaecol Obstet 1999 Apr; 65(l):35-8.

Another embodiment of the invention is a method of treating or preventing anxiety in a mammal in need thereof by administering to the mammal a therapeutically effective amount of any of the compounds or pharmaceutical compositions described above. The contribution of estrogen receptors in the modulation of emotional processes, such as anxiety has been described in the art, see Krezel, W., et al, "Increased anxiety and synaptic plasticity in estrogen receptor beta- deficient mice." Proc Natl Acad Sci USA 2001 Oct 9;98 (21): 12278-82. Exemplifying the invention is the use of any of the compounds described above in the preparation of a medicament for the treatment and or prevention of osteoporosis in a mammal in need thereof. Still further exemplifying the invention is the use of any of the compounds described above in the preparation of a medicament for the treatment and/or prevention of: bone loss, bone resorption, bone fractures, metastatic bone disease and/or disorders related to estrogen functioning. The compounds of this invention may be administered to mammals, preferably humans, either alone or, preferably, in combination with pharmaceutically acceptable carriers or diluents, optionally with known adjuvants, such as alum, in a pharmaceutical composition, according to standard pharmaceutical practice. The compounds can be administered orally or parenterally, including the intravenous, intramuscular, intraperitoneal, subcutaneous, rectal and topical routes of administration.

In the case of tablets for oral use, carriers which are commonly used include lactose and corn starch, and lubricating agents, such as magnesium stearate, are commonly added. For oral administration in capsule form, useful diluents include lactose and dried corn starch. For oral use of a therapeutic compound according to this invention, the selected compound may be administered, for example, in the form of tablets or capsules, or as an aqueous solution or suspension. For oral administration in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose, starch, sucrose, glucose, methyl cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like; for oral administration in liquid form, the oral drug components can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like. Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents and coloring agents can also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening and/or flavoring agents may be added. For intramuscular, intraperitoneal, subcutaneous and intravenous use, sterile solutions of the active ingredient are usually prepared, and the pH of the solutions should be suitably adjusted and buffered. For intravenous use, the total concentration of solutes should be controlled in order to render the preparation isotonic. The compounds of the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines. Compounds of the present invention may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled. The compounds of the present invention may also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxy-ethylaspartamide-phenol, or polyethyleneoxide-polylysine substituted with palmitoyl residues. Furthermore, the compounds of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polyactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and crosslinked or amphipathic block copolymers of hydrogels. The instant compounds are also useful in combination with known agents useful for treating or preventing bone loss, bone fractures, osteoporosis, metastatic bone disease, Paget' s disease, periodontal disease, cartilage degeneration, endometriosis, uterine fibroid disease, hot flashes, increased levels of LDL cholesterol, cardiovascular disease, impairment of cognitive functioning, cerebral degenerative disorders, restenosis, gynecomastia, vascular smooth muscle cell proliferation, obesity, incontinence, anxiety, depression resulting from an estrogen deficiency, and cancer, in particular of the breast, uterus and prostate. Combinations of the presently disclosed compounds with other agents useful in treating or preventing the disorders disclosed herein are within the scope of the invention. A person of ordinary skill in the art would be able to discern which combinations of agents would be useful based on the particular characteristics of the drugs and the disease involved. Such agents include the following: an organic bisphosphonate; a cathepsin K inhibitor; an estrogen or an estrogen receptor modulator; an androgen receptor modulator; an inhibitor of osteoclast proton ATPase; an inhibitor of HMG- CoA reductase; an integrin receptor antagonist; an osteoblast anabolic agent, such as PTH; calcitonin; Vitamin D or a synthetic Vitamin D analogue; selective serotonin reuptake inhibitors (SSRIs); aromatase inhibitors; and the pharmaceutically acceptable salts and mixtures thereof. A preferred combination is a compound of the present invention and an organic bisphosphonate. Another preferred combination is a compound of the present invention and a cathepsin K inhibitor. Another preferred combination is a compound of the present invention and an estrogen. Another preferred combination is a compound of the present invention and an androgen receptor modulator. Another preferred combination is a compound of the present invention and an osteoblast anabolic agent.

"Organic bisphosphonate" includes, but is not limited to, compounds of the chemical formula

P0₃H₂ A (CH₂)_n C X P0₃H₂ wherein n is an integer from 0 to 7 and wherein A and X are independently selected from the group consisting of H, OH, halogen, NH2, SH, phenyl, C _3Q alkyl, 03.30 branched or cycloalkyl, bicyclic ring structure containing two or three N, C _30 substituted alkyl, Cχ_χo alkyl substituted NH2, C3_ o branched or cycloalkyl substituted NH2, Cχ.χo dialkyl substituted NH2, Cχ_χø alkoxy, Cχ_χo ^kyl substituted thio, thiophenyl, halophenylthio, Cχ_χo alkyl substituted phenyl, pyridyl, furanyl, pyrrolidinyl, imidazolyl, imidazopyridinyl, and benzyl, such that both A and X are not selected from H or OH when n is 0; or A and X are taken together with the carbon atom or atoms to which they are attached to form a C^. χo ring.

In the foregoing chemical formula, the alkyl groups can be straight, branched, or cyclic, provided sufficient atoms are selected for the chemical formula. The C _3o substituted alkyl can include a wide variety of substituents, nonlimiting examples which include those selected from the group consisting of phenyl, pyridyl, furanyl, pyrrolidinyl, imidazonyl, NH2, Cχ_χo alkyl or dialkyl substituted NH2, OH, SH, and C _χo alkoxy.

The foregoing chemical formula is also intended to encompass complex carbocyclic, aromatic and hetero atom structures for the A and or X substituents, nonlimiting examples of which include naphthyl, quinolyl, isoquinolyl, adamantyl, and chlorophenylthio.

Pharmaceutically acceptable salts and derivatives of the bisphosphonates are also useful herein. Non-Umiting examples of salts include those selected from the group consisting alkali metal, alkaline metal, ammonium, and mono-, di-, tri-, or letra-Cχ_3 alkyl-subslituted ammonium. Preferred salts are those selected from the group consisting of sodium, potassium, calcium, magnesium, and ammonium salts. More preferred are sodium salts. Non-limiting examples of derivatives include those selected from the group consisting of esters, hydrates, and amides.

It should be noted that the terms "bisphosphonate" and "bisphosphonates", as used herein in referring to the therapeutic agents of the present invention are meant to also encompass diphosphonates, biphospho ic acids, and diphosphonic acids, as well as salts and derivatives of these materials. The use of a specific nomenclature in referring to the bisphosphonate or bisphosphonates is not meant to limit the scope of the present invention, unless specifically indicated. Nonlimiting examples of bisphosphonates include alendronate, cimadronate, clodronate, etidronate, ibandronate, incadronate, minodronate, neridronate, olpadronate, pamidronate, piridronate, risedronate, tiludronate, and zolendronate, and pharmaceutically acceptable salts and esters thereof. A particularly preferred bisphosphonate is alendronate, especially a sodium, potassium, calcium, magnesium or ammonium salt of alendronic acid. Exemplifying the preferred bisphosphonate is a sodium salt of alendronic acid, especially a hydrated sodium salt of alendronic acid. The salt can be hydrated with a whole number of moles of water or non whole numbers of moles of water. Further exemplifying the preferred bisphosphonate is a hydrated sodium salt of alendronic acid, especially when the hydrated salt is alendronate monosodium trihydrate.

The precise dosage of the organic bisphosphonate will vary with the dosing schedule, the particular bisphosphonate chosen, the age, size, sex and condition of the mammal or human, the nature and severity of the disorder to be treated, and other relevant medical and physical factors. For humans, an effective oral dose of bisphosphonate is typically from about 1.5 to about 6000 μg/kg body weight and preferably about 10 to about 2000 μg kg of body weight. In alternative dosing - regimens, the bisphosphonate can be administered at intervals other than daily, for example once-weekly dosing, twice-weekly dosing, biweekly dosing, and twice- monthly dosing. In a once weekly dosing regimen, alendronate monosodium trihydrate would be administered at dosages of 35 mg/week or 70 mg week. The bisphosphonates may also be administered monthly, ever six months, yearly or even less frequently, see WO 01/97788 (published December 27, 2001) and WO 01/89494 (published November 29, 2001). "Estrogen" includes, but is not limited to naturally occurring estrogens

[7-estradiol (E₂), estrone (E ), and estriol (E₃)], synthetic conjugated estrogens, oral contraceptives and sulfated estrogens. See, Gruber CJ, Tschugguel W, Schneeberger C, Huber JC, "Production and actions of estrogens" N Engl J Med 2002 Jan 31;346(5):340-52. "Estrogen receptor modulators" refers to compounds which interfere or inhibit the binding of estrogen to the receptor, regardless of mechanism. Examples of estrogen receptor modulators include, but are not limited to, estrogen, progestogen, estradiol, droloxifene, raloxifene, lasofoxifene, TSE-424, tamoxifen, idoxifene, LY353381, LY117081, toremifene, fulvestrant, 4-[7-(2,2-dimethyl-l-oxopropoxy-4- methyl-2-[4-[2-(l-piperidinyl)ethoxy]phenyl]-2H-l-benzopyran-3-yl]-ρhenyl-2,2- dimethylpropanoate, 4,4'-dihydroxybenzophenone-2,4-dinitrophenyl- hydrazone, and SH646.

"Cathepsin inhibitors" refers to compounds which interfere with the activity of the cysteine protease cathepsin K. Nonlimiting examples of cathepsin K inhibitors can be found in PCT publications WO 00/55126 to Axys Pharmaceuticals and WO 01/49288 to Merck Frosst Canada & Co. and Axys Pharmaceuticals.

"Androgen receptor modulators" refers to compounds which interfere or inhibit the binding of androgens to the receptor, regardless of mechanism. Examples of androgen receptor modulators include finasteride and other 5α-reductase inhibitors, nilutamide, flutamide, bicalutamide, liarozole, and abiraterone acetate.

"An inhibitor of osteoclast proton ATPase" refers to an inhibitor of the proton ATPase, which is found on the apical membrane of the osteoclast, and has been reported to play a significant role in the bone resorption process. This proton pump represents an attractive target for the design of inhibitors of bone resorption which are potentially useful for the treatment and prevention of osteoporosis and related metabolic diseases. See C. Farina et al, "Selective inhibitors of the osteoclast vacuolar proton ATPase as novel bone antiresorptive agents," DDT, 4: 163-172 (1999), which is hereby incorporated by reference in its entirety. "HMG-CoA reductase inhibitors" refers to inhibitors of 3-hydroxy-

3-methylglutaryl-Co reductase. Compounds which have inhibitory activity for HMG-CoA reductase can be readily identified by using assays well-known in the art. For example, see the assays described or cited in U.S. Patent 4,231,938 at col. 6, and WO 84/02131 at pp. 30-33. The terms "HMG-CoA reductase inhibitor" and "inhibitor of HMG-CoA reductase" have the same meaning when used herein.

Examples of HMG-CoA reductase inhibitors that may be used include but are not limited to lovastatin (MEVACOR®; see U.S. Patent Nos.4,231,938, 4,294,926 and 4,319,039), simvastatin (ZOCOR® see U.S. Patent Nos. 4,444,784, 4,820,850 and 4,916,239), pravastatin (PRAVACHOL®; see U.S. Patent Nos. 4,346,227, 4,537,859, 4,410,629, 5,030,447 and 5,180,589), fluvastatin (LESCOL® see U.S. Patent Nos. 5,354,772, 4,911,165, 4,929,437, 5,189,164, 5,118,853, 5,290,946 and 5,356,896), atorvastatin (LIPITOR®; see U.S. Patent Nos. 5,273,995, 4,681,893, 5,489,691 and 5,342,952) and cerivastatin (also known as rivastatin and BAYCHOL® see US Patent No. 5,177,080). The structural formulas of these and additional HMG-CoA reductase inhibitors that may be used in the instant methods are described at page 87 of M. Yalpani, "Cholesterol Lowering Drugs", Chemistry & Industry, pp. 85-89 (5 February 1996) and US Patent Nos. 4,782,084 and 4,885,314. The term HMG-CoA reductase inhibitor as used herein includes all pharmaceutically acceptable lactone and open-acid forms (i.e., where the lactone ring is opened to form the free acid) as well as salt and ester forms of compounds which have HMG-CoA reductase inhibitory activity, and therefor the use of such salts, esters, open-acid and lactone forms is included within the scope of this invention. An illustration of the lactone portion and its corresponding open-acid form is shown below as structures I andll.

Lactone Open-Acid i π

In HMG-CoA reductase inhibitors where an open-acid form can exist, salt and ester forms may preferably be formed from the open-acid, and all such forms are included within the meaning of the term "HMG-CoA reductase inhibitor" as used herein. Preferably, the HMG-CoA reductase inhibitor is selected from lovaslatin and simvastatin, and most preferably simvastatin. Herein, the term "pharmaceutically acceptable salts" with respect to the HMG-CoA reductase inhibitor shall mean nontoxic salts of the compounds employed in this invention which are generally prepared by reacting the free acid with a suitable organic or inorganic base, particularly those formed from cations such as sodium, potassium, aluminum, calcium, lithium, magnesium, zinc and tetramelhylammonium, as well as those salts formed from amines such as ammonia, ethylenediamine, N-methylglucamine, lysine, arginine, ornithine, choline, N,N'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, l-p-chlorobenzyl-2-pyrrolidine-r-yl-methylbenz- imidazole, diethylamine, piperazine, and tris(hydroxymethyl) aminomethane. Further examples of salt forms of HMG-CoA reductase inhibitors may include, but are not limited to, acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynapthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, niethylsulfate, ucate, napsylate, nitrate, oleate, oxalate, pamaote, palmitate, panthothenate, phosphate/diphosphate, polygalacturonate, salicylate, stearate, subacetate, succinate, tannate, tartrate, teoclate, tosylate, triethiodide, and valerate.

Ester derivatives of the described HMG-CoA reductase inhibitor compounds may act as prodrugs which, when absorbed into the bloodstream of a warm-blooded animal, may cleave in such a manner as to release the drug form and permit the drug to afford improved therapeutic efficacy.

As used above, "integrin receptor antagonists" refers to compounds which selectively antagonize, inhibit or counteract binding of a physiological ligand to the α_vβ3 integrin, to compounds which selectively antagonize, inhibit or counter- act binding of a physiological ligand to the αvβ5 integrin, to compounds which antagonize, inhibit or counteract binding of a physiological ligand to both the α_vβ3 integrin and the γβ5 integrin, and to compounds which antagonize, inhibit or counteract the activity of the particular integrin(s) expressed on capillary endothelial cells. The term also refers to antagonists of the γβ6_> oc_vβ8, ocχβχ, 2βl, o sβ , «6β and 6β4 integrins. The term also refers to antagonists of any combination of α_vβs, α_vβ5, _vβ6, α_vβδ, oqβl, «2βl, «5β «6βl and όβ4 integrins. H.N. Lode and coworkers in PNAS USA 96: 1591-1596 (1999) have observed synergistic effects between an antiangiogenic αv integrin antagonist and a tumor-specific antibody-cytokine (interleukin-2) fusion protein in the eradication of spontaneous tumor metastases. Their results suggested this combination as having potential for the treatment of cancer and metastatic tumor growth. α_vβ₃ integrin receptor antagonists inhibit bone resorption through a new mechanism distinct from that of all currently available drugs. Integrins are heterodimeric transmembrane adhesion receptors that mediate cell-cell and cell-matrix interactions. The α and β integrin subunits interact non-covalently and bind extracellular matrix ligands in a divalent cation-dependent manner. The most abundant integrin on osteoclasts is o β₃ (>10⁷/osteoclast), which appears to play a rate-limiting role in cytoskeletal organization important for cell migration and polarization. The θyβ₃ antagonizing effect is selected from inhibition of bone resorption, inhibition of restenosis, inhibition of macular degeneration, inhibition of arthritis, and inhibition of cancer and metastatic growth.

"An osteoblast anabolic agent" refers to agents that build bone, such as PTH. The intermittent administration of parathyroid hormone (PTH) or its amino- terminal fragments and analogues have been shown to prevent, arrest, partially reverse bone loss and stimulate bone formation in animals and humans. For a discussion refer to D.W. Dempster et al. , "Anabolic actions of parathyroid hormone on bone," Endocr Rev 14: 690-709 (1993). Studies have demonstrated the clinical benefits of parathyroid hormone in stimulating bone formation and thereby increasing bone mass and strength. Results were reported by RM Neer et al, in New Eng J Med 344 1434- 1441 (2001). In addition, parathyroid hormone-related protein fragments or analogues, such as PTHrP-(l-36) have demonstrated potent anticalciuric effects [see M.A. Syed et al, "Parathyroid hormone-related protein-(l-36) stimulates renal tubular calcium reabsorption in normal human volunteers: implications for the pathogenesis of humoral hypercalcemia of malignancy," JCEM 86: 1525-1531 (2001)] and may also have potential as anabolic agents for treating osteoporosis.

Calcitonin is a 32 amino acid pepetide produced primarily by the thyroid which is known to participate in calcium and phosphorus metabolism. Calcitonin suppresses resorption of bone by inhibiting the activity of osteoclasts. Thus, calcitonin can allow osteoblasts to work more effectively and build bone. "Vitamin D" includes, but is not limited to, vitamin D₃

(cholecalciferol) and vitamin D₂ (ergocalciferol), which are naturally occurring, biologically inactive precursors of the hydroxylated biologically active metabolites of vitamin D: lα-hydroxy vitamin D; 25-hydroxy vitamin D, and lα ,25-dihydroxy vitamin D. Vitamin D and vitamin D₃ have the same biological efficacy in humans. When either vitamin D or D₃ enters the circulation, it is hydroxylated by cytochrome P₄₅₀- vitamin D-25-hydroxylase to give 25-hydroxy vitamin D. The 25-hydroxy vitamin D metabolite is biologically inert and is further hydroxylated in the dney by cytochrome P450-monooxygenase, 25 (OH) D-lα -hydroxylase to give 1 ,25- dihydroxy vitamin D. When serum calcium decreases, there is an increase in the production of parathyroid hormone (PTH), which regulates calcium homeostasis and increases plasma calcium levels by increasing the conversion of 25-hydroxy vitamin D to 1,25-dihydroxy vitamin D.

