BG107676A - 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 the 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, rustiness, gynacomastia, vascular smooth muscle cell proliferation, obesity, incontinence and cancer, in particular of the breast, uterus and prostate. 20 claims

Description

BACKGROUND OF THE INVENTION

Natural and synthetic estrogens have wide therapeutic uses, including: relieving menopausal symptoms, treating acne, treating dysmenorrhea and dysfunctional uterine bleeding, treating osteoporosis, treating hair (hirsutism), treating prostate cancer, treating hot and prevention of cardiovascular disease. Because estrogen is therapeutically valuable, the interest in finding substances that have estrogen-like behavior in estrogen-dependent tissues is very high.

For example, estrogen-like compounds have a beneficial effect in the treatment and prevention of bone loss. Bone loss is observed in various patients such as postmenopausal women or after hysterectomy, patients who have been or are currently being treated with corticosteroids, and patients with gonadal dysgenesis. Currently, the major diseases of social significance are osteoporosis, hypercalcemia in malignancies, osteopenia due to bone metastases, periodontal disease, hyperparathyroidism, peri-articular erosion in rheumatoid arthritis, immaturity of Paget All these diseases are characterized by bone loss that results from imbalance between bone resorption, ie. destruction, and bone formation that lasts a lifetime at an average rate of about 14% per year. However, the rate of change is different from place to place, for example, it is greater in the trabecular bone of the spine and alveolar bone of the jaws than in the cortices of the long bones. The tendency for bone loss is directly related to the change and can amount to more than 5% per year in the spine immediately after menopause, a disease that leads to an increased risk of fractures.

There are currently about 20 million people in the United States with osteoporosis-related spine fractures. w In addition, there are about 250,000 hip fractures per year due to osteoporosis. This clinical picture accounts for 12% of mortality in the first two years, and 30% of patients need care at home after a fracture.

In the US alone, osteoporosis affects approximately 20 to 25 million postmenopausal women. There is a theoretical assumption that rapid bone loss in these women is due to the discontinuation of estrogen production by the ovaries. Since studies have shown that estrogen slows / decreases bone mass due to osteoporosis, estrogen replacement therapy has been recognized for the treatment of postmenopausal osteoporosis.

In addition to bone mass, estrogen is likely to have an effect on cholesterol biosynthesis and cardiovascular health. Statistically, the prevalence of cardiovascular disease is approximately the same in postmenopausal women and men; however, in pre-menopausal women, cardiovascular disease is much less prevalent than in men. Due to estrogen deficiency in postmenopausal women, estrogen is thought to play a favorable role in preventing cardiovascular disease. The mechanism has not been fully elucidated, but there is evidence that estrogen can regulate low lipid density (LDL) cholesterol receptors in the liver, which eliminate excess cholesterol.

Post-menopausal women who have been administered estrogen replacement therapy regain lipid levels to concentrations comparable to pre-menopausal levels. So, estrogen replacement therapy can be an effective treatment for such a disease. But the side effects of long-term use of estrogen limit the use of this possibility.

Other conditions that affect post-menopausal women are estrogen-dependent breast and uterine cancer. Anti-estrogenic compounds such as tamoxifen are commonly used for chemotherapy for breast cancer patients. Tamoxifen, which is a dual antagonist and estrogen receptor agonist, has a beneficial effect in the treatment of estrogen-dependent breast cancer. However, tamoxifen is far from being an ideal drug because of its agonist behavior, it exacerbates the undesired estrogenic side effects. For example, tamoxifen and other compounds that are estrogen receptor agonists tend to increase the production of cancer cells in the uterus. A better therapy for such cancers is to use an anti-estrogenic compound that has little or no agonist properties.

Although estrogen can be useful for treating pathologies such as bone loss, increased lipid levels and cancer, long-term estrogen therapy plays a role in many disorders, including increasing the risk of uterine and endometrial cancers. These and other side effects of estrogen replacement therapy are not acceptable to many women and limit its use.

Alternatively, a combination drug of progestogen and estrogen may be used to reduce the risk of cancer. However, such treatment results in bleeding, which is undesirable for a large number of older women. In addition, the combination of estrogen with progestogen reduces the beneficial effect of lowering

A

X-cholesterol in estrogen therapy. There are no known side effects of prolonged progestogen therapy.

In addition to post-menopausal women, anti-estrogen therapy is also beneficial for the treatment of men with prostate cancer. Prostate cancer is often endocrine sensitive; androgen stimulation promotes tumor growth, while androgen inhibition slows tumor growth. Estrogen administration supports the treatment and control of prostate cancer, since administration of C estrogen leads to a decrease in gonadotropin levels and, accordingly, to androgen levels.

The estrogen receptor has been found to have two forms: ERcc and ERp. The ligands bind differently to these two forms and each of the forms has a different tissue specificity than the binding ligands. For example, some compounds may be selective for ERoc or ERP and thus impart some tissue specificity to a ligand.

SUMMARY OF THE INVENTION

Compounds that produce the same positive responses as estrogen replacement therapy without its negative side effects are needed.

The compounds of the present invention are estrogen receptor ligands and as such are useful for treating or preventing various diseases related to the action of estrogen such as bone loss, bone fractures, osteoporosis, joint degeneration, endometriosis, uterine fibroid disease, hot waves, increased LDL cholesterol levels, cardiovascular disease, cognitive impairment, cerebral degenerative disorders, restenosis, gynecomastia, vascular smooth muscle cell proliferation, obese No, incontinence and cancer, especially cancer of the breast, uterus and prostate.

SUMMARY OF THE INVENTION

The present invention relates to a compound having the following chemical formula:

(CH _{2) n N} (Z) ₂ wherein R ^1, R ^2, R 'and R ⁴ are each independently selected from the group consisting of hydrogen, C 1-5 alkyl, C ₃ _s cycloalkyl, _C2 -5 alkenyl, C ₂ . ₃ alkynyl, C ₃ _8 cycloalkenyl, phenyl, heteroaryl, heterocyclyl, CF _3, OR ^6, halogen, C |. ₅ alkylthio, thiocyanato, cyano, -CO ₂ H,

-S00S | .5 alkyl, -S0S | .5 alkyl, -CONZ _2, -SO ₂ NZ _2, and -SO ₂ C | _ ₅ alkyl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, phenyl, heteroaryl, heterocyclic groups may be substituted by C 1. ₅ alkyl, C ₃ . ₈ cycloalkyl, CF ₃ , phenyl, heteroaryl, heterocyclic group, -OR ⁶ , halogen, amino, C _1-3 . ₅ alkylthio, thiocyanato, cyano, -CO ₂ H, -COOC | _5 alkyl, -COC | _ ₅ alkyl, -CONZ _2, -SO ₂ NZ _2, and -SO ₂ Ci. ₅ alkyl;

R 1 is selected from the group consisting of C 1-5 alkyl, C ₃ . ₈ cycloalkyl, C ₂ . ₅ alkenyl, C ₂ . ₃ alkynyl, C ₃ .§ cycloalkenyl, phenyl, heteroaryl, heterocyclic groups which may be substituted with a C _t _ ₅ alkyl, C _{3. 8} cycloalkyl, CF _3, phenyl, heteroaryl, heterocyclic groups, OR ^6, halogen, amino, C | .5 alkylthio, thiocyanato, cyano, -CO2H, -SOOS1.5 alkyl, -COC, .5 alkyl, -CONZ2, - SO2NZ2, and -SO2C, .5 alkyl, wherein those alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, phenyl, heteroaryl, heterocyclic groups may be substituted by C1-5 alkyl, C3-8 cycloalkyl, CF3, phenyl, heteroaryl; , -OR ⁶ , halogen, amino, C (C 5 alkylthio, thiocyanato, cyano, -CO ₂ H, -COOC 1-5 alkyl, -CO ₂ 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 independently selected from the group consisting of C 1.5

Ί alkyl, benzyl, methoxymethyl, triorganosilyl, C]. ₅ alkylcarbonyl, alkoxycarbonyl and CONZ ?;

each is independently selected from the group consisting of hydrogen, C1-5 alkyl, trifluoromethyl, where the alkyl group may be substituted by C1-4. ₅ alkyl, CF ₃ , -OR ⁶ , halogen, amino, C _1-5 alkylthio, thiocyanato, cyano, -CO ₂ H, -COOC]. ₅ alkyl, -000, -5 alkyl, CONV ₂ , -SO ₂ NV ₂ , and -SO ₂ C, - ₅ alkyl;

or both Zs and the nitrogen to which they are attached may form together a 3-8 membered ring which may contain atoms selected from the group consisting of carbon, oxygen, sulfur and nitrogen, the ring being saturated or unsaturated and the ring carbon atoms may have from one to three substituents selected from the group consisting of C 1-5 alkyl, CF ₃ , -OR ⁶ , halogen, amino, C 1-4. ₅ alkylthio, thiocyanato, cyano, -CO ₂ H, -CO ₂ C 1-5 alkyl, -CO 2-1 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 1-4. ₅ alkylthio, thiocyanato, cyano, -CO ₂ H, -CO ₃ . ₅ alkyl, -COC1-5 alkyl, and -SO ₂ C 1-5 alkyl;

each η is an independent number from one to five;

and pharmaceutically acceptable salts thereof.

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

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

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

The present invention also relates to methods of eliciting, if necessary, a modulating effect on mammalian estrogen receptors by administering the compounds and pharmaceutical compositions of the present invention.

The present invention also relates to methods of inducing, if necessary, an antagonistic effect on mammalian estrogen receptors by administering the compounds and pharmaceutical compositions of the present invention. The antagonistic effect on estrogen receptors can be either an ERot antagonist effect and an ER3 antagonist effect or a mixed ERct and ER3 antagonist effect.

The present invention also relates to methods of treating or preventing diseases having links with estrogenic function, bone loss, bone fractures, osteoporosis, joint degeneration, endometriosis, uterine fibroid disease, breast, uterine or prostate cancer, hot flashes , cardiovascular disease, impairment of cognitive function, cerebral degenerative disorders, restenosis, gynecomastia, cellular proliferation of vascular smooth muscle, obesity and incontinence in mammals by admission when necessary bridge of the compounds and pharmaceutical compositions of the present invention.

The present invention also relates to methods of reducing bone loss, lowering LDL cholesterol levels and inducing a mammalian vasodilator effect by administering, if necessary, the compounds and pharmaceutical compositions of the present invention.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to compounds that are useful as modulators of estrogen receptors. The compounds of the present invention are described by the following chemical formula:

0 RV R .R ⁵ 3 / R toaa Yc R ⁴ Y ^ A _o / (CH2) nN (Z) 2 where R ¹ , R ² , R ³ and R ⁴ are each independently selected from the group,

which consists of hydrogen, C 1-5 alkyl, C _{3. 8} cycloalkyl, C ₂ h alkenyl, C ₂ .z alkynyl, C _{3. 8} cycloalkenyl, phenyl, heteroaryl, heterocyclic group, CF ₃ , -OR ⁶ , halogen, C]. ₅ alkylthio, thiocyanato, cyano, -CO ₂ H, -COOC 1-5 alkyl, -CO ₂ ]. ₅ alkyl, -CONZ ₂ , -SO ₂ NZ ₂ , and -SO ₂ C 1-5 alkyl, wherein those alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, phenyl, heteroaryl, heterocyclic groups may be substituted by C 1-5 alkyl, C ₃ . ₈ cycloalkyl, CF ₃ , phenyl, heteroaryl, heterocyclic group, -OR ⁶ , halogen, amino, C 1-5 alkylthio, thiocyanato, cyano,

-CO ₂ H, -COOC 1-5 alkyl, -COC ,. ₅ alkyl, -CONZ ₂ ,

-SO ₂ N ₂ , and -SO ₂ C 1-5 alkyl;

R ³ 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 which may be substituted by C 1-5 alkyl, C 3-8 cycloalkyl, CF 3, phenyl, heteroaryl, heterocyclic groups, -OR ⁶ , halogen, amino, C 1-5 alkylSt '*' thio, thiocyanato, cyano, -CO ₂ H, -COOCl .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 independently selected from the group consisting of 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] _5 alkyl, trifluoromethyl where the alkyl group may be substituted with C] _5 alkyl, CF _3, -OR ^6, halo, amino, C ₅ alkylthio, thiocyanato , cyano, -CO ₂ H, -COOC 1-5 alkyl, -COC, .5 alkyl, -CONV ₂ , -SO ₂ NV ₂ , and -SO ₂ C,. ₅ alkyl;

or both Zs and the nitrogen to which they are attached may form together a 3-8 membered ring which may contain atoms selected from the group consisting of carbon, oxygen, sulfur and nitrogen,

the ring may be saturated or unsaturated and the carbon ring atoms may have from one to three substituents selected from the group consisting of C _1-5 alkyl, CF ₃ , -OR ⁶ , halogen, amino, C 1-3 alkylthio, thiocyanato, cyano, -CO ₂ H, -COOO]. ₅ alkyl, -COC. 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, halo, amino, C1-5 alkylthio, thiocyanato, cyano, -COH, -SOO1.5 alkyl -SOS1.5

V alkyl, and -SO ₂ C |. ₅ alkyl;

each n is an independent number from one to five;

and pharmaceutically acceptable salts thereof.

In one class of compounds of the present invention, R, R, R and R are each independently selected from the group consisting of hydrogen, C 1-5 alkyl, C ₃ .g cycloalkyl, C | _ ₃ alkenyl, Ci_ ₅ alkynyl, -OR ⁶ and halogen.

In one class of compounds of the present invention, R? is selected from the group consisting of C1-5 alkyl, _C3 .8 cycloalkyl, phenyl, heteroaryl, heterocyclic groups which may be substituted with -OR ⁶ and halogen.

In one class of compounds of the present invention, R ⁶ is preferably selected from the group consisting of hydrogen, C 1-5 alkyl, benzyl, methoxymethyl and triisopropylsilyl.

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

wherein 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 is C |. ₅ alkyl, C ₃ . ₈ cycloalkyl, C ₃ . ₈ cycloalkenyl, phenyl, heteroaryl, or heterocyclic groups which may be substituted by C _1-5 alkyl, C ₃ . ₈ cycloalkyl, CF _3, phenyl, heteroaryl, heterocyclic groups, -OR ^6, halo, amino, C _b 5 alkylthio, thiocyanato, cyano, carboxyl (-CO ₂ H), carboalkoxy (-COOC _{(. 5} alkyl), carbonyl ( -COC 1. ₅ alkyl), carboxamido (-CONZ ₂ ), sulfonamido (-SO ₂ NZ ₂ ), and sulfonyl (-SO ₂ C ₅ alkyl);

R ⁶ is H, benzyl, methyl, methoxymethyl or triisopropylsilyl, provided that when OR ^{6 is present,} it is chemically distinguishable;

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, the alkyl group being optionally substituted by C 1-5 alkyl, CF ₃ , -OR ⁶ , halogen, amino, C 1-5 alkylthio , thiocyanato, cyano, -CO ₂ H, -COOC 1-5 alkyl, -COOC 1.5 alkyl, -CONV ₂ , -SO ₂ NV ₂ , and -SO ₂ C 1. ₅ alkyl;

or both Zs and the nitrogen to which they are attached may form together a 3-8 membered ring which may contain atoms selected from the group consisting of carbon, oxygen, sulfur and nitrogen, the ring being saturated or unsaturated and the ring carbon atoms may have from one to three substituents selected from the group consisting of C 1-5 alkyl, CF ₃ , -OR ⁶ , halogen, amino, C _1-5 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 C 1-5 alkyl, CF _3, -OR ^6, halo, amino, C]. ₅ alkylthio, thiocyanato, cyano, -CO ₂ H, -COO 5-5 alkyl, -CO ₂ . ₅ alkyl, and -SO ₂ C |. ₅ alkyl;

η is a number from one to five;

and the stereoisomer is cis;

or pharmaceutically acceptable salts thereof, which consists of the steps

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

to form a compound of formula IV

IV

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

c) removing the protecting group R ⁶ to give a substituted phenol of formula VI

d) alkylation of the substituted phenol of formula VI from a step with the reagent HO (CH ₂ ) _n N (Z) ₂ to give a compound of formula I

f) removing the protecting group from I in step d to give either a compound of formula VIII or a compound of formula IX

I

f) removing the remaining protecting group in either VIII or IX of step is to give a compound of formula I.

The present compound also relates to a process for preparing a compound of formula ID

wherein R ¹ is H, F, or Cl;

R ³ eH;

R ⁴ is H or CH ₃ ;

or a pharmaceutically acceptable salt thereof, consisting of the steps and the stereoisomer is cis;

and the optical isomer is right-handed (+) with absolute configuration (2S, 3R);

a) reaction of a compound of formula IID with a compound of formula IIID under basic conditions,

to give a compound of formula IVD

B) cyclizing the IVD from step a under acidic conditions in the presence of a reducing agent to give the cis compound of formula VD

c) chiral chromatography with VD of step b to separate the enantiomeric forms to give the right-handed (+) isomer VID;

(+) - UJ

d) alkylation of the dextrorotatory (+) isomer VID from step 1 with piperidinethanol to give a compound of formula VIID

f) removing the remaining protecting group from either VIID or VIIID from step d to give a compound of formula IXD

f) removing the remaining protecting group from either VIIID or IXD from step f to give a compound of formula

I (+) - 1E where

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

R 1 and R ⁴ are each H;

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

and the stereoisomer is cis and the optical isomer is right-handed (+) with absolute configuration (2S, 37?);

or a pharmaceutically acceptable salt thereof, consisting of the steps

a) reaction of a compound of formula IIE with a compound of formula III under basic conditions,

to give a compound of formula IVE

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

c) selectively removing the protecting group in the VE from step b to give the substituted phenol of formula VIE

d) alkylation of the substituted phenol of formula VIE from step c

1-piperidinethanol to give a compound of formula VIIE

f) removing a VIIE protecting group to obtain either a compound of formula VIIIE or a compound of formula IXE

ΥΠΙΕ

f) removing the remaining protecting group from either VIII or IX, in step is to obtain racemic I.

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

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

An embodiment of the invention is an intermediate of formula:

wherein 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 ³ is C 1-5 alkyl, C ₃ . ₈ cycloalkyl, C ₃ . ₈ cycloalkenyl, phenyl, heteroaryl, or heterocyclic groups which may be substituted by C1-8alkyl; ₅ alkyl, C ₃ . ₈ cycloalkyl, CF ₃ , phenyl, heteroaryl, heterocyclic groups, -OR ⁶ , halogen, amino, C _1-5 alkylthio, thiocyanato, cyano, carboxyl (-CO ₂ H), carboalkoxyl (-COOC 1-5 alkyl), carbonyl (-CO 1) .5 alkyl), carboxamido (-CONZ ₂ ), sulfonamido (-SO ₂ NZ ₂ ), and sulfonyl (-SO ₂ C 1 - ₅ alkyl);

R ⁶ is H, benzyl, methyl, methoxymethyl or triisopropylsilyl, provided that when OR ^{6 is present,} it is chemically distinguishable;

each Z is independently selected from the group consisting of hydrogen, C 1-5 alkyl, trifluoromethyl, the alkyl group being substituted with C 1-5. ₅ alkyl, CF _3, -OR ^6, halo, amino, C]. ₅ alkylthio, thiocyanato, cyano, -CO ₂ H, -COOC 1-5 alkyl, -COOC 1-5 alkyl, -CONV ₂ , -SO ₂ NV ₂ , and -SO ₂ C 1-5 alkyl;

or both Zs and the nitrogen to which they are attached may form together a 3-8 membered ring which may contain atoms selected from the group consisting of carbon, oxygen, sulfur and nitrogen, the ring being saturated or unsaturated and the ring carbon atoms may have one to three substituents selected from the group consisting of C 1-5 alkyl, CF _3, -OR ^6, halo, amino, Ci_ ₅ alkylthio, thiocyanato, cyano, -CO ₂ H, -COOC 1-5 alkyl, -COCC. ₅ alkyl, -CONV ₂ , -SO ₂ NV ₂ , and -SO ₂ C 5 alkyl;

each V is independently selected from the group consisting of C 1.5 alkyl, CF ₃ , -OR ⁶ , halogen, amino, C 1. ₅ alkylthio, thiocyanato, cyano, -CO ₂ H, -COO. ₅ alkyl, -COCX alkyl, and -SO ₂ C 1-5 alkyl;

Another embodiment of the invention is an intermediate of formula:

wherein R ¹ is H, F, or Cl;

R ² is H or OR ⁶ ;

R ^J is H or OR ⁶ ;

R ⁴ is H or CH ₃ ;

R1 is C1. ₅ alkyl, C ₃ . ₈ cycloalkyl, C ₃ . ₈ cycloalkenyl, phenyl, heteroaryl, or heterocyclic groups which may be substituted by C1-8alkyl; ₅ alkyl, C ₃ . ₈ cycloalkyl, CF ₃ , phenyl, heteroaryl, heterocyclic groups, -OR ⁶ , halogen, amino, C 1-5 alkylthio, thiocyanato, cyano, carboxyl (-CO ₂ H), carboalkoxyl (-COOC), ₅ alkyl), carbonyl ( -COC 1-5 alkyl), carboxamido (-CONZ ₂ ), sulfonamido (-SO ₂ NZ ₂ ), and sulfonyl (-SO ₂ C). ₅ alkyl);

