AU2002232381B2 - Estrogen receptor modulators - Google Patents

Description

WO 02/32377 PCT/US01/42735 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 dysmenon-hea and dysfunctional uterine bleeding, treatment of osteoporosis, treatment of hirsutism, treatment of prostatic cancer, treatment of hot flashes and prevention of cardiovascular disease. Because estrogen is very therapeutically valuable, there has been great interest in discovering compounds that mimic estrogen-like behavior in estrogen responsive tissues.

For example, estrogen-like compounds would be beneficial in the treatment and prevention of bone loss. Bone loss occurs in a wide range of subjects, including women that are post-menopausal or have had a hysterectomy, patients who were or are currently being treated with corticosteroids, and patient's having gonadal dysgenesis. The current major bone diseases of public concern are osteoporosis, hypercalcemia of malignancy, osteopenia cue to bone metastases, periodontal disease, hyperparathyroidism, periarticular erosions in rheumatoid arthritis, Paget's disease, immobilization-induced osteopenia, and glucocorticoid-induced osteoporosis. All of these conditions are characterized by bone loss, resulting from an imbalance between bone resorption, i.e. breakdown, and bone formation, which continues throughout life at the rate of about 14% 7 per year on the average. However, the rate of bone turnover differs from site to site, for example, it is higher in the trabecular bone of the vertebrae and the alveolar bone in the jaws than in the cortices of the long bones. The potential for bone loss is directly related to turnover and can amount to over 5% per year in vertebrae immediately following menopause, a condition which leads to increased fracture risk.

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

Osteoporosis affects approximately 20 to 25 million post-menopausal women in the U.S. alone. It has been theorized that the rapid loss of bone mass in these women is due to the cessation of estrogen production of the ovaries. Since WO 02/32377 PCT/US01/42735 studies have shown that estrogen slows the reduction of bone mass due to osteoporosis, estrogen replacement therapy is a recognized treatment for postmenopausal osteoporosis, In addition to bone mass, estrogen appears to have an effect on the biosynthesis of cholesterol and cardiovascular health. Statistically, the rate of occurrence of cardiovascular disease is roughly equal in postmenopausal women and men; however, premenopausal women have a much lower incidence of cardiovascular disease than men. Because postmenopausal women are estrogen deficient, it is believed that estrogen plays a beneficial role in preventing cardiovascular disease.

The mechanism is not well understood, but evidence indicates that estrogen can upregulate the low density lipid (LDL) cholesterol receptors in the liver to remove excess cholesterol.

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

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

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

Alternative regimens, such as a combined progestogen and estrogen dose, have been suggested in an attempt to lessen the risk of cancer. However, such regimens cause the patient to experience withdrawal bleeding, which is unacceptable WO 02/32377 PCT/USU1/42735 to many older women. Furthermore, combining estrogen with progestogen reduces the beneficial cholesterol-lowering effect of estrogen therapy. In addition, the long term effects of progestogen treatment are unknown.

In addition to post-menopausal women, men suffering from prostatic cancer can also benefit from anti-estrogen compounds. Prostatic cancer is often endocrine-sensitive; androgen stimulation fosters tumor growth, while androgen suppression retards tumor growth. The administration of estrogen is helpful in the treatment and control of prostatic cancer because estrogen administration lowers the level of gonadotropin and, consequently, androgen levels.

The estrogen receptor has been found to have two forms: ERa and ER3. 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 ERcx or ERB, and therefore confer a degree of tissue specificity to a particular ligand.

What is needed in the art are compounds that can produce the same positive responses as estrogen replacement therapy without the negative side effects.

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

The compounds of the instant invention are ligands for estrogen receptors and as such may be useful for treatment or prevention of a variety of conditions related to estrogen functioning including: bone loss, bone fractures, osteoporosis, 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.

WO 02/32377 WO 0232377PCT/USOI/42735 SUMMARY OF THE INVENTION~ The present invention relates to compounds of the following chemical formul-1a:

R

1 R 2-Y" R R 3

X

R 4 0 (CH 2 2 wherein RI, R 2

R

3 and R 4 are each independently selected from the group consisting of hydrogen, C[-5 alkyl, C3-8 cycloalkyl, alkenyl, C?2 alkynyl, C3-8 cycloalkenyl. phenyl, heteroaryl, heterocyclical, CF3,

OR

6 ha~Le, Cv Ilythio, thiocyanato, cyano, -COH, -COOCv alkyl, -COCp-5 alkyl, -CONZ?, -SONZ?, and -SO2CPS5 alkyl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, phenyl, heteroaryl, heterocyclical groups can be optionally substitted with C1alkyl, C3-8 cycloalkyl, CF3, phenyl, heteroaryl, heterocyclical, -OR 6 halogen, amino, C-1- alkylthio, rhiocyanato, cyano, -CO2H, -COOCjalkyl, -COCIp5 alkyl, -CONZ2, -SONZ2, and -SO-Cp-5 alkyl; is selected fromn the group consisting- Of Ci-5 alkyl, C3-8 cycloalkyl, alkenyl, alkynyl, C3-8 cycloalkenyl, phenyl, heteroaryl, heterocyclical groups wherein said groups can be optional ly substituted with alkyl, C3-8 cycloalkyl, CF 3 phenyl. heteroaryl, heterocyclical, -OR 6 halogen, amino, C alkylthio, thiocyanato, cyano, -CO2H, -COOC I alkyl. -COCI.5 alkyl, -CONZ2 -SONZ2? and -SO2CIA5 alkyl: X and Y are each indcpendently selected fromn the group consisting of oxygen, sulfur, sulfoxide and Suilfone; 295 pR 6 i s selected fromn the group consistingo of hydrogen, Cl1-5 atlkyl, benzyl, methoxymethyl, triorganosilyl, C alkylcarbonyl, ci koxy'carbon yl and CONZ9; Each Z is independently selected Fromn the grouIp consisting of hydrogen, C 1 5 alkyl, triflunlromethyl, wherein said alkyl g-ouIp can be optionally substituted WO 02/32377 PCT/USU1/42735 with CI-5 alkyl, CF3, -OR 6 halogen, amino, CI-5 alkylthio, thiocyanato, cyano, -CO2H, -COOC l 5 alkyl, -COC -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 alkyl, CF3, -OR6, halogen, amino, C1-5 alkylthio, thiocyanato, cyano, -CO2H, -COOC1-5 alkyl, -COC1-5 alkyl, -CON V2, -S02NV2, and SO2C1-5 alkyl; Each V is independently selected from the group consisting of C1-5 alkyl, CF3, -OR 6 halogen, amino, C1-5 alkylthio, thiocyanato, cyano, -C02H, -COOCI- 5 alkyl, -COC1-5 alkyl, and -SO2C1-5 alkyl; Each n is independently an integer from one to five; and the pharmaceutically acceptable salts thereof.

The present invention also relates to pharmaceutical compositions 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 processes and intermediates useful for making the compounds and pharmaceutical compositions of the present invention.

The present invention also relates to methods for eliciting an estrogen receptor modulating effect in a mammal in need thereof by administering the compounds and pharmaceutical compositions of the present invention.

The present invention also relates to methods for eliciting an estrogen receptor antagonizing effect in a mammal in need thereof by administering the compounds and pharmaceutical compositions of the present invention. The estrogen receptor antagonizing effect can be either an ERa antagonizing effect, and ER3 antagonizing effect or a mixed ERc. and ER( antagonizing effect.

WO 02/32377 PCT/USU1/42735 The present invention also relates to methods for eliciting an estrogen receptor agonizing effect in a mammal in need thereof by administering the compounds and pharmaceutical compositions of the present invention. The estrogen receptor agonizing effect can be either an ERa agonizing effect, and ERP agonizing effect or a mixed ERa and ERP agonizing effect.

The present invention also relates to methods for treating or preventing disorders related to estrogen functioning, bone loss, 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 smooth 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 The present invention relates to compounds useful as estrogen receptor modulators. Compounds of the present invention are described by the following chemical formula:

R

2 Y R

R

3

XI

R4 (CH2)nN(Z) 2 wherein R R2, R 3 and R 4 are each independently selected from the group consisting of hydrogen, C1-5 alkyl, C3-8 cycloalkyl, C2-5 alkenyl, C2alkynyl, C3 8 cycloalkenyl, phenyl, heteroaryl, heterocyclical, CF3, OR6, halogen, C 1 5 alkylthio, thiocyanato, cyano. -CO2H, alkyl. -COCi-5 alkyl, -CONZ2, -SO2NZ2, and -S02C 1 5 alkyl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, phenyl, WO 02/32377 WO 0232377PCT/1JS01/42735 he teroarylI, heterocyclIic alI groups caLn be option IlIlIy SUbStitLIted with C I.

alkyl. C3-8 cycloalkyl, CF3, phenyl, heteroaryl, helerocyclical, -OR 6 halogen, amino, C 1-5 alkylthio, thi ocyanato, cyano, -COHF, -COOCIalkyL, -COCi-S alkyl, -CONZ?, -SOW-NZ2, and -SO-'Cls5 alkyl;

R

5 is selected f'rom the g-roup consisting of' CI-5 alkyl, C3-8 cycloalkyl, C2-5 alkenYl.

alkynyl, C3-8 cycloalkenyl, phenyl, heteroaryl, heterocyclical groups wherein said groups can be optionally substittuted with alkyl, C3-8 cycloalkyl, CF3, phenyl, heteroaryl, heterocyclical, -OR 6 halogen, amino, Cvs5 alkylthio, thiocyanato, cyano, -CO2H, -COOCfalkyl, -COCI-5 alkyl, -CONZ2), -SO2NZ2, and -SO2C 1-5 alkyl; X and Y are each independently selected from the group consisting of oxygen, sul Fur.

sulfoxide and sulfone;

R

6 is selected from thet group consisting of hydrogen, Cj-5 alkyl, benzyl, methoxymnethyl, triorganosi lyl, Cj 5 alkylcarbonyl, al koxycarbonyl and CONZ?; Each Z is independently selected from the group consisting of hydrogen, C 1- alkyl, ti-iluormethyl, wherein said alkyl grouIp can be optionally Suibstituted with Ct1- alkyl, CE3, -OR 6 halogen, amino, Cp-5 alkylthio, thiocyanato, cyano, -CO"H, -COOCt-5 alkyl, -COC al kyl, CON V2, -SO2NV2, and -SO2CI-5 alkyk 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 he saturated or unsaturated, and the carbon atoms of said ring maybe optionally substituted with one to three substituents selected from thle grouIp consisting Of Cl alkyl, CF3, -OR 6 halogen, amino, Ci-5 alkylthio, thiocyanato, cyano, -CO2?H, -COOCj'- alkyl, -COCIp5 alkyl, -CONV-? -SO9)NV-), and S02)CI5 alkyl; Each V is independently selected from the grouIp consisting Of C 1- alkyl, CF3. -OR 6 halogen, amino, CJ-5 alkylthio, thiocyanato, cyano, -COH, -COOCIalkyl, -COC 1 alkyl, and -SO-2C 1- alkyl; Each n is independently an integer from one to five-, and the pharmaceutically acceptable salts thereof.

WO 02/32377 PCT/USU1/42735 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, RI ,R 2

,R

3 and R 4 are selected from the group consisting of hydrogen, C1-5 alkyl, C3-8 cycloalkyl, C alkenyl, C1-5 alkynyl, -OR 6 and halogen.

In one class of compounds of the present invention R 5 is selected from the group consisting of C3-8 cycloalkyl, phenyl, heteroaryl and heterocyclical groups wherein said groups can be optionally substituted with -OR 6 and halogen.

In one class of compounds of the present invention, R 6 is preferably selected from the group consisting of hydrogen, C1-5 alkyl, benzyl, methoxymethyl and triisopropylsilyl.

The present invention also relates to a process for preparing a comnpound of formula I R y

R

3

X

R

R 2 1 Ra 3j X 1 R (CH2),N(Z)2 wherein R 1 is H, F, or Cl;

R

2 is H or OR 6

R

3 is H or OR 6 R4 is H orCH3:

R

5 is C -5 alkyl, C3-8 cycloalkyl, C3-8 cycloalkenyl, phenyl, heteroaryl, or heterocyclical groups wherein said groups can be optionally substituted with C alkyl, C3-8 cycloalkyl, CF3, phenyl, heteroaryl, heterocyclical, -OR 6 halogen, amino, C1-5 alkylthio, thiocyanato, cyano, carboxyl (-CO2H), carboalkoxyl COOC 1-_5 alkyl), carbonyl (-COC1-5 alkyl, carboxamido (-CONZ2), sulfonamido SO2NZ2), and sulfonyl (-SO2C 1-5 alkyl);

R

6 is H, benzyl. methyl, methoxymethyl, or triisopropylsilyl, with the proviso that when OR 6 exists elsewhere, it is chemically differentiable WO 02/32377 PCT/USU1/42735 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, C1-5 alkyl, trifluoromethyl, wherein said alkyl group can be optionally substituted with C alkyl, CF3, -OR 6 halogen, amino, C 1-5 alkylthio, thiocyanato, cyano, -CO2H,

COOC

1 -5 alkyl, -COC1t-5 alkyl, -CONV9, -SO2NV2, and -SO2C 1-5 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 C1-5 alkyl, CF3, -OR6, halogen, amino, C1- 5 alkylthio, thiocyanato, cyano, -CO2H, -COOC1- 5 alkyl, -COC 1 5 alkyl, -CONV2, -SO2NV2, and alkyl: Each V is independently selected from the group consisting of C 1 5 alkyl, CF 3

-OR

6 halogen, amino, C1-5 alkylthio, thiocyanato, cyano, -CO2H, -COOC1-5 alkyl, alkyl, and -SO2C1- 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 compound of formula III under basic conditions

R

1

R

2 l YH Br Rs R Br R XH R 4 OR 6 II III to form a compound of formula IV WO 02/32377 PCT/USU1/42735 b) cyclizing IV, of step a, under acidic conditions in the presence of a reducing agent, to provide the cis compound of formula V c) removing the protecting group R 6 to yield the substituted phenol of formula VI d) alkylating the substituted phenol of formula VI, from step c, with a reagent, HO(CH2)nN(Z)2, to give a compound of formula I WO 02/32377 PCT/USU1/42735 R' (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

R

1 f removing the remaining protecting group from either VIII or IX, from step e, to give a compound of formula I.

The present invention also relates to a process for preparing a compound of formula ID WO 02/32377 WO 0232377PCT/1JS01/42735

OH

HO# S Ru 0

()ID

wherein RI is H, F, or Cl; R3 is H;1-

R

4 is Hor CH3; and the stereoisomer is cis, and the optical isomer is dextrorotatory having the absolute configuration: (2S, 3)R): or a pharmaceutically acceptable salt thereof, comprising the step-, of a) reacting a compound of formula lID with a compou-nd Of formula HID uinder basic conditions OrIPS BnO SH Br OH 0 lID O0H HID0 to) Form a Compound of formla IVD WO 02/32377 WO 0232377PCT/1JS01/42735 OHS C OTIPS9 BnO

IVD

b) cyclizing IVD, of step a, uinder acidic conditions in the presence of a reducing agent to provide the racemic, cis compound of formula VD

,OTIPS

BnO.

c) performing a chiral chromatography with VD, from step b, to resolve the enantiomaeric forms to provide the dextrorotatory ±)isomer VID;

OTIPS

BnO S

OH

D

d) alkylating, the dextrorotatory isomer VID. from step c, with 1-piperidineethanol to g~ive a compound of formula VILD 13 WO 02/32377 PCT/USU1/42735

OTIPS

N

VIID

e) removing either protecting group from VIID, from step d, to afford either a compound of formula VIIID or a compound of formula IXD HO,

OTIPS

0 I

N

VIIID

IXD

f) removing the remaining protecting group from either VILID or IXD, from step e, to give a compound of formula 1.

The present invention also comprises a process according for preparing a compound of formula IE WO 02/32377 PCT/USU1/42735

IE

wherein RI is selected from the group consisting of H, F, or Cl;

R

3 and R 4 are each H;

R

7 is selected from the group consisting of H or OH; the stereoisomer is cis, and the optical isomer is dextrorotatory having the absolute configuration (2S, 3R); or a pharmaceutically acceptable salt thereof comprising the steps of a) reacting a compound of formula IHE with a compound of formula IIIE under basic conditions R1 H Br 7 BnL -SH Br, rto form a compound of formula IVE WO 02/32377 PCT/USU1/42735

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 c) selectively removing the protecting group of VE, from step b, to yield the substituted phenol of formula VIE R S

R

7

R

1 r R Bn(O S._

VIE

d) alkylating the substituted phenol of formula VIE, from step c, with 1 piperidineethanol to give a compound of formula VIIE WO 02/32377 PCT/USU1/42735 R 1

R

7 BnO R S 0ON

VIIE

e) removing either protecting group from VIIE to afford either a compound of formula VIIIE or a compound of formula IXE

VIIIE

IXE

f) removing the remaining protecting group from either VIII or IX, 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 herein, i.e compounds of formula I, IA, IB, IC, ID and IE.

An emobidment of the invention is an intermediate of the formula: WO 02/32377 WO 0232377PCT/1JS01/42735 R 3 0

OR

6 wherein RI is H, F, or Cl;

R

2 is H or OR 6 Ris H or OR 6

R

4 is Hor CH-3; is CI-5 alkyl, C3-8 cycloalkyl, C3-8 cycloalkenyl, phenyl, heteroaryl, or heterocyclical groups wherein said gr1oLIps can be optionally Substituted with Cy-5 alkyl, C3-8 cycloalkyl, CF3, phenyl. heteroaryl, heterocyclical, -OR 6 halogen, amino, Cp-5 alkylthio. thiocyanato, cyano, carboxyl carboalkoxyl (-C00CI 1 5 alkyl), carbonyl

COCI-

5 alkyl, carboxamidto (-CONZa)), sulfonamido (-SC2NZ2), and sulfonyi (-SO2-Cp-5 alkyl),

R

6 is H, benzyl, methyl, methoxymethyl, or trisopropylsilyl, with the proviso that when OR 6 exists elsewhere, it is chemically differentiable; Each Z is independently selected from the group consisting of hydrogen, alkyl, trifluoromethyl, wherein said alkyl group can be optionally Suibstituted with Cp-5 alkyl, CF3, -OR 6 halogen, amnino, a! kylthio, thiocyanato, cyano, -COH, -COOCj-5 alkyl, -COC alkyl, -CONV?, -SONV?. and -SO2CI-5 alkyl; Or both Zs and the nitrogen to which they are attached may be taken together to form a 3-8 rmembered ring, said ring may optionally contain atomns 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 Cl1.5 alkyl, CF3, -OR 6 aoeaio p alkylthio, thiocyanato, cyano, -COH, -COOCIp 5 alkyl, -COCI-5 alkyl, -CON V2, -SO2?NV2, and -SOQ)CIS-_ alkyl: WO 02/32377 WO 0232377PCT/1JS01/42735 Each V is 'Independently selected from tho group consisting of C1-5 alkyl, CF3, -O)R 6 ha loge n, amrino, Cl-5 alIkylthio, thiocyanato, cyano, -CO9H-, -COOC 1

.I

alkyl, -COC- alkyl, and -SO'-C 1 5 alkyl.

Another embodiment of the invention is an intermediate of the formu1Lla:

R

R 4 0 R N wlitieiii RI is H, F, or Cl,

R

2 is Hor0 OR 6

R

3 is H or OR 6

R

4 is HorCH3;

R

5 is Cj-5 alkyl, C3-8 cycloalkyl, C3-8 cycloalkenyl, phenyl, heteroaryl, or heterocyclical gr-oups wherein said groups can be optionally substituted with Cp-5 alkyl, C3-8 cycloalkyl, CF3. phenyl, heteroaryl, heterocyclical, -OR 6 halogen, amino, CI-5 alkylthio, thiocyanato, cyano, carboxyl carboalkoxyl (-COOCIy5 alkyl), carbonyl alkyl, carboxamido (-CONZ2)), sulfonamido (-SO9NZ9)), and sulfonyl (-S02?C15 alkyl):

R

6 is H, benzyl, methyl, methoxymethyl, or triisopropylsilyl, with the proviso that when OR 6 exists elsewhere, it is chemically di fferenti able; Each Z is independently selected from the group consisting 01:hydrogen, alkyl, trifluoromethyl, wherein said alkyl gr-oup can be optionally Substituted with CI-5 alkyl, CF3, -OR 6 halogen, amino, alkylthio, thiocyanato, cyano, -CO2H, -COOCI-5 alkyl, -C0CIalkyl, -CON V2, -SO2)NV2), and -S02C1-5 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 ring mnay either be saturated or unsaturated, aind the carbon atoms of said ring maybe optionally Substituted with Ct-5 alkyl, CF3, -OR 6 halogen, amino, 19 WO 02/32377 WO 0232377PCT/1JS01/42735 Ci 1- alkyhthio, thiocyanato. cyano. -CO)H, -COOC 1 5 alkyl, -COC I alkyl, -CONV), -S0WNV), and -SO?)Cf.5 a'lkyl.

Each V is independently selected fr-om the gopcon'sisting Of C 1- alkyl, CF3, -OR, 6 halogen, amino, C 1- alkylthio. thiocyanato. cyano, -COH, -COOC I alkyl, -COC 1-5 alkyl, aind -SO)C alkyl.

Another embodiment of the invention is an intermediate of-the formul Ia:

,OR

6 W± wherein RI is H, F, or Cl; R6 is benzyl, methyl, methoxymethvl, or triisopr-opylsilyl, with the proviso that all existing R 6 groups are chemically differentiable.

Another embodiment of the invention is an intermediate of the forml1a:

R

6 0-

N

wherein RI is Fl,. F. or CL: R6 is benzvl, methyl, mnerhoxymnethyl, or trisopropylsilyl, with the proviso that all existing R 6 gr-oups are chemically differentiable.

Another embodiment of the invention is an intermediate of the forl-Ma: 0 WO 02/32377 WO 0232377PCT/1JS01/42735 R 4 D "OR wherein RIt is H, F, or Cl;

R

2 is H or OR 6 R' RisH or OR 6

R

4 is HNor CH3;

R

5 is Cv-5 alkyl, CM3 cycloalkyl, C3-8 cycloalkenyl, phenyl, heteroaryl, or heterocyclical groups wherein said grouIps can be optionally substituted with CI-5 alkyl, C3-8 cycloalkyl. CF3, phenyl, heteroaryl, heterocyclical, -OR 6 halogen, amino, CI-5 alkylthio, thiocyanato, c vano, carboxyl (-COWH), carboalkoxyl (-COOC 1-5 alkyl), carbonyl alkyl, carboxamido (-CONZ9II), sulfonamido (-S02NZ2), and sulfonyl (-SO2CI-5 alkyl);

R

6 is H, benzyl, methyl, methoxymethyl. or triisopropylsilyl, with the proviso that when OR 6 exists elsewhere, it is chemically differentiable; Each Z is independently selected from the group consisting of hydrogen, alkyl, trifluoromethyl. wherein said alkyl group can be optionally substituited with Cp- 5 alkyl, CF3, -OR 6 halogen, amino, alkyithic, thiocyanato, cyano, -CO)H, -COOC 1 alkyl, alkyl, -CONy?, -SONV?, and -S02C 15 alkyl;- Or both Zs and the nitrogen to which they are attached may be taken to tog~ether 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 C1- 5 alkyl, CF3, -OR 6 halogen, amino, C 1- alkylthio, thiocyanato, cyano, -CO2H, -COOC 1 alkyl, -COC 1- alkyl, -CONV,). -SO9)NV2, and -SO2Cl-5 all:l' WO 02/32377 WO 0232377PCT/1JS01/42735 Each V is independently selected From' the grouLIP consisting- o1f 1C-5 alkyl, CF_3, -OR6, halogen, amnino, C1-5 alkylthio. thiocyanato, cyano, -CO2-FI. -COOC I.

alkyl, -COCI.5 alkyl, and -S02'C1-5 aIlkvl.

Another embodiment of the invention is ain i ntermediaLte oF the formula: wherein R I is H, F, or Cl:I R 6 0,

R

6 is I-1, benzyl, methyl, methoxymethyl, or tr-iisopropylsilyl, with the proviso that all existing R6 groups are chemnically differentiable.

