SK4772003A3 - Estrogen receptor modulators - Google Patents

Abstract

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

Description

Technical field

I ''

The present invention relates to estrogen receptor modulators, to a pharmaceutical composition comprising them, and to their use in the treatment or prevention of various estrogen-related conditions.

BACKGROUND OF THE INVENTION

Naturally occurring and synthetic estrogens have a wide therapeutic utility, including alleviating menopausal symptoms, treating acne, treating dysmenorrhea and dysfunctional uterine bleeding, treating osteoporosis, treating excessive hair, treating prostate cancer, treating hot flashes, and preventing cardiovascular diseases. Since estrogen is therapeutically very valuable, there is a great interest in discovering compounds that mimic estrogen behavior in tissues that respond to estrogen.

For example, estrogen-like compounds would be useful in the treatment and prevention of bone loss. Bone loss occurs in a wide range of subjects, including postmenopausal women or who have had hysterectomy, patients who are or are currently being treated with corticosteroids, and patients who have malformed gonads. At present, the major bone disease of interest to the public is osteoporosis, hypercalcemia from malignant tumors, osteopenia due to bone metastasis, periodontal disease, hyperparathyroidism, periarticular erosion in rheumatoid arthritis, Paget's disease, osteoporosis, induced neo-haemorrhage, and induced neo-haemorrhage, induced neo-haemorrhage. All these conditions are characterized by bone loss resulting from an imbalance between bone resorption, i. j. its degradation, and bone formation, which continues throughout life at an average rate of about 14% per year. However, the rate of bone change varies from place to place, for example, it is higher in vertebral vertebra bone and dental bed bone in the jaws than in superficial layers

-2long bones. The possibility of bone loss is directly related to conversion and can reach more than 5% per annum in vertebrates immediately after menopause, a condition that leads to an increased risk of fracture.

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

Osteoporosis affects about 20 to 25 million postmenopausal women in the US alone. It has been hypothesized that the rapid loss of bone mass in these women is due to the cessation of estrogen production by the ovaries. Because studies have shown that estrogen slows bone loss due to osteoporosis, estrogen replacement therapy is a recognized treatment for postmenopausal osteoporosis.

In addition to bone mass, estrogen has been shown to affect cholesterol biosynthesis and cardiovascular health. Statistically, the proportion of cardiovascular disease rates is about the same in postmenopausal women and men; however, women before menopause have a much lower incidence of cardiovascular disease than men. Since postmenopausal women have estrogen deficiency, estrogen is believed to play a useful role in preventing cardiovascular disease. The mechanism is not well known, but data suggests that estrogen can activate low density cholesterol (LDL) receptors in the liver to remove excess cholesterol.

Postmenopausal women undergoing estrogen replacement therapy return lipid levels to concentrations that are comparable to pre-menopausal levels. Thus, estrogen replacement therapy could be an effective treatment for such diseases. However, the side effects associated with long-term use of estrogen limit the use of this alternative.

Other conditions that affect postmenopausal women include estrogen-dependent breast cancer and uterine cancer. Anti-estrogen compounds such as tamoxifen are commonly used as chemotherapy for the treatment of breast cancer patients. Tamoxifen, a dual estrogen receptor antagonist and agonist, is beneficial in the treatment of estrogen-dependent cancer

-3prsníka. However, tamoxifen therapy is not ideal because the agonistic behavior of tamoxifen increases the undesirable side effects of estrogen. For example, tamoxifen and other compounds that agonize estrogen receptors tend to increase uterine cancer cell production. A better therapy for such cancers would be an anti-estrogen compound having negligible or no agonist properties.

Although estrogen may be beneficial for the treatment of pathological conditions such as bone loss, elevated lipid levels and cancer, long-term estrogen therapy has been implicated in various disorders, including an increased risk of uterine and endometrial cancer. These and other side effects of estrogen replacement therapy are not acceptable for many women, limiting its use.

Alternative schemes, such as a combined dose of progestogen and estrogen, have been suggested as an attempt to reduce the risk of cancer. However, such schemes cause bleeding to be missed in patients, which is unacceptable to many older women. In addition, combining estrogen with a progestogen reduces the useful effect of estrogen therapy on lowering cholesterol. In addition, the long-term effects of treatment with progestogen are not known.

In addition to postmenopausal women, men suffering from prostate cancer may benefit from antiestrogen compounds. Prostate cancer is often hormone sensitive: androgen stimulation promotes tumor growth, while androgen inhibition slows tumor growth. Estrogen administration is useful in the treatment and control of prostate cancer, since estrogen administration reduces gonadotropin levels and, consequently, androgen levels.

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

What is needed in the art is compounds that can produce the same positive responses as estrogen replacement therapy, but

-4without negative side effects. Also required are estrogen-like compounds that exhibit selective effects on various body tissues.

The compounds of the invention are ligands for estrogen receptors, which as such may be useful for treating or preventing various estrogen-related conditions, including bone loss, bone fractures, osteoporosis, cartilage degeneration, endometriosis, fibroid uterine disease, hot flushes, elevated LDL cholesterol levels, cardiovascular diseases, cognitive disorders, cerebral degenerative diseases, restenosis, gynecomastia, vascular smooth muscle cell proliferation, obesity, incontinence and cancer, particularly breast, uterus and prostate.

SUMMARY OF THE INVENTION

The present invention provides compounds of formula IA

wherein each of R ¹ , R ² , R ³ and R ⁴ is independently selected from the group consisting of hydrogen, C 1-5 -alkyl, C 3-8 -cycloalkyl, C 2-5 -alkenyl, C 2-5 -alkynyl, C 3-8- cycloalkenyl, phenyl, heteroaryl, heterocycle, CF 3, -OR ⁶ , halogen, C ^1-6 -alkylthio, thiocyanato, cyano, -CO 2 H, -COOC 2 -alkyl, -COC 2 -alkyl, -CON ₂ , -SO ₂ NZ ₂ and -SO ₂ Ci. _5- alkyl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, phenyl, heteroaryl, heterocyclic groups may be optionally substituted with C 1-6 alkyl; C ₅ alkyl. ₈ -cycloalkyl, CF ₃ , phenyl, heteroaryl, heterocycle, -OR ⁶ , halogen, amino, C 1-4 -alkylthio, thiocyanato, cyano, -CO ₂ H, -COOC 1-5 -alkyl, -COC 1-4 -alkyl, - CONZ ₂ , -SO ₂ NZ ₂ and -SO ₂ Ci. _5- alkyl;

-5R ⁵ is selected from the group consisting of C 1-5 -alkyl, C 3-8 -cycloalkyl, C 2-5 -alkenyl, C 2-5 -alkynyl, C 3-8 -cycloalkenyl, phenyl, heteroaryl, heterocyclic groups, wherein said groups may be optionally substituted with C 1-5 alkyl, C 3-8 cycloalkyl, CF 3, phenyl, heteroaryl, heterocycle, -OR ⁶ , halogen, amino, C 1-5 -alkylthio, thiocyanato, cyano, -CO ₂ H, -COOCi-5- alkyl, -COCl. _5- alkyl, -CONZ ₂ , -SO ₂ NZ _2, and -SO ₂ C 1-5 -alkyl;

X and Y are each independently selected from the group consisting of oxygen, sulfur, sulfoxide, and sulfone;

R ⁶ is selected from the group consisting of hydrogen, CR-alkyl, benzyl, methoxymethyl, triorganosilyl, C 1-5 -alkylcarbonyl, alkoxycarbonyl and CONZ ₂ ;

each Z is independently selected from the group consisting of hydrogen, C 1-6 -alkyl, trifluoromethyl, wherein said alkyl group may be optionally substituted with CR-alkyl,

CF ₃ , -OR ⁶ , halogen, amino, C 1 -C 6; _5- alkylthio, thiocyanato, cyano, -CO ₂ H, -COOC-is-alkyl, -COC 1-6 -alkyl, -CONV ₂ , -SO ₂ NV ₂ and

-SO ₂ C 1-5 -alkyl;

or both Z together with the nitrogen to which they are attached form a 3- to 8-membered ring, wherein said ring may optionally contain atoms selected from the group consisting of carbon, oxygen, sulfur and nitrogen, wherein said ring may be either saturated or unsaturated and the carbon atoms of said ring may be optionally substituted with one to three substituents selected from the group consisting of CR-alkyl, CF ₃ , -OR ⁶ , halogen, amino, C ^1-6 -alkylthio, thiocyanato, cyano, -CO ₂ H, -COOC 1-5 -alkyl, -COC 1-5 -alkyl, -CONV ₂ , -SO ₂ NV ₂ and -SO ₂ C 1-5 -alkyl;

each V is independently selected from the group consisting of CR-alkyl, CF ₃ , -OR ⁶ , halogen, amino, C 1-5 alkylthio, thiocyanato, cyano, -CO ₂ H, -COOC ₁₅ -alkyl, -COCi. _5- alkyl and -SO ₂ C ₁ . _5- alkyl;

each n is independently an integer from one to five;

and pharmaceutically acceptable salts thereof.

The present invention also relates to pharmaceutical compositions comprising the compounds of the invention and a pharmaceutically acceptable carrier.

The present invention also relates to methods of preparing the pharmaceutical compositions of the invention.

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

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

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

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

The invention also relates to methods of treating or preventing diseases related to estrogen, bone loss, bone fracture, osteoporosis, cartilage degeneration, endometriosis, uterine fibroid disease, breast, uterine or prostate cancer, hot flashes, cardiovascular diseases, cognitive impairment. , brain degenerative diseases, restenosis, gynecomastia, vascular smooth muscle cell proliferation, obesity and incontinence in a mammal in need thereof, by administering the compounds and pharmaceutical compositions of the invention.

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

The present invention relates to compounds useful as estrogen receptor modulators. The compounds of the invention are given by the general chemical formula IA

wherein each of R ¹ , R ² , R ³ and R ⁴ is independently selected from the group consisting of hydrogen, C 1-8 -alkyl, C 3-8 -cycloalkyl, C 2-5 -alkenyl, C 2-5 -alkynyl, C 3-8 -alkynyl, cycloalkenyl, phenyl, heteroaryl, heterocycle, CF 3, -OR ⁶ , halogen, C 1-5 -alkylthio, thiocyanato, cyano, -CO ₂ H, -COOC 5 -alkyl, -COC 1. _5- alkyl, -CONZ ₂ , -SO ₂ NZ _2, and -SO ₂ Ci. _5- alkyl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, phenyl, heteroaryl, heterocyclic groups may be optionally substituted with C 1-5 alkyl, C ₃ . ₈ -cycloalkyl, CF ₃ , phenyl, heteroaryl, heterocycle, -OR ⁶ , halogen, amino, C 1-6 alkyl; _5- alkylthio, thiocyanato, cyano, -CO ₂ H, -COOC 2-6 -alkyl, -COC _1-5 -alkyl, -CONZ ₂ , -SO ₂ NZ _2, and -SO ₂ C 1-6 alkyl; _5- alkyl;

R ⁵ is selected from the group consisting of C 1-5 -alkyl, C 3-8 -cycloalkyl, C 2-8 alkenyl, C 2-5 -alkynyl, C 3-8 -cycloalkenyl, phenyl, heteroaryl, heterocyclic groups, said groups being optionally substituted with C 1-5 alkyl, C 3-8 -cycloalkyl, CF 3, phenyl, heteroaryl, heterocycle, -OR ⁶ , halogen, amino, C 1-5 alkylthio, thiocyanato, cyano, -CO ₂ H, -COOC 1-5 -alkyl, - COC 1-6 -alkyl, -CONZ ₂ , -SO ₂ NZ _2, and -SO ₂ C 1-5 -alkyl;

X and Y are each independently selected from the group consisting of oxygen, sulfur, sulfoxide, and sulfone;

R ⁶ is selected from the group consisting of hydrogen, C 1-5 -alkyl, benzyl, methoxymethyl, triorganosilyl, C 1-5 -alkylcarbonyl, alkoxycarbonyl and CONZ 2; each Z is independently selected from the group consisting of hydrogen, C 1-5 -alkyl, trifluoromethyl, wherein said alkyl group may be optionally substituted with C 1-5 alkyl, CF 3, -OR ⁶ , halogen, amino, C 1-5 -alkylthio, thiocyanato- 8-cyano, -CO ₂ H, -COOCl. _5- alkyl, -COCl. _5- alkyl, -CONV ₂ , -SO ₂ NV ₂ and -SO _{2 C} 1-5 -alkyl;

or both Z together with the nitrogen to which they are attached form a 3- to 8-membered ring, wherein said ring may optionally contain atoms selected from the group consisting of carbon, oxygen, sulfur and nitrogen, wherein said ring may be either saturated or unsaturated and the carbon atoms of said ring may be optionally substituted with one to three substituents selected from the group consisting of C 1-6 alkyl. _5- alkyl, CF ₃ , -OR ⁶ , halogen, amino, C 1-6 -alkyl; _5- alkylthio, thiocyanato, cyano, -CO ₂ H, -COOC 3-6 -alkyl, -COC 1. _5- alkyl, -CONV ₂ , -SO ₂ NV _2, and -SO ₂ C _1-5 -alkyl;

each V is independently selected from the group consisting of C 1-6 alkyl; _5- alkyl, CF ₃ , -OR ⁶ , halogen, amino, C ^1-6 -alkylthio, thiocyanato, cyano, -CO ₂ H, -COOC- | _5- alkyl, -COC-1-5-alkyl and -SO ₂ C 1-5 -alkyl;

each n is independently an integer from one to five;

and pharmaceutically acceptable salts thereof.

In one class of compounds of the invention, X is oxygen and Y is sulfur.

In one class of compounds of the invention, R ¹ , R ² , R ³ and R ^{4 are} selected from the group consisting of hydrogen, C 1-6. _5- alkyl, C 3-8 -cycloalkyl, C 1-5 -alkenyl, C 1-5 -alkynyl, -OR ⁶ and halogen.

In one class of compounds of the invention R ⁵ is selected from the group consisting of _C3-.8 cycloalkyl, phenyl, heteroaryl, and heterocyclic groups, wherein said groups being optionally substituted by -OR ⁶ and halogen.

In one class of compounds of the invention, R ^{6 is} preferably selected from the group consisting of hydrogen, C 1-6. _5- alkyl, benzyl, methoxymethyl and triisopropylsilyl.

The present invention also relates to a process for the preparation of a compound of formula I

(I)

-9kde

R ¹ is H, F or Cl;

R ² jeHalebo OR ^6;

R ³ is H or OR ⁶ ;

R ⁴ is H or CH 3;

R ⁵ is C 1-5 -alkyl, C 3-8 -cycloalkyl, C 3-8 -cycloalkenyl, phenyl, heteroaryl or heterocyclic, wherein said groups may be optionally substituted by C 1-8 -alkyl, C 3-8 -cycloalkyl, CF 3, phenyl , heteroaryl, heterocycle, -OR ⁶ , halogen, amino, C 1-5 -alkylthio, thiocyanato, cyano, carboxyl (-CO 2 H), carboalkoxy (-COOC 1-5 -alkyl), carbonyl (-COC 5-6 -alkyl), carboxamido (- CONZ2), sulfonamido (-SO ₂ NZ ₂ ) and sulfonyl (-SO ₂ C 1-5 -alkyl);

R ⁶ is H, benzyl, methyl, methoxymethyl or triisopropylsilyl, provided that if OR ⁶ exists elsewhere, it is chemically degradable;

X and Y are each independently selected from the group consisting of oxygen, sulfur, sulfoxide, and sulfone;

each Z is independently selected from the group consisting of hydrogen, C 1-5 -alkyl, trifluoromethyl, wherein said alkyl group may be optionally substituted with C 1-5 -alkyl, CF ₃ , -OR ⁶ , halogen, amino, C 1-5 -alkylthio, thiocyanato, cyano , -CO ₂ H, -COOC 1-5 alkyl, -COC- | _5- alkyl, -CONV ₂ , -SO ₂ NV ₂ and -SO ₂ C 1-5 -alkyl;

or both Z together with the nitrogen to which they are attached form a 3- to 8-membered ring, wherein said ring may optionally contain atoms selected from the group consisting of carbon, oxygen, sulfur and nitrogen, wherein said ring may be either saturated or unsaturated and the carbon atoms of said ring may be optionally substituted by C 1-8. _5- alkyl, CF ₃ , -OR ⁶ , halogen, amino, C 1-5 -alkylthio, thiocyanato, cyano, -CO ₂ H, -COOCl. _5- alkyl, -COC 1-6 -alkyl, -CONV ₂ , -SO ₂ NV ₂ and -SO ₂ Ci. ₅ alkyl;

each V is independently selected from the group consisting of C 1-6 alkyl; _5- alkyl, CF ₃ , -OR ⁶ , halogen, amino, C 1-5 -alkylthio, thiocyanato, cyano, -CO ₂ H, -COOC-is-alkyl, -COC 1-5 -alkyl and -SO ₂ C 1-5 -alkyl;

each n is an integer from one to five;

and the stereoisomer is cis / s;

or a pharmaceutically acceptable salt thereof,

-10which includes the following steps:

a) reacting a compound of formula II with a compound of formula III under basic conditions

to form a compound of formula IV R ⁴ XH

(IV)

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

R ¹

(IN)

c) removing the protecting group R ^{6 of} formula VI to form a substituted phenol generally;

R ⁵ (VI)

OH

D) alkylating said substituted phenol of formula VI from step c) with a reagent HO (CH 2) _n N (Z) 2 to give a compound of formula I

e) removing one or the other protecting group from the compound of formula I from step d) to obtain either a compound of formula VIII or a compound of formula IX

(IX) (IX)

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

The present invention also relates to a process for the preparation of a compound of the general formula

ID

((+) - ID)

- 12where

R ¹ is H, F or Cl;

R ³ is H;

R ⁴ is H or CH ₃ ;

and the stereoisomer is cis;

and the optical isomer is dextrorotatory (+) with absolute configuration (2S, 3F?); or a pharmaceutically acceptable salt thereof, comprising the steps of:

a) reacting a compound of formula IID with a compound of formula IND under basic conditions

to form a compound of formula IVD

(IVD)

b) cyclizing the compound of formula IVD from step a) under acidic conditions in the presence of a reducing agent to form the racemic cis-compound of formula VD

(VD)

13c) performing chiral chromatography with a compound of formula VD from step b) to separate the enantiomeric form, to give the dextrorotatory (+) isomer of formula VID

((+) - VID)

d) alkylating this dextrorotatory (+) isomer of formula VID from step c) with 1-piperidineethanol to form a compound of formula VIID

(VIId)

e) removing one or the other protecting group from the compound of formula VIID from step d) to obtain either a compound of formula VIID or a compound of formula IXD

BnO 4 OH

(IXD)

-14f) removing the remaining protecting group from either the compound of formula VIIID or the compound of formula IXD from step e) to give a compound of formula I.

This invention also encompasses a process for preparing a compound of Formula IE

((+) - IE) where

R ¹ is selected from the group consisting of H, F and Cl;

each of R ³ and R ⁴ is H;

R ⁷ is selected from the group consisting of H and OH;

the stereoisomer is cis and the optical isomer is dextrorotatory (+) with the absolute configuration (2S, 3R);

or a pharmaceutically acceptable salt thereof, which includes the following steps: (a) reacting a compound of general formula (I); IIIE under basic conditions of formula IIE with compound of the general formula R ¹ | R ⁷ _X SH ^Βγ ί AJ > DH c / (IIE) JA 'OR ⁶

(IIIE) to form a compound of formula IVE

(IVE)

b) cyclizing the compound of formula IVE from step a) under acidic conditions in the presence of a reducing agent to form the racemic cis compound of formula VE

c) selectively deprotecting the compound of formula VE from step b) to form a substituted phenol of formula VIE

(HE KNOWS)

d) alkylating the substituted phenol of formula VIE from step c) with 1-piperidineethanol to form a compound of formula VIIE

e) removing one or the other protecting group from a compound of formula VIIE to give either a compound of formula VIIIE or a compound of formula IXE

(Viii)

(IXE)

f) removing the remaining protecting group from either a compound of formula VIII or a compound of formula IX from step e) to form a racemic compound of formula I;

g) separating the enantiomeric forms of the compound of formula I to form the dextrorotatory (+) isomer of the compound of formula I with the absolute configuration (2S, 3 R).

The present invention also relates to novel intermediates useful for the preparation of the compounds and compositions described herein, i. j. compounds of formula I, IA, IB, IC, ID and IE.

One embodiment of the invention is an intermediate of formula

(I) where

R ¹ is H, F or Cl;

R ² is H or OR ^6;

R ³ is H or OR ⁶ ;

R ⁴ is H or CH 3;

R ⁵ is C 1-5 -alkyl, C 3-8 -cycloalkyl, C 3-8 -cycloalkenyl, phenyl, heteroaryl or heterocyclic, wherein said groups may be optionally substituted by C 1-5 -alkyl, C 3-8 -cycloalkyl, CF 3 -phenyl , heteroaryl, heterocycle, -OR ⁶ , halogen, amino, C 1-5 -alkylthio, thiocyanato, cyano, carboxyl (-CO 2 H), carboalkoxy (-COOC 5-6 -alkyl), carbonyl (-COC 5-6 -alkyl), carboxamido (-CONZ 2) , sulfonamido (-SO ₂ NH 2) and sulfonyl (-SO ₂ C _1-5 -alkyl);

R ⁶ is H, benzyl, methyl, methoxymethyl or triisopropylsilyl, provided that if OR ⁶ exists elsewhere, it is chemically distinguishable;

each Z is independently selected from the group consisting of hydrogen, C 1-6 alkyl; _5- alkyl, trifluoromethyl, wherein said alkyl group may be optionally substituted with C 1-6 alkyl; _5- alkyl, CF ₃ , -OR ⁶ , halogen, amino, C 1-6 alkyl; ₅ alkylthio, thiocyanato, cyano, -CO ₂ H, -COOC1.5alkylom, -COC. ₅ -alkyl, -CONV2, -SO ₂ NV ₂ -SO 2 Cl and _1, 5-alkyl;

or both Z together with the nitrogen to which they are attached form a 3- to 8-membered ring, said ring optionally having atoms selected from the group consisting of carbon, oxygen, sulfur and nitrogen, wherein said ring may be either saturated or unsaturated and the carbon atoms of said ring may be optionally substituted with C 1-5 -alkyl, CF ₃ , -OR ⁶ , halogen, amino, C _1-5 -alkylthio, thiocyanato, cyano, -CO 2 H, -COOCi. _5- alkyl, -COC 1-6 -alkyl, -CONV ₂ , -SO ₂ NV ₂ and -SO ₂ Cl-5alkyl;

-18 each V is independently selected from the group consisting of C 1-6 alkyl; _5- alkyl, CF ₃ , -OR ⁶ , halogen, amino, C 1-5 -alkylthio, thiocyanato, cyano, -CO ₂ H, -COOC 15 -alkyl, -COC _1-5 alkyl, and -SO ₂ C _1-5 alkyl.

Another embodiment of the invention is an intermediate of formula

where

R ¹ is H, F or Cl;

R ² jeHalebo OR ^6;

R ³ is H or OR ⁶ ;

R ⁴ is H or CH ₃ ;

R ⁵ is a C 1-5 -alkyl, C 3-8 -cycloalkyl, C 3-8 -cycloalkenyl, phenyl, heteroaryl or heterocyclic group, wherein said groups may be optionally substituted with a C 1-5 -alkyl, a C 3-8 -cycloalkyl, a CF 3 , phenyl, heteroaryl, heterocycle, -OR ⁶ , halogen, amino, C 1-5 -alkylthio, thiocyanato, cyano, carboxyl (-CO ₂ H), carboalkoxy (-COOC 1-5 -alkyl), carbonyl (-COC _1-5 -alkyl) ), carboxamido (-CONZ2), sulfonamido (-SO ₂ NZ ₂₎ and sulfonyl (-SO ₂ C _{first 5} alkyl);

R ⁶ is H, benzyl, methyl, methoxymethyl or triisopropylsilyl, provided that if OR ⁶ exists elsewhere, it is chemically distinguishable;

each Z is independently selected from the group consisting of hydrogen, C _1-5 -alkyl, trifluoromethyl, wherein said alkyl group may be optionally substituted with C _1-5 alkyl, CF ₃ , -OR ⁶ , halogen, amino, C 1-5 -alkylthio, thiocyanato, cyano, -CO ₂ H, -COOC-i-5 alkyl, -COC. _5- alkyl, -CONV ₂ , -SO ₂ NV ₂ and -SO ₂ C _1-5 -alkyl; or both Z together with the nitrogen to which they are attached form a 3- to 8-membered ring, said ring optionally having atoms selected from the group consisting of carbon, oxygen, sulfur and nitrogen, wherein said ring may be either saturated or unsaturated and the carbon atoms of said ring may be optionally

-19substituted Ci. _5- alkyl, CF ₃ , -OR ⁶ , halogen, amino, C _1-5 -alkylthio, thiocyanato, cyano, -CO ₂ H, -COOCl. _5- alkyl, -COC 1-6 -alkyl, -CONV ₂ , -SO ₂ NV ₂ and -SO ₂ Ci. ₅ alkyl;

each V is independently selected from the group consisting of C _1-5 -alkyl, CF ₃ , -OR ⁶ ;

halo, amino, C 1-6 alkylthio, thiocyanato, cyano, -CO ₂ H, -COOC 15-5 -alkyl, -COC _1-5 alkyl, and -SO ₂ C 1-5 -alkyl.

Another embodiment of the invention is an intermediate of formula

where

R ¹ is H, F or Cl;

R ⁶ is H, benzyl, methyl, methoxymethyl or triisopropylsilyl, provided that all existing R ⁶ groups are chemically distinguishable.

Another embodiment of the invention is an intermediate of formula

where

R ¹ is H, F or Cl;

R ⁶ is H, benzyl, methyl, methoxymethyl or triisopropylsilyl, provided that all existing R ⁶ groups are chemically differentiable.