R is H, benzyl, methyl, methoxymethyl or triisopropylsilyl, provided that when OR ^{6 is present,} it is chemically distinguishable;

each Z is independently selected from the group consisting of hydrogen, C 1-5 alkyl, trifluoromethyl, the alkyl group being optionally substituted by C 1-4 alkyl, CF ₃ , -OR ⁶ , halogen, amino, C 1-4 alkylthio, thiocyanato, cyano, -CO ₂ H, -COOCi-5 alkyl, -CO ₂ . ₅ alkyl, -CONV ₂ , -SO ₂ NV ₂ , and -SO ₂ C 1-5 alkyl;

or both Zs and the nitrogen to which they are attached may form together a 3-8 membered ring which may contain atoms selected from the group consisting of carbon, oxygen, sulfur and nitrogen, the ring being saturated or unsaturated and the ring carbon atoms may have from one to three substituents selected from the group consisting of C _t . ₅ alkyl, CF ₃ , -OR ⁶ , halogen, amino, C 1-4 alkylthio, thiocyanato, cyano, -CO ₂ H, -COOCl. ₅ alkyl, -COC. ₅ alkyl, -CONV ?, -SO ₂ NV ₂ , and -SO ₂ C |. ₅ alkyl;

each V is independently selected from the group consisting of C 1.5 alkyl, CF ₃ , -OR ⁶ , halogen, amino, C _1-5 alkylthio, thiocyanato, cyano, -CO ₂ H, -COO 1.5 alkyl, -COC 1.5 alkyl, and -SO ₂ C 1-5 alkyl;

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

R (+) -

wherein R ¹ is H, F, or Cl;

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

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

wherein R ¹ is H, F, or Cl;

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

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

wherein R ¹ is H, F, or Cl;

R ² is H or OR ⁶ ;

R ^J is H or OR ⁶ ;

R ⁴ is H or CH ₃ ;

R 1 is C 1-5 alkyl, C ₃ . ₈ cycloalkyl, C ₃ . ₈ cycloalkenyl, phenyl, heteroaryl, or heterocyclic groups which may be substituted by C _1-5 alkyl, C ₃ . ₈ cycloalkyl, CF ₃ , phenyl, heteroaryl, heterocyclic groups, -OR ⁶ , halogen, amino, C _1-5 alkylthio, thiocyanato, cyano, carboxyl (-CO ₂ H), carboalkoxyl (-COOC 1-5 alkyl), carbonyl

(-COC | ._5 alkyl), carboxamido (-CONZ?), Sulfonamido (-SO ₂ NZ _2), and sulfonyl (-SO ₂ C | _ ₅ alkyl);

R ⁶ is H, benzyl, methyl, methoxymethyl or triisopropylsilyl, provided that when OR ^{6 is present,} it is chemically distinguishable;

each Z is independently selected from the group consisting of hydrogen, C 1-5 alkyl, trifluoromethyl, the alkyl group being substituted by C 1-5 alkyl, CF ₃ , -OR ⁶ , halogen, amino, C 1-5 alkylthio, thiocyanato, cyano, -CO ₂ H, -COOCi-5 alkyl, -COC 1-5 alkyl, -CONV ₂ , -SO ₂ NV ₂ , and -SO ₂ Ci. ₅ alkyl;

or both Zs and the nitrogen to which they are attached may form together a 3-8 membered ring which may contain atoms selected from the group consisting of carbon, oxygen, sulfur and nitrogen, the ring being saturated or unsaturated and the ring carbon atoms may have from one to three substituents selected from the group consisting of C 1-5 alkyl, CF ₃ , -OR ⁶ , halogen, amino, C _1-5 alkylthio, thiocyanato, cyano, -CO ₂ H, -COOC 1-5 alkyl, -COC 1.5 alkyl, -CONV ₂ , -SO2NV2, and -SO2C1-5 alkyl;

each V is independently selected from the group consisting of C 1.5 alkyl, CF ₃ , -OR ⁶ , halogen, amino, C 1 alkylthio, thiocyanato, cyano, -CO 2 H, -CO _{5b 5} alkyl, -COC 1.5 alkyl, and -SO 2 Cl .5 alkyl;

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

wherein R ¹ is H, F, or Cl;

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

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

wherein R ¹ is H, F, or Cl;

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

Non-limiting examples of the present invention are:

(+)

GL <CH3

Ο

CH ₃

Ο f '

One embodiment of the invention is a method for evaluating the mammalian estrogen receptor modulating effect as required, which comprises administering to the mammal a therapeutically effective amount of any of the compounds or pharmaceutical compositions described above.

One class of this embodiment is the method in which the modulating effect on the estrogen receptor has an antagonistic effect.

A subclass of this embodiment is the method in which the estrogen receptor is the ERα receptor.

A second subclass of this embodiment is the method in which the estrogen receptor is the ER3 receptor.

A third subclass of this embodiment is the method in which the modulating effect on the estrogen receptor is mixed

ERα and ERP receptor antagonistic effect.

A second class of this embodiment is the method in which the modulating effect on the estrogen receptor is an agonist effect.

A subclass of this embodiment is the method in which the estrogen receptor is the ERα receptor.

A second subclass of this embodiment is the method in which the estrogen receptor is the ER3 receptor.

A third subclass of this embodiment is the method wherein the estrogen receptor modulating effect is a combined ERα and ER3 receptor agonist effect.

Another embodiment of the invention is a method of treating or preventing, if necessary, post-menopausal osteoporosis in mammals by administering to the mammal a therapeutically effective amount of any of the compounds or any of the above pharmaceutical compositions.

Another embodiment of the invention is a method of treating or preventing, if necessary, uterine fibroids in a mammal by administering to the mammal a therapeutically effective amount of any of the compounds or any of the above pharmaceutical compositions.

Another embodiment of the invention is a method of treating or preventing, if necessary, restenosis in a mammal by administering to the mammal a therapeutically effective amount of any of the compounds or any of the above pharmaceutical compositions.

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

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

An example illustrating the invention is a pharmaceutical composition comprising any of the above compounds and a pharmaceutically acceptable carrier. Also exemplifying the invention is a pharmaceutical composition made by combining any of the above compounds and a pharmaceutically acceptable carrier. An illustration of the invention is a method of preparing a pharmaceutical composition by combining any of the above compounds and a pharmaceutically acceptable carrier.

Another illustration of the invention is the use of any of the above compounds for the preparation of a medicament for the treatment and / or prevention of osteoporosis in mammals. Another illustration of the invention is the use of any of the above compounds for the preparation of a medicament for the treatment and / or prevention of: bone loss, bone resorption, bone fractures, joint degeneration, endometriosis, fibrotic disease of the uterus, cancer breast, uterus or prostate, hot flashes, cardiovascular disease, impairment of cognitive function, cerebral degenerative disorder, restenosis, vascular smooth muscle cell proliferation, incontinence and / or estrogen related disorders o action.

The present invention is also directed to combinations of any of the above compounds or pharmaceutically acceptable compositions with one or more agents useful in the prevention or treatment of osteoporosis. For example, the compounds of the present invention can be administered effectively in combination with effective amounts of other agents such as an organic bisphosphonate or cathepsin K inhibitor. Non-limiting examples of these organic bisphosphonates are alendronate, clodronate, etidronate, ibandronate, incadronate, minodronate, neridronate, risedronate, pyridronate, pamidronate, tildudronate, zoledronate and their pharmaceutically acceptable salts or esters thereof. Preferred organic bisphosphonates are alendronate and their pharmaceutically acceptable salts or esters, and mixtures thereof. Most preferred is alendronate monosodium trihydrate.

The precise dosage of bisphosphonate varies depending on the dosage regimen, the oral potency of the specific bisphosphonate selected, the age, size, sex and condition of the mammal or human, the nature and severity of the disease to be treated, and other related medical and physical factors. Thus, the effective pharmaceutical amount cannot be determined in advance and can be easily determined by the physician or clinician. Appropriate amounts can be determined by routine animal models and human clinical trials. In general, suitable amounts of bisphosphonate are selected to obtain an inhibitory effect on bone resorption, i. E. an amount inhibiting bone resorption is administered. In 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.

The unit dose for human oral compositions with alendronate, its pharmaceutically acceptable salts or its pharmaceutically acceptable derivatives typically contains from about 8.75 mg to about 140 mg of alendronate as a compound based on the active weight of alendronic acid, i.e. based on the corresponding acid.

For use in medicine, only the non-toxic "pharmaceutically acceptable salts" of a compound (w, the invention) are contemplated. However, other salts may be used to prepare the compounds of the invention or their pharmaceutically acceptable salts. When the compounds of the present invention contain a base group salts included in the term "pharmaceutically acceptable salts" are non-toxic salts that are usually obtained by the reaction of a free base with a suitable organic or inorganic acid. salts without limitation thereof are: acetate, benzenesulfonate, benzoate, d-bicarbonate, bisulfate, bitartarate, borate, bromide, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, gilatate, fumarate , glutamate, glycolsanilate, hexylresorcinate, hydrobamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, mandelate, mesylate, methylbromide, methylbromide, , oleate, oxalate, pamoate (embonate) , palmitate, pantothenate, phosphate / diphosphate, polygalacturonate, salicylate, stearate, sulfate, subacetate, succinate, tannate, tartrate, theoclate, tosylate, triiodide and valerate. Furthermore, when the compounds of the invention have an acid group, their pharmaceutically acceptable salts are alkali metal salts, sodium salts or potassium salts; alkaline earth metal salts, such as calcium or magnesium salts and salts with suitable organic ligands, such as quaternary ammonium salts.

The compounds of the present invention may have chiral centers and be obtained as racemates, racemic mixtures, diastereomeric mixtures and as individual diastereomers or enantiomers of all isomeric forms, all of which are included in the invention. Therefore, when the compound is chiral, the individual enantiomers containing no other enantiomer are within the scope of the invention; all mixtures of two enantiomers are included. Also included within the scope of the invention are polymorphs, hydrates and solvates of the compounds thereof.

The scope of the present invention includes pre-drugs of the compounds therein. In general, prodrugs are functional derivatives of the compounds of this invention that are readily converted into the desired compounds in vivo. Thus, in the methods of treatment of the present invention, the term &quot; administration &quot; includes treating the various diseases described with a specifically described compound or with a compound that may not be specifically described but which is converted to the specifically described compound in vivo upon administration to the patient . Conventional methods for selecting and obtaining suitable pre-drug derivatives are described, for example, in Design of Prodrugs, ed. H. Bundgaard, Elservier, 1985, as cited herein. The metabolites of these compounds are active substances that are produced when the compounds of the invention are introduced into the biological environment.

The term "pharmaceutically effective amount" means that the amount of drug or pharmaceutical agent triggers the biological or medical response of the tissue, animal or human system to the investigator or clinician.

The term "bone resorption" as used herein refers to the process of bone degradation by osteoclasts.

The term "basic conditions" as used herein refers to the inclusion or use of a base in the reaction medium. By definition, the Lowry-Bronsted base is a substance that accepts a proton; or, by definition, a Lewis base is a substance that creates an electronic pair that forms a covalent bond. Non-limiting examples of the bases used herein are tertiary amines such as triethylamine, diisopropylethylamine, and the like.

The term "acidic conditions" as used herein refers

for including or using acid in the reaction medium. According to the definition of Lowry-Bronsted, acid is a substance that gives off a proton; or, by definition, Lewis acid is a substance that accepts an electron pair that forms a covalent bond. Non-limiting examples of acids used herein are strong carboxylic acids such as trifluoroacetic acid or the like, strong sulfonic acids such as trifluoromethane sulfonic acid or the like, and Lewis acids such as boron trifluoride etherate or tin chloride or the like.

The term "reducing agent" as used herein refers to an agent that causes a reduction. Reduction is the conversion of a functional group or intermediate from one valence to another lower valency.

Examples of reducing agents used herein are triorganosilanes or moieties, such as triethylsilane, triphenylsilane and tri-n-butyl tin hydride and the like.

The term "chemically distinguishable" refers to two or more unidentified R ⁶ substituents whose unique structures are such that the ordinary person skilled in the art can choose the reaction conditions for converting the unidentified R ⁶ substituents to H without affecting another R ⁶ substituent.

The term "alkyl" means a substituent monovalent group obtained by breaking a straight or branched hydrogen atom of an acyclic saturated hydrocarbon (i.e. -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 , -C (CH ₃ O) ₃ , and TN).

The term "alkenyl" means a substituent monovalent group obtained by breaking one straight atom or branched chain of an acyclic unsaturated hydrocarbon containing at least one double bond (i.e. -CH = CH ₂ , -CH ₂ CH = CH ₂ , -CH = CHCH ₃ , -CH ₂ CH = C (CH ₃ ) ₂ , and TN).

The term &quot; alkynyl &quot; means a substituent monovalent group obtained by breaking one straight atom or branched chain of an acyclic unsaturated hydrocarbon containing at least one triple bond (i.e. -CH = CH, -CH ₂ OCH, -C = CHO ₃ , -CH ₂ CH ₂ C = CHCH ₃ , etc.).

The term "cycloalkyl" means a substituent monovalent group obtained by the removal of one hydrogen atom from a saturated monocyclic hydrocarbon (i.e.

cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl).

The term "cycloalkenyl" means a substituent monovalent group obtained by the removal of one hydrogen atom from an unsaturated monocyclic hydrocarbon containing a double bond (i.e. cyclopentenyl or cyclohexenyl).

The term "heterocyclic group" means a substituent monovalent group obtained by the removal of one hydrogen atom from a heterocycloalkane, this heterocycloalkane being obtained from the corresponding saturated monocyclic hydrocarbon by substituting one or two carbon atoms with atoms selected from N, O or S. examples of heterocyclic groups are oxiranyl, azetidinyl, pinolidinyl, piperidinyl, piperazinyl and morpholinyl.

Heterocyclic substituents can be bonded to a carbon atom. If the substituent is a nitrogen-containing heterocyclic substituent, it may be bonded to a nitrogen atom.

The term "heteroaryl" as used herein refers to a monovalent substituent group obtained by the removal of one hydrogen atom from a monocyclic or bicyclic aromatic ring containing 1, 2, 3 or 4 heteroatoms selected from N, O or S. Non-limiting Examples of the heterocyclic groups are pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridyl, pyrimidinyl, pyrazinyl, benzimidazolyl, indolyl and purinyl. Heteroaryl substituents may be bonded to a carbon atom or to a heteroatom.

The term "triorganosilyl" means those silyl groups trisubstituted with lower alkyl groups or aryl groups or a combination thereof and where one of the substituents may be a lower alkoxy group. Examples of tri-substituted organosilyl groups are trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, triisopropylsilyl, triphenylsilyl, dimethylphenylsilyl, t-butyldiphenylsilyl, phenyl-butylmethoxysilyl and the like.

In the compounds of the present invention, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclic and heteroaryl groups may, in turn, be substituted by replacing one or more hydrogen atoms with an alternative non-hydrogen group. Non-limiting such groups are halo, hydroxy, mercapto, amino, carboxy, cyano and carbamoyl.

When the term "alkyl" or "aryl" or their root words are prefixes in the name of a substituent (for example, aryl Co-s alkyl), they are subject to the same restrictions as those given above for "alkyl" and "aryl". The indicated numbers of carbon atoms (for example, C 1-10) refer independently to the number of carbon atoms in an alkyl or cyclic alkyl group or to the alkyl moiety of a larger substituent in which alkyl appears as a root prefix.

The terms "arylalkyl" and "arylaryl" are an alkyl moiety in which alkyl is defined as above and includes an aryl moiety where aryl is defined as above.

Non-limiting examples of arylalkyls are benzyl, fluorobenzyl, chlorobenzyl, phenylethyl, phenylpropyl, fluorophenylethyl, chlorophenylethyl, thienylmethyl, thienylethyl and thienylpropyl. Non-limiting examples of alkylaryl toluyl, ethylphenyl and propylphenyl.

The term "heteroarylalkyl" as used herein refers to a system that includes a heteroaryl moiety wherein heteroaryl is defined as above and contains an alkyl moiety. Non-limiting examples of heteroarylalkyls are pyridylmethyl, pyridylethyl and imidazoylmethyl.

The term "halo" refers to iodine, bromo, chloro and fluoro.

The term "oxy" means an oxygen (O) atom.

The term "thio" means a sulfur (S) atom. The term "oxo" means = 0. The term "oximino" means an = N-O group.

The term "substituted" means the inclusion of multiple degrees of substitution under the name substituted. When multiple substituent groups are considered or claimed, the substituted compound is independently substituted singly or multiply by one or more of the substituent groups under consideration or by those groups for which it is claimed. Independently substituted means that (two or more) substituents may be the same or different.

According to the standard nomenclature used in the present invention, the last part of the side chain described is first recorded, followed by adjacent functionalities in the direction of the binding site. For example, C1-5 alkylcarbonylamino C 1, alkyl substituent is equivalent to -C 1 -C 6 alkyl-NH-C-C 7 -alkyl

When selecting compounds of the present invention, one skilled in the art will appreciate that the various substituents, i. R ¹ , R ² , R ^J , R ⁴ , R ³ , R ⁶ , R ⁷ , R ⁸ , V, X, Y, Ζ, n, m and p are selected in accordance with known principles of bonding in chemical structures.

Representatives of the compounds of the present invention exhibit a typical submicromolar affinity for alpha and / or beta estrogen receptors. Therefore, the compounds of this invention are useful for the treatment of mammals suffering from disorders related to estrogenic function. Pharmaceutically effective amounts of the compound, including its effective salts, are administered to mammals for the treatment of disorders related to estrogenic function, such as bone loss, hot flashes, and cardiovascular disease.

The compounds of the present invention are in the form of racemic mixtures or as individual enantiomers. For convenience, some structures are represented graphically as one enantiomer, but unless otherwise indicated, racemic and enantiomeric forms are also considered. When cis or trans stereochemistry is indicated for a compound of the present invention, it should be noted that stereochemistry can be understood as relative, unless otherwise indicated.

I

It is generally preferred to administer compounds of structure (I) as enantiomerically pure compositions, since most or all of the bioactivity is inherent in one of the enantiomers. The racemic mixtures can be separated into individual enantiomers using conventional methods. These are chiral chromatography, chiral additive derivatization followed by separation by chromatography or crystallization, and fractional crystallization of diastereomeric salts.

The compounds of the present invention may be used in combination with other agents useful in the treatment of estrogen-mediated diseases. The individual components of these combinations may be administered individually at different times during therapy or together in separate or common forms of the combination.

It is to be understood that the present invention encompasses all such regimens of concomitant or alternative treatment and the term '' administration '' is to be interpreted accordingly. It should be clear that the scope of combinations of the compounds of this invention with other agents useful in the treatment of estrogen-mediated diseases includes, in principle, any combination with any pharmaceutical composition useful in the treatment of estrogen-related disorders functioning.

As used herein, the term "composition (composition)" refers to a product that contains specific ingredients in specific amounts, as well as any product that is obtained directly or indirectly from a combination of specific ingredients in specific quantities.

The compounds of the present invention may be administered in oral dosage forms such as tablets, capsules (each of which includes controlled-release or batch-release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups and emulsions. They may also be administered intravenously (bolus or infusion), intraperitoneally, topically (e.g., eye drops), subcutaneous, intramuscular, or transdermal (e.g., patches), all of these formulations well known to those of skill in the art of pharmacy.

The dosage regimens used for the compounds of the present invention are selected according to a variety of factors such as the type, type, weight, sex, and medical condition of the patient; the severity of the disease being treated; the method of administration; the renal function of the patient; and the compound or salt thereof used. An ordinary physician, veterinarian or clinician can easily determine and prescribe the effective amount of medication needed to prevent, control or stop the progression of the disease.

The oral doses of the present invention used for said effects range from about 0.01 mg per kg of body weight per day (mg / kg / day) to about 100 mg / kg / day, preferably 0.01 to 10 mg / kg / day, and most preferably 0.1 to 5.0 mg / kg / day. Oral administration compositions are preferably provided in the form of tablets containing 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100 and 500 milligrams of active ingredient for symptomatic dose adjustment for the patient being treated. The medicine

typically contains from about 0.01 mg to about 500 mg of active ingredient, preferably from about 1 mg to about 100 mg of active ingredient. The most preferred doses for intravenous administration range from about 0.1 to about 10 mg / kg / minute at a constant infusion rate. The advantageous administration of the compounds of the present invention may be in a single daily dose or the total daily dose may be divided into two, three or four doses per day. Furthermore, preferred compounds of the present invention may be administered intranasally by topical use of suitable intranasal agents, or by a transdermal route using transdermal skin patches known to those skilled in the art. For administration in the form of a transdermal delivery system, dosage administration should be continuous and not at dosing intervals.

According to the methods of the present invention, the compounds described herein form the active ingredient and are generally mixed with suitable pharmaceutical diluents, excipients or carriers (generally referred to as carrier materials), selected appropriately depending on the intended form of administration, i.e. oral tablets, capsules, elixirs, and syrups and the like, in accordance with customary pharmaceutical practice.

For example, for oral administration in the form of a tablet or capsule, the active ingredient may be combined with an oral, non-toxic, pharmaceutically acceptable inert carrier such as lactose, starch, sucrose, glucose, methyl cellulose, magnesium stearate, dicalcium phosphate, calcium sorbitol and similar; for oral administration in liquid form, the oral active ingredient may be combined with any oral, non-toxic, pharmaceutically acceptable excipient such as ethanol, glycerol, water and the like. In addition, suitable binders, lubricants, disintegrants and coloring agents can be added to the mixture if desired or necessary. Suitable binders are starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic resins such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like.

The lubricants used in these dosage forms are sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like.

Non-limiting examples of disintegrants are starch, methyl cellulose, agar, bentonite, xanthan gum and the like.

The compounds of the present invention may also be administered in the form of liposomal release systems such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes are formed by numerous phospholipids such as cholesterol, stearylamine or phosphatidylcholines.