1,25-dihydroxy vitamin D is thought to be reponsible for the effects of vitamin D on calcium and bone metabolism. The 1,25-dihydroxy metabolite is the active hormone required to maintain calcium absorption and skeletal integrity. Calcium homeostasis is maintained by 1,25 dihydroxy vitamin D by inducing monocytic stem cells to differentiate into osteoclasts and by maintaining calcium in the normal range, which results in bone mineralization by the deposition of calcium hydroxyapatite onto the bone surface, see Holick, MF, Vitamin D photobiology, metabolism, and clinical applications, In: DeGroot L, Besser H, Burger HG, eg al., eds. Endocrinology, 3^rd ed., 990-1013 (1995). However, elevated levels of lα,25- dihydroxy vitamin D₃ can result in an increase of calcium concentration in the blood and in the abnormal control of calcium concentration by bone metabolism, resulting in hypercalcemia. lα,25-dihydroxy vitamin D₃ also indirectly regulates osteoclastic activity in bone metabolism and elevated levels may be expected to increase excessive bone resorption in osteoporosis.

"Synthetic vitamin D analogues" includes non-naturally occurring compounds that act like vitamin D.

Selective Serotonin Reuptake Inhibitors act by increasing the amount of serotonin in the brain. SSRIs have been used successfully for a decade in the

United States to treat depression. Non-limiting examples of SSRIs include fluoxetine, paroxetine, sertraline, citalopram, and fluvoxamine. SSRIs are also being used to treat disoreders realted to estrogen functioning, suchs as premenstrual syndrome and premenstrual dysmorphic disorder. See Sundstrom-Poromaa I, Bixo M, Bjorn I, Nordh O., "Compliance to antidepressant drug therapy for treatment of premenstrual syndrome," J Psychosom Obstet Gynaecol 2000 Dec;21(4):205-ll.

Aromitase is an enzyme which effects aromatisation of ring A in the metabolic formation of various steroid hormones, including estrogen. Various cancers, including breast and uterine cancer, are dependent upon circulating steroid hormones that have an aromatic ring A. Such hormone-dependent cancers can be treated by removing the source of ring A aromatised steroid hormones by administering an inhibitor of aromitase. The aromitase inhibitors may be steroidal or non-steroidal. Non-limiting examples of aromitase inhibitors include anastrozole, letrozole and aminoglutethimide. See, Brueggemeier, R.W., "Aromistase inhibitors in breast cancer therapy," Expert Rev Anticancer Ther 2002 Apr;2(2) : 181 -91 ; de Jong, P.C. and Blijham, G.H., "New aromitase inhibitors for the treatment of advanced breast cancer in post menopausal women," Neth J Med 1999 Aug;55(2):50-8.

If formulated as a fixed dose, such combination products employ the compounds of this invention within the dosage range described below and the other pharmaceutically active agent(s) within its approved dosage range. Compounds of the instant invention may alternatively be used sequentially with known pharmaceutically acceptable agent(s) when a combination formulation is inappropriate.

The term "administration" and variants thereof (e.g., "administering" a compound) in reference to a compound of the invention means introducing the compound or a prodrug of the compound into the system of the animal in need of treatment. When a compound of the invention or prodrug thereof is provided in combination with one or more other active agents (e.g., a bisphosphonate, etc.), "administration" and its variants are each understood to include concurrent and sequential introduction of the compound or prodrug thereof and other agents. The present invention includes within its scope prodrugs of the compounds of this invention. In general, such prodrugs will be functional derivatives of the compounds of this invention which are readily convertible in vivo into the required compound. Thus, in the methods of treatment of the present invention, the term "administering" shall encompass the treatment of the various conditions described with the compound specifically disclosed or with a compound which may not be specifically disclosed, but which converts to the specified compound in vivo after administration to the patient. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs," ed. H. Bundgaard, Elsevier, 1985, which is incorporated by reference herein in its entirety. Metabolites of these compounds include active species produced upon introduction of compounds of this invention into the biological milieu.

The present invention also encompasses a pharmaceutical composition useful in the treatment of osteoporosis or other bone disorders, comprising the administration of a therapeutically effective amount of the compounds of this invention, with or without pharmaceutically acceptable carriers or diluents. Suitable compositions of this invention include aqueous solutions comprising compounds of this invention and pharmacologically acceptable carriers, e.g., saline, at a pH level, e.g., 7.4. The solutions may be introduced into a patient's bloodstream by local bolus injection.

When a compound according to this invention is administered into a human subject, the daily dosage will normally be determined by the prescribing physician with the dosage generally varying according to the age, weight, and response of the individual patient, as well as the severity of the patient's symptoms. In one exemplary application, a suitable amount of compound is administered to a mammal undergoing treatment. Oral dosages of the present invention, when used for the indicated effects, will range between about 0.01 mg per kg of body weight per day (mg/kg/day) to about 100 mg/kg/day, preferably 0.01 to 10 mg/kg/day, and most preferably 0.1 to 5.0 mg/kg/day. For oral administration, the compositions are preferably provided in the form of tablets containing 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100 and 500 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. A medicament typically contains from about 0.01 mg to about 500 mg of the active ingredient, preferably, from about 1 mg to about 100 mg of active ingredient. Intravenously, the most preferred doses will range from about 0.1 to about 10 mg/kg/minute during a constant rate infusion. Advantageously, compounds of the present invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three or four times daily. Furthermore, preferred compounds for the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in the art. To be administered in the form of a transdermal delivery system, the dosage administration will, of course, be continuous rather than intermittant throughout the dosage regimen. The compounds of the present invention can be used in combination with other agents useful for treating estrogen-mediated conditions. The individual components of such combinations can be administered separately at different times during the course of therapy or concurrently in divided or single combination forms. The instant invention is therefore to be understood as embracing all such regimes of simultaneous or alternating treatment and the term "administering" is to be interpreted accordingly. It will be understood that the scope of combinations of the compounds of this invention with other agents useful for treating cathepsin-medialed conditions includes in principle any combination with any pharmaceutical composition useful for treating disorders related to estrogen functioning. The scope of the invention therefore encompasses the use of the instantly claimed compounds in combination with a second agent selected from: an organic bisphosphonate; a cathepsin K inhibitor; an estrogen; an estrogen receptor modulator; an androgen receptor modulator; an inhibitor of osteoclast proton ATPase; an inhibitor of HMG-CoA reductase; an integrin receptor antagonist; an osteoblast anabolic agent; calcitonin; Vitamin D; a synthetic Vitamin D analogue; a selective serotonin reuptake inhibitor; and the pharmaceutically acceptable salts and mixtures thereof.

These and other aspects of the invention will be apparent from the teachings contained herein. Definitions

As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.

The term "therapeutically effective amount" as used herein means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician. The terms "treating" or "treatment" of a disease as used herein includes: preventing the disease, i.e. causing the clinical symptoms of the disease not to develop in a mammal that may be exposed to or predisposed tothe disease but does not yet experience or display symptoms of the disease; inhibiting the disease, i.e., arresting or reducing the development of the disease or its clinical symptoms; or relieving the disease, i.e., causing regression of the disease or its clinical symptoms.

The term "bone resorption," as used herein, refers to the process by which osteoclasts degrade bone.

The term "alkyl" shall mean a substituting univalent group derived by conceptual removal of one hydrogen atom from a straight or branched-chain acyclic saturated hydrocarbon (i.e., -CH₃, -CH₂CH₃, -CH₂CH₂CH₃, -CH(CH₃)₂,

-CH₂CH CH₂CH₃, -CH CH(CH )₂, -C(CH₃) etc ).

The term "alkenyl⁵⁵ shall mean a substituting univalent group derived by conceptual removal of one hydrogen atom from a straight or branched-chain acyclic unsaturated hydrocarbon containing at least one double bond (i.e., -CH=CH₂, -CH₂CH=CH₂, -CH=CHCH₃, -CH₂CH=C(CH₃)₂, etc.).

The term "alkynyl" shall mean a substituting univalent group derived by conceptual removal of one hydrogen atom from a straight or branched-chain acyclic unsaturated hydrocarbon containing at least one triple bond (i.e., -C≡CH, -CH₂C≡CH, -C≡CCH₃, -CH₂C≡CCH₂(CH₃)₂, etc.). The term "alkylene" shall mean a substituting bivalent group derived from a straight or branched-chain acyclic saturated hydrocarbon by conceptual removal of two hydrogen atoms from different carbon atoms (i.e., -CH CH₂-,

-CH₂CH₂CH₂CH₂-, -CH₂C(CH₃)₂CH₂-, etc.).

The term "alkylidene" shall mean a substituting bivalent group derived from a straight or branched-chain acyclic saturated hydrocarbon by conceptual removal of two hydrogen atoms from the same carbon atom (i.e., =CH₂, =CHCH₃, =C(CH₃)₂, etc.).

The term "alkenylene" shall mean a substituting bivalent group derived from a straight or branched-chain acyclic unsaturated hydrocarbon by conceptual removal of two hydrogen atoms from different carbon atoms (i.e., -CH=CH-, -CH₂CH=CH-, CH₂CH=CHCH₂-, -C(CH₃)=C(CH₃)-, etc.).

The term "cycloalkyl" shall mean a substituting univalent group derived by conceptual removal of one hydrogen atom from a saturated monocyclic hydrocarbon (i.e., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl). The term "cycloalkenyl" shall mean a substituting univalent group derived by conceptual removal of one hydrogen atom from an unsaturated monocyclic hydrocarbon containing a double bond (i.e., cyclopentenyl or cyclohexenyl).

The term "heterocycloalkyl" shall mean a substituting univalent group derived by conceptual removal of one hydrogen atom from a heterocycloalkane wherein said heterocycloalkane is derived from the corresponding saturated monocyclic hydrocarbon by replacing one or two carbon atoms with atoms selected from N, O or S. Examples of heterocycloalkyl groups include, but are not Umited to, oxiranyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, and morpholinyl. Heterocycloalkyl substituents can be attached at a carbon atom. If the substituent is a nitrogen containing heterocycloalkyl substituent, it can be attached at the nitrogen atom.

The term "aryl⁵⁵ as used herein refers to a substituting univalent group derived by conceptual removal of one hydrogen atom from a monocyclic or bicyclic aromatic hydrocarbon. Examples of aryl groups are phenyl, indenyl, and naphthyl. The term "heteroaryl" as used herein refers to a substituting univalent group derived by the conceptual removal of one hydrogen atom from a monocyclic or bicyclic aromatic ring system containing 1, 2, 3, or 4 heteroatoms selected from N, O, or S. Examples of heteroaryl groups include, but are not limited to, pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridyl, pyrimidinyl, pyrazinyl, benzimidazolyl, indolyl, and purinyl. Heteraryl substituents can be attached at a carbon atom or through the heteroatom.

In the compounds of the present invention, alkyl, alkenyl, alkynyl, alkylidene, alkenylene, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl and heteroaryl groups can be further substituted by replacing one or more hydrogen atoms by alternative non-hydrogen groups. These include, but are not limited to, halo, hydroxy, mercapto, amino, carboxy, cyano, carbamoyl, and oxo.

Whenever the term "alkyl" or "aryl" or either of their prefix roots appear in a name of a substituent (e.g., aryl Cχ_8 alkyl) it shall be interpreted as including those limitations given above for "alkyl" and "aryl." Designated numbers of carbon atoms (e.g., Cχ_χo) shall refer independently to the number of carbon atoms in an alkyl or cyclic alkyl moiety or to the alkyl portion of a larger substituent in which alkyl appears as its prefix root.

The terms "arylalkyl" and "alkylaryl" include an alkyl portion where alkyl is as defined above and to include an aryl portion where aryl is as defined above.

Examples of arylalkyl include, but are not limited to, benzyl, fluorobenzyl, chlorobenzyl, phenylethyl, phenylpropyl, fluorophenylethyl, and chlorophenylethyl.

Examples of alkylaryl include, but are not limited to, toluyl, ethylphenyl, and propylphenyl. The term "(heteroaryl)alkyl," as used herein, shall refer to a system that includes a heteroaryl portion, where heteroaryl is as defined above, and contains an alkyl portion. Examples of (heteroaryl)alkyl include, but are not limited to, thienylmethyl, thienylethyl, thienylpropyl, pyridylmethyl, pyridylethyl and imidazoylmethyl. The term "(cycloalkyl)alkyl," as used herein, shall refer to a system that includes a 3- to 7-membered fully saturated cyclic ring portion and also includes an alkyl portion, wherein cycloalkyl and alkyl are as defined above.

The term "(cycloalkyl)alkenyl ," as used herein, shall refer to a system that includes a 3- to 7-membered fully saturated cyclic ring portion and also includes an alkenyl portion, wherein cycloalkyl and alkenyl are as defined above.

The term "(cycloalkenyl)alkyl," as used herein, shall refer to a system that includes a 3- to 7-membered cyclic ring portion containing at least one carbon to carbon double bond and also includes an alkyl portion, wherein cycloalkenyl and alkyl are as defined above. The term "(heterocycloalkyl)alkyl," as used herein, shall refer to a system that includes a 3- to 7-membered heterocycloalkyl ring portion and also includes an alkyl portion, wherein heterocycloalkyl and alkyl are as defined above. In the compounds of the present invention, Rl and R2 can be taken together with the carbon atom to which they are attached to form a 3-6 membered ring. In the compounds of the present invention, R^a and Rb can be taken together with any of the atoms to which they may be attached or are between them to form a 4-6 membered ring system.

The term "halo" shall include iodo, bromo, chloro and fluoro. The term "oxy" means an oxygen (O) atom. The term "thio" means a sulfur (S) atom. The term "oxo" means =O. The term "oximino" means the =N-O group.

The term "substituted" shall be deemed to include multiple degrees of substitution by a named substitutent. Where multiple substituent moieties are disclosed or claimed, the substituted compound can be independently substituted by one or more of the disclosed or claimed substituent moieties, singly or plurally. By independently substituted, it is meant that the (two or more) substituents can be the same or different.

The present invention also includes N-oxide derivatives and protected derivatives of compounds of Formula I. For example, when compounds of Formula I contain an oxidizable nitrogen atom, the nitrogen atom can be converted to an N- oxide by methods well known in the art. Also when compounds of Formula I contain groups such as hydroxy, carboxy, thiol or any group containing a nitrogen atom(s), these groups can be protected with a suitable protecting groups. A comprehensive list of suitable protective groups can be found in T.W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, Inc. 1981, the disclosure of which is incorporated herein by reference in its entirety. The protected derivatives of compounds of Formula I can be prepared by methods well known in the art. The alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocycloalkyl and heteroaryl substituents may be unsubstituted or unsubstituted, unless specifically defined otherwise. For example, a Cχ_χoalkyl may be substituted with one or more substituents selected from hydroxy, oxo, halogen, alkoxy, dialkylamino, or carboxy, and so on. In the case of a disubstituted alkyl, for instance, wherein the substituents are oxo and OH, the following are included in the definition: -(C=O)CH₂CH(OH)CH3, -(C=O)OH, -CH₂(OH)CH₂CH(O), and so on. In the case of substituted alkyl, for instance, where the substituents are 1-5 fluoro, the following are included in the definition: -CHF2, -CF3, -CF2CH3, -CH2CF3, -CF2CF3, -CH₂CF₂CH₃, -CH₂CH₂CF₃, -CH₂CF₂CF₃, -CH2CF2CH2CH3, -CH₂CH2CF₂CH₃, -CH2CH2CF2CF3, -CH₂CF(CH₃)₂, ^"and so on. In the case of a cycloalkylalkyl group, for instance, wherein the substituents are 1-3 Cχ_3alkyl, the following are included in the definition:

The compounds of the present invention may have asymmetric centers, chiral axes, and chiral planes (as described in: E.L. Eliel and S.H. Wilen, Stereochemistry of Carbon Compounds, John Wiley & Sons, New York, 1994, pages 1119- 1190), and occur as racemates, racemic mixtures, and as individual diastereomers, with all possible isomers and mixtures thereof, including optical isomers, being included in the present invention. In addition, the compounds disclosed herein may exist as tautomers and both tautomeric forms are intended to be encompassed by the scope of the invention, even though only one tautomeric structure is depicted. For example, any claim to compound A below is understood to include tautomeric structure B, and vice versa, as well as mixtures thereof.

A B

When any variable (e.g. R^a Rb, R^C etc.) occurs more than one time in any constituent, its definition on each occurrence is independent at every other occurrence. Also, combinations of substituents and variables are permissible only if such combinations result in stable compounds. Lines drawn into the ring systems from substituents indicate that the indicated bond may be attached to any of the sub- stitutable ring carbon atoms. If the ring system is polycyclic, it is intended that the bond be attached to any of the suitable carbon atoms on the proximal ring only. It is understood that substituents and substitution patterns on the compounds of the instant invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art, as well as those methods set forth below, from readily available starting materials. If a substituent is itself substituted with more than one group, it is understood that these multiple groups may be on the same carbon or on different carbons, so long as a stable structure results. The phrase "optionally substituted with one or more substituents" should be taken to be equivalent to the phrase "optionally substituted with at least one substituent" and in such cases the preferred embodiment will have from zero to three substituents.

Under standard nonmenclature used throughout this disclosure, the terminal portion of the designated side chain is described first, followed by the adjacent functionality toward the point of attachment. For example, a Cχ_5 alkylcarbonylamino Cχ_6 alkyl substituent is equivalent to

O

-Ci-galkyl-NH-C-Cj-salkyl

In choosing compounds of the present invention, one of ordinary skill in the art will recognize that the various substituents, i.e. Rl, R^, R3, R _S R5₅ R6₅ R7_? R^, R^, R10₅ Ra _and Rb _me t₀ χ>_e chosen in conformity with well-known principles of chemical structure connectivity.