Another embodiment of the present invention is an intermediate of of the formula:

,OR

6 wherein RI is H, F, or Cl:

R

6 is H, benzyl, methyl, methoxyrnethyl, or triisopr-opylsilyl. with the proviso that all existing R 6 gr-oups are chemically differentiable.

Non-limitingc examples of the present invention include: -22- WO 02/32377 WO 0232377PCT/1JS01/42735

OH

HO, S 0,N

OH

HO S J I f 00 s0 H

H

OH

HO

OH

HO S N ICH 3 OH,,

'OH

3 -23- WO 02/32377 WO 0232377PCT/1JS01/42735 HO S 0\ OH N2 H 0 O H 0"

N

HOI S O 0 0 HO S aOH

OH

3

~CH

3 0 r1 WO 02/32377 WO 0232377PCT/1JS01/42735 IF

OH

HO, S W 0 F

OH

HOS O -N CH 3 F

OH

0 ,0

OH

\k

OH

01 r ""OJH 3 WO 02/32377 WO 0232377PCT/1JS01/42735 HO

'SH

H

3 0 H 3

N

HO S OH 3 OH3 HO S

I~\

NOOH

HO Sa

O

0 N

CH

3

NO

0 0 WO 02/32377 WO 0232377PCT/1JS01/42735

OH

HO-a 0

H

3 N-

CH

3 I' O H 3

OH

OH

130

OH

3 NO CH 3 bH3 0 WO 02/32377 WO 0232377PCT/1JS01/42735 I-

OH

H

OH

3 N H 3

OH

3 C OH: 3 N OH

OH

3 HO S

H

I N CH 3 HO~a

SO

0

COH

0 0- N H 3 WO 02/32377 WO 0232377PCT/1JS01/42735

SU

HO,, )S "\W 00 O-I H 3 CH3 HO S

OH

ND

OH

OH

3 HO a S 0 H

N

0H HO,_C S O N ~H

OHH

-29- WO 02/32377 WO 0232377PCT/1JS01/42735 HO S

OH

0 ND 1CH 3

CH

3 0OH OH 3 r yl

'CH

3 0

OH

HO-S,\

0

CH

2 0H 3

CH

3 0H 2 0H 3 30 WO 02/32377 WO 0232377PCT/1JS01/42735 H 0 0 S a HOTS--

OH

CH

3

'CH

3 HO a S a OH 0 H+ N

CH

2

CH

3

CH

3 rK .CH 2

CH

3 N "CH 2

CH

3

HO

0~ WO 02/32377 WO 0232377PCT/1JS01/42735

OH

HO 's 00 HO S

OH

HO 0

CH

2

CH

3 I rH 3 0H 2 0H 3 N

CH

3

OH

HO,

HO--

N 'CH 2

CH

3 NC> "0JH 2 0H 3 -HO

S

00

CH

3

OH

3 -22- WO 02/32377 PCT/USU1/42735 HO S ,OH Q '1o .ND CH2CH 3

HO.

HO

yCH 3 "0 N CH 2

CHCH

'OH

CH

3 N jCHCH

S'"ICH

3 CH3 An embodiment of the invention is 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 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 ERca receptor.

WO 02/32377 PCT/USU1/42735 A second subclass of the embodiment is the method wherein the estrogen receptor is an ER3 receptor.

A third subclass of the embodiment is the method wherein the estrogen receptor modulating effect is a mixed ERra and ERp 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 ERa receptor.

A second subclass of the embodiment is the method wherein the estrogen receptor is an ER3 receptor.

A third subclass of the embodiment is the method wherein the estrogen receptor modulating effect is a mixed ERa and ER3 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.

Another embodiment of the invention is a method of treating or preventing endometriosis in a mammal in need thereof by administering to the mammal a therapeutically effective amount of any of the compounds or pharmaceutical compositions described above.

Another embodiment of the invention is a method of treating or preventing hyperlipidemia in a mammal in need thereof by administering to the mammal a therapeutically effective amount of any of the compounds or pharmaceutical compositions described above.

Exemplifying the invention is a pharmaceutical composition comprising any of the compounds described above and a pharmaceutically acceptable canrier. Also exemplifying the invention is a pharmaceutical composition made by -34- WO 02/32377 PCT/US01/42735 combining any of the compounds described above and a pharmaceutically acceptable carrier. An illustration of the invention is a process for making a pharmaceutical composition comprising combining any of the compounds described above and a pharmaceutically acceptable carrier.

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 and/or prevention of: bone loss, bone resorption, bone fractures, cartilage 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, clodronate, etidronate, ibandronate, incadronate, minodronate, neridronate, risedronate, 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 resorption inhibiting effect, i.e. a bone resorption inhibiting amount of the bisphosphonate is administered. For humans, an effective oral dose of bisphosphonate is typically from WO 02/32377 PCT/USU1/42735 about 1.5 to about 6000 Ag/kg body weight and preferably about 10 to about 2000 lpg/kg 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 8.75 mg to about 140 mg of the alendronate compound, on an alendronic acid active weight basis, i.e. on the basis of the corresponding 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-Loxic 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, estolae, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, 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, sodium or potassium salts; alkaline earth metal salts, calcium or magnesium salts; and salts formed with suitable organic ligands, quaternary ammonium salts.

The compounds of the present invention can have chiral centers and occur as racemates. racemic mixtures, diastereomeric mixtures, and as individual diastereomers, or enantiomers with all isomeric 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 -36- WO 02/32377 PCT/USU1/42735 the invention are polymorphs, hydrates and solvates of the compounds of the instant invention.

The present invention includes within its scope prodrugs of the compounds of this invention. In general, such prodrugs will he functional derivatives of the compounds of this invention which are readily convertible in vivo into the required compound. Thus, in the methods of treatment of the present invention, the term "administering" shall encompass the treatment of the various conditions described with the compound specifically disclosed or with a compound which may not be specifically disclosed, but which converts to the specified compound in vivo after administration to the patient. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs," ed. H. Bundgaard, Elsevier, 1985, which is incorporated by reference herein in its entirety. Metabolites of these compounds include active species produced upon introduction of compounds of this invention into the biological milieu.

The 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 or human that is being sought by a researcher or clinician.

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

The term "basic conditions," as used herein, refers to the incorporation or use of a base in the reaction medium. According to the Lowry-Bronsted definition, a base is a substance that accepts a proton; or according to the Lewis definition, a base is a substance that can furnish an electron pair to form a covalent bond. Examples of bases used herein, but are not limited to, are tertiary amine bases such as triethylamine, diisopropylethylamine, or the like.

The term "acidic conditions," as used herein, refers to the incorporation or use of an acid in the reaction medium. According to the Lowry- 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 covalent bond. Examples of acids used herein, but are not limited to, are strong carboxylic acids such as trifluoroacetic acid, or the like, strong sulfonic acids, such as trifluoromethane sulfonic acid, or the like, and Lewis acids, such as boron trifluoride 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 -37- WO 02/32377 PCT/USU1/42735 intermediate from one category to a lower one. Examples of reducing agents used herein, but arc not limited to. are triorganosilanes or stannanes, such as triethylsilane, triphenylsilane, and tri-n-butyl tin hydride, or the like.

The term "chemically differentiable" refers to two or more nonidentical R 6 substituents whose unique structures are such that one of ordinary skill in the art could choose reaction conditions which would convert one of the non-identical

R

6 substituents to H, without affecting the other R 6 substituent.

The term "alkyl" shall mean a substituting univalent group derived by conceptual removal of one hydrogen atom from a straight or branched-chain acyclic saturated hydrocarbon -CH 3

-CH

2

CH

3 -CH2CH2CH 3

-CH(CH

3 )2, -CIIHCH2CH 2

CH

3

-CH

2

CH(CH

3

-C(CH

3 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 -CH=CH,? -CHCH=CH2, -CH=CHCH 3 -CH2CH=C(CH3) 2 etc.).

The term "alkynyl" shall mean a substituting univalent group derived by conceptual removal of one hydrogen atom from a straight or branched-chain acyclic unsaturated hydrocarbon containing at least one triple bond -CH=CH,

-CH

2 C-CH, -C=CCH 3 -CH2CH 2

C-CCH

3 etc.).

The term "cycloalkyl" shall mean a substituting univalent group derived by conceptual removal of one hydrogen atom from a saturated monocyclic hydrocarbon cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl).

The term "cycloalkenyl" shall mean a substituting univalent group derived by conceptual removal of one hydrogen atom from an unsaturated monocyclic hydrocarbon containing a double bond cyclopentenyl or cyclohexenyl).

The term "heterocyclical" shall mean a substituting univalent group derived by conceptual removal of one hydrogen atom from a heterocycloalkane wherein said heterocycloalkane is derived from the corresponding saturated monocyclic hydrocarbon by replacing one or two carbon atoms with atoms selected from N, O or S. Examples of heterocyclical groups include, but are not limited to, oxiranyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, 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 group derived by the conceptual removal of one hydrogen atom from a monocyclic or -38 WO 02/32377 PCT/USU1/42735 bicyclic aromatic ring system containing 1, 2, 3, or 4 heteroatoms selected from N, O, or S. Examples ofheteroaryl groLups include, but are not limited to, pyrrolVI. furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridyl, pyrimiclinyl, pyrazinyl, benzimidazolyl, indolyl, and purinyl. Heteraryl substituents can be attached at a carbon atom 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.

In the compounds of the present invention, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, 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, mercapto, amino, carboxy, cyano and carbamoyl.

Whenever the term "alkyl" or "aryl" or either of their prefix roots appear in a name of a substituent aryl CO- 8 alkyl) it shall be interpreted as including those limitations given above for "alkyl" and "aryl." Designated numbers of carbon atoms C1-1 0 shall refer independently to the number of carbon atoms in an alkyl or cyclic alkyl moiety or to the alkyl portion of a larger substituent in which alkyl appears as its prefix root.

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

Examples of arylalkyl include, but are not limited to, benzyl, fluorobenzyl, chlorobenzyl, phenylethyl, phenylpropyl, fluorophenylethyl, 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 portion. 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 atom. The term "thio" means a sulfur atom. The term "oxo' means The term "oximino" means the =N-O group.

WO 02/32377 PCT/USU1/42735 The term "substituted" shall be deemed to include multiple degrees of substitution by a named substitutent. Where multiple substitucnt 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 portion of the designated side chain is described first, followed by the adjacent functionality toward the point of attachment. For example, a alkylcarbonylamino CI_ 6 alkyl substituent is equivalent to 0

II

-C 6 alkyl-NH- C- C- 5 al kyl In choosing compounds of the present invention, one of ordinary skill in the art will recognize that the various substituents, i.e. R 1

R

2

R

3

R

4 R5, R 6

R

7

R

8 V, X, Y, Z, n, m and p are to be chosen in conformity with well-known principles of chemical structure connectivity.

Representative compounds of the present invention typically display submicromolar affinity for alpha and/or beta estrogen receptors. Compounds of this invention are therefore useful in treating mammals suffering from disorders related to estrogen functioning. Pharmacologically effective amounts of the compound, 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 compounds of the present invention are available in racemic form or as individual enantiomers. For convenience, some structures are graphically represented as a single enantiomer but, unless otherwise indicated, is meant to include both racemic and enantiomeric forms. Where cis and trans 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.

WO 02/32377 PCT/USU1/42735

R

,(CH2),N(Z)2

I

It is generally preferable to administer compounds of structure as enantiomerically pure formulations since most or all of the desired bioactivity resides with a single enantiomer. Racemic mixtures can be separated into their individual enantiomers by any of a number of conventional methods. These include chiral chromatography, derivatization with a chiral auxillary 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 forms.

The instant invention is therefore to be understood as embracing all such regimes of simultaneous or alternating treatment and the term "administering" is to be interpreted accordingly. It will be understood that the scope of combinations of the compounds of this invention with other agents useful for treating estrogen-mediated conditions includes in principle any combination with any pharmaceutical composition useful for treating disorders related to estrogen functioning.

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 ocular eyedrop), subcutaneous, -41- WO 02/32377 PCT/USU1/42735 intramuscular or transdermal patch) form, all using forms well known to those of ordinary skill in the pharmaceutical arts.

The dosage regimen utilizing the compounds of the present invention is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient: the severity of the condition to be treated; the route of administration: the renal and hepatic function of the patient; and the particular compound or salt thereof employed. An ordinarily skilled physician, veterinarian or clinician can readily determine and prescribe the effective amount of the drug required to prevent, counter or arrest the progress of the condition.

Oral dosages of the present invention, when used for the indicated effects, will range between about 0.01 mg per kg of body weight per day (mg/kgiday) to about 100 mg/kg/day, preferably 0.01 to 10 mg/kg/day, and most preferably 0.1 to mg/kg/day. For oral administration, the compositions are preferably provided in the form of tablets containing 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100 and 500 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. A medicament typically contains from about 0.01 mg to about 500 mg of the active ingredient, preferably, from about 1 mg to about 100 mg of active ingredient. Intravenously, the most preferred doses will range from about 0.1 to about 10 mg/kg/minute during a constant rate infusion. Advantageously, compounds of the present invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three or four times daily. Furthermore, preferred compounds for the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in the art. To be administered in the form of a transdermal delivery system, the dosage administration will, of course, be continuous rather than intermittant throughout the dosage regimen.

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 refen-ed to herein as 'carrier' materials) suitably selected with respect to the intended form of administration, that is, oral tablets, capsules, elixirs, syrups and the like, and consistent with conventional pharmaceutical practices.

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 WO 02/32377 PCT/USU1/42735 acceptable, inert carrier such as lactose, starch, sucrose, glucose, methyl cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like: for oral administration in liquid form, the oral drug components can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol. water and the like. Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents and coloring agents can also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like.

Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like.

Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gumr and the like.

The compounds of the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.

Compounds of the present invention may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled. The compounds of the present invention may also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxy-ethylaspartamide-phenol, or polyethyleneoxide-polylysine substituted with palmitoyl residues. Furthermore, the compounds of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polyactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and crosslinked or amphipathic block copolymers of hydrogels.

The 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 illustrate details for the preparation of the compounds of the present invention. Those WO 02/32377 PCT/USU1/42735 skilled in the art will readily understand that known variations of the conditions and processes of the Following preparative procedures can be used to prepare these compounds. All temperatures are degrees Celsius unless otherwise noted.

The compounds of the present invention are prepared according to the Following generic Scheme I: -44- WO 02/32377 WO 0232377PCT/1JS01/42735 SCHEME 1. GENERAL SYNTHESIS FOR CIS-DIHYDROBENZOXATHIINS AND BENZODIOXANES Base Reductive Cyclization OR 6 'OR 6 Deproteotion Mitsunobu Reaction z j HO(CH 2 2 Deprotection of OR6 (if necessary) WO 02/32377 PCT/USU1/42735 In words relative to the scheme, an appropriately 'unctionalized bisphenol II which are readily available, or a mercapto-phenol II (X=O, which are prepared according to literature procedures, was reacted with a bromo-ketone derivative III, which was readily prepared from the corresponding ketone by bromination with phenyltrimethylammonium tribromide (PTAB), in the presence of a tertiary amine base, such as triethylamine, diisopropylethylamine, or the like, in a solvent such as dimethylformamide (DMF), formamide, acetonitrile, dimethylsulfoxide (DMSO), tetrahydrofuran (THF), dichloromethane, or the like, at a temperature of from -200C to 800C for as long as it takes for the reaction to complete to provide the displacement product IV. When X=Y=O, only R 3 maybe -OR 6 Alternatively, when X=Y=O and R 2 is -OR 6 the requisite cyclization intermediate is obtained by interchangement of the ketone and bromide functionalities. 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 phenolic oxygen atoms.

Intermediate IV was reductively cyclized in the presence of an organic acid such as trifluo-oacetic acid, triflic acid, or the like, or a Lewis acid such as boron trifluoride etherate, stannous chloride, or the like, and a reducing agent such as a trisubstituted silane, such triethylsilane, or the like, in a solvent such as dichloromethane, chloroform, THF, toluene, or the like at a temperature of from 400C to 1000C 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 5 in the newly created ring is exclusively cis. The formation of the intermediates with analogous trans stereochemistry is depicted in the next general Scheme II.

In product V, when R 6 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, Protective Groups in Organic Synthesis, Third Ed.,Wiley, New York (1999).

Further, it is understood that it is possible to have any number of the substitutents R1-

R

4 be or contain-OR 6 or R5 may contain-OR 6 where R6 is a protecting group, and it is further understood that in these instances the protecting groups are chemically differentiable, ie., they maybe selectively removed when necessary. For example in product V, R 6 is a methoxymethyl (MOM) group, R 2 is -OR 6 wherein R 6 is a benzyl (Bn) group, R 5 is a phenyl ring substituted by R 7 where R 7 is OR6, wherein

R

6 is a triisopropylsilyl (TIPS) group, and all unspecified substitutents are hydrogen.

-46- WO 02/32377 PCT/USU1/42735 As indicated, as part of the synthetic sequence it is necessary to selectively remove the MOM group in preference to either the TIPS or Bz groups. Utilizing methods found in Green and Wuts, it is possible to generate the preferred intermediate V, wherein R 6 is H, R 2 is -OBn, R 5 is para-OTIPS-phenyl, and all unspecified substitutents are hydrogen. It is also noted that in product V, that when either R 2 or R 3 is OR 6

R

6 must be a protecting group, and that prior to its removal, the existing -OR 6 group must be covered by a differentiable protecting group.

The alcohol intermediate VI was then reacted with a reagent HO(CH2)nNZ2 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 QOC to 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. Synthesis, 1981, 1; Castro, B.R. Org.

React. 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 -OR 6 wherein R 6 is a protecting group, it was removed utilizing the appropriate method found in Green and Wuts to give the final product where R6 is H.

-47- WO 02/32377 WO 0232377PCT/1JS01/42735 SCHEME 11. GENERAL SYNTHESIS FOR TRANS-DIHYDROBENZOXATHIINS AND BENZODIOXANES Cyclization_ .OR 6 Deprotection

~OH

VilI Ix Mitsunobu Reaction HO(CH 2

,N(Z)

2 Deprotection of OR 6 (if necessary)

,(CH

2 )nN(Z) 2 In words relative to the above scheme for the general preparation of the tr-ans isomers of 1, the ketone intermediate IV from Sc-heme II was reduced with sodium horohydride, super hydride, or the like, in a mixture of methanol and di chioro methane, or THE or the like at from QOC to ambient temperature for from a few minutes to a few hours to provide the analogoUs hydroxyl intermediate VII.

-48- WO 02/32377 WO 0232377PCT/1JS01/42735 Cvclizaition of intermediate VII was accomnplished in the presence of ain acid catalyst such as amberlyst 15, or triflic acid or the like. in a solvent such toluene, or dichioromethane or the like, at a temper-atureC of [rom ambient to reflUX to afford the frans Compound ViII as the major isomer.

The remainder of the synthetic sequence to produce traIitS 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 LO DIHYDROBENZOXATHIIN DIOXIDES R

I

R 4 0

H

2 N(Z) 2 R 0 2 Peroxidation

R

3 0 4

(CH

2 2 X 0 0 0 Selective IDeoxygenation R 2

R

WO 02/32377 PCT/USU1/42735 In words relative to Scheme II, the compounds I of the invention are peroxidized with an oxidant such as im-chloroperbenzoic acid, or per-trifluoroacetic acid, or the like, in a solvent such dichloromethane or the like, at a temperature of from OoC to reflux to produce the trioxide intermediate X. In turn X was selectively deoxygenated at the nitrogen atom by treatment with a reducing agent such as sodium bisulfite 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 0, and Y is preferably S.

In the compounds of the present invention, RI ,R 2

,R

3 and R 4 are preferably selected from the group consisting of hydrogen, C 1 -5 alkyl, C3-8 cycloalkyl, C1-5 alkenyl, CI-5 alkynyl, -OR 6 and halogen.

In the compounds of the present invention, R 5 is preferably selected from the group consisting of C3-g cycloalkyl, phenyl, and substituted phenyl.

In the compounds of the present invention, R 6 is preferably selected from the group consisting of hydrogen. C1-5 alkyl, benzyl, methoxymethyl and trisopropylsilyl.

In the compounds of the present invention, a preferred subset is found where RI and R 4 are hydrogen, R 2 and R 3 are independently -OH, and R 5 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 R1 is independently selected fluorine and chlorine, R 4 is hydrogen, R 2 and R 3 are independently -OH, and R 5 is independently selected from the group consisting of phenyl and substituted phenyl.

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

WO 02/32377 PCT/USU1/42735 SCHEME IV. GENERAL SYNTHESIS FOR

OXIDES

R

1 R2 S R 5

R

2 Mono-oxidation

R

3 j O" R 3

R

4 6

OR

6

DIHYDROBENZOXATHIIN

R O(CH2)nN(Z)2 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 m-chloroperbenzoic acid, or dimethyldioxirane, or the like, in a solvent such as dichloromethane, ether, acetone, or the like, at a temperature of from 780C to ambient temperature for from a few minutes to a few hours to give the corresponding sulfoxide intermediate XI. The remainder of the synthetic sequence to produce I is identical to that outlined in Scheme I and detailed above.

In the compounds of the present invention, X is preferably 0, and Y is preferably S.

In the compounds of the present invention, RI ,R 2 ,R3 and R 4 are preferably selected from the group consisting of hydrogen, C1-5 alkyl, C3- 8 cycloalkyl. C 1 .5 alkenyl, Cl-5 alkynyl, -OR6 and halogen.

-51 WO 02/32377 PCT/US01/42735 In the compounds of the present invention, R 5 is preferably selected from the group consisting of C3-8 cycloalkyl, phonyl. and substituted phenyl.

In the compounds of the present invention, R 6 is preferably selected from the group consisting of hydrogen, C -5 alkyl, benzyl, methoxymethyl and trisopropylsilyl.

In the compounds of the present invention, a preferred subset is found where R and R4 are hydrogen, R 2 and R 3 are independently -OH, and R5 is independently selected from the group consisting of phenyl and substituted phenyl.

In the compounds of the present invention, another preferred subset is found where RI is independently selected fluorine and chlorine, R 4 is hydrogen, R 2 and R 3 are independently -OH, and R 5 is independently selected from the group consisting of phenyl and substituted phenyl.

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

WO 02/32377 WO 0232377PCT/1JS01/42735 EXAMPLE 1 GENERAL PREPARATION OF THIOPI-IENOLS CUSO 4 NH 4 SCN

R

Protection 1. NaGH The Functionalized thiophenuls were prepared by the known procedure, with minormodification, which is depicted in above scheme:. Wermer, Biebrich, W. US Patent 2,276,553 and 2,332,41,8.

0 Thi*ourea HCl 0 IfNH 2 C] Heat >0

NH

2 HO< S PhCH 2 Br 0 BaseI 0 BnO "CS 1. NaOJJ

OH

Bno'

SH

53 WO 02/32377 WO 0232377PCT/1JS01/42735 The thiophenol depicted above was prepared aiccording to the following references: Maxwell, S. J, Am. Chtem. Soc. 1947, 69. 712: Hanzlik, R. R et. Ort'. Chemi.

1990, 55, 2736.

EXAMPLE 2 PREPARATION OF 21-THIOPHENE4-METHOXY-B EN ZOPHEN ONE 0 S MeDw To a stirred solution of anisole (1.49 g, 13.8 mmol) in anhydrous dichlorornethane mL) was added AIC1 3 (J.2320 g, 9.2 mmol) followed by dropwise addition of 2thiophene- acetyl chloride (0.57 mL, 4.6 mmol) at 0OT under N2. The reaction was stirred for 1.5 h, then poured into a separatory funnel containing ice/brine/EtOAc.

The organic layer was washed furtLher with brine, dried over Na')S0 4 and concentrated in vacita. The resulting residue was purified by silica gel chromatography with EtOAc/hexane as the eluant to afford the desired prodLIct as a yellow oil. 'H 500MHZ

NMR,(CDCI

3 ppm(a): 3.89 4.46 2H), 6.98 Cmn, 4H), 7.24 1B1), and 8.05 211).