The compounds of the present invention may also be administered using monoclonal antibodies as individual carriers to which the molecules of the compound bind. The compounds of the present invention may also bind to soluble polymers as target carriers of the drug. Such polymers are polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, or polyethylene oxide-polylysine substituted with palmitoyl residues. In addition, the compounds of the present invention can also be coupled with biodegradable polymers by which controlled release of the drug is achieved, for example, polylactic acid, polyglycolic acid, polymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acids, , polyacetals, polyhydropyrans, polycyanoacrylates and crosslinked or hydrogels of amphipathic block copolymers.

The novel compounds of the present invention can be prepared according to the methods given in the following schemes and examples using suitable starting materials and are further illustrated with specific examples. The compounds of the examples cannot be regarded as the sole representatives of the invention. The following examples further illustrate details of the procedures for preparing the compounds of the present invention. One skilled in the art will appreciate that certain variations of conditions and reactions in preparative procedures can be used to prepare these compounds. Unless otherwise stated, all temperatures are in degrees Celsius.

The compounds of the present invention are prepared according to the following general scheme I:

SCHEME I. GENERAL SCHEME OF SYNTHESIS OF

Gs-Dihydrobenzoxazines and benzodioxanes

liberation protection ----------------> R

VI

I

According to the scheme, suitably functionalized bisphenol II (X = O, Y = O) or mercapto-phenol II (X = O, Y = S), readily available by the literature, reacts with the bromo-ketone derivative III which is readily available 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 or the like, in a solvent such as dimethylformamide (DMF), formamide, acetonitrile, dimethylsulfonyl (dimethylsulfonyl) dimethylsulfonate THF), dichloromethane or the like, m.p. temperature from -20 ° C to 80 ° C for a sufficient time to complete the reaction, a substituted product IV was obtained. When X = Y = O, only R ³ can be -OR ⁶ . Alternatively, when X = Y = O and R ² is -OR ⁶ , the desired intermediate cyclization is obtained by the substitution of ketone and bromide groups. These conditions must be fulfilled to obtain the compounds of the invention when the presence of some substituents may alter the reactivity of the phenolic oxygen atom.

Intermediate IV is cyclically reduced in the presence of an organic acid such as trifluoroacetic acid, triflic acid or the like, or Lewis acid such as boron trifluoride ether, tin stanate or the like, and a reducing agent such as tri-substituted silane, for example triethylsilane, chloroform, THF, toluene or the like, at a temperature of 40 ° C to 100 ° C for a time sufficient to complete the reaction to give the cyclic product V, in which the stereochemistry of the aryl substituent and R ³ in the newly formed ring is extremely cis. The formation of intermediates with similar trans stereochemistry is shown in the following general scheme I.

In product V, when R ⁶ is a protecting group, it is then removed by a method appropriate to its type. These methods are well described in the literature and are included in conventional guides such as Greene, T. W. and Wuts, P. GM. Protective Groups in Organic Synthesis, Third Ed., Wiley, New York (1999). Of course, there may be any number of substituents R ¹ - R ⁴ which are either -OR ⁶ or R ~ may contain -OR ⁶ , where R ⁶ is a protecting group. It is clear that in these cases the protecting groups are chemically different, i.e. if necessary, they can be selectively removed. For example, in product VR ⁶ is a methoxymethyl (MOM) group, R is -OR, where R is a benzyl (Bn) group, R ⁵ is a phenyl ring substituted with R ⁷ , where R ⁷ is OR ⁶ , and where R ⁶ is the triisopropylsilyl (TIPS) group, and the other substituents not mentioned are hydrogen. As indicated in the scheme, as part of sequential syntheses, it is necessary to selectively remove the MOM group over TIPS or Bz groups. Using the methods found by Green and Wuts, it is possible to form the preferred intermediate V, where R ⁶ is H, R ² is -OPn, R 'is napa-OTIPS-phenyl and all indeterminate substituents are hydrogen. It should also be noted that in product V, when R ² or R ³ is OR ⁶ , R ⁶ must be a protecting group and before its removal the existing -OR ⁶ group must be covered with a different protecting group.

The alcohol intermediate VI is then reacted with HO (CH ₂ ) _n NZ ₂ according to the Mitsunobu reaction in which they are combined with tri-substituted phosphine such as triphenylphosphine and diazodicarboxylate such as diisopropylazodicarboxylate in a suitable solvent such as THF at 0 ° C at 0 ° C. time sufficient to complete the reaction to give product I. Variants of the Mitsunobu reaction have been described, which are cited here: Mitsunobu, 0., Synthesis, 1981, 1; Castro, BR Org. React. 1983, 29, 1; Hughes, DL Org. React. 1992, 42, 335.

Finally, it is clear that after the Mitsunobu reaction, if in compound I, any R group is or contains -OR ⁶ , where R ⁶ is a protecting group, it is removed by a suitable method described in Green and Wuts, wherein the final product is obtained, wherein R ⁶ is H.

then

SCHEME II. GENERAL SCHEME OF SYNTHESIS OF

77MEAD-Dihydrobenzoxazines and benzodioxanes

According to the general scheme for the preparation of the trans isomers of I, the intermediate ketone IV of Scheme I is reduced with sodium boron hydride, superhydride or the like in a mixture of methanol and dichloromethane or THF or the like at 0 ° C to room temperature. time from a few minutes to a few hours to give an analogous hydroxyl intermediate VII.

Cyclization of intermediate VII is carried out in the presence of an acid catalyst such as amberlyst 15

or triflic acid or the like, in a solvent such as toluene or dichloromethane or the like at room temperature to reflux to give trans compound VIII as the major isomer.

The remaining synthesis steps to obtain trans I are the same as in Scheme I and are described in detail above.

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

SCHEME III. GENERAL SCHEME OF SYNTHESIS OF

Dihydrobenzoxazine dioxides

peroxidation

----------------------->.

selective deoxygenation

------------->

I

According to Scheme III, compounds I of the invention are peroxidized with an oxidizing agent such as t-chloroperbenzoic acid or perfluoroacetic acid or the like, in a solvent such as dichloromethane or the like, at a temperature of 0 ° C to reflux to give intermediate trioxide X X is, in turn, deoxygenated at the nitrogen atom by treatment with a reducing agent such as sodium bisulfite or the like in two-phase media such as ethyl acetate and water or the like to give I.

In the compounds of the present invention, X is O and Y is 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). ₅ alkenyl, C]. ₅ alkynyl, -OR ⁶ and halogen.

In the compounds of the present invention, R ⁵ is preferably selected from the group consisting of C ₃ . ₈ cycloalkyl, phenyl and substituted phenyl.

In the compounds of the present invention, R ⁶ is preferably selected from the group consisting of hydrogen, C 1-5 alkyl, benzyl, methoxymethyl and triisopropylsilyl.

In the compounds of the present invention, a preferred subgroup is one in which 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 present invention, the most preferred subgroup is one in which R ¹ and R ⁴ are hydrogen, R ² is -OH, and R ^? is independently selected from the group consisting of phenyl and para-hydroxyphenyl.

SCHEME IV. GENERAL SCHEME OF SYNTHESIS OF

Dihydrobenzoxazine oxides

R ¹ 0

V

V

According to Scheme IV, intermediate V of Scheme I is monoxidized by careful treatment with one equivalent or small excess of an oxidizing agent such as t-chloroperbenzoic acid or dimethyldioxidated or the like, in a solvent such as dichloromethane, ether, acetone or the like at -78 ° Up to room temperature for a few minutes to a few hours to give intermediate sulfoxide XI. The remaining synthesis steps to obtain I are the same as in Scheme I and are described in detail above.

In the compounds of the present invention, X is preferred

0, and Y is preferably S.

In the compounds of the present invention R, R ',

R 1 and R ⁴ are preferably selected from the group consisting of hydrogen, C _1-3 alkyl, C ₃ . ₈ cycloalkyl C. ₅ alkenyl, C _1-5 alkynyl,

-OR ⁶ and halogen.

In the compounds of the present invention, R ⁵ is preferably selected from the group consisting of C ₃ . ₈ cycloalkyl, phenyl and substituted phenyl.

In the compounds of the present invention, R ⁶ is preferably selected from the group consisting of hydrogen, C 1-5 alkyl, benzyl, methoxymethyl and triisopropylsilyl.

In the compounds of the present invention, a preferred subgroup is one in which 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 present invention, another preferred subgroup is one in which 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 of phenyl and substituted phenyl.

In the compounds of the present invention, the most preferred subgroup is one in which R ¹ and R ⁴ are hydrogen, R ² is -OH, and R ⁵ is independently selected from the group consisting of phenyl, L (e) -hydroxyphenyl, and g / p-hydroxyphenyl.

EXAMPLE 1

GENERAL SCHEME FOR THE PREPARATION OF THIOPHENOLS

The functionalized thiophenols were prepared by the known method of minimal modification, which is shown in the above scheme: Wermer, G .; Biebrich, W. US Patent 2,276,553 and 2,332,418.

The phenol shown above was prepared by the method of: Maxwell, S. J. Am. Chem. Soc. 1947, 69, 712; Hanzlik, R. P. et. al. J. Org, Chem. 1990, 55, 2736.

EXAMPLE 2

Preparation of 2-Thiophene-4-Methoxy-benzophenone

MeO

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) and then 2-thiophenacetyl chloride (0.57 mL, 4.6 mmol) was added dropwise. at 0 ° C under N ₂ . The reaction mixture was stirred for 1.5 hours and poured into a separating funnel containing ice / saturated saline / EtOAc. The organic layer was washed with a further saturated saline solution, dried over Na ₂ SO ₄ and concentrated in vacuo. The resulting residue was purified by chromatography over silica gel with eluent EtOAc / hexane to give the desired product as a yellow oil. 1 H 500 MHz H NMR (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).

EXAMPLE 3

PREPARATION OF HA 2-THIOPHENE-4-HYDROXYBENZOPHENONE

HO

A mixture of 2-thiophene-4-methoxy-benzophenone (0.8294 g, 3.5 mmol) obtained in Example 2 and pyridine-HCl (4. 0627 g, 35.2 mmol) was obtained.

heated at 190 ° C below N ₂ for 6 hours. The reaction was monitored by analysis of aliquots taken with 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 saturated brine, dried over Na ₂ SO ₄ and concentrated in vacuo. The resulting brown residue was purified by chromatography over silica gel with eluent 30% EtOAc / hexane to give the desired product as a yellow / orange solid. 1 H 500MHz NMR (CDCl ₃ ) ppm (δ): 4.43 (s, 2Η), 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 Scheme for the Preparation of Cycloalkyl-4-Hydroxy-benzophenones

To a stirred solution of 2-cycloalkyl-1- (4-methoxyphenyl) -ethanone [prepared according to the method of Barrio, et al, J. Med. Chem., 1971, 14, 898] in dry metal chloride at 0 ° C are added

3.6 equivalents of aluminum chloride and 3.0 equivalents of isopropyl mercaptan. The ice bath was removed and the reaction mixture was further heated overnight under an inert nitrogen atmosphere. The reaction mixture was poured onto a mixture of 2N HCl / ice and extracted with ethyl acetate. The ethyl acetate extract was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and evaporated.

Chromatographic purification over silica gel gave the corresponding 2-cycloalkyl-1- (4-hydroxyphenyl) -ethanone.

The following compounds were obtained using the following experimental procedure:

2-Cyclohexyl-1- (4-hydroxy-phenyl) -ethanone: 70% yield, using chromatographic eluent, metal chloride-ethyl acetate (50: 1). ¹H 500 MHz NMR (CDCI ₃₎ ppm (5): 1-2.0 (m, 11H) ,

2. 96 (d, 1H), 5.6 (bs, 1H), 6.92 (d, 2H), and 7.95 (d, 2H).

2-Cyclopentyl-1- (4-hydroxy-phenyl) -ethanone: 74% yield, using chromatographic eluent, metal chloride-ethyl acetate (50: 1). 'H 500MHz NMR (CDC1 ₃₎ ppm (5): 1.2-1.92 (m, 10H) , 2.4 (m, 1H), 2.96 (d, 1 H), 5. 6 (bs, IH), 6.91 ( d, 2H), and 7. 95 (d, 2H).

EXAMPLE 5

PREPARATION OF HA 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 at 80 ° C for about 3.5 hours. The reaction mixture was poured into ice / 2N HCl and extracted with EtOAc. The organic extract was washed with saturated 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 chromatography over silica gel with eluent 30% EtOAc / hexane. After standing at room temperature, the oil solidifies into a white substance. 'H 500MHz

NMR (CDCl ₃ ) ppm (δ): 1.01 (d, 6Η), 2.27 (m, 1H), 2.81 (d, 2H),

6.99 (d, 2H), 7.93 (d, 2H).

EXAMPLE 6

Preparation of HA 4-Pyridyl-4-hydroxybenzophenone

A dry flask equipped with a stirrer was charged with 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 min, 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 min before being removed from the ice bath. A solution of cyanophenol (2.5670 g, 21.4 mmol) in distilled THF (20 mL) was added dropwise over a 30 minute period. After the phenol was added, the reaction mixture became a thick slurry on which a red-brown resin was separated. The additional addition of THF does not alleviate the difficult stirring. The reaction mixture was left at room temperature for 16 hours and then poured into ice / sat. NH ₄ Cl / EtOAc. The intermediate enamine is precipitated from the mixture as insoluble yellow matter and isolated by filtration under vacuum. The solid was dissolved in 2N HCl. The layer of

EtOAc from the filtrate was also collected and extracted with 2N HCl / ice. The acidic aqueous extract was combined with the enamine solution in 2N HCl and stirred for 16 hours at room temperature. The acidic solution was washed with EtOAc, cooled to 0 ° C and neutralized to pH 7 with us. NaHCO ₃ . The desired product precipitates from the solution as a yellow substance, is isolated, washed with cold water and dried in vacuo. * H 500MHz

NMR (d-acetone) ppm (δ): 4.37 (s, 2Η), 6.97 (d, 2H), 7.31 (d, 2H), 8.01 (d, 2H), 8.52 (bs, 2H).

EXAMPLE 7

Preparation of 3-Pyridyl-4-hydroxybenzophenone

3-Pyridyl-4-hydroxy-benzophenone was prepared from 3-picoline according to the procedure of Example 6, except that 1 equivalent of HMP in THF was added to the reaction mixture, followed by the addition of diisopropylamine. The treatment differs slightly in that no hydrolysis with 2N HCl is required. Instead, the reaction mixture is simply partitioned between ice / us. NH ₄ C1 and EtOAc. The organic layer was washed with saturated 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. 1 H 500MHz NMR (d-acetone) ppm (δ): 4.39 (s, 2Η), 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 scheme for the preparation of cycloalkyl-4-triisopropylsilyloxy-benzophenones

TIPSO

To a stirred solution of 2-cycloalkyl-1- (4-hydroxyphenyl) -ethanone obtained in Example 4 in dry DMF at 0 ° C was added 1.3 equivalents of diisopropylethylamine and 1.2 equivalents of triisopropylchlorosilane (TIPSC1). The ice-water bath was removed and stirring continued until the reaction was complete, as evidenced by TLC (1-3 hours) in an inert nitrogen atmosphere. The reaction mixture was partitioned between ετερ / 2Ν HCl / ice and the organic layer was separated, washed twice with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and evaporated. Chromatographic purification over silica gel gave the corresponding 2cycloalkyl-1- (4-triisopropyloxy-phenyl) -ethanone.

The following compounds were obtained using the following experimental procedure:

2-cyclohexyl-1- (4-triisopropyloxy-phenyl) -ethanone; methylene chloride: hexanes (1: 1) was used as the chromatographic eluent. 1 H 500MHz NMR (CDCl ₃ ) ppm (δ): 1.13 (d, 18Η), 1.2-1.99 (m, 14H), 2.78 (d, 1H), 6.91 (d, 2H), and 7.89 (d, 2H) .

2-cyclopentyl-1- (4-triisopropyloxy-phenyl) -ethanone; methylene chloride: hexanes (1: 1) was used as the chromatographic eluent. &Lt; 1 &gt; H 500MHz NMR (CDCl3) 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 scheme for the preparation of alkyl-4-triisopropylsilyloxy-benzophenones

To a solution of 2-cycloalkyl-1- (4-triisopropyloxy-phenyl) ethanone prepared in Examples 3, 6 and 7 in distilled THF was added 1.3 equivalents of 60% NaH in mineral oil at 0 ° C under nitrogen. When gas evolution ceases, 1.1 equivalents are added dropwise and the resulting solution is stirred for 30 minutes. The reaction mixture is partitioned between ice / water and EtOAc. The organic layer was washed with saturated brine, dried over Na ₂ SO ₄ and concentrated in vacuo. Chromatographic purification over silica gel gave the corresponding 2-alkyl-1- (4-triisopropyloxy-phenyl) -ethanones.

The following compounds were obtained using the following experimental procedure:

2- (2-thiophene) -1- (4-triisopropyloxy-phenyl) -ethanone; isolated as an orange-yellow substance when used as chromatographic eluent of 15% EtOAc / hexane. 'H 500MHz

NMR (CDCl3) ppm (δ): 1.14 (d, 18Η), 1.30 (m, 3H), 4.42 (s, 2H), and

6.93-7.98 (m, 7H).

2- (4-Pyridyl-1- (4-triisopropyloxy-phenyl) -ethanone; isolated as a yellow substance using as a chromatographic eluent 40% EtOAc / hexane. 1 H 500MHz NMR (CDCl ₃ ) ppm (δ): 1.14 ( d, 18Η), 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-triizopropiloksi-phenyl) -ethanone; isolated as a yellow solid using as chromatographic eluent of 40% EtOAc / hexane. ^'H 500 MHz NMR (CDC1 ₃₎ ppm (δ): 1.14 (d, 18Η), 1.20 (m, 3H), 4.18 (s, 2H), 6.82 (d, 2H), 7.10 (d, 2H), 7.82 (d, 2H), and 8.43 (d, 2H).

EXAMPLE 10

GENERAL SCHEME OF METHODOLOGY FOR BORING

Alkyl and cycloalkyl-4-triisopropylsilyloxy-benzophenones

TIPSO

R

To a stirred solution of 2-alkyl and 2-cycloalkyl-1- (4A triisopropylsilyloxyphenyl) -ethanones prepared in Examples w

and 9, 1.0 equivalent of trimethylammonium phenyl perbromide was added to dry THF at 0 ° C. The ice-water bath was removed and the reaction mixture was stirred for 1 hour under an inert atmosphere under nitrogen. The reaction mixture was partitioned between ethyl acetate / saturated saline / 5% sodium thiosulfate / sodium bicarbonate and the organic layer was separated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and evaporated. Chromatographic purification over silica gel gave the corresponding 2-cycloalkyl-2-bromo-1- (4-triisopropyloxy-phenyl) -ethanone.

Using the following experimental methodology, they are

the following compounds are obtained:

2-cyclohexyl-2-bromo-1- (4-triisopropylsilyloxy-phenyl) ethanone; when used as chromatographic eluent of methylene chloride / hexanes (1: 1). 1H 500MHz NMR (CDCl3) ppm (δ): 1.14 (d, 18 1.1), 0.98-2.27 (m, 15H), 4.91 (d, 1H), 6.94 (d, 2H), and 7.94 (d, 2H).

2-cyclopentyl-2-bromo-1- (4-triisopropylsilyloxy-phenyl) ethanone; when used as chromatographic eluent of methylene chloride / hexanes (1: 1). 1 H 500 MHz NMR (CDCl 3) ppm (δ): 1.13 (d, 18Η), 1.1-2.2 (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-triisopropylsilyloxy-phenyl) ethanone: stirring at 0 ° C for 40 min; isolated as a dark brown oil and used in the next reaction without purification.

1 H 500 MHz NMR (CDCl 3) ppm (δ): 1.13 (d, 18Η), 1.30 (m, 3H), 6.73 (s, 1H), 6.97 (d, 2H), 7.00 (m, 1H), 7.30 ( m, 1H), 7.49 (d, 1H), and 8.00 (d, 2H).

2- (4-pyridyl) -2-bromo-1- (4-triisopropylsilyloxy-phenyl) ethanone: add 2 equivalents of trimethylammonium phenyl perbromide and stir at 0 ° C for 1 hour; Isolated as an orange-yellow oil and used in the next reaction without purification. 'H 500MHz NMR (CDC1 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-triisopropylsilyloxy-phenyl) ethanone: add 2 equivalents of trimethylammonium phenyl perbromide and stir at 0 ° C for 3 hours; Isolated as an orange-yellow oil and used in the next reaction without purification. * H 500MHz NMR (CDCl3) ppm (δ): 1.13 (d, 18H),

1.30 (m, 3H), 6.30 (s, 1H), 6.98 (d, 2H), and 7.39-8.75 (m, 6H).

EXAMPLE 11

PREPARATION OF HA 2-ISOPROPYL-2-BROMO-1- (4 HYDROXYPHENYL) -ETHANONE

According to the procedure described in Example 10 and using the product obtained in Example 5, 2-isopropyl-2-bromo-1- (4hydroxyphenyl) -ethanone was isolated as a yellow oil and used in the next reaction without purification. 1 H 500MHz NMR (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 SCHEME OF HA PREPARATION OF HA BROMOKETONS

L = Neely MOM

Stage A

To a stirred solution of 3.0g (13.2mmole) of dry deoxybenzoin (freshly distilled by azeotropic distillation with toluene) in 25mL DMF at 0 ° C was added 5.7mL (5.7mmole) of pure diisopropylethylamine. To this stirred solution was added

slow 1.25mL (19.73 mmole) chloromethylmethyl ether (MOMC1). The ice-water bath was removed and the mixture was stirred for an additional 18 hours under a nitrogen atmosphere. The mixture was poured into saturated NaHCO ₃ solution, extracted with EtOAc and the extract washed with water and dried over anhydrous MgSO ₄ . After evaporation of the solvent, the residue was purified by chromatography over silica gel (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).