Another embodiment of the invention is an intermediate of formula

where

R ¹ is H, F or Cl;

R ² is H or OR ^6;

R ³ is OR OR ⁶ ;

R ⁴ is H or CH ₃ ;

R ⁵ is C 1-5 -alkyl, C 3-8 -cycloalkyl, C 3-8 -cycloalkenyl, phenyl, heteroaryl or heterocyclic, wherein said groups may be optionally substituted by C 1-5 -alkyl, C 3-8 -cycloalkyl, CF 3, phenyl, heteroaryl, heterocycle, -OR ⁶ , halogen, amino, C 1-6 -alkylthio, thiocyanato, cyano, carboxyl (-CO 2 H), carboalkoxy (-COOC 1-5 -alkyl), carbonyl (-COC-1-5-alkyl) ), carboxamido (-CONZ2), sulfonamido (-SO ₂ NZ ₂₎ and sulfonyl (-SO ₂ C _{first 5} alkyl);

R ⁶ is H, benzyl, methyl, methoxymethyl or triisopropylsilyl, provided that if OR ⁶ exists elsewhere, it is chemically distinguishable;

each Z is independently selected from the group consisting of hydrogen, C _1-5 -alkyl, trifluoromethyl, wherein said alkyl group may be optionally substituted with C 1-6 alkyl; _5- alkyl, o

CF ₃ , -OR, halogen, amino, C _1-5 -alkylthio, thiocyanato, cyano, -CO ₂ H, -COOC-1-5alkyl, -COCl. _5- alkyl, -CONV ₂ , -SO ₂ NV ₂ and -SO ₂ C ₁ . _5- alkyl; or both Z together with the nitrogen to which they are attached form a 3- to 8-membered ring, said ring optionally having atoms selected from the group consisting of carbon, oxygen, sulfur and nitrogen, wherein said ring may be either saturated or unsaturated, and the carbon atoms of said ring may be optionally substituted with C _1-5 -alkyl, CF ₃ , -OR ⁶ , halogen, amino, C 1-6 -alkyl; _5- alkylthio, thiocyanato, cyano, -CO ₂ H, -COOC-1-5-alkyl, -COC 1-5 -alkyl, -CONV ₂ , -SO ₂ NV ₂ and -SO ₂ Cl-5alkyl;

-21 each V is independently selected from the group consisting of C 1-6 alkyl; _5- alkyl, CF ₃ , -OR ⁶ , halogen, amino, C ^1-6 -alkylthio, thiocyanato, cyano, -CO ₂ H, -COOC 2-6 -alkyl, -COC 2-6 -alkyl and -SO ₂ C ₁ . ₅ -alkyl.

Another embodiment of the invention is an intermediate of formula

where

R ¹ is H, F or Cl;

R ⁶ is H, benzyl, methyl, methoxymethyl or triisopropylsilyl, provided that all existing R ⁶ groups are chemically differentiable.

Another embodiment of the present invention is an intermediate of formula

where

R ¹ is H, F or Cl;

R ⁶ is H, benzyl, methyl, methoxymethyl or triisopropylsilyl, provided that all existing R ⁶ groups are chemically differentiable.

Non-limiting examples of the invention include:

OH

N

-22 (+) r ° ° UX ^U '0

.N

CH, UX ^U

.N

HO (+) -

OH

CH, n-OH;

-22 (+) HO (+) -

ΌΗ

HO

ch ₃

OH

-N

HO (+) S

OH

N-i

CHc

HO (+) V '

ABOUT

-25ΟΗ

₃ £ η ₃

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^{, 1} CH ₂ CH ₃

CH ₃

CH ₃

An embodiment of the invention is a method of inducing an estrogen receptor modulating effect in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of any of the above-described compounds or any of the above-described pharmaceutical compositions.

One class of this embodiment is a method wherein the estrogen receptor modulating effect is an antagonistic effect.

A subclass of this embodiment is a method wherein the estrogen receptor is an ERα-receptor.

A second subclass of this embodiment is a method wherein the estrogen receptor is an ERβ receptor.

A third subclass of this embodiment is a method wherein the estrogen receptor modulating effect is a mixed antagonist effect on ERα and ER receptors.

A second class of this embodiment is a method wherein the estrogen receptor modulating effect is an agonizing effect.

A subclass of this embodiment is a method wherein the estrogen receptor is an ERα-receptor.

A second subclass of this embodiment is a method wherein the estrogen receptor is an ERβ receptor.

A third subclass of this embodiment is a method wherein the estrogen receptor modulating effect is a mixed agonist effect on the ERα and ER receptors.

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 above-described compounds or any of the above-described pharmaceutical compositions.

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 above-described compounds or any of the above-described pharmaceutical compositions.

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 above-described compounds or any of the above-described pharmaceutical compositions.

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 above-described compounds or any of the above-described pharmaceutical compositions.

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

An example of the invention is a pharmaceutical composition comprising any of the compounds described above and a pharmaceutically acceptable carrier. Also an example of the invention is a pharmaceutical composition made by combining any of the above-described compounds and a pharmaceutically acceptable carrier. Illustrative of the invention is a method of making a pharmaceutical composition comprising a combination of any of the above-described compounds and a pharmaceutically acceptable carrier.

Another example of 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. Yet another example of 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, , cardiovascular diseases, cognitive disorders, cerebral degenerative diseases, restenosis, vascular smooth muscle cell proliferation, incontinence and / or diseases related to estrogen function.

The present invention is also directed to combinations of any of the above compounds or any of the above-described pharmaceutical compositions with one or more agents useful in the prevention or treatment of osteoporosis. For example, the compounds of the invention can be effectively administered in combination with effective amounts of other agents such as an organic bisphosphonate or cathepsin K inhibitor. 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 sodium trihydrate.

The exact dosage of the bisphosphonate will vary according to the dosage regimen, the oral efficacy of the particular bisphosphonate selected, the age, size, sex and condition of the mammal or human, the nature and severity of the disorder to be treated, and other important medical and physical factors. Thus, the exact pharmaceutically effective amount cannot be specified in advance and is readily determined by the attending or clinician. The respective amounts can be determined by routine testing in animal models

-35a clinical trials in humans. Generally, a suitable amount of bisphosphonate is selected to provide an inhibitory effect on bone resorption, i. j. an amount of bisphosphonate that inhibits bone resorption is administered. For humans, an effective oral dose of bisphosphonate is typically from about 1.5 to about 6000 pg / kg body weight, and preferably from about 10 to about 2000 pg / kg body weight.

For human oral compositions comprising alendronate, pharmaceutically acceptable salts or pharmaceutically acceptable derivatives thereof, a unit dose typically contains from about 8.75 mg to about 140 mg of the alendronate compound based on the active weight of alendronic acid, i. j. based on the corresponding acid.

For use in medicine, the salts of the compounds of this invention relate to non-toxic pharmaceutically acceptable salts. However, other salts may be useful in the preparation of the compounds of this invention or their pharmaceutically acceptable salts. When the compounds of this invention contain a basic group, salts which fall within the scope of the term pharmaceutically acceptable salts refer to non-toxic salts, which are generally prepared by reacting the free base with a suitable organic or inorganic acid. Representative salts include, but are not limited to, acetate, benzenesulfonate, benzoate, bicarbonate, hydrogen tartrate, borate, bromide, calcium salts, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumaran, gluceptate , gluconate, glutamate, glycolylarzanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methyl sulphate, nitrate, sulphate, nitrate methylglucamine ammonium salt, oleate, oxalate, pamoate (embonate), palmitate, pantothenate, phosphate / diphosphate, polygalacturonate, salicylate, stearate, sulfate, subacetate, succinate, tannate, tartrate, theoclate, tosylate, triethiodide and valerate. Further, where the compounds of the invention have an acidic group, suitable pharmaceutically acceptable salts thereof may include alkali metal salts, for example sodium or potassium salts; alkaline earth metal salts, for example calcium or magnesium salts; and salts formed with suitable organic ligands, for example, quaternary ammonium salts.

The compounds of the invention may have chiral centers and occur as racemates, racemic mixtures, diastereomeric mixtures, and as individual diastereomers or enantiomers, all of which isomeric forms are included in the invention. Therefore, where the compound is chiral, separate enantiomers, substantially free of the other, are included within the scope of the invention; all mixtures of the two enantiomers are further included. Also included within the scope of the present invention are polymorphs, hydrates, and solvates of the compounds of the present invention.

The present invention includes within its scope prodrugs of the compounds of the invention. In general, such prodrugs will be derivatives of compounds of the invention having functional groups that can be readily converted in vivo to the desired compound. Thus, in the methods of treatment of the invention, the term administration will include treatment of the various conditions described by a specifically described compound or a compound that need not be specifically described but which is converted 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 hereby incorporated by reference in its entirety. Metabolites of these compounds include the active ingredients produced when introducing the compounds of this invention into the biological environment.

The term "therapeutically effective amount" shall mean that amount of drug or pharmaceutical composition that elicits a 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 a process in which osteoclasts disrupt bone.

The term basic conditions, as used herein, refers to the inclusion or use of a base in a reaction medium. By Lowry-Bronsted definition, a base is a substance that receives a proton; or, by the Lewis definition, the base is a substance that can provide an electron pair to form a covalent bond. Examples of bases used herein include, but are not limited to, tertiary amine bases such as triethylamine, diisopropylethylamine and the like.

The term acidic conditions as used herein refers to the inclusion or use of an acid in a reaction medium. By Lowry-Bronsted definition, an acid is a substance that imparts a proton; or, according to the Lewis definition, an acid is a substance that can receive an electron pair to form a covalent bond. Examples here

The acids used, but not limited to, are strong carboxylic acids such as trifluoroacetic acid and the like, strong sulfonic acids such as trifluoromethanesulfonic acid and the like, and Lewis acids such as boron trifluoride etherate or stannous chloride and the like.

The term reducing agent as used herein refers to an agent that is capable of effecting a reduction. Reduction is the conversion of a functional group or intermediate from one category to a lower one. Examples of reducing agents used herein, but are not limited to, are triorganosilanes or tentanes such as triethylsilane, triphenylsilane, and tri-n-butyltin hydride, and the like.

The term chemically distinguishable refers to two or more non-identical R ⁶ substituents whose unique structures are such that one skilled in the art can select reaction conditions that would convert one of the non-identical R ⁶ substituents to H without affecting the other R ⁶ substituent.

The term alkyl will mean a substituent monovalent group, derived in principle by the removal of one hydrogen atom from a straight or branched chain acyclic saturated hydrocarbon (ie -CH 3, -CH 2 CH ₃ , -CH ₂ CH ₂ CH ₃ , -CH (CH ₃ ) ₂ , -CH ₂ CH ₂ CH ₂ CH ₃ , -CH ₂ CH (CH ₃ ) ₂ , -CH (CH ₃ ) ₃ , etc.).

The term alkenyl will mean a substituent monovalent group, derived by the principally removal of one hydrogen atom from a straight or branched chain acyclic unsaturated hydrocarbon containing at least one double bond (ie -CH = CH ₂ , -CH ₂ CH = CH ₂ , -CH = CHCH ₃₎ -CH ₂ CH = C (CH ₃ ) ₂ , etc.).

The term alkynyl will mean a substituent monovalent group derived by the principally removal of one hydrogen atom from a straight or branched chain acyclic unsaturated hydrocarbon containing at least one triple bond (ie -CH = CH, -CH ₂ C = CH, -C = CCH ₃ , -CH ₂ CH ₂ C = CCH ₃ , etc.).

The term cycloalkyl will mean a substituent monovalent group derived by principally removing one hydrogen atom from a saturated monocyclic hydrocarbon (i.e., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl).

The term cycloalkenyl will mean a substituent monovalent group, derived in principle by the removal of one hydrogen atom from the unsaturated

-38 a monocyclic hydrocarbon containing a double bond (i.e. cyclopentenyl or cyclohexenyl).

The term heterocycle will mean a substituent monovalent group derived by principally removing one hydrogen atom from a heterocycloalkane, said heterocycloalkane being derived from the corresponding saturated monocyclic hydrocarbon by replacing one or two carbon atoms with atoms selected from N, O and S. Examples of heterocyclic groups include, but are not limited to and oxiranyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl. The heterocyclic substituents may be bonded by a carbon atom. If the substituent is a nitrogen-containing heterocyclic substituent, it may be attached by a nitrogen atom.

The term heteroaryl, as used herein, refers to a substituent monovalent group derived by principally removing one hydrogen atom from a monocyclic or bicyclic aromatic ring system containing 1, 2, 3 or 4 heteroatoms selected from N, O, and S. Examples of heteroaryl groups include but are not limited to pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridyl, pyrimidinyl, pyrazinyl, benzimidazolyl, indolyl and purinyl. Heteroaryl substituents may be bonded through a carbon atom or through a heteroatom.

The term triorganosilyl means those silyl groups that are trisubstituted by lower alkyl or aryl groups, or combinations thereof, and wherein one substituent may be a lower alkoxy group. Examples of triorganosilyl groups include trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, triisopropylsilyl, triphenylsilyl, dimethylphenylsilyl, tert-butyldiphenylsilyl, phenyl-tert-butylmethoxysilyl and the like.

I

In the compounds of this invention, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclic and heteroaryl groups may be further substituted by the replacement of one or more hydrogen atoms with alternative non-hydrogen groups. These include, but are not limited to, halogen, hydroxy, mercapto, amino, carboxy, cyano, and carbamoyl.

Whenever the term alkyl or aryl or any of its prefix roots appears in the name of a substituent (e.g. aryl-C 0-6 -alkyl), it will be interpreted as including the limitations set forth above for alkyl and aryl.

The indicated numbers of carbon atoms (e.g., C 40) will refer independently to the number of carbon atoms in the alkyl or cyclic alkyl group, or the alkyl portion of the larger substituent in which alkyl appears as its prefix root.

The terms arylalkyl and alkylaryl include an alkyl moiety wherein alkyl is as defined above, and include an aryl moiety wherein 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 akylaryl include, but are not limited to, toluyl, ethylphenyl, and propylphenyl.

The term heteroarylalkyl, as used herein, will refer to a system that includes a heteroaryl moiety, wherein heteroaryl is as defined above, and includes an alkyl moiety. Examples of heteroarylalkyl include, but are not limited to, pyridylmethyl, pyridyl ethyl and imidazoylmethyl.

The term halogen includes iodine, bromine, chlorine and fluorine.

The term oxy means an oxygen atom (O). The term thio means a (S) sulfur atom. The term oxo means = O. The term oximino means an = N-O group.

The term substituted is intended to include multiple degrees of substitution by a named substituent. Where multiple substituent groups are described or claimed, the substituted compound may be independently substituted with one or more described or claimed substituent groups, either singly or simultaneously. By independently substituted, we mean that (two or more) substituents are the same or different.

In the standard nomenclature used throughout this specification, the end portion of the labeled side chain is described first, followed by an adjacent functional group toward the point of attachment. For example, a C 1-5 -alkylcarbonylamino-C 1-6 -alkyl substituent is equivalent

ABOUT

II

-C 6 -alkyl-NH-CC ,. _5- alkyl

When selecting compounds of the invention, one skilled in the art will recognize that various substituents, ie, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , V, X, Y, Z, n , maps should be chosen to meet the well-known principles of connectivity of the chemical structure.

Representative compounds of the invention typically exhibit submicromolar affinity for alpha and / or beta-estrogen receptors. The compounds of the invention are therefore useful in the treatment of mammals suffering from estrogen-related disorders. The mammal is administered a pharmacologically effective amount of a compound, including its pharmaceutically active salts, for the treatment of disorders related to estrogen action such as bone loss, heat flush, and cardiovascular disease.

The compounds of the invention are available in racemic form or as individual enantiomers. For simplicity, some structures are graphically represented as a single enantiomer, but unless otherwise stated, they are meant to include both racemic and enantiomeric forms. Where cis and trans stereochemistry is indicated for a compound of the invention, it should be understood that this stereochemistry is to be understood as relative unless otherwise noted.

In general, it is preferable to administer the compounds of formula I as enantiomerically pure formulations since most or all of the bioactivity is in one enantiomer. Racemic mixtures can be resolved into their individual enantiomers by any of several conventional methods. These include chiral chromatography, derivatization with a chiral auxiliary followed by separation by chromatography or crystallization, and fractional crystallization of diastereomeric salts.

The compounds of this invention can be used in combination with other agents useful in the treatment of estrogen-mediated conditions. The individual components of such combinations may be administered separately at different times during therapy or concurrently in divided or single combination forms. Therefore, the present invention is to be understood to include all such simultaneous or simultaneous modes

-41 alternating treatment and the term administration should be interpreted accordingly. It will be appreciated that the scope of combinations of the compounds of this invention with other agents useful in the treatment of estrogen-mediated conditions includes, in principle, any combination with any pharmaceutical composition useful for the treatment of estrogen-related disorders.

The term composition as used herein is intended to include an article comprising specified ingredients in specified amounts, as well as any product that results, directly or indirectly, from combinations of specified ingredients in specified amounts.

The compounds of this invention may be administered in such oral dosage forms as tablets, capsules (each including sustained release or timed release formulations), pills, powders, granules, elixirs, elixirs, suspensions, syrups and emulsions. Similarly, they can be administered in an intravenous (bolus or infusion), intraperitoneal, topical (e.g., eye drop), subcutaneous, intramuscular or transdermal form (e.g., patch), all of which forms are well known to those skilled in the pharmaceutical art.

The dosage regimen utilizing the compounds of this 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; route of administration; the kidney and liver function of the patient; and the particular compound or salt thereof used. The skilled physician, veterinarian or clinician can readily determine and prescribe the effective amount of the drug required to prevent, counteract or arrest the development of the condition.

Oral dosages of the present invention, when used for indicated purposes, will range between about 0.01 mg per kg body weight per day (mg / kg / day) and about 100 mg / kg / day, preferably from 0.01 to 10 mg. mg / kg / day, and most preferably 0.1 to 5.0 mg / kg / day. For oral administration, the compositions are preferably formulated as tablets containing 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25, 0, 50.0, 100 and 500 milligrams of active ingredient for symptomatic dose adjustment per patient to be treated. The 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 the active ingredient. Intravenously, dosages in the range of about 0.1 to about 10 mg / kg / minute during a constant rate infusion will be most preferred. The compounds of the invention may preferably be administered

-42 in a single daily dose or the total daily dose may be administered in divided doses two, three or four times daily. Further, preferred compounds of the invention can be administered in intranasal form with topical use of suitable intranasal vehicles or by transdermal routes using those forms of transdermal skin patches well known to those skilled in the art. For administration in the form of a transdermal delivery system, dosage administration will of course be continuous and uninterrupted throughout the dosage regimen.

In the methods of the invention, the compounds described in detail herein may form the active ingredient and are typically administered in admixture with suitable pharmaceutical diluents, vehicles or carriers (hereinafter referred to collectively as carrier materials) suitably selected with respect to the intended purpose. the form of administration, i.e., oral tablets, capsules, elixirs, syrups and the like, and consistent with conventional pharmaceutical practice.

For example, for oral administration in the form of a tablet or capsule, the active drug may be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose, starch, sucrose, glucose, methylcellulose, magnesium stearate, calcium phosphate, calcium sulfate, mannitol, sorbitol and similarly, for oral administration in liquid form, the oral drug components may be combined with any oral, non-toxic, pharmaceutically acceptable, inert carrier such as ethanol, glycerol, water and the like. In addition, if necessary or necessary, suitable binders, lubricants, disintegrants and colorants may 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, methylcellulose, agar, bentonite, xanthan gum, and the like.

The compounds of the invention may 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 various phospholipids such as cholesterol, stearylamine or phosphatidylcholines.

The compounds of this invention may also be administered using monoclonal antibodies as individual carriers to which the compound molecules are coupled. The compounds of the invention may also be coupled with soluble polymers as targetable drug carriers. Such polymers may include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide phenol, polyhydroxyethylaspartamidephenol or polyethylene oxide polylysine substituted with palmitoyl residues. Further, the compounds of the invention may be associated with a class of biodegradable polymers useful in achieving controlled drug release, for example, polylactic acid, polyglycolic acid, polylactic acid and polyglycolic acid copolymers, polyepsilon caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydrate copolymers hydrogels.

The novel compounds of this invention can be prepared by following the procedures of the following schemes and examples using appropriate materials and are further illustrated by the following specific examples. However, the compounds illustrated in the examples are not to be construed as forming the only group considered to be the present invention. The following examples further illustrate details of the preparation of the compounds of the invention. Those skilled in the art will readily appreciate that known variations of the conditions and methods of the following preparation procedures can be used to prepare these compounds. All temperatures are in degrees Celsius unless otherwise indicated.

The compounds of the invention are prepared according to the following Generic Scheme I.

Scheme I

I

General synthesis of cis-dihydrobenzoxathines and benzodioxanes

+

br

ABOUT'

(III)

removal of protecting groups

CVQ

Expressed verbally with respect to the scheme, bisphenol II with appropriately established functional groups (X = O, Y = O), which are readily available, or mercaptophenol II (X = O, Y = S), prepared by procedures known from the art. of the literature, is reacted with a bromoketone derivative III, which is readily prepared from the corresponding ketone by bromination with phenyltrimethylammonium tribromide (PTAB) in the presence of a tertiary amine base such as triethylamine, diisopropylethylamine and the like in a solvent such as dimethylformamide, DMF. dimethyl sulfoxide (DMSO), tetrahydrofuran (THF), dichloromethane and the like at -20 ° C to 80 ° C until the reaction is complete to give the displaced product IV. If X = Y = O, then only R ³ can be -OR ⁶ . Alternatively, when X = Y = O and R ² is -OR ⁶ , the necessary cyclization intermediate is obtained by exchange of the ketone and bromide functional groups. These conditions are required to allow the preparation of those

Compounds of the invention wherein the presence of certain substituents alters the reactivity of phenolic oxygen atoms.

Intermediate IV was reductively cyclized in the presence of an organic acid such as trifluoroacetic acid, triflic acid and the like, or a Lewis acid such as boron trifluoride etherate, stannous chloride and the like, and a reducing agent such as a trisubstituted silane such as triethylsilane and the like in a solvent. such as dichloromethane, chloroform, THF, toluene and the like at -40 ° C to 100 ° C until the reaction is complete to give the cyclized product V wherein the stereochemistry of the aryl substituent and R ^{5 is} in the newly formed ring exclusively cis. The formation of intermediates with analogous trans stereochemistry is shown in Scheme II.

In product V, when R ⁶ is a protecting group, it is removed in a manner appropriate to its nature. Such methods are well documented in texts in the literature which are part of standard textbooks such as Greene TW and Wuts PGM, Protective groups in organic synthesis, 3rd ed., Wiley, New York 1999. It is further understood that it is possible to have any the number of substituents R ¹ to R ⁴ that are or contain -OR ⁶ , or R ⁵ may contain -OR ⁶ , where R ⁶ is a protecting group, and it is further understood that in this situation, the protecting groups are chemically distinguishable, i.e. selectively remove if necessary. For example, in VR ^{6 the} product is methoxymethyl (MOM), R ² is -OR ⁶ , where R ⁶ is benzyl (Bn), R ⁵ is a phenyl ring, substituted with R ⁷ , where R ⁷ is OR ⁶ , where R ⁶ is triisopropylsilyl (TIPS) and all unspecified substituents are hydrogen. As indicated, as part of the synthetic sequence, it is necessary to selectively remove the MOM group, preferably over the TIPS or Bz groups. Using the methods found in Green and Wuts, it is possible to form the preferred intermediate V wherein R ⁶ is H, R ² is -OB 11, R ⁵ is para-OTIPS-phenyl and all unspecified substituents are hydrogen. It will also be noted that if either R ² or R ³ OR ⁶ is present in the product V, R ⁶ must be a protecting group, and that the existing -OR ⁶ group must be covered by a resolvable protecting group before removal.

The alcohol intermediate VI was then reacted with the HO (CH ₂ ) _n NZ ₂ 'reagent in a Mitsunobu reaction procedure in which these are coupled with a trisubstituted phosphine such as triphenylphosphine and a diazodicarboxylate such as diisopropylazodicarboxylate in a suitable solvent such as THF in a suitable solvent such as THF. temperature from 0 ° C to 80 ° C so

- 46 until the reaction is complete to produce the coupled product I. Variables for the Mitsunobu reaction are well documented and are incorporated herein by reference: Mitsunobu, O. Synthesis 1981, 1; Castro B.R., Org. React. 29, 1, 1983; Hughes D.

L., Org. React. 42, 335 (1992).

Finally, after the Mitsunobu reaction, it is understood that if any R group is or contains -OR ⁶ where R ⁶ is a protecting group, it has been removed using the appropriate method found in the Green and Wuts book to produce the final product, wherein R ⁶ is H.

Scheme II

General synthesis of trans-dihydrobenzoxathines and benzodioxanes

Expressed verbally with respect to the above scheme for the general preparation of the trans-isomers I, the ketone intermediate IV of Scheme I was reduced with sodium borohydride, superhydride and the like in a mixture of methanol and dichloromethane or THF and the like at a temperature of 0 ° C to ambient temperature over a few minutes to several hours to form the analogous hydroxyl intermediate VII.

Cyclization of intermediate VII was carried out in the presence of an acid catalyst such as amberlyst 15 or triflic acid and the like in a solvent such as toluene or dichloromethane and the like at ambient temperature to reflux to afford the trans compound VIII as the major isomer.

The remainder of the synthetic sequence for trans- formation is identical to the procedure outlined in Scheme I and discussed in detail above.

Compounds of the invention wherein X = O and Y = SO or SO ₂ are prepared as outlined in the specific schemes that follow.

Scheme III

General Synthesis of Dihydrobenzoxathine Dioxides

Expressed verbally with respect to Scheme III, compounds I of this invention are peroxidized with an oxidizing agent such as m-chloroperbenzoic acid or pertrifluoroacetic acid and the like in a solvent such as dichloromethane and the like at a temperature of from 0 ° C to reflux to Intermediate X was then selectively deoxygenated at a nitrogen atom by treatment with a reducing agent such as sodium bisulfite and the like in a biphasic medium such as ethyl acetate and water and the like to give a compound of formula I.

