CA2424729A1 - Estrogen receptor modulators - Google Patents

Abstract

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

Description

TITLE OF THE INVENTION
ESTROGEN RECEPTOR MODULATORS
BACKGROUND OF THE INVENTION
Naturally occurring and synthetic estrogens have broad therapeutic utility, including: relief of menopausal symptoms, treatment of acne, treatment of dysmenorrhea and dysfunctional uterine bleeding, treatment of osteoporosis, treatment of hirsutism, treatment of prostatic cancer, treatment of hot flashes and prevention of cardiovascular disease. Because estrogen is very therapeutically valuable, there has been great interest in discovering compounds that mimic estrogen-like behavior in estrogen responsive tissues.
For example, estrogen-like compounds would be beneficial in the treatment and prevention of bone loss. Bone loss occurs in a wide range of subjects, including women that are post-menopausal or have had a hysterectomy, patients who were or are currently being treated with carticosteroids, and patient's having gonadal dysgenesis. The cuwent major bone diseases of public concern are osteoporosis, hyperealcemia of malignancy, osteopenia due to bone metastases, periodontal disease, hypetparathyroidism, periarticular erosions in rheumatoid arthritis, Pager's disease, immobilization-induced osteopenia, and glucocorticoid-induced osteoporosis.
All of these conditions are characterized by bane loss, resulting From an imbalance between bone resorption, i.e. breakdawn, and bone formation, which cantinues throughout life at the rate of abaut 1~1%a per year on the average. However, the rate of bane turnover differs from site to site, for example, it is higher in the trabecular bone of the vertebrae and the alveolar bane in the jaws than in the cortices of the long bones. The potential For bone loss is directly related to turnover and can amount to over 5%a per year in vertebrae immediately Following menopause, a condition which leads to increased Fracture risk.
In the I~.S., there Ire cut~rently about 20 million people with detectable Fractures of the vertebrae due to osteoporosis. In addition, there are about X50,000 hip Fractures per year attributed ro osteoporosis. This clinical situation is associated with a 12°l~ mortality rare within the first two years, while 30~/~ of the patients require nursing home care after the fracture.
Osteoporosis affects approximately 20 to 25 million past-menopausal women in the C.S. alone. It has been theorized than the rapid loss of bone mass in these women is due to the cessation of estragen production of the avaries.
Since studies have shown that estrogen slows the reduction of bone mass due to osteoporosis, estrogen replacement therapy is a recognized treatment t'or past-menopausal osteoporosis, In addition to bane mass, estrogen appears to have an eFfect on the biosynthesis ol~ cholesterol and cardiovascular health. Statistically, the rate of occurrence of cardiovascular disease is roughly equal in pos~tmenapausal women and men; however, premenapausal women have a much lower incidence of cardiovascular disease than men. Because pastmenopausal women are estrogen deficient, it is believed that estrogen plays a beneficial role in preventing cardiovascular disease.
The mechanism is not well understood, but evidence indicates that estrogen can upregulate the low density lipid (LDL) cholesterol receptors in the liver to remove excess cholesterol.
Postmenopausal women given estrogen replacement therapy experience a return of lipid levels to concentrations comparable to levels associated with the premenapausal state. Thus, estrogen replacement therapy could be an effective treatment for such disease. However, the side effects associated with long term estrogen use limit the use of this alternative.
Other disease states that affect postmenopausal women include estrogen-dependent breast cancer and uterine cancer. Anti-estrogen compounds, such as tamoxifen, have commonly been used as chemotherapy to treat breast cancer patients. Tamoxifen, a dual antagonist and agonist of estrogen receptors, is beneficial in treating estrogen-dependent breast cancer. However, treatment with tamoxifen is less than ideal because tamoxifen's agonist behavior enhances its unwanted estrogenic side effects. For example, tamoxifen and other compounds that agonize estrogen receptors tend to increase cancer cell production in the uterus. A better therapy for such cancers would be an anti-estrogen compound that has negligible or nonexistent agonist properties.
Although estrogen can be beneficial for treating pathologies such as bone loss, increased lipid levels, and cancer, lonb term estrogen therapy has been implicated 3n a variety of disorders, including an increase in the risk of uterine and endametrial cancers. These and other side effects of estrogen replacement therapy are not acceptable to many women, thus limiting its use.
Alternative regimens, such as a combined progestagen and estrogen dose, have been suggested in an attempt to lessen the rislt of cancer.
However, such regimens cause the patient to experience withdrawal bleeding, which is unacceptable to many older women. Furthermore, combining estrogen with progestogen reduces the beneficial cholesterol-lowering effect of estrogen therapy. In addition, the long term effects of progestogen treatment are unknown.
In addition to post-menopausal women, men suffering from prostatic cancer can also benefit from anti-estrogen compounds. Prostatic cancer is often endocrine-sensitive; androgen stimulation Fosters tumor growth, while androgen suppression retards tumor growth. The administration of estrogen is helpful in the treatment and control of prostatie cancer because estrogen administration lowers the level of ganadotropin and, consequently, androgen levels.
The estrogen receptor has been found to have two forms: ERcc and ER(3. Ligands bind differently to these two forms, and each form has a different tissue specificity to binding ligands. Thus, it Is possible to have compounds that are selective for ERa or ER~3, and therefare confer a degree of tissue specificity to a particular ligand.
What is needed in the art are compounds that can praduce the same positive responses as estrogen replacement therapy without the negative side effects.
Also need are estrogen-like compaunds that exert selective effects on different tissues of the body.
The compounds of the instant invention are ligands for estrogen receptors and as such may be useful for treatment or prevention of a variety of conditions related to estrogen functioning including: bone loss, bone fractures, osteoporosis, cartilage degeneration, endometriosis, uterine fibroid disease, hot flashes, increased levels of LDL cholesterol, cardiovascular disease, impairment of cognitive functioning, cerebral degenerative disorders, restinosis, gynacomastia, vascular smooth muscle cell proliferation, obesity, incontinence, and cancer, in particular of the breast, uterus and prostate.
-3 _ SUMMARY OF THE INVENTION
The present invention relates to compounds of the following chemical formula:

R2 \ Y R5 R~ / ~i(CH2)nNtz)z wherein R~, R2, R3, and R'~ are each independently selected from the group consisting of hydrogen, C f_S alkyl, C3_g cycloallcyl, C?_5 alkenyl, C?_ 5 alkynyl, C3_g cycloalkenyl, phenyl, heteroaryl, heterocyclical, CF3, -OR6, halogen, C f-5 alkylthio, thiocyanato, cyano, -CO?H, -COOC f_S
alkyl, -COC f_5 alkyl, -CONZ?, -S02NZ?, and -SO~C~..S alkyl, wherein said alkyl, allcenyl, alkynyl, cycloalkyl, cycloalkenyl, phenyl, heteraaryl, heterocyelical groups can be optionally substituted with C1_ 5 alkyl, C3_g cycloalkyl, CF3, phenyl, heteroaryl, heterocyclical, -OR6, halogen, amino, C f_~ alkylthio, thiocyanato, cyano, -COSH> -COOL f_ 5 alkyl, -COC~_5 alkyl, -CONZ~, -SO?NZ~, and -SO?C I_~ alkyl;
RS is selected from the group consisting of C ~_5 alkyl, C3-g cycloalkyl, C~_5 alkenyl, C~_5 alkynyl, C3_g cycloalkenyl, phenyl, heteroaryl, heterocyclical groups wherein said groups can be optionally substituted with C1_S
alkyl, C3_g cycloalkyl, CF3, phenyl, heteroaryl, heterocyclical, -ORS, halogen, amino, C~_5 allcylthio, thiocyanato, cyano, -CO?H, -COOC1_ ~ alkyl, -COC1_5 alkyl, -CONZ?, -SO?NZ?, and -SO?C I_5 alkyl;
~ and Y are each independently selected from the group consisting of oxygen, sulfur, sulfoxide and sulfone;
?5 R~ is selected from the group consisting of hydrogen, Cf_5 alkyl, ben~yl, methoxymethyl, triorganosilyl, C~_5 alkylcarbonyl, alkoxycarbonyl and CONZ?;
Each Z is independently selected From the group consisting of hydrogen, C f_~
alkyl, trifluoromethyl, wherein said alkyl group can be optionally substituted with C1_5 alkyl, CF,, -ORS, halogen, amino, C1_5 allcylthio, thiocyanato, cyano, -CO?H, -COOC 1_5 alkyl, -COC 1_5 alkyl, -CONV?, -SO?NV~, and-SO?Cl_5 alkyl;
Or both Zs and the nitrogen to which they are attached may be taken together to form a 3-8 membered ring, said ring may optionally contain atoms selected from the group consisting of carbon, oxygen, sulfur, and nitrogen, wherein said ring may either be saturated or unsaturated, and the carbon atoms of said ring maybe optionally substituted with one to three substituents selected from the group consisting of C1-5 alkyl, CF3, -ORS, halogen, amino, C 1-~ alkylthio, thiocyanato, cyano, -CO?>'I, -COOC~_5 alkyl, -COC f_5 alkyl, -CONV?, -SO?NV~, and -SO?C l_$ alkyl;
Each V is independently selected from the group consisting of C~_~ alkyl, CF3, -ORS, halogen, amino, C~_~ alkylthio, thiocyanato, cyano, -COSH> -COOC~-5 alkyl, -COC1-5 alkyl, and -SO~Cf_5 alkyl;
Each n is independently an integer from one to five;
and the pharmaceutically acceptable salts thereof.
The present invention also relates to pharmaceutical compasitions comprising the compounds of the present invention and a pharmaceutically acceptable carrier.
The present invention also relates to methods for making the pharmaceutical compositions of the present invention.
The present invention also related to pracesses and intermediates useful for making the compounds and pharmaceutical compositions of the present invention.
The present invention also relates to methods far eliciting an estrogen receptor modulating effect in a mammal in need thereof by administering the compounds and pharmaceutical compositions of the present invention.
The present invention also relates to methods for eliciting an estrogen receptor antagonizing effect in a mammal in need thereof by administering the compounds and pharmaceutical compositions of the present invention. The estrogen receptor antagonizing efFect can be either an ERcx, antagonizing effect, and ER(3 antagonizing effect or a mixed ERcc and ER(3 antagonizing effect.
_5_ The present invention also relates to methods For eliciting an estrogen receptor agonizing effect in a mammal in need thereoF by administering the compounds and pharmaceutical compositions of the present invention. The estragen receptor agonizing effect can be either an ERCC agonizing effect, and ER~3 agonizing eFFect or a mixed ERcx and ER(3 agonizing effect.
The present invention also relates to methods for treating or preventing disorders related to estrogen functioning, bone lass, bone Fractures, osteoporosis, cartilage degeneration, endometriosis, uterine fibroid disease, cancer of the breast, uterus or prostate, hot flashes, cardiovascular disease, impairment of cognitive function, cerebral degenerative disorders, restenosis, gynacomastia, vascular smaoth muscle cell proliferation, obesity and incontinence 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 reducing bone loss, lowering LDL cholesterol levels and eliciting 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
?0 The present inventian relates to compounds useful as estragen receptor modulators. Compounds of the present invention era described by the following chemical formula:

R2 \ Y R5 R'~ / ~i(C1-12)nN~Z)2 wherein R F, R~, R3, and R'F are each independently selected from the group consisting of hydrogen, C f-5 alkyl, C3-g cycloall<yl, C~_5 alkenyl, C?_ $ alkynyl, C3-g cycloalkenyl, phenyl, heteroaryl, heterocyclical, CF3, -OR~, halogen, C1_~ alkylthio> thiocyanato, cyano, -CO?H, -GOOC1-5 alkyl, -COCI_~ alkyl, -CONZ?, -SO?NZ?, and -SO?CF_5 alkyl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, phenyl, heteroaryl, heterocyclical groups can be optionally substituted with C 1-alkyl, C~_g cyeloallcyl, CI~3, phenyl, heteroaryl, heterocyclical, -ORb, halogen, amino, Cl_5 alkylthio, thiocyanato, cyano, -CO?fI, -COOCI_ 5 alkyl, -COC1-5 alkyl, -CONZ?, -SO?NZ?, and -SO?C1_5 alkyl;
5 R~ is selected from the group consisting of C1_5 alkyl, C3-g cycloalkyl, C~_5 all<enyl, C?_5 alkynyl, C3_g cycloalkenyl, phenyl, heteroaryl, heterocyclical groups wherein said groups can be optionally substituted with C~_~
alkyl, C3_g cycloalkyl, CF3, phenyl, heteroaryl, heterocyclical, -ORS, halogen, amino, C t-S alkylthio, thiocyanato, cyano, -CO?H, -COOC f-5 alkyl, -COC l-5 alkyl, -CONZ?, -SO?NZ~, and -SO~C 1_5 alkyl;
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 f_S alkyl, benzyl, methoxymethyl, triorganosilyl, C~-~ alkylcarbonyl, alkoxycarbonyl and CONZ?;
Each Z is independently selected from the group consisting of hydrogen, C f-5 alkyl, trifluoromethyl, wherein said alkyl group can be optionally substituted with CL_5 alkyl, CF3, -ORS, halogen, amino, C~_~ allcylthio, thiocyanato, cyano, -CO?H, -COOC~_5 alkyl, -COC1_5 alkyl, CONV?, -SO?NV~, and -SO?C~_5 alkyl;
Or both Zs and the nitrogen to which they are attached may be taken together to form a 3-8 membered ring, said ring may optionally contain atoms selected from the group consisting of carbon, oxygen, sulFur, and nitrogen, wherein said ring may either be saturated or unsaturated, and the carbon atoms of said ring maybe optionally substituted with ane to three substituents selected from the group consisting of C f_~
alkyl, CF3, -ORS, halogen, amino, Cl_5 alkylthio, thiocyanato, cyano, -CO?H, -COOC~_~ alkyl, -COC f_S alkyl, -CONVL, -SO?NV~, and SO?C~_5 alkyl;
Each V is independently selected From the group consisting of C 1-s alkyl, CF3, -OR6, halogen, amino, C f-$ alkylthio, thiocyanato, cyano, -CO?H, -COOC~_ ~ alkyl, -COC f-5 alkyl, and -SO?C 1_~ alkyl;
Each n is independently an integer from one to five;
and the pharmaceutically acceptable salts thereoF.

In one class of compounds of the present invention, X is Oxygen, and Y is Sulfur.
In one class of compounds of the present invention, Rl ,R~ ,R'~ and R'F
are selected from the group consisting of hydrogen, C ~_5 alkyl, C3_g cycloalkyl, C l_5 s alkcnyl, Cl_~ allcynyl,-ORS and halogen.
In one class of compounds of the present invention RS is selected From the group cansisting of C3_g cycloalleyl, phenyl, heteroaryl and heterocyclical groups wherein said groups can be optionally substituted with -ORS and halogen.
In one class of compounds of the present invention, R~ is preferably selected from the group consisting of hydrogen, C~_$ alkyl, benzyl, methoxymethyl and triisopropylsilyl.
The present invention also relates to a process for preparing a compound of formula I

Rs / X ~ \
R4 / ~~(CH2)nN~z)2 >,s wherein R~ is H, F, or CI;
R? is H or OR6;
R3 is H or ORS;
Rd is H or CH3;
R5 is C 1_5 alkyl, C3_g cycloalkyl, C3_g cycloalkenyl, phenyl, heteroaryl, or heterocyclical groups wherein said groups can be optionally substituted with C
t_~
alkyl, C3_g cycloall<yl, CF3, phenyl, heteroaryl, heterocyclical, -OR6, halogen, amino, Cl_S alkylthio, thiocyanato, cyano, carboxyl (-CO?H), carboalkoxyl (-2s COOCI_5 alkyl), carbonyl (-COCI_5 alkyl, carboxamido (-CON~~), sulfonamido (-S02NZ?), and sulfonyl {-SO?C1_5 alkyl);
Rb is H, benzyl, methyl, methoxymethyl, or triisopropylsilyl, with the proviso that when ORS exists elsewhere, it is chemically differentiable;
_g_ 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, C I_5 alkyl, trifluoromethyl, wherein said alkyl group can be optionally substituted with CI_5 alkyl, CF3, -ORG, halogen, amino, C f-5 alkylthio, thiocyanato, cyano, -CO?>-I, COOC f-~ alkyl, -COCA-S alkyl, -CONV?, -SO?NV~, and -S02C I-~ alkyl;
Or both Zs and the nitrogen to which they are attached may be taken together to form a 3-8 membered ring, said ring may optionally contain atoms selected from the group consisting of carbon, oxygen, sulfur, and nitrogen, wherein said ring may either be L0 saturated or unsaturated, and the carbon atoms of said ring maybe optionally substituted with C~_5 alkyl, CF3, -ORS, halogen, amino, C f-~ alkylthio, thiocyanato, cyano, -COSH, -COOL f-~ alkyl, -COC f_$ alkyl, -CONV2, -SO~NV~, and -SO~C~-5 alkyl;
Each V is independently selected from the group consisting of C1_5 alkyl, CF3, -ORS, halogen, amino, C~-5 alkylthio, thiocyanato, cyano, -COSH, -COOC f-5 alkyl, -COC1_~ alkyl, and-SO?Cf-5 alkyl;
n is an integer from one to five;
and the stereoisomer is cis;
or a pharmaceutically acceptable salt thereof, comprising the steps of a) reacting a compound of formula II with a campound of formula III
under basic conditions Rz \ YH Br R
Rs / XH O~ \
Ra / ORs II III
?5 to form a compound of formula IV
_c~_ R~ XH
R3 ~ ~ Y R5 R2 R1 O \

b) cyclizing IV, of step a, under acidic conditions in the presence of a reducing agent, to provide the cis compound of formula V

R3 / X \

c) removing the protecting group R6 to yield the substituted phenol of formula VI

R2 Y Rs R3 / X \

VI OH
d) alkylating the substituted phenol of farmula VI, from step c, with a reagent, HO(CH?)nN(Z)?, to give a compound of formula I
-10~

Y R~
R3 / X \
R'~ / Oi(CH2)nN~z)2 e) removing either protecting group From I, from step d, to afFord either a compound of formula VIII or a compound of Formula IX

HO \ Y R5--(OR6) R3 / X \
R~ vm / o~t~H2)nN(z)2 R60 \ Y R~-(OH) R3 / X \
R4 / O~(CH2)nN~z)2 IX
F~ removing the remaining protecting group From either VIII or IX, From step e, to give a compound of formula 1.
The present invention also relates to a process for preparing a compound of Formula ID

/ OH
R
HO \ S
Ra / O .,,>> \
R~ / O
(+) - I D
wherein Rl is H, F, or Cl;
R~ is H;
R'~isHorCH3;
and the stereoisomer is ci,~~;
and the optical isomer is dextrorotatory {+), having the absolute configuration: {?S, 3R);
or a pharmaceutically acceptable salt thereof, camprising the steps of a) reacting a compound of formula lID with a compound of Formula ll~D under basic conditions '~TI PS
Bn0 ~ SH Br OH C
IID
IIID
to Form a compaund of l:ormula IVD
- 1? -OH TIPS
S
Bn0 O
H
IVD
b) cyclizing IVD, of step a, under acidic conditions in the presence of a reducing agent to provide the racemic, cis compound of formula VD
TIPS
B
VD
c) performing a chiral chromatography with VD, From step b, to resolve the en antiomeric Forms to provide the dextrorotatory (+) isomer VID;
OTI PS
Bn0 ~ S
~...
O ,, OH
(+)-V I D
d) alkylating the dextrorotatory (+) isomer VID, from step c, with 1-piperidineethanol to give a compound of formula VILD

/ OTI PS
B n O ~ S ,,,v \
/ O .,,u \
/ O~ N
VIID
e) removing either protecting group from VIID, foam step d, to aFFord either a compound aF Formula VIIID or a compound of Formula LYD
/ OTIPS
H O \ S ,,~~ \
/ O .,..i \
/ O~ N
VIIID
/ OH
B n0 ~ S ,,,~ \
O ,, \
O~ N
IXD
f) removing the remaining protecting group From either VI LID or LXD, from step e, to give a compound of Formula I.
LO
The present invention also comprises a process according for preparing a compound of formula IE

/ R~
R
H O \ S ,,,v m R3 p ~''u \
Ra / O~ N
(+)-IE
wherein R~ is selected From the group consisting oFH, F, or Cl;
R3 and R~ are each H;
R~ is selected From the group consisting of H or OH;
the stereoisamer is cis, antl the optical isomer is dextroratatory (+), having the absolute canfiguration (2S, 3R);
or a pharmaceutically acceptable salt thereoF
comprising the steps of a) reacting a compound of Formula IIE with a compound of Formula IIIE under basic conditions R1 R~
Bn0 ~ SH E
OH
IIE ORS
IIIE
to Form a compound of formula IVE
1 _5 OH
Bn0 R1 IVE
b) cyclizing IVE, of step a, under acidic conditions in the presence of a reducing agent to provide the racemic, cis compound of Formula VE
Bn Rs VE
c) selectively removing the protecting group of VE, from step b, to yield the substituted phenol of formula VIE
Bn H
VIE
l0 d) alkylating the subsfiituted phenol of formula VIE, From step c, with l~
piperidineethanol to give a compound of formula VIIE

Bn0 S
/ O
~O~ N
VIIE
e) removing either protecting group from VIIE to afford either a compound of formula VIIIE or a compound of formula IXE
R~ TI PS
HO ~ S
/ O
V~ N
VIIIE

Bn0 ~ S
/
O
/ O~ N
S IXE
f) removing the remaining protecting group from either VIII or I~, from step e, to provide racemic I.
g) performing a resolution of the enantiomeric forms of I to provide the dextrorotatory (+) isomer I, having the (2S, 3R) absolute configuration.
The present invention also relates to novel intermediates useful for preparing compounds and compositions described heroin, i.e compounds of formula I, IA, IB, IC, ID and I:E.
An emobidment of the invention is an intermediate of the formula:

R2 \ S Rs R3 ~ O \
R~

wherein R1 is H, F, or CI;
R? is H or ORS;
R3 is H or ORS;
R'~ is H or CH3;
R$ is Cl-~ alkyl, C3_8 cycloalkyl, C3_g cycloalkenyl, phenyl, heteroaryl, or heterocyelical groups wherein said groups can be optionally substituted with C~-5 alkyl, C3-g cycloalkyl, CF3, phenyl, heteroaryl, heterocyclical, -OR6, halogen, amino, C1_~ all<ylthio, thiocyanato, cyano, carboxyl (-CO?H), carboallcoxyl (-COOC1_5 alkyl), carbonyl (-COCl-~ alkyl, carboxamido (-CO ~ 'Z?), sulfonamido (-SO~NZ~), and sulfonyl (-SO?C1-~ alkyl);
R~ is H, benzyl, methyl, methoxymethyl, or trisopropylsilyl, with the proviso that when OR6 exists elsewhere, it is chemically differentiable;
J 5 Each Z is independently selected From the group consisting of hydrogen, C1_~
alkyl, trifluoromethyl, wherein said alkyl group can be optionally substituted with C~-S alkyl, CF3, -ORS, halogen, amino, C1_~
alkylthio, thiocyanato, cyano, -CO?H, -COOC1_5 alkyl, -COC 1-5 alkyl, -CONV~, -SO?NV~, and -SO~C1-5 alkyl;
Or both Zs and the nitrogen to which they are attached may be taken together to form a 3-8 membered ring, said ring may optionally cantain atoms selected from the group consisting of carbon, oxygen, sulFur, and nitrogen, wherein said ring may either be saturated or unsaturated, and the carbon atoms of said ring maybe optionally substituted with C1_S alkyl, CF3, -ORS, halogen, amino, C1_5 alkylthio, thiocyanato, cyano, -CO?H, -COOCI-5 alkyl, -COCI_~ alkyl, -CONV?, -SO?NV?, and-SO?Cl_s alkyl;

Mach V is independently selected from the group consisting of C I_5 alkyl, CF3, -ORb, halogen, amino, C I_5 alkylthio, thiocyanato, cyano, -CO?I-I, -COOL I_ alkyl, -coCl_5 alkyl, and ~so~cl_5 alkyl.
Another embodiment of the invention is an intermediate of the Formula:

R2 \ S R5 R3 O \
R~ / O~ N
wherein Rf is H, F> or Cl;
R~ is H or ORS;
R3 is H or OR6;
LO R't is H or CH3;
RS is C1_S alkyl, C3-g cycloalkyl, C3_g cycloalkenyl, phenyl, heteroaryl, or heterocyclical groups wherein said groups can be optionally substituted with C~_5 alkyl, C3_g cycloalkyl, CF3, phenyl, heteroaryl, heterocyclical, -ORd, halogen, amino, C~_5 alkylthio, thiocyanato, cyano, carboxyl (-CO?H), carboalkoxyl (-COOC1_5 alkyl), carbonyl ~-COCA-S alkyl, carboxamido (-CONZ?), sulFonamido (-SO~NZ?), and sulFonyl ~-SO?C1_~ alkyl);
R~ is H, benzyl, methyl, methoxymethyl, or triisopropylsilyl, with the proviso that when ORS exists elsewhere, it is chemically diFferentiable;
Each Z is independently selected From the group consisting of hydrogen, C~_~
alkyl, trifluoromethyl, wherein said alkyl group can be optionally substituted with C~_~ alkyl, CF3, -OR~> halogen, amino, CL_~
all<ylthio, thiocyanato, cyano, -CO?H, -COOC1-5 alkyl, -COC1_~
alkyl, -CONV?, -SO?NV~, and -SO?C~_5 alkyl;
Or both Zs may be taken together Form a 3-8 membered ring, said ring may optionally contain atoms selected from the group consisting of carbon, oxygen, sulfur, and nitrogen, wherein said rind may either be saturated or unsaturated, rind the carbon atoms of said ring maybe optionally substituted with CI_5 alkyl, CF3>-ORS, halogen, amino, I 9 .-C 1 _5 allcylthio, thiocyanato, cyano, -CO? H, -COOC 1 _5 alkyl, -COC 1 _ alkyl, -CONV~, -SO?NV?, and -SO?C f_5 alkyl.
Each V is independently selected from the group consisting of Cl_5 alkyl, CF's, -ORS, halogen, amino, C 1_5 rLlkylthio, thiocyanato, cyano, -C02H, -COOC 1_ 5 S alkyl, -COC 1_~ alkyl, and -SO~C 1 _5 alkyl.
Another embodiment of the invention is an intermediate of the formula:
R~ / ORs R60 ~ S
~~-) _ ~ /
O

wherein R1 is H, F, or Cl;
~0 R~ is H, benzyl, methyl, methoxymethyl, or triisopropylsilyl, wifh the proviso that all existing R~ groups are chemically differentiable.
Another embodiment of the invention is an intermediate of the formula:

R60 ~ S
t.~-> _ ~ /

N
wherein R1 is H, F, or Cl;
R~ is H, ben~yl, methyl, methoxymethyl, or tnisopropylsilyl, with the proviso that all existing R~ groups are chemically differentiable.
Another embodiment of the invention is an intermediate of the formula:

R2 \ S ,,~~ R~
(+) -Rs ~ O ,.>>i \
R~

wherein R t is H, F, or Cl;
R~ is H or ORG;
R3 is H or ORS;
R~ is H or CH3;
R5 is Cl_s alkyl, C3_g cycloalkyl, C3_g cycloallcenyl, phenyl, heteroaryl, or heterocyclical groups wherein said groups can be optionally substituted with C~_5 alkyl, C3_g cycloall<yl, CF3> phenyl, heteroaryl, heterocyclical, -ORS, halogen, amino, C1_S alkylthio, thiocyanato, cyano, carboxyl (-CO?H), carboalkoxyl {.-COOCI_~ alkyl), carbonyl {-COC~_~ alkyl, carboxamido (-CONZ?), sulfonamido {-SO?NZ?), and sulfonyl {-SO~C~_~ alkyl);
R~ is H, ben~yl, methyl, methoxymethyl, or triisopropylsilyl, with the proviso that when O.R6 exists elsewhere, it is chemically differentiable;
Each Z is independently selected from the group consisting of hydrogen, C~_~
alkyl, trifluoromethyl, wherein said alkyl group can be optionally substituted with C~_S alkyl, CF3, -ORS, halogen, amino, C~_5 alkylthio, thiocyanato, cyano, -CO?H, -COOCf_5 alkyl, -COC~_~
alkyl, -CONV~, -SO~NV~, and -SO?C f-5 alkyl;
Or both ~s and the nitrogen to which they are attached may be taken to together form a 3-8 membered ring, said ring may optionally contain atoms selected from the group consisting of carbon, oxygen, sulfur, and nitrogen, wherein said ring may either be saturated or unsaturated, ?5 and the carbon atoms of said ring maybe optionally substituted with Cl_s alkyl, CF3, -OR6, halogen, amino, Cl_5 alkylthio, thiocyanato, cyano, -CO?H, -COOC1_~ alkyl, -COCI_~ alkyl, -CONV~, -SO~NV~, and -SO?Cf_~ alkyl;