Stage B

To a stirred solution of the product obtained in Step A (423mg, 1.55mmole) and imidazole (211 mg, 3.1mmole) in 20 mL dry DMF at 0 ° C was added triisopropylsilyl chloride (3.1 mmole) and the reaction mixture was allowed to warm. to room temperature and then stirred for another 2-3 hours. The reaction was quenched by the addition of aqueous NaHCO ₃ and extracted with EtOAc. The organic layer was washed with saturated brine and dried with MgSO ₄ . Chromatography (10% EtOAc / hexane) gave 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).

Stage C

To a mixture of the compound of Step B (0.5g, 1.16mmole) in 100mL anhydrous THF was added 0.39g (1.16mmole) of trimethylphenylammonium perbromide (PTAB) at 0 ° C. The ice-water bath was removed and the mixture was stirred for one hour. The solution was then filtered and washed with water and saturated brine and dried over MgSO ₄ . Removal of the solvent yields a mixture of bromoketones (MOM group partially removed), which is used without further purification due to their instability in 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: '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).

EXAMPLE 13

RECEIVING HA

The required bromoketone was prepared according to 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, 2H), 6.4 (s, 1H), 3.8 (s, 3H). 1.28 (m, 3H), 1.1 (d, 18H).

EXAMPLE 14

OBTAINING

The required bromoketone was prepared according to the procedure in 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

RECEIVING HA

Stage A

To a stirred solution of a mixture of O.Ig (0.37 mmole) monophenolic compound of Step A in Example 12 and diisopropylethylamine (0.13mL, 2eq) in 5 mL DMF at room temperature was slowly added pure MOMCl (0.05mL, 2eq) and the mixture was added. heated at 85 ° C below N ₂ for three hours. The mixture was poured into saturated aqueous NaHCO ₃ , extracted with

EtOAc. washed with water and dried over MgSO ₄ . After evaporation of the solvent, the residue was purified by chromatography over silica gel with eluent (EtOAc / hexane = 1: 1) to give a pure double-protected MOM product as a solid. H NMR (400 _{MHz, CDC1?) 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).

Stage B

The product from Step A was treated with bromine to give the bromo ketone. ^! H NMR (400 MHz, CDCl3) 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 SCHEME FOR GETTING A MOMO

To a stirred freshly prepared solution of 2-thiophenol (0.2g, 1.6mmole) and Et ₃ N (0.34mL, 2eq) in 15mL DMF at 0 ° C was slowly added a solution of 0.627g (1.232mmole) of bromoketone (obtained in Step C in Example 12) in 13mL DMF. The reaction mixture was stirred for three hours at room temperature and partitioned between saturated NaHCO ₃ and EtOAc, the layers separated and the aqueous layer 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 column chromatography (EtOAc / Hex = 1/4) to give the desired product as an oil. 1 H NMR (400 MHz, acetone-bb) δ (ppm): 8.0 (d, 2H). 7.2-6.6 (m, 8H), 6.8 (d, 2H), 6.2 (s, 1H), 5.24 (s,

2H), 3.4 (s, 3H), 1.22 (m, 3H), 1.1 (d, 18H);

MS m / z 575 (M + 23).

EXAMPLE 17

CYCLIZING HA BUYED PRODUCT

MOMO

According to the procedure given in Example 16, 1,2-dihydrobenzene and the bromide of Example 15 were converted into the product which was purified by chromatography over silica gel with EtOAc / hexane eluent (1/4). MS m / z 448 (M ⁺ + 23).

EXAMPLE 18

OBTAINING

momo

ORs

A

IN

According to the procedure of Example 16 and using 0.83g (3.6mmole) of 4-benzyloxy-thiophenol prepared in Example 1, after chromatographic purification over silica gel with eluent EtOAc / hexane (1/5), product A and product B were obtained.

A: ^] H NMR (400 MHz, acetone-cC) δ (ppm): 8.15 (s, 1H), 7.8 (d, 2H), 7.4 (m, 5H), 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-de) 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).

EXAMPLE 19

RECEIVING HA

TIPSO

According to the procedure of Example 16 and using lg (2.3mmole) the bromoketone of Example 14, after chromatographic purification over silica gel with eluent EtOAc / hexane (1/5), the desired product was obtained. 1 H NMR (400 MHz, acetone de) 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, 1H),

6.1 (s, 1H), 5.04 (s, 2H), 3.72 (s, 3H), 1.25 (m, 3H), 1.1 (d, 18H).

EXAMPLE 20

OBTAINING

According to the procedure of Example 16 and using 0.74g (1.5mmole) bromoketone from Example 12 Step C), after chromatographic purification over silica gel with eluent EtOAc / hexane (1/5), the desired product was obtained. 1 H NMR (400 MHz, acetone d ₆ ) δ (ppm): 7.92 (d, 2H), 7.46-7.1 (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).

EXAMPLE 21

RECEIVING HA

According to the procedure of Example 16, and using 0.8g (1.57mmole), the bromoketone of Example 12 (Step C) with the thiophenol derivative obtained in Example 1, after chromatographic purification over silica gel with eluent EtOAc / hexane (1/5), was obtained product. 1 H NMR (400 MHz, acetone d ₆ ) 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

RECEIVING HA

According to the procedure of Example 16 and using 0.56g (1.1 mmole) bromoketone of Example 12 (Step C) with 0.19g (0.73mmole) thiophenol derivative obtained in Example 1 after chromatographic purification over silica gel with EtOAc / hexane (1 (5) the desired product is obtained. 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, 1I), 5.1 (s, 2H), 2.6 (q, 2H), 1.22 (m, 3H), 1.1 (d , 18H), 1.1 (t, 3H).

EXAMPLE 23

OBTAINING

According to the procedure of Example 16, and using 2.04g (4.33mmole), the bromoketone of Example 12 (Step C) with the thiophenol derivative obtained in Example 1, after chromatographic purification over silica gel with EtOAc / hexane (1/5) eluent, was obtained. product. 1 H NMR (400 MHz, acetone d ₆ ) 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

RECEIVING HA

OBn

According to the procedure of Example 16, and using 2.04g (4.33mmole), the bromoketone of Example 12 (Step C) with the thiophenol derivative obtained in Example 1, after chromatographic purification over silica gel with EtOAc / hexane (1/5) eluent, was obtained. product. 1 H NMR (400 MHz, acetone d ₆ ) 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 (2H, d), 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).

EXAMPLE 25

RECEIVING HA

TIPSO

According to the procedure of Example 16 and using 1.6g (3.51 mmole) of the bromoketone of Example 13 with the thiophenol derivative obtained in Example 1, after chromatographic purification over silica gel with eluent EtOAc / hexane (1/5), the desired product was obtained. 1 H NMR (400 MHz, acetone d ₆ ) δ (ppm): 8.0 (d, 2H), 7.5-7.2 (m, 10H), 7.0 (d, 1H), 6.92 (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

OBTAINING

TIPSO

According to the procedure of Example 16 and using 2.6g (5.82mmole), the bromoketone of Example 13 with the thiophenol derivative obtained in Example 1, after chromatographic purification over silica gel with eluent EtOAc / hexane (1/5), gave the desired product. 1 H NMR (400 MHz, acetone άβ) δ (ppm): 8.0 (d, 2H), 7.4-7.2 (m, 10H), 6.94 (d, 2H), 6.84-6.74 (m, 3H), 6.24 (s , 1H), 4.85 (s, 2H), 1.23 (m, 3H), 1.1 (d, 18H).

EXAMPLE 27

RECEIVING HA

TIPSO

According to the procedure of Example 16 and using the bromoketone of Example 12 (Step C) with the thiophenol derivative obtained in Example 1, after chromatographic purification over silica gel with eluent EtOAc / hexane (1/5), the desired product was obtained. 1 H NMR (400 MHz, acetone d ₆ ) δ (ppm): 8.0 (d, 2H), 7.47.2 (m, 7H), 7.0 (m, 5H), 6.54 (d, 1H), 6.28 (dd, 1H). 1H), 6.14 (s, 1H),

5.08 (s, 2H), 1.23 (m, 3H), 1.1 (d, 18H).

EXAMPLE 28

RECEIVING HA

TIPSO

According to the procedure of Example 16 and using the bromoketone of Example 12 (Step C) with the thiophenol derivative obtained in Example 1, after chromatographic purification over silica gel with eluent EtOAc / hexane (1/5), the desired product was obtained. 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 C (dd, 1H), 5.80 (s, 1H), 5.00 (s, 2H), 1.24 (m, 3H), 1.10 (d, 18H).

EXAMPLE 29

RECEIVING HA

OBn

According to the procedure of Example 16 and using the bromoketone of Example 13 with the corresponding thiophenol derivative obtained in Example 1, chromatographic purification over silica gel with eluent EtOAc / hexane (1/5) gave the desired product. 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

RECEIVING HA

According to the procedure of Example 16 and using the bromoketone of Example 12 with the thiophenol derivative obtained in Example 1, chromatographic purification over silica gel with eluent EtOAc / hexane (1/5) gave the desired product. 1 NMR (500 MHz, CDCI 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

According to the procedure of Example 16 and using the bromoketone of Example 12 with the thiophenol derivative obtained in Example 1, chromatographic purification over silica gel with eluent EtOAc / hexane (1/5) gave the desired product. * NMR (500 MHz, CDC1 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 (d, 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

RECEIVING HA

According to the procedure of Example 16 and using the bromoketone of Example 12 with the thiophenol derivative obtained in Example 1, chromatographic purification over silica gel with eluent EtOAc / hexane (1/5) gave the desired product. 1 H NMR (500 MHz, CDCl ₃ ) 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

RECEIVING HA

According to the procedure of Example 16 and using the bromoketone of Example 12 with the thiophenol derivative obtained in Example 1, chromatographic purification over silica gel with eluent EtOAc / hexane (1/5) gave the desired product. 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

RECEIVING HA

According to the procedure of Example 16 and using the bromoketone of Example 12 with the thiophenol derivative obtained in Example 1, the desired product was obtained after chromatography over silica gel with EtOAc / hexane (1/5). 1 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

RECEIVING HA

TIPSO

OBn

According to the procedure of Example 16 and using the bromoketone of Example 12 with the thiophenol derivative obtained in Example 1, chromatographic purification over silica gel with eluent EtOAc / hexane (1/5) gave the desired product. 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

RECEIVING HA

TIPSO

OBn

According to the procedure of Example 16 and using the bromoketone of Example 13 with the thiophenol derivative obtained in Example 1, chromatographic purification over silica gel with eluent EtOAc / hexane (1/5) gave the desired product. 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), 1.23 (m, 3H), 1.10 (m, 18H).

EXAMPLE 37

RECEIVING HA

According to the procedure of Example 16 and using the bromoketone of Example 13 with a mixture of the two thiophenol derivatives obtained in Example 1, after chromatographic purification over silica gel with eluent EtOAc / hexane (1/5), the desired product was obtained.

I: 1 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 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

OBTAINING

According to the procedure of Example 16 and using the bromoketone of Example 12 with the thiophenol derivative X obtained in Example 1, chromatographic purification over silica gel with eluent EtOAc / hexane (1/5) gave the desired product. 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 39

GENERAL SCHEME HA RECEIVING HA

Using the bromides obtained in Example 10 and the corresponding mercaptan obtained in Example 1 and the method of

The following compounds were obtained from Example 16:

Cyclohexyl derivative: methylene chloride: hexanes (3: 1) was used as the chromatographic eluent. 'NMR (500 MHz,

CDCl ₃ ) δ (ppm): 1.12 (d, 18H), 1.11-2.34 (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: Methyl chloride: hexanes (2: 1) was used as the chromatographic eluent. 1 H NMR (500 MHz, CDCl ₃ ) δ (ppm): 1.12 (d, 18H), 1.28-2. 49 (m, 12H), 4.18 (d, 1H), 5.0 (s, 2H), 6.45-7.77 (m, 12H).

EXAMPLE 40

RECEIVING HA

Using the bromide obtained in Example 11 and the corresponding mercaptan obtained in Example 1 and the procedure of Example 9, the desired product was obtained as a yellow oil in 77% yield after chromatographic purification over silica gel with 30% EtOAc / hexane. 1 H NMR (500 MHz, CDCl ₃ ) δ (ppm): 1.00 (d, 3H), 1.21 (d, 3 Η). 2.30 (m, 1Η), 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 SCHEME FOR RECEIPT OF

HE

Using the bromides obtained in Example 10 and the corresponding mercaptan obtained in Example 1 and the method of

The following compounds were obtained from Example 16:

Cyclohexyl derivative: methylene chloride: hexanes (3: 1) was used as the chromatographic eluent. 'NMR (500 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: Methyl chloride: hexanes (2: 1) was used as the chromatographic eluent. 1 H NMR (500 MHz, CDCl 3) δ (ppm): 1.12 (d, 18H), 1.26-2.12 (m, UH), 2.5 (m, 1H),

4.24 (d, 1H), 4.9 (m, 2H), 6.8-7.69 (m, 12H).

4-Pyridyl derivative: recovered as a yellow oil after chromatographic purification with eluent 30% EtOAc / hexane.

1 H NMR (500 MHz, CDCl 3) δ (ppm): 1.12 (d, 18H), 1.28 (m, 3H),

4.84 (q, 2H), 4.88 (s, 1H), 5.63 (s, 1H), and 6.69-8.50 (m, 16H).

3-Pyridyl derivative: recovered as a yellow oil after chromatographic purification with eluent 30% EtOAc / hexane. 1 H NMR (500 MHz, CDCl 3) δ (ppm): 1.12 (d, 18H), 1.28- (m, 3H),

4.84 (q, 2H), 4.90 (s, 1H), 5.79 (s, 1H), and 6.70-8.50 (m, 16H).

EXAMPLE 42

RECEIVING HA

OH

Ph

OH

Using the bromide obtained in Example 11 and the corresponding mercaptan obtained in Example 1 and the procedure of Example 16, the desired product was obtained as a yellow oil in 77% yield after chromatographic purification over silica gel with 30% EtOAc / hexane. 1 H NMR (500 MHz, CDCl 3) δ (ppm): 1.02 (d, 3H), 1.21 (d, 3 Η), 2.34 (m, 1H), 4.13 (d, 1H), 4. 90 (q, 2H) , 6.25 (bs, 1H), 6.79-7.70 (m, 12H).

EXAMPLE 43

RECEIVING HA

Using the appropriate bromide obtained in Example 10 and mercaptoquinol [obtained by the method of Burton, et al, J. Chem. Soc., 1952, 2193], and using the procedure of Example 16, the desired product was obtained as an orange-red oil after chromatographic purification over silica gel with 30% C EtOAc / hexane eluent. ^! H 500MHz NMR (CDC1 ₃₎ ppm (δ): 1.10 ( d, 18Η),

1.27 (m, 3H), 6.00 (s, 1H), and 6.76-7.89 (m, 10H); MS m / z 515 (M ⁺ ).

OTIPS

EXAMPLE 44

OBTAINING

Et

HE

In a flask charged with 0.1 g (0.16mmole) of thioketone obtained in

Example 22, in dichloromethane (ca 0.04M) was added slowly

trifluoroacetic acid (TFA) (2 x 0.062mL, 4eq) below N ₂ at room temperature. Triethylsilane (2 x 0.05mL, 4eq) was slowly added to the stirred reaction mixture and the resulting mixture was stirred until complete consumption of the starting material (approximately 5-6 hours, monitored by TLC). The reaction mixture was poured into saturated NaHCO3 / ice water, stirred for 10 minutes and extracted with dichloromethane. The organic extract was washed with saturated brine (2 x 50mL), dried over Na ₂ SO ₄ H, concentrated in vacuo to give a pale yellow oil. Purification by column chromatography (EtOAc / hexane = 1: 5) gave the desired product as an oil. 'HNMR (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, 1- = 2.3 Hz, 1H),

5.10 (s, 2H), 4.74 (brs, 1H), 4.32 (d, J = 2.3Hz, 1H), 2.77 (qd, 2H),

1.22 (m, 3H), 1.08 (d, 18H), 1.1 (m, 3H); MS m / z 628.5 (M ⁺ + 1).

EXAMPLE 45

OBTAINING

Using the procedure of Example 44, the desired dihydrobenzoxathine without MOM protection was isolated after chromatographic purification over silica gel with 10% EtOAc / hexane as eluent. 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 = 2.1Hz, 1H), 1.22 (m, 3H), 1.1 (d, 18H); MS m / z 515 (M ^{+ +} 23).

The other dihydrobenzooxathine with MOM protection is 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, tH) , 5.14 (s, 2H), 4.35 C (d, J = 2. 1 Hz, 1H), 3.48 (s, 3H), 1.22 (m, 3H), 1.1 (d, 18H).

EXAMPLE 46

RECEIVING HA

OMOM

Using the procedure of Example 71 (Step C), the dihydrobenzooxathine obtained in Example 45 was desilylated and the product was obtained. 1 H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.2-6.96 (m, 4H), 6.92 (two d, 4H), 6.82 (d, 2H), 6.6 (d, 2H), 5.52 (d. J = 2.2Hz, 1H), 5.16 (s, 2H), 4.68 (br s, 1H), 4.38 (d, J = 2.2Hz, 1H), 3.48 (s, 3H).

EXAMPLE 47

RECEIVING HA

The ketone of 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 complete the reaction. The MOM group was removed by treatment with soft 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

OBTAINING

The ketone of Example 18 is converted to the desired product according to the procedure described in Example 44, except that 20 TFA equivalents and 15 Et ₃ SiH equivalents are required to complete the reaction. The desired product was isolated after chromatographic purification with 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 = 2.2Hz, 1H), 5.04 ( br q, 2H), 4.68 (s, 1H), 4.3 (d, J = 2.2Hz, 1H), 1.22 (m, 3H), 1.1 (d, 18H); MS m / z 515 (M ^{+ +} 23).

EXAMPLE 49

RECEIVING HA

The ketone of Example 98 was converted to dihydrooxathine according to 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 [recovery of 20% of starting material] was isolated after chromatographic purification with 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 = 1.9Hz, 1H), 5.06 (dd, 2H) ), 4.32 (d, 1H), 3.74 (s, 3H), 1.22 (m, 3H), 1.1 (d, 18H).

EXAMPLE 50

RECEIVING HA

Following the procedure of Example 44 and using the ketone derivative of Example 20, the desired product was obtained after chromatographic purification over silica gel with 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 = 2.2Hz, 1H), 4.35 (d, 1H), 2.28 (s, 3H), 1.22 (m, 3H), 1.1 (d, 18H).

100

EXAMPLE 51

OBTAINING

According to the procedure of Example 44 and using the ketone derivative of Example 21, the desired product was obtained after> · *.

chromatographic purification over silica gel with 5% EtOAc / hexane as eluent. 1 H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.5-7.3 (m, 5H), 6.98 (d, 1H), 6.9 (d, 1H), 6.76 (d, 2H), 6.6 (m, 5H) ), 5.51 (d, J = 2.2Hz, 1H), 5.1 (s, 2H), 4.8 (s, 1H), 4.32 (d, 1H), 2. 2. 4 (s, 3H).

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

EXAMPLE 52

RECEIVING HA

By the procedure of Example 44 and using the ketone derivative of Example 22, the desired product was obtained after chromatographic purification over silica gel with 5% eluent

EtOAc / hexane. 1 H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.5-7 3 (m,

5H), 6.85 (d, 2H), 6.78 (d, 2H), 6.66 (m, 5H), 6.56 (d, 1H), 5.48 (d,

101

J = 2.0Hz, 1H), 5.04 (br q, 2H), 4.74 (br s, 1H), 4.34 (d, J = 2.0Hz,

1H), 2.64 (q, 2H), 1.3 (t, 3H), 1.24 (m, 3H), 1.1 (d, 18H).

EXAMPLE 53

RECEIVING HA

Following the procedure of Example 44 and using the ketone derivative of Example 23, the desired product was obtained after chromatographic purification over silica gel with 5% EtOAc / hexane as eluent. 1 H NMR (400 MHz, CDCl 3) δ (ppm): 7.5-7.3 (m, 5H), 6.98 (d, 1H), 6.9 (d, 2H), 6.74 (d, 2H), 6.7-6.6 (three d , 5H), 5.5 (d, J = 2.3Hz, 1H), 5.1 (s, 2H), 4.74 (br s, 1H), 4.32 (d, J = 2.4Hz, 1H), 2.79 (m, 2H) , 1.22 (m, 3H), 1.1 (d &amp;21H); MS m / z 628.5 (M% 1).

EXAMPLE 54

RECEIVING HA

OH

102

Following the procedure of Example 44 and using the ketone derivative of Example 24, the desired product was obtained after chromatographic purification over silica gel with 5% EtOAc / hexane as eluent. 1 H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.5-7.3 (m, 10H), 6.84 (d, 2H), 6.78 (d, 2H), 6.66 (two d, 4H), 6.38 (s. 2H),

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

EXAMPLE 55

RECEIVING HA

Following the procedure of Example 44 and using the ketone derivative of Example 25, the desired product was obtained after chromatographic purification over silica gel with 5% EtOAc / hexane as eluent. 1 H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.5-7.32 (m, 5H), 7.2-7.1 (m, 4H), 6.9-6.82 (m, 4H), 6.76-6.7 (m, 4H) , 5.56 (d, 1H), 5.06 (br q, 2H), 4.36 (d, 1H), 1.22 (m, 3H), 1.1 (d, 18H).