EXAMPLE 3 PREPARATION OF 2-TH-IOPHENE-4-HYDROXY-BENZOPHE-NONE 0 S

HUO

A mixture of the 2-thophene-4-methoxy-benzophenone (0.8294 g, 3.5 mrnol), generated in Example 2, and pyridine-HCI (4.0627 g, 35.2 mnmol) was heated to 190 WO 02/32377 PCT/USU1/42735 "C under N, for 6 h. The reaction was monitored by examining worked-up aliquots of the reaction by TLC (30% EtOAc/hexane). The reaction was cooled in an ice bath and ice/HO was added. The resulting mixture was extracted with EtOAc. The organic extract was washed with 2 N HCI and brine, dried over Na2SO 4 and concentrated in vacuo. The resulting brown residue was purified by silica gel chromatography with 30% EtOAc/hexane as the eluant to afford the desired product as a yellow/orange solid. 'H 500MHz NMR(CDCI 3 ppm(s): 4.43 2H), 5.60 (bs, 1H), 6.90 2H), 6.92 1 6.97 1H), 7.22 I H) and 8.00 2H).

EXAMPLE 4 GENERAL PREPARATION OF CYCLOALKYL-4-HYDROXY-

BENZOPHENONES

H

To a stirred solution of the 2-cycloalkyl-t-(4-methoxy-phenyl)-ethanone [prepared according to the method of Barrio, etal, J. Med. Chem.,1971, 14, 898] in dry methylene chloride at 0 0 C was added 3.6 equivalents of aluminum chloride and equivalents of isopropyl mercaptan. The ice-water bath was removed and the reaction mixture was stirred further overnight under an inert atmosphere of nitrogen. The reaction mixture was poured onto a mixture of 2N HCl/ice and extracted with ethyl acetate. The ethyl acetate extract was washed with brine, dried over anhydrous sodium sulfate, filtered, and evaporated. Purification by silica gel chromatography afforded the corresponding 2-cycloalkyl-l-(4-hydroxy-phenyl)-ethanone.

Utilizing the foregoing experimental procedure the following compounds were prepared: 2-cyclohexyl-l-(4-hydroxy-phenyl)-ethanone: 70% yield using methylene chlorideethyl acetate(50:l) as the chromatography eluant. 'FH 500MHz NMR(CDCI 3 ppm(8): 1-2.0 11H), 2.96 1H), 5.6 (bs, 111), 6.92 2H), and 7.95 2H).

55 WO 02/32377 WO 0232377PCT/1JS01/42735 2-cyclopentyl- I-(4-hvdroxy-phenyl)-Erthanone: 74% yield Usingy methylene chlorideethy! acetate(50: 1) as the chromaitogyraphy eluant. 1H 500MHz NMR(CDCI 3

I)

ppmn(6)l,2-1.92 (in, IGOH), 2.4 (in, IH), 2.96 I 5.6 (bs, I 6M9 2H), and 7.95 (di, 2H).

EXAMPLE PREPARATION OF ISOPROPYL-4-HYDROXY-BFNZOPH-ENONE H0I To a Mixture of isovaleric acid (1.4 rnL,13.0 mmol) and phenol (1.0253 g,10.9 inmol) was added BF 3 OEt-1 (15 mL) under nitrogen. The resulting mixture was heated to TC for approximately 3.5 h. The reaction was pouired into ice/2 N HCI and extracted with EtOAc. The organic extract was washed with brine, dried over Na 2

SO

4 and concentrated in vacito to give a yellow residue. The final product was isolated as a pale yellow oil after silica gel chromatography with 30% EtOAc/hexane as the eluant.

Upon standing at ambient temperature, the oil solidified to give a white solid. 1H 500MHz NMR(CDCI 3 ppmC5):I1.01 6H4), 2.27 (mn, 114), 2.81 2H), 6.99 2H), 7.931 2H), WO 02/32377 PCT/USU1/42735 EXAMPLE 6 PREPARATION OF 4-PYRIDYL-4-HYDROXY-BENZOPHENONE 0 N

HO

A dried flask equipped with a stirrer bar was charged with a 2.5 M solution of nBuLi in hexane (18 mL, 45.0 mmol) and cooled to 0°C under Nz. A solution of diisopropylamine (6.4 mL, 45.7 mmol) in distilled THF (20 mL) was added slowly.

After stirring for 25 min., a solution of 4-picoline (2.0 mL, 21.4 mmol) in distilled THF (8 mL) was added to the reaction. The resulting red solution was stirred for min. before removing the ice bath. A solution of cyanophenol (2.5670 g, 21.4 mmol) in distilled THF (20 mL) was added via a dropping funnel over 30 min. Upon addition of the phenol, the reaction became a thick slurry with oiling out of a red/brown tar. Further addition of THF did not alleviate the difficulty in stirring. The reaction stood at ambient temperature for 16 h, and was poured into a mixture of ice/sat. NH 4 Cl/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 HCI. 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 HCI 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 3 The desired product precipitated from the solution as a yellow solid and was collected, washed with cold water, and dried in vacuo. 'H 500MHz NMR(dacetone) ppm(5): 4.37 2H), 6.97 2H), 7.31 2H), 8.01 2H), 8.52 (bs, 2H).

WO 02/32377 PCT/USU1/42735 EXAMPLE 7 PREPARATION OF 3-PYRIDYL-4-HYDROXY-BENZOPHENONE HO N 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 ice/sat. NH 4 CI and EtOAc. The organic layer was washed with brine, dried over Na 2

SO

4 and concentrated in vacuo. The residue was triturated with CH 2 C1 2 and EtOAc to give the desired product as an orange solid. 'H 500MHz NMR(d-acetone) ppm(8): 4.39 2H), 6.97 2H), 7.31 1H), 7.68 1 8.01 2H), 8.43 1H), 8.52 1H).

EXAMPLE 8 GENERAL PREPARATION OF CYCLOALKYL-4-TRIISOPROPYLSILYLOXY-

BENZOPHENONES

TIPSO

To a stirred solution of the 2-cycloalkyl-l-(4-hydroxy-phenyl)-ethanone, prepared in Example 4, in dry DMF at 0C was added 1.3 equivalents of driisopropylethylamine and 1.2 equivalents of triisopropylchlorosilane(TIPSCI), The ice-water bath was removed and the reaction mixture was stirred further until tic showed the reaction to be complete (1-3 hours) under an inert atmosphere of nitrogen. The reaction mixture 58- WO 02/32377 WO 0232377PCT/1JS01/42735 was partitioned between ether/2N HCI/ice and the org-anic phase was separated.

washed twice with water, washed with brine, dried over anhydrlouIs sodium sulf'ate, filtered, and evaporated. PUrification by silica gel chromatography afforded the corresponding 2-cycloallkyl- I 4 -tr-iisoprop~yloxy-phienyl)-ethanone.

Utilizing the foregoing experimental procedure the following Compouinds were prepared: 7 -cyclohexyl- t-(4-tiisopr-opylsi lyloxy-phenyl)-ethanone: use methylene chloridehex anes(J: 1) as the ch romato graphy el uant. 1 H 500MHz NMR(CDC1 3 lpp15):I.13 I8H), 1-1.99 (in, 14H), 2.78 6.91 2H), and 7.89 2H).

2-cyc lopentyl- I-(4-trii sopropylsi lyloxy-phenyl)-eth anon e: use methylenle chloridehexanes(t: 1) as the chromatography eluant. IH 500MHz NM4R(CDCI 2 ppm(5): 1.12 18H-), 1.2-1.91 (in, 13H-), 2.4 (in, 1Hl), 2.95 1H), 6.92 2H), and 7.9 2H).

EXAMPLE 9 GENERAL PREPARATION OF ALKYL-4-TRIIS OPROPYLSILYLOXY- BENZOPHiENONES 0

R

T IPSO" To a Solution of the 2-alkyl-J,-(4-hydr-oxy-phenyl)-ethanone, prepared in Examples 3, 6, and 7, in distilled TI-W was added 1.3 equivalents of 60% NaH in mineral oil atO0 TC Under After the gas evolu-tion ceased, 1. 1 equiivalents 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 Na-'S0 4 and concentrated in vacua. Purification by silica gel chromatography afforded the Corresponding 2-al kyl- I -(4-tr-iisopr-opylsi lyloxy-phenyl)-ethanones.

Utilizing the foregoing experimental procedure the following compounds were prepared: 59 WO 02/32377 WO 0232377PCT/USOI/42735 22- -h iop hene)- I -(4-tri isopropyls Ily fox y-ph en yl)-ethanone: isolated as an orange/yellow solid Using 15% EtOAc/hexane as the chromatography eluant. IH 500MHz NM4R(CDC1 3 pprn(6): 1,14 18H), 1.30 (in, 3H), 4.42 and 6.93- 7.98 (On, 7 H).

2-C4-pyidvcl)- L(4-tr-iisopropylsilyloxy-phenyl)-ethanone: isolated as a yellow solid using 40%7 EtOAc/hexane as the chromatography elUant. H 500MHz NMR(CDCI 3 ppm(6):J,.l4 18H), 1.30 Cm, 3H), 4.28 21-1), 6.97 2H), 7.35 (in, IH), 7.69 (i.

1H), 7.97 2H), and 8.56 Cbs, 2H)i.

2-(3-pyr-idvl)-1-(4-tr-ii sopropylsi lyloxy-phienyl)-ethianone: isolated as a yellow solid using 40% EtOAc/hexane as the chromatography eluant. 'H 50NMz NMR(CDCI 3 ppm(6): 1. 14 18h). 1.20 Cm, 3H1), 4.18 2H), 6.82 211), 7. 10 2H), 7.82 (d, 2H), and 8.43 Cd, 2H).

EXAMPLE GENERAL BROMIh4ATION PROCEDURE OF ALKYL AND CYCLOALKYL-4- TR-USOIPROPYLSIIIYLOXY-BENZOPHENOiNES 0

R

TIPSO[ B To a stirred Solution of the 2-alkyl- and 2-cycloalkvl-1-C4-tr-iisopr-opylsilyloxyph enyl)-eth an ones, prepared in Examples 8 and 9, in dry THE at 0 0 C was added equivalent of trimiethylat-nnoniumphenyl perbroinide. The ice-water bath was removed and the reaction mixture was stirred further for I hour under an inert atmosphere of nitrogen. Thc reaction MiXturc was partitioned between ethyl aceetate/br-ine/ice/S %PsodiuIm thiosuilfate/sodiurn bicarbonate and the organic phase was separated, washed with brine, dried over anhydrous Sodium Sulfate, filtered, and WO 02/32377 WO 0232377PCT/1JS01/42735 evaIporated. Purification by silica gel c hromatography afforded the corresponding 2cyc loal kyl -2-hromo- I -4-tri i sopropyls i lylo xv-phen yl)-ethan ore.

Utilizing the f~oregoing experimental Procedure the Following compounds were prepared: 2-cyclIohex yl-2-bromo- 1-(4-tri i sopropyl si lyl ox y-phen yD)-eth allone: use methylene chloride-hexanes(1:1D as the chromatography eluant. 'H500MIHz NMR(CDCl 3 ppm(6): 1.14 181-1), 0.98-2.27 (in, I5H), 4.91 11-1), 6.94 211), and 7.94 (d, 2H).

2-cyclopentyl-2-bf-orno-1-(4-tiisopr-opylsi lyloxy-plhenyl)-ethiatnone: use rnethylene chloride-hexanes(1:1) as the chromatography eluant. 'H 500NMz NMR(CDC1 3 ppm(6):1.[3 18H), 1.1-2.2 (in, 11Hi), I.S (in, IH). 4.98 IH), 6.94 2H), and 7.96 2H-).

2-(2-thiophene)-2-brono-11(4-tri isopr-opyl si lyloxy-phenyl)-ethanone: stirred at 0 'C for 40 min.; isolated as a dark brown oil and used in the next reaction Without Purification.

'H 50MIz NMR(CDCI 3 ppm(6):1.13 181-), 1.30 3B), 6.73 6.97 (d.

2H), 7.00 (in, Iff), 7.30 (in, IH), 7.49 IH), and 8.00 2H).

2-(4-pyri dyl)-2-brorno- i-(4--trii sopropyls ilyloxy-phenyl)-eth an one: added 2 equivalents of trimethylammoniu~mphenyl perbromide and Stirred at 0 0 C for I h:, isolated as an orangelyellow oil and used in the next reaction without purification. 1H 500Mz NMR(CDC1 3 ppmn(8): 1.03 18H), 1.21 6.2 1 IH), 6.98 (d, 21-1), 7.40 2H), 7.90 2H), and S.57 2H), 2-(.3-pyridyl)-2-bromo- I -(4-triisopiropylsilyloxy-phenyl)-ethanone: added 2 equivalents of tri methylammoniuIMphenyl perbrornide and stirred at OTC for 3 h-, isolated as an orange/yellow oil and used in the next reaction without purification. HT 500MHz NMR(CDC1 3 ppm(6): 1.13 I SH), 1.30 Cm, 6.30 IlH), 6.98 (d, 2H), and 7.39-8.7 5 (in, 6H).

WO 02/32377 WO 0232377PCT/1JS01/42735 EXAMPLE I1I PREPARATION OF 2-ISOPROPYL-2-BROrvlO- I -(4-HYDROXYPIIE NYL)-

ETHANONE

0 HO~ Br Following the procednire Outlined in Example 10 and using the product obtained from Example 5, 2-isopropyl-2-bromo- I-(4-hvdiroxyphenyl )-ethanone was isolated as a yellow oil and used in the next reaction without purification. 'H 500M1-Iz

NNIR(CDCI

3 PPM(6): J.01 3H1), 1.21 3H), 2.46 (in, 4.93 111), 6.96 (d, 2H), and 7.96 2H).

-62 WO 02/32377 PCT/USU1/42735 EXAMPLE 12 GENERAL PREPARATION OF BROMOKETONES

OTIPS

Br

OR

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 0 C was added 5.7mL (5.7mmole) of neat diisopropylethylamine. To this stirred solution was added slowly 1.25mL (19.73 mmole) of chloromethylmethylether (MOMC1). 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 4 After evaporation of the solvent, the residue was purified by silica gel chromatography (EtOAc/Hexane to provide the product, as a solid. H NMR (400 MHz, CDCl 3 6 (ppm): 8.0 2H), 7.19(d, 2H), 7.10 2H), 6.8 2H), 5.23 2H), 4.8 1H), 4.2 2H), 3.5 3H).

Step B To a stirred solution of the product obtained from Step A (423mg, 1.55mmole) and imidazole (211 mg, 3.1mmole) in 20mL of dry DMF at 0°C was added triisopropylsilyl chloride (3.1mmole) and the reaction mixture was allowed to warm to room temperature and stirred further for 2-3 hours. The reaction was quenched by the addition of aqueous NaHCO 3 solution and extracted with EtOAc. The organic layer was washed with brine and dried with MgSO 4 Chromatography EtOAc/hexane) yielded the desired product. IH NMR (400 MHz, CDC13) (ppm): 2H), 7.12 2H), 7.08 2H). 6.82 2H). 5.21 2H). 4.18 2H), 3.5 (s, 3H), 1.24 3H), 1.I 18H).

-63- WO 02/32377 PCT/US01/42735 Step C To a mixture of the compound from Step B (0.5g, 1.16mmole) in 100mL of anhydrous TI-IF was added 0.39g (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 4 Removal of the solvent afforded the mixture of bromoketones (MOM group was partially removed), which was used without further purification due to their instability toward chromatography.

Bromoketone with MOM group: 'H NMR (400 MHz, CDC13) 5 (ppm): 8.0 2H), 7.4 2H), 6.88 2H), 6.86 2H), 6.36 1H), 1.24 3H), 1.1 18H); Bromoketone without MOM group: 'H NMR (400 MHz, CDCI 3 8 (ppm): 7.94 (d, 2H), 7.4 2H), 6.88 2H), 6.86 2H), 6.36 1.24 3H), 1.1 18H).

EXAMPLE 13 PREPARATION OF Br 0

OTIPS

The required bromoketone was prepared using the procedure in Example 12 (Step C).

HNMR (400 MHz, CDC13) 5 (ppm) 7.94 2H), 7.56 7.38 3H), 6.9 (d, 2H), 6.36 2H), 1.28 3H), 1.1 18H).

-64- WO 02/32377 WO 0232377PCT/1JS01/42735 EXAMPLEF 14 PREPARATION OF Br OMe 0

OTIPS

The required bromoketone was prepared using- the procedure in Example 12 (Step C).

1-IlNMR (400 MHz, CDC13) 6 (ppm) 7.9 2H), 7.5 2H), 6.9 (d d, 4B1), 6.4 (s, IH), 3.8 3H1), 1.28 (in, 3H), 1.1 18H).

EXAMPLE PREPARATION OF

OMOM

Br

OMOM

Step A To a stirred Solution of a mixture of the 0.1Ig (0.B7mmole) mono phenolic compound from Step A in Example 12 and diisopropylethylamine (0.l3mL, 2eq) in 5mL of DMF 'it rooum temnper-atur-e was added slowly neat MOMCI (0.05mL, 2eq), and the mixture was heated at 85'C under N 2 for three hours. The mixture was then poured into a satur-ated NaH7CO 3 Solution, extracted with EtOAc, washed with water, and dried over Mg-S0 4 After evaporation of the solvent, the residue was purified by silica gel chromatography (EtOAc/Hexane 1) to provide the pure bis-protected MOM product, as a solid. 'H NMR. (400 MHz, CDCI-,) 6 (ppm): 8.0 2H), 7.19(d, 214).

7. 10 2H1), 7.02 2H4), 5.23 21H), 5.2 211), 4.2 2H), 3.5 (two s, 6H).

WO 02/32377 WO 0232377PCT/USOI/42735 Step B The Product o1f Step A was treated with bromine to give the bromoketone. IH NMR (400 MHz, CDCI 3 6 (ppm): 8.0 2H), 7.45(d, 1H), 7-10 (twNo d, 4H), 6A4 IH), 5.23 (two s, 4H), 3.5 (two s, 6H).

EXAMPLE 16 GENERAL PREPARATION OF o OTIPS To a stirred, fr-eshly prepared solution of 2-thiophenol (0.2g, .6mmole) and Et 3

N

(0.34mL., 2eq) in I5mL DMF at 0 0 C was slowly added a Solution of 0.627g, (1.232mmole) of bromoketone (prepared from Step C in Example .12) in 13mL of LDiN'F. The reaction mixture was stirred for three hours at room temperature and was then partitioned between saturated NaHC0 3 and EtOAc, the layers were separated, and the aqueous layer was extracted again with EtOAc. The combined org-anic layers were dried (Na2SO 4 Filtered, and evaporated iin vcio. The resulting oil was purified by flash chromatography (EtOAc/LHex=1J4) to provide the desired product as an oil.

'H NMIR (400 MHz, acetone-d 6 8 (PPM): 8.0 2H), 7.2-6.6 (in, SH), 6.8 21-), 6.2 IH), 5.24 2H), 3.4 3M1), 1. 22 3H), 1. 1 I 8H); MS mlz 575 (W/f+23).

-66- WO 02/32377 WO 0232377PCT/1JS01/42735 EXAMPLE 17 CYCLIZATLON OF COUPLED PRODUCT 0OMOM OH OMOM 00, MOMW 0 '0 HO 0 0 MOM Following the procedure outlined in Example 16, 1,2-dihydi-oxybenzene aInd the bromide of Example 15 was converted to the product which was purified by silica gel chromatography using EtOAc/hexane as eluant. MIS mlz 448 (M 4 +23).

EXAMPLE 18 PREPARATION OF OTI PS OTIPS 0 -~0 S S HOo MOMO" H O H O OBn B OBn

A

Following the procedure outlined in Example 16 and using 0.83g (3.6mmole) of 4benzyloxy-thiophenol, prepared from Example 1, product A and product B were obtained after silica gel chromatography using EtOAc/hexane (115) as eluant.

A: HE NMR (400 MHz, acctone-Q~ 6 (Ppm): 8.15 IH), 7.8 2H), 7.4 (in, 6.98 2H)7 6.98 IH). 6.75 (d 41H), 6.0 s, I 5.62 I 5.0 2H), 1. 22 (in, 3 H) 1,15 I SH).

WO 02/32377 WO 0232377PCT/1JS01/42735 B: 1FL NMIR (400 MH7z. acotone-d() a (ppm): 8.0 (di, 2H), 7.5 (in, 51-1), 7. 18 21-1), 7.04 2HI), 6.96 114), 6 8 6.56 I 6.3 2 (dd, I 6.1 11-1), 5.25 21-H), 5. 09 1t-H), 3.4 31-1), 1.22 (in, 3HR), 1. 1 t1SR).

~EXAMPLE 1 9 PREPARATION OF OMe

TIPSO<S

HO O~n Following the procedure outlined in Example 16 and Using I. Ig (2.3minole) of the bromoketone from Example 14, the desired product was obtained after silica gel chromatogr-aphy uSing E'tOAc/hexaie as eluant. 1{NMR (400 M~z, acetone-

Q

6 8 (PPM): 8.46 (br s, III), 7.98 2H), 7.48-7.3 (in, 5H), 7.24 2H), 7.4 III), 6.92 21-1), 6.82 21c1). 6.56 6.38 (dd, IH), 6.1 5.04 2H), 3.72 314), 1.25 3H), 1.1 18H).

EXAMPLE PREPARATION OF 0 "aOTIPS HO~ Me OBn WO 02/32377 WO 0232377PCT/1JS01/42735 Following the prouedure outlined in Example 16 and usingy 0,74o (I.5mmole) of' the bromoketone from Example 12 (Step the desired product was obtained after silica gel chromatography using EtOAc/hexane as elLiant. 'Fl NMR (400 MHz, acetone-d 6 6 (ppm); 7.92 2H), 7.46-7.1 7. 18 2H), 6,84 2H), 6.78 21H), 6.42 1H), 6.36 5.98 5.02 2H), 2.2 3H), 1.22 (in, 3H), 1.1 181-1.

EXAMPLE 2 t PREPARATION OF

OTIPS

HOO

Me O13n Following the procedure outlined in Example 1 6 and using O.8g (I.S7mmole) of the bromoketone from Example 12 (Step C) with the thiophenol derivative prepared from Example 1, the desired product was obtained after silica 1gel chromatography using- EtOAc/hexane as elUant. 11 NMR (400 MI-z, acetone-d 6 6(ppm):7.9 7.5-7.3 (in, 511), 7.12 2H), 6.9 111), 6.84 2H), 6.79 211), 6.4 tH), 5.1 2H1), 2.1L 3Hl), 1.25 (mn, 3H), 1. 1 18H).

WO 02/32377 WO 0232377PCT/USOI/42735 EXAM~PLE -1 PREPARATION OF 0

OTIPS

HOJ:) S

F

HO OBn Following the procedure outlined in Example 16 and using- 0.56g Immole) of the bramoketone from Example 12 (Step C) with 0.19gc (0.l3mmole) of thiophenol derivative prepared from Example I, the desired product was obtained after silica gel chromatography using EtOAc/hexane as eluiant. 'H NMR (400 MHz, acetonedb) 6 (ppm): 7.9 2H), 7.48-7.3 (in, 5H), 7.16 2H), 6.84 2B), 6.78 2H), 6.42 1H), 6.38 IH), 5.96 1H), 5.1 21H), 2.6 2H), 1.22 (in, 3H), 1.1 (d, IS 1. 1 3H).

EXAMPLE 23 PREPARATIOIN OF 0 OTIPS

HO-

Et OBn Following the procedure outlined in Example 16 and using 2.04g, (4.33mmole) of the bromoketone from Example 12 (Step C) with the thiophenol derivative prepared from 70 WO 02/32377 WO 0232377PCT/USOI/42735 Example 1, the desired product was obtained after silica gel chromatography Using EtOAcxane (1/15) as elualnt. I H NMR (400 MHz, atCetoneC-Cr) 6 (ppmn): 7.9 2H), 7.5-7.3 (in, 5H), 7.12 (di, 2H), 6.92 1H), 6.84 (cd, 2H), 6.78 2H), 6.42 1H), 5.1 21-I), 2.7 2H1), 1.24 (in, L.I (d t. 2!1 H).

EXAM4PLE 24 PREPARATION OF 0 u

OTIPS

HoN S OBn OBn Following the procedure Outlined in Example 16 and using 2.Og (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 as eluant. 1H NMR (400 MHz, acetone-d 6 6 (ppm): 7.8 2H), 7.62 2H). 7.48-7.3 (in, 814I), 7.12 21-1), 6.8 2H), 6.76 (2H, 6.28 IHU), 6.18 IH). 6.0 1H), 5.24 2H), 5.05 2H), 1.22 (mn, 3H), 1.1 1811).