Representative compounds of the present invention typically display submicromolar affinity for alpha and/or beta estrogen receptors, and preferably agonize the beta estrogen receptor. Compounds of this invention are therefore useful in treating mammals suffering from disorders related to estrogen functioning.

The compounds of the present invention are available in racemic form or as individual enantiomers. For convenience, some structures are graphically represented as a single enantiomer but, unless otherwise indicated, is meant to include both racemic and enantiomerically pure forms. Where cis and trans sterochemistry is indicated for a compound of the present invention, it should be noted that the stereochemistry should be construed as relative, unless indicated otherwise. For example, a (+) or (-) designation should be construed to represent the indicated compound with the absolute stereochemistry as shown.

Racemic mixtures can be separated into their individual enantiomers by any of a number of conventional methods. These include, but are not limited to, chiral chromatography, derivatization with a chiral auxiliary followed by separation by chromatography or crystallization, and fractional crystallization of diastereomeric salts. Deracemization procedures may also be employed, such as enantiomeric protonation of a pro-chiral intermediate anion, and the like.

The compounds of the present invention can be used in combination with other agents useful for treating estrogen-mediated conditions. The individual components of such combinations can be administered separately at different times during the course of therapy or concurrently in divided or single combination forms. The instant invention is therefore to be understood as embracing all such regimes of simultaneous or alternating treatment and the term "administering" is to be interpreted accordingly. It will be understood that the scope of combinations of the compounds of this invention with other agents useful for treating estrogen-mediated conditions includes in principle any combination with any pharmaceutical composition useful for treating disorders related to estrogen functioning.

The dosage regimen utilizing the compounds of the present invention is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound or salt thereof employed. An ordinarily skilled physician, veterinarian or clinician can readily determine and prescribe the effective amount of the drug required to prevent, counter or arrest the progress of the condition. Li the methods of the present invention, the compounds herein described in detail can form the active ingredient, and are typically administered in admixture with suitable pharmaceutical diluents, excipients or carriers (collectively referred to herein as 'carrier' materials) suitably selected with respect to the intended form of administration, that is, oral tablets, capsules, elixirs, syrups and the like, and consistent with conventional pharmaceutical practices.

The pharmaceutically acceptable salts of the compounds of this invention include the conventional non-toxic salts of the compounds of this invention as formed inorganic or organic acids. For example, conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like, as well as salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxy-benzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, trifluoroacetic and the like. The preparation of the pharmaceutically acceptable salts described above and other typical pharmaceutically acceptable salts is more fully described by Berg et al, "Pharmaceutical Salts," J. Pharni. Sci, 1977:66:1-19, hereby incorporated by reference. The pharmaceutically acceptable salts of the compounds of this invention can be synthesized from the compounds of this invention which contain a basic or acidic moiety by conventional chemical methods. Generally, the salts of the basic compounds are prepared either by ion exchange chromatography or by reacting the free base with stoichiometric amounts or with an excess of the desired salt-forming inorganic or organic acid in a suitable solvent or various combinations of solvents. Similarly, the salts of the acidic compounds are formed by reactions with the appropriate inorganic or organic base.

The novel compounds of the present invention can be prepared according to the following gneral procedures, using appropriate materials, and are exemplified by the subsequent specific examples. The compounds illustrated in the examples are not, however, to be construed as forming the only genus that is considered as the invention. Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparative procedures can be used to prepare these compounds. All temperatures are degrees Celsius unless otherwise noted.

For purposes of this specification, the following abbreviations have the indicated meanings:

AcOH = acetic acid

AJJBN = 2.2⁵-Azobisisobutyronitrile

BF3 • 2H2O = boron trifluoride dihydrate

BBr3 = boron tribromide CC1₄ = carbon tetrachloride

CH₂C1₂ = methylene chloride

CH₃CN = acetonitrile

CHC1₃ = chloroform

CH₃I = methylene iodide CaCO3 = calcium carbonate

CUSO4 = copper sulfate

DMAP = 4-(dimethylamino)pyridine

DMF = N,N-dimethylformamide

DMSO = dimethylsulfoxide Et₃N = triethylamine EtOAc = ethyl acetate

EtOH = ethanol

HCl = hydrochloric acid

H3PO4 = phosphoric acid

H2SO4 = sulfuric acid

K₂CO₃ = potassium carbonate

KI = potassium iodide

KMnθ4 = potassium permanganate

KN(SiMe₃)2 = potassium trimethylsilyl amine

KOH = potassium hydroxide

KOAc = potassium acetate

LAH = lithium aluminum hydride

MeLi = methyl lithium

Mel = methyl iodide

MeOH = methanol

MgSO₄ = magnesium sulfate

Mnθ2 = manganese dioxide

NaHCOs = sodium hydrogencarbonate

Na₂SO₃ = sodium sulfite

NaNO2 = sodium nitrite

NaOH = sodium hydroxide

NaOMe = sodium methoxide

NBS = N-bromosuccinimide

NCS = N-chlorosuccinimide

NH_tCl = ammonium chloride

Pd/C = palladium on carbon

Pd(PPh3)2Cl = palladium triphenylphosphine chloride

PG = protecting group

SnCl2 = stannous chloride rt = room temperature sat. aq. = saturated aqueous

THF = tetrahydrofuran tic = thin layer chromatography

Me = methyl

Et = ethyl GENERAL PROCEDURES FOR THE SYNTHESIS OF 3-HYDROXY-6H- BENZO[C]CHROMEN-6-ONES

Method 1

In Method 1, a suitably substituted resorcinol was reacted with a suitably substituted 2-bromo-benzoic acid or a 2-iodo-benzoic acid in the presence of 2 equivalents of sodium hydroxide in the presence of a catalytic amount of CUSO4, at 100o to 140° (sealed tube) to give the product, which usually precipitated out of the reaction mixture on cooling. In some cases, acidification of the reaction mixture after cooling, and then refluxing the resulting solution for 2 to 18 hr, was required to effect lactone formation.

Method 2

In Method 2, a suitably substituted arylboronic acid was coupled to a 2-brom-benzoic ester in the presence of a Palladium catalyst and a base, such as sodium carbonate, in a solvent, such as EtOH, dimethoxyethane, DMF etc. at a temperature of 80°-100° from 1 to 24 hr, to give the coupled biphenyl derivative. Removal of the protecting groups on the phenolic OH and the ester using a reagent such as BBr₃ gave the desired 3- hydroxy-6H-benzo[c]chromen-6-ones.

PREPARATIVE EXAMPLE 1

Synthesis of 2-ethylresorcinol

Step 1: 2,6-dimethoxy- 1 -( 1 -hydroxyethyD-benzene

To a solution of 2,6-dimethoxyacetophenone (180 mg, 1 mmol) in THF (10 mL), under N2, was added LAH (1 mL, 1.0 M in THF) drop wise, and the resulting solution stirred at room temp for 0.5 hr. HCl (2N) was added and the reaction mixture was partitioned between EtOAc (20 mL) and water (20 mL). The organic phase was washed with water (10 mL), 5% NaHCO3 (20 mL), and brine (10 mL), dried over MgSO4, filtered, and evaporated under vacuum to afford the product.

Step 2: 2,6-dimethoxy- 1 -ethylbenzene

To a solution of 2,6-dimethoxy-l-(l-hydroxyethyl)-benzene (180 mg) in CH2CI2 (4 mL) was added triethylsilane (0.795 mL, 5 eq.) and trifluoroacetic acid (0.770 mL, 10 eq.) and the mixture allowed to stir at room temperature for 1 hr. The reaction mixture was evaporated to dryness to give the product.

Step 3: 2-ethylresorcinol To a solution of 2,6-dimethoxy-l-ethylbenzene (190 mg) in CH2CI2 (4 mL), under nitrogen, was added dropwise a solution of BBr₃ (1 M) in CH2CI2. The reaction mixture was stirred at room temperature for 1.5 hr. Water was added to the reaction mixture and the mixture was partitioned between EtOAc and water. The organic phase was washed with water (10 mL), 5% NaHCO3 (20 mL), and brine (10 mL), dried over MgSO4, filtered, and evaporated under vacuum. The residue was triturated with hexane to give a solid product.

1HNMR (CDC13, 400 MHz): 1.19 (t, 3H), 2.68 (q, 2H), 6.4 (d, 2H), 6.93 (t, IH).

PREPARATIVE EXAMPLE 2

Synthesis of 2-bromoresorcinol.

Prepared from 2,4,6-tribromoresorcinol by reduction with Na2SO3 as described by Davis and Harrington, J. A er. Chem. Soc; 56, 129 (1934).

1HNMR (CDC13, 400 MHz): 5.37(s_s 2H), 6.64 (d, 2H), 7.13 (t, IH).

. PREPARATIVE EXAMPLE 3

Synthesis of 3-chloro-2,4-dimethoxyphenylboronic acid

Step 1: 2,2-Dichlorocycloheaxane-1.3-dione.

Prepared from cyclohexane 1,3-dione by reaction with chlorine as described by Schamp, N and Verzele, M, Bull. Soc. Chim. Belg. 73, 38 (1964).

Step 2: 2-chlororesorcinol.

2,2-Dichlorocycloheaxane-l,3-dione was heated in an oil bath at 120° for 25 min., allowed to cool to room temperature. The residue was chromatographed on silica gel using 15% EtOAc Hexane as eluant to give the product. Step 3: 2-chloro-6-bromo-resorcinol.

To a solution of 2-chlororesorcinol (2.59 g) in 1, 2-dichloroethane (10 mL) and acetonitrile (10 mL) was added NBS (3.19 g, 1 eq.) and the reaction stirred at room temperature for 1 hr. The reaction mixture was diluted with water and methylene chloride, the phases separated and the organic phase was washed with water (10 mL), 5% NaHCO3 (20 mL), and brine (10 mL), dried over MgSO4, filtered, and evaporated under vacuum to give the product.

Step 4: 2-chloro-6-bromo- 1.6-dimethoxybenzene. To a solution of 2-chloro-6-bromo-resorcinol (3.8 g) in CH2CI2 (30 mL) and MeOH (10 mL), cooled to Oo was added trimethylsilyldiazomethane (25.5 mL, 2 M in hexane, 1.5 eq.). After 1 hr the ice bath was removed and the reaction allowed to proceed at room temperature overnight. The solvent was removed under reduced pressure to give the product.

Step 5: 3-ehloro-2,4-dimethoxyphenylboronic acid.

To a solution of 2-chloro-6-bromo-l, 6-dimethoxybenzene (3.5 g) in THF (70 mL) under nitrogen, cooled in a liquid nitrogen bath, was added t-butyl lithium (9.8 mL, 1.7 M). After 10 min the liquid nitrogen bath was replaced by a dry ice/acetone bath. Stirred at -78° for 15 min. Triisopropyl borane (3.5 mL, 1.1 eq.) was added and the mixture stirred at -78° for 45 min. to give a clear solution and allowed to stir at room temperature overnight. Water was added and the THF evaporated under reduced pressure. The residue acidified with HCl (2N) to pH 1, stirred 10 min and extracted with EtOAc. The organic phase was extracted with NaOH (2 N), and the NaOH extract was acidified, the precipitate formed was cooled to 5° and filtered and washed with water, dried under vacuum to give the product.

1H NMR (CDC13, 500 MHz): 3.97 (s, 6H), 6.82 (d, IH), 7.75 (d, IH). PREPARATIVE EXAMPLE 4

Synthesis of 3-chloro-5-fluoro-2,4-dimethoxyphenylboronic acid-

Step 1: 2-chloro-4-fluororesorcinol.

To a solution of 2-chlororesorcinol (1.1 g) in MeOH (20 mL), under nitrogen, was added Selectfluor (3.24 g, 1.2 eq.). The reaction mixture was heated at 50° overnight. The MeOH was evaporated under reduced pressure, the residue was taken up in EtOAc washed with water and brine, dried over MgSO4 and evaporated to give the product which was used without purification in step 2.

Step 2: 6-bromo-2-chloro-4-fluororesorcinol.

The product from step 1 was treated with NBS as described in step 3, preparative example 3, to give the product.

Step 3: 2-chloro-4-fluoro-6-bromo-l,3-dimethoxybenzene.

The product from step 2 was reacted with trimethylsilyldiazomethane as described in Step 4, preparative example 3, to give the product.

Step 4: 3-chloro-5-fluoro-2,4-dimethoxyphenylboronic acid.

The product from step 3, was converted to the boronic acid following the procedure of step 5, preparative example 3.

H NMR (CDC13, 500 MHz): 3.96 (s, 6H), 4.07 (d, 3H), 7.5 (d, IH).

PREPARATIVE EXAMPLE 5

Synthesis of 3-methyl-5-fluoro-2,4-dimethoxyphenylboronic acid.

The desired product is obtained by substituting 2-methyhesorcinol in place 2- chlororesorcinol and following the procedures of steps 1 through 4 of preparative example 4.

1H NMR (CDC13, 600 MHz): 2.20 (s, 3H), 3.76 (s, 3H), 3.97 (d, 3H), 7.39 (d, IH). PREPARATIVE EXAMPLE 6

Synthesis of 2.5.-dibromo-4-methylbenzoic acid.

Step 1: l-bromomethyl-2,5.-dibromo-4-methylbenzene.

To a solution of l,4-dibromo-3,6-dimethylbenzene (10 g) in carbon tetrachloride (50 mL), NBS (7.4 g, 1.1 eq.) and AJJBN (100 mg) were added and the mixture refluxed under nitrogen for 3 hrs. The reaction mixture was cooled and diluted with methylene chloride, washed with water, and brine and dried over MgSO4 and evaporated to dryness to give the product.

Step 2: l-hydroxymethyl-2,5,-dibromo-4-methylbenzene.

To a solution of l-bromomethyl-2,5,-dibromo-4-methylbenzene (12.8 g) in dioxane (50 mL), was added water (50 mL) followed by CaCO3 (11.4g, 3 eq.). The reaction mixture was refluxed under nitrogen overnight, cooled and filtered. The residue was washed with a little dioxane and the combined filtrate and washings were evaporated under reduced pressure to remove most of the dioxane. The residue was extracted with EtOAc and the organic phase was washed with water and brine, dried over MgSO4 and evaporated to give the crude product which was crystallized from EtOAc/hexane to give the product.

Step 3: 2.5,-dibromo-4-methylbenzoic acid.

A solution of l-hydroxymethyl-2,5,-dibromo-4-methylbenzene ( 1 g) in acetone (20 mL) was added drop wise to a solution of KMnθ4 (0.73 g, 1.3 eq.) in water (20 mL) heated under a reflux condenser to 100° in an oil bath. The reaction mixture was allowed to reflux for 0.5 hr, cooled and acidified with HCl (2N) and treated with NaHSOs to dissolve the brown precipitate of Mnθ2- The mixture was extracted with EtOAc and the extract washed with water and brine, dried over MgSO4and evaporated to give the acid. 1H NMR (CDC13, 500 MHz): 2.45 (s, 3H), 7.61 (s, IH), 8.2 (s, IH). PREP AR ATΓVE EXAMPLE 7

Synthesis of 2-bromo-3-methyl-5-methoxybenzoic acid.

Step 1: 2-bromo-3-methyl-5-methoxytoluene.

To a solution of 2-bromo-3-methyl-5-hydroxytoluene (0.5 g) in DMF (2 mL) under nitrogen was added sodium hydride (125 mg, 50% in oil, 1.1 eq.). After stirring for 0.5 hr, methyl iodide (0.5 mL) was added and the reaction mixture was allowed to stir at room temperature overnight. The reaction mixture was diluted with water, extracted with ether, the ether extract was washed with water 4 times, then with brine, dried over MgSO4 and evaporated to give the product.

Step 2: 2-bromo-3-bromomethyl-5-methoxytoluene.

2-Bromo-3-methyl-5-methoxytoluene was treated with NBS according to the procedure of step 1, preparative example 6, to give the desired product 57% after chromatographic purification.

Step 3: 2-bromo-3-hvdroxymethyl-5-methoxytoluene.

2-Bromo-3-bromomethyl-5-meιhoxytoluene was treated according to the procedure of step 2, preparative example 6 to give the product.

Step 4: 2-bromo-3-methyl-5-methoxybenzoic acid.

2-Bromo-3-hydroxymethyl-5-methoxytoluene was oxidized with KMnθ4 as described in step 3, preparative example 6 to give the product.

1H NMR (CDC13, 400 MHz): 2.45 (s, 3H), 3.83 (s, 3H), 6.98 (s, IH), 7.26 (s, IH).

PREPARATIVE EXAMPLE 8

Synthesis of 2-Bromo-5-methoxy-3-methylbenzoic acid

Step 1: 2-Bromo-l-bromomethyl-5-methoχy-3-methylbenzene

The title compound was prepared from 4-bromo-l-methoxy-3,5- dimethylbenzene (1.9 g) and 1 eq. of NBS following the procedure of step 1, preparative example 19. Step 2: 2-Bromo-l-hydroxymethyl-5-methoxy-3-methylbenzene.

The title compound (0.5g) was prepared from 2-bromo-l- bromomethyl-5-methoxy-3-methylbenzene following the procedure of step 2, preparative example 19.

Step 3: 2-Bromo-5-methoxy-3-methylbenzaladehvde

The title compound (0.5g) was prepared from 2-bromo-l- hydroxymethyl-5-methoxy-3-methylbenzene (0.5g) following the procedure of step 2, preparative example 16.

Step 4: 2-Bromo-5-methoxy-3-methylbenzoic acid

The title compound (0.36g) was prepared from 2-bromo-5-methoxy-3- methylbenzaladehyde (0.5g) following the procedure of step 4, preparative example 22.

1H NMR (CDC1₃, 300 MHz): 2.48 (s, 3H), 3.83 (s, 3H), 7.00 (s, IH), 7.28 (s, IH).