Each V is independently selected from the group consisting of C 1 _5 alleyl, CF3, -ORS, halogen, amino, C1_5 alkylthio, thiocyanato, cyano,-CO?I-I,-COOCI_ alkyl, -COC I-5 alkyl, and -SO?C I_~ alkyl.
Another embodiment of the invention is an intermediate of the 5 Formula:
wherein R~ is H, F, or Cl;
R1 / ORs Rs0 \ S ,,,~ \
(+) _ ~ /
/ ORS
R6 is H, benzyl, methyl, methoxymethyl, or triisoprapylsilyl, with the proviso that all existing R~ groups are chemically differentiable.
Anather embodiment of the present invention is an intermediate of of the Formula:

Rs0 \ S .,,v \
+) _ / O ''~, \
/ O~ N
wherein R~ is H, F, or Cl;
R~ is H, benzyl, methyl, methoxymethyl, or triisopropylsilyl, with the proviso that all existing R6 groups are chemically differentiable.
Non-limiting examples of the present invention include:

/ OH
HO \ S ,~~I\
/ O ,,,, \ ~i /' ~ N
O
/ OH
HO \ S ,,,~I\
t+) -/ O ''lf \
~ 'NCHs O
/ OH
HO \ S ~~'\ Pil + ~ / ~.,1/
/ O~ N
/ OH
HO .~ S ,,,v\
~+) _ ti / ~I 'n~ \
O ~~~ ~'~CHs O~ N CH3 OH
HO
t+) _ n O ~~, \~ ~.~~CH3 ~ N
O
/ OH
H O .~ S
~+> - ~~ ~ CH3 / p ''~~ \
f~~ /i ~N CHa O

HO \ S ~~' \ I OH
p 1'~~ i \
~ N
O
I
HO \ S .~~'I\ I OH
/ O ~'~, \
~CH3 / O~ N
/
HO I \ S .,~''w I OH
(+) ~ /' O
/ O~ N
/
HO \ S .,~'~~ ~I OH
(+) _ p ~II / ~ N
O
HO \ S .,~' \ ~ OH
-) _ o .,,> ~ \
/ N~CH3 O~
I/
HO \ S ~~' \ l OH
t~) _ , / ~A, C H3 O ',~~ \

/ O~ N
?~ _ F / OH
i HO ~ S , +) - ~ ~,.
N
O~
OH
F
y HO ~ S
O ~~ / NCH
O ------~~~
F / OH
i HO ~ S
~+) _ o .,,, ,~n~CH3 N
O~
F
HO ~, S ,,,vv ~,' OH
O '~
N
O~
F /
HO ~ S
t+) - I~~ i~~\ ~ off /

/ N~~° C H3 O~
F /
HO ~ S ~~' ~ OH
~+) _ 16 / i ~L,y O
i ~v'~i'CH3 / N
O~
?5 OH
~I I
HO ~ S ,''~~ H C
(+) - ~ ~ ~~', 3 CH3 O ,''y ~ 'w i O~ N
HO ~, S I,,,v w ~ ~ OH H3C CH
JfJ,, ~
O
~ , o~ N
HO ~ S ~''~~ l OH
t+> -~>>,, O ~Ii , N~~ ~ ~CH3 O~
OH
HO ~ S ,,'v~\
(+) _ , / ~ ~.~ HaC
O ~~y \
.r~CH3 / O~ ~~''N
i HO ~ S '~'' ~ OH
) H C,, / ~,'i !) I
~'CH3 / O~N

/ OH
HO \ S
,,~~ \
\CHs ''l~ \ ~ ~
~_CH3 O ~ .~N
OH
HO \ S
,,v \
I ~~. CH3 O .,,1, \
~~,~ fiCHs / ~N~
O
/ OH
H O \ S I' I
,,~~ \
~+) _ I ., / O ill i II ~ CHs /, O~N
CHs / OH
HO \ S , ~~I\ II
I O.
O .,,1~ .~ HsC
I ~~~C H s / O~N
OH
HO \ S \ I
/ O ,,l/ I \
~1CH3 /' O~N
CHs a_~ _ HO ~ S
(+) _ I, ~I,,.'' \

/ O '''j \
/' N~CHa O~
HO \ S ,, (+) _ ~1 OH CH3 / O '''~ \
~. nCH3 O~N
HO \ S
(+) _ I ~ '~'~~\ OH
/ ~~'r p 1I \

O

HO \, S ,~''I\ I OH
(+) _ y~~, H C
p / ~I NCHa O~
HO \ S
OH
(+) -/ p ''>> \
~~C H 3 /, O~N

m?S-OH
HO ~ S
~+~ _ y't~
~l,~nCH
/ O~ N s HO ~ S .~'' ~ I OH
~ O ,,,, ~ nCH3 N
O~

OH
HO ~ S
O .,,j I ~ H3Cu,, ~~'"CH3 / O~ N
HO ~ S
OH
H C~, O~.r O ,, ~ 3 ,.
~~nCH3 /' O~N
/ OH
HO ~ S
~+~
n'CH
/ O~ N a I
HO \ S .,~~~OH
~+) O 1''' ,~~iCH3 /' O~N
CHs OH
HO \ S
+) -o ~I
/ o~N
OH CHs HO \ S ,,,~'\ III
(+) _ ~I~ ~ ., / O t~r I \
/ ~ O~ N
~CH3 / I I OH
HO \ S
(+) - I
O:~j O ,, P \
CH2CHs /' O~N
CHs OH
,,v ~ \
H O .~ S
+) -O '~~~ \
N~CH2CH3 O

H O ~ I S ,,,' ~ I
II ~; OH
yIl ~ I
~N
O
CHI
HO ~ S ,,'~ ~ OH
/ N
O~
~~CH3 HO ~ S ~~'' ~ OH
(+) I
/ O '''f CHzCH3 / O~ N

HO ~ S
) _ ~ OH
/ O
~'CH~CH3 O~N
HO ~ S ,,~'' ~ OH
)_ O j~~~~~i ~ ,~N~CH2CH3 N~, / O~

/ OH
HO \ S ' '~'~\ ~ i ~I~>, CH CH
O ~, ~ \
~~~sCH3 ~ O~ N
HO \ S I' I
OH
(+) -~'>, CH CH
p ~i \ I ~ i'2 3 ~nCH3 O~N
/ OH
HO \ S ' (+) _ i / O '''l, \
~~~nCH2CH3 / ~N

/
Ho \ s .,,,, \
OH
I ~,~nCH2CH3 / O~ ~,~N
/ OH
HO \ S ',~~ \
~,'.
/ O ~,~~ \
'I .~~iCH3 j O~N

- 3?

/ OH
HO \ S , ~''\ i ' , / O '''j~ \
~h ~.~hGCH~CH3 / O~ N
/ OH
HO \
O.
~ ~ O ~ ,,,~ \
f ~CH3 / I O~N ~CH~CH3 ~+) -HO I \ I S .~'' \ OH
/ ~~'i p '' I \ ~'CH3 / O~N ~~CH2CH3 HO I \I S ,,~'~\ OH
~+) _ ~ '.
/ O '''i \
"nCH3 /~ O~N

An embodiment of the invention is a method of eliciting an estrogen receptor modulating cFFect in a mammal in need thereof: comprising administering to the mammal a therapeutically effective amaunt of any of the compounds or any of the above pharmaceutical compositions described above.
A class of the embodiment is the method wherein the estrogen receptor modulating effect is an antagonizing effect.
A subclass of the embodiment is the method wherein the estrogen receptor is an ERcc receptor.

A second subclass of the embodiment is the method wherein the estrogen receptor is an ER~3 receptor.
A third subclass of the embodiment is the method wherein the estrogen receptor modulating effect is a mixed ERcc and ER(3 receptor antagonizing eFfect.
A second class of the embodiment is the method wherein the estrogen receptor modulating eFFect is an agonizing eFFect.
A subclass of the embodiment is the method wherein the estrogen receptor is an ERc~, receptor.
A second subclass of the embodiment is the method wherein the estrogen receptor is an ER(3 receptor.
A third subclass of the embodiment is the method wherein the estrogen receptor modulating efFect is a mixed ERce and ER(3 receptor agonizing efFect.
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.
?5 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 campos3tlons 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.
ExempliFying the invention is a pharmaceutical compasition comprising any ol~ the compounds described above and a pharmaceutically acceptable cawier, Also exernpliFying the invention is a pharmaceutical composition made by 3~ -combining any of the compounds described above and a pharmaceutically acceptable carrier. An illustration oC the invention is a process Cor making a pharmaceutical composition comprising combining any of the compounds described above and a pharmaceutical 1y acceptable ca o-ier.
Further exemplifying the invention is the use of any of the compounds described above in the preparation of a medicament for the treatment and/or prevention of osteoporosis in a mammal in need thereof. Still further' exemplifying the invention is the use of any of the compounds described above in the preparation of a medicament for the treatment andlar prevention of: bone loss, bone reso~ption, bone Fractures, cacti loge degeneration, endometriosis, uterine fibroid disease, breast cancer, uterine cancer, prostate cancer, hot flashes, cardiovascular disease, impairment of cognitive functioning, cerebral degenerative disorder, restenosis, vascular smooth muscle cell proliferation, incontinence, and/or disorders related to estrogen functioning.
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 instant invention may be effectively administered in combination with effective amounts of other agents such as an organic bisphosphonate or a cathepsin K inhibitor. Nonlimiting examples of said organic bisphosphonates include alendronate, cladronate, etidronate, ibandronate, incadronate, minodronate, neridranate, risedranate, piridronate, pamidronate, tiludronate, zoledronate, pharmaceutically acceptable salts or esters thereof, and mixtures thereof.
Preferred organic bisphosphonates include alendronate and pharmaceutically acceptable salts and mixtures thereof. Most preferred is alendronate monosodium trihydrate.
The precise dosage of the bisphosphonate will vary with the dosing schedule, the oral potency of the particular bisphosphonate chosen, the age, size, sex and condition of the mammal or human, the nature and severity of the disorder to be treated, and other relevant medical and physical factors. Thus, a precise pharmaceutically effective amount cannot be specified in advance and can be readily determined by the caregiver or clinician. Appropriate amounts can be determined by routine experimentation From animal models and human clinical studies.
Generally, an appropriate amount of bisphosphonate is chosen to obtain a bone resarption inhibiting effect, i.e. a bone reso~ption inhibiting amount of the bisphosphonate is administered. Far humans, an effective oral dose of bisphasphonate is typically from _3_5-about l ,_5 to about 6000 ~.~/k~ body weight and preferably about 10 to about ~,g/Icg of body weight.
For human oral compositions comprising alendronate, pharmaceutically acceptable salts thereof, or pharmaceutically acceptable derivatives thereof, a unit dosage typically comprises From about $.75 mg to about 140 mg of the alendronate compound, on an alendronic acid active weight basis, i.e. on the basis of the con-esponding acid.
For use in medicine, the salts of the compounds of this invention refer to non-toxic "pharmaceutically acceptable salts." Other salts may, however, be useful in the preparation of the compounds according to the invention or of their pharmaceutically acceptable salts. When the compounds of the present invention contain a basic group, 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, bromide, calcium, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lact0bionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt, oleate, oxalate, pamoate (embonate), palmitate, pantothenate, phosphate/diphosphate, polygalacturonate, salicylate, stearate, sulfate, subacetate, succinate, tannate, tartrate, teoclate, tosylate, triethiodide and valerate.
Furthermore, where the compounds of the invention carry an acidic moiety, suitable pharmaceutically acceptable salts thereof may include alkali metal salts, e.g., sodium or potassium salts; alkaline earth metal salts, e.g., calcium or magnesium salts; and salts formed with suitable organic ligands, e.g., quaternary ammonium salts.
The compounds of the present invention can have chiral centers and occur as racemates, racemic mixtures, diastereomerlc mixtures, and as individual diastereomers, or enantiomers with all isameric Forms being included in the present invention. Therefore, where a compound is chiral, the separate enantiomers, substantially free of the other, are included within the scope of the invention; further included are all mixtures of the two enantiomers. Also included within the scope of the invention are polymorphs, hydrates unci solvates of the compounds of the instant mventian.
The present invention includes wifhin its scope prodrugs of the compounds of this invention. In general, such pradrugs will be functional derivatives of the compounds of this invention which are readily convertible in vine into the required compound, Thus, in the methods of treatment of the present invention, the term "administering" shall encompass the treatment of the various conditions described with the compound specifically disclosed or with a compound which may not be specifically disclosed, but which converts to the specified compound in vivo after administration to the patient. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, far example, in ''Design of Prodrugs," ed. H. Bundgaard, Elsevier, 1985, which is incorporated by reference herein in its entirety. Metabolites of these compounds include active species produced upon introduction of compounds of this invention into the biological milieu.
The term "therapeutically effective amount" shall mean that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal an human that is being sought by a researcher or clinician.
The term "bone resarption," as used herein, refers to the process by which asteoclasts 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 the Lewis definition, a base is a substance that can furnish an electron pair to form a covalent hoed.
Examples of bases used herein, but are not limited to, are tertiary amine bases such as triethylamine, diisoprapylethylamine, 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 Lawry-Bronsted definition, an acid is a substance That gives up a proton; or according to the Lewis definition, an acid is a substance that can take up an electron pair to form a ~0 covalent bond. Examples of acids used herein, but are not limited to, are strong carboxylic acids such as trifluaroacetic acid, or the like, strong sulfonic acids, such as trifluoromethane sulfonic acid, or the like, and Lewis acids, such as boron tritluoride etherate, or stannous chloride, or the like.
The term " reducing agent," as used herein, refers to a reagent capable of performing a reduction. A reduction is the conversion of a functional group or an intermediate From one category to a lower one. Examples of reducing agents used herein, but are not limited to, are triorganosilanes or stannanes, such as triethylsilane, triphenylsilane, and tri-n-butyl tin hydride, or the like.
The term °°ehemically diFFerentiable" reFers to two or more non-identical Rb substituents whose unique structures are such that one of ordinary skill in the art could choose reaction conditions which would convert one of the nan-identical R~ substituents to H> without affecting the other R~ substituent.
The term ''alkyl" shall mean a substituting univalent group derived by conceptual removal of one hydrogen atom from a straight or branched-chain acyelie IO saturated hydrocarbon (i.e., -CH3, -CH?CH3, -CH~CH~CH3, -CH(CH3)~, -CH~CH?CH2CH3, -CH~CH(CH3)?, -C(CH3)3, etc.).
The term "alkenyl" shall mean a substituting univalent group derived by conceptual removal of one hydrogen atom From a straight or branched-chain acyclic unsaturated hydrocarbon containing at least one double bond (i.e., -CH=CH2, 15 -CH~CH=CH?> -CH=CHCH~, -GH~CH=C(CH~)~, etc.).
The term '°alkynyl" shall mean a substituting univalent group derived by conceptual removal of one hydrogen atom from a straight or branched-chain acyclic unsaturated hydrocarbon containing at least one triple bond (i.e., -CH---CH, -CHaC=CH, -C---CCH3, -CH~CH2C=CCH~, etc.).
20 The term °'cycloalkyl" shall mean a substituting univalent group derived by conceptual removal of one hydrogen atom From a saturated monocyclie hydrocarbon (i.e., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl).
The term "cycloalkenyl" shall mean a substituting univalent group derived by conceptual removal of one hydrogen atom from an unsaturated monoeyclic 25 hydrocarbon containing a double bond (i.e., cyclopentenyl or cyelohexenyl).
The term "heterocyclical" shall mean a substituting univalent group derived by conceptual removal of one hydragen atom from a heteracycloalkane wherein said heterocyeloalkane is derived From the corresponding saturated monocyclic hydrocarbon by replacing one or two carbon atoms with atoms selected 30 from N, O or S. Examples of heterocyclical graups include, but are not limited to, oxiranyl, azetidinyl, pyn-olidinyl, piperidinyl, pipera zinyl, and morpholinyl.
Heterocyclical substituents can be attached at a carbon atom. If the substituent is a nitrogen containing heterocyclical substituent, it can be attached at the nitrogen atom.
The term "heteroaryl" as used herein reFers to a substituting univalent 3S group derived by the conceptual removal of one hydrogen atom from a monocyclic or bicyclic aromatic ring system containing I , 2, 3, or ~- heteroatoms selected From N', O, or S. Examples of heteroaryl groups include, but are not limited to, pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thia~olyl, py~~~dyl, py~~~lnldlnyl, pyrazinyl, ben7imida~olyl, indolyl, and purinyl. Heteraryl substituents can be S attached at a carbon atam or through the heteroatom.
The term "triorganosilyl" means those silyl groups trisubstituted by lower alkyl groups or aryl groups or combinations thereof and wherein one substituent may be a lower alkoxy group. Examples of triorganosilyl groups include trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, triisopropylsilyl, triphenylsilyl, dimethylphenylsilyl, t-butyldiphenylsilyl, phenyl-t-butylmethoxysilyl and the like.
Tn the compounds of the present invention, alkyl, alkenyl, alkynyl, cycloalkyl, cyclaalkenyl, heterocyclical and heteroaryl groups can be further substituted by replacing one or more hydrogen atoms be alternative non-hydrogen groups. These include, but are not limited to, halo, hydroxy, mereapto, amino, carboxy, cyano and carbamoyl.
Whenever the term "alkyl" or "aryl" or either of their prefix roots appear in a name of a substituent (e.g., aryl Cp-g alkyl) it shall be interpreted as including those limitations given above for "alkyl" and "aryl." Designated numbers of carbon atoms (e.g., C~-gyp) shall refer independently to the number of carbon atoms in an alkyl or cyclic alkyl moiety or to the alkyl portion of a larger substituent in which alkyl appears as its prefix root.
The terms "arylall<yl" and "alkylaryl" include an alkyl portion where alkyl is as defined above and to include an aryl portion where aryl is as defined above.
Examples of arylalkyl include, but are not limited to, benzyl, fluoroben~yl, chlorobenzyl, phenylethyl, phenylpropyl, fluorophenylethyl, chlorophenylethyl, thienylmethyl, thienylethyl, and thienylpropyl, examples of alkylaryl include, but are not limited to, toluyl, ethylphenyl, and propylphenyl.
The term "heteroarylalkyl," as used herein, shall refer to a system that includes a heteroaryl portion, where heteroaryl is as defined above, and contains an alkyl poution. Examples of heteroarylalkyl include, but are limited to, pyridylmethyl, pyridylethyl and imidazoylmethyl.
The term "halo" shall include iodo, bromo, chloro and fluoro.
The term "oxy'' means an oxygen (O) atom. The term "thio" means a sulfur (S) atom. The term "oxo" means =O. The term '~oximino" means the =N-O
3S group.
_39_ The term "substituted" shall be deemed to include multiple degrees of substitution by a named substitutent. Where multiple substituent moieties are disclosed or claimed, the substituted compound can be independently substituted by one or more of the disclosed or claimed substituent moieties, singly or plurally. By independently substituted, it is meant that the (two or more) substituents can be the same or difFerent.
Under standard nonmenclature used throughout this disclosure, the terminal pouion of the designated side chain is described first, followed by the adjacent functionality toward the point of attachment. For example, a Cl-S
allcylcarbonylamino Cl_~ alkyl substituent Is equivalent to O
I I
-C ~-~allcyl-~1H-C-C ~-salkyl In choosing compounds of the present invention, one of ordinary skill in the art will recognize that the various substituents, i.e. R1, R~, R3, R~, R5, R~'> R~, R~, V, X, Y, Z, n, m and p are to be chosen in conformity with well-known principles l5 of chemical structure connectivity.
Representative compounds of the present invention typically display submicromolar affinity for alpha and/or beta estrogen receptors. Compounds of this invention are therefore useful in ti°eating mammals suffering from disorders related to estrogen functioning. Pharmacologically effective amounts of the compound, 2Q including the pharmaceutically effective salts thereof, are administered to the mammal, to treat disorders related to estrogen functioning, such as bone loss, hot flashes and cardiovascular disease.
The campounds of the present invention are available in racemic form or as individual enantiomers. For convenience, some structures are graphically 2S represented as a single enantiomer but, unless otherwise indicated, is meant to include both racemic and enantiomeric forms. Where cia~ and lr-cans sterochemistry is indicated for a compound of the present invention, it should be noted that the stereochemistry can be construed as relative, unless indicated otherwise, _~p_ R~ ~ Y R~
R3 / X \
R~ / ~~(CH2)nN~Z)2 Tt is generally preferable to administer compounds of structure {I) as enantiamerically puce formulations since most or all of the desired bioactivity resides with a single enant3omer. Racemic mixtures can be separated into their individual enantiomers by any of a number of conventional methods. These include chiral chromatography, derivatizatian with a chiral auxiliary followed by separation by chromatography or crystallization, and fractional crystallization of diastereomeric salts.
The compounds of the present invention can be used in combination with other agents useful for treating estrogen-mediated conditions. The individual components of such combinations can be administered separately at different times during the course of therapy or concurrently in divided or single combination farms.
The instant invention is therefore to be understood as embracing all such regimes of simultaneous or alternating treatment and the teen "administering" is to be interpreted accordingly. It will be understood that the scope of combinations of the compounds of this invention with other agents useful for treating estrogen-mediated conditions includes in principle any combination with any pharmaceutical composition useful for treating disorders related to estrogen functioning.
As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts, The compounds of the present invention can be administered in such oral dosage forms as tablets, capsules {each of which includes sustained release or timed release formulations), pills, powders, granules, elixers, tinctures, suspensions, syrups and emulsions. Likewise, they may also be administered in intravenous {bolus or infusion), intraperitoneal, topical {e.g., ocular eyedrap), subcutaneous, ~~1 -intramuscular or transdermal (e.g., patch) form, all using Forts well known to those oFordinary skill in the pharmaceutical arts.
The dosage regimen utilising the compounds of the present invention is selected in accordance with a variety aF Factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated;
the route of administration; the renal and hepatic Function of the patient;
and the particular compound or salt thereof employed. An ordinarily skilled physician, veterinarian or clinician can readily determine and prescribe the effective amount of the drug required to prevent, counter or arrest the progress of the condition.
Oral dosages of the present invention, when used far the indicated effects, will range between about 0.01 mg per kg of body weight per day (mglleg/day) to about 100 mg/kglday, preferably 0.01 to 10 mg/kg/day, and most preferably 0.1 to 5.0 mglkg/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, I00 and 500 milligrams of the active ingredient For the symptomatic adjustment of the dosage to the patient to be treated. A medicament typically contains from about 0.01 mg to about 500 mg of the active ingredient, preferably, from about 1 mg to about 100 mg of active ingredient. Intravenously, the most preferred doses will range from about 0.1 to about 10 mg/lcg/minute during a constant rate infusion.
Advantageously, compounds of the present invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three or four times daily, Furthermore, preferred compounds for the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in the art. To be administered in the form of a transdermal delivery system, the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.
In the methods of the present invention, the compounds herein described in detail can Form the active ingredient, and are typically administered in admixture with suitable pharmaceutical diluents, excipients or carriers (collectively refewed to herein as 'carrier' materials) suitably selected with respect to the intended Farm of administration, that is, oral tablets, capsules, elixirs, syrups and the like, and consistent with conventional pharmaceutical practices.
For instance, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic, pharmaceutically _ ~2 acceptable, inert carrier such a s lactose, starch, sucrase, glucose, methyl cellulose, magnesium siearafe, dicalcium phosphate, calcium sulfate, mannitol, sorbifal and the like; For aril administration in liquid Dorm, the oral drub components can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, S glycerol, water and the like. Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents and coloring agents can also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, com sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethyleellulose, polyethylene glycal, wages and the like.
Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, radium acetate, sodium chloride and the like.
Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like.
The compounds of fhe present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Lipasomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.
Compounds of the present invention may also be delivered by the use of monoclonal antibodies as individual can-iers to which the compound molecules are coupled. The compounds of the present invention may also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinylpywolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxy-ethylaspartamide-phenal, or polyethyleneoxide-polylysine substituted with palmitoyl residues. Furthermore, the compounds of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolie acid, copolymers of polyactic and polyglycolic acid, polyepsilon caprolaetone, polyhydroxy butyric acid, palyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and crosslinked or amphipa Chic 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 appropriate materials and are further exemplified by the following specific examples. The compounds illustrated in the examples are not, however, to be construed as forming the only genus that is considered as the invention. The following examples further 3S illustrate details for the preparation of the compounds of the present invention. Those skilled in the art will readily understand that Known variations oFthe conditions and processes of the Following preparative procedures can be used to prepare these compounds. All temperatures are degrees Celsius unless otherwise nated.
The compounds of the present invention are prepared according to the Following generic Scheme 1:
~d4-SCHEME I. GENERAL SYNTHESIS FOR
CIS-DIHYDROBENZOXATHIINS AND BENZODIOXANES

R2 ~ YH Br R Base R3 / XH O~ ~ \
Ra / ORs R~ XH R1 R3 ~ ~ Y R5 R2 ~ Y
Reductive R2 R1 ~ Cyclization R3 / X
p 4 s R / ORs IV OR V
R' Deprotection R2 ~ Y
Mitsunobu Reaction R3 ~ ~( \ HO(CH2)nNtz)2 R~ / OH
VI