EXAM\PLE- PREPARATION OF 0

TIPSO

HO OBn -71 WO 02/32377 WO 0232377PCT/1JS01/42735 Foll Iowing the procedUr-e outlIined in Example 16 an d rISing al.6c (3.5 1mmole) of the bromoketone fromn Example 13 with [he thiophenol derivative prepared fromn Example 1, the desired produIct was obtained after silica gel chromatography uIsing EtOAc/hexane as elu-ant. 'H NMR (400 MEz, acetone-d 6 6 (ppm); 8.0 211), 7.5-7.2 (mn, 10H), 7.0 tH), 6.92 2H), 6.54 (cd, MK), 6.35 (dd, 1H), 6.12 1H), 5.06 2H), 1L22 (in, 1.1 1814).

EXAMPLE 26 PREPARATION OF 0

TIPSO<S

Fbollowing the procedure outlined in Example 16 and using 2.6g (5.S2minole) of the bronioketone from Example 13 with the thiophenol cierivatix'e prepared from Example 1, the desired product was obtained after silica gel chromatography using, EtOAc/hexane as eluant. 'III NMR, (400 M11z, acetone-C1 6 6 (PPM): 8.0 2H), 7.4-7.2 (in, 1011). 6.94 2H), 6.84-6.74 (in, 3H), 6.24 1H1), 4.85 1.23 (in, 3H), 1.1 1811).

EXAMPLE 27 PREPARATION OF TIPSO fo HO OBn WO 02/32377 WO 0232377PCT/1JS01/42735 Following the procedure outlined in Example 16 and using the bromoketone frorn Example 12 (Step C) with the thiophenol derivative prepared from Example 1, the desired product was obtained after silica gel chromatography using EtOAc/hexane as the elUant. 'H NMR (400 MHz, acetone-d 6 (PPM): 8.0 7.4-7.2 (in, 711I), 7.(0 (mn, 5H), 6.54 I 6.28 (dd, 6. 14 lI 5.08 2H), 1. 23 3H), 1. 1 (df, t 8H).

EXAMPLE 28 PREPARATION OE 0 TIPSO S F

HO-

Oin Following the procedure outlined in Example 16 and using the brornoketone from Example 13 with the appropriate thiopheno] derivative prepared from Example 1, the desired produict was obtained after silica gel chromatography using EtOAc/hexane as the elUant. H1 NIR (500 MIHz, CDCI 3 a (PPM) 8.28 IH), 7.82 211), 7.40 511). 7.22 (mn, 5H), 6.80 (dl 21H), 6.40 IH), 6.2t (dd. IH), 5.80 111).

5.00 2H1), 1.24 311), 1. L0 1811).

WO 02/32377 WO 0232377PCT/1JS01/42735 EXAMPLE 29 PREPARATION OF 0 S C TIPSO":D

HO-

OBn Following-. the procedure Outlined in Example 16 and using the bromoketone from Example 13 with the appropriate thiophenol deri vati ve prepared From Example the desired pr-oduct was obtained after SiO 2 Wsing EtOAc/hexane as eluant, 'H1 NMR (500 MIHz, CDCI.

3 8 (ppm) 8.19(s, IH), 7.82(d, 2H1), 7.40(m, 511), 7.24(m, 6.80(d, 2Ti), 6.64(d, I 6.44(d, 111), 5.84(s, lH), 5.00(s, 2H1), 1.23(mn, 311), 1.10(m, 18H).

EXAMPJLE PREPARATION OF

OTIPS

HOja S F 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 ELOAc/hexane as eluant. IH NMR (500 MI-z, CDCI 3 8 (ppmn): 8.20 I 7.81 2H), '7.40 (in, WO 02/32377 WO 0232377PCT/1JS01/42735 51-1), 7.02 6.75 4H), 6.36 I 6.20 (dd, I 5.78 11-1), 4.95 21-I), 1I_ ~3(m,3 1. 10(m, IS1-H).

EXAMPLE 31 PREPARATION OF 0

OTIPS

HON OC HO OBn Following the procedure outlined in Example 16 and using the bromoketone from Example 12 with the thiophenol derivative prepared from Example the desired product was obtained after silica gel chromatography using EtOAc/hexane as eluant. 1H NMR, (500 MHz, CDCI 3 8 (PPM): 8.24 11H), 7.80 2H1), 7.40 (in, 511), 7.10 2H), 6.78 4H1), 6.62 1H), 6.42 111), 5.84 111), 4.98 211), 1. 23 (mn, 3H1), 1. 10 (mn, I18H); MIS m/z 6 50 EXAMPLE 32 PREPARATION OF O OTIPS HO j HO O~r 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 Wvas obtained after silica gel chromatographly Uising EtOAc/hexane as WO 02/32377 WO 0232377PCT/1JS01/42735 eluant. 1H NMR (500 Ml-z, acetonC-dC6) 6 (ppm): 7.95 2H), 7,40 (in, 514), 7.20 (d, 6.30 hii, 71-1), 6-20 I1-H), 4.85 2H), 1,23 3H), 1. 10 (in, 18H), MS mix EXAMPLE 33 PREPARATION OF HO

S

HO \-Me OBn Following the procedure outlined in Example 169 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 EtOAc/hexane as eluant. 'H NMR (500 MVHz, CDC8,) 6 (ppm): 7.82 211), 7.40 (mn, 511), 7.05 (d, 6.95 .111), 6.30 4H), 6.52 IH)7 5.64 1H), 5.00 2H) 1.23 (in, 3H), 1.10 18.1): MS m/x 629 EXAMPLE 34 PREPARATION OF

HOO

13n WO 02/32377 WO 0232377PCT/US01/42735 Following the procedure Outlined ini Example 16 anld using the bromoketone from Example 12 with the thiophenol derivative p~repared frorn Example 1, the desired product was obtained after silica gel chromatography using EfOAc/hexane (11/5) as eluant. 1H NMR (500 MHz, CDCI 3 6 (PPM: 8.24 1H), 7.80 2H), 7.40 (in, 7. 10 6.78 2H), 6.76 2H1), 6.64 2H), 6.45 2H), 5.86 I 4.98 2H1), -23 (in, 3H), 1.10 (in. 18H), MS mh/ 650 CM-1).

EXAMPLE PREPARATION OF 0 TIPSO 'N

S

HO- \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 EtOAc/hiexane as eluiant. 'H NM/R (500 MHz, CDC1 3 a (ppm): 7.82 2B), 7.40 5H), 7.24 (in, 3141), 7.20 2H), 6.82 2H4), 6.80 211), 6.58 5.65 111), 4.80 21-1)j 2.22 3H), 1.23 (in, 314), 1.10 (in, 18H).

EXAMPLE 36 PREPARATION OF TIPSO 'N

S

HO /\OBn Cl WO 02/32377 WO 0232377PCT/1JS01/42735 Following the proceduire ou-tlined in Example 16 and the bromoketone from Example 13 with thce thiophenol derivative prepared fromn Example 1, the desired product was obtained after silica gel chromatography Using EtOAc/hexane 1/5) as eluant, 1H NMNR (500 MHz, CDC]I 3 6 (ppm): 7.98 1H), 7.82 2H), 7.40 (in. 5H-) 7.25 (in.

3H), 7.20 2H), 7.00 6.80 6.60 IH), 5.78 1H), 4.78 2H), 1.23 (mn, 3 1.10O (in, 18H).

EXAMPLE 37 PREPARATION OF 0

I

TIPSOJO S is-

C

H O0Bn TiPSO S c 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 I and 11 were obtained after silica gel chromatography using EtOAc/hexane (115) as eluant.

1: 'H1 NMR (500 MHz, CDCI.

3 8 (ppm): 7.80 2H), 7.40 (in, 51-1), 7.25 (in, 3H), 7.16 2H1). 7.04 114), 6.80 2H)7 6.60 IH), 5.78 IH), 4.80 2H1), 1.23 (in, 1 .10 (in 1811).

11: 1HNMR (500 MHz. CDCI.

3 6 (ppmn): 7.80 2H), 7.65 1H), 7.44 111), 7.40 (mn, 5H), 7.25 (in, 5H), 6.96 1H), 6.80 3H1), 6.00 5.15 211), 1.23 (in, 311), 1.10t (in, 1811).

WO 02/32377 WO 0232377PCT/USOI/42735 EXAMvPLE 38 PREPARATION OF 0

F

T1PSO Sj Following the procedure outlined in Example 16 and using the bromoketone from Example 12 with the thiophenol derivative prepared from Example L, the desired product was obtained after silica gel chromatography using EtOAc/hexane as eluant. 'H NMR (500 MHz, CDC1 3 8 (ppm): 7.80 2H), 7.40 (in, 5F1), 7.14 (mn, 2HI), 6.96 (mn, 6.84 (mn, 211), 6.32 2H), 6.70 IB), 5.68 1H), 4.86 d, 211), 1.23 (mn, 311), 1.10 (in, 18H).

EXAMPLE 39 GENERAL PREPARATION OF

OTIPS

Ph-f-O a OH0 Utilizing the bromides prepared in the Example 10 and the appropriate mercaptan prepared in Example I and employing the procedure Outlined in Example 16 the following compounds were prepared: Cyc lohex v] derivative: uIse methylene ch Ion de/hexanes(3: 1) as the chromatography eluant. 1 H 500MHz NM/R(CDCJ 3 PPMA(5I 12 (dI, 18H), 1.1 11-2.34 15,H)l, 4.19 ILH), 5.0 6.44 (dd, I 6.54 IH), 6.86 (in, 3H), 7.25-7.72 (in, 7H).

WO 02/32377 WO 0232377PCT/US01/42735 Cyclopentyl dcrivatiVC: use methylene ch lori dc/hex anes(2: I1) as the chromatography elUant. 500NIHz NMR,(CDCI, 2 ppm(8): 1. 12 (di, 1I1-1), 1 .28-2.49 (in, 121]), 4.18 I 5.0 2H), 6.45-7.77 (mn, 12H).

EXAMPLE PREPARATION OF S, raOH Ph OjaOH 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% yield after silica gel chromatography with 30% EtOAc/hexane as the eluant. 'H 500M1-lz NMR(CDCl-,) ppm(6): 1.00 31-1). 1.21 3 2.30 (rn, IH), 4.13 11-1), 4.99 2141), 6.41- 7.72 (mn, 12H-), 8.02 (bs, 114), 8.80 (bs, li- MS mlz 409 EXAMPLE 41 GENERAL PREPARATION OF WO 02/32377 WO 0232377PCT/1JS01/42735 Utilizing the bromides p~reparedl in Examnple 10 and the appropriate mercaptan prepared in Exaimple I and employing- the proccdiire ouitlined in Example 16 the following compounds were prepared: Cyclohexyl derivative: use methylene ch loridc/hexanes(3: 1) as the chromatography eluiant. 1H 500MHz NMR(CDC 3 ppm(6): 1.12 18H), 1.11-2.3 (in, 15H), 4.24 (d, 4.89 (in, 2H), 6.8-7.6 (mn, 12H).

Cyclopentyl derivatiVe: use rnethylene chloride/hexanes(2: t) as the chromatography eluant. 1H1 500M~z NMR(CDCII) ppm(8): 1. 12 I8H), 1.26-2.12 (in, I IH), 2.5 (in, 1IH), 4.24 I 4.9 (mn, 2H), 6.8-7.69 (mn, 12H).

4-Pyridyl derivative: isolated as a yellow oil using 30% EtOAc/hexane as the chromnatography eluant. 'H 500MHz NMR(CDCI, 3 ppin(6:1. 12 lSH), 1.28 (in, 3H), 4.84 2 4.88 Iii), 5.63 and 6.69-8.50 (in, 16H), 3-Pyridyl derivative: isolated as a yellow Oil using 30% EtOAc/hexane as the chromatography elUant. 1H 500MHz NMR(CDCl 3 ppm,(8):1. 12 18H), 1.28- (in, 31-1), 4.84 4.90 11-1), 5.79 and 6.70-8.50 (mn, 16,H).

EXAMPLE 42 PREPARATION OF

OH

Ph 0 Utilizing the bromide prepared in Example tIt and the appropriate inercaptan prepared in Example 1 and employing the procedure- outlined in Example 16, the desired produIct was obtained us a yellow oil after silica gel chromatography with EtOAcihexane as the eluant. 'H 500MHz NMR(CDCI 3 ppm(6): 1.02 3H), 1.21 (cd, 3 2.34 (mn, I 4.13 IlH), 4-90 11), 6.25 (bs, 11-1), 6-79-7,70 (mn, 12H).

S1 WO 02/32377 PCT/USU1/42735 EXAMPLE 43 PREPARATION OF S OTIPS HO

S

S 0

OH

Utilizing the appropriate bromide prepared in Example 10 and the mercaptoquinol [prepared according to the method of Burton, eial, J Clhem. 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 30% EtOAc/hexane as the eluant. 'H 500MHz NMR(CDC13) ppm(6): 1.10 18H), 1.27 3H), 6.00 1H), and 6.76-7.89 10H); MS m/z 515 EXAMPLE 44 PREPARATION OF

OTIPS

S

BnOO

OH

To a flask charged with 0. Ig 16mmole) of thio-ketone generated in Example 22 in dichloromethane (ca 0.04M) was slowly added trifluoroacetic acid(TFA) (2 X 0.062mL, 10eq) under an N 2 atmosphere at room temperature. To the stirred 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 3 /ice water, stirred minutes, and extracted with dichloromethane. The organic extract was washed with brine (2 X 50mL), dried with NaSO4, and concentrated in vacuo to afford a light yellow oil, Purification via flash chromatography (EtOAc/Hex=l:5) provided the desired compound as an oil. H NMR (400 MHz, CDCI 3 6 (ppm): 7.44 5H), 6.98 WO 02/32377 WO 0232377PCT/1JS01/42735 I 6.90 (cd, 2H), 6.75 6,68 2H), 6.65 (cd, 114), 6 63 (di, 2H), 5.51 (ci, J=2,3Hz, IH), 5. 10(s, 4.74 (brs, I1-H), 4.32 (ci J=2_3Hz, 2.77 (grl, 2H), 1.22 (in, 1L08 18H), L.I (in, MS mn/z 628.5 (M41± EXAMPLE PREPARATION OF OTIPS OTIPS S S 00 a OH OMOM Utilizing the procedure From Example 44, the desired dihydrobenzoxathiin without MOM protection was isolated after purification by silica gel chromatography with EtOAc/hexane. 'HNMR (400 MvHz, CDC13) 65 (ppm): 7.2-6.98 (mn, 4H), 6.85 (di, 2H), 6,78 2H), 6.66 (two d, 4H1), 5.5 Jz-2_ 2 Hz, 111, 4.8 111), 4.33 (d, J=2.1Hz, 11-1), 1.22 (mn, 31-1). 1.1 181-1); MS rn~z 515 (W 4 +23).

The other dihydrobenzooxathiin with MOM protection was also isolated. I NMR, (400 M-z, CDCI 3 85 (ppm): 7.2-6.6 (in, 8H1), 6.78 (di, 211). 6.66 (di, 5.5 (di, JI'-)_414z, 111), 5.14 2H), 4.35 (di, J=2.1H4z, 111), 3.48 3H), 1.22 (mn, 31-H), 1. 1 (di, 1814).

EXAN/PLE 46 PREPARATION OF

OH

S

(0

OMOM

WO 02/32377 WO 0232377PCT/1JS01/42735 Utilizing the procedure fromn Example 71 (Step the dihydrobenzoxathiin generated fromn Example 45, was desilylated to give the product'. IH NMR (400 MI-z, CDCI 3 6 (ppm); 7.2-6.96 (in, 6.92 (two di, 4H)7 6.82 2H), 6.6 (ci, 2H), 5,5 J=2_2Hz, 11-1), 5,16 2H), 4.68 (br s, Ifi), 4.38 J=&2.2Hz, I 3.48 3H-).

EXAMPLE 47 PREPARATION OF OMOMI OH 0 0 Ki MOM DH The ketone generated in Example 17 was converted to the desired product following the pr'ocedu-re described in Example 44 with the exception that 5 equivalents of TEA and 2 equivalents of Et 3 SiI was necessary to drive the reaction to completion. The MOM group was removed with mild acid treatment (2N-UCI, 75 0 C) to give the desired product. 'H NMR (400 MlHz, CDCI 3 8 (ppm): 7.0 (mn 4H), 6.85 (di, 2H), 6.65 (ci, 211), 5.38 211), MS m/z 343 (M++i23).

EXAMPLE 48 PREPARATION OF

OTIPS

BnOja0

OH

The ketone generated in Example 18 was converted to the dihydrobenzoxathiin utilizing the procedure from Example 44 with the exception that 20 equi\ alents of 84 WO 02/32377 WO 0232377PCT/1JS01/42735 TFA an d 15 equivalents of Et 3 -S IH were necessary to drive the reactionl to completion.

The desired product was isolated after puriFication by silica gel chromatography uising l1% EtOAc/hexane as eluant. 'H NMR (400 MHz, CDC1 3 7,5-7.34(in, 7.08 11-1), 6.84 2H), 6.76 (cd, 21-1). 6.7 (dcl. 11-1), 6.67 I 6.68 (two d, 4H), 5.5 J=2_ 9 Hz, 114), 5.04 (br q, 2H), 4.68 IH). 4.3 J=2.2Hz, 111). 1.22 (in, 3H), 1. 1 18H), MS m/z 5 15 EXAMPLE 49 PREPARATION OF OMe

S

BnO 0:C

OTIPS

The ketone generated in Example 19 was converted to the dihydr-obenzoxathiin utilizing the procedure from Example 44 with the exception that the reaction was run at -10 0 C for 48 hours in the presence of 20 equivalents of TFA and 2 equivalents of E(-,SiH. The desired product [with 20% recovered starting material] was isolated after Purification by silica gel chromatography using 10% EtOAc/hexane as eluant. IH NMR (400 Mffz, CDC1 3 8 (ppm): 7.5-7.3 5H), 7.1-6.6 (mn, I 111), 5.54 (d, hl-.9Hrz, 11-1), 5.06 (dcl, 2H4), 4.32 IH4), 3.74 311), 1.22 (in, 31-1), 1-1 1811).

EXAMPLE PREPARATION OF Me

-~OTIPS

BnO 0 WO 02/32377 WO 0232377PCT/1JS01/42735 Following the procedure Outlined in Example 44 and Using the ketone derivative in Example 20, the desired product was obtained after puriication by silica gel chromatography Using 5% EtOAc/hexane as el~ant. HR NMR (400 MHz, CDCI-) 6 (ppm): 7.46-7.32 (in, SH), 6.84 2H), 6.78 2H), 6-66 (two dl, 6.62 IH), 6.57 (ci. IH), 5.3 J=2.2Hz, IH), 4,35 1H), 2.28 1.22 (mn, 31-H), 1. 1 (d, t8H).

EXAMPLE 51 PREPARATION OF

,OTIPS

'oH Following the procedure outlined in Example 44 and using the ketone derivative from Example the desired product was obtained after purification by silica gel chromatography using 5% EtOAc/hexane as eluant. I NMR (400 MHz, CJDCI 3 (ppm): 7.5-7.3 (in, 5B), 6.98 1H), 6.9 (di, 1h), 6.76 2H), 6.6 (in, 5H), 5.51 (di, J=2.2Hz, 1H), 5.1 2H), 4.8 IH), 4.32 1ii), 2.4 3H), 1.22 (mn, 3H), 1.1 (d, 18M) EXAMPLE 52 PREPARATION OF E1

OTIPS

BnO 0

OH

Following the procedure outlined in Example 44 aind using the ketone derivative from Example 22) the desired product was obtained after purification by silica gel 86 WO 02/32377 WO 0232377PCT/1JS01/42735 chromatogr-aphy using 511' EtOAc/hexane as eluant. H NMR (400 MHz, CDC1 3 a (ppm): 7.5-7.3 (in, 5H), 6.85 (cd, 2H), 6.78 6.66 (in, 5H). 6.56 -5.48 J=2.0Hz_ I 5.04 (br 2H), 4.74 (br s, I 4.34 J=2.0H4z, I 2.64 2H-), 1.3 3H), 1 .24 (in, 311I), LI 1 811).

EXAMPLE 53 PREPARATION

OF

OTIPS

S

BnO 0 Following, the procedure outlined in Example 44 and using the ketone derivative from Example 23, the dlesired. product was obtained after purification by silica gel chromatography using 5% EtO)Ac/hexane as eluant. I1 H NM (400 MI-z, CDCI 3 a (ppm: 7.5-7.3 (in, 5H), 6.98 1H), 6.9 2H), 6.74 2H), 6.7-6.6 (three d, (ci, J=2.3Hz, IH), 5.1 2H), 4.74 (br s, IN), 4.32 J=2.4Hz, 1H), 2.79 (mn, 2HJ), 1.22 (in, 3H), 1.1I (d t, 21H); MS in/z 628.5 EXAMPLE 54 PREPARATION

OF

0O3n

OTIPS

BnO f) 0

OH

Following the procedure Outlined in Example 44 and using, the ketone derivative from Example 24, the desired product was obtained after purification by silica gel chromatography using 5% EtOAc/hexane as elUant. H NM-R (400 MJ-z, C.DCI.

3 8 (ppin): 7.5-7.3 (in, 101-I0, 6.84 2H), 6.78 2H), 6.66 (two di, 4H), 6.38 21-), 87 WO 02/32377 WO 0232377PCT/1JS01/42735 5.48 J=2.lIHz. IH), 5.14 2H), 5,0 4.76 (brs, 1H), 4.32 (di, J=2. IHZ' I 1. 2 2 3 1. 1 (di, 18SH).

EXAMPLE PREPARATION OF

S

BnO< 0 ec

OTIPS

Following the procedure outlined in Example 44 and using the ketone deivative obtained from Example 25, the desired product was obtained after Purification by silica gel chromatography using 5%c EtOAc/hexane as eluant. 'H NMR (400 MHz,

CDCI

2 8 (ppm): 7.5-7.32 (mn, 5H), 7.2-7.1 4H), 6.9-6.82 (in, 4H). 6.76-6.7 (mn, 4H), 5.56 114), 5 06 (bi-q, 2H), 4.36 Ili1), 1.22 (mn 31-1), 1.1 (di, ISH).

EXAMPLE 56 PREPARATION OF

OTIPS

Following the procedure outlined in Example 44, with the exception that the reaction wvas ruLn at O'C for three hours, and using 1.7a(2.S'mmole) of the ketone derivative obtained from Example 26, the desired product was obtained after purification by silica gel chromatography Using 5% EtOAc/hexane as eluant. 'H NMR (400 MHz,

CDCI

3 8 (ppm): 7,5-7.34 (mn, 5F1), 7.2-7.1 (mn, 6.94 (di, 114), 6.9-6.82 (in, 6.4 (in, 3H), 5.48 (di, J4.-9Hz, 1H), 5.05 NH), 4.36 J1.9Hz, 114), 1.22 (in, 317), 1.1 (,1814).

88 WO 02/32377 PCT/USU1/42735 EXAMPLE 57 PREPARATION OF

F

BnO 0O

OH

Following the procedure outlined in Example 44 and using the ketone derivative obtained from Example 27, the desired product was obtained, which was subsequently desilylated using the procedure described in Example 71 (Step The desired product was obtained as an oil after purification by silica gel chromatography using EtOAc/hexane as eluant. 'H NMR (400 MHz, CDCI 3 6 (ppm): 7.5-7.32 (m, 5H), 7.09 1H), 6.9-6.8 6H), 6.73-6.7 4H), 5.52 IH), 5.04 (br q, 2H), 4.34 1H), 1.22 3H), 1.1 18H).