PREPARATIVE EXAMPLE 9

Synthesis of 2-iodo-4,5-difluorobenzoic acid

Cone. H2SO4 (4.3 ml) was dissolved in water 14 (mL).4,5-difluoroanthranalic acid (590 mg) was treated with a solution of H2SO4 (10 mL) and the mixture heated to 100° and filtered. The filtrate was cooled to 5° and treated with a solution of NaNθ2 (140 mg) in water (5 mL). The reaction mixture was stirred at 5° for 0.75 hr and treated with a solution of KI (1 g) in water (5 mL). After stirring for 10 min the reaction mixture was heated to 100° for 20 min. The precipitate formed was cooled and filtered, washed with water and dried to give the iodo acid.

1H NMR (CDC13, 400 MHz): 7.9 (2q, 2H). PREPARATIVE EXAMPLE 10

Synthesis of 2.5-dibromo-4-(l-butenylVbenzoic acid.

Step 1: Methyl-2,5,-dibromo-4-methylbenzoate

2,5,-dibromo-4-methylbenzoic acid from step 3, preparative example 6 (0.66 g) was treated with trimethylsilyldiazomethane as described in step 4, preparative example 3, to give the methyl ester.

Step 2: Methyl-2,5-dibromo-4-hvdroxymethylbenzoate

Reaction of methyl-2,5,-dibromo-4-methylbenzoate with NBS as described in step 1, preparative example 6 (6 hrs reflux), followed by hydrolysis according to step 2, preparative example 6, and chromatography on silica gel gave the product.

Step 3: Methyl-2,5-dibromo-4-formylbenzoate

A solution of oxalyl chloride (0.71 mL, 2M solution in CH2CI2, 2 eq.) in CH2CI2 (10 mL) cooled to -78° was added DMSO (0.221 mL, 4 eq.) and the mixture stirred for 10 min. A solution of methyl-2,5-dibromo-4- hydroxymethylbenzoate (170 mg) in CH2CI2 (5 ml) was added drop wise and the reaction stirred another 30 min. Triethylamine (0.5 mL, 5 eq.) was added drop wise and stirring continued for 10 min. The dry-ice bath was removed and the reaction allowed to reach room temperature and stirred another 30 min. The reaction mixture was diluted with CH2CI2 and washed with water, 10% NaHCO3, brine and dried over MgSO4. Evaporation to dryness gave the product.

Step 4: Methyl 2,5-dibromo-4-( 1 -butenyD-benzoate.

To a suspension of propyltriphenylphosphonium chloride (211 mg, 2 eq.) in THF (2 mL), cooled to 0°, under nitrogen was added drop wise KN(SiMe₃)₂ solution (0.5 M, 1.2 mL, 2 eq.) and the mixture allowed to stir for 20 min. A solution of methyl-2,5-dibromo-4-formylbenzoate (84 mg) in THF (1 mL) was added drop wise and the stirring was continued for 0.5 hr. The reaction mixture was evaporated to dryness and chromatographed on a silica gel plate using 10% EtOAc/Hexane as eluant, to give the pure product (mixture of cis and trans isomers in 1:1 ratio). Step 5: 2.5-dibromo-4-(l-butenyl)-benzoic acid.

Methyl 2,5-dibromo-4-(l-butenyl)-benzoate (68 mg) was dissolved in MeOH (0.5 mL) and water (0.4 mL) and NaOH (0.078 mL, 5N, 2 eq.) was added and the mixture heated at 60° for 3 hr. The reaction mixture was acidified and extracted with EtOAc, washed with brine, dried and evaporated to give the acid.

PREPAR ATΓVE EXAMPLE 11

Synthesis of 2,6-dibromo-3,5-dimethyl-4-methoxy benzoic acid.

Step 1: 3.5-dibromo-2.4.6-trimethylphenol

To a solution of 2,4,6-trimethylphenol (13.6 g) in carbon tetrachloride (200 mL) was added bromine (20.5 mL) drop wise over 15 min and the mixture was heated in an oil bath at 75° for 3 hr. The reaction mixture was cooled to room temperature, washed with NaHSO3 solution, water and brine, dried over MgSO4 and evaporated to give the product.

Step 2: 3.5-dibromo-2.6-dimethyl-4-bromomethylphenol

To a solution of 3,5-dibromo-2,4,6-trimethylphenol (7.2 g) in CCI4 (50 mL) was added bromine (4 g, 1 eq.) and the mixture was refluxed under nitrogen overnight. The solvent was removed under reduced pressure to give the product mixed with the 2-bromomethyl isomer.

Step 3: 3.5-dibromo-2,6-dimethyl-4-hydroxymethylphenol Reaction of the mixture of products from step 2 Under the conditions described for step 2, preparative example 6, followed by chromatographic separation on silica gel using 25% EtOAc/Hexane gave the product.

Step 4: 2,6-dibromo-3,5-dimethyl-4-methoxybenzylalcohol. The procedure of step 1, preparative example 7 was carried out on the product of step 3 (0.74 g) to give the product.

Step 5: 2.6-dibromo-3,5-dimethyl-4-methoxybenzaldehvde.

The product from step 3 (139 mg) was oxidized using the procedure of step 3, preparative example 10 to give the aldehyde. Step 6: 2,6-dibromo-3,5-dimethyl-4-methoxy benzoic acid.

To a solution of the aldehyde in a 0.5 M solution of NaOMe in MeOH (6 mL, 4 eq) was added H2O2, (30%, 2 ml). After 1 hr of gentle reflux a further quantity of H2O2 ( 2 mL) was added and the reflux continued for another hr. Tic showed complete reaction to acid. The MeOH was removed under reduced pressure, the residue was extracted with EtOAc and the aqueous phase was acidified and extracted with EtOAc, washed with brine, dried over MgSO4 and evaporated. The residue was the pure acid.

1H NMR (CDC13, 400 MHz): 2.38 (s, 6H), 3.74 (s, 3H).

PREPARATIVE EXAMPLE 12

Synthesis of 2-bromo-6-ethyl-5-methoxybenzoic acid.

Step 1: Methyl 3-hydroxy-2-methylbenzoate

3-Hydroxy-2-methylbenzoic acid (4.0 g) was esterified following the procedure of step 4, preparative example 3 to give the methyl ester.

Step 2: Methyl 3-methoxy-2-methylbenzoate

To a solution of methyl 3-hydroxy-2-methylbenzoate (4.5 g) in DMF (20 mL) was added K2CO3 (7.1 g, 2 eq.) and CH3I (2.5 mL, 2 eq.). The reaction mixture was heated at 50° overnight. Water was added and the mixture was extracted with ether, washed with water 4 times then brine and dried over MgSO4and evaporated to give the product.

Step 3: Methyl 3-methoxy-2-bromomethylbenzoate

Reaction of the product from step 2, under the conditions of step 1, preparative example 6 gave the product (2.2 g) after chromatographic purification on silica gel, using 10%EtOAc/hexane as eluant.

Step 4: Methyl 3-methoxy-2-ethylbenzoate

To a suspension of Cul (190 mg) in dry ether (2 mL), under nitrogen, cooled to 0° was added MeLi (1.3 mL, 1.5 M, 2 eq.). The reaction mixture was allowed to stir for 0.5 hr, then cooled to -78°. Methyl 3-methoxy-2- bromomethylbenzoate (174 mg, 0.66 eq.) in THF (2 mL) was added drop wise. After 1 hr the temperature was raised to 0° and stirred 0.5 hr. thin layer chromatography shows only a trace of starting material. The reaction mixture was quenched with NH4CI (saturated solution) and extracted with ether, washed with water and brine, dried over MgSO4and evaporated. The residue was purified by preparative chromatography on silica gel plate, 10% EtOAc/hexane as eluant to give the product.

Step 5: 3-methoχy-2-ethylbenzoic acid.

The product from step 3 (233 mg) was hydrolyzed to give the product (196 mg) following the procedure of step 5, preparative example 10.

Step 6: 2-bromo-6-ethyl-5-methoxybenzoic acid.

To a solution of 3-methoxy-2-ethylbenzoic acid (196 mg) in acetic acid (2 mL) was added bromine (0.062 mL, 1.1 eq.). The reaction mixture was allowed to stir at room temperature for 3 hr and the mixture was evaporated to dryness, taken up in toluene and evaporated again to give the product.

1H-NMR (CDC13, 500 MHz): 1.2 (t, 3H), 2.7 (q, 2H), 3.84 (s, 3H), 6.82 (d, IH), 7.41 (d, IH).

PREPARATIVE EXAMPLE 13

Synthesis of 2-bromo-3,6-dimethyl-5-methoxybenzoic acid.

Step 1: Sodium 2,5-dimethyl-3-carboxybenzenesulfonate.

To a mixture of H2SO4 (15 mL) and fuming sulfuric acid (35 mL) was added 2,5-dimethylbenzoic acid. The mixture was heated to 110° for 2 hr and cooled to 10° and added slowly to ice (200 g). Cooled again to 10° and treated with NaHCOs

(10 g) added in small batches. To this was added NaCl (25 g) and the mixture was heated at 110° until desolution was complete. The solution was cooled at 10° overnight and the precipitate formed was filtered and washed with a little saturated NaCl solution and then with acetonitrile (50 mL). The precipitate was dried under vacuum to give the product. Step 2: 3.6-dimethyl-5-hvdroxybenzoic acid.

Sodium 2,5-dimethyl-3-carboxybenzenesulfonate (23 g) and KOH (80 g) were fused together in a porcelain dish until all components were melted and the reaction mixture appeared to bubble gently. The reaction mixture was cooled to room temperature and dissolved in water (200 mL). Cold H2SO4 (50% solution) was added until the pH was 9. The reaction mixture was cooled to 10° and the precipitated potassium sulfate salts were filtered off. The filtrate was evaporated to about half volume and cooled again to 10° and a second crop of salts were filtered off. The filtrate was acidified with cone HCl and the precipitated acid was filtered off, dissolved in EtOAc, dried over MgSO4and evaporated to give the product.

Step 3: 2-bromo-3,6-dimethyl-5-hydroxybenzoic acid.

Bromination of 3,6-dimethyl-5-hydroxybenzoic acid (166 mg, 1 mmol) following the procedure of step 6, preparative example 12 gave the product.

Step 4: Methyl 2-bromo-3,6-dimethyl-5-hydroxybenzoate.

Esterification of 2-bromo-3,6-dimethyl-5-hydroxybenzoic acid (1.2 g) ollowing the procedure of step 4, preparative example 3 gave the product.

Step 5: Methyl 2-bromo-3.6-dimethyl-5-methoxybenzoate

The product from the above step was methylated following the procedure of step 2, preparative example 12, to give the product.

Step 6: 2-bromo-3 ,6-dimethyl-5-methoxybenzoic acid. To a solution of methyl 2-bromo-3,6-dimethyl-5-methoxybenzoate

(600 mg) in MeOH (10 L) was added NaOH (2.2 mL, 5N, 5 eq.), followed by water (4 mL). The react mixture was refluxed overnight, cooled and extracted with ether. The aqueous phase was acidified and extracted with EtOAc, the EtOAc extract was washed with brine, dried and evaporated to give the product. Unreacted ester was recovered from the ether extract.

1H NMR (CDC13, 500 MHz): 2.24 (s, 3H), 2.41 (s, 3H), 3.83 (s, 3H), 6.78 (s, IH). PREPARATIVE EXAMPLE 14

2-bromo-3,6-dimethylbenzoic acid.

Step 1: 2,5-dimethyl-3-nitrobenzoic acid.

The acid was prepared by nitration of 2,5-dimethylbenzoic acid as described in Can. J. Chem., 48, 1346 (1970).

Step 2: Methyl 2.5-dimethyl-3-nitrobenzoate Esterification of 2,5-dimethyl-3-nitrobenzoic acid (1.55 g) following the procedure of step 4, preparative example 3, gave the product.

Step 3: Methyl 3-amino-2,5-dimethylbenzoate.

To a solution of methyl 2,5-dimethyl-3-nitrobenzoate (1.7 g) in EtOAc (20 mL) and EtOH (20 mL) was added 5% Pd/C (150 mg) and the mixture reduced in a Parr shaker under hydrogen at 40 lb, overnight. The catalyst was filtered and washed with a little EtOAc and the filtrate and washings were evaporated to give the product.

Step 4 : Methyl 3-amino-2-bromo-2,5-dimethylbenzoate. To a solution of methyl 3-amino-2,5-dimethylbenzoate (358 mg) in

CCI4 (7 mL), under nitrogen was added NBS (356 mg) and the mixture was stirred at room temperature for 1 hr, after which the starch iodide test was negative. The reaction mixture was diluted with CH2CI2 and washed with water and brine, dried and evaporated to give the crude product (478 mg). Chromatography on silica gel, using 20% EtOAc/hexane as eluant gave the pure product along with the dibrominated product.

Step 5: 3-amino-2-bromo-2,5-dimethylbenzoic acid.

Methyl 3-amino-2-bromo-2,5-dimethylbenzoate (160 mg) was hydrolyzed following the procedure of step 6, preparative example 13, to give the acid.

Step 6: 2-bromo-3.6-dimethylbenzoic acid

To a solution of 3-amino-2-bromo-2,5-dimethylbenzoic acid in (105 mg) in HCl (10%, 2 ml), cooled to -10°, was added NaNO2 (32 mg). Reaction mixture was stirred at 0° for 15 min. To this was added a solution of H3PO2 (50%, 2 mL). The mixture was stirred at -10° for 0.5 hr and the allowed to stand at 10° overnight. The reaction mixture was diluted with water and extracted with EtOAc, washed with brine, dried over MgSO4 and evaporated to give the product. 1H NMR (CDC13, 400 MHz): 2.42 (s, 6H),7.09 (d, IH), 7.2 (d, IH).

PREPARATIVE EXAMPLE 15

Synthesis of Σ-Bromo-S-fethoxymethv benzoic acid

Step 1: Methyl 2-bromo-3-methylbenzoate

To a solution of 2-Bromo-3-methylbenzoic acid (2.15 g) in MeOH (50 mL) and EtOAc (50mL) was added trimethylsilyldiazomethane (lOmL, 2M). The mixture was allowed to stir at room temperature overnight. The solvent was removed. The residue was taken up into CH2CI2 and washed with IN NaOH, H2O and brine, dried over MgSO4, filtered, and evaporated under vacuum to afford the product.

Step 2: Methyl 2-bromo-3-bromomethylbenzoate

To a solution of methyl 2-bromo-3-bromomethylbenzoate (2 g) in CCI4 (40mL), under nitrogen, was added NBS (1.6 g) and catalyst amount of AIBN.

The mixture was refluxed for 5 hours. The solvent was removed. The residue was chromatographed over silica gel (Hex:EtOAc = 85:15) to give the product.

Step 3: Methyl 2-bromo-3-fethoxymethyl benzoate To a solution of methyl 2-bromo-3-bromomethylbenzoate (0.5 g) in

EtOH (50 mL) was added sodium ethoxide (1.08 mL, 3.0M). The mixture was refluxed for 4 hours. The solvent was removed. The residue was taken up into CH2CI2 and washed with H2O and brine, dried over MgSO4, filtered, and evaporated under vacuum to give a yellow oil as the desired product.

Step 4: 2-Bromo-3-(ethoxymethyl)benzoic acid

To a solution of methyl 2-bromo-(3-ethoxymethyl)benzoate (0.27 g) in MeOH (30 mL) was added sodium hydroxide (1.8 mL, 5.0N). The mixture was heated at 65°C for 5 hours. The solvent was removed. The residue was taken up into H2O and acidified with 2N HCl. It was extracted with EtOAc. The organic layer was washed with H2O and brine, dried over Na2SO4, filtered, and evaporated under vacuum to give a white solid as desired product.

1H NMR (CDCI₃, 300 MHz): 1.35 (t, 3H), 3.68 (q, 2H), 4.65 (s, 2H), 7.42 (t, IH), 7.70 (d, IH), 7.84 (d, IH).

PREPARATIVE EXAMPLE 16

Synthesis of 2-Bromo-3-vinylbenzoic acid

Step 1: Methyl 2-bromo-3-hvdroxymethylbenzoate

The mixture of methyl 2-bromo-3 -bromomethylbenzoate (prepared following the procedure of step 2 in preparative example 15) (0.7 g), CaCO3 (0.52 g), 1 ,4-dioxane (10 mL) and water (lOmL) was refluxed overnight. The solid was filtered off. The solution was extracted with EtOAc. The organic layer was dried over Na2SO4 and evaporated under vacuum to give yellow oil as desired product.

Step 2: Methyl 2-bromo-3-formylbenzoate To a solution of oxalyl chloride (1.8 mL, 2.0M) in CH2CI2 (10 mL) was added DMSO (0.52 mL) at -78°C. After it was stirred for 10 min, a solution of methyl 2-bromo-3-hydroxymethylbenzoate (0„45g) in CH2CI2 was added al -78°C.

The mixture was stirred for 30 min. Et₃N (0.52mL) was then added. After stirred at - 78°C for 10 min, it was warmed up to room temperature for 30 min. The mixture was diluted with Et₂O, and washed with aq. NaHCO3 (5%), water, brine. The organic layer was dried over MgSO4 and evaporated under vacuum to give a yellow solid as desired product.

Step 3: Methyl 2-bromo-3-vinylbenzoate To a suspension of methyltriphenylphosphonium bromide (0.44 g) in

THF (30 mL) was added potassium bis (trimethylsilyl) amide (2.47 mL, 0.5M) at 0°C.

The mixture was stirred for 0.5 hr. A solution of methyl 2-bromo-3-formylbenzoate was added. It was stirred at room temperature overnight. The solid was filtered off.

The solvent was evaporated. The residue was taken up into EtOAc and washed with water, brine, dried over Na2SO4 and evaporated under vacuum. The crude mixture was purified by prep TLC plate (Hex:EtOAc=8:2) to give a colorless oil as desired product.

Step 4: 2-Bromo-3-vinylbenzoic acid The product from step 3 was hydrolyzed to the title compound following the procedure of step 4, preparative example 15.

1H NMR (CDC1₃, 300 MHz): 5.44 (d, IH), 5.70 (d, IH), 7.20 (m, IH), 7.40 (t, IH), 7.70 (d, IH), 7.80 (d, IH).