103

EXAMPLE 56

OBTAINING

By the method of Example 44, except that

The V * reaction was carried out at 0 ° C for three hours and using

1.7g (2.83mmole) of the ketone derivative of Example 26 was obtained the desired product after chromatographic purification over silica gel with 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), 6.9-6.82 (m, 5H), 6.4 (m, 3H) , 5.48 (d, J = 1.9Hz, 1H), 5.05 (s, 2H), 4.36 (d, J = 1.9Hz, 1H), 1.22 (m, 3H), 1.1 (d, 18H).

EXAMPLE 57

RECEIVING HA

According to the procedure of Example 44 and using the ketone derivative of Example 27, the desired product was obtained which

104 was accordingly desilylated using the procedure described in Example 71 (Step C). The desired product is obtained as an oil after chromatographic purification over silica gel with eluent of 15% EtOAc / hexane. 1 H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.5-7.32 (m, 5H), 7.09 (d, 1H), 6.9-6.8 (m, 6H), 6.73-6.7 (m, 4H), 5.52 (d, 1H), 5.04 (brq, 2H), 4.34 (d, 1H), 1.22 (m, 3H), 1.1 (d, 18H).

EXAMPLE 58

RECEIVING HA

Following the procedure of Example 44 and using the ketone derivative of Example 25, the desired product was obtained after chromatographic purification over silica gel with 5% EtOAc / hexane as eluent. 1 H NMR (500 MHz, CDCl ₃ ) δ (ppm): 7.5-7.3 (m, 5H), 7.22-7.10 (m, 3H), 6.90-6.80 (2d, 4H), 6.75 (d, 2H), 6.55 (d, 2H), 5.55 (d, J = 2. 1Hz, 1H), 5.05 (d, 2H), 4.40 (d, J = 2.1Hz, 1H),

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

105

EXAMPLE 59

OBTAINING

OTIPS

Following the procedure of Example 44 and using the ketone derivative of Example 25, the desired product was obtained after chromatographic purification over silica gel with 5% EtOAc / hexane as eluent. 1 H NMR (500 MHz, CDCl ₃ ) δ (ppm): 7.5-7.3 (m,

5H), 7.22-7.10 (m, 3H), 6.90-6.80 (2d, 4H), 6.73 (d, 2H), 6.64 (d, 2H), 5.50 (d, J = 2.1Hz, 1H), 5.05 (d , 2H), 4.43 (d, J = 2.2 Hz, 1H),

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

EXAMPLE 60

RECEIVING HA

According to the procedure of Example 44 and using the ketone derivative of Example 30, the desired product was obtained after chromatographic purification over silica gel with 5% eluent

EtOAc / hexane. 1 H NMR (500 MHz, CDCl ₃ ) δ (ppm): 7.5-7.3 (m,

5H), 6.82 (d, 2H), 6.68 (d, 2H), 6.64 (d, 2H), 6.62 (d, 2H), 6.46 (d,

2H), 5.44 (d, J = 1.9 Hz, 1H), 5.02 (d, 2H), 4.30 (d, J = 2.0 Hz, 1H),

1.22 (m, 3H), 1.10 (d, 18H); MS m / z 618 (M ⁺ +1).

106

EXAMPLE 61

OBTAINING

Following the procedure of Example 44 and using the ketone derivative of Example 31, the desired product was obtained after chromatographic purification over silica gel with 5% EtOAc / hexane as eluent. 1 H NMR (400 MHz, GDC1 ₃ ) δ (ppm): 7.5-7.3 (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 = 2.0Hz, 1H), 5.04 (s, 2H), 4.38 (d, J = 1.9Hz, 1H), 1.23 (m , 3H), 1.10 (d, 18H); MS m / z 634 (M ⁺ + 1).

EXAMPLE 62

RECEIVING HA

By the procedure of Example 44 and using the ketone derivative of Example 32, the desired product was obtained after chromatographic purification over silica gel with 5% eluent

107

EtOAc / hexane. 1 H NMR (500 MHz, CDCl ₃ ) δ (ppm): 7.5-7.3 (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 = 2.1Hz, 1H). 5.05 (d, 2H), 4.30 (d, J = 2.1 Hz, 1H),

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

EXAMPLE 63

RECEIVING HA

Following the procedure of Example 44 and using the ketone derivative of Example 33, the desired product was obtained after chromatographic purification over silica gel with 5% EtOAc / hexane as eluent. 1 H NMR (500 MHz, CDCl ₃ ) δ (ppm): 7.5-7.3 (m, 5H), 6.88 (s, 1H), 6.84 (d, 2H), 6.82 (d, 2H), 6.70 (d, 2H) ), 6.68 (d, 2H), 6.66 (s, 1H), 5.50 (d, 1H), 5.05 (s, 2H), 4.43 (d, 1H), 2.35 (s, 3H), 1.23 (m, 3H) , 1.10 (d, 18H).

EXAMPLE 64

RECEIVING HA

OH

108

Following the procedure of Example 44 and using the ketone derivative of Example 34, the desired product was obtained after chromatographic purification over silica gel with 5% EtOAc / hexane as eluent. 1 H NMR (500 MHz, CDCl ₃ ) δ (ppm): 7.5-7.3 (m, 5H), 7.24 (s, fH), 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

RECEIVING HA

OTIPS

Following the procedure of Example 44 and using the ketone derivative of Example 35, the desired product was obtained after chromatographic purification over silica gel with 5% EtOAc / hexane as eluent. 1 H NMR (500 MHz, CDCl ₃ ) δ (ppm): 7.5-7.3 (m,

X 5H), 7.05-7.20 (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 = 1.8Hz, 1H), 5.05 (d, 2H),

4.20 (d, J = 2.3 Hz, 1H), 1.23 (m, 3H), 1.10 (d, 18H).

109

EXAMPLE 66

OBTAINING

Following the procedure of Example 44 and using the ketone derivative of Example 36, the desired product was obtained after chromatographic purification over silica gel with 5% EtOAc / hexane as eluent. 7.5-7.3 (m, 5H), 7.05-7.20 (t, 2H), 7.10 (t, 2H), 6.98 (d, 2H), 6.88 (t, 2H), 6.80 (t, 1H), 6.60 (d, 1H), 5.56 (d, J = 1.8Hz, 1H), 5.05 (d, 2H), 4.44 (d, J = 2. 3Hz, 1H), 1.23 (m, 3H),

1.10 (d, 18H).

EXAMPLE 67

RECEIVING HA

OTIPS

According to the procedure of Example 44 and using the ketone derivative of Example 36, the desired product was obtained after chromatographic purification over silica gel with 5% eluent

EtOAc / hexane. 1 H NMR (500 MHz, CDCl 3) δ (ppm): 7.55 (d, 2H),

7.45 (t, 2H), 7.35 (t, 1fil), 7.20 (d, LH), 7.15 (m, 3H), 6.88 (d, 2H),

110

6.84 (d, 3H), 6.78 (d, 2H), 5.46 (d, J = 2.1Hz, 1H), 5.15 (s, 2H), 4.39 (d, J = 2. 1Hz, 1H), 1.23 (m. 3H), 1.10 (d, 18H).

EXAMPLE 68

RECEIVING HA

Following the procedure of Example 44 and using the ketone derivative of Example 37 (II), the desired product was obtained after chromatographic purification over silica gel with 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), 6.80-6.90 (m, 4H), 6.78 (d, 2H), 6.76 (d, 2H) , 5.42 (d, J = 2.1Hz, 1H), 5.18 (s, 2H), 4.42 (d, J = 2.1Hz, 1H), 1.23 (m, 3H), 1.10 (d, 18H).

EXAMPLE 69

RECEIVING HA

OTIPS

Following the procedure of Example 44 and using the ketone derivative of Example 38, the desired product was obtained after chromatographic purification over silica gel with 5% EtOAc / hexane as eluent. 1 H NMR (500 MHz, CDCl ₃ ) δ (ppm): 7.36-7.50 (m,

Ill

5H), 6.96 (d, 2H), 6.80-6.90 (m, 4H), 6.70-6.78 (m, 5H), 5.42 (d, .1 = 2.1 Hz, 1H), 5.18 (s, 2H), 4.38 ( d, J = 2.1 Hz, 1H), 1.23 (m, 3H),

1.10 (d, 18H).

EXAMPLE 70

CHIRAL DIVISION OF HA

/ ΟΤΙ PS ВПО A A AA ιΓΆ kA ^{x he} Each enantiomer on the racemic dihydrobenzoxathine, obtained in Example 62, it's working using chiral

chromatography using a column of Chiralpak AD and eluent 30% isopropanol in hexane.

Fast-moving isomer: [a] _D = +18.44 (c = 0.725, MeOH).

Slow moving isomer: [a] o = -18.85 (c = 0.74, MeOH).

EXAMPLE 71

COMMON SCHEME FOR TINS

OBTAINING

Oh

112

Stage A

To a stirred solution of a mixture of dihydrobenzoxathine (60mg, 0.1 mmole) prepared in Example 48 (which was dried by azeotropic method before use), triphenylphosphine (157mg, 0.6mmole) and 1-piperidinethanol (0.08mL, 0.6mmole) in 4 mL anhydrous THF at 0 ° C was added dropwise 0.118mL (0.6mmole) of diisopropyl azodicarboxylate (DIAD) for 0.2 hours. The resulting pale yellow solution was stirred for 2-3 hours at room temperature. The volatiles were removed in vacuo and the residue was purified by column 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, 1 IS), 4.2 (t, 2H), 2.75 (t, 2H), 2.5 (br s, 4H) ), 1.6 (m, 4H), 1.48 (m, 2H), 1.22 (m, 3H),

1.1 (d, 18H); MS m / z 712.4 (M ⁺ + 1).

Stage B

To a stirred solution of the adduct (71 mg, 0.098mmole) obtained in Step A, in 2 mL EtOH / EtOAc / H ₂ O (7: 2: 1) was added 13mg (1.2 eq) of black palladium and ammonium formate (62mg, 10 EQ). The resulting mixture was heated at 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,

CDCI3) δ (ppm): 7.01 (d, 1H), 6.8 (d, 2H), 6.75 (d, 2H), 6.66 (two d, 4H), 6.54 (dd, 1H), 6.5 (d, 1H). 5.45 (d, J = 2.3 Hz, 1H), 4.28 (d,

113

J = 2.3Hz, 1H), 4.08 (t, 2H), 2.8 (t, 2H), 2.6 (br s, 4H), 1.68 (m, 4H),

1.5 (m, 2H), 1.22 (m, 3H), 1.1 (d, 18H).

Stage C

To a stirred solution of the mixture of the debenzylated product obtained in Step B and (10 eq) mL THF was added a solution of tetrabutylammonium fluoride (3 eq) at THF at room temperature, the resulting solution was stirred for another two hours at room temperature and poured into saturated aqueous NaHCO ₃ solution and extracted with EtOAc. The organic layer was washed with saturated brine, dried over MgSO ₄ , filtered and evaporated. Chromatographic purification over silica gel with eluent of 5-7% MeOH in methylene chloride 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 (br s, 4H), 1.66 (m, 4H), 1.5 (m, 2H).

EXAMPLE 72

RECEIVING HA

Stage A

According to the procedure described in Example 71 (Step A), the dihydrobenzoxazine obtained in Example 53 was reacted with 1 piperidinethanol. Chromatographic purification over silica gel with eluent of 3% MeOH in methylene chloride gave

114 the desired adduct. 1 H NMR (400 MHz, CDO 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, 1H).

2H), 2.5 (m, 4H), 1.6 (m, 4H), 1.45 (m, 2H), 1.22 (m, 3H), 1.1 (m,

21H).

Stage B

The adduct obtained in Step A was debenzylated according to the procedure of 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 = 2.2 Hz, 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).

Stage C

The de-benzylated product of Step B was desilylated according to the procedure of Example 71 (Step C). The desired product is obtained as a white 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 = 2.2Hz, 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

RECEIVING HA

Oh

115

Stage A

According to the procedure described in Example 71 (Step A), the dihydrobenzoxazine obtained in Example 45 was reacted with 1-piperidinethanol. Chromatographic purification over silica gel with 3% MeOH eluent in methylene chloride gave the desired adduct. 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 = 2.2 Hz, 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).

Stage B

The adduct of Step A was desilylated according to the procedure of Example 71 (Step C) to give the desired product as a white substance. ^! 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 = 2.1H, 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 (M ⁺ + 1).

EXAMPLE 74

RECEIVING HA

Stage A

According to the procedure described in Example 71 (Step A), the dihydrobenzoxazine obtained in Example 46 was reacted with 1-piperidinethanol. After chromatographic purification over silica gel with

116 eluent 3% MeOH in methylene chloride gives 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 = 2.1Hz, 1H), 5.12 (s, 2H), 4.5 (d, J = 2.1Hz, 1H), 4.04 (t, 2H), 3.42 (s, 3H), 2.75 (t, 2H), 2.55 ( br s, 4H), 1.6 (m, 4H), 1.48 (m, 2H); MS m / z 495.2 (M + 1).

Stage B

The adduct (lOmg, 0.02 mmole) 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 = 2.2Hz, 1H), 4.45 (d, J = 2.2Hz, 1H), 4.05 (t, 2H), 2.8 (1, 2H), 2.6 (br s, 4H), 1.6 (m, 4H), 1.5 ( m, 2H); MS m / z 450.2 (M ⁺ + 1).

EXAMPLE 75

RECEIVING HA

In the procedure described in Example 71 (Step A), the dioxane derivative obtained in Example 47 was reacted with 1-piperidinethanol to give the desired product. 1 H NMR (400

MHz, CD3OD) 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, 2H).

117

J = 3.0Hz, 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

RECEIVING HA

Stage A

Using the procedure described in Example 49, the dihydrobenzoxazine of Example 71 (Step C) was desilylated. The desired product is obtained as a white substance. 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, 3H).

Stage B

The desilylated product obtained in Step A was reacted with 1piperidinethanol according to the procedure described in Example 71 (Step

A). Chromatographic purification over silica gel with 3% MeOH eluent in methylene chloride 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), 3.75 (s, 3H), 2.75 (t, 2H),

2.5 (br s, 4H), 1.6 (m, 4H), 1.45 (m, 2H).

118

Stage C.

The adduct obtained in Step B was debenzylated according to the procedure described in Example 71 (Step B) until the product was obtained. 1 H NMR (400 MHz, CD ₃ OD) δ (ppm): 6.96 (d, 2H), 6.92 (d, 1H),

6.82 (d, 2H), 6.78 (d, 2H), 6.63 (d, 2H), 6.48 (dd, 1H), 6.44 (d, 1H),

5.5 (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 (br s. 4H), 1.6 (m, 4H), 1.48 (m, 2H); MS m / z 479. 4 (M +1).

EXAMPLE 77

RECEIVING HA

Stage A

According to the procedure described in Example 71 (Step A), the dihydrobenzoxazine obtained in Example 50 was reacted with 1-piperidinethanol. Chromatographic purification over silica gel with 3% MeOH eluent in methylene chloride 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, 18H).

Stage B

The adduct of Step A is debenzylated according to the procedure of

Example 71 (Step B).

119

Stage C.

The de-benzylated product of Step B was desilylated according to the procedure described in Example 71 (Step C). The desired product is obtained as a white substance. 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 = 2.3Hz, 1H), 4.4 (d, J = 2.3Hz, 1H), 4.08 (t, 2H), 2.8 (t, 2H), 2.6 (br s , 4H), 2.18 (s, 3H), 1.64 (m, 4H), 1.5 (m, 2H); MS m / z 479.2 (M ⁺ + 1).

EXAMPLE 78

RECEIVING HA he

HO

Stage A

According to the procedure described in Example 71 (Step A), the dihydrobenzoxazine obtained in Example 51 was reacted with 1-piperidinethanol. Chromatographic purification over silica gel with 3% MeOH eluent in methylene chloride gave the desired adduct.

Stage B

The adduct of Step A is debenzylated according to the procedure described in

Example 71 (Step B). Chromatographic purification over silica gel with eluent 5% MeOH in methylene chloride 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

120 s, 4H), 2.2 (s, 3H), 1.6 (m, 4H), 1.5 (m, 2H), 1.22 (m, 3H), 1.1 (d, 18H).

Stage C

The de-benzylated product of Step B was desilylated according to the procedure of Example 71 (Step C). The desired product is obtained as a white substance. 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 = 2.3Hz, 1H), 4.38 (d, J = 2.3Hz, 1H), 4.1 (t, 2H), 2.8 (t, 2H), 2.6 (br s, 4H), 2.1 (s, 3H), 1.6 (m, 4H), 1.5 (m, 2H); MS m / z 479. 2 (M ⁺ +1).

EXAMPLE 79

RECEIVING HA

Stage A

According to the procedure described in Example 71 (Step A), the dihydrobenzoxazine obtained in Example 53 was reacted with 1-piperidinethanol. Chromatographic purification over silica gel with 3% MeOH eluent in methylene chloride gave the desired adduct.

Stage B

The adduct of Step A is debenzylated according to the procedure described in

Example 71 (Step B).

121

Stage C.

The de-benzylated product of Step B was desilylated according to the procedure of Example 71 (Step C). The desired product is obtained as a white substance after chromatography over silica gel with 5% MeOH / CH ₂ Cl ₂ eluent. 1 H NMR (400 MHz, CD ₃ OD) δ (ppm): 6.94 (d, 2H), 6.76 (d, 2H), 6.7 (2H, d), 6.48 (d, 2H), 6.41 (d, 1H) , 6.3 (d, 1H), 5.44 (d, J = 2.2Hz, 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), 1.45 (m, 2H), 1.2 (t, 3H); MS m / z 493.2

EXAMPLE 80

RECEIVING HA

According to the procedure described in Example 71 (Step A), the dihydrobenzoxazine obtained in Example 54 was reacted with 1-piperidinethanol. Chromatographic purification over silica gel with 3% MeOH eluent in methylene chloride 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).

122

Stage B

The adduct of Step A is debenzylated according to the procedure described in

Example 71 (Step B). Chromatographic purification over silica gel with eluent 5% MeOH in methylene chloride gave the desired product as an oil.

Stage C.

The de-benzylated product of Step B was desilylated according to the procedure of Example 71 (Step C). The desired product is obtained as a white substance. 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 = 2.2Hz, 1H), 4.33 (d, J = 2.2Hz, 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

RECEIVING HA

Stage A

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

123

Stage B

The desilylated product of Step A was reacted with 1piperidinethanol according to the procedure described in Example 71 (Step

IN). Chromatographic purification over silica gel with 3% MeOH eluent in methylene chloride 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 (t, 2H), 2.76 (t, 2H), 2.5 (br s, 4H).

1.6 (m, 4H), 1.42 (m, 2H).

Stage C

The Step B adduct was debenzylated according to the procedure of Example 71 (Step C) to afford 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, 1H), 5.53 (d, J = 2, 3Hz, 1H), 4.46 (d, 1H), 4.06 (t, 2H), 2.78 (t, 2H), 2.58 (br s, 4H). 1.62 (m, 4H), 1.5 (m, 2H); MS m / z 449.2 (M ⁺ + 1).

EXAMPLE 82

RECEIVING HA

Stage A

The dihydrobenzoxathine obtained in Example 56 was desilylated according to the procedure described in Example 71 (Step A). The desired product is obtained as a white substance. 1 H NMR (400 MHz,

CDCI3) δ (ppm): .5-7.3 (m, 5H), 7.2-7.1 (m, 3H), 6.96 (m, 2H), 6.

124 (d, 1H), 6.88 (d, 2H), 6.84 (d, 1H), 6.74 (dd, 1H), 6.66 (d, 2H),

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).

Stage B

The desilylated product of Step A was reacted with 1piperidinethanol according to the procedure described in Example 71 (Step B). Chromatographic purification over silica gel with 3% MeOH eluent in methylene chloride gave the desired adduct.

Stage C.

The Step B adduct was debenzylated according to the procedure of Example 71 (Step C) to afford the desired product. ^! H NMR (400 MHz, CD ₃ OD) δ (ppm): 7.14-7.02 (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

RECEIVING HA

Stage A

To a well stirred solution of dihydrobenzoxathine (30mg,

0.061 mmole), obtained in Example 74 (Step A), was added 5 equivalents of meta-chloroperbenzoic acid (m-CPBA) in methylene chloride at 0 ° C. The ice bath is also removed

125 the reaction mixture was stirred for 3 hours at room temperature, the reaction mixture was deactivated with saturated NaHSO ₃ solution and stirred for another 30 minutes. The aqueous layer was extracted with EtOAc and the organic layer was washed with saturated brine, dried over MgSO ₄ and evaporated to give a residue which was used in 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, 2H), 7.03 (d, 2H) , 6.92 (d, 2H), 6. 82 (d, 2H), 6.32 (d, 1H), 5.12 (s, 2H), 4.84 (d, 1H), 4.2 (br t, 2H), 3.40 (s. 3H), 3.2 (m, 2H), 3.0 (m, 4H), 1.75 (m, 4H), 1.6 (m, 2H).

c

Stage B

The MOM protecting group was removed according to the procedure of Example 74 (Step B). Chromatographic purification over silica gel with 5% MeOH / CH3CE eluent afforded the desired product. 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, 1H), 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).

c

EXAMPLE 84

RECEIVING HA

Η

126

Stage A

To a well stirred solution of dihydrobenzoxathine (60mg) obtained in Example 73 (Step A) was added 5 equivalents (m-CPBA) in methylene chloride at 0 ° C. The ice bath was removed and the reaction mixture was stirred for 3 hours at room temperature, the reaction mixture was deactivated with saturated NaHSO ₃ solution and saturated with NaH ₃ , then stirred for another 30 minutes. The aqueous layer was extracted with EtOAc and the combined organic layer was washed with saturated brine and dried over MgSO ₄ . The solvent was evaporated to give an oily residue, which was purified by chromatography over silica gel with 3% MeOH / CH ₂ Cl ₂ eluent to give a 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 = 2.1Hz, 1H), 4.72 (d, J = 2.3Hz, 1H), 4.08 (m, 2H). 2.8 (t, 2H), 2.6 (br s, 4H), 1.6 (m, 4H),

1.5 (m, 2H), 1.22 (m, 3H), 1.1 (d, 18H); MS m / z 637 (M ^{+ +} 23).