R ~ Y R Deprotection of OR6 R3 / X ~ (if necessary) R~ / Oi(CH2)nNtz)2 _ ~5 _ In words relative to the scheme, an appropriately Functionalized bis-phenol II (X=O, Y=O), which are readily available, or a mereapto-phenol II
(X=O, Y=S), which are prepared according to literature procedures, was reacted with a bromo-ketone derivative III, which was readily prepared From the corresponding 1<etone by bromination with phenyltrimethylammonium tribromide (PTAB), in the presence of a teutiary amine base, such as triethylamine, diisopropylethylamine, or the like, in a solvent such as dimethylformamide (DMF), formamide, acetonitrile, dimethylsulFoxide (DMSO), tetrahydrofuran (T1~F), dichloromethane, or the like, at a temperature of from -20oC to 80oC for as long as it takes For the reaction to complete to provide the displacement product IV. When X--Y=O, only R3 maybe -ORS.
Alternatively, when X--Y=O and R~ is -ORS, the requisite cyclization intermediate is obtained by interchangement of the ketone and bromide Functianalities. These stipulations are required to allow For the preparation of these compounds of the invention where the presence of certain substituents will alter the reactivity of the t5 phenolic oxygen atoms.
Intermediate IV was reductively cyclized in the presence of an organic acid such as triFluoraacetic acid, triFlie acid, or the like, or aLewis acid such as boron trifluoride etherate, stannous chloride, or the like, and a reducing agent such as a trisubstituted silane, such triethylsilane, or the like, in a solvent such as dichloromethane, chloroform, Tt~F, toluene, or the like at a temperature of from --40oC to 100oC For as long as it takes for the reaction to complete to provide the cyclized product V, in which the stereochemistry of the aryl substituent and R$ in the newly created ring is exclusively cia~. The Formation of the intermediates with analogous traps stereochemistry is depicted in the next general Scheme II.
In product V, when Rd is a protecting group it is then removed in a manner consistent with its nature. Such methods are well documented in the literature which are incorporated in standard textbooks, such as Greene, T.W. and Wuts, P.G.M., Protective Groups in O~ aanic S nty h~sis, Third Ed.,Wiley, New York (1999).
Further, it is understood that it is possible to have any number of the substitutents Rl-Rd be or contain-ORS, or RS may contain-ORS, where Rd is a protecting group, and it is Further understood that in these instances the protecting groups are chemically diFFerentiable, re., they maybe selectively removed when necessary. Far example in product V, RG is a methoxymethyl (MOM) group, R~ is -OR6, wherein R6 is a benzyl (Bp) group, R~ is a phenyl ring substituted by R~ where R~ is ORb, wherein Rd is a triisopropylsilyl (TIPS) group, and all unspecified substitutents are hydrogen.
-~4G-As indicated, as part of the synthetic seduence it is necessary to selectively remove the MOM group in preference to either the TIPS or B~, groups. Utilizing methods found in Green and Wuts, it is possible to generate the preferred intermediate V, wherein R~ is H, R2 is-OBn, R~ ispcrr~cr-OTIPS-phenyl, and all unspecified substitutents are hydrogen. ~t is also noted that in product V, that when either R? or R3 is ORS, R~
must be a protecting group, and that prior to its removal, the existing -ORS
group must be covered by a differentiable protecting group.
The alcohol intermediate VI was then reacted with a reagent HO(CH2)nNZ~ in a Mitsunobu reaction protocol, in which they are combined with a trisubstituted phosphine, such as triphenylphosphine and a diazodicarboxylate, such as diisopropylazodicarboxylate, in a suitable solvent such as THF at from 0oC to 80oC
for as long as it takes For the reaction to complete to provide the coupled product I.
The variables for the Mitsunobu reaction have been well documented and are incorporated herein by reference: Mitsunobu, O. Syntlre,~i,~, 1981, 1; Castro, B.R. Org.
Rr?crct. 1983, 29, 1; Hughes, D.L. Org. React. 1992, 42, 335.
Finally, after the Mitsunobu reaction, it is understood that in I if any R
group is or contains -ORS, wherein R~ is a protecting group, it was removed utilizing the appropriate method found in Green and Wuts to give the final praduct where R~
is H.
_47--SCHEME II. GENERAL SYNTHESIS FOR
TRANS-DIHYDROBENZOXATHIINS AND BENZODIOXANES
R~ XH R4 XH
R3 ~ ~ Y R5 R3 ~ ~ Y R5 Reduction Cyclization R2 R1 O \ R2 R~ O \
i s H /
IV OR VII ORS
_5 R2 \ Y R5 R~ \ Y R5 Deprotection R3 ~ X ~'''~ \ ~ R3 / X ~''~~ \

R / OR6 R ~ OH
VIII
IX

Mitsunobu Reaction R \ Y R Deprotection of OR6 HO(CH2)nN(Z)2 Ra / X w.~, \ (if necessary) R~ / Oi~CH2)nN~z)2 IO In words relative to the above scheme for the general preparation of the trons isomers of I, the ketone intermediate IV from Scheme I was reduced with sodium borohydrlde, super hydride, or the like, in a mixture of methanol and dichlaromethane, or THF or the like at From OoC to ambient temperature For from a Few minutes to a few hours to provide the analogous hydroxyl intermediate VII, _ dg _ Cycli7ation of intermediate VII was accomplished in the presence of an acid catalyst such as amberlyst 15, or triflic acid or the like, in a solvent such toluene, or dichloromethane or the like, at a temperature of (from ambient to reflex to afford the trczn,~ campound VIII as the major isomer.
The remainder of the synthetic sequence to produce tr-~nt,~ I is identical to that outlined in Scheme I and detailed above.
The compounds of the invention where X=O and Y=SO or SO? are prepared as outlined in the specific schemes that follow.
SCHEME III. GENERAL SYNTHESIS FOR
fp DIHYDROBENZOXATHIIN DIOXIDES
R~
Rz \ S Rs R3 / p \
R~ / O~ (CHz)nNtZ)z R2 O\SO R5 Peroxidation I \
R3 / O \
R4 ~ / i ~CHz)nN~z)2 O
X OCR

Rz O Sl0 Rs Selective Deoxygenation R ~ ,O
R'~ / Oi ~CHz)nN~Z)2 -~9-In words relative to Scheme III, the compounds I of the invention are peroxidi~ed with an oxidant such as m-chlaroperben7aic acid, or per-triFluoroacetic acid, or the like, in a solvent such diehloromethane or the like, at a temperature of From OoC to reflex to produce the trioxide intermediate X. In tru~n X was selectively deoxygenated at the nitrogen atom by treatment with a reducing agent such as sodium bisulfate or the like in a biphasic 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 is l~l preFerably S.
In the compounds of the present invention, RI ,R~ ,R3 and R'I are preferably selected from the group consisting of hydrogen, C~_5 alkyl, C3_g cycloallcyl, CI-5 all<enyl, C,I_5 alkynyl, -ORS and halogen.
In the compounds of the present invention, R~ is preferably selected IS From the group consisting of C3-g cyeloalkyl, phenyl, and substituted phenyl.
In the compounds of the present invention, R~ is preferably selected from the group consisting of hydrogen, CI_5 alkyl, benzyl, methoxymethyl and trisopropylsilyl.
In the compounds of the present invention, a preFer-r-ed subset is found 20 where RI and R'I are hydrogen, R? and R3 are independently -OH, and RS is independently selected from the group consisting of phenyl and substituted phenyl.
In the compounds of the present invention, another preferred subset is found where R~ is independently selected fluorine and chlorine, R4 is hydrogen, R~
and R3 are independently -OH, and R~ is independently selected from the group 25 consisting of phenyl and substituted phenyl.
In the compounds of the present invention, the most preferred subset is Found where RI and R'~ are hydrogen and, R~ is -OH, and R~ is independently selected from the group consisting of phenyl and par-cr-hydroxy-phenyl.

SCHEME IV. GENERAL SYNTHESIS FOR DIHYDROBENZOXATHIIN
OXIDES
R~ R1 O

\ Mono-oxidation R3 / p \ R3 / O \
R~ / 6 R~ ~ ~ s OR OR
V XI

R2 S Rs R3 / p \
R~ / pi~CH2)nN~Z)2 S
In words relevant to Scheme IV, the intermediate V of Scheme I was mono-oxidized by careful treatment with one equivalent or a slight excess of an oxidant such as nr-chloroperbenzoic acid, ar dimethyldioxirane, or the like, in a 1Q solvent such as dichloromethane, ether, acetone, or the like, at a temperature of from -78oC to ambient temperature for from a few minutes to a few hours to give the con'esponding sulfoxide intermediate .YI. The remainder of the synthetic sequence to produce I is identical to that outlined in Scheme 1 and detailed above.
In the compounds of the present invention, X is preferably O, and Y is I S preferably S.
In the compounds of the present invention, Rl ,R~ ,R3 and R~ are preferably selected From the group consisting of hydrogen, C1-5 alkyl, C3_g cycloalkyl. C1_5 alkenyl, CI-~ alkynyl, -ORG and halogen.

In the compounc(s of the present invention, R~ is preFerably selected From the group consisting of C3_g cycloalkyl, phenyl, and substituted phenyl In the compounds of the present invention, R~' is preferably selected From the group consisting of hydrogen, C 1_5 alkyl, ben~yl, methoxymethyl and trisopropylsilyl.
In the compounds of the present invention, a preferred subset is Found where R~ and R~ are hydrogen, R2 and R~ are independently-OH, and RS is independently selected from the group consisting of phenyl and substituted phenyl.
In the compounds of the present invention, another' prefewed subset is found where Rl is independently selected fluarine and chlorine, R't is hydrogen, R
and R3 are independently-OH, and RS is independently selected from the group consisting of phenyl and substituted phenyl.
In the compounds of the present invention, the most prefen -ed subset is found where R~ and R~ are hydrogen and, R? is -OH, and R~ is independently selected from the group consisting of phenyl, t~leta-hydroxy-phenyl, and przrcz-hydro~y-phenyl.
_ 5~

GENERAL PREPARATION OF THIOPHENOLS

CuSO~, NH~SGN
/ / S
~O
HO \ OH HO \ O

Protection / S 1. NaOH / SH
O
\ ~ ~ 2. H~ \
PO ~ PO ~ ~OH

The Functionali~ed thiophenals were prepared by the known procedure, with minor modification, which is depicted in above scheme: Wermer, G.; Biebrich, W. US
Patent 2,276,553 and 2,332,4 18.
O OH
Thiourea / S NH2C1~ / O
Heat ~ O
HCl \ NH2 HO \ S
O OH
PhCH2Br / ~ O OH
1. NaOH
Base \
Bn0 2. H+ Bn0 \ SH
_53_ The thiophenol depicted above was prepared according to the following references:
Maxwell, S. J. flat. Cltr.~nt. Suc. 197, G9, 712; Hanzlik, R. P. et. al. J, pry. CJtcllt.
1990, s5, 2736.

O s Me0 To a stirred solution of anisole (1.49 g, 13.8 mmol) in anhydrous dichloromethane (5 mL) was added AICI~ (1.2320 g, 9.2 mmol) followed by dropwise addition of 2-thiophene acetyl chloride (0.57 mL, 4.6 mmol) at 0 °C Lender I~F~. The reaction was stirred for 1.5 h, then poured into a separatory funnel containing icelbrinelElOAc.
The organic layer was washed further with brine, dried over Na~SO~, and concentrated 112 lltlCllp. The resulting residue was purified by silica gel chromatography with 30°lo EtOAclhexane as the eluant to afford the desired product as a yellow oil. ~H
500MHz NMR(CDCl3) ppm(b): 3.89 (s, 3H), 4.46 (s, 2H), 6.98 (m, 4H), 7.24 (d, 1H), and 8.05 (d, 2H).

O s w HO
A mixture of the 2-thophene-4-methoxy-benzaphenone (p.8294 g, 3.5 mmol), generated in Example 2, and pyridine-HCl (4.0627 g, 35.2 mmol) was heated to _5d_ C'C under N~ for 6 h. The reaction was monitored by examining worked-up aliquots of the reaction by TLC {30~'If EtOAclhexane). The reaction was cooled in an ice bath and icelH~O was added. The resulting mixture was extracted with EtOAc. The organic extract was washed with 2 N HCI and brine, dried over Na~SO;~, and concentrated r'n vcrcuo. The resulting brown residue was purified by silica gel chromatography with 30%a EtOAclhexane as the eluant to afford the desired product as a yellow/orange solid. ~H 500MHz NMR(CDCI~) ppm{S): ~..~.3 (s, 2H), 5.60 (bs, 1H), G,90 {d, 2H), 6.92 {m, 1 H), 6.97 {m, 1H), 7.22 (d, 1 H) and 8.00 {d, 2H).
LO
EXAMPLE ~

BENZOPHENONES
O
a U
HO
To a stirred solution of the 2-cycloalkyl-1-(4-methoxy-phenyl)-ethanone [prepared according to the method of Bawio, ~tcrl, J. Med. Ch~n~.,1971, 1~, 898] in dry methylene chloride at 0°C was added 3.6 equivalents of aluminum chloride and 3.0 equivalents of isopropyl mercaptan. The ice-water bath was removed and the reaction mixture was stiu-ed further overnight under an inert atmosphere of nitrogen.
The reaction mixture was poured onto a mixture of 2N HCI/ice and extracted with ethyl acefiate. The ethyl acetate extract was washed with brine, dried over anhydrous sodium sulfate, filfered, and evaporated. Purification by silica gel chromatography afforded the con-esponding 2-cycloalkyl-I-(4-hydroxy-phenyl)-ethanone.
ZS Utilizing the foregoing experimental procedure the following campounds were prepared:
2-cyclohexyl-1-(~-hydroxy-phenyl)-ethanone: 70~'~c~ yield using methylene chloride-ethyl acetate(50:1) as the chromatography eluant. jH 500MHz NMR{CDCI~) ppm{b): l-2.0 {m, 1 IH), 2.96 {d, 1H), 5.6 (bs, 1 H), 6.92 (d, 2H), and 7.9_5 (d, 2H).
-55_ 2-cyclopentyl-1-(~l-hydroxy-phenyl)-ethanone: 7~°lc~ yield using methylene chloride-ethyi acetate(50:1) a s the chromatography eluant. ~H 500MHz NMR(CDCI~) ppm(b):1,2-1.92 (m, l OH), 2.~ (m, 1 H), 2.96 (d, 1 H), 5.6 (bs, 1 H), 6.91 (d, 2H), and 7,95 (d, ?H).
s O
v ~
HO
To a mixture of isovaleric acid (1.4 mL,13.0 mmol) and phenol (1.0253 g, 10.9 mmol) was added BF~OEt2 (15 mL) under nitrogen. The resulting mixture was heated to °C for approximately 3.5 h. The reaction was poured into ice/2 N HCl and extracted with EtOAc. The organic extract was washed with brine, dried over Na2S0,~, and concentrated isi vaGaao to give a yellow residue. The final product was isolated as a pale yellow oil aFter silica gel chromatography with 30~7o EtOAc/hexane as the eluant.
Upon standing at ambient temperature, the oil solidified to give a white solid. 'H
500MHz N'MR(CDCI~) ppm(~):1.01 (d, 6H)> 2.2'7 (m, 1H), 2.81 (d, 2H), 6.99 (d, 2H), 7.93 (d, 2H).
_56_ EXAMPLE G
PREPARATION OF 4-PYRIDYL-~l-HYDROXY-BENZOP1-IENONE
O ~ ~N
HO
A dried flask equipped with a stin-er bar was charged with a 2.5 M solution of nBuLi in hexane (18 mL, X5.0 mmol) and cooled to 0°C under NZ. A solution of diisopropylamine (6.~ mL, d5.7 mmol) in distilled THF (20 mL) was added slowly.
After stirring for 25 min., a solution of 4-picoline (2.0 mL, Zl.d mmol) in distilled THF (8 mL) was added to the reaction. The resulting red solution was stirc~ed for 25 min. before removing the ice bath. A solution of cyanophenol 0.5670 g, 21.d.
mmol) in distilled THF (?0 mL) was added vin a dropping funnel over 30 min. Upon addition of the phenol, the reaction became a thick slurry with oiling out of a redlbrown tar. Further addition of THF did not alleviate the difficulty in stio-ing. The reaction stood at ambient temperature for 1~ h, and was poured into a mixture of ice/sat. NH~CI/EtOAc. The intermediate enamine precipitated from the mixture as an insoluble yellow solid and was collected by vacuum filtration. The solid was redissolved in 2 N HC1. The EtOAc layer from the filtrate was also collected and extracted with 2 N HCl/ice. The acidic aqueous extract was combined with the enamine solution in 2 N HCl and stirred at ambient temperature for 16 h. The acidic solution was washed with EtOAc, cooled to 0°C, and neutralized to pH7 with sat.
NaHCO~. The desired product precipitated from the solution as a yellow solid and was collected, washed with cold water, and dried in vacuo. 1H 500MHz NMR(d-acetone) ppm{~): x.37 (s, 2H), 6.97 (d, 2H), 7.31 {d, ?H), 8.01 {d, 2H), 8.5?
{bs, 2H).
_57_ O
\ N
HO
Following the procedure outlined in Example 6 with the exception that 1 equivalent of HMPA in THF was added to the reaction following addition of diisopropylamine, the 3-pyridyl-4-hydroxy-benzophenone was prepared from 3-picoline, The work-up differed slightly in that hydrolysis with 2 N HCI was unnecessary. Instead, the reaction was simply partitioned between icelsat. NH~CI and EtOAc. The organic layer was washed with brine, dried over ~ 'a~S04, and concentrated icT
nrcceto. The residue was triturated with CH~CI~ and EtOAc to give the desired product as an orange solid. 'H 500MHz NMR{d-acetone) ppm{8): 4.39 (s, 2H), 6.97 ~d, 2H), 7.31 {m, LH), 7.68 {m, 1 H), 8.01 {d, 2H), 8.~3 (m, 1H), 8.52 (m, 1H).
EXAMPLE $

BENZOPHENONES
O
~ ~/
TIPSO
To a stirred solution of the ?-cycloalkyl-1-{4-hydroxy-phenyl)-ethanone, prepared in Example 4, in dry DMF at 0~'C was added 1.3 equivalents of diisopropylethylamine and 1,2 equivalents of triisopropylchlorosilane{T>PSCI). The ice-water bath was removed and the reaction mixture was stirred further until tlc showed the reaction to be complete ( I-3 hours) under an inert atmosphere of nitrogen. The reaction mixture _5g_ was partitioned between ether/2N HCI/ice and the organic phase was separated, washed twice with water, washed with brine, dried over anhydrous sodium sulfate, filtered, and evaporated. Purification by silica gel chromatography afforded the corresponding '?-cycloal l<yl-1-(~I-triisopropyloxy-phenyl)-ethanone.
Utilizing the foregoing experimental procedure the following compounds were prepared:
2-cyclohexyl-1-(~-triisopropylsilyloxy-phenyl)-ethanone: use methylene chloride-hexanes(1:1) as the chromatography eluant. 'H 500MHz NMR(CDCI~) ppm(~);1.13 (d, 18H), 1-1.99 (m, l~IH), 2.78 (d, 1H), 6.91 (d, 2H), and 7.89 (d, 2H).
2-cyclopentyl-1-(4-triisopropylsilyloxy-phenyl)-ethanone: use methylene chlorlde-hexanes(1:1) as the chromatography eluant. 'H 500MHz NMR(CDC1~) ppm(~):1.12 (d, 18H), 1.2-1.91 (m, 13H), 2.4 (m, 1H), 2.95 (d, 1H), 6.92 (d, 2H), and 7.9 (d, 2H).
1~ EXAMPLE 9 BENZOPHENONES
O
R
TI PSO
To a solution of the 2-alkyl-1-(4-hydroxy-phenyl)-ethanane, 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 N~. After the gas evolution ceased, 1.1 equivalents of was added dropwise and the resulting solution stirred for 30 min. The reaction was partitioned between ice/water and EtOAc. The organic layer was washed with brine, dried over ~
~aaSO~, and concentrated in vczc~to. Purification by silica gel chromatography afforded the coiTesponding 2-alkyl-1-(4-triisopropylsilyloxy-phenyl)-ethanones.
Utilizing the foregoing experimental procedure the following compounds were prepared:
_ 5 c~ -2-(2-thiophene)-1-(~l-triisopropylsilyloxy-phenyl)-ethanone: isolated as an orange/yellow solid using 15~'l~ EtOAc/hexane as the chromatography cluant. ~t-500MHz NMR(CDCI;) ppm(c~): l,1~ (d, l8H), 1.30 (m, 3H ), tl..~? (s, 2H), and 6.93-7.98 (m, 7 H).
2-(~-pyridyl)-1-(4-triisopropylsilyloxy-phenyl)-ethanone: isolated as a yellow solid using ~0'~o EtOAc/hexane as the chromatography eluant. ~H 500MHz NMR(CDCI~) ppm(b):1.1~. (d, 18H), 1,30 (m, 3H), 4.28 (s, 2H), 6.97 (d, 2H), 7.35 (m, 1H), 7.69 (m, 1H), 7.97 (d, 2H), and 8,56 (bs> 2H).
2-(3-pyridyl)~l-(~-triisopropylsilyloxy-phenyl)-ethanone: isolated as a yellow solid using ~0°lp EtOAclhexane as the chromatography eluant. ~H 500MHz NMR{CDC13) ppm(~):1.1~ (d, 18H), 1.20 (m, 3H), x.18 (s, 2H), 6.82 (d, 2H), 7.10 (d, 2H), 7.82 (d, 2H), and 8.43 (d, 2H).

GENERAL BROMINAT10N PROCEDURE OF ALKYL AND CYCLOALKYL-~-O
R
Br TIPSO
To a stiu~ed solution of the 2-alkyl- and 2-cycloall<yl-1-(4-triisopropylsilyloxy-phenyl)-ethanones> prepared in Examples 8 and 9, in dry THF at OpC was added 1.0 equivalent of trimethylammoniumphenyl perbromide. The ice-water bath was removed and the reaction mixture was stilted further for 1 hour under an inert atmosphere of nitrogen. The reaction mixture was partitioned between ethyl acetate/brine/ice/5°~osodium thiosulFate/sodium bicarbonate and the organic phase was separated, washed with brine, dried over anhydrous sodium sulFate, Filtered, and evaporated. Purificafian by silica gel chromatography afforded the corresponding 2-cycloall<yl-2-bromo-1-(4-triisopropylsilyloxy-phenyl)-ethanone.
Utilizing the foregoing experimental procedure the following compounds were prepared:
_5 2-cyclohexyl-2-bromo-1-{4-triisopropylsilyloxy-phenyl)-cthanone: use methylene chloride-hexanes{1:1) as the chromatography eluant. ~H 500MHz NMR(CDCI~) ppm{8): 1.14 {d, 18H), 0.98-2.27 (m> 1~H), 4.91 {d, 1H), 6.94 (d, 2H), and 7.94 (d>
2H).
LO 2-cyclopentyl-2-bromo-1-{4-triisopropylsilyloxy-phenyl)-ethanone: use methylene chloride-hexanes{1:1) as the chromatography eluant. ~H 500MHz NMR(CDCIs) ppm{8):1.13 {d, 18H), 1.1-2.2 {m, 11H), 2.8 {m, 1H), 4.98 (d, 1H), 6.94 (d, 2H), and 7.96 {d, 2H).
15 2-(2-thiophene)-2-bromo-1-(4-triisopropylsilyloxy-phenyl)-ethanone: stirred at 0 °C
for 40 min.; isolated as a dark brown oil and used in the next reaction without purification.
~H SOOMHz ~1MR(CDCI;) ppm{0:1.13 {d, 18H), 1.30 (m, 3H), 6.73 {s, 1H), 6.97 (d, 2H), 7.00 {m, 1H ), 7.30 (m, 1H), 7.49 {d, 1H), and 8.00 (d, 2H).
2-(4-pyridyl)-2-bromo-1-{4-triisopropylsilyloxy-phenyl)-ethanone: added 2 equivalents of trimethylammoniumphenyl perbromide and stirred at 0 °C
for 1 h;
isolated as an orangelyellow oil and used in the next reaction without purification. ~H
500MHz NMR{CDCI;) ppm(8):1.03 {d, 18H), 1.21 {m, 3H), 6.21 (s, 1H), 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: added 2 equivalents of trimethylammoniumphenyl perbromide and stirred at 0 °C
for 3 h;
isolated as an orangelyellow oil and used in the next reaction without purification, IH
SOOMHz NMR(CDCI~) ppm{8):1.13 {d, 18H), 1.30 {m, 3H), 6.30 (s, ll~, 6.98 (d, 2H), and 7.39-8.75 {m, 6H).

PREPARATION OF' 2-ISOPROPYL-2-BROMO-1-(~.-HYDROXYPHENYL) ETHA NO NE
O
~w HO \ ~ IBr Following the procedure outlined in Example 10 and using the product obtained from Example 5, 2-isopropyl-2-bromo-1-(~.-hydroxyphenyl)-ethanone was isolated as a yellow oil and used in the next reaction without purification. ~H SOOMHz NMR(CDC13) ppm(8): 1.01 (d, 3H), 1.2I. (d, 3H)> 2.46 (m, 1H}, 4.93 (d, 1H}, G.96 ~d, 2H), and 7.9G (d, 2H}.
- G? _ GENERAL PREPARATfON OF BROMOKETONES
PS
R=H or MOM
Step A
To a stirred solution of 3.0g {13.2mmole) of dry desoxybenzoin {freshly azeotroped with toluene) in 25mL of DMF at 0°C was added 5.7mL {5.7mmale) of neat diisopropylethylamine. To this stirred solution was added slowly 1.25mL (19.73 mmole) of chloromethylmethylether (MOMCI). The ice-water bath was removed and the mixture was stirred further under an atmosphere of nitrogen for 18 hours.
The mixture was then poured into a saturated NaHC03 solution, extracted with EtOAc, and the extract washed with water, and dried over anhydrous MgSO~. After evaporation of the solvent, the residue was purified by silica gel chromatography (EtOAc/Hexane =1:1) to provide the product, as a solid. 'H NMR (400 MHz, CDC13) 8 (ppm): 8.0 (d, 2H), 7.19(d, 2H), 7.10 (d, 2H), 6.8 (d, 2H), 5.23 (s, 2H), ~1.8 (s, 1H), 4.2 {s, 2H), 3.S (s, 3H}.
St-ep B
To a stirred solution of the product obtained from Step A (~?3mg, 1.55mmole) and imidazole (21 1 mg, 3.lmmole) in 20mL of dry DMF at 0°C was added triisopropylsilyl chloride (3.lmmole) and the reaction mixture was allowed to warm to room temperature and stirred further for ?-3 hours. The reaction was quenched by the addition of aqueous NaHCO~ solution and extracted with EtOAc. The organic layer was washed with brine and dried with MgSO;~. Chromatography (10%
EtOAc/hexane) yielded the desired product. 'H NMR (~00 MHz, CDCI.,) b (ppm):
8.0 (d, 2H), 7.12 (d, ?H), 7.08 (d, 2H). 6.82 (d, ~H>, _5.21 (s, 2H), x.18 (s, 2H), 3.5 (s, 3H), 1.21 (m, 3H), I.I (d, 18H).

Step C
To a mixture of the compound from Step B (0.5g, 1. l6mmole) in LOOmL of anhydrous TI-IF was added 0.398 {1.16mmole) of trimethylphenylammonium perbromide (PTAB) at 0°C. The ice-water bath was removed, and the mixture was stirred further for one hour, The solution was then filtered and washed with water and brine and dried over MgSO~. Removal of the solvent afforded the mixture of bromo-ketones (MOM group was partially removed), which was used without further purification due to their instability toward chromatography.
Bromolcetone with MOM group: 'H NMR (400 MHz, CDCI;) ~ (ppm): 8.0 (d, ZH), '7.4 (d, 2H), 6.88 (d, 2H), 6.86 (d, 2H), 6.36 {s, 1H), I.24 (m, 3H}, 1.I (d, I8H};
Bromolcetone without MOM group: 'H NMR (400 MHz, CDCI;} 8 (ppm): 7.94 {d, 2H), 7.4 (d, 2H), 6.88 {d, 2H), 6.86 (d, 2H), 6.36 (s, IH), 1.2~ (m, 3H), 1.1 (d, I8H).

PREPARATION OF
i Br O I \
OTIPS
The required bromoketone was prepared using the procedure in Example I2 (Step C).
'H NMR (400 MHz, CDCI~,) b (ppm) 7.94 {d, 2H), 7.56 (m, 2H), 7.38 (m, 3H}, 6.9 {d, 2H), 6.36 {s, 2H), 1.28 (m, 3H), 1.1 (d, I8H).

EXAMPLE I==1 PREPARATION OF
OMe Br O' ~~
~ OTIPS
The required bromoketone was prepared using the procedure in Example 12 (Step C).
IH NMR 0100 MHO, CDCI~) b {ppm) 7.9 (d, 2H), 7.5 {d, 2H), 6.9 (d & d, 4~-I), 6.~ {s, 1H), 3.8 (s, 3H), 1.28 (m, 3H), 1.1 (d, 18H).
EXAMPLE 1_5 OMOM
Br O
OMOM
St._ ep A
To a sowed solution of a mixture of the 0.1g (0.37mmale) mano phenolie compound from Step A in Example 12 and diisopropylethylamine (0.13mL, 2eq) in SmL of DMF
at room temperature was added slowly neat MOMCI (O.OSmL, 2eq), and the mixture was heated at 85°C under N~ for three hours. The mixture was then poured into a saturated NaHCO~ solution, extracted with EtOAc, washed with water, and dried over MgSO..~. After evaporation of the solvent, the residue was purified by silica gel chromatography (EtOAclHexane =1:1) to provide the pure bis-protected MOM
product, as a solid. ~H NMR (400 MHO, CDCI=) ~ (ppm): 8.0 {d, 2H), 7.19(d, 2H~, 7.10 (d, 2H), 7.02 (d, 2H), 5.23 {s, 2H), 5.2 (s, 2H), ~1.? (s, 2H), 3.5 (two s, 6H).