PREPARATIVE EXAMPLE 17

Synthesis of 2-bromo-3-(l-propenylVbenzoic acid

The title compound (105mg) was prepared from methyl 2-bromo-3- formylbenzoate(150mg) and ethyl triphenylphosphonium bromide (0.45g) following the procedure of step 3 and step 4, of preparative example 16.

1H NMR (CDCI₃, 300 MHz): 1.76 (d, 3H), 5.92 (m, -12H), 6.34 (d, IH), 7.40 (m, 2H), 7.78 (d, IH).

PREPARATIVE EXAMPLE 18

Synthesis of 2-bromo-3(l-butenyl -benzoic acid

The title compound (65mg) was prepared from methyl 2-bromo-3- formylbenzoate(80mg) and propyl triphenylphosphonium bromide (0.25g) following the procedure of step 3 and step 4, preparative example 16.

1H NMR (Acetone-d6, 300 MHz): 1.02 (t, 3H), 2.15 (q, 2H), 5.83 (m, IH), 6.45 (d, IH), 7.43 (m, 2H), 7.61 (m, IH). PREPARATIVE EXAMPLE 19

Synthesis of 2-Bromo-6-methylbenzoic acid

Step 1: 1 -Bromo-2-(bromomethyl)-3 -methylbenzene

The mixture of l-bromo-2,3-dimethylbenzene (2g), NBS (2.02g), ATBN (cat. Amount) and CCI4 (50mL) was refluxed under nitrogen for 4 hr. The reaction mixture was washed with water, brine and dried over Na2SO4 and evaporated under vacuum to give a mixture of two isomers, l-bromo-2- (bromomethyl)-3-methylbenzene and l-bromo-2-methyl-3-(bromomethyl)benzene, in about 5:6 ratio.

Step 2: l-Bromo-2-(hydroxymethyl^')-3-methylbenzene

The mixture from Step 1 and CaCO3 (2.16g) in l,4-dioxane(30mL) and water (30mL) was heated at 100°C overnight. The solid was filtered. The product was extracted with EtOAc and dried and concentrated in vacuum. The residue was chromatographed over silica gel (Hex:EA=8:2) to give the desired product as white solid.

Step 3: 2-Bromo-6-methylbenzoic acid

To a hot solution of l-bromo-2-(hydroxymethyl)-3- methylbenzene(0.78g) in acetone(15mL) was added a solution of KM11O4 (0.98 g) in water (20 mL) slowly over 30 min. After addition, the mixture was brought to reflux for 1 hr. After the reaction mixture was cooled to room temperature, it was acidified with aq.HCl (2N). Aq.NaHSO3 solution was added until the reaction solution was clear. It was then acidified with aq.HCl (2N), and extracted with EtOAc, washed with water, brine and dried over Na2SO4 and evaporated under vacuum. The residue was recrystallized in ether- pet. either to remove the crystal of l-bromo-2- (hydroxymethyl)-3-methylbenzene. The mother liquid was basified with aq. NaHCO3. The aq. solution was then acidified and extracted with EtOAc, dried over Na2SO4 and evaporated under vacuum to give a white solid product.

1H NMR (CDCI₃, 300 MHz): 2.28 (s, 3H), 7.20 (d, 2H), 7.45 (m, IH). PREPARATIVE EXAMPLE 20

Synthesis of 2-Bromo-4-hvdroxvmethvlbenzoic acid

Step 1: Methyl 2-bromo-4-methylbenzoate

The title compound was prepared from 2-bromo-4-methylbenzoic acid (2.15g) following the procedure of step 1, preparative example 15.

Step 2: Methyl 2-bromo-4-bromomethylbenzoate The title compound was prepared from methyl 2-bromo-4- methylbenzoate (0.9 g) following the procedure of step 2, preparative example 15.

Step 3: Methyl 2-bromo-4-hvdroxymethylbenzoate

The title compound was prepared from methyl 2-bromo-4-bromomethylbenzoate following the procedure of step 2, preparative example 19.

Step 4: 2-Bromo-4-hvdroxymethylbenzoic acid

The product from step 3 was hydrolyzed to the title compound following the procedure of step 4, preparative example 15.

1H NMR (Acetone-d6, 300 MHz): 4.72 (s, 2H), 7.44 (d, IH), 7.73 (s, IH), 7.84 (d, IH).

PREPARATIVE EXAMPLE 21

Synthesis of 2-iodo-3-bromo-5-methylbenzoic acid

A suspension of 2-amino-3-bromo-5-methylbenzoic acid (Ig) in water (8 mL) was added cone. H2SO4 (2.8 mL). It was heated at 100°C until homogeneous. After cooled to 10°C, a solution of NaNO2(0.3g) in water (0.7 mL) was added. The result reaction mixture was filtered and a solution KI (2.17g) in water (10 mL) was added to the filtrate. It was heated to 100°C for 15 min, and cooled to room temperature. The precipitate formed was collected by filtration and dissolved in aq.NaHCO3 solution.

The solid was filtered off. The solution was reacidified and extracted with EtOAc. The organic layer was washed with water, brine, dried over Na2SO4 and evaporated under vacuum to give a yellow solid product.

1H NMR (Acetone-d6, 300 MHz): 2.35 (s, 3H), 7.42 (s, IH), 7.72 (s, IH).

PREPARATIVE EXAMPLE 22

Synthesis of 2,4-Dibromo-3,5-dimethylbenzoic acid

Step 1: 2.4-Dibromo-l-bromomethyl-3,5-dimethylbenzene

The title compound was prepared from 2,4-dibromo- 1,3 ,5- trimethylbenzene (3 g) following the procedure of step 1, preparative example 19.

Step 2: 2.4-Di bromo- 1 -hvdroxymethyl-3 ,5-dimethylbenzene

The title compound was prepared from 2,4-dibromo-l-bromomethyl- 3,5-dimethylbenzene following the procedure of step 2, preparative example 19.

Step 3: 2.4-Dibromo-3,5-dimethylbenzaldehyde The title compound was prepared from 2,4-dibromo- 1-hydroxymethyl-

3,5-dimethylbenzene (0.16 g) following the procedure of step 2, preparative example 16.

Step 4: 2.4-Dibromo-3 ,5-dimethylbenzoic acid To a solution of 2,4-dibromo-3,5-dimethylbenzaldehyde (0.16 g) in

EtOH (20 mL) was added a solution of AgNO₃ at 0°C. A solution of KOH (0.17 g) in water (1.1 mL) was then added dropwise. After addition, the mixture was kept at 0°C for 1 hr. the solid was filtered off through celite. The filtration was concentrated and diluted with water. It was then acidified with 2N HCl, extracted with EtOAc, washed with water, brine, dried over Na₂SO and evaporated under vacuum to give a yellow solid product.

1H NMR (Acetone-d6, 300 MHz): 2.42 (s, 3H), 2.68 (s, 3H), 7.53 (s, IH). PREPARATIVE EXAMPLE 23

Synthesis of 2-Bromo-5-methoxy-3-vinylbenzoic acid

Step 1: 4-bromo-l-methoxy-3.5-dimethylbenzene

To a solution of 4-bromo-3,5-dimethylphenol (5g) in DMF (lOOmL) was added NaH (lg, 60% in mineral oil) at 0°C. After 0.5hr, Mel (1.53 mL) was added. The mixture was stirred at room temperature for 4 hr and diluted with Et₂O. The solution was washed with water, brine, dried over Na₂SO₄ and evaporated under vacuum to give a yellow oil product.

Step 2: 4-bromo-l-methoxy-3.5-di(bromomethyl)benzene

The title compound was prepared from 4-bromo-l-methoxy-3,5- dimethylbenzene (7.3 g) and 2 eq. of NBS following the procedure of step 1, preparative example 19. The compound was purified by chromatography.

Step 3: 4-bromo-l-methoxy-3,5-di(hydroxymethy benzene

The title compound was prepared from 4-bromo-l-methoxy-3,5- di(bromomethyl)benzene (4 g) following the procedure of step 2, preparative example 19.

Step 4: 2-bromo-5-methQxyisophthalaldehyde

The title compound was prepared from 4-bromo-l-methoxy-3,5- di(hydoxymethyl)benzene (1 g) following the procedure of step 2, preparative example 16.

Step 5: 2-bromo-5-methoxy-3-vinylbenzaldehyde

To a suspension of methyltriphenylphosphonium bromide (0.74g) in THF was added potassium bisørimethyl silyl)amide (4.14 mL, 0.5M) at 0°C. After stirring for 0.5 hr, a solution of 2-bromo-5-methoxyisophthalaldehyde (0.5g) in THF (1 mL) was added. The mixture was stirred for another 0.5 hr. The solid was filtered off. The solution was concentrated and chromatographed over silica gel (Hex:EA=95:5) to give the desired product. Step 6: 2-Bromo-5-methoxy-3-vinylbenzoic acid

The title compound was prepared from 2-bromo-5-methoxy-3- vinylbenzaldehyde (0.23 g) following the procedure of step 4, preparative example 22.

1H NMR (CDC1₃, 300 MHz): 3.88 (s, 3H), 5.44 (d, IH), 5.70 (d, IH), 7.15 (m, IH), 7.24 (d, IH), 7.35 (d, IH).

PREPARATIVE EXAMPLE 24

Synthesis of 2-bromo-5-methoxy-6-methylbenzoic acid

Step 1: Methyl 3-hydroxy-2-methylbenzoate

The title compound was prepared from 3-hydroxy-2-methylbenzoic acid (3g) following the procedure of step 1, preparative example 15.

Step 2: Methyl 3-methoxy-2-methylbenzoate

A mixture of methyl 3-hydroxy-2-methylbenzoate (3.17g), K₂CO₃ (5.3 g), Mel(1.4 mL) and acetone (150 mL) was refluxed overnight. The solid was filtered off and solvent was removed in vacuum. The residue was diluted with EtOAc, washed with water, brine, dried over Na₂SO and evaporated under vacuum to give a yellow oil product.

Step 3: 3-Methoxy-2-meιhylbenzoic acid

The product (3.4g) from step 3 was hydrolyzed to the title compound following the procedure of step 4, preparative example 15.

Step 4: 2-bromo-5-methoxy-6-methylbenzoic acid

To a solution of 3-methoxy-2-methylbenzoic acid (lg) in HO Ac (50mL) was added bromine (0.31 mL). The mixture was stirred at room temperature overnight. The solvent was removed in vacuum to give the desired product.

1H NMR (CDC1₃, 300 MHz): 2.32 (s, 3H), 3.84 (s, 3H), 6.79 (d, IH), 7.40 (d, IH). PREPARATIVE EXAMPLE 25

Synthesis of 6-Bromo-3-(methoxymethyloxyV2-methylbenzoicacid

Step 1: 6-Bromo-3-hydroxy-2methylbenzoic acid

The title compound was prepared from 3-hydroxy-2-methylbenzoic acid (1.52g) following the procedure of step 4, preparative example 24.

Step 2: Methoxymethyl 6-bromo-3-(methoxymethoxy)2-methylbenzoate To a solution of 6-bromo-3-hydroxy-2-methylbenzoic acid (1.9 g), diisopropyethylamine (8.58 mL) in CH₂C1₂ was added chloromethyl methyl ether (3.74 mL) at 0°C. the mixture was stirred at room temperature for 2.5 hr followed by washing with water and carefully acidified with 2N HCl. The organic layer was washed with water, brine, dried over Na₂SO . Evaporation of solvent gave yellow oil as desired product.

Step 3: 6-Bromo-3-(methoxymethyloxy)-2-methylbenzoicacid

A mixture of methoxymethyl 6-bromo-3-(methoxymethoxy)2- methylbenzoate (1.3 g), aq.NaOH (8 mL, 5N) and MeOH was healed at 65°C for 4 hr. MeOH was removed in vacuum. The residue was dissolved in water, washed with EtOAc The aq. layer was acidified with 2N HCl. The product was extracted with EtOAc, washed with water, brine, dried over Na₂SO₄. Evaporation of solvent gave white solid as desired product.

1H NMR (CDC1₃, 400 MHz): 2.33 (s, 3H), 3.50 (s, 3H), 5.21 (s, 2H), 7.04 (d, IH), 7.38 (d, IH).

PREPARATIVE EXAMPLE 26

Synthesis of 5-Bromo-lH-indazole-4-carboxylic acid

Step 1: Methyl 3-amino-2-methylbenzoate

A solution of methyl 3-nitro-2-methylbenzoate (2 g) in MeOH (25 mL) was subjected to hydrogenation with hydrogen balloon and Pd on carbon (0.4 g, 5%) as catalyst at room temperature for 3 hr. The solid was filtered off. The solvent was removed under vacuum to give the product.

Step 2: Methyl 2-bromo-5-amino-6-methylbenzoate The mixture of methyl 3-amino-2-methylbenzoate (1.55 g), NBS (1.67 g) and CH₂C1₂ was stirred at room temperature for 1 hr. After the solvent was removed, the residue was chromatographed over silica gel (Hex:EA=8:2) to give the product.

Step 3: Methyl 5-bromo-lH-indazole-4-carboxylate

To a mixture of methyl 2-bromo-5-amino-6-methylbenzoate (2.44g), AcOH (10 mL) and aq.HCl (10 mL, 2N) was added a solution of NaNO₂ (0.76 g) in 1 mL of water at 0°C. the mixture was stirred for 15 min. Saturated aq. solution of potassium hexafluorophosphate (18 mL) was added. A precipitate was formed. The mixture was continued to stir for 15 min. The solid product was collected by filtration and washed with water and air-dried. The solid was then dissolved in CH₂C1₂ (40 mL) and CH₃CN (20 mL) and cooled to -10°C. To it was added KOAc (1.4g) and dibenzo- 18-crown-6 (0.134g). The mixture was stirred for 1.5 hr at -10-+15°C. Solvent was then removed and the residue was dissolved in water. The product was extracted into EtOAc, dried over Na₂SO and concentrated. The residue was chromatographed over silica gel (Hex:EA=2:l) to give orange solid as desired product.

Step 4: 5-Bromo- lif-indazole-4-earboxylic acid

The title compound was prepared from methyl 5-bromo-lH-indazole- 4-carboxylate following the procedure of step 4, preparative example 15.

1H NMR (CDCI₃, 400 MHz): 7.42 (d, IH), 7.54 (d, IH), 8.21 (s, IH).

PREP ARATIVE EXAMPLE 27

Synthesis of methyl 5-amino-2-bromo-6-chlorobenzoate

Step 1: Methyl 2-chloro-3-nitrobenzoate

The title compound was prepared from 2-chloro-3-nitrobenzoic acid (1 g) following the procedure of step 1, preparative example 15. Step 2: Methyl 3-amino-2-chlorobenzoate

To a solution of methyl 2-chloro-3-nitrobenzoate (1 g) in HO Ac (10 mL) was added SnCl₂.2HCl (3.68 g) and cone HCl (3 mL) at 0°C. The mixture was then stirred at room temperature for 3 hr. The solvent was removed under vacuum. The residue was dissolved in water, basified with aq. NaOH (5 N). The product was extracted into EtOAc. The organic layer was washed with water, brine, dried over Na₂SO₄. Evaporation of the solvent gave the desired product.

Step 3: Methyl 5-amino-2-bromo-6-chlorobenzoate The title compound was prepared from methyl 3-amino-2- chlorobenzoate (0.78 g) following the procedure of step 2, preparative example 26.

¹HNMR (CDC1₃, 500 MHz): 3.98 (s, 3H), 6.68 (d, IH), 7.24 (d, IH).

PREPARATIVE EXAMPLE 28

Synthesis of 2-iodo-3-naphthoic acid

3-Amino-2-naphthoic acid (2 g) was dissolved in cone H₂SO (6.9 mL) and water (25 mL). The solution was cooled to 10 °C. A solution of NaNO₂ (0.738 g) in water (1.8 mL) was added. The mixture was stirred for 15 min. and a solution of KI (5.34 g) in water (25 mL) was added. The solution was heated at 100°C for 30 min. After cooled to room temperature, the solid was collected by filtration and redissolved in 2M NaOH solution. The undissolved solid was filtered off. The mother liquid was acidified with 2N HCl. The solid product was collected by filtration, washed with water and dried under vacuum.

1HNMR (CDCI₃, 300 MHz): 7.60 (m, 3H), 7.75 (d, IH), 7.88 (d, IH), 7.56 (d, IH).

PREPARATIVE EXAMPLE 29

Synthesis of 2-Bromo-6-methyl-5-r(methylsulfonyl')anιino1benzoic acid

Step 1: Methyl 2-bromo-6-methyl-5-r(methylsulfonyl^')aminolbenzoate A solution of methyl 2-bromo-5-amino-6-methylbenzoate (0.22 g) (from preparative examle 44), pyridine (0.072 mL) and CH2CI2 (~5 mL) was added methyl sulfonyl chloride (0.070 mL). It was heated at 40°C overnight. The mixture was chromatographed over silica gel to give the desired product.

Step 2: 2-Bromo-6-methyl-5-r(methylsulfonyl aminolbenzoic acid

The title compound was prepared from methyl 2-bromo-6-methyl-5- [(methylsulfonyl)amino]benzoate (0.66 g) following the procedure of step 4, preparative example 15.

1H NMR (CDCI₃, 400 MHz): 2.20 (s, 3H), 3.02 (s, 3H), 7.48 ( , 2H).

PREPARATIVE EXAMPLE 30

Synthesis of methyl 2-bromo-6-chloro-5-methoxy-benzoate

Step 1: 2-bromo-5-methoxybenzyl alcohol

To a solution of methyl 2-bromo-5-methoxy-benzoate (2.45 g) in THF (20 mL), under nitrogen, cooled to 0°, was added drop wise a ether solution of lithium aluminum hydride (10 mL, IM). After 0.5 hr, water was added cautiously followed by HCl (2N) to dissolve the aluminum salts. Extraction with EtOAc followed by washing with water and brine, drying and evaporation gave the product.