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

In the compounds of the invention, R ¹ , R ² , R ³ and R ⁴ are preferably selected from the group consisting of hydrogen, C 1-6. ₅ -alkyl, C _3-8 -cycloalkyl, C. _5- alkenyl, C 1-5 alkynyl, -OR ⁶ and halogen.

In the compounds of the invention, R ^{5 is} preferably selected from the group consisting of C ₃ . _8- cycloalkyl, phenyl and substituted phenyl.

In the compounds of the invention, R ^{6 is} preferably selected from the group consisting of hydrogen, C 1-6. _5- alkyl, benzyl, methoxymethyl and triisopropylsilyl.

In the compounds of the invention, a preferred subgroup has been found wherein R ¹ 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 invention, another preferred subgroup has been found wherein R ¹ is independently selected from fluoro and chloro, 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 invention, the most preferred subgroup has been found wherein R ¹ and R ⁴ are hydrogen and R ² is -OH, and R ⁵ is independently selected from the group consisting of phenyl and para-hydroxyphenyl.

-49Scheme IV

General synthesis of dihydrobenzoxatin oxides

Expressed verbally with respect to Scheme IV, intermediate V of Scheme I was monooxidized by treatment with one equivalent or with a slight excess of an oxidizing agent such as m-chloroperbenzoic acid or dimethyldioxirane and the like in a solvent such as dichloromethane, ether, acetone and the like , at a temperature of from -78 ° C to ambient temperature, from a few minutes to several hours to give the corresponding sulfoxide intermediate XI. The remainder of the synthetic sequence to produce the product of Formula I is identical to that outlined in Scheme I and is described in detail above.

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

In the compounds of the present invention, R ¹ , R ² , R ³ and R ⁴ are preferably selected from the group consisting of hydrogen, C _1-5 -alkyl, C 3-8 -cycloalkyl, C 1-6 -alkyl. _5- alkenyl, C 1-5 alkynyl, -OR ⁶ and halogen.

In the compounds of this invention, R ^{5 is} preferably selected from the group consisting of C 3-6 -cycloalkyl, phenyl and substituted phenyl.

In the compounds of the invention, R ^{6 is} preferably selected from the group consisting of hydrogen, C 1-6. _5- alkyl, benzyl, methoxymethyl and triisopropylsilyl.

In the compounds of this invention, a preferred subgroup has been found wherein R ¹ 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.

Another preferred subgroup has been found in the compounds of this invention wherein R ¹ is independently selected from 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 subgroup has been found wherein R ¹ and R ⁴ are hydrogen and R ² is -OH, and R ⁵ is independently selected from the group consisting of phenyl, meta-hydroxyphenyl and para-hydroxyphenyl.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

General preparation of thiophenols

R ² R ²

Functionalized thiophenols were prepared by the known small variation procedure shown in the above scheme: Werner G., Biebrich W., US Pat. 2,276,553 and 2,332,418.

The phenol shown above was prepared according to the following references: Maxwell S., J. Am. Chem. Soc. 69, 712 (1946); Hanzlik R. P. et al., J. Org. Chem. 55, 2736 (1990).

Example 2

Preparation of 2-thiophene-4-methoxybenzophenone

To a stirred solution of anisole (1.49 g, 13.8 mmol) in anhydrous dichloromethane (5 mL) was added AlCl 3 (1.2320 g, 9.2 mmol) followed by dropwise addition of 2-thiopheneacetyl chloride (0.57) mL, 4.6 mmol) at 0 ° C under N ₂ . The reaction mixture was stirred for 1.5 h, then poured into a separatory funnel containing ice / brine / EtOAc. The organic layer was further washed with brine, dried over Na ₂ SO 4 and concentrated in vacuo. The resulting residue was purified by silica gel chromatography with 30% EtOAc / hexane as eluent to afford the desired product as a yellow oil. ¹ H 500 MHz NMR (400 MHz, CDCl ₃ ) ppm (δ): 3.89 (s, 3H), 4.46 (s, 2H), 6.98 (m, 4H), 7.24 (d, 1H) and 8.05 (d, 2H).

-52Example 3

Preparation of 2-thiophene-4-hydroxybenzophenone

HO

A mixture of 2-thiophene-4-methoxybenzophenone (0.8294 g, 3.5 mmol) formed in Example 2 and pyridine-HCl (4.0627 g, 35.2 mmol) was heated to 190 ° C under N ₂ 6 h. The reaction was monitored by checking the removed aliquots of the reaction by TLC (30% EtOAc / hexane). The reaction mixture was cooled in an ice bath and ice / H ₂ O was added. The resulting mixture was extracted with EtOAc. The organic extract was washed with 2N HCl and brine, dried over Na ₂ SO ₄ and concentrated in vacuo. The resulting brown residue was purified by silica gel chromatography with 30% EtOAc / hexane as eluent to afford the desired product as a yellow-orange solid. ¹ H 500 MHz NMR (400 MHz, CDCl 3) ppm (δ): 4.43 (s, 2H), 5.60 (bs, 1H), 6.90 (d, 2H), 6.92 (m, 1H) 6.97 (m, 1H), 7.22 (d, 1H) and 8.00 (d, 2H).

Example 4

General preparation of cycloalkyl-4-hydroxybenzophenones

HO '

To a stirred solution of 2-cycloalkyl-1- (4-methoxyphenyl) -ethanone (prepared according to the method of Barrio et al., J. Med. Chem. 14, 898, 1971) in dry methylene chloride at 0 ° C was added 3.6 equivalents aluminum chloride and 3.0 equivalents of isopropyl mercaptan. The ice-water bath was removed and the reaction mixture was stirred overnight under an inert nitrogen atmosphere. The reaction mixture was poured onto 2N HCl / ice and extracted with ethyl acetate. The ethyl acetate extract was washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated. Cleaning

53-silica gel chromatography gave the corresponding 2-cycloalkyl-1- (4-hydroxyphenyl) -ethanone.

Using the previous experimental procedure, the following compounds were prepared:

2-Cyclohexyl-1- (4-hydroxyphenyl) -ethanone: 70% yield using methylene chloride-ethyl acetate (50: 1) as eluent of chromatography. ¹ H 500 MHz NMR (400 MHz, CDCl 3) ppm (Ô): 1 to 2.0 (m, 11 H), 2.96 (d, 1H), 5.6 (bs, 1H), 6, 92 (d, 2H); and 7.95 (d, 2H). 2-Cyclopentyl-1- (4-hydroxyphenyl) -ethanone: 74% yield using methylene chloride-ethyl acetate (50: 1) as eluent of chromatography. ¹ H 500 MHz NMR (400 MHz, CDCl 3) ppm (δ): 1.2-1.92 (m, 10H), 2.4 (m, 1H), 2.96 (d, 1H), 5.6 (bs, 1H), 6.91 (d, 2H) and 7.95 (d, 2H).

Example 5

Preparation of isopropyl-4-hydroxybenzophenone

To a mixture of isovaleric acid (1.4 mL, 13.0 mmol) and phenol (1.0253 g, 10.9 mmol) was added BF ₃ OEt ₂ (15 mL) under nitrogen. The resulting mixture was heated to 80 ° C for about 3.5 h. The reaction mixture was poured into ice / 2N HCl and extracted with EtOAc. The organic extract was washed with brine, dried over Na ₂ SO ₄ and concentrated in vacuo to give a yellow residue. The final product was isolated as a pale yellow oil after silica gel chromatography with 30% EtOAc / hexane as eluent. Upon standing at ambient temperature, this oil solidified and gave a white solid. ¹ H 500 MHz NMR (400 MHz, CDCl 3) ppm (δ): 1.01 (d, 6H), 2.27 (m, 1H), 2.81 (d, 2H), 6.99 (d, 2H) 7.93 (d, 2H).

Example 6

Preparation of 4-pyridyl-4-hydroxybenzophenone

-54ΗΟ

In a dry flask equipped with a stir bar was charged a 2.5 M solution of nBuLi in hexane (18 mL, 45.0 mmol) and cooled to 0 ° C under N ₂ . A solution of diisopropylamine (6.4 mL, 45.7 mmol) in distilled THF (20 mL) was added slowly. After stirring for 25 minutes, a solution of 4-picoline (2.0 mL, 21.4 mmol) in distilled THF (8 mL) was added to the reaction mixture. The resulting red solution was stirred for 25 minutes before removing the ice bath. A solution of cyanophenol (2.5670 g, 21.4 mmol) in distilled THF (20 mL) was added via dropping funnel over 30 minutes. Upon addition of phenol, the reaction mixture became a thick slurry which formed a reddish brown tar. Further addition of THF did not lessen the difficulty of stirring. The reaction mixture was allowed to stand at ambient temperature for 16 h and then poured into ice / saturated NH ₄ Cl / EtOAc. The amine intermediate precipitated from the mixture as an insoluble solid and was collected by vacuum filtration. This solid was redissolved in 2N HCl. The EtOAc layer from the filtrate was also collected and extracted with 2N HCl / ice. The acidic aqueous extract was combined with a solution of enamine in 2N HCl and stirred at ambient temperature for 16 h. The acidic solution was washed with EtOAc, cooled to 0 ° C and neutralized to pH 7 with saturated NaHCO 3 solution. The desired product precipitated out of solution as a yellow solid and was collected, washed with cold water and dried in vacuo. ¹ H 500 MHz NMR (d-acetone) ppm (δ): 4.37 (s, 2H), 6.97 (d, 2H), 7.31 (d, 2H), 8.01 (d, 2H) 8.52 (bs, 2H).

Example 7

Preparation of 3-pyridyl-4-hydroxybenzophenone

HO '

Following the procedure described in Example 6, except that 1 equivalent of HMPA in THF was added to the reaction mixture after the addition of diisopropylamine, 3-pyridyl-4-hydroxybenzophenone was prepared from 3-picoline. The treatment was slightly different in that hydrolysis with 2N HCl was not necessary. Instead, the reaction mixture was simply partitioned between ice / saturated NH ₄ Cl solution 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 Cl ₂ and EtOAc to give the desired product as an orange solid. ¹ H 500 MHz NMR (d-acetone) ppm (δ): 4.39 (s, 2H), 6.97 (d, 2H), 7.31 (m, 1H), 7.68 (m, 1H) 8.01 (d, 2H); 8.43 (m, 1H); 8.52 (m, 1H).

Example 8

General preparation of cycloalkyl-4-triisopropylsilyloxy-benzophenones

To a stirred solution of 2-cycloalkyl-1- (4-hydroxyphenyl) -ethanone prepared in Example 4 in dry DMF at 0 ° C was added 1.3 equivalents of diisopropylethylamine and 1.2 equivalents of triisopropylchlorosilane (TIPSCI). The ice-water bath was removed and the reaction mixture was stirred further until TLC showed that the reaction was complete (1-3 hours) under an inert nitrogen atmosphere. The reaction mixture was partitioned between ether (2N HCl) ice and the organic phase separated, washed twice with water, washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated. Purification by silica gel chromatography gave the corresponding 2-cycloalkyl-1- (4-triisopropyloxyphenyl) -ethanone.

Using the previous experimental procedure, the following compounds were prepared:

2-Cyclohexyl-1- (4-triisopropylsilyloxyphenyl) -ethanone: methylene chloride-hexanes (1: 1) was used as the eluent of the chromatography. ¹ H 500 MHz NMR (400 MHz, CDCl 3) ppm (Ô): 1.13 (d, 18H), 1 to 1.99 (m, 14H), 2.78 (d, 1H), 6.91 (d , 2H) and 7.89 (d, 2H).

-562-Cyclopentyl-1- (4-triisopropylsilyloxyphenyl) -ethanone: methylene chloride-hexanes (1: 1) was used as the eluent of the chromatography. ¹ H 500 MHz NMR (400 MHz, CDCl ₃ ) ppm (δ): 1.12 (d, 18H), 1.2-1.91 (m, 13H), 2.4 (m, 1H), 2, 95 (d, 1H), 6.92 (d, 2H), and 7.9 (d, 2H).

Example 9

General preparation of alkyl-4-triisopropylsilyloxy-benzophenones

To a solution of 2-alkyl-1- (4-hydroxyphenyl) -ethanone prepared in Examples 3, 6 and 7 in distilled THF was added 1.3 equivalents of 60% NaH in mineral oil at 0 ° C under N ₂ . After gas evolution had ceased, 1.1 equivalents were added dropwise and the resulting solution was stirred for 30 minutes. The reaction mixture was partitioned between ice / water and EtOAc. The organic layer was washed with brine, dried over Na ₂ SO ₄ and concentrated in vacuo. Purification by silica gel chromatography gave the corresponding 2-alkyl-1- (4-triisopropylsilyloxyphenyl) -ethanones.

Using the previous experimental procedure, the following compounds were prepared:

2- (2-Thiophene) -1- (4-triisopropylsilyloxyphenyl) -ethanone: isolated as an orange-yellow solid using 15% EtOAc / hexane as the eluent of chromatography. ¹ H 500 MHz NMR (400 MHz, CDCl ₃ ) ppm (δ): 1.14 (d, 18H), 1.30 (m, 3H), 4.42 (s, 2H) and 6.93-7, 98 (m, 7 H).

2- (4-Pyridyl) -1- (4-triisopropylsilyloxyphenyl) -ethanone: isolated as a yellow solid using 40% EtOAc / hexane as eluent of chromatography. ¹ H 500 MHz NMR (400 MHz, CDCl ₃ ) δ (δ): 1.14 (d, 18H), 1.30 (m, 3H), 4.28 (s, 2H), 6.97 (d, 2H), 7.35 (m, 1H), 7.69 (m, 1H), 7.97 (d, 2H) and 8.56 (bs, 2H).

2- (3-Pyridyl) -1- (4-triisopropylsilyloxyphenyl) -ethanone: isolated as a yellow solid using 40% EtOAc / hexane as the eluent of chromatography. ¹ H 500 MHz NMR (400 MHz, CDCl ₃ ) ppm (δ): 1.14 (d, 18H), 1.20 (m, 3H), 4.18 (s, 2H), 6.82 (d, 2H), 7.10 (d, 2H), 7.82 (d, 2H) and 8.43 (d, 2H).

-57Example 10

General procedure for brominating alkyl- and cycloalkyl-4-triisopropylsilyloxy-benzophenones

To a stirred solution of 2-alkyl- and 2-cycloalkyl-1- (4-triisopropylsilyloxyphenyl) ethanones, prepared in Examples 8 and 9, in dry THF at 0 ° C was added 1.0 equivalents of trimethylammonium phenylbromomethane. The ice-water bath was removed and the reaction mixture was further stirred for 1 hour under an inert nitrogen atmosphere. The reaction mixture was partitioned between ethyl acetate / brine / ice / 5% sodium thiosulfate / sodium bicarbonate and the organic phase separated, washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated. Purification by silica gel chromatography gave the corresponding 2-cycloalkyl-2-bromo-1- (4-triisopropylsilyloxyphenyl) -ethanone.

Using the foregoing experimental procedure, the following compounds were prepared;

2-Cyclohexyl-2-bromo-1- (4-triisopropylsilyloxyphenyl) -ethanone: methylene chloride hexanes (1: 1) were used as the eluent of the chromatography. ¹ H 500 MHz NMR (400 MHz, CDCl 3) ppm (δ): 1.14 (d, 18H), 0.98 to 2.27 (m, 15H), 4.91 (d, 1H), 6, 94 (d, 2H) and 7.94 (d, 2H).

2-Cyclopentyl-2-bromo-1- (4-triisopropylsilyloxyphenyl) -ethanone: methylene chloride-hexanes (1: 1) was used as the eluent of the chromatography. ¹ H 500 MHz NMR (400 MHz, CDCl 3) ppm (δ): 1.13 (d, 18H), 1.1 to 2.2 (m, 11H), 2.8 (m, 1H), 4, 98 (d, 1H), 6.94 (d, 2H) and 7.96 (d, 2H).

2- (2-Thiophene) -2-bromo-1- (4-triisopropylsilyloxyphenyl) ethanone: stirred at 0 ° C for 40 minutes; isolated as a dark brown oil and used in the next reaction without purification. ¹ H 500 MHz NMR (400 MHz, CDCl ₃ ) ppm (?): 1.13 (d, 18H), 1.30 (m, 3H), 6.73 (s, 1H), 6.97 (d, 2H), 7.00 (m, 1H), 7.30 (m, 1H), 7.49 (d, 1H) and 8.00 (d, 2H).

2- (4-Pyridyl) -2-bromo-1- (4-triisopropylsilyloxyphenyl) -ethanone: 2 equivalents of trimethylammoniumphenyl bromomethane added and stirred at 0 ° C for 1 hour; isolated as

-58 orange-yellow oil and used in the next reaction without purification. ¹ H 500 MHz NMR (400 MHz, CDCl ₃ ) ppm (δ): 1.03 (d, 18Η), 1.21 (m, 3H), 6.21 (s, 1H), 6.98 (d, 2H);

7.40 (d, 2H), 7.90 (d, 2H) and 8.57 (d, 2H).

2- (3-Pyridyl) -2-bromo-1- (4-triisopropylsilyloxyphenyl) -ethanone: 2 equivalents of trimethylammonium phenyl bromoethane added and stirred at 0 ° C for 3 h; isolated as an orange-yellow oil and used in the next reaction without purification. ¹ H 500 MHz NMR (400 MHz, CDCl 3) ppm (δ): 1.13 (d, 18H), 1.30 (m, 3H), 6.30 (s, 1H), 6.98 (d, 2H) 7.39 to 8.75 (m, 6H).

Example 11

Preparation of 2-isopropyl-2-bromo-1- (4-hydroxyphenyl) -ethanone

Following the procedure described in Example 10, using the product obtained from Example 5, 2-isopropyl-2-bromo-1- (4-hydroxyphenyl) -ethanone was isolated as a yellow oil and used in the next reaction without purification. ¹ H 500 MHz NMR (400 MHz, CDCl 3) ppm (δ): 1.01 (d, 3H), 1.21 (d, 3H), 2.46 (m, 1H), 4.93 (d, 1H), 6.96 (d, 2H) and 7.96 (d, 2H).

Example 12

General preparation of bromoketones

R = H or MOH

Step A

To a stirred solution of 3.0 g (13.2 mmol) dry deoxybenzoin (freshly azeotroped with toluene) in 25 mL DMF at 0 ° C was added 5.7 mL (5.7 mmol)

-59 pure diisopropylethylamine. To this stirred solution was slowly added 1.25 mL (19.73 mmol) of chloromethyl methyl ether (MOMCI). The ice-water bath was removed and the mixture was further stirred under a nitrogen atmosphere for 18 hours. The mixture was then poured into saturated NaHCO ₃ solution, extracted with EtOAc, and the extract was washed with water and

I dried over anhydrous MgSO ₄ . After evaporation of the solvent, the residue was purified by silica gel chromatography (EtOAc / hexane = 1: 1) to give the product as a solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 8.0 (d, 2H), 7.19 (d, 2H), 7.10 (d, 2H), 6.8 (d, 2H) 5.23 (s, 2H), 4.8 (s, 1H), 4.2 (s, 2H), 3.5 (s, 3H).

Step B

To a stirred solution of the product obtained from Step A (423 mg, 1.55 mmol) and imidazole (211 mg, 3.1 mmol) in 20 mL of dry DMF at 0 ° C was added triisopropylsilyl chloride (3.1 mmol) and reaction mixture. the mixture was allowed to warm to ambient temperature and stirred for a further 2-3 hours. The reaction was quenched by addition of aqueous NaHCO ₃ solution and extracted with EtOAc. The organic layer was washed with brine and dried over MgSO ₄ . Chromatography (10% EtOAc / hexane) provided the desired product. ¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 8.0 (d, 2H), 7.12 (d, 2H), 7.08 (d, 2H), 6.82 (d, 2H) 5.21 (s, 2H), 4.18 (s, 2H), 3.5 (s, 3H), 1.24 (m, 3H), 1.1 (d, 18H).

Step C

To a mixture of the compound of Step B (0.5 g, 1.16 mmol) in 100 mL of anhydrous THF at 0 ° C was added 0.39 g (1.16 mmol) of trimethylphenylammonium bromide (PTAB). The ice-water bath was removed and the mixture was further stirred for one hour. The solution was then filtered and washed with water and brine and dried over MgSO ₄ . Removal of the solvent gave a mixture of bromoketones (the MOM group was partially removed), which was used without further purification due to its instability to chromatography. Bromoketone with MOM group: ¹ H NMR (400 MHz, CDCl 3) δ (ppm): 8.0 (d, 2H), 7.4 (d, 2H), 6.88 (d, 2H), 6.86 ( d, 2H), 6.36 (s, 1H), 1.24 (m, 3H), 1.1 (d, 18H); Bromoketone without MOM group: ¹ H NMR (400 MHz, CDCl 3) δ (ppm): 7.94 (d, 2H), 7.4 (d, 2H), 6.88 (d, 2H), 6.86 ( d, 2H), 6.36 (s, 1H), 1.24 (m, 3H), 1.1 (d, 18H).

-60Example 13

Preparation of a compound of formula

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

Example 14

Preparation of a compound of formula

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

Example 15

Preparation of a compound of formula

Step A

To a stirred solution of a mixture of 0.1 g (0.37 mmol) of the monophenol compound from Step A in Example 12 and diisopropylethylamine (0.13 mL, 2 eq.) In 5 mL of DMF at

Pure MOMCI (0.05 mL, 2 eq) was slowly added to room -61 and the mixture was heated to 85 ° C under N _{2 for} three hours. The mixture was then poured into saturated NaHCO 3, extracted with EtOAc, washed with water and dried over MgSO 4. After evaporation of the solvent, the residue was purified by silica gel chromatography (EtOAc / hexane = 1: 1) to give

The pure bis-protected MOM product was formed as a solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 8.0 (d, 2H), 7.19 (d, 2H), 7.10 (d, 2H), 7.02 (d, 2H) 5.23 (s, 2H), 5.2 (s, 2H), 4.2 (s, 2H), 3.5 (two s, 6H).

Step B

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

Example 16

General preparation

To a stirred, freshly prepared solution of 2-thiophenol (0.2 g, 1.6 mmol) and Et ₃ N (0.34 mL, 2 eq) in 15 mL DMF at 0 ° C was slowly added a solution of 0.627 g (1.232) mmol) of bromoketone (prepared in Step C of Example 12) in 13 mL of DMF. The reaction mixture was stirred at room temperature for three hours and then partitioned between saturated NaHCO ₃ solution and EtOAc, the layers were separated and the aqueous layer was extracted again with EtOAc. The combined organic layers were dried (Na ₂ SO ₄ ), filtered and evaporated in vacuo. The resulting oil was purified by flash chromatography (EtOAc / hex = 1/4) to give the desired product as an oil. ¹ H NMR (400 MHz, acetone-d ₆ ) δ (ppm): 8.0 (d, 2H), 7.2-6.6 (m, 8H), 6.8 (d, 2H), 2 (s, 1H), 5.24 (s, 2H), 3.4 (s, 3H), 1.22 (m, 3H), 1.1 (d, 18H); MS m / z 575 (M < ^{+ >} +23).

-62Example 17

Cyclization of the Binding Product

Following the procedure described in Example 16, 1,2-dihydroxybenzene and bromide of Example 15 were converted to the product, which was purified by silica gel chromatography using EtOAc / hexane (1/4) as eluent. MS m / z 448 (M < ^{+ >} +23).

Example 18

Preparation of a compound of formula

OTIPS

Following the procedure described in Example 16 and using 0.83 g (3.6 mmol) of the 4-benzyloxy-thiophenol prepared in Example 1, product A and product B were obtained after silica gel chromatography using EtOAc / hexane (1/5) as eluent.

A: ¹ H NMR (400 MHz, acetone-d ₆ ) δ (ppm): 8.15 (s, 1H), 7.8 (d, 2H), 7.4 (m, 5H), 6.98 ( d, 2H), 6.98 (d, 1H), 6.75 (d & d, 4H), 6.0 (s, 1H), 5.62 (s, 1H), 5.0 (s, 2H) 1.22 (m, 3H), 1.15 (d, 18H).

B: ¹ H NMR (400 MHz, acetone-d ₆ ) δ (ppm): 8.0 (d, 2H), 7.5 (m, 5H), 7.18 (d, 2H), 7.04 ( d, 2H), 6.96 (d, 1H), 6.8 (d, 2H), 6.56 (d, 1H), 6.32 (dd, 1H), 6.1 (s, 1H), 5.25 (s, 2H), 5.09 (s, 1H), 3.4 (s, 3H), 1.22 (m, 3H), 1.1 (d, 18H).

-63Example 19

Preparation of a compound of formula

Following the procedure described in Example 16, using 1.1 g (2.3 mmol) of the bromoketone of Example 14, the desired product was obtained after silica gel chromatography using EtOAc / hexane (1/5) as eluent. ¹ H NMR (400 MHz, acetone-d ₆ ) δ (ppm): 8.46 (br s, 1H), 7.98 (d, 2H), 7.48-7.3 (m, 5H), 7 24 (d, 2H); 7.4 (d, 1H); 6.92 (d, 2H); 6.82 (d, 2H); 6.56 (d, 1H); 6.38 (dd, 2H); 1H), 6.1 (s, 1H), 5.04 (s, 2H), 3.72 (s, 3H), 1.25 (m, 3H), 1.1 (d, 18H).

Example 20

Preparation of a compound of formula

Following the procedure described in Example 16 and using 0.74 g (1.5 mmol) of the bromoketone of Example 12 (Step C), the desired product was obtained after silica gel chromatography using EtOAc / hexane (1/5) as eluent. ¹ H NMR (400 MHz, acetone-de) δ (ppm): 7.92 (d, 2H), 7.46 to 7.1 (m, 5H), 7.18 (d, 2H), 6.84 (d, 2H)

6.78 (d, 2H), 6.42 (d, 1H), 6.36 (d, 1H), 5.98 (s, 1H), 5.02 (s, 2H), 2.2 (s) 3H), 1.22 (m, 3H), 1.1 (d, 18H).