EXAMPLE 58 PREPARATION OF

F

BnO 0 Y

OTIPS

Following the procedure outlined in Example 44 and using the ketone derivative from Example 28, the desired product was obtained after purification by silica gel chromatography using 5% EtOAc/hexane as eluant. 'H NMR (500 MHz, CDCI 3 (ppm): 7.5-7.3 5H), 7.22-7.10 3H), 6.90-6.80 (2d, 4H), 6.75 2H), 6.55 (d, 2H), 5.55 J=2.1Hz, 5.05 2H), 4.40 J=2.1Hz, 1H), 1.22 (m 3H), 1. L (d, 18H)- WO 02/32377 WO 0232377PCT/1JS01/42735 EXAMPLE -59 PREPARATION OF

CI

BrOA 0

I

OTIPS

Following the procedure outlined in Example 44 and using the ketone derivative from Example 29, the desired product was obtained after Purification by silica gel chromatography using 5% EtOAc/hexane as eluant. 'H NNM (500 MHz, CDCI 3 6 (ppm): 7.5-7.3 (in, 7.22-7.10 (in, 3B), 6.90-6.80 (2d, 4H), 6.73 2H4): 6.64 (d, 2H), 5.50 Jzz2.lHz, 1H), 5.05 2H), 4.43 J=22_Nlz, 1H), 1.23 (mn, 3H), 1.10 t18 H) EXAMPLE PREPARATION OF F

OTIPS

Bno 0S o OH 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 5% EtOAc/hexane as eluant. 1 HI NMR (500 MHz. CDCI 3 6 (ppmn): 7.5-7.3 (in, 511), 6.82 2H), 6.68 2H), 6.64 2B), 6.62 6.46 (d, 2H), 5.44 J--I.9H-z, 1H1), 5.02 2H), 4.30 (di, J=2.OHZ, IR), 1.22 (mn, 3H1), 181-I); MIS m/z 618 WO 02/32377 WO 0232377PCT/US01/42735 EXAMPLE 61 PREPARATION OF C1

OTIPS

BnO 0

OH

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. '11 NMR (400 MHz, CDCl 3 8 (ppm: 7.5-7.3 (in, 5H), 6.86 11-1), 6.82 21-1), 6.76 211), 6.70 I 6.67(d, 211), 6.65(d, 2H), 5.44 (ci, J=2.0Hz, 1H), 5.04 2H), 4.38 J=1.9tlz, IH), 1.23 (mn, 314), 1.10 1814); MS mlz 634 (M 4 ±1I).

EXAMPLE 62 PREPARATION OF

OTIPS

BnO S

OH

Following inhe procedure Outlined in Example 44 and using the ketone derivative fromn Example 32, the desired product was obtained after purification by silica gel chromatography using 5% EtOAc/hexane as eluaint, 'HNMR (500 MHZ, CDCI 3 (ppm): 7.5-7.3 (in, 5H), 6.94 (ci, 6.85 (di 2H), 6.80 (ci, 2H), 6.74 (cd, 21H), 6.65(m, 4H), 5.43 J=2. [Hz, 1H), 5.05 (di, 2H), 4.30 (di, J=2.lHz, 1.23 (in, 314), 10 (di, 18H).

WO 02/32377 WO 0232377PCT/1JS01/42735 EXAMPLE 63 PREPARATION OF

OTIPS

Men S BnOC o 0&

O

Following the procedure outlined in Example 44 and using the ketone derivative from Example 33, the desired product was obtained after purification by silica gel chromatography using 501 EtOAc/hexane as eluant. 'B NMvR (500 MT-z, CDCI 3 (ppm): 7.5-7.3 (in, 5H), 6.88 111), 6.84 211), 6.82 211), 6.70 2H), 6.68 (d, 211). 6.66 1H), 5.50 111), 5.05 214I), 4.43 11H), 2.35 3H), 1.23 (in. 3H1), 1.10 18H).

EXAMPLE 64 PREPARATION OF

OTIPS

C1 S Bno 0 O H Following the procedure outlined in Example 44 and uisingy the ketone derivative from Example 34, the desired product was obtained after purification by silica gel chromatography using 5% EtOAc/hexane, as eluant. H1- NMR (500 M-Hz, CDCI 3 8 (ppm): 7.5-7.3 (in, 7.24 1H), 7.20 111), 6.82 2H), 6.68 2H), 6.64 (in, 411), 5.44 J=2.OHz. 111), 5.05 2H), 4.28 J=2.311z, 111f), 1.23 (in, 3H), 1.10 I SH).

WO 02/32377 WO 0232377PCT/1JS01/42735 EXAMVPLE PREPARATION OF Bn 0 OTI PS Following the procedure outlined in Example 44 and using the ketone derivative from Example 35, the desired product was obtained after purification silica gel chromatography using 5%1 EtOAc/hexane as eluant. 1 H NMR (500 M~z, CDCI 3 6 (ppm): 7.5-7.3 (mn, 5H), 7.05-7.20 (in, 4H), 6.90 2H), 6.88 2H), 6.78 2K), 6.70 Cd, 1H), 6.65 1K), 5.30 J=1.8Hz, 1KH), 5-05 2H), 4.20 J=2 3H z, IH-).

1.23 (in, 3H), 1.10 18H).

EXAMPLE 66 PREPARATION OF BnO S "N OTIPS Following the procedure outlined in Example 44 and using the ketone derivative from Example 36, the desired product was obtained after purification by silica gel chromatography using 5% EtOAc/hexane as eluant. '14 NMR (500 M~z, CDCtV) 6 (ppm): 7.5-7.3 (in. 5H), 7.05-7.20 (in, 7. 10 214), 6.98 2KH), 6.88 (in, 2H), 6.80 11H), 6.60 111), 5.56 J=1.SHz, IH), 5.05 2H), 4.44 J=2.3Hz.

1K), 1.23 (in, 3111), 1. 10 181-1).

-93 WO 02/32377 WO 0232377PCT/US01/42735 EXAMPLEF 67 PREPARATION OF BnO S

II

Ol-IPS 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 EtOAc/hexane as eluant. I NMR (500 MHz, CDCI 3 8 (ppm): 7.55 2H), 7.45 2H), 7.35 1H), 7.20 tH), 7.15 (in, 3H1), 6.88 (d.

2H), 6.84 3H), 6.78 2H), 5.46 1Hz, 5.15 2H), 4.39 J=2.il~z, 1H), 1.23 (in, 3H), 1.10 i8H).

EXAMPLE 68 PREPARATION OF

CI

EBnO S

OTIPS

Following the procedure Outlined in 44 and using the ketone derivative from Example 37(11), the desired product was obtained after purification by silica gel chromatography using 5%,7 EtOAc/hcxane as eluant. 'H NMR (500 M.Hz, CDCI 3 8 (ppm): 7.55 2H), 7.45 2H), 7.35 7.20 1H), 7.15 6.80-6,90 4H), 6.7 8 6.76 2H), 5.42 J=2.IIHz, 1W), 5.18 2H), 4.42 (d, J=2 1Hz, IH), L.23 (in, 3B), 1.10 18H1).

94 WO 02/32377 WO 0232377PCT/1JS01/42735 EXAMPLE 69 PREPARATION OF

F

BnO S

<Q(

OTIPS

Following the procedure outlined in Example 44 and using the ketone derivative fo Example 38, the desired product was obtained after purification by silica gel chromatography using 5% EtOAc/hexane as eluant. 'H1 NMR (500 MJz, CDCI,,) 8 (ppm): 7.36-7.50 (mn, 5H), 6.96 2H1), 6.80-6.90 (in, 411), 6.70-6.78 (in, 5F1), 5.42 J=2.1IHz, 111), 5.18 2H), 4.38 J=2. tHz, 111), 1.23 (in. 3H), 1. 10 181-1).

EXAMPLE CHIRAL SEPARATION OF

OTIPS

OH

Each enantiomner of the raceniic dihydrohenzoxathiin, obtained from Example 62, was obtained via chiral chromatography using a Chiralpak AD column, with isopropanol in hexane as the eluant.

The fast moving isomer: +1 8.44'(c=0.7'5, MeOH).

The slow moving isomer: [cuir)= -t8.85 0 (c=0.74, MeOH).

WO 02/32377 WO 0232377PCT/USOI/42735 EXAMVP1. 71 GENERAL PREPARATION OF TW[INS PREPARATION OF

OH

S

HO 0( Z 0- W Step A To a stirred solution of a m-ixturc of dihydrobenzoxathiin (60mg, 0.1 mmole), obtained fromn Example 48 (which was dried by the azeotropic method prior to use), triphenylphosphine (I157mg, 0.6mrnole), and I1-piperidineethanol (0.08rnL, 0.6rnmole) in 4mL of anhydrous THF at 0 0 C was added dropwise Oil,8mL (0.6mmole)of diisopropyl azodicarboxylate (D1AD) over 0.2 hours. The resulting pale yellow solution was stirred at room temperature for 2-3 hours. The volatile components were removed in vacuo and the residue puirified by Hash chromatography followed by 2-3% MeOHldichlIoro meth ane) to give desired product. IH NMP. (400 MHz, CDCI-,) 6 (ppm): 7.5-7.34 5H), 7.08 6.86 2H), 6.78-6.64 (mn, 811), 5.5 1H), 5.01 (br q, 2H), 4.3 111), 4.2 214), 2.75 2H1). 2.5 (br s, 4H), 1.6 (in, 4H), 1.48 (in, 2H), 1.22 (in, 3B), 1.1 18H); MS m/z 712.4(M 1.

Step B To a stirred solution of the adduct (71mg, 0.O9Smmole), generated in Step A, in 2mL of EtOH/EtOAc/EI2O 1) was added [3mg (1 .2eq) of palladium black and ammonium formate (62mg, I0eq).The resulting miXture was heated at 80"C and monitored by TLC. After 3hours, the reaction mixture was cooled to room ternperatfl-re, filtered through a pad of Celite to remnuve the catalyst, and the filtrate was partitioned between water and EtOAc. The organic phase was separated, dried WO 02/32377 WO 0232377PCT/1JS01/42735 over Mg-SO 4 and concentrated in Vacuo to give desired product. I-1 NMR (400 M4Hz, CDC13) 6 (ppmn): 7.01 I 6.8 2H), 6.75 2H), 6,66 (two d, 4H), 6.54 (dd, 114), 6.5 (di, IN), 5.45 J=2.3Hz, IH). 4.28 J=2.3Hz. IHl), 4.08 2.8 (t, 21-I). 2.6 (br s, 68 (in, 4H), 1.5 2H), 1.22 (in, 314), 1.1 18H).

Step C To a stirred Solution of a Mixture of the debenzylated product generated in Step B and HOAc (10eq) in mL of THF was added a Solution of tctr-abuitylammonium Fluoride (3eq) in TI-IF at room temperature. The resulting solution was allowed to stir for two hours at room temperature and then poured into saturated aqueous NaHC0 3 and extracted with EtOAc. 'the organic layer was washed with brine. dried over MgSO 4 filtered, and evaporated. Purification by silica gel chromatography using 5-7% MeOll in methylene chloride as eluant afforded the desired product. IH NIVIR (400 M~z,

CD

3 OD) 8 (ppm): 6.95 2H4), 6.92 tH), 6.78 2HB), 6.7 1 2H). 6.48 2H1), 6.47 lH), 6.44 (dd, 111), 5.47 J=2.IH7z, IH), 4.37 J=2.1Hz, Iii), 4.1 2H), 2.85 2H), 2.65 (br s, 4H), 1.66 4H), 1.5 (in, 211).

EXAMPLE 72 PREPARATION OF

OH

S

HO 0( Et N Using the procedure described in Example 71 (Step the dithydrobenizoxathiu obtained fr-om Example 53 was coupled with t-piperidineethanol. After purification by silica gel chromatography, Using 3% MeO4HlCl-, as eluant, the desired adduict was obtained. 'H NMIR(400 M~z, CDCI-) 6 (ppm): 6.98 6.92 21), 6.74 (two d, 4H), 6.65 IlH). 6.62 2H), 5.5 111), 5.1t 2H), 4.31 1IH), 4.09 (mn, 2H), 2.75 2.55 (in, 2H), 2.5 (mn, 4H), 1.6 (in, 4H), 1.45 (rn, 2H), t.22 (rn, 31-1), 1.1 21H), -97 WO 02/32377 WO 0232377PCT/1JS01/42735 Step B The aidduct generated in Step A was debenzylnted using the procedure described in Example 7 1 (Step B) to give the desired prodUCt. 'H NMR (400 MHz, CDC13) 8 (ppm): 6.92 I 6.89 21-1), 6.72 (d d, 411), 6.62 6.5 11-1), 5.5 (d, J=2.2 Hz, 1H), 4.3 J=2_9Hz, 1H), 4.1 (in, 2H), 2.8 2H), 2.68 (in. 2.58 (br S, 4H), 1.64 (mn, 4H), 1.48 (in, 1H), 1.2 (in. 3H), 1.09 (d m, 21H).

Step C The debenzylated product from Step B was desilylated using the procedure described in Example 71 (Step The desired product was obtained as a white solid. 'a1 NMR (400 MHz, CD 3 OD) 6 (ppm): 7.0 2H1), 6.79 211), 6.76 6.71 2H), 6.47 3H), 5.46 J=2.2Hz, 1H1), 4.38 11H), 4.08 211), 2.8 211), 2.5 (in, 2H1), 2.6 (mn, 4H), 1.62 (in. 4H), 1.5 (in. 2H), 1.1 3H); MS inlz 493.2 EXAMPLE 73 PREPARATION OF

OH

s 0 Ste p A The dihydrobenzoxathiin obtained from Example 45 was Coupled with Ipiperidlineethanol using the procedure described in Example 71 (Step After pur1ification by silica gel chromatography Using 3% MeOH-/CH 2

CI

2 as elanit, thet desired adduct was obtained. 1HNMR (400 MHz, CDC1 3 8 (ppm): 7.14-6.92 (in, 411), 6.8 6.76 214), 6.72 211), 6.64 21), 5.48 J=9_ 9 Hz, 11-1). 4.34 J=2.1-1z, 11H), 4.1L (mn, 2H1), 2.85 (rn, 2H), 2.6 (mn,4H), 1. 65 (in, 411), 1.5 (mn, 2H), 1.22 (in, 3H), LI 18H).

Step B The adduct from Step A was desilylated Using the procedure described in Example 7].

(Step The desired product was obtained as a white solid. 1 JJ NMR (400 MHz,

CD

3 ,OD) 5 (ppm): 7,14-6.92 (in, 4H), 6.06 6.78 2H), 6.72 2H), 6.48 (d, 98 WO 02/32377 WO 0232377PCT/1JS01/42735 2H), 5.43 J=2. 1 Hz, 4.44 (di, I H1), 4. 1 2.78 2H), 2,58 (br s, 41-), 1.64 (in, 1.5 (mn, 2W) MVS m/z 450.2 EXAMPLE 74 PREPARATION OF

OH

0 Step A The dihydrobenzoxathiin obtained from Example 46 was coupled with Ipiperidineethanol using the procedure described in Example 71 (Step After purification by silica gel chromatography with 3% MeOH!CH 2 Cl 2 the desired adduct was obtained as an oil. 'H NMR (400 MHz, CDCI 3 8 (ppm): 7.14-6.94 (in, 4H), 6.96 2H), 6.84 (two d, 4H), 6.66 2H), 5.5 J=2.1Hz, 1H), 5.12 2H), 4.5 (d, J=2. IHz, IH), 4.04 2H), 3.42 3H), 2.75 2H), 2.55 (br s, 4H), 1.6 (in, 4), 1.43 (mn, MS inlz 495.2 Step B The adduct (10mg, 0.02 mnmole) from Step A was deprotected with TEA (l0eq) and MeOW (6eq) in CH 2

CI

2 at room temperature to afford the desired product. 'H NMR (400 ML-z, CD 3 OD) 8 (ppm): 7. 14-6.92 (in, 4IH), 6.84l (two d, 4H), 6.66 2W), 6.6 2H), 5.45 J+2.2Hz, 1H), 4.45 J=2_2Hz, 1H), 4.05 21-1), 2.8 2H1), 2.6 (hr s, 4H), 1.6 (mn, 1.5 (mn, 2W) ;MS m/z 450.2 (MW±1), EXAMPLE PREPARATION OF WO 02/32377 WO 0232377PCT/1JS01/42735

OH

0 0 The dioxane derivative obtained from Example 47 was coupled with Ipiperidineethanol using the procedure described in Example T71, (Step A) to give the product. 'H NMR (400 MHz, CD 3 OD) 8 (ppm): 7.04 2H), 6.98-6.84 (in, 41-), 6.82 (d7 2H), 6.74 6.63 2H1), 6.56 2H), 5.36 IRl). 5.33 J=3.01-Z, 1H1), 4.02 (mn, 2H),2.8 2H), 2.6 (br s, 411), 1.62 (in, 4H1), 1.5 (in, 2H1): MIS mlz 432

(M}

EXAMPLE 76 PREPARATION OF OMe S 0

N

Step A The dihydrobenzoxathiin generated from Example 49 was desilylated using the procedure described in Example 71 (Step The desired product was obtained as a white solid. iHNMR, (400 MHz. CDCI 3 8 7.5-7.3 (in, 5H), 7.2 I 6.9 2141), 6.88 6.68 (mn, 61-1), 5.53 J=:22-Hz, IHI). 4.33 Jz- 3H-z, I H), 3.75 3HI).

Step B The desilylated product obtained from Step A was coupled with [-piperidineerhanol using, the procedure described in Example 71 (Step After purification by silica gel chr~omatography w~ith 3% MtOH/CI-BCI2, the desired adduct was obtained. 'H NMR (400 MI-z, CDCI 3 6 (ppm): 7.5.-7.3 (mn, 511), 7.08 6.9 2H), 6.84 2H), -100- WO 02/32377 WO 0232377PCT/1JS01/42735 6,76 Wd, 6.66 (in, 4H), 55 I 5 03 2H), 4.32 I1-1), 4.06 2H), 3.75 31-1), 2175 21-1), 2.5 (br s, 4H), 1.6 (in. 4H), 1-45 (in, 21H), Step2 C The adduIct generated in Step B was debenzylated LUsing the procedure described in Example 71 (Step B) to give the product. NMR (400 Mfiz, CD3OD) 8 (ppm): 6.96 6.92 IM), 6.82 2H), 6.78 214), 6.63 2H), 6.48 (dd, 111), 6.44 1H), 5.5 J=2.2Hz, IH), 4.42 J=2_ 9 J-z, 1H4), 4.08 214), 3.68 314), 2.78 214). 2.59 (br s, 414), 1.6 (in, 414), 1.48 (in, 214); MS mlz 479.4 EXAM4PLE 77 PREPARATION OF Me

-~OH

S

The dihydrobenzoxathiin obtained from Example 50 was Coupled with Ipiperidineethanol using the procedure described in Example 71 (Step After purification by silica gel chromatography with 3% MeOICH 2 Cl 2 the desired adduct was obtained. I1H NMR (400 Mi~z, CDCI 3 6 (ppm): 6.83 214), 6.75 214), 6.69 2H), 6.62 214), 6.5 114), 6.48 114), 5.42 (br s, 1H4), 4.3 (bi- s, 1H4), 4.06 (t, 214), 2.78 214), 2.5 (br s, 4H), 1.6 (mn, 4H), 1.44 (in, 214), 1.22 (in, 3H), 1.1 (d, I8H).

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

Step C The debenzylated product fr-om Step B was desilylated using the pr-ocedure described in Example- 71 (Step The desired product was obtained as a white solid. 'Hl NMR 101 WO 02/32377 WO 0232377PCT/UStil/42735 (400 MHz, CD-,OD) 6 (ppm): 6.94 (cd, 2H), 6,76 (di, 2H), 6.7 (cd, 2H), 6.49 2H), 6.4 11-1), 6.32 I 5.43 J=2.3Hz, ti-I), 4.4 J=2.3Hz, I 4.08 2.8 (t, 2.6 (br s, 4H), 2.18 1.64 (mn, 1.5 (mn, MS m/z 479.2 EXAMIPLE 78 PREPARATION OF

OH

S

HO (0 Me 0 Step A The dihydrobenzoxathiin obtained from Example 51 was coupled with Ipiperidineethanol using the procedure described in Example 71 (Step After purification by silica gel chromatography with 3%7 MeOH!CHC1 2 the desired adduct was obtained.

StepEB The adduct generated in Step A was debenzylated using the procedure described in Example 71 (Step After purification by silica gel chromatography using 5%7 MeOHICH 2 CI2) as the eluant, the desired product was obtained as an oil. 'HNIVR (400 MI~z, CDC1 3 8 (ppm): 6.9 2H), 6.89 (di, 1H), 6.73 (in, 4E1), 6.62 2H), 6.52 I1H), 5.5 1H), 4.3 (di, I1-1), 4.1 (br s, 211), 8 (br t, 211), 2.6 (br s, 4H), 2.2) 3H1), 1.6 (in, 411). 1.5 2H), 1 .22 3H), 1.1, (di, 18H1).

Step C The debenzylated product from Step B was desilylated ulsingy the procedure described in Example 71 (Step The desired product was obtained as a white solid. 'H NMR (400 MHz. CD3OD) 6 (ppm): 7.02 2H1), 6.76 (di, 2H1), 6.7 (di, 2H), 6.47 (two cl, 3H1), 5.48 (di, 5=2.31z, I1H), 4.38 (di, J=9 3Hz, 1H1), 4. 1 211), 2.8 2B1), 2.6 (br s, 411), 2.1 3H), 1.6 Cm, 4H), 1.5 211); MS m/z 479.2 (1\1 WO 02/32377 PCT/USU1/42735 EXAMPLE 79 PREPARATION OF Et O- N 0 Step A The dihydrobenzoxathiin obtained from Example 53 was coupled with 1piperidineethanol using the procedure described in Example 71 (Step After purification by silica gel chromatography with 3% MeOH/CH2Cl?, 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 in Example 71 (Step The desired product was obtained as a white solid after silical gel chromatography with 5% MeOH/CH 2 C2 as eluant. 'H NMR (400 MHz, CD30D) 6 (ppm): 6.94 2H), 6.76 2H), 6.7 (2H, 6.48 2H), 6.41 1H), 6.3 1H), 5.44 J=2.2Hz, IH), 4.4 J=2.2Hz, 1H), 4.08 2H), 2.8 2H), 2.62 (br s, 4H), 2.6 2H), 1.6 4H), 1.45 2H), 1.2 3H); MS m/z 493.2 103- WO 02/32377 WO 0232377PCT/1JS01/42735 EXAMPLE S0 PREPARATIODN OF OH

OH

HO 0 r

N

Step A The dihydrobenzoxathiin obtained from Example 54 was coupled with Ipiperidineethanol using the procedure described in Example 71 (Step After Purification by silica gel chromatography with 3% MeOFHII 2 Cl 2 the desired addUCt was obtained. 'H NM~R (400 M.I-z. CDC1 3 8 (ppm): 7.5-7.3 (mn, ICGH), 6.86 2h 6.78 2H), 6.74 2H), 6.64 2H), 6.38 2H), 5.48 5.14 211), 5.02 2H), 4.32 IH), 4.08 214), 2.8 2H), 2.5 (bn s, 4H), 1.62 (in, 414), 1.5 (in, 2H), 1.22 (mn, 3H), 1. 1 I 8H).

Step B The adduct generated in Step A was debenzylated using the procedure described in Example 71t (Step After purification by silIica gel chromatography usingc MeOHICH 2 CI, as eluant, the desired product was obtained as an oil.

Ste-C- The debenzylated product from Step B was desilylated using the procedure described in Example 7.1 (Step The desired product was obtained as a white solid. 'HNMR (400 M\/Hz, CD 3 OD) 5 (ppm): 6.94 2H), 6.78 2H), 6.72 214), 6.5 2Ki', 6.06 I 6.02 IH), 5.42 J=2.2Hz, 4.33 J=2.2Hz, I 4.09 2H), 2.8 2.6 (bn s, 414), 1.64 (in, 4H), 1.5 (mn, MS m/z 482.2 (MW+1).

104 WO 02/32377 WO 0232377PCT/USOI/42735 EXAMPLE 81 PREPARATION OF

NJN

Step A The dihydrobenzoxathiin generated from Example 55 was desilylated using the procedure described in Example 71 (Step The desired product was obtained as a white solid. 'HNMR (400 N'IHz, CDCI 3 8(ppm: 7.48-7.32 (in,5H), 7.2-7.1(in, 41-1), 6.94-6.84 (two d, 4H): 6.7 (in. 4H1), 5.56 J=2.IHz, IH), 5.04 (br q, 2H), 4.74 (s, Step B The desilylated product obtained from Step A was coupled with 1-piperidineethanol using the procedure described in Example 71 (Step After purification by silica gel chromatography with 3% NMeOHIH 2

CI

2 the desired adduct was obtained. 'HNM/R (400 MHz, CDCI 3 6 (ppm); 7.5-7.32 (in, 5H), 7.2-7.04 (in. 4H), 6.94-6.86 4H), 6.76-6.66 (in, 411), 5.54 (br s, IH), 5.04 (br s, 2H), 4.38 (br s, 111), 4.06 211), 2.76 2H), 2.5 (br s, 4H), 1.6 (mn, 4H1), 1.42 (in, 2H).