-- 65 n S t_ e.p B
The product ol~ Step A was treated with bromine to give the bromolcetone. 1H
NMR
(400 MHz, CDCI;) b (ppm); 8.0 (d, 2H), 7.45(d, ?1-1), 7.10 (two d, 4H), 6.~
(s, 1H), 5.23 (two s, 4H), 3.5 (two s, 6H).

GENERAL PREPARATION OF
O / OTIPS
MOMO ~ I S
Ho To a stirred, freshly prepared solution of 2-thiophenol (0.2g, l.6mmole) and Et3N
(0.34mL, 2eq) in ISmL DMF at 0°C was slowly added a solution of 0.6278 (I.232mmole) of bromoketone (prepared from Step C in Example 12) in I3mL of DMF. The reaction mixture was stirred for three hours at room temperature and was then pautitioned between saturated I~aHCO~ and EtOAc, the layers were separated, and the aqueous layer was extracted again with EtOAc. The combined organic layers were dried (Na~SO~), Filtered, and evaporated in uczcato. The resulting ail was purified by flash chromatography (EtOAc/Hex=Ll4) to provide the desired product as an oil.
~H NMR (400 MHz, acetone-d~) b (ppm): 8.0 (d, 2H). 7.2-6.6 (m, 8H), 6.8 (d, 2H), ?0 6.2 (s, 1H), 5.21 (s, 2H), 3.4 (s, 3H), .1.22 (m, 3H), 1. l (d, I8H); MS
mlz 575 (M~'~+23).

CYCLIZATION OF COUPLED PRODUCT
O / OMOM MOM
\ ~ O
MOMO
HO ~ ~ MOM
Follawing the procedure outlined in Example 16, 1,2-dihydroxybenzene and the bromide oFExample 15 was converted to the product which was puriFied by silica gel chromatography using EtOAc/hexane (1/4) as eluant. MS ml~ 448 (M~+2~).

OTIPS OT(PS
O
/ \
HO \ S MO
HO
OBn A
L5 Following the procedure outlined in Example 16 and using 0.838 (3.6mmole) of 4-benzyloxy-thiophenol, prepared from Example 1, product A and produ cfi I3 were obtained aFter silica gel chromatography using EtOAclhexane (1/5) as eluant.
A: ~H NMR {400 MHz, acetone-d~) ~ (ppm): 8.15 (s, 1H), 7.8 (d, 2H), 7.4 (m, SH), 6.98 (d, 2H), 6.98 (d, 1H), 6.7_5 (d & d, 4H), G.0 ( s, 1H), 5.62 (s, 1H), 5.0 (s, 2H), 1.22 (m, 3H), 1.15 ~d, 18H).

B; ~H NMR 0100 MHL, acetone-d~,) S (ppm): 8.0 (d, 2H), 7.5 (m, 5H), 7.18 (d, 2H), 7.0~ (d, 2I-I), G.9G (d, 1I-I), G.8 (d, 2H), G.SG (d, 1 H), G.32 (dd, 1 H), G.
l (s, I I-I), 5.35 (s, 2H), 5.09 (s, II-I), 3.~. (s, 3H), 1.22 (m, 3HI}, I.I (d, 18I-I).

PREPARATION OF
O / OMe I
TIPSO \ ~ S
No OBn Following the procedure outlined in Example 1G and using 1.1g (2.3mmole} of the bromoketone from Example 14, the desired product was obtained after silica gel chramatography using EtOAc/hexane (1/5) as eluant. ~HNMR (~00 MHz, acetone-d~} ~ (ppm): 8.4G (br s, 1H), 7.98 (d, 2H), 7.~8-7.3 (m, 5H), 7.24 (d, 2H), 7.~ (d, 1H), 6.92 (d, 2H), 6.82 (d, 2H), 6.56 (d, 1H), 6.38 (dd, IH), 6.1 (s, 1H), 5.0~ (s, 2H), 3.72 (s, 3H), 1.25 (m, 3H), 1.1 (d, 18H).

PREPARATION OF
PS
H
2p OBn Following the procedure outlined in Example 1G and using 0,748 (I._Smmole) of the bromol<etone from l;xample 12 (Step C), the desired product was obtained after silica gel chromatography using EtOAc/hexane (1/5) as eluant. ~k(NMR (400 MHz, acetone-d~) ~ (ppm): 7.92 (d, 2I-I), 7.46-7.1 (m, 5H), 7,18 (d, 2H), 6.84 (d>
2I-I), 6.78 {d, 2I-I), 6.~2 (d, 1 H)> 6.36 (d, IH), 5.98 (s, 1H), 5.02 (s, 2H), 2.2 {s, 3H), 1.22 (m, 3H), l, l (d> 18H).

PREPARATION OF
OTIPS
H
Me Utin Following the procedure outlined in Example 16 and using 0.8g (1.57mmole) of the bromoketone fram Example 12 (Step C) with the thiophenol derivative prepared from Example 1, the desired product was obfiained after silica gel chromatography using EtOAc/hexane (ll5) as eluant. 'H NMR (400 Ml-lz, acetone-d~) 8 {ppm): 7.9 (d, 2H), 7.5-7.3 (m, 5H), 7.12 (d, 2H), 6,9 (d, 1H)> 6.84 (d, 2H), 6.79 (d, 2H), 6.4 (d, 1H), 6.0 (s, 1H), 5.1 (s, 2H), 2,1 (s, 3H), 1.?5 (m, 3H), 1.1 (d, 18H).

EXAMPL.sE 22 PREPARATION OF
O / OTIPS
\ ~ S Et NO
HO
OBn Following the procedure outlined in Example 16 and using 0.568 (l.lmmole) of the bromoketone from Example 12 (Step C) with 0.198 (0.73mmole) of thiophenol derivative prepared from Example 1, the desired product was obtained after silica gel ~0 chromatography using EtOAe/hexane (1/5) as eluant. 1H NMR (400 MHz, acetone-d~) ~ (ppm); 7.9 (d, 2H), 7.~8-7.3 (m, SH), 7,16 (d, 2H), 6.8~ (d, 2H), 6.78 (d, 2H), 6.12 (d, 1H), 6.38 (d, 1H), 5.96 (s, 1H), 5.1 (s, 2H), 2.6 (q, 2H), J .22 (m, 3H), 1.1 (d, 18H), 1.1 (t, 3H).

PREPARATION OF
O / OTIPS
\
I
HO \ ~ S
HO
Et OBn 20 Following the procedure outlined in Example 16 and using ?.04g (~.33mmole) of the bromoketone from Example 12 (Step C) with the thiophenol derivative prepared from _70-Example 1, the desired product was obtained alter silica gel chromatography using EtOAclhexanc ( 1/5) as eluant. ~H NMR (400 MI-Iz, acetone-dc,) ~ (ppm); 7.9 (d, 2H), 7.5-7.3 (m, SH), 7.12 (d, 2H), 6.92 (rl, LH), 6.84 (d, 2H), 6,78 (d, 2I-I), 6.42 (d, 11~), 6.0 (s, lI-I), 5.1 (s, ?H), 2.7 (q, 2H), 1.24 (m, 3H), 1,1 (d & t, 21H).

PREPARATION OF
O / OTIPS
\
\ ~ S OBn NO
Ho OBn Following the procedure outlined in Example 16 and using 2.0g (4.33mmole) of the bromoketone from Example 12 (Step C) with the thiophenol derivative prepared from Example 1, the desired product was obtained after silica gel chromatography using EtOAc/hexane (1l5) as eluant. ~H NMR (400 MHz, acetone-d~) 8 (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, 1H), 6.18 (d, LH), 6.0 (s, 1H), 5.24 (s, 2H), 5.05 (s, 2H), 1.22 (m, 3H), 1.1 (d, 18H).

TIPSO \ I s Ho OBn Following the procedure outlined in Example l6 and using l.Gg (3.S lmmole) of the bromoi<etone From Example 13 with the thiophenol derivative prepared From Example l, the desired product was obtained otter silica gel chromatography using EtOAc/hexane (1/S) as eluant. ~H NMR (400 MHz, acetone-ci~,) ~ (ppm): 8.0 (d, 2H), 7.5-7.2 (m, 10H), 7.0 (d, 1H), 6.92 (d, 2H), 6.54 (d, 1H), G.35 (dd, 1 H), 6.12 (s, 1H), S.OG (s, 2H), 1.22 (m, 3H), 1.1 (d, 18H).

TI
~Bn Following the procedure outlined in Example 1G and using 2,6g (5.82mmole) of the bromoketone from Example 13 with the thiophenol derivative prepared from Example 1, the desired product was obtained after silica gel chromatography using EtOAc/hexane (1l5) as eluant. ~H NMR (400 MHz, acetone-d~) b (ppm): 8.0 (d, 2H), 7.4-7.2 (m, 10H), 6.94 (d, 2H), 6.84-6.74 (m, 3H), G.24 (s, 1H), 4.85 (s, 2H), 1.23 (m, 3H), 1.1 (d, 18H).

F
TIPS
OBn Following the procedure outlined in Example 16 and using the bromoketone From Example 12 (Stop G) with the thiophenol derivative prepared From Example l, the desired product wus obtained aFter silica gel chromatography using EtOAc/hexane (I/5) as the eluant. 'H NMR (~00 MHz, acetone-dr,) ~ (ppm): 8.0 (d, 2H), 7,4-7.2 (m, 7H), 7.0 (m, SI-I), 6.5~ (d, LH), 6.28 (dd, 1H), 6.1~ (s, IH), 5.08 (s, 2H), 1.23 (m, 3H), I.l (d, 18H).

PREPARATION OF
O
I
TIPSO \ I S F
HO
OBn Following the procedure outlined in Example 16 and using the bromoketone from Example 13 with the appropriate thiophenol derivative prepared from Example 1, the desired product was obtained after silica gel chromatography using EtOAc/hexane (1l5) as the eluant. IHNMR (500 MHz> CDC13) ~ (ppm) 8.28 (s, lH), 7.82 (d, 2H), 7.40 (m, SH), 7.22 (m, SH), 6.80 (d, 2H), 6.d0 (d, 1H), 6.21 (dd, 1H), 5.80 (s, LH), 5.00 (s, 2H), 1.24. (m, 3H), 1. LO (d, 18H).
~- 73 PREPARATION OF
O
TIPSO \ S CI
HO
OBn Following the procedure outlined in Example 16 and using the bromoketone from Example 13 with the appropriate thiophenol deuivative prepared from Example 1, the desired product was obtained alter SiOZ using EtOAc/hexane (1/5) as eluant. 'H
NMR (500 MHz, CDCI;} 8 (ppm) 8.19(s, 1H), 7.82(d, 2H), 7.~0{m, 5H), 7.24(m, 5H), 6.80(d, 2H), 6.64(d, 1H), 6.~.~{d, 11~~, 5.84{s, 1H), 5.00(s, 2H), 1.?3(m, 3H), 1.10(m, 18H).

PREPARATION OF
IPS
OBn Following the procedure outlined in Example 16 and using the bromoketone from Example I2 with the thiophenol derivative prepared from Example l, the desired product was obtained after silica gel chromatography using EtOAclhexane (1/5}
as eluant. ' H NMR (500 MHz, CDC13) 8 (ppm): 8.?0 (s, I I-I), 7.81 (d, 2H), 7.40 (m, _ 7 5I-I), 7.0? (d, 2H), 6.75 (ri, 4H), 6.36 (d, 1 H), 6.20 (dd. 1 H), 5.78 (s, 1~-I), x.95 (s, 2H), 1.23 (m, 3H), 1.10 (m, 18I-I).

S PREPARATION OF
OTIPS
OBn Following the procedure outlined in Example 16 and using the bromoketone from Example 12 with the thiophenol derivative prepared from Example 1, the desired product was obtained after silica gel chromatography using EIOAc/hexane (1/5) as eluant. 'H NMR (500 MHz, CDC13) ~ (ppm): 8,24 (s, IH), 7.80 (d, 2H), 7.40 (m, 5H), '7.10 (d, 2H), 6.'78 (d, 4H), 6.62 (d, 1H), 6.42 (d, 1H), 5.84 (s, ~H), 4.98 (s, 2H), 1.23 (m, 3H), 1.10 (m, 18H); MS m/z 650 (M~+1).

PREPARATION OF
IPS
Following the procedure outlined in Example 16 and using the bramoketone from Example 12 with the thiophenol derivative prepared from Example 1, the desired product was obtained after silica gel chromnto~raphy using EtOAc/hexane (1/5) as eluant. ~H NMR {500 MHz, acetone-d~,) 8 {ppm): 7.95 {d, 2H), 7.~0 {m, SH), 7.20 {d, 2I-I), G.80 {m, 7I-I), G.?0 {s, 1H), x.85 {s, 2H), 1.23 {m, 3H), 1.10 {m, 18H); MS mlz G 1 G {M~+1 ), PREPARATIO~F OF
O / OTIPS
I
HO ~ ~ S
HO ~ ~ Me OBn Following the procedure outlined in Example 1G9 and using the bromoketone from Example 12 with the thiophenol derivative prepared from Example 1, the desired product was obtained after silica gel chromatography using EtOAclhexane {1/5) as eluant. 'H NMR {500 MHz, CDCI3) 8 (ppm): 7.82 {d, 2H~, 7.~0 (m, 5H), 7.05 (d, 2H), 6.95 {s, 1H), G.80 {d, 4H), G.52 {s, 1H), S.G~ {s, 1H), 5.00 {s, 2H), 1.23 {m, 3H), 1 S 1.10 {m, I 8H); MS mlz 629 {M~+1).

PREPARAT10~1 OF
OTI PS
H
OBn Following the procedure outlined in Example IG and using the bromoleetone From Example 12 with the thiophenol derivative prepared from Example 1, the desired product was abtained aFter silica gel chromatography using EtOAc/hexane (1/5) as eluant. 'H NMR (500 MHz, CDCI~) cS (ppm: 8.24 (s, IH), 7.80 (d, 2H), 7.40 (m, 5I-I), _5 7.10 (d, 2H), G.78 (d, 2H), G.7G (d, 2H), G.64 (d, 2H), G.~._5 (d, 2H}, S.BG (s, IH), 4.98 (s, 2H), 1,23 (m, 3H)> 1.10 (m, 18H); MS m/z G50 (M~+1).

TI
Bn Following the procedure outlined in Example 1G and using the bromoketone Pram Example 12 with the thiophenol derivative prepared from Example 1, the desired product was obtained after silica gel chromatography using EtOAc/hexane (1/5) as eluant. 'H NMR (500 MHz, CDCI~} 8 {ppm): 7.82 (d, 2H), 7.40 (m, 5H), 7.24 (m, 3H), 7.20 (d, 2H), 6.82 (d, 2H), G.80 {d, 2H), G.58 {d, 2H), S.GS {s, 1H), 4.80 (d, 2H), 2.22 {s, 3H}, 1.23 (m, 3H), 1.10 {m, 18H).

PREPARATIO ~ ~ OF
TIPS
Bn CI

Following the procedure outlined in Example 16 and the bromol<etone from Example 13 with the thiophenol derivative prepared from Example I, the desired product was obtained after silica gel chromatography using EtOAc/hexane (1l5) as eluant.
~H
N'MR (500 MHz, CDCI~) b (ppm): 7.98 (s, 1 H), 7.82 (d, 2H), 7.~0 (m, 5H), 7.25 (m, S 3I-I), 7.20 (d, 2H), 7.00 (d, 1H), 6.80 (d, 2H), 6.60 (d, 1H), 5.78 (s, 1H), x.78 (d, 2H), 1.23 (m, 3H), 1.10 (m, 18H).

PREPARATION OF
O
O
TIPSO \ S TIPSO ~ I S CI
HO ~ ~ OBn HO ~ ~ OBn CI
IL
Following the procedure outlined in Example 16 and using the bromoketone from Example 13 with the mixture of the two thiophenol derivatives prepared from Example 1, the two desired products 71 and II were obtained after silica gel chromatography using EtOAc/hexane (1l5) as eluant.
I: ~H NMR (500 MHz, CDC13) 8 (ppm): 7.80 (d, 2H), 7.40 (m, 5H), 7.25 r;m, 3H), 7.16 (d, 2H), 7.04 (s, 1H), 6.80 (d, 2H), 6.60 (s, 1H), 5.78 (s, 1H), 4.80 (d, 2H), 1.23 (m, 3H), 1.10 (m, 18H).
II: ~H NMR (500 MHz, CDC13) ~ (ppm): 7.80 (d, 2H), 7.65 (s, 1H), 7.~1~. (d, 1H), 7.40 (m, 5H), 7.25 (m, 5H), 6.96 (d, 1H), 6.80 (m, 3H), 6.00 (s, 1H), 5.15 (s, 2H), 1.23 (m, 3H), 1.10 (m, 18H).
,78-PREPARATION OF' o ~ F
I
TiPSO ~ I s Ho ~ ~ oBn Following the procedm°e outlined in Example 16 and using the bromoketone from Example 12 with the thiophenol derivative prepared from Example 1, the desired product was obtained after silica gel chromatography using EtOAclhexane {1/5) as eluant. iH NMR (500 MHz, CDC1~) ~ (ppm): 7.80 {d, 2H), 7.~I0 (m, 5H), '7.14 {m, 2H), 6.96 {m, 2H), 6.8~. {m, 2H), 6.82 {d, 2H), 6.70 {d, 1H), 5.68 {s, 1H), 4.86 d, 2H), 1.23 {m, 3H), 1.10 {m, 18H).

OTIPS
S
O
Ph~O \ OH
Utilizing the bromides prepared in the Example 10 and the appropriate mercaptan prepared in Example 1 and employing the procedure outlined in Example 16 the following compaunds were prepared:
Cyclohexyl derivative: use methylene chloride/hexanes{3:1) as the chromatography eluant. ~H 500MHz NMR{CDC13) ppm(~): 1.12 {d, 18H), 1.11-2.34 {m, 15H), x.19 (d, 1H), 5,0 (s, 2I-I), 6.4~ {dd, 1H), 6.5~ (d, 1H), 6.86 Vim, 3H), 7.25-7.72 (m, 7H).

Cyclopentyl derivative: use methylene chloride/hexanes(2: I ) as the chromatography eluant. ~ H 500MHz NMR(CDCI;~) ppm(~): I .12 (d, 181-1), 1.28-2.49 {m, 12H), x.18 {d, 1I-I), 5.0 {s, 2H), 6.45-7.77 {m, I2H).

PREPARATION OF
OH
S ~ v O
Ph~O \ OH
Utilizing the bromide prepared in Example 11 and the appropriate mercaptan prepared in Example I and employing the procedure outlined in Example 9, the desired product was obtained as a yellow oil in 77°~o yield after silica gel chromatography with 30°~° EtOAc/hexane as the eluant. ~H 500MHz NMR{CDCI~) IS ppm{8): 1.00 {d, 3H), L21 {d, 3 H), 2.30 (m, 1H), X1.13 (d, 1H), X1.99 {s, 2H), 6.~1.1-7.72 {m, 12H), 8.02 {bs, 1H), 8.80 (bs, 1H); MS m/z X09 (M+) EXAMPLE ~I I
GENERAL PREPARATION OF
OTIPS
Ph.~O / S
O
OH

Lltiliring the bromides prepared in Example 10 and the appropriate mercaptan prepared in Example 1 and employing the procedure outlined in Example 16 the Following compounds were prepared:
Cyclohexyl dcrivafiive: use methylene chloride/hexanes(3:1) as the chromatography eluant. ~H 500MHz NMR(CDCI~) ppm(c~): 1.12 {d, 18H), 1.11-2.3 (m, 15H), 4.2~.
(d, 11-I), ~-.89 (m, 2H), 6.8-7.6 {m, 12H).
Cyclopenfiyl derivative: use methylene chloride/hexanes~2:1) as the chromatography eluant. ~H 500MHz NMR(CDC13) ppm(~):1.12 (d, 18H), 1.26-2.12 (m, 11H}, 2.5 {m, 1H), x..24 (d, 1H), 4.9 (m, 2H), 6.8-7.69 {m, 12H).
4-Pyridyl derivative: isolated as a yellow oil using 30% EtOAc/hexane as the chromatography eluant. ~H 500MHz NMR(CDCIs) ppm(~):1.12 (d, 18H), 1.28 (m, 3H), 4.8~ (q, 2 H), x.88 {s, 1H), 5.63 (s, 1H), and 6.69-8.50 {m, 16H).
3-Pyridyl derivative: isolated as a yellow oil using 30% EtOAclhexane as the chromatography eluant. 'H 500MH2 NMR{CDC13) ppm(~):1.12 (d, 18H), 1.28- (m, 3H), 4.81 (q, 2H), 4.90 (s, 1H), 5.79 (s, 1H), and 6.70-8.50 (m, 16H).
EXAMPLE ~.2 OH
Ph~O , S
O
OH
Utilizing the bromide prepared in Example 11 and the appropriate mercaptan prepared in Example l and employing the procedure autlined in Example 16, the desired product was obtained as a yellow oil aFter silica gel chroma tography with 30%a EtOAc/hexane a s the eluant. ~ H 500MHz NMR(CDC13) ppm{8): 1.02 (d, 3H), 1.21 (d, 3 H), 2.31 (m, I H), x.13 (d, 1 H), x.90 (q, 2H), 6.25 (bs, 1H), 6.79-7.70 (m, 12H).

PREPARATION OF
S / , OTIPS
HO , S
O
\ OH
Utilizing the appropriate bromide prepared in Example 10 and the mercaptoquinol [prepared according to the method of Burton, elcrl, J. Chejn. Soc., 1952, 2193] and employing the procedure outlined in Example 16, the desired product was obtained as an orange/red oil after silica gel chromatography with 30Q1o EtOAclhexane as the eluant. ~H S00MHz NMR(CDCI~) ppm(8): 1.10 (d, 18H), 1.27 (m, 3H), 6.00 {s, 1H), and 6.76-7.89 {m, 10H)> MS m/z S1S (M~).
EXAMPLE 4~1 PREPARATION OF
PS
Bn vn To a flask charged with O.lg {0. l6mmole) of thio-1<etone generated in Example 22 in dichloromethane {ca 0.04M) was slowly added trifluoroacetic acid(TFA) (2 X
0.062mL, l0eq) under an N~ atmosphere at room temperature. To the sowed reaction mixture was slowly added triethylsilane (2 X 0.05mL, 4eq) and the resulting mixture until starting material was consumed (approximately 5-6 hours, as monitored by TLC). The reaction mixture was poured into saturated NaHCO~lice water, stin-ed l0 minutes, and extracted with dichloromethane. The organic extract was washed with brine {2 X SOmL), dried with Na~SO,~, and concentrated in vac~co to afford a light yellow oil. Purification via flash chromatography (EtOAc/Hex=1:5) provided the desired compound as an oil. ~H NMR {100 MHz> CDCI;) cS (ppm): 7.44 (m, 5H), 6.98 _g~_ (d, I I-I), 6.90 (d, 2H), 6.7_5 (d, 21-I), 6.68 (d, 2H), 6.65 (d, IH), 6.63 (d, 2H), 5_51 (d, J=2.3Hz, 1 H), 5.10 (s, 2H), 4.74 (brs, 1 H), 4_32 (d, J=2.31-lz, 1 H), 2.77 (dd, 2H), l .?2 (m, 3H), 1.08 (d, 18H), 1.1 (m, 31-I); MS mlz 6?8.5 (M~+1).

PREPARATION OF
PS IPS
OM
Utilizing the procedure from Example 44, the desired dihydrobenzoxathiin without MOM protection was isolated after purification by silica gel chromatography with 10% EtOAclhexane. 1H NMR (400 MHz, CDC13) b (ppm): 7.2-G.98 (m, 4H), 6.85 (d, 2H), 6.78 (d, 2H), 6.66 (two d, 4H), 5.5 (d, J=2.2Hz, 1H}, 4.8 (s, 1H), 4.33 (d, J=2.lHz, IH), 1.22 (m, 3H), 1.1 (d, 18H); MS mlz 515 (M~+23).
The other dihydrobenzooxathiin with MOM protection was also isolated. 1H NMR
(400 MHz, CDCI~) ~ (ppm): 7.2-6.6 (m, 8H), 6.78 (d, 2H), G.66 (d, 2H), 5.5 (d, J=2.4Hz, 1H), 5.14 (s, 2H), 4.35 (d, J=2.lHz, 11-1), 3.48 (s, 3H), 1.22 (m, 3H), 1.1 (d, 18H).

PREPARATION OF
OH
OMOM
_g3_ Utilizing the procedure from Example 71 (Step C), the dihydrobenzoxafhiin generated From Example ~.5, was desilylated to give the product- ~H NMR 0100 MI-Iz, CDCI~) ~
(ppm): 7.2-G.9G (m, ~1H), G.92 two d, ~1.H), G.82 (d, 2H), G.G (d, 2H}, 5,52 (d, J=2.2Hz, 1H), S.1G (s, 2H), ~..GB tbr s, 1H}, x,38 (d, J=2.2Hz, 1H}, 3.x.8 (s, 3H).

PREPARATION OF
'~" "~M OH
M OH
The ketone generated in Example 17 was conveated to the desired product Following the procedure described in Example X14 with the exception that 5 equivalents of TFA
and 2 equivalents of EtsSiH was necessary to drive the reaction to completion.
The MOM group was removed with mild acid treatment (2N-HCI, 75°C) to give the desired product. 'H NMR 0100 MHz, CDCl3) ~ (ppm): 7.0 (m, ~.H), G.85 (d, 2H), 6.G5 (d, 2H), 5.38 (s, 2H); MS mfz 313 (M++23}.

PREPARATION OF
~TIPS
Bn H
The l:etone generated in Example 18 was converted to the dihydrobenzoxathiin utilizing the procedure From Example ~1~I with the exception that 20 equivalents of _$~_ TI=~A and 15 equivalents of Et~SiH were necessary to drive the reaction to completion.
The desired product was isolated aFter puriOication by silica gel chromatography using 10%~ EIOAc/hexane as eluant. ~H NMR (~00 MHz, CDCI~} ~ (ppm): 7.5-7.34 {m, 5H), 7.08 (d, LH), 6.84 (d, 21-1), 6.76 (d, 21-I), 6.7 (dd, 1H), 6.67 (d, 1 H), 6.68 (two d, 4H), 5.5 (d, J=2.2Hz, 1H), 5.04 (br q, 2H), 4.68 (s, 1H), ~.3 (d, J=2.2I-lz, 1H), 1.22 (m, 3H), 1.1 (d, 18H); MS mlz 515 {M~+23).

PREPARATION OF
OMe B
IO OTIPS
The ketone generated in Example 19 was converted to the dihydrobenzoxathiin utilizing the procedure from Example 4~1 with the exception that the reaction was run at -10°C for A~8 hours in the presence of 20 equivalents of TFA and 2 equivalents of Et~SiH. The desired product [with 20% recovered starting material] was isolated after purification by silica gel chromatography using 10% EtOAc/hexane as eluant. ~H
NMR (400 MHz, CDCl3) & (ppm): 7.5-7.3 (m, 5H), 7.1-6.6 (m, 11H), 5.54 (d, T=l.9Hz, 1H), 5.06 (dd, 2H)> 4.32 (d, 1H), 3.74 (s, 3H), 1.22 (m, 3H), 1.1 (d, 18H).

PREPARATION OF
Me / OTIPS
/ S \
Bn0 \ O ~ \
OH
_85_ Following the procedure outlined in Example 44 and using the 1<etone derivative in Example 20, the desired product was obtained after purification by silica gel chromatography using S~l~ EtOAc/hexane as eluant. ~H NMR (400 MHz, CDCI~,) b (ppm): 7.46-7.32 (m, 5H), 6.84 (d, 2H), 6.78 (d, 2H), 6.66 (two d, ~-H), 6.62 (d, LH), 6._57 (d, 1 H}, 5.3 (d, J=2,2Hz, 1 H), 4,35 (d, 1H), 2.28 (s, 3H), 1.22 (m, 3H), 1. L (d, L8H).

PREPARATION OF
OTIPS
Bn LO OH
Following the procedure outlined in Example 44 and using the ketone derivative from Example 21, the desired product was obtained after purification by silica gel chromatography using 5°~c~ EtOAclhexane as eluant. 'H NMR (400 MHz, CDC13) 8 (ppm): 7.5-7.3 (m, 5H), 6.98 (d, 1H), 6.9 (d, 1H), 6.76 (d, 2H}, 6.6 {m, 5H), 5.5~ (d, J=2.2Hz, 1H), 5. J~ (s, 2H), 4.8 (s, LH), 4.32 (d, 1T~, 2.4 (s, 3H), 1.22 (m, 3H), 1.1 (d, 18H).

PREPARATION OF
Et IPS
Bn0 \
Following the procedure outlined in Example ~~ and using the ketone derivative from Example 22, the desired product was obtained after purification by silica pel chromatography using 5°l~ EtOAc/hexane as eluant. ~H NMR (400 MHz, CDCI~) ~
(ppm): 7.5-7.3 (m> 5I-I), G.85 (d, 2H), G.78 (d> ?H), G.GG (m, 5H), G.SG (d, 1H). 5,x-8 (d, J=2.OHz> 1H), 5.0~- (br q, 2H), 4.74 (br s, 1 H), 4.34 (d, J-2.OHZ, 1 H), 2.G4 (q, 2H), I .3 (t, 3H), I.2~ (m> 3H), t. l (d, 18f-I).

PREPARATION OF
OTIPS
Bn0 OH
Following the procedure outlined in Example ~~ and using the ketone derivative From Example 23, the desired product was obtained after purification by silica gel chromatography using 5%a EtOAc/hexane as eluant. 1HNMR (400 MHz, CDCI~) 8 (ppm: 7.5-7.3 (m, 5H), G.98 (d, 1H), G.9 (d, 2H), G.74 (d, 2H), 6.7-G.6 {three d, 5H), 5.5 (d, J=2.3Hz, 1H), 5.1 (s, 2H), 4.74 (br s, 1H), 4..32 (d, J-2.4Hz, 1H), 2.79 (m, 2H), 1.~? (m, 3H), 1.1 (d & t, 21H); MS m/z 628.5 (M++I).

PREPARATION OF
PS
Bn ?0 Following the procedure outlined in Example 44 and using the ketone derivative from Example 24, the desired product was obtained alter purification by silica gel chromatography using 5% EtOAc/hexane as eluant. ~H NMR (400 MHz, CDCI~) 8 (ppm): 7.5r7,3 Vim, l OH), G.84 {d, ?H)> 6.78 (d, 2H), G.GG (two d, 4H), 6.38 (s> 2H), _87-5.48 (d, J=2.1 H7a, 1 H), 5.14 (s, 2H), 5.0 (d, 2H), 4.76 (br s, l I-I), 4.32 (d, J=2.1 Hz, 1 H), I.?? (m, 3I-I), L1 (d, 18H).

PREPARATION OF' Bn IPS
Following the procedure outlined in Example 44 and using the ketone derivative obtained from Example 25, the desired product was obtained after purification by silica gel chromatography using 5~/c. EtOAclhexane as eluant. ~H NMR {400 MHO, CDCI,;) ~ (ppm): 7.5-7.32 (m, 5H), 7.2-7.1 (m, 4H), G.9-6.82 (m, ~-H), 6.76-6.7 (m, 4H), 5.56 (d, 1H), 5.06 (br q, 2H), 4.36 {d, 1H), 1.22 (m, 3H), 1.1 (d, 18H).

PREPARATION OF
Bn0 / S \
O
OTIPS
Following the procedure autlined in Example 44, with the exception that the reaction was run at 0'~C for three hours, and using 1.7g{2.83mmole) of the ketane derivative ?0 obtained from Example 26, the desired product was obtained after purification by silica gel chromatography using 5~7o EtOAclhexane as eluant. ~H NMR (400 MHO, CDC1;) S (ppm): 7.5-7.34 (m, 5H), 7.2-7.1 (m, 3H), 6.94 (d, 1H), 6.9-6.82 (m, 5H), 6.4 (m, 3H), 5.48 (d, J=1.9H~, 1H), 5.05 (s, 2H), 4.36 (d, J=l.9Hz, 1H), 1.22 (m, 3H), 1.1 (d, 18H).
-88~

PREPARATION OF
F
S
Bn0 O
OH
Following fihe procedure outlined in Example ~~ and using the ketone derivative obtained from Example 27, the desired product was obfiained, which was subseduenfily desilylated using the procedure described in Example 71 (Step C). The desired product was obtained as an oil after purification by silica gel chromatography using 15ala EtOAc/hexane as eluant. 1H NMR (400 MHz, CDCl3) ~ (ppm): 7.5-7.32 (m, 5H), 7.09 (d, 1H), 6.9-6.8 (m, 6H), 6.73-6.7 (m, 4H), 5.52 (d, 1H), 5.04 (br d, 2H), 4.34 (d, 1H), 1.22 (m, 3H), 1.1 (d, 18H).

PREPARATION OF
Bn0 OTIPS
Following fihe procedure oufilined in Example 44 and using the ketone derivative from Example 28, the desired product was obtained after purification by silica gel chromatography using 5°l~ EfOAelhexane as eluanfi. ~H NMR (500 MHz, CDCI,,) ~
(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.lPlz> LH), 5.05 (d, 2H), 4.40 (d, J=2. LHz> 1H), 1.22 (m>
3H), 1.1 (d, 18H).
_89~

PREPARATION OI~
Bn TIPS
Following the procedure outlined in Example ~~ and using the ketone derivative from Example 29, the desired product was obtained after purification by silica gel chromatography using 5% EtOAclhexane as eluant. 'H NMR (500 MHz, CDC13} ~
{ppm): 7.S-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.lHz, 1H), 5.05 (d, 2H), 4.43 (d, J=2.2Hz, 1H}, 1.23 (m, 31-1), 1.10 (d, 18H).

PREPARATION OF
IPS
Bn0 Following the procedure outlined in Example 44 and using the ketone derivative from Example 30, the desired product was obtained after purification by silica gel chromatography using S~lo EtOAc/hexane as eluant. ~H NMR {500 MHz, CDCI~} b (ppm): 7.5-7.3 {m, 5H}, 6.82 {d, 2H), 6.G8 {d, 2H), 6.64 (d, 2H), 6.62 (d, 2H), 6,46 {d, 2H), 5.44 {d, J~l.9Hz, 1H), 5.02 ~d, 2H), 4.30 {d, J=2.0Hz, 1H}, 1.22 (m, 3H), 1.10 (d, 18H); MS m/z 618 (M++1).
m90~

PREPARATION OF
"TIPS
Bn H
Following the procedure outlined in Example 44 and using the ketone derivative from Example 31, the desired product was obtained after purification by silica gel chromatography using 5% EtOAc/hexane as eluant. 1H NMR (400 MHz, CDC13) b (ppm: 7.5-7.3 {m, 5H), 6.86 (d, 1H~, 6.82 {d, 2H), 6.76 {d, 2H), 6.70 {d, IH), 6.67(d, 2H), 6.65(d, 2H), 5.41 {d, J=2.OHz, 1H), 5.04 {s, 2H), 4.38 {d, J=l.9Hz, 1H), 1.23 {m, 31-I), 1.10 (d, 18H); MS m/z 634 (M~+I).

PREPARATION OF
PS
Bn0 Following the procedure outlined in Example 44 and using the ketone derivative from Example 32, the desired product was obtained after purification by silica gel chromatography using 5~/n EtOAc/hexane as eluant. 'H NMR {500 MHz, CDCI;~) b {ppm): 7.5-7.3 {m, 5H), 6.94 {d, LH), 6.85 {d, 2H), 6.80 {d, 2H), 6.74 (dd, 2H), 6.65{m, 4H), 5.43 (d, J=2. LHz, 1H), 5.05 (d, 2H), 4.30 (d, J=2.lHz, LH), I.23 {m, 3H), 1.10 (d, 18H).

PREPARATION OF
IPS
M
Bn Following the pracedure outlined in Exttmple 44 and using the ketone derivative from Example 33, the desired product was obtained after purification by silica gel chromatography using 5°7o EtOAclhexane as eluant. ~H NMR (500 MHz, CDC13) b (ppm): 7.5-7.3 (m, 5H), 6.88 (s, 1H), 6.84 (d, 2H), 6.82 (d, 2H), 6.70 (d, 2H), 6.68 (d, 2H), 6.66 (s, 1H), 5.50 (d, 1H), 5.05 (s, 2H), 4.43 (d, 1H}, 2.35 (s, 3H), 1.23 (m, 3H), 1.10 (d, 18H).

PREPARATION OF
IPS
C
Bn LS
Following the procedure outlined in Example 44 and using the ketone derivative from Example 34, the desired product was obtained after puriFication by silica gel chromatography using 5°~o EtOAc/hexane as eluant. ~H NMR (500 MHz, CDCI~) ~
(ppm): 7.5-7.3 (m, 5H), 7.24 (s, LH), 7.20 (s, lH), 6.82 (d, 2H), 6.68 (d, 2H), 6.64 (m, 4H), 5,44 (d, J=2.OHz, 1H), 5.05 (d, 2H), 4.28 (d, J=2.3Hz, IH), 1.23 (m, 3H), 1.10 (d, I8H).
_9?~

PREPARATION OF
Bn0 / S
~O

S
Following the procedure outlined in Example 44 and using the ketone deoivative from Example 35, the desired product was obtained after purification silica gel chromatography using S% EtOAe/hexane as eluant. 'H NMR {500 MHz, CDCI~) 8 (ppm): 7.5-7.3 (m, 5H), 7.05-7.20 (m, ~1H), 6.90 (d, 2H), 6.88 (d, 2H), 6,78 (d, 2H), 6.70 (d, 1H), 6.65 (d, 1H), 5.30 (d, J=l.BHz, 1H), 5.05 (d, 2H), 4.20 (d, J=2.3Hz, 1H), 1.23 (m, 3H), 1.10 (d, 18H).

PREPARATION OF
B
OTIPS
Following the procedure outlined in Example 44 and using the ketane derivative from Example 36, the desired product was abtained after purification by silica gel chromatography using 5% EtOAclhexane as eluant. 1H NMR X500 MHz, CDCI;~) ~
(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, 1H), 6.60 {d, LH), 5.56 (d, J=l.BHz, 1H), 5.05 (d, 2H), 4.~4. (d, J=2.3Hz, 1H), 1.23 (m, 3H), 1.10 (d, 18H).
93 _ PREPARATION OF
B
TIPS
Following the procedure outlined in Example 44 and using the ketone derivative From Example 37(1), the desired product was obtained after purification by silica gel chromatography using 5°la EtOAc/hexane as eluant. 1H NMR (500 MHz, CDCI~) b (ppm)_ 7.55 (d, 2H), 7.45 (t, 2H), 7.35 (t, 1H), 7.20 (d, LH), 7.15 {m, 3H), 6.88 (d, 2H), 6.84 (d, 3H), 6.78 (d, 2H), 5.46 (d, J=2.lHz, 1H), 5.15 (s, 2H), x.39 (d, J=2.lHz, 1H), 1.23 {m, 3H), 1.10 (d, 18H).

PREPARATTO.N OF
Bn TIPS
Following the procedure outlined in 44 and using the ketone derivative from Example 37(TI), the desired product was obtained after purification by silica gel chromatography using 5 to EtOAc/hexane as eluant. 'H NMR (500 MHz, CDCI~) 8 (ppm): 7.55 (d, 2H), 7.45 (t, 2H), 7.35 (t, 1H), 7.20 (d, 1H), 7.15 (t, 2H), 6.80-6.90 (m, 4H), 6.78 (d, 2H), 6.76 (d, 2H), 5.42 (d, J=2.~Hz, 1H), 5.18 (s, 2H), ~.~I2 (d, J=2. lHz, 1 H), 1.23 (m, 3H), 1.10 (d, 18H).

PREPARATION OF
Bn0 IPS
Following the procedure outlined in Example 44 and using the ketone derivative from Example 38, the desired product was obtained aFter purification by silica gel chromatography using 5°Ic~ EtOAc/hexane as eluant. 'H NMR (500 MHz, CDC1~) ~
(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.lHz, 1H), 5.18 (s, 2H), 4.38 (d, J=2. LHz, 1H}, 1.23 (m, 3H}, 1.10 (d, 18H}.

OTIPS
Bn0 / S
O
OH
Each enantiomer of the racemic dihydrobenzoxathiin, obtained from Example 62, was obtained via chiral chromatography using a Chiralpak AD column, with 30°lp isopropanol in hexane as the eluant.
The fast moving isomer: [cc]o= +18.44°(c=0.725, MeOH).
The slow moving isomer: [ecJ~= -18.85°(c=0.74, MeOH}.

GENERAL PREPARATION Oh TWINS
PREPARATION' OF
OH
S
Ho 0 i ~ N

sty To a stirred solution of a mixture of dihydrobenzoxathiin (60mg, 0.1 mmole), obtained from Example 48 (which was dried by the azeotropic method prior to use), triphenylphosphine {157mg, 0.6mmole), and 1-piperidlneethanol (0.08mL, 0.6mmole) in 4mL of anhydrous THF at 0°C was added dropwise 0.118mL {0.6mmale)of diisapropyl azodicarboxylate {DIAD) over 0.2 hours. The resulting pale yellow solution was stin-ed at room temperature for 2-3 hours. The volatile components were remaved in vacuo and the residue puriFied by flash chromatagraphy {EtOAclhexane=1:5, followed by 2-3% MeOH/dichloromethane) to give desired product. jH NMR (400 MHO, CDC13) ~ (ppm): 7.5-7.34 (m, SH), 7.08 (d, LH), 6.86 {d, 2H), 6.78=6.64 (m, 8H), 5.5 (d> 1H), 5.01 {br q> 2H)> 4.3 (d> 1H)> 4.2 (t, 2H), 2.75 {t, 2H), 2.5 (br s, 4H), 1.6 (m, 4H), 1.48 (m, 2H), 1.22 {m, 3H), 1.1 (d, 18H); MS mlz~
712.4 {Nl~+1).
S te~B
To a stirred solution of the adduct {7lmg, 0.09$mmole), generated in Step A, in 2mL
or' EtOH/EtOAcIH~O (7:2:1) was added l3mg ( 1.2eq) of palladium black and ammonium formate (62mg, l0eq).The resulting mixture was heated at 80°C
and monitored by TLC. After 3hours, the reaction mixture was cooled to room temperature, Filtered thraugh a pad of Celite to remove the catalyst, and the filtrate was partitioned between water and EtOAc. The organic phase was separated, dried over MgSO.~ and concentrated in vacuo to give desired product. ~H NMR (400 MI-Iz, CDCI~) c~ (ppm): 7.01 (d, I H), 6.8 (d, 2H), 6.75 (d, 2I-I), 6.66 (two d, 4I-I), 6.54 (dd, II-1), 6.5 (d, I I-I}, 5.45 (d, J=2.3Hz, LH), x.28 (d, J=2.3Hz, IH), d.08 (t, 2I-I), 2.8 (t, 2H), 2.6 (br s, 4H), 1.68 (m, 4H), 1.5 (m, ?I-I), 1.22 (m, 31-I), 1.1 (d, 18H).
_5 Step C
To a stin-ed solution of a mixture of the debenzylated product generated in Step B and HOAc (l0eq) in mL of THF was added a solution of tetrabutylammonium fluoride (3eq) in Tl-IF at room temperature. The resulting solution was allowed to stir for two hours at room temperature and then poured into saturated aqueous NaHC03 and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO~, filtered, and evaporated. Purification by silica gel chromatography using 5-7%p MeOH
in methylene chloride as eluant afforded the desired product. ~H NMR (400 MHz, CD~OD) ~ (ppm): 6.95 (d, 2H), 6.92 (d, 1H), 6.78 (d, ZH), 6.71 (d, 2H), 6.48 (d, 2H), 6.47 (d, 1H), 6.44 (dd, 1H), 5.47 (d, J=2.lHz, 1H}, 4.37 (d, J=2.lHz, 1H), 4.1 (t, 2H), 2.85 (t, 2H), 2.65 (br s, 4H), 1.66 (m, 4H), 1.5 (m, 2H).

PREPARATION OF
H
N
Step A
Using the procedure described in Example 71 (Step A), the dihydrobenzoxathiin ?5 obtained from Example 53 was coupled with 1-piperidineethanol. After purification by silica gel chromatography, using 3% MeOHICH~CI~ as eluant, the desired adduct was obtained. ~H NMR (400 MHz, CDCI~) ~ (ppm): 6.98 (d, 1H), 6.92 (d, 2H), 6.74 (two d, 4H), 6.65 (d, IH), 6.62 (d, 2H), 5.5 (d, 1H), 5.1 (s, 2H), 4.31 (d, 1 H), 4.09 (m, 2H), 2.75 (t, 2H), 2.5_5 (m, 2H), 2.5 (m, 4H), 1.6 (m, 4H), 1.4_5 (m, 2H), 1.22 (m, 3H), 1.1 (m, 21H).

PREPARATION OF
St_ en B
The adduct generated in Step A was debeW ylated using the procedure described in Example 71 (Step B) to give the desired product. ~H N'MR (x.00 MHz, CDCI~) c~
(ppm): 6.92 (d, 1 H), 6.89 (d, 21-1), 6.72 (d & d, 4H), 6.62 (d, 21-1), 6.5 (d, I H), 5.5 (d, J=2.2 Hz, IH), ~..3 (d, J=?.2Hz, 1H), ~.1 (m, 2H), 2.8 {t, 2H), 2.68 (m, 2H), 2.58 (br s, ~H), 1.61 (m, ~1H), 1.18 (m, 2H), 1.2 (m, 3H), 1.09 {d & m, 21H).
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. 'H
NMR
(d00 MHz, CD30D) ~ {ppm): 7.0 (d, 2H), 6.79 {d, 2H), 6.76 (d, 1H), 6.71 (d, 2H), 6.~7 (d, 3H), 5.~6 {d, J=2.2Hz, 1H), d.38 (d, 1H), X1.08 (t, 2H), 2.8 (t, 2H), 2.5 (m, 2H), 2.6 (m, 4H), 1.62 (m, ~H), 1.5 {m, 2H), 1.1 (t, 3H); MS m/z ~-93.2 (M~+I).

OH
S \
\ O \
O
Step A
The dihydrobenzoxathiin obtained from Example 45 was coupled with 1-piperidineethanol using the procedure described in Example 71 (Step A). After purification by silica gel chromatography using 3% MeOHICH~CI~ as eluant, the desired adduct was obtained. jH NMR (400 MHz, CDC13) 8 {ppm): 7.14-6.92 (m, 4H}, 6.8 {d, ZH), 6.76 {d, 2H}, 6.72 (d, 2H), 6.64 (d, 2H), 5.48 (d, J-2.2Hz, 1H), ~.3A
{d, J=2.1 Hz, IH), 4.1 (m, 2H), 2.85 (m, 2H), 2.6 (m, ~H), 1.65 {m, ~.H), 1.5 (m, 2H), 1.22 (m, 3H), 1.1 (d, 18H).
S tee 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. 'H NMR 0400 MHz, CD;OD) ~ (ppm): 7.1~-a6.92 (m,~-H), 6.06 (d, 2H), 6.78 (d, 21-1), 6,72 (d, 2H), 6.~fi8 (d, _ 9g 2H), 5.48 (d, J=2.1 Hz, 1 H), 4.44 (d, 1 I-I), 4. I (t. 2H), 2.78 (t, 2I-I), 2.58 (br s, 4H), I.64 (m, 4I-I), 1.5 (m, 2H); MS m/z 450.2 (M~+1).

PREPARATIOL~I' OF
ON
~ N
O
Step A
The dihydrobenzoxathiin obtained from Example 46 was coupled with 1-piperidineethanol using the procedure described in Example 71 (Step A). After purification by silica gel chromatography with 3% MeOH/CHzCl2, the desired adduct was obtained as an oil. 'H NMR (400 MHz, CDCI~) ~ (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.lHz, 1H), 5.12 (s, 2H), 4,5 (d, J=2.lHz, 1H), 4.04 (t, 2H), 3.42 (s, 3H), 2.75 (t, 2H), 2.55 (br s, 4H), 1.6 Vim, 4H), 1.48 (m, 2H); MS mlz 495.2 (M'~+1).
Step B
The adduct (lOmg, 0.02 mmole) from Step A was deprotected with TFA (l0eq) and MeOH (6eq) in CH~C12 at room temperature to afford the desired product. 'H NMR
(400 MHz, CD;OD) ~ (ppm): 7.14-6.92 (m, 4H), 6.84 (two d, 4H), 6.66 (d, 2H), G.6 (d, 2H), 5.45 (d, J=2.2Hz, 1H), 4.45 (d, J=2.2Hz, 1H), 4.05 (t, 2H), 2.8 (i, 2H), 2.6 (br s, 4H), 1.6 (m, 4H), 1.5 (m, 2H) ; MS m/z 450.2 (M'~+1).

PREPARATION OF

OH
O \
O I \
~ N
O
The dioxane derivative obtained from Example 47 was coupled with 1-piperidineethanol using the procedure described in Example 71 (Step A) to give the product. ~HNMR (400 MHz, CD~OD) ~ (ppm): 7.04 (d, 2H), 6.98-G.84 (m, ~-H), G.82 (d, 2I~, G,74 (d, 1H), G.G3 (d, 2I~, G.SG (d, ?H), 5.3G (d, 1H), 5.33 (d, J=3,0Hz, 1H), 4.02 (m, ?H), 2.8 (m, 2H), 2.G (br s, 4H), 1.G2 (m, 4H), 1.5 (m, 2H); MS
mlz 43~?
(M+).

OMe S
HO ~ O ~ \
~ N
O
Step A
The dihydrobenzoxathiin generated from Example d.9 was desilylated using the procedure described in Example 7l (Step C). The desired product was obtained as a white solid. 'H NMR (400 MHz, CDCI~) ~ (ppm): 7.5-7.3 (m, 5H), 7.2 (d, 1H), 6.9 (d, 2H), 6.88 (d, 2H), 6.G8 (m, GH), 5.53 (d, J='?.2PIz, 1H), 4.33 (d, J=?.3Hz, lH), 3.75 (s, 3H).
Std The desilylated product abtained from Step A was coupled with 1-piperidineethanol using the procedure described in Example 71 (Step A). After purification by silica gel chromatography with 3~Q MeOH/CH~CI~, the desired adduct was obtained. 'H NMR
(400 MHz, CDCI~) ~ (ppm): 7.57.3 (m, 5H), 7.08 td, LH), G,9 (d, 2H), 6.84 (d, 2H), l Op -6.76 (d, 2I-I), 6.66 (m, 4H), 5.52 (d, 1H), 5.03 (s, 2H), 4.32 (d, II-I), 4.06 (t, 2H), 3.75 (s, 3I-1), 2.75 (t, 2H), 2.5 (br s, 4H), 1.6 (m, 4H), 1_45 {m, 2I-I).
Step C, The adduct generated in Step B was debenzylated using the procedure described in Example 71 (Step B) to give the product. ~H NMR {400 MHz, CD~OD) ~ {ppm):
6.96 (d, 2H), 6.92 (d, 1H), 6.82 {d, 2H), 6.78 {d, 2H), 6.63 (d, 2H), 6.48 (dd, 1H), 6.44 (d, 1H)> 5.S {d, J=2.2Hz, 1H), 4.42 (d, J=2.2Hz, 1H)> 4.08 (t, 2H), 3.68 (s, 3I~), 2.78 {t, 2H)> 2.59 (br s, 4H), 1.6 {m, 4H), 1.48 {m, 21~; MS mlz 479.4 {M~+1).

PREPARATION OF
Me HO
N
Step A, The dihydrobenzoxathiln obtained from Example 50 was coupled with 1-piperidineethanol using the procedure described in Example 71 {Step A). After purification by silica gel chromatography with 3% MeOHICH~CI~, the desired adduct was obtained. 'H NMR {400 MHz, CDCI;) ~ {ppm): 6.83 (d, 2H), 6.75 {d, 2H), 6.69 (d, 2H), 6.62 (d, 2H), 6.5 (d, 1H), 6.48 {d, 1H), 5.42 {br s, 1H), 4.3 (br s, 1H), 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, l8H).
St_ ep B, The adduct generated in Step A was debenzylated using the procedure described in Example 71 {Step B).
Step G
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. ~H
NMR
l01 -(400 MHz, CDw,OD) ~ (ppm): 6.94 (d, 2I-I), 6,76 {d, 2H), 6.7 (d, 2H), 6.49 (d, 2H), 6.4 (d, 1I-I), 6.32 (d, 1H), 5.43 (d, J=2.3I-I7, 11-I), ~..4 {d, J=2,3Hz, 1I-I), 4,08 (t, 2H}, 2.8 (t, 2H), 2.6 (br s, 4H), 2.18 (s, 3H), 1.64 (m, 4I-I), 1.5 (m, 2I-I); MS m/z 479,2 {M~+1).
_5 EXAMPLE 78 PREPARATION OF
H
N
St-ep A
The dihydrobenzoxathiin obtained from Example 51 was coupled with 1-piperidineethanol using the procedure described in Example 71 (Step A}. After purification by silica gel chromatography with 3°~o MeOH/CH~C12, 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 silica gel chromatography using 5%
MeOHICH~CI~ as the eluant, the desired product was obtained as an oil. ~H NMR
(400 MHz, CDCI,;) 8 {ppm): 6.9 {d, ZH), 6.89 {d, 1H), 6.73 {m, 4H), 6.62 {d, 2H), 6.52 {d, 1H), 5.5 {d, 1H), 4.3 (d, LH), 4.1 {br s, 2H), 2.8 {br t, 2H), 2.6 {br s, 4H), 2.2 (s, 3H), 1.6 (m, 4H), L.5 {m, 2H), 1.22 {m, 3H), 1. L (d, 18H).
St_ePC, The debenzylated product from Step B was desilylated using the procedure described in Example 7l (Step C). The desired product was obtained as a white solid. ~H
NMR
(400 MHz, CD~OD) ~ {ppm): 7.02 (d, 2H), 6.76 (d, 2H}, 6.7 {d, 2H), 6.47 {two d, 3H), 5.48 {d, J=2.3Hz, I H), 4.38 (d, J=2.3Hz, 1H), ~. L (t, 2I-I), 2.8 {t, 2H), 2.6 {br s, 4H), 2.1 (s, 3H), 1.6 {m, 4H), L.5 {m, 2H); MS m/z 479.2 ~M*+I}.
I02 _ PREPARATION OF
S
HO ~ O
Et N
Step A
The dihydrobenzoxathiin obtained from Example 53 was coupled with 1-piperidineethanol using the procedure described in Example 7I (Step A). After purification by silica gel chromatography with 3%a MeOH/CH~CI~, the desired adduct LO was obtained.
Step B
The adduct generated in Step A was debenzylated using the procedure described in Example 71 (Step B).
Step G
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 after silical gel chromatagraphy with 5~/o MeOH/CH~C1~ as eluant. 'H NMR (400 MHz, CD~OD) b (ppm): 6.94 (d> 2H)> 6.76 (d, 2H), 6.7 (2H, d)> 6.48 (d> 2H), 6.41 (d, 1H), 6.3 (d, 1H), 5.44 (d, J=2.2Hz> IH), 4.4 (d, J=2.2Hz, ~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, 3H); MS mlz 493.2 (M~+1).

PREPARATION OF
OH
H
O~ N
St! ep A
The dihydrobenzoxathiin obtained from Example 54 was coupled with 1-piperidineethanol using the pracedure described in Example 71 (Step A). After purification by silica gel chromatagraphy with 3% MeOH/CH~CI~, the desired adduct was obtained. 1H NMR (400 MHz, CDC1~) b (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, 1H), 5.14 (s, 2H), 5.02 (q, 2H), 4.32 (d, 1H), ~-.08 (t, 2H), 2.8 (t, 2H), 2.5 (br s, 4H), 1.62 (m, 4I-~, 1.5 (m, 2H), 1.22 (m, 3H), 1.1 (d, l8H).
Step B
The adduct generated in Step A was debenzylated using the procedure described in Example 71 (Step B). After purification by silica gel chromatography using 5%
MeOH/CHfCl2 as eluant, the desired product was obtained as an oil.
St_ ep 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.
~HNMR
(400 MHz, CD~OD) ~ (ppm): 6.94 (d, 2H), 6.78 (d, 2H), 6.72 (d, 2H), 6.5 (d, 2H), 6,06 (d, 1 H), 6.02 (d, 1H), 5.42 (d, J-2.?Hz, 1H), 4.33 (d, J=2.2Hz, IH), 4.09 (t, 2H), 2.8 (t, 2H), 2.6 (br s, 4H), 1.64 (m, 4H), 1.5 (m, 2H); MS m/z 48?.? (M'~+1).

PREPARATION OF

S w HO O
~ N
O
St-ep A
The dihydrobenzoxathiin generated from Example 55 was desilylated using the procedure described in Example 71 {Step C). The desired product was obtained as a white solid. ~HNMR (400 MHz, CDCI~) ~ {ppm: 7.48-7.32 (m, 5H), 7.2-7.1 (m, 4H), 6.94-6.84 (two d, 4H), G.7 {m, 4H), 5.56 (d, J=2.lHz, 1H), 5.04 (br q, 2H), 4.74 (s, 1H), 4.37 (d, J=2.lHz, 1H).
Ste~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 silica gel ehromatogl°aphy with 3%~ MeOH/CHZC12, the desired adduct was obtained.
~HNMR
(400 MHz, CDCI~) 8 (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, 1H), 5.04 (br s, 2H), 4.38 {br s, 1H), 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 debenzylated using the procedure described in Example 71 (Step B) to afford the desired product. 'H NMR (400 MHz, CD30D) 8 (ppm): 7.2-7.14 (m, 3H), 6.94 (m, 3H), 6.9 (d, 2H), 6.74 (d, 2H), 6.48 add, 1H), 6.45 {d, 1H), 5.53 (d, J=2,3Hz, 1H), 4.46 (d, 1H), 4.06 {t, 2H), 2.78 (t, ZH~, 2.58 (br s, 4H), 1.62 (m, 4H), 1.5 (m, 2H); MS m/z 449.2 (M~+1 ).
-10_5-E~CAMPLE 82 PREPARATION OF
H
Step A
i O , S
O ~ ~ ~ N
O
The dihydrobenzoxathiin generated from Example SG was desilylated using the procedure described in Example 71 (Step C). The desired product was obtained as a white solid. ~H NMR {400 MHz, CDC13) 8 (ppm): 7.5-7.3 {m, SH), 7.2-7.1 {m, 3H), G.9G {m, 2H), G.92 (d, 1H), G.88 {d, 2H), G.84 (d, 1H), 6.74 (dd, 1H), 6.66 (d, 2H), 5.48 (d, J=2.lHz, 1H~, 5.04 (s, 2H), 4.37 {d, J=2. LHz, 1H); MS m/z 428,2 {M++1).
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 silica gel l5 chromatography with 3% MeOH/CH~C12, 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 afford the desired product, 'H NMR {400 MHz, CD30D) 8 (ppm): 7.14-7.02 (m, 3H), 6.92 (m, 4H), G.8 {d, 1H), G.74 (d, 2H), G.58 (d, 1H), 6.51 {dd, 1H), 5.42 {br s, 1H), 4.45 {br s, 1H), 4.0G (t, 2H), 2.78 {t, 2H), 2.55 (br s, 4H), 1.6 {m, 4H), 1.5 {m, 2H); MS mlz 449.2 {M~+1).

PREPARATION OF
/ OH
O \
\ \
O SAO
/ O~ N
Step A
To a well stilled solution of the dihydrobenzoxathiin (30mg, 0.061mmole) prepared from Example 74 (Step A) was added Sequivalents of meta-chloroperbenzoic acid {m-CPBA) in methylene chloride at 0°C. The ice bath was removed and the reaction mixture was stirred at room temperature for three hours. The reaction mixture was quenched with a saturated solution of NaHS03 and stic7-ed for additional 30 minutes.
The aqueous layer was extracted with EtOAe and the organic layer was washed with brine, dried with MgSO~, and evaporated to give a residue which was used for next step without further purification. 'H NMR {400 MHz, CD~OD) 8 (ppm): 7.82 (dd, 1H), 7.67 {dt, 1H), 7.28 {m, 2H), 7.2 {d, 2H), 7.03 {d, 2H), 6.92 (d, 2H), 6.82 (d, 2H), 6.32 (d, 1H), 5.12 (s, 2H), 4.84 (d, 1H), 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).
Ste ep B
The MOM protecting group was removed following the procedure outlined in Example 74 (Step B). The desired product was isolated after purification by silica gel chromatography using 5°lo MeOH/CH-~Cl~ as the eluant. ~H NMR (400 MHz, CD~OD) b {ppm): 7.82 {dd, 1H), 7.64 (dt, 1H), 7.'26 (m, 2H), 7.04 (d, 2H), 6.06 (d, 2H), 6.76 (d, 2H), 6.65 (d, 2H), 6.24 (d, J=l,9Hz, 1H), 4.71 (d, 1H), 4.1 (t, 2H), 2,72 (t, 2H), 2.5 (br s, 4H), I,G {m, ~H), 1.45 (m, 2H); MS mlz 481.1 (M~+1).

EXAMPLE 8~
PREPARATION OF
OH
~ OAc ~N
°J
H
Step A
To a well stirred solution of the dihydrobenzoxathiin (60mg) prepared from Example 73 (Step A) was added 5 equivalents of m-CPBA in CH~C12 at OQC. The ice bath was removed and the reaction mixture was stitTed at room temperature for 3 hours.
The reaction mixture was quenched with a saturated solution of NaHS03 and saturated NaHCO~, and stirred for additional 30 minutes. The aqueous layer was extracted with EtOAc and the combined organic layer was washed with brine and dried with MgSO~.
The solvent was removed by evaporation to give an oily residue, which was purified by silica gel chromatography with 3% MeOH/CH~CI~ as the eluant to give the pure product. ~H NMR 0100 MHz, CD~OD) 8 (ppm): 7.85 (dd, 1H), 7.66 (m, 1H), 7.28 (m, 2H), 7.12 (d, 2H), 6.86 (d, 2I~, 6.8 (d, 2H), 6.7 (d, 2H), 6.22 (d, J=2.lHz, 1H), 4.72 (d, J=2.3Hz, IH), 4.08 (m, 2H), 2.8 (t, 2F~, 2.6 (br s, 4H), 1.6 (m, 4H), 1.5 (m, 2H), 1.22 (m, 3H), 1.J (d, 18H); MS mlz 637 (M~+23).
Step B
The silyl protecting group was removed following the procedure outlined in Example 71 (Step C). The desired product was isolated after purification by silica gel chromatography using 5% MeOH/CH~CI~ as the eluant. ~H NMR (400 MHz, CD~OD) ~ (ppm): 7.81 (dd, IH), 7.64 (m, 1H), 7.35 (m, 2H), 7.2 (d, 2H), 6.82 (two d, 4H), 6.6 (d, 2H), 6.28 (d, J=2.2Hz, 1H), X1.69 (d, J=2.2Hz, IH), 4.2 (t, 2H), 3.08 (t, 2H), 2.85 (br s, ~H), 1.7 (m, ~IH), I.55 (m, 2H).

PREPARATION' OF
OH
HO~O
/ n~ N
Step A
Utilizing the procedure from Example 83 (Step A), the dihydrobenzoxathiin (20mg, 0.028 mmole) obtained from Example 71 (Step A), was oxidized by m-GPBA at roam temperature. The crude material was used for next step without further purification.
jH NMR (400 MHz, GDG1~} ~ tppm): 7.84 (d, 1H), 7.7-7.4 (m, 5H), 7,02 (d, 2H}, 6.88 (dd, 1H), 6.82 (d, 2H), 6.76 (two d, 4H), 6.72 (d, 1H), 6.22 (d, J=2.2Hz, 1H), 5.18 (q, 2H), 4.28 (d, J=2.lHz, tH}, 4.09 (t, 2H), 2.8 (t, 2H), 2.55 (br s, 4H), 1.63 (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 afford the debenzylated product, which was used without fuuther purification.
S t The silyl protecting group was removed following the procedure outlined in Example 71 (Step C). The final product was isolated after purification by silica gel chromatography using 5% MeOH/GH~CI~ as the eluant. 1H NMR (400 MHz, GD~OD} 8 (ppm): 7.62 (d, 1H), 7.14 (d, 2H), 6.84 (two d, 4H), 6.68 (dd, I H), 6.6 (d, 2H), 6.55 (d, 1H), 6.22 (d, tH), 4.55 (d, J=2,IHz, 1H), 4.1 (t, 2H), 2.8 (t, 2H), 2.6 (br s, 4H), 1.64 (M, 4H), 1.5 (M, 2H); MS mlz 496. I (M++I).

PREPARATION OF
~ N
H
Step A
To a solution of dihydrobenzoxathiin (100mg, 0. I67 mmole) generated from Example 48 in CHZCI~ was added triethylamine (0.07mL), a catalytic amount of N,N-dimethylaminopyridine (DMAP) and acetic anhydride (0.034mL, 2eq) at room temper°ature. The ~°esultant mixture was stirred For 30 minutes and then poured into saturated NaHC03. The aqueous layer was extracted with CHZCIZ and then dried over anhydrous Na~SO~. The solvent was evaporated to give an oil, which was subjected to silica gel chromatography with 10% EtOAclhexane as eluant to give the product.
IH NMR {400 MHz, CDC13) b (ppm): 7.48-7.34 (m, 5H), 7.08 (d, 1H), 6.99 {d, 2H), 6.94 (d, 2H), 6.76 (d, 2H), 6.72-6.67 (m, 4H), 5.56 (d, 1H), 5.06 (br q, 2H), 4.34 (d, 1H), 2.3 (d, 3H), 1.22 (m, 3H), ~.l (d, 18 H).
Step B
The silyl protecting group was removed following the procedure outlined in Example 71 (Step C). The desired product was isolated after purification by silica gel chromatography using 5~1o MeOH/CH~CI~ as the eluant. ~H NMR (400 MHz, CDC1;) 8 (ppm): 7.48-7.34 (m, 5H), 7.09 (d, 1H), 7.04 ~d, 2H), 6.98 (d, 2H), 6.78 (d, 2H), 6.7 {m, 2H), 6.59 (d, 2~, 5.56 (d, 1H), 5.06 (br q, 2H), 4.74 (s, LH), 4.36 (d, 1 H), 2.2 (s, 3H).
Sto ~~C
The desilylated product (80mg, 0.165mmole) obtained from Step B was coupled with 1-piperidineethanal using the procedure described in Example 71 (Step A).
After purification by silica gel chromatography with 3°la MeOH/CH~C1~, the desired adduct was obtained. ~ H NMR (400 MHz, CDCI~) b (ppm): 7.48-7.34 {m, 5H), 7.08 {d, 1 H), 7.04 {d, 2H), G,98 (d, 2I-I), G.82 (ci, 2I-I), G.7 (dd, 11-1), 6.G8 (d, l I-I), G.GB (d, 2H), 5.58 {d, J=2.2Hz, I H), 5.05 {br d, 2H), 4.3G (d, J=2.2Hz, 1 H), 4.05 (t, 2H), 2.G8 (t, 2H), 2.5 (br s, 4H), 2.25 (s, 3H), I.G (m, 4H), 1.45 (m, 2H); MS m/z 597,3 (M~+l.
Step D
To a solution of IOmg (O.Ol7mmole) of the adduct, generated from Step, in anhydrous TELF was added Four equivalents of a I.OM Super hydride solution in THF. The resulting mixture was stirred For 2 hours at 0°C and then allowed to room temperature (30 minutes). The reaction mixture was hydi°olyzed with H~OINaHCO;. The aqueous layer was extracted with EtOAc, the organic layer separated, dried, and evaporated to give an oil, which was used for next step withaut further purification.
Step E
IS The crude product From Step D was deblocked using the standard procedure described in Example 71 (Step B) to aFford the final product, alter puriFication by silica gel chromatography using 5% MeOHICH~CI~ as the eluant. 1H NMR (400 MHz, CD~OD) 8 (ppm): G.92 {d, IH), G.83 (d, 2H), G.82 (d, 2H), 6.G5 (d, 2H), 6.58 (d, 2H), G.4G (dd, IH), 6.42 (d, 1H), 5.44 {d, J=2.IHz, IH), 4.38 (d, IH, J=2.3Hz, 1H), 4.04 {t, 2H), 2.78 (t, 2H), 2.G (br s, 4H), I.G (m, 4H), 1.5 {m, 2H); MS m/z 4G5 (M~+1).

PREPARATION OF
r S
O O I / ~ N
I JO
St_ ep A
The desilylated product obtained from Example 57 was coupled with l~
pieridineethanol using the procedure described in Example 7I (Step A). AFter puriFication by silica gel chromatography with 3% MeOH/CH~CI~, the desired adduct was obtained.
St. ep B
The adduct generated in Step A was debenzylated using the procedure described in Example 7 L (Step B) to aFFord the desired product. ~ H NMR 0100 MHz, CD~OD) ~
(ppm): 6.98-G.7G (m, 9H)> G.5 (dd, IH), 6.4G (d, 1H), 5.52 (d, J=2.3Hz, 1H), d..5 (d, LH), 1,05 {t, 2H), 2.80 (t, 2H), 2.G2 (br s, ~H), L.G2 (m, ~.H), 1.5 (m, 2H)>
MS m/z 4GG.2 (M'~).

CHIRAL SEPARATION OF
The racemic dihydrobenzoxathiin obtained From Example 81 (Step C) was resolved via chiral chromatography on a Chiralpak AD column, using 20% EtOH in hexane as the eluant. The Fast moving isomer: [cx]D=+33.43°(c=L.205, MeOH).
The slow moving isomer: [a]D=-3~.2°(c=1.09, MeOH).

CHTRAL SEPARATION OF
HO
N
-Ll~_ The racemie dihydrobenzoxathiin obtained from Example 82 (Step C} was resolved via chiral chromatography on a Chiralpalc AD column, using ?0"/~ EtOH in hexane as the eluant. The fast moving isomer: [cxJ,~=+32.4"(c=1.36, MeOH).
The slow moving isomer: [ccJ,~= -31.3°(c=1.37, MeOH).

PREPARATION OF
H
~~ N
The dihydrobenzoxathiin generated from Example 58 was desilylated using the procedure described in Example 71 (Step C). The desired product was obtained as a white solid. 'H NMR (500 MHz, CDC13) b (ppm): 7.5-7.3 (m, SH), 7.2-7.1 (m, 3H), 6.85 (2d, 4H), 6.68 (d, 2H), 6.55 (d, 2H), 5.55 (d, 1H), 5.04 (s, 2H), 4.40(d, 1H}.
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 silica gel chromatography with 3%a MeOH/CH~C1~, the desired adduct was obtained.
Step C
A mixture of the adduct {80mg, O.l44mmole), generated in Step B, 20 mg of palladium black and 5 drops of AcOH in 4 mL of ethanol, was stirred under a balloon of hydrogen gas and monitored by TLC. 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~ solution and extracted by EtOAc.
The organic layer was separated, dried over MgSO~ and concentrated in vacuo to give the desired product. ~H NMR (500 MHz, CD~OD) ~ (ppm): 7.20-7.02 (m, 3H), 6.92 (m, 4H), 6.78 (d, 2H), 6.30 (d, 2H), 5.55 (d, J=2.lHz, 1H}, 4.50(d, J=2.3Hz, IH}, 4.06 (t, 2H), 2.78 (t, ?H), 2.55 (br s, 4H), 1.6 (m, 4H), 1.5 (m, 2H}; MS mlz 467 (M~+1).

PREPARATION OF
H
~N
St_ ep A
The dihydrobenzoxathiin generated from Example 59 was desllylated using the procedure described in Example 71 (Step C). The desired product was obtained as a white solid. 'H NMR (500 MHz, CDC13} 8 (ppm): 7.5-7.3 (m, SH), 7.2-7.1 (m, 3H), 6.95 (d, 2H), 6.90 (d, 1H), 6.85 (d, 2H)> 6.70 (d, 2H}, 6.65 (d, LH), 5.50 (d, 1H), 5.04 (s, 2~I~, 4.4? (d, 1H).
St_ ep B
The desilylated praduct obtained from Step A was coupled with 1-piperidineethanol using the procedure described in Example 71 (Step A). After purification by silica gel chromatography with 3% MeOHICH~CIz, the desired adduct was obtained.
St_ eP C
The adduct, generated in Step B, was debenzylated using the procedure described in Example 71 (Step B) to afford the desired product. 'H NMR (500 MHz, CD_;OD) b (ppm): 7.1~1~7.02 (m, 3H}, 6.92 (d, 2H}, 6.85 (d, 2H), 6.74 (d, 2H}, 6.58 (d, 1~, 6.41 (d, LH), S.S2 (d, J-2.3Hz, 1H), 4.55 (d, J=2.3Hz, 1H), 4.06 (t, 2H}, 2.78 (t, 2H), ?.55 ~br s, 4H), 1.6 (m, 4H), 1.5 (m, 2H); MS mlz 483 (M~+1}.

PREPARATION OF
/ ~ r-i / S \
O \ O I \
/ ~ N
O
Step A
The dihydrobenzoxathiin, obtained from Example 60, was coupled with 1-piperidineethanol using the procedure described in Example 71 (Step A). After purification by silica gel chramatography with 3% MeOH/CHaCl2 the desired adduct was obtained. ~H NMR (500 MHz, CDCI~) ~ (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, 1H), 4.90 (d, 2H), 4.20 (s, 1H), 4.08 (t, 2H), 2.8 (t, 2H), 2.5 (br s, 4H), 1.62 (m, 4H), 1.5 (m, ZH), 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 G
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. 'H
NMR
{500 MHz, CD,,OD) 8 (ppm): 6.93 (d, 3H), 6.78 (d, 2H), 6.69 (d, 2H), 6.50 {d, 2H), 6.28 {m, 1H), _5.46 (d, J=l.BHz, 1H), 4.39 (d, J=2.2Hz, 1H), 4.05 (t, 2H), 2.8 {t, 2H), 2.6 {br s, 4H), 1.64 (m, 4H), 1.5 {m, 2H); MS m/z 482.2 (M++1).

PREPARATLON O F
CI / vh s o ~ o i St_ ep A
The dihydrobenzoxathiin, obtained from Example 61, was coupled with 1-piperidineethanol using the procedure described in Example 71 (Step A). After purification by silica gel chromatography with 3°/a MeOH/CHzCl2 the desired adduct was obtained. ~H NMR (500 MHz, CDC13) 8 (ppm): 7.5-7.3 (m, 5H), 6.85 (m, 3H), 6.70 (d, 4H), 6.63 (d, 2H), 6.60 (d, 1H), 5.42 (s, llTj, 5.02 {d, 2H), 4.40 (s, 1H), 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).
Ste~B
The adduct, generated in Step A, was debenzylated using the procedure described in Example 71 (Step B) to afford the desired product. 'H ~NMR (500 MHz, CD30D) 8 (ppm): 6.82 (d, 2H), 6.78 (d, H), 6.70 {2d, 4H), 6.62 {d, 2H), 6.58 {d, 1H), 5.40 (d, 1H), 4.30 (d, 1H), 4.06 (t, 2H), 2.78 (t, 2H), 2.55 (br s, 4H), 1.6 (m, 4H), 1.5 (m, 2H);
MS mlz 655 (M++1).
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. jH
NMR
(500 MHz, CD~OD) 8 (ppm): 6.92 (d, 2H), 6.75 (d, 2H), 6.68(d, 2H), 6.60 (d, 1 H), 6.50 (d, 2H), 6.42(d, 1 H), 5.42 {d, J-2.2Hz, 1H), 4.42 (d, J-2.3Hz, LH), 4.07 {t, 2H), 2.78 {t, 2H), 2.55 (brs, 4H), 1.62 (m, 4H), 1.48 (m, 2H); MS mlz 499 {M++1).

PREPARATION OF"
OH
H
~ N
O
s step A
The dihydrobenzoxathiin, obtained from Example 62, was coupled with 1-piperidineethanol using the procedure described in Example 71 (Step A). After purification by silica gel chromatagraphy with 3~1o MeOH/CHzCI~ the desired adduct was obtained.
Ste ~~B
The adduct, generated in Step A, was debenzylated using the procedure described in Example 71 (Step B).
Step C
The debenzylated product from Step B was desilylated using the pracedure described in Example 71 (Step C). The desired product was obtained as a white solid after purification by silica gel chromatography with S% MeOH/CH~C1~ as eluant. 'H
NMR
(500 MHz, acetone-d~) ~ {ppm): 7.04 (d, 2H), 6.90 (dd, 3H), 6.72 (d, 2H), 6.64 {d, 1H), 6.59 (d, 2H), 6.57(dd, 1H), 5.44 (d, J=2.3Hz, 1H), 4.52 (d, J-2.lHz, 1H), 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 mlz 465 (M~+1).

PREPARATLON OI~
Me /
NO
N
St_ ep A
The dihydrobenzoxathiin, obtained from Example 63, was coupled with 1-piperidineethanol using the procedure described in Example 71 (Step A). After purification by silica gel chromatography with 3%n MeOH/CH~C1~ the desired adduct was obtained.
Step B
The adduct, generated in Step A, was debenzylated using the procedure described in Example 71 {Step B).
Step C:
The debenzylated product from Step B was desilylated using the procedure described 3n Example 71 (Step C). The desired product was obtained as a white solid after purification by silica gel chromatography with 5% MeOH/CH~CI~ as eluant. ~H
NMR
(500 MHz, acetone-dG) ~ (ppm): 7.00 (d, 2H), 6.85 (s, LH), 6.80 (d, 2H), 6.78 (d, 2H), 6.59 (d, 2H), 6.52 (s, LH), 5.49 (d, J=2.3Hz, LH), 4.65(d, J=2.2Hz, LH), 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).

CI
HO
N
Ste~A
The dihydrobenzoxathiin, obtained from Example G4, was coupled with 1-piperidineethanol using the procedure described in Example 71 (Step A). After purification by silica gel chromatography with 3~1o MeOH/CH~CI~ the desired adduct was obtained. 'H NMR (500 MHz, CDC13) 8 (ppm): 7.5-7.3 (m, 5H), 7.20 (s, 1H), G.85 {d, 2H), 6.70 (2d, 4H}, G.G3 (d, 2H), G.GO (s, IH), 5.42 {s, 1H), 5.02 {q, 2H}, 4.30 (s, 1H), 4.08 (t, 2H), 2.8 (t, 2H), 2.5 (br s, 4H), 1.G2 (m, d-H), 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 afford the desired product. IH NMR (500 MHz, acetone-d~) ~
(ppm): 7.10 (s, LH), 6.98 (d, 2H), 6.82 {d, 2H), G.78 (d, 2H), G.70 {d, 2H), 6.G8 (s, 1H), 5.50 (d, 1H), 4.50 (d, 1H}, 4.0G (t, 2H}, 2.78 (t, 2H}, 2.55 (br s, 4H), 1.6 {m, 4H), 1.5 (m, 2H).
Step_C
The debenzylated product fram Step B was desilylated using the procedure described in Example 71 (Step C). The desired product was obtained as a white solid. 'H
NMR
(500 MHz, acetone-d~} 8 (ppm): 7.12 (s, 1H), 7.02 (d, 2H}, G.80 (dd, 4H), 6.69 {s, 1H), 6.G0 {d, 2H}, G.42 (d, 1H), 5.55 (d, J=2.3Hz, 1H), d.54 (d, J=2. I Hz, 1H}, 4.07 (t, 2H}, 2.78 (t, 2H), 2.55 (brs, 4H), 1.62 (m, 4H), 1.48 (m, 2H); MS m/z 499 (M~+I ).

PREPARATION O1~
H
St- ep A
O , S
O ~ ~ ~ N
O
The dihydrobenzoxathiin generated from Example 65 was desilylated using the procedure described in Example 71 (Step C). The desired product was obtained as a white salid. 'H NMR (500 MHz, CDC13) 8 (ppm): 7.5-7.3 (m, SH), 7.2-7.1 (m, 5H), 6.95 (m, 3H), 6.64-6.7D (m, 2H), 5.46 (d, 3=l.8Hz, 1H), 5.04 (s, 2H), 4.42 (d, J=2.OHz, 1H).
Step $
The desilylated pi°oduct obtained from Step A was coupled with 1-piperidineethanol using the procedure described in Example 7l (Step A). After purification by silica gel chromatography with 3% MeOHlCH2C12, the desired adduct was obtained.
St_ ep C
The adduct, generated in Step B, was debenzylated using the procedure described in Example 71 (Step B) to afford the desired product. 'H NMR (SOD MHz, CD~OD) b (ppm: 7.00-7.12 (m, 6H), 6.90 (d, 2H), 6.75 (d, 2H), 6.42 (s, 1H), 5.42 (d, J=2.lHz, IH), 4.48 (d, J=2.3Hz, 1H), 4.06 (t, 2H), 2.7$ (t, 2H), 2.55 (br s, 4H), 1.6 (m, 4H), 1.5 (m, 2H); MS m/z 463 (M~+1).
12D _ HO , S
O
C I I / ~ N
O
Step A
The dihydrobenzoxathiin generated from Example 66 was desilylated using the procedure described in Example 71 {Step C). The desired product was obtained as a white solid. 'H NMR {500 MHz, CDC13) ~ {ppm): 7.5-7.3 (m, 5H), 7.2-7.1 (m, 3H), 6.95 {d, 2H), 6.92 {d, 2H), 6.90 {d, 1H), 6.78 {d, 1H), 6.70 {d, 2H), 5.52 (d, J-2.lHz, 1H), 5.04 {s, 2H), 4.46 {d, J=2.2Hz, 1H).
Step B
The desilylated product obtained from Step A was coupled with 1-piperidineethanol using the procedure described in Example 71 (Step A). At'ter purification by silica gel chromatography with 3% MeOH/CH?C1~, the desired adduct was obtained.
S t~e~C
The adduct, generated in Step B, was debenzylated using the procedure described in Example 71 (Step B) to afford the desired product. 'H NMR (S00 MHz, CD~OD) 8 {ppm): 7.05-7.15 {m, 5H), 6.90 {d, 2H), 6.79 (d, 2H), 6.65 {d, 1H}, 6.55 ~d, 1H), 5.50 (d, J=2.lHz, 1 H), 4.62 {d, J=2.3Hz, 1 H}, 4.10 (t, 2H), 2.80 (t, 2H}, 2.60 {br s, 4H), 1.6 {m, 4H), 1.5 {m, 2H); MS m/z 483 {M++1 ).
_1~1_ EXAMP>fE 99 PREPARATION OF
H
C
~~ N
Ste~A
The dihydrobenzoxathiin generated from Example G7 was desilylated using the procedure described in Example 71 (Step C). The desired product was obtained as a LO white solid. 'H NMR (500 MHz, CDCI~) c~ (ppm): 7.5-7.3 (m, 5H), 7.2-7.1 (m, 3H)>
7.08 (s, 1H~, 6.95 (d, ZH), 6.8G (m, 3H), 6.70 (d, ZH), 5.42 (d, J=Z.IHz, 1H), 5.14 (s, 2H), d.40 (d, J=2.OHz, 1H).
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 silica gel chromatography with 3~1o MeOHlCH2C12, the desired adduct was obtained.
Std The adduct, generated in Step B, was debenzylated using the procedure described in Example 71 (Step B) to afford the desired product. 'H NMR (500 MHz, CD~OD) 8 (ppm): 7.05-7.15 (m, 3H), 6.95 (m, 3H), 6.90 (d, ZH), 6.75 (d, ZH), 6.72 {s, LH), 5.45 (d, J=Z.OHz, 1H), 4.52 (d, J=2.3Hz, 1H), x.10 (t, ZH), 2.80 (fi, 2H), 2.60 (br s, 4H), 1.6 (m, ~LH), 1.5 (m, ZH); MS mlz 483 (M++1).
- 1?~ _ PREPARATION OF
CI
HO
N
St__ ep A
The dihydrobenzoxathiin generated from Example G8 was desilylated using the procedure described in Example 71 (Step C). The desired product was obtained as a white solid. ~HNMR (500 MHz, CDC13) ~ (ppm): 7.5-7.3 (m, 5H), 7.2-7.1 (m, 3H), G.92-6.80 (m, SIB, G.78 (d, 2H), 6.70 (d, 2H), 5.40 (d, J=2.lHz, 1H), 5.20 (s, ZH), 4.4G (d, J=2.0Hz, 1H).
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 silica gel chromatography with 3% MeOH/CHzCl2, the desired adduct was obtained.
St. ep C
The adduct, generated in Step B, was debenzylated using the procedure described in 71 (Step B) to afford the desired product. 'H NMR (500 MHz, CD30D) 8 (ppm):
7.05-7.15 (m, 3H), G.95 (d, 2H), 6.90 (d, 2H), G.80 (d, 1H), 6.75 (d, 2H), G.70 (d, 1H), 5.38 (d, J=l.BHz, lH), 4.5G (d, J=2. LHz, 1H), 4,06 (t, 2H), 2.78 (t, 2H), 2.G0 (br s, 4H), 1.6 (m, 4H), 1.5 (m, 2H); MS mlz 483 (M~+1).
_ 123 Cl-IIRAL SEPARATION OF
CI
HO
O~ N
The racemic dihydrobenzoxathiin obtained from Example 100 (Step C) was resalved via chiral chromatography on a Chiralpak AD calumn, using 20~/o EtOH in hexane as the eluant. The fast moving isomer: [ec]D= +26.09°(e=1.025, MeOH).
The slaw moving isomer: [oc]p= -25.44°(c=0.95, MeOH).
EXAMPLE IO?
PREPARATION OF
H
r O / S
O
O
Step A
The dihydrobenzoxathiin generated from Example 69 was desilylated using the procedure described in Example 71 (Step C). The desired product was obtained as a white solid. ~H NMR (500 MHz, CDCI~) ~ (ppm): 7.5-7.3 (m, 5H), 6.95 (d, 2H), 6.90(m, 3H), 6.85 (m, 3H), 6.74 (dd, 1H), 6.70 (d, 2H), 5.45 (d, J=l.9Hz, LH), 5.05 {s, 2H), 4.35 (d, J-?.lHz, III.
I2~

St_ ep 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 silica gel chromatography with 3~1a MeOH/CH~C1~, the desired adduct was obtained, which was used without Fuuher puriFication.
Step C
The adduct, generated in Step B, was debenzylated using the procedure described in Example 71 (Step B) to afford the desired product. ~H NMR {500 MHz, CD;OD) 8 (ppm): 6.98 {d, ZH), 6,94 (m, ZH), 6.80 (m, 5H), 6.60 (d, 1H), 6.75 (dd, 1H), 5.40 (d, J=l.BHz, 1H), 4.50 {d, J=Z.lHz, 1H), 4.08 (t, ZH), 2.78 (t, ZH), 2.60 (br s, ~H), 1,6 {m, 4.H), 1.5 (m, ZH); MS mlz 466 (M~+1).

/ OH
HO / S
\ O ,,,.~ \
/ O~ N
(+) isomer St_ e~A
The Fast moving {+)-dihydrobenzoxathiin obtained From Example 70 was coupled with 1-piperidlneethanol using the procedure described in Example 71 {Step A).
After purification by silica gel chromatography with 3~1~ MeOHICH~CIz, the desired adduct was obtained.

St~P B
The adduct, generated in Step A, was deben~ylnted using the procedure described in Example 71 (Step B).
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 aFter purification by silica gel chromatography with 5%p MeOH/CH~CI~ as eluant. 'H
NMR
(500 MHz, acetone-d~) 8 (ppm): 6.90 (d, 2H), 6.78 (d, 1H), 6.72 (d, 2H), 6.70 (d, 2H), 6.60 (d, 1H), 6.50 (d, 1H), 6.x.8 (d, 2H), 5.38 (d, J=2.OHz, 1H), 4.38 (d, J=2.3Hz, 1H), 4-.08 (t, 2H), 2.8 (t, 2H), 2.62 (br s, 4H), 2.6 (q, 2H), 1.6 (m, ~.H), 1.45 (m, 2H), 1.2 (t, 2H); MS mlz X65 (M++1); [cc]p= +27.68°(c=0.~9, MeOH).
EXAMPLE 10~
CHTRAL PREPARATION OF
H
HO / S
O
~N
(-) isom~x St-- ep A
The slow moving (-)-dihydrobenzoxathiin obtained From Example 70 was coupled with 1-piperidineethanol using the procedure described in Example 71 (Step A).
AFter purification by silica gel chromatography with 3~/o MeOHICH~CIZ, the desired adduct was obtained.

St-ep B
The adduct, generated in Step A, was debenzylated using the procedure described in Example 71 {Step B).
_5 Step C
The debenzylated product from Step B was desilylated using the procedure described in Example 71 {Step C). The desfired product was obtained as a white solid after purification by silica gel chromatography with 5% MeOH/CH~CI~ as eluant. 1H
NMR
{500 MHz, acetone-d~} ~ {ppm}: 6.90 {d, 2H), 6.78 {d, 1H}, 6.72 {d, 2H), 6.70 (d, 2H), 6.60 {d, 1H), 6.50 {d, 1H), 6.48 {d, 2H}, 5.38 {d, J=2.OHz, IH), 4.38 {d, J=2.3Hz, IH), 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 mlz 4G5 {M~+I); [cx)D= -26.33°{c=0.515, MeOH).

GENERAL PREPARATION OF
HO ~ S
O
-~. NJ
O
Step A: Reductive Cyelization To a stirred solution of I02.2mg (0.17mmole) of the cyclopentyl-thio-ketone generated in Example 41 in 1mL of dichloromethane at ~-23°C under an N
atmosphere was added 681,~L {0.087mmole) of neat trifluoroaeetic acid{TFA). To the stirred reaction mixture at-23°C was slowly added 41.4~,L {0.259mmale) of neat triethylsilane and the resulting mixture was stirred further far three hours.
The reaction mixture was partitioned between ethyl acetate/saturated NaHCO~/ice/
brine, and the organic phase was separated, washed with brine, dried over anhydrous sadium sulfate, filtered, and evaporated. The residue was purified by silica gel chromatography using methylene chloride/hexanes{ 1:1) as eluant to provide the ci,s-127 _ cyclopentyl-dihydrobenzoaxathiin derivative. ~F-I 500MHz NMR(CDCI~) ppm{b):1.12 (d, I 8H), 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, 12I-I).
Starting with the cyclohexyl derivative prepared in Example 41 and utilizing the above procedure the con-esponding cis-cyclohexyl-benzooxathiin was prepared after purification by silica gel chromatography using methylene chloride-hexanes(1:1). 'H
500MHz NMR(CDCI~) ppm{~): 1.14 (d, 18H), 1.11-1.9 (m, 14H), 3.2 (t, 1H), 5.03 (s, 2H), 5.44 (d, J=2.5Hz, 1H), 6.66-7.47 (m, 12H).
Step B: Desilylation To a stirred solution of 89.6mg (0.156mmole) of the cis-cyclopentyl derivative prepared in Step A above in 1mL of THF at 0 °C was added sequentially 13.31.~L
(0.234mmole) of acetic acid and then 1711uL (0.171mmole) of a 1M solution of tetrabutylammonium Fluoride in THF. The mixture was sowed at 0 °C For 0.5 hour and then partitioned between ethyl acetatel2N HC1/lce/brine, and the organic phase was separated, washed with brine, dried over anhydrous sodium sulFate, filtered, and evaporated. The residue was puriFied by silica gel chromatography using methylene chloride-ethyl acetate (50:1) as eluant to provide the phenolic derivative. ~H
500MHz NMR(CDGI~) ppm(b):1.32-1.94 (m, 9H), 3.51 (dd, J=5.5, 2.5Hz, 11~, 5.03 (s, 2H), 5.42 (d, J-2.3Hz, 1H), 6.67-7.~7 (m, 12H).
Starting with the cyclahexyl derivative prepared in the previous example and utilizing the above procedure the cou-esponding cis-cyclohexyl-benzooxathiin phenol was prepared. ~H 500MHz NMR~CDC13) ppm(~):1.11-1.93 (m, 11H), 3.23 (t, J=3Hz, 1H), 5.03 (s, 2H), 5.44 (d, J=2.3Hz, 1H), 6.66-7.47 (m, 12H).
Ste~G: Mitsunobu reaction To a stirred solution of a mixture of 56.3mg (0.135mmole) of the cis-cyclopentyl derivative prepared in Step B above, 53.6~L (O.~lO~mmole) of 1-piperidineethanol, and 123.5mg {0.47mmole) of triphenylphosphine in 1mL of anhydrous THF at 0°C
was added 87.41~L {0.444mmole) of neat diisopropylazodicarbaxylate {D1AD). The ice-water bath was removed and the mixture was stit~t~ed Further for six hours. The ~. 12 8 mixture was partitioned between ethyl acetate/2N HCl/icel brine, and the organic phase was separated, washed with brine, dried over anhydrous sodium sulfate, Filtered, and evaporated. The residue was purified by silica gel chromatography using ethyl acetate-methanol(9:1) as eluant to provide the adduct. 'H 500MHz NMR(CDCI~) ppm(8):1.33-2.0 (m, 15H), 2.56 (m, 4H)> 2.82 (t, J=6Hz, 2H), 3.51 (dd, J=5.4, 2.4Hz, 1H), 4.16 (t, J=6Hz, 2H), 5.02 (s, 2H), 5.42 (d> J=2.3Hz, 1H), 6.66-7.46 (m, 12H).
Starting with the cyelohexyl derivative prepared in the previous example and utilizing the above procedure the corresponding cis-cyclohexyl-benzooxathiin adduct was prepared. 'H 500MHz NMR(CDCI~) ppm(8):l.ll-1.93 (m, 17H), 2.6 (m, 4H), 2.87 (m, 2H), 3.2 (d, J=2.5Hz, 1H), 4.2 (m, 2H), 5.02 (s, 2H), 5.44 (d, J=2.lHz, 1H), 6.65-7.46 (m, 12H).
Step D: Debenzylation:
A stirred mixture of 36.6mg (0.0069mmole) of the cis-cyclopentyl derivative prepared in Step C above, 14.7mg (0.014mmole) of palladium black, and 87.1mg (0.138mmole) of ammonium formate in 2mL of ethanol-ethyl acetate-water(7:2:1) was heated at 80°C for two hours. The mixture was filtered through celite, washed well 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 anhydrous sodium sulfate, filtered, and evaporated. The residue was purified by silica gel chromatography using ethyl acetate-methanol(9:1) as eluant to provide the final product. ~H 500MHz NMR(CDC13) ppm(8):1.33-2.0 (m, 15H), 2.6 (m, 4H), 2.88 (m, 2H), 3.48 (t, J=2.3Hz, 1H), 4.18 (m, 2H), 5.38 (d, J=2.3Hz, 1H), 6.5 (m, 1H), 6.63 (d, 2.9Hz, 1H) 6.74 (d, J=8.7Hz, 1H), 6.89 (d, J=8.7Hz, 2H), and 7.34 (d, J=8.7 Hz, 2H).
Starting with the cyclohexyl derivative prepared in the previous example and utilizing the above procedure the corresponding cis-cyclohexyl-benzooxathiin adduct was prepared. 'H 500MHz NMR(CDC13) ppm(8):1.00-1.90 (m, 18H), 2.6 (m, 4H), 2.81 (t, 2H), 3.19 (t, J=3.0 Hz,lH), 4.18 (m, 2H), 5.38 (d, J=2.3Hz, LH), 6.43 (m, 1H), 6.62 (d> J=3.0 Hz, 1H), 6.68 (d, J=8.7 Hz, 1H), 6.87 (d, J=8.7 Hz, 2 H), and 7.34 (d, J=8.7 Hz, ?H); MS m/z 454 (M~).
_ 129 EXAMPLE IOG
PREPARATION OF
H
N
Step A: Reductive C clization Starting with the isopropyl adduct (0.0208 g, 0.049 mmol) prepared in Example and utilizing the procedure outlined in Example 105 (Step A), the crude product was isolated after stirring at -23 °C for 6 h 20 min. Purification by silica gel chromatography with 30~/a EtOAc/hexane as the eluant afforded the desired product as a yellow oil. ~H 500MHz NMR(CDC13) ppm(8): 0.95 (d, 3H), 0.98 (d, 3H), 1.95 (m, LH), 3.30 (t, J=3 Hz, 1H), 5.03 (s, ZH), 5.42 (d, J=2.6 Hz, 1H), 6.66-7.47 (m, 12H).
Step B: Mitsunobu reaction The dihydrobenzoxathiin prepared in Step A above was coupled with 1-piperidineethanol using the procedure described in Example 105 (Step C) with the exception that the reaction was allowed to slowly warm from 0 °C to ambient temperature over 3.5 h. Purification by silica gel chromatography with 10°70 MeOH/CH~C12 as the eluant afforded the desired product as a pale yellow oil.
~H
500MHz NMR(CDC13) ppm(8): 0.95 (d, 3H), 0.98 (d, 3H), 1.50-1.68 (m, 6H), 1.95 (m, 1H), 2.60 (m, 4H), 2.86 (t, 2H), 3.30 (t, J=3 Hz, 1H), 4.20 (t, ZH), 5.03 (s, ZH), 5.42 (d, J=2.6 Hz, 1H), 6.66-7.49 (m, 12H).
Step C: Debenz, lation Starting with the compound prepared in Step B above, and utilizing the procedure outlined in Example 105 (Step D), the cowesponding ci,~-isopropyl-benzoxathiin adduct was prepared after silica gel chromatography with IOIa MeOH/CHZC1~ as the eluant. ~H 500M1-Iz NMR(CDCI~) ppm(c~): 0.95 (d, 3H), 0.98 (d, 31-1), 1.50-1.68 (m, 6f-I), 1.95 (m, 1H), 2.60 (m, ~H), 2.86 (t, 2H), 3.26 (t, J=3.0 Hz, 1H), ~l.'~0 (t, 21-I), 5.37 (d, J=2.5 Hz, 1H), 6.47 (dd, 11-1), 6.65 (d, J=3 Hz, 1H), 6.72 (d, J=8.6 Hz, 2H), and 7.35 (d, J=8.7 Hz, 2I-1); MS m/z 414 (M~).

PREPARATION OF
H
S
O ~ S w ~NJ

Step A: Reductive Cyclization Starting with the 2-thiophene adduct (0.0208 g, .049 mmol) prepared in Example and slightly modiFying the procedure outlined in Example 105 (Step A), the crude product was isolated after sowing at 0 °C to ambient temperature For 1 h 40 min.
Purification by silica gel chromatography with 30%a EtOAclhexane as the eluant afforded the desired product as a red oil. 'H 500MHz NMR(CDCI_;) ppm(8):1.11 (d, 18H), 1.24 (m, 3H), 4.67 (d, J=2.0 Hz, 1H), 5.50 (d, J=1.8 Hz, 1H), 6.60-7.12 (m, 10H}.
Step B: Protection with MOM
To a solution of the didhydrabenzoxathiin (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 N~. AFter the gas evolution had ceased, MOMCI
(0.013 mL, 0.16 mmol) was added dropwise to the reaction. After 30 min., another 1.3 equivalents of MOMC1 was added to the reaction. Within 5 min., the reaction was complete by TLC. The resulting dark red solution was partitioned between EtOAc and ice/HzO. The organic layer was washed with brine, dried over Na~SO~, and concentrated in vacrto. The desired product was used in the next reaction without purification. tH 500MH~ NMR(CDCI~) ppm(8):1.11 (d, 1$H}, 1.24 (m, 3H), 3.52 (s, ~131-3H), 4,G7 (d, J=2.1 Hz, IH), 5.14 (m, 2H), 5.50 (d, J=1.8 Hz, 1H), G.GO-7.12 (m, 101-1 ).
Step C: Desilyla Lion The dihydrobenzoxathiin prepared in Step B above was desilylated using the procedure described in Example 105 (Step B) to afford the desired product as a colorless oil after silica gel chromatography with 30% EtOAc/hexane as the eluant.
jH 500MHz NMR{CDCI~) ppm{~): 3.52 (s, 3H), 4.G9 {d, J=1.8 Hz, 1H), 5.15 (m, 2H), 5.51 (d, J=1.8 Hz, 1H), G.60-7.15 (m, lOH).
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 ambient temperature over 4 h, the material prepared in the previous step was converted to the desired product after silica gel chromatography (one elution with 30%n EtOAclhexane followed by a second elution with 10% MeOHlCH2Clz). 1H 500MHz NMR~CDC13) ppm{8): 1.40-2.G0 (m, lOH), 2.79 {t, 2H), 3.52 (s, 3H), 4-.10 (t, 2H), 4.69 (d, J=1.8 Hz, 1H), 5.15 {m, 2H), 5.51 {d, J=1.8 Hz, 1H), 6.60-7.15 (m, lOH).
Step E: Deprotection of MOM
A mixture of the material {0.0401 g, 0.080 mmol) prepared in Step D above and HCl (0.20 mL, 0.40 mmol) in MeOH ( 1.0 mL) was heated to GO °C under N~
for 2.5 h.
The reaction was partitioned between EfOAc and ice/sat. NaHCO~. The organic layer was washed with brine, dried over Na~SO~, and concentrated in uacuo. The residue was triturated with Et~O and desired product was obtained as a white solid. 'H
500MHz NMR(d~-acetone + CD30D) ppm(~): 1.50-3.19 {m, lOH), 3.23 (t, 2H), 4.30 (t, ?H), 5.00 (d, J=1.8 Hz, 1H), 5._51 (d, J=1.8 Hz, 11~, G.57-7.25 {m, 10H);
MS m/z 454 (M'~) _ 132 PREPARATION OF
H
O~ N
Step A: Reductive Cyclization Following the procedure outlined in Example ~1~., 0.0792 g of the 3-pyridyl derivative prepared in Example ~.1 was converted to its corresponding benzoxathiin after stirring at ambient temperature For 5 h. The desired product was isolated from the reaction mixture after silica gel chramatography using 30% EtOAclhexane as the eluant.
'H
500MHz NMR(CDCI~) ppm{8):l.l 1 {d, 18H), 1.2~I (m, 3H), ~.3G {d, J=2.1 Hz, 1H), 5.05 (s> 2H), 5.50 {d, J=1.G Hz, 1H), 6.77-8.~3 (m, 1GH).
Step B: Desilylation Following the procedure outlined in Example 105 (Step B), the dihydrobenzoxathiin generated in Step A above was desilylated to afford the desired product after silica gel chromatography (one elution with 50%a EtOAc/hexane followed by a second elution with 30% EtOAc/hexane}. 'H 500MHz NMR{CDCI,,) ppm{8): 4.~2 (d, J=2.1 Hz, 1H), 5.07 (s, ~H), 5.50 {d, J=1.6 Hz, 1H), 6.77-8.x.3 {m, 1GH).
Step C: 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 ambient temperature over ~1 h, the material prepared in the previous step was converted to the desired product after silica gel chromatography using 10% MeOH/CH~CI~ as the eluant. ' H 500MHz NMR(CDCI_;) ppm(~):1.~10-2.G0 (m, 10H), 2.80 (t, 2H), x..10 (t, ZH), 4.38 (d, J=1.8 Hz, 1H), 5.07 {s, 2H), 5.50 {d, J=1.8 Hz, 1H), G.77-8.43 {m, 1GH).

Stop D: Deben7yla tion Starting with the material prepared in Step C above, and utilizing the procedure outlined in Example 105 (Stop D), the corresponding cr's-3-pyridyl-dihydrobenzoxa thiin adduct was prepared aFter silica gel chromatography with 10%
MeOHICH~CI~ as the oluant. ~H500MHz NMR(CDCI,,) ppm(cS):1.40-2.60 (m, 10H), 2.80 {t, 2H), 4.10 (t, 2H), 4.36 (d, J=2.1 Hz, 1H), 5.45 (d, J=1.9 Hz, 1H), 6.59-8.43 {m, I1H); MS mlz 449 (M+) PREPARATION OF
~ ~N
HO ~ S
O \
~NJ
O
Stop A: Reductive G clization Following the procedure outlined in Example 44, 0.1871 g of the 4-pyridyl derivative prepared in Example 41 was converted to its corresponding dihydrobenzoxathiin after sowing at ambient temperature for 30 h. The desired product was isolated from the reaction mixture after silica gel chromatography using 30% EtOAclhexane as the eluant. 'H 500MHz NMR{CDCI~) ppm(~):1.11 (d, 18H), 1.24 {m, 3H), 4.32 (d, 1H), 5.08 (s, 2H), 5.50 (d, IH), 6.60-8.39 (m, 16H).
Stop B: Desilylation Following the procedure outlined in Example 105 {Stop B), the dihydrabenzoxathiin generated in Stop A above was desilylated to afFord the desired product after silica gel chromatography (ono elution with 50°lp EtOAclhexane followed by a second elution with 30% EtOAclhexane). ~H 500MHz NMR(CDCI~) ppm(~): 4.33 (d, 1 H), 5.07 {s, 2H), 5.46 (d, 1H), 6.63-8.37 (m, 16H).
Step C: 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 ambient temperature over 5 h, the material prepared in the previous step was converted to the desired product aFter silica gel chromatography {one elution with 10°~a MeOH/CH4C1~ Followed by a second elution with 20alo EtOAc/CH~C14). ~H 500MHz NMR(CDCI~) ppm(S):1.40-2.G0 (m, 10H), 2.80 (t, 2H), 4.14 (t, 2H), 4.32 {d, J=3.0 Hz, 1H), 5.0G (s, 2H), 5.49 (d, J=2.I Hz, l H), 6.79-8.38 (m, 1GH).
Stop D: Debenzylation Starting with the material prepared in Step C above, and utilizing the procedure outlined in Example 105 {Step D), the desired product was obtained as a 4:1 cis/trans mixture after silica gel chromatography (1X elution with 30°Io EtOAc/hexane Followed by a second elution with 10% MeOH/CHZCI~).
Cis isomer: ~H 500MHz NMR{CDC1~) ppm(~):1.40-2.70 (m, 1 OH), 2.80 (t, 2H), 4.10 (t, 2H), 4.30 (d, J=2.0 Hz, 1H), 5.44 (d, J=1.8 Hz, 1H), G.59-8.40 (m, I1H).
Traps isomer: 1H 500MHz NMR(CDC1~) ppm{0:1.40-2.70 (m, 10H), 2.80 {t, 2H), 4.15 (t, 2H), 4.38 (d, T=8.7 Hz, 1H), 4.92 (d, J=8.7 Hz, 1H), 6.59-8.46 (m, 11H);
MS m/z 449 (M+).

PREPARATION OF
HO \ S
O ~''e \
Step A: Reduction To a stin-ed solution of 2G5.lmg (0.449mmole) of the cyclopentyl-thio-ketone generated in Example 41 In 3mL of methanol-dlchloromethane(1: L) at 0 °C to room temperature was added portion-wise suFficient sodium borohydride to complete the reduction. The reaction mixture was partitioned between ethyl acetate/2N
HC1/ice/
r135-brine, and the organic phase was separated, washed with brine, dried over anhydrous sodium sulfate, filtered, and evaporated to provide crude cyclopentyl-thio-carbinols, which was used without Further purification in the next step.
Step B: Cyelization A mixture of 2GGmg (0.449mmole) of the crude product, prepared in Step A
above, and 89mg of amberlyst 15 in 3mL of toluene was stin-ed at ambient temperature for iwo hours. The resin was removed by filtration and washed well with ethyl acetate.
The filtrate was evaporated and the residue obtained was purified by silica gel chromatography using dichlot°omethane-hexanes(1:1) as eluant to provide the trans-dihydro-benzoxathiin derivative. tH 500MHz NMR(CDCI~) ppm(8):1.13 (d, 18H), 1.26-1.94 (m, 12H), 3.G4 (dd, J=7.8Hz, 5.5Hz, 1H), x.78 (d, J=7.8Hz, 1H), 5.02 (s, 2H)> 6.6-7.45 (m, 12H).
Step C: Desil lation Follawing the procedure outlined in Step B of Example 105, 228.5mg (0.397mmole) of material prepared in the previous step was desilylated to give the correspanding phenol.
Stea D: Mitsunobu reach Following the procedure detailed in Step C of Example 105, the material prepared in the previous step was converted to the coa-esponding tram-cyclopentyl-dihydrobenzoxathiin adduct. tH 500MHz NMR(CDC13) ppm(c~):1.39-2.0 (m, lSITj, 2.6 (m, 4H), 2.88 (m, 2H), 3.66 (dd, J=7.8Hz, 5.5Hz, 1H~, x.21 (m, 2H), 4.81 (t, J=7.8Hz, 2H), 5.01 (s, 2H), 6.G4-7.~9 (m, 12H).
Step E: Debenz lation Following the procedure detailed in Step D of Example 105, the material prepared in the previous step was converted to the corresponding trcrns-cyclopentyl-dihydrobenzoxathiin product. tH 500MHz NMR(CDCI~) ppm(8):1.29-2.0 (m, 15H), 2.6 (m, 4H), 2.88 (m, 2H), 3.67 (dd, J=8Hz, SHz, 1H), 4.18 (m, 2H), 4.77 (t, J=8Hz, 2H), 6.5 (dd. J= 2.7Hz, 8.7Hz, 1H), 6.65 (d, 2.7Hz, lH) 6.77 (d, J=8.7Hz, 1H), 6.88 (d, J=7.5Hz, 2H), and 7.27 (d, J=7.5Hz, 2H).

GENERAL PREPARATION Oh S
HO ~ O
~ , O~ NJ
Steps A and B: Reduction and Cyclizatian Utilizing the thio-ketanes prepared in Example 39 and employing the procedures outlined above in Step A and B of Example 110, the Following compounds were prepared:
Traps-cyclohexyl derivative: 'H 500MHz NMR(CDCI~) ppm(~): 1.14 (d, 18H), 0.98-1.8 (m, 14H), 3.37 (dd, J=2.5Hz, 8.lHz, 1H), 5.01 (s, 2H), 5.05 (d, J=8.lHz, 1H), 6.6-7.44 (m, 12H).
Traps-cyclopentyl derivative: 'H 500MHz NMR(CDCI~) ppm(~):1.1~1 (d, 18H), 1.28-1.9 (m, 12H), 4.53 (m, 1H), 4.93 (d,lH), 5.01 (s, 2H), 6.6-7.43 (m, 12H).
Ste~C: Desil, lation Utilizing the traps-dihydrobenzoxathiiins prepared in the previous step and employing the procedure outlined above in Step B oFExample 105, the Following compounds were prepared:
Traps-cyclohexyl phenol: ~H 500MHz NMR(CDCI~) ppm(~):1.0-1.8 (m, 11H), 3.3 (m, LH), 5.05 (s, 2H), 5.1 (d, 1H), 6.6-7.44 (m, 12H).
Trcrvs-cyclopentyl phenol: 1H 500MHz NMR(CDC1;) ppm(~): l.?9-2.0 (m, 9H), 3.55 (dd, J=5.7Hz, 7.6Hz, 1H)> 4.95 (d, J=7.6Hz, 1H)> 5.0? (s, 2H), G.6-7.45 (m, 12H).