-64Example 21

Preparation of a compound of formula

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

Example 22

Preparation of a compound of formula

OTIPS

Following the procedure described in Example 16, using 0.56 g (1.1 mmol) of the bromoketone of Example 12 (Step C) with 0.19 g (0.73 mmol) of the thiophenol derivative prepared in Example 1, the desired product was obtained. obtained after silica gel chromatography using EtOAc / hexane (1/5) as eluent. ¹ H NMR (400 MHz, acetone-d ₆ ) δ (ppm): 7.9 (d, 2H), 7.48-7.3 (m, 5H), 7.16 (d, 2H), 6, 84 (d, 2H), 6.78 (d, 2H), 6.42 (d, 1H), 6.38 (d, 1H), 5.96 (s, 1H), 5.1 (s, 2H) ), 2.6 (q, 2H), 1.22 (m, 3H), 1.1 (d, 18H), 1.1 (t, 3H).

-65Example 23

Preparation of a compound of formula

Following the procedure described in Example 16 and using 2.04 g (4.33 mmol) of the bromoketone of Example 12 (Step C) with the thiophenol derivative prepared in Example 1, the desired product was obtained after silica gel chromatography using EtOAc / hexane ( 1/5) as eluent. ¹ H NMR (400 MHz, acetone-de) δ (ppm): 7.9 (d, 2H), 7.5-7.3 (m, 5H), 7.12 (d, 2H), 6.92 (d, 1H), 6.84 (d, 2H), 6.78 (d, 2H), 6.42 (d, 1H), 6.0 (s, 1H), 5.1 (s, 2H) 2.7 (q, 2H), 1.24 (m, 3H), 1.1 (d & t, 21H).

Example 24

Preparation of a compound of formula

Following the procedure described in Example 16 and using 2.0 g (4.33 mmol) of the bromoketone of Example 12 (Step C) with the thiophenol derivative prepared in Example 1, the desired product was obtained after silica gel chromatography using EtOAc / hexane ( 1/5) as eluent. ¹ H NMR (400 MHz, acetone-de) δ (ppm): 7.8 (d, 2H), 7.62 (d, 2H), 7.48-7.3 (m, 8H), 7.12 (d, 2H), 6.8 (d, 2H), 6.76 (d, 2H), 6.28 (d, 1H), 6.18 (d, 1H), 6.0 (s, 1H) 5.24 (s, 2H), 5.05 (s, 2H), 1.22 (m, 3H), 1.1 (d, 18H).

-66Example 25

Preparation of a compound of formula

Following the procedure described in Example 16, using 1.6 g (3.51 mmol) of the bromoketone of Example 13 with the thiophenol derivative prepared in Example 1, the desired product was obtained after silica gel chromatography using EtOAc / hexane (1/5). ) as eluent. ¹ H NMR (400 MHz, acetone-d ₆ ) δ (ppm): 8.0 (d, 2H), 7.5-7.2 (m, 10H), 7.0 (d, 1H), 92 (d, 2H), 6.54 (d, 1H), 6.35 (dd, 1H), 6.12 (s, 1H), 5.06 (s, 2H), 1.22 (m, 3H) , 1.1 (d, 18H).

Example 26

Preparation of a compound of formula

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

Example 27

Preparation of a compound of formula

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

Example 28

Preparation of a compound of formula

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

Example 29

Preparation of a compound of formula

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

Example 30

Preparation of a compound of formula

Following the procedure described in Example 16, and using the bromoketone of Example 12 with the thiophenol derivative prepared in Example 1, the desired product was obtained after silica gel chromatography using EtOAc / hexane (1/5) as eluent. ¹ H NMR (500 MHz, CDCl 3) δ (ppm): 8.20 (s, 1H), 7.81 (d, 2H), 7.40 (m, 5H), 7.02 (d, 2H), 6.75 (d, 4H), 6.36 (d, 1H), 6.20 (dd, 1H), 5.78 (s, 1H), 4.95 (s, 2H), 1.23 (m 3H), 1.10 (m, 18H).

Example 31

Preparation of a compound of formula

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

Example 32

Preparation of a compound of formula

Following the procedure described in Example 16, and using the bromoketone of Example 12 with the thiophenol derivative prepared in Example 1, the desired product was obtained after silica gel chromatography using EtOAc / hexane (1/5) as eluent. ¹ H NMR (500 MHz, acetone-d ₆ ) δ (ppm): 7.95 (d, 2H), 7.40 (m, 5H), 7.20 (d, 2H), 6.80 (m, 7H), 6.20 (s, 1H), 4.85 (s, 2H), 1.23 (m, 3H), 1.10 (m, 18H); MS m / z 616 (M ⁺ +1).

Example 33

Preparation of a compound of formula

Following the procedure described in Example 16, and using the bromoketone of Example 12 with the thiophenol derivative prepared in Example 1, the desired product was obtained after silica gel chromatography using EtOAc / hexane (1/5) as eluent. ¹ H NMR (500 MHz, CDCl ₃ ) δ (ppm): 7.82 (d, 2H), 7.40 (m, 5H), 7.05 (d, 2H), 6.95 (s, 1H) 6.80 (d, 4H), 6.52 (s, 1H), 5.64 (s, 1H), 5.00 (s, 2H), 1.23 (m, 3H), 1.10 ( m, 18H); MS m / z 629 (M ⁺ +1).

Example 34

Preparation of a compound of formula

OTIPS

Following the procedure described in Example 16, and using the bromoketone of Example 12 with the thiophenol derivative prepared in Example 1, the desired product was obtained after silica gel chromatography using EtOAc / hexane (1/5) as eluent. ¹ H NMR (500 MHz, CDCl ₃ ) δ (ppm): 8.24 (s, 1H), 7.80 (d, 2H), 7.40 (m, 5H), 7.10 (d, 2H) 6.78 (d, 2H), 6.76 (d, 2H), 6.64 (d, 2H), 6.45 (d, 2H), 5.86 (s, 1H), 4.98 ( s, 2H),

1.23 (m, 3H); 1.10 (m, 18H); MS m / z 650 (M ⁺ +1).

Example 35

Preparation of a compound of formula

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

1.23 (m, 3H); 1.10 (m, 18H).

Example 36

Preparation of a compound of formula

Following the procedure described in Example 16, and using the bromoketone of Example 13 with the thiophenol derivative prepared in Example 1, the desired product was obtained after silica gel chromatography using EtOAc / hexane (1/5) as eluent. ¹ H NMR (500 MHz, CDCl ₃ ) δ (ppm): 7.98 (s, 1H), 7.82 (d, 2H), 7.40 (m, 5H), 7.25 (m, 3H) 7.20 (d, 2H); 7.00 (d, 1H); 6.80 (d, 2H); 6.60 (d, 1H); 5.78 (s, 1H); 4.78 (d, 2H); d, 2H),

1.23 (m, 3H); 1.10 (m, 18H).

Example 37

Preparation of a compound of formula

(11)

Following the procedure described in Example 16, and using the bromoketone of Example 13 with a mixture of the two thiophenol derivatives prepared in Example 1, the two desired products I and II were obtained after silica gel chromatography using EtOAc / hexane (1/5) as eluent.

I: ¹ H NMR (500 MHz, CDCl ₃ ) δ (ppm): 7.80 (d, 2H), 7.40 (m, 5H), 7.25 (m, 3H), 7.16 (d, 2H), 7.04 (s, 1H), 6.80 (d, 2H), 6.60 (s, 1H), 5.78 (s, 1H), 4.80 (d, 2H), 1, 23 (m, 3H), 1.10 (m, 18H).

II: ¹ H NMR (500 MHz, CDCl ₃ ) δ (ppm): 7.80 (d, 2H), 7.65 (s, 1H), 7.44 (d, 1H), 7.40 (m, 5H), 7.25 (m, 5H), 6.96 (d, 1H), 6.80 (m, 3H), 6.00 (s, 1H), 5.15 (s, 2H), 1, 23 (m, 3H), 1.10 (m, 18H).

Example 38

Preparation of a compound of formula

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

Example 73

General preparation

.OT1PS

Using the bromides prepared in Example 10 and the corresponding mercaptan prepared in Example 1 and using the procedure described in Example 16, the following compounds were prepared:

Cyclohexyl derivative: use of methylene chloride / hexanes (3: 1) as chromatographic eluent. ¹ H 500 MHz NMR (400 MHz, CDCl 3) δ (ppm): 1.12 (d, 18H), 1.11 to 2.34 (m, 15H), 4.19 (d, 1H), 5.0 (s, 2H), 6.44 (dd, 1H), 6.54 (d, 1H), 6.86 (m, 3H), 7.25-7.72 (m, 7H).

Cyclopentyl derivative: use of methylene chloride / hexanes (2: 1) as chromatographic eluent. ¹ H 500 MHz NMR (400 MHz, CDCl ₃ ) δ (ppm): 1.12 (d, 18H),

1.28 to 2.49 (m, 12H), 4.18 (d, 1H), 5.0 (s, 2H), 6.45 to 7.77 (m, 12H).

Example 40

Preparation of a compound of formula

OH

Ph O '

OH

Using the bromide prepared in Example 11 and the corresponding mercaptan prepared in Example 1, and using the procedure described in Example 9, the desired product was obtained as a yellow oil in 77% yield after silica gel chromatography with 30% EtOAc / hexane as eluent. ¹ H 500 MHz NMR (400 MHz, CDCl ₃ ) δ (ppm): 1.00 (d, 3H),

-741.21 (d, 3H), 2.30 (m, 1H), 4.13 (d, 1H), 4.99 (s, 2H), 6.41-7.72 (m, 12H), 8.02 (bs, 1H); 8.80 (bs, 1H); MS m / z 409 (M < ^{+ >} ).

Example 41

General Preparation of Compounds of Formula

ph

OTIPS

Using the bromides prepared in Example 10 and the corresponding mercaptan prepared in Example 1, and using the procedures described in Example 16, the following compounds were prepared:

Cyclohexyl derivative: use of methylene chloride / hexanes (3: 1) as chromatographic eluent. ¹ H 500 MHz NMR (400 MHz, CDCl ₃ ) δ (ppm): 1.12 (d, 18H), 1.11-2.3 (m, 15H), 4.24 (d, 1H), 4.89 (m, 2H), 6.8-7.6 (m, 12H).

Cyclopentyl derivative: use of methylene chloride / hexanes (2: 1) as chromatographic eluent. ¹ H 500 MHz NMR (400 MHz, CDCl 3) δ (ppm): 1.12 (d, 18H),

1.26 to 2.12 (m, 11H), 2.5 (m, 1H), 4.24 (d, 1H), 4.9 (m, 2H), 6.8 to 7.69 (m , 12H). 4-Pyridyl derivative: isolated as a yellow oil using 30% EtOAc / hexane as chromatographic eluent. ¹ H 500 MHz NMR (400 MHz, CDCl 3) δ (ppm): 1.12 (d, 18H), 1.28 (m, 3H), 4.84 (q, 2H), 4.88 (s, 1) H, 5.63 (s, 1H) and 6.69-8.50 (m, 16H). 3-Pyridyl derivative: isolated as a yellow oil using 30% EtOAc / hexane as chromatographic eluent. 500 MHz ¹ H NMR (400 MHz, CDCl 3) δ (ppm) 1 _f 12 (d, 18H), 1.28 (m, 3H), 4.84 (q, 2H), 4.90 (s, 1 H, 5.79 (s, 1H) and 6.70-8.50 (m, 16H).

Example 42

Preparation of a compound of formula

OH

Ph ^ / O.

OH

Using the bromide prepared in Example 11 and the corresponding mercaptan prepared in Example 1 and using the procedure described in Example 16, the desired product was obtained as a yellow oil after silica gel chromatography with 30% EtOAc / hexane as eluent. ¹ H 500 MHz NMR (400 MHz, CDCl ₃ ) δ (ppm): 1.02 (d, 3H), 1.21 (d, 3H), 2.34 (m, 1H), 4.13 (d, Δ), 4.90 (q, 2H), 6.25 (bs, 1H), 6.79-7.70 (m, 12H).

Example 43

Preparation of a compound of formula

OTIPS

Using the appropriate bromide prepared in Example 10 and mercaptoquinol [prepared according to the method of Burton et al., J. Chem. Soc. 2193, 1952] and using the procedure described in Example 16, the desired product was obtained as an orange-red oil after silica gel chromatography with 30% EtOAc / hexane as eluent. ¹ H 500 MHz NMR (400 MHz, CDCl ₃ ) δ (ppm): 1.10 (d, 18H), 1.27 (m, 3H), 6.00 (s, 1H) and 6.76-7, 89 (m, 10 H); MS m / z 515 (M < ^{+ >} ).

Example 44

Preparation of a compound of formula

To a flask of 0.1 g (0.16 mmol) of the thioketone formed in Example 22 in dichloromethane (about 0.04M) was slowly added trifluoroacetic acid (TFA) (2 x 0.062 mL, 10 eq.) Under N ₂ atmosphere. at room temperature. To the stirred reaction mixture was added

Triethylsilane (2 x 0.05 mL, 4 eq) was added slowly and the resulting mixture until the starting material was consumed (about 5-6 hours as monitored by TLC). The reaction mixture was poured into saturated NaHCO 3 solution of ice water, stirred for 10 minutes and extracted with dichloromethane. The organic extract was washed with brine (2 x 50 mL), dried over Na 2 SO 4 and concentrated in vacuo to give a light yellow oil. Purification by flash chromatography (EtOAc / hex = 1: 5) gave the desired compound as an oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.44 (m, 5H), 6.98 (d, 1H), 6.90 (d, 2H), 6.75 (d, 2H) 6.68 (d, 2H), 6.65 (d, 1H), 6.63 (d, 2H), 5.51 (d, J = 2.3 Hz, 1H), 5.10 (s, 2H), 4.74 (brs, 1H), 4.32 (d, J = 2.3 Hz, 1H), 2.77 (qd, 2H), 1.22 (m, 3H), 1.08 ( m, 18H), 1.1 (m, 3H); MS m / z 628.5 (M ⁺ +1).

Example 45

Preparation of a compound of formula

Using the procedure of Example 44, the desired dihydrobenzoxathine without MOM protecting group was isolated after purification by silica gel chromatography with 10% EtOAc / hexane. ¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.2-6.98 (m, 4H), 6.85 (d, 2H), 6.78 (d, 2H), 6.66 ( two d, 4H), 5.5 (d, J = 2.2Hz, 1H), 4.8 (s, 1H), 4.33 (d, J =

2.1 Hz, 1H), 1.22 (m, 3H), 1.1 (d, 18H); MS m / z 515 (M < ^{+ >} +23).

A second dihydrobenzoxathiin with an MOM protecting group was also isolated. ¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.2-6.6 (m, 8H), 6.78 (d, 2H), 6.66 (d, 2H), 5.5 ( d, J = 2.4Hz, 1H), 5.14 (s, 2H), 4.35 (d, J = 2.1Hz, 1H), 3.48 (s, 3H), 1.22 ( m, 3H),

M / z 1.1 (d, 18H).

Example 46

Preparation of a compound of formula

Using the procedure of Example 71 (Step C), the dihydrobenzoxathiin formed in Example 45 was desilylated to give the product ¹ H NMR (400 MHz, CDCl 3) δ (ppm):

7.2 to 6.96 (m, 4H), 6.92 (two d, 4H), 6.82 (d, 2H), 6.6 (d, 2H), 5.52 (d, J = 2) 2 Hz, 1H), 5.16 (s, 2H), 4.68 (brs, 1H), 4.38 (d, J = 2.2 Hz, 1H), 3.48 (s, 3H).

Example 47

Preparation of a compound of formula

The ketone formed in Example 17 was converted to the desired product according to the procedure described in Example 44, except that 5 equivalents of TFA and 2 equivalents of Et ₃ SiH were required to bring the reaction to completion. The MOM group was removed by gentle treatment with acid (2N HCl, 75 ° C) to give the desired product. ¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.0 (m, 4H), 6.85 (d, 2H),

6.65 (d, 2H); 5.38 (s, 2H); MS m / z 343 (M < ^{+ >} +23).

Example 48

Preparation of a compound of formula

The ketone formed in Example 18 was converted to dihydrobenzoxathine using the procedure of Example 44, except that 20 equivalents of TFA and 15 equivalents of Et ₃ SiH were required to bring the reaction to completion. The desired product was isolated after purification by silica gel chromatography using 10% EtOAc / hexane as eluent. ¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.5-7.34 (m, 5H), 7.08 (d, 1H), 6.84 (d, 2H), 6.76 ( d, 2H), 6.7 (dd, 1H), 6.67 (d, 1H), 6.68 (two d, 4H), 5.5 (d, J = 2.2 Hz, 1H), 5 0.04 (br q, 2H), 4.68 (s, 1H), 4.3 (d, J = 2.2 Hz, 1H),

1.22 (m, 3H); 1.1 (d, 18H); MS m / z 515 (M < ^{+ >} +23).

Example 49

Preparation of a compound of formula

The ketone formed in Example 19 was converted to dihydrobenzoxathine using the procedure described in Example 44, except that the reaction was carried out at -10 ° C for 48 hours in the presence of 20 equivalents of TFA and 2 equivalents of Et ₃ SiH. The desired product [with 20% recovered starting material] was isolated after purification by silica gel chromatography using 10% EtOAc / hexane as eluent. ¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.5-7.3 (m, 5H), 7.1-6.6 (m, 11H), 5.54 (d, J = 1) 9 Hz, 1H), 5.06 (dd, 2H), 4.32 (d, 1H), 3.74 (s, 3H), 1.22 (m, 3H), 1.1 (d, 18H) ).

Example 50

Preparation of a compound of formula

Following the procedure described in Example 44, and using the ketone derivative of Example 20, the desired product was obtained after purification by silica gel chromatography using 5% EtOAc / hexane as eluent. ¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.46-7.32 (m, 5H), 6.84 (d, 2H), 6.78 (d, 2H), 6.66 ( two d, 4H), 6.62 (d, 1H), 6.57 (d, 1H), 5.3 (d, J = 2.2 Hz, 1H), 4.35 (d, 1H), 2 28 (s, 3H), 1.22 (m, 3H), 1.1 (d, 18H).

Example 51

Preparation of a compound of formula

Following the procedure described in Example 44, using the ketone derivative of Example 21, the desired product was obtained after purification by silica gel chromatography using 5% EtOAc / hexane as eluent. ¹ H NMR (400 MHz, _CDCl3) δ (ppm): 7.5 to

7.3 (m, 5H), 6.98 (d, 1H), 6.9 (d, 1H), 6.76 (d, 2H), 6.6 (m, 5H), 5.51 (d) J = 2.2 Hz, 1H), 5.1 (s, 2H), 4.8 (s, 1H), 4.32 (d, 1H), 2.4 (s, 3H), 1.22 (m, 3H); 1.1 (d, 18H).

Example 52

Preparation of a compound of formula

ABOUT'

OTIPS

BnO '

OH

Following the procedure described in Example 44, using the ketone derivative of Example 22, the desired product was obtained after purification by silica gel chromatography using 5% EtOAc / hexane as eluent. ¹ H NMR (400 MHz, _CDCl3) δ (ppm): 7.5 to

7.3 (m, 5H), 6.85 (d, 2H), 6.78 (d, 2H), 6.66 (m, 5H), 6.56 (d, 1H), 5.48 (d) J = 2.0 Hz, 1H), 5.04 (br q, 2H), 4.74 (br s, 1H), 4.34 (d, J = 2.0 Hz, 1H), 2.64 (q, 2H), 1.3 (t, 3H), 1.24 (m, 3H), 1.1 (d, 18H).

Example 53

Preparation of a compound of formula

Following the procedure described in Example 44, using the ketone derivative of Example 23, the desired product was obtained after purification by silica gel chromatography using 5% EtOAc / hexane as eluent. ¹ H NMR (400 MHz, _CDCl3) δ (ppm): 7.5 to

7.3 (m, 5H), 6.98 (d, 1H), 6.9 (d, 2H), 6.74 (d, 2H), 6.7-6.6 (tri d, 5H), Δ (d, J =

2.3 Hz, 1H), 5.1 (s, 2H), 4.74 (brs, 1H), 4.32 (d, J = 2.4 Hz, 1H), 2.79 (m, 2H), 1 22 (m, 3H); 1.1 (d ', 21 H); MS m / z 628.5 (M ⁺ +1).

Example 54

Preparation of a compound of formula

Following the procedure described in Example 44 and using the ketone derivative of Example 24, the desired product was obtained after purification by silica gel chromatography using 5% EtOAc / hexane as eluent. ¹ H NMR (400 MHz, _CDCl3) δ (ppm): 7.5 to

7.3 (m, 10H), 6.84 (d, 2H), 6.78 (d, 2H), 6.66 (two d, 4H), 6.38 (s, 2H), 5.48 ( d, J =

-81 2.1 Hz, 1H), 5.14 (s, 2H), 5.0 (q, 2H), 4.76 (br s, 1H), 4.32 (d, J = 2.1 Hz) 1 H, 1.22 (m, 3H), 1.1 (d, 18H).

Example 55

Preparation of a compound of formula

Following the procedure described in Example 44 and using the ketone derivative of Example 25, the desired product was obtained after purification by silica gel chromatography using 5% EtOAc / hexane as eluent. ¹ H NMR (400 MHz, _CDCl3) δ (ppm): 7.5 to

7.32 (m, 5H), 7.2 to 7.1 (m, 4H), 6.9 to 6.82 (m, 4H), 6.76 to 6.7 (m, 4H), 56 (d, 1H), 5.06 (br q, 1H), 4.36 (d, 1H), 1.22 (m, 3H), 1.1 (d, 18H).

Example 56

Preparation of a compound of formula

Following the procedure described in Example 44, except that the reaction was run at 0 ° C for three hours and using 1.7 g (2.83 mmol) of the ketone derivative obtained in Example 26, the desired product was obtained after purification by silica gel chromatography using 5% EtOAc / hexane as eluent. ¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.5-7.34 (m, 5H), 7.2-7.1 (m, 3H), 6.94 (d, 1H), 6.9 to 6.82 (m, 5H), 6.4 (m, 3H), 5.48 (d, J = 1.9 Hz, 1H), 5.05 (s, 2H), 4.36 (d, J = 1.9 Hz, 1 H),

1.22 (m, 3H); 1.1 (d, 18H).

-82Example 57

Preparation of a compound of formula

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

Example 58

Preparation of a compound of formula

Following the procedure described in Example 44, and using the ketone derivative of Example 28, the desired product was obtained after purification by silica gel chromatography using 5% EtOAc / hexane as eluent. ^{@ 1} H NMR (500 MHz, CDCl3) .delta

7.3 (m, 5H), 7.22-7.10 (m, 3H), 6.90-6.80 (2d, 4H), 6.75 (d, 2H), 6.55 (d, 2H);

5.55 (d, J = 2.1Hz, 1H), 5.05 (d, 2H), 4.40 (d, J = 2.1Hz, 1H), 1.22 (m, 3H), 1.1 (d, 18H).

Example 59

Preparation of a compound of formula

Following the procedure described in Example 44, using the ketone derivative of Example 29, the desired product was obtained after purification by silica gel chromatography using 5% EtOAc / hexane as eluent. ¹ H NMR (500 MHz, _CDCl3) δ (ppm): 7.5 to

7.3 (m, 5H), 7.22-7.10 (m, 3H), 6.90-6.80 (2d, 4H), 6.73 (d, 2H), 6.64 (d, 2H);

5.50 (d, J = 2.1Hz, 1H), 5.05 (d, 2H), 4.43 (d, J = 2.2Hz, 1H), 1.23 (m, 3H), 1.10 (d, 18H).

Example 60

Preparation of a compound of formula

Following the procedure described in Example 44 and using the ketone derivative of Example 30, the desired product was obtained after purification by silica gel chromatography using 5% EtOAc / hexane as eluent. ¹ H NMR (500 MHz, _CDCl3) δ (ppm): 7.5 to

7.3 (m, 5H), 6.82 (d, 2H), 6.68 (d, 2H), 6.64 (d, 2H), 6.62 (d, 2H), 6.46 (d) 2H, 5.44 (d, J = 1.9Hz, 1H), 5.02 (d, 2H), 4.30 (d, J = 2.0Hz, 1H), 1.22 (m) 3H), 1.10 (d, 18H); MS m / z 618 (M ⁺ +1).

Example 61

Preparation of a compound of formula

Following the procedure described in Example 44, using the ketone derivative of Example 31, the desired product was obtained after purification by silica gel chromatography using 5% EtOAc / hexane as eluent. ^{@ 1} H NMR (400 MHz, CDCl3) .delta

7.3 (m, 5H), 6.86 (d, 1H), 6.82 (d, 2H), 6.76 (d, 2H), 6.70 (d, 1H), 6.67 ( d, 2H), 6.65 (d, 2H), 5.44 (d, J = 2.0 Hz, 1H), 5.04 (s, 2H), 4.38 (d, J = 1, 9 Hz, 1H), 1.23 (m, 3H), 1.10 (d, 18H); MS m / z 634 (M ⁺ +1).

Example 62

Preparation of a compound of formula

Following the procedure described in Example 44, using the ketone derivative of Example 32, the desired product was obtained after purification by silica gel chromatography using 5% EtOAc / hexane as eluent. ^{@ 1} H NMR (500 MHz, CDCl3) .delta

7.3 (m, 5H), 6.94 (d, 1H), 6.85 (d, 2H), 6.80 (d, 2H), 6.74 (dd, 2H), 6.65 (m) , 4H),

5.43 (d, J = 2.1 Hz, 1H), 5.05 (d, 2H), 4.30 (d, J = 2.1 Hz, 1H), 1.23 (m, 3H) 1.10 (d, 18H).