Step C The adduct generated in Step B was debeozylated using the procedure described in Example 71 (Step B) to afford the desired product. 'H NMR (400 MIHz, CDOD) 6 (ppmn): 7.2-7.14 (in, 3H1), 6.94 (in, 3H), 6.9 211), 6.74 2K), 6.48 (dd, IH), 6.45 IH), 5.53 J=2 3Hz, IH), 4.46 111), 4.06 2H), 2.78 211), 2.58 (bi- s, 4H), 1 .62 4H1), 1.5 (in, 2H): MS rnlz 449.2 t05 WO 02/32377 PCT/USU1/42735 EXAMPLE 82 PREPARATION OF HO S Step A The dihydrobenzoxathiin generated from Example 56 was desilylated using the procedure described in Example 71 (Step The desired product was obtained as a white solid. 'H NMR (400 MHz, CDCI1) 8 (ppm): 7.5-7.3 5H), 7.2-7.1 3H), 6.96 2H), 6.92 1H), 6.88 2H), 6.84 1H), 6.74 (dd, 1H), 6.66 2H), 5.48 J=2.1Hz, IH), 5.04 2H), 4.37 J=2. Hz, 1H); MS m/z 428.2 Step B The desilylated product obtained from Step A was coupled with 1-piperidineethanol using the procedure described in Example 71 (Step After purification by silica gel chromatography with 3% MeOH/CHZCI 2 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) 6 (ppm): 7.14-7.02 3H), 6.92 4H), 6.8 1H), 6.74 2H), 6.58 1H), 6.51 (dd, tH), 5.42 (br s, 1H), 4.45 (br s, 1H), 4.06 2H), 2.78 2H), 2.55 (br s, 4H), 1.6 4H), 1.5 2H); MS m/z 449.2 (Mlf+).

106 WO 02/32377 PCT/USU1/42735 EXAMPLE 83 PREPARATION OF

OH

O N Step A To a well stirred 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 NaHSO3 and stirred for additional 30 minutes.

The aqueous layer was extracted with EtOAc and the organic layer was washed with brine, dried with MgSO 4 and evaporated to give a residue which was used for next step without further purification. 'H NMR (400 MHz, CD 3 OD) 6 (ppm): 7.82 (dd, 1H), 7.67 (dt, 1H), 7.28 2H), 7.2 2H), 7.03 2H), 6.92 2H), 6.82 2H), 6.32 1H), 5.12 2H), 4.84 1H), 4.2 (br t, 3.40 3H), 3.2 2H), 4H), 1.75 4H), 1.6 2H).

Step B The MOM protecting group was removed following the procedure outlined in Example 74 (Step The desired product was isolated after purification by silica gel chromatography using 5% MeOH/CH2CI as the eluant. 'H NMR (400 MHz,

CD

3 OD) 8 (ppm): 7.82 (dd, 1H), 7.64 (dt, 1H), 7.26 2H), 7.04 2H), 6.06 (d, 2H), 6.76 2H), 6.65 2H), 6.24 J=1.9Hz, IH), 4.71 1H), 4.1 2H), 2.72 2H), 2.5 (br s, 4H), 1L6 4H), 1.45 2H): MS m/z 481.1 (M 107- WO 02/32377 PCT/USU1/42735 EXAMPLE 84 PREPARATION OF

OH

O0 SOAc O N 0

H

StepA To a well stirred solution of the dihydrobenzoxathiin (60mg) prepared from Example 73 (Step A) was added 5 equivalents of m-CPBA in CHCl at 0°C. The ice bath was removed and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was quenched with a saturated solution of NaHSO.

3 and saturated NaHCO 3 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 4 The solvent was removed by evaporation to give an oily residue, which was purified by silica gel chromatography with 3% MeOH/CH 2 CI, as the eluant to give the pure product. 'H NMR (400 MHz, CD30D) 8 (ppm): 7.85 (dd, 1H), 7.66 1H), 7.28 2H), 7.12 2H), 6.86 2H), 6.8 2H), 6.7 2H), 6.22 J=2.1Hz, 1H), 4.72 J=2.3Hz, tH), 4.08 2H), 2.8 2H), 2.6 (br s, 4H), 1.6 4H), 1.5 (m, 2H), 1.22 3H), 1.1 18H); MS n/z 637 (M+23).

Step B The silyl protecting group was removed following the procedure outlined in Example 71 (Step The desired product was isolated after purification by silica gel chromatography using 5% MeOH/CHzCIl as the eluant. IH NMR (400 MHz, 8 (ppm): 7.81 (dd, 1H), 7.64 1H), 7.35 2H), 7.2 2H), 6.82 (two d, 6.6 2H), 6.28 J=2.2Hz, 1H), 4.69 J=2.2Hz, 1H), 4.2 2H), 3.08 (t, 2H), 2.85 (br s, 4H), 1.7 4H), 1.55 2H).

108- WO 02/32377 PCT/USU1/42735 EXAMPLE PREPARATION OF 0, I OH HO N Step A Utilizing the procedure from Example 83 (Step the dihydrobenzoxathiin 0.028 mmole) obtained from Example 71 (Step was oxidized by m-CPBA at room temperature. The crude material was used for next step without further purification.

'H NMR (400 MHz, CDC13) 5 (ppm): 7.84 1H), 7.7-7.4 5H), 7.02 2H), 6.88 (dd, 1H), 6.82 2H), 6.76 (two d, 4H), 6.72 1H), 6.22 J=2.2Hz, 1H), 5.18 2H), 4.28 J=2.1Hz, 1H), 4.09 2H), 2.8 2H), 2.55 (br s, 4H), 1.63 (m, 4H), 1.48 2H), 1.22 3H), L.1 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 further purification.

Step_C The silyl protecting group was removed following the procedure outlined in Example 71 (Step The final product was isolated after purification by silica gel chromatography using 5% MeOH/CH 2 CI2 as the eluant. 'H NMR (400 MHz,

CD

3 OD) 6 (ppm): 7.62 IH), 7.14 2H), 6.84 (two d, 4H), 6.68 (dd, IH), 6.6 (d, 2H), 6.55 1H), 6.22 1H), 4.55 J=2. Hz, 1H), 4.1 2H), 2.8 2H), 2.6 (br s, 4H), 1.64 4H). 1.5 2H); MS m/z 496.1 (M 109- WO 02/32377 PCT/USU1/42735 EXAMPLE 86 PREPARATION OF

S

HO aO O

OH

Step A To a solution of dihydrobenzoxathiin (100mg 0. 167 mmole) generated from Example 48 in CH 2 C12 was added triethylamine (0.07mL), a catalytic amount of N,Ndimethylaminopyridine (DMAP) and acetic anhydride (0.034mL, 2eq) at room temperature. The resultant mixture was stirred for 30 minutes and then poured into saturated NaHCO 3 The aqueous layer was extracted with CH 2

CI

2 and then dried over anhydrous Na 2

SO

4 The solvent was evaporated to give an oil, which was subjected to silica gel chromatography with 10% EtOAc/hexane as eluant to give the product.

NMR (400 MHz, CDC13) 5 (ppm): 7.48-7.34 5H), 7.08 1H), 6.99 2H), 6.94 6.76 2H), 6.72-6.67 4H), 5.56 1H), 5.06 (br q, 2H), 4.34 (d, IH), 2.3 3H), 1.22 3H), 1.1 18 H).

Step B The silyl protecting group was removed following the procedure outlined in Example 71 (Step The desired product was isolated after purification by silica gel chromatography using 5% MeOH/CH 2 Cb2 as the eluant. H NMR (400 MHz, CDCl3) 8 (ppm): 7.48-7.34 5H), 7.09 1H), 7.04 2H), 6.98 2H), 6.78 2H), 6.7 2H), 6.59 2H), 5.56 1H), 5.06 (br q, 2H), 4.74 1H), 4.36 1H), 2.2 (s, 3H).

Step C The desilylated product (80mg, 0.165mmole) obtained from Step B was coupled with 1-piperidineethanol using the procedure described in Example 71 (Step After purification by silica gel chromatography with 3% MeOH/CH2C12, the desired adduct -110- WO 02/32377 PCT/USU1/42735 was obtained. 'H NMR (400 MHz, CDCI 3 (ppm): 7,48-7.34 5H), 7.08 1H), 7.04 2H), 6.98 2H), 6.82 2H), 6.7 (dd, 1H), 6.68 6.68 2H), 5.58 J=2.2Hz, IH), 5.05 (br q, 2H), 4.36 J=2.2Hz, 1 4.05 2H), 2.68 2H), (br s, 4H). 2.25 3H), 1.6 4H), 1.45 2H); MS m/z 597.3 (MN'+I, Step D To a solution of 10mg (0.017mmole) of the adduct, generated from Step, in anhydrous THF was added four equivalents of a 1.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 hydrolyzed with H 2 0/NaHCO 3 The aqueous layer was extracted with EtOAc, the organic layer separated, dried, and evaporated to give an oil, which was used for next step without further purification.

StepE The crude product from Step D was deblocked using the standard procedure described in Example 71 (Step B) to afford the final product, after purification by silica gel chromatography using 5% MeOH/CH 2 Cb2 as the eluant. 'H NMR (400 MHz, 8 (ppm): 6.92 1H), 6.83 2H), 6.82 2H), 6.65 2H), 6.58 2H), 6.46 (dd, 1H), 6.42 1H), 5.44 J=2.1Hz, 111H) 4.38 IH, J=2.3Hz, 1H), 4.04 (t, 2H), 2.78 2H), 2.6 (br s, 4H), 1.6 4H), 1.5 2H); MS m/z 465 (M+l1).

EXAMPLE 87 PREPARATION OF

F

S HO 0 op

N

Step A The desilylated product obtained from Example 57 was coupled with 1pieridineethanol using the procedure described in Example 71 (Step After 111- WO 02/32377 WO 0232377PCT/1JS01/42735 purification by silica gel chromnatograp)hy with 3%11 McIOH/C-Cl,, the desired adduIct was obtained.

Step 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 (400 TMHz, CD 3 OD) 6 (ppm): 6.98-6.76 (in, 9H), 6.5 (dd, IH). 6.46 111), 5.52 J=2.3Hz, 114). 4.5 (d, 11-1), 4.05 2.80 2H), 2.62 (br s, 4H), 1.62 (in, 4H). 1.5 (mn, 211); MS mn/z 466.2 EXAMPLE 88 CHIRAL SEPARATION OF

S

HO 0XO

N

0 The racemic dihydrobenzoxathiin obtained from Example 81 (Step C) was resolved via chiral chromatography on a Chiralpak AD column, u~sing 20% EtOH in hexane as the eluant. The fast moving isomer: [ct]D= +33.43'(c= 1 .205, MeOH).

The slow moving isomer: [cx]g 0 34.2'(c=1.09, MeOH).

EXAMPLE 89 CIRAL SEPARATION OF HO aS 0

N

0 f WO 02/32377 PCT/USU1/42735 The racemic dihydrobenzoxathiin obtained from Example 82 (Step C) was resolved via chiral chromatography on a Chiralpak AD column, using 20% EtOH in hexane as the eluant. The fast moving isomer: +32.4'(c=1.36, MeOH).

The slow moving isomer: -31 .3(c=1.37, MeOH).

EXAMPLE PREPARATION OF

F

S

HOo 0 O,

N

The dihydrobenzoxathiin generated from Example 58 was desilylated using the procedure described in Example 71 (Step The desired product was obtained as a white solid. 'HNMR (500 MHz, CDCI 3 5 (ppm): 7.5-7.3 5H), 7.2-7.1 3H), 6.85 (2d, 4H), 6.68 2H), 6.55 2H), 5.55 1H), 5.04 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 After purification by silica gel chromatography with 3% MeOH/CH 2 Cl, the desired adduct was obtained.

Step C A mixture of the adduct (80mg, 0.144mmole), 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 3 solution and extracted by EtOAc. The organic layer was separated, dried over MgSO 4 and concentrated in vacuo to give the desired product. 'H NMR (500 MHz, CD30D) 6 (ppm): 7.20-7.02 3H), 6.92 (m, 4H), 6.78 2H), 6.30 2H), 5.55 J=2.1Hz, 4.50(d, J=2.3Hz, 1H), 4.06 (t, 2H), 2.78 2H), 2.55 (br s, 4H), 1.6 4H), 1,5 2H); MS m/z 467 (M -113- WO 02/32377 WO 0232377PCT/1JS01/42735 EXAM/PLE 91 PREPARATION OF HOA0 'x ND

D

Step A The cihydrobenzoxathiin generated from Example 59 was desilylated using the procedure described in Example 71 (Step The desired product was obtained as a white solid. 'H NMR (500 IMlHz. CDCI 3 5 (ppm): 7.5-7.3 (in, 511), 7.2-7.1 (in, 2H1), 6.95 2H), 6.90 11-1), 6.85 2H), 6.70 2H), 6.65 1H), 5.50 111), 5.04 211), 4.42 I H).

Step B The desilylated product obtained from Step A was coupled with 1-piperidineethanol using the procedure described in Example 71 (Step After purification by silica gel chromatography with 3% MeOH!CB12C 2 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. 'R NMR. (500 Mliz, CD-,OD) 6 (ppm): 7.14-7.02 (in, 3H1), 6.92 2H), 6.85 2H), 6.74 2HT), 6.58 111), 6.41 111), 5.52 J=2.3141z, tH), 4.55 J=2.3FHz, 1H). 4.06 2 2.78 2H), 2.55 (br s, 4H), 1.6 (in, 4H1), 1.5 (in, MIS mlz 483 (Mi-iI).

114- WO 02/32377 WO 0232377PCT/1JS01/42735 EXAMPLE 92 PREPARATION OF

OH

S

HO'6 0 0

N

StepA The dihydrobenzoxathiin, obtained from Example 60, was Coupled with Ipiperidineethanol Using the procedure described in Example 71 (Step After purification by silica gel chromatography with 3% MeOHICH 2

CI

2 the desired adduct was obtained. 1HNMR (500 MHz, CDCIk) 3 (ppm): 7.5-7.3 (in, 51N), 6.80 2H), 6.70 (2d, 6.60 2H), 6.40 (2d, 5.40 1H), 4.90 2H), 4.20 IH), 4.08 2H), 2.8 2H), 2.5 (br s, 4H), 1.62 (mn, 4H), 1.5 (mn, 2H), 1.22 (in, 3H). 1.1 18H).

Step B The adduct, generated in Step A. was dehenzylated using the procedlure described in Example 71 (Step B).

Step C The debenzylated product from Step B was desilylated using the procedure described in Example 71 (Step The desired product was obtained as a white solid. 'H NMR (500 MHz. CD 3 OD) 8 (ppmn): 6.93 3H), 6.78 2H), 6.69 2H), 6.50 2H).

6.28 (in, 5.46 Jkl.8Hz, JH), 4.39 J=2.2Hz, JH), 4.05 21H), 2.8 2H), 2. 6 (br s, 4H), 64 (in, 4H1), 1. 5 (in, 2HR); MS mlz 48 2.2 (W+L) 115 WO 02/32377 WO 0232377PCT/1JS01/42735 EXAMIPLE 93 PREPARATION 0 F C1

OH

S

HOJ 0O 0

N

Step A The dihydrobenzoxathiin. obtained from Example 61, was Coupled with Ipiperidinecthanol using the procedure described in Example 71, (Step After purification by silica gel chromatography with 3% MeOHICH-?Cl 2 the desired adduct was obtained. 1H1 NM (500 MHz, CDCI 3 6 (ppm): 7.5-7.3 (in, 5H), 6.85 (in, 311), 6.70 41H). 6.63 2H1), 6.60 5.42 1H), 5.02 2H), 4.40 1H), 4.08 2H), 2.8 2H), 2.5 (br s, 4H), 1.62 (mn, 411), 1.5 (in, 2H1), 1.22 (in, 3H), L.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 MiHz, CD 3 OD) 6 (ppm): 6.82 214), 6.78 6.70 (2d, 4H), 6.62 2H), 6.58 IH). 5.40 (d, 111), 4.30 (di, 1H), 4.06 211), 2.78 2H), 2.55 (br s, 4H1), 1.6 (in, 4H), 1.5 (mn, 211); MIS mlz 655 Step C The debenzylated product from Step B was desilylated using the procedure described in Example 7 t (Step The desired product was obtained as a white solid. 1H NMR (500 MHz, CD 3 OD) 8 (ppm): 6.92 2H), 6.75 2H), 6.68(d, 2H), 6.60 1,H), 6.50 2H), 6.42(d, IH), 5.49- J=2.2Hz, lH), 4.42 J=2.3Hz, 111), 4.07 2H), -2.78 2H), 2.55 (brs,, 41H), 1.62 4H), 1.48 (in, MS mlz 499 (M 116- WO 02/32377 PCT/USU1/42735 EXAMPLE 94 PREPARATION OF

OH

HO S Step A The dihydrobenzoxathiin, obtained from Example 62, was coupled with 1piperidineethanol using the procedure described in Example 71 (Step After purification by silica gel chromatography with 3% MeOH/CB 2 Cl2 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 in Example 71 (Step The desired product was obtained as a white solid after purification by silica gel chromatography with 5% MeOH/CHaCI as eluant. 'H NMR (500 MHz, acetone-d 6 5 (ppm): 7.04 2H), 6.90 (dd, 3H), 6.72 2H), 6.64 (d, 1H), 6.59 2H), 6.57(dd, IH), 5.44 J=2.3Hz, 1H), 4.52 J=2.1Hz, 1H), 4.08 (t, 2H), 2.8 2H), 2.62 (br s, 4H), 2.6 2H), 1.6 4H), 1.45 2H), 1.2 2H); MS m/z 465 (NM+1).

117- WO 02/32377 WO 0232377PCT/1JS01/42735 EXAMPLE PREPARATION OF

OH

Me S 'Stp A The dihydrobenzoxathiin, obtained from Example 63, was coupled with 1 piperidineethanol using the procedure described in Example 71 (Step After purification by silica gel chromatography with 301 MeOl-IJCH&-)l, the desired adduct was obtained.

Stop B The adduct, ,enerated 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 in Example 7.1 (Step The desired product was obtained as a white solid after puirification by silica gel chrom-atogra9phy with 5% MeOHICH 2 Cl 2 as eluant. 'HNMR (500 M~z, acetone-d 6 85 (ppm): 7.00 2H). 6.85 IH), 6.80 2H4), 6.78 2H4), 6.59 2H4), 6.52 114), 5.49 J=-2.3Hz, IH), 4.65(d, J=2.2Hz. IH). 4.08 214T), 2.8 2H), 2.62 (br s, 4H1), 2. 6 2H), 1.6 (in, 4H4), 1.45 (in, 2H), 1.2 2H); MS mIz 479 (M41+).

118- WO 02/32377 WO 0232377PCT/1JS01/42735 EXAMPLE 96 PREPARATION OF

OH

HO0 Step A The dihydrobenzoxathiin, obtained from Example 64, was coupled with 1piperidinecthanol using the procedure described in Example 71 (Step After Purification by silica gel chromatography with 3% MeOHICH 2

CI

2 the desired adduct was obtained. 1 HNMR (500 M.Hz, CDC1 3 6 (ppm): 7.5-7.3 (in, 5H), 7.20 I1Hf, 6.85 6.70 (2d, 414), 6.63 214), 6.60 5.42 IH), 5.02 2H), 4.30 1H), 4.08 2H), 2.8 214), 2.5 (br s, 4H), 1.62 (in, 4H), 1.5 (mn, 2H), 1.22 (m, 3H), 1. 1 1811).

Step B The adduIct, generated in Step A, was debenzylated using the procedure described in Example 71 (Step B) to afford the desired product. 'H NMR (500 MHz, acetone-d 6 8 (ppm): 7.10 114), 6.98 21-1), 6.82 214), 6.78 214), 6.70 2H), 6.68 (s, 114), 5.50 111), 4.50 1H), 4.06 211), 2.78 2H), 2.55 (br s, 4H4), 1.6 (1m, 4H), 214).

Step C The dcbenzylated product from Step B was desilylated Lusing the procedure described in Example 71 (Step The desired product was obtained as a white solid. 1H NMR (500 MHz, acetone-d 6 6 (ppm): 7.12 Cs, 7.02 2H), 6.80 (dd, 4H), 6.69 Cs.

6.60 214), 6.42 114), 5.55 J=2.3Hz, 1H), 4.54 J7:2.lIHz, IH), 4.07 (t, 214), 2.78 2H), 9.55 (brs, 414), 1.62 Cm, 4H), 1.48 II): MS ml/z 499 119- WO 02/32377 PCT/US01/42735 EXAMPLE 97 PREPARATION OF HOx S

N

Step A The dihydrobenzoxathiin generated from Example 65 was desilylated using the procedure described in Example 71 (Step The desired product was obtained as a white solid. 1H NMR (500 MHz, CDC13) (ppm): 7.5-7.3 5H), 7.2-7.1 6.95 3H), 6.64-6.70 2H), 5.46 J=1.8Hz, 1H), 5.04 2H), 4.42 (d, J=2.0Hz, IH).

Step B The desilylated product obtained from Step A was coupled with 1-piperidineethanol using the procedure described in Example 7 L (Step After purification by silica gel chromatography with 3% MeOH/CH 2 C1 2 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. 'I NMR (500 MHz, CD30D) (ppm: 7.00-7.12 6H), 6.90 2H), 6.75 2H), 6.42 1H), 5.42 J=2.1Hz, 1H), 4.48 J=2.3Hz, 1H), 4.06 2H), 2.78 2H), 2.55 (br s, 4H), 1.6 4H), 2H); MS m/z 463 (Ml+I).

120- WO 02/32377 WO 0232377PCT/1JS01/42735 EXAMPLE 98 PREPARATION OF HON. S Step A The dihydrobenzoxathiin generated from Example 66 was desilylated using- the procedure described in Example 71 (Step The desired product was obtained as a white solid. 1 H NMR (500 MHz, CDCl 3 6 (ppm): 7.5-7.3 (in, 5H), 7.2-7.1 (in, 3H), 6.95 2H), 6.92 2H), 6.90 IH), 6.78 IH), 6.70 2H), 5.52 f=2.1Hz, 111), 5.04 2H), 4.46 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 After purification by silica gel chromatography with 3% MeOH-/C1 2 ,C1 2 the desired adduct was obtained.

Step C The addUCt, generated in Step B, was debenzylated using the procedure described in Example 71t (Step B) to afford the desired product. 'H NMR (500 MI-z, CD 3 OD) 8 (ppm): 7.05-7.15 (in, 5H), 6.90 6.79 2H), 6.65 (di, J H)7 6.55 I 5.50 J=2. IHz, I 4.62 J=2.3Hz, I 4. 10 2H), 2.80 214), 2.60 (br s, 4H), 1. 6 (mn, 4H), t. 5 (in, 2H); MNS m/z 4 83 12)1 WO 02/32377 WO 0232377PCT/1JS01/42735 EXAMIPLE 99 PREPARATION OF HO S Step A The dihydrobenzoxathiin generated from Example 67 was desilylated using the procedure described in Example 71 (Step The desired product was obtained as a white solid. 1H NMR (500 MHz, CDCI 3 8 (ppm): 7.5-7.3 (in, 5B), 7.2-7.J (in, 3H), 7.08 111), 6.95 2H), 6.86 (in, 3H), 6.70 2H), 5.422 J=2.lHz, 111), 5.14 (s, 21H), 4.40 J=2.OHz, IH).

Step B The desilylated product obtained from Step A was coupled with 1-piperidineethanol using the procedure described in Example 71 (Step After purification by silica gel chromatography with 3% NMeORlCThCI0 2 the desired adduct was obtained.

step C The adduIct, generated in Step B, was debenzylated using the procedure described in Example 71 (Step B) to afford the desired product. 'HR NMR (500 MIHz, CD 3 OD) 8 (ppm): 7.05-7,15 (in, 314), 6.95 (in, 3H), 6.90 2H) 6.75 2H), 6.72 5.45 .1=2.0H-z, I1-H), 4.52 J=2.3Hz, 1H4), 4. 10 2H), 2.80 2H), 2.60 (br s, 4H), 1.6 (mn,4H), 1.5 (mn, 2HW MS iniz 483 (MW±1).

12) WO 02/32377 PCT/USU1/42735 EXAMPLE 100 PREPARATION OF HO,. S oN Step A The dihydrobenzoxathiin generated from Example 68 was desilylated using the procedure described in Example 71 (Step The desired product was obtained as a white solid. 'H NMR (500 MHz, CDC13) 8 (ppm): 7.5-7.3 5H), 7.2-7.1 3H), 6.92-6.80 5H), 6.78 2H), 6.70 2H), 5.40 J=2.1Hz, IH), 5.20 2H), 4.46 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 After purification by silica gel chromatography with 3% MeOH/CH2Cl2, the desired adduct was obtained.

Step 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) 6 (ppm): 7.05-7.15 3H), 6.95 2H1), 6.90 2H), 6.80 1H), 6.75 2H), 6.70 1H), 5.38 J=1.8Hz, 1H), 4.56 J-2.1Hz, 1H), 4.06 2H), 2.78 2H), 2.60 (br s, 4H), 1.6 4H), 1.5 2H); MS m/z 483 WO 02/32377 WO 0232377PCT/1JS01/42735 EXAMIPLE 101 CH-IRAL SEPARATION OF Cl HO_ S 0 0

N

The racemic dihydrobenzoxathiin obtained from Example 100 (Step C) was resolved via chiral chromatography on a Chiralpak AD column, using 20% IEtOLI in hexane as the eluant. The fast moving isomer: [ul 0 D= +26.09')(c=I.025, MeOH).

The slow moving isomer: -25.44'(c=0.95, MeOEQ.

EXAMPLE 102 PREPARATION OF

F

H 0 0 Step A The dihydrobenzoxathiin generated from Example 69 was desilylated usin- the procedure described in Example 7 1 (Step The desired product was obtained as a white solid. 'H NMR (500 M41z, CDCI 3 8 (ppm): 7.5-7.3 (in, 5H), 6.95 2H), 6.90(m, 3H), 6.85 (mn, 6.74 (dd, I 6.70 5.45 J=1.9Hz, I1-H), 5.05 (s, 21-1),4-35 J=?2IHz, lIT) 124 WO 02/32377 PCT/USU1/42735 Step B The desilylated product obtained from Step A was coupled with l-piperidineethanol using the procedure described in Example 71 (Step After purification by silica gel chromatography with 3% MeOHtCH2C12, the desired adduct was obtained, which was used without further purification.

Step C The adduct, generated in Step B, was debenzylated using the procedure described in Example 71 (Step B) to afford the desired product. 'H NMR (500 MHz, CD30D) 8 (ppm): 6.98 2H), 6.94 2H), 6.80 5H), 6.60 IH), 6.75 (dd, IH), 5.40 (d, J=1.8Hz, 1H), 4.50 J=2.1Hz, 1H), 4.08 2H), 2.78 2H), 2.60 (br s, 4H), 1.6 4H), 1.5 2H); MS m/z 466 (M1+1).

EXAMPLE 103 CHIRAL PREPARATION OF HO S H,, m01-1 isomer Step A The fast moving (+)-dihydrobenzoxathiin obtained from Example 70 was coupled with 1-piperidineethanol using the procedure described in Example 71 (Step After purification by silica gel chromatography with 3% MeOH/CH 2 CI, the desired adduct was obtained.

125 WO 02/32377 WO 0232377PCT/1JS01/42735 Step B The adduct, ,en1erated in Step A, was debenzylated using the procedure described in Example 71 (Step B).

Step C The debenizylated product from Step LB was desilylated using the procedure described in Example 71 (Step CQ. The desired product was obtained as a white solid after Purification by silica gel chromatography with 5% MeOHICH 2

C]

2 as eluant. 'H -NMR (500 MHz, acetone-d 6 8 (ppm): 6.90 2H), 6.78 IFI). 6.72 2H), 6-70 (dI, 2H), 6.60 111), 6.50 1H), 6.48 2H), 5.38 J=2.0Hz, 1H), 4.38 J=2.3Hz, 111), 4.08 2H), 2.8 211, 2.62 (br s, 4H), 2.6 2H1), 1.6 (in, 4H), 1.45 21-1), 1.2 (t, 2H), MS mlz 465 Lc'io= MeOH).

EXAMPLE 104 CHIRAL PREPARATION OF

OH

HOC(S

0

N

0 (0 isomer Step A The slow moving (-)-dihydrobenzoxathiin obtained from Example 70 was coupled with 1-piperidineethanol using the procedure described in Example 71 (Step After purification by silica gel chromatography with 3% MeOHICH C12, the desired adduct was obtained.

-126 WO 02/32377 PCT/USU1/42735 StepB 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 in Example 71 (Step The desired product was obtained as a white solid after purification by silica gel chromatography with 5% MeOH/CH 2

CI

2 as eluant. 'H NMR (500 MHz, acetone-d.) 6 (ppm): 6.90 2H), 6.78 1H), 6.72 2H). 6.70 2H), 6.60 1H), 6.50 IH), 6.48 2H), 5.38 J=2.0Hz, 1H), 4.38 J=2.3Hz, 1H), 4.08 2H), 2.8 2H), 2.62 (br s, 4H), 2.6 2H), 1.6 4H), 1.45 2H), 1.2 (t, 2H); MS m/z 465 (M 4 -26.33°(c=0.515, MeOH).

EXAMPLE 105 GENERAL PREPARATION OF HO S OHO O OK N 0 Step A: Reductive Cyclization To a stirred solution of 102.2mg (0.17mmole) of the cyclopentyl-thio-ketone generated in Example 41 in ImL of dichloromethane at -23 0 C under an N, atmosphere was added 68pL (0.087mmole) of neat trifluoroacetic acid(TFA). To the stirred reaction mixture at -23 0 C was slowly added 41.4|tL (0.259mmole) of neat triethylsilane and the resulting mixture was stirred further for three hours. The reaction mixture was partitioned between ethyl acetate/saturated NaHCO 3 /ice/ 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/hexanes(l: 1) as eluant to provide the cs- 127- WO 02/32377 WO 0232377PCT/1JS01/42735 cyclopentyl-dihyclr-obenzooxaithiin derivativye. 'H 500MVI-z >NMR(CDCI 3 ppm(6): 112 I 1.26-2,12 (in, 12H), 2.5 (in, I 4.24 I1-H), 4.9 (in, 2HW) 6.3-7.69 (i-n7 12H).

with the cyclohcxyl derivative prepared in Example 41, and uitilizing the above procedure the corresponding cis-cyclohexyl-benzooxathiin was prepared after purification by silica gel chromatography using mnethylene chloride-hexanes(1:1). IH 500MHz NMR(CDCI 3 ppm(6): 1.14 l8HI), 1.1 1-1.9(in, 14H), 3.2 (L1B 5.03 (s, 5.44 k=.5Hz, IHM, 6.66-7.47 (in, [2H).

Step B: Des ilylation To a stirred solution of 89.6mg (0.lS6inmole) of the cis-cyclopentyl derivative prepared in Step A above in lmL of THF at 0OT was added sequentially 13.31tL (0.234minole) of acetic acid and then 17111L (0.17Iminole) of a IM solution of tetrabutylammoniUM fluoride in THEF. The mixture was stirred at 0 "C For 0.5 hour and then partitioned between ethyl acetate/2N UCI/ice/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 inethylene chloride-ethyl acetate (50:1) as eluant to provide the phenolic derivative. 'H 500MIz

NMR(CDCI

3 ppm(6): 1.32-1.94 (in, 9H), 3.51t (dd, J=5,5, 2.5Hz, IH), 5.03 2H), 5.42 Jz--23Hz, IH). 6.67-7.47 (mn, 12B).

Starting with the cyclohexyl derivative prepared in the previous example and utilizing the above procedure the corresponding cis-cyclohexyl-benzooxathiin phenol was prepared. 'H 500MHz NMR(CDCI3) ppin(a)-1.11-1.93(in, IIH), 3.23 J=3Bz, IH), 5.03 2H), 5.44 J=2.3Hz, IH), 6.66-7.47 (in, 12H).

Step C: NMitsunobU reaction To a stirred Solution of a mixture of 56.3mg 135mmole) of the cis-cyclopentyl derivative prepared in Step B above, 53.6ltL (0.4O4inmole) of 1-piperidineethanol, and 123.5img (0.47mmole) of triphenyiphosphine in lInL of anhydr~ous TI-F at 0 0

C

was added 87.4 (tL (0.444mmole) of neat diisopropylazodicarboxylate (DIAD). The ice-water bath was removed and the Mixture Was stirred further for six hours. The WO 02/32377 WO 0232377PCT/IJSO1/42735 mixture was partitioned between ethyl acetate/2N HCI/ice/ brine, and the oi-oanic phase was separated, washed with brine, dried over anhydrous sodium SUlMAe, Filtered, and evaporated. The residue was Purified by silica gel chromatography using ethyl acetate-methanol(9: 1) ais eluant to provide the adduct. 'H 500MIHz NMR(CDC1 3 ppm(6): 1.33-2.0 (in, 15H), 2.56 4H). 2.82 J=6Hz, 2HR), 3.51 (dd, 2.4H-z, I 4- 16 1=-6Hz, 2H), 5.02 2H4), 5.42 J=2.3Hz, IH), 6.66-7.46 (in, 12H).

Starting, with the cyclohoxyl derivative pr-epared in the previous example and utilizing the above procedure the corresponding cis-cyclohexyl-benzoexathiin adduct was prepared. 'H 500NMz NNMCDCI 3 ppm(§):1.11-1.93 (in, 17H), 2.6 (in, 4H), 2.87 (mn, 2H4), 3.2 1=2.51-1z, IH). 4.2 (in, 2H), 5.02 2H), 5.44 J=2.lHz, IH), 6.65- 7.46 (in, 12H).

Step D: Debenzylation: A stirred mixture of 36.6mg (0.OO69mmole) of the cis-cyclopentyl derivative prepared in Step C above, 1 4 .7mg (0.Ol4mmole) of palladium black, and 87.1mg, (0.l138mmole) of ammonium formate in 2mL of ethanol-ethyl acetate-water(7:2: 1) was heated at 80 0 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 elant to provide the final product. 1 H- 500M~z NMR(CDCl 3 ppm(8):1.33-2.0 (mn, 15H). 2.6 (mn. 4H), 2.88 (mn, 2H), 3.48 J1=2.3Hz, IH), 4.18 (in, 2H), 5.38 J=2.3Hz. 1H). (in, IF). 6.63 2.9Hz, IH) 6.74 1=8.7Hz, IH). 6.89 J=8.7Hz, 2H), and 7.34 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. fiH500Miz NMR(CDCI 3 ppm(8):I.00-t.90 (i,18IH), 2.6(in, 2.81 2H), 3.19 J=3.0 Hz, IH), 4. 18 (mn, 2H), 5.38 1=2.3Hz, I1H), 6.43 (mn. I 6.62 1= 3.0 Hz. 6.68 J=8.7 Hz, 111), 6.87 J=8.7 Hz, 2 and 7.34 f=8.7 Hz, 2H) MIS m/z 454 [,19 WO 02/32377 PCT/USU1/42735 EXAMPLE 106 PREPARATION OF HO S 0 0 ON Step A: Reductive Cyclization Starting with the isopropyl adduct (0.0208 g, 0.049 mmol) prepared in Example 42 and utilizing the procedure outlined in Example 105 (Step the crude product was isolated after stirring at -23 °C for 6 h 20 min. Purification by silica gel chromatography with 30% EtOAc/hexane as the eluant afforded the desired product as a yellow oil. 'H 500MHz NMR(CDCI3) ppm(6): 0.95 3H), 0.98 3H), 1.95 LH), 3.30 J=3 Hz, 1H), 5.03 2H), 5.42 J=2.6 Hz, IH), 6.66-7.47 (m, 12H).

Step B: Mitsunobu reaction The dihydrobenzoxathiin prepared in Step A above was coupled with 1piperidineethanol using the procedure described in Example 105 (Step C) with the exception that the reaction was allowed to slowly warm from 0 OC to ambient temperature over 3.5 h. Purification by silica gel chromatography with MeOH/CH 2

CI

2 as the eluant afforded the desired product as a pale yellow oil. 'H 500MHz NMR(CDCI3) ppm(8): 0.95 3H). 0.98 3H), 1.50-1.68 6H), 1.95 2.60 4H), 2.86 2H), 3.30 J=3 Hz, 1H), 4.20 2H), 5.03 2H), 5.42 J=2.6 Hz, IH), 6.66-7.49 12H).

Step C: Debenzvlation Starting with the compound prepared in Step B above, and utilizing the procedure outlined in Example 105 (Step the corresponding cis-isopropyl-benzoxathiin adduct was prepared after silica gel chromatography with 10% MeOH/CH2C2 as the 130- WO 02/32377 PCT/USU1/42735 eluant. 'H 500MIHz NMR(CDCl3) ppm(6): 0.95 3H), 0.98 3H), 1.50-1.68 (in, 6H), 1.95 1H), 2.60 4H), 2.86 2H), 3.26 J=3.0 Hz, 11-1), 4.20 2H), 5.37 J=2.5 Hz, 1H), 6.47 (dd, 1H), 6.65 J=3 Hz, 1H), 6.72 J=8.6 Hz, 2H), and 7.35 J=8.7 Hz. 2H); MS m/z 414 EXAMPLE 107 PREPARATION OF

S

H O, S 0 Step A: Reductive Cyclization Starting with the 2-thiophene adduct (0.0208 g, .049 mmol) prepared in Example 43 and slightly modifying the procedure outlined in Example 105 (Step the crude product was isolated after stirring at 0 C to ambient temperature for 1 h 40 min.

Purification by silica gel chromatography with 30% EtOAc/hexane as the eluant afforded the desired product as a red oil. 1H 500MHz NMR(CDC1 3 ppm(8):l.ll (d, 18H), 1.24 3H), 4.67 J=2.0 Hz, 1H), 5.50 J=1.8 Hz, 1H), 6.60-7.12 (m, 101).

Step B: Protection with MOM To a solution of the didhydrobenzoxathiin (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.L9 mmol) at 0 C under N 2 After the gas evolution had ceased, MOMC1 (0.013 mL, 0.16 mmol) was added dropwise to the reaction. After 30 min., another 1.3 equivalents of MOMCI 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/HO 2 The organic layer was washed with brine, dried over Na 2

SO

4 and concentrated in vacuo. The desired product was used in the next reaction without purification. 'H 500MHz NMR(CDCI3) ppm(8):l.ll 18H), 1.24 3H), 3.52 (s, 131 WO 02/32377 PCT/USU1/42735 3H), 4.67 (dc, J2.1 Hz, 1H), 5.14 2H), 5.50 J=1.8 Hz, IH), 6.60-7.12 (m, Step C: Desilylation 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.

H 500MHz NMR(CDC13) ppm(S): 3.52 3H), 4.69 J=1.8 Hz, IH), 5.15 (m, 2H), 5.51 J=1.8 Hz, 1H), 6.60-7.1.5 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 oC 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% EtOAc/hexane followed by a second elution with 10% MeOH/CH 2 C1 2 'H 500MHz NMR(CDCI 3 ppm(8): 1.40-2.60 2.79 2H), 3.52 3H), 4.10 2H), 4.69 J= .8 Hz, 1H), 5.15 2H), 5.51 (d, J=1.8 Hz, IH), 6.60-7.15 Step E: Deprotection of MOM A mixture of the material (0.0401 g, 0.080 mmol) prepared in Step D above and 2 N HCI (0.20 mL, 0.40 mmol) in MeOH (1.0 mL) was heated to 60 °C under N 2 for 2.5 h.

The reaction was partitioned between EtOAc and ice/sat. NaHCO 3 The organic layer was washed with brine, dried over Na 2

SO

4 and concentrated in vacuo. The residue was triturated with EtzO and desired product was obtained as a white solid. 'H 500MHz NMR(d 6 -acetone CD 3 OD) ppm(8): 1.50-3.19 I0H), 3.23 2H), 4.30 2H), 5.00 J=1.8 Hz, 1H), 5.51 J=.8 Hz, 1H), 6.57-7.25 1OH); MS m/z 454 132- WO 02/32377 PCT/USU1/42735 EXAMPLE 108 PREPARATION OF HO\ S N NO N Step A: Reductive Cyclization Following the procedure outlined in Example 44, 0.0792 g of the 3-pyridyl derivative prepared in Example 41 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 chromatography using 30% EtOAc/hexane as the eluant. 'H 500MHz NMR(CDCl 3 ppm(8):l. 1 18H), 1.24 3H), 4.36 J=2.1 Hz, 1H), 5.05 2H), 5.50 J=1.6 Hz, 1H), 6.77-8.43 16H).

Step B: Desilylation Following the procedure outlined in Example 105 (Step the dihydrobenzoxathiin generated in Step A above was desilylated to afford the desired product after silica gel chromatography (one elution with 50% EtOAc/hexane followed by a second elution with 30% EtOAc/hexane). 'H 500MHz NMR(CDCI 3 ppm(8): 4.42 J=2.1 Hz, IH), 5.07 2H), 5.50 J=1.6 Hz, 1H), 6.77-8.43 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 4 h, the material prepared in the previous step was converted to the desired product after silica gel chromatography using 10% MeOH/CH 2

CI

2 as the eluant. 'H 500MHz NMR(CDCI 3 ppm(S): 1.40-2.60 10H), 2.80 2H), 4.10 2H), 4.38 J=1.8 Hz, 1H), 5.07 (s, 2H), 5.50 J=1.8 Hz, IH), 6.77-8.43 16H).

133 WO 02/32377 PCT/USU1/42735 Step D: Debenzylation Starting with the material prepared in Step C above, and utilizing the proccdure outlined in Example 105 (Step the corresponding cis-3-pyridyldihydrobenzoxathiin adduct was prepared after silica gel chromatography with MeOH/CH 2

CI

2 as the eluant. H 500MHz NMR(CDCI3) ppm(6):1.40-2.60 2.80 2H), 4.10 2H), 4.36 J=2.1 Hz, IH), 5.45 J=1.9 Hz, 1H), 6.59-8.43 I MS m/z 449 [M EXAMPLE 109 PREPARATION OF HO S O N Step A: Reductive Cyclization 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 stirring at ambient temperature for 30 h. The desired product was isolated from the reaction mixture after silica gel chromatography using 30% EtOAc/hexane as the eluant. 'H 500MHz NMR(CDCI1) ppm(8):1.ll 18H), 1.24 3H), 4.32 1H), 5.08 2H), 5.50 1H), 6.60-8.39 16H).

Step B: Desilvlation Following the procedure outlined in Example 105 (Step the dihydrobenzoxathiin generated in Step A above was desilylated to afford the desired product after silica gel chromatography (one elution with 50%/ EtOAc/hexane followed by a second elution with 30% EtOAc/hexane). 'H 500MHz NMR(CDCI 3 ppm(8): 4.33 1H), 5.07 (s, 2H), 5.46 IH), 6.63-8.37 16H).

Step C: Mitsunobu reaction 134- WO 02/32377 WO 0232377PCT/1JS01/42735 Following the procedure detailed in Example 105 (Step CQ with the exception that thle reaction Was allowed to warm from 0 "C to ambient temperature over 5 h, the material prepared InI thle previous step was converted to the desired product after silica gel chromatography (one elution with 10% MeOl-ICH-)CI followed by a second elation with 20% EtOAcICH 2

CI

2 'H 500MHz NMR(C-DCI 3 ppm(6): 1.40-2.60 (in, 2.80 2ff), 4.14 2H), 4.32 J=3.0 Hz, 11-1), 5.06 2H), 5.49 J-2 1IHz, IH), 6.79-8.38 (in, 16H).

Step D: Debenzylation Starting, with the material prepared in Step C above, and utilizing the procedure outlined in Example 105 (Step the desired Product was obtained as a 4:1 cis/trans mixture after silica gel chromatography (IX elution with 30% EtOAc/hexane followed by a second elution with 10% MeOH/CH 2 -Cl 2 Cis isomer: 'H 5OM~z NMR(CDCi~) ppm(6):1.40-2.70 10-H), 2.80 2H), 4. 2H), 4.30 J=2.0 Hz, IFH), 5.44 J=1.8 Hiz, 1H), 6.59-8.40 (in, 111H).

Trans isomer: IH 500MHz NMR(CDCI 3 pprn(6):1.40-2.70 (in, 10H), 2.80 Ct. 2H), 4.1,5 2H), 4.38 1=8.7 Hz, IH), 4.92 J=8.7 ]Hz, 1H), 6.59-3.46 (in, I lH); MS rn/z 449 EXAMPLE 110 PREPARATION OF HO S 00 Step A: Reduction To a stirred solution of 2 65 .Img (0.449mmole) of the cyclopentyl-thio-ketone generated in Example 41 in 3mL of methanol -di chlIoromethanc(1: 1) at 0 'C to r-oom temperature was added portion-wise Sufficient sodium borohydride to complete the reduction. The reaction mixture was partitioned between ethyl acetate/2N HCI/ice/ WO 02/32377 PCT/USU1/42735 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: Cyclization A mixture of 266mg (0.449mmole) of the crude product, prepared in Step A above, and 89mg of amberlyst 15 in 3mL of toluene was stirred at ambient temperature for two hours. The resin was removed by filtration and washed well with ethyl acetate.

The filtrate was evaporated and the residue obtained was purified by silica gel chromatography using dichloromethane-hexanes(l:l) as eluant to provide the transdihydro-benzoxathiin derivative. 1 H 500MHz NMR(CDCl 3 ppm( 8 ):l.13 18H), 1.26-1.94 12H), 3.64 (dd, J=7.8Hz, 5.5Hz, 1H), 4.78 J=7.8Hz, 1H), 5.02 (s, 2H), 6.6-7.45 12H).

Step C: Desilylation Following 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 corresponding phenol.

Step D: Mitsunobu reaction Following the procedure detailed in Step C of Example 105, the material prepared in the previous step was converted to the corresponding trons-cyclopentyldihydrobenzoxathiin adduct. 'H 500MHz NMR(CDCl 3 ppm( 8 ):1.39-2.0 2.6 4H), 2.88 2H), 3.66 (dd, J=7.8Hz, 5.5Hz, 1H), 4.21 2H), 4.81 (t, J=7.8Hz, 2H), 5.01 2H), 6.64-7.49 12H).

Step E: Debenzylation Following the procedure detailed in Step D of Example 105, the material prepared in the previous step was converted to the corresponding trans-cyclopentyldihydrobenzoxathiin product. 'H 500MHz NMR(CDCl 3 ppm(6): 1.29-2.0 2.6 4H), 2.88 2H), 3.67 (dd, J=8Hz, 5Hz, IH), 4.18 2H), 4.77 J=8Hz, 2H), 6.5 (dd. J= 2.7Hz, 8.7Hz, 1H), 6.65 2.7Hz, 6.77 J=8.7Hz, 1H), 6.88 J=7.5Hz, 2H), and 7.27 J=7.5Hz, 2H).

WO 02/32377 WO 0232377PCT/1JS01/42735 EXAMvPLE I1I1 GENERAL, PREPARATION OF HO 0 Steps A and B: Reduction and Cyclization Utilizing the thio-ketones prepared in Example 39 and employing the procedures ou~tlined above in Step A and B of Example 110, the following compounds were prepared: Traizs-cyclohexvl derivative: 'H 500MHz NMRECDCI 3 PPM(b): 1.14 1811). 0.98- 1.8 (rn, 14H), 3.37 (dd, Jz-5ffz, 8.111z, 1H1), 5.01 2H), 5.05 J=8.lHz, 1H), 6.6- 7.44 (in, 12H1).

Trans-cyclopentyl derivative: 'H 500MHz NMR(CDCl 3 ppm(5): 1.14 18H), 1.28- 1.9 (in, 12H), 4.53 (in, 1H), 4.93 5.01 2H), 6.6-7.43 (in, 12H).

Step C: Desilylation Utilizing the trans-dihydrobenzoxathi iins prepared in the previous step and employing the procedure Outlined above in Step B of Example 105, the following compounds were prepared: Trans-cyclohexyl phenol: 'H 500M~z NMR(CDCI 3 ppm(5):tL0- 1-8 (Mn, II1H), 3.3 (in, I1H), 5.05 2H), 5.1 1H1), 6.6-7.44 (in, 1211).

Trans-cyclopentyl phenol: 'H500MHz NMR(CDCI, 3 ppm(6)I 129-.0 (in, 911). 3.55 (dd, J=5.7Hz, 7.6Hz, 1H), 4.95 J=7.6Hz, 1H1), 5.02 211), 6.6-7.45 (mn, 12H-).

137 WO 02/32377 WO 0232377PCT/1JS01/42735 Step D: MitSUnobU reaction: Utilizing the tu-cmus,-dihydobenzoxaithiiin phenols prepared in the p-eViouIs step and employing the pr-ocedUreC Outlined above in Step C of Example 105, the following Compounds were prepared: Trans-cyclohexyl adduct: H1 -500MHz, NMR(CDCI 3 PPM(8): 1.0-1l.8 (in, 17H), 2.58 4H), 2.84 (in, 2H), 3.37 I 4.17 J=6Hz, 2H), 5.0 2H), 5.08 (d, J=7.81-Iz, 6.6-7.43 t2H).

Traits-eye Iopen tyl adduct: HB 500M~z NMR(CDCI 3 ppm(6):1.29-2.0 (in, 151-), 2.58 411), 2.84 (1m, 2H), 3.55 111), 4.17 21-1), 4.94 J=7.3Hz, 111), 5.0 211).

6.6-7.72 12H).

Step E: Dehenzvtation: Utilizing the trans-dlihydrobenzoxathiiin adducts prepared in the previouIs step and employing the procedure outlined above in Step D of lExample 105, the following compounds were prepared: Trans-cyclohexyl adduct: 1H 500MHz NMR(CDCl 3 ppm(8):1.-0-Lt8 (in, 17H), 2.58 4H1), 2.86 2H), 3.33 1H), 4.16 Cm, 2H1), 5.08 Jz-7.8HT-z, 11-1), 6.4-7.23 (m,7H).

Trans-cyclopentyl adduct: H1 50014Hz NMR(CDCI 2 ppm(8): 1.29-2.0 (mn, 1,5H), 2.68 (in, 411), 2.94 2H1), 3.51 1H), 4.2 (in, 2W), 4.95 J=7.4Hz, IH), 6.45-7.31 7H).

EXAMPLE 112 PREPARATION OF HO S 0ND 138 WO 02/32377 PCT/USU1/42735 Step A: Silylation To a stirred solution of the isopropyl-thio-ketone (0.0395 g, 0.097 mmol) generated in Example 42 in distilled THF (1 mL) at 0 0 C was added 60% NaH in mineral oil (0.0183 g, 0.20 mmol) Followed by TIPSCI (0.048 mL, 0.22 mmol). After 35 min., another equivalent of TIPSCI was added to drive the reaction to completion. The reaction was partitioned between EtOAc and ice/H 2 0, and the organic layer was washed with brine, dried over Na 2

SO

4 and concentrated in vacuo to afford the desired product. The crude material was used in the next step without further purification.

Step B: Reduction To a solution of the crude product (0.097 mmol) prepared in Step A above in distilled THF (1 mL) was added a 1 M solution of super-hydride in THF (0.15 mL, 0.15 mmol) at 0 C under N 2 The reaction mixture was stirred for 20 min. before partitioning between EtOAc and ice/H 2 0. The organic layer was further washed with brine, dried over Na 2

SO

4 and concentrated in vacuo to give the desired product. The crude material was used in the next step without further purification. 'H 500MHz NMR(CDCl3) ppm(6): 0.90-1.40 49H), 1.69 1H), 3.10 (dd, 1H), 4.60 1H), 5.05 2 6.70-7.50 12H).

Step C: Desilylation 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 OC under N2 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 ice/sat. NaHCO>. The organic layer was washed with brine, dried over Na2SO 4 and concentrated in vacuo. Purification by silica gel chromatography using 40% EtOAc/hexane as the eluant afforded the desired product as a yellow foam. 'H 500MHz NMR(CDCI 3 ppm(5): 0.92 3H), 0.98 3H), 1.59 2.86 (dd, 1H), 4.62 IH), 5.02 2 6.77-7.45 (m, 12H).

Step D: Cyclization Following the procedure outlined in Example 110 (Step the material (0.0366 g, 0.089 mmol) generated in the previous step was converted to its corresponding transdihydrobenzoxathiin after stirring for 5 h 15 min. at ambient temperature.

139- WO 02/32377 WO 0232377PCT/1JS01/42735 Pur-ification by silica gel chromatography Using 30% EtOAc/hexane as the eluant afforded the desired product as a white solid. 1H 500MHz NMR(CDC13) ppm(6): 0.98 31-1), 1.03 3H), 1.78 (in, 3.57 (dd, .1H3,7 Hz, Jz-8,5 Hz, 11-4), 4.32 (d, J=8.4 Hz, Ili), 5.02 2 6.63-7.46 (mn, 12h).

Step E: Mitsunobu reaction Following the procedure detailed in Example 105 (Step the material (0.0266 g, 0.068 mmol) generated in the previous step was converted to its corresponding trilsisopropyl-dihydrobenzoxathiin addUct after warming from 0 0 C to ambient temperature over 4 h 20 min. Purification by silica gel chromatography (one elution with 10% MeOHIVCH 2

CI

2 followed by a second elution with 30% EtOAc/hexane) afforded the desired product as a white solid. 'H 500MHz NMR(CDCI 3 ppm(6): 0.98 3H), 1.02 3H), 1.29-1.67 (in, 6H), 1.78 (in, l14), 2.58 (in, 4H), 2.85 (t, 2H), 3.57 (dd, J=3.7 Hiz, J=8.5 Hz, 111), 4.18 2H), 4.83 J=8.4 Hz, 111), 5.02 (s.

2 6.63-7.46 12H).

Step F: Debenzylation Following the procedure detailed in Example 105 (Step the material (0.0395 g, 0.068 inmol) generated in the previous step was converted to its coITesponding lransisopr-opyl-dihydrobenzoxathiin product. Purification was accomplished by silica gel chromatography u~sing 10% MeOH1CH 2

CI

2 as the eluant. 'H500MHz NMR(CDCI3) ppm(6): 0.98 3H), 1.02 31-1), J.29-1.67 (in, 601), 1-78 (in, IH), 2.58 4H), 2.85 2H), 3.57 Cdd, J=3.7 Hz, J=8.5 Hz, 1H), 4.18 2H), 4.83 J=8.4 Hz, 1,H), 6,48-7.29 (in, 7H); MIS mn/z 414 (MAD.

EXAMPLE 113 PREPARATION OF

S

No -140- WO 02/32377 PCT/USU1/42735 Step A: Silylation Following the procedure outlined in Example 112 (Step the isopropyl-thio-ketone (0.6314 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 product as a yellow oil. H 500MHz NMR(CDCl 3 ppm(a): 0.98-1.30 49H), 2.35 1H), 4.38 IH), 4.99 2H), 6.33-7.79 12H).

Step B: Reduction Following the procedure outlined in Example 112 (Step 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(CDC13) ppm(s): 0.98-1.30 49H), 1.90 1H), 2.92 (dd, 1H), 4.59 1H), 5.05 2 6.47- 7.43 12H).

Step C: Desilylation Following the procedure outlined in Example 112 (Step the material (0.022 mmol) isolated in Step B above was deprotected to afford the desired product which was used in the next step without purification.

Step D: Cvclization Following the procedure outlined in Example 110 (Step the material generated in the previous step was converted to its corresponding trcias-dihydrobenzoxathiin after stirring for 22 h at ambient temperature. Purification by silica gel chromatography using 30% EtOAc/hexane as the cluant afforded the desired product as a colorless oil.

'H 500MHz NMR(CDCl 3 ppm(5): 0.98 3H), 1.03 3H). 1.79 1H), 3.45 (dd, IH), 4.98 IH), 5.02 2 6.59-7.46 12H); MS m/z 393 (M 4 Step E: Mitsunobu reaction Following the procedure detailed in Example 105 (Step the material (0.008 g, 0.020 mmol) generated in the previous step was converted to its corresponding transisopropyl-dihydrobenzoxathiin adduct after warming from 0 OC to ambient temperature over 6 h. Purification by silica gel chromatography using MeOH/CHaCl as the eluant afforded the desired product as a pale yellow oil. 'H 141 WO 02/32377 WO 0232377PCT/1JS01/42735 500Ml-z NMR(CDCI 3 PPM(6): 0.98 02 3H), 1.29-1.67 (in, 6H), 1.79 (mn, 2.58 (in, 2.81 3.50 (dd, J=3.8 1Hz, J=8.3 Hz. 4.18 2141), 4.97 J=8,2 Hz, IH), 5.01 2 6.59-7.46 (mn, 12H).

Step F: Debenzvlation Following the procedure detailed in Example 105 (Step the material (0.0085 g 0.0 17 mmol) generated in the previous step was converted to its corresponding tranisisopropyl-dihvdrobenzoxathiin prodUCt. Purification was accomplished by silica gel chromatography using 10% MeO/CH 2 CI, as the eluant. 'H 500MHz NMR(CDCl 3 ppm(6): 0.98 3H1), 1.02 3H), 1 .49-1.70 (in, 611), 1.75 (in, IH), 2.61 (in. 4H), 2.85 211), 3.41 (dd, J='3.8 Hz, J=8.3 Hz, 4.18 (t7 2H), 4.96 J=8.2 Hz, 6.43-7.26 (in, 711); MS in/z 414 EXAMPLE 11.4 PREPARATION OF

OTIPS

0

S

HO"

HS-

Following the procedure outlined in Example 16 and using 0.36g (2.Sminole) of 1,2benzenedithiol, purchased from Aldrich, 221mg (ca 20%11, impure) of desired product was obtained after silica gel chromatography Lising EtOAc/hexane as eluant.

EXAMPLE 115 PREPARATION OF 142 WO 02/32377 PCT/USU1/42735 OTPS OTIPS

OTIPS

S 'N IOH OH "OH A B C Utilizing the procedure from Example 44, 121mg of a mixture of three products (A B C 1 0.1 0.25) was isolated after purification by silica gel chromatography with 10% EtOAc/hexane.

EXAMPLE 116 PREPARATION OF OH OH S\ S S 'N S 'N O^ A TFA B TFA Step A The :hiin obtained from Example xx was coupled with 1-piperidineethanol using the procedure described in Example 71 (Step After purification by silica gel chromatography using 3% MeOHI-I/CH:C as eluant, the desired adducts were obtained as a mixture.

Ste B The adducts from Step A were desilylated using the procedure described in Example 71 (Step The desired product A was separated by HPLC (Meta Chem Polaris C 184.6x50, 5 micron: gradient 5 to 75% of acetonitrile on Reverse Phase Column) as a white solid. A: 'H NMR (400 MHz, CDOD) 6 (ppm):7.2 2H), 7.1 2H), 6.9 143 WO 02/32377 PCT/USU1/42735 2H), 6.8 4H), 6.55 2H), 4.75 2H), 4.3 2H), 3.6 (br d, 2H), 3.5 (m, 2H), 3.0 (br t, 2H), 1.95 2H), 1.8 4H); MS m/z 464 (M B: 'H NMR (400 MHz, CD 3 OD) 8 (ppm): 7.4 2H), 7.3 2H), 7.1 2H), 6.95 2H), 6.8 2H), 6,6 2H), 4.3 (br t, 2H), 3.6 (br d, 2H), 3.5 (br t, 2H), 3.05 (br t, 2H), (br d, 2H), 1.8 4H); MS m/z 462 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-a and ER-3 proteins are produced in a bacculoviral expression system. ER-a or ER-P extracts are diluted 1:400 in phosphate buffered saline containing 6 mM a-monothiolglycerol.

200 ptL aliquots of the diluted receptor preparation are added to each well of a 96-well Flashplate. Plates are covered with Saran Wrap and incubated at 4 C overnight.

The following morning, a 20 ul aliquot of phosphate buffered saline containing 10% bovine serum albumin is added to each well of the 96 well plate and allowed to incubate at 4 0 C for 2 hours. Then the plates are washed with 200 ul of buffer containing 20 mM Tris (pH 1 mM EDTA, 10% Glycerol, 50 mM KC1, and 6 mM ca-monothiolglycerol. To set up the assay in these receptor coated plates, add 178 ul of the same buffer to each well of the 96 well plate. Then add 20 ul of a 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% DMSO at 100X the final concentration desired for testing in the assay. The amount of DMSO in the test wells of the 96 well plate should not exceed The final addition to the assay plate is a 2 ul aliquot of the test compound which has been made up in 100% DMSO. Seal the plates and allow them to equilibrate at room temperature for 3 hours. Count the plates in a scintillation counter equipped for counting 96 well plates.

144 WO 02/32377 PCT/USU1/42735 Ovariectomized Rat Assay In the ovariectomized (OVX) Rat Assay, estrogen-deficiency is used to induce cancellous osteopenia low bone mineral density [BMD; mg/cm2]), associated with accelerated bone resorption and formation. Both the BMD and bone resorption/formation outcomes are used to model the changes in bone that occur as women pass through menopause. The OVX Rat Assay is the principal in vivo assay used by all major academic and industrial laboratories studying the efficacy of new chemical entities in preventing estrogen-deficiency bone loss.

Sprague-Dawley female rats aged 6-8 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 or 17-13-estradiol-treated (.004 mg/kg 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 calcein (8 mg/kg by subcutaneous injection), a bone seeking fluorochrome, 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 metaphysis, a region that contains about 20% 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 absorptiometry (DXA, Hologic 4500A; Waltham, MA). For bone resorption, the endpoint is urinary deoxypyridinoline 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 mineralizing suLrface and mineral apposition rate, histomorphometric measures of osteoblast number and activity. This measurement is done on 51m sections of the non-decalcified proximal tibial metaphysis, using a semiautomated system (Bioquant; R&M Biometrics; Nashville, TN). Similar endpoints and measuring techniques for each endpoint are commonly used in postmenopausal women.

145- WO 02/32377 PCT/USU1/42735 Rat Cholesterol Lowering Assay Sprague-Dawley rats (5 per group) weighing about 250g were subculaneously dosed with compounds of the present invention dissolved in propylene glycol for 4 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 Estrogen 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 10%. 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 referred to as Estrogen Depleted Media (EDM). The addition of estradiol to EDM stimulates the growth of the MCF-7 cells in a dose dependent manner with an EC5o 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 180ul/well. On day 1 test compounds are diluted in a 10-fold dilution series in EDM and 20ul of these dilutions added to the 180ul 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 2X 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 0.001nM to 1000nM. The assay in the above format is employed to determine the estradiol agonist potential of a test compound.

146- WO 02/32377 PCT/USU1/42735 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 ISOul/well. On day L 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 appropriate controls reach 80-90% confluency and the protein content of each well is determined as above.

Rat endometriosis model Animals: Species: Rattus norvegicus 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 a12/12 light/dark cycle.

Rats are anesthetized with TelazolT M (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 betadine/ isopropyl alcohol or Duraprep® 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 4-0 chromic gut. The skin 147- WO 02/32377 PCT/USU1/42735 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) (BVIDS, Seaford, DE) is injected subcutaneously in the dorsoscapular region.

The rats are observed until fully ambulatory, and allowed to recover from surgery undisturbed for 3 weeks.

Three weeks after transplantation of the endometrial 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 14 days. Body temperature is recorded every other day at 10:00 am using the BMDS scanner.

At the end of the 14 day treatment period, the animals are euthanized by CO 2 overdose. Blood is collected by cardiocentesis for 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.

148

Claims (12)

1. 2. The compound of Claim I wherein Y is sulfur and X is oxygen, and the pharmaceutically acceptable salts thereof.
2. 3. The compound of Claim 2 wherein R 1 R 2 R 3 and R 4 are each independently selected from the group consisting of hydrogen, C_-5 alkyl, C3-8 cycloalkyl, C2-5 alkenyl, C2-5 alkynyl, OR 6 and halogen, provided that one of R 2 and R 3 is -OH; R 5 is selected from the group consisting of C3-8 cycloalkyl, phenyl, heteroaryl and heterocyclical groups wherein said groups can be optionally substituted with -OR 6 and halogen; R 6 is selected from the group consisting of hydrogen, C1-5 alkyl, benzyl, methoxymethyl and triisopropylsilyl; and the pharmaceutically acceptable salts thereof.
3. 4. The compound of Claim 3 selected from the group consisting of:
4. 150- WO 02/32377 WO 0232377PCT/1JS01/42735 N and the pharmaceutically acceptable salts thereof. The com-rpound of Claim 3 of the formula: (R 7 )m 2 R S R 0 wvherein RI, R 2 R 3 and R 4 are each independently selected from the group consisting of hydrogen, C1- 5 alkyl, C3-8 cycloalkyl, C2-5 alkenyl. C?, alkynyl, -OR 6 and halogen, provided that one of R 2 and R 3 is -OHK 151 WO 02/32377 PCT/USU1/42735 R 6 is selected from the group consisting of hydrogen. C1-5 alkyl, benzyl, methoxymethyl and triisopropylsilyl; R 7 is selected from the group selected from the group consisting of hydrogen, alkyl, halogen, trifluoromethyl, and -OR 6 Each Z is independently selected from the group consisting of hydrogen, C 1-5 alkyl, trifluoromethyl, wherein said alkyl group can be optionally substituted with C1-5 alkyl, CF3, -OR 6 halogen, amino, CI-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 alkyl, CF3, -OR6, halogen, amino, C -5 alkylthio, thiocyanato, cyano, -CO2H, -COOCI-5 alkyl, -COCl-5 alky), -CONV2, -SO2NV2, and alkyl; Each V is independently selected from the group consisting of C1-5 alkyl, CF 3 -OR 6 halogen, amino, CI-5 alkylthio, thiocyanato, cyano, -CO2H, -COOC1- alkyl, -COCl-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:
5. 152- WO 02/32377 WO 0232377PCT/1JS01/42735 OH HO S 0 NO HO OH 0" OH HO S H 3 COH o N HO OH H 3 COH and the pharmaceutically acceptable salts thereof. 7. The compound of Claim 5 of the formula: (R 7 )m R 1 2 R S R 3 0 AR)P R40 N
6. 153- WO 02/32377 PCT/USU1/42735 wherein RI, R 2 1 R 3 and R 4 are each independently selected from the group consisting of hydrogen, Ci-5 alkyl, C3-8 cycloalkyl, C2-5 alkenyl, C2 alkynyl, -OR 6 and halogen, provided that one of R 2 and R 3 is -01-I: R 6 is selected from the group consisting of hydrogen, C -5 alkyl, benzyl, methoxymethyl and triisopropylsilyl; R 7 is selected from the group selected from the group consisting of hydrogen, alkyl, halogen, trifluoromethyl, and -OR 6 R 8 is independently selected from the group consisting of hydrogen, C1-5 alkyl, CF3, -OR 6 halogen, amino, Cl-5 alkylthio, thiocyanato, cyano, -C02H, COOC1-5 alkyl, -COCI-5 alkyl, -CONV2,. -SO2NV2, and -SO2C1-5 alkyl; Each V is independently selected from the group consisting of C1-5 alkyl, CF3, -OR 6 halogen, amino, C1-5 alkylthio, thiocyanato, cyano, -CO2H, -COOC1I alkyl, -COC 1_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:
7. 154- WO 02/32377 WO 0232377PCT/1JS01/42735 HO S OH N o0 N "OH CH 3 N H 3 F~q S \aOH HO 0 F ND S IC OH HO 0 ci ND WO 02/32377 WO 0232377PCT/1JS01/42735 11 OH HO S 0" N OH HO S 0"N OH HO S H -Oo H 3 OH HO O N "'OH HOH (4-)-OH 0 OH 3
8. 156- WO 02/32377 WO 0232377PCT/1JS01/42735 HO S O HO OH 0ONHH 0 '-CH Nr: HO S OH -x N -CH 3 HOS aOHOH 0 H 3 -157- WO 02/32377 WO 0232377PCT/1JS01/42735 F HO, S, W 0' OH 01 N~ O)-H 3 ND I''OH 3 OH lo~aOH 0 1 N N OH 3
9. 158- WO 02/32377 WO 0232377PCT/USO1/42735 F HO~ S O O "O'IH 3 N OH F S HO 0 FN HO' HO, NJ OH 159 WO 02/32377 WO 0232377PCT/1JS01/42735 ,,OH 0 H 3 N H 3 0 COH N H 3 OHH OH3 -D OH 3 IN OH N OH 3 0 OH 3 160 WO 02/32377 WO 0232377PCT/1JS01/42735 HO) as H aOH :CH 3 OH 3 CH 3 NI OCH 3 HO_ S O HO S a\OH HO, S OH OH 3 -161 WO 02/32377 WO 0232377PCT/USO1/42735 H 0 S 0 OH NO ""CH 3 O OH, HO S NN OH 0 0 HO N N "H bH3 O-,IH 3 OH HO aS. lllll c N "OH 3 N 'OH 3 OH 3 162 WO 02/32377 WO 0232377PCT/1JS01/42735 N CH 3 00 0 OH OHCH HO S OH\ OH HO C S O ,N CH 2 CH 3 163 WO 02/32377 WO 0232377PCT/1JS01/42735 HO H HO S 0 HO S OH 3 'OH 'OH N CH 2 CH 3 CH 3 'OH N CHO -OH N "H 2 0H 3
10. 164- WO 02/32377 WO 0232377PCT/1JS01/42735 OH HO, HO. CH 2 CH 3 N CH 3 IN 0 1CH2 0H 3 HO OH 0~ 1 'CIIH 2 CH3 NO OCH 3 -165- WO 02/32377 WO 0232377PCT/1JS01/42735 OH HO aS N ICH 2 OH 3 OH HO S 0 r\ OH 3 N H 2 CH 3 OD ""H 3 N ldHCH, OH 3 and the pharmaceutically acceptable salts thereof. 9. The compound of Claim .5 of the formula: WO 02/32377 PCT/USU1/42735 R2 S R 3 0 R 4 N wherein RI. R 2 R 3 and R 4 are each independently selected from the group consisting of hydrogen, C1-5 alkyl, -OR 6 and halogen, provided that one of R 2 and R 3 is -OH; R 6 is selected from the group consisting of hydrogen, C -5 alkyl, benzyl, methoxymethyl and trisiopropylsilyl; R 7 is selected from the group selected from the group consisting of hydrogen, alkyl, halogen, trifluoromethyl, and -OR 6 Each m is independently an integer from one or two; and the pharmaceutically acceptable salts thereof. The compound of Claim 9 selected from the group consisting of: WO 02/32377 WO 0232377PCT/1JS01/42735 HO, S 0:: 0 OH HO, S N N -168- WO 02/32377 WO 0232377PCT/1JS01/42735 ND -169- WO 02/32377 WO 0232377PCT/1JS01/42735 HO~ 0 N 0 HO' 0 0 N
11. 170- WO 02/32377 WO 0232377PCT/1JS01/42735 OH H(D'aS NC F OH HO 0 00 HOl XS \\a0 00 Fo,_, 171 WO 02/32377 PCT/USU1/42735 HO 0 aON OH HO 0 CH 3 ON and the pharmaceutically acceptable salts thereof. 11. The compound according to Claim 1 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 WO 02/32377 PCT/USU1/42735 HO- S S, a" OH OH Oy 0 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 I 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 ERa receptor agonizing effect.
12. 173- WO 02/32377 PCT/US01/42735 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. A method of treating or preventing a disorder selected from the gIToup 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. 174 "z 175 21. A compound as claimed in claim 1 and substantially as herein described with reference to any one of Examples 71 113 or 116. 0 z 22. A pharmaceutical composition comprising a compound as claimed in claim 21 together with a pharmaceutically acceptable carrier. 23. A process of making a compound as claimed in claim 1 which process is substantially as herein described with reference to any one of Examples 71 113 or 116. 0024. A process of making a compound as claimed in claim 1 which process is N substantially as herein described with reference to any one of Schemes Ito IV. (Ni Use of a compound of any one of claims 1 to 12 or 21 for the preparation of a lo medicament for eliciting an estrogen receptor modulating effect in a mammal in need thereof. 26. A compound as defined in any one of claims 1 to 12 or 21 or a composition as defined in claim 13 or 22 when used for eliciting an estrogen receptor modulating effect in a mammal in need thereof. 27. 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 of claim 21 or a composition of claim 22. 28. The method of any one of claims 16 to 18 or 27 wherein the mammal is a human. 29. The method of claim 19 or 20 wherein the female is a human female. Dated 29 October, 2004 MERCK CO., INC. Patent Attorneys for the Applicant/Nominated Person SPRUSON FERGUSON I 73.doc:njc