Step 2: 2-bromo-6-chloro-5-methoxybenzyl alcohol To a solution of 2-bromo-5-methoxybenzyl alcohol (217 mg, 1 mmol) in C1CH₂CH₂C1 (2 mL) was added NCS (133 mg, 1 mmol) and the reaction heated at 80° overnight. Dilution with CH₂CI₂, washing with water and brine, drying and evaporation gave the product as a mixture of isomers. Crystallization from hot hexane gave 2-bromo-4-chloro-5-methoxybenzyl alcohol. From the mother liquor was obtained 2-bromo-6-chloro-5-methoxybenzyl alcohol.

Step 3: 2-formyl-3-chloro-4-methoxy-brornobenzene

2-bromo-6-chloro-5-mefhoxybenzyl alcohol (1.08 g) was oxidized to the product following the procedure of step 3, preparative example 10. Step 4: 2-bromo-6-chloro-5-methoxy-benzoic acid.

2-formyl-3-chloro-4-methoxy-bromobenzene was oxidized to the acid following the procedure of step 5, preparative example 11.

Step 5: Methyl 2-bromo-6-chloro-5-methoxy-benzoate

2-bromo-6-chloro-5-methoxy-benzoic acid was esterified following the procedure of step 4, preparative example 3 to give the product.

PREPARATIVE EXAMPLE 31

Methyl 6-bromo-2-chloro-3-methoxy-4-fluorobenzoate

Step 1: 2-chloro-3 -methoxy-4-fluorobenzoic acid.

2-chloro-3-methoxy-4-fluorobenzaldehyde (188 mg) was prepared from 4-fluoro-3-metoxy benzaldehyde following the chlorination procedure described by McCarthy J. R. et al, J. Med. Chem. 29(9),1586(1986). It was oxidized to the acid following the procedure of step 5, preparative example 11 to give the product.

Step 2: 2-chloro-3 -hydro v-4-fluorobenzoic acid. To a solution of 2-chloro-3-methoxy-4-fluorobenzoic acid in CH₂C1₂

(8 mL) unde nitrogen was added a solution of BBr₃ (4 mL, 1 M, 4 eq). The reaction mixture was allowed to stir at room temperature overnight. The reaction mixture was treated with water and HCl (2 N) and stirred for 15 min, extracted with EtOAc and the extract washed with water and brine, dried and evaporated to give the product.

Step 3: 6-bromo-2-chloro-3-hvdroxy-4-fluorobenzoic acid

To a solution of 2-chloro-3-hydroxy-4-fluorobenzoic acid (178 mg) in C1CH₂CH₂C1 (2 mL) and CH₃CN (2 mL), was added NBS (178 mg). The reaction stirred at 80° for 3 hr. The react mixture was diluted with EtOAc and washed with acidic Na₂SO₃ solution and with water and brine, dried over MgSO and evaporated to give the product. Step 4: Methyl 6-bromo-2-chloro-3-methoxy-4-fluorobenzoate.

Reaction of 6-bromo-2-chloro-3-hydroxy-4-fluorobenzoic acid under the conditions of step 4, preparative example 3, using excess trimethylsilyldiazomethane gave the product.

1H NMR (CDC13, 600 MHz): 3.75 (d, 3H), 3.8 (s, 3H), 7.3 (d, IH).

PREPARATIVE EXAMPLE 32

Synthesis of Methyl 2-bromo-4-chloro-5-methoxy-6-methylbenzoate.

Step 1: 2-methyl-3 -hydroxy-6-bromobenzoic acid

To a solution of 2-methyl-3-hydroxybenzoic acid (304 mg) in acetic acid (3 mL) was added bromine (0.103 mL, 1 eq) Reaction mixture was stirred at room temperature for 1.25 hr. The solvent was removed under reduced pressure to give the product.

Step 2: 2-methyl-3-hydroxy-4-chloro-6-bromobenzoic acid

Carrying out the procedure of step 2, preparative example 30 on 2- methyl-3-hydroxy-6-bromobenzoic acid gave the product.

Step 3: Methyl 2-bromo-4-chloro-5-methoxy-6-methylbenzoate.

Reaction of 2-methyl-3-hydroxy-4-ehloro-6-bromobenzoic acid under the conditions of step 4, preparative example 3 gave the product.

1H NMR (CDC13, 500 MHz): 2.29 (s, 3H), 3.83 (s, 3H), 3.97 (s, 3H), 7.49 (s, IH)..

PREPARATIVE EXAMPLE 33

Synthesis of methyl 6-bromo-2,4-dichloro-3-methoxy-5-methylbenzoate.

Step 1: 4-bromo-2,6-dichloro-3.5-dimethylphenol

To a solution of 4-bromo-3,5-dimethylphenol (4.04 g) in C1CH₂CH₂C1 (10 mL) and CH₃CN (10 mL) was added NCS (5.34 g) and the reaction heated to 80° overnight. The reaction mixture was diluted with CH₂C1₂ and washed with water and brine, dried over MgSO and evaporated to give the product.

Step 2: 3,5-dichloro-2,6-dimethyl-4-methoxy-bromobenzene Reaction of 4-bromo-2,6-dichloro-3,5-dimethylphenol (703 mg) under the conditions of step 4, preparative example 3, gave the product.

Step 3: 2-bromo-4,6-dichloro-5-methoxy-3-methyl-benzyl bromide

Reaction of 3,5-dichloro-2,6-dimethyl-4-methoxy-bromobenzene under the conditions of step 1, preparative example 6 gave the product.

Step 4: 2-bromo-4,6-dichloro-5-methoxy-3-methyl-benzyl alcohol

Reaction of 2-bromo-4,6-dichloro-5-methoxy-3-methyl-benzyl bromide (900 mg) under the conditions of step 2, preparative example 6, gave the product after chromatographic purification on silica gel, 10% EtOAc/Hexane as eluant.

Step 5: 2-bromo-4,6-dichloro-5-methoxy-3-methyl-benzaldehvde

Reaction of 2-bromo-4,6-dichloro-5-methoxy-3-methyl-benzyl alcohol (201 mg) under the conditions of step 3, preparative example 10 gave the product.

Step 6: 2-bromo-4,6-dichloro-5-methoxy-3-methyl-benzoic acid

Reaction of 2-bromo-4,6-dichloro-5 -methoxy-3 -methyl-benzaldehyde under the conditions of step 5, preparative example 11 to give the product.

Step 7: Methyl 2-bromo-4,6-dichloro-5-methoxy-3-methyl-benzoate

Reaction of 2-bromo-4,6-dichloro-5-melhoxy-3-methyl-benzoic acid under the conditions of step 4, preparative example 3 gave the product after preparative tic on silica gel, 10% EtOAc/Hexane as eluant.

1H NMR (CDC13, 600 MHz): 2.54 (s, 3H), 3.89 (s, 3H), 3.99 (s, 3H). PREPARATIVE EXAMPLE 34

Synthesis of methvl 5-amino-2-bromo-6-chlorobenzoate

Step 1: Methyl 2-chloro-3-nitrobenzoate

The title compound was prepared from 2-chloro-3-nitrobenzoic acid (1 g) following the procedure of step 1, preparative example 15.

Step 2: Methyl 3-amino-2-chlorobenzoate To a solution of methyl 2-chloro-3-nitrobenzoate (lg) in HO Ac (10 mL) was added SnCl₂.2HCl (3.68 g) and cone HCl (3 mL) at 0°C. The mixture was then stirred at room temperature for 3 hr. The solvent was removed under vacuum. The residue was dissolved in water, basified with aq. NaOH (5 N). The product was extracted into EtOAc. The organic layer was washed with water, brine, dried over Na₂SO . Evaporation of the solvent gave the desired product.

Step 3: Methyl 5-amino-2-bromo-6-chlorobenzoate

The title compound was prepared from methyl 3-amino-2- chlorobenzoate (0.78 g) following the procedure of step 2, preparative example 26.

1H NMR (CDC1₃, 500 MHz): 3.98 (s, 3H), 6.68 (d, IH), 7.24 (d, IH).

PREPARATIVE EXAMPLE 35

Synthesis of 2A6-tribromo-5-methoxybenzoic acid

Step 1: Methyl 2,4,6-tribromo-5-methoχybenzoate

To a solution of 2,4,6-tribromo-5-hydroxybenzoic acid (375 mg, Immole) in DMF (4 mL) under nitrogen was added NaH (120 mg, 50% in oil) and the mixture was stirred at room temperature for 0.5 hr. To this was added CH₃I (0.15 mL) and the reaction was stirred at 50° overnight. The reaction was cooled, diluted with water and extracted with ether. The ether extract was washed with water 4 times then brine and dried and evaporated to give the product after chromatographic purification over silica gel (10% EtOAc/Hexane). Step 2: 2,4.6-tribromo-5-methoxybenzoic acid.

The product from step 1 (200 mg) was hydrolyzed following the procedure of step 5 of preparative example 10, except that reflux was carried out overnight to give the product.

PREPARATIVE EXAMPLE 36

Synthesis of 2-bromo-5-amino-6-methylbenzoic acid

Step 1: Methyl 2-bromo-5-amino-6-methylbenzoate

To a solution of methyl -3-amino-2-methylbenzoate (165 mg, 1 mmole) from step 2, preparative example 30, in CCI4 (2 mL) under nitrogen, was added NBS (178 mg, 1 mmole). The reaction mixture was stirred at room temperature for 1 hr, diluted with CH₂CI₂ and washed with water and brine, then dried over MgSO and evaporated to the product.

Step 2: 2-bromo-5-amino-6-methylbenzoic acid

Methyl 2-bromo-5-amino-6-methylbenzoate was hydrolyzed following the procedure of step 2 of preparative example 35, to give the product.

PREPARATIVE EXAMPLE 37

Synthesis of methyl 2-bromo-6-chloro-5-methoxy-3-methylbenzoate

Step 1: 2-bromo-5-hvdroxy-6-methylbenzoic acid

Reaction of 3-hydroxy-2-methylbenzoic acid (304 mg) following the procedure of step 6, preparative example 12, gave the product .

Step 2: 2-bromo-4-chloro-5-hydroxy-6-methylbenzoic acid To a solution of 2-bromo-5-hydroxy-6-methylbenzoic acid from step 1, in C1CH₂CH₂C1 (4 mL) and CH₃CN (4 mL) was added NCS (293 mg, 1 eq). The reaction was heated at 80° overnight, then diluted with CH₂C1₂, washed with water followed by brine, dried over MgSO₄ and evaporated to give the product. Step 3: Methyl 2-bromo-4-chloro-5-methoxy-6-methylbenzoate.

2-bromo-4-chloro-5-hydroxy-6-methylbenzoic acid was reacted following the procedure of step 4, preparative example 3, to give the product after silica gel chromatography (10%EtOAc/Hexane as eluant).

PREPARATIVE EXAMPLE 38

Synthesis of 6-bromo-2.3-dimethoxybenzoic acid

Step 1: 6-Bromo-2,3-methyoxybenzaldehvde

A mixture of 6-bromo-2-hydroxy-3-methoxybenzaldehyde (0.56 g), K₂CO₃ (0.65 g), Mel (0.22 mL) and DMF (10 mL) was heated at 40°C for 3 hr. The reaction mixture was diluted with water, extracted with Et₂O. The organic layer was washed with water, brine, dried over Na₂SO . Evaporation of solvent gave the product.

Step 2: 6-Bromo-2,3-dimethoxybenzoic acid

The product from step 1 (0.55 g) was oxidized using the procedure of step 5, preparative example 11 to give the title compound.

^!H NMR (CDCI₃, 400 MHz): 3.90 (s, 3H), 3.95 (s, 3H), 6.87 (d, IH), 7.50 (d, IH).

PREPARATΓVE EXAMPLE 39

Synthesis of Methyl 2-bromo-4-chloro-5-methoxy-3,6-dimethylbenzoic acid

Step 1: 2-bromo-4-chloro-5-hydroxy-3 ,6-dimethylbenzoic acid

The product from step 3, preparative example 13, (2 g), was dissolved in CH₃CN (20 mL) and treated with NCS (1.14 g, 1.05 eq.) and heated at 78° overnight. The solvent was removed under reduced pressure and the residue taken up in EtOAc, washed with water and brine, dried and evaporated, gave the product.

Step 2: Methyl 2-bromo-4-chloro-5-methoxy-3 ,6-dimethylbenzoate

To a solution of 2-bromo-4-chloro-5-hydroxy-3,6-dimethylbenzoic acid (2.3 g) in acetone (40 mL) was added K₂CO₃ (2.4 g, 2.2 eq) and CH₃I (2.4 mL, excess). The reaction mixture was refluxed overnight. The acetone was evaporated off and the residue was taken up in EtOAc and water, the phases were separated and the organic phase was washed with water and brine, dried and evaporated. The residue was chromatographed to give the pure product.

1H NMR (CDC1₃, 600 MHz): 2.25 (s, 3H), 2.55 (s, 3H), 3.8 (s, 3H), 3.96 (s, 3H).

PREPARATIVE EXAMPLE 40

Synthesis of 2-fluororesorcinol

Step 1: 2.4-dimethoxy-3-fluoro-nitrobenzene

To a solution of 2,3,4-trifluoronitrobenzene (4.78 g) in MeOH (50 mL), cooled to 0°, was added drop wise, NaOMe (12.5 mL, 25% solution in MeOH, 2.2 eq). The reaction mixture was allowed to warm to room temperature and stirred overnight. Aqueous citric acid (2.7 mL, 1 M, 0.1 eq) was added and the MeOH was removed under vacuum. The residue was taken up in Et₂O, washed with aqueous citric acid (1 M) then water and brine, dried and evaporated to give the product.

Step 2: 2.4-dimethoxy-3-fluoro-aniline

2,4-Dimethoxy-3-fluoro-nitrobenzene was reduced to the aniline, following the procedure of step 1, preparative example 26 to give the product.

Step 3: 2.6-dimethoxyfluorobenzene 2,4-Dimethoxy-3-fluoro-aniline (1 g) was reduced following the procedure of step 6, preparative example 14, to give the product.

Step 4: 2-fluororesorcinol

2,6-Dimethoxyfluorobenzene was treated with BBr3, following the procedure of example 45.

1H NMR (CDCI₃, 500 MHz): 6.57 (t, 2H), 6.7 (d of t, IH). PREPARATIVE EXAMPLE 41

Synthesis of 3-methyl-2.4-dimethoxyphenylboronic acid.

The desired product is obtained by staring with 2-methylresorcinol in place of 2- chlororesorcinol in step 3, of preparative example 3 and following the procedures of steps 3 to 5 of preparative example 3.

EXAMPLE 1

Synthesis of 3-hvdroxy-8-bromo-4-methyl-6H-benzorclchromene-6-one

2,5-dibromobenzoic acid (280 mg, Immol) and 2-methyl resorcinol (248 mg, 2 mmol), placed in a scalable tube were treated with water (0.4 mL) and NaOH (5 N, 0.4mL). The reaction was heated to 100° for 15 min, to give a dark solution. CuSO (10% solution, 0.12 mL) was added and the reaction tube was sealed and the mixture stirred al 100° for 3 hr. The reaction mixture was cooled lo room temperature and filtered, washed with water and dried under vacuum to give the product.

1H NMR (CDC13+10%CD₃OD, 500 MHz): 2.21 (s, 3H), 6.75 (d, 1H),7.62 (d, IH), 7.77 (m, 2H), 8.2 (s, IH).

EXAMPLE 2

Synthesis of 3-hvdroxy-8-vinyl-4-methyl-6H-benzorclchromene-6-one

Step 1: 3-t-butyldimethylsilyloxy-8-bromo-4-methyl-6H-benzo[c]chromene-

6-one

To a suspension of 3-hydroxy-8-bromo-4-methyl-6H- benzo[c]chromene-6-one in CH₂C1₂ (10 mL) was added Et₃N (0.223 mL, 1.2 eq) and t-butyldimethylsilyl chloride (0.237 g, 1.2 eq). The reaction mixture was stirred under nitrogen for 3 hr, then diluted with CH₂C1₂ and washed with water and brine, dried over MgSO and evaporated to give the product.

Step 2: 3-t-butyldimethylsilyloxy-8-vinyl-4-methyl-6H-benzo[c]chromene-

6-one

To a solution of 3-t-butyldimethylsilyloxy-8-bromo-4-methyl-6H- benzo[c]chromene-6-one (20 mg) in dry toluene (0.5 mL) was added tri-n- butyl(vinyl)tin (0.02 mL, 1.2 eq). The solution was degassed under nitrogen. [(PlfbPj/tPd (4 mg) was added and the mixture heated at 100°. After 1 hr, tic showed absence of starting material. The reaction mixture was purified by preparative tic to give the product.

Step3: 3-hydroχy-8-vinyl-4-methyl-6H-benzorc1chromene-6-one To a solution of 3-t-butyldimethylsilyloxy-8-vinyl-4-methyl-6H- benzo[c]chromene-6-one in THF (0.5 mL), HOAc (0.5 mL) and water (0.25 mL) was added KF (5 mg). The reaction mixture was allowed to stir al room temperature for 2 hr. The solvents were removed under reduce pressure, the residue was taken up in EtOAc and filtered and the solvent evaporated to give the product.

1H NMR (CDC13+10%CD₃OD, 500 MHz): 2.22 (s, 3H), 5.25 (d, IH), 5.77 (d, IH), 6.7 (q, IH), 6.72 (d, IH), 7.61 (d, IH), 7.50 (d, IH), 7.83 (d, IH), 8.17 (s, IH).

EXAMPLE 3

Synthesis of 3-hvdroxy-4,8-dimethyl-10-vinyl-6H-benzorc1chromen-6-one

Step 1: 10-Bromo-3-{ [tert-butyl(dimethyl)silyl]oxy}-4,8-dimethyl-6H- benzorclchromen- 6-one

A solution of 10-bromo-3-hydroxy-4,8-dimethyl-6H- benzo[c]chromen-6-one (example 35) (0.63 g), Et₃N (0.85 mL) and CΗ₂C1₂ (-10 mL) was added tert-butyldimethylsilyl chloride (0.33 g). It was stirred at room temperature overnight. The mixture was diluted with CH₂C1₂, washed with IN HCl, water, brine, dried over Na₂SO₄ and concentrated. The residue was chromatographed over silica gel (He EtOAc = 8:2) to give the product.