Example 63

Preparation of a compound of formula

Following the procedure described in Example 44, using the ketone derivative of Example 33, the desired product was obtained after purification by silica gel chromatography using 5% EtOAc / hexane as eluent. ^{@ 1} H NMR (500 MHz, CDCl3) .delta

7.3 (m, 5H), 6.88 (s, 1H), 6.84 (d, 2H), 6.82 (d, 2H), 6.70 (d, 2H), 6.68 ( d, 2H), 6.66 (s, 1H), 5.50 (d, 1H), 5.05 (s, 2H), 4.43 (d, 1H), 2.35 (s, 3H), 1.23 (m, 3H); 1.10 (d, 18H).

Example 64

Preparation of a compound of formula

Following the procedure described in Example 44 and using the ketone derivative of Example 34, the desired product was obtained after purification by silica gel chromatography using 5% EtOAc / hexane as eluent. ^{@ 1} H NMR (500 MHz, CDCl3) .delta

7.3 (m, 5H), 7.24 (s, 1H), 7.20 (s, 1H), 6.82 (d, 2H), 6.68 (d, 2H), 6.64 (m 4H), 5.44 (d, J = 2.0Hz, 1H), 5.05 (d, 2H), 4.28 (d, J = 2.3Hz, 1H), 1.23 (m 3H), 1.10 (d, 18H).

Example 65

Preparation of a compound of formula

Following the procedure described in Example 44, and using the ketone derivative of Example 35, the desired product was obtained after purification by silica gel chromatography using 5% EtOAc / hexane as eluent. ^{@ 1} H NMR (500 MHz, CDCl3) .delta

7.3 (m, 5H), 7.05 to 7.20 (m, 4H), 6.90 (d, 2H), 6.88 (d, 2H), 6.78 (d, 2H), 6 70 (d, 1H), 6.65 (d, 1H), 5.30 (d, J = 1.8 Hz, 1H), 5.05 (d, 2H), 4.20 (d, J) = 2.3 Hz, 1H), 1.23 (m, 3H), 1.10 (d, 18H).

Example 66

Preparation of a compound of formula

OTIPS

Following the procedure described in Example 44, using the ketone derivative of Example 36, the desired product was obtained after purification by silica gel chromatography using 5% EtOAc / hexane as eluent. ¹ H NMR (500 MHz, _CDCl3) δ (ppm): 7.5 to

7.3 (m, 5H), 7.05 to 7.20 (m, 2H), 7.10 (m, 2H), 6.98 (d, 2H), 6.88 (m, 2H), 6 80 (m, 1H); 6.60 (d, 1H); 5.56 (d, J = 1.8Hz, 1H); 5.05 (d, 2H); 2.3 Hz, 1H), 1.23 (m, 3H), 1.10 (d, 18H).

Example 67

Preparation of a compound of formula

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

Example 68

Preparation of a compound of formula

OTIPS

Following the procedure described in Example 44 and using the ketone derivative of Example 37 (II), the desired product was obtained after purification by silica gel chromatography using 5% EtOAc / hexane as eluent. ¹ H NMR (500 MHz, CDCl 3) δ (ppm): 7.55 (d, 2H), 7.45 (t, 2H), 7.35 (t, 1H), 7.20 (d, 1H), 7.15 (t, 2H).

6.80 to 6.90 (m, 4H), 6.78 (d, 2H), 6.76 (d, 2H), 5.42 (d, J = 2.1 Hz, 1H), 5.18 (s, 2H), 4.42 (d, J = 2.1Hz, 1H), 1.23 (m, 3H), 1.10 (d, 18H).

Example 69

Preparation of a compound of formula

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

Example 70

Chiral division

Each enantiomer of the racemic dihydrobenzoxathine obtained in Example 62 was obtained by chiral chromatography using a Chiralpak AD column, with 30% isopropanol in hexane as eluent.

Fast moving isomer: [α] D = + 18.44 ° (c = 0.725, MeOH).

Slow moving isomer: [α] _D = -18.85 ° (c = 0.74, MeOH).

Example 71

General preparation of shadows

HO '

'0'

-89Step A

To a stirred solution of a mixture of dihydrobenzoxathine (60 mg, 0.1 mmol) obtained from Example 48 (which was dried by azeotropic method before use), triphenylphosphine (157 mg, 0.6 mmol) and 1-piperidineethanol (0.08 mL, 0 6 mmol) in 4 mL of anhydrous THF at 0 ° C was added dropwise 0.118 mL (0.6 mmol) of diisopropylazodicarboxylate (DIAD) over 0.2 h. The resulting pale yellow solution was stirred at room temperature for 2 to 3 hours. The volatiles were removed in vacuo and the residue was purified by flash chromatography (EtOAc / hexane = 1: 5 followed by 2-3% MeOH / dichloromethane) to give the desired product. ¹ H NMR (400 MHz, CDCl 3) δ (ppm): 7.5-7.34 (m, 5H), 7.08 (d, 1H), 6.86 (d, 2H), 6.78-6 64 (m, 8H), 5.5 (d, 1H), 5.01 (br q, 2H), 4.3 (d, 1H), 4.2 (t, 2H), 2.75 (t (2H), 2.5 (brs, 4H), 1.6 (m, 4H),

1.48 (m, 2H), 1.22 (m, 3H), 1.10 (d, 18H); MS m / z 712.4 (M ⁺ +1).

Step B

To a stirred solution of the adduct (71 mg, 0.098 mmol) formed in Step A in 2 mL of EtOH / EtOAc / H ₂ O (7: 2: 1) was added 13 mg (1.2 eq) of palladium black and ammonium formate. (62 mg, 10 eq). The resulting mixture was heated to 80 ° C and monitored by TLC. After 3 hours, the reaction mixture was cooled to room temperature, filtered through a pad of Celite to remove the catalyst, and the filtrate was partitioned between water and EtOAc. The organic phase was separated, dried over MgSO ₄ and concentrated in vacuo to give the desired product. ¹ H NMR (400 MHz, CDCl 3) δ (ppm): 7.01 (d, 1H), 6.8 (d, 2H), 6.75 (d, 2H), 6.66 (two d, 4H) 6.54 (dd, 1 H), 6.5 (d, 1 H), 5.45 (d, J = 2.3 Hz, 1 H), 4.28 (d, J = 2.3 Hz, 1 H) 4.08 (t, 2H), 2.8 (t, 2H), 2.6 (br s, 4H), 1.68 (m, 4H), 1.5 (m, 2H), 1.22 (m, 3H), 1.10 (d, 18H).

Step C

To a stirred solution of a mixture of the debenzylated product formed in Step B and HOAc (10 eq) in mL of THF was added a solution of tetrabutylammonium fluoride (3 eq) in THF at room temperature. The resulting solution was allowed to stir for two hours at room temperature and then poured into saturated NaHCO ₃ solution 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 to 7% MeOH v

-90 methylene chloride as eluent gave the desired product. ¹ H NMR (400 MHz, CD ₃ OD) δ (ppm): 6.95 (d, 2H), 6.92 (d, 1H), 6.78 (d, 2H), 6.71 (d, 2H) 6.48 (d, 2H);

6.47 (d, 1H), 6.44 (dd, 1H), 5.47 (d, J = 2.1Hz, 1H), 4.37 (d, J = 2.1Hz, 1H), 4.1 (t, 2H), 2.85 (t, 2H), 2.65 (brs, 4H), 1.66 (m, 4H), 1.5 (m, 2H).

Example 72

Preparation of a compound of formula

Step A

Using the procedure described in Example 71 (Step A), the dihydrobenzoxathiin obtained in Example 53 was combined with 1-piperidineethanol. Purification by silica gel chromatography using 3% MeOH / CH 2 Cl 2 as eluent gave the desired product. ¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm); 6.98 (d, 1H), 6.92 (d, 2H), 6.74 (two d, 4H), 6.65 (d, 1H), 6.62 (d, 2H), 5.5 (d, 1H), 5.1 (s, 2H), 4.31 (d, 1H), 4.09 (m, 2H),

2.75 (t, 2H), 2.55 (m, 2H), 2.5 (m, 4H), 1.6 (m, 4H), 1.45 (m, 2H), 1.22 (m) (3H), 1.1 (m, 21H).

Step B

The adduct formed in Step A was debenzylated using the procedure described in Example 71 (Step B) to give the desired product. ¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 6.92 (d, 1H), 6.89 (d, 2H), 6.72 (d & d, 4H), 6.62 (d , 2H), 6.5 (d, 1H), 5.5 (d, J = 2.2Hz, 1H), 4.3 (d, J = 2.2Hz, 1H), 4.1 ( m, 2H), 2.8 (t, 2H), 2.68 (m, 2H), 2.58 (br s, 4H), 1.64 (m, 4H), 1.48 (m, 2H) 1.2 (m, 3H), 1.09 (d & m, 21H).

Step C

The debenzylated product of Step B was desilylated using the procedure described in Example 71 (Step C). The desired product was obtained as a white solid

-91 substance. ¹ H NMR (400 MHz, CD ₃ OD) δ (ppm): 7.0 (d, 2H), 6.79 (d, 2H), 6.76 (d, 1H),

6.71 (d, 2H), 6.47 (d, 3H), 5.46 (d, J = 2.2 Hz, 1H), 4.38 (d, 1H), 4.08 (t, 2H) ), 2.8 (t, 2H), 2.5 (m, 2H), 2.6 (m, 4H), 1.62 (m, 4H), 1.5 (m, 2H), 1.1 (t, 3H); MS m / z 493.2 (M ⁺ +1).

Example 73

Preparation of a compound of formula

Step A

The dihydrobenzoxathiamine obtained in Example 45 was coupled with 1-piperidinoethanol using the procedure described in Example 71 (Step A). Purification by silica gel chromatography using 3% MeOH / CH 2 Cl 2 as eluent gave the desired product. ¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.14-6.92 (m, 4H), 6.8 (d, 2H), 6.76 (d, 2H), 6.72 ( d, 2H), 6.64 (d, 2H), 5.48 (d, J = 2.2Hz, 1H), 4.34 (d, J = 2.1Hz, 1H), 4.1 ( m, 2H), 2.85 (m, 2H), 2.6 (m, 4H), 1.65 (m, 4H), 1.5 (m, 2H), 1.22 (m, 3H), 1.1 (d, 18H).

Step B

The adduct from step A was desilylated using the procedure described in Example 71 (step C). The desired product was obtained as a white solid. ¹ H NMR (400 MHz, CD ₃ OD) δ (ppm): 7.14-6.92 (m, 4H), 6.06 (d, 2H), 6.78 (d, 2H), 6.72 (d, 2H), 6.48 (d, 2H), 5.48 (d, J = 2.1Hz, 1H), 4.44 (d, 1H), 4.1 (t, 2H), 2 78 (t, 2H), 2.58 (br s, 4H), 1.64 (m, 4H), 1.5 (m, 2H); MS m / z 450.2 (M ⁺ +1).

Example 74

Preparation of a compound of formula

Step A

The dihydrobenzoxathiin obtained from Example 46 was coupled with 1-piperidineethanol using the method described in Example 71 (Step A). Purification by silica gel chromatography with 3% MeOH / CFhCl gave the desired adduct as an oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.14-6.94 (m, 4H), 6.96 (d, 2H), 6.84 (two d, 4H),

6.66 (d, 2H); 5.5 (d, J = 2.1 Hz, 1H); 5.12 (s, 2H); 4.5 (d, 2.1 Hz, 1H); 04 (t, 2H);

3.42 (s, 3H), 2.75 (t, 2H), 2.55 (br s, 4H), 1.6 (m, 4H), 1.48 (m, 2H); MS m / z 495.2 (M ⁺ +1).

Step B

The adduct (10 mg, 0.02 mmol) of Step A was deprotected with TFA (10 eq) and MeOH (6 eq) in CH 2 Cl 2 at room temperature to give the desired product. ¹ H NMR (400 MHz, CD ₃ OD) δ (ppm): 7.14-6.92 (m, 4H),

6.84 (two d, 4H), 6.66 (d, 2H), 6.6 (d, 2H), 5.45 (d, J = 2.2 Hz, 1H), 4.45 (d, J = 2.2 Hz, 1H), 4.05 (t, 2H), 2.8 (t, 2H), 2.6 (br s, 4H), 1.6 (m, 4H), 1.5 (m, 2H); MS m / z 450.2 (M ⁺ +1).

Example 75

Preparation of a compound of formula

ABOUT'

The 93-dioxane derivative obtained from Example 47 was coupled with 1-piperidinoethanol using the method described in Example 71 (Step A) to give the product. ¹ H NMR (400 MHz, CD ₃ OD) δ (ppm): 7.04 (d, 2H), 6.98-6.84 (m, 4H), 6.82 (d, 2H), 6.74 (d, 1H), 6.63 (d, 2H), 6.56 (d, 2H), 5.36 (d, 1H), 5.33 (d, J = 3.0 Hz, 1H), 4 02 (m, 2H), 2.8 (m, 2H), 2.6 (br s, 4H), 1.62 (m, 4H), 1.5 (m, 2H); MS m / z 432 (M < ^{+ >} ).

Example 76

Preparation of a compound of formula

Step A

The dihydrobenzoxathiin formed in Example 49 was desilylated using the method described in Example 71 (Step C). The desired product was obtained as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.5-7.3 (m, 5H), 7.2 (d, 1H), 6.9 (d, 2H), 6.88 ( d, 2H), 6.68 (m, 6H), 5.53 (d, J = 2.2Hz, 1H), 4.33 (d, J = 2.3Hz, 1H),

3.75 (s, 3 H).

Step B

The desilylated product obtained from Step A was combined with 1-piperidineethanol using the method described in Example 71 (Step A). Purification by silica gel chromatography with 3% MeOH / CH 2 Cl 2 gave the desired adduct. ¹ H NMR (400 MHz, CDCl 3) δ (ppm): 7.5-7.3 (m, 5H), 7.08 (d, 1H), 6.9 (d, 2H), 6.84 (d , 2H),

6.76 (d, 2H), 6.66 (m, 4H), 5.52 (d, 1H), 5.03 (s, 2H), 4.32 (d, 1H), 4.06 (t, 2H) 1.75 (s, 3H), 2.75 (t, 2H), 2.5 (br s, 4H), 1.6 (m, 4H), 1.45 (m, 2H).

Step C

The adduct formed in Step B was debenzylated using the method described in Example 71 (Step B) to give the product. ¹ H NMR (400 MHz, CD ₃ OD) δ (ppm):

-946.96 (d, 2H), 6.92 (d, 1H), 6.82 (d, 2H), 6.78 (d, 2H), 6.63 (d, 2H), 6.48 (d, 2H) d, 2H)

6.44 (d, 1H), 5.5 (d, J = 2.2Hz, 1H), 4.42 (d, J = 2.2Hz, 1H), 4.08 (t, 2H), 3.68 (s, 3H), 2.78 (t, 2H), 2.59 (brs, 4H), 1.6 (m, 4H), 1.48 (m, 2H); MS m / z 479.4 (M ⁺ +1).

Example 77

Preparation of a compound of formula

Step A

The dihydrobenzoxathiin obtained from Example 50 was coupled with 1-piperidineethanol using the method described in Example 71 (Step A). Purification by silica gel chromatography with 3% MeOH / _CH2 Cl2 gave the desired adduct. ¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 6.83 (d, 2H), 6.75 (d, 2H), 6.69 (d, 2H), 6.62 (d, 2H) 6.5 (d, 1H), 6.48 (d, 1H), 5.42 (br s, 1H), 4.3 (br s, 1H), 4.06 (t, 2H), 2, 78 (t, 2H), 2.5 (br s, 4H), 1.6 (m, 4H), 1.44 (m, 2H), 1.22 (m, 3H), 1.1 (d, 18 H).

Step B

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

Step C

The debenzylated product of Step B was desilylated using the method described in Example 71 (Step C). The desired product was obtained as a white solid. ¹ H NMR (400 MHz, CD ₃ OD) δ (ppm): 6.94 (d, 2H), 6.76 (d, 2H), 6.7 (d, 2H),

6.49 (d, 2H), 6.4 (d, 1H), 6.32 (d, 1H), 5.43 (d, J = 2.3 Hz, 1H), 4.4 (d, J) = 2.3 Hz, 1H), 4.08 (t, 2H), 2.8 (t, 2H), 2.6 (brs, 4H), 2.18 (s, 3H), 1.64 (m 4H), 1.5 (m, 2H); MS m / z 479.2 (M ⁺ +1).

95Example 78

Preparation of a compound of formula

Step A

The dihydrobenzoxathiin obtained from Example 51 was coupled with 1-piperidineethanol using the method described in Example 71 (Step A). Purification by silica gel chromatography with 3% MeOH / CF 3 Cl 2 gave the desired adduct.

Step B

The adduct formed in Step A was debenzylated using the method described in Example 71 (Step B). Purification by silica gel chromatography using 5% MeOH / CH 2 Cl 2 as eluent gave the desired product as an oil. ¹ H NMR (400 MHz, CDCl 3) δ (ppm): 6.9 (d, 2H), 6.89 (d, 1H), 6.73 (m, 4H), 6.62 (d, 2H) 6.52 (d, 1H), 5.5 (d, 1H), 4.3 (d, 1H), 4.1 (br s, 2H), 2.8 (br t, 2H) ), 2.6 (br s, 4H), 2.2 (s, 3H), 1.6 (m, 4H), 1.5 (m, 2H), 1.22 (m, 3H), 1, 1 (d, 18H).

Step C

The debenzylated product of Step B was desilylated using the method described in Example 71 (Step C). The desired product was obtained as a white solid. ¹ H NMR (400 MHz, CD ₃ OD) δ (ppm): 7.02 (d, 2H), 6.76 (d, 2H), 6.7 (d, 2H),

6.47 (two d, 3H), 5.48 (d, J = 2.3 Hz, 1H), 4.38 (d, J = 2.3 Hz, 1H), 4.1 (t, 2H) 2.8 (t, 2H), 2.6 (br s, 4H), 2.1 (s, 3H), 1.64 (m, 4H), 1.5 (m, 2H); MS m / z 479.2 (M ⁺ +1).

Example 79

Preparation of a compound of formula

Step A

The dihydrobenzoxathiamine obtained from Example 53 was coupled with 1-piperidinoethanol using the method described in Example 71 (Step A). Purification by silica gel chromatography with 3% MeOH / _CH2 Cl2 gave the desired adduct.

Step B

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

Step C

The debenzylated product of Step B was desilylated using the method described in Example 71 (Step C). The desired product was obtained as a white solid after purification by silica gel chromatography with 5% MeOH / CH ₂ Cl ₂ as eluent. ¹ H NMR (400 MHz, CD ₃ OD) δ (ppm): 6.94 (d, 2H), 6.76 (d, 2H), 6.7 (d, 2H), 6.48 (d, 2H) 6.41 (d, 1H), 6.3 (d, 1H), 5.44 (d, J = 2.2Hz, 1H), 4.4 (d, J = 2.2Hz, 1H) 4.08 (t, 2H); 2.8 (t, 2H); 2.62 (br s, 4H); 2.6 (q, 2H); 1.6 (m, 4H); 45 (m, 2H); 1.2 (t, 3H); MS m / z 493.2 (M ⁺ +1).

Example 80

Preparation of a compound of formula

HO '

ABOUT

-97Step A

The dihydrobenzoxathiamine obtained from Example 54 was coupled with 1-piperidinoethanol using the method described in Example 71 (Step A). Purification by silica gel chromatography with 3% MeOH / CH ₂ Cl ₂ gave the desired adduct. ¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.5-7.3 (m, 10H), 6.86 (d, 2H), 6.78 (d, 2H), 6.74 ( d, 2H), 6.64 (d, 2H), 6.38 (s, 2H), 5.48 (d, 1H) / 5.14 (s, 2H), 5.02 (q, 2H) 4.32 (d, 1H), 4.08 (t, 2H), 2.8 (t, 2H), 2.5 (br s, 4H), 1.62 (m, 4H), 1.5 (m, 2H), 1.22 (m, 3H), 1.1 (d, 18H).

Step B

The adduct formed in Step A was debenzylated using the method described in Example 71 (Step B). Purification by silica gel chromatography using 5% MeOH / CH ₂ Cl ₂ as eluent gave the desired product as an oil.

Step C

The debenzylated product of Step B was desilylated using the method described in Example 71 (Step C). The desired product was obtained as a white solid. ¹ H NMR (400 MHz, CD ₃ OD) δ (ppm): 6.94 (d, 2H), 6.78 (d, 2H), 6.72 (d, 2H),

6.5 (d, 2H), 6.06 (d, 1H), 6.02 (d, 1H), 5.42 (d, J = 2.2 Hz, 1H), 4.33 (d, J) = 2.2 Hz, 1H), 4.09 (t, 2H), 2.8 (t, 2H), 2.6 (br s, 4H), 1.64 (m, 4H), 1.5 (m, 2H); MS m / z 482.2 (M ⁺ +1).

Example 81

Preparation of a compound of formula

Step A

The dihydrobenzoxathiin produced in Example 55 was desilylated using the method described in Example 71 (Step C). The desired product was obtained as white

-98 solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.48 to 7.32 (m, 5H), 7.2 to 7.1 (m, 4H), 6.94 to 6.84 (two d, 4H), 6.7 (m, 4H), 5.56 (d, J = 2.1Hz, 1H), 5.04 (br q, 2H),

4.74 (s, 1H), 4.37 (d, J = 2.1 Hz, 1H).

Step B

The desilylated product obtained from Step A was combined with 1-piperidineethanol using the method described in Example 71 (Step A). Purification by silica gel chromatography with 3% MeOH / CH ₂ Cl ₂ gave the desired adduct. ¹ H NMR (400 MHz, CDCl 3) δ (ppm): 7.5-7.32 (m, 5H), 7.2-7.04 (m, 4H), 6.94-6.86 (m, 4H), 6.76-6.66 (m, 4H), 5.54 (br s, 1H), 5.04 (br s, 2H), 4.38 (br s, 1H), 4.06 (br s) t, 2H), 2.76 (t, 2H), 2.5 (br s, 4H), 1.6 (m, 4H), 1.42 (m, 2H).

Step C

The adduct formed in Step B was debenzylated using the method described in Example 71 (Step B) to give the desired product. ¹ H NMR (400 MHz, CD ₃ OD) δ (ppm): 7.2-7.14 (m, 3H), 6.94 (m, 3H), 6.9 (d, 2H), 6, 74 (d, 2H); 6.48 (dd, 1H);

6.45 (d, 1 H), 5.53 (d, J = 2.3 Hz, 1 H), 4.46 (d, 1 H), 4.06 (t, 2 H), 2.78 (t, 2 H) 1.58 (br s, 4H), 1.62 (m, 4H), 1.5 (m, 2H); MS m / z 449.2 (M ⁺ +1).

Example 82

Preparation of a compound of formula

Step A

The dihydrobenzoxathiin formed in Example 56 was desilylated using the method described in Example 71 (Step C). The desired product was obtained as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.5-7.3 (m, 5H), 7.2-7.1 (m, 3H), 6.96 (m, 2H), 6.92 (d, 1H), 6.88 (d, 2H), 6.84 (d, 1H), 6.74 (dd, 1H), 6.66 (d, 1H),

-992 °, 5.48 (d, J = 2.1Hz, 1H), 5.04 (s, 2H), 4.37 (d, J = 2.1Hz, 1H); MS m / z 428.2 (M ⁺ +1).

Step B

The desilylated product obtained from Step A was combined with 1-piperidineethanol using the method described in Example 71 (Step A). Purification by silica gel chromatography with 3% MeOH / CH ₂ Cl ₂ gave the desired adduct.

Step C

The adduct formed in Step B was debenzylated using the method described in Example 71 (Step B) to give the desired product. ¹ H NMR (400 MHz, CD ₃ OD) δ (ppm): 7.14 to 7.02 (m, 3H), 6.92 (m, 4H), 6.8 (d, 1H), 6, 74 (d, 2H); 6.58 (d, 1H);

6.51 (dd, 1H), 5.42 (br s, 1H), 4.45 (br s, 1H), 4.06 (t, 2H), 2.78 (t, 2H), 2 55 (br s, 4H), 1.6 (m, 4H), 1.5 (m, 2H); MS m / z 449.2 (M ⁺ +1).

Example 83

Step A

To a well stirred solution of dihydrobenzoxathine (30 mg, 0.061 mmol) prepared in Example 74 (Step A) was added 5 equivalents of metachloroperbenzoic 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 saturated NaHSO ₃ and stirred for an additional 30 minutes. The aqueous layer was extracted with EtOAc and the organic layer was washed with brine, dried over MgSO ₄ and evaporated to give a residue which was used for the next step without further purification. ¹ H NMR (400 MHz, CD ₃ OD) δ (ppm): 7.82 (dd, 1H), 7.67 (dt, 1H), 7.28 (m, 2H), 7.2 (d,

-100 2Η), 7.03 (d, 2H), 6.92 (d, 2H), 6.82 (d, 2H), 6.32 (d, 1H), 5.12 (s, 2H), 4.84 (d, 1H), 4.2 (br t, 2H), 3.40 (s, 3H), 3.2 (m, 2H), 3.0 (m, 4H), 1.75 ( m, 4H), 1.6 (m, 2H).

Step B

The MOM protecting group was removed according to the procedure outlined in Example 74 (Step B). The desired product was isolated after purification by silica gel chromatography using 5% MeOH / CH ₂ Cl 2 as eluent. ¹ H NMR (400 MHz, CD ₃ OD) δ (ppm): 7.82 (dd, 1H), 7.64 (dt, 1H), 7.26 (m, 2H), 7.04 (d, 2H) ), 6.06 (d, 2H), 6.76 (d, 2H), 6.65 (d, 2H), 6.24 (d, J = 1.9 Hz, 1H), 4.71 (d 1 H, 4.1 (t, 2H);

2.72 (t, 2H), 2.5 (br s, 4H), 1.6 (m, 4H), 1.45 (m, 2H); MS m / z 481.1 (M ⁺ +1).

Example 84

Preparation of a compound of formula

Step A

To a well stirred solution of dihydrobenzoxathine (60 mg) prepared in Example 73 (Step A) was added 5 equivalents of m-CPBA in CH ₂ Cl ₂ 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 saturated NaHSO ₃ and stirred for an additional 30 minutes. The aqueous layer was extracted with EtOAc and the combined organic layer was washed with brine and dried with 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 Cl ₂ as eluent to give pure product. ¹ H NMR (400 MHz, CD ₃ OD) δ (ppm): 7.85 (dd, 1H), 7.66 (m, 1H), 7.28 (m, 2H), 7.12 (d, 2H) 6.86 (d, 2H), 6.8 (d, 2H), 6.7 (d, 2H), 6.22 (d, J = 2.1 Hz, 1H), 4.72 (d J = 2.3 Hz, 1H), 4.08 (m, 2H), 2.8 (t, 2H), 2.6

101 (br s, 4H), 1.6 (m, 4H), 1.5 (m, 2H), 1.22 (m, 3H), 1.1 (d, 18H); MS m / z 637 (M < ^{+ >} +23).

Step B

The silyl protecting group was removed according to the procedure outlined in Example 71 (Step C). The desired product was isolated after purification by silica gel chromatography using 5% MeOH / CH ₂ Cl ₂ as eluent. ¹ H NMR (400 MHz, CD ₃ OD) δ (ppm): 7.81 (dd, 1H), 7.64 (m, 1H), 7.35 (m, 2H), 7.2 (d, 2H) 6.82 (two d, 4H), 6.6 (d, 2H), 6.28 (d, J = 2.2 Hz, 1H), 4.69 (d, J = 2.2 Hz, 1H), 4.2 (t, 2H), 3.08 (t, 2H), 2.85 (br s, 4H), 1.7 (m, 4H), 1.55 (m, 2H).

Example 85

Preparation of a compound of formula

Step A

Using the method of Example 83 (Step A), the dihydrobenzoxathiin (20 mg, 0.028 mmol) obtained from Example 71 (Step A) was oxidized to m-CPBA at room temperature. The crude material was used for the next step without further purification. ¹ H NMR (400 MHz, CDCl 3) δ (ppm): 7.84 (d, 1H), 7.7-7.4 (m, 5H), 7.02 (d, 2H), 6.88 (dd) (1H), 6.82 (d, 2H), 6.76 (two d, 4H), 6.72 (d, 1H), 6.22 (d, J = 2.2 Hz, 1H), 5, 18 (q, 2 H),

4.28 (d, J = 2.1Hz, 1H), 4.09 (t, 2H), 2.8 (t, 2H), 2.55 (br s, 4H), 1.63 (m, 4H), 1.48 (m, 2H), 1.22 (m, 3H), 1.1 (d, 18H).

Step B

The product of Step A was deblocked using the standard method described in Example 71 (Step B) to give a debenzylated product which was used without further purification.

-102 Step C

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

Example 86

Preparation of a compound of formula

Step A

To a solution of the dihydrobenzoxathiin (100 mg, 0.167 mmol) formed in Example 48 in CH 2 Cl 2 was added triethylamine (0.07 mL), a catalytic amount of Λ, ΛΖ-dimethylaminopyridine (DMAP) and acetic anhydride (0.034 mL, 2 eq.) At room temperature. The resulting mixture was stirred for 30 minutes and then poured into a saturated NaHCO 3 solution. The aqueous layer was extracted with CH ₂ Cl 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 eluent to give the product. ¹ H NMR (400 MHz, CDCl 3) δ (ppm): 7.48-7.34 (m, 5H), 7.08 (d, 1H), 6.99 (d, 2H), 6.94 (d (2H), 6.76 (d, 2H), 6.72-6.67 (m, 4H), 5.56 (d, 1H), 5.06 (br q, 2H), 4.34 (d) (1H),

2.3 (d, 3H), 1.22 (m, 3H), 1.1 (d, 18H).

Step B

The silyl protecting group was removed according to the procedure outlined in Example 71 (Step C). The desired product was isolated after purification by silica gel chromatography using 5% MeOH / CH ₂ Cl ₂ as eluent. ¹ H NMR (400 MHz,

-103 CD ₃ OD) δ (ppm): 7.48 to 7.34 (m, 5H), 7.09 (d, 1H), 7.04 (d, 2H), 6.98 (d, 2H) 6.78 (d, 2H), 6.7 (m, 2H), 6.59 (d, 2H), 5.56 (d, 1H), 5.06 (br q, 2H), 4.74 (s, 1H), 4.36 (d, 1H), 2.2 (s, 3H).

Step C

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

Step D

To a solution of the adduct formed from Step E (10 mg, 0.017 mmol) in anhydrous THF was added four equivalents of a 1.0 M super hydride solution in THF. The resulting mixture was stirred at 0 ° C for 2 hours and then allowed to warm to room temperature (30 minutes). The reaction mixture was hydrolyzed with H 2 O / NaHCO ₃ . The aqueous layer was extracted with EtOAc, the organic layer was separated, dried and evaporated to give an oil which was used for the next step without further purification.

Step E

The crude product from Step D was deblocked using the standard method described in Example 71 (Step B) to give the final product after purification by silica gel chromatography using 5% MeOH / CH ₂ Cl ₂ as eluent. ¹ H NMR (400 MHz, CD ₃ OD) δ (ppm): 6.92 (d, 1H), 6.83 (d, 2H), 6.82 (d, 2H), 6.65 (d, 2H) )

6.58 (d, 2H), 6.46 (dd, 1H), 6.42 (d, 1H), 5.44 (d, J = 2.1 Hz, 1H), 4.38 (d, J) = 2.3 Hz, 1H), 4.04 (t, 2H), 2.78 (t, 2H), 2.6 (br s, 4H), 1.6 (m, 4H), 1.5 ( m, 2H); MS m / z 465 (M ⁺ +1).

Example 87

Preparation of a compound of formula

-104 -

Step A

The desilylated product obtained from Example 57 was combined with 1-piperidinoethanol using the method described in Example 71 (Step A). Purification by silica gel chromatography with 3% MeOH / CH 2 Cl 2 gave the desired adduct.

Step B

The adduct formed in Step A was debenzylated using the method described in Example 71 (Step B) to give the desired product. ¹ H NMR (400 MHz, CD ₃ OD) δ (ppm): 6.98-6.76 (m, 9H), 6.5 (dd, 1H), 6.46 (d, 1H), 5.52 (d, J = 2.3 Hz, 1 H),

4.5 (d, 1H); 4.05 (t, 2H); 2.80 (t, 2H); 2.62 (br s, 4H); 1.62 (m, 4H); 1.5 ( m, 2H); MS m / z 466.2 (M < ^{+ >} ).

Example 88

Chiral division

The racemic dihydrobenzoxathine obtained from Example 81 (Step C) was separated by chiral chromatography on a Chiralpak AD column using 20% EtOH in hexane as eluent.

Fast moving isomer: [α] _D = + 33.43 ° (c = 1.205, MeOH).

Slow moving isomer: [α] _D = -34.2 ° (c = 1.09, MeOH).

Example 89 Chiral division

The racemic dihydrobenzoxathine obtained from Example 82 (Step C) was separated by chiral chromatography on a Chiralpak AD column using 20% EtOH in hexane as eluent.

Fast moving isomer: [α] D = + 32.4 ° (c = 1.36, MeOH).

Slow moving isomer: [α] D = -31.3 ° (c = 1.37, MeOH).

Example 90

Preparation of a compound of formula

The dihydrobenzoxathiin produced in Example 58 was desilylated using the method described in Example 71 (Step C). The desired product was obtained as a white solid. ¹ H NMR (500 MHz, CDCl ₃ ) δ (ppm): 7.5-7.3 (m, 5H), 7.2-7.1 (m, 3H), 6.85 (2d, 4H), 6.68 (d, 2H), 6.55 (d, 2H), 5.55 (d, 1H), 5.04 (s, 2H), 4.40 (d, 1H).

Step B

The desilylated product obtained from Step A was combined with 1-piperidineethanol using the method described in Example 71 (Step A). Purification by silica gel chromatography with 3% MeOH / CH 2 Cl 2 gave the desired adduct.

- 106Step C

A mixture of the adduct (80 mg, 0.144 mmol) formed 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 addition of saturated aqueous NaHCO ₃ and extracted with EtOAc. The organic layer was separated, dried over MgSO ₄ and concentrated in vacuo to give the desired product. ¹ H NMR (500 MHz, CD ₃ OD) δ (ppm): 7.20-7.02 (m, 3H), 6.92 (m, 4H),

6.78 (d, 2H), 6.30 (d, 2H), 5.55 (d, J% 2.1 Hz, 1H), 4.50 (d, J = 2.3 Hz, 1H), 4.06 (t, 2H), 2.78 (t, 2H), 2.55 (br s, 4H), 1.6 (m, 4H), 1.5 (m, 2H); MS m / z 467 (M ⁺ +1).

Example 91

Preparation of a compound of formula

Step A

The dihydrobenzoxathiin formed in Example 59 was desilylated using the method described in Example 71 (Step C). The desired product was obtained as a white solid. ¹ H NMR (500 MHz, CDCl ₃ ) δ (ppm): 7.5-7.3 (m, 5H), 7.2-7.1 (m, 3H), 6.95 (d, 2H), 6.90 (d, 1H), 6.85 (d, 2H), 6.70 (d, 2H), 6.65 (d, 1H), 5.50 (d, 1H), 5.04 ( s, 2H), 4.42 (d, 1H).

Step B

The desilylated product obtained from Step A was combined with 1-piperidineethanol using the method described in Example 71 (Step A). Purification by silica gel chromatography with 3% MeOH / _CH2 Cl2 gave the desired adduct.

-107 Step C

The adduct formed in Step B was debenzylated using the method of Example 71 (Step B) to give the desired product. ¹ H NMR (500 MHz, CD 3 OD) δ (ppm):

7.14 to 7.02 (m, 3H), 6.92 (d, 2H), 6.85 (d, 2H), 6.74 (d, 2H), 6.58 (d, 1H), 6 1.41 (d, 1H), 5.52 (d, J = 2.3Hz, 1H), 4.55 (d, J = 2.3Hz, 1H), 4.06 (t, 2H), 2.78 (t, 2H), 2.55 (br s, 4H), 1.6 (m, 4H), 1.5 (m, 2H); MS m / z 483 (M ⁺ +1).

Example 92

Preparation of a compound of formula

Step A

The dihydrobenzoxathiamine obtained from Example 60 was coupled with 1-piperidineethanol using the method described in Example 71 (Step A). Purification by silica gel chromatography with 3% MeOH / CH 2 Cl 2 gave the desired adduct. ¹ H NMR (500 MHz, CDCl 3) δ (ppm): 7.5-7.3 (m, 5H), 6.80 (d, 2H), 6.70 (2d, 4H), 6.60 (d , 2H),

6.40 (2d, 2H), 5.40 (s, 1H), 4.90 (d, 2H), 4.20 (s, 1H), 4.08 (t, 2H), 2.8 (t H, 2.5 (brs, 4H), 1.62 (m, 4H), 1.5 (m, 2H), 1.22 (m, 3H), 1.1 (d, 18H).

Step B

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

Step C

The debenzylated product of Step B was desilylated using the method described in Example 71 (Step C). The desired product was obtained as a white solid. ¹ H NMR (500 MHz, CD ₃ OD) δ (ppm): 6.93 (d, 3H), 6.78 (d, 2H), 6.69 (d, 2H),

6.50 (d, 2H), 6.28 (m, 1H), 5.46 (d, J = 1.8 Hz, 1H), 4.39 (d, J = 2.2 Hz, 1H), 4.05 (t, 2H), 2.8 (t, 2H), 2.6 (br s, 4H), 1.64 (m, 4H), 1.5 (m, 2H); MS m / z 482.2 (M ⁺ +1).

- 108-

Example 93

Preparation of a compound of formula

Step A

The dihydrobenzoxathiin obtained from Example 61 was coupled with 1-piperidineethanol using the method described in Example 71 (Step A). Purification by silica gel chromatography with 3% MeOH / CH 2 Cl 2 gave the desired adduct. ¹ H NMR (500 MHz, CDCl ₃ ) δ (ppm): 7.5-7.3 (m, 5H), 6.85 (m, 3H), 6.70 (d, 4H), 6.63 ( d, 2H), 6.60 (d, 1H), 5.42 (s, 1H), 5.02 (d, 2H), 4.40 (s, 1H), 4.08 (t, 2H) 2.8 (t, 2H), 2.5 (br s, 4H), 1.62 (m, 4H), 1.5 (m, 2H), 1.22 (m, 3H), 1.1 (d, 18H).

Step B

The adduct formed in Step A was debenzylated using the method described in Example 71 (Step B) to give the desired product. ¹ H NMR (500 MHz, CD ₃ OD) δ (ppm): 6.82 (d, 2H), 6.78 (d, H), 6.70 (2d, 4H), 6.62 (d, 2H) ), 6.58 (d, 1H), 5.40 (d, 1H), 4.30 (d, 1H), 4.06 (t, 2H), 2.78 (t, 2H), 2 55 (br s, 4H), 1.6 (m, 4H), 1.5 (m, 2H); MS m / z 655 (M ⁺ +1).

Step C

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

Example 94

Preparation of a compound of formula

-109-

Step A

The dihydrobenzoxathiamine obtained from Example 62 was coupled with 1-piperidineethanol using the method described in Example 71 (Step A). Purification by silica gel chromatography with 3% MeOH / CHCl 3 gave the desired adduct.

Step B

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

Step C ' ¹

The debenzylated product of Step B was desilylated using the method described in Example 71 (Step C). The desired product was obtained as a white solid after purification by silica gel chromatography with 5% MeOH / CHLCl as eluent. ¹ H NMR (500 MHz, acetone-d ₆ ) δ (ppm): 7.04 (d, 2H), 6.90 (dd, 3H), 6.72 (d, 2H), 6.64 (d, 1H), 6.59 (d, 2H), 6.57 (dd, 1H), 5.44 (d, J = 2.3Hz, 1H), 4.52 (d, J = 2.1Hz, 1H), 4.08 (t, 2H), 2.8 (t, 2H), 2.62 (brs, 4H), 2.6 (q, 2H), 1.6 (m, 4H), 1, 45 (m, 2H); 1.2 (t, 2H); MS m / z 465 (M ⁺ +1).

Example 95

Preparation of a compound of formula

Me

HO

'0'

-110Step A

The dihydrobenzoxathiin, obtained from Example 63, was coupled with 1-piperidinoethanol using the method described in Example 71 (Step A). Purification by silica gel chromatography with 3% MeOH / CH ₂ Cl ₂ gave the desired adduct.

Step B

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

Step C

The debenzylated product of Step B was desilylated using the method described in Example 71 (Step C). The desired product was obtained as a white solid after purification by silica gel chromatography with 5% MeOH / CH ₂ Cl ₂ as eluent. ¹ H NMR (500 MHz, acetone-d ₆ ) δ (ppm): 7.00 (d, 2H), 6.85 (s, 1H), 6.80 (d, 2H), 6.78 (d, 2H), 6.59 (d, 2H), 6.52 (s, 1H), 5.49 (d, J = 2.3 Hz, 1H), 4.65 (d, J = 2.2 Hz, 1H), 4.08 (t, 2H), 2.8 (t, 2H), 2.62 (br s, 4H), 2.6 (q, 2H), 1.6 (m, 4H), 1 45 (m, 2H); 1.2 (t, 2H); MS m / z 479 (M ⁺ +1).

Example 96

Preparation of a compound of formula

Step A

The dihydrobenzoxathiamine obtained from Example 64 was coupled with 1-piperidineethanol using the method described in Example 71 (Step A). Purification by silica gel chromatography with 3% MeOH / CH ₂ Cl ₂ gave the desired adduct. ¹ H NMR (500 MHz, CDCl 3) δ (ppm): 7.5-7.3 (m, 5H), 7.20 (s, 1H), 6.85 (d, 2H), 6.70 (2d) , 4H),

-111 6.63 (d, 2H), 6.60 (s, 1H), 5.42 (s, 1H), 5.02 (q, 2H), 4.30 (s, 1H), 4.08 (t, 2H), 2.8 (t, 2H), 2.5 (brs, 4H), 1.62 (m, 4H), 1.5 (m, 2H), 1.22 (m, 3H) 1.1 (d, 18H).

Step B

The adduct formed in Step A was debenzylated using the method described in Example 71 (Step B) to give the desired product. ¹ H NMR (500 MHz, acetone ₆ ) δ (ppm): 7.10 (s, 1H), 6.98 (d, 2H), 6.82 (d, 2H), 6.78 (d, 2H) 6.70 (d, 2H); 6.68 (s, 1H); 5.50 (d, 1H); 4.50 (d, 1H); 4.06 (t, 2H); t, 2H), 2.55 (br s, 4H), 1.6 (m, 4H), 1.5 (m, 2H).

Step C

The debenzylated product of Step B was desilylated using the method described in Example 71 (Step C). The desired product was obtained as a white solid. ¹ H NMR (500 MHz, acetone-d ₆ ) δ (ppm): 7.12 (s, 1H), 7.02 (d, 2H), 6.80 (dd, 4H), 6.69 (s, 1H), 6.60 (d, 2H), 6.42 (d, 1H), 5.55 (d, J = 2.3Hz, 1H), 4.54 (d, J =

2.1 Hz, 1H), 4.07 (t, 2H), 2.78 (t, 2H), 2.55 (br s, 4H), 1.62 (m, 4H), 1.48 (m , 2H); MS m / z 499 (M ⁺ +1).

Example 97

Preparation of a compound of formula

Step A

The dihydrobenzoxathiin formed in Example 65 was desilylated using the method described in Example 71 (Step C). The desired product was obtained as a white solid. ¹ H NMR (500 MHz, CDCl ₃ ) δ (ppm): 7.5-7.3 (m, 5H), 7.2-7.1 (m, 5H), 6.95 (m, 3H), 6.64 to 6.70 (m, 2H), 5.46 (d, J = 1.8 Hz, 1H), 5.04 (s, 2H), 4.42 (d, J = 2.0 Hz) , 1H).

-112Step B

The desilylated product obtained from Step A was combined with 1-piperidineethanol using the method described in Example 71 (Step A). Purification by silica gel chromatography with 3% MeOH / CH ₂ Cl ₂ gave the desired adduct.

Step C

The adduct formed in Step B was debenzylated using the method described in Example 71 (Step B) to give the desired product. ¹ H NMR (500 MHz, CD ₃ OD) δ (ppm): 7.00 to 7.12 (m, 6H), 6.90 (d, 2H), 6.75 (d, 2H), 6.42 (s, 1H). 5.42 (d, J =

2.1 Hz, 1H), 4.48 (d, J = 2.3 Hz, 1H), 4.06 (t, 2H), 2.78 (t, 2H), 2.55 (br s, 4H) 1.6 (m, 4H), 1.45 (m, 2H); MS m / z 463 (M ⁺ +1).

Example 98

Preparation of a compound of formula

Step A

The dihydrobenzoxathiin formed in Example 66 was desilylated using the method described in Example 71 (Step C). The desired product was obtained as a white solid. ¹ H NMR (500 MHz, CDCl ₃ ) δ (ppm): 7.5-7.3 (m, 5H), 7.2-7.1 (m, 3H), 6.95 (d, 2H), 6.92 (d, 2H), 6.90 (d, 1H), 6.78 (d, 1H), 6.70 (d, 2H), 5.52 (d, J =

2.1 Hz, 1H), 5.04 (s, 2H), 4.46 (d, J = 2.2 Hz, 1H).

Step B

The desilylated product obtained from Step A was combined with 1-piperidineethanol using the method described in Example 71 (Step A). Purification by silica gel chromatography with 3% MeOH / CH ₂ Cl ₂ gave the desired adduct.

-113Step C

The adduct formed in Step B was debenzylated using the method described in Example 71 (Step B) to give the desired product. ¹ H NMR (500 MHz, CD ₃ OD) δ (ppm): 7.05 to 7.15 (m, 5H), 6.90 (d, 2H), 6.79 (d, 2H), 6.65 (d, 1H); 6.55 (d, 1H);

5.50 (d, J = 2.1Hz, 1H), 4.62 (d, J = 2.3Hz, 1H), 4.10 (t, 2H), 2.80 (t, 2H), 2.60 (br s, 4H), 1.6 (m, 4H), 1.5 (m, 2H); MS m / z 483 (M ⁺ +1).

Example 99

Preparation of a compound of formula

Step A

The dihydrobenzoxathiin formed in Example 67 was desilylated using the method described in Example 71 (Step C). The desired product was obtained as a white solid. ¹ H NMR (500 MHz, CDCl ₃ ) δ (ppm): 7.5-7.3 (m, 5H), 7.2-7.1 (m, 3H), 7.08 (s, 1H), 6.95 (d, 2H), 6.86 (m, 3H), 6.70 (d, 2H), 5.42 (d, J = 2.1 Hz, 1H),

5.14 (s, 2H); 4.40 (d, J = 2.0 Hz, 1H).

Step B

The desilylated product obtained from Step A was combined with 1-piperidineethanol using the method described in Example 71 (Step A). Purification by silica gel chromatography with 3% MeOH / CH ₂ Cl ₂ gave the desired adduct.

Step C

The adduct formed in Step B was debenzylated using the method described in Example 71 (Step B) to give the desired product. ¹ H NMR (500 MHz, CD ₃ OD) δ (ppm): 7.05 to 7.15 (m, 3H), 6.95 (m, 3H), 6.90 (d, 2H), 6.75 (d, 2H), 6.72 (s, 1 H),

-1145.45 (d, J = 2.0Hz, 1H), 4.52 (d, J = 2.3Hz, 1H), 4.10 (t, 2H), 2.80 (t, 2H) 2.60 (br s, 4H), 1.6 (m, 4H), 1.5 (m, 2H); MS m / z 483 (M ⁺ +1).

Example 100

Preparation of a compound of formula

Step A

The dihydrobenzoxathiin formed in Example 68 was desilylated using the method described in Example 71 (Step C). The desired product was obtained as a white solid. ¹ H NMR (500 MHz, CDCl ₃ ) δ (ppm): 7.5-7.3 (m, 5H), 7.2-7.1 (m, 3H), 6.92-6.80 (m 5H), 6.78 (d, 2H), 6.70 (d, 2H), 5.40 (d, J = 2.1Hz, 1H), 5.20 (s, 2H), 4.46 (d, J = 2.0 Hz, 1 H).

Step B

The desilylated product obtained from Step A was combined with 1-piperidineethanol using the method described in Example 71 (Step A). Purification by silica gel chromatography with 3% MeOH / CH 2 Cl 2 gave the desired adduct.

Step C

The adduct formed in Step B was debenzylated using the method described in Example 71 (Step B) to give the desired product. ¹ H NMR (500 MHz, CD ₃ OD) δ (ppm): 7.05 to 7.15 (m, 3H), 6.95 (d, 2H), 6.90 (d, 2H), 6.80 (d, 1H), 6.75 (d, 2H), 6.70 (d, 1H), 5.38 (d, J = 1.8 Hz, 1H), 4.56 (d, J = 2, 1 Hz, 1H), 4.06 (t, 2H), 2.78 (t, 2H), 2.60 (br s, 4H), 1.6 (m, 4H), 1.5 (m, 2H) ); MS m / z 483 (M ⁺ +1).

Example 101

Chiral division

-115-

The racemic dihydrobenzoxathine obtained from Example 100 (Step C) was separated by chiral chromatography on a Chiralpak AD column using 20% EtOH in hexane as eluent.

Fast moving isomer: [α] D = + 26.9 ° (c = 1.025, MeOH).

Slow moving isomer: [α] D = -25.44 ° (c = 0.95, MeOH).

Example 102

Preparation of a compound of formula

Step A

The dihydrobenzoxathiin formed in Example 69 was desilylated using the method described in Example 71 (Step C). The desired product was obtained as a white solid. ¹ H NMR (500 MHz, CDCl ₃ ) δ (ppm): 7.5-7.3 (m, 5H), 6.95 (d, 2H), 6.90 (m, 3H), 6.85 ( m, 3H), 6.74 (dd, 1H), 6.70 (d, 2H), 5.45 (d, J = 1.9 Hz, 1H), 5.05 (s, 2H), 4 35 (d, J = 2.1 Hz, 1H).

Step B

The desilylated product obtained from Step A was combined with 1-piperidinoethanol using the method described in Example 71 (Step A). Purification by silica gel chromatography with 3% MeOH / CH 2 Cl 2 gave the desired adduct which was used without further purification.

-116KrokC

The adduct formed in Step B was debenzylated using the method described in Example 71 (Step B) to give the desired product. ¹ H NMR (500 MHz, CD ₃ OD) δ (ppm): 6.98 (d, 2H), 6.94 (m, 2H), 6.80 (m, 5H), 6.60 (d, 1H) H). 6.75 (dd, 1H), 5.40 (d, J = 1.8Hz, 1H), 4.50 (d, J = 2.1Hz, 1H), 4.08 (t, 2H), 2.78 (t, 2H); 2.60 (br s,

4H), 1.6 (m, 4H), 1.5 (m, 2H); MS m / z 466 (M ⁺ +1).

Example 103

Chiral division

Step A

The fast-moving (+) - dihydrobenzoxathine obtained from Example 70 was coupled with 1-piperidinoethanol using the method described in Example 71 (Step A). Purification by silica gel chromatography with 3% MeOH / CH ₂ Cl ₂ gave the desired adduct.

I

Step B

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

Step C

The debenzylated product of Step B was desilylated using the method described in Example 71 (Step C). The desired product was obtained as a white solid after purification by silica gel chromatography with 5% MeOH / CH ₂ Cl ₂ as eluent. ¹ H

NMR (500 MHz, acetone-d ₆₎ δ (ppm): 6.90 (d, 2H), 6.78 (d, 1H), 6.72 (d, 2H), 6.70 (d,

2H), 6.60 (d, 1H), 6.50 (d, 1H), 6.48 (d, 2H), 5.38 (d, J = 2.0 Hz, 1H), 4.38 (d) d, J =

1172.3 Hz, 1H), 4.08 (t, 2H), 2.8 (t, 2H), 2.62 (br s, 4H), 2.6 (q, 2H), 1.6 ( m, 4H), 1.45 (m, 2H), 1.2 (t, 2H); MS m / z 465 (M ⁺ +1); [α] _D = + 27.68 ° (c = 0.49, MeOH).