Step D: Mitsunobu reaction:
Utilizing the trcrn,l~-dihydrobonzoxathiiin phenols prepared In the previous stop and employing the pracedure outlined above in Step C of Example 105, the following compounds were prepared:
Turns-cyclohoxyl adduct: ~H 500MHz NMR(CDC1~) ppmC~):1.0-1.8 {m, 17H), 2.58 (m, 4H}, 2.84 (m, 2H), 3.37 (m, 1H), 4.17 (t, J=6Hz, 2H), 5.0 (s, 2H}, 5.08 (d, J=7.8Hz, 1 H), 6.6-7.43 (m, 12H).
Traps-cyclopontyl adduct: 'H 500MHz NMR(CDC1~) ppm(8}:1.29-2.0 (m, 15H), 2.58 (m, 4H), 2.84 (m, 2H), 3.55 (m, 1H), 4.17 (m, 2H}, 4.94 {d, J=7.3Hz, 1H), 5.0 (s, 2H), 6.6-7.72 (m, 12H).
Stop E: Debenz la~tion:
Utilizing the tr-a~2s-dihydrobenzoxathiiin adducts prepared in the previous stop and employing the procedure outlined above in Stop D of Example 105, the following compounds wore prepared:
Tr-nf2s-cyclohexyl adduct: ~H 500MHz NMR(CDCI~) ppm(b}:1.0-1.8 (m, 17H), 2.58 (m, 4H)> 2.86 (m, 2H), 3.33 (m, 1H), 4.16 (m, 2H), 5.08 (d, J=7.8Hz, 1H), 6.4-7.23 (m, 7H).
Traps-cyclopontyl adduct: 'H 500MHz NMR(CDC13) ppm(b):1.29-2.0 (m, 15H), 2.68 (m, 4H), 2.94 (m, 2H), 3.51 (m, 1H), 4.2 {m, 2H}, 4.95 (d, J=7.4Hz, 1H), 6.45-7.31 (m, 7H).

PREPARATION OF
HO \ S
/ ~ ~''e \
/ O~N

Step A. Silylation To a stirred solution oFthe isopropyl-thio-1<etone {0.0395 g, 0.097 mmol) generated in Example 42 in distilled THF (1 mL) at 0°C was added 60% NaH in mineral oil (0.0183 g, 0.20 mmol) Followed by T1PSC1 (0.048 mL, 0.22 mmol). After 35 min., another equivalent of TIPSCI was added to di°ive the reaction to completion. The reaction was partitioned between EtOAc and ice/HZO, and the organic layer was washed with brine, dried over Na2S0~, and concentrated in vacito to afFord the desired product. The crude material was used in the next step without Further purification.

Stet B: Reduction To a solution of the crude product (0.097 mmol) prepared in Step A above in distilled THF (1 mL) was added a 1 M solution of super-hydride in THF {0.15 mL, 0.15 mmol) at 0 °C under NZ. The reaction mixture was stirred For 20 min. before partitioning between EtOAc and icelHzO. The organic layer was Further washed with brine, dried over Na~SOa, and concentrated izz vacico to give the desired praduet. The crude material was used in the next step without further purification. IH 500MHz NMR(CDC1~) ppm(8): 0.90-1.40 (m, 49H), 1.69 (m, 1H), 3.10 (dd, 1H), 4.60 (d, 1H), 5.05 (s, 2 H), 6.70-7.50 (m, 12H).
Step C: Desil lation To a solution of the material (0.097 mmol) prepared in the previous step in distilled THF (1 mL) was added AcOH {0.018 mL, 0.32 mmol) at 0 °C under NZ
Followed by the addition of a 1 M solution of TBAF in THF (0.29 mL, 0.29 mmol). After 15 min., the reaction was partitioned between EtOAc and icelsat. NaHCO~. The organic layer was washed with brine, dried over Na~SO~, and concentrated llz vrrcaco.
PuriFicatian by silica gel chromatography using 40%a EtOAc/hexane as the eluant afforded the desired product as a yellow Foam. ~H SOOMHz NMR(CDC1.,) ppm{~): 0.92 (d, 3H), 0.98 (d, 3H), 1.59 (m, lH), 2.86 (dd, 1H), 4.62 (d, 1H), 5.02 (q, 2 H), 6.77-7.45 (m, 12H).
Step D: C clization Following the procedure outlined in Example l 10 (Step B), the material (0.0366 g, 0.089 mmol) generated in the previous step was converted to its corresponding irafZs-dihydrobenzoxathiin aFter stirring for 5 h 15 min. at ambient temperature.

Purification by silica gel chromatography using 30%a EtOAclhexane as the eluant afforded the desired product as a white solid. ~ H 500MHz NMR(CDC1~) ppm(~):
0.98 (d, 3I-1), 1.03 (d, 3H), 1.78 {m, 1H), 3.57 (dd, J=3.7 Hz, J=8,5 Hz, lII), 4.82 (d, J=8.4 Hz, 1H), 5.02 (s, 2 H), 6.63-7.46 {m, 12I-1).
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 convec-ted to its carresponding trans-isopropyl-dihydrobenzoxathiin adduct after warming from 0 °C to ambient temperature over 4 h 20 min. Purificatian by silica gel chromatography (one elution with 10% MoOH/CH~CIZ followed by a second elution with 30%~ EtOAc/hexane) afforded the desired product as a white solid. 'H 500MHz NMR{CDC1~) ppm(8):
0.98 (d, 3H), 1.02 (d, 3H), 1.29-1.67 (m, GH), 1.78 (m, 1H), 2.58 (m, 4H), 2.85 {t, 2H), 3.57 {dd, J=3.7 Hz, J=8.5 Hz, 1H), 4.18 {t, 2H), x.83 (d, J=8.4. Hz, 1H), 5.02 (s, 2 H), 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 its corresponding trans-isoprapyl-dihydrobenzoxathiin product. Purification was accomplished by silica gel chromatography using 10%a MeOH/CH2Clz as the eluant. 'H 500MHz NMR{CDCI;) ppm(~): 0.98 (d, 3H), 1.02 (d, 3H), 1.29-1.67 {m, 6H), 1.78 (m, 1H), 2.58 {m, 4H), 2.85 (t, 2H), 3.57 {dd, J=3.7 Hz, J=8.5 Hz, 1H), 4.18 fit, 2H), X1.83 {d, J=8.4 Hz, LH~, 6.48-7.29 {m, 7H); MS mlz 414 (M+).

PREPARATION OF
S
HO ~ O
' - o-~-NJ
.- 140 Step A: Silyla tion Following the procedure outlined in Example 1 12 (Step A), the isopropyl-thio-1<etone ~0.631~- g, 1.5 mmol) generated in Example 40 was silylated. Purification by silica gel chromatography using 30% EtOAc/hexane as the eluant afforded the desired praduct as a yellow oil. ~H 500MHz 1~1MR(CDC1~) ppm(b): 0.98-1.30 (m, 49H), 2.35 (m, LH), 4.38 (d, lH), 4.99 (q, 2H), 6.33-7.79 (m, 12H).
Step B: Reduction Following the procedure outlined in Example 112 (Step B), the material (0.8009 g, 1.1 mmol) isolated in Step A above was reduced to its corresponding alcohol and used without Further purification in the next step. 'H 500MHz NMR(CDC1~) ppm(8):
0.98-1.30 (m, 49H), 1.90 (m, 1H), 2.92 (dd, 1H), 4.59 (d, 1H), 5.05 (q, 2 H), 6.47-7.43 (m, t2H).
Step C: Desil l~n Following the procedure outlined in Example 112 (Step C), the material (0,022 mmol) isalated in Step B above was deprotected to afford the desired product which was used in the next step without purification.
Step D: Cyclization Following the procedure outlined in Example 110 (Step B), the material generated in the previous step was converted to its corresponding trczns-dihydrobenzoxathiin after stirring for 22 h at ambient temperature. Purification by silica gel chromatography using 30% ECOAc/hexane as the eluant afForded the desired product as a colorless oil.
'H 500MHz NMR(CDCI~) ppm(8): 0.98 (d, 3H), 1.03 (d, 3H), 1.79 (m, 1H), 3.45 (dd, 1H), 4.98 (d, 1I-1), 5.02 (s, 2 H), G.~9-7.46 (m, 12H); MS m/z 393 (M~).
Step E: Mitsunobu reaction Fallowing the procedure detailed in Example 105 (Step C), the material (0.008 g, 0.020 mmol) generated in the previous step was converted to its corresponding rr-ans-isopropyl-dihydrobenzoxathiin adduct aFter warming From 0 °C to ambient temperature over 6 h. Purification by silica gel chromatography using 10~'~p MeOH/CH~CI~ as the eluant aFForded the desired product as a pale yellow oil.
'H

500MHz NMR(CDCI~) ppm(c~): 0.98 (d, 3H), 1_0? (d, 3H), 1.29-1.67 (m, 6H), 1.79 (m, I H), ?.58 (m, 4H), 2.81 (t, 2H), 3.50 (dd, J=3.8 Hz, J=8.3 Hz, 1 H), ~. I
8 (t, 2I-1), 4.97 (d, J=8.2 Hz, 1H), 5.01 (s, 2 1-1), 6.59-7.d6 (m, 12H).
Step F: Debenz, lation Following the procedure detailed in Example 105 (Step D), the material (0.0085 g, 0.017 mmol} generated in the previous step was converted to its corresponding trccrZS-isopropyl-dihydrobenzoxathiin product. Purification was accomplished by silica gel chromatography using 10~/o MeOH/CHZC12 as the eluant. 'H SOOMHz NMR(CDC1;) ppm(8}: 0.98 (d, 3H), 1.02 (d, 31T), 1.49-1.70 (m, GH}, 1.75 (m, 1H), 2.61 (m, 4H), 2.85 (t, 2H}, 3.41 (dd, J=3.8 Hz, J=8.3 Hz, 1H), 4.18 (t, 2H), 4.96 (d, J=8.2 Hz, LH), 6.43-7.26 (m, 7H}; MS m/z 414 (M+}.

O / OTIPS
/ \
NO \ S
HS
Following the procedure outlined in Example 16 and using 0.36g (2.Smmole) of 1,2-benzenedithiol, purchased from Aldrich, 221mg (ca 20%, impure} of desired product was obtained after silica gel chromatography using EtOAc/hexane (1/5) as eluant.

- 14~

/ OTIPS / OTIPS OTIPS
/ S ~ I / S ~ ( S
.,,i S ~ S
/ I / S
OH OH / OH
A g C
Utilizing the procedure from Example d~, I2lmg (80%p) of a mixture of three products (A : B : C = 1 : O.I : 0.25) was isolated after purification by silica gel chromatography with 10%~ EtOAe/hexane.

PREPARATION OF
/ S
S
TFA B TFA
St_ ep A
The thiin obtained from Example xx was coupled with 1-piperidineethanol using the procedure described in Example 71 (Step A). After purification by silica gel chromatography using 3%a MeOHICH~CI~ as eluant, the desired adducts were obtained as a mixture.
St_ eP B, The adducts from Step A were desilylated using the procedure described in Example 71 (Step C). The desired product A was separated by HPLC (Meta Chem Polaris C
184.6x50, 5 micron; gradient 5 to 75%~ of acetanitrile on Reverse Phase Column) as a while solid. A: ~H NMR (400 MHz, CD~OD) b (ppm):7.2 (m, 2H), 7.1 (m, 2H), 6.9 - 1 ~L~

(m, 2H), 6.8 (m, 4H), 6,55 (d, 2I-I), 4.75 (m, 2H), ~-.3 (m, 2H), 3,6 (br d, 2H), 3.5 (m, 2I-I), 3.0 (br t, 2H), 1.95 (m, 2H}, 1.8 (m, 4I-I); ( MS m/z 464 (M~}. B: ~ H
I~tMR
(400 MI-Iz, CD~OD) ~ (ppm): 7.d (m, 2H), 7,3 (m, 2H), 7.1 (d, 2H), 6.9_5 (d, 2H), 6.8 (d, 2H), 6,6 (d, 2H), ~-.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 (M~) Assay Methods The utility of the compounds of the instant invention can be readily 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 The estrogen receptor ligand binding assays are designed as scintillation proximity assays employing the use of tritiated estradiol and recombinant expressed estrogen receptors. The full length recombinant human ER-cx and ER-(3 proteins are produced in a bacculoviral expression system. ER-oc or ER-(3 extracts are diluted 1:400 in phosphate buffered saline containing 6 mM cc-monothiolglycerol.
200 ~,L aliquots of the diluted receptor preparation are added to each well of a 96-well Flashplate. Plates are covered with Saran Wrap and incubated at 4 ° C
overnight.
The Following morning, a 20 u1 aliquot of phosphate buffered saline containing 10°70 bovine serum albumin is added to each well of the 96 well plate and allowed to incubate at 4° C for 2 hours. Then the plates are washed with 200 u1 of buffer containing 20 mM Tris (pH 7.2), 1 mM EDTA, 10% Glycerol, 50 mM KCI, and 6 mM a-monathiolglycerol. To set up the assay in these receptor coated plates, add 178 u1 of the same buffer to each well of the 96 well plate. Then add 20 u1 of a 10 nM solution of ~H-estradiol to each well of the plate.
Test compounds are evaluated over a range of concentrations from 0.01 nM to 1000 nM. The test compound stock solutions should be made in 100/0 DMSO at 100X the final concentration desired far testing in the assay. The amount of DMSO in the test wells of the 96 well plate should not exceed l~/o. The final addition to the assay plate is a 2 u1 aliquot of the test compound which has been made up in J.00°~Q DMSO. Seal the plates and allow them to equilibrate at room temperature Far 3 hours. Count the plates in a scintillation counter equipped for counting 96 well plates.
- 144 a Ovariectomit~ed Rat Assay In the ovariectomiaed (OVX) Rat Assay, estrogen-deficiency is used to induce cancellous osteopenia (e.g. low bone mineral density [BMD; mg/cm?]), associated with accelerated bone resotption and formation. Both the BMD and bone resolptionlformation outcomes are used to model the changes in bone that occur as women pass through menopause. The OVX Rat Assay is the principal in uivo assay used by all major academic and industrial laboratories studying the efficacy of new chemical entities in preventing estrogen-deficiency bone loss.
Spl°ague-Dawley female rats aged 6-$ months are OVXd and, within 24 hours, started on treatment for 42 days with vehicle or multiple doses of test compound. Untreated sham-OVX and alendronate-treated (.003 mg/kg s.c., q.d.) or 17-13-estradiol-treated (.004 mglkg s.c., q.d.) groups are included as positive controls.
Test compounds may be administered orally, subcutaneously, or by infusion through subcutaneously-implanted minipump. Before necropsy, in vivo dual labeling with caleein ($ mg/kg by subcutaneous injection), a bone seeking fluoroehrome, is completed. At necropsy, blood, femurs, a vertebral body segment, and the uterus, are obtained.
The routine endpoints for the OVX Rat Assay include assessments of bone mass, bone resorption, and bone formation. For bone mass, the endpoint is BMD of the distal femoral metaphysic, a region that contains about 20~/o cancellous bone. The vertebral segment, a region with ~25%~ cancellous bone may also be used for BMD determination. The BMD measurement is made by dual energy x-ray absoiptiometry (DXA, Hologic 4500A; Waltham, MA). For bone resoiption, the endpoint is urinary deoxypyr 3dinoline crosslinks, a bone collagen breakdown product (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 endpoints are mineralising surface and mineral apposition rate, histomorphometric measures of osteoblast number and activity. This measurement is done on S~,m sections of the non-decalcified proximal tibial metaphysic, using a semi-automated system (Bioquant; R&M Biometrics; Nashville, TN). Similar endpoints and measuring techniques for each endpoint are commonly used in postmenopausal women.

Rat Cholesterol LowErin~ Assay Sprague-Da wley rats (5 per group) weighing about 2508 were subcutancously dosed with compounds of the present invention dissolved in propylene glycol For ~ days. A group of 5 rats were dosed with vehicle only.
On the FiFth day, rats were euthanized with carbon dioxide and their blood samples were obtained. Plasma levels of cholesterol were assayed From these samples with commercially available cholesterol determination kits from Sigma.
MCF-7 Estro en Dependent Proliferation Assay MCF-7 cells (ATCC #HTB-22) are human mammary gland adenocarcinoma cells that require estrogen for growth. The growth media (GM) for the MCF-7 cells is Minimum Essential Media (without phenol red) supplemented with fetal bovine serum{FBS) to LO%. The FBS serves as the sole source of estrogen and this GM supports the full growth of the cells and is used for the routine growth of the cell cultures. When MCF-7 cells are placed in a media in which 10%
Charcoal-Dextran treated fetal bovine serum (CD-FBS) is substituted for FBS, the cells will cease to divide but will remain viable. The CD-FBS does not contain detectable levels of estrogen and the media containing this sera is refen-ed to as Estrogen Depleted Media (EDM). The addition of estradiol to EDM stimulates the growth of the MCF-cells in a dose dependent manner with an EC~~ of 2pM.
Growing MCF-7 cells are washed several times with EDM and the cultures then maintained in EDM for a minimum of 6 days in order to deplete the cells of endogenous estrogen. On day 0 {at the startof the assay), these estrogen depleted cells are plated into 96-well cell culture plates at a density of 1000 cells/well in EDM
in a volume of 180ullwell. On day 1 test compounds are diluted in a 10-fold dilution series in EDM and 20u1 of these dilutions added to the 180u1 of media In the appropriate well of the cell plate resulting in a Further 1:10 dilution of the test compounds. On days 4 and 7 of the assay, the culture supernatant is aspirated and replaced with Fresh EDM and test compound dilutions as above. The assay is terminated at day 8-10 when the appropriate controls reach 80-90% conFluency.
At this point, the culture supernatants are aspirated, the cells washed 2~ with PBS, the wash solution aspirated and the protein content of each well determined. Each drug dilution is evaluated on a minimum of 5 wells and the range of dilution of the test compounds in the assay is 0.OOlnM to 1000nM. The assay in the above format is employed to determine the estradiol agonist potential of a test compound.
1 ~6 In order to evaluate the antagonist activity of a test compound, the MCF-7 cells are maintained in EDM for a minimum of 6 days. Then on day 0 (at the start of the assay), these estrogen depleted cells are plated into 96-well cell culture plates at a density of 1000 cells/well in EDM in a volume of 180u1/well. On day 1 the 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 assay is terminated at day 8-10 when the apprapriate controls reach 80-90% conFluency and the protein content of each well is determined as above.
Rat endometriosis model Animals:
Species: Rattus norvegicus .15 Strain: Sprague-Dawley CD
Supplier: Charles River Laboratories, Raleigh, NC
Sex: Female Weight : 200 - 240 gram Rats are single-housed in polycarbonate cages and are provided Teklad Global Diet 2016 (Madison, WI) and bottled reverse osmosis purified H20 ad libitum. They are maintained on a12/J2 light/dark cycle.
Rats are anesthetized with TelazolT~' (20 mg/kg, ip) and oxymorphone (0.2 mg/kg sc) and positioned dorsoventrally on a sterile drape. Body temperature is maintained using a underlying circulating water blanket. The surgical sites are shaved with clippers and cleaned using three cycles of betadinel isapropyl alcahol or Duraprep0 (3M). The incisional area is covered with a sterile drape.
Using aseptic technique, a 5 cm midline lower abdominal incision is made through the skin, subcutaneous and muscle layers. A bilateral ovariectomy is performed. The left uterine blood vessels are ligated and a 7 mm segment of the left uterine horn is excised. The uterus is closed with 4-0 gut suture. The myometrium is aseptically separated from the endometrium and trimmed to 5X5 mm. The trimmed section of the endometrium is transplanted to the ventral peritoneal wall with the epithelial lining of the segment opposed to the peritoneal wall. The explanted endometrial tissue is sutured at its four corners to the body wall using sterile 6-0 silk.
The abdominal muscular layer is closed using sterile ~l-0 chramic gut. The skin 1 ~7 incision is closed using sterile stainless surgical clips. A sterile 90-day sustained release estrogen pellet (Innovative Research of America, 0.72 ng/pellet;
circulating estrogen equivalent of 200-250 pg/mL) is implanted subcutaneously in the dorsal lateral scapular area. A sterile implantable programmable temperature transponder (IPTT) (BMDS, Seaford, D>J) is injected subcutaneausly in the dorsoscapular region.
The rats are observed until Fully ambulatory, and allowed to recover from surgery undisturbed for 3 weeks.
Three weeks after ti°ansplantation of the endometr3al tissue, the animals undergo a repeat laparotomy using aseptic surgical site preparation and technique. The explant is evaluated for graft acceptance, and the area is measured with calipers and recorded. The animals with rejected grafts are removed from the study. Animals are sorted to create similar average explant volume per group.
Drug or vehicle(control) treatment is initiated one day after the second laparotomy and continued for 1~ days. Body temperature is recorded every other day at 10:00 am using the BMDS scanner.
At the end of the 1~ day treatment period, the animals are euthanized by COZ overdose. Blood is collected by cardiocentesis far circulating estrogen levels.
The abdomen is opened, the explant is examined, measured, excised, and wet weight is recorded. The right uterine horn is excised, and wet and dry weights are recorded.
Pharmaceutical Composition As a specific embodiment of this invention, 25 mg of the compound from Example 71, is formulated with sufficient finely divided lactose to provide a total amound of 580 to 590 mg to fill a size 0, hard-gelatin capsule.

Claims (20)

WHAT IS CLAIMED IS:

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-alkynyl, C3-8 cycloalkenyl, phenyl, heteroaryl, heterocyclical, CF3, -OR6, halogen, C1-5 alkylthio, thiocyanato, cyano, -CO2H, -COOC1-5 alkyl, -COC1-5 alkyl, -CONZ2, -SO2NZ2, and -SO2C1-5 alkyl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, phenyl, heteroaryl, heterocyclical groups can be optionally substituted with C1-5 alkyl, C3-8 cycloalkyl, CF3, phenyl, heteroaryl, heterocyclical, -OR6, halogen, amino, C1-5 alkylthio, thiocyanato, cyano, -CO2H, -COOC1-5 alkyl, -COC1-5 alkyl, -CONZ2, -SO2NZ2, and -SO2C1-5 alkyl;
R5 is selected from the group consisting of C1-5 alkyl, C3-8 cycloalkyl, C2-5 alkenyl, C2-5 alkynyl, C3-8 cycloalkenyl, phenyl, heteroaryl, heterocyclical groups wherein said groups can be optionally substituted with C1-5 alkyl, C3-8 cycloalkyl, CF3, phenyl, heteroaryl, heterocyclical, -OR6, halogen, amino, C1-5 alkylthio, thiocyanato, cyano, -CO2H, -COOC1-5 alkyl, -COC1-5 alkyl, -CONZ2, -SO2NZ2, and -SO2C1-5 alkyl;
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, C1-5 alkyl, trifluoromethyl, wherein said alkyl group can be optionally substituted with C1-5 alkyl, CF3, -OR6, halogen, amino, C1-5 alkylthio.

thiacyanato, cyano, -CO2H, -COOC1-5 alkyl, -COC1-5 alkyl, -CONV2, -SO2NV2, and -SO2C1-5 alkyl;

Or both Zs and the nitrogen to which they are attached may be taken together to form a 3-8 membered ring, said ring may optionally contain atoms selected from the group consisting of carbon, oxygen, sulfur, and nitrogen, wherein said ring may either be saturated or unsaturated, and the carbon atoms of said ring maybe optionally substituted with one to three substituents selected from the group consisting of C1-5 alkyl, CF3, -OR6, halogen, amino, C1-5 alkylthio, thiocyanato, cyano, -CO2H, -COOC1-5 alkyl, -COC1-5 alkyl, -CONV2, -SO2NV2, and -SO2C1-5 alkyl;
Each V is independently selected from the group consisting of C1-5 alkyl, CF3, -OR6, halogen, amino, C1-5 alkylthio, thiocyanato, cyano, -CO2H, -COOC1-alkyl, -COC1-5 alkyl, and -SO2C1-5 alkyl;
Each n is independently an integer from one to five;
and the pharmaceutically acceptable salts thereof.

2. The compound of Claim 1 wherein Y is sulfur and X is oxygen, and the pharmaceutically acceptable salts thereof.

3. The compound of Claim 2 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, -OR6 and halogen, provided that one of R2 and R3, is -OH;
R5 is selected from the group consisting of C3-8 cycloalkyl, phenyl, heteroaryl and heterocyclical groups wherein said groups can be optionally substituted with -OR6 and halogen;
R6 is selected from the group consisting of hydrogen, C1-5 alkyl, benzyl, methoxymethyl and triisopropylsilyl;
and the pharmaceutically acceptable salts thereof.

4. The compound of Claim 3 selected from the group consisting of:

and the pharmaceutically acceptable salts thereof.

5. The compound of Claim 3 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-alkynyl, -OR6 and halogen, provided that 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 selected from the group consisting of hydrogen, alkyl, halogen, trifluoromethyl, and -OR6;
Each Z is independently selected from the group consisting of hydrogen, C1-5 alkyl, trifluoromethyl, wherein said alkyl group can be optionally substituted with C1-5 alkyl, CF3, -OR6, halogen, amino, C1-5 alkylthio, thiocyanato, cyano, -CO2H, -COOC1-5 alkyl, -COC1-5 alkyl, -CONV2, -SO2NV2, and -SO2C1-5 alkyl;
Or both Zs and the nitrogen to which they are attached may be taken together to form a 3-8 membered ring, said ring may optionally contain atoms selected from the group consisting of carbon, oxygen, sulfur, and nitrogen, wherein said ring may either be saturated or unsaturated, and the carbon atoms of said ring maybe optionally substituted with one to three substituents selected from the group consisting of C1-5 alkyl, CF3, -OR6, halogen, amino, C1-5 alkylthio, thiocyanato, cyano, -CO2H, -COOC1-5 alkyl, -COC1-5 alkyl, -CONV2, -SO2NV2, and -SO2C1-5 alkyl;
Each V is independently selected from the group consisting of C1-5 alkyl, CF3, -OR6, halogen, amino, C1-5 alkylthio, thiocyanato, cyano, -CO2H, -COOC1-alkyl, -COC1-5 alkyl, and -SO2C1-5 alkyl;
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 of Claim 5 selected from the group consisting of:

and the pharmaceutically acceptable salts thereof.

7. The compound of Claim 5 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-alkynyl, -OR6 and halogen, provided that 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 selected from the group consisting of hydrogen, alkyl, halogen, trifluoromethyl, and -OR6;
R8 is independently selected from the group consisting of hydrogen, C1-5 alkyl, CF3, -OR6, halogen, amino, C1-5 alkylthio, thiocyanato, cyano, -CO2H, -COOC1-5 alkyl, -COC1-5 alkyl, -CONV2, -SO2NV2, and -SO2C1-5 alkyl;
Each V is independently selected from the group consisting of C1-5 alkyl, CF3, -OR6, halogen, amino, C1-5 alkylthio, thiocyanato, cyano, -CO2H, -COOC1-5 alkyl, -COC1-5 alkyl, and -SO2C1-5 alkyl;
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 of Claim 7 selected from the group consisting of:

and the pharmaceutically acceptable salts thereof.

9. The compound of Claim 5 of the formula:

wherein R1, R2, R3, and R4 are each independently selected from the group consisting of hydrogen, C1-5 alkyl, -OR6 and halogen, provided that one of R2 and R3 is -OH;
R6 is selected from the group consisting of hydrogen, C1-5 alkyl, benzyl, methoxymethyl and trisiopropylsilyl;
R7 is selected from the group selected from the group consisting of hydrogen, alkyl, halogen, trifluoromethyl, and -OR6;
Each m is independently an integer from one or two;
and the pharmaceutically acceptable salts thereof.

10. The compound of Claim 9 selected from the group consisting of:

and the pharmaceutically acceptable salts thereof.

11. The compound according to Claim L wherein X is sulfur and Y
is sulfur, and the pharmaceutically acceptable salts thereof.

12. The compound according to Claim 11 selected from the group consisting of and the pharmaceutically acceptable salts thereof.

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

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

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

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

17. The method according to Claim 16 wherein the estrogen receptor modulation effect is an estrogen receptor agonizing effect.

18. The method according to Claim 17 wherein the estrogen receptor agonizing effect is an ER.ALPHA. receptor agonizing effect.

19, A method of treating or preventing post-menopausal osteoporosis in a female in need thereof by administering to the female a therapeutically effective amount of a compound according to Claim 1.

20, A method of treating or preventing a disorder selected From the grroup consisting of: estrogen-dependent breast cancer, uterine fibroids, restenosis, endometriosis, and hyperlipidemia in a female in need thereof by administering to the female a therapeutically effective amount of a compound according to Claim 1.