Step 2: 3-{ [tert-Butyl(dimethyl)silyl]oxy}-4,8-dimethyl-10-vinyl-6H- benzorclchromen-6-one

A solution of 10-bromo-3-{[tβrt-butyl(dimethyl)silyl]oxy}-4,8- dimethyl-6H-benzo[c]chromen-6-one (100 mg), Iributylvinyltin (0.67 mL), tetrakis(triphenylphosphine)palldium(0) (6 mg) in toluene was heated at 100°C under nitrogen overnight. The solvent was evaporated. The residue was separated by preparative TLC plate to give the product.

Step 3: 3-Hvdroxy-4,8-dimethyl-10-vinyl-6H-benzorc]chromen-6-one 3-{ [tert-Butyl(dimethyl)silyl]oxy }-4,8-dimethyl-10-vinyl-6H- benzo[c]chromen-6-one (60 mg) was treated with KF (30 mg) in mixed solvent of ΗOAc (3 mL), TΗF (3 mL) and water (1.5 mL) at 50 °C for 1 hr. The solvent was evaporated and the residue was separated by preparative TLC plate to give the title product. 1H NMR (CDCI₃+ 10% CD₃OD, 400 MHz): 2.25 (s, 3H), 2.38 (s, 3H), 5.39 (d, IH), 5.60 (d, IH), 6.70 (d, IH), 7.15 (m, IH), 7.46 (s, IH), 7.88 (d, IH), 8.05 (s, IH).

EXAMPLE 4

Synthesis of 10-allyl-3-hydroxy-4.8-dimethyl-6H-benzorc1chromen-6-one

The title compound was prepared from 10-bromo-3-{ [tert- butyl(dimethyl)silyl]oxy}-4,8-dimethyl-6H-benzo[c]chromen-6-one (0.22 g) following the procedure of step 2, and step 3 of example 3, using tributylallyltin in place of tributylvinyltin in step 2.

1H NMR (CDCI3+ 10% CD3OD, 300 MHz): 2.22 (s, 3H), 2.39 (s, 3H), 3.80 (d, 2H), 4.95 (d, IH), 5.15 (d, IH), 6.10 (m, IH), 6.72 (d, IH), 7.38 (s, IH), 7.78 (d, IH), 8.05 (s, IH).

EXAMPLE 5

Synthesis of 3.8-dihydroxy-4,7-dichloro-6H-benzorclchromene-6-one

Step 1: 3 ,3 ' -dichloro-2' -mefhoχycarbonyl-2 ,4,4' -trimethoxybiphenyl

To a solution of 3-chloro-2,4-dimethoxyphenylboronic acid from preparative example 3 (216 mg, 1 mmol) and methyl 2-bromo-6-chloro-5-methoxy- benzoate from preparative example 33 (310 mg, 1.1 mmol) in CH₃OCH₂CH₂OCH₃ (4 mL) and EtOH (4 mL) was degassed under nitrogen and treated with aqNa₂CO₃ (4 mL, 2M ) and [(C₆H₅)₃P] Pd (69 mg). The reaction mixture was heated to 60° for 1 hr, cooled and diluted with water and extracted with ether. The ether extract was washed with water and brine, dried over MgSO , and evaporated to give after chromatography on silica gel (10% EtOAc Hexane eluant), the product.

Step 2: 3.8-dihydroxy-4.7-dichloro-6H-benzorclchromene-6-one

To a solution of 3,3'-dichloro-2'-methoxycarbonyl-2,4,4'- trimethoxybiphenyl (110 mg) in CH₂C1₂ (2 mL), cooled to 0° under nitrogen, was added drop wise BBr₃ (1.9 mL, 1.0 M in CH2CI2, 6 eq). After 15 min the ice bath was removed and the mixture allowed tostir at room temperature. After 1 hr, water was added and the mixture was stirred for 15 min and then extracted with EtOAc, washed with water and brine, dried over MgSO and evaporated. The residue was triturated with hot CHCI₃ to give the product.

1H NMR (CDCI₃+ 10% CD₃OD, 500 MHz): 6.74 (d, IH), 7.23 (d, IH), 7.54 (d, IH), 7.66 (d, IH).

EXAMPLE 6

Synthesis of 3-Hvdroxy-4-methyl-10-propyl-6H-benzorc1clιromen-6-one

3-Ηydroxy-4-methyl-10-(prop-l-enyl)-6H-benzo[c]chromen-6-one (example 22, 7 mg) was subjected hydrogenation under a Η₂ balloon and Pd on C (5%, 7 mg) in MeOH (10 mL) at room temperature for 4 hr. The solid was filtered off and solvent was removed. The residue was purified with Prep. TLC plate to give the product. 1HNMR (CDCI₃+ 10% CD₃OD, 400 MHz): 1.05 (t, 3H), 1.74 (m, 2H), 2.29 (s, 3H), 3.05 (t, 2H), 6.76 (d, IH), 7.33 (t, IH), 7.55 (d, IH), 7.80 (d, IH), 8.24 (d, IH). EXAMPLE 7

Synthesis of 10-Ethyl-3-hvdroxy-8-methoxy-4-methyl-6H-benzorclchromen-6-one

3-Ηydroxy-8-methoxy-4-methyl- 10-vinyl-6H-benzo[c]chromen-6-one (example 36, 35 mg) was subjected hydrogenation with H₂ balloon and Pd on C (5%, 35 mg) in MeOH (20 mL) at room temperature for 4 hr. The solid was filtered off and solvent was removed to give the title compound.

1H NMR (CDC1₃+ 10% CD₃OD, 400 MHz): 1.35 (t, 3H), 2.26 (s, 3H), 3.08 (q, 2H), 3.84 (s, 3H), 6.75 (d, IH), 7.06 (s, IH), 7.65 (s, IH), 7.80 (d, IH).

EXAMPLE S

Synthesis of 3.8-Dihydroxy-4-methyl -6H-benzorc1chromen-6-one

3-Hydroxy-8-methoxy-4-methyl-6H-benzo[c]chromen-6-one , example 23 (100 mg) was treated with BBr₃ (l.OM, 1.9 mL) in CΗ₂CI2 at room temperature overnight. The mixture was quenched with water, extracted with EtOAc. The organic layer was washed with brine, dried over NaSO₄ and concentrated. The residue was purified by preparative TLC plate to give the title compound.

1H NMR (CDCI₃+ 10% CD₃OD, 300 MHz): 2.30 (s, 3H), 6.82 (d, IH), 7.30 (d, IH), 7.60 (s, IH), 7.80 (d, IH), 8.02 (d, IH). EXAMPLE 9

Synthesis of 4,7-Dimethyl-6H-benzorclchromene-3.8-diol

To a solution of 3,8-dihydroxy-4,7-dimethyl-6H-benzo[c]chromen-6-one (example 49, 49 mg) and BF₃ Et₂O (0.47 mL) in TΗF (10 mL) was added NaΗB₄ (25 mg). The mixture was refluxed for 1.5 hr. After cooled to room temperature, it was quenched with water, acidified with 2N HCl, extracted with EtOAc. The organic layer was washed with brine, dried over NaSO and concentrated. The residue was purified by Prep. TLC plate to give the title compound.

1H NMR (CDC1₃+ 10% CD₃OD, 300 MHz): 2.10 (s, 3H), 5.05 (s, 2H), 6.41 (d, IH), 6.72 (d, IH), 7.22 (m, 2H).

EXAMPLE 10

Synthesis of 4,6- Dimethyl-6H-benzorc1ehromen-3-ol

Step 1: 6-Methoxy-4-methyl-6H-benzorclchromen-3-ol

To a solution of 3-hydroxy-4-methyl-6H-benzo[c]chromen-6-one (0.3 g) in TΗF (10 mL) was added DIB AL (IM, 1.7 mL) at -78°C. The mixture was kept at -78°C for 2 hr. It was then quenched with water, acidified with 2N ΗC1, extracted with EtOAc. The organic layer was concentrated. The residue was dissolved in MeOΗ and water and 2N ΗC1 was added. The mixture was stirred for 2 hr and extracted with EtOAc. The organic layer was washed with brine, dried over NaSO₄ and concentrated. The residue was purified by prep TLC to give the product.

Step 2: 4,6- Dimethyl-6H-benzorc1chromen-3-ol 6-Methoxy-4-methyl-6H-benzo[c]chromen-3-ol (70 mg) was treated with methyl magnisium bromide (3.0M, 0.4 mL) in benzene (5 mL) at room temperature overnight. The reaction was quenched with water, acidified with 2N ΗC1 and extracted with EtOAc. The organic layer was washed with brine, dried over NaSO and concentrated. The residue was purified by prep TLC to give the title compound.

1HNMR (CDC1₃, 400 MHz): 1.62 (d, 3H), 2.20 (s, 3H), 5.28 (q, IH), 6.55 (d, IH), 7.16 (d, IH), 7.23 (t, IH), 7.35 (t, IH), 7.46 (d, IH), 7.62 (d, IH).

EXAMPLE 11

Synthesis of 4,6,6,7-tetramethyl-6H-benzorclchromene-3,8-diol

Step 1: 3-[(2,2-dimethylpropanoyl)oxy]-4,7-dimethyl-6-oxo-6H- benzorclchrornen-8-yl pivalate

To a solution of 3,8-dihydroxy-4,7-dimethyl-6H-benzo[c]chromen-6- one (40 mg) in pyridine (4 mL) was added tert-butanoyl chloride (0.4 mL). The mixture was stirred at room temperature overnight. The solvent was removed in vacuum, the residue was dissolved in CΗ₂C1₂, washed with IN HCl, water, brine, dried over NaSO and concentrated to give the product.

Step 2: 4,6,6,7-tetramethyl-6H-benzorclchromene-3.8-diol 3-[(2,2-Dimethylpropanoyl)oxy]-4,7-dimethyl-6-oxo-6H- benzo[c]chromen-8-yl pivalate (20 mg) was treated with CΗsMgBr (3.0 M, 0.15 mL) in benzene. The solution was refluxed overnight. The reaction was then quenched with water, acidified with 2N HCl and extracted with EtOAc. The organic layer was washed with brine, dried over NaSO and concentrated. The residue was treated with BF₃ Et₂O (0.070 mL) in benzene at room temperature for 2hr. The reaction was quenched with water, extracted with EtOAc The organic layer was washed with brine, dried over NaSO₄ and concentrated. The residue was purified by prep. TLC to give the title compound.

1H NMR (CDC1₃, 400 MHz): 1.75 (s, 6H), 2.20 (s, 3H), 2.35 (s, 3H), 4.70 (s, IH), 4.75 (s, IH), 6.48 (d, IH), 6.78 (d, IH), 7.30 (d, IH), 7.40 (d, IH).

EXAMPLE 12

Synthesis of 8-Hvdroxy-l,3 -trimethyl-6H-benzorclchromen-6-one

Step 1: 3,5-Dimethylphenyl 6-bromo-6-bromo-3-metl oxy-2-methylbenzoate

To a solution of 2-bromo-5-methoxy-6-methyl benzoic acid (from preparative example 24, 0.3 g) in CH₂C1₂ was added 2 drops of DMF and oxalyl chloride (2.0 M, 1.22mL) at 0°C. The mixture was stirred for 2 hr. and the solvent was removed in vacuum. The residue was redissolved in CH₂CI₂. Et₃N (0.35 mL) and 3,5- dimethylphenol (0.16 g) were added. The mixture was stirred at room temperature overnight, washed with water, 5% aq. NaHCO₃, brine dried over NaSO and evaporated to give the crude product which was chromatographed over silica gel to give the product.

Step 2: 8-Methoxy-l,3,7-trimethyl-6H-benzoMchromen-6-one

A mixture of 3,5-dimethylphenyl 6-bromo-6-bromo-3-methoxy-2- ethylbenzoate (0.2 g), Pd(PPh₃)₂Cl₂ (80 mg), NaOAc (70 mg) and DMF (~3 mL) was heated at 130°C for 2 hr. The mixture was diluted with water, extracted with Et_2- O. The organic layer was washed with water, brine, dried over Na₂SO , evaporated to give the crude product, which was chromatographed over silica gel to give the product. Step 3: 8-Hydroχy-l,3,7-trimethyl-6H-benzofclchromen-6-one

The title compound was obtained by treating 8-methoxy- 1,3,7- trimethyl-6H-benzo[c]chromen-6-one with BBr3 following the procedure of step 2, example 5

1HNMR (CDC1₃+ 10% CD₃OD, 500 MHz): 2.30 (s, 3H), 2.68 (s, 3H), 2.71 (s, 3H), 6.86 (s, IH), 6.93 (s, IH), 7.20 (d, IH), 7.96 (d, IH).

EXAMPLE 13

Synthesis of 8-Hvdroxy-3-methoxy- 1 ,4,7-trimethyl-6H-benzorc1chromen-6-one

Step 1: 3-Ηydroxy-8-(methoxymethyloxy) -l,4,7-trimethyl-6H- benzorclchromen-6-one

3-Hydroxy-8-(methoxymethyloxy) -l,4,7-trimethyl-6H- benzo[c]clιromen-6-one (45 mg) was obtained by the coupling of acid from preparative example 25 and 2,5-dimelhylresorcinal following the procedure of example 1.

Step 2: 3-Methoxy-8-(methoxymethoxy) -l,4,7-trimethyl-6H- benzorclchromen-6-one

A mixture of 3-hydroxy-8-(methoxymethyloxy) -l,4,7-trimethyl-6H- benzo[c]chromen-6-one (45 mg), iodomethane (0.012 mL), K₂CO3 (38 mg) and DMF was heated at 40°C for 4 hr. The mixture was diluted with water, extracted with EtOAc. The organic layer was washed with water, brine, dried over NaSO , evaporated to give the crude product, which was purified by prep. TLC plate to give the pure product. Step 3: 8-Hydroxy-3-methoxy-l,4,7-trimethyl-6H-benzorclchromen-6-one

3-Methoxy-8-(methoxymethyloxy) -1 ,4,7-trimethyl-6H- benzo[c]chromen-6-one (18 mg) was treated with 2N ΗC1 (2 mL) in MeOΗ (5 mL) at 70°C for 3 hr. After the solvent was evaporated, the residue was diluted with water, extracted with EtOAc, dried over silica gel and evaporated to give the title compound. 1H NMR (CDC1₃+ 10% CD3OD, 400 MHz): 2.24 (s, 3H), 2.70 (s, 3H), 2.74 (s, 3H), 3.85 (s, 3H), 6.60 (s, IH), 7.18 (d, IH), 7.88 (d, IH).

10 Table 1

The procedure described in Example 1, was followed to give the products of example 14 to 47 , by reacting the corresponding acids, shown in table 1, with 2- methylresorcinol. In some cases the reaction mixture was acidified and refluxed

15 overnight to effect lactonization. The acids were either commercially available or were prepared as indicated in the table.

EXAMPLE 45

Synthesis of 3,8-dihvdroxy-4-methyl-6H-benzorc1chromen-6-one

The product of Example 23,was dissolved in CH₂CI₂, and cooled to 0° under nitrogen. Boron tribromide (6 eq, IM in CH₂CI₂) was added and the reaction mixture stirred 15 min at 0° and then stirred at room temperature from 3 hr. The reaction mixture was treated with water, stirred for 15 min and then extracted with EtOAc. The EtOAc extract was washed with water and brine, dried and evaporated to give the product.

1H NMR (CDCI₃+ 10% CD₃OD, 300 MHz): 2.30 (s, 3H), 6.82 (d, IH), 7.30 (d, IH), 7.60 (s, IH), 7.80 (d, IH), 8.02 (d, IH). Following the procedure of Example 45, the products of Examples 46 to 53 were obtained, starting with the indicated starting materials as shown in Table 2.

Table 2

The products of Table 3, Examples 54 to 61 were prepared by reaction of the indicated acid and the corresponding phenol under the conditions of Example 1, followed by conversion of the 8-methoxy group to the hydroxy group, by treatment with BBr₃, under the conditions of Example 45. Table 3

The products of Table 4, Examples 62 to 67 were prepared by reacting the indicated boronic acid with the corresponding bromo ester, following the procedure of Example

5.

Table 4

The products of Table 5, Examples 68 to 69, were prepared from the indicated starting materials, following the procedure of Example 9.

Table 5

The products of table 6, Examples 70 to 77, were prepared from the indicated starting materials, following the procedure of Example 10, using the indicated Grignard reagent.

Table 6

The product of Table 7, Example 78 was prepared, from the indicated starting material following the procedure of Example 11.

Table 7

Estrogen Receptor Binding Assay

The estrogen receptor ligand binding assays are designed as scintillation proximity assays employing the use of tritiated estradiol and recombinant expressed estrogen receptors. The full length recombinant human ER-α and ER-β proteins are produced in a bacculoviral expression system. ER-α or ER-β extracts are diluted 1:400 in phosphate buffered saline containing 6 mM α-monothiolglycerol. 200 μL aliquots of the diluted receptor preparation are added to each well of a 96-well Flashplate. Plates are covered with Saran Wrap and incubated at 4 ° C overnight. The following morning, a 20 ul aliquot of phosphate buffered saline containing 10% bovine serum albumin is added to each well of the 96 well plate and allowed to incubate at 4° C for 2 hours. Then the plates are washed with 200 ul of buffer containing 20 mM Tris (pH 7.2), 1 mM EDTA, 10% Glycerol, 50 mM KC1, and 6 mM α-monothiolglycerol. To set up the assay in these receptor coated plates, add 178 ul of the same buffer to each well of the 96 well plate. Then add 20 ul of a 10 nM solution of ³H-estradiol to each well of the plate.

Test compounds are evaluated over a range of concentrations from 0.01 nM to 1000 nM. The test compound stock solutions should be made in 100% DMSO at 100X the final concentration desired for testing in the assay. The amount of DMSO in the test wells of the 96 well plate should not exceed 1%. The final addition to the assay plate is a 2 ul aliquot of the test compound which has been made up in 100% DMSO. Seal the plates and allow them to equilibrate at room temperature for 3 hours. Count the plates in a scintillation counter equipped for counting 96 well plates.

The compounds of the preceeding examples exhibit binding affinities to the estrogen receptor α-subtype in the range of IC₅₀ = 75 to >10000 nm, and to the estrogen receptor β-subtype in the range of IC₅₀ = 9 to 250 nm.

Pharmaceutical Composition

As a specific embodiment of this invention, 25 mg of compound of Example 5, is formulated with sufficient finely divided lactose to provide a total amount of 580 to 590 mg to fill a size 0, hard-gelatin capsule.

Claims

WHAT IS CLAIMED IS:

1. A compound of Formula I

I

wherein Rl is hydrogen, chloro, bromo, iodo, cyano, OR^a, Cχ-io alkyl, C2-10 alkenyl, C2-10 alkynyl, C3.7 cycloalkyl, C4-.7 heterocycloalkyl, cycloalkylalkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, aryl and heteroaryl groups are optionally substituted with one, two or three groups selected from fluoro, chloro, bromo, iodo, cyano, OR^a, NRaRb, O(C=O)R^a, O(C=O)NRaRb, NRa(C=O)Rb (C=O)Ra CO2R^a;

R2 is hydrogen, hydroxy, methyl, fluoro, chloro, bromo or trifluoromethyl;

R5 is hydrogen, Cχ_ιo alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-.7 cycloalkyl, wherein said alkyl, alkenyl and alkynyl groups are optionally substituted with one, two or three groups selected from fluoro, chloro, bromo, iodo, cyano, OR^a, NRaRb, O(C=O)R^a, O(C=O)NRaRb NR^a(C=O)Rb, (C=O)R^a, CO2R^a, C(O)H, or C(O)(Ci-4 alkyl);

R6 is hydrogen, Cχ.χo alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-7 cycloalkyl, wherein said alkyl, alkenyl and alkynyl groups are optionally substituted with one, two or three groups selected from fluoro, chloro, bromo, iodo, cyano, OR^a, NRaRb, O(C=O)R^a, O(C=O)NRaRb NR^a(C=O)Rb, (C=O)R^a, CO2R^a,C(O)H, or C(O)(Cι_4 alkyl); or R5 and R when taken together with the carbon atom to which they are attached, form a carbonyl group;

R7 is hydrogen, Cχ_6 alkyl, C2-6 alkenyl, C2-6 alkynyl, heteroaryl, OR^a, fluoro, chloro, bromo or iodo;

R8 is hydrogen, fluoro, chloro, bromo, iodo, cyano, NRaRb, NO2, NHSO3CH3, ORa, Ci-io alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-7 cycloalkyl, C4-7 heterocycloalkyl, cycloalkylalkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, aryl and heteroaryl groups are optionally substituted with one, two or three groups selected from fluoro, chloro, bromo, iodo, cyano, OR^a, NRaRb, O(C=O)Ra, O(C=O)NR^aRb, NR^a(C=O)Rb, (C=O)R^a, CO2R^a;

R9 is hydrogen, fluoro, chloro, bromo, iodo, cyano, OR^a, Cχ-io alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-7 cycloalkyl, C4..7 heterocycloalkyl, cycloalkylalkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl, wherem said alkyl, alkenyl, alkynyl, cycloalkyl, aryl and heteroaryl groups are optionally substituted with one, two or three groups selected from fluoro, chloro, bromo, iodo, cyano, OR^a NRaRb, O(C=O)R^a, O(C=O)NR Rb NR^a(C=O)Rb, (C=O)R^a, CO2R^a;

RlO is hydrogen, fluoro, chloro, bromo, iodo, cyano, OR^a, Cχ_io alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-7 cycloalkyl, C4-7 heterocycloalkyl, cycloalkylalkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, aryl and heteroaryl groups are optionally substituted with one, two or three groups selected from fluoro, chloro, bromo, iodo, cyano, OR^a, NRaRb, O(C=O)R^a, O(C=O)NR^aRb, NR^a(C=O)Rb, (C=O)R , CO2R^a;

Or R8 and R9 can be taken with the two intervening carbon atoms to which they are attached to form a 5-6 membered cycloalkyl or aryl ring which is optionally substituted with one, two or three substituents selected from Cl-4 alkyl, OH, O(Cl_4 alkyl), NH2, NH(Ci-4 alkyl), N(Cχ_4 alkyl)2, halo, cyano, NO2, COOH, CO2(Ci-4 alkyl), C(O)H and C(0)(Cμ alkyl); Or R9 and RlO can be taken with the two intervening carbon atoms to which they are attached to form a 5-6 membered cycloalkyl or aryl ring which is optionally substituted with one, two or three substituents selected from Cl-4 alkyl, OH, O(Ci-4 alkyl), NH2, NH(Cχ_4 alkyl), N(Cχ-4 alkyl)2, halo, cyano, NO2, COOH, Cθ2(Cχ-4 alkyl), C(O)H and C(O)(Cχ_4 alkyl);

R^a is hydrogen, Cχ_χo alkyl, benzyl or phenyl, wherein the phenyl is optionally substituted with one, two or three substituents selected from Cχ_4 alkyl, OH, O(Cχ_4 alkyl), NH2, NH(Cχ_4 alkyl), N(Cχ_4 alkyl)2, halo, cyano, NO2, COOH, Cθ2(Cχ-4 alkyl), C(O)H and C(O)(Cχ-₄ alkyl);

Rb is hydrogen, Cχ_χo alkyl, benzyl or phenyl, wherein the phenyl is optionally substituted with one, two or three substituents selected from Cl-4 alkyl, OH, O(Cχ_4 alkyl), NH2, NH(Ci_4 alkyl), N(Cχ_4 alkyl)2, halo, cyano, NO2, COOH, Cθ2(Cχ_4 alkyl), C(O)H and C(O)(Cχ- alkyl);

or the pharmaceutically acceptable salts and slereoisomers thereof.

2. The compound of Claim 1 wherein R5 is hydrogen or Cχ_io alkyl; R6 is hydrogen or Cχ_χo alkyl; or R5 and R when taken together with the carbon atom to which they are attached, form a carbonyl group; or the pharmaceutically acceptable salts and stereoisomers thereof.

3. The compound of Claim 2 wherein R is hydrogen or Cχ_3 alkyl; R2 is hydrogen or fluoro; or the pharmaceutically acceptable salts and stereoisomers thereof.

4. The compound of Claim 3 wherein R7 is hydrogen, Cχ_6 alkyl, heteroaryl, OR^a, chloro or bromo; and the pharmaceutically acceptable salts and stereoisomers thereof.

5. The compound of Claim 4 wherein R^§ is hydrogen, fluoro, bromo, iodo, NR^aRb, NO2, NHSO3CH3, OR^a, Cχ_5 alkyl, C2-5 alkenyl, aryl or arylalkyl wherein said aryl group is optionally substituted with one, two or three groups selected from fluoro, chloro, bromo, iodo, cyano, ORa, NRaRb, O(C=O)R^a, O(C=O)NRaRb NRa(C=O)Rb, (C=O)Ra CO2R^a; or the pharmaceutically acceptable salts and stereoisomers thereof.

6. The compound of Claim 5 wherein R9 is hydrogen, fluoro, chloro, bromo, OR^a, Ci-5 alkyl, C2-5 alkenyl, C2-10 alkynyl or aryl wherein said aryl group is optionally substituted with one, two or three groups selected from fluoro, chloro, bromo, iodo, cyano, OR^a, NRaRb, O(C=O)Ra, O(C=O)NR^aRb NRa(C=O)Rb (C=O)R^a, CO2R^a; or the pharmaceutically acceptable salts and stereoisomers thereof.

7. The compound of Claim 1 selected from the group consisting of:

3-hydroxy-8-bromo-4-methyl-6H-benzo[c]chromene-6-one; 3-hydroxy-8-vinyl-4-methyl-6H-benzo[c]chromene-6-one;

3-hydroxy-4,8-dimethyl-10-vinyl-6H-benzo[c]chromen-6-one;

10-allyl-3-hydroxy-4,8-dimethyl-6H-benzo[c]chromen-6-one;

3,8-dihydroxy-4,7-dichloro-6H-benzo[c]chromene-6-one;

3-Hydroxy-4-methyl-10-propyl-6H-benzo[c]chromen-6-one; 10-Ethyl-3-hydroxy-8-methoxy-4-methyl-6H-benzo[c]chromen-6-one;

3,8-Dihydroxy-4-methyl -6H-benzo[c]chromen-6-one;

4,7-Dimethyl-6H-benzo[c]chromene-3,8-diol;

4,6- Dimethyl-6H-benzo[c]chromen-3-ol;

4,6,6,7 -tetramethyl-6H-benzo[c]chromene-3,8-diol; 8-Ηydroxy-l ,3,7-trimethyl-6H-benzo[c]chromen-6-one;

8-Ηydroxy-3-methoxy-l,4,7-trimethyl-6H-benzo[c]chromen-6-one;

3 -hydroxy-4,7-dimethyl-6H-benzo [c] chromene-6-one;

3-hydroxy-4,8-dimethyl-6H-benzo[c]chromene-6-one;

3-hydroxy-4-methyl-8-methoxy-6H-benzo[c]chromene-6-one; 3-hydroxy-4-methyl-8-iodo-6H-benzo[c]chromene-6-one;

3-hydroxy-4-methyl-9-fluoro-6H-benzo[c]chromene-6-one;

3-hydroxy-4-methyl-9-bromo-6H-benzo[c]chromene-6-one;

3-hydroxy-4-methyl-10-methyl-6H-benzo[c]chromene-6-one;

3-hydroxy-4-methyl- 10-vinyl-6H-benzo [c]chromene-6-one; -hydroxy-4-methyl-10-(l-propenyl)-6H-benzo[c]chromene-6-one; -hydroxy-4,7-dimethyl-8-methoxy-6H-benzo[c]chromene-6-one; -hydroxy-4,7-dimethyl-8-amino-6H-benzo[c]chromene-6-one; -hydroxy-4-methyl-7ethyl-8-methoxy-6H-benzo[c]chromene-6-one; -hydroxy-4-methyl- 8 ,9-difluoro-6H-benzo [c] chromene-6-one; -hydroxy-4,9-dimethyl-8-bromo-6H-benzo[c]chromene-6-one; -hydroxy-4-methyl-8-methoxy-9-bromo-6H-benzo[c]chromene-6-one; -hydroxy-4-methyl-8-bromo-9-(l-propenyl)-6H-benzo[c]chromene-6-one; -hydroxy-4,7,10-trimethyl-6H-benzo[c]chromene-6-one; -hydroxy-4-methyl-7,9dibromo-6H-benzo[c]chromene-6-one; -hydroxy-4-methyl-6H-naphtho[2,l-c]chromen-6-one; -hydroxy-4-methyl-6H-naphtho[2,3-c]chromen-6-one; -hydroxy-4,8,10-trimethyl-6H-benzo[c]chromene-6-one; -hydroxy-4,8-dimethyl-10-bromo-6H-benzo[c]chromene-6-one; -hydroxy-4-methyl-8-methoxy-10-vinyl-6H-benzo[c]chromene-6-one; -hydroxy-4,8,10-trimethyl-9-bromo-6H-benzo[c]chromene-6-one; -hydroxy-4,8,10-trimethyl-9-methoxy-6H-benzo[c]chromene-6-one; -hydroxy-4,8,10-trimethyl-8-bromo-9-methoxy-6H-benzo[c]chromene-6-one; -hydroxy-4,10-dimethyl-8-methoxy-6H-benzo[c]chromene-6-one; -hydroxy-4,7-dimethyl-8-methylsulfonamido-6H-benzo[c]chromene-6-one; -hydroxy-4-methyl- 17H-6-oxa- 16,17-diaza-cyclopenta[a] -phenanthren-7-one ; -hydroxy-4,7,10-trimethyl-8-methoxy-6H-benzo[c]chromene-6-one; -hydroxy-l,3,6-trimethyl-3H- chromeno[3,4-c]pyrazol-4-one; -hydroxy-l,3-diethyl-6-methyl-3H- chromeno[3,4-c]pyrazol-4-one; -hydroxy-l-ethyl-3,6-dimethyl-3H- chromeno[3,4-c]pyrazol-4-one; -hydroxy-l,6-dimethyl-3-propyl-3H- chromeno[3,4-c]pyrazol-4-one; ,8-dihydroxy-7,8-dimethoxy-4-methyl-6H-benzo[c]chromen-6-one; ,8-dihydroxy-4-methyl-6H-benzo[c]chromen-6-one; ,8-dihydroxy-4,7-dimethyl-6H-benzo[c]chromene-6-one; ,7, 8-trihydroxy-4-methyl-6H-benzo [c]chromene-6-one ; , 8 -dihydroxy-4-methyl-6H-benzo [c] chromene-6-one; ,8-dihydroxy-7-ethyl-4-methyl-6H-benzo[c]chromene-6-one; ,9-dihydroxy-4, 8 , 10-trimethyl-6H-benzo [c]chromene-6-one ; ,8-dihydroxy-4,10-dimethyl-6H-benzo[c]chromene-6-one; , 8-dihydroxy- 10-ethyl-4-methyl-6H-benzo [c]chromene-6-one ; 3,8-dihydroxy-4,7,10-trimethyl-6H-benzo[c]chromene-6-one;

3,8-dihydroxy-l-methyl-6H-benzo[c]chromene-6-one;

3,8-dihydroxy-l,7-dimethyl-6H-benzo[c]chromene-6-one;

3 ,8-dihydroxy- 1 ,4-dimethyl-6H-benzo[c]chromene-6-one; 3,8-dihydroxy-l-ethyl-6H-benzo[c]chromene-6-one;

3,8-dihydroxy-4-fluorol-7-methyl-6H-benzo[c]chromene-6-one;

3 , 8-dihydroxy-4-fluoro 1 -7-ethyl-6H-benzo [c] chromene-6-one ;

3,8-dihydroxy-4-brom-7-methyl-6H-benzo[c]chromene-6-one;

3,8-dihydroxy-l,4,7-trimethyl-6H-benzo[c]chromene-6-one; 3,8-dihydroxy-4,7-dichloro-9-fluoro-6H-benzo[c]chromene-6-one;

3,8-dihydroxy-4,7-dimethyl-9-chloro-6H-benzo[c]chromene-6-one;

3,8-dihydroxy-4,7-dichloro-10-methyl-6H-benzo[c]chromene-6-one;

3,8-dihydroxy-4,7-dimethyl-2-fluoro-9-chloro-6H-benzo[c]chromene-6-one;

3,8-dihydroxy-4,9-dichloro-7,10-dimethyl-6H-benzo[c]chromene-6-one; 8-amino-3-hydroxy-4,7-dichloro-6H-benzo[c]chromene-6-one;

3,8-dihydroxy-4,10-dimelhyl -6H-benzo[c]chromene;

3,8-dihydroxy-4,7, 10-trimelhyl -6H-benzo[c]chromene;

3 ,8-dihydroxy-4,6 , 10-trimethyl -6H-benzo[c]chromene;

3,8-dihydroxy-4,6,7-trimethyl -6H-benzo[c]chromene; 3,8-dihydroxy-6-ethyl-4,7-dimethyl -6H-benzo[c]chromene;

3,8-dihydroxy-6-n-propyl-4, 10-dimethyl -6H-benzo[c]chromene;

3,8-dihydroxy-6-ethyl-4 , 10-dimethyl -6H-benzo[c]chromene;

3,8-dihydroxy-6-ethyl-4 ,7, 10-trimethyl -6H-benzo[c]chromene;

3,8-dihydroxy-4,6,7,10-tetramethyl -6H-benzo[c]chromene; 3, 8-dihydroxy-6-isobutyl-4, 10-dimethyl -6H-benzo[c]clιromene;

3,8-dihydroxy-4,6,6,10-teramethyl -6H-benzo[c]chromene; and the pharmaceutically acceptable salts and stereoisomers thereof.

8. A pharmaceutical composition comprising a compound according to Claim 1 and a pharmaceutically acceptable carrier.

9. A pharmaceutical composition made by combining a compound according to Claim 1 and a pharmaceutically acceptable carrier.

10. A process for making a pharmaceutical composition comprising combining a compound according to Claim 1 and a pharmaceutically acceptable carrier.

11. A method of eliciting an estrogen receptor modulating effect in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of a compound according to Claim 1.

12. A method of treating or preventing a disease in a mammal in need thereof by administering to the mammal a therapeutically effective amount of a compound according to Claim 1, wherein said disease is: bone loss, bone fractures, osteoporosis, metastaic bone disease, Paget' s disease, periodontal disease, cartilage degeneration, endometriosis, uterine fibroid disease, hot flashes, increased levels of LDL cholesterol, cardiovascular disease, impairment of cognitive functioning, cerebral degenerative disorders, restenosis, gynecomastia, vascular smooth muscle cell proliferation, obesity, incontinence, anxiety, depression, an estrogen dependent cancer.

13. The method of Claim 12 wherein the disease is hot flashes.

14. The method of Claim 12 wherein the disease is depression.

15. A method of treating or preventing an estrogen dependent cancer in a mammal in need thereof by administering to the mammal a therapeutically effective amount of a compound according to Claim 1.

16. A pharmaceutical composition comprising a compound of Claim 1 and another agent selected from: an organic bisphosphonate; a cathepsin K inhibitor; an estrogen; an estrogen receptor modulator; an androgen receptor modulator; an inhibitor of osteoclast proton ATPase; an inhibitor of HMG-CoA reductase; an integrin receptor antagonist; an osteoblast anabolic agent; calcitonin; Vitamin D; a synthetic Vitamin D analogue; a selective serotonin reuptake inhibitor; or an aromitase inhibitor; or a pharmaceutically acceptable salt or mixture thereof.