Example 104;

Chiral division

(-) isomer

Step A

The slow-moving (-) - dihydrobenzoxathine, obtained from Example 70, was coupled with 1-piperidineethanol using the method described in Example 71 (Step A). Purification by silica gel chromatography with 3% MeOH / CH 2 Cl 2 gave the desired adduct.

Step B

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

Step C

The debenzylated product of Step B was desilylated using the method described in Example 71 (Step C). The desired product was obtained as a white solid after purification by silica gel chromatography with 5% MeOH / CH ₂ Cl ₂ as eluent. ¹ H NMR (500 MHz, acetone-d ₆ ) δ (ppm): 6.90 (d, 2H), 6.78 (d, 1H), 6.72 (d, 2H), 6.70 (d, 2H), 6.60 (d, 1H), 6.50 (d, 1H), 6.48 (d, 2H), 5.38 (d, J = 2.0 Hz, 1H), 4.38 (d) d, J =

2.3 Hz, 1H), 4.08 (t, 2H), 2.8 (t, 2H), 2.62 (br s, 4H), 2.6 (q, 2H), 1.6 (m 4H), 1.45 (m, 2H), 1.2 (t, 2H); MS m / z 465 (M ⁺ +1); [ _α ] _D = -26.33 ° (c = 0.515, MeOH).

Example 105

General Preparation of Compound of Formula

-118-

Step A: Reductive cyclization

To a stirred solution of 102.2 mg (0.17 mmol) of cyclopentylthioketone formed in Example 41 in dichloromethane at -23 ° C under N ₂ atmosphere was added 68 μΙ (0.087 mmol) of pure trifluoroacetic acid (TFA). 41.4 μΙ (0.259 mmol) of pure triethylsilane was slowly added to the stirred reaction mixture at -23 ° C and the resulting mixture was stirred for an additional 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 (1: 1) as eluent to give the cis -cyclopentyldihydrobenzoxathiin derivative. ¹ H NMR (500 MHz, CDCl ₃ ) δ (ppm): 1.12 (d, 18H), 1.26-2.12 (m, 12H), 2.5 (m, 1H), 4.24 ( d, 1H), 4.9 (m, 2H), 6.8-7.69 (m, 12H).

Starting from the cyclohexyl derivative prepared in Example 41 and using the above method, the corresponding cis -cyclohexylbenzoxathine was prepared after purification by silica gel chromatography using methylene chloride / hexanes (1: 1). ¹ H NMR (500 MHz, CDCl 3) δ (ppm): 1.14 (d, 18H), 1.11-1.9 (m, 14H), 3.2 (t, 1H), 5.03 ( s, 2H), 5.44 (d, J = 2.5 Hz, 1H), 6.66-7.47 (m, 12H).

Step B: Desilylation

To a stirred solution of 89.6 mg (0.156 mmol) of the cis -cyclopentyl derivative prepared in Step A above in 1 mL of THF at 0 ° C was gradually added

13.3 μΙ (0.234 mmol) of acetic acid and then 171 μΙ (0.171 mmol) of a 1M solution of tetrabutylammonium fluoride in THF. The mixture was stirred at 0 ° C for 0.5 h and then partitioned between ethyl acetate / 2N HCl / ice / brine, and the organic phase was separated,

Washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated. The residue was purified by silica gel chromatography using methylene chloride / ethyl acetate (50: 1) as eluent to give the phenol derivative. ¹ H NMR (500 MHz, CDCl ₃ ) δ (ppm): 1.32-1.94 (m, 9H), 3.51 (dd, J = 5.5, 2.5 Hz, 1H), 5 03 (s, 2H), 5.42 (d, J = 2.3 Hz, 1H), 6.67-7.47 (m, 12H).

Starting from the cyclohexyl derivative prepared in the previous example and using the above process, the corresponding cis -cyclohexylbenzoxathiophenol was prepared. ¹ H NMR (500 MHz, CDCl ₃ ) δ (ppm): 1.11-1.93 (m, 11H), 3.23 (t, J = 3 Hz, 1H), 5.03 (s, 2H), 5.44 (d, J = 2.3 Hz, 1H), 6.66-7.47 (m, 12H).

Step C: Mitsunobu reaction

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

Starting from the cyclohexyl derivative prepared in the previous example, and using the above process, the corresponding cis -cyclohexylbenzoxathiin adduct was prepared. ¹ H NMR (500 MHz, CDCl ₃ ) δ (ppm): 1.11-1.93 (m, 17H),

2.6 (m, 4H), 2.87 (m, 2H), 3.2 (d, J = 2.5 Hz, 1H), 4.2 (m, 2H), 5.02 (s, 2H) 5.44 (d, J = 2.1 Hz, 1H), 6.65-7.46 (m, 12H).

Step D: Debenzylation

A mixed mixture of 36.6 mg (0.0069 mmol) of the cis-cyclopentyl derivative prepared in Step C above, 14.7 mg (0.014 mmol) of palladium black

120a 87.1 mg (0.138 mmol) of ammonium formate in 2 ml of ethanol-ethyl acetate-water (7: 2: 1) was heated at 80 ° C for two hours. The mixture was filtered through celite, washed well with ethyl acetate, and the filtrate was partitioned between ethyl acetate / saturated sodium carbonate / brine, and the organic phase was separated, washed with brine, dried over

Even with anhydrous sodium sulfate, filtered and evaporated. The residue was purified by silica gel chromatography using ethyl acetate / methanol (9: 1) as eluent to give the final product. ¹ H NMR (500 MHz, CDCl ₃ ) δ (ppm): 1.33-2.0 (m, 15H), 2.6 (m, 4H), 2.88 (m, 3H), 3.48 ( t, J = 2.3 Hz, 1H), 4.18 (m, 2H), 5.38 (d, J = 2.3 Hz, 1H),

6.5 (m, 1H), 6.63 (d, J = 2.9Hz, 1H), 6.74 (d, J = 8.7Hz, 1H), 6.89 (d, J = 8.7) Hz, 2H) and 7.34 (d, J = 8.7 Hz, 2H).

Starting from the cyclohexyl derivative prepared in the previous example, and using the above process, the corresponding cis -cyclohexylbenzoxathiin adduct was prepared. ¹ H NMR (500 MHz, CDCl ₃ ) δ (ppm): 1.00 to 1.90 (m, 18H),

2.6 (m, 4H), 2.81 (t, 2H), 3.19 (t, J = 3.0 Hz, 1H), 4.18 (m, 2H), 5.38 (d, J = 2) 3 Hz, 1H), 6.43 (m, 1H), 6.62 (d, J = 3.0 Hz, 1H), 6.68 (d, J = 8.7 Hz, 1H), 6, 87 (d, J = 8.7 Hz, 2H) and 7.34 (d, J = 8.7 Hz, 2H): MS m / z 454 (M < ^{+ >} ).

Example 106

Preparation of a compound of formula

Step A: Reductive cyclization

Starting from the isopropyl adduct (0.0208 g, 0.049 mmol) prepared in Example 42, and using the method described in Example 105 (Step A), the crude product was isolated after stirring at -23 ° C for 6 hours and 20 minutes. Purification by silica gel chromatography with 30% EtOAc / hexane as eluent gave the desired product as a yellow oil. ¹ H NMR (500 MHz, CDCl ₃ ) δ (ppm): 0.95 (d, 3H), 0.98 (d, 3H),

121-195 (m, 1H); 3.30 (t, J = 3 Hz, 1H). 5.03 (s, 2H); 5.42 (d, J = 2.6 Hz, 1H);

7.47 (m, 12H).

Step B: Mitsunobu reaction 1

The dihydrobenzoxathiin prepared in Step A was combined with 1-piperidinoethanol using the method described in Example 105 (Step C), except that the reaction mixture was allowed to slowly warm from 0 ° C to ambient temperature for 3.5 h. . Purification by silica gel chromatography with 10% MeOH / CH ₂ Cl ₂ as eluent gave the desired product as a pale yellow oil. ¹ H NMR (500 MHz, CDCl 3) δ (ppm): 0.95 (d, 3H), 0.98 (d, 3H), 1.50 to 1.68 (m, 6H), 1.95 (m 1H, 2.60 (m, 4H), 2.86 (t, 2H), 3.30 (t, J = 3Hz, 1H), 4.20 (t, 2H), 5.03 (s) 2 H, 5.42 (d, J = 2.6 Hz, 1 H), 6.66-7.49 (m, 12H).

Step C: Debenzylation

Starting from the compound prepared in Step B above, using the method described in Example 105 (Step D), the corresponding cis -isopropylbenzoxathine adduct was prepared after purification by silica gel chromatography with 10% MeOH / CH ₂ Cl ₂ as eluent. ¹ H NMR (500 MHz, CDCl ₃ ) δ (ppm): 0.95 (d, 3H), 0.98 (d, 3H), 1.50 to 1.68 (m, 6H), 1.95 ( m, 1H), 2.60 (m, 4H), 2.86 (t, 2H), 3.26 (t, J = 3.0 Hz, 1H), 4.20 (t, 2H), 5, 37 (d, J = 2.5Hz, 1H), 6.47 (dd, 1H), 6.65 (d, J = 3Hz, 1H), 6.72 (d, J = 8.6Hz) , 2H) and 7.35 (d, J = 8.7 Hz, 2H): MS m / z 414 (M < ^{+ >} ).

Example 107

Preparation of a compound of formula

Step A: Reductive cyclization

Starting from the 2-thiophene adduct (0.0208 g, 0.049 mmol) prepared in Example 43 and slightly modified as described in Example 105 (Step A),

The crude product was isolated after stirring from 0 ° C to ambient temperature for 1 hour and 40 minutes. Purification by silica gel chromatography with 30% EtOAc / hexane as eluent gave the desired product as a red oil. ¹ H NMR (500 MHz, CDCl 3) δ (ppm): 1.11 (d, 18H), 1.24 (m, 3H), 4.67 (d, J = 2.0 Hz, 1H), 50 (d, J = 1.8 Hz, 1H), 6.60-7.12 (m, 10H).

Step B: MOM Protection

To a solution of dihydrobenzoxathiin (0.0629 g, 0.13 mmol) prepared in Step A above in distilled THF (1 mL) was added 60% NaH in mineral oil (0.0090 g, 0.19 mmol) at 0 ° C under N ₂ . After gas evolution was complete, MOMCI (0.013 mL, 0.16 mmol) was added dropwise to the reaction mixture. After 30 minutes, an additional 1.3 equivalents of MOMCI was added to the reaction mixture. Within 5 minutes the reaction was complete by TLC. The resulting dark red solution was partitioned between EtOAc and ice / H 2 O. The organic layer was washed with brine, dried over Na ₂ SO 4 and concentrated in vacuo. The desired product was used in the next reaction without purification. ¹ H NMR (500 MHz, CDCl ₃ ) δ (ppm): 1.11 (d, 18H), 1.24 (m, 3H), 3.52 (s, 3H), 4.67 (d, J = 2.1 Hz, 1H), 5.14 (m, 2H), 5.50 (d, J = 1.8 Hz, 1H), 6.60-7.12 (m, 10H).

Step C: Desilylation

The dihydrobenzoxathiin prepared in Step B above was desilylated using the method described in Example 105 (Step B) to give the desired product as a colorless oil after purification by silica gel chromatography with 30% EtOAC / hexane as eluent. ¹ H NMR (500 MHz, CDCl ₃ ) δ (ppm): 3.52 (s, 3H), 4.69 (d, J = 1.8 Hz, 1H), 5.15 (m, 2H), 5 51 (d, J = 1.8 Hz, 1H); 6.60-7.15 (m, 10H).

Step D: Mitsunobu reaction

According to the method detailed in Example 105 (Step C), except that the reaction mixture 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

- 123 product after silica gel chromatography (one eluting with 30% EtOAc / hexane followed by a second elution with 10% MeOH / CH ₂ Cl ₂ ). ¹ H NMR (500 MHz, CDCl ₃ ) δ (ppm): 1.10 to 2.60 (m, 10H), 2.79 (t, 2H), 3.52 (s, 3H), 4.10 ( t, 2H), 4.69 (d, J = 1.8 Hz, 1H), 5.15 (m, 2H), 5.51 (d, J = 1.8 Hz, 1H), 6.60 to 7.15 (m, 10H).

Step E: Removal of the MOM protecting group

A mixture of the material (0.0401 g, 0.080 mmol) prepared in Step D above and 2N HCl (0.20 mL, 0.40 mmol) in MeOH (1.0 mL) was heated to 60 ° C under N ₂ 2,5 h. The reaction mixture was partitioned between EtOAc and ice / saturated NaHCO ₃ solution. The organic layer was washed with brine, dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was triturated with Et ₂ O and the desired product was obtained as a white solid. ¹ H NMR (500 MHz, CDCl ₃ ) δ (ppm) (cb-acetone + CD ₃ OD): 1.50 to 3.19 (m, 10H), 3.23 (t, 2H), 4.30 ( t, 2H), 5.00 (d, J = 1.8Hz, 1H),

5.51 (d, J = 1.8 Hz, 1H), 6.75-7.25 (m, 10H); MS m / z 454 (M < ^{+ >} ).

Example 108

Preparation of a compound of formula

Step A: Reductive cyclization

According to the method described 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 eluent. ¹ H NMR (500 MHz, CDCl ₃ ) δ (ppm): 1.11 (d, 18H), 1.24 (m, 3H), 4.36 (d, J = 2.1 Hz, 1H), 5 0.05 (s, 2H); 5.50 (d, J = 1.6 Hz, 1H); 6.77-8.43 (m, 16H).

Step B: Desilylation

Following the method described in Example 105 (Step B), the dihydrobenzoxathiin formed in Step A above was desilylated to give the desired product after silica gel chromatography (one eluting with 50% EtOAc / hexane followed by a second elution with 30% EtOAc). / hexane). ¹ H NMR (500MHz, CDCl 3) δ (ppm): 4.42 (d, J = 2.1 Hz, 1 H), 5.07 (s, 2H), 5.50 (d, J = 1, 6 Hz, 1H), 6.77-8.43 (m, 16H).

Step C: Mitsunobu reaction

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

Step D: Debenzylation

Starting from the material prepared in Step C above, using the method described in Example 105 (Step D), the corresponding cis -pyridyl dihydrobenzoxathine adduct was prepared after silica gel chromatography with 10% MeOH / CH ₂ Cl ₂ as eluent. ¹ H NMR (500 MHz, CDCl ₃ ) δ (ppm): 1.40-2.60 (m, 10H), 2.80 (t, 2H), 4.10 (t, 2H), 4.36 ( d, J = 2.1 Hz, 1H), 5.45 (d, J = 1.9 Hz, 1H),

6.59 to 8.43 (m, 11H); MS m / z 449 (M < ^{+ >} ).

Example 109

Preparation of a compound of formula

Step A: Reductive cyclization

According to the method described in Example 44, 0.1871 g of the 4-pyridyl derivative prepared in Example 41 was converted to the corresponding benzoxathine 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 eluent. ¹ H NMR (500 MHz, CDCl ₃ ) δ (ppm): 1.11 (d, 18H), 1.24 (m, 3H), 4.32 (d, 1H), 5.08 (s, 2H) 5.50 (d, 1H); 6.60-8.39 (m, 16H).

Step B: Desilylation

According to the method described in Example 105 (Step B), the dihydrobenzoxathine formed in Step A above was desilylated to give the desired product after silica gel chromatography (one eluting with 50% EtOAc / hexane followed by a second elution with 30% EtOAc / hexane). ). ¹ H NMR (500 MHz, CDCl ₃ ) δ (ppm): 4.33 (d, 1H), 5.07 (s, 2H), 5.46 (d, 1H), 6.63-8.37 ( m, 16H).

Step C: Mitsunobu reaction

Following the method detailed in Example 105 (Step C), except that the reaction mixture was allowed to warm from 0 ° C to ambient temperature for 5 h, the material prepared in the previous step was converted to the desired product after silica gel chromatography One elution with 10% MeOH / CH 2 Cl 2 followed by a second elution with 20% EtOAc / CPkCl 3. ¹ H NMR (500 MHz, CDCl ₃ ) δ (ppm): 1.40-2.60 (m, 10H), 2.80 (t, 2H), 4.14 (t, 2H), 4.32 ( d, J = 3.0 Hz, 1H), 5.06 (s, 2H), 5.49 (d, J = 2.1 Hz, 1H), 6.79-8.38 (m, 16H).

Step D: Debenzylation

Starting from the material prepared in Step C above using the method described in Example 105 (Step D), the desired product was obtained as a 4: 1 cis / trans-mixture after silica gel chromatography (1x eluting with 30% EtOAc / hexane, after followed by a second elution with 10% MeOH / CH 2 Cl 2).

126 C / s isomer: ¹ H NMR (500 MHz, CDCl ₃ ) δ (ppm): 1.40-2.70 (m, 10H), 2.80 (t, 2H), 4.10 (t, 2H), 4.30 (d, J = 2.0 Hz, 1H), 5.44 (d, J = 1.8 Hz, 1H), 6.59 to 8.40 (m, 11H).

7-trans isomer: ¹ H NMR (500 MHz, CDCl ₃ ) δ (ppm): 1.40-2.70 (m, 10H), 2.80 (t, 2H), 4.15 (t, 2H), 4.38 (d, J = 8.7 Hz, 1H), 4.92 (d, J = 8.7 Hz, 1H), 6.59 to 8.46 (m, 11H); MS m / z 449 (M < ^{+ >} ).

Example 110

Preparation of a compound of formula

Step A: Reduction

To a stirred solution of the cyclopentylthioketone 265.1 mg (0.449 mmol) formed in Example 41 in 3 mL of methanol-dichloromethane (1: 1) at 0 ° C to room temperature was added portionwise enough sodium borohydride to complete the reduction. The reaction mixture was partitioned between ethyl acetate / 2N HCl / ice / brine, and the organic phase was separated, washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated to give crude cyclopentylthiocarbinols which were used without further purification in the next step.

Step B: Cyclization

A mixture of 266 mg (0.449 mmol) of the crude product prepared in Step A above and 89 mg of Amberlyst 15 in 3 mL of toluene was stirred at ambient temperature for two hours. The resin was removed by filtration and washed well with ethyl acetate. The filtrate was evaporated and the obtained residue was purified by silica gel chromatography using dichloromethane-hexanes (1: 1) as eluent to give the trans-dihydrobenzoxathiin derivative. ¹ H NMR (500 MHz, CDCl ₃ ) δ (ppm): 1.13 (d, 18H), 1.26-1.94 (m, 12H),

-127 3.64 (dd, J = 7.8 Hz, 1H), 4.78 (d, J = 7.8 Hz, 1H), 5.02 (s, 2H), 6.6 to 7.45 (m, 12H).

Step C: Desilylation

According to the method described in Step B of Example 105, 228.5 mg (0.397 mmol) of the material prepared in the previous step was desilylated to give the corresponding phenol.

Step D: Mitsunobu reaction

According to the method described in detail in Step C of Example 105, the material prepared in the previous step was converted to the corresponding trans-cyclopentyldihydrobenzoxathine adduct. ¹ H NMR (500 MHz, CDCl ₃ ) δ (ppm): 1.39-2.0 (m, 15H), 2.6 (m, 4H), 2.88 (m, 2H), 3.66 (dd, J = 7.8Hz, 5.5Hz, 1H), 4.21 (m, 2H),

4.81 (t, J = 7.8 Hz, 2H), 5.01 (s, 2H), 6.64-7.49 (m, 12H).

Step E: Debenzylation

According to the method detailed in Step D of Example 105, the material prepared in the previous step was converted to the corresponding trans-cyclopentyldihydrobenzoxathiin product. ¹ H NMR (500 MHz, CDCl ₃ ) δ (ppm): 1.29-2.0 (m, 15H), 2.6 (m, 4H), 2.88 (m, 2H), 3.67 ( dd, J = 8Hz, 5Hz, 1H), 4.18 (m, 2H),

4.77 (t, J = 8Hz, 2H), 6.5 (dd, J = 2.7Hz, 8.7Hz, 1H), 6.65 (d, J = 2.7Hz, 1H) 6.77 (d, J = 8.7 Hz, 1H), 6.88 (d, J = 7.5 Hz, 2H) and 7.27 (d, J = 7.5 Hz, 2H).

Example 111

General Preparation of Compound of Formula

O ', N

- 128 Steps A and B: Reduction and cyclization

Using the thioketones prepared in Example 39 and using the methods described in Example 110, step A and B above, the following compounds were prepared: 7-trans-cyclohexyl derivative: ¹ H NMR (500 MHz, CDCl ₃ ) δ (ppm): 1.14 ( d, 18H), 0.98-1.8 (m, 14H), 3.37 (dd, J = 2.5 Hz, 1.8 Hz, 1H), 5.01 (s, 2H), 5 0.05 (d, J = 8.1 Hz, 1H), 6.6-7.44 (m, 12H).

Trans-cyclopentyl derivative: ¹ H NMR (500 MHz, CDCl ₃ ) δ (ppm): 1.14 (d, 18H),

1.28-1.9 (m, 12H), 4.53 (m, 1H), 4.93 (d, 1H), 5.01 (s, 2H), 6.6-7.43 (m, 12H).

Step C: Desilylation

Using the trans-dihydrobenzoxathiins prepared in the previous step, and using the method described in step 105 of Example 105 above, the following compounds were prepared:

Trans-cyclohexylphenol: ¹ H NMR (500 MHz, CDCl ₃ ) δ (ppm): 1.0 to 1.8 (m, 11 H), 3.3 (m, 1H), 5.05 (s, 2H) 5.1 (d, 1H); 6.6-7.44 (m, 12H).

Trans-cyclopentylphenol: ¹ H NMR (500 MHz, CDCl ₃ ) δ (ppm): 1.29 to 2.0 (m, 9H),

3.55 (dd, J = 5.7 Hz, 7.6 Hz, 1H), 4.95 (d, J = 7.6 Hz, 1H), 5.02 (s, 2H), 6.6- 7.45 (m, 12H).

Step D: Mitsunobu reaction

Using the trans-dihydrobenzoxathiophenols prepared in the previous step, and using the method described in step 105 of Example 105 above, the following compounds were prepared:

Trans-cyclohexyl adduct: ¹ H NMR (500 MHz, CDCl ₃ ) δ (ppm): 1.0 to 1.8 (m, 17H), 2.58 (m, 4H), 2.84 (m, 2H) 3.37 (m, 1H); 4.17 (t, J = 6Hz, 2H); 5.0 (s, 2H); 5.08 (d, J = 7.8Hz, 1H); 6 to 7.43 (m, 12H).

Trans-cyclopentyl adduct: ¹ H NMR (500 MHz, CDCl ₃ ) δ (ppm): 1.29 to 2.0 (m, 15H), 2.58 (m, 4H), 2.84 (m, 2H) 3.55 (m, 1H), 4.17 (m, 2H), 4.94 (d, J = 7.3 Hz, 1H), 5.0 (s, 2H), 6.6-7, 72 (m, 12 H).

Step E: Debenzylation

Using the trans-dihydrobenzoxathiin adducts prepared in the previous step, and using the method described in Example 105, Step D, the following compounds were prepared:

7-Trans-cyclohexyl adduct: ¹ H NMR (500 MHz, CDCl ₃ ) δ (ppm): 1.0 to 1.8 (m, 17H), 2.58 (m, 4H), 2.86 (m, 2H) 3.33 (m, 1H); 4.16 (m, 2H); 5.08 (d, J = 7.8 Hz, 1H); 6.4-7.23 (m, 7H).

Trans-cyclopentyl adduct: ¹ H NMR (500 MHz, CDCl 3) δ (ppm): 1.29-2.0 (m, 15H), 2.68 (m, 4H), 2.94 (m, 2H), 3.51 (m, 1H), 4.2 (m, 2H), 4.95 (d, J = 7.4 Hz, 1H), 6.45-7.31 (m, 7H).

Example 112

Preparation of a compound of formula

Step A: Silyiation

To a stirred solution of isopropylthioketone (0.0395 g, 0.097 mmol) formed in Example 42 in distilled THF (1 mL) at 0 ° C was added 60% NaH in mineral oil (0.0183 g, 0.20 mmol), followed by TIPSCI (0.048 mL, 0.22 mmol). After 35 minutes, an additional equivalent of TIPSCI was added to bring the reaction to completion. The reaction mixture was partitioned between EtOAc and ice / H 2 O, and the organic layer was 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.

Step B: Reduction

To a solution of the crude product (0.097 mmol) prepared in Step A in distilled THF (1 mL) was added a 1M solution of superhydride in THF (0.15 mL, 0.15 mmol) at 0 ° C under N 2. The reaction mixture was stirred for 20 minutes before partitioning between EtOAc and ice / H ₂ O. The organic layer was further washed with brine, dried over Na ₂ SO ₄ and

130 was concentrated in vacuo to give the desired product. The crude material was used in the next step without further purification. ¹ H NMR (500 MHz, CDCl 3) δ (ppm): 0.90 to 1.40 (m, 49H), 1.69 (m, 1H), 3.10 (dd, 1H), 4.60 (d 1H, 5.05 (s, 2H), 6.70-7.50 (m, 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 ° C under N ₂ , followed by addition of 1M solution of TBAF in THF ( 0.29 mL, 0.29 mmol). After 15 minutes, the reaction mixture was partitioned between EtOAc and ice / saturated NaHCO 3 solution. The organic layer was washed with brine, dried over Na ₂ SO ₄ and concentrated in vacuo. Purification by silica gel chromatography using 40% EtOAc / hexane as eluent gave the desired product as a yellow foam. ¹ H NMR (500 MHz, CDCl ₃ ) δ (ppm): 0.92 (d, 3H), 0.98 (d, 3H), 1.59 (m, 1H), 2.86 (dd, 1H) 4.62 (d, 1H); 5.02 (q, 2H); 6.77-7.45 (m, 12H).

Step D: Cyclization

According to the method described in Example 110 (Step B), the material formed in the previous step was converted to the appropriate trans-dihydrobenzoxathiin after stirring for 5 h 15 min at ambient temperature. Purification by silica gel chromatography using 30% EtOAc / hexane as eluent gave the desired product as a white solid. ¹ H NMR (500 MHz, CDCl ₃ ) δ (ppm): 0.98 (d, 3H), 1.03 (d, 3H), 1.78 (m, 1H), 3.57 (dd, J = 3.7 Hz, J = 8.5 Hz, 1H), 4.82 (d, J = 8.4 Hz, 1H), 5.02 (s, 2H), 6.63-7.46 (m, 12H).

Step E: Mitsunobu reaction

According to the method described in Example 105 (Step C), the material (0.0266 g, 0.068 mmol) formed in the previous step was converted to the corresponding trans-isopropyldihydrobenzoxathine adduct after heating from 0 ° C to ambient temperature over 4 h 20 min. Purification by silica gel chromatography (one eluting with 10% MeOH / CH ₂ Cl ₂ followed by a second elution with 30% EtOAc / hexane) to

131 gave the desired product as a white solid. ¹ H NMR (500 MHz, CDCl 3) δ (ppm): 0.98 (d, 3H), 1.02 (d, 3H), 1.29-1.67 (m, 6H), 1.78 (m (1H), 2.58 (m, 4H),

2.85 (t, 2H), 3.57 (dd, J = 3.7 Hz, J = 8.5 Hz, 1H), 4.18 (t, 2H), 4.83 (d, J = 8) 4 Hz, 1H), 5.02 (s, 2H), 6.63-7.46 (m, 12H).

Step F: Debenzylation

Following the method detailed in Example 105 (Step D), the material (0.0395 g, 0.068 mmol) formed in the previous step was converted to the corresponding trans-isopropyldihydrobenzoxathiin product. Purification was by silica gel chromatography using 10% MeOH / CH ₂ Cl ₂ as eluent. ¹ H NMR (500 MHz, CDCl 3) δ (ppm): 0.98 (d, 3H), 1.02 (d, 3H), 1.29-1.67 (m, ΌΗ), 1.78 (m (1H), 2.58 (m, 4H), 2.85 (t, 2H), 3.57 (dd, J = 3.7 Hz, J = 8.5 Hz, 1H), 4.18 (t , 2H),

4.83 (d, J = 8.4 Hz, 1H), 6.63-7.46 (m, 12H); MS m / z 414 (M < ^{+ >} ).

Example 113

Preparation of a compound of formula

Step A: Silylation

Following the method described in Example 112 (Step A), the isopropylthioketone (0.6314 g, 1.5 mmol) formed in Example 40 was silylated. Purification by silica gel chromatography using 30% EtOAc / hexane as eluent gave the desired product as a yellow oil. ¹ H NMR (500 MHz, CDCl ₃ ) δ (ppm): 0.98 to 1.30 (m, 49H), 2.35 (m, 1H), 4.38 (d, 1H), 4, 99 (q, 2H), 6.33-7.79 (m, 12H).

Step B: Reduction

According to the method described in Example 112 (Step B), the material (0.8009 g, 1.1 mmol) isolated in Step A above was reduced to the corresponding alcohol and used in the next step without further purification. ¹ H NMR (500 MHz, CDCl ₃ )

- 132δ (ppm): 0.98 to 1.30 (m, 49H), 1.90 (m, 1H), 2.92 (dd, 1H), 4.59 (d, 1H), 5.05 ( q, 2H), 6.47-7.43 (m, 12H).

Step G: Desilylation _;

According to the method described in Example 112 (Step C), the material (0.022 mmol) isolated in Step B above was deprotected to give the desired product, which was used in the next step without purification.

Step D: Cyclization

According to the method described in Example 110 (Step B), the material formed in the previous step was converted to the corresponding trans -dihydrobenzoxathiin after stirring for 22 h at ambient temperature. Purification by silica gel chromatography using 30% EtOAc / hexane as eluent gave the desired product as a colorless oil. ¹ H NMR (500 MHz, CDCl ₃ ) δ (ppm): 0.98 (d, 3H), 1.03 (d, 3H), 1.79 (m, 1H), 3.45 (dd, 1H) 1.98 (d, 1H), 5.02 (s, 2H), 6.59-7.46 (m, 12H); MS m / z 393 (M < ^{+ >} ).

Step E: Mitsunobu reaction

According to the method detailed in Example 105 (Step C), the material (0.008 g, 0.020 mmol) formed in the previous step was converted to the corresponding trans-isopropyldihydrobenzoxathine adduct after heating from 0 ° C to ambient temperature for 6 h. Purification by silica gel chromatography using 10% MeOH / CH ₂ Cl 2 as eluent gave the desired product as a pale yellow oil. ¹ H NMR (500 MHz, CDCl ₃ ) δ (ppm): 0.98 (d, 3H), 1.02 (d, 3H), 1.29-1.67 (m, 6H),

1.79 (m, 1H), 2.58 (m, 4H), 2.81 (t, 2H), 3.50 (dd, J = 3.8 Hz, J = 8.3 Hz, 1H), 4.18 (t, 2H), 4.97 (d, J = 8.2 Hz, 1H), 5.01 (s, 2H), 6.59-7.46 (m, 12H).

Step F: Debenzylation

Following the method detailed in Example 105 (Step D), the material (0.0085 g, 0.017 mmol) formed in the previous step was converted to the corresponding trans-isopropyldihydrobenzoxathiin product. Purification was by silica gel chromatography using 10% MeOH / CH ₂ Cl ₂ as eluent. ¹ H NMR (500 MHz, CDCl ₃ ) δ (ppm): 0.98 (d, 3H), 1.02 (d, 3H), 1.49-1.70

133 (m, 6H), 1.75 (m, 1H), 2.61 (m, 4H), 2.85 (t, 2H), 3.41 (dd, J = 3.8 Hz, J = 8.3 Hz, 1H), 4.18 (t, 2H), 4.96 (d, J = 8.2 Hz, 1H), 6.43-7.26 (m, 7H); MS m / z 414 (M < ^{+ >} ).

Example 114

Preparation of a compound of formula

Following the procedure described in Example 16, using 0.36 g (2.5 mmol) of 1,2-benzenedithiol purchased from Aldrich, 221 mg (about 20%, impure) of the desired product was obtained after silica gel chromatography using EtOAc / hexane (1/5) as eluent.

Example 115

Preparation of compounds of formula

Example 116

Preparation of Compounds of Formula mg (80%) by Three Chromatography with 10%

Using the method of Example 44, 121 products (A: B: C = 1: 0.1: 0.25) were isolated after silica gel purification

EtOAc / hexane.

- 134-

Step A

The thiine obtained from Example xx was coupled with 1-piperidinoethanol using the method described in Example 71 (Step A). Purification by silica gel chromatography using 3% MeOH / CH 2 Cl 2 as eluent gave the desired adducts as a mixture.

Step B

The adducts of Step A were desilylated using the method described in Example 71 (Step C). The desired product A was separated by HPLC (Metá Chem Polaris C

184.6 x 50.5 microns: gradient of 5-75% acetonitrile on a reverse phase column) as a white solid.

A: ¹ H NMR (400 MHz, CD ₃ OD) δ (ppm): 7.2 (m, 2H), 7.1 (m, 2H), 6.9 (m, 2H), 6.8 (m 4H), 6.55 (d, 2H), 4.75 (m, 2H), 4.3 (m, 2H), 3.6 (br d, 2H), 3.5 (m, 2H), 3.0 (br t, 2H); 1.95 (m, 2H); 1.8 (m, 4H); MS m / z 464 (M < ^{+ >} ).

B: ¹ H NMR (400 MHz, CD ₃ OD) δ (ppm): 7.4 (m, 2H), 7.3 (m, 2H), 7.1 (d, 2H), 6.95 (d (2H), 6.8 (d, 2H), 6.6 (d, 2H), 4.3 (br t, 2H), 3.6 (br d, 2H), 3.5 (br t, 2H) 1.05, 3.05 (br t, 2H), 2.0 (br d, 2H), 1.8 (m, 4H); MS m / z 462 (M < ^{+ >} ).

Test methods

The utility of the compounds of this invention can be readily determined by methods well known to those skilled in the art. These methods may include, but are not limited to, those described in detail below.

Estrogen receptor binding testing

Estrogen receptor ligand binding assays are designed as scintillation related assays using the use of tritiated estradiol and receptors

- 135 recombinantly expressed estrogen. Full-length recombinant human ER-α and ER-β proteins are produced in the baculovirus expression system. ER-α or ER-β extracts are diluted 1: 400 in phosphate buffered saline containing 6 mM α-monothiol glycerol. A 200 μl aliquot of the diluted receptor preparation is 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 μl aliquot of phosphate buffered saline containing 10% bovine serum albumin is added to each well of a 96-well plate and incubated for 2 hours at 4 ° C. The plates are then washed with 200 μΙ of buffer containing 20 mM Tris (pH 7.2), 1 mM EDTA, 10% glycerol, 50 mM KCl and 6 mM α-monothiol glycerol. To prepare the test in these

Also, receptor-coated plates are added 178 μΙ of the same buffer to each well of a 96-well plate. Then, 20 μΙ of a 10 nM solution of ³ H-estradiol is added to each well.

Test compounds are evaluated over a concentration range of 0.01 nM to 1000 nM. A stock solution of the test compound should be made in 100% DMSO at 100 times the final concentration required for testing in the assay. The amount of DMSO in the assay wells of a 96-well plate should not exceed 1%. The final addition to the assay plate is a 2 μΙ aliquot of the test compound, which was made in 100% DMSO. The plates are sealed and allowed to equilibrate at room temperature for 3 hours. Plates are read in a scintillation counter equipped to count 96-well plates.

Rat test with ovaries removed

In the ovariectomized (OVX) rat test, estrogen deficiency is used to induce spongy osteopenia (e.g., low bone mineral density [BMD; mg / cm ² ]) associated with acceleration of bone resorption and bone formation. The results of both BMD and bone resorption / formation are used to model the changes in bone that occur when women undergo menopause. The OVX rat test is a principal in vivo test used by all major academic and industrial

-136 laboratories investigating the effectiveness of new chemical entities in preventing bone loss due to estrogen deficiency.

Sprague-Dawley rats 6 to 8 months of age were ovarian removed and 42-day treatment with vehicle or multiple doses of test compound was started within 24 hours. Untreated simulated OVX and alendronate treated (0.003 mg / kg s.c., q.d.) or 17-β-estradiol treated (0.004 mg / kg s.c., q.d.) groups were included as positive controls. Test compounds can be administered orally, subcutaneously, or by infusion through a minipump introduced under the skin. Before necropsy, double labeling with calcein (8 mg / kg by subcutaneous injection), a bone-seeking fluorochrome, is completed in vivo. At necropsy, blood, femurs, vertebral body segment and uterus are collected.

Typical end results of the OVX rat test include bone mass determination, bone resorption, and bone formation. For bone mass, the end result of BMD is distal metaphysis of the femur, an area that contains about 20% of spongy bone. The vertebral segment, an area of ~ 25% spongy bone, can also be used to determine BMD. BMD measurements are made by measuring the absorption of dual energy X-ray radiation (DXA, Hologic 4500 A; Waltham, MA). For bone resorption, the end result is transverse binding of urinary deoxypyrrolidine, 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 end result is mineralized surfaces and mineral deposition rates, histomorphometric values of osteoblast count and activity. This measurement is made on 5 µm sections of undecalcified proximal whistle metaphysis using a semi-automated system (Bioquant; R&M Biometrics; Nashville, TN). Similar endpoints and measurement techniques for each endpoint are commonly used in postmenopausal women.

Rat Cholesterol Lowering Test

Sprague-Dawley rats (5 per group) weighing about 250 g were dosed subcutaneously with compounds of the invention dissolved in propylene glycol for 4 days. A group of 5 rats received vehicle only. For the fifth day

137, rats were sacrificed with carbon dioxide and blood samples were taken. Plasma cholesterol levels were measured on these samples with commercially available Sigma cholesterol determination kits.

I]

Estrogen-dependent proliferation assay of MCF-7

MCF-7 cells (ATCC # HTB-22) are human mammary adenocarcinoma cells that need estrogen to grow. The growth medium (GM) for MCF-7 cells is Minimum Essential Medium (without phenol red), supplemented with fetal bovine serum (FBS) to 10%. FBS serves as the only source of estrogen and this GM promotes complete cell growth and is used for routine cultivation of cell cultures. When the MCF-7 cells are placed in medium in which 10% charcoal-dextran-treated fetal bovine serum (CD-FBS) is replaced by FBS, the cells stop dividing but remain viable. CD-FBS does not contain detectable levels of estrogen and the medium containing this serum is referred to as estrogen depleted medium (EDM). Addition of estradiol to EDM stimulates the growth of MCF-7 cells in a dose-dependent manner with EC ₅ of 2 µM.

The growing cells are washed several times with EDM and the cultures are then held in the EDM for at least 6 days to deplete endogenous estrogen in the cells. On day 0 (at the start of the assay), these estrogen-poor cells are plated in 96-well cell culture plates at a density of 1000 cells / well in EDM at a volume of 180 μΙ / well. On day 1, test compounds are diluted in 10-fold dilution series in EDM and 20 μΙ of these dilutions are added to 180 μΙ medium in the appropriate well of the cell plate, resulting in an additional 1:10 dilution of test compounds. On days 4 and 7 of the assay, the culture supernatant is aspirated and replaced with fresh EDM and dilute solutions of test compounds as above. The test ends on days 8-10 when the respective controls reach an 80-90% overlap. At this point, the culture supernatants are aspirated, the cells are washed twice with PBS, the wash solution is aspirated and the protein content of each well is determined. Each diluted drug solution is evaluated in a minimum of 5 wells and the dilution range of the test compounds in the assay is 0.001 nM to 1000 nM. The assay in this form is used to determine the agonist ability of the test compound to estradiol.

In order to evaluate the antagonist activity of the test compound, MCF-7 cells are maintained in the EDM for at least 6 days. Then, on day 0 (at the start of the assay), these estrogen-poor cells are plated in 96-well cell culture plates at a density of 1000 cells / well in an EDM of 180 μΙ / well. On day 1, test compounds are applied to cells in fresh medium containing 3 µM estradiol. On days 4 and 7 of the assay, the culture supernatant is aspirated and replaced with pure EDM containing 3 µM estradiol and test compound. The assay is terminated on days 8-10 when the respective controls reach an 80-90% overlap, and the protein content of each well is determined as above.

Rat Endometriosis Model

The animals:

Species: Rattus norvegicus

Tribe: Sprague-Dawley CD

Supplier: Charles River Laboratories, Raleigh, NC ₍

Gender: Female Weight: 200 to 240 grams

Rats are placed individually in polycarbonate cages and provided with Teklad Global Diet 2016 (Madison, Wl) and a reverse osmosis bottle of purified H ₂ O to taste. They are maintained at 12/12 light / dark cycle.

Rats are anesthetized with Telazol ™ (20 mg / kg, ip) and oxymorphone (0.2 mg / kg, sc) and placed on their side on a sterile drape. Body temperature is maintained by a padded blanket with water circulation. Surgical sites are shaved with scissors and cleaned using three cycles of betadine / isopropyl alcohol or Duraprep® (3M). The incisal area is covered with a sterile drape.

Using aseptic technique, a 5 cm abdominal incision is made along the midline through the skin, subcutaneous and muscle layers. The ovaries are removed on both sides. The left uterine blood vessels are ligated and a 7 mm segment of the left corner of the uterus is excised. The uterus is closed with a 4-0 gut suture. The myometrium is separated aseptically from the endometrium and cut to 5 x 5 mm. The cut endometrium is transplanted into the anterior peritoneal wall with epithelial sewing of the segment opposite

-139 peritoneal wall. The explanted endometrial tissue is sutured on its four corners to the abdominal wall using sterile 6-0 silk. The abdominal muscle layer is sealed using sterile 4-0 chromgut. The skin incision is closed with sterile stainless steel surgical clips. A 90-day sustained-release sterile estrogen pellet (Innovative Research of America, 0.72 ng / pellet; equivalent to 200-250 pg / ml circulating estrogen) is inserted subcutaneously into the posterior lateral scapula. A sterile implantable programmable transponder (IPTT) (BMDS, Seaford, DE) is inserted subcutaneously into the posterior region of the scapula. Rats are monitored until complete mobility and allowed to recover from surgery for 3 weeks undisturbed.

Three weeks after endometrial tissue transplantation, the animals are subjected to repeated laparotomy using aseptic surgical site preparation and technique. The explants are evaluated for graft acceptance and the area is measured with calipers and recorded. Animals with grafts not received are excluded from the study. The animals are sorted to create a similar average of the amount of explants per group.

Treatment with the substance or vehicle (control) is started one day after the second laparotomy and continued for 14 days. Body temperature is recorded every other day at 10:00 using a BMDS scanner.

At the end of the 14 day treatment period, animals are sacrificed with an excess of ΟΟ ₂ . Blood is collected by cardiocentesis to determine circulating estrogen levels. The abdomen is opened, the explant is examined, measured, excised and the wet weight recorded. The right corner of the uterus was excised and the wet and dry weight recorded.

Pharmaceutical composition

As a specific embodiment of the invention, 25 mg of the compound of Example 71 is mixed with a sufficiently finely divided lactose to give a total amount of 580 to 590 mg to fill a 0 size hard gelatin capsule.

Claims (7)

PATENT CLAIMS Estrogen receptor modulators of the formula IA wherein each of R ¹ , R ² , R ³ and R ⁴ is independently selected from the group consisting of hydrogen, C 1-6 -alkyl, C 3-8 -cycloalkyl, C 2-5 -alkenyl, C 2. 5-alkynyl, C 3-8 -cycloalkenyl, phenyl, heteroaryl, heterocycle, CF 3, -OR ⁶ , halogen, C 1-5 -alkylthio, thiocyanato, cyano, -CO 2 H, -COOC-1-5-alkyl, -COC 1-8 -alkyl, -CONZ 2, -SO ₂ NZ ₂ and -SO ₂ Ci. _5-alkyl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, phenyl, heteroaryl, heterocyclic moieties may be optionally substituted with Cys-alkyl, C _3-8 cycloalkyl, CF _3, phenyl, heteroaryl, heterocycle, -OR ^6, halo , amino, Ci. _5- alkylthio, thiocyanato, cyano, -CO 2 H, -COOC 3-6 -alkyl, -COC 1. _5- alkyl, -CONZ ₂ , -SO ₂ NZ _2, and -SO ₂ C 1-5 -alkyl; R ⁵ is selected from the group consisting of C 1-5 -alkyl, C 3-8 -cycloalkyl, C 2-5 -alkenyl, C 2-5 -alkynyl, C 3-8 -cycloalkenyl, phenyl, heteroaryl, heterocyclic groups, said groups being optionally Cvsalkylom substituted, C 3-8 cycloalkyl, CF 3, phenyl, heteroaryl, heterocycle, -OR ^6, halo, amino, Cys-alkylthio, tiokyanatoskupinou, cyano, -CO 2 H, -COOCvs-alkyl, -COCvs-alkyl, -CONZ _2, -SO ₂ NZ ₂ and -SO ₂ C 1-5 -alkyl; X and Y are each independently selected from the group consisting of oxygen, sulfur, sulfoxide, and sulfone; R ⁶ is selected from the group consisting of hydrogen, C 1-6 -alkyl, benzyl, methoxymethyl, triorganosilyl, C 1-6 -alkylcarbonyl, alkoxycarbonyl and CONZ ₂ ; each Z is independently selected from the group consisting of hydrogen, C 1-5 -alkyl, trifluoromethyl, wherein said alkyl group may be optionally substituted with C 1-5 -alkyl, -141 CF ₃ -OR ⁶ , halogen, amino, C 1-6 -halo; _5- alkylthio, thiocyanato, cyano, -CO ₂ H, -COOC 3-6 -alkyl, -COC 1. _5- alkyl, -CONV ₂ , -SO ₂ NV ₂ and -SO ₂ C _1-5 -alkyl; or both Z together with the nitrogen to which they are attached form a 3- to 8-membered ring, said ring optionally having atoms selected from the group consisting of carbon, oxygen, sulfur and nitrogen, wherein said ring may be either saturated or unsaturated and the carbon atoms of said ring may be optionally substituted with one to three substituents selected from the group consisting of C 1-6 alkyl. _5- alkyl, CF ₃ , -OR ⁶ , halogen, amino, C ^1-6 -alkylthio, thiocyanato, cyano, -CO ₂ H, -COOC 1-6 -alkyl, -COC 1. _5- alkyl, -CONV ₂ , -SO ₂ NV _2, and -SO ₂ C _1-5 -alkyl; each V is independently selected from the group consisting of C 1-5 -alkyl, CF ₃ , -OR ⁶ , halogen, amino, C 1-6 alkyl, C 1-6 alkyl, C 1-6 alkyl; _5- alkylthio, thiocyanato, cyano, -CO ₂ H, -COOCl ₅ -alkyl, -COCl. _5- alkyl and -SO ₂ C 1-6 alkyl; _5- alkyl; each n is independently an integer from one to five; and pharmaceutically acceptable salts thereof. A compound according to claim 1, wherein Y is sulfur and X is oxygen, and pharmaceutically acceptable salts thereof. The compound of claim 2, wherein each of R ¹ , R ² , R ³ and R ⁴ is independently selected from the group consisting of hydrogen, C 1-5 alkyl, C ₃ . ₈ cycloalkyl, C _{2nd 5} -alkenyl, C _{2nd 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 C ₃ . _8- cycloalkyl, phenyl, heteroaryl and heterocyclic groups, said groups optionally being substituted with -OR ⁶ and halogen; R ⁶ is preferably selected from the group consisting of hydrogen, C 1-6 -alkyl, benzyl, methoxymethyl and triisopropylsilyl; and pharmaceutically acceptable salts thereof. A compound according to claim 3, selected from the group consisting of - 142 wherein each of R ¹ , R ² , R ³ and R ⁴ is independently selected from the group consisting of hydrogen, C 1-8 -alkyl, C 3-8 -cycloalkyl, C 2-8 5-alkenyl, _C2 -5 alkynyl, ^-OR6 and halogen, provided that one of R ² and R ³ is -OH; R ⁶ is selected from the group consisting of hydrogen, C 1-6. _5- alkyl, benzyl, methoxymethyl and triisopropylsilyl; R ⁷ is selected from the group consisting of hydrogen, C 1-5 -alkyl, halogen, trifluoromethyl and -OR ⁶ ; -143 each Z is independently selected from the group consisting of hydrogen, C 1-6 -alkyl, trifluoromethyl, wherein said alkyl group may be optionally substituted with C 1-5 alkyl, CF 3, -OR ⁶ , halogen, amino, C 1-6 alkyl; _5- alkylthio, thiocyanato, cyano, -CO ₂ H, -COOCl. _5- alkyl, -COC-is-alkyl, -CONV ₂ , -SO ₂ NV ₂ and -SO ₂ C ₁ . _5- alkyl; or both Z together with the nitrogen to which they are attached form a 3- to 8-membered ring, wherein said ring may optionally contain atoms selected from the group consisting of carbon, oxygen, sulfur and nitrogen, wherein said ring may be either saturated or unsaturated and the carbon atoms of said ring may be optionally substituted with one to three substituents selected from the group consisting of C 1-6 -alkyl, CF ₃ , -OR ⁶ , halogen, amino, C 1-6 -alkyl; _5- alkylthio, thiocyanato, cyano, -CO ₂ H, -COOC-is-alkyl, -COC 1-6 -alkyl, -CONV ₂₁ -SO ₂ NV ₂ and -SO ₂ C ₁ . _5- alkyl; each V is independently selected from the group consisting of C 1-8 -alkyl, CF 3, -OR ⁶ , halogen, amino, C 1-6 -alkyl, C 1-6 -alkyl; _5- alkylthio, thiocyanato, cyano, -CO ₂ H, -COOC 1-5 -alkyl, -COC 1-5 -alkyl and -SO _{2 C} 1-5 -alkyl; each n is independently an integer from one to five; each m is independently an integer from one to four; and pharmaceutically acceptable salts thereof. A compound according to claim 5, selected from the group consisting of ΗΟ (+) - 144 χχ. _s „xr H. C CH, HO. WOX / rfsf and pharmaceutically acceptable salts thereof. wherein each of R ^1, R ^2, R ³ and R ⁴ are independently selected from the group consisting of hydrogen: cis-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 ⁶ is selected from the group consisting of hydrogen, C 1-6. _5- alkyl, benzyl, methoxymethyl and triisopropylsilyl; R ⁷ is selected from the group consisting of hydrogen, C 1-5 -alkyl, halogen, trifluoromethyl and -OR ⁶ ; R ⁸ is independently selected from the group consisting of hydrogen, C 1-5 -alkyl, CF ₃ , -OR ⁶ , halogen, amino, C _1-5 -alkylthio, thiocyanato, cyano, -CO ₂ H, -COOC 5 -alkyl, -COC 1-6 -alkyl, -CONV ₂ , -SO ₂ NV ₂ and -SO ₂ C ₁ . _5- alkyl; -145 each V is independently selected from the group consisting of Ci. _5- alkyl, CF ₃ , -OR ⁶ , halogen, amino, C 1-6 -alkyl; _5- alkylthio, thiocyanato, cyano, -CO ₂ H, -COOC- | ₅ -alkyl, -COC p-alkyl and -SO ₂ C _{1st 5-} alkyl; each m is independently an integer from one to four; each p is independently an integer from one to four; and pharmaceutically acceptable salts thereof. A compound according to claim 7, selected from the group consisting of