Stage B

The strong protecting group is removed according to the procedure of Example 71 (Step C). Chromatographic purification over silica gel with 5% MeOH / CH ₂ Cl ₂ eluent afforded the desired product. 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 = 2.2Hz, 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).

127

EXAMPLE 85

OBTAINING

Stage A

In accordance with the procedure of Example 83 (Step A), the dihydrobenzoxazine (20mg, 0.028 mmole) of Example 71 (Step A) was oxidized with mCBA at room temperature, and the crude product was used in the next step without 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 = 2.2Hz, 1H), 5.18 (q, 2H), 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).

Stage B

The product from Step A was released according to the standard procedure described in Example 71 (Step B) until a debenzylated product was obtained which was used without further purification.

Stage C.

The strong protecting group is removed by the method of

Example 71 (Step C). Chromatographic purification over silica gel with 5% MeOH / CH3CE eluent afforded the final product. ^! H NMR (400 MHz, CD3OD) 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),

128

6.22 (d, 1H), 4.55 (d, J = 2.1Hz, 1H), 4.1 (t, 2H), 2.8 (t, 2H), 2.6 (br s, 4H), 1.64 (Μ, 4H), 1.5 ( Μ, 2H); MS m / z 496.1 (M > 1).

EXAMPLE 86

RECEIVING HA

Stage A

Triethylamine (0.07mL), catalytic amount of N, N-dimethylaminopyridine (DMAP) and acetic anhydride (0.034mL, 2eq) were added at room temperature to a solution of dihydrobenzoxathine (100mg, 0.167mmole) obtained in Example 48. The resulting mixture was stirred for 30 minutes and poured into saturated NaHCO 3 - the aqueous layer was extracted with CH 3 Cl 2 and the organic layer was dried over anhydrous Na ₂ SO ₄ . The solvent was evaporated to give an oil which was purified by chromatography over silica gel with eluent 10% EtOAc / hexane 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. 18 H).

Stage B

The strong protecting group is removed by the method of

Example 71 (Step C). Chromatographic purification over silica gel with 5% MeOH / CH2Cl2 eluant gave the desired

129 product. 1 H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.48-7.34 (m, 5H),

7.09 (d, 1H), 7.04 (d, 2H), 6.98 (d, 2H), 6.78 (d, 2H), 6.7 (m, 2H),

6.59 (d, 2H), 5.56 (d, 1H), 5.06 (br q, 2H), 4.74 (s, 1H), 4.36 (d,

1H), 2.2 (s, 3H).

Stage C

The desilylated product (80mg, 0.165mmole) obtained in Step

B, was reacted with 1-piperidinethanol according to the procedure described in Example 71 (Step A). Chromatographic purification over silica gel with 3% MeOH / CH ₂ Cl ₂ eluent afforded 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, 2H0, 5.58 (d, J = 2.2Hz, 1H), 5.05 (br q, 2H), 4.36 (d, J = 2.2Hz, 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).

Stage D

To a solution of lOmg (0.017mmole) of the adduct obtained in Step

C, in anhydrous THF, four equivalents of 1.0 M superhydride solution in THF were added. The resulting mixture was stirred for 2 hours at 0 ° C and 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 without further purification.

Stage E

The crude product of Step D was released by the standard procedure described in Example 71 (Step B) and after chromatographic purification over silica gel with 5% eluent

130

MeOH / CH ₂ Cl ₂ gave the final product. 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 = 2.1Hz, 1H), 4. 38 (d, 1H, J = 2.3Hz, 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

RECEIVING HA

Stage A

The desilylated product obtained in Example 57 was reacted with 1piperidinethanol according to the procedure described in Example 71 (Step A). Chromatographic purification over silica gel with 3% MeOH / CH ₂ Cl ₂ eluent afforded the desired adduct.

Stage B rf

The adduct of Step A was debenzylated according to the procedure 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 = 2.3Hz, 1H), 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 ~).

131

EXAMPLE 88

CHIRAL DIVISION OF

The racemic dihydrobenzoxathine obtained in Example 81 (Step C) was separated by chiral chromatography over a column of Chiralpak AD and eluent 20% EtOH in hexane. The fast moving isomer: [oc] _D ⁼ +33.43 (c = 1.205, MeOH).

Slow moving isomer: [cc] _D = -34. 2 (c = 1.09, MeOH).

EXAMPLE 89

CHIRAL DIVISION OF

The racemic dihydrobenzoxathine obtained in Example 82 (Step C) was separated by chiral chromatography over a column of Chiralpak AD and eluent 20% EtOH in hexane. The fast moving isomer: [a] _O = + 32.4 (c = 1.36, MeOH).

Slow moving isomer: [cc] _D = -31.3 (c = 1.37, MeOH).

132

EXAMPLE 90

OBTAINING

The dihydrobenzoxathine obtained in Example 58 was desilylated according to the procedure described in Example 71 (Step C). The desired product is obtained as a white substance. 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).

Stage B

The desilylated product obtained in Step A was reacted with 1piperidinethanol according to the procedure described in Example 71 (Step A). Chromatographic purification over silica gel with 3% eluent MeOH / CHiCE as eluant afforded the desired adduct.

Stage C.

A mixture of adduct (80mg, 0.144mmole) obtained in Step B, 20 mg of black palladium and 5 drops of AcOH in ethanol was stirred under a hydrogen gas balloon and the reaction monitored by TLC. After 18 hours, the reaction mixture was filtered through a pad of Celite to remove the catalyst and the filtrate was neutralized by the addition of saturated aqueous NaHCO ₃ and extracted with EtOAc. The organic layer was separated, dried over

133

MgSO ₄ and concentrated in vacuo to give the desired product. 1 NMR (500 MHz, CD 3 OD) δ (ppm): 7.20-7.02 (m, 3H),

6.92 (rn, 4H), 6.78 (d, 2H), 6.30 (d, 2H), 5.55 (d, J = 2.1Hz, 1H),

4.50 (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 467 (M ⁺ + 1).

EXAMPLE 91

RECEIVING HA

Stage A

The dihydrobenzoxathine obtained from Example 59 was desilylated according to the procedure described in Example 71 (Step C). The desired product is obtained as a white substance. 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).

Stage B

The desilylated product obtained in Step A was reacted with 1piperidinethanol according to the procedure described in Example 71 (Step A). Chromatographic purification over silica gel with 3% MeOH / CHCl3 as eluant afforded the desired adduct.

Stage C.

The Step B adduct was debenzylated according to the procedure in Example 71 (Step B) until the desired product was obtained. &Lt; 1 &gt; H NMR (500

134

MHz, CD ₃ OD) δ (ppm): 7.14-7.02 (m, 3H), 6.92 (d, 2H), 6.85 (d,

2H), 6.74 (d, 2H), 6.58 (d, 1H), 6.41 (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

RECEIVING HA

Stage A

The dihydrobenzoxathine obtained from Example 60 was reacted with 1piperidinethanol according to the procedure described in Example 71 (Step

C). Chromatographic purification with 3% MeOH / CH ₂ Cl ₂ eluent afforded 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, 2H), 2.5 (br s, 4H), 1.62 (m, 4H) , 1.5 (m, 2H), 1.22 (m, 3H),

1.1 (d, 18H).

Stage B

The adduct of Step A is debenzylated according to the procedure described in

Example 71 (Step B).

Stage C.

The debenzylated product obtained in Step B was desilylated according to the procedure described in Example 71 (Step A). The desired product is obtained as a white substance. 1 H NMR (500 MHz, CD 3 OD) δ

135 (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 = 1.8Hz, 1H) ), 4.39 (d, J = 2.2Hz, 1H), 4.05 (t, 2H),

2.8 (t, 2H), 2.6 (br s, 4H), 1.64 (m, 4H), 1.5 (m, 2H); MS m / z 482.2 (M ⁺ + 1).

EXAMPLE 93

RECEIVING HA

Stage A

The dihydrobenzoxathine obtained from Example 61 was reacted with 1piperidinethanol according to the procedure described in Example 71 (Step A). Chromatographic purification with 3% MeOH / CH ₂ Cl ₂ eluent afforded the desired adduct. ^! H NMR (500 MHz, CDCl3) 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, IM, 5.02 (d, 2H) 4.40 (s, 1H), 4. 08 (t, 2H), C 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).

Stage B

The adduct of Step A was debenzylated according to the procedure described in Example 71 (Step B) to afford the desired product. 1 H NMR (500 MHz, CD 3 OD) δ (ppm): 6.82 (d, 2H), 6.78 (d, Η), 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).

136

Stage C.

The debenzylated product obtained in Step B was desilylated according to the procedure described in Example 71 (Step C). The desired product is obtained as a white substance. 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 (brs. 4H), 1.62 (m, 4H), 1.48 (m, 2H); MS m / z 499 (M ⁺ + 1).

EXAMPLE 94

RECEIVING HA

Stage A

The dihydrobenzoxathine obtained from Example 62 was reacted with 1piperidinethanol according to the procedure described in Example 71 (Step A). Chromatographic purification with 3% MeOH / CH ₂ Cl ₂ eluent afforded the desired adduct.

Stage B

The adduct of Step A is debenzylated according to the procedure described in

Example 71 (Step B).

Stage C.

The debenzylated product obtained in Step B was desilylated according to the procedure described in Example 71 (Step C). The desired product is obtained as a white substance after chromatography

137 Purification over silica gel with eluent 5% MeOH / CHCl3. 1 H NMR (500 MHz, acetone-f) 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,> 2.3Hz, 1H), 4.52 (d, J = 2.1Hz, 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).

EXAMPLE 95

RECEIVING HA

Stage A

The dihydrobenzoxathine obtained from Example 63 was reacted with 1 piperidinethanol according to the procedure described in Example 71 (Step A). Chromatographic purification with 3% MeOH / CH ₂ Cl ₂ eluent afforded the desired adduct.

Stage B

The adduct of Step A was debenzylated according to the procedure described in Example 71 (Step B).

Stage C.

The debenzylated product obtained in Step B was desilylated according to the procedure described in Example 71 (Step C). The desired product is obtained as a white substance after chromatographic purification over silica gel with 5% MeOH / CH ₂ Cl ₂ eluent. * H

138

NMR (500 MHz, aueTOH-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 = 2.3Hz, 1H), 4.65 (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), 1.45 (m, 2H), 1.2 (t, 2H); MS m / z 479 (M '+ 1).

EXAMPLE 96

RECEIVING HA

Stage A

The dihydrobenzoxathine obtained from Example 64 was reacted with 1piperidinethanol according to the procedure described in Example 71 (Step A). Chromatographic purification with 3% MeOH / CH ₂ Cl ₂ eluent afforded 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), 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 (br s, 4H) , 1.62 (m, 4H), 1.5 (m, 2H), 1.22 (m, 3H), 1.1 (d, 18H).

Stage B

The adduct of Step A is debenzylated according to the procedure described in

Example 71 (Step B) to afford the desired product. * 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), 2.78 (t, 2H), 2.55 (br s, 4H), 1.6 (m, 4H),

1.5 (m, 2H).

139

Stage C.

The debenzylated product obtained in Step B was desilylated according to the procedure described in Example 71 (Step C). The desired product is obtained as a white substance. 1 H NMR (500 MHz, acetone-de) 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 = 2.1Hz, 1H), 4.07 (t, 2H), 2.78 (t, 2H), 2.55 (brs. 4H), 1.62 (m, 4H), 1.48 (m, 2H); MS m / z 499 (M ⁺ + 1).

EXAMPLE 97

RECEIVING HA

Stage A

The dihydrobenzoxathine obtained from Example 65 was desilylated according to the procedure described in Example 71 (Step C). The desired product is obtained as a white substance. 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), 6.64-6.70 (m, 2H), 5.46 (d, J = 1.8Hz, 1H), 5.04 (s, 2H), 4.42 (d, J = 2.01Hz, 1H).

Stage B

The desilylated product of Step A was reacted with 1piperidinethanol according to the procedure described in Example 71 (Step

140

A). After chromatographic purification over silica gel with eluent

3% MeOH / CHoCL afforded the desired adduct.

Stage C.

The Step B adduct was debenzylated according to the procedure described in Example 71 (Step B) to afford the desired product. 1 H NMR (500 MHz, CD ₃ OD) δ (ppm): 7.00-7.12 (m, 6H), 6.90 (d, 2H), 6.75 (d, 2H), 6.42 (s, 1H), 5.42 (d. J = 2.1Hz, 1H), 4.48 (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 463 (M ⁺ + 1).

EXAMPLE 98

RECEIVING HA

Stage A

The dihydrobenzoxathine obtained from Example 66 was desilylated according to the procedure described in Example 71 (Step C). The desired product is obtained as a white substance. 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 = 2.1Hz, 1H), 5.04 (s, 2H), 4.46 (d, J = 2.2Hz, 1H).

Stage B

The desilylated product of Step A was reacted with 1piperidinethanol according to the procedure described in Example 71 (Step

141

A). After chromatographic purification over silica gel with eluent

3% MeOH / CH2Cl2 gave the desired adduct.

Stage C.

The Step B adduct was debenzylated according to the procedure described in Example 71 (Step B) to afford the desired product. 1 H NMR (500 MHz, CD ₃ OD) δ (ppm): 7.05-7.15 (m, 5H), 6.90 (d, 2H), 6.79 (d, 2H), 6.65 (d, 1H), 6.55 (d. 1H), 5.50 (d, J = 2.1Hz, 1H), 4.62 (d, J = 2.3Hz, 1H), 4.10 (t, 2H), 2.80 (t, 2H), 2.60 (brs, 4H), 1.6 ( m, 4H), 1.5 (m, 2H); MS m / z 483 (M ⁺ + 1).

EXAMPLE 99

RECEIVING HA

Stage A

W The dihydrobenzoxathine obtained from Example 67 was desilylated according to the procedure described in Example 71 (Step C). The desired product is obtained as a white substance. 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 = 2.1Hz, 1H), 5.14 (s, 2H), 4.40 (d,> 2.0Hz, 1H) .

Stage B

The desilylated product of Step A was reacted with 1piperidinethanol according to the procedure described in Example 71 (Step

142

A). After chromatographic purification over silica gel with eluent

3% MeOH / CH ₂ Cl ₂ gave the desired adduct.

Stage C.

The Step B adduct was debenzylated according to the procedure described in Example 71 (Step B) to afford the desired product. 1 H NMR (500 MHz, CD ₃ OD) δ (ppm): 7.05-7.15 (m, 3H), 6.95 tm, 3H), 6.90 (d, 2H), 6.75 (d, 2H), 6.72 (s, 1H ), 5.45 (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

RECEIVING HA

Stage A

The dihydrobenzoxathine obtained from Example 68 was desilylated according to the procedure described in Example 71 (Step C). The desired product is obtained as a white substance. 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 = 2.1 Hz, 1H), 5.20 (s, 2H),

4.46 (d, J = 2.0 Hz, 1H).

Stage B

The desilylated product of Step A was reacted with 1piperidinethanol according to the procedure described in Example 71 (Step

143

A). After chromatographic purification over silica gel with eluent

3% MeOH / CEG afforded the desired adduct.

Stage C.

The Step B adduct was debenzylated according to the procedure described in Example 71 (Step B) to afford the desired product. 1 H NMR (500 MHz, CD ₃ OD) δ (ppm): 7.05-7.15 (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 = 1.8Hz, 1H), 4.56 (d, J = 2.1Hz, 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 OF HA

The racemic dihydrobenzoxathine obtained in Example 100 (Step C) was chromatographed on a column of Chiralpak AD with eluent 20% EtOH in hexane. Fast-moving isomer: [a] _D = +26.09 (c = 1.025, MeOH).

Slow moving isomer: [ct] _D = -25.44 (c = 0.95, MeOH).

144

EXAMPLE 102

OBTAINING

Stage A

The dihydrobenzoxathine obtained from Example 69 was desilylated according to the procedure described in Example 71 (Step C). The desired product is obtained as a white substance. 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 = 1.9Hz, 1H), 5.05 (s, 2H), 4.35 (d, J = 2.1Hz, 1H).

Stage B

The desilylated product of Step A was reacted with 1piperidinethanol according to the procedure described in Example 71 (Step A). Chromatographic purification over silica gel with 3% MeOH / CH ₂ Cl ₂ eluent afforded the desired adduct which was used without further purification.

Stage C.

The Step B adduct was debenzylated according to the procedure described in Example 71 (Step B) to afford 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), 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).

145

EXAMPLE 103

CHIRAL RECEIVING OF

Stage A

The fast moving (+) - dihydrobenzoxathine of Example 70 was reacted with 1-piperidinethanol according to the procedure described in Example 71 (Step A). Chromatographic purification over silica gel with 3% MeOH / CH ₂ Cl ₂ eluent afforded the desired adduct.

Stage B

The adduct of Step A was debenzylated according to the procedure described in Example 71 (Step B).

Stage C.

The de-benzylated product of Step B was desilylated according to the procedure described in Example 71 (Step C). After chromatographic purification over silica gel with eluent 5% MeOH / CH ₂ Cl ₂ . 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 = 2.0Hz, 1H), 4.38 (d, J = 2.3Hz, 1H), 4.08 (t, 2H), 2.8 ( t, 2H), 2.62 (br s, 4H), 2.6 (q, 2H), 1.6 (m, 4H), 1.45 (m, 2H), 1.2 (t, 2H); MS m / z 465 (M ⁺ + 1); [a] _D = + 27.68 (c = 0.49, MeOH).

146

EXAMPLE 104

CHIRAL RECEIVING OF

Stage A

The slow moving (-) - dihydrobenzoxazine of Example 70 was reacted with 1-piperidinethanol according to the procedure described in Example 71 (Step A). Chromatographic purification over silica gel with 3% MeOH / CH ₂ Cl ₂ eluent afforded the desired adduct.

Stage B

The adduct of Step A was debenzylated according to the procedure described in Example 71 (Step B).

D * '

Stage C.

The de-benzylated product of Step B was desilylated according to the procedure described in Example 71 (Step C). Chromatographic purification over silica gel with 5% MeOH / CH ₂ Cl ₂ eluent gave the desired product as a white solid. 1 H NMR (500 MHz, acetone-cC) 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 = 2.0Hz, 1H), 4.38 (d, J = 2.3Hz, 1H), 4.08 (t, 2H), 2.8 (t, 2H), 2.62 (br s, 4H), 2.6 (q, 2H), 1.6 (m, 4H), 1.45 (m,

147

2H), 1.2 (t, 2H); MS m / z 465 (M ⁺ + 1); [a] _D = -26.33 (c = 0.515,

Meon).

EXAMPLE 105

GENERAL SCHEME FOR PREPARING NO.

Step A: Reduction cyclization

To a stirred solution of 102.2mg (0.17mmole) of cyclopentylthio-ketone, obtained in Example 41, in 1 mL of dichloromethane at -23 ° C under nitrogen atmosphere was added 68 pL (0.087mmole) of pure trifluoroacetic acid (TFA). 41.4 pL (0.259mmole) of pure triethylsilane was slowly added to the stirred solution at -23 ° C and the resulting mixture was stirred for an additional three hours. The reaction mixture was partitioned between ethyl acetate / saturated HANCO ₃ / ice / saturated brine and the organic phase separated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and evaporated. The residue was purified by chromatography over silica gel with methylene chloride / hexanes (1: 1) as eluant to afford the cis-cyclopentyl dihydrobenzoxazine derivative. 'H 500MHz NMR (CDC1 ₃₎ ppm (δ): 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 obtained in

Example 41, by the above procedure, after chromatographic purification over silica gel with methylene chloride / hexanes eluent (1: 1), the corresponding cis-cyclohexyl-benzoxathine was obtained.

148 'H 500MHz NMR (CDCl ₃ ) ρρτη (δ): 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 C: Desilylation

To a stirred solution of 89.6mg (0.156mmole) of the ciscyclopentyl derivative obtained in Step A, in 1 mL of THF at 0 ° C was added successively 13.3 pL (0.234mmole) of acetic acid and then 171 pL (0.171mmole) of 1M tetrabutylammonium solution. fluoride in THF. The mixture was stirred for 0.5 h at 0 ° C and then partitioned between ethyl acetate (2N HCl / ice) saturated brine, the organic phase was separated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and evaporated . The residue was purified by chromatography over silica gel with eluent methylene chloride / ethyl acetate (50: 1) to give the phenolic derivative. * H 500MHz NMR (CDCl3) ppm (δ): 1.32-1.94 (m, 9Η), 3.51 (dd, J = 5.5, 2.5Hz, 1H), 5.03 (s, 2H), 5.42 (d, J = 2.3Hz) , 1H), 6.67-7.47 (m, 12H).

Starting from the cyclohexyl derivative obtained in the preceding example, the corresponding cis-cyclohexyl-benzoxathine phenol was prepared by the above procedure. 1 H 500MHz NMR (CDCl 3) ρρπι (δ): 1.11-1.93 (m, HH), 3.23 (t, J = 3Hz, 1H), 5.03 (s, 2H), 5.44 (d, J = 2.3Hz, 1H) , 6.66-7.47 (m, 12H).

