MXPA03003485A

MXPA03003485A - Estrogen receptor modulators.

Info

Publication number: MXPA03003485A
Application number: MXPA03003485A
Authority: MX
Inventors: Frank P Dininno
Original assignee: Merck & Co Inc
Priority date: 2000-10-19
Filing date: 2001-10-15
Publication date: 2003-07-14
Also published as: WO2002032377A2; PE20021083A1; ECSP034558A; HUP0303563A2; PL361053A1; NO20031737L; KR20030042020A; AU2002232381B2; NO20031737D0; JP2004511502A; EA200300474A1; BR0114689A; CN1469743A; EP1333827A2; CA2424729A1; IS6761A; SK4772003A3; IL154984A0; WO2002032377A3; BG107676A

Abstract

The present invention relates to compounds and derivatives thereof, their synthesis and their use as modulators of the estrogen receptor, the compounds of the present invention are ligands for estrogen receptors, and as such can be useful for the treatment or prevention of a diversity of conditions related to the functioning of estrogens including: bone loss, bone fractures, osteoporosis, cartilage degeneration, endometriosis, uterine fibroid disease, hot flashes, increased levels of LDL cholesterol, cardiovascular disease, cognitive impairment, degenerative disorders cerebral, restinosis, gynecomastia, vascular smooth muscle cell proliferation, obesity, incontinence and cancer, in particular breast, uterus and prostate

Description

MODULATORS OF THE ESTROGEN RECEIVER BACKGROUND OF THE INVENTION Estrogens that occur naturally and synthetic estrogens have a wide 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 prostate cancer, treatment of hot flashes and prevention of cardiovascular diseases. Because estrogens are therapeutically very valuable, there has been great interest in the discovery of compounds that mimic the behavior of the estrogen type in tissues with an estrogen response. 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 who are post-menopausal or who have had a hysterectomy, patients who were or are currently being treated with corticosteroids, and patients who have gonadal dysgenesis. The main current bone diseases of public concern are osteoporosis, hypercalcemia of malignancy, osteopenia due to bone metastasis, periodontal disease, hyperparathyroidism, periarticular erosions in rheumatoid arthritis, Paget's disease, osteopenia induced by immobilization, and osteoporosis induced by glucocorticoids. All these conditions are characterized by the loss of bone, resulting in an imbalance between bone resorption, that is, breakage, and bone formation, which continues throughout life at a rate of about 14% per year on average. However, the rate of return of the bones differs from site to site, for example, it is higher in the trabecular bone of the vertebrae and in the alveolar bone in the jaws than in the crusts of the long bones. The potential for bone loss is directly related to the return, and can mean up to more than 5% per year in the vertebrae immediately after menopause, a condition that leads to a risk of increasing fracture. In the United States, there are currently around 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 patients require nursing care at home after the fracture. Osteoporosis affects approximately 20 to 25 million post-menopausal women in the United States alone. The theory has been established that the rapid loss of bone mass in these women is due to the cessation of ovarian estrogen production. Since studies have shown that estrogen decreases the reduction of bone mass due to osteoporosis, estrogen replacement therapy is a recognized treatment for osteoporosis after menopause. In addition to bone mass, estrogen seems to have an effect on coierterol biosynthesis and cardiovascular health. Statistically, the rate of occurrence of cardiovascular disease is grossly the same in post-menopausal women and in men; however, premenopausal women have a much lower incidence of cardiovascular disease than men. Because post-menopausal 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 co-cholesterol receptors of low density lipids (LDL) in the liver to eliminate excess cholesterol. Post-menopausal women who are given estrogen replacement therapy experience a return of lipid levels to concentrations comparable to levels associated with the premenopausal state. A) Yes, estrogen replacement therapy can be an effective treatment for such a disease. However, the side effects associated with the use of long-lasting estrogens limit the use of this alternative. Other disease states that affect post-menopausal women include estrogen-dependent breast cancer and uterine cancer. Antiestrogen compounds, such as tamoxifen, have been commonly used as chemotherapy to treat patients with breast cancer. Tamoxifen, an antagonist and dual estrogen receptor agonist, is beneficial in the treatment of estrogen-dependent breast cancer. However, treatment with tamoxifen is less than ideal due to tamoxifen's agonist behavior which increases its undesirable estrogenic side effects. For example, tamoxifen and other compounds that agonize estrogen receptors tend to increase the production of cancer cells in the uterus. A better therapy for such cancers would be an anti-estrogen compound that has negligible or non-existent agonist properties. Although estrogen may be beneficial in treating conditions such as bone loss, increased lipid levels, and cancer, long-term estrogen therapy has been implicated with a variety of disorders, including an increased risk of uterine cancers and of the endometrium. These and other side effects of estrogen replacement therapy are not acceptable for many women, limiting their use. Alternative regimens, such as a combined dose of progestogen and estrogen, have been suggested in an attempt to decrease the risk of cancer. However, such regimens cause the patient to experience bleeding with withdrawal, which is unacceptable for many older women. In addition, by combining estrogen with progestogen, the beneficial effect of cholesterol lowering of estrogen therapy is reduced.

In addition, the long-term effects of treatment with progestogens are unknown. In addition to post-menopausal women, men suffering from prostate cancer can also benefit from anti-estrogen compounds. Prosthetic cancer is often sensitive to the endocrine; Androgen stimulation encourages tumor growth, while androgen suppression slows tumor growth. The administration of estrogens is useful in the treatment and control of prostate cancer because the administration of estrogen decreases the level of gonadotropin and consequently, androgen levels. The estrogen receptor has been found to have two forms: ERa and ER. The ligands bind differently to these two forms, and each form has a different tissue specificity to bind ligands. Thus, it is possible to have compounds that are selective for ERa or ERp and therefore confer a degree of tissue specificity to a particular ligand. What is needed in the art, are compounds that can produce the same positive responses as estrogen replacement therapy, without the negative side effects. Estrogen-type compounds that exert selective effects on different tissues of the body are also needed. The compounds of the present invention are ligands of the estrogen receptors and as such, may be useful for the treatment or prevention of a variety of conditions related to the functioning of estrogens including: bone loss, bone fractures, osteoporosis, degeneration of cartilage, endometriosis, uterine fibroid disease, hot flashes, increased levels of LDL cholesterol, cardiovascular disease, impaired cognitive functioning, cerebral degenerative disorders, restinosis, gynecomastia, proliferation of vascular smooth muscle cells, obesity, incontinence and cancer, in particular breast, uterus and prostate.

BRIEF DESCRIPTION OF THE INVENTION The present invention relates to compounds of the following chemical formula: wherein R1, R2, R3, and R4 are each independently selected from the group consisting of hydrogen, C-us alkyl, C3-8 cycloalkyl, C2-5 alkenyl, 2-5 alkynyl, cycloalkenyl C, e phenyl, heteroaryl , heterocyclic, CF3, -OR6, halogen, C1-5 alkylthio, thiocyanate, cyano, -CO2H, -COOalkylCi-s, -COalkylCi-5, -CONZ2, -S02NZ2, and -S02alkylCi-5, wherein the alkyl heterocyclic groups , alkenyl, alkynyl, cycloalkyl, cycloalkenyl, phenyl, heteroaryl can optionally be substituted with C1.5alkyl, C3 cycloalkyl. 8, CF3) phenyl, heteroaryl, heterocyclic, -OR6, halogen, amino, Ci-5 alkylate, thiocyanate, cyano, -CO2H, -COOalkylCi-5, -COalkylCi-5, -CONZ2, -S02NZ2l and -S02alkulloCi 5; R5 is selected from the group consisting of heterocyclic groups Ci-5 alkyl, C3-8 cycloalkyl, C2-5 alkenyl, C2-5 alkynyl, C3-8 cycloalkenyl, phenyl, heteroaryl, wherein the groups may optionally be substituted with Ci-alkyl. 5, C3-8 cycloalkyl, CF3, phenyl, heteroaryl, heterocyclic, -OR6, halogen, amino, alkylthioCi.5, thiocyanate, cyano, -CO2H, -COOalkylCi-5, -COalkylCi-5, -CONZ2, -SO2NZ2, and -SO2alkylCi-5; X and Y are each independently selected from the group consisting of oxygen, sulfur, sulfoxide and sulfone; R6 is selected from the group consisting of hydrogen, C1-5 alkyl, benzyl, methoxymethyl, triorganosilyl, C1.5 alkylcarbonyl, alkoxycarbonyl and CONZ2; each Z is independently selected from the group consisting of hydrogen, Ci-5 alkyl, trifluoromethyl, wherein the alkyl group can optionally be substituted with C-5 alkyl, CF 3, -OR 6, halogen, amino, C 1-5 alkylthio, thiocyanate, cyano , -CO2H, -COOalkylCi-5, -COalkylCi. 5, -CONV2, -SO2NV2, and -SO2alkylCi-5; or both Z and the nitrogen to which they are linked, can be taken together to form a 3-8 membered ring, the ring may optionally contain atoms selected from the group consisting of carbon, oxygen, sulfur, and nitrogen, wherein the ring may be be saturated or unsaturated, and the ring carbon atoms may be optionally substituted with one to three substituents selected from the group consisting of C1.5 alkyl, CF3, -OR6, halogen, amino, Ci-5 alkylthio, thiocyanate, cyano , -C02H, -COOalkylC1-5, -C1-5alkyl, -CONV2, -S02NV2, and -SOaalkylCi.s; each V is independently selected from the group consisting of C1-5 alkyl, CF3, -OR6, halogen, amino, alkylthio Ci-5, thiocyanate, cyano, -C02H, -COOalkylCi.s.-CoalkylCS, and -S02alkylC1- 5; each n is independently an integer from one to five; and the pharmaceutically acceptable salts thereof. The present invention relates to pharmaceutical compositions comprising the compounds of the present invention and a pharmaceutically acceptable carrier. The present invention also relates to methods for the preparation of pharmaceutical compositions of the present invention. The present invention also relates to processes and intermediates useful for the preparation of the compounds and pharmaceutical compositions of the present invention. The present invention also relates to methods for obtaining 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 obtaining an antagonist effect of the estrogen receptor in a mammal in need thereof, when administering the compounds and pharmaceutical compositions of the present invention. The antagonist effect of the estrogen receptor can be an ERa antagonist effect, and an ERp antagonist effect or a mixed antagonist effect ERa and ERp. The present invention also relates to methods for obtaining an estrogen receptor agonist effect in a mammal in need thereof, when administering the compounds and pharmaceutical compositions of the present invention. The estrogen receptor agonist effect can be an ERa agonist effect, and an ERp agonist effect, or a mixed agonist effect ERa and ERp. The present invention also relates to methods for the treatment or prevention of disorders related to the functioning of estrogens, bone loss, bone fractures, osteoporosis, cartilage degeneration, endometriosis, uterine fibroid disease, breast cancer, uterus or prostate, hot flashes, cardiovascular disease, incapacity of cognitive function, cerebral degenerative disorders, restenosis, gynecomastia, proliferation of vascular smooth muscle cells, obesity and incontinence, in a mammal in need thereof, when administering the compounds and pharmaceutical compositions of the present invention.

The present invention also relates to methods for reducing bone loss, lowering LDL cholesterol levels and obtaining a vasodilatory effect, in a mammal in need thereof, by administering the compounds and pharmaceutical compositions of the present invention.

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to compounds useful as modulators of the estrogen receptor. The compounds of the present invention are described by the following chemical formula: wherein R1, R2, R3, and R4 are each independently selected from the group consisting of hydrogen, Ci-5alkyl, cycloalkyl C2, C2-5alkenyl, C2-5alkyl, C3-acycloalkenyl, phenyl, heteroaryl , heterocyclic, CF3, -OR6, halogen, alkylthio CLS, thiocyanate, cyano, -C02H, -COOalkylC ^ s, -COalkylCi-5, -CONZ2, -S02NZ2, and -SO2alkylCi-5, wherein the heterocyclic alkyl, alkenyl groups alkynyl, cycloalkyl, cycloalkenyl can optionally be substituted with Ci-5 alkyl, C3-e cycloalkyl, CF3, phenyl, heteroaryl, heterocyclic, -OR6, halogen, amino, C1-5 alkylthio, thiocyanate, cyano, -C02H, -COOalkylCi 5, -C1-5alkyl, -CONZ2, -S02NZ2, and -S02alkylCi-5; R5 is selected from the group consisting of heterocyclic groups C1-5 alkyl, C3-8 cycloalkyl, C2.5 alkenyl, C2-5 alkynyl, C3-8 cycloalkenyl, phenyl, heteroaryl, wherein the groups may optionally be substituted with C1-6alkyl 5, C3-8 cycloalkyl, CF3, phenyl, heteroaryl, heterocyclic, -OR6, halogen, amino, C1-5 alkylthio, thiocyanate, cyano, -C02H, -COOalkylCi-5, -C1-5alkyl, -CONZ2, -S02NZ2, and -S02alkylC1.5; X and Y are each independently selected from the group consisting of oxygen, sulfur, sulfoxide and sulfone; R8 is selected from the group consisting of hydrogen, C-i-5 alkyl, benzyl, methoxymethyl, triorganosilyl, C1.5 alkylcarbonyl, alkoxycarbonyl and CONZ2; each Z is independently selected from the group consisting of hydrogen, C 1-5 alkyl, trifluoromethyl, wherein the alkyl group can optionally be substituted with Ci-5 alkyl, CF 3, -OR 6, halogen, amino, alkylthio Ci-s, thiocyanate, cyano , -C02H, -COOalkylCi.s, -COalkylC ^ s, -CONV2, -S02NV2, and -S02alkylC-5; or both Z and the nitrogen to which they are linked, can be taken together to form a 3-8 membered ring, the ring may optionally contain atoms selected from the group consisting of carbon, oxygen, sulfur, and nitrogen, wherein the ring may be be saturated or unsaturated, and the ring carbon atoms may be optionally substituted with one to three substituents selected from the group consisting of Ci, 5, CF3, -OR6, halogen, amino, C1-5 alkylate, thiocyanate, cyano , -CO2H, -COOalkylCi-5, -COalkylCi-5, -CONV2, -S02NV2, and -S02alkylCi-5; each V is independently selected from the group consisting of Ci-5 alkyl, CF3, -OR6, halogen, amino, Ci-5 alkylthio, thiocyanate, cyano, -CO2H, -COOalkylCi-5, -COalkylCi-5, and -SO2alkylCi 5; each n is independently an integer from one to five; and the pharmaceutically acceptable salts thereof. In a class of compounds of the present invention, X is oxygen, and Y is sulfur. 1 2 3 In a class of compounds of the present invention, R, R, R and R4 are selected from the group consisting of hydrogen, C1.5 alkyl, C3.8 cycloalkyl, Ci "5 alkenyl, C1-5 alkynyl, -OR6 and halogen . In a class of compounds of the present invention R5 is selected from the group consisting of cycloalkyl 03- ?, phenol, heteroaryl and heterocyclic groups wherein the groups can optionally be substituted with -OR6 and halogen. In a class of compounds of the present invention, R6 is preferably selected from the group consisting of hydrogen, C1-5 alkyl, benzyl, methoxymethyl and triisopropylsilyl. The present invention also relates to a process for preparing a compound of the formula I wherein R1 is H, F, or Cl; R2 is H or OR6; R3 is H or OR6; R4 is H or CH3; R5 is Ci-5 alkyl, C3-8 cycloalkyl, cycloalkenyl C, e, phenol, heteroaryl, or heterocyclic groups wherein the groups can optionally be substituted with C1-5 alkyl, C3-8 cycloalkyl, CF3, phenyl, heteroaryl, heterocyclic, -OR6, halogen, amino, C1-5 alkylthio, thiocyanate, cyano, carboxyl (-CO2H), carboalkoxy (-COOalkylCi-5), carbonyl (-COalkylCi-5, carboxamido (-CONZ2), sulfonamido (-SO2NZ2), and sulfonyl (-SOaalkylCi-s); R6 is H, benzyl, methyl, methoxymethyl, or triisopropylsilyl, with the proviso that when OR exists by itself, it is chemically differentiated, X and Y are each independently selected from the group consisting of oxygen, sulfur, sulfoxide and sulfone, each Z is independently selected from the group consisting of hydrogen, Ci-5 alkyl, trifluoromethyl, wherein the alkyl group can optionally be substituted with alkyl Ci-s, CF3, -OR, halogen, amino, alkylthio Ci_5, thiocyanate, cyano, -C02H, -COOalkylCi-5, -CO Ci-5 alkyl, -CONV2, -SO2NV2, and -S02alkylCi-5; or both Z and the nitrogen to which they are linked, can be taken together to form a 3-8 membered ring, the ring may optionally contain atoms selected from the group consisting of carbon, oxygen, sulfur, and nitrogen, wherein the ring may be be saturated or unsaturated, and the ring carbon atoms may optionally be substituted with Ci-5 alkyl, CF 3, -OR 6, halogen, amino, C 1. 5 alkylthio, thiocyanate, cyano, -C0 2 H, -COOalkylCi-5, -COalkylCi -5, -CONV2, -S02NV2, and -S02alkylCi-5; each V is independently selected from the group consisting of C1-5alkyl, CF3, -OR6, halogen, amino, alkylthio Ci-5l thiocyanate, cyano, -C02H, -COOalkylCi-5, -COalkylCi-s, and -S02alkylCi-5; n is an integer from one to five; and the stereoisomer is cls; or a pharmaceutically acceptable salt thereof, comprising the steps of a) reacting a compound of formula II with a compound of formula III under basic conditions, III to form a compound of formula IV b) cyclize IV, from step a, under acidic conditions in the presence of a reducing agent, to provide the compound of formula cis V c) separating the protecting group R6 to obtain the substituted phenol of formula VI d) alkylating the substituted phenol of formula VI of step c, with a reagent, HO (CH2) nN (Z) 2, to give a compound of formula I e) separating the protecting group of I, from step d, to result in a compound of formula VIII or a compound of formula IX f) separating the remaining protecting group of VIII or IX from step e, to give a compound of formula I. The present invention also relates to a process for the preparation of a compound of formula ID R3 is H; R4 is H or CH3; and the stereoisomer is cis; and the optical isomer is dextrorotatory (+) having the absolute configuration (2S, 3R); or a pharmaceutically acceptable salt thereof, comprising the steps of: a) reacting a compound of formula I ID with a compound of formula IIID under basic conditions IIID to form a compound of formula IVD b) cyclizing IVD from step a, under acidic conditions in the presence of a reducing agent to provide the racemic cis compound of formula VD c) performing a chiral chromatography with RV from step b, to resolve the enantiomeric forms to provide the dextrorotatory (+) isomer VID; d) renting the dextrorotatory isomer (+) from step c, with 1-piperidinetanol to give a compound of formula VIID VIID e) separating the VIID protecting group, from step d, to result in a compound of formula VIIID or a compound of formula IXD VIIID IXD f) separating the remaining protecting group of VIIID or IXD from step e, to give a compound of formula I. The present invention also comprises a conformance process for preparing a compound of formula IE.

(+) - IE wherein R is selected from the group consisting of H, F, or Cl; R3 and R4 are each H; R7 is selected from the group consisting of H or OH; the stereoisomer is cis and the optical isomer is dextrorotatory (+), which has the absolute configuration (2S, 3R); or a pharmaceutically acceptable salt thereof comprising the steps of: a) reacting a compound of formula ME with a compound of formula MIE under basic conditions to form a compound of formula IVE b) cyclize IVE from step a, under acidic conditions, presence of a reducing agent to provide a racic compound of formula VE c) selectively separating the VE protective group, from step b, to produce the substituted phenol of formula VIE d) alkylating the substituted phenol of formula VIE of step c, with 1-piperidinetanol to give a compound of formula VIIE VIIE e) separating the VIIE protecting group to result in a compound of formula VIME or a compound of formula IXE VIIIE IXE f) separating the remaining protecting group of VIII or IX from step e, to provide the racemic I. g) effecting a resolution of the enantomorphic forms of 1 to provide the dextrorotatory isomer (+) having the absolute configuration (2S, 3R). The present invention also relates to novel intermediates useful for the preparation of compounds and compositions described herein, ie, compounds of formula I, IA, IB, IC, ID and IE. One embodiment of the invention is an intermediary of the formula: wherein R is H, F, or Cl; R2 is H or OR6; R3 is H or OR6; R4 is H or CH3; R5 is Ci-5 alkyl, C3-8 cycloalkyl, C3-8 cycloalkenyl, phenol, heteroaryl, or heterocyclic groups wherein the groups may optionally be substituted with C1-5 alkyl, C3-8 cycloalkyl, CF3, phenol, heteroaryl, heterocyclic, -OR6, halogen, amino, Ci-5 alkylthio, thiocyanate, cyano, carboxyl (-C02H), carboalkoxy (-COOalkylCi-5), carbonyl (-COalkylCi-5, carboxamido (-CONZ2), sulfonamido (-SO2NZ2), and sulfonyl (-S02alkylCi-5): R6 is H, benzyl, methyl, methoxymethyl, or triisopropylsilyl, with the proviso that when OR6 exists by itself, it is chemically differentiable, each Z is independently selected from the group consisting of hydrogen, alkyl ds, trifluoromethyl, wherein the alkyl group may optionally be substituted with Ci-5 alkyl, CF3, -OR6, halogen, amino, alkylthio ds, thiocyanate, cyano, -C02H, -COOalkylC-is, -COalkylCi-5, -CONV2, -S02NV7, and -S02alkylCi-5, or both Z and the nitrogen to which they are bound, can be taken together In order to form a ring of 3-8 members, the ring may optionally contain atoms selected from the group consisting of carbon, oxygen, sulfur, and nitrogen, wherein the ring may be saturated or unsaturated, and ring carbon atoms they may optionally be substituted with Ci-5 alkyl, CF 3, -OR 6, halogen, amino, Ci-5 alkylthio, thiocyanate, cyano, -CO 2 H, -COOalkylCi-5, -C 1-6 -COalkyl, -CONV 2, -SO 2 NV 2, and -SO 2alkylCi. 5; each V is independently selected from the group consisting of alkyl Ci-s, CF3, -OR, halogen, amino, alkylthio Ci-5, thiocyanate, cyano, -C02H, -COOalkylC1-5i -COalkylCi-5, and -S02alkylCi.5 . Another embodiment of the invention is an intermediate of the formula: wherein R1 is H, F, or Cl; R2 is H or OR6; R3 is H or OR6; R4 as H or CH3; R5 is Ci_5 alkyl, C3-6 cycloalkyl, C3-8 cycloalkenyl, phenyl, heteroaryl, or heterocyclic groups wherein the groups can optionally be substituted with Ci-5 alkyl, C3-8 cycloalkyl, CF3, phenyl, heteroaryl, heterocyclic, -OR6 , halogen, amino, Ci-5 alkylthio, thiocyanate, cyano, carboxyl (-CO2H), carboalkoxy (-COOalkylC-5), carbonyl (-COalkylCi-5, carboxamide (-CONZ2), sulfonamido (-S02NZ2), and sulfonyl ( -S02alkylC1-5), R6 is H, benzyl, methyl, methoxymethyl, or triisopropylsilyl, with the proviso that when OR6 exists by itself, it is chemically differentiable, each Z is independently selected from the group consisting of hydrogen, C-alkyl US, trifluoromethyl, wherein the alkyl group may optionally be substituted with Ci-5 alkyl, CF3, -OR6, halogen, amino, Ci-5 alkylthio, thiocyanate, cyano, -C02H, -COOalkylC-5, -COalkylCi-5, - CONV2, -SO2NV2, and -S02alkylCi.5; or the Z can be taken together form a ring of 3-8 members, the The ring may optionally contain atoms selected from the group consisting of carbon, oxygen, sulfur, and nitrogen, wherein the ring may be saturated or unsaturated, and the ring carbon atoms may optionally be substituted with Ci-5 alkyl) CF3, - OR8, halogen, amino, alkylthio Ci-5, thiocyanate, cyano, -C02H, -COOalkylCi-5, -COalkylC1-5, -CONV2, -S02NV2, and -S02alkylC1-5, each V is independently selected from the group consisting of alkyl d-5, CF3, -OR6, halogen, amino, alkylthio Ci-5, thiocyanate, cyano, -C02H, -COOalkylC-5, -COalkylC1-5, and -S02alkylC1.5. Another embodiment of the invention is an intermediate of the formula: wherein R1 is H, F, or Cl; R6 is H, benzyl, methyl, methoxymethyl, or triisopropylsilyl, with the proviso that all existing R6 groups are chemically differentiable. Another embodiment of the invention is an intermediate of the formula: wherein R1 is H, F, or Cl; R6 is H, benzyl, methyl, methoxymethyl, or triisopropylsilyl, with the proviso that all existing R6 groups are chemically different. Another embodiment of the invention is an intermediate of the formula: wherein R1 is H, F, or Cl; R2 is H or OR6; R3 is H or OR6; R4 is H or CH3; R5 is Ci-5 alkyl, C3-cycloalkyl, C3.8 cycloalkenyl, phenyl, heteroaryl, or heterocyclic groups wherein the groups can optionally be substituted with Ci-5 alkyl, C3-8 cycloalkyl, CF3, phenyl, heteroaryl, heterocyclic, -OR6, halogen, amino, Ci-5 alkylthio, thioclanate, clade, carboxyl (-CO2H), carboalkoxy (-COOalkylCi-s), carbonyl (-COalkylCi-5, carboxamido (-ConZ2), sulfonamido (-S02NZ2), and sulfonyl (-SO2alkylC1-5); R is H, benzyl, methyl, methoxymethyl, or trilsopropyl silyl, with the proviso that when OR6 exists by itself, it is chemically differentiable; each Z is independently selected from the group consisting of hydrogen, alkyl d-5, trifluoromethyl, wherein the alkyl group can optionally be substituted with C- | 5 alkyl, CF 3, -OR 6, halogen, amino, C 1. 5 alkylthio, thiocyanate , cyano, -CC ^ H, -COOalkylCi-5, -COalkylCi-5, -CONV2, -S02NV2, and -S02alkylC-5; or both Z and the nitrogen to which they are linked can be taken together to form a 3-8 membered ring, the ring may optionally contain atoms selected from the group consisting of carbon, oxygen, sulfur, and nitrogen, wherein the ring may be saturated or unsaturated, and the ring carbon atoms can be optionally substituted with C-us alkyl, CF3, -OR6, halogen, amino, C-us alkylthio, thiocyanate, cyano, -C02H, -COOalkylloC1-5, -COalkylCi 5, -CONV2, -S02NV2, and -S02alkylCi-5; each V is independently selected from the group consisting of Ci-5 alkyl, CF3, -OR6, halogen, amino, Ci-5 alkylthio, thiocyanate, cyano, -C02H, -COOalkylCi-5, -COalkylCi-5, and -S02alkylC- i.5. Another embodiment of the invention is an intermediate of the formula: wherein R1 is H, F, or Cl; R6 is H, benzyl, methyl, methoxymethyl, or triisopropylsyl, with the proviso that all existing R6 groups are chemically differentiable. Another embodiment of the present invention is an intermediate of the formula: wherein R1 is H, F, or Cl; R6 is H, benzyl, methyl, methoxymethyl, or triisopropylsyl, with the proviso that all existing R6 groups are chemically differentiable. Non-limiting examples of the present invention include: twenty One embodiment of the invention is a method for obtaining an estrogen receptor modulating effect in a mammal in need thereof, which comprises administering to the mammal a therapeutically amount of any of the compounds or any of the above described pharmaceutical compositions. One type of modality is the method in which the modulating effect of the estrogen receptor is an antagonistic effect. A subclass of the modality is the method where the estrogen receptor is an ER receptor. A second subclass of the modality is the method in which the estrogen receptor is an ERp receptor. A third subclass of the modality is the method in which the modulating effect of the estrogen receptor is an antagonistic effect of the mixed receptor ERa and ERp. A second class of the modality is the method in which the modulating effect of the estrogen receptor is an agonist effect. A subclass of the modality is the method where the estrogen receptor is an ERa receptor. A second subclass of the modality is the method in which the estrogen receptor is an ERp receptor. A third subclass of the modality is the method in which the modulating effect of the estrogen receptor is an agonist effect of the mixed receptor ERa and ERp.

Another embodiment of the invention is a method of treating or preventing post-menopausal osteoporosis 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. Another embodiment of the invention is a method of treating or preventing uterine fibroids 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. Another embodiment of the invention is a method of treating or preventing restenosis 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. 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. Another embodiment of the invention is a method of treating or preventing hyperlipidemia 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. To exemplify the invention, there is a pharmaceutical composition comprising any of the compounds described above and a pharmaceutically acceptable carrier. Also to exemplify the invention is a pharmaceutical composition made by the combination of any of the compounds described above and a pharmaceutically acceptable carrier. An illustration of the invention is a process for the manufacture of a pharmaceutical composition comprising combining any of the compounds described above and a pharmaceutically acceptable carrier. It also exemplifies the invention, 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 exemplifies the Invention, 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, cartilage degeneration, endometriosis, uterine fibroid disease, breast cancer, cancer uterine, prostate cancer, hot flashes, cardiovascular disease, impaired cognitive functioning, cerebral degenerative disorder, restenosis, proliferation of vascular smooth muscle cells, incontinence and / or disorders related to the functioning of estrogen. The present invention is also directed to combinations of any of the compounds or any of the pharmaceutical compositions described above with one or more agents useful in the prevention or treatment of osteoporosis. For example, the compounds of the present invention can be effectively administered in combination with effective amounts of other agents such as the organic bisphosphonate or a cathepsin K inhibitor. Non-limiting examples of organic bisphosphonates include alendronate, clodronate, etidronate, ibandronate incadronate, minodronate, neridronate, risedronate, pyridronate, pamidronate, tiludronate, soledronate, pharmaceutically acceptable salts or esters thereof and mixtures thereof. Preferred organic bisphosphonates include alendronate and pharmaceutically acceptable salts and mixtures thereof. More preferred is the monosodium trihydrate of alendronate. The precise dose of the bisphosphonate will vary with the dosing schedule, the oral potency of the particular bisphosphonate chosen, the age, size, sex and condition of the mammal or human, the nature and severity of the disorder to be treated, and other relevant medical and physical factors. Thus, a precise pharmaceutically effective amount can not be specified in advance and can be easily determined by the trader or pharmacists. Adequate amounts can be determined by routine experimentation from animal models and clinical studies in humans. Generally, an appropriate amount of bisphosphonate is chosen to obtain an inhibitory effect of bone resorption, that is, an inhibitory amount of the bone resorption of the bisphosphonate is administered. For humans, an effective oral dose of bisphosphonate is typically from about 1.5 to about 6000 μ of body weight and preferably about 10 to about 2000 μg kg of body weight.

For human oral compositions comprising alendronate, pharmaceutically acceptable salts thereof or pharmaceutically acceptable derivatives thereof, a unit dose typically comprises from about 8.75 mg to about 140 mg of alendronate compound, on an active weight basis of alendronic acid, that is, on the basis of the corresponding acid. For use in medicine the salts of the compounds of this invention are referred to as "non-toxic pharmaceutically acceptable salts". Other salts may, however, be useful in the preparation of the compounds according to the invention or their pharmaceutically acceptable salts. When the compounds of the present invention contain a basic group the salts encompassed within the term "pharmaceutically acceptable salts" refer to non-toxic salts which are generally prepared by reacting the free base with a suitable organic or inorganic acid. Representative salts include but are not limited to the following: acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromine, calcium, camsylate, carbonate, chlorine, clavulanate, citrate, dichlorohydrate, edetate, edisilate, estolate, fumarate, gluceptate, gluconate, glutamate, glycolylaminosanilate, hexylresorcinate, hydrabamine, bromohydrate, hydrochloride, hydroxynaphthoate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methyl bromide, methylnitrate, methyl sulfate, mucate, napsilate, nitrate, N- ammonium salt methylglucamine, oleate, oxalate, pamoate (embonate), palmitate, pantothenate, phosphate / disphosphate, polygalacturonate, salicylate, stearate, sulfate, subacetate, succinate, tannate, tartrate, teoclate, triethyliodide and valerate. In addition, wherein the compounds of the invention carry an acidic portion, suitable pharmaceutically acceptable salts thereof may include alkali metal salts, eg, sodium or potassium salts, alkaline earth metal salts, eg, calcium or magnesium salts.; and salts formed with suitable organic ligands, for example quaternary ammonium salts. The compounds of the present invention can have chiral centers and be presented as racemates, racemic mixtures, diastereomeric mixtures and as individual diastereomers or enantiomers with all isomeric forms included in the present invention. Therefore, where one compound is chiral, the separated enantiomers substantially free of the other, are included within the scope of the invention; all mixtures of the two enantiomers are also included. Polymorphs, hydrates and solvates of the compounds of the present invention are also included within the scope of the invention. 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 converted in vivo to the required compound. Thus, in the methods of treatment of the present invention, the term "administer" will encompass the treatment of the various conditions described with the specifically described compound, or with a compound that may not be specifically described, but which converts the specified amount in vivo afterwards. from administration to the patient. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs," de. H. Bundgaard, Elsevier, 1985, which is incorporated herein by reference in its entirety. The metabolites of these compounds include active species produced with the introduction of compounds of this invention into the biological sites. The term "therapeutically effective amount" will mean the amount of a drug or a pharmaceutical agent that will obtain the modest or biological response of a tissue, animal or human system that is sought by a researcher or physician. The term "bone resorption" as used herein, refers to the process by which osteoclasts degrade bone. The term "basic conditions" as used herein, refers to the incorporation or use of a base in the reaction medium. According to the Lowry-Bronsted definition, a base is a substance that accepts a proton; or according to Lewis's definition, a base is a substance that can prepare a pair of electrons to form a covalent bond. Examples of the bases used herein are not limited to tertiary amine base such as triethylamine, diisopropylethylamine or the like. The term "acidic conditions" as used herein, refers to the incorporation or use of an acid in the reaction medium. According to the definition of Lowry.Bronsted, an acid is a substance that yields a proton, or according to the definition of Lewis, an acid is a substance that can take a pair of electrons to form a covalent bond. Examples of acids used herein are, but are not limited to, strong carboxylic acids such as trifluoroacid acid or the like, strong sulfonic acids such as trifluoromethanesulfonic acid or the like, and Lewis acids such as boron trifluoride etherate. or the stannous chloride or the like. The term "reducing agent" as used herein, refers to a reagent capable of effecting a reduction. A reduction is the conversion of a functional group or an intermediary of a category a or a lower one. Examples of the reducing agents used herein are, but are not limited to, triorganosilanes or stannanes such as triethylsilane, triphenylsilane or tri-n-butyl tin hydride or the like. The term "chemically differential" refers to two or more non-identical substitutes R6, whose particular structures are such that one of ordinary skill in the art may choose reaction conditions, which would convert one of the substituents R5 not identical to H, without affecting the another substituent R. The term "alkyl" shall mean a substituent substituent group derived by the conceptual removal of a hydrogen atom from a straight or branched chain acyclic saturated hydrocarbon (i.e., -CH3, -CH2CH3, -CH2CH2CH3, -CH (CH3) 2, -CH2CH2CH2CH3, -CH2CH (CH3) 3, etc.).

The term "alkenyl" shall mean a substituent substituent group derived by the conceptual separation of a hydrogen atom from a straight or branched chain acyclic unsaturated hydrocarbon containing at least one double bond (ie, CH = CH2, -CH2CH = CH2, -CH = CHCH3, -CH2CH = (CH3) 2, etc.). The term "alkynyl" shall mean a univalent substituent group derived by the conceptual separation of a hydrogen atom from a straight or branched chain acyclic unsaturated hydrocarbon containing at least one triple bond (i.e., -CH = CH, -CH2C = CH , -C = CCH3, -CH2CH2C = CCH3, etc.). The term "cycloalkyl" will mean a univalent substituent group derived by the conceptual separation of a hydrogen atom from a saturated monocyclic hydrocarbon (ie, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl). The term "cycloalkenyl" will mean a univalent substituent group derived by the conceptual separation of a hydrogen atom from an unsaturated monocyclic hydrocarbon containing a double bond (ie, cyclopentenyl or cyclohexenyl). The term "heterocyclic" will mean a substituted univalent group derived by the conceptual separation of a hydrogen atom from a heterocycloalkane wherein the heterocycloalkane is derived from the corresponding saturated monocyclic hydrocarbon, by replacing one or two carbon atoms with the selected atoms of N, O, or S. Examples of the heterocyclic groups include, but are not limited to, oxiranyl, azetidyl, pyrrolidinyl, piperidinyl, piperazinyl, and morpholinyl. The heterocyclic substituents can be placed at a carbon atom. If the substituent is a nitrogen-containing heterocyclic substituent, it can be placed on the nitrogen atom. The term "heteroaryl" as used herein, refers to a substituent substituent group derived by the conceptual separation of a hydrogen atom from a monocyclic or bicyclic aromatic ring system containing 1, 2, 3, or 4 selected heteroatoms of N, O, or S. Examples of the heteroaryl groups include, but are not limited to, plrrolll, furyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridyl, pyrimidinyl, pyrazinyl, benzimidazolyl, indolll, and purinyl . The heteroaryl substituents can be placed on a carbon atom or through the heteroatom. The term "triorganosilyl" means those sulphonyl groups trisubstltuido by lower alkyl groups or aryl groups or combinations thereof, and wherein a substituent may be a lower alkoxy group. Examples of the triorganosilyl groups include trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, triisopropylsilyl, triphenylsilyl, dimethylphenylsilyl, t-butyldiphenylsilyl, phenyl-t-butylmethoxysilyl, and the like. In the compounds of the present invention, the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclic and heteroaryl groups can be further substituted by replacing one or more hydrogen atoms which are alternative non-hydrogen groups. These include, but are not limited to, halo, hydroxy, mercapto, amino, carboxyl, cyano and carbamoyl. Where the term "alkyl" or "aryl" or any of its prefix roots appear in the name of a substituent (eg, aryl Co-e alkyl) shall be construed as including those limitations given above for "alkyl" and " aril. " The designated numbers of carbon atoms (for example C-MO) will independently refer to the number of carbon atoms in the alkyl or cyclic alkyl portion or the alkyl portion of a larger substituent in which the alkyl appears as its prefix root . The terms "arylalkyl" and "alkylaryl" include an alkyl portion wherein the alkyl is as defined above and to include an aryl portion wherein the aryl is as defined above. Examples of arylalkyl include but are not limited to benzyl, fluorobenzyl, chlorobenzyl, phenylethyl, fluorophenylethyl, chlorophenylethyl, thienylmethyl, thienylethyl, and thienylpropyl. Examples of the alkylaryl include, but are not limited to, tolutyl, ethylphenyl, and propylphenyl. The term "heteroarylalkyl" as used herein, will refer to a system that includes a heteroaryl portion, wherein the heteroaryl is as defined above, and contains an alkyl portion. Examples of the heteroarylalkyl include but are not limited to priridylmethyl, pyridylethyl and imidazolylmethyl. The term "halo" will include iodine, bromine, chlorine, and fluoro.

The term "oxy" will mean an oxygen atom (O). The term "uncle" means a sulfur atom (S). The term "oxo" means = 0. The term "oximino" means the group = N-0. The term "substituted" shall refer to include multiple degrees of substitution by a named substituent. Where multiple portions of substituents are described or claimed, the substituted compound can be independently substituted by one or more of the described or claimed substituent moieties, simply or plurally. By independently substituted, it means that the two or more substituents may be the same or different. Under the standard nomenclature used throughout this description, the terminal portion of the designated side chain is described first, followed by the functionality adjt to the point of plent. For example, an alkylcarbonylamino substituent Ci-5 alkyl Ci-6 is equivalent to O II -alkyl Cie-NH-C-C-5 alkyl by choosing the compounds of the present invention, one of ordinary skill in the art will recognize that the various substituents, that is, R1, R2, R3, R4, R5, R6, R7, R8, V, X, Y, Z, n, and p, will be chosen in accordance with well-known collective principles of the chemical structure.

Representative compounds of the present invention typically display a submicromolar affinity for estrogen receptors alpha and beta. The compounds of this invention are therefore useful in the treatment of mammals, which suffer from disorders related to the functioning of estrogens. The pharmacologically effective amounts of the compound, including the pharmtically effective salts thereof, are administered to the mammal to treat disorders related to the functioning of estrogens, such as bone loss, hot flashes and cardiovascular diseases. The compounds of the present invention are available in racotic form or as individual enantiomers. For convenience, some structures are graphically represented as a single enantiomer but, unless otherwise indicated, it means that it includes both the racometal and enantiomeric forms. Where the cis and trans stereochemistry is indicated for a compound of the present invention, it should be noted that the stereochemistry can be constituted as relative, unless indicated otherwise.

It is generally preferred to administer compounds of structure (I) as enantiomerically pure formulations since most or all of the desired bioactivity resides with a single enantiomer. The ric mixtures can be separated into their individual enantiomers by any of several conventional methods. These include chiral chromatography, derivatization with a chiral auxiliary followed by separation by chromatography or crystallization, and fractional crystallization of the diastereomeric salts. The compounds of the present invention can be used in combination with other agents useful for the treatment of estrogen-mediated conditions. The individual components of such combinations can be administered separately at different times during the course of therapy, or in parallel in simple or divided combination forms. The present invention will therefore be understood to encompass all such simultaneous or alternate treatment regimens, and the term "administration" will be construed in this manner. It will be understood that the scope of the combinations of the compounds of this invention with other agents useful for the treatment of estrogen-mediated conditions, include in principle any combination with some pharmtical composition useful for the treatment of disorders related to the functioning of estrogens. As used herein, the term "composition" is intended to encompass a product that comprises the specific ingredients in the specific amounts, as well as any product that results directly or indirectly., of the combination of specified ingredients in specified amounts. The compounds of the present invention can be administered in such oral dosage forms as tablets, capsules (each of which includes sustained release or scheduled release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups and emulsions. Simultaneously, they can also be administered in intravenous (bolus or infusion), intraperitoneal, topical (e.g. eye drops), subcutaneous, intramuscular or transdermal form (e.g., in patches), using all forms well known to those ordinary experts in the art. pharmaceutical arts. The dose regimen using the compounds of the present invention is selected according to 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 of the same employee. An ordinarily experienced physician, veterinarian, or clinical technician can easily determine and prescribe the effective amount of the drug required to prevent counterattack or suspend the advancement of the condition. The oral doses of the present invention when used for the indicated effects will be in the 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 at 10 mg / kg / day, and more 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 active ingredient for adjustment symptomatic of the dose to the patient to be treated. A medicament typically contains from about 0.01 mg to about 500 mg of active ingredient, preferably from about 1 mg to about 100 mg of active ingredient. Intravenously, the most preferred doses will be in the range of from about 0.1 to about 10 mg / kg / minute during an infusion at a constant rate. Advantageously, the compounds of the present invention can be administered in a single daily dose, or the total daily dose can be administered in divided doses of two, three, or four times a day. In addition, the preferred compounds of the present invention may be administered in an intranasal form through the local use of suitable intranasal vehicles, or via transdromic routes using those forms of transdermal skin patches well known to those of ordinary experience in the art. technique. To be administered in the form of a transdermal delivery system, the administration of the dose will of course be continuous rather than intermittent through the dose regimen. In the methods of the present invention, the compounds described herein in detail may form the active ingredient, and are typically administered in admixture with suitable diluents, excipients or pharmaceutical carriers (collectively referred to herein as carrier materials), suitably selected with respect to the intended route of administration, ie, oral tablets, capsules, elixirs, syrups, and the like, and consistent with conventional pharmaceutical practices. For example, for oral administration in the form of a tablet or capsule, the active component of the drug can be combined with an inert pharmaceutically acceptable, non-toxic oral carrier, such as lactose, starch, sucrose, glucose, methyl cellulose, magnesium stearate, phosphate. dicalcium, calcium sulfate, mannitol, sorbitol, and the like; for oral administration in liquid form, the oral components of the drug can be combined with any non-toxic, oral pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like. In addition, 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 betalactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxylmethylcellulose polyethylene glycol, waxes and the like. The lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. Disintegrants include, without limitation, starch, methylcellulose, agar, bentonite, xanthan gum, and the like.

The compounds of the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids such as cholesterol, stearylamine or phosphatidylcholines. The compounds of the present invention can also be delivered by the use of monoclonal antibodies as individual carriers to which the molecules of the compound are coupled. The compounds of the present invention can also be coupled with soluble polymers as carriers of objective drugs. Such polymers may include polyvinylpyrrolldone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxy-ethylaspartamide-phenol, or polyethylene-polysine oxide substituted with palmitoyl residues. Additionally, the compounds of the present invention can be coupled to a type of biodegradable polymers useful in achieving the controlled release of a drug, for example, polylactic acid, polyglycolic acid, polylactic and polyglycolic acid copolymers, polyepsilon caprolactone, polyhydroxybutyric acid, polyorthoesters , polyacetals, polydihydropyrans, polycyanoacrylates and retiled or amphipathic block copolymers of hydrogels. The novel compounds of the present invention can be prepared according to the procedure of the following schemes and examples, using suitable materials and which are further exemplified by the following specific examples. The compounds illustrated in the examples, however, are not constituted as forming the only genus that is considered as the invention. The following examples further illustrate details for the preparation of the compounds of the present invention. Those skilled in the art will readily understand that known variations of the conditions and methods of the following preparative procedures can be used to prepare these compounds. All temperatures are in degrees Celsius unless otherwise indicated. The compounds of the present invention are prepared according to the following generic reaction scheme I.

In words relating to the scheme, a bisphenol II (X = 0, Y = 0), suitably functionalized, which is readily available, or a mercaptophenol II (X = 0, Y = S), which is prepared in accordance with the procedures of the literature was reacted with a bromoketone derivative III, which was easily prepared from the corresponding acetone by bromination with phenyltrimethylammonium tribromide (P ), in the presence of a tertiary amine base, such as trlethylamine, diisopropylethylamine, or similar, in a solvent such as dimethylformamide (DMF), formamide, acetonitrile, dimethylsulfoxide (DMSO), tetrahydrofuran (THF), dichloromethane, or the like, at a temperature from 20 ° C to 80 ° C therefore take the reaction to complete to provide the displacement product IV. When X = Y = 0, only R3 can be -OR6. Alternatively, when X = Y = 0 and R2 is OR6, the required cyclization intermediate is obtained by exchanging the ketone and bromide functionalities. These stipulations are required to allow the preparation of these compounds of the invention, wherein the presence of certain substituents will alter the reactivity of the phenolic oxygen atoms. Intermediate IV cycles reductively in the presence of an organic acid such as trifluoroacid acid, triflic acid or the like, or a Lewis acid such as boron trifluoride etherate, stannous chloride or the like, and a reducing agent such as a silane. trisubstituted such as triethylisilane, or the like, in a solvent such as dichloromethane, chloroform, THF, toluene, or the like at a temperature from 40 ° C to 100 ° C so that the reaction is completed to provide the cyclized product V, in which the stereochemistry of the aryl substituent and R5 in the newly created ring is exclusively cis. The formation of the intermediates with the analogous trans stereochemistry is detailed in the general scheme of reaction II below. In the product V when R6 is a protecting group, it is then separated in a manner consistent with its nature. Such methods are well documented in the literature that is incorporated into standard texts such as Greene, T.W. and Wuts, P.G.M., Protective Groups in Orqanlc Synthesls, Third DE., Wiley, New York (1999). Furthermore, it is understood that it is possible to have any number of substituents R1-R4 or that they are contained -OR6, or R5 may contain -OR6, wherein R6 is a protecting group, and it is further understood that in these cases the protecting groups are chemically differentiable, that is, they can be selectively separated when necessary. For example in the product V, R6 is a methoxymethyl group (MOM), R2 is -OR6, where R6 is the benzyl group (Bn), R5 is a phenyl ring substituted by R7 where R7 is OR6, wherein R6 is a triisopropylsilyl group (TIPS), and all unspecified substituents are hydrogen. As indicated, as part of the synthetic sequence, it is necessary to selectively separate the MOM group in preference to the TIPS or Bz groups. By using the methods found in Green and Wuts, it is possible to generate the preferred intermediate V, wherein R6 is H, R2 is -OBn, R5 is para-OTIPS-phenyl, and all substituents not specified with hydrogen. It is also observed that in product V, that when either R2 or R3 is OR6, R6 must be a protecting group, and that prior to their separation, the existing group -OR6 must be covered by a differentiable protective group. The alcohol intermediate VI, then reacts with a reagent HO (CH2) nNZ2 in a Mitsunobu reaction protocol, in which it is combined with a trisubstituted phosphine such as triphenylphosphine and diazodicarboxylate, such as diisopropylazole carboxylate in an appropriate solvent such as THF from 0 ° C or 80 ° C, the time the reaction takes to complete to provide the coupled product 1. The variables for the Mitsunobu reaction have been well documented and are incorporated herein by reference: Mitsunobu, O. Synthesis, 1981; Castro, B.R. Org. React. 1983, 29, 1; Hughes, D.L. Org. React 1992, 42, 335. Finally, after the reaction of Mitsunobu, it will be understood that in I if any group R is or contains -OR6, where R6 is a protective group, it is separated using the appropriate method found in Green and Wuts to give the final product where Re is H.

SCHEME II General synthesis for trans-dlhldrobenzoxatllnas and benzodloxanes In words relative to the above scheme for the general preparation of the trans isomer of I, the ketone intermediate IV of scheme I is reduced with sodium borohydride, super hydride or the like, in a mixture of methanol and dichloromethane, or THF or the like of 0 ° C to room temperature for from a few minutes to a few hours to provide an analogous intermediate of hydroxyl VII. The cyclization of intermediate VII is achieved in the presence of an acid catalyst such as amberlist 15, or a triflic acid or the like, in a solvent such as toluene or dichloromethane or the like, at a temperature from ambient to reflux to allow the trans VIII compound as the main isomer. The rest of the synthetic sequence to produce trans I is identical to that indicated in reaction scheme I and detailed above. The compounds of the invention, wherein X = and Y = SO or SO2 are prepared as detailed in the specific schemes that follow.

MY REACTION SCHEME General synthesis for dioxides of dlhldrobanzoxanthine.

In words relating to Scheme III, the compounds I of the invention are peroxidated with an oxidant such as m-chloroperbenzoic acid or pertrifluoroacetic acid or the like, in a solvent such as dichloromethane or the like, at a temperature of 0 ° C to reflux for In turn, X is selectively deoxygenated at the nitrogen atom by treatment with a reducing people such as sodium bisulfite or the like in a two-phase medium such as ethyl acetate and water or the like to provide I.

In the compounds of the present invention, X is preferably O, and Y preferably is S. In the compounds of the present invention, R, R2, R3 and R4 is preferably selected from the group consisting of hydrogen, C-us alkyl, cycloalkyl alkenyl Ci-5, -OR6 and halogen. In the compounds of the present invention, R5 is preferably selected from the group consisting of C3-8 cycloalkyl, phenyl, and substituted phenyl. In the compounds of the present invention, R6 is preferably selected from the group consisting of hydrogen, Ci-5 alkyl, benzyl, methoxymethyl and triisopropylsilyl. In the compounds of the present invention, a preferred subset is found wherein R1 and R4 are hydrogen, R2 and R3 are independently -OH, and R5 is independently selected from the group consisting of phenyl and substituted phenyl. In the compounds of the present invention, another preferred subset is found wherein R1 is independently selected from fluoro and chloro, R4 is hydrogen, R2 and R3 are independently -OH, and R5 is independently selected from the group consisting of phenyl and substituted phenol. In the compounds of the present invention, the most preferred subset is where R1 and R4 are hydrogen and, R2 is -OH, and R5 is independently selected from the group consisting of phenyl and para-hydroxy-phenyl.

SCHEME IV General synthesis for oxides of dlhldrobanzoxatllna In words relevant to scheme IV, intermediate V of scheme I is mono-oxidized by a careful treatment with an equivalent or slight excess of an oxidant such as m-chloroperbenzoic acid or dimethyldioxirane or the like, in a solvent such as dichloromethane, ether, acetone or the like at a temperature of from 78 ° C to room temperature for from a few minutes to a few hours give the corresponding intermediate of sulfoxide XI. The remainder of the synthetic sequence for producing I is identical to that indicated in reaction scheme I and detailed above. In the compounds of the present invention, X is preferably O, and Y is preferably S. In the compounds of the present invention, R1, R2, R3 and R4 is preferably selected from the group consisting of hydrogen, Ci-5 alkyl, cycloalkyl C ", alkenyl Ci-5, -OR6 and halogen. In the compounds of the present invention, R5 is preferably selected from the group consisting of C3-8 cycloalkyl, phenyl, and substituted phenyl. In the compounds of the present invention R6 is selected from the group consisting of hydrogen, C- | 5 alkyl, benzyl, methoxymethyl and trisopropylsilyl. In the compounds of the present invention, a preferred subset is where R1 and R4 are hydrogen, R2 and R3 are independently -OH, and R5 is independently selected from the group consisting of phenyl and substituted phenyl. In the compounds of the present invention, another preferred subset is wherein R1 is independently selected from fluorine and chlorine, R4 is hydrogen, R2 and R3 are independently -OH, and R5 is independently selected from the group consisting of phenyl and substituted phenyl .

In the compounds of the present invention the most preferred subset is where R and R 4 is hydrogen and R 2 is -OH and R 5 is independently selected from the group consisting of phenyl, methahydroxy phenyl, and para-hydroxy phenyl.

EXAMPLE 1 General preparation of tofenols The functionalized thiophenols were prepared by the known method, with minor modification, which is described in the previous scheme: Wermer, G .; Biebrich, W. Patents of E.U.A. 2,276,553 and 2,332,418.

The thiophenol described above was prepared according to the following references: Maxwell, S.J. Am. Chem. Soc. 1947, 69, 712; Hanzlik, R. P. et. to the. J. Org. Chem. 1990, 55, 2736.

EXAMPLE 2 Preparation of 2-thiophene-4-methoxy-benzophenone To a stirred solution of anisole (1.49 g, 13.8 mmol) in anhydrous dichloromethane (5 mL) was added AICI3 (1.2320 g, 9.2 mmol) followed by the dropwise addition of 2-thiophene acetyl chloride (0.57 mL). , 4.6 mmol) at 0 ° C under N2. The reaction was stirred for 1.5 h, then was poured over a separatory funnel containing ice / brine / EtOAc. The organic layer was further washed with brine, dried over Na 2 SO 4, and concentrated in vacuo. The resulting residue was purified by chromatography on silica gel with 30% EtOAc / hexane as the eluent to provide the desired product as a yellow oil. 1 H 500 MHz NMR (CDCl 3) ppm (5): 3.89 (s, 3 H), 4.46 (s, 2 H), 6.98 (m, 4 H), 7.24 (d, 1 H), and 8.05 (d, 2 H).

EXAMPLE 3 Preparation of 2-thiophene-4-hydroxybenzophenone A mixture of 2-thiophene-4-methoxy-benzophenone (0.8294 g, 3.5 mmol), generated in Example 2, and pyridine-HCl (4.0627 g, 35.2 mmol) was heated at 190 ° C under N2 for 6 h. The reaction was monitored by gradually examining aliquots of the reaction by CCD (30% EtOAc / hexane). The reaction was cooled in an ice bath and ice / H20 was added. The resulting mixture was extracted with EtOAc. The organic extract was washed with 2 N HCl and brine, dried over Na 2 SO, and concentrated in vacuo. The resulting brown residue was purified by chromatography on silica gel with 30% EtOAc / hexane as the eluent to give the desired product as a yellow / orange solid. H 500 MHz RN (CDCl 3) ppm (6): 4.43 (s, 2H), 5.60 (bs, 1 H), 6.90 (d, 2H), 6.92 (m, 1 H), 6.97 (m, 1 H), 7.22 (d, 1 H) and 8.00 (d, 2H).

EXAMPLE 4 General preparation of cycloalkull-4-hydroxy-benzophenones To a stirred solution of 2-cycloalkyl-1- (4-methoxy-phenyl) -ethanone [prepared according to the method of Barrio, et al, J. Med. Chem., 1971, 14, 898] in methylene chloride dried at 0 ° C, 3.6 equivalents of aluminum chloride and 3.0 equivalents of isopropyl mercaptan were added. The ice-water bath was stirred and the reaction mixture was further stirred overnight under an inert nitrogen atmosphere. The reaction mixture was poured into a mixture of 2N HCl / ice and extracted with ethyl acetate. The ethyl acetate extract was washed with brine, dried over anhydrous sodium sulfate, filtered, and evaporated. Purification by chromatography on silica gel provided the corresponding 2-cycloalkyl-1- (4-hydroxy-phenyl) -ethanone.

Using the above experimental procedure the following compounds were prepared: 2-Clclohexyl-1- (4-hydroxy-phenyl) -ethanone: 70% yield using methylene chloride-ethyl acetate (50: 1) as the eluant of chromatography. 1H 500 MHz NMR (CDCl 3) ppm (5): 1-2.0 (m, 1 1 H), 2.96 (d, 1 H), 5.6 (bs, 1 H), 6.92 (d, 2 H), and 7.95 (d , 2H). 2-Cyclopentyl-1- (4-hydroxy-phenyl) -ethanone: 74% yield using methylene chloride-ethyl acetate (50: 1) as the eluant of chromatography. 1 H 500 MHz NMR (CDCl 3) ppm (6): 1.2-1.92 (m, 10H), 2.4 (m, 1 H), 2.96 (d, 1 H), 5.6 (bs, 1 H), 6.91 (d , 2H), and 7.95 (d, 2H).

EXAMPLE 5 Preparation of lsopropyl-4-hydroxybenzophenone To a mixture of isovaleric acid (1.4 ml_, 13.0 mmol) and phenol (1.0253 g, 10.9 mmol) was added BF3OEt2 (15 mL) under nitrogen. The resulting mixture was heated at 80 ° C for about 3.5 h. The reaction was emptied on ice / 2 N HCl and extracted with EtOAc. The organic extract was washed with brine, dried over Na2SO4, and concentrated in vacuo to give a yellow residue. The final product was isolated as a pale yellow oil then it was processed by chromatography on silica gel with 30% EtOAc / hexane as the eluent. During standing at room temperature, the oil solidified to give a white solid. H 500 MHz NMR (CDCl 3) ppm (8): 1.01 (d, 6H), 2.27 (m, 1 H), 2.81 (d, 2H), 6.99 (d, 2H), 7.93 (d, 2H).

EXAMPLE 6 Preparation of 4-pyridyl-4-hydroxybenzophenone A dry flask equipped with a stir bar was charged with a 2.5 M solution of nBuLi in hexane (18 mL, 45.0 mmol) and cooled to 0 ° C under N2. A solution of diisopropylamine (6.4 mL, 45.7 mmol) in distilled THF (20 mL) was slowly added. After stirring for 25 min., A solution of 4-picoline (2.0 mL, 21.4 mmol) in distilled THF (8 mL) was added to the reaction. The resulting red solution was stirred for 25 min. Before removing the ice bath. A solution of cyanophenol (2.5670 g, 21.4 mmol) in distilled THF (20 mL) was added via a dropping funnel for 30 min. During the addition of the phenol, the reaction became a thick mixture with an oily output of a red / brown tar. The additional addition of THF did not alleviate the difficulty in agitation. The reaction was maintained at room temperature for 16 h, and was emptied onto a mixture of ice / saturated NH 4 Cl / EtOAc. The intermediate enamine was precipitated from the mixture as an insoluble yellow solid and was collected by vacuum filtration. The solid was redissolved in 2 N HCl. The EtOAc layer of the filtrate was also collected and extracted with 2N HCl / ice. The acidic aqueous extract was combined with the enamine solution in 2 N HCl and stirred at room temperature for 16 h. The acid solution was washed with EtOAc, cooled to 0 ° C, and neutralized to pH 7 with saturated NaHCO 3. The desired product was precipitated from the solution as a yellow solid and was collected, washed with cold water, and dried in vacuo. 1H 500 MHz NMR (d-acetone) ppm (8): 4.37 (s, 2H), 6.97 (d, 2H), 7.31 (d, 2H), 8.01 (d, 2H), 8.52 (bs, 2H).

EXAMPLE 7 Preparation of 3-pyrldyl-4-hydroxybenzophenone Following the procedure detailed in Example 6 with the exception that 1 equivalent of HMPA in THF was added to the reaction following the addition of diisopropylamine, 3-pyridyl-4-hydroxy-benzophenone was prepared from 3-picoline. The work was slightly different in that hydrolysis with 2N HCl was unnecessary. Instead, the reaction was simply divided between ice / saturated NH 4 Cl and EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was triturated with CH2Cl2 and EtOAc to give the desired product as an orange solid. 1H 500 MHz NMR (d-acetone) ppm (d): 4.39 (s, 2H), 6.97 (d, 2H), 7.31 (m, 1 H), 7.68 (m, 1 H), 8.01 (d, 2H) , 8.43 (m, 1 H), 8.52 (m, 1 H).

EXAMPLE 8 General preparation of cycloalkull-4-triisopropylsilyloxybenzophenones To a stirred solution of the 2-cycloalkyl-1- (4-hydroxy-phenyl) -ethanone, prepared in Example 4, in dry DMF at 0 ° C, 1.3 equivalents of diisopropylethylamine and 1.2 equivalents of triisopropylchlorosllane (TIPSCI) were added. ). The ice-water bath was stirred and the reaction mixture was further stirred until the ccd showed that the reaction was complete (1 -3 hours) under an inert nitrogen atmosphere. The reaction mixture was partitioned between ether / 2N HCl / ice and the organic phase was separated, washed twice with water, washed with brine, dried over anhydrous sodium sulfate, filtered, and evaporated. Purification by chromatography on silica gel provided the corresponding 2-cycloalkyl-1- (4-triisopropyloxy-phenyl) -ethanone. Using the above experimental procedure the following compounds were prepared: 2-cyclohexyl-1- (4-triisopropylsilyloxy-phenyl) -ethanone: using methylene chloride-hexanes (1: 1) as the eluant of chromatography. 1H 500 MHz NMR (CDCl 3) ppm (5): 1.13 (d, 18H), 1-1.99 (m, 14H), 2.78 (d, 1 H), 6.91 (d, 2H), and 7.89 (d, 2H). 2-Cyclopentyl-1- (4-triisopropylsilyloxy-phenyl) -ethanone: using methylene chloride-hexanes (1: 1) as the eluant of chromatography. H 500 MHz NMR (CDCl 3) ppm (6): 1.12 (d, 18H), 1.2-1.91 (m, 13H), 2.4 (m, 1 H), 2.95 (d, 1 H), 6.92 (d, 2H) , and 7.9 (d, 2H).

EXAMPLE 9 General preparation of alkyl-4-triisopropylsilyloxy-benzophenpins YOU To a solution of 2-alkyl-1- (4-hydroxy-phenyl) -ethanone, prepared in Examples 3, 6, and 7, in distilled THF, was added 1.3 equivalents of 60% NaH in mineral oil at 0 ° C under N2. After the evolution of gas was finished, 1.1 equivalents were added drop by drop and the resulting solution was stirred for 30 min. The reaction was partitioned between ice / water and EtOAc. The organic layer was washed with brine, dried over Na 2 SO 4, and concentrated in vacuo. Purification by chromatography on silica gel provided the corresponding 2-alkyl-1- (4-triisopropylsilyloxy-phenol) -ethanones. Using the above experimental procedure, the following compounds were prepared: 2- (2-thiophene) -1- (4-triisopropylsilyloxy-phenyl) -ethanone: it was isolated as an orange / yellow solid using 15% EtOAc / hexane as the eluent of chromatography 1H 500 MHz NMR (CDCl 3) ppm (6): 1.14 (d, 18H), 1.30 (m, 3H), 4.42 (s, 2H), and 6.93-7.98 (m, 7H). 2- (4-pyridyl) -1- (4-triisopropylsilyloxy-phenyl) -ethanone: was isolated as a yellow solid using 40% EtOAc / hexane as the eluant of chromatography. 1H 500 MHz NMR (CDCl 3) ppm (5): 1.14 (d, 18H), 1.30 (m, 3H), 4.28 (s, 2H), 6.97 (d, 2H), 7.35 (m, 1 H), 7.69 (m, H), 7.97 (d, 2H), and 8.56 (bs, 2H). 2- (3-pyridyl) -1 - (4-trisopropylsilyloxy-phenyl) -ethanone: was isolated as a yellow solid using 40% EtOAc / hexane as the eluant of chromatography. 1H 500 MHz NMR (CDCl 3) ppm (d): 1.14 (d, 18H), 1.20 (m, 3H), 4.18 (s, 2H), 6.82 (d, 2H), 7.10 (d, 2H), 7.82 (d , 2H), and 8.43 (d, 2H).

EXAMPLE 10 Procedure of general bromination of alkyl and cycloalkull-4-triisopropylsilyloxy-benzophenones To a stirred solution of the 2-alkyl- and 2-cycloalkyl-1- (4-triisopropylsilyloxy-phenyl) -ethanones, prepared in Examples 8 and 9, in dry THF at 0 ° C, was added 1.0 equivalent. of trlmethylammoniofenyl perbromide. The ice-water bath was stirred and the reaction mixture was further stirred for 1 hour under an inert nitrogen atmosphere. The reaction mixture was partitioned between ethyl acetate / brine / ice / 5% sodium thiosulfate / sodium bicarbonate and the organic phase was separated, washed with brine, dried over anhydrous sodium sulfate, filtered, and evaporated Purification by chromatography on silica gel provided the corresponding 2-cycloalkyl-2-bromo-1- (4-triisopropylsilyloxy-phenyl) -ethanone. Using the above experimental procedure the following compounds were prepared: 2-cyclohexyl-2-bromo-1- (4-t-isopropylsilyloxy-phenyl) -ethanone: using methylene chloride-hexanes (1: 1) as the eluant of chromatography. 1H 500 MHz NMR (CDC) ppm (5): 1.1 (d, 18H), 0.98-2.27 (m, 15H), 4.91 (d, 1 H), 6.94 (d, 2H), and 7.94 (d, 2H). 2-Cyclopentyl-2-bromo-1- (4-triisopropylsilyloxy-phenyl) -ethanone: using methylene chloride-hexanes (1: 1) as the eluant of chromatography. 1H 500 MHz NMR (CDCl 3) ppm (5): 1.13 (d, 18H), 1.1-2.2 (m, 1 1 H), 2.8 (m, 1 H), 4.98 (d, 1 H), 6.94 (d, 2H), and 7.96 (d, 2H). 2- (2-thiophene) -2-bromo-1- (4-triisopropylsilyloxy-phenol) -ethanone: was stirred at 0 ° C for 40 min .; it was isolated as a dark brown oil and used in the next reaction without purification. H 500 MHz NMR (CDCl 3) ppm (5): 1.13 (d, 18H), 1.30 (m, 3H), 6. 73 (s, 1 H), 6.97 (d, 2H), 7.00 (m, 1 H), 7.30 (m, 1 H), 7.49 (d, 1 H), and 8.00 (d, 2H). 2- (4-pyridyl) -2-bromo-1- (4-triisopropylsilyloxy-phenyl) -ethanone: 2 equivalents of trimethylammonium phenyl perbromide were added and stirred at 0 ° C for 1 h; it was isolated as an orange / yellow oil and used in the next reaction without purification. 1H 500 MHz NMR (CDCl 3) ppm (5): 1.03 (d, 18H), 1.21 (m, 3H), 6.21 (s, 1 H), 6.98 (d, 2H), 7.40 (d, 2H), 7.90 (d, 2H), and 8.57 (d, 2H). 2- (3-pyridyl) -2-bromo-1- (4-triisopropylsilyloxy-phenyl) -ethanone: 2 equivalents of trimethylammonium phenyl perbromide were added and stirred at 0 ° C for 3 h; it was isolated as an orange / yellow oil and used in the next reaction without purification, 1 H 500 MHz NMR (CDCl 3) ppm (5): 1.13 (d, 18 H), 1.30 (m, 3 H), 6.30 (s, 1 H ), 6.98 (d, 2H), and 7.39-8.75 (m, 6H) EXAMPLE 11 Preparation of 2-isopropyl-2-bromo-1- (4-hydroxyphenyl) -ethanone Following the procedure detailed in Example 10 and using the product obtained from Example 5, 2-isopropyl-2-bromo-1- (4-hydroxyphenyl) -ethanone was isolated as a yellow oil and used in the next reaction without purification . 1 H 500 MHz NMR (CDCl 3) ppm (5): 1.01 (d, 3 H), 1.21 (d, 3 H), 2.46 (m, 1 H), 4.93 (d, 1 H), 6.96 (d, 2 H), and 7.96) d, 2H).

EXAMPLE 12 General preparation of bromoketones = H or MOM Step A To a stirred solution of 3.0 g (13.2 mmol) of dry deoxybenzoin (freshly azeotroped with toluene) in 25 mL of DMF at 0 ° C, 5.7 mL (5.7 mmol) of pure diisopropylethylamine was added. To this stirred solution was added 1.25 mL (19.73 mmol) of chloromethylmethyl ether (MOMCI) slowly. The ice-water bath was stirred and the mixture was further stirred under a nitrogen atmosphere for 18 hours. The mixture was then poured into a saturated NaHCO 3 solution, extracted with EtOAc, and the extract was washed with water, and dried over anhydrous MgSO 4. After evaporation of the solvent, the residue was purified by chromatography on silica gel (EtOAc / Hexane = 1: 1) to provide the product as a solid. H NMR (400 MHz, CDCl 3) d (ppm): 8.0 (d, 2 H), 7.19 (d, 2 H), 7.10 (d, 2 H), 6.8 (d, 2 H), 5.23 (s, 2 H), 4.8 ( s, 1 H), 4.2 (s, 2H), 3.5 (s, 3H).

Step B: To a stirred solution of the product obtained from Step A (423 mg, 1.55 mmol) and imidazole (21 mg, 3.1 mmol) in 20 mL of dry DMF at 0 ° C, triisopropylsilyl chloride (3.1 mmol) was added and the reaction mixture was allowed to warm to room temperature and further stirred for 2-3 hours. The reaction was quenched by the addition of aqueous NaHC03 solution and extracted with EtOAc. The organic layer was washed with brine and dried with MgSO4. Chromatography (10% EtOAc / hexane) provided the desired product. HRN (400 MHz, CDCl 3) d (ppm): 8.0 (d, 2H), 7.12 (d, 2H), 7.08 (d, 2H), 6.82 (d, 2H), 5.21 (s, 2H), 4.18 (s) , 2H), 3.5 (s, 3H), 1.24 (m, 3H), 1 .1 (d, 18H).

Step C To a mixture of the compound from Step B (0.5 g, 1.16 mmol) in 100 mL of anhydrous THF was added 0.39 g (1.16 mmol) of trimethylphenylammonium perbromide (P ) at 0 ° C. The ice-water bath was removed, and the mixture was further stirred for one hour. The solution was then filtered and washed with water and brine and dried over MgSO4. The transfer of the solvent provided the bromo-ketone mixture (the MOM group was partially removed), which was used without further purification due to its instability towards chromatography. Bromocetone with MOM group: 1 H NMR (400 MHz, CDCl 3) d (ppm): 8.0 (d, 2H), 7.4 (d, 2H), 6.8-8 (d, 2H), 6.86 (d, 2H), 6.36 ( s, 1 H), 1.24 (m, 3H), 1 .1 (d, 18H); Bromocetone without MOM group: H NMR (400 MHz, CDCl 3) d (ppm): 7:94 (d, 2H), 7.4 (d, 2H), 6.88 (d, 2H), 6.86 (d, 2H), 6.36 ( s, 1 H), 1.24 (m, 3H), 1.1 (d, 18H).

EXAMPLE 13 Preparation of The required bromoketone was prepared using the procedure of Example 12 (Step C). 1 H NMR (400 MHz, CDCl 3) d (ppm) 7.94 (d, 2 H), 7.56 (m, 2 H), 7.38 (m, 3 H), 6.9 (d, 2 H), 6.36 (s, 2 H), 1.28 (m , 3H), 1.1 (d, 18H).

EXAMPLE 14 Preparation of The required bromoketone was prepared using the procedure of Example 12 (Step C). 1 H NMR (400 MHz, CDCl 3) d (ppm) 7.9 (d, 2 H), 7.5 (d, 2 H), 6.9 (d and d, 4 H), 6.4 (s, 1H), 3.8 (s, 3H), 1.28 (m, 3H), 1.1 (d, 18H).

EXAMPLE 15 Preparation of Step AA: a stirred solution of a mixture of the phenolic mono compound 0.1 g (0.37 mmol) from Step A in Example 12 and diisopropylethylamine (0.13 ml_, 2 eq) in 5 mL of DMF at room temperature, was slowly added pure MOMO (0.05 mL, 2 eq), and the mixture was heated to 85 ° C under N2 for three hours. The mixture was then poured into a saturated NaHCO 3 solution, extracted with EtOAc, washed with water, and dried over MgSO 4. After evaporation of the solvent, the residue was purified by chromatography on silica gel (EtOAc / Hexane = 1: 1) to give the bis-protected MOM product, as a solid. 1 H NMR (400 MHz, CDCl 3) 6 (ppm): 8.0 (d, 2 H), 7.19 (d, 2 H), 7.10 (d, 2 H), 7.02 (d, 2 H), 5.23 (s, 2 H), 5.2 ( s, 2H), 4.2 (s, 2H), 3.5 (two s, 6H).

Step B The product from Step A was treated with bromine to give bromoketone, 1 H NMR (400 MHz, CDCl 3) d (ppm): 8.0 (d, 2 H), 7.45 (d, 2 H), 7.10 (two d, 4 H ), 6.4 (s, 1 H), 5.23 (two s, 4H), 3.5 (two s, 6H).

EXAMPLE 16 General preparation of To a recently prepared, stirred solution of 2-thiophenol (0.2 g, 1.6 mmol) and Et3N (0.34 mL, 2 eq) in 15 mL DMF at 0 ° C, was slowly added a solution of 0.627 g (1.232 mmol) of bromoketone (prepared from Step C in the Example 12) in 13 mL of DMF. The reaction mixture was stirred for three hours at room temperature and then partitioned between saturated NaHCO3 and EtOAc, the layers were separated, and the aqueous layer was extracted again with EtOAc. The combined organic layers were dried (Na2SO4), filtered, and evaporated in vacuo. The resulting oil was purified by flash chromatography (EtOAc / Hex = 1/4) to provide the desired product as an oil. 1H RN (400 MHz, acetone-de) d (ppm): 8.0 (d, 2H), 7.2-6.6 (m, 8H), 6.8 (d, 2H), 6.2 (s, 1 H), 5.24 (s, 2H), 3.4 (s, 3H), 1.22 (m, 3H), 1.1 (d, 18H); MS m / z 575 (M ++ 23).

EXAMPLE 17 Cyclization of the coupled product Following the procedure detailed in Example 16, the 1,2-dihydroxybenzene and the bromide of Example 15 were converted to the product which was purified by chromatography on silica gel using EtOAc / hexane (1/4) as eluent. MS m / z 448 (M ++ 23).

EXAMPLE 18 Preparation of Following the procedure detailed in Example 16 and using 0.83 g (3.6 mmol) of 4-benzyloxy-thiophenol, prepared from Example 1, product A and product B were obtained after chromatography on silica gel using EtOAc / hexane (1 / 5) as eluent. A: 1 H NMR (400 MHz, acetone-d 6) d (ppm): 8.15 (s, 1 H), 7.8 (d, 2 H), 7.4 (m, 5 H), 6.98 (d, 2 H), 6.98 (d, 1 H), 6.75 (d and d, 4 H), 6.0 (s, 1 H), 5.62 (s, 1 H), 5.0 (s, 2 H), 1.22 (m, 3 H), 1.15 (d, 18 H). B: 1 H NMR (400 MHz. Acetone-d 6) d (ppm): 8.0 (d, 2 H), 7.5 (m, 5 H), 7.18 (d, 2 H), 7.04 (d, 2 H), 6.96 (d, 1 H), 6.8 (d, 2H), 6.56 (d, 1 H), 6.32 (dd, 1 H), 6.1 (s, 1 H), 5.25 (s, 2H), 5.09 (s, 1 H), 3.4 (s, 3H), 1.22 (m, 3H), 1 .1 (d, 18H).

EXAMPLE 19 Preparation of Following the procedure detailed in Example 16 and using 1.1 g (2.3 mmol) of the bromoketone of Example 14, the desired product was obtained after chromatography on silica gel using EtOAc / hexane (1/5) as eluent. 1 H NMR (400 MHz, acetone-d 6) d (ppm): 8.46 (br s, 1 H), 7.98 (d, 2 H), 7.48-7.3 (m, 5 H), 7.24 (d, 2 H), 7.4 (d) , 1 H), 6.92 (d, 2H), 6.82 (d, 2H), 6.56 (d, 1 H), 6.38 (dd, 1 H), 6.1 (s, 1 H), 5.04 (s, 2H), 3.72 (s, 3H), 1.25 (m, 3H), 1.1 (d, 18H).

EXAMPLE 20 Preparation of Following the procedure detailed in Example 16 and using 0. 74 g (1.5 mmol) of the bromoketone of Example 12 (Step C), the desired product was obtained after chromatography on silica gel using EtOAc / hexane (1/5) as eluent. 1 H NMR (400 MHz, acetone-d 6) d (ppm): 7.92 (d, 2 H), 7.46-7.1 (m, 5 H), 7.18 (d, 2 H), 6.84 (d, 2 H), 6.78 (d, 2 H) ), 6.42 (d, 1 H), 6.36 (d, 1 H), 5.98 (s, 1 H), 5.02 (s, 2H), 2.2 (s, 3H), 1.22 (m, 3H), 1.1 (d) , 18H).

EXAMPLE 21 Preparation of PS Following the procedure detailed in Example 16 and using 0.8 g (1.57 mmol) of the bromoketone of Example 12 (Step C) with the thiophenol derivative prepared from Example 1, the desired product was obtained after chromatography on silica gel using EtOAc / hexane (1/5) as eluent. 1 H NMR (400 MHz, acetone-d 6) d (ppm): 7.9 (d, 2 H), 7.5-7.3 (m, 5 H), 7.12 (d, 2 H), 6.9 (d, 1 H), 6.84 (d, 2H), 6.79 (d, 2H), 6.4 (d, 1 H), 6.0 (s, 1 H), 5.1 (s, 2H), 2.1 (s, 3H), 1.25 (m, 3H), 1.1 (d) , 18H).

EXAMPLE 22 Following the procedure detailed in Example 16 and using 0.56 g (1.1 mmol) of the bromoketone of Example 12 (Step C) with 0.19 g (0.73 mmol) of thiophenol derivative prepared from Example 1, the desired product was obtained after chromatography on silica gel using EtOAc / hexane (1/5) as eluent. 1 H NMR (400 MHz, acetone-de) d (ppm): 7.9 (d, 2 H), 7.48-7.3 (m, 5 H), 7.16 (d, 2 H), 6.84 (d, 2 H), 6.78 (d, 2 H) ), 6.42 (d, 1 H), 6.38 (d, 1 H), 5.96 (s, 1 H), 5.1 (s, 2H), 2.6 (q, 2H), 1.22 (m, 3H), 1.1 (d) , 18H), 1.1 (t, 3H).

EXAMPLE 23 Preparation of Following the procedure detailed in Example 16 and using 2.04 g (4.33 mmol) of the bromoketone of Example 12 (Step C) with the thiophenol derivative prepared from Example 1, the desired product was obtained after chromatography on silica gel using EtOAc / hexane (1/5) as eluent. 1 H NMR (400 MHz, acetone-d 6) d (ppm): 7.9 (d, 2 H), 7.5-7.3 (m, 5 H), 7.12 (d, 2 H), 6.92 (d, 1 H), 6.84 (d, 2H), 6.78 (d, 2H), 6.42 (d, 1 H), 6.0 (s, 1 H), 5.1 (s, 2H), 2.7 (q, 2H), 1.24 (m, 3H), 1.1 (d & t, 2 H).

EXAMPLE 24 Preparation of Following the procedure detailed in Example 16 and using 2. 0 g (4.33 mmol) of the bromoketone of Example 12 (Step C) with the thiophenol derivative prepared from Example 1, the desired product was obtained after chromatography on silica gel using EtOAc / hexane (1/5) as eluent . H NMR (400 MHz, acetone-d6) d (ppm): 7.8 (d, 2H), 7.62 (d, 2H), 7.48-7.3 (m, 8H), 7.12 (d, 2H), 6.8 (d, 2H ), 6.76 (2H, d), 6.28 (d, 1 H), 6.18 (d, 1 H), 6.0 (s, 1 H), 5.24 (s, 2H), 5.05 (s, 2H), 1 .22 (m, 3H), 1.1 (d, 18H).

EXAMPLE 25 Preparation of Following the procedure detailed in Example 16 and using 1.6 g (3.51 mmol) of the bromoketone of Example 13 with the thiophenol derivative prepared from Example 1, the desired product was obtained after chromatography on silica gel using EtOAc / hexane ( 1/5) as eluent. 1 H NMR (400 MHz, acetone-d 6) d (ppm): 8.0 (d, 2 H), 7.5-7.2 (m, 10 H), 7.0 (d, 1 H), 6.92 (d, 2 H), 6.54 (d, 1 H), 6.35 (dd, 1 H), 6.12 (s, 1 H), 5.06 (s, 2H), 1.22 (m, 3H), 1 .1 (d, 18H).

EXAMPLE 26 Preparation of Following the procedure detailed in the E.}. Using 16 and using 2.6 g (5.82 mmol) of the bromoketone of Example 13 with the thiophenol derivative prepared from Example 1, the desired product was obtained after chromatography on silica gel using EtOAc / hexane (1/5) as eluent 1 H NMR (400 MHz, acetone-d 6) d (ppm): 8.0 (d, 2H), 7.4-7.2 (m, 10H), 6.94 (d, 2H), 6.84-6.74 (m, 3H), 6.24 (s) , 1 H), 4.85 (s, 2H), 1.23 (m, 3H), 1.1 (d, 18H).

EXAMPLE 27 Following the procedure detailed in Example 16 and using the bromoketone of Example 12 (Step C) with the thiophenol derivative prepared from Example 1, the desired product was obtained after chromatography on silica gel using EtOAc / hexane (1/5 ) as eluent. 1 H NMR (400 MHz, acetone-d 6) 5 (ppm): 8.0 (d, 2H), 7.4-7.2 (m, 7H), 7.0 (m, 5H), 6.54 (d, 1 H), 6.28 (dd, 1 H), 6.14 (s, 1 H), 5.08 (s, 2H), 1.23 (m, 3H), 1.1 (d, 18H).

EXAMPLE 28 Following the procedure detailed in Example 16 and using the bromoacetone of Example 13 with the appropriate thiophenol derivative prepared from Example 1, the desired product was obtained after chromatography on silica gel using EtOAc / hexane (1/5) as the eluent 1 H NMR (500 MHz, CDCl 3) d (ppm) 8.28 (s, 1 H), 7.82 (d, 2 H), 7.40 (m, 5 H), 7.22 (m, 5 H), 6.80 (d, 2 H), 6.40 (d, 1 H), 6.21 (dd, 1 H), 5.80 (s, 1 H), 5.00 (s, 2H), 1.24 (m, 3H), 1.10 (d, 18H).

EXAMPLE 29 Following the procedure detailed in Example 16 and using the bromoketone of Example 13 with the appropriate thiophenol derivative prepared from Example 16, the desired product was obtained after Si02 using EtOAc / hexane (1/5) as eluent. 1 H NMR (500 MHz, CDCl 3) d (ppm) 8.19 (s, 1 H), 7.82 (d, 2 H), 7.40 (m, 5 H), 7.24 (m, 5 H), 6.80 (d, 2 H), 6.64 ( d, 1 H), 6.44 (d, 1 H), 5.84 (s, 1 H), 5.00 (s, 2H), 1.23 (m, 3H), 1.10 (m, 18H).

EXAMPLE 30 Preparation of Following the procedure detailed in Example 16 and using the bromoketone of Example 12 with the thiophenol derivative prepared from Example 1, the desired product was obtained after chromatography on silica gel using EtOAc / hexane (1/5) as eluent. 1 H NMR (500 Hz, CDCl 3) d (ppm): 8.20 (s, 1 H), 7.81 (d, 2 H), 7.40 (m, 5 H), 7.03 (d, 2 H), 6.75 (d, 4 H), 6.36 (d, 1 H), 6.20 (dd, 1 H), 5.78 (s, 1 H), 4.95 (s, 2H), 1.23 (m, 3H), 1.10 (m, 18H).

EXAMPLE 31 Preparation of Following the procedure detailed in Example 16 and using the bromoketone of Example 12 with the thiophenol derivative prepared from Example 1, the desired product was obtained after chromatography on silica gel using EtOAc / hexane (1/5) as eluent. H NMR (500 MHz, CDCl 3) d (ppm): 8.24 (s, 1 H), 7.80 (d, 2 H), 7.40 (m, 5 H), 7.10 (d, 2 H), 6.78 (d, 4 H), 6.62 (d, 1 H), 6.42 (d, 1 H), 5.84 (s, 1 H), 4.98 (s, 2 H), 1.23 (m, 3 H), 1.10 (m, 18 H); MS m / z 650 (++ 1).

EXAMPLE 32 Preparation of Following the procedure detailed in Example 16 and using the bromoketone of Example 12 with the thiophenol derivative prepared from Example 1, the desired product was obtained after chromatography on silica gel using EtOAc / hexane (1/5) as eluent. H NMR (500 MHz, acetone-de) d (ppm): 7.95 (d, 2H), 7.40 (m, 5H), 7.20 (d, 2H), 6.80 (m, 7H), 6.20 (s, 1 H) , 4.85 (s, 2H), 1.23 (m, 3H), 1 .10 (m, 18H); MS m / z 616 (M ++ 1).

EXAMPLE 33 Preparation of Following the procedure detailed in Example 169 and using the bromoketone of Example 12 with the thiophenol derivative prepared from Example 1, the desired product was obtained after chromatography on silica gel using EtOAc / hexane (1/5) as eluent. 1 H NMR (500 Hz, CDCl 3) d (ppm): 7.82 (d, 2 H), 7.40 (m, 5 H), 7.05 (d, 2 H), 6.95 (s, 1 H), 6.80 (d, 4 H), 6.52 (s, 1 H), 5.64 (s, 1 H), 5.00 (s, 2H), 1.23 (m, 3H), 1.10 (m, 18H); MS m / z 629 (M ++ 1).

EXAMPLE 34 Preparation of Following the procedure detailed in Example 16 and using the bromoketone of Example 12 with the thiophenol derivative prepared from Example 1, the desired product was obtained after chromatography on silica gel using EtOAc / hexane (1/5) as eluent. 1 H NMR (500 MHz, CDCl 3) d (ppm: 8.24 (s, 1 H), 7.80 (d, 2 H), 7.40 (m, 5 H), 7.10 (d, 2 H), 6.78 (d, 2 H), 6.76 ( d, 2H), 6.64 (d, 2H), 6.45 (d, 2H), 5.86 (s, 1 H), 4.98 (s, 2H), 1.23 (m, 3H), 1.10 (m, 18H); / z 650 (M ++ 1).

EXAMPLE 35 Preparation of Following the procedure detailed in Example 16 and using the bromoketone of Example 12 with the thiophenol derivative prepared from Example 1, the desired product was obtained after chromatography on silica gel using EtOAc / hexane (1/5) as eluent. H NMR (500 MHz, CDCl 3) d (ppm): 7.82 (d, 2H), 7.40 (m, 5H), 7.24 (m, 3H), 7.20 (d, 2H), 6.82 (d, 2H), 6.80 ( d, 2H), 6.58 (d, 2H), 5.65 (s, 1 H), 4.80 (d, 2H), 2.22 (s, 3H), 1.23 (m, 3H), 1.10 (m, 18H).

EXAMPLE 36 Following the procedure detailed in Example 16 and the bromoketone of Example 13 with the thiophenol derivative prepared from Example 1, the desired product was obtained after chromatography on silica gel using EtOAc / hexane (1/5) as eluent. 1H RN (500 Hz, CDCl 3) d (ppm): 7.98 (s, 1 H), 7.82 (d, 2H), 7.40 (m, 5H), 7.25 (m, 3H), 7.20 (d, 2H), 7.00 (d, 1 H), 6.80 (d, 2H), 6.60 (d, 1 H), 5.78 (s, 1 H), 4.78 (d, 2H), 1.23 (m, 3H), 1.10 (m, 18H) .

EXAMPLE 37 Preparation of I 11 Following the procedure detailed in Example 16 and using the bromoketone of Example 13 with the mixture of the two thiophenol derivatives prepared from Example 1, the two desired products I and II were obtained after chromatography on silica gel using EtOAc hexane ( 1/5) as eluent. I: 1 H NMR (500 MHz, CDCl 3) d (ppm): 7.80 (d, 2 H), 7.40 (m, 5 H), 7.25 (m, 3 H), 7.16 (d, 2 H), 7.04 (s, 1 H) , 6.80 (d, 2H), 6.60 (s, 1 H), 5.78 (s, 1 H), 4.80 (d, 2H), 1.23 (m, 3H), 1.10 (m, 18H). II: 1 H NMR (500 MHz, CDCl 3) d (ppm): 7.80 (d, 2 H), 7.65 (s, 1 H), 7.44 (d, 1 H), 7.40 (m, 5 H), 7.25 (m, 5 H) ), 6.96 (d, 1 H), 6.80 (m, 3H), 6.00 (s, 1 H), 5.15 (s, 2H), 1.23 (m, 3H), 1.10 (m, 18H).

EXAMPLE 38 Following the procedure detailed in Example 16 and using the bromoketone of Example 12 with the thiophenol derivative prepared from Example 1, the desired product was obtained after chromatography on silica gel using EtOAc / hexane (1/5) as eluent. 1 H NMR (500 MHz, CDCl 3) d (ppm): 7.80 (d, 2H), 7.40 (m, 5H), 7.14 (m, 2H), 6.96 (m, 2H), 6.84 (m, 2H), 6.82 (d, 2H), 6.70 (d, 1 H), 5.68 (s, 1 H), 4.86 d, 2H), 1.23 (m, 3H), 1.10 (m, 18H).

EXAMPLE 39 General preparation of Using the bromides prepared in Example 10 and the appropriate mercaptan prepared in Example 1 and employing the procedures outlined in Example 16 the following compounds were prepared: cyclohexyl derivative: using methylene chloride / hexanes (3: 1) as the eluant chromatography. 1H 500 MHz NMR (CDCl 3) ppm (6): 1.12 (d, 18H), 1.1 1-2.34 (m, 15H), 4.19 (d, 1 H), 5.0 (s, 2H), 6.44 (dd, 1 H ), 6.54 (d, 1 H), 6.86 (m, 3H), 7.25-7.72 (m, 7H). Cyclopentyl derivative: using methylene chloride / hexanes (2: 1) as the chromatography eluent. 1H 500 MHz NMR (CDCl 3) ppm (5): 1.12 (d, 18H), 1.28-2.49 (m, 12H), 4.18 (d, 1 H), 5.0 (s, 2H), 6.45-7.77 (m, 12H ).

EXAMPLE 40 Using the bromide prepared in Example 11 and the appropriate mercaptan prepared in Example 1 and using the procedure detailed in Example 9, the desired product was obtained as a yellow oil in 77% yield after chromatography on silica gel with 30% EtOAc / hexane as the eluent. H 500 MHz NMR (CDCl 3) ppm (6): 1.00 (d, 3 H), 1.21 (d, 3 H), 2.30 (m, 1 H), 4.13 (d, 1 H), 4.99 (s, 2 H) , 6.41 -7.72 (m, 12H), 8.02 (bs, 1 H), 8.80 (bs, 1 H); MS m / z 409 (M +).

EXAMPLE 41 General preparation of Using the bromides prepared in Example 10 and the appropriate mercaptan prepared in Example 1 and using the procedure detailed in Example 16 the following compounds were prepared: cyclohexyl derivative: using methylene chloride / hexanes (3: 1) as the eluant chromatography. 1H 500 MHz NMR (CDCl 3) ppm (5): 1.12 (d, 18H), 1.1 .1.2.3 (m, 15H), 4.24 (d, 1 H), 4.89 (m, 2H), 6.8-7.6 (m, 12H). Cyclopentyl derivative: which uses methylene chloride / hexanes (2: 1) as the eluent of the chromatography. H 500 MHz NMR (CDCl 3) ppm (3): 1.12 (d, 18H), 1.26-2.12 (m, 1 1 H), 2.5 (m, 1 H), 4.24 (d, 1 H), 4, 9 (m, 2H), 6.8-7.69 (m, 12H). Derivative of 4-Pyridyl: it is isolated as a yellow oil using 30% EtOAc / hexane as the eluent of the chromatography. 1H 500 MHz NMR (CDCl 3) ppm (5): 1.12 (d, 18H), 1.28 (m, 3H), 4.84 (q, 2H), 4.88 (s, 1 H), 5.63 (s, 1 H) , and 6.69-8.50 (m, 16H). Derivative of 3-Pyridyl: it is isolated as a yellow oil using 30% EtOAc / hexane as the eluent of the chromatography. 1H 500 MHz NMR (CDCl 3) ppm (5): 1.12 (d, 18H), 1.28- (m, 3H), 4.84 (q, 2H), 4.90 (s, 1 H), 5.79 (s, 1 H), and 6.70-8.50 (m, 16H).

EXAMPLE 42 Preparation of Using the bromide prepared in Example 11 and the appropriate mercaptan prepared in Example 1 and using the procedure detailed in Example 16, the desired product was obtained as a yellow oil after chromatography on silica gel with 30% EtOAc / hexane as the eluent. 1H 500 MHz NMR (CDCl 3) ppm (6): 1.02 (d, 3H), 1.21 (d, 3H), 2.34 (m, 1 H), 4.13 (d, 1 H), 4.90 (q, 2H), 6.25 (bs, 1 H), 6.79-7.70 (m, 12H).

EXAMPLE 43 Preparation of Using the appropriate bromide prepared in Example 10 and mercaptoquinol [prepared according to the method of Burton, et al, J. Chem, Soc, 1952, 2193] and using the procedure detailed in Example 16, the desired product was obtained as an orange / red oil after chromatography on silica gel with 30% EtOAc / hexane as the eluent. 1H 500 MHz NMR (CDCl 3) ppm (5): 1.10 (d, 18H), 1.27 (m, 3H), 6.00 (s, 1 H), and 6.76-7.89 (m, 10H); MS m / z 515 (M +).

EXAMPLE 44 Preparation of To a flask loaded with 0.1 g (0.16 mmol) of thio-ketone generated in Example 22 in dichloromethane (ca 0.04M) was added trifluoroacitic acid (TFA) (2 X 0.062 mL, 10eq) under a N2 atmosphere at room temperature. ambient. To the stirred reaction mixture was slowly added triethylsilane (2 X 0.05 mL, 4 eq) and the resulting mixture until a starting material was consumed (approximately 5-6 hours, as observed by CCD). The reaction mixture was poured into saturated NaHC03 / ice water, stirring for 10 minutes, and extracted with dichloromethane. The organic extract was washed with brine (2 X 50 mL), dried with Na2SO4, and concentrated in vacuo to give a bright yellow oil. Purification by flash chromatography (EtOAc / Hex = 1: 5) provided the desired compound as an oil. 1 H, NMR (400 MHz, CDCl 3) d (ppm): 7.44 (m, 5 H), 6.98 (d, 1 H), 6.90 (d, 2 H), 6.75 (d, 2 H), 6.68 (d, 2 H), 6.65 (d, 1 H), 6.63 (d, 2H), 5.51 (d, J = 2.3 Hz, 1 H), 5.10 (s, 2H), 4.74 (brs, 1 H), 4.32 (d, J = 2.3 Hz, 1 H), 2.77 (qd, 2H), 1.22 (m, 3H), 1.08 (d, 18H), 1.1 (m, 3H); MS m / z 628.5 (M ++ 1).

EXAMPLE 45 Preparation of Using the procedure of Example 44, the desired dihydrobenzoxathine without MOM protection was isolated after purification by chromatography on silica gel with 10% EtOAc / hexane. H NMR (400 MHz, CDCl 3) d (ppm): 7.2-6.98 (m, 4H), 6.85 (d, 2H), 6.78 (d, 2H), 6.66 (two d, 4H), 5.5 (d, J = 2.2 Hz, 1 H), 4.8 (s, 1 H), 4.33 (d, J = 2.1 Hz, 1 H), 1.22 (m, 3 H), 1.1 (d, 18 H); MS m / z 515 (M ++ 23). The other dihydrobenzoxathine with MOM protection was also isolated. 1 H NMR (400 MHz, CDCl 3) d (ppm): 7.2-6.6 (m, 8H), 6.78 (d, 2H), 6.66 (d, 2H), 5.5 (d, J = 2.4 Hz, 1 H), 5.14 (s, 2H), 4.35 (d, J = 2.1 Hz, 1 H), 3.48 (s, 3H), 1.22 (m, 3H), 1.1 (d, 18H).

EXAMPLE 46 Preparation of Using the procedure of Example 71 (Step C), the dihydrobenzoxathine generated from Example 45 was desilylated to give the product. H NMR (400 MHz, CDCl 3) d (ppm): 7.2-6.96 (m, 4H), 6.92 (two d, 4H), 6.82 (d, 2H), 6.6 (d, 2H), 5.52 (d, J = 2.2 Hz, 1 H), 5.16 (s, 2 H), 4.68 (br s, 1 H), 4.38 (d, J = 2.2 Hz, 1 H), 3.48 (s, 3 H).

EXAMPLE 47 Preparation of The ketone generated in Example 17 was converted to the desired product by following the procedure described in Example 44 with the exception that 5 equivalents of TFA and 2 equivalents of EÍ3SÍH were necessary to drive the reaction to completion. The MOM group was removed with mild acid treatment (2N-HCl, 75 ° C) to give the desired product. 1 H NMR (400 MHz, CDCl 3) d (ppm): 7.0 (m, 4 H), 6.85 (d, 2 H), 6.65 (d, 2 H), 5.38 (s, 2 H); MS m / z 343 (M ++ 23).

EXAMPLE 48 Preparation of The ketone generated in Example 18 was converted to the dihydrobenzoxathine using the procedure of Example 44 with the exception that 20 equivalents of TFA and 15 equivalents of EtaSiH were necessary to drive the reaction to completion. The desired product was isolated after purification by chromatography on silica gel using 10% EtOAc / hexane as eluent. 1 H NMR (400 Hz, CDCl 3) d (ppm): 7.5-7.34 (m, 5H), 7.08 (d, 1 H), 6.84 (d, 2H), 6.76 (d, 2H), 6.7 (dd, 1 H ), 6.67 (d, 1 H), 6.68 (two d, 4 H), 5.5 (d, J = 2.2 Hz, 1 H), 5.04 (br q, 2 H), 4.68 (s, 1 H), 4.3 (d , J = 2.2 Hz, 1 H), 1.22 (m, 3H), 1.1 (d, 18H); MS m / z 515 (M ++ 23).

EXAMPLE 49 The ketone generated in Example 19 was converted to the dihydrobenzoxathine using the procedure of Example 44 with the exception that the reaction was run at -10 ° C for 48 hours in the presence of 20 equivalents of TFA and 2 equivalents of Et 3 SiH. The desired product [with 20% recovered starting material] was isolated after purification by chromatography on silica gel using 10% EtOAc / hexane as eluent. 1 H NMR (400 MHz, CDCl 3) d (ppm): 7.5-7.3 (m, 5H), 7.1-6.6 (m, 11 H), 5.54 (d, J = 1.9 Hz, 1 H), 5.06 (dd, 2H ), 4.32 (d, 1 H), 3.74 (s, 3H), 1.22 (m, 3H), 1.1 (d, 18H).

EXAMPLE 50 Preparation of Following the procedure detailed in Example 44 and using the ketone derivative in Example 20, the desired product was obtained after purification by chromatography on silica gel using 5% EtOAc / hexane as eluent. H NMR (400 MHz, CDCl 3) d (ppm): 7.46-7.32 (m, 5H), 6.84 (d, 2H), 6.78 (d, 2H), 6.66 (two d, 4H), 6.62 (d, 1 H ), 6.57 (d, 1 H), 5.3 (d, J = 2.2 Hz, 1 H), 4.35 (d, 1 H), 2.28 (s, 3 H), 1 .22 (m, 3 H), 1.1 (d) , 18H).

EXAMPLE 51 Preparation of Following the procedure detailed in Example 44 and using the ketone derived from Example 21, the desired product was obtained after purification by chromatography on silica gel using 5% EtOAc / hexane as eluent. 1 H NMR (400 MHz, CDCl 3) d (ppm): 7.5-7.3 (m, 5H), 6.98 (d, 1 H), 6.9 (d, 1 H), 6.76 (d, 2H), 6.6 (m, 5H) ), 5.51 (d, J = 2.2 Hz, 1 H), 5.1 (s, 2H), 4.8 (s, 1 H), 4.32 (d, 1 H), 2.4 (s, 3H), 1 .22 (m , 3H), 1.1 (d, 18H).

EXAMPLE 52 Preparation of Following the procedure detailed in Example 44 and using the ketone derived from Example 22, the desired product was obtained after purification by chromatography on silica gel using 5% EtOAc / hexane as eluent. 1 H NMR (400 MHz, CDCl 3) d (ppm): 7.5-7.3 (m, 5H), 6.85 (d, 2H), 6.78 (d, 2H), 6.66 (m, 5H), 6.56 (d, 1 H) 5.48 (d, J = 2.0 Hz, 1 H), 5.04 (br q, 2 H), 4.74 (br s, 1 H), 4.34 (d, J = 2.0 Hz, 1 H), 2.64 (q, 2 H), 1.3 (t, 3H), 1.24 (m, 3H), 1 .1 (d, 18H).

EXAMPLE 53 Preparation of Following the procedure detailed in Example 44 and using the ketone derived from Example 23, the desired product was obtained after purification by chromatography on silica gel using 5% EtOAc / hexane as eluent. 1 H NMR (400 MHz CDCl 3) d (ppm: 7.5-7.3 (m, 5H), 6.98 (d, 1 H), 6.9 (d, 2H), 6.74 (d, 2H), 6.7-6.6 (three d, 5H ) 5.5 (d, J = 2.3 Hz, 1 H), 5.1 (s, 2H), 4.74 (br s, 1 H), 4.32 (d, J = 2.4 Hz, 1 H), 2.79 (m, 2H) 1.22 (m, 3H), 1.1 (dt, 21 H); S m / z 628.5 (M ++ 1).

EXAMPLE 54 Preparation of Following the procedure detailed in Example 44 and using the ketone derived from Example 24, the desired product was obtained after purification by chromatography on silica gel using 5% EtOAc / hexane as eluent. 1 H NMR (400 MHz, CDCl 3) d (ppm): 7.5-7.3 (m, 10H), 6.84 (d, 2H), 6.78 (d, 2H), 6.66 (two d, 4H), 6.38 (s, 2H) , 5.48 (d, J = 2.1 Hz, 1 H), 5.14 (s, 2H), 5.0 (q, 2H), 4.76 (br s, 1 H), 4.32 (d, J = 2.1 Hz, 1 H), 1.22 (m, 3H), 1.1 (d, 18H).

EXAMPLE 55 Preparation of Following the procedure detailed in Example 44 and using the derivatized ketone obtained from Example 25, the desired product was obtained after purification by chromatography on silica gel using 5% EtOAc / hexane as eluent. 1 H NMR (400 MHz, CDCl 3) d (ppm): 7.5-7.32 (m, 5H), 7.2-7.1 (m, 4H), 6.9-6.82 (m, 4H), 6.76-6-7 (m, 4H) , 5.56 (d, 1 H), 5.06 (br q, 2H), 4.36 (d, 1 H), 1.22 (m, 3H), 1.1 (d, 18H).

EXAMPLE 56 Following the procedure detailed in Example 44, with the exception that the reaction was run at 0 ° C for three hours, and using 1.7 g (2.83 mmol) of the derived ketone obtained from Example 26, the desired product was obtained after Purification by chromatography on silica gel using 5% EtOAc / hexane as eluent. 1 H NMR (400 MHz, CDCl 3) d (ppm): 7.5-7.34 (m, 5H), 7.2-7.1 (m, 3H), 6.94 (d, 1 H), 6.9-6.82 (m, 5H), 6.4 ( m, 3H), 5.48 (d, J = 1.9 Hz, 1 H), 5.05 (s, 2H), 4.36 (d, J = 1 .9 Hz, 1 H), 1.22 (m, 3H), 1.1 (d) , 18H).

EXAMPLE 57 Preparation of Following the procedure detailed in Example 44 and using the derivatized ketone obtained from Example 27, the desired product was obtained, which was subsequently desilylated using the procedure described in Example 71 (Step C). The desired product was obtained as an oil after purification by chromatography on silica gel using 15% EtOAc / hexane as eluent. 1 H NMR (400 MHz, CDCl 3) d (ppm): 7.5-7.32 (m, 5H), 7.09 (d, 1 H), 6.9-6.8 (m, 6H), 6.73-6.7 (m, 4H), 5.52 ( d, 1 H), 5.04 (br q, 2H), 4.34 (d, 1 H), 1.22 (m, 3H), 1.1 (d, 18H).

EXAMPLE 58 Following the procedure detailed in Example 44 and using the ketone derived from Example 28, the desired product was obtained after purification by chromatography on silica gel using 5% EtOAc / hexane as eluent. 1 H NMR (500 MHz, CDCl 3) d (ppm): 7.5-7.3 (m, 5H), 7.22-7.10 (m, 3H), 6.90-6.80 (2d, 4H), 6.75 (d, 2H), 6.55 (d , 2H), 5.55 (d, J = 2.1 Hz, 1 H), 5.05 (d, 2H), 4.40 (d, J = 2.1 Hz, 1 H), 1.22 (m, 3H), 1 .1 ( d 18H).

EXAMPLE 59 Following the procedure detailed in Example 44 and using the ketone derived from Example 29, the desired product was obtained after purification by chromatography on silica gel using 5% EtOAc / hexane as eluent. 1 H NMR (500 MHz, CDCl 3) d (ppm): 7.5-7.3 (m, 5H), 7.22-7.10 (m, 3H), 6.90-6.80 (2d, 4H), 6.73 (d, 2H), 6.64 (d , 2H), 5.50 (d, J = 2.1 Hz, 1 H), 5.05 (d, 2H), 4.43 (d, J = 2.2 Hz, 1 H), 1.23 (m, 3H), 1.10 (d, 18H) .

EXAMPLE 60 Preparation of Following the procedure detailed in Example 44 and using the ketone derived from Example 30, the desired product was obtained after purification by chromatography on silica gel using 5% EtOAc / hexane as eluent. 1 H NMR (500 MHz, CDCl 3) d (ppm): 7.5-7.3 (m, 5H), 6.82 (d, 2H), 6.68 (d, 2H), 6.64 (d, 2H), 6.62 (d, 2H), 6.46 (d, 2H), 5.44 (d, J = 1.9 Hz, 1 H), 5.02 (d, 2H), 4.30 (d, J = 2.0 Hz, 1 H), 1.22 (m, 3H), 1 .10 (d, 18H); MS m / z 618 (M ++ 1).

EXAMPLE 61 Preparation of Following the procedure detailed in Example 44 and using the ketone derived from Example 31, the desired product was obtained after purification by chromatography on silica gel using 5% EtOAc / hexane as eluent. 1 H NMR (400 MHz, CDCl 3) d (ppm: 7.5-7.3 (m, 5 H), 6.86 (d, 1 H), 6.82 (d, 2 H), 6.76 (d, 2 H), 6.70 (d, 1 H) , 6.67 (d 2H), 6.65 (d, 2H), 5.44 (d, J = 2.0 Hz, 1 H), 5.04 (s, 2H), 4.38 (d, J = 1.9 Hz, 1 H), 1.23 (m 3H), 1.10 (d, 18H), MS m / z 634 (M ++ 1).

EXAMPLE 62 Preparation of Following the procedure detailed in Example 44 and using the ketone derived from Example 32, the desired product was obtained after purification by chromatography on silica gel using 5% EtOAc / hexane as eluent. 1 H NMR (500 Hz, CDCl 3) d (ppm): 7.5-7.3 (m, 5H), 6.94 (d, 1 H), 6.85 (d, 2H), 6.80 (d, 2H), 6.74 (dd, 2H) , 6.65 (m, 4H), 5.43 (d, J = 2.1 Hz, 1 H), 5.05 (d, 2H), 4.30 (d, J = 2.1 Hz, 1 H), 1.23 (m, 3H), 1.10 ( d, 18H).

EXAMPLE 63 Preparation of Following the procedure detailed in Example 44 and using the ketone derived from Example 33, the desired product was obtained after purification by chromatography on silica gel using 5% EtOAc / hexane as eluent. 1 H NMR (500 MHz, CDCl 3) d (ppm): 7.5-7.3 (m, 5H), 6.88 (s, H), 6.84 (d, 2H), 6.82 (d, 2H), 6.70 (d, 2H), 6.68 (d, 2H), 6.66 (s, 1 H), 5.50 (d, 1 H), 5.05 (s, 2H), 4.43 (d, 1 H), 2.35 (s, 3H), 1.23 (m, 3H) ), 1.10 (d, 18H).

EXAMPLE 64 Preparation of Following the procedure detailed in Example 44 and using the ketone derived from Example 34, the desired product was obtained after purification by chromatography on silica gel using 5% EtOAc / hexane as eluent. 1 H NMR (500 MHz, CDCl 3) d (ppm): 7.5-7.3 (m, 5H), 7.24 (s, 1 H), 7.20 (s, 1 H), 6.82 (d, 2 H), 6.68 (d, 2 H) ), 6.64 (m, 4H), 5.44 (d, J = 2.0 Hz, 1 H), 5.05 (d, 2H), 4.28 (d, J = 2.3 Hz, 1 H), 1.23 (m, 3H), 1.10 (d, 18H).

EXAMPLE 65 Preparation of Following the procedure detailed in Example 44 and using the ketone derived from Example 35, the desired product was obtained after purification by chromatography on silica gel using 5% EtOAc / hexane as eluent. 1 H NMR (500 MHz, CDCl 3) (ppm): 7.5-7.3 (m, 5H), 7.05-7.20 (m, 4H), 6.90 (d, 2H), 6.88 (d, 2H), 6.78 (d, 2H) , 6.70 (d, 1 H), 6.65 (d, 1 H), 5.30 (d, J = 1.8 Hz, 1 H), 5.05 (d, 2H), 4.20 (d, J = 2.3 Hz, 1 H), 1.2 (m, 3H), 1.10 (d, 18H).

EXAMPLE 66 Preparation of Following the procedure detailed in Example 44 and using the ketone derived from Example 36, the desired product was obtained after purification by chromatography on silica gel using 5% EtOAc / hexane as eluent. 1 H NMR (500 MHz, CDCl 3) d (ppm): 7.5-7.3 (m, 5H), 7.05-7.20 (m, 2H), 7.10 (m, 2H), 6.98 (d, 2H), 6.88 (m, 2H ), 6.80 (m, 1 H), 6.60 (d, 1 H), 5.56 (d, J = 1.8 Hz, 1 H), 5.05 (d, 2 H), 4.44 (d, J = 2.3 Hz, 1 H), 1.23 (m, 3H), 1.10 (d, 18H).

EXAMPLE 67 Following the procedure detailed in Example 44 and using the ketone derived from Example 37 (1), the desired product was obtained after purification by chromatography on silica gel using 5% EtOAc / hexane as eluent. 1 H NMR (500 MHz, CDCl 3) 5 (ppm): 7.55 (d, 2 H), 7.45 (t, 2 H), 7.35 (t, 1 H), 7.20 (d, 1 H), 7.15 (m, 3 H), 6.88 (d, 2H), 6.84 (d, 3H), 6.78 (d, 2H), 5.46 (d, J = 2.1 Hz, 1 H), 5.15 (s, 2H), 4.39 (d, J = 2.1 Hz, 1 H), 1.23 (m, 3H), 1.10 (d, 18H).

EXAMPLE 68 Preparation of Following the procedure detailed in 44 and using the ketone derived from Example 37 (H), the desired product was obtained after purification by chromatography on silica gel using 5% EtOAc / hexane as eluent. 1 H NMR (500 MHz, CDCl 3) d (ppm): 7.55 (d, 2 H), 7.45 (t, 2 H), 7.35 (t, 1 H), 7.20 (d, 1 H), 7.15 (t, 2 H), 6.80-6.90 (m, 4H), 6.78 (d, 2H), 6.76 (d, 2H), 5.42 (d, J = 2.1 Hz, 1 H), 5.18 (s, 2H), 4.42 (d, J = 2.1 Hz, 1 H), 1.23 (m, 3H), 1.10 (d, 18H).

EXAMPLE 69 Preparation of Following the procedure detailed in Example 44 and using the ketone derived from Example 38, the desired product was obtained after purification by chromatography on silica gel using 5% EtOAc / hexane as eluent. 1 H NMR (500 MHz, CDCl 3) 5 (ppm): 7.36-7.50 (m, 5H), 6.96 (d, 2H), 6.80-6.90 (m, 4H), 6.70-6.78 (m, 5H), 5.42 (d , J = 2.1 Hz, 1 H), 5.18 (s, 2H), 4.38 (d, J = 2.1 Hz, 1 H), 1.23 (m, 3H), 1.10 (d, 18H).

EXAMPLE 70 Qulral separation of Each enantiomer of the racemic dihydrobenzoxathine, obtained from Example 62, was obtained by means of chiral chromatography using a Chiralpak AD column, with 30% isopropanol in hexane as the eluent. The fast mobile isomer: [a] D = + 18.44 ° (c = 0.725, MeOH). The slow mobile isomer: [] D- -18.85 ° (c = 0.74, MeOH).

EXAMPLE 71 General preparation of THIINS Preparation of Step AA a stirred solution of a mixture of dihydrobenzoxathine (60 mg, 0.1 mmol), obtained from Example 48 (which was dried by the azeotropic method before use), triphenylphosphine (157 mg, 0.6 mmol), and 1-piperidine ethanol (0.08 mL, 0.6 mmol) in 4 mL of anhydrous THF at 0 ° C, 0.1 18 mL (0.6 mmol) of dlisopropyl azodicarboxylate (DIAD) was added dropwise during 0.2 hours. The resulting pale yellow solution was stirred at room temperature for 2-3 hours. The volatiles were removed in vacuo and the residue was purified by flash chromatography (EtOAc / hexane = 1: 5, followed by 2-3% MeOH / dichloromethane) to give the desired product. 1 H NMR (400 MHz, CDCl 3) d (ppm): 7.5-7.34 (m, 5H), 7.08 (d, 1 H), 6.86 (d, 2H), 6.78-6.64, (m, 8H), 5.5 (d , 1 H), 5.01 (br q, 2 H), 4.3 (d, 1 H), 4.2 (t, 2 H), 2.75 (t, 2 H), 2.5 (br s, 4 H), 1 .6 (m, 4 H) ), 1.48 (m, 2H), 1.22 (m, 3H), 1.1 (d, 18H); MS m / z 712.4 (M ++ 1).

Step BA a stirred solution of the adduct (71 mg, 0.098 mmol), generated in Step A, in 2 mL of EtOH / EtOAc / H20 (7: 2: 1), was added 13 mg (1.2 eq) of palladium black and ammonium formate (62 mg, 10 eq). The resulting mixture was heated to 80 ° C and observed by CCD. After 3 hours, the reaction mixture was cooled to room temperature, filtered through a pad of celite to remove the catalyst, and the filtrate was partitioned between water and EtOAc. The organic phase was separated, dried over MgSO4 and concentrated in vacuo to give the desired product. 1 H NMR (400 MHz, CDCl 3) S (ppm): 7.01 (d, 1 H), 6.8 (d, 2 H), 6.75 (d, 2 H), 6.66 (two d, 4 H), 6.54 (dd, 1 H) , 6.5 (d, 1 H), 5.45 (d, J = 2.3 Hz, 1 H), 4.28 (d, J = 2.3 Hz, 1 H), 4.08 (t, 2H), 2.8 (t, 2H), 2.6 (br s, 4H), 1.68 (m, 4H), 1.5 (m, 2H), 1.22 (m, 3H), 1 .1 (d, 18H).

Step C To a stirred solution of a mixture of the debenzylated product generated in Step B and HOAc (10 eq) in mL of THF was added a solution of tetrabutylammonium fluoride (3 eq) in THF at room temperature. The resulting solution was allowed to stir for two hours at room temperature and then was poured into saturated aqueous NaHCO3 and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered, and evaporated. Purification by chromatography on silica gel using 5-7% MeOH in methylene chloride as eluent provided the desired product. H NMR (400 MHz CD3OD) d (ppm): 6.95 (d, 2H), 6.92 (d, 1H), 6.78 (d, 2H), 6.71 (d, 2H), 6.48 (d, 2H), 6.47 ( d, 1 H), 6.44 (dd, 1 H), 5.47 (d, J = 2.1 Hz, 1 H), 4.37 (d, J = 2.1 Hz, 1 H), 4.1 (t, 2H), 2.85 (t , 2H), 2.65 (br s, 4H), 1.66 (m, 4H), 1.5 (m, 2H).

EXAMPLE 72 Preparation of Step A: Using the procedure described in Example 71 (Step A), the dihydrobenzoxathine obtained from Example 53 was coupled with 1-piperidine ethanol. After purification by chromatography on silica gel, using 3% MeOH / CH 2 Cl 2 as eluent, the desired adduct was obtained. 1H NMR (400 MHz, CDCl3) d (ppm): 6.98 (d, 1H), 6.92 (d, 2H), 6.74 (two d, 4H), 6.65 (d, 1H), 6.62 (d, 2H) , 5.5 (d, 1 H), 5.1 (s, 2H), 4.31 (d, 1 H), 4.09 (m, 2H), 2.75 (t, 2H), 2.55 (m, 2H), 2.5 (m, 4H) ), 1.6 (m, 4H), 1.45 (m, 2H), .22 (m, 3H), 1.1 (m, 21 H).

Step B: The adduct generated in Step A was debonded using the procedure described in Example 71 (Step B) to give the desired product. 1H NMR (400 MHz, CDCl3) d (ppm): 6.92 (d, 1H), 6.89 (d, 2H), 6.72 (d & d, 4H), 6.62 (d, 2H), 6.5 (d, 1 H), 5.5 (d, J = 2.2 Hz, 1 H), 4.3 (d, J = 2.2 Hz, 1 H), 4.1 (m, 2 H), 2.8 (t, 2 H), 2.68 (m, 2 H), 2.58 (br s, 4H), 1.64 (m, 4H), 1.48 (m, 2H), .2 (m, 3H), 1.09 (d and m, 21 H).

Step C: The debenzylated product from Step B was desilylated using the procedure described in Example 71 (Step C). The desired product was obtained as a white solid. 1H NMR (400 MHz, CD3OD) d (ppm): 7.0 (d, 2H), 6.79 (d, 2H), 6.76 (d, 1H), 6.71 (d, 2H), 6.47 (d, 3H), 5.46 (d, J = 2.2 Hz, 1 H), 4.38 (d, 1 H), 4.08 (t, 2H), 2.8 (t, 2H), 2.5 (m, 2H), 2.6 (m, 4H), 1.62 ( m, 4H), 1.5 (m, 2H), 1.1 (t, 3H); MS miz 493.2 (M ++ 1).

EXAMPLE 73 Preparation of Step A The dihydrobenzoxathine obtained from Example 45 was coupled with 1-piperidinetanol using the procedure described in Example 71 (Step A). After purification by chromatography on silica gel using 3% MeOH / CH2Cl2 as eluent, the desired adduct was obtained. 1H NMR (400 MHz, CDCl3) 6 (ppm): 7.14-6.92 (m, 4H), 6.8 (d, 2H), 6.76 (d, 2H), 6.72 (d, 2H), 6.64 (d, 2H), 5.48 (d, J = 2.2 Hz, 1 H), 4.34 (d, J = 2.1 Hz, 1 H), 4.1 (m, 2H), 2.85 (m, 2H), 2.6 (m, 4H), 1.65 (m , 4H), 1.5 (m, 2H), 1.22 (m, 3H), 1.1 (d, 18H).

Step B The adduct from Step A was desilylated using the procedure described in Example 71 (Step C). The desired product was obtained as a white solid. 1 H NMR (400 MHz CD 3 OD) 5 (ppm): 7.14-6.92 (m, 4 H), 6.06 (d, 2 H), 6.78 (d, 2 H), 6.72 (d, 2 H), 6.48 (d, 2 H), 5.48 (d, J = 2.1 Hz, 1 H), 4.44 (d, 1 H), 4.1 (t, 2 H), 2.78 (t, 2 H), 2.58 (br s, 4 H), 1 .64 (m, 4 H) , 1.5 (m, 2H): MS m / z 450.2 (++ 1).

EXAMPLE 74 Preparation of Step A The dihydrobenzoxathine obtained from Example 46 was coupled with 1-piperidlnetanol using the procedure described in Example 71 (Step A). After purification by chromatography on silica gel with 3% MeOH / CH 2 Cl 2, the desired adduct was obtained as an oil. 1 H NMR (400 MHz, CDCl 3) 5 (ppm): 7.14-6.94 (m, 4H), 6.96 (d, 2H), 6.84 (two d, 4H), 6.66 (d, 2H), 5.5 (d, J = 2.1 Hz, 1 H), 5.12 (s, 2H), 4.5 (d, J = 2.1 Hz, 1 H), 4.04 (t, 2H), 3.42 (s, 3H), 2.75 (t, 2H), 2.55 ( br s, 4H), 1.6 (m, 4H), 1.48 (m, 2H); MS m / z 495.2 (M ++ 1).

Step B The adduct (10 mg, 0.02 mmol) from Step A was deprotected with TFA (10eq) and eOH (6eq) in CH2Cl2 at room temperature to provide the desired product. 1H NMR (400 MHz, CD3OD) d (ppm): 7.14-6.92 (m, 4H), 6.84 (two d, 4H), 6.66 (d, 2H), 6.6 (d, 2H), 5.45 (d, J = 2.2 Hz, 1 H), 4.45 (d, J = 2.2 Hz, 1 H), 4.05 (t, 2 H), 2.8 (t, 2 H), 2.6 (br s, 4 H), 1.6 (m, 4 H), 1.5 (m, 2H); MS m / z 450.2 (++ 1).

EXAMPLE 75 Preparation of The derived dloxane obtained from Example 47 was coupled with 1-piperidinetanol using the procedure described in Example 71 (Step A) to give the product. H NMR (400 MHz, CD3OD) d (ppm): 7.04 (d, 2H), 6.98-6.84 (m, 4H), 6.82 (d, 2H), 6.74 (d, 1 H), 6.63 (d, 2H) , 6.56 (d, 2H), 5.36 (d, 1 H), 5.33 (d, J = 3.0 Hz, 1 H), 4.02 (m, 2H), 2.8 (m, 2H), 2.6 (br s, 4H) , 1.62 (m, 4H), 1.5 (m, 2H); MS m / z 432 (M +).

EXAMPLE 76 Preparation of Step A The dihydrobenzoxathine generated from Example 49 was desilylated using the procedure described in Example 71 (Step C). The desired product was obtained as a white solid. 1 H NMR (400 MHz, CDCl 3) d (ppm): 7.5-7.3 (m, 5H), 7.2 (d, 1 H), 6.9 (d, 2H), 6.88 (d, 2H), 6.68 (m, 6H) , 5.53 (d, J = 2.2 Hz, 1 H), 4.33 (d, J = 2.3 Hz, 1 H), 3.75 (s, 3H).

Step B: The desilylated product obtained from Step A was coupled with 1-piperidineethanol using the procedure described in Example 71 (Step A). After purification by chromatography on silica gel with 3% MeOH / CH2Cl2, the desired adduct was obtained. 1 H NMR (400 MHz, CDCl 3) d (ppm): 7.5-7.3 (m, 5H), 7.08 (d, 1 H), 6.9 (d, 2H), 6.84 (d, 2H), 6.76 (d, 2H) , 6.66 (m, 4H), 5.52 (d, 1 H), 5.03 (s, 2H), 4.32 (d, 1 H), 4.06 (t, 2H), 3.75 (s, 3H), 2.75 (1, 2H) ), 2.5 (br s, 4H), 1.6 (m, 4H), 1.45 (m, 2H).

Step C: The adduct generated in Step B was debenzylated using the procedure described in Example 71 (Step B) to give the product. 1 H NMR (400 MHz, CD 3 OD) d (ppm): 6.96 (d, 2 H), 6.92 (d, 1 H), 6.82 (d, 2 H), 6.78 (d, 2 H), 6.63 (d, 2 H), 6.48 (dd, 1 H), 6.44 (d, 1 H), 5.5 (d, J = 2.2 Hz, 1 H), 4.42 (d, J = 2.2 Hz, 1 H), 4.08 (t, 2H), 3.68 ( s, 3H), 2.78 (t, 2H), 2.59 (br s, 4H), 1.6 (m, 4H), 1.48 (m, 2H); MS m / z 479.4 (M ++ 1).

EXAMPLE 77 Preparation of Step A The dihydrobenzoxathine obtained from Example 50 was coupled with 1-piperidinetanol using the procedure described in Example 71 (Step A). After purification by chromatography on silica gel with 3% MeOH / CH2Cl2) the desired adduct was obtained. 1 H NMR (400 MHz, CDCl 3) d (ppm): 6.83 (d, 2 H), 6.75 (d, 2 H), 6.69 (d, 2 H), 6.62 (d, 2 H), 6.5 (d, 1 H) , 6.48 (d, 1 H), 5.42 (br s, 1 H), 4.3 (br s, 1 H), 4.06 (t, 2H), 2.78 (t, 2H), 2.5 (br s, 4H) , 1.6 (m, 4H), 1.44 (m, 2H), 1.22 (m, 3H), 1.1 (d, 18H).

Step B The adduct generated in Step A was debenzylated using the procedure described in Example 71 (Step B).

Step C The debenzylated product of Step B was desilylated using the procedure described in Example 71 (Step C). The desired product was obtained as a white solid. 1 H NMR (400 MHz, CD 3 OD) d (ppm): 6.94 (d, 2 H), 6.76 (d, 2 H), 6.7 (d, 2 H), 6.49 (d, 2 H), 6.4 (d, 1 H), 6.32 (d, 1 H), 5.43 (d, J = 2.3 Hz, 1 H), 4.4 (d, J = 2.3 Hz, 1 H), 4.08 (t, 2H), 2.8 (t, 2H), 2.6 (brs) , 4H), 2.18 (s, 3H), 1.64 (m, 4H), 1.5 (m, 2H): MS m / z 479.2 (M ++ 1).

EXAMPLE 78 Preparation of Step A The dihydrobenzoxathine obtained from Example 51 was coupled with 1-pperidineethanol using the procedure described in Example 71 (Step A). After purification by chromatography on silica gel with 3% MeOH / CH2Cl2, the desired adduct was obtained.

Step B The adduct generated in Step A was debenzylated using the procedure described in Example 71 (Step B). After purification by chromatography on silica gel using 5% MeOH / CI-bCb as the eluent, the desired product was obtained as an oil. 1 H NMR (400 Hz. CDCl 3) d (ppm): 6.9 (d, 2 H), 6.89 (d, 1 H), 6.73 (m, 4 H), 6.62 (d, 2 H), 6.52 (d, 1 H), 5.5 (d, 1 H), 4.3 (d, 1 H), 4.1 (br s, 2 H), 2.8 (br t, 2 H), 2.6 (br s, 4 H), 2.2 (s, 3 H), 1.6 (m , 4H), 1.5 (m, 2H), 1.22 (m, 3H), 1.1 (d, 18H).

Step C The debenzylated product of Step B was desilylated using the procedure described in Example 71 (Step C). The desired product was obtained as a white solid. 1 H NMR (400 MHz, CD 3 OD) d (ppm): 7.02 (d, 2 H), 6.76 (d, 2 H), 6.7 (d, 2 H), 6.47 (two d, 3 H), 5.48 (d, J = 2.3 Hz , 1 H), 4.38 (d, J = 2.3 Hz, 1 H), 4.1 (t, 2H), 2.8 (t, 2H), 2.6 (br s, 4H), 2.1 (s, 3H), 1 .6 (m, 4H), 1.5 (m, 2H); MS m / z 479.2 (M ++ 1).

Step A The dihydrobenzoxathine obtained from Example 53 was coupled with 1-piperidinetanol using the procedure described in Example 71 (Step A). After purification by chromatography on silica gel with 3% eOH / CH2Cl2, the desired adduct was obtained.

Step C The debenzylated product from Step B was stripped using the procedure described in Example 71 (Step C). The desired product was obtained as a white solid after chromatography on silica gel with 5% MeOH / CH 2 Cl 2 as eluent. 1 H NMR (400 MHz, CD 3 OD) d (ppm): 6.94 (d, 2 H), 6.76 (d, 2 H), 6.7 (2 H, d), 6.48 (d, 2 H), 6.41 (d, 1 H), 6.3 (d, 1 H), 5.44 (d, J = 2.2 Hz, 1 H), 4.4 (d, J = 2.2 Hz, 1 H), 4.08 (t, 2 H), 2.8 (t, 2 H), 2.62 (br s, 4H), 2.6 (q, 2H), 1.6 (m, 4H), 1.45 (m, 2H), 1.2 (t, 3H); MS m / z 493.2 (M ++ 1).

EXAMPLE 80 Preparation of Step A The dihydrobenzoxatin obtained from Example 54 was coupled with 1-piperidinetanol using the procedure described in Example 71 (Step A). After purification by chromatography on silica gel with 3% MeOH / CH2Cl2, the desired adduct was obtained. H NMR (400 MHz, CDCl 3) d (ppm): 7.5-7.3 (m, 10H), 6.86 (d, 2h), 6.78 (d, 2H), 6.74 (d, 2H), 6.64 (d, 2H), 6.38 (s, 2H), 5.48 (d, 1 H), 5.14 (s, 2H), 5.02 (q, 2H), 4.32 (d, 1 H), 4.08 (t, 2H), 2.8 (t, 2H) , 2.5 (br s, 4H), 1.62 (m, 4H), 1.5 (m, 2H), 1.22 (m, 3H), 1.1 (d, 18H).

Step B The adduct generated in Step A was debenzylated using the procedure described in Example 71 (Step B). After purification by chromatography on silica gel using 5% MeOH / CH2Cl2 as eluent, the desired product was obtained as an oil.

Step C The debenzylated product of Step B was desilylated using the procedure described in Example 71 (Step C). The desired product was obtained as a white solid. 1 H NMR (400 MHz, CD 3 OD) d (ppm): 6.94 (d, 2 H), 6.78 (d, 2 H), 6.72 (d, 2 H), 6.5 (d, 2 H), 6.06 (d, 1 H), 6.02 (d, 1 H), 5.42 (d, J = 2.2 Hz, 1 H), 4.33 (d, J = 2.2 Hz, 1 H), 4.09 (t, 2 H), 2.8 (t, 2 H), 2.6 (br s, 4H), 1.64 (m, 4H), 1.5 (m, 2H); MS m / z 482.2 (M ++ 1).

Step A The dihydrobenzoxathine generated from Example 55 was desilylated using the procedure described in Example 71 (Step C). The desired product was obtained as a white solid. 1 H NMR (400 MHz, CDCl 3) d (ppm: 7.48-7.32 (m, 5H), 7.2-7.1 (m, 4H), 6.94-6.84 (two d, 4H), 6.7 (m, 4H), 5.56 (d, J = 2.1 Hz, 1 H), 5.04 (br q, 2 H), 4.74 (s, 1 H), 4.37 (d, J = 2.1 Hz, 1 H).

Step B The desilllated product obtained from Step A was coupled with 1-piperidinetanol using the procedure described in Example 71 (Step A). After purification by chromatography on silica gel with 3% MeOH / CH2Cl2, the desired adduct was obtained. 1 H NMR (400 MHz, CDCl 3) d (ppm): 7.5-7.32 (m, 5H), 7.2-7.04 (m, 4H), 6.94-6.86 (m, 4H), 6.76-6.66 (m, 4H), 5.54 (br s, 1 H), 5.04 (br s, 2 H), 4.38 (br s, 1 H), 4.06 (t, 2H), 2.76 (t, 2H), 2.5 (br s, 4H), 1.6 (m , 4H), 1.42 (m, 2H).

Step C The adduct generated in Step B was debenched using the procedure described in Example 71 (Step B) to provide the desired product. 1 H NMR (400 MHz, CD 3 OD) d (ppm): 7.2-7.14 (m, 3 H), 6.94 (m, 3 H), 6.9 (d, 2 H), 6.74 (d, 2 H), 6.48 (dd, 1 H) , 6.45 (d, 1 H), 5.53 (d, J = 23 Hz, 1 H), 4.46 (d, 1 H), 4.06 (t, 2 H), 2.78 (t, 2 H), 2.58 (br s, 4 H ), 1.62 (m, 4H), 1.5 (m, 2H); MS m / z 449.2 (M ++ 1).

EXAMPLE 82 Preparation of Step A The dihydrobenzoxathine generated from Example 56 was desilylated using the procedure described in Example 71 (Step C). The desired product was obtained as a white solid. 1 H NMR (400 MHz, CDCl 3) d (ppm): 7.5-7.3 (m, 5H), 7.2-7.1 (m, 3H), 6.96 (m, 2H), 6.92 (d, 1 H), 6.88 (d, 2H), 6.84 (d, 1 H), 6.74 (dd, 1 H), 6.66 (d, 2H), 5.48 (d, J = 2.1 Hz, 1 H), 5.04 (s, 2H), 4.37 (d, J = 2.1 Hz, H); MS m / z 428.2 (M ++ 1).

Step B The unraved product of Step A was coupled with 1-piperidineethanol using the procedure described in Example 71 (Step A). After purification by chromatography on silica gel with 3% MeOH / CH2Cl2, the desired adduct was obtained.

Step C: The adduct generated in Step B was debenzylated using the procedure described in Example 71 (Step B) to provide the desired product. 1 H NMR (400 MHz, CD 3 OD) d (ppm): 7.14-7.02 (m, 3 H), 6.92 (m, 4 H), 6.8 (d, 1 H), 6.74 (d, 2 H), 6.58 (d, 1 H ), 6.51 (dd, 1 H), 5.42 (br s, 1 H), 4.45 (br s, 1 H), 4.06 (t, 2H), 2.78 (t, 2H), 2.55 (br s, 4H), 1.6 (m, 4H), 1.5 (m, 2H); MS m / z 449.2 (M ++ 1).

EXAMPLE 83 Preparation of Step A To a well-stirred solution of the dihydrobenzoxathine (30 mg, 0.061 mmol) prepared from Example 74 (Step A), was added 5 equivalents of meta-chloroperbenzoic acid (m-CPBA) in methylene chloride at 0 ° C. The ice bath was stirred and the reaction mixture was stirred at room temperature for three hours. The reaction mixture was quenched with a saturated solution of NaHS03 and stirred for an additional 30 minutes. The aqueous layer was extracted with EtOAc and the organic layer was washed with brine, dried with MgSO 4, and evaporated to give a residue which was used during the next step without further purification. H NMR (400 MHz, CD3OD) d (ppm): 7.82 (dd, 1 H), 7.67 (dt, 1 H), 7.28 (m, 2H), 7.2 (d, 2H), 7.03 (d, 2H), 6.92 (d, 2H), 6.82 (d, 2H), 6.32 (d, 1 H), 5.12 (s, 2H), 4.84 (d, 1 H), 4.2 (br t, 2H), 3.40 (s, 3H) ), 3.2 (m, 2H), 3.0 (m, 4H), 1.75 (m, 4H), 1.6 (m, 2H).

Step B The MOM protecting group was removed following the procedure detailed in Example 74 (Step B). The desired product was isolated after purification by chromatography on silica gel using 5% MeOH / CH 2 Cl 2 as the eluent. 1 H NMR (400 MHz, CD 3 OD) d (ppm): 7.82 (dd, 1 H), 7.64 (dt, 1 H), 7.26 (m, 2 H), 7.04 (d, 2 H), 6.06 (d, 2 H), 6.76 (d, 2H), 6.65 (d, 2H), 6.24 (d, J = 1.9 Hz, 1 H), 4.71 (d, 1 H), 4.1 (t, 2H), 2.72 (t, 2H), 2.5 (br s, 4H), 1.6 (m, 4H), 1.45 (m, 2H); MS m / z 481.1 (M ++ 1).

EXAMPLE 84 Preparation of H Step A To a well-stirred solution of the dihydrobenzoxathine (60 mg) prepared from Example 73 (Step A) was added 5 equivalents of m-CPBA in CH 2 Cl 2 at 0 ° C. The ice bath was stirred and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was quenched with a saturated solution of NaHS03 and saturated NaHCO3, and stirred for an additional 30 minutes. The aqueous layer was extracted with EtOAc and the combined organic layer was washed with brine and dried with MgSO4. The solvent was removed by evaporation to give an oily residue, which was purified by chromatography on silica gel with 3% MeOH / CH2Cl2 as the eluent to give the crude product. 1 H NMR (400 Hz, CD 3 OD) d (ppm): 7.85 (dd, 1 H), 7.66 (m, 1 H), 7.28 (m, 2 H), 7.12 (d, 2 H), 6.86 (d, 2 H), 6.8 (d, 2H), 6.7 (d, 2H), 6.22 (d, J = 2.1 Hz, 1 H), 4.72 (d, J = 2.3 Hz, 1 H), 4.08 (m, 2H), 2.8 (t , 2H), 2.6 (br s, 4H), 1.6 (m, 4H), 1.5 (m, 2H), 1.22 (m, 3H), 1.1 (d, 18H); MS m / z 637 (M ++ 23).

Step B The silyl protecting group was removed following the procedure detailed in Example 71 (Step C). The desired product was isolated after purification by chromatography on silica gel using 5% MeOH / CH 2 Cl 2 as the eluent. H NMR (400 MHz, CD3OD) d (ppm): 7.81 (dd, 1 H), 7.64 (m, 1 H), 7.35 (m, 2 H), 7.2 (d, 2 H), 6.82 (two d, 4 H) , 6.6 (d, 2H), 6.28 (d, J = 2.2 Hz, 1 H), 4.69 (d, J = 2.2 Hz, 1 H), 4.2 (t, 2H), 3.08 (t, 2H), 2.85 ( br s, 4H), 1.7 (m, 4H), 1.55 (m, 2H).

EXAMPLE 85 Preparation of Step A: Using the procedure of Example 83 (Step A), the dihydrobenzoxathine (20 mg, 0.028 mmol) obtained from Example 71 (Step A), was oxidized by m-CPBA at room temperature. The crude material was used during the next step without further purification. 1 H NMR (400 MHz, CDCl 3) d (ppm): 7.84 (d, H), 7.7-7.4 (m, 5H), 7.02 (d, 2H), 6.88 (dd, 1 H), 6.82 (d, 2H) , 6.76 (two d, 4H), 6.72 (d, 1 H), 6.22 (d, J = 2.2 Hz, 1 H), 5.18 (q, 2H), 4.28 (d, J = 2.1 Hz, 1 H), 4.09 (t, 2H), 2.8 (t, 2H), 2.55 (br s, 4H), .63 (m, 4H), 1.48 (m, 2H), 1.22 (m, 3H), 1.1 (d, 18H) .

Step B: The product from Step A was deblocked using the standard procedure described in Example 71 (Step B) to provide the debenzylated product, which was used without further purification.

Step C The siloyl protecting group was removed following the procedure detailed in Example 71 (Step C). The final product was isolated after purification by chromatography on silica gel using 5% MeOH / CH2Cl2 as the eluent. 1 H NMR (400 MHz, CD 3 OD) d (ppm): 7.62 (d, 1 H), 7.14 (d, 2 H), 6.84 (two d, 4 H), 6.68 (dd, 1 H), 6.6 (d, 2 H) , 6.55 (d, 1 H), 6.22 (d, 1 H), 4.55 (d, J = 2.1 Hz, 1 H), 4.1 (t, 2 H), 2.8 (t, 2 H), 2.6 (br s, 4 H ), 1.64 (M, 4H), 1.5 (M, 2H); MS m / z 496.1 (M ++ 1).

EXAMPLE 86 Preparation of Step AA: a solution of dlhydrobenzoxatin (100 mg, 0.167 mmol) generated from Example 48 in CH2Cl2 was added triethylamine (0.07 ml_), a catalytic amount of α, β-dimethylaminopyridine (DMAP) and acetic anhydride (0.034 ml_, 2 eq) a room temperature. The resulting mixture was stirred for 30 minutes and then emptied over saturated NaHCO 3. The aqueous layer was extracted with CH 2 Cl 2 and then dried over anhydrous Na 2 SO 4. The solvent was evaporated to an oil, which was subjected to chromatography on silica gel with 10% EtOAc / hexane as eluent to give the product. 1 H NMR (400 MHz, CDCl 3) d (ppm): 7.48-7.34 (m, 5 H), 7.08 (d, 1 H), 6.99 (d, 2 H), 6.94 (d, 2 H), 6.76 (d, 2 H) , 6.72-6.67 (m, 4H), 5.56 (d, 1 H), 5.06 (br q, 2H), 4.34 (d, 1 H), 2.3 (d, 3H), 1.22 (m, 3H), 1. 1 (d, 18H).

Step B The silyl protecting group was removed following the procedure detailed in Example 71. (Step C). The desired product was isolated after purification by chromatography on silica gel using 5% MeOH / CH2Cl2 as the eluent. 1 H NMR (400 MHz, CDCl 3) d (ppm): 7.48-7.34 (m, 5H), 7.09 (d, 1 H), 7.04 (d, 2H), 6.98 (d, 2H), 6.78 (d, 2H) , 6.7 (m, 2H), 6.59 (d, 2H), 5.56 (d, 1 H), 5.06 (br q, 2H), 4.74 (s, 1 H), 4.36 (d, 1 H), 2.2 (s) , 3H).

Step C The desilylated product (80 mg, 0.165 mmol) obtained from the Step B was coupled with 1-piperidinetanol using the procedure described in Example 71 (Step A). After purification by chromatography on silica gel with 3% MeOH / CH2Cl2, the desired adduct was obtained. 1 H NMR (400 MHz, CDCl 3) d (ppm): 7.48-7.34 (m, 5H), 7.08 (d, 1 H), 7.04 (d, 2H), 6.98 (d, 2H), 6.82 (d, 2H) , 6.7 (dd, 1 H), 6.68 (d, 1 H), 6.68 (d, 2H), 5.58 (d, J = 2.2 Hz, 1 H), 5.05 (br q, 2H), 4.36 (d, J = 2.2 Hz, 1 H), 4.05 (t, 2H), 2.68 (t, 2H), 2.5 (br, 4H), 2.25 (s, 3H), 1.6 (m, 4H), 1.45 (m, 2H); MS m / z 597.3 (M ++ 1).

Step D To a solution of 10 mg (0.017 mmol) of the adduct, generated from the Step, in anhydrous THF was added four equivalents of a 1.0 M super hydride solution in THF. The resulting mixture was stirred for 2 hours at 0 ° C and then allowed at room temperature (30 minutes). The reaction mixture was hydrolyzed with H ^ O / NaHCOa. The aqueous layer was extracted with EtOAc, the separated organic layer, dried, and evaporated to give an oil, which was used during the next step without further purification.

Step E: The crude product from Step D was deblocked using the standard procedure described in Example 71 (Step B) to provide the final product, after purification by silica gel chromatography using 5% MeOH / CH 2 Cl 2 as the eluent. 1 H NMR (400 MHz, CD 3 OD) d (ppm): 6.92 (d, 1 H), 6.83 (d, 2 H), 6.82 (d, 2 H), 6.65 (d, 2 H), 6.58 (d, 2 H), 6.46 (dd, 1 H), 6.42 (d, 1 H), 5.44 (d, J = 2.1 Hz, 1 H), 4.38 (d, 1 H, J = 2.3 Hz, 1 H), 4.04 (t, 2H) , 2.78 (t, 2H), 2.6 (br s, 4H), 1.6 (m, 4H), 1.5 (m, 2H); MS m / z 465 (M ++ 1).

EXAMPLE 87 Preparation of Step A: The desilylated product obtained from Example 57 was coupled with 1-pieridinetanol using the procedure described in Example 71 (Step A). After purification by chromatography on silica gel with 3% MeOH / CH2Cl2, the desired adduct was obtained.

Step B: The adduct generated in Step A was debenzyzed using the procedure described in Example 71 (Step B) to provide the desired product. 1 H NMR (400 MHz, CD 3 OD) d (ppm): 6.98-6.76 (m, 9 H), 6.5 (dd, 1 H), 6.46 (d, 1 H), 5.52 (d, J = 2.3 Hz, 1 H) , 4.5 (d, 1 H), 4.05 (t, 2H), 2.80 (t, 2H), 2.62 (br s, 4H), 1.62 (m, 4H), 1.5 (m, 2H); MS m / z 466.2 (M +).

EXAMPLE 88 Chiral separation from The racic dihydrobenzoxatlin obtained from Example 81 (Step C) was resolved by means of chiral chromatography on a Chiralpak AD column, using 20% EtOH in hexane as the eluent. The fast mobile isomer: [a] D = + 33.43 ° (c = 1.205, MeOH). The slow mobile isomer: [a] D = -34.2 ° (c = 1.09, MeOH).

EXAMPLE 89 Chiral separation from The racemic dihydrobenzoxathine obtained from Example 82 (Step C) was resolved by means of chiral chromatography on a Chiralpak AD column, using 20% EtOH in hexane as the eluent. The fast mobile isomer: [a] D = + 32.4 ° (c = 1.36, MeOH). The slow mobile isomer: [a] D = -31.3 ° (c = 1 .37, MeOH).

EXAMPLE 90 Preparation of The dihydrobenzoxathine generated from Example 58 was desilylated using the procedure described in Example 71 (Step C). The desired product was obtained as a white solid. 1 H NMR (500 Hz, CDCl 3) d (ppm): 7.5-7.3 (m, 5H), 7.2-7.1 (m, 3H), 6.85 (2d, 4H), 6.68 (d, 2H), 6.55 (d, 2H ), 5.55 (d, 1 H), 5.04 (s, 2H), 4.40 (d, 1 H).

Step B: The desilylated product obtained from Step A was coupled with 1-piperidlnetanol using the procedure described in Example 71 (Step A). After purification by chromatography on silica gel with 3% MeOH / CH2Cl2, the desired adduct was obtained.

Step C A mixture of the adduct (80 mg, 0.144 mmol), generated in Step B, 20 mg of black palladium and 5 drops of AcOH in 4 ml of ethanol, was stirred under a balloon of hydrogen gas and observed by CCD . After 18 hours, the reaction mixture was filtered through a pad of celite to remove the catalyst, and the filtrate was neutralized by the addition of saturated aqueous NaHCO 3 solution and extracted by EtOAc. The organic layer was separated, dried over MgSO4 and concentrated in vacuo to give the desired product. 1 H NMR (500 MHz, CD 3 OD) S (ppm): 7.20-7.02 (m, 3 H), 6.92 (m 4 H), 6.78 (d, 2 H), 6.30 (d, 2 H), 5.55 (d, J = 2.1 Hz , 1 H), 4.50 (d, J = 2.3 Hz, 1 H), 4.06 (t, 2H), 2.78 (t, 2H), 2.55 (br s, 4H), 1.6 (m, 4H), 1.5 (m, 2H); MS m / z 467 (M ++ 1).

EXAMPLE 91 Preparation of Step A The dihydrobenzoxathine generated from Example 59 was desilylated using the procedure described in Example 71 (Step C). The desired product was obtained as a white solid. 1 H NMR (500 MHz, CDCl 3) d (ppm): 7.5-7.3 (m, 5H), 7.2-7.1 (m, 3H), 6.95 (d, 2H), 6.90 (d, 1 H), 6.85 (d, 2H), 6.70 (d, 2H), 6.65 (d, 1 H), 5.50 (d, 1 H), 5.04 (s, 2H), 4.42 (d, 1 H).

Step B: The desilylated product obtained from Step A was coupled with 1-piperidineethanol using the procedure described in Example 71 (Step A). After purification by chromatography on silica gel with 3% MeOH / CH2Cl2, the desired adduct was obtained.

Step C: The adduct, generated in Step B, was debenzylated using the procedure described in Example 71 (Step B) to provide the desired product. HRN (500 MHz, CD3OD) d (ppm): 7.14-7.02 (m, 3H), 6.92 (d, 2H), 6.85 (d, 2H), 6.74 (d, 2H), 6.58 (d, 1 H), 6.41 (d, 1 H), 5.52 (d, J = 2.3 Hz, 1 H), 4.55 (d, J = 2.3 Hz, 1 H), 4.06 (t, 2H), 2.78 (t, 2H), 2.55 ( br s, 4H), 1.6 (m, 4H), 1.5 (m, 2H); MS m / z 483 (M ++ 1).

EXAMPLE 92 Preparation of Step A The dihydrobenzoxathine, obtained from Example 60, was coupled with 1-piperidinetanol using the procedure described in Example 71 (Step A). After purification by chromatography on silica gel with 3% MeOH / CH2Cl2 the desired adduct was obtained. 1 H NMR (500 MHz, CDCl 3) d (ppm): 7.5-7.3 (m, 5H), 6.80 (d, 2H), 6.70 (2d, 4H), 6.60 (d, 2H), 6.40 (2d, 2H), 5.40 (s, 1 H), 4.90 (d, 2H), 4.20 (s, 1 H), 4.08 (t, 2H), 2.8 (t, 2H), 2.5 (br s, 4H), 1.62 (m, 4H) ), 1.5 (m, 2H), 1.22 (m, 3H) 1.1 (d, 18H).

Step B: The adduct, generated in Step A, was debenzylated using the procedure described in Example 71 (Step B).

Step C The debenzylated product of Step B was desilylated using the procedure described in Example 71 (Step C). The desired product was obtained as a white solid. 1 H NMR (500 MHz, CD 3 OD) d (ppm): 6.93 (d, 3 H), 6.78 (d, 2 H), 6.69 (d, 2 H), 6.50 (d, 2 H), 6.28 (m, 1 H), 5.46 (d, J = 1.8 Hz, 1 H), 4.39 (d, J = 2.2 Hz, 1 H), 4.05 (t, 2 H), 2.8 (t, 2 H), 2.6 (br s, 4 H), 1 .64 (m, 4H), 1.5 (m, 2H); MS m / z 482.2 (M ++ 1).

EXAMPLE 93 Step A The dihydrobenzoxathine, obtained from Example 61, was coupled with 1-piperidinetanol using the procedure described in Example 71 (Step A). After purification by chromatography on silica gel with 3% MeOH / CH2Cl2 the desired adduct was obtained. 1 H NMR (500 MHz, CDCl 3) d (ppm): 7.5-7.3 (m, 5H), 6.85 (m, 3H), 6.70 (d, 4H), 6.63 (d, 2H), 6.60 (d, 1 H) , 5.42 (s, 1 H), 5.02 (d, 2H), 4.40 (s, 1 H), 4.08 (t, 2H), 2.8 (t, 2H), 2.5 (br s, 4H), 1.62 (m, 4H), 1.5 (m, 2H), 1.22 (m, 3H) 1.1 (d 18H).

Step B The adduct, generated in Step A, was debenzylated using the procedure described in Example 71 (Step B) to provide the desired product. 1 H NMR (500 MHz, CD 3 OD) d (ppm): 6.82 (d, 2 H), 6.78 (d, H), 6.70 (2 d, 4 H), 6.62 (d, 2 H), 6.58 (d, 1 H), 5.40 (d, 1 H), 4.30 (d, 1 H), 4.06 (t, 2H), 2.78 (t, 2H), 2.55 (br s, 4H), 1.6 (m, 4H), 1.5 (m, 2H); MS m / z 655 (M ++ 1).

Step C The debenzylated product of Step B was desilylated using the procedure described in Example 71 (Step C). The desired product was obtained as a white solid. 1 H NMR (500 MHz, CD 3 OD) d (ppm): 6.92 (d, 2 H), 6.75 (d, 2 H), 6.68 (d, 2 H), 6.60 (d, 1 H), 6.50 (d, 2 H), 6.42 (d, 1 H), 5.42 (d, J = 2.2 Hz, 1 H), 4.42 (d, J = 2.3 Hz, 1 H), 4.07 (t, 2H), 2.78 (t, 2H), 2.55 (br s, 4H), 1.62 (m, 4H), 1.48 (m, 2H); MS m / z 499 (M ++ 1).

EXAMPLE 94 Preparation of Step A: The dihydrobenzoxatlin, obtained from Example 62, was coupled with 1-ppllyldlnetanol using the procedure described in Example 71 (Step A). After purification by chromatography on silica gel with 3% MeOH / CHbC the desired adduct was obtained.

Stage B The adduct. generated in Step A, was debenzyzed using the procedure described in Example 71 (Step B).

Step C The debenzylated product of Step B was desilylated using the procedure described in Example 71 (Step C). The desired product was obtained as a white solid after purification by silica gel chromatography with 5% MeOH / CH2Cl2 as eluent. 1 H NMR (500 MHz, acetone-d 6) d (ppm): 7.04 (d, 2H), 6.90 (dd, 3H), 6.72 (d, 2H), 6.64 (d, 1 H), 6.59 (d, 2H) , 6.57 (dd, 1 H), 5.44 (d, J = 2.3 Hz, 1 H), 4.52 (d, J = 2.1 Hz, 1 H), 4.08 (t, 2H), 2.8 (t, 2H), 2.62 (br s, 4H), 2.6 (q, 2H), 1.6 (m, 4H), 1.45 (m, 2H), 1.2 (t, 2H); S m / z 465 (M ++ 1).

EXAMPLE 95 Preparation of Step A The dihydrobenzoxathine, obtained from Example 63, was coupled with 1-piperidinetanol using the procedure described in Example 71 (Step A). After purification by chromatography on silica gel with 3% MeOH / CH 2 Cl 2; the desired adduct was obtained.

Step C The debenzylated product of Step B was desilylated using the procedure described in Example 71 (Step C). The desired product was obtained as a white solid after purification by chromatography on silica gel with 5% MeOH / CH 2 Cl 2 as eluent. 1 H NMR (500 MHz, acetone-d 6) d (ppm): 7.00 (d, 2H), 6.85 (s, 1 H), 6.80 (d, 2H), 6.78 (d, 2H), 6.59 (d, 2H), 6.52 (s, 1 H), 5.49 (d, J = 2.3 Hz, 1 H), 4.65 (d, J = 2.2 Hz, 1 H), 4.08 (t, 2H), 2.8 (t, 2H) , 2.62 (br s, 4H), 2.6 (q, 2H), 1.6 (m, 4H), 1.45 (m, 2H), 1.2 (t, 2H); MS m / z 479 (M ++ 1).

EXAMPLE 96 Preparation of Step A The dihydrobenzoxathine, obtained from Example 64, was coupled with 1-piperidinetanol using the procedure described in Example 71 (Step A). After purification by chromatography on silica gel with 3% MeOH / CH2Cl2 the desired adduct was obtained. 1 H NMR (500 MHz, CDCl 3) d (ppm): 7.5-7.3 (m, 5H), 7.20 (s, 1 H), 6.85 (d, 2H), 6.70 (2d, 4H), 6.63 (d, 2H), 6.60 (s, 1 H), 5.42 (s, 1 H), 5.02 (q, 2H), 4.30 (s, 1 H), 4.08 (t, 2H), 2.8 (t, 2H), 2.5 ( br s, 4H), 1.62 (m, 4H), 1.5 (m, 2H), 1.22 (m, 3H), 1.1 (d, 18H).

Step B The adduct, generated in Step A, was debenzylated using the procedure described in Example 71 (Step B) to provide the desired product. H NMR (500 MHz, acetone-d 6) d (ppm): 7.10 (s, 1 H), 6.98 (d, 2 H), 6.82 (d, 2 H), 6.78 (d, 2 H), 6.70 (d, 2 H) , 6.68 (s, 1 H), 5.50 (d, 1 H), 4.50 (d, 1 H), 4.06 (t, 2H), 2.78 (t, 2H), 2.55 (br s, 4H), 1 .6 (m, 4H), 1.5 (m, 2H).

Step C The debenzylated product of Step B was desilylated using the procedure described in Example 71 (Step C). The desired product was obtained as a white solid. 1 H NMR (500 MHz, acetone-d 6) d (ppm): 7.12 (s, 1 H), 7.02 (d, 2 H), 6.80 (dd, 4 H), 6.69 (s, 1 H), 6.60 (d, 2 H) ), 6.42 (d, 1 H), 5.55 (d, J = 2.3 Hz, 1 H), 4.54 (d, J = 2.1 Hz, 1 H), 4.07 (t, 2H), 2.78 (t, 2H), 2.55 (br s, 4H), 1.62 (m, 4H), 1.48 (m, 2H); MS m / z 499 (M ++ 1).

EXAMPLE 97 Preparation of Step A The dihldrobenzoxatin generated from Example 65 was desilylated using the procedure described in Example 71 (Step C). The desired product was obtained as a white solid. 1 H NMR (500 MHz, CDCl 3) d (ppm): 7.5-7.3 (m, 5H), 7.2-7.1 (m, 5H), 6.95 (m, 3H), 6.64-6.70 (m, 2H), 5.46 (d , J = 1.8 Hz, 1 H), 5.04 (s, 2H), 4.42 (d, J = 2.0 Hz, 1 H).

Step B The frayed product obtained from Step A was coupled with 1-piperidineethanol using the procedure described in Example 71 (Step A). After purification by chromatography on silica gel with 3% MeOH / CH2Cl2, the desired adduct was obtained.

Step C The adduct, generated in Step B, was debenzylated using the procedure described in Example 71. (Step B) to provide the desired product. 1H RN (500 MHz, CD3OD) d (ppm: 7.00-7.12 (m, 6H), 6.90 (d, 2H), 6.75 (d, 2H), 6.42 (s, 1 H), 5.42 (d, J = 2.1 Hz, 1 H), 4.48 (d, J = 2.3 Hz, 1 H), 4.06 (t, 2H), 2.78 (t, 2H), 2.55 (br s, 4H), 1.6 (m, 4H), 1.5 ( m, 2H); MS m / z 463 (M ++ 1).

Step A The dihydrobenzoxatin generated from Example 66 was desilylated using the procedure described in Example 71 (Step C). The desired product was obtained as a white solid. 1 H NMR (500 MHz. CDCl 3) d (ppm): 7.5-7.3 (m, 5H), 7.2-7.1 (m, 3H), 6.95 (d, 2H), 6.92 (d, 2H), 6.90 (d, 1 H), 6.78 (d, 1 H), 6.70 (d, 2H), 5.52 (d, J = 2.1 Hz, 1 H), 5.04 (s, 2H), 4.46 (d, J = 2.2 Hz, 1 H) .

Step C: The adduct, generated in Step B, was debenzylated using the procedure described in Example 71 (Step B) to provide the desired product. 1H RN (500 MHz, CD3OD) d (ppm): 7.05-7.15 (m, 5H), 6.90 (d, 2H), 6.79 (d, 2H), 6.65 (d, 2H), 6.55 (d, 1 H) , 50 (d, J = 2.1 Hz, 1 H), 4.62 (d, J = 2.3 Hz, 1 H), 4.10 (t, 2 H), 2.80 (t, 2 H), 2.60 (br s, 4 H), 1.6 (m, 4H), 1.5 (m, 2H); MS m / z 483 (M ++ 1).

EXAMPLE 99 Preparation of Step A The dihydrobenzoxathine generated from Example 67 was desilylated using the procedure described in Example 71 (Step C). The desired product was obtained as a white solid. H NMR (500 MHz, CDCl 3) d (ppm): 7.5-7.3 (m, 5H), 7.2-7.1 (m, 3H), 7.08 (s, 1 H), 6.95 (d, 2H), 6.86 (m, 3H), 6.70 (d, 2H), 5.42 (d, J = 2.1 Hz, 1 H), 5.14 (s, 2H), 4.40 (d, J = 2.0 Hz, 1 H).

Step B: The desilylated product obtained from Step A was coupled with 1-piperidineethanol using the procedure described in Example 71 (Step A). After purification by chromatography on silica gel with 3% MeOH / CH2Cl2) the desired adduct was obtained.

Step C: The adduct, generated in Step B, was debenzylated using the procedure described in Example 71 (Step B) to provide the desired product. 1 H NMR (500 MHz, CD 3 OD) d (ppm): 7.05-7.15 (m, 3 H), 6.95 (m, 3 H), 6.90 (d, 2 H), 6.75 (d, 2 H), 6.72 (s, 1 H) , 5.45 (d, J = 2.0 Hz, 1 H), 4.52 (d, J = 2.3 Hz, 1 H), 4.10 (t, 2 H), 2.80 (t, 2 H), 2.60 (br s, 4 H), 1.6 (m, 4H), 1.5 (m, 2H); MS m / z 483 (M ++ 1).

EXAMPLE 100 Preparation of Step A The dihydrobenzoxathine generated from example 68 was shuffled using the procedure described in Example 71 (Step C). The desired product was obtained as a white solid. 1 H NMR (500 MHz, CDCl 3) d (ppm): 7.5-7.3 (m, 5H), 7.2-7.1 (m, 3H), 6.92-6.80 (m, 5H), 6.78 (d, 2H), 6.70 (d , 2H), 5.40 (d, J = 2.1 Hz, 1 H), 5.20 (s, 2H) 4.46 (d, J = 2.0 Hz, 1 H).

Step C The adduct, generated in Step B, was debenzyzed using the procedure described in 71 (Step B) to provide the desired product. H NMR (500 MHz, CD3OD) 6 (ppm): 7.05-7.15 (m, 3H), 6.95 (d, 2H), 6.90 (d, 2H), 6.80 (d, 1 H), 6.75 (d, 2H) , 6.70 (d, 1 H), 5.38 (d, J = 1.8 Hz, 1 H), 4.56 (d, J = 2.1 Hz, 1 H), 4.06 (t, 2H), 2.78 (t, 2H), 2.60 (br s, 4H), 1.6 (m, 4H), 1.5 (m, 2H); MS m / z 483 (M ++ 1).

EXAMPLE 101 Chiral separation from The racemic dihydrobenzoxatiin obtained from Example 100 (Step C) was resolved by means of chiral chromatography on a Chiralpak AD column, using 20% EtOH in hexane as the eluent. The fast mobile isomer: [a] D = + 26.09 ° (C = 1.025,? T ??). The slow mobile isomer: [ct] D = -25.44 ° (c = 0.95, MeOH).

EXAMPLE 102 Step A The dihydrobenzoxathine generated from example 69 was broken up using the procedure described in Example 71 (Step C). The desired product was obtained as a white solid. 1 H NMR (500 MHz, CDCl 3) 6 (ppm): 7.5-7.3 (m, 5H), 6.95 (d, 2H), 6.90 (m, 3H), 6.85 (m, 3H), 6.74 (dd, 1 H) , 6.70 (d, 2H), 5.45 (d, J = 1 .9 Hz, 1 H), 5.05 (s, 2H), 4.35 (d, J = 2.1 Hz, 1 H).

Step B The frayed product obtained from Step A was coupled with 1-piperidineethanol using the procedure described in Example 71 (Step A). After purification by chromatography on silica gel with 3% MeOH / CH2Cl2, the desired adduct was obtained, which was used without further purification.

Step C: The adduct, generated in Step B, was debenzylated using the procedure described in Example 71 (Step B) to provide the desired product. 1H RN (500 Hz, CD3OD) d (ppm): 6.98 (d, 2H), 6.94 (m, 2H), 6.80 (m, 5H), 6.60 (d, 1 H), 6.75 (dd, 1 H), 5.40 (d, J = 1.8 Hz, 1 H), 4.50 (d, J = 2.1 Hz, 1 H), 4.08 (t, 2H), 2.78 (t, 2H), 2.60 (br s, 4H), 1.6 ( m, 4H), 1.5 (m, 2H); MS m / z 466 (M ++ 1).

EXAMPLE 103 Chiral preparation of (+) isomer Step A The quick mobile (+) - dihldrobenzoxathine obtained from Example 70 was coupled with 1-piperidinetanol using the procedure described in Example 71 (Step A). After purification by chromatography on silica gel with 3% MeOH / CH2Cl2, the desired adduct was obtained.

Step C: The debenzylated product of Step B was broken up using the procedure described in Example 71 (Step C). The desired product was obtained as a white solid after purification by chromatography on silica gel with 5% MeOH / CH 2 Cl 2 as eluent. H NMR (500 MHz, acetone-d 6) d (ppm): 6.90 (d, 2H), 6.78 (d, H), 6.72 (d, 2H), 6.70 (d, 2H), 6.60 (d, 1 H) , 6.50 (d, 1 H), 6.48 (d, 2H), 5.38 (d, J = 2.0 Hz, 1 H), 4.38 (d, J = 2.3 Hz, 1 H), 4.08 (t, 2H), 2.8 (t, 2H), 2.62 (br s, 4H), 2.6 (q, 2H), 1.6 (m, 4H), 1.45 (m, 2H), 1.2 (t, 2H); MS m / z 465 (M ++ 1); [ct] D = + 27.68 ° (c = 0.49, MeOH).

EXAMPLE 104 Chiral preparation of (-) isomer Step A The (-) - dihydrobenzoxathine obtained from Example 70 was coupled with 1-piperidinetanol using the procedure described in Example 71 (Step A). After purification by chromatography on silica gel with 3% MeOH / CH2Cl2, the desired adduct was obtained.

Step C The debenzylated product of Step B was desilylated using the procedure described in Example 71 (Step C). The desired product was obtained as a white solid after purification by chromatography on silica gel with 5% MeOH / CH 2 Cl 2 as eluent. 1 H NMR 10 (500 MHz, acetone-d 6) d (ppm): 6.90 (d, 2 H), 6.78 (d, H), 6.72 (d, 2 H), 6.70 (d, 2 H), 6.60 (d, 1 H ), 6.50 (d, 1 H), 6.48 (d, 2H), 5.38 (d, J = 2.0 Hz, 1 H), 4.38 (d, J = 2.3 Hz, 1 H), 4.08 (t, 2H), 2.8 (t, 2H), 2.62 (br s, 4H), 2.6 (q, 2H), 1.6 (m, 4H), 1.45 (m, 2H), 1.2 (t, 2H); MS m / z 465 (M ++ 1); [α] D = -26.33 ° (c = 0.515, MeOH).

EXAMPLE 105 General preparation of Step A: Reductive Cyclization To a stirred solution of 102.2 mg (0.17 mmol) of the cyclopentyl thio ketone generated in Example 41 in 1 ml_ of dichloromethane at -23 ° C under an atmosphere of N2, was added 68 μ? _ (0.087 mmol) of pure trifluoroacetic acid (TFA). To the stirred reaction mixture at -23 ° C, 41.4 μl (0.259 mmol) of pure triethylsilane was slowly added and the resulting mixture was stirred an additional three hours. The reaction mixture was partitioned between ethyl acetate / saturated NaHC03 / ice / brine, and the organic phase was separated, washed with brine, dried over anhydrous sodium sulfate, filtered, and evaporated. The residue was purified by chromatography on silica gel using methylene chloride / hexanes (1: 1) as eluent to provide the cis-cyclopentyl-dihydrobenzooxathine derivative. 1H 500 MHz NMR (CDCl 3) ppm (5): 1.12 (d, 18H), 1.26-2.12 (m, 12H), 2.5 (m, 1 H), 4.24 (d, 1 H), 4.9 (m, 2H) , 6.8-7.69 (m, 12H). Starting with the cyclohexyl derivative prepared in Example 41 and using the above procedure, the corresponding cyclohexyl-benzoxathine was prepared after purification by chromatography on silica gel using methylene chloride-hexanes (1: 1). 1H 500 MHz NMR (CDCl 3) ppm (5): 1.14 (d, 18H), 1.1 1-1.9 (m, 14H), 3.2 (t, 1 H), 5.03 (s, 2H), 5.44 (d, J = 2.5 Hz, 1 H), 6.66-7.47 (m, 12H).

Step B: Desaltion To a stirred solution of 89.6 mg (0.156 mmol) of the cis-cyclopentyl derivative prepared in Step A above in 1 mL of THF at 0 ° C, 13.3 μL · (0.234 mmol) of acid was added sequentially. acetic and then 171 μ? _ (0.171 mmol) of a 1 M solution of tetrabutylammonium fluoride in THF. The mixture was stirred at 0 ° C for 0.5 hour and then partitioned between ethyl acetate / 2N HCl / ice / brine, and the organic phase was separated, washed with brine, dried over anhydrous sodium sulfate, filtered, and it evaporated. The residue was purified by chromatography on silica gel using methylene chloride-ethyl acetate (50: 1) as eluent to provide ewl phenolic derivative. H 500 MHz NMR (CDCl 3) ppm (5): 1.32-1.94 (m, 9H), 3.51 (dd, J = 5.5, 2.5 Hz, 1 H), 5.03 (s, 2H), 5.42 (d, J = 2.3 Hz, 1 H), 6.67-7.47 (m, 12H). Starting with the cyclohexyl derivative prepared in the previous examples and using the above procedure, the corresponding cis-cyclohexyl-benzooxathiin phenol was prepared. 1H 500 MHz NMR (CDCl 3) ppm (8): 1.1 .1 .93 (m, 1 1 H), 3.23 (t, J = 3 Hz, 1 H), 5.03 (s, 2H), 5.44 ( d, J = 2.3 Hz, 1 H), 6.66-7.47 (m, 12H).

Step C: Mitsunobu Reaction To a stirred solution of a mixture of 56.3 mg (0.135 mmol) of the cis-cyclopentyl derivative prepared in Step B above, 53.6 μl (0.404 mmol) of 1-piperidiethylene, and 123.5 mg (0.47 mmol) of triphenylphosphine in 1 ml_ of anhydrous THF at 0 ° C was added with 87.4 μl (0.444 mmol) of pure diisopropylazodicarboxylate (DIAD). The ice-water bath was removed and the mixture was stirred an additional six hours. The mixture was partitioned between ethyl acetate / 2N HCl / ice / brine and the organic phase was separated, washed with brine, dried over anhydrous sodium sulfate, filtered, and evaporated. The residue was purified by chromatography on silica gel using ethyl acetate-methanol (9: 1) as eluent to provide the adduct. 1H 500 MHz NMR (CDCl 3) ppm (6): 1.33-2.0 (m, 15H), 2.56 (m, 4H), 2.82 (t, J = 6 Hz, 2H), 3.51 (dd, J = 5.4, 2.4 Hz , 1 H), 4.16 (t, J = 6 Hz, 2H), 5.02 (s, 2H), 5.42 (d, J = 2.3 Hz, 1 H), 6.66-7.46 (m, 12H).

Starting with the cyclohexyl derivative prepared in the previous example and using the above procedure, the corresponding cis-cyclohexyl-benzooxathine adduct was prepared. 1H 500 Hz NMR (CDCl 3) ppm (6): 1.11-1.93 (m, 17H), 2.6 (m, 4H), 2.87 (m, 2H), 3.2 (d, J = 2.5 Hz, 1 H), 4.2 ( m, 2H), 5.02 (s, 2H), 5.44 (d, J = 2.1 Hz, 1 H), 6.65-7.46 (m, 12H).

Step D: Debenzylation A stirred mixture of 36.6 mg (0.0069 mmol) of the cis-cyclopentyl derivative prepared in Step C above, 14.7 mg (0.014 mmol) of palladium black, and 87.1 mg (0.138 mmol) of ammonium formate in 2 ml_ of ethanol-ethyl acetate-water (7: 2: 1), was heated at 80 ° C for two hours. hours. The mixture was filtered through celite, washed with ethyl acetate and the filtrate was partitioned between ethyl acetate / saturated sodium bicarbonate / brine, and the organic phase was separated, washed with brine, dried over sodium sulfate. anhydrous, filtered, and evaporated. The residue was purified by chromatography on silica gel using ethyl acetate-methanol (9: 1) as eluent to provide the final product. 1H 500 MHz NMR (CDCl 3) ppm (5): 1.33-2.0 (m, 15H), 2.6 (m, 4H), 2.88 (m, 2H), 3.48 (t, J = 2.3 Hz, 1 H), 4.18 (m, 2H), 5.38 (d, J = 2.3 Hz, 1 H), 6.5 (m, 1 H), 6.63 (d, 2.9 Hz, 1 H) 6.74 (d, J = 8.7 Hz, 1 H) , 6.89 (d, J = 8.7 Hz, 2H), and 7.34 (d, J = 8.7 Hz, 2H). Starting with the cyclohexyl derivative prepared in the previous example, and using the above procedure, the corresponding cis-cyclohexyl-benzooxathine adduct was prepared. 1H 500 MHz NMR (CDCl 3) ppm (5): 1.00-1.90 (m, 18H), 2.6 (m, 4H), 2.81 (t, 2H), 3.19 (t, J = 3.0 Hz, 1 H), 4.18 ( m, 2H), 5.38 (d, J = 2.3 Hz, 1 H), 6.43 (m, 1 H), 6.62 (d, J = 3.0 Hz, 1 H), 6.68 (d, J = 8.7 Hz, 1 H ), 6.87 (d, J = 8.7 Hz, 2H), and 7.34 (d, J = 8.7 Hz, 2H); MS m / z 454 (M +).

EXAMPLE 106 Preparation of Step A: Reductive Cyclization Starting with the isopropyl adduct (0.0208 g 0.049 mmol) prepared in Example 42 and using the procedure detailed in Example 05 (Step A), the crude product was isolated after stirring at -23 ° C. for 6 hours 20 minutes. Purification by chromatography on silica gel with 30% EtOAc / hexane as the eluent afforded the desired product as a yellow oil. 1H 500 MHz NMR (CDCl 3) ppm (5): 0.95 (d, 3H), 0.98 (d, 3H), 1.95 (m, H), 3.30 (t, J = 3 Hz, 1 H), 5.03 (s, 2H), 5.42 (d, J = 2.6 Hz, 1 H), 6.66-7.47 (m, 12H).

Step B: Mitsunobu reaction The dihydrobenzoxathine prepared in Step A above, was coupled with 1-piperidinetanol using the procedure described in Example 105 (Step C) with the exception that the reaction was allowed to warm slowly from 0 ° C to room temperature for 3.5 hours. Purification by chromatography on silica gel with 10% MeOH / CH2Cl2 as the eluent gave the desired product as a pale yellow oil. 1H 500 MHz NMR (CDCl 3) ppm (5): 0.95 (d, 3H), 0.98 (d, 3H), 1.50-1.68 (m, 6H), 1.95 (m, 1 H), 2.60 (m, 4H ), 2.86 (t, 2H), 3.30 (t, J = 3 Hz, 1 H), 4.20 (t, 2H), 5.03 (s, 2H), 5.42 (d, J = 2.6 Hz, 1 H), 6.66 -7.49 (m, 12H).

Step C: Debenzylation Starting with the compound prepared in Step B above, and using the procedure detailed in Example 105 (Step D), the corresponding cis-isopropyl-benzoxathiine adduct was prepared after chromatography on silica gel with 10% MeOH / CH2Cl2 as the eluent. 1H 500 MHz NMR (CDCl 3) ppm (5): 0.95 (d, 3H), 0.98 (d, 3H), 1.50-1.68 (m, 6H), 1.95 (m, 1 H), 2.60 (m , 4H), 2.86 (t, 2H), 3.26 (t, J = 3.0 Hz, 1 H), 4.20 (t, 2H), 5.37 (d, J = 2.5 Hz, 1 H), 6.47 (dd, 1 H) ), 6.65 (d, J = 3 Hz, 1 H), 6.72 (d, J = 8.6 Hz, 2H), and 7.35 (d, J = 8.7 Hz, 2H); MS m / z 414 (M +).

EXAMPLE 107 Preparation of Step A: Reductive Cyclization Starting with the adduct of 2-tlofen (0.0208 g, 0.049 mmol) prepared in Example 43 and slightly modifying the procedure detailed in Example 105 (Step A), the crude product was isolated after stirring. 0 ° C to room temperature for 1 hour 40 minutes. Purification by chromatography on silica gel with 30% EtOAc / hexane as the eluent provided the desired product as a red oil. 1H 500 Hz NMR (CDCl 3) ppm (6): 1.1 1 (d, 18H), 1.24 (m, 3H), 4.67 (d, J = 2.0 Hz, 1 H), 5.50 (d, J = 1.8 Hz, 1 H), 6.60-7.12 (m, 10H).

Step B: Protection with MO To a solution of the dihydrobenzoxathine (0.0629 g, 0.13 mmol) prepared in Step A above in distilled THF (1 mL) was added 60% NaH in mineral oil (0.0090 g, 0.19 mmol) at 0 ° C under N2. After gas evolution ceased, MOMCI (0.013 mL, 0.16 mmol) was added dropwise to the reaction. After 30 minutes, another 1.3 equivalents of MOMCI was added to the reaction. Within 5 minutes, the reaction was completed by CCD. The resulting dark red solution was partitioned between EtOAc and ice / H20. The organic layer was washed with brine, dried over Na 2 SO 4, and concentrated in vacuo. The desired product was used in the next reaction without purification. 1 H 500 MHz NMR (CDCl 3) ppm (5): 1.1 1 (d, 18 H), 1.24 (m, 3 H), 3.52 (s, 3 H), 4.67 (d, J = 2.1 Hz, 1 H), 5.14 (m, 2H), 5.50 (d, J = 1.8 Hz, 1 H), 6.60-7.12 (m, 10H).

Step C: Desilylation The dihydrobenzoxathine prepared in Step B above, was desilylated using the procedure described in Example 105 (Step B) to provide the desired product as a colorless oil after chromatography on silica gel with 30% EtOAc / hexane as the eluent 1 H 500 MHz NMR (CDCl 3) ppm (5): 3.52 (s, 3 H), 4.69 (d, J = 1.8 Hz, 1 H), 5.15 (m, 2 H), 5.51 (d, J = 1.8 Hz, 1 H ), 6.60-7.15 (m, 10H).

Step D: Mitsunobu Reaction Following the procedure detailed in Example 105 (Step C) with the exception that the reaction was allowed to warm from 0 ° C to room temperature for 4 hours, the material prepared in the previous step was converted to the desired product after chromatography on silica gel (a dilution with 30% EtOAc / hexane followed by a second elution with 10% MeOH / CH 2 Cl 2). 1H 500 MHz NMR (CDCl 3) ppm (5): 1.40-2.60 (m, 10H), 2.79 (t, 2H), 3.52 (s, 3H), 4.10 (t, 2H), 4.69 (d, J = 1.8 Hz , 1 H), 5.15 (m, 2H), 5.51 (d, J = 1.8 Hz, 1 H), 6.60-7.15 (m, 10H).

Step E: Deprotection of MOM A mixture of the material (0.0401 g, 0.080 mmol) prepared in Step D above and HCI 2 N (0.20 ml_, 0.40 mmol) in MeOH (1.0 ml_) was heated to 60 ° C under N2 for 2.5 hours. The reaction was partitioned between EtOAc and ice / saturated NaHCO 3. The organic layer was washed with brine, dried over Na 2 SO 4, and concentrated in vacuo. The residue was triturated with EtaO and the discarded product was obtained as a white solid. 1H 500 MHz NMR (deacetone + CD3OD) ppm (6): 1.50-3.19 (m, 10H), 3.23 (t, 2H), 4.30 (t, 2H), 5.00 (d, J = 1.8 Hz, 1 H ), 5.51 (d, J = 1.8 Hz, 1 H), 6.57-7.25 (m, 10H); MS m / z 454 (M +) EXAMPLE 108 Preparation of Step A: Reductive Cyclization Following the procedure detailed in Example 44, 0.0792 g of the 3-pyridyl derivative prepared in Example 41 was converted to the corresponding benzoxathine after stirring at room temperature for 5 hours. The desired product was isolated from the reaction mixture after chromatography on silica gel using 30% EtOAc / hexane as the eluent. 1H 500 MHz RN (CDCl 3) ppm (5): 1.11 (d, 18H), 1.24 (m, 3H), 4.36 (d, J = 2.1 Hz, 1 H), 5.05 (s, 2H), 5.50 ( d, J = 1.6 Hz, 1 H), 6.77-8.43 (m, 16H).

Step B: Desilylation Following the procedure detailed in Example 105 (Step B), the dihydrobenzoxathine generated in Step A above was desilylated to provide the desired product after chromatography on silica gel (elution with 50% EtOAc / hexane followed by a second elution with 30% EtOAc / hexane). 1H 500 MHz NMR (CDCl 3) ppm (5): 4.42 (d, J = 2.1 Hz, 1 H), 5.07 (s, 2H), 5.50 (d, J = 1.6 Hz, 1 H), 6.77-8.43 (m , 16H).

Step C: itsunobu reaction Following the procedure detailed in Example 105 (Step C) with the exception that the reaction was allowed to warm from 0 ° C to room temperature for 4 hours, the material prepared in the previous step was converted to the desired product after chromatography on silica gel using 10% MeOH / CH2Cl2 as the eluent. 1H 500 MHz NMR (CDCl 3) ppm (6): 1.40-2.60 (m, 10H), 2.80 (t, 2H), 4.10 (t, 2H), 4.38 (d, J = 1.8 Hz, 1 H), 5.07 ( s, 2H), 5.50 (d, J = 1.8 Hz, 1 H), 6.77-8.43 (m, 16H).

Step D: Debenzylation Starting with the material prepared in Step C above, and using the procedure detailed in Example 105 (Step D), the corresponding cIS-3-pyridyl-dihydrobenzoxatin adduct was prepared after chromatography on silica gel with 10%. % MeOH / CH2Cl2 as the eluent. 1H 500 MHz NMR (CDCl 3) ppm (5): 1.40-2.60 (m, 10H), 2.80 (t, 2H), 4.10 (t, 2H), 4.36 (d, J = 2.1 Hz, 1 H), 5.45 ( d, J = 1 .9 Hz, 1 H), 6.59-8.43 (m, 1 1 H); MS m / z 449 (M +).

EXAMPLE 109 Preparation of Step A: Reductive Cyclization Following the procedure detailed in Example 44, 0.1871 g of the 4-pyridyl derivative prepared in Example 41 was converted to the corresponding dihydrobenzoxathine after stirring at room temperature for 30 hours. The desired product was isolated from the reaction mixture after chromatography on silica gel using 30% EtOAc / hexane as the eluent. 1 H 500 MHz NMR (CDCl 3) ppm (6): 1.1 1 (d, 18 H), 1.24 (m, 3 H), 4.32 (d, 1 H), 5.08 (s, 2 H), 5.50 (d, 1 H ), 6.60-8.39 (m, 16H).

Step B: Desallation Following the procedure detailed in Example 105 (Step B), the dihydrobenzoxathine generated in Step A above was stripped to give the desired product after chromatography on silica gel (elution with 50% EtOAc / hexane followed by a second elution with 30% EtOAc / hexane). 1H 500 Hz NMR (CDCl 3) ppm (5): 4.33 (d, 1 H), 5.07 (s, 2H), 5.46 (d, 1 H), 6.63-8.37 (m, 16H).

Step C: Mitsunobu reaction Following the procedure detailed in Example 105 (Step Q with the exception that the reaction was allowed to warm from 0 ° C to room temperature for 5 hours, the material prepared in the previous step was converted to the desired product after chromatography on silica gel (elution with 10% eOH / CH2CI2 followed by a second elution with 20% EtOAc / CH2CI2). 1H 500 MHz NMR (CDCl3) ppm (5): 1.40-2.60 (m, 10H), 2.80 (t, 2H), 4.14 (t, 2H), 4.32 (d, J = 3.0 Hz, 1 H), 5.06 (s, 2H), 5.49 (d, J = 2.1 Hz H), 6.79-8.38 (m, 16H).

Step D: Debencylation Starting with the material prepared in Step C above, and using the procedure detailed in Example 05 (Step D), the desired product was obtained as a 4: 1 cls / trans mixture after chromatography on silica gel (1X elution with 30% EtOAc / hexane followed by a second elution with 10% MeOH / CH2Cl2). Cis isomer: 1H 500 MHz NMR (CDCl 3) ppm (6): 1.40-2.70 (m, 10H), 2.80 (t, 2H), 4.10 (t 2H), 4.30 (d, J = 2.0 Hz, 1 H), 5.44 (d, J = 1.8 Hz, 1 H), 6.59-8.40 (m, 11 H).

Trans isomer: 1H 500 MHz NMR (CDCl 3). ppm (5): 1.40-2.70 (m, 10H), 2.80 (t, 2H), 4.15 (t, 2H), 4.38 (d, J = 8.7 Hz, 1 H), 4.92 (d, J = 8.7 Hz, 1 H), 6.59-8.46 (m, 1 1 H); MS m / z 449 (M +).

EXAMPLE 110 Preparation of Step A: Reduction To a stirred solution of 265.1 mg (0.449 mmol) of the cyclopentyl thio ketone generated in Example 41 in 3 mL of methanol-dichloromethane (1: 1) at 0 ° C to room temperature was added. in enough portions sodium borohydride to complete the reduction. The reaction mixture was partitioned between ethyl acetate / 2N HCl / ice / brine, and the organic phase was separated, washed with brine, dried over anhydrous sodium sulfate, filtered, and evaporated to give the cyclopentylthio. -carbohydles crude, which were used without further purification in the next stage.

Step B: Cyclization A mixture of 266 mg (0.449 mmol) of the crude product, prepared in Step A above, and 89 mg of amberlyst 15 in 3 mL of toluene, was stirred at room temperature for two hours. The resin was removed by filtration and washed well with ethyl acetate. The filtrate was evaporated and the residue obtained was purified by chromatography on silica gel using dichloromethane-hexanes (1: 1) as eluent to give the trans-dihydro-benzoxathiine derivative. 1H 500 Hz NMR (CDCl 3) ppm (5): 1.13 (d, 18H), 1.26-1.94 (m, 12H), 3.64 (dd, J = 7.8 Hz, 5.5 Hz, 1 H), 4.78 (d, J = 7.8 Hz, 1 H), 5 02 (s, 2H), 6.6-7.45 (m, 12H).

Step C: Desillation Following the procedure detailed in Step B of Example 105, 228.5 mg (0.397 mmol) of the material prepared in the previous step was desilylated to give the corresponding phenol.

Step D: Mitsunobu Reaction Following the procedure detailed in Step C of Example 105, the material prepared in the previous step was converted to the corresponding trans-cyclopentyl-dihydrobenzoxathine adduct. H 500 MHz NMR (CDCl 3) ppm (5): 1.39-2.0 (m, 15H), 2.6 (m, 4H), 2.88 (m, 2H), 3.66 (dd, J = 7.8 Hz, 5.5 Hz, 1 H) , 4.21 (m, 2H), 4.81 (t, J = 7.8 Hz, 2H), 5.01 (s, 2H), 6-64-7.49 (m, 12H).

Step E: Debenzylation Following the procedure detailed in Step D of Example 105, the material prepared in the previous step was converted to the corresponding trans-cyclopentyl-dihydrobenzoxathine product. 1H 500 MHz NMR (CDCl 3) ppm (5): 1.29-2.0 (m, 15H), 2.6 (m, 4H), 2.88 (m, 2H), 3.67 (dd, J = 8Hz, 5Hz, 1 H) , 4.18 (m, 2H), 4.77 (t, J = 8Hz, 2H), 6.5 (dd, J = 2.7 Hz, 8.7 Hz, 1 H), 6.65 (d, 2.7 Hz, 1 H) 6.77 (d, J = 8.7 Hz, H), 6.88 (d, J = 7.5 Hz, 2H), and 7.27 (d, J = 7.5 Hz, 2H).

EXAMPLE 111 General preparation of Steps A and B: Reduction and Cyclization Using the thio-ketones prepared in Example 39 and employing the procedures detailed above in Steps A and B of Example 1 10, the following compounds were prepared: Derivative of trans-cyclohexyl: 1 H 500 MHz NMR (CDCl 3) ppm (5): 1.14 (d, 18 H), 0.98-1.8 (m, 14 H), 3.37 (dd, J = 2.5 Hz, 8.1 Hz, 1 H), 5.01 (s, 2H), 5.05 (d, J = 8.1 Hz, 1 H), 6.6-7.44 (m, 12H). Derivative of trans-cyclopentyl: 1 H 500 MHz NMR (CDCl 3) ppm (5): 1.14 (d, 18 H), 1.28-1.9 (m, 12 H), 4.53 (m, 1 H), 4.93 (d, 1 H), 5.01 (s, 2H), 6.6-7.43 (m, 12H).

Step C: Desilylation Using the trans-dihydrobenzoxatyines prepared in the previous step and using the procedure detailed above in Step B of Example 105, the following compounds were prepared: Trans-cyclohexyl phenol: 1H 500 MHz NMR (CDCl 3) ppm (5) : 1.0-1.8 (m, 1 1 H), 3.3 (m, 1 H), 5.05 (s, 2H), 5.1 (d, 1 H), 6.6-7.44 (m, 12H). Trans-cyclopentyl phenol: H 500 MHz NMR (CDCl 3) ppm (6): 1.29-2.0 (m, 9H), 3.55 (dd, J = 5.7 Hz, 7.6 Hz, 1 H), 4.95 (d, J = 7.6 Hz , 1 H), 5.02 (s, 2H), 6.6-7.45 (m, 12H).

Step D: Reaction of Mltsunobu Using the trans-dihydrobenzoxatiline phenols prepared in the previous step and using the procedure detailed above in Step C of Example 105, the following compounds were prepared: Trans-cyclohexyl adduct: 1H 500 MHz NMR (CDCl 3) ppm (5): 1.0-1.8 (m, 17H), 2.58 (m, 4H), 2.84 (m, 2H), 3.37 (m, 1 H), 4.17 (t, J = 6 Hz, 2H), 5.0 (s, 2H), 5.08 (d, J = 7.8 Hz, 1H), 6.6-7.43 (m, 12H). Trans-cyclopentyl adduct: 1H 500 MHz NMR (CDCl 3) ppm (5): 1.29-2.0 (m, 15H), 2.58 (m, 4H), 2.84 (m, 2H), 3.55 (m, 1 H) , 4.17 (m, 2H), 4.94 (d, J = 7.3 Hz, 1 H), 5.0 (s, 2H), 6.6-7.72 (m, 12H).

Step E: Debenzylation Using the adducts of trans-dihydrobenzoxatiline prepared in the previous step and using the procedure detailed above in Step D of Example 105, the following compounds were prepared: Trans-cyclohexyl adduct: 1 H 500 MHz NMR (CDCl 3) ppm ( 5): 1.0-1.8 (m, 17H), 2.58 (m, 4H), 2.86 (m, 2H), 3.33 (m, 1 H), 4.16 (m, 2H), 5.08 (d, J = 7.8 Hz, 1 H), 6.4-7.23 (m, 7H). Trana-cyclopentyl adduct: 1H 500 MHz NMR (CDCl 3) ppm (5): 1. 29-2.0 (m, 15H), 2.68 (m, 4H), 2.94 (m, 2H), 3.51 (m, 1 H), 4.2 (m, 2H), 4.95 (d, J = 7.4 Hz, 1H), 6.45-7.31 (m, 7H).

EXAMPLE 112 Step A: Silylation To a stirred solution of the isopropyl thio ketone (0.0395 g, 0.097 mmol) generated in Example 42 in distilled THF (1 mL) at 0 ° C, 60% NaH in mineral oil (0.0183) was added. g, 0.20 mmol) followed by TIPSCI (0.048 mL, 0.22 mmol). After 35 minutes, another equivalent of TIPSCI was added to complete the reaction. The reaction was partitioned between EtOAc and ice / H20, and the organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo to provide the desired product. The crude material was used in the next step without further purification.

Step B: Reduction To a solution of the crude product (0.097 mmol) prepared in Step A above in distilled THF (1 mL), a 1 M solution of super-hydride in THF (0.15 mL, 0.15 mmol) was added at 0 ° C under N2. The reaction mixture was stirred for 20 minutes before dividing between EtOAc and ice / H20.

The organic layer was further washed with brine, dried over Na 2 SO 4, and concentrated in vacuo to give the desired product. The crude material was used in the next step without further purification. 1H 500 MHz NMR (CDCl 3) ppm (5): 0.90-1.40 (m, 49H), 1.69 (m, 1 H), 3.10 (dd, 1 H), 4.60 (d, 1 H), 5.05 (s, 2H ), 6.70-7.50 (m, 12H).

Stage C: Depletion To a solution of the material (0.097 mmol) prepared in the previous step in distilled THF (1 ml_), AcOH (0.08 ml_, 0.32 mmol) was added at 0 ° C under N2 followed by the addition of a 1 M solution of TBAF in THF (0.29 mL, 0.29 mmol). After 15 minutes, the reaction was partitioned between EtOAc and ice / saturated NaHCO 3. The organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. Purification by chromatography on silica gel using 40% EtOAc / hexane as the eluent afforded the desired product as a yellow foam. 1 H 500 MHz NMR (CDCl 3) ppm (6): 0.92 (d, 3 H), 0.98 (d, 3 H), 1.59 (m, 1 H), 2.86 (dd, 1 H), 4.62 (d, 1 H), 5.02 (q, 2H), 6.77-7.45 (m 12H).

Step D: Cyclization Following the procedure detailed in Example 1 10 (Step B), the material (0.0366 g, 0.089 mmol) generated in the previous step was converted to the corresponding trans-dihydrobenzoxathine after stirring for 5 hours 15 minutes at room temperature.

Purification by chromatography on silica gel using 30% EtOAc / hexane as the eluent afforded the desired product as a white solid. 1 H 500 MHz NMR (CDCl 3) ppm (5): 0.98 (d, 3 H), 1.03 (d, 3 H), 1.78 (m, 1 H), 3.57 (dd, J = 3.7 Hz, J = 8.5 Hz, 1 H ), 4.82 (d, J = 8.4 Hz, 1 H), 5.02 (s, 2H), 6.63-7.46 (m, 12H).

Step E: Mitsunobu reaction Following the procedure detailed in Example 105 (Step C), the material (0.0266 g, 0.068 mmol) generated in the previous step was converted to the corresponding trans-isopropyl-dihydrobenzoxathine adduct after warming from 0 ° C to room temperature for 4 hours 20 minutes. Purification by chromatography on silica gel (elution with 10% MeOH / CH2CI2 followed by a second elution with 30% EtOAc / hexane) provided the desired product as a white solid. 1H 500 MHz NMR (CDCl 3) Ppm (6): 0.98 (d, 3H), 1.02 (d, 3H), 1.29-1.67 (m, 6H), 1.78 (m, 1 H), 2.58 (m, 4H), 2.85 (t, 2H), 3.57 (dd, J = 3.7 Hz, J = 8.5 Hz, 1 H), 4.18 (t, 2H), 4.83 (d, J = 8.4 Hz, 1 H), 5.02 (s, 2H), 6.63-7.46 (m, 12H).

Step F: Debenzylation Following the procedure detailed in Example 105 (Step D), the material (0.0395 g, 0.068 mmol) generated in the previous step was converted to the corresponding trans-isopropyl-dihydrobenzoxatilna product. Purification was carried out by chromatography on silica gel using 10% MeOH / CH2Cl2 as the eluent. 1H 500 MHz NMR (CDCl 3) ppm (5): 0.98 (d, 3H), 1.02 (d, 3H), 1.29-1.67 (m, 6H), 1.78 (m, 1 H), 2.58 (m, 4H ), 2.85 (t, 2H), 3.57 (dd, J = 3.7 Hz, J = 8.5 Hz, 1 H), 4.18 (t, 2H), 4.83 (d, J = 8.4 Hz, 1 H), 6.48-7.29 (m, 7H); MS m / z 414 (M +).

EXAMPLE 113 Step A: Silylation Following the procedure detailed in Example 112 (Step A), the Isopropyl thio-ketone (0.6314 g, 1.5 mmol) generated in Example 40 was silylated. Purification by chromatography on silica gel using 30% EtOAc / hexane as the eluent, gave the desired product as a yellow oil. H 500 MHz NMR (CDCl 3) ppm (5): 0.98-1.30 (m, 49H), 2.35 (m, 1 H), 4.38 (d, 1 H), 4.99 (q, 2H), 6.33-7.79 (m, 12H).

Step B: Reduction Following the procedure detailed in Example 112 (Step B), the material (0.8009 g, 1.1 mmol) isolated in Step A above, was reduced to the corresponding alcohol and used without further purification in the next step. 1H 500 MHz NMR (CDCl 3) ppm (5); 0.98-1.30 (m, 49H), 1.90 (m, 1 H), 2.92 (dd, 1 H), 4.59 (d, 1 H), 5.05 (q, 2H), 6.47-7.43 (m, 12H).

Step C: Desilylation Following the procedure detailed in Example 1 12 (Step C), the material (0.022 mmol) isolated in Step B above was deprotected to provide the desired product which was used in the next step without purification.

Stage D: Cyclization Following the procedure detailed in Example 1 10 (Stage B), the material generated in the previous step was converted to its corresponding trans-dihydrobenzoxathine after stirring for 22 hours at room temperature. Purification by chromatography on silica gel using 30% EtOAc / hexane as the eluent, gave the desired product as a colorless oil. 1 H 500 MHz NMR (CDCl 3) ppm (6): 0.98 (d, 3 H), 1.03 (d, 3 H), 1.79 (m, 1 H), 3.45 (dd, 1 H), 4.98 (d, 1 H), 5.02 (s, 2 H), 6.59-7.46 (m, 12H); MS m / z 393 (M +) Step E: Mitsunobu Reaction Following the procedure detailed in Example 105 (Step C), the material (0.008 g, 0.020 mmol) generated in the previous step was converted to the corresponding trans-isopropyl-dihydrobenzoxatin adduct after warming from 0 ° C to room temperature for 6 hours. Purification by chromatography on silica gel using 10% MeOH / CH 2 Cl 2 as the eluent to provide the desired product as a pale yellow oil. 1H 500 MHz NMR (CDCl 3) ppm (5): 0.98 (d, 3H), 1.02 (d, 3H), 1.29-1.67 (m, 6H), 1.79 (m, 1 H), 2.58 (m, 4H), 2.81 (t, 2H), 3.50 (dd, J = 3.8 Hz, J = 8.3 Hz, 1 H), 4.18 (t, 2H), 4.97 (d, J = 8.2 Hz, 1 H), 5.01 (s) , 2H), 6.59-7.46 (m, 12H).

Step F: Debenzylation Following the procedure detailed in Example 105 (Step D), the material (0.0085 g, 0.01 mmol) generated in the previous step was converted to the corresponding trans-isopropyl-dihydrobenzoxathine product. Purification was carried out by chromatography on silica gel using 10% MeOH / CH2Cl2 as the eluent. 1H 500 MHz NMR (CDCl 3) ppm (5): 0.98 (d, 3H), 1.02 (d, 3H), 1.49-1.70 (m, 6H), 1.75 (m, 1 H), 2.61 (m, 4H), 2.85 (t, 2H), 3.41 (dd, J = 3.8 Hz, J = 8.3 Hz, 1 H), 4.18 (t, 2H), 4.96 (d, J = 8.2 Hz, 1 H), 6.43-7.26 (m , 7H); MS m / z 414 (M +).

EXAMPLE 114 Preparation of Following the procedure detailed in Example 6 and using 0. 36 g (2.5 mmol) of 1,2-benzenedithiol, purchased from Aldrich, 221 mg (ca 20%, impure) of the desired product was obtained after chromatography on silica gel using EtOAc / hexane (1/5) as eluent.

EXAMPLE 115 Preparation of Using the procedure of Example 44, 121 mg (80%) of a mixture of the three products (A: B: C ~ 1: 0.1: 0.25) was isolated after purification by chromatography on silica gel with 10% EtOAc / Hexane EXAMPLE 116 Preparation of Step A The thiin obtained from Example xx was coupled with 1-piperidinetanol using the procedure described in Example 71 (Step A). After purification by chromatography on silica gel using 3% MeOH / CH 2 Cl 2 as eluent, the desired adduct is obtained as a mixture.

Step B The adducts from Step A were distilled using the procedure described in Example 71 (Step C). The desired product A was separated by HPLC (Meta Chem Polaris C 184.6 x 50.5 micron, gradient 5 to 75% acetonitrile in Reverse Phase Column) as a white solid. A: 1 H NMR (400 MHz, CD 3 OD) d (ppm): 7.2 (m, 2 H), 7.1 (m, 2 H), 6.9 (m, 2 H), 6.8 (m, 4 H), 6.55 (d, 2 H), 4.75 (m, 2H), 4.3 (m, 2H), 3.6 (br d, 2H), 3.5 (m, 2H), 3.0 (br t, 2H), 1.95 (m, 2H), 1.8 (m, 4H) (MS m / z 464 (M +). B: 1 H NMR (400 MHz, CD 3 OD) d (ppm): 7.4 (m, 2 H), 7.3 (m, 2 H), 7.1 (d, 2 H), 6.95 (d , 2H), 6.8 (d, 2H), 6.6 (d, 2H), 4.3 (br t, 2H), 3.6 (br d, 2H), 3.5 (br t, 2H), 3.05 (br t, 2H), 2.0 (br d, 2H), 1.8 (m, 4H);); MS m / z 462 (+).

Test Methods The utility of the compounds of the present invention can be easily determined by methods well known to one of ordinary skill in the art. These methods may include but are not limited to, the methods described in detail below.

Estrogen Receptor Binding Assay Estrogen receptor ligand binding assays are designed as scintillation proximity assays that employ the use of titrated estradiol and recombinant expressed estrogen receptors. The full length recombinant human ER-a and ER-β proteins are produced in a baculoviral expression system. The ER-a or ER-β extracts are diluted 1: 400 in phosphate buffered saline containing 6 mM α-monothiolglycerol. Aliquots of 200 μ? of the diluted receptor preparation to each well of a 96 well instant plate. The plates are covered with a Saran wrap and incubated at 4 ° C overnight. The next morning, an aliquot of 20 ul 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. The plates are then washed with 200 ul of buffer solution containing 20 mM Tris (pH 7.2), 1 mM EDTA, 10% Glycerol, 50 mM KCl, and 6 mM a-monothiolglycerol. To prepare the assay on these plates coated with the receptor, 178 ul of the same buffer is added to each well of the 96-well plate. Then 20 ul of a 10 nM solution of H-estradiol is added to each well of the plate. The test compounds are evaluated over a range of concentrations from 0.01 nM to 1000 nM. Reserve solutions of the test compound should be made in 100% DMSO at 100X, the final concentration desired for the test in the assay. The amount of DMSO in the test wells of the 96-well plate should not exceed 1%. The final addition for the assay plate is a 2 ul aliquot of the test compound that has been prepared in 100% DMSO. The plates are sealed and allowed to equilibrate at room temperature for 3 hours. Plates are counted in a scintillation counter equipped for 96-well plate count.

Ovariectomized Rat Test In the ovariectomized rat (OVX) test, estrogen deficiency is used to induce cancellous osteopenia (eg, low bone mineral density [BMD; mg / cm2]), associated with resorption and accelerated formation of bones. Both BMD results and bone formation / resorption are used to model the changes in bone that occur when a woman goes through menopause. The OVX rat assays are the main in vivo assay used by all major academic and industrial laboratories that study the efficacy of new chemical entities in the prevention of bone loss due to estrogen deficiencies. Sprague-Dawley female rats 6-8 months old have their ovaries removed and within 24 hours, begin with the treatment with 42 days with vehicle or multiple doses of the test compound. Unexpected imitation OVX treated with alendronate (.003 mg / kg s.c., q.d.) or with treatment with 17- -estradiol (.004 mg / kg s.c., q.d.) are included in groups as positive controls. The test compounds can be administered orally, subcutaneously or by infusion through a mini pump implanted subcutaneously. Before necropsy, in vivo dual labeling with calcein (8 mg / kg per subcutaneous injection), a fluorochrome is finalized in search of bone. At necropsy, blood, femurs, a segment of the vertebral body and the uterus are obtained. Routine endpoints for testing OVX rats include evaluations of bone mass, bone resorption and bone formation. For bone mass, the end point is BMD of the distal femoral metaphysis, a region that contains about 20% of cancellous bone. The vertebral segment, a region with around 25% cancellous bone can also be used for the determination of BMD. The BMD measurement is made by a dual X-ray energy absorptiometry (DXA, Hologic 4500A; Waltham, MA). For bone resorption, the end point is reticulated with urinary deoxypyridinoline, a breakdown product of bone collagen (uDPD, expressed as nM DPD / nM creatinine). This measurement is made with a commercially available kit (Pyrilinks, Metra Biosystems, Mountain View, CA). For bone formation, the end points are mineralized surface and mineral deposition rate, histomorphometric measurements of the number of osteoblasts and activity. This measurement is done in sections of 5 μ ?? of the proximal tibial metaphysis without decalcification, using a semi-automated system (Bioquant; R &M Biometrics; Nashville, TN). Similar endpoints and measurement techniques are commonly used for each endpoint in post-menopausal women.

Rat Cholesterol Decrease Assay Sprague-Dawley rats (5 per group) weighing about 250 g were dosed subcutaneously with the compounds of the present invention dissolved in propylene glycol for 4 days. A group of 5 rats was dosed only with the vehicle. On the fifth day, euthanasia was applied to the rats with carbon dioxide and their blood samples were obtained. Plasma cholesterol levels were assayed from these samples with cholesterol determination kit commercially available from Sigma.

MCF-7 Estrogen-dependent Proliferation Assay MCF-7 cells (ATCC # HTB-22) are adenocarcinoma cells of human mammary glands that require estrogen for growth. Growth media (GM) for MCF-7 cells are minimal essential media (without phenol red) supplemented with 10% fetal bovine serum (FMS). FBS serves as the sole source of estrogen and this GM supports the complete growth of cells and is used for the routine growth of cell cultures. When the MCF-7 cells are placed in a medium in which carbon-mineral dextran-treated fetal bovine serum (CD-FBS) is replaced with FBS, the cells will cease dividing but remain viable. CD-FBS does not contain detectable levels of estrogen in the media containing these sera and is referred to as estrogen suppressed media (EDM). The addition of estradiol to EDM stimulates the growth of MCF-7 cells in a dose-dependent manner with an EC5o of 2 pM. The growing MCF-7 cells are washed several times with EDM and then the cultures are maintained in EDM for a minimum of 6 days, in order to suppress the endogenous estrogen cells. On day 0 (at the beginning of the assay), these estrogen suppressed cells are plated onto 96-well cell culture plates at a density of 1000 cells / well in EDM in a volume of 180 ul / well. On the first day, the test compounds are diluted in a 10-fold dilution series in EDM and 20 ul of these dilutions are added to the 180 ul of the media in the appropriate well of the cell plate resulting in a dilution additional 1: 10 of the test compounds. On days 4 and 7 of the assay, the culture supernatant is aspirated and replaced with fresh EDM and dilutions of the test compound are made as above. The test is completed on day 8-10 when the appropriate controls reach 80-90% confluence. At this point, the culture supernatants are aspirated, the two 2X cells are washed with PBS, the wash solution is aspirated and the protein content of each well is determined. Each drug dilution is evaluated in a minimum of 5 wells and the dilution range of test compounds in the assay is 0.001 nM to 1000 nM. The assay in the above format is used to determine the potential of the estradiol agonist of a test compound. In order to evaluate the antagonist activity of a test compound, the MCF-7 cells are maintained in EDM with a minimum of 6 days. Then on day 0 (at the beginning of the assay), these estrogen suppressed cells are placed in 96-well cell culture plates at a density of 1000 cells / well in EDM in a volume of 180 ul / well. On day 1, test compounds in fresh media containing 3 pM estradiol are applied to the cells. On days 4 and 7 of the assay, the culture supernatant is aspirated and replaced with fresh EDM containing 3 pM estradiol and the test compound. The test is terminated on day 8-10 when the appropriate controls reach 80-90% confluence and the protein content of each well is determined as above.

Rat Endometriosis Model. Animals: Species: Rattus norvegicus Strain: Sprague-Dawley CD Provider: Charles River Laboratories, Raleigh, NC Sex: female Weight: 200-240 grams The rats are each housed in polycarbonate cages and supplied with a global diet Tekiad 2016 ( Madison, Wl) and water purified by bottled reverse osmosis ad libitum. They stay in a light / dark cycle of 12/12. The rats are anesthetized with Telazol ™ (20 mg / kg, ip) and oxymorphone (0.2 mg / kg se) and placed dorsoventrally in an esterile blanket. Body temperature is maintained using a cover of underlying circulating water. The surgical sites are shaved with tweezers and cleaned using three cycles of betadine / isopropyl alcohol or Duraprep® (3M). The area of the incision is covered with a sterile blanket. When using an aseptic technique, a lower abdominal incision is made in the midline of 5 cm across the skin, subcutaneously and in the muscle layers. A bilateral ovariectomy is performed. The left uterine blood vessels are ligated and a 7 mm segment of the left uterine canal is removed. The uterus is closed with a 4-0 gut suture. The myometrium is aseptically separated from the endometrium and fragmented to 5X5 mm. The fragmented section of the endometrium is transplanted to the dentral peritoneal wall with the epithelial lining of the segment opposite the peritoneal wall. The removed endometrial tissue is sutured at its four corners to the body wall using sterile 6-0 silk. The abdominal muscle layer is closed using 4-0 sterile chronic gut. The incision is closed in the skin using sterile stainless steel surgical tweezers. A 90-day sterile sustained-release estrogen pelletizer is implanted subcutaneously (Innovative Research of America, 0.72 ng / pelletized; equivalent to circulating estrogens of 200-250 pg / mL) in the lateral dorsal scapular area. A sterile implantable programmable temperature transponder (IPTT) (B DS, Seaford, DE) is injected subcutaneously into the dorsal scapular region. The rats are observed until they are completely ambulant and are allowed to recover from surgeries without disturbance for three weeks. Three weeks after the transplantation of the endometrial tissue, the animals undergo a repeated laparotomy using a preparation and an aseptic surgical site technique. The explantation is evaluated for graft acceptance, and it is measured in area with calibrators and recorded. Animals with rejected grafts are separated from the study. The animals are selected to create a similar average explant volume per group. Treatment with drug or vehicle (control) is started one day after the second laparotomy and is continued for 14 days. The body temperature is recorded every third day at 10:00 am using an optical BMDS reader.

At the end of the 14-day treatment period, animals are euthanized by an overdose of carbon dioxide. Blood is collected by cardiocentesis for circulating levels of estrogen. The abdomen is opened, the explant is examined, measured and excised and the weight is recorded in number. The right uterine canal is removed, and dry, wet wells are recorded.

Pharmaceutical Composition As a specific embodiment of this invention, 25 mg of the compound of Example 71 is formulated with finely divided lactose sufficient to provide a total amount of 580 to 590 mg to fill a size 0 hard gelatin capsule.

Claims

NOVELTY OF THE INVENTION CLAIMS 1. - A compound of the formula: wherein R1, R2, R3, and R4 are each independently selected from the group consisting of hydrogen, C1.5 alkyl, C3-8 cycloalkyl, C2-5 alkenyl, C2-5 alkynyl, C3-8 cycloalkenyl, phenyl, heteroaryl , heterocyclic, CF3, -OR, halogen, alkylthio Ci-5, thiocyanate, cyano, -CO2H, -COOalkylC-i.5, -COalkylCi-5, -CONZ2, -S02NZ2, and -S02alkylC1-5, wherein the groups heterocyclic alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, phenyl, heteroaryl can optionally be substituted with Ci-5 alkyl, C3-8 cycloalkyl, CF3, phenyl, heteroaryl, heterocyclic, -OR, halogen, amino, alkylthio Ci_5, thiocyanate, cyano, -C02H, -COOalkylC-5, -CalkylC1-5, -CONZ2, -S02NZ2, and -S02alkylCi-5; R5 is selected from the group consisting of heterocyclic groups C1.5 alkyl, C4 cycloalkyl, C2-5 alkenyl, C2-5 alkynyl, C3-8 cycloalkenyl, phenyl, heteroaryl, wherein the groups may optionally be substituted with C1-6 alkyl. 5, C3-8 cycloalkyl, CF3, phenyl, heteroaryl, heterocyclic, -OR6, halogen, amino, alkylthio Ci-s, thiocyanate, cyano, -C02H, -COOalkylCi-5, -COalkylCi-5, -CONZ2, -S02NZ2, and -S02alkyl Ci-5; X and Y are each independently selected from the group consisting of oxygen, sulfur, sulfoxide and sulfone; R6 is selected from the group consisting of hydrogen, C-i-s alkyl, benzyl, methoxymethyl, triorganosilyl, Ci-5 alkylcarbonyl, alkoxycarbonyl and CONZ2; Each Z is independently selected from the group consisting of hydrogen, C1-5 alkyl, trifluoromethyl, wherein the alkyl group may optionally be substituted with alkyl ds, CF3, -OR6, halogen, amino, C1-5 alkylthio, thiocyanate, clade, - C02H, -COOalkylCi-5l -C1-5alkyl, -CONV2, -S02NV2, and -SO2alkylCi-5; Or, both Z and the nitrogen to which they are linked can be taken together to form a 3-8 membered ring, the ring can optionally contain atoms selected from the group consisting of carbon, oxygen, sulfur, and nitrogen, wherein the ring can be be saturated or unsaturated, and the ring carbon atoms may be optionally substituted with one to three substituents selected from the group consisting of Ci-5 alkyl, CF 3) -OR 6, halogen, amino, Ci-5 alkylthio, thiocyanate, cyano , -CO2H, -COOalkylC1-5, -C1-5alkylC1-5, -CONV2, -SO2NV2, and -SO2alkylCi.5i each V is independently selected from the group consisting of Ci-5 alkyl, CF3) -OR6, halogen, amino, alkylthio Ci-5, thiocyanate, cyano, -C02H, -COOalkylC1-5, -COalkylC1-5, and -SO2alkylCi-5; each n is independently an integer from one to five; and the pharmaceutically acceptable salts thereof. 2. The compound according to claim 1, further characterized in that Y is sulfur and X is oxygen, and the pharmaceutically acceptable salts thereof. 3. The compound according to claim 2, further characterized in that R, R2, R3, and R4 are each independently selected from the group consisting of hydrogen, Ci-5 alkyl, C3-8 cycloalkyl, C2-5 alkenyl, C 2-5 alkynyl, -OR 6 and halogen, provided that one of R 2 and R 3 is -OH; R5 is selected from the group consisting of heterocyclic C3-8 cycloalkyl groups, phenyl, heteroaryl, wherein the groups may optionally be substituted with -OR6 and halogen; R6 is selected from the group consisting of hydrogen, Ci-5 alkyl, benzyl, methoxymethyl and triisopropylsilyl; and the pharmaceutically acceptable salts thereof. 4. The compound according to claim 3, further characterized in that it is selected from the group consisting of: and the pharmaceutically acceptable salts thereof. 5. The compound according to claim 3 of the (CH2) nN (2) 2 further characterized in that R1, R2, R3, and R4 are each independently selected from the group consisting of hydrogen, C1-5 alkyl, cycloalkyl Ca-a, C2-5 alkenyl, C2-5 alkynyl , -OR6 and halogen, provided that one of R2 and R3 is -OH; R6 is selected from the group consisting of hydrogen, Ci-5 alkyl, benzyl, methoxymethyl and triisopropylsilyl; R7 is selected from the group consisting of hydrogen, Ci-5 alkyl, halogen, trifluoromethyl, and OR6; each Z is independently selected from the group consisting of hydrogen, C 1-5 alkyl, trifluoromethyl, wherein the alkyl group may optionally be substituted with Ci.5 alkyl, CF3, -OR, halogen, amino, C1.5 alkylthio, thiocyanate, cyano , -CO2H, -COOalkylC-is, -COalkylCi-5, -CONV2, -SO2NV2) and -SO2alkylCi-5; or both Z and the nitrogen to which they are linked, can be taken together to form a 3-8 membered ring, the ring may optionally contain atoms selected from the group consisting of carbon, oxygen, sulfur, and nitrogen, wherein the ring may be be saturated or unsaturated, and the ring carbon atoms may be optionally substituted with one to three substituents selected from the group consisting of Ci-5 alkyl, CF3, -OR6, halogen, amino, C1-5 alkylthio, thiocyanate, cyano , -CO2H, -COOalkylCi-5, -COalkylod-s, -CONV2, -SO2NV2, and -SO2alkylCi.5; each V is independently selected from the group consisting of C1-5 alkyl, CF3, -OR6, halogen, amino, C1-5 alkylthio, thiocyanate, cyano, -CO2H, -COOalkylod-s, -COalkylCi-5, and -SO2alkylC- 5; each n is independently an integer from one to five; each m is independently an integer from one to four; and the pharmaceutically acceptable salts thereof. 6. The compound according to claim 5 further characterized in that it is selected from the group consisting of: and the pharmaceutically acceptable salts thereof. 7. The compound according to claim 5 of the formula: further characterized in that R1, R2, R3, and R4 are each independently selected from the group consisting of hydrogen, C1-5 alkyl, C3-8 cycloalkyl, C2-5 alkenyl, C2-5 alkynyl, -OR6, and halogen, provided that one of R2 and R3 is -OH; R6 is selected from the group consisting of hydrogen, C-i-5 alkyl, benzyl, methoxymethyl and triisopropylsyl; R7 is selected from the group consisting of hydrogen, C1.5 alkyl, halogen, trifluoromethyl, and -OR6; R8 is independently selected from the group consisting of hydrogen, C1-5alkyl, CF3, -OR6, halogen, amino, alkylthio d-5, thiocyanate, cyano, -CO2H, -COOalkylCi, 5, -CalkylCi-5, -CONV2, -SO2NV2, and -SO2alkylCi-5; each V is independently selected from the group consisting of Ci-5 alkyl, CF3, -OR6, halogen, amino, C1.5 alkylthio, thiocyanate, cyano, -CO2H, -COOalkylCi-5, -COalkylCi-5, and -SO2alkylC1- 5; each m is independently an integer from one to four; each p is independently an integer from one to four; and the pharmaceutically acceptable salts thereof. 8. The compound according to claim 7, further characterized in that it is selected from the group consisting of: ??? ??? ??? ??? 240 241 242 43 44 ??? and the pharmaceutically acceptable salts thereof. 9. The compound according to claim 5 of the formula: further characterized in that R1, R2, R3, and R4 are each independently selected from the group consisting of hydrogen, Ci_5 alkyl, OR6, and halogen, provided one of R2 and R3 is -OH; R6 is selected from the group consisting of hydrogen, C1-5 alkyl, benzyl, methoxymethyl and triisopropylsilyl; R7 is selected from the group consisting of hydrogen, C1.5 alkyl, halogen, trifluoromethyl, and -OR6; Each m is independently an integer from one to four; and the pharmaceutically acceptable salts thereof. 10. The compound according to claim 9, further characterized in that it is selected from the group consisting of: ??? ??? 250 252 and the pharmaceutically acceptable salts thereof. 1. The compound according to claim 1, further characterized in that X is sulfur and Y is sulfur, and the pharmaceutically acceptable salts thereof. 12. The compound according to claim 1 1, further characterized in that it is selected from the group consisting of and the pharmaceutically acceptable salts thereof. 13. A pharmaceutical composition, characterized comprising a compound of claim 1 and a pharmaceutically acceptable. 14. - A pharmaceutical composition characterized in that it is made by combination with a compound of claim 1 and a pharmaceutically acceptable carrier. 15. - A process for making a pharmaceutical composition, characterized in that it comprises combining a compound of claim 1 and a pharmaceutically acceptable carrier. 16. The use of a compound according to claim 1, to prepare a composition obtain an estrogen receptor modulating effect in a mammal. 17. The use as claimed in claim 16, wherein the modulating effect of the estrogen receptor is an estrogen receptor agonist effect. 18. The use as claimed in claim 17, wherein the estrogen receptor agonist effect is an agonist effect of the ER a receptor.