Stage C: Mitsunobu reaction

To a stirred solution of a mixture of 56.3mg (0. 135mmole) of the cyclopentyl derivative of Step B, 53.6 pL (0.404mmole) of 1-piperidinethanol and 123.5mg (0. 47mmole) of triphenylphosphine in 1 mL of anhydrous THF at 0 ° C was added 87.4pL (0.444mmole)

149 pure diisopropylazodicarboxylate (DIAD). The ice-water bath was removed and the mixture was stirred for another 6 hours. The mixture was partitioned between ethyl acetate / 2H HCl / ice / saturated brine and the organic phase separated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and evaporated. The residue was purified by chromatography over silica gel with eluent ethyl acetate / methylene chloride (9: 1) to give the adduct. &Lt; 1 > H 500MHz NMR (CDCl3) ppm (5): 1.33-2.0 (m, 15H), 2.56 (m, 4H), 2.82 (t, J = 6Hz, 2H), 3.51 (dd,> 5.4, 2.4Hz, 1H ), 4.16 (t, J = 6Hz, 2H), 5.02 (s, 2H), 5.42 (d, J = 2.3Hz, 1H), 6.66-

7.46 (m, 12H).

Starting from the cyclohexyl derivative obtained in the preceding example, the corresponding cis-cyclohexyl-benzoxathine adduct is obtained by the above procedure. 1H 500MHz NMR (CDCl3) ppm (5): 1.11-1.93 (m, 17H), 2.6 (m, 4H), 2.87 (m, 2H), 3.2 (d, J = 2.5Hz, 1H), 4.2 (m , 2H), 5.02 (s, 2H), 5.44 (d, J = 2.1 Hz, 1H), 6.65-7.46 (m, 12H).

Step D: Debenzylation

A stirred mixture of 36.6mg (0.0069mmole) of the cis-cyclopentyl derivative of Step C, 14.7mg (0.014mmole) of black palladium and 87.1mg (0.138mmole) of ammonium formate in 2mL of ethanol-ethyl acetate-water (7: 2: 1) heated at 80 ° C for two hours. The mixture was filtered through Celite, washed well with ethyl acetate / saturated sodium bicarbonate / saturated brine and the organic phase separated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and evaporated. The residue was purified by chromatography over silica gel with eluent ethyl acetate / methylene chloride (9: 1) to give the final product. 1 H 500MHz NMR (CDCI3)

150 ppm (5): 1.33-2.0 (m, 15Η), 2.6 (m, 4H), 2.88 (m, 2H), 3.48 (t,

J = 2.3Hz, 1H), 4.18 (m, 2H), 5.38 (d, J = 2.3Hz, 1H), 6.5 (m, 1H),

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

Starting from the cyclohexyl derivative obtained in the preceding example, the corresponding cis-cyclohexyl-benzoxathine adduct is obtained by the above procedure. 1 H 500MHz NMR (CDCl ₃ ) ppm (5): 1.00-1.90 (m, 18H), 2.6 (m, 4H), 2.81 (t, 2H), 3.19 (t, J = 3. 0 Ηζ, 3). 4.18 (m, 2H), 5.38 (d, J = 2.3 Hz, LH), 6.43 (m, 1H), 6.62 (d, J = 3.0 Hz, 1H), 6.68 (d, J = 8.7 Hz, 1H). 6.87 (d, J = 8.7 Hz, 2H), and 7.34 (d, J = 8.7 Hz, 2H); MS m / z 454 (M ⁺ ).

EXAMPLE 106

RECEIVING HA

Step A: Reduction cyclization

Starting from the isopropyl adduct (0.0208g, 0.049 mmol) obtained in Example 42, and using the procedure described in Example 105 (Step A), after stirring at -23 ° C for 6 hours and 20 minutes, the crude product was isolated. Chromatographic purification over silica gel with 30% EtOAc / hexane as eluant gave the desired product as a yellow oil. 1 H 500MHz NMR (CDCl 3) ρρΐϋ (δ): 0.95 (d, 3H), 0.98 (d, 3H), 1.95 (m, 1H), 3.30 (t, J = 3 Hz, 1H), 5.03 (s, 2H) ), 5.42 (d, J = 2.6 Hz, 1H), 6.66-7.47 (m, 12H).

151

Stage C: Mitsunobu reaction

The dihydrobenzoxathine obtained in Step A above was reacted with 1-piperidinethanol according to the procedure described in Example 105 (Step C), except that the reaction mixture was allowed to warm slowly from 0 ° C to room temperature over at 3.5 hours. Chromatographic purification over silica gel with eluent of 10% MeOH / CHCl3 gave the desired product as a pale yellow oil. 1 H 500MHz NMR (CDCl ₃ ) ppm (5): 0.95 (d, 3H), 0.98 (d, 3H), 1.50-1.68 (m, 6H), 1.95 (m, 1H), 2.60 (m, 4H). 2.86 (t, 2H), 3.30 (t, J = 3 Hz, 1H), 4.20 (t, 2H), 5.03 (s, 2H), 5.42 (d, J = 2.6 Hz, 1H), 6.66-7.49 (m , 12H).

Step C: Debenzylation

Starting from the compound obtained above in Step B and using the procedure of Example 105 (Step D), after chromatographic purification over silica gel with eluent of 10% MeOH / CHCl3, the corresponding cis-isopropyl-benzoxathine adduct is obtained. 1H 500MHz NMR (CDCl3) ppm (5): 0.95 (d, 3H), 0.98 (d, 3H), 1.50-1.68 (m, 6H), 1.95 (m, 1H), 2.60 (m, 4H), 2.86 (t, 2H), 3.26 (t, J = 3.0 Hz, 1H), 4.20 (t, 2H), 5.37 (d, J = 2.5 Hz, 1H),

6.47 (dd, 1H), 6.65 (d,> 3 Hz, 1H), 6.72 (d, J = 8.6 Hz, 2H), and 7.35 (d, J = 8.7 Hz, 2H); MS m / z 414 (M ⁺ ).

EXAMPLE 107

RECEIVING HA

Step A: Reduction cyclization

152

Starting from the 2-thiophene adduct (0.0208g, 0.049 mmol) obtained in Example 43, and by slightly modifying the procedure described in Example 105 (Step A) after stirring at 0 ° C to room temperature for 1 hour and 40 the crude product is isolated for minutes. Chromatographic purification over silica gel with eluent 30% EtOAc / hexane gave the desired product as a red oil. 'H 500MHz NMR (CDC1 ₃₎ ppm (5): 1.11 (d, 18H) ,

1.24 (m, 3H), 4.67 (d, J = 2.0 Hz, 1H), 5.50 (d, J = 1.8 Hz, 1H), 6.607.12 (m, 10H).

Stage C: Protection with MOM

To a solution of dihydrobenzoxathine (0.0629 g, 0.13 mmol) obtained in Step A 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 the gas evolution ceased, MOMCl (0.013 mL, 0.16 mmol) was added dropwise to the reaction mixture. After 30 min, a new 1.3 MOMC1 equivalents were added. The reaction was complete in 5 min, which was detected by TLC. The resulting dark red solution was partitioned between EtOAc and ice / H ₂ O. The organic layer was washed with saturated brine, dried over Na ₂ SO ₄ and concentrated in vacuo. The desired product is used in the next reaction without purification. 1 H 500MHz NMR (CDCl ₃ ) ppm (5): 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 dihydrobenzoxathine obtained in Step B was desilylated according to the procedure described in Example 105 (Step B) to give the desired product as a colorless oil after chromatographic purification over silica gel with 30% EtOAc / hexane. 'N

153

500MHz NMR (CDC1 ₃₎ ppm (5): 3.52 (s, 3H) , 4.69 (d,> 1.8 Hz, 1H), 5.15 (m, 2H), 5.51 (d,> 1.8 Hz, 1H), 6.60-7.15 (m, 10H).

Stage D: Mitsunobu reaction

According to the procedure described in Example 105 (Step C), except that the reaction mixture was allowed to warm slowly from 0 ° C to room temperature for 4 hours, the material of the previous step was converted to the desired product after chromatographic silica gel purification with 30% EtOAc / hexane as eluant, followed by repeated elution with 10% MeOH / CH ₂ Cl ₂ . 1 H 500MHz NMR (CDCl ₃ ) ppm (5): 1.40-2.60 (m, 10H), 2.79 (t, 2H), 3.52 (s, 3H), 4.10 (ΐ, 2H), 4.69 (d,> 1.8 Hz) , 1H), 5.15 (m, 2H), 5.51 (d, > 1.8 Hz, 1H), 6.60-7.15 (m, 10H).

Stage E: MOM exemption

A mixture of the material (0.0401 g, 0.080 mmol) obtained in Step D and 2 N HCl (0.20 mL, 0.40 mmol) in MeOH (1.0 mL) was heated at 60 ° C under N ₂ for 2.5 hours. The reaction mixture was partitioned between EtOAc / saturated NaHCO ₃ . The organic layer was washed with brine, dried over NaSO 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 500MHz NMR (d ₆ -acetone + CD ₃ OD) ppm (δ): 1.50-3.19 (m, 10H), 3.23 (t, 2H), 4.30 (t, 2H), 5.00 (d,> 1.8 Hz. 1H), 5.51 (d, > 1.8 Hz, 1H), 6.57-7.25 (m, 10H); MS m / z 454 (M ⁺ ).

154

EXAMPLE 108

OBTAINING

Step A: Reduction cyclization

According to the procedure of Example 44 0.0792 g of the 3-pyridyl derivative obtained in Example 41 was converted to the corresponding dihydrobenzoxathine after 5 hours stirring at room temperature, after chromatographic purification over silica gel with 30% EtOAc / hexane, the desired product was isolated. 1 H 500MHz NMR (CDCl ₃ ) ppm (δ): 1.1 l (d, 18H), 1.24 (m, 3H), 4.36 (d, J = 2.1 Hz, 1H), 5.05 (s, 2H), 5.50 (d , J = 1.6 Hz, 1H), 6.77-8.43 (m, 16H).

Step C: Desilylation

In accordance with the procedure of Example 105 (Step B), the dihydrobenzoxazine derivative of Step A was desilylated and, after chromatographic purification over silica gel, first with 50% EtOAc / hexane eluent and a second elution with 30% EtOAc / hexane gave the desired product. 1 H 500 MHz H NMR (CDCl ₃ ) ppm (δ): 4.42 (d, J = 2.1 Hz, 1H), 5.07 (s, 2H), 5.50 (d, J = 1.6 Hz, 1H), 6.77-8.43 (m. 16H).

Stage C: Mitsunobu reaction

According to the procedure described in Example 105 (Step C), except that the reaction mixture was allowed to slowly warm from

155

0 ° C to room temperature for 4 hours, the material of the previous step was converted to the desired product after chromatographic purification over silica gel with 30% EtOAc / hexane eluent, followed by re-elution with 10% MeOH / CH ₂ Cl ₂ . 1 H 500MHz NMR (CDCl ₃ ) ppm (5): 1.40-2.60 (m, 1OH), 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 obtained in Step C and using the procedure of Example 105 (Step D), the corresponding cis-pyridyl-dihydrobenzoxathine was obtained after chromatographic purification with 10% MeOH / CH ₂ Cl ₂ eluent. 1 H 500MHz NMR (CDCl ₃ ) ppm (6): 1.40-2.60 (m, 10H), 2.80 (t, 2H), 4.10 (t, 2H), 4. 36 (d, J = 2.1 Hz, 1H). 5.45 (d, J = 1.9 Hz, 1H), 6.59-8.43 (m, HH); MS m / z 449 (M ⁺ ).

EXAMPLE 109

RECEIVING HA

Step A: Reduction cyclization

According to the procedure of Example 44 0.1871 g of the 4-pyridyl derivative obtained in Example 41 was converted to the corresponding dihydrobenzoxathine after 30 hours of stirring at room temperature. After chromatographic purification in

156 silica gel with eluent 30% EtOAc / hexane was isolated the desired product. 1 H 500MHz NMR (CDCl ₃ ) ppm (δ): 1.11 (d, 18H), 1.24 (m, 3H), 4.32 (d, 1H), 5.08 (s, 2H), 5.50 (d, H), 6.60- 8.39 (m, 16H). Step B: Desilylation According to the procedure of Example 105 (Step B), the dihydrobenzoxazine of Step A was desilylated and, after chromatographic purification over silica gel, first with 50% EtOAc / hexane as eluent and second with 30% EtOAc / hexane. Γ w * · ' receives the desired product. 'H 500MHz NMR (CDC1 ₃₎ ppm (δ): 4.33 ( d, 1Η), 5.07 (s, 2H), 5.46 (d, 1H), 6.63-8.37 (m, 16H). Step C: Mitsunobu Reaction Following the procedure described in Example 105 (Step C), except that the reaction mixture was allowed to warm slowly from 0 ° C to room temperature for 5 hours, the material of the previous step was converted to the desired product after chromatographic purification over silica gel with eluent 10% you * EtOAc / hexane followed by re-elution with 20% MeOH / CH ₂ Cl ₂ . 1 H 500MHz NMR (CDCl ₃ ) ρρτη (δ): 1.40-2.60 (m, 10Η), 2.80 (t, 2H), 4.14 (t, 2H), 4.32 (d, A3.0 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 obtained in Step C and using the procedure of Example 105 (Step D), the corresponding 4: 1 cis / trans-pyridyl-dihydrobenzoxazine mixture was obtained after chromatographic purification with eluent (first 30% EtOAc / hexane and second elution with 10% MeOH / CH ₂ Cl ₂ .

157

Cis isomer: 1 H 500MHz NMR (CDCl 3) ppm (5): 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), 6.59-8.40 (m, 11H).

Trans Isomer: * H 500MHz NMR (CDCl ₃ ) ppm (5): 1.40-2.70 (m, 1OH), 2.80 (t, 2H), 4.15 (t, 2H), 4.38 (d, J = 8.7 Hz. 1H), 4.92 (d, J = 8.7 Hz, 1H), 6.59-8.46 (m, 11H); MS m / z 449 (M ⁺ ).

EXAMPLE 110

RECEIVING HA

Step A: Reduction

To a stirred solution of 265.1 mg (0.449mmole) of cyclopentyl-thio-ketone of Example 41 in 3mL of methanol dichloromethane (1: 1) at 0 ° C was added at room temperature enough sodium boron hydride to complete the reaction. The reaction mixture was partitioned between ethyl aueTaT / 2N HCl / ice / saturated brine, the organic layer was separated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and evaporated to give cyclopentylthiocarbinols which are used without purification in the next step.

Stage C: Cyclization

A mixture of 266mg (0.449mmole) of the crude product from Step A and 89mg of Amberlyst 15 in 3mL of toluene was stirred for two hours at

158 room temperature, the resin was removed by filtration with thorough washing with ethyl acetate. The filtrate was evaporated and the resulting residue was purified by chromatography over silica gel with dichloromethane / hexanes (1: 1) as eluent to give the trans-dihydrobenzoxazine derivative. 'H 500MHz NMR (CDC1 ₃₎ ppm (5): 1.13 (d, 18H) , 1.26-1.94 (m, 12H), 3.64 (dd, J = 7.8Hz, 5.5Hz, 1H), 4.78 (d, J = 7.8Hz, 1H), 5.02 (s, 2H), 6.6-7.45 (m, 12H).

Step C: Desilylation

According to the procedure of Step B of Example 105, 228.5mg (0.397mmole) of the material obtained in the previous step was desilylated to give the corresponding phenol.

Stage D: Mitsunobu reaction

In accordance with the procedure of Step C of Example 105, the material obtained in the previous step was converted to the corresponding transcyclopentyl-dihydrobenzoxathine adduct. ^! H, 500MHz NMR (CDCl3) ρρηι (δ): 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 = 7.8Hz, 2H), 5.01 (s, 2H), 6.64-7.49 (m, 12H).

Stage E: Debenzylation

According to the procedure of Example 105 (Step D), the material obtained in

Step D is converted to the corresponding trans-cyclopentyl dihydrobenzoxathine. &Lt; 1 &gt; H 500MHz NMR (CDCl3) ppm (5): 1.292.0 (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, 2.7Hz, 1H) 6.77 (d,> 8.7Hz, 1H), 6.88 (d, J = 7.5Hz,

2H), and 7.27 (d, J = 7.5 Hz, 2H).

159

EXAMPLE 111

GENERAL SCHEME FOR RECEIPT OF

/ * · *

Starting with the thio-ketones obtained in Example 39 and using the procedures set forth above in Steps A and B of Example 110 were obtained the following compounds: 7ra «c-cyclohexyl ^derivative:! H, 500MHz NMR (CDCl3) ppm (5): 1.14 (d, 18H), 0.981.8 (m, 14H), 3.37 (dd, J = 2.5Hz, 8.1Hz, 1H), 5.01 (s, 2H), 5.05 (d, J = 8.1 Hz, 1H), 6.67.44 (m, 12H). 7)% b-cyclopentyl derivative: * H 500MHz NMR (CDCl3) ppm (d): 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

Starting from trans-dihidrobenzoksatiinite obtained in the preceding step, and using the procedures set forth above in Step B of Example 105 were obtained the following compounds: 7 / dtns-cyclohexylene derivative: H 500MHz NMR (CDC1 ₃₎ ppm (b): 1.0-1.8 (m, 11H), 3.3 (m, 1H), 5.05 (s, 2H), 5.1 (d, 1H), 6.6-7.44 (m, 12H).

7/7 <2ns-cyclopentyl derivative: 'Η 500MHz NMR (CDCl ₃ ) ρρτη (δ): 1.29-2.0 (m, 9H), 3.55 (dd, J = 5.7Hz, 7.6Hz, 1H), 4.95 (d,

J-7.6Hz, 1H), 5. 02 (s, 2H), 6.6-7.45 (m, 12H).

160

Stage D: Mitsunobu reaction

Starting from the trans-dihydrobenzoxathine phenols obtained in the previous step and using the procedure given in Step C of Example 105 above, the following compounds were obtained:

7-Rans-cyclohexylene adduct : ^! H, 500MHz NMR (CDCl3) ppm (5): 1.0-1.8 (m, 17H), 2.58 (m, 4H), 2.84 (m, 2H), 3.37 (m, 1H), 4.17 (t, J = 6Hz). 2H), 5.0 (s, 2H), 5.08 (d, J = 7.8Hz, 1H), 6.6-7.43 (m, 12H).

Grais-cyclopentyl derivative: 'Η 500MHz NMR (CDC1 ₃₎ ρρτη (δ): 1.29-2.0 ( m, 15H), 2.58 (m, 4H), 2.84 (m, 2H), 3.55 (m, 1H), 4.17 ( m, 2H), 4.94 (d, J = 7.3 Hz, 1H), 5.0 (s, 2H), 6.6-7.72 (m, 12H).

Stage E: Debenzylation

Starting from the trans-dihydrobenzoxazine adducts obtained in the previous step and using the procedure given above in Step D of Example 105, the following compounds were obtained:

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

Trans-cyclopentyl derivative ^:! H, 500MHz NMR (CDCl3) ρρτη (δ): 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).

161

EXAMPLE 112

OBTAINING

Step A: Silylation

To a stirred solution of isopropylthio-ketone (0.0395 g, 0.097 mmol) of Example 42 in distilled THF (1 mL) at 0 ° C was added 60% NaH in mineral oil (0.0183 g, 0.20 mmol) and then added. TIPSC1 (0.048 mL, 0.22 mmol). After 35 min, another TIPSC1 equivalent was added to complete the reaction. The reaction mixture was partitioned between EtOAc and ice / H ₂ O and the organic layer was washed with saturated brine, dried over Na ₂ SO ₄ and concentrated in vacuo to give the desired product. The crude product is used without purification in the next step.

Stage C: Reduction

To a solution of the crude product (0.097 mmol) obtained 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 min, then partitioned between EtOAc and ice / H ₂ O. The organic layer was washed with saturated brine, dried over Na ₂ SO ₄ and concentrated in vacuo to give the desired product. The crude product is used without purification in the next step. 1 H 500MHz NMR (CDCl ₃ ) ppm (5): 0.90-1.40 (m, 49H), 1.69 (m, 1H),

3.10 (dd, 1H), 4. 60 (d, 1H), 5.05 (s, 2H), 6.70-7.50 (m, 12H).

162

Step C: Desilylation

To a solution of the material (0.097 mmol) obtained in the previous step, in distilled THF (1 mL) was added AcOH (0.018 mL, 0.32 mmol) at 0 ° C below N ₂ and then a 1M solution of TBAF in THF ( 0.29 mL, 0.29 mmol). After 15 min, the reaction mixture was partitioned between EtOAc and ice / saturated NaHCO3. The organic layer was washed with saturated brine, dried over Na ₂ SO ₄ and concentrated in vacuo. Chromatographic purification over silica gel with EtOAc / hexane as eluant gave the desired product as a yellow foam. 1 H 500MHz NMR (CDCl 3) ppm (5): 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).

Stage D: Cyclization

According to the procedure of Example 110 (Step B), the material (0.0366 g, 0.089 mmol) obtained in the previous step was converted to the corresponding trans-dihydrobenzoxathine after stirring for 1 hour and 15 minutes at room temperature. Chromatographic purification over silica gel with eluent 30% EtOAc / hexane gave the desired product as a white solid. 1 H 500MHz NMR (CDCl 3) ρριη (δ): 0.98 (d, 3H), 1.03 (d, 3H), 1.78 (m, 1H), 3.57 (dd,> 3.7 Hz,> 8.5 Hz, 1H), 4.82 ( d, > 8.4 Hz, 1H), 5.02 (s, 2 H), 6.63-7.46 (m, 12H).

Stage E: Mitsunobu reaction

According to the procedure described in Example 105 (Step C), the material (0.0266 g, 0.068 mmol) obtained in the previous step was converted to the corresponding trans-isopropyl-dihydrobenzoxazine adduct after warming from 0 ° C to room temperature for 1 hour.

163

hours and 20 minutes After chromatographic purification over silica gel with eluent (first elution with 10% MeOH / CH ₂ Cl ₂ and second elution with 30% EtOAc / hexane) the desired product is obtained as a white solid. &Lt; 1 &gt; H 500MHz NMR (CDCl3) ppm (5): 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, 2 H). 6.63-7.46 (m, 12H).

Step F: Debenzylation

According to the procedure described in Example 105 (Step D), the material (0.0395 g, 0.068 mmol) obtained in the previous step was converted to the corresponding trans-isopropyl-dihydrobenzoxathine product. Chromatographic purification over silica gel with eluent 10% MeOH / CH ₂ Cl ₂ . 1 H 500MHz NMR (CDCl ₃ ) ppm (5): 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), 6.48-7.29 (m, 7H ); MS m / z 414 (M ⁺ ).

EXAMPLE 113

RECEIVING HA

HO

Step A: Silylation

According to the procedure of Example 112 (Step A), the isopropylthio-ketone obtained in Example 40 was silylated. Chromatographic purification over silica gel with EtOAc / hexane as eluent gave the desired product as a yellow oil. H 500MHz NMR (CDC1 ₃₎

164 ρρττι (δ): 0.98-1.30 (m, 49H), 2.35 (m, 1H), 4.38 (d, 1H), 4.99 (q,

2H), 6.33-7.79 (m, 12H).

Stage C: Reduction

According to the procedure of Example 112 (Step B), the material (0.8009 g,

1.1 mmol), isolated in Step A, is reduced to the corresponding alcohol and used without purification in the next step. 1 H 500MHz NMR (CDCl ₃ ) ρρτη (δ): 0.98-1.30 (m, 49H), 1.90 (m, 1H), 2.92 (dd, 1H), 4.59 (d, 1H), 5.05 (q, 2H) , 6.477.43 (m, 12H).

Step C: Desilylation

According to the procedure of Example 112 (Step C), the material (0.022 mmol) isolated in Step B was deprotected to obtain the desired product, which was used without purification in the next step.

Stage D: Cyclization

According to the procedure of Example 110 (Step B), the material obtained in the previous step was converted to the corresponding trans dihydrobenzoxathine after stirring for 22 hours at room temperature. Chromatographic purification over silica gel with 30% EtOAc / hexane as eluent gave the desired product as a colorless oil. 1 H 500MHz NMR (CDCl ₃ ) ρρηι (δ): 0.98 (d, 3H), 1.03 (d, 3H), 1.79 (m, 1H), 3.45 (dd, 1H), 4.98 (d, 1H), 5.02 ( s, 2H), 6.59-7.46 (m, 12H); MS m / z 393 (M ⁺ ).

Stage E: Mitsunobu reaction

Following the procedure described in Example 105 (Step C), the material (0.008 g, 0.020 mmol) obtained in the previous step was converted to the corresponding trans-isopropyl-dihydrobenzoxazine adduct

165

after warming from 0 ° C to room temperature for 6 hours. Chromatographic purification over silica gel with eluent (first elution with 10% MeOH / CH ₂ Cl ₂ and second elution with 10% MeOH / CH ₂ Cl ₂ gave the desired product as a pale yellow oil. 1 H 500MHz NMR (CDCl ₃ ) ppm ( 5): 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, 2 H), 6.59-7.46 (m, 12H).

Step F: Debenzylation

According to the procedure described in Example 105 (Step D), the material (0.0085 g, 0.017 mmol) obtained in the previous step was converted to the corresponding trans-isopropyl-dihydrobenzoxathine product. Chromatographic purification over silica gel with eluent 10% MeOH / CH ₂ Cl ₂ . 'H 500MHz NMR (CDC1 ₃₎ ppm (6): 0.98 (d, H), 1.02 (d, H), 1.49-1.70 (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

RECEIVING HA

HO

OTIPS

166

According to the procedure of Example 16, using 0.36g (2.5mmole) of 1,2-benzenedithiol (Aldrich) and chromatographic purification over silica gel with eluent EtOAc / hexane (1/5) gave 221 mg (ca. 20%, impurity). of the desired product.

EXAMPLE 115

OBTAINING

Following the procedure of Example 44, 121 mg (80%) of a mixture of three products (A: B: C = 1: 0.1: 0.25) was obtained after chromatographic purification over silica gel with 10% EtOAc / hexane as eluent.

EXAMPLE 116 PREPARATION OF

Stage A

The thiene obtained in Example xx was reacted with 1-piperidinethanol according to the procedure described in Example 71 (Step A). After chromatographic purification over silica gel with eluent 3%

MeOH / USE afford the desired adducts as a mixture.

167

Stage B

The adducts of Step A were desilylated according to the procedure described in Example 71 (Step C). The desired product A was separated by HPLC (Meta Chem Polaris C 184.6x50, 5 microns; gradient 5 to 75% acetonitrile on reverse phase column) as a white solid. A ^:! H 400MHz NMR (CD ₃ OD) ppm (5): 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, 2FI), 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 400MHz NMR (CD ₃ OD) ppm (5): 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) ), 3.05 (br t, 2H), 2.0 (br d, 2H), 1.8 (m, 4H); MS m / z 462 (M ⁺ ).

Methods of analysis

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

Estrogen receptor binding assay

Estrogen receptor ligand binding assays are scintillation approximation tests using tritiated estradiol and recombinant expressed estrogen receptors. Recombinant human

Full-length ER-α and full-length ER-β proteins are produced in a baculoviral expression system. The ER-α and ER-β extracts were diluted 1: 400 in phosphate-containing buffer

168 mM α-monothiol-glycerol. 200 µL aliquots of the diluted preparation were added to all wells of the 96 well assay plate. The plates are coated with packaging foil

Saran and incubated at 4 ° C overnight.

The following morning, 20 µL aliquots of phosphate buffer containing 10% bovine serum albumin were added to each well and incubated for 2 hours at 4 ° C. The plates were then washed with 200 µL buffer containing 20 mM Tris (pH 7.2), 1 mM EDTA, 10% glycerol, 50 mM KCl, and 6 mM ammonothioglycerol. Further, these receptor-coated plates were treated by adding 178 µL of the same buffer to each well and then to a 10 nM solution of ³ H-estradiol. Test compounds were analyzed at a concentration range of 0.01 nM to 1000 nM. Stock solutions of test compounds were prepared in 100% DMSO at 100x the final concentration tested in this assay. The amount of DMSO in the wells of the 96-well plate should not exceed 1%. Lastly, 2 µL aliquots of test compound were added to the assay plate, which was dissolved in 100% DMSO. Plates are sealed and left for 3 hours to reach equilibrium with ambient temperature. Plates are counted with a scintillation counter that is suitable for counting 96-well plates.

Analysis of rats with ovarian ectomy

Ovarian ectomy (OVX) rat analysis used estrogen deficiency to induce balanced osteopenia (eg, low bone mineral density [BMD; mg / cm ² ]) resulting from accelerated bone resorption and formation. The results for both BMD and

169 resorption / formation are used to model bone changes that occur in menopausal women. OVX rat analysis is the primary in vivo assay used by all major academic and industrial laboratories examining the efficacy of new chemical agents for the prevention of bone loss in estrogen deficiency.

Sprague-Dawley female rats 6-8 months of age are exposed to OVX and at the latest 24 hours later treatment is initiated for 42 days with the preparation or multiple doses of test compound. Groups of untreated sham-OVX and treated with alendronate (.003 mg / kg s.c., q.d.) or treated with 17-p-estradiol (.004 mg / kg s.c., q.d.) as positive controls were included. Test compounds are administered orally, subcutaneously or infusion via a subcutaneously implanted mini-pump. Before necropsy, double labeling in vivo with calcein (8 mg / kg by subcutaneous injection), which is fluorochrome accumulating in the bones, is performed. After necropsy, blood, thighs, a segment of the spine and the uterus are used.

The routine parameters that are determined in OVX rat analysis are bone mass, bone resorption, and bone formation. For bone mass, the parameter is the BMD of the distal femoral metaphysis - an area that contains about 20% balanced bone mass. For BMD determination, a segment of the spine - an area with ~ 25% balanced bone mass can also be used. BMD determination is performed by measuring the absorption of a double X-ray beam (DXA, Hologic 4500A; Waltham, MA). The parameter determining bone resorption is the crosslinking of urinary deoxypyridinoline,

170 resulting from collagen breakdown (uDPD; expressed as nM DPD / nM creatinine). This measurement is performed using commercial kits (Pyrilinks; Metra Biosystems, Mountain View, CA). Parameters for bone formation are mineralized surface and velocity of mineral apposition, histomorphometric determination of the number and activity of osteoblasts. This measurement was performed on a transverse sectioned sample 5 μτη thick from the non-decalcified proximal tibial metaphysis using a semi-automated system (Bioquant; R&M Biometrics; Nashville, TN). The parameters used and the methods used to measure women are similar.

Cholesterol lowering assay in rats

Sprague-Dawley rats (5 in a group) weighing about 250 g were administered subcutaneously doses of the compounds of the present invention dissolved in propylene glycol for 4 days. On the fifth day, the rats were euthanized with carbon dioxide and blood samples were analyzed. Plasma cholesterol levels were determined in blood samples using commercial Sigma cholesterol determination kits.

Analysis of MCF-7 estrogen dependent proliferation

MCF-7 cells (ATCC # NTV-22) are human mammary adenocarcinoma cells that require estrogen for growth. The growth medium (GM) for MCF-7 cells is

Minimum Base Medium (no phenolic red) supplemented with fetal bovine serum (FBS) up to 10%. FBS serves as the sole source of estrogen and this GM helps the full

171 cell growth and is used for routine cell culture cultivation. When MCF-7 cells are placed in an environment in which FBS is replaced with 10% carbon-dextral fetal bovine serum (CD-FBS) treatment, the cells cease to divide but remain viable. CD-FBS does not contain detectable estrogen levels, and the medium containing this serum is referred to as estrogen depleted medium (EDM). The addition of estradiol to EDM stimulates the growth of MCF-7 cells in a dose-dependent manner with EC ₅₀ at 2 pM.

The resulting MCF-7 cells were washed several times with EDM and the cultures were then maintained in EDM for a minimum of 6 days to deplete the endogenous estrogen cells. On day 0 (at the beginning of the assay), these estrogen-depleted cells were placed in 96-well cell culture plates with a density of 1000 cells / well in an EDM of 180 and 1 / well. On day 1, the test compounds were diluted in a 10-fold dilution series in EDM and 20ul of these dilutions were added to 180ul medium in the appropriate cell plate well, resulting in another 1:10 dilution of the test compounds. On days 4 and 7 of the assay, the culture supernatant was aspirated and replaced with fresh EDM and dilutions as above for the test compound. The analysis ends on days 8-10 when the respective controls reach 80-90% confluence. At this point, the culture supernatant was aspirated, the cells were washed 2x with PBS, the washing solution was aspirated and the protein content was determined in each well. Each drug dilution was evaluated based on a minimum of 5 wells and the dilution interval of the test compounds was 0.001nM to 100OOm. The analysis described above is used to determine

172 estradiol agonist potential of the test compound.

To determine the antagonistic activity of the tested compound MCF-7 cells were kept in EDM for a minimum of 6 days. Then on day 0 (at the beginning of the assay) these cells with depleted estrogen were placed in 96 well cell culture plates with a density of 1000 cells / well in an EDM of 180 and 1 / well. On day 1, test compounds in fresh medium containing 3 pM estradiol were added to the cells. On days 4 and 7 of the assay, the culture supernatant was aspirated and replaced with fresh EDM containing 3 pM estradiol and the test compound. The assay ends on days 8-10 when the corresponding controls reach 80-90% confluence and the protein content of each well is determined as above.

Model of endometriosis in rats

Animals:

Species: Rattus norvegicus

Breed: Sprague-Dawley CD Manufacturer: Charles River Laboratories, Raleigh, NC Gender: female Weight: 200-240 g

Rats were reared in single polycarbonate cells and supplied with Teklad Global Diet 2016 (Madison, WI) and bottled reverse osmosis H ₂ O ad libitum. They are kept at 12/12 light / dark.

Rats were anesthetized with Telazol (20 mg / kg, ip) and oxymorphone (0.2 mg / kg sc) and placed dorsoventrally on a sterile canvas. Body temperature is maintained by means of a blanket lined with a layer of circulating water. Places for

173 surgical procedures are shaved with a shaver and cleaned three times with betadine / propyl alcohol or

Duraprep® (3M). The site of the incision is covered with a sterile cloth.

Using an aseptic technique 5 cm below the midline, an abdominal incision is made through the skin, subcutaneous and muscle layers. Bilateral ovariectomy is performed. The left blood vessels of the uterus are ligated and a 7 mm segment is cut from the left uterine tip. The uterus is closed by a 4-0 stitch with catgut. The myometrium is aseptically separated from the endometrium and a 5x5 mm piece is cut. The excised portion of the endometrium is transplanted to the ventral peritoneal wall with the epithelial layer opposite. The explanted endometrial tissue is sutured at its four ends to the wall with sterile 6-0 silk threads. The abdominal muscle layer is closed with a sterile 4-0 chromium catgut. The skin incision is closed with sterile steel surgical forceps. In the dorsal lateral scapular area, a sterile 90-day estrogen-releasing pellet is implanted subcutaneously (Innovative Research of America, 0.72 ng / pellet having a circulating estrogen equivalent of 200-250 pg / mL). A subcutaneously sterile implantable programmable temperature transponder (IPTT) (BMDS, Seaford, DE) is injected into the dorsascapular region. The rats were monitored until fully mobile and left undisturbed for 3 weeks after surgery until complete recovery.

Three weeks after the endometrial tissue transplantation of the animals, a laparotomy was performed with aseptic site preparation and technique.

174

The explant is checked for graft acceptance and the area is measured with a caliper and recorded. Animals with rejected grafts are removed from the study. Animals are grouped according to the creation of a similar average volume of explants.

The (control) treatment with the drug or drug begins one day after repeated laparotomy and continues for 14 days. Body temperature was measured daily at 10:00 am using a BMDS scanner.

At the end of the 14-day treatment period, the animals were euthanized with CO ₂ overdose. Blood is collected by cardiosynthesis to determine circulating estrogen levels. The abdomen is opened, the explant is examined, measured, excised and wet weight is measured. Cut off the right uterine tip and measure wet and dry weight.

Pharmaceutical composition

One specific embodiment of this invention is the formulation of a composition of 25 mg of the compound of Example 71 and sufficiently finely ground lactose to a total amount of 580 to 590 mg to fill a size 0 hard gelatin capsule.

Claims (7)

Claims 1. A compound of formula: wherein R ¹ , R ² , R ³ and R ⁴ are each independently selected from the group consisting of hydrogen, C 1. ₅ alkyl, C ₃ . ₈ cycloalkyl, C _{2 to} 5 alkenyl, C _{2. 5} alkynyl, C ₃ . ₈ cycloalkenyl, phenyl, heteroaryl, heterocyclic, CF ₃ , OR ⁶ , halogen, C 1-4 alkylthio, thiocyanato, cyano, -CO ₂ H, -COOC 1-4 alkyl, -COC 1-5 alkyl, -CONZ ₂ , -SO ₂ NZ ₂ , and -SO _{2 C} 1-5 alkyl, where those alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, phenyl, heteroaryl, heterocyclic groups may be substituted by C 1-4 alkyl, C ₃ . ₈ cycloalkyl, CF ₃ , phenyl, heteroaryl, heterocyclic group, -OR ⁶ , halogen, amino, C 1-5 alkylthio, thiocyanato, cyano, -CO ₂ H, -COOCl alkyl, -COCl alkyl, -CONZ ?, -SO ₂ NZ ₂ , and -SO ₂ C 1 alkyl; R ° is selected from the group consisting of Cl alkyl, C _{3. 8} cycloalkyl, C ₂ . ₅ alkenyl, C ₂ . ₅ alkynyl, C ₃ . ₈ cycloalkenyl, phenyl, heteroaryl, heterocyclic groups which may be substituted by C 1-4 alkyl, C ₃ . ₈ cycloalkyl, CF ₃ , phenyl, heteroaryl, heterocyclic groups, OR ⁶ , 176 halogen, amino, C 1-6 alkylthio, thiocyanato, cyano, -CO ₂ H, -COOC 1.5 alkyl, -COC. ₅ alkyl, -CONZ ?, -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 ?; each Z is independently selected from the group consisting of hydrogen, C 1-5 alkyl, trifluoromethyl, where the alkyl group may be substituted by C 1-5 alkyl, CF ₃ , -OR ⁶ , halogen, amino, C 1-5 alkylthio , thiocyanato, cyano, -CO ₂ H, -COOC] -5 alkyl, -COC 1-5 alkyl, CONV ₂ , -SO ₂ NV ₂ , and -SO ₇ C 1-5 alkyl; or both Zs and the nitrogen to which they are attached may form together a 3-8 membered ring which may contain atoms selected from the group consisting of carbon, oxygen, sulfur and nitrogen, the ring being saturated or unsaturated and the ring carbon atoms may have one to three substituents selected from the group consisting of C 1-5 alkyl, CF _3, -OR ^6, halo, amino, C1-5 alkylthio, thiocyanato, cyano, - CO ₂ H, -COOCi-5 alkyl, -COC1.5 alkyl, -CONV ₂ , -SO ₂ NV ₂ , and -SO ₂ C]. ₅ alkyl; each V is independently selected from the group consisting of C]. ₅ alkyl, CF ₃ , -OR ⁶ , halogen, amino, C 1-5 alkylthio, thiocyanato, cyano, -CO ₂ H, -COO _1-5 alkyl, -COC 1.5 alkyl, and -SO _{2 C} 1-5 alkyl; 177 each η is an independent number from one to five; and pharmaceutically acceptable salts thereof. A compound according to claim 1, wherein Υ is sulfur and X is oxygen and its pharmaceutically acceptable salts. The compound of claim 2, wherein R, R, R 'and R are each independently selected from the group consisting of hydrogen, C 1-4. ₅ alkyl, C3. ₈ cycloalkyl, C _{2 to} 5 alkenyl, C _{2. 3} - alkynyl, -OR ⁶ and halogen, provided that one of R and R is -OH; R ³ is selected from the group consisting of C 3. ₈ cycloalkyl, phenyl, heteroaryl and heterocyclic groups which may be substituted by -OR ⁶ or halogen; R ⁶ is independently selected from the group consisting of hydrogen, C 1-5 alkyl, benzyl, methoxymethyl and triisopropylsilyl; and pharmaceutically acceptable salts thereof. 178 and its pharmaceutically acceptable salts. A compound according to claim 3 of the formula: 1 7/1 where R, R, R ^J and R are each independently selected from the group consisting of hydrogen, C 1-5 alkyl, C _{3. 8} cycloalkyl, C ₂ .5 alkenyl, C _{2. 5} alkynyl, OR ⁶ and halogen, provided that one of R and R is -OH; R ⁶ is selected from the group consisting of hydrogen, C 1. 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 ; each Z is independently selected from the group consisting of hydrogen, C 1. ₅ alkyl, trifluoromethyl, where the alkyl group may be substituted by C 1. ₅ alkyl, CF ₃ , -OR ⁶ , halogen, amino, C _1-5 alkylthio, thiocyanato, cyano, 179 - CO ₂ H, -COOOS]. ₅ alkyl, -COC. ₅ alkyl, CONV ₂ , -SO ₂ NV ₂ , and -SO ₂ C 1-5 alkyl; or both Zs and the nitrogen to which they are attached may form together a 3-8 membered ring which may contain atoms selected from the group consisting of carbon, oxygen, sulfur and nitrogen, the ring being saturated or unsaturated and the ring carbon atoms may have one to three substituents selected from the group consisting of C 1-5 alkyl, CF _3, -OR ^6, halo, amino, C1-5 alkylthio, thiocyanato, cyano, - CO ₂ H, -COOC 1-5 alkyl, -COC 1-5 alkyl, -CONV ?, -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 _1-5 alkylthio, thiocyanato, cyano, -CO ₂ H, -COO 1.5 alkyl, - COC 1.5 alkyl, and -SO ₂ C 1. ₅ alkyl; each η is an independent number from one to five; each m is an independent number from one to four; and pharmaceutically acceptable salts thereof. A compound according to Claim 5 selected from the group consisting of: 180 and its pharmaceutically acceptable salts. A compound according to claim 5 of the formula: where R ¹ , R ² , R ^J and R ⁴ are each independently selected from the group, 181 which consists of hydrogen, C] _5 alkyl, Sz.§ cycloalkyl, _C2 -5 alkenyl, C _{2. 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 1-5 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 selected from the group consisting of hydrogen, C _t . ₅ alkyl, CF ₃ , -OR ⁶ , halogen, amino, C _1-5 alkylthio, thiocyanato, C cyano, -CO ₂ H, -COOC 1-5 alkyl, -COCI- ₅ alkyl, -CONV ?, -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 1-5 alkylthio, thiocyanato, cyano, -CO ₂ H, -COOC 1-5 alkyl, -COC 1.5 alkyl, and -SO ₂ C _1-5 alkyl; each m is an independent number from one to four; each p is an independent number from one to four; and pharmaceutically acceptable salts thereof. A compound according to Claim 7 selected from the group